U.S. patent application number 10/840986 was filed with the patent office on 2004-10-21 for 11-c-substituted derivatives of clarithromycin.
Invention is credited to Farmer, Jay Judson, Or, Yat Sun, Phan, Ly Tam.
Application Number | 20040209827 10/840986 |
Document ID | / |
Family ID | 29999134 |
Filed Date | 2004-10-21 |
United States Patent
Application |
20040209827 |
Kind Code |
A1 |
Phan, Ly Tam ; et
al. |
October 21, 2004 |
11-C-substituted derivatives of clarithromycin
Abstract
There are described 11-C-substituted derivatives of
clarithromycin and pharmaceutically acceptable compositions
comprising a therapeutically effective amount of a compound of the
invention in combination with a pharmaceutically acceptable
carrier. Also described is a method for treating bacterial
infections by administering to an animal a pharmaceutical
composition containing a therapeutically-effective amount of a
compound of the invention, and processes for the preparation of
such compounds.
Inventors: |
Phan, Ly Tam; (Malden,
MA) ; Farmer, Jay Judson; (New Haven, CT) ;
Or, Yat Sun; (Watertown, MA) |
Correspondence
Address: |
ENANTA PHARMACEUTICALS, INC.
ATTN: PATENT DEPT.
500 ARSENAL STREET
WATERTOWN
MA
02472
US
|
Family ID: |
29999134 |
Appl. No.: |
10/840986 |
Filed: |
May 7, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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10840986 |
May 7, 2004 |
|
|
|
10178991 |
Jun 25, 2002 |
|
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Current U.S.
Class: |
514/29 ;
536/7.4 |
Current CPC
Class: |
A61K 31/70 20130101;
C07H 17/08 20130101 |
Class at
Publication: |
514/029 ;
536/007.4 |
International
Class: |
A61K 031/7048; C07H
017/08 |
Claims
What is claimed is:
1. A compound represented by the formula 14or a pharmaceutically
acceptable ester, salt or prodrug thereof, wherein A is selected
from the group consisting of: (1) C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl or C.sub.2-C.sub.6-alkynyl, optionally
substituted with one or more substituents selected from the group
consisting of: i. halogen; ii. aryl; iii. substituted aryl; iv.
heterocyclic; v. substituted heterocyclic; vi. --O--R.sub.5,
wherein each R.sub.5 is independently selected from the group
consisting of: a. hydrogen; b. aryl; c. substituted aryl; d.
heterocyclic; and e. substituted heterocyclic; vii.
--O--C.sub.1-C.sub.6-alkyl-R.sub.5; viii.
--O--C.sub.2-C.sub.6-alkenyl-R.- sub.5; ix.
--O--C.sub.2-C.sub.6-alkynyl-R.sub.5; and x. --NR.sub.6R.sub.7,
where R.sub.6 and R.sub.7 are each independently selected from the
group consisting of: a. hydrogen; b. C.sub.1-C.sub.6-alkyl,
optionally substituted with one or more substituents selected from
the group consisting of: (I) halogen; (II) aryl; (III) substituted
aryl; (IV) heterocyclic; and (V) substituted heterocyclic; c.
C.sub.2-C.sub.6-alkenyl, optionally substituted with one or more
substituents selected from the group consisting of: (I) halogen;
(II) aryl; (III) substituted aryl; (IV) heterocyclic; and (V)
substituted heterocyclic; and d. C.sub.2-C.sub.6-alkynyl,
optionally substituted with one or more substituents selected from
the group consisting of: (I) halogen; (II) aryl; (III) substituted
aryl; (IV) heterocyclic; and (V) substituted heterocyclic; or e.
R.sub.6 R.sub.7 taken with the nitrogen atom to which they are
connected form a 3- to 7-membered ring which may optionally contain
one or more functions selected from the group consisting of: (I)
--O--; (II) --NH--; (III) --N(C.sub.1-C.sub.6-alkyl)-; (IV)
--N(aryl); (V) --N(heteroaryl)-; (VI) --S--; (VII) --S(O)--; and
(VIII) --S(O).sub.2--(IX) --C(O)--. (2) --C(O)--R.sub.5; (3)
--C(O)--C.sub.1-C.sub.6-alkyl-R.sub.5; (4)
--C(O)--C.sub.2-C.sub.6-alkeny- l-R.sub.5; (5)
--C(O)--C.sub.2-C.sub.6-alkynyl-R.sub.5; (6)
C.sub.1-C.sub.6-alkyl-M-R.sub.5, where each M is independently
selected from --OC(O)--, --OC(O)O--, --OC(O)NR.sub.6--,
--C(O)NR.sub.6, --NR.sub.6C(O)--, --NR.sub.6C(O)O--,
--NR.sub.6C(O)NR.sub.7--, --NR.sub.6C(NH)NR.sub.7-- or
S(O).sub.n--, where n=0, 1 or 2; (7)
--C.sub.2-C.sub.6-alkenyl-M-R.sub.5; and (8)
--C.sub.2-C.sub.6-alkynyl-M-- R.sub.5; B, C, and D may be present
singly or in combination and are independently selected from the
group consisting of: (1) O--R.sub.5; (2) B and C taken together are
.dbd.O; (3) B and C taken together are .dbd.N--O--R.sub.5; R.sub.1
is selected from the group consisting of: (1) hydrogen; (2)
R.sub.3, where each R.sub.3 is independently selected from
C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl- , optionally substituted with one or more
substituents selected from the group consisting of: i. halogen; ii.
aryl; iii. substituted-aryl; iv. heteroaryl; v.
substituted-heteroaryl; vi. --O--C.sub.1-C.sub.6-alkyl-R.s- ub.5;
and vii. --N--R.sub.6R.sub.7; (3) --C(O)--R.sub.4, where each
R.sub.4 is independently selected from hydrogen or R.sub.3; (4)
--C(O)O--R.sub.3; and (5) --C(O)N--R.sub.6R.sub.7; R.sub.2 is
selected from the group consisting of: (1) a hydroxy protecting
group; (2) R.sub.5; (3) --X--Y--R.sub.5, where X is --C(O),
--C(O)O--, --C(O)NR.sub.6--, or absent, and Y is
C.sub.1-C.sub.6-alkyl or absent; and (4) C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl or C.sub.2-C.sub.6-alkynyl optionally
substituted with one or more substituents selected from the group
consisting of: i. halogen; ii. aryl; iii. substituted-aryl; iv.
heteroaryl; v. substituted-heteroaryl; vi. --O--R.sub.5 where
R.sub.5; vii. --O--C.sub.1-C.sub.6-alkyl-R.sub.5; viii.
--O----C.sub.2-C.sub.6-alkenyl-R.sub.5; ix.
--O--C.sub.2-C.sub.6-al- kynyl-R.sub.5; and x. --N--R.sub.6R.sub.7;
Rp.sub.1 is hydrogen or a hydroxy protecting group; and Z is
selected from the group consisting of: (1) hydrogen; (2) a hydroxy
protecting group; and (3) --X--R.sub.3.
2. A compound according to claim 1 which is represented by the
formula: 15
3. A compound according to claim 2 wherein R.sub.1 and Z are
hydrogen.
4. A compound according to claim 1 which is represented by formula:
16
5. A compound according to claim 4 wherein R.sub.1 is hydrogen.
6. A compound according to claim 1 which is represented by the
formula: 17
7. A compound according to claim 6 wherein R.sub.1 and Z are
hydrogen.
8. A compound according to claim 1 which is represented by the
formula: 18
9. A compound according to claim 8 wherein R.sub.1 is hydrogen.
10. A pharmaceutical composition for treating bacterial infections
comprising a therapeutically effective amount of a compound of
claim 1, or a pharmaceutically acceptable salt, ester or prodrug
thereof, alone or in combination with a pharmaceutically acceptable
carrier.
11. A method for treating bacterial infections comprising
administering to an animal in need of such treatment a
pharmaceutical composition comprising a therapeutically-effective
amount of a compound of claim 1 or a pharmaceutically acceptable
salt, ester or prodrug thereof.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/178,991 (Atty. Docket No. ENP-041), filed
Jun. 25, 2002. This application is also related to commonly
assigned U.S. patent application Ser. No. 10/179,590 (Attorney
Docket No. ENP042), filed on Jun. 25, 2002.
TECHNICAL FIELD
[0002] The present invention relates to novel macrolides having
antibacterial activity and useful in the treatment and prevention
of bacterial infections. More particularly, the invention relates
to a novel class of 11-C-substituted erythromycin derivatives,
compositions containing such compounds and methods for using the
same, as well as processes for making such compounds.
BACKGROUND OF THE INVENTION
[0003] Macrolide antibiotics play a therapeutically important role,
particularly with the emergence of new pathogens. Structural
differences are related to the size of the lactone ring and to the
number and nature (neutral or basic) of the sugars. Macrolides are
classified according to the size of the lactone ring (12, 14, 15 or
16 atoms). The macrolide antibiotic family (14-, 15- and
16-membered ring derivatives) shows a wide range of characteristics
(antibacterial spectrum, side-effects and bioavailability). Among
the commonly used macrolides are erythromycin and clarithromycin.
1
[0004] The search for macrolides active against MLS.sub.B-resistant
strains (MLS.sub.B=Macrolides-Lincosamides-type B Streptogramines)
has become a major goal, together with retaining the overall
profile of the macrolides in terms of stability, tolerance and
pharmacokinetics.
SUMMARY OF THE INVENTION
[0005] The present invention provides a novel class of
11-C-substituted derivatives of clarithromycin possessing
antibacterial activity toward Gram positive and Gram negative
bacteria as well as macrolide Gram positives.
[0006] In one embodiment, the present invention provides compounds
represented by formulae I, II, III or IV, as well as the
pharmaceutically acceptable salts, esters and prodrugs thereof.
2
[0007] In formulae I-IV above,
[0008] A is selected from the group consisting of
[0009] (1) C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl, optionally substituted with one or more
substituents selected from the group consisting of:
[0010] i. halogen;
[0011] ii. aryl;
[0012] iii. substituted aryl;
[0013] iv. heterocyclic;
[0014] v. substituted heterocyclic;
[0015] vi. --O--R.sub.5, where R.sub.5 is selected from the group
consisting of:
[0016] a. hydrogen;
[0017] b. aryl;
[0018] c. substituted aryl;
[0019] d. heterocyclic; and
[0020] e. substituted heterocyclic;
[0021] vii. --O--C.sub.1-C.sub.6-alkyl-R.sub.5, where R.sub.5 is as
previously defined;
[0022] viii. --O--C.sub.2-C.sub.6-alkenyl-R.sub.5, where R.sub.5 is
as previously defined;
[0023] ix. --O--C.sub.2-C.sub.6-alkynyl-R.sub.5, where R.sub.5 is
as previously defined; and
[0024] x. --NR.sub.6R.sub.7, where R.sub.6 and R.sub.7 are each
independently selected from the group consisting of:
[0025] a. hydrogen;
[0026] b. C.sub.1-C.sub.6-alkyl, optionally substituted with one or
more substituents selected from the group consisting of:
[0027] (I) halogen;
[0028] (II) aryl;
[0029] (III) substituted aryl;
[0030] (IV) heterocyclic; and
[0031] (V) substituted heterocyclic;
[0032] c. C.sub.2-C.sub.6-alkenyl, optionally substituted with one
or more substituents selected from the group consisting of:
[0033] (I) halogen;
[0034] (II) aryl;
[0035] (III) substituted aryl;
[0036] (IV) heterocyclic; and
[0037] (V) substituted heterocyclic;
[0038] d. C.sub.2-C.sub.6-alkynyl, optionally substituted with one
or more substituents selected from the group consisting of:
[0039] (I) halogen;
[0040] (II) aryl;
[0041] (III) substituted aryl;
[0042] (IV) heterocyclic; and
[0043] (V) substituted heterocyclic, or
[0044] e. R.sub.6 R.sub.7 taken with the nitrogen atom to which
they are connected form a 3- to 7-membered ring which may
optionally contain one or more functions selected from the group
consisting of:
[0045] (I) --O--;
[0046] (II) --NH--;
[0047] (III) --N(C.sub.1-C.sub.6-alkyl)-;
[0048] (IV) --N(aryl)-;
[0049] (V) --N(heteroaryl)-;
[0050] (VI) --S--;
[0051] (VII) --S(O)--;
[0052] (VIII) --S(O).sub.2--; and
[0053] (IX) --C(O)--;
[0054] (2) --C(O)--R.sub.5, where R.sub.5 is as previously
defined;
[0055] (3) --C(O)--C.sub.1-C.sub.6-alkyl-R.sub.5, where R.sub.5 is
as previously defined;
[0056] (4) --C(O)--C.sub.2-C.sub.6-alkenyl-R.sub.5, where R.sub.5
is as previously defined;
[0057] (5) --C(O)--C.sub.2-C.sub.6-alkynyl-R.sub.5, where R.sub.5
is as previously defined;
[0058] (6) C.sub.1-C.sub.6-alkyl-M-R.sub.5, where M is --OC(O)--,
--OC(O)O--, --OC(O)NR.sub.6--, --C(O)NR.sub.6, --NR.sub.6C(O)--,
--NR.sub.6C(O)O--, --NR.sub.6C(O)NR7--, --NR.sub.6C(NH)NR.sub.7--
or S(O).sub.n--, where n=0, 1 or 2, and where R.sub.5, R.sub.6,
R.sub.7 are as previously defined;
[0059] (7) --C.sub.2-C.sub.6-alkenyl-M-R.sub.5, where M and R.sub.5
are as previously defined; and
[0060] (8) --C.sub.2-C.sub.6-alkynyl-M-R.sub.5, where M and R.sub.5
are as previously defined; B, C, and D may be present singly or in
combination and are independently selected from the group
consisting of:
[0061] (1) hydrogen;
[0062] (2) halogen;
[0063] (3) C.sub.1-C.sub.6-alkyl;
[0064] (4) aryl;
[0065] (5) substituted aryl;
[0066] (6) heteroaryl;
[0067] (7) substituted heteroaryl;
[0068] (8) O--R.sub.5 where R.sub.5 is as previously defined;
[0069] (9) B and C taken together are .dbd.O;
[0070] (10) B and C taken together are .dbd.N--O--R.sub.5, where
R.sub.5 is as previously defined;
[0071] (11) B and C taken together are .dbd.N--N--R.sub.6R.sub.7,
where R.sub.6 and R.sub.7 are as previously defined;
[0072] (12) B and D taken together are --O--;
[0073] (13) B and D taken together are --S--;
[0074] (14) B and D taken together are --N(R.sub.6)--, where
R.sub.6 is as previously defined; and
[0075] (15) B and D taken together with the carbon atoms to which
they are attached form a 4- to 8-membered ring which may optionally
contain one or more functions selected from the group consisting
of:
[0076] i. --O--;
[0077] ii. --NH--;
[0078] iii. --N(C.sub.1-C.sub.6-alkyl)-;
[0079] iv. --N(aryl)-;
[0080] V. --N(heteroaryl)-;
[0081] vi. --S--;
[0082] vii. --S(O)--;
[0083] viii. --S(O).sub.2--; and
[0084] ix. --C(O)--;
[0085] R.sub.1 is selected from the group consisting of:
[0086] (1) hydrogen;
[0087] (2) R.sub.3, where R.sub.3 is C.sub.1-C.sub.6-alkyl,
C.sub.2-C.sub.6-alkenyl or C.sub.2-C.sub.6-alkynyl, optionally
substituted with one or more substituents selected from the group
consisting of:
[0088] i. halogen;
[0089] ii. aryl;
[0090] iii. substituted-aryl;
[0091] iv. heteroaryl;
[0092] v. substituted-heteroaryl;
[0093] vi. --O--C.sub.1-C.sub.6-alkyl-R.sub.5, where R.sub.5 is as
previously defined; and
[0094] vii. --N--R.sub.6R.sub.7, where R.sub.6 and R.sub.7 are as
previously defined;
[0095] (3) --C(O)--R.sub.4, where R.sub.4 is hydrogen or R.sub.3,
where R.sub.3 is as previously defined;
[0096] (4) --C(O)O--R.sub.3, where R.sub.3 is as previously
defined; and
[0097] (5) --C(O)N--R.sub.6R.sub.7, where R.sub.6 and R.sub.7 are
as previously defined;
[0098] R.sub.2 is selected from the group consisting of:
[0099] (1) a hydroxy protecting group;
[0100] (2) R.sub.5, where R.sub.5 is as previously defined;
[0101] (3) --X--Y--R.sub.5, where X is --C(O), --C(O)O--,
--C(O)NR.sub.6--, or absent, and Y is C.sub.1-C.sub.6-alkyl or
absent, where R.sub.5 and R.sub.6 are as previously defined;
and
[0102] (4) C.sub.1-C.sub.6-alkyl, C.sub.2-C.sub.6-alkenyl or
C.sub.2-C.sub.6-alkynyl optionally substituted with one or more
substituents selected from the group consisting of:
[0103] i. halogen;
[0104] ii. aryl;
[0105] iii. substituted-aryl;
[0106] iv. heteroaryl;
[0107] v. substituted-heteroaryl;
[0108] vi. --O--R.sub.5 where R.sub.5, is as previously
defined;
[0109] vii. --O--C.sub.1-C.sub.6-alkyl-R.sub.5, where R.sub.5 is as
previously defined;
[0110] viii. --O--C.sub.2-C.sub.6-alkenyl-R.sub.5, where R.sub.5 is
as previously defined;
[0111] ix. --O--C.sub.2-C.sub.6-alkynyl-R.sub.5, where R.sub.5 is
as previously defined; and
[0112] x. --N--R.sub.6R.sub.7, where R.sub.6 and R.sub.7 are as
previously defined;
[0113] Rp.sub.1 is hydrogen or a hydroxy protecting group; and
[0114] Z is selected from the group consisting of:
[0115] (1) hydrogen;
[0116] (2) a hydroxy protecting group; and
[0117] (3) --X--R.sub.3, where X and R.sub.3 are as previously
defined.
[0118] In other embodiments, the present invention provides
processes for preparing the compounds represented by formulae I-IV,
compositions containing such compounds and methods for using the
same.
DETAILED DESCRIPTION OF THE INVENTION
[0119] A first embodiment of the invention is a compound
represented by formula I as described above, or a pharmaceutically
acceptable salt, ester or prodrug thereof.
[0120] A second embodiment of the invention is a compound
represented by formula II as described above, or a pharmaceutically
acceptable salt, ester or prodrug thereof.
[0121] A third embodiment of the invention is a compound
represented by formula III as described above, or a
pharmaceutically acceptable salt, ester or prodrug thereof.
[0122] A fourth embodiment of the invention is a compound
represented by formula IV as described above, or a pharmaceutically
acceptable salt, ester or prodrug thereof.
[0123] Other preferred embodiments of the invention are: compounds
of formula I where R.sub.1 and Z are each hydrogen and A and
Rp.sub.1 are as previously defined; compounds of formula II where
R.sub.1 is hydrogen and A, R.sub.2 and Rp.sub.1 are as previously
defined; compounds of formula III where R.sub.1 and Z are each
hydrogen and A, B, C, D and Rp.sub.1 are as previously defined; and
compounds of formula IV where R.sub.1 is hydrogen and A, B, C, D,
R.sub.2 and Rp.sub.1 are as previously defined.
[0124] Representative compounds of the invention are those selected
from the group consisting of:
[0125] Compound of formula I: A=CHO, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H;
[0126] Compound of formula I: A=CH.sub.2OH, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H;
[0127] Compound of formula I: A=CH.sub.2OCO-[3-quinolyl],
R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0128] Compound of formula I: A=CH.sub.2OCO-[4-quinolyl],
R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0129] Compound of formula I: A=CH.dbd.CH-phenyl, R.sub.1.dbd.H,
Z=Ac and Rp.sub.1=H;
[0130] Compound of formula I: A=CH.sub.2NH-benzyl, R.sub.1.dbd.H,
Z=Ac and Rp.sub.1=H;
[0131] Compound of formula I: A=CH.sub.2NH-allyl, R.sub.1.dbd.H,
Z=Ac and Rp.sub.1=H;
[0132] Compound of formula II: A=CHO, R.sub.1.dbd.H, R.sub.2.dbd.H
and Rp.sub.1=H;
[0133] Compound of formula II: A=CHO, R.sub.1.dbd.H,
R.sub.2=benzoyl and Rp.sub.1=H;
[0134] Compound of formula II: A=CH.sub.2OH, R.sub.1.dbd.H,
R.sub.2.dbd.H and Rp.sub.1=H;
[0135] Compound of formula II: A=CH.sub.2OCO-[3-quinolyl],
R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0136] Compound of formula II: A=CH.sub.2OCO-[3-quinolyl],
R.sub.1.dbd.H, R.sub.2=benzoyl and Rp.sub.1=H;
[0137] Compound of formula II: A=CH.sub.2OCO-[4-quinolyl],
R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0138] Compound of formula II: A=CH.dbd.CH-phenyl, R.sub.1.dbd.H,
R.sub.2.dbd.H and Rp.sub.1=H;
[0139] Compound of formula II: A=CH.sub.2NH-benzyl, R.sub.1.dbd.H,
R.sub.2.dbd.H and Rp.sub.1=H;
[0140] Compound of formula II: A=CH.sub.2NH-benzyl, R.sub.1.dbd.H,
R.sub.2=benzoyl and Rp.sub.1=H;
[0141] Compound of formula II: A=CH.sub.2NH-allyl, R.sub.1.dbd.H,
R.sub.2.dbd.H and Rp.sub.1=H;
[0142] Compound of formula III: A=CHO, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0143] Compound of formula III: A=CHO, B and D taken together
.dbd.--O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0144] Compound of formula III: A=CHO, B and C taken together are
.dbd.O, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0145] Compound of formula III: A=CHO, B.dbd.OH, D=OH, C.dbd.H,
R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0146] Compound of formula III: A=CH.sub.2OH, B.dbd.H, C.dbd.H,
D=H, R.sub.1=H, Z=Ac and Rp.sub.1=H;
[0147] Compound of formula III: A=CH.sub.2OH, B and D taken
together are --O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H;
[0148] Compound of formula III: A=CH.sub.2OH, B and C taken
together are .dbd.--O, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0149] Compound of formula III: A=CH.sub.2OH, B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0150] Compound of formula III: A=CH.sub.2OCO-[3-quinolyl],
B.dbd.H, C.dbd.H, D=H, R.sub.1=H, Z=Ac and Rp.sub.1=H;
[0151] Compound of formula III: A=CH.sub.2OCO-[3-quinolyl], B and D
taken together .dbd.--O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H;
[0152] Compound of formula III: A=CH.sub.2OCO-[3-quinolyl], B and C
taken together are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H;
[0153] Compound of formula III: A=CH.sub.2OCO-[3-quinolyl],
B.dbd.OH, D=OH, C.dbd.H, R.sub.1=H, Z=Ac and Rp.sub.1=H;
[0154] Compound of formula III: A=CH.sub.2OCO-[4-quinolyl],
B.dbd.H, C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0155] Compound of formula III: A=CH.sub.2OCO-[4-quinolyl], B and D
taken together .dbd.--O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H;
[0156] Compound of formula III: A=CH.sub.2OCO-[4-quinolyl], B and C
taken together are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H;
[0157] Compound of formula III: A=CH.sub.2OCO-[4-quinolyl],
B.dbd.OH, D=OH, C.dbd.H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0158] Compound of formula III: A=CH.dbd.CH-phenyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0159] Compound of formula III: A=CH.sub.2NH-benzyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0160] Compound of formula III: A=CH.sub.2NH-benzyl, B and D taken
together .dbd.--O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H;
[0161] Compound of formula III: A=CH.sub.2NH-benzyl, B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0162] Compound of formula III: A=CH.sub.2NH-benzyl, B.dbd.OH,
D=OH, C.dbd.H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0163] Compound of formula III: A=CH.sub.2NH-allyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1=H, Z=Ac and Rp.sub.1=H;
[0164] Compound of formula III: A=CH.sub.2NH-allyl, B and D taken
together .dbd.--O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H;
[0165] Compound of formula III: A=CH.sub.2NH-allyl, B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0166] Compound of formula III: A=CH.sub.2NH-allyl, B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H;
[0167] Compound of formula IV: A=CHO, B.dbd.H, C.dbd.H, D=H,
R.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0168] Compound of formula IV: A=CHO, B and D taken together
.dbd.--O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H and
Rp.sub.1=H;
[0169] Compound of formula IV: A=CHO, B and C taken together are
.dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0170] Compound of formula IV: A=CHO, B.dbd.OH, D=OH, C.dbd.H,
R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0171] Compound of formula IV: A=CH.sub.2OH, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0172] Compound of formula IV: A=CH.sub.2OH, B and D taken together
.dbd.--O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H and
Rp.sub.1=H;
[0173] Compound of formula IV: A=CH.sub.2OH, B and C taken together
are .dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0174] Compound of formula IV: A=CH.sub.2OH, B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0175] Compound of formula IV: A=CH.sub.2OCO-[3-quinolyl], B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0176] Compound of formula IV: A=CH.sub.2OCO-[3-quinolyl], B and D
taken together .dbd.--O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H
and Rp.sub.1=H;
[0177] Compound of formula IV: A=CH.sub.2OCO-[3-quinolyl], B and C
taken together are .dbd.O, D=H, R1=H, R.sub.2.dbd.H and
Rp.sub.1=H;
[0178] Compound of formula IV: A=CH.sub.2OCO-[3-quinolyl],
B.dbd.OH, D=OH, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H and
Rp.sub.1=H;
[0179] Compound of Formula IV: A=CH.sub.2OCO-[4-quinolyl], B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0180] Compound of Formula IV: A=CH.sub.2OCO-[4-quinolyl], B and D
taken together .dbd.--O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H
and Rp.sub.1=H;
[0181] Compound of Formula IV: A=CH.sub.2OCO-[4quinolyl], B and C
taken together are .dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and
Rp.sub.1=H;
[0182] Compound of Formula IV: A=CH.sub.2OCO-[4-quinolyl],
B.dbd.OH, D=OH, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H and
Rp.sub.1=H;
[0183] Compound of formula IV: A=CH.dbd.CH-phenyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0184] Compound of Formula IV: A=CH.sub.2NH-benzyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and Rp1=H;
[0185] Compound of Formula IV: A=CH.sub.2NH-benzyl, B and D taken
together .dbd.--O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H and
Rp.sub.1=H;
[0186] Compound of Formula IV: A=CH.sub.2NH-benzyl, B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and
Rp.sub.1=H;
[0187] Compound of Formula IV: A=CH.sub.2NH-benzyl, B.dbd.OH,
C.dbd.OH, D=H, R.sub.1=H, R.sub.2.dbd.H and Rp.sub.1=H;
[0188] Compound of Formula IV: A=CH.sub.2NH-allyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H;
[0189] Compound of Formula IV: A=CH.sub.2NH-allyl, B and D taken
together .dbd.--O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H and
Rp.sub.1=H;
[0190] Compound of Formula IV: A=CH.sub.2NH-allyl, B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H and
Rp.sub.1=H; and
[0191] Compound of Formula IV: A=CH.sub.2NH-allyl, B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H.
[0192] Definitions
[0193] The terms "C.sub.1-C.sub.3 alkyl," "C.sub.1-C.sub.6 alkyl"
or "C.sub.1-C.sub.12 alkyl," as used herein, refer to saturated,
straight- or branched-chain hydrocarbon radicals containing between
one and three, one and twelve, or one and six carbon atoms,
respectively. Examples of C.sub.1-C.sub.3 alkyl radicals include
methyl, ethyl, propyl and isopropyl radicals; examples of
C.sub.1-C.sub.6 alkyl radicals include, but are not limited to,
methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl
and n-hexyl radicals; and examples of C.sub.1-C.sub.12 alkyl
radicals include, but are not limited to, ethyl, propyl, isopropyl,
n-hexyl, octyl, decyl, dodecyl radicals.
[0194] The terms "C.sub.2-C.sub.12 alkenyl" or "C.sub.2-C.sub.6
alkenyl," as used herein, denote a monovalent group derived from a
hydrocarbon moiety containing from two to twelve or two to six
carbon atoms having at least one carbon-carbon double bond by the
removal of a single hydrogen atom. Alkenyl groups include, but are
not limited to, for example, ethenyl, propenyl, butenyl,
1-methyl-2-buten-1-yl, and the like.
[0195] The terms "C.sub.2-C.sub.12 alkynyl" or "C.sub.2-C.sub.6
alkynyl," as used herein, denote a monovalent group derived from a
hydrocarbon moiety containing from two to twelve or two to six
carbon atoms having at least one carbon-carbon triple bond by the
removal of two hydrogen atoms. Representative alkynyl groups
include, but are not limited to, for example, ethynyl, 1-propynyl,
1-butynyl, and the like.
[0196] The terms "halo" and "halogen," as used herein, refer to an
atom selected from fluorine, chlorine, bromine and iodine.
[0197] The term "haloalkyl" denotes an alkyl group, as defined
above, having one, or more halogen atoms attached thereto, and is
exemplified by such groups as chloromethyl, bromoethyl,
trifluoromethyl, and the like.
[0198] The term "aryl," as used herein, refers to a mono- or
bicyclic carbocyclic ring system having one or two aromatic rings
including, but not limited to, phenyl, naphthyl,
tetrahydronaphthyl, indanyl, idenyl and the like. Aryl groups
(including bicyclic aryl groups) can be unsubstituted or
substituted with one, two or three substituents independently
selected from lower alkyl, substituted lower alkyl, haloalkyl,
alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, acylamino,
cyano, hydroxy, halo, mercapto, nitro, carboxaldehyde, carboxy,
alkoxycarbonyl and carboxamide. In addition, substituted aryl
groups include tetrafluorophenyl and pentafluorophenyl.
[0199] The term "substituted aryl," as used herein, refers to an
aryl group, as defined herein, substituted by independent
replacement of one, two or three of the hydrogen atoms thereon with
F, Cl, Br, I, OH, NO.sub.2, CN, C(O)--C.sub.1-C.sub.6-alkyl,
C(O)-aryl, C(O)-heteroaryl, CO.sub.2-alkyl, CO.sub.2-aryl,
CO.sub.2-heteroaryl, CONH.sub.2, CONH--C.sub.1-C.sub.6-alkyl,
CONH-aryl, CONH-heteroaryl, OC(O)--C.sub.1-C.sub.6-alkyl,
OC(O)-aryl, OC(O)-heteroaryl, OCO.sub.2-alkyl, OCO.sub.2-aryl,
OCO.sub.2-heteroaryl, OCONH.sub.2, OCONH--C.sub.1-C.sub.6-alkyl,
OCONH-aryl, OCONH-heteroaryl, NHC(O)--C.sub.1-C.sub.6-alkyl,
NHC(O)-aryl, NHC(O)-heteroaryl, NHCO.sub.2-alkyl, NHCO.sub.2-aryl,
NHCO.sub.2-heteroaryl, NHCONH.sub.2, NHCONH--C.sub.1-C.sub.6-alkyl,
NHCONH-aryl, NHCONH-heteroaryl, SO.sub.2--C.sub.1-C.sub.6-alkyl,
SO.sub.2-aryl, SO.sub.2-heteroaryl, SO.sub.2NH.sub.2,
SO.sub.2NH--C.sub.1-C.sub.6-alkyl, SO.sub.2NH-aryl,
SO.sub.2NH-heteroaryl, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, CF.sub.3, CH.sub.2CF.sub.3, CHCl.sub.2,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2NH.sub.2,
CH.sub.2SO.sub.2CH.sub.3, aryl, heteroaryl, benzyl, benzyloxy,
aryloxy, heteroaryloxy, C.sub.1-C.sub.6-alkoxy, methoxymethoxy,
methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino,
C.sub.1-C.sub.3-alkylamino, thio, aryl-thio, heteroarylthio,
benzyl-thio, C.sub.1-C.sub.6-alkyl-thio, or methylthiomethyl.
[0200] The term "heteroaryl," as used herein, refers to a cyclic
aromatic radical having from five to ten ring atoms of which one
ring atom is selected from S, O and N; zero, one or two ring atoms
are additional heteroatoms independently selected from S, O and N;
and the remaining ring atoms are carbon, the radical being joined
to the rest of the molecule via any of the ring atoms, such as, for
example, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl,
imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl,
oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, and
the like.
[0201] The term "substituted heteroaryl," as used herein, refers to
a heteroaryl group as defined herein, substituted by independent
replacement of one, two or three of the hydrogen atoms thereon with
F, Cl, Br, I, OH, NO.sub.2, CN, C(O)--C.sub.1-C.sub.6-alkyl,
C(O)-aryl, C(O)-heteroaryl, CO.sub.2-alkyl, CO.sub.2-aryl,
CO.sub.2-heteroaryl, CONH.sub.2, CONH--C.sub.1-C.sub.6-alkyl,
CONH-aryl, CONH-heteroaryl, OC(O)--C.sub.1-C.sub.6-alkyl,
OC(O)-aryl, OC(O)-heteroaryl, OCO.sub.2-alkyl, OCO.sub.2-aryl,
OCO.sub.2-heteroaryl, OCONH.sub.2, OCONH--C.sub.1-C.sub.6-alkyl,
OCONH-aryl, OCONH-heteroaryl, NHC(O)--C.sub.1-C.sub.6-alkyl,
NHC(O)-aryl, NHC(O)-heteroaryl, NHCO.sub.2-alkyl, NHCO.sub.2-aryl,
NHCO.sub.2-heteroaryl, NHCONH.sub.2, NHCONH--C.sub.1-C.sub.6-alkyl,
NHCONH-aryl, NHCONH-heteroaryl, SO.sub.2--C.sub.1-C.sub.6-alkyl,
SO.sub.2-aryl, SO.sub.2-heteroaryl, SO.sub.2NH.sub.2,
SO.sub.2NH--C.sub.1-C.sub.6-alkyl, SO.sub.2NH-aryl,
SO.sub.2NH-heteroaryl, C.sub.1-C.sub.6-alkyl,
C.sub.3-C.sub.6-cycloalkyl, CF.sub.3, CH.sub.2CF.sub.3, CHCl.sub.2,
CH.sub.2OH, CH.sub.2CH.sub.2OH, CH.sub.2NH.sub.2,
CH.sub.2SO.sub.2CH.sub.3, aryl, heteroaryl, benzyl, benzyloxy,
aryloxy, heteroaryloxy, C.sub.1-C.sub.6-alkoxy, methoxymethoxy,
methoxyethoxy, amino, benzylamino, arylamino, heteroarylamino,
C.sub.1-C.sub.3-alkyl-amino, thio, aryl-thio, heteroarylthio,
benzyl-thio, C.sub.1-C.sub.6-alkyl-thio, or methylthiomethyl.
[0202] The term "C.sub.3-C.sub.12-cycloalkyl" denotes a monovalent
group derived from a monocyclic or bicyclic saturated carbocyclic
ring compound by the removal of a single hydrogen atom. Examples
include, but are not limited to, cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, bicyclo[2.2.1]heptyl, and
bicyclo[2.2.2]octyl.
[0203] The term, "heterocycloalkyl," as used herein, refers to a
non-aromatic 5-, 6- or 7-membered ring or a bi- or tri-cyclic group
comprising fused six-membered rings having between one and three
heteroatoms independently selected from oxygen, sulfur and
nitrogen, wherein (i) each 5-membered ring has 0 to 1 double bonds
and each 6-membered ring has 0 to 2 double bonds, (ii) the nitrogen
and sulfur heteroatoms may optionally be oxidized, (iii) the
nitrogen heteroatom may optionally be quaternized, and (iv) any of
the above heterocyclic rings may be fused to a benzene ring.
Representative heterocycles include, but are not limited to,
pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl,
imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl,
isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, and
tetrahydrofuryl.
[0204] The term "heterocyclic", as used herein, refers to
heterocycloalkyl and heteroaryl. The term "substituted
heterocyclic", as used herein, refers to substituted
heterocycloalkyl and substituted heteroalkyl.
[0205] The term "C.sub.1-C.sub.6 alkoxy," as used herein, refers to
a C.sub.1-C.sub.6 alkyl group, as previously defined, attached to
the parent molecular moiety through an oxygen atom. Examples of
C.sub.1-C.sub.6-alkoxy include, but are not limited to, methoxy,
ethoxy, propoxy, isopropoxy, n-butoxy, tert-butoxy, neopentoxy and
n-hexoxy.
[0206] The term "C.sub.1-C.sub.3-alkyl-amino," as used herein,
refers to one or two C.sub.1-C.sub.3-alkyl groups, as previously
defined, attached to the parent molecular moiety through a nitrogen
atom. Examples of C.sub.1-C.sub.3-alkyl-amino include, but are not
limited to, methylamino, dimethylamino, ethylamino, diethylamino,
and propylamino.
[0207] The term "alkylamino" refers to a group having the structure
--NH(C.sub.1-C.sub.12 alkyl) where C.sub.1-C.sub.12 alkyl is as
previously defined.
[0208] The term "dialkylamino" refers to a group having the
structure --N(C.sub.1-C.sub.12 alkyl) (C.sub.1-C.sub.12 alkyl),
where C.sub.1-C.sub.12 alkyl is as previously defined. Examples of
dialkylamino are, but not limited to, dimethylamino, diethylamino,
methylethylamino, piperidino, and the like.
[0209] The term "alkoxycarbonyl" represents an ester group, i.e.,
an alkoxy group, attached to the parent molecular moiety through a
carbonyl group such as methoxycarbonyl, ethoxycarbonyl, and the
like.
[0210] The term "carboxaldehyde," as used herein, refers to a group
of the formula --CHO.
[0211] The term "carboxy," as used herein, refers to a group of the
formula --COOH.
[0212] The term "carboxamide," as used herein, refers to a group of
the formula --C(O)NH(C.sub.1-C.sub.12 alkyl) or
--C(O)N(C.sub.1-C.sub.12 alkyl)(C.sub.1-C.sub.12 alkyl).
[0213] "Hydroxy protecting group," as used herein, refers to an
easily removable group which is known in the art to protect a
hydroxyl group against undesirable reaction during synthetic
procedures and to be selectively removable. The use of
hydroxy-protecting groups is well known in the art for protecting
groups against undesirable reactions during a synthetic procedure
and many such protecting groups are known, cf, for example, T. H.
Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis,
3rd edition, John Wiley & Sons, New York (1999). Examples of
hydroxy protecting groups include, but are not limited to,
methylthiomethyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,
acyl substituted with an aromatic group and the like.
[0214] The term "protected hydroxy" refers to a hydroxy group
protected with a hydroxy protecting group, as defined above,
including benzoyl, acetyl, trimethylsilyl, triethylsilyl,
methoxymethyl groups, for example.
[0215] The term "aprotic solvent," as used herein, refers to a
solvent that is relatively inert to proton activity, i.e., not
acting as a proton-donor. Examples include, but are not limited to,
hydrocarbons, such as hexane and toluene, for example, halogenated
hydrocarbons, such as, for example, methylene chloride, ethylene
chloride, chloroform, and the like, heterocyclic compounds, such
as, for example, tetrahydrofuran and N-methylpyrrolidinone, and
ethers such as diethyl ether, bis-methoxymethyl ether. Such
compounds are well known to those skilled in the art, and it will
be obvious to those skilled in the art that individual solvents or
mixtures thereof may be preferred for specific compounds and
reaction conditions, depending upon such factors as the solubility
of reagents, reactivity of reagents and preferred temperature
ranges, for example. Further discussions of aprotic solvents may be
found in organic chemistry textbooks or in specialized monographs,
for example: Organic Solvents Physical Properties and Methods of
Purification, 4th ed., edited by John A. Riddick et al., Vol. II,
in the Techniques of Chemistry Series, John Wiley & Sons, NY,
1986.
[0216] The term "protic solvent" or "protogenic solvent" as used
herein, refers to a solvent that tends to provide protons, such as
an alcohol, for example, methanol, ethanol, propanol, isopropanol,
butanol, t-butanol, water and the like. Such solvents are well
known to those skilled in the art, and it will be obvious to those
skilled in the art that individual solvents or mixtures thereof may
be preferred for specific compounds and reaction conditions,
depending upon such factors as the solubility of reagents,
reactivity of reagents and preferred temperature ranges, for
example. Further discussions of protogenic solvents may be found in
organic chemistry textbooks or in specialized monographs, for
example: Organic Solvents Physical Properties and Methods of
Purification, 4th ed., edited by John A. Riddick et al., Vol. II,
in the Techniques of Chemistry Series, John Wiley & Sons, NY,
1986.
[0217] Numerous asymmetric centers may exist in the compounds of
the present invention. Except where otherwise noted, the present
invention contemplates the various stereoisomers and mixtures
thereof. Accordingly, whenever a bond is represented by a wavy
line, it is intended that a mixture of stereo-orientations or an
individual isomer of assigned or unassigned orientation may be
present.
[0218] As used herein, the term "pharmaceutically acceptable salt"
refers to those salts which are, within the scope of sound medical
judgment, suitable for use in contact with the tissues of humans
and lower animals without undue toxicity, irritation, allergic
response and the like, and are commensurate with a reasonable
benefit/risk ratio. Pharmaceutically acceptable salts are well
known in the art. For example, S. M. Berge, et al. describes
pharmaceutically acceptable salts in detail in J. Pharmaceutical
Sciences, 66: 1-19 (1977), incorporated herein by reference. The
salts can be prepared in situ during the final isolation and
purification of the compounds of the invention, or separately by
reacting the free base function with a suitable organic acid.
Examples of pharmaceutically acceptable, nontoxic acid addition
salts are salts of an amino group formed with inorganic acids such
as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric
acid and perchloric acid or with organic acids such as acetic acid,
oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid
or malonic acid or by using other methods used in the art such as
ion exchange. Other pharmaceutically acceptable salts include
adipate, alginate, ascorbate, aspartate, benzenesulfonate,
benzoate, bisulfate, borate, butyrate, camphorate,
camphorsulfonate, citrate, cyclopentanepropionate, digluconate,
dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate,
glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate,
hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate,
laurate, lauryl sulfate, malate, maleate, malonate,
methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate,
oleate, oxalate, palmitate, pamoate, pectinate, persulfate,
3-phenylpropionate, phosphate, picrate, pivalate, propionate,
stearate, succinate, sulfate, tartrate, thiocyanate,
p-toluenesulfonate, undecanoate, valerate salts, and the like.
Representative alkali or alkaline earth metal salts include sodium,
lithium, potassium, calcium, magnesium, and the like. Further
pharmaceutically acceptable salts include, when appropriate,
nontoxic ammonium, quaternary ammonium, and amine cations formed
using counterions such as halide, hydroxide, carboxylate, sulfate,
phosphate, nitrate, alkyl having from 1 to 6 carbon atoms,
sulfonate and aryl sulfonate.
[0219] As used herein, the term "pharmaceutically acceptable ester"
refers to esters that hydrolyze in vivo and include those that
break down readily in the human body to leave the parent compound
or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic
acids, particularly alkanoic, alkenoic, cycloalkanoic and
alkanedioic acids, in which each alkyl or alkenyl moiety
advantageously has not more than 6 carbon atoms. Examples of
particular esters include, but are not limited to, formates,
acetates, propionates, butyrates, acrylates and
ethylsuccinates.
[0220] The term "pharmaceutically acceptable prodrugs" as used
herein refers to those prodrugs of the compounds of the present
invention which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of humans and lower
animals with undue toxicity, irritation, allergic response, and the
like, commensurate with a reasonable benefit/risk ratio, and
effective for their intended use, as well as the zwitterionic
forms, where possible, of the compounds of the present invention.
The term "prodrug" refers to compounds that are rapidly transformed
in vivo to yield the parent compound of the above formula, for
example by hydrolysis in blood. A thorough discussion is provided
in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems,
Vol. 14 of the ACS Symposium Series, and in Edward B. Roche, ed.,
"Bioreversible Carriers in Drug Design", American Pharmaceutical
Association and Pergamon Press, 1987, both of which are
incorporated herein by reference.
[0221] Antibacterial Activity
[0222] Susceptibility tests can be used to quantitatively measure
the in vitro activity of an antimicrobial agent against a given
bacterial isolate. Compounds were tested for in vitro antibacterial
activity by a micro-dilution method. Minimal Inhibitory
Concentration (MIC) was determined in 96 well microtiter plates
utilizing the appropriate Mueller Hinton Broth medium (CAMHB) for
the observed bacterial isolates. Antimicrobial agents were serially
diluted (2-fold) in DMSO to produce a concentration range from
about 64 .mu.g/ml to about 0.03 .mu.g/ml. The diluted compounds (2
.mu.l/well) were then transferred into sterile, uninoculated CAMHB
(0.2 mL) by use of a 96 fixed tip-pipetting station. The inoculum
for each bacterial strain was standardized to 5.times.10.sup.5
CFU/mL by optical comparison to a 0.5 McFarland turbidity standard.
The plates were inoculated with 10 .mu.l/well of adjusted bacterial
inoculum. The 96 well plates were covered and incubated at
35.+-.2.degree. C. for 24 hours in ambient air environment.
Following incubation, plate wells were visually examined by Optical
Density measurement for the presence of growth (turbidity). The
lowest concentration of an antimicrobial agent at which no visible
growth occurs was defined as the MIC. The compounds of the
invention generally demonstrated an MIC in the range from about 64
.mu.g/ml to about 0.03 .mu.g/ml.
[0223] All in vitro testing follows the guidelines described in the
Approved Standards M7-A4 protocol, published by the National
Committee for Clinical Laboratory Standards (NCCLS).
[0224] Pharmaceutical Compositions
[0225] The pharmaceutical compositions of the present invention
comprise a therapeutically effective amount of a compound of the
present invention formulated together with one or more
pharmaceutically acceptable carriers. As used herein, the term
"pharmaceutically acceptable carrier" means a non-toxic, inert
solid, semi-solid or liquid filler, diluent, encapsulating material
or formulation auxiliary of any type. Some examples of materials
which can serve as pharmaceutically acceptable carriers are sugars
such as lactose, glucose and sucrose; starches such as corn starch
and potato starch; cellulose and its derivatives such as sodium
carboxymethyl cellulose, ethyl cellulose and cellulose acetate;
powdered tragacanth; malt; gelatin; talc; excipients such as cocoa
butter and suppository waxes; oils such as peanut oil, cottonseed
oil, safflower oil, sesame oil, olive oil, corn oil and soybean
oil; glycols such as propylene glycol; esters such as ethyl oleate
and ethyl laurate; agar; buffering agents such as magnesium
hydroxide and aluminun hydroxide; alginic acid; pyrogen-free water;
isotonic saline; Ringer's solution; ethyl alcohol, and phosphate
buffer solutions, as well as other non-toxic compatible lubricants
such as sodium lauryl sulfate and magnesium stearate, as well as
coloring agents, releasing agents, coating agents, sweetening,
flavoring and perfuming agents, preservatives and antioxidants can
also be present in the composition, according to the judgment of
the formulator. The pharmaceutical compositions of this invention
can be administered to humans and other animals orally, rectally,
parenterally, intracisternally, intravaginally, intraperitoneally,
topically (as by powders, ointments, or drops), buccally, or as an
oral or nasal spray.
[0226] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, microemulsions, solutions,
suspensions, syrups and elixirs. In addition to the active
compounds, the liquid dosage forms may contain inert diluents
commonly used in the art such as, for example, water or other
solvents, solubilizing agents and emulsifiers such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl
alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,
dimethylformamide, oils (in particular, cottonseed, groundnut,
corn, germ, olive, castor, and sesame oils), glycerol,
tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid
esters of sorbitan, and mixtures thereof. Besides inert diluents,
the oral compositions can also include adjuvants such as wetting
agents, emulsifying and suspending agents, sweetening, flavoring,
and perfuming agents.
[0227] Injectable preparations, for example, sterile injectable
aqueous or oleaginous suspensions, may be formulated according to
the known art using suitable dispersing or wetting agents and
suspending agents. The sterile injectable preparation may also be a
sterile injectable solution, suspension or emulsion in a nontoxic
parenterally acceptable diluent or solvent, for example, as a
solution in 1,3-butanediol. Among the acceptable vehicles and
solvents that may be employed are water, Ringer's solution, U.S.P.
and isotonic sodium chloride solution. In addition, sterile, fixed
oils are conventionally employed as a solvent or suspending medium.
For this purpose any bland fixed oil can be employed including
synthetic mono- or diglycerides. In addition, fatty acids such as
oleic acid are used in the preparation of injectables.
[0228] The injectable formulations can be sterilized, for example,
by filtration through a bacterial-retaining filter, or by
incorporating sterilizing agents in the form of sterile solid
compositions which can be dissolved or dispersed in sterile water
or other sterile injectable medium prior to use.
[0229] In order to prolong the effect of a drug, it is often
desirable to slow the absorption of the drug from subcutaneous or
intramuscular injection. This may be accomplished by the use of a
liquid suspension of crystalline or amorphous material with poor
water solubility. The rate of absorption of the drug then depends
upon its rate of dissolution, which, in turn, may depend upon
crystal size and crystalline form. Alternatively, delayed
absorption of a parenterally administered drug form is accomplished
by dissolving or suspending the drug in an oil vehicle. Injectable
depot forms are made by forming microencapsule matrices of the drug
in biodegradable polymers such as polylactide-polyglycolide.
Depending upon the ratio of drug to polymer and the nature of the
particular polymer employed, the rate of drug release can be
controlled. Examples of other biodegradable polymers include
poly(orthoesters) and poly(anhydrides). Depot injectable
formulations are also prepared by entrapping the drug in liposomes
or microemulsions that are compatible with body tissues.
[0230] Compositions for rectal or vaginal administration are
preferably suppositories which can be prepared by mixing the
compounds of this invention with suitable non-irritating excipients
or carriers such as cocoa butter, polyethylene glycol or a
suppository wax which are solid at ambient temperature but liquid
at body temperature and therefore melt in the rectum or vaginal
cavity and release the active compound.
[0231] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. In such solid dosage forms,
the active compound is mixed with at least one inert,
pharmaceutically acceptable excipient or carrier such as sodium
citrate or dicalcium phosphate and/or: a) fillers or extenders such
as starches, lactose, sucrose, glucose, mannitol, and silicic acid,
b) binders such as, for example, carboxymethylcellulose, alginates,
gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants
such as glycerol, d) disintegrating agents such as agar-agar,
calcium carbonate, potato or tapioca starch, alginic acid, certain
silicates, and sodium carbonate, e) solution retarding agents such
as paraffin, f) absorption accelerators such as quaternary ammonium
compounds, g) wetting agents such as, for example, cetyl alcohol
and glycerol monostearate, h) absorbents such as kaolin and
bentonite clay, and i) lubricants such as talc, calcium stearate,
magnesium stearate, solid polyethylene glycols, sodium lauryl
sulfate, and mixtures thereof. In the case of capsules, tablets and
pills, the dosage form may also comprise buffering agents.
[0232] Solid compositions of a similar type may also be employed as
fillers in soft and hard-filled gelatin capsules using such
excipients as lactose or milk sugar as well as high molecular
weight polyethylene glycols and the like.
[0233] The solid dosage forms of tablets, dragees, capsules, pills,
and granules can be prepared with coatings and shells such as
enteric coatings and other coatings well known in the
pharmaceutical formulating art. They may optionally contain
opacifying agents and can also be of a composition that they
release the active ingredient(s) only, or preferentially, in a
certain part of the intestinal tract, optionally, in a delayed
manner. Examples of embedding compositions that can be used include
polymeric substances and waxes.
[0234] Dosage forms for topical or transdermal administration of a
compound of this invention include ointments, pastes, creams,
lotions, gels, powders, solutions, sprays, inhalants or patches.
The active component is admixed under sterile conditions with a
pharmaceutically acceptable carrier and any needed preservatives or
buffers as may be required. Ophthalmic formulation, ear drops, eye
ointments, powders and solutions are also contemplated as being
within the scope of this invention.
[0235] The ointments, pastes, creams and gels may contain, in
addition to an active compound of this invention, excipients such
as animal and vegetable fats, oils, waxes, paraffins, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones,
bentonites, silicic acid, talc and zinc oxide, or mixtures
thereof.
[0236] Powders and sprays can contain, in addition to the compounds
of this invention, excipients such as lactose, talc, silicic acid,
aluminum hydroxide, calcium silicates and polyamide powder, or
mixtures of these substances. Sprays can additionally contain
customary propellants such as chlorofluorohydrocarbons.
[0237] Transdermal patches have the added advantage of providing
controlled delivery of a compound to the body. Such dosage forms
can be made by dissolving or dispensing the compound in the proper
medium. Absorption enhancers can also be used to increase the flux
of the compound across the skin. The rate can be controlled by
either providing a rate controlling membrane or by dispersing the
compound in a polymer matrix or gel.
[0238] According to the methods of treatment of the present
invention, bacterial infections are treated or prevented in a
patient such as a human or other animals by administering to the
patient a therapeutically effective amount of a compound of the
invention, in such amounts and for such time as is necessary to
achieve the desired result. By a "therapeutically effective amount"
of a compound of the invention is meant a sufficient amount of the
compound to treat bacterial infections, at a reasonable
benefit/risk ratio applicable to any medical treatment. It will be
understood, however, that the total daily usage of the compounds
and compositions of the present invention will be decided by the
attending physician within the scope of sound medical judgment. The
specific therapeutically effective dose level for any particular
patient will depend upon a variety of factors including the
disorder being treated and the severity of the disorder; the
activity of the specific compound employed; the specific
composition employed; the age, body weight, general health, sex and
diet of the patient; the time of administration, route of
administration, and rate of excretion of the specific compound
employed; the duration of the treatment; drugs used in combination
or coincidental with the specific compound employed; and like
factors well known in the medical arts.
[0239] The total daily dose of the compounds of this invention
administered to a human or other animal in single or in divided
doses can be in amounts, for example, from 0.01 to 50 mg/kg body
weight or more usually from 0.1 to 25 mg/kg body weight. Single
dose compositions may contain such amounts or submultiples thereof
to make up the daily dose. In general, treatment regimens according
to the present invention comprise administration to a patient in
need of such treatment from about 10 mg to about 1000 mg of the
compound(s) of this invention per day in single or multiple
doses.
[0240] The pharmaceutical compositions of this invention can be
administered to fish by blending them in the fish feed to be
administered orally or may be dissolved in water in which sick fish
are placed to swim around (a method using a so-called "medicated
bath"). The dosage for the treatment of fish differs depending upon
the purpose of administration (prevention or cure of disease) and
type, size and extent of infection of the fish to be treated.
Generally, a dosage of 5-1000 mg, preferably 20-100 mg, per kg of
body weight of fish may be administered per day, either at one time
or divided into several times. It will be recognized that the
above-specified dosage is only a general range which may be reduced
or increased depending upon the age, body weight, condition of
disease, etc. of the fish.
[0241] Abbreviations
[0242] Abbreviations which may be used in the descriptions of the
schemes and the examples that follow are: Ac for acetyl; AcOOH for
peroxyacetic acid; AIBN for azobisisobutyronitrile; BHT for
2,6-di-tert-butyl4-methylp- henol, Bn for benzyl; Bz for benzoyl;
Boc for tert-butoxycarbonyl; BSA for bis-trimethylsilyl acetamide,
t-BuOOH for tertiary-butyl hydroperoxide, Bu.sub.3SnH for
tributyltin hydride; CAMHB for cation adjusted Mueller-Hinton
broth, CDI for carbonyldiimidazole; DBA for dibenzylidene acetone;
DBU for 1,8-diazabicyclo[5.4.0]undec-7-ene; DCC for
dicyclohexylcarbodiimide, DEAD for diethylazodicarboxylate; DIBAL-H
for diisobutylaluminum hydride, DMAP for
4-N,N-dimethylamino-pyridine; DME for 1,2-dimethoxyethane, DMF for
dimethyl formamide; DMSO for dimethylsulfoxide; DPPA for
diphenylphosphoryl azide; DPPB for diphenylphosphino butane; EtOAc
for ethyl acetate; HMDS for hexamethyldisilazane; KHMDS for
potassium bis(trimethylsilyl)amide; LAH for lithium aluminum
hydride, LDA for lithium diisopropyl amide; m-CPBA for
3-chloroperoxybenzoic acid, MeOH for methanol; MOM for
methoxymethyl; NaHMDS for sodium bis(trimethylsilyl)amide; NMO for
N-methylmorpholine N-oxide; Ph for phenyl; Red-Al for sodium
bis-(2-methoxyethoxy)aluminum hydride, RT for room temperature;
TBAF for tetrabutylammonium fluoride; TBS for tert-butyl
dimethylsilyl; TEA for triethylamine; TFA for trifluoroacetic acid;
THF for tetrahydrofuran; TMS for trimethyl silyl; and TPP for
triphenylphosphine
[0243] Synthetic Methods
[0244] The compounds and processes of the present invention will be
better understood in connection with the following synthetic
schemes that are illustrative of the methods by which the compounds
of the invention may be prepared. The groups A, B, C, D, R.sub.2,
Rp.sub.1, and Z are as defined previously, unless otherwise noted
below. 34
[0245] One process of the present invention for the preparations of
compounds of formula I is as shown in Scheme 1. According to this
synthetic scheme, the preparation of the compounds of formula I
includes the step of protecting Clarithromycin (compound 1 of
Scheme 1) with an acid anhydride, acid chloride or a silylating
reagent such as silyl chloride, HMDS, BSA and the like in an
aprotic solvent such as methylene chloride, THF, chloroform, DMF,
acetonitrile or the like at a temperature from about 0.degree. C.
to about 50.degree. C. for 3-72 hours to provide compound 2.
Compound 2 is treated with ethylene carbonate, either as a neat
mixture or in an aprotic solvent at room temperature to about
150.degree. C. to provide compound 3. Alternatively, compound 2 is
treated with a sulfonic acid chloride or sulfonic acid anhydride in
the presence of TEA, pyridine or the like in an aprotic solvent at
a temperature of from about 0.degree. C. to about 50.degree. C. to
provide the corresponding 11-O-sulfonate ester which is eliminated
in a separate step by treatment with a base such as DBU, DMAP,
KOt-Bu, or the like at from room temperature to about 100.degree.
C. to provide compound 3. Compound 3 further reacts with a reducing
agent such as sodium borohydride, sodium triacetoxy borohydride, or
the like in a protic solvent such as methanol, ethanol,
isopropanol, or the like, or mixtures thereof, with an aprotic
solvent such as THF, DME, or the like at from about -20.degree. C.
to about 50.degree. C., to provide compound 4. Alternatively,
compound 3 is treated with DIBAL-H, LAH, RedAl or the like in an
aprotic solvent at from about -80.degree. C. to about room
temperature to provide compound 4. Compound 4 is alkylated
selectively at the 9 oxygen by treatment with a vinyl ether such as
ethyl vinyl ether, or butyl vinyl ether in the presence of a
mercury (II) salt, either as a neat mixture or in an aprotic
solvent, at from room temperature to about 100.degree. C. to afford
compound 5. Compound 5 is thermolyzed in an aprotic solvent such as
toluene, xylenes, or decahydronaphthalene at a temperature of from
about 80.degree. C. to about 200.degree. C. for 3 to 72 hours, to
afford the Claisen rearrangement product 6. Compound 6 is treated
with methanol at from about 0.degree. C. to about 60.degree. C. to
remove the Rp, protecting group at the 2' position to form compound
7. Compound 7 is deprotected to form compound 8. When Z is a silyl
protecting group, the deprotection process includes, for example,
but is not limited to, acid hydrolysis with dilute aqueous acid
(0.1-2 N) such as hydrochloric acid, hydrofluoric acid, sulfuric
acid, trifluoroacetic acid, acetic acid or the like, optionally in
an organic solvent such as acetone, acetonitrile, methanol, ethanol
or the like, or combinations thereof, or TBAF or the like; When Z
is an ester protecting group, the deprotection process includes,
for example, but is not limited to, base hydrolysis with an
alkaline hydroxide aqueous solution, optionally in an organic
solvent such as THF, methanol, acetonitrile or the like, at from
about room temperature to 70.degree. C. for 1-24 hours or other
like conditions. Compound 8 may be further derivatized at the
4"-hydroxy position as described in Antimicrob. Agents Chemother.
1989, vol 33, page 78-81 or European Patent 895999. 5
[0246] In another process of the present invention, for the
preparation of the compounds of formula I (as shown in Scheme 2),
compound 6 from Scheme 1 is reacted further by reductive amination
methods with primary or secondary amines in the presence of sodium
cyanoborohydride or similar reducing agents, in a protic solvent
such as methanol, ethanol, isopropanol or the like to afford
compound 9, where R.sub.6 and R.sub.7 are as defined previously.
Compound 9 is treated with methanol as described in Scheme 1 to
form compound 10. Compound 10 is then deprotected to provide
compound 11 as described in Scheme 1. 67
[0247] In another process of the present invention for the
preparation of the compounds of formula I (as shown in Scheme 3),
compound 6 from Scheme 1 is reduced with sodium cyanoborohydride,
lithium borohydride, or the like, in a protic solvent such as
methanol, ethanol, isopropanol or the like, or mixtures thereof,
with an aprotic solvent such as THF, DME, or the like, at from
about -20.degree. C. to about 50.degree. C., to provide compound
12. Compound 12 is then either alkylated or acylated to produce
compound 13 where X is --R.sub.5 or --C(O)R.sub.5, and R.sub.5 is
as defined previously. The alkylating process is either performed
with palladium catalyzed allylation with a tert-butyl allyl
carbonate or is done with other alkylating agents, such as, for
example, an alkyl halide, alkyl sulfonate, propargyl halide, allyl
halide, benzylic halide, or the like, in the presence of a base
such as sodium hydride, potassium hydride, potassium tert-butoxide,
potassium hydroxide, KHMDS, or the like in an aprotic solvent such
as THF, DMSO, DMF, dioxane, or the like, or mixtures thereof, at a
temperature of from about -20.degree. C. to about 60.degree. C. The
acylation process involves the use of a carboxylic acid, its
anhydride or mixed anhydride, an acid halide or other activated
acyl derivatives, optionally with the addition of a coupling agent
such as DCC or the like, and optionally with the addition of DMAP
and imidazole or the like. Compound 13 is treated with methanol as
described in Scheme 1 to form compound 14. Compound 14 is then
deprotected to provide compound 15 as described in Scheme 1. 8
[0248] In another process of the present invention for the
preparation of the compounds of formula I (as shown in Scheme 4),
compound 6 from Scheme 1 is reacted with an alkyl, substituted
alkyl, allylic, or propargylic phosphorane or phosphonate ylide in
an aprotic solvent at a temperature of from about -20.degree. C. to
about 80.degree. C. to afford compounds of formula 16, where
R.sub.1 is as defined previously. Compound 16 is optionally
hydrogenated with palladium on carbon, platinum oxide, or the like
under 14 atmospheres of hydrogen in an organic solvent such as
methanol, ethanol, ethyl acetate or the like at a temperature of
from about 0.degree. C. to about 50.degree. C. for 1-36 hours to
provide the corresponding saturated linker at the C-11 position.
Compound 16 is treated with methanol as described in Scheme 1 to
form compound 17. Compound 17 is then deprotected to provide
compound 18 as described in Scheme 1. 9
[0249] A process of the present invention for the preparation of
the compounds of formula II (as shown in Scheme 5) includes the
step of reacting compound 19 with dilute aqueous acid (0.1-2N) such
as hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic
acid or the like, optionally in a solvent such as water, acetone,
acetonitrile, methanol, ethanol or the like, or combinations
thereof, at a temperature of from about 0.degree. C. to about
70.degree. C. for 1-24 hours to provide compound 20. Compound 20 is
then either alkylated or acylated to produce compound 21. The
alkylating process is either done with palladium catalyzed
allylation with tert-butyl allyl carbonate, as described in scheme
1, or is done with other alkylating agents, such as, for example,
an alkyl halide, alkyl sulphonate, propargyl halide, allyl halide,
benzylic halide, or the like, in the presence of a base such as
sodium hydride, potassium hydride, potassium tert-butoxide,
potassium hydroxide, KHMDS, or the like in an aprotic solvent such
as THF, DMSO, DMF, dioxane, or the like, or mixtures thereof, at a
temperature of from about -20.degree. C. to about 60.degree. C. The
acylation process involves the use of a carboxylic acid, its
anhydride or mixed anhydride, acid halide or other activated acyl
derivatives, optionally with the addition of a coupling agent such
as DCC or the like, and optionally with the addition of DMAP and
imidazole or the like. Compound 21 can be treated with methanol as
described in Scheme 1 to produce compound 22. 10
[0250] A process of the present invention for the preparation of
the compounds of formula III (as shown in Scheme 6) includes the
step of reacting compound 19 of Scheme 5 with palladium on carbon,
platinum oxide, or the like under 1-50 atmospheres of hydrogen in
an organic solvent such as methanol, ethanol, ethyl acetate or the
like at a temperature of from about 0.degree. C. to about
100.degree. C. for 1-36 hours to provide the corresponding compound
23. Compound 23 is treated with methanol as described in Scheme 1
to form compound 24. Compound 24 is then deprotected as described
in Scheme 1 to provide compound 25. 11
[0251] Another process of the present invention for the preparation
of the compounds of formula III (as shown in Scheme 7) includes the
step of reacting compound 19 of Scheme 5 with an oxidant such as
m-CPBA, AcOOH, t-BuOOH or the like in an aprotic solvent to provide
compound 26. Compound 26 is treated with methanol as described in
Scheme 1 to form compound 27. Compound 27 is then deprotected as
described in Scheme 1 to provide compound 28. 12
[0252] Another process of the present invention for the preparation
of the compounds of formula III (as shown in Scheme 8) includes the
step of alkylating compound 26 of Scheme 7 with an appropiate
nucleophile, such as, for example, an alkyl, allylic, propargylic
or aryl cuprate, or with azide, halide or cyanide anion, or the
like, to afford compound 29 where B is an alkyl, allyl, or
propargyl group, or a nitrile, halide or azide. Alternatively,
compound 26 may be treated with a Lewis acid such as
BF.sub.3-etherate, MgBr.sub.2-etherate, and the like, in an aprotic
solvent to afford compound 30. 13
[0253] Another process of the present invention for the preparation
of the compounds of formula IV (as shown in Scheme 9) includes the
step of reacting compound 31 with dilute aqueous acid (0.1-2N) such
as, for example, hydrochloric acid, sulfuric acid, trifluoroacetic
acid, acetic acid or the like, optionally in a solvent such as
water, acetone, acetonitrile, methanol, ethanol or the like, or
combinations thereof, at a temperature of from about 0.degree. C.
to about 70.degree. C. for 1-24 hours to provide compound 32.
Compound 32 is then either alkylated or acylated to produce
compound 33. The alkylating process is either done with palladium
catalyzed allylation with tert-butyl allyl carbonate as described
in scheme 1, or is done with other alkylating agents, such as, for
example, an alkyl halide, alkyl sulphonate, propargyl halide, allyl
halide, benzylic halide, or the like, in the presence of a base
such as sodium hydride, potassium hydride, potassium tert-butoxide,
potassium hydroxide, KHMDS, or the like in an aprotic solvent such
as THF, DMSO, DMF, dioxane, or the like, or mixtures thereof, at a
temperature of from about -20.degree. C. to about 60.degree. C. The
acylation process involves the use of a carboxylic acid, its
anhydride or mixed anhydride, acid halide or other activated acyl
derivatives, optionally with the addition of a coupling agent such
as DCC or the like, and optionally with the addition of DMAP and
imidazole or the like. Compound 33 is treated with methanol as
described in Scheme 1 to produce compound 34.
EXAMPLES
[0254] The procedures described above for preparing the compounds
of the present invention will be better understood in connection
with the following examples, which are intended to be illustrative
only and not limiting of the scope of the invention. Various
changes and modifications to the disclosed embodiments will be
apparent to those skilled in the art. Such changes and
modifications, including without limitation, those relating to the
chemical structures, substituents, derivatives, intermediates,
syntheses, formulations and/or methods of the invention may be made
without departing from the spirit of the invention and the scope of
the appended claims.
Example 1
Compound of Formula I: A=-CHO, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H
Step 1a. Compound 2 of Scheme (1): Z=Ac and Rp.sub.1=Ac
[0255] Acetic anhydride (2.1 mL, 22 mmol) was added dropwise over 5
minutes to a stirred 0.degree. C. solution of clarithromycin (7.48
g, 10 mmol), triethylamine (3.5 ml, 25 mmol), and DMAP (122 mg, 1
mmol) in 50 mL THF. The solution was stirred at 0.degree. C. for 1
h, then allowed to warm to RT and stirred 14 hours. The reaction
mixture was diluted with CH.sub.2Cl.sub.2 (200 mL) and washed with
10% aqueous CuSO.sub.4 (2.times.200 mL) and with brine (1.times.100
mL). The aqueous washes were back-extracted with CH.sub.2Cl.sub.2
(3.times.200 mL) and the combined organic extracts dried on
K.sub.2CO.sub.3, filtered, and concentrated in vacuo to give the
title compound as a white solid (8.2 g). This material was
subjected to silica gel chromatography (elution with 3% MeOH in
CH.sub.2Cl.sub.2) to afford 8.1 g (97%) of analytically pure
diacetate 2.
[0256] MS (ESI) m/z=832 (M+H).sup.+. .sup.13C NMR (100 MHz,
CDCl.sub.3): .delta. 221.3, 175.7, 170.6, 100.1, 95.9, 80.3, 78.7,
78.4, 77.8, 76.7, 74.4, 72.9, 72.1, 69.3, 67.4, 63.3 (2), 50.7,
49.5, 45.4, 45.0, 40.9, 38.8, 38.7, 37.4, 35.3, 31.3, 21.7, 21.3
(2), 21.1, 19.9, 18.5, 18.1, 16.3, 16.1, 14.4, 12.5, 10.7, 9.2.
Step 1b. Compound 3 of Scheme 1: Z=Ac and Rp.sub.1=Ac
[0257] A pressure tube was charged with the title compound of step
1a (832 mg, 1 mmol), triethylamine (0.42 mL, 3 mmol), and ethylene
carbonate (5 g). The mixture was flushed with nitrogen, sealed, and
heated in an oil bath maintained at 85-90.degree. C. for 6 h. The
mixture was then cooled, diluted with 50 mL CH.sub.2Cl.sub.2, and
washed with H.sub.2O (100 mL) followed by brine (50 mL). The
aqueous washes were back-extracted with CH.sub.2Cl.sub.2
(2.times.50 mL) and the combined organic extracts were dried
(K.sub.2CO.sub.3), filtered, and concentrated in vacuo to give 3.9
g of a yellow solid. Purification by silica gel chromatography
afforded the title compound (450 mg) along with 360 mg of
unconverted starting material.
[0258] MS (ESI) m/z=815 (M+H).sup.+.
Step 1c. Compound 4 of Scheme 1: Z=Ac and Rp.sub.1=Ac
[0259] Sodium borohydride (0.5 g, 13.3 mmol) was added portion-wise
to a stirred methanolic solution of the compound from step 1b (3.6
g in 50 mL). This solution was allowed to warm to room temperature
and stirred for 1 hour. The reaction mixture was diluted with 200
mL aqueous NaHCO.sub.3 and extracted with ether (4.times.100 mL).
The combined organic extracts were dried over K.sub.2CO.sub.3,
filtered, and concentrated in vacuo to give 3.9 g of a solid
residue which was purified by silica gel chromatography (elution
with 2.5% MeOH/CH.sub.2Cl.sub.2, cont. NH.sub.3) to afford 2.8 g
(78%) of the title compound as a colorless solid.
[0260] MS (ESI) m/z=816 (M+H).sup.+.
Step 1d. Compound 5 of Scheme 1: Z=Ac and Rp.sub.1=Ac
[0261] A 1 dram vial was charged with the compound of step 1c (100
mg, 0.12 mmol), butylvinyl ether (1 mL), and HgOAc (43 mg, 0.13
mmol). The vial was sealed and heated in a 60.degree. C. oil bath
for 2 h. The reaction mixture was cooled, diluted to 50 mL with
ether, and washed with aqueous NaHCO.sub.3 (2.times.25 mL). The
aqueous washes were back-extracted with ether (2.times.30 mL). The
combined organic extracts were dried on K.sub.2CO.sub.3, filtered,
and concentrated in vacuo to give 125 mg of a colorless oil which
was purified by silica gel chromatography (elution with 2% MeOH in
CH.sub.2Cl.sub.2 containing 0.2% NH.sub.3) to afford the title
compound as a colorless solid (94 mg, 93%).
[0262] MS (ESI) m/z=842 (M+H).sup.+.
Step 1e. Compound of formula I: A=CHO, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=Ac
[0263] A pressure tube equipped with a purge valve and thermowell
was charged with the compound of step 1d (450 mg, 0.53 mmol), BHT
(12 mg, 0.05 mmol), and toluene (150 mL). The mixture was degassed
by alternately stirring under vacuum, and purging with dry
nitrogen. The vessel was sealed and heated via electric heating
tape secured to the outside of the tube and controlled with
thermocouple regulation to maintain an internal temperature of
200.degree. C. The reaction mixture was maintained at this
temperature for 6 h then cooled and concentrated in vacuo to give
510 mg of yellow oil. The crude product was purified by silica gel
chromatography (elution with 2.5% MeOH/CH.sub.2Cl.sub.2 cont. 0.2%
NH.sub.3) to afford 290 mg of the title compound, and 105 mg of
unconverted starting material. The product is a mixture of two
diastereomers at the hemiacetal in a ratio of 2:1.
[0264] MS (ESI) m/z=842 (M+H).sup.+. .sup.13C NMR (100 MHz,
CDCl.sub.3): .delta. 176.5, 170.8, 170.2, 135.5, 129.9, 99.8,
95.36, 95.6, 86.6, 84.9, 83.2, 80.0, 79.7, 78.9, 76.1, 73.2, 72.5,
67.5, 63.3, 63.1, 56.8, 53.1, 51.6, 49.5, 45.7, 44.8, 43.0, 40.9,
40.0, 35.4, 31.6, 28.2, 23.9, 22.6, 21.8, 21.7, 21.5, 21.1, 18.7,
17.9, 15.7, 14.6, 10.8, 10.6.
Step 1f. Compound of formula I: A=CHO, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H
[0265] The title compound of Step 1e (10 mg, 12 .mu.mol) was taken
up in 1 mL methanol and heated at 50.degree. C. for 4 hours. The
solution was concentrated in vacuo to afford 9 mg of the title
compound as a colorless solid.
[0266] MS (ESI) m/z=800 (M+H).sup.+.
Example 2
Compound of formula I: A=CH.sub.2H, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H
Step 2a. Compound of formula I: A=CH.sub.2OH, R.sub.1.dbd.H, Z=Ac
and Rp.sub.1=Ac
[0267] The title compound from Example 1, Step 1e (50 mg, 59
.mu.mol) was taken up in 2 mL absolute methanol and cooled to
0.degree. C. Sodium borohydride (12 mg, 300 .mu.mol) was added in
one portion and the mixture was stirred at 0.degree. C. for 30 min.
then warmed to RT and stirred for an additional 1 h. The reaction
mixture was diluted with 10 mL sat. aqueous NaHCO.sub.3 and
extracted with CH.sub.2Cl.sub.2 (4.times.10 mL) the combined
organic extracts were dried on K.sub.2CO.sub.3, filtered, and
concentrated to give 55 mg of a colorless solid. The crude product
was purified by silica gel chromatography (elution with 3% MeOH in
CH.sub.2Cl.sub.2 cont. 0.3% NH.sub.3) to afford 42 mg of the title
compound.
[0268] MS (ESI) m/z=844 (M+H).sup.+.
Step 2b. Compound of formula I: A=CH.sub.2OH, R.sub.1.dbd.H, Z=Ac
and Rp.sub.1=H
[0269] The title compound of Step 2a (10 mg, 12 .mu.mol) was taken
up in 1 mL methanol and heated at 50.degree. C. for 4 hours. The
solution was concentrated in vacuo to afford 10 mg of the title
compound as a colorless solid.
[0270] MS (ESI) m/z=802 (M+H).sup.+.
Example 3
Compound of formula I: A=CH.sub.2OCO-[3-quinolyl], R.sub.1.dbd.H,
Z=Ac and Rp.sub.1=H
Step 3a. Compound of formula I: A=CH.sub.2OCO-[3-quinolyl],
R.sub.1.dbd.H, Z=Ac and Rp.sub.1=Ac
[0271] The title compound from Example 2 step 2a (5 mg, 7.2
.mu.mol) was taken in 100 .mu.L CH.sub.2Cl.sub.2. To this stirred
solution was added sequentially 3-quinolinecarboxylic acid (1.2 mg,
7.2 .mu.mol), DMAP (1.0 mg, 7.2 .mu.mol), and DCC (36 .mu.L of a
0.2M CH.sub.2Cl.sub.2 soln.). The mixture was stirred at RT for 1.5
h. then the entire solution was placed directly on a small silica
gel column and eluted with 1.75% MeOH in CH.sub.2Cl.sub.2 to afford
5.3 mg of the title compound as a colorless solid (5.3 .mu.mol
90%).
[0272] MS (ESI) m/z=999 (M+H).sup.+.
Step 3b. Compound of formula I: A=CH.sub.1OCO-[3-quinolyl],
R.sub.1=H, Z=Ac and Rp.sub.1=H
[0273] A methanolic solution of the compound of step 3a (3.5 mg in
0.25 mL) was heated at 50.degree. C. for 18 h. The mixture was
concentrated in vacuo and the crude product (3.5 mg) submitted to
silica gel chromatography (elution with 2% MeOH in CH.sub.2Cl.sub.2
cont. 0.2% NH.sub.3) to afford 1.8 mg of the title compound.
[0274] MS (ESI) m/z=957 (M+H).sup.+.
Example 4
Compound of formula I: A=CH.sub.1OCO-[4-quinolyl], R.sub.1.dbd.H, Z
=Ac and Rp.sub.1=H
[0275] The title compound of Example 4 is prepared from the title
compound of Step 2a and 4-quinolinecarboxylic acid according to the
methods of Example 3.
Example 5
Compound of formula I: A=CH.dbd.CH-phenyl, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H
Step 5a. Compound of formula I: A=CH.dbd.CH-phenyl, R.sub.1.dbd.H,
Z=Ac and Rp.sub.1=Ac
[0276] I) Formation of Ylide: To a stirred THF slurry of
benzyltriphenylphosphonium bromide (216 mg, 0.5 mmol, in 1 mL THF)
was added 0.5 mL NaHMDS (1M in THF) dropwise. The mixture was
stirred at room temperature for 15 minutes and then cooled to
-20.degree. C.
[0277] II) Olefination: A THF solution of the title compound from
Step 1e (200 mg, 240 .mu.mol in 1 mL) was added dropwise to the
above ylide solution. The mixture was stirred at -20.degree. C. for
30 minutes, warmed to room temperature and stirred an additional 14
hours. The mixture was poured into sat. aq. NaHCO.sub.3 (50 mL) and
extracted with CH.sub.2Cl.sub.2 (3.times.25 mL). The combined
organic extracts were dried (K.sub.2CO.sub.3), filtered, and
concentrated to afford 430 mg of solid residue which was purified
by silica gel chromatography to give the title compound as a
mixture of E and Z isomers (158 mg, 170 .mu.mol).
[0278] MS (ESI) m/z=916 (M+H).sup.+.
Step 5b. Compound of formula I: A=CH.dbd.CH-phenyl, R.sub.1.dbd.H,
Z=Ac, and Rp.sub.1=H
[0279] The title compound of Step 5a (100 mg, 109 .mu.mol) was
taken up in 5 mL methanol and heated at 50.degree. C. for 4 hours.
The solution was concentrated in vacuo to afford 89 mg of the title
compound as a colorless solid.
[0280] MS (ESI) m/z=874 (M+H).sup.+.
Example 6
Compound of formula I: A=CH.dbd.NH-benzyl, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H
Step 6a. Compound of formula I: A=CH.sub.2NH-benzyl, R.sub.1.dbd.H,
Z=Ac and Rp.sub.1=Ac
[0281] To a methanol solution of the title compound of Step 1e of
Example 1 (50 mg, 59 .mu.mol in 0.5 mL) was added sequentially
acetic acid (10 .mu.L, 180 .mu.mol), benzyl amine (7.8 .mu.L 71),
and sodium cyanoborohydride (8 mg, 120 .mu.mol). The mixture was
stirred at RT for 1 h. Mixture was quenched with 2 mL sat. aqueous
NH.sub.4Cl, and extracted with ether (3.times.2 mL). The aqueous
layer was then raised to pH 10 by addition of 1N KOH and further
extracted with CH.sub.2Cl.sub.2 (3.times.2 mL). The
CH.sub.2Cl.sub.2 extracts were dried on K.sub.2CO.sub.3, filtered
and concentrated to give 44 mg of residue which was purified by
silica gel chromatography to give the title compound (30 mg) as a
colorless solid.
[0282] MS (ESI) m/z=933 (M+H).sup.+.
Step 6b. Compound of formula I: A=CH.sub.2NH-benzyl, R.sub.1.dbd.H,
Z=Ac and Rp.sub.1=H
[0283] The title compound from step 6a (5.0 mg) was dissolved in
0.5 mL methanol and stirred at 50.degree. C. for 16 hours. The
solution was concentrated in vacuo to give the title compound (4.8
mg) as a solid.
[0284] MS (ESI) m/z=945 (M+H).sup.+.
Example 7
Compound of formula I: A=CH.sub.2NH-allyl, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=H
Step 7a. Compound of formula I: A=CH.sub.2NH-allyl, R.sub.1.dbd.H,
Z=Ac and Rp.sub.1=Ac
[0285] To a methanol solution of the title compound from Example 1,
Step 1e (40 mg, 48 .mu.mol in 0.2 mL) was added sequentially acetic
acid (10 .mu.L, 180 .mu.mol), allyl amine (4.4 .mu.L 58 .mu.mol),
and sodium cyanoborohydride (6 mg, 96 .mu.mol). The mixture was
stirred at RT for 1 h. Mixture was quenched with 1 mL sat. aqueous
NH.sub.4Cl, and extracted with ether (3.times.2 mL). The aqueous
layer was then raised to pH 10 by addition of 1N KOH and further
extracted with CH.sub.2Cl.sub.2 (3.times.2 mL). The
CH.sub.2Cl.sub.2 extracts were dried on K.sub.2CO.sub.3, filtered
and concentrated to give 46 mg of residue which was purified by
silica gel chromatography to give the title compound (27 mg) as an
oil.
[0286] MS (ESI) m/z=883 (M+H).sup.+.
Step 7b. Compound of formula I: A=CH.sub.2NH-allyl, R.sub.1.dbd.H,
Z=Ac and Rp.sub.1=H
[0287] The compound of Step 7a (10 mg) was treated according to the
conditions described in Step 3b to afford 8 mg of the title
compound.
Example 8
Compound of formula II: A=CHO, R.sub.1.dbd.H, R.sub.2.dbd.H, and
Rp.sub.1=H
Step 8a. Compound of formula II: A=CHO, R.sub.1.dbd.H,
R.sub.2.dbd.H, and Rp.sub.1=Ac
[0288] The title compound of Step 1e is taken up in 0.2 N aqueous
hydrochloric acid and stirred at 50.degree. C. for 2 hours. The
solution is neutralized with saturated NaHCO.sub.3 and extracted
with CH.sub.2Cl.sub.2. The combined organic extracts are washed
with brine, dried over K.sub.2CO.sub.3, filtered and concentrated
to give the title compound.
Step 8b. Compound of formula II: A=CHO, R.sub.1.dbd.H,
R.sub.2.dbd.H, and Rp.sub.1=H
[0289] The product of Step 8a is treated according the procedure of
Step 1f of Example I to afford the title compound.
Example 9
Compound of formula II: A=CHO, R.sub.1.dbd.H, R.sub.2=benzoyl, and
Rp.sub.1=H
Step 9a. Compound of formula II: A=CHO, R.sub.1.dbd.H,
R.sub.2=benzoyl, and Rp.sub.1=Ac
[0290] The title compound of step 8a is taken up in
CH.sub.2Cl.sub.2 and stirred at -20.degree. C. Triethylamine, DMAP,
and benzoic anhydride are added sequentially to the stirred
solution. The mixture is allowed to warm to room temperature and
stirred for 6 hours. The reaction mixture is poured into saturated
NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2. The combined
organic extracts are washed with brine, dried over K.sub.2CO.sub.3,
filtered and concentrated to give the title product which is
further purified by silica gel chromatography.
Step 9b. Compound of formula II: A=CHO, R.sub.1.dbd.H,
R.sub.2=benzoyl, and Rp.sub.1=H
[0291] The product of Step 9a is treated according the procedure of
Step 1f of Example I to afford the title compound.
Example 10
Compound of formula II: A=CH.sub.2OH, R.sub.1.dbd.H, R.sub.2.dbd.H,
and Rp.sub.1=H
Step 10a. Compound of formula II: A=CH.sub.2OH, R.sub.1.dbd.H,
R.sub.2.dbd.H, and Rp.sub.1=Ac
[0292] The product of Step 2a of Example 2 is treated according to
the procedure of Step 8a of Example 8 to provide the title
compound.
Step 10b. Compound of formula II: A=CH.sub.2OH, R.sub.1.dbd.H,
R.sub.2.dbd.H, and Rp.sub.1=H
[0293] The product of Step 10a is treated according the procedure
of Step 1f of Example 1 to afford the title compound.
Example 11
Compound of formula II: A=CH.sub.2OCO-[3-quinolyl], R.sub.1.dbd.H,
R.sub.2.dbd.H and Rp.sub.1=H
Step 11a. Compound of formula I: A=CH.sub.2OCO-[3-quinolyl],
R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=Ac
[0294] The compound of Step 3a of Example 3 (22 mg) was taken up in
0.3 mL of 0.2N aqueous HCl. The solution was stirred at 50.degree.
C. for 2 hours. The reaction mixture was quenched with aqueous
NaHCO.sub.3 and extracted with CH.sub.2Cl.sub.2. The organic
extracts were dried on K.sub.2CO.sub.3, filtered, and concentrated
to afford 20 mg of residue. Purification of the crude product by
silica gel chromatography gave 14 mg of the title compound as a
white solid.
[0295] MS (ESI) m/z 799 (M+H).sup.+
Step 11b. Compound of formula I: A=CH.sub.2OCO-[3-quinolyl],
R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=H
[0296] The title compound from step 11a (5.0 mg) was dissolved in
0.5 mL methanol and stirred at 50.degree. C. for 12 hours. The
solution was concentrated in vacuo to give the title compound (4.7
mg)
[0297] MS (ESI) m/z 747 (M+H).sup.+
Example 12
Compound of formula II: A=CH.sub.2OCO-[3-quinolyl], R.sub.1.dbd.H,
R.sub.2=benzoyl and Rp.sub.1.dbd.H
Step 12a. Compound of formula II: A=CH.sub.2OCO-[3-quinolyl],
R.sub.1=H, R.sub.2=benzoyl and Rp.sub.1=Ac
[0298] The product of Step 11a of Example 11 is treated according
to the procedure of Step 9a of Example 9 to provide the title
compound.
Step 12b. Compound of formula II: A=CH.sub.2OCO-[3-quinolyl],
R.sub.1.dbd.H, R.sub.2=benzoyl and Rp.sub.1=H
[0299] The product of Step 12a is treated according the procedure
of Step 1f of Example 1 to afford the title compound.
Example 13
Compound of formula II: A=CH.sub.2OCO-[4-quinolyl], R.sub.1.dbd.H,
R.sub.2.dbd.H, and Rp.sub.1=H
Step 13a. Compound of formula II: A=CH.sub.2OCO-[4-quinolyl],
R.sub.1.dbd.H, and R.sub.2.dbd.H, and Rp.sub.1=Ac
[0300] The product of Step 4a of Example 4 is treated according to
the procedure of Step 8a of Example 8 to provide the title
compound.
Step 13b. Compound of formula II: A=CH.sub.2OCO-[4-quinolyl],
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0301] The product of Step 13a is treated according the procedure
of Step 1f of Example 1 to afford the title compound.
Example 14
Compound of formula II: A=CH.sub.2.dbd.CH-phenyl, R.sub.1.dbd.H,
R.sub.1.dbd.H, and Rp.sub.1=H
Step 14a. Compound of formula II: A=CH.sub.2.dbd.CH-phenyl,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=Ac
[0302] The product of Step 5a of Example 5 is treated according to
the procedure of Step 8a of Example 8 to provide the title
compound.
Step 14b. Compound of formula II: A=CH.sub.2.dbd.CH-phenyl,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0303] The product of Step 14a is treated according the procedure
of Step 1f of Example 1 to afford the title compound.
Example 15
Compound of formula II: A=CH.sub.2NH-benzyl, R.sub.1.dbd.H,
R.sub.2.dbd.H, and Rp.sub.1=H
Step 15a. Compound of formula II: A=CH.sub.2NH-benzyl,
R.sub.1.dbd.H, R.sub.2.dbd.H and Rp.sub.1=Ac
[0304] The product of Step 6a is treated according to the procedure
of Step 8a of Example 8 to provide the title compound.
Step 15b. Compound of formula II: A=CH.sub.2NH-benzyl,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0305] The product of Step 15a is treated according the procedure
of Step 1f of Example 1 to afford the title compound.
Example 16
Compound of formula II: A=CH.sub.2NH-benzyl, R.sub.1.dbd.H,
R.sub.2=benzoyl, and Rp.sub.1=H
Step 16a. Compound of formula II: A=CH.sub.2NH-benzyl,
R.sub.1.dbd.H, R.sub.2=benzoyl and Rp.sub.1=Ac
[0306] The product of Step 15a of Example 15 is treated according
to the procedure of Step 9a of Example 9 to provide the title
compound.
Step 16b. Compound of formula II: A=CH.sub.2NH-benzyl,
R.sub.1.dbd.H, R.sub.2=benzoyl, and Rp.sub.1=H
[0307] The product of Step 16a is treated according to the
procedure of Step 1f of Example 1 to provide the title
compound.
Example 17
Compound of formula II: A=CH.sub.2NH-allyl, R.sub.1.dbd.H,
R.sub.2.dbd.H, and Rp.sub.1=H
Step 17a. Compound of formula II: A=CH.sub.2NH-allyl,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=Ac
[0308] The product of Step 7a of Example 7 is treated according to
the procedure of Step 8a of Example 8 to provide the title
compound.
Step 17b. Compound of formula II: A=CH.sub.2NH-allyl,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0309] The product of Step 17a is treated according the procedure
of Step 1f of Example 1 to afford the title compound.
Example 18
Compound of formula III: A=CHO, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, Z=Ac, and R.sub.1.dbd.H
Step 18a. Compound of formula III: A=CHO, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=Ac
[0310] The title compound of Example 1, Step 1e is taken up in
ethanol and stirred under hydrogen pressure (1 to 3 atm.) in the
presence of palladium catalyst (10% Pd on C). The reaction mixture
is filtered and concentrated in vacuo to afford the title
compound.
Step 18b. Compound of formula III: A=CHO, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0311] The title compound of Step 18a is treated according to the
process of Step 1f of Example 1 to afford the title compound.
Example 19
Compound of formula III: A=CHO, B and D taken together are --O--,
C.dbd.H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
Step 19a. Compound of formula III: A=CHO, B and D taken together
are --O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=Ac
[0312] The product of Step 1e of Example 1 and 10% molar excess of
mCPBA are taken up in CH.sub.2Cl.sub.2 and stirred at room
temperature for 2 hours. The reaction mixture is washed with dilute
aqueous NaHSO.sub.3 and the aqueous washes further extracted with
CH.sub.2Cl.sub.2. The combined organic extracts are dried over
K.sub.2CO.sub.3, filtered, and concentrated to give the crude
product which is further purified by silica gel chromatography to
afford the title compound.
Step 19b. Compound of formula III: A=CHO, B and D taken together
are --O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0313] The product of Step 19a is treated according the procedure
of Step 1f of Example 1 to afford the title compound.
Example 20
Compound of formula III: A=CHO, B and C taken together are .dbd.O,
D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
Step 20a. Compound of formula III: A=CHO, B and C taken together
are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=Ac
[0314] The product of Step 19a of Example 19 is taken up in
anhydrous ether and stirred at -78.degree. C. while a 1.5-fold
molar excess of BF.sub.3Et.sub.2O is added dropwise. The solution
is allowed to warm slowly to room temperature and stirred at this
temperature for 4 hours. The reaction mixture is partitioned
between sat. aq. NaHCO.sub.3 and ether. The aqueous layer is
separated and further extracted with CH.sub.2Cl.sub.2. The combined
organic extracts are dried on MgSO.sub.4, filtered and concentrated
to give the title compound.
Step 20b. Compound of formula III: A=CHO, B and C taken together
are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0315] The product of Step 20a is treated according the procedure
of Step 1f of Example 1 to afford the title compound.
Example 21
Compound of formula III: A=CHO, B.dbd.OH, D=OH, C.dbd.H,
R.sub.1.dbd.H, Z=H, and Rp.sub.1=H
[0316] The product of Step 1f of Example 1 and an equimolar
quantity of NMO are taken up in t-BuOH and stirred at room
temperature. A catalytic quantity of OsO.sub.4 (4% solution in
H.sub.20) is then added dropwise and the mixture stirred at room
temperature for 16 hours. The reaction mixture is diluted with
water and extracted with CH.sub.2Cl.sub.2. The combined organic
extracts are washed with brine, dried over K.sub.2CO.sub.3,
filtered, and concentrated in vacuo to give the crude title product
which is further purified by silica gel chromatography.
Example 22
Compound of formula III: A=CH.sub.2OH, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
Step 22a. Compound of formula III: A=CH.sub.2OH, B.dbd.H, C.dbd.H,
D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=Ac
[0317] The title compound of Example 2, Step 2a is taken up in
ethanol and stirred under hydrogen pressure (1 to 3 atm.) in the
presence of palladium catalyst (10% Pd on C). The reaction mixture
is filtered and concentrated in vacuo to afford the title
compound.
Step 22b. Compound of formula III: CH.sub.2OH, B.dbd.H, C.dbd.H,
D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0318] The title compound of Step 22a is treated according to the
process of Step 1f of Example 1 to afford the title compound.
Example 23
Compound of formula III: A=CH.sub.2OH, B and D taken together are
--O--, C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
Step 23a. Compound of formula III: A=CH.sub.2OH, B and C taken
together are --O--, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=Ac
[0319] The product of Step 2a of Example 2 is treated according to
the procedure of Step 19a of Example 19 to afford the title
compound.
Step 23b. Compound of formula III: A=CH.sub.2OH, B and C taken
together are --O--, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H;
[0320] The product of Step 23a is treated according to the
procedure of Step 1f of Example 1 to afford the title compound.
Example 24
Compound of formula III: A=CH.sub.2OH, B and C taken together are
.dbd.O, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
Step 24a. Compound of formula III: A=CH.sub.2OH, B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=Ac
[0321] The product of Step 23a of Example 23 is treated according
to the procedure of Step 20a of Example 20 to afford the title
compound.
Step 24b. Compound of formula III: A=CH.sub.2OH, B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0322] The product of Step 24a is treated according to the
procedure of Step 1f of Example 1 to afford the title compound.
Example 25
Compound of formula III: A=CH.sub.2OH, B.dbd.OH, D=OH, C.dbd.H,
R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0323] The product of Step 2b of Example 2 is treated according to
the procedure of Step 21a of example 21 to provide the title
compound.
Example 26
Compound of formula III: A=CH.sub.2OCO-[3-quinolyl], B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H
Step 26a. Compound of formula I: A=CH.sub.2OCO-[3-quinolyl],
B.dbd.H, C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=Ac
[0324] The title compound of Step 22a is processed according the
procedures of Step 3a to afford the title compound.
Step 26b. Compound of formula I: A=CH2OCO-[3-quinolyl], B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac and Rp.sub.1=H
[0325] The compound of Step 26a is treated according to the process
of Step 3b to afford the title compound.
Example 27
Compound of formula III: A=CH.sub.2OCO-[3-quinolyl], B and D taken
together are --O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and
Rp.sub.1=H
Step 27a. Compound of formula III: A=CH.sub.2OCO-[3-quinolyl], B
and D taken together are --O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac and
Rp.sub.1=Ac
[0326] The product of Step 3a of Example 3 is treated according to
the procedure of Step 19a of Example 19 to afford the title
compound.
Step 27b. A=CH.sub.2OCO-[3-quinolyl], B and D taken together are
--O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0327] The product of Step 27a is treated according to the
procedure of Step 1f of Example 1 to afford the title compound.
Example 28
Compound of formula III: A=CH.sub.2OCO-[3-quinolyl], B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0328] The title compound is prepared according to the procedures
of Example 20 using the product of Step 27b of Example 27 as the
starting material.
Example 29
Compound of formula III: A=CH.sub.7OCO-[3-quinolyl], B.dbd.OH,
D=OH, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0329] The title compound is synthesized according to the
procedures of Example 21 using the product of Step 3b of Example 3
as the starting material.
Example 30
Compound of formula II: A=CH.sub.2OCO-[4-quinolyl], B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0330] The product of Step 4b of Example 4 is treated according to
the procedure of Step 18a of Example 18 to afford the title
compound.
Example 31
Compound of formula III: A=CH.sub.2OCO-[4-quinolyl], B and D taken
together are --O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and
Rp.sub.1=H
[0331] The title compound is formed according to the procedures of
Example 19 using the compound of Step 4a of Example 4 as the
starting material.
Example 32
Compound of formula III: A=CH.sub.2OCO-[4-quinolyl], B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0332] The title compound is formed according to the procedures of
Example 20 using the title compound of Example 31 as the starting
material.
Example 33
Compound of formula III: A=CH.sub.2OCO-[4-quinolyl], B.dbd.OH,
D=OH, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0333] The title compound is synthesized according to the
procedures of Example 21 using the product of Step 4b of Example 4
as the starting material.
Example 34
Compound of formula III: A=CH.dbd.CH-phenyl, B.dbd.H, C.dbd.H, D=H,
Z=Ac, and Rp.sub.1=H
Step 34a. Compound of formula III: A=CH.dbd.CH-phenyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=Ac
[0334] The product of Step 18a of Example 18 is treated according
to the procedure of Step 5a of Example 5 to afford the title
compound.
Step 34b. Compound of formula III: A=CH.dbd.CH-phenyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0335] The product of Step 34a is treated according to the
procedure of Step 1f of Example a to afford the title compound.
Example 35
Compound of formula III: A=CH.sub.2NH-benzyl, B.dbd.H, C.dbd.H,
D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
Step 35. Compound of formula III: A=CH.sub.2NH-benzoyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0336] The product of step 18b is treated according to the
procedure of step 6a to afford the title compound.
Example 36
Compound of formula III: A=CH.sub.2NH-benzyl, B and D taken
together are --O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and
Rp.sub.1=H
Step 36a. Compound of formula III: A=CH.sub.2NH-benzyl, B and D
taken together are --O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and
Rp.sub.1=Ac
[0337] The title compound is prepared according to the procedures
of step 21a of Example 21 using compound 6a of Example 6 as the
starting material.
Step 36b. Compound of formula III: A=CH.sub.2NH-benzyl, B and D
taken together are --O--, C.dbd.H, R.sub.1.dbd.H, Z=Ac, and
Rp.sub.1=H
[0338] The product of Step 36a is treated according to the
procedure of Step 1f of Example a to afford the title compound.
Example 37
Compound of formula III:: A=CH.sub.2NH-benzyl, B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0339] The title compound is formed according to the procedures of
Example 20 using the title compound of Step 36a as the starting
material.
Example 38
Compound of formula III: A=CH.sub.2NH-benzyl, B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H;
[0340] The title compound is synthesized according to the
procedures of Example 21 using the product of Step 6b of Example 6
as the starting material.
Example 39
Compound of formula III: A=CH.sub.2NH-allyl, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
Step 39a. Compound of formula III: A=CH.sub.2NH-allyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=Ac
[0341] The product of Step 18a of Example 18 is treated according
to the procedure of Step 7a of Example 7 to afford the title
compound.
Step 39b. Compound of formula III: A=CH.sub.2NH-allyl, B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, Z=H, and Rp.sub.1=H
[0342] The product of Step 39a is treated according to the
procedure of Step 1f of Example 1 to afford the title compound.
Example 40
Compound of formula III: A=CH.sub.2NH-allyl, B and D taken together
are --O--, C.dbd.H, R.sub.1.dbd.H, Z==Ac and Rp.sub.1=H
[0343] The title compound is formed according to the processes of
Example 19 using product of Step 7a of Example 7 as the starting
material.
Example 41
Compound of formula III: A=CH.sub.2NH-allyl, B and C taken together
are .dbd.O, D=H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0344] The title compound is formed according to the procedures of
Example 20 using the title compound of Example 40 as the starting
material.
Example 42
Compound of formula III: A=CH.sub.2NH-allyl, B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, Z=Ac, and Rp.sub.1=H
[0345] The title compound is synthesized according to the
procedures of Example 21 using the product of Step 7b of Example 7
as the starting material.
Example 43
Compound of formula IV: A=CHO, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0346] The product of Step 18a is treated according to the
processes of Example 8 to afford the title compound.
Example 44
Compound of formula IV: A=CHO, B and D taken together are --O--,
C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0347] The product of Step 19a is treated according to the
processes of Example 8 to afford the title compound.
Example 45
Compound of formula IV: A=CHO, B and C taken together are .dbd.O,
D=H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0348] The product of step 20a is treated according to the
processes of Example 8 to afford the title compound.
Example 46
Compound of formula IV: A=CHO, B.dbd.OH, D=OH, C.dbd.H,
R.sub.1.dbd.H, R.sub.2'H, and Rp.sub.1=H
[0349]
[0350] The product of Step 21a of Example 21 is treated according
to the processes of Example 8 to afford the title compound.
Example 47
Compound of formula IV: A=CH.sub.2OH, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0351] The product of Step 22a is treated according to the
processes of Example 8 to afford the title compound.
Example 48
Compound of formula IV: A=CH.sub.2OH, B and D taken together are
--O--, C.dbd.H, R.sub.1=H, R.sub.2.dbd.H, and Rp.sub.1=H
[0352] The product of Step 23a is treated according to the
processes of Example 8 to afford the title compound.
Example 49
Compound of formula IV: A=CH.sub.2OH, B and C taken together are
.dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0353] The product of Step 24a of Example 24 is treated according
to the processes of Example 8 to afford the title compound.
Example 50
Compound of formula IV: A=CH.sub.2OH, B.dbd.OH, D=OH, C.dbd.H,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0354] The product of step 25 is treated according to the processes
of Example 8 to afford the title compound.
Example 51
Compound of formula IV A=CH.sub.2OCO-[3-quinolyl], B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H,and Rp.sub.1=H
[0355] The product of Step 26a of Example 26 is treated according
to the processes of Example 8 to afford the title compound.
Example 52
Compound of formula IV: A=CH.sub.2OCO-[3-quinolyl], B and D taken
together are --O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H, and
Rp.sub.1=H
[0356] The product of Step 27a of Example 27 is treated according
to the processes of Example 8 to afford the title compound.
Example 53
Compound of formula IV: A=CH.sub.2OCO-[3-quinolyl], B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H, and
Rp.sub.1=H
[0357] The product of Example 28 is treated according to the
processes of Example 8 to afford the title compound.
Example 54
Compound of formula IV: A=CH.sub.2OCO-[3-quinolyl], B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0358] The product of Example 29 is treated according to the
processes of Example 8 to afford the title compound.
Example 55
Compound of formula IV: A=CH.sub.2OCO-[4-quinolyl], B.dbd.H,
C.dbd.H, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0359] The product of Example 30 is treated according to the
processes of Example 8 to afford the title compound.
Example 56
Compound of formula IV: A=CH.sub.2OCO-[4-quinolyl], B and D taken
together are --O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H, and
Rp.sub.1=H
[0360] The product of Example 31 is treated according to the
processes of Example 8 to afford the title compound.
Example 57
Compound of formula IV: A=CH.sub.2OCO-[4-quinolyl], B and C taken
together are .dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H, and
Rp.sub.1=H
[0361] The product of Example 32 is treated according to the
processes of Example 8 to afford the title compound.
Example 58
Compound of formula IV: A=CH.sub.2OCO-[4-quinolyl], B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0362] The product of Example 33 is treated according to the
processes of Example 8 to afford the title compound.
Example 59
Compound of formula IV: A=CH.dbd.CH-phenyl, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0363] The product of Step 34a of Example 34 is treated according
to the processes of Example 8 to afford the title compound.
Example 60
Compound of formula IV: A=CH.sub.2NH-benzyl, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0364] The product of Example 35 is treated according to the
processes of Example 8 to afford the title compound.
Example 61
Compound of formula IV: A=CH.sub.2NH-benzyl, B and D taken together
are --O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H, and
Rp.sub.1=H
[0365] The product of Step 36a of Example 36 is treated according
to the processes of Example 8 to afford the title compound.
Example 62
Compound of formula IV: A=CH.sub.2NH-benzyl, B and C taken together
are .dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0366] The product of Example 37 is treated according to the
processes of Example 8 to afford the title compound.
Example 63
Compound of formula IV: A=CH.sub.2NH-benzyl, B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0367] The product of Example 38 is treated according to the
processes of Example 8 to afford the title compound.
Example 64
Compound of formula IV: A=CH.sub.2NH-allyl, B.dbd.H, C.dbd.H, D=H,
R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0368] The product of Step 39a of Example 39 is treated according
to the processes of Example 8 to afford the title compound.
Example 65
Compound of formula IV: A=CH.sub.2NH-allyl, B and D taken together
are --O--, C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H, and
Rp.sub.1=H
[0369] The product of Example 40 is treated according to the
processes of Example 8 to afford the title compound.
Example 66
Compound of formula IV: A=CH.sub.2NH-allyl, B and C taken together
are .dbd.O, D=H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0370] The product of Example 41 is treated according to the
processes of Example 8 to afford the title compound.
Example 67
Compound of formula IV: A=CH.sub.2NH-allyl, B.dbd.OH, D=OH,
C.dbd.H, R.sub.1.dbd.H, R.sub.2.dbd.H, and Rp.sub.1=H
[0371] The product of Example 42 is treated according to the
processes of Example 8 to afford the title compound.
[0372] Although the invention has been described with respect to
various preferred embodiments, it is not intended to be limited
thereto, but rather those skilled in the art will recognize that
variations and modifications may be made therein which are within
the spirit of the invention and the scope of the appended
claims.
* * * * *