U.S. patent application number 14/043223 was filed with the patent office on 2014-01-30 for poly aromatic sodium channel blockers.
This patent application is currently assigned to PARION SCIENCES, Inc.. The applicant listed for this patent is Michael Ross JOHNSON. Invention is credited to Michael Ross JOHNSON.
Application Number | 20140031371 14/043223 |
Document ID | / |
Family ID | 40998513 |
Filed Date | 2014-01-30 |
United States Patent
Application |
20140031371 |
Kind Code |
A1 |
JOHNSON; Michael Ross |
January 30, 2014 |
POLY AROMATIC SODIUM CHANNEL BLOCKERS
Abstract
Polyaromatic sodium channel blockers represented by the formula:
##STR00001## are provided where the structural variables are
defined herein. The invention also includes a variety of
compositions, combinations and methods of treatment using these
inventive sodium channel blockers.
Inventors: |
JOHNSON; Michael Ross;
(Chapel Hill, NC) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
JOHNSON; Michael Ross |
Chapel Hill |
NC |
US |
|
|
Assignee: |
PARION SCIENCES, Inc.
Durham
NC
|
Family ID: |
40998513 |
Appl. No.: |
14/043223 |
Filed: |
October 1, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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13353018 |
Jan 18, 2012 |
8575176 |
|
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14043223 |
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12393252 |
Feb 26, 2009 |
8124607 |
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13353018 |
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61031466 |
Feb 26, 2008 |
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Current U.S.
Class: |
514/255.05 ;
514/255.06 |
Current CPC
Class: |
A61P 35/00 20180101;
A61P 11/08 20180101; A61P 43/00 20180101; A61P 27/02 20180101; A61P
11/00 20180101; C07D 405/14 20130101; C07D 405/12 20130101; A61P
9/00 20180101; A61P 13/00 20180101; A61P 1/00 20180101; A61P 11/02
20180101; A61P 11/06 20180101; C07D 241/32 20130101; C07D 241/26
20130101 |
Class at
Publication: |
514/255.05 ;
514/255.06 |
International
Class: |
C07D 405/14 20060101
C07D405/14; C07D 241/26 20060101 C07D241/26 |
Claims
1-47. (canceled)
48. A method of treating chronic bronchitis, bronchiectasis, cystic
fibrosis, sinusitis, ventilator-induced pneumonia, asthma, chronic
obstructive pulmonary disease, emphysema, pneumonia or
rhinosinusitis, comprising administering to a human in need thereof
an effective amount of a compound represented by the formula (I):
##STR00069## and racemates, enantiomers, diastereomers, tautomers
and pharmaceutically acceptable salts, thereof, wherein: X is
hydrogen, halogen or lower alkyl; Y is hydrogen or
--N(R.sup.2).sub.2; R.sup.1 is hydrogen or lower alkyl; each
R.sup.2 is, independently, --R.sup.7, --(CH.sub.2).sub.m--OR.sup.8,
--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7, or
##STR00070## R.sup.3 and R.sup.4 are each, independently, hydrogen,
lower alkyl, hydroxyl-lower alkyl, phenyl, (phenyl)-lower alkyl,
(halophenyl)-lower alkyl, ((lower-alkyl)phenyl)-lower-alkyl,
((lower-alkoxy)phenyl)-lower-alkyl, (naphthyl)-lower-alkyl, or
(pyridyl)-lower-alkyl, or a group represented by formula A or
formula B, with the proviso that at least one of R.sup.3 and
R.sup.4 is a group represented by the formula A or formula B;
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.1
formula A: A.sup.1 is a C.sub.7-C.sub.15-membered aromatic
carbocycle substituted with at least one R.sup.5 and the remaining
substituents are R.sup.6; each R.sup.L is, independently,
--R.sup.7, --(CH.sub.2).sub.n--OR.sup.8,
--O--(CH.sub.2).sub.m--OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--O--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7,
--O--(CH.sub.2).sub.m--CO.sub.2R.sup.7, --OSO.sub.3H,
--O-glucuronide, --O-glucose, ##STR00071## each o is,
independently, an integer from 0 to 10; each p is, independently,
an integer from 0 to 10; with the proviso that the sum of o and p
in each contiguous chain is from 1 to 10; each x is, independently,
O, NR.sup.10, C(.dbd.O), CHOH, C(.dbd.N--R.sup.10,
CHNR.sup.7R.sup.10, or a single bond; each R.sup.5 is,
independently, Link-(CH.sub.2).sub.n--CAP,
Link-(CH.sub.2).sub.n--(Z).sub.g--CAP,
Link-(CH.sub.2)(Z).sub.g--(CH.sub.2).sub.m--CAP,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8 or
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8; each R.sup.6 is, independently, R.sup.5,
--R.sup.7, --OR.sup.11, --N(R.sup.7).sub.2,
--(CH.sub.2).sub.m--OR.sup.8, --O--(CH.sub.2).sub.m--OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--O--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7,
--O--(CH.sub.2).sub.m--CO.sub.2R.sup.7, --OSO.sub.3H,
--O-glucuronide, --O-glucose, ##STR00072## wherein when two R.sup.6
are --OR.sup.11 and are located adjacent to each other on the
aromatic carbocycle or aromatic heterocycle, the two OR.sup.11 may
form a methylenedioxy group; each R.sup.7 is, independently,
hydrogen, lower alkyl, phenyl or substituted phenyl; each R.sup.8
is, independently, hydrogen, lower alkyl, --C(.dbd.O)--R.sup.11,
glucuronide, 2-tetrahydropyranyl, or ##STR00073## each R.sup.9 is,
independently, --CO.sub.2R.sup.7, --CON(R.sup.7).sub.2,
--SO.sub.2CH.sub.3, --C(.dbd.O)R.sup.7, --CO.sub.2R.sup.13,
--CON(R.sup.13).sub.2, --SO.sub.2CH.sub.2R.sup.13, or
--C(.dbd.O)R.sup.13; each R.sup.10 is, independently, --H,
--SO.sub.2CH.sub.3, --CO.sub.2R.sup.7, --C(.dbd.O)NR.sup.7R.sup.9,
--C(.dbd.O)R.sup.7, or --CH.sub.2--(CHOH).sub.n--CH.sub.2OH; each Z
is, independently, --(CHOH)--, --C(.dbd.O)--,
--(CHNR.sup.7R.sup.10)--, --(C.dbd.NR.sup.10)--, --NR.sup.10--,
--(CH.sub.2).sub.n--, --(CHNR.sup.13R.sup.13)--,
--(C.dbd.NR.sup.13)--, or --NR.sup.13--; each R.sup.11 is,
independently, hydrogen, lower alkyl, phenyl lower alkyl or
substituted phenyl lower alkyl; each R.sup.12 is, independently,
--SO.sub.2CH.sub.3, --CO.sub.2R.sup.7, --C(.dbd.O)NR.sup.7R.sup.9,
--C(.dbd.O)R.sup.7, --CH.sub.2(CHOH).sub.n--CH.sub.2OH,
--CO.sub.2R.sup.13, --C(.dbd.O)NR.sup.13R.sup.13, or
--C(.dbd.O)R.sup.13; each R.sup.13 is, independently, R.sup.7,
R.sup.19, --(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.m--NR.sup.7R.sup.7,
--(CH.sub.2).sub.m--NR.sup.11R.sup.11,
--(CH.sub.2).sub.m--(NR.sup.11R.sup.11R.sup.11).sup.+,
--(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--(CH.sub.2).sub.mNR.sup.11R.sup.11-
, --(CH.sub.2).sub.m--(CHOR.sup.8).sub.m13
(CH.sub.2).sub.mNR.sup.7R.sup.10,
--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
--(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--(CH.sub.2).sub.m--(NR.sup.11R.sup-
.11R.sup.11).sup.+,
--(CH.sub.2).sub.m--(CHOR.sup.8).sub.m(CH.sub.2).sub.mNR.sup.7R.sup.7,
##STR00074## with the proviso that in the moiety
--NR.sup.13R.sup.13, the two R.sup.13 along with the nitrogen to
which they are attached may, optionally, form a ring selected from:
##STR00075## each V is, independently,
--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.m--NR.sup.7R.sup.7, --(CH.sub.2).sub.m13
(NR.sup.11R.sup.11R.sup.11).sup.+,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(CH.sub.2).sub.mNR.sup.7R.sup.10,
--(CH.sub.2).sub.n--NR.sup.10R.sup.10
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(CH.sub.2).sub.mNR.sup.7R.sup.7,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(CH.sub.2).sub.m--(NR.sup.11R.sup-
.11R.sup.11).sup.+ with the proviso that when V is attached
directly to a nitrogen atom, then V can also be, independently,
R.sup.7, R.sup.10, or (R.sup.11).sub.2; each R.sup.14 is,
independently, H, R.sup.12, --(CH.sub.2).sub.n--SO.sub.2CH.sub.3,
--(CH.sub.2).sub.n--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.13,
--(CH.sub.2).sub.n--(CHOH).sub.n--CH.sub.2OH,
--NH--(CH.sub.2).sub.n--SO.sub.2CH.sub.3,
NH--(CH.sub.2).sub.n--C(.dbd.O)R.sup.11,
NH--C(.dbd.O)--NH--C(.dbd.O)R.sup.11, --C(.dbd.O)NR.sup.13R.sup.13,
--OR.sup.11, --NH--(CH.sub.2).sub.n--R.sup.10, --Br, --Cl, --F,
--I, SO.sub.2NHR.sup.11, --NHR.sup.13,
--NH--C(.dbd.O)--NR.sup.13R.sup.13, --(CH.sub.2).sub.n--NHR.sup.13,
or --NH--(CH.sub.2).sub.n--C(.dbd.O)--R.sup.13; each g is,
independently, an integer from 1 to 6; each m is, independently, an
integer from 1 to 7; each n is, independently, an integer from 0 to
7; each -Het- is, independently, --N(R.sup.7)--, --N(R.sup.10)--,
--S--, --SO--, --SO.sub.2--, --O--, --SO.sub.2NH--, --NHSO.sub.2--,
--NR.sup.7CO--, --CONR.sup.7--, --N(R.sup.13)--,
--SO.sub.2NR.sup.13--, --NR.sup.13CO--, or --CONR.sup.13--; each
Link is, independently, --O--, --(CH.sub.2).sub.n--,
--O(CH.sub.2).sub.m--, --NR.sup.13--C(.dbd.O)--NR.sup.13--,
--NR.sup.13--C(.dbd.O)--(CH.sub.2).sub.m--,
--C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m--,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.n--, --S--, --SO--,
--SO.sub.2--, --SO.sub.2NR.sup.7--, or --SO.sub.2NR.sup.10--; each
CAP is, independently, thiazolidinedione, oxazolidinedione,
-heteroaryl-C(.dbd.O)N R.sup.13R.sup.13, heteroaryl-W, --CN,
--O--C(.dbd.S)NR.sup.13R.sup.13, -(Z).sub.gR.sup.13,
--CR.sup.10((Z).sub.gR.sup.13)((Z).sub.gR.sup.13), --C(.dbd.O)OAr,
--C(.dbd.O)NR.sup.13Ar, imidazoline, tetrazole, tetrazole amide,
--SO.sub.2NHR.sup.13,
--SO.sub.2NH--C(R.sup.13R.sup.13)--(Z).sub.g--R.sup.13, a cyclic
sugar or oligosaccharide, a cyclic amino sugar, oligosaccharide,
--CR.sup.10(--(CH.sub.2).sub.m--R.sup.9)(--(CH.sub.2).sub.m--R.sup.9),
--N(--(CH.sub.2).sub.m--R.sup.9)(--(CH.sub.2).sub.m--R.sup.9),
--NR.sup.13(--(CH.sub.2).sub.m--CO.sub.2R.sup.13), ##STR00076##
wherein CAP is not hydrogen or lower alkyl; each Ar is,
independently, phenyl, substituted phenyl, wherein the substituents
of the substituted phenyl are 1-3 substituents independently
selected from the group consisting of OH, OCH.sub.3,
NR.sup.13R.sup.13, Cl, F, and CH.sub.3, or heteroaryl; and each W
is, independently, thiazolidinedione, oxazolidinedione,
heteroaryl-C(.dbd.O)N R.sup.13R.sup.13, --CN,
--O--C(.dbd.S)NR.sup.13R.sup.13, --(Z).sub.gR.sup.13,
--CR.sup.10((Z).sub.gR.sup.13)((Z).sub.gR.sup.13), --C(.dbd.O)OAr,
--C(.dbd.O)N R.sup.13Ar, imidazoline, tetrazole, tetrazole amide,
--SO.sub.2NHR.sup.13,
--SO.sub.2NH--C(R.sup.13R.sup.13)--(Z).sub.g--R.sup.13, a cyclic
sugar or oligosaccharide, a cyclic amino sugar, oligosaccharide,
##STR00077## with the proviso that when any --CHOR.sup.8-- or
--CH.sub.2OR.sup.8 groups are located 1,2- or 1,3- with respect to
each other, the R.sup.8 groups may, optionally, be taken together
to form a cyclic mono- or di-substituted 1,3-dioxane or
1,3-dioxolane.
49. The method of claim 48, wherein the compound is represented by
the formula: ##STR00078## and racemates, enantiomers,
diastereomers, tautomers, and pharmaceutically acceptable salts,
thereof.
50. The method of claim 48, wherein A.sup.1 is selected from
indenyl, napthalenyl, 1,2-dihydronapthalenyl,
1,2,3,4-tetrahydronapthalenyl, anthracenyl, fluorenyl,
phenanthrenyl, azulenyl, cyclohepta-1,3,5-trienyl or
5H-dibenzo[a,d]cycloheptenyl, substituted with at least one R.sup.5
and the remaining substituents are R.sup.6.
51. The method of claim 48, wherein R.sup.3 is hydrogen and R.sup.4
is a group represented by formula A.
52. The method of claim 48, wherein R.sup.3 is hydrogen and A.sup.1
is a group represented by the formula: ##STR00079## wherein each Q
is, independently, C--H, C--R.sup.5, C--R.sup.6, or a nitrogen
atom, with the proviso that at least one Q is C--R.sup.5.
53. The method of claim 52, wherein one Q is C--R.sup.5 and the
remaining Q are C--H.
54. The method of claim 48, wherein R.sup.3 is hydrogen and A.sup.1
is a group represented by the formula: ##STR00080##
55. The method of claim 48, wherein R.sup.5 is
Link-(CH.sub.2).sub.n--CAP.
56. The method of claim 48, wherein R.sup.5 is
Link-(CH.sub.2).sub.n--(Z).sub.g--CAP.
57. The method of claim 48, wherein R.sup.5 is
Link-(CH.sub.2)(Z).sub.g--(CH.sub.2).sub.m--CAP.
58. The method of claim 48, wherein R.sup.5 is
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8.
59. The method of claim 48, wherein R.sup.5 is
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8.
60. The method of claim 48, wherein CAP is --(Z.sub.g)R.sup.13.
61. The method of claim 48, wherein CAP is
--CR.sup.10((Z).sub.gR.sup.13)((Z).sub.gR.sup.13).
62. The method of claim 48, wherein the compound of formula (I) is
an acid addition salt of an acid selected from the consisting of
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, nitric acid, acetic acid, oxalic acid, tartaric acid,
succinic acid, maleic acid, fumaric acid, gluconic acid, citric
acid, malic acid, ascorbic acid, benzoic acid, tannic acid,
palmitic acid, alginic acid, polyglutamic acid, naphthalensulfonic
acid, methanesulfonic acid, p-toluenesulfonic acid,
naphthalenedisulfonic acid, polygalacturonic acid, malonic acid,
sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate,
pamoate, salicylic acid, stearic acid, phthalic acid, mandelic
acid, and lactic acid.
63. The method of claim 48, wherein X, Y, R.sup.1, R.sup.2 and
R.sup.3 are each hydrogen; R.sup.4 is represented by formula A,
A.sup.1 is a naphthalenyl or 1,2,3,4-tetrahydronaphthalenyl group,
which is substituted by one R.sup.5 group and the remaining
substituents are hydrogen; each R.sup.L group is hydrogen; x is a
single bond; and the sum of 0 and p is from 2 to 6.
64. The method of claim 63, wherein A.sup.1 is a naphthalenyl group
which is substituted by one R.sup.5 group and the remaining
substituents are hydrogen.
65. The method of claim 63, wherein R.sup.5 is
Link-(CH.sub.2).sub.n--CAP.
66. The method of claim 63, wherein R.sup.5 is
Link-(CH.sub.2).sub.n--(Z).sub.g--CAP.
67. The method of claim 63, wherein R.sup.5 is
Link-(CH.sub.2)(Z).sub.g--(CH.sub.2).sub.in--CAP.
68. The method of claim 63, wherein R.sup.5 is
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8.
69. The method of claim 63, wherein R.sup.5 is
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8.
70. The method of claim 63, wherein CAP is --(Z.sub.g)R.sup.13.
71. The method of claim 63, wherein CAP is
--CR.sup.10((Z).sub.gR.sup.13)((Z).sub.gR.sup.13).
72. The compound of claim 48, wherein X, Y, R.sup.1 R.sup.2 and
R.sup.3 are each hydrogen; each R.sup.L group is hydrogen; x is a
single bond; and the sum of 0 and p is from 2 to 6.
73. The method of claim 72, wherein R.sup.5 is
Link-(CH.sub.2).sub.n--CAP.
74. The method of claim 72, wherein R.sup.5 is
Link-(CH.sub.2).sub.n--(Z).sub.g--CAP.
75. The method of claim 72, wherein R.sup.5 is
Link-(CH.sub.2)(Z).sub.g--(CH.sub.2).sub.m--CAP.
76. The method of claim 72, wherein R.sup.5 is
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8.
77. The method of claim 72, wherein R.sup.5 is
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8.
78. The method of claim 72, wherein CAP is --(Z.sub.g)R.sup.13.
79. The method of claim 72, wherein CAP is
--CR.sup.10((Z).sub.gR.sup.13)((Z).sub.gR.sup.13).
80. The method of claim 48, wherein the compound of formula (I) is
represented by the formula, or a pharmaceutically acceptable salt
thereof: ##STR00081##
81. The method of claim 48, wherein the compound of formula (I) is
represented by the formula: ##STR00082## Or or a pharmaceutically
acceptable salt thereof.
82. The method of claim 48, wherein the compound of formula (I) is
represented by the formula: ##STR00083## or a pharmaceutically
acceptable salt thereof.
Description
[0001] This application is a Divisional application of U.S.
application Ser. No. 13/353,018, filed on Jan. 18, 2012, which is a
Continuation of U.S. patent application Ser. No. 12/393,252, filed
on Feb. 26, 2009, now U.S. Pat. No. 8,124,607, which claims
priority to U.S. provisional application Ser. No. 61/031,466, filed
on Feb. 26, 2008, each incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to sodium channel blockers.
The present invention also includes a variety of methods of
treatment using these inventive sodium channel blockers.
[0004] 2. Description of the Background
[0005] The mucosal surfaces at the interface between the
environment and the body have evolved a number of "innate defense",
i.e., protective mechanisms. A principal form of such innate
defense is to cleanse these surfaces with liquid. Typically, the
quantity of the liquid layer on a mucosal surface reflects the
balance between epithelial liquid secretion, often reflecting anion
(Cl.sup.- and/or HCO.sub.3.sup.-) secretion coupled with water (and
a cation counter-ion), and epithelial liquid absorption, often
reflecting Na.sup.+ absorption, coupled with water and counter
anion (Cl.sup.- and/or HCO.sub.3.sup.-). Many diseases of mucosal
surfaces are caused by too little protective liquid on those
mucosal surfaces created by an imbalance between secretion (too
little) and absorption (relatively too much). The defective salt
transport processes that characterize these mucosal dysfunctions
reside in the epithelial layer of the mucosal surface.
[0006] One approach to replenish the protective liquid layer on
mucosal surfaces is to "re-balance" the system by blocking Na.sup.+
channel and liquid absorption. The epithelial protein that mediates
the rate-limiting step of Na.sup.+ and liquid absorption is the
epithelial Na.sup.+ channel (ENaC). ENaC is positioned on the
apical surface of the epithelium, i.e. the mucosal
surface-environmental interface. Therefore, to inhibit ENaC
mediated Na.sup.+ and liquid absorption, an ENaC blocker of the
amiloride class (which blocks from the extracellular domain of
ENaC) must be delivered to the mucosal surface and, importantly, be
maintained at this site, to achieve therapeutic utility. The
present invention describes diseases characterized by too little
liquid on mucosal surfaces and "topical" sodium channel blockers
designed to exhibit the increased potency, reduced mucosal
absorption, and slow dissociation ("unbinding" or detachment) from
ENaC required for therapy of these diseases.
[0007] Chronic obstructive pulmonary diseases are characterized by
dehydration of airway surfaces and the retention of mucous
secretions in the lungs. Examples of such diseases include cystic
fibrosis, chronic bronchitis, and primary or secondary ciliary
dyskinesia. Such diseases affect approximately 15 million patients
in the United States, and are the sixth leading cause of death.
Other airway or pulmonary diseases characterized by the
accumulation of retained mucous secretions include sinusitis (an
inflammation of the paranasal sinuses associated with upper
respiratory infection) and pneumonia.
[0008] Chronic bronchitis (CB), including the most common lethal
genetic form of chronic bronchitis, cystic fibrosis (CF), are
diseases that reflect the body's failure to clear mucus normally
from the lungs, which ultimately produces chronic airways
infection. In the normal lung, the primary defense against chronic
intrapulmonary airways infection (chronic bronchitis) is mediated
by the continuous clearance of mucus from bronchial airway
surfaces. This function in health effectively removes from the lung
potentially noxious toxins and pathogens. Recent data indicate that
the initiating problem, i.e., the "basic defect," in both CB and CF
is the failure to clear mucus from airway surfaces. The failure to
clear mucus reflects an imbalance between the amount of liquid and
mucin on airway surfaces. This "airway surface liquid" (ASL) is
primarily composed of salt and water in proportions similar to
plasma (i.e., isotonic). Mucin macromolecules organize into a well
defined "mucus layer" which normally traps inhaled bacteria and is
transported out of the lung via the actions of cilia which beat in
a watery, low viscosity solution termed the "periciliary liquid"
(PCL). In the disease state, there is an imbalance in the
quantities of mucus as ASL on airway surfaces. This results in a
relative reduction in ASL which leads to mucus concentration,
reduction in the lubricant activity of the PCL, and a failure to
clear mucus via ciliary activity to the mouth. The reduction in
mechanical clearance of mucus from the lung leads to chronic
bacterial colonization of mucus adherent to airway surfaces. It is
the chronic retention of bacteria, the failure of local
antimicrobial substances to kill mucus-entrapped bacteria on a
chronic basis, and the consequent chronic inflammatory responses of
the body to this type of surface infection, that lead to the
syndromes of CB and CF.
[0009] The current afflicted population in the U.S. is 12,000,000
patients with the acquired (primarily from cigarette smoke
exposure) form of chronic bronchitis and approximately 30,000
patients with the genetic form, cystic fibrosis. Approximately
equal numbers of both populations are present in Europe. In Asia,
there is little CF but the incidence of CB is high and, like the
rest of the world, is increasing.
[0010] There is currently a large, unmet medical need for products
that specifically treat CB and CF at the level of the basic defect
that cause these diseases. The current therapies for chronic
bronchitis and cystic fibrosis focus on treating the symptoms
and/or the late effects of these diseases. Thus, for chronic
bronchitis, .beta.-agonists, inhaled steroids, anti-cholinergic
agents, and oral theophyllines and phosphodiesterase inhibitors are
all in development. However, none of these drugs treat effectively
the fundamental problem of the failure to clear mucus from the
lung. Similarly, in cystic fibrosis, the same spectrum of
pharmacologic agents is used. These strategies have been
complemented by more recent strategies designed to clear the CF
lung of the DNA ("Pulmozyme"; Genentech) that has been deposited in
the lung by neutrophils that have futilely attempted to kill the
bacteria that grow in adherent mucus masses and through the use of
inhaled antibiotics ("TOBI") designed to augment the lungs' own
killing mechanisms to rid the adherent mucus plaques of bacteria. A
general principle of the body is that if the initiating lesion is
not treated, in this case mucus retention/obstruction, bacterial
infections became chronic and increasingly refractory to
antimicrobial therapy. Thus, a major unmet therapeutic need for
both CB and CF lung diseases is an effective means of re-hydrating
airway mucus (i.e., restoring/expanding the volume of the ASL) and
promoting its clearance, with bacteria, from the lung.
[0011] R. C. Boucher, in U.S. Pat. No. 6,264,975, describes the use
of pyrazinoylguanidine sodium channel blockers for hydrating
mucosal surfaces. These compounds, typified by the well-known
diuretics amiloride, benzamil, and phenamil, are effective.
However, these compounds suffer from the significant disadvantage
that they are (1) relatively impotent, which is important because
the mass of drug that can be inhaled by the lung is limited; (2)
rapidly absorbed, which limits the half-life of the drug on the
mucosal surface; and (3) are freely dissociable from ENaC. The sum
of these disadvantages embodied in these well known diuretics
produces compounds with insufficient potency and/or effective
half-life on mucosal surfaces to have therapeutic benefit for
hydrating mucosal surfaces.
[0012] R. C. Boucher, in U.S. Pat. No. 6,926,911, suggests the use
of the relatively impotent sodium channel blockers such as
amiloride, with osmolytes for the treatment of airway diseases.
This combination gives no practical advantage over either treatment
alone and is clinically not useful, see Donaldson et al, N Eng J.
Med., 2006; 353:241-250. Amiloride was found to block the water
permeability of airways and negate the potential benefit of
concurrent use of hypertonic saline and amiloride.
[0013] U.S. Pat. No. 5,817,028 to Anderson describes a method for
the provocation of air passage narrowing (for evaluating
susceptibility to asthma) and/or the induction of sputum in
subjects via the inhalation of mannitol. It is suggested that the
same technique can be used to induce sputum and promote mucociliary
clearance. Substances suggested include sodium chloride, potassium
chloride, mannitol and dextrose.
[0014] Clearly, what is needed are drugs that are more effective at
restoring the clearance of mucus from the lungs of patients with
CB/CF. The value of these new therapies will be reflected in
improvements in the quality and duration of life for both the CF
and the CB populations.
[0015] Other mucosal surfaces in and on the body exhibit subtle
differences in the normal physiology of the protective surface
liquids on their surfaces but the pathophysiology of disease
reflects a common theme, i.e., too little protective surface
liquid. For example, in xerostomia (dry mouth) the oral cavity is
depleted of liquid due to a failure of the parotid sublingual and
submandibular glands to secrete liquid despite continued Na.sup.+
(ENaC) transport mediated liquid absorption from the oral cavity.
Similarly, keratoconjunctivitis sira (dry eye) is caused by failure
of lacrimal glands to secrete liquid in the face of continued
Na.sup.+ dependent liquid absorption on conjunctional surfaces. In
rhinosinusitis, there is an imbalance, as in CB, between mucin
secretion and relative ASL depletion. Finally, in the
gastrointestinal tract, failure to secrete C1-(and liquid) in the
proximal small intestine, combined with increased Na.sup.+ (and
liquid) absorption in the terminal ileum leads to the distal
intestinal obstruction syndrome (DIOS). In older patients excessive
Na.sup.+ (and volume) absorption in the descending colon produces
constipation and diverticulitis.
[0016] Fifty million Americans and hundreds of millions of others
around the world suffer from high blood pressure and the subsequent
sequalae leading to congestive heart failure and increasing
mortality. It is the Western World's leading killer and there is a
need there for new medicines to treat these diseases. Thus, in
addition, some of the novel sodium channel blockers of this
invention can be designed to target the kidney and as such they may
be used as diuretics for the treatment of hypertension, congestive
heart failure (CHF) and other cardiovascular diseases. These new
agents may be used alone or in combination with beta-blockers, ACE
inhibitors, HMGCoA reductase inhibitors, calcium channel blockers
and other cardiovascular agents.
SUMMARY OF THE INVENTION
[0017] It is an object of the present invention to provide
compounds that are more potent and/or absorbed less rapidly from
mucosal surfaces, and/or are less reversible as compared to known
compounds.
[0018] It is another aspect of the present invention to provide
compounds that are more potent and/or absorbed less rapidly and/or
exhibit less reversibility, as compared to compounds such as
amiloride, benzamil, and phenamil. Therefore, the compounds will
give a prolonged pharmacodynamic half-life on mucosal surfaces as
compared to known compounds.
[0019] It is another object of the present invention to provide
compounds which are (1) absorbed less rapidly from mucosal
surfaces, especially airway surfaces, as compared to known
compounds and; (2) when absorbed from mucosal surfaces after
administration to the mucosal surfaces, are converted in vivo into
metabolic derivatives thereof which have reduced efficacy in
blocking sodium channels as compared to the administered parent
compound. It is another object of the present invention to provide
compounds that are more potent and/or absorbed less rapidly and/or
exhibit less reversibility, as compared to compounds such as
amiloride, benzamil, and phenamil. Therefore, such compounds will
give a prolonged pharmacodynamic half-life on mucosal surfaces as
compared to previous compounds.
[0020] It is another object of the present invention to provide
compounds that target the kidney for use in the treatment of
cardiovascular disease.
[0021] It is another object of the present invention to provide
methods of treatment that take advantage of the pharmacological
properties of the compounds described above.
[0022] In particular, it is an object of the present invention to
provide methods of treatment which rely on rehydration of mucosal
surfaces.
[0023] In particular, it is an object of the present invention to
provide methods of treating cardiovascular disease.
[0024] The objects of the present invention may be accomplished
with a class of pyrazinoylguanidine represented by a compound of
formula (I)
##STR00002##
and includes racemates, enantiomers, diastereomers, tautomers,
polymorphs, pseudopolymorphs and pharmaceutically acceptable salts,
thereof, wherein:
[0025] X is hydrogen, halogen, trifluoromethyl, lower alkyl,
unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower
alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower
alkyl-sulfonyl;
[0026] Y is hydrogen, hydroxyl, mercapto, lower alkoxy, lower
alkyl-thio, halogen, lower alkyl, unsubstituted or substituted
mononuclear aryl, or --N(R.sup.2).sub.2;
[0027] R.sup.1 is hydrogen or lower alkyl;
[0028] each R.sup.2 is, independently, --R.sup.7,
--(CH.sub.2).sub.m--OR.sup.8, --(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7, or
##STR00003##
[0029] R.sup.3 and R.sup.4 are each, independently, hydrogen, lower
alkyl, hydroxyl-lower alkyl, phenyl, (phenyl)-lower alkyl,
(halophenyl)-lower alkyl, ((lower-alkyl)phenyl)-lower-alkyl,
((lower-alkoxy)phenyl))-lower alkyl, (naphthyl)-lower alkyl, or
(pyridyl)-lower alkyl, or a group represented by formula A or
formula B, with the proviso that at least one of R.sup.3 and
R.sup.4 is a group represented by the formula A or formula B;
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.1
formula A:
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.2
formula B:
[0030] A.sup.1 is a C.sub.7-C.sub.15-membered aromatic carbocycle
substituted with at least one R.sup.5 and the remaining
substituents are R.sup.6;
[0031] A.sup.2 is a seven to fifteen-membered aromatic heterocycle
substituted with at least one R.sup.5 and the remaining
substituents are R.sup.6 wherein said aromatic heterocycle
comprises 1-4 heteroatoms selected from the group consisting of O,
N, and S;
[0032] each R.sup.L is, independently, --R.sup.7,
--(CH.sub.2).sub.n--OR.sup.8, --O--(CH.sub.2).sub.m--OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--O--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7,
--O--(CH.sub.2).sub.m--CO.sub.2R.sup.7, --OSO.sub.3H,
--O-glucuronide, --O-glucose,
##STR00004##
[0033] each o is, independently, an integer from 0 to 10;
[0034] each p is, independently, an integer from 0 to 10;
[0035] with the proviso that the sum of o and p in each contiguous
chain is
[0036] from 1 to 10;
[0037] each x is, independently, O, NR.sup.10, C(.dbd.O), CHOH,
C(.dbd.N--R.sup.10), CHNR.sup.7R.sup.10, or a single bond;
[0038] each R.sup.5 is, independently, OH,
--(CH.sub.2).sub.m--OR.sup.8, --O--(CH.sub.2).sub.m--OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--O--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7,
--O--(CH.sub.2).sub.m--CO.sub.2R.sup.7, --OSO.sub.3H,
--O-glucuronide, --O-glucose,
##STR00005##
--(CH.sub.2).sub.n--CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CO.sub-
.2R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CO.-
sub.2R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m(Z).sub.g--CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g(CHOR.sup.8).sub.m--(Z).sub.g--CO.sub.2R.sup-
.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CO.s-
ub.2R.sup.13,
--(CH.sub.2).sub.n--CONH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--CO--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13-
,
-Het-(CH.sub.2).sub.n--(Z).sub.g--CONH--C(.dbd.NR.sup.13)--NR.sup.13R.su-
p.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--C-
ONH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
H--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONH--C(.dbd.NR.sup.13)--NR.sup.1-
3R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONH--C(.dbd.NR.sup.-
13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONH--C(.dbd.NR.sup.13-
)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONH--C(.dbd.NR.sup-
.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONH--C(.dbd.NR.sup.13)--N-
R.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONH--C(.dbd.NR.sup.13)-
--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONH--C(.db-
d.NR.sup.13)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONH--C(.-
dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--CONR.sup.7--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--CONR.sup.7--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CONR.s-
up.7--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
R.sup.7--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.7--CONR.sup.13R.sup.13,
Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.7--CONR.sup.13R.sup.13-
,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7--CONR.sup.-
13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CNR.sup.7--CONR.sup-
.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7--CONR.sup.13R.s-
up.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7--CONR.-
sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7--C-
ONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7-
--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--CONR.sup.7SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--CONR.sup.7SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CONR.sup.7SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CONR.s-
up.7SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.m--CON-
R.sup.7SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.7SO.sub.2NR.sup.13R.sup.-
13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.rn--CONR.sup.7SO.sub.2NR.sup.1-
3R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7SO-
.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7SO.sub.2N-
R.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7SO.sub.2NR.sup.1-
3R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7SO.-
sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7S-
O.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup-
.7SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--SO.sub-
.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.m--SO.-
sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--SO.sub.2NR.sup.13R.sup-
.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--SO.sub.2NR.sup.-
13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mSO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mSO.sub.2NR.sup.13R.sup.-
13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--SO.sub.2-
NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--SO.sub.2-
NR.sup.13R.sup.13, --(CH.sub.2).sub.n--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CONR.s-
up.13R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
R.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.13R.sup.13-
,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.13-
R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--
-CONR.sup.13R.sup.13, --(CH.sub.2).sub.n--CONR.sup.7COR.sup.13,
-Het-(CH.sub.2).sub.m--CONR.sup.7COR.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7COR.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CONR.sup.7COR.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CONR.s-
up.7COR.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
R.sup.7COR.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.7COR.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7COR.sup.1-
3,
--(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7COR.sup.13-
,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7COR.sup.-
13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7COR.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7COR.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup-
.7COR.sup.13, --(CH.sub.2).sub.n--CONR.sup.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CONR.sup.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CONR.s-
up.7CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
R.sup.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.7CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--CONR.sup.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7CO.sub.2R.su-
p.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7CO.s-
ub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7CO.sub.2R.sup.13-
,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7CO.sub.2R.su-
p.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.s-
up.7CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup-
.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.1-
3,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--NH---
C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--NH--
-C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R-
.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--NH--C(.dbd.NR.sup.13)--
-NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--
-NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.1-
3)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)--NR.-
sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--NH--C(.dbd.-
NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--NH--C(.d-
bd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.m--C(.dbd.NH)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--C(.dbd.NH)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.m--(Z).sub.g--C(.dbd.NH)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--C(.dbd-
.NR.sup.13)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--C(.d-
bd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--C(.dbd.NR.sup.13)--NR.sup.13R.sup-
.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--C(.dbd.NR.sup.13)--NR.sup.-
13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--C(.dbd.NR.sup.13)--NR.-
sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--C(.dbd.NHC(.dbd.NR.sup.1-
3)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--C(.dbd.NR.sup.13)--NR.-
sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--C(.dbd.NR.s-
up.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--C(.dbd.N-
R.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.m--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.m(Z).sub.gR.sup.12,
--(CH.sub.2).sub.nNR.sup.11R.sup.11,
--O--(CH.sub.2).sub.mNR.sup.11R.sup.11,
--(CH.sub.2).sub.n--N.sup..sym.--(R.sup.11).sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
--O--(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.12R.sup.12,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.12R.sup.12,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.m--(C.dbd.O)NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.m--(CHOR.sup.8).sub.mCH.sub.2NR.sup.10--(Z).sub.g--R.-
sup.10,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.mCH.sub.2--NR.sup.10--(Z).sub-
.g--R.sup.10,
--(CH.sub.2).sub.nNR.sup.10--O(CH.sub.2).sub.m(CHOR.sup.8).sub.nCH.sub.2N-
R.sup.10--(Z).sub.g--R.sup.10,
--O(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m--(CHOR.sup.8).sub.nCH.su-
b.2NR.sup.10--(Z).sub.g--R.sup.10,
-(Het)-(CH.sub.2).sub.m--OR.sup.8,
-(Het)-(CH.sub.2).sub.m--NR.sup.7R.sup.10,
-(Het)-(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
-(Het)-(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
-(Het)-(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
-(Het)-(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
-(Het)-(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
-(Het)-(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.-
n--CH.sub.2OR.sup.8, -(Het)-(CH.sub.2).sub.m--CO.sub.2R.sup.7,
-(Het)-(CH.sub.2).sub.m--NR.sup.12R.sup.12,
-(Het)-(CH.sub.2).sub.n--NR.sup.12R.sup.12,
-(Het)-(CH.sub.2).sub.m--(Z).sub.gR.sup.12,
-(Het)-(CH.sub.2).sub.mNR.sup.11R.sup.11,
-(Het)-(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
-(Het)-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
-(Het)-(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.12R.sup.12,
-(Het)-(CH.sub.2).sub.m--(C.dbd.O)NR.sup.12R.sup.12,
-(Het)-(CH.sub.2).sub.m--(CHOR.sup.8).sub.mCH.sub.2NR.sup.10--(Z).sub.g---
R.sup.10,
-(Het)-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m--(CHOR.sup.-
8).sub.nCH.sub.2NR.sup.10--(Z).sub.g--R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, Link-(CH.sub.2).sub.n--CAP,
Link-(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CAP,
Link-(CH.sub.2CH.sub.2O).sub.m--CH.sub.2--CAP,
Link-(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2--CAP,
Link-(CH.sub.2).sub.n(Z).sub.g--CAP,
Link-(CH.sub.2).sub.n(Z).sub.g--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.n--NR.sup.13--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CAP,
Link-(CH.sub.2).sub.n--(CHOR.sup.8).sub.mCH.sub.2--NR.sup.13--(Z).su-
b.g--CAP,
Link-(CH.sub.2).sub.nNR.sup.13--(CH.sub.2).sub.m(CHOR.sup.8).sub-
.nCH.sub.2NR.sup.13--(Z).sub.g--CAP,
-Link-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--CAP,
Link-NH--C(.dbd.O)--NH--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.m--C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m--C(.dbd.O)NR.-
sup.10R.sup.10,
Link-(CH.sub.2).sub.m--C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.m--C(.dbd.O)NR.sup.11R.sup.11,
Link-(CH.sub.2).sub.mC(.dbd.O)NR.sup.12R.sup.12,
Link-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--(Z).sub.g--CAP,
Link-(Z).sub.g--(CH.sub.2).sub.m-Het-(CH.sub.2).sub.m--CAP, Link
--(CH.sub.2).sub.n--CR.sup.11R.sup.11--CAP, Link
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CR.sup.11R.sup.11--CAP,
Link --(CH.sub.2CH.sub.2O).sub.m--CH.sub.2--CR.sup.11R.sup.11--CAP,
Link
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2--CR.sup.11R.sup.11--CAP,
Link --(CH.sub.2).sub.n--(Z).sub.g--CR.sup.11R.sup.11--CAP,
Link-(CH.sub.2).sub.n(Z).sub.g--(CH.sub.2).sub.m--CR.sup.11R.sup.11--CAP,
Link
--(CH.sub.2).sub.n--NR.sup.13--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.-
n--CR.sup.11R.sup.11--CAP, Link
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.mCH.sub.2--NR.sup.13--(Z).sub.g--CR.-
sup.11R.sup.11--CAP, Link
--(CH.sub.2).sub.nNR.sup.13--(CH.sub.2).sub.m(CHOR.sup.8).sub.nCH.sub.2NR-
.sup.13--(Z).sub.g--CR.sup.11R.sup.11--CAP, Link --(CH.sub.2)
.sub.m--(Z).sub.g--(CH.sub.2).sub.m--CR.sup.11R.sup.11--CAP, Link
NH--C(.dbd.O)--NH--(CH.sub.2).sub.m--CR.sup.11R.sup.11--CAP, Link
--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m--CR.sup.11R.sup.-
11--CAP, Link
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--(Z).sub.g--CR.sup.11R.su-
p.11--CAP, or Link
--(Z).sub.g--(CH.sub.2).sub.m-Het-(CH.sub.2).sub.m--CR.sup.11R.sup.11--CA-
P;
[0039] each R.sup.6 is, independently, R.sup.5, --R.sup.7,
--OR.sup.11, --N(R.sup.7).sub.2, --(CH.sub.2).sub.m--OR.sup.8,
--O--(CH.sub.2).sub.m--OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--O--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(--O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.19--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7,
--O--(CH.sub.2).sub.m--CO.sub.2R.sup.7, --OSO.sub.3H,
--O-glucuronide, --O-glucose,
##STR00006##
[0040] wherein when two R.sup.6 are --OR.sup.11 and are located
adjacent to each other on the aromatic carbocycle or aromatic
heterocycle, the two OR.sup.11 may form a methylenedioxy group;
[0041] each R.sup.7 is, independently, hydrogen, lower alkyl,
phenyl, substituted phenyl or
--CH.sub.2(CHOR.sup.8).sub.m--CH.sub.2OR.sup.8;
[0042] each R.sup.8 is, independently, hydrogen, lower alkyl,
--C(.dbd.O)--R.sup.11, glucuronide, 2-tetrahydropyranyl, or
##STR00007##
[0043] each R.sup.9 is, independently, --CO.sub.2R.sup.7,
--CON(R.sup.7).sub.2, --SO.sub.2CH.sub.3, --C(.dbd.O)R.sup.7,
--CO.sub.2R.sup.13, --CON(R.sup.13).sub.2,
--SO.sub.2CH.sub.2R.sup.13, or --C(.dbd.O)R.sup.13;
[0044] each R.sup.10 is, independently, --H, --SO.sub.2CH.sub.3,
--CO.sub.2R.sup.7, --C(.dbd.O)NR.sup.7R.sup.9, --C(.dbd.O)R.sup.7,
or --CH.sub.2--(CHOH).sub.n--CH.sub.2OH;
[0045] each Z is, independently, --(CHOH)--, --C(.dbd.O)--,
--(CHNR.sup.7R.sup.10)--, --(C.dbd.NR.sup.10)--, --NR.sup.10--,
--(CH.sub.2).sub.n--, --(CHNR.sup.13R.sup.13)--,
--(C.dbd.NR.sup.13)--, or --NR.sup.13--;
[0046] each R.sup.11 is, independently, hydrogen, lower alkyl,
phenyl lower alkyl or substituted phenyl lower alkyl;
[0047] each R.sup.12 is, independently, --SO.sub.2CH.sub.3,
--CO.sub.2R.sup.7, --C(.dbd.O)NR.sup.7R.sup.9, --C(.dbd.O)R.sup.7,
--CH.sub.2(CHOH).sub.n--CH.sub.2OH, --CO.sub.2R.sup.13,
--C(.dbd.O)NR.sup.13R.sup.13, or --C(.dbd.O)R.sup.13;
[0048] each R.sup.13 is, independently, R.sup.7, R.sup.10,
--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.m--NR.sup.7R.sup.7,
--(CH.sub.2).sub.m--NR.sup.11R.sup.11,
--(CH.sub.2).sub.m--(NR.sup.11R.sup.11R.sup.11).sup.+,
--(CH.sub.2).sub.m--(CHOR.sup.8),(CH.sub.2).sub.mNR.sup.11R.sup.11,
--(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--(CH.sub.2).sub.mNR.sup.7R.sup.10,
--(CH.sub.2).sub.m--NR.sup.19R.sup.10,
--(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--(CH.sub.2).sub.m--(NR.sup.11R.sup-
.11R.sup.11).sup.+,
--(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--(CH.sub.2).sub.mNR.sup.7R.sup.7,
##STR00008##
[0049] with the proviso that in the moiety --NR.sup.13R.sup.13, the
two R.sup.13 along with the nitrogen to which they are attached
may, optionally, form a ring selected from:
##STR00009##
[0050] each V is, independently,
--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.m--NR.sup.7R.sup.7,
--(CH.sub.2).sub.m--(NR.sup.11R.sup.11R.sup.11).sup.+,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(CH.sub.2).sub.mNR.sup.7R.sup.10,
--(CH.sub.2).sub.n--NR.sup.10R.sup.10--(CH.sub.2).sub.n--(CHOR.sup.8).sub-
.m--(CH.sub.2).sub.mNR.sup.7R.sup.7,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(CH.sub.2).sub.m--(NR.sup.11R.sup-
.11R.sup.11).sup.+ with the proviso that when V is attached
directly to a nitrogen atom, then V can also be, independently,
R.sup.7, R.sup.10, or (R.sup.11).sub.2;
[0051] each R.sup.14 is, independently, H, R.sup.12,
--(CH.sub.2).sub.n--SO.sub.2CH.sub.3,
--(CH.sub.2).sub.n--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--C(.dbd.O)R.sup.13,
--(CH.sub.2).sub.n--(CHOH).sub.n--CH.sub.2OH,
--NH--(CH.sub.2).sub.n--SO.sub.2CH.sub.3,
NH--(CH.sub.2).sub.n--C(.dbd.O)R.sup.11,
NH--C(.dbd.O)--NH--C(.dbd.O)R.sup.11, --C(.dbd.O)NR.sup.13R.sup.13,
--OR.sup.11, --NH--(CH.sub.2).sub.n--R.sup.10, --Br, --Cl, --F,
--I, SO.sub.2NHR.sup.11, --NHR.sup.13,
--NH--C(.dbd.O)--NR.sup.13R.sup.13, --(CH.sub.2).sub.n--NHR.sup.13,
or --NH--(CH.sub.2).sub.n--C(.dbd.O)--R.sup.13;
[0052] each g is, independently, an integer from 1 to 6;
[0053] each m is, independently, an integer from 1 to 7;
[0054] each n is, independently, an integer from 0 to 7;
[0055] each -Het- is, independently, --N(R.sup.7)--),
--N(R.sup.10)--, --S--, --SO--, --SO.sub.2--; --O--,
--SO.sub.2NH--, --NHSO.sub.2--, --NR.sup.7CO--, --CONR.sup.7--,
--N(R.sup.13)--, --SO.sub.2NR.sup.13--, --NR.sup.13CO--, or
--CONR.sup.13--;
[0056] each Link is, independently, --O--, --(CH.sub.2).sub.n--,
--O(CH.sub.2).sub.m--, --NR.sup.13--C(.dbd.O)--NR.sup.13--,
--NR.sup.13--C(.dbd.O)--(CH.sub.2).sub.m--,
--C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m.sup.-,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.n--, --S--, --SO--,
--SO.sub.2--, --SO.sub.2NR.sup.7--, --SO.sub.2NR.sup.10--, or
-Het-;
[0057] each CAP is, independently, thiazolidinedione,
oxazolidinedione, -heteroaryl-C(.dbd.O)N R.sup.13R.sup.13,
heteroaryl-W, --CN, --O--C(.dbd.S)NR.sup.13R.sup.13,
--(Z).sub.gR.sup.13,
--CR.sup.10((Z).sub.gR.sup.13)((Z).sub.gR.sup.13), --C(.dbd.O)OAr,
--C(.dbd.O)NR.sup.13Ar, imidazoline, tetrazole, tetrazole amide,
--SO.sub.2NHR.sup.13,
--SO.sub.2NH--C(R.sup.13R.sup.13)--(Z).sub.g--R.sup.13, a cyclic
sugar or oligosaccharide, a cyclic amino sugar, oligosaccharide,
--CR.sup.10(--(CH.sub.2).sub.m--R.sup.9)(--(CH.sub.2).sub.m--R.sup.9),
--N(--(CH.sub.2).sub.m--R.sup.9)(--(CH.sub.2).sub.m--R.sup.9),
--NR.sup.13(--(CH.sub.2).sub.m--CO.sub.2R.sup.13),
##STR00010##
[0058] each Ar is, independently, phenyl, substituted phenyl,
wherein the substituents of the substituted phenyl are 1-3
substituents independently selected from the group consisting of
OH, OCH.sub.3, NR.sup.13R.sup.13, Cl, F, and CH.sub.3, or
heteroaryl; and
[0059] each W is, independently, thiazolidinedione,
oxazolidinedione, heteroaryl-C(.dbd.O)N R.sup.13R.sup.13, --CN,
--O--C(.dbd.S)NR.sup.13R.sup.13, --(Z).sub.gR.sup.13,
--CR.sup.10((Z).sub.gR.sup.13)((Z).sub.gR.sup.13), --C(.dbd.O)OAr,
--C(.dbd.O)N R.sup.13Ar, imidazoline, tetrazole, tetrazole amide,
--SO.sub.2NHR.sup.13,
--SO.sub.2NH--C(R.sup.13R.sup.13)--(Z).sub.g--R.sup.13, a cyclic
sugar or oligosaccharide, a cyclic amino sugar,
oligosaccharide,
##STR00011##
[0060] with the proviso that when any --CHOR.sup.8-- or
--CH.sub.2OR.sup.8 groups are located 1,2- or 1,3- with respect to
each other, the R.sup.8 groups may, optionally, be taken together
to form a cyclic mono- or di-substituted 1,3-dioxane or
1,3-dioxolane.
[0061] The present also provides pharmaceutical compositions which
comprise a compound described herein.
[0062] The present invention also provides a method of promoting
hydration of mucosal surfaces, comprising:
[0063] administering an effective amount of a compound described
herein to a mucosal surface of a subject.
[0064] The present invention also provides a method of restoring
mucosal defense, comprising:
[0065] topically administering an effective amount of compound
described herein to a mucosal surface of a subject in need
thereof.
[0066] The present invention also provides a method of blocking
ENaC, comprising:
[0067] contacting sodium channels with an effective amount of a
compound represented by described herein.
[0068] The present invention also provides a method of promoting
mucus clearance in mucosal surfaces, comprising:
[0069] administering an effective amount of a compound represented
described herein to a mucosal surface of a subject.
[0070] The present invention also provides a method of treating
chronic bronchitis, comprising:
[0071] administering an effective amount of a compound described
herein to a subject in need thereof.
[0072] The present invention also provides a method of treating
cystic fibrosis, comprising:
[0073] administering an effective amount of compound described
herein to a subject in need thereof.
[0074] The present invention also provides a method of treating
rhinosinusitis, comprising:
[0075] administering an effective amount of a compound described
herein to a subject in need thereof.
[0076] The present invention also provides a method of treating
nasal dehydration, comprising:
[0077] administering an effective amount of a compound described
herein to the nasal passages of a subject in need thereof.
[0078] In a specific embodiment, the nasal dehydration is brought
on by administering dry oxygen to the subject.
[0079] The present invention also provides a method of treating
sinusitis, comprising:
[0080] administering an effective amount of a compound described
herein to a subject in need thereof.
[0081] The present invention also provides a method of treating
pneumonia, comprising:
[0082] administering an effective amount of a compound described
herein to a subject in need thereof.
[0083] The present invention also provides a method of treating
ventilator-induced pneumonia, comprising:
[0084] administering an effective compound described herein to a
subject by means of a ventilator.
[0085] The present invention also provides a method of treating
asthma, comprising:
[0086] administering an effective amount of a compound described
herein to a subject in need thereof.
[0087] The present invention also provides a method of treating
primary ciliary dyskinesia, comprising:
[0088] administering an effective amount of a compound described
herein to a subject in need thereof.
[0089] The present invention also provides a method of treating
otitis media, comprising:
[0090] administering an effective amount of a compound described
herein to a subject in need thereof.
[0091] The present invention also provides a method of inducing
sputum for diagnostic purposes, comprising:
[0092] administering an effective amount of compound described
herein to a subject in need thereof.
[0093] The present invention also provides a method of treating
chronic obstructive pulmonary disease, comprising:
[0094] administering an effective amount of a compound described
herein to a subject in need thereof.
[0095] The present invention also provides a method of treating
emphysema, comprising:
[0096] administering an effective amount of a compound described
herein to a subject in need thereof.
[0097] The present invention also provides a method of treating dry
eye, comprising:
[0098] administering an effective amount of a compound described
herein to the eye of the subject in need thereof.
[0099] The present invention also provides a method of promoting
ocular hydration, comprising:
[0100] administering an effective amount of a compound described
herein to the eye of the subject.
[0101] The present invention also provides a method of promoting
corneal hydration, comprising:
[0102] administering an effective amount of a compound described
herein to the eye of the subject.
[0103] The present invention also provides a method of treating
Sjogren's disease, comprising:
[0104] administering an effective amount of compound described
herein to a subject in need thereof.
[0105] The present invention also provides a method of treating
vaginal dryness, comprising:
[0106] administering an effective amount of a compound described
herein to the vaginal tract of a subject in need thereof.
[0107] The present invention also provides a method of treating dry
skin, comprising:
[0108] administering an effective amount of a compound described
herein to the skin of a subject in need thereof.
[0109] The present invention also provides a method of treating dry
mouth (xerostomia), comprising:
[0110] administering an effective amount of compound described
herein to the mouth of the subject in need thereof.
[0111] The present invention also provides a method of treating
distal intestinal obstruction syndrome, comprising:
[0112] administering an effective amount of compound described
herein to a subject in need thereof.
[0113] The present invention also provides a method of treating
esophagitis, comprising:
[0114] administering an effective amount of a compound described
herein to a subject in need thereof.
[0115] The present invention also provides a method of treating
bronchiectasis, comprising:
[0116] administering an effective amount of a compound described
herein to a subject in need thereof.
[0117] The present invention also provides a method of treating
constipation, comprising:
[0118] administering an effective amount of a compound described
herein to a subject in need thereof. In one embodiment of this
method, the compound is administered either orally or via a
suppository or enema.
[0119] The present invention also provides a method of treating
chronic diverticulitis comprising:
[0120] administering an effective amount of a compound described
herein to a subject in need thereof.
[0121] The present invention also provides a method of treating
hypertension, comprising administering the compound described
herein to a subject in need thereof.
[0122] The present invention also provides a method of reducing
blood pressure, comprising administering the compound described
herein to a subject in need thereof.
[0123] The present invention also provides a method of treating
edema, comprising administering the compound described herein to a
subject in need thereof.
[0124] The present invention also provides a method of promoting
diuresis, comprising administering the compound described herein to
a subject in need thereof.
[0125] The present invention also provides a method of promoting
natriuresis, comprising administering the compound described herein
to a subject in need thereof.
[0126] The present invention also provides a method of promoting
saluresis, comprising administering the compound described herein
to a subject in need thereof.
[0127] It is an object of the present invention to provide
treatments comprising the use of osmolytes together with sodium
channel blockers of formula (I) that are more potent, more
specific, and/or absorbed less rapidly from mucosal surfaces,
and/or are less reversible as compared to compounds such as
amiloride, benzamil, and phenamil
[0128] It is another aspect of the present invention to provide
treatments using sodium channel blockers of formula (I) that are
more potent and/or absorbed less rapidly and/or exhibit less
reversibility, as compared to compounds such as amiloride,
benzamil, and phenamil when administered with an osmotic enhancer.
Therefore, such sodium channel blockers when used in conjunction
with osmolytes will give a prolonged pharmacodynamic half-life on
mucosal surfaces as compared to either compound used alone.
[0129] It is another object of the present invention to provide
treatments using sodium channel blockers of formula (I) and
osmolytes together which are absorbed less rapidly from mucosal
surfaces, especially airway surfaces, as compared to compounds such
as amiloride, benzamil, and phenamil
[0130] It is another object of the invention to provide
compositions which contain sodium channel blockers of formula (I)
and osmolytes.
[0131] The objects of the invention may be accomplished with a
method of treating a disease ameliorated by increased mucociliary
clearance and mucosal hydration comprising administering an
effective amount of a compound of formula (I) as defined herein and
an osmolyte to a subject to a subject in need of increased
mucociliary clearance and mucosal hydration.
[0132] The objects of the invention may also be accomplished with a
method of inducing sputum for diagnostic purposes, comprising
administering an effective amount of a compound of formula (I) as
defined herein and an osmolyte to a subject in need thereof.
[0133] The objects of the invention may also be accomplished with a
method of treating anthrax, comprising administering an effective
amount of a compound of formula (I) as defined herein and an
osmolyte to a subject in need thereof.
[0134] The objects of the invention may also be accomplished with a
method of prophylactic, post-exposure prophylactic, preventive or
therapeutic therapeutic treatment against diseases or conditions
caused by pathogens, particularly pathogens which may be used in
bioterrorism, comprising administering an effective amount of a
compound of formula (I) to a subject in need thereof.
[0135] The objects of the invention may also be accomplished with a
composition, comprising a compound of formula (I) as defined herein
and an osmotically active compound.
DETAILED DESCRIPTION OF THE INVENTION
[0136] The present invention is based on the discovery that the
compounds of formula (I) are more potent and/or, absorbed less
rapidly from mucosal surfaces, especially airway surfaces, and/or
less reversible from interactions with ENaC as compared to
compounds such as amiloride, benzamil, and phenamil. Therefore, the
compounds of formula (I) have a longer half-life on mucosal
surfaces as compared to these compounds.
[0137] The present invention is also based on the discovery that
certain compounds embraced by formula (I) are converted in vivo
into metabolic derivatives thereof that have reduced efficacy in
blocking sodium channels as compared to the parent administered
compound, after they are absorbed from mucosal surfaces after
administration. This important property means that the compounds
will have a lower tendency to cause undesired side-effects by
blocking sodium channels located at untargeted locations in the
body of the recipient, e.g., in the kidneys.
[0138] The present invention is also based on the discovery that
certain compounds embraced by formula (1) target the kidney and
thus may be used as cardiovascular agents.
[0139] In the compounds represented by formula (I), X may be
hydrogen, halogen, trifluoromethyl, lower alkyl, lower cycloalkyl,
unsubstituted or substituted phenyl, lower alkyl-thio, phenyl-lower
alkyl-thio, lower alkyl-sulfonyl, or phenyl-lower alkyl-sulfonyl.
Halogen is preferred.
[0140] Examples of halogen include fluorine, chlorine, bromine, and
iodine. Chlorine and bromine are the preferred halogens. Chlorine
is particularly preferred. This description is applicable to the
term "halogen" as used throughout the present disclosure.
[0141] As used herein, the term "lower alkyl" means an alkyl group
having less than 8 carbon atoms. This range includes all specific
values of carbon atoms and subranges there between, such as 1, 2,
3, 4, 5, 6, and 7 carbon atoms. The term "alkyl" embraces all types
of such groups, e.g., linear, branched, and cyclic alkyl groups.
This description is applicable to the term "lower alkyl" as used
throughout the present disclosure. Examples of suitable lower alkyl
groups include methyl, ethyl, propyl, cyclopropyl, butyl, isobutyl,
etc.
[0142] Substituents for the phenyl group include halogens.
Particularly preferred halogen substituents are chlorine and
bromine.
[0143] Y may be hydrogen, hydroxyl, mercapto, lower alkoxy, lower
alkyl-thio, halogen, lower alkyl, lower cycloalkyl, mononuclear
aryl, or --N(R.sup.2).sub.2. The alkyl moiety of the lower alkoxy
groups is the same as described above. Examples of mononuclear aryl
include phenyl groups. The phenyl group may be unsubstituted or
substituted as described above. The preferred identity of Y is
--N(R.sup.2).sub.2. Particularly preferred are such compounds where
each R.sup.2 is hydrogen.
[0144] R.sup.1 may be hydrogen or lower alkyl. Hydrogen is
preferred for R.sup.1.
[0145] Each R.sup.2 may be, independently, --R.sup.7,
--(CH.sub.2).sub.m--OR.sup.8, --(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7, or
##STR00012##
[0146] Hydrogen and lower alkyl, particularly C.sub.1-C.sub.3
alkyl, are preferred for R.sup.2. Hydrogen is particularly
preferred.
[0147] R.sup.3 and R.sup.4 may be, independently, hydrogen, lower
alkyl, hydroxyl-lower alkyl, phenyl, (phenyl)-lower alkyl,
(halophenyl)-lower alkyl, ((lower-alkyl)phenyl)-lower-alkyl),
(lower-alkoxyphenyl)-lower alkyl, (naphthyl)-lower alkyl,
(pyridyl)-lower alkyl or a group represented by
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.1 or
--(C(R.sup.1).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.2,
provided that at least one of R.sup.3 and R.sup.4 is a group
represented by
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.1 or
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.2.
[0148] Preferred compounds are those where one of R.sup.3 and
R.sup.4 is hydrogen and the other is represented by
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.1 or
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.2. In a
particularly preferred aspect one of R.sup.3 and R.sup.4 is
hydrogen and the other of R.sup.3 or R.sup.4 is represented by
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.1. In
another particularly preferred aspect one of R.sup.3 and R.sup.4 is
hydrogen and the other of R.sup.3 or R.sup.4 is represented by
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.2.
[0149] A moiety
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.p-- defines an
alkylene group bonded to the group A.sup.1 or A.sup.2. The
variables o and p may each, independently, be an integer from 0 to
10, subject to the proviso that the sum of o and p in the chain is
from 1 to 10. Thus, o and p may each be 0, 1, 2, 3, 4, 5, 6, 7, 8,
9, or 10. Preferably, the sum of o and p is from 2 to 6. In a
particularly preferred embodiment, the sum of o and p is 4.
[0150] The linking group in the alkylene chain, x, may be,
independently, O, NR.sup.10, C(.dbd.O), CHOH, C(.dbd.N--R.sup.10),
CHNR.sup.7R.sup.10, or a single bond;
[0151] Therefore, when x is a single bond, the alkylene chain
bonded to the ring is represented by the formula
--(C(R.sup.L).sub.2).sub.o+p--, in which the sum o+p is from 1 to
10.
[0152] Each R.sup.L may be, independently, --R.sup.7,
--(CH.sub.2).sub.n--OR.sup.8, --O--(CH.sub.2).sub.m--OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--O--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7,
--O--(CH.sub.2).sub.m--CO.sub.2R.sup.7, --OSO.sub.3H,
--O-glucuronide, --O-glucose,
##STR00013##
[0153] The term --O-glucuronide, unless otherwise specified, means
a group represented by
##STR00014##
wherein the O means the glycosidic linkage can be above or below
the plane of the ring.
[0154] The term --O-glucose, unless otherwise specified, means a
group represented by
##STR00015##
wherein the O means the glycosidic linkage can be above or below
the plane of the ring.
[0155] The preferred R.sup.L groups include --H, --OH,
--N(R.sup.7).sub.2, especially where each R.sup.7 is hydrogen.
[0156] In the alkylene chain in
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.1 or
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.pA.sup.2, it is
preferred that when one R.sup.L group bonded to a carbon atoms is
other than hydrogen, then the other R.sup.L bonded to that carbon
atom is hydrogen, i.e., the formula --CHR.sup.L--. It is also
preferred that at most two R.sup.L groups in an alkylene chain are
other than hydrogen, wherein the other R.sup.L groups in the chain
are hydrogens. Even more preferably, only one R.sup.L group in an
alkylene chain is other than hydrogen, wherein the other R.sup.L
groups in the chain are hydrogens. In these embodiments, it is
preferable that x is a single bond.
[0157] In another particular embodiment of the invention, all of
the R.sup.L groups in the alkylene chain are hydrogen. In these
embodiments, the alkylene chain is represented by the formula
--(CH.sub.2).sub.o-x-(CH.sub.2).sub.p--.
[0158] A.sup.1 is a C.sub.7-C.sub.15-membered aromatic carbocycle
substituted with at least one R.sup.5 and the remaining
substituents are R.sup.6. The term aromatic is well known term of
chemical art and designates conjugated systems of 4n'+2 electrons
that are within a ring system, that is with 6, 10, 14, etc.
.pi.-electrons wherein, according to the rule of Huckel, n' is 1,
2, 3, etc. The 4n'+2 electrons may be in any size ring including
those with partial saturation so long as the electrons are
conjugated. For instance, but not by way of limitation,
5H-cyclohepta-1,3,5-triene, benzene, naphthalene,
1,2,3,4-tetrahydronaphthalene etc. would all be considered
aromatic.
[0159] The C.sub.7-C.sub.15 aromatic carbocycle may be monocyclic,
bicyclic, or tricyclic and may include partially saturated rings.
Non-limiting examples of these aromatic carbocycles comprise
5H-cyclohepta-1,3,5-triene, naphthalene, phenanthrene, azulene,
anthracene, 1,2,3,4-tetrahydronapthalene, 1,2-dihydronaphthalene,
indene, 5H-dibenzo[a,d]cycloheptene, etc.
[0160] The C.sub.7-C.sub.15 aromatic carbocycle may be attached to
the --(C(R.sup.L).sub.2).sub.o)-x-(C(R.sup.L).sub.2).sub.p-- moiety
through any ring carbon atom as appropriate, unless otherwise
specified. Therefore, when partially saturated bicyclic aromatic is
1,2-dihydronapthalene, it may be 1,2-dihydronapthalen-1-yl,
1,2-dihydronapthalen-3-yl, 1,2-dihydronapthalen-5-yl, etc. In a
preferred embodiment A.sup.1 is indenyl, napthalenyl,
1,2-dihydronapthalenyl, 1,2,3,4-tetrahydronapthalenyl, anthracenyl,
fluorenyl, phenanthrenyl, azulenyl, cyclohepta-1,3,5-trienyl or
5H-dibenzo[a,d]cycloheptenyl. In another preferred embodiment,
A.sup.1 is napthalen-1-yl. In another preferred embodiment, A.sup.1
is napthalen-2-yl.
[0161] In another preferred embodiment, A.sup.1 is
##STR00016##
wherein each Q is, independently, C--H, C--R.sup.5, or C--R.sup.6,
with the proviso that at least one Q is C--R.sup.5. Therefore, Q
may be 1, 2, 3, 4, 5, or 6 C--H. Therefore, Q may be 1, 2, 3, 4, 5,
or 6 C--R.sup.6. In a particularly preferred embodiment, each
R.sup.6 is H.
[0162] In another preferred embodiment, A.sup.1 is
##STR00017##
wherein each Q is, independently, C--H, C--R.sup.5, C--R.sup.6,
with the proviso that at least one Q is C--R.sup.5. Therefore, Q
may be 1, 2, 3, 4, 5, or 6 C--H. Therefore, Q may be 1, 2, 3, 4, 5,
or 6 C--R.sup.6. In a particularly preferred embodiment, each
R.sup.6 is H.
[0163] In a particularly preferred embodiment, A.sup.1 is
##STR00018##
[0164] In another particularly preferred embodiment, A.sup.1 is
##STR00019##
[0165] A.sup.2 is a seven to fifteen-membered aromatic heterocycle
substituted with at least one R.sup.5 and the remaining
substituents are R.sup.6 wherein the aromatic heterocycle comprises
1-4 heteroatoms selected from the group consisting of O, N, and
S.
[0166] The seven to fifteen-membered aromatic heterocycle may be
monocyclic, bicyclic, or tricyclic and may include partially
saturated rings. Non limiting examples of these aromatic
heterocycles include 1H-azepine, benzo[b]furan, benzo[b]thiophene,
isobenzofuran, isobenzothiophene, 2,3-dihydrobenzo[b]furan,
benzo[b]thiophene, 2,3-dihydrobenzo[b]thiophene, indolizine,
indole, isoindole benzoxazole, benzimidazole, indazole,
benzisoxazole, benzisothizole, benzopyrazole, benzoxadiazole,
benzothiadiazole, benzotriazole, purine, quinoline,
1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-chromene,
3,4-dihydro-2H-thiochromene, isoquinoline, cinnoline, quinolizine,
phthalazine, quinoxaline, quinazoline, naphthiridine, pteridine,
benzopyrane, pyrrolopyridine, pyrrolopyrazine, imidazopyrdine,
pyrrolopyrazine, thienopyrazine, furopyrazine, isothiazolopyrazine,
thiazolopyrazine, isoxazolopyrazine, oxazolopyrazine,
pyrazolopyrazine, imidazopyrazine, pyrrolopyrimidine,
thienopyrimidine, furopyrimidine, isothiazolopyrimidine,
thiazolopyrimidine, isoxazolopyrimidine, oxazolopyrimidine,
pyrazolopyrimidine, imidazopyrimidine, pyrrolopyridazine,
thienopyridazine, furopyridazine, isothiazolopyridazine,
thiazolopyridazine, oxazolopyridazine, thiadiazolopyrazine,
oxadiazolopyrimidine, thiadiazolopyrimidine, oxadiazolopyridazine,
thiazolopyridazine, imidazooxazole, imidazothiazole,
imidazoimidazole, isoxazolotriazine, isothiazolotriazine,
oxazolotriazine, thiazolotriazine, carbazole, acridine, phenazine,
phenothiazine, phenooxazine, and 5H-dibenz[b,f]azepine,
10,11-dihydro-5H-dibenz[b,f]azepine, etc.
[0167] The seven to fifteen-membered aromatic heterocycle may be
attached to the
--(C(R.sup.L).sub.2).sub.o-x-(C(R.sup.L).sub.2).sub.p-- moiety
through any ring carbon atom or ring nitrogen atom so long as a
quanternary nitrogen atom is not formed by the attachment.
Therefore, when partially saturated aromatic heterocycle is
1H-azepine, it may be 1H-azepin-1-yl, 1H-azepin-2-yl,
1H-azepin-3-yl, etc. Preferred aromatic heterocycles are
indolizinyl, indolyl, isoindolyl, indolinyl, benzo[b]furanyl,
2,3-dihydrobenzo[b]furanyl, benzo[b]thiophenyl,
2,3-dihydrobenzo[b]thiophenyl, indazolyl, benzimidazolyl,
benzthiazolyl, purinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl,
3,4-dihydro-2H-chromenyl, 3,4-dihydro-2H-thiochromenyl,
isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl,
acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
dibenzofuranyl, dibenzothiophenyl, 1H-azepinyl,
5H-dibenz[b,f]azepinyl, are
10,11-dihydro-5H-dibenz[b,f]azepinyl.
[0168] In another preferred embodiment, A.sup.2 is
##STR00020##
wherein each Q is, independently, C--H, C--R.sup.5, C--R.sup.6, or
a nitrogen atom, with the proviso that at least one Q is nitrogen
and one Q is C--R.sup.5, and at most three Q in a ring are nitrogen
atoms. Therefore, in any one ring, each Q may be 1, 2, or 3
nitrogen atoms. In a preferred embodiment, only one Q in each ring
is nitrogen. In another preferred embodiment, only a single Q is
nitrogen. Optionally, 1, 2, 3, 4, or 5 Q may be C--R.sup.6.
Optionally, Q may be 1, 2, 3, 4, or 5 C--H. In a particularly
preferred embodiment, each R.sup.6 is H.
[0169] In another preferred embodiment, A.sup.2 is
##STR00021##
wherein each Q is, independently, C--H, C--R.sup.5, C--R.sup.6, or
a nitrogen atom, with the proviso that at least one Q is nitrogen
and one Q is C--R.sup.5, and at most three Q in a ring are nitrogen
atoms. Therefore, in any one ring, each Q may be 1, 2, or 3
nitrogen atoms. In a preferred embodiment, only one Q in each ring
is nitrogen. In another preferred embodiment, only a single Q is
nitrogen. Optionally, Q may be 1, 2, 3, 4, or 5 C--H. Optionally,
1, 2, 3, 4, or 5 Q may be C--R.sup.6. In a particularly preferred
embodiment, each R.sup.6 is H.
[0170] Each R.sup.5 is, independently, OH,
--(CH.sub.2).sub.m--OR.sup.8, --O--(CH.sub.2).sub.m--OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--O--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7,
--O--(CH.sub.2).sub.m--CO.sub.2R.sup.7, --OSO.sub.3H,
--O-glucuronide, --O-glucose,
##STR00022##
--(CH.sub.2).sub.n--CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CO.sub-
.2R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CO.-
sub.2R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m(Z).sub.g--CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g(CHOR.sup.8).sub.m--(Z).sub.g--CO.sub.2R.sup-
.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CO.s-
ub.2R.sup.13,
--(CH.sub.2).sub.n--CONH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--CO--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13-
,
-Het-(CH.sub.2).sub.n--(Z).sub.g--CONH--C(.dbd.NR.sup.13)--NR.sup.13R.su-
p.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--C-
ONH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
H--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONH--C(.dbd.NR.sup.13)--NR.sup.1-
3R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONH--C(.dbd.NR.sup.-
13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONH--C(.dbd.NR.sup.13-
)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONH--C(.dbd.NR.sup-
.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONH--C(.dbd.NR.sup.13)--N-
R.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONH--C(.dbd.NR.sup.13)-
--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONH--C(.db-
d.NR.sup.13)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONH--C(.-
dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--CONR.sup.7--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--CONR.sup.7--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CONR.s-
up.7--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
R.sup.7--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.7--CONR.sup.13R.sup.13,
Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.n--CONR.sup.7--CONR.sup.13R.sup.13-
,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7--CONR.sup.-
13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CNR.sup.7--CONR.sup-
.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.n--CONR.sup.7--CONR.sup.13R-
.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7--CON-
R.sup.13R.sup.13,
--(CH.sub.2).sub.n(Z).sub.g(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7--CON-
R.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7-
--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--CONR.sup.7SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--CONR.sup.7SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CONR.sup.7SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CONR.s-
up.7SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
R.sup.7SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.7SO.sub.2NR.sup.13R.sup.-
13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--CONR.sup.7SO.sub.2NR.sup.13-
R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7SO.-
sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7SO.sub.2N-
R.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7SO.sub.2NR.sup.1-
3R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7SO.-
sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7S-
O.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup-
.7SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2)--SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.12).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--SO.su-
b.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--SO.-
sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--SO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m1SO.sub.2NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--SO.sub.2NR.sup.13R.sup-
.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--SO.sub.2NR.sup.-
13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mSO.sub.2NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mSO.sub.2NR.sup.13R.sup.-
13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--SO.sub.2-
NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--SO.sub.2-
NR.sup.13R.sup.13, --(CH.sub.2).sub.n--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CONR.s-
up.13R.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.13R.sup.13-
,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.13-
R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m-(Z).sub.g---
CONR.sup.13R.sup.13, --(CH.sub.2).sub.n--CONR.sup.7COR.sup.13,
-Het-(CH.sub.2).sub.m--CONR.sup.7COR.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7COR.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CONR.sup.7COR.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CONR.s-
up.7COR.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
R.sup.7COR.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.7COR.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--CONR.sup.7COR.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7COR.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7COR.sup.1-
3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7COR.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7COR.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup-
.7COR.sup.13, --(CH.sub.2).sub.n--CONR.sup.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--CONR.sup.7CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--CONR.sup.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.m--CONR.s-
up.7CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--CON-
R.sup.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CONR.sup.7CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--CONR.sup.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7CO.sub.2R.su-
p.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup.7CO.s-
ub.2R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7CO.sub.2R.sup.13-
,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mCONR.sup.7CO.sub.2R.su-
p.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.s-
up.7CO.sub.2R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--CONR.sup-
.7CO.sub.2R.sup.13,
--(CH.sub.2).sub.n--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.1-
3,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--NH---
C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--NH--
-C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R-
.sup.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--NH--C(.dbd.NR.sup.13)--
-NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--
-NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.1-
3)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)--NR.-
sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--NH--C(.dbd.-
NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--NH--C(.d-
bd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.m--C(.dbd.NH)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--C(.dbd.NH)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.m--(Z).sub.g--C(.dbd.NH)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.10--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--C(.d-
bd.NR.sup.13)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m(CHOR.sup.8).sub.n--C(.d-
bd.NR.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--C(.dbd.NR.sup.13)--NR.sup.13R.sup-
.13,
-Het-(CH.sub.2).sub.m--(CHOR.sup.8).sub.m--C(.dbd.NR.sup.13)--NR.sup.-
13R.sup.13,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--C(.dbd.NR.sup.13)--NR.-
sup.13R.sup.13,
--Het-(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--(Z).sub.g--C(.dbd.NR.sup.13)--
-NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--C(.dbd.NHC(.dbd.NR.sup.1-
3)--NR.sup.13R.sup.13,
Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--C(.dbd.NR.sup.13)--NR.-
sup.13R.sup.13,
--(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--C(.dbd.NR.s-
up.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CHOR.sup.8).sub.m--(Z).sub.g--C(.dbd.N-
R.sup.13)--NR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.m--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.m(Z).sub.gR.sup.12,
--(CH.sub.2).sub.nNR.sup.11R.sup.11,
--O--(CH.sub.2).sub.mNR.sup.11R.sup.11,
--(CH.sub.2).sub.n--N.sup..sym.--(R.sup.11).sub.3,
--O--(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
--O--(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.12R.sup.12,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.12R.sup.12,
--(CH.sub.2).sub.n--(C.dbd.O)NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.m--(C.dbd.O)NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.m--(CHOR.sup.8).sub.mCH.sub.2NR.sup.10--(Z).sub.g--R.-
sup.10,
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.m--CH.sub.2--NR.sup.10--(Z).s-
ub.g--R.sup.10,
--(CH.sub.2).sub.nNR.sup.10--O(CH.sub.2).sub.m(CHOR.sup.8).sub.nCH.sub.2N-
R.sup.10--(Z).sub.g--R.sup.10,
--O(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m--(CHOR.sup.8).sub.nCH.su-
b.2NR.sup.10--(Z).sub.g--R.sup.10,
-(Het)-(CH.sub.2).sub.m--OR.sup.8,
-(Het)-(CH.sub.2).sub.m--NR.sup.7R.sup.10,
-(Het)-(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
-(Het)-(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
-(Het)-(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
-(Het)-(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
-(Het)-(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
-(Het)-(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.-
n--CH.sub.2OR.sup.8, -(Het)-(CH.sub.2).sub.m--CO.sub.2R.sup.7,
-(Het)-(CH.sub.2).sub.m--NR.sup.12R.sup.12,
-(Het)-(CH.sub.2).sub.n--NR.sup.12R.sup.12,
-(Het)-(CH.sub.2).sub.m--(Z).sub.gR.sup.12,
-(Het)-(CH.sub.2).sub.mNR.sup.11R.sup.11,
-(Het)-(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
-(Het)-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
-(Het)-(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.12R.sup.12,
-(Het)-(CH.sub.2).sub.m--(C.dbd.O)NR.sup.12R.sup.12,
-(Het)-(CH.sub.2).sub.m--(CHOR.sup.8).sub.mCH.sub.2NR.sup.10--(Z).sub.g---
R.sup.10,
-(Het)-(CH.sub.2).sub.m--NR.sup.10--(CH.sub.2).sub.m--(CHOR.sup.-
8).sub.nCH.sub.2NR.sup.10--(Z).sub.g--R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, Link-(CH.sub.2).sub.n--CAP,
Link-(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CAP,
Link-(CH.sub.2CH.sub.2O).sub.m--CH.sub.2--CAP,
Link-(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2--CAP,
Link-(CH.sub.2).sub.n--(Z).sub.g--CAP,
Link-(CH.sub.2).sub.n(Z).sub.g--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.n--NR.sup.13--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CAP,
Link-(CH.sub.2).sub.n--(CHOR.sup.8).sub.mCH.sub.2--NR.sup.13--(Z).su-
b.g--CAP,
Link-(CH.sub.2).sub.nNR.sup.13--(CH.sub.2).sub.m(CHOR.sup.8).sub-
.nCH.sub.2NR.sup.13--(Z).sub.g--CAP,
-Link-(CH.sub.2).sub.m-(4-(CH.sub.2).sub.m--CAP,
Link-NH--C(.dbd.O)--NH--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.m--C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m--C(.dbd.O)NR.-
sup.10R.sup.10,
Link-(CH.sub.2).sub.m--C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.m--C(.dbd.O)NR.sup.11R.sup.11,
Link-(CH.sub.2).sub.m--C(.dbd.O)NR.sup.12R.sup.12,
Link-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--(Z).sub.g--CAP,
Link-(Z).sub.g--(CH.sub.2).sub.m-Het-(CH.sub.2).sub.m--CAP, Link
--(CH.sub.2).sub.n--CR.sup.11R.sup.11--CAP, Link
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CR.sup.11R.sup.11--CAP,
Link --(CH.sub.2CH.sub.2O).sub.m--CH.sub.2--R.sup.11R.sup.11--CAP,
Link
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2--CR.sup.11R.sup.11--CAP,
Link --(CH.sub.2).sub.n--(Z).sub.g--CR.sup.11R.sup.11--CAP, Link
--(CH.sub.2).sup.n(Z).sub.g--(CH.sub.2).sub.m--CR.sup.11R.sup.11--CAP,
Link
--(CH.sub.2).sub.nNR.sup.13--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CR.sup.11R.sup.11--CAP, Link
--(CH.sub.2).sub.n--(CHOR.sup.8).sub.mCH.sub.2--NR.sup.13--(Z).sub.g--CR.-
sup.11R.sup.11--CAP, Link
--(CH.sub.2).sub.nNR.sup.13--(CH.sub.2).sub.m(CHOR.sup.8).sub.nCH.sub.2NR-
.sup.13--(Z).sub.g--CR.sup.11R.sup.11--CAP, Link
--(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--CR.sup.11R.sup.11--CAP,
Link NH--C(.dbd.O)--NH--(CH.sub.2).sub.m--CR.sup.11R.sup.11--CAP,
Link
--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m--CR.sup.11R.sup.1-
1--CAP, Link
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--(Z).sub.g--CR.sup.11R.su-
p.11--CAP, or Link
--(Z).sub.g--(CH.sub.2).sub.m-Het-(CH.sub.2).sub.m--CR.sup.11R.sup.11--CA-
P.
[0171] In a preferred embodiment, R.sup.5 is --OH,
--O--(CH.sub.2).sub.m(Z).sub.gR.sup.12,
-Het-(CH.sub.2).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
-Link-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--CAP,
-Het-(CH.sub.2).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.mNR.sup.11R.sup.11,
--O--(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
-Het-(CH.sub.2).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.1-
3,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7, or
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8.
[0172] In another preferred embodiment R.sup.5 is one of the
following: --(CH.sub.2).sub.m--OR.sup.8, --(CH.sub.2).sub.4--OH,
--O--(CH.sub.2).sub.m--OR.sup.8, --O--(CH.sub.2).sub.4--OH,
--(CH.sub.2).sub.n--NR.sup.7R.sup.10, --NHSO.sub.2CH.sub.3,
--CH.sub.2NH(C.dbd.O)--(OCH.sub.3).sub.3, --NH(C.dbd.O)CH.sub.3,
--CH.sub.2NH.sub.2, --NH--CO.sub.2C.sub.2H.sub.5,
--CH.sub.2NH(C.dbd.O)CH.sub.3, --CH.sub.2NHCO.sub.2CH.sub.3,
--CH.sub.2NHSO.sub.2CH.sub.3,
--(CH.sub.2).sub.4--NH(C.dbd.O)O(CH.sub.3).sub.3,
--(CH.sub.2).sub.4--NH.sub.2,
--(CH.sub.2).sub.3--NH(C.dbd.O)O(CH.sub.3).sub.3,
--(CH.sub.2).sub.3--NH.sub.2,
--O--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--OCH.sub.2CH.sub.2NHCO.sub.2(CH.sub.3).sub.3,
--OCH.sub.2CH.sub.2NHCO.sub.2C.sub.2H.sub.5,
--O--(CH.sub.2).sub.3--NH--CO.sub.2--(CH.sub.3).sub.3,
--O(CH.sub.2).sub.3--NH.sub.2,
--OCH.sub.2CH.sub.2NHSO.sub.2CH.sub.3,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--OCH.sub.2CHOHCH.sub.2O-glucuronide,
--OCH.sub.2CH.sub.2CHOHCH.sub.2OH,
--OCH.sub.2--(.alpha.-CHOH).sub.2CH.sub.2OH,
--OCH.sub.2--(CHOH).sub.2CH.sub.2OH,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--O--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10, --C(.dbd.O)NH.sub.2,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--O--CH.sub.2--(C.dbd.O)NHCH.sub.2CHOH,
--O--CH.sub.2--(C.dbd.O)NHCH.sub.2CHOHCH.sub.2OH,
--O--CH.sub.2(C.dbd.O)NHCH.sub.2(CHOH).sub.2CH.sub.2OH,
--O--CH.sub.2C(C.dbd.O)NHSO.sub.2CH.sub.3,
--O--CH.sub.2(C.dbd.O)NHCO.sub.2CH.sub.3,
--O--CH.sub.2--C(C.dbd.O)NH--C(C.dbd.O)NH.sub.2,
--O--CH.sub.2--(C.dbd.O)NH--(C.dbd.O)CH.sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.n--(C.dbd.N)--NH.sub.2, --(C.dbd.NH)NH.sub.2,
--(CH.sub.2).sub.n--NH--C(.dbd.NH)--NH.sub.2,
--(CH.sub.2).sub.3--NH--C(.dbd.NH)--NH.sub.2,
--CH.sub.2NH--C(.dbd.NH)--NH.sub.2,
--(CH.sub.2).sub.n--CONHCH.sub.2(CHOH).sub.n--CH.sub.2OH,
--NH--C(.dbd.O)--CH.sub.2--(CHOH).sub.nCH.sub.2OH,
--NH--(C.dbd.O)--NH--CH.sub.2(CHOH).sub.2CHOH,
--NHC(C.dbd.O)NHCH.sub.2CH.sub.2OH,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
--O--(CH.sub.2).sub.m--NH--C(.dbd.NH)--N(R.sup.7).sub.2,
--O(CH.sub.2).sub.3--NH--C(.dbd.NH)--NH.sub.2,
--O--(CH.sub.2).sub.m--CHNH.sub.2--CO.sub.2NR.sup.7R.sup.10,
--OCH.sub.2--CHNH.sub.2--CO.sub.2NH.sub.2,
--O--(CH.sub.2).sub.m--CHNH.sub.2--CO.sub.2NR.sup.7R.sup.10
(anomeric center is the (R) enantiomer),
--O--(CH.sub.2).sub.m--CHNH.sub.2--CO.sub.2NR.sup.7R.sup.10
(anomeric center is the (5) enantiomer),
--OCH.sub.2CHOH--CH.sub.2NHCO.sub.2(CH.sub.3).sub.3,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8, --NHCH.sub.2(CHOH).sub.2CH.sub.2OH,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, --O--(CH.sub.2).sub.m--CO.sub.2R.sup.7,
--OCH.sub.2CH.sub.2CO.sub.2(CH.sub.3).sub.3, --OCH.sub.2CO.sub.2H,
--OCH.sub.2CO.sub.2C.sub.2H.sub.5, --O--(CH.sub.2).sub.m-Boc,
--(CH.sub.2).sub.m-Boc,
--O--(CH.sub.2).sub.m--NH--C(.dbd.NH)--N(R.sup.7).sub.2,
--(CH.sub.2).sub.n--NH--C(.dbd.NH)--N(R.sup.7).sub.2,
--(CH.sub.2).sub.m--NH--C(.dbd.O)--OR.sup.7,
--O--(CH.sub.2).sub.m--NH--C(.dbd.O)--OR.sup.7,
--(CH.sub.2).sub.n--NH--C(.dbd.O)--R.sup.11,
--O--(CH.sub.2).sub.m--NH--C(.dbd.O)--R.sup.11,
--O--(CH.sub.2).sub.m--C(.dbd.O)N(R.sup.7).sub.2,
--(CH.sub.2).sub.m--CHOH--CH.sub.2--NHBoc,
--O--(CH.sub.2).sub.m--CHOH--CH.sub.2--NHBoc,
--(CH.sub.2).sub.m--NHC(O)OR.sup.7,
--O--(CH.sub.2).sub.m--NHC(O)OR.sup.7,
--O--(CH.sub.2).sub.m--C(.dbd.NH)--N(R.sup.7).sub.2, or
--(CH.sub.2).sub.n--C(.dbd.NH)--N(R.sup.7).sub.2.
[0173] In another embodiment, R.sup.5 is selected from the group
consisting of --O--(CH.sub.2).sub.3--OH, --NH.sub.2,
--O--CH.sub.2--(CHOH).sub.2--CH.sub.2OH
--O--CH.sub.2--CHOH--CH.sub.2OH,
--O--CH.sub.2CH.sub.2--O-tetrahydropyran-2-yl,
--O--CH.sub.2CHOH--CH.sub.2--O-glucuronide,
--O--CH.sub.2CH.sub.2OH, --O--(CH.sub.2CH.sub.2O).sub.4--CH.sub.3,
--O--CH.sub.2CH.sub.2OCH.sub.3,
--O--CH.sub.2--(CHOC(.dbd.O)CH.sub.3)--CH.sub.2--OC(.dbd.O)CH.sub.3,
--O--(CH.sub.2CH.sub.2O).sub.2--CH.sub.3,
--OCH.sub.2--CHOH--CHOH--CH.sub.2OH, --CH.sub.2OH,
--CO.sub.2CH.sub.3,
##STR00023##
[0174] In another embodiment, R.sup.5 is selected from the group
consisting of --O--(CH.sub.2).sub.3--OH, --NH.sub.2,
--O--CH.sub.2--(CHOH).sub.2--CH.sub.2OH,
--O--CH.sub.2--CHOH--CH.sub.2OH,
--O--CH.sub.2CH.sub.2--O-tetrahydropyran-2-yl,
--O--CH.sub.2CHOH--CH.sub.2--O-glucuronide,
--O--CH.sub.2CH.sub.2OH, --O--(CH.sub.2CH.sub.2O).sub.4--CH.sub.3,
--O--CH.sub.2CH.sub.2OCH.sub.3,
--O--CH.sub.2--(CHOC(.dbd.O)CH.sub.3)--CH.sub.2--OC(.dbd.O)CH.sub.3,
--O--(CH.sub.2CH.sub.2O).sub.2--CH.sub.3,
--OCH.sub.2--CHOH--CHOH--CH.sub.2OH, --CH.sub.2OH,
--CO.sub.2CH.sub.3, --SO.sub.3H, --O-glucuronide,
##STR00024##
[0175] In a preferred embodiment, each
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7 falls within the scope of
the structures described above and is, independently,
--(CH.sub.2).sub.n--(C.dbd.N)--NH.sub.2,
--(CH.sub.2).sub.n--NH--C(.dbd.NH)NH.sub.2,
--(CH.sub.2).sub.n--CONHCH.sub.2(CHOH).sub.n--CH.sub.2OH, or
--NH--C(.dbd.O)--CH.sub.2--(CHOH).sub.nCH.sub.2OH.
[0176] In another a preferred embodiment, each
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7 falls within the scope of
the structures described above and is, independently,
[0177] --O--(CH.sub.2).sub.m--NH--C(.dbd.NH)--N(R.sup.7).sub.2,
or
[0178]
--O--(CH.sub.2).sub.m--CHNH.sub.2--CO.sub.2NR.sup.7R.sup.10.
[0179] In another preferred embodiment, R.sup.5 may be one of the
following: --O--CH.sub.2CHOHCH.sub.2O-glucuronide,
--OCH.sub.2CHOHCH.sub.3, --OCH.sub.2CH.sub.2NH.sub.2,
--OCH.sub.2CH.sub.2NHCO(CH.sub.3).sub.3, --CH.sub.2CH.sub.2OH,
--OCH.sub.2CH.sub.2OH, --O--(CH.sub.2).sub.m-Boc,
--(CH.sub.2).sub.m-Boc, --OCH.sub.2CH.sub.2OH,
--OCH.sub.2CO.sub.2H,
--O--(CH.sub.2).sub.m--NH--C(.dbd.NH)--N(R.sup.7).sub.2,
--(CH.sub.2).sub.n--NH--C(.dbd.NH)--N(R.sup.7).sub.2,
--NHCH.sub.2(CHOH).sub.2--CH.sub.2OH, --OCH.sub.2CO.sub.2Et,
--NHSO.sub.2CH.sub.3, --(CH.sub.2).sub.m--NH--C(.dbd.O)--OR.sup.7,
--O--(CH.sub.2).sub.m--NH--C(.dbd.O)--OR.sup.7,
--(CH.sub.2).sub.n--NH--C(.dbd.O)--R.sup.11,
--O--(CH.sub.2).sub.m--NH--C(.dbd.O)--R.sup.11,
--O--CH.sub.2C(.dbd.O)NH.sub.2, --CH.sub.2NH.sub.2, --NHCO.sub.2Et,
--OCH.sub.2CH.sub.2CH.sub.2CH.sub.2OH,
--CH.sub.2NHSO.sub.2CH.sub.3, --OCH.sub.2CH.sub.2CHOHCH.sub.2OH,
--OCH.sub.2CH.sub.2NHCO.sub.2Et, --NH--C(.dbd.NH.sub.2)--NH.sub.2,
--OCH.sub.2-(.alpha.-CHOH).sub.2--CH.sub.2OH,
--OCH.sub.2CHOHCH.sub.2NH.sub.2,
--(CH.sub.2).sub.m--CHOH--CH.sub.2--NHBoc,
--O--(CH.sub.2).sub.m--CHOH--CH.sub.2--NHBoc,
--(CH.sub.2).sub.m--NHC(O)OR.sup.7,
--O--(CH.sub.2).sub.m--NHC(O)OR.sup.7,
--OCH.sub.2CH.sub.2CH.sub.2NH.sub.2,
--OCH.sub.2CH.sub.2NHCH.sub.2(CHOH).sub.2CH.sub.2OH,
--OCH.sub.2CH.sub.2NH(CH.sub.2[(CHOH).sub.2CH.sub.2OH)].sub.2,
--(CH.sub.2).sub.4--NHBoc, --(CH.sub.2).sub.4--NH.sub.2,
--(CH.sub.2).sub.4--OH, --OCH.sub.2CH.sub.2NHSO.sub.2CH.sub.3,
--O--(CH.sub.2).sub.m--C(.dbd.NH)--N(R.sup.7).sub.2,
--(CH.sub.2).sub.n--C(.dbd.NH)--N(R.sup.7).sub.2,
--(CH.sub.2).sub.3--NH Boc, --(CH.sub.2).sub.3NH.sub.2,
--O--(CH.sub.2).sub.m--NH--NH--C(.dbd.NH)--N(R.sup.7).sub.2,
--(CH.sub.2).sub.n--NH--NH--C(.dbd.NH)--N(R.sup.7).sub.2, or
--O--CH.sub.2--CHOH--CH.sub.2--NH--C(.dbd.NH)--N(R.sup.7).sub.2.
[0180] In another preferred embodiment, R.sup.5 is --OH,
--O--(CH.sub.2).sub.m(Z).sub.gR.sup.12,
-Het-(CH.sub.2).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
-Link-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.n--CR.sup.11R.sup.11--CAP,
-Het-(CH.sub.2).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.m--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.mNR.sup.11R.sup.11,
--O--(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
-Het-(CH.sub.2).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.1-
3,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7, or
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8.
[0181] In a particularly preferred embodiment, R.sup.5 is
--O--CH.sub.2--(CHOH)--CH.sub.2OH, --OH,
--O--(CH.sub.2).sub.3NH.sub.2,
--O--(CH.sub.2).sub.3NH(C.dbd.NH)NH.sub.2,
--O--(CH.sub.2).sub.2NH(C.dbd.NH)NH.sub.2,
--O--CH.sub.2(CO)NH.sub.2,
--O--(CH.sub.2).sub.2--N.sup..sym.--(CH.sub.3).sub.3,
##STR00025##
[0182] Selected substituents within the compounds of the invention
are present to a recursive degree. In this context, "recursive
substituent" means that a substituent may recite another instance
of itself. Because of the recursive nature of such substituents,
theoretically, a large number of compounds may be present in any
given embodiment. For example, R.sup.9 contains a R.sup.13
substituent. R.sup.13 can contain an R.sup.10 substituent and
R.sup.10 can contain a R.sup.9 substituent. One of ordinary skill
in the art of medicinal chemistry understands that the total number
of such substituents is reasonably limited by the desired
properties of the compound intended. Such properties include, by
way of example and not limitation, physical properties such as
molecular weight, solubility or log P, application properties such
as activity against the intended target, and practical properties
such as ease of synthesis.
[0183] By way of example and not limitation, R.sup.9, R.sup.13 and
R.sup.10 are recursive substituents in certain embodiments.
Typically, each of these may independently occur 20, 19, 18, 17,
16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0, times
in a given embodiment. More typically, each of these may
independently occur 12 or fewer times in a given embodiment. More
typically yet, R.sup.9 will occur 0 to 8 times in a given
embodiment, R.sup.13 will occur 0 to 6 times in a given embodiment
and R.sup.10 will occur 0 to 6 times in a given embodiment. Even
more typically yet, R.sup.9 will occur 0 to 6 times in a given
embodiment, R.sup.13 will occur 0 to 4 times in a given embodiment
and R.sup.10 will occur 0 to 4 times in a given embodiment.
[0184] Recursive substituents are an intended aspect of the
invention. One of ordinary skill in the art of medicinal chemistry
understands the versatility of such substituents. To the degree
that recursive substituents are present in an embodiment of the
invention, the total number will be determined as set forth
above.
[0185] Each -Het- is, independently, --N(R.sup.7)--,
--N(R.sup.10)--, --S--, --SO--, --SO.sub.2--; --O--,
--SO.sub.2NH--, --NHSO.sub.2--, --NR.sup.7CO--, --CONR.sup.7--,
--N(R.sup.13)--, --SO.sub.2NR.sup.13--, --NR.sup.13CO--, or
--CONR.sup.13--. In a preferred embodiment, -Het- is --O--,
--N(R.sup.7)--, or --N(R.sup.10)--. Most preferably, -Het- is
--O--.
[0186] Each -Link- is, independently, --O--, --(CH.sub.2).sub.n--,
--O(CH.sub.2).sub.m--, --NR.sup.13--C(.dbd.O)--NR.sup.13--,
--NR.sup.13--C(.dbd.O)--(CH.sub.2).sub.m--,
--C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m--,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.n.sup.-, --S--,
--SO--, --SO.sub.2--, --SO.sub.2NR.sup.7--, --SO.sub.2NR.sup.10--,
or -Het-. In a preferred embodiment, -Link- is --O--,
--(CH.sub.2).sub.n--, --NR.sup.13--C(.dbd.O)--(CH.sub.2).sub.m--,
or --C(.dbd.O)NR.sup.13--(CH.sub.2).sub.m.sup.-.
[0187] Each --CAP is, independently, thiazolidinedione,
oxazolidinedione, -heteroaryl-C(.dbd.O)NR.sup.13R.sup.13,
heteroaryl-W, --CN, --O--C(.dbd.S)NR.sup.13R.sup.13,
--(Z).sub.gR.sup.13,
--CR.sup.10((Z).sub.gR.sup.13)((Z).sub.gR.sup.13), --C(.dbd.O)OAr,
--C(.dbd.O)NR.sup.13Ar, imidazoline, tetrazole, tetrazole amide,
--SO.sub.2NHR.sup.13,
--SO.sub.2NH--C(R.sup.13R.sup.13)--(Z).sub.g--R.sup.13, a cyclic
sugar or oligosaccharide, a cyclic amino sugar, oligosaccharide,
--CR.sup.10(--(CH.sub.2).sub.m--R.sup.9)(--(CH.sub.2).sub.m--R.sup.9),
--N(--(CH.sub.2).sub.m--R.sup.9)(--(CH.sub.2).sub.m--R.sup.9),
--NR.sup.13(--(CH.sub.2).sub.m--CO.sub.2R.sup.13),
##STR00026##
[0188] In a preferred embodiment, CAP is
##STR00027##
[0189] Each Ar is, independently, phenyl, substituted phenyl,
wherein the substituents of the substituted phenyl are 1-3
substituents independently selected from the group consisting of
OH, OCH.sub.3, NR.sup.13R.sup.13, Cl, F, and CH.sub.3, or
heteroaryl.
[0190] Examples of heteroaryl include pyridinyl, pyrazinyl,
furanyl, thienyl, tetrazolyl, thiazolidinedionyl, imidazoyl,
pyrrolyl, quinolinyl, indolyl, adeninyl, pyrazolyl, thiazolyl,
isoxazolyl, benzimidazolyl, purinyl, isoquinolinyl, pyridazinyl,
pyrimidinyl, 1,2,3-triazinyl, 1,2,4-triazinyl, 1,3,5-triazinyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, and pterdinyl
groups.
[0191] Each W is, independently, thiazolidinedione,
oxazolidinedione, heteroaryl-C(.dbd.O)N R.sup.13R.sup.13, --CN,
--O--C(.dbd.S)NR.sup.13R.sup.13, --(Z).sub.gR.sup.13,
--CR.sup.10((Z).sub.gR.sup.13)((Z).sub.gR.sup.13), --C(.dbd.O)OAr,
--C(.dbd.O)N R.sup.13Ar, imidazoline, tetrazole, tetrazole amide,
--SO.sub.2NHR.sup.13,
--SO.sub.2NH--C(R.sup.13R.sup.13)--(Z).sub.g--R.sup.13, a cyclic
sugar or oligosaccharide, a cyclic amino sugar,
oligosaccharide,
##STR00028##
[0192] There is at least one R.sup.5 on A.sup.1 and A.sup.2 and the
remaining substituents are R.sup.6. Each R.sup.6 is, independently,
R.sup.5, --R.sup.7, --OR.sup.11, --N(R.sup.7).sub.2,
--(CH.sub.2).sub.m--OR.sup.8, --O--(CH.sub.2).sub.m--OR.sup.8,
--(CH.sub.2).sub.n--NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--NR.sup.7R.sup.10,
--(CH.sub.2).sub.n(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--O--(CH.sub.2CH.sub.2O).sub.m--R.sup.8,
--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--O--(CH.sub.2CH.sub.2O).sub.m--CH.sub.2CH.sub.2NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--(CH.sub.2).sub.n--(Z).sub.g--R.sup.7,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7,
--(CH.sub.2).sub.n--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--CH-
.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8, --(CH.sub.2).sub.n--CO.sub.2R.sup.7,
--O--(CH.sub.2).sub.m--CO.sub.2R.sup.7, --OSO.sub.3H,
--O--glucuronide, --O-glucose,
##STR00029##
[0193] When two R.sup.6 are --OR.sup.11 and are located adjacent to
each other on the aromatic carbocycle or aromatic heterocycle, the
two OR.sup.11 may form a methylenedioxy group; i.e., a group of the
formula --O--CH.sub.2--O--.
[0194] In addition, one or more of the R.sup.6 groups can be one of
the R.sup.5 groups which fall within the broad definition of
R.sup.6 set forth above.
[0195] R.sup.6 may be hydrogen. Therefore, provided that the
aromatic carbocycle or aromatic heterocycle is substituted with
R.sup.5, the remaining R.sup.6 may be hydrogen. Preferably, at
most, 3 of the R.sup.6 groups are other than hydrogen. More
preferably, provided that the aromatic carbocycle or aromatic
heterocycle is substituted with R.sup.5, then R.sup.6 is H.
[0196] Each g is, independently, an integer from 1 to 6. Therefore,
each g may be 1, 2, 3, 4, 5, or 6.
[0197] Each m is an integer from 1 to 7. Therefore, each m may be
1, 2, 3, 4, 5, 6, or 7.
[0198] Each n is an integer from 0 to 7. Therefore, each n may be
0, 1, 2, 3, 4, 5, 6, or 7.
[0199] Each Z is, independently, --(CHOH)--, --C(.dbd.O)--,
--(CHNR.sup.7R.sup.10)--, --(C.dbd.NR.sup.10)--, --NR.sup.10--,
--(CH.sub.2).sub.n--, --(CHNR.sup.13R.sup.13)--,
--(C.dbd.NR.sup.13)--, or --NR.sup.13--. As designated by (Z).sub.g
in certain embodiments, Z may occur one, two, three, four, five or
six times and each occurrence of Z is, independently, --(CHOH)--,
--C(.dbd.O)--, --(CHNR.sup.7R.sup.10)--, --(C.dbd.NR.sup.10--,
--NR.sup.10--, --(CH.sub.2).sub.n--, --(CHNR.sup.13R.sup.13)--,
--(C.dbd.NR.sup.13)--, or --NR.sup.13--. Therefore, by way of
example and not by way of limitation, (Z).sub.g can be
--(CHOH)--(CHNR.sup.7R.sup.10)--,
--(CHOH)--(CHNR.sup.7R.sup.10--C(.dbd.O)--,
--(CHOH)--(CHNR.sup.7R.sup.10)--C(.dbd.O)--(CH.sub.2).sub.n--,
--(CHOH)--(CHNR.sup.7R.sup.10)--C(.dbd.O)--(CH.sub.2).sub.n--(CHNR.sup.13-
R.sup.13)--,
--(CHOH)--(CHNR.sup.7R.sup.10)--C(.dbd.O)--(CH.sub.2).sub.n--(CHNR.sup.13-
R.sup.13)--C(.dbd.O)--, and the like.
[0200] In any variable containing --CHOR.sup.8-- or
--CH.sub.2OR.sup.8 groups, when any --CHOR.sup.8-- or
--CH.sub.2OR.sup.8 groups are located 1,2- or 1,3- with respect to
each other, the R.sup.8 groups may, optionally, be taken together
to form a cyclic mono- or di-substituted 1,3-dioxane or
1,3-dioxolane.
[0201] More specific examples of suitable compounds represented by
formula (I) are shown in formulas II and III below wherein A.sup.1
and A.sup.2 are defined as above:
##STR00030##
[0202] In a preferred aspect of formula II, A.sup.1 is selected
from indenyl, napthalenyl, 1,2-dihydronapthalenyl,
1,2,3,4-tetrahydronapthalenyl, anthracenyl, fluorenyl,
phenanthrenyl, azulenyl, cyclohepta-1,3,5-trienyl or
5H-dibenzo[a,d]cycloheptenyl.
[0203] In another preferred aspect of formula II, A.sup.1 is
##STR00031##
[0204] wherein each Q is, independently, C--H, C--R.sup.5, or
C--R.sup.6, with the proviso that at least one Q is C--R.sup.5.
Preferably, six Q are C--H. Preferably, each R.sup.6 is H.
Preferably, R.sup.5 is --OH,
--O--(CH.sub.2).sub.m(Z).sub.gR.sup.12,
-Het-(CH.sub.2).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
-Link-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.n--CR.sup.11R.sup.11--CAP,
-Het-(CH.sub.2).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.mNR.sup.11R.sup.11,
--O--(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
-Het-(CH.sub.2).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.1-
3,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7, or
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8. More preferably, six Q are C--H and R.sup.5 is
--OH, --O--(CH.sub.2).sub.m(Z).sub.gR.sup.12,
-Het-(CH.sub.2).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
-Link-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.n--CR.sup.11R.sup.11--CAP,
-Het-(CH.sub.2).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.mNR.sup.11R.sup.11,
--O--(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
-Het-(CH.sub.2).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.1-
3,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7, or
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8. More preferably, R.sup.5 is
--O--CH.sub.2--(CHOH)--CH.sub.2OH, --OH,
--O--(CH.sub.2).sub.3NH.sub.2,
--O--(CH.sub.2).sub.3NH(C.dbd.NH)NH.sub.2,
--O--(CH.sub.2).sub.2NH(C.dbd.NH)NH.sub.2,
--O--CH.sub.2(CO)NH.sub.2,
--O--(CH.sub.2).sub.2--N'--(CH.sub.3).sub.3,
##STR00032##
[0205] Most preferably, R.sup.5--O--CH.sub.2--(CHOH)--CH.sub.2OH,
--OH, --O--(CH.sub.2).sub.3NH.sub.2,
--O--(CH.sub.2).sub.3NH(C.dbd.NH)NH.sub.2,
--O--(CH.sub.2).sub.2NH(C.dbd.NH)NH.sub.2,
--O--CH.sub.2(CO)NH.sub.2,
--O--(CH.sub.2).sub.2--N.sup..sym.--(CH.sub.3).sub.3,
##STR00033##
and six Q are C--H.
[0206] In another preferred aspect of formula II, A.sup.1 is
##STR00034##
[0207] Preferably, R.sup.5 is --OH,
--O--(CH.sub.2).sub.m(Z).sub.gR.sup.12,
-Het-(CH.sub.2).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
-Link-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.n--CR.sup.11R.sup.11--CAP,
-Het-(CH.sub.2).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.mNR.sup.11R.sup.11,
--O--(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
-Het-(CH.sub.2).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.1-
3,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7, or
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8. Most preferably, R.sup.5 is
--O--CH.sub.2--(CHOH)--CH.sub.2OH, --OH,
--O--(CH.sub.2).sub.3NH.sub.2,
--O--(CH.sub.2).sub.3NH(C.dbd.NH)NH.sub.2,
--O--(CH.sub.2).sub.2NH(C.dbd.NH)NH.sub.2,
--O--CH.sub.2(CO)NH.sub.2,
--O--(CH.sub.2).sub.2--N.sup.e-(CH.sub.3).sub.3,
##STR00035##
[0208] In a preferred aspect of formula III, A.sup.2 is selected
from indolizinyl, indolyl, isoindolyl, indolinyl, benzo[b]furanyl,
2,3-dihydrobenzo[b]furanyl, benzo[b]thiophenyl,
2,3-dihydrobenzo[b]thiophenyl, indazolyl, benzimidazolyl,
benzthiazolyl, purinyl, quinolinyl, 1,2,3,4-tetrahydroquinolinyl,
3,4-dihydro-2H-chromenyl, 3,4-dihydro-2H-thiochromenyl,
isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl,
quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl,
acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl,
dibenzofuranyl, dibenzothiophenyl, 1H-azepinyl,
5H-dibenz[b,f]azepinyl, or
10,11-dihydro-5H-dibenz[b,f]azepinyl.
[0209] In another preferred aspect of formula III, A.sup.2 is
##STR00036##
wherein each Q is, independently, C--H, C--R.sup.5, C--R.sup.6, or
a nitrogen atom, with the proviso that at least one Q is nitrogen
and one Q is C--R.sup.5, and at most three Q in a ring are nitrogen
atoms. In a preferred embodiment, only one Q in each ring is
nitrogen. In another preferred embodiment, only a single Q is
nitrogen. In a particularly preferred embodiment, a single Q is
nitrogen, one Q is C--R.sup.5, and the remaining Q are C--H. In
another preferred embodiment, each R.sup.6 is H. Preferably,
R.sup.5 is --OH, --O--(CH.sub.2).sub.m(Z).sub.gR.sup.12,
-Het-(CH.sub.2).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
-Link-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.n--CR.sup.11R.sup.11--CAP,
-Het-(CH.sub.2).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.mNR.sup.11R.sup.11,
--O--(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
-Het-(CH.sub.2).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.1-
3,
--O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8).sub.n--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7, or
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8. More preferably, one Q is nitrogen, five Q are
C--H and R.sup.5 is --OH, --O--(CH.sub.2).sub.m(Z).sub.gR.sup.12,
-Het-(CH.sub.2).sub.m--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.13,
-Het-(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.mNH--C(.dbd.NR.sup.13)---
NR.sup.13R.sup.13,
-Link-(CH.sub.2).sub.m--(Z).sub.g--(CH.sub.2).sub.m--CAP,
Link-(CH.sub.2).sub.n--CR.sup.11R.sup.11--CAP,
-Het-(CH.sub.2).sub.m--CONR.sup.13R.sup.13,
--(CH.sub.2).sub.n--NR.sup.12R.sup.12,
--O--(CH.sub.2).sub.mNR.sup.11R.sup.11,
--O--(CH.sub.2).sub.m--N.sup..sym.--(R.sup.11).sub.3,
--(CH.sub.2).sub.n--(Z).sub.g--(CH.sub.2).sub.m--NR.sup.10R.sup.10,
-Het-(CH.sub.2).sub.m--(Z).sub.g--NH--C(.dbd.NR.sup.13)--NR.sup.13R.sup.1-
3, --O--(CH.sub.2).sub.m(CHOR.sup.8)(CHOR.sup.8),
--CH.sub.2OR.sup.8,
--O--(CH.sub.2).sub.m--C(.dbd.O)NR.sup.7R.sup.10,
--O--(CH.sub.2).sub.m--(Z).sub.g--R.sup.7, or
--O--(CH.sub.2).sub.m--NR.sup.10--CH.sub.2(CHOR.sup.8)(CHOR.sup.8).sub.n--
-CH.sub.2OR.sup.8. More preferably, R.sup.5 is
--O--CH.sub.2--(CHOH)--CH.sub.2OH, --OH,
--O--(CH.sub.2).sub.3NH.sub.2,
--O--(CH.sub.2).sub.3NH(C.dbd.NH)NH.sub.2,
--O--(CH.sub.2).sub.2NH(C.dbd.NH)NH.sub.2,
--O--CH.sub.2(CO)NH.sub.2,
--O--(CH.sub.2).sub.2--N.sup..sym.--(CH.sub.3).sub.3,
##STR00037##
[0210] Most preferably, R.sup.5 is
--O--CH.sub.2--(CHOH)--CH.sub.2OH, --OH,
--O--(CH.sub.2).sub.3NH.sub.2,
--O--(CH.sub.2).sub.3NH(C.dbd.NH)NH.sub.2,
--O--(CH.sub.2).sub.2NH(C.dbd.NH)NH.sub.2,
--O--CH.sub.2(CO)NH.sub.2,
--O--(CH.sub.2).sub.2--N.sup..sym.--(CH.sub.3).sub.3,
##STR00038##
a single Q is nitrogen and five Q are C--H.
[0211] In a particularly preferred embodiment, the compounds of
formula I, formula II, or formula III are:
##STR00039##
[0212] In another preferred embodiment, the compounds of the
present invention are represented by the following formulas:
##STR00040## ##STR00041##
[0213] The compounds described herein may be prepared and used as
the free base. Alternatively, the compounds may be prepared and
used as a pharmaceutically acceptable salt. Pharmaceutically
acceptable salts are salts that retain or enhance the desired
biological activity of the parent compound and do not impart
undesired toxicological effects. Examples of such salts are (a)
acid addition salts formed with inorganic acids, for example,
hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric
acid, nitric acid and the like; (b) salts formed with organic acids
such as, for example, acetic acid, oxalic acid, tartaric acid,
succinic acid, maleic acid, fumaric acid, gluconic acid, citric
acid, malic acid, ascorbic acid, benzoic acid, tannic acid,
palmitic acid, alginic acid, polyglutamic acid, naphthalenesulfonic
acid, methanesulfonic acid, p-toluenesulfonic acid,
naphthalenedisulfonic acid, polygalacturonic acid, malonic acid,
sulfosalicylic acid, glycolic acid, 2-hydroxy-3-naphthoate,
pamoate, salicylic acid, stearic acid, phthalic acid, mandelic
acid, lactic acid and the like; and (c) salts formed from elemental
anions for example, chlorine, bromine, and iodine.
[0214] It is to be noted that all enantiomers, diastereomers, and
racemic mixtures, tautomers, polymorphs, pseudopolymorphs and
pharmaceutically acceptable salts of compounds within the scope of
formula (I), formula II, or formula III are embraced by the present
invention. All mixtures of such enantiomers and diastereomers are
within the scope of the present invention.
[0215] A compound of formula I-III and its pharmaceutically
acceptable salts may exist as different polymorphs or
pseudopolymorphs. As used herein, crystalline polymorphism means
the ability of a crystalline compound to exist in different crystal
structures. The crystalline polymorphism may result from
differences in crystal packing (packing polymorphism) or
differences in packing between different conformers of the same
molecule (conformational polymorphism). As used herein, crystalline
pseudopolymorphism means the ability of a hydrate or solvate of a
compound to exist in different crystal structures. The
pseudopolymorphs of the instant invention may exist due to
differences in crystal packing (packing pseudopolymorphism) or due
to differences in packing between different conformers of the same
molecule (conformational pseudopolymorphism). The instant invention
comprises all polymorphs and pseudopolymorphs of the compounds of
formula I-III and their pharmaceutically acceptable salts.
[0216] A compound of formula I-III and its pharmaceutically
acceptable salts may also exist as an amorphous solid. As used
herein, an amorphous solid is a solid in which there is no
long-range order of the positions of the atoms in the solid. This
definition applies as well when the crystal size is two nanometers
or less. Additives, including solvents, may be used to create the
amorphous forms of the instant invention. The instant invention
comprises all amorphous forms of the compounds of formula I-III and
their pharmaceutically acceptable salts.
[0217] The compounds of formula I-III may exist in different
tautomeric forms. One skilled in the art will recognize that
amidines, amides, guanidines, ureas, thioureas, heterocycles and
the like can exist in tautomeric forms. By way of example and not
by way of limitation, compounds of formula I-III can exist in
various tautomeric forms as shown below:
##STR00042##
All possible tautomeric forms of the amidines, amides, guanidines,
ureas, thioureas, heterocycles and the like of all of the
embodiments of formula I-III are within the scope of the instant
invention.
[0218] "Enantiomers" refer to two stereoisomers of a compound which
are non-superimposable mirror images of one another.
[0219] Stereochemical definitions and conventions used herein
generally follow S. P. Parker, Ed., McGraw-Hill Dictionary of
Chemical Terms (1984) McGraw-Hill Book Company, New York; and
Eliel, E. and Wilen, S., Stereochemistry of Organic Compounds
(1994) John Wiley & Sons, Inc., New York. Many organic
compounds exist in optically active forms, i.e., they have the
ability to rotate the plane of plane-polarized light. In describing
an optically active compound, the prefixes D and L or R and S are
used to denote the absolute configuration of the molecule about its
chiral center(s). The prefixes d and l, D and L, or (+) and (-) are
employed to designate the sign of rotation of plane-polarized light
by the compound, with S, (-), or 1 meaning that the compound is
levorotatory while a compound prefixed with R, (+), or d is
dextrorotatory. For a given chemical structure, these stereoisomers
are identical except that they are mirror images of one another. A
specific stereoisomer may also be referred to as an enantiomer, and
a mixture of such isomers is often called an enantiomeric mixture.
A 50:50 mixture of enantiomers is referred to as a racemic mixture
or a racemate, which may occur where there has been no
stereoselection or stereospecificity in a chemical reaction or
process. The terms "racemic mixture" and "racemate" refer to an
equimolar mixture of two enantiomeric species, devoid of optical
activity.
[0220] A single stereoisomer, e.g. an enantiomer, substantially
free of its stereoisomer may be obtained by resolution of the
racemic mixture using a method such as formation of diastereomers
using optically active resolving agents ("Stereochemistry of Carbon
Compounds," (1962) by E. L. Eliel, McGraw Hill; Lochmuller, C. H.,
(1975) J. Chromatogr., 113:(3) 283-302). Racemic mixtures of chiral
compounds of the invention can be separated and isolated by any
suitable method, including: (1) formation of ionic, diastereomeric
salts with chiral compounds and separation by fractional
crystallization or other methods, (2) formation of diastereomeric
compounds with chiral derivatizing reagents, separation of the
diastereomers, and conversion to the pure stereoisomers, and (3)
separation of the substantially pure or enriched stereoisomers
directly under chiral conditions.
[0221] "Diastereomer" refers to a stereoisomer with two or more
centers of chirality and whose molecules are not mirror images of
one another. Diastereomers have different physical properties, e.g.
melting points, boiling points, spectral properties, and
reactivities. Mixtures of diastereomers may separate under high
resolution analytical procedures such as electrophoresis and
chromatography.
[0222] Without being limited to any particular theory, it is
believed that the compounds of formula (I), formula II, or formula
III function in vivo as sodium channel blockers. By blocking
epithelial sodium channels present in mucosal surfaces the
compounds of formula (I), formula II, or formula III reduce the
absorption of water by the mucosal surfaces. This effect increases
the volume of protective liquids on mucosal surfaces, rebalances
the system, and thus treats disease.
[0223] The present invention also provides methods of treatment
that take advantage of the properties of the compounds described
herein as discussed above. Thus, subjects that may be treated by
the methods of the present invention include, but are not limited
to, patients afflicted with cystic fibrosis, primary ciliary
dyskinesia, chronic bronchitis, bronchiectasis chronic obstructive
airway disease, artificially ventilated patients, patients with
acute pneumonia, etc. The present invention may be used to obtain a
sputum sample from a patient by administering the active compounds
to at least one lung of a patient, and then inducing or collecting
a sputum sample from that patient. Typically, the invention will be
administered to respiratory mucosal surfaces via aerosol (liquid or
dry powders) or lavage.
[0224] Subjects that may be treated by the method of the present
invention also include patients being administered supplemental
oxygen nasally (a regimen that tends to dry the airway surfaces);
patients afflicted with an allergic disease or response (e.g., an
allergic response to pollen, dust, animal hair or particles,
insects or insect particles, etc.) that affects nasal airway
surfaces; patients afflicted with a bacterial infection e.g.,
staphylococcus infections such as Staphylococcus aureus infections,
Hemophilus influenza infections, Streptococcus pneumoniae
infections, Pseudomonas aeuriginosa infections, etc.) of the nasal
airway surfaces; patients afflicted with an inflammatory disease
that affects nasal airway surfaces; or patients afflicted with
sinusitis (wherein the active agent or agents are administered to
promote drainage of congested mucous secretions in the sinuses by
administering an amount effective to promote drainage of congested
fluid in the sinuses), or combined, Rhinosinusitis. The invention
may be administered to rhino-sinal surfaces by topical delivery,
including aerosols and drops.
[0225] The present invention may be used to hydrate mucosal
surfaces other than airway surfaces. Such other mucosal surfaces
include gastrointestinal surfaces, oral surfaces, genito-urethral
surfaces, ocular surfaces or surfaces of the eye, the inner ear and
the middle ear. For example, the active compounds of the present
invention may be administered by any suitable means, including
locally/topically, orally, or rectally, in an effective amount.
[0226] The compounds of the present invention are also useful for
treating a variety of functions relating to the cardiovascular
system. Thus, the compounds of the present invention are useful for
use as antihypertensive agents. The compounds may also be used to
reduce blood pressure and to treat edema. In addition, the
compounds of the present invention are also useful for promoting
diuresis, natriuresis, and saluresis. The compounds may be used
alone or in combination with beta blockers, ACE inhibitors, HMGCoA
reductase inhibitors, calcium channel blockers and other
cardiovascular agents to treat hypertension, congestive heart
failure and reduce cardiovascular mortality.
[0227] The present invention is concerned primarily with the
treatment of human subjects, but may also be employed for the
treatment of other mammalian subjects, such as dogs and cats, for
veterinary purposes.
[0228] As discussed above, the compounds used to prepare the
compositions of the present invention may be in the form of a
pharmaceutically acceptable free base. Because the free base of the
compound is generally less soluble in aqueous solutions than the
salt, free base compositions are employed to provide more sustained
release of active agent to the lungs. An active agent present in
the lungs in particulate form which has not dissolved into solution
is not available to induce a physiological response, but serves as
a depot of bioavailable drug which gradually dissolves into
solution.
[0229] Another aspect of the present invention is a pharmaceutical
composition, comprising a compound of formula (I), formula II, or
formula III in a pharmaceutically acceptable carrier (e.g., an
aqueous carrier solution). In general, the compound of formula (I),
formula II, or formula III is included in the composition in an
amount effective to inhibit the reabsorption of water by mucosal
surfaces.
[0230] Without being limited to any particular theory, it is
believed that sodium channel blockers of the present invention
block epithelial sodium channels present in mucosal surfaces the
sodium channel blocker, described herein reduce the absorption of
salt and water by the mucosal surfaces. This effect increases the
volume of protective liquids on mucosal surfaces, rebalances the
system, and thus treats disease. This effect is enhanced when used
in combination with osmolytes.
[0231] The compounds of formula (I), formula II, or formula III may
also be used in conjunction with osmolytes thus lowering the dose
of the compound needed to hydrate mucosal surfaces. This important
property means that the compound will have a lower tendency to
cause undesired side-effects by blocking sodium channels located at
untargeted locations in the body of the recipient, e.g., in the
kidneys when used in combination with an osmolyte.
[0232] Active osmolytes of the present invention are molecules or
compounds that are osmotically active (i.e., are "osmolytes").
"Osmotically active" compounds of the present invention are
membrane-impermeable (i.e., essentially non-absorbable) on the
airway or pulmonary epithelial surface. The terms "airway surface"
and "pulmonary surface," as used herein, include pulmonary airway
surfaces such as the bronchi and bronchioles, alveolar surfaces,
and nasal and sinus surfaces. Active compounds of the present
invention may be ionic osmolytes (i.e., salts), or may be non-ionic
osmolytes (i.e., sugars, sugar alcohols, and organic osmolytes). It
is specifically intended that both racemic forms of the active
compounds that are racemic in nature are included in the group of
active compounds that are useful in the present invention. It is to
be noted that all racemates, enantiomers, diastereomers, tautomers,
polymorphs and pseudopolymorphs and racemic mixtures of the
osmotically active compounds are embraced by the present
invention.
[0233] Active osmolytes useful in the present invention that are
ionic osmolytes include any salt of a pharmaceutically acceptable
anion and a pharmaceutically acceptable cation. Preferably, either
(or both) of the anion and cation are non-absorbable (i.e.,
osmotically active and not subject to rapid active transport) in
relation to the airway surfaces to which they are administered.
Such compounds include but are not limited to anions and cations
that are contained in FDA approved commercially marketed salts,
see, e.g., Remington: The Science and Practice of Pharmacy, Vol.
II, pg. 1457 (19.sup.th Ed. 1995), incorporated herein by
reference, and can be used in any combination including their
conventional combinations.
[0234] Pharmaceutically acceptable osmotically active anions that
can be used to carry out the present invention include, but are not
limited to, acetate, benzenesulfonate, benzoate, bicarbonate,
bitartrate, bromide, calcium edetate, camsylate (camphorsulfonate),
carbonate, chloride, citrate, dihydrochloride, edetate, edisylate
(1,2-ethanedisulfonate), estolate (lauryl sulfate), esylate
(1,2-ethanedisulfonate), fumarate, gluceptate, gluconate,
glutamate, glycollylarsanilate (p-glycollamidophenylarsonate),
hexylresorcinate, hydrabamine
(N,N'-Di(dehydroabietypethylenediamine), hydrobromide,
hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate,
lactobionate, malate, maleate, mandelate, mesylate, methylbromide,
methylnitrate, methylsulfate, mucate, napsylate, nitrate, nitrte,
pamoate (embonate), pantothenate, phosphate or diphosphate,
polygalacturonate, salicylate, stearate, subacetate, succinate,
sulfate, tannate, tartrate, teoclate (8-chlorotheophyllinate),
triethiodide, bicarbonate, etc. Particularly preferred anions
include chloride, sulfate, nitrate, gluconate, iodide, bicarbonate,
bromide, and phosphate.
[0235] Pharmaceutically acceptable cations that can be used to
carry out the present invention include, but are not limited to,
organic cations such as benzathine (N,N'-dibenzylethylenediamine),
chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine
(N-methyl D-glucamine), procaine, D-lysine, L-lysine, D-arginine,
L-arginine, triethylammonium, N-methyl D-glycerol, and the like.
Particularly preferred organic cations are 3-carbon, 4-carbon,
5-carbon and 6-carbon organic cations. Metallic cations useful in
the practice of the present invention include but are not limited
to aluminum, calcium, lithium, magnesium, potassium, sodium, zinc,
iron, ammonium, and the like. Particularly preferred cations
include sodium, potassium, choline, lithium, meglumine, D-lysine,
ammonium, magnesium, and calcium.
[0236] Specific examples of osmotically active salts that may be
used with the sodium channel blockers described herein to carry out
the present invention include, but are not limited to, sodium
chloride, potassium chloride, choline chloride, choline iodide,
lithium chloride, meglumine chloride, L-lysine chloride, D-lysine
chloride, ammonium chloride, potassium sulfate, potassium nitrate,
potassium gluconate, potassium iodide, ferric chloride, ferrous
chloride, potassium bromide, etc. Either a single salt or a
combination of different osmotically active salts may be used to
carry out the present invention. Combinations of different salts
are preferred. When different salts are used, one of the anion or
cation may be the same among the differing salts.
[0237] Osmotically active compounds of the present invention also
include non-ionic osmolytes such as sugars, sugar-alcohols, and
organic osmolytes. Sugars and sugar-alcohols useful in the practice
of the present invention include but are not limited to 3-carbon
sugars (e.g., glycerol, dihydroxyacetone); 4-carbon sugars (e.g.,
both the D and L forms of erythrose, threose, and erythrulose);
5-carbon sugars (e.g., both the D and L forms of ribose, arabinose,
xylose, lyxose, psicose, fructose, sorbose, and tagatose); and
6-carbon sugars (e.g., both the D and L forms of altose, allose,
glucose, mannose, gulose, idose, galactose, and talose, and the D
and L forms of allo-heptulose, allo-hepulose, gluco-heptulose,
manno-heptulose, gulo-heptulose, ido-heptulose, galacto-heptulose,
talo-heptulose). Additional sugars useful in the practice of the
present invention include raffinose, raffinose series
oligosaccharides, and stachyose. Both the D and L forms of the
reduced form of each sugar/sugar alcohol useful in the present
invention are also active compounds within the scope of the
invention. For example, glucose, when reduced, becomes sorbitol;
within the scope of the invention, sorbitol and other reduced forms
of sugar/sugar alcohols (e.g., mannitol, dulcitol, arabitol) are
accordingly active compounds of the present invention.
[0238] Osmotically active compounds of the present invention
additionally include the family of non-ionic osmolytes termed
"organic osmolytes." The term "organic osmolytes" is generally used
to refer to molecules used to control intracellular osmolality in
the kidney. See e.g., J. S. Handler et al., Comp. Biochem. Physiol,
117, 301-306 (1997); M. Burg, Am. J. Physiol. 268, F983-F996
(1995), each incorporated herein by reference. Although the
inventor does not wish to be bound to any particular theory of the
invention, it appears that these organic osmolytes are useful in
controlling extracellular volume on the airway/pulmonary surface.
Organic osmolytes useful as active compounds in the present
invention include but are not limited to three major classes of
compounds: polyols (polyhydric alcohols), methylamines, and amino
acids. The polyol organic osmolytes considered useful in the
practice of this invention include, but are not limited to,
inositol, myo-inositol, and sorbitol. The methylamine organic
osmolytes useful in the practice of the invention include, but are
not limited to, choline, betaine, carnitine (L-, D- and DL forms),
phosphorylcholine, lyso-phosphorylcholine,
glycerophosphorylcholine, creatine, and creatine phosphate. The
amino acid organic osmolytes of the invention include, but are not
limited to, the D- and L-forms of glycine, alanine, glutamine,
glutamate, aspartate, proline and taurine. Additional osmolytes
useful in the practice of the invention include tihulose and
sarcosine. Mammalian organic osmolytes are preferred, with human
organic osmolytes being most preferred. However, certain organic
osmolytes are of bacterial, yeast, and marine animal origin, and
these compounds are also useful active compounds within the scope
of the present invention.
[0239] Under certain circumstances, an osmolyte precursor may be
administered to the subject; accordingly, these compounds are also
useful in the practice of the invention. The term "osmolyte
precursor" as used herein refers to a compound which is converted
into an osmolyte by a metabolic step, either catabolic or anabolic.
The osmolyte precursors of this invention include, but are not
limited to, glucose, glucose polymers, glycerol, choline,
phosphatidylcholine, lyso-phosphatidylcholine and inorganic
phosphates, which are precursors of polyols and methylamines.
Precursors of amino acid osmolytes within the scope of this
invention include proteins, peptides, and polyamino acids, which
are hydrolyzed to yield osmolyte amino acids, and metabolic
precursors which can be converted into osmolyte amino acids by a
metabolic step such as transamination. For example, a precursor of
the amino acid glutamine is poly-L-glutamine, and a precursor of
glutamate is poly-L-glutamic acid.
[0240] Also intended within the scope of this invention are
chemically modified osmolytes or osmolyte precursors. Such chemical
modifications involve linking to the osmolyte (or precursor) an
additional chemical group which alters or enhances the effect of
the osmolyte or osmolyte precursor (e.g., inhibits degradation of
the osmolyte molecule). Such chemical modifications have been
utilized with drugs or prodrugs and are known in the art. (See, for
example, U.S. Pat. Nos. 4,479,932 and 4,540,564; Shek, E. et al.,
J. Med. Chem. 19:113-117 (1976); Bodor, N. et al., J. Pharm. Sci.
67:1045-1050 (1978); Bodor, N. et al., J. Med. Chem. 26:313-318
(1983); Bodor, N. et al., J. Pharm. Sci. 75:29-35 (1986), each
incorporated herein by reference.
[0241] In general, osmotically active compounds of the present
invention (both ionic and non-ionic) that do not promote, or in
fact deter or retard bacterial growth are preferred.
[0242] The compounds of formula (I), formula II, or formula III
described herein and osmotically active compounds disclosed herein
may be administered in any order and/or concurrently to mucosal
surfaces such as the eye, the nose, and airway surfaces including
the nasal passages, sinuses and lungs of a subject by any suitable
means known in the art, such as by nose drops, mists, aerosols,
continuous overnight nasal cannulation, etc. In one embodiment of
the invention, the compounds of formula (I), formula II, or formula
III and osmotically active compounds of the present invention are
administered concurrently by transbronchoscopic lavage. In a
preferred embodiment of the invention, the compounds of formula
(I), formula II, or formula III and osmotically active compounds of
the present invention are deposited on lung airway surfaces by
administering by inhalation an respirable aerosol respirable
particles comprised of the compounds of formula (I), formula II, or
formula III and the osmotically active compounds, in which the
compounds of formula (I), formula II, or formula III can precede or
follow the independent delivery of an osmotically active compound
within a sufficiently short time for their effects to be additive.
The respirable particles may be liquid or solid. Numerous inhalers
for administering aerosol particles to the lungs of a subject are
known. In another preferred embodiment of the invention, the
compounds of formula (I), formula II, or formula III and
osmotically active compounds can be given concurrently as defined
herein.
[0243] The compounds of formula (I), formula II, or formula III and
osmotically active compounds of the present invention are
administered sequentially (in any order) or concurrently to the
subject in need thereof. As used herein, the term "concurrently"
means sufficiently close in time to produce a combined effect (that
is, concurrently may be simultaneously, or it may be two or more
events occurring within a short time period before or after each
other). Concurrently also embraces the delivery of the compounds of
formula (I), formula II, or formula III and osmolytes as a mixture
or solution of the two components as well as when delivered from
two different nebulizers. An example of that would be the delivery
of compound 1 in one nebulizer and hypertonic saline in a second
nebulizer connected by a T-piece. When administered with other
active agents, the active compounds of the present invention may
function as a vehicle or carrier for the other active agent, or may
simply be administered concurrently with the other active agent.
The active compound of the present invention may be used as a dry
or liquid vehicle for administering other active ingredients to
airway surfaces. Such other active agents may be administered for
treating the disease or disorder for which they are intended, in
their conventional manner and dosages, in combination with the
active compounds of the present invention, which may be thought of
as serving as a vehicle or carrier for the other active agent. Any
such other active ingredient may be employed, particularly where
hydration of the airway surfaces (i.e., the activity of the
osmotically active compounds of the present invention) facilitates
the activity of the other active ingredient (e.g., by facilitating
or enhancing uptake of the active ingredient, by contributing to
the mechanism of action of the other active ingredient, or by any
other mechanisms). In a preferred embodiment of the invention, when
the active compound of the present invention is administered
concurrently with another active agent, the active compound of the
present invention has an additive effect in relation to the other
active agent; that is, the desired effect of the other active agent
is enhanced by the concurrent administration of the active
compounds of the present invention.
[0244] The compounds of formula (I), formula II, or formula III of
the present invention are also useful for treating airborne
infections. Examples of airborne infections include, for example,
RSV. The compounds of formula (I), formula II, or formula III of
the present invention are also useful for treating an anthrax
infection. The present invention relates to the use of the
compounds of formula (I), formula II, or formula III of the present
invention for prophylactic, post-exposure prophylactic, preventive
or therapeutic treatment against diseases or conditions caused by
pathogens. In a preferred embodiment, the present invention relates
to the use of the compounds of formula (I), formula II, or formula
III for prophylactic, post-exposure prophylactic, preventive or
therapeutic treatment against diseases or conditions caused by
pathogens which may be used in bioterrorism.
[0245] In recent years, a variety of research programs and
biodefense measures have been put into place to deal with concerns
about the use of biological agents in acts of terrorism. These
measures are intended to address concerns regarding bioterrorism or
the use of microorganisms or biological toxins to kill people,
spread fear, and disrupt society. For example, the National
Institute of Allergy and Infectious Diseases (NIAID) has developed
a Strategic Plan for Biodefense Research which outlines plans for
addressing research needs in the broad area of bioterrorism and
emerging and reemerging infectious diseases. According to the plan,
the deliberate exposure of the civilian population of the United
States to Bacillus anthracis spores revealed a gap in the nation's
overall preparedness against bioterrorism. Moreover, the report
details that these attacks uncovered an unmet need for tests to
rapidly diagnose, vaccines and immunotherapies to prevent, and
drugs and biologics to cure disease caused by agents of
bioterrorism.
[0246] Much of the focus of the various research efforts has been
directed to studying the biology of the pathogens identified as
potentially dangerous as bioterrorism agents, studying the host
response against such agents, developing vaccines against
infectious diseases, evaluating the therapeutics currently
available and under investigation against such agents, and
developing diagnostics to identify signs and symptoms of
threatening agents. Such efforts are laudable but, given the large
number of pathogens which have been identified as potentially
available for bioterrorism, these efforts have not yet been able to
provide satisfactory responses for all possible bioterrorism
threats. Additionally, many of the pathogens identified as
potentially dangerous as agents of bioterrorism do not provide
adequate economic incentives for the development of therapeutic or
preventive measures by industry. Moreover, even if preventive
measures such as vaccines were available for each pathogen which
may be used in bioterrorism, the cost of administering all such
vaccines to the general population is prohibitive.
[0247] Until convenient and effective treatments are available
against every bioterrorism threat, there exists a strong need for
preventative, prophylactic or therapeutic treatments which can
prevent or reduce the risk of infection from pathogenic agents.
[0248] The present invention provides such methods of prophylactic
treatment. In one aspect, a prophylactic treatment method is
provided comprising administering a prophylactically effective
amount of the compounds of formula (I), formula II, or formula III
to an individual in need of prophylactic treatment against
infection from one or more airborne pathogens. A particular example
of an airborne pathogen is anthrax.
[0249] In another aspect, a prophylactic treatment method is
provided for reducing the risk of infection from an airborne
pathogen which can cause a disease in a human, said method
comprising administering an effective amount of the compounds of
formula (I), formula II, or formula III to the lungs of the human
who may be at risk of infection from the airborne pathogen but is
asymptomatic for the disease, wherein the effective amount of a
sodium channel blocker and osmolye are sufficient to reduce the
risk of infection in the human. A particular example of an airborne
pathogen is anthrax.
[0250] In another aspect, a post-exposure prophylactic treatment or
therapeutic treatment method is provided for treating infection
from an airborne pathogen comprising administering an effective
amount of the compounds of formula (I), formula II, or formula III
to the lungs of an individual in need of such treatment against
infection from an airborne pathogen. The pathogens which may be
protected against by the prophylactic post exposure, rescue and
therapeutic treatment methods of the invention include any
pathogens which may enter the body through the mouth, nose or nasal
airways, thus proceeding into the lungs. Typically, the pathogens
will be airborne pathogens, either naturally occurring or by
aerosolization. The pathogens may be naturally occurring or may
have been introduced into the environment intentionally after
aerosolization or other method of introducing the pathogens into
the environment. Many pathogens which are not naturally transmitted
in the air have been or may be aerosolized for use in bioterrorism.
The pathogens for which the treatment of the invention may be
useful includes, but is not limited to, category A, B and C
priority pathogens as set forth by the NIAID. These categories
correspond generally to the lists compiled by the Centers for
Disease Control and Prevention (CDC). As set up by the CDC,
Category A agents are those that can be easily disseminated or
transmitted person-to-person, cause high mortality, with potential
for major public health impact. Category B agents are next in
priority and include those that are moderately easy to disseminate
and cause moderate morbidity and low mortality. Category C consists
of emerging pathogens that could be engineered for mass
dissemination in the future because of their availability, ease of
production and dissemination and potential for high morbidity and
mortality. Particular examples of these pathogens are anthrax and
plague. Additional pathogens which may be protected against or the
infection risk therefrom reduced include influenza viruses,
rhinoviruses, adenoviruses and respiratory syncytial viruses, and
the like. A further pathogen which may be protected against is the
coronavirus which is believed to cause severe acute respiratory
syndrome (SARS).
[0251] The compounds of the present invention may also be used in
conjunction with a P2Y2 receptor agonist or a pharmaceutically
acceptable salt thereof (also sometimes referred to as an "active
agent" herein). The composition may further comprise a P2Y2
receptor agonist or a pharmaceutically acceptable salt thereof
(also sometimes referred to as an "active agent" herein). The P2Y2
receptor agonist is typically included in an amount effective to
stimulate chloride and water secretion by airway surfaces,
particularly nasal airway surfaces. Suitable P2Y2 receptor agonists
are described in columns 9-10 of U.S. Pat. No. 6,264,975, U.S. Pat.
No. 5,656,256, and U.S. Pat. No. 5,292,498, each of which is
incorporated herein by reference.
[0252] Bronchodiloators can also be used in combination with
compounds of the present invention. These bronchodilators include,
but are not limited to, .beta.-adrenergic agonists including but
not limited to epinephrine, isoproterenol, fenoterol, albutereol,
terbutalin, pirbuterol, bitolterol, metaproterenol, isoetharine,
salmeterol xinofoate, as well as anticholinergic agents including
but not limited to ipratropium bromide, as well as compounds such
as theophylline and aminophylline. These compounds may be
administered in accordance with known techniques, either prior to
or concurrently with the active compounds described herein.
[0253] Another aspect of the present invention is a pharmaceutical
formulation, comprising an active compound as described above in a
pharmaceutically acceptable carrier (e.g., an aqueous carrier
solution). In general, the active compound is included in the
composition in an amount effective to treat mucosal surfaces, such
as inhibiting the reabsorption of water by mucosal surfaces,
including airway and other surfaces.
[0254] The active compounds disclosed herein may be administered to
mucosal surfaces by any suitable means, including topically,
orally, rectally, vaginally, ocularly and dermally, etc. For
example, for the treatment of constipation, the active compounds
may be administered orally or rectally to the gastrointestinal
mucosal surface. The active compound may be combined with a
pharmaceutically acceptable carrier in any suitable form, such as
sterile physiological or dilute saline or topical solution, as a
droplet, tablet or the like for oral administration, as a
suppository for rectal or genito-urethral administration, etc.
Excipients may be included in the formulation to enhance the
solubility of the active compounds, as desired.
[0255] The active compounds disclosed herein may be administered to
the airway surfaces of a patient by any suitable means, including
as a spray, mist, or droplets of the active compounds in a
pharmaceutically acceptable carrier such as physiological or dilute
saline solutions or distilled water. For example, the active
compounds may be prepared as formulations and administered as
described in U.S. Pat. No. 5,789,391 to Jacobus, the disclosure of
which is incorporated by reference herein in its entirety.
[0256] Solid or liquid particulate active agents prepared for
practicing the present invention could, as noted above, include
particles of respirable or non-respirable size; that is, for
respirable particles, particles of a size sufficiently small to
pass through the mouth and larynx upon inhalation and into the
bronchi and alveoli of the lungs, and for non-respirable particles,
particles sufficiently large to be retained in the nasal airway
passages rather than pass through the larynx and into the bronchi
and alveoli of the lungs. In general, particles ranging from about
1 to 5 microns in size (more particularly, less than about 4.7
microns in size) are respirable. Particles of non-respirable size
are greater than about 5 microns in size, up to the size of visible
droplets. Thus, for nasal administration, a particle size in the
range of 10-500 .mu.m may be used to ensure retention in the nasal
cavity.
[0257] In the manufacture of a formulation according to the
invention, active agents or the physiologically acceptable salts or
free bases thereof are typically admixed with, inter alia, an
acceptable carrier. Of course, the carrier must be compatible with
any other ingredients in the formulation and must not be
deleterious to the patient. The carrier must be solid or liquid, or
both, and is preferably formulated with the compound as a unit-dose
formulation, for example, a capsule, that may contain 0.5% to 99%
by weight of the active compound. One or more active compounds may
be incorporated in the formulations of the invention, which
formulations may be prepared by any of the well-known techniques of
pharmacy consisting essentially of admixing the components.
[0258] Compositions containing respirable or non-respirable dry
particles of micronized active agent may be prepared by grinding
the dry active agent with a mortar and pestle, and then passing the
micronized composition through a 400 mesh screen to break up or
separate out large agglomerates.
[0259] The particulate active agent composition may optionally
contain a dispersant which serves to facilitate the formulation of
an aerosol. A suitable dispersant is lactose, which may be blended
with the active agent in any suitable ratio (e.g., a 1 to 1 ratio
by weight).
[0260] Active compounds disclosed herein may be administered to
airway surfaces including the nasal passages, sinuses and lungs of
a subject by a suitable means know in the art, such as by nose
drops, mists, etc. In one embodiment of the invention, the active
compounds of the present invention and administered by
transbronchoscopic lavage. In a preferred embodiment of the
invention, the active compounds of the present invention are
deposited on lung airway surfaces by administering an aerosol
suspension of respirable particles comprised of the active
compound, which the subject inhales. The respirable particles may
be liquid or solid. Numerous inhalers for administering aerosol
particles to the lungs of a subject are known.
[0261] Inhalers such as those developed by Inhale Therapeutic
Systems, Palo Alto, Calif., USA, may be employed, including but not
limited to those disclosed in U.S. Pat. Nos. 5,740,794; 5,654,007;
5,458,135; 5,775,320; and 5,785,049, each of which is incorporated
herein by reference. The Applicant specifically intends that the
disclosures of all patent references cited herein be incorporated
by reference herein in their entirety. Inhalers such as those
developed by Dura Pharmaceuticals, Inc., San Diego, Calif., USA,
may also be employed, including but not limited to those disclosed
in U.S. Pat. Nos. 5,622,166; 5,577,497; 5,645,051; and 5,492,112,
each of which is incorporated herein by reference. Additionally,
inhalers such as those developed by Aradigm Corp., Hayward, Calif.,
USA, may be employed, including but not limited to those disclosed
in U.S. Pat. Nos. 5,826,570; 5,813,397; 5,819,726; and 5,655,516,
each of which is incorporated herein by reference. These
apparatuses are particularly suitable as dry particle inhalers.
[0262] Aerosols of liquid particles comprising the active compound
may be produced by any suitable means, such as with a
pressure-driven aerosol nebulizer (L C Star)or an ultrasonic
nebulizer (Pari eFlow). See, e.g., U.S. Pat. No. 4,501,729, which
is incorporated herein by reference. Nebulizers are commercially
available devices which transform solutions or suspensions of the
active ingredient into a therapeutic aerosol mist either by means
of acceleration of compressed gas, typically air or oxygen, through
a narrow venturi orifice or by means of ultrasonic agitation.
Suitable formulations for use in nebulizers consist of the active
ingredient in a liquid carrier, the active ingredient comprising up
to 40% w/w of the formulation, but preferably less than 20% w/w.
The carrier is typically water (and most preferably sterile,
pyrogen-free water) or dilute aqueous alcoholic solution.
Perfluorocarbon carriers may also be used. Optional additives
include preservatives if the formulation is not made sterile, for
example, methyl hydroxybenzoate, antioxidants, flavoring agents,
volatile oils, buffering agents and surfactants.
[0263] Aerosols of solid particles comprising the active compound
may likewise be produced with any solid particulate medicament
aerosol generator. Aerosol generators for administering solid
particulate medicaments to a subject produce particles which are
respirable, as explained above, and generate a volume of aerosol
containing predetermined metered dose of medicament at a rate
suitable for human administration. One illustrative type of solid
particulate aerosol generator is an insufflator. Suitable
formulations for administration by insufflation include finely
comminuted powders which may be delivered by means of an
insufflator or taken into the nasal cavity in the manner of a
snuff. In the insufflator, the powder (e.g., a metered dose thereof
effective to carry out the treatments described herein) is
contained in capsules or cartridges, typically made of gelatin or
plastic, which are either pierced or opened in situ and the powder
delivered by air drawn through the device upon inhalation or by
means of a manually-operated pump. The powder employed in the
insufflator consists either solely of the active ingredient or of
powder blend comprising the active ingredient, a suitable powder
diluent, such as lactose, and an optional surfactant. The active
ingredient typically comprises of 0.1 to 100% w/w of the
formulation. A second type of illustrative aerosol generator
comprises a metered dose inhaler. Metered dose inhalers are
pressurized aerosol dispensers, typically containing a suspension
or solution formulation of active ingredient in a liquified
propellant. During use, these devices discharge the formulation
through a valve adapted to deliver a metered volume, typically from
10 to 150 p. 1, to produce a fine particle spray containing the
active ingredient. Suitable propellants include certain
chlorofluorocarbon compounds, for example, dichlorodifluoromethane,
trichlorofluoromethane, dichlorotetrafluoroethane and mixtures
thereof. The formulation may additionally contain one of more
co-solvents, for example, ethanol, surfactants, such as oleic acid
or sorbitan trioleate, antioxidants and suitable flavoring
agents.
[0264] The aerosol, whether formed from solid or liquid particles,
may be produced by the aerosol generator at a rate of from about 10
to 150 liters per minute, more preferable from 30 to 150 liters per
minute, and most preferably about 60 liters per minute. Aerosols
containing greater amounts of medicament may be administered more
rapidly.
[0265] The dosage of the active compounds disclosed herein will
vary depending on the condition being treated and the state of the
subject, but generally may be from about 0.01, 0.03, 0.05, 0.1 to
1, 5, 10 or 20 mg of the pharmaceutic agent, deposited on the
airway surfaces. The daily dose may be divided among one or
multiple unit dose administrations. The goal is to achieve a
concentration of the pharmaceutic agents on lung airway surfaces of
between 10.sup.-9-10.sup.4 M.
[0266] In another embodiment, they are administered by
administering an aerosol suspension of respirable or non-respirable
particles (preferably non-respirable particles) comprised of active
compound, which the subject inhales through the nose. The
respirable or non-respirable particles may be liquid or solid. The
quantity of active agent included may be an amount of sufficient to
achieve dissolved concentrations of active agent on the airway
surfaces of the subject of from about 10.sup.-9, 10.sup.-8, or
10.sup.-7 to about 10.sup.-3, 10.sup.-2, 10.sup.-1 moles/liter, and
more preferably from about 10.sup.-9 to about 10.sup.-4
moles/liter.
[0267] The dosage of active compound will vary depending on the
condition being treated and the state of the subject, but generally
may be an amount sufficient to achieve dissolved concentrations of
active compound on the nasal airway surfaces of the subject from
about 10.sup.-9, 10.sup.-8, 10.sup.-7 to about 10.sup.-3,
10.sup.-2, or 10.sup.-1 moles/liter, and more preferably from about
10.sup.-7 to about 10.sup.-4 moles/liter. Depending upon the
solubility of the particular formulation of active compound
administered, the daily dose may be divided among one or several
unit dose administrations. The daily dose by weight may range from
about 0.01, 0.03, 0.1, 0.5 or 1.0 to 10 or 20 milligrams of active
agent particles for a human subject, depending upon the age and
condition of the subject. A currently preferred unit dose is about
0.5 milligrams of active agent given at a regimen of 2-10
administrations per day. The dosage may be provided as a
prepackaged unit by any suitable means (e.g., encapsulating a
gelatin capsule).
[0268] In one embodiment of the invention, the particulate active
agent composition may contain both a free base of active agent and
a pharmaceutically acceptable salt to provide both early release
and sustained release of active agent for dissolution into the
mucus secretions of the nose. Such a composition serves to provide
both early relief to the patient, and sustained relief over time.
Sustained relief, by decreasing the number of daily administrations
required, is expected to increase patient compliance with the
course of active agent treatments.
[0269] Pharmaceutical formulations suitable for airway
administration include formulations of solutions, emulsions,
suspensions and extracts. See generally, J. Nairn, Solutions,
Emulsions, Suspensions and Extracts, in Remington: The Science and
Practice of Pharmacy, chap. 86 (19.sup.th ed. 1995), incorporated
herein by reference. Pharmaceutical formulations suitable for nasal
administration may be prepared as described in U.S. Pat. Nos.
4,389,393 to Schor; 5,707,644 to Illum; 4,294,829 to Suzuki; and
4,835,142 to Suzuki, the disclosures of which are incorporated by
reference herein in their entirety.
[0270] Mists or aerosols of liquid particles comprising the active
compound may be produced by any suitable means, such as by a simple
nasal spray with the active agent in an aqueous pharmaceutically
acceptable carrier, such as a sterile saline solution or sterile
water. Administration may be with a pressure-driven aerosol
nebulizer or an ultrasonic nebulizer. See e.g. U.S. Pat. Nos.
4,501,729 and 5,656,256, both of which are incorporated herein by
reference. Suitable formulations for use in a nasal droplet or
spray bottle or in nebulizers consist of the active ingredient in a
liquid carrier, the active ingredient comprising up to 40% w/w of
the formulation, but preferably less than 20% w/w. Typically the
carrier is water (and most preferably sterile, pyrogen-free water)
or dilute aqueous alcoholic solution, preferably made in a 0.12% to
0.8% solution of sodium chloride. Optional additives include
preservatives if the formulation is not made sterile, for example,
methyl hydroxybenzoate, antioxidants, flavoring agents, volatile
oils, buffering agents, osmotically active agents (e.g. mannitol,
xylitol, erythritol) and surfactants.
[0271] Compositions containing respirable or non-respirable dry
particles of micronized active agent may be prepared by grinding
the dry active agent with a mortar and pestle, and then passing the
micronized composition through a 400 mesh screen to break up or
separate out large agglomerates.
[0272] The particulate composition may optionally contain a
dispersant which serves to facilitate the formation of an aerosol.
A suitable dispersant is lactose, which may be blended with the
active agent in any suitable ratio (e.g., a 1 to 1 ratio by
weight).
[0273] The compounds of formula I-III may be synthesized according
to procedures known in the art. A representative synthetic
procedure is shown in the scheme below:
##STR00043##
These procedures are described in, for example, E. J. Cragoe, "The
Synthesis of Amiloride and Its Analogs" (Chapter 3) in Amiloride
and Its Analogs, pp. 25-36, incorporated herein by reference. Other
methods of preparing the compounds are described in, for example,
U.S. Pat. No. 3,313,813, incorporated herein by reference. See in
particular Methods A, B, C, and D described in U.S. Pat. No.
3,313,813. Additional methods of preparing intermediates used in
the preparation of compounds of the instant invention are disclosed
in U.S. Pat. No. 7,064,129, U.S. Pat. No. 6,858,615, U.S. Pat. No.
6,903,105, WO 2004/073629, WO 2007/146869, and WO 2007/018640, each
of which is expressly incorporated by reference.
[0274] Several assays may be used to characterize the compounds of
the present invention. Representative assays are discussed
below.
[0275] In Vitro Measure of Sodium Channel Blocking Activity and
Reversibility
[0276] One assay used to assess mechanism of action and/or potency
of the compounds of the present invention involves the
determination of lumenal drug inhibition of airway epithelial
sodium currents measured under short circuit current (I.sub.SC)
using airway epithelial monolayers mounted in Using chambers. Cells
obtained from freshly excised human, dog, sheep or rodent airways
are seeded onto porous 0.4 micron Snapwell.TM. Inserts (CoStar),
cultured at air-liquid interface (ALI) conditions in hormonally
defined media, and assayed for sodium transport activity (I.sub.SC)
while bathed in Krebs Bicarbonate Ringer (KBR) in Using chambers.
All test drug additions are to the lumenal bath with half-log dose
addition protocols (from 1.times.10.sup.-11 M to 3.times.10.sup.-5
M), and the cumulative change in I.sub.sc (inhibition) recorded.
All drugs are prepared in dimethyl sulfoxide as stock solutions at
a concentration of 1.times.10.sup.-2 M and stored at -20.degree. C.
Eight preparations are typically run in parallel; two preparations
per run incorporate amiloride and/or benzamil as positive controls.
After the maximal concentration (5.times.10.sup.-5 M) is
administered, the lumenal bath is exchanged three times with fresh
drug-free KBR solution, and the resultant I.sub.SC measured after
each wash for approximately 5 minutes in duration. Reversibility is
defined as the percent return to the baseline value for sodium
current after the third wash. All data from the voltage clamps are
collected via a computer interface and analyzed off-line.
[0277] Dose-effect relationships for all compounds are considered
and analyzed by the Prism 3.0 program. IC.sub.50 values, maximal
effective concentrations, and reversibility are calculated and
compared to amiloride and benzamil as positive controls. The
potency of the sodium channel blocking activity of representative
compounds relative to amiloride in freshly excised cell from human
airways is shown in Table 1.
TABLE-US-00001 TABLE 1 Potency of sodium channel blocking activity
of compounds compared to amiloride. Compound Potency of Sodium
Channel Number Blockade Relative to Amiloride 26 30 34 63 72 164 76
347
[0278] The potency of the sodium channel blocking activity of
representative compounds in freshly excised cell from dog airways
is shown in Table 2.
TABLE-US-00002 TABLE 2 Compound Number IC.sub.50 nM Amiloride 781
79 23.5 34 18.8 26 25.4 72 6.3 75 4.3 91 6.1 94 9.6 107 8.1 105
23.5 116 2.7 118 3.2
Pharmacological Assays of Absorption
(1) Apical Disappearance Assay
[0279] Bronchial cells (dog, human, sheep, or rodent cells) are
seeded at a density of 0.25.times.10.sup.6/cm.sup.2 on a porous
Transwell-Col collagen-coated membrane with a growth area of 1.13
cm.sup.2 grown at an air-liquid interface in hormonally defined
media that promotes a polarized epithelium. From 12 to 20 days
after development of an air-liquid interface (ALI) the cultures are
expected to be >90% ciliated, and mucins will accumulate on the
cells. To ensure the integrity of primary airway epithelial cell
preparations, the transepithelial resistance (R.sub.t) and
transepithelial potential differences (PD), which are indicators of
the integrity of polarized nature of the culture, are measured.
Human cell systems are preferred for studies of rates of absorption
from apical surfaces. The disappearance assay is conducted under
conditions that mimic the "thin" films in vivo (.about.25 .mu.l)
and is initiated by adding experimental sodium channel blockers or
positive controls (amiloride, benzamil, phenamil) to the apical
surface at an initial concentration of 10 .mu.M. A series of
samples (5 .mu.l volume per sample) is collected at various time
points, including 0, 5, 20, 40, 90 and 240 minutes. Concentrations
are determined by measuring intrinsic fluorescence of each sodium
channel blocker using a Fluorocount Microplate Fluorometer or HPLC.
Quantitative analysis employs a standard curve generated from
authentic reference standard materials of known concentration and
purity. Data analysis of the rate of disappearance is performed
using nonlinear regression, one phase exponential decay (Prism V
3.0).
[0280] 2. Confocal Microscopy Assay of Amiloride Congener
Uptake
[0281] Virtually all amiloride-like molecules fluoresce in the
ultraviolet range. This property of these molecules may be used to
directly measure cellular update using x-z confocal microscopy.
Equimolar concentrations of experimental compounds and positive
controls including amiloride and compounds that demonstrate rapid
uptake into the cellular compartment (benzamil and phenamil) are
placed on the apical surface of airway cultures on the stage of the
confocal microscope. Serial x-z images are obtained with time and
the magnitude of fluorescence accumulating in the cellular
compartment is quantitated and plotted as a change in fluorescence
versus time.
[0282] 3. In vitro Assays of Compound Metabolism
[0283] Airway epithelial cells have the capacity to metabolize
drugs during the process of transepithelial absorption. Further,
although less likely, it is possible that drugs can be metabolized
on airway epithelial surfaces by specific ectoenzyme activities.
Perhaps more likely as an ecto-surface event, compounds may be
metabolized by the infected secretions that occupy the airway
lumens of patients with lung disease, e.g. cystic fibrosis. Thus, a
series of assays is performed to characterize the compound
metabolism that results from the interaction of test compounds with
human airway epithelia and/or human airway epithelial lumenal
products.
[0284] In the first series of assays, the interaction of test
compounds in KBR as an "ASL" stimulant are applied to the apical
surface of human airway epithelial cells grown in the T-Col insert
system. For most compounds, metabolism (generation of new species)
is tested for using high performance liquid chromatography (HPLC)
to resolve chemical species and the endogenous fluorescence
properties of these compounds to estimate the relative quantities
of test compound and novel metabolites. For a typical assay, a test
solution (25 .mu.l KBR, containing 10 .mu.M test compound) is
placed on the epithelial lumenal surface. Sequential 5 to 10 .mu.l
samples are obtained from the lumenal and serosal compartments for
HPLC analysis of (1) the mass of test compound permeating from the
lumenal to serosal bath and (2) the potential formation of
metabolites from the parent compound. In instances where the
fluorescence properties of the test molecule are not adequate for
such characterizations, radiolabeled compounds are used for these
assays. From the HPLC data, the rate of disappearance and/or
formation of novel metabolite compounds on the lumenal surface and
the appearance of test compound and/or novel metabolite in the
basolateral solution is quantitated. The data relating the
chromatographic mobility of potential novel metabolites with
reference to the parent compound are also quantitated.
[0285] To analyze the potential metabolism of test compounds by CF
sputum, a "representative" mixture of expectorated CF sputum
obtained from 10 CF patients (under IRB approval) has been
collected. The sputum has been be solubilized in a 1:5 mixture of
KBR solution with vigorous vortexing, following which the mixture
was split into a "neat" sputum aliquot and an aliquot subjected to
ultracentrifugation so that a "supernatant" aliquot was obtained
(neat=cellular; supernatant=liquid phase). Typical studies of
compound metabolism by CF sputum involve the addition of known
masses of test compound to "neat" CF sputum and aliquots of CF
sputum "supernatant" incubated at 37.degree. C., followed by
sequential sampling of aliquots from each sputum type for
characterization of compound stability/metabolism by HPLC analysis
as described above. As above, analysis of compound disappearance,
rates of formation of novel metabolites, and HPLC mobilities of
novel metabolites are then performed.
[0286] 4. Pharmacological Effects and Mechanism of Action of the
Drug in Animals
[0287] The effect of compounds for enhancing mucociliary clearance
(MCC) can be measured using an in vivo model described by Sabater
et al., Journal of Applied Physiology, 1999, pp. 2191-2196,
incorporated herein by reference.
Methods
Animal Preparation:
[0288] Adult ewes (ranging in weight from 25 to 35 kg) were
restrained in an upright position in a specialized body harness
adapted to a modified shopping cart. The animals' heads were
immobilized and local anesthesia of the nasal passage was induced
with 2% lidocaine. The animals were then nasally intubated with a
7.5 mm internal diameter endrotracheal tube (ETT). The cuff of the
ETT was placed just below the vocal cords and its position was
verified with a flexible bronchoscope. After intubation the animals
were allowed to equilibrate for approximately 20 minutes prior to
initiating measurements of mucociliary clearance.
Administration of Radio-Aerosol:
[0289] Aerosols of .sup.99mTc-Human serum albumin (3.1 mg/ml;
containing approximately 20 mCi) were generated using a Raindrop
Nebulizer which produces a droplet with a median aerodynamic
diameter of 3.6 .mu.m. The nebulizer was connected to a dosimetry
system consisting of a solenoid valve and a source of compressed
air (20 psi). The output of the nebulizer was directed into a
plastic T connector; one end of which was connected to the
endrotracheal tube, the other was connected to a piston respirator.
The system was activated for one second at the onset of the
respirator's inspiratory cycle. The respirator was set at a tidal
volume of 500 mL, an inspiratory to expiratory ratio of 1:1, and at
a rate of 20 breaths per minute to maximize the central airway
deposition. The sheep breathed the radio-labeled aerosol for 5
minutes. A gamma camera was used to measure the clearance of
.sup.99mTc-Human serum albumin from the airways. The camera was
positioned above the animal's back with the sheep in a natural
upright position supported in a cart so that the field of image was
perpendicular to the animal's spinal cord. External radio-labeled
markers were placed on the sheep to ensure proper alignment under
the gamma camera. All images were stored in a computer integrated
with the gamma camera. A region of interest was traced over the
image corresponding to the right lung of the sheep and the counts
were recorded. The counts were corrected for decay and expressed as
percentage of radioactivity present in the initial baseline image.
The left lung was excluded from the analysis because its outlines
are superimposed over the stomach and counts can be swallowed and
enter the stomach as radio-labeled mucus.
Treatment Protocol (Assessment of Activity at t-Zero):
[0290] A baseline deposition image was obtained immediately after
radio-aerosol administration. At time zero, after acquisition of
the baseline image, vehicle control (distilled water), positive
control (amiloride), or experimental compounds were aerosolized
from a 4 ml volume using a Pari LC JetPlus nebulizer to
free-breathing animals. The nebulizer was driven by compressed air
with a flow of 8 liters per minute. The time to deliver the
solution was 10 to 12 minutes. Animals were extubated immediately
following delivery of the total dose in order to prevent false
elevations in counts caused by aspiration of excess radio-tracer
from the ETT. Serial images of the lung were obtained at 15-minute
intervals during the first 2 hours after dosing and hourly for the
next 6 hours after dosing for a total observation period of 8
hours. A washout period of at least 7 days separated dosing
sessions with different experimental agents.
Treatment Protocol (Assessment of Activity at t-4 Hours):
[0291] The following variation of the standard protocol was used to
assess the durability of response following a single exposure to
vehicle control (distilled water), positive control compounds
(amiloride or benzamil), or investigational agents. At time zero,
vehicle control (distilled water), positive control (amiloride), or
investigational compounds were aerosolized from a 4 ml volume using
a Pari LC JetPlus nebulizer to free-breathing animals. The
nebulizer was driven by compressed air with a flow of 8 liters per
minute. The time to deliver the solution was 10 to 12 minutes.
Animals were restrained in an upright position in a specialized
body harness for 4 hours. At the end of the 4-hour period animals
received a single dose of aerosolized .sup.99mTc-Human serum
albumin (3.1 mg/ml; containing approximately 20 mCi) from a
Raindrop Nebulizer. Animals were extubated immediately following
delivery of the total dose of radio-tracer. A baseline deposition
image was obtained immediately after radio-aerosol administration.
Serial images of the lung were obtained at 15-minute intervals
during the first 2 hours after administration of the radio-tracer
(representing hours 4 through 6 after drug administration) and
hourly for the next 2 hours after dosing for a total observation
period of 4 hours. A washout period of at least 7 days separated
dosing sessions with different experimental agents.
[0292] Statistics: Data were analyzed using SYSTAT for Windows,
version 5. Data were analyzed using a two-way repeated ANOVA (to
assess overall effects), followed by a paired t-test to identify
differences between specific pairs. Significance was accepted when
P was less than or equal to 0.05. Slope values (calculated from
data collected during the initial 45 minutes after dosing in the
t-zero assessment) for mean MCC curves were calculated using linear
least square regression to assess differences in the initial rates
during the rapid clearance phase.
EXAMPLES
[0293] Having generally described this invention, a further
understanding can be obtained by reference to certain specific
examples which are provided herein for purposes of illustration
only and are not intended to be limiting unless otherwise
specified.
Preparation of Sodium Channel Blockers
[0294] Materials and methods. All reagents and solvents were
purchased from Aldrich Chemical Corp. and used without further
purification. Proton and carbon NMR spectra were obtained on a
Bruker AC 300 spectrometer at 300 MHz and 75 MHz, respectively.
Proton spectra were referenced to tetramethylsilane as an internal
standard and the carbon spectra were referenced to CDCl.sub.3,
CD.sub.3OD, acetone-d.sub.6 or DMSO-d.sub.6 (purchased from Aldrich
or Cambridge Isotope Laboratories, unless otherwise specified).
Melting points were obtained on a MeI-Temp II apparatus and are
uncorrected. ESI Mass spectra were obtained on a Shimadzu LCMS-2010
EV Mass Spectrometer. HLPC analyses were obtained using a Waters
XTerra RP C18 Analytical Column detected at 220 nm (unless
otherwise specified) on a Shimadzu Prominence HPLC system. With a
flow rate of 1.0 mL per minute, the following time program was
utilized:
TABLE-US-00003 Percent A Percent B Time (H.sub.2O with 0.05% TFA)
(CH.sub.3CN with 0.05% TFA) 0:00 90 10 20:00 10 90 30:00 10 90
35:00 90 10
[0295] The following definitions for abbreviations will apply
unless otherwise indicated.
TABLE-US-00004 Abbreviation Definition THF tetrahydrofuran Cbz
Benzyloxycarbonyl i.e. --(CO)O-benzyl AUC Area under the curve or
peak EtOAc Ethyl acetate R.sub.f Retardation factor HPLC High
performance liquid chromatography MTBE Methyl tertiary butyl ether
t.sub.R Retention time GC-MS Gas chromatography-mass spectrometry
wt % Percent by weight h hours min minutes MHz megahertz MeOH
methanol TFA Trifluoroacetic acid UV Ultraviolet
##STR00044## ##STR00045##
Preparation of 4-Bromonaphthol (13)
[0296] To a solution of naphthol (12, 5.0 g, 35 mmol) in CH.sub.3CN
(125 mL) at 0.degree. C. was added N-bromosuccinimide (7.9 g, 45
mmole) in several portions. The reaction mixture was warmed to room
temperature, stirred for 1 h, and concentrated. The residue was
dissolved in EtOAc (500 mL) and the solution was washed with water
(300 mL) and brine (300 mL). The organic layer was dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
column chromatography (silica gel, 4:1 hexanes/EtOAc) to afford
4-bromonaphthol (13, 5.0 g, 64%) as a white solid: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.22-8.16 (m, 2H), 7.62-7.26 (m, 3H), 6.71
(d, J=8.0 Hz, 1H), 5.46 (s, 1H).
Preparation of
(4-Bromonaphthalen-1-yloxy)(tert-butyl)dimethylsilane (14)
[0297] To a solution of imidazole (2.3 g, 34 mmole) and
4-bromonaphthol (13, 5.0 g, 22 mmole) in DMF (10 mL) at 0.degree.
C. was added t-butyldimethylsilyl chloride (3.7 g, 24.6 mmole) in
several portions. The mixture was warmed to room temperature and
stirred for 2 h. The reaction mixture was partitioned between
Et.sub.2O (500 mL) and water (300 mL) and the aqueous layer was
back-extracted with Et.sub.2O (300 mL). The combined organic layers
were washed with water (300 mL) and brine (300 mL), dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
column chromatography (silica gel, hexanes) to afford
(4-bromonaphthalen-1-yloxy)(tert-butyl)dimethylsilane (14, 6.4 g,
85%) as a white solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.21-8.14 (m, 2H), 7.61-7.49 (m, 3H), 6.74 (d, J=8.2 Hz, 1H), 1.10
(s, 9H), 0.28 (s, 6H).
Preparation of tert-Butyl (4-Bromonaphthalen-1-yloxy)dimethylsilane
(15)
[0298] n-Butyllithium (1.6 M in hexanes, 6.8 mL) was added dropwise
to a solution of
(4-bromonaphthalen-1-yloxy)(tert-butyl)dimethylsilane (14, 3.0 g,
9.0 mmole) in anhydrous THF (30 mL) at -78.degree. C. and the
mixture was stirred for 1 h. Iodine (3.4 g, 14 mmole) in THF (20
mL) was added dropwise at the same temperature and the reaction
mixture was stirred for 2 h. The reaction mixture was diluted with
Et.sub.2O (500 mL), washed with 1:1 saturated
Na.sub.2S.sub.2O.sub.3/NaHCO.sub.3 (2.times.300 mL) and 1:1
H.sub.2O/brine (300 mL), dried over MgSO.sub.4, filtered, and
concentrated. The residue was purified by column chromatography
(silica gel, hexanes) to afford tert-butyl
(4-bromonaphthalen-1-yloxy)dimethylsilane (15, 1.8 g, 52%) as a
white solid: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 8.15 (d,
J=8.4 Hz, 1H), 8.02 (d, J=8.6 Hz, 1H), 7.89 (d, J=8.1 Hz, 1H),
7.59-7.47 (m, 2H), 6.64 (d, J=8.1 Hz, 1H), 1.09 (s, 9H), 0.28 (s,
6H).
Preparation of 3-Butyn-1-amine (17)
[0299] To a solution of 4-pentynoic acid (16, 15 g, 150 mmole),
benzyl alcohol (17 mL, 170 mmole), and 4-methyl morpholine (17 mL,
150 mmole) in anhydrous toluene (80 mL) was added dropwise diphenyl
phosphoryl azide (33 mL, 150 mmole) at room temperature. The
reaction mixture was stirred for 15 min. The reaction temperature
was carefully raised to 60-70.degree. C., during which vigorous
efflorescence was observed. The reaction mixture was stirred at the
same temperature for 2 h and then at 110.degree. C. for 18 h. The
reaction mixture was cooled to room temperature and concentrated to
a thick brown slurry. The residue was dissolved in CH.sub.2Cl.sub.2
(300 mL) and the solution was stirred for an additional 30 min. The
mixture was washed with water (2.times.300 mL) and the combined
aqueous layers were back-extracted with CH.sub.2Cl.sub.2
(2.times.300 mL). The combined organic layers were dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
column chromatography (silica gel, 4:1 hexanes/EtOAc) to afford
amine 17 (16 g, 52%) as a light yellow oil: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.37-7.33 (m, 5H), 5.11 (br s, 3H), 3.36 (q,
J=6.4 Hz, 2H), 2.41 (td, J=6.4, 2.4 Hz, 2H), 1.99 (t, J=2.6 Hz,
1H).
Preparation of Benzyl
4-[4-(tert-Butyldimethylsilyloxy)naphthalen-1-yl]-3-butynylcarbamate
(18)
[0300] A solution of tert-butyl
(4-bromonaphthalen-1-yloxy)dimethylsilane (15, 3.1 g, 8.2 mmole),
amine 17 (3.3 g, 16 mmole), and triethyl amine (4.5 mL, 33 mmole)
in CH.sub.3CN (70 mL) pre-cooled to -78.degree. C. was degassed
with argon. Tri-tert-butyl phosphine (10% in hexanes, 3.3 g, 1.6
mmole), Pd(PPh.sub.3).sub.4 (940 mg, 0.82 mmole), and CuI (78 mg,
0.41 mmole) were added rapidly in one portion at the same
temperature. The mixture was warmed to -30.degree. C. and shaken
until a homogeneous solution was formed, then cooled to -78.degree.
C., and degassed with argon. The mixture was warmed to room
temperature and stirred for 18 h. Water (10 mL) was added to the
reaction mixture and the mixture was concentrated. The residue was
diluted with EtOAc (500 mL) and the organic layer was washed with
water (300 mL) and brine (300 mL), dried over Na.sub.2SO.sub.4,
filtered, and concentrated. The residue was purified by column
chromatography (silica gel, 4:1 hexanes/EtOAc) to afford carbamate
18 (2.0 g, 52%) as a light yellow oil: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.24-8.16 (m, 2H), 7.53-7.45 (m, 3H), 7.38-7.30
(m, 5H), 6.77 (d, J=7.9 Hz, 1H), 5.14 (br s, 3H), 3.56-3.49 (m,
2H), 2.76 (t, J=6.5 Hz, 2H), 1.09 (s, 9H), 0.29 (s, 6H).
Preparation of Benzyl
4-[4-(tert-Butyldimethylsilyloxy)naphthalen-1-yl]butylcarbamate
(19)
[0301] A solution of carbamate 18 (2.0 g, 4.3 mmole) and 10% Pd/C
(300 mg) in MeOH (60 mL) was subjected to hydrogenation conditions
(50 psi) for 8 h at room temperature. The reaction mixture was
filtered through a plug of diatomaceous earth and the plug was
washed with MeOH (2.times.20 mL). The filtrate was then
concentrated in vacuo to afford crude amine (1.4 g) which was
dissolved in 1:1 CH.sub.2Cl.sub.2/NaHCO.sub.3 (saturated solution)
(30 mL). Benzyl chloroformate (0.62 mL) was added dropwise at room
temperature and the reaction mixture was stirred for 1 h. The
mixture was concentrated, the residue was dissolved in EtOAc (500
mL), and the solution was washed with water (300 mL) and brine (300
mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified by column chromatography
(silica gel, 4:1 hexanes/EtOAc) to afford butylcarbamate 19 (1.5 g,
77%) as a light yellow oil: .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 8.24 (m, 1H), 7.91 (d, J=7.4 Hz, 1H), 7.51-7.42 (m, 2H),
7.34-7.28 (m, 5H), 7.12 (d, J=7.6 Hz, 1H), 6.77 (d, J=7.6 Hz, 1H),
5.08 (br s, 2H), 4.75 (br s, 1H), 3.22 (q, J=6.4 Hz, 2H), 2.99 (q,
J=7.4 Hz, 2H), 1.76-1.71 (m, 2H), 1.67-1.56 (m, 2H), 1.09 (s, 9H),
0.27 (s, 6H).
Preparation of Benzyl 4-(4-Hydroxynaphthalen-1-yl)butylcarbamate
(20)
[0302] Tetrabutylammonium fluoride (1 M in THF, 1.0 mL) was added
to a solution of benzyl
4-[4-(tert-butyldimethylsilyloxy)naphthalen-1-yl]butylcarbamate
(19, 380 mg, 0.80 mmol) in anhydrous THF (15 ml) at room
temperature. The reaction mixture was stirred for 2 h and
concentrated to dryness. The residue was purified by column
chromatography (silica gel, 3:1 hexanes/EtOAc) to afford
butylcarbamate 20 (287 mg, 99%) as white solid: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 8.23-8.21 (m, 1H), 7.84-7.81 (m, 1H),
7.42-7.34 (m, 2H), 7.25-7.15 (m, 5H), 6.96 (d, J=7.5 Hz, 1H), 6.62
(d, J=7.5 Hz, 1H), 5.00 (br s, 2H), 4.65 (br s, 1H), 3.13 (q, J=6.6
Hz, 2H), 2.87 (t, J=7.5 Hz, 2H), 1.64-1.47 (m, 4H).
Preparation of Benzyl
4-[4-(2,3-Dihydroxypropoxy)naphthalen-1-yl]butylcarbamate (22)
[0303] A solution of benzyl
4-(4-hydroxynaphthalen-1-yl)butylcarbamate (20, 287 mg, 0.82
mmole), oxiran-2-ylmethanol (21, 0.07 mL, 1.00 mmole) and
triethylamine (0.01 mL, 0.05 mmole) in absolute EtOH (9.28 mL) was
subjected to microwave irradiation at 130.degree. C. for 30 min.
The reaction mixture was concentrated in vacuo and the residue was
purified by column chromatography (silical gel, 95:5
CH.sub.2Cl.sub.2/MeOH) to afford butylcarbamate 22 (293 mg, 83%) as
a light yellow thick oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta.
8.24 (d, J=7.7 Hz, 1H), 7.94 (d, J=8.1 Hz, 1H), 7.52-7.45 (m, 2H),
7.37-7.28 (m, 5H), 7.18 (d, J=7.7 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H),
5.09 (br s, 2H), 4.71 (br s, 1H), 4.29-4.20 (m, 3H), 3.98-3.81 (m,
2H), 3.23 (q, J=6.5 Hz, 2H), 3.00 (t, J=7.5 Hz, 2H), 2.65 (d, J=4.5
Hz, 1H), 2.06 (t, J=5.8 Hz, 1H), 1.83-1.53 (m, 4H).
Preparation of
3-[4-(4-Aminobutyl)naphthalen-1-yloxy]propane-1,2-diol (23)
[0304] A solution of benzyl
4-[4-(2,3-dihydroxypropoxy)naphthalen-1-yl]butylcarbamate (22, 340
mg, 0.80 mmole) and 10% Pd/C (50 mg) in MeOH (50 mL) was subjected
to hydrogenation conditions (1 atm) for 2 h at room temperature.
The reaction mixture was filtered through a plug of diatomaceous
earth and the plug was washed with MeOH. The filtrate was then
concentrated in vacuo to afford diol 23 (226 mg, 97%) as a yellow
solid: MS m/z 290 [C.sub.17H.sub.23NO.sub.3+H].sup.+. Diol 23 was
used in the next step without further purification.
Preparation of
2,4-Diamino-5-chloro-N-{N-[4-(4-(2,3-dihydroxypropoxy)naphthalen-1-yl)but-
yl]carbamimidoyl}benzamide (24)
[0305] To a solution of
3-[4-(4-aminobutyl)naphthalen-1-yloxy]propane-1,2-diol (23, 226 mg,
0.78 mmole) and methyl
3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 455
mg, 1.17 mmole) in EtOH (10 mL) was added diisopropylethylamine
(0.82 mL, 4.69 mmole) at room temperature. The reaction mixture was
heated at 70.degree. C. in a sealed tube for 7 h, then cooled to
room temperature, and concentrated in vacuo. The residue was
purified by column chromatography (silica gel, 80:18:2
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford benzamide 24 (140 mg,
36%) as a yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
8.31 (d, J=8.2 Hz, 1H), 7.98 (d, J=8.2 Hz, 1H), 7.53-7.40 (m, 2H),
7.23 (d, J=7.9 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.22-4.10 (m, 3H),
3.84-3.72 (m, 2H), 3.31-3.25 (m, 2H), 3.08-3.03 (m, 2H), 1.89-1.70
(m, 4H).
Preparation of
3,5-Diamino-6-chloro-N-(N-{4-[6-(2,3-dihydropropoxy)naphthalen-2-yl]butyl-
}carbamimidoyl)pyrazine-2-carboxamide Methanesulfonic Acid Salt
(25)
[0306] To a solution of
3,5-diamino-6-chloro-N-(N-{4-[6-(2,3-dihydropropoxy)naphthalen-2-yl]butyl-
}carbamimidoyl)pyrazine-2-carboxamide (24, 119 mg, 0.24 mmole) in
EtOH (5 mL) was added methanesulfonic acid (22.7 mg, 0.24 mmole) at
room temperature. The reaction mixture was stirred for 15 min. The
solution was concentrated and the residue was azeotroped with MeOH.
The residue was dissolved in H.sub.2O (4 mL) and lyophilized to
afford methanesulfonic acid salt 25 (130 mg, 92%) as a yellow
solid: mp 129-132.degree. C.; .sup.1H NMR (300 MHz, DMSO-d.sub.6)
.delta. 10.45 (br s, 1H), 9.12 (br s, 1H), 8.86 (br s, 1H), 8.70
(br s, 1H), 8.27 (dd, J=8.0, 1.3 Hz, 1H), 8.02 (d, J=8.2 Hz, 1H),
7.59-7.49 (m, 2H), 7.47 (br s, 2H), 7.26 (d, J=7.8, 1H), 6.87 (d,
J=7.9 Hz, 1H), 5.06 (d, J=4.7 Hz, 1H), 4.71 (t, J=5.4, 1H),
4.16-3.93 (m, 3H), 3.55 (td, J=5.6, 1.5 Hz, 2H), 3.16 (d, J=5.3 Hz,
2H), 3.00 (t, J=7.0 Hz, 2H), 2.29 (s, 3H), 1.76-1.57 (m, 4H);
ESI-MS m/z 524 [C.sub.23H.sub.28ClN.sub.7O.sub.4+H].sup.+.
Preparation of
2,4-Diamino-5-chloro-N-(N-{4-[4-(2,3-dihydroxypropoxy)naphthalen-1-yl]but-
yl}carbamimidoyl)benzamide L-(+)-Lactic Acid Salt (26)
[0307] To a solution of
2,4-diamino-5-chloro-N-(N-{4-[4-(2,3-dihydroxypropoxy)naphthalen-1-yl]but-
yl}carbamimidoyl)benzamide (24, 28 mg, 0.06 mmole) in EtOH (10 mL)
was added L-(+)-lactic acid (5.20 mg, 0.06 mmole) at room
temperature and the reaction mixture was stirred for 15 min. The
solution was concentrated and the residue was azeotroped with MeOH.
The residue was dissolved in H.sub.2O (3 mL) and lyophilized to
afford lactic acid salt 26 (28 mg, 84%) as a yellow solid: mp
115-118.degree. C.; .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.32
(d, J=8.4 Hz, 1H), 8.01 (d, J=8.4 Hz, 1H), 7.53-7.40 (m, 2H), 7.24
(d, J=7.8 Hz, 1H), 6.83 (d, J=7.8 Hz, 1H), 4.21-4.10 (m, 3H),
4.01-3.94 (m, 1H), 3.82-3.73 (m, 2H), 3.35-3.33 (m, 2H), 3.08 (t,
J=7.0, Hz, 1H), 1.89-1.77 (m, 4H), 1.31 (d, J=7.0 Hz, 3H); ESI-MS
m/z 524 [C.sub.23H.sub.28ClN.sub.7O.sub.4+H].sup.+.
##STR00046## ##STR00047##
Preparation of
(6-Bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (28)
[0308] A solution of 6-bromonaphthalen-2-ol (5.0 g, 22.4 mmol) and
imidazole (2.3 g, 33.6 mmole) in N,N-dimethylformamide (DMF) (5.0
mL) was added t-butyldimethylsilyl chloride (TBDMSCl) (3.7 g, 24.6
mmole) in one portion at 0.degree. C. The mixture was allowed to
warm to room temperature and stirred for 3 h. The reaction mixture
was partitioned between EtOAc (500 mL) and water (300 mL). The
aqueous layer was separated and extracted with EtOAc (2.times.100
mL) and the combined organic extracts were washed with brine (300
mL), dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by column chromatography (silica gel, hexanes)
to afford (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane
(28, 7.4 g, 98%) as a white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.91 (d, J=1.8 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H),
7.56 (d, J=8.7 Hz, 1H), 7.48 (dd, J=8.7, 1.8 Hz, 1H), 7.15 (d,
J=2.4 Hz, 1H), 7.09 (dd, J=9.0, 2.4 Hz, 1H), 1.01 (s, 9H), 0.24 (s,
6H).
Preparation of Benzyl
4-[6-(tert-Butyldimethylsilyloxy)naphthalen-2-yl]but-3-ynylcarbamate
(29)
[0309] A solution of
(6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (28, 3.4 g,
10.0 mmol), benzyl but-3-ynylcarbamate (17, 2.0 g, 10 mmole), and
triethylamine (20 mL) in anhydrous THF (60 mL) pre-cooled to
-78.degree. C. was degassed with argon. The mixture was warmed to
room temperature and dichlorobis(triphenylphosphine)palladium(II)
(PdCl.sub.2(PPh.sub.3).sub.2 (702 mg, 1 mmole) and CuI (381 mg, 2
mmole) were added rapidly in one portion under argon. The mixture
was heated at 60.degree. C. for 4 h, then at room temperature for
48 h. The reaction mixture was filtered through a plug of
diatomaceous earth and the filtrate was partitioned between EtOAc
(500 mL) and 1 N HCl (200 mL). The aqueous layer was separated and
back-extracted with EtOAc (300 mL) The combined organic extracts
were washed with water (300 mL) and brine (300 mL), dried over
Na.sub.2SO.sub.4, filtered, and concentrated. The residue was
purified by column chromatography (silical gel, 10:1 hexanes/EtOAc)
to afford carbamate 29 (1.24 g, 37%) as a brown thick oil: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.83 (s, 1H), 7.65 (d, J=9.0 Hz,
1H), 7.60 (d, J=8.7 Hz, 1H), 7.39-7.29 (m, 6H), 7.13 (d, J=2.1 Hz,
1H), 7.07 (dd, J=8.7, 2.4 Hz, 1H), 5.17 (br s, 1H), 5.13 (s, 2H),
3.46 (q, J=6.3 Hz, 2H), 2.67 (t, J=6.3 Hz, 2H), 1.01 (s, 9H), 0.25
(s, 6H).
Preparation of Benzyl
4-(6-Hydroxynaphthalen-2-yl)but-3-ynylcarbamate (30)
[0310] To a solution of benzyl
4-[6-(tert-butyldimethylsilyloxy)naphthalen-2-yl]but-3-ynylcarbamate
(29, 578 mg, 1.26 mmol) in anhydrous THF (60 mL) was added dropwise
tetrabutylammonium fluoride (1 M in THF, 1.38 mL) and the mixture
was stirred for 2 h at room temperature. The resulting solution was
concentrated in vacuo and the residue was purified by column
chromatography (silical gel, 95:5 CH.sub.2Cl.sub.2/MeOH) to afford
carbamate 30 (418 mg, 96%) as a pale yellow solid: .sup.1H NMR (300
MHz, CDCl.sub.3) .delta. 7.82 (s, 1H), 7.67 (d, J=9.6 Hz, 1H), 7.58
(d, J=8.4 Hz, 1H), 7.37-7.29 (m, 6H), 7.11-7.08 (m, 2H), 5.30 (br
s, 2H), 5.14 (s, 2H), 3.48 (q, J=6.3 Hz, 2H), 2.68 (t, J=6.6 Hz,
2H).
Preparation of Benzyl
4-[6-(2,3-Dihydroxypropoxy)naphthalen-2-yl]but-3-ynylcarbamate
(31)
[0311] A solution of
4-(6-hydroxynaphthalen-2-yl)but-3-ynylcarbamate (30, 390 mg, 1.1
mmole), oxiran-2-ylmethanol (21, 0.1 mL, 1.4 mmole), and
triethylamine (0.01 mL, 0.06 mmole) in absolute EtOH (8.8 mL) was
subjected to microwave irradiation at 130.degree. C. for 30 min.
The reaction mixture was concentrated in vacuo and the residue was
purified by column chromatography (silical gel, 95:5
CH.sub.2Cl.sub.2/MeOH) to afford carbamate 31 (236 mg, 42%) as a
white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.80 (s,
1H), 7.68 (dd, J=8.7, 3.9 Hz, 2H), 7.38-7.16 (m, 8H), 5.10 (s, 2H),
4.18 (dd, J=9.6, 4.2 Hz, 1H), 4.11-4.01 (m, 2H), 3.76-3.67 (m, 2H),
3.39-3.31 (m, 4H), 2.63 (t, J=6.9 Hz, 2H).
Preparation of
3-[6-(4-Aminobutyl)naphthalen-2-yloxy]propane-1,2-diol (32)
[0312] A suspension of benzyl
4-[6-(2,3-dihydroxypropoxy)naphthalen-2-yl]but-3-ynylcarbamate (31,
236 mg, 0.5 mmole) and 10% Pd/C (96 mg) in MeOH (70 mL) was
subjected to hydrogenation conditions (1 atm) for 1 h at room
temperature. The reaction mixture was filtered through a plug of
diatomaceous earth and the plug was washed with MeOH. The filtrate
was then concentrated in vacuo to afford diol 32 (123 mg, 78%) as a
white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.67 (d,
J=8.4 Hz, 2H), 7.56 (s, 1H), 7.30 (dd, J=8.4, 1.5 Hz, 1H), 7.20 (d,
J=2.4 Hz, 1H), 7.14 (dd, J=8.7, 2.4 Hz, 1H), 4.18-3.99 (m, 3H),
3.76-3.65 (m, 2H), 2.75 (dt, J=10.8, 7.2 Hz, 4H), 1.80-1.70 (m,
2H), 1.62-1.52 (m, 2H).
Preparation of
3,5-Diamino-6-chloro-N-(N-{4-[6-(2,3-dihydropropoxy)naphthalen-2-yl]butyl-
}carbamimidoyl)pyrazine-2-carboxamide (33)
[0313] To a solution of
3-[6-(4-aminobutyl)naphthalen-2-yloxy]propane-1,2-diol (32, 51 mg,
0.2 mmole) and methyl
3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 103
mg, 0.3 mmole) in EtOH (2 mL) was added diisopropylethylamine (0.2
mL, 1.1 mmole) at room temperature. The reaction mixture was heated
at 70.degree. C. in a sealed tube for 7 h, then cooled to room
temperature, and concentrated in vacuo. The residue was purified by
column chromatography (silica gel, 80:18:2
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford carboxamide 33 (34 mg,
68%) as a yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.67 (d, J=8.7 Hz, 2H), 7.56 (s, 1H), 7.30 (dd, J=8.4, 1.5 Hz, 1H),
7.19 (d, J=2.4 Hz, 1H), 7.13 (dd, J=9.0, 2.4 Hz, 1H), 4.22-3.99 (m,
3H), 3.76-3.65 (m, 2H), 3.25-3.23 (m, 2H), 2.79 (t, J=7.2 Hz, 2H),
1.84-1.65 (m, 4H).
Preparation of
3,5-Diamino-6-chloro-N-(N-{4-[6-(2,3-dihydropropoxy)naphthalen-2-yl]butyl-
}carbamimidoyl)pyrazine-2-carboxamide Methanesulfonic Acid Salt
(34)
[0314] To a solution of
3,5-diamino-6-chloro-N-(N-{4-[6-(2,3-dihydropropoxy)naphthalen-2-yl]butyl-
}carbamimidoyl)pyrazine-2-carboxamide (33, 190 mg, 0.4 mmole) in
EtOH (10 mL) was added methanesulfonic acid (72.7 mg, 0.8 mmole) at
room temperature and the reaction mixture was stirred for 15 min.
The solution was concentrated and the residue was azeotroped with
MeOH. The residue was dissolved in 8:2 MeOH/H.sub.2O (10 mL) and
lyophilized to afford methanesulfonic acid salt 34 (185 mg, 81%) as
a yellow solid: mp 146-149.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.4 (s, 1H), 9.14 (br s, 1H), 8.87 (br s,
1H), 8.71 (br s, 1H), 7.74 (d, J=8.7 Hz, 2H), 7.62 (s, 1H), 7.44
(br s, 2H), 7.34 (dd, J=8.4, 0.9 Hz, 1H), 7.26 (d, J=2.1 Hz, 1H),
7.14 (dd, J=9.0, 2.4 Hz, 1H), 5.76 (s, 1H), 4.09 (dd, J=9.9, 4.2
Hz, 1H), 3.98-3.81 (m, 2H), 3.48 (d, J=5.4 Hz, 2H), 3.32 (q, J=5.7
Hz, 2H), 2.75 (t, J=7.2 Hz, 2H), 2.34 (s, 6H), 1.72-1.59 (m, 4H);
ESI-MS m/z 502 [C.sub.23H.sub.28ClN.sub.7O.sub.4+H].sup.+.
##STR00048## ##STR00049##
Preparation of Benzyl 4-(4-Hydroxynaphthalen-1-yl)butylcarbamate
(20)
[0315] Tetrabutylammoniumfluoride (1.0 M in THF, 1.1 mL) was added
to a solution of benzyl
4-[4-(tert-butyldimethylsilyloxy)naphthalen-1-yl]butylcarbamate
(19, 500 mg, 1.1 mmole) in THF (5 ml) at room temperature. The
reaction mixture was stirred for 2 h. The reaction mixture was
concentrated to dryness. The residue was purified by column
chromatography (silica gel, 3:1 hexanes/EtOAc) to afford carbamate
20 (230 mg, 61%) as a white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 8.25-8.21 (m, 1H), 7.91 (dd, J=6.6, 1.8 Hz,
1H), 7.52-7.43 (m, 2H), 7.35-7.27 (m, 5H), 7.05 (d, J=7.5 Hz, 1H),
6.72 (d, J=7.5 Hz, 1H), 5.10 (s, 2H), 4.75 (br s, 1H), 3.23 (q,
J=6.6 Hz, 2H), 2.95 (t, J=7.2 Hz, 2H), 1.76-1.56 (m, 4H).
Preparation of tert-Butyl 3-Hydroxypropylcarbamate (67)
[0316] To a solution of 3-aminopropanol (66, 5.0 g, 67 mmole) in
1:1 dioxane/2 N NaOH (100 mL) was added di-tert-butyl dicarbonate
(17.0 g, 80 mmole) in dioxane (10 mL) at 0.degree. C. The reaction
mixture was warmed to room temperature and stirred for 1 h. The
mixture was first acidified to pH 1 with concentrated HCl and then
neutralized to pH 7 with 2 N NaOH. The mixture was then extracted
with EtOAc (3.times.200 mL). The combined organic layers were dried
over MgSO.sub.4 and concentrated. The residue was purified by
column chromatography (silica gel, 3:1 hexanes/EtOAc) to afford
tert-butyl 3-hydroxypropylcarbamate (67, 11.0 g, 94%) as a light
yellow oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 4.80 (br s,
1H), 3.66 (q, J=5.7 Hz, 2H), 3.33 (q, J=6.3 Hz, 2H), 2.97 (br s,
1H), 1.71-1.63 (m, 2H), 1.45 (s, 9H).
Preparation of Compound (68)
[0317] Diisopropylazodicarboxylate (120 mg, 0.59 mmole) was added
dropwise to a solution of benzyl
4-(4-hydroxynaphthalen-1-yl)butylcarbamate (20, 206 mg, 0.59
mmole), tert-butyl 3-hydroxypropylcarbamate (67, 104 mg, 0.59
mmole), and triphenylphosphine (187 mg, 0.71 mmole) in anhydrous
THF (5 mL) at 0.degree. C. The reaction mixture was warmed to room
temperature and stirred for 5 h. The reaction mixture was
concentrated and the residue was purified by column chromatography
(silica gel, 2:1 hexanes/EtOAc) to afford a mixture of ether 68 and
hydrazine byproduct (630 mg) which was used in the next step
without further purification.
Preparation of tert-Butyl
3-[4-(4-Aminobutyl)naphthalene-1-yloxy]propylcarbamate (69)
[0318] A suspension of mixture 68 (630 mg) and 10% Pd/C (300 mg) in
MeOH (25 mL) was subject to hydrogenation conditions (1 atm) for 1
h at room temperature. The reaction mixture was filtered through a
plug of diatomaceous earth and the plug was washed with MeOH. The
filtrate was concentrated in vacuo and the residue was purified by
column chromatography (silica gel, 80:18:2
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford carbamate 69 (260 mg,
68% over two steps) as a white solid: .sup.1NMR (300 MHz,
CD.sub.3OD) .delta. 8.28 (dd, J=8.4, 1.2 Hz, 1H), 7.98 (d, J=8.1
Hz, 1H), 7.55-7.42 (m, 2H), 7.22 (d, J=7.8 Hz, 1H), 6.79 (d, J=8.1
Hz, 1H), 4.15 (t, J=6.0 Hz, 2H), 3.32-3.30 (m, 2H), 3.05 (t, J=6.9
Hz, 2H), 2.90 (t, J=7.5 Hz, 2H), 2.11-2.03 (m, 2H), 1.79-1.68 (m,
4H), 1.42 (s, 9H).
Preparation of tert-Butyl
3-{4-[4-(3-(3,5-Diamino-6-chloropyrazine-2-carbonyl)guanidine)butyl]napht-
halen-1-yloxy}propylcarbamate (70)
[0319] To a solution of tert-butyl
3-[4-(4-aminobutyl)naphthalene-1-yloxy]propylcarbamate (69, 350 mg,
0.94 mmole) and methyl
3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 600
mg, 1.41 mmole) in EtOH (20 mL) was added diisopropylethylamine
(1.6 mL, 5.2 mmole) at room temperature. The reaction mixture was
heated at 70.degree. C. in a sealed tube for 7 h, cooled to room
temperature and concentrated to dryness. The residue was dissolved
in CHCl.sub.3 (300 mL) and washed with saturated NaHCO.sub.3
(2.times.200 mL). The organic layer was dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by column
chromatography (silica gel, 90:9:1
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford carbamate 70 (350 mg,
64%) as a light yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 8.27 (dd, J=8.1, 0.9 Hz, 1H), 7.99 (d, J=8.1 Hz, 1H), 7.50
(td, J=6.6, 1.2 Hz, 1H), 7.42 (td, J=6.6, 1.2 Hz, 1H), 7.23 (d,
J=7.8 Hz, 1H), 6.80 (d, J=7.8 Hz, 1H), 4.17 (t, J=6.0 Hz, 2H),
3.66-3.54 (m, 2H), 3.16-3.05 (m, 4H), 2.12-2.03 (m, 2H), 1.84-1.76
(m, 4H), 1.41 (s, 9H).
Preparation of
3,5-Diamino-N-(N-{4-[4-(3-aminopropoxy)naphthalen-1-yl]butyl}carbamimidoy-
l)-6-chloropyrazine-2-carboxamide (71)
[0320] To a solution of carbamate 70 (350 mg, 0.6 mmole) in
CH.sub.2Cl.sub.2 (35 mL) was added dropwise trifluoroacetic acid
(2.0 mL) at room temperature. The reaction mixture was stirred for
3 h. The reaction mixture was concentrated in vacuo and azeotroped
with MeOH (2.times.100 mL). The residue was dissolved in water and
the solution was neutralized with saturated NaHCO.sub.3 which
resulted in the precipitation of carboxamide 71. Compound 71 was
collected by filtration and purified by column chromatography
(silica gel, 80:18:2 CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford
amine 71 (185 mg, 64%) as an off-white solid: .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 8.23 (dd, J=8.1, 0.6 Hz, 1H), 7.99 (d, J=8.1
Hz, 1H), 7.50 (td, J=6.9, 1.5 Hz, 1H), 7.41 (td, J=6.9, 1.2 Hz,
1H), 7.22 (d, J=7.8 Hz, 1H), 6.81 (d, J=7.8 Hz, 1H), 4.20 (t, J=6.3
Hz, 2H), 3.25 (t, J=6.3 Hz, 2H), 3.05 (t, J=6.9 Hz, 2H), 2.97 (t,
J=6.9 Hz, 2H), 2.14-2.05 (m, 2H), 1.89-1.69 (m, 4H).
Preparation of
3,5-Diamino-N-(N-[4-{4-(3-aminopropoxy)naphthalen-1-yl]butyl}carbamimidoy-
l)-6-chloropyrazine-2-carboxamide Methanesulfonic Acid Salt
(72)
[0321] To a solution of carboxamide 71 (120 mg, 0.247 mmole) in
EtOH (10 mL) was added methanesulfonic acid (48 mg, 0.495 mmole) at
room temperature and the reaction mixture was stirred for 15 min.
The solvent was removed in vacuo. The residue was dissolved in
water (10 mL) and lyophilized to afford methanesulfonic acid salt
72 (160 mg, 95%) as a yellow solid: .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.44 (s, 1H), 9.15 (br s, 1H), 8.86 (br s,
1H), 8.72 (br s, 1H), 8.22 (dd, J=8.1, 0.9, Hz, 1H), 8.03 (d, J=8.1
Hz, 1H), 7.80 (br s, 4H), 7.61-7.49 (m, 3H), 7.42 (br s, 2H), 7.28
(d, J=7.8 Hz, 1H), 6.89 (d, J=7.8 Hz, 1H), 4.22 (t, J=5.7 Hz, 2H),
3.35-3.33 (m, 2H), 3.17-2.99 (m, 4H), 2.32 (s, 6H), 2.20-2.10 (m,
2H), 1.68 (br s, 4H); ESI-MS m/z 485
[C.sub.23H.sub.29ClN.sub.8O.sub.2+H].sup.+.
##STR00050##
Preparation of Compound (74)
[0322] To a solution of amine 71 (60 mg, 0.12 mmole) and Goodman's
reagent 73 (100 mg, 0.19 mmole) in MeOH (10 mL) was added
diisopropylethylamine (0.2 mL, 1.0 mmole) at room temperature. The
reaction mixture was stirred for 6 h and then concentrated. The
residue was dissolved in CHCl.sub.3 (100 mL) and washed with
saturated NaHCO.sub.3 (2.times.100 mL). The organic layer was dried
over MgSO.sub.4, filtered, and concentrated. The residue was
purified by column chromatography (silica gel, 90:9:1
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford 74 (82 mg, 92%) as a
light yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 8.26
(dd, J=8.1, 0.9 Hz, 1H), 7.96 (d, J=8.1 Hz, 1H), 7.48 (td, J=6.6,
1.2 Hz, 1H), 7.41 (td, J=6.9, 1.2 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H),
6.77 (d, J=7.8 Hz, 1H), 4.19 (t, J=5.7 Hz, 2H), 3.65 (t, J=6.6 Hz,
2H), 3.25 (t, J=6.6 Hz, 2H), 3.01 (t, J=7.2 Hz, 2H), 2.22-2.14 (m,
2H), 1.82-1.65 (m, 4H), 1.41 (s, 9H), 1.42 (s, 9H).
Preparation of Compound (75)
[0323] To a solution of compound 74 (130 mg, 0.18 mmole) in
CH.sub.2Cl.sub.2 (20 mL) was added dropwise trifluoroacetic acid
(2.5 mL) at room temperature. The reaction mixture was stirred for
6 h and the solvent was removed in vacuo. The residue was dissolved
in water (10 mL) and the solution was basified to pH 10 with 2 N
NaOH which resulted in the precipitation of crude 75. Compound 75
was collected by filtration and purified by column chromatography
(silica gel, 6:3:1 CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford
compound 75 (48 mg, 51%) as a light yellow solid: .sup.1H NMR (300
MHz, CD.sub.3OD) .delta. 8.27 (dd, J=8.1, 0.9 Hz, 1H), 8.01 (d,
J=8.1 Hz, 1H), 7.53 (td, J=6.9, 1.5 Hz, 1H), 7.45 (td, J=6.9, 1.2
Hz, 1H), 7.26 (d, J=7.8 Hz, 1H), 6.85 (d, J=7.8 Hz, 1H), 4.24 (t,
J=6.0 Hz, 2H), 3.51 (t, J=6.9 Hz, 2H), 3.35-3.33 (m, 2H), 3.08 (t,
J=6.9 Hz, 2H), 2.24-2.19 (m, 2H), 1.84-1.80 (m, 4H).
Preparation of Methanesulfonic Acid Salt (76)
[0324] To a solution of compound 75 (48 mg, 0.09 mmole) in EtOH (5
mL) was added CH.sub.3SO.sub.3H (17.5 mg, 0.18 mmole) at room
temperature and the reaction mixture was stirred for 15 min. The
solvent was removed in vacuo. The residue was dissolved in water (5
mL) and lyophilized to afford methanesulfonic salt 76 (60 mg, 90%)
as a yellow solid: mp 85-87.degree. C.; .sup.1H NMR (300 MHz,
DMSO-d.sub.6) .delta. 10.44 (s, 1H), 9.15 (br s, 1H), 8.86 (br s,
1H), 8.70 (br s, 1H), 8.24 (dd, J=8.1, 1.5 Hz, 1H), 8.03 (d, J=8.4
Hz, 1H), 7.66-7.42 (m, 6H), 7.42 (br s 2H), 7.28 (d, J=6.9 Hz, 2H),
7.10 (s, 1H), 6.90 (t, J=6.0 Hz, 2H), 4.18 (t, J=6.0 Hz, 2H),
3.43-3.33 (m, 4H), 3.01 (t, J=6.9 Hz, 2H), 2.33 (s, 9H), 2.11-2.06
(m, 2H), 1.68 (br s, 4H); ESI-MS m/z 528
[C.sub.24H.sub.31ClN.sub.10O.sub.2+H].sup.+.
##STR00051##
Preparation of
4-[6-(tert-Butyldimethylsilyloxy)naphthalen-2-yl]butan-1-amine
(77)
[0325] A suspension of crude 29 (900 mg) and 10% Pd/C (400 mg) in
MeOH (50 mL) was subject to hydrogenation conditions (1 atm) for 6
h at room temperature. The reaction mixture was filtered through a
plug of diatomaceous earth and the plug was washed with MeOH. The
filtrate was concentrated in vacuo and the residue was purified by
column chromatography (silica gel, 80:18:2
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford amine 77 (405 mg, 27%
over two steps) as a white solid: .sup.1H NMR (300 MHz, CDCl.sub.3)
.delta. 7.62 (t, J=8.9, 2H), 7.52 (br s, 1H), 7.26 (dd, J=8.4, 1.7
Hz, 1H), 7.15 (d, J=2.2 Hz, 1H), 7.04 (dd, J=8.8, 2.5 Hz, 1H),
3.03-2.37 (br s, 1H), 2.74 (t, J=7.5 Hz, 2H), 1.78-1.65 (m, 2H),
1.58-1.47 (m, 2H), 1.01 (s, 9H), 0.23 (s, 6H).
Preparation of
3,5-Diamino-N-(N-{4-[6-(tert-butyldimethylsilyloxy)naphthalen-2-yl]butyl}-
carbamimidoyl)-6-chloropyrazine-2-carboxamide (78)
[0326] To a solution of amine 77 (337 mg, 1.02 mmole) and methyl
3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 596
mg, 1.53 mmole) in EtOH (20 mL) was added diisopropylethylamine
(1.06 mL, 6.13 mmole) at room temperature. The reaction mixture was
heated at 70.degree. C. in a sealed tube for 6 h, then cooled to
room temperature, and concentrated to dryness. The residue was
purified by column chromatography (silica gel, 80:18:2
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford carboxamide 78 (280 mg,
50%) as a light yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.67 (d, J=9.2 Hz, 1H), 7.63 (d, J=8.6 Hz, 1H), 7.57 (br s,
1H), 7.30 (d, J=8.1 Hz, 1H), 7.14 (br s, 1H), 7.03 (dd, J=9.2, 1.7
Hz, 1H), 3.30 (m, 2H), 2.81 (t, J=7.0 Hz, 2H), 1.95-1.62 (m, 4H),
1.03 (s, 9H), 0.24 (s, 6H).
Preparation of
3,5-Diamino-6-chloro-N-{N-[4-(6-hydroxynaphthalen-2-yl)butyl]carbamimidoy-
l}pyrazine-2-carboxamide (79)
[0327] To a solution of carboxamide 78 (24 mg, 0.05 mmol) in
absolute ethanol (5 mL) was added dropwise 1 N HCl (2 mL) at room
temperature and the mixture was stirred for 12 h. The reaction
mixture was neutralized with saturated NaHCO.sub.3 and compound 79
precipitated out. Compound 79 was collected by filtration and
washed with water (2.times.10 mL) and hexanes (2.times.10 mL) to
afford
3,5-diamino-6-chloro-N-{N-[4-(6-hydroxynaphthalen-2-yl)butyl]carbamimidoy-
l}pyrazine-2-carboxamide (79, 10 mg, 53%), after air-drying, as a
light yellow solid: .sup.111NMR (300 MHz, CD.sub.3OD) .delta.
7.63-7.53 (m, 3H), 7.26 (dd, J=8.3, 1.5 Hz, 1H), 7.07-6.98 (m, 2H),
3.36-3.30 (m, 2H), 2.80
##STR00052## ##STR00053##
Preparation of
(6-Bromonaphthalen-2-yloxy)(tert-Butyl)dimethylsilane (81);
[0328] A solution of 6-bromonaphthalen-2-ol (12.0 g, 53.7 mmol) and
imidazole (6.0 g, 79.5 mmol) in DMF (12.0 mL) was added
t-butyldimethylsilyl chloride (TBDMSC1) (9.0 g, 59.0 mmol) in one
portion at 0.degree. C. The mixture was allowed to warm to room
temperature and stirred for 3 h. The reaction mixture was
partitioned between EtOAc (500 mL) and water (300 mL) The aqueous
layer was separated and extracted with EtOAc (2.times.100 mL) and
the combined organic extracts were washed with brine (300 mL),
dried over Na.sub.2SO.sub.4, filtered, and concentrated. The
residue was purified by column chromatography (silica gel, hexanes)
to afford (6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane
(81, 18.0 g, 98%) as a white solid: .sup.1H NMR (300 MHz,
CDCl.sub.3) .delta. 7.91 (d, J=1.8 Hz, 1H), 7.64 (d, J=8.7 Hz, 1H),
7.56 (d, J=8.7 Hz, 1H), 7.48 (dd, J=8.7, 1.8 Hz, 1H), 7.15 (d,
J=2.4 Hz, 1H), 7.09 (dd, J=9.0, 2.4 Hz, 1H), 1.01 (s, 9H), 0.24 (s,
6H).
Preparation of Benzyl
4-[6-(tert-butyldimethylsilyloxy)naphthalen-2-yl]but-3-ynylcarbamate
(83)
[0329] A solution of
(6-bromonaphthalen-2-yloxy)(tert-butyl)dimethylsilane (81, 16.1 g,
47.7 mmol), benzyl but-3-ynylcarbamate (82, 9.0 g, 47.7 mmol), and
triethylamine (95 mL) in anhydrous THF (100 mL) was cooled to
-78.degree. C. and degassed with argon. The mixture was warmed to
room temperature and dichlorobis(triphenylphosphine)palladium(II)
(3.3 g, 4.8 mmol) and CuI (1.8 g, 9.6 mmol) were added rapidly in
one portion under argon. The mixture was heated at 50.degree. C.
for 12 h. The reaction mixture was filtered through a plug of
diatomaceous earth and the filtrate was concentrated. The residue
was purified by column chromatography (silical gel, 10:1
hexanes/EtOAc) to afford carbamate 83 (8.5 g, 38%) as a thick brown
oil: .sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 7.83 (s, 1H), 7.65
(d, J=9.0 Hz, 1H), 7.60 (d, J=8.7 Hz, 1H), 7.39-7.29 (m, 6H), 7.13
(d, J=2.1 Hz, 1H), 7.07 (dd, J=8.7, 2.4 Hz, 1H), 5.17 (br s, 1H),
5.13 (s, 2H), 3.46 (q, J=6.3 Hz, 2H), 2.67 (t, J=6.3 Hz, 2H), 1.01
(s, 9H), 0.25 (s, 6H).
Preparation of Benzyl
4-(6-hydroxynaphthalen-2-yl)but-3-ynylcarbamate (84)
[0330] To a solution of benzyl
4-[6-(tert-butyldimethylsilyloxy)naphthalen-2-yl]but-3-ynylcarbamate
(83, 2.5 g, 5.44 mmol) in anhydrous THF (25 mL) at 0.degree. C. was
added dropwise tetrabutylammonium fluoride (1 M in THF, 6.0 mL) and
the mixture was stirred for 2 h at room temperature. The resulting
solution was concentrated in vacuo and the residue was purified by
column chromatography (silica gel, 95:5 CH.sub.2Cl.sub.2/MeOH) to
afford carbamate 84 (2.0 g, 50%) as a pale yellow solid: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.82 (s, 1H), 7.67 (d, J=9.6 Hz,
1H), 7.58 (d, J=8.4 Hz, 1H), 7.37-7.29 (m, 6H), 7.11-7.08 (m, 2H),
5.30 (br s, 2H), 5.14 (s, 2H), 3.48 (q, J=6.3 Hz, 2H), 2.68 (t,
J=6.6 Hz, 2H).
Preparation of tert-Butyl 3-hydroxypropylcarbamate (66)
[0331] To a solution of 3-aminopropanol (55, 5.0 g, 67 mmol) in
dioxane/2 N NaOH (1:1, 100 mL) was added a solution of
di-tert-butyl dicarbonate (17.0 g, 80 mmol) in dioxane (10 mL) at
0.degree. C. The reaction mixture was warmed to room temperature
and stirred for 1 h. The mixture was first acidified to pH 1 with
concentrated HCl and then neutralized to pH 7 with 2 N NaOH. The
mixture was then extracted with EtOAc (3.times.200 mL). The
combined organic layers were dried over MgSO.sub.4 and
concentrated. The residue was purified by column chromatography
(silica gel, 3:1 hexanes/EtOAc) to afford tert-butyl
3-hydroxypropylcarbamate (86, 11.7 g, 99%) as a light yellow oil:
.sup.1H NMR (300 MHz, CDCl.sub.3) .delta. 4.80 (br s, 1H), 3.66 (q,
J=5.7 Hz, 2H), 3.33 (q, J=6.3 Hz, 2H), 2.97 (br s, 1H), 1.71-1.63
(m, 2H), 1.45 (s, 9H).
Preparation of Boc-protected carbamate (87)
[0332] Diisopropylazodicarboxylate (557 mg, 2.75 mmol) was added
dropwise to a solution of
4-(6-hydroxynaphthalen-2-yl)but-3-ynylcarbamate (84, 638 mg, 1.83
mmol), tert-butyl 3-hydroxypropylcarbamate (86, 355 mg, 2.01 mmol),
and triphenylphosphine (980 mg, 3.70 mmol) in anhydrous THF (20 mL)
at 0.degree. C. The reaction mixture was warmed to room temperature
and stirred for 12 h. The reaction mixture was concentrated and the
residue was purified by column chromatography (silica gel, 2:1
hexanes/EtOAc) to afford a mixture of ether 87 and the hydrazine
by-product (4.0 g) which was used in the next step without further
purification.
Preparation of tert-Butyl
3-[6-(4-aminobutyl)naphthalen-2-yloxy]propylcarbamate (88)
[0333] A suspension of 87 (4.0 g) and 10% Pd/C (500 mg) in
MeOH/EtOAc (4:1, 350 mL) was subjected to hydrogenation conditions
(1 atm) for 6 h at room temperature. The reaction mixture was
filtered through a plug of diatomaceous earth and the plug was
washed with MeOH. The filtrate was concentrated in vacuo and the
residue was purified by column chromatography (silica gel, 90:9:1
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford carbamate 88 (437 mg,
64% over two steps) as a white solid: .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.70 (dd, J=9.0 Hz, 2H), 7.59 (s, 1H),
7.34-7.31 (m, 1H), 7.21 (d, J=2.4 Hz, 1H), 7.12 (d, J=9.0, 2.4 Hz,
1H), 4.13 (t, J=6.0 Hz, 2H), 3.30 (t, J=6.3 Hz, 2H), 2.91-2.80 (m,
4H), 2.03-1.99 (m, 2H), 1.90-1.60 (m, 4H), 1.46 (s, 9H).
Preparation of tert-Butyl
3-(6-{4-[3-(3,5-diamino-6-chloropyrazine-2-carbonyl)guanidino]butyl}napht-
halen-2-yloxy)propylcarbamate (89)
[0334] To a solution of carbamate 88 (500 mg, 1.34 mmol) and methyl
3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 790
mg, 2.01 mmol) in EtOH (30 mL) was added DIPEA (1.75 mL, 9.39 mmol)
at room temperature. The reaction mixture was heated at 70.degree.
C. in a sealed tube for 2 h, then cooled to room temperature, and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 90:9:1
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford carbamate 89 (660 mg,
84%) as a yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.65 (d, J=7.5 Hz, 2H), 7.56 (s, 1H), 7.31 (dd, J=8.4, 1.5 Hz, 1H),
7.16 (d, J=2.4 Hz, 1H), 7.08 (dd, J=8.7, 2.4 Hz, 1H), 4.10 (t,
J=6.3 Hz, 2H), 2.81 (t, J=6.6 Hz, 2H), 2.01-1.97 (m, 2H), 1.83-1.60
(m, 4H), 1.43 (s, 9H).
Preparation of
3,5-Diamino-N-(N-{4-[6-(3-aminopropoxy)naphthalen-2-yl]butyl}carbainimido-
yl-6-chloropyrazine-2-carboxamide (90)
[0335] To a solution of compound 89 (725 mg, 1.24 mmol) in
CH.sub.2Cl.sub.2 (45 mL) was added dropwise trifluoroacetic acid
(6.0 mL) at room temperature. The reaction mixture was stirred for
4 h and the solvent was removed in vacuo. The residue was dissolved
in water (10 mL) and the solution was basified to pH 7 with
saturated NaHCO.sub.3 which resulted in the precipitation of crude
20. This was filtered and purified by column chromatography (silica
gel, 80:18:2 CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford compound
90 (289 mg, 48%) as a light yellow solid: .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.65 (d, J=7.5 Hz, 2H), 7.56 (s, 1H), 7.31 (dd,
J=8.4, 1.5 Hz, 1H), 7.16 (d, J=2.4 Hz, 1H), 7.08 (dd, J=8.7, 2.4
Hz, 1H), 4.10 (t, J=6.3 Hz, 2H), 2.81 (t, J=6.6 Hz, 2H), 2.01-1.97
(m, 2H), 1.83-1.60 (m, 4H).
Preparation of
3,5-Diamino-N-(N-{4-[6-(3-aminopropoxy)naphthalen-2-yl]butyl}carbamimidoy-
l-6-chloropyrazine-2-carboxamide Methanesulphonate Salt (91)
[0336] To a solution of
3,5-diamino-N-(N-{4-[6-(3-aminopropoxy)naphthalen-2-yl]butyl}carbamimidoy-
l-6-chloropyrazine-2-carboxamide (20, 30 mg, 0.062 mmol) in EtOH (5
mL) was added methanesulphonic acid (12.5 mg, 0.13 mmol) at room
temperature and the reaction mixture was stirred for 15 min. The
solution was concentrated and the residue was azeotroped with MeOH.
The residue was dissolved in H.sub.2O/MeOH (8:2, 10 mL) and
lyophilized to afford methanesulphonate salt 91 (33 mg, 79%) as a
yellow solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 10.4 (s,
1H), 9.13 (br s, 1H), 8.85 (br s, 1H), 8.74 (br s, 1H), 7.76-7.71
(m, 5H), 7.62 (s, 1H), 7.50-7.33 (m, 3H), 7.26 (s, 1H), 7.13 (dd,
J=8.8, 2.2 Hz, 1H), 4.15 (t, J=6.0 Hz, 5H), 3.32-3.04 (m, 2H),
3.01-2.97 (m, 2H), 2.77-2.72 (m, 2H), 2.38 (s, 1H), 2.10-2.01 (m,
2H), 1.74-1.59 (m, 4H); ESI-MS m/z 485
[C.sub.23H.sub.29ClN.sub.8O.sub.2+H].sup.+.
##STR00054## ##STR00055##
Preparation of Boc-urea 92
[0337] To a solution of amine 90 (300 mg, 0.62 mmol) and Goodman's
reagent (392 mg, 1.00 mmol) in MeOH (60 mL) was added DIPEA (0.45
mL, 2.5 mmol) at room temperature. The reaction mixture was stirred
for 7 h and then concentrated. The residue was dissolved in
CHCl.sub.3 (200 mL) and washed with saturated NaHCO.sub.3
(2.times.100 mL). The organic layer was dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by column
chromatography (silica gel, 90:9:1
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford Boc-urea 92 (280 mg,
62%) as a light yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.67 (t, J=7.8 Hz, 2H), 7.57 (s, 1H), 7.31 (d, J=8.1 Hz,
1H), 7.19 (s, 2H), 4.18 (t, J=5.4 Hz, 2H), 3.62 (t, J=6.0 Hz, 2H),
2.82 (t, J=6.3 Hz, 2H), 2.12 (t, J=5.7 Hz, 2H), 1.85-1.70 (m, 4H),
1.54 (s, 9H), 1.45 (s, 9H).
Preparation of Urea 93
[0338] To a solution of Boc-urea 92 (280 mg, 0.39 mmol) in
CH.sub.2Cl.sub.2 (30 mL) was added dropwise trifluoroacetic acid
(6.0 mL) at room temperature. The reaction mixture was stirred for
4 h and the solvent was removed in vacuo. The residue was dissolved
in water (10 mL) and the solution was basified to pH 10 with 2 N
NaOH which resulted in the precipitation of crude 23. This was
filtered and purified by column chromatography (silica gel, 6:3:1
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford urea 93 (99 mg, 49%) as
a light yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.66 (dd, J=4.5, 8.1 Hz, 2H), 7.57 (s, 1H), 7.32 (d, J=8.1 Hz, 1H),
7.20 (s, 1H), 7.10 (dd, J=2.4, 8.7 Hz, 1H), 4.17 (t, J=5.7 Hz, 2H),
3.43 (t, J=6.6 Hz, 2H), 2.82 (t, J=6.3 Hz, 2H), 2.16-2.08 (m, 2H),
1.84-1.70 (m, 4H).
Preparation of Methanesulphonate Salt 94
[0339] To a solution of compound 93 (99 mg, 0.19 mmol) in EtOH (6
mL) was added CH.sub.3SO.sub.3H (36 mg, 0.40 mmol) at room
temperature and the reaction mixture was stirred for 15 min. The
solvent was removed in vacuo. The residue was dissolved in water (5
mL) and lyophilized to afford methanesulphonate salt 94 (115 mg,
85%) as a yellow solid: .sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta.
10.42 (s, 1H), 9.12 (br s, 1H), 8.85 (br s, 1H), 8.68 (br s, 1H),
7.76-6.90 (m, 16H), 4.10 (t, J=5.4 Hz, 2H), 3.31 (d, J=5.4 Hz, 4H),
2.74-2.71 (m, 2H), 2.30 (s, 6H), 2.07-1.96 (m, 2H), 1.71-1.59 (m,
4H); ESI-MS m/z 527
[C.sub.24H.sub.31ClN.sub.10O.sub.2+H].sup.+.
##STR00056## ##STR00057## ##STR00058##
Preparation of Benzyl
4-[6-(tert-butyldimethylsilyloxy)naphthalen-2-yl]butan-1-amine
(95)
[0340] A suspension of 83 (8.0 g, 17.41 mmol) and 10% Pd/C (3.6 g)
in MeOH (240 mL) was subjected to hydrogenation conditions (1 atm)
for 6 h at room temperature. The reaction mixture was filtered
through a plug of diatomaceous earth and the plug was washed with
MeOH. The filtrate was concentrated in vacuo and the residue was
purified by column chromatography (silica gel, 90:9:1
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford amine 95 (3.2 g, 56%)
as a yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.64
(d, J=6.3 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.30 (d, J=1.5 Hz,
1H), 7.15 (s, 1H), 7.03 (dd, J=8.9 Hz, 2.3 Hz, 1H), 2.76 (t, J=7.4
Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.79-1.69 (m, 2H), 1.59-1.49 (m,
2H), 1.04 (s, 9H), 0.25 (s, 6H).
Preparation of Benzyl
4-[6-(tert-butyldimethylsilyloxy)naphthalen-2-yl]carbamate (96)
[0341] To a solution of amine 95 (3.2 g, 9.7 mmol) in
CH.sub.2Cl.sub.2/saturated aqueous NaHCO.sub.3 (1:1, 135 mL),
benzyl chloroformate (2.1 mL) was added dropwise at room
temperature and the reaction mixture was stirred for 2 h. The
mixture was concentrated, the residue was dissolved in EtOAc (500
mL), and the solution was washed with water (300 mL) and brine (300
mL). The organic layer was dried over Na.sub.2SO.sub.4, filtered,
and concentrated. The residue was purified by column chromatography
(silica gel, 4:1 hexanes/EtOAc) to afford carbamate 96 (4.0 g, 89%)
as a light yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta.
7.64 (d, J=6.3 Hz, 1H), 7.60 (s, 1H), 7.55 (s, 1H), 7.37-7.26 (m,
6H), 7.15 (s, 1H), 7.03 (dd, J=8.9 Hz, 2.3 Hz, 1H), 5.10 (s, 1H),
2.77 (t, J=7.4 Hz, 2H), 2.70 (t, J=7.2 Hz, 2H), 1.79-1.69 (m, 2H),
1.59-1.49 (m, 2H), 1.04 (s, 9H), 0.25 (s, 6H).
Preparation of Benzyl 4-[6-(hydroxynaphthalen-2-yl)]carbamate
(97)
[0342] To a solution of carbamate 96 (4.0 g, 6.47 mmol) in THF (30
mL) was added dropwise tetrabutylammonium fluoride (1 M in THF, 7.2
mL, 7.2 mmol) at room temperature. The reaction mixture was stirred
for 2 h and the solvent was removed in vacuo. The residue was
purified by column chromatography (silica gel, 7:3 hexanes/EtOAc)
to afford compound 97 (2.1 g, 70%) as a light yellow solid: .sup.1H
NMR (300 MHz, CDCl.sub.3) .delta. 7.63 (d, J=8.7 Hz, 1H), 7.56 (d,
J=8.4 Hz, 1H), 7.48 (s, 1H), 7.37-7.26 (m, 5H), 7.21 (dd, J=8.5 Hz,
1.3 Hz, 1H), 7.11 (d, J=2.1 Hz, 1H), 7.08 (d, J=2.4 Hz, 1H), 7.05
(d, J=2.4 Hz, 1H), 5.10 (s, 2H), 4.75 (br, 1H), 3.23 (q, J=6.5 Hz,
2H), 2.72 (t, J=7.5 Hz, 2H), 1.75-1.65 (m, 2H), 1.60-1.47 (m,
2H).
Preparation of Ether 98
[0343] Diisopropylazodicarboxylate (2.45 g, 12.0 mmol) was added
dropwise to a solution of benzyl
4-(6-hydroxynaphthalen-2-yl)carbamate (97, 2.1 g, 6.0 mmol),
tert-butyl 3-hydroxypropylcarbamate (86, 2.1 g, 12.0 mmol), and
triphenylphosphine (4.8 g, 18.0 mmol) in anhydrous THF (63 mL) at
0.degree. C. The reaction mixture was warmed to room temperature
and stirred for 12 h. The reaction mixture was concentrated and the
residue was purified by column chromatography (silica gel, 7:3
hexanes/EtOAc) to afford a mixture of ether 98 and the hydrazine
by-product (3.0 g) which was used in the next step without further
purification.
Preparation of Amine 29
[0344] To a solution of compound 98 (5.5 g, 11.0 mmol) in
CH.sub.2Cl.sub.2 (350 mL) was added dropwise trifluoroacetic acid
(84 mL) at room temperature. The reaction mixture was stirred for 2
h and the solvent was removed in vacuo. The residue was dissolved
in CHCl.sub.3 (300 mL) and washed with saturated aqueous
NaHCO.sub.3, the organic layer was dried over MgSO.sub.4, filtered,
concentrated in vacuo, and purified by column chromatography
(silica gel, 90:9:1 CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford
compound 99 (1.74 g, 71% over two steps) as a light
[0345] yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.65
(d, J=8.4 Hz, 2H), 7.53 (s, 1H), 7.31-7.26 (m, 6H), 7.19 (s, 1H),
7.08 (dd, J=8.7 Hz, 2.4 Hz, 1H), 5.05 (s, 2H), 4.17 (t, J=6.0 Hz,
2H), 3.15 (t, J=6.9 Hz, 2H), 2.96 (t, J=6.9 Hz, 2H), 2.73 (t, J=7.5
Hz, 2H), 2.09-2.00 (m, 2H), 1.80-1.65 (m, 2H), 1.59-1.49 (m,
2H).
Preparation of Benzyl
4-[6-(3-{(2S,3R)-2,3-dihydroxy-3-[(4R,5R)-5-hydroxy-2-methyl-1,3-dioxan-4-
-yl]propylamino}propoxy)naphthalene-2-yl]carbamate (101)
[0346] A solution of carbamate 99 (1.74 g, 4.28 mmol), triol 100
(922 mg, 4.28 mmol), and sodium triacetoxyborohydride (1.43 g, 6.42
mmol) in CH.sub.2Cl.sub.2 (18 mL) was stirred at room temperature
for 8 h. The reaction mixture was concentrated to dryness and the
residue was purified by column chromatography (silica gel,
86:12.5:1.5 CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH) to afford
carbamate 101 (508 mg, 20%) as an white gummy solid: .sup.1H NMR
(300 MHz, CD.sub.3OD) .delta. 7.65 (d, J=8.4 Hz, 2H), 7.53 (s, 1H),
7.31-7.26 (m, 6H), 7.19 (s, 1H), 7.11 (dd, J=9.0 Hz, 2.4 Hz, 1H),
5.05 (s, 2H), 4.67 (q, J=4.9 Hz, 1H), 4.18 (t, J=6.0 Hz, 2H),
4.07-3.94 (m, 2H), 3.82-3.74 (m, 2H), 3.46 (dd, J=9.3 Hz, 2.1 Hz,
1H), 3.37 (d, J=10.5 Hz, 1H), 3.15 (t, J=6.9 Hz, 2H), 3.08-2.72 (m,
6H), 2.13-2.04 (m, 2H), 1.75-1.66 (m, 2H), 1.59-1.52 (m, 2H), 1.25
(d, J=5.1 Hz, 3H).
Preparation of Benzyl
4-{6-[3-(bis{(2S,3R)-2,3-dihydroxy-3-[(4R,5R)-5-hydroxy-2-methyl-1,3-diox-
an-4-yl]propyl}amino)propoxy]naphthalene-2-yl}carbamate (102)
[0347] A solution of carbamate 101 (368 mg, 0.62 mmol), triol 100
(675 mg, 3.10 mmol), sodium cyanoborohydride (338 mg, 4.96 mmol),
and HOAc (290 mg, 4.96 mmol) in MeOH (15 mL) was stirred at room
temperature for 7 d. The reaction mixture was concentrated to
dryness; the residue was washed with saturated NaHCO.sub.3, and
extracted with EtOAc (3.times.200 mL). The organic layers was dried
over MgSO.sub.4, filtered, concentrated, and purified by column
chromatography (silica gel, 80:18:2
CH.sub.2Cl.sub.2/CH.sub.3OH/NH.sub.4OH) to afford carbamate 102
(318 mg, 65%) as an white gummy solid: .sup.1H NMR (300 MHz,
CD.sub.3OD) .delta. 7.67 (d, J=8.4 Hz, 2H), 7.54 (s, 1H), 7.31-7.27
(m, 6H), 7.21 (s, 1H), 7.11 (dd, J=9.0 Hz, 2.4 Hz, 1H), 5.06 (s,
2H), 4.48 (q, J=5.0 Hz, 2H), 4.17 (t, J=5.7 Hz, 2H), 3.98 (dd,
J=10.5 Hz, 5.4 Hz, 2H), 3.92-3.87 (m, 2H), 3.79-3.72 (m, 4H), 3.35
(d, J=2.1 Hz, 2H), 3.23 (t, J=10.5 Hz, 2H), 3.15 (t, J=6.9 Hz, 2H),
2.82-2.84 (m, 2H), 2.77-2.72 (m, 4H), 2.67-2.60 (m, 2H), 2.03-1.99
(m, 2H), 1.76-1.66 (m, 2H), 1.59-1.52 (m, 2H), 1.20 (d, J=5.1 Hz,
6H).
Preparation of
(R,R,1R,1'R,2S,2'S)-3,3'-{3-[6-(4-Aminobutyl)naphthalene-2-yloxy]propylaz-
anediyl}bis{1-[(4R,5R)-5-hydroxy-2-methyl-1,3-dioxan-4-yl]propane-1,2-diol-
} (103)
[0348] A suspension of carbamate 102 (318 mg) and 10% Pd/C (300 mg)
in MeOH (15 mL) was subjected to hydrogenation conditions (1 atm)
for 2 h at room temperature. The reaction mixture was filtered
through a plug of diatomaceous earth and the plug was washed with
MeOH. The filtrate was concentrated in vacuo and the residue was
purified by column chromatography (silica gel, 80:18:2
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford amine 103 (212 mg, 80%)
as a white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .delta. 7.68
(d, J=7.2 Hz, 2H), 7.56 (s, 1H), 7.30 (d, J=8.1 Hz, 1H), 7.21 (s,
1H), 7.11 (d, J=8.7 Hz, 1H), 4.50-4.49 (m, 2H), 4.17-4.15 (m, 2H),
4.02-3.96 (m, 2H), 3.88 (br s, 2H), 3.79-3.78 (m, 4H), 3.36-3.35
(m, 2H), 7.22 (d, J=10.5 Hz, 2H), 2.80-2.58 (m, 10H), 2.10-1.90 (m,
2H), 1.75-1.73 (m, 2H), 1.65-1.45 (m, 2H), 1.22-1.20 (m, 6H).
Preparation of Carboxamide 104
[0349] To a solution of amine 103 (212 mg, 0.33 mmol) and methyl
3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 202
mg, 0.52 mmol) in EtOH (15 mL) was added DIPEA (0.40 mL, 2.28 mmol)
at room temperature. The reaction mixture was heated at 70.degree.
C. in a sealed tube for 2 h, then cooled to room temperature, and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 80:18:2
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford carboxamide 104 (120
mg, 43%) as a yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD)
.delta. 7.69-7.65 (m, 2H), 7.57 (s, 1H), 7.30 (d, J=8.1 Hz, 1H),
7.19 (s, 1H), 7.10 (dd, J=9.0 Hz, 2.4 Hz, 1H), 4.50 (q, J=4.8 Hz,
2H), 4.16-4.15 (m, 2H), 4.02-3.96 (m, 2H), 3.90-3.86 (m, 2H),
3.80-3.72 (m, 4H), 3.36-3.20 (m, 6H), 2.83-2.58 (m, 8H), 2.02-1.98
(m, 2H), 1.82-1.79 (m, 2H), 1.71-1.69 (m, 2H), 1.21-1.16 (m,
6H).
Preparation of Carboxamide Lactate Salt 105
[0350] To a solution of carboxamide 104 (120 mg, 0.14 mmol) in EtOH
(5 mL) was added lactic acid (27 mg, 0.30 mmol) at room temperature
and the reaction mixture was stirred for 15 min. The solution was
concentrated and the residue was azeotroped with MeOH. The residue
was dissolved in H.sub.2O/MeOH (8:2, 10 mL) and lyophilized to
afford lactate salt 105 (147 mg, >99%) as a yellow solid:
.sup.1H NMR (300 MHz, DMSO-d.sub.6) .delta. 7.74 (d, J=8.1 Hz, 2H),
7.63 (s, 1H), 7.34 (d, J=8.4 Hz, 1H), 7.27 (s, 1H), 7.19 (s, 1H),
7.12 (dd, J=9.0 Hz, 2.1 Hz, 1H), 5.14-5.06 (m, 1H), 4.90 (q, J=7.0
Hz, 1H), 4.60 (q, J=5.0 Hz, 2H), 4.23-4.13 (m, 3H), 4.03-3.91 (m,
4H), 3.78-3.77 (m, 2H), 3.70-3.62 (m, 5H), 3.38-3.19 (m, 13H),
2.78-2.58 (m, 8H), 1.97-1.93 (m, 2H), 1.73-1.71 (m, 2H), 1.56-1.62
(m, 2H), 1.47 (d, J=6.9 Hz, 1H), 1.40 (d, J=7.0 Hz, 2H), 1.30 (d,
J=6.9 Hz, 2H), 1.23 (d, J=6.9 Hz, 6H), 1.17 (d, J=5.1 Hz, 6H);
ESI-MS m/z 887 [C.sub.39H.sub.57ClN.sub.8O.sub.12+Na].sup.+.
Alternate Synthesis of
N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N-{4-[4-(3-guanidino-propoxy-
)-naphthalen-1-yl]-butyl}-guanidine 75
1. {3-[4-(4-Azido-but-1-enyl)-naphthalen-1-yloxy]-propyl}-carbamic
acid tert-butyl ester
##STR00059##
[0351] a. [3-(4-formyl-naphthalen-1-yloxy)-propyl]-carbamic acid
tert-butyl ester
[0352] To a solution of 4-hydroxy-naphthalene-1-carbaldehyde (15.2
g, 58.1 mmol) in DMF (50 mL) at r.t. was added N-Boc
3-bromo-propylamine (15.2 g, 63.9 mmol), followed by potassium
carbonate (12 g, 87.2 mmol). The reaction mixture was stirred at
room temperature overnight. Water was added to the reaction mixture
and extracted by CH.sub.2Cl.sub.2. The combined organic layers were
washed with water, brine, dried over MgSO.sub.4, filtered, and
concentrated. The residue was recrystallized from EtOAc/hexane to
afford [3-(4-formyl-naphthalen-1-yloxy)-propyl]-carbamic acid
tert-butyl ester (13.8 g, 72%) as a light yellow solid.
b. {3-[4-(4-Azido-but-1-enyl)-naphthalen-1-yloxy]-propyl}-carbamic
acid tert-butyl ester
[0352] [0353] To a mixture of Wittig reagent
(3-azido-propyl)-triphenyl-phosphonium bromide (15.35 g, 36 mmol)
in THF (150 mL) at -76.degree. C., was added LIHMDS (0.5M in THF
solution, 66 mL, 66 mmol). The mixture was stirred at this
temperature for 1 h.
[3-(4-formyl-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl
ester (10 g, 30 mmol) in 20 mL of THF solution was added. The
reaction mixture was stirred for 1 hour. Then warm up to r.t. in 1
h. Water was added to quench the reaction, and extracted with
EtOAc. The organic layer was washed with water, brine, dried over
MgSO.sub.4, filtered, and concentrated. The residue was purified by
column chromatography to afford
{3-[4-(4-azido-but-1-enyl)-naphthalen-1-yloxy]-propyl}-carbamic
acid tert-butyl ester, 11 g, 88% as a solid
c. Wittig reagent (3-azido-propyl)-triphenyl-phosphonium
bromide
[0354] ##STR00060## [0355] (3-Bromo-propyl)-triphenyl-phosphonium
bromide was dissolved in ethanol/water (1/1). To it sodium azide
was added. The reaction mixture was heated up to reflux overnight.
Solvents were removed by evaporation. The residue was extracted by
dry ethanol. Filtered and evaporated to give crude
(3-azido-propyl)-triphenyl-phosphonium bromide and was used
directly for the next step reaction without further
purification.
2.
N-{4-[4-(3-Amino-propoxy)-naphthalen-1-yl]-butyl}-N-(3,5-diamino-6-chlo-
ro-pyrazine-2-carbonyl)-guanidine
[0356] ##STR00061## [0357]
{3-[4-(4-Azido-but-1-enyl)-naphthalen-1-yloxy]-propyl}-carbamic
acid tert-butyl ester 3.5 g was hydrogenated in ethanol with 5%
Pd/C (50% wet) for 2 h. Catalyst was removed, and the filtrate was
concentrated to give 2.94 g of
{3-[4-(4-Amino-butyl)-naphthalen-1-yloxy]-propyl}-carbamic acid
tert-butyl ester. One gram (2.66 mmol) of free amine was stirred
with
1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea
(1.55 g, 3.99 mmol) in dry ethanol (25 mL). Di-isopropyl-ethylamine
(1.39 mL, 7.98 mmol) of was added and the reaction mixture was
warmed to 45.degree. C. overnight. Ethanol was added and the
reaction filtered. After concentration of the filtrate, the residue
was purified by flash chromatography (0-10% MeOH/CH.sub.2Cl.sub.2)
to give 0.92 g of
[3-(4-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-butyl}-
-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester.
[3-(4-{4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-butyl}-
-naphthalen-1-yloxy)-propyl]-carbamic acid tert-butyl ester (2.7 g
was stirred with 4M HCl in p-dioxane for 1 hour at room
temperature. Solvents were removed in vacuo. [0358] A small amount
of the product was purified by flash chromatography to give 7
GS-426675
N-{4-[4-(3-Amino-propoxy)-naphthalen-1-yl]-butyl}-N'-(3,5-diamino-6-chlor-
o-pyrazine-2-carbonyl)-guanidine as an HCl salt.
3.
N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N'-{4-[4-(3-guanidino-prop-
oxy)-naphthalen-1-yl]-butyl}-guanidine 75
[0359] ##STR00062## [0360]
N-{4-[4-(3-Amino-propoxy)-naphthalen-1-yl]-butyl}-N'-(3,5-diamino-6-chlor-
o-pyrazine-2-carbonyl)-guanidine HCl salt from reaction was stirred
with Goodman's reagent [(tert-butoxycarbonylamino-trifluoromethane
sulfonylimino-methyl)-carbamic acid tert-butyl ester] in methanol.
Diisopropylethylamine (1.18 mL) was added and the reaction mixture
was stirred at room temperature overnight. Solvents were removed in
vacuo and the residue was purified by silica gel chromatography
(0-10% MeOH(MeOH/NH.sub.4OH=9/1)/CH.sub.2Cl.sub.2) to give 2.7 g of
8, which was dissolve in 30 mL of methanol and treated with 300 mL
of 4M HCl in p-dioxane at room temperature for 4 hour to give 9,
N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N'-{4-[4-(3-guanidino-propox-
y)-naphthalen-1-yl]-butyl}-guanidine as a crude product. About 200
mL of the solvents were removed by reduced pressure, then cool to
room temperature, and let the product precipitated out. Filtration
to collect the product, and the product was further refluxed with
dry EtOH, and cool down to room temperature. Filtration to give
2.08 g of 75 as an HCl salt (yellow solid).
##STR00063##
[0360] Preparation of
(1R,2S)-3-{3-[6-(4-Aminobutyl)naphthalene-2-yloxy]propylamino}-[1-[(4R,5R-
)-5-hydroxy-2-methyl-1,3-dioxan-4-yl]propane-1,2-diol} (105)
[0361] A suspension of 101 (76 mg) and 10% Pd/C (76 mg) in MeOH (5
mL) was subjected to hydrogenation conditions (1 atm) for 2 h at
room temperature. The reaction mixture was filtered through a plug
of diatomaceous earth and the plug was washed with MeOH. The
filtrate was concentrated in vacuo and the residue was purified by
column chromatography (silica gel, 80:18:2
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford amine 105 (46 mg, 80%)
as a white solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .quadrature.
7.65 (d, J=8.7 Hz, 2H), 7.53 (s, 1H), 7.28 (d, J=8.4 Hz, 1H), 7.18
(s, 1H), 7.10 (dd, J=8.7 Hz, 1.8 Hz, 1H), 4.66 (q, J=4.8 Hz, 1H),
4.14 (t, J=6.0 Hz, 2H), 4.06 (q, J=5.3 Hz, 1H), 3.98-3.92 (m, 1H),
3.83-3.74 (m, 2H), 3.45 (dd, J=9.0 Hz, 1.5 Hz, 1H), 3.37 (d, J=10.5
Hz, 1H), 2.93-2.66 (m, 8H), 2.08-2.00 (m, 2H), 1.77-1.67 (m, 2H),
1.58-1.49 (m, 2H), 1.25 (d, J=4.8 Hz, 3H).
Preparation of Guanidine 106
[0362] To a solution of amine 105 (46 mg, 0.10 mmol) and methyl
3,5-diamino-6-chloropyrazine-2-carbonylcarbamimidothioate (10, 70
mg, 0.16 mmol) in EtOH (6 mL) was added DIPEA (0.13 mL, 0.7 mmol)
at room temperature. The reaction mixture was heated at 70.degree.
C. in a sealed tube for 2 h, then cooled to room temperature, and
concentrated in vacuo. The residue was purified by column
chromatography (silica gel, 80:18:2
CHCl.sub.3/CH.sub.3OH/NH.sub.4OH) to afford guanidine 106(16 mg,
24%) as a yellow solid: .sup.1H NMR (300 MHz, CD.sub.3OD)
.quadrature. 7.66 (d, J=7.5 Hz, 2H), 7.55 (s, 1H), 7.30 (d, J=8.1
Hz, 1H), 7.17 (s, 1H), 7.10 (d, J=8.7 Hz, 1H), 4.67-4.66 (m, 1H),
4.16 (s, 2H), 4.08-3.97 (m, 2H), 3.82-3.77 (m, 2H), 3.64-3.58 (m,
2H), 3.46 (d, J=9.0 Hz, 1H), 3.40 (d, J=3.3 Hz, 1H), 2.05-2.09 (m,
2H), 1.82-1.70 (m, 4H), 1.25 (d, J=4.8 Hz, 3H).
Preparation of Guanidine Lactate Salt 107
[0363] To a solution of guanidine 106 (16 mg, 0.024 mmol) in EtOH
(5 mL) was added lactic acid (4.5 mg, 0.048 mmol) at room
temperature and the reaction mixture was stirred for 15 min. The
solution was concentrated and the residue was azeotroped with MeOH.
The residue was dissolved in H.sub.2O/MeOH (8:2, 10 mL) and
lyophilized to afford lactate salt 107 (20 mg, >95%) as a yellow
solid: .sup.1H NMR (300 MHz, CD.sub.3OD) .quadrature. 7.78 (t,
J=7.8 Hz, 2H), 7.62 (s, 1H), 7.35 (d, J=8.4 Hz, 1H), 7.27 (s, 1H),
7.13 (dd, J=8.8 Hz, 2.3 Hz, 1H), 7.00 (br s, 1H), 5.10-5.05 (m,
1H), 4.85 (q, J=7.0 Hz, 1H), 4.63 (q, J=5.0 Hz, 1H), 4.21-4.12 (m,
3H), 3.99-3.87 (m, 4H), 3.73 (d, J=5.1 Hz, 1H), 3.68-3.59 (m, 2H),
3.44-3.23 (m, 4H), 3.06-3.00 (m, 4H), 2.90-2.83 (m, 1H), 2.75 (t,
J=6.7 Hz, 2H), 2.11-2.07 (m, 2H), 1.71-1.57 (m, 4H), 1.46 (d, J=6.9
Hz, 1H), 1.37 (d, J=7.2 Hz, 3H), 1.28 (d, J=6.6 Hz, 3H), 1.24-1.13
(m, 10H), 0.86-0.82 (m, 1H); ESI-MS m/z 675
[C.sub.31H.sub.43ClN.sub.8O.sub.7+H].sup.+.
Preparation of
N-{4-[4-(3-Amino-propoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-butyl}-N'-(-
3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine (116) and
N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N'-{4-[4-(3-guanidino-propox-
y)-5,6,7,8-tetrahydro-naphthalen-1-yl]-butyl}-guanidine (118)
1. 4-hydroxy-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde
(109)
##STR00064##
[0365] 5, 6, 7, 8-Tetrahydro-naphthalen-1-ol (108, 20 g, 135 mmol)
was stirred in 100 mL of ethanol, and potassium hydroxide (7.57 g,
135 mmol) as an aqueous solution was added. The mixture was stirred
for 15 minutes and went clear. Solvents were removed and dried. PEG
(MW 380-420, 53 mL) was added, followed by chloroform (32.3 mL, 405
mmol) and toluene (34 mL). An aqueous potassium hydroxide solution
(50% by weight, 54.4 mL) was introduced dropwise with stirring over
15 minutes. The stirring was continued for another 30 minutes. 1M
HCl was added to acidify the reaction mixture and it was extracted
with EtOAc three times. The combined organic layers were washed
with water and brine The combined organic layers were dried over
MgSO.sub.4, filtered, concentrated, and purified by flash
chromatography (0-40% EtOAc/hexane) to give 4-hydroxy-5,6,7,
8-tetrahydro-naphthalene-1-carbaldehyde (109, 4.7 g).
2.
[3-(4-Formyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic
acid tert-butyl ester (111)
##STR00065##
[0367] 4-Hydroxy-5,6,7,8-tetrahydro-naphthalene-1-carbaldehyde
(109, 4.6 g, 29.1 mmol) (3-Bromopropyl)-carbamic acid tert-butyl
ester (110, 4.6 g, 32 mmol), and potassium carbonate (6.03 g, 43.7
mmol) were stirred in 140 mL of dry DMF over night. The reaction
mixture was poured into water and extracted with dichloromethane.
The organic layer was washed with water and brine., dried with
magnesium sulfate, filtered, concentrated and purified by flash
chromatography (0-30% EtOAc/hexane) to give crude product, which
was recrystallized from EtOAc/Hexane to give 5.8 g of 111,
[3-(4-formyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic
acid tert-butyl ester.
3.
{3-[4-(4-Azido-but-1-enyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-propy-
l}-carbamic acid tert-butyl ester (113)
##STR00066##
[0369] (3-Azido-propyl)-triphenylphosphonium bromide (112, 11.5 g,
27 mmol) was stirred with 100 mL of dry THF at -76.degree. C.
LiHMDS (0.5 M in toluene, 27 mL) was added and the mixture was
stirred for 30 minutes.
[3-(4-Formyl-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic
acid tert-butyl ester (111, 6 g, 18 mmol) in 12 mL dry THF solution
was introduced. The reaction mixture was stirred at this
temperature for another 30 minutes, and slowly warmed to room
temperature. The mixture was poured into water and extracted twice
with ethyl acetate. The combined organic layers were washed with
water and brine, dried over magnesium sulfate, filtered,
concentrated, and purified by flash chromatography (0-25%
EtOAc/Hexane) to give 3.5 g 113
{3-[4-(4-azido-but-1-enyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-propyl}-
-carbamic acid tert-butyl ester.
4.
N-{4-[4-(3-Amino-propoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-butyl}-V--
(3, 5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine (116)
##STR00067##
[0371]
{3-[4-(4-Azido-but-1-enyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-p-
ropyl}-carbamic acid tert-butyl ester 113, 3.5 g was hydrogenated
in ethanol with 5% Pd/C (50% wet) for 2 h. Catalyst was removed,
and the filtrate was concentrated to give 2.94 g of 114,
{3-[4-(4-amino-butyl)-5,6,7,8-tetrahydro-naphthalen-1-yloxy]-propyl}-carb-
amic acid tert-butyl ester.
[0372] One gram (2.66 mmol) of free amine 114 was stirred with
1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl-isothiourea
(1.55 g, 3.99 mmol) in dry ethanol (25 mL). Di-isopropyl-ethylamine
(1.39 mL, 7.98 mmol) of was added and the reaction mixture was
warmed to 45.degree. C. overnight. Ethanol was added and the
reaction filtered. After concentration of the filtrate, the residue
was purified by flash chromatography (0-10% MeOH/CH.sub.2Cl.sub.2)
to give 0.92 g of 115
[3-(4-{4-[N'-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidino]-butyl}-
-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-propyl]-carbamic acid
tert-butyl ester.
[0373]
N-{4-[4-(3-Amino-propoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-butyl-
}-N'-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine was
stirred with 4M HCl in p-dioxane for 30 minutes at room
temperature. Solvents were removed n vacuo, and the product was
purified by amine column (0-40% MeOH/CH.sub.2Cl.sub.2) to give 116
N-{4-[4-(3-amino-propoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-butyl}-NT-(-
3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine as an HCl
salt.
5.
N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N'-{4-[4-(3-guanidino-prop-
oxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-butyl}-guanidine GS-429269
(11)
##STR00068##
[0375]
N-{4-[4-(3-Amino-propoxy)-5,6,7,8-tetrahydro-naphthalen-1-yl]-butyl-
}-N'-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-guanidine HCl salt
116 (0.81 g, 1.37 mmol) was stirred with Goodman's reagent
[(tert-butoxycarbonylamino-trifluoromethane
sulfonylimino-methyl)-carbamic acid tert-butyl ester] in methanol.
Diisopropylethylamine (1.18 mL) was added and the reaction mixture
was stirred at room temperature overnight. Solvents were removed in
vacuo and the residue was purified by silica gel chromatography
(0-10% MeOH/CH.sub.2Cl.sub.2) to give 820 mg of 117, which was
treated with 4M HCl in p-dioxane at room temperature for 1 hour to
give 118,
N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-N'-{4-[4-(3-guanidino-propox-
y)-5,6,7,8-tetrahydro-naphthalen-1-yl]-butyl}-guanidine as a crude
product. Purification by flash chromatography (0-40%
(MeOH/NH.sub.4OH; 3/1)/CH.sub.2Cl.sub.2) followed by further
purification on an amine column (0-30% MeOH/CH.sub.2Cl.sub.2) gave
the free base, which was dissolved in ethanol and a few drops of 1M
HCl aq was added. The clear solution was filtered and lyophilized
to give final product as a yellow solid.
[0376] All references cited herein are hereby incorporated in their
entirety as if each reference was individually and specifically
incorporated in its entirety.
* * * * *