U.S. patent application number 11/196154 was filed with the patent office on 2006-01-12 for arylindenopyridines and related therapeutic and prophylactic methods.
Invention is credited to Kristin M. Averill, John H. Dodd, Geoffrey R. Heintzelman.
Application Number | 20060009481 11/196154 |
Document ID | / |
Family ID | 29248340 |
Filed Date | 2006-01-12 |
United States Patent
Application |
20060009481 |
Kind Code |
A1 |
Heintzelman; Geoffrey R. ;
et al. |
January 12, 2006 |
Arylindenopyridines and related therapeutic and prophylactic
methods
Abstract
This invention provides novel arylindenopyridines of the
formula: ##STR1## and pharmaceutical compositions comprising same,
useful for treating disorders ameliorated by reducing PDE activity
in appropriate cells. This invention also provides therapeutic and
prophylactic methods using the instant pharmaceutical
compositions.
Inventors: |
Heintzelman; Geoffrey R.;
(Annandale, NJ) ; Averill; Kristin M.; (High
Bridge, NJ) ; Dodd; John H.; (Stockton, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
29248340 |
Appl. No.: |
11/196154 |
Filed: |
August 3, 2005 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10123389 |
Apr 16, 2002 |
6958328 |
|
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11196154 |
Aug 3, 2005 |
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60284465 |
Apr 18, 2001 |
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Current U.S.
Class: |
514/290 ;
546/79 |
Current CPC
Class: |
A61P 25/28 20180101;
C07D 401/04 20130101; C07D 409/04 20130101; C07D 491/04 20130101;
C07D 221/16 20130101; C07D 405/04 20130101; C07D 401/12
20130101 |
Class at
Publication: |
514/290 ;
546/079 |
International
Class: |
C07D 221/22 20060101
C07D221/22; A61K 31/473 20060101 A61K031/473 |
Claims
1. A compound having the structure ##STR377## wherein (a) R.sub.1
is selected from the group consisting of: (i) --COR.sub.5, wherein
R.sub.5 is selected from H, optionally substituted C.sub.1-8
straight or branched chain alkyl, optionally substituted aryl and
optionally substituted arylalkyl; wherein the substituents on the
alkyl, aryl and arylalkyl group are selected from C.sub.1-8 alkoxy,
phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino,
cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and
R.sub.21 are independently selected from the group consisting of
hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7
cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken
together form a heterocycle or heteroaryl; (ii) COOR.sub.6, wherein
R.sub.6 is selected from H, optionally substituted C.sub.1-8
straight or branched chain alkyl, optionally substituted aryl and
optionally substituted arylalkyl; wherein the substituents on the
alkyl, aryl and arylalkyl group are selected from C.sub.1-8 alkoxy,
phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino,
cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and
R.sub.21 are independently selected from the group consisting of
hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7
cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken
together form a heterocycle or heteroaryl; (iii) cyano; (iv) a
lactone or lactam formed with R.sub.4; (v) --CONR.sub.7R.sub.8
wherein R.sub.7 and R.sub.8 are independently selected from H,
C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 cycloalkyl,
trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl,
arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl,
cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl,
heteroaryl and heterocyclyl groups may be substituted with
carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted
heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid,
sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or
R.sub.7 and R.sub.8 taken together with the nitrogen to which they
are attached form a heterocycle or heteroaryl group; (b) R.sub.2 is
selected from the group consisting of optionally substituted alkyl,
optionally substituted aryl, optionally substituted heteroaryl,
optionally substituted heterocyclyl and optionally substituted
C.sub.3-7 cycloalkyl; or R.sub.2 is ##STR378## (c) R.sub.3 is from
one to four groups independently selected from the group consisting
of: (i) hydrogen, halo, C.sub.1-8 straight or branched chain alkyl,
arylalkyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4
carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen,
nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, aryl,
heteroaryl, and heterocyclyl; (ii) --NR.sub.10R.sub.11 wherein
R.sub.10 and R.sub.11 are independently selected from H, C.sub.1-8
straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl,
carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R.sub.10 and
R.sub.11 taken together with the nitrogen form a heteroaryl or
heterocyclyl group; (iii) --NR.sub.12COR.sub.13 wherein R.sub.12 is
selected from hydrogen or alkyl and R.sub.13 is selected from
hydrogen, alkyl, substituted alkyl, C.sub.1-3 alkoxyl,
carboxyalkyl, R.sub.30R.sub.31N (CH.sub.2).sub.p--,
R.sub.30R.sub.31NCO(CH.sub.2).sub.p--, aryl, arylalkyl, heteroaryl
and heterocyclyl or R.sub.12 and R.sub.13 taken together with the
carbonyl form a carbonyl containing heterocyclyl group, wherein ,
R.sub.30 and R.sub.31 are independently selected from H, OH, alkyl,
and alkoxy, and p is an integer from 1-6, (d) R.sub.4 is selected
from the group consisting of (i) hydrogen, (ii) C.sub.1-3 straight
or branched chain alkyl, (iii) benzyl and (iv) --NR.sub.13R.sub.14,
wherein R.sub.13 and R.sub.14 are independently selected from
hydrogen and C.sub.1-6 alkyl; wherein the C.sub.1-3alkyl and benzyl
groups are optionally substituted with one or more groups selected
from C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4
carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen,
nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, amino,
NR.sub.13R.sub.14, aryl and heteroaryl; and (e) X is selected from
S and O; with the proviso that when R.sub.4 is isopropyl, then
R.sub.3 is not halogen, and with the proviso that one or more of
R.sub.1, R.sub.2, R.sub.3 or R.sub.4 comprses heteroaryl or
heterocycle and the pharmaceutically acceptable salts, esters and
pro-drug forms thereof.
2. The compound of claim 1, wherein R.sub.1 is COOR.sub.6, wherein
R.sub.6 is selected from H, optionally substituted C.sub.1-8
straight or branched chain alkyl, optionally substituted aryl and
optionally substituted arylalkyl.
3. The compound of claim 2, wherein R.sub.6 is selected from H, or
C.sub.1-8 straight or branched chain alkyl which may be optionally
substituted with a substituent selected from CN and hydroxy.
4. The compound of claim 1, wherein R.sub.2 is selected from
optionally substituted aryl and optionally substituted
heteroaryl.
5. The compound of claim 4 wherein the aryl or heteroaryl groups
are substituted with one to five members selected from the group
consisting of halogen, alkyl, alkoxy, alkoxyphenyl, halo,
triflouromethyl, trifluoro or difluoromethoxy, amino, alkylamino,
hydroxy, cyano, and nitro.
6. The compound of claim 4 wherein, R.sub.2 is optionally
substituted phenyl or napthyl or R.sub.2 is ##STR379## optionally
substituted, wherein the optional substituents are from one to
three members selected from the group consisting of halogen, alkyl,
hydroxy, cyano, and nitro.
7. The compound of claim 1 wherein R.sub.3 is selected from: (i)
hydrogen, halo, C.sub.1-8 straight or branched chain alkyl,
C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy, trifluoromethyl,
C.sub.1-8 alkylsulfonyl, halogen, nitro, and hydroxy; (ii)
--NR.sub.10R.sub.11 wherein R.sub.10 and R.sub.11 are independently
selected from H, C.sub.1-8 straight or branched chain alkyl,
arylC.sub.1-8alkyl, C.sub.3-.sub.7 cycloalkyl,
carboxyC.sub.1-8alkyl, aryl, heteroaryl, and heterocyclyl or
R.sub.10 and R.sub.11 taken together with the nitrogen form a
heteroaryl or heterocyclyl group; (iii) --NR.sub.12COR.sub.13
wherein R.sub.12 is selected from hydrogen or alkyl and R.sub.13 is
selected from hydrogen, alkyl, substituted alkyl, C.sub.1-3alkoxyl,
carboxyC.sub.1-8alkyl, aryl, arylalkyl, R.sub.30R.sub.31N
(CH.sub.2).sub.p--, R.sub.30R.sub.31NCO(CH.sub.2).sub.p--,
heteroaryl and heterocyclyl or R.sub.12 and R.sub.13 taken together
with the carbonyl form a carbonyl containing heterocyclyl group,
wherein, R.sub.30 and R.sub.31 are independently selected from H,
OH, alkyl, and alkoxy, and p is an integer from 1-6.
8. The compound of claim 7, wherein R.sub.3 is selected from the
group consisting of: ##STR380##
9. The compound of claim 1 wherein R.sub.4 is selected from
hydrogen, and C.sub.1-3 straight or branched chain alkyl.
10. The compound of claim 9, wherein R.sub.4 is selected from
methyl and amino.
11. The compound of claim 1 wherein R.sub.1 is COOR.sub.6 and
R.sub.2 is selected from the group consisting of substituted
phenyl, and substituted naphthyl.
12. The compound of claim 1 wherein R.sub.1 is COOR.sub.6 where
R.sub.6 is alkyl, R.sub.2 is substituted phenyl or naphthyl, and
R.sub.3 is selected from the group consisting of H, nitro, amino,
NHAc, halo, hydroxy, alkoxy, or a moiety of the formulae:
##STR381## and R.sub.4 is selected from hydrogen, C.sub.1-3
straight or branched chain alkyl and amino and X is Oxygen.
13. A compound having the structure: ##STR382## wherein (a) R.sub.1
is selected from the group consisting of: (i) --COR.sub.5, wherein
R.sub.5 is selected from H, optionally substituted C.sub.1-8
straight or branched chain alkyl, optionally substituted aryl and
optionally substituted arylalkyl; wherein the substituents on the
alkyl, aryl and arylalkyl group are selected from C.sub.1-8 alkoxy,
phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino,
cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and
R.sub.21 are independently selected from the group consisting of
hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7
cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken
together form a heterocycle or heteroaryl; (ii) COOR.sub.6, wherein
R.sub.6 is selected from H, optionally substituted C.sub.1-8
straight or branched chain alkyl, optionally substituted aryl and
optionally substituted arylalkyl; wherein the substituents on the
alkyl, aryl and arylalkyl group are selected from C.sub.1-8 alkoxy,
phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino,
cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and
R.sub.21 are independently selected from the group consisting of
hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7
cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken
together form a heterocycle or heteroaryl; (iii) cyano; (iv) a
lactone or lactam formed with R.sub.4; (v) --CONR.sub.7R.sub.8
wherein R.sub.7 and R.sub.8 are independently selected from H,
C.sub.1-8 straight or branched chain alkyl, C.sub.3-7 cycloalkyl,
trifluoromethyl, hydroxy, alkoxy, acyl, alkylcarbonyl, carboxyl,
arylalkyl, aryl, heteroaryl and heterocyclyl; wherein the alkyl,
cycloalkyl, alkoxy, acyl, alkylcarbonyl, carboxyl, arylalkyl, aryl,
heteroaryl and heterocyclyl groups may be substituted with
carboxyl, alkyl, aryl, substituted aryl, heterocyclyl, substituted
heterocyclyl, heteroaryl, substituted heteroaryl, hydroxamic acid,
sulfonamide, sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, or
R.sub.7 and R.sub.8 taken together with the nitrogen to which they
are attached form a heterocycle or heteroaryl group; (b) R.sub.2 is
--NR.sub.15R.sub.16 wherein R.sub.15 and R.sub.16 are independently
selected from hydrogen, optionally substituted C.sub.1-8 straight
or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl, aryl,
heteroaryl, and heterocyclyl or R.sub.15 and R.sub.16 taken
together with the nitrogen form a heteroaryl or heterocyclyl group;
with the proviso that when R.sub.2 is NHR.sub.16, R.sub.1 is not
--COOR.sub.6 where R.sub.6 is ethyl; (c) R.sub.3 is from one to
four groups independently selected from the group consisting of:
(i) hydrogen, halo, C.sub.1-8 straight or branched chain alkyl,
arylalkyl, C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4
carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen,
nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, aryl,
heteroaryl, and heterocyclyl; (ii) --NR.sub.10R.sub.11 wherein
R.sub.10 and R.sub.11 are independently selected from H, C.sub.1-8
straight or branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl,
carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R.sub.10 and
R.sub.11 taken together with the nitrogen form a heteroaryl or
heterocyclyl group; (iii) --NR.sub.12COR.sub.13 wherein R.sub.12 is
selected from hydrogen or alkyl and R.sub.13 is selected from
hydrogen, alkyl, substituted alkyl, C.sub.1-3alkoxyl, carboxyalkyl,
R.sub.30R.sub.31N (CH.sub.2).sub.p--,
R.sub.30R.sub.31NCO(CH.sub.2).sub.p--, aryl, arylalkyl, heteroaryl
and heterocyclyl or R.sub.12 and R.sub.13 taken together with the
carbonyl form a carbonyl containing heterocyclyl group, wherein,
R.sub.30 and R.sub.31 are independently selected from H, OH, alkyl,
and alkoxy, and p is an integer from 1-6, wherein the alkyl group
may be substituted with carboxyl, alkyl, aryl, substituted aryl,
heterocyclyl, substituted heterocyclyl, heteroaryl, substituted
heteroaryl, hydroxamic acid, sulfonamide, sulfonyl, hydroxy, thiol,
alkoxy or arylalkyl; (d) R.sub.4 is selected from the group
consisting of (i) hydrogen, (ii) C.sub.13 straight or branched
chain alkyl, (iii) benzyl and (iv) --NR.sub.13R.sub.14, wherein
R.sub.13 and R.sub.14 are independently selected from hydrogen and
C.sub.1-6 alkyl; wherein the C.sub.1-3alkyl and benzyl groups are
optionally substituted with one or more groups selected from
C.sub.3-7 cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4
carboalkoxy, trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen,
nitro, hydroxy, trifluoromethoxy, C.sub.1-8 carboxylate, amino,
NR.sub.13R.sub.14, aryl and heteroaryl; and (e) X is selected from
S and O; with the proviso that one or more of R.sub.1, R.sub.2,
R.sub.3 or R.sub.4 comprises heteroaryl or heterocycle and the
pharmaceutically acceptable salts, esters and pro-drug forms
thereof.
14. The compound of claim 13, wherein R.sub.1 is COOR.sub.6 wherein
R.sub.6 is alkyl, R.sub.2 is NR.sub.6R.sub.7, and R.sub.3 is
selected from the group consisting of ##STR383## halogen, and
hydrogen, and R.sub.4 is selected from hydrogen, C.sub.1-3 straight
or branched chain alkyl and amino and X is Oxygen.
15-47. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit under 35 U.S.C. .sctn.
119(e) of provisional application Ser. No. 60/284,465, filed on
Apr. 18, 2001 which is incorporated herein by reference.
FIELD OF THE INVENTION
[0002] This invention relates to novel arylindenopyridines and
their therapeutic and prophylactic uses. Disorders treated and/or
prevented using these compounds include inflammatory and
AIDS-related disorders.
BACKGROUND OF THE INVENTION
[0003] There are eleven known families of phosphodiesterases (PDE)
widely distributed in many cell types and tissues. In their
nomenclature, the number indicating the family is followed by a
capital letter that indicates a distinct gene. A PDE inhibitor
increases the concentration of cAMP in tissue cells, and hence, is
useful in the prophylaxis or treatment of various diseases caused
by the decrease in cAMP level which is induced by the abnormal
metabolism of cAMP. These diseases include conditions such as
hypersensitivity, allergy, arthritis, asthma, bee sting, animal
bite, bronchospasm, dysmenorrhea, esophageal spasm, glaucoma,
premature labor, a urinary tract disorder, inflammatory bowel
disease, stroke, erectile dysfunction, HIV/AIDS, cardiovascular
disease, gastrointestinal motility disorder, and psoriasis.
[0004] Among known phosphodiesterases today, PDE1 family are
activated by calcium-calmodulin; its members include PDE1A and
PDE1B, which preferentially hydrolyze cGMP, and PDE1C which
exhibits a high affinity for both cAMP and cGMP. PDE2 family is
characterized as being specifically stimulated by cGMP. PDE2A is
specifically inhibited by erythro-9-(2-hydroxy-3-nonyl)adenine
(EHNA). Enzymes in the PDE3 family (e.g. PDE3A, PDE3B) are
specifically inhibited by cGMP. PDE4 (e.g. PDE4A, PDE4B, PDE4C,
PDE4D) is a cAMP specific PDE present in T-cells, which is involved
in inflammatory responses. A PDE3 and/or PDE4 inhibitor would be
predicted to have utility in the following disorders: autoimmune
disorders (e.g. arthritis), inflammatory bowel disease, bronchial
disorders (e.g. asthma), HIV/AIDS, and psoriasis. A PDE5 (e.g.
PDE5A) inhibitor would be useful for the treatment of the following
disorders: cardiovascular disease and erectile dysfunction. The
photoreceptor PDE6 (e.g. PDE6A, PDE6B, PDE6C) enzymes specifically
hydrolyze cGMP. PDE8 family exhibits high affinity for hydrolysis
of both cAMP and cGMP but relatively low sensitivity to enzyme
inhibitors specific for other PDE families.
[0005] Phosphodiesterase 7 (PDE7A, PDE7B) is a cyclic nucleotide
phosphodiesterase that is specific for cyclic adenosine
monophosphate (cAMP). PDE7 catalyzes the conversion of cAMP to
adenosine monophosphate (AMP) by hydrolyzing the 3'-phosphodiester
bond of cAMP. By regulating this conversion, PDE7 allows for
non-uniform intracellular distribution of cAMP and thus controls
the activation of distinct kinase signalling pathways. PDE7A is
primarily expressed in T-cells, and it has been shown that
induction of PDE7A is required for T-cell activation (Li, L.; Yee,
C.; Beavo, J. A. Science 1999, 283, 848). Since PDE7A activation is
necessary for T-cell activation, small molecule inhibitors of PDE7
would be useful as immunosuppressants. An inhibitor of PDE7A would
be predicted to have immunosuppressive effects with utility in
therapeutic areas such as organ transplantation, autoimmune
disorders (e.g. arthritis), HIV/AIDS, inflammatory bowel disease,
asthma, allergies and psoriasis.
[0006] Few potent inhibitors of PDE7 have been reported. Most
inhibitors of other phosphodiesterases have IC.sub.50's for PDE7 in
the 100 .mu.M range. Recently, Martinez, et al. (J. Med. Chem.
2000, 43, 683) reported a series of PDE7 inhibitors, among which
the two best compounds have PDE7 IC.sub.50's of 8 and 13 .mu.M.
However, these compounds were only 2-3 times selective for PDE7
over PDE4 and PDE3.
[0007] Finally, the following compounds have been disclosed, and
some of them are reported to show antimicrobial activity against
strains such as Plasmodium falciparum, Candida albicans and
Staphylococcus aureus (Gorlitzer, K.; Herbig, S.; Walter, R. D.
Pharmazie 1997, 504): ##STR2##
SUMMARY OF THE INVENTION
[0008] This invention provides a compound having the structure of
Formula I ##STR3##
[0009] or a pharmaceutically acceptable salt thereof, wherein
[0010] (a) R.sub.1 is selected from the group consisting of: [0011]
(i) --COR.sub.5, wherein R.sub.5 is selected from H, optionally
substituted C.sub.1-8 straight or branched chain alkyl, optionally
substituted aryl and optionally substituted arylalkyl; [0012]
wherein the substituents on the alkyl, aryl and arylalkyl group are
selected from C.sub.1-8 alkoxy, phenylacetyloxy, hydroxy, halogen,
p-tosyloxy, mesyloxy, amino, cyano, carboalkoxy, or
NR.sub.20R.sub.21 wherein R.sub.20 and R.sub.21 are independently
selected from the group consisting of hydrogen, C.sub.1-8 straight
or branched chain alkyl, C.sub.3-7 cycloalkyl, benzyl, aryl, or
heteroaryl or NR.sub.20R.sub.21 taken together form a heterocycle
or heteroaryl; [0013] (ii) COOR.sub.6, wherein R.sub.6 is selected
from H, optionally substituted C.sub.1-8 straight or branched chain
alkyl, optionally substituted aryl and optionally substituted
arylalkyl; [0014] wherein the substituents on the alkyl, aryl and
arylalkyl group are selected from C.sub.1-8 alkoxy,
phenylacetyloxy, hydroxy, halogen, p-tosyloxy, mesyloxy, amino,
cyano, carboalkoxy, or NR.sub.20R.sub.21 wherein R.sub.20 and
R.sub.21 are independently selected from the group consisting of
hydrogen, C.sub.1-8 straight or branched chain alkyl, C.sub.3-7
cycloalkyl, benzyl, aryl, or heteroaryl or NR.sub.20R.sub.21 taken
together form a heterocycle or heteroaryl; [0015] (iii) cyano;
[0016] (iv) a lactone or lactam formed with R.sub.4; [0017] (v)
--CONR.sub.7R.sub.8 wherein R.sub.7 and R.sub.8 are independently
selected from H, C.sub.1-8 straight or branched chain alkyl,
C.sub.3-7 cycloalkyl, trifluoromethyl, hydroxy, alkoxy, acyl,
alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and
heterocyclyl; [0018] wherein the alkyl, cycloalkyl, alkoxy, acyl,
alkylcarbonyl, carboxyl, arylalkyl, aryl, heteroaryl and
heterocyclyl groups may be substituted with carboxyl, alkyl, aryl,
substituted aryl, heterocyclyl, substituted heterocyclyl,
heteroaryl, substituted heteroaryl, hydroxamic acid, sulfonamide,
sulfonyl, hydroxy, thiol, alkoxy or arylalkyl, [0019] or R.sub.7
and R.sub.8 taken together with the nitrogen to which they are
attached form a heterocycle or heteroaryl group;
[0020] (b) R.sub.2 is selected from the group consisting of
optionally substituted alkyl, optionally substituted aryl,
optionally substituted heteroaryl, optionally substituted
heterocyclyl and optionally substituted C.sub.3-7 cycloalkyl;
[0021] (c) R.sub.3 is from one to four groups independently
selected from the group consisting of: [0022] (i) hydrogen, halo,
C.sub.1-8 straight or branched chain alkyl, arylalkyl, C.sub.3-7
cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy,
trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen, nitro, hydroxy,
trifluoromethoxy, C.sub.1-8 carboxylate, aryl, heteroaryl, and
heterocyclyl; [0023] (ii) --NR.sub.10R.sub.11 wherein R.sub.10 and
R.sub.11 are independently selected from H, C.sub.1-8 straight or
branched chain alkyl, arylalkyl, C.sub.3-7 cycloalkyl,
carboxyalkyl, aryl, heteroaryl, and heterocyclyl or R.sub.10 and
R.sub.11 taken together with the nitrogen form a heteroaryl or
heterocyclyl group; [0024] (iii) --NR.sub.12COR.sub.13 wherein
R.sub.12 is selected from hydrogen or alkyl and R.sub.13 is
selected from hydrogen, alkyl, substituted alkyl, C.sub.1-3alkoxyl,
carboxyalkyl, R.sub.30R.sub.13N (CH.sub.2).sub.p--,
R.sub.30R.sub.31NCO(CH.sub.2).sub.p--, aryl, arylalkyl, heteroaryl
and heterocyclyl or R.sub.12 and R.sub.13 taken together with the
carbonyl form a carbonyl containing heterocyclyl group, wherein,
R.sub.30 and R.sub.31 are independently selected from H, OH, alkyl,
and alkoxy, and p is an integer from 1-6, [0025] wherein the alkyl
group may be substituted with carboxyl, alkyl, aryl, substituted
aryl, heterocyclyl, substituted heterocyclyl, heteroaryl,
substituted heteroaryl, hydroxamic acid, sulfonamide, sulfonyl,
hydroxy, thiol, alkoxy or arylalkyl;
[0026] (c) R.sub.4 is selected from the group consisting of (i)
hydrogen, (ii) C.sub.1-3 straight or branched chain alkyl, (iii)
benzyl and (iv) --NR.sub.13R.sub.14, wherein R.sub.13 and R.sub.14
are independently selected from hydrogen and C.sub.1-6 alkyl;
[0027] wherein the C.sub.1-3alkyl and benzyl groups are optionally
substituted with one or more groups selected from C.sub.3-7
cycloalkyl, C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy,
trifluoromethyl, C.sub.1-8 alkylsulfonyl, halogen, nitro, hydroxy,
trifluoromethoxy, C.sub.1-8 carboxylate, amino, NR.sub.13R.sub.14,
aryl and heteroaryl; and
[0028] (e) X is selected from S and O;
[0029] with the proviso that when R.sub.4 is isopropyl, then
R.sub.3 is not halogen.
[0030] In an alternative embodiment, the invention is directed to
compounds of Formula I wherein R.sub.1, R.sub.3 and R.sub.4 are as
described above and R.sub.2 is --NR.sub.15R.sub.16 wherein R.sub.15
and R.sub.16 are independently selected from hydrogen, optionally
substituted C.sub.1-8 straight or branched chain alkyl, arylalkyl,
C.sub.3-7 cycloalkyl, aryl, heteroaryl, and heterocyclyl or
R.sub.15 and R.sub.16 taken together with the nitrogen form a
heteroaryl or heterocyclyl group; with the proviso that when
R.sub.2 is NHR.sub.16, R.sub.1 is not --COOR.sub.6 where R.sub.6 is
ethyl.
[0031] This invention also provides a pharmaceutical composition
comprising the instant compound and a pharmaceutically acceptable
carrier.
[0032] This invention further provides a method of treating a
subject having a disorder ameliorated by reducing PDE activity in
appropriate cells, which comprises administering to the subject a
therapeutically effective dose of the instant pharmaceutical
composition.
[0033] Finally, this invention provides a method of preventing a
disorder ameliorated by reducing PDE activity in appropriate cells
in a subject, comprising administering to the subject a
prophylactically effective dose of the compound of claim 1 either
preceding or subsequent to an event anticipated to cause a disorder
ameliorated by reducing PDE activity in appropriate cells in the
subject.
DETAILED DESCRIPTION OF THE INVENTION
[0034] Compounds of Formula I are potent small molecule
phosphodiesterase inhibitors that have demonstrated potency for
inhibition of PDE7, PDE5, and PDE4. Some of the compounds of this
invention are potent small molecule PDE7 inhibitors which have also
demonstrated good selectivity against PDE5 and PDE4.
[0035] Preferred embodiments for R.sub.1 are COOR.sub.6, wherein
R.sub.6 is selected from H, optionally substituted C.sub.1-8
straight or branched chain alkyl, optionally substituted aryl and
optionally substituted arylalkyl. Preferably R.sub.6 is H, or
C.sub.1-8 straight or branched chain alkyl which may be optionally
substituted with a substituent selected from CN and hydroxy.
[0036] Preferred embodiments for R.sub.2 are optionally substituted
aryl and optionally substituted heteroaryl. Preferred substituents
are from one to three members selected from the group consisting of
halogen, alkyl, alkoxy, alkoxyphenyl, halo, triflouromethyl,
trifluoro or difluoromethoxy, amino, alkylamino, hydroxy, cyano,
and nitro. Preferably, R.sub.2 is optionally substituted phenyl or
napthyl or R.sub.2 is ##STR4## optionally substituted with from one
to three members selected from the group consisting of halogen,
alkyl, hydroxy, cyano, and nitro. In another embodiment of the
instant compound, R.sub.2 is --NR.sub.15R.sub.16.
[0037] Preferred substituents for R.sub.3 include: [0038] (i)
hydrogen, halo, C.sub.1-8 straight or branched chain alkyl,
C.sub.1-8 alkoxy, cyano, C.sub.1-4 carboalkoxy, trifluoromethyl,
C.sub.1-8 alkylsulfonyl, halogen, nitro, and hydroxy; [0039] (ii)
--NR.sub.10R.sub.11 wherein R.sub.10and R.sub.11 are independently
selected from H, C.sub.1-8 straight or branched chain alkyl,
arylC.sub.1-8alkyl, C.sub.3-7 cycloalkyl, carboxyC.sub.1-8alkyl,
aryl, heteroaryl, and heterocyclyl or R.sub.10 and R.sub.11 taken
together with the nitrogen form a heteroaryl or heterocyclyl group;
[0040] (iii) --NR.sub.12COR.sub.13 wherein R.sub.12 is selected
from hydrogen or alkyl and R.sub.13 is selected from hydrogen,
alkyl, substituted alkyl, C.sub.1-3alkoxyl, carboxyC.sub.1-8alkyl,
aryl, arylalkyl, R.sub.30R.sub.31N (CH.sub.2).sub.p--,
R.sub.30R.sub.31NCO(CH.sub.2).sub.p--, heteroaryl and heterocyclyl
or R.sub.12 and R.sub.13 taken together with the carbonyl form a
carbonyl containing heterocyclyl group, wherein , R.sub.30 and
R.sub.31 are independently selected from H, OH, alkyl, and alkoxy,
and p is an integer from 1-6. Particularly, R.sub.3 is selected
from the group consisting of ##STR5##
[0041] Preferred embodiments for R.sub.4 include hydrogen,
C.sub.1-3 straight or branched chain alkyl, particularly methyl,
and amino.
[0042] In a further embodiment of the instant compound, R.sub.1 is
COOR.sub.6 and R.sub.2 is selected from the group consisting of
substituted phenyl, and substituted naphthyl or R.sub.2 is
NR.sub.15R.sub.16.
[0043] More particularly, R.sub.1 is COOR.sub.6 where R.sub.6 is
alkyl, R.sub.2 is substituted phenyl or naphthyl or R.sub.2 is
NR.sub.15R.sub.16, and R.sub.3 is selected from the group
consisting of H, nitro, amino, NHAc, halo, hydroxy, alkoxy, or a
moiety of the formulae: ##STR6## and R.sub.4 is selected from
hydrogen, C.sub.1-3 straight or branched chain alkyl, particularly
methyl, and amino.
[0044] In a preferred embodiment, the compound is selected from the
group of compounds shown in Table 1 hereinafter.
[0045] More preferably, the compound is selected from the following
compounds: ##STR7##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
2-amino-4-(1,3-benzodioxol-5-yl)-5-oxo-, ethyl ester
[0046] ##STR8##
5H-indeno[1,2-b]pyridine-3-carboxylic acid, 4-(6-bromo-
1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
[0047] ##STR9##
5H-indeno[1,2-b]pyridine-3-carboxylic acid, 7-amino-4-(
1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl ester
[0048] ##STR10##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
4-(6-bromo-1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, methyl ester
[0049] ##STR11##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
[0050] ##STR12##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
8-(acetylamino)-4-(1,3-benzodioxol-5-yl)-2-methyl-5-oxo-, ethyl
ester
[0051] ##STR13##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
2-methyl-4-(3-methylphenyl)-5-oxo-, methyl ester
[0052] ##STR14##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
7-amino-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl ester
[0053] ##STR15##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
7-amino-2-methyl-4-(4-methyl-1-naphthalenyl)-5-oxo-, methyl
ester
[0054] ##STR16##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-8-nitro-5-oxo-, methyl
ester
[0055] ##STR17##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
7,8-dichloro-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-,
methyl ester
[0056] ##STR18##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
7-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl
ester
[0057] ##STR19##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
8-bromo-4-(3,5-dibromo-4-hydroxyphenyl)-2-methyl-5-oxo-, methyl
ester
[0058] ##STR20##
5H-indeno[1,2-b]pyridine-3-carboxylic acid, 8-[(3-carboxy-
1-oxopropyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-, methyl
ester
[0059] ##STR21##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
8-[(3-carboxy-1-oxopropyl)amino]-2-methyl-4-(4-methyl-
1-naphthalenyl)-5-oxo-, methyl ester
[0060] ##STR22##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
4-(3,5-dimethylphenyl)-8-[[4-(hydroxyamino)-
1,4-dioxobutyl]amino]-2-methyl-5-oxo-, methyl ester
[0061] ##STR23##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)amino]acetyl]amino]-2-methyl--
5-oxo-, methyl ester
[0062] ##STR24##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
8-[(4-carboxy-1-oxobutyl)amino]-4-(3,5-dimethylphenyl)-2-methyl-5-oxo-,
methyl ester
[0063] ##STR25##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
4-(3,5-dimethylphenyl)-8-[[[(2-hydroxyethyl)methylamino]acetyl]amino]-2-m-
ethyl-5-oxo-, methyl ester
[0064] ##STR26##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
4-(3,5-dimethylphenyl)-2-methyl-8-[(4-morpholinylacetyl)amino]-5-oxo-,
methyl ester
[0065] ##STR27##
5H-indeno[1,2-b]pyridine-3-carboxylic acid,
4-(3,5-dimethylphenyl)-2-methyl-5-oxo-8-[(1-piperazinylacetyl)amino]-,
methyl ester
[0066] The instant compounds can be isolated and used as free
bases. They can also be isolated and used as pharmaceutically
acceptable salts. Examples of such salts include hydrobromic,
hydroiodic, hydrochloric, perchloric, sulfuric, maleic, fumaric,
malic, tartaric, citric, benzoic, mandelic, methanesulfonic,
hydroethanesulfonic, benzenesulfonic, oxalic, palmoic,
2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic and
saccharic.
[0067] This invention also provides a pharmaceutical composition
comprising the instant compound and a pharmaceutically acceptable
carrier.
[0068] Pharmaceutically acceptable carriers are well known to those
skilled in the art and include, but are not limited to, from about
0.01 to about 0.1 M and preferably 0.05 M phosphate buffer or 0.8%
saline. Such pharmaceutically acceptable carriers can be aqueous or
non-aqueous solutions, suspensions and emulsions. Examples of
non-aqueous solvents are propylene glycol, polyethylene glycol,
vegetable oils such as olive oil, and injectable organic esters
such as ethyl oleate. Aqueous carriers include water, ethanol,
alcoholic/aqueous solutions, glycerol, emulsions or suspensions,
including saline and buffered media. Oral carriers can be elixirs,
syrups, capsules, tablets and the like. The typical solid carrier
is an inert substance such as lactose, starch, glucose,
methyl-cellulose, magnesium stearate, dicalcium phosphate, mannitol
and the like. Parenteral carriers include sodium chloride solution,
Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's
and fixed oils. Intravenous carriers include fluid and nutrient
replenishers, electrolyte replenishers such as those based on
Ringer's dextrose and the like. Preservatives and other additives
can also be present, such as, for example, antimicrobials,
antioxidants, chelating agents, inert gases and the like. All
carriers can be mixed as needed with disintegrants, diluents,
granulating agents, lubricants, binders and the like using
conventional techniques known in the art.
[0069] This invention further provides a method of treating a
subject having a condition ameliorated by reducing PDE activity in
appropriate cells, which comprises administering to the subject a
therapeutically effective dose of the instant pharmaceutical
composition.
[0070] In one embodiment, the disorder is an inflammatory disorder.
In another embodiment, the disorder is an AIDS-related disorder.
Examples of disorders treacle by the instant pharmaceutical
composition include, without limitation, organ transplantation,
autoimmune disorders (e.g. arthritis), immune challenge such as a
bee sting, inflammatory bowel disease, bronchial disorders (e.g.
asthma), HIV/AIDS, cardiovascular disorder, erectile dysfunction,
allergies, and psoriasis. In the preferred embodiment, the disorder
is rheumatoid arthritis.
[0071] As used herein, the term "subject" includes, without
limitation, any animal or artificially modified animal having a
disorder ameliorated by reducing PDE activity in appropriate cells.
In a preferred embodiment, the subject is a human. In a more
preferred embodiment, the subject is a human.
[0072] As used herein, "appropriate cells" include, by way of
example, cells which display PDE activity. Specific examples of
appropriate cells include, without limitation, T-lymphocytes,
muscle cells, neuro cells, adipose tissue cells, monocytes,
macrophages, fibroblasts.
[0073] Administering the instant pharmaceutical composition can be
effected or performed using any of the various methods known to
those skilled in the art. The instant compounds can be
administered, for example, intravenously, intramuscularly, orally
and subcutaneously. In the preferred embodiment, the instant
pharmaceutical composition is administered orally. Additionally,
administration can comprise giving the subject a plurality of
dosages over a suitable period of time. Such administration
regimens can be determined according to routine methods.
[0074] As used herein, a "therapeutically effective dose" of a
pharmaceutical composition is an amount sufficient to stop, reverse
or reduce the progression of a disorder. A "prophylactically
effective dose" of a pharmaceutical composition is an amount
sufficient to prevent a disorder, i.e., eliminate, ameliorate
and/or delay the disorder's onset. Methods are known in the art for
determining therapeutically and prophylactically effective doses
for the instant pharmaceutical composition. The effective dose for
administering the pharmaceutical composition to a human, for
example, can be determined mathematically from the results of
animal studies.
[0075] In one embodiment, the therapeutically and/or
prophylactically effective dose is a dose sufficient to deliver
from about 0.001 mg/kg of body weight to about 200 mg/kg of body
weight of the instant pharmaceutical composition. In another
embodiment, the therapeutically and/or prophylactically effective
dose is a dose sufficient to deliver from about 0.05 mg/kg of body
weight to about 50 mg/kg of body weight. More specifically, in one
embodiment, oral doses range from about 0.05 mg/kg to about 100
mg/kg daily. In another embodiment, oral doses range from about
0.05 mg/kg to about 50 mg/kg daily, and in a further embodiment,
from about 0.05 mg/kg to about 20 mg/kg daily. In yet another
embodiment, infusion doses range from about 1.0 .mu.g/kg/min to
about 10 mg/kg/min of inhibitor, admixed with a pharmaceutical
carrier over a period ranging from about several minutes to about
several days. In a further embodiment, for topical administration,
the instant compound can be combined with a pharmaceutical carrier
at a drug/carrier ratio of from about 0.001 to about 0.1.
[0076] This invention still further provides a method of preventing
an inflammatory response in a subject, comprising administering to
the subject a prophylactically effective amount of the instant
pharmaceutical composition either preceding or subsequent to an
event anticipated to cause the inflammatory response in the
subject. In the preferred embodiment, the event is an insect sting
or an animal bite.
DEFINITIONS AND NOMENCLATURE
[0077] Unless otherwise noted, under standard nomenclature used
throughout this disclosure the terminal portion of the designated
side chain is described first, followed by the adjacent
functionality toward the point of attachment.
[0078] As used herein, the following chemical terms shall have the
meanings as set forth in the following paragraphs: "independently",
when in reference to chemical substituents, shall mean that when
more than one substituent exists, the substituents may be the same
or different;.
[0079] "Alkyl" shall mean straight, cyclic and branched-chain
alkyl. Unless otherwise stated, the alkyl group will contain 1-20
carbon atoms. Unless otherwise stated, the alkyl group may be
optionally substituted with one or more groups such as halogen, OH,
CN, mercapto, nitro, amino, C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkoxyl, C.sub.1-C.sub.8-alkylthio,
C.sub.1-C.sub.8-alkyl-amino, di(C.sub.1-C.sub.8-alkyl)amino,
(mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy,
alkoxycarbonyl, C.sub.1-C.sub.8-alkyl-CO--O--,
C.sub.1-C.sub.8-alkyl-CO--NH--, carboxamide, hydroxamic acid,
sulfonamide, sulfonyl, thiol, aryl, aryl(c.sub.1-c.sub.8)alkyl,
heterocyclyl, and heteroaryl.
[0080] "Alkoxy" shall mean --O-alkyl and unless otherwise stated,
it will have 1-8 carbon atoms.
[0081] "Halogen" shall mean fluorine, chlorine, bromine or iodine;
"PH" or "Ph" shall mean phenyl; "Ac" shall mean acyl; "Bn" shall
mean benzyl.
[0082] The term "acyl" as used herein, whether used alone or as
part of a substituent group, means an organic radical having 2 to 6
carbon atoms (branched or straight chain) derived from an organic
acid by removal of the hydroxyl group. The term "Ac" as used
herein, whether used alone or as part of a substituent group, means
acetyl.
[0083] "Aryl" or "Ar," whether used alone or as part of a
substituent group, is a carbocyclic aromatic radical including, but
not limited to, phenyl, 1- or 2-naphthyl and the like. The
carbocyclic aromatic radical may be substituted by independent
replacement of 1 to 5 of the hydrogen atoms thereon with halogen,
OH, CN, mercapto, nitro, amino, C.sub.1-C.sub.8-alkyl,
C.sub.1-C.sub.8-alkoxyl, C.sub.1-C.sub.8-alkylthio,
C.sub.1-C.sub.8-alkyl-amino, di(C.sub.1-C.sub.8-alkyl)amino,
(mono-, di-, tri-, and per-) halo-alkyl, formyl, carboxy,
alkoxycarbonyl, C.sub.1-C.sub.8-alkyl-CO--O--,
C.sub.1-C.sub.8-alkyl-CO--NH--, or carboxamide. Illustrative aryl
radicals include, for example, phenyl, naphthyl, biphenyl,
fluorophenyl, difluorophenyl, benzyl, benzoyloxyphenyl,
carboethoxyphenyl, acetylphenyl, ethoxyphenyl, phenoxyphenyl,
hydroxyphenyl, carboxyphenyl, trifluoromethylphenyl,
methoxyethylphenyl, acetamidophenyl, tolyl, xylyl,
dimethylcarbamylphenyl and the like. "Ph" or "PH" denotes
phenyl.
[0084] Whether used alone or as part of a substituent group,
"heteroaryl" refers to a cyclic, fully unsaturated radical having
from five to ten ring atoms of which one ring atom is selected from
S, O, and N; 0-2 ring atoms are additional heteroatoms
independently selected from S, O, and N; and the remaining ring
atoms are carbon. The radical may be joined to the rest of the
molecule via any of the ring atoms. Exemplary heteroaryl groups
include, for example, pyridinyl, pyrazinyl, pyrimidinyl,
pyridazinyl, pyrroyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl,
isoxazolyl, thiadiazolyl, triazolyl, triazinyl, oxadiazolyl,
thienyl, furanyl, quinolinyl, isoquinolinyl, indolyl, isothiazolyl,
2-oxazepinyl, azepinyl, N-oxo-pyridyl, 1-dioxothienyl,
benzothiazolyl, benzoxazolyl, benzothienyl, quinolinyl-N-oxide,
benzimidazolyl, benzopyranyl, benzisothiazolyl, benzisoxazolyl,
benzodiazinyl, benzofurazanyl, benzothiopyranyl, indazolyl,
indolizinyl, benzofuryl, chromonyl, coumarinyl, cinnolinyl,
quinoxalinyl, indazolyl, pyrrolopyridinyl, furopyridinyl (such as
furo[2,3-c]pyridinyl, furo[3,2-b]pyridinyl, or
furo[2,3-b]pyridinyl), imidazopyridinyl (such as
imidazo[4,5-b]pyridinyl or imidazo[4,5-c]pyridinyl),
naphthyridinyl, phthalazinyl, purinyl, pyridopyridyl, quinazolinyl,
thienofuryl, thienopyridyl, thienothienyl, and furyl. The
heteroaryl group may be substituted by independent replacement of 1
to 5 of the hydrogen atoms thereon with halogen, OH, CN, mercapto,
nitro, amino, C.sub.1-C.sub.8-alkyl, C.sub.1-C.sub.8-alkoxyl,
C.sub.1-C.sub.8-alkylthio, C.sub.1-C.sub.8-alkyl-amino,
di(C.sub.1-C.sub.8-alkyl)amino, (mono-, di-, tri-, and per-)
halo-alkyl, formyl, carboxy, alkoxycarbonyl,
C.sub.1-C.sub.8-alkyl-CO--O--, C.sub.1-C.sub.8-alkyl-CO--NH--, or
carboxamide. Heteroaryl may be substituted with a mono-oxo to give
for example a 4-oxo-1H-quinoline.
[0085] The terms "heterocycle," "heterocyclic," and "heterocyclo"
refer to an optionally substituted, fully or partially saturated
cyclic group which is, for example, a 4- to 7-membered monocyclic,
7- to 11-membered bicyclic, or 10- to 15-membered tricyclic ring
system, which has at least one heteroatom in at least one carbon
atom containing ring. Each ring of the heterocyclic group
containing a heteroatom may have 1, 2, or 3 heteroatoms selected
from nitrogen atoms, oxygen atoms, and sulfur atoms, where the
nitrogen and sulfur heteroatoms may also optionally be oxidized.
The nitrogen atoms may optionally be quaternized. The heterocyclic
group may be attached at any heteroatom or carbon atom.
[0086] Exemplary monocyclic heterocyclic groups include
pyrrolidinyl; oxetanyl; pyrazolinyl; imidazolinyl; imidazolidinyl;
oxazolyl; oxazolidinyl; isoxazolinyl; thiazolidinyl;
isothiazolidinyl; tetrahydrofuryl; piperidinyl; piperazinyl;
2-oxopiperazinyl; 2-oxopiperidinyl; 2-oxopyrrolidinyl;
4-piperidonyl; tetrahydropyranyl; tetrahydrothiopyranyl;
tetrahydrothiopyranyl sulfone; morpholinyl; thiomorpholinyl;
thiomorpholinyl sulfoxide; thiomorpholinyl sulfone; 1,3-dioxolane;
dioxanyl; thietanyl; thiiranyl; and the like. Exemplary bicyclic
heterocyclic groups include quinuclidinyl; tetrahydroisoquinolinyl;
dihydroisoindolyl; dihydroquinazolinyl (such as
3,4-dihydro-4-oxo-quinazolinyl); dihydrobenzofuryl;
dihydrobenzothienyl; dihydrobenzothiopyranyl;
dihydrobenzothiopyranyl sulfone; dihydrobenzopyranyl; indolinyl;
isochromanyl; isoindolinyl; piperonyl; tetrahydroquinolinyl; and
the like.
[0087] Substituted aryl, substituted heteroaryl, and substituted
heterocycle may also be substituted with a second substituted-aryl,
a second substituted-heteroaryl, or a second
substituted-heterocycle to give, for example, a
4-pyrazol-1-yl-phenyl or 4-pyridin-2-yl-phenyl.
[0088] Designated numbers of carbon atoms (e.g., C.sub.1-8) shall
refer independently to the number of carbon atoms in an alkyl or
cycloalkyl moiety or to the alkyl portion of a larger substituent
in which alkyl appears as its prefix root.
[0089] Unless specified otherwise, it is intended that the
definition of any substituent or variable at a particular location
in a molecule be independent of its definitions elsewhere in that
molecule. It is understood that substituents and substitution
patterns on the compounds of this invention can be selected by one
of ordinary skill in the art to provide compounds that are
chemically stable and that can be readily synthesized by techniques
known in the art as well as those methods set forth herein.
[0090] Where the compounds according to this invention have at
least one stereogenic center, they may accordingly exist as
enantiomers. Where the compounds possess two or more stereogenic
centers, they may additionally exist as diastereomers. Furthermore,
some of the crystalline forms for the compounds may exist as
polymorphs and as such are intended to be included in the present
invention. In addition, some of the compounds may form solvates
with water (i.e., hydrates) or common organic solvents, and such
solvates are also intended to be encompassed within the scope of
this invention.
[0091] Some of the compounds of the present invention may have
trans and cis isomers. In addition, where the processes for the
preparation of the compounds according to the invention give rise
to mixture of stereoisomers, these isomers may be separated by
conventional techniques such as preparative chromatography. The
compounds may be prepared as a single stereoisomer or in racemic
form as a mixture of some possible stereoisomers. The non-racemic
forms may be obtained by either synthesis or resolution. The
compounds may, for example, be resolved into their components
enantiomers by standard techniques, such as the formation of
diastereomeric pairs by salt formation. The compounds may also be
resolved by covalent linkage to a chiral auxiliary, followed by
chromatographic separation and/or crystallographic separation, and
removal of the chiral auxiliary. Alternatively, the compounds may
be resolved using chiral chromatography.
[0092] This invention will be better understood by reference to the
Experimental Details which follow, but those skilled in the art
will readily appreciate that these are only illustrative of the
invention as described more fully in the claims which follow
thereafter. Additionally, throughout this application, various
publications are cited. The disclosure of these publications is
hereby incorporated by reference into this application to describe
more fully the state of the art to which this invention
pertains.
EXPERIMENTAL DETAILS
I. General Synthetic Schemes
[0093] Representative compounds of the present invention can be
synthesized in accordance with the general synthetic methods
described below and illustrated in the following general schemes.
The products of some schemes can be used as intermediates to
produce more than one of the instant compounds. The choice of
intermediates to be used to produce subsequent compounds of the
present invention is a matter of discretion that is well within the
capabilities of those skilled in the art. ##STR28##
[0094] Procedures described in Scheme 1, wherein R.sub.3a,
R.sub.3b, R.sub.3c, and R.sub.3d are independently any R.sub.3
group, and R.sub.1, R.sub.2, R.sub.3, and R.sub.4 are as described
above, can be used to prepare compounds of the invention wherein X
is O.
[0095] Benzylidenes 2 may be obtained by known methods (Bullington,
J. L; Cameron, J. C.; Davis, J. E.; Dodd, J. H.; Harris, C. A.;
Henry, J. R.; Pellegrino-Gensey, J. L.; Rupert, K. C.; Siekierka,
J. J. Bioorg. Med. Chem. Lett. 1998, 8, 2489; Petrow, V.; Saper,
J.; Sturgeon, B. J. Chem. Soc. 1949, 2134). Hantzsch reaction of
the benzylidene compounds with enamines 3 can be performed in
refluxing acetic acid (Petrow et al., supra). When the desired
enamines are not available, alternate Hantzsch conditions may be
utilized which involve adding ammonium acetate to the reaction. The
resulting dihydropyridines 4 are oxidized with chromium trioxide to
obtain the desired pyridines 1 (Petrow et al., supra). In cases
where the substitution pattern on the fused aromatic ring (R.sub.3)
leads to a mixture of regioisomers, the products can be separated
by column chromatography.
[0096] In some cases, especially where R.sub.2 is an alkyl group,
another modification of the Hantzsch may be performed which uses
three components (Bocker, R. H.; Buengerich, P. J. Med. Chem. 1986,
29, 1596). Where R.sub.2 is an alkyl group it is also necessary to
perform the oxidation with DDQ or MnO.sub.2 instead of chromium
(VI) oxide (Vanden Eynde, J. J.; Delfosse, F.; Mayence, A.; Van
Haverbeke, Y. Tetrahedron 1995, 51, 6511). ##STR29##
[0097] In order to obtain the corresponding carboxylic acids and
amides, the cyanoethyl esters 5 are prepared as described above.
The esters are converted to the carboxylic acids by treatment with
sodium hydroxide in acetone and water (Ogawa, T.; Matsumoto, K.;
Yokoo, C.; Hatayama, K.; Kitamura, K. J. Chem. Soc., Perkin Trans.
1 1993, 525). The corresponding amides can then be obtained from
the acids using standard means. ##STR30##
[0098] The procedure for making compounds where R.sub.4 is NH.sub.2
may be slightly modified. These compounds are prepared in one step
from the benzylidenes 2 and alkyl amidinoacetate (Kobayashi, T.;
Inoue, T.; Kita, Z.; Yoshiya, H.; Nishino, S.; Oizumi, K.; Kimura,
T. Chem. Pharm. Bull. 1995, 43, 788) as depicted in Scheme 4
wherein R is R.sub.5 or R.sub.6 as described above. ##STR31##
[0099] The dihydropyridine lactones 9 can be synthesized from
benzylidenes 8 (Zimmer, H.; Hillstrom, W. W.; Schmidt, J. C.;
Seemuth, P. D.; Vogeli, R. J. Org. Chem. 1978, 43, 1541) and
1,3-indanedione, as shown in Scheme 5, and the corresponding
pyridine is then obtained by oxidation with manganese dioxide.
##STR32##
[0100] Representative schemes to modify substituents on the fused
aromatic ring are shown below. The amines 11 are obtained from the
corresponding nitro compounds 10 by reduction with tin (II)
chloride (Scheme 6). Reaction of the amines with acetyl chloride
provide the amides 12. ##STR33##
[0101] In accordance with Scheme 7 wherein Y is O, and n is an
integer from 1-3, an alkyl chain with a carboxylic acid at the
terminal end can also be added to the amines 11. For example,
reaction with either succinic anhydride (Omuaru, V. O. T.; Indian
J. Chem., Sect B. 1998, 37, 814) or .beta.-propiolactone (Bradley,
G.; Clark, J.; Kernick, W. J. Chem. Soc., Perkin Trans. 1 1972,
2019) can provide the corresponding carboxylic acids 13. These
carboxylic acids are then converted to the hydroxamic acids 14 by
treatment with ethyl chloroformate and hydroxylamine (Reddy, A. S.;
Kumar, M. S.; Reddy, G. R. Tetrahedron Lett. 2000, 41, 6285).
##STR34##
[0102] The amines 11 can also be treated with glycolic acid to
afford alcohols 15 (Jursic, B. S.; Zdravkovski, Z. Synthetic Comm.
1993, 23, 2761) as shown in Scheme 8. ##STR35##
[0103] As shown in Scheme 9, the aminoindenopyridines 11 may also
be treated with chloroacetylchloride followed by amines to provide
the more elaborate amines 16 (Weissman, S. A.; Lewis, S.; Askin,
D.; Volante, R. P.; Reider, P. J. Tetrahedron Lett. 1998, 39,
7459). Where R.sub.6 is a hydroxyethyl group, the compounds can be
further converted to piperazinones 17. ##STR36##
[0104] The 4-aminoindenopyridines 18 can be synthesized from the
4-chloroindenopyridines 19 using a known procedure (Gorlitzer, K.;
Herbig, S.; Walter, R. D. Pharmazie 1997, 504) or via palladium
catalyzed coupling (Scheme 10). ##STR37## II. Specific Compound
Syntheses
[0105] Specific compounds which are representative of this
invention can be prepared as per the following examples. No attempt
has been made to optimize the yields obtained in these reactions.
Based on the following, however, one skilled in the art would know
how to increase yields through routine variations in reaction
times, temperatures, solvents and/or reagents.
[0106] The products of certain syntheses can be used as
intermediates to produce more than one of the instant compounds. In
those cases, the choice of intermediates to be used to produce
compounds of the present invention is a matter of discretion that
is well within the capabilities of those skilled in the art.
EXAMPLE 1
Hantzsch Condensation to Form Dihydropyridine 4 (R.sub.1.dbd.COOMe;
R.sub.2=3,5-dimethylphenyl; R.sub.3b,c.dbd.Cl; R.sub.3a,b.dbd.H;
R.sub.4=Me)
[0107] To a refluxing solution of benzylidene 2 (0.500 g, 1.5 mmol)
in acetic acid (10 mL) was added methyl-3-aminocrotonate (0.695 g,
6.0 mmol). The reaction was heated to reflux for 20 minutes, then
water was added until a precipitate started to form. The reaction
was cooled to room temperature. The mixture was filtered and washed
with water to obtain 0.354 g (55%) of a red solid. MS m/z 450
(M.sup.++23), 428 (M.sup.++1).
EXAMPLE 2
Alternate Hantzsch Conditions to Form Dihydropyridine 4
(R.sub.1.dbd.CO.sub.2Me; R.sub.2=2,4-dimethylphenyl; R.sub.3.dbd.H;
R.sub.4=Et)
[0108] To a refluxing solution of benzylidene 2 (1.00 g, 3.82 mmol)
in acetic acid (12 Ml) was added methyl propionylacetate (1.98 g,
15.2 mmol) and ammonium acetate (1.17 g, 15.2 mmol). The reaction
was heated for 20 min and then cooled to room temperature. No
product precipitated from the solution, so the reaction was heated
to reflux and then water was added until a solid began to
precipitate. After cooling to room temperature, the mixture was
filtered and the red solid washed with water to yield 1.29 g (90%)
of product. MS m/z 396 (M.sup.++23), 374 (M.sup.++1).
EXAMPLE 3
Oxidation of Dihydropyridine 4 to Pyridine 1 (R.sub.1.dbd.COOMe;
R.sub.2=3,5-dimethylphenyl; R.sub.3b,c.dbd.Cl; R.sub.3a,d.dbd.H;
R.sub.4=Me)
[0109] To a refluxing solution of dihydropyridine 4 (0.250 g, 0.58
mmol) in acetic acid (10 mL) was added a solution of chromium (VI)
oxide (0.584 g, 0.58 mmol) in 1 mL water. After 30 minutes at
reflux, the reaction was diluted with water until a precipitate
started to form. The mixture was cooled to room temperature and
allowed to stand overnight. The mixture was filtered and washed
with water to give 0.199 g (81%) of a yellow solid. MS m/z 448
(M.sup.++23), 426 (M.sup.++1).
EXAMPLE 4
Oxidation of Dihydropyridine 4 to Pyridine 1 (R.sub.1.dbd.COOMe;
R.sub.2=(4-methyl)-1-naphthyl; R.sub.3b,c.dbd.H, NO.sub.2/NO.sub.2,
H; R=Me)
[0110] To a refluxing suspension of regioisomeric dihydropyridines
4 (3.59 g, 8.16 mmol) in acetic acid (40 mL) was added a solution
of chromium (VI) oxide (0.816 g, 8.16 mmol) in 3 mL water. After 20
minutes at reflux, the reaction was diluted with water until a
precipitate started to form. The mixture was cooled to room
temperature and allowed to stand overnight. The mixture was
filtered and washed with water to yield the mixture of regioisomers
as a yellow solid. The products were purified by column
chromatography eluting with hexanes:ethyl acetate to yield 1.303 g
(37%) of pyridine 1 (R.sub.3b.dbd.NO.sub.2; R.sub.3c.dbd.H) and
0.765 g (21%) of its regioisomer (R.sub.3b.dbd.H:
R.sub.3c.dbd.NO.sub.2). MS m/z 461 (M.sup.++23), 439
(M.sup.++1).
EXAMPLE 5
Alternate Three Component Hantzsch Reaction to Form Dihydropyridine
4 (R.sub.1.dbd.CO.sub.2Me; R.sub.2=cyclohexyl; R.sub.3.dbd.H;
R.sub.4=Me)
[0111] Cyclohexane carboxaldehyde (2.0 g, 17.8 mmol),
1,3-indandione (2.6 g, 17.8 mmol), methylacetoacetate (2.0 g, 17.8
mmol), and ammonium hydroxide (1 mL) were refluxed in 8 mL of
methanol for 1.5 hours. The temperature was lowered to
approximately 50.degree. C. and the reaction was stirred overnight.
The reaction was cooled to room temperature, filtered and the solid
washed with water. The residue was then dissolved in hot ethanol
and filtered while hot. The filtrate was concentrated to yield 4.1
g (68%) of the product which was used without purification. MS m/z
336 (M.sup.--1).
EXAMPLE 6
DDQ Oxidation of Dihydropyridine 4 (R.sub.1.dbd.CO.sub.2Me;
R.sub.2=cyclohexyl; R.sub.3.dbd.H; R.sub.4=Me)
[0112] To a solution of dihydropyridine 4 (2.50 g, 7.40 mmol) in 15
mL of dichloromethane was added
2,3-dichloro-3,6-dicyano-1,4-benzoquinone (1.70 g, 7.40 mmol). The
reaction was stirred at room temperature for four hours. The
mixture was filtered and the residue was washed with
dichloromethane. After the filtrate was concentrated, the residue
was purified by column chromatography eluting with ethyl acetate:
hexanes to yield 0.565 g (23%) of a yellow solid. MS m/z 358
(M.sup.++23), 336 (M.sup.++1).
EXAMPLE 7
MnO.sub.2 Oxidation of Dihydropyridine 4 (R.sub.1.dbd.CO.sub.2Me;
R.sub.2=4-(dimethylamino)phenyl; R.sub.3.dbd.H; R.sub.4=Me)
[0113] To a solution of dihydropyridine 4 (0.50 g, 1.3 mmol) in 10
mL of dichloromethane was added manganese dioxide (2.5 g, 28.7
mmol). The reaction was stirred at room temperature overnight
before filtering and washing with dichloromethane. The filtrate was
concentrated to yield 0.43 g (88%) of orange solid 1. MS m/z 395
(M.sup.++23), 373 (M.sup.++1).
EXAMPLE 8
Cleavage of Carboxylic Ester 5 (R.sub.2=2,4-dimethylphenyl;
R.sub.3.dbd.H; R.sub.4=Me)
[0114] To a suspension of ester 5 (2.75 g, 6.94 mmol) in acetone
(50 mL) was added aqueous 1 M NaOH (100 mL). After stirring at room
temperature for 24 hours, the reaction mixture was diluted with 100
mL of water and washed with dichloromethane (2.times.100 mL). The
aqueous layer was cooled to 0.degree. C. and acidified with
concentrated HCl. The mixture was filtered and washed with water to
yield 1.84 g (77%) yellow solid 6. MS m/z 366 (M.sup.++23), 343
(M.sup.++1).
EXAMPLE 9
Preparation of Amide 7 (R.sub.2=2,4-dimethylphenyl; R.sub.3.dbd.H;
R.sub.4=Me; R.sub.5.dbd.H; R.sub.6=Me)
[0115] A solution of carboxylic acid 6 (0.337 g, 0.98 mmol) in
thionyl chloride (10 mL) was heated at reflux for 1 hour. The
solution was cooled and concentrated in vacuo. The residue was
diluted with CCl.sub.4 and concentrated to remove the residual
thionyl chloride. The residue was then dissolved in THF (3.5 mL)
and added to a 0.degree. C. solution of methylamine (1.47 mL of 2.0
M solution in THF, 2.94 mmol) in 6.5 mL THF. The reaction was
warmed to room temperature and stirred overnight. The mixture was
poured into water, filtered, washed with water and dried to yield
0.263 g (75%) of tan solid. MS m/z 357 (M.sup.++1).
EXAMPLE 10
Preparation of Pyridine 1 (R.sub.1.dbd.CO.sub.2Et;
R.sub.2=4-nitrophenyl; R.sub.3.dbd.H; R.sub.4.dbd.NH.sub.2)
[0116] To a refluxing solution of benzylidene 2 (1.05 g, 3.76 mmol)
in 10 mL of acetic acid was added ethyl amidinoacetate acetic acid
salt (0.720 g, 3.76 mmol). The resulting solution was heated at
reflux overnight. After cooling to room temperature, the resulting
precipitate was removed by filtration and washed with water. This
impure residue was heated in a minimal amount of ethanol and then
filtered to yield 0.527 g (35%) of a yellow solid. MS m/z 412
(M.sup.++23), 390 (M.sup.++1).
EXAMPLE11
Hantzsch Condensation of Benzylidene 8 (R.sub.2=3-methoxyphenyl)
and 1,3-indandione)
[0117] The benzylidene 8 (2.00 g, 9.2 mmol), 1,3-indandione (1.34
g, 0.2 mmmol) and ammonium acetate (2.83 g, 36.7 mmol) were added
to 30 mL of ethanol and heated to reflux overnight. The reaction
mixture was cooled to room temperature and diluted with ethanol. A
yellow precipitate was collected by filtration, washed with
ethanol, and dried under vacuum to yield 1.98 g (63%) of the
dihydropyridine 9. MS m/z 346 (M.sup.++1).
EXAMPLE 12
Reduction to Prepare Amine 11 (R.sub.1.dbd.CO.sub.2Me;
R.sub.2=4-methylnaphthyl; R.sub.4=Me)
[0118] To a refluxing suspension of pyridine 10 (0.862 g, 1.97
mmol) in 35 mL of ethanol was added a solution of tin (II) chloride
dihydrate (1.33 g, 5.90 mmol) in 6 mL of 1:1 ethanol: concentrated
HCl. The resulting solution was heated at reflux overnight. Water
was added until a precipitate started to form and the reaction was
cooled to room temperature. The mixture was then filtered and
washed with water. After drying, the residue was purified by column
chromatography eluting with hexanes: ethyl acetate to yield 0.551 g
(69%) of an orange solid. MS m/z 431 (M.sup.++23), 409
(M.sup.++1).
EXAMPLE 13
Acetylation of Amine 11 (R.sub.1.dbd.CO.sub.2Et;
R.sub.2=3,4-methylenedioxyphenyl; R.sub.4=Me)
[0119] To a solution of amine 11 (0.070 g, 0.174 mmol) in 15 mL of
dichloromethane was added triethylamine (0.026 g, 0.261 mmol) and
acetyl chloride (0.015 g, 0.192 mmol). After stirring overnight at
room temperature, the reaction mixture was diluted with water and
then extracted with dichloromethane (3.times.35 mL). The combined
organics were washed with brine, dried over MgSO.sub.4, and
concentrated. The residue was purified by silica gel chromatography
eluting with hexanes: ethyl acetate to yield 0.054 g (70%) of amide
12. MS m/z 467 (M.sup.++23), 445 (M.sup.++1).
EXAMPLE 14
Preparation of Carboxylic Acid 13 (R.sub.1.dbd.CO.sub.2Me;
R.sub.2=3.5-dimethylphenyl; R.sub.4=Me; Y.dbd.O; n=2)
[0120] To a suspension of amine 11 (0.079 g, 0.212 mmol) in 5 mL of
benzene was added succinic anhydride (0.021 g, 0.212 mmol). After
heating at reflux for 24 hours, the reaction mixture was filtered
and washed with benzene. The residue was dried under high vacuum
and then washed with ether to remove the excess succinic anhydride.
This yielded 0.063 g (63%) of carboxylic acid 13. MS m/z 473
(M.sup.++1).
EXAMPLE 15
Preparation of Carboxylic Acid 13 (R.sub.1.dbd.CO.sub.2Me;
R.sub.2=3,5-dimethylphenyl; R.sub.4=Me; Y.dbd.H.sub.2; n=1)
[0121] To a refluxing solution of amine 11 (0.078 g, 0.210 mmol) in
5 mL of acetonitrile was added .beta.-propiolactone (0.015 g, 0.210
mmol). The reaction was heated to reflux for 72 hours before
cooling to room temperature. The reaction mixture was concentrated.
The residue was mixed with 10% aqueous sodium hydroxide and washed
sequentially with ether and ethyl acetate. The aqueous layer was
acidified with concentrated HCl and extracted with dichloromethane
(2.times.25 mL). The combined organics were dried over MgSO.sub.4,
filtered, and concentrated. The residue was purified by column
chromatography eluting with 5% MeOH in dichloromethane to yield
0.020 g (21%) of an orange solid. MS m/z 467 (M.sup.++23), 445
(M.sup.++1).
EXAMPLE 16
Preparation of Hydroxamic Acid 14 (R.sub.1.dbd.CO.sub.2Me;
R.sub.2=(4-methyl)-1-naphthyl; Y.dbd.O; n=2; R.sub.4=Me)
[0122] To a 0.degree. C. suspension of carboxylic acid 13 (0.054 g,
0.106 mmol) in 10 mL of diethyl ether was added triethylamine
(0.014 g, 0.138 mmol) and then ethyl chloroformate (0.014 g, 0.127
mmol). The mixture was stirred at 0.degree. C. for 30 minutes and
them warmed to room temperature. A solution of hydroxylamine (0.159
mmol) in methanol was added and the reaction was stirred overnight
at room temperature. The mixture was filtered and the residue was
washed with ether and dried under vacuum to yield 0.030 g (54%) of
a yellow solid. MS m/z 524 (M.sup.++1).
EXAMPLE 17
Preparation of Amide 15 (R.sub.1.dbd.CO.sub.2Me;
R.sub.2=3,5-dimethylphenyl; R.sub.4=Me)
[0123] A mixture of amine 11 (0.201 g, 0.54 mmol) and glycolic acid
(0.049 g, 0.65 mmol) was heated at 120-160.degree. C. for 30
minutes. During heating, more glycolic acid was added to ensure
that excess reagent was present. Once the starting material was
consumed, the reaction was cooled to room temperature, and diluted
with dichloromethane. The resulting mixture was extracted with 20%
NaOH, followed by 10% HCl, and finally water. The combined organics
were concentrated and triturated with ether. Purification by column
chromatography eluting with ethyl acetate: hexanes yielded 0.012 g
(5%) of a yellow solid. MS m/z 453 (M.sup.++23), 431
(M.sup.++1).
EXAMPLE 18
Preparation of Amide 16 (R.sub.1.dbd.CO.sub.2Me;
R.sub.2=3,5-dimethylphenyl; R.sub.4=Me;
NR.sub.6R.sub.7=morpholino)
[0124] To a 0.degree. C. mixture of amine 11 (0.123 g, 0.331 mmol)
in 2 mL of 20% aqueous NaHCO.sub.3 and 3 mL of ethyl acetate was
added chloroacetyl chloride (0.047 g, 0.413 mmol). The reaction was
warmed to room temperature and stirred for 45 minutes. The mixture
was poured into a separatory funnel and the aqueous layer was
removed. The organic layer containing the crude chloroamide was
used without purification. To the ethyl acetate solution was added
morpholine (0.086 g, 0.992 mmol) and the reaction was heated to
approx. 65.degree. C. overnight. The reaction was diluted with
water and cooled to room temperature. After extraction with ethyl
acetate (3.times.25 mL), the combined organics were washed with
brine, dried over MgSO.sub.4 and concentrated to yield 0.130 g
(79%) of a yellow solid. MS m/z 522 (M.sup.++23), 500
(M.sup.++1).
EXAMPLE 19
Preparation of piperazinone 17 (R.sub.1.dbd.CO.sub.2Me;
R.sub.2=3,5-dimethylphenyl; R.sub.4=Me; R.sub.7.dbd.H)
[0125] To a 0.degree. C. solution of amide 16
(R.sub.6.dbd.CH.sub.2CH.sub.2OH) (0.093 g, 0.20 mmol), tri
n-butylphosphine (0.055 g, 0.27 mmol) in 0.35 mL ethyl acetate was
slowly added di-tert-butyl azodicarboxylate (0.062 g, 0.27 mmol) in
0.20 mL ethyl acetate. The reaction was allowed to stand for 15
minutes and then heated to 40.degree. C. overnight. 4.2 M ethanolic
HCl was added dropwise. The mixture was cooled to 0.degree. C. and
allowed to stand for 2 hours. The mixture was filtered and washed
with cold ethyl acetate. Purification by column chromatography with
1-5% MeOH in CH.sub.2Cl.sub.2 yielded 0.011 (12%) of a white solid.
MS m/z 478 (M.sup.++23), 456 (M.sup.++1).
EXAMPLE 20
Preparation of 4-Aminoindenopyridine 19 (R.sub.1.dbd.CO.sub.2Me;
R.sub.4=Me; R.sub.6=Me; R.sub.7=phenyl)
[0126] To a solution of 4-chloroindenopyridine 18 (0.069 g, 0.240
mmol) in 10 mL of 2-ethoxyethanol was added N-methylaniline (0.026
g, 0.240 mmol). The reaction was heated at reflux for 96 hours.
After cooling to room temperature, the solution was concentrated.
The residue was purified by column chromatography eluting with
hexanes: ethyl acetate to yield 0.029 g (34%) of an orange solid.
MS m/z 359 (M.sup.++1).
EXAMPLE 21
Preparation of 4-Aminoindenopyridine 19 (R.sub.1.dbd.CO.sub.2Me;
R.sub.4=Me; R.sub.6.dbd.H; R.sub.7=cyclopentyl) by Palladium
Catalyzed Coupling
[0127] A mixture of 4-chloroindenopyridine 18 (0.100 g, 0.347
mmol), cyclopentylamine (0.035 g, 0.416 mmol), palladium (II)
acetate (0.004 g, 0.0017 mmol), 2-(di-t-butylphosphino)biphenyl
(0.010 g, 0.0035 mmol), and cesium carbonate (0.124 g, 0.382 mmol)
in 10 mL of dioxane was heated at reflux overnight. The reaction
was cooled to room temperature, diluted with water, and extracted
with ethyl acetate (3.times.35 mL). The combined organics were
washed with brine, dried over Na.sub.2SO.sub.4, and concentrated.
The residue was purified by column chromatography eluting with
ethyl acetate: hexanes. The purified oil was dissolved in ether and
cooled to 0.degree. C. To this solution was slowly added 1.0 M HCl
in ether. The resulting precipitate was isolated by filtration,
washed with ether, and dried under vacuum to yield 0.032 g (25%) of
a yellow solid. MS m/z 359 (M.sup.++23), 337 (M.sup.++1).
[0128] Following the general synthetic procedures outlined above
and in Examples 1-21, the compounds of Table 1 below were prepared.
TABLE-US-00001 TABLE 1 ##STR38## No. R.sub.1 R.sub.2 R.sub.3a
R.sub.3b R.sub.3c R.sub.3d R.sub.4 MS (M + 1) 1 CN ##STR39## H H H
H Me 341 C.sub.7H.sub.5O.sub.2 2 CO.sub.2Et ##STR40## H H H H Me
388 C.sub.7H.sub.5O.sub.2 3 CO.sub.2t-Bu ##STR41## H H H H Me 416
C.sub.7H.sub.5O.sub.2 4 CO.sub.2t-Bu ##STR42## H H H H Me 432
C.sub.8H.sub.9O.sub.2 5 CO.sub.2Et ##STR43## H H H H Me 389
C.sub.6H.sub.4NO.sub.2 6 CO.sub.2H ##STR44## H H H H Me 360
C.sub.7H.sub.5O.sub.2 7 CO.sub.2Et ##STR45## H H H H Me 480
C.sub.14H.sub.13O.sub.2 8 CO.sub.2Et ##STR46## H H H H Me 482
C.sub.8H.sub.8BrO.sub.2 9 CO.sub.2Et ##STR47## H H H H Me 424
C.sub.11H.sub.9O 10 CO.sub.2H ##STR48## H H H H Me 376
C.sub.8H.sub.9O.sub.2 11 CO.sub.2Et Ph H H H H Me 344 12 CO.sub.2Et
##STR49## H H H H Me 374 C.sub.7H.sub.7O 13 CO.sub.2Et ##STR50## H
H H H Me 434 C.sub.9H.sub.11O.sub.3 14 CO.sub.2Et ##STR51## H H H H
Me 454 C.sub.6H.sub.4BrO.sub.2 15 CO.sub.2Bn ##STR52## H H H H Me
450 C.sub.7H.sub.5O.sub.2 16 ##STR53## ##STR54## H H H H Me 507
C.sub.11H.sub.14NO.sub.2 C.sub.7H.sub.5O.sub.2 17 CO.sub.2Me
##STR55## H H H H Me 390 C.sub.8H.sub.9O.sub.2 18 CO.sub.2Me
##STR56## H H H H Me 374 C.sub.7H.sub.5O.sub.2 19 CO.sub.2Et
##STR57## H H H H Me 404 C.sub.8H.sub.9O.sub.2 20 CO.sub.2Et
##STR58## H H H H Me 404 C.sub.8H.sub.9O.sub.2 21 CO.sub.2Et
##STR59## H H H H Me 454 C.sub.7H.sub.6BrO 22 CO.sub.2Et ##STR60##
H H H H NH.sub.2 411 (M + 23) C.sub.7H.sub.5O.sub.2 23 CO.sub.2Et
##STR61## H H H H Me 388 C.sub.7H.sub.5O.sub.2 25 CO.sub.2Et
##STR62## H H H H NH.sub.2 405 C.sub.8H.sub.9O.sub.2 26 CO.sub.2Et
##STR63## H H H H NH.sub.2 390 C.sub.6H.sub.4NO.sub.2 27 CO.sub.2Et
Ph H H H H NH.sub.2 345 28 CO.sub.2Et ##STR64## H H H H Me 402
C.sub.9H.sub.11O 29 CO.sub.2Et ##STR65## H H H H Me 483
C.sub.8H.sub.8BrO.sub.2 30 CO.sub.2Me Ph H H H H Me 330 31
CO.sub.2Et ##STR66## H H H H Me 402 C.sub.8H.sub.7O.sub.2 32
CO.sub.2Et ##STR67## H NO.sub.2 H H Me 433 C.sub.7H.sub.5O.sub.2 33
##STR68## ##STR69## H H H H Me 413 C.sub.4H.sub.4NO.sub.2
C.sub.7H.sub.5O.sub.2 34 CO.sub.2Et ##STR70## H H H H Me 433
C.sub.7H.sub.4NO.sub.4 35 CO.sub.2Et ##STR71## H H NO.sub.2 H Me
433 C.sub.7H.sub.5O.sub.2 36 CO.sub.2Me ##STR72## H H H H Me 398
C.sub.7H.sub.4F.sub.3 37 CO.sub.2Et ##STR73## H H NH.sub.2 H Me 403
C.sub.7H.sub.5O.sub.2 38 CONH.sub.2 ##STR74## H H H H Me 359
C.sub.7H.sub.5O.sub.2 39 CO.sub.2Et ##STR75## H H H H Me 372
C.sub.8H.sub.9 40 CO.sub.2Et ##STR76## H NH.sub.2 H H Me 403
C.sub.7H.sub.5O.sub.2 41 CO.sub.2Et ##STR77## H H H H Me 334
C.sub.4H.sub.3O 42 CO.sub.2Et 2-Thienyl H H H H Me 350 43
CO.sub.2Me ##STR78## H H H H Me 358 C.sub.8H.sub.9 44 CO.sub.2Me
##STR79## H H H H Me 388 C.sub.8H.sub.7O.sub.2 45 CO.sub.2Me
##STR80## H H H H Me 419 C.sub.7H.sub.4NO.sub.4 46 CO.sub.2Me
##STR81## H H H H Me 388 C.sub.9H.sub.11O 47 CO.sub.2Me 4-Pyridyl H
H H H Me 331 48 CO.sub.2Me ##STR82## H H H H Me 374
C.sub.7H.sub.5O.sub.2 49 CO.sub.2Me ##STR83## H H H H Me 454
C.sub.7H.sub.4BrO.sub.2 50 CO.sub.2Me ##STR84## H H H H Me 439
C.sub.7H.sub.6BrO 51 CO.sub.2Me ##STR85## H H H H Me 358
C.sub.8H.sub.9 52 CO.sub.2Et ##STR86## H H H H Me 372
C.sub.8H.sub.9 53 CO.sub.2Me ##STR87## H H H H Me 410
C.sub.11H.sub.9O 54 CO.sub.2Me ##STR88## H H H H Me 375
C.sub.6H.sub.4NO.sub.2 55 CO.sub.2Et ##STR89## H NHAc H H Me 445
C.sub.7H.sub.5O.sub.2 56 CO.sub.2Et ##STR90## H H NHAc H Me 445
C.sub.7H.sub.5O.sub.2 57 CO.sub.2Et ##STR91## H H H H Me 358
C.sub.7H.sub.7 58 CO.sub.2Et ##STR92## H H H H Me 358
C.sub.7H.sub.7 59 CO.sub.2Et ##STR93## H H H H Me 358
C.sub.7H.sub.7 60 CO.sub.2Et ##STR94## H NO.sub.2 H H Me 457
C.sub.7H.sub.4F.sub.3 61 CO.sub.2Et ##STR95## H H NO.sub.2 H Me 457
C.sub.7H.sub.4F.sub.3 62 CO.sub.2Me ##STR96## H H H H Me 344
C.sub.7H.sub.7 63 CO.sub.2Et ##STR97## H NH.sub.2 H H Me 427
C.sub.7H.sub.4F.sub.3 64 CO.sub.2Et ##STR98## H H NH.sub.2 H Me 427
C.sub.7H.sub.4F.sub.3 65 CO.sub.2Me ##STR99## H H H H Me 466
C.sub.8H.sub.3F.sub.6 66 CO.sub.2Me ##STR100## H H H H Me 344
C.sub.7H.sub.7 67 CO.sub.2Me ##STR101## H H H H Me 344
C.sub.7H.sub.7 68 CO.sub.2Me ##STR102## H NO.sub.2 H H Me 443
C.sub.7H.sub.4F.sub.3 69 CO.sub.2Me ##STR103## H H NO.sub.2 H Me
443 C.sub.7H.sub.4F.sub.3 70 CO.sub.2Et ##STR104## H H H H i-Pr 400
C.sub.8H.sub.9 71 CO.sub.2Me ##STR105## H NH.sub.2 H H Me 413
C.sub.7H.sub.4F.sub.3 72 CO.sub.2Me ##STR106## H H H H Me 399
C.sub.6H.sub.3Cl.sub.2 73 CO.sub.2Me ##STR107## H H H H Et 372
C.sub.8H.sub.9 74 CO.sub.2Me ##STR108## H H H H Me 398
C.sub.7H.sub.4F.sub.3 75 CO.sub.2Me ##STR109## H H H H Me 394
C.sub.11H.sub.9 76 CO.sub.2Me ##STR110## H H H H Me 372
C.sub.9H.sub.11 77 CO.sub.2Me ##STR111## H NO.sub.2 H H Me 403
C.sub.8H.sub.9 78 CO.sub.2Me ##STR112## H H NO.sub.2 H Me 403
C.sub.8H.sub.9 79 CO.sub.2Me ##STR113## H H H H Me 394
C.sub.11H.sub.9 80 CO.sub.2Me ##STR114## H NHAc H H Me 455
C.sub.7H.sub.4F.sub.3 81 CO.sub.2Me ##STR115## H H H H Me 488
C.sub.6H.sub.3Br.sub.2 82 CO.sub.2Me ##STR116## H NH.sub.2 H H Me
373 C.sub.8H.sub.9
83 CO.sub.2Me ##STR117## H H NH.sub.2 H Me 373 C.sub.8H.sub.9 84
CO.sub.2Me ##STR118## H H H H Me 362 C.sub.7H.sub.6F 85 CO.sub.2Me
##STR119## H H H H Me 431 C.sub.6H.sub.4Br 86 CO.sub.2Me ##STR120##
H H H H Me 380 C.sub.10H.sub.7 87 CO.sub.2Me ##STR121## H NO.sub.2
H H Me 439 C.sub.11H.sub.9 88 CO.sub.2Me ##STR122## H H NO.sub.2 H
Me 439 C.sub.11H.sub.9 89 CO.sub.2Me ##STR123## H H H H Me 430
C.sub.14H.sub.9 90 CO.sub.2Me ##STR124## H NH.sub.2 H H Me 409
C.sub.11H.sub.9 91 CO.sub.2Me ##STR125## H H NH.sub.2 H Me 409
C.sub.11H.sub.9 92 ##STR126## ##STR127## H H H H Me 397
C.sub.4H.sub.4NO.sub.2 C.sub.8H.sub.9 93 CN ##STR128## H H H H Me
325 C.sub.8H.sub.9 94 CO.sub.2Me ##STR129## H H H H NH.sub.2 359
C.sub.8H.sub.9 95 CO.sub.2Me ##STR130## H H H H NH.sub.2 395
C.sub.11H.sub.9 96 CO.sub.2H ##STR131## H H H H Me 344
C.sub.8H.sub.9 97 ##STR132## ##STR133## H H H H Me 433
C.sub.4H.sub.4NO.sub.2 C.sub.11H.sub.9 98 CN ##STR134## H H H H Me
361 C.sub.11H.sub.9 99 ##STR135## ##STR136## H H H H
C.sub.2H.sub.2O.sub.2 358 C.sub.2H.sub.2O.sub.2
C.sub.7H.sub.5O.sub.2 100 ##STR137## ##STR138## H H H H
C.sub.2H.sub.2O.sub.2 357 C.sub.2H.sub.2O.sub.2/ C.sub.8H.sub.10N
101 ##STR139## Ph H H H H C.sub.2H.sub.2O.sub.2 314
C.sub.2H.sub.2O.sub.2 102 ##STR140## ##STR141## H H H H
C.sub.2H.sub.2O.sub.2 361 C.sub.2H.sub.2O.sub.2
C.sub.6H.sub.6NO.sub.2 103 ##STR142## ##STR143## H H H H
C.sub.2H.sub.2O.sub.2 364 C.sub.2H.sub.2O.sub.2 C.sub.10H.sub.7 104
##STR144## ##STR145## H H H H C.sub.2H.sub.2O.sub.2 342
C.sub.2H.sub.2O.sub.2 C.sub.8H.sub.9 105 CO.sub.2H ##STR146## H H H
H Me 380 C.sub.11H.sub.9 106 CONH.sub.2 ##STR147## H H H H Me 343
C.sub.8H.sub.9 107 CONHMe ##STR148## H H H H Me 357 C.sub.8H.sub.9
108 CONMe.sub.2 ##STR149## H H H H Me 371 C.sub.8H.sub.9 109
##STR150## ##STR151## H H H H C.sub.2H.sub.2O.sub.2 378
C.sub.2H.sub.2O.sub.2 C.sub.11H.sub.9 110 ##STR152## ##STR153## H H
H H C.sub.2H.sub.2O.sub.2 328 C.sub.2H.sub.2O.sub.2 C.sub.7H.sub.7
111 ##STR154## ##STR155## H H H H C.sub.2H.sub.2O.sub.2 356
C.sub.2H.sub.2O.sub.2 C.sub.9H.sub.11 112 ##STR156## ##STR157## H H
H H C.sub.2H.sub.2O.sub.2 328 C.sub.2H.sub.2O.sub.2 C.sub.7H.sub.7
113 CO.sub.2Me ##STR158## H H H H Me 375 C.sub.6H.sub.4NO.sub.2 114
##STR159## ##STR160## H H H H C.sub.2H.sub.2O.sub.2 328
C.sub.2H.sub.2O.sub.2 C.sub.7H.sub.7 115 CO.sub.2Me ##STR161## H H
H H Me 373 C.sub.8H.sub.10N 116 CONH.sub.2 ##STR162## H H H H Me
379 C.sub.11H.sub.9 117 ##STR163## ##STR164## H H H H
C.sub.2H.sub.2O.sub.2 365 C.sub.2H.sub.2O.sub.2 C.sub.9H.sub.6N 118
CO.sub.2Me ##STR165## H H H H Me 375 C.sub.6H.sub.4NO.sub.2 119
CONHMe ##STR166## H H H H Me 393 C.sub.11H.sub.9 120 CONMe.sub.2
##STR167## H H H H Me 407 C.sub.11H.sub.9 121 CO.sub.2Me ##STR168##
H H H H Me 381 C.sub.9H.sub.6N 122 CO.sub.2Me ##STR169## H Cl Cl H
Me 463 C.sub.11H.sub.9 123 CO.sub.2Me ##STR170## H Cl Cl H Me 427
C.sub.8H.sub.9 124 CO.sub.2Me ##STR171## H H H H Me 381
C.sub.9H.sub.6N 125 CO.sub.2Et ##STR172## H H H H Me 408
C.sub.11H.sub.9 126 CO.sub.2Me ##STR173## H Cl Cl H Me 555
C.sub.6H.sub.3Br.sub.2 127 CO.sub.2Me ##STR174## Cl H H Cl Me 427
C.sub.8H.sub.9 128 CO.sub.2Me ##STR175## H H H H Me 421
C.sub.7H.sub.6NO.sub.4 129 CO.sub.2Me ##STR176## Cl H H Cl Me 558
C.sub.6H.sub.3Br.sub.2 130 CO.sub.2Me ##STR177## H H H H Me 345
C.sub.6H.sub.6N 131 CO.sub.2Et ##STR178## H Cl Cl H Me 477
C.sub.11H.sub.9 132 CO.sub.2Me ##STR179## H H H H Me 503
C.sub.6H.sub.4Br.sub.2N 133 Ac ##STR180## H H H H Me 472
C.sub.6H.sub.3Br.sub.2 134 Ac ##STR181## H H H H Me 342
C.sub.8H.sub.9 135 CO.sub.2Me ##STR182## H H H H Me 331
C.sub.5H.sub.4N 136 ##STR183## ##STR184## H H H H Me 527
C.sub.4H.sub.4NO.sub.2 C.sub.6H.sub.3Br.sub.2 137 ##STR185##
##STR186## H H H H Me 397 C.sub.4H.sub.4NO.sub.2 C.sub.8H.sub.9 138
CO.sub.2Me OH ##STR187## H H H H Me 362 C.sub.6H.sub.5O.sub.2 139
CO.sub.2H ##STR188## H H H H Me 474 C.sub.6H.sub.3Br.sub.2 140
CO.sub.2H ##STR189## H H H H Me 344 C.sub.8H.sub.9 141 CO.sub.2Me
##STR190## H H H H Me 346 C.sub.6H.sub.5O 142 CO.sub.2Me ##STR191##
H H H H Me 380 C.sub.10H.sub.7 143 CO.sub.2Me ##STR192## H H H H Me
486 C.sub.16H.sub.25O 144 CO.sub.2Me ##STR193## H H H H Me 436
C.sub.13H.sub.11O 145 CO.sub.2Me ##STR194## H H H H Me 518
C.sub.7H.sub.5Br.sub.2O 146 ##STR195## ##STR196## H H H H Me 557
C.sub.4H.sub.4NO.sub.2 C.sub.7H.sub.5Br.sub.2O 147 ##STR197##
##STR198## H Cl Cl H Me 466 C.sub.4H.sub.4NO.sub.2 C.sub.8H.sub.9
148 CO.sub.2Et --NHPh H H H H Me 359 149 CO.sub.2Me ##STR199## H H
H H Me 360 C.sub.7H.sub.7O 150 CO.sub.2Me ##STR200## H H H H Me 504
C.sub.6H.sub.3Br.sub.2O 151 ##STR201## ##STR202## H H H H Me 420
C.sub.4H.sub.4NO.sub.2 C.sub.9H.sub.6N 152 C.sub.3H.sub.5O.sub.3
##STR203## H H H H Me 534 C.sub.6H.sub.3Br.sub.2O 153 ##STR204##
##STR205## H H H H Me 385 C.sub.4H.sub.4NO.sub.2 C.sub.6H.sub.5O
154 ##STR206## ##STR207## H H H H Me 373 C.sub.2H.sub.4NO.sub.2
C.sub.8H.sub.9 155 ##STR208## ##STR209## H H NO.sub.2 H Me 574
C.sub.4H.sub.4NO.sub.2 C.sub.6H.sub.3Br.sub.2 156 CO.sub.2Me
##STR210## H Br H H Me 473 C.sub.11H.sub.9 157 CO.sub.2Me
##STR211## H H Br H Me 473 C.sub.11H.sub.9 158 ##STR212##
##STR213## H Cl Cl H Me 489 C.sub.4H.sub.4NO.sub.2 C.sub.9H.sub.6N
159 ##STR214## ##STR215## H H NO.sub.2 H Me 590
C.sub.4H.sub.4NO.sub.2 C.sub.6H.sub.3Br.sub.2O 160 ##STR216##
##STR217## H H H H Me 411 C.sub.3H.sub.5O.sub.3 C.sub.9H.sub.6N 161
CO.sub.2Me ##STR218## H Br H H Me 436 C.sub.8H.sub.9 162 CO.sub.2Me
##STR219## H H Br H Me 438 C.sub.8H.sub.9 163 CO.sub.2Me ##STR220##
H Br Br H Me 516 C.sub.8H.sub.9 164 ##STR221## ##STR222## H Cl Cl H
Me 597 C.sub.4H.sub.4NO.sub.2 C.sub.6H.sub.3Br.sub.2 165 ##STR223##
##STR224## H Cl Cl H Me 480 C.sub.3H.sub.5O.sub.3 C.sub.9H.sub.6N
166 CO.sub.2Me ##STR225## H Br Br H Me 552 C.sub.11H.sub.9
167 CO.sub.2Et ##STR226## H Br Br H Me 530 C.sub.8H.sub.9 168
CO.sub.2Me ##STR227## F H H F Me 540 C.sub.6H.sub.3Br.sub.2O 169
CO.sub.2Me ##STR228## H H NO.sub.2 H Me 551 C.sub.6H.sub.3Br.sub.2O
170 CO.sub.2Me ##STR229## H Cl Cl H Me 573 C.sub.6H.sub.3Br.sub.2O
171 ##STR230## ##STR231## H H NO.sub.2 H Me 444
C.sub.4H.sub.4NO.sub.2 C.sub.8H.sub.9 172 ##STR232## ##STR233## H
NO.sub.2 H H Me 444 C.sub.4H.sub.4NO.sub.2 C.sub.8H.sub.9 173
CO.sub.2Me ##STR234## F H H F Me 394 C.sub.8H.sub.9 174 ##STR235##
##STR236## F H H F Me 433 C.sub.4H.sub.4NO.sub.2 C.sub.8H.sub.9 175
CO.sub.2Me ##STR237## H Br Br H Me 548 C.sub.8H.sub.9O.sub.2 176
CO.sub.2Me ##STR238## H H H H Me 355 C.sub.7H.sub.4N 177 CO.sub.2Me
##STR239## H NO.sub.2 H H Me 421 C.sub.8H.sub.9O 178 CO.sub.2Me
##STR240## H H NO.sub.2 H Me 453 (M + 23) C.sub.8H.sub.9O 179
CO.sub.2Me ##STR241## H Cl Cl H Me 443 C.sub.8H.sub.9O 180 CN
##STR242## H H H H Me 341 C.sub.8H.sub.9O 181 CO.sub.2Me ##STR243##
H H H H Me 598 C.sub.6H.sub.3I.sub.2O 182 CO.sub.2Me ##STR244## H
Cl Cl H Me 435 C.sub.6H.sub.3F.sub.2 183 CO.sub.2Et ##STR245## H H
H H Me 387 C.sub.8H.sub.10N 184 CO.sub.2Et ##STR246## H H H H Me
373 C.sub.7H.sub.8N 185 CO.sub.2Me ##STR247## H H H H Me 612
C.sub.7H.sub.5I.sub.2O 186 CO.sub.2Et ##STR248## H H H H Me 410
C.sub.9H.sub.7N.sub.2 187 CO.sub.2Me ##STR249## H H NO.sub.2 H Me
345 C.sub.6H.sub.3I.sub.2O 188 CO.sub.2Me ##STR250## H Cl Cl H Me
668 C.sub.6H.sub.3I.sub.2O 189 CO.sub.2Me ##STR251## H H NO.sub.2 H
Me 413 C.sub.6H.sub.3F.sub.2 190 CO.sub.2H ##STR252## H Cl Cl H Me
544 C.sub.6H.sub.3Br.sub.2 191 CN ##STR253## H H H H Me 565
C.sub.6H.sub.3I.sub.2O 192 CO.sub.2Me ##STR254## H Br H H Me 606 (M
+ 23) C.sub.6H.sub.3Br.sub.2O 193 CO.sub.2Me ##STR255## H H Br H Me
584 C.sub.6H.sub.3Br.sub.2O 194 CO.sub.2Et ##STR256## H H H H Me
373 C.sub.7H.sub.8N 195 CO.sub.2Et ##STR257## H H H H Me 427
C.sub.6H.sub.4Cl.sub.2N 196 CO.sub.2Et ##STR258## H Cl Cl H Me 587
C.sub.6H.sub.3Br.sub.2O 197 CO.sub.2Et ##STR259## H H H H Me 437
C.sub.6H.sub.5BrN 198 CO.sub.2Et ##STR260## H H H H Me 389
C.sub.7H.sub.8NO 199 CO.sub.2Et ##STR261## H H H H Me 612
C.sub.6H.sub.3I.sub.2O 200 CO.sub.2Et ##STR262## H Cl Cl H Me 449
C.sub.6H.sub.3F.sub.2 201 CO.sub.2Me ##STR263## H Cl Cl H Me 450
C.sub.9H.sub.6N 202 CO.sub.2Me ##STR264## H Cl Cl H Me 465
C.sub.7H.sub.5F.sub.2O 203 CO.sub.2Me ##STR265## H H H H Me 396
C.sub.7H.sub.5F.sub.2O 204 CO.sub.2Me ##STR266## H ##STR267## H H
Me 473 C.sub.8H.sub.9 C.sub.4H.sub.6NO.sub.3 205 CO.sub.2Me
##STR268## H H H H Me 345 C.sub.6H.sub.6N 206 CO.sub.2Me ##STR269##
H H H H Me 359 C.sub.7H.sub.8N 207 CO.sub.2Me ##STR270## H Cl Cl H
Me 444 C.sub.6H.sub.4NO.sub.2 208 CO.sub.2Me ##STR271## H H H H Me
355 C.sub.7H.sub.4N 209 CO.sub.2H ##STR272## H H H H Me 366
C.sub.10H.sub.7 210 CO.sub.2Me ##STR273## H Cl Cl H Me 444
C.sub.6H.sub.4NO.sub.2 211 CO.sub.2Me ##STR274## H Cl Cl H Me 430
C.sub.7H.sub.6F 212 CO.sub.2Me ##STR275## H H H H Me 416
C.sub.7H.sub.3F.sub.4 213 CO.sub.2Me ##STR276## H Cl Cl H Me 430
C.sub.7H.sub.6F 214 CO.sub.2Me ##STR277## H H H H Me 413
C.sub.6H.sub.4Cl.sub.2N 215 CO.sub.2Me ##STR278## H OMe OMe H Me
418 C.sub.8H.sub.9 216 CO.sub.2Me ##STR279## H OMe OMe H Me 454
C.sub.11H.sub.9 217 CO.sub.2Me ##STR280## H H H H Me 362
C.sub.7H.sub.6F 218 CO.sub.2Me ##STR281## H ##STR282## H H Me 445
C.sub.8H.sub.9 C.sub.3H.sub.6NO.sub.2 219 CO.sub.2Me ##STR283## H H
H H Me 35 C.sub.7H.sub.8N 220 CO.sub.2Me --NHPh H H H H Me 345 221
CO.sub.2Me ##STR284## H H H H Me 423 C.sub.6H.sub.5BrN 222
CO.sub.2Me 2-Pyridyl H H H H Me 353 (M + 23) 223 CO.sub.2Me
##STR285## H OMe OMe H Me 459 C.sub.6H.sub.3Cl.sub.2 224 CO.sub.2Me
##STR286## H Cl Cl H Me 485 C.sub.7H.sub.3F.sub.4 225 CO.sub.2Me
##STR287## H H H H Me 345 C.sub.6H.sub.6N 226 CO.sub.2Me ##STR288##
H H NO.sub.2 H Me 420 C.sub.6H.sub.4NO.sub.2 227 CO.sub.2Me
##STR289## H H NO.sub.2 H Me 420 C.sub.6H.sub.4NO.sub.2 228
CO.sub.2Me ##STR290## H H H H Me 359 C.sub.7H.sub.8N 229 CO.sub.2Me
##STR291## H H H H Me 396 C.sub.9H.sub.7N.sub.2 230 CO.sub.2Me
##STR292## H OH OH H Me 426 C.sub.11H.sub.9 231 CO.sub.2Me
##STR293## H H F H Me 376 C.sub.8H.sub.9 232 CO.sub.2Me ##STR294##
H H NO.sub.2 H Me 461 C.sub.7H.sub.3F.sub.4 233 CO.sub.2Me
##STR295## H Cl Cl H Me 468 C.sub.10H.sub.6F 234 CO.sub.2Me
##STR296## H H H H Me 373 C.sub.8H.sub.10N 235 CO.sub.2Me
##STR297## H H H H Me 375 C.sub.7H.sub.8NO 236 CO.sub.2Me
##STR298## H NO.sub.2 H H Me 443 C.sub.10H.sub.6F 237 CO.sub.2Me
##STR299## H H NO.sub.2 H Me 443 C.sub.10H.sub.6F 238 CO.sub.2Me
##STR300## H H H H Me 398 C.sub.10H.sub.6F 239 CO.sub.2Me
##STR301## H Cl Cl H Me 491 C.sub.12H.sub.12N 240 CO.sub.2Me
##STR302## H ##STR303## H H Me 509 C.sub.11H.sub.9 H
C.sub.4H.sub.6NO.sub.3 241 CO.sub.2Me ##STR304## H H ##STR305## H
Me 473 C.sub.8H.sub.9 C.sub.4H.sub.6NO.sub.3 242 CO.sub.2Me
##STR306## H H ##STR307## H Me 509 C.sub.11H.sub.9
C.sub.4H.sub.6NO.sub.3 243 CO.sub.2Me ##STR308## H H H H Me 310
C.sub.4H.sub.9 244 CO.sub.2Me ##STR309## H ##STR310## H H Me 524
C.sub.11H.sub.9 C.sub.4H.sub.7N.sub.2O.sub.3 245 CO.sub.2Me
##STR311## H H ##STR312## H Me 488 C.sub.8H.sub.9
C.sub.4H.sub.7N.sub.2O.sub.3 246 CO.sub.2Me ##STR313## H H H H Me
308 C.sub.4H.sub.7 247 CO.sub.2Me i-Pr H H H H Me 296 248
CO.sub.2Me ##STR314## H H H H Me 336 Cyclohexyl 249 CO.sub.2Me Me H
H H H Me 268 250 CO.sub.2Me ##STR315## H H ##STR316## H Me 474
C.sub.8H.sub.9 C.sub.4H.sub.9N.sub.2O.sub.2 251 CO.sub.2Me
##STR317## H H ##STR318## H Me 487 C.sub.8H.sub.9
C.sub.5H.sub.8NO.sub.3
252 CO.sub.2Me N- Morpholino H H H H Me 339 253 CO.sub.2Me
##STR319## H H H H Me 337 C.sub.5H.sub.10N 254 CO.sub.2Me
##STR320## H H ##STR321## H Me 488 C.sub.8H.sub.9
C.sub.5H.sub.11N.sub.2O.sub.2 255 CO.sub.2Me ##STR322## H
##STR323## H H Me 474 C.sub.8H.sub.9 C.sub.4H.sub.9N.sub.2O.sub.2
256 CO.sub.2Me ##STR324## H ##STR325## H H Me 456 C.sub.8H.sub.9
C.sub.4H.sub.7N.sub.2O 257 CO.sub.2Me ##STR326## H ##STR327## H H
Me 431 C.sub.8H.sub.9 C.sub.2H.sub.4NO.sub.2 258 CO.sub.2Me
##STR328## H ##STR329## H H Me 500 C.sub.8H.sub.9
C.sub.6H.sub.11N.sub.2O.sub.2 259 CO.sub.2Me ##STR330## H
##STR331## H H Me 499 C.sub.8H.sub.9 C.sub.6H.sub.12N.sub.3O 260
CO.sub.2Me ##STR332## H ##STR333## H H Me 481 C.sub.8H.sub.9
C.sub.5H.sub.6N.sub.3O 261 CO.sub.2Me ##STR334## H H ##STR335## H
Me 500 C.sub.8H.sub.9 C.sub.6H.sub.11N.sub.2O.sub.2 262 CO.sub.2Me
##STR336## H H ##STR337## H Me 499 C.sub.8H.sub.9
C.sub.6H.sub.12N.sub.3O 263 CO.sub.2Me ##STR338## H H ##STR339## H
Me 431 C.sub.8H.sub.9 C.sub.2H.sub.4NO.sub.2
III. Biological Assays and Activity
[0129] The assay of phosphodiesterase activity follows the
homogeneous SPA (scintillation proximity assay) format under the
principle that linear nucleotides preferentially bind yttrium
silicate beads in the presence of zinc sulfate.
[0130] In this assay, the enzyme converts radioactively tagged
cyclic nucleotides (reaction substrate) to linear nucleotides
(reaction product) which are selectively captured via ion chelation
on a scintillant-containing bead. Radiolabeled product bound to the
bead surface results in energy transfer to the bead scintillant and
generation of a quantifiable signal. Unbound radiolabel fails to
achieve close proximity to the scintillant and therefore does not
generate any signal.
[0131] Specifically, enzyme was diluted in PDE buffer (50 mM pH 7.4
Tris, 8.3 mM MgCl.sub.2, 1.7 mM EGTA) with 0.1% ovalbumin such that
the final signal:noise (enzyme:no enzyme) ratio is 5-10. Substrate
(2,8-.sup.3H-cAMP or 8-.sup.3H-cGMP, purchased from Amersham
Pharmacia) was diluted in PDE (4, 5, 7A) buffer to 1 nCi per .mu.l
(or 1 gCi/ml). For each test well, 48 .mu.l of enzyme was mixed
with 47 .mu.l substrate and 5 .mu.l test compound (or DMSO) in a
white Packard plate, followed by shaking to mix and incubation for
15 minutes at room temperature. A 50 .mu.l aliquot of evenly
suspended yttrium silicate SPA beads in zinc sulfate was added to
each well to terminate the reaction and capture the product. The
plate was sealed using Topseal-S (Packard) sheets, and the beads
were allowed to settle by gravity for 15-20 minutes prior to
counting on a Packard TopCount scintillation counter using a
.sup.3H glass program with color quench correction. Output was in
color quench-corrected dpm.
[0132] Test compounds were diluted in 100% DMSO to a concentration
20.times. final assay concentration. DMSO vehicle alone was added
to uninhibited control wells. Inhibition (%) was calculated as
follows: Nonspecific .times. .times. binding .times. .times. ( NSB
) = the .times. .times. mean .times. .times. of .times. .times. CPM
.times. .times. of .times. .times. the .times. .times. substrate +
buffer + DMSO .times. .times. wells ##EQU1## Total .times. .times.
Binding .times. .times. ( TB ) = the .times. .times. mean .times.
.times. of .times. .times. the .times. .times. enzyme + substrate +
DMSO .times. .times. wells ##EQU1.2## % .times. .times. Inhibition
.times. .times. listed .times. .times. in .times. .times. Table
.times. .times. 1 = ( 1 - ( Sample .times. .times. CPM - NSB ) TB -
NSB ) .times. 100 ##EQU1.3##
[0133] The IC.sub.50 values were calculated using the Deltagraph
4-parameter curve-fitting program. The IC.sub.50 and % Inhibition
data on PDE 4, 5, and 7A are listed for the indicated compounds in
Table 2 below. TABLE-US-00002 TABLE 2 Ia ##STR340## MS IC.sub.20
(.mu.M)/% inh. @ .mu.M No. R.sub.1 R.sub.2 R.sub.3a R.sub.3b
R.sub.3c R.sub.3d R.sub.4 (M + 1) PDE7A PDE4 PDE5 6 CO.sub.2H
##STR341## H H H H Me 360 45% @20 49% @5 51 CO.sub.2Me ##STR342## H
H H H Me 358 0.055 0.353 2.7 56 CO.sub.2Et ##STR343## H H NHAc H Me
445 0.074 0.333 2.5 70 CO.sub.2Et ##STR344## H H H H i-Pr 400 2.11
73 CO.sub.2Me ##STR345## H H H H Et 372 1.54 0.998 82 CO.sub.2Me
##STR346## H NH.sub.2 H H Me 373 0.021 0.204 1.11, 0.864 90
CO.sub.2Me ##STR347## H NH.sub.2 H H Me 409 0.005 0.237, 0.172 2.33
98 CN ##STR348## H H H H Me 361 1.13 119 CONHMe ##STR349## H H H H
Me 393 0.658 41% @20 133 Ac ##STR350## H H H H Me 472 1.54 134 Ac
##STR351## H H H H Me 342 1.14 169 CO.sub.2Me ##STR352## H H
NO.sub.2 H Me 551 0.0053 0.184 170 CO.sub.2Me ##STR353## H Cl Cl H
Me 573 0.0087 0.557 190 CO.sub.2H ##STR354## H Cl Cl H Me 544 5.9
191 CN ##STR355## H H H H Me 565 0.593 197 CO.sub.2Et ##STR356## H
H H H Me 437 0.728 69% @5 0.362 219 CO.sub.2Me ##STR357## H H H H
Me 359 0.964 61% @5 1.1 220 CO.sub.2Me --NHPh H H H H Me 345 0.084
1.8 0.637 241 CO.sub.2Me ##STR358## H H ##STR359## H Me 473 0.0035
0.954 0.183 242 CO.sub.2Me ##STR360## H H ##STR361## H Me 509
0.0038 0.782 0.141 243 CO.sub.2Me ##STR362## H H H H Me 310 2.6 245
CO.sub.2Me ##STR363## H H ##STR364## H Me 488 0.0053 0.875 0.185
248 CO.sub.2Me ##STR365## H H H H Me 336 0.783 0.171 0.649 250
CO.sub.2Me ##STR366## H H ##STR367## H Me 474 0.0074 0.684 2.4 251
CO.sub.2Me ##STR368## H H ##STR369## H Me 487 0.0054 0.754 0.26 253
CO.sub.2Me ##STR370## H H H H Me 337 0.905 0.85 0.303 254
CO.sub.2Me ##STR371## H H ##STR372## H Me 488 0.0067 0.664 0.765
261 CO.sub.2Me ##STR373## H H ##STR374## H Me 500 0.0063 0.477 0.63
262 CO.sub.2Me ##STR375## H H ##STR376## H Me 499 0.008 0.702
3.7
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