U.S. patent application number 09/969851 was filed with the patent office on 2002-09-26 for neuraminic acid derivatives, their preparation and their medical use.
This patent application is currently assigned to SANKYO COMPANY, LIMITED. Invention is credited to Honda, Takeshi, Kobayashi, Yoshiyuki, Yamashita, Makoto.
Application Number | 20020137791 09/969851 |
Document ID | / |
Family ID | 27739546 |
Filed Date | 2002-09-26 |
United States Patent
Application |
20020137791 |
Kind Code |
A1 |
Honda, Takeshi ; et
al. |
September 26, 2002 |
NEURAMINIC ACID DERIVATIVES, THEIR PREPARATION AND THEIR MEDICAL
USE
Abstract
Compounds of formula (I) or their salts or esters: 1 [wherein
R.sup.1 is alkyl or haloalkyl; R.sup.2 and R.sup.3 each represents
hydrogen or aliphatic acyl; X is hydroxy, halogen, alkoxy, or a
group of formula R.sup.aO--, where R.sup.a is aliphatic acyl; Y is
a group of formula R.sup.bR.sup.cN-- or R.sup.bR.sup.cN--O--, where
R.sup.b and R.sup.c each is hydrogen or alkyl; and Z is oxygen or
sulfur] have excellent sialidase inhibitory activity and are
therefore useful for the treatment and prevention of influenza and
other viral diseases where the replication of the virus is
susceptible to sialidase inhibitors.
Inventors: |
Honda, Takeshi; (Tokyo,
JP) ; Kobayashi, Yoshiyuki; (Sagamihara-shi, JP)
; Yamashita, Makoto; (Urawa-shi, JP) |
Correspondence
Address: |
FRISHAUF, HOLTZ, GOODMAN &
LANGER & CHICK, PC
767 THIRD AVENUE
25TH FLOOR
NEW YORK
NY
10017-2023
US
|
Assignee: |
SANKYO COMPANY, LIMITED
Tokyo
JP
|
Family ID: |
27739546 |
Appl. No.: |
09/969851 |
Filed: |
October 3, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
09969851 |
Oct 3, 2001 |
|
|
|
09301672 |
Apr 28, 1999 |
|
|
|
Current U.S.
Class: |
514/459 ;
549/480 |
Current CPC
Class: |
C07D 309/28 20130101;
Y10S 530/807 20130101 |
Class at
Publication: |
514/459 ;
549/480 |
International
Class: |
A61K 031/351; C07D
39/30 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 22, 1996 |
JP |
191862/1996 |
Apr 4, 1997 |
JP |
86888/1997 |
Aug 13, 1996 |
JP |
HEI 8-213456 |
Claims
We claim:
1. A compound of formula (I): 78wherein: R.sup.1 represents an
alkyl group having from 1 to 4 carbon atoms or a haloalkyl group
having from 1 to 4 carbon atoms; R.sup.2 and R.sup.3 are the same
as or different from each other and each represents a hydrogen atom
or an aliphatic acyl group having from 2 to 25 carbon atoms; X
represents a hydroxy group, a halogen atom, an alkoxy group having
from 1 to 4 carbon atoms, or a group of formula R.sup.aO--, where
R.sup.a represents an aliphatic acyl group having from 2 to 25
carbon atoms; Y represents a group of formula R.sup.bR.sup.cN-- or
R.sup.bR.sup.cN--O--, where R.sup.b and R.sup.c are the same as or
different from each other and each represents a hydrogen atom or an
alkyl group having from 1 to 4 carbon atoms; and Z represents an
oxygen atom or a sulfur atom; PROVIDED THAT, when Y represents an
amino group and Z represents an oxygen atom, then X represents a
halogen atom or an alkoxy group; and pharmaceutically acceptable
salts and esters thereof.
2. The compound of claim 1, wherein R.sup.1 represents a methyl or
halomethyl group.
3. The compound of claim 1, wherein R.sup.1 represents a methyl
group or a methyl group having at least one flourine
substituent.
4. The compound of claim 1, wherein R.sup.1 represents a methyl,
fluoromethyl or difluoromethyl group.
5. The compound of claim 1, wherein R.sup.1 represents a methyl
group.
6. The compound of claim 1, wherein R.sup.2 represents a hydrogen
atom or an aliphatic carboxylic acyl group having from 6 to 25
carbon atoms.
7. The compound of claim 1, wherein R.sup.2 represents a hydrogen
atom or an aliphatic carboxylic acyl group having from 8 to 16
carbon atoms.
8. The compound of claim 1, wherein R.sup.2 represents a hydrogen
atom or an aliphatic carboxylic acyl group having from 8 to 16
carbon atoms and R.sup.3 represents a hydrogen atom.
9. The compound of claim 1, wherein R.sup.2 represents an octanoyl,
decanoyl, dodecanoyl, myristoyl or palmitoyl group.
10. The compound of claim 1, wherein R.sup.2 represents an
octanoyl, decanoyl, dodecanoyl, myristoyl or palmitoyl group and
R.sup.3 represents a hydrogen atom.
11. The compound of claim 1, wherein R.sup.3 represents a hydrogen
atom or an aliphatic carboxylic acyl group having from 6 to 25
carbon atoms.
12. The compound of claim 1, wherein R.sup.3 represents a hydrogen
atom or an aliphatic carboxylic acyl group having from 8 to 16
carbon atoms.
13. The compound of claim 1, wherein R.sup.3 represents a hydrogen
atom, or an octanoyl, decanoyl, dodecanoyl, myristoyl or palmitoyl
group.
14. The compound of claim 1, wherein X represents a halogen atom or
an alkoxy group having from 1 to 4 carbon atoms.
15. The compound of claim 1, wherein X represents a fluorine atom,
a methoxy group or an ethoxy group.
16. The compound of claim 1, wherein Y represents an amino group or
a group of formula R.sup.bR.sup.cN--O--, where R.sup.b and R.sup.c
are as defined in claim 1.
17. The compound of claim 1, wherein Y represents an amino group or
an aminooxy group.
18. The compound of claim 1, wherein Y represents an amino
group.
19. The compound of claim 1, wherein Z represents an oxygen
atom.
20. The compound of claim 1, wherein: R.sup.1 represents a methyl
or halomethyl group; R.sup.2 represents a hydrogen atom or an
aliphatic carboxylic acyl group having from 6 to 25 carbon atoms;
R.sup.3 represents a hydrogen atom or an aliphatic carboxylic acyl
group having from 6 to 25 carbon atoms; X represents a halogen atom
or an alkoxy group having from 1 to 4 carbon atoms; Y represents an
amino group or a group of formula R.sup.bR.sup.cN--O--, where
R.sup.b and R.sup.c are as defined above; and Z represents an
oxygen atom.
21. The compound of claim 1, wherein: R.sup.1 represents a methyl
group or a methyl group having at least one flourine substituent;
R.sup.2 represents a hydrogen atom or an aliphatic carboxylic acyl
group having from 8 to 16 carbon atoms; R.sup.3 represents a
hydrogen atom or an aliphatic carboxylic acyl group having from 8
to 16 carbon atoms; X represents a fluorine atom, a methoxy group
or an ethoxy group; Y represents an amino group or an aminooxy
group; and Z represents an oxygen atom.
22. The compound of claim 1, wherein: R.sup.1 represents a methyl
group or a methyl group having at least one flourine substituent;
R.sup.2 represents a hydrogen atom or an aliphatic carboxylic acyl
group having from 8 to 16 carbon atoms; R.sup.3 represents a
hydrogen atom; X represents a fluorine atom, a methoxy group or an
ethoxy group; Y represents an amino group or an aminooxy group; and
Z represents an oxygen atom.
23. The compound of claim 1, wherein: R.sup.1 represents a methyl,
fluoromethyl or difluoromethyl group; R.sup.2 represents an
octanoyl, decanoyl, dodecanoyl, myristoyl or palmitoyl group;
R.sup.3 represents a hydrogen atom, or an octanoyl, decanoyl,
dodecanoyl, myristoyl or palmitoyl group; X represents a fluorine
atom, a methoxy group or an ethoxy group; Y represents an amino
group; and Z represents an oxygen atom.
24. The compound of claim 1, wherein: R.sup.1 represents a methyl
group; R.sup.2 represents an octanoyl, decanoyl, dodecanoyl,
myristoyl or palmitoyl group and R.sup.3 represents a hydrogen
atom; X represents a fluorine atom, a methoxy group or an ethoxy
group; Y represents an amino group; and Z represents an oxygen
atom.
25. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-
-non-2-enopyranosoic acid and pharmaceutically acceptable salts and
esters thereof.
26. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gl-
ycero-D-galacto-non-2-enopyranosoic acid and pharmaceutically
acceptable salts and esters thereof.
27. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gly-
cero-D-galacto-non-2-enopyranosoic acid and pharmaceutically
acceptable salts and esters thereof.
28. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-palmitoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gly-
cero-D-galacto-non-2-enopyranosoic acid and pharmaceutically
acceptable salts and esters thereof.
29. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galact-
o-non-2-enopyranosoic acid and pharmaceutically acceptable salts
and esters thereof.
30. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-gl-
ycero-D-galacto-non-2-enopyranosoic acid and pharmaceutically
acceptable salts and esters thereof.
31. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-
-non-2-enopyranosoic acid and pharmaceutically acceptable salts and
esters thereof.
32. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoic acid and pharmaceutically
acceptable salts and esters thereof.
33. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-gl-
ycero-D-galacto-non-2-enopyranosoic acid and pharmaceutically
acceptable salts and esters thereof.
34. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-gly-
cero-D-galacto-non-2-enopyranosoic acid and pharmaceutically
acceptable salts and esters thereof.
35. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-palmitoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-gly-
cero-D-galacto-non-2-enopyranosoic acid and pharmaceutically
acceptable salts and esters thereof.
36. A method of treating or preventing an infection in a mammal
caused by a sialidase-bearing virus, which method comprises
administering to said mammal an effective amount of a sialidase
inhibitory compound, wherein the sialidase inhibitory compound is
at least one compound selected from the group consisting of
compounds of formula (I) and pharmaceutically acceptable salts and
esters thereof, as claimed in claim 1.
37. The method of claim 36, wherein: R.sup.1 represents a methyl or
halomethyl group; R.sup.2 represents a hydrogen atom or an
aliphatic carboxylic acyl group having from 6 to 25 carbon atoms;
R.sup.3 represents a hydrogen atom or an aliphatic carboxylic acyl
group having from 6 to 25 carbon atoms; X represents a halogen atom
or an alkoxy group having from 1 to 4 carbon atoms; Y represents an
amino group or a group of formula R.sup.bR.sup.cN--O--, where
R.sup.b and R.sup.c are as defined above; and Z represents an
oxygen atom.
38. The method of claim 36, wherein: R.sup.1 represents a methyl
group or a methyl group having at least one flourine substituent;
R.sup.2 represents a hydrogen atom or an aliphatic carboxylic acyl
group having from 8 to 16 carbon atoms; R.sup.3 represents a
hydrogen atom or an aliphatic carboxylic acyl group having from 8
to 16 carbon atoms; X represents a fluorine atom, a methoxy group
or an ethoxy group; Y represents an amino group or an aminooxy
group; and Z represents an oxygen atom.
39. The method of claim 36, wherein: R.sup.1 represents a methyl
group or a methyl group having at least one flourine substituent;
R.sup.2 represents a hydrogen atom or an aliphatic carboxylic acyl
group having from 8 to 16 carbon atoms; R.sup.3 represents a
hydrogen atom; X represents a fluorine atom, a methoxy group or an
ethoxy group; Y represents an amino group or an aminooxy group; and
Z represents an oxygen atom.
40. The method of claim 36, wherein: R.sup.1 represents a methyl,
fluoromethyl or difluoromethyl group; R.sup.2 represents an
octanoyl, decanoyl, dodecanoyl, myristoyl or palmitoyl group;
R.sup.3 represents a hydrogen atom, or an octanoyl, decanoyl,
dodecanoyl, myristoyl or palmitoyl group; X represents a fluorine
atom, a methoxy group or an ethoxy group; Y represents an amino
group; and Z represents an oxygen atom.
41. The method of claim 36, wherein: R.sup.1 represents a methyl
group; R.sup.2 represents an octanoyl, decanoyl, dodecanoyl,
myristoyl or palmitoyl group and R.sup.3 represents a hydrogen
atom; X represents a fluorine atom, a methoxy group or an ethoxy
group; Y represents an amino group; and Z represents an oxygen
atom.
42. The method of claim 36, wherein the sialidase inhibitory
compound is selected from the group consisting of:
5-acetamido-4-guanidino-2,3,4,5,7--
pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gl-
ycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-myri-
stoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoi-
c acid;
5-acetamido-4-guanidino-9-O-palmitoyl-2,3,4,5,7-pentadeoxy-7-fluor-
o-D-glycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-2,-
3,4,5,7-pentadeoxy-7-methoxy-D-glycero-1-galacto-non-2-enopyranosoic
acid;
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-gl-
ycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-2,3,4,5,-
7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-dodeca-
noyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid;
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-
-D-glycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-
-palmitoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyra-
nosoic acid; and pharmaceutically acceptable salts and esters
thereof.
43. A pharmaceutical composition for the treatment or prevention of
infections in a mammal caused by sialidase-bearing viruses, which
composition comprises a sialidase inhibitory compound in admixture
with a pharmaceutically acceptable carrier or diluent, wherein the
sialidase inhibitory compound is at least one compound selected
from the group consisting of compounds of formula (I) and
pharmaceutically acceptable salts and esters thereof, as claimed in
claim 1.
44. The composition of claim 43, wherein: R.sup.1 represents a
methyl or halomethyl group; R.sup.2 represents a hydrogen atom or
an aliphatic carboxylic acyl group having from 6 to 25 carbon
atoms; R.sup.3 represents a hydrogen atom or an aliphatic
carboxylic acyl group having from 6 to 25 carbon atoms; X
represents a halogen atom or an alkoxy group having from 1 to 4
carbon atoms; Y represents an amino group or a group of formula
R.sup.bR.sup.cN--O--, where R.sup.b and R.sup.c are as defined
above; and Z represents an oxygen atom.
45. The composition of claim 43, wherein: R.sup.1 represents a
methyl group or a methyl group having at least one flourine
substituent; R.sup.2 represents a hydrogen atom or an aliphatic
carboxylic acyl group having from 8 to 16 carbon atoms; R.sup.3
represents a hydrogen atom or an aliphatic carboxylic acyl group
having from 8 to 16 carbon atoms; X represents a fluorine atom, a
methoxy group or an ethoxy group; Y represents an amino group or an
aminooxy group; and Z represents an oxygen atom.
46. The composition of claim 43, wherein: R.sup.1 represents a
methyl group or a methyl group having at least one flourine
substituent; R.sup.2 represents a hydrogen atom or an aliphatic
carboxylic acyl group having from 8 to 16 carbon atoms; R.sup.3
represents a hydrogen atom; X represents a fluorine atom, a methoxy
group or an ethoxy group; Y represents an amino group or an
aminooxy group; and Z represents an oxygen atom.
47. The composition of claim 43, wherein: R.sup.1 represents a
methyl, fluoromethyl or difluoromethyl group; R.sup.2 represents an
octanoyl, decanoyl, dodecanoyl, myristoyl or palmitoyl group;
R.sup.3 represents a hydrogen atom, or an octanoyl, decanoyl,
dodecanoyl, myristoyl or palmitoyl group; X represents a fluorine
atom, a methoxy group or an ethoxy group; Y represents an amino
group; and Z represents an oxygen atom.
48. The composition of claim 43, wherein: R.sup.1 represents a
methyl group; R.sup.2 represents an octanoyl, decanoyl, dodecanoyl,
myristoyl or paimitoyl group and R.sup.3 represents a hydrogen
atom; X represents a fluorine atom, a methoxy group or an ethoxy
group; Y represents an amino group; and Z represents an oxygen
atom.
49. The composition of claim 43, wherein the sialidase inhibitory
compound is selected from the group consisting of:
5-acetamido-4-guanidino-2,3,4,5-
,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic
acid;
5-acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gl-
ycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-myri-
stoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoi-
c acid;
5-acetamido-4-guanidino-9-O-palmitoyl-2,3,4,5,7-pentadeoxy-7-fluor-
o-D-glycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-2,-
3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid;
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-gl-
ycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-2,3,4,5,-
7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-dodeca-
noyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid;
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-
-D-glycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-
-palmitoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyra-
nosoic acid; and pharmaceutically acceptable salts and esters
thereof.
50. A compound represented by the formula (1): 79or a
pharmacologically acceptable salt thereof, wherein: R.sup.1
represents a methyl group which may be substituted with a halogen
atom; R.sup.2, R.sup.3 and R.sup.4 may be the same or different and
each is selected from the group consisting of hydrogen atoms and
aliphatic acyl groups having from 3 to 25 carbon atoms; and W is
selected from the group consisting of hydrogen atoms and ester
residues; PROVIDED THAT compounds of formula (1) wherein each of
R.sup.2, R.sup.3, R.sup.4 and W is a hydrogen atom are
excluded.
51. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.1 is a methyl group which may
be substituted with a fluorine atom.
52. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.1 is selected from the group
consisting of methyl, monofluoromethyl and difluoromethyl
groups.
53. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.1 is a methyl group.
54. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.2 is selected from the group
consisting of hydrogen atoms and aliphatic acyl groups having from
6 to 25 carbon atoms.
55. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.2 is selected from the group
consisting of hydrogen atoms and aliphatic acyl groups having from
6 to 20 carbon atoms.
56. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.2 is selected from the group
consisting of hydrogen atoms and hexanoyl, octanoyl, decanoyl,
dodecanoyl, myristoyl, palmitoyl and stearoyl groups.
57. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.3 is selected from the group
consisting of hydrogen atoms and aliphatic acyl groups having from
6 to 25 carbon atoms.
58. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.3 is selected from the group
consisting of hydrogen atoms and aliphatic acyl groups having from
6 to 20 carbon atoms.
59. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.3 is selected from the group
consisting of hydrogen atoms and hexanoyl, octanoyl, decanoyl,
dodecanoyl, myristoyl, palmitoyl and stearoyl groups.
60. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.4 is selected from the group
consisting of hydrogen atoms and aliphatic acyl groups having from
6 to 25 carbon atoms.
61. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.4 is selected from the group
consisting of hydrogen atoms and aliphatic acyl groups having from
6 to 20 carbon atoms.
62. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.4 is selected from the group
consisting of hydrogen atoms and hexanoyl, octanoyl, decanoyl,
dodecanoyl, myristoyl, palmitoyl and stearoyl groups.
63. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.2 is an aliphatic acyl group
having from 3 to 25 carbon atoms, and each of R.sup.3 and R.sup.4
is a hydrogen atom.
64. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.2 is an aliphatic acyl group
having from 6 to 25 carbon atoms, and each of R.sup.3 and R.sup.4
is a hydrogen atom.
65. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.2 is an aliphatic acyl group
having from 6 to 20 carbon atoms, and each of R.sup.3 and R.sup.4
is a hydrogen atom.
66. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.2 is selected from the group
consisting of hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl,
palmitoyl and stearoyl groups, and each of R.sup.3 and R.sup.4 is a
hydrogen atom.
67. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein W is selected from the group
consisting of hydrogen atoms and alkyl groups having from 1 to 18
carbon atoms.
68. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein W is a hydrogen atom.
69. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein W is an ester residue.
70. The compound or pharmacologically acceptable salt thereof
according according to claim 50, wherein W is an alkyl group having
from 6 to 18 carbon atoms.
71. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein each of R.sup.2, R.sup.3 and R.sup.4
is a hydrogen atom, and W is an ester residue.
72. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein each of R.sup.2, R.sup.3 and R.sup.4
is a hydrogen atom, and W is an alkyl group having from 6 to 18
carbon atoms.
73. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.1 is a methyl group which may
be substituted with a fluorine atom, R.sup.2 is an aliphatic acyl
group having from 3 to 25 carbon atoms, each of R.sup.3 and R.sup.4
is a hydrogen atom, and W is selected from the group consisting of
hydrogen atoms and ester residues.
74. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.1 is a methyl group, R.sup.2
is an aliphatic acyl group having from 6 to 25 carbon atoms, each
of R.sup.3 and R.sup.4 is a hydrogen atom, and W is selected from
the group consisting of hydrogen atoms and alkyl groups having from
1 to 18 carbon atoms.
75. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.1 is a methyl group, R.sup.2
is an aliphatic acyl group having from 6 to 20 Carbon atoms, and
each of R.sup.3, R.sup.4 and W is a hydrogen atom.
76. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.1 is a methyl group which may
be substituted with a fluorine atom, each of R.sup.2, R.sup.3 and
R.sup.4 is a hydrogen atom, and W is an ester residue.
77. The compound or pharmacologically acceptable salt thereof
according to claim 50, wherein R.sup.1 is a methyl group, each of
R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom, and W is an alkyl
group having from 6 to 18 carbon atoms.
78. The compound or pharmacologically acceptable salt thereof
according to claim 50, selected from the following group of
compounds:
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-hexanoyl-D-glycero-D-galac-
to-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9--
O-octanoyl-D-glycero-D-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-decanoyl-D-glycero-D-galac-
to-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9--
O-dodecanoyl-D-glycero-D-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-myristoyl-D-glycero-D-gala-
cto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-
-O-palmitoyl-D-glycero-D-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-stearoyl-D-glycero-D-galac-
to-non-2-enopyranosoic acid, hexyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanid-
ino-D-glycero-D-galacto-non-2-enopyranosoate, myristyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enop-
yranosoate, cetyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-g-
alacto-non-2-enopyranosoate, and stearyl
5-acetamido-2,3,4,5-tetradeoxy-4--
guanidino-D-glycero-D-galacto-non-2-enopyranosoate.
79. A pharmaceutical composition comprising an effective amount of
a pharmacologically active compound together with a
pharmacologically acceptable diluent or carrier therefor, wherein
said compound is a compound of formula (1): 80or a
pharmacologically acceptable salt thereof, wherein: R.sup.1
represents a methyl group which may be substituted with a halogen
atom; R.sup.2, R.sup.3 and R.sup.4 may be the same or different and
each is selected from the group consisting of hydrogen atoms and
aliphatic acyl groups having from 3 to 25 carbon atoms; and W is
selected from the group consisting of hydrogen atoms and ester
residues; PROVIDED THAT compounds of formula (1) wherein each of
R.sup.2, R.sup.3, R.sup.4 and W is a hydrogen atom are
excluded.
80. The pharmaceutical composition according to claim 79, wherein
R.sup.1 is a methyl group which may be substituted with a fluorine
atom.
81. The pharmaceutical composition according to claim 79, wherein
R.sup.1 is selected from the group consisting of methyl,
monofluoromethyl and difluoromethyl groups.
82. The pharmaceutical composition according to claim 79, wherein
R.sup.1 is a methyl group.
83. The pharmaceutical composition according to claim 79, wherein
R.sup.2 is selected from the group consisting of hydrogen atoms and
aliphatic acyl groups having from 6 to 25 carbon atoms.
84. The pharmaceutical composition according to claim 79, wherein
R.sup.2 is selected from the group consisting of hydrogen atoms and
aliphatic acyl groups having from 6 to 20 carbon atoms.
85. The pharmaceutical composition according to claim 79, wherein
R.sup.2 is selected from the group consisting of hydrogen atoms and
hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl, palmitoyl and
stearoyl groups.
86. The pharmaceutical composition according to claim 79, wherein
R.sup.3 is selected from the group consisting of hydrogen atoms and
aliphatic acyl groups having from 6 to 25 carbon atoms.
87. The pharmaceutical composition according to claim 79, wherein
R.sup.3 is selected from the group consisting of hydrogen atoms and
aliphatic acyl groups having from 6 to 20 carbon atoms.
88. The pharmaceutical composition according to claim 79, wherein
R.sup.3 is selected from the group consisting of hydrogen atoms and
hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl, palmitoyl and
stearoyl groups.
89. The pharmaceutical composition according to claim 79, wherein
R.sup.4 is selected from the group consisting of hydrogen atoms and
aliphatic acyl groups having from 6 to 25 carbon atoms.
90. The pharmaceutical composition according to claim 79, wherein
R.sup.4 is selected from the group consisting of hydrogen atoms and
aliphatic acyl groups having from 6 to 20 carbon atoms.
91. The pharmaceutical composition according to claim 79, wherein
R.sup.4 is selected from the group consisting of hydrogen atoms and
hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl, palmitoyl and
stearoyl groups.
92. The pharmaceutical composition according to claim 79, wherein
R.sup.2 is an aliphatic acyl group having from 3 to 25 carbon
atoms, and each of R.sup.3 and R.sup.4 is a hydrogen atom.
93. The pharmaceutical composition according to claim 79, wherein
R.sup.2 is an aliphatic acyl group having from 6 to 25 carbon
atoms, and each of R.sup.3 and R.sup.4 is a hydrogen atom.
94. The pharmaceutical composition according to claim 79, wherein
R.sup.1 is an aliphatic acyl group having from 6 to 20 carbon
atoms, and each of R.sup.3 and R.sup.4 is a hydrogen atom.
95. The pharmaceutical composition according to claim 79, wherein
R.sup.2 is selected from the group consisting of hexanoyl,
octanoyl, decanoyl, dodecanoyl, myristoyl, palmitoyl and stearoyl
groups, and each of R.sup.3 and R.sup.4 is a hydrogen atom.
96. The pharmaceutical composition according to claim 79, wherein W
is selected from the croup consisting of hydrogen atoms and alkyl
groups having from 1 to 18 carbon atoms.
97. The pharmaceutical composition according to claim 79, wherein W
is a hydrogen atom.
98. The pharmaceutical composition according to claim 79, wherein W
is an ester residue.
99. The pharmaceutical composition according according to claim 79,
wherein W is an alkyl group having from 6 to 18 carbon atoms.
100. The pharmaceutical composition according to claim 79, wherein
each of R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom, and W is
an ester residue.
101. The pharmaceutical composition according to claim 79, wherein
each of R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom, and W is
an alkyl group having from 6 to 18 carbon atoms.
102. The pharmaceutical composition according to claim 79, wherein
R.sup.1 is a methyl group which may be substituted with a fluorine
atom, R.sup.2 is an aliphatic acyl group having from 3 to 25 carbon
atoms, each of R.sup.3 and R.sup.4 is a hydrogen atom, and W is
selected from the group consisting of hydrogen atoms and ester
residues.
103. The pharmaceutical composition according to claim 79, wherein
R.sup.1 is a methyl group, R.sup.2 is an aliphatic acyl group
having from 6 to 25 carbon atoms, each of R.sup.3 and R.sup.4 is a
hydrogen atom, and W is selected from the group consisting of
hydrogen atom s and alkyl groups having from 1 to 18 carbon
atoms.
104. The pharmaceutical composition according to claim 79, wherein
R.sup.1 is a methyl group, R.sup.2 is an aliphatic acyl group
having from 6 to 20 carbon atoms, and each of R.sup.3, R.sup.4 and
W is a hydrogen atom.
105. The pharmaceutical composition according to claim 79, wherein
R.sup.1 is a methyl group which may be substituted with a fluorine
atom, each of R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom, and
W is an ester residue.
106. The pharmaceutical composition according to claim 79, wherein
R.sup.1 is a methyl group, each of R.sup.2, R.sup.3 and R.sup.4 is
a hydrogen atom, and W is an alkyl group having from 6 to 18 carbon
atoms.
107. The pharmaceutical composition according to claim 79, wherein
said compound of formula (1) or pharmacologically acceptable salt
thereof is selected from the following group of compounds:
5-acetamido-2,3,4,5-tetra-
deoxy-4-guanidino-9-O-hexanoyl-D-glycero-D-galacto-non-2-enopyranosoic
acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-octanoyl-D-glycero-D-
-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanid-
ino-9-O-decanoyl-D-glycero-D-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-dodecanoyl-D-glycero-D-gal-
acto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino--
9-O-myristoyl-D-glycero-D-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-palmitoyl-D-glycero-D-gala-
cto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-
-O-stearoyl-D-glycero-D-galacto-non-2-enopyranosoic acid, hexyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enop-
yranosoate, myristyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero--
D-galacto-non-2-enopyranosoate, cetyl
5-acetamido-2,3,4,5-tetradeoxy-4-gua-
nidino-D-glycero-D-galacto-non-2-enopyranosoate, and stearyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enop-
yranosoate.
108. A method for the treatment or prevention of viral infections,
which method comprises administering a pharmacologically effective
amount of an anti-viral compound to a mammal suffering from or
susceptible to a viral infection, wherein said anti-viral compound
is a compound represented by the formula (1): 81or a
pharmacologically acceptable salt thereof, wherein: R.sup.1
represents a methyl group which may be substituted with a halogen
atom; R.sup.2, R.sup.3 and R.sup.4 may be the same or different and
each is selected from the group consisting of hydrogen atoms and
aliphatic acyl groups having from 3 to 25 carbon atoms; and W is
selected from the group consisting of hydrogen atoms and ester
residues; PROVIDED THAT compounds of formula (1) wherein each of
R.sup.2, R.sup.3, R.sup.4 and W is a hydrogen atom are
excluded.
109. The method according to claim 108, wherein R.sup.1 is a methyl
group which may be substituted with a fluorine atom.
110. The method according to claim 108, wherein R.sup.1 is selected
from the group consisting of methyl, monofluoromethyl and
difluoromethyl groups.
111. The method according to claim 108, wherein R.sup.1 is a methyl
group.
112. The method according to claim 108, wherein R.sup.2 is selected
from the group consisting of hydrogen atoms and aliphatic acyl
groups having from 6 to 25 carbon atoms.
113. The method according to claim 108, wherein R.sup.2 is selected
from the group consisting of hydrogen atoms and aliphatic acyl
groups having from 6 to 20 carbon atoms.
114. The method according to claim 108, wherein R.sup.2 is selected
from the group consisting of hydrogen atoms and hexanoyl, octanoyl,
decanoyl, dodecanoyl, myristoyl, palmitoyl and stearoyl groups.
115. The method according to claim 108, wherein R.sup.3 is selected
from the group consisting of hydrogen atoms and aliphatic acyl
groups having from 6 to 25 carbon atoms.
116. The method according to claim 108, wherein R.sup.3 is selected
from the group consisting of hydrogen atoms and aliphatic acyl
groups having from 6 to 20 carbon atoms.
117. The method according to claim 108, wherein R.sup.3 is selected
from the group consisting of hydrogen atoms and hexanoyl, octanoyl,
decanoyl, dodecanoyl, myristoyl, palmitoyl and stearoyl groups.
118. The method according to claim 108, wherein R.sup.4 is selected
from the group consisting of hydrogen atoms and aliphatic acyl
groups having from 6 to 25 carbon atoms.
119. The method according to claim 108, wherein R.sup.4 is selected
from the group consisting of hydrogen atoms and aliphatic acyl
groups having from 6 to 20 carbon atoms.
120. The method according to claim 108, wherein R.sup.4 is selected
from the group consisting of hydrogen atoms and hexanoyl, octanoyl,
decanoyl, dodecanoyl, myristoyl, palmitoyl and stearoyl groups.
121. The method according to claim 108, wherein R.sup.2 is an
aliphatic acyl group having from 3 to 25 carbon atoms, and each of
R.sup.3 and R.sup.4 is a hydrogen atom.
122. The method according to claim 108, wherein R.sup.2 is an
aliphatic acyl group having from 6 to 25 carbon atoms, and each of
R.sup.3 and R.sup.4 is a hydrogen atom.
123. The method according to claim 108, wherein R.sup.2 is an
aliphatic acyl group having from 6 to 20 carbon atoms, and each of
R.sup.3 and R.sup.4 is a hydrogen atom.
124. The method according to claim 108, wherein R.sup.2 is selected
from the group consisting of hexanoyl, octanoyl, decanoyl,
dodecanoyl, myristoyl, palmitoyl and stearoyl groups, and each of
R.sup.3 and R.sup.4 is a hydrogen atom.
125. The method according to claim 108 wherein W is selected from
the group consisting of hydrogen atoms and alkyl groups having from
1 to 18 carbon atoms.
126. The method according to claim 108, wherein W is a hydrogen
atom.
127. The method according to claim 108, wherein W is an ester
residue.
128. The method according according to claim 108, wherein W is an
alkyl group having from 6 to 18 carbon atoms.
129. The method according to claim 108, wherein each of R.sup.2,
R.sup.3 and R.sup.4 is a hydrogen atom, and W is an ester
residue.
130. The method according to claim 108, wherein each of R.sup.2,
R.sup.3 and R.sup.4 is a hydrogen atom, and W is an alkyl group
having from 6 to 18 carbon atoms.
131. The method according to claim 108, wherein R.sup.1 is a methyl
group which may be substituted with a fluorine atom, R.sup.2 is an
aliphatic acyl group having from 3 to 25 carbon atoms, each of
R.sup.3 and R.sup.4 is a hydrogen atom, and W is selected from the
group consisting of hydrogen atoms and ester residues.
132. The method according to claim 108, wherein R.sup.1 is a methyl
group, R.sup.2 is an aliphatic acyl group having from 6 to 25
carbon atoms, each of R.sup.3 and R.sup.4 is a hydrogen atom, and W
is selected from the group consisting of hydrogen atoms and alkyl
groups having from 1 to 18 carbon atoms.
133. The method according to claim 108, wherein R.sup.1 is a methyl
group, R.sup.2 is an aliphatic acyl group having from 6 to 20
carbon atoms, and each of R.sup.3, R.sup.4 and W is a hydrogen
atom.
134. The method according to claim 108, wherein R.sup.1 is a methyl
group which may be substituted with a fluorine atom, each of
R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom, and W is an ester
residue.
135. The method according to claim 108, wherein R.sup.1 is a methyl
group, each of R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom, and
W is an alkyl group having from 6 to 18 carbon atoms.
136. The method according to claim 108, wherein said compound of
formula (1) or pharmacologically acceptable salt thereof is
selected from the following group of compounds:
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino--
9-O-hexanoyl-D-glycero-D-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-octanoyl-D-galacto-non-2-e-
nopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-decanoyl-
-D-glycero-D-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetrade-
oxy-4-guanidino-9-O-dodecanoyl-D-glycero-D-galacto-non-2-enopyranosoic
acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-myristoyl-D-glycero--
D-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guani-
dino-9-O-palmitoyl-D-glycero-D-galacto-non-2-enopyranosoic acid,
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-stearoyl-D-glycero-D-non-2-
-enopyranosoic acid, hexyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-gl-
ycero-D-galacto-non-2-enopyranosoate, myristyl
5-acetamido-2,3,4,5-tetrade-
oxy-guanidino-D-glycero-D-galacto-non-2-enopyranosoate, cetyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-enop-
yranosoate, and stearyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glyce-
ro-D-galacto-non-2-enopyranosoate.
137. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-gly-
cero-D-galacto-non-2-enopyranosoic acid, and pharmaceutically
acceptable salts and esters thereof.
138. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-decanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-gly-
cero-D-galacto-non-2-enopyranosoic acid, and pharmaceutically
acceptable salts and esters thereof.
139. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-g-
lycero-D-galacto-non-2-enopyranosoic acid, and pharmaceutically
acceptable salts and esters thereof.
140. The compound of claim 1, selected from the group consisting of
5-acetamido-4-guanidino-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-
-glycero-D-galacto-non-2-enopyranosoic acid, and pharmaceutically
acceptable salts and esters thereof.
141. The method of claim 36, wherein the sialidase inhibitory
compound is selected from the group consisting of
5-acetamido-4-guanidino-9-O-octanoy-
l-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid;
5-acetamido-4-guanidino-9-O-decanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-
-D-glycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-
-dodecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopy-
ranosoic acid;
5-acetamido-4-guanidino-9-O-hexadecanoyl-2,3,4,5,7-pentadeo-
xy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic acid; and
pharmaceutically acceptable salts and esters thereof.
142. The composition of claim 43, wherein the sialidase inhibitory
compound is selected from the group consisting of
5-acetamido-4-guanidino-
-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-eno-
pyranosoic acid;
5-acetamido-4-guanidino-9-O-decanoyl-2,3,4,5,7-pentadeoxy-
-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-g-
lycero-D-galacto-non-2-enopyranosoic acid;
5-acetamido-4-guanidino-9-O-hex-
adecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyra-
nosoic acid; and pharmaceutically acceptable salts and esters
thereof.
143. A compound of formula 1: 82wherein: R.sup.1 represents an
alkyl group having from 1 to 4 carbon atoms or a haloalkyl group
having from 1 to 4 carbon atoms; R.sup.2 and R.sup.3 the same as or
different from each other and each represents a hydrogen atom or an
aliphatic acyl group having from 2 to 25 carbon atoms; W represents
alkyl having 1 to 30 carbon atoms; X represents a hydroxy group, a
halogen atom, an alkoxy group having from 1 to 4 carbon atoms, or a
group of formula R.sup.aO--, where R.sup.a represents an aliphatic
acyl group having from 2 to 25 carbon atoms; Y represent a group of
formula R.sup.bR.sup.cN-- or R.sup.bR.sup.cN--O--, where R.sup.b
and R.sup.c are the same as or different from each other and each
represents a hydrogen atom or an alkyl group having from 1 to 4
carbon atoms; and Z represents an oxygen atom or a sulfur atom;
PROVIDED THAT, when Y represents an amino group and Z represents an
oxygen atom, then X represents a halogen atom or an alkoxy group;
or a pharmaceutically acceptable salt thereof.
144. The compound of claim 137, wherein W represents an alkyl group
having 1 to 25 carbon atoms.
145. The compound of claim 143, wherein W represents an alkyl group
having from 6 to 25 carbon atoms.
146. The compound of claim 143, wherein W represents a hexyl,
undecyl, tetradecyl, hexadecyl or octadecyl group.
147. The compound of claim 143, wherein: R.sup.1 represents a
methyl group; R.sup.2 represents a hydrogen atom or an aliphatic
carboxylic acyl group having from 6 to 25 carbon atoms; R.sup.3
represents a hydrogen atom or an aliphatic carboxylic acyl group
having from 6 to 25 carbon atoms; X represents a fluorine atom, a
methoxy group or an ethoxy group; Y represents an amino group; Z
represents an oxygen atom; and W represents an alkyl group having 6
to 25 carbon atoms.
148. The compound of claim 143 wherein: R.sup.2 and R.sup.3
represent a hydrogen atom; X represents methoxy; and W represents
an alkyl group having 6 to 22 carbon atoms.
149. The compound of claim 143 wherein: W represents an alkyl group
having 6 to 18 carbon atoms.
150. The compound of claim 143, selected from the group consisting
of
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galact-
o-non-2-enopyranosoic acid hexyl ester and pharmaceutically
acceptable salts thereof.
151. The compound of claim 143, selected from the group consisting
of
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galact-
o-non-2-enopyranosoic acid undecyl ester and pharmaceutically
acceptable salts thereof.
152. The compound of claim 143, selected from the group consisting
of
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galact-
o-non-2-enopyranosoic acid tetradecyl ester and pharmaceutically
acceptable salts thereof.
153. The compound of claim 143, selected from the group consisting
of
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galact-
o-non-2-enopyranosoic acid hexadecyl ester and pharmaceutically
acceptable salts thereof.
154. The compound of claim 143, selected from the group consisting
of
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galact-
o-non-2-enopyranosoic acid octadecyl ester and pharmaceutically
acceptable salts thereof.
155. A method for the treatment or prevention of viral infections,
which method comprises administering a pharmacologically effective
amount of an anti-viral compound to a mammal suffering from or
susceptible to a viral infection, wherein said anti-viral compound
is a compound as claimed in claim 143.
156. The method of claim 155, wherein the sialidase inhibitory
compound is selected from the group consisting of
5-acetamido-4-guanidino-2,3,4,5,7-p-
entadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic acid
hexyl ester;
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-
-galacto-non-2-enopyranosoic acid undecyl ester;
5-acetamido-4-guanidino-2-
,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid tetradecyl ester;
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy--
D-glycero-D-galacto-non-2-enopyranosoic acid hexadecyl ester;
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galact-
o-non-2-enopyranosoic acid octadecyl ester; and pharmaceutically
acceptable salts thereof.
157. A pharmaceutical composition comprising an effective amount of
a pharmacologically active compound as claimed in claim 143
together with a pharmacologically acceptable diluent or carrier
therefor.
158. The composition of claim 157 wherein the sialidase inhibitory
compound is selected from the group consisting of
5-acetamido-4-guanidino-
-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid hexyl ester;
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy--
D-glycero-D-galacto-non-2-enopyranosoic acid undecyl ester;
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galact-
o-non-2-enopyranosoic acid tetradecyl ester;
5-acetamido-4-guanidino-2,3,4-
,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid hexadecyl ester;
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-
-glycero-D-galacto-non-2-enopyranosoic acid octadecyl ester; and
pharmaceutically acceptable salts thereof.
Description
[0001] This application is:
[0002] (1) a C-I-P of Ser. No. 09/232,539 filed Jan. 18, 1999,
which is a continuation of Ser. No. 08/895,952 filed Jul. 17, 1997;
and
[0003] (2) a C-I-P of Ser. No. 09/249,420 filed Feb. 12, 1999,
which is a continuation of International Application No.
PCT/JP97/02810 filed Aug. 12, 1997.
BACKGROUND OF THE INVENTION
[0004] The present invention relates to a series of new neuraminic
acid derivatives which have excellent sialidase inhibitory activity
and which are therefore useful for the treatment and prevention of
influenza and other viral diseases where the replication of the
virus is susceptible to sialidase inhibitors. The invention also
provides methods and compositions using these compounds for the
treatment or prevention of influenza and similar viral infections,
as well as processes for the preparation of these compounds.
[0005] The compounds of the present invention have a
2-deoxy-2,3-didehydro-N-acylneuraminic acid structure. Sialic acid
is N-acetylneuraminic acid.
[0006] The influenza virus, as well as a number of other types of
virus, have sialidase on the surface of the virus particles. As one
of the processes by which such viruses proliferate, subviruses that
have budded on the cell surface dissociate from the cell. Such
subviruses are coupled to sialic acid on the cell surface mediated
by hemagglutinin of the subvirus surface. Subviruses dissociate
from the cell as a result of sialidase on the subvirus surface
breaking down the sialic acid, thereby resulting in secondary
infection of surrounding cells. Thus, inhibition of sialidase would
make it possible to inhibit dissociation of subviruses from the
cell surface, thereby preventing secondary infection. Accordingly,
a substance that has the effect of inhibiting sialidase is
considered to be effective in treating or preventing (but
preferably treating) influenza.
[0007] A number of compounds having a sialidase inhibitory activity
and a 2-deoxy-2,3-didehydro-N-acylneuraminic acid backbone are
known from WO91/16320 (equivalent to Japanese Patent Publication
(Kokoku) No. Hei 5-507068). Other such compounds are known from
WO96/26933. These compounds (described in WO91/16320 (Japanese PCT
Application (Kokai) No. Hei 5-507068)) include Compound A (GG-167),
represented by the following formula which is being developed as a
drug for the treatment of influenza. 2
[0008] We have now discovered a series of new compounds having a
2-deoxy-2,3-didehydro-N-acylneuraminic acid backbone which have
excellent sialidase inhibitory activity, which is significantly
greater than that of the prior art compounds referred to above, and
which can thus be used for the treatment and prevention of
influenza and other diseases caused by sialidase-bearing
viruses.
BRIEF SUMMARY OF INVENTION
[0009] It is, therefore, an object of the present invention to
provide a series of novel compounds having sialidase inhibitory
activity.
[0010] Other objects and advantages of the present invention will
become apparent as the description proceeds.
[0011] The compounds of the present invention are those compounds
of formula (I): 3
[0012] wherein:
[0013] R.sup.1 represents an alkyl group having from 1 to 4 carbon
atoms or a haloalkyl group having from 1 to 4 carbon atoms;
[0014] R.sup.2 and R.sup.3 are the same as or different from each
other and each represents a hydrogen atom or an aliphatic acyl
group having from 2 to 25 carbon atoms;
[0015] X represents a hydroxy group, a halogen atom, an alkoxy
group having from 1 to 4 carbon atoms, or a group of formula
R.sup.aO--, where R.sup.a represents an aliphatic acyl group having
from 2 to 25 carbon atoms;
[0016] Y represents a group of formula R.sup.bR.sup.cN-- or
R.sup.bR.sup.cN--O--, where R.sup.b and R.sup.c are the same as or
different from each other and each represents a hydrogen atom or an
alkyl group having from 1 to 4 carbon atoms; and
[0017] Z represents an oxygen atom or a sulfur atom;
[0018] and pharmaceutically acceptable salts and esters
thereof.
[0019] The invention also provides a pharmaceutical composition for
the treatment or prevention of infections in a mammal, which may be
human, caused by sialidase-bearing viruses, such as viruses of the
influenza family, which composition comprises a sialidase
inhibitory compound in admixture with a pharmaceutically acceptable
carrier or diluent, wherein the sialidase inhibitory compound is at
least one compound selected from the group consisting of compounds
of formula (I) and pharmaceutically acceptable salts and esters
thereof.
[0020] The invention still further provides a method of treating or
preventing an infection in a mammal, which may be human, caused by
a sialidase-bearing virus, such as a virus of the influenza family,
which method comprises administering to said mammal an effective
amount of a sialidase inhibitory compound, wherein the sialidase
inhibitory compound is at least one compound selected from the
group consisting of compounds of formula (I) and pharmaceutically
acceptable salts and esters thereof.
[0021] The invention also provides processes for the preparation of
the compounds of the present invention which processes are
described in greater detail hereafter.
DETAILED DESCRIPTION OF THE INVENTION
[0022] In a first embodiment, there is provided a compound of
formula (I): 4
[0023] wherein:
[0024] R.sup.1 represents an alkyl group having from 1 to 4 carbon
atoms or a haloalkyl group having from 1 to 4 carbon atoms;
[0025] R.sup.2 and R.sup.3 are the same as or different from each
other and each represents a hydrogen atom or an aliphatic acyl
group having from 2 to 25 carbon atoms;
[0026] X represents a hydroxy group, a halogen atom, an alkoxy
group having from 1 to 4 carbon atoms, or a group of formula
R.sup.aO--, where R.sup.a represents an aliphatic acyl group having
from 2 to 25 carbon atoms;
[0027] Y represents a group of formula R.sup.bR.sup.cN-- or
R.sup.bR.sup.cN--O--, where R.sup.b and R.sup.c are the same as or
different from each other and each represents a hydrogen atom or an
alkyl group having from 1 to 4 carbon atoms; and
[0028] Z represents an oxygen atom or a sulfur atom;
[0029] PROVIDED THAT, when Y represents an amino group and Z
represents an oxygen atom, then X represents a halogen atom or an
alkoxy group;
[0030] and pharmaceutically acceptable salts and esters
thereof.
[0031] The compounds of the present invention are named on the
basis of saccharide terminology, in which the main positions are
numbered as shown in the following formula: 5
[0032] The compounds are named as derivatives of the unsaturated
sugar non-2-enopyranosoic acid, of formula: 6
[0033] The configurations of the carbon atoms at the 4 to 7
positions are D-galacto, while that of the carbon atom at the 8
position is D-glycero, as can be seen from the following partial
formula: 7
[0034] In the compounds of the present invention, where R.sup.1
represents an alkyl group, this may be a straight or branched chain
group having from 1 to 4 carbon atoms, and examples of such groups
include the methyl, ethyl, propyl, isopropyl, butyl, isobutyl,
sec-butyl and t-butyl groups, of which we prefer the methyl
group.
[0035] Where R.sup.1 represents a haloalkyl group, the halogen atom
may be a fluorine, chlorine, bromine or iodine atom, preferably a
fluorine, chlorine or bromine atom, and more preferably a fluorine
atom. The alkyl part of this haloalkyl group may be any of the
alkyl groups having from 1 to 4 carbon atoms listed above. Specific
examples of such haloalkyl groups include the fluoromethyl,
difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl,
1-fluoropropyl, 2-fluoropropyl, 3-fluoropropyl, 4-fluorobutyl,
chloromethyl, 1-chloroethyl, 2-chloroethyl, 1-chloropropyl,
2-chloropropyl, 3-chloropropyl, bromomethyl, 1-bromoethyl,
2-bromoethyl, 1-bromopropyl, 2-bromopropyl, and 3-bromopropyl
groups, of which we prefer a methyl group substituted with at least
one fluorine atom, particularly the fluoromethyl or difluoromethyl
groups.
[0036] More preferably R.sup.1 represents a methyl group or a
halomethyl group, particularly a methyl, fluoromethyl or
difluoromethyl group, more preferably a methyl group.
[0037] Where R.sup.2, R.sup.3 or R.sup.a represents an aliphatic
carboxylic acyl group having from 2 to 25 carbon atoms, this may be
a straight or branched chain group, and is preferably an alkanoyl
(alkylcarbonyl) group having from 2 to 25 carbon atoms. Specific
examples of such groups include the acetyl, propionyl, butyryl,
isobutyryl, pivaloyl, valeryl, isovaleryl, octanoyl, nonylcarbonyl,
decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl,
3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl,
dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl,
pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl,
14-methylpentadecylcarbony- l, 13, 13-dimethyltetradecylcarbonyl,
heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl,
1-methylheptadecylcarbonyl- , nonadecylcarbonyl, icosylcarbonyl and
tricosylcarbonyl groups. Of these, we prefer those alkylcarbonyl
group having from 6 to 25 carbon atoms, more preferably those
alkylcarbonyl groups having from 8 to 16 carbon atoms [and
particularly the octanoyl, nonylcarbonyl, undecylcarbonyl (i.e.
dodecanoyl), tridecylcarbonyl (i.e. myristoyl) and
pentadecylcarbonyl (i.e. palmitoyl) groups].
[0038] R.sup.2 preferably represents a hydrogen atom or an
aliphatic carboxylic acyl group having from 6 to 25 carbon atoms,
more preferably an aliphatic carboxylic acyl group having from 8 to
16 carbon atoms, particularly an octanoyl, nonylcarbonyl,
undecylcarbonyl, tridecylcarbonyl or pentadecylcarbonyl group.
[0039] R.sup.3 preferably represents a hydrogen atom or an
aliphatic carboxylic acyl group having from 6 to 25 carbon atoms,
more preferably a hydrogen atom or an aliphatic carboxylic acyl
group having from 8 to 16 carbon atoms, particularly an octanoyl,
nonylcarbonyl, undecylcarbonyl, tridecylcarbonyl or
pentadecylcarbonyl group.
[0040] Still more preferably, R.sup.2 represents an aliphatic acyl
group having from 8 to 16 carbon atoms (particularly an octanoyl,
nonylcarbonyl, undecylcarbonyl, tridecylcarbonyl or
pentadecylcarbonyl group), and R.sup.3 represents a hydrogen
atom.
[0041] Where X represents a halogen atom, this may be a fluorine,
chlorine, bromine or iodine atom, preferably a fluorine, chlorine
or bromine atom, and more preferably a fluorine atom;
[0042] Where X represents an alkoxy group having from 1 to 4 carbon
atoms, this may be a straight or branched chain group, and examples
include the methoxy, ethoxy, propoxy, isopropoxy, butoxy,
isobutoxy, sec-butoxy and t-butoxy groups, of which we prefer the
methoxy and ethoxy groups.
[0043] X preferably represents a fluorine atom, or a methoxy or
ethoxy group.
[0044] Where Y represents a group of formula R.sup.bR.sup.cN-- or
R.sup.bR.sup.cN--O-- and R.sup.b and/or R.sup.c represents an alkyl
group having from 1 to 4 carbon atoms, this may be a straight or
branched chain group, and examples include the methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl groups,
of which we prefer the methyl group. However, we most prefer that
at least one, and preferably both, of R.sup.b and R.sup.c should
represent a hydrogen atom. Thus, the preferred group represented by
R.sup.bR.sup.cN--O-- is a group of formula NH.sub.2--O--, and the
preferred group represented by R.sup.bR.sup.cN-- is N.sub.2--, i.e.
an amino group.
[0045] Y preferably represents a group of formula N.sub.2 or
N.sub.2--O--, more preferably an amino group of formula
NH.sub.2.
[0046] Z preferably represents an oxygen atom.
[0047] The compounds of the present invention contain a carboxy
group, and can, therefore, form salts with cations. There is no
particular restriction on the nature of these salts, provided that,
where the compounds are to be used medically, the salts should be
pharmaceutically acceptable, that is they should not be more toxic
(or unacceptably more toxic) than the free acid, nor should they be
less active (or unacceptably less active) than the free acid. When
the compound is to be used for other purposes, for example as
intermediates in the preparation of other, and possibly more active
compounds, even this restriction does not apply. Examples of such
salts include: alkali metal salts, such as the sodium salt,
potassium and lithium salts; alkaline earth metal salts, such as
the calcium and magnesium salts; other metal salts, such as the
aluminum, iron, zinc, copper, nickel and cobalt salts; other
inorganic salts, such as the ammonium salt; amine salts, such as
the t-octylamine, dibenzylamine, morpholine, glucosamine,
phenylglycine alkyl ester, ethylenediamine, methylglucamine,
guanidine, diethylamine, triethylamine, dicyclohexylamine,
N,N'-dibenzylethylenediamine, chloroprocaine, procaine,
diethanolamine, benzyl-phenethylamine, piperazine,
tetramethylammonium and tris(hydroxymethyl)aminomethane salts.
[0048] Furthermore, when the compound of the present invention
contains a guadinino group, it can be also converted to a salt.
Such salts, likewise, are not particularly restricted, except that,
where they are for medical use, they should be pharmaceutically
acceptable. Examples of such salts include: hydrohalides, such as
the hydrofluoride, hydrochloride, hydrobromide or hydroiodide;
other inorganic acid salts, such as the nitrate, perchlorate, a
sulfate or phosphate; lower alkanesulfonates, such as the
methanesulfonate, trifluoromethanesulfonate or ethanesulfonate;
arylsulfonates, such as the benzenesulfonate or p-toluenesulfonate;
organic acid salts, especially carboxylic acid salts, such as the
acetate, trifluoroacetate, malate, fumarate, succinate, citrate,
tartarate, oxalate or maleate; and amino acid salts, such as the
glycine, lysine, arginine, ornithine, glutamic acid salt or
aspartic acid salt. Of these, we prefer the alkali metal salts,
such as the sodium, potassium and lithium salts, organic acid
salts, such as the acetate and trifluoroacetate and inorganic acid
salts, such as the hydrochloride and sulfate.
[0049] Since the compounds of the present invention contain a
carboxy group, they can form esters. There is no particular
restriction on the nature of these esters, provided that, where the
compounds are to be used medically, the esters should be
pharmaceutically acceptable, that is they should not be more toxic
(or unacceptably more toxic) than the free acid, nor should they be
less active (or unacceptably less active) than the free acid. When
the compound is to be used for other purposes, for example as
intermediates in the preparation of other, and possibly more active
compounds, even this restriction does not apply. Examples of groups
which can form such esters include:
[0050] alkyl groups, preferably having from 1 to 30, more
preferably from 1 to 25 carbon atoms, such as the methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl,
isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, hexyl,
isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl,
1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl,
2,3-dimethylbutyl, 2-ethylbutylheptyl, 1-methylhexyl,
2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl,
2-methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl,
6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl,
nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl,
1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl,
1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl,
3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl,
dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl,
hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl,
14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl,
15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl,
icosyl, 3,7,11,15-tetramethylhexadecyl, henicosyl and docosyl
groups;
[0051] alkenyl groups, preferably having from 2 to 10, and more
preferably from 2 to 8 carbon atoms, such as the ethenyl,
1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl,
2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl,
1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl,
3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl,
1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl,
1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,
3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl,
1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl and 5-hexenyl groups;
[0052] alkynyl groups, preferably having from 2 to 10, and more
preferably from 2 to 8 carbon atoms, such as the ethynyl,
2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl,
2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl,
2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl,
1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl,
2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl,
1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl,
1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl,
4-hexynyl and 5-hexynyl groups;
[0053] haloalkyl groups, preferably having from 1 to 6, more
preferably from 1 to 4, carbon atoms, such as the trifluoromethyl,
trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl,
fluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl,
2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2-iodoethyl,
3-chloropropyl, 4-fluorobutyl, 6-iodohexyl and 2,2-dibromoethyl
groups;
[0054] hydroxyalkyl groups, preferably having from 1 to 6, more
preferably from 1 to 4, carbon atoms, such as the 2-hydroxyethyl,
2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl and
4-hydroxybutyl groups;
[0055] aliphatic acyl-substituted alkyl groups, in which the alkyl
part preferably has from 1 to 6 carbon atoms, and may be any such
group of those listed above, and the aliphatic acyl group, such as
those exemplified above in relation to R.sup.2, and especially
those having from 2 to 5 carbon atoms, such as the acetylmethyl
group;
[0056] aralkyl groups in which an alkyl group having from 1 to 6
carbon atoms is substituted with from 1 to 3 unsubstituted
carbocyclic aryl groups, such as the benzyl, phenethyl,
3-phenylpropyl, .alpha.-naphthylmethyl, .beta.-naphthylmethyl,
diphenylmethyl, triphenylmethyl, 6-phenylhexyl,
.alpha.-naphthyldiphenylmethyl and 9-anthrylmethyl groups;
[0057] aralkyl groups in which an alkyl group having from 1 to 6
carbon atoms is substituted with from 1 to 3 substituted
carbocyclic aryl groups, the subsituents being, for example, the
alkyl, alkoxy, nitro, halogen, cyano oralkoxycarbonyl groups, such
as the 4-methylbenzyl, 2,4,6-trimethylbenzyl,
3,4,5-trimethylbenzyl, 4-methoxybenzyl,
4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl,
4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl,
4-cyanobenzyldiphenylmethyl- , bis(2-nitrophenyl)methyl, piperonyl
and 4-methoxycarbonylbenzyl groups;
[0058] silyl groups, including trialkylsilyl, dialkylarylsilyl and
alkyldiarylsilyl groups (the alkyl groups preferably having from 1
to 6 carbon atoms), such as the trimethylsilyl, triethylsilyl,
isopropyldimethylsilyl, t-butyldimethylsilyl,
methyldiisopropylsilyl, methyldi-t-butylsilyl, triisopropylsilyl,
methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl and
phenyldiisopropylsilyl groups;
[0059] alkoxyalkyl groups in which the alkoxy and alkyl parts both
have from 1 to 6, preferably from 1 to 4, carbon atoms, such as the
methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl,
1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl,
1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl,
isopropoxymethyl, butoxymethyl and t-butoxymethyl groups;
[0060] alkoxyalkoxyalkyl groups in which each of the alkoxy parts
and the alkyl part all have from 1 to 6, preferably from 1 to 4,
carbon atoms, such as the 2-methoxyethoxymethyl group;
[0061] aryloxyalkyl groups in which the alkyl part has from 1 to 6,
preferably from 1 to 4, carbon atoms, such as the phenoxymethyl
group;
[0062] halogenated alkoxyalkyl groups in which the alkoxy and alkyl
parts both have from 1 to 6, preferably from 1 to 4, carbon atoms,
such as the 2,2,2-trichloroethoxymethyl and
bis(2-chloroethoxy)methyl groups;
[0063] alkoxycarbonylalkyl groups in which the alkoxy and alkyl
parts both have from 1 to 6, preferably from 1 to 4, carbon atoms,
such as the methoxycarbonylmethyl group;
[0064] cyanoalkyl groups in which the alkyl part has from 1 to 6,
preferably from 1 to 4, carbon atoms, such as the cyanomethyl and
2-cyanoethyl groups; alkylthiomethyl groups in which the alkyl part
has from 1 to 6, preferably from 1 to 4, carbon atoms, such as the
methylthiomethyl and ethylthiomethyl groups;
[0065] arylthiomethyl groups, such as the phenylthiomethyl and
naphthylthiomethyl groups;
[0066] alkylsulfonylalkyl groups in which each of the alkyl parts
has from 1 to 6, preferably from 1 to 4, carbon atoms and which may
be substituted with one or more halogen atoms, such as the
2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl
groups;
[0067] arylsulfonylalkyl groups in which the alkyl part has from 1
to 6, preferably from 1 to 4, carbon atoms, such as the
2-benzenesulfonylethyl and 2-toluenesulfonylethyl groups;
[0068] acyloxyalkyl groups, including
[0069] aliphatic carboxylic acyloxyalkyl groups in which the alkyl
part has from 1 to 6, preferably from 1 to 4, carbon atoms and the
aliphatic acyl part has from 1 to 8, preferably from 2 to 5, carbon
atoms, such as the formyloxymethyl, acetoxymethyl,
propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl,
valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl,
1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl,
1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl,
1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl,
2-acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl,
2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl,
2-hexanoyloxyethyl, 1-formyloxypropyl, 1-acetoxypropyl,
1-propionyloxypropyl, 1-butyryloxypropyl, 1-pivaloyloxypropyl,
1-valeryloxypropyl, 1-isovaleryloxypropyl, 1-hexanoyloxypropyl,
1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl,
1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl,
1-butyryloxypentyl, 1-pivaloyloxypentyl and 1-pivaloyloxyhexyl
groups;
[0070] cycloalkylcarbonyloxyalkyl groups in which the alkyl part
has from 1 to 6, preferably from 1 to 4, carbon atoms and the
cycloalkyl part has from 3 to 8, preferably 5 or 6, carbon atoms,
such as the cyclopentanecarbonyloxymethyl,
cyclohexanecarbonyloxymethyl, 1-cyclopentanecarbonyloxyethyl,
1-cyclohexanecarbonyloxyethyl, 1-cyclopentanecarbonyloxypropyl,
1-cyclohexanecarbonyloxypropyl, 1-cyclopentanecarbonyloxybutyl and
1-cyclohexanecarbonyloxybutyl groups;
[0071] aromatic acyloxyalkyl groups in which the alkyl part has
from 1 to 6, preferably from 1 to 4, carbon atoms, such as the
benzoyloxymethyl group;
[0072] (alkoxycarbonyloxy)alkyl groups in which the alkoxy and
alkyl parts both have from 1 to 6, preferably from 1 to 4, carbon
atoms, such as the methoxycarbonyloxymethyl,
ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl,
isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl,
isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl,
hexyloxycarbonyloxymethyl, 1-(methoxycarbonyloxy)ethyl,
1-(ethoxycarbonyloxy)ethyl, 1-propoxycarbonyloxyethyl,
1-(isopropoxycarbonyloxy)ethyl, 1-butoxycarbonyloxyethyl,
1-isobutoxycarbonyloxyethyl, 1-(tert-butoxycarbonyloxy)ethyl,
1-pentyloxycarbonyloxyethyl, 1-hexyloxycarbonyloxyethyl,
1-(ethoxycarbonyloxy)propyl, 2-methoxycarbonyloxyethyl,
2-ethoxycarbonyloxyethyl, 2-propoxycarbonyloxyethyl,
2-isopropoxycarbonyloxyethyl, 2-butoxycarbonyloxyethyl,
2-isobutoxycarbonyloxyethyl, 2-pentyloxycarbonyloxyethyl,
2-hexyloxycarbonyloxyethyl, 1-methoxycarbonyloxypropyl,
1-ethoxycarbonyloxypropyl, 1-propoxycarbonyloxypropyl,
1-isopropoxycarbonyloxypropyl, 1-butoxycarbonyloxypropyl,
1-isobutoxycarbonyloxypropyl, 1-pentyloxycarbonyloxypropyl,
1-hexyloxycarbonyloxypropyl, 1-methoxycarbonyloxybutyl,
1-ethoxycarbonyloxybutyl, 1-propoxycarbonyloxybutyl,
1-isopropoxycarbonyloxybutyl, 1-butoxycarbonyloxybutyl,
1-isobutoxycarbonyloxybutyl, 1-methoxycarbonyloxypentyl,
1-ethoxycarbonyloxypentyl, 1-methoxycarbonyloxyhexyl and
1-ethoxycarbonyloxyhexyl groups;
[0073] (cycloalkyloxycarbonyloxy)alkyl and
(cycloalkyloxycarbonyloxy)(cycl- oalkyl)alkyl groups in which the
alkyl part has from 1 to 6, preferably from 1 to 4, carbon atoms
and the cycloalkyl part has from 3 to 8, preferably 5 or 6, carbon
atoms, such as the cyclohexyloxycarbonyloxymeth- yl,
cyclohexyloxycarbonyloxy(cyclohexyl)methyl,
1-cyclopentyloxycarbonylox- yethyl,
1-cyclopentyloxycarbonyloxypropyl, 1-cyclohexyloxycarbonyloxypropy-
l, 1-cyclopentyloxycarbonyloxybutyl,
1-cyclohexyloxycarbonyloxybutyl and
1-(cyclohexyloxycarbonyloxy)ethyl groups;
[0074] carbonyloxyalkyl groups in which the alkyl part has from 1
to 6, preferably from 1 to 4, carbon atoms, including
oxodioxolenylmethyl groups, such as the
(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,
[5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
(2-oxo-1,3-dioxolen-4-yl)methyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl- ,
(5-ethyl-2-oxo-1,3-dioxolen-4-yl)methyl,
(5-propyl-2-oxo-1,3-dioxolen-4-- yl)methyl,
(5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and
(5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl groups;
[0075] phthalidyl and substituted phthalidyl groups, such as the
phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl groups;
[0076] aryl groups, preferably having from 6 to 14 carbon atoms in
one or more carbocyclic rings, such as the phenyl and indanyl
groups;
[0077] carboxyalkyl groups in which the alkyl part has from 1 to 6,
preferably from 1 to 4, carbon atoms, such as the carboxymethyl
group; and
[0078] amide forming residues of amino acid.
[0079] Of the ester groups listed above, the following are
cleavable by a biological method such as hydrolysis in a living
body;. that is the esters produce free acids or salts by hydrolysis
or a similar reaction in a human body, specifically:
[0080] allyl groups, alkoxyalkyl groups, alkoxyalkoxyalkyl groups,
aryloxyalkyl groups, halogenated alkoxyalkyl groups,
alkoxycarbonylalkyl groups, cyanoalkyl groups, alkylthiomethyl
groups, alkylsulfonylalkyl groups, arylsulfonylalkyl groups,
acyloxyalkyl groups, (alkoxycarbonyloxy)alkyl groups,
(cycloalkyloxycarbonyloxy)alkyl groups,
(cycloalkyloxycarbonyloxy)(cycloalkyl)alkyl groups,
carbonyloxyalkyl groups, phthalidyl and substituted phthalidyl
groups, aryl groups, carboxyalkyl groups, and amide forming
residues of amino acid.
[0081] Of these, we prefer the straight or branched alkyl groups
having from 6 to 25 carbon atoms, more preferably an alkyl group
having 16 to 25 carbon atoms.
[0082] The compound of the present invention, when it is allowed to
stand in the atmosphere, may absorb some moisture, and it may, as a
result, be associated with adsorption water or it may be converted
to a hydrate. Such hydrates also form part of the present
invention.
[0083] Preferred classes of compounds of the present invention are
those compounds of formula (I) and pharmaceutically acceptable
salts and esters thereof in which:
[0084] (A) R.sup.1 represents a methyl or halomethyl group.
[0085] (B) R.sup.2 represents a hydrogen atom or an aliphatic
carboxylic acyl group having from 6 to 25 carbon atoms.
[0086] (C) R.sup.3 represents a hydrogen atom or an aliphatic
carboxylic acyl group having from 6 to 25 carbon atoms.
[0087] (D) X represents a halogen atom or an alkoxy group having
from 1 to 4 carbon atoms.
[0088] (E) Y represents an amino group or a group of formula
R.sup.bR.sup.cN--O--, where R.sup.b and R.sup.c are as defined
above.
[0089] Of the above compounds, we particularly prefer those
compounds of formula (I) and pharmaceutically acceptable salts and
esters thereof wherein R.sup.1 is as defined in (A) above, R.sup.2
is as defined in (B) above, R.sup.3 is as defined in (C) above, X
is as defined in (D) above, and Y is as defined in (E) above,
especially those in which R.sup.1 is as defined in (A) above,
R.sup.2 is as defined in (B) above, R.sup.3 is as defined in (C)
above, X is as defined in (D) above, Y is as defined in (E) above,
and Z represents an oxygen atom.
[0090] More preferred classes of compounds of the present invention
are those compounds of formula (I) and pharmaceutically acceptable
salts and esters thereof wherein:
[0091] (F) R.sup.1 represents a methyl group or a methyl group
having at least one flourine substituent.
[0092] (G) R.sup.2 represents a hydrogen atom or an aliphatic
carboxylic acyl group having from 8 to 16 carbon atoms.
[0093] (H) R.sup.3 represents a hydrogen atom or an aliphatic
carboxylic acyl group having from 8 to 16 carbon atoms.
[0094] (I) X represents a fluorine atom, a methoxy group or an
ethoxy group.
[0095] (J) Y represents an amino group or an aminooxy group.
[0096] (K) Z represents an oxygen atom.
[0097] Of the above compounds, we particularly prefer those
compounds of formula (I) and pharmaceutically acceptable salts and
esters thereof wherein R.sup.1 is as defined in (F) above, R.sup.2
is as defined in (G) above, R.sup.3 is as defined in (H) above, X
is as defined in (I) above, Y is as defined in (J) above, and Z is
as defined in (K) above.
[0098] A still more preferred class of compounds of the present
invention are those compounds of formula (I) and pharmaceutically
acceptable salts and esters thereof wherein:
[0099] (L) R.sup.2 represents a hydrogen atom or an aliphatic
carboxylic acyl group having from 8 to 16 carbon atoms and R.sup.3
represents a hydrogen atom.
[0100] Of the above compounds, we particularly prefer those
compounds of formula (I) and pharmaceutically acceptable salts and
esters thereof wherein R.sup.1 is as defined in (F) above, R.sup.2
and R.sup.3 are as defined in (L) above, X is as defined in (I)
above, Y is as defined in (J) above, and Z is as defined in (K)
above.
[0101] Further more preferred classes of compounds of the present
invention are those compounds of formula (I) and pharmaceutically
acceptable salts and esters thereof wherein:
[0102] (M) R.sup.1 represents a methyl, fluoromethyl or
difluoromethyl group.
[0103] (N) R.sup.2 represents an octanoyl, decanoyl, dodecanoyl,
myristoyl or palmitoyl group.
[0104] (O) R.sup.3 represents a hydrogen atom, or an octanoyl,
decanoyl, dodecanoyl, myristoyl or palmitoyl group.
[0105] (P) Y represents an amino group.
[0106] Of the above compounds, we particularly prefer those
compounds of formula (I) and pharmaceutically acceptable salts and
esters thereof wherein R.sup.1 is as defined in (M) above, R.sup.2
is as defined in (N) above, R.sup.3 is as defined in (O) above, X
is as defined in (I) above, Y is as defined in (P) above, and Z is
as defined in (K) above.
[0107] Further more preferred classes of compounds of the present
invention are those compounds of formula (I) and pharmaceutically
acceptable salts and esters thereof wherein:
[0108] (Q) R.sup.1 represents a methyl group.
[0109] (R) R.sup.2 represents an octanoyl, decanoyl, dodecanoyl,
myristoyl or palmitoyl group and R.sup.3 represents a hydrogen
atom.
[0110] Of the above compounds, we particularly prefer those
compounds of formula (I) and pharmaceutically acceptable salts and
esters thereof wherein R.sup.1 is as defined in (Q) above, R.sup.2
and R.sup.3 are as defined in (R) above, X is as defined in (I)
above, Y is as defined in (P) above, and Z is as defined in (K)
above.
[0111] Specific compounds of the present invention are exemplified
below by the following formula (I'), in which the substituent
groups are as defined in the following Tables 1 and 2. Any
individual compound may be defined by taking the combination of
definitions of R.sup.1, X, Y and Z in any row of Table 1 and
combining them with the combination of definitions of R.sup.2,
R.sup.3 and W in any row of Table 2. The compound may then be
identified by a number in the form .alpha.-.beta., where .alpha. is
the number of the respective row of Table 1 and .beta. is the
number of the respective row of Table 2. Thus, for example, the
compound of formula (I"), given below, which is a compound of
formula (I') in which R.sup.1 represents a methyl group, X
represents a fluorine atom, Y represents an amino group, Z
represents an oxygen atom (row 1 of Table 1), R.sup.2 represents a
hydrogen atom, R.sup.3 represents a hydrogen atom and W represents
an undecyl group (row 4 of Table 2) is Compound No. 1-4. 8
[0112] In the Tables, the following abbreviations are used:
1TABLE 1 Cpd. No. R.sup.1 X Y Z 1 CH.sub.3 F NH.sub.2 O 2 CF.sub.2H
F NH.sub.2 O 3 CFH.sub.2 F NH.sub.2 O 4 CH.sub.3 F NH.sub.2 S 5
CF.sub.2H F NH.sub.2 S 6 CFH.sub.2 F NH.sub.2 S 7 CH.sub.3 F
ONH.sub.2 O 8 CF.sub.2H F ONH.sub.2 O 9 CFH.sub.2 F ONH.sub.2 O 10
CH.sub.3 F ONH.sub.2 S 11 CF.sub.2H F ONH.sub.2 S 12 CFH.sub.2 F
ONH.sub.2 S 13 CH.sub.3 F ONHMe O 14 CF.sub.2H F ONHEt O 15
CFH.sub.2 F ONHPr O 16 CH.sub.3 F ONHMe S 17 CF.sub.2H F ONHBu S 18
CFH.sub.2 F ONHMe S 19 CH.sub.3 F ON(Me).sub.2 O 20 CF.sub.2H F
ON(Et).sub.2 O 21 CFH.sub.2 F ON(Pr).sub.2 O 22 CH.sub.3 F
ON(Me).sub.2 S 23 CF.sub.2H F ON(Bu).sub.2 S 24 CFH.sub.2 F
ON(Me)Et S 25 CH.sub.3 Cl NH.sub.2 O 26 CF.sub.2H Br NH.sub.2 O 27
CFH.sub.2 Br NH.sub.2 O 28 CH.sub.3 Cl NH.sub.2 S 29 CF.sub.2H Cl
NH.sub.2 S 30 CFH.sub.2 Br NH.sub.2 S 31 CH.sub.3 OH NH.sub.2 S 32
CF.sub.2H OH NH.sub.2 S 33 CFH.sub.2 OH NH.sub.2 S 34 CH.sub.3 OH
ONH.sub.2 O 35 CF.sub.2H OH ONH.sub.2 O 36 CFH.sub.2 OH ONH.sub.2 O
37 CH.sub.3 OH ONH.sub.2 S 38 CF.sub.2H OH ONH.sub.2 S 39 CFH.sub.2
OH ONH.sub.2 S 40 CH.sub.3 OH ONHMe O 41 CF.sub.2H OH ONHEt O 42
CFH.sub.2 OH ONHPr O 43 CH.sub.3 OH ONHMe S 44 CF.sub.2H OH ONHBu S
45 CFH.sub.2 OH ONHMe S 46 CH.sub.3 OH ON(Me).sub.2 O 47 CF.sub.2H
OH ON(Et).sub.2 O 48 CFH.sub.2 OH ON(Pr).sub.2 O 49 CH.sub.3 OH
ON(Me).sub.2 S 50 CF.sub.2H OH ON(Bu).sub.2 S 51 CFH.sub.2 OH
ON(Me)Et S 52 Et F NH.sub.2 O 53 CF.sub.3CH.sub.2 F NH.sub.2 O 54
Pr F NH.sub.2 O 55 Bu F NH.sub.2 S 56 iPr F NH.sub.2 S 57 iBu F
NH.sub.2 S 58 Bu OH NH.sub.2 S 59 iPr OH NH.sub.2 S 60 iBu OH
NH.sub.2 S 61 Et F ONH.sub.2 O 62 CF.sub.3CH.sub.2 F ONH.sub.2 O 63
Pr F ONH.sub.2 O 64 Bu F ONH.sub.2 S 65 iPr F ONH.sub.2 S 66 iBu F
ONH.sub.2 S 67 Et CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 O 68
CF.sub.3CH.sub.2 CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 O 69 Pr
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 O 70 Bu
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 S 71 iPr
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 S 72 iBu
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 S 73 CH.sub.3
CH.sub.3(CH.sub.2).sub.4COO NH.sub.2 S 74 CF.sub.2H
CH.sub.3(CH.sub.2).sub.4COO NH.sub.2 S 75 CFH.sub.2
CH.sub.3(CH.sub.2).sub.4COO NH.sub.2 S 76 CH.sub.3
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 O 77 CF.sub.2H
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 O 78 CFH.sub.2
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 O 79 CH.sub.3
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 S 80 CF.sub.2H
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 S 81 CFH.sub.2
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 S 82 CH.sub.3
CH.sub.3(CH.sub.2).sub.4COO ONHMe O 83 CF.sub.2H
CH.sub.3(CH.sub.2).sub.4COO ONHEt O 84 CFH.sub.2
CH.sub.3(CH.sub.2).sub.4COO ONHPr O 85 CH.sub.3
CH.sub.3(CH.sub.2).sub.4COO ONHMe S 86 CF.sub.2H
CH.sub.3(CH.sub.2).sub.4COO ONHBu S 87 CFH.sub.2
CH.sub.3(CH.sub.2).sub.4COO ONHMe S 88 CH.sub.3
CH.sub.3(CH.sub.2).sub.4COO ON(Me).sub.2 O 89 CF.sub.2H
CH.sub.3(CH.sub.2).sub.4COO ON(Et).sub.2 O 90 CFH.sub.2
CH.sub.3(CH.sub.2).sub.4COO ON(Pr).sub.2 O 91 CH.sub.3
CH.sub.3(CH.sub.2).sub.4COO ON(Me).sub.2 S 92 CF.sub.2H
CH.sub.3(CH.sub.2).sub.4COO ON(Bu).sub.2 S 93 CFH.sub.2
CH.sub.3(CH.sub.2).sub.4COO ON(Me)Et S 94 Bu
CH.sub.3(CH.sub.2).sub.4COO NH.sub.2 S 95 iPr
CH.sub.3(CH.sub.2).sub.4COO NH.sub.2 S 96 iBu
CH.sub.3(CH.sub.2).sub.4COO NH.sub.2 S 97 Et
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 O 98 CF.sub.3CH.sub.2
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 O 99 Pr
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 O 100 Bu
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 S 101 iPr
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 S 102 iBu
CH.sub.3(CH.sub.2).sub.4COO ONH.sub.2 S 103 CH.sub.3
CH.sub.3(CH.sub.2).sub.12COO NH.sub.2 S 104 CF.sub.2H
CH.sub.3(CH.sub.2).sub.12COO NH.sub.2 S 105 CFH.sub.2
CH.sub.3(CH.sub.2).sub.12COO NH.sub.2 S 106 CH.sub.3
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 O 107 CF.sub.2H
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 O 108 CFH.sub.2
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 O 109 CH.sub.3
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 S 110 CF.sub.2H
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 S 111 CFH.sub.2
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 S 112 CH.sub.3
CH.sub.3(CH.sub.2).sub.12COO ONHMe O 113 CF.sub.2H
CH.sub.3(CH.sub.2).sub.12COO ONHEt O 114 CFH.sub.2
CH.sub.3(CH.sub.2).sub.12COO ONHPr O 115 CH.sub.3
CH.sub.3(CH.sub.2).sub.12COO ONHMe S 116 CF.sub.2H
CH.sub.3(CH.sub.2).sub.12COO ONHBu S 117 CFH.sub.2
CH.sub.3(CH.sub.2).sub.12COO ONHMe S 118 CH.sub.3
CH.sub.3(CH.sub.2).sub.12COO ON(Me).sub.2 O 119 CF.sub.2H
CH.sub.3(CH.sub.2).sub.12COO ON(Et).sub.2 O 120 CFH.sub.2
CH.sub.3(CH.sub.2).sub.12COO ON(Pr).sub.2 O 121 CH.sub.3
CH.sub.3(CH.sub.2).sub.12COO ON(Me).sub.2 S 122 CF.sub.2H
CH.sub.3(CH.sub.2).sub.12COO ON(Bu).sub.2 S 123 CFH.sub.2
CH.sub.3(CH.sub.2).sub.12COO ON(Me)Et S 124 Bu
CH.sub.3(CH.sub.2).sub.12COO NH.sub.2 S 125 iPr
CH.sub.3(CH.sub.2).sub.12COO NH.sub.2 S 126 iBu
CH.sub.3(CH.sub.2).sub.12COO NH.sub.2 S 127 Et
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 O 128 CF.sub.3CH.sub.2
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 O 129 Pr
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 O 130 Bu
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 S 131 iPr
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 S 132 iBu
CH.sub.3(CH.sub.2).sub.12COO ONH.sub.2 S 133 CH.sub.3
CH.sub.3(CH.sub.2).sub.2COO NH.sub.2 S 134 CF.sub.2H
CH.sub.3(CH.sub.2).sub.3COO NH.sub.2 S 135 CFH.sub.2
CH.sub.3(CH.sub.2).sub.5COO NH.sub.2 S 136 CH.sub.3
CH.sub.3(CH.sub.2).sub.6COO ONH.sub.2 O 137 CF.sub.2H
CH.sub.3(CH.sub.2).sub.8COO ONH.sub.2 O 138 CFH.sub.2
CH.sub.3(CH.sub.2).sub.10COO ONH.sub.2 O 139 CH.sub.3
CH.sub.3(CH.sub.2).sub.14COO ONH.sub.2 S 140 CF.sub.2H
CH.sub.3(CH.sub.2).sub.16COO ONH.sub.2 S 141 CFH.sub.2
CH.sub.3(CH.sub.2).sub.18COO ONH.sub.2 S 142 CH.sub.3
CH.sub.3(CH.sub.2).sub.20COO ONHMe O 143 CF.sub.2H
CH.sub.3(CH.sub.2).sub.22COO ONHEt O 144 CFH.sub.2
CH.sub.3CH.sub.2COO ONHPr O 145 CH.sub.3 CH.sub.3(CH.sub.2).sub.2C-
OO ONHMe S 146 CF.sub.2H CH.sub.3(CH.sub.2).sub.3COO ONHBu S 147
CFH.sub.2 CH.sub.3(CH.sub.2).sub.5COO ONHMe S 148 CH.sub.3
CH.sub.3(CH.sub.2).sub.6COO ON(Me).sub.2 O 149 CF.sub.2H
CH.sub.3(CH.sub.2).sub.8COO ON(Et).sub.2 O 150 CFH.sub.2
CH.sub.3(CH.sub.2).sub.10COO ON(Pr).sub.2 O 151 CH.sub.3
CH.sub.3(CH.sub.2).sub.14COO ON(Me).sub.2 S 152 CF.sub.2H
CH.sub.3(CH.sub.2).sub.16COO ON(Bu).sub.2 S 153 CFH.sub.2
CH.sub.3(CH.sub.2).sub.18COO ON(Me)Et S 154 Bu
CH.sub.3(CH.sub.2).sub.2COO NH.sub.2 S 155 iPr
CH.sub.3(CH.sub.2).sub.3COO NH.sub.2 S 156 iBu
CH.sub.3(CH.sub.2).sub.5COO NH.sub.2 S 157 Et
CH.sub.3(CH.sub.2).sub.6COO ONH.sub.2 O 158 CF.sub.3CH.sub.2
CH.sub.3(CH.sub.2).sub.8COO ONH.sub.2 O 159 Pr
CH.sub.3(CH.sub.2).sub.10COO ONH.sub.2 O 160 Bu
CH.sub.3(CH.sub.2).sub.14COO ONH.sub.2 S 161 iPr
CH.sub.3(CH.sub.2).sub.16COO ONH.sub.2 S 162 iBu
CH.sub.3(CH.sub.2).sub.18COO ONH.sub.2 S 163 CH.sub.3 OMe NH.sub.2
O 164 CF.sub.2H OMe NH.sub.2 O 165 CFH.sub.2 OMe NH.sub.2 O 166
CH.sub.3 OMe NH.sub.2 S 167 CF.sub.2H OMe NH.sub.2 S 168 CFH.sub.2
OMe NH.sub.2 S 169 CH.sub.3 OMe ONH.sub.2 O 170 CF.sub.2H OMe
ONH.sub.2 O 171 CFH.sub.2 OMe ONH.sub.2 O 172 CH.sub.3 OMe
ONH.sub.2 S 173 CF.sub.2H OMe ONH.sub.2 S 174 CFH.sub.2 OMe
ONH.sub.2 S 175 CH.sub.3 OMe ONHMe O 176 CF.sub.2H OMe ONHEt O 177
CFH.sub.2 OMe ONHPr O 178 CH.sub.3 OMe ONHMe S 179 CF.sub.2H OMe
ONHBu S 180 CFH.sub.2 OMe ONHMe S 181 CH.sub.3 OMe ON(Me).sub.2 O
182 CF.sub.2H OMe ON(Et).sub.2 O 183 CFH.sub.2 OMe ON(Pr).sub.2 O
184 CH.sub.3 OMe ON(Me).sub.2 S 185 CF.sub.2H OMe ON(Bu).sub.2 S
186 CFH.sub.2 OMe ON(Me)Et S 187 Et OMe NH.sub.2 O 188
CF.sub.3CH.sub.2 OMe NH.sub.2 O 189 Pr OMe NH.sub.2 O 190 Bu OMe
NH.sub.2 S 191 iPr OMe NH.sub.2 S 192 iBu OMe NH.sub.2 S 193 Et OMe
ONH.sub.2 O 194 CF.sub.3CH.sub.2 OMe ONH.sub.2 O 195 Pr OMe
ONH.sub.2 O 196 Bu OMe ONH.sub.2 S 197 iPr OMe ONH.sub.2 S 198 iBu
OMe ONH.sub.2 S 199 CH.sub.3 OEt NH.sub.2 O 200 CF.sub.2H OEt
NH.sub.2 O 201 CFH.sub.2 OEt NH.sub.2 O 202 CH.sub.3 OEt NH.sub.2 S
203 CF.sub.2H OEt NH.sub.2 S 204 CFH.sub.2 OEt NH.sub.2 S 205
CH.sub.3 OEt ONH.sub.2 O 206 CF.sub.2H OEt ONH.sub.2 O 207
CFH.sub.2 OEt ONH.sub.2 O 208 CH.sub.3 OEt ONH.sub.2 S 209
CF.sub.2H OEt ONH.sub.2 S 210 CFH.sub.2 OEt ONH.sub.2 S 211
CH.sub.3 OEt ONHMe O 212 CF.sub.2H OEt ONHEt O 213 CFH.sub.2 OEt
ONHPr O 214 CH.sub.3 OEt ONHMe S 215 CF.sub.2H OEt ONHBu S 216
CFH.sub.2 OEt ONHMe S 217 CH.sub.3 OEt ON(Me).sub.2 O 218 CF.sub.2H
OEt ON(Et).sub.2 O 219 CFH.sub.2 OEt ON(Pr).sub.2 O 220 CH.sub.3
OEt ON(Me).sub.2 S 221 CF.sub.2H OEt ON(Bu).sub.2 S 222 CFH.sub.2
OEt ON(Me)Et S 223 Et OEt NH.sub.2 O 224 CF.sub.3CH.sub.2 OEt
NH.sub.2 O 225 Pr OEt NH.sub.2 O 226 Bu OEt NH.sub.2 S 227 iPr OEt
NH.sub.2 S 228 iBu OEt NH.sub.2 S 229 Et OEt ONH.sub.2 O 230
CF.sub.3CH.sub.2 OEt ONH.sub.2 O 231 Pr OEt ONH.sub.2 O 232 Bu OEt
ONH.sub.2 S 233 iPr OEt ONH.sub.2 S 234 iBu OEt ONH.sub.2 S Bu
butyl iBu isobutyl Et ethyl Me methyl Pr propyl iPr isopropyl
[0113]
2TABLE 2 Cpd. No. R.sup.2 R.sup.3 W 1 H H H 2 H H CH.sub.3 3 H H
(CH.sub.2).sub.5CH.sub.- 3 4 H H (CH.sub.2).sub.10CH.sub.3 5 H H
(CH.sub.2).sub.13CH.sub.3 6 H H (CH.sub.2).sub.15CH.sub.3 7 H H
(CH.sub.2).sub.17CH.sub.3 8 H H (CH.sub.2).sub.21CH.sub.3 9 H
CH.sub.3CO H 10 H CH.sub.3CH.sub.2CO H 11 H
CH.sub.3(CH.sub.2).sub.2CO H 12 H CH.sub.3(CH.sub.2).sub.3CO H 13 H
CH.sub.3(CH.sub.2).sub.4CO H 14 H CH.sub.3(CH.sub.2).sub.5- CO H 15
H CH.sub.3(CH.sub.2).sub.6CO H 16 H CH.sub.3(CH.sub.2).sub.8CO H 17
H CH.sub.3(CH.sub.2).sub.10CO H 18 H CH.sub.3(CH.sub.2).sub.12CO H
19 H CH.sub.3(CH.sub.2).sub.14CO H 20 H CH.sub.3(CH.sub.2).sub.16CO
H 21 H CH.sub.3(CH.sub.2).sub.18CO H 22 H
CH.sub.3(CH.sub.2).sub.20CO H 23 H CH.sub.3(CH.sub.2).sub.22CO H 24
H CH.sub.3(CH.sub.2).sub.4CO CH.sub.3 25 H
CH.sub.3(CH.sub.2).sub.4CO (CH.sub.2).sub.5CH.sub.3 26 H
CH.sub.3(CH.sub.2).sub.4CO (CH.sub.2).sub.10CH.sub.3 27 H
CH.sub.3(CH.sub.2).sub.4CO (CH.sub.2).sub.13CH.sub.3 28 H
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3 29 H CH.sub.3(CH.sub.2).sub.1-
2CO (CH.sub.2).sub.5CH.sub.3 30 H CH.sub.3(CH.sub.2).sub.12CO
(CH.sub.2).sub.10CH.sub.3 31 H CH.sub.3(CH.sub.2).sub.12CO
(CH.sub.2).sub.13CH.sub.3 32 CH.sub.3CO H H 33 CH.sub.3CH.sub.2CO H
H 34 CH.sub.3(CH.sub.2).sub.2CO H H 35 CH.sub.3(CH.sub.2).sub.3CO H
H 36 CH.sub.3(CH.sub.2).sub.4CO H H 37 CH.sub.3(CH.sub.2).sub.5CO H
H 38 CH.sub.3(CH.sub.2).sub.6- CO H H 39 CH.sub.3(CH.sub.2).sub.8CO
H H 40 CH.sub.3(CH.sub.2).sub.10CO H H 41
CH.sub.3(CH.sub.2).sub.12CO H H 42 CH.sub.3(CH.sub.2).sub.14CO H H
43 CH.sub.3(CH.sub.2).sub.16CO H H 44 CH.sub.3(CH.sub.2).sub.18CO H
H 45 CH.sub.3(CH.sub.2).sub.20CO H H 46 CH.sub.3(CH.sub.2).sub.4CO
H CH.sub.3 47 CH.sub.3(CH.sub.2).sub.4C- O H
(CH.sub.2).sub.5CH.sub.3 48 CH.sub.3(CH.sub.2).sub.4CO H
(CH.sub.2).sub.10CH.sub.3 49 CH.sub.3(CH.sub.2).sub.4CO H
(CH.sub.2).sub.13CH.sub.3 50 CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3
51 CH.sub.3(CH.sub.2).sub.12CO H (CH.sub.2).sub.5CH.sub.3 52
CH.sub.3(CH.sub.2).sub.12CO H (CH.sub.2).sub.10CH.sub.3 53
CH.sub.3(CH.sub.2).sub.12CO H (CH.sub.2).sub.13CH.sub.3 54
CH.sub.3CO CH.sub.3CO H 55 CH.sub.3CH.sub.2CO CH.sub.3CH.sub.2CO H
56 CH.sub.3(CH.sub.2).sub.2CO CH.sub.3(CH.sub.2).sub.2CO H 57
CH.sub.3(CH.sub.2).sub.3CO CH.sub.3(CH.sub.2).sub.3CO H 58
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO H 59
CH.sub.3(CH.sub.2).sub.5CO CH.sub.3(CH.sub.2).sub.5CO H 60
CH.sub.3(CH.sub.2).sub.6CO CH.sub.3(CH.sub.2).sub.6CO H 61
CH.sub.3(CH.sub.2).sub.8CO CH.sub.3(CH.sub.2).sub.8CO H 62
CH.sub.3(CH.sub.2).sub.10CO CH.sub.3(CH.sub.2).sub.10CO H 63
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO H 64
CH.sub.3(CH.sub.2).sub.14CO CH.sub.3(CH.sub.2).sub.14CO H 65
CH.sub.3(CH.sub.2).sub.16CO CH.sub.3(CH.sub.2).sub.16CO H 66
CH.sub.3(CH.sub.2).sub.18CO CH.sub.3(CH.sub.2).sub.18CO H 67
CH.sub.3(CH.sub.2).sub.20CO CH.sub.3(CH.sub.2).sub.20CO H 68
CH.sub.3(CH.sub.2).sub.22CO CH.sub.3(CH.sub.2).sub.22CO H 69
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.6CO H 70
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO H 71
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO CH.sub.3 72
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
(CH.sub.2).sub.5CH.sub.3 73 CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.4CO (CH.sub.2).sub.10CH.sub.3 74
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
(CH.sub.2).sub.13CH.sub.3 75 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3 76 CH.sub.3(CH.sub.2).sub.12C-
O CH.sub.3(CH.sub.2).sub.12CO (CH.sub.2).sub.5CH.sub.3 77
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
(CH.sub.2).sub.10CH.sub.3 78 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO (CH.sub.2).sub.13CH.sub.3 79
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3 80
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO
(CH.sub.2).sub.5CH.sub.3 81 CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO (CH.sub.2).sub.10CH.sub.3 82
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO
(CH.sub.2).sub.13CH.sub.3 83 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3 84 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.4CO (CH.sub.2).sub.5CH.sub.3 85
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
(CH.sub.2).sub.10CH.sub.3 86 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.4CO (CH.sub.2).sub.13CH.sub.3 87
CH.sub.3(CH.sub.2).sub.6CO H CH.sub.3 88 CH.sub.3(CH.sub.2).sub.8C-
O H CH.sub.3 89 CH.sub.3(CH.sub.2).sub.10CO H CH.sub.3 90
CH.sub.3(CH.sub.2).sub.14CO H CH.sub.3 91 CH.sub.3(CH.sub.2).sub.1-
6CO H CH.sub.3 92 CH.sub.3(CH.sub.2).sub.6CO H CH.sub.2CH.sub.3 93
CH.sub.3(CH.sub.2).sub.8CO H CH.sub.2CH.sub.3 94
CH.sub.3(CH.sub.2).sub.10CO H CH.sub.2CH.sub.3 95
CH.sub.3(CH.sub.2).sub.12CO H CH.sub.2CH.sub.3 96
CH.sub.3(CH.sub.2).sub.14CO H CH.sub.2CH.sub.3 97
CH.sub.3(CH.sub.2).sub.16CO H CH.sub.2CH.sub.3
[0114] Thus, the following compounds are disclosed: Compounds No.,
1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-9, 1-10, 1-11, 1-12,
1-13, 1-14, 1-15, 1-16, 1-17, 1-18, 1-19, 1-20, 1-21, 1-22, 1-23,
1-24, 1-25, 1-26, 1-27, 1-28, 1-29, 1-30, 1-31, 1-32, 1-33, 1-34,
1-35, 1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 1-45,
1-46, 1-47, 1-48, 1-49, 1-50, 1-51, 1-52, 1-53, 1-54, 1-55, 1-56,
1-57, 1-58, 1-59, 1-60, 1-61, 1-62, 1-63, 1-64, 1-65, 1-66, 1-67,
1-68, 1-69, 1-70, 1-71, 1-72, 1-73, 1-74, 1-75, 1-76, 1-77, 1-78,
1-79, 1-80, 1-81, 1-82, 1-83, 1-84, 1-85, 1-86, 1-87, 1-88, 1-89,
1-90, 1-91, 1-92, 1-93, 1-94, 1-95, 1-96, 1-97,
[0115] 2-1, 2-2, 2-3, 2-4, 2-5, 2-6, 2-7, 2-8, 2-9, 2-10, 2-11,
2-12, 2-13, 2-14, 2-15, 2-16, 2-17, 2-18, 2-19, 2-20, 2-21, 2-22,
2-23, 2-24, 2-25, 2-26, 2-27, 2-28, 2-29, 2-30, 2-31, 2-32, 2-33,
2-34, 2-35, 2-36, 2-37, 2-38, 2-39, 2-40, 2-41, 2-42, 2-43, 2-44,
2-45, 2-46, 2-47, 2-48, 2-49, 2-50, 2-51, 2-52, 2-53, 2-54, 2-55,
2-56, 2-57, 2-58, 2-59, 2-60, 2-61, 2-62, 2-63, 2-64, 2-65, 2-66,
2-67, 2-68, 2-69, 2-70, 2-71, 2-72, 2-73, 2-74, 2-75, 2-76, 2-77,
2-78, 2-79, 2-80, 2-81, 2-82, 2-83, 2-84, 2-85, 2-86, 2-87, 2-88,
2-89, 2-90, 2-91, 2-92, 2-93, 2-94, 2-95, 2-96, 2-97,
[0116] 3-1, 3-2, 3-3, 3-4, 3-5, 3-6, 3-7, 3-8, 3-9, 3-10, 3-11,
3-12, 3-13, 3-14, 3-15, 3-16, 3-17, 3-18, 3-19, 3-20, 3-21, 3-22,
3-23, 3-24, 3-25, 3-26, 3-27, 3-28, 3-29, 3-30, 3-31, 3-32, 3-33,
3-34, 3-35, 3-36, 3-37, 3-38, 3-39, 3-40, 3-41, 3-42, 3-43, 3-44,
3-45, 3-46, 3-47, 3-48, 3-49, 3-50, 3-51, 3-52, 3-53, 3-54, 3-55,
3-56, 3-57, 3-58, 3-59, 3-60, 3-61, 3-62, 3-63, 3-64, 3-65, 3-66,
3-67, 3-68, 3-69, 3-70, 3-71, 3-72, 3-73, 3-74, 3-75, 3-76, 3-77,
3-78, 3-79, 3-80, 3-81, 3-82, 3-83, 3-84, 3-85, 3-86, 3-87, 3-88,
3-89, 3-90, 3-91, 3-92, 3-93, 3-94, 3-95, 3-96, 3-97,
[0117] 4-1, 4-2, 4-3, 4-4, 4-5, 4-6, 4-7, 4-8, 4-9, 4-10, 4-11,
4-12, 4-13, 4-14, 4-15, 4-16, 4-17, 4-18, 4-19, 4-20, 4-21, 4-22,
4-23, 4-24, 4-25, 4-26, 4-27, 4-28, 4-29, 4-30, 4-31, 4-32, 4-33,
4-34, 4-35, 4-36, 4-37, 4-38, 4-39, 4-40, 4-41, 4-42, 4-43, 4-44,
4-45, 4-46, 4-47, 4-48, 4-49, 4-50, 4-51, 4-52, 4-53, 4-54, 4-55,
4-56, 4-57, 4-58, 4-59, 4-60, 4-61, 4-62, 4-63, 4-64, 4-65, 4-66,
4-67, 4-68, 4-69, 4-70, 4-71, 4-72, 4-73, 4-74, 4-75, 4-76, 4-77,
4-78, 4-79, 4-80, 4-81, 4-82, 4-83, 4-84, 4-85, 4-86, 4-87, 4-88,
4-89, 4-90, 4-91, 4-92, 4-93, 4-94, 4-95, 4-96, 4-97,
[0118] 5-1, 5-2, 5-3, 5-4, 5-5, 5-6, 5-7, 5-8, 5-9, 5-10, 5-11,
5-12, 5-13, 5-14, 5-15, 5-16, 5-17, 5-18, 5-19, 5-20, 5-21, 5-22,
5-23, 5-24, 5-25, 5-26, 5-27, 5-28, 5-29, 5-30, 5-31, 5-32, 5-33,
5-34, 5-35, 5-36, 5-37, 5-38, 5-39, 5-40, 5-41, 5-42, 5-43, 5-44,
5-45, 5-46, 5-47, 5-48, 5-49, 5-50, 5-51, 5-52, 5-53, 5-54, 5-55,
5-56, 5-57, 5-58, 5-59, 5-60, 5-61, 5-62, 5-63, 5-64, 5-65, 5-66,
5-67, 5-68, 5-69, 5-70, 5-71, 5-72, 5-73, 5-74, 5-75, 5-76, 5-77,
5-78, 5-79, 5-80, 5-81, 5-82, 5-83, 5-84, 5-85, 5-86, 5-87, 5-88,
5-89, 5-90, 5-91, 5-92, 5-93, 5-94, 5-95, 5-96, 5-97,
[0119] 6-1, 6-2, 6-3, 6-4, 6-5, 6-6, 6-7, 6-8, 6-9, 6-10, 6-11,
6-12, 6-13, 6-14, 6-15, 6-16, 6-17, 6-18, 6-19, 6-20, 6-21, 6-22,
6-23, 6-24, 6-25, 6-26, 6-27, 6-28, 6-29, 6-30, 6-31, 6-32, 6-33,
6-34, 6-35, 6-36, 6-37, 6-38, 6-39, 6-40, 6-41, 6-42, 6-43, 6-44,
6-45, 6-46, 6-47, 6-48, 6-49, 6-50, 6-51, 6-52, 6-53, 6-54, 6-55,
6-56, 6-57, 6-58, 6-59, 6-60, 6-61, 6-62, 6-63, 6-64, 6-65, 6-66,
6-67, 6-68, 6-69, 6-70, 6-71, 6-72, 6-73, 6-74, 6-75, 6-76, 6-77,
6-78, 6-79, 6-80, 6-81, 6-82, 6-83, 6-84, 6-85, 6-86, 6-87, 6-88,
6-89, 6-90, 6-91, 6-92, 6-93, 6-94, 6-95, 6-96, 6-97,
[0120] 7-1, 7-2, 7-3, 7-4, 7-5, 7-6, 7-7, 7-8, 7-9, 7-10, 7-11,
7-12, 7-13, 7-14, 7-15, 7-16, 7-17, 7-18, 7-19, 7-20, 7-21, 7-22,
7-23, 7-24, 7-25, 7-26, 7-27, 7-28, 7-29, 7-30, 7-31, 7-32, 7-33,
7-34, 7-35, 7-36, 7-37, 7-38, 7-39, 7-40, 7-41, 7-42, 7-43, 7-44,
7-45, 7-46, 7-47, 7-48, 7-49, 7-50, 7-51, 7-52, 7-53, 7-54, 7-55,
7-56, 7-57, 7-58, 7-59, 7-60, 7-61, 7-62, 7-63, 7-64, 7-65, 7-66,
7-67, 7-68, 7-69, 7-70, 7-71, 7-72, 7-73, 7-74, 7-75, 7-76, 7-77,
7-78, 7-79, 7-80, 7-81, 7-82, 7-83, 7-84, 7-85, 7-86, 7-87, 7-88,
7-89, 7-90, 7-91, 7-92, 7-93, 7-94, 7-95, 7-96, 7-97,
[0121] 8-1, 8-2, 8-3, 8-4, 8-5, 8-6, 8-7, 8-8, 8-9, 8-10, 8-11,
8-12, 8-13, 8-14, 8-15, 8-16, 8-17, 8-18, 8-19, 8-20, 8-21, 8-22,
8-23, 8-24, 8-25, 8-26, 8-27, 8-28, 8-29, 8-30, 8-31, 8-32, 8-33,
8-34, 8-35, 8-36, 8-37, 8-38, 8-39, 8-40, 8-41, 8-42, 8-43, 8-44,
8-45, 8-46, 8-47, 8-48, 8-49, 8-50, 8-51, 8-52, 8-53, 8-54, 8-55,
8-56, 8-57, 8-58, 8-59, 8-60, 8-61, 8-62, 8-63, 8-64, 8-65, 8-66,
8-67, 8-68, 8-69, 8-70, 8-71, 8-72, 8-73, 8-74, 8-75, 8-76, 8-77,
8-78, 8-79, 8-80, 8-81, 8-82, 8-83, 8-84, 8-85, 8-86, 8-87, 8-88,
8-89, 8-90, 8-91, 8-92, 8-93, 8-94, 8-95, 8-96, 8-97,
[0122] 9-1, 9-2, 9-3, 9-4, 9-5, 9-6, 9-7, 9-8, 9-9, 9-10, 9-11,
9-12, 9-13, 9-14, 9-15, 9-16, 9-17, 9-18, 9-19, 9-20, 9-21, 9-22,
9-23, 9-24, 9-25, 9-26, 9-27, 9-28, 9-29, 9-30, 9-31, 9-32, 9-33,
9-34, 9-35, 9-36, 9-37, 9-38, 9-39, 9-40, 9-41, 9-42, 9-43, 9-44,
9-45, 9-46, 9-47, 9-48, 9-49, 9-50, 9-51, 9-52, 9-53, 9-54, 9-55,
9-56, 9-57, 9-58, 9-59, 9-60, 9-61, 9-62, 9-63, 9-64, 9-65, 9-66,
9-67, 9-68, 9-69, 9-70, 9-71, 9-72, 9-73, 9-74, 9-75, 9-76, 9-77,
9-78, 9-79, 9-80, 9-81, 9-82, 9-83, 9-84, 9-85, 9-86, 9-87, 9-88,
9-89, 9-90, 9-91, 9-92, 9-93, 9-94, 9-95, 9-96, 9-97,
[0123] 10-1, 10-2, 10-3, 10-4, 10-5, 10-6, 10-7, 10-8, 10-9, 10-10,
10-11, 10-12, 10-13, 10-14, 10-15, 10-16, 10-17, 10-18, 10-19,
10-20, 10-21, 10-22, 10-23, 10-24, 10-25, 10-26, 10-27, 10-28,
10-29, 10-30, 10-31, 10-32, 10-33, 10-34, 10-35, 10-36, 10-37,
10-38, 10-39, 10-40, 10-41, 10-42, 10-43, 10-44, 10-45, 10-46,
10-47, 10-48, 10-49, 10-50, 10-51, 10-52, 10-53, 10-54, 10-55,
10-56, 10-57, 10-58, 10-59, 10-60, 10-61, 10-62, 10-63, 10-64,
10-65, 10-66, 10-67, 10-68, 10-69, 10-70, 10-71, 10-72, 10-73,
10-74, 10-75, 10-76, 10-77, 10-78, 10-79, 10-80, 10-81, 10-82,
10-83, 10-84, 10-85, 10-86, 10-87, 10-88, 10-89, 10-90, 10-91,
10-92, 10-93, 10-94, 10-95, 10-96, 10-97,
[0124] 11-1, 11-2, 11-3, 11-4, 11-5, 11-6, 11-7, 11-8, 11-9, 11-10,
11-11, 11-12, 11-13, 11-14, 11-15, 11-16, 11-17, 11-18, 11-19,
11-20, 11-21, 11-22, 11-23, 11-24, 11-25, 11-26, 11-27, 11-28,
11-29, 11-30, 11-31, 11-32, 11-33, 11-34, 11-35, 11-36, 11-37,
11-38, 11-39, 11-40, 11-41, 11-42, 11-43, 11-44, 11-45, 11-46,
11-47, 11-48, 11-49, 11-50, 11-51, 11-52, 11-53, 11-54, 11-55,
11-56, 11-57, 11-58, 11-59, 11-60, 11-61, 11-62, 11-63, 11-64,
11-65, 11-66, 11-67, 11-68, 11-69, 11-70, 11-71, 11-72, 11-73,
11-74, 11-75, 11-76, 11-77, 11-78, 11-79, 11-80, 11-81, 11-82,
11-83, 11-84, 11-85, 11-86, 11-87, 11-88, 11-89, 11-90, 11-91,
11-92, 11-93, 11-94, 11-95, 11-96, 11-97,
[0125] 12-1, 12-2, 12-3, 12-4, 12-5, 12-6, 12-7, 12-8, 12-9, 12-10,
12-11, 12-12, 12-13, 12-14, 12-15, 12-16, 12-17, 12-18, 12-19,
12-20, 12-21, 12-22, 12-23, 12-24, 12-25, 12-26, 12-27, 12-28,
12-29, 12-30, 12-31, 12-32, 12-33, 12-34, 12-35, 12-36, 12-37,
12-38, 12-39, 12-40, 12-41, 12-42, 12-43, 12-44, 12-45, 12-46,
12-47, 12-48, 12-49, 12-50, 12-51, 12-52, 12-53, 12-54, 12-55,
12-56, 12-57, 12-58, 12-59, 12-60, 12-61, 12-62, 12-63, 12-64,
12-65, 12-66, 12-67, 12-68, 12-69, 12-70, 12-71, 12-72, 12-73,
12-74, 12-75, 12-76, 12-77, 12-78, 12-79, 12-80, 12-81, 12-82,
12-83, 12-84, 12-85, 12-86, 12-87, 12-88, 12-89, 12-90, 12-91,
12-92, 12-93, 12-94, 12-95, 12-96, 12-97,
[0126] 13-1, 13-2, 13-3, 13-4, 13-5, 13-6, 13-7, 13-8, 13-9, 13-10,
13-11, 13-12, 13-13, 13-14, 13-15, 13-16, 13-17, 13-18, 13-19,
13-20, 13-21, 13-22, 13-23, 13-24, 13-25, 13-26, 13-27, 13-28,
13-29, 13-30, 13-31, 13-32, 13-33, 13-34, 13-35, 13-36, 13-37,
13-38, 13-39, 13-40, 13-41, 13-42, 13-43, 13-44, 13-45, 13-46,
13-47, 13-48, 13-49, 13-50, 13-51, 13-52, 13-53, 13-54, 13-55,
13-56, 13-57, 13-58, 13-59, 13-60, 13-61, 13-62, 13-63, 13-64,
13-65, 13-66, 13-67, 13-68, 13-69, 13-70, 13-71, 13-72, 13-73,
13-74, 13-75, 13-76, 13-77, 13-78, 13-79, 13-80, 13-81, 13-82,
13-83, 13-84, 13-85, 13-86, 13-87, 13-88, 13-89, 13-90, 13-91,
13-92, 13-93, 13-94, 13-95, 13-96, 13-97,
[0127] 14-1, 14-2, 14-3, 14-4, 14-5, 14-6, 14-7, 14-8, 14-9, 14-10,
14-11, 14-12, 14-13, 14-14, 14-15, 14-16, 14-17, 14-18, 14-19,
14-20, 14-21, 14-22, 14-23, 14-24, 14-25, 14-26, 14-27, 14-28,
14-29, 14-30, 14-31, 14-32, 14-33, 14-34, 14-35, 14-36, 14-37,
14-38, 14-39, 14-40, 14-41, 14-42, 14-43, 14-44, 14-45, 14-46,
14-47, 14-48, 14-49, 14-50, 14-51, 14-52, 14-53, 14-54, 14-55,
14-56, 14-57, 14-58, 14-59, 14-60, 14-61, 14-62, 14-63, 14-64,
14-65, 14-66, 14-67, 14-68, 14-69, 14-70, 14-71, 14-72, 14-73,
14-74, 14-75, 14-76, 14-77, 14-78, 14-79, 14-80, 14-81, 14-82,
14-83, 14-84, 14-85, 14-86, 14-87, 14-88, 14-89, 14-90, 14-91,
14-92, 14-93, 14-94, 14-95, 14-96, 14-97,
[0128] 15-1, 15-2, 15-3, 15-4, 15-5, 15-6, 15-7, 15-8, 15-9, 15-10,
15-11, 15-12, 15-13, 15-14, 15-15, 15-16, 15-17, 15-18, 15-19,
15-20, 15-21, 15-22, 15-23, 15-24, 15-25, 15-26, 15-27, 15-28,
15-29, 15-30, 15-31, 15-32, 15-33, 15-34, 15-35, 15-36, 15-37,
15-38, 15-39, 15-40, 15-41, 15-42, 15-43, 15-44, 15-45, 15-46,
15-47, 15-48, 15-49, 15-50, 15-51, 15-52, 15-53, 15-54, 15-55,
15-56, 15-57, 15-58, 15-59, 15-60, 15-61, 15-62, 15-63, 15-64,
15-65, 15-66, 15-67, 15-68, 15-69, 15-70, 15-71, 15-72, 15-73,
15-74, 15-75, 15-76, 15-77, 15-78, 15-79, 15-80, 15-81, 15-82,
15-83, 15-84, 15-85, 15-86, 15-87, 15-88, 15-89, 15-90, 15-91,
15-92, 15-93, 15-94, 15-95, 15-96, 15-97,
[0129] 16-1, 16-2, 16-3, 16-4, 16-5, 16-6, 16-7, 16-8, 16-9, 16-10,
16-11, 16-12, 16-13, 16-14, 16-15, 16-16, 16-17, 16-18, 16-19,
16-20, 16-21, 16-22, 16-23, 16-24, 16-25, 16-26, 16-27, 16-28,
16-29, 16-30, 16-31, 16-32, 16-33, 16-34, 16-35, 16-36, 16-37,
16-38, 16-39, 16-40, 16-41, 16-42, 16-43, 16-44, 16-45, 16-46,
16-47, 16-48, 16-49, 16-50, 16-51, 16-52, 16-53, 16-54, 16-55,
16-56, 16-57, 16-58, 16-59, 16-60, 16-61, 16-62, 16-63, 16-64,
16-65, 16-66, 16-67, 16-68, 16-69, 16-70, 16-71, 16-72, 16-73,
16-74, 16-75, 16-76, 16-77, 16-78, 16-79, 16-80, 16-81, 16-82,
16-83, 16-84, 16-85, 16-86, 16-87, 16-88, 16-89, 16-90, 16-91,
16-92, 16-93, 16-94, 16-95, 16-96, 16-97,
[0130] 17-1, 17-2, 17-3, 17-4, 17-5, 17-6, 17-7, 17-8, 17-9, 17-10,
17-11, 17-12, 17-13, 17-14, 17-15, 17-16, 17-17, 17-18, 17-19,
17-20, 17-21, 17-22, 17-23, 17-24, 17-25, 17-26, 17-27, 17-28,
17-29, 17-30, 17-31, 17-32, 17-33, 17-34, 17-35, 17-36, 17-37,
17-38, 17-39, 17-40, 17-41, 17-42, 17-43, 17-44, 17-45, 17-46,
17-47, 17-48, 17-49, 17-50, 17-51, 17-52, 17-53, 17-54, 17-55,
17-56, 17-57, 17-58, 17-59, 17-60, 17-61, 17-62, 17-63, 17-64,
17-65, 17-66, 17-67, 17-68, 17-69, 17-70, 17-71, 17-72, 17-73,
17-74, 17-75, 17-76, 17-77, 17-78, 17-79, 17-80, 17-81, 17-82,
17-83, 17-84, 17-85, 17-86, 17-87, 17-88, 17-89, 17-90, 17-91,
17-92, 17-93, 17-94, 17-95, 17-96, 17-97,
[0131] 18-1, 18-2, 18-3, 18-4, 18-5, 18-6, 18-7, 18-8, 18-9, 18-10,
18-11, 18-12, 18-13, 18-14, 18-15, 18-16, 18-17, 18-18, 18-19,
18-20, 18-21, 18-22, 18-23, 18-24, 18-25, 18-26, 18-27, 18-28,
18-29, 18-30, 18-31, 18-32, 18-33, 18-34, 18-35, 18-36, 18-37,
18-38, 18-39, 18-40, 18-41, 18-42, 18-43, 18-44, 18-45, 18-46,
18-47, 18-48, 18-49, 18-50, 18-51, 18-52, 18-53, 18-54, 18-55,
18-56, 18-57, 18-58, 18-59, 18-60, 18-61, 18-62, 18-63, 18-64,
18-65, 18-66, 18-67, 18-68, 18-69, 18-70, 18-71, 18-72, 18-73,
18-74, 18-75, 18-76, 18-77, 18-78, 18-79, 18-80, 18-81, 18-82,
18-83, 18-84, 18-85, 18-86, 18-87, 18-88, 18-89, 18-90, 18-91,
18-92, 18-93, 18-94, 18-95, 18-96, 18-97,
[0132] 19-1, 19-2, 19-3, 19-4, 19-5, 19-6, 19-7, 19-8, 19-9, 19-10,
19-11, 19-12, 19-13, 19-14, 19-15, 19-16, 19-17, 19-18, 19-19,
19-20, 19-21, 19-22, 19-23, 19-24, 19-25, 19-26, 19-27, 19-28,
19-29, 19-30, 19-31, 19-32, 19-33, 19-34, 19-35, 19-36, 19-37,
19-38, 19-39, 19-40, 19-41, 19-42, 19-43, 19-44, 19-45, 19-46,
19-47, 19-48, 19-49, 19-50, 19-51, 19-52, 19-53, 19-54, 19-55,
19-56, 19-57, 19-58, 19-59, 19-60, 19-61, 19-62, 19-63, 19-64,
19-65, 19-66, 19-67, 19-68, 19-69, 19-70, 19-71, 19-72, 19-73,
19-74, 19-75, 19-76, 19-77, 19-78, 19-79, 19-80, 19-81, 19-82,
19-83, 19-84, 19-85, 19-86, 19-87, 19-88, 19-89, 19-90, 19-91,
19-92, 19-93, 19-94, 19-95, 19-96, 19-97,
[0133] 20-1, 20-2, 20-3, 20-4, 20-5, 20-6, 20-7, 20-8, 20-9, 20-10,
20-11, 20-12, 20-13, 20-14, 20-15, 20-16, 20-17, 20-18, 20-19,
20-20, 20-21, 20-22, 20-23, 20-24, 20-25, 20-26, 20-27, 20-28,
20-29, 20-30, 20-31, 20-32, 20-33, 20-34, 20-35, 20-36, 20-37,
20-38, 20-39, 20-40, 20-41, 20-42, 20-43, 20-44, 20-45, 20-46,
20-47, 20-48, 20-49, 20-50, 20-51, 20-52, 20-53, 20-54, 20-55,
20-56, 20-57, 20-58, 20-59, 20-60, 20-61, 20-62, 20-63, 20-64,
20-65, 20-66, 20-67, 20-68, 20-69, 20-70, 20-71, 20-72, 20-73,
20-74, 20-75, 20-76, 20-77, 20-78, 20-79, 20-80, 20-81, 20-82,
20-83, 20-84, 20-85, 20-86, 20-87, 20-88, 20-89, 20-90, 20-91,
20-92, 20-93, 20-94, 20-95, 20-96, 20-97,
[0134] 21-1, 21-2, 21-3, 21-4, 21-5, 21-6, 21-7, 21-8, 21-9, 21-10,
21-11, 21-12, 21-13, 21-14, 21-15, 21-16, 21-17, 21-18, 21-19,
21-20, 21-21, 21-22, 21-23, 21-24, 21-25, 21-26, 21-27, 21-28,
21-29, 21-30, 21-31, 21-32, 21-33, 21-34, 21-35, 21-36, 21-37,
21-38, 21-39, 21-40, 21-41, 21-42, 21-43, 21-44, 21-45, 21-46,
21-47, 21-48, 21-49, 21-50, 21-51, 21-52, 21-53, 21-54, 21-55,
21-56, 21-57, 21-58, 21-59, 21-60, 21-61, 21-62, 21-63, 21-64,
21-65, 21-66, 21-67, 21-68, 21-69, 21-70, 21-71, 21-72, 21-73,
21-74, 21-75, 21-76, 21-77, 21-78, 21-79, 21-80, 21-81, 21-82,
21-83, 21-84, 21-85, 21-86, 21-87, 21-88, 21-89, 21-90, 21-91,
21-92, 21-93, 21-94, 21-95, 21-96, 21-97,
[0135] 22-1, 22-2, 22-3, 22-4, 22-5, 22-6, 22-7, 22-8, 22-9, 22-10,
22-11, 22-12, 22-13, 22-14, 22-15, 22-16, 22-17, 22-18, 22-19,
22-20, 22-21, 22-22, 22-23, 22-24, 22-25, 22-26, 22-27, 22-28,
22-29, 22-30, 22-31, 22-32, 22-33, 22-34, 22-35, 22-36, 22-37,
22-38, 22-39, 22-40, 22-41, 22-42, 22-43, 22-44, 22-45, 22-46,
22-47, 22-48, 22-49, 22-50, 22-51, 22-52, 22-53, 22-54, 22-55,
22-56, 22-57, 22-58, 22-59, 22-60, 22-61, 22-62, 22-63, 22-64,
22-65, 22-66, 22-67, 22-68, 22-69, 22-70, 22-71, 22-72, 22-73,
22-74, 22-75, 22-76, 22-77, 22-78, 22-79, 22-80, 22-81, 22-82,
22-83, 22-84, 22-85, 22-86, 22-87, 22-88, 22-89, 22-90, 22-91,
22-92, 22-93, 22-94, 22-95, 22-96, 22-97,
[0136] 23-1, 23-2, 23-3, 23-4, 23-5, 23-6, 23-7, 23-8, 23-9, 23-10,
23-11, 23-12, 23-13, 23-14, 23-15, 23-16, 23-17, 23-18, 23-19,
23-20, 23-21, 23-22, 23-23, 23-24, 23-25, 23-26, 23-27, 23-28,
23-29, 23-30, 23-31, 23-32, 23-33, 23-34, 23-35, 23-36, 23-37,
23-38, 23-39, 23-40, 23-41, 23-42, 23-43, 23-44, 23-45, 23-46,
23-47, 23-48, 23-49, 23-50, 23-51, 23-52, 23-53, 23-54, 23-55,
23-56, 23-57, 23-58, 23-59, 23-60, 23-61, 23-62, 23-63, 23-64,
23-65, 23-66, 23-67, 23-68, 23-69, 23-70, 23-71, 23-72, 23-73,
23-74, 23-75, 23-76, 23-77, 23-78, 23-79, 23-80, 23-81, 23-82,
23-83, 23-84, 23-85, 23-86, 23-87, 23-88, 23-89, 23-90, 23-91,
23-92, 23-93, 23-94, 23-95, 23-96, 23-97,
[0137] 24-1, 24-2, 24-3, 24-4, 24-5, 24-6, 24-7, 24-8, 24-9, 24-10,
24-11, 24-12, 24-13, 24-14, 24-15, 24-16, 24-17, 24-18, 24-19,
24-20, 24-21, 24-22, 24-23, 24-24, 24-25, 24-26, 24-27, 24-28,
24-29, 24-30, 24-31, 24-32, 24-33, 24-34, 24-35, 24-36, 24-37,
24-38, 24-39, 24-40, 24-41, 24-42, 24-43, 24-44, 24-45, 24-46,
24-47, 24-48, 24-49, 24-50, 24-51, 24-52, 24-53, 24-54, 24-55,
24-56, 24-57, 24-58, 24-59, 24-60, 24-61, 24-62, 24-63, 24-64,
24-65, 24-66, 24-67, 24-68, 24-69, 24-70, 24-71, 24-72, 24-73,
24-74, 24-75, 24-76, 24-77, 24-78, 24-79, 24-80, 24-81, 24-82,
24-83, 24-84, 24-85, 24-86, 24-87, 24-88, 24-89, 24-90, 24-91,
24-92, 24-93, 24-94, 24-95, 24-96, 24-97,
[0138] 25-1, 25-2, 25-3, 25-4, 25-5, 25-6, 25-7, 25-8, 25-9, 25-10,
25-11, 25-12, 25-13, 25-14, 25-15, 25-16, 25-17, 25-18, 25-19,
25-20, 25-21, 25-22, 25-23, 25-24, 25-25, 25-26, 25-27, 25-28,
25-29, 25-30, 25-31, 25-32, 25-33, 25-34, 25-35, 25-36, 25-37,
25-38, 25-39, 25-40, 25-41, 25-42, 25-43, 25-44, 25-45, 25-46,
25-47, 25-48, 25-49, 25-50, 25-51, 25-52, 25-53, 25-54, 25-55,
25-56, 25-57, 25-58, 25-59, 25-60, 25-61, 25-62, 25-63, 25-64,
25-65, 25-66, 25-67, 25-68, 25-69, 25-70, 25-71, 25-72, 25-73,
25-74, 25-75, 25-76, 25-77, 25-78, 25-79, 25-80, 25-81, 25-82,
25-83, 25-84, 25-85, 25-86, 25-87, 25-88, 25-89, 25-90, 25-91,
25-92, 25-93, 25-94, 25-95, 25-96, 25-97,
[0139] 26-1, 26-2, 26-3, 26-4, 26-5, 26-6, 26-7, 26-8, 26-9, 26-10,
26-11, 26-12, 26-13, 26-14, 26-15, 26-16, 26-17, 26-18, 26-19,
26-20, 26-21, 26-22, 26-23, 26-24, 26-25, 26-26, 26-27, 26-28,
26-29, 26-30, 26-31, 26-32, 26-33, 26-34, 26-35, 26-36, 26-37,
26-38, 26-39, 26-40, 26-41, 26-42, 26-43, 26-44, 26-45, 26-46,
26-47, 26-48, 26-49, 26-50, 26-51, 26-52, 26-53, 26-54, 26-55,
26-56, 26-57, 26-58, 26-59, 26-60, 26-61, 26-62, 26-63, 26-64,
26-65, 26-66, 26-67, 26-68, 26-69, 26-70, 26-71, 26-72, 26-73,
26-74, 26-75, 26-76, 26-77, 26-78, 26-79, 26-80, 26-81, 26-82,
26-83, 26-84, 26-85, 26-86, 26-87, 26-88, 26-89, 26-90, 26-91,
26-92, 26-93, 26-94, 26-95, 26-96, 26-97,
[0140] 27-1, 27-2, 27-3, 27-4, 27-5, 27-6, 27-7, 27-8, 27-9, 27-10,
27-11, 27-12, 27-13, 27-14, 27-15, 27-16, 27-17, 27-18, 27-19,
27-20, 27-21, 27-22, 27-23, 27-24, 27-25, 27-26, 27-27, 27-28,
27-29, 27-30, 27-31, 27-32, 27-33, 27-34, 27-35, 27-36, 27-37,
27-38, 27-39, 27-40, 27-41, 27-42, 27-43, 27-44, 27-45, 27-46,
27-47, 27-48, 27-49, 27-50, 27-51, 27-52, 27-53, 27-54, 27-55,
27-56, 27-57, 27-58, 27-59, 27-60, 27-61, 27-62, 27-63, 27-64,
27-65, 27-66, 27-67, 27-68, 27-69, 27-70, 27-71, 27-72, 27-73,
27-74, 27-75, 27-76, 27-77, 27-78, 27-79, 27-80, 27-81, 27-82,
27-83, 27-84, 27-85, 27-86, 27-87, 27-88, 27-89, 27-90, 27-91,
27-92, 27-93, 27-94, 27-95, 27-96, 27-97,
[0141] 28-1, 28-2, 28-3, 28-4, 28-5, 28-6, 28-7, 28-8, 28-9, 28-10,
28-11, 28-12, 28-13, 28-14, 28-15, 28-16, 28-17, 28-18, 28-19,
28-20, 28-21, 28-22, 28-23, 28-24, 28-25, 28-26, 28-27, 28-28,
28-29, 28-30, 28-31, 28-32, 28-33, 28-34, 28-35, 28-36, 28-37,
28-38, 28-39, 28-40, 28-41, 28-42, 28-43, 28-44, 28-45, 28-46,
28-47, 28-48, 28-49, 28-50, 28-51, 28-52, 28-53, 28-54, 28-55,
28-56, 28-57, 28-58, 28-59, 28-60, 28-61, 28-62, 28-63, 28-64,
28-65, 28-66, 28-67, 28-68, 28-69, 28-70, 28-71, 28-72, 28-73,
28-74, 28-75, 28-76, 28-77, 28-78, 28-79, 28-80, 28-81, 28-82,
28-83, 28-84, 28-85, 28-86, 28-87, 28-88, 28-89, 28-90, 28-91,
28-92, 28-93, 28-94, 28-95, 28-96, 28-97,
[0142] 29-1, 29-2, 29-3, 29-4, 29-5, 29-6, 29-7, 29-8, 29-9, 29-10,
29-11, 29-12, 29-13, 29-14, 29-15, 29-16, 29-17, 29-18, 29-19,
29-20, 29-21, 29-22, 29-23, 29-24, 29-25, 29-26, 29-27, 29-28,
29-29, 29-30, 29-31, 29-32, 29-33, 29-34, 29-35, 29-36, 29-37,
29-38, 29-39, 29-40, 29-41, 29-42, 29-43, 29-44, 29-45, 29-46,
29-47, 29-48, 29-49, 29-50, 29-51, 29-52, 29-53, 29-54, 29-55,
29-56, 29-57, 29-58, 29-59, 29-60, 29-61, 29-62, 29-63, 29-64,
29-65, 29-66, 29-67, 29-68, 29-69, 29-70, 29-71, 29-72, 29-73,
29-74, 29-75, 29-76, 29-77, 29-78, 29-79, 29-80, 29-81, 29-82,
29-83, 29-84, 29-85, 29-86, 29-87, 29-88, 29-89, 29-90, 29-91,
29-92, 29-93, 29-94, 29-95, 29-96, 29-97,
[0143] 30-1, 30-2, 30-3, 30-4, 30-5, 30-6, 30-7, 30-8, 30-9, 30-10,
30-11, 30-12, 30-13, 30-14, 30-15, 30-16, 30-17, 30-18, 30-19,
30-20, 30-21, 30-22, 30-23, 30-24, 30-25, 30-26, 30-27, 30-28,
30-29, 30-30, 30-31, 30-32, 30-33, 30-34, 30-35, 30-36, 30-37,
30-38, 30-39, 30-40, 30-41, 30-42, 30-43, 30-44, 30-45, 30-46,
30-47, 30-48, 30-49, 30-50, 30-51, 30-52, 30-53, 30-54, 30-55,
30-56, 30-57, 30-58, 30-59, 30-60, 30-61, 30-62, 30-63, 30-64,
30-65, 30-66, 30-67, 30-68, 30-69, 30-70, 30-71, 30-72, 30-73,
30-74, 30-75, 30-76, 30-77, 30-78, 30-79, 30-80, 30-81, 30-82,
30-83, 30-84, 30-85, 30-86, 30-87, 30-88, 30-89, 30-90, 30-91,
30-92, 30-93, 30-94, 30-95, 30-96, 30-97,
[0144] 31-1, 31-2, 31-3, 31-4, 31-5, 31-6, 31-7, 31-8, 31-9, 31-10,
31-11, 31-12, 31-13, 31-14, 31-15, 31-16, 31-17, 31-18, 31-19,
31-20, 31-21, 31-22, 31-23, 31-24, 31-25, 31-26, 31-27, 31-28,
31-29, 31-30, 31-31, 31-32, 31-33, 31-34, 31-35, 31-36, 31-37,
31-38, 31-39, 31-40, 31-41, 31-42, 31-43, 31-44, 31-45, 31-46,
31-47, 31-48, 31-49, 31-50, 31-51, 31-52, 31-53, 31-54, 31-55,
31-56, 31-57, 31-58, 31-59, 31-60, 31-61, 31-62, 31-63, 31-64,
31-65, 31-66, 31-67, 31-68, 31-69, 31-70, 31-71, 31-72, 31-73,
31-74, 31-75, 31-76, 31-77, 31-78, 31-79, 31-80, 31-81, 31-82,
31-83, 31-84, 31-85, 31-86, 31-87, 31-88, 31-89, 31-90, 31-91,
31-92, 31-93, 31-94, 31-95, 31-96, 31-97,
[0145] 32-1, 32-2, 32-3, 32-4, 32-5, 32-6, 32-7, 32-8, 32-9, 32-10,
32-11, 32-12, 32-13, 32-14, 32-15, 32-16, 32-17, 32-18, 32-19,
32-20, 32-21, 32-22, 32-23, 32-24, 32-25, 32-26, 32-27, 32-28,
32-29, 32-30, 32-31, 32-32, 32-33, 32-34, 32-35, 32-36, 32-37,
32-38, 32-39, 32-40, 32-41, 32-42, 32-43, 32-44, 32-45, 32-46,
32-47, 32-48, 32-49, 32-50, 32-51, 32-52, 32-53, 32-54, 32-55,
32-56, 32-57, 32-58, 32-59, 32-60, 32-61, 32-62, 32-63, 32-64,
32-65, 32-66, 32-67, 32-68, 32-69, 32-70, 32-71, 32-72, 32-73,
32-74, 32-75, 32-76, 32-77, 32-78, 32-79, 32-80, 32-81, 32-82,
32-83, 32-84, 32-85, 32-86, 32-87, 32-88, 32-89, 32-90, 32-91,
32-92, 32-93, 32-94, 32-95, 32-96, 32-97,
[0146] 33-1, 33-2, 33-3, 33-4, 33-5, 33-6, 33-7, 33-8, 33-9, 33-10,
33-11, 33-12, 33-13, 33-14, 33-15, 33-16, 33-17, 33-18, 33-19,
33-20, 33-21, 33-22, 33-23, 33-24, 33-25, 33-26, 33-27, 33-28,
33-29, 33-30, 33-31, 33-32, 33-33, 33-34, 33-35, 33-36, 33-37,
33-38, 33-39, 33-40, 33-41, 33-42, 33-43, 33-44, 33-45, 33-46,
33-47, 33-48, 33-49, 33-50, 33-51, 33-52, 33-53, 33-54, 33-55,
33-56, 33-57, 33-58, 33-59, 33-60, 33-61, 33-62, 33-63, 33-64,
33-65, 33-66, 33-67, 33-68, 33-69, 33-70, 33-71, 33-72, 33-73,
33-74, 33-75, 33-76, 33-77, 33-78, 33-79, 33-80, 33-81, 33-82,
33-83, 33-84, 33-85, 33-86, 33-87, 33-88, 33-89, 33-90, 33-91,
33-92, 33-93, 33-94, 33-95, 33-96, 33-97,
[0147] 34-1, 34-2, 34-3, 34-4, 34-5, 34-6, 34-7, 34-8, 34-9, 34-10,
34-11, 34-12, 34-13, 34-14, 34-15, 34-16, 34-17, 34-18, 34-19,
34-20, 34-21, 34-22, 34-23, 34-24, 34-25, 34-26, 34-27, 34-28,
34-29, 34-30, 34-31, 34-32, 34-33, 34-34, 34-35, 34-36, 34-37,
34-38, 34-39, 34-40, 34-41, 34-42, 34-43, 34-44, 34-45, 34-46,
34-47, 34-48, 34-49, 34-50, 34-51, 34-52, 34-53, 34-54, 34-55,
34-56, 34-57, 34-58, 34-59, 34-60, 34-61, 34-62, 34-63, 34-64,
34-65, 34-66, 34-67, 34-68, 34-69, 34-70, 34-71, 34-72, 34-73,
34-74, 34-75, 34-76, 34-77, 34-78, 34-79, 34-80, 34-81, 34-82,
34-83, 34-84, 34-85, 34-86, 34-87, 34-88, 34-89, 34-90, 34-91,
34-92, 34-93, 34-94, 34-95, 34-96, 34-97,
[0148] 35-1, 35-2, 35-3, 35-4, 35-5, 35-6, 35-7, 35-8, 35-9, 35-10,
35-11, 35-12, 35-13, 35-14, 35-15, 35-16, 35-17, 35-18, 35-19,
35-20, 35-21, 35-22, 35-23, 35-24, 35-25, 35-26, 35-27, 35-28,
35-29, 35-30, 35-31, 35-32, 35-33, 35-34, 35-35, 35-36, 35-37,
35-38, 35-39, 35-40, 35-41, 35-42, 35-43, 35-44, 35-45, 35-46,
35-47, 35-48, 35-49, 35-50, 35-51, 35-52, 35-53, 35-54, 35-55,
35-56, 35-57, 35-58, 35-59, 35-60, 35-61, 35-62, 35-63, 35-64,
35-65, 35-66, 35-67, 35-68, 35-69, 35-70, 35-71, 35-72, 35-73,
35-74, 35-75, 35-76, 35-77, 35-78, 35-79, 35-80, 35-81, 35-82,
35-83, 35-84, 35-85, 35-86, 35-87, 35-88, 35-89, 35-90, 35-91,
35-92, 35-93, 35-94, 35-95, 35-96, 35-97,
[0149] 36-1, 36-2, 36-3, 36-4, 36-5, 36-6, 36-7, 36-8, 36-9, 36-10,
36-11, 36-12, 36-13, 36-14, 36-15, 36-16, 36-17, 36-18, 36-19,
36-20, 36-21, 36-22, 36-23, 36-24, 36-25, 36-26, 36-27, 36-28,
36-29, 36-30, 36-31, 36-32, 36-33, 36-34, 36-35, 36-36, 36-37,
36-38, 36-39, 36-40, 36-41, 36-42, 36-43, 36-44, 36-45, 36-46,
36-47, 36-48, 36-49, 36-50, 36-51, 36-52, 36-53, 36-54, 36-55,
36-56, 36-57, 36-58, 36-59, 36-60, 36-61, 36-62, 36-63, 36-64,
36-65, 36-66, 36-67, 36-68, 36-69, 36-70, 36-71, 36-72, 36-73,
36-74, 36-75, 36-76, 36-77, 36-78, 36-79, 36-80, 36-81, 36-82,
36-83, 36-84, 36-85, 36-86, 36-87, 36-88, 36-89, 36-90, 36-91,
36-92, 36-93, 36-94, 36-95, 36-96, 36-97,
[0150] 37-1, 37-2, 37-3, 37-4, 37-5, 37-6, 37-7, 37-8, 37-9, 37-10,
37-11, 37-12, 37-13, 37-14, 37-15, 37-16, 37-17, 37-18, 37-19,
37-20, 37-21, 37-22, 37-23, 37-24, 37-25, 37-26, 37-27, 37-28,
37-29, 37-30, 37-31, 37-32, 37-33, 37-34, 37-35, 37-36, 37-37,
37-38, 37-39, 37-40, 37-41, 37-42, 37-43, 37-44, 37-45, 37-46,
37-47, 37-48, 37-49, 37-50, 37-51, 37-52, 37-53, 37-54, 37-55,
37-56, 37-57, 37-58, 37-59, 37-60, 37-61, 37-62, 37-63, 37-64,
37-65, 37-66, 37-67, 37-68, 37-69, 37-70, 37-71, 37-72, 37-73,
37-74, 37-75, 37-76, 37-77, 37-78, 37-79, 37-80, 37-81, 37-82,
37-83, 37-84, 37-85, 37-86, 37-87, 37-88, 37-89, 37-90, 37-91,
37-92, 37-93, 37-94, 37-95, 37-96, 37-97,
[0151] 38-1, 38-2, 38-3, 38-4, 38-5, 38-6, 38-7, 38-8, 38-9, 38-10,
38-11, 38-12, 38-13, 38-14, 38-15, 38-16, 38-17, 38-18, 38-19,
38-20, 38-21, 38-22, 38-23, 38-24, 38-25, 38-26, 38-27, 38-28,
38-29, 38-30, 38-31, 38-32, 38-33, 38-34, 38-35, 38-36, 38-37,
38-38, 38-39, 38-40, 38-41, 38-42, 38-43, 38-44, 38-45, 38-46,
38-47, 38-48, 38-49, 38-50, 38-51, 38-52, 38-53, 38-54, 38-55,
38-56, 38-57, 38-58, 38-59, 38-60, 38-61, 38-62, 38-63, 38-64,
38-65, 38-66, 38-67, 38-68, 38-69, 38-70, 38-71, 38-72, 38-73,
38-74, 38-75, 38-76, 38-77, 38-78, 38-79, 38-80, 38-81, 38-82,
38-83, 38-84, 38-85, 38-86, 38-87, 38-88, 38-89, 38-90, 38-91,
38-92, 38-93, 38-94, 38-95, 38-96, 38-97,
[0152] 39-1, 39-2, 39-3, 39-4, 39-5, 39-6, 39-7, 39-8, 39-9, 39-10,
39-11, 39-12, 39-13, 39-14, 39-15, 39-16, 39-17, 39-18, 39-19,
39-20, 39-21, 39-22, 39-23, 39-24, 39-25, 39-26, 39-27, 39-28,
39-29, 39-30, 39-31, 39-32, 39-33, 39-34, 39-35, 39-36, 39-37,
39-38, 39-39, 39-40, 39-41, 39-42, 39-43, 39-44, 39-45, 39-46,
39-47, 39-48, 39-49, 39-50, 39-51, 39-52, 39-53, 39-54, 39-55,
39-56, 39-57, 39-58, 39-59, 39-60, 39-61, 39-62, 39-63, 39-64,
39-65, 39-66, 39-67, 39-68, 39-69, 39-70, 39-71, 39-72, 39-73,
39-74, 39-75, 39-76, 39-77, 39-78, 39-79, 39-80, 39-81, 39-82,
39-83, 39-84, 39-85, 39-86, 39-87, 39-88, 39-89, 39-90, 39-91,
39-92, 39-93, 39-94, 39-95, 39-96, 39-97,
[0153] 40-1, 40-2, 40-3, 40-4, 40-5, 40-6, 40-7, 40-8, 40-9, 40-10,
40-11, 40-12, 40-13, 40-14, 40-15, 40-16, 40-17, 40-18, 40-19,
40-20, 40-21, 40-22, 40-23, 40-24, 40-25, 40-26, 40-27, 40-28,
40-29, 40-30, 40-31, 40-32, 40-33, 40-34, 40-35, 40-36, 40-37,
40-38, 40-39, 40-40, 40-41, 40-42, 40-43, 40-44, 40-45, 40-46,
40-47, 40-48, 40-49, 40-50, 40-51, 40-52, 40-53, 40-54, 40-55,
40-56, 40-57, 40-58, 40-59, 40-60, 40-61, 40-62, 40-63, 40-64,
40-65, 40-66, 40-67, 40-68, 40-69, 40-70, 40-71, 40-72, 40-73,
40-74, 40-75, 40-76, 40-77, 40-78, 40-79, 40-80, 40-81, 40-82,
40-83, 40-84, 40-85, 40-86, 40-87, 40-88, 40-89, 40-90, 40-91,
40-92, 40-93, 40-94, 40-95, 40-96, 40-97,
[0154] 41-1, 41-2, 41-3, 41-4, 41-5, 41-6, 41-7, 41-8, 41-9, 41-10,
41-11, 41-12, 41-13, 41-14, 41-15, 41-16, 41-17, 41-18, 41-19,
41-20, 41-21, 41-22, 41-23, 41-24, 41-25, 41-26, 41-27, 41-28,
41-29, 41-30, 41-31, 41-32, 41-33, 41-34, 41-35, 41-36, 41-37,
41-38, 41-39, 41-40, 41-41, 41-42, 41-43, 41-44, 41-45, 41-46,
41-47, 41-48, 41-49, 41-50, 41-51, 41-52, 41-53, 41-54, 41-55,
41-56, 41-57, 41-58, 41-59, 41-60, 41-61, 41-62, 41-63, 41-64,
41-65, 41-66, 41-67, 41-68, 41-69, 41-70, 41-71, 41-72, 41-73,
41-74, 41-75, 41-76, 41-77, 41-78, 41-79, 41-80, 41-81, 41-82,
41-83, 41-84, 41-85, 41-86, 41-87, 41-88, 41-89, 41-90, 41-91,
41-92, 41-93, 41-94, 41-95, 41-96, 41-97,
[0155] 42-1, 42-2, 42-3, 42-4, 42-5, 42-6, 42-7, 42-8, 42-9, 42-10,
42-11, 42-12, 42-13, 42-14, 42-15, 42-16, 42-17, 42-18, 42-19,
42-20, 42-21, 42-22, 42-23, 42-24, 42-25, 42-26, 42-27, 42-28,
42-29, 42-30, 42-31, 42-32, 42-33, 42-34, 42-35, 42-36, 42-37,
42-38, 42-39, 42-40, 42-41, 42-42, 42-43, 42-44, 42-45, 42-46,
42-47, 42-48, 42-49, 42-50, 42-51, 42-52, 42-53, 42-54, 42-55,
42-56, 42-57, 42-58, 42-59, 42-60, 42-61, 42-62, 42-63, 42-64,
42-65, 42-66, 42-67, 42-68, 42-69, 42-70, 42-71, 42-72, 42-73,
42-74, 42-75, 42-76, 42-77, 42-78, 42-79, 42-80, 42-81, 42-82,
42-83, 42-84, 42-85, 42-86, 42-87, 42-88, 42-89, 42-90, 42-91,
42-92, 42-93, 42-94, 42-95, 42-96, 42-97,
[0156] 43-1, 43-2, 43-3, 43-4, 43-5, 43-6, 43-7, 43-8, 43-9, 43-10,
43-11, 43-12, 43-13, 43-14, 43-15, 43-16, 43-17, 43-18, 43-19,
43-20, 43-21, 43-22, 43-23, 43-24, 43-25, 43-26, 43-27, 43-28,
43-29, 43-30, 43-31, 43-32, 43-33, 43-34, 43-35, 43-36, 43-37,
43-38, 43-39, 43-40, 43-41, 43-42, 43-43, 43-44, 43-45, 43-46,
43-47, 43-48, 43-49, 43-50, 43-51, 43-52, 43-53, 43-54, 43-55,
43-56, 43-57, 43-58, 43-59, 43-60, 43-61, 43-62, 43-63, 43-64,
43-65, 43-66, 43-67, 43-68, 43-69, 43-70, 43-71, 43-72, 43-73,
43-74, 43-75, 43-76, 43-77, 43-78, 43-79, 43-80, 43-81, 43-82,
43-83, 43-84, 43-85, 43-86, 43-87, 43-88, 43-89, 43-90, 43-91,
43-92, 43-93, 43-94, 43-95, 43-96, 43-97,
[0157] 44-1, 44-2, 44-3, 44-4, 44-5, 44-6, 44-7, 44-8, 44-9, 44-10,
44-11, 44-12, 44-13, 44-14, 44-15, 44-16, 44-17, 44-18, 44-19,
44-20, 44-21, 44-22, 44-23, 44-24, 44-25, 44-26, 44-27, 44-28,
44-29, 44-30, 44-31, 44-32, 44-33, 44-34, 44-35, 44-36, 44-37,
44-38, 44-39, 44-40, 44-41, 44-42, 44-43, 44-44, 44-45, 44-46,
44-47, 44-48, 44-49, 44-50, 44-51, 44-52, 44-53, 44-54, 44-55,
44-56, 44-57, 44-58, 44-59, 44-60, 44-61, 44-62, 44-63, 44-64,
44-65, 44-66, 44-67, 44-68, 44-69, 44-70, 44-71, 44-72, 44-73,
44-74, 44-75, 44-76, 44-77, 44-78, 44-79, 44-80, 44-81, 44-82,
44-83, 44-84, 44-85, 44-86, 44-87, 44-88, 44-89, 44-90, 44-91,
44-92, 44-93, 44-94, 44-95, 44-96, 44-97,
[0158] 45-1, 45-2, 45-3, 45-4, 45-5, 45-6, 45-7, 45-8, 45-9, 45-10,
45-11, 45-12, 45-13, 45-14, 45-15, 45-16, 45-17, 45-18, 45-19,
45-20, 45-21, 45-22, 45-23, 45-24, 45-25, 45-26, 45-27, 45-28,
45-29, 45-30, 45-31, 45-32, 45-33, 45-34, 45-35, 45-36, 45-37,
45-38, 45-39, 45-40, 45-41, 45-42, 45-43, 45-44, 45-45, 45-46,
45-47, 45-48, 45-49, 45-50, 45-51, 45-52, 45-53, 45-54, 45-55,
45-56, 45-57, 45-58, 45-59, 45-60, 45-61, 45-62, 45-63, 45-64,
45-65, 45-66, 45-67, 45-68, 45-69, 45-70, 45-71, 45-72, 45-73,
45-74, 45-75, 45-76, 45-77, 45-78, 45-79, 45-80, 45-81, 45-82,
45-83, 45-84, 45-85, 45-86, 45-87, 45-88, 45-89, 45-90, 45-91,
45-92, 45-93, 45-94, 45-95, 45-96, 45-97,
[0159] 46-1, 46-2, 46-3, 46-4, 46-5, 46-6, 46-7, 46-8, 46-9, 46-10,
46-11, 46-12, 46-13, 46-14, 46-15, 46-16, 46-17, 46-18, 46-19,
46-20, 46-21, 46-22, 46-23, 46-24, 46-25, 46-26, 46-27, 46-28,
46-29, 46-30, 46-31, 46-32, 46-33, 46-34, 46-35, 46-36, 46-37,
46-38, 46-39, 46-40, 46-41, 46-42, 46-43, 46-44, 46-45, 46-46,
46-47, 46-48, 46-49, 46-50, 46-51, 46-52, 46-53, 46-54, 46-55,
46-56, 46-57, 46-58, 46-59, 46-60, 46-61, 46-62, 46-63, 46-64,
46-65, 46-66, 46-67, 46-68, 46-69, 46-70, 46-71, 46-72, 46-73,
46-74, 46-75, 46-76, 46-77, 46-78, 46-79, 46-80, 46-81, 46-82,
46-83, 46-84, 46-85, 46-86, 46-87, 46-88, 46-89, 46-90, 46-91,
46-92, 46-93, 46-94, 46-95, 46-96, 46-97,
[0160] 47-1, 47-2, 47-3, 47-4, 47-5, 47-6, 47-7, 47-8, 47-9, 47-10,
47-11, 47-12, 47-13, 47-14, 47-15, 47-16, 47-17, 47-18, 47-19,
47-20, 47-21, 47-22, 47-23, 47-24, 47-25, 47-26, 47-27, 47-28,
47-29, 47-30, 47-31, 47-32, 47-33, 47-34, 47-35, 47-36, 47-37,
47-38, 47-39, 47-40, 47-41, 47-42, 47-43, 47-44, 47-45, 47-46,
47-47, 47-48, 47-49, 47-50, 47-51, 47-52, 47-53, 47-54, 47-55,
47-56, 47-57, 47-58, 47-59, 47-60, 47-61, 47-62, 47-63, 47-64,
47-65, 47-66, 47-67, 47-68, 47-69, 47-70, 47-71, 47-72, 47-73,
47-74, 47-75, 47-76, 47-77, 47-78, 47-79, 47-80, 47-81, 47-82,
47-83, 47-84, 47-85, 47-86, 47-87, 47-88, 47-89, 47-90, 47-91,
47-92, 47-93, 47-94, 47-95, 47-96, 47-97,
[0161] 48-1, 48-2, 48-3, 48-4, 48-5, 48-6, 48-7, 48-8, 48-9, 48-10,
48-11, 48-12, 48-13, 48-14, 48-15, 48-16, 48-17, 48-18, 48-19,
48-20, 48-21, 48-22, 48-23, 48-24, 48-25, 48-26, 48-27, 48-28,
48-29, 48-30, 48-31, 48-32, 48-33, 48-34, 48-35, 48-36, 48-37,
48-38, 48-39, 48-40, 48-41, 48-42, 48-43, 48-44, 48-45, 48-46,
48-47, 48-48, 48-49, 48-50, 48-51, 48-52, 48-53, 48-54, 48-55,
48-56, 48-57, 48-58, 48-59, 48-60, 48-61, 48-62, 48-63, 48-64,
48-65, 48-66, 48-67, 48-68, 48-69, 48-70, 48-71, 48-72, 48-73,
48-74, 48-75, 48-76, 48-77, 48-78, 48-79, 48-80, 48-81, 48-82,
48-83, 48-84, 48-85, 48-86, 48-87, 48-88, 48-89, 48-90, 48-91,
48-92, 48-93, 48-94, 48-95, 48-96, 48-97,
[0162] 49-1, 49-2, 49-3, 49-4, 49-5, 49-6, 49-7, 49-8, 49-9, 49-10,
49-11, 49-12, 49-13, 49-14, 49-15, 49-16, 49-17, 49-18, 49-19,
49-20, 49-21, 49-22, 49-23, 49-24, 49-25, 49-26, 49-27, 49-28,
49-29, 49-30, 49-31, 49-32, 49-33, 49-34, 49-35, 49-36, 49-37,
49-38, 49-39, 49-40, 49-41, 49-42, 49-43, 49-44, 49-45, 49-46,
49-47, 49-48, 49-49, 49-50, 49-51, 49-52, 49-53, 49-54, 49-55,
49-56, 49-57, 49-58, 49-59, 49-60, 49-61, 49-62, 49-63, 49-64,
49-65, 49-66, 49-67, 49-68, 49-69, 49-70, 49-71, 49-72, 49-73,
49-74, 49-75, 49-76, 49-77, 49-78, 49-79, 49-80, 49-81, 49-82,
49-83, 49-84, 49-85, 49-86, 49-87, 49-88, 49-89, 49-90, 49-91,
49-92, 49-93, 49-94, 49-95, 49-96, 49-97,
[0163] 50-1, 50-2, 50-3, 50-4, 50-5, 50-6, 50-7, 50-8, 50-9, 50-10,
50-11, 50-12, 50-13, 50-14, 50-15, 50-16, 50-17, 50-18, 50-19,
50-20, 50-21, 50-22, 50-23, 50-24, 50-25, 50-26, 50-27, 50-28,
50-29, 50-30, 50-31, 50-32, 50-33, 50-34, 50-35, 50-36, 50-37,
50-38, 50-39, 50-40, 50-41, 50-42, 50-43, 50-44, 50-45, 50-46,
50-47, 50-48, 50-49, 50-50, 50-51, 50-52, 50-53, 50-54, 50-55,
50-56, 50-57, 50-58, 50-59, 50-60, 50-61, 50-62, 50-63, 50-64,
50-65, 50-66, 50-67, 50-68, 50-69, 50-70, 50-71, 50-72, 50-73,
50-74, 50-75, 50-76, 50-77, 50-78, 50-79, 50-80, 50-81, 50-82,
50-83, 50-84, 50-85, 50-86, 50-87, 50-88, 50-89, 50-90, 50-91,
50-92, 50-93, 50-94, 50-95, 50-96, 50-97,
[0164] 51-1, 51-2, 51-3, 51-4, 51-5, 51-6, 51-7, 51-8, 51-9, 51-10,
51-11, 51-12, 51-13, 51-14, 51-15, 51-16, 51-17, 51-18, 51-19,
51-20, 51-21, 51-22, 51-23, 51-24, 51-25, 51-26, 51-27, 51-28,
51-29, 51-30, 51-31, 51-32, 51-33, 51-34, 51-35, 51-36, 51-37,
51-38, 51-39, 51-40, 51-41, 51-42, 51-43, 51-44, 51-45, 51-46,
51-47, 51-48, 51-49, 51-50, 51-51, 51-52, 51-53, 51-54, 51-55,
51-56, 51-57, 51-58, 51-59, 51-60, 51-61, 51-62, 51-63, 51-64,
51-65, 51-66, 51-67, 51-68, 51-69, 51-70, 51-71, 51-72, 51-73,
51-74, 51-75, 51-76, 51-77, 51-78, 51-79, 51-80, 51-81, 51-82,
51-83, 51-84, 51-85, 51-86, 51-87, 51-88, 51-89, 51-90, 51-91,
51-92, 51-93, 51-94, 51-95, 51-96, 51-97,
[0165] 52-1, 52-2, 52-3, 52-4, 52-5, 52-6, 52-7, 52-8, 52-9, 52-10,
52-11, 52-12, 52-13, 52-14, 52-15, 52-16, 52-17, 52-18, 52-19,
52-20, 52-21, 52-22, 52-23, 52-24, 52-25, 52-26, 52-27, 52-28,
52-29, 52-30, 52-31, 52-32, 52-33, 52-34, 52-35, 52-36, 52-37,
52-38, 52-39, 52-40, 52-41, 52-42, 52-43, 52-44, 52-45, 52-46,
52-47, 52-48, 52-49, 52-50, 52-51, 52-52, 52-53, 52-54, 52-55,
52-56, 52-57, 52-58, 52-59, 52-60, 52-61, 52-62, 52-63, 52-64,
52-65, 52-66, 52-67, 52-68, 52-69, 52-70, 52-71, 52-72, 52-73,
52-74, 52-75, 52-76, 52-77, 52-78, 52-79, 52-80, 52-81, 52-82,
52-83, 52-84, 52-85, 52-86, 52-87, 52-88, 52-89, 52-90, 52-91,
52-92, 52-93, 52-94, 52-95, 52-96, 52-97,
[0166] 53-1, 53-2, 53-3, 53-4, 53-5, 53-6, 53-7, 53-8, 53-9, 53-10,
53-11, 53-12, 53-13, 53-14, 53-15, 53-16, 53-17, 53-18, 53-19,
53-20, 53-21, 53-22, 53-23, 53-24, 53-25, 53-26, 53-27, 53-28,
53-29, 53-30, 53-31, 53-32, 53-33, 53-34, 53-35, 53-36, 53-37,
53-38, 53-39, 53-40, 53-41, 53-42, 53-43, 53-44, 53-45, 53-46,
53-47, 53-48, 53-49, 53-50, 53-51, 53-52, 53-53, 53-54, 53-55,
53-56, 53-57, 53-58, 53-59, 53-60, 53-61, 53-62, 53-63, 53-64,
53-65, 53-66, 53-67, 53-68, 53-69, 53-70, 53-71, 53-72, 53-73,
53-74, 53-75, 53-76, 53-77, 53-78, 53-79, 53-80, 53-81, 53-82,
53-83, 53-84, 53-85, 53-86, 53-87, 53-88, 53-89, 53-90, 53-91,
53-92, 53-93, 53-94, 53-95, 53-96, 53-97,
[0167] 54-1, 54-2, 54-3, 54-4, 54-5, 54-6, 54-7, 54-8, 54-9, 54-10,
54-11, 54-12, 54-13, 54-14, 54-15, 54-16, 54-17, 54-18, 54-19,
54-20, 54-21, 54-22, 54-23, 54-24, 54-25, 54-26, 54-27, 54-28,
54-29, 54-30, 54-31, 54-32, 54-33, 54-34, 54-35, 54-36, 54-37,
54-38, 54-39, 54-40, 54-41, 54-42, 54-43, 54-44, 54-45, 54-46,
54-47, 54-48, 54-49, 54-50, 54-51, 54-52, 54-53, 54-54, 54-55,
54-56, 54-57, 54-58, 54-59, 54-60, 54-61, 54-62, 54-63, 54-64,
54-65, 54-66, 54-67, 54-68, 54-69, 54-70, 54-71, 54-72, 54-73,
54-74, 54-75, 54-76, 54-77, 54-78, 54-79, 54-80, 54-81, 54-82,
54-83, 54-84, 54-85, 54-86, 54-87, 54-88, 54-89, 54-90, 54-91,
54-92, 54-93, 54-94, 54-95, 54-96, 54-97,
[0168] 55-1, 55-2, 55-3, 55-4, 55-5, 55-6, 55-7, 55-8, 55-9, 55-10,
55-11, 55-12, 55-13, 55-14, 55-15, 55-16, 55-17, 55-18, 55-19,
55-20, 55-21, 55-22, 55-23, 55-24, 55-25, 55-26, 55-27, 55-28,
55-29, 55-30, 55-31, 55-32, 55-33, 55-34, 55-35, 55-36, 55-37,
55-38, 55-39, 55-40, 55-41, 55-42, 55-43, 55-44, 55-45, 55-46,
55-47, 55-48, 55-49, 55-50, 55-51, 55-52, 55-53, 55-54, 55-55,
55-56, 55-57, 55-58, 55-59, 55-60, 55-61, 55-62, 55-63, 55-64,
55-65, 55-66, 55-67, 55-68, 55-69, 55-70, 55-71, 55-72, 55-73,
55-74, 55-75, 55-76, 55-77, 55-78, 55-79, 55-80, 55-81, 55-82,
55-83, 55-84, 55-85, 55-86, 55-87, 55-88, 55-89, 55-90, 55-91,
55-92, 55-93, 55-94, 55-95, 55-96, 55-97,
[0169] 56-1, 56-2, 56-3, 56-4, 56-5, 56-6, 56-7, 56-8, 56-9, 56-10,
56-11, 56-12, 56-13, 56-14, 56-15, 56-16, 56-17, 56-18, 56-19,
56-20, 56-21, 56-22, 56-23, 56-24, 56-25, 56-26, 56-27, 56-28,
56-29, 56-30, 56-31, 56-32, 56-33, 56-34, 56-35, 56-36, 56-37,
56-38, 56-39, 56-40, 56-41, 56-42, 56-43, 56-44, 56-45, 56-46,
56-47, 56-48, 56-49, 56-50, 56-51, 56-52, 56-53, 56-54, 56-55,
56-56, 56-57, 56-58, 56-59, 56-60, 56-61, 56-62, 56-63, 56-64,
56-65, 56-66, 56-67, 56-68, 56-69, 56-70, 56-71, 56-72, 56-73,
56-74, 56-75, 56-76, 56-77, 56-78, 56-79, 56-80, 56-81, 56-82,
56-83, 56-84, 56-85, 56-86, 56-87, 56-88, 56-89, 56-90, 56-91,
56-92, 56-93, 56-94, 56-95, 56-96, 56-97,
[0170] 57-1, 57-2, 57-3, 57-4, 57-5, 57-6, 57-7, 57-8, 57-9, 57-10,
57-11, 57-12, 57-13, 57-14, 57-15, 57-16, 57-17, 57-18, 57-19,
57-20, 57-21, 57-22, 57-23, 57-24, 57-25, 57-26, 57-27, 57-28,
57-29, 57-30, 57-31, 57-32, 57-33, 57-34, 57-35, 57-36, 57-37,
57-38, 57-39, 57-40, 57-41, 57-42, 57-43, 57-44, 57-45, 57-46,
57-47, 57-48, 57-49, 57-50, 57-51, 57-52, 57-53, 57-54, 57-55,
57-56, 57-57, 57-58, 57-59, 57-60, 57-61, 57-62, 57-63, 57-64,
57-65, 57-66, 57-67, 57-68, 57-69, 57-70, 57-71, 57-72, 57-73,
57-74, 57-75, 57-76, 57-77, 57-78, 57-79, 57-80, 57-81, 57-82,
57-83, 57-84, 57-85, 57-86, 57-87, 57-88, 57-89, 57-90, 57-91,
57-92, 57-93, 57-94, 57-95, 57-96, 57-97,
[0171] 58-1, 58-2, 58-3, 58-4, 58-5, 58-6, 58-7, 58-8, 58-9, 58-10,
58-11, 58-12, 58-13, 58-14, 58-15, 58-16, 58-17, 58-18, 58-19,
58-20, 58-21, 58-22, 58-23, 58-24, 58-25, 58-26, 58-27, 58-28,
58-29, 58-30, 58-31, 58-32, 58-33, 58-34, 58-35, 58-36, 58-37,
58-38, 58-39, 58-40, 58-41, 58-42, 58-43, 58-44, 58-45, 58-46,
58-47, 58-48, 58-49, 58-50, 58-51, 58-52, 58-53, 58-54, 58-55,
58-56, 58-57, 58-58, 58-59, 58-60, 58-61, 58-62, 58-63, 58-64,
58-65, 58-66, 58-67, 58-68, 58-69, 58-70, 58-71, 58-72, 58-73,
58-74, 58-75, 58-76, 58-77, 58-78, 58-79, 58-80, 58-81, 58-82,
58-83, 58-84, 58-85, 58-86, 58-87, 58-88, 58-89, 58-90, 58-91,
58-92, 58-93, 58-94, 58-95, 58-96, 58-97,
[0172] 59-1, 59-2, 59-3, 59-4, 59-5, 59-6, 59-7, 59-8, 59-9, 59-10,
59-11, 59-12, 59-13, 59-14, 59-15, 59-16, 59-17, 59-18, 59-19,
59-20, 59-21, 59-22, 59-23, 59-24, 59-25, 59-26, 59-27, 59-28,
59-29, 59-30, 59-31, 59-32, 59-33, 59-34, 59-35, 59-36, 59-37,
59-38, 59-39, 59-40, 59-41, 59-42, 59-43, 59-44, 59-45, 59-46,
59-47, 59-48, 59-49, 59-50, 59-51, 59-52, 59-53, 59-54, 59-55,
59-56, 59-57, 59-58, 59-59, 59-60, 59-61, 59-62, 59-63, 59-64,
59-65, 59-66, 59-67, 59-68, 59-69, 59-70, 59-71, 59-72, 59-73,
59-74, 59-75, 59-76, 59-77, 59-78, 59-79, 59-80, 59-81, 59-82,
59-83, 59-84, 59-85, 59-86, 59-87, 59-88, 59-89, 59-90, 59-91,
59-92, 59-93, 59-94, 59-95, 59-96, 59-97,
[0173] 60-1, 60-2, 60-3, 60-4, 60-5, 60-6, 60-7, 60-8, 60-9, 60-10,
60-11, 60-12, 60-13, 60-14, 60-15, 60-16, 60-17, 60-18, 60-19,
60-20, 60-21, 60-22, 60-23, 60-24, 60-25, 60-26, 60-27, 60-28,
60-29, 60-30, 60-31, 60-32, 60-33, 60-34, 60-35, 60-36, 60-37,
60-38, 60-39, 60-40, 60-41, 60-42, 60-43, 60-44, 60-45, 60-46,
60-47, 60-48, 60-49, 60-50, 60-51, 60-52, 60-53, 60-54, 60-55,
60-56, 60-57, 60-58, 60-59, 60-60, 60-61, 60-62, 60-63, 60-64,
60-65, 60-66, 60-67, 60-68, 60-69, 60-70, 60-71, 60-72, 60-73,
60-74, 60-75, 60-76, 60-77, 60-78, 60-79, 60-80, 60-81, 60-82,
60-83, 60-84, 60-85, 60-86, 60-87, 60-88, 60-89, 60-90, 60-91,
60-92, 60-93, 60-94, 60-95, 60-96, 60-97,
[0174] 61-1, 61-2, 61-3, 61-4, 61-5, 61-6, 61-7, 61-8, 61-9, 61-10,
61-11, 61-12, 61-13, 61-14, 61-15, 61-16, 61-17, 61-18, 61-19,
61-20, 61-21, 61-22, 61-23, 61-24, 61-25, 61-26, 61-27, 61-28,
61-29, 61-30, 61-31, 61-32, 61-33, 61-34, 61-35, 61-36, 61-37,
61-38, 61-39, 61-40, 61-41, 61-42, 61-43, 61-44, 61-45, 61-46,
61-47, 61-48, 61-49, 61-50, 61-51, 61-52, 61-53, 61-54, 61-55,
61-56, 61-57, 61-58, 61-59, 61-60, 61-61, 61-62, 61-63, 61-64,
61-65, 61-66, 61-67, 61-68, 61-69, 61-70, 61-71, 61-72, 61-73,
61-74, 61-75, 61-76, 61-77, 61-78, 61-79, 61-80, 61-81, 61-82,
61-83, 61-84, 61-85, 61-86, 61-87, 61-88, 61-89, 61-90, 61-91,
61-92, 61-93, 61-94, 61-95, 61-96, 61-97,
[0175] 62-1, 62-2, 62-3, 62-4, 62-5, 62-6, 62-7, 62-8, 62-9, 62-10,
62-11, 62-12, 62-13, 62-14, 62-15, 62-16, 62-17, 62-18, 62-19,
62-20, 62-21, 62-22, 62-23, 62-24, 62-25, 62-26, 62-27, 62-28,
62-29, 62-30, 62-31, 62-32, 62-33, 62-34, 62-35, 62-36, 62-37,
62-38, 62-39, 62-40, 62-41, 62-42, 62-43, 62-44, 62-45, 62-46,
62-47, 62-48, 62-49, 62-50, 62-51, 62-52, 62-53, 62-54, 62-55,
62-56, 62-57, 62-58, 62-59, 62-60, 62-61, 62-62, 62-63, 62-64,
62-65, 62-66, 62-67, 62-68, 62-69, 62-70, 62-71, 62-72, 62-73,
62-74, 62-75, 62-76, 62-77, 62-78, 62-79, 62-80, 62-81, 62-82,
62-83, 62-84, 62-85, 62-86, 62-87, 62-88, 62-89, 62-90, 62-91,
62-92, 62-93, 62-94, 62-95, 62-96, 62-97,
[0176] 63-1, 63-2, 63-3, 63-4, 63-5, 63-6, 63-7, 63-8, 63-9, 63-10,
63-11, 63-12, 63-13, 63-14, 63-15, 63-16, 63-17, 63-18, 63-19,
63-20, 63-21, 63-22, 63-23, 63-24, 63-25, 63-26, 63-27, 63-28,
63-29, 63-30, 63-31, 63-32, 63-33, 63-34, 63-35, 63-36, 63-37,
63-38, 63-39, 63-40, 63-41, 63-42, 63-43, 63-44, 63-45, 63-46,
63-47, 63-48, 63-49, 63-50, 63-51, 63-52, 63-53, 63-54, 63-55,
63-56, 63-57, 63-58, 63-59, 63-60, 63-61, 63-62, 63-63, 63-64,
63-65, 63-66, 63-67, 63-68, 63-69, 63-70, 63-71, 63-72, 63-73,
63-74, 63-75, 63-76, 63-77, 63-78, 63-79, 63-80, 63-81, 63-82,
63-83, 63-84, 63-85, 63-86, 63-87, 63-88, 63-89, 63-90, 63-91,
63-92, 63-93, 63-94, 63-95, 63-96, 63-97,
[0177] 64-1, 64-2, 64-3, 64-4, 64-5, 64-6, 64-7, 64-8, 64-9, 64-10,
64-11, 64-12, 64-13, 64-14, 64-15, 64-16, 64-17, 64-18, 64-19,
64-20, 64-21, 64-22, 64-23, 64-24, 64-25, 64-26, 64-27, 64-28,
64-29, 64-30, 64-31, 64-32, 64-33, 64-34, 64-35, 64-36, 64-37,
64-38, 64-39, 64-40, 64-41, 64-42, 64-43, 64-44, 64-45, 64-46,
64-47, 64-48, 64-49, 64-50, 64-51, 64-52, 64-53, 64-54, 64-55,
64-56, 64-57, 64-58, 64-59, 64-60, 64-61, 64-62, 64-63, 64-64,
64-65, 64-66, 64-67, 64-68, 64-69, 64-70, 64-71, 64-72, 64-73,
64-74, 64-75, 64-76, 64-77, 64-78, 64-79, 64-80, 64-81, 64-82,
64-83, 64-84, 64-85, 64-86, 64-87, 64-88, 64-89, 64-90, 64-91,
64-92, 64-93, 64-94, 64-95, 64-96, 64-97,
[0178] 65-1, 65-2, 65-3, 65-4, 65-5, 65-6, 65-7, 65-8, 65-9, 65-10,
65-11, 65-12, 65-13, 65-14, 65-15, 65-16, 65-17, 65-18, 65-19,
65-20, 65-21, 65-22, 65-23, 65-24, 65-25, 65-26, 65-27, 65-28,
65-29, 65-30, 65-31, 65-32, 65-33, 65-34, 65-35, 65-36, 65-37,
65-38, 65-39, 65-40, 65-41, 65-42, 65-43, 65-44, 65-45, 65-46,
65-47, 65-48, 65-49, 65-50, 65-51, 65-52, 65-53, 65-54, 65-55,
65-56, 65-57, 65-58, 65-59, 65-60, 65-61, 65-62, 65-63, 65-64,
65-65, 65-66, 65-67, 65-68, 65-69, 65-70, 65-71, 65-72, 65-73,
65-74, 65-75, 65-76, 65-77, 65-78, 65-79, 65-80, 65-81, 65-82,
65-83, 65-84, 65-85, 65-86, 65-87, 65-88, 65-89, 65-90, 65-91,
65-92, 65-93, 65-94, 65-95, 65-96, 65-97,
[0179] 66-1, 66-2, 66-3, 66-4, 66-5, 66-6, 66-7, 66-8, 66-9, 66-10,
66-11, 66-12, 66-13, 66-14, 66-15, 66-16, 66-17, 66-18, 66-19,
66-20, 66-21, 66-22, 66-23, 66-24, 66-25, 66-26, 66-27, 66-28,
66-29, 66-30, 66-31, 66-32, 66-33, 66-34, 66-35, 66-36, 66-37,
66-38, 66-39, 66-40, 66-41, 66-42, 66-43, 66-44, 66-45, 66-46,
66-47, 66-48, 66-49, 66-50, 66-51, 66-52, 66-53, 66-54, 66-55,
66-56, 66-57, 66-58, 66-59, 66-60, 66-61, 66-62, 66-63, 66-64,
66-65, 66-66, 66-67, 66-68, 66-69, 66-70, 66-71, 66-72, 66-73,
66-74, 66-75, 66-76, 66-77, 66-78, 66-79, 66-80, 66-81, 66-82,
66-83, 66-84, 66-85, 66-86, 66-87, 66-88, 66-89, 66-90, 66-91,
66-92, 66-93, 66-94, 66-95, 66-96, 66-97,
[0180] 67-1, 67-2, 67-3, 67-4, 67-5, 67-6, 67-7, 67-8, 67-9, 67-10,
67-11, 67-12, 67-13, 67-14, 67-15, 67-16, 67-17, 67-18, 67-19,
67-20, 67-21, 67-22, 67-23, 67-24, 67-25, 67-26, 67-27, 67-28,
67-29, 67-30, 67-31, 67-32, 67-33, 67-34, 67-35, 67-36, 67-37,
67-38, 67-39, 67-40, 67-41, 67-42, 67-43, 67-44, 67-45, 67-46,
67-47, 67-48, 67-49, 67-50, 67-51, 67-52, 67-53, 67-54, 67-55,
67-56, 67-57, 67-58, 67-59, 67-60, 67-61, 67-62, 67-63, 67-64,
67-65, 67-66, 67-67, 67-68, 67-69, 67-70, 67-71, 67-72, 67-73,
67-74, 67-75, 67-76, 67-77, 67-78, 67-79, 67-80, 67-81, 67-82,
67-83, 67-84, 67-85, 67-86, 67-87, 67-88, 67-89, 67-90, 67-91,
67-92, 67-93, 67-94, 67-95, 67-96, 67-97,
[0181] 68-1, 68-2, 68-3, 68-4, 68-5, 68-6, 68-7, 68-8, 68-9, 68-10,
68-11, 68-12, 68-13, 68-14, 68-15, 68-16, 68-17, 68-18, 68-19,
68-20, 68-21, 68-22, 68-23, 68-24, 68-25, 68-26, 68-27, 68-28,
68-29, 68-30, 68-31, 68-32, 68-33, 68-34, 68-35, 68-36, 68-37,
68-38, 68-39, 68-40, 68-41, 68-42, 68-43, 68-44, 68-45, 68-46,
68-47, 68-48, 68-49, 68-50, 68-51, 68-52, 68-53, 68-54, 68-55,
68-56, 68-57, 68-58, 68-59, 68-60, 68-61, 68-62, 68-63, 68-64,
68-65, 68-66, 68-67, 68-68, 68-69, 68-70, 68-71, 68-72, 68-73,
68-74, 68-75, 68-76, 68-77, 68-78, 68-79, 68-80, 68-81, 68-82,
68-83, 68-84, 68-85, 68-86, 68-87, 68-88, 68-89, 68-90, 68-91,
68-92, 68-93, 68-94, 68-95, 68-96, 68-97,
[0182] 69-1, 69-2, 69-3, 69-4, 69-5, 69-6, 69-7, 69-8, 69-9, 69-10,
69-11, 69-12, 69-13, 69-14, 69-15, 69-16, 69-17, 69-18, 69-19,
69-20, 69-21, 69-22, 69-23, 69-24, 69-25, 69-26, 69-27, 69-28,
69-29, 69-30, 69-31, 69-32, 69-33, 69-34, 69-35, 69-36, 69-37,
69-38, 69-39, 69-40, 69-41, 69-42, 69-43, 69-44, 69-45, 69-46,
69-47, 69-48, 69-49, 69-50, 69-51, 69-52, 69-53, 69-54, 69-55,
69-56, 69-57, 69-58, 69-59, 69-60, 69-61, 69-62, 69-63, 69-64,
69-65, 69-66, 69-67, 69-68, 69-69, 69-70, 69-71, 69-72, 69-73,
69-74, 69-75, 69-76, 69-77, 69-78, 69-79, 69-80, 69-81, 69-82,
69-83, 69-84, 69-85, 69-86, 69-87, 69-88, 69-89, 69-90, 69-91,
69-92, 69-93, 69-94, 69-95, 69-96, 69-97,
[0183] 70-1, 70-2, 70-3, 70-4, 70-5, 70-6, 70-7, 70-8, 70-9, 70-10,
70-11, 70-12, 70-13, 70-14, 70-15, 70-16, 70-17, 70-18, 70-19,
70-20, 70-21, 70-22, 70-23, 70-24, 70-25, 70-26, 70-27, 70-28,
70-29, 70-30, 70-31, 70-32, 70-33, 70-34, 70-35, 70-36, 70-37,
70-38, 70-39, 70-40, 70-41, 70-42, 70-43, 70-44, 70-45, 70-46,
70-47, 70-48, 70-49, 70-50, 70-51, 70-52, 70-53, 70-54, 70-55,
70-56, 70-57, 70-58, 70-59, 70-60, 70-61, 70-62, 70-63, 70-64,
70-65, 70-66, 70-67, 70-68, 70-69, 70-70, 70-71, 70-72, 70-73,
70-74, 70-75, 70-76, 70-77, 70-78, 70-79, 70-80, 70-81, 70-82,
70-83, 70-84, 70-85, 70-86, 70-87, 70-88, 70-89, 70-90, 70-91,
70-92, 70-93, 70-94, 70-95, 70-96, 70-97,
[0184] 71-1, 71-2, 71-3, 71-4, 71-5, 71-6, 71-7, 71-8, 71-9, 71-10,
71-11, 71-12, 71-13, 71-14, 71-15, 71-16, 71-17, 71-18, 71-19,
71-20, 71-21, 71-22, 71-23, 71-24, 71-25, 71-26, 71-27, 71-28,
71-29, 71-30, 71-31, 71-32, 71-33, 71-34, 71-35, 71-36, 71-37,
71-38, 71-39, 71-40, 71-41, 71-42, 71-43, 71-44, 71-45, 71-46,
71-47, 71-48, 71-49, 71-50, 71-51, 71-52, 71-53, 71-54, 71-55,
71-56, 71-57, 71-58, 71-59, 71-60, 71-61, 71-62, 71-63, 71-64,
71-65, 71-66, 71-67, 71-68, 71-69, 71-70, 71-71, 71-72, 71-73,
71-74, 71-75, 71-76, 71-77, 71-78, 71-79, 71-80, 71-81, 71-82,
71-83, 71-84, 71-85, 71-86, 71-87, 71-88, 71-89, 71-90, 71-91,
71-92, 71-93, 71-94, 71-95, 71-96, 71-97,
[0185] 72-1, 72-2, 72-3, 72-4, 72-5, 72-6, 72-7, 72-8, 72-9, 72-10,
72-11, 72-12, 72-13, 72-14, 72-15, 72-16, 72-17, 72-18, 72-19,
72-20, 72-21, 72-22, 72-23, 72-24, 72-25, 72-26, 72-27, 72-28,
72-29, 72-30, 72-31, 72-32, 72-33, 72-34, 72-35, 72-36, 72-37,
72-38, 72-39, 72-40, 72-41, 72-42, 72-43, 72-44, 72-45, 72-46,
72-47, 72-48, 72-49, 72-50, 72-51, 72-52, 72-53, 72-54, 72-55,
72-56, 72-57, 72-58, 72-59, 72-60, 72-61, 72-62, 72-63, 72-64,
72-65, 72-66, 72-67, 72-68, 72-69, 72-70, 72-71, 72-72, 72-73,
72-74, 72-75, 72-76, 72-77, 72-78, 72-79, 72-80, 72-81, 72-82,
72-83, 72-84, 72-85, 72-86, 72-87, 72-88, 72-89, 72-90, 72-91,
72-92, 72-93, 72-94, 72-95, 72-96, 72-97,
[0186] 73-1, 73-2, 73-3, 73-4, 73-5, 73-6, 73-7, 73-8, 73-9, 73-10,
73-11, 73-12, 73-13, 73-14, 73-15, 73-16, 73-17, 73-18, 73-19,
73-20, 73-21, 73-22, 73-23, 73-24, 73-25, 73-26, 73-27, 73-28,
73-29, 73-30, 73-31, 73-32, 73-33, 73-34, 73-35, 73-36, 73-37,
73-38, 73-39, 73-40, 73-41, 73-42, 73-43, 73-44, 73-45, 73-46,
73-47, 73-48, 73-49, 73-50, 73-51, 73-52, 73-53, 73-54, 73-55,
73-56, 73-57, 73-58, 73-59, 73-60, 73-61, 73-62, 73-63, 73-64,
73-65, 73-66, 73-67, 73-68, 73-69, 73-70, 73-71, 73-72, 73-73,
73-74, 73-75, 73-76, 73-77, 73-78, 73-79, 73-80, 73-81, 73-82,
73-83, 73-84, 73-85, 73-86, 73-87, 73-88, 73-89, 73-90, 73-91,
73-92, 73-93, 73-94, 73-95, 73-96, 73-97,
[0187] 74-1, 74-2, 74-3, 74-4, 74-5, 74-6, 74-7, 74-8, 74-9, 74-10,
74-11, 74-12, 74-13, 74-14, 74-15, 74-16, 74-17, 74-18, 74-19,
74-20, 74-21, 74-22, 74-23, 74-24, 74-25, 74-26, 74-27, 74-28,
74-29, 74-30, 74-31, 74-32, 74-33, 74-34, 74-35, 74-36, 74-37,
74-38, 74-39, 74-40, 74-41, 74-42, 74-43, 74-44, 74-45, 74-46,
74-47, 74-48, 74-49, 74-50, 74-51, 74-52, 74-53, 74-54, 74-55,
74-56, 74-57, 74-58, 74-59, 74-60, 74-61, 74-62, 74-63, 74-64,
74-65, 74-66, 74-67, 74-68, 74-69, 74-70, 74-71, 74-72, 74-73,
74-74, 74-75, 74-76, 74-77, 74-78, 74-79, 74-80, 74-81, 74-82,
74-83, 74-84, 74-85, 74-86, 74-87, 74-88, 74-89, 74-90, 74-91,
74-92, 74-93, 74-94, 74-95, 74-96, 74-97,
[0188] 75-1, 75-2, 75-3, 75-4, 75-5, 75-6, 75-7, 75-8, 75-9, 75-10,
75-11, 75-12, 75-13, 75-14, 75-15, 75-16, 75-17, 75-18, 75-19,
75-20, 75-21, 75-22, 75-23, 75-24, 75-25, 75-26, 75-27, 75-28,
75-29, 75-30, 75-31, 75-32, 75-33, 75-34, 75-35, 75-36, 75-37,
75-38, 75-39, 75-40, 75-41, 75-42, 75-43, 75-44, 75-45, 75-46,
75-47, 75-48, 75-49, 75-50, 75-51, 75-52, 75-53, 75-54, 75-55,
75-56, 75-57, 75-58, 75-59, 75-60, 75-61, 75-62, 75-63, 75-64,
75-65, 75-66, 75-67, 75-68, 75-69, 75-70, 75-71, 75-72, 75-73,
75-74, 75-75, 75-76, 75-77, 75-78, 75-79, 75-80, 75-81, 75-82,
75-83, 75-84, 75-85, 75-86, 75-87, 75-88, 75-89, 75-90, 75-91,
75-92, 75-93, 75-94, 75-95, 75-96, 75-97,
[0189] 76-1, 76-2, 76-3, 76-4, 76-5, 76-6, 76-7, 76-8, 76-9, 76-10,
76-11, 76-12, 76-13, 76-14, 76-15, 76-16, 76-17, 76-18, 76-19,
76-20, 76-21, 76-22, 76-23, 76-24, 76-25, 76-26, 76-27, 76-28,
76-29, 76-30, 76-31, 76-32, 76-33, 76-34, 76-35, 76-36, 76-37,
76-38, 76-39, 76-40, 76-41, 76-42, 76-43, 76-44, 76-45, 76-46,
76-47, 76-48, 76-49, 76-50, 76-51, 76-52, 76-53, 76-54, 76-55,
76-56, 76-57, 76-58, 76-59, 76-60, 76-61, 76-62, 76-63, 76-64,
76-65, 76-66, 76-67, 76-68, 76-69, 76-70, 76-71, 76-72, 76-73,
76-74, 76-75, 76-76, 76-77, 76-78, 76-79, 76-80, 76-81, 76-82,
76-83, 76-84, 76-85, 76-86, 76-87, 76-88, 76-89, 76-90, 76-91,
76-92, 76-93, 76-94, 76-95, 76-96, 76-97,
[0190] 77-1, 77-2, 77-3, 77-4, 77-5, 77-6, 77-7, 77-8, 77-9, 77-10,
77-11, 77-12, 77-13, 77-14, 77-15, 77-16, 77-17, 77-18, 77-19,
77-20, 77-21, 77-22, 77-23, 77-24, 77-25, 77-26, 77-27, 77-28,
77-29, 77-30, 77-31, 77-32, 77-33, 77-34, 77-35, 77-36, 77-37,
77-38, 77-39, 77-40, 77-41, 77-42, 77-43, 77-44, 77-45, 77-46,
77-47, 77-48, 77-49, 77-50, 77-51, 77-52, 77-53, 77-54, 77-55,
77-56, 77-57, 77-58, 77-59, 77-60, 77-61, 77-62, 77-63, 77-64,
77-65, 77-66, 77-67, 77-68, 77-69, 77-70, 77-71, 77-72, 77-73,
77-74, 77-75, 77-76, 77-77, 77-78, 77-79, 77-80, 77-81, 77-82,
77-83, 77-84, 77-85, 77-86, 77-87, 77-88, 77-89, 77-90, 77-91,
77-92, 77-93, 77-94, 77-95, 77-96, 77-97,
[0191] 78-1, 78-2, 78-3, 78-4, 78-5, 78-6, 78-7, 78-8, 78-9, 78-10,
78-11, 78-12, 78-13, 78-14, 78-15, 78-16, 78-17, 78-18, 78-19,
78-20, 78-21, 78-22, 78-23, 78-24, 78-25, 78-26, 78-27, 78-28,
78-29, 78-30, 78-31, 78-32, 78-33, 78-34, 78-35, 78-36, 78-37,
78-38, 78-39, 78-40, 78-41, 78-42, 78-43, 78-44, 78-45, 78-46,
78-47, 78-48, 78-49, 78-50, 78-51, 78-52, 78-53, 78-54, 78-55,
78-56, 78-57, 78-58, 78-59, 78-60, 78-61, 78-62, 78-63, 78-64,
78-65, 78-66, 78-67, 78-68, 78-69, 78-70, 78-71, 78-72, 78-73,
78-74, 78-75, 78-76, 78-77, 78-78, 78-79, 78-80, 78-81, 78-82,
78-83, 78-84, 78-85, 78-86, 78-87, 78-88, 78-89, 78-90, 78-91,
78-92, 78-93, 78-94, 78-95, 78-96, 78-97,
[0192] 79-1, 79-2, 79-3, 79-4, 79-5, 79-6, 79-7, 79-8, 79-9, 79-10,
79-11, 79-12, 79-13, 79-14, 79-15, 79-16, 79-17, 79-18, 79-19,
79-20, 79-21, 79-22, 79-23, 79-24, 79-25, 79-26, 79-27, 79-28,
79-29, 79-30, 79-31, 79-32, 79-33, 79-34, 79-35, 79-36, 79-37,
79-38, 79-39, 79-40, 79-41, 79-42, 79-43, 79-44, 79-45, 79-46,
79-47, 79-48, 79-49, 79-50, 79-51, 79-52, 79-53, 79-54, 79-55,
79-56, 79-57, 79-58, 79-59, 79-60, 79-61, 79-62, 79-63, 79-64,
79-65, 79-66, 79-67, 79-68, 79-69, 79-70, 79-71, 79-72, 79-73,
79-74, 79-75, 79-76, 79-77, 79-78, 79-79, 79-80, 79-81, 79-82,
79-83, 79-84, 79-85, 79-86, 79-87, 79-88, 79-89, 79-90, 79-91,
79-92, 79-93, 79-94, 79-95, 79-96, 79-97,
[0193] 80-1, 80-2, 80-3, 80-4, 80-5, 80-6, 80-7, 80-8, 80-9, 80-10,
80-11, 80-12, 80-13, 80-14, 80-15, 80-16, 80-17, 80-18, 80-19,
80-20, 80-21, 80-22, 80-23, 80-24, 80-25, 80-26, 80-27, 80-28,
80-29, 80-30, 80-31, 80-32, 80-33, 80-34, 80-35, 80-36, 80-37,
80-38, 80-39, 80-40, 80-41, 80-42, 80-43, 80-44, 80-45, 80-46,
80-47, 80-48, 80-49, 80-50, 80-51, 80-52, 80-53, 80-54, 80-55,
80-56, 80-57, 80-58, 80-59, 80-60, 80-61, 80-62, 80-63, 80-64,
80-65, 80-66, 80-67, 80-68, 80-69, 80-70, 80-71, 80-72, 80-73,
80-74, 80-75, 80-76, 80-77, 80-78, 80-79, 80-80, 80-81, 80-82,
80-83, 80-84, 80-85, 80-86, 80-87, 80-88, 80-89, 80-90, 80-91,
80-92, 80-93, 80-94, 80-95, 80-96, 80-97,
[0194] 81-1, 81-2, 81-3, 81-4, 81-5, 81-6, 81-7, 81-8, 81-9, 81-10,
81-11, 81-12, 81-13, 81-14, 81-15, 81-16, 81-17, 81-18, 81-19,
81-20, 81-21, 81-22, 81-23, 81-24, 81-25, 81-26, 81-27, 81-28,
81-29, 81-30, 81-31, 81-32, 81-33, 81-34, 81-35, 81-36, 81-37,
81-38, 81-39, 81-40, 81-41, 81-42, 81-43, 81-44, 81-45, 81-46,
81-47, 81-48, 81-49, 81-50, 81-51, 81-52, 81-53, 81-54, 81-55,
81-56, 81-57, 81-58, 81-59, 81-60, 81-61, 81-62, 81-63, 81-64,
81-65, 81-66, 81-67, 81-68, 81-69, 81-70, 81-71, 81-72, 81-73,
81-74, 81-75, 81-76, 81-77, 81-78, 81-79, 81-80, 81-81, 81-82,
81-83, 81-84, 81-85, 81-86, 81-87, 81-88, 81-89, 81-90, 81-91,
81-92, 81-93, 81-94, 81-95, 81-96, 81-97,
[0195] 82-1, 82-2, 82-3, 82-4, 82-5, 82-6, 82-7, 82-8, 82-9, 82-10,
82-11, 82-12, 82-13, 82-14, 82-15, 82-16, 82-17, 82-18, 82-19,
82-20, 82-21, 82-22, 82-23, 82-24, 82-25, 82-26, 82-27, 82-28,
82-29, 82-30, 82-31, 82-32, 82-33, 82-34, 82-35, 82-36, 82-37,
82-38, 82-39, 82-40, 82-41, 82-42, 82-43, 82-44, 82-45, 82-46,
82-47, 82-48, 82-49, 82-50, 82-51, 82-52, 82-53, 82-54, 82-55,
82-56, 82-57, 82-58, 82-59, 82-60, 82-61, 82-62, 82-63, 82-64,
82-65, 82-66, 82-67, 82-68, 82-69, 82-70, 82-71, 82-72, 82-73,
82-74, 82-75, 82-76, 82-77, 82-78, 82-79, 82-80, 82-81, 82-82,
82-83, 82-84, 82-85, 82-86, 82-87, 82-88, 82-89, 82-90, 82-91,
82-92, 82-93, 82-94, 82-95, 82-96, 82-97,
[0196] 83-1, 83-2, 83-3, 83-4, 83-5, 83-6, 83-7, 83-8, 83-9, 83-10,
83-11, 83-12, 83-13, 83-14, 83-15, 83-16, 83-17, 83-18, 83-19,
83-20, 83-21, 83-22, 83-23, 83-24, 83-25, 83-26, 83-27, 83-28,
83-29, 83-30, 83-31, 83-32, 83-33, 83-34, 83-35, 83-36, 83-37,
83-38, 83-39, 83-40, 83-41, 83-42, 83-43, 83-44, 83-45, 83-46,
83-47, 83-48, 83-49, 83-50, 83-51, 83-52, 83-53, 83-54, 83-55,
83-56, 83-57, 83-58, 83-59, 83-60, 83-61, 83-62, 83-63, 83-64,
83-65, 83-66, 83-67, 83-68, 83-69, 83-70, 83-71, 83-72, 83-73,
83-74, 83-75, 83-76, 83-77, 83-78, 83-79, 83-80, 83-81, 83-82,
83-83, 83-84, 83-85, 83-86, 83-87, 83-88, 83-89, 83-90, 83-91,
83-92, 83-93, 83-94, 83-95, 83-96, 83-97,
[0197] 84-1, 84-2, 84-3, 84-4, 84-5, 84-6, 84-7, 84-8, 84-9, 84-10,
84-11, 84-12, 84-13, 84-14, 84-15, 84-16, 84-17, 84-18, 84-19,
84-20, 84-21, 84-22, 84-23, 84-24, 84-25, 84-26, 84-27, 84-28,
84-29, 84-30, 84-31, 84-32, 84-33, 84-34, 84-35, 84-36, 84-37,
84-38, 84-39, 84-40, 84-41, 84-42, 84-43, 84-44, 84-45, 84-46,
84-47, 84-48, 84-49, 84-50, 84-51, 84-52, 84-53, 84-54, 84-55,
84-56, 84-57, 84-58, 84-59, 84-60, 84-61, 84-62, 84-63, 84-64,
84-65, 84-66, 84-67, 84-68, 84-69, 84-70, 84-71, 84-72, 84-73,
84-74, 84-75, 84-76, 84-77, 84-78, 84-79, 84-80, 84-81, 84-82,
84-83, 84-84, 84-85, 84-86, 84-87, 84-88, 84-89, 84-90, 84-91,
84-92, 84-93, 84-94, 84-95, 84-96, 84-97,
[0198] 85-1, 85-2, 85-3, 85-4, 85-5, 85-6, 85-7, 85-8, 85-9, 85-10,
85-11, 85-12, 85-13, 85-14, 85-15, 85-16, 85-17, 85-18, 85-19,
85-20, 85-21, 85-22, 85-23, 85-24, 85-25, 85-26, 85-27, 85-28,
85-29, 85-30, 85-31, 85-32, 85-33, 85-34, 85-35, 85-36, 85-37,
85-38, 85-39, 85-40, 85-41, 85-42, 85-43, 85-44, 85-45, 85-46,
85-47, 85-48, 85-49, 85-50, 85-51, 85-52, 85-53, 85-54, 85-55,
85-56, 85-57, 85-58, 85-59, 85-60, 85-61, 85-62, 85-63, 85-64,
85-65, 85-66, 85-67, 85-68, 85-69, 85-70, 85-71, 85-72, 85-73,
85-74, 85-75, 85-76, 85-77, 85-78, 85-79, 85-80, 85-81, 85-82,
85-83, 85-84, 85-85, 85-86, 85-87, 85-88, 85-89, 85-90, 85-91,
85-92, 85-93, 85-94, 85-95, 85-96, 85-97,
[0199] 86-1, 86-2, 86-3, 86-4, 86-5, 86-6, 86-7, 86-8, 86-9, 86-10,
86-11, 86-12, 86-13, 86-14, 86-15, 86-16, 86-17, 86-18, 86-19,
86-20, 86-21, 86-22, 86-23, 86-24, 86-25, 86-26, 86-27, 86-28,
86-29, 86-30, 86-31, 86-32, 86-33, 86-34, 86-35, 86-36, 86-37,
86-38, 86-39, 86-40, 86-41, 86-42, 86-43, 86-44, 86-45, 86-46,
86-47, 86-48, 86-49, 86-50, 86-51, 86-52, 86-53, 86-54, 86-55,
86-56, 86-57, 86-58, 86-59, 86-60, 86-61, 86-62, 86-63, 86-64,
86-65, 86-66, 86-67, 86-68, 86-69, 86-70, 86-71, 86-72, 86-73,
86-74, 86-75, 86-76, 86-77, 86-78, 86-79, 86-80, 86-81, 86-82,
86-83, 86-84, 86-85, 86-86, 86-87, 86-88, 86-89, 86-90, 86-91,
86-92, 86-93, 86-94, 86-95, 86-96, 86-97,
[0200] 87-1, 87-2, 87-3, 87-4, 87-5, 87-6, 87-7, 87-8, 87-9, 87-10,
87-11, 87-12, 87-13, 87-14, 87-15, 87-16, 87-17, 87-18, 87-19,
87-20, 87-21, 87-22, 87-23, 87-24, 87-25, 87-26, 87-27, 87-28,
87-29, 87-30, 87-31, 87-32, 87-33, 87-34, 87-35, 87-36, 87-37,
87-38, 87-39, 87-40, 87-41, 87-42, 87-43, 87-44, 87-45, 87-46,
87-47, 87-48, 87-49, 87-50, 87-51, 87-52, 87-53, 87-54, 87-55,
87-56, 87-57, 87-58, 87-59, 87-60, 87-61, 87-62, 87-63, 87-64,
87-65, 87-66, 87-67, 87-68, 87-69, 87-70, 87-71, 87-72, 87-73,
87-74, 87-75, 87-76, 87-77, 87-78, 87-79, 87-80, 87-81, 87-82,
87-83, 87-84, 87-85, 87-86, 87-87, 87-88, 87-89, 87-90, 87-91,
87-92, 87-93, 87-94, 87-95, 87-96, 87-97,
[0201] 88-1, 88-2, 88-3, 88-4, 88-5, 88-6, 88-7, 88-8, 88-9, 88-10,
88-11, 88-12, 88-13, 88-14, 88-15, 88-16, 88-17, 88-18, 88-19,
88-20, 88-21, 88-22, 88-23, 88-24, 88-25, 88-26, 88-27, 88-28,
88-29, 88-30, 88-31, 88-32, 88-33, 88-34, 88-35, 88-36, 88-37,
88-38, 88-39, 88-40, 88-41, 88-42, 88-43, 88-44, 88-45, 88-46,
88-47, 88-48, 88-49, 88-50, 88-51, 88-52, 88-53, 88-54, 88-55,
88-56, 88-57, 88-58, 88-59, 88-60, 88-61, 88-62, 88-63, 88-64,
88-65, 88-66, 88-67, 88-68, 88-69, 88-70, 88-71, 88-72, 88-73,
88-74, 88-75, 88-76, 88-77, 88-78, 88-79, 88-80, 88-81, 88-82,
88-83, 88-84, 88-85, 88-86, 88-87, 88-88, 88-89, 88-90, 88-91,
88-92, 88-93, 88-94, 88-95, 88-96, 88-97,
[0202] 89-1, 89-2, 89-3, 89-4, 89-5, 89-6, 89-7, 89-8, 89-9, 89-10,
89-11, 89-12, 89-13, 89-14, 89-15, 89-16, 89-17, 89-18, 89-19,
89-20, 89-21, 89-22, 89-23, 89-24, 89-25, 89-26, 89-27, 89-28,
89-29, 89-30, 89-31, 89-32, 89-33, 89-34, 89-35, 89-36, 89-37,
89-38, 89-39, 89-40, 89-41, 89-42, 89-43, 89-44, 89-45, 89-46,
89-47, 89-48, 89-49, 89-50, 89-51, 89-52, 89-53, 89-54, 89-55,
89-56, 89-57, 89-58, 89-59, 89-60, 89-61, 89-62, 89-63, 89-64,
89-65, 89-66, 89-67, 89-68, 89-69, 89-70, 89-71, 89-72, 89-73,
89-74, 89-75, 89-76, 89-77, 89-78, 89-79, 89-80, 89-81, 89-82,
89-83, 89-84, 89-85, 89-86, 89-87, 89-88, 89-89, 89-90, 89-91,
89-92, 89-93, 89-94, 89-95, 89-96, 89-97,
[0203] 90-1, 90-2, 90-3, 90-4, 90-5, 90-6, 90-7, 90-8, 90-9, 90-10,
90-11, 90-12, 90-13, 90-14, 90-15, 90-16, 90-17, 90-18, 90-19,
90-20, 90-21, 90-22, 90-23, 90-24, 90-25, 90-26, 90-27, 90-28,
90-29, 90-30, 90-31, 90-32, 90-33, 90-34, 90-35, 90-36, 90-37,
90-38, 90-39, 90-40, 90-41, 90-42, 90-43, 90-44, 90-45, 90-46,
90-47, 90-48, 90-49, 90-50, 90-51, 90-52, 90-53, 90-54, 90-55,
90-56, 90-57, 90-58, 90-59, 90-60, 90-61, 90-62, 90-63, 90-64,
90-65, 90-66, 90-67, 90-68, 90-69, 90-70, 90-71, 90-72, 90-73,
90-74, 90-75, 90-76, 90-77, 90-78, 90-79, 90-80, 90-81, 90-82,
90-83, 90-84, 90-85, 90-86, 90-87, 90-88, 90-89, 90-90, 90-91,
90-92, 90-93, 90-94, 90-95, 90-96, 90-97,
[0204] 91-1, 91-2, 91-3, 91-4, 91-5, 91-6, 91-7, 91-8, 91-9, 91-10,
91-11, 91-12, 91-13, 91-14, 91-15, 91-16, 91-17, 91-18, 91-19,
91-20, 91-21, 91-22, 91-23, 91-24, 91-25, 91-26, 91-27, 91-28,
91-29, 91-30, 91-31, 91-32, 91-33, 91-34, 91-35, 91-36, 91-37,
91-38, 91-39, 91-40, 91-41, 91-42, 91-43, 91-44, 91-45, 91-46,
91-47, 91-48, 91-49, 91-50, 91-51, 91-52, 91-53, 91-54, 91-55,
91-56, 91-57, 91-58, 91-59, 91-60, 91-61, 91-62, 91-63, 91-64,
91-65, 91-66, 91-67, 91-68, 91-69, 91-70, 91-71, 91-72, 91-73,
91-74, 91-75, 91-76, 91-77, 91-78, 91-79, 91-80, 91-81, 91-82,
91-83, 91-84, 91-85, 91-86, 91-87, 91-88, 91-89, 91-90, 91-91,
91-92, 91-93, 91-94, 91-95, 91-96, 91-97,
[0205] 92-1, 92-2, 92-3, 92-4, 92-5, 92-6, 92-7, 92-8, 92-9, 92-10,
92-11, 92-12, 92-13, 92-14, 92-15, 92-16, 92-17, 92-18, 92-19,
92-20, 92-21, 92-22, 92-23, 92-24, 92-25, 92-26, 92-27, 92-28,
92-29, 92-30, 92-31, 92-32, 92-33, 92-34, 92-35, 92-36, 92-37,
92-38, 92-39, 92-40, 92-41, 92-42, 92-43, 92-44, 92-45, 92-46,
92-47, 92-48, 92-49, 92-50, 92-51, 92-52, 92-53, 92-54, 92-55,
92-56, 92-57, 92-58, 92-59, 92-60, 92-61, 92-62, 92-63, 92-64,
92-65, 92-66, 92-67, 92-68, 92-69, 92-70, 92-71, 92-72, 92-73,
92-74, 92-75, 92-76, 92-77, 92-78, 92-79, 92-80, 92-81, 92-82,
92-83, 92-84, 92-85, 92-86, 92-87, 92-88, 92-89, 92-90, 92-91,
92-92, 92-93, 92-94, 92-95, 92-96, 92-97,
[0206] 93-1, 93-2, 93-3, 93-4, 93-5, 93-6, 93-7, 93-8, 93-9, 93-10,
93-11, 93-12, 93-13, 93-14, 93-15, 93-16, 93-17, 93-18, 93-19,
93-20, 93-21, 93-22, 93-23, 93-24, 93-25, 93-26, 93-27, 93-28,
93-29, 93-30, 93-31, 93-32, 93-33, 93-34, 93-35, 93-36, 93-37,
93-38, 93-39, 93-40, 93-41, 93-42, 93-43, 93-44, 93-45, 93-46,
93-47, 93-48, 93-49, 93-50, 93-51, 93-52, 93-53, 93-54, 93-55,
93-56, 93-57, 93-58, 93-59, 93-60, 93-61, 93-62, 93-63, 93-64,
93-65, 93-66, 93-67, 93-68, 93-69, 93-70, 93-71, 93-72, 93-73,
93-74, 93-75, 93-76, 93-77, 93-78, 93-79, 93-80, 93-81, 93-82,
93-83, 93-84, 93-85, 93-86, 93-87, 93-88, 93-89, 93-90, 93-91,
93-92, 93-93, 93-94, 93-95, 93-96, 93-97,
[0207] 94-1, 94-2, 94-3, 94-4, 94-5, 94-6, 94-7, 94-8, 94-9, 94-10,
94-11, 94-12, 94-13, 94-14, 94-15, 94-16, 94-17, 94-18, 94-19,
94-20, 94-21, 94-22, 94-23, 94-24, 94-25, 94-26, 94-27, 94-28,
94-29, 94-30, 94-31, 94-32, 94-33, 94-34, 94-35, 94-36, 94-37,
94-38, 94-39, 94-40, 94-41, 94-42, 94-43, 94-44, 94-45, 94-46,
94-47, 94-48, 94-49, 94-50, 94-51, 94-52, 94-53, 94-54, 94-55,
94-56, 94-57, 94-58, 94-59, 94-60, 94-61, 94-62, 94-63, 94-64,
94-65, 94-66, 94-67, 94-68, 94-69, 94-70, 94-71, 94-72, 94-73,
94-74, 94-75, 94-76, 94-77, 94-78, 94-79, 94-80, 94-81, 94-82,
94-83, 94-84, 94-85, 94-86, 94-87, 94-88, 94-89, 94-90, 94-91,
94-92, 94-93, 94-94, 94-95, 94-96, 94-97,
[0208] 95-1, 95-2, 95-3, 95-4, 95-5, 95-6, 95-7, 95-8, 95-9, 95-10,
95-11, 95-12, 95-13, 95-14, 95-15, 95-16, 95-17, 95-18, 95-19,
95-20, 95-21, 95-22, 95-23, 95-24, 95-25, 95-26, 95-27, 95-28,
95-29, 95-30, 95-31, 95-32, 95-33, 95-34, 95-35, 95-36, 95-37,
95-38, 95-39, 95-40, 95-41, 95-42, 95-43, 95-44, 95-45, 95-46,
95-47, 95-48, 95-49, 95-50, 95-51, 95-52, 95-53, 95-54, 95-55,
95-56, 95-57, 95-58, 95-59, 95-60, 95-61, 95-62, 95-63, 95-64,
95-65, 95-66, 95-67, 95-68, 95-69, 95-70, 95-71, 95-72, 95-73,
95-74, 95-75, 95-76, 95-77, 95-78, 95-79, 95-80, 95-81, 95-82,
95-83, 95-84, 95-85, 95-86, 95-87, 95-88, 95-89, 95-90, 95-91,
95-92, 95-93, 95-94, 95-95, 95-96, 95-97,
[0209] 96-1, 96-2, 96-3, 96-4, 96-5, 96-6, 96-7, 96-8, 96-9, 96-10,
96-11, 96-12, 96-13, 96-14, 96-15, 96-16, 96-17, 96-18, 96-19,
96-20, 96-21, 96-22, 96-23, 96-24, 96-25, 96-26, 96-27, 96-28,
96-29, 96-30, 96-31, 96-32, 96-33, 96-34, 96-35, 96-36, 96-37,
96-38, 96-39, 96-40, 96-41, 96-42, 96-43, 96-44, 96-45, 96-46,
96-47, 96-48, 96-49, 96-50, 96-51, 96-52, 96-53, 96-54, 96-55,
96-56, 96-57, 96-58, 96-59, 96-60, 96-61, 96-62, 96-63, 96-64,
96-65, 96-66, 96-67, 96-68, 96-69, 96-70, 96-71, 96-72, 96-73,
96-74, 96-75, 96-76, 96-77, 96-78, 96-79, 96-80, 96-81, 96-82,
96-83, 96-84, 96-85, 96-86, 96-87, 96-88, 96-89, 96-90, 96-91,
96-92, 96-93, 96-94, 96-95, 96-96, 96-97,
[0210] 97-1, 97-2, 97-3, 97-4, 97-5, 97-6, 97-7, 97-8, 97-9, 97-10,
97-11, 97-12, 97-13, 97-14, 97-15, 97-16, 97-17, 97-18, 97-19,
97-20, 97-21, 97-22, 97-23, 97-24, 97-25, 97-26, 97-27, 97-28,
97-29, 97-30, 97-31, 97-32, 97-33, 97-34, 97-35, 97-36, 97-37,
97-38, 97-39, 97-40, 97-41, 97-42, 97-43, 97-44, 97-45, 97-46,
97-47, 97-48, 97-49, 97-50, 97-51, 97-52, 97-53, 97-54, 97-55,
97-56, 97-57, 97-58, 97-59, 97-60, 97-61, 97-62, 97-63, 97-64,
97-65, 97-66, 97-67, 97-68, 97-69, 97-70, 97-71, 97-72, 97-73,
97-74, 97-75, 97-76, 97-77, 97-78, 97-79, 97-80, 97-81, 97-82,
97-83, 97-84, 97-85, 97-86, 97-87, 97-88, 97-89, 97-90, 97-91,
97-92, 97-93, 97-94, 97-95, 97-96, 97-97,
[0211] 98-1, 98-2, 98-3, 98-4, 98-5, 98-6, 98-7, 98-8, 98-9, 98-10,
98-11, 98-12, 98-13, 98-14, 98-15, 98-16, 98-17, 98-18, 98-19,
98-20, 98-21, 98-22, 98-23, 98-24, 98-25, 98-26, 98-27, 98-28,
98-29, 98-30, 98-31, 98-32, 98-33, 98-34, 98-35, 98-36, 98-37,
98-38, 98-39, 98-40, 98-41, 98-42, 98-43, 98-44, 98-45, 98-46,
98-47, 98-48, 98-49, 98-50, 98-51, 98-52, 98-53, 98-54, 98-55,
98-56, 98-57, 98-58, 98-59, 98-60, 98-61, 98-62, 98-63, 98-64,
98-65, 98-66, 98-67, 98-68, 98-69, 98-70, 98-71, 98-72, 98-73,
98-74, 98-75, 98-76, 98-77, 98-78, 98-79, 98-80, 98-81, 98-82,
98-83, 98-84, 98-85, 98-86, 98-87, 98-88, 98-89, 98-90, 98-91,
98-92, 98-93, 98-94, 98-95, 98-96, 98-97,
[0212] 99-1, 99-2, 99-3, 99-4, 99-5, 99-6, 99-7, 99-8, 99-9, 99-10,
99-11, 99-12, 99-13, 99-14, 99-15, 99-16, 99-17, 99-18, 99-19,
99-20, 99-21, 99-22, 99-23, 99-24, 99-25, 99-26, 99-27, 99-28,
99-29, 99-30, 99-31, 99-32, 99-33, 99-34, 99-35, 99-36, 99-37,
99-38, 99-39, 99-40, 99-41, 99-42, 99-43, 99-44, 99-45, 99-46,
99-47, 99-48, 99-49, 99-50, 99-51, 99-52, 99-53, 99-54, 99-55,
99-56, 99-57, 99-58, 99-59, 99-60, 99-61, 99-62, 99-63, 99-64,
99-65, 99-66, 99-67, 99-68, 99-69, 99-70, 99-71, 99-72, 99-73,
99-74, 99-75, 99-76, 99-77, 99-78, 99-79, 99-80, 99-81, 99-82,
99-83, 99-84, 99-85, 99-86, 99-87, 99-88, 99-89, 99-90, 99-91,
99-92, 99-93, 99-94, 99-95, 99-96, 99-97,
[0213] 100-1, 100-2, 100-3, 100-4, 100-5, 100-6, 100-7, 100-8,
100-9, 100-10, 100-11, 100-12, 100-13, 100-14, 100-15, 100-16,
100-17, 100-18, 100-19, 100-20, 100-21, 100-22, 100-23, 100-24,
100-25, 100-26, 100-27, 100-28, 100-29, 100-30, 100-31, 100-32,
100-33, 100-34, 100-35, 100-36, 100-37, 100-38, 100-39, 100-40,
100-41, 100-42, 100-43, 100-44, 100-45, 100-46, 100-47, 100-48,
100-49, 100-50, 100-51, 100-52, 100-53, 100-54, 100-55, 100-56,
100-57, 100-58, 100-59, 100-60, 100-61, 100-62, 100-63, 100-64,
100-65, 100-66, 100-67, 100-68, 100-69, 100-70, 100-71, 100-72,
100-73, 100-74, 100-75, 100-76, 100-77, 100-78, 100-79, 100-80,
100-81, 100-82, 100-83, 100-84, 100-85, 100-86, 100-87, 100-88,
100-89, 100-90, 100-91, 100-92, 100-93, 100-94, 100-95, 100-96,
100-97,
[0214] 101-1, 101-2, 101-3, 101-4, 101-5, 101-6, 101-7, 101-8,
101-9, 101-10, 101-11, 101-12, 101-13, 101-14, 101-15, 101-16,
101-17, 101-18, 101-19, 101-20, 101-21, 101-22, 101-23, 101-24,
101-25, 101-26, 101-27, 101-28, 101-29, 101-30, 101-31, 101-32,
101-33, 101-34, 101-35, 101-36, 101-37, 101-38, 101-39, 101-40,
101-41, 101-42, 101-43, 101-44, 101-45, 101-46, 101-47, 101-48,
101-49, 101-50, 101-51, 101-52, 101-53, 101-54, 101-55, 101-56,
101-57, 101-58, 101-59, 101-60, 101-61, 101-62, 101-63, 101-64,
101-65, 101-66, 101-67, 101-68, 101-69, 101-70, 101-71, 101-72,
101-73, 101-74, 101-75, 101-76, 101-77, 101-78, 101-79, 101-80,
101-81, 101-82, 101-83, 101-84, 101-85, 101-86, 101-87, 101-88,
101-89, 101-90, 101-91, 101-92, 101-93, 101-94, 101-95, 101-96,
101-97,
[0215] 102-1, 102-2, 102-3, 102-4, 102-5, 102-6, 102-7, 102-8,
102-9, 102-10, 102-11, 102-12, 102-13, 102-14, 102-15, 102-16,
102-17, 102-18, 102-19, 102-20, 102-21, 102-22, 102-23, 102-24,
102-25, 102-26, 102-27, 102-28, 102-29, 102-30, 102-31, 102-32,
102-33, 102-34, 102-35, 102-36, 102-37, 102-38, 102-39, 102-40,
102-41, 102-42, 102-43, 102-44, 102-45, 102-46, 102-47, 102-48,
102-49, 102-50, 102-51, 102-52, 102-53, 102-54, 102-55, 102-56,
102-57, 102-58, 102-59, 102-60, 102-61, 102-62, 102-63, 102-64,
102-65, 102-66, 102-67, 102-68, 102-69, 102-70, 102-71, 102-72,
102-73, 102-74, 102-75, 102-76, 102-77, 102-78, 102-79, 102-80,
102-81, 102-82, 102-83, 102-84, 102-85, 102-86, 102-87, 102-88,
102-89, 102-90, 102-91, 102-92, 102-93, 102-94, 102-95, 102-96,
102-97,
[0216] 103-1, 103-2, 103-3, 103-4, 103-5, 103-6, 103-7, 103-8,
103-9, 103-10, 103-11, 103-12, 103-13, 103-14, 103-15, 103-16,
103-17, 103-18, 103-19, 103-20, 103-21, 103-22, 103-23, 103-24,
103-25, 103-26, 103-27, 103-28, 103-29, 103-30, 103-31, 103-32,
103-33, 103-34, 103-35, 103-36, 103-37, 103-38, 103-39, 103-40,
103-41, 103-42, 103-43, 103-44, 103-45, 103-46, 103-47, 103-48,
103-49, 103-50, 103-51, 103-52, 103-53, 103-54, 103-55, 103-56,
103-57, 103-58, 103-59, 103-60, 103-61, 103-62, 103-63, 103-64,
103-65, 103-66, 103-67, 103-68, 103-69, 103-70, 103-71, 103-72,
103-73, 103-74, 103-75, 103-76, 103-77, 103-78, 103-79, 103-80,
103-81, 103-82, 103-83, 103-84, 103-85, 103-86, 103-87, 103-88,
103-89, 103-90, 103-91, 103-92, 103-93, 103-94, 103-95, 103-96,
103-97,
[0217] 104-1, 104-2, 104-3, 104-4, 104-5, 104-6, 104-7, 104-8,
104-9, 104-10, 104-11, 104-12, 104-13, 104-14, 104-15, 104-16,
104-17, 104-18, 104-19, 104-20, 104-21, 104-22, 104-23, 104-24,
104-25, 104-26, 104-27, 104-28, 104-29, 104-30, 104-31, 104-32,
104-33, 104-34, 104-35, 104-36, 104-37, 104-38, 104-39, 104-40,
104-41, 104-42, 104-43, 104-44, 104-45, 104-46, 104-47, 104-48,
104-49, 104-50, 104-51, 104-52, 104-53, 104-54, 104-55, 104-56,
104-57, 104-58, 104-59, 104-60, 104-61, 104-62, 104-63, 104-64,
104-65, 104-66, 104-67, 104-68, 104-69, 104-70, 104-71, 104-72,
104-73, 104-74, 104-75, 104-76, 104-77, 104-78, 104-79, 104-80,
104-81, 104-82, 104-83, 104-84, 104-85, 104-86, 104-87, 104-88,
104-89, 104-90, 104-91, 104-92, 104-93, 104-94, 104-95, 104-96,
104-97,
[0218] 105-1, 105-2, 105-3, 105-4, 105-5, 105-6, 105-7, 105-8,
105-9, 105-10, 105-11, 105-12, 105-13, 105-14, 105-15, 105-16,
105-17, 105-18, 105-19, 105-20, 105-21, 105-22, 105-23, 105-24,
105-25, 105-26, 105-27, 105-28, 105-29, 105-30, 105-31, 105-32,
105-33, 105-34, 105-35, 105-36, 105-37, 105-38, 105-39, 105-40,
105-41, 105-42, 105-43, 105-44, 105-45, 105-46, 105-47, 105-48,
105-49, 105-50, 105-51, 105-52, 105-53, 105-54, 105-55, 105-56,
105-57, 105-58, 105-59, 105-60, 105-61, 105-62, 105-63, 105-64,
105-65, 105-66, 105-67, 105-68, 105-69, 105-70, 105-71, 105-72,
105-73, 105-74, 105-75, 105-76, 105-77, 105-78, 105-79, 105-80,
105-81, 105-82, 105-83, 105-84, 105-85, 105-86, 105-87, 105-88,
105-89, 105-90, 105-91, 105-92, 105-93, 105-94, 105-95, 105-96,
105-97,
[0219] 106-1, 106-2, 106-3, 106-4, 106-5, 106-6, 106-7, 106-8,
106-9, 106-10, 106-11, 106-12, 106-13, 106-14, 106-15, 106-16,
106-17, 106-18, 106-19, 106-20, 106-21, 106-22, 106-23, 106-24,
106-25, 106-26, 106-27, 106-28, 106-29, 106-30, 106-31, 106-32,
106-33, 106-34, 106-35, 106-36, 106-37, 106-38, 106-39, 106-40,
106-41, 106-42, 106-43, 106-44, 106-45, 106-46, 106-47, 106-48,
106-49, 106-50, 106-51, 106-52, 106-53, 106-54, 106-55, 106-56,
106-57, 106-58, 106-59, 106-60, 106-61, 106-62, 106-63, 106-64,
106-65, 106-66, 106-67, 106-68, 106-69, 106-70, 106-71, 106-72,
106-73, 106-74, 106-75, 106-76, 106-77, 106-78, 106-79, 106-80,
106-81, 106-82, 106-83, 106-84, 106-85, 106-86, 106-87, 106-88,
106-89, 106-90, 106-91, 106-92, 106-93, 106-94, 106-95, 106-96,
106-97,
[0220] 107-1, 107-2, 107-3, 107-4, 107-5, 107-6, 107-7, 107-8,
107-9, 107-10, 107-11, 107-12, 107-13, 107-14, 107-15, 107-16,
107-17, 107-18, 107-19, 107-20, 107-21, 107-22, 107-23, 107-24,
107-25, 107-26, 107-27, 107-28, 107-29, 107-30, 107-31, 107-32,
107-33, 107-34, 107-35, 107-36, 107-37, 107-38, 107-39, 107-40,
107-41, 107-42, 107-43, 107-44, 107-45, 107-46, 107-47, 107-48,
107-49, 107-50, 107-51, 107-52, 107-53, 107-54, 107-55, 107-56,
107-57, 107-58, 107-59, 107-60, 107-61, 107-62, 107-63, 107-64,
107-65, 107-66, 107-67, 107-68, 107-69, 107-70, 107-71, 107-72,
107-73, 107-74, 107-75, 107-76, 107-77, 107-78, 107-79, 107-80,
107-81, 107-82, 107-83, 107-84, 107-85, 107-86, 107-87, 107-88,
107-89, 107-90, 107-91, 107-92, 107-93, 107-94, 107-95, 107-96,
107-97,
[0221] 108-1, 108-2, 108-3, 108-4, 108-5, 108-6, 108-7, 108-8,
108-9, 108-10, 108-11, 108-12, 108-13, 108-14, 108-15, 108-16,
108-17, 108-18, 108-19, 108-20, 108-21, 108-22, 108-23, 108-24,
108-25, 108-26, 108-27, 108-28, 108-29, 108-30, 108-31, 108-32,
108-33, 108-34, 108-35, 108-36, 108-37, 108-38, 108-39, 108-40,
108-41, 108-42, 108-43, 108-44, 108-45, 108-46, 108-47, 108-48,
108-49, 108-50, 108-51, 108-52, 108-53, 108-54, 108-55, 108-56,
108-57, 108-58, 108-59, 108-60, 108-61, 108-62, 108-63, 108-64,
108-65, 108-66, 108-67, 108-68, 108-69, 108-70, 108-71, 108-72,
108-73, 108-74, 108-75, 108-76, 108-77, 108-78, 108-79, 108-80,
108-81, 108-82, 108-83, 108-84, 108-85, 108-86, 108-87, 108-88,
108-89, 108-90, 108-91, 108-92, 108-93, 108-94, 108-95, 108-96,
108-97,
[0222] 109-1, 109-2, 109-3, 109-4, 109-5, 109-6, 109-7, 109-8,
109-9, 109-10, 109-11, 109-12, 109-13, 109-14, 109-15, 109-16,
109-17, 109-18, 109-19, 109-20, 109-21, 109-22, 109-23, 109-24,
109-25, 109-26, 109-27, 109-28, 109-29, 109-30, 109-31, 109-32,
109-33, 109-34, 109-35, 109-36, 109-37, 109-38, 109-39, 109-40,
109-41, 109-42, 109-43, 109-44, 109-45, 109-46, 109-47, 109-48,
109-49, 109-50, 109-51, 109-52, 109-53, 109-54, 109-55, 109-56,
109-57, 109-58, 109-59, 109-60, 109-61, 109-62, 109-63, 109-64,
109-65, 109-66, 109-67, 109-68, 109-69, 109-70, 109-71, 109-72,
109-73, 109-74, 109-75, 109-76, 109-77, 109-78, 109-79, 109-80,
109-81, 109-82, 109-83, 109-84, 109-85, 109-86, 109-87, 109-88,
109-89, 109-90, 109-91, 109-92, 109-93, 109-94, 109-95, 109-96,
109-97,
[0223] 110-1, 110-2, 110-3, 110-4, 110-5, 110-6, 110-7, 110-8,
110-9, 110-10, 110-11, 110-12, 110-13, 110-14, 110-15, 110-16,
110-17, 110-18, 110-19, 110-20, 110-21, 110-22, 110-23, 110-24,
110-25, 110-26, 110-27, 110-28, 110-29, 110-30, 110-31, 110-32,
110-33, 110-34, 110-35, 110-36, 110-37, 110-38, 110-39, 110-40,
110-41, 110-42, 110-43, 110-44, 110-45, 110-46, 110-47, 110-48,
110-49, 110-50, 110-51, 110-52, 110-53, 110-54, 110-55, 110-56,
110-57, 110-58, 110-59, 110-60, 110-61, 110-62, 110-63, 110-64,
110-65, 110-66, 110-67, 110-68,.110-69, 110-70, 110-71, 110-72,
110-73, 110-74, 110-75, 110-76, 110-77, 110-78, 110-79, 110-80,
110-81, 110-82, 110-83, 110-84, 110-85, 110-86, 110-87, 110-88,
110-89, 110-90, 110-91, 110-92, 110-93, 110-94, 110-95, 110-96,
110-97,
[0224] 111-1, 111-2, 111-3, 111-4, 111-5, 111-6, 111-7, 111-8,
111-9, 111-10, 111-11, 111-12, 111-13, 111-14, 111-15, 111-16,
111-17, 111-18, 111-19, 111-20, 111-21, 111-22, 111-23, 111-24,
111-25, 111-26, 111-27, 111-28, 111-29, 111-30, 111-31, 111-32,
111-33, 111-34, 111-35, 111-36, 111-37, 111-38, 111-39, 111-40,
111-41, 111-42, 111-43, 111-44, 111-45, 111-46, 111-47, 111-48,
111-49, 111-50, 111-51, 111-52, 111-53, 111-54, 111-55, 111-56,
111-57, 111-58, 111-59, 111-60, 111-61, 111-62, 111-63, 111-64,
111-65, 111-66, 111-67, 111-68, 111-69, 111-70, 111-71, 111-72,
111-73, 111-74, 111-75, 111-76, 111-77, 111-78, 111-79, 111-80,
111-81, 111-82, 111-83, 111-84, 111-85, 111-86, 111-87, 111-88,
111-89, 111-90, 111-91, 111-92, 111-93, 111-94, 111-95, 111-96,
111-97,
[0225] 112-1, 112-2, 112-3, 112-4, 112-5, 112-6, 112-7, 112-8,
112-9, 112-10, 112-11, 112-12, 112-13, 112-14, 112-15, 112-16,
112-17, 112-18, 112-19, 112-20, 112-21, 112-22, 112-23, 112-24,
112-25, 112-26, 112-27, 112-28, 112-29, 112-30, 112-31, 112-32,
112-33, 112-34, 112-35, 112-36, 112-37, 112-38, 112-39, 112-40,
112-41, 112-42, 112-43, 112-44, 112-45, 112-46, 112-47, 112-48,
112-49, 112-50, 112-51, 112-52, 112-53, 112-54, 112-55, 112-56,
112-57, 112-58, 112-59, 112-60, 112-61, 112-62, 112-63, 112-64,
112-65, 112-66, 112-67, 112-68, 112-69, 112-70, 112-71, 112-72,
112-73, 112-74, 112-75, 112-76, 112-77, 112-78, 112-79, 112-80,
112-81, 112-82, 112-83, 112-84, 112-85, 112-86, 112-87, 112-88,
112-89, 112-90, 112-91, 112-92, 112-93, 112-94, 112-95, 112-96,
112-97,
[0226] 113-1, 113-2, 113-3, 113-4, 113-5, 113-6, 113-7, 113-8,
113-9, 113-10, 113-11, 113-12, 113-13, 113-14, 113-15, 113-16,
113-17, 113-18, 113-19, 113-20, 113-21, 113-22, 113-23, 113-24,
113-25, 113-26, 113-27, 113-28, 113-29, 113-30, 113-31, 113-32,
113-33, 113-34, 113-35, 113-36, 113-37, 113-38, 113-39, 113-40,
113-41, 113-42, 113-43, 113-44, 113-45, 113-46, 113-47, 113-48,
113-49, 113-50, 113-51, 113-52, 113-53, 113-54, 113-55, 113-56,
113-57, 113-58, 113-59, 113-60, 113-61, 113-62, 113-63, 113-64,
113-65, 113-66, 113-67, 113-68, 113-69, 113-70, 113-71, 113-72,
113-73, 113-74, 113-75, 113-76, 113-77, 113-78, 113-79, 113-80,
113-81, 113-82, 113-83, 113-84, 113-85, 113-86, 113-87, 113-88,
113-89, 113-90, 113-91, 113-92, 113-93, 113-94, 113-95, 113-96,
113-97,
[0227] 114-1, 114-2, 114-3, 114-4, 114-5, 114-6, 114-7, 114-8,
114-9, 114-10, 114-11, 114-12, 114-13, 114-14, 114-15, 114-16,
114-17, 114-18, 114-19, 114-20, 114-21, 114-22, 114-23, 114-24,
114-25, 114-26, 114-27, 114-28, 114-29, 114-30, 114-31, 114-32,
114-33, 114-34, 114-35, 114-36, 114-37, 114-38, 114-39, 114-40,
114-41, 114-42, 114-43, 114-44, 114-45, 114-46, 114-47, 114-48,
114-49, 114-50, 114-51, 114-52, 114-53, 114-54, 114-55, 114-56,
114-57, 114-58, 114-59, 114-60, 114-61, 114-62, 114-63, 114-64,
114-65, 114-66, 114-67, 114-68, 114-69, 114-70, 114-71, 114-72,
114-73, 114-74, 114-75, 114-76, 114-77, 114-78, 114-79, 114-80,
114-81, 114-82, 114-83, 114-84, 114-85, 114-86, 114-87, 114-88,
114-89, 114-90, 114-91, 114-92, 114-93, 114-94, 114-95, 114-96,
114-97,
[0228] 115-1, 115-2, 115-3, 115-4, 115-5, 115-6, 115-7, 115-8,
115-9, 115-10, 115-11, 115-12, 115-13, 115-14, 115-15, 115-16,
115-17, 115-18, 115-19, 115-20, 115-21, 115-22, 115-23, 115-24,
115-25, 115-26, 115-27, 115-28, 115-29, 115-30, 115-31, 115-32,
115-33, 115-34, 115-35, 115-36, 115-37, 115-38, 115-39, 115-40,
115-41, 115-42, 115-43, 115-44, 115-45, 115-46, 115-47, 115-48,
115-49, 115-50, 115-51, 115-52, 115-53, 115-54, 115-55, 115-56,
115-57, 115-58, 115-59, 115-60, 115-61, 115-62, 115-63, 115-64,
115-65, 115-66, 115-67, 115-68, 115-69, 115-70, 115-71, 115-72,
115-73, 115-74, 115-75, 115-76, 115-77, 115-78, 115-79, 115-80,
115-81, 115-82, 115-83, 115-84, 115-85, 115-86, 115-87, 115-88,
115-89, 115-90, 115-91, 115-92, 115-93, 115-94, 115-95, 115-96,
115-97,
[0229] 116-1, 116-2, 116-3, 116-4, 116-5, 116-6, 116-7, 116-8,
116-9, 116-10, 116-11, 116-12, 116-13, 116-14, 116-15, 116-16,
116-17, 116-18, 116-19, 116-20, 116-21, 116-22, 116-23, 116-24,
116-25, 116-26, 116-27, 116-28, 116-29, 116-30, 116-31, 116-32,
116-33, 116-34, 116-35, 116-36, 116-37, 116-38, 116-39, 116-40,
116-41, 116-42, 116-43, 116-44, 116-45, 116-46, 116-47, 116-48,
116-49, 116-50, 116-51, 116-52, 116-53, 116-54, 116-55, 116-56,
116-57, 116-58, 116-59, 116-60, 116-61, 116-62, 116-63, 116-64,
116-65, 116-66, 116-67, 116-68, 116-69, 116-70, 116-71, 116-72,
116-73, 116-74, 116-75, 116-76, 116-77, 116-78, 116-79, 116-80,
116-81, 116-82, 116-83, 116-84, 116-85, 116-86, 116-87, 116-88,
116-89, 116-90, 116-91, 116-92, 116-93, 116-94, 116-95, 116-96,
116-97,
[0230] 117-1, 117-2, 117-3, 117-4, 117-5, 117-6, 117-7, 117-8,
117-9, 117-10, 117-11, 117-12, 117-13, 117-14, 117-15, 117-16,
117-17, 117-18, 117-19, 117-20, 117-21, 117-22, 117-23, 117-24,
117-25, 117-26, 117-27, 117-28, 117-29, 117-30, 117-31, 117-32,
117-33, 117-34, 117-35, 117-36, 117-37, 117-38, 117-39, 117-40,
117-41, 117-42, 117-43, 117-44, 117-45, 117-46, 117-47, 117-48,
117-49, 117-50, 117-51, 117-52, 117-53, 117-54, 117-55, 117-56,
117-57, 117-58, 117-59, 117-60, 117-61, 117-62, 117-63, 117-64,
117-65, 117-66, 117-67, 117-68, 117-69, 117-70, 117-71, 117-72,
117-73, 117-74, 117-75, 117-76, 117-77, 117-78, 117-79, 117-80,
117-81, 117-82, 117-83, 117-84, 117-85, 117-86, 117-87, 117-88,
117-89, 117-90, 117-91, 117-92, 117-93, 117-94, 117-95, 117-96,
117-97,
[0231] 118-1, 118-2, 118-3, 118-4, 118-5, 118-6, 118-7, 118-8,
118-9, 118-10, 118-11, 118-12, 118-13, 118-14, 118-15, 118-16,
118-17, 118-18, 118-19, 118-20, 118-21, 118-22, 118-23, 118-24,
118-25, 118-26, 118-27, 118-28, 118-29, 118-30, 118-31, 118-32,
118-33, 118-34, 118-35, 118-36, 118-37, 118-38, 118-39, 118-40,
118-41, 118-42, 118-43, 118-44, 118-45, 118-46, 118-47, 118-48,
118-49, 118-50, 118-51, 118-52, 118-53, 118-54, 118-55, 118-56,
118-57, 118-58, 118-59, 118-60, 118-61, 118-62, 118-63, 118-64,
118-65, 118-66, 118-67, 118-68, 118-69, 118-70, 118-71, 118-72,
118-73, 118-74, 118-75, 118-76, 118-77, 118-78, 118-79, 118-80,
118-81, 118-82, 118-83, 118-84, 118-85, 118-86, 118-87, 118-88,
118-89, 118-90, 118-91, 118-92, 118-93, 118-94, 118-95, 118-96,
118-97,
[0232] 119-1, 119-2, 119-3, 119-4, 119-5, 119-6, 119-7, 119-8,
119-9, 119-10, 119-11, 119-12, 119-13, 119-14, 119-15, 119-16,
119-17, 119-18, 119-19, 119-20, 119-21, 119-22, 119-23, 119-24,
119-25, 119-26, 119-27, 119-28, 119-29, 119-30, 119-31, 119-32,
119-33, 119-34, 119-35, 119-36, 119-37, 119-38, 119-39, 119-40,
119-41, 119-42, 119-43, 119-44, 119-45, 119-46, 119-47, 119-48,
119-49, 119-50, 119-51, 119-52, 119-53, 119-54, 119-55, 119-56,
119-57, 119-58, 119-59, 119-60, 119-61, 119-62, 119-63, 119-64,
119-65, 119-66, 119-67, 119-68, 119-69, 119-70, 119-71, 119-72,
119-73, 119-74, 119-75, 119-76, 119-77, 119-78, 119-79, 119-80,
119-81, 119-82, 119-83, 119-84, 119-85, 119-86, 119-87, 119-88,
119-89, 119-90, 119-91, 119-92, 119-93, 119-94, 119-95, 119-96,
119-97,
[0233] 120-1, 120-2, 120-3, 120-4, 120-5, 120-6, 120-7, 120-8,
120-9, 120-10, 120-11, 120-12, 120-13, 120-14, 120-15, 120-16,
120-17, 120-18, 120-19, 120-20, 120-21, 120-22, 120-23, 120-24,
120-25, 120-26, 120-27, 120-28, 120-29, 120-30, 120-31, 120-32,
120-33, 120-34, 120-35, 120-36, 120-37, 120-38, 120-39, 120-40,
120-41, 120-42, 120-43, 120-44, 120-45, 120-46, 120-47, 120-48,
120-49, 120-50, 120-51, 120-52, 120-53, 120-54, 120-55, 120-56,
120-57, 120-58, 120-59, 120-60, 120-61, 120-62, 120-63, 120-64,
120-65, 120-66, 120-67, 120-68, 120-69, 120-70, 120-71, 120-72,
120-73, 120-74, 120-75, 120-76, 120-77, 120-78, 120-79, 120-80,
120-81, 120-82, 120-83, 120-84, 120-85, 120-86, 120-87, 120-88,
120-89, 120-90, 120-91, 120-92, 120-93, 120-94, 120-95, 120-96,
120-97,
[0234] 121-1, 121-2, 121-3, 121-4, 121-5, 121-6, 121-7, 121-8,
121-9, 121-10, 121-11, 121-12, 121-13, 121-14, 121-15, 121-16,
121-17, 121-18, 121-19, 121-20, 121-21, 121-22, 121-23, 121-24,
121-25, 121-26, 121-27, 121-28, 121-29, 121-30, 121-31, 121-32,
121-33, 121-34, 121-35, 121-36, 121-37, 121-38, 121-39, 121-40,
121-41, 121-42, 121-43, 121-44, 121-45, 121-46, 121-47, 121-48,
121-49, 121-50, 121-51, 121-52, 121-53, 121-54, 121-55, 121-56,
121-57, 121-58, 121-59, 121-60, 121-61, 121-62, 121-63, 121-64,
121-65, 121-66, 121-67, 121-68, 121-69, 121-70, 121-71, 121-72,
121-73, 121-74, 121-75, 121-76, 121-77, 121-78, 121-79, 121-80,
121-81, 121-82, 121-83, 121-84, 121-85, 121-86, 121-87, 121-88,
121-89, 121-90, 121-91, 121-92, 121-93, 121-94, 121-95, 121-96,
121-97,
[0235] 122-1, 122-2, 122-3, 122-4, 122-5, 122-6, 122-7, 122-8,
122-9, 122-10, 122-11, 122-12, 122-13, 122-14, 122-15, 122-16,
122-17, 122-18, 122-19, 122-20, 122-21, 122-22, 122-23, 122-24,
122-25, 122-26, 122-27, 122-28, 122-29, 122-30, 122-31, 122-32,
122-33, 122-34, 122-35, 122-36, 122-37, 122-38, 122-39, 122-40,
122-41, 122-42, 122-43, 122-44, 122-45, 122-46, 122-47, 122-48,
122-49, 122-50, 122-51, 122-52, 122-53, 122-54, 122-55, 122-56,
122-57, 122-58, 122-59, 122-60, 122-61, 122-62, 122-63, 122-64,
122-65, 122-66, 122-67, 122-68, 122-69, 122-70, 122-71, 122-72,
122-73, 122-74, 122-75, 122-76, 122-77, 122-78, 122-79, 122-80,
122-81, 122-82, 122-83, 122-84, 122-85, 122-86, 122-87, 122-88,
122-89, 122-90, 122-91, 122-92, 122-93, 122-94, 122-95, 122-96,
122-97,
[0236] 123-1, 123-2, 123-3, 123-4, 123-5, 123-6, 123-7, 123-8,
123-9, 123-10, 123-11, 123-12, 123-13, 123-14, 123-15, 123-16,
123-17, 123-18, 123-19, 123-20, 123-21, 123-22, 123-23, 123-24,
123-25, 123-26, 123-27, 123-28, 123-29, 123-30, 123-31, 123-32,
123-33, 123-34, 123-35, 123-36, 123-37, 123-38, 123-39, 123-40,
123-41, 123-42, 123-43, 123-44, 123-45, 123-46, 123-47, 123-48,
123-49, 123-50, 123-51, 123-52, 123-53, 123-54, 123-55, 123-56,
123-57, 123-58, 123-59, 123-60, 123-61, 123-62, 123-63, 123-64,
123-65, 123-66, 123-67, 123-68, 123-69, 123-70, 123-71, 123-72,
123-73, 123-74, 123-75, 123-76, 123-77, 123-78, 123-79, 123-80,
123-81, 123-82, 123-83, 123-84, 123-85, 123-86, 123-87, 123-88,
123-89, 123-90, 123-91, 123-92, 123-93, 123-94, 123-95, 123-96,
123-97,
[0237] 124-1, 124-2, 124-3, 124-4, 124-5, 124-6, 124-7, 124-8,
124-9, 124-10, 124-11, 124-12, 124-13, 124-14, 124-15, 124-16,
124-17, 124-18, 124-19, 124-20, 124-21, 124-22, 124-23, 124-24,
124-25, 124-26, 124-27, 124-28, 124-29, 124-30, 124-31, 124-32,
124-33, 124-34, 124-35, 124-36, 124-37, 124-38, 124-39, 124-40,
124-41, 124-42, 124-43, 124-44, 124-45, 124-46, 124-47, 124-48,
124-49, 124-50, 124-51, 124-52, 124-53, 124-54, 124-55, 124-56,
124-57, 124-58, 124-59, 124-60, 124-61, 124-62, 124-63, 124-64,
124-65, 124-66, 124-67, 124-68, 124-69, 124-70, 124-71, 124-72,
124-73, 124-74, 124-75, 124-76, 124-77, 124-78, 124-79, 124-80,
124-81, 124-82, 124-83, 124-84, 124-85, 124-86, 124-87, 124-88,
124-89, 124-90, 124-91, 124-92, 124-93, 124-94, 124-95, 124-96,
124-97,
[0238] 125-1, 125-2, 125-3, 125-4, 125-5, 125-6, 125-7, 125-8,
125-9, 125-10, 125-11, 125-12, 125-13, 125-14, 125-15, 125-16,
125-17, 125-18, 125-19, 125-20, 125-21, 125-22, 125-23, 125-24,
125-25, 125-26, 125-27, 125-28, 125-29, 125-30, 125-31, 125-32,
125-33, 125-34, 125-35, 125-36, 125-37, 125-38, 125-39, 125-40,
125-41, 125-42, 125-43, 125-44, 125-45, 125-46, 125-47, 125-48,
125-49, 125-50, 125-51, 125-52, 125-53, 125-54, 125-55, 125-56,
125-57, 125-58, 125-59, 125-60, 125-61, 125-62, 125-63, 125-64,
125-65, 125-66, 125-67, 125-68, 125-69, 125-70, 125-71, 125-72,
125-73, 125-74, 125-75, 125-76, 125-77, 125-78, 125-79, 125-80,
125-81, 125-82, 125-83, 125-84, 125-85, 125-86, 125-87, 125-88,
125-89, 125-90, 125-91, 125-92, 125-93, 125-94, 125-95, 125-96,
125-97,
[0239] 126-1, 126-2, 126-3, 126-4, 126-5, 126-6, 126-7, 126-8,
126-9, 126-10, 126-11, 126-12, 126-13, 126-14, 126-15, 126-16,
126-17, 126-18, 126-19, 126-20, 126-21, 126-22, 126-23, 126-24,
126-25, 126-26, 126-27, 126-28, 126-29, 126-30, 126-31, 126-32,
126-33, 126-34, 126-35, 126-36, 126-37, 126-38, 126-39, 126-40,
126-41, 126-42, 126-43, 126-44, 126-45, 126-46, 126-47, 126-48,
126-49, 126-50, 126-51, 126-52, 126-53, 126-54, 126-55, 126-56,
126-57, 126-58, 126-59, 126-60, 126-61, 126-62, 126-63, 126-64,
126-65, 126-66, 126-67, 126-68, 126-69, 126-70, 126-71, 126-72,
126-73, 126-74, 126-75, 126-76, 126-77, 126-78, 126-79, 126-80,
126-81, 126-82, 126-83, 126-84, 126-85, 126-86, 126-87, 126-88,
126-89, 126-90, 126-91, 126-92, 126-93, 126-94, 126-95, 126-96,
126-97,
[0240] 127-1, 127-2, 127-3, 127-4, 127-5, 127-6, 127-7, 127-8,
127-9, 127-10, 127-11, 127-12, 127-13, 127-14, 127-15, 127-16,
127-17, 127-18, 127-19, 127-20, 127-21, 127-22, 127-23, 127-24,
127-25, 127-26, 127-27, 127-28, 127-29, 127-30, 127-31, 127-32,
127-33, 127-34, 127-35, 127-36, 127-37, 127-38, 127-39, 127-40,
127-41, 127-42, 127-43, 127-44, 127-45, 127-46, 127-47, 127-48,
127-49, 127-50, 127-51, 127-52, 127-53, 127-54, 127-55, 127-56,
127-57, 127-58, 127-59, 127-60, 127-61, 127-62, 127-63, 127-64,
127-65, 127-66, 127-67, 127-68, 127-69, 127-70, 127-71, 127-72,
127-73, 127-74, 127-75, 127-76, 127-77, 127-78, 127-79, 127-80,
127-81, 127-82, 127-83, 127-84, 127-85, 127-86, 127-87, 127-88,
127-89, 127-90, 127-91, 127-92, 127-93, 127-94, 127-95, 127-96,
127-97,
[0241] 128-1, 128-2, 128-3, 128-4, 128-5, 128-6, 128-7, 128-8,
128-9, 128-10, 128-11, 128-12, 128-13, 128-14, 128-15, 128-16,
128-17, 128-18, 128-19, 128-20, 128-21, 128-22, 128-23, 128-24,
128-25, 128-26, 128-27, 128-28, 128-29, 128-30, 128-31, 128-32,
128-33, 128-34, 128-35, 128-36, 128-37, 128-38, 128-39, 128-40,
128-41, 128-42, 128-43, 128-44, 128-45, 128-46, 128-47, 128-48,
128-49, 128-50, 128-51, 128-52, 128-53, 128-54, 128-55, 128-56,
128-57, 128-58, 128-59, 128-60, 128-61, 128-62, 128-63, 128-64,
128-65, 128-66, 128-67, 128-68, 128-69, 128-70, 128-71, 128-72,
128-73, 128-74, 128-75, 128-76, 128-77, 128-78, 128-79, 128-80,
128-81, 128-82, 128-83, 128-84, 128-85, 128-86, 128-87, 128-88,
128-89, 128-90, 128-91, 128-92, 128-93, 128-94, 128-95, 128-96,
128-97,
[0242] 129-1, 129-2, 129-3, 129-4, 129-5, 129-6, 129-7, 129-8,
129-9, 129-10, 129-11, 129-12, 129-13, 129-14, 129-15, 129-16,
129-17, 129-18, 129-19, 129-20, 129-21, 129-22, 129-23, 129-24,
129-25, 129-26, 129-27, 129-28, 129-29, 129-30, 129-31, 129-32,
129-33, 129-34, 129-35, 129-36, 129-37, 129-38, 129-39, 129-40,
129-41, 129-42, 129-43, 129-44, 129-45, 129-46, 129-47, 129-48,
129-49, 129-50, 129-51, 129-52, 129-53, 129-54, 129-55, 129-56,
129-57, 129-58, 129-59, 129-60, 129-61, 129-62, 129-63, 129-64,
129-65, 129-66, 129-67, 129-68, 129-69, 129-70, 129-71, 129-72,
129-73, 129-74, 129-75, 129-76, 129-77, 129-78, 129-79, 129-80,
129-81, 129-82, 129-83, 129-84, 129-85, 129-86, 129-87, 129-88,
129-89, 129-90, 129-91, 129-92, 129-93, 129-94, 129-95, 129-96,
129-97,
[0243] 130-1, 130-2, 130-3, 130-4, 130-5, 130-6, 130-7, 130-8,
130-9, 130-10, 130-11, 130-12, 130-13, 130-14, 130-15, 130-16,
130-17, 130-18, 130-19, 130-20, 130-21, 130-22, 130-23, 130-24,
130-25, 130-26, 130-27, 130-28, 130-29, 130-30, 130-31, 130-32,
130-33, 130-34, 130-35, 130-36, 130-37, 130-38, 130-39, 130-40,
130-41, 130-42, 130-43, 130-44, 130-45, 130-46, 130-47, 130-48,
130-49, 130-50, 130-51, 130-52, 130-53, 130-54, 130-55, 130-56,
130-57, 130-58, 130-59, 130-60, 130-61, 130-62, 130-63, 130-64,
130-65, 130-66, 130-67, 130-68, 130-69, 130-70, 130-71, 130-72,
130-73, 130-74, 130-75, 130-76, 130-77, 130-78, 130-79, 130-80,
130-81, 130-82, 130-83, 130-84, 130-85, 130-86, 130-87, 130-88,
130-89, 130-90, 130-91, 130-92, 130-93, 130-94, 130-95, 130-96,
130-97,
[0244] 131-1, 131-2, 131-3, 131-4, 131-5, 131-6, 131-7, 131-8,
131-9, 131-10, 131-11, 131-12, 131-13, 131-14, 131-15, 131-16,
131-17, 131-18, 131-19, 131-20, 131-21, 131-22, 131-23, 131-24,
131-25, 131-26, 131-27, 131-28, 131-29, 131-30, 131-31, 131-32,
131-33, 131-34, 131-35, 131-36, 131-37, 131-38, 131-39, 131-40,
131-41, 131-42, 131-43, 131-44, 131-45, 131-46, 131-47, 131-48,
131-49, 131-50, 131-51, 131-52, 131-53, 131-54, 131-55, 131-56,
131-57, 131-58, 131-59, 131-60, 131-61, 131-62, 131-63, 131-64,
131-65, 131-66, 131-67, 131-68, 131-69, 131-70, 131-71, 131-72,
131-73, 131-74, 131-75, 131-76, 131-77, 131-78, 131-79, 131-80,
131-81, 131-82, 131-83, 131-84, 131-85, 131-86, 131-87, 131-88,
131-89, 131-90, 131-91, 131-92, 131-93, 131-94, 131-95, 131-96,
131-97,
[0245] 132-1, 132-2, 132-3, 132-4, 132-5, 132-6, 132-7, 132-8,
132-9, 132-10, 132-11, 132-12, 132-13, 132-14, 132-15, 132-16,
132-17, 132-18, 132-19, 132-20, 132-21, 132-22, 132-23, 132-24,
132-25, 132-26, 132-27, 132-28, 132-29, 132-30, 132-31, 132-32,
132-33, 132-34, 132-35, 132-36, 132-37, 132-38, 132-39, 132-40,
132-41, 132-42, 132-43, 132-44, 132-45, 132-46, 132-47, 132-48,
132-49, 132-50, 132-51, 132-52, 132-53, 132-54, 132-55, 132-56,
132-57, 132-58, 132-59, 132-60, 132-61, 132-62, 132-63, 132-64,
132-65, 132-66, 132-67, 132-68, 132-69, 132-70, 132-71, 132-72,
132-73, 132-74, 132-75, 132-76, 132-77, 132-78, 132-79, 132-80,
132-81, 132-82, 132-83, 132-84, 132-85, 132-86, 132-87, 132-88,
132-89, 132-90, 132-91, 132-92, 132-93, 132-94, 132-95, 132-96,
132-97,
[0246] 133-1, 133-2, 133-3, 133-4, 133-5, 133-6, 133-7, 133-8,
133-9, 133-10, 133-11, 133-12, 133-13, 133-14, 133-15, 133-16,
133-17, 133-18, 133-19, 133-20, 133-21, 133-22, 133-23, 133-24,
133-25, 133-26, 133-27, 133-28, 133-29, 133-30, 133-31, 133-32,
133-33, 133-34, 133-35, 133-36, 133-37, 133-38, 133-39, 133-40,
133-41, 133-42, 133-43, 133-44, 133-45, 133-46, 133-47, 133-48,
133-49, 133-50, 133-51, 133-52, 133-53, 133-54, 133-55, 133-56,
133-57, 133-58, 133-59, 133-60, 133-61, 133-62, 133-63, 133-64,
133-65, 133-66, 133-67, 133-68, 133-69, 133-70, 133-71, 133-72,
133-73, 133-74, 133-75, 133-76, 133-77, 133-78, 133-79, 133-80,
133-81, 133-82, 133-83, 133-84, 133-85, 133-86, 133-87, 133-88,
133-89, 133-90, 133-91, 133-92, 133-93, 133-94, 133-95, 133-96,
133-97,
[0247] 134-1, 134-2, 134-3, 134-4, 134-5, 134-6, 134-7, 134-8,
134-9, 134-10, 134-11, 134-12, 134-13, 134-14, 134-15, 134-16,
134-17, 134-18, 134-19, 134-20, 134-21, 134-22, 134-23, 134-24,
134-25, 134-26, 134-27, 134-28, 134-29, 134-30, 134-31, 134-32,
134-33, 134-34, 134-35, 134-36, 134-37, 134-38, 134-39, 134-40,
134-41, 134-42, 134-43, 134-44, 134-45, 134-46, 134-47, 134-48,
134-49, 134-50, 134-51, 134-52, 134-53, 134-54, 134-55, 134-56,
134-57, 134-58, 134-59, 134-60, 134-61, 134-62, 134-63, 134-64,
134-65, 134-66, 134-67, 134-68, 134-69, 134-70, 134-71, 134-72,
134-73, 134-74, 134-75, 134-76, 134-77, 134-78, 134-79, 134-80,
134-81, 134-82, 134-83, 134-84, 134-85, 134-86, 134-87, 134-88,
134-89, 134-90, 134-91, 134-92, 134-93, 134-94, 134-95, 134-96,
134-97,
[0248] 135-1, 135-2, 135-3, 135-4, 135-5, 135-6, 135-7, 135-8,
135-9, 135-10, 135-11, 135-12, 135-13, 135-14, 135-15, 135-16,
135-17, 135-18, 135-19, 135-20, 135-21, 135-22, 135-23, 135-24,
135-25, 135-26, 135-27, 135-28, 135-29, 135-30, 135-31, 135-32,
135-33, 135-34, 135-35, 135-36, 135-37, 135-38, 135-39, 135-40,
135-41, 135-42, 135-43, 135-44, 135-45, 135-46, 135-47, 135-48,
135-49, 135-50, 135-51, 135-52, 135-53, 135-54, 135-55, 135-56,
135-57, 135-58, 135-59, 135-60, 135-61, 135-62, 135-63, 135-64,
135-65, 135-66, 135-67, 135-68, 135-69, 135-70, 135-71, 135-72,
135-73, 135-74, 135-75, 135-76, 135-77, 135-78, 135-79, 135-80,
135-81, 135-82, 135-83, 135-84, 135-85, 135-86, 135-87, 135-88,
135-89, 135-90, 135-91, 135-92, 135-93, 135-94, 135-95, 135-96,
135-97,
[0249] 136-1, 136-2, 136-3, 136-4, 136-5, 136-6, 136-7, 136-8,
136-9, 136-10, 136-11, 136-12, 136-13, 136-14, 136-15, 136-16,
136-17, 136-18, 136-19, 136-20, 136-21, 136-22, 136-23, 136-24,
136-25, 136-26, 136-27, 136-28, 136-29, 136-30, 136-31, 136-32,
136-33, 136-34, 136-35, 136-36, 136-37, 136-38, 136-39, 136-40,
136-41, 136-42, 136-43, 136-44, 136-45, 136-46, 136-47, 136-48,
136-49, 136-50, 136-51, 136-52, 136-53, 136-54, 136-55, 136-56,
136-57, 136-58, 136-59, 136-60, 136-61, 136-62, 136-63, 136-64,
136-65, 136-66, 136-67, 136-68, 136-69, 136-70, 136-71, 136-72,
136-73, 136-74, 136-75, 136-76, 136-77, 136-78, 136-79, 136-80,
136-81, 136-82, 136-83, 136-84, 136-85, 136-86, 136-87, 136-88,
136-89, 136-90, 136-91, 136-92, 136-93, 136-94, 136-95, 136-96,
136-97,
[0250] 137-1, 137-2, 137-3, 137-4, 137-5, 137-6, 137-7, 137-8,
137-9, 137-10, 137-11, 137-12, 137-13, 137-14, 137-15, 137-16,
137-17, 137-18, 137-19, 137-20, 137-21, 137-22, 137-23, 137-24,
137-25, 137-26, 137-27, 137-28, 137-29, 137-30, 137-31, 137-32,
137-33, 137-34, 137-35, 137-36, 137-37, 137-38, 137-39, 137-40,
137-41, 137-42, 137-43, 137-44, 137-45, 137-46, 137-47, 137-48,
137-49, 137-50, 137-51, 137-52, 137-53, 137-54, 137-55, 137-56,
137-57, 137-58, 137-59, 137-60, 137-61, 137-62, 137-63, 137-64,
137-65, 137-66, 137-67, 137-68, 137-69, 137-70, 137-71, 137-72,
137-73, 137-74, 137-75, 137-76, 137-77, 137-78, 137-79, 137-80,
137-81, 137-82, 137-83, 137-84, 137-85, 137-86, 137-87, 137-88,
137-89, 137-90, 137-91, 137-92, 137-93, 137-94, 137-95, 137-96,
137-97,
[0251] 138-1, 138-2, 138-3, 138-4, 138-5, 138-6, 138-7, 138-8,
138-9, 138-10, 138-11, 138-12, 138-13, 138-14, 138-15, 138-16,
138-17, 138-18, 138-19, 138-20, 138-21, 138-22, 138-23, 138-24,
138-25, 138-26, 138-27, 138-28, 138-29, 138-30, 138-31, 138-32,
138-33, 138-34, 138-35, 138-36, 138-37, 138-38, 138-39, 138-40,
138-41, 138-42, 138-43, 138-44, 138-45, 138-46, 138-47, 138-48,
138-49, 138-50, 138-51, 138-52, 138-53, 138-54, 138-55, 138-56,
138-57, 138-58, 138-59, 138-60, 138-61, 138-62, 138-63, 138-64,
138-65, 138-66, 138-67, 138-68, 138-69, 138-70, 138-71, 138-72,
138-73, 138-74, 138-75, 138-76, 138-77, 138-78, 138-79, 138-80,
138-81, 138-82, 138-83, 138-84, 138-85, 138-86, 138-87, 138-88,
138-89, 138-90, 138-91, 138-92, 138-93, 138-94, 138-95, 138-96,
138-97,
[0252] 139-1, 139-2, 139-3, 139-4, 139-5, 139-6, 139-7, 139-8,
139-9, 139-10, 139-11, 139-12, 139-13, 139-14, 139-15, 139-16,
139-17, 139-18, 139-19, 139-20, 139-21, 139-22, 139-23, 139-24,
139-25, 139-26, 139-27, 139-28, 139-29, 139-30, 139-31, 139-32,
139-33, 139-34, 139-35, 139-36, 139-37, 139-38, 139-39, 139-40,
139-41, 139-42, 139-43, 139-44, 139-45, 139-46, 139-47, 139-48,
139-49, 139-50, 139-51, 139-52, 139-53, 139-54, 139-55, 139-56,
139-57, 139-58, 139-59, 139-60, 139-61, 139-62, 139-63, 139-64,
139-65, 139-66, 139-67, 139-68, 139-69, 139-70, 139-71, 139-72,
139-73, 139-74, 139-75, 139-76, 139-77, 139-78, 139-79, 139-80,
139-81, 139-82, 139-83, 139-84, 139-85, 139-86, 139-87, 139-88,
139-89, 139-90, 139-91, 139-92, 139-93, 139-94, 139-95, 139-96,
139-97,
[0253] 140-1, 140-2, 140-3, 140-4, 140-5, 140-6, 140-7, 140-8,
140-9, 140-10, 140-11, 140-12, 140-13, 140-14, 140-15, 140-16,
140-17, 140-18, 140-19, 140-20, 140-21, 140-22, 140-23, 140-24,
140-25, 140-26, 140-27, 140-28, 140-29, 140-30, 140-31, 140-32,
140-33, 140-34, 140-35, 140-36, 140-37, 140-38, 140-39, 140-40,
140-41, 140-42, 140-43, 140-44, 140-45, 140-46, 140-47, 140-48,
140-49, 140-50, 140-51, 140-52, 140-53, 140-54, 140-55, 140-56,
140-57, 140-58, 140-59, 140-60, 140-61, 140-62, 140-63, 140-64,
140-65, 140-66, 140-67, 140-68, 140-69, 140-70, 140-71, 140-72,
140-73, 140-74, 140-75, 140-76, 140-77, 140-78, 140-79, 140-80,
140-81, 140-82, 140-83, 140-84, 140-85, 140-86, 140-87, 140-88,
140-89, 140-90, 140-91, 140-92, 140-93, 140-94, 140-95, 140-96,
140-97,
[0254] 141-1, 141-2, 141-3, 141-4, 141-5, 141-6, 141-7, 141-8,
141-9, 141-10, 141-11, 141-12, 141-13, 141-14, 141-15, 141-16,
141-17, 141-18, 141-19, 141-20, 141-21, 141-22, 141-23, 141-24,
141-25, 141-26, 141-27, 141-28, 141-29, 141-30, 141-31, 141-32,
141-33, 141-34, 141-35, 141-36, 141-37, 141-38, 141-39, 141-40,
141-41, 141-42, 141-43, 141-44, 141-45, 141-46, 141-47, 141-48,
141-49, 141-50, 141-51, 141-52, 141-53, 141-54, 141-55, 141-56,
141-57, 141-58, 141-59, 141-60, 141-61, 141-62, 141-63, 141-64,
141-65, 141-66, 141-67, 141-68, 141-69, 141-70, 141-71, 141-72,
141-73, 141-74, 141-75, 141-76, 141-77, 141-78, 141-79, 141-80,
141-81, 141-82, 141-83, 141-84, 141-85, 141-86, 141-87, 141-88,
141-89, 141-90, 141-91, 141-92, 141-93, 141-94, 141-95, 141-96,
141-97,
[0255] 142-1, 142-2, 142-3, 142-4, 142-5, 142-6, 142-7, 142-8,
142-9, 142-10, 142-11, 142-12, 142-13, 142-14, 142-15, 142-16,
142-17, 142-18, 142-19, 142-20, 142-21, 142-22, 142-23, 142-24,
142-25, 142-26, 142-27, 142-28, 142-29, 142-30, 142-31, 142-32,
142-33, 142-34, 142-35, 142-36, 142-37, 142-38, 142-39, 142-40,
142-41, 142-42, 142-43, 142-44, 142-45, 142-46, 142-47, 142-48,
142-49, 142-50, 142-51, 142-52, 142-53, 142-54, 142-55, 142-56,
142-57, 142-58, 142-59, 142-60, 142-61, 142-62, 142-63, 142-64,
142-65, 142-66, 142-67, 142-68, 142-69, 142-70, 142-71, 142-72,
142-73, 142-74, 142-75, 142-76, 142-77, 142-78, 142-79, 142-80,
142-81, 142-82, 142-83, 142-84, 142-85, 142-86, 142-87, 142-88,
142-89, 142-90, 142-91, 142-92, 142-93, 142-94, 142-95, 142-96,
142-97,
[0256] 143-1, 143-2, 143-3, 143-4, 143-5, 143-6, 143-7, 143-8,
143-9, 143-10, 143-11, 143-12, 143-13, 143-14, 143-15, 143-16,
143-17, 143-18, 143-19, 143-20, 143-21, 143-22, 143-23, 143-24,
143-25, 143-26, 143-27, 143-28, 143-29, 143-30, 143-31, 143-32,
143-33, 143-34, 143-35, 143-36, 143-37, 143-38, 143-39, 143-40,
143-41, 143-42, 143-43, 143-44, 143-45, 143-46, 143-47, 143-48,
143-49, 143-50, 143-51, 143-52, 143-53, 143-54, 143-55, 143-56,
143-57, 143-58, 143-59, 143-60, 143-61, 143-62, 143-63, 143-64,
143-65, 143-66, 143-67, 143-68, 143-69, 143-70, 143-71, 143-72,
143-73, 143-74, 143-75, 143-76, 143-77, 143-78, 143-79, 143-80,
143-81, 143-82, 143-83, 143-84, 143-85, 143-86, 143-87, 143-88,
143-89, 143-90, 143-91, 143-92, 143-93, 143-94, 143-95, 143-96,
143-97,
[0257] 144-1, 144-2, 144-3, 144-4, 144-5, 144-6, 144-7, 144-8,
144-9, 144-10, 144-11, 144-12, 144-13, 144-14, 144-15, 144-16,
144-17, 144-18, 144-19, 144-20, 144-21, 144-22, 144-23, 144-24,
144-25, 144-26, 144-27, 144-28, 144-29, 144-30, 144-31, 144-32,
144-33, 144-34, 144-35, 144-36, 144-37, 144-38, 144-39, 144-40,
144-41, 144-42, 144-43, 144-44, 144-45, 144-46, 144-47, 144-48,
144-49, 144-50, 144-51, 144-52, 144-53, 144-54, 144-55, 144-56,
144-57, 144-58, 144-59, 144-60, 144-61, 144-62, 144-63, 144-64,
144-65, 144-66, 144-67, 144-68, 144-69, 144-70, 144-71, 144-72,
144-73, 144-74, 144-75, 144-76, 144-77, 144-78, 144-79, 144-80,
144-81, 144-82, 144-83, 144-84, 144-85, 144-86, 144-87, 144-88,
144-89, 144-90, 144-91, 144-92, 144-93, 144-94, 144-95, 144-96,
144-97,
[0258] 145-1, 145-2, 145-3, 145-4, 145-5, 145-6, 145-7, 145-8,
145-9, 145-10, 145-11, 145-12, 145-13, 145-14, 145-15, 145-16,
145-17, 145-18, 145-19, 145-20, 145-21, 145-22, 145-23, 145-24,
145-25, 145-26, 145-27, 145-28, 145-29, 145-30, 145-31, 145-32,
145-33, 145-34, 145-35, 145-36, 145-37, 145-38, 145-39, 145-40,
145-41, 145-42, 145-43, 145-44, 145-45, 145-46, 145-47, 145-48,
145-49, 145-50, 145-51, 145-52, 145-53, 145-54, 145-55, 145-56,
145-57, 145-58, 145-59, 145-60, 145-61, 145-62, 145-63, 145-64,
145-65, 145-66, 145-67, 145-68, 145-69, 145-70, 145-71, 145-72,
145-73, 145-74, 145-75, 145-76, 145-77, 145-78, 145-79, 145-80,
145-81, 145-82, 145-83, 145-84, 145-85, 145-86, 145-87, 145-88,
145-89, 145-90, 145-91, 145-92, 145-93, 145-94, 145-95, 145-96,
145-97,
[0259] 146-1, 146-2, 146-3, 146-4, 146-5, 146-6, 146-7, 146-8,
146-9, 146-10, 146-11, 146-12, 146-13, 146-14, 146-15, 146-16,
146-17, 146-18, 146-19, 146-20, 146-21, 146-22, 146-23, 146-24,
146-25, 146-26, 146-27, 146-28, 146-29, 146-30, 146-31, 146-32,
146-33, 146-34, 146-35, 146-36, 146-37, 146-38, 146-39, 146-40,
146-41, 146-42, 146-43, 146-44, 146-45, 146-46, 146-47, 146-48,
146-49, 146-50, 146-51, 146-52, 146-53, 146-54, 146-55, 146-56,
146-57, 146-58, 146-59, 146-60, 146-61, 146-62, 146-63, 146-64,
146-65, 146-66, 146-67, 146-68, 146-69, 146-70, 146-71, 146-72,
146-73, 146-74, 146-75, 146-76, 146-77, 146-78, 146-79, 146-80,
146-81, 146-82, 146-83, 146-84, 146-85, 146-86, 146-87, 146-88,
146-89, 146-90, 146-91, 146-92, 146-93, 146-94, 146-95, 146-96,
146-97,
[0260] 147-1, 147-2, 147-3, 147-4, 147-5, 147-6, 147-7, 147-8,
147-9, 147-10, 147-11, 147-12, 147-13, 147-14, 147-15, 147-16,
147-17, 147-18, 147-19, 147-20, 147-21, 147-22, 147-23, 147-24,
147-25, 147-26, 147-27, 147-28, 147-29, 147-30, 147-31, 147-32,
147-33, 147-34, 147-35, 147-36, 147-37, 147-38, 147-39, 147-40,
147-41, 147-42, 147-43, 147-44, 147-45, 147-46, 147-47, 147-48,
147-49, 147-50, 147-51, 147-52, 147-53, 147-54, 147-55, 147-56,
147-57, 147-58, 147-59, 147-60, 147-61, 147-62, 147-63, 147-64,
147-65, 147-66, 147-67, 147-68, 147-69, 147-70, 147-71, 147-72,
147-73, 147-74, 147-75, 147-76, 147-77, 147-78, 147-79, 147-80,
147-81, 147-82, 147-83, 147-84, 147-85, 147-86, 147-87, 147-88,
147-89, 147-90, 147-91, 147-92, 147-93, 147-94, 147-95, 147-96,
147-97,
[0261] 148-1, 148-2, 148-3, 148-4, 148-5, 148-6, 148-7, 148-8,
148-9, 148-10, 148-11, 148-12, 148-13, 148-14, 148-15, 148-16,
148-17, 148-18, 148-19, 148-20, 148-21, 148-22, 148-23, 148-24,
148-25, 148-26, 148-27, 148-28, 148-29, 148-30, 148-31, 148-32,
148-33, 148-34, 148-35, 148-36, 148-37, 148-38, 148-39, 148-40,
148-41, 148-42, 148-43, 148-44, 148-45, 148-46, 148-47, 148-48,
148-49, 148-50, 148-51, 148-52, 148-53, 148-54, 148-55, 148-56,
148-57, 148-58, 148-59, 148-60, 148-61, 148-62, 148-63, 148-64,
148-65, 148-66, 148-67, 148-68, 148-69, 148-70, 148-71, 148-72,
148-73, 148-74, 148-75, 148-76, 148-77, 148-78, 148-79, 148-80,
148-81, 148-82, 148-83, 148-84, 148-85, 148-86, 148-87, 148-88,
148-89, 148-90, 148-91, 148-92, 148-93, 148-94, 148-95, 148-96,
148-97,
[0262] 149-1, 149-2, 149-3, 149-4, 149-5, 149-6, 149-7, 149-8,
149-9, 149-10, 149-11, 149-12, 149-13, 149-14, 149-15, 149-16,
149-17, 149-18, 149-19, 149-20, 149-21, 149-22, 149-23, 149-24,
149-25, 149-26, 149-27, 149-28, 149-29, 149-30, 149-31, 149-32,
149-33, 149-34, 149-35, 149-36, 149-37, 149-38, 149-39, 149-40,
149-41, 149-42, 149-43, 149-44, 149-45, 149-46, 149-47, 149-48,
149-49, 149-50, 149-51, 149-52, 149-53, 149-54, 149-55, 149-56,
149-57, 149-58, 149-59, 149-60, 149-61, 149-62, 149-63, 149-64,
149-65, 149-66, 149-67, 149-68, 149-69, 149-70, 149-71, 149-72,
149-73, 149-74, 149-75, 149-76, 149-77, 149-78, 149-79, 149-80,
149-81, 149-82, 149-83, 149-84, 149-85, 149-86, 149-87, 149-88,
149-89, 149-90, 149-91, 149-92, 149-93, 149-94, 149-95, 149-96,
149-97,
[0263] 150-1, 150-2, 150-3, 150-4, 150-5, 150-6, 150-7, 150-8,
150-9, 150-10, 150-11, 150-12, 150-13, 150-14, 150-15, 150-16,
150-17, 150-18, 150-19, 150-20, 150-21, 150-22, 150-23, 150-24,
150-25, 150-26, 150-27, 150-28, 150-29, 150-30, 150-31, 150-32,
150-33, 150-34, 150-35, 150-36, 150-37, 150-38, 150-39, 150-40,
150-41, 150-42, 150-43, 150-44, 150-45, 150-46, 150-47, 150-48,
150-49, 150-50, 150-51, 150-52, 150-53, 150-54, 150-55, 150-56,
150-57, 150-58, 150-59, 150-60, 150-61, 150-62, 150-63, 150-64,
150-65, 150-66, 150-67, 150-68, 150-69, 150-70, 150-71, 150-72,
150-73, 150-74, 150-75, 150-76, 150-77, 150-78, 150-79, 150-80,
150-81, 150-82, 150-83, 150-84, 150-85, 150-86, 150-87, 150-88,
150-89, 150-90, 150-91, 150-92, 150-93, 150-94, 150-95, 150-96,
150-97,
[0264] 151-1, 151-2, 151-3, 151-4, 151-5, 151-6, 151-7, 151-8,
151-9, 151-10, 151-11, 151-12, 151-13, 151-14, 151-15, 151-16,
151-17, 151-18, 151-19, 151-20, 151-21, 151-22, 151-23, 151-24,
151-25, 151-26, 151-27, 151-28, 151-29, 151-30, 151-31, 151-32,
151-33, 151-34, 151-35, 151-36, 151-37, 151-38, 151-39, 151-40,
151-41, 151-42, 151-43, 151-44, 151-45, 151-46, 151-47, 151-48,
151-49, 151-50, 151-51, 151-52, 151-53, 151-54, 151-55, 151-56,
151-57, 151-58, 151-59, 151-60, 151-61, 151-62, 151-63, 151-64,
151-65, 151-66, 151-67, 151-68, 151-69, 151-70, 151-71, 151-72,
151-73, 151-74, 151-75, 151-76, 151-77, 151-78, 151-79, 151-80,
151-81, 151-82, 151-83, 151-84, 151-85, 151-86, 151-87, 151-88,
151-89, 151-90, 151-91, 151-92, 151-93, 151-94, 151-95, 151-96,
151-97,
[0265] 152-1, 152-2, 152-3, 152-4, 152-5, 152-6, 152-7, 152-8,
152-9, 152-10, 152-11, 152-12, 152-13, 152-14, 152-15, 152-16,
152-17, 152-18, 152-19, 152-20, 152-21, 152-22, 152-23, 152-24,
152-25, 152-26, 152-27, 152-28, 152-29, 152-30, 152-31, 152-32,
152-33, 152-34, 152-35, 152-36, 152-37, 152-38, 152-39, 152-40,
152-41, 152-42, 152-43, 152-44, 152-45, 152-46, 152-47, 152-48,
152-49, 152-50, 152-51, 152-52, 152-53, 152-54, 152-55, 152-56,
152-57, 152-58, 152-59, 152-60, 152-61, 152-62, 152-63, 152-64,
152-65, 152-66, 152-67, 152-68, 152-69, 152-70, 152-71, 152-72,
152-73, 152-74, 152-75, 152-76, 152-77, 152-78, 152-79, 152-80,
152-81, 152-82, 152-83, 152-84, 152-85, 152-86, 152-87, 152-88,
152-89, 152-90, 152-91, 152-92, 152-93, 152-94, 152-95, 152-96,
152-97,
[0266] 153-1, 153-2, 153-3, 153-4, 153-5, 153-6, 153-7, 153-8,
153-9, 153-10, 153-11, 153-12, 153-13, 153-14, 153-15, 153-16,
153-17, 153-18, 153-19, 153-20, 153-21, 153-22, 153-23, 153-24,
153-25, 153-26, 153-27, 153-28, 153-29, 153-30, 153-31, 153-32,
153-33, 153-34, 153-35, 153-36, 153-37, 153-38, 153-39, 153-40,
153-41, 153-42, 153-43, 153-44, 153-45, 153-46, 153-47, 153-48,
153-49, 153-50, 153-51, 153-52, 153-53, 153-54, 153-55, 153-56,
153-57, 153-58, 153-59, 153-60, 153-61, 153-62, 153-63, 153-64,
153-65, 153-66, 153-67, 153-68, 153-69, 153-70, 153-71, 153-72,
153-73, 153-74, 153-75, 153-76, 153-77, 153-78, 153-79, 153-80,
153-81, 153-82, 153-83, 153-84, 153-85, 153-86, 153-87, 153-88,
153-89, 153-90, 153-91, 153-92, 153-93, 153-94, 153-95, 153-96,
153-97,
[0267] 154-1, 154-2, 154-3, 154-4, 154-5, 154-6, 154-7, 154-8,
154-9, 154-10, 154-11, 154-12, 154-13, 154-14, 154-15, 154-16,
154-17, 154-18, 154-19, 154-20, 154-21, 154-22, 154-23, 154-24,
154-25, 154-26, 154-27, 154-28, 154-29, 154-30, 154-31, 154-32,
154-33, 154-34, 154-35, 154-36, 154-37, 154-38, 154-39, 154-40,
154-41, 154-42, 154-43, 154-44, 154-45, 154-46, 154-47, 154-48,
154-49, 154-50, 154-51, 154-52, 154-53, 154-54, 154-55, 154-56,
154-57, 154-58, 154-59, 154-60, 154-61, 154-62, 154-63, 154-64,
154-65, 154-66, 154-67, 154-68, 154-69, 154-70, 154-71, 154-72,
154-73, 154-74, 154-75, 154-76, 154-77, 154-78, 154-79, 154-80,
154-81, 154-82, 154-83, 154-84, 154-85, 154-86, 154-87, 154-88,
154-89, 154-90, 154-91, 154-92, 154-93, 154-94, 154-95, 154-96,
154-97,
[0268] 155-1, 155-2, 155-3, 155-4, 155-5, 155-6, 155-7, 155-8,
155-9, 155-10, 155-11, 155-12, 155-13, 155-14, 155-15, 155-16,
155-17, 155-18, 155-19, 155-20, 155-21, 155-22, 155-23, 155-24,
155-25, 155-26, 155-27, 155-28, 155-29, 155-30, 155-31, 155-32,
155-33, 155-34, 155-35, 155-36, 155-37, 155-38, 155-39, 155-40,
155-41, 155-42, 155-43, 155-44, 155-45, 155-46, 155-47, 155-48,
155-49, 155-50, 155-51, 155-52, 155-53, 155-54, 155-55, 155-56,
155-57, 155-58, 155-59, 155-60, 155-61, 155-62, 155-63, 155-64,
155-65, 155-66, 155-67, 155-68, 155-69, 155-70, 155-71, 155-72,
155-73, 155-74, 155-75, 155-76, 155-77, 155-78, 155-79, 155-80,
155-81, 155-82, 155-83, 155-84, 155-85, 155-86, 155-87, 155-88,
155-89, 155-90, 155-91, 155-92, 155-93, 155-94, 155-95, 155-96,
155-97,
[0269] 156-1, 156-2, 156-3, 156-4, 156-5, 156-6, 156-7, 156-8,
156-9, 156-10, 156-11, 156-12, 156-13, 156-14, 156-15, 156-16,
156-17, 156-18, 156-19, 156-20, 156-21, 156-22, 156-23, 156-24,
156-25, 156-26, 156-27, 156-28, 156-29, 156-30, 156-31, 156-32,
156-33, 156-34, 156-35, 156-36, 156-37, 156-38, 156-39, 156-40,
156-41, 156-42, 156-43, 156-44, 156-45, 156-46, 156-47, 156-48,
156-49, 156-50, 156-51, 156-52, 156-53, 156-54, 156-55, 156-56,
156-57, 156-58, 156-59, 156-60, 156-61, 156-62, 156-63, 156-64,
156-65, 156-66, 156-67, 156-68, 156-69, 156-70, 156-71, 156-72,
156-73, 156-74, 156-75, 156-76, 156-77, 156-78, 156-79, 156-80,
156-81, 156-82, 156-83, 156-84, 156-85, 156-86, 156-87, 156-88,
156-89, 156-90, 156-91, 156-92, 156-93, 156-94, 156-95, 156-96,
156-97,
[0270] 157-1, 157-2, 157-3, 157-4, 157-5, 157-6, 157-7, 157-8,
157-9, 157-10, 157-11, 157-12, 157-13, 157-14, 157-15, 157-16,
157-17, 157-18, 157-19, 157-20, 157-21, 157-22, 157-23, 157-24,
157-25, 157-26, 157-27, 157-28, 157-29, 157-30, 157-31, 157-32,
157-33, 157-34, 157-35, 157-36, 157-37, 157-38, 157-39, 157-40,
157-41, 157-42, 157-43, 157-44, 157-45, 157-46, 157-47, 157-48,
157-49, 157-50, 157-51, 157-52, 157-53, 157-54, 157-55, 157-56,
157-57, 157-58, 157-59, 157-60, 157-61, 157-62, 157-63, 157-64,
157-65, 157-66, 157-67, 157-68, 157-69, 157-70, 157-71, 157-72,
157-73, 157-74, 157-75, 157-76, 157-77, 157-78, 157-79, 157-80,
157-81, 157-82, 157-83, 157-84, 157-85, 157-86, 157-87, 157-88,
157-89, 157-90, 157-91, 157-92, 157-93, 157-94, 157-95, 157-96,
157-97,
[0271] 158-1, 158-2, 158-3, 158-4, 158-5, 158-6, 158-7, 158-8,
158-9, 158-10, 158-11, 158-12, 158-13, 158-14, 158-15, 158-16,
158-17, 158-18, 158-19, 158-20, 158-21, 158-22, 158-23, 158-24,
158-25, 158-26, 158-27, 158-28, 158-29, 158-30, 158-31, 158-32,
158-33, 158-34, 158-35, 158-36, 158-37, 158-38, 158-39, 158-40,
158-41, 158-42, 158-43, 158-44, 158-45, 158-46, 158-47, 158-48,
158-49, 158-50, 158-51, 158-52, 158-53, 158-54, 158-55, 158-56,
158-57, 158-58, 158-59, 158-60, 158-61, 158-62, 158-63, 158-64,
158-65, 158-66, 158-67, 158-68, 158-69, 158-70, 158-71, 158-72,
158-73, 158-74, 158-75, 158-76, 158-77, 158-78, 158-79, 158-80,
158-81, 158-82, 158-83, 158-84, 158-85, 158-86, 158-87, 158-88,
158-89, 158-90, 158-91, 158-92, 158-93, 158-94, 158-95, 158-96,
158-97,
[0272] 159-1, 159-2, 159-3, 159-4, 159-5, 159-6, 159-7, 159-8,
159-9, 159-10, 159-11, 159-12, 159-13, 159-14, 159-15, 159-16,
159-17, 159-18, 159-19, 159-20, 159-21, 159-22,.159-23, 159-24,
159-25, 159-26, 159-27, 159-28, 159-29, 159-30, 159-31, 159-32,
159-33, 159-34, 159-35, 159-36, 159-37, 159-38, 159-39, 159-40,
159-41, 159-42, 159-43, 159-44, 159-45, 159-46, 159-47, 159-48,
159-49, 159-50, 159-51, 159-52, 159-53, 159-54, 159-55, 159-56,
159-57, 159-58, 159-59, 159-60, 159-61, 159-62, 159-63, 159-64,
159-65, 159-66, 159-67, 159-68, 159-69, 159-70, 159-71, 159-72,
159-73, 159-74, 159-75, 159-76, 159-77, 159-78, 159-79, 159-80,
159-81, 159-82, 159-83, 159-84, 159-85, 159-86, 159-87, 159-88,
159-89, 159-90, 159-91, 159-92, 159-93, 159-94, 159-95, 159-96,
159-97,
[0273] 160-1, 160-2, 160-3, 160-4, 160-5, 160-6, 160-7, 160-8,
160-9, 160-10, 160-11, 160-12, 160-13, 160-14, 160-15, 160-16,
160-17, 160-18, 160-19, 160-20, 160-21, 160-22, 160-23, 160-24,
160-25, 160-26, 160-27, 160-28, 160-29, 160-30, 160-31, 160-32,
160-33, 160-34, 160-35, 160-36, 160-37, 160-38, 160-39, 160-40,
160-41, 160-42, 160-43, 160-44, 160-45, 160-46, 160-47, 160-48,
160-49, 160-50, 160-51, 160-52, 160-53, 160-54, 160-55, 160-56,
160-57, 160-58, 160-59, 160-60, 160-61, 160-62, 160-63, 160-64,
160-65, 160-66, 160-67, 160-68, 160-69, 160-70, 160-71, 160-72,
160-73, 160-74, 160-75, 160-76, 160-77, 160-78, 160-79, 160-80,
160-81, 160-82, 160-83, 160-84, 160-85, 160-86, 160-87, 160-88,
160-89, 160-90, 160-91, 160-92, 160-93, 160-94, 160-95, 160-96,
160-97,
[0274] 161-1, 161-2, 161-3, 161-4, 161-5, 161-6, 161-7, 161-8,
161-9, 161-10, 161-11, 161-12, 161-13, 161-14, 161-15, 161-16,
161-17, 161-18, 161-19, 161-20, 161-21, 161-22, 161-23, 161-24,
161-25, 161-26, 161-27, 161-28, 161-29, 161-30, 161-31, 161-32,
161-33, 161-34, 161-35, 161-36, 161-37, 161-38, 161-39, 161-40,
161-41, 161-42, 161-43, 161-44, 161-45, 161-46, 161-47, 161-48,
161-49, 161-50, 161-51, 161-52, 161-53, 161-54, 161-55, 161-56,
161-57, 161-58, 161-59, 161-60, 161-61, 161-62, 161-63, 161-64,
161-65, 161-66, 161-67, 161-68, 161-69, 161-70, 161-71, 161-72,
161-73, 161-74, 161-75, 161-76, 161-77, 161-78, 161-79, 161-80,
161-81, 161-82, 161-83, 161-84, 161-85, 161-86, 161-87, 161-88,
161-89, 161-90, 161-91, 161-92, 161-93, 161-94, 161-95, 161-96,
161-97,
[0275] 162-1, 162-2, 162-3, 162-4, 162-5, 162-6, 162-7, 162-8,
162-9, 162-10, 162-11, 162-12, 162-13, 162-14, 162-15, 162-16,
162-17, 162-18, 162-19, 162-20, 162-21, 162-22, 162-23, 162-24,
162-25, 162-26, 162-27, 162-28, 162-29, 162-30, 162-31, 162-32,
162-33, 162-34, 162-35, 162-36, 162-37, 162-38, 162-39, 162-40,
162-41, 162-42, 162-43, 162-44, 162-45, 162-46, 162-47, 162-48,
162-49, 162-50, 162-51, 162-52, 162-53, 162-54, 162-55, 162-56,
162-57, 162-58, 162-59, 162-60, 162-61, 162-62, 162-63, 162-64,
162-65, 162-66, 162-67, 162-68, 162-69, 162-70, 162-71, 162-72,
162-73, 162-74, 162-75, 162-76, 162-77, 162-78, 162-79, 162-80,
162-81, 162-82, 162-83, 162-84, 162-85, 162-86, 162-87, 162-88,
162-89, 162-90, 162-91, 162-92, 162-93, 162-94, 162-95, 162-96,
162-97,
[0276] 163-1, 163-2, 163-3, 163-4, 163-5, 163-6, 163-7, 163-8,
163-9, 163-10, 163-11, 163-12, 163-13, 163-14, 163-15, 163-16,
163-17, 163-18, 163-19, 163-20, 163-21, 163-22, 163-23, 163-24,
163-25, 163-26, 163-27, 163-28, 163-29, 163-30, 163-31, 163-32,
163-33, 163-34, 163-35, 163-36, 163-37, 163-38, 163-39, 163-40,
163-41, 163-42, 163-43, 163-44, 163-45, 163-46, 163-47, 163-48,
163-49, 163-50, 163-51, 163-52, 163-53, 163-54, 163-55, 163-56,
163-57, 163-58, 163-59, 163-60, 163-61, 163-62, 163-63, 163-64,
163-65, 163-66, 163-67, 163-68, 163-69, 163-70, 163-71, 163-72,
163-73, 163-74, 163-75, 163-76, 163-77, 163-78, 163-79, 163-80,
163-81, 163-82, 163-83, 163-84, 163-85, 163-86, 163-87, 163-88,
163-89, 163-90, 163-91, 163-92, 163-93, 163-94, 163-95, 163-96,
163-97,
[0277] 164-1, 164-2, 164-3, 164-4, 164-5, 164-6, 164-7, 164-8,
164-9, 164-10, 164-11, 164-12, 164-13, 164-14, 164-15, 164-16,
164-17, 164-18, 164-19, 164-20, 164-21, 164-22, 164-23, 164-24,
164-25, 164-26, 164-27, 164-28, 164-29, 164-30, 164-31, 164-32,
164-33, 164-34, 164-35, 164-36, 164-37, 164-38, 164-39, 164-40,
164-41, 164-42, 164-43, 164-44, 164-45, 164-46, 164-47, 164-48,
164-49, 164-50, 164-51, 164-52, 164-53, 164-54, 164-55, 164-56,
164-57, 164-58, 164-59, 164-60, 164-61, 164-62, 164-63, 164-64,
164-65, 164-66, 164-67, 164-68, 164-69, 164-70, 164-71, 164-72,
164-73, 164-74, 164-75, 164-76, 164-77, 164-78, 164-79, 164-80,
164-81, 164-82, 164-83, 164-84, 164-85, 164-86, 164-87, 164-88,
164-89, 164-90, 164-91, 164-92, 164-93, 164-94, 164-95, 164-96,
164-97,
[0278] 165-1, 165-2, 165-3, 165-4, 165-5, 165-6, 165-7, 165-8,
165-9, 165-10, 165-11, 165-12, 165-13, 165-14, 165-15, 165-16,
165-17, 165-18, 165-19, 165-20, 165-21, 165-22, 165-23, 165-24,
165-25, 165-26, 165-27, 165-28, 165-29, 165-30, 165-31, 165-32,
165-33, 165-34, 165-35, 165-36, 165-37, 165-38, 165-39, 165-40,
165-41, 165-42, 165-43, 165-44, 165-45, 165-46, 165-47, 165-48,
165-49, 165-50, 165-51, 165-52, 165-53, 165-54, 165-55, 165-56,
165-57, 165-58, 165-59, 165-60, 165-61, 165-62, 165-63, 165-64,
165-65, 165-66, 165-67, 165-68, 165-69, 165-70, 165-71, 165-72,
165-73, 165-74, 165-75, 165-76, 165-77, 165-78, 165-79, 165-80,
165-81, 165-82, 165-83, 165-84, 165-85, 165-86, 165-87, 165-88,
165-89, 165-90, 165-91, 165-92, 165-93, 165-94, 165-95, 165-96,
165-97,
[0279] 166-1, 166-2, 166-3, 166-4, 166-5, 166-6, 166-7, 166-8,
166-9, 166-10, 166-11, 166-12, 166-13, 166-14, 166-15, 166-16,
166-17, 166-18, 166-19, 166-20, 166-21, 166-22, 166-23, 166-24,
166-25, 166-26, 166-27, 166-28, 166-29, 166-30, 166-31, 166-32,
166-33, 166-34, 166-35, 166-36, 166-37, 166-38, 166-39, 166-40,
166-41, 166-42, 166-43, 166-44, 166-45, 166-46, 166-47, 166-48,
166-49, 166-50, 166-51, 166-52, 166-53, 166-54, 166-55, 166-56,
166-57, 166-58, 166-59, 166-60, 166-61, 166-62, 166-63, 166-64,
166-65, 166-66, 166-67, 166-68, 166-69, 166-70, 166-71, 166-72,
166-73, 166-74, 166-75, 166-76, 166-77, 166-78, 166-79, 166-80,
166-81, 166-82, 166-83, 166-84, 166-85, 166-86, 166-87, 166-88,
166-89, 166-90, 166-91, 166-92, 166-93, 166-94, 166-95, 166-6,
166-97,
[0280] 167-1, 167-2, 167-3, 167-4, 167-5, 167-6, 167-7, 167-8,
167-9, 167-10, 167-11, 167-12, 167-13, 167-14, 167-15, 167-16,
167-17, 167-18, 167-19, 167-20, 167-21, 167-22, 167-23, 167-24,
167-25, 167-26, 167-27, 167-28, 167-29, 167-30, 167-31, 167-32,
167-33, 167-34, 167-35, 167-36, 167-37, 167-38, 167-39, 167-40,
167-41, 167-42, 167-43, 167-44, 167-45, 167-46, 167-47, 167-48,
167-49, 167-50, 167-51, 167-52, 167-53, 167-54, 167-55, 167-56,
167-57, 167-58, 167-59, 167-60, 167-61, 167-62, 167-63, 167-64,
167-65, 167-66, 167-67, 167-68, 167-69, 167-70, 167-71, 167-72,
167-73, 167-74, 167-75, 167-76, 167-77, 167-78, 167-79, 167-80,
167-81, 167-82, 167-83, 167-84, 167-85, 167-86, 167-87, 167-88,
167-89, 167-90, 167-91, 167-92, 167-93, 167-94, 167-95, 167-96,
167-97,
[0281] 168-1, 168-2, 168-3, 168-4, 168-5, 168-6, 168-7, 168-8,
168-9, 168-10, 168-11, 168-12, 168-13, 168-14, 168-15, 168-16,
168-17, 168-18, 168-19, 168-20, 168-21, 168-22, 168-23, 168-24,
168-25, 168-26, 168-27, 168-28, 168-29, 168-30, 168-31, 168-32,
168-33, 168-34, 168-35, 168-36, 168-37, 168-38, 168-39, 168-40,
168-41, 168-42, 168-43, 168-44, 168-45, 168-46, 168-47, 168-48,
168-49, 168-50, 168-51, 168-52, 168-53, 168-54, 168-55, 168-56,
168-57, 168-58, 168-59, 168-60, 168-61, 168-62, 168-63, 168-64,
168-65, 168-66, 168-67, 168-68, 168-69, 168-70, 168-71, 168-72,
168-73, 168-74, 168-75, 168-76, 168-77, 168-78, 168-79, 168-80,
168-81, 168-82, 168-83, 168-84, 168-85, 168-86, 168-87, 168-88,
168-89, 168-90, 168-91, 168-92, 168-93, 168-94, 168-95, 168-96,
168-97,
[0282] 169-1, 169-2, 169-3, 169-4, 169-5, 169-6, 169-7, 169-8,
169-9, 169-10, 169-11, 169-12, 169-13, 169-14, 169-15, 169-16,
169-17, 169-18, 169-19, 169-20, 169-21, 169-22, 169-23, 169-24,
169-25, 169-26, 169-27, 169-28, 169-29, 169-30, 169-31, 169-32,
169-33, 169-34, 169-35, 169-36, 169-37, 169-38, 169-39, 169-40,
169-41, 169-42, 169-43, 169-44, 169-45, 169-46, 169-47, 169-48,
169-49, 169-50, 169-51, 169-52, 169-53, 169-54, 169-55, 169-56,
169-57, 169-58, 169-59, 169-60, 169-61, 169-62, 169-63, 169-64,
169-65, 169-66, 169-67, 169-68, 169-69, 169-70, 169-71, 169-72,
169-73, 169-74, 169-75, 169-76, 169-77, 169-78, 169-79, 169-80,
169-81, 169-82, 169-83, 169-84, 169-85, 169-86, 169-87, 169-88,
169-89, 169-90, 169-91, 169-92, 169-93, 169-94, 169-95, 169-96,
169-97,
[0283] 170-1, 170-2, 170-3, 170-4, 170-5, 170-6, 170-7, 170-8,
170-9, 170-10, 170-11, 170-12, 170-13, 170-14, 170-15, 170-16,
170-17, 170-18, 170-19, 170-20, 170-21, 170-22, 170-23, 170-24,
170-25, 170-26, 170-27, 170-28, 170-29, 170-30, 170-31, 170-32,
170-33, 170-34, 170-35, 170-36, 170-37, 170-38, 170-39, 170-40,
170-41, 170-42, 170-43, 170-44, 170-45, 170-46, 170-47, 170-48,
170-49, 170-50, 170-51, 170-52, 170-53, 170-54, 170-55, 170-56,
170-57, 170-58, 170-59, 170-60, 170-61, 170-62, 170-63, 170-64,
170-65, 170-66, 170-67, 170-68, 170-69, 170-70, 170-71, 170-72,
170-73, 170-74, 170-75, 170-76, 170-77, 170-78, 170-79, 170-80,
170-81, 170-82, 170-83, 170-84, 170-85, 170-86, 170-87, 170-88,
170-89, 170-90, 170-91, 170-92, 170-93, 170-94, 170-95, 170-96,
170-97,
[0284] 171-1, 171-2, 171-3, 171-4, 171-5, 171-6, 171-7, 171-8,
171-9, 171-10, 171-11, 171-12, 171-13, 171-14, 171-15, 171-16,
171-17, 171-18, 171-19, 171-20, 171-21, 171-22, 171-23, 171-24,
171-25, 171-26, 171-27, 171-28, 171-29, 171-30, 171-31, 171-32,
171-33, 171-34, 171-35, 171-36, 171-37, 171-38, 171-39, 171-40,
171-41, 171-42, 171-43, 171-44, 171-45, 171-46, 171-47, 171-48,
171-49, 171-50, 171-51, 171-52, 171-53, 171-54, 171-55, 171-56,
171-57, 171-58, 171-59, 171-60, 171-61, 171-62, 171-63, 171-64,
171-65, 171-66, 171-67, 171-68, 171-69, 171-70, 171-71, 171-72,
171-73, 171-74, 171-75, 171-76, 171-77, 171-78, 171-79, 171-80,
171-81, 171-82, 171-83, 171-84, 171-85, 171-86, 171-87, 171-88,
171-89, 171-90, 171-91, 171-92, 171-93, 171-94, 171-95, 171-96,
171-97,
[0285] 172-1, 172-2, 172-3, 172-4, 172-5, 172-6, 172-7, 172-8,
172-9, 172-10, 172-11, 172-12, 172-13, 172-14, 172-15, 172-16,
172-17, 172-18, 172-19, 172-20, 172-21, 172-22, 172-23, 172-24,
172-25, 172-26, 172-27, 172-28, 172-29, 172-30, 172-31, 172-32,
172-33, 172-34, 172-35, 172-36, 172-37, 172-38, 172-39, 172-40,
172-41, 172-42, 172-43, 172-44, 172-45, 172-46, 172-47, 172-48,
172-49, 172-50, 172-51, 172-52, 172-53, 172-54, 172-55, 172-56,
172-57, 172-58, 172-59, 172-60, 172-61, 172-62, 172-63, 172-64,
172-65, 172-66, 172-67, 172-68, 172-69, 172-70, 172-71, 172-72,
172-73, 172-74, 172-75, 172-76, 172-77, 172-78, 172-79, 172-80,
172-81, 172-82, 172-83, 172-84, 172-85, 172-86, 172-87, 172-88,
172-89, 172-90, 172-91, 172-92, 172-93, 172-94, 172-95, 172-96,
172-97,
[0286] 173-1, 173-2, 173-3, 173-4, 173-5, 173-6, 173-7, 173-8,
173-9, 173-10, 173-11, 173-12, 173-13, 173-14, 173-15, 173-16,
173-17, 173-18, 173-19, 173-20, 173-21, 173-22, 173-23, 173-24,
173-25, 173-26, 173-27, 173-28, 173-29, 173-30, 173-31, 173-32,
173-33, 173-34, 173-35, 173-36, 173-37, 173-38, 173-39, 173-40,
173-41, 173-42, 173-43, 173-44, 173-45, 173-46, 173-47, 173-48,
173-49, 173-50, 173-51, 173-52, 173-53, 173-54, 173-55, 173-56,
173-57, 173-58, 173-59, 173-60, 173-61, 173-62, 173-63, 173-64,
173-65, 173-66, 173-67, 173-68, 173-69, 173-70, 173-71, 173-72,
173-73, 173-74, 173-75, 173-76, 173-77, 173-78, 173-79, 173-80,
173-81, 173-82, 173-83, 173-84, 173-85, 173-86, 173-87, 173-88,
173-89, 173-90, 173-91, 173-92, 173-93, 173-94, 173-95, 173-96,
173-97,
[0287] 174-1, 174-2, 174-3, 174-4, 174-5, 174-6, 174-7, 174-8,
174-9, 174-10, 174-11, 174-12, 174-13, 174-14, 174-15, 174-16,
174-17, 174-18, 174-19, 174-20, 174-21, 174-22, 174-23, 174-24,
174-25, 174-26, 174-27, 174-28, 174-29, 174-30, 174-31, 174-32,
174-33, 174-34, 174-35, 174-36, 174-37, 174-38, 174-39, 174-40,
174-41, 174-42, 174-43, 174-44, 174-45, 174-46, 174-47, 174-48,
174-49, 174-50, 174-51, 174-52, 174-53, 174-54, 174-55, 174-56,
174-57, 174-58, 174-59, 174-60, 174-61, 174-62, 174-63, 174-64,
174-65, 174-66, 174-67, 174-68, 174-69, 174-70, 174-71, 174-72,
174-73, 174-74, 174-75, 174-76, 174-77, 174-78, 174-79, 174-80,
174-81, 174-82, 174-83, 174-84, 174-85, 174-86, 174-87, 174-88,
174-89, 174-90, 174-91, 174-92, 174-93, 174-94, 174-95, 174-96,
174-97,
[0288] 175-1, 175-2, 175-3, 175-4, 175-5, 175-6, 175-7, 175-8,
175-9, 175-10, 175-11, 175-12, 175-13, 175-14, 175-15, 175-16,
175-17, 175-18, 175-19, 175-20, 175-21, 175-22, 175-23, 175-24,
175-25, 175-26, 175-27, 175-28, 175-29, 175-30, 175-31, 175-32,
175-33, 175-34, 175-35, 175-36, 175-37, 175-38, 175-39, 175-40,
175-41, 175-42, 175-43, 175-44, 175-45, 175-46, 175-47, 175-48,
175-49, 175-50, 175-51, 175-52, 175-53, 175-54, 175-55, 175-56,
175-57, 175-58, 175-59, 175-60, 175-61, 175-62, 175-63, 175-64,
175-65, 175-66, 175-67, 175-68, 175-69, 175-70, 175-71, 175-72,
175-73, 175-74, 175-75, 175-76, 175-77, 175-78, 175-79, 175-80,
175-81, 175-82, 175-83, 175-84, 175-85, 175-86, 175-87, 175-88,
175-89, 175-90, 175-91, 175-92, 175-93, 175-94, 175-95, 175-96,
175-97,
[0289] 176-1, 176-2, 176-3, 176-4, 176-5, 176-6, 176-7, 176-8,
176-9, 176-10, 176-11, 176-12, 176-13, 176-14, 176-15, 176-16,
176-17, 176-18, 176-19, 176-20, 176-21, 176-22, 176-23, 176-24,
176-25, 176-26, 176-27, 176-28, 176-29, 176-30, 176-31, 176-32,
176-33, 176-34, 176-35, 176-36, 176-37, 176-38, 176-39, 176-40,
176-41, 176-42, 176-43, 176-44, 176-45, 176-46, 176-47, 176-48,
176-49, 176-50, 176-51, 176-52, 176-53, 176-54, 176-55, 176-56,
176-57, 176-58, 176-59, 176-60, 176-61, 176-62, 176-63, 176-64,
176-65, 176-66, 176-67, 176-68, 176-69, 176-70, 176-71, 176-72,
176-73, 176-74, 176-75, 176-76, 176-77, 176-78, 176-79, 176-80,
176-81, 176-82, 176-83, 176-84, 176-85, 176-86, 176-87, 176-88,
176-89, 176-90, 176-91, 176-92, 176-93, 176-94, 176-95, 176-96,
176-97,
[0290] 177-1, 177-2, 177-3, 177-4, 177-5, 177-6, 177-7, 177-8,
177-9, 177-10, 177-11, 177-12, 177-13, 177-14, 177-15, 177-16,
177-17, 177-18, 177-19, 177-20, 177-21, 177-22, 177-23, 177-24,
177-25, 177-26, 177-27, 177-28, 177-29, 177-30, 177-31, 177-32,
177-33, 177-34, 177-35, 177-36, 177-37, 177-38, 177-39, 177-40,
177-41, 177-42, 177-43, 177-44, 177-45, 177-46, 177-47, 177-48,
177-49, 177-50, 177-51, 177-52, 177-53, 177-54, 177-55, 177-56,
177-57, 177-58, 177-59, 177-60, 177-61, 177-62, 177-63, 177-64,
177-65, 177-66, 177-67, 177-68, 177-69, 177-70, 177-71, 177-72,
177-73, 177-74, 177-75, 177-76, 177-77, 177-78, 177-79, 177-80,
177-81, 177-82, 177-83, 177-84, 177-85, 177-86, 177-87, 177-88,
177-89, 177-90, 177-91, 177-92, 177-93, 177-94, 177-95, 177-96,
177-97,
[0291] 178-1, 178-2, 178-3, 178-4, 178-5, 178-6, 178-7, 178-8,
178-9, 178-10, 178-11, 178-12, 178-13, 178-14, 178-15, 178-16,
178-17, 178-18, 178-19, 178-20, 178-21, 178-22, 178-23, 178-24,
178-25, 178-26, 178-27, 178-28, 178-29, 178-30, 178-31, 178-32,
178-33, 178-34, 178-35, 178-36, 178-37, 178-38, 178-39, 178-40,
178-41, 178-42, 178-43, 178-44, 178-45, 178-46, 178-47, 178-48,
178-49, 178-50, 178-51, 178-52, 178-53, 178-54, 178-55, 178-56,
178-57, 178-58, 178-59, 178-60, 178-61, 178-62, 178-63, 178-64,
178-65, 178-66, 178-67, 178-68, 178-69, 178-70, 178-71, 178-72,
178-73, 178-74, 178-75, 178-76, 178-77, 178-78, 178-79, 178-80,
178-81, 178-82, 178-83, 178-84, 178-85, 178-86, 178-87, 178-88,
178-89, 178-90, 178-91, 178-92, 178-93, 178-94, 178-95, 178-96,
178-97,
[0292] 179-1, 179-2, 179-3, 179-4, 179-5, 179-6, 179-7, 179-8,
179-9, 179-10, 179-11, 179-12, 179-13, 179-14, 179-15, 179-16,
179-17, 179-18, 179-19, 179-20, 179-21, 179-22, 179-23, 179-24,
179-25, 179-26, 179-27, 179-28, 179-29, 179-30, 179-31, 179-32,
179-33, 179-34, 179-35, 179-36, 179-37, 179-38, 179-39, 179-40,
179-41, 179-42, 179-43, 179-44, 179-45, 179-46, 179-47, 179-48,
179-49, 179-50, 179-51, 179-52, 179-53, 179-54, 179-55, 179-56,
179-57, 179-58, 179-59, 179-60, 179-61, 179-62, 179-63, 179-64,
179-65, 179-66, 179-67, 179-68, 179-69, 179-70, 179-71, 179-72,
179-73, 179-74, 179-75, 179-76, 179-77, 179-78, 179-79, 179-80,
179-81, 179-82, 179-83, 179-84, 179-85, 179-86, 179-87, 179-88,
179-89, 179-90, 179-91, 179-92, 179-93, 179-94, 179-95, 179-96,
179-97,
[0293] 180-1, 180-2, 180-3, 180-4, 180-5, 180-6, 180-7, 180-8,
180-9, 180-10, 180-11, 180-12, 180-13, 180-14, 180-15, 180-16,
180-17, 180-18, 180-19, 180-20, 180-21, 180-22, 180-23, 180-24,
180-25, 180-26, 180-27, 180-28, 180-29, 180-30, 180-31, 180-32,
180-33, 180-34, 180-35, 180-36, 180-37, 180-38, 180-39, 180-40,
180-41, 180-42, 180-43, 180-44, 180-45, 180-46, 180-47, 180-48,
180-49, 180-50, 180-51, 180-52, 180-53, 180-54, 180-55, 180-56,
180-57, 180-58, 180-59, 180-60, 180-61, 180-62, 180-63, 180-64,
180-65, 180-66, 180-67, 180-68, 180-69, 180-70, 180-71, 180-72,
180-73, 180-74, 180-75, 180-76, 180-77, 180-78, 180-79, 180-80,
180-81, 180-82, 180-83, 180-84, 180-85, 180-86, 180-87, 180-88,
180-89, 180-90, 180-91, 180-92, 180-93, 180-94, 180-95, 180-96,
180-97,
[0294] 181-1, 181-2, 181-3, 181-4, 181-5, 181-6, 181-7, 181-8,
181-9, 181-10, 181-11, 181-12, 181-13, 181-14, 181-15, 181-16,
181-17, 181-18, 181-19, 181-20, 181-21, 181-22, 181-23, 181-24,
181-25, 181-26, 181-27, 181-28, 181-29, 181-30, 181-31, 181-32,
181-33, 181-34, 181-35, 181-36, 181-37, 181-38, 181-39, 181-40,
181-41, 181-42, 181-43, 181-44, 181-45, 181-46, 181-47, 181-48,
181-49, 181-50, 181-51, 181-52, 181-53, 181-54, 181-55, 181-56,
181-57, 181-58, 181-59, 181-60, 181-61, 181-62, 181-63, 181-64,
181-65, 181-66, 181-67, 181-68, 181-69, 181-70, 181-71, 181-72,
181-73, 181-74, 181-75, 181-76, 181-77, 181-78, 181-79, 181-80,
181-81, 181-82, 181-83, 181-84, 181-85, 181-86, 181-87, 181-88,
181-89, 181-90, 181-91, 181-92, 181-93, 181-94, 181-95, 181-96,
181-97,
[0295] 182-1, 182-2, 182-3, 182-4, 182-5, 182-6, 182-7, 182-8,
182-9, 182-10, 182-11, 182-12, 182-13, 182-14, 182-15, 182-16,
182-17, 182-18, 182-19, 182-20, 182-21, 182-22, 182-23, 182-24,
182-25, 182-26, 182-27, 182-28, 182-29, 182-30, 182-31, 182-32,
182-33, 182-34, 182-35, 182-36, 182-37, 182-38, 182-39, 182-40,
182-41, 182-42, 182-43, 182-44, 182-45, 182-46, 182-47, 182-48,
182-49, 182-50, 182-51, 182-52, 182-53, 182-54, 182-55, 182-56,
182-57, 182-58, 182-59, 182-60, 182-61, 182-62, 182-63, 182-64,
182-65, 182-66, 182-67, 182-68, 182-69, 182-70, 182-71, 182-72,
182-73, 182-74, 182-75, 182-76, 182-77, 182-78, 182-79, 182-80,
182-81, 182-82, 182-83, 182-84, 182-85, 182-86, 182-87, 182-88,
182-89, 182-90, 182-91, 182-92, 182-93, 182-94, 182-95, 182-96,
182-97,
[0296] 183-1, 183-2, 183-3, 183-4, 183-5, 183-6, 183-7, 183-8,
183-9, 183-10, 183-11, 183-12, 183-13, 183-14, 183-15, 183-16,
183-17, 183-18, 183-19, 183-20, 183-21, 183-22, 183-23, 183-24,
183-25, 183-26, 183-27, 183-28, 183-29, 183-30, 183-31, 183-32,
183-33, 183-34, 183-35, 183-36, 183-37, 183-38, 183-39, 183-40,
183-41, 183-42, 183-43, 183-44, 183-45, 183-46, 183-47, 183-48,
183-49, 183-50, 183-51, 183-52, 183-53, 183-54, 183-55, 183-56,
183-57, 183-58, 183-59, 183-60, 183-61, 183-62, 183-63, 183-64,
183-65, 183-66, 183-67, 183-68, 183-69, 183-70, 183-71, 183-72,
183-73, 183-74, 183-75, 183-76, 183-77, 183-78, 183-79, 183-80,
183-81, 183-82, 183-83, 183-84, 183-85, 183-86, 183-87, 183-88,
183-89, 183-90, 183-91, 183-92, 183-93, 183-94, 183-95, 183-96,
183-97,
[0297] 184-1, 184-2, 184-3, 184-4, 184-5, 184-6, 184-7, 184-8,
184-9, 184-10, 184-11, 184-12, 184-13, 184-14, 184-15, 184-16,
184-17, 184-18, 184-19, 184-20, 184-21, 184-22, 184-23, 184-24,
184-25, 184-26, 184-27, 184-28, 184-29, 184-30, 184-31, 184-32,
184-33, 184-34, 184-35, 184-36, 184-37, 184-38, 184-39, 184-40,
184-41, 184-42, 184-43, 184-44, 184-45, 184-46, 184-47, 184-48,
184-49, 184-50, 184-51, 184-52, 184-53, 184-54, 184-55, 184-56,
184-57, 184-58, 184-59, 184-60, 184-61, 184-62, 184-63, 184-64,
184-65, 184-66, 184-67, 184-68, 184-69, 184-70, 184-71, 184-72,
184-73, 184-74, 184-75, 184-76, 184-77, 184-78, 184-79, 184-80,
184-81, 184-82, 184-83, 184-84, 184-85, 184-86, 184-87, 184-88,
184-89, 184-90, 184-91, 184-92, 184-93, 184-94, 184-95, 184-96,
184-97,
[0298] 185-1, 185-2, 185-3, 185-4, 185-5, 185-6, 185-7, 185-8,
185-9, 185-10, 185-11, 185-12, 185-13, 185-14, 185-15, 185-16,
185-17, 185-18, 185-19, 185-20, 185-21, 185-22, 185-23, 185-24,
185-25, 185-26, 185-27, 185-28, 185-29, 185-30, 185-31, 185-32,
185-33, 185-34, 185-35, 185-36, 185-37, 185-38, 185-39, 185-40,
185-41, 185-42, 185-43, 185-44, 185-45, 185-46, 185-47, 185-48,
185-49, 185-50, 185-51, 185-52, 185-53, 185-54, 185-55, 185-56,
185-57, 185-58, 185-59, 185-60, 185-61, 185-62, 185-63, 185-64,
185-65, 185-66, 185-67, 185-68, 185-69, 185-70, 185-71, 185-72,
185-73, 185-74, 185-75, 185-76, 185-77, 185-78, 185-79, 185-80,
185-81, 185-82, 185-83, 185-84, 185-85, 185-86, 185-87, 185-88,
185-89, 185-90, 185-91, 185-92, 185-93, 185-94, 185-95, 185-96,
185-97,
[0299] 186-1, 186-2, 186-3, 186-4, 186-5, 186-6, 186-7, 186-8,
186-9, 186-10, 186-11, 186-12, 186-13, 186-14, 186-15, 186-16,
186-17, 186-18, 186-19, 186-20, 186-21, 186-22, 186-23, 186-24,
186-25, 186-26, 186-27, 186-28, 186-29, 186-30, 186-31, 186-32,
186-33, 186-34, 186-35, 186-36, 186-37, 186-38, 186-39, 186-40,
186-41, 186-42, 186-43, 186-44, 186-45, 186-46, 186-47, 186-48,
186-49, 186-50, 186-51, 186-52, 186-53, 186-54, 186-55, 186-56,
186-57, 186-58, 186-59, 186-60, 186-61, 186-62, 186-63, 186-64,
186-65, 186-66, 186-67, 186-68, 186-69, 186-70, 186-71, 186-72,
186-73, 186-74, 186-75, 186-76, 186-77, 186-78, 186-79, 186-80,
186-81, 186-82, 186-83, 186-84, 186-85, 186-86, 186-87, 186-88,
186-89, 186-90, 186-91, 186-92, 186-93, 186-94, 186-95, 186-96,
186-97,
[0300] 187-1, 187-2, 187-3, 187-4, 187-5, 187-6, 187-7, 187-8,
187-9, 187-10, 187-11, 187-12, 187-13, 187-14, 187-15, 187-16,
187-17, 187-18, 187-19, 187-20, 187-21, 187-22, 187-23, 187-24,
187-25, 187-26, 187-27, 187-28, 187-29, 187-30, 187-31, 187-32,
187-33, 187-34, 187-35, 187-36, 187-37, 187-38, 187-39, 187-40,
187-41, 187-42, 187-43, 187-44, 187-45, 187-46, 187-47, 187-48,
187-49, 187-50, 187-51, 187-52, 187-53, 187-54, 187-55, 187-56,
187-57, 187-58, 187-59, 187-60, 187-61, 187-62, 187-63, 187-64,
187-65, 187-66, 187-67, 187-68, 187-69, 187-70, 187-71, 187-72,
187-73, 187-74, 187-75, 187-76, 187-77, 187-78, 187-79, 187-80,
187-81, 187-82, 187-83, 187-84, 187-85, 187-86, 187-87, 187-88,
187-89, 187-90, 187-91, 187-92, 187-93, 187-94, 187-95, 187-96,
187-97,
[0301] 188-1, 188-2, 188-3, 188-4, 188-5, 188-6, 188-7, 188-8,
188-9, 188-10, 188-11, 188-12, 188-13, 188-14, 188-15, 188-16,
188-17, 188-18, 188-19, 188-20, 188-21, 188-22, 188-23, 188-24,
188-25, 188-26, 188-27, 188-28, 188-29, 188-30, 188-31, 188-32,
188-33, 188-34, 188-35, 188-36, 188-37, 188-38, 188-39, 188-40,
188-41, 188-42, 188-43, 188-44, 188-45, 188-46, 188-47, 188-48,
188-49, 188-50, 188-51, 188-52, 188-53, 188-54, 188-55, 188-56,
188-57, 188-58, 188-59, 188-60, 188-61, 188-62, 188-63, 188-64,
188-65, 188-66, 188-67, 188-68, 188-69, 188-70, 188-71, 188-72,
188-73, 188-74, 188-75, 188-76, 188-77, 188-78, 188-79, 188-80,
188-81, 188-82, 188-83, 188-84, 188-85, 188-86, 188-87, 188-88,
188-89, 188-90, 188-91, 188-92, 188-93, 188-94, 188-95, 188-96,
188-97,
[0302] 189-1, 189-2, 189-3, 189-4, 189-5, 189-6, 189-7, 189-8,
189-9, 189-10, 189-11, 189-12, 189-13, 189-14, 189-15, 189-16,
189-17, 189-18, 189-19, 189-20, 189-21, 189-22, 189-23, 189-24,
189-25, 189-26, 189-27, 189-28, 189-29, 189-30, 189-31, 189-32,
189-33, 189-34, 189-35, 189-36, 189-37, 189-38, 189-39, 189-40,
189-41, 189-42, 189-43, 189-44, 189-45, 189-46, 189-47, 189-48,
189-49, 189-50, 189-51, 189-52, 189-53, 189-54, 189-55, 189-56,
189-57, 189-58, 189-59, 189-60, 189-61, 189-62, 189-63, 189-64,
189-65, 189-66, 189-67, 189-68, 189-69, 189-70, 189-71, 189-72,
189-73, 189-74, 189-75, 189-76, 189-77, 189-78, 189-79, 189-80,
189-81, 189-82, 189-83, 189-84, 189-85, 189-86, 189-87, 189-88,
189-89, 189-90, 189-91, 189-92, 189-93, 189-94, 189-95, 189-96,
189-97,
[0303] 190-1, 190-2, 190-3, 190-4, 190-5, 190-6, 190-7, 190-8,
190-9, 190-10, 190-11, 190-12, 190-13, 190-14, 190-15, 190-16,
190-17, 190-18, 190-19, 190-20, 190-21, 190-22, 190-23, 190-24,
190-25, 190-26, 190-27, 190-28, 190-29, 190-30, 190-31, 190-32,
190-33, 190-34, 190-35, 190-36, 190-37, 190-38, 190-39, 190-40,
190-41, 190-42, 190-43, 190-44, 190-45, 190-46, 190-47, 190-48,
190-49, 190-50, 190-51, 190-52, 190-53, 190-54, 190-55, 190-56,
190-57, 190-58, 190-59, 190-60, 190-61, 190-62, 190-63, 190-64,
190-65, 190-66, 190-67, 190-68, 190-69, 190-70, 190-71, 190-72,
190-73, 190-74, 190-75, 190-76, 190-77, 190-78, 190-79, 190-80,
190-81, 190-82, 190-83, 190-84, 190-85, 190-86, 190-87, 190-88,
190-89, 190-90, 190-91, 190-92, 190-93, 190-94, 190-95, 190-96,
190-97,
[0304] 191-1, 191-2, 191-3, 191-4, 191-5, 191-6, 191-7, 191-8,
191-9, 191-10, 191-11, 191-12, 191-13, 191-14, 191-15, 191-16,
191-17, 191-18, 191-19, 191-20, 191-21, 191-22, 191-23, 191-24,
191-25, 191-26, 191-27, 191-28, 191-29, 191-30, 191-31, 191-32,
191-33, 191-34, 191-35, 191-36, 191-37, 191-38, 191-39, 191-40,
191-41, 191-42, 191-43, 191-44, 191-45, 191-46, 191-47, 191-48,
191-49, 191-50, 191-51, 191-52, 191-53, 191-54, 191-55, 191-56,
191-57, 191-58, 191-59, 191-60, 191-61, 191-62, 191-63, 191-64,
191-65, 191-66, 191-67, 191-68, 191-69, 191-70, 191-71, 191-72,
191-73, 191-74, 191-75, 191-76, 191-77, 191-78, 191-79, 191-80,
191-81, 191-82, 191-83, 191-84, 191-85, 191-86, 191-87, 191-88,
191-89, 191-90, 191-91, 191-92, 191-93, 191-94, 191-95, 191-96,
191-97,
[0305] 192-1, 192-2, 192-3, 192-4, 192-5, 192-6, 192-7, 192-8,
192-9, 192-10, 192-11, 192-12, 192-13, 192-14, 192-15, 192-16,
192-17, 192-18, 192-19, 192-20, 192-21, 192-22, 192-23, 192-24,
192-25, 192-26, 192-27, 192-28, 192-29, 192-30, 192-31, 192-32,
192-33, 192-34, 192-35, 192-36, 192-37, 192-38, 192-39, 192-40,
192-41, 192-42, 192-43, 192-44, 192-45, 192-46, 192-47, 192-48,
192-49, 192-50, 192-51, 192-52, 192-53, 192-54, 192-55, 192-56,
192-57, 192-58, 192-59, 192-60, 192-61, 192-62, 192-63, 192-64,
192-65, 192-66, 192-67, 192-68, 192-69, 192-70, 192-71, 192-72,
192-73, 192-74, 192-75, 192-76, 192-77, 192-78, 192-79, 192-80,
192-81, 192-82, 192-83, 192-84, 192-85, 192-86, 192-87, 192-88,
192-89, 192-90, 192-91, 192-92, 192-93, 192-94, 192-95, 192-96,
192-97,
[0306] 193-1, 193-2, 193-3, 193-4, 193-5, 193-6, 193-7, 193-8,
193-9, 193-10, 193-11, 193-12, 193-13, 193-14, 193-15, 193-16,
193-17, 193-18, 193-19, 193-20, 193-21, 193-22, 193-23, 193-24,
193-25, 193-26, 193-27, 193-28, 193-29, 193-30, 193-31, 193-32,
193-33, 193-34, 193-35, 193-36, 193-37, 193-38, 193-39, 193-40,
193-41, 193-42, 193-43, 193-44, 193-45, 193-46, 193-47, 193-48,
193-49, 193-50, 193-51, 193-52, 193-53, 193-54, 193-55, 193-56,
193-57, 193-58, 193-59, 193-60, 193-61, 193-62, 193-63, 193-64,
193-65, 193-66, 193-67, 193-68, 193-69, 193-70, 193-71, 193-72,
193-73, 193-74, 193-75, 193-76, 193-77, 193-78, 193-79, 193-80,
193-81, 193-82, 193-83, 193-84, 193-85, 193-86, 193-87, 193-88,
193-89, 193-90, 193-91, 193-92, 193-93, 193-94, 193-95, 193-96,
193-97,
[0307] 194-1, 194-2, 194-3, 194-4, 194-5, 194-6, 194-7, 194-8,
194-9, 194-10, 194-11, 194-12, 194-13, 194-14, 194-15, 194-16,
194-17, 194-18, 194-19, 194-20, 194-21, 194-22, 194-23, 194-24,
194-25, 194-26, 194-27, 194-28, 194-29, 194-30, 194-31, 194-32,
194-33, 194-34, 194-35, 194-36, 194-37, 194-38, 194-39, 194-40,
194-41, 194-42, 194-43, 194-44, 194-45, 194-46, 194-47, 194-48,
194-49, 194-50, 194-51, 194-52, 194-53, 194-54, 194-55, 194-56,
194-57, 194-58, 194-59, 194-60, 194-61, 194-62, 194-63, 194-64,
194-65, 194-66, 194-67, 194-68, 194-69, 194-70, 194-71, 194-72,
194-73, 194-74, 194-75, 194-76, 194-77, 194-78, 194-79, 194-80,
194-81, 194-82, 194-83, 194-84, 194-85, 194-86, 194-87, 194-88,
194-89, 194-90, 194-91, 194-92, 194-93, 194-94, 194-95, 194-96,
194-97,
[0308] 195-1, 195-2, 195-3, 195-4, 195-5, 195-6, 195-7, 195-8,
195-9, 195-10, 195-11, 195-12, 195-13, 195-14, 195-15, 195-16,
195-17, 195-18, 195-19, 195-20, 195-21, 195-22, 195-23, 195-24,
195-25, 195-26, 195-27, 195-28, 195-29, 195-30, 195-31, 195-32,
195-33, 195-34, 195-35, 195-36, 195-37, 195-38, 195-39, 195-40,
195-41, 195-42, 195-43, 195-44, 195-45, 195-46, 195-47, 195-48,
195-49, 195-50, 195-51, 195-52, 195-53, 195-54, 195-55, 195-56,
195-57, 195-58, 195-59, 195-60, 195-61, 195-62, 195-63, 195-64,
195-65, 195-66, 195-67, 195-68, 195-69, 195-70, 195-71, 195-72,
195-73, 195-74, 195-75, 195-76, 195-77, 195-78, 195-79, 195-80,
195-81, 195-82, 195-83, 195-84, 195-85, 195-86, 195-87, 195-88,
195-89, 195-90, 195-91, 195-92, 195-93, 195-94, 195-95, 195-96,
195-97,
[0309] 196-1, 196-2, 196-3, 196-4, 196-5, 196-6, 196-7, 196-8,
196-9, 196-10, 196-11, 196-12, 196-13, 196-14, 196-15, 196-16,
196-17, 196-18, 196-19, 196-20, 196-21, 196-22, 196-23, 196-24,
196-25, 196-26, 196-27, 196-28, 196-29, 196-30, 196-31, 196-32,
196-33, 196-34, 196-35, 196-36, 196-37, 196-38, 196-39, 196-40,
196-41, 196-42, 196-43, 196-44, 196-45, 196-46, 196-47, 196-48,
196-49, 196-50, 196-51, 196-52, 196-53, 196-54, 196-55, 196-56,
196-57, 196-58, 196-59, 196-60, 196-61, 196-62, 196-63, 196-64,
196-65, 196-66, 196-67, 196-68, 196-69, 196-70, 196-71, 196-72,
196-73, 196-74, 196-75, 196-76, 196-77, 196-78, 196-79, 196-80,
196-81, 196-82, 196-83, 196-84, 196-85, 196-86, 196-87, 196-88,
196-89, 196-90, 196-91, 196-92, 196-93, 196-94, 196-95, 196-96,
196-97,
[0310] 197-1, 197-2, 197-3, 197-4, 197-5, 197-6, 197-7, 197-8,
197-9, 197-10, 197-11, 197-12, 197-13, 197-14, 197-15, 197-16,
197-17, 197-18, 197-19, 197-20, 197-21, 197-22, 197-23, 197-24,
197-25, 197-26, 197-27, 197-28, 197-29, 197-30, 197-31, 197-32,
197-33, 197-34, 197-35, 197-36, 197-37, 197-38, 197-39, 197-40,
197-41, 197-42, 197-43, 197-44, 197-45, 197-46, 197-47, 197-48,
197-49, 197-50, 197-51, 197-52, 197-53, 197-54, 197-55, 197-56,
197-57, 197-58, 197-59, 197-60, 197-61, 197-62, 197-63, 197-64,
197-65, 197-66, 197-67, 197-68, 197-69, 197-70, 197-71, 197-72,
197-73, 197-74, 197-75, 197-76, 197-77, 197-78, 197-79, 197-80,
197-81, 197-82, 197-83, 197-84, 197-85, 197-86, 197-87, 197-88,
197-89, 197-90, 197-91, 197-92, 197-93, 197-94, 197-95, 197-96,
197-97,
[0311] 198-1, 198-2, 198-3, 198-4, 198-5, 198-6, 198-7, 198-8,
198-9, 198-10, 198-11, 198-12, 198-13, 198-14, 198-15, 198-16,
198-17, 198-18, 198-19, 198-20, 198-21, 198-22, 198-23, 198-24,
198-25, 198-26, 198-27, 198-28, 198-29, 198-30, 198-31, 198-32,
198-33, 198-34, 198-35, 198-36, 198-37, 198-38, 198-39, 198-40,
198-41, 198-42, 198-43, 198-44, 198-45, 198-46, 198-47, 198-48,
198-49, 198-50, 198-51, 198-52, 198-53, 198-54, 198-55, 198-56,
198-57, 198-58, 198-59, 198-60, 198-61, 198-62, 198-63, 198-64,
198-65, 198-66, 198-67, 198-68, 198-69, 198-70, 198-71, 198-72,
198-73, 198-74, 198-75, 198-76, 198-77, 198-78, 198-79, 198-80,
198-81, 198-82, 198-83, 198-84, 198-85, 198-86, 198-87, 198-88,
198-89, 198-90, 198-91, 198-92, 198-93, 198-94, 198-95, 198-96,
198-97,
[0312] 199-1, 199-2, 199-3, 199-4, 199-5, 199-6, 199-7, 199-8,
199-9, 199-10, 199-11, 199-12, 199-13, 199-14, 199-15, 199-16,
199-17, 199-18, 199-19, 199-20, 199-21, 199-22, 199-23, 199-24,
199-25, 199-26, 199-27, 199-28, 199-29, 199-30, 199-31, 199-32,
199-33, 199-34, 199-35, 199-36, 199-37, 199-38, 199-39, 199-40,
199-41, 199-42, 199-43, 199-44, 199-45, 199-46, 199-47, 199-48,
199-49, 199-50, 199-51, 199-52, 199-53, 199-54, 199-55, 199-56,
199-57, 199-58, 199-59, 199-60, 199-61, 199-62, 199-63, 199-64,
199-65, 199-66, 199-67, 199-68, 199-69, 199-70, 199-71, 199-72,
199-73, 199-74, 199-75, 199-76, 199-77, 199-78, 199-79, 199-80,
199-81, 199-82, 199-83, 199-84, 199-85, 199-86, 199-87, 199-88,
199-89, 199-90, 199-91, 199-92, 199-93, 199-94, 199-95, 199-96,
199-97,
[0313] 200-1, 200-2, 200-3, 200-4, 200-5, 200-6, 200-7, 200-8,
200-9, 200-10, 200-11, 200-12, 200-13, 200-14, 200-15, 200-16,
200-17, 200-18, 200-19, 200-20, 200-21, 200-22, 200-23, 200-24,
200-25, 200-26, 200-27, 200-28, 200-29, 200-30, 200-31, 200-32,
200-33, 200-34, 200-35, 200-36, 200-37, 200-38, 200-39, 200-40,
200-41, 200-42, 200-43, 200-44, 200-45, 200-46, 200-47, 200-48,
200-49, 200-50, 200-51, 200-52, 200-53, 200-54, 200-55, 200-56,
200-57, 200-58, 200-59, 200-60, 200-61, 200-62, 200-63, 200-64,
200-65, 200-66, 200-67, 200-68, 200-69, 200-70, 200-71, 200-72,
200-73, 200-74, 200-75, 200-76, 200-77, 200-78,.200-79, 200-80,
200-81, 200-82, 200-83, 200-84, 200-85, 200-86, 200-87, 200-88,
200-89, 200-90, 200-91, 200-92, 200-93, 200-94, 200-95, 200-96,
200-97,
[0314] 201-1, 201-2, 201-3, 201-4, 201-5, 201-6, 201-7, 201-8,
201-9, 201-10, 201-11, 201-12, 201-13, 201-14, 201-15, 201-16,
201-17, 201-18, 201-19, 201-20, 201-21, 201-22, 201-23, 201-24,
201-25, 201-26, 201-27, 201-28, 201-29, 201-30, 201-31, 201-32,
201-33, 201-34, 201-35, 201-36, 201-37, 201-38, 201-39, 201-40,
201-41, 201-42, 201-43, 201-44, 201-45, 201-46, 201-47, 201-48,
201-49, 201-50, 201-51, 201-52, 201-53, 201-54, 201-55, 201-56,
201-57, 201-58, 201-59, 201-60, 201-61, 201-62, 201-63, 201-64,
201-65, 201-66, 201-67, 201-68, 201-69, 201-70, 201-71, 201-72,
201-73, 201-74, 201-75, 201-76, 201-77, 201-78, 201-79, 201-80,
201-81, 201-82, 201-83, 201-84, 201-85, 201-86, 201-87, 201-88,
201-89, 201-90, 201-91, 201-92, 201-93, 201-94, 201-95, 201-96,
201-97,
[0315] 202-1, 202-2, 202-3, 202-4, 202-5, 202-6, 202-7, 202-8,
202-9, 202-10, 202-11, 202-12, 202-13, 202-14, 202-15, 202-16,
202-17, 202-18, 202-19, 202-20, 202-21, 202-22, 202-23, 202-24,
202-25, 202-26, 202-27, 202-28, 202-29, 202-30, 202-31, 202-32,
202-33, 202-34, 202-35, 202-36, 202-37, 202-38, 202-39, 202-40,
202-41, 202-42, 202-43, 202-44, 202-45, 202-46, 202-47, 202-48,
202-49, 202-50, 202-51, 202-52, 202-53, 202-54, 202-55, 202-56,
202-57, 202-58, 202-59, 202-60, 202-61, 202-62, 202-63, 202-64,
202-65, 202-66, 202-67, 202-68, 202-69, 202-70, 202-71, 202-72,
202-73, 202-74, 202-75, 202-76, 202-77, 202-78, 202-79, 202-80,
202-81, 202-82, 202-83, 202-84, 202-85, 202-86, 202-87, 202-88,
202-89, 202-90, 202-91, 202-92, 202-93, 202-94, 202-95, 202-96,
202-97,
[0316] 203-1, 203-2, 203-3, 203-4, 203-5, 203-6, 203-7, 203-8,
203-9, 203-10, 203-11, 203-12, 203-13, 203-14, 203-15, 203-16,
203-17, 203-18, 203-19, 203-20, 203-21, 203-22, 203-23, 203-24,
203-25, 203-26, 203-27, 203-28, 203-29, 203-30, 203-31, 203-32,
203-33, 203-34, 203-35, 203-36, 203-37, 203-38, 203-39, 203-40,
203-41, 203-42, 203-43, 203-44, 203-45, 203-46, 203-47, 203-48,
203-49, 203-50, 203-51, 203-52, 203-53, 203-54, 203-55, 203-56,
203-57, 203-58, 203-59, 203-60, 203-61, 203-62, 203-63, 203-64,
203-65, 203-66, 203-67, 203-68, 203-69, 203-70, 203-71, 203-72,
203-73, 203-74, 203-75, 203-76, 203-77, 203-78, 203-79, 203-80,
203-81, 203-82, 203-83, 203-84, 203-85, 203-86, 203-87, 203-88,
203-89, 203-90, 203-91, 203-92, 203-93, 203-94, 203-95, 203-96,
203-97,
[0317] 204-1, 204-2, 204-3, 204-4, 204-5, 204-6, 204-7, 204-8,
204-9, 204-10, 204-11, 204-12, 204-13, 204-14, 204-15, 204-16,
204-17, 204-18, 204-19, 204-20, 204-21, 204-22, 204-23, 204-24,
204-25, 204-26, 204-27, 204-28, 204-29, 204-30, 204-31, 204-32,
204-33, 204-34, 204-35, 204-36, 204-37, 204-38, 204-39, 204-40,
204-41, 204-42, 204-43, 204-44, 204-45, 204-46, 204-47, 204-48,
204-49, 204-50, 204-51, 204-52, 204-53, 204-54, 204-55, 204-56,
204-57, 204-58, 204-59, 204-60, 204-61, 204-62, 204-63, 204-64,
204-65, 204-66, 204-67, 204-68, 204-69, 204-70, 204-71, 204-72,
204-73, 204-74, 204-75, 204-76, 204-77, 204-78, 204-79, 204-80,
204-81, 204-82, 204-83, 204-84, 204-85, 204-86, 204-87, 204-88,
204-89, 204-90, 204-91, 204-92, 204-93, 204-94, 204-95, 204-96,
204-97,
[0318] 205-1, 205-2, 205-3, 205-4, 205-5, 205-6, 205-7, 205-8,
205-9, 205-10, 205-11, 205-12, 205-13, 205-14, 205-15, 205-16,
205-17, 205-18, 205-19, 205-20, 205-21, 205-22, 205-23, 205-24,
205-25, 205-26, 205-27, 205-28, 205-29, 205-30, 205-31, 205-32,
205-33, 205-34, 205-35, 205-36, 205-37, 205-38, 205-39, 205-40,
205-41, 205-42, 205-43, 205-44, 205-45, 205-46, 205-47, 205-48,
205-49, 205-50, 205-51, 205-52, 205-53, 205-54, 205-55, 205-56,
205-57, 205-58, 205-59, 205-60, 205-61, 205-62, 205-63, 205-64,
205-65, 205-66, 205-67, 205-68, 205-69, 205-70, 205-71, 205-72,
205-73, 205-74, 205-75, 205-76, 205-77, 205-78, 205-79, 205-80,
205-81, 205-82, 205-83, 205-84, 205-85, 205-86, 205-87, 205-88,
205-89, 205-90, 205-91, 205-92, 205-93, 205-94, 205-95, 205-96,
205-97,
[0319] 206-1, 206-2, 206-3, 206-4, 206-5, 206-6, 206-7, 206-8,
206-9, 206-10, 206-11, 206-12, 206-13, 206-14, 206-15, 206-16,
206-17, 206-18, 206-19, 206-20, 206-21, 206-22, 206-23, 206-24,
206-25, 206-26, 206-27, 206-28, 206-29, 206-30, 206-31, 206-32,
206-33, 206-34, 206-35, 206-36, 206-37, 206-38, 206-39, 206-40,
206-41, 206-42, 206-43, 206-44, 206-45, 206-46, 206-47, 206-48,
206-49, 206-50, 206-51, 206-52, 206-53, 206-54, 206-55, 206-56,
206-57, 206-58, 206-59, 206-60, 206-61, 206-62, 206-63, 206-64,
206-65, 206-66, 206-67, 206-68, 206-69, 206-70, 206-71, 206-72,
206-73, 206-74, 206-75, 206-76, 206-77, 206-78, 206-79, 206-80,
206-81, 206-82, 206-83, 206-84, 206-85, 206-86, 206-87, 206-88,
206-89, 206-90, 206-91, 206-92, 206-93, 206-94, 206-95, 206-96,
206-97,
[0320] 207-1, 207-2, 207-3, 207-4, 207-5, 207-6, 207-7, 207-8,
207-9, 207-10, 207-11, 207-12, 207-13, 207-14, 207-15, 207-16,
207-17, 207-18, 207-19, 207-20, 207-21, 207-22, 207-23, 207-24,
207-25, 207-26, 207-27, 207-28, 207-29, 207-30, 207-31, 207-32,
207-33, 207-34, 207-35, 207-36, 207-37, 207-38, 207-39, 207-40,
207-41, 207-42, 207-43, 207-44, 207-45, 207-46, 207-47, 207-48,
207-49, 207-50, 207-51, 207-52, 207-53, 207-54, 207-55, 207-56,
207-57, 207-58, 207-59, 207-60, 207-61, 207-62, 207-63, 207-64,
207-65, 207-66, 207-67, 207-68, 207-69, 207-70, 207-71, 207-72,
207-73, 207-74, 207-75, 207-76, 207-77, 207-78, 207-79, 207-80,
207-81, 207-82, 207-83, 207-84, 207-85, 207-86, 207-87, 207-88,
207-89, 207-90, 207-91, 207-92, 207-93, 207-94, 207-95, 207-96,
207-97,
[0321] 208-1, 208-2, 208-3, 208-4, 208-5, 208-6, 208-7, 208-8,
208-9, 208-10, 208-11, 208-12, 208-13, 208-14, 208-15, 208-16,
208-17, 208-18, 208-19, 208-20, 208-21, 208-22, 208-23, 208-24,
208-25, 208-26, 208-27, 208-28, 208-29, 208-30, 208-31, 208-32,
208-33, 208-34, 208-35, 208-36, 208-37, 208-38, 208-39, 208-40,
208-41, 208-42, 208-43, 208-44, 208-45, 208-46, 208-47, 208-48,
208-49, 208-50, 208-51, 208-52, 208-53, 208-54, 208-55, 208-56,
208-57, 208-58, 208-59, 208-60, 208-61, 208-62, 208-63, 208-64,
208-65, 208-66, 208-67, 208-68, 208-69, 208-70, 208-71, 208-72,
208-73, 208-74, 208-75, 208-76, 208-77, 208-78, 208-79, 208-80,
208-81, 208-82, 208-83, 208-84, 208-85, 208-86, 208-87, 208-88,
208-89, 208-90, 208-91, 208-92, 208-93, 208-94, 208-95, 208-96,
208-97,
[0322] 209-1, 209-2, 209-3, 209-4, 209-5, 209-6, 209-7, 209-8,
209-9, 209-10, 209-11, 209-12, 209-13, 209-14, 209-15, 209-16,
209-17, 209-18, 209-19, 209-20, 209-21, 209-22, 209-23, 209-24,
209-25, 209-26, 209-27, 209-28, 209-29, 209-30, 209-31, 209-32,
209-33, 209-34, 209-35, 209-36, 209-37, 209-38, 209-39, 209-40,
209-41, 209-42, 209-43, 209-44, 209-45, 209-46, 209-47, 209-48,
209-49, 209-50, 209-51, 209-52, 209-53, 209-54, 209-55, 209-56,
209-57, 209-58, 209-59, 209-60, 209-61, 209-62, 209-63, 209-64,
209-65, 209-66, 209-67, 209-68, 209-69, 209-70, 209-71, 209-72,
209-73, 209-74, 209-75, 209-76, 209-77, 209-78, 209-79, 209-80,
209-81, 209-82, 209-83, 209-84, 209-85, 209-86, 209-87, 209-88,
209-89, 209-90, 209-91, 209-92, 209-93, 209-94, 209-95, 209-96,
209-97,
[0323] 210-1, 210-2, 210-3, 210-4, 210-5, 210-6, 210-7, 210-8,
210-9, 210-10, 210-11, 210-12, 210-13, 210-14, 210-15, 210-16,
210-17, 210-18, 210-19, 210-20, 210-21, 210-22, 210-23, 210-24,
210-25, 210-26, 210-27, 210-28, 210-29, 210-30, 210-31, 210-32,
210-33, 210-34, 210-35, 210-36, 210-37, 210-38, 210-39, 210-40,
210-41, 210-42, 210-43, 210-44, 210-45, 210-46, 210-47, 210-48,
210-49, 210-50, 210-51, 210-52, 210-53, 210-54, 210-55, 210-56,
210-57, 210-58, 210-59, 210-60, 210-61, 210-62, 210-63, 210-64,
210-65, 210-66, 210-67, 210-68, 210-69, 210-70, 210-71, 210-72,
210-73, 210-74, 210-75, 210-76, 210-77, 210-78, 210-79, 210-80,
210-81, 210-82, 210-83, 210-84, 210-85, 210-86, 210-87, 210-88,
210-89, 210-90, 210-91, 210-92, 210-93, 210-94, 210-95, 210-96,
210-97,
[0324] 211-1, 211-2, 211-3, 211-4, 211-5, 211-6, 211-7, 211-8,
211-9, 211-10, 211-11, 211-12, 211-13, 211-14, 211-15, 211-16,
211-17, 211-18, 211-19, 211-20, 211-21, 211-22, 211-23, 211-24,
211-25, 211-26, 211-27, 211-28, 211-29, 211-30, 211-31, 211-32,
211-33, 211-34, 211-35, 211-36, 211-37, 211-38, 211-39, 211-40,
211-41, 211-42, 211-43, 211-44, 211-45, 211-46, 211-47, 211-48,
211-49, 211-50, 211-51, 211-52, 211-53, 211-54, 211-55, 211-56,
211-57, 211-58, 211-59, 211-60, 211-61, 211-62, 211-63, 211-64,
211-65, 211-66, 211-67, 211-68, 211-69, 211-70, 211-71, 211-72,
211-73, 211-74, 211-75, 211-76, 211-77, 211-78, 211-79, 211-80,
211-81, 211-82, 211-83, 211-84, 211-85, 211-86, 211-87, 211-88,
211-89, 211-90, 211-91, 211-92, 211-93, 211-94, 211-95, 211-96,
211-97,
[0325] 212-1, 212-2, 212-3, 212-4, 212-5, 212-6, 212-7, 212-8,
212-9, 212-10, 212-11, 212-12, 212-13, 212-14, 212-15, 212-16,
212-17, 212-18, 212-19, 212-20, 212-21, 212-22, 212-23, 212-24,
212-25, 212-26, 212-27, 212-28, 212-29, 212-30, 212-31, 212-32,
212-33, 212-34, 212-35, 212-36, 212-37, 212-38, 212-39, 212-40,
212-41, 212-42, 212-43, 212-44, 212-45, 212-46, 212-47, 212-48,
212-49, 212-50, 212-51, 212-52, 212-53, 212-54, 212-55, 212-56,
212-57, 212-58, 212-59, 212-60, 212-61, 212-62, 212-63, 212-64,
212-65, 212-66, 212-67, 212-68, 212-69, 212-70, 212-71, 212-72,
212-73, 212-74, 212-75, 212-76, 212-77, 212-78, 212-79, 212-80,
212-81, 212-82, 212-83, 212-84, 212-85, 212-86, 212-87, 212-88,
212-89, 212-90, 212-91, 212-92, 212-93, 212-94, 212-95, 212-96,
212-97,
[0326] 213-1, 213-2, 213-3, 213-4, 213-5, 213-6, 213-7, 213-8,
213-9, 213-10, 213-11, 213-12, 213-13, 213-14, 213-15, 213-16,
213-17, 213-18, 213-19, 213-20, 213-21, 213-22, 213-23, 213-24,
213-25, 213-26, 213-27, 213-28, 213-29, 213-30, 213-31, 213-32,
213-33, 213-34, 213-35, 213-36, 213-37, 213-38, 213-39, 213-40,
213-41, 213-42, 213-43, 213-44, 213-45, 213-46, 213-47, 213-48,
213-49, 213-50, 213-51, 213-52, 213-53, 213-54, 213-55, 213-56,
213-57, 213-58, 213-59, 213-60, 213-61, 213-62, 213-63, 213-64,
213-65, 213-66, 213-67, 213-68, 213-69, 213-70, 213-71, 213-72,
213-73, 213-74, 213-75, 213-76, 213-77, 213-78, 213-79, 213-80,
213-81, 213-82, 213-83, 213-84, 213-85, 213-86, 213-87, 213-88,
213-89, 213-90, 213-91, 213-92, 213-93, 213-94, 213-95, 213-96,
213-97,
[0327] 214-1, 214-2, 214-3, 214-4, 214-5, 214-6, 214-7, 214-8,
214-9, 214-10, 214-11, 214-12, 214-13, 214-14, 214-15, 214-16,
214-17, 214-18, 214-19, 214-20, 214-21, 214-22, 214-23, 214-24,
214-25, 214-26, 214-27, 214-28, 214-29, 214-30, 214-31, 214-32,
214-33, 214-34, 214-35, 214-36, 214-37, 214-38, 214-39, 214-40,
214-41, 214-42, 214-43, 214-44, 214-45, 214-46, 214-47, 214-48,
214-49, 214-50, 214-51, 214-52, 214-53, 214-54, 214-55, 214-56,
214-57, 214-58, 214-59, 214-60, 214-61, 214-62, 214-63, 214-64,
214-65, 214-66, 214-67, 214-68, 214-69, 214-70, 214-71, 214-72,
214-73, 214-74, 214-75, 214-76, 214-77, 214-78, 214-79, 214-80,
214-81, 214-82, 214-83, 214-84, 214-85, 214-86, 214-87, 214-88,
214-89, 214-90, 214-91, 214-92, 214-93, 214-94, 214-95, 214-96,
214-97,
[0328] 215-1, 215-2, 215-3, 215-4, 215-5, 215-6, 215-7, 215-8,
215-9, 215-10, 215-11, 215-12, 215-13, 215-14, 215-15, 215-16,
215-17, 215-18, 215-19, 215-20, 215-21, 215-22, 215-23, 215-24,
215-25, 215-26, 215-27, 215-28, 215-29, 215-30, 215-31, 215-32,
215-33, 215-34, 215-35, 215-36, 215-37, 215-38, 215-39, 215-40,
215-41, 215-42, 215-43, 215-44, 215-45, 215-46, 215-47, 215-48,
215-49, 215-50, 215-51, 215-52, 215-53, 215-54, 215-55, 215-56,
215-57, 215-58, 215-59, 215-60, 215-61, 215-62, 215-63, 215-64,
215-65, 215-66, 215-67, 215-68, 215-69, 215-70, 215-71, 215-72,
215-73, 215-74, 215-75, 215-76, 215-77, 215-78, 215-79, 215-80,
215-81, 215-82, 215-83, 215-84, 215-85, 215-86, 215-87, 215-88,
215-89, 215-90, 215-91, 215-92, 215-93, 215-94, 215-95, 215-96,
215-97,
[0329] 216-1, 216-2, 216-3, 216-4, 216-5, 216-6, 216-7, 216-8,
216-9, 216-10, 216-11, 216-12, 216-13, 216-14, 216-15, 216-16,
216-17, 216-18, 216-19, 216-20, 216-21, 216-22, 216-23, 216-24,
216-25, 216-26, 216-27, 216-28, 216-29, 216-30, 216-31, 216-32,
216-33, 216-34, 216-35, 216-36, 216-37, 216-38, 216-39, 216-40,
216-41, 216-42, 216-43, 216-44, 216-45, 216-46, 216-47, 216-48,
216-49, 216-50, 216-51, 216-52, 216-53, 216-54, 216-55, 216-56,
216-57, 216-58, 216-59, 216-60, 216-61, 216-62, 216-63, 216-64,
216-65, 216-66, 216-67, 216-68, 216-69, 216-70, 216-71, 216-72,
216-73, 216-74, 216-75, 216-76, 216-77, 216-78, 216-79, 216-80,
216-81, 216-82, 216-83, 216-84, 216-85, 216-86, 216-87, 216-88,
216-89, 216-90, 216-91, 216-92, 216-93, 216-94, 216-95, 216-96,
216-97,
[0330] 217-1, 217-2, 217-3, 217-4, 217-5, 217-6, 217-7, 217-8,
217-9, 217-10, 217-11, 217-12, 217-13, 217-14, 217-15, 217-16,
217-17, 217-18, 217-19, 217-20, 217-21, 217-22, 217-23, 217-24,
217-25, 217-26, 217-27, 217-28, 217-29, 217-30, 217-31, 217-32,
217-33, 217-34, 217-35, 217-36, 217-37, 217-38, 217-39, 217-40,
217-41, 217-42, 217-43, 217-44, 217-45, 217-46, 217-47, 217-48,
217-49, 217-50, 217-51, 217-52, 217-53, 217-54, 217-55, 217-56,
217-57, 217-58, 217-59, 217-60, 217-61, 217-62, 217-63, 217-64,
217-65, 217-66, 217-67, 217-68, 217-69, 217-70, 217-71, 217-72,
217-73, 217-74, 217-75, 217-76, 217-77, 217-78, 217-79, 217-80,
217-81, 217-82, 217-83, 217-84, 217-85, 217-86, 217-87, 217-88,
217-89, 217-90, 217-91, 217-92, 217-93, 217-94, 217-95, 217-96,
217-97,
[0331] 218-1, 218-2, 218-3, 218-4, 218-5, 218-6, 218-7, 218-8,
218-9, 218-10, 218-11, 218-12, 218-13, 218-14, 218-15, 218-16,
218-17, 218-18, 218-19, 218-20, 218-21, 218-22, 218-23, 218-24,
218-25, 218-26, 218-27, 218-28, 218-29, 218-30, 218-31, 218-32,
218-33, 218-34, 218-35, 218-36, 218-37, 218-38, 218-39, 218-40,
218-41, 218-42, 218-43, 218-44, 218-45, 218-46, 218-47, 218-48,
218-49, 218-50, 218-51, 218-52, 218-53, 218-54, 218-55, 218-56,
218-57, 218-58, 218-59, 218-60, 218-61, 218-62, 218-63, 218-64,
218-65, 218-66, 218-67, 218-68, 218-69, 218-70, 218-71, 218-72,
218-73, 218-74, 218-75, 218-76, 218-77, 218-78, 218-79, 218-80,
218-81, 218-82, 218-83, 218-84, 218-85, 218-86, 218-87, 218-88,
218-89, 218-90, 218-91, 218-92, 218-93, 218-94, 218-95, 218-96,
218-97,
[0332] 219-1, 219-2, 219-3, 219-4, 219-5, 219-6, 219-7, 219-8,
219-9, 219-10, 219-11, 219-12, 219-13, 219-14, 219-15, 219-16,
219-17, 219-18, 219-19, 219-20, 219-21, 219-22, 219-23, 219-24,
219-25, 219-26, 219-27, 219-28, 219-29, 219-30, 219-31, 219-32,
219-33, 219-34, 219-35, 219-36, 219-37, 219-38, 219-39, 219-40,
219-41, 219-42, 219-43, 219-44, 219-45, 219-46, 219-47, 219-48,
219-49, 219-50, 219-51, 219-52, 219-53, 219-54, 219-55, 219-56,
219-57, 219-58, 219-59, 219-60, 219-61, 219-62, 219-63, 219-64,
219-65, 219-66, 219-67, 219-68, 219-69, 219-70, 219-71, 219-72,
219-73, 219-74, 219-75, 219-76, 219-77, 219-78, 219-79, 219-80,
219-81, 219-82, 219-83, 219-84, 219-85, 219-86, 219-87, 219-88,
219-89, 219-90, 219-91, 219-92, 219-93, 219-94, 219-95, 219-96,
219-97,
[0333] 220-1, 220-2, 220-3, 220-4, 220-5, 220-6, 220-7, 220-8,
220-9, 220-10, 220-11, 220-12, 220-13, 220-14, 220-15, 220-16,
220-17, 220-18, 220-19, 220-20, 220-21, 220-22, 220-23, 220-24,
220-25, 220-26, 220-27, 220-28, 220-29, 220-30, 220-31, 220-32,
220-33, 220-34, 220-35, 220-36, 220-37, 220-38, 220-39, 220-40,
220-41, 220-42, 220-43, 220-44, 220-45, 220-46, 220-47, 220-48,
220-49, 220-50, 220-51, 220-52, 220-53, 220-54, 220-55, 220-56,
220-57, 220-58, 220-59, 220-60, 220-61, 220-62, 220-63, 220-64,
220-65, 220-66, 220-67, 220-68, 220-69, 220-70, 220-71, 220-72,
220-73, 220-74, 220-75, 220-76, 220-77, 220-78, 220-79, 220-80,
220-81, 220-82, 220-83, 220-84, 220-85, 220-86, 220-87, 220-88,
220-89, 220-90, 220-91, 220-92, 220-93, 220-94, 220-95, 220-96,
220-97,
[0334] 221-1, 221-2, 221-3, 221-4, 221-5, 221-6, 221-7, 221-8,
221-9, 221-10, 221-11, 221-12, 221-13, 221-14, 221-15, 221-16,
221-17, 221-18, 221-19, 221-20, 221-21, 221-22, 221-23, 221-24,
221-25, 221-26, 221-27, 221-28, 221-29, 221-30, 221-31, 221-32,
221-33, 221-34, 221-35, 221-36, 221-37, 221-38, 221-39, 221-40,
221-41, 221-42, 221-43, 221-44, 221-45, 221-46, 221-47, 221-48,
221-49, 221-50, 221-51, 221-52, 221-53, 221-54, 221-55, 221-56,
221-57, 221-58, 221-59, 221-60, 221-61, 221-62, 221-63, 221-64,
221-65, 221-66, 221-67, 221-68, 221-69, 221-70, 221-71, 221-72,
221-73, 221-74, 221-75, 221-76, 221-77, 221-78, 221-79, 221-80,
221-81, 221-82, 221-83, 221-84, 221-85, 221-86, 221-87, 221-88,
221-89, 221-90, 221-91, 221-92, 221-93, 221-94, 221-95, 221-96,
221-97,
[0335] 222-1, 222-2, 222-3, 222-4, 222-5, 222-6, 222-7, 222-8,
222-9, 222-10, 222-11, 222-12, 222-13, 222-14, 222-15, 222-16,
222-17, 222-18, 222-19, 222-20, 222-21, 222-22, 222-23, 222-24,
222-25, 222-26, 222-27, 222-28, 222-29, 222-30, 222-31, 222-32,
222-33, 222-34, 222-35, 222-36, 222-37, 222-38, 222-39, 222-40,
222-41, 222-42, 222-43, 222-44, 222-45, 222-46, 222-47, 222-48,
222-49, 222-50, 222-51, 222-52, 222-53, 222-54, 222-55, 222-56,
222-57, 222-58, 222-59, 222-60, 222-61, 222-62, 222-63, 222-64,
222-65, 222-66, 222-67, 222-68, 222-69, 222-70, 222-71, 222-72,
222-73, 222-74, 222-75, 222-76, 222-77, 222-78, 222-79, 222-80,
222-81, 222-82, 222-83, 222-84, 222-85, 222-86, 222-87, 222-88,
222-89, 222-90, 222-91, 222-92, 222-93, 222-94, 222-95, 222-96,
222-97,
[0336] 223-1, 223-2, 223-3, 223-4, 223-5, 223-6, 223-7, 223-8,
223-9, 223-10, 223-11, 223-12, 223-13, 223-14, 223-15, 223-16,
223-17, 223-18, 223-19, 223-20, 223-21, 223-22, 223-23, 223-24,
223-25, 223-26, 223-27, 223-28, 223-29, 223-30, 223-31, 223-32,
223-33, 223-34, 223-35, 223-36, 223-37, 223-38, 223-39, 223-40,
223-41, 223-42, 223-43, 223-44, 223-45, 223-46, 223-47, 223-48,
223-49, 223-50, 223-51, 223-52, 223-53, 223-54, 223-55, 223-56,
223-57, 223-58, 223-59, 223-60, 223-61, 223-62, 223-63, 223-64,
223-65, 223-66, 223-67, 223-68, 223-69, 223-70, 223-71, 223-72,
223-73, 223-74, 223-75, 223-76, 223-77, 223-78, 223-79, 223-80,
223-81, 223-82, 223-83, 223-84, 223-85, 223-86, 223-87, 223-88,
223-89, 223-90, 223-91, 223-92, 223-93, 223-94, 223-95, 223-96,
223-97,
[0337] 224-1, 224-2, 224-3, 224-4, 224-5, 224-6, 224-7, 224-8,
224-9, 224-10, 224-11, 224-12, 224-13, 224-14, 224-15, 224-16,
224-17, 224-18, 224-19, 224-20, 224-21, 224-22, 224-23, 224-24,
224-25, 224-26, 224-27, 224-28, 224-29, 224-30, 224-31, 224-32,
224-33, 224-34, 224-35, 224-36, 224-37, 224-38, 224-39, 224-40,
224-41, 224-42, 224-43, 224-44, 224-45, 224-46, 224-47, 224-48,
224-49, 224-50, 224-51, 224-52, 224-53, 224-54, 224-55, 224-56,
224-57, 224-58, 224-59, 224-60, 224-61, 224-62, 224-63, 224-64,
224-65, 224-66, 224-67, 224-68, 224-69, 224-70, 224-71, 224-72,
224-73, 224-74, 224-75, 224-76, 224-77, 224-78, 224-79, 224-80,
224-81, 224-82, 224-83, 224-84, 224-85, 224-86, 224-87, 224-88,
224-89, 224-90, 224-91, 224-92, 224-93, 224-94, 224-95, 224-96,
224-97,
[0338] 225-1, 225-2, 225-3, 225-4, 225-5, 225-6, 225-7, 225-8,
225-9, 225-10, 225-11, 225-12, 225-13, 225-14, 225-15, 225-16,
225-17, 225-18, 225-19, 225-20, 225-21, 225-22, 225-23, 225-24,
225-25, 225-26, 225-27, 225-28, 225-29, 225-30, 225-31, 225-32,
225-33, 225-34, 225-35, 225-36, 225-37, 225-38, 225-39, 225-40,
225-41, 225-42, 225-43, 225-44, 225-45, 225-46, 225-47, 225-48,
225-49, 225-50, 225-51, 225-52, 225-53, 225-54, 225-55, 225-56,
225-57, 225-58, 225-59, 225-60, 225-61, 225-62, 225-63, 225-64,
225-65, 225-66, 225-67, 225-68, 225-69, 225-70, 225-71, 225-72,
225-73, 225-74, 225-75, 225-76, 225-77, 225-78, 225-79, 225-80,
225-81, 225-82, 225-83, 225-84, 225-85, 225-86, 225-87, 225-88,
225-89, 225-90, 225-91, 225-92, 225-93, 225-94, 225-95, 225-96,
225-97,
[0339] 226-1, 226-2, 226-3, 226-4, 226-5, 226-6, 226-7, 226-8,
226-9, 226-10, 226-11, 226-12, 226-13, 226-14, 226-15, 226-16,
226-17, 226-18, 226-19, 226-20, 226-21, 226-22, 226-23, 226-24,
226-25, 226-26, 226-27, 226-28, 226-29, 226-30, 226-31, 226-32,
226-33, 226-34, 226-35, 226-36, 226-37, 226-38, 226-39, 226-40,
226-41, 226-42, 226-43, 226-44, 226-45, 226-46, 226-47, 226-48,
226-49, 226-50, 226-51, 226-52, 226-53, 226-54, 226-55, 226-56,
226-57, 226-58, 226-59, 226-60, 226-61, 226-62, 226-63, 226-64,
226-65, 226-66, 226-67, 226-68, 226-69, 226-70, 226-71, 226-72,
226-73, 226-74, 226-75, 226-76, 226-77, 226-78, 226-79, 226-80,
226-81, 226-82, 226-83, 226-84, 226-85, 226-86, 226-87, 226-88,
226-89, 226-90, 226-91, 226-92, 226-93, 226-94, 226-95, 226-96,
226-97,
[0340] 227-1, 227-2, 227-3, 227-4, 227-5, 227-6, 227-7, 227-8,
227-9, 227-10, 227-11, 227-12, 227-13, 227-14, 227-15, 227-16,
227-17, 227-18, 227-19, 227-20, 227-21, 227-22, 227-23, 227-24,
227-25, 227-26, 227-27, 227-28, 227-29, 227-30, 227-31, 227-32,
227-33, 227-34, 227-35, 227-36, 227-37, 227-38, 227-39, 227-40,
227-41, 227-42, 227-43, 227-44, 227-45, 227-46, 227-47, 227-48,
227-49, 227-50, 227-51, 227-52, 227-53, 227-54, 227-55, 227-56,
227-57, 227-58, 227-59, 227-60, 227-61, 227-62, 227-63, 227-64,
227-65, 227-66, 227-67, 227-68, 227-69, 227-70, 227-71, 227-72,
227-73, 227-74, 227-75, 227-76, 227-77, 227-78, 227-79, 227-80,
227-81, 227-82, 227-83, 227-84, 227-85, 227-86, 227-87, 227-88,
227-89, 227-90, 227-91, 227-92, 227-93, 227-94, 227-95, 227-96,
227-97,
[0341] 228-1, 228-2, 228-3, 228-4, 228-5, 228-6, 228-7, 228-8,
228-9, 228-10, 228-11, 228-12, 228-13, 228-14, 228-15, 228-16,
228-17, 228-18, 228-19, 228-20, 228-21, 228-22, 228-23, 228-24,
228-25, 228-26, 228-27, 228-28, 228-29, 228-30, 228-31, 228-32,
228-33, 228-34, 228-35, 228-36, 228-37, 228-38, 228-39, 228-40,
228-41, 228-42, 228-43, 228-44, 228-45, 228-46, 228-47, 228-48,
228-49, 228-50, 228-51, 228-52, 228-53, 228-54, 228-55, 228-56,
228-57, 228-58, 228-59, 228-60, 228-61, 228-62, 228-63, 228-64,
228-65, 228-66, 228-67, 228-68, 228-69, 228-70, 228-71, 228-72,
228-73, 228-74, 228-75, 228-76, 228-77, 228-78, 228-79, 228-80,
228-81, 228-82, 228-83, 228-84, 228-85, 228-86, 228-87, 228-88,
228-89, 228-90, 228-91, 228-92, 228-93, 228-94, 228-95, 228-96,
228-97,
[0342] 229-1, 229-2, 229-3, 229-4, 229-5, 229-6, 229-7, 229-8,
229-9, 229-10, 229-11, 229-12, 229-13, 229-14, 229-15, 229-16,
229-17, 229-18, 229-19, 229-20, 229-21, 229-22, 229-23, 229-24,
229-25, 229-26, 229-27, 229-28, 229-29, 229-30, 229-31, 229-32,
229-33, 229-34, 229-35, 229-36, 229-37, 229-38, 229-39, 229-40,
229-41, 229-42, 229-43, 229-44, 229-45, 229-46, 229-47, 229-48,
229-49, 229-50, 229-51, 229-52, 229-53, 229-54, 229-55, 229-56,
229-57, 229-58, 229-59, 229-60, 229-61, 229-62, 229-63, 229-64,
229-65, 229-66, 229-67, 229-68, 229-69, 229-70, 229-71, 229-72,
229-73, 229-74, 229-75, 229-76, 229-77, 229-78, 229-79, 229-80,
229-81, 229-82, 229-83, 229-84, 229-85, 229-86, 229-87, 229-88,
229-89, 229-90, 229-91, 229-92, 229-93, 229-94, 229-95, 229-96,
229-97,
[0343] 230-1, 230-2, 230-3, 230-4, 230-5, 230-6, 230-7, 230-8,
230-9, 230-10, 230-11, 230-12, 230-13, 230-14, 230-15, 230-16,
230-17, 230-18, 230-19, 230-20, 230-21, 230-22, 230-23, 230-24,
230-25, 230-26, 230-27, 230-28, 230-29, 230-30, 230-31, 230-32,
230-33, 230-34, 230-35, 230-36, 230-37, 230-38, 230-39, 230-40,
230-41, 230-42, 230-43, 230-44, 230-45, 230-46, 230-47, 230-48,
230-49, 230-50, 230-51, 230-52, 230-53, 230-54, 230-55, 230-56,
230-57, 230-58, 230-59, 230-60, 230-61, 230-62, 230-63, 230-64,
230-65, 230-66, 230-67, 230-68, 230-69, 230-70, 230-71, 230-72,
230-73, 230-74, 230-75, 230-76, 230-77, 230-78, 230-79, 230-80,
230-81, 230-82, 230-83, 230-84, 230-85, 230-86, 230-87, 230-88,
230-89, 230-90, 230-91, 230-92, 230-93, 230-94, 230-95, 230-96,
230-97,
[0344] 231-1, 231-2, 231-3, 231-4, 231-5, 231-6, 231-7, 231-8,
231-9, 231-10, 231-11, 231-12, 231-13, 231-14, 231-15, 231-16,
231-17, 231-18, 231-19, 231-20, 231-21, 231-22, 231-23, 231-24,
231-25, 231-26, 231-27, 231-28, 231-29, 231-30, 231-31, 231-32,
231-33, 231-34, 231-35, 231-36, 231-37, 231-38, 231-39, 231-40,
231-41, 231-42, 231-43, 231-44, 231-45, 231-46, 231-47, 231-48,
231-49, 231-50, 231-51, 231-52, 231-53, 231-54, 231-55, 231-56,
231-57, 231-58, 231-59, 231-60, 231-61, 231-62, 231-63, 231-64,
231-65, 231-66, 231-67, 231-68, 231-69, 231-70, 231-71, 231-72,
231-73, 231-74, 231-75, 231-76, 231-77, 231-78, 231-79, 231-80,
231-81, 231-82, 231-83, 231-84, 231-85, 231-86, 231-87, 231-88,
231-89, 231-90, 231-91, 231-92, 231-93, 231-94, 231-95, 231-96,
231-97,
[0345] 232-1, 232-2, 232-3, 232-4, 232-5, 232-6, 232-7, 232-8,
232-9, 232-10, 232-11, 232-12, 232-13, 232-14, 232-15, 232-16,
232-17, 232-18, 232-19, 232-20, 232-21, 232-22, 232-23, 232-24,
232-25, 232-26, 232-27, 232-28, 232-29, 232-30, 232-31, 232-32,
232-33, 232-34, 232-35, 232-36, 232-37, 232-38, 232-39, 232-40,
232-41, 232-42, 232-43, 232-44, 232-45, 232-46, 232-47, 232-48,
232-49, 232-50, 232-51, 232-52, 232-53, 232-54, 232-55, 232-56,
232-57, 232-58, 232-59, 232-60, 232-61, 232-62, 232-63, 232-64,
232-65, 232-66, 232-67, 232-68, 232-69, 232-70, 232-71, 232-72,
232-73, 232-74, 232-75, 232-76, 232-77, 232-78, 232-79, 232-80,
232-81, 232-82, 232-83, 232-84, 232-85, 232-86, 232-87, 232-88,
232-89, 232-90, 232-91, 232-92, 232-93, 232-94, 232-95, 232-96,
232-97,
[0346] 233-1, 233-2, 233-3, 233-4, 233-5, 233-6, 233-7, 233-8,
233-9, 233-10, 233-11, 233-12, 233-13, 233-14, 233-15, 233-16,
233-17, 233-18, 233-19, 233-20, 233-21, 233-22, 233-23, 233-24,
233-25, 233-26, 233-27, 233-28, 233-29, 233-30, 233-31, 233-32,
233-33, 233-34, 233-35, 233-36, 233-37, 233-38, 233-39, 233-40,
233-41, 233-42, 233-43, 233-44, 233-45, 233-46, 233-47, 233-48,
233-49, 233-50, 233-51, 233-52, 233-53, 233-54, 233-55, 233-56,
233-57, 233-58, 233-59, 233-60, 233-61, 233-62, 233-63, 233-64,
233-65, 233-66, 233-67, 233-68, 233-69, 233-70, 233-71, 233-72,
233-73, 233-74, 233-75, 233-76, 233-77, 233-78, 233-79, 233-80,
233-81, 233-82, 233-83, 233-84, 233-85, 233-86, 233-87, 233-88,
233-89, 233-90, 233-91, 233-92, 233-93, 233-94, 233-95, 233-96,
233-97,
[0347] 234-1, 234-2, 234-3, 234-4, 234-5, 234-6, 234-7, 234-8,
234-9, 234-10, 234-11, 234-12, 234-13, 234-14, 234-15, 234-16,
234-17, 234-18, 234-19, 234-20, 234-21, 234-22, 234-23, 234-24,
234-25, 234-26, 234-27, 234-28, 234-29, 234-30, 234-31, 234-32,
234-33, 234-34, 234-35, 234-36, 234-37, 234-38, 234-39, 234-40,
234-41, 234-42, 234-43, 234-44, 234-45, 234-46, 234-47, 234-48,
234-49, 234-50, 234-51, 234-52, 234-53, 234-54, 234-55, 234-56,
234-57, 234-58, 234-59, 234-60, 234-61, 234-62, 234-63, 234-64,
234-65, 234-66, 234-67, 234-68, 234-69, 234-70, 234-71, 234-72,
234-73, 234-74, 234-75, 234-76, 234-77, 234-78, 234-79, 234-80,
234-81, 234-82, 234-83, 234-84, 234-85, 234-86, 234-87, 234-88,
234-89, 234-90, 234-91, 234-92, 234-93, 234-94, 234-95, 234-96,
234-97
[0348] Among the combinations of groups given in Table 1 above, we
prefer those identified as Nos. 1, 2, 3, 4, 5, 6, 7, 8, 9, 31, 34,
35, 36, 76, 77, 78, 106, 107, 108, 136, 137, 138, 163 and 199, and
more prefer those identified as Nos. 1, 163 and 199.
[0349] Among the combinations of groups in Table 2 above, we prefer
those identified as Nos. 1 to 8, 32 to 53, and 87 to 97, and more
prefer those identified as Nos. 1, 38, 40, 41 and 42.
[0350] Among the compounds represented by the combinations of
groups selected from Table 1 and Table 2, we prefer Compounds Nos.
1-1, 1-2, 1-3, 1-4, 1-5, 1-6, 1-7, 1-8, 1-32, 1-33, 1-34, 1-35,
1-36, 1-37, 1-38, 1-39, 1-40, 1-41, 1-42, 1-43, 1-44, 1-45, 1-48,
1-49, 1-50, 1-51, 1-52, 1-53, 7-1, 7-2, 7-3, 7-4, 7-5, 7-6, 7-7,
7-8, 7-32, 7-33, 7-34, 7-35, 7-36, 7-37, 7-38, 7-39, 7-40, 7-41,
7-42, 7-43, 7-44, 7-45, 7-48, 7-49, 7-50, 7-51, 7-52, 7-53, 163-1,
163-38, 163-39, 163-40, 163-41, 163-42, 199-1, 199-38, 199-39,
199-40, 199-41 and 199-42.
[0351] The most preferred compounds are Compounds No.:
[0352] 1-1.
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycer-
o-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(1-fluoro--
2,3-dihydroxypropyl)-4-(R)-guanidino-2-(S)-3-(R)-dihydropyran-2-carboxylic
acid;
[0353] 1-40.
5-acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-
-fluoro-12-glycero-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(1-fluoro-2-hydroxy-3-dodecanoyloxypropyl)-4-(R)-guanidino--
2-(S)-3-(R)-dihydropyran-2-carboxylic acid;
[0354] 1-41.
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy-7--
fluoro-D-glycero-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(1-fluoro-2-hydroxy-3-myristoyloxypropyl)-4-(R)-guanidino-2-
-(S)-3-(R)-dihydropyran-2-carboxylic acid;
[0355] 1-42.
5-acetamido-4-guanidino-9-O-palmitoyl-2,3,4,5,7-pentadeoxy-7--
fluoro-D-glycero-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(1-fluoro-2-hydroxy-3-palmitoyloxypropyl)-4-(R)-guanidino-2-
-(S)-3-(R)-dihydropyran-2-carboxylic acid;
[0356] 163-1.
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-gly-
cero-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(2,3-dihydroxy-1-methoxypropyl)
(R)-guanidino-2-(S)-3-(R)-d- ihydropyran-2-carboxylic acid;
[0357] 163-41.
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy--
7-methoxy-2-glycero-D-galacto-non-2-enopyranosoic acid:
5-acetamido-6-(2-hydroxy-1-methoxy-3-myristoyloxypropyl)-4-(R)-guanidino--
2-(S)-3-(R)-dihydropyran-2-carboxylic acid;
[0358] 199-1.
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(1-ethoxy-2,3-dihydroxypropyl)-4-(R)-guanidino-2-(S)-3-(R)--
dihydropyran-2-carboxylic acid;
[0359] 199-38.
5-acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-
-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(1-ethoxy-2-hydroxy-3-octanoyloxypropyl)-4-(R)-guanidino-2--
(S)-3-(R)-dihydropyran-2-carboxylic acid;
[0360] 199-40.
5-acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-
-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(1-ethoxy-2-hydroxy-3-dodecanoyloxypropyl)-4-(R)-guanidino--
2-(S)-3-(R)-dihydropyran-2-carboxylic acid;
[0361] 199-41.
5-acetamido-4-guanidino-9-O-myristoyl-2,3,4,5,7-pentadeoxy--
7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(1-ethoxy-2-hydroxy-3-myristoyloxypropyl)-4-(R)-guanidino-2-
-(S)-3-(R)-dihydropyran-2-carboxylic acid; and
[0362] 199-42.
5-acetamido-4-guanidino-9-O-palmitoyl-2,3,4,5,7-pentadeoxy--
7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic acid; IUPAC name:
5-acetamido-6-(1-ethoxy-2-hydroxy-3-palmitoyloxypropyl)-4-(R)-guanidino-2-
-(S)-3-(R)-dihydropyran-2-carboxylic acid;.
[0363] The compounds of the present invention may be prepared by a
variety of processes well known in the art for the preparation of
compounds of this type, for example as illustrated by the following
Methods A, B and C.
[0364] The compound of formula (2), which is used as a starting
material in Method A or B, can be prepared by the following Methods
D, E, F or G.
[0365] The compound of formula (5), which is used as a starting
material in Method C, can be prepared by the following Method
H.
Method A
[0366] 9
[0367] In the above formulae:
[0368] R.sup.1, R.sup.2, R.sup.3, X and Z are as defined above;
[0369] R.sup.2a represents any of the groups or atoms represented
by R.sup.2 or a hydroxy-protecting group, preferably
t-butyldimethylsilyl group;
[0370] R.sup.3a represents any of the groups or atoms represented
by R.sup.3 or a hydroxy-protecting group, preferably
t-butyldimethylsilyl group;
[0371] X.sup.a represents any of the groups or atoms represented by
X or a protected hydroxy group, preferably t-butyldimethylsilyloxy
group;
[0372] W represents a hydrogen atom or an ester residue;
[0373] W.sup.a represents any of the groups or atoms represented by
W or a carboxy-protecting group, preferably an allyl group, a
methoxymethyl group, a methylthiomethyl group, a
[2-(trimethylsilyl)ethoxy]methoxy group or a diphenylmethyl group,
more preferably a diphenylmethyl group; and
[0374] Boc represents a t-butoxycarbonyl group.
[0375] In this Method, a compound of formula (1a) is prepared by
reacting a compound of formula (2) with
N,N'-di-t-butoxycarbonylthiourea to give a compound of formula (3),
which is then deprotected.
[0376] Step A1
[0377] In this Step, a compound of formula (3) is prepared by
reacting the compound of formula (2) with
N,N'-di-t-butoxycarbonylthiourea in the presence of a base and
mercuric chloride and in an inert solvent.
[0378] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aromatic hydrocarbons, such as benzene,
toluene and xylene; ethers, such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene
glycol dimethyl ether, and amides, such as N,N-dimethylacetamide,
and dimethylformamide. Of these, we prefer the amides, particularly
N,N-dimethylacetamide or dimethylformamide.
[0379] There is likewise no particular restriction on the nature of
the bases used, and any base commonly used in reactions of this
type may equally be used here. Examples of such bases include:
organic bases, such as triethylamine or dimethylaminopyridine.
[0380] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents, base and solvent employed. However, provided that the
reaction is effected under the preferred conditions outlined above,
a period of from 1 hour to 24 hours, more preferably from 5 to 10
hours, will usually suffice.
[0381] After completion of the reaction, the desired compound can
be obtained by conventional means. For example, one suitable
recovery procedure comprises: filtering the reaction solution under
reduced pressure to remove the insolubles; adding a
water-immiscible organic solvent, such as ethyl acetate, thereto,
separating the organic layer containing the desired compound after
washing with water; and distilling off the solvent after the
organic layer is dried, for example over anhydrous magnesium
sulfate.
[0382] The desired compound can, if desired, be further purified by
recrystallization or by the various forms of chromatography, such
as column chromatography or preparative thin layer
chromatography.
[0383] Step A2
[0384] In this Step, a compound of formula (1a), which is a
compound of the present invention, is prepared by treating the
compound of formula (3) with a reagent which can remove a
t-butoxycarbonyl group, in an inert solvent.
[0385] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: alcohols, such as methanol and ethanol;
water; or a mixture of any two or more thereof.
[0386] There is likewise no particular restriction on the nature of
the reagents used to remove the t-butoxycarbonyl group, and any
reagent commonly used in reactions of this type may equally be used
here. Examples of such reagents include acids, and any acid
commonly used as an acid catalyst may be used, for example a
Bronsted acid, such as an inorganic acid (e.g. hydrochloric acid,
hydrobromic acid, sulfuric acid, perchloric acid or phosphoric
acid) or an organic acid (e.g. acetic acid, formic acid, oxalic
acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic
acid or trifluoromethanesulfonic acid), preferably an organic acid
(particularly acetic acid or trifluoroacetic acid).
[0387] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents and solvent employed. However, provided that the reaction
is effected under the preferred conditions outlined above, a period
of from 15 minutes to 10 hours, more preferably from 1 to 5 hours,
will usually suffice.
[0388] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: neutralising
the reaction solution and purifying the residue obtained by
distilling off the solvent under reduced pressure by means of
silica gel chromatography.
[0389] Where R.sup.2a or R.sup.3a represents a hydroxy-protecting
group, X.sup.a represents a protected hydroxy group or W.sup.a
represents a carboxy-protecting group, a compound of the present
invention can be prepared by deprotecting these protecting groups
further.
[0390] The reaction employed for the removal of the protecting
group will vary, depending on the nature of the protecting group.
However it can be carried out by conventional means, for example,
by the method described in "Protective Groups in Organic
Synthesis", Second Edition (written by Greene and Wuts, John Wiley
& Sons, Inc., published in 1991), the disclosures of which are
incorporated herein by reference.
[0391] Where the hydroxy-protecting group is a trialkylsilyl group,
such as a t-butyldimethylsilyl group, acetic acid in a mixture of
water and tetrahydrofuran or tetrabutylammonium fluoride in
tetrahydrofuran can preferably be used. Where the
carboxy-protecting group is a diphenylmethyl group, catalytic
reduction using hydrogen gas and a catalyst such as palladium black
in a mixture of methanol and tetrahydrofuran, trifluoroacetic acid
in phenol, acetic acid as an acid and a solvent or
trifluoroboran-diethyl ether complex in acetic acid can be
used.
Method B
[0392] In this Method, a compound of formula (1) is prepared by
reacting the compound of formula (2) with ammonia or a
hydroxylamine which may be substituted by an alkyl group having
from 1 to 4 carbon atoms at the amino moiety, if desired, followed
by deprotection. 10
[0393] In the above formulae, R.sup.1, R.sup.2, R.sup.3, R.sup.2a,
R.sup.3a, X, Y, W, Z, X.sup.a and W.sup.a are as defined above.
[0394] Step B1
[0395] In this Step, a compound of formula (4) is prepared by
reacting the compound of formula (2) with a cyanating agent in an
inert solvent.
[0396] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: alcohols, such as methanol, ethanol,
propanol, isopropanol, butanol, isobutanol, t-butanol, isoamyl
alcohol, diethylene glycol, glycerin, octanol, cyclohexanol and
ethylene glycol monomethyl ether (methyl Cellosolve--"Cellosolve"
is a trade mark); amides, such as formamide, dimethylformamide,
N,N-dimethylacetamide, N-methyl-2-pyrrolidone,
N-methylpyrrolidinone and hexamethylphosphoric triamide and
sulfoxides, such as dimethyl sulfoxide and sulfolane. Of these, we
prefer the alcohols (particularly methanol).
[0397] There is likewise no particular restriction on the nature of
the cyanating agents used, and any cyanating agent commonly used in
reactions of this type may equally be used here. Examples of such
cyanating agents include cyanogen bromide, in which case, sodium
acetate is simultaneously used as a base.
[0398] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 40.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents, base and solvent employed. However, provided that the
reaction is effected under the preferred conditions outlined above,
a period of from 15 minutes to 10 hours, more preferably from 1 to
5 hours, will usually suffice.
[0399] After completion of the reaction the desired compound can,
for example, be obtained by using silica gel chromatography to
purify the residue obtained by distilling off the solvent.
[0400] Step B2
[0401] In this Step, a compound of formula (1), which is a compound
of the present invention, is prepared by reacting the compound of
formula (4) with ammonia or a hydroxylamine which may be
substituted by an alkyl group having from 1 to 4 carbon atoms at
the amino moiety, if desired, followed by deprotection.
[0402] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include alcohols particularly methanol).
[0403] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 40.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents and solvent employed. However, provided that the reaction
is effected under the preferred conditions outlined above, a period
of from 15 minutes to 10 hours, more preferably from 1 to 5 hours,
will usually suffice.
[0404] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises using silica gel
chromatography to purify the residue obtained by distilling off the
solvent.
[0405] Where R.sup.2a or R.sup.3a represents a hydroxy-protecting
group , X.sup.a represents a protected hydroxy group or W.sup.a
represents a carboxy-protecting group, a compound of the present
invention can be prepared by the subsequent removal of these
protecting groups as described in Method A.
Method C
[0406] In this Method, a compound of formula (1c) is prepared by
reacting the compound of formula (5) with an acylating agent,
followed by deprotection. 11
[0407] In the above formulae:
[0408] R.sup.1, R.sup.2, R.sup.3, W, Z and W.sup.a are as defined
above;
[0409] R.sup.5 represents a halogen atom, a hydroxy group or an
alkoxy group having from 1 to 4 carbon atoms; and
[0410] X.sup.b represents a halogen atom, an aliphatic acyloxy
group having from 2 to 25 carbon atoms or an alkoxy group having
from 1 to 4 carbon atoms.
[0411] Step C1
[0412] In this Step, a compound of formula (6) is prepared by
introducing a desired acyl group into the compound of formula (5)
in an inert solvent.
[0413] The acylation method may be carried out by any of the
following Processes 1, 2 and 3.
[0414] Process 1
[0415] In this Process, a compound of formula (5) is reacted with a
compound of formula RCO--L or a compound of formula RCO--O--COR,
wherein R represents an alkyl group having from 1 to 24 carbon
atoms; and L represents a leaving group. There is no particular
restriction on the nature of the leaving groups used, and any
nucleophilic leaving group commonly used in reactions of this type
may equally be used here. Examples of such leaving groups include:
halogen atoms, such as the chlorine, bromine and iodine atoms;
alkoxycarbonyloxy groups having from 1 to 6 carbon atoms in the
alkoxy part, such as the methoxycarbonyloxy and ethoxycarbonyloxy
groups; halogenated alkanoyloxy groups, such as the chloroacetoxy,
dichloroacetoxy, trichloroacetoxy and trifluoroacetoxy groups;
alkanesulfonyloxy groups having from 1 to 6 carbon atoms in the
alkyl part, such as the methanesulfonyloxy and ethanesulfonyloxy
groups; halogenated alkanesulfonyloxy groups having from 1 to 6
carbon atoms in the alkyl part, such as the
trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy
groups; and arylsulfonyloxy groups, such as the benzenesulfonyloxy,
p-toluenesulfonyloxy and p-nitrobenzenesulfonylox- y groups. Of
these, we prefer the halogen atoms, halogenated alkanesulfonyloxy
groups and arylsulfonyloxy groups.
[0416] The reaction may take place in the presence or absence of a
base and in a solvent.
[0417] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane
and heptane; aromatic hydrocarbons, such as benzene, toluene and
xylene; halogenated hydrocarbons, such as methylene chloride,
chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and
dichlorobenzene; esters, such as ethyl formate, ethyl acetate,
propyl acetate, butyl acetate and diethyl carbonate; ethers, such
as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether, nitriles,
such as acetonitrile and isobutyronitrile; and amides, such as
formamide, dimethylformamide, N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone and
hexamethylphosphoric triamide.
[0418] There is likewise no particular restriction on the nature of
the bases used, and any base commonly used in reactions of this
type may equally be used here. Examples of such bases include:
organic bases, such as N-methylmorpholine, triethylamine,
tributylamine, diisopropylethylamine, dicyclohexylamine,
N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,
4-(N,N-dimethylamino)-pyridine, 2,6-di(t-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline and N,N-diethylaniline.
[0419] 4-(N,N-Dimethylamino)pyridine and 4-pyrrolidinopyridine can
be used in a catalytic amount in combination with one or more other
bases. In addition, it may facilitate the reaction to carry it out
in the presence of one or more of: quaternary ammonium salts, such
as benzyltriethylammonium chloride and tetrabutylammonium chloride;
and crown ethers, such as dibenzo-18-crown-6.
[0420] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
-20.degree. C. to the reflux temperature of the solvent used, more
preferably from 0.degree. C. to the reflux temperature of the
solvent used. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the reagents, base and solvent employed. However,
provided that the reaction is effected under the preferred
conditions outlined above, a period of from 10 minutes to 3 days,
more preferably from 1 hour to 6 hours, will usually suffice.
[0421] Process 2
[0422] In this Process, a compound of formula: RCOOH [wherein R is
as defined above] is reacted with the compound of formula (5) in
the presence of an esterifying agent and in the presence or absence
of a catalytic amount of a base in a solvent. The reaction may also
be effected in the presence of a condensing agent.
[0423] There is no particular restriction on the nature of the
esterifying agents used, and any esterifying agent commonly used in
reactions of this type may equally be used here. Examples of such
esterifying agents include active esters, especially: alkyl
haloformates, such as methyl chloroformate and ethyl chloroformate;
and cyanophosphoric acid diesters, such as diethyl cyanophosphate.
Esterification with such active esters preferably takes place in
the presence of at least one condensing agent. Specific examples of
such condensing agents include: N-hydroxy derivatives, such as
N-hydroxysuccinimide, 1-hydroxybenzotriazole and
N-hydroxy-5-norbornene-2,3-dicarboximide; disulfide compounds, such
as 2,2'-dipyridyl disulfide; succinic acid compounds, such as
N,N'-disuccinimidyl carbonate; phosphinic chloride compounds, such
as N,N'-bis(2-oxo-3-oxazolidinyl)phosphinic chloride; oxalate
derivatives, such as N,N'-disuccinimidyl oxalate (DSO),
N,N'-diphthalimidoxalate (DPO), N,N'-bis(norbornenylsuccinimidyl)
oxalate (BNO), 1,1'-bis(benzotriazolyl)oxalate (BBTO),
1,1'-bis(6-chlorobenzotriazolyl)o- xalate (BCTO) and
1,1'-bis(6-trifluoromethylbenzotriazolyl)oxalate (BTBO);
triarylphosphines including triarylphosphines, such as
triphenylphosphine, dialkyl azodicarboxylate-triarylphosphines in
which the alkyl part has from 1 to 6 carbon atoms, such as diethyl
azodicarboxylatetriphenylphosphine;
N-alkyl-5-arylisoxazolium-3'-sulfonat- es in which the alkyl part
has from 1 to 6 carbon atoms, such as
N-ethyl-5-phenylisoxazolium-3'-sulfonate; carbodiimide derivatives
including N',N'-dicycloalkylcarbodiimides, such as
N',N"-dicyclohexylcarbodiimide (DCC) and
1-ethyl-3-(3-dimethylaminopropyl- )carbodiimide (EDAPC);
diheteroaryldiselenides, such as di-2-pyridyldiselenide;
arylsulfonyltriazolides, such as p-nitrobenzenesulfonyltriazolide;
2-halo-1-alkylpyridinium halides in which the alkyl part has from 1
to 6 carbon atoms, such as 2-chloro-1-methylpyridinium iodide;
diarylphosphorylazides, such as diphenylphosphorylazide (DPPA);
imidazole derivatives, such as 1,1'-oxalyldiimidazole and
N,N'-carbonyldiimidazole; benzotriazole derivatives, such as
1-hydroxybenzotriazole (HOBT); and dicarboximide derivatives, such
as N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), preferably the
diarylphosphorylazides.
[0424] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane
and heptane; aromatic hydrocarbons, such as benzene, toluene and
xylene; halogenated hydrocarbons, such as methylene chloride,
chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and
dichlorobenzene; esters, such as ethyl formate, ethyl acetate,
propyl acetate, butyl acetate and diethyl carbonate; ethers, such
as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; nitriles,
such as acetonitrile and isobutyronitrile; amides, such as
formamide, dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone and
hexamethylphosphoric triamide.
[0425] There is likewise no particular restriction on the nature of
the bases used, and any base commonly used in reactions of this
type may equally be used here. Examples of such bases include those
described in relation to Process 1, above.
[0426] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
-20.degree. C. to 80.degree. C., more preferably from 0.degree. C.
to room temperature. The time required for the reaction may also
vary widely, depending on many factors, notably the reaction
temperature and the nature of the reagents and solvent employed.
However, provided that the reaction is effected under the preferred
conditions outlined above, a period of from 10 minutes to 3 days,
more preferably from 30 minutes to 1 day, will usually suffice.
[0427] Process 3
[0428] In this Process, a compound of formula: RCOOH [wherein R is
as defined above] is reacted with the compound of formula (5) in
the presence of a halogenated phosphoric acid dialkyl ester, such
as diethyl chlorophosphate, and a base in a solvent.
[0429] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane
and heptane; aromatic hydrocarbons, such as benzene, toluene and
xylene; halogenated hydrocarbons, such as methylene chloride,
chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and
dichlorobenzene; esters, such as ethyl formate, ethyl acetate,
propyl acetate, butyl acetate and diethyl carbonate; ethers, such
as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; nitrites,
such as acetonitrile and isobutyronitrile; amides, such as
formamide, N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone and
hexamethylphosphoric triamide.
[0430] There is likewise no particular restriction on the nature of
the bases used, and any base commonly used in reactions of this
type may equally be used here. Examples of such bases include those
described in relation to Process 1, above.
[0431] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
0.degree. C. to the reflux temperature of the solvent used, more
preferably from room temperature to 50.degree. C. The time required
for the reaction may also vary widely, depending on many factors,
notably the reaction temperature and the nature of the reagents and
solvent employed. However, provided that the reaction is effected
under the preferred conditions outlined above, a period of from 10
minutes to 3 days, more preferably from 30 minutes to 1 day, will
usually suffice.
[0432] The number of acyl groups introduced varies depending on the
amount of acylating agent employed.
[0433] After completion of the reaction of any of the above
Processes, the desired compound of formula (6) may be collected
from the reaction mixture by conventional means. For example, the
desired compound can be obtained by the following procedure:
appropriately neutralising the reaction mixture; adding a
water-immiscible organic solvent, such as ethyl acetate, thereto
after the insolubles have, if necessary, been removed by
filtration; washing with water; separating the organic layer
containing the desired compound; drying the organic layer over
anhydrous magnesium sulfate; and distilling off the solvent.
[0434] The compound thus obtained can be separated and purified, if
necessary, by any suitable combination conventional methods, for
example, recrystallization, reprecipitation or other methods
commonly used for the separation and purification of organic
compounds, for example: adsorption column chromatography in which a
carrier such as silica gel, alumina or a magnesium silicate gel
(such as that available under the trade mark "Florisil") is used; a
method in which a synthesis adsorbing agent is used such as
partition chromatography, using a carrier such as Sephadex LH-20 (a
trade mark for a materiel produced by Pharmacia Co., Ltd.),
Amberlite XAD-11 (a trade mark for a material produced by Rohm
& Haas Co., Ltd.) or Diaion HP-20 (a trade mark for a material
produced by Mitsubishi Kasei Co., Ltd.); or normal phase or reverse
phase column chromatography (preferably high performance liquid
chromatography) using silica gel or an alkylated silica gel and
elution with a suitable eluent.
[0435] Step C2
[0436] In this Step, a compound of formula (1c), which is a
compound of the present invention is prepared by treating the
compound of formula (6) with a reagent which can remove a
t-butoxycarbonyl group. The reaction is normally and preferably
effected in the presence of an inert solvent.
[0437] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as in Step A2 of Method A.
[0438] Where W.sup.a represents a carboxy-protecting group, a
compound of the present invention can be prepared by the subsequent
removal of these protecting groups as mentioned in Step A2.
Method D
[0439] This Method illustrates the preparation of a compound of
formula (2a), which is one of starting materials used in Methods A
and B. 12
[0440] In the above formulae:
[0441] R.sup.1, R.sup.5, Z and W.sup.a are as defined above;
[0442] R.sup.4 represents a halogen atom, an acetoxy group or an
alkoxy group having from 1 to 4 carbon atoms;
[0443] Ac represents an acetyl group;
[0444] Boc represents a t-butoxycarbonyl group; and
[0445] Me represents a methyl group.
[0446] Step D1
[0447] In this Step, a compound of formula (8) is prepared by
reacting the compound of formula (7) with a base in an inert
solvent.
[0448] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; halogenated hydrocarbons, such as
methylene chloride, chloroform, carbon tetrachloride,
dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; and alcohols,
such as methanol. Of these, we prefer the halogenated hydrocarbons
and methanol.
[0449] There is likewise no particular restriction on the nature of
the bases used, provided that it does not affect other functional
groups (for example methyl ester groups), and any base commonly
used in reactions of this type may equally be used here. Examples
of such bases include the alkali metal methoxides, such as sodium
methoxide and potassium methoxide.
[0450] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents, base and solvent employed. However, provided that the
reaction is effected under the preferred conditions outlined above,
a period of from 15 minutes to 10 hours, more preferably from 1 to
5 hours, will usually suffice.
[0451] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: neutralising
the reaction solution with a solution of hydrogen chloride in
dioxane; distilling off the solvent under reduced pressure; and
purifying the residue thus obtained by silica gel
chromatography.
[0452] Step D2
[0453] In this Step, a compound of formula (9) is prepared by
reacting the compound of formula (8) with a reagent for introducing
an isopropylidene group.
[0454] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; ethers, such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethylene glycol dimethyl ether; and ketones, such as acetone,
methyl ethyl ketone, methyl isobutyl ketone, isophorone and
cyclohexanone. Of these, we prefer the ketones (particularly
acetone).
[0455] The reagent used to introduce an isopropylidene group is
preferably 2,2-dimethoxypropane. The reaction is usually effected
in the presence of an acid, such as p-toluenesulfonic acid, as a
catalyst.
[0456] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents, base and solvent employed. However, provided that the
reaction is effected under the preferred conditions outlined above,
a period of from 15 minutes to 10 hours, more preferably from 1 to
5 hours, will usually suffice.
[0457] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: adding a
water-immiscible solvent, such as ethyl acetate, and an aqueous
solution of sodium hydrogencarbonate to the reaction solution;
extracting the desired compound with a solvent such as ethyl
acetate; and distilling off the solvent. The desired compound can
be further purified by recrystallization or by the various types of
chromatography, such as column chromatography or preparative thin
layer chromatography, if necessary.
[0458] Step D3
[0459] This Step may be carried out, if desired, by:
[0460] 1) converting the methyl group of the carboxylic acid ester
into another substituent;
[0461] 2) hydrolysing the carboxylic acid ester; or
[0462] 3) carrying out 2) above and then protecting the resulting
free carboxylic acid.
[0463] 1. Ester Conversion
[0464] In this Step, a compound of formula (10) is prepared by
reacting the compound of formula (9) with an alcohol which is
capable of giving the desired ester group, in the presence of a
base and in an inert solvent.
[0465] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; halogenated hydrocarbons, such as
methylene chloride, chloroform, carbon tetrachloride,
dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether, alcohols,
such as methanol, ethanol, propanol, isopropanol, butanol,
isobutanol, t-butanol, isoamyl alcohol, diethylene glycol,
glycerin, octanol, cyclohexanol and ethylene glycol monomethyl
ether (such as that available under the trade mark "Methyl
Cellosolve"). Of these, we prefer those alcohols which form the
desired ester group.
[0466] There is likewise no particular restriction on the nature of
the bases used, and any base commonly used in reactions of this
type may equally be used here. Examples of such bases include
organic bases, such as pyridine, triethylamine, diethylamine and
4-N,N-dimethylaminopyridine.
[0467] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: neutralising
the reaction mixture with an acid; adding a water-immiscible
organic solvent such as ethyl acetate; extracting the desired
compound with a solvent such as ethyl acetate; washing the extract;
and distilling off the solvent. The desired compound can be further
purified by recrystallization or the various types of
chromatography, such as column chromatography or preparative thin
layer chromatography, if necessary.
[0468] The same compound of formula (10) can be also obtained by
reacting a carboxylic acid [obtained by removing a methyl group of
the compound of formula (9)] with an alcohol of formula W.sup.d--OH
or an alkyl halide of formula W.sup.d--Hal (where W.sup.d
represents an alkyl group and Hal represents a halogen atom).
[0469] 2. Hydrolysis
[0470] In this Step, the compound of formula (10) is prepared by
reacting the compound of formula (9) with a base in an inert
solvent.
[0471] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include water or a mixture of water and one or
more organic solvents. Suitable such organic solvents include:
alcohols, such as methanol and ethanol; and ethers, such as diethyl
ether, tetrahydrofuran and dioxane. Of these solvents, we prefer
water or a mixture of water and one or more alcohols.
[0472] There is likewise no particular restriction on the nature of
the bases used, and any base commonly used in reactions of this
type may equally be used here. Examples of such bases include
alkali metal hydroxides, such as sodium hydroxide and potassium
hydroxide.
[0473] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents, base and solvent employed. However, provided that the
reaction is effected under the preferred conditions outlined above,
a period of from 15 minutes to 10 hours, more preferably from 1 to
5 hours, will usually suffice.
[0474] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: adding
Dowex-50x8 (H.sup.+ type) (Dowex is a trade mark) to the reaction
solution to neutralize it; distilling off the solvent under reduced
pressure; and purifying the residue thus obtained by silica gel
chromatography.
[0475] 3. Diphenylmethylation
[0476] In this Step, a compound of formula (10) is prepared by
reacting diphenyldiazomethane with the compound of formula (9) in
the presence of a Lewis acid and in an inert solvent.
[0477] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; halogenated hydrocarbons, such as
methylene chloride, chloroform, carbon tetrachloride,
dichloroethane, chlorobenzene and dichlorobenzene; ethers, such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether, alcohols,
such as methanol, ethanol, propanol, isopropanol, butanol,
isobutanol, t-butanol, isoamyl alcohol, diethylene glycol,
glycerin, octanol, cyclohexanol and ethylene glycol monomethyl
ether (such as that available under the trade mark "Methyl
Cellosolve"). Of these, we prefer the alcohols (particularly
methanol), the halogenated hydrocarbons (particularly
dichloromethane) and mixtures thereof.
[0478] The Lewis acid which may be employed in this reaction is
preferably boron trifluoride-diethyl ether complex.
[0479] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
0.degree. C. to 50.degree. C., more preferably at about room
temperature. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the reagents and solvent employed. However,
provided that the reaction is effected under the preferred
conditions outlined above, a period of from 10 minutes to 5 hours,
more preferably from 1 to 3 hours, will usually suffice.
[0480] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: adding an acid,
such as acetic acid, to the reaction mixture; distilling off the
solvent; and purifying the residue by recrystallization or
chromatography.
[0481] Step D4
[0482] In this Step, a compound of formula (11) is prepared from
the compound of formula (10), using a reducing agent in an inert
solvent.
[0483] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; ethers, such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethylene glycol dimethyl ether; alcohols, such as methanol,
ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol,
isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol
and ethylene glycol monomethyl ether (such as that available under
the trade mark "Methyl Cellosolve"); ketones, such as acetone,
methyl ethyl ketone, methyl isobutyl ketone, isophorone and
cyclohexanone; nitrites, such as acetonitrile and isobutyronitrile;
amides, such as formamide, dimethylformamide,
N,N-dimethylacetamide, N-methyl-2-pyrrolidone,
N-methylpyrrolidinone and hexamethylphosphoric triamide;
sulfoxides, such as dimethyl sulfoxide and sulfolane; fatty acids,
such as acetic acid; and mixtures of water and any one or more of
these organic solvents. Of these, we prefer the alcohols
(particularly methanol), the ethers, such as tetrahydrofuran and
dioxane, the fatty acids, such as acetic acid, and mixtures of one
or more of these organic solvents and water.
[0484] There is likewise no particular restriction on the nature of
the reducing agents used, and any reducing agent commonly used in
reactions of this type may equally be used here. Examples of such
reducing agents include a hydrogenation catalyst, such as
palladium-on-carbon, platinum or Raney nickel, in the presence of
hydrogen gas. We particularly prefer to use a Lindlar catalyst
(Pd--BaSO.sub.4 or Pd--CaCO.sub.3 and quinoline or lead acetate in
combination).
[0485] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents, reducing agent and solvent employed. However, provided
that the reaction is effected under the preferred conditions
outlined above, a period of from 15 minutes to 10 hours, more
preferably from 1 to 5 hours, will usually suffice.
[0486] After completion of the reaction, the desired compound can
be obtained, for example, by filtering the reaction solution under
reduced pressure to remove the catalyst and distilling off the
solvent under reduced pressure. The desired compound can be further
purified by recrystallization or the various types of
chromatography, such as column chromatography or preparative thin
layer chromatography, if necessary.
[0487] Step D5
[0488] In this Step, a compound of formula (2a) is prepared by
deprotecting the isopropylidene group of a compound of formula (11)
in an inert solvent.
[0489] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: halogenated hydrocarbons, such as
methylene chloride or chloroform.
[0490] The reagent employed for deprotecting the isopropylidene
group is preferably an acid. There is likewise no particular
restriction on the nature of the acids used, and any acid commonly
used as an acid catalyst in reactions of this type may equally be
used here. Examples of such acids include: Bronsted acids, such as
inorganic acids (e.g. hydrochloric acid, hydrobromic acid, sulfuric
acid, perchloric acid or phosphoric acid) or organic acids (e.g.
formic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic
acid, trifluoroacetic acid or trifluoromethanesulfonic acid); Lewis
acids, such as zinc chloride, tin tetrachloride, boron trichloride,
boron trifluoride or boron tribromide; and acidic ion exchange
resins. Of these, we prefer the organic acids particularly
trifluoroacetic acid).
[0491] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents and solvent employed. However, provided that the reaction
is effected under the preferred conditions outlined above, a period
of from 15 minutes to 10 hours, more preferably from 1 to 5 hours,
will usually suffice.
[0492] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: neutralising
the reaction solution; and distilling off the solvent under reduced
pressure. The desired compound can, if desired, be further purified
by recrystallization or the various types of chromatography, such
as column chromatography or preparative thin layer
chromatography.
Method E
[0493] In Method E, a compound of formula (2b) or a compound of
formula (2c), which are amongst the starting materials which may be
used in Method A or B, is prepared. 13
[0494] In the above formulae:
[0495] R.sup.1, Z and W.sup.a are as defined above;
[0496] R.sup.5a represents a hydroxy group; and
[0497] R.sup.6 represents an aliphatic acyl group having from 2 to
25 carbon atoms.
[0498] Step E1
[0499] In this Step, a compound of formula (12) is prepared by
introducing a desired acyl group into the compound of formula (10a)
in an inert solvent.
[0500] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step C1 of Method C.
[0501] Step E2
[0502] In this Step, a compound of formula (13) is prepared by
deprotecting the isopropylidene group of a compound of formula (12)
in an inert solvent.
[0503] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D5 of Method D.
[0504] Step E3
[0505] In this Step, a compound of formula (2b) is prepared from
the compound of formula (13) by using a reducing agent in an inert
solvent.
[0506] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D4of Method D.
[0507] Step E4
[0508] In this Step, a compound of formula (14) is prepared by
treating the compound of formula (12) with a reagent which removes
an isopropylidene group in the presence of an acid catalyst and in
a suitable solvent.
[0509] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. The solvent
employed is preferably a mixture of water and acetic acid (which
simultaneously functions as an acid catalyst).
[0510] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from 10 to
70.degree. C., more preferably from 30 to 60.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents and solvent employed. However, provided that the reaction
is effected under the preferred conditions outlined above, a period
of from 15 minutes to 24 hours, more preferably from 10 to 20
hours, will usually suffice.
[0511] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: distilling off
the solvent under reduced pressure; adding a water-immiscible
solvent, such as ethyl acetate, and an aqueous solution of sodium
hydrogencarbonate to the reaction solution; extracting the desired
compound with a suitable solvent, such as ethyl acetate, and
distilling off the solvent. The desired compound can, if desired,
be further purified by recrystallization or the various types of
chromatography, such as column chromatography or preparative thin
layer chromatography.
[0512] Step E5
[0513] In this Step, a compound of formula (2c) is prepared from
the compound of formula (14) using a reducing agent in an inert
solvent.
[0514] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D4 of Method D.
Method F
[0515] In Method F, a compound of formula (2d) or a compound of
formula (2e), which are amongst the starting materials used in
Methods A and B, are prepared. 14
[0516] In the above formulae:
[0517] R.sup.1, R.sup.3a, R.sup.6, Z and W.sup.a are as defined
above;
[0518] R.sup.2b represents a hydroxy-protecting group, preferably a
t-butyldimethylsilyl group; and
[0519] R.sup.7 represents an aliphatic acyl group having from 2 to
25 carbon atoms.
[0520] Step F1
[0521] In this Step, a compound of formula (15) is prepared by
reacting the compound of formula (14) with a reagent which protects
a primary hydroxy group in an inert solvent.
[0522] There is no particular restriction on the nature of the
protecting group, provided that it can selectively protect a
primary hydroxy group, and any hydroxy-protecting group commonly
used in organic synthesis can be used here. Examples of such groups
include trialkylsilyl, dialkylarylsilyl and alkyldiarylsilyl
groups, such as the t-butyldimethylsilyl group and the
t-butyldiphenylsilyl group.
[0523] Silylation can be carried out by any conventional method.
For example, silylation can be carried out by reacting the compound
of formula (14) with a t-butyldimethylsilyl halide (particularly
the chloride) in the presence of a base, such as triethylamine or
4-(N,N-dimethylamino)pyridine in a solvent such as
dimethylformamide.
[0524] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 40.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents and solvent employed. However, provided that the reaction
is effected under the preferred conditions outlined above, a period
of from 15 minutes to 24 hours, more preferably from 10 to 20
hours, will usually suffice.
[0525] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: adding a
water-immiscible solvent, such as ethyl acetate, and an aqueous
solution of sodium hydrogencarbonate to the reaction solution;
extracting the desired compound with a suitable solvent, such as
ethyl acetate; and distilling off the solvent. The desired compound
can, if desired, be further purified by recrystallization or the
various types of chromatography, such as column chromatography or
preparative thin layer chromatography.
[0526] Step F2
[0527] In this Step, a compound of formula (16) is prepared by
introducing a desired acyl group into the compound of formula (15)
in an inert solvent.
[0528] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step C1 of Method C.
[0529] Step F3
[0530] In this Step, a compound of formula (17) is prepared by
reacting the compound of formula (16) with a reagent which removes
the protecting group for the primary hydroxy group.
[0531] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: alcohols, such as methanol and ethanol;
water; or a mixture of any two or more of these solvents.
[0532] There is likewise no particular restriction on the nature of
the deprotecting agents used, and any deprotecting agent commonly
used in reactions of this type may equally be used here. Examples
of such deprotecting agents include acids. The nature of the acid
is not critical, and any acid commonly used in conventional
reactions as an acid catalyst may be used here. Examples include:
Bronsted acids, such as inorganic acids (e.g. hydrochloric acid,
hydrobromic acid, sulfuric acid, perchloric acid and phosphoric
acid) and organic acids, such as acetic acid, formic acid, oxalic
acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic
acid and trifluoromethanesulfonic acid; Lewis acids, such as zinc
chloride, tin tetrachloride, boron trichloride, boron trifluoride
and boron tribromide; and acidic ion exchange resins. Of these, we
prefer the organic acids particularly acetic acid and
trifluoroacetic acid).
[0533] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents and solvent employed. However, provided that the reaction
is effected under the preferred conditions outlined above, a period
of from 15 minutes to 10 hours, more preferably from 1 to 5 hours,
will usually suffice.
[0534] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: neutralising
the reaction solution; distilling off the solvent under reduced
pressure; and purifying the residue thus obtained by silica gel
chromatography.
[0535] In this step, the acyl group (R.sup.7) at the 8-position is
shifted to the 9-position.
[0536] A reagent for forming a fluoride anion such as
tetrabutylammonium fluoride can be used, if desired, as the
deprotecting agent.
[0537] Step F4
[0538] This step may be carried out by:
[0539] 1) acylating the hydroxy group in the 8-position; or
[0540] 2) protecting the hydroxy group.
[0541] The reaction of step 1) is essentially the same as and may
be carried out in the same manner as and using the same reagents
and reaction conditions as Step C1 of Method C.
[0542] The reaction of step 2) can be carried out by using
t-butyldimethylsilyl triflate as the reagent for introducing a
protecting group, and using lutidine as a base in methylene
chloride as the solvent.
[0543] Step F5
[0544] In this Step, a compound of formula (2d) is prepared from
the compound of formula (18) by using a reducing agent in an inert
solvent.
[0545] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D4 of Method D.
[0546] Step F6
[0547] In this Step, a compound of formula (2e) is prepared from
the compound of formula (16) by using a reducing agent in an inert
solvent.
[0548] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D4 of Method D.
Method G
[0549] In Method G, a compound of formula (2f) or a compound of
formula (2g), which are among the starting materials used in
Methods A and B, are prepared. 15
[0550] In the above formulae:
[0551] R.sup.1, R.sup.6, Z and W.sup.a are as defined above;
and
[0552] R.sup.8 represents an aliphatic acyl group having from 2 to
25 carbon atoms.
[0553] Step G1
[0554] In this Step, a compound of formula (19) is prepared by
introducing a desired acyl group into the compound of formula (13)
in an inert solvent.
[0555] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step C1 of Method C.
[0556] Step G2
[0557] In this Step, a compound of formula (2f) is prepared from
the compound of formula (19) by using a reducing agent in an inert
solvent.
[0558] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D4 of Method D.
[0559] Step G3
[0560] In this Step, a compound of formula (20) is prepared by
introducing a desired acyl group into the compound of formula (14)
in an inert solvent.
[0561] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step C1 of Method C.
[0562] Step G4
[0563] In this Step, a compound of formula (2g) is prepared from
the compound of formula (20) by using a reducing agent in an inert
solvent.
[0564] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D4 of Method D.
Method H
[0565] In Method H, a compound of formula (5), which is among the
staring materials used in Method C is prepared. 16
[0566] In the above formulae:
[0567] R.sup.1, R.sup.4, R.sup.5, Z, W.sup.a, Ac, Boc and Me are as
defined above;
[0568] X.sup.c represents an alkoxy group having from 1 to 4 carbon
atoms; and
[0569] Bz represents a benzyl group.
[0570] In this Step, a compound of formula (22) is prepared by
reacting an alkyl halide with a compound of formula (21) [described
in Carbohydrate Research 83, 163-169 (1980)] in the presence of a
base and in an inert solvent.
[0571] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; ethers, such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethylene glycol dimethyl ether-, amides, such as formamide,
dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone,
N-methylpyrrolidinone and hexamethylphosphoric triamide; and
sulfoxides, such as dimethyl sulfoxide and sulfolane. Of these, we
prefer the amides (particularly dimethylformamide).
[0572] There is likewise no particular restriction on the nature of
the bases used, and any base commonly used in reactions of this
type may equally be used here. Examples of such bases include:
alkali metal hydrides, such as lithium hydride, sodium hydride and
potassium hydride; alkali metal alkoxides, such as sodium
methoxide, sodium ethoxide, potassium methoxide, potassium
ethoxide, potassium t-butoxide and lithium methoxide; alkali metal
mercaptans, such as methylmercaptan sodium and ethylmercaptan
sodium; organic bases, such as N-methylmorpholine, triethylamine,
tripropylamine, tributylamine, diisopropylethylamine,
dicyclohexylamine, N-methylpiperidine, pyridine,
4-pyrrolidinopyridine, picoline, 4-(N,N-dimethylamino)pyridine,
2,6-di(t-butyl)-4-methylpyridine- , quinoline, N,N-dimethylaniline,
N,N-diethylaniline, 1,5-diazabicyclo[4.3.0]non-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU); and organic metal bases,
such as butyllithium, lithium diisopropylamide and lithium
bis(trimethylsilyl)amide. Of these, we prefer the alkali metal
hydrides particularly sodium hydride).
[0573] There is likewise no particular restriction on the nature of
the alkyl halides used, and any alkyl halide commonly used in
reactions of this type may equally be used here. Preferred such
alkyl halides include the alkyl bromides and alkyl iodides.
[0574] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
0.degree. C. to 50.degree. C., more preferably at about room
temperature. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the reagents, base and solvent employed. However,
provided that the reaction is effected under the preferred
conditions outlined above, a period of from 15 minutes to 24 hours,
more preferably from 2 to 10 hours, will usually suffice.
[0575] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: adding a
water-immiscible solvent, such as ethyl acetate, and an aqueous
solution of sodium hydrogencarbonate to the reaction solution;
extracting the desired compound with a suitable solvent, such as
ethyl acetate; and distilling off the solvent. The desired compound
can, if desired, be further purified by recrystallization or the
various types of chromatography, such as column chromatography or
preparative thin layer chromatography.
[0576] Step H2
[0577] In this Step, a compound of formula (23) is prepared by
reacting a reducing agent with the compound of formula (22) in an
inert solvent.
[0578] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: alcohols, such as methanol and ethanol;
ethers, such as tetrahydrofuran and dioxane; fatty acids, such as
acetic acid; or a mixture of any one or more of these organic
solvents and water. Of these, we prefer acetic acid.
[0579] The reduction is preferably effected by means of hydrogen in
the presence of a hydrogenation catalyst. There is likewise no
particular restriction on the nature of the hydrogenation catalysts
used, and any hydrogenation catalyst commonly used in reactions of
this type may equally be used here. Examples of such hydrogenation
catalysts include: palladium-on-carbon, platinum and Raney nickel,
preferably palladium-on-carbon.
[0580] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
0.degree. C. to 50.degree. C., more preferably at about room
temperature. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the reagents and solvent employed. However,
provided that the reaction is effected under the preferred
conditions outlined above, a period of from 15 minutes to 24 hours,
more preferably from 2 to 10 hours, will usually suffice.
[0581] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: removing the
hydrogenation catalyst by filtration; distilling off the solvent;
and purifying the residue thus obtained by recrystallization or by
the various forms of chromatography.
[0582] Step H3
[0583] In this Step, a compound of formula (24) is prepared by
reacting sodium pyruvate with the compound of formula (23) in the
presence of N-acetylneuraminic acid aldolase and sodium azide in an
inert solvent.
[0584] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. A preferred
solvent is water.
[0585] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
0.degree. C. to 50.degree. C., more preferably at about room
temperature. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the reagents and solvent employed. However,
provided that the reaction is effected under the preferred
conditions outlined above, a period of from 5 hours to 5 days, more
preferably from 1 to 3 days, will usually suffice.
[0586] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: desalting the
compound by means of a cation exchange resin; and purifying the
compound by chromatography using an anion exchange resin.
[0587] Step H4
[0588] In this Step, a compound of formula (25) is prepared by
esterifying the compound of formula (24) in the presence of an acid
in a methanol solvent.
[0589] There is no particular restriction on the nature of the
acids used, and any acid commonly used as an acid catalyst in
reactions of this type may equally be used here. Examples of such
acids include: Bronsted acids, such as inorganic acids (e.g.
hydrochloric acid, hydrobromic acid, sulfuric acid, perchloric acid
or phosphoric acid) or organic acids (e.g. acetic acid, formic
acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid,
trifluoroacetic acid or trifluoromethanesulfonic acid); Lewis
acids, such as zinc chloride, stannous tetrachloride, boron
trichloride, boron trifluoride and boron tribromide; and cation
exchange resins. Of these, we prefer the cation exchange
resins.
[0590] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
0.degree. C. to 50.degree. C., more preferably at about room
temperature. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the reagents and solvent employed. However,
provided that the reaction is effected under the preferred
conditions outlined above, a period of from 1 to 48 hours, more
preferably from 5 to 24 hours, will usually suffice.
[0591] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: removing the
cation exchange resin by filtration; distilling off the solvent;
and purifying the residue thus obtained by recrystallization or by
the various forms of chromatography.
[0592] Step H5
[0593] In this Step, a compound of formula (25) is acylated in an
inert solvent.
[0594] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step C1 of Method C.
[0595] Step H6
[0596] In this Step, the compound obtained in Step H5 is
chlorinated by reacting the compound obtained in Step H5 with
hydrogen chloride in an inert solvent.
[0597] The reaction is normally and preferably effected in the
presence of a solvent There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; and ethers, such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethylene glycol dimethyl ether. Of these, we prefer the ethers
(particularly dioxane).
[0598] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
0.degree. C. to 50.degree. C., more preferably at about room
temperature. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the reagents and solvent employed. However,
provided that the reaction is effected under the preferred
conditions outlined above, a period of from 5 hours to 2 days, more
preferably from 10 to 24 hours, will usually suffice.
[0599] After completion of the reaction, the solvent and hydrogen
chloride are distilled off under reduced pressure and the product
is used as such for the next reaction.
[0600] Step H7
[0601] In this Step, a compound of formula (26a) is prepared by
reacting a base with the compound obtained in Step H6 to carry out
dehydrochlorination.
[0602] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; and ethers, such as diethyl ether,
diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and
diethylene glycol dimethyl ether. Of these, we prefer the aromatic
hydrocarbons particularly benzene).
[0603] There is likewise no particular restriction on the nature of
the bases used, and any base commonly used in reactions of this
type may equally be used here. Examples of such bases include:
alkali metal alkoxides, such as sodium methoxide, sodium ethoxide,
potassium methoxide, potassium ethoxide, potassium t-butoxide and
lithium methoxide; mercaptan alkali metals, such as methylmercaptan
sodium and ethylmercaptan sodium; organic bases, such as
N-methylmorpholine, triethylamine, tripropylamine, tributylamine,
diisopropylethylamine, dicyclohexylamine, N-methylpiperidine,
pyridine, 4-pyrrolidinopyridine, picoline,
4-(N,N-dimethylamino)pyridine, 2,6-di(t-butyl)-4-methylpyridine- ,
quinoline, N,N-dimethylaniline, N,N-diethylaniline,
1,5-diazabicyclo[4.3.0]noN-5-ene (DBN),
1,4-diazabicyclo[2.2.2]octane (DABCO) and
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), more preferably DBU.
[0604] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from
0.degree. C. to 50.degree. C., more preferably at about room
temperature. The time required for the reaction may also vary
widely, depending on many factors, notably the reaction temperature
and the nature of the reagents and solvent employed. However,
provided that the reaction is effected under the preferred
conditions outlined above, a period of from 5 hours to 2 days, more
preferably from 10 to 24 hours, will usually suffice.
[0605] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: adding a
water-immiscible solvent, such as methylene chloride, and an
aqueous solution of ammonium chloride to the reaction solution;
extracting the desired compound; and distilling off the solvent.
The desired compound can be purified by further recrystallization
and the various types of chromatography, such as column
chromatography or preparative thin layer chromatography.
[0606] Step H8
[0607] In this Step, a compound of formula (27) is prepared by
reacting the compound of formula (26a), prepared as described in
Step H7, or another compound of formula (26), which may have been
prepared as described in WO95/32955, with an azidating agent in an
inert solvent.
[0608] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aromatic hydrocarbons, such as benzene,
toluene and xylene; halogenated hydrocarbons, such as methylene
chloride and chloroform; ethers, such as ether, tetrahydrofuran,
dioxane and dimethoxyethane, and nitrites, such as
acetonitrile.
[0609] There is likewise no particular restriction on the nature of
the azidating agents used, and any azidating agent commonly used in
reactions of this type may equally be used here. Examples of such
azidating agents include: diarylphosphoric azide derivatives, such
as diphenylphosphoric azide; trialkylsilyl azides, such as
trimethylsilyl azide and triethylsilyl azide; and alkali metal
azides, such as sodium azide and potassium azide. Of these, we
prefer sodium azide.
[0610] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents and solvent employed. However, provided that the reaction
is effected under the preferred conditions outlined above, a period
of from 15 minutes to 10 hours, more preferably from 1 to 5 hours,
will usually suffice.
[0611] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: neutralising
the reaction solution with a solution of hydrogen chloride in
dioxane; distilling off the solvent under reduced pressure; and
purifying the residue thus obtained by silica gel
chromatography.
[0612] Step H9
[0613] In this Step, a compound of formula (28) is prepared by
reacting the compound of formula (27) with a t-butoxycarbonylating
agent in an inert solvent.
[0614] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aromatic hydrocarbons, such as benzene,
toluene and xylene; halogenated hydrocarbons, such as methylene
chloride and chloroform; ethers, such as ether, tetrahydrofuran,
dioxane and dimethoxyethane, and amides, such as
dimethylformamide.
[0615] The t-butoxycarbonylation can be carried out by reacting
di-t-butyl dicarbonate or
2-(t-butoxycarbonyloxyimino)-2-phenylacetonitrile in the presence
of a base, for example 4-(N,N-dimethylamino)pyridine.
[0616] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: neutralising
the reaction solution; distilling off the solvent under reduced
pressure; adding a water-immiscible solvent, such as ethyl acetate,
and water to the residue; extracting the desired compound with a
suitable solvent, such as ethyl acetate; and distilling off the
solvent. The desired compound can, if desired, be further purified
by recrystallization or the various types of chromatography, such
as column chromatography or preparative thin layer
chromatography.
[0617] Step H10
[0618] In this Step, a compound of formula (29) is prepared by
reacting the compound of formula (28) with a base in an inert
solvent.
[0619] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D1 of Method D.
[0620] Step H11
[0621] In this Step, the compound of formula (29) is acetylated in
an inert solvent.
[0622] The acetylation may be carried out by conventional means,
commonly used for the protection of a hydroxy group. For example,
the acetylation may be carried out 1) by reacting the compound of
formula (29) with acetic anhydride in pyridine or 2) by reacting
the compound of formula (29) with an acetyl halide (particularly
the chloride) in the presence of a base catalyst (for example,
triethylamine, 4-N,N-dimethylaminopyridine) in methylene
chloride.
[0623] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: distilling off
the solvent under reduced pressure; adding a water-immiscible
solvent, such as ethyl acetate, and an aqueous solution of sodium
hydrogencarbonate to the residue; extracting the desired compound
with a suitable solvent, such as ethyl acetate; and distilling off
the solvent. The desired compound can, if desired, be further
purified by recrystallization or the various types of
chromatography, such as column chromatography or preparative thin
layer chromatography.
[0624] Step H12
[0625] In this Step, a compound of formula (30) is prepared by
treating the compound obtained in Step H11 with a reagent which
eliminates a t-butoxycarbonyl group in an inert solvent.
[0626] Elimination of the t-butoxycarbonyl group may be carried out
by conventional processes.
[0627] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; halogenated hydrocarbons, such as
methylene chloride, chloroform, carbon tetrachloride,
dichloroethane, chlorobenzene and dichlorobenzene; esters, such as
ethyl formate, ethyl acetate, propyl acetate, butyl acetate and
diethyl carbonate; ethers, such as diethyl ether, diisopropyl
ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene
glycol dimethyl ether, amides, such as formamide,
dimethylformamide, N,N-dimethylacetamide, N-methyl-2-pyrrolidone,
N-methylpyrrolidinone and hexamethylphosphoric triamide; and
sulfoxides, such as dimethyl sulfoxide and sulfolane. Of these, we
prefer the halogenated hydrocarbons (particularly methylene
chloride).
[0628] There is likewise no particular restriction on the nature of
the reagent used to eliminate the t-butoxycarbonyl group, and any
reagent commonly used in reactions of this type may equally be used
here. An example of such a reagent is hydrochloric acid.
[0629] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from -10
to 50.degree. C., more preferably from 10 to 30.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents and solvent employed. However, provided that the reaction
is effected under the preferred conditions outlined above, a period
of from 15 minutes to 24 hours, more preferably from 1 to 10 hours,
will usually suffice.
[0630] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: distilling off
the solvent under reduced pressure; adding a water-immiscible
solvent, such as ethyl acetate, and an aqueous solution of sodium
hydrogencarbonate to the reaction solution; extracting the desired
compound with a suitable solvent, such as ethyl acetate; and
distilling off the solvent. The desired compound can, if desired,
be further purified by recrystallization or the various types of
chromatography, such as column chromatography or preparative thin
layer chromatography.
[0631] Step H13
[0632] In this Step, an acyl group is introduced into the compound
of formula (30) by reaction with an acylating agent in an inert
solvent.
[0633] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step C1 of Method C.
[0634] Step H14
[0635] In this Step, a compound of formula (31) is prepared by
reacting the compound obtained in Step H13 with a reagent which
converts a carbonyl group into a thiocarbonyl group in an inert
solvent.
[0636] The reaction is normally and preferably effected in the
presence of a solvent. There is no particular restriction on the
nature of the solvent to be employed, provided that it has no
adverse effect on the reaction or on the reagents involved and that
it can dissolve the reagents, at least to some extent. Examples of
suitable solvents include: aliphatic hydrocarbons, such as hexane,
heptane, ligroin and petroleum ether; aromatic hydrocarbons, such
as benzene, toluene and xylene; halogenated hydrocarbons, such as
methylene chloride, chloroform, carbon tetrachloride,
dichloroethane, chlorobenzene and dichlorobenzene; and ethers, such
as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether. Of these, we
prefer the ethers (particularly tetrahydrofuran).
[0637] There is no particular restriction on the nature of the
reagent employed to convert the carbonyl group into a thiocarbonyl
group is preferably Lawesson's reagent.
[0638] The reaction can take place over a wide range of
temperatures, and the precise reaction temperature is not critical
to the invention. The preferred reaction temperature will depend
upon such factors as the nature of the solvent, and the starting
material or reagent used. However, in general, we find it
convenient to carry out the reaction at a temperature of from 10 to
100.degree. C., more preferably from 40 to 70.degree. C. The time
required for the reaction may also vary widely, depending on many
factors, notably the reaction temperature and the nature of the
reagents and solvent employed. However, provided that the reaction
is effected under the preferred conditions outlined above, a period
of from 15 minutes to 10 hours, more preferably from 1 to 5 hours,
will usually suffice.
[0639] After completion of the reaction, the desired compound can
be recovered from the reaction mixture by conventional means. For
example, one suitable recovery procedure comprises: adding a
water-immiscible solvent, such as ethyl acetate, and an aqueous
solution of sodium hydrogencarbonate to the reaction solution;
extracting the desired compound with a suitable solvent, such as
ethyl acetate; and distilling off the solvent. The desired compound
can, if desired, be further purified by recrystallization or the
various types of chromatography, such as column chromatography or
preparative thin layer chromatography.
[0640] Step H15
[0641] In this Step, a compound of formula (32) is prepared from
the compound of formula (31) by using a reducing agent in an inert
solvent.
[0642] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D4 of Method D.
[0643] Step H16
[0644] In this Step, a compound of formula (33) is prepared by
reacting the compound of formula (32) with
N,N'-di-t-butoxycarbonylthiourea in the presence of a base and
mercuric chloride in an inert solvent.
[0645] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step A1 of Method A.
[0646] Step H17
[0647] In this Step, a compound of formula (34) is prepared by
reacting the compound of formula (33) described later with a base
in an inert solvent.
[0648] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D1 of Method D.
[0649] Step H18
[0650] The present step may be carried out, if desired, by 1)
converting a methyl group of a carboxylic acid ester into another
substituent, 2) hydrolysing a carboxylic acid ester or 3)
protecting the carboxylic acid after step 2) above.
[0651] This reaction is essentially the same as and may be carried
out in the same manner as and using the same reagents and reaction
conditions as Step D3 of Method D.
[0652] In some cases, the compounds of the present invention can be
prepared efficiently by carrying out the above steps in a different
order, as will be appreciated by the skilled reader.
[0653] The compounds of the present invention may be administered
alone or in admixture with conventional pharmaceutically acceptable
carriers, diluents or adjuvants and in various formulations, as is
well known in the art. For example, the compounds of the present
invention may be given by oral or intranasal administration as a
liquid preparation, such as a solution or suspension (optionally in
an aqueous medium or in a mixture or such a medium and an aqueous
cosolvent), or as an aerosol or a powder preparation. The liquid
preparations, such as solutions, optionally including an aqueous
cosolvent, may be prepared by conventional means, for example using
purified water, a pharmaceutically acceptable organic solvent (for
example, ethanol, propylene glycol or PEG400), a stabilizing agent
(a paraoxybenzoate, such as methylparaben or propylparaben; an
alcohol, such as chlorobutanol, benzyl alcohol or phenylethyl
alcohol; a benzalkonium chloride; a phenol, such as phenol or
cresol; thimerosal; or dehydroacetic acid). Aerosols may be
prepared by conventional means, using a propellant, such as the
various Freon (trade mark) gases or nitrogen gas and a surface
active agent, such as lecithin. Powder preparations may be prepared
by conventional means, using any one or more of an excipient, a
lubricant, a stabilizing agent, a corrigent and a diluent. Examples
of such excipients include organic excipients including: sugar
derivatives, such as lactose, sucrose, glucose, mannitol and
sorbitol; starch derivatives, such as corn starch, potato starch,
.alpha.-starch, dextrin and carboxymethyl starch; cellulose
derivatives, such as crystalline cellulose, low substitution
hydroxypropyl cellulose, hydroxypropylmethyl cellulose,
carboxymethyl cellulose, calcium carboxymethyl cellulose and
internally crosslinked sodium carboxymethyl cellulose; gum arabic;
dextran; and pullulan. Othere excipients include inorganic
excipients including: silicate derivatives, such as soft silicic
anhydride, synthetic aluminum silicate and magnesium aluminate
metasilicate; phosphates, such as calcium phosphate; carbonates,
such as calcium carbonate; and sulfates, such as calcium sulfate.
Examples of lubricants include: stearic acid; metal salts of
stearic acid such as calcium stearate and magnesium stearate; talc;
colloid silica; waxes, such as beeswax and sperm whale; boric acid;
adipic acid; sulfates, such as sodium sulfate; glycol; fumaric
acid; sodium benzoate; DL-leucine; fatty acid sodium salts;
laurylsulfates, such as sodium laurylsulfate and magnesium
laurylsulfate; silicic acids, such as silicic anhydride and silicic
hydrate; and the above starch derivatives. Examples of stabilizing
agent include: paraoxybenzoates, such as methylparaben and
propylparaben; alcohols, such as chlorobutanol, benzyl alcohol and
phenylethyl alcohol; benzalkonium chlorides; phenols, such as
phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid.
Examples of corrigents include sweeteners, souring agents and
flavors.
[0654] The amount of the active component to be used will vary
depending on the symptoms, age, and body weight of the patient, as
well as upon the mode of administration and the severity of the
disease. However, in general, it is desirable to administer the
active component in an amount of from 0.1 mg per day (preferably 1
mg) to 1000 mg (preferably 500 mg) in the case of liquid
preparations; in the case of dry powder preparations, the active
component is preferably administered in an amount of from 0.1 mg
per day (preferably 1 mg) to 1000 mg (preferably 500 mg); in the
case of aerosols, the active component is preferably administered
in an amount of from 0.1 mg per day (preferably 1 mg) to 1000 mg
(preferably 500 mg). This may be administered in a single dose or
in divided doses, depending on the condition.
BIOLOGICAL ACTIVITY
[0655] The 2-deoxy-2,3-didehydro-N-acylneuraminic acid derivatives
of the present invention have excellent sialidase inhibitory
activity, and are, accordingly, useful in the prophylaxis and
therapy of influenza. The activity of compounds of the present
invention is further illustrated by the following Experiments.
Experiment 1
Influenza Virus Replication Inhibitory Activity
[0656] Influenza virus strain A/Yamagata/32189(H1N1) was
proliferated in a live hen's egg, and the virus produced by this
technique was then applied to plates of MDCK cells (derived from
canine kidney) to obtain plaques. MDCK cells were infected with
virus in the presence or absence of various concentrations of test
compound. Influenza virus replication inhibitory activity of test
compounds could then be calculated by comparing the amounts of
plaques in the control and test samples.
[0657] The methodology of the present Experiment was generally in
accordance with Antimicrobial Agents And Chemotherapy, 17,
pp.865-870 (1980).
[0658] More specifically, MDCK cells were cultured to a single,
confluent layer on the surface of petri-dishes having a diameter of
35 mm. The culture conditions of the MDCK cells on these plates
were 37.degree. C. under a sterile atmosphere containing 5% v/v
carbon dioxide gas. After the cells had reached confluence, the
culture liquid was sucked off. An amount of phosphate buffered
physiological saline solution containing 50-100 pfu (plaque forming
units) of virus was then added to the plates.
[0659] The resulting plates were then left to stand for 1 hour at
37.degree. C. to permit adsorption of the virus, after which time
the remaining phosphate buffered physiological saline solution was
sucked off and replaced with MEM medium (Gibco BRL) containing 1
.mu.g/ml of trypsin (Cooper Biomedical), 0.01% w/w DEAE dextran
(Pharmacia LKB), 0.6% w/w agar (Sigma) together with an amount of
between 0.00056 and 5.6 .mu.g/ml of test compound.
[0660] Cultivation of the plates was continued at 37.degree. C. for
40 hours under a sterile atmosphere containing 5% carbon dioxide
gas, after which time solidified agar medium was recovered. Crystal
violet (Merck) was dissolved in 19% methanol to a final
concentration of 0.01% and was added to the recovered agar in order
to fix and stain the cells, thereby permitting determination of the
number of plaques.
[0661] The number of plaques formed in the absence of test compound
is taken as 100% (the control). It was then possible to calculate
IC.sub.50 (the concentration in nM/ml at which the test compound
reduces the number of observed plaques to 50%,) as a measure of
influenza virus replication inhibitory activity.
[0662] The compounds of the present invention were found to exhibit
high influenza virus replication inhibitory activity, as shown in
Tables 3 and 4, below.
3 TABLE 3 Test Compound IC.sub.50 (nM) Compound A 4.7 Compound of
Example 28 1.7
[0663]
4 TABLE 4 Test Compound IC.sub.50 (nM) Compound A 11 Compound of
Example 30 0.8
[0664] Compound A in the above Tables 3 and 4, as well as in Tables
5 and 6 below, is the compound prepared in Example 3 of
Toku-Hyo-Hei 5-507068. Its structure is shown below: 17
Experiment 2
Influenza Virus Sialidase Inhibitory Activity
[0665] In this experiment, a sample of influenza virus strain
A/PR/8/34(H1N1) was dissolved by means of a surfactant, after which
the virus membrane fraction was purified by centrifugation. The
thus purified fraction was used as a crude influenza virus
sialidase, and p-nitrophenyl-N-acetylneuraminic acid (Wako Pure
Chemical) was used as a substrate to perform similar tests to those
described in Analytical Biochemistry, 94, 287-296 (1979).
[0666] An enzyme solution was first prepared such that the final
enzyme activity was 0.0011 units/ml (1 unit corresponds to that
amount of enzyme which hydrolyzes 1 .mu.mole of substrate in 1
minute). Also prepared beforehand were aqueous solutions of test
compound in various concentrations; an aqueous solution of the
substrate to a concentration of 33 .mu.g/ml, and a 20 mM
2-(N-morpholino)ethanesulfonic acid buffer (pH 6.5) containing 50
mM calcium chloride. These solutions were combined to prepare a
mixture having a final volume of 150 .mu.l, and which was then left
to stand at 37.degree. C. for 20 minutes. The absorbance of any
p-nitrophenol formed in the mixture was measured at 415 nm. The
absorbance measured at 415 nm where the mixture was prepared by
adding water in place of the aqueous solution of test compound was
taken as 100%. Thus, IC.sub.50 (nM) was determined as the
concentration of the sample at which the absorbance was reduced by
50%, to provide a measure of influenza virus sialidase inhibitory
activity.
[0667] The results are shown below in Table 5.
5 TABLE 5 Test Compound IC.sub.50 (nM) Compound A 9.0 Compound of
Example 28 13 Compound of Example 30 7.0
Experiment 3
Mouse Infection Test
[0668] A solution of 1500 pfu of mouse-adapted influenza virus
strain A/PR/8/34 in 50 .mu.l of a 0.42 % v/v bovine serum
albumin-containing phosphate buffer was prepared, and mice (BALB/C,
female, age: 5 to 6 weeks, 20 g) were infected dropwise,
intranasally, with the resulting solution. Test compound was
suspended in a physiological saline solution to provide a dosage of
0.9 .mu.mol/kg/50 .mu.l. The resulting suspension was administered
dropwise intranasally 3 times in total, once 4 hours before the
virus infection, once 4 hours after the infection and once at 17
hours after the infection. The result is shown in terms of the
number of mice surviving after 6 days, 8 days, 10 days and 15 days
from infection. The test was conducted on groups of mice, each
group consisting of 12 animals. The results are shown in Table 6
below.
6 TABLE 6 6th day 8th day 10th day 15th day Physiological saline
only 2 0 0 0 Compound A 12 2 1 0 Compound of Example 29 12 12 12 12
Compound of Example 34 12 12 11 10
[0669] Thus, it can be seen that the compounds of the present
invention greatly enhance the survival ate of animals exposed to
the influenza virus.
EXAMPLE 1
5-Acetamido-4-(C-aminooxy-C-iminomethylamino)-7-O-hexanoyl-2,3,4,5-tetrade-
oxy-D-glycero-D-galacto-non-2-enopyranosoic Acid (Compound No.
76-1)
[0670] 18
[0671] 1(i) Methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-D-glycero-D-gala-
cto-non-2-enopyranosoate
[0672] 7 g (15.3 mmol) of methyl
5-acetamido-7,8,9-tri-O-acetyl-4-azido-2,-
3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoate were
dissolved in 20 ml of methanol, and 0.2 ml of a 4.9 M methanolic
solution of sodium methoxide (0.98 mmol) was added dropwise to the
resulting solution, while stirring at room temperature. The
reaction mixture was then stirred at room temperature for 2 hours,
after which a 4 M solution of hydrogen chloride in dioxane was
added dropwise thereto. The pH of the mixture was adjusted to a
value of 6 to 7, and then the mixture was evaporated to dryness
under a vacuum. The resulting residue was subjected to silica gel
column chromatography, using a 10:1 by volume mixture of methylene
chloride and methanol as the eluent, to obtain 3.56 g (yield 69%)
of the title compound as a colorless solid.
[0673] Rf=0.63 (5:1=methylene chloride: methanol).
[0674] Mass Spectrum (FAB) m/e 331 (M.sup.++H).
[0675] ("FAB" is "Fast Atom Bombardment".)
[0676] [.alpha.].sub.D.sup.25 +28.4.degree. (c=0.21, methanol).
[0677] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 2100,
1731, 1657.
[0678] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[0679] 5.92 (1H, doublet, J=2.3 Hz);
[0680] 4.34 (1H, doublet of doublets, J=9.3 & 2.5 Hz);
[0681] 4.27 (1H, doublet of doublets, J=10.7 & 1.2 Hz);
[0682] 4.13 (1H, doublet of doublets, J=10.8 & 9.4 Hz);
[0683] 3.82-3.92 (2H, multiplet);
[0684] 3.79 (3H, singlet);
[0685] 3.66 (1H, doublet of doublets, J=11.4 & 5.0 Hz);
[0686] 3.60 (1H, broad doublet, J=9.3 Hz);
[0687] 2.03 (3H, singlet).
[0688] 1(ii) Methyl
5-acetamido-4-azido-8,9-O-isopropylidene-2,3,4,5-tetra-
deoxy-D-glycero-D-galacto-non-2-enopyranosoate
[0689] 3.33 g (10.1 mmol) of methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-
-D-glycero-D-galacto-non-2-enopyranosoate [prepared as described in
step (i) above] were dissolved in 10 ml of acetone, and 3.7 ml of
2,2-dimethoxypropane (30.2 mmol) and 100 mg of p-toluenesulfonic
acid 1 hydrate (0.52 mmol) were added to the resulting solution
while stirring at room temperature. The mixture was then stirred
for 30 minutes. At the end of this time, 200 ml of ethyl acetate
and 60 ml of a saturated aqueous solution of sodium
hydrogencarbonate were added to the reaction mixture, and the
mixture was partitioned to separate the organic layer. The organic
layer was washed three times, each time with 50 ml of a saturated
aqueous solution of sodium hydrogencarbonate, and then once with 10
ml of a saturated aqueous solution of sodium chloride. It was then
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure to obtain a residue. This
residue was subjected to silica gel column chromatography, using a
2:1 by volume mixture of ethyl acetate and hexane as the eluent, to
obtain 3.24 g (yield 87%) of the title compound as a colorless
solid.
[0690] Rf=0.38 (20:1=methylene chloride:methanol).
[0691] Mass Spectrum (FAB) m/e 371 (M.sup.++H.)
[0692] [.alpha.].sub.D.sup.25 +160.93.degree. (c=0.32,
CHCl.sub.3).
[0693] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 2094,
1734, 1656.
[0694] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[0695] 5.98 (1H, doublet, J=2.5 Hz);
[0696] 5.66 (1H, broad doublet, J=6.9 Hz);
[0697] 4.32-4.41 (1H, multiplet);
[0698] 4.03-4.28 (6H, multiplet);
[0699] 3.81 (3H, singlet);
[0700] 3.57 (1H, doublet of doublets, J=7.9 & 5.2 Hz);
[0701] 2.12 (3H, singlet);
[0702] 1.66 (1H, singlet);
[0703] 1.39 (3H, singlet);
[0704] 1.36 (3H, singlet).
[0705] 1(iii) Methyl
5-acetamido-4-azido-7-O-hexanoyl-8,9-O-isopropylidene-
-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoate
[0706] 1.35 g (3.65 mmol) of methyl
5-acetamido-4-azido-8,9-O-isopropylide- ne
2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in step (ii) above] were dissolved in 30 ml
of methylene chloride, and 490 mg (4.01 mmol) of
dimethylaminopyridine and 0.61 ml (4.37 mmol) of hexanoyl chloride
were added to the resulting solution while stirring and
ice-cooling. The reaction mixture was then stirred at room
temperature for 30 minutes, after which 0.56 ml of triethylamine
were added dropwise while ice-cooling. The mixture was then stirred
at room temperature for a further 2 days. 200 ml of ethyl acetate
and 100 ml of a saturated aqueous solution of sodium
hydrogencarbonate were added to the resulting solution, and the
mixture was partitioned to separate the organic layer. The organic
layer was washed three times, each time with 50 ml of a saturated
aqueous solution of sodium chloride and dried over anhydrous sodium
sulfate, after which the solvent was removed by distillation under
reduced pressure to obtain a residue. This residue was subjected to
silica gel column chromatography, using a 100:1 by volume mixture
of methylene chloride and methanol as the eluent, to obtain 0.69 g
(yield 34%) of the title compound as a yellow oil.
[0707] Rf=0.46 (20:1=methylene chloride:methanol).
[0708] Mass Spectrum (FAB) m/e 469 (M.sup.++H).
[0709] [.alpha.].sub.D.sup.25 +87.7.degree. (c=0.26,
CHCl.sub.3).
[0710] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 2099,
1745, 1660.
[0711] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[0712] 5.95 (1H, doublet, J=2.6 Hz);
[0713] 5.76 (1H, broad doublet, J=7.8 Hz);
[0714] 5.34 (1H, doublet of doublets, J=5.3 & 1.8 Hz);
[0715] 4.85 (1H, doublet of doublets, J=9.0 & 2.7 Hz);
[0716] 4.73 (1H, doublet of doublets, J=10.4 & 1.7 Hz);
[0717] 4.39 (1H, doublet of doublets, J=11.4 & 6.1 Hz);
[0718] 4.14 (1H, doublet of doublets, J=12.3 & 6.3 Hz);
[0719] 3.95 (1H, doublet of doublets, J=8.8 & 6.2 Hz);
[0720] 3.81 (3H, singlet);
[0721] 3.40 (1H, doublet of doublets, J=18.7 & 8.6 Hz);
[0722] 2.28-2.52 (2H, multiplet);
[0723] 2.02 (3H, singlet);
[0724] 1.53-1.72 (2H, multiplet);
[0725] 1.37 (3H, singlet);
[0726] 1.35 (3H, singlet);
[0727] 1.25-1.43 (4H, multiplet);
[0728] 0.86-0.94 (3H, multiplet).
[0729] 1(iv) Methyl
5-acetamido-4-amino-7-O-hexanoyl-8,9-O-isopropylidene--
2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoate
[0730] 650 mg (1.38 mmol) of methyl
5-acetamido-4-azido-7-O-hexanoyl-8,9-O-
-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoat-
e [prepared as described in step (iii) above] were dissolved in 20
ml of methanol, and 400 mg of a Lindlar catalyst were added to the
resulting solution while stirring at room temperature. The reaction
system was then deaerated and the air was replaced with hydrogen.
The reaction mixture was then stirred at room temperature for 2
hours, after which it was filtered under reduced pressure, and the
solvent was removed from the filtrate by distillation under reduced
pressure to obtain a residue. The resulting residue was subjected
to silica gel column chromatography, using a 20:1 by volume mixture
of methylene chloride and methanol, followed by a 10:1 by volume
mixture of methylene chloride and methanol, as the eluent, to
obtain 0.63 g (yield 100%) of the title compound as a yellow
amorphous substance.
[0731] Rf=0.17 (10:1=methylene chloride:methanol).
[0732] Mass Spectrum (FAB) m/e 443 (M.sup.++H).
[0733] [.alpha.].sub.D.sup.25 +30.6.degree. (c=0.32,
CHCl.sub.3).
[0734] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1743,
1660.
[0735] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[0736] 5.97 (1H, doublet, J=2.3 Hz);
[0737] 5.51 (1H, broad doublet, J=9.0 Hz);
[0738] 5.43 (1H, doublet of doublets, J=5.0 & 1.9 Hz);
[0739] 4.40 (1H, doublet of doublets, J=17.2 & 6.5 Hz);
[0740] 4.37 (1H, doublet of doublets, J=9.9 & 1.4 Hz);
[0741] 4.15 (1H, doublet of doublets, J=8.9 & 6.3 Hz);
[0742] 3.95 (1H, doublet of doublets, J=8.7 & 6.8 Hz);
[0743] 3.80 (3H, singlet);
[0744] 3.73-3.80 (1H, multiplet);
[0745] 3.60 (1H, doublet of doublets, J=19.0 & 9.3 Hz);
[0746] 2.24-2.49 (2H, multiplet);
[0747] 2.02 (3H, singlet);
[0748] 1.53-1.70 (2H, multiplet);
[0749] 1.37 (3H, singlet);
[0750] 1.35 (3H, singlet);
[0751] 1.25-1.43 (4H, multiplet);
[0752] 0.86-0.94 (3H, multiplet).
[0753] 1(v)
5-Acetamido-4-amino-7-O-hexanoyl-8,9-O-isopropylidene-2,3,4,5--
tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
[0754] 470 mg (1.06 mmol) of methyl
5-acetamido-4-amino-7-O-hexanoyl-8,9-O-
-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoat-
e [prepared as described in step (iv) above] were dissolved in a
mixture of 4 ml of methanol and 4 ml of water, and 47 mg (1.12
mmol) of lithium hydroxide 1 hydrate were added to the resulting
solution, while stirring at room temperature. The mixture was then
stirred for a further 30 minutes. At the end of this time,
Dowex-50Wx8 (H.sup.+) resin (Dowex is a trade mark) was gradually
added to the mixture, and the pH of the mixture was adjusted to a
value of about 7.5. Immediately after the pH adjustment, the
resulting suspension was rapidly filtered under reduced pressure.
The residue obtained by distilling off the filtrate under reduced
pressure was subjected to silica gel column chromatography, using a
2:5:1 by volume mixture of isopropanol, ethyl acetate and water as
the eluent, to obtain 375 mg (yield 82%) of the title compound as a
colorless solid.
[0755] Rf=0.26 (2:5:1=isopropanol:ethyl acetate:methanol).
[0756] Mass Spectrum (FAB) m/e 429 (M.sup.++H).
[0757] [.alpha.].sub.D.sup.25 +8.3.degree. (c=0.48,
CH.sub.3OH).
[0758] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1750,
1666.
[0759] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[0760] 5.60 (1H, doublet, J=2.1 Hz);
[0761] 5.41 (1H, doublet of doublets, J=5.4 & 1.9 Hz);
[0762] 4.58 (1H, triplet, J=6.0 Hz);
[0763] 4.15-4.28 (3H, multiplet);
[0764] 3.92 (1H, doublet of doublets, J=10.8 & 6.1 Hz);
[0765] 3.79-3.87 (1H, multiplet);
[0766] 2.30-2.40 (2H, multiplet);
[0767] 1.96 (3H, singlet);
[0768] 1.53-1.70 (2H, multiplet);
[0769] 1.35 (3H, singlet);
[0770] 1.32 (3H, singlet);
[0771] 1.25-1.43 (4H, multiplet);
[0772] 0.87-0.96 (3H, multiplet).
[0773] 1(vi)
5-Acetamido-4-amino-7-O-hexanoyl-2,3,4,5-tetradeoxy-D-glycero-
-D-galacto-non-2-enopyranosoic Acid
[0774] 270 mg (0.63 mmol) of
5-acetamido-4-amino-7-O-hexanoyl-8,9-O-isopro-
pylidene-2,3,4,5-tetradeoxy-D-glycero-O-galacto-non-2-enopyranosoic
acid [prepared as described in step (v) above] were dissolved in a
mixture of 12 ml of acetic acid and 3 ml of water at room
temperature, and the mixture was then stirred at 60.degree. C. for
2.5 hours. At the end of this time, the residue obtained by
distilling off the solvent under reduced pressure was subjected to
azeotropic distillation with benzene, followed by concentration to
dryness under a vacuum. The resulting residue was subjected to
silica gel column chromatography, using a 2:5:1 by volume mixture
of isopropanol, ethyl acetate and water as the eluent, to obtain
174 mg (yield 71%) of the title compound as a colorless solid.
[0775] Rf=0.32 (5:1:1=isopropanol:ethyl acetate:methanol).
[0776] Mass Spectrum (FAB) m/e 389 (M.sup.++H).
[0777] [.alpha.(].sub.D.sup.25 +1.1.degree. (c=0.14,
CH.sub.3OH).
[0778] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1745,
1662.
[0779] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[0780] 5.66 (1H, doublet, J=2.2 Hz);
[0781] 5.13 (1H, doublet of doublets, J=9.3 & 1.7 Hz);
[0782] 4.47 (1H, doublet of doublets, J=10.5 & 1.3 Hz);
[0783] 4.17 (1H, triplet, J=10.0 Hz);
[0784] 4.00-4.10 (2H, multiplet);
[0785] 3.59 (1H, doublet of doublets, J=12.0 & 3.1 Hz);
[0786] 3.39 (1H, doublet of doublets, J=12.0 & 6.1 Hz);
[0787] 2.32-2.39 (2H, multiplet);
[0788] 1.91 (3H, singlet);
[0789] 1.45-1.63 (2H, multiplet);
[0790] 1.20-1.28 (4H, multiplet);
[0791] 0.78-0.86 (3H, multiplet).
[0792] 1(vii)
5-Acetamido-4-cyanamido-7-O-hexanoyl-2,3,4,5-tetradeoxy-D-gl-
ycero-D-galacto-non-2-enopyranosoic Acid
[0793] 155 mg (0.40 mmol) of
5-acetamido-4-amino-7-O-hexanoyl-2,3,4,5-tetr-
adeoxy-D-glycero-D-galacto-non-2-enopyranosoic acid [prepared as
described in step (vi) above] were dissolved in 4 ml of methanol,
and 65 mg (0.80 mmol) of sodium acetate and 53 mg (0.50 mmol) of
cyanogen bromide were added to the resulting solution, while
stirring at room temperature. The reaction mixture was then stirred
at room temperature for a further 40 minutes, after which the
solvent was removed by distillation under reduced pressure. The
resulting residue was subjected to silica gel column
chromatography, using a 2:5:1 by volume mixture of isopropanol,
ethyl acetate and water as the eluent, to obtain 144 mg (yield 85%)
of the title compound as a colorless solid.
[0794] Rf=0.21 (2:5:1=isopropanol:ethyl acetate:methanol).
[0795] Mass Spectrum (FAB) m/e 436 (M.sup.++Na), 452
(M.sup.++K).
[0796] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[0797] 5.73 (1H, doublet, J=1.0 Hz);
[0798] 5.07 (1H, doublet of doublets, J=7.8 & 1.2 Hz);
[0799] 4.49 (1H, doublet, J=10.6 Hz);
[0800] 4.47 (1H, doublet of doublets, J=10.5 & 1.3 Hz);
[0801] 4.05-4.18 (2H, multiplet);
[0802] 3.85 (1H, doublet of doublets, J=9.8 & 1.8 Hz);
[0803] 3.63-3.73 (1H, multiplet);
[0804] 3.48-3.58 (1H, multiplet);
[0805] 2.28-2.48 (2H, multiplet);
[0806] 1.95 (3H, singlet);
[0807] 1.54-1.68 (2H, multiplet);
[0808] 1.28-1.40 (4H, multiplet);
[0809] 0.87-0.96 (3H, multiplet).
[0810] 1(viii)
5-Acetamido-(C-aminooxy-C-iminomethylamino)-7-O-hexanol-2,3-
,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
[0811] 88 mg (0.21 mmol) of
5-acetamido-4-cyanamido-7-O-hexanoyl-2,3,4,5-t-
etradeoxy-D-glycero-D-galacto-non-2-enopyranosoic acid [prepared as
described in step (vii) above] were dissolved in 4 ml of methanol,
and 15 mg (0.21 mmol) of hydroxylamine hydrochloride were added to
the resulting solution, while stirring at room temperature. The
reaction mixture was then stirred at room temperature for 2.5
hours, after which the solvent was removed by distillation under
reduced pressure. The resulting residue was subjected to silica gel
column chromatography, using a 2:5:12 by volume mixture of
isopropanol, ethyl acetate and water as the eluent, to obtain 43 mg
(yield 45%) of the title compound as a colorless solid.
[0812] Rf=0.50 (5:1:1=isopropanol:ethyl acetate:methanol).
[0813] Mass Spectrum (FAB) m/e 447 (M.sup.++H).
[0814] [.alpha.].sub.D.sup.25 +28.0.degree. (c=0.035,
CH.sub.3OH).
[0815] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1727,
1661, 1631.
[0816] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[0817] 5.57 (1H, doublet, J=1.9 Hz);
[0818] 5.13 (1H, doublet of doublets, J=8.7 & 1.9 Hz);
[0819] 4.47 (1H, broad doublet, J=10.2 Hz);
[0820] 4.29 (1H, broad doublet, J=9.3 Hz);
[0821] 4.21 (1H, triplet, J=9.9 Hz);
[0822] 4.00-4.09 (1H, multiplet);
[0823] 3.58 (1H, doublet of doublets, J=8.7 & 3.4 Hz);
[0824] 3.43 (1H, doublet of doublets, J=11.5 & 5.7 Hz);
[0825] 2.30-2.40 (2H, multiplet);
[0826] 1.91 (3H, singlet);
[0827] 1.52-1.68 (2H, multiplet);
[0828] 1.28-1.40 (4H, multiplet);
[0829] 0.88-0.96 (3H, multiplet).
EXAMPLE 2
5-Acetamido-4-(C-aminooxy-C-iminomethylamino)-2,3,4,5-tetradeoxy-D-glycero-
-D-galacto-non-2-enopyranosoic Acid (Compound No. 34-1)
[0830] 19
[0831] 2(i)
5-Acetamido-4-(C-aminooxy-C-iminomethylamino)-2,3,4,5-tetradeo-
xy-D-glycero-D-galacto-non-2-enopyranosoic Acid
[0832] 20 mg (0.05 mmol) of
5-acetamido-4-(C-aminooxy-C-iminomethylamino)--
7-O-hexanoyl-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid (prepared as described in Example 1) were dissolved in 20 ml
of methanol, and 2.1 ml of a 4.9 M methanolic solution of sodium
methoxide (0.01 mmol) were added to the resulting solution, while
stirring at room temperature. The solution was then stirred at room
temperature for a further 2 hours, after which a 4 M solution of
hydrogen chloride in dioxane was added, to adjust the pH to a value
of 6-7. The mixture was then evaporated to dryness under a vacuum.
The resulting residue was applied to a silica gel chromatography
column, using a 5:1:1 by volume mixture of isopropanol, ethyl
acetate and water, to obtain 7.3 mg (yield 50%) of the title
compound as a colorless solid.
[0833] Rf=0.30 (4:1:1=isopropanol:ethyl acetate:methanol).
[0834] Mass Spectrum (FAB) m/e 325 (M.sup.++H).
[0835] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[0836] 5.58 (1H, doublet, J=2.0 Hz);
[0837] 4.42 (1H, doublet of doublets, J=10.0 & 2.0 Hz);
[0838] 4.30 (1H, doublet, J=10.0 Hz);
[0839] 4.20 (1H, doublet of doublets, J=10.0 & 10.0 Hz);
[0840] 3.90 (1H, multiplet);
[0841] 3.85 (1H, doublet of doublets, J=12.0 & 2.2 Hz);
[0842] 3.55-3.65 (2H, multiplet);
[0843] 1.99 (3H, singlet).
EXAMPLE 3
5-Acetamido-4-(C-aminooxy-C-iminomethylamino)-9-O-hexanoyl-2,3,4,5-tetrade-
oxy-D-glycero-D-galacto-non-2-enopyranosoic Acid (Compound No.
34-36)
[0844] 20
[0845] 3(i)
5-Acetamido-4-amino-9-O-hexanoyl-2,3,4,5-tetradeoxy-D-glycero--
D-galacto-non-2-enopyranosoic Acid
[0846] 80 mg (0.21 mmol) of
5-acetamido-4-amino-7-O-hexanoyl-2,3,4,5-tetra-
deoxy-D-glycero-D-galacto-non-2-enopyranosoic acid [prepared as
described in Example 1 (vi)] were dissolved in a mixture of 3 ml of
trifluoroacetic acid and 6 ml of methylene chloride at room
temperature, and the mixture was then stirred at room temperature
for a further 6 hours. At the end of this time, the solvent was
removed by distillation under reduced pressure to obtain a residue.
This residue was subjected to azeotropic distillation with benzene,
after which it was evaporated to dryness under a vacuum. The
resulting residue was then subjected to silica gel column
chromatography, using a 2:5:1 by volume mixture of isopropanol,
ethyl acetate and water as the eluent, to obtain 55 mg (yield 68%)
of the title compound as a colorless solid.
[0847] Rf=0.39 (5:1:1=isopropanol:ethyl acetate:methanol).
[0848] Mass Spectrum (FAB) m/e 389 (M.sup.++H).
[0849] [.alpha.].sub.D.sup.25 +10.0.degree. (c=0.07,
CH.sub.3OH).
[0850] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1724,
1664.
[0851] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[0852] 5.56 (1H, doublet, J=2.1 Hz);
[0853] 4.38 (1H, doublet of doublets, J=11.1 & 1.9 Hz);
[0854] 4.30 (1H, singlet);
[0855] 4.28 (1H, doublet, J=1.9 Hz);
[0856] 4.07-4.25 (2H, multiplet);
[0857] 3.93-4.02 (1H, multiplet);
[0858] 3.58 (1H, doublet, J=9.3 Hz);
[0859] 2.37 (2H, triplet, J=7.4 Hz);
[0860] 2.04 (3H, singlet);
[0861] 1.57-1.71 (2H, multiplet);
[0862] 1.27-1.40 (4H, multiplet);
[0863] 0.88-0.96 (3H, multiplet).
[0864] 3(ii)
5-Acetamido-4-cyanamido-9-O-hexanoyl-2,3,4,5-tetradeoxy-D-gly-
cero-D-galacto-non-2-enopyranosoic Acid
[0865] 46 mg (0.12 mmol) of
5-acetamido-4-amino-9-O-hexanoyl-2,3,4,5-tetra-
deoxy-D-glycero-D-galacto-non-2-enopyranosoic acid. [prepared as
described in step (i) above] were dissolved in 10 ml of methanol,
and 29 mg (0.35 mmol) of sodium acetate and 17 mg (0.16 mmol) of
cyanogen bromide were added to the resulting solution, while
stirring at room temperature. The reaction mixture was stirred at
room temperature for a further 40 minutes, and then the solvent was
removed by distillation under reduced pressure to obtain a residue.
This residue was subjected to silica gel column chromatography,
using a 2:5:12 by volume mixture of isopropanol, ethyl acetate and
water as the eluent, to obtain 29 mg (yield 60%) of the title
compound as a colorless solid.
[0866] Rf=0.43 (2:5:1=isopropanol:ethyl acetate:methanol).
[0867] Mass Spectrum (FAB) m/e 436 (M.sup.++Na), 458
(M.sup.++2Na--H).
[0868] [.alpha.].sub.D.sup.25 +8.27.degree. (c=0.075,
CH.sub.3OH).
[0869] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[0870] 5.66 (1H, doublet, J=2.0 Hz);
[0871] 3.95-4.36 (6H, multiplet);
[0872] 3.67 (1H, doublet, J=7.4 Hz);
[0873] 2.36 (2H, triplet, J=7.5 Hz);
[0874] 2.05 (3H, singlet);
[0875] 1.55-1.71 (2H, multiplet);
[0876] 1.27-1.40 (4H, multiplet);
[0877] 0.88-0.96 (3H, multiplet).
[0878] 3(iii)
5-Acetamido-4-(C-aminooxy-C-iminomethylamino)-9-O-hexanoyl-2-
,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
[0879] 24 mg (0.06 mmol) of
5-acetamido-4-cyanamido-9-O-hexanoyl-2,3,4,5-t-
etradeoxy-D-glycero-D-galacto-non-2-enopyranosoic acid [prepared as
described in step (ii) above] were dissolved in 4 ml of methanol,
and 4.5 mg (0.06 mmol) of hydroxylamine hydrochloride were added to
the resulting solution, while stirring at room temperature. The
reaction mixture was stirred at room temperature for a further 4
hours, and then the solvent was removed by distillation under
reduced pressure to obtain a residue. This residue was subjected to
silica gel column chromatography, using a 2:5:1 by volume mixture
of isopropanol, ethyl acetate and water as the eluent, to obtain 18
mg (yield 70%) of the title compound as a colorless solid.
[0880] Rf=0.58 (5:1:1=isopropanol:ethyl acetate:methanol).
[0881] Mass Spectrum (FAB) m/e 447 (M.sup.++H).
[0882] [.alpha.].sub.D.sup.25 +39.2.degree. (c=0.025,
CH.sub.3OH).
[0883] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1723,
1656, 1630.
[0884] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[0885] 5.57 (1H, doublet, J=2.0 Hz);
[0886] 4.30-4.46 (3H, multiplet);
[0887] 4.08-4.25 (3H, multiplet);
[0888] 3.68 (1H, doublet, J=9.4 Hz);
[0889] 2.37 (2H, triplet, J=7.3 Hz);
[0890] 1.98 (3H, singlet);
[0891] 1.50-1.64 (2H, multiplet);
[0892] 1.18-1.32 (4H, multiplet);
[0893] 0.77-0.86 (3H, multiplet).
EXAMPLE 4
5-Acetamido-4-(C-aminooxy-C-iminomethylamino)-7-O-tetradecanoyl-2,3,4,5-te-
tradeoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid (Compound No.
106-1)
[0894] 21
[0895] 4(i) Methyl
5-acetamido-4-azido-7-O-tetradecanoyl-8,9-O-isopropylid-
ene-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoate
[0896] 1.50 g (4.05 mmol) of methyl
5-acetamido-4-azido-8,9-O-isopropylide-
ne-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in Example 1(ii)] were dissolved in 30 ml of
methylene chloride, and 545 mg (4.45 mmol) of dimethylaminopyridine
and 1.32 ml (4.86 mmol) of tetradecanoyl chloride were added to the
resulting solution, while stirring in an ice bath. The reaction
mixture was then stirred at room temperature for 40 minutes, after
which 0.62 ml (4.45 mmol) of triethylamine was added dropwise to
the mixture in an ice bath. The mixture was then stirred at room
temperature for 20 hours. At the end of this time, 200 ml of ethyl
acetate and 100 ml of a saturated aqueous solution of sodium
hydrogencarbonate were added to the reaction mixture, and the
mixture was partitioned to separate the organic layer. The organic
layer was washed three times, each time with 50 ml of a saturated
aqueous solution of sodium chloride. It was then dried over
anhydrous sodium sulfate anhydride, after which the solvent was
removed by distillation under reduced pressure. The resulting
residue was subjected to silica gel column chromatography, using a
100:1 by volume mixture of methylene chloride and methanol as the
eluent, to obtain 1.57 g (yield 67%) of the title compound as a
yellow oil.
[0897] Rf=0.49 (20:1=methylene chloride:methanol).
[0898] Mass Spectrum (FAB) m/e 603 (M.sup.++Na).
[0899] [.alpha.].sub.D.sup.25 -56.4.degree. (c=0.11,
CHCl.sub.3).
[0900] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 2100,
1745, 1661.
[0901] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[0902] 6.14 (1H, doublet, J=5.8 Hz);
[0903] 5.77 (1H, broad doublet, J=9.8 Hz);
[0904] 5.42 (1H, doublet of doublets, J=5.2 & 2.1 Hz);
[0905] 4.37-4.53 (2H, multiplet);
[0906] 4.10-4.27 (3H, multiplet);
[0907] 3.94 (1H, doublet of doublets, J=8.7 & 6.7 Hz);
[0908] 3.83 (3H, singlet);
[0909] 2.21-2.47 (2H, multiplet);
[0910] 1.99 (3H, singlet);
[0911] 1.52-1.68 (2H, multiplet);
[0912] 1.37 (3H, singlet);
[0913] 1.35 (3H, singlet);
[0914] 1.20-1.48 (20H, multiplet);
[0915] 0.85-0.92 (3H, multiplet).
[0916] 4(ii) Methyl
5-acetamido-4-amino-7-O-tetradecanoyl-8,9-O-isopropyli-
dene-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoate
[0917] 1.50 g (2.65 mmol) of methyl
5-acetamido-4-azido-7-O-tetradecanoyl--
8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-O-galacto-non-2-enopyran-
osoate [prepared as described in step (i) above] were dissolved in
20 ml of methanol, and 600 mg of a Lindlar catalyst were added to
the resulting solution, while stirring at room temperature. The
atmosphere in the reaction system was then replaced by hydrogen,
and the mixture was stirred at room temperature for 2 hours. At the
end of this time, it was filtered under reduced pressure using a
Celite (trade mark) filter aid, and the solvent was removed from
the filtrate by distillation under reduced pressure. The resulting
residue was subjected to silica gel column chromatography, using a
20:1 by volume mixture of methylene chloride and methanol and then
a 10:1 by volume mixture of methylene chloride and methanol as the
eluent, to obtain 710 mg (yield 50%)of the title compound as a
yellow amorphous substance.
[0918] Rf=0.29 (10:1=methylene chloride:methanol).
[0919] Mass Spectrum (FAB) m/e 555 (M.sup.++H).
[0920] [.alpha.].sub.D.sup.25 +25.2.degree. (c=0.25,
CHCl.sub.3).
[0921] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1753,
1738, 1660.
[0922] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[0923] 5.98 (1H, doublet, J=2.01 Hz);
[0924] 5.61 (1H, broad singlet);
[0925] 5.43 (1H, doublet of doublets, J=5.1 & 1.9 Hz);
[0926] 4.35-4.45 (2H, multiplet);
[0927] 4.15 (1H, doublet of doublets, J=8.9 & 6.3 Hz);
[0928] 3.95 (1H, doublet of doublets, J=8.9 & 6.8 Hz);
[0929] 3.83 (1H, broad singlet);
[0930] 3.80 (3H, singlet);
[0931] 3.64 (1H, broad doublet, J=8.4 Hz);
[0932] 2.25-2.50 (2H, multiplet);
[0933] 2.01 (3H, singlet);
[0934] 1.77 (1H, broad singlet);
[0935] 1.53-1.69 (2H, multiplet);
[0936] 1.37 (3H, singlet);
[0937] 1.35 (3H, singlet);
[0938] 1.22-1.35 (20H, multiplet);
[0939] 0.85-0.92 (3H, multiplet).
[0940] 4(iii)
5-Acetamido-4-amino-7-O-tetradecanoyl-8,9-O-isopropylidene-2-
,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
[0941] 710 mg (1.28 mmol) of methyl
5-acetamido-4-amino-7-O-tetradecanoyl--
8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyran-
osoate [prepared as described in step (ii) above] were dissolved in
a mixture of 4 ml of methanol and 4 ml of water, and 59 mg (1.41
mmol) of lithium hydroxide 1 hydrate were added to the resulting
solution, while stirring at room temperature. The mixture was then
stirred for a further 30 minutes at room temperature. Dowex-50Wx8
(H.sup.+) resin (Dowex is a trade mark) was then gradually added to
the resulting mixture to adjust the pH to a value of about 7.5.
Immediately after the adjustment, the resulting suspension was
rapidly filtered under reduced pressure. The residue obtained by
distilling the solvent from the filtrate under reduced pressure was
subjected to silica gel column chromatography, using a 2:5:1 by
volume mixture of isopropanol, ethyl acetate and water as the
eluent, to obtain 490 mg (yield 71%) of the title compound as a
colorless solid.
[0942] Rf=0.29 (2:5:1=isopropanol:ethyl acetate:methanol).
[0943] Mass Spectrum (FAB) m/e 541 (M.sup.++H).
[0944] [.alpha.].sub.D.sup.25 +10.8.degree. (c=0.12,
CH.sub.3OH).
[0945] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1750,
1666.
[0946] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[0947] 5.61 (1H, doublet, J=1.9 Hz);
[0948] 5.41 (1H, doublet of doublets, J=6.0 & 1.4 Hz);
[0949] 4.59 (1H, doublet of doublets, J=12.0 & 6.2 Hz);
[0950] 4.13-4.28 (3H, multiplet);
[0951] 3.93 (1H, doublet of doublets, J=9.0 & 6.4 Hz);
[0952] 3.79-3.86 (1H, multiplet);
[0953] 2.28-2.42 (2H, multiplet);
[0954] 1.96 (3H, singlet);
[0955] 1.52-1.70 (2H, multiplet);
[0956] 1.35 (3H, singlet);
[0957] 1.33 (3H, singlet);
[0958] 1.26-1.43 (20H, multiplet);
[0959] 0.87-0.95 (3H, multiplet).
[0960] 4(iv)
5-Acetamido-4-amino-7-O-tetradecanoyl-2,3,4,5-tetradeoxy-D-gl-
ycero-D-galacto-non-2-enopyranosoic Acid
[0961] 480 mg (0.89 mmol) of
5-acetamido-4-amino-7-O-tetradecanoyl-8,9-O-i-
sopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid [prepared as described in step (iii) above] were dissolved in
a mixture of 10 ml of acetic acid and 10 ml of water at room
temperature, and the mixture was stirred for 5 hours at room
temperature. The solvent was then removed by distillation under
reduced pressure and the resulting residue was subjected to
azeotropic distillation with benzene, after which it was evaporated
to dryness under a vacuum. The resulting residue was subjected to
silica gel column chromatography, using a 2:5:1 by volume mixture
of isopropanol, ethyl acetate and water as the eluent, to obtain
110 mg (yield 25%) of the title compound as a colorless solid.
[0962] Rf=0.37 (5:1:1=isopropanol:ethyl acetate:methanol).
[0963] Mass Spectrum (FAB) m/e 501 (M.sup.++H).
[0964] [.alpha.].sub.D.sup.25 +7.50.degree. (c=0.07,
CH.sub.3OH).
[0965] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1740,
1661.
[0966] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[0967] 5.59 (1H, doublet, J=2.2 Hz);
[0968] 5.14 (1H, doublet of doublets, J=9.4 & 1.8 Hz);
[0969] 4.42 (1H, doublet of doublets, J=10.7 & 1.7 Hz);
[0970] 4.23 (1H, triplet, J=10.1 Hz);
[0971] 4.01-4.09 (1H, multiplet);
[0972] 3.83 (1H, doublet of doublets, J=9.4 & 2.1 Hz);
[0973] 3.56 (1H, doublet of doublets, J=11.8 & 3.2 Hz);
[0974] 3.40 (1H, doublet of doublets, J=11.7 & 6.3 Hz);
[0975] 2.28-2.38 (2H, multiplet);
[0976] 1.95 (3H, singlet);
[0977] 1.52-1.68 (2H, multiplet);
[0978] 1.26-1.38 (20H, multiplet);
[0979] 0.87-0.95 (3H, multiplet).
[0980] 4(v)
5-Acetamido-4-cyanamido-7-O-tetradecanoyl-2,3,4,5-tetradeoxy-D-
-glycero-D-galacto-non-2-enopyranosoic Acid
[0981] 108 mg (0.22 mmol) of
5-acetamido-4-amino-7-O-tetradecanoyl-2,3,4,5-
-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic acid [prepared
as described in step (iv) above] were dissolved in 4 ml of
methanol, and 46 mg (0.56 mmol) of sodium acetate and 31 mg (0.29
mmol) of cyanogen bromide were added to the resulting solution,
while stirring at room temperature. The reaction solution was
stirred at room temperature for 150 minutes, and then the solvent
was removed by distillation under reduced pressure to obtain a
residue. This residue was then subjected to azeotropic distillation
with benzene. The resulting residue was subjected to silica gel
column chromatography, using a 2:5:1 by volume mixture of
isopropanol, ethyl acetate and water as the eluent, to obtain 66 mg
(yield 58%) of the title compound as a colorless solid.
[0982] Rf=0.30 (2:5:1=isopropanol:ethyl acetate:methanol).
[0983] Mass Spectrum (FAB) m/e 526 (M.sup.++H).
[0984] [.alpha.].sub.D.sup.25 -36.3.degree. (c=0.07,
CH.sub.3OH).
[0985] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 2223,
1746, 1662.
[0986] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[0987] 5.71 (1H, doublet, J=2.1 Hz);
[0988] 5.08 (1H, doublet of doublets, J=8.2 & 1.8 Hz);
[0989] 4.46 (1H, doublet of doublets, J=10.6 & 1.7 Hz);
[0990] 4.04-4.20 (2H, multiplet);
[0991] 3.85 (1H, doublet of doublets, J=9.5 & 2.2 Hz);
[0992] 3.66 (1H, doublet of doublets, J=11.5 & 3.5 Hz);
[0993] 3.45-3.54 (1H, multiplet);
[0994] 2.25-2.50 (2H, multiplet);
[0995] 1.96 (3H, singlet);
[0996] 1.53-1.68 (2H, multiplet);
[0997] 1.26-1.40 (20H, multiplet);
[0998] 0.87-0.96 (3H, multiplet).
[0999] 4(vi)
5-Acetamido-4-(C-aminooxy-C-iminomethylamino)-7-O-tetradecano-
yl-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic
Acid
[1000] 51 mg (0.1 mmol) of
5-acetamido-4-cyanamido-7-O-tetradecanoyl-2,3,4-
,5-tetradeoxy-D-glycero-2-galacto-non-2-enopyranosoic acid
[prepared as described in step (v) above] were dissolved in 4 ml of
methanol, and 7.6 mg (0.1 mmol) of hydroxylamine hydrochloride were
added to the resulting solution, while stirring at room
temperature. The reaction mixture was then stirred at room
temperature for a further 3 hours, after which the solvent was
removed by distillation under reduced pressure. The resulting
residue was subjected to silica gel column chromatography, using a
2:5:1 by volume mixture of isopropanol, ethyl acetate and water as
the eluent, to obtain 34 mg (yield 63%) of the title compound as a
colorless solid.
[1001] Rf=0.37 (5:1:1=isopropanol:ethyl acetate:methanol).
[1002] Mass Spectrum (FAB) m/e 559 (M.sup.++H).
[1003] [.alpha.].sub.D.sup.25 +22.5.degree. (c=0.063,
CH.sub.3OH).
[1004] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1743,
1726, 1664, 1633.
[1005] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1006] 5.55 (1H, doublet, J=1.9 Hz);
[1007] 5.12 (1H, doublet of doublets, J=9.2 & 2.0 Hz);
[1008] 4.44 (1H, doublet of doublets, J=10.2 & 1.5 Hz);
[1009] 4.17-4.33 (2H, multiplet);
[1010] 3.98-4.08 (1H, multiplet);
[1011] 3.56 (1H, doublet of doublets, J=11.8 & 3.2 Hz);
[1012] 3.40 (1H, doublet of doublets, J=11.7 & 6.1 Hz);
[1013] 2.28-2.42 (2H, multiplet);
[1014] 1.91 (3H, singlet);
[1015] 1.53-1.70 (2H, multiplet);
[1016] 1.26-1.39 (20H, multiplet);
[1017] 0.87-0.94 (3H, multiplet).
EXAMPLE 5
5-Acetamido-4-(C-aminooxy-C-iminomethylamino)-9-O-tetradecanoyl-2,3,4,5-te-
tradeoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid (Compound No.
34-41)
[1018] 22
[1019] 5(i)
5Acetamido-4-amino-9-O-tetradecanoyl-2,3,4,5-tetradeoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoic Acid
[1020] 55 mg (1.01 mmol) of
5-acetamido-4-amino-7-O-tetradecanoyl-8,9-O-is-
opropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic
acid [prepared as described in Example 4(iii)] were dissolved in a
mixture of 2 ml of trifluoroacetic acid and 4 ml of methylene
chloride at room temperature, and the mixture was then stirred at
room temperature for a further 3 days. At the end of this time, the
solvent was removed by distillation under reduced pressure to
obtain a residue. This residue was then subjected to azeotropic
distillation with benzene, after which it was evaporated to dryness
under a vacuum. The resulting residue was subjected to silica gel
column chromatography, using a 2:5:1 by volume mixture of
isopropanol, ethyl acetate and water as the eluent, to obtain 51 mg
(yield 100%) of the title compound as a colorless solid.
[1021] Rf=0.49 (5:1:1=isopropanol:ethyl acetate:methanol).
[1022] Mass Spectrum (FAB) m/e 501 (M.sup.++H).
[1023] [.alpha.].sub.D.sup.25 +3.56.degree. (c=0.09,
CH.sub.3OH).
[1024] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1): 1734,
1628.
[1025] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1026] 5.68 (1H, doublet, J=1.9 Hz);
[1027] 4.01-4.38 (3H, multiplet);
[1028] 3.84-4.00 (4H, multiplet);
[1029] 3.71 (1H, doublet, J=7.7 Hz);
[1030] 2.30-2.42 (2H, multiplet);
[1031] 2.06 (3H, singlet);
[1032] 1.53-1.71 (2H, multiplet);
[1033] 1.26-1.40 (20H, multiplet);
[1034] 0.87-0.93 (3H, multiplet).
[1035] 5(ii)
5-Acetamido-4-cyanamido-9-O-tetradecanoyl-2,3,4,5-tetradeoxy--
D-glycero-D-galacto-non-2-enopyranosoic Acid
[1036] 90 mg (0.18 mmol) of
5-acetamido-4-amino-9-O-tetradecanoyl-2,3,4,5--
tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic acid [prepared
as described in step (i) above] were dissolved in 10 ml of
methanol, and 44 mg (0.54 mmol) of sodium acetate and 19 mg (0.18
mmol) of cyanogen bromide were added to the resulting solution,
while stirring at room temperature. The reaction mixture was then
stirred at room temperature for 10 hours, after which the solvent
was removed by distillation under reduced pressure. The resulting
residue was subjected to silica gel column chromatography, using a
2:5:1 by volume mixture of isopropanol, ethyl acetate and water as
the eluent, to obtain 75 mg (yield 79%) of the title compound as a
colorless solid.
[1037] Rf=0.52 (2:5:1=isopropanol:ethyl acetate:methanol).
[1038] Mass Spectrum (FAB) m/e 526 (M.sup.++H).
[1039] [.alpha.].sub.D.sup.25 -56.7.degree. (c=0.060,
CH.sub.3OH).
[1040] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1041] 5.70 (1H, doublet, J=1.9 Hz);
[1042] 4.05-4.32 (3H, multiplet);
[1043] 3.78-4.02 (4H, multiplet);
[1044] 2.32-2.38 (2H, multiplet);
[1045] 2.06 (3H, singlet);
[1046] 1.55-1.68 (2H, multiplet);
[1047] 1.26-1.40 (20H, multiplet);
[1048] 0.87-0.93 (3H, multiplet).
[1049] 5(iii)
5-Acetamido-4-(C-aminooxy-C-iminomethylamino)-9-O-tetradecan-
oyl-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic
Acid
[1050] 55 mg (0.11 mmol) of
5-acetamido-4-cyanamido-9-O-tetradecanoyl-2,3,-
4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoic acid
[prepared as described in step (ii) above] were dissolved in 4 ml
of methanol, and 27 mg (0.39 mmol) of hydroxylamine hydrochloride
were added to the resulting solution, while stirring at room
temperature. The reaction mixture was then stirred at room
temperature for a further 2 hours, after which the solvent was
removed by distillation under reduced pressure. The resulting
residue was subjected to silica gel column chromatography, using a
2:5:1 by volume mixture of isopropanol, ethyl acetate and water as
the eluent, to obtain 11 mg (yield 19%) of the title compound as a
colorless solid.
[1051] Rf=0.28 (2:5:1=isopropanol:ethyl acetate:methanol).
[1052] Mass Spectrum (FAB) m/e 559 (M.sup.++H).
[1053] [.alpha.].sub.D.sup.25 +53.3.degree. (c=0.015,
CH.sub.3OH).
[1054] Infrared Absorption Spectrum .nu..sub.max (cm.sup.-1):
1679.
[1055] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz .delta. (ppm):
[1056] 5.53 (1H, doublet, J=1.9 Hz);
[1057] 4.30-4.43 (2H, multiplet);
[1058] 4.03-4.28 (3H, multiplet);
[1059] 3.55-3.65 (2H, multiplet);
[1060] 2.32-2.40 (2H, multiplet);
[1061] 2.00 (3H, singlet);
[1062] 1.55-1.68 (2H, multiplet);
[1063] 1.26-1.37 (20H, multiplet);
[1064] 0.85-0.93 (3H, multiplet).
EXAMPLE 6
5-Acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto--
non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (Compound No.
1-1)
[1065] 23
[1066] 6(i) Methyl
5-acetamido-4-azido-8,9-di-O-acetyl-2,3,4,5,7-pentadeox-
y-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[1067] 300 mg (0.70 mmol) of methyl
5-acetamido-4,8,9-tri-O-acetyl-2,6-anh-
ydro-3,5,7-trideoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[prepared according to the procedure described in WO 95/32955] were
dissolved in 10 ml of anhydrous methylene chloride, and 25 mg (0.78
mmol) of methanol were added to the resulting solution. The
atmosphere in the reaction system was replaced by nitrogen, and
then 1.0 g (7.0 mmol) of a boron trifluoride diethyl ether complex
salt was added to the reaction system, and the mixture was stirred
at room temperature for 24 hours. At the end of this time, the
reaction mixture was poured into a mixture of 50 ml of water, 10 g
of ice, 10 g, of solid sodium hydrogencarbonate and 50 ml of ethyl
acetate, and the mixture was vigorously stirred for 10 minutes. The
organic layer was separated, washed with 10 ml of a saturated
aqueous solution of sodium chloride and dried over anhydrous sodium
sulfate, after which the solvent was removed by distillation under
reduced pressure. The resulting residue (210 mg) was dissolved in 4
ml of dimethylformamide, and 400 mg of a cation exchange resin,
Dowex-50x8 (H.sup.+) (Dowex is a trade mark) and 100 mg (1.53 mmol)
of sodium azide were added to the resulting solution. The mixture
was then stirred at 80.degree. C. for 4 hours. At the end of this
time, the Dowex-50x8 (H.sup.+) was separated by filtration and the
solvent was removed by distillation under reduced pressure. 30 ml
of ethyl acetate and 20 ml of a saturated aqueous solution of
sodium hydrogencarbonate were then added to dissolve the residue.
The organic layer was separated, washed with a saturated aqueous
solution of sodium chloride and dried over anhydrous sodium
sulfate, after which the solvent was removed by distillation under
reduced pressure. The resulting residue was purified by silica gel
column chromatography, using a 50:1 by volume mixture of methylene
chloride and methanol as the eluent, to obtain 170 mg (yield 59%)
of the title compound as a colorless viscous substance.
[1068] Rf=0.31 (20:1=methylene chloride:methanol).
[1069] [.alpha.].sub.D.sup.25 +69.4.degree. (c=0.18,
CHCl.sub.3).
[1070] Mass Spectrum (FAB) m/e 417 (M.sup.++H).
[1071] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1072] 2.07 (9H, singlet);
[1073] 3.58 (1H, doubled doublet of doublets, J=9.0, 9.0 & 9.0
Hz);
[1074] 3.80 (3H, singlet);
[1075] 4.22 (1H, doubled doublet of doublets, J=1.8, 5.2 & 13.0
Hz);
[1076] 4.65-5.00 (4H, multiplet);
[1077] 5.45 (1H, multiplet);
[1078] 5.98 (1H, doublet, J=2.8 Hz);
[1079] 6.00 (1H, doublet, J=8.5 Hz).
[1080] 6(ii) Methyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanidino)-8,9-
-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopy-
ranosoate
[1081] 36 mg (0.08 mmol) of methyl
5-acetamido-4-azido-8,9-di-O-acetyl-2,3-
,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in step (i) above] were dissolved in 3 ml of
methanol, and 10 mg of a Lindlar catalyst were added to the
resulting solution. The atmosphere in the reaction system was
replaced by hydrogen, and then the mixture was stirred for 2 hours.
The catalyst was then separated by filtration, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was dissolved in 2 ml of dimethylformamide, and 26 mg
(0.093 mmol) of N,N'-di-t-butoxycarbonylthio- urea, 19 mg (0.186
mmol) of triethylamine and 25 mg (0.093 mmol) of mercuric chloride
were added to the resulting solution. The mixture was then stirred
at room temperature for 1 hour. The solid was separated by
filtration and the filtrate was poured into a 2-layer mixture of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate. The organic layer was separated, washed
with a saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate, after which the solvent was removed by
distillation under reduced pressure. The residue was purified by
silica gel column chromatography, using a 2:1 by volume mixture of
ethyl acetate and hexane as the eluent, to obtain 32 mg (yield 59%)
of the title compound as a colorless amorphous substance.
[1082] Rf=0.35 (2:1=ethyl acetate:hexane).
[1083] [.alpha.].sub.D.sup.25 +5.6.degree. (c=0.16,
CHCl.sub.3).
[1084] Mass Spectrum (FAB) m/e 633 (M.sup.++H).
[1085] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1086] 1.49 (9H, singlet);
[1087] 1.52 (9H, singlet);
[1088] 1.98 (3H, singlet);
[1089] 2.05 (3H, singlet);
[1090] 2.07 (3H, singlet);
[1091] 3.80 (3H, singlet);
[1092] 4.00-4.30 (3H, multiplet);
[1093] 4.75 (1H, doublet of doublets, J=9.2, 50 Hz);
[1094] 4.78 (1H, doublet, J=18 Hz);
[1095] 5.23 (1H, doublet of doublets, J=9.0, 9.0 Hz);
[1096] 5.43 (1H, multiplet);
[1097] 5.88 (1H, doublet, J=2.8 Hz);
[1098] 6.80 (1H, doublet, J=8.2 Hz);
[1099] 8.60 (1H, doublet, J=8.5 Hz).
[1100] 6(iii)
5-Acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-fluoro-D-glyc-
ero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt
[1101] 32 mg (0.05 mmol) of methyl
5-acetamido-4-(N,N'-bis-t-butoxycarbony-
lguanidino)-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-gala-
cto-non-2-enopyranosoate [prepared as described in step (ii) above]
were dissolved in 2 ml of methanol, and 0.5 ml of a 0.1 N
methanolic solution of sodium methoxide was added to the resulting
solution. The mixture was then stirred at room temperature for 1
hour. At the end of this time, the reaction mixture was neutralized
with a 4 M solution of hydrogen chloride in dioxane, and the
solvent was removed by distillation under reduced pressure. The
residue was then dissolved in a 3:1 by volume mixture of methylene
chloride-trifluoroacetic acid, and the mixture was stirred at room
temperature for 5 hours. At the end of this time, the solvent was
removed by distillation under reduced pressure, and the resulting
residue was dissolved in 1 ml of distilled water, and then 70 ml of
a 1 N aqueous solution of sodium hydroxide were added to the
resulting solution. The mixture was then stirred at room
temperature for 1 hour. Dowex-50x8 (H.sup.+) (Dowex is a trade
mark) was added to the resulting mixture to neutralize it, and then
the water was removed by distillation. The resulting residue was
purified by silica gel column chromatography, using a 5:1:1 by
volume mixture of isopropanol, ethyl acetate and water as the
eluent, to obtain 16 mg (yield 71%) of the title compound as a
colorless solid.
[1102] Rf=0.30 (4:1:1=isopropanol:acetic acid:water).
[1103] [.alpha.].sub.D.sup.25 +28.0.degree. (c=0.10, H.sub.2O).
[1104] Mass Spectrum (FAB) m/e 335 (M.sup.++H).
[1105] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[1106] 2.00 (3H, singlet);
[1107] 3.65 (1H, doubled doublet of doublets, J=2.4, 5.5 & 12.0
Hz);
[1108] 3.85 (1H, doubled doublet of doublets, J=2.5,2.5 & 12
Hz);
[1109] 4.15 (1H, multiplet);
[1110] 4.23 (1H, doublet, J=9.0 Hz);
[1111] 4.30-4.60 (3H, multiplet);
[1112] 5.63 (1H, singlet).
EXAMPLE 7
Tetradecyl
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-
-D-galacto-non-2-enopyranosoate Trifluoroacetic Acid Salt (Compound
No. 1-5)
[1113] 24
[1114] 7(i) Methyl
5-acetamido-4-azido-8,9-O-isopropylidene-2,3,4,5,7-pent-
adeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[1115] 300 mg (0.72 mmol) of methyl
5-acetamido-4-azido-8,9-di-O-acetyl-2,-
3,4,5,7-pentadeoxy-7-fluoro-2-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in Example 6(i)] were dissolved in 5 ml of
methanol, and 0.2 ml of a 1 M methanolic solution of sodium
methoxide was added to the resulting solution. The mixture was then
stirred at room temperature for 1 hour. At the end of this time,
the reaction mixture was neutralized with a 4 M solution of
hydrogen chloride in dioxane, and then the solvent was removed by
distillation under reduced pressure. The resulting residue was
dissolved in 5 ml of acetone, and 400 mg (3.85 mmol) of
2,2-dimethoxypropane and 20 mg (0.11 mmol) of p-toluenesulfonic
acid were added to the resulting solution. The mixture was then
stirred at room temperature for 3 hours. The solids were separated
by filtration and the solvent was removed from the filtrate by
distillation under reduced pressure. The residue was purified by
silica gel column chromatography, using a 50:1 by volume mixture of
methylene chloride and methanol as the eluent, to obtain 140 mg
(yield 52%) of the title compound as a colorless amorphous
substance.
[1116] Rf=0.33 (20:1=methylene chloride:methanol).
[1117] [.alpha.].sub.D.sup.25 +111.degree. (c=0.13,
CHCl.sub.3).
[1118] Mass Spectrum (FAB) m/e 373 (M.sup.++H).
[1119] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1120] 1.37 (3H, singlet);
[1121] 1.42 (3H, singlet);
[1122] 2.05 (3H, singlet);
[1123] 3.50 (1H, doubled doublet of doublets, J=7.5, 7.5 & 9.5
Hz);
[1124] 3.80 (3H, singlet);
[1125] 4.13 (1H, doubled doublet of doublets, J=1.2, 6.0 & 9.0
Hz);
[1126] 4.20 (1H, doubled doublet of doublets, J=1.2, 6.0 & 9.0
Hz);
[1127] 4.45 (1H, multiplet);
[1128] 4.70 (1H, doubled doublet of doublets, J=1.5, 5.7 & 47.0
Hz);
[1129] 4.90 (1H, doublet of doublets, J=2.8 & 9.5 Hz);
[1130] 4.92 (1H, doubled doublet of doublets, J=1.0, 11.0 &
28.0 Hz);
[1131] 5.90 (1H, doublet, J=7.3 Hz);
[1132] 5.96 (1H, doublet, J=2.8 Hz).
[1133] 7(ii) Tetradecyl
5-acetamido-4-azido-8,9-O-isopropylidene-2,3,4,5,7-
-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[1134] 113 mg (0.31 mmol) of methyl
5-acetamido-4-azido-8,9-O-isopropylide-
ne-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in step (i) above] were dissolved in 4 ml of
a 6:1 by volume mixture of methanol and water, and 0.33 ml of a 1 M
aqueous solution of potassium hydroxide was added to the resulting
solution. The mixture was then stirred at room temperature for 2
hours. At the end of this time, the solvent was removed by
distillation under reduced pressure, and the residue was dried over
anhydrous sodium sulfate at room temperature and under reduced
pressure for 2 hours to obtain a pale yellow solid. The solid was
dissolved in 8 ml of acetonitrile, and 80 mg (0.3 mmol) of
18-crown-6 and 415 mg (1.5 mmol) of tetradecyl bromide were added
to the resulting solution. The mixture was then stirred at
80.degree. C. for 2 hours. At the end of this time, the reaction
mixture was poured into a 2-layer solution of 15 ml of ethyl
acetate and 10 ml of a saturated aqueous solution of sodium
hydrogencarbonate, and the organic layer was separated, washed with
a saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate, after which the solvent was removed by
distillation under reduced pressure. The residue was purified by
silica gel column chromatography, using a 50:1 by volume mixture of
methylene chloride and methanol as the eluent, to obtain 110 mg
(yield 64%) of the title compound as a colorless viscous
substance.
[1135] Rf=0.47 (20:1=methylene chloride:methanol).
[1136] [.alpha.].sub.D.sup.25 +52.9.degree. (c=0.09,
CHCl.sub.3).
[1137] Mass Spectrum (FAB) m/e 555 (M.sup.++H).
[1138] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1139] 0.80-0.95 (3H, singlet);
[1140] 1.20-1.50 (24H, multiplet);
[1141] 1.37 (3H, singlet);
[1142] 1.42 (3H, singlet);
[1143] 1.60-1.80 (2H, multiplet);
[1144] 2.05 (3H, singlet);
[1145] 4.10-4.30 (2H, multiplet);
[1146] 4.45 (1H, multiplet);
[1147] 4.72 (1H, doubled doublet of doublets, J=1.5, 5.3 & 38.0
Hz);
[1148] 4.90 (1H, doublet of doublets, J=2.4 & 9.3 Hz);
[1149] 4.92 (1H, doubled doublet of doublets, J=1.0, 10.0 &
28.0 Hz);
[1150] 5.97 (1H, doublet, J=6.5 Hz);
[1151] 5.95 (1H, doublet, J=2.4 Hz).
[1152] 7(iii) Tetradecyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanidino-
)-8,9-O-isopropylidene2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-no-
n-2-enopyranosoate
[1153] 110 mg (0.20 mmol) of tetradecyl
5-acetamido-4-azido-8,9-O-isopropy-
lidene-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranoso-
ate [prepared as described in step (ii) above] were dissolved in 5
ml of methanol, and 30 mg of a Lindlar catalyst were added to the
resulting solution. The atmosphere in the reaction system was then
replaced by hydrogen. The mixture was then stirred for 2 hours. At
the end of this time, the catalyst was separated by filtration and
the solvent was removed by distillation under reduced pressure. The
residue was dissolved in 4 ml of dimethylformamide, and 47 mg (0.17
mmol) of N,N-di-t-butoxycarbonylthiourea, 35 mg (0.342 mmol) of
triethylamine and 47 mg (0.17 mmol) of mercuric chloride were added
to the resulting solution. The mixture was then stirred at room
temperature for 1 hour. The solid was separated by filtration and
the filtrate was poured into a 2-layer solution of 15 ml of ethyl
acetate and 10 ml of a saturated aqueous solution of sodium
hydrogencarbonate. The organic layer was separated, washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate, after which the solvent was removed by
distillation under reduced pressure. The residue was purified by
silica gel column chromatography, using a 2:1 by volume mixture of
ethyl acetate and hexane as the eluent, to obtain 98 mg (yield 63%)
of the title compound as a colorless viscous substance.
[1154] Rf=0.30 (20:1=methylene chloride:methanol).
[1155] [.alpha.].sub.D.sup.25 +2.2.degree. (c=0.14,
CHCl.sub.3).
[1156] Mass Spectrum (FAB) m/e 771 (M.sup.++H)
[1157] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1158] 0.80-0.95 (3H, singlet);
[1159] 1.20-1.40 (24H, multiplet);
[1160] 1.36 (3H, singlet);
[1161] 1.41 (3H, singlet);
[1162] 1.49 (9H, singlet);
[1163] 1.50 (9H, singlet);
[1164] 1.60-1.80 (2H, multiplet);
[1165] 2.05 (3H, singlet);
[1166] 4.10-4,70 (6H, multiplet);
[1167] 5.20 (1H, doubled doublet of doublets, J=2.4, 7.5 & 7.5
Hz);
[1168] 5.83 (1H, doublet, J=2.4 Hz);
[1169] 5.65 (1H, doublet, J=7.0 Hz);
[1170] 8.60 (1H, doublet, J=8.5 Hz).
[1171] 7(iv) Tetradecyl
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-flu-
oro-D-glycero-D-galacto-non-2-enopyranosoate Trifluoroacetic Acid
Salt
[1172] 80 mg (0.11 mmol) of tetradecyl
5-acetamido-4-(N,N'-bis-t-butoxycar-
bonylguanidino)-8,9-O-isopropylidene-2,3,4,5,7-pentadeoxy-7-fluoro-D-glyce-
ro-D-galacto-non-2-enopyranosoate [prepared as described in step
(iii) above] were dissolved in of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 4 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:8:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 40 mg (yield 56%) of the title compound as
a colorless solid.
[1173] Rf=0.35 (5:1:1=t-butanol:acetic acid:water).
[1174] [.alpha.].sub.D.sup.25 +22.4.degree. (c=0.13,
CH.sub.3OH).
[1175] Mass Spectrum (FAB) m/e 531 (M.sup.++H).
[1176] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[1177] 0.70-0.85 (3H, singlet);
[1178] 1.10-1.30 (24H, multiplet);
[1179] 1.50-1.80 (2H, multiplet);
[1180] 2.00 (3H, singlet);
[1181] 3.60-3.80 (2H, multiplet);
[1182] 4.10-4.30 (3H, multiplet);
[1183] 4.40-4.60 (2H, multiplet);
[1184] 5.88 (1H, singlet).
EXAMPLE 8
4-Guanidino-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-e-
nopyranosoic Acid Trifluoroacetic Acid Salt (Compound No. 31-1)
[1185] 25
[1186] 8(i) Methyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanidino)-7,8,-
9-tri-O-acetyl-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoate
[1187] 2.0 g (4.63 mmol) of
5-acetamido-4-amino-7,8,9-tri-O-acetyl-3,4,5-t-
etradeoxy-D-glycero-D-galacto-non-2-enopyranosoate were dissolved
in 40 ml of dimethylformamide, and 1.54 g (5.58 mmol) of
N,N'-bis-t-butoxycarbonyl- thiourea, 1.1 g (11.2 mmol) of
triethylamine and 1.54 g (5.58 mmol) of mercuric chloride were
added to the resulting solution. The mixture was then stirred at
room temperature for 2 hours. The insolubles were separated by
filtration and the filtrate was poured into a 2-layer solution of
50 ml of ethyl acetate and 25 ml of a saturated aqueous solution of
sodium hydrogencarbonate. The organic layer was separated, washed
with a saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate, after which the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 1:1 by volume
mixture of ethyl acetate and hexane as the eluent, to obtain 3.0 g
(yield 96%) of the title compound as a colorless amorphous
substance.
[1188] Rf=0.20 (1:1=ethyl acetate:hexane).
[1189] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1190] 1.49 (18H, singlet);
[1191] 1.88 (3H, singlet);
[1192] 2.07 (3H, singlet);
[1193] 2.09 (3H, singlet);
[1194] 2.13 (3H, singlet);
[1195] 3.80 (3H, singlet);
[1196] 4.15 (1H, doublet of doublets, 3 8.0 & 13.0 Hz);
[1197] 4.20 4.30 (2H, multiplet);
[1198] 4.67 (1H, doublet of doublets, J=3.0 & 13.0 Hz);
[1199] 5.15 (1H, doubled doublet of doublets, J=2.5, 8.5 & 8.5
Hz);
[1200] 5.30 (1 H, multiplet);
[1201] 5.43 (1H, doublet of doublets, J=2.5 & 5.3 Hz);
[1202] 5.90 (1H, doublet, J=2.5 Hz);
[1203] 6.20 (1H, doublet, J=8.2 Hz);
[1204] 8.50 (1H, doublet, J=8.5 Hz).
[1205] 8(ii) Methyl
4-(N,N'-bis-t-butoxycarbonylguanidino)-5-thioacetamido-
-7,8,9-tri-O-acetyl-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyrano-
soate
[1206] 1.95 g (2.89 mmol) of methyl
5-acetamido-4-(N,N'-bis-t-butoxycarbon-
ylguanidino)-7,8,9-tri-O-acetyl-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in step (i) above] were
dissolved in 40 ml of tetrahydrofuran, and 2.15 g (5.32 mmol) of
Lawesson's reagent were added to the resulting solution. The
mixture was then stirred at 60.degree. C. for 2 hours. The reaction
mixture was then poured into a 2-layer solution of 50 ml of ethyl
acetate and 30 ml of a saturated aqueous solution of sodium
hydrogencarbonate. The organic layer was separated, washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate, after which the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 2:1 by volume
mixture of ethyl acetate and hexane as the eluent, to obtain 1.0 g
(yield 50%) of the title compound as a colorless amorphous
substance.
[1207] Rf=0.40 (1:1=ethyl acetate:hexane).
[1208] [.alpha.].sub.D.sup.25 +19.0.degree. (c=0.11,
CHCl.sub.3).
[1209] Mass Spectrum (FAB) m/e 689 (M.sup.++H).
[1210] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1211] 1.46 (9H, singlet);
[1212] 1.49 (9H, singlet);
[1213] 1.95 (3H, singlet);
[1214] 1.97 (3H, singlet);
[1215] 1.99 (3H, singlet);
[1216] 2.42 (3H, singlet);
[1217] 3.80 (3H, singlet);
[1218] 4.15 (1H, doublet of doublets, J=8.0 & 13.0 Hz);
[1219] 4.45 (1H, doublet of doublets, J=3.0 & 8.5 Hz);
[1220] 4.70 (1H, doublet of doublets, J=3.0 & 13.0 Hz);
[1221] 5.20-5.35 (3H, multiplet);
[1222] 5.40 (1H, doublet of doublets, J=2.5 & 4.5 Hz);
[1223] 5.92 (1H, doublet, J=2.5 Hz);
[1224] 7.95 (1H, doublet, J=8.2 Hz);
[1225] 8.55 (1H, doublet, J=8.5 Hz).
[1226] 8(iii)
4-Guanidino-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero-D-g-
alacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
[1227] 800 mg (1.16 mmol) of methyl
4-(N,N'-bis-t-butoxycarbonylguanidino)-
-5-thioacetamido-7,8,9-tri-O-acetyl-2,3,4,5-tetradeoxy-D-glycero-D-galacto-
-non-2-enopyranosoate [prepared as described in step (ii) above]
were dissolved in 10 ml methanol, and 1.5 ml of a 0.1 N methanolic
solution of sodium methoxide were added to the resulting solution.
The mixture was then stirred at room temperature for 2 hours, after
which it was neutralized with a 4 M solution of hydrogen chloride
in dioxane and the solvent was removed by distillation under
reduced pressure. The resulting residue was dissolved in 20 ml of a
3:1 by volume mixture of methylene chloride and trifluoroacetic
acid, and the resulting solution was stirred at room temperature
for 5 hours. At the end of this time, the solvent was removed by
distillation under reduced pressure, and the resulting residue was
dissolved in 10 ml of distilled water, and then 2.0 ml of a 1 N
aqueous solution of sodium hydroxide were added to the resulting
solution. The mixture was then stirred at room temperature for 1
hour. Dowex-50x8 (H.sup.+) (Dowex is a trade mark) was then added
to neutralize the reaction mixture, and water was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 5:1:1 by
volume mixture of isopropanol ethyl acetate and water as the
eluent, to obtain 215 mg (yield 40%) of the title compound as a
colorless solid.
[1228] Rf=0.30 (4:1:1=isopropanol:ethyl acetate:water).
[1229] [.alpha.].sub.D.sup.25 +41.0.degree. (c=0.11, H.sub.2O).
[1230] Mass Spectrum (FAB) m/e 349 (M.sup.++H).
[1231] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[1232] 2.51 (3H, singlet);
[1233] 3.55 (1H, doublet, J=10 Hz);
[1234] 3.62 (1H, doublet of doublets, J=7.0 & 14.0 Hz);
[1235] 3.85 (1H, doublet of doublets, J=3.5 & 14.0 Hz);
[1236] 3.92 (1H, multiplet);
[1237] 4.40-4.60 (2H, multiplet);
[1238] 4.50 (1H, multiplet);
[1239] 5.63 (1H, doublet, J=2.5 Hz).
EXAMPLE 9
Hexyl
5-thioacetamido-4-guanidino-2,3,4,5-tetradeoxy-D-glycero-D-galacto-n-
on-2-enopyranosoate Trifluoroacetic Acid Salt (Compound No.
31-3)
[1240] 26
[1241] 9(i) Methyl
5-thioacetamido-4-(N,N'-bis-t-butoxycarbonylguanidine)--
8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyran-
osoate
[1242] 700 mg (1.01 mmol) of methyl
4-(N,N'-bis-t-butoxycarbonylguanidino)-
-5-thioacetamido-7,8,9-tri-O-acetyl-2,3,4,5-tetradeoxy-D-glycero-D-galacto-
-non-2-enopyranosoate [prepared as described in Example 8(ii)] were
dissolved in 20 ml of methanol, and 0.2 ml of a 1 M methanolic
solution of sodium methoxide was added to the resulting solution.
The mixture was then stirred at room temperature for 1 hour. At the
end of this time, the reaction mixture was neutralized with a 4 M
solution of hydrogen chloride in dioxane, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was dissolved in 30 ml of acetone, and 1.0 g (9.71 mmol) of
2,2-dimethoxypropane and 40 mg (0.22 mmol) of p-toluenesulfonic
acid were added to the resulting solution. The mixture was then
stirred at room temperature for 3 hours. 100 mg of solid sodium
hydrogencarbonate were then added to the mixture, and the mixture
was stirred for 30 minutes. The solids were then separated by
filtration and the solvent was removed from the filtrate by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 450 mg (yield 74%) of the title compound as a colorless
amorphous substance.
[1243] Rf=0.33 (20:1=methylene chloride:methanol).
[1244] [.alpha.].sub.D.sup.25 +14.4.degree. (c=0.18,
CHCl.sub.3).
[1245] Mass Spectrum (FAB) m/e 603 (M.sup.++H).
[1246] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1247] 1.37 (3H, singlet);
[1248] 1.41 (3H, singlet);
[1249] 1.48 (9H, singlet);
[1250] 1.51 (9H, singlet);
[1251] 2.55 (3H, singlet);
[1252] 3.50 (1H, doublet of doublets, 3 4.8 & 8.5 Hz);
[1253] 3.80 (3H, singlet);
[1254] 4.05 (1H, doublet of doublets, J=5.0 & 9.0 Hz);
[1255] 4.13 (1H, doublet of doublets, J=7.3 & 9.2 Hz);
[1256] 4.20 (1H, doublet, J=10.0 Hz);
[1257] 4.40 (1H, multiplet);
[1258] 4.55 (1H, doubled doublet of doublets, J=7.4, 10.0 &
10.0 Hz);
[1259] 5.30 (1H, doubled doublet of doublets, J=2.4, 8.0 & 10.0
Hz);
[1260] 5.84 (1H, doublet, J=2.8 Hz);
[1261] 8.68 (1H, J=8.0 Hz);
[1262] 9.04 (1H, J=7.2 Hz).
[1263] 9(ii) Hexyl
5-thioacetamido-4-(N,N'-bis-t-butoxycarbonylguanidino)--
8,9O-isopropylidene-2,3,4,5tetradeoxy-D-glycero-D-galacto-non-2-enopyranos-
oate
[1264] 190 mg (0.31 mmol) of methyl
5-thioacetamido-4-(N,N'-bis-t-butoxyca-
rbonylguanidino)-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galac-
to-non-2-enopyranosoate [prepared as described in step (i) above]
were dissolved in 12 ml of a 6:1 by volume mixture of methanol and
water, and 0.32 ml of a 1 M aqueous solution of potassium hydroxide
was added to the resulting solution. The mixture was then stirred
at room temperature for 3 hours. At the end of this time, the
solvent was removed by distillation under reduced pressure, and the
residue was dried under reduced pressure at room temperature for 2
hours to obtain a pale yellow solid. The solid was dissolved in 8
ml of acetonitrile, and 76 mg (0.29 mmol) of 18-crown-6 and 236 mg
(1.43 mmol) of hexyl bromide were added to the resulting solution.
The mixture was then stirred at 80.degree. C. for 2 hours, after
which it was poured into a 2-layer solution of 30 ml of ethyl
acetate and 20 ml of a saturated aqueous solution of sodium
hydrogencarbonate. The organic layer was separated, washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate, after which the solvent was removed by
distillation under reduced pressure. The residue was purified by
silica gel column chromatography, using a 3:1 by volume mixture of
ethyl acetate and hexane as the eluent, to obtain 73 mg (yield 35%)
of the title compound as a colorless amorphous solid.
[1265] Rf=0.57 (20:1=methylene chloride:methanol).
[1266] [.alpha.].sub.D.sup.25 +19.2.degree. (c=0.12,
CHCl.sub.3).
[1267] Mass Spectrum (FAB) m/e 673 (M.sup.++H).
[1268] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1269] 0.85-0.95 (3H, singlet);
[1270] 1.20-1.50 (8H, multiplet);
[1271] 1.36 (3H, singlet);
[1272] 1.41 (3H, singlet);
[1273] 1.48 (9H, singlet);
[1274] 1.51 (9H, singlet);
[1275] 1.60-1.80 (2H, multiplet);
[1276] 2.56 (3H, singlet);
[1277] 3.52 (1H, doublet of doublets, J=4.8 & 8.5 Hz);
[1278] 4.00-4.30 (3H, multiplet);
[1279] 4.40 (1H, multiplet);
[1280] 4.55 (1H, doubled doublet of doublets, J=7.4, 10.0 &
10.0 Hz);
[1281] 5.30 (1H, doubled doublet of doublets, J=2.2, 8.0 & 10.0
Hz);
[1282] 5.82 (1H, doublet, J=2.2 Hz);
[1283] 8.68 (1H, J=8.0 Hz);
[1284] 9.02 (1H, J=7.2 Hz).
[1285] 9(iii) Hexyl
5-thioacetamido-4-guanidino-2,3,4,5-tetradeoxy-D-glyce-
ro-D-galacto-non-2-enopyranosoate Trifluoroacetic Acid Salt
[1286] 100 mg (0.15 mmol) of hexyl
5-thioacetamido-4-(N,N'-bis-t-butoxycar-
bonylguanidino)-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galact-
o-non-2-enopyranosoate [prepared as described in step (ii) above]
were dissolved in 12 ml of a 3:1 by volume mixture of methylene
chloride and trifluoroacetic acid, and the mixture was stirred at
room temperature for 4 hours. At the end of this time, the solvent
was removed by distillation under reduced pressure, and the residue
was purified by silica gel column chromatography, using a 15:1:1 by
volume mixture of t-butanol, ethyl acetate and water as the eluent,
to obtain 65 mg (yield 79%) of the title compound as a colorless
solid.
[1287] Rf=0.75 (5:1:1=t-butanol:acetic acid:water).
[1288] [.alpha.].sub.D.sup.25 -1.9.degree. (c=0.11,
CH.sub.3OH).
[1289] Mass Spectrum (FAB) m/e 433 (M.sup.++H).
[1290] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[1291] 0.70-0.85 (3H, singlet);
[1292] 1.10-1.40 (8H, multiplet);
[1293] 1.60-1.70 (2H, multiplet);
[1294] 2.50 (3H, singlet);
[1295] 3.51 (1H, doublet, J=8.5 Hz);
[1296] 3.80 (1H, doublet, J=10.0 Hz);
[1297] 4.20 (2H, multiplet);
[1298] 4.40-4.70 (2H, multiplet);
[1299] 5.10 (1H, multiplet);
[1300] 5.98 (1H, broad singlet).
EXAMPLE 10
Tetradecyl
5-thioacetamido-4-guanidino-2,3,4,5-tetradeoxy-D-glycero-D-gala-
cto-non-2-enopyranosoate Trifluoroacetic Acid Salt (Compound No.
31-5)
[1301] 27
[1302] 10(i) Tetradecyl
5-thioacetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-eno-
pyranosoate
[1303] 234 mg (0.39 mmol) of methyl
5-thioacetamido-4-(N,N'-bis-t-butoxyca-
rbonylguanidino)-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galac-
to-non-2-enopyranosoate [prepared as described in Example 9(i)]
were dissolved in 12 ml of a 6:1 by volume mixture of methanol and
water, and 0.43 ml of a 1 M aqueous solution of potassium hydroxide
was added to the resulting solution. The mixture was then stirred
at room temperature for 3 hours. At the end of this time, the
solvent was removed by distillation under reduced pressure and the
residue was dried under reduced pressure at room temperature for 2
hours to obtain a pale yellow solid. The solid was dissolved in 8
ml of acetonitrile and 103 mg (0.39 mmol) of 18-crown-6 and 593 mg
(1.94 mmol) of tetradecyl bromide were added to the resulting
solution. The mixture was then stirred at 80.degree. C. for 2
hours. At the end of this time, the reaction mixture was poured
into a 2-layer solution of 30 ml of ethyl acetate and 20 ml of a
saturated aqueous solution of sodium hydrogencarbonate. The organic
layer was separated, washed with a saturated aqueous solution of
sodium chloride and dried over anhydrous sodium sulfate, after
which the solvent was removed by distillation under reduced
pressure. The resulting residue was purified by silica gel column
chromatography, using a 3:1 by volume mixture of ethyl acetate and
hexane as the eluent, to obtain 100 mg (yield 33%) of the title
compound as a colorless amorphous substance.
[1304] Rf=0.45 (2:1=hexane:ethyl acetate).
[1305] [.alpha.].sub.D.sup.25 +18.2.degree. (c=0.11,
CHCl.sub.3).
[1306] Mass Spectrum (FAB) m/e 785 (M.sup.++H).
[1307] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1308] 0.85-0.95 (3H, singlet);
[1309] 1.20-1.50 (24H, multiplet);
[1310] 1.36 (3H, singlet);
[1311] 1.40 (3H, singlet);
[1312] 1.48 (9H, singlet);
[1313] 1.51 (9H, singlet);
[1314] 1.60-1.80 (2H, multiplet);
[1315] 2.54 (3H, singlet);
[1316] 3.51 (1H, doublet of doublets, J=4.8 & 8.5 Hz);
[1317] 4.00-4.30 (3H, multiplet);
[1318] 4.40 (1H, mstiplet);
[1319] 4.55 (1H, doubled doublet of doublets, J=7.4, 10.0 &
10.0 Hz);
[1320] 5.30 (1H, doubled doublet of doublets, J=2.2, 8.0 & 10.0
Hz);
[1321] 5.82 (1H, doublet, J=2.2 Hz);
[1322] 8.66 (1H, J=8.0 Hz);
[1323] 9.00 (1H, J=7.2 Hz).
[1324] 10(i) Tetradecyl
5-thioacetamido-4-guanidino-2,3,4,5-tetradeoxy-D-g-
lycero-D-galacto-non-2-enopyranosoate Trifluoroacetic Acid Salt
[1325] 90 mg (0.11 mmol) of tetradecyl
5-thioacetamido-(N,N'-bis-t-butoxyc-
arbonylguanidino)-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-gala-
cto-non-2-enopyranosoate [prepared as described in step (i) above]
were dissolved in 12 ml of a 3:1 by volume mixture of methylene
chloride and trifluoroacetic acid, and the mixture was stirred at
room temperature for 4 hours. At the end of this time, the solvent
was removed by distillation under reduced pressure and the
resulting residue was purified by silica gel column chromatography,
using a 5:1:1 by volume mixture of t-butanol, ethyl acetate and
water as the eluent, to obtain 40 mg (yield 47%) of the title
compound as a colorless solid.
[1326] Rf=0.80 (5:1:1=t-butanol:acetic acid:water).
[1327] [.alpha.].sub.D.sup.25 -1.4.degree. (c=0.15,
CH.sub.3OH).
[1328] Mass Spectrum (FAB) m/e 545 (M.sup.++H).
[1329] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[1330] 0.70-0.85 (3H, singlet);
[1331] 1.10-1.40 (24H, multiplet);
[1332] 1.60-1.70 (2H, multiplet);
[1333] 2.50 (3H, singlet);
[1334] 3.60-3.90 (2H, multiplet);
[1335] 4.15 (2H, multiplet);
[1336] 4.40-4.70 (2H, multiplet);
[1337] 5.10 (1H, multiplet);
[1338] 5.90 (1H, broad singlet).
EXAMPLE 11
4-Guanidino-9-O-hexanoyl-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero-D-ga-
lacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (Compound
No. 31-36)
[1339] 28
[1340] 11(i) Methyl
5-thioacetamido-4-(N,N'-bis-t-butoxycarbonylguanidino)-
-7-O-hexanoyl-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galacto--
non-2-enopyranosoate
[1341] 500 mg (0.83 mmol) of methyl
5-thioacetamido-4-(N,N'-bis-t-butoxyca-
rbonylguanidino)-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-1-glycero-D-galac-
to-non-2-enopyranosoate [prepared as described in Example 9(i)]
were dissolved in 15 ml of methylene chloride, and 110 mg (0.91
mmol) of dimethylaminopyridine and 122 mg (0.91 mmol) of hexanoyl
chloride were added to the resulting solution. The mixture was then
stirred at room temperature for 30 minutes. 92 mg (0.91 mmol) of
triethylamine were then added to the resulting mixture and the
mixture was stirred for 15 hours. At the end of this time, the
reaction mixture was poured into a 2-layer solution of 30 ml of
ethyl acetate and 15 ml of a saturated aqueous solution of sodium
hydrogencarbonate. The organic layer was separated, washed with a
saturated aqueous solution of sodium chloride and dried over
anhydrous sodium sulfate, after which the solvent was removed by
distillation under reduced pressure. The residue was purified by
silica gel column chromatography, using a 50:1 by volume mixture of
methylene chloride and methanol as the eluent, to obtain 432 mg
(yield 74%) of the title compound as a colorless amorphous
substance.
[1342] Rf=0.30 (20:1=methylene chloride:methanol).
[1343] [.alpha.].sub.D.sup.25 -18.0.degree. (c=0.10,
CHCl.sub.3).
[1344] Mass Spectrum (FAB) m/e 701 (M.sup.++H).
[1345] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1346] 0.85-0.95 (3H, singlet);
[1347] 1.20-1.70 (6H, multiplet);
[1348] 1.35 (3H, singlet);
[1349] 1.38 (3H, singlet);
[1350] 1.47 (9H, singlet);
[1351] 1.48 (9H, singlet);
[1352] 2.20-2.50 (2H, multiplet);
[1353] 2.42 (3H, singlet);
[1354] 3.80 (3H, singlet);
[1355] 3.92 (1H, doublet of doublets, J=6.6 & 8.5 Hz);
[1356] 4.10 (1H, doublet of doublets, J=6.2 & 8.5 Hz);
[1357] 4.35-4.45 (2H, multiplet);
[1358] 5.15-5.35 (2H, multiplet);
[1359] 5.90 (1H, doublet, J=2.0 Hz);
[1360] 7.55 (1H, J=10.0 Hz);
[1361] 8.55 (1H, J=9.5 Hz).
[1362] 11(ii)
4-(N,N'-Bis-t-butoxycarbonylguanidino)-7-O-hexanoyl-8,9-O-is-
opropylidene-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2--
enopyranosoic Acid
[1363] 89 mg (0.13 mmol) of methyl
5-thioacetamido-4-(N,N'-bis-t-butoxycar-
bonylguanidino)-7-O-hexanoyl-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-gly-
cero-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 6:1 by volume mixture of
methanol and water, and 5.5 mg (0.13 mmol) of lithium hydroxide 1
hydrate were added to the resulting solution. The mixture was then
stirred at room temperature for 3 hours. At the end of this time,
the reaction mixture was neutralized with a 4 N solution of
hydrogen chloride in dioxane, and the solvent was removed by
distillation under reduced pressure. The residue was purified by
silica gel column chromatography, using a 2:5:1 by volume mixture
of isopropanol, ethyl acetate and water as the eluent, to obtain 48
mg (yield 64%) of the title compound as a colorless solid.
[1364] Rf=0.67 (2:5:1=isopropanol:ethyl acetate:water).
[1365] [.alpha.].sub.D.sup.25 -25.0.degree. (c=0.10,
CHCl.sub.3).
[1366] Mass Spectrum (FAB) m/e 687 (M.sup.++H).
[1367] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm): 0.85-0.95 (3H, singlet);
[1368] 1.20-1.70 (6H, multiplet);
[1369] 1.32 (3H, singlet);
[1370] 1.35 (3H, singlet);
[1371] 1.45 (9H, singlet);
[1372] 1.51 (9H, singlet);
[1373] 2.20-2.50 (2H, multiplet);
[1374] 2.35 (3H, singlet);
[1375] 3.40 (1H, multiplet);
[1376] 4.20 (1H, doublet of doublets, J=6.2 & 8.5 Hz);
[1377] 4.40 (1H, doublet of doublets, J=1.5 & 10.0 Hz);
[1378] 4.55 (1H, multiplet);
[1379] 5.00 (1H, doublet of doublets, J=10.0 & 10.0 Hz);
[1380] 5.10 (1H, doublet of doublets, J=2.1 & 10.0 Hz);
[1381] 5.30 (1H, doublet of doublets, J=2.0 & 5.5 Hz);
[1382] 5.73 (1H, doublet, J=2.1 Hz).
[1383] 11(iii)
4-Guanidino-9-O-hexanoyl-5-thioacetamido-2,3,4,5-tetradeoxy-
-D-glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt
[1384] 100 mg (0.15 mmol) of
4-(N,N'-bis-t-butoxycarbonylguanidino)-7-O-he-
xanoyl-8,9-O-isopropylidene-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero-D-
-galacto-non-2-enopyranosoic acid [prepared as described in step
(ii) above] were dissolved in 12 ml of a 2:6:1 by volume mixture of
methylene chloride, trifluoroacetic acid and thiophenol, and the
mixture was stirred at room temperature for 8 hours. At the end of
this time, the solvent was removed by distillation under reduced
pressure, and the resulting residue was purified by silica gel
column chromatography, using a 2:5:1 by volume mixture of
isopropanol, ethyl acetate and water as the eluent, to obtain 54 mg
(yield 53%) of the title compound as a colorless solid.
[1385] Rf=0.55 (5:1:1=t-butanol acetic acid:water).
[1386] [.alpha.].sub.D.sup.25 +2.3.degree. (c=0.10,
CH.sub.3OH).
[1387] Mass Spectrum (FAB) m/e 447 (M.sup.++H).
[1388] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[1389] 0.70-0.85 (3H, singlet);
[1390] 1.20-1.70 (6H, multiplet);
[1391] 2.30-2.50 (2H, multiplet);
[1392] 2.52 (3H, singlet);
[1393] 3.51 (1H, doublet, J=8.5 Hz);
[1394] 4.15 (1H, multiplet);
[1395] 4.23 (1H, doublet of doublets, J=5.5 & 12.0 Hz);
[1396] 4.35 (1H, doublet of doublets, J=2.5 & 12.0 Hz);
[1397] 4.40-4.60 (2H, multiplet);
[1398] 5.10 (1H, multiplet);
[1399] 5.63 (1H, doublet, J=2.4 Hz).
EXAMPLE 12
4-Guanidino-9-O-tetradecanoyl-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero-
-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 31-41)
[1400] 29
[1401] 12(i) Methyl
4-(N,N'-bis-t-butoxycarbonylguanidino)-7-tetradecanoyl-
-8,9-O-isopropylidene-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero-D)-gala-
cto-non-2-enopyranosoate
[1402] 440 mg (0.73 mmol) of methyl
5-thioacetamido-4-(N,N'-bis-t-butoxyca-
rbonylguanidino)-8,9-O-isopropylidene-2,3,4,5-tetradeoxy-D-glycero-D-galac-
to-non-2-enopyranosoate [prepared as described in Example 9(i)]
were dissolved in 15 ml of methylene chloride, and 132 mg (1.08
mmol) of dimethylaminopyridine and 247 mg (1.0 mmol) of
tetradecanoyl chloride were added to the resulting solution. The
mixture was then stirred at room temperature for 30 minutes, after
which 109 mg (1.08 mmol) of triethylamine were added, and the
mixture was stirred for 15 hours. The reaction mixture was then
poured into a 2-layer solution of 30 ml of ethyl acetate and 15 ml
of a saturated aqueous solution of sodium hydrogencarbonate. The
organic layer was separated, washed with a saturated aqueous
solution of sodium chloride and dried over anhydrous sodium
sulfate, after which the solvent was removed by distillation under
reduced pressure. The residue was purified by silica gel column
chromatography, using a 50:1 by volume mixture of methylene
chloride and methanol as the eluent, to obtain 350 mg (yield 59%)
of the title compound as a colorless amorphous substance.
[1403] Rf=0.35 (1:1=ethyl acetate:hexane).
[1404] [.alpha.].sub.D.sup.25 -17.6.degree. (c=0.15,
CHCl.sub.3).
[1405] Mass Spectrum (FAB) m/e 813 (M.sup.++H).
[1406] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1407] 0.85-0.95 (3H, singlet);
[1408] 1.20-1.70 (22H, multiplet);
[1409] 1.35 (3H, singlet);
[1410] 1.38 (3H, singlet);
[1411] 1.47 (9H, singlet);
[1412] 1.49 (9H, singlet);
[1413] 2.20-2.50 (2H, multiplet);
[1414] 2.42 (3H, singlet);
[1415] 3.80 (3H, singlet);
[1416] 3.92 (1H, doublet of doublets, J=6.6 & 8.5 Hz);
[1417] 4.10 (1H, doublet of doublets, J=6.2 & 8.5 Hz);
[1418] 4.35-4.45 (2H, multiplet);
[1419] 5.15-5.35 (2H, multiplet);
[1420] 5.90 (1H, doublet, J=2.0 Hz);
[1421] 7.55 (1H, J=10.0 Hz);
[1422] 8.55 (1H, J=9.5 Hz).
[1423] 12(ii)
4-(N,N'-Bis-t-butoxycarbonylguanidino)-7-O-tetradecanoyl-8,9-
-O-isopropylidene-5-thioacetamido-2,3,4,5-tetradeoxy-D-glycero-D-galacto-n-
on-2-enopyranosoic Acid
[1424] 320 mg (0.39 mmol) of methyl
4-(N,N'-bis-t-butoxycarbonylguanidino)-
-7-O-tetradecanoyl-8,9-O-isopropylidene-5-thioacetamido-2,3,4,5-tetradeoxy-
-D-glycero-D-galacto-non-2-enopyranosoate [prepared as described in
step (i) above] were dissolved in 7 ml of a 6:1 by volume mixture
of methanol and water, and 18 mg (0.41 mmol) of lithium hydroxide 1
hydrate were added to the resulting solution. The mixture was then
stirred at room temperature for 3 hours. At the end of this time,
the reaction mixture was neutralized with a 4 N solution of
hydrogen chloride in dioxane, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 5:1 by volume
mixture of methylene chloride and methanol as the eluent, to obtain
240 mg (yield 77%) of the title compound as a colorless solid.
[1425] Rf=0.30 (10:1=methylene chloride:methanol).
[1426] [.alpha.].sub.D.sup.25 -25.0.degree. (c=0.12,
CHCl.sub.3).
[1427] Mass Spectrum (FAB) m/e 799 (++H).
[1428] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1429] 0.85-0.95 (3H, singlet);
[1430] 1.20-1.70 (22H, multiplet);
[1431] 1.32 (3H, singlet);
[1432] 1.35 (3H, singlet);
[1433] 1.45 (9H, singlet);
[1434] 1.50 (9H, singlet);
[1435] 2.20-2.50 (2H, multiplet);
[1436] 2.35 (3H, singlet);
[1437] 3.95 (1H, doublet of doublets, J=6.2 & 8.5 Hz);
[1438] 4.20 (1H, doublet of doublets, J=6.2 & 8.5 Hz);
[1439] 4.40 (1H, doublet of doublets, J=1.5 & 10.0 Hz);
[1440] 4.55 (1H, multiplet);
[1441] 5.00 (1H, doublet of doublets, J=10.0 & 10.0 Hz);
[1442] 5.10 (1H, doublet of doublets, J=2.1 & 10.0 Hz);
[1443] 5.30 (1H, doublet of doublets, J=2.0 & 5.5 Hz);
[1444] 5.73 (1H, doublet, J=2.1 Hz).
[1445] 12(iii)
4-Guanidino-9-O-tetradecanoyl-5-thioacetamido-2,3,4,5-tetra-
deoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic
Acid Salt
[1446] 220 mg (0.27 mmol) of
4-(N,N'-bis-t-butoxycarbonylguanidino)-7-O-te-
tradecanoyl-8,9-O-isopropylidene-5-thioacetamido-2,3,4,5-tetradeoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoic acid [prepared as described in
step (ii) above] were dissolved in 12 ml of a 2:6:1 by volume
mixture of methylene chloride, trifluoroacetic acid and thiophenol,
and the mixture was stirred at room temperature for 8 hours. At the
end of this time, the solvent was removed by distillation under
reduced pressure and the resulting residue was purified by silica
gel column chromatography, using a 2:5:1 by volume mixture of
isopropanol, ethyl acetate and water as the eluent, to obtain 120
mg (yield 56%) of the title compound as a colorless solid.
[1447] Rf=0.60 (5:1:1=t-butanol:acetic acid:water).
[1448] [.alpha.].sub.D.sup.25 +2.2.degree. (c=0.10,
CH.sub.3OH).
[1449] Mass Spectrum (FAB) m/e 559 (M.sup.++H).
[1450] .sup.1 H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[1451] 0.70-0.85 (3H, singlet);
[1452] 1.20-1.70 (22H, multiplet);
[1453] 2.30-2.50 (2H, multiplet);
[1454] 2.54 (3H, singlet);
[1455] 3.61 (1H, doublet, J=8.5 Hz);
[1456] 4.15 (1H, multiplet);
[1457] 4.20 (1H, doublet of doublets, J=5.5 & 12.0 Hz);
[1458] 4.30 (1H, doublet of doublets, J=2.5 & 12.0 Hz);
[1459] 4.40-4.60 (2H, multiplet);
[1460] 5.10 (1H, multiplet);
[1461] 5.60 (1H, broad singlet).
EXAMPLE 13
5-Acetamido-4-guanidino-9-O-hexanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glyce-
ro-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 1-36)
[1462] 30
[1463] 13(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoat-
e
[1464] 100 mg (0.24 mmol) of methyl
5-acetamido-4-(N,N'-bis-t-butoxycarbon-
ylguanidino)-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-gal-
acto-non-2-enopyranosoate [prepared as described in Example 6(ii)]
were dissolved in 3 ml of methanol, and 0.5 ml of a 0.1 N
methanolic solution of sodium methoxide was added to the resulting
solution. The mixture was then stirred at room temperature for 1
hour, after which the reaction mixture was neutralized with a 4 M
solution of hydrogen chloride in dioxane, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was dissolved in 1 ml of distilled water and 280 ml of a 1
N aqueous solution of sodium hydroxide were added to the resulting
solution. The mixture was then stirred at room temperature for 1
hour, after which the reaction mixture was neutralized with a 4 M
solution of hydrogen chloride in dioxane and then the water was
removed by distillation. The resulting residue was dissolved in 3
ml of a 6:1 by volume mixture of methanol and water, and 100 mg
(0.52 mmol) of diphenyldiazomethane and 8 mg (0.06 mmol) of a boron
trifluoride-diethyl ether complex were added to the resulting
solution. The mixture was then stirred at room temperature for 2
hours. At the end of this time, acetic acid was added to the
reaction mixture, and the solvent was removed by distillation under
reduced pressure. The residue was purified by silica gel column
chromatography, using a 20:1 by volume mixture of methylene
chloride and methanol as the eluent, to obtain 82 mg (yield 50%) of
the title compound as a colorless amorphous substance.
[1465] Rf=0.45 (20:1=methylene chloride:methanol).
[1466] [.alpha.].sub.D.sup.25 =-12.2.degree. (c=0.1,
CHCl.sub.3).
[1467] Mass Spectrum (FAB) m/e 701 (M.sup.++H).
[1468] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1469] 1.50 (9H, singlet);
[1470] 1.51 (9H, singlet);
[1471] 1.95 (3H, singlet);
[1472] 3.25 (2H, multiplet);
[1473] 3.90 (2H, multiplet);
[1474] 4.20-4.70 (3H, multiplet);
[1475] 5.25 (1H, multiplet);
[1476] 5.95 (1H, doublet, J=2.5 Hz);
[1477] 6.93 (1H, singlet);
[1478] 7.10 (1H, doublet, J=8.5 Hz);
[1479] 7.20-7.40 (10H, multiplet);
[1480] 8.60 (1H, doublet, J=8.5 Hz).
[1481] 13(ii) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguani-
dino)-9-O-hexanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-
-enopyranosoate
[1482] 50 mg (0.072 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in step (i) above] were
dissolved in 2 ml of methylene chloride, and 11 mg (0.11 mmol) of
triethylamine and 11 mg (0.086 mmol) of hexanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was separated and
washed with a saturated aqueous solution of sodium chloride. It was
then dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
50:1 by volume mixture of methylene chloride and methanol as the
eluent, to obtain 47 mg (yield 83%) of the title compound as a
colorless amorphous substance.
[1483] Rf=0.6 (20:1=methylene chloride:methanol).
[1484] [.alpha.].sub.D.sup.25 =4.0.degree. (c=0.1, CHCl.sub.3).
[1485] Mass Spectrum (FAB) m/e 786 (M.sup.++H).
[1486] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) (ppm):
[1487] 0.90 (3H, multiplet);
[1488] 1.20-1.40 (6H, multiplet);
[1489] 1.48 (9H, singlet);
[1490] 1.50 (9H, singlet);
[1491] 1.97 (3H, singlet);
[1492] 2.35 (2H, triplet, J=7.5 Hz);
[1493] 2.95 (1H, doublet, J=5.0 Hz);
[1494] 4.20-4.60 (6H, multiplet);
[1495] 5.25 (1H, multiplet);
[1496] 5.97 (1H, doublet, J=2.6 Hz);
[1497] 6.65 (1H, doublet, J=8.5 Hz);
[1498] 6.93 (1H, singlet);
[1499] 7.20-7.40 (10H, multiplet);
[1500] 8.60 (1H, doublet, J=8.5 Hz).
[1501] 13(iii)
5-Acetamido-4-guanidino-9-O-hexanoyl-2,3,4,5,7-pentadeoxy-7-
-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1502] 40 mg (0.05 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-9-O-hexanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-
-galacto-non-2-enopyranosoate [prepared as described in step (ii)
above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 18 mg (yield 65%) of the title compound as
a colorless solid.
[1503] Rf=0.3 (2:5:1=isopropanol:ethyl acetate:water).
[1504] [.alpha.].sub.D.sup.25 =+60.0.degree. (c=0.1,
CH.sub.3OH).
[1505] Mass Spectrum (FAB) m/e 433 (M.sup.++H).
[1506] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1507] 0.85-0.95 (3H, multiplet);
[1508] 1.25-1.40 (4H, multiplet);
[1509] 1.55-1.70 (2H, multiplet);
[1510] 2.00 (3H, singlet);
[1511] 2.35 (2H, triplet, J=4.5 Hz);
[1512] 4.10-4.40 (5H, multiplet);
[1513] 4.45-4.70 (2H, multiplet);
[1514] 5.60 (1H, doublet, J=2.4 Hz).
EXAMPLE 14
5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glyce-
ro-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 1-38)
[1515] 31
[1516] 14(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2--
enopyranosoate
[1517] 50 mg (0.072 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml methylene chloride, and 11 mg (0.11 mmol) of
triethylamine and 16 mg (0.086 mmol) of octanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was separated and
washed with a saturated aqueous solution of sodium chloride. It was
then dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
50:1 by volume mixture of methylene chloride and methanol as the
eluent, to obtain 45 mg (yield 77%) of the title compound as a
colorless amorphous substance.
[1518] Rf=0.5 (20:1=methylene chloride:methanol).
[1519] [.alpha.].sub.D.sup.25 =-5.2.degree. (c=0.2,
CHCl.sub.3).
[1520] Mass Spectrum (FAB) m/e 814 (M.sup.++H).
[1521] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1522] 1.48 (9H, singlet);
[1523] 1.50 (9H, singlet);
[1524] 1.95 (3H, singlet);
[1525] 3.65 (1H, doublet of doublets, J=5.0 & 18 Hz);
[1526] 3.80 (1H, doublet of doublets, J=1.8 & 18 Hz);
[1527] 4.15 (1H, multiplet);
[1528] 4.23 (1H, doublet, J=8.5 Hz);
[1529] 4.30-4.60 (3H, multiplet);
[1530] 5.95 (1H, doublet, J=2.3 Hz).
[1531] 14(ii)
5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7--
fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic
Acid Salt
[1532] 40 mg (0.05 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-
-galacto-non-2-enopyranosoate [prepared as described in step (i)
above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 18 mg (yield 64%) of the title compound as
a colorless solid.
[1533] Rf=0.3 (2:5:1=isopropanol:ethyl acetate:water).
[1534] [.alpha.].sub.D.sup.25 =+56.degree. (c=0.2 CH.sub.3OH).
[1535] Mass Spectrum (FAB) m/e 461 (M.sup.++H).
[1536] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1537] 0.85-0.95 (3H, multiplet);
[1538] 1.25-1.40 (8H, multiplet);
[1539] 1.55-1.70 (2H, multiplet);
[1540] 2.00 (3H, singlet);
[1541] 2.35 (2H, triplet, J=4.5 Hz);
[1542] 4.10-4.40 (5H, multiplet);
[1543] 4.45-4.70 (2H, multiplet);
[1544] 5.60 (1H, doublet, J=2.4 Hz).
EXAMPLE 15
5-Acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gly-
cero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 1-40)
[1545] 32
[1546] 15(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non--
2-enopyranosoate
[1547] 55 mg (0.078 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of methylene chloride, 10 mg (0.10 mmol) of
triethylamine and 21 mg (0.094 mmol) of dodecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was separated and
washed with a saturated aqueous solution of sodium chloride. It was
then dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
1:1 by volume mixture of ethyl acetate and hexane as the eluent, to
obtain 48 mg (yield 69%) of the title compound as a colorless
amorphous substance.
[1548] Rf=0.4 (1:1=ethyl acetate:hexane).
[1549] [.alpha.].sub.D.sup.25 =-5.7.degree. (c=0.12,
CHCl.sub.3).
[1550] Mass Spectrum (FAB) m/e 883 (M.sup.++H).
[1551] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1552] 0.90 (3H, multiplet);
[1553] 1.20-1.40 (18H, multiplet);
[1554] 1.48 (9H, singlet);
[1555] 1.50 (9H, singlet);
[1556] 1.97 (3H, singlet);
[1557] 2.35 (2H, triplet, J=7.5 Hz);
[1558] 2.95 (1H, doublet, J=5.0 Hz);
[1559] 4.20-4.60 (6H, multiplet);
[1560] 5.25 (1H, multiplet);
[1561] 5.97 (1H, doublet, J=2.6 Hz);
[1562] 6.65 (1H, doublet, J=8.5 Hz);
[1563] 6.93 (1H, singlet);
[1564] 7.20-7.40 (10H, multiplet);
[1565] 8.60 (1H, doublet, J=8.5 Hz).
[1566] 15(ii)
5-Acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy--
7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1567] 43 mg (0.05 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-
-D-galacto-non-2-enopyranosoate [prepared as described in step (i)
above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 33 mg (yield 91%) of the title compound as
a colorless solid.
[1568] Rf=0.4 (2:5:1=isopropanol:ethyl acetate:water).
[1569] [.alpha.].sub.D.sup.25 =+22.7.degree. (c=0.1,
CH.sub.3OH).
[1570] Mass Spectrum (FAB) m/e 517 (M.sup.++H).
[1571] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1572] 0.85-0.95 (3H, multiplet);
[1573] 1.25-1.40 (16H, multiplet);
[1574] 1.55-1.70 (2H, multiplet);
[1575] 2.00 (3H, singlet);
[1576] 2.35 (2H, triplet, J=7.0 Hz);
[1577] 4.10-4.40 (5H, multiplet);
[1578] 4.45-4.70 (2H, multiplet);
[1579] 5.60 (1H, doublet, J=2.4 Hz).
EXAMPLE 16
5-Acetamido-4-guanidino-9-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D--
glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt (Compound No. 1-41)
[1580] 33
[1581] 16(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-n-
on-2-enopyranosoate
[1582] 50 mg (0.072 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-4-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of methylene chloride, and 11 mg (0.11 mmol) of
triethylamine and 21 mg (0.086 mmol) of tetradecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was separated and
washed with a saturated aqueous solution of sodium chloride. It was
then dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
50:1 by volume mixture of methylene chloride and methanol as the
eluent, to obtain 50 mg (yield 77%) of the title compound as a
colorless amorphous substance.
[1583] Rf=0.4 (1:1=ethyl acetate:hexane).
[1584] [.alpha.].sub.D.sup.25 =-7.0.degree. (c=0.10,
CDCl.sub.3).
[1585] Mass Spectrum (FAB) m/e 898 (M.sup.++H).
[1586] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm): 0.90 (3H, multiplet); 1.20-1.40 (22H,
multiplet); 1.48 (9H, singlet); 1.50 (9H, singlet); 1.97 (3H,
singlet); 2.35 (2H, triplet, J=7.5 Hz); 2.95 (1H, doublet, J=5.0
Hz); 4.20-4.60 (6H, multiplet);
[1587] 5.25 (1H, multiplet);
[1588] 5.97 (1H, doublet, J=2.6 Hz);
[1589] 6.65 (1H, doublet, J=8.5 Hz);
[1590] 6.93 (1H, singlet);
[1591] 7.20-7.40 (10H, multiplet);
[1592] 8.60 (1H, doublet, J=8.5 Hz).
[1593] 16(ii)
5-Acetamido-4-guanidino-9-O-tetradecanoyl-2,3,4,5,7-pentadeo-
xy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1594] 40 mg (0.05 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-9-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glyc-
ero-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 21 mg (yield 64%) of the title compound as
a colorless solid.
[1595] Rf=0.4 (2:5:1=isopropanol:ethyl acetate:water).
[1596] [.alpha.].sub.D.sup.25=+22.0.degree. (c=0.06,
CH.sub.3OH).
[1597] Mass Spectrum (FAB) m/e 545 (M.sup.++H).
[1598] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1599] 0.85-0.95 (3H, multiplet);
[1600] 1.25-1.70 (20H, multiplet);
[1601] 1.55-1.70 (2H, multiplet);
[1602] 2.00 (3H, singlet);
[1603] 2.35 (2H, triplet, J=4.5 Hz);
[1604] 4.10-4.40 (5H, multiplet);
[1605] 4.45-4.70 (1H, multiplet);
[1606] 5.60 (1H, doublet, J=2.4 Hz).
EXAMPLE 17
5-Acetamido-4-guanidino-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-g-
lycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 1-42)
[1607] 34
[1608] 17(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-no-
n-2-enopyranosoate
[1609] 58 mg (0.08 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non--
2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of methylene chloride, and 10 mg (0.10 mmol) of
triethylamine and 26 mg (0.0946 mmol) of hexadecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 1:1 by volume
mixture of ethyl acetate and hexane as the eluent, to obtain 50 mg
(yield 67%) of the title compound as a colorless amorphous
substance.
[1610] Rf=0.4 (1:1=ethyl:acetate:hexane).
[1611] [.alpha.].sub.D.sup.25=11.0.degree. (c=0.11,
CHCl.sub.3).
[1612] Mass Spectrum (FAB) m/e 939 (M.sup.++H).
[1613] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm) 0.90 (3H, multiplet);
[1614] 1.20-1.40 (22H, multiplet);
[1615] 1.48 (9H, singlet);
[1616] 1.50 (9H, singlet);
[1617] 1.97 (3H, singlet);
[1618] 2.35 (2H, triplet, J=7.5 Hz);
[1619] 2.95 (1H, doublet, J=5.0 Hz);
[1620] 4.20-4.60 (6H, multiplet);
[1621] 5.25 (1H, multiplet);
[1622] 5.97 (1H, doublet, J=2.6 Hz);
[1623] 6.65 (1H, doublet, J=8.5 Hz);
[1624] 6.93 (1H, singlet);
[1625] 7.20-7.40 (10H, multiplet);
[1626] 8.60 (1H, doublet, J=8.5 Hz).
[1627] 17(ii)
5-Acetamido-4-guanidino-9-O-hexadecanoyl-2,3,4,5,7-pentadeox-
y-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1628] 45 mg (0.05 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glyce-
ro-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 28 mg (yield 73%) of the title compound as
a colorless solid.
[1629] Rf=0.4 (2:5:1=isopropanol:ethyl acetate:water).
[1630] [.alpha.].sub.D.sup.25=+19.7.degree. (c=0.1,
CH.sub.3OH).
[1631] Mass Spectrum (FAB) m/e 573 (M.sup.++H).
[1632] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1633] 0.85-0.95 (3H, multiplet);
[1634] 1.25-1.40 (16H, multiplet);
[1635] 1.55-1.70 (2H, multiplet);
[1636] 2.00 (3H, singlet);
[1637] 2.35 (2H, triplet, J=7.0 Hz);
[1638] 4.10-4.40 (5H, multiplet);
[1639] 4.45-4.70 (2H, multiplet);
[1640] 5.60 (1H, doublet, J=2.4 Hz).
EXAMPLE 18
5-Acetamido-4-guanidino-9-O-octadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-g-
lycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 1-43)
[1641] 35
[1642] 18(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-octadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-no-
n-2-enopyranosoate
[1643] 55 mg (0.08 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
y-carbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of methylene chloride, and 10 mg (0.10 mmol) of
triethylamine and 29 mg (0.094 mmol) of octadecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 1:1 by volume
mixture of ethyl acetate and hexane as the eluent, to obtain 51 mg
(yield 67%) of the title compound as a colorless amorphous
substance.
[1644] Rf=0.5 (1:1=ethyl acetate:hexane).
[1645] [.alpha.].sub.D.sup.25=-8.1.degree. (c=0.16,
CHCl.sub.3).
[1646] Mass Spectrum (FAB) m/e 967 (M.sup.++H).
[1647] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1648] 0.90 (3H, multiplet);
[1649] 1.20-1.40 (30H, multiplet);
[1650] 1.48 (9H, singlet);
[1651] 1.50 (9H, singlet);
[1652] 1.97 (3H, singlet);
[1653] 2.35 (2H, triplet, J=7.5 Hz);
[1654] 2.95 (1H, doublet, J=5.0 Hz);
[1655] 4.20-4.60 (6H, multiplet);
[1656] 5.25 (1H, multiplet);
[1657] 5.97 (1H, doublet, J=2.6 Hz);
[1658] 6.65 (1H, doublet, J=8.5 Hz);
[1659] 6.93 (1H, singlet);
[1660] 7.20-7.40 (10H, multiplet);
[1661] 8.60 (1H, doublet, J=8.5 Hz).
[1662] 18(ii)
5-Acetamido-4-guanidino-9-O-octadecanoyl-2,3,4,5,7-pentadeox-
y-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1663] 45 mg (0.047 mmol) of diphenylmethyl
5-acetamido-4-(N-bis-t-butoxyc-
arbonylguanidino)-9-O-octadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-
-D-galacto-non-2-enopyranosoate [prepared as described in step (i)
above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 24 mg (yield 62%) of the title compound as
a colorless solid.
[1664] Rf=0.4 (2:5:1=isopropanol:ethyl acetate:water).
[1665] [.alpha.].sub.D.sup.25=+14.3.degree. (c=0.15,
CH.sub.3OH).
[1666] Mass Spectrum (FAB) m/e 601 (M.sup.++H).
[1667] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1668] 0.85-0.95 (3H, multiplet);
[1669] 1.25-1.40 (28H, multiplet);
[1670] 1.55-1.70 (2H, multiplet);
[1671] 2.00 (3H, singlet);
[1672] 2.35 (2H, triplet, J=7.0 Hz);
[1673] 4.10-4.40 (5H, multiplet);
[1674] 4.45-4.70 (2H, multiplet);
[1675] 5.60 (1H, doublet, J=2.4 Hz).
EXAMPLE 19
5-Acetamido-4-guanidino-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gl-
ycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 1-54)
[1676] 36
[1677] 19(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-
-2-enopyranosoate
[1678] 58 mg (0.083 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of pyridine, and 0.5 ml of acetic anhydride was
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at room temperature for 3 hours. At the end of
this time, the reaction mixture was poured into a 2-layer solution
of 5 ml of ethyl acetate and 3 ml of a 1 N aqueous hydrochloric
acid solution, and the organic layer was separated and washed with
a saturated aqueous solution of sodium hydrogencarbonate and then
with a saturated aqueous solution of sodium chloride. It was then
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 1:1 by volume
mixture of hexane and ethyl acetate as the eluent, to obtain 59 mg
(yield 91%) of the title compound as a colorless amorphous
substance.
[1679] Rf=0.47 (1:1=hexane:ethyl acetate).
[1680] [.alpha.].sub.D.sup.25=+2.5.degree. (c=0.12,
CHCl.sub.3).
[1681] Mass Spectrum (FAB) m/e 785 (M.sup.++H).
[1682] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1683] 1.48 (9H, singlet);
[1684] 1.49 (9H, singlet);
[1685] 1.99 (3H, singlet);
[1686] 2.04 (3H, singlet);
[1687] 2.07 (3H, singlet);
[1688] 4.00-4.30 (3H, multiplet);
[1689] 4.75 (1H, doublet, J=13 Hz);
[1690] 4.80 (1H, doublet of doublets, J=7.5 & 45 Hz);
[1691] 5.20 (1H, doubled doublet of doublets, J=1.0, 9.0 & 9.0
Hz);
[1692] 5.50 (1H, multiplet);
[1693] 5.92 (1H, doublet, J=2.4 Hz);
[1694] 6.72 (1H, doublet, J=7.5 Hz);
[1695] 6.94 (1H, singlet);
[1696] 7.20-7.50 (10H, multiplet);
[1697] 8.60 (1H, doublet, J=8.5 Hz).
[1698] 19(ii)
5-Acetamido-4-guanidino-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-
-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1699] 50 mg (0.064 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-8,9di-O-acetyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycer-
o-D-galacto-non-2-enopyranosoate [prepared as described in step (i)
above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 23 mg (yield 56%) of the title compound as
a colorless solid.
[1700] Rf=0.16 (2:5:1=isopropanol:ethyl acetate:water).
[1701] [.alpha.].sub.D.sup.25=+36.9.degree. (c=0.15,
CH.sub.3OH).
[1702] Mass Spectrum (FAB) m/e 419 (M.sup.++H).
[1703] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1704] 2.00 (3H, singlet);
[1705] 2.03 (3H, singlet);
[1706] 2.05 (3H, singlet);
[1707] 4.10-4.40 (4H, multiplet);
[1708] 4.70-5.00 (2H, multiplet);
[1709] 5.50 (1H, multiplet);
[1710] 5.70 (1H, doublet, J=3.0 Hz).
EXAMPLE 20
5-Acetamido-4-guanidino-8,9-di-O-propionyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-
-glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt (Compound No. 1-55)
[1711] 37
[1712] 20(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-8,9-di-O-propionyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto--
non-2-enopyranosoate
[1713] 52 mg (0.074 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of pyridine, and 0.5 ml of propionic anhydride
was added to the resulting solution, whilst ice-cooling. The
mixture was then stirred at room temperature for 3 hours. At the
end of this time, the reaction mixture was poured into a 2-layer
solution of 5 ml of ethyl acetate and 3 ml of a 1 N aqueous
hydrochloric acid solution, and the organic layer was separated and
washed with a saturated aqueous solution of sodium
hydrogencarbonate and then with a saturated aqueous solution of
sodium chloride. It was then dried over anhydrous sodium sulfate,
and the solvent was removed by distillation under reduced pressure.
The resulting residue was purified by silica gel column
chromatography, using a 1:1 by volume mixture of hexane and ethyl
acetate as the eluent, to obtain 54 mg (yield 90%) of the title
compound as a colorless amorphous substance.
[1714] Rf=0.54 (1:1=hexane:ethyl acetate).
[1715] [.alpha.].sub.D.sup.25=+9.6.degree. (c=0.14,
CHCl.sub.3).
[1716] Mass Spectrum (FAB) m/e 813 (M.sup.++H).
[1717] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1718] 1.11 (9H, triplet, 7.5 Hz);
[1719] 1.48 (9H, singlet);
[1720] 1.49 (9H, singlet);
[1721] 2.04 (3H, singlet);
[1722] 2.20-2.35 (4H, multiplet);
[1723] 4.00-4.30 (3H, multiplet);
[1724] 4.75 (1H, doublet, J=13 Hz);
[1725] 4.80 (1H, doublet of doublets, J=7.5 & 45 Hz);
[1726] 5.20 (1H, doubled doublet of doublets, J=1.0, 9.0 & 9.0
Hz);
[1727] 5.50 (1H, multiplet);
[1728] 5.92 (1H, doublet, J=2.4 Hz);
[1729] 6.72 (1H, doublet, J=7.5 Hz);
[1730] 6.94 (1H, singlet);
[1731] 7.20-7.50 (10H, multiplet);
[1732] 8.60 (1H, doublet, J=8.5 Hz).
[1733] 20(ii)
5-Acetamido-4-guanidino-8,9-di-O-propionyl-2,3,4,5,7-pentade-
oxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1734] 46 mg (0.057 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-8,9-di-O-propionyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gl-
ycero-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 24 mg (yield 63%) of the title compound as
a colorless solid.
[1735] Rf=0.25 (2:5:1=isopropanol:ethyl acetate:water).
[1736] [.alpha.].sub.D.sup.25=+32.30 (c=0.14, CH.sub.3OH).
[1737] Mass Spectrum (FAB) m/e 447 (M.sup.++H).
[1738] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1739] 1.10 (6H, triplet, J=7.5 Hz);
[1740] 2.00 (3H, singlet);
[1741] 2.35 (4H, quartet, J=7.5 Hz);
[1742] 4.10-4.40 (4H, multiplet);
[1743] 4.70-5.00 (2H, multiplet);
[1744] 5.50 (1H, multiplet);
[1745] 5.60 (1H, doublet, J=3.0 Hz).
EXAMPLE 21
5-Acetamido-4-guanidino-8,9-di-O-hexanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D--
glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt (Compound No. 1-58)
[1746] 38
[1747] 21(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-8,9-di-O-hexanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-n-
on-2-enopyranosoate
[1748] 44 mg (0.063 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-2-galacto-non-
-2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of methylene chloride, and 19 mg (0.17 mmol) of
4-dimethylaminopyridine and 19 mg (0.14 mmol) of hexanoyl chloride
were added to the resulting solution, whilst ice-cooling. The
mixture was then stirred at room temperature for 1 hour. At the end
of this time, the reaction mixture was poured into a 2-layer
solution of 5 ml of ethyl acetate and 3 ml of a saturated aqueous
solution of sodium hydrogencarbonate, and the organic layer was
washed with a saturated aqueous solution of sodium chloride. It was
then dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
3:1 by volume mixture of hexane and ethyl acetate as the eluent, to
obtain 49 mg (yield 87%) of the title compound as a colorless
amorphous substance.
[1749] Rf=0.28 (3:1=hexane:ethyl acetate).
[1750] [.alpha.].sub.D.sup.25=+6.5.degree. (c=0.10,
CHCl.sub.3).
[1751] Mass Spectrum (FAB) m/e 897 (M.sup.++H).
[1752] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1753] 0.80-1.00 (6H, multiplet);
[1754] 1.20-1.40 (8H, multiplet);
[1755] 1.48 (9H, singlet);
[1756] 1.49 (9H, singlet);
[1757] 1.50-1.70 (4H, multiplet);
[1758] 1.98 (3H, singlet);
[1759] 2.20-2.30 (4H, multiplet);
[1760] 4.00-4.30 (3H, multiplet);
[1761] 4.75 (1H, doublet, J=13 Hz);
[1762] 4.80 (1H, doublet of doublets, J=7.4 & 45 Hz);
[1763] 5.18 (1H, doubled doublet of doublets, J=1.0, 9.0 & 9.0
Hz);
[1764] 5.50 (1H, multiplet);
[1765] 5.93 (1H, doublet, J=2.4 Hz);
[1766] 6.70 (1H, doublet, J=7.5 Hz);
[1767] 6.93 (1H, singlet);
[1768] 7.20-7.50 (10H, multiplet);
[1769] 8.60 (1H, doublet, J=8.5 Hz).
[1770] 21(ii)
5-Acetamido-4-guanidino-8,9-di-O-hexanoyl-2,3,4,5,7-pentadeo-
xy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1771] 42 mg (0.047 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-8,9-di-O-hexanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gly-
cero-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 21 mg (yield 59%) of the title compound as
a colorless solid.
[1772] Rf=0.34 (2:5:1=isopropanol:ethyl acetate:water).
[1773] [.alpha.].sub.D.sup.25=+23.7.degree. (c=0.11,
CH.sub.3OH).
[1774] Mass Spectrum (FAB) m/e 531 (M.sup.++H).
[1775] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1776] 0.85-0.95 (6H, multiplet);
[1777] 1.20-1.40 (8H, multiplet);
[1778] 1.55-1.70 (4H, multiplet);
[1779] 2.00 (3H, singlet);
[1780] 2.30 (2H, triplet, J=7.5 Hz);
[1781] 4.10-4.40 (4H, multiplet);
[1782] 4.70-5.00 (2H, multiplet);
[1783] 5.55 (1H, multiplet);
[1784] 5.65 (1H, doublet, J=3.0 Hz).
EXAMPLE 22
5-Acetamido-4-guanidino-8,9-di-O-decanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D--
glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt (Compound No. 1-61)
[1785] 39
[1786] 22(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-8,9-di-O-decanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-n-
on-2-enopyranosoate
[1787] 42 mg (0.06 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non--
2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of methylene chloride, and 18 mg (0.15 mmol) of
4-dimethylaminopyridine and 26 mg (0.14 mmol) of decanoyl chloride
were added to the resulting solution, whilst ice-cooling. The
mixture was then stirred at room temperature for 1 hour. At the end
of this time, the reaction mixture was poured into a 2-layer
solution of 5 ml of ethyl acetate and 3 ml of a saturated aqueous
solution of sodium hydrogen-carbonate, and the organic layer was
washed with a saturated aqueous solution of sodium chloride. It was
then dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
3:1 by volume mixture of hexane and ethyl acetate as the eluent, to
obtain 52 mg (yield 86%) of the title compound as a colorless
amorphous substance.
[1788] Rf=0.28 (3:1=hexane:ethyl acetate).
[1789] [.alpha.].sub.D.sup.25=+13.3.degree. (c=0.17,
CHCl.sub.3).
[1790] Mass Spectrum (FAB) m/e 1009 (M.sup.++H).
[1791] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1792] 0.80-0.90 (6H, multiplet);
[1793] 1.20-1.40 (24H, multiplet);
[1794] 1.48 (9H, singlet);
[1795] 1.49 (9H, singlet);
[1796] 1.50-1.65 (4H, multiplet);
[1797] 1.98 (3H, singlet);
[1798] 2.20-2.30 (4H, multiplet);
[1799] 4.00-4.30 (3H, multiplet);
[1800] 4.75 (1H, doublet, J=13 Hz);
[1801] 4.80 (1H, doublet of doublets, J=7.5 & 45 Hz);
[1802] 5.20 (1H, doubled doublet of doublets, J=1.0, 9.0 & 9.0
Hz);
[1803] 5.50 (1H, multiplet);
[1804] 5.92 (1H, doublet, J=2.4 Hz);
[1805] 6.65 (1H, doublet, J=7.5 Hz);
[1806] 6.93 (1H, singlet);
[1807] 7.20-7.50 (10H, multiplet);
[1808] 8.60 (1H, doublet, J=8.5 Hz).
[1809] 22(ii)
5-Acetamido-4-guanidino-8,9-di-O-decanoyl-2,3,4,5,7-pentadeo-
xy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1810] 45 mg (0.045 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-8,9-di-O-decanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gly-
cero-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 29 mg (yield 75%) of the title compound as
a colorless solid.
[1811] Rf=0.3 (2:5:1=isopropanol:ethyl acetate:water).
[1812] [.alpha.].sub.D.sup.25=+20.6.degree. (c=0.14,
CH.sub.3OH).
[1813] Mass Spectrum (FAB) m/e 643 (M.sup.++H).
[1814] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1815] 0.85-0.95 (6H, multiplet);
[1816] 1.20-1.40 (24H, multiplet);
[1817] 1.55-1.70 (4H, multiplet);
[1818] 2.00 (3H, singlet);
[1819] 2.30 (2H, triplet, J=7.0 Hz);
[1820] 4.10-4.40 (4H, multiplet);
[1821] 4.70-5.00 (2H, multiplet);
[1822] 5.55 (1H, multiplet);
[1823] 5.70 (1H, doublet, J=3.0 Hz).
EXAMPLE 23
5-Acetamido
4-guanidino-8,9-di-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-fluo-
ro-D-glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic
Acid Salt (Compound No. 1-63)
[1824] 40
[1825] 23(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-8,9-di-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-gala-
cto-non-2-enopyranosoate
[1826] 43 mg (0.06 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non--
2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of methylene chloride, and 19 mg (0.15 mmol) of
4-dimethylaminopyridine and 26 mg (0.14 mmol) of tetradecanoyl
chloride were added to the resulting solution, whilst ice-cooling.
The mixture was then stirred at room temperature for 1 hour. At the
end of this time, the reaction mixture was poured into a 2-layer
solution of 5 ml of ethyl acetate and 3 ml of a saturated aqueous
solution of sodium hydrogencarbonate, and the organic layer was
washed with a saturated aqueous solution of sodium chloride. It was
then dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
3:1 by volume mixture of hexane and ethyl acetate as the eluent, to
obtain 60 mg (yield 87%) of the title compound as a colorless
amorphous substance.
[1827] Rf=0.28 (3:1=hexane:ethyl acetate).
[1828] [.alpha.].sub.D.sup.25=+15.5.degree. (c=0.11,
CDCl.sub.3).
[1829] Mass Spectrum (FAB) m/e 1121 (M.sup.++H).
[1830] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1831] 0.80-0.90 (6H, multiplet);
[1832] 1.20-1.40 (40H, multiplet);
[1833] 1.48 (9H, singlet);
[1834] 1.49 (9H, singlet);
[1835] 1.50-1.65 (4H, multiplet);
[1836] 1.98 (3H, singlet);
[1837] 2.20-2.30 (4H, multiplet);
[1838] 4.00-4.30 (3H, multiplet);
[1839] 4.75 (1H, doublet, J=13 Hz);
[1840] 4.80 (1H, doublet of doublets, J=7.5 & 45 Hz);
[1841] 5.18 (1H, doubled doublet of doublets, J=1.0, 9.0 & 9.0
Hz);
[1842] 5.50 (1H, multiplet);
[1843] 5.93 (1H, doublet, J=2.4 Hz);
[1844] 6.66 (1H, doublet, J=7.5 Hz);
[1845] 6.93 (1H, singlet);
[1846] 7.20-7.50 (10H, multiplet);
[1847] 8.60 (1H, doublet, J=8.5 Hz).
[1848] 23(ii)
5-Acetamido-4-guanidino-8,9-di-O-tetradecanoyl-2,3,4,5,7-pen-
tadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1849] 52 mg (0.046 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-8,9-di-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro--
D-glycero-D-galacto-non-2-enopyranosoate [prepared as described in
step (i) above] were dissolved in 3 ml of a 3:1 by volume mixture
of methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 38 mg (yield 83%) of the title compound as
a colorless solid.
[1850] Rf=0.3 (2:5:1=isopropanol:ethyl acetate:water).
[1851] [.alpha.].sub.D.sup.25=+28.0.degree. (c=0.16,
CH.sub.3OH).
[1852] Mass Spectrum 755 (FAB) m/e 545 (M.sup.++H).
[1853] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1854] 0.85-0.95 (6H, multiplet);
[1855] 1.20-1.40 (40H, multiplet);
[1856] 1.55-1.70 (4H, multiplet);
[1857] 2.00 (3H, singlet);
[1858] 2.30 (2H, triplet, J=7.0 Hz);
[1859] 4.10-4.40 (4H, multiplet);
[1860] 4.70-5.00 (2H, multiplet);
[1861] 5.55 (1H, multiplet);
[1862] 5.70 (1H, doublet, J=3.0 Hz).
EXAMPLE 24
5-Acetamido-4-guanidino-8,9-di-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-fluor-
o-D-glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt (Compound No. 1-64)
[1863] 41
[1864] 24(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-8,9-di-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galac-
to-non-2-enopyranosoate
[1865] 37 mg (0.053 mmol) of diphenylmethyl
5-acetamido-4-(N,-bis-t-butoxy-
carbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-
-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of methylene chloride, and 16 mg (0.13 mmol) of
4-dimethylaminopyridine and 34 mg (0.12 mmol) of hexadecanoyl
chloride were added to the resulting solution, whilst ice-cooling.
The mixture was then stirred at room temperature for 1 hour. At the
end of this time, the reaction mixture was poured into a 2-layer
solution of 5 ml of ethyl acetate and 3 ml of a saturated aqueous
solution of sodium hydrogencarbonate, and the organic layer was
washed with a saturated aqueous solution of sodium chloride. It was
then dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
3:1 by volume mixture of hexane and ethyl acetate as the eluent, to
obtain 52 mg (yield 84%) of the title compound as a colorless
amorphous substance.
[1866] Rf=0.3 (3:1=hexane:ethyl acetate).
[1867] [.alpha.].sub.D.sup.25=+10.9.degree. (c=0.11,
CHCl.sub.3).
[1868] Mass Spectrum (FAB) m/e 1177 (M.sup.++H).
[1869] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1870] 0.80-0.90 (6H, multiplet);
[1871] 1.20-1.40 (48H, multiplet);
[1872] 1.48 (9H, singlet);
[1873] 1.49 (9H, singlet);
[1874] 1.50-1.65 (4H, multiplet);
[1875] 1.98 (3H, singlet);
[1876] 2.20-2.30 (4H, multiplet);
[1877] 4.00-4.30 (3H, multiplet);
[1878] 4.75 (1H, doublet, J=13 Hz);
[1879] 4.80 (1H, doublet of doublets, J=7.5 & 45 Hz);
[1880] 5.20 (1H, doubled doublet of doublets, J=1.0, 9.0 & 9.0
Hz);
[1881] 5.50 (1H, multiplet);
[1882] 5.92 (1H, doublet, J=2.4 Hz);
[1883] 6.65 (1H, doublet, J=7.5 Hz);
[1884] 6.93 (1H, singlet);
[1885] 7.20-7.50 (10H, multiplet);
[1886] 8.60 (1H, doublet, J=8.5 Hz).
[1887] 24(ii)
5-Acetamido-4-guanidino-8,9-di-O-hexadecanoyl-2,3,4,5,7-pent-
adeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1888] 42 mg (0.036 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-8,9-di-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-
-glycero-D-galacto-non-2-enopyranosoate [prepared as described in
step (i) above] were dissolved in 3 ml of a 3:1 by volume mixture
of methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 22 mg (yield 59%) of the title compound as
a colorless solid.
[1889] Rf=0.4 (2:5:1=isopropanol:ethyl acetate:water).
[1890] [.alpha.].sub.D.sup.25=+15.3.degree. (c=0.11,
CH.sub.3OH).
[1891] Mass Spectrum (FAB) m/e 811 (M.sup.++H).
[1892] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1893] 0.85-0.95 (6H, multiplet);
[1894] 1.20-1.40 (48H, multiplet);
[1895] 1.55-1.70 (4H, multiplet);
[1896] 2.00 (3H, singlet);
[1897] 2.30 (2H, triplet, J=7.0 Hz);
[1898] 4.10-4.40 (4H, multiplet);
[1899] 4.70-5.00 (2H, multiplet);
[1900] 5.55 (1H, multiplet);
[1901] 5.70 (1H, doublet, J=3.0 Hz).
EXAMPLE 25
5-Acetamido-4-guanidino-8,9-di-O-octadecanoyl-2,3,4,5,7-pentadeoxy-7-fluor-
o-D-glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt (Compound No. 65-1)
[1902] 42
[1903] 25(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-8,9-di-O-octadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galac-
to-non-2-enopyranosoate
[1904] 35 mg (0.05 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non--
2-enopyranosoate [prepared as described in Example 13(i)] were
dissolved in 2 ml of methylene chloride, and 15 mg (0.13 mmol) of
triethylamine and 35 mg (0.115 mmol) of octadecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at room temperature for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 3:1 by volume
mixture of hexane and ethyl acetate as the eluent, to obtain 57 mg
(yield 93%) of the title compound as a colorless amorphous
substance.
[1905] Rf=0.3 (3:1=hexane:ethyl acetate).
[1906] [.alpha.].sub.D.sup.25=+11.2.degree. (c=0.18,
CHCl.sub.3).
[1907] Mass Spectrum (FAB) m/e 1233 (M.sup.++H).
[1908] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1909] 0.80-0.90 (6H, multiplet);
[1910] 1.20-1.40 (56H, multiplet);
[1911] 1.48 (9H, singlet);
[1912] 1.49 (9H, singlet);
[1913] 1.50-1.65 (4H, multiplet);
[1914] 1.98 (3H, singlet);
[1915] 2.20-2.30 (4H, multiplet);
[1916] 4.00-4.30 (3H, multiplet);
[1917] 4.75 (1H, doublet, J=13 Hz);
[1918] 4.80 (1H, doublet of doublets, J=7.5 & 45 Hz);
[1919] 5.20 (1H, doubled doublet of doublets, J=1.0, 9.0 & 9.0
Hz);
[1920] 5.50 (1H, multiplet);
[1921] 5.92 (1H, doublet, J=2.4 Hz);
[1922] 6.65 (1H, doublet, J=7.5 Hz);
[1923] 6.93 (1H, singlet);
[1924] 7.20-7.50 (10H, multiplet);
[1925] 8.60 (1H, doublet, J=8.5 Hz).
[1926] 25(ii)
5-Acetamido-4-guanidino-8,9-di-O-octadecanoyl-2,3,4,5,7-pent-
adeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[1927] 47 mg (0.04 mmol) of diphenylmethyl
5-acetamido-(N,N'-bis-t-butoxyc-
arbonylguanidino)-8,9-di-O-octadecanoyl-2,3,4,5,7-pentadeoxy-7-fluoro-D-gl-
ycero-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 28 mg (yield 67%) of the title compound as
a colorless solid.
[1928] Rf=0.4 (2:5:1=isopropanol:ethyl acetate:water).
[1929] [.alpha.].sub.D.sup.25=+14.5.degree. (c=0.14,
CH.sub.3OH).
[1930] Mass Spectrum (FAB) m/e 867 (M.sup.++H).
[1931] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[1932] 0.85-0.95 (6H, multiplet);
[1933] 1.20-1.40 (56H, multiplet);
[1934] 1.55-1.70 (4H, multiplet);
[1935] 2.00 (3H, singlet);
[1936] 2.30 (2H, triplet, J=7.0 Hz);
[1937] 4.10-4.40 (4H, multiplet);
[1938] 4.70-5.00 (2H, multiplet);
[1939] 5.55 (1H, multiplet);
[1940] 5.70 (1H, doublet, J=3.0 Hz).
EXAMPLE 26
Hexadecyl
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero--
D-galacto-non-2-enopyranosoate Trifluoroacetic Acid Salt (Compound
No. 1-6)
[1941] 43
[1942] 26(i) Hexadecyl
5-acetamido-4-azido-8,9-O-isopropylidene-2,3,4,5,7--
pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[1943] 275 mg (0.74 mmol) of methyl
5-acetamido-4-azido-8,9-O-isopropylide-
ne-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in Example 7(i)] were dissolved in 7 ml of a
6:1 by volume mixture of methanol and water, and 0.82 ml of a 1 M
aqueous solution of potassium hydroxide was added to the resulting
solution. The mixture was then stirred at room temperature for 2
hours. At the end of this time, the solvent was removed by
distillation under reduced pressure, and dried under reduced
pressure at room temperature for 2 hours to obtain a pale yellow
solid. This solid was dissolved in 8 ml of acetonitrile, and 195 mg
(0.74 mmol) of 18-crown-6 and 677 mg (2.2 mmol) of hexadecyl
bromide were added to the resulting solution. The mixture was then
stirred at 80.degree. C. for 30 minutes. At the end of this time,
the solvent was removed by distillation under reduced pressure. A
2-layer solution of 15 ml of ethyl acetate and 10 ml of a saturated
aqueous solution of sodium hydrogencarbonate was poured onto the
resulting residue, and the organic layer was separated and washed
with a saturated aqueous solution of sodium chloride. It was then
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 240 mg (yield 56%) of the title compound as a colorless
amorphous substance.
[1944] Rf=0.50 (20:1=methylene chloride:methanol).
[1945] [.alpha.].sub.D.sup.25=+65.0.degree. (c=0.5,
CHCl.sub.3).
[1946] Mass Spectrum (FAB) m/e 583 (M.sup.++H).
[1947] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1948] 0.80-0.95 (3H, multiplet);
[1949] 1.20-1.40 (28H, multiplet);
[1950] 1.37 (3H, singlet);
[1951] 1.42 (3H, singlet);
[1952] 1.60-1.80 (2H, multiplet);
[1953] 2.05 (3H, singlet);
[1954] 4.10-4.30 (3H, multiplet);
[1955] 4.40 (1H, multiplet);
[1956] 4.72 (1H, doubled doublet of doublets, J=1.3, 5.3 & 47.0
Hz);
[1957] 4.90 (1H, doublet of doublets, J=2.4 & 9.3 Hz);
[1958] 4.92 (1H, doubled doublet of doublets, J=1.4, 10.0 &
28.0 Hz);
[1959] 5.92 (1H, doublet, J=7.2 Hz);
[1960] 5.94 (1H, doublet, J=2.6 Hz).
[1961] 26(ii) Hexadecyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanidino)-
-8,9-O-isopropylidene-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-no-
n-2-enopyranosoate
[1962] 240 mg (0.41 mmol) of hexadecyl
5-acetamido-4-azido-8,9-O-isopropyl-
idene-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoa-
te [prepared as described in step (i) above] were dissolved in 10
ml of methanol, and 60 mg of a Lindlar catalyst were added to the
resulting solution. The mixture was then stirred under a hydrogen
atmosphere for 2 hours. At the end of this time, the catalyst was
separated by filtration, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
dissolved in 4 ml of dimethylformamide, and 145 mg (0.53 mmol) of
N,N-di-t-butoxycarbonylthiourea, 106 mg (1.05 mmol) of
triethylamine and 142 mg (0.53 mmol) of mercuric chloride were
added to the resulting solution. The mixture was then stirred at
room temperature for 1 hour. At the end of this time, the solid was
separated by filtration, and the filtrate was poured into a 2-layer
solution of 15 ml of ethyl acetate and 10 ml of a saturated aqueous
solution of sodium hydrogencarbonate. The organic layer was washed
with a saturated aqueous solution of sodium chloride, and dried
over anhydrous sodium sulfate, after which the solvent was removed
by distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 1:2 by volume
mixture of ethyl acetate and hexane as the eluent, to obtain 220 mg
(yield 67%) of the title compound as a colorless viscous
substance.
[1963] Rf=0.40 (20:1=methylene chloride:methanol).
[1964] [.alpha.].sub.D.sup.25=-11.6.degree. (c=0.06,
CHCl.sub.3).
[1965] Mass Spectrum (FAB) m/e 799 (M.sup.++H).
[1966] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[1967] 0.80-0.95 (3H, multiplet);
[1968] 1.20-1.40 (28H, multiplet);
[1969] 1.37 (3H, singlet);
[1970] 1.41 (3H, singlet);
[1971] 1.49 (9H, singlet);
[1972] 1.50 (9H, singlet);
[1973] 1.60-1.80 (2H, multiplet);
[1974] 1.97 (3H, singlet);
[1975] 4.10-4.30 (4H, multiplet);
[1976] 4.40-4.65 (2H, multiplet);
[1977] 5.20 (1H, doubled doublet of doublets, J=2.4, 7.5 & 7.5
Hz);
[1978] 5.83 (1H, doublet, J=2.4 Hz);
[1979] 5.65 (1H, doublet, J=7.0 Hz);
[1980] 8.60 (1H, doublet, J=8.5 Hz).
[1981] 26(iii) Hexadecyl
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-fl-
uoro-D-glycero-D-galacto-non-2-enopyranosoate Trifluoroacetic Acid
Salt
[1982] 200 mg (0.25 mmol) of hexadecyl
5-acetamido-4-(N'-bis-t-butoxycarbo-
nylguanidino)-8,9-O-isopropylidene-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-
-D-galacto-non-2-enopyranosoate [prepared as described in step (i)
above] were dissolved in 10 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:8:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 130 mg (yield 77%) of the title compound
as a colorless solid.
[1983] Rf=0.55 (5:1:1=t-butanol:acetic acid:water).
[1984] [.alpha.].sub.D.sup.25=+14.7.degree. (c=0.1,
CH.sub.3OH).
[1985] Mass Spectrum (FAB) m/e 559 (M.sup.++H).
[1986] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[1987] 0.70-0.85 (3H, multiplet);
[1988] 1.10-1.30 (28H, multiplet);
[1989] 1.60-1.80 (2H, multiplet);
[1990] 2.00 (3H, singlet);
[1991] 3.60-3.85 (2H, multiplet);
[1992] 4.00-4.30 (3H, multiplet);
[1993] 4.50-4.80 (2H, multiplet);
[1994] 5.88 (1H, singlet).
EXAMPLE 27
Octadecyl
5-acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero--
D-galacto-non-2-enopyranosoate Trifluoroacetic Acid Salt (Compound
No. 1-7)
[1995] 44
[1996] 27(i) Octadecyl
5-acetamido-4-azido-8,9-O-isopropylidene-2,3,4,5,7--
pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[1997] 45 mg (0.12 mmol) of methyl
5-acetamido-4-azido-8,9-O-isopropyliden-
e-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in Example 7(i)] were dissolved in 4 ml of a
6:1 by volume mixture of methanol and water, and 0.13 ml of a 1 M
aqueous solution of potassium hydroxide was added to the resulting
solution. The mixture was then stirred at room temperature for 2
hours. At the end of this time, the solvent was removed by
distillation under reduced pressure, and the residue was dried
under reduced pressure at room temperature for 2 hours to obtain a
pale yellow solid. This solid was dissolved in 2 ml of
acetonitrile, and 32 mg (0.12 mmol) of 18-crown-6 and 121 mg (0.36
mmol) of octadecyl bromide were added to the resulting solution.
The mixture was then stirred at 80.degree. C. for 30 minutes. The
resulting residue was poured into a 2-layer solution of 7 ml of
ethyl acetate and 5 ml of a saturated aqueous solution of sodium
hydrogencarbonate, and the organic layer was separated and washed
with a saturated aqueous solution of sodium chloride. It was then
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 2:1 by volume
mixture of hexane and ethyl acetate as the eluent, to obtain 42 mg
(yield 58%) of the title compound as a colorless amorphous
substance.
[1998] Rf=0.50 (20:1=methylene chloride:methanol).
[1999] [.alpha.].sub.D.sup.25=+76.degree. (c=0.05, CHCl.sub.3).
[2000] Mass Spectrum (FAB) m/e 611 (M.sup.++H).
[2001] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2002] 0.85-0.95 (3H, multiplet);
[2003] 1.20-1.40 (32H, multiplet);
[2004] 1.37 (3H, singlet);
[2005] 1.42 (3H, singlet);
[2006] 1.60-1.80 (2H, multiplet);
[2007] 2.05 (3H, singlet);
[2008] 4.10-4.30 (3H, multiplet);
[2009] 4.40 (1H, multiplet);
[2010] 4.72 (1H, doubled doublet of doublets, J=1.3, 5.3 & 47.0
Hz);
[2011] 4.90 (1H, doublet of doublets, J=2.6 & 9.5 Hz);
[2012] 4.92 (1H, doubled doublet of doublets, J=1.4, 10.0 &
28.0 Hz);
[2013] 5.94 (1H, doublet, J=7.2 Hz);
[2014] 5.91 (1H, doublet, J=2.6 Hz).
[2015] 27(ii) Octadecyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanidino)-
-8,9-O-isopropylidene-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-no-
n-2-enopyranosoate
[2016] 40 mg (0.066 mmol) of octadecyl
5-acetamido-4-azido-8,9-O-isopropyl-
idene-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycero-D-galacto-non-2-enopyranosoa-
te [prepared as described in step (i) above] were dissolved in 3 ml
of methanol, and 10 mg of a Lindlar catalyst were added thereto.
The mixture was then stirred under a hydrogen atmosphere for 2
hours. At the end of this time, the catalyst was separated by
filtration, and the solvent was removed by distillation under
reduced pressure. The resulting residue was dissolved in 2 ml of
dimethylformamide, and then 25 mg (0.09 mmol) of
N,N'-di-t-butoxycarbonylthiourea, 18 mg (0.18 mmol) of
triethylamine and 25 mg (0.09 mmol) of mercuric chloride were added
to the resulting solution. The mixture was then stirred at room
temperature for 1 hour. At the end of this time, the solid produced
was separated by filtration. The filtrate was poured into a 2-layer
solution of 5 ml of ethyl acetate and 3 ml of a saturated aqueous
solution of sodium hydrogencarbonate, and the organic layer was
separated and washed with a saturated aqueous solution of sodium
chloride. It was then dried over anhydrous sodium sulfate, and the
solvent was removed by distillation under reduced pressure. The
resulting residue was purified by silica gel column chromatography,
using a 1:1 by volume mixture of hexane and ethyl acetate as the
eluent, to obtain 39 mg (yield 71%) of the title compound as a
colorless viscous substance.
[2017] Rf=0.40 (20:1=methylene chloride:methanol).
[2018] [.alpha.].sub.D.sup.25=7.4.degree. (c=0.10, CDCl.sub.3).
[2019] Mass Spectrum (FAB) m/e 827 (M.sup.++H).
[2020] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2021] 0.80-0.95 (3H, multiplet);
[2022] 1.20-1.40 (32H, multiplet);
[2023] 1.37 (3H, singlet);
[2024] 1.41 (3H, singlet);
[2025] 1.49 (9H, singlet);
[2026] 1.50 (9H, singlet);
[2027] 1.60-1.80 (2H, multiplet);
[2028] 1.97 (3H, singlet);
[2029] 4.10-4.30 (4H, multiplet);
[2030] 4.40-4.65 (2H, multiplet);
[2031] 5.20 (1H, doubled doublet of doublets, J=2.4, 7.5 & 7.5
Hz);
[2032] 5.83 (1H, doublet, J=2.3 Hz);
[2033] 5.65 (1H, doublet, J=7.0 Hz);
[2034] 8.60 (1H, doublet, J=8.5 Hz).
[2035] 27(iii) Octadecyl
5-acetamido-4-guanidino-2,3.4,5,7-pentadeoxy-7-fl-
uoro-D-glycero-D-galacto-non-2-enopyranosoate Trifluoroacetic Acid
Salt
[2036] 30 mg (0.04 mmol) of octadecyl
5-acetamido-4-(N,N'-bis-t-butoxycarb-
onylguanidino)-8,9-O-isopropylidene-2,3,4,5,7-pentadeoxy-7-fluoro-D-glycer-
o-D-galacto-non-2-enopyranosoate [prepared as described in step
(ii) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:8:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 20 mg (yield 79%) of the title compound as
a colorless solid.
[2037] Rf=0.55 (5:1:1=t-butanol acetic acid:water).
[2038] [.alpha.].sub.D.sup.25=+14.0.degree. (c=0.10,
CH.sub.3OH).
[2039] Mass Spectrum (FAB) m/e 587 (M.sup.++H).
[2040] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[2041] 0.70-0.85 (3H, multiplet);
[2042] 1.10-1.30 (32H, multiplet);
[2043] 1.60-1.80 (2H, multiplet);
[2044] 2.00 (3H, singlet);
[2045] 3.60-3.85 (2H, multiplet);
[2046] 4.00-4.30 (3H, multiplet);
[2047] 4.50-4.80 (2H, multiplet);
[2048] 5.88 (1H, singlet).
EXAMPLE 28
5-Acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-
-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (Compound No.
163-1)
[2049] 45
[2050] 28(i) Benzyl
N-acetyl-3,6-di-O-benzyl-4-methyl-.alpha.-D-glucosamin- e
[2051] 4.48 g (9.12 mmol) of benzyl
N-acetyl-3,6-di-O-benzyl-.alpha.-D-glu- cosamine [prepared
according to the procedure described in Carbohydrate Res. 83,
163-169 (1980)] were dissolved in 50 ml of dimethylformamide, and
1.0 g (22.5 mmol) of sodium hydride was added to the resulting
solution. The mixture was then stirred at room temperature for 30
minutes, after which 1.42 g (10.0 mmol) of methyl iodide were added
at 0.degree. C., and the mixture was stirred at room temperature
for a further 5 hours. At the end of this time, the reaction
mixture was poured into a 2-layer solution of 100 ml of ethyl
acetate and 50 ml of a saturated aqueous solution of sodium
hydrogencarbonate, and the organic layer was separated and washed
with a saturated aqueous solution of sodium chloride. It was then
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 4:1 by volume
mixture of methylene chloride and ethyl acetate as the eluent, to
obtain 3.6 g (yield 78%) of the title compound as a colorless
solid.
[2052] Rf=0.55 (20:1=methylene chloride:methanol).
[2053] [.alpha.].sub.D.sup.25=+126.degree. (c=1.15,
CHCl.sub.3).
[2054] Mass Spectrum (FAB) m/e 506 (M.sup.++H).
[2055] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2056] 1.80 (3H, singlet);
[2057] 3.48 (3H, singlet);
[2058] 3.40-3.80 (5H, multiplet);
[2059] 4.23 (1H, doubled doublet of doublets, J=3.5, 10.0 &
10.0 Hz);
[2060] 4.40-4.90 (7H, multiplet);
[2061] 5.25 (1H, doublet, J=10.0 Hz);
[2062] 7.20-7.40 (15H, multiplet).
[2063] 28(ii) N-Acetyl-4-O-methyl-.alpha.-D-glucosamine
[2064] 3.6 g (7.12 mmol) of benzyl
N-acetyl-3,6-di-O-benzyl-4-O-methyl-.al- pha.-D-glucosamine
[prepared as described in step (i) above] were dissolved in 40 ml
of acetic acid, and 5.0 g of palladium-on-carbon were added to the
resulting solution. The mixture was then stirred under a hydrogen
atmosphere at 3 atmospheres. for 30 hours. At the end of this time,
the catalyst was separated by filtration, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
gradient elution method, with mixtures of methylene chloride and
methanol ranging from 10:1 to 5:1 by volume as the eluent, to
obtain 1.42 g (yield 83%) of the title compound as a colorless
solid.
[2065] Rf=0.35 (5:1=methylene chloride:methanol).
[2066] [.alpha.].sub.D.sup.25=+72.2.degree. (c=2.9,
CH.sub.3OH).
[2067] Mass Spectrum (FAB) m/e 236 (M.sup.++H).
[2068] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2069] 1.98 (3H, singlet);
[2070] 3.57 (3H, singlet);
[2071] 3.60-3.80 (6H, multiplet);
[2072] 5.05 (1H, doublet, J=3.2 Hz).
[2073] 28(iii)
5-Acetamido-3,5-dideoxy-7-O-methyl-D-glycero-D-galacto-2-no-
nuropyranosoic Acid
[2074] 5.0 g (21.3 mmol) of
N-acetyl-4-O-methyl-.alpha.-D-glucosamine [prepared as described in
step (ii) above] were dissolved in distilled water, and 100 mg of
sodium azide and 5.0 g (45.5 mmol) of sodium pyruvate were added to
the resulting solution. The pH of the reaction mixture was then
adjusted to a value of 10 to 11 by the addition of a 1 N aqueous
solution of sodium hydroxide, after which 25 mg (660U) of
N-acetyl-neuraminic acid aldolase (produced by TOYOBO K.K.) were
added to the mixture, and the mixture was stirred at 20.degree. C.
for 3 days. At the end of this time, the reaction mixture was
desalted using a Dowex 50x8 (H.sup.+) resin (Dowex is a trade mark)
and purified by column chromatography through Dowex 1 (HCOOH),
eluted with a 1.0 M aqueous solution of formic acid, to obtain 1.8
g (yield 26%) of the title compound as a colorless viscous
substance.
[2075] Rf=0.30 (4:1:1=isopropanol:acetic acid:water).
[2076] [.alpha.].sub.D.sup.25=-19.7.degree. (c=1.2, H.sub.2O).
[2077] Mass Spectrum (FAB) m/e 324 (M.sup.++H).
[2078] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[2079] 1.80 (1H, doublet of doublets, J=12.0 & 12.0 Hz);
[2080] 2.00 (3H, singlet);
[2081] 2.10 (1H, doublet of doublets, J=4.5 & 12.0 Hz);
[2082] 3.48 (3H, singlet);
[2083] 3.50-3.80 (7H, multiplet).
[2084] 28(iv) Methyl
5-acetamido-3,5-dideoxy-7-O-methyl-D-glycero-D-galact-
o-2-nonuropyranosoate
[2085] 680 mg (2.10 mmol) of
5-acetamido-3,5-dideoxy-7-O-methyl-D-glycero--
D-galacto-2-nonuropyranosoic acid [prepared as described in step
(iii) above] were dissolved in 20 ml of methanol, and 500 mg of a
Dowex 50x8 (H.sup.+) cation exchange resin (Dowex is a trade mark)
were added to the resulting solution. The mixture was then stirred
at room temperature for 15 hours. At the end of this time, the
cation exchange resin was separated by filtration, and the solvent
was removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
5:1 by volume mixture of methylene chloride and methanol as the
eluent, to obtain 340 mg (yield 48%) of the title compound as a
colorless amorphous substance.
[2086] Rf=0.15 (5:1=methylene chloride:methanol).
[2087] [.alpha.].sub.D.sup.25=+30.2.degree. (c=1.1,
CH.sub.3OH).
[2088] Mass Spectrum (FAB) m/e 338 (M.sup.++H).
[2089] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2090] 1.90 (1H, doublet of doublets, J=12.0 & 14.0 Hz);
[2091] 2.00 (3H, singlet);
[2092] 2.16 (1H, doublet of doublets, J=4.5 & 12.0 Hz);
[2093] 3.40 (1H, multiplet);
[2094] 3.45 (3H, singlet);
[2095] 3.50-3.80 (3H, multiplet);
[2096] 3.77 (3H, singlet);
[2097] 3.80-4.00 (2H, multiplet);
[2098] 4.20 (1H, doublet of doublets, J=1.5 & 9.5 Hz).
[2099] 28(v) Methyl
5-acetamido-4,8,9-tri-O-acetyl-2,3,5-trideoxy-7-O-meth-
yl-D-glycero-D-galacto-non-2-enopyranosoate
[2100] 686 mg (2.03 mmol) of methyl
5-acetamido-3,5-dideoxy-7-O-methyl-D-g-
lycero-D-galacto-2-nonuropyranosoate [prepared as described in step
(iv) above] were dissolved in a mixture of 10 ml of pyridine and 10
ml of acetic anhydride, and the mixture was stirred at room
temperature for 15 hours. At the end of this time, the solvent was
removed by distillation under reduced pressure, and the residue was
dissolved in 20 ml of a 4 M solution of hydrogen chloride in
dioxane, after which it was stirred at room temperature for 15
hours. At the end of this time, the solvent was dissolved in
benzene, and 182 mg (1.20 mmol) of 1,8-diazabicyclo[5.4.0]-7-
-undecene were added to the resulting solution, and the mixture was
stirred at room temperature for 2 hours. The reaction mixture was
then poured into a 2-layer solution of 30 ml of methylene chloride
and 15 ml of a saturated aqueous ammonium chloride solution, and
the organic layer was separated and washed with a saturated aqueous
solution of sodium chloride. It was then dried over anhydrous
sodium sulfate, and the solvent was removed by distillation under
reduced pressure. The resulting residue was purified by silica gel
column chromatography, using a 50:1 by volume mixture of methylene
chloride and methanol as the eluent, to obtain 310 mg (yield 34%)
of the title compound as a colorless amorphous substance.
[2101] Rf=0.30 (20:1=methylene chloride:methanol).
[2102] [.alpha.].sub.D.sup.25=+206.degree. (c=0.15,
CHCl.sub.3).
[2103] Mass Spectrum (FAB) m/e 446 (M.sup.++H).
[2104] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2105] 2.00 (3H, singlet);
[2106] 2.06 (3H, singlet);
[2107] 2.08 (3H, singlet);
[2108] 2.10 (3H, singlet);
[2109] 3.50 (3H, singlet);
[2110] 3.65 (1H, doublet of doublets, J=3.0 & 3.0 Hz);
[2111] 3.80 (3H, singlet);
[2112] 4.20-4.35 (2H, multiplet);
[2113] 4.45 (1H, multiplet);
[2114] 4.70 (1H, doublet of doublets, J=3.0 & 12.0 Hz);
[2115] 5.35 (1H, multiplet);
[2116] 5.50 (1H, doublet of doublets, J=3.0 & 7.0 Hz);
[2117] 5.55 (1H, doublet, J=8.0 Hz);
[2118] 6.00 (1H, doublet, J=2.8 Hz).
[2119] 28(vi) Methyl
5-acetamido-4-azido-8,9-di-O-acetyl-2,3,4,5,7-pentade-
oxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoate
[2120] 303 mg (0.67 mmol) of methyl
5-acetamido-4,8,9-tri-O-acetyl-2,3,5-t-
rideoxy-7-O-methyl-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in step (v) above] were dissolved in 10 ml
of anhydrous methylene chloride, and 22 mg (0.67 mmol) of methanol
were added to the resulting solution. 956 mg (6.74 mmol) of a boron
trifluoride-diethyl ether complex were added to the resulting
mixture under a nitrogen atmosphere, and the mixture was stirred at
room temperature for 24 hours. At the end of this time, the
reaction mixture was poured into a mixture of 20 ml of water, 10 g
of ice, 5 g of solid sodium hydrogencarbonate and 20 ml of ethyl
acetate, and the mixture was vigorously stirred for 10 minutes. The
organic layer was then separated, washed with 10 ml of a saturated
aqueous solution of sodium chloride, and dried over anhydrous
sodium sulfate, after which the solvent was removed by distillation
under reduced pressure. The resulting residue (270 mg) was
dissolved in 10 ml of dimethylformamide, and 270 mg of a cation
exchange resin [Dowex 50x8 (H.sup.+)--Dowex is a trade mark] and 90
mg (1.37 mmol) of sodium azide were added to the resulting
solution. The mixture was then stirred at 90.degree. C. for 4
hours. At the end of this time, the Dowex 50x8 (H.sup.+) resin was
separated by filtration, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
dissolved in a 2-layer solution of 20 ml of ethyl acetate and 10 ml
of a saturated aqueous solution of sodium hydrogencarbonate, and
the organic layer was washed with a saturated aqueous solution of
sodium chloride. It was then dried over anhydrous sodium sulfate,
and the solvent was removed by distillation under reduced pressure.
The resulting residue was purified by silica gel column
chromatography, using a 50:1 by volume mixture of methylene
chloride and methanol as the eluent, to obtain 250 mg (yield 70%)
of the title compound as a colorless viscous substance.
[2121] Rf=0.30 (20:1=methylene chloride:methanol).
[2122] [.alpha.].sub.D.sup.25=+97.2.degree. (c=0.25,
CHCl.sub.3).
[2123] Mass Spectrum (FAB) m/e 429 (M.sup.++H).
[2124] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2125] 2.06 (6H, singlet);
[2126] 2.10 (3H, singlet);
[2127] 3.50 (3H, singlet);
[2128] 3.65 (1H, doublet of doublets, J=1.8 & 4.0 Hz);
[2129] 3.80 (3H, singlet);
[2130] 4.25 (1H, doublet of doublets, J=5.0 & 12.0 Hz);
[2131] 4.45-4.55 (2H, multiplet);
[2132] 4.75 (1H, doublet of doublets, J=3.2 & 12.0 Hz);
[2133] 5.35 (1H, multiplet);
[2134] 5.52 (1H, doublet, J=8.2 Hz);
[2135] 5.98 (1H, doublet, J=2.7 Hz).
[2136] 28(vii) Methyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanidino)-8-
,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-en-
opyranosoate
[2137] 80 mg (0.42 mmol) of methyl
5-acetamido-4-azido-8,9-di-O-acetyl-2,3-
,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in step (vi) above] were dissolved in 10 ml
of methanol, and 130 mg of a Lindlar catalyst were added to the
resulting solution. The mixture was then stirred under a hydrogen
atmosphere for 2 hours. At the end of this time, the catalyst was
separated by filtration, and the solvent was removed by
distillation under reduced pressure. The resulting residue (120 mg)
was dissolved in 10 ml of dimethylformamide, and 100 mg (0.37 mmol)
of N,N'-di-t-butoxycarbonylthiourea, 75 mg (0.74 mmol) of
triethylamine and 100 mg (0.37 mmol) of mercuric chloride were
added to the resulting solution. The mixture was then stirred at
room temperature for 1 hour. At the end of this time, the solid was
separated by filtration, and the filtrate was poured into a 2-layer
solution of 10 ml of ethyl acetate and 50 ml of a saturated aqueous
solution of sodium hydrogencarbonate. The organic layer was
separated, washed with a saturated aqueous solution of sodium
chloride and dried over anhydrous sodium sulfate, after which the
solvent was removed by distillation under reduced pressure. The
resulting residue was purified by silica gel column chromatography,
using a 2:1 by volume mixture of hexane and ethyl acetate as the
eluent, to obtain 180 mg (yield 64 %) of the title compound as a
colorless amorphous substance.
[2138] Rf=0.50 (20:1=methylene chloride:methanol).
[2139] [.alpha.].sub.D.sup.25=+2.8.degree. (c=0.65,
CHCl.sub.3).
[2140] Mass Spectrum (FAB) m/e 645 (M.sup.++H).
[2141] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2142] 1.49 (9H, singlet);
[2143] 1.50 (9H, singlet);
[2144] 1.97 (3H, singlet);
[2145] 2.05 (3H, singlet);
[2146] 2.07 (3H, singlet);
[2147] 3.52 (3H, singlet);
[2148] 3.55 (1H, multiplet);
[2149] 3.78 (3H, singlet);
[2150] 4.10 (1H, doublet of doublets, J=1.0 & 10.5 Hz);
[2151] 4.25-4.40 (2H, multiplet);
[2152] 4.82 (1H, doublet of doublets, J=3.2 & 12.0 Hz);
[2153] 5.12 (1H, doubleted doublet of doublets, J=2.5 & 11.0
& 11.0 Hz);
[2154] 5.30 (1H, multiplet);
[2155] 5.85 (1H, doublet, J=2.3 Hz);
[2156] 6.35 (1H, doublet, J=8.8 Hz).
[2157] 28(viii)
5-Acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-methoxy-D-g-
lycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt
[2158] 53 mg (0.083 mmol;) of methyl 5
acetamido-4-(N,N'-bis-t-butoxycarbo-
nylguanidino)-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-g-
alacto-non-2-enopyranosoate [prepared as described in step (vii)
above] were dissolved in 2 ml of methanol, and 0.2 ml of a 0.1 N
methanolic solution of sodium methoxide was added to the resulting
solution. The mixture was then stirred at room temperature for 1
hour. At the end of this time, the reaction mixture was neutralized
with a 4 M solution of hydrogen chloride in dioxane, and the
solvent was removed by distillation under reduced pressure. The
resulting residue was dissolved in 3 ml of a 3:1 by volume mixture
of methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was dissolved in 1 ml of distilled water. 72 .mu.l of a
1N aqueous solution of sodium hydroxide were then added to the
reaction mixture, which was then stirred at room temperature for 1
hour. At the end of this time, the reaction mixture was neutralized
with a Dowex 50x8 (H.sup.+) resin (Dowex is a trade mark), and then
the water was removed by distillation. The resulting residue was
purified by silica gel column chromatography, using a 5:1:1: by
volume mixture of isopropanol, ethyl acetate and water as the
eluent, to obtain 24 mg (yield 85%) of the title compound as a
colorless solid.
[2159] Rf=0.30 (4:1:1=isopropanol:acetic acid:water).
[2160] [.alpha.].sub.D.sup.25=-9.3.degree. (c=0.1, CH.sub.3OH).
[2161] Mass Spectrum (FAB) m/e 347 (M.sup.++H).
[2162] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2163] 2.00 (3H, singlet);
[2164] 3.37 (3H, singlet);
[2165] 3.55 (1H, doublet, J=8.5 Hz);
[2166] 3.65 (1H, doublet of doublets, J=5.0 & 12 Hz);
[2167] 3.90 (3H, multiplet);
[2168] 4.20 (1H, doublet of doublets, J=10 & 10 Hz);
[2169] 4.40-4.50(2H, multiplet);
[2170] 5.85 (1H, doublet, J=1.8 Hz).
EXAMPLE 29
5-Acetamido-4-guanidino-9-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-
-glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt (Compound No. 163-41)
[2171] 46
[2172] 29(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoa-
te
[2173] 87 mg (0.14 mmol) of methyl 5
acetamido-4-(N,N'-bis-t-butoxycarbony-
lguanidino)-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-gal-
acto-non-2-enopyranosoate [prepared as described in Example
28(vii)] were dissolved in 5 ml of methanol, and 2 ml of a 0.4 N
methanolic solution of sodium methoxide were added to the resulting
solution. The mixture was then stirred at room temperature for 1
hour. At the end of this time, the reaction mixture was neutralized
with a 4 M solution of hydrogen chloride in dioxane, and the
solvent was removed by distillation under reduced pressure. The
resulting residue was dissolved in 4 ml of distilled water and 0.2
ml of a 1 N aqueous solution of sodium hydroxide was added to the
resulting solution. The mixture was then stirred at room
temperature for 1 hour. At the end of this time, the reaction
mixture was neutralized with a 4 M solution of hydrogen chloride in
dioxane, and then the water was removed by distillation, after
which the residue was dissolved in a 1:1 by volume mixture of
methanol and methylene chloride, and 47 mg (0.24 mmol) of
diphenyldiazomethane and 50 mg (0.38 mmol) of a boron
trifluoride-diethyl ether complex were added to the resulting
solution. The mixture was then stirred at room temperature for 2
hours. At the end of this time, acetic acid was added, and the
solvent was removed by distillation under reduced pressure. The
resulting residue was purified by silica gel column chromatography,
using a 20:1 by volume mixture of methylene chloride and methanol
as the eluent, to obtain 29 mg (yield 30%) of the title compound as
a colorless amorphous substance.
[2174] Rf=0.3 (20:1=methylene chloride:methanol).
[2175] [.alpha.].sub.D.sup.25=+22.0.degree. (c=0.4,
CHCl.sub.3).
[2176] Mass Spectrum (FAB) m/e 713 (M.sup.++H).
[2177] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2178] 1.46 (9H, singlet);
[2179] 1.52 (9H, singlet);
[2180] 1.95 (3H, singlet);
[2181] 3.48 (1H, doublet, J=9.0 Hz);
[2182] 3.68 (1H, doublet of doublets, J=4.0 & 12 Hz);
[2183] 3.85 (1H, doublet of doublets, J=2.5 & 12 Hz);
[2184] 3.95 (1H, multiplet);
[2185] 4.32 (1H, doublet of doublets, J=10 & 10 Hz);
[2186] 4.43 (1H, doublet, J=10 Hz);
[2187] 5.05 (1H, doublet of doublets, J=2.2 & 10 Hz);
[2188] 6.02 (1H, doublet, J=2.2 Hz);
[2189] 6.90 (1H, singlet);
[2190] 7.20-7.50 (10H, multiplet).
[2191] 29(ii) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguani-
dino)-9-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-
-non-2-enopyranosoate
[2192] 28 mg (0.039 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-no-
n-2-enopyranosoate [prepared as described in step (i) above] were
dissolved in 2 ml of methylene chloride, and 6 mg (0.06 mmol) of
triethylamine and 8 mg (0.05 mmol) of tetradecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 22 mg (yield 61%) of the title compound as a colorless
amorphous substance.
[2193] Rf=0.45 (20:1=methylene chloride:methanol).
[2194] [.alpha.].sub.D.sup.25=+40.5.degree. (c=0.2,
CHCl.sub.3).
[2195] Mass Spectrum (FAB) m/e 923 (M.sup.++H).
[2196] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2197] 0.85 (3H, multiplet);
[2198] 1.20-1.30 (20H, multiplet);
[2199] 1.48 (9H, singlet);
[2200] 1.50 (9H, singlet);
[2201] 1.55-1.70 (2H, multiplet);
[2202] 1.98 (3H, singlet);
[2203] 2.33 (2H, triplet, J=7.5 Hz);
[2204] 3.40 (1H, multiplet);
[2205] 3.48 (3H, singlet);
[2206] 4.10-4.50 (5H, multiplet);
[2207] 5.18 (1H, doubled doublet of doublets, J=2.4, 9.0 & 9.0
Hz);
[2208] 5.95 (1H, doublet, J=2.3 Hz);
[2209] 6.18 (1H, doublet, J=8.7 Hz);
[2210] 6.92 (1H, singlet);
[2211] 7.20-7.50 (10H, multiplet);
[2212] 8.55 (1H, doublet, J=8.7 Hz).
[2213] 29(iii)
5-Acetamido-4-guanidino-9-O-tetradecanoyl-2,3,4,5,7-pentade-
oxy-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[2214] 22 mg (0.024 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-9-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-gl-
ycero-D-galacto-non-2-enopyranosoate [prepared as described in step
(ii) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 10 mg (yield 74%) of the title compound as
a colorless solid.
[2215] Rf=0.4 (2:5:1=isopropanol:ethyl acetate:water).
[2216] [.alpha.].sub.D.sup.25=+24.0.degree. (c=0.1,
CH.sub.3OH).
[2217] Mass Spectrum (FAB) m/e 557 (M.sup.++H).
[2218] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2219] 0.90 (3H, multiplet);
[2220] 1.25-1.40 (20H, multiplet);
[2221] 1.60-1.70 (2H, multiplet);
[2222] 2.00 (3H, singlet);
[2223] 2.37 (2H, triplet, J=7.5 Hz);
[2224] 3.38 (3H, singlet);
[2225] 3.45 (1H, multiplet);
[2226] 4.10-4.40 (6H, multiplet);
[2227] 5.53 (1H, doublet, J=1.8 Hz).
EXAMPLE 30
5-Acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto--
non-2-enoic Acid Trifluoroacetic Acid Salt (Compound No. 199-1)
[2228] 47
[2229] 30(i) Benzyl
N-acetyl-3.6-di-O-benzyl-4-O-ethyl-.alpha.-D-glucosami- ne
[2230] 8.35 g (16.8 mmol) of benzyl
N-acetyl-3,6-di-O-benzyl-.alpha.-D-glu- cosamine [prepared
according to the procedure described in Carbohydrate Res. 8,
163-169 (1980)] were dissolved in 80 ml of dimethylformamide, and
1.84 g (42.2 mmol) sodium hydride were added to the resulting
solution. The mixture was then stirred at room temperature for 30
minutes, after which 2.86 g (18.5 mmol) of ethyl iodide were added
to the mixture at 0.degree. C., and the mixture was stirred at room
temperature for 5 hours. At the end of this time, the reaction
mixture was poured into a 2-layer solution of 200 ml of ethyl
acetate and 100 ml of a saturated aqueous solution of sodium
hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 4:1 by volume
mixture of methylene chloride and ethyl acetate as the eluent, to
obtain 7.0 g (yield 80%) of the title compound as a colorless
solid.
[2231] Rf=0.55 (20:1=methylene chloride:methanol).
[2232] [.alpha.].sub.D.sup.25=+123.degree. (c=2.3, CHCl.sub.3).
[2233] Mass Spectrum (FAB) m/e 520 (M.sup.++H).
[2234] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2235] 1.10 (3H, triplet, J=7.0 Hz);
[2236] 1.80 (3H, singlet);
[2237] 3.40-3.90 (7H, multiplet);
[2238] 4.21 (1H, doubled doublet of doublets, J=3.5, 10.0 &
10.0 Hz);
[2239] 4.40-4.90 (7H, multiplet);
[2240] 5.22 (1H, doublet, J=10.0 Hz);
[2241] 7.20-7.40 (15H, multiplet).
[2242] 30(ii) N-Acetyl-4-O-ethyl-.alpha.-D-glucosamine
[2243] 7.0 g (13.4 mmol) of benzyl
N-acetyl-3,6-di-O-benzyl-4-O-ethyl-.alp- ha.-D-glucosamine
[prepared as described in step (i) above] were dissolved in 60 ml
of acetic acid, and 10 g of palladium-on-carbon were added to the
resulting solution. The mixture was then stirred under hydrogen
atmosphere at 3 atmospheres pressure for 30 hours. At the end of
this time, the catalyst was separated by filtration, and the
solvent was removed by distillation under reduced pressure. The
resulting residue was purified by silica gel column chromatography,
using a gradient elution method, with mixtures of methylene
chloride and methanol ranging from 10:1 to 5:1 by volume as the
eluent, to obtain 2.4 g (yield 81%) of the title compound as a
colorless solid.
[2244] Rf=0.35 (5:1=methylene chloride:methanol).
[2245] [.alpha.].sub.D.sup.25=+66.1.degree. (c=2.1,
CH.sub.3OH).
[2246] Mass Spectrum (FAB) m/e 250 (M.sup.++H).
[2247] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[2248] 1.15 (3H, triplet, J=7.0 Hz);
[2249] 2.00 (3H, singlet);
[2250] 3.33 (2H, quartet, J=7.0 Hz);
[2251] 3.60-3.90 (6H, multiplet);
[2252] 5.15 (1H, singlet).
[2253] 30(iii)
5-Acetamido-3,5-dideoxy-7-O-ethyl-D-glycero-D-galacto-2-non-
uropyranosoic Acid
[2254] 5.0 g (20.1 mmol) of
N-acetyl-4-O-ethyl-.alpha.-D-glucosamine [prepared as described in
step (iii) above] were dissolved in distilled water, and 100 mg of
sodium azide and 5.0 g (45.5 mmol) of sodium pyruvate were added to
the resulting solution. The pH of the reaction mixture was adjusted
to a value of 10 to 11 using a 1 N aqueous solution of sodium
hydroxide, after which 25 mg (660U) of N-acetyl-neuraminic acid
aldolase (produced by TOYOBO K.K.) were added, and the mixture was
stirred at 20.degree. C. for 3 days. At the end of this time, the
reaction mixture was desalted using a Dowex 50x8 (H.sup.+) resin
(Dowex is a trade mark) and purified over chromatography using a
Dowex 1 (HCOOH) resin with a 1.0 M aqueous solution of formic acid
as the eluent, to obtain 500 mg (yield 7.4%) of the title compound
as a colorless viscous substance.
[2255] Rf=0.20 (4:1:1=isopropanol:acetic acid:water).
[2256] [.alpha.].sub.D.sup.25=-8.4.degree. (c=0.19,
CH.sub.3OH).
[2257] Mass Spectrum (FAB) m/e 338 (M.sup.++H).
[2258] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[2259] 1.05 (3H, triplet, J=7.0 Hz);
[2260] 1.80 (1H, doublet of doublets, J=12.0 & 12.0 Hz);
[2261] 2.00 (3H, singlet);
[2262] 2.20 (1H, doublet of doublets, J=4.5 & 12.0 Hz);
[2263] 3.50-3.80 (7H, multiplet).
[2264] 30(iv) Methyl
5-acetamido-3,5-dideoxy-7-O-ethyl-D-glycero-D-galacto-
-D-nonuropyranosoate
[2265] 1.9 g (5.64 mmol) of
5-acetamido-3,5-dideoxy-7-O-ethyl-D-glycero-D--
galacto-2-nonuropyranosoic acid [prepared as described in step
(iii) above] were dissolved in 60 ml of methanol, and 600 mg of a
cation exchange resin [Dowex 50x8 (H.sup.+)--Dowex is a trade mark]
were added to the resulting solution. The mixture was then stirred
at room temperature for 15 hours. At the end of this time, the
Dowex 50x8 (H.sup.+) was separated by filtration, and the solvent
was removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
5:1 by volume mixture of methylene chloride and methanol as the
eluent, to obtain 1.4 g (yield 71%) of the title compound as an
amorphous substance.
[2266] Rf=0.3 (5:1=methylene chloride:methanol).
[2267] [.alpha.].sub.D.sup.25=-7.5.degree. (c=0.10,
CHCl.sub.3).
[2268] Mass Spectrum (FAB) m/e 352 (M.sup.++H).
[2269] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2270] 1.17 (3H, triplet, J=7.0 Hz);
[2271] 1.95 (1H, doublet of doublets, J=12.0 & 14.0 Hz);
[2272] 2.00 (3H, singlet);
[2273] 2.16 (1H, doublet of doublets, J=4.5 & 12.0 Hz);
[2274] 3.42 (1H, doublet of doublets, J=1.5 & 8.0 Hz);
[2275] 3.60 (2H, quartet, J=7.0 Hz);
[2276] 3.77 (3H, singlet);
[2277] 3.70-4.00 (4H, multiplet);
[2278] 4.15 (1H, doublet of doublets, J=1.5 & 9.5 Hz).
[2279] 30(v) Methyl
5-acetamido-4,8,9,-tri-O-acetyl-2,3,5,7-tetradeoxy-7-e-
thoxy-D-glycero-D-galacto-non-2-enopyranosoate
[2280] 1.4 g (3.99 mmol) of methyl
5-acetamido-3,5-dideoxy-7-O-ethyl-D-gly-
cero-D-galacto-2-nonuropyranosoate [prepared as described in step
(iv) above] were dissolved in a mixture of 20 ml of pyridine and 10
ml of acetic anhydride, and the mixture was stirred at room
temperature for 15 hours. At the end of this time, the solvent was
removed by distillation under reduced pressure, and the residue was
dissolved in 50 ml of a 4 M solution of hydrogen chloride in
dioxane. The mixture was then stirred at room temperature for 15
hours. At the end of this time, the solvent was removed by
distillation under reduced pressure, and the residue was dissolved
in benzene. 952 mg (6.30 mmol) of 1,8-diazabicyclo[5.4.0]-7-und-
ecene were then added to the reaction mixture, and the mixture was
stirred at room temperature for 2 hours. At the end of this time,
the reaction mixture was poured into a 2-layer solution of 30 ml of
methylene chloride and 15 ml of a saturated aqueous ammonium
chloride solution, and the organic layer was separated and washed
with a saturated aqueous solution of sodium chloride. It was then
dried over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 1.1 g (yield 60%) of the title compound as a colorless
amorphous substance.
[2281] Rf=0.30 (20:1=methylene chloride:methanol).
[2282] [.alpha.].sub.D.sup.25=+24.1.degree. (c=0.5,
CHCl.sub.3).
[2283] Mass Spectrum (FAB) m/e 460 (M.sup.++H).
[2284] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2285] 1.20 (3H, triplet, J=7.0 Hz);
[2286] 1.98 (3H, singlet);
[2287] 2.05 (3H, singlet);
[2288] 2.08 (3H, singlet);
[2289] 3.50-3.80 (3H, multiplet);
[2290] 3.80 (3H, singlet);
[2291] 4.20-4.35 (2H, multiplet);
[2292] 4.45 (1H, multiplet);
[2293] 4.70 (1H, doublet of doublets, J=3.2 & 12.0 Hz);
[2294] 5.33 (1H, multiplet);
[2295] 5.47 (1H, doublet of doublets, J=3.3 & 7.0 Hz);
[2296] 5.51 (1H, doublet, J=7.0 Hz);
[2297] 6.00 (1H, doublet, J=3.3 Hz).
[2298] 30(vi) Methyl
5-acetamido-4-azido-8,9-di-O-acetyl-2,3,4,5,7-pentade-
oxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoate
[2299] 1000 mg (2.18 mmol) of methyl
5-acetamido-4,8,9,-tri-O-acetyl-2,3,5-
,7-tetradeoxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in step (v) above] were dissolved in 20 ml
of anhydrous methylene chloride, and 25 mg (0.78 mmol) of methanol
were added to the resulting solution, after which 3.1 g (21.8 mmol)
of a boron trifluoride-diethyl ether complex were added under a
nitrogen atmosphere, and the mixture was stirred at room
temperature for 24 hours. At the end of this time, the reaction
mixture was poured into a mixture of 50 ml of water, 10 g of ice,
10 g of solid sodium hydrogencarbonate and 50 ml of ethyl acetate,
and the mixture was vigorously stirred for 10 minutes. The organic
layer was then washed with 10 ml of a saturated aqueous solution of
sodium chloride and dried over anhydrous sodium sulfate, after
which the solvent was removed by distillation under reduced
pressure. The resulting residue (800 mg) was dissolved in 10 ml of
dimethylformamide, and 800 mg of a cation exchange resin [Dowex
50x8 (H.sup.+)--Dowex is a trade mark] and 400 mg (6.15 mmol) of
sodium azide were added. The mixture was then stirred at 90.degree.
C. for 4 hours. At the end of this time, the Dowex 50x8 (H.sup.+)
was separated by filtration, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
dissolved in a 2-layer solution of 30 ml of ethyl acetate and 20 ml
of a saturated aqueous solution of sodium hydrogencarbonate, and
the organic layer was separated and washed with a saturated aqueous
solution of sodium chloride. It was then dried over anhydrous
sodium sulfate, and the solvent was removed by distillation under
reduced pressure. The resulting residue was purified by silica gel
column chromatography, using a 50:1 by volume mixture of methylene
chloride and methanol as the eluent, to obtain 600 mg (yield 63%)
of the title compound as a colorless viscous substance.
[2300] Rf=0.30 (20:1=methylene chloride:methanol).
[2301] [.alpha.].sub.D.sup.25=+72.6.degree. (c=0.05,
CHCl.sub.3).
[2302] Mass Spectrum (FAB) m/e 443 M.sup.++H).
[2303] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2304] 1.25 (3H, triplet, J=7.0 Hz);
[2305] 2.09 (3H, singlet);
[2306] 2.10 (3H, singlet);
[2307] 2.13 (3H, singlet);
[2308] 3.50-3.80 (3H, multiplet);
[2309] 3.80 (3H, singlet);
[2310] 4.05 (1H, multiplet);
[2311] 4.25 (1H, doublet of doublets, J=5.0 & 12.0 Hz);
[2312] 4.45-4.55 (2H, multiplet);
[2313] 4.80 (1H, doublet of doublets, J=3.2 & 12.0 Hz);
[2314] 5.35 (1H, multiplet);
[2315] 5.51 (1H, doublet, J=8.2 Hz);
[2316] 6.00 (1H, doublet, J=2.7 Hz).
[2317] 30(vii) Methyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanidino)-8-
,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-galacto-non-2-enopy-
ranosoate
[2318] 580 mg (1.31 mmol) of methyl
5-acetamido-4-azido-8,9-di-O-acetyl-2,-
3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoate
[prepared as described in step (vi) above] were dissolved in 10 ml
of methanol, and 270 mg of a Lindlar catalyst were added to the
resulting solution. The mixture was then stirred under a hydrogen
atmosphere for 2 hours. At the end of this time, the catalyst was
separated by filtration, and the solvent was removed by
distillation under reduced pressure. The resulting residue (400 mg)
was dissolved in 10 ml of dimethylformamide, and 408 mg (1.48 mmol)
of N,N-di-t-butoxycarbonylthiourea, 300 mg(2.95 mmol) of
triethylamine and 402 mg (1.48 mmol) of mercuric chloride were
added to the resulting solution. The mixture was then stirred at
room temperature for 1 hour. At the end of this time, the solid was
separated by filtration and the filtrate was poured into a 2-layer
solution of 20 ml of ethyl acetate and 10 ml of a saturated aqueous
solution of sodium hydrogencarbonate. The organic layer was
separated, washed with a saturated aqueous solution of sodium
chloride and dried over anhydrous sodium sulfate, after which the
solvent was removed by distillation under reduced pressure. The
resulting residue was purified by silica gel column chromatography,
using a 2:1 by volume mixture of hexane and ethyl acetate as the
eluent, to obtain 530 mg (yield 61%) of the title compound as a
colorless amorphous substance.
[2319] Rf=0.40 (20:1=methylene chloride:methanol).
[2320] [.alpha.].sub.D.sup.25=+2.8.degree. (c=0.05,
CHCl.sub.3).
[2321] Mass Spectrum (FAB) m/e 659 (M.sup.++H).
[2322] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2323] 1.20 (3H, triplet, J=7.0 Hz);
[2324] 1.49 (9H, singlet);
[2325] 1.50 (9H, singlet);
[2326] 1.95 (3H, singlet);
[2327] 2.06 (3H, singlet);
[2328] 2.09 (3H, singlet);
[2329] 3.50-3.80 (3H, multiplet);
[2330] 3.80 (3H, singlet);
[2331] 4.10 (1H, doublet of doublets, J=1.0 & 10.5 Hz);
[2332] 4.25-4.40 (2H, multiplet);
[2333] 4.80 (1H, doublet of doublets, J=3.2 & 12.0 Hz);
[2334] 5.10 (1H, doubled doublet of doublets, J=2.5, 11.0 &
11.0 Hz);
[2335] 5.30 (1H, multiplet);
[2336] 5.83 (1H, doublet, J=2.3 Hz);
[2337] 6.20 (1H, doublet, J=8.8 Hz).
[2338] 30(viii)
5-Acetamido-4-guanidino-2,3,4,5,7-pentadeoxy-7-ethoxy-D-gl-
ycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt
[2339] 50 mg (0.076 mmol) of methyl
5-acetamido-4-(N,N-bis-t-butoxycarbony-
lguanidino)-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-gala-
cto-non-2-enopyranosoate [prepared as described in step (vii)
above] were dissolved in 2 ml of methanol, and 0.2 ml of a 0.1 N
methanolic solution of sodium methoxide was added to the resulting
solution. The mixture was then stirred at room temperature for 1
hour. At the end of this time, the reaction mixture was neutralized
with a 4 M solution of hydrogen chloride in dioxane, and the
solvent was removed by distillation under reduced pressure. The
resulting residue was dissolved in 3 ml of a 3:1 by volume mixture
of methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was dissolved in 1 ml of distilled water. 110 .mu.l of
a 1 N aqueous solution of sodium hydroxide were then added to the
reaction mixture, which was then stirred at room temperature for 1
hour. At the end of this time, the reaction mixture was neutralized
with a Dowex 50x8 (H.sup.+) resin (Dowex is a trade mark), and then
the water was removed by distillation. The resulting residue was
purified by silica gel column chromatography, using a 5:1:1 by
volume mixture of isopropanol, ethyl acetate and water as the
eluent, to obtain 27 mg (yield 75%) of the title compound as a
colorless solid.
[2340] Rf=0.30 (4:1:1=isopropanol:acetic acid:water).
[2341] [.alpha.].sub.D.sup.25=+32.5.degree. (c=0.1,
CH.sub.3OH).
[2342] Mass Spectrum (FAB) m/e 361 (M.sup.++H).
[2343] .sup.1H-Nuclear Magnetic Resonance Spectrum (D.sub.2O, 270
MHz) .delta. (ppm):
[2344] 1.05 (3H, triplet, J=7.0 Hz);
[2345] 1.97 (3H, singlet);
[2346] 3.40 (1H, multiplet);
[2347] 3.50-3.65 (3H, multiplet);
[2348] 3.80 (1H, doublet of doublets, J=5.0 & 12 Hz);
[2349] 3.90 (1H, multiplet);
[2350] 4.15 (1H, doublet of doublets, J=10 & 10 Hz);
[2351] 4.40-4.50 (2H, multiplet);
[2352] 5.55 (1H, doublet, J=1.8 Hz).
EXAMPLE 31
5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glyce-
ro-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 199-38)
[2353] 48
[2354] 31(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoat-
e
[2355] 495 mg (0.75 mmol) of methyl
5-acetamido-4-(N,N'-bis-t-butoxycarbon-
ylguanidino)-8,9-di-O-acetyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-gal-
acto-non-2-enopyranosoate [prepared as described in Example
30(vii)] were dissolved in 10 ml of methanol, and 2 ml of a 0.1 N
methanolic solution of sodium methoxide were added to the resulting
solution. The mixture was then stirred at room temperature for 1
hour. At the end of this time, the reaction mixture was neutralized
with a 4 M solution of hydrogen chloride in dioxane, and the
solvent was removed by distillation under reduced pressure. The
resulting residue was dissolved in 10 ml of distilled water, and
1.0 ml of a 1 N aqueous solution of sodium hydroxide was added
thereto. The mixture was then stirred at room temperature for 1
hour. At the end of this time, the reaction mixture was neutralized
with a 4 M solution of hydrogen chloride in dioxane, and then the
water was removed by distillation. The resulting residue was
dissolved in a 6:1 by volume mixture of methanol and methylene
chloride, and 500 mg (2.60 mmol) of diphenyldiazomethane and 50 mg
(0.38 mmol) of a boron trifluoride-diethyl ether complex were added
to the resulting solution. The mixture was then stirred at room
temperature for 2 hours, after which acetic acid was added thereto,
and the solvent was removed by distillation under reduced pressure.
The resulting residue was purified by silica gel column
chromatography, using a 20:1 by volume mixture of methylene
chloride and methanol as the eluent, to obtain 450 mg (yield 82%)
of the title compound as a colorless amorphous substance.
[2356] Rf=0.25 (10:1=methylene chloride:methanol).
[2357] [.alpha.].sub.D.sup.25=-10.7.degree. (c=0.13,
CHCl.sub.3).
[2358] Mass Spectrum (FAB) m/e 727 (M.sup.++H).
[2359] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2360] 1.20 (3H, triplet, J=7.0 Hz);
[2361] 1.48 (9H, singlet);
[2362] 1.50 (9H, singlet);
[2363] 1.95 (3H, singlet);
[2364] 3.60-4.10 (6H, multiplet);
[2365] 4.30-4.50 (2H, multiplet);
[2366] 5.10 (1H, multiplet);
[2367] 5.95 (1H, doublet, J=2.7 Hz);
[2368] 6.55 (1H, doublet, J=8.0 Hz);
[2369] 6.95 (1H, singlet);
[2370] 7.20-7.50 (10H, multiplet);
[2371] 8.50 (1H, doublet, J=8.5 Hz).
[2372] 31(ii) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguani-
dino)-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-2-
-enopyranosoate
[2373] 30 mg (0.041 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in step (i) above] were
dissolved in 2 ml of methylene chloride, and 6 mg (0.06 mmol) of
triethylamine and 8 mg (0.05 mmol) of octanoyl chloride were added
to the resulting solution, whilst ice-cooling. The mixture was then
stirred at 0.degree. C. for 1 hour. At the end of this time, the
reaction mixture was poured into a 2-layer solution of 5 ml of
ethyl acetate and 3 ml of a saturated aqueous solution of sodium
hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 24 mg (yield 69%) of the title compound as a colorless
amorphous substance.
[2374] Rf=0.30 (20:1=methylene chloride:methanol).
[2375] [.alpha.].sub.D.sup.25-14.0.degree. (c=0.05,
CHCl.sub.3).
[2376] Mass Spectrum (FAB) m/e 854 (M.sup.++H).
[2377] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2378] 0.85 (3H, multiplet);
[2379] 1.20 (3H, triplet, J=7.0 Hz);
[2380] 1.20-1.30 (8H, multiplet);
[2381] 1.48 (9H, singlet);
[2382] 1.50 (9H, singlet);
[2383] 1.55-1.70 (2H, multiplet);
[2384] 1.95 (3H, singlet);
[2385] 2.33 (2H, triplet, J=7.5 Hz);
[2386] 3.50 (1H, triplet, J=5.5 Hz);
[2387] 3.59 (2H, quartet, J=7.0 Hz);
[2388] 4.10-4.50 (5H, multiplet);
[2389] 5.10 (1H, doubled doublet of doublets, J=2.4, 9.0 & 9.0
Hz);
[2390] 5.95 (1H, doublet, J=2.3 Hz);
[2391] 6.10 (1H, doublet, J=8.7 Hz);
[2392] 6.94 (1H, singlet);
[2393] 7.20-7.50 (10H, multiplet);
[2394] 8.55 (1H, doublet, J=8.7 Hz).
[2395] 31(iii)
5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-
-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[2396] 20 mg (0.023 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero--
D-galacto-non-2-enopyranosoate [prepared as described in step (ii)
above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 10 mg (yield 73%) of the title compound as
a colorless solid.
[2397] Rf=0.3 (2:5:1=isopropanol:ethyl acetate:water).
[2398] [.alpha.].sub.D.sup.25=+55.degree. (c=0.10, CH.sub.3OH).
[2399] Mass Spectrum (FAB) m/e 487 (M.sup.++H).
[2400] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta.(ppm):
[2401] 0.90 (3H, multiplet);
[2402] 1.15 (3H, triplet, J=7.0 Hz);
[2403] 1.20-1.40 (8H, multiplet);
[2404] 1.55-1.70 (2H, multiplet);
[2405] 2.00 (3H, singlet);
[2406] 2.35 (2H, triplet, J=7.5 Hz);
[2407] 3.45-3.60 (3H, multiplet);
[2408] 4.10-4.40 (6H, multiplet);
[2409] 5.53 (1H, doublet, J=1.8 Hz).
EXAMPLE 32
5-Acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-gly-
cero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 199-40)
[2410] 49
[2411] 32(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non--
2-enopyranosoate
[2412] 30 mg (0.041 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-ethoxy-2-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 31(i)] were
dissolved in 2 ml of methylene chloride, and 6 mg (0.06 mmol) of
triethylamine and 11 mg (0.05 mmol) of dodecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 29 mg (yield 78%) of the title compound as a colorless
amorphous substance.
[2413] Rf=0.35 (20:1=methylene chloride:methanol).
[2414] [.alpha.].sub.D.sup.25=-9.0.degree. (c=0.1, CHCl.sub.3).
[2415] Mass Spectrum (FAB) m/e 910 (M.sup.++H).
[2416] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2417] 0.85 (3H, multiplet);
[2418] 1.20 (3H, triplet, J=7.0 Hz);
[2419] 1.20-1.30 (16H, multiplet);
[2420] 1.48 (9H, singlet);
[2421] 1.50 (9H, singlet);
[2422] 1.55-1.70 (2H, multiplet);
[2423] 1.95 (3H, singlet);
[2424] 2.33 (2H, triplet, J=7.5 Hz);
[2425] 3.50 (1H, triplet, J=5.5 Hz);
[2426] 3.59 (2H, quartet, J=7.0 Hz);
[2427] 4.10-4.50 (5H, multiplet);
[2428] 5.10 (1H, doubled doublet of doublets, J=2.4, 9.0 & 9.0
Hz);
[2429] 5.95 (1H, doublet, J=2.3 Hz);
[2430] 6.10 (1H, doublet, J=8.7 Hz);
[2431] 6.94 (1H, singlet);
[2432] 7.20-7.50 (10H, multiplet);
[2433] 8.55 (1H, doublet, J=8.7 Hz).
[2434] 32(ii)
5-Acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy--
7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[2435] 28 mg (0.03 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-
-D-galacto-non-2-enopyranosoate [prepared as described in step (i)
above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 12 mg (yield 61%) of the title compound as
a colorless solid.
[2436] Rf=0.3 (2:5:1=isopropanol:ethyl acetate:water).
[2437] [.alpha.].sub.D.sup.25=+50.degree. (c=0.05, CH.sub.3OH).
[2438] Mass Spectrum (FAB) m/e 543 (M.sup.++H).
[2439] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2440] 0.90 (3H, multiplet);
[2441] 1.15 (3H, triplet, J=7.0 Hz);
[2442] 1.20-1.40 (16H, multiplet);
[2443] 1.55-1.70 (2H, multiplet);
[2444] 2.00 (3H, singlet);
[2445] 2.35 (2H, triplet, 3 7.5 Hz);
[2446] 3.45-3.60 (3H, multiplet);
[2447] 4.10-4.40 (6H, multiplet);
[2448] 5.53 (1H, doublet, J=1.8 Hz).
EXAMPLE 33
5-Acetamido-4-guanidino-9-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D--
glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt (Compound No. 199-41)
[2449] 50
[2450] 33(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-n-
on-2-enopyranosoate
[2451] 30 mg (0.041 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-ethoxy-2-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 31(i)] were
dissolved in 2 ml of methylene chloride, and 6 mg (0.06 mmol) of
triethylamine and 12 mg (0.05 mmol) of tetradecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 30 mg (yield 78%) of the title compound as a colorless
amorphous substance.
[2452] Rf=0.35 (20:1=methylene chloride:methanol).
[2453] [.alpha.].sub.D.sup.25=-8.0.degree. (c=0.1, CHCl.sub.3).
[2454] Mass Spectrum (FAB) m/e 938 (M.sup.++H).
[2455] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2456] 0.85 (3H, multiplet);
[2457] 1.20 (3H, triplet, J=7.0 Hz);
[2458] 1.20-1.30 (20H, multiplet);
[2459] 1.48 (9H, singlet);
[2460] 1.50 (9H, singlet);
[2461] 1.55-1.70 (2H, multiplet);
[2462] 1.95 (3H, singlet);
[2463] 2.33 (2H, triplet, J=7.5 Hz);
[2464] 3.50 (1H, triplet, J=5.5 Hz);
[2465] 3.59 (2H, quartet, J=7.0 Hz);
[2466] 4.10-4.50 (5H, multiplet);
[2467] 5.10 (1H, doubled doublet of doublets, J=2.4, 9.0 & 9.0
Hz);
[2468] 5.95 (1H, doublet, J=2.3 Hz);
[2469] 6.10 (1H, doublet, J=8.7 Hz);
[2470] 6.94 (1H, singlet);
[2471] 7.20-7.50 (10H, multiplet);
[2472] 8.55 (1H, doublet, J=8.7 Hz).
[2473] 33(i)
5-Acetamido-4-guanidino-9-O-tetradecanoyl-2,3,4,5,7-pentadeox-
y-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[2474] 28 mg (0.03 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-9-O-tetradecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 13 mg (yield 74%) of the title compound as
a colorless solid.
[2475] Rf=0.3 (2:5:1=isopropanol:ethyl acetate:water).
[2476] [.alpha.].sub.D.sup.25=+38.0.degree. (c=0.05,
CH.sub.3OH).
[2477] Mass Spectrum (FAB) m/e 571 (M.sup.++H).
[2478] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2479] 0.90 (3H, multiplet);
[2480] 1.15 (3H, triplet, J=7.0 Hz);
[2481] 1.20-1.40 (20H, multiplet);
[2482] 1.55-1.70 (2H, multiplet);
[2483] 2.00 (3H, singlet);
[2484] 2.35 (2H, triplet, J=7.5 Hz);
[2485] 3.45-3.60 (3H, multiplet);
[2486] 4.10-4.40 (6H, multiplet);
[2487] 5.53 (1H, doublet, J=1.8 Hz).
EXAMPLE 34
5-Acetamido-4-guanidino-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-g-
lycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 199-42)
[2488] 51
[2489] 34(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-no-
n-2-enopyranosoate
[2490] 30 mg (0.041 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 31(i)] were
dissolved in 2 ml of methylene chloride, and 6 mg (0.06 mmol) of
triethylamine and 14 mg (0.05 mmol) of hexadecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 31 mg (yield 78%) of the title compound as a colorless
amorphous substance.
[2491] Rf=0.35 (20:1=methylene chloride:methanol).
[2492] [.alpha.].sub.D.sup.25=-7.5.degree. (c=0.1, CHCl.sub.3).
[2493] Mass Spectrum (FAB) m/e 966 (M.sup.++H).
[2494] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2495] 0.85 (3H, multiplet);
[2496] 1.20 (3H, triplet, J=7.0 Hz);
[2497] 1.20-1.30 (24H, multiplet);
[2498] 1.48 (9H, singlet);
[2499] 1.50 (9H, singlet);
[2500] 1.55-1.70 (2H, multiplet);
[2501] 1.95 (3H, singlet);
[2502] 2.33 (2H, triplet, J=7.5 Hz);
[2503] 3.50 (1H, triplet, J=5.5 Hz);
[2504] 3.59 (2H, quartet, J=7.0 Hz);
[2505] 4.10-4.50 (5H, multiplet);
[2506] 5.10 (1H, doubled doublet of doublets, J=2.4, 9.0 & 9.0
Hz);
[2507] 5.95 (1H, doublet, J=2.3 Hz);
[2508] 6.10 (1H, doublet, J=8.7 Hz);
[2509] 6.94 (1H, singlet);
[2510] 7.20-7.50 (10H, multiplet);
[2511] 8.55 (1H, doublet, J=8.7 Hz).
[2512] 34(iii)
-Acetamido-4-guanidino-9-O-hexadecanoyl-2,3,4,5,7-pentadeox-
y-7-ethoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid Salt
[2513] 28 mg (0.029 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-ethoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours.
[2514] At the end of this time, the solvent was removed by
distillation under reduced pressure, and the residue was purified
by silica gel column chromatography, using a 2:5:1 by volume
mixture of isopropanol, ethyl acetate and water as the eluent, to
obtain 12 mg (yield 58%) of the title compound as a colorless
solid.
[2515] Rf=0.3 (2:5:1=isopropanol:ethyl acetate water).
[2516] [.alpha.].sub.D.sup.25=+30.0.degree. (c=0.1,
CH.sub.3OH).
[2517] Mass Spectrum (FAB) m/e 599 (M.sup.++H).
[2518] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2519] 0.90 (3H, multiplet);
[2520] 1.15 (3H, triplet, J=7.0 Hz);
[2521] 1.20-1.40 (24H, multiplet);
[2522] 1.55-1.70 (2H, multiplet);
[2523] 2.00 (3H, singlet);
[2524] 2.35 (2H, triplet, J=7.5 Hz);
[2525] 3.45-3.60 (3H, multiplet);
[2526] 4.10-4.40 (6H, multiplet);
[2527] 5.53 (1H, doublet, J=1.8 Hz).
EXAMPLE 35
5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 163-38)
[2528] 52
[2529] 35(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-O-octanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-e-
nopyranosoate
[2530] 57 mg (0.08 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 29(i)] were
dissolved in 2 ml of methylene chloride, and 11 mg (0.10 mmol) of
triethylamine and 16 mg (0.09 mmol) of octanoyl chloride were added
to the resulting solution, whilst ice-cooling. The mixture was then
stirred at 0.degree. C. for 1 hour. At the end of this time, the
reaction mixture was poured into a 2-layer solution of 5 ml of
ethyl acetate and 3 ml of a saturated aqueous solution of sodium
hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 38 mg (yield 58%) of the title compound as a colorless
amorphous substance.
[2531] Rf=0.5 (10:1=methylene chloride:methanol).
[2532] [.alpha.].sub.D.sup.25=+2.7.degree. (c=0.11,
CHCl.sub.3).
[2533] Mass Spectrum (FAB) m/e 839 (M.sup.++H).
[2534] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2535] 0.85 (3H, multiplet);
[2536] 1.20-1.30 (8H, multiplet);
[2537] 1.48 (9H, singlet);
[2538] 1.50 (9H, singlet);
[2539] 1.55-1.70 (2H, multiplet);
[2540] 1.98 (3H, singlet);
[2541] 2.33 (2H, triplet, J=7.5 Hz);
[2542] 3.40 (1H, multiplet);
[2543] 3.48 (3H, singlet);
[2544] 4.10-4.50 (5H, multiplet);
[2545] 5.18 (1H, doubled doublet of doublets, J=2.4, 9.0 & 9.0
Hz);
[2546] 5.95 (1H, doublet, J=2.3 Hz);
[2547] 6.18 (1H, doublet, J=8.7 Hz);
[2548] 6.92 (1H, singlet);
[2549] 7.20-7.50 (10H, multiplet);
[2550] 8.55 (1H, doublet, J=8.7 Hz).
[2551] 35(ii)
5-Acetamido-4-guanidino-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7--
methoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid
[2552] 31 mg (0.037 mmol) of diphenylmethyl
5-acetamido-44,N-bis-t-butoxyc-
arbonylguanidino)-9-O-octanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D--
galacto-non-2-enopyranosoate [prepared as described in step (i)
above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:1 by volume mixture of isopropanol, ethyl acetate and water as
the eluent, to obtain 15 mg (yield 69%) of the title compound as a
colorless solid.
[2553] Rf=0.34 (2:5:1=isopropanol:ethyl acetate:water).
[2554] [.alpha.].sub.D.sup.25=+38.2.degree. (c=0.11,
CH.sub.3OH)
[2555] Mass Spectrum (FAB) m/e 473 (M.sup.++H)
[2556] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2557] 0.90 (3H, multiplet);
[2558] 1.25-1.40 (8H, multiplet);
[2559] 1.60-1.70 (2H, multiplet);
[2560] 2.00 (3H, singlet);
[2561] 2.37 (2H, triplet, J=7.5 Hz);
[2562] 3.38 (3H, singlet);
[2563] 3.45 (1H, multiplet);
[2564] 4.10-4.40 (6H, multiplet);
[2565] 5.53 (1H, doublet, J=1.8 Hz).
EXAMPLE 36
5-Acetamido-4-guanidino-9-O-decanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glyc-
ero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 163-39)
[2566] 53
[2567] 36(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-decanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-2-
-enopyranosoate
[2568] 56 mg (0.08 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 29(i)] were
dissolved in 2 ml of methylene chloride, and 11 mg (0.10 mmol) of
triethylamine and 18 mg (0.09 mmol) of decanoyl chloride were added
to the resulting solution, whilst ice-cooling. The mixture was then
stirred at 0.degree. C. for 1 hour. At the end of this time, the
reaction mixture was poured into a 2-layer solution of 5 ml of
ethyl acetate and 3 ml of a saturated aqueous solution of sodium
hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 40 mg (yield 50%) of the title compound as a colorless
amorphous substance.
[2569] Rf=0.5 (10:1=methylene chloride:methanol).
[2570] [.alpha.].sub.D.sup.25=+13.9.degree. (c=0.11,
CHCl.sub.3)
[2571] Mass Spectrum (FAB) m/e 867 (M.sup.++H)
[2572] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2573] 0.85 (3H, multiplet);
[2574] 1.20-1.30 (12H, multiplet);
[2575] 1.48 (9H, singlet);
[2576] 1.50 (9H, singlet);
[2577] 1.55-1.70 (2H, multiplet);
[2578] 1.98 (3H, singlet);
[2579] 2.33 (2H, triplet, J=7.5 Hz);
[2580] 3.40 ( (H, multiplet);
[2581] 3.48 (3H, singlet);
[2582] 4.10-4.50 (5H, multiplet);
[2583] 5.18 (1H, doubled doublet of doublets, J=2.4, 9.0 & 9.0
Hz);
[2584] 5.95 (1H, doublet, J=2.3 Hz);
[2585] 6.18 (1H, doublet, J=8.7 Hz);
[2586] 6.92 (3H, singlet);
[2587] 7.20-7.50 (10H, multiplet);
[2588] 8.55 (1H, doublet, J=8.7 Hz).
[2589] 36(ii)
5-Acetamido-4-guanidino-9-O-decanoyl-2,3,4,5,7-pentadeoxy-7--
methoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid
[2590] 33 mg (0.04 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-9-O-decanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero--
D-galacto-non-2-enopyranosoate [prepared as described in Example
36(i)] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 20 mg (yield 85%) of the title compound as
a colorless solid.
[2591] Rf=0.34 (2:5:1=isopropanol:ethyl acetate:water).
[2592] [.alpha.].sub.D.sup.25=+33.3.degree. (c=0.11,
CH.sub.3OH).
[2593] Mass Spectrum (FAB) m/e 501 (M.sup.++H)
[2594] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2595] 0.90 (3H, multiplet);
[2596] 1.25-1.40 (12H, multiplet);
[2597] 1.60-1.70 (2H, multiplet);
[2598] 2.00 (3H, singlet);
[2599] 2.37 (2H, triplet, J=7.5 Hz);
[2600] 3.38 (3H, singlet);
[2601] 3.45 (1H, multiplet);
[2602] 4.10-4.40 (6H, multiplet);
[2603] 5.53 (1H, doublet, J=1.8 Hz).
EXAMPLE 37
5-Acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-gl-
ycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(Compound No. 163-40)
[2604] 54
[2605] 37(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-
-2-enopyranosoate
[2606] 51 mg (0.07 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 29(i)] were
dissolved in 2 ml of methylene chloride, and 9 mg (0.09 mmol) of
triethylamine and 19 mg (0.09 mmol) of dodecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was washed with a
saturated aqueous solution of sodium chloride. It was then dried
over anhydrous sodium sulfate, and the solvent was removed by
distillation under reduced pressure. The resulting residue was
purified by silica gel column chromatography, using a 50:1 by
volume mixture of methylene chloride and methanol as the eluent, to
obtain 39 mg (yield 61%) of the title compound as a colorless
amorphous substance.
[2607] Rf=0.6 (20:1=methylene chloride:methanol).
[2608] [.alpha.].sub.D.sup.25=+2.4.degree. (c=0.13, CHCl.sub.3)
[2609] Mass Spectrum (FAB) m/e 895 (M.sup.++H)
[2610] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2611] 0.85 (3H, multiplet);
[2612] 1.20-1.30 (16H, multiplet);
[2613] 1.48 (9H, singlet);
[2614] 1.50 (9H, singlet);
[2615] 1.55-1.70 (2H, multiplet);
[2616] 1.98 (3H, singlet);
[2617] 2.33 (2H, triplet, J=7.5 Hz);
[2618] 3.40 (1H, multiplet);
[2619] 3.48 (3H, singlet);
[2620] 4.10-4.50 (5H, multiplet);
[2621] 5.18 (1H, doubled doublet of doublets, J=2.4, 9.0 & 9.0
Hz);
[2622] 5.95 (1H, doublet, J=2.3 Hz);
[2623] 6.18 (1H, doublet, J=8.7 Hz);
[2624] 6.92 (1H, singlet);
[2625] 7.20-7.50 (10H, multiplet);
[2626] 8.55 (1H, doublet, J=8.7 Hz).
[2627] 37(ii)
5-Acetamido-4-guanidino-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy--
7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid
[2628] 31 mg (0.035 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-9-O-dodecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glyce-
ro-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 22 mg (yield 98%) of the title compound as
a colorless solid.
[2629] Rf=0.31 (2:5:1=isopropanol:ethyl acetate:water).
[2630] [.alpha.].sub.D.sup.25=+25.8.degree. (c=0.16,
CH.sub.3OH).
[2631] Mass Spectrum (FAB) m/e 529 (M.sup.++H).
[2632] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2633] 0.90 (3H, multiplet);
[2634] 1.25-1.40 (16H, multiplet);
[2635] 1.60-1.70 (2H, multiplet);
[2636] 2.00 (3H, singlet);
[2637] 2.37 (2H, triplet, J=7.5 Hz);
[2638] 3.38 (3H, singlet);
[2639] 3.45 (1H, multiplet);
[2640] 4.10-4.40 (6H, multiplet);
[2641] 5.53 (1H, doublet, J=1.8 Hz).
EXAMPLE 38
5-Acetamido-4-guanidino-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D--
glycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid
Salt (Compound No. 163-42)
[2642] 55
[2643] 38(i) Diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butoxycarbonylguanid-
ino)-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-n-
on-2-enopyranosoate
[2644] 50 mg (0.07 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-butox-
ycarbonylguanidino)-2,3,4,5,7-pentadeoxy-7-methoxy-D-glycero-D-galacto-non-
-2-enopyranosoate [prepared as described in Example 29(i)] were
dissolved in 2 ml of methylene chloride, and 9 mg (0.09 mmol) of
triethylamine and 23 mg (0.084 mmol) of hexadecanoyl chloride were
added to the resulting solution, whilst ice-cooling. The mixture
was then stirred at 0.degree. C. for 1 hour. At the end of this
time, the reaction mixture was poured into a 2-layer solution of 5
ml of ethyl acetate and 3 ml of a saturated aqueous solution of
sodium hydrogencarbonate, and the organic layer was separated and
washed with a saturated aqueous solution of sodium chloride. It was
then dried over anhydrous sodium sulfate, and the solvent was
removed by distillation under reduced pressure. The resulting
residue was purified by silica gel column chromatography, using a
50:1 by volume mixture of methylene chloride and methanol as the
eluent, to obtain 40 mg (yield 60%) of the title compound as a
colorless amorphous substance.
[2645] Rf=0.6 (10:1=methylene chloride:methanol).
[2646] [.alpha.].sub.D.sup.25=+5.5.degree. (c=0.11,
CHCl.sub.3).
[2647] Mass Spectrum (FAB) m/e 951 (M.sup.++H).
[2648] .sup.1H-Nuclear Magnetic Resonance Spectrum (CDCl.sub.3, 270
MHz) .delta. (ppm):
[2649] 0.85 (3H, multiplet);
[2650] 1.20-1.30 (24H, multiplet);
[2651] 1.48 (9H, singlet);
[2652] 1.50 (9H, singlet);
[2653] 1.55-1.70 (2H, multiplet);
[2654] 1.98 (3H, singlet);
[2655] 2.33 (2H, triplet, J=7.5 Hz);
[2656] 3.40 (1H, multiplet);
[2657] 3.48 (3H, singlet);
[2658] 4.10-4.50 (5H, multiplet);
[2659] 5.18 (1H, doubled doublet of doublets, J=2.4, 9.0 & 9.0
Hz);
[2660] 5.95 (1H, doublet, J=2.3 Hz);
[2661] 6.18 (1H, doublet, J=8.7 Hz);
[2662] 6.92 (1H, singlet);
[2663] 7.20-7.50 (10H, multiplet);
[2664] 8.55 (1H, doublet, J=8.7 Hz).
[2665] 38(ii)
5-Acetamido-4-guanidino-9-O-hexadecanoyl-2,3,4,5,7-pentadeox-
y-7-methoxy-D-glycero-D-galacto-non-2-enopyranosoic Acid
Trifluoroacetic Acid
[2666] 34 mg (0.036 mmol) of diphenylmethyl
5-acetamido-4-(N,N'-bis-t-buto-
xycarbonylguanidino)-9-O-hexadecanoyl-2,3,4,5,7-pentadeoxy-7-methoxy-D-gly-
cero-D-galacto-non-2-enopyranosoate [prepared as described in step
(i) above] were dissolved in 3 ml of a 3:1 by volume mixture of
methylene chloride and trifluoroacetic acid, and the mixture was
stirred at room temperature for 5 hours. At the end of this time,
the solvent was removed by distillation under reduced pressure, and
the residue was purified by silica gel column chromatography, using
a 2:5:1 by volume mixture of isopropanol, ethyl acetate and water
as the eluent, to obtain 23 mg (yield 92%) of the title compound as
a colorless solid.
[2667] Rf=0.47 (2:5:1=isopropanol:ethyl acetate:water).
[2668] [.alpha.].sub.D.sup.25=+21.6.degree. (c=0.12,
CH.sub.3OH).
[2669] Mass Spectrum (FAB) m/e 585 (M.sup.++H).
[2670] .sup.1H-Nuclear Magnetic Resonance Spectrum (CD.sub.3OD, 270
MHz) .delta. (ppm):
[2671] 0.90 (3H, multiplet);
[2672] 1.25-1.40 (24H, multiplet);
[2673] 1.60-1.70 (2H, multiplet);
[2674] 2.00 (3H, singlet);
[2675] 2.37 (2H, triplet, J=7.5 Hz);
[2676] 3.38 (3H, singlet);
[2677] 3.45 (1H, multiplet);
[2678] 4.10-4.40 (6H, multiplet);
[2679] 5.53 (1H, doublet, J=1.8 Hz).
[2680] The present inventors found that acyl derivatives of the
hydroxyl group at the 7- and 8- positions and/or the 9-position and
ester derivatives of the carboxyl group at the 1-position of
Compound A (GG-167) described in WO91/16320 (Japanese PCT
Application (Kokai) No. Hei 5-507068) exhibit excellent in vivo
viral replication inhibitory activity and sialidase inhibitory
activity similar to Compound A, while also exhibiting infection
therapeutic effects superior to Compound A when administered to
mice infected with influenza virus, therefore being useful as an
anti-influenza drug, and they accomplished the present invention.
Therefore, in a further embodiment of the invention wherein formula
I is in the ester form, the neuraminic acid of the present
invention has the formula: 56
[2681] [wherein R.sup.1 represents an alkyl group having from 1 to
4 carbon atoms which may be substituted with a halogen atom;
R.sup.2, R.sup.3 and R.sup.4 are the same or different and each
represents a hydrogen atom or an aliphatic acyl group having from 3
to 25 carbon atoms, and W represents a hydrogen atom or an ester
residue, provided that the case where R.sup.1 is a methyl group and
each of R.sup.2, R.sup.3, R.sup.4 and W is a hydrogen atom is
excluded].
[2682] In the above general formula (1):
[2683] "The alkyl group having from 1 to 4 carbon atoms" of "the
alkyl group having from 1 to 4 carbon atoms which may be
substituted with a halogen atom" of R.sup.1 includes, for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl and
tert-butyl groups, preferably a methyl group.
[2684] "The halogen atom" of "the alkyl group having from 1 to 4
carbon atoms which may be substituted with a halogen atom" of
R.sup.1 includes, for example, fluorine, chlorine and bromine
atoms, preferably a fluorine atom.
[2685] "The alkyl group having from 1 to 4 carbon atoms substituted
with a halogen atom" of "the alkyl group having from 1 to 4 carbon
atoms which may be substituted with a halogen atom" of R.sup.1
includes, for example, monofluoromethyl, difluoromethyl,
trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 1-fluoropropyl,
2-fluoropropyl, 3-fluoropropyl, 4-fluorobutyl, monochloromethyl,
dichloromethyl, trichloromethyl, 1-chloroethyl, 2-chloroethyl,
1-chloropropyl, 2-chloropropyl, 3-chloropropyl, 4-chlorobutyl,
monobromomethyl, 1-bromoethyl, 2-bromoethyl, 1-bromopropyl,
2-bromopropyl, 3-bromopropyl, 4-bromobutyl and fluorochloromethyl
groups, preferably a methyl group substituted with a fluorine atom,
more preferably monofluoromethyl and difluoromethyl groups.
[2686] Therefore, "the alkyl group having from 1 to 4 carbon atoms
which may be substituted with a halogen atom" of R.sup.1 as a whole
includes preferably a methyl group which may be substituted with a
fluorine atom, more preferably methyl, monofluoromethyl and
difluoromethyl groups, most preferably a methyl group,
[2687] "The aliphatic acyl group having from 3 to 25 carbon atoms"
of R.sup.2, R.sup.3 and R.sup.4 includes, for example, an
alkylcarbonyl group such as propionyl, butyryl, isobutyryl,
pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonylcarbonyl,
decylcarbonyl, 3-methylnonylcarbonyl, 8-methylnonylcarbonyl,
3-ethyloctylcarbonyl, 3,7-dimethyloctylcarbonyl, undecylcarbonyl,
dodecylcarbonyl, tridecylcarbonyl, tetradecylcarbonyl,
pentadecylcarbonyl, hexadecylcarbonyl, 1-methylpentadecylcarbonyl,
14-methylpentadecylcarbony- l, 13,13-dimethyltetradecylcarbonyl,
heptadecylcarbonyl, 15-methylhexadecylcarbonyl, octadecylcarbonyl,
1-methylheptadecylcarbonyl- , nonadecylcarbonyl, eicosylcarbonyl,
tricosylcarbonyl and tetracosylcarbonyl, preferably an aliphatic
acyl group having from 6 to 25 carbon atoms, more preferably an
aliphatic acyl group having from 6 to 20 carbon atoms, particularly
preferably a hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl,
palmitoyl or stearoyl group.
[2688] R.sup.2, R.sup.3 and R.sup.4 as a whole each are preferably
a hydrogen atom or an aliphatic acyl group having from 6 to 25
carbon atoms, more preferably a hydrogen atom or an aliphatic acyl
group having from 6 to 20 carbon atoms, particularly preferably a
hydrogen atom or a hexanoyl, octanoyl, decanoyl, dodecanoyl,
myristoyl, palmitoyl or stearoyl group.
[2689] As the combination of R.sup.2, R.sup.3 and R.sup.4,
[2690] (a) the combination wherein R.sup.2 is an aliphatic acyl
group having from 3 to 25 carbon atoms (preferably an aliphatic
acyl group having from 6 to 25 carbon atoms, more preferably an
aliphatic acyl group having from 6 to 20 carbon atoms, particularly
preferably a hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl,
palmitoyl or stearoyl group), and each of R.sup.3 and R.sup.4 is a
hydrogen atom,
[2691] (b) the combination wherein R.sup.3 is an aliphatic acyl
group having from 3 to 25 carbon atoms (preferably an aliphatic
acyl group having from 6 to 25 carbon atoms, more preferably an
aliphatic acyl group having from 6 to 20 carbon atoms, particularly
preferably a hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl,
palmitoyl or stearoyl group), and each of R.sup.2 and R.sup.4 is a
hydrogen atom,
[2692] (c) the combination wherein R.sup.4 is an aliphatic acyl
group having from 3 to 25 carbon atoms (preferably an aliphatic
acyl group having from 6 to 25 carbon atoms, more preferably an
aliphatic acyl group having from 6 to 20 carbon atoms, particularly
preferably a hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl,
palmitoyl or stearoyl group), and each of R.sup.2 and R.sup.3 is a
hydrogen atom,
[2693] (d) the combination wherein each of R.sup.2 and R.sup.3 is
an aliphatic acyl group having from 3 to 25 carbon atoms
(preferably an aliphatic acyl group having from 6 to 25 carbon
atoms, more preferably an aliphatic acyl group having from 6 to 20
carbon atoms, particularly preferably a hexanoyl, octanoyl,
decanoyl, dodecanoyl, myristoyl, palmitoyl or stearoyl group), and
R.sup.4 is a hydrogen atom,
[2694] (e) the combination wherein each of R.sup.2 and R.sup.4 is
an aliphatic acyl group having from 3 to 25 carbon atoms
(preferably an aliphatic acyl group having from 6 to 25 carbon
atoms, more preferably an aliphatic acyl group having from 6 to 20
carbon atoms, particularly preferably a hexanoyl, octanoyl,
decanoyl, dodecanoyl, myristoyl, palmitoyl or stearoyl group), and
R.sup.3 is a hydrogen atom,
[2695] (f) the combination wherein each of R.sup.3 and R.sup.4 is
an aliphatic acyl group having from 3 to 25 carbon atoms
(preferably an aliphatic acyl group having from 6 to 25 carbon
atoms, more preferably an aliphatic acyl group having from 6 to 20
carbon atoms, particularly preferably a hexanoyl, octanoyl,
decanoyl, dodecanoyl, myristoyl, palmitoyl or stearoyl group), and
R.sup.2 is a hydrogen atom,
[2696] (g) the combination wherein each of R.sup.2, R.sup.3 and
R.sup.4 is an aliphatic acyl group having from 3 to 25 carbon atoms
(preferably the aliphatic acyl group having from 6 to 25 carbon
atoms, more preferably the aliphatic acyl group having from 6 to 20
carbon atoms, particularly preferably hexanoyl, octanoyl, decanoyl,
dodecanoyl, myristoyl, palmitoyl and stearoyl groups), and
[2697] (h) the combination wherein each of R.sup.2, R.sup.3 and
R.sup.4 is a hydrogen atom.
[2698] Of these combinations, the combination of (a) or (h) is
preferred.
[2699] "The ester residue" of W includes, for example, "an alkyl
group" such as methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl,
neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl,
3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl,
2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl,
1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1-methylhexyl,
2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl,
1-propylbutyl, 4,4-dimethylpentyl, octyl, 1-methylheptyl,
2-methylheptyl, 3-methylheptyl, 4methylheptyl, 5-methylheptyl,
6-methylheptyl, 1-propylpentyl, 2-ethylhexyl, 5,5-dimethylhexyl,
nonyl, 3-methyloctyl, 4-methyloctyl, 5-methyloctyl, 6-methyloctyl,
1-propylhexyl, 2-ethylheptyl, 6,6-dimethylheptyl, decyl,
1-methylnonyl, 3-methylnonyl, 8-methylnonyl, 3-ethyloctyl,
3,7-dimethyloctyl, 7,7-dimethyloctyl, undecyl, 4,8-dimethylnonyl,
dodecyl, tridecyl, tetradecyl, pentadecyl, 3,7,11-trimethyldodecyl,
hexadecyl, 4,8,12-trimethyltridecyl, 1-methylpentadecyl,
14-methylpentadecyl, 13,13-dimethyltetradecyl, heptadecyl,
15-methylhexadecyl, octadecyl, 1-methylheptadecyl, nonadecyl,
eicosyl, 3,7,11,15-tetramethylhexadecyl, heneicosyl, docosyl,
tricosyl and tetracosyl groups; "an alkenyl group" such as ethenyl,
1-propenyl, 2-propenyl, 1-methyl-2-propenyl, 1-methyl-1-propenyl,
2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl,
1-butenyl, 2-butenyl, 1-methyl-2-butenyl, 1-methyl-1-butenyl,
3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl,
1-methyl-3-butenyl, 2-methyl-3-butenyl, 1-ethyl-3-butenyl,
1-pentenyl, 2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl,
3-pentenyl, 1-methyl-3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl,
1-methyl-4-pentenyl, 2-methyl-4-pentenyl, 1-hexenyl, 2-hexenyl,
3-hexenyl, 4-hexenyl and 5-hexenyl; "an alkynyl group" such as
ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-methyl-2-propynyl,
2-ethyl-2-propynyl, 2-butynyl, 1-methyl-2-butynyl,
2-methyl-2-butynyl, 1-ethyl-2-butynyl, 3-butynyl,
1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl,
2-pentynyl, 1-methyl-2-pentynyl, 2-methyl-2-pentynyl, 3-pentynyl,
1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4-pentynyl,
1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl,
4-hexynyl and 5-hexynyl; "a halogeno lower alkyl group" such as
trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl,
dibromomethyl, fluoromethyl, 2,2,2-trifluoroethyl,
2,2,2-trichloroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl,
2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl and
2,2-dibromoethyl; "a hydroxy lower alkyl group" such as
2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl,
3,4-dihydroxybutyl and 4-hydroxybutyl; "an aliphatic acyl lower
alkyl group" such as acetylmethyl; "a lower alkyl group substituted
with from 1 to 3 aryls" such as benzyl, phenethyl, 3-phenylpropyl,
.alpha.-naphthylmethyl, .beta.-naphthylmethyl, diphenylmethyl,
triphenylmethyl, 6-phenylhexyl, .alpha.-naphthyldiphenylmethyl and
9-anthrylmethyl; "an aralkyl group of which the aryl ring is
substituted with lower alkyl, lower alkoxy, nitro, halogen, cyano
or alkoxycarbonyl" such as 4-methylbenzyl, 2,4,6-trimethylbenzyl,
3,4,5-trimethylbenzyl, 4-methoxybenzyl,
4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl,
4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl,
4-cyanobenzyldiphenylmethyl- , bis(2-nitrophenyl)methyl, piperonyl
and 4-methoxycarbonylbenzyl; "a tri(alkyl and/or phenyl)silyl
group" such as trimethylsilyl, triethylsilyl,
isopropyldimethylsilyl, tert-butyldimethylsilyl,
methyldiisopropylsilyl, methyldi-tert-butylsilyl,
triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl,
butyldiphenylsilyl and phenyldiisopropylsilyl; "a protecting group
which is cleavable according to a biological method such as
hydrolysis in a living body", that is, an ester which produces a
free acid or a salt thereof by being hydrolized in a human body,
for example, "a lower alkoxy lower alkyl group" such as
methoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyl,
1-(isopropoxy)ethyl, 2-methoxyethyl, 2-ethoxyethyl,
1,1-dimethyl-1-methoxymethyl, ethoxymethyl, n-propoxymethyl,
isopropoxymethyl, n-butoxymethyl and tert-butoxymethyl; "a lower
alkoxylated lower alkoxy lower alkyl group" such as
2-methoxyethoxymethyl; "an aryloxy lower alkyl group" such as
phenoxymethyl; "a halogenated lower alkoxy lower alkyl group" such
as 2,2,2-trichloroethoxymethyl and bis(2-chloroethoxy)methyl; "a
lower alkoxycarbonyl lower alkyl group" such as
methoxycarbonylmethyl; "a cyano lower alkyl group" such as
cyanomethyl and 2-cyanoethyl; "a lower alkylthiomethyl group" such
as methylthiomethyl and ethylthiomethyl; "an arylthiomethyl group"
such as phenylthiomethyl and naphthylthiomethyl; "a lower
alkylsulfonyl lower alkyl group which may be substituted with
halogen" such as 2-methanesulfonylethyl and
2-trifluoromethanesulfonyleth- yl; "an arylsulfonyl lower alkyl
group" such as 2-benzenesulfonylethyl and 2-toluenesulfonylethyl;
"an aliphatic acyloxy lower alkyl group" such as formyloxymethyl,
acetoxymethyl, propionyloxymethyl, butyryloxymethyl,
pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl,
hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl,
1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl,
1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl,
2-formyloxyethyl, 2-acetoxyethyl, 2-propionyloxyethyl,
2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl,
2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxypropyl,
1-acetoxypropyl, 1-propionyloxypropyl, 1-butyryloxypropyl,
1-pivaloyloxypropyl, 1-valeryloxypropyl, 1-isovaleryloxypropyl,
1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl,
1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl,
1-propionyloxypentyl, 1-butyryloxypentyl, 1-pivaloyloxypentyl and
1-pivaloyloxyhexyl; "a cycloalkylcarbonyloxy lower alkyl group"
such as cyclopentanoyloxymethyl, cyclohexanoyloxymethyl,
1-cyclopentanoyloxyethyl, 1-cyclohexanoyloxyethyl- ,
1-cyclopentanoyloxypropyl, 1-cyclohexanoyloxypropyl,
1-cyclopentanoyloxybutyl and 1-cyclohexanoyloxybutyl; "an aromatic
acyloxy lower alkyl group" such as benzoyloxymethyl; "an
(alkoxycarbonyloxy)alkyl group" such as methoxycarbonyloxymethyl,
ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl,
isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl,
isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl,
hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl,
cyclohexyloxycarbonyloxy(cyclohexyl)methyl,
1-(methoxycarbonyloxy)ethyl, 1-(ethoxycarbonyloxy)ethyl,
1-propoxycarbonyloxyethyl, 1-(isopropoxycarbonyloxy)ethyl,
1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl,
1-(tert-butoxycarbonyloxy)ethyl, 1-pentyloxycarbonyloxyethyl,
1-hexyloxycarbonyloxyethyl, 1-cyclopentyloxycarbonyloxyethyl,
1-cyclopentyloxycarbonyloxypropyl,
1-cyclohexyloxycarbonyloxypropyl, 1-cyclopentyloxycarbonyloxybutyl,
1-cyclohexyloxycarbonyloxybutyl, 1-(cyclohexyloxycarbonyloxy)ethyl,
1-(ethoxycarbonyloxy)propyl, 2-methoxycarbonyloxyethyl,
2-ethoxycarbonyloxyethyl, 2-propoxycarbonyloxyethyl,
2-isopropoxycarbonyloxyethyl, 2-butoxycarbonyloxyethyl,
2-isobutoxycarbonyloxyethyl, 2-pentyloxycarbonyloxyethyl,
2-hexyloxycarbonyloxyethyl, 1-methoxycarbonyloxypropyl,
1-ethoxycarbonyloxypropyl, 1-propoxycarbonyloxypropyl,
1-isopropoxycarbonyloxypropyl, 1-butoxycarbonyloxypropyl,
1-isobutoxycarbonyloxypropyl, 1-pentyloxycarbonyloxypropyl,
1-hexyloxycarbonyloxypropyl, 1-methoxycarbonyloxybutyl,
1-ethoxycarbonyloxybutyl, 1-propoxycarbonyloxybutyl,
1-isopropoxycarbonyloxybutyl, 1-butoxycarbonyloxybutyl,
1-isobutoxycarbonyloxybutyl, 1-methoxycarbonyloxypentyl,
1-ethoxycarbonyloxypentyl, 1-methoxycarbonyloxyhexyl and
1-ethoxycarbonyloxyhexyl; "an oxodioxolenylmethyl group" such as
(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,
[5-(4-methylphenyl)-2-oxo-1,3-d- ioxolen-4-yl]methyl,
[5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
[5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,
(2-oxo-1,3-dioxolen-4-yl)methyl,
(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl- ,
(5-ethyl-2-oxo-1,3-dioxolenl-4-yl)methyl,
(5-propyl-2-oxo-1,3-dioxolen-4- -yl)methyl,
(5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl and
(5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl; "a phthalidyl group" such
as phthalidyl, dimethylphthalidyl and dimethoxyphthalidyl; "an aryl
group" such as phenyl and indanyl; and "a carboxyalkyl group" such
as carboxymethyl, preferably "an alkyl group", more preferably an
alkyl group having from 1 to 18 carbon atoms.
[2700] In the case where at least one of R.sup.2, R.sup.3 and
R.sup.4 is an aliphatic acyl group having from 3 to 25 carbon
atoms, "the ester residue" of W is preferably an alkyl group having
from 1 to 18 carbon atoms. In this case, W is, as a whole,
preferably a hydrogen atom or an alkyl group having from 1 to 18
carbon atoms, more preferably a hydrogen atom.
[2701] In the case where each of R.sup.2, R.sup.3 and R.sup.4 is a
hydrogen atom, "the ester residue" of W is preferably an alkyl
group having from 1 to 18 carbon atoms, more preferably an alkyl
group having from 6 to 18 carbon atoms. In this case, W is, as a
whole, preferably an ester residue, more preferably an alkyl group
having from 6 to 18 carbon atoms.
[2702] "The pharmacologically acceptable salt thereof" includes
alkali metal salts such as salts of sodium, potassium and lithium,
alkali earth metal salts such as salts of calcium and magnesium,
metal salts such as salts of aluminium, iron, zinc, copper, nickel
and cobalt; inorganic amine salts such as ammonium salts, organic
amine salts such as salts of t-octylamine, dibenzylamine,
morpholine, glucosamine, phenylglycinealkyl ester, ethylenediamine,
N-methylglucamine, guanidine, diethylamine, triethylamine,
dicyclohexylamine, N,N'-dibenzylethylenediamine, chloroprocaine,
procaine, diethanolamine, N-benzylphenethylamine, piperazine,
tetramethylammonium and tris(hydroxymethyl)aminomethane;
halogenated hydroacid salts such as hydrofluoride, hydrochloride,
hydrobromide and hydroiodide, inorganic acid salts such as nitrate,
perchlorate, sulfate and phosphate; organic acid salts including
lower alkanesulfonates such as methanesulfonate,
trriluoromethanesulfonate and ethanesulfonate, arylsulfonates such
as benzenesulfonate and p-toluenesulfonate, acetate,
trifluoroacetate, malate, fumarate, succinate, citrate, tartrate,
oxalate and maleate; and amino acid salts such as glycine salt,
lysine salt, arginine salt, ornithine salt, glutamate and
aspartate, preferably alkali metal salts such as sodium, potassium
and lithium salts, and organic acid salts such as acetate and
trifluoroacetate, and inorganic acid salts such as hydrochloride
and sulfate.
[2703] Of the compounds of the present invention, the preferable
one includes the following:
[2704] (1) compounds in which R.sup.1 is a methyl group which may
be substituted with a fluorine atom,
[2705] (2) compounds in which R.sup.1 is a methyl, monofluoromethyl
or difluoromethyl group,
[2706] (3) compounds in which R.sup.1 is a methyl group,
[2707] (4) compounds in which R.sup.2 is a hydrogen atom or an
aliphatic acyl group having from 6 to 25 carbon atoms,
[2708] (5) compounds in which R.sup.2 is a hydrogen atom or an
aliphatic acyl group having from 6 to 20 carbon atoms,
[2709] (6) compounds in which R.sup.2 is a hydrogen atom, or a
hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl, palmitoyl or
stearoyl group,
[2710] (7) compounds in which R.sup.3 is a hydrogen atom or an
aliphatic acyl group having from 6 to 25 carbon atoms,
[2711] (8) compounds in which R.sup.3 is a hydrogen atom or an
aliphatic acyl group having from 6 to 20 carbon atoms,
[2712] (9) compounds in which R.sup.3 is a hydrogen atom, or a
hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl, palmitoyl or
stearoyl group,
[2713] (10) compounds in which R.sup.4 is a hydrogen atom or an
aliphatic acyl group having from 6 to 25 carbon atoms,
[2714] (11) compounds in which R.sup.4 is a hydrogen atom or an
aliphatic acyl group having from 6 to 20 carbon atoms,
[2715] (12) compounds in which R.sup.4 is a hydrogen atom, or a
hexanoyl, octanoyl, decanoyl, dodecanoyl, myristoyl, palmitoyl or
stearoyl group,
[2716] (13) compounds in which R.sup.2 is an aliphatic acyl group
having from 3 to 25 carbon atoms, and each of R.sup.3 and R.sup.4
is a hydrogen atom,
[2717] (14) compounds in which R.sup.2 is an aliphatic acyl group
having from 6 to 25 carbon atoms, and each of R.sup.3 and R.sup.4
is a hydrogen atom,
[2718] (15) compounds in which R.sup.2 is an aliphatic acyl group
having from 6 to 20 carbon atoms, and each of R.sup.3 and R.sup.4
is a hydrogen atom,
[2719] (16) compounds in which R.sup.2 is a hexanoyl, octanoyl,
decanoyl, dodecanoyl, myristoyl, palmitoyl or stearoyl group, and
each of R.sup.3 and R.sup.4 is a hydrogen atom,
[2720] (17) compounds in which W is a hydrogen atom or an alkyl
group having from 1 to 18 carbon atoms,
[2721] (18) compounds in which W is a hydrogen atom,
[2722] (19) compounds in which W is an ester residue,
[2723] (20) compounds in which W is an alkyl group having from 6 to
18 carbon atoms.
[2724] Further, the compounds obtained by combining the
substituents R.sup.1, R.sup.2, R.sup.3, R.sup.4 and W selected in
the compounds of the above (1) to (20) are more preferable and
includes, for example, the following compounds.
[2725] (21) compounds in which each of R.sup.2, R.sup.3 and R.sup.4
is a hydrogen atom, and W is an ester residue,
[2726] (22) compounds in which each of R.sup.2, R.sup.3 and R.sup.4
is a hydrogen atom, and W is an alkyl group having from 6 to 18
carbon atoms,
[2727] (23) compounds in which R.sup.1 is a methyl group which may
be substituted with a fluorine atom, R.sup.2 is an aliphatic acyl
group having from 3 to 25 carbon atoms, each of R.sup.3 and R.sup.4
is a hydrogen atom, and W is a hydrogen atom or an ester
residue,
[2728] (24) compounds in which R.sup.1 is a methyl group, R.sup.2
is an aliphatic acyl group having from 6 to 25 carbon atoms, each
of R.sup.3 and R.sup.4 is a hydrogen atom, and W is a hydrogen atom
or an alkyl group having from 1 to 18 carbon atoms,
[2729] (25) compounds in which R.sup.1 is a methyl group, R.sup.2
is an aliphatic acyl group having from 6 to 20 carbon atoms, and
each of R.sup.3, R.sup.4 and W is a hydrogen atom,
[2730] (26) compounds in which R.sup.1 is a methyl group which may
be substituted with a fluorine atom, each of R.sup.2, R.sup.3 and
R.sup.4 is a hydrogen atom, and W is an ester residue, and
[2731] (27) compounds in which R.sup.1 is a methyl group, each of
R.sup.2, R.sup.3 and R.sup.4 is a hydrogen atom, and W is an alkyl
group having from 6 to 18 carbon atoms.
[2732] In the following, the compounds of the present invention are
exemplified but the present invention is not limited to these.
7TABLE 1 57 No. R.sup.1 R.sup.2 R.sup.3 R.sup.4 W 1 CH.sub.3 H H H
H 2 CH.sub.3 H H CH.sub.3CO H 3 CH.sub.3 H H
CH.sub.3(CH.sub.2).sub.5C- O H 4 CH.sub.3 H H
CH.sub.3(CH.sub.2).sub.10CO H 5 CH.sub.3 H H
CH.sub.3(CH.sub.2).sub.13CO H 6 CH.sub.3 H H
CH.sub.3(CH.sub.2).sub.15CO H 7 CH.sub.3 H H
CH.sub.3(CH.sub.2).sub.17CO H 8 CH.sub.3 H H
CH.sub.3(CH.sub.2).sub.21CO H 9 CH.sub.3 H CH.sub.3CO H H 10
CH.sub.3 H CH.sub.3CH.sub.2CO H H 11 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.2CO H H 12 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.3CO H H 13 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.4CO H H 14 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.5CO H H 15 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.6CO H H 16 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.8CO H H 17 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.10CO H H 18 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.12CO H H 19 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.14CO H H 20 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.16CO H H 21 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.18CO H H 22 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.20CO H H 23 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.22CO H H 24 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO H 25 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.5CO H 26 CH.sub.3
H CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.10CO H 27
CH.sub.3 H CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.13CO H
28 CH.sub.3 H CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO H 29 CH.sub.3
H CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO H 30
CH.sub.3 H CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.10CO
H 31 CH.sub.3 H CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.1- 3CO H 32 CH.sub.3 CH.sub.3CO H H H 33
CH.sub.3 CH.sub.3CH.sub.2CO H H H 34 CH.sub.3
CH.sub.3(CH.sub.2).sub.2CO H H H 35 CH.sub.3
CH.sub.3(CH.sub.2).sub.3CO H H H 36 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO H H H 37 CH.sub.3
CH.sub.3(CH.sub.2).sub.5CO H H H 38 CH.sub.3
CH.sub.3(CH.sub.2).sub.6CO H H H 38a CH.sub.3
CH.sub.3(CH.sub.2).sub.7CO H H H 39 CH.sub.3
CH.sub.3(CH.sub.2).sub.8CO H H H 39a CH.sub.3
CH.sub.3(CH.sub.2).sub.9CO H H H 40 CH.sub.3
CH.sub.3(CH.sub.2).sub.10CO H H H 40a CH.sub.3
CH.sub.3(CH.sub.2).sub.11CO H H H 41 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO H H H 41a CH.sub.3
CH.sub.3(CH.sub.2).sub.13CO H H H 42 CH.sub.3
CH.sub.3(CH.sub.2).sub.14CO H H H 42a CH.sub.3
CH.sub.3(CH.sub.2).sub.15CO H H H 43 CH.sub.3
CH.sub.3(CH.sub.2).sub.16CO H H H 43a CH.sub.3
CH.sub.3(CH.sub.2).sub.17CO H H H 44 CH.sub.3
CH.sub.3(CH.sub.2).sub.18CO H H H 44a CH.sub.3
CH.sub.3(CH.sub.2).sub.19CO H H H 45 CH.sub.3
CH.sub.3(CH.sub.2).sub.20CO H H H 45a CH.sub.3
CH.sub.3(CH.sub.2).sub.21CO H H H 45b CH.sub.3
CH.sub.3(CH.sub.2).sub.22CO H H H 45c CH.sub.3
CH.sub.3(CH.sub.2).sub.23CO H H H 46 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3CO H 47 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3(CH.sub.2).sub.5CO H 48
CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3(CH.sub.2).sub.10CO H
49 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO H
CH.sub.3(CH.sub.2).sub.13CO H 50 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3CO H 51 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3(CH.sub.2).sub.5CO H 52
CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3(CH.sub.2).sub.10CO
H 53 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO H
CH.sub.3(CH.sub.2).sub.1- 3CO H 54 CH.sub.3 CH.sub.3CO CH.sub.3CO H
H 55 CH.sub.3 CH.sub.3CH.sub.2CO CH.sub.3CH.sub.2CO H H 56 CH.sub.3
CH.sub.3(CH.sub.2).sub.2CO CH.sub.3(CH.sub.2).sub.2CO H H 57
CH.sub.3 CH.sub.3(CH.sub.2).sub.3CO CH.sub.3(CH.sub.2).sub.3CO H H
58 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO H
H 59 CH.sub.3 CH.sub.3(CH.sub.2).sub.5CO CH.sub.3(CH.sub.2).sub.5CO
H H 60 CH.sub.3 CH.sub.3(CH.sub.2).sub.6CO
CH.sub.3(CH.sub.2).sub.6CO H H 61 CH.sub.3
CH.sub.3(CH.sub.2).sub.8CO CH.sub.3(CH.sub.2).sub.- 8CO H H 62
CH.sub.3 CH.sub.3(CH.sub.2).sub.10CO CH.sub.3(CH.sub.2).sub.10CO H
H 63 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO H H 64 CH.sub.3
CH.sub.3(CH.sub.2).sub.14CO CH.sub.3(CH.sub.2).sub.14CO H H 65
CH.sub.3 CH.sub.3(CH.sub.2).sub.16CO CH.sub.3(CH.sub.2).sub.16CO H
H 66 CH.sub.3 CH.sub.3(CH.sub.2).sub.18CO
CH.sub.3(CH.sub.2).sub.18C- O H H 67 CH.sub.3
CH.sub.3(CH.sub.2).sub.20CO CH.sub.3(CH.sub.2).sub.20CO H H 68
CH.sub.3 CH.sub.3(CH.sub.2).sub.22CO CH.sub.3(CH.sub.2).sub.22CO H
H 69 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.6CO H H 70 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO H H 71
CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3CO H 72 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.5CO H 73 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO H 74 CH.sub.3 CH.sub.3(CH.sub.2).sub.4-
CO CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.13CO H 75
CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3CO H 76 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO H 77
CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.10CO H 78 CH.sub.3 CH.sub.3(CH.sub.2).sub.1-
2CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.13CO H 79
CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3COO H 80 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO H 81
CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.10CO H 82 CH.sub.3 CH.sub.3(CH.sub.2).sub.4-
CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.13CO H 83
CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3CO H 84 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.5CO H 85 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO H 86 CH.sub.3 CH.sub.3(CH.sub.2).sub.1-
2CO CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.13CO H 87
CH.sub.3 H H H (CH.sub.2).sub.5CH.sub.3 87a CH.sub.3 H H H
(CH.sub.2).sub.6CH.sub.3 87b CH.sub.3 H H H
(CH.sub.2).sub.7CH.sub.3 87c CH.sub.3 H H H
(CH.sub.2).sub.8CH.sub.3 87d CH.sub.3 H H H
(CH.sub.2).sub.9CH.sub.3 87e CH.sub.3 H H H
(CH.sub.2).sub.10CH.sub.3 87f CH.sub.3 H H H
(CH.sub.2).sub.11CH.sub.3 87g CH.sub.3 H H H
(CH.sub.2).sub.12CH.sub.3 88 CH.sub.3 H H H
(CH.sub.2).sub.13CH.sub.3 88a CH.sub.3 H H H
(CH.sub.2).sub.14CH.sub.3 89 CH.sub.3 H H H
(CH.sub.2).sub.15CH.sub.3 90 CH.sub.3 H H H
(CH.sub.2).sub.16CH.sub.3 91 CH.sub.3 H H H
(CH.sub.2).sub.17CH.sub.3 92 CH.sub.3 H H H
(CH.sub.2).sub.18CH.sub.3 92a CH.sub.3 H H H
(CH.sub.2).sub.19CH.sub.3 93 CH.sub.3 H H H
(CH.sub.2).sub.20CH.sub.3 94 CH.sub.3 H H H
(CH.sub.2).sub.21CH.sub.3 94a CH.sub.3 H H H
(CH.sub.2).sub.22CH.sub.3 94b CH.sub.3 H H H
(CH.sub.2).sub.23CH.sub.3 95 CH.sub.3 H H CH.sub.3(CH.sub.2).sub.5-
CO (CH.sub.2).sub.5CH.sub.3 96 CH.sub.3 H H
CH.sub.3(CH.sub.2).sub.- 10CO (CH.sub.2).sub.13CH.sub.3 97 CH.sub.3
H H CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 98
CH.sub.3 H H CH.sub.3(CH.sub.2).sub.15CO (CH.sub.2).sub.13CH.sub.3
99 CH.sub.3 H H CH.sub.3(CH.sub.2).sub.17CO
(CH.sub.2).sub.5CH.sub.3 100 CH.sub.3 H H
CH.sub.3(CH.sub.2).sub.21CO (CH.sub.2).sub.13CH.sub.3 101 CH.sub.3
H CH.sub.3CO H (CH.sub.2).sub.5CH.sub.3 102 CH.sub.3 H
CH.sub.3CH.sub.2CO H (CH.sub.2).sub.13CH.sub.3 103 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.2CO H (CH.sub.2).sub.5CH.sub.3 104 CH.sub.3
H CH.sub.3(CH.sub.2).sub.3CO H (CH.sub.2).sub.13CH.sub.3 105
CH.sub.3 H CH.sub.3(CH.sub.2).sub.4CO H (CH.sub.2).sub.5CH.sub.3
106 CH.sub.3 H CH.sub.3(CH.sub.2).sub.5CO H
(CH.sub.2).sub.13CH.sub.- 3 107 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.6CO H (CH.sub.2).sub.5CH.sub.3 108 CH.sub.3
H CH.sub.3(CH.sub.2).sub.8CO H (CH.sub.2).sub.13CH.sub.3 109
CH.sub.3 H CH.sub.3(CH.sub.2).sub.- 10CO H (CH.sub.2).sub.5CH.sub.3
110 CH.sub.3 H CH.sub.3(CH.sub.2).sub.12CO H
(CH.sub.2).sub.13CH.sub.3 111 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.14CO H (CH.sub.2).sub.5CH.sub.3 112 CH.sub.3
H CH.sub.3(CH.sub.2).sub.16CO H (CH.sub.2).sub.13CH.sub.3 113
CH.sub.3 H CH.sub.3(CH.sub.2).sub.18CO H (CH.sub.2).sub.5CH.sub.3
114 CH.sub.3 H CH.sub.3(CH.sub.2).sub.20CO H
(CH.sub.2).sub.13CH.sub.3 115 CH.sub.3 H CH.sub.3(CH.sub.2).sub.22-
CO H (CH.sub.2).sub.5CH.sub.3 116 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO (CH.sub.2).sub.13CH.sub.3 117
CH.sub.3 H CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.5CO
(CH.sub.2).sub.5CH.sub.3 118 CH.sub.3 H CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.13CH.sub.3 119 CH.sub.3
H CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.13CO
(CH.sub.2).sub.5CH.sub.3 120 CH.sub.3 H CH.sub.3(CH.sub.2).sub.12C-
O CH.sub.3CO (CH.sub.2).sub.13CH.sub.3 121 CH.sub.3 H
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO
(CH.sub.2).sub.5CH.sub.3 122 CH.sub.3 H CH.sub.3(CH.sub.2).sub.12C-
O CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.13CH.sub.3 123
CH.sub.3 H CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.13CO
(CH.sub.2).sub.5CH.sub.3 124 CH.sub.3 CH.sub.3CO H H
(CH.sub.2).sub.13CH.sub.3 125 CH.sub.3 CH.sub.3CH.sub.2CO H H
(CH.sub.2).sub.5CH.sub.3 126 CH.sub.3 CH.sub.3(CH.sub.2).sub.2CO H
H (CH.sub.2).sub.13CH.sub.3 127 CH.sub.3 CH.sub.3(CH.sub.2).sub.3C-
O H H (CH.sub.2).sub.5CH.sub.3 128 CH.sub.3
CH.sub.3(CH.sub.2).sub.- 4CO H H (CH.sub.2).sub.13CH.sub.3 129
CH.sub.3 CH.sub.3(CH.sub.2).sub.5CO H H (CH.sub.2).sub.5CH.sub.3
130 CH.sub.3 CH.sub.3(CH.sub.2).sub.6CO H H
(CH.sub.2).sub.13CH.sub.3 131 CH.sub.3 CH.sub.3(CH.sub.2).sub.8CO H
H (CH.sub.2).sub.5CH.sub.3 132 CH.sub.3 CH.sub.3(CH.sub.2).sub.10CO
H H (CH.sub.2).sub.13CH.sub.3 133 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO H H (CH.sub.2).sub.5CH.sub.3 134
CH.sub.3 CH.sub.3(CH.sub.2).sub.14CO H H (CH.sub.2).sub.13CH.sub.3
135 CH.sub.3 CH.sub.3(CH.sub.2).sub.- 16CO H H
(CH.sub.2).sub.5CH.sub.3 136 CH.sub.3 CH.sub.3(CH.sub.2).sub.18CO H
H (CH.sub.2).sub.13CH.sub.3 137 CH.sub.3
CH.sub.3(CH.sub.2).sub.20CO H H (CH.sub.2).sub.5CH.sub.3 138
CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3CO
(CH.sub.2).sub.13CH.sub.3 139 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO H
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 140 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.13CH.sub.3 141 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO H
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 142 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3CO (CH.sub.2).sub.13CH.sub-
.3 143 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO H
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 144 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.13CH.sub.3 145 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO
H CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 146 CH.sub.3
CH.sub.3CO CH.sub.3CO (CH.sub.2).sub.13CH.sub.3 147 CH.sub.3
CH.sub.3CHCO CH.sub.3CHCO CH.sub.3 148 CH.sub.3
CH.sub.3(CH.sub.2).sub.2CO CH.sub.3(CH.sub.2).sub.2CO H
(CH.sub.2).sub.5CH.sub.3 149 CH.sub.3 CH.sub.3(CH.sub.2).sub.3CO
CH.sub.3(CH.sub.2).sub.3CO H (CH.sub.2).sub.10CH.sub.3 150 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO H
(CH.sub.2).sub.13CH.sub.3 151 CH.sub.3 CH.sub.3(CH.sub.2).sub.5CO
CH.sub.3(CH.sub.2).sub.5CO H (CH.sub.2).sub.15CH.sub.3 152 CH.sub.3
CH.sub.3(CH.sub.2).sub.6CO CH.sub.3(CH.sub.2).sub.6CO H
(CH.sub.2).sub.17CH.sub.3 153 CH.sub.3 CH.sub.3(CH.sub.2).sub.8CO
CH.sub.3(CH.sub.2).sub.8CO H (CH.sub.2).sub.21CH.sub.3 154 CH.sub.3
CH.sub.3(CH.sub.2).sub.10CO CH.sub.3(CH.sub.2).sub.10CO H CH.sub.3
155 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO H (CH.sub.2).sub.5CH.sub.3 156 CH.sub.3
CH.sub.3(CH.sub.2).sub.14CO CH.sub.3(CH.sub.2).sub.14CO H
(CH.sub.2).sub.10CH.sub.3 157 CH.sub.3 CH.sub.3(CH.sub.2).sub.16CO
CH.sub.3(CH.sub.2).sub.16CO H (CH.sub.2).sub.13CH.sub.3 158
CH.sub.3 CH.sub.3(CH.sub.2).sub.18CO CH.sub.3(CH.sub.2).sub.18CO H
(CH.sub.2).sub.15CH.sub.3 159 CH.sub.3 CH.sub.3(CH.sub.2).sub.20CO
CH.sub.3(CH.sub.2).sub.20CO H (CH.sub.2).sub.17CH.sub.3 160
CH.sub.3 CH.sub.3(CH.sub.2).sub.22CO CH.sub.3(CH.sub.2).sub.22CO H
(CH.sub.2).sub.21CH.sub.3 161 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.6CO H CH.sub.3 162 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO H
(CH.sub.2).sub.5CH.sub.3 163 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO (CH.sub.2).sub.10CH.sub.3 164
CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.13CH.sub.3 165 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.15CH.sub.3 166 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.17CH.sub.3 167 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO
(CH.sub.2).sub.21CH.sub.3 168 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO CH.sub.3 169
CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.5CH.sub.3 170 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.10CH.sub.3 171 CH.sub.3
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3COO
(CH.sub.2).sub.13CH.sub.3 172 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO
(CH.sub.2).sub.15CH.sub.3 173 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.17CH.sub.3 174 CH.sub.3 CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.13CO
(CH.sub.2).sub.21CH.sub.3 175 CH.sub.3 CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO CH.sub.3 176 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 177 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.10CH.sub.3 178 CH.sub.3
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.13CH.sub.3 179 CH.sub.2F
H H H H 180 CH.sub.2F H H CH.sub.3CO H 181 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.5CO H 182 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.10CO H 183 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.13CO H 184 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.15CO H 185 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.17CO H 186 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.21CO H 187 CH.sub.2F H CH.sub.3CO H H 188
CH.sub.2F H CH.sub.3CH.sub.2CO H H 189 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.2CO H H 190 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.3CO H H 191 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.4CO H H 192 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.5CO H H 193 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.6CO H H 194 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.8CO H H 195 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.10CO H H 196 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.12CO H H 197 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.14CO H H 198 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.16CO H H 199 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.18CO H H 200 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.20CO H H 201 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.22CO H H 202 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO H 203 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.5CO H 204
CH.sub.2F H CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.10CO
H 205 CH.sub.2F H CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.13CO H 206 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO H 207 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO H 208
CH.sub.2F H CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.10CO
H 209 CH.sub.2F H CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.13CO H 210 CH.sub.2F CH.sub.3CO H H H 211
CH.sub.2F CH.sub.3CH.sub.2CO H H H 212 CH.sub.2F
CH.sub.3(CH.sub.2).sub.2CO H H H 213 CH.sub.2F
CH.sub.3(CH.sub.2).sub.3CO H H H 214 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO H H H 215 CH.sub.2F
CH.sub.3(CH.sub.2).sub.5CO H H H 216 CH.sub.2F
CH.sub.3(CH.sub.2).sub.6CO H H H 217 CH.sub.2F
CH.sub.3(CH.sub.2).sub.8CO H H H 218 CH.sub.2F
CH.sub.3(CH.sub.2).sub.10CO H H H 219 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO H H H 220 CH.sub.2F
CH.sub.3(CH.sub.2).sub.14CO H H H 221 CH.sub.2F
CH.sub.3(CH.sub.2).sub.16CO H H H 222 CH.sub.2F
CH.sub.3(CH.sub.2).sub.18CO H H H 223 CH.sub.2F
CH.sub.3(CH.sub.2).sub.20CO H H H 224 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3CO H 225 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3(CH.sub.2).sub.5CO H 226
CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3(CH.sub.2).sub.10CO
H 227 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO H
CH.sub.3(CH.sub.2).sub.13CO H 228 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3CO H 229 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3(CH.sub.2).sub.5CO H 230
CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3(CH.sub.2).sub.10CO
H 231 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO H
CH.sub.3(CH.sub.2).sub.13CO H 232 CH.sub.2F CH.sub.3CO CH.sub.3CO H
H 233 CH.sub.2F CH.sub.3CH.sub.2CO CH.sub.3CH.sub.2CO H H 234
CH.sub.2F CH.sub.3(CH.sub.2).sub.2CO CH.sub.3(CH.sub.2).sub.2CO H H
235 CH.sub.2F CH.sub.3(CH.sub.2).sub.3CO CH.sub.3(CH.sub.2).sub.3CO
H H 236 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.4CO H H 237 CH.sub.2F
CH.sub.3(CH.sub.2).sub.5CO CH.sub.3(CH.sub.2).sub.5C- O H H 238
CH.sub.2F CH.sub.3(CH.sub.2).sub.6CO CH.sub.3(CH.sub.2).sub.6CO H H
239 CH.sub.2F CH.sub.3(CH.sub.2).sub.8CO CH.sub.3(CH.sub.2).sub.8CO
H H 240 CH.sub.2F CH.sub.3(CH.sub.2).sub.10CO
CH.sub.3(CH.sub.2).sub.10CO H H 241 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO H H 242
CH.sub.2F CH.sub.3(CH.sub.2).sub.14CO CH.sub.3(CH.sub.2).sub.14CO H
H 243 CH.sub.2F CH.sub.3(CH.sub.2).sub.16CO
CH.sub.3(CH.sub.2).sub.16CO H H 244 CH.sub.2F
CH.sub.3(CH.sub.2).sub.18CO CH.sub.3(CH.sub.2).sub.18CO H H 245
CH.sub.2F CH.sub.3(CH.sub.2).sub.20CO CH.sub.3(CH.sub.2).sub.20CO H
H 246 CH.sub.2F CH.sub.3(CH.sub.2).sub.22CO
CH.sub.3(CH.sub.2).sub.22CO H H 247 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.6CO H H 248
CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO H
H 249 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO H 250 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.5CO H 251 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO H 252 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.13CO H 253 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO
H 254 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO H 255
CH.sub.2F CH.sub.3(CH.sub.2).sub.- 12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.10CO H 256 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.13CO H 257 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO H
258 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO H 259
CH.sub.2F CH.sub.3(CH.sub.2).sub.- 4CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.10CO H 260 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.13CO H 261 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO H
262 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.5CO H 263
CH.sub.2F CH.sub.3(CH.sub.2).sub.- 12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO H 264 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.13CO H 265 CH.sub.2F H H H
(CH.sub.2).sub.5CO 266 CH.sub.2F H H H (CH.sub.2).sub.13CO 267
CH.sub.2F H H H (CH.sub.2).sub.15CO 268 CH.sub.2F H H H
(CH.sub.2).sub.16CO 269 CH.sub.2F H H H (CH.sub.2).sub.17CO 270
CH.sub.2F H H H (CH.sub.2).sub.18CO 271 CH.sub.2F H H H
(CH.sub.2).sub.20CO 272 CH.sub.2F H H H (CH.sub.2).sub.21CO 273
CH.sub.2F H H CH.sub.3CO (CH.sub.2).sub.13CH.sub.3 274 CH.sub.2F H
H CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 275 CH.sub.2F
H H CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.13CH.sub.3 276
CH.sub.2F H H CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3
277 CH.sub.2F H H CH.sub.3(CH.sub.2).sub.- 15CO
(CH.sub.2).sub.13CH.sub.3 278 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.17CO (CH.sub.2).sub.5CH.sub.3 279 CH.sub.2F
H H CH.sub.3(CH.sub.2).sub.21CO (CH.sub.2).sub.13CH.sub.3 280
CH.sub.2F H CH.sub.3CO H (CH.sub.2).sub.5CH.sub.3 281 CH.sub.2F H
CH.sub.3CH.sub.2CO H (CH.sub.2).sub.13CH.sub.3 282 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.2CO H (CH.sub.2).sub.5CH.sub.3 283 CH.sub.2F
H CH.sub.3(CH.sub.2).sub.3CO H (CH.sub.2).sub.13CH.sub.3 284
CH.sub.2F H CH.sub.3(CH.sub.2).sub.4CO H (CH.sub.2).sub.5CH.sub.3
285 CH.sub.2F H CH.sub.3(CH.sub.2).sub.5CO H
(CH.sub.2).sub.13CH.sub.3 286 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.6CO H (CH.sub.2).sub.5CH.sub.3 287 CH.sub.2F
H CH.sub.3(CH.sub.2).sub.8C- O H (CH.sub.2).sub.13CH.sub.3 288
CH.sub.2F H CH.sub.3(CH.sub.2).sub.10CO H (CH.sub.2).sub.5CH.sub.3
289 CH.sub.2F H CH.sub.3(CH.sub.2).sub.12CO H
(CH.sub.2).sub.13CH.sub.3 290 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.14CO H (CH.sub.2).sub.5CH.sub.3 291
CH.sub.2F H CH.sub.3(CH.sub.2).sub.16CO H (CH.sub.2).sub.13CH.sub.3
292 CH.sub.2F H CH.sub.3(CH.sub.2).sub.1- 8CO H
(CH.sub.2).sub.5CH.sub.3 293 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.20CO H (CH.sub.2).sub.13CH.sub.3 294
CH.sub.2F H CH.sub.3(CH.sub.2).sub.22CO H (CH.sub.2).sub.5CH.sub.3
295 CH.sub.2F H CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO
(CH.sub.2).sub.13CH.sub.3 296 CH.sub.2F H CH.sub.3(CH.sub.2).sub.4-
CO CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 297
CH.sub.2F H CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.13CH.sub.3 298 CH.sub.2F H CH.sub.3(CH.sub.2).sub.4-
CO CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 299
CH.sub.2F H CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO
(CH.sub.2).sub.13CH.sub.3 300 CH.sub.2F H CH.sub.3(CH.sub.2).sub.1-
2CO CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 301
CH.sub.2F H CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.13CH.sub.3 302 CH.sub.2F H CH.sub.3(CH.sub.2).sub.1-
2CO CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 303
CH.sub.2F CH.sub.3CO H H (CH.sub.2).sub.13CH.sub.3 304 CH.sub.2F
CH.sub.3CH.sub.2CO H H (CH.sub.2).sub.5CH.sub.3 305 CH.sub.2F
CH.sub.3(CH.sub.2).sub.2CO H H (CH.sub.2).sub.13CH.sub.3 306
CH.sub.2F CH.sub.3(CH.sub.2).sub.3CO H H (CH.sub.2).sub.5CH.sub.3
307 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO H H
(CH.sub.2).sub.13CH.sub.3 308 CH.sub.2F CH.sub.3(CH.sub.2).sub.5CO
H H (CH.sub.2).sub.5CH.sub.3 309 CH.sub.2F
CH.sub.3(CH.sub.2).sub.6CO H H (CH.sub.2).sub.13CH.sub.3 310
CH.sub.2F CH.sub.3(CH.sub.2).sub.8CO H H (CH.sub.2).sub.5CH.sub.3
311 CH.sub.2F CH.sub.3(CH.sub.2).sub.- 10CO H H
(CH.sub.2).sub.13CH.sub.3 312 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
H H (CH.sub.2).sub.5CH.sub.3 313 CH.sub.2F
CH.sub.3(CH.sub.2).sub.14CO H H (CH.sub.2).sub.13CH.sub.3 314
CH.sub.2F CH.sub.3(CH.sub.2).sub.16CO H H (CH.sub.2).sub.5CH.sub.3
315 CH.sub.2F CH.sub.3(CH.sub.2).sub.18CO H H
(CH.sub.2).sub.13CH.sub.3 316 CH.sub.2F CH.sub.3(CH.sub.2).sub.20C-
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318 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO H
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 319 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.13CH.sub.3 320 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
H CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 321
CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3CO
(CH.sub.2).sub.13CH.sub.3 322 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
H CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 323 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.13CH.sub.3 324 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
H CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 325
CH.sub.2F CH.sub.3CO CH.sub.3CO H (CH.sub.2).sub.13CH.sub.3 326
CH.sub.2F CH.sub.3CH.sub.2CO CH.sub.3CH.sub.2CO H CH.sub.3 327
CH.sub.2F CH.sub.3(CH.sub.2).sub.2CO CH.sub.3(CH.sub.2).sub.2CO H
(CH.sub.2).sub.5CH.sub.3 328 CH.sub.2F CH.sub.3(CH.sub.2).sub.3CO
CH.sub.3(CH.sub.2).sub.3CO H (CH.sub.2).sub.10CH.sub.3 329
CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO H
(CH.sub.2).sub.13CH.sub.3 330 CH.sub.2F CH.sub.3(CH.sub.2).sub.5CO
CH.sub.3(CH.sub.2).sub.5CO H (CH.sub.2).sub.15CH.sub.3 331
CH.sub.2F CH.sub.3(CH.sub.2).sub.6CO CH.sub.3(CH.sub.2).sub.6CO H
(CH.sub.2).sub.17CH.sub.3 332 CH.sub.2F CH.sub.3(CH.sub.2).sub.8CO
CH.sub.3(CH.sub.2).sub.8CO H (CH.sub.2).sub.21CH.sub.3 333
CH.sub.2F CH.sub.3(CH.sub.2).sub.10CO CH.sub.3(CH.sub.2).sub.10CO H
CH.sub.3 334 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO H (CH.sub.2).sub.5CH.sub.3 335
CH.sub.2F CH.sub.3(CH.sub.2).sub.14CO CH.sub.3(CH.sub.2).sub.14CO H
(CH.sub.2).sub.10CH.sub.3 336 CH.sub.2F CH.sub.3(CH.sub.2).sub.16C-
O CH.sub.3(CH.sub.2).sub.16CO H (CH.sub.2).sub.13CH.sub.3 337
CH.sub.2F CH.sub.3(CH.sub.2).sub.18CO CH.sub.3(CH.sub.2).sub.18CO H
(CH.sub.2).sub.15CH.sub.3 338 CH.sub.2F CH.sub.3(CH.sub.2).sub.20C-
O CH.sub.3(CH.sub.2).sub.20CO H (CH.sub.2).sub.17CH.sub.3 339
CH.sub.2F CH.sub.3(CH.sub.2).sub.22CO CH.sub.3(CH.sub.2).sub.22CO H
(CH.sub.2).sub.21CH.sub.3 340 CH.sub.2F CH.sub.3(CH.sub.2).sub.12C-
O CH.sub.3(CH.sub.2).sub.6CO H CH.sub.3 341 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO H
(CH.sub.2).sub.5CH.sub.3 342 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO (CH.sub.2).sub.10CH.sub.3 343
CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.13CH.sub.3 344 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.15CH.sub.3 345 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.17CH.sub.3 346 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO
(CH.sub.2).sub.21CH.sub.3 347 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO CH.sub.3 348
CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.5CH.sub.3 349 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.10CH.sub.3 350 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO
(CH.sub.2).sub.13CH.sub.3 351 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO
(CH.sub.2).sub.15CH.sub.3 352 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.17CH.sub.3 353 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.13CO
(CH.sub.2).sub.21CH.sub.3 354 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO CH.sub.3 355 CH.sub.2F
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CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 356 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.10CH.sub.3 357 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12C- O CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.13CH.sub.3 358 CH.sub.2F
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CH.sub.3(CH.sub.2).sub.5CO H 361 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.10CO H 362 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.13CO H 363 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.15CO H 364 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.17CO H 365 CH.sub.2F H H
CH.sub.3(CH.sub.2).sub.21CO H 366 CH.sub.2F H CH.sub.3CO H H 367
CH.sub.2F H CH.sub.3CH.sub.2CO H H 368 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.2CO H H 369 CH.sub.2F H
CH.sub.3(CH.sub.3).sub.2CO H H 370 CH.sub.2F H
CH.sub.3(CH.sub.4).sub.2CO H H 371 CH.sub.2F H
CH.sub.3(CH.sub.5).sub.2CO H H 372 CH.sub.2F H
CH.sub.3(CH.sub.6).sub.2CO H H 373 CH.sub.2F H
CH.sub.3(CH.sub.8).sub.2CO H H 374 CH.sub.2F H
CH.sub.3(CH.sub.10).sub.2CO H H 375 CH.sub.2F H
CH.sub.3(CH.sub.12).sub.2CO H H 376 CH.sub.2F H
CH.sub.3(CH.sub.14).sub.2CO H H 377 CH.sub.2F H
CH.sub.3(CH.sub.16).sub.2CO H H 378 CH.sub.2F H
CH.sub.3(CH.sub.18).sub.2CO H H 379 CH.sub.2F H
CH.sub.3(CH.sub.20).sub.2CO H H 380 CH.sub.2F H
CH.sub.3(CH.sub.22).sub.2CO H H 381 CH.sub.2F H
CH.sub.3(CH.sub.4).sub.2CO CH.sub.3CO H 382 CH.sub.2F H
CH.sub.3(CH.sub.4).sub.2CO CH.sub.3(CH.sub.2).sub.5CO H 383
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CH.sub.3(CH.sub.2).sub.13CO H 385 CH.sub.2F H
CH.sub.3(CH.sub.12).sub.2CO CH.sub.3CO H 386 CH.sub.2F H
CH.sub.3(CH.sub.12).sub.2CO CH.sub.3(CH.sub.2).sub.5CO H 387
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CH.sub.3(CH.sub.3).sub.2CO H H H 393 CH.sub.2F
CH.sub.3(CH.sub.4).sub.2CO H H H 394 CH.sub.2F
CH.sub.3(CH.sub.5).sub.2CO H H H 395 CH.sub.2F
CH.sub.3(CH.sub.6).sub.2CO H H H 396 CH.sub.2F
CH.sub.3(CH.sub.8).sub.2CO H H H 397 CH.sub.2F
CH.sub.3(CH.sub.10).sub.2CO H H H 398 CH.sub.2F
CH.sub.3(CH.sub.12).sub.2CO H H H 399 CH.sub.2F
CH.sub.3(CH.sub.14).sub.2CO H H H 400 CH.sub.2F
CH.sub.3(CH.sub.16).sub.2CO H H H 401 CH.sub.2F
CH.sub.3(CH.sub.18).sub.2CO H H H 402 CH.sub.2F
CH.sub.3(CH.sub.20).sub.2CO H H H 403 CH.sub.2F
CH.sub.3(CH.sub.4).sub.2CO H CH.sub.3CO H 404 CH.sub.2F
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CH.sub.3(CH.sub.2).sub.4CO H H 416 CH.sub.2F
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CH.sub.3(CH.sub.2).sub.10CO H H 420 CH.sub.2F
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CH.sub.3(CH.sub.2).sub.22CO H H 426 CH.sub.2F
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(CH.sub.2).sub.5CH.sub.3 445 CH.sub.2F H H H
(CH.sub.2).sub.13CH.sub.3 446 CH.sub.2F H H H
(CH.sub.2).sub.15CH.sub.3 447 CH.sub.2F H H H
(CH.sub.2).sub.16CH.sub.3 448 CH.sub.2F H H H
(CH.sub.2).sub.17CH.sub.3 449 CH.sub.2F H H H
(CH.sub.2).sub.18CH.sub.3 450 CH.sub.2F H H H
(CH.sub.2).sub.20CH.sub.3 451 CH.sub.2F H H H
(CH.sub.2).sub.21CH.sub.3 452 CH.sub.2F H H CH.sub.3CO
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CH.sub.3(CH.sub.2).sub.17CO (CH.sub.2).sub.5CH.sub.3 458 CH.sub.2F
H H CH.sub.3(CH.sub.2).sub.- 21CO (CH.sub.2).sub.13CH.sub.3 459
CH.sub.2F H CH.sub.3CO H (CH.sub.2).sub.5CH.sub.3 460 CH.sub.2F H
CH.sub.3CH.sub.2CO H (CH.sub.2).sub.13CH.sub.3 461 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.2- CO H (CH.sub.2).sub.5CH.sub.3 462
CH.sub.2F H CH.sub.3(CH.sub.2).sub.3CO H (CH.sub.2).sub.13CH.sub.3
463 CH.sub.2F H CH.sub.3(CH.sub.2).sub.4CO H
(CH.sub.2).sub.5CH.sub.3 464 CH.sub.2F H CH.sub.3(CH.sub.2).sub.5CO
H (CH.sub.2).sub.13CH.sub.3 465 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.6CO H (CH.sub.2).sub.5CH.sub.3 466 CH.sub.2F
H CH.sub.3(CH.sub.2).sub.8CO H (CH.sub.2).sub.13CH.sub.3 467
CH.sub.2F H CH.sub.3(CH.sub.2).sub.1- 0CO H
(CH.sub.2).sub.5CH.sub.3 468 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.12CO H (CH.sub.2).sub.13CH.sub.3 469
CH.sub.2F H CH.sub.3(CH.sub.2).sub.14CO H (CH.sub.2).sub.5CH.sub.3
470 CH.sub.2F H CH.sub.3(CH.sub.2).sub.16CO H
(CH.sub.2).sub.13CH.sub.3 471 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.18CO H (CH.sub.2).sub.5CH.sub.3 472
CH.sub.2F H CH.sub.3(CH.sub.2).sub.20- CO H
(CH.sub.2).sub.13CH.sub.3 473 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.22CO H (CH.sub.2).sub.5CH.sub.3 474
CH.sub.2F H CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO
(CH.sub.2).sub.13CH.sub- .3 475 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.5CO
(CH.sub.2).sub.5CH.sub.3 476 CH.sub.2F H CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.13CH.sub.3 477 CH.sub.2F
H CH.sub.3(CH.sub.2).sub.4- CO CH.sub.3(CH.sub.2).sub.13CO
(CH.sub.2).sub.5CH.sub.3 478 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO (CH.sub.2).sub.13CH.sub.3
479 CH.sub.2F H CH.sub.3(CH.sub.2).sub.1- 2CO
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 480 CH.sub.2F H
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.13CH.sub.3 481 CH.sub.2F H CH.sub.3(CH.sub.2).sub.1-
2CO CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 482
CH.sub.2F CH.sub.3CO H H (CH.sub.2).sub.13CH.sub.3 483 CH.sub.2F
CH.sub.3CH.sub.2CO H H (CH.sub.2).sub.5CH.sub.3 484 CH.sub.2F
CH.sub.3(CH.sub.2).sub.2CO H H (CH.sub.2).sub.13CH.sub.3 485
CH.sub.2F CH.sub.3(CH.sub.2).sub.3CO H H (CH.sub.2).sub.5CH.sub.3
486 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO H H
(CH.sub.2).sub.13CH.sub.3 487 CH.sub.2F CH.sub.3(CH.sub.2).sub.5CO
H H (CH.sub.2).sub.5CH.sub.3 488 CH.sub.2F
CH.sub.3(CH.sub.2).sub.6CO H H (CH.sub.2).sub.13CH.sub.3 489
CH.sub.2F CH.sub.3(CH.sub.2).sub.8CO H H (CH.sub.2).sub.5CH.sub.3
490 CH.sub.2F CH.sub.3(CH.sub.2).sub.- 10CO H H
(CH.sub.2).sub.13CH.sub.3 491 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
H H (CH.sub.2).sub.5CH.sub.3 492 CH.sub.2F
CH.sub.3(CH.sub.2).sub.14CO H H (CH.sub.2).sub.13CH.sub.3 493
CH.sub.2F CH.sub.3(CH.sub.2).sub.16CO H H (CH.sub.2).sub.5CH.sub.3
494 CH.sub.2F CH.sub.3(CH.sub.2).sub.18CO H H
(CH.sub.2).sub.13CH.sub.3 495 CH.sub.2F CH.sub.3(CH.sub.2).sub.20C-
O H H (CH.sub.2).sub.5CH.sub.3 496 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3CO (CH.sub.2).sub.13CH.sub.3
497 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO H
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 498 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO H CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.13CH.sub.3 499 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
H CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 500
CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3CO
(CH.sub.2).sub.13CH.sub.3 501 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
H CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 502 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO H CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.13CH.sub.3 503 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
H CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.5CH.sub.3 504
CH.sub.2F CH.sub.3CO CH.sub.3CO H (CH.sub.2).sub.13CH.sub.3 505
CH.sub.2F CH.sub.3CH.sub.2CO CH.sub.3CH.sub.2CO H CH.sub.3 506
CH.sub.2F CH.sub.3(CH.sub.2).sub.2CO CH.sub.3(CH.sub.2).sub.2CO H
(CH.sub.2).sub.5CH.sub.3 507 CH.sub.2F CH.sub.3(CH.sub.2).sub.3CO
CH.sub.3(CH.sub.2).sub.3CO H (CH.sub.2).sub.10CH.sub.3 508
CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO H
(CH.sub.2).sub.13CH.sub.3 509 CH.sub.2F CH.sub.3(CH.sub.2).sub.5CO
CH.sub.3(CH.sub.2).sub.5CO H (CH.sub.2).sub.15CH.sub.3 510
CH.sub.2F CH.sub.3(CH.sub.2).sub.6CO CH.sub.3(CH.sub.2).sub.6CO H
(CH.sub.2).sub.17CH.sub.3 511 CH.sub.2F CH.sub.3(CH.sub.2).sub.8CO
CH.sub.3(CH.sub.2).sub.8CO H (CH.sub.2).sub.21CH.sub.3 512
CH.sub.2F CH.sub.3(CH.sub.2).sub.10CO CH.sub.3(CH.sub.2).sub.10CO H
CH.sub.3 513 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO H (CH.sub.2).sub.5CH.sub.3 514
CH.sub.2F CH.sub.3(CH.sub.2).sub.14CO CH.sub.3(CH.sub.2).sub.14CO H
(CH.sub.2).sub.10CH.sub.3 515 CH.sub.2F CH.sub.3(CH.sub.2).sub.16C-
O CH.sub.3(CH.sub.2).sub.16CO H (CH.sub.2).sub.13CH.sub.3 516
CH.sub.2F CH.sub.3(CH.sub.2).sub.18CO CH.sub.3(CH.sub.2).sub.18CO H
(CH.sub.2).sub.15CH.sub.3 517 CH.sub.2F CH.sub.3(CH.sub.2).sub.20C-
O CH.sub.3(CH.sub.2).sub.20CO H (CH.sub.2).sub.17CH.sub.3 518
CH.sub.2F CH.sub.3(CH.sub.2).sub.22CO CH.sub.3(CH.sub.2).sub.22CO H
(CH.sub.2).sub.21CH.sub.3 519 CH.sub.2F CH.sub.3(CH.sub.2).sub.12C-
O CH.sub.3(CH.sub.2).sub.6CO H CH.sub.3 520 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO H
(CH.sub.2).sub.5CH.sub.3 521 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO (CH.sub.2).sub.10CH.sub.3 522
CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.13CH.sub.3 523 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.15CH.sub.3 524 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.17CH.sub.3 525 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO
(CH.sub.2).sub.21CH.sub.3 526 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO CH.sub.3 527
CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.5CH.sub.3 528 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.10CH.sub.3 529 CH.sub.2F
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3(CH.sub.2).sub.12CO CH.sub.3CO
(CH.sub.2).sub.13CH.sub.3 530 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.5CO
(CH.sub.2).sub.15CH.sub.3 531 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.10CO
(CH.sub.2).sub.17CH.sub.3 532 CH.sub.2F CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.13CO
(CH.sub.2).sub.21CH.sub.3 533 CH.sub.2F CH.sub.3(CH.sub.2).sub.12CO
CH.sub.3(CH.sub.2).sub.4CO CH.sub.3CO CH.sub.3 534 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.5CO (CH.sub.2).sub.5CH.sub.3 535 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12CO CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.10CO (CH.sub.2).sub.10CH.sub.3 536 CH.sub.2F
CH.sub.3(CH.sub.2).sub.12C- O CH.sub.3(CH.sub.2).sub.4CO
CH.sub.3(CH.sub.2).sub.13CO (CH.sub.2).sub.13CH.sub.3
[2733] Of the above exemplary compounds, preferred are Compounds
36, 37, 38, 38a, 39, 39a, 40, 40a, 41, 41a 42, 42a, 43, 43a, 44,
44a, 45, 45a 45b, 45c,87, 87a, 87b, 87c, 87d, 87e, 87f, 87g, 88,
88a, 89, 90, 91, 92, 92a, 93, 94, 94a, 94b, 214, 215, 216, 217,
218, 219, 220, 221, 222, 223, 265, 266, 267, 268, 269, 270, 271,
272, 393, 394, 395, 396, 397, 398, 399, 400, 401, 402, 444, 445,
446, 447, 448, 449, 450 and 451.
[2734] More preferred are Compounds 36, 37, 38, 38a, 39, 39a, 40,
40a, 41, 41a, 42, 42a, 43, 43a, 44, 44a, 45, 45a, 45b, 45c, 87,
87a, 87b, 87c, 87d, 87e, 87f, 87g, 88, 88a, 89, 90, 91, 92, 92a,
93, 94, 94a, 94b, 219, 220, 221, 222, 269, 270, 271, 272, 398, 399,
400, 401, 448, 449, 450 and 451.
[2735] The following compounds are most preferred.
[2736]
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-hexanoyl-D-glycero-D-
-galacto-non-2-enopyranosoic acid (Exemplary compound No. 36)
[2737]
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-octanoyl-D-glycero-D-
-galacto-non-2-enopyranosoic acid (Exemplary compound No. 38)
[2738]
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-decanoyl-D-glycero-D-
-galacto-non-2-enopyranosoic acid (Exemplary compound No. 39)
[2739]
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-dodecanoyl-D-glycero-
-D-galacto-non-2-enopyranosoic acid (Exemplary compound No. 40)
[2740]
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-myristoyl-D-glycero--
D-galacto-non-2-enopyranosoic acid (Exemplary compound No. 41)
[2741]
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-palmitoyl-D-glycero--
D-galacto-non-2-enopyranosoic acid (Exemplary compound No. 42)
[2742]
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-stearoyl-D-glycero-D-
-galacto-non-2-enopyranosoic acid (Exemplary compound No. 43)
[2743] hexyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galact-
o-non-2-enopyranosoate (Exemplary compound No. 87)
[2744] myristyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-gal-
acto-non-2-enopyranosoate (Exemplary compound No. 88)
[2745] cetyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galact-
o-non-2-enopyranosoate (Exemplary compound No. 89)
[2746] stearyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-gala-
cto-non-2-enopyranosoate (Exemplary compound No. 91)
[2747] In the following, the process for preparing the compound (1)
of the present invention will be described.
[2748] The compound (1) of the present invention can be prepared
according to the process described in Process A, B or C shown
below. Further, the compound (1) can be also prepared according to
Process J described later.
[2749] The raw material compound (2) used in Processes A and B can
be prepared according to the processes described in Process D, E, F
or G shown below. Further, the raw material compound (5) used in
Process C can be prepared according to the process described in
Process H shown below.
[2750] The meanings of R.sup.1, R.sup.2, R.sup.2a, R.sup.2b,
R.sup.3, R.sup.3a, R.sup.4, R.sup.4a, R.sup.6, R.sup.7, R.sup.8, W,
W.sup.a, Me, Ac and Boc used in the steps of Processes A to J are
shown below.
[2751] That is, R.sup.1, R.sup.2, R.sup.3, R.sup.4 and W have the
same meanings as defined above,
[2752] R.sup.a has the same meaning as defined for the above
R.sup.2 or represents a protecting group of the hydroxyl group
(preferably a t-butyldimethylsilyl group or an isopropylidene group
taken together with the protecting group of the hydroxyl group of
R.sup.3a),
[2753] R.sup.2b represents a protecting group of the hydroxyl group
(preferably a t-butyldimethylsilyl group),
[2754] R.sup.3a has the same meaning as defined for the above
R.sup.3 or represents a protecting group of the hydroxyl group
(preferably a t-butyldimethylsilyl group or an isopropylidene group
taken together with the protecting group of the hydroxyl group of
R.sup.2a),
[2755] R.sup.4a has the same meaning as defined for the above
R.sup.4 or represents a protected hydroxyl group (preferably a
t-butyldimethylsilyl group),
[2756] R.sup.6, R.sup.7 and R.sup.8 may be the same or different
and each represent an aliphatic acyl group having from 3 to 25
carbon atoms,
[2757] W.sup.a has the same meaning as defined for the above W or
represents a protecting group of the carboxyl group (preferably a
methyl, ethyl, benzyl, allyl, methoxymethyl, methylthiomethyl,
2-(trimethylsilyl)ethoxymethoxy or diphenylmethyl group, more
preferably a methyl, benzyl or diphenylmethyl group),
[2758] Ac represents an acetyl group,
[2759] Boc represents a t-butoxycarbonyl group, and
[2760] Me represents a methyl group.
[2761] In the following, each Process will be described in detail.
58
[2762] Process A is a process for preparing the compound (i) of the
present invention by eliminating the protecting group of the
compound (3) obtained by reacting the raw material compound (2)
which is easily available according to the method described later
with N,N'-di-t-butoxycarbonylthiourea.
[2763] (Step A-1)
[2764] The present step is to prepare the compound (3) by reacting
the compound (2) with N,N'-di-t-butoxycarbonylthiourea in an inert
solvent in the presence of a base and mercuric chloride.
[2765] The solvent employable is not particularly limited so long
as it does not affect the reaction and includes aromatic
hydrocarbons such as benzene, toluene and xylene; ethers such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; and amides
such as N,N-dimethylacetamide and dimethylformamide, preferably
amides (particularly N,N-dimethylacetamide and
dimethylformamide).
[2766] The base employable here includes preferably organic bases
such as triethylamine and dimethylaminopyridine.
[2767] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 30.degree. C.
[2768] The reaction time varies depending on the material used, the
base, the reaction temperature, etc. and is usually from 1 to 24
hours, preferably from 5 to 10 hours.
[2769] After the reaction, the desired compound is obtained, for
example, by filtering the reaction mixture under reduced pressure
to remove insolubles, adding a water-immiscible organic solvent
such as ethyl acetate thereto, washing the mixture with water,
separating the organic layer containing the desired compound,
drying the layer over anhydrous magnesium sulfate, and distilling
off the solvent.
[2770] If necessary, the desired compound can be further purified
by recrystalization or various kinds of chromatographies.
[2771] (Step A-2)
[2772] The present step is to prepare the compound (1) of the
present invention by reacting the compound (3) with a reagent for
eliminating the tert-butoxycarbonyl group in an inert solvent.
[2773] The solvent employable is not particularly limited so long
as it does not affect the reaction and includes preferably alcohols
such as methanol and ethanol, water and a mixture thereof.
[2774] The reagent for elimination is preferably an acid, and the
acid is not particularly limited so long as it is used as an acid
catalyst in the usual reaction and includes Bronsted acids such as
inorganic acids, e.g. hydrochloric acid, hydrobromic acid, sulfuric
acid, perchloric acid and phosphoric acid, and organic acids, e.g.
acetic acid, formic acid, oxalic acid, methanesulfonic acid,
para-toluenesulfonic acid, trifluoroacetic acid and
trifluoromethanesulfonic acid; Lewis acids such as zinc chloride,
tin tetrachloride, boron trichloride, boron trifluoride and boron
tribromide; and acidic ion exchange resins, preferably organic
acids (particularly acetic acid and trifluoroacetic acid).
[2775] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 30.degree. C.
[2776] The reaction time varies depending on the material, the
base, the reaction temperature, etc. and is usually from 15 minutes
to 10 hours, preferably from 1 to 5 hours.
[2777] After the reaction, the desired compound can be obtained,
for example, by neutralizing the reaction mixture, distilling off
the solvent under reduced pressure, and then purifying the residue
over silica gel column chromatography.
[2778] Further, in the case where R.sup.2a, R.sup.3a or R.sup.4a is
a protecting group of a hydroxyl group or W.sup.a is a protecting
group of a carboxyl group, they are further eliminated to obtain
the compound (1) of the present invention.
[2779] The method for eliminating the protecting group varies
depending on the kind of the protecting group and can be carried
out according to the methods usually used, for example, the methods
described in Protective Groups in Organic Synthesis, Second Edition
(1991, Green et al.).
[2780] In the case where the protecting group of a hydroxyl group
is a trialkylsilyl group such as a tert-butyldimethylsilyl group,
acetic acid is preferably used in a mixture of water and
tetrahydrofuran, or tetrabutylammonium fluoride is used in
tetrahydrofuran.
[2781] In the case where the protecting group of a hydroxyl group
is an isopropylidene group, the method of Step E-2 or E-4 described
later is used.
[2782] In the case where the protecting group of a carboxyl group
is a diphenylmethyl group, catalytic reduction is carried out, an
acid such as acetic acid and trifluoroacetic acid is used or
trifluoroboran-diethyl ether complex is used.
[2783] In the case where the protecting group of a carboxyl group
is a benzyl group, catalytic reduction is carried out, and in the
case where the protecting group is the methyl group, hydrolysis is
carried out. 59
[2784] Process B is a process for preparing the compound (1) of the
present invention by reacting the raw material compound (2), which
is easily available according to the method described later, with a
cyanating agent, reacting the resulting compound with ammonia, and
further, if necessary, eliminating the protecting group.
[2785] (Step B-1)
[2786] The present step is to prepare a compound (4) by reacting
the compound (2) with a cyanating agent in an inert solvent.
[2787] The solvent employable is not particularly limited so long
as it does not affect the reaction and includes alcohols such as
methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol,
t-butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol,
cyclohexanol and methyl cellosolve; amides such as formamide,
N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone and
hexamethylphosphoric triamide; and sulfoxides such as dimethyl
sulfoxide and sulfolane, preferably alcohols (particularly
methanol).
[2788] The cyanating agent employable includes preferably cyanogen
bromide, and sodium acetate is simultaneously employed as a
base.
[2789] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 40.degree. C.
[2790] The reaction time varies depending on the material used, the
base, the reaction temperature, etc. and is usually from 15 minutes
to 10 hours, preferably from 1 to 5 hours.
[2791] After the reaction, the desired compound can be obtained,
for example, by distilling off the solvent and then purifying the
residue by recrystalization or silica gel column
chromatography.
[2792] (Step B-2)
[2793] The present step is to prepare the compound (1) of the
present invention by reacting the compound (4) with ammonia in an
inert solvent.
[2794] The solvent employable is not particularly limited so long
as it does not affect the reaction and includes preferably alcohols
(particularly methanol).
[2795] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 40.degree. C.
[2796] The reaction time varies depending on the material used, the
base, the reaction temperature, etc. and is usually from 15 minutes
to 10 hours, preferably from 1 to 5 hours.
[2797] After the reaction, the desired compound can be obtained,
for example, by distilling off the solvent and then purifying the
residue by recrystalization or silica gel column
chromatography.
[2798] Incidentally, in the case where R.sup.2a, R.sup.3a or
R.sup.4a is a protecting group of a hydroxyl group, or W.sup.a is a
protecting group of a carboxyl group, the compound of the present
invention is obtained by eliminating the protecting group in a
similar manner to Process A. 60
[2799] Process C is a process for preparing the compound (1) of the
present invention by acylating partly or entirely the hydroxyl
groups of the raw material compound (5) which is easily available
according to the method described later, and then eliminating the
protecting group of the resulting compound.
[2800] (Step C-1)
[2801] The present step is to prepare the compound (6) by
introducing a desired acyl group to the compound (5) in an inert
solvent.
[2802] The acylation method includes the following methods 1 to
3.
[2803] <Method 1>
[2804] Method 1 is to react a compound of the general formula:
RCO--Hal or a compound of the general formula: RCO--O--COR
[2805] [wherein,
[2806] R represents an alkyl group, Hal represents a group to be
eliminated, and the group to be eliminated is not particularly
limited so long as it is a group to be eliminated as a nucleophilic
residue and includes preferably a halogen atom such as chlorine,
bromine and iodine; a lower alkoxycarbonyloxy group such as
methoxycarbonyloxy and ethoxycarbonyloxy; a halogenated
alkylcarbonyloxy group such as chloroacetyloxy, dichloroacetyloxy,
trichloroacetyloxy and trifluoroacetyloxy; a lower
alkanesulfonyloxy group such as methanesulfonyloxy and
ethanesulfonyloxy; a halogeno lower alkanesulfonyloxy group such as
trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; and
an arylsulfonyloxy group such as benzenesulfonyloxy,
p-toluenesulfonyloxy and p-nitrobenzenesulfonyloxy, more preferably
a halogen atom, a halogeno lower alkanesulfonyloxy group and an
arylsulfonyloxy group]
[2807] with the compound (5) in a solvent in the presence or
absence of a base.
[2808] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably aliphatic
hydrocarbons such as hexane and heptane; aromatic hydrocarbons such
as benzene, toluene and xylene; halogenated hydrocarbons such as
methylene chloride, chloroform, carbon tetrachloride,
dichloroethane, chlorobenzene and dichlorobenzene; esters such as
ethyl formate, ethyl acetate, propyl acetate, butyl acetate and
diethyl carbonate; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol
dimethyl ether; nitriles such as acetonitrile and isobutyronitrile;
and amides such as formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methyl-2-pyrrolidone,
N-methylpyrrolidinone and hexamethylphosphoric triamide.
[2809] The base employable is not particularly limited so long as
it is used as a base in the usual reaction and includes preferably
organic bases such as N-methylmorpholine, triethylamine,
tributylamine, diisopropylethylamine, dicyclohexylamine,
N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline,
4-(N,N-dimethylamino)pyridine, 2,6-di(tert-butyl)-4-methylpyridine,
quinoline, N,N-dimethylaniline and N,N-diethylaniline.
[2810] Incidentally, 4-(N,N-dimethylamino)pyridine and
4-pyrrolidinopyridine can be used at a catalytic amount by
combining it with other bases, and further quaternary ammonium
salts such as benzyltriethylammonium chloride and
tetrabutylammonium chloride and crown ethers such as
dibenzo-18-crown-6 can be also added thereto in order to
effectively carry out the reaction.
[2811] The reaction is usually carried out at from -20.degree. C.
to the refluxing temperature of the solvent used, preferably from
0.degree. C. to the refluxing temperature of the solvent used.
[2812] The reaction time varies mainly depending on the reaction
temperature, the raw material compound, the base used or the kind
of the solvent used, and is usually from 10 minutes to 3 days,
preferably from 1 to 6 hours.
[2813] <Method 2>
[2814] Method 2 is to react a compound of the general formula:
RCOOH [wherein R has the same meaning as defined above] with the
compound (5) in a solvent in the presence or absence of "an
esterifying agent" and a catalytic amount of base.
[2815] The "esterifying agent" employable includes a condensing
agent; halogenated formates such as methyl chloroformate and ethyl
chloroformate; and cyanophosphoric acid diesters such as diethyl
cyanophosphate. Such "condensing agents" includes N-hydroxy
derivatives such as N-hydroxysuccinimide, 1-hydroxybenzotriazole
and N-hydroxy-5-norbornene-2,3-dicarboxyimide; disulfide compounds
such as 2,2'-dipyridyl disulfide; succinic acid compounds such as
N,N'-disuccinimidyl carbonate; phosphinic chloride compounds such
as N,N'-bis(2-oxo-3-oxazolidinyl)phosphinic chloride; oxalate
derivatives such as N,N'-disuccinimidyl oxalate (DSO),
N,N'-diphthalimide oxalate (DPO),
N,N'-bis(norbornenylsuccinimidyl)oxalate (BNO),
1,1'-bis(benzotriazolyl)oxalate (BBTO),
1,1'-bis(6-chlorobenzotriazolyl)o- xalate (BCTO) and
1,1'-bis(6-trifluoromethylbenzotriazolyl)oxalate (BTBO);
triarylphosphines such as triarylphosphines, e.g.
triphenylphosphine and azodicarboxylic acid di-lower
alkyl-triarylphosphines such as diethyl
azodicarboxylate-triphenylphosphine; N-lower
alkyl-5-arylisoxazolium-3'-s- ulfonates such as
N-ethyl-5-phenylisoxazolium-3'-sulfonate; carbodiimide derivatives
such as N',N'-dicycloalkylcarbodiimides, e.g.
N',N'-dicyclohexylcarbodiimide (DCC) and
1-ethyl-3-(3-dimethylaminopropyl- )carbodiimide (EDAPC);
diheteroaryldiselenides such as di-2-pyridyldiselenide;
arylsulfonyltriazolides such as p-nitrobenzenesulfonyltriazolide;
2-halo-1-lower alkylpyridinium halides such as
2-chloro-1-methylpyridinium iodide; diarylphosphorylazides such as
diphenylphosphorylazide (DPPA); and imidazole derivatives such as
1,1'-oxazolyldiimidazole and N,N'-carbonyldiimidazole, preferably
diarylphosphorylazides.
[2816] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably aliphatic
hydrocarbons such as hexane and heptane; aromatic hydrocarbons such
as benzene, toluene and xylene; halogenated hydrocarbons such as
methylene chloride, chloroform, carbon tetrachloride,
dichloroethane, chlorobenzene and dichlorobenzene; esters such as
ethyl formate, ethyl acetate, propyl acetate, butyl acetate and
diethyl carbonate; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol
dimethyl ether; nitriles such as acetonitrile and isobutyronitrile;
amides such as formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methyl-2-pyrrolidone,
N-methylpyrrolidinone and hexamethylphosphoric triamide.
[2817] As the base to be used, similar bases to those described in
the above <Method 1> can be employed.
[2818] The reaction is carried out at from -20.degree. C. to
80.degree. C., preferably from 0.degree. C. to room
temperature.
[2819] The reaction time varies depending mainly on the reaction
temperature, the raw material compound, the reaction reagent or the
kind of solvent used, and is usually from 10 minutes to 3 days,
preferably from 30 minutes to one day.
[2820] <Method 3>
[2821] Method 3 is to react the compound of the general formula:
RCOOH [wherein R has the same meaning as defined above] with the
compound (5) in a solvent in the presence of halogenated phosphoric
acid dialkyl ester such as diethyl chlorophosphate and a base.
[2822] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably aliphatic
hydrocarbons such as hexane and heptane; aromatic hydrocarbons such
as benzene, toluene and xylene; halogenated hydrocarbons such as
methylene chloride, chloroform, carbon tetrachloride,
dichloroethane, chlorobenzene and dichlorobenzene; esters such as
ethyl formate, ethyl acetate, propyl acetate, butyl acetate and
diethyl carbonate; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol
dimethyl ether; nitriles such as acetonitrile and isobutyronitrile;
and amides such as formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methyl-2-pyrrolidone,
N-methylpyrrolidinone and hexamethylphosphoric triamide.
[2823] As the base used, similar bases to those described in the
above <Method 1> can be employed.
[2824] The reaction is carried out at from 0.degree. C. to the
refluxing temperature of the solvent used, preferably from room
temperature to 50.degree. C.
[2825] The reaction time varies depending mainly on the reaction
temperature, the raw material compound, the reaction reagent or the
kind of solvent used, and is usually from 10 minutes to 3 days,
preferably from 30 minutes to one day.
[2826] In the above <Method 1>, <Method 2> and
<Method 3>, the compound (6) in which from 1 to 3 acyl groups
are introduced to the compound (5) can be obtained by appropriately
controlling an equivalent amount of the acylating agent used
relative to the compound (5).
[2827] After the reaction, the desired compound (6) of the present
reaction is collected from the reaction mixture according to the
conventional method.
[2828] For example, the desired compound can be obtained by
appropriately neutralizing the reaction mixture, eliminating
insolubles by filtration if they exist, adding a water-immiscible
organic solvent such as ethyl acetate thereto, washing it with
water, separating the organic layer containing the desired
compound, drying the layer over anhydrous magnesium sulfate and
distilling off the solvent.
[2829] The desired compound thus obtained can be separated and
purified, if necessary, by appropriately combining the conventional
methods, for example, recrystalization, reprecipitation or a method
usually employable for separation and purification of organic
compounds, for example, adsorption column chromatography using
carriers such as silica gel, alumina, Florisil of magnesium-silica
gel system; a method using a synthesized adsorbing agent such as
partition column chromatography using carriers such as Sephadex
LH-20 (manufactured by Pharmacia Co., Ltd.), Amberlite XAD-11
(manufactured by Rohm & Haas Co., Ltd.) and Diaion BP-20
(Mitsubishi Chemical Corp.), or normal phase-reversed phase column
chromatography using silica gel or alkylated silica gel (preferably
high performance liquid chromatography), and eluting it with
appropriate eluting solutions.
[2830] (Step C-2)
[2831] The present step is to prepare the compound (1) of the
present invention by eliminating a t-butoxycarbonyl group in the
compound (6) in an inert solvent.
[2832] The present step can be carried out similarly to the
procedures of Step A-2.
[2833] Further, in the case where W.sup.a is a protecting group of
a carboxyl group, the compound (1) of the present invention can be
obtained by further eliminating them similarly to the procedures of
Step A-2. 61
[2834] Process D is to prepare the compound (2a) which is one of
the raw material compounds in Processes A and B using the raw
material compound (7) easily available according to the method
described later.
[2835] (Step D-1)
[2836] The present step is to prepare a compound (8) by reacting
the compound (7) with a base in an inert solvent.
[2837] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably aliphatic
hydrocarbons such as hexane, heptane, ligroin and petroleum ether,
aromatic hydrocarbons such as benzene, toluene and xylene;
halogenated hydrocarbons such as methylene chloride, chloroform,
carbon tetrachloride, dichloroethane, chlorobenzene and
dichlorobenzene; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol
dimethyl ether; and methanol, preferably halogenated hydrocarbons
and methanol.
[2838] The base employable is not particularly limited so long as
it does not affect other functional groups (for example, methyl
ester) and includes preferably alkali metal methoxides such as
sodium methoxide and potassium methoxide.
[2839] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 30.degree. C.
[2840] The reaction time varies depending on the material used, the
base, the reaction temperature, etc., and is usually from 15
minutes to 10 hours, preferably from 1 to 5 hours.
[2841] After the reaction, the desired compound can be obtained,
for example, by neutralizing the reaction mixture with hydrochloric
acid/dioxane solution, distilling off the solvent under reduced
pressure, and then purifying the residue over silica gel column
chromatography.
[2842] (Step D-2)
[2843] The present step is to prepare the compound (9) by reacting
the compound (8) with a reagent for introducing an isopropylidene
group in an inert solvent.
[2844] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes aliphatic hydrocarbons such
as hexane, heptane, ligroin and petroleum ether; aromatic
hydrocarbons such as benzene, toluene and xylene; ethers such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; and ketones
such as acetone, methyl ethyl ketone, methyl isobutyl ketone,
isophorone and cyclohexanone, preferably ketones (particularly
acetone).
[2845] The reagent employable includes preferably
2,2-dimethoxypropane and acids such as p-toluenesulfonic acid are
used as a catalyst.
[2846] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 30.degree. C.
[2847] The reaction time varies depending on the material used, the
base, the reaction temperature, etc., and is usually from 15
minutes to 10 hours, preferably from 1 to 5 hours.
[2848] After the reaction, the desired compound can be obtained,
for example, by adding a water-immiscible solvent such as ethyl
acetate and an aqueous sodium hydrogencarbonate solution to the
reaction mixture, extracting the desired compound with ethyl
acetate, and distilling off the solvent. The desired compound can
be further purified, if necessary, by recrystalization or various
kinds of chromatographies.
[2849] (Step D-3)
[2850] The present step is, if necessary, 1) to substitute the
methyl group of the methyl carboxylate portion with other ester
residue, 2) to hydrolize the methyl carboxylate portion or 3) to
introduce a protecting group of the carboxyl group or the ester
residue after hydrolysis of 2).
[2851] (Ester Interchange)
[2852] The present step is to prepare the compound (10) by reacting
the compound (9) with an alcohol which can give the desired ester
group in an inert solvent in the presence of a base.
[2853] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and includes, for example,
aliphatic hydrocarbons such as hexane, heptane, ligroin and
petroleum ether; aromatic hydrocarbons such as benzene, toluene and
xylene; halogenated hydrocarbons such as methylene chloride,
chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and
dichlorobenzene; ethers such as diethyl ether, diisopropyl ether,
tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol
dimethyl ether; and alcohols such as methanol, ethanol, n-propanol,
isopropanol, n-butanol, isobutanol, t-butanol, isoamyl alcohol,
diethylene glycol, glycerin, octanol, cyclohexanol and methyl
cellosolve. Preferably, an alcohol forming the desired ester group
may be employed as the solvent.
[2854] The base employable includes preferably organic bases such
as pyridine, triethylamine, diethylamine and
4-N,N-dimethylaminopyridine.
[2855] After the reaction, the desired compound can be obtained,
for example, by neutralizing the reaction mixture with an acid,
adding a water-immiscible solvent such as ethyl acetate to the
mixture, extracting the desired compound with ethyl acetate, etc.,
washing it with water, and distilling off the solvent. The desired
compound can be further purified, if necessary, by recrystalization
or various kinds of chromatographies.
[2856] (Diphenylmethylation)
[2857] The present step is to prepare the compound (10) by reacting
the compound (9) with diphenyldiazomethane in an inert solvent in
the presence of Lewis acid.
[2858] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably aliphatic
hydrocarbons such as hexane, heptane, ligroin and petroleum ether;
aromatic hydrocarbons such as benzene, toluene and xylene;
halogenated hydrocarbons such as methylene chloride, chloroform,
carbon tetrachloride, dichloroethane and chlorobenzene; ethers such
as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and ethylene glycol dimethyl ether; and alcohols
such as methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, isoamyl alcohol, diethylene glycol,
glycerin, octanol, cyclohexanol and methyl cellosolve, more
preferably alcohols (particularly methanol), halogenated
hydrocarbons (dichloromethane); and mixtures thereof.
[2859] The Lewis acid employable includes preferably boron
trifluoride-ether complex.
[2860] The reaction temperature is usually from 0 to 50.degree. C.,
preferably room temperature.
[2861] The reaction time varies depending on the starting material,
Lewis acid and the reaction temperature, and is usually from 10
minutes to 5 hours, preferably from 1 to 3 hours.
[2862] After the reaction, the solvent is distilled off and
purification by recrystalization or chromatography is carried out
to obtain the desired compound.
[2863] (Hydrolysis)
[2864] The present step is to prepare the compound (10) in which
W.sup.a is a hydrogen atom by hydrolizing the compound (9) in an
inert solvent in the presence of a base.
[2865] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes aromatic hydrocarbons such as
benzene and toluene; ethers such as diethyl ether and
tetrahydrofuran; halogenated hydrocarbons such as dichloromethane
and chloroform; ketones such as acetone and methyl ethyl ketone;
water; and mixtures of these organic solvents and water.
[2866] The base employable includes alkali metal hydroxides such as
lithium hydroxide, sodium hydroxide and potassium hydroxide; and
alkali metal hydrogencarbonates such as sodium hydrogencarbonate
and potassium hydrogencarbonate.
[2867] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 30.degree. C.
[2868] The reaction time varies depending on the raw material used,
the base, the reaction temperature, etc., and is usually from 15
minutes to 10 hours, preferably from 1 to 5 hours.
[2869] After the reaction, the desired compound can be obtained,
for example, by cooling the reaction mixture, making it weakly
acidic using dilute hydrochloric acid, adding a water-immiscible
solvent such as ethyl acetate to the reaction mixture, extracting
the desired compound with ethyl acetate, and distilling off the
solvent. The desired compound can be further purified by
recrystalization or various kinds of chromatographies.
[2870] (Introduction of the Protecting Group of Carboxyl Group or
the Ester Residue)
[2871] The present step is to prepare the compound (10) by
introducing the protecting group or the ester residue to the
carboxyl group at the 1-position of the compound (9) in which
W.sup.a is a hydrogen atom.
[2872] Introduction of the protecting group or the ester residue
varies depending on the kind of ester residue or the protecting
group, and can be carried out according to the methods generally
used in the field of organic synthesis chemistry, for example, the
methods described in Protective Groups in Organic Synthesis, Second
Edition (1991, Green et al.).
[2873] (Step D-4)
[2874] The present step is to prepare the compound (2a) from the
compound (10) using a reducing agent in an inert solvent.
[2875] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably aliphatic
hydrocarbons such as hexane, heptane, ligroin and petroleum ether;
aromatic hydrocarbons such as benzene, toluene and xylene; ethers
such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; alcohols such
as methanol, ethanol, n-propanol, isopropanol, n-butanol,
isobutanol, t-butanol, isoamyl alcohol, diethylene glycol,
glycerin, octanol, cyclohexanol and methyl cellosolve; ketones such
as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone
and cyclohexanone; nitriles such as acetonitrile and
isobutyronitrile; amides such as formamide, N,N-dimethylformamide,
N,N-dimethylacetamide, N-methyl-2-pyrrolidone,
N-methylpyrrolidinone and hexamethylphosphoric triamide; sulfoxides
such as dimethyl sulfoxide and sulfolane; aliphatic carboxylic
acids such as acetic acid; and mixtures of these organic solvents
and water, preferably the alcohols (particularly methanol), the
ethers such as tetrahydrofuran and dioxane, the aliphatic
carboxylic acids such as acetic acid, and mixtures of these organic
solvents and water.
[2876] As the reducing agent used, a catalyst such as
palladium-carbon, platinum and Raney nickel may be employed in the
presence of hydrogen gas, and a Lindlar catalyst (Pd--BaSO.sub.4 or
Pd--CaCO.sub.3 and quinoline or lead acetate are employed in
combination) is particularly preferably employed.
[2877] The reaction temperature is usually from -10.degree. C. to
50.degree. C., preferably from 10 to 30.degree. C.
[2878] The reaction time varies depending on the raw material used,
the base, the reaction temperature, etc., and is usually from 15
minutes to 10 hours, preferably from 1 to 5 hours.
[2879] After the reaction, the desired compound can be obtained,
for example, by filtering the reaction mixture under reduced
pressure to remove the catalyst, and distilling off the solvent
under reduced pressure. The desired compound can be further
purified, if necessary, by recrystalization or various kinds of
chromatographies. 62
[2880] Process E is a process for preparing the compound (2b) or
(2c) which is one of the raw material compounds in Processes A and
B using the raw material compound (10) which is easily available
according to the above method.
[2881] (Step E-1)
[2882] The present step is to prepare the compound (12) by
introducing the desired acyl group to the compound (10) in an inert
solvent.
[2883] Further, the present step can be carried out similarly to
the procedures of the above Step C-1.
[2884] (Step E-2)
[2885] The present step is to prepare the compound (13) by treating
the compound (12) with a reagent for eliminating the isopropylidene
group in an inert solvent.
[2886] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably halogenated
hydrocarbons such as methylene chloride and chloroform.
[2887] As the reagent used for the elimination, an acid is
preferable, and the acid is not particularly limited so long as it
is used as an acid catalyst in the usual reaction and includes
Bronsted acids such as inorganic acids, e.g. hydrochloric acid,
hydrobromic acid, sulfuric acid, perchloric acid and phosphoric
acid, and organic acids such as formic acid, oxalic acid,
methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic acid
and trifluoromethanesulfonic acid; and Lewis acids such as zinc
chloride, tin tetrachloride, boron trichloride, boron trifluoride
and boron tribromide and acidic ion exchange resins, preferably
organic acids (particularly the trifluoroacetic acid).
[2888] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 30.degree. C.
[2889] The reaction time varies depending on the raw material used,
the base, the reaction temperature, etc., and is usually from 15
minutes to 10 hours, preferably from 1 to 5 hours.
[2890] After the reaction, the desired compound can be obtained,
for example, by neutralizing the reaction mixture, distilling off
the solvent under reduced pressure, and then purifying the residue
over silica gel chromatography.
[2891] Further, in the present step, the acyl group (R.sup.6) at
the 7-position is transferred to the 9-position.
[2892] (Step E-3)
[2893] The present step is to prepare the desired raw material
compound (2b) from the compound (13) using a reducing agent in an
inert solvent.
[2894] The present step can be carried out similarly to the
procedures of the above Step D4.
[2895] (Step E-4)
[2896] The present step is to prepare the compound (14) of the
present invention by treating the compound (12) with a reagent for
eliminating the isopropylidene group in an inert solvent in the
presence of an acid catalyst.
[2897] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably a mixture of
acetic acid (which is simultaneously utilized as the acid catalyst)
and water.
[2898] The reaction temperature is usually from 10 to 70.degree.
C., preferably from 30 to 60.degree. C.
[2899] The reaction time varies depending on the raw material used,
the base, the reaction temperature, etc., and is usually from 15
minutes to 24 hours, preferably from 10 to 20 hours.
[2900] After the reaction, the desired compound can be obtained,
for example, by distilling off the solvent under reduced pressure,
adding a water-immiscible solvent such as ethyl acetate and an
aqueous sodium hydrogencarbonate solution to the reaction mixture,
extracting the desired compound with ethyl acetate, and distilling
off the solvent. The desired compound can be further purified, if
necessary, by recrystalization or various kinds of
chromatographies.
[2901] (Step E-5)
[2902] The present step is to prepare the desired raw material
compound (2c) from the compound (14) using a reducing agent in an
inert solvent.
[2903] The present step can be carried out similarly to the
procedures in the above Step D4. 63
[2904] Process F is a process for preparing the compound (2d) or
(2c) which is one of the raw material compounds in Processes A and
B using the raw material compound (14) which is easily available
according to the above method.
[2905] (Step F-1)
[2906] The present step is to prepare the compound (15) by reacting
the compound (14) with a reagent for protecting the hydroxyl group
in an inert solvent.
[2907] The protecting group is not particularly limited and
includes preferably a tert-butyldimethylsilyl group and a
tert-butyldiphenylsilyl group.
[2908] Silylation can be carried out according to the usual
methods. For example, silylation can be carried out by reacting
tert-butyldimethylsilyl halide (particularly chloride) in
dimethylformamide in the presence of a base such as triethylamine
and 4-(N,N-dimethylamino)pyridine.
[2909] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 40.degree. C.
[2910] The reaction time varies depending on the raw material used,
the base, the reaction temperature, etc., and is usually from 15
minutes to 24 hours, preferably from 10 to 20 hours.
[2911] After the reaction, the desired compound can be obtained,
for example, by adding a water-immiscible solvent such as ethyl
acetate and an aqueous sodium hydrogencarbonate solution to the
reaction mixture, extracting the desired compound with ethyl
acetate, and distilling off the solvent. The desired compound can
be further purified, if necessary, by recrystalization or various
kinds of chromatographies.
[2912] (Step F-2)
[2913] The present step is to prepare the compound (16) by
introducing the desired acyl group to the compound (15) in an inert
solvent.
[2914] The present step can be carried out similarly to the
procedures of Step C-1.
[2915] (Step F-3)
[2916] The present step is to prepare the compound (17) by reacting
the compound (16) with a reagent for eliminating the protecting
group (preferably a tert-butyldimethylsilyl group or a
tert-butyldiphenylsilyl group) of the hydroxyl group in an inert
solvent.
[2917] The solvent employable includes preferably alcohols such as
methanol and ethanol, water and mixtures thereof.
[2918] Acids are preferably used as the reagent for the
elimination, and the acid is not particularly limited so long as it
is used as the acid catalyst in the usual reactions and includes
Bronsted acids such as inorganic acids, e.g. hydrochloric acid,
hydrobromic acid, sulfuric acid, perchloric acid and phosphoric
acid, and organic acids, e.g. acetic acid, formic acid, oxalic
acid, methanesulfonic acid, p-toluenesulfonic acid, trifluoroacetic
acid and trifluoromethanesulfonic acid, and Lewis acids such as
zinc chloride, tin tetrachloride, boron trichloride, boron
trifluoride and boron tribromide, and acidic ion exchange resins,
preferably organic acids (particularly acetic acid and
trifluoroacetic acid).
[2919] Reagents which produce a fluoride ion such as
tetrabutylammonium fluoride can be also used, as desired.
[2920] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 30.degree. C.
[2921] The reaction time varies depending on the raw material used,
the base, the reaction temperature, etc., and is usually from 15
minutes to 10 hours, preferably from 1 to 5 hours.
[2922] After the reaction, the desired compound can be obtained,
for example, by neutralizing the reaction mixture, distilling off
the solvent under reduced pressure, and then purifying the residue
over silica gel chromatography.
[2923] In the present step, the acyl group (R.sup.7) at the
8-position is transferred to the 9-position.
[2924] (Step F-4)
[2925] The present step is to prepare the compound (18) by 1)
protecting the hydroxyl group at the 8-position of the compound
(17) or 2) introducing the desired acyl group, as desired.
[2926] (Introduction of the Acyl Group)
[2927] The present step can be carried out similarly to the
procedures of Step C-1.
[2928] (Introduction of the Protecting Group)
[2929] As the protecting group, tert-butyldimethylsilyl group is
preferable, and introduction of the protecting group is carried out
using tert-butyldimethylsilyl triflate and lutidine in methylene
chloride.
[2930] (Step F-5)
[2931] The present step is to prepare the desired raw material
compound (2d) from the compound (18) using a reducing agent in an
inert solvent.
[2932] The present step can be carried out similarly to the
procedures of Step D-4.
[2933] (Step F-6)
[2934] The present step is to prepare the desired raw material
compound (2e) from the compound (16) using a reducing agent in an
inert solvent.
[2935] The present step can be carried out similarly to the
procedures of Step D4. 64
[2936] Process G is a process for preparing the compound (2f) or
(2g) which is one of the raw material compounds in Processes A and
B using the above compound (13) or (14) described above.
[2937] (Step G-1)
[2938] The present step is to prepare the compound (19) by
introducing the desired acyl group to the compound (13) in an inert
solvent.
[2939] The present step can be carried out similarly to the
procedures of Step C-1.
[2940] (Step G-2)
[2941] The present step is to prepare the desired raw material
compound (2f) from the compound (19) using a reducing agent in an
inert solvent.
[2942] The present step can be carried out similarly to the
procedures of Step D-4.
[2943] (Step G-3)
[2944] The present step is to prepare the compound (20) by
introducing the desired acyl group to the compound (14) in an inert
solvent.
[2945] The present step can be carried out similarly to the
procedures of Step C-1.
[2946] (Step G-4)
[2947] The present step is to prepare the desired raw material
compound (2g) from the compound (20) using a reducing agent in an
inert solvent.
[2948] The present step can be carried out similarly to the
procedures of Step D4. 65
[2949] Process H is a process for preparing the compound (5) which
is the raw material compound in Process C using the well known
compound (26) described in Carbohydrate Research, 83, 163-169
(1980) or WO 95/32955.
[2950] (Step H-1)
[2951] The present step is to prepare the compound (27) by reacting
the known compound (26) with an azidating agent in an inert
solvent.
[2952] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably aromatic
hydrocarbons such as benzene, toluene and xylene; halogenated
hydrocarbons such as methylene chloride and chloroform; ethers such
as diethyl ether, tetrahydrofuran, dioxane and dimethoxyethane; and
nitrites such as acetonitrile.
[2953] The reagent employable is not particularly limited so long
as it is usually used for azidation and includes preferably diaryl
phosphoric azide derivatives such as diphenyl phosphoric azide;
trialkylsilylazides such as trimethylsilylazide and
triethylsilylazide and azidated alkali metal salts such as sodium
azide and potassium azide, preferably the sodium azide.
[2954] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 30.degree. C.
[2955] The reaction time varies depending on the raw material used,
the base, the reaction temperature, etc., and is usually from 15
minutes to 10 hours; preferably from 1 to 5 hours.
[2956] After the reaction, the desired compound can be obtained,
for example, by neutralizing the reaction mixture with a
hydrochloric acid/dioxane solution, and purifying the residue
obtained by distilling off the solvent under reduced pressure over
silica gel chromatography.
[2957] (Step H-2)
[2958] The present step is to prepare the compound (28) by reacting
the compound (27) with a t-butoxycarbonylating agent in an inert
solvent.
[2959] The t-butoxycarbonylation can be carried out by reacting
di-tert-butyl dicarbonate or
2-(tert-butoxycarbonyloxyimino)-2-phenylacet- onitrile in an inert
solvent (for example, aromatic hydrocarbons such as benzene and
toluene; halogenated hydrocarbons such as methylene chloride and
chloroform; ethers such as diethyl ether, tetrahydrofuran and
dioxane; and amides such as dimethylformamide) in the presence of a
base (for example, 4-(N,N-dimethylamino)pyridine).
[2960] After the reaction, the desired compound can be obtained,
for example, by neutralizing the reaction mixture, distilling off
the solvent under reduced pressure, adding a water-immiscible
solvent such as ethyl acetate thereto, extracting the desired
compound with ethyl acetate, and distilling off the solvent. The
desired compound can be further purified, if necessary, by
recrystalization or various kinds of chromatographies.
[2961] (Step H-3)
[2962] The present step is to prepare the compound (29) by reacting
the compound (28) with a base in an inert solvent.
[2963] The present step can be carried out similarly to the
procedures of Step D-1.
[2964] (Step H-4)
[2965] The present step is to acetylate the compound (29) in an
inert solvent. The acetylation is carried out according to the
usual method for protecting a hydroxyl group. For example, the
acetylation can be carried out by 1) reacting with acetic anhydride
in pyridine or 2) reacting with acetyl halide (particularly
chloride) in methylene chloride in the presence of a base catalyst
(for example, triethylamine and 4-N,N-dimethylaminopyridine).
[2966] After the reaction, the desired compound can be obtained by
distilling off the solvent under reduced pressure, adding a
water-immiscible solvent such as ethyl acetate and an aqueous
sodium hydrogencarbonate solution to the residue, extracting the
desired compound with ethyl acetate, and distilling off the
solvent. The desired compound can be further purified, if
necessary, by recrystalization or various kinds of
chromatographies.
[2967] (Step H-5)
[2968] The present step is to prepare the compound (30) by treating
the compound obtained in Step H-4 with a reagent which eliminates a
t-butoxycarbonyl group in an inert solvent.
[2969] The elimination of the t-butoxycarbonyl group is carried out
according to the usual methods.
[2970] The solvent employable is not particularly limited so long
as it does not inhibit the reaction and dissolves the starting
material to some extent, and includes preferably aliphatic
hydrocarbons such as hexane, heptane, ligroin and petroleum ether;
aromatic hydrocarbons such as benzene, toluene and xylene;
halogenated hydrocarbons such as methylene chloride, chloroform,
carbon tetrachloride, dichloroethane, chlorobenzene and
dichlorobenzene; esters such as ethyl formate, ethyl acetate,
propyl acetate, butyl acetate and diethyl carbonate; ethers such as
diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane,
dimethoxyethane and diethylene glycol dimethyl ether; amides such
as formamide, N,N-dimethylformamide, N,N-dimethylacetamide,
N-methyl-2-pyrrolidone, N-methylpyrrolidinone and
hexamethylphosphoric triamide; and sulfoxides such as dimethyl
sulfoxide and sulfolane, preferably the halogenated hydrocarbons
(particularly methylene chloride).
[2971] The reagent employable is not particularly limited so long
as it is usually used and includes preferably hydrochloric
acid.
[2972] The reaction temperature is usually from -10 to 50.degree.
C., preferably from 10 to 30.degree. C.
[2973] The reaction time varies depending on the raw material used,
the base, the reaction temperature, etc., and is usually from 15
minutes to 24 hours, preferably from 1 to 10 hours.
[2974] After the reaction, the desired compound can be obtained,
for example, by distilling off the solvent under reduced pressure,
adding a water-immiscible solvent such as ethyl acetate and an
aqueous sodium hydrogencarbonate solution to the reaction mixture,
extracting the desired compound with ethyl acetate, and distilling
off the solvent. The desired compound can be further purified, if
necessary, by recrystalization or various kinds of
chromatographies.
[2975] (Step H-6)
[2976] The present step is to prepare the compound (7) by
introducing the desired acyl group to the compound (30) in an inert
solvent.
[2977] The present step can be carried out similarly to the
procedures of Step C-1.
[2978] (Step H-7)
[2979] The present step is to prepare the compound (32) from the
compound (7) using a reducing agent in an inert solvent.
[2980] The present step can be carried out similarly to the
procedures of Step D-4.
[2981] (Step H-8)
[2982] The present step is to prepare the compound (33) by reacting
the compound (32) with N,N'-di-t-butoxycarbonylthiourea in an inert
solvent in the presence of a base and mercuric chloride.
[2983] The present step can be carried out similarly to the
procedures of Step A-1.
[2984] (Step H-9)
[2985] The present step is to prepare the compound (34) by reacting
the compound (33) with a base in an inert solvent.
[2986] The present step can be carried out similarly to the
procedures of Step D-1.
[2987] (Step H-10) Ester Interchange, Hydrolysis, Protection or
Esterification
[2988] The present step is 1) to substitute the methyl group of the
methyl carboxylate portion with another ester residue, 2) to
hydrolize the methyl carboxylate portion, or 3) to introduce a
protecting group of the carboxyl group or an ester residue after
hydrolysis in 2), as desired.
[2989] The present step can be carried out similarly to the
procedures of Step D-3.
[2990] The compound (1) of the present invention can be also
prepared according to processes other than those described above.
Particularly, it is possible to prepare the compound (1) of the
present invention by changing the order of the steps of Processes A
to H described above depending on the situations. For example, the
compound (1) of the present invention can be prepared according to
Process J shown below using the compound (10) obtained as an
intermediate in Process D. 66
[2991] (Step J-1)
[2992] The present step is carried out if necessary, and is to
prepare the compound (35) by introducing the desired acyl group to
the compound (10) in an inert solvent.
[2993] The present step can be carried out similarly to the
procedures of Step C-1 described above.
[2994] (Step J-2)
[2995] The present step is to prepare the compound (36) by reacting
the compound (35) with a reducing agent in an inert solvent.
[2996] The present step can be carried out similarly to the
procedures of Step D4 described above.
[2997] (Step J-3)
[2998] The present step is to prepare the compound (37) by reacting
the compound (36) with N,N'-di-t-butoxycarbonylthiourea in an inert
solvent in the presence of a base and mercuric chloride.
[2999] The present step can be carried out similarly to the
procedures of Step A-1 described above.
[3000] (Step J-4)
[3001] The present step is carried out if necessary, and is to
prepare the compound (38) by eliminating the protecting group of
the carboxyl group of the compound (37).
[3002] The elimination method of the protecting group varies
depending on the kind of the protecting group, and can be carried
out according to the methods usually used, for example, the methods
described in Protective Groups in Organic Synthesis, Second Edition
(1991, Green et al.).
[3003] In the case where the protecting group is a diphenylmethyl
group, catalytic reduction is carried out, acids such as acetic
acid and trifluoroacetic acid are used or a boron
trifluoride-diethyl ether complex is used.
[3004] In the case where the protecting group of the carboxyl group
is a benzyl group, catalytic reduction is carried out, and in the
case where the protecting group is an alkyl group such as methyl
and ethyl, hydrolysis is carried out.
[3005] (Step J-5)
[3006] The present step is to prepare the compound (1) of the
present invention by reacting the compound (38) with a reagent for
eliminating the tert-butoxycarbonyl group and isopropylidene group
in an inert solvent.
[3007] The present step can be carried out similarly to the
procedures of Step E-2.
[3008] The neuraminic acid compound (1) thus obtained or the salt
thereof can be converted, if necessary, to other pharmacologically
acceptable salts.
[3009] The neuraminic acid compound (1) of the present invention
undergoes hydrolysis by hydrolase present in a living body and
exhibits excellent viral replication inhibitory activity and
sialidase inhibitory activity. In addition, if the neuraminic acid
compound (1) is administered to mice infected with influenza virus,
the compound exhibits infection therapeutic effects superior to
Compound A (GG-167) described in WO91/16320 (Japanese PCT
application (Kokai) No. Hei 5-507068. Thus, the neuraminic acid
compound (1) of the present invention is useful as a therapeutic
agent or a preventive agent (preferably a therapeutic agent) for
viral infections (preferably influenza viral infections).
[3010] The administration form of the neuraminic acid compound of
the present invention includes, for example, oral administration or
intranasal administration by solutions such as liquid agents,
aqueous co-solvents, etc., aerosols, powders, etc. Of these
preparations, solutions such as liquid agents and aqueous
co-solvents are prepared by the well known methods using purified
water, pharmacologically acceptable organic solvents (for example,
ethanol, propylene glycol, PEG 400, etc.), and stabilizers
(paraoxybenzoates such as methylparaben and propylparaben; alcohols
such as chlorobutanol, benzyl alcohol and phenylethyl alcohol;
benzalkonium chloride; phenols such as phenol and cresol;
thimerosal; dehydroacetic acid, etc.). The aerosols are prepared by
the well known methods using a propellant such as various kinds of
Freon gases and nitrogen gas, and a surface active agent such as
lecitin. The powders are prepared by the well known methods using
excipients (for example, organic excipients such as sugars, e.g.
lactose, sucrose, glucose, mannitol and sorbitol; starches, e.g.
corn starch, potato starch, .alpha.-starch, dextrin and
carboxymethyl starch; celluloses, e.g. crystalline cellulose,
low-substituted hydroxypropyl cellulose, hydroxypropyl cellulose,
hydroxypropylmethyl cellulose, carboxymethyl cellulose,
carboxymethyl cellulose calcium and internally bridged
carboxymethyl cellulose sodium; gum arabic; dextran; and Pullulan,
and inorganic excipients such as silicates, e.g. light silicic
anhydride, synthesized aluminium silicate and magnesium aluminate
metasilicate; phosphates, e.g. calcium phosphate; carbonates, e.g.
calcium carbonate; and sulfates, e.g. calcium sulfate), lubricants
(for example, stearic acid, stearic acid metal salts such as
calcium stearate and magnesium stearate; talc; colloidal silica;
waxes such as bee gum and spermaceti; boric acid; adipic acid;
sulfates, e.g. sodium sulfate; glycol; fumaric acid; sodium
benzoate; DL-leucine; fatty acid sodium salt; laurylsulfates such
as sodium laurylsulfate and magnesium laurylsulfate; silicic acids
such as silicic anhydride and silicic acid hydrate; and the above
starches), stabilizers (paraoxybenzoates such as methylparaben and
propylparaben; alcohols such as chlorobutanol, benzyl alcohol and
phenylethyl alcohol; benzalkonium chloride; phenols such as phenol
and cresol; thimerosal; dehydroacetic acid; and sorbic acid),
corrigents (for example, sweeteners, vinegars, perfumes, etc.
usually used), diluents, etc.
[3011] While the dose of the active ingredients will vary depending
on the condition of disease, age of the patient, administration
methods, etc., for example, in the case of solutions, it is
desirable to administer the active ingredient in an amount of 0.1
mg (preferably 1 mg) as a lower limit and 1000 mg (preferably 500
mg) as an upper limit, in the case of dry powders, it is desirable
to administer the active ingredient in an amount of 0.1 mg
(preferably 1 mg) as a lower limit and 1000 mg (preferably 500 mg)
as an upper limit, and in the case of aerosols, it is desirable to
administer the active ingredient in an amount of 0.1 mg (preferably
1 mg) as a lower limit and 1000 mg (preferably 500 mg) as an upper
limit, once or several times a day in the above administration
methods, depending on the condition of disease.
[3012] The present invention will be described in more detail by
way of Examples, Preparation examples and Test examples below but
the scope of the present invention is not limited to these.
Example 1
Myristyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-no-
n-2-enopyranosoate Trifluoroacetic Acid Salt (E8) (Exemplary
Compound No. 88)
[3013] 67
[3014] i) Methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropylide-
ne-D-glycero-D-galacto-non-2-enopyranosoate (E3)
[3015] 1.3 g (2.8 mmol) of methyl
5-acetamido-7,8,9-tri-O-acetyl-4-azido-2-
,3,4,5-tetradeoxy-D-glycero-D-galacto-non-2-enopyranosoate (E1)
(which was synthesized according to the processes described in Mark
von Itzstein et al., Carbohydr. Res., 244, 181-185 (1993) and
Carbohydr. Res., 259, 293-299 (1993)) were dissolved in 26 ml
(20-times volume) at room temperature, and a catalytic amount of
sodium methoxide was added to the system under the same conditions,
followed by further stirring of the mixture for 1 hour. After
confirmation of completion of the reaction, Dowex-50x8 (H.sup.+)
was added to the system to neutralize the mixture. The reaction
mixture was filtered and the filtered product was washed with
methanol. The filtrate and the washing water were distilled off
under reduced pressure, and the residue was purified over silica
gel column chromatography (Kiesel gel 60, 100 g, methylene
chloride:methanol=5:1) to obtain 620 mg (yield: 66%) of the
compound (E2) as a pale yellow solid.
[3016] Rf value: 0.3 (methylene chloride:methanol=5:1)
[3017] 580 mg (1.8 mmol) of the resulting compound E2) were
dissolved in 29 ml (50-times volume) of acetone at room
temperature, and subsequently 0.7 ml (5.2 mmol) of
2,2-dimethoxypropane and 42 mg (0.18 mmol) of DL-10-camphorsulfonic
acid were added to the system under ice-cooling, followed by
stirring of the mixture at room temperature for 1 hour. After
confirmation of completion of the reaction, triethylamine was
poured into the system to neutralize the mixture. The reaction
mixture was distilled off under reduced pressure, and the residue
was purified over silica gel column chromatography (Kiesel gel 60,
60 g, benzene:acetonitrile=1:1) to obtain 540 mg (yield: 84%) of
the title compound (E3) as a white solid.
[3018] Rf value: 0.76 (benzene:acetonitrile=1:1).
[3019] .sup.1H-NMR (270MHz, CDCl.sub.3, TMS): .delta. (ppm) 5.97
(1H, d, J=2.4Hz), 5.63 (1H, d, J=7.1Hz), 4.36 (1H, ddd, J=7.9, 6.4,
4.8Hz), 4.30-4.00 (6H, m), 3.81 (3H, s), 3.57 (1H, dd, J=7.9,
5.3Hz), 2.12 (3H, s), 1.40 (3H, s), 1.36 (3H, s);
[3020] [.alpha.].sub.D.sup.24=+122.4.degree. (c=1.0,
CHCl.sub.3).
[3021] ii)
5-Acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropylidene-D-g-
lycero-D-galacto-non-2-enopyranosoic Acid (E4)
[3022] 460 mg (1.2 mmol) of the compound (ES) were dissolved in 24
ml (30-times volume) of methanol at room temperature, and
subsequently 2.9 ml (1.4 mmol) of 1M aqueous sodium hydroxide
solution were added to the system at room temperature, followed by
stirring of the mixture at room temperature for 1 hour. After
confirmation of completion of the reaction, Dowex-50W was added to
the system to neutralize the mixture. The reaction mixture was
filtered, and the filtered product was washed with water. The
filtrate and the washing solution were combined and distilled off
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, 60 g, ethyl
acetate:2-propanol:water=2:2:1- ) to obtain 0.44 g (yield: 100%) of
the title compound (E4) as a white solid.
[3023] Rf value: 0.25 (ethyl acetate:2-propanol:water=5:2:1);
[3024] .sup.1H-NMR (270 MHz, CD.sub.3OD, TMS): .delta. (ppm) 5.72
(1H, d, J=2.1Hz), 4.37 (1H, dt, J=8.8, 5.5Hz), 4.27 (1H, dd, J=6.9,
1.4Hz), 4.20-4.04 (3H, m), 4.00 (1H, dd, J=8.8, 5.0Hz), 3.54 (1H,
d, J=8.8Hz), 2.03 (3H, s), 1.37 (3H, s), 1.32 (3H, s);
[3025] [.alpha.].sub.D.sup.24=+43.4.degree. (c=0.53, MeOH).
[3026] iii) Myristyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropy-
lidene-D-glycero-D-galacto-non-2-enopyranosoate (E5)
[3027] 460 mg (1.2 mmol) of the compound (E4), 530 mg (2.5 mmol) of
myristyl alcohol and 510 mg (1.9 mmol) of 2-bromo-1-ethylpyridinium
tetrafluoroborate were dissolved in 22 ml (50-times volume) of
formamide. Subsequently, 0.9 ml (3.8 mmol) of tri-n-butylamine were
poured into the system, and the mixture was stirred in an oil bath
at 50.degree. C. for 6 hours. The reaction mixture was separated
with ethyl acetate and a saturated aqueous NaCl solution, and the
aqueous layer was extracted with ethyl acetate. The organic layer
was dried over magnesium sulfate and filtered, followed by
distilling off under reduced pressure. The residue was purified
over silica gel column chromatography (Kiesel gel 60, 100 g,
benzene:ethyl acetate=1:1) to obtain 0.19 g (yield: 28%) of the
title compound (E5) as a white solid.
[3028] Rf value: 0.4 (benzene:ethyl acetate=1:1);
[3029] .sup.1-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 5.95
(1H, d, J=2.4Hz), 5.60 (1H, d, J=7.0Hz), 4.36 (1H, dt, J=7.7,
5.7H), 4.30-4.00 (8H, m), 3.58 (1H, d, J=7.7Hz), 2.12 (3H, s), 1.69
(2H, quintet, J=6.3Hz), 1.40 (3H, s), 1.35 (3H, s), 1.26 (22H, bs),
0.88 (3H, t, J=6.3Hz);
[3030] [.alpha.].sub.D.sup.24=+83.3.degree. (c=0.54,
CHCl.sub.3).
[3031] iv) Myristyl
5-acetamido-4-amino-2,3,4,5-tetradeoxy-8,9-O-isopropyl-
idene-D-glycero-D-galacto-non-2-enopyranosoate (E6)
[3032] 134 mg (0.24 mmol) of the compound (E5) were dissolved in
6.7 ml (50-times volume) of ethanol at room temperature, and
subsequently 47 mg (0.35-times volume) of Lindlar catalyst were
added to the system at room temperature, followed by stirring of
the mixture at room temperature under a hydrogen atmosphere of 1
atm. for 2 hours. After confirmation of completion of the reaction,
the reaction mixture was filtered, and the filtered product was
washed with ethanol. The filtrate and the washing solution were
combined and distilled off under reduced pressure. The residue thus
obtained was purified over silica gel column chromatography (Kiesel
gel 60, 60 g, ethyl acetate:2-propanol:water=5:2:1) to obtain 0.11
g (yield: 88%) of the title compound (E6) as a white solid.
[3033] Rf value: 0.28 (ethyl acetate:2-propanol:water=8:2:1);
[3034] .sup.1H-NMR (270 MHz, CD.sub.3OD, TMS): .delta. (ppm) 5.93
(1H, d, J=2.6Hz), 4.31 (1H, quintet, J=6.9Hz), 4.23-3.93 (5H, m),
3.88 (1H, t, J=9.0 Hz), 3.67-3.50 (2H, m), 2.05 (3H, s), 1.68 (2H,
quintet, J=8.1Hz), 1.37 (3H, s), 1.33 (3H, s), 1.27 (22H, bs), 0.88
(3H, t, J=8.1Hz).
[3035] v) Myristyl
5-acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2-
,3,4,5-tetradeoxy-8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enopyrano-
soate (E7)
[3036] 110 mg (0.21 mmol) of the compound (E6), 72 mg (0.26 mmol)
of N,N'-bis-tert-butoxycarbonylthiourea and 80 ml (0.57 mmol) of
triethylamine were dissolved in 22 ml (50-times volume) of
dimethylformamide at room temperature. Subsequently, 70.5 mg (0.26
mmol) of mercuric chloride were added to the system under
ice-cooling, followed by stirring of the mixture at room
temperature for 2 hours. The reaction mixture was diluted with
ethyl acetate, and the mixture was filtered using Celite, and the
filtered product was washed with ethyl acetate. The filtrate thus
obtained and the washing solution were combined, and ethyl acetate
and a saturated aqueous NaCl solution were added to the mixture,
followed by separation. The organic layer was dried over magnesium
sulfate and filtered, followed by distilling off of the solvent
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, 100 g, hexane:ethyl
acetate=3:2) to obtain 120 mg (yield: 71%) of the title compound
(E7) as a white solid.
[3037] Rf value: 0.65 (hexane:ethyl acetate=3:2);
[3038] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H s), 8.63 (1H, d, J=7.8Hz), 7.99 (1H, d, J=4.8Hz), 5.78 (1H, d,
J=2.4Hz), 5.32 (1H, d, J=4.4Hz), 5.14 (1H, tt, J=7.8, 1.6Hz), 4.40
(1H, dt, J=10.6, 4.8Hz), 4.33-3.90 (6H, m), 3.52 (1H, dd, J=8.7,
3.9Hz), 2.02 (3H, s), 1.641 (2H, m), 1.52 (9H, s), 1.49 (9H, s),
1.43 (3H, s), 1.36 (3H, s), 1.26 (22H, bs), 0.88 (3H, t,
J=6.7Hz);
[3039] [.alpha.].sub.D.sup.24=-20.9.degree. (c:0.58,
CHCl.sub.3).
[3040] vi) Myristyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-
-galacto-non-2-enopyranosoate Trifluoroacetic Acid Salt (E8)
[3041] 84 mg (0.11 mmol) of the compound (E7) were dissolved in 4.7
ml (50-times volume) of methylene chloride at room temperature, and
subsequently 0.85 ml (10-times volume) of trifluoroacetic acid were
added to the system at room temperature, followed by stirring of
the mixture at room temperature for 22 hours. After confirmation of
completion of the reaction, the reaction mixture was concentrated
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, 15 g, ethyl
acetate:2-propanol:water=8:2:1) to obtain 82 mg (yield: 88%) of the
title compound (E8) as a white solid.
[3042] Rf value: 0.6 (ethyl acetate:2-propanol:water=8:2:1);
[3043] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.83 (1H,
d, J=2.7Hz), 4.44 (1H, dd, J=9.0, 2.7Hz), 4.38 (1H, dd, J=9.0,
<1Hz), 4.18 (2H, t, J=6.2Hz), 4.17 (1H, t, J=9.0 Hz), 3.90-3.74
(2H, m), 3.68 (1H, dd, J=12.0, 4.5Hz), 3.65 (1H, d, J=9.0 Hz), 1.99
(3H, s), 1.67 (2H, quintet, J=6.2Hz), 1.26 (24H, bs), 0.87 (3H, t,
J=6.2Hz);
[3044] FAB-MS (positive): 529 (M+H).sup.+;
[3045] HR-MS: Calcd. for C.sub.26H.sub.49N.sub.4O.sub.7, 529.3597,
Found 529.3605 (M+H).sup.+.
Example 2
Hexyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-
-enopyranosoate Trifluoroacetic Acid Salt (E12) (Exemplary Compound
No. 87)
[3046] 68
[3047] i) Hexyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropyliden-
e-D-glycero-D-galacto-non-2-enopyranosoate (E9)
[3048] 940 mg (2.6 mmol) of the compound (E4), 0.66 ml (5.3 mmol)
of 1-hexanol and 1.1 g (4.0 mmol) of 2-bromo-1-ethylpyridinium
tetrafluoroborate were dissolved in 47 ml (50-times volume) of
dimethylformamide at room temperature. Subsequently, 1.9 ml (8.0
mmol) of tri-n-butylamine were poured into the system, and the
mixture was stirred in an oil bath at 50.degree. C. for 6 hours.
Ethyl acetate and a saturated aqueous NaCl solution were added to
the reaction mixture, and the mixture was separated. The organic
layer thus obtained was dried over magnesium sulfate and filtered,
followed by concentration under reduced pressure. The residue was
purified over silica gel column chromatography (Kiesel gel 60, 150
g, benzene:acetonitrile=2:1) to obtain 560 mg (yield: 44%) of the
title compound (E9) as a pale brown solid.
[3049] Rf value: 0.43 (benzene:acetonitrile=2:1);
[3050] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 6.53
(1H, d, J=6.9Hz), 5.92 (1H, d, J=2.5Hz), 4.48 (1H, bs), 4.41-4.29
(2H, m), 4.24-4.00 (7H, m), 3.63 (1H, bd, J=7.3Hz), 1.70 (2H,
quintet, J=6.5Hz), 1.40 (3H, s), 1.35 (9H, bs), 1.30 (3H, s), 0.89
(3H, t, J=6.5Hz);
[3051] [.alpha.].sub.D.sup.24=+8.degree. (c=0.4, CHCl.sub.3).
[3052] ii) Hexyl
5-acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2,3-
,4,5-tetradeoxy-8,9-O-isopropylidene-D-glycero-D-galacto-non-2-enopyranoso-
ate (E11)
[3053] 533 mg (1.1 mmol) of the compound (E9) were dissolved in 25
ml (50-times volume) of ethanol at room temperature, and
subsequently 190 mg (0.35-times volume) of Lindlar catalyst were
added to the system at room temperature, followed by stirring of
the mixture at room temperature under a hydrogen atmosphere of 1
atm. for 2.5 hours. After confirmation of completion of the
reaction, the reaction mixture was filtered. The filtered product
was washed with ethanol, and the filtrate and the washing solution
were combined, followed by concentration under reduced pressure.
The residue was purified over silica gel column chromatography
(Kiesel gel 60, 50 g, ethyl acetate:2-propanol:water=5:2:1) to
obtain 303 mg (yield: 60%) of the title compound (E10) as a pale
brown foamy solid.
[3054] Rf value: 0.44 (ethyl acetate:2-propanol:water=5:2:1).
[3055] 290 mg (0.63 mmol) of the resulting compound (E10), 210 mg
(0.75 mmol) of N,N'-bis-tert-butoxycarbonylthiourea and 0.22 ml
(1.6 mmol) of triethylamine were dissolved in 15 ml (50-times
volume) of dimethylformamide at room temperature. Subsequently, 220
mg (0.8 mmol) of mercury chloride were added to the system under
ice-cooling and the mixture was stirred at room temperature for 2
hours. The reaction mixture was diluted with ethyl acetate and
filtered using Celite, and the filtered product was washed with
ethyl acetate. The filtrate thus obtained and the washing solution
were combined, and ethyl acetate and a saturated aqueous NaCl
solution were added thereto to separate the mixture, followed by
extraction of the aqueous layer with ethyl acetate. The organic
layer was dried over magnesium sulfate and filtered, followed by
concentration under reduced pressure. The residue was purified over
silica gel column chromatography (Kiesel gel 60, 75 g, hexane:ethyl
acetate=1:1) to obtain 273 mg (yield: 66%) of the desired compound
(E11) as a white solid.
[3056] Rf value: 0.38 (benzene:ethyl acetate=5:1);
[3057] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.64 (1H, d, J=7.7Hz), 7.99 (1H, d, J=4.7Hz), 5.78 (1H, d,
J=2.4Hz), 5.33 (1H, d, J=4.4Hz), 5.14 (1H, tt, J=7.9, <1Hz),
4.40 (1H, dt, J=7.8, 5.7Hz), 4.23-3.90 (7H, m), 3.51 (1H, dd,
J=8.2, 4.5Hz), 2.01 (3H, s), 1.68 (2H, quintet, J=6.4Hz), 1.51 (9H,
s), 1.49 (9H, s), 1.43 (3H s), 1.36 (3H, s), 1.35-1.20 (6H, m),
0.89 (3H, t, J=6.4Hz);
[3058] [.alpha.].sub.D.sup.24=22.0.degree. (c:0.5, CHCl.sub.3).
[3059] iii) Hexyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-g-
alacto-non-2-enopyranosoate Trifluoroacetic Acid Salt (E12)
[3060] 158 mg (0.24 mmol) of the compound (E11) were dissolved in
8.0 ml (50-times volume) of methylene chloride at room temperature,
and subsequently 1.6 ml (10-times volume) of trifluoroacetic acid
were added to the system at room temperature, followed by stirring
of the mixture at room temperature for 18 hours. After confirmation
of completion of the reaction, the reaction mixture was
concentrated under reduced pressure. The residue was purified over
silica gel column chromatography (Kiesel gel 60, 15 g, ethyl
acetate:2-propanol:water=5:2:1) to obtain 155 mg (yield: 100%) of
the title compound (E12) as a white solid.
[3061] Rf value: 0.8 (ethyl acetate:2-propanol:water=5:2:1);
[3062] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.94 (1H,
d, J=2.4Hz), 4.46 (1H, dd, J=9.3, 2.4Hz), 4.38 (1H, dd, J=10.4,
1.3Hz), 4.20 (1H, t, J=9.3Hz), 4.20 (2H, t, J=6.2Hz), 3.91-3.76
(2H, m), 3.66 (1H, bd, J=9.3Hz), 3.61 (1H, dd, J=12.5, 6.3Hz), 1.97
(3H, s), 1.63 (2H, quintet, J=6.3Hz), 1.40-1.10 (6H, m), 0.80 (3H,
t, J=6.3Hz);
[3063] [.alpha.].sub.D.sup.24=+18.1.degree. (c=0.48,
CHCl.sub.3).
Example 3
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-myristoyl-D-glycero-D-galac-
to-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (E17)
(Exemplary Compound No. 14)
[3064] 69
[3065] i) Methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropylide-
ne-7-O-myristoyl-D-glycero-D-galacto-non-2-enopyranosoate (E13)
[3066] 61 mg (0.16 mmol) of the compound (E3) were dissolved in 3.
0 ml (50-times volume) of methylene chloride at room temperature,
and subsequently 54 ml (0.2 mmol) of myristoyl chloride and 24.1 mg
(0.2 mmol) of 4-dimethylaminopyridine were added to the system
under ice-cooling, followed by stirring of the mixture at room
temperature for 30 minutes. Next, 27 ml (0.2 mmol) of triethylamine
were poured into the reaction mixture at room temperature, followed
by further stirring of the mixture for 6 hours. After confirmation
of completion of the reaction, methanol was poured into the system,
followed by stirring of the mixture for 30 minutes. Next, ethyl
acetate and a saturated aqueous NaCl solution were added to the
reaction mixture to separate the mixture. The organic layer thus
obtained was dried over magnesium sulfate and filtered, followed by
concentration under reduced pressure. The residue was purified over
silica gel column chromatography (Kiesel gel 60, 15 g,
benzene:ethyl acetate=1:1) to obtain 70 mg (yield: 74%) of the
desired compound (E13) as a colorless transparent syrup.
[3067] Rf value: 0.42 (benzene:ethyl acetate=2:1);
[3068] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 5.95
(1H, d, J=2.7Hz), 5.88 (1H, d, J=7.9Hz), 5.35 (1H, dd, J=6.0,
1.8Hz), 4.80 (1H, dd, J=9.1, 2.7Hz), 4.71 (1H, dd, J=10.5, 1.8Hz),
4.39 (1H, q, J=6.0Hz), 4.14 (1H, dd, J=8.8, 6.0Hz), 4.71 (1H, dd,
J=10.5, 1.8Hz), 4.39 (1H, q, J=6.0Hz), 4.14 (1H, dd, J=8.8, 6.0Hz),
3.945 (1H, dd, J=8.8, 6.0Hz), 3.81 (3H, s), 3.45 (1H, ddd, J=10.5,
9.1, 7.9Hz), 2.41 (1H, t, J=7.5Hz), 2.39 (1H, t, J=7.5Hz), 2.02
(3H, s), 1.63 (2H, quintet, J=7.5Hz), 1.37 (3H, s), 1.35 (3H, s),
1.26 (20H, s), 0.88 (3H, t, J=7.5Hz).
[3069] ii) Methyl
5-acetamido-4-amino-2,3,4,5-tetradeoxy-8,9-O-isopropylid-
ene-7-O-myristoyl-D-glycero-D-galacto-non-2-enopyranosoate
(E14)
[3070] 70 mg (0.12 mmol) of the compound (E13) were dissolved in
3.5 ml (50-times volume) of ethanol at room temperature, and
subsequently 25 mg (0.35-times volume) of Lindlar catalyst were
added to the system at room temperature, followed by stirring of
the mixture at room temperature under a hydrogen atmosphere of 1
atm. for 1.5 hours. After confirmation of completion of the
reaction, the reaction mixture was filtered. The filtered product
was washed with ethanol, and the filtrate and the washing solution
were combined, followed by concentration under reduced pressure.
The residue was purified over silica gel column chromatography
(Kiesel gel 60, 15 g, ethyl acetate:2-propanol:water=5:2:1) to
obtain 57 mg (yield: 84%) of the title compound (E14) as a white
solid.
[3071] Rf value: 0.49 (methylene chloride:methanol=10:1);
[3072] .sup.1H-NMR (270 MHz, CD.sub.3OD, TMS): .delta. (ppm) 5.94
(1H, d, J=2.4Hz), 5.42 (1H, dd, J=4.7, 1.8Hz), 4.39 (1H, dt, J=7.1,
6.0Hz), 4.18 (1H, dd, J=9.5, 1.6Hz), 4.14 (1H, dd, J=8.7, 6.4Hz),
3.93 (1H, dd, J=8.7, 6.4Hz), 3.87 (1H, t, J=9.5Hz), 3.78 (3H, s),
3.44 (1H, dd, J=9.5, 2.4Hz), 2.35 (2H, q, J=7.3Hz), 1.94 (3H, s),
1.60 (2H, quintet, J=7.3Hz), 1.32 (3H, s), 1.31 (3H, s), 1.27 (20H,
s), 0.88 (3H, t, J=7.3Hz).
[3073] iii) Methyl
5-acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2-
,3,4,5-tetradeoxy-8,9-O-isopropylidene-7-O-myristoyl-D-glycero-D-galacto-n-
on-2-enopyranosoate (E15)
[3074] 57 mg (0.1 mmol) of the compound (E14), 34 mg (0.12 mmol) of
N,N'-bis-tert-butoxycarbonylthiourea and 35 ml (0.25 mmol) of
triethylamine were dissolved in 28 ml (50-times volume) of
dimethylformamide at room temperature. Subsequently, 35 mg (0.13
mmol) of mercury chloride were added to the system under
ice-cooling, and the mixture was stirred at room temperature for 2
hours. Ethyl acetate was added to the reaction mixture to dilute
it, followed by filtration using Celite. The filtered product was
washed with ethyl acetate. The filtrate thus obtained and the
washing solution were combined, and ethyl acetate and a saturated
aqueous NaCl solution were added to the mixture to separate it. The
organic layer was dried over magnesium sulfate and filtered,
followed by concentration under reduced pressure. The residue was
purified over silica gel column chromatography (Kiesel gel 60, 15
g, hexane:ethyl acetate=2:1) to obtain 75 mg (yield: 100%) of the
title compound as a colorless transparent syrup.
[3075] Rf value: 0.33 (hexane:ethyl acetate=2:1);
[3076] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.46 (1H, d, J=8.7Hz), 6.06 (1H, d, J=8.7Hz), 5.88 (1H, d,
J=2.4Hz), 5.37 (1H, dd, J=6.4, 1.5Hz), 5.15 (1H, dt, J=8.7, 2.4Hz),
4.38 (1H, q, J=6.4Hz), 4.28 (1H, dd, J=8.7, 1.5Hz), 4.23 (1H, t,
J=8.7Hz), 4.10 (1H, dd, J=9.6, 6.4Hz), 3.95 (1H, dd, J=9.6, 6.4Hz),
3.80 (3H, s), 2.453 (1H, dt, J=16.0, 7.5Hz), 2.33 (1H, dt, J=16.0,
7.5Hz), 1.87 (3H, s), 1.61 (2H, quintet, J=7.5Hz), 1.49 (9H, s),
1.48 (9H, s), 1.38 (3H, s), 1.35 (3H, s), 1.25 (20H, bs), 0.88 (3H,
t, J=7.5Hz).
[3077] iv)
5-Acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2,3,4,5-t-
etradeoxy-8,9-O-isopropylidene-7-O-myristoyl-D-glycero-D-galacto-non-2-eno-
pyranosoic Acid (E16)
[3078] 51 mg (0.07 mmol) of the compound (E15) were dissolved in a
mixture of 2 ml (40-times volume) of methanol and 0.5 ml (10-times
volume) of water, and 3.3 mg (0.078 mmol) of lithium hydroxide
monohydrate were added to the system at room temperature, followed
by stirring of the mixture at room temperature for 8 hours. After
confirmation of completion of the reaction, Dowex-50W was added to
the system to neutralize the mixture. The reaction mixture was
filtered, and the filtered product was washed with methanol. The
filtrate and the washing solution were combined and concentrated
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, 60 g, ethyl
acetate:2-propanol:water=10:2:1) to obtain 33 mg (yield: 66%) of
the desired compound (E16) as a white solid.
[3079] Rf value: 0.45 (methylene chloride:methanol=10:1);
[3080] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.48 (1H, d, J=8.0Hz), 6.31 (1H, dull s), 5.90 (1H, bs),
5.30 (1H, bs), 5.10 (1H, bs), 4.60-3.30(7H, m), 2.48 (1H, dt,
J=13.5, 6.5Hz), 2.32 (1H, dt, J=13.5, 6.5Hz), 1.88 (3H, s), 1.60
(2H, quintet, J=6.5Hz), 1.48 (18H, s), 1.39 (3H, s), 1.37 (3H, s),
1.25 (20H, bs), 0.88 (3H, t, J=6.5Hz).
[3081] v)
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-myristoyl-D-glyce-
ro-D-galacto-non-2-enopyranosoic acid trifluoroacetic acid salt
(E17)
[3082] 33 mg (0.046 mmol) of the compound (E16) were dissolved in
1.6 ml (50-times volume) of methylene chloride at room temperature,
and subsequently 60 ml (10-times volume) of trifluoroacetic acid
were added to the system at room temperature, followed by stirring
of the mixture at room temperature for 22 hours. After confirmation
of completion of the reaction, the reaction mixture was
concentrated under reduced pressure. The residue was purified over
silica gel column chromatography (Kiesel gel 60, 5 g,
2-propanol:water=5:1) to obtain 30 mg (yield: 84%) of the title
compound (E17) as a pale yellow solid.
[3083] Rf value: 0.4 (2-propanol:water=5:1);
[3084] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.63 (1H,
d, J=2.3Hz), 4.49 (1H, dd, J=9.3, 2.3Hz), 4.39 (1H, d, J=10.6Hz),
4.25-4.00 (4H, m), 3.77 (1H, d, J=9.3Hz), 2.36 (2H, t, J=7.4Hz),
1.92 (3H, s), 1.70-1.50 (2H, m), 1.30 (20H, bs), 0.90 (3H, t,
J=7.4Hz);
[3085] FAB-MS (positive): 543 (M+H).sup.+;
[3086] HR-MS Calcd. for C.sub.26H.sub.47O.sub.8N.sub.4, 543.3378,
Found 543.3412 (M+H).sup.-;
[3087] [.alpha.].sub.D.sup.24=+25.degree. (c=0.12, MeOH).
Example 4
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-hexanoyl-D-glycero-D-galact-
o-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (22)
(Exemplary Compound No. 36)
[3088] 70
[3089] i) Methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropylide-
ne-7-O-hexanoyl-D-glycero-D-galacto-non-2-enopyranosoate (E18)
[3090] 270 mg (0.73 mmol) of the compound (E3) were dissolved in
13.5 ml (50-times volume) of methylene chloride, and subsequently
0.14 ml (1.0 mmol) of hexanoyl chloride and 110 mg (0.9 mmol) of
4-dimethylaminopyridine were added to the system under ice-cooling,
followed by stirring of the mixture at room temperature for 30
minutes. Next, 0.13 ml (0.9 mmol) of triethylamine were poured into
the reaction mixture at room temperature, followed by further
stirring of the mixture for 19 hours. After confirmation of
completion of the reaction, methanol was poured into the system,
followed by stirring of the mixture for 30 minutes. Next, ethyl
acetate and a saturated aqueous NaCl solution were added to the
reaction mixture to separate the mixture. The organic layer was
dried over magnesium sulfate and filtered, followed by
concentration under reduced pressure. The residue thus obtained was
purified over silica gel column chromatography (Kiesel gel 60, 75
g, benzene:ethyl acetate=1:1) to obtain 220 mg (yield: 74%) of the
title compound (E18) as a colorless transparent syrup.
[3091] Rf value: 0.45 (benzene:ethyl acetate=1:1);
[3092] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 6.11
(1H, d, J=8.0Hz), 5.95 (1H, d, J=2.6Hz), 5.38 (1H, d, J=5.3,
2.0Hz), 4.69 (1H, dd, J=9.2, 2.6Hz), 4.65 (1H, dd, J=10.6, 2.0Hz),
4.38 (1H, q, J=5.5Hz), 4.14 (1H, dd, J=9.5, 5.5Hz), 3.95 (1H, dd,
J=9.5, 5.4Hz), 3.81 (3H, s), 3.59 (1H, ddd, J=10.6, 9.2, 8.0Hz),
2.44 (1H, dt, J=15.9, 7.4Hz), 2.36 (1H, dt, J=15.9, 7.4Hz), 2.01
(3H, s), 1.64 (2H, quintet, J=7.4Hz), 1.37 (3H, s), 1.35 (3H, s),
1.35-1.30 (4H, m). 0.90 (3H, t, J=7.4Hz);
[3093] [.alpha.].sub.D.sup.24=+94.3.degree. (c:0.35,
CHCl.sub.3).
[3094] ii) Methyl
5-acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2,-
3,4,5-tetradeoxy-8,9-O-isopropylidene-7-O-hexanoyl-D-glycero-D-galacto-non-
-2-enopyranosoate (E20)
[3095] 190 mg (0.41 mmol) of the compound (E18) were dissolved in
9.3 ml (50-times volume) of ethanol at room temperature, and
subsequently 70 mg (0.38-times volume) of Lindlar catalyst were
added to the system at room temperature, followed by stirring of
the mixture at room temperature under a hydrogen atmosphere of 1
atm. for 2.5 hours. After confirmation of completion of the
reaction, the reaction mixture was filtered. The filtered product
was washed with ethanol, and the filtrate and the washing solution
were combined, followed by concentration under reduced pressure.
The residue was purified over silica gel column chromatography
(Kiesel gel 60, 60 g, ethyl acetate:2-propanol:water=5:2:1) to
obtain 140 mg (yield: 80%) of the compound (E19) as a pale yellow
foamy solid.
[3096] Rf value: 0.4 (ethyl acetate:2-propanol=5:2:1 ).
[3097] 140 mg (0.3 mmol) of the resulting compound (E19), 120 mg
(0.43 mmol) of N,N'-bis-tert-butoxycarbonylthiourea and 0.12 ml
(0.86 mmol) of triethylamine were dissolved in 7 ml (50-times
volume) of dimethylformamide at room temperature. Subsequently, 110
mg (0.41 mmol) of mercury chloride were added to the system under
ice-cooling, followed by stirring of the mixture at room
temperature for 1.5 hours. Ethyl acetate was added to the reaction
mixture to dilute it, and the mixture was filtered using Celite,
followed by washing of the filtered product with ethyl acetate. The
filtrate and the washing solution were combined, and ethyl acetate
and a saturated aqueous NaCl solution were added thereto to
separate it. The organic layer was dried over magnesium sulfate and
filtered, followed by concentration under reduced pressure. The
residue was purified over silica gel column chromatography (Kiesel
gel 60, 50 g, benzene:ethyl acetate=3:1) to obtain 220 mg (yield:
100%) of the title compound (E20) as a white foamy solid.
[3098] Rf value: 0.5 (benzene:ethyl acetate=3:1);
[3099] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.46 (1H, d, J=8.7Hz), 5.97 (1H, d, J=8.7Hz), 5.88 (1H, d,
J=2.3Hz), 5.37 (1H, dd, J=6.3, 1.6Hz), 5.15 (1H, dt, J=8.7, 2.3Hz),
4.37 (1H, q, J=6.4Hz), 4.29 (1H, dd, J=8.7, 1.5Hz), 4.24 (1H, t,
J=8.7Hz), 4.11 (1H, dd, J=8.8, 6.4Hz), 3.96 (1H, dd, J=8.8, 6.4Hz),
3.81 (3H, s), 2.46 (1H, dt, J=15.9, 7.4Hz), 2.33 (1H, dt, J=15.9,
7.4Hz), 1.88 (3H, s), 1.70-1.50 (2H, m), 1.49 (9H, s), 1.48 (9H,
s), 1.38 (3H, s), 1.37 (3H, s), 1.40-1.25 (4H, m), 0.89 (3H, t,
J=7.4Hz);
[3100] [.alpha.].sub.D.sup.24=-28.3.degree. (c=0.4,
CHCl.sub.3).
[3101] iii)
5-Acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2,3,4,5--
tetradeoxy-8,9-O-isopropylidene-7-O-hexanoyl-D-glycero-D-galacto-non-2-eno-
pyranosoic Acid (E21)
[3102] 180 mg (0.26 mmol) of the compound (E20) were dissolved in a
mixture of 10.8 ml (60-times volume) of methanol and 1.8 ml
(10-times volume) of water, and 12 mg (0.29 mmol) of lithium
hydroxide monohydrate were added to the system at room temperature,
followed by stirring of the mixture at room temperature for 17
hours. After confirmation of completion of the reaction, Dowex-50W
was added to the system to neutralize it. The reaction mixture was
filtered, and the filtered product was washed with methanol. The
filtrate and the washing solution were combined and concentrated
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, 50 g, methylene
chloride:methanol=10:1) to obtain 0.13 g (yield: 75%) of the title
compound (E21) as a white foamy solid.
[3103] Rf value: 0.24 (methylene chloride:methanol=10:1);
[3104] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, bs), 8.52 (1H, bs), 5.95 (2H, bs), 5.32 (1H, bs), 5.15 (1H,
bs), 4.60-4.10 (3H, m), 3.95 (1H, bs), 2.70-2.20 (2H, m), 1.89 (3H,
s), 1.75-1.00 (28H, m), 0.85 (3H, m).
[3105] iv)
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-hexanoyl-D-glyce-
ro-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(E22)
[3106] 95 mg (0.15 mmol) of the compound (E21) were dissolved in
4.8 ml (50-times volume) of methylene chloride, and subsequently
0.95 ml (10-times volume) of trifluoroacetic acid were added to the
system at room temperature, followed by stirring of the mixture at
room temperature for 4.5 hours. After confirmation of completion of
the reaction, the reaction mixture was concentrated under reduced
pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, 20 g, ethyl
acetate:2-propanol:water=4:2:1) to obtain 54 mg (yield: 57%) of the
desired compound as a white solid.
[3107] Rf value: 0.3 (ethyl acetate:2-propanol:water=4:2:1);
[3108] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.53 (1H,
d, J=2.2Hz), 4.50-4.00 (6H, m), 3.59 (1H, d, J=9.2Hz), 2.35 (2H, t,
J=7.5Hz), 2.01 (3H, s), 1.70-1.50 (2H, m), 1.40-1.20 (4H, m), 0.91
(3H, t, J=7.5Hz);
[3109] IR(KBr) (cm.sup.-1) 3333, 1665, 1617, 1401, 1385, 1176;
[3110] FAB-MS (positive) 431 (M+H).sup.+;
[3111] HR-MS Calcd. for C.sub.11H.sub.31N.sub.4O.sub.8 431.2165,
Found 431.2125 (M+H).sup.+;
[3112] [.alpha.].sub.D.sup.24=+29.degree. (c=0.2, MeOH).
Example 5
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-octanoyl-D-glycero-D-galact-
o-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (E27)
(Exemplary Compound No. 38)
[3113] 71
[3114] i) Methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropylide-
ne-7-O-myristoyl-D-glycero-D-galacto-non-2-enopyranosoate (E23)
[3115] 185 mg (0.5 mmol) of the compound (E3) were dissolved in 5.0
ml of methylene chloride at room temperature, and 132 .mu.l (0.75
mmol) of octanoyl chloride and 91 mg (0.75 mmol) of
4-dimethylaminopyridine were added to the system under ice-cooling,
followed by stirring of the mixture at room temperature for 30
minutes. Next, 104 .mu.l (0.75 mmol) of triethylamine were poured
into the reaction mixture at room temperature, followed by further
stirring of the mixture for 6 hours. After confirmation of
completion of the reaction, methanol was poured into the system,
followed by stirring of the mixture for 30 minutes. Next, ethyl
acetate and a saturated aqueous NaCl solution were added to the
reaction mixture to separate it. The organic layer thus obtained
was dried over magnesium sulfate and filtered, followed by
concentration under reduced pressure. The residue was purified over
silica gel column chromatography (Kiesel gel 60, methylene
chloride:methanol=50:1) to obtain 150 mg (yield: 64%) of the
desired compound (E23) as a colorless transparent syrup.
[3116] Rf value: 0.50 (methylene chloride:methanol=20:1);
[3117] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 5.95
(1H, d, J=2.7Hz), 5.88 (1H, d, J=7.9Hz), 5.35 (1H, dd, J=6.0,
1.8Hz), 4.80 (1H, dd, J=9.1, 2.7Hz), 4.71 (1H, dd, J=10.5, 1.8Hz),
4.39 (1H, q, J=6.0Hz), 4.14 (1H, dd, J=8.8, 6.0Hz), 4.71 (1H, dd,
J=10.5, 1.8Hz), 4.39 (1H, q, J=6.0Hz), 4.14 (1H, dd, J=8.8, 6.0Hz),
3.945 (1H, dd, J=8.8, 6.0Hz), 3.81 (3H, s), 3.45 (1H, ddd, J=10.5,
9.1, 7.9Hz), 2.41 (1H, t, J=7.5Hz), 2.39 (1H, t, J=7.5Hz), 2.02
(3H, s), 1.63 (2H, quintet, J=7.5Hz), 1.37 (3H, s), 1.35 (3H, s),
1.26 (8H, s), 0.88 (3H, t, J=7.5Hz).
[3118] ii) Methyl
5-acetamido-4-amino-2,3,4,5-tetradeoxy-8,9-O-isopropylid-
ene-7-O-octanoyl-D-glycero-D-galacto-non-2-enopyranosoate (E24)
[3119] 130 mg (0.28 mmol) of the compound (3) were dissolved in 6.0
ml of ethanol at room temperature, and subsequently 46 mg
(0.35-times volume) of Lindlar catalyst were added to the system at
room temperature, followed by stirring of the mixture at room
temperature under a hydrogen atmosphere of 1 atm. for 1.5 hours.
After confirmation of completion of the reaction, the reaction
mixture was filtered. The filtered product was washed with ethanol,
and the filtrate and the washing solution were combined, followed
by concentration under reduced pressure. The residue was purified
over silica gel column chromatography (Kiesel gel 60, 15 g, ethyl
acetate:2-propanol:water=5:2:1) to obtain 95 mg (yield: 77%) of the
title compound (E24) as a white solid.
[3120] Rf value: 0.35 (n-hexane:ethyl acetate=2:1);
[3121] .sup.1H-NMR (270 MHz, CD.sub.3OD, TMS): .delta. (ppm) 5.94
(1H, d, J=2.4Hz), 5.42 (1H, dd, J=4.7, 1.8Hz), 4.39 (1H, dt, J=7.1,
6.0Hz), 4.18 (1H, dd, J=9.5, 1.6Hz), 4.14 (1H, dd, J=8.7, 6.4Hz),
3.93 (1H, dd, J=8.7, 6.4Hz), 3.87 (1H, t, J=9.5Hz), 3.78 (3H, s),
3.44 (1H, dd, J=9.5, 2.4Hz), 2.35 (2H, q, J=7.3Hz), 1.94 (3H, s),
1.60 (2H, quintet, J=7.3Hz), 1.32 (3H, s), 1.31 (3H, s), 1.27 (8H,
s), 0.88 (3H, t, J=7.3Hz).
[3122] iii) Methyl
5-acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2-
,3,4,5-tetradeoxy-8,9-O-isopropylidene-7-O-octanoyl-D-glycero-D-galacto-no-
n-2-enopyranosoate (E25)
[3123] 90 mg (0.2 mmol) of the compound (E24), 83 mg (0.30 mmol) of
N,N'-bis-tert-butoxycarbonylthiourea and 84 .mu.l (0.25 mmol) of
triethylamine were dissolved in 5 ml of dimethylformamide at room
temperature. Subsequently, 82 mg (0.30 mmol) of mercury chloride
were added to the system under ice-cooling, followed by stirring of
the mixture at room temperature for 2 hours. Ethyl acetate was
added to the reaction mixture to dilute it and the mixture was
filtered using Celite. The filtered product was washed with ethyl
acetate. The filtrate thus obtained and the washing solution were
combined, and ethyl acetate and a saturated aqueous NaCl solution
were added to the mixture to separate it. The organic layer was
dried over magnesium sulfate and filtered, followed by
concentration under reduced pressure. The residue was purified over
silica gel column chromatography (Kiesel gel 60, 15 g, hexane:ethyl
acetate=2:1) to obtain 120 mg (yield: 88%) of the title compound
(E25) as a colorless transparent syrup.
[3124] Rf value: 0.30 (hexane:ethyl acetate=2:1);
[3125] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.46 (1H, d, J=8.7Hz), 6.06 (1H, d, J=8.7Hz), 5.88 (1H, d,
J=2.4Hz), 5.37 (1H, dd, J=6.4, 1.5Hz), 5.15 (1H, dt, J=8.7, 2.4Hz),
4.38 (1H, q, J=6.4Hz), 4.28 (1H, dd, J=8.7, 1.5Hz), 4.23 (1H, t,
J=8.7Hz), 4.10 (1H, dd, J=9.6, 6.4Hz), 3.95 (1H, dd, J=9.6, 6.4Hz),
3.80 (3H, s), 2.453 (1H, dt, J=16.0, 7.5Hz), 2.33 (1H, dt, J=16.0,
7.5Hz), 1.87 (3H, s), 1.61 (2H, quintet, J=7.5Hz), 1.49 (9H, s),
1.48 (9H, s), 1.38 (3H, s), 1.35 (31H, s), 1.25 (8H, bs), 0.88 (3H,
t, J=7.5Hz).
[3126] iv)
5-Acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2,3,4,5-t-
etradeoxy-8,9-O-isopropylidene-7-O-octanoyl-D-glycero-D-galacto-non-2-enop-
yranosoic Acid (E26)
[3127] 100 mg (0.15 mmol) of the compound (E25) were dissolved in a
mixture of 4 ml (40-times volume) of methanol and 1 ml (10-times
volume) of water, and 7.0 mg (0.165 mmol) of lithium hydroxide
monohydrate were added to the system at room temperature, followed
by stirring of the mixture at room temperature for 8 hours After
confirmation of completion of the reaction, Dowex-50W was added to
the system to neutralize it. The reaction mixture was filtered, and
the filtered product was washed with methanol. The filtrate and the
washing solution were combined and concentrated under reduced
pressure. The residue thus obtained was purified over silica gel
column chromatography (Kiesel gel 60, ethyl
acetate:2-propanol:water=10:2:1) to obtain 56 mg (yield: 56%) of
the desired compound (E26) as a white solid.
[3128] Rf value: 0.35 (methylene chloride:methanol=10:1);
[3129] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.48 (1H, d, J=8.0Hz), 6.31 (1H, dull s), 5.90 (1H, bs),
5.30 (1H, bs), 5.10 (1H, bs), 4.60-3.30 (7H, m), 2.48 (1H, dt,
J=13.5, 6.5Hz), 2.32 (1H, dt, J=13.5, 6.5Hz), 1.88 (3H, s), 1.60
(2H, quintet, J=6.5Hz), 1.48 (18H, s), 1.39 (3H, s), 1.37 (3H, s),
1.25 (8H, bs), 0.88(3H, t, J=6.5Hz).
[3130] v)
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-octanoyl-D-glycer-
o-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(E27)
[3131] 50 mg (0.075 mmol) of the compound (E26) were dissolved in 3
ml (50-times volume) of methylene chloride at room temperature, and
subsequently 1 ml (10-times volume) of trifluoroacetic acid was
added to the system at room temperature, followed by stirring of
the mixture at room temperature for 22 hours. After confirmation of
completion of the reaction, the reaction mixture was concentrated
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, 5 g, 2-propanol:water=5:1) to
obtain 38 mg (yield: 88%) of the title compound (E27) as a pale
yellow solid.
[3132] Rf value: 0.3 (2-propanol:water=5:1);
[3133] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.55 (1H,
bs), 4.40-4.10 (7H, m), 3.65 (1H, d, J=9.0Hz), 2.36 (2H, t,
J=7.0Hz), 2.00 (3H, s), 1.70-1.50 (2H, m), 1.30 (8H, bs), 0.90 (3H,
t, J=7.0Hz);
[3134] FAB-MS (positive): 459 (M+H).sup.+;
[3135] [.alpha.].sub.D.sup.24=+19.2.degree. (c=0.26, MeOH).
Example 6
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-decanoyl-D-glycero-D-galact-
o-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (E32)
(Exemplary Compound No. 39)
[3136] 72
[3137] i) Methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropylide-
ne-7-O-decanoyl-D-glycero-D-galacto-non-2-enopyranosoate (E28)
[3138] 214 mg (0.58 mmol) of the compound (E3) were dissolved in
6.0 ml of methylene chloride at room temperature, and subsequently
152 .mu.l (0.87 mmol) of decanoyl chloride and 106 mg (0.87 mmol)
of 4-dimethylaminopyridine were added to the system under
ice-cooling, followed by stirring of the mixture at room
temperature for 30 minutes. Next, 106 .mu.l (0.87 mmol) of
trimethylamine were poured into the reaction mixture at room
temperature, followed by further stirring of the mixture for 6
hours. After confirmation of completion of the reaction, methanol
was poured into the system and the mixture was stirred for 30
minutes. Next, ethyl acetate and a saturated aqueous NaCl solution
were added to the reaction mixture to separate it. The organic
layer thus obtained was dried over magnesium sulfate and filtered,
followed by concentration under reduced pressure. The residue was
purified over silica gel column chromatography (Kiesel gel 60,
methylene chloride:methanol 50:1) to obtain 180 mg (yield: 63%) of
the desired compound (E28) as a colorless transparent syrup.
[3139] Rf value: 0.56 (methylene chloride:methanol=20:1);
[3140] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 5.95
(1H, d, J=2.7Hz), 5.88 (1H, d, J=7.9Hz), 5.35 (1H, dd, J=6.0,
1.8Hz), 4.80 (1H, dd, J=9.1, 2.7Hz), 4.71 (1H, dd, J=10.5, 1.8Hz),
4.39 (1H, q, J=6.0Hz), 4.14 (1H, dd, J=8.8, 6.0Hz), 3.945 (1H, dd,
J=8.8, 6.0Hz), 3.81 (3H, s), 3.45 (1H, ddd, J=10.5, 9.1, 7.9Hz),
2.41 (1H, t, J=7.5Hz), 2.39 (1H, t, J=7.5Hz), 2.02 (3H, s), 1.63
(2H, quintet, J=7.5Hz), 1.37 (3H, s), 1.35 (3H, s), 1.26 (12H, s),
0.88 (3H, t, J=7.5Hz).
[3141] ii) Methyl
5-acetamido-4-amino-2,3,4,5-tetradeoxy-8,9-O-isopropylid-
ene-7-O-decanoyl-D-glycero-D-galacto-non-2-enopyranosoate (E29)
[3142] 170 mg (0.32 mmol) of the compound (E28) were dissolved in
10 ml of ethanol at room temperature, and subsequently 60 mg
(0.35-times volume) of Lindlar catalyst were added to the system at
room temperature, followed by stirring of the mixture at room
temperature under a hydrogen atmosphere of 1 atm. for 1.5 hours.
After confirmation of completion of the reaction, the reaction
mixture was filtered. The filtered product was washed with ethanol,
and the filtrate and the washing solution were combined, followed
by concentration under reduced pressure. The residue was purified
over silica gel column chromatography (Kiesel gel 60, 15 g, ethyl
acetate:2-propanol:water=5:2:1) to obtain 120 mg (yield: 80%) of
the title compound (E29) as a white solid.
[3143] Rf value: 0.40 (n-hexane:ethyl acetate=2:1);
[3144] .sup.1H-NMR (270 MHz, CD.sub.3OD, TMS): .delta. (ppm) 5.94
(1H, d, J=2.4Hz), 5.42 (1H, dd, J=4.7, 1.8Hz), 4.39 (1H, dt, J=7.1,
6.0Hz), 4.18 (1H, dd, J=9.5, 1.6Hz), 4.14 (1H, dd, J=8.7, 6.4Hz),
3.93 (1H, dd, J=8.7, 6.4Hz), 3.87 (1H, t, J=9.5Hz), 3.78 (3H, s),
3.44 (1H, dd, J=9.5, 2.4Hz), 2.35 (2H, q, J=7.3Hz), 1.94 (3H, s),
1.60 (2H, quintet, J=7.3Hz), 1.32 (3H, s), 1.31 (3H, s), 1.27 (12H,
s), 0.88 (3H, t, J=7.3Hz).
[3145] iii) Methyl
5-acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2-
,3,4,5-tetradeoxy-8,9-O-isopropylidene-7-O-decanoyl-D-glycero-D-galacto-no-
n-2-enopyranosoate (E30)
[3146] 100 mg (0.21 mmol) of the compound (E29), 87 mg (0.31 mmol)
of N,N'-bis-tert-butoxycarbonylthiourea and 87 .mu.l (0.63 mmol) of
triethylamine were dissolved in 5 ml of dimethylformamide at room
temperature. Subsequently, 84 mg (0.31 mmol) of mercury chloride
were added to the system under ice-cooling, and the mixture was
stirred at room temperature for 2 hours. Ethyl acetate was added to
the reaction mixture to dilute it and the mixture was filtered
using Celite. The filtered product was washed with ethyl acetate.
The filtrate thus obtained and the washing solution were combined,
and ethyl acetate and a saturated aqueous NaCl solution were added
thereto to separate the mixture. The organic layer was dried over
magnesium sulfate and filtered, followed by concentration under
reduced pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, hexane:ethyl acetate=2:1) to obtain
120 mg (yield: 87%) of the title compound (E30) as a colorless
transparent syrup.
[3147] Rf value: 0.30 (hexane:ethyl acetate=2:1);
[3148] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.46 (1H, d, J=8.7Hz), 6.06 (1H, d, J=8.7Hz), 5.88 (1H, d,
J=2.4Hz), 5.37 (1H, dd, J=6.4, 1.5Hz), 5.15 (1H, J=8.7, 2.4Hz),
4.38 (1H, q, J=6.4Hz), 4.28 (1H, dd, J=8.7, 1.5Hz), 4.23 (1H, t,
J=8.7Hz), 4.10 (1H, dd, J=9.6, 6.4Hz), 3.95 (1H, dd, J=9.6, 6.4Hz),
3.80 (3H, s), 2.453 (1H, dt, J=16.0, 7.5Hz), 2.33 (1H, dt, J=16.0,
7.5Hz), 1.87(3H, s), 1.61 (2H, quintet, J=7.5Hz), 1.49 (9H, s),
1.48 (9H, s), 1.38 (3H, s), 1.35 (3H, s), 1.25 (12H, bs), 0.88 (3H,
t, J=7.5Hz).
[3149] iv)
5-Acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2,3,4,5-t-
etradeoxy-8,9-O-isopropylidene-7-O-decanoyl-D-glycero-D-galacto-non-2-enop-
yranosoic Acid (E31)
[3150] 100 mg (0.14 mmol) of the compound (E30) were dissolved in a
mixture of 4 ml (40-times volume) of methanol and 1 ml (10-times
volume) of water, and 6.5 mg (0.154 mmol) of lithium hydroxide
monohydrate were added to the system at room temperature, followed
by stirring of the mixture at room temperature for 8 hours. After
confirmation of completion of the reaction, Dowex-50W was added to
the system to neutralize it. The reaction mixture was filtered, and
the filtered product was washed with methanol. The filtrate and the
washing solution were combined and concentrated under reduced
pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, ethyl acetate:2-propanol:water=-
10:2:1) to obtain 53 mg (yield: 55%) of the desired compound (E31)
as a white solid.
[3151] Rf value: 0.38 (methylene chloride:methanol=10:1);
[3152] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.48 (1H, d, J=8.0Hz), 6.31 (1H, dull s), 5.90 (1H, bs),
5.30 (1H, bs), 5.10 (1H, bs), 4.60-3.30 (7H, m), 2.48 (1H, dt,
J=13.5, 6.5Hz), 2.32 (1H, dt, J=13.5, 6.5Hz), 1.88 (3H, s), 1.60
(2H, quintet, J=6.5Hz), 1.48 (18H, s), 1.39 (3H, s), 1.37 (3H, s),
1.25 (12H, bs), 0.88 (3H, t, J=6.5Hz).
[3153] v)
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-decanoyl-D-glycer-
o-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(E32)
[3154] 40 mg (0.057 mmol) of the compound (E31) were dissolved in 3
ml (50-times volume) of methylene chloride at room temperature, and
subsequently 1 ml (10-times volume) of trifluoroacetic acid was
added to the system at room temperature, followed by stirring of
the mixture at room temperature for 22 hours. After confirmation of
completion of the reaction, the reaction mixture was concentrated
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, 5 g, 2-propanol:water=5:1) to
obtain 30 mg (yield: 87%) of the title compound (E32) as a pale
yellow solid.
[3155] Rf value: 0.3 (2-propanol:water=5:1);
[3156] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.55 (1H,
bs), 4.40-4.10 (7H, m), 3.65 (1H, d, J=9.0Hz), 2.36 (2H, t,
J=7.0Hz), 2.00 (3H, s), 1.70-1.50 (2H, m), 1.30 (12H, bs), 0.90
(3H, t, J=7.0Hz);
[3157] FAB-MS (positive): 487(M+H).sup.+;
[3158] [.alpha.].sub.D.sup.24=+17.2.degree. (c=0.15, MeOH).
Example 7
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-palmitoyl-D-glycero-D-galac-
to-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (E37)
(Exemplary Compound No. 42)
[3159] 73
[3160] i) Methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropylide-
ne-7-O-palmitoyl-D-glycero-D-galacto-non-2-enopyranosoate (E33)
[3161] 1.35 g (3.66 mmol) of the compound (E3) were dissolved in 10
ml of methylene chloride at room temperature, and subsequently 1.88
ml (6.22 mmol) of palmitoyl chloride and 759 mg (4.33 mmol) of
4-dimethylaminopyridine were added to the system under ice-cooling,
followed by stirring of the mixture at room temperature for 30
minutes. Next, 104 .mu.l (6.21 mmol) of triethylamine were poured
into the reaction mixture at room temperature, and the resulting
mixture was further stirred for 15 hours. After confirmation of
completion of the reaction, methanol was poured to the system, and
the mixture was stirred for 30 minutes. Next, ethyl acetate and a
saturated aqueous NaCl solution were added to the reaction mixture
to separate it. The organic layer thus obtained was dried over
magnesium sulfate and filtered, followed by concentration under
reduced pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, n-hexane:ethyl acetate=2:1) to
obtain 1.42 g (yield: 64%) of the desired compound (E33) as a
colorless foam.
[3162] Rf value: 0.53 (n-hexane:ethyl acetate=1:1);
[3163] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 5.95
(1H, d, J=2.7Hz), 5.88 (1H, d, J=7.9Hz), 5.35 (1H, dd, J=6.0,
1.8Hz), 4.80 (1H, dd, J=9.1, 2.7Hz), 4.71 (1H, dd, J=10.5, 1.8Hz),
4.39 (1H, q, J=6.0Hz), 4.14 (1H, dd, J=8.8, 6.0Hz), 3.945 (1H, dd,
J=8.8, 6.0Hz), 3.81 (3H, s), 3.45 (1H, ddd, J=10.5, 9.1, 7.9Hz),
2.41 (1H, t, J=7.5Hz), 2.39 (1H, t, J=7.5Hz), 2.02 (3H, s), 1.63
(2H, quintet, J=7.5Hz), 1.37 (3H, s), 1.35 (3H, s), 1.26 (24H, s),
0.88 (3H, t, J=7.5Hz).
[3164] ii) Methyl
5-acetamido-4-amino-2,3,4,5-tetradeoxy-8,9-O-isopropylid-
ene-7-O-palmitoyl-D-glycero-D-galacto-non-2-enopyranosoate
(E34)
[3165] 1.42 g (2.34 mmol) of the compound (E33) were dissolved in
15 ml of ethanol at room temperature, and subsequently 477 mg
(0.34-times volume) of Lindlar catalyst were added to the system at
room temperature, followed by stirring of the mixture at room
temperature under a hydrogen atmosphere of 1 atm. for 2 hours.
After confirmation of completion of the reaction, the reaction
mixture was filtered. The filtered product was washed with ethanol,
and the filtrate and the washing solution were combined, followed
by concentration under reduced pressure. The residue was purified
over silica gel column chromatography (Kiesel gel 60, 15 g, ethyl
acetate:methanol=10:1) to obtain 1.16 g (yield: 85%) of the title
compound (E34) as a colorless foam.
[3166] Rf value: 0.18 (ethyl acetate:methanol=5:1);
[3167] .sup.1H-NMR (270 MHz, CD.sub.3OD, TMS): .delta. (ppm) 5.94
(1H, d, J=2.4Hz), 5.42 (1H, dd, J=4.7, 1.8Hz), 4.39 (1H, dt, J=7.1,
6.0Hz), 4.18 (1H, dd, J=9.5, 1.6Hz), 4.14 (1H, dd, J=8.7, 6.4Hz),
3.93 (1H, dd, J=8.7, 6.4Hz), 3.87 (1H, t, J=9.5Hz), 3.78 (3H, s),
3.44 (1H, dd, J=9.5, 2.4Hz), 2.35 (2H, q, J=7.3Hz), 1.94 (3H, s),
1.60 (2H, quintet, J=7.3Hz), 1.32 (3H, s), 1.31 (3H, s), 1.27 (24H,
s), 0.88 (3H, t, J=7.3Hz).
[3168] iii) Methyl
5-acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2-
,3,4,5-tetradeoxy-8,9-O-isopropylidene-7-O-palmitoyl-D-glycero-D-galacto-n-
on-2-enopyranosoate (E35)
[3169] 1.16 g (2.0 mmol) of the compound (E34), 828 mg (2.99 mmol)
of N,N'-bis-tert-butoxycarbonylthiourea and 0.42 ml (3.03 mmol) of
triethylamine were dissolved in 12 ml of dimethylformamide at room
temperature. Subsequently, 813 mg (2.99 mmol) of mercury chloride
were added to the system under ice-cooling, and the mixture was
stirred at room temperature for 2 hours. Ethyl acetate was added to
the reaction mixture to dilute it and the mixture was filtered
using Celite. The filtered product was washed with ethyl acetate.
The filtrate thus obtained and the washing solution were combined,
and ethyl acetate and a saturated aqueous NaCl solution were added
thereto to separate the mixture. The organic layer was dried over
magnesium sulfate and filtered, followed by concentration under
reduced pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, 15 g, hexane:ethyl acetate=2:1) to
obtain 1.0 g (yield: 61%) of the title compound (E35) as a
colorless foam.
[3170] Rf value: 0.52 (hexane:ethyl acetate=2:1);
[3171] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.46 (1H, d, J=8.7Hz), 6.06 (1H, d, J=8.7Hz), 5.88 (1H, d,
J=2.4Hz), 5.37 (1H, dd, J=6.4, 1.5Hz), 5.15 (1H, dt, J=8.7, 2.4Hz),
4.38 (1H, q, J=6.4Hz), 4.28 (1H, dd, J=8.7, 1.5Hz), 4.23 (1H, t,
J=8.7Hz), 4.10 (1H, dd, J=9.6, 6.4Hz), 3.95 (1H, dd, J=9.6, 6.4Hz),
3.80 (3H, s), 2.453 (1H, dt, J=16.0, 7.5Hz), 2.33 (1H, dt, J=16.0,
7.5Hz), 1.87 (3H, s), 1.61 (2H, quintet, J=7.5Hz), 1.49 (9H, s),
1.48 (9H, s), 1.38 (3H, s), 1.35 (3H, s), 1.25 (24H, bs), 0.88 (3H,
t, J=7.5Hz).
[3172] iv)
5-Acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2,3,4,5-t-
etradeoxy-8,9-O-isopropylidene-7-O-palmitoyl-D-glycero-D-galacto-non-2-eno-
pyranosoic Acid (E36)
[3173] 61 mg (0.07 mmol) of the compound (E35) were dissolved in a
mixture of 1.2 ml (40-times volume) of methanol and 0.15 ml
(10-times volume) of water, and 3.4 mg (0.08 mmol) of lithium
hydroxide monohydrate were added to the system at room temperature,
followed by stirring of the mixture at room temperature for 3
hours. After confirmation of completion of the reaction, Dowex-50W
was added to the system to neutralize it, and the reaction mixture
was filtered. The filtered product was washed with methanol. The
filtrate and the washing solution were combined, and the mixture
was concentrated under reduced pressure. The residue was purified
over silica gel column chromatography (Kiesel gel 60, ethyl
acetate:methanol=10:1) to obtain 33 mg (yield: 55%) of the desired
compound (E36) as a colorless foam.
[3174] Rf value: 0.61 (ethyl acetate:methanol=5:1);
[3175] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.48 (1H, d, J=8.0Hz), 6.31 (1H, dull s), 5.90 (1H, bs),
5.30 (1H, bs), 5.10 (1H, bs), 4.60-3.30 (7H, m), 2.48 (1H, dt,
J=13.5, 6.5Hz), 2.32 (1H, dt, J=13.5, 6.5Hz), 1.88 (3H, s), 1.60
(2H, quintet, J=6.5Hz), 1.48 (24H, s), 1.39 (3H, s), 1.37 (3H, s),
1.25 (8H, bs), 0.88 (3H, t, J=6.5Hz).
[3176] v)
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-palmitoyl-D-glyce-
ro-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(E37)
[3177] 289 mg (0.36 mmol) of the compound (E36) were dissolved in 3
ml (50-times volume) of methylene chloride at room temperature, and
subsequently 1 ml (10-times volume) of trifluoroacetic acid was
added to the system at room temperature, followed by stirring of
the mixture at room temperature for 22 hours. After confirmation of
completion of the reaction, the reaction mixture was concentrated
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, 5 g, ethyl
acetate:2-propanol:water=5:2:1) to obtain 206 mg (yield: 84%) of
the title compound (E37) as a colorless foam.
[3178] Rf value: 0.44 (2-propanol:water=5:1);
[3179] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.55 (1H,
bs), 4.40-4.10 (7H, m), 3.65 (1H, d, J=9.0Hz), 2.36 (2H, t,
J=7.0Hz), 2.00 (3H, s), 1.70-1.50 (2H, m), 1.30 (24H, bs), 0.90
(3H, t, J=7.0Hz);
[3180] FAB-MS (positive): 571 (M+H).sup.+;
[3181] [.alpha.].sub.D.sup.24=+18.5.degree. (c=0.12, MeOH).
Example 8
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-dodecanoyl-D-glycero-D-gala-
cto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (E42)
(Exemplary Compound No. 40)
[3182] 74
[3183] i) Methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropylide-
ne-7-O-dodecanoyl-D-glycero-D-galacto-non-2-enopyranosoate
(E38)
[3184] 1.07 g (2.89 mmol) of the compound (E3) were dissolved in 11
ml of methylene chloride at room temperature, and subsequently 1.03
ml (4.33 mmol) of dodecanoyl chloride and 529 mg (4.33 mmol) of
4-dimethylaminopyridine were added to the system under ice-cooling,
followed by stirring of the mixture at room temperature for 30
minutes. Next, 0.6 ml (4.33 mmol) of triethylamine were poured into
the reaction mixture at room temperature, and the mixture was
further stirred for 2.5 hours. After confirmation of completion of
the reaction, methanol was poured into the system, and the mixture
was stirred for 30 minutes. Next, ethyl acetate and a saturated
aqueous NaCl solution were added to the reaction mixture to
separate it. The organic layer thus obtained was dried over
magnesium sulfate and filtered, followed by concentration under
reduced pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, n-hexane:ethyl acetate=2:1) to
obtain 1.07 mg (yield: 67%) of the desired compound (E38) as a
colorless foam.
[3185] Rf value: 0.44 (n-hexane:ethyl acetate=1:1);
[3186] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 5.95
(1H, d, J=2.7Hz), 5.88 (1H, d, J=7.9Hz), 5.35 (1H, dd, J=6.0,
1.8Hz), 4.80 (1H, dd, J=9.1, 2.7Hz), 4.71 (1H, dd, J=10.5, 1.8Hz),
4.39 (1H, q, J=6.0Hz), 4.14 (1H, dd, J=8.8, 6.0Hz), 3.945 (1H, dd,
J=8.8, 6.0Hz), 3.81 (3H, s), 3.45 (1H, ddd, J=10.5, 9.1, 7.9Hz),
2.41 (1H, t, J=7.5Hz), 2.39 (1H, t, J=7.5Hz), 2.02 (3H, s), 1.63
(2H, quintet, J=7.5Hz), 1.37 (3H, s), 1.35 (3H, s), 1.26 (16H, s),
0.88 (3H, t, J=7.5Hz).
[3187] ii) Methyl
5-acetamido-4-amino-2,3,4,5-tetradeoxy-8,9-O-isopropylid-
ene-7-O-dodecanoyl-D-glycero-D-galacto-non-2-enopyranosoate
(E39)
[3188] 1.06 g (1.92 mmol) of the compound (E38) were dissolved in
10 ml of ethanol at room temperature, and subsequently 353 mg
(0.33-times volume) of Lindlar catalyst were added to the system at
room temperature, followed by stirring of the mixture at room
temperature under a hydrogen atmosphere of 1 atm. for 1.5 hours.
After confirmation of completion of the reaction, the reaction
mixture was filtered. The filtered product was washed with ethanol,
and the filtrate and the washing solution were combined, followed
by concentration under reduced pressure. The residue was purified
over silica gel column chromatography (Kiesel gel 60, 15 g, ethyl
acetate:methanol=5:1) to obtain 871 mg (yield: 86%) of the title
compound (E39) as a colorless foam.
[3189] Rf value: 0.36 (ethyl acetate:methanol=5:1);
[3190] .sup.1H-NMR (270 MHz, CD.sub.3OD, TMS): .delta. (ppm) 5.94
(1H, d, J=2.4Hz), 5.42 (1H, dd, J=4.7, 1.8Hz), 4.39 (1H, dt, J=7.1,
6.0Hz), 4.18 (1H, dd, J=9.5, 1.6Hz), 4.14 (1H, dd, J=8.7, 6.4Hz),
3.93 (1H, dd, J=8.7, 6.4Hz), 3.87 (1H, t, J=9.5Hz), 3.78 (3H, s),
3.44 (1H, dd, J=9.5, 2.4Hz), 2.35 (2H, q, J=7.3Hz), 1.94 (3H, s),
1.60 (2H, quintet, J=7.3Hz), 1.32 (3H, s), 1.31 (3H, s), 1.27 (16H,
s), 0.88 (3H, t, J=7.3Hz).
[3191] iii) Methyl
5-acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2-
,3,4,5-tetradeoxy-8,9-O-isopropylidene-7-O-dodecanoyl-D-glycero-D-galacto--
non-2-enopyranosoate (E40)
[3192] 868 mg (1.65 mmol) of the compound (E39), 940 mg (3.4 mmol)
of N,N'-bis-tert-butoxycarbonylthiourea and 0.95 ml (6.90 mmol) of
triethylamine were dissolved in 10 ml of dimethylformamide at room
temperature. Subsequently, 926 mg (3.4 mmol) of mercury chloride
were added to the system under ice-cooling, and the mixture was
stirred at room temperature for 2 hours. Ethyl acetate was added to
the reaction mixture to dilute it and the mixture was filtered
using Celite. The filtered product was washed with ethyl acetate.
The filtrate and the washing solution were combined, and ethyl
acetate and a saturated aqueous NaCl solution were added thereto to
separate the mixture. The organic layer was dried over magnesium
sulfate and filtered, followed by concentration under reduced
pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, 15 g, hexane:ethyl acetate=2:1) to
obtain 1.3 g (yield: 100%) of the title compound (E40) as a
colorless foam.
[3193] Rf value: 0.47 (hexane:ethyl acetate=2:1);
[3194] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.46 (1H, d, J=8.7Hz), 6.06 (1H, d, J=8.7Hz), 5.88 (1H, d,
J=2.4Hz), 5.37 (1H, dd, J=6.4, 1.5Hz), 5.15 (1H, dt, J=8.7, 2.4Hz),
4.38 (1H, q, J=6.4Hz), 4.28 (1H, dd, J=8.7, 1.5Hz), 4.23 (1H, t,
J=8.7Hz), 4.10 (1H, dd, J=9.6, 6.4Hz), 3.95 (1H, dd, J=9.6, 6.4Hz),
3.80 (3H, s), 2.453 (1H, dt, J=16.0, 7.5Hz), 2.33 (1H, dt, J=16.0,
7.5Hz), 1.87 (3H, s), 1.61 (2H quintet, J=7.5Hz), 1.49 (9H, s),
1.48 (9H, s), 1.38 (3H, s), 1.35 (3H, s), 1.25 (16H bs), 0.88 (3H,
t, J=7.5Hz).
[3195] iv)
5-Acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2,3,4,5-t-
etradeoxy-8,9-O-isopropylidene-7-O-dodecanoyl-D-glycero-D-galacto-non-2-en-
opyranosoic Acid (E41)
[3196] 100 mg (0.15 mmol) of the compound (E40) were dissolved in a
mixture of 4 ml (40-times volume) of methanol and 1 ml (10-times
volume) of water, and 7.0 mg (0.165 mmol) of lithium hydroxide
monohydrate were added to the system at room temperature, followed
by stirring of the mixture at room temperature for 8 hours. After
confirmation of completion of the reaction, Dowex-50W was added to
the system to neutralize it, and the reaction mixture was filtered.
The filtered product was washed with methanol. The filtrate and the
washing solution were combined, and the mixture was concentrated
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, ethyl
acetate:2-propanol:water=10:2:1) to obtain 56 mg (yield: 56%) of
the desired compound (E41) as a white solid.
[3197] Rf value: 0.35 (methylene chloride:methanol=10:1);
[3198] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.48 (1H, d, J=8.0Hz), 6.31 (1H, dull s), 5.90 (1H, bs),
5.30 (1H, bs), 5.10 (1H, bs), 4.60-3.30 (7H, m), 2.48 (1H, dt,
J=13.5, 6.5Hz), 2.32 (1H, dt, J=13.5, 6.5Hz), 1.88 (3H, s), 1.60
(2H, quintet, J=6.5Hz), 1.48 (18H, s), 1.39 (3H, s), 1.37 (3H, s),
1.25 (8H, bs), 0.88 (3H, t, J=6.5Hz).
[3199] v)
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-dodecanoyl-D-glyc-
ero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(E42)
[3200] 50 mg (0.075 mmol) of the compound (E41) were dissolved in 3
ml (50-times volume) of methylene chloride at room temperature, and
subsequently 1 ml (10-times volume) of trifluoroacetic acid was
added to the system at room temperature, followed by stirring of
the mixture at room temperature for 22 hours. After confirmation of
completion of the reaction, the reaction mixture was concentrated
under reduced pressure. The residue was purified over silica gel
column chromatography (Kiesel gel 60, 5 g, 2-propanol:water=5:1) to
obtain 38 mg (yield: 88%) of the title compound (E42) as a pale
yellow solid.
[3201] Rf value: 0.3 (2-propanol:water=5:1);
[3202] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.55 (1H,
bs), 4.40-4.10 (7H, m), 3.65 (1H, d, J=9.0Hz), 2.36 (2H, t,
J=7.0Hz), 2.00 (3H, s), 1.70-1.50 (2H, m), 1.30 (8H, bs), 0.90 (3H,
t, J=7.0Hz);
[3203] FAB-MS (positive): 515 (M+H).sup.+;
[3204] [.alpha.].sub.D.sup.24=+20.5.degree. (c=0.08, MeOH).
Example 9
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-octadecanoyl-D-glycero-D-ga-
lacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt (E47)
(Exemplary Compound No. 43)
[3205] 75
[3206] i) Methyl
5-acetamido-4-azido-2,3,4,5-tetradeoxy-8,9-O-isopropylide-
ne-7-O-octadecanoyl-D-glycero-D-galacto-non-2-enopyranosoate
(E43)
[3207] 1.10 g (2.98 mmol) of the compound (E3) were dissolved in 11
ml of methylene chloride at room temperature, and subsequently 1.70
ml (5.03 mmol) of stearoyl chloride and 620 mg (5.07 mmol) of
4-dimethylaminopyridine were added to the system under ice-cooling,
followed by stirring of the mixture at room temperature for 30
minutes. Next, 0.70 ml (5.05 mmol) of triethylamine were poured
into the reaction mixture at room temperature, and the resulting
mixture was further stirred for 15 hours. After confirmation of
completion of the reaction, methanol was poured into the system,
and the mixture was stirred for 30 minutes. Next, ethyl acetate and
a saturated aqueous NaCl solution were added to the reaction
mixture to separate it. The organic layer was dried over magnesium
sulfate and filtered, followed by concentration under reduced
pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, n-hexane:ethyl acetate=2:1) to
obtain 1.21 g (yield: 64%) of the desired compound (E43) as a
colorless foam.
[3208] Rf value: 0.51 (n-hexane:ethyl acetate=1:1);
[3209] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 5.95
(1H, d, J=2.7Hz), 5.88 (1H, d, J=7.9Hz), 5.35 (1H, dd, J=6.0,
1.8Hz), 4.80 (1H, dd, J=9.1, 2.7Hz), 4.71 (1H, dd, J=10.5, 1.8Hz),
4.39 (1H, q, J=6.0Hz), 4.14 (1H, dd, J=8.8, 6.0Hz), 3.945 (1H, dd,
J=8.8, 6.0Hz), 3.81 (3H, s), 3.45 (1H, ddd, J=10.5, 9.1, 7.9Hz),
2.41 (1H, t, J=7.5Hz), 2.39 (1H, t, J=7.5Hz), 2.02 (3H, s), 1.63
(2H, quintet, J=7.5Hz), 1.37 (3H, s), 1.35 (3H, s), 1.26 (28H, s),
0.88 (3H, t, J=7.5Hz).
[3210] ii) Methyl
5-acetamido-4-amino-2,3,4,5-tetradeoxy-8,9-O-isopropylid-
ene-7-O-octadecanoyl-D-glycero-D-galacto-non-2-enopyranosoate
(E44)
[3211] 1.20 g (1.88 mmol) of the compound (E43) were dissolved in
12 ml of ethanol at room temperature, and subsequently 399 mg
(0.33-times volume) of Lindlar catalyst were added to the system at
room temperature, followed by stirring of the mixture at room
temperature under a hydrogen atmosphere of 1 atm. for 3 hours.
After confirmation of completion of the reaction, the reaction
mixture was filtered. The filtered product was washed with ethanol.
The filtrate and the washing solution were combined, and the
mixture was concentrated under reduced pressure. The residue was
purified over silica gel column chromatography (Kiesel gel 60, 15
g, ethyl acetate:methanol=10:1) to obtain 924 mg (yield: 80%) of
the title compound (E44) as a colorless foam.
[3212] Rf value: 0.37 (ethyl acetate:methanol=4:1);
[3213] .sup.1H-NMR (270 MHz, CD.sub.3OD, TMS): .delta. (ppm) 5.94
(1H, d, J=2.4Hz), 5.42 (1H, dd, J=4.7, 1.8Hz), 4.39 (1H, dt, J=7.1,
6.0Hz), 4.18 (1H, dd, J=9.5, 1.6Hz), 4.14 (1H, dd, J=8.7, 6.4Hz),
3.93 (1H, dd, J=8.7, 6.4Hz), 3.87 (1H, t, J=9.5Hz), 3.78 (3H, s),
3.44 (1H, dd, J=9.5, 2.4Hz), 2.35 (2H, q, J=7.3Hz), 1.94 (3H, s),
1.60 (2H, quintet, J=7.3Hz), 1.32 (3H, s), 1.31 (3H, s), 1.27 (28H,
s), 0.88 (3H, t, J=7.3Hz).
[3214] iii) Methyl
5-acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2-
,3,4,5-tetradeoxy-8,9-O-isopropylidene-7-O-octadecanoyl-D-glycero-D-galact-
o-non-2-enopyranosoate (E45)
[3215] 916 mg (1.50 mmol) of the compound (E44), 539 mg (1.95 mmol)
of N,N'-bis-tert-butoxycarbonylthiourea and 0.27 ml (1.95 mmol) of
triethylamine were dissolved in 12 ml of dimethylformamide at room
temperature. Subsequently, 529 mg (1.95 mmol) of mercury chloride
were added to the system under ice-cooling, and the mixture was
stirred at room temperature for 4 hours. Ethyl acetate was added to
the reaction mixture to dilute it, and the mixture was filtered
using Celite. The filtered product was washed with ethyl acetate.
The filtrate and the washing solution were combined, and ethyl
acetate and a saturated aqueous NaCl solution were added to the
mixture separate it. The organic layer was dried over magnesium
sulfate and filtered, followed by concentration under reduced
pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, 15 g, hexane:ethyl acetate=2:1) to
obtain 750 mg (yield: 59%) of the title compound (E45) as a
colorless foam.
[3216] Rf value: 0.29 (hexane:ethyl acetate 2:1);
[3217] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.46 (1H, d, d=8.7Hz), 6.06 (1H, d, J=8.7Hz), 5.88 (1H, d,
J=2.4Hz), 5.37 (1H, dd, J=6.4, 1.5Hz), 5.15 (1H, dt, J=8.7, 2.4Hz),
4.38 (1H, q, J=6.4Hz), 4.28 (1H, dd, J=8.7, 1.5Hz), 4.23 (1H, t,
J=8.7Hz), 4.10 (1H, dd, J=9.6, 6.4Hz), 3.95 (1H, dd, J=9.6, 6.4Hz),
3.80 (3H, s), 2.453 (1H, dt, J=16.0, 7.5Hz), 2.33 (1H, dt, J=16.0,
7.5Hz), 1.87 (3H, s), 1.61 (2H, quintet, J=7.5Hz), 1.49 (9H, s),
1.48 (9H, s), 1.38 (3H, s), 1.35 (3H, s), 1.25 (28H, bs), 0.88 (3H,
t, J=7.5Hz).
[3218] iv)
5-Acetamido-4-(N,N'-bis-tert-butoxycarbonyl)guanidino-2,3,4,5-t-
etradeoxy-8,9-O-isopropylidene-7-O-octadecanoyl-D-glycero-D-galacto-non-2--
enopyranosoic Acid (E46)
[3219] 741 mg (0.87 mmol) of the compound (E45) were dissolved in a
mixture of 15 ml of methanol and 1.5 ml of water, and 38 mg (0.91
mmol) of lithium hydroxide monohydrate were added to the system at
room temperature, followed by stirring of the mixture at room
temperature for 6 hours. After confirmation of completion of the
reaction, a solution of 4N HCl in dioxane was added to the system
to neutralize it, followed by concentration under reduced pressure.
The residue was purified over silica gel column chromatography
(Kiesel gel 60, ethyl acetate:methanol=10:1) to obtain 430 mg
(yield: 59%) of the desired compound (E46) as a colorless foam.
[3220] Rf value: 0.40 (ethyl acetate:methanol=5:1);
[3221] .sup.1H-NMR (270 MHz, CDCl.sub.3, TMS): .delta. (ppm) 11.4
(1H, s), 8.48 (1H, J=8.0Hz), 6.31 (1H, dull s), 5.90 (1H, bs), 5.30
(1H, bs), 5.10 (1H, bs), 4.60-3.30 (7H, m), 2.48 (1H, dt, J=13.5,
6.5Hz), 2.32 (1H, dt, J=13.5, 6.5Hz), 1.88 (3H, s), 1.60 (2H,
quintet, J=6.5Hz), 1.48 (24H, s), 1.39 (3H, s), 1.37 (3H, s), 1.25
(28H, bs), 0.88 (3H, t, J=6.5Hz).
[3222] v)
5-Acetamido-2,3,4,5-tetradeoxy-4-guanidino-9-O-octadecanoyl-D-gl-
ycero-D-galacto-non-2-enopyranosoic Acid Trifluoroacetic Acid Salt
(E47)
[3223] 422 mg (0.50 mmol) of the compound (E46) were dissolved in 3
ml of methylene chloride at room temperature, and subsequently 1 ml
of trifluoroacetic acid was added to the system at room
temperature, followed by stirring of the mixture at room
temperature for 22 hours. After confirmation of completion of the
reaction, the reaction mixture was concentrated under reduced
pressure. The residue was purified over silica gel column
chromatography (Kiesel gel 60, 5 g, ethyl
acetate:2-propanol:water=5:2:1) to obtain 300 mg (yield: 84%) of
the title compound (E47) as a colorless foam.
[3224] Rf value: 0.44 (2-propanol:water=5:1);
[3225] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.55 (1H,
bs), 4.40-4.10 (7H, m), 3.65 (1H, d, J=9.0Hz), 2.36 (2H, t,
J=7.0Hz), 2.00 (3H, s), 1.70-1.50 (2H, m), 1.30 (28H, bs), 0.90
(3H, t, J=7.0Hz);
[3226] FAB-MS (positive): 599 (M+H).sup.+;
[3227] [.alpha.].sub.D.sup.24=+19.8.degree. (c=0.15, MeOH).
Example 10
Cetyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-2-
-enopyranosoate Trifluoroacetic Acid Salt (E48) (Exemplary Compound
No. 89)
[3228] 76
[3229] The procedures were carried out in a similar manner to those
in Example 1 using cetyl alcohol instead of myristyl alcohol to
obtain the title compound.
[3230] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.83 (1H,
d, J=2.7Hz), 4.44 (1H, dd, J=9.0, 2.7Hz), 4.38 (1H, dd, J=9.0,
<1Hz), 4.18 (2H, t, J=6.2Hz), 4.17 (1H, t, J=9.0Hz), 3.90-3.74
(2H, m), 3.68 (1H, dd, J=12.0, 4.5Hz), 3.65 (1H, d, J=9.0Hz), 1.99
(3H, s), 1.67 (2H, quintet, J=6.2Hz), 1.26 (28H, bs), 0.87 (3H, t
J=6.2Hz).
Example 11
Stearyl
5-acetamido-2,3,4,5-tetradeoxy-4-guanidino-D-glycero-D-galacto-non-
-2-enopyranosoate Trifluoroacetic Acid Salt (E49) (Exemplary
Compound No. 91)
[3231] 77
[3232] The procedures were carried out in a similar manner to those
in Example 1 using stearyl alcohol instead of myristyl alcohol to
obtain the title compound.
[3233] .sup.1H-NMR (270 MHz, CD.sub.3OD): .delta. (ppm) 5.83 (1H,
d, J=2.7Hz), 4.44 (1H, dd, J=9.0, 2.7Hz), 4.38 (1H, dd, J=9.0,
<1Hz), 4.18 (2H, t, J=6.2Hz), 4.17(1H, t, J=9.0Hz), 3.90-3.74
(2H, m), 3.68 (1H, dd, J=12.0, 4.5Hz), 3.65 (1H, d, J=9.0Hz), 1.99
(3H s), 1.67 (2H, quintet, J=6.2Hz), 1.26 (32H, bs), 0.87 (3H, t,
J=6.2Hz).
Preparation Example 1
[3234] An aqueous solution was prepared so that the compound of
Example 4 was 10% (W/W), benzalkonium chloride 0.04% (W/W),
phenylethyl alcohol 0.40% (W/W), and purified water 89.56%
(W/W).
Preparation Example 2
[3235] An aqueous co-solvent solution was prepared so that the
compound of Example 4 was 10% (W/W), benzalkonium chloride 0.04%
(W/W), polyethylene glycol 400 10.0% (W/W), propylene glycol 30%
(W/W), and purified water 39.96% (W/W).
Preparation Example 3
[3236] A dry powder was prepared so that the compound of Example 4
was 40% (W/W) and lactose was 60% (W/W).
Preparation Example 4
[3237] An aerosol agent was prepared so that the compound of
Example 4 was 10% (W/W), lecithin 0.5% (W/W), Freon 11 34.5% and
Freon 12 55%.
Test Example 1
[3238] Influenza Virus Sialidase Inhibitory Activity
[3239] A cannula was inserted into the trachea of mice (BALB/C,
females, 5 to 6 weeks old, body weight: 20 g) under anesthesia
followed by injection of 0.5 ml of phosphate-buffered physiological
saline. Lung washings were then obtained by collecting the liquid
by aspiration, repeating the procedure three times. 1 .mu.M of the
test compound (sample), 10 .mu.g of lung washings in terms of the
amount of protein, and phosphate-buffered physiological saline were
mixed and incubated at 37.degree. C. for one to three days at a
final volume of 100 .mu.l. After sampling 10 .mu.l of this reaction
mixture, a sialidase reaction was carried out in 32.5 mM
2-(N-morpholino)ethanesulfonate buffer (pH 6.5) containing 40 mM
calcium chloride using influenza virus A/PR/8/34 (equivalent to
5.times.10.sup.5 plaque-forming units) as the sialidase enzyme and
0.1 mM ammonium 4-methylumbelliferyl-N-acetyl-.alpha.-D-neuraminate
as the substrate. The fluorescence intensity of the
4-methylumbelliferone produced in the reaction mixture was measured
at an excitation wavelength of 360 nm and measurement wavelength of
460 nm. On the other hand, a concentration vs. inhibition curve was
prepared by carrying out similar reactions using as sample various
concentrations of Compound A (GG-167). The amount of substance
having sialidase inhibitory activity formed in the lung washings
from the test compound was quantitatively determined as the amount
of Compound A using the above inhibition curve.
[3240] Although the compound of the present invention did not
exhibit influenza virus sialidase inhibitory activity directly, by
treating with biological fractions containing hydrolase (e.g.,
mouse lung washings), the compound of the present invention
exhibited influenza virus sialidase inhibitory activity similar to
that of Compound A.
Test Example 2
[3241] Mouse Infection Treatment Experiment 1
[3242] A solution was prepared containing 500 pfu (plaque-forming
units) of mouse-acclimated influenza virus A/PR/8/34 strain in 50
.mu.l of phosphate buffer containing 0.42% bovine serum albumin
which was then used to infect mice (BALB/C, females, 5-6 weeks old,
20 g) by dropping into the nose for infection. The compounds of the
present invention were prepared to a dose level of 0.6
.mu.mol/kg/50 .mu.l by suspending in physiological saline, and
administered to the animals by dropping into the nose on a total of
3 occasions at 4 hours before, 4 hours after and 17 hours after
viral infection. The test was performed on groups of 7 or 8
animals, and results were indicated as the number of surviving mice
divided by the number of test mice at 6, 8 and 10 days after
infection. Incidentally, Compound A (GG-167) was used as the
comparative compound.
8 TABLE 2 Day 6 Day 8 Day 10 Physiological saline only 1/7 0/7 0/7
Compound A 7/7 3/7 0/7 Compound of Example 1' 8/8 5/8 3/8 Compound
of Example 2' 8/8 2/8 1/8
[3243] Although all of the animals in the group dosed with Compound
A were dead on day 10 after infection, 3 or 1 of the animals in the
groups dosed with the compounds of Example 1 or Example 2 were
still alive. These results indicate that the compound of Example 1
or Example 2 of the present invention possesses influenza infection
therapeutic effects superior to those of Compound A.
Test Example 3
[3244] Mouse Infection Treatment Experiment-2
[3245] A solution was prepared containing 500 pfu (plaque-forming
units) of mouse-acclimated influenza virus A/PR18/34 strain in 50
.mu.l of phosphate buffer containing 0.42% bovine serum albumin
which was then used to infect mice (BALB/C, females, 5-6 weeks old,
20 g) by dropping into the nose for infection. The compounds of the
present invention were prepared to a dose level of 0.9
.mu.mol/kg/50 .mu.l by suspending in physiological saline, and
administered to the animals by dropping into the nose on a total of
3 occasions at 4 hours before, 4 hours after and 17 hours after
viral infection. The test was performed on groups of 4 to 12
animals, and results were indicated as the number of surviving mice
divided by the number of test mice at 8 and 10 days after
infection. Incidentally, Compound A (GG-167) was used as the
comparative compound.
9 TABLE 3 Day 8 Day 10 Physiological saline only 0/4 0/4 Compound A
0/8 0/8 Compound of Example 1' 4/12 2/12 Compound of Example 10'
10/12 5/12 Compound of Example 11' 11/11 5/11
[3246] Although all of the animals in the group dosed with Compound
A were dead on day 10 after infection, 2 to 5 of the animals in the
groups dosed with the compounds of Example 1, 10 or 11 were still
alive. These results indicate that the compound of Example 1,
Example 10 or Example 11 of the present invention possesses
influenza infection therapeutic effects superior to those of
Compound A.
Test Example 4
[3247] Mouse Infection Treatment Experiment-3
[3248] A solution was prepared containing 500 pfu (plaque-forming
units) of mouse-acclimated influenza virus A/PR/8/34 strain in 50
.mu.l of phosphate buffer containing 0.42% bovine serum albumin
which was then used to infect mice (BALB/C, females, 5-6 weeks old,
20 g) by dropping into the nose for infection. The compounds of the
present invention were prepared to a dose level of 0.3
.mu.mol/kg/50 .mu.l by suspending in physiological saline, and
administered to the animals by dropping into the nose on a total of
3 occasions at 4 hours before, 4 hours after and 17 hours after
viral infection. The test was performed on groups of 10 or 11
animals, and results were indicated as the number of surviving mice
divided by the number of test mice at 6 and 8 days after infection.
Incidentally, Compound A (GG-167) was used as the comparative
compound.
10 TABLE 4 Day 6 Day 8 Physiological saline only 0/10 0/10 Compound
A 10/10 1/10 Compound of Example 3' 10/10 10/10 Compound of Example
4' 10/10 6/10 Compound of Example 5' 11/11 10/11 Compound of
Example 6' 11/11 10/11 Compound of Example 7' 10/10 3/10 Compound
of Example 8' 11/11 2/11 Compound of Example 9' 10/10 4/10
[3249] Although only one of the animals in the group dosed with
Compound A was alive on day 8 after infection, 2 to 10 animals in
the groups dosed with the compound of any one of Examples 3 to 9
were still alive. These results indicate that the compounds of
Examples 3 to 9 of the present invention possess influenza
infection therapeutic effects superior to those of Compound A.
Industrial Applicability
[3250] The neuraminic acid compound (1) of the present invention
undergoes hydrolysis by hydrolase present in a living body and
exhibits excellent viral replication inhibitory activity and
sialidase inhibitory activity. In addition, if the neuraminic acid
compound (1) is administered to mice infected with influenza virus,
the compound exhibits infection therapeutic effects superior to
Compound A (GG-167) described in WO91/16320 (Japanese PCT
application (Kokai) No. Hei 5-507068. Thus, the neuraminic acid
compound (1) of the present invention is useful as a therapeutic
agent or preventive agent (preferably therapeutic agent) for viral
infections (preferably influenza viral infections).
* * * * *