U.S. patent application number 10/404628 was filed with the patent office on 2003-11-13 for salts of zopolrestat.
Invention is credited to Mylari, Banavara L..
Application Number | 20030212072 10/404628 |
Document ID | / |
Family ID | 26878632 |
Filed Date | 2003-11-13 |
United States Patent
Application |
20030212072 |
Kind Code |
A1 |
Mylari, Banavara L. |
November 13, 2003 |
Salts of zopolrestat
Abstract
This invention relates to
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethy-
l)-3,4-dihydro-phthalazin-1-yl]-acetic acid ethanolamine salt,
pharmaceutical compositions thereof and methods of treating
diabetic complications in mammals comprising administering to said
mammals said salt and said compositions. This invention is also
directed to combinations of said diethylamine salt with NHE-1
inhibitors, selective serotonin retuptake inhibitors (SSRIs),
glycogen phosphorylase inhibitors (GPIs), sorbitol dehydrogenase
inhibitors (SDIs) and antihypertensive agents. Said combinations
are useful in treating diabetic complications in mammals.
Inventors: |
Mylari, Banavara L.;
(Waterford, CT) |
Correspondence
Address: |
PFIZER INC.
PATENT DEPARTMENT, MS8260-1611
EASTERN POINT ROAD
GROTON
CT
06340
US
|
Family ID: |
26878632 |
Appl. No.: |
10/404628 |
Filed: |
April 1, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10404628 |
Apr 1, 2003 |
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09782798 |
Feb 13, 2001 |
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6570013 |
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60183004 |
Feb 16, 2000 |
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Current U.S.
Class: |
514/248 ;
544/237 |
Current CPC
Class: |
A61K 31/495 20130101;
A61K 31/47 20130101; A61K 31/495 20130101; A61K 2300/00 20130101;
A61K 2300/00 20130101; C07D 417/06 20130101; A61K 31/47
20130101 |
Class at
Publication: |
514/248 ;
544/237 |
International
Class: |
A61K 031/502; C07D
417/02 |
Claims
1. A compound selected from the group consisting of
4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin--
1-yl]-acetic acid ethanolamine salt;
[4-oxo-(5-trifluoromethyl-benzothiazo-
l-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid
diethanolamine salt; and
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro--
phthalazin-1-yl]-acetic acid triethanolamine salt.
2. A pharmaceutical composition comprising a compound of claim 1
and a pharmaceutically acceptable carrier, vehicle or diluent.
3. A method of treating a diabetic complication in a mammal
comprising administering to said mammal a compound of claim 1.
4. A method of claim 3 wherein said diabetic complication is
diabetic neuropathy.
5. A method of claim 3 wherein said diabetic complication is
diabetic nephropathy.
6. A method of claim 3 wherein said diabetic complication is
diabetic cardiomyopathy.
7. A method of claim 3 wherein said diabetic complication is
diabetic retinopathy.
8. A method of claim 3 wherein said diabetic complication is
cataracts.
9. A method of claim 3 wherein said diabetic complication is
myocardial infarction.
10. A method of claim 3 wherein said diabetic complication is
microangiopathy or macroangiopathy.
11. A method of treating a diabetic complication in a mammal
comprising administering to said mammal
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylm-
ethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid ethanolamine salt
and a second pharmaceutical agent selected from NHE-1 inhibitor or
a pharmaceutically acceptable salt thereof, a SSRI or a
pharmaceutically acceptable salt thereof, a GPI or a
pharmaceutically acceptable salt thereof, a SDI or a
pharmaceutically acceptable salt thereof or an antihypertensive
agent or a pharmaceutically acceptable salt thereof.
12. A method of claim 11 wherein said second pharmaceutical agent
is a NHE-1 inhibitor or a pharmaceutically acceptable salt
thereof.
13. A composition of claim 12 wherein said NHE-1 inhibitor is
selected from the group consisting of
[1-(8-bromoquinolin-5-yl)-5-cyclopropyl-1H-p-
yrazole-4-carbonyl]guanidine;
[1-(6-chloroquinolin-5-yl)-5-cyclopropyl-1H--
pyrazole-4-carbonyl]guanidine;
[1-(indazol-7-yl)-5-cyclopropyl-1H-pyrazole- -4-carbonyl]guanidine;
[1-(benzimidazol-5-yl)-5-cyclopropyl-1H-pyrazole-4--
carbonyl]guanidine;
[1-(1-isoquinolyl)-5-cyclopropyl-1H-pyrazole-4-carbony-
l]guanidine;
[5-cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanid- ine;
[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine;
[1-(indazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(indazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(benzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(1-methylbenzimidazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
1-(5-quinolinyl)-5-n-propyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(5-quinolinyl)-5-isopropyl-1H-pyrazole-4-carbonyl]guanidine;
[5-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-methylbenzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(1,4-benzodioxan-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(benzotriazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(3-chloroindazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(5-quinolinyl)-5-butyl-1H-pyrazole-4-carbonyl]guanidine;
[5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-4-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl-
]guanidine;
[1-(2-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guani-
dine;
[1-(2-trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-ca-
rbonyl]guanidine;
[1-(2-bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]-
guanidine;
[1-(2-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanid-
ine;
[1-(2-chloro-5-methoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]gu-
anidine;
[1-(2-chloro-4-methylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazo-
le-4-carbonyl]guanidine;
[1-(2,5-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-
-4-carbonyl]guanidine;
[1-(2,3-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-
-carbonyl]guanidine;
[1-(2-chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H--
pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-5-aminosulfonylphenyl)-5-cyclo-
propyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-fluoro-6-trifluoromethylphe-
nyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-5-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl-
]guanidine;
[1-(2-chloro-5-dimethylaminosulfonylphenyl)-5-cyclopropyl-1H-p-
yrazole-4-carbonyl]guanidine;
[1-(2-trifluoromethyl-4-chlorophenyl)-5-cycl-
opropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chlorophenyl)-5-methyl-1H-- pyrazole-4-carbonyl]guanidine;
[5-methyl-1-(2-trifluoromethylphenyl)-1H-py-
razole-4-carbonyl]guanidine;
[5-ethyl-1-phenyl-1H-pyrazole-4-carbonyl]guan- idine;
[5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]g-
uanidine; [5-cyclopropyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]guanidine;
or a pharmaceutically acceptable salt thereof.
14. A method of claim 11 wherein said second pharmaceutical agent
is a SSRI or a pharmaceutically acceptable salt thereof.
15. A method of claim 14 wherein said SSRI is fluoxetine,
sertraline or sibutramine or a pharmaceutically acceptable salt of
said fluoxetine, sertraline or sibutramine.
16. A method of claim 15 wherein said SSRI is sertraline
hydrochloride.
17. A method of claim 11 wherein said second pharmaceutical agent
is a GPI or a pharmaceutically acceptable salt thereof.
18. A method of claim 17 wherein said GPI is
5-chloro-1H-indole-2-carboxyl- ic acid
((1S)-benzyl-3-(3R,4S)-dihydroxy-pyrrolidin-1-yl)-(2R)-hydroxy-3-o-
xo-propyl)-amide or a pharmaceutically acceptable salt thereof.
19. A method of claim 11 wherein said second pharmaceutical agent
is a SDI or a pharmaceutically acceptable salt thereof.
20. A method of claim 19 wherein said SDI compound is
1R-(4-{1'-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-[4,4']bipiperidinyl-1-yl}-
-pyrimidin-2-yl)-ethanol;
furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-
-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methanone;
(4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-y-
l]-3R,5S-dimethyl-piperazin-1-yl}-methanone;
{4-[2-(1R-hydroxy-ethyl)-pyri-
midin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(4-pyrrolidin-1-yl-furo[3,2-c]p-
yridin-2-yl)-methanone;
{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dim-
ethyl-piperazin-1-yl}-(4-morpholin-4-yl-furo[3,2-c]pyridin-2-yl)-methanone-
;
{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}--
imidazo[1,2-a]pyridin-2-yl-methanone;
furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hy-
droxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carbo-
xylic acid pyridin-3-yl ester;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,-
6S-dimethyl-piperazine-1-carboxylic acid 2-methyl-pyridin-3-yl
ester;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carbo-
xylic acid 5-chloro-pyridin-3-yl ester;
4-[2-(1R-hydroxy-ethyl)-pyrimidin--
4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid
6-methyl-pyridin-3-yl ester;
(E)-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-pipe-
razin-1-yl}-3-thiophen-2-yl-propenone;
1R-{4-[4-(4,6-dimethyl-pyrimidin-2--
yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperaz-
in-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrim-
idin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-pipe-
razin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)--
pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piper-
azin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-i-
midazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-p-
iperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(4-isopropyl-piperazin-
-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-etha-
nol;
1R-(4-{3R,5S-dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1-yl)-[1,3,5]-
triazin-2-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazi-
n-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2--
yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-ethoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-
-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-isopropoxy-6-methyl-[1,3,5]tri-
azin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-py-
rimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methoxy-[1,3,5]triazin--
2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-isopropoxy-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-pipe-
razin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-isopropyl-[1,3,5]triazin--
2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-ethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-
-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-2R,-
6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperaz-
in-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-[1,2,4]triazo-
l-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyr-
imidin-2-yl}-ethanol;
1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-
-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[4-(2-hydroxymeth-
yl-6-methyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-
-ethanol;
1R-(4-{4-[2-(1S-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-pi-
perazin-1-yl}-pyrimidin-2-yl)-ethanol;
1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyri-
midin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidi-
n-2-yl}-ethanone;
1RS-(4-{4-[2-(1RS-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-d-
imethyl-piperazin-1-yl)-pyrimidin-2-yl}-ethanol;
(4-{4-[2-(1R-hydroxy-ethy-
l)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone-
;
1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yl-
]-pyrimidin-2-yl)-ethanol;
1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-piperazin--
1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-piperazin--
1-yl]-pyrimidin-2-yl}-ethanol;
1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4--
yl]-2R,6R-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piper-
azin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-i-
midazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-p-
iperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-morphol-
in-4-yl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazi-
n-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2--
yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-py-
rimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)--
3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(2-hydroxymeth-
yl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-3S-methyl-piperazin-1--
yl]-py-rimidin-2-yl}-ethanol;
1R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-y-
l-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;
1R-[4-(3S-methyl-4-oxazolo[4,5--
b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;
1R-[4-(3S-methyl-4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethano-
l;
(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,5S-dimethyl-piperazin-1--
yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-3-
R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[3R,5S-dimethyl-4-(4-methyl-6-phenyl-[1,3,5]triazin-2-yl)-piperazin-
-1-yl]pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl-
)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-y-
l]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-2R-
,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-pi-
perazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-(4-[4-methoxy-6-methoxymethyl-
-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethan-
ol;
1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-
-pyrimidin-2-yl-ethanol;
1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R*,6S*-dimethy-
l-piperazin-1-yl]-pyrimidin-2-yl}-ethanone;
1-(-4-{4-[2-(1R-hydroxy-ethyl)-
-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone;
1R-{4-[4-(4-methoxymethyl-6-phenyl-[1,3,5]-triazin-2-yl)-2R,6S-dimethyl-p-
iperazin-1-yl]-pyrimidin-2-yl}-ethanol; or
1S-(4-{4-[2-(1R-hydroxy-ethyl)--
pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
21. A method of claim 20 wherein said SDI compound is
1R-(4-(4-(4,6-dimethyl)-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-y-
l)-pyrimidin-2-yl)-ethanol.
22. A method of claim 11 wherein said second pharmaceutical agent
is an antihypertensive agent or a pharmaceutically acceptable salt
thereof.
23. A method of claim 22 wherein said antihypertensive agent is an
ACE inhibitor or a pharmaceutically acceptable salt thereof.
24. A method of claim 23 wherein said ACE inhibitor is enalapril,
lisinopril, quinapril, ramipril or captopril.
25. The compound of claim 1 which is
[4-oxo-(5-trifluoromethyl-benzothiazo-
l-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid ethanolamine
salt.
26. The compound of claim 1 which is
[4-oxo-(5-trifluoromethyl-benzothiazo-
l-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid
diethanolamine salt.
27. The compound of claim 1 which is
[4-oxo-(5-trifluoromethyl-benzothiazo-
l-2-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid
triethanolamine salt.
28. A kit comprising: a) a first unit dosage form comprising
zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat
triethanolamine and a pharmaceutically acceptable carrier, vehicle
or diluent; b) a second unit dosage form comprising a second
pharmaceutical agent, a prodrug thereof or a pharmaceutically
acceptable salt of said second pharmaceutical agent or said prodrug
and a pharmaceutically acceptable carrier, vehicle or diluent; and
c) a container.
29. A kit of claim 28 wherein said second pharmaceutical agent is a
sodium/hydrogen ion exchange (NHE-1) inhibitor, a selective
serotonin retuptake inhibitor (SSRI), a glycogen phosphorylase
inhibitor (GPI), a sorbitol dehydrogenase inhibitor (SDI) or an
antihypertensive agent.
30. A pharmaceutical composition comprising a compound of claim 1,
a second pharmaceutical agent or a pharmaceutically acceptable salt
of said second pharmaceutical agent and a pharmaceutically
acceptable carrier or diluent.
31. A pharmaceutical composition of claim 30 wherein said second
pharmaceutical agent is a sodium/hydrogen ion exchange (NHE-1)
inhibitor, a selective serotonin retuptake inhibitor (SSRI), a
glycogen phosphorylase inhibitor (GPI), a sorbitol dehydrogenase
inhibitor (SDI) or an antihypertensive agent.
32. A method of treating a diabetic complication in a mammal
comprising administering to said mammal a pharmaceutical
composition of claim 30.
33. A method of claim 32 wherein said diabetic complication is
diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy,
diabetic retinopathy, cataracts, myocardial infarction,
microangiopathy or macroangiopathy.
Description
BACKGROUND OF THE INVENTION
[0001] This invention relates to
[4-oxo-(5-trifluoromethyl-benzothiazol-2--
ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid ethanolamine
salt, diethanolamine salt and triethanolamine salt, pharmaceutical
compositions thereof and methods of treating diabetic complications
in mammals comprising administering to said mammals said salts or
said compositions. This invention is also directed to combinations
of said salts with sodium hydrogen ion exchange (NHE-1) inhibitors,
selective serotonin retuptake inhibitors (SSRIs), glycogen
phosphorylase inhibitors (GPIs), sorbitol dehydrogenase inhibitors
(SDIs) and antihypertensive agents. Said combinations are also
useful in treating diabetic complications in mammals.
[0002] Zopolrestat, also known as
[4-oxo-(5-trifluoromethyl-benzothiazol-2-
-ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid, is disclosed
in U.S. Pat. No. 4,939,140, which is incorporated herein by
reference.
[0003] It is well known in the art that highly water soluble
medicinal preparations, when administered orally, result in
efficient absorption of such preparations from the gastrointestinal
tract into systemic circulation. Another hallmark of such
preparations is the rapid rate at which they are absorbed into the
systemic circulation resulting in a high concentration of the
active agent in the blood. Also, water soluble preparations are
especially suitable for parenteral administration, for example,
intravenous adminstration. The instant ethanolamine salt of this
invention exhibits a surprising degree of water solubility.
SUMMARY OF THE INVENTION
[0004] This invention is directed to a salt form of zopolrestat
selected from
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phtha-
lazin-1-yl]-acetic acid ethanolamine salt, also known as
zopolrestat ethanolamine;
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihy-
dro-phthalazin-1-yl]-acetic acid diethanolamine salt, also known as
zopolrestat diethanolamine; and
[4-oxo-(5-trifluoromethyl-benzothiazol-2--
ylmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid triethanolamine
salt, also known as zopolrestat triethanolamine. These compounds
are salt forms of zopolrestat, which is the compound of the formula
I 1
[0005] Zopolrestat ethanolamine has a water solubility of 40 mg/mL,
zopolrestat diethanolamine has a water solubility of 100 mg/mL and
zopolrestat triethanolamine has a water solubility of 6.6 mg/mL. As
such, these salt forms of zopolrestat are highly water soluble
forms of zopolrestat. Accordingly, these compounds are each
advantageous salt forms of zopolrestat.
[0006] This invention is also directed to pharmaceutical
compositions comprising zopolrestat ethanolamine, zopolrestat
diethanolamine or zopolrestat triethanolamine and a
pharmaceutically acceptable carrier, vehicle or diluent.
[0007] This invention is also directed to a pharmaceutical
composition comprising zopolrestat ethanolamine, zopolrestat
diethanolamine or zopolrestat triethanolamine and a second
pharmaceutical agent. Said second pharmaceutical agents include
NHE-1 inhibitors, SSRIs, GPIs, SDIs and antihypertensive agents.
Particularly preferred SSRIs for use in this invention are
fluoxetine, sertraline and sibutramine or a pharmaceutically
acceptable salt of said fluoxetine, sertraline or sibutramine. It
is particularly preferred that said SSRI is sertraline
hydrochloride. It is also preferred that said antihypertensive
agents are ACE inhibitors. Particularly preferred ACE inhibitors
for use in this invention are enalapril and captopril.
[0008] This invention is also directed to a method of treating
diabetic complications in mammals comprising administering to said
mammal zopolrestat ethanolamine, zopolrestat diethanolamine or
zopolrestat triethanolamine. Diabetic complications which are
treated by zopolrestat ethanolamine, zopolrestat diethanolamine or
zopoirestat triethanolamine, pharmaceutical compositions comprising
zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat
triethanolamine and the combinations of this invention include, but
are not limited to, diabetic neuropathy, diabetic nephropathy,
diabetic cardiomyopathy, diabetic retinopathy, microangiopathy,
macroangiopathy, cataracts and myocardial infarction.
[0009] This invention is also directed to a method of treating
diabetic complications in mammals comprising administering to said
mammal a pharmaceutical composition comprising a combination of
zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat
triethanolamine and a second pharmaceutical agent or a
pharmaceutically acceptable salt of said second pharmaceutical
agent where said second pharmaceutical agent is an NHE-1 inhibitor,
a SSRI, a GPI, a SDI or an antihypertensive agent.
[0010] This invention is also directed to a kit comprising:
[0011] a) a first unit dosage form comprising zopoirestat
ethanolamine, zopolrestat diethanolamine or zopolrestat
triethanolamine and a pharmaceutically acceptable carrier, vehicle
or diluent;
[0012] b) a second unit dosage form comprising a second
pharmaceutical agent, a prodrug thereof or a pharmaceutically
acceptable salt of said second pharmaceutical agent or said prodrug
and a pharmaceutically acceptable carrier, vehicle or diluent;
and
[0013] c) a container.
[0014] 25. This invention is particularly directed to such a kit
wherein said second pharmaceutical agent is a sodium/hydrogen ion
exchange (NHE-1) inhibitor, a selective serotonin retuptake
inhibitor (SSRI), a glycogen phosphorylase inhibitor (GPI), a
sorbitol dehydrogenase inhibitor (SDI) or an antihypertensive
agent.
[0015] The term "treating", "treat" or "treatment" as used herein
includes curative, preventative (e.g., prophylactic) and palliative
treatment.
DETAILED DESCRIPTION OF THE INVENTION
[0016] The salts of this invention, i.e., zopolrestat ethanolamine,
also known as
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-p-
hthalazin-1-yl]-acetic acid ethanolamine salt; zopolrestat
diethanolamine, also known as
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihy-
dro-phthalazin-1-yl]-acetic acid diethanolamine salt; and
zopolrestat triethanolamine, also known as
[4-oxo-(5-trifluoromethyl-benzothiazol-2-y-
lmethyl)-3,4-dihydro-phthalazin-1-yl]-acetic acid ethanolamine
salt, are readily prepared as set forth below.
[0017]
4-Oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phtha-
lazin-1-yl]-acetic acid, also known as zopolrestat, is dissolved in
an appropriate reaction inert solvent. As used herein, the
expression "reaction inert solvent" refers to a solvent or mixture
of solvents which does not interact with starting materials,
reagents, intermediates or products in a manner which adversely
affects the yield of the desired product. Preferred solvents
include methanol, ethanol, n-propanol, isopropanol, acetone, ethyl
methyl ketone, diethyl ketone and methyl isobutyl ketone. A
particularly preferred solvent for this reaction is acetone. To
this solution is added ethanolamine, diethanolamine or
triethanolamine. The reaction mixture is stirred at about ambient
temperature to about the refluxing temperature of the solvent being
used for about two hours to about six hours, preferably at ambient
temperature for about two hours. The salt of this invention is
isolated from the reaction mixture by methods well known to those
skilled in the art. It is preferred that the reaction mixture is
directly evaporated. The residue from the evaporation is preferably
crystallized from an appropriate solvent or mixture of
solvents.
[0018] Zopolrestat is prepared as disclosed in U.S. Pat. No.
4,939,140, which is incorporated herein by reference. Methods for
measuring the aldose reductase inhibitory activity of the compounds
and compositions of this invention are disclosed therein.
[0019] Measurement of the water solubility of the salts of this
invention is accomplished by using methods well known to those
skilled in the art. Specifically, to a weighed amount of
zopolrestat ethanolamine, zopolrestat diethanolamine or zopolrestat
triethanolamine, distilled water is added in small portions until a
clear solution is obtained. The total volume of the solution is
measured. The water solubility of the particular zopolrestat salt,
in mg/mL, is calculated by dividing the weight of the salt, in mg,
by the volume of the solution, in mL. The water solubility of
zopolrestat ethanolamine salt, when measured using the above
technique, was determined to be 40 mg/mL. Likewise, the water
solubility of zopolrestat diethanolamine was determined to be 100
mg/mL and the water solubility of zopoirestat triethanolamine was
determined to be 6.6 mg/mL.
[0020] Any selective serotonin reuptake inhibitor (SSRI) may be
used as the second pharmaceutical agent in the pharmaceutical
compositions, methods and kits of this invention. The term
selective serotonin reuptake inhibitor refers to a compound which
inhibits the reuptake of serotonin by afferent neurons. Such
inhibition is readily determined by those skilled in the art
according to standard assays such as those disclosed in U.S. Pat.
No. 4,536,518 and other U.S. patents recited in the next
paragraph.
[0021] Preferred selective serotonin reuptake inhibitors (SSRI)
which may be used in accordance with this invention include, but
are not limited to: femoxetine, which may be prepared as described
in U.S. Pat. No. 3,912,743; fluoxetine, which may be prepared as
described in U.S. Pat. No. 4,314,081; fluvoxamine, which may be
prepared as described in U.S. Pat. No. 4,085,225; indalpine, which
may be prepared as described in U.S. Pat. No. 4,064,255;
indeloxazine, which may be prepared as described in U.S. Pat. No.
4,109,088; milnacipran, which may be prepared as described in U.S.
Pat. No. 4,478,836; paroxetine, which may be prepared as described
in U.S. Pat. No. 3,912,743 or U.S. Pat. No. 4,007,196; sertraline,
which may be prepared as described in U.S. Pat. No. 4,536,518;
sibutramine, which may be prepared as described in U.S. Pat. No.
4,929,629; and zimeldine, which may be prepared as described in
U.S. Pat. No. 3,928,369. Fluoxetine is also known as Prozac.RTM..
Sertraline is also known as Zoloft.RTM.. Sibutramine is also known
as Meridia.RTM.. The disclosures thereof are incorporated herein by
reference.
[0022] Any antihypertensive agent may be used as the second
pharmaceutical agent in the pharmaceutical compositions, methods
and kits of this invention. Preferred classes of antihypertensive
agents include angiotensin converting enzyme (ACE) inhibitors,
calcium channel blockers, angiotensin (A-II) antagonists,
diuretics, endopeptidase inhibitors, beta-adrenergic receptor
blockers, vasodilators and alpha-adrenergic receptor blockers.
[0023] ACE inhibitors which are within the scope of this invention
include, but are not limited to: alacepril, which may be prepared
as disclosed in U.S. Pat. No. 4,248,883; benazepril, which may be
prepared as disclosed in U.S. Pat. No. 4,410,520; captopril, which
may be prepared as disclosed in U.S. Pat. Nos. 4,046,889 and
4,105,776; ceronapril, which may be prepared as disclosed in U.S.
Pat. No. 4,452,790; delapril, which may be prepared as disclosed in
U.S. Pat. No. 4,385,051; enalapril, which may be prepared as
disclosed in U.S. Pat. No. 4,374,829; tosinopril, which may be
prepared as disclosed in U.S. Pat. No. 4,337,201; imadapril, which
may be prepared as disclosed in U.S. Pat. No. 4,508,727;
lisinopril, which may be prepared as disclosed in U.S. Pat. No.
4,555,502; moveltopril, which may be prepared as disclosed in
Belgian Patent No. 893,553; perindopril, which may be prepared as
disclosed in U.S. Pat. No. 4,508,729; quinapril, which may be
prepared as disclosed in U.S. Pat. No. 4,344,949; ramipril, which
may be prepared as disclosed in U.S. Pat. No. 4,587,258; spirapril,
which may be prepared as disclosed in U.S. Pat. No. 4,470,972;
temocapril, which may be prepared as disclosed in U.S. Pat. No.
4,699,905; and trandolapril, which may be prepared as disclosed in
U.S. Pat. No. 4,933,361. The disclosures of all such U.S. patents
are incorporated herein by reference.
[0024] Calcium channel blockers which are within the scope of this
invention include, but are not limited to: bepridil, which may be
prepared as disclosed in U.S. Pat. No. 3,962,238 or U.S. Reissue
No. 30,577; clentiazem, which may be prepared as disclosed in U.S.
Pat. No. 4,567,175; diltiazem, which may be prepared as disclosed
in U.S. Pat. No. 3,562,257 fendiline, which may be prepared as
disclosed in U.S. Pat. No. 3,262,977; gallopamil, which may be
prepared as disclosed in U.S. Pat. No. 3,261,859; mibefradil, which
may be prepared as disclosed in U.S. Pat. No. 4,808,605;
prenylamine, which may be prepared as disclosed in U.S. Pat. No.
3,152,173; semotiadil, which may be prepared as disclosed in U.S.
Pat. No. 4,786,635; terodiline, which may be prepared as disclosed
in U.S. Pat. No. 3,371,014; verapamil, which may be prepared as
disclosed in U.S. Pat. No. 3,261,859; amlodipine, which may be
prepared as disclosed in U.S. Pat. No. 4,5723,909; aranipine, which
may be prepared as disclosed in U.S. Pat. No. 4,572,909;
barnidipine, which may be prepared as disclosed in U.S. Pat. No.
4,220,649; benidipine, which may be prepared as disclosed in
European Patent Application Publication No. 106,275; cilnidipine,
which may be prepared as disclosed in U.S. Pat. No. 4,672,068;
efonidipine, which may be prepared as disclosed in U.S. Pat. No.
4,885,284; elgodipine, which may be prepared as disclosed in U.S.
Pat. No. 4,952,592; felodipine, which may be prepared as disclosed
in U.S. Pat. No. 4,264,611; isradipine, which may be prepared as
disclosed in U.S. Pat. No. 4,466,972; lacidipine, which may be
prepared as disclosed in U.S. Pat. No. 4,801,599; lercanidipine,
which may be prepared as disclosed in U.S. Pat. No. 4,705,797;
manidipine, which may be prepared as disclosed in U.S. Pat. No.
4,892,875; nicardipine, which may be prepared as disclosed in U.S.
Pat. No. 3,985,758; nifedipine, which may be prepared as disclosed
in U.S. Pat. No. 3,485,847; nilvadipine, which may be prepared as
disclosed in U.S. Pat. No. 4,338,322; nimodipine, which may be
prepared as disclosed in U.S. Pat. No. 3,799,934; nisoldipine,
which may be prepared as disclosed in U.S. Pat. No. 4,154,839;
nitrendipine, which may be prepared as disclosed in U.S. Pat. No.
3,799,934; cinnarizine, which may be prepared as disclosed in U.S.
Pat. No. 2,882,271; flunarizine, which may be prepared as disclosed
in U.S. Pat. No. 3,773,939; lidoflazine, which may be prepared as
disclosed in U.S. Pat. No. 3,267,104; lomerizine, which may be
prepared as disclosed in U.S. Pat. No. 4,663,325; bencyclane, which
may be prepared as disclosed in Hungarian Patent No. 151,865;
etafenone, which may be prepared as disclosed in German Patent No.
1,265,758; and perhexiline, which may be prepared as disclosed in
British Patent No. 1,025,578. Amlodipine besylate, a preferred salt
of amlodipine, is disclosed in U.S. Pat. No. 4,879,303. The
disclosures thereof are incorporated herein by reference.
[0025] Angiotensin-II receptor antagonists (A-II antagonists) which
are within the scope of this invention include, but are not limited
to: candesartan, which may be prepared as disclosed in U.S. Pat.
No. 5,196,444; eprosartan, which may be prepared as disclosed in
U.S. Pat. No. 5,185,351; irbesartan, which may be prepared as
disclosed in U.S. Pat. No. 5,270,317; losartan, which may be
prepared as disclosed in U.S. Pat. No. 5,138,069; and valsartan,
which may be prepared as disclosed in U.S. Pat. No. 5,399,578. The
disclosures thereof are incorporated herein by reference.
[0026] Beta-adrenergic receptor blockers (beta- or .beta.-blockers)
which are within the scope of this invention include, but are not
limited to: acebutolol, which may be prepared as disclosed in U.S.
Pat. No. 3,857,952; alprenolol, which may be prepared as disclosed
in Netherlands Patent Application No. 6,605,692; amosulalol, which
may be prepared as disclosed in U.S. Pat. No. 4,217,305;
arotinolol, which may be prepared as disclosed in U.S. Pat. No.
3,932,400; atenolol, which may be prepared as disclosed in U.S.
Pat. No. 3,663,607 or 3,836,671; befunolol, which may be prepared
as disclosed in U.S. Pat. No. 3,853,923; betaxolol, which may be
prepared as disclosed in U.S. Pat. No. 4,252,984; bevantolol, which
may be prepared as disclosed in U.S. Pat. No. 3,857,981;
bisoprolol, which may be prepared as disclosed in U.S. Pat. No.
4,171,370; bopindolol, which may be prepared as disclosed in U.S.
Pat. No. 4,340,541; bucumolol, which may be prepared as disclosed
in U.S. Pat. No. 3,663,570; bufetolol, which may be prepared as
disclosed in U.S. Pat. No. 3,723,476; bufuralol, which may be
prepared as disclosed in U.S. Pat. No. 3,929,836; bunitrolol, which
may be prepared as disclosed in U.S. Pat. Nos. 3,940,489 and
3,961,071; buprandolol, which may be prepared as disclosed in U.S.
Pat. No. 3,309,406; butiridine hydrochloride, which may be prepared
as disclosed in French Patent No. 1,390,056; butofilolol, which may
be prepared as disclosed in U.S. Pat. No. 4,252,825; carazolol,
which may be prepared as disclosed in German Patent No. 2,240,599;
carteolol, which may be prepared as disclosed in U.S. Pat. No.
3,910,924; carvedilol, which may be prepared as disclosed in U.S.
Pat. No. 4,503,067; celiprolol, which may be prepared as disclosed
in U.S. Pat. No. 4,034,009; cetamolol, which may be prepared as
disclosed in U.S. Pat. No. 4,059,622; cloranolol, which may be
prepared as disclosed in German Patent No. 2,213,044; dilevalol,
which may be prepared as disclosed in Clifton et al., Journal of
Medicinal Chemistry, 1982, 25, 670; epanolol, which may be prepared
as disclosed in European Patent Publication Application No. 41,491;
indenolol, which may be prepared as disclosed in U.S. Pat. No.
4,045,482; labetalol, which may be prepared as disclosed in U.S.
Pat. No. 4,012,444; levobunolol, which may be prepared as disclosed
in U.S. Pat. No. 4,463,176; mepindolol, which may be prepared as
disclosed in Seeman et al., Helv. Chim. Acta, 1971, 54, 241;
metipranolol, which may be prepared as disclosed in Czechoslovakian
Patent Application No. 128,471; metoprolol, which may be prepared
as disclosed in U.S. Pat. No. 3,873,600; moprolol, which may be
prepared as disclosed in U.S. Pat. No. 3,501,769; nadolol, which
may be prepared as disclosed in U.S. Pat. No. 3,935, 267;
nadoxolol, which may be prepared as disclosed in U.S. Pat. No.
3,819,702; nebivalol, which may be prepared as disclosed in U.S.
Pat. No. 4,654,362; nipradilol, which may be prepared as disclosed
in U.S. Pat. No. 4,394,382; oxprenolol, which may be prepared as
disclosed in British Patent No. 1,077,603; perbutolol, which may be
prepared as disclosed in U.S. Pat. No. 3,551,493; pindolol, which
may be prepared as disclosed in Swiss Patent Nos. 469,002 and
472,404; practolol, which may be prepared as disclosed in U.S. Pat.
No. 3,408,387; pronethalol, which may be prepared as disclosed in
British Patent No. 909,357; propranolol, which may be prepared as
disclosed in U.S. Pat. Nos. 3,337,628 and 3,520,919; sotalol, which
may be prepared as disclosed in Uloth et al., Journal of Medicinal
Chemistry, 1966, 9, 88; sufinalol, which may be prepared as
disclosed in German Patent No. 2,728,641; talindol, which may be
prepared as disclosed in U.S. Pat. Nos. 3,935,259 and 4,038,313;
tertatolol, which may be prepared as disclosed in U.S. Pat. No.
3,960,891; tilisolol, which may be prepared as disclosed in U.S.
Pat. No. 4,129,565; timolol, which may be prepared as disclosed in
U.S. Pat. No. 3,655,663; toliprolol, which may be prepared as
disclosed in U.S. Pat. No. 3,432,545; and xibenolol, which may be
prepared as disclosed in U.S. Pat. No. 4,018,824. The disclosures
thereof are incorporated herein by reference.
[0027] Endopeptidase inhibitors which are within the scope of this
invention include, but are not limited to sampatrilat, which may be
prepared as disclosed in European Patent Application Publication
No. EP 358398; candoxatril and candoxatrilat, each of which may be
prepared as disclosed in European Patent Application Publication
No. EP 274234; and omapatrilat, which may be prepared as disclosed
in U.S. Pat. No. 5,508,272. The disclosures thereof are
incorporated herein by reference.
[0028] Alpha-adrenergic receptor blockers (alpha- or
.alpha.-blockers) which are within the scope of this invention
include, but are not limited to: amosulalol, which may be prepared
as disclosed in U.S. Pat. No. 4,217,307; arotinolol, which may be
prepared as disclosed in U.S. Pat. No. 3,932,400; dapiprazole,
which may be prepared as disclosed in U.S. Pat. No. 4,252,721;
doxazosin, which may be prepared as disclosed in U.S. Pat. No.
4,188,390; fenspiride, which may be prepared as disclosed in U.S.
Pat. No. 3,399,192; indoramin, which may be prepared as disclosed
in U.S. Pat. No. 3,527,761; labetolol, which may be prepared as
disclosed above; naftopidil, which may be prepared as disclosed in
U.S. Pat. No. 3,997,666; nicergoline, which may be prepared as
disclosed in U.S. Pat. No. 3,228,943; prazosin, which may be
prepared as disclosed in U.S. Pat. No. 3,511,836; tamsulosin, which
may be prepared as disclosed in U.S. Pat. No. 4,703,063;
tolazoline, which may be prepared as disclosed in U.S. Pat. No.
2,161,938; trimazosin, which may be prepared as disclosed in U.S.
Pat. No. 3,669,968; and yohimbine, which may be isolated from
natural sources according to methods well known to those skilled in
the art. The disclosures thereof are incorporated herein by
reference.
[0029] The term "vasodilator," where used herein, is meant to
include cerebral vasodilators, coronary vasodilators and peripheral
vasodilators. Cerebral vasodilators within the scope of this
invention include, but are not limited to: bencyclane, which may be
prepared as disclosed above; cinnarizine, which may be prepared as
disclosed above; citicoline, which may be isolated from natural
sources as disclosed in Kennedy et al., Journal of the American
Chemical Society, 1955, 77, 250 or synthesized as disclosed in
Kennedy, Journal of Biological Chemistry, 1956, 222, 185;
cyclandelate, which may be prepared as disclosed in U.S. Pat. No.
3,663,597; ciclonicate, which may be prepared as disclosed in
German Patent No. 1,910,481; diisopropylamine dichloroacetate,
which may be prepared as disclosed in British Patent No. 862,248;
eburnamonine, which may be prepared as disclosed in Hermann et al.,
Journal of the American Chemical Society, 1979, 101, 1540; fasudil,
which may be prepared as disclosed in U.S. Pat. No. 4,678,783;
fenoxedil, which may be prepared as disclosed in U.S. Pat. No.
3,818,021; flunarizine, which may be prepared as disclosed in U.S.
Pat. No. 3,773,939; ibudilast, which may be prepared as disclosed
in U.S. Pat. No. 3,850,941; ifenprodil, which may be prepared as
disclosed in U.S. Pat. No. 3,509,164; lomerizine, which may be
prepared as disclosed in U.S. Pat. No. 4,663,325; nafronyl, which
may be prepared as disclosed in U.S. Pat. No. 3,334,096;
nicametate, which may be prepared as disclosed in Blicke et al.,
Journal of the American Chemical Society, 1942, 64, 1722;
nicergoline, which may be prepared as disclosed above; nimodipine,
which may be prepared as disclosed in U.S. Pat. No. 3,799,934;
papaverine, which may be prepared as reviewed in Goldberg, Chem.
Prod. Chem. News, 1954, 17, 371; pentifylline, which may be
prepared as disclosed in German Patent No. 860,217; tinofedrine,
which may be prepared as disclosed in U.S. Pat. No. 3,563,997;
vincamine, which may be prepared as disclosed in U.S. Pat. No.
3,770,724; vinpocetine, which may be prepared as disclosed in U.S.
Pat. No. 4,035,750; and viquidil, which may be prepared as
disclosed in U.S. Pat. No. 2,500,444. The disclosures thereof are
incorporated herein by reference.
[0030] Coronary vasodilators within the scope of this invention
include, but are not limited to: amotriphene, which may be prepared
as disclosed in U.S. Pat. No. 3,010,965; bendazol, which may be
prepared as disclosed in J. Chem. Soc. 1958, 2426; benfurodil
hemisuccinate, which may be prepared as disclosed in U.S. Pat. No.
3,355,463; benziodarone, which may be prepared as disclosed in U.S.
Pat. No. 3,012,042; chloracizine, which may be prepared as
disclosed in British Patent No. 740,932; chromonar, which may be
prepared as disclosed in U.S. Pat. No. 3,282,938; clobenfural,
which may be prepared as disclosed in British Patent No. 1,160,925;
clonitrate, which may be prepared from propanediol according to
methods well known to those skilled in the art, e.g., see Annalen,
1870, 155, 165; cloricromen, which may be prepared as disclosed in
U.S. Pat. No. 4,452,811; dilazep, which may be prepared as
disclosed in U.S. Pat. No. 3,532,685; dipyridamole, which may be
prepared as disclosed in British Patent No. 807,826;
droprenilamine, which may be prepared as disclosed in German Patent
No. 2,521,113; efloxate, which may be prepared as disclosed in
British Patent Nos. 803,372 and 824,547; erythrityl tetranitrate,
which may be prepared by nitration of erythritol according to
methods well-known to those skilled in the art; etafenone, which
may be prepared as disclosed in German Patent No. 1,265,758;
fendiline, which may be prepared as disclosed in U.S. Pat. No.
3,262,977; floredil, which may be prepared as disclosed in German
Patent No. 2,020,464; ganglefene, which may be prepared as
disclosed in U.S.S.R. Patent No. 115,905; hexestrol, which may be
prepared as disclosed in U.S. Pat. No. 2,357,985; hexobendine,
which may be prepared as disclosed in U.S. Pat. No. 3,267,103;
itramin tosylate, which may be prepared as disclosed in Swedish
Patent No. 168,308; khellin, which may be prepared as disclosed in
Baxter et al., Journal of the Chemical Society, 1949, S 30;
lidoflazine, which may be prepared as disclosed in U.S. Pat. No.
3,267,104; mannitol hexanitrate, which may be prepared by the
nitration of mannitol according to methods well-known to those
skilled in the art; medibazine, which may be prepared as disclosed
in U.S. Pat. No. 3,119,826; nitroglycerin; pentaerythritol
tetranitrate, which may be prepared by the nitration of
pentaerythritol according to methods well-known to those skilled in
the art; pentrinitrol, which may be prepared as disclosed in German
Patent No. 638,422-3; perhexilline, which may be prepared as
disclosed above; pimefylline, which may be prepared as disclosed in
U.S. Pat. No. 3,350,400; prenylamine, which may be prepared as
disclosed in U.S. Pat. No. 3,152,173; propatyl nitrate, which may
be prepared as disclosed in French Patent No. 1,103,113; trapidil,
which may be prepared as disclosed in East German Patent No.
55,956; tricromyl, which may be prepared as disclosed in U.S. Pat.
No. 2,769,015; trimetazidine, which may be prepared as disclosed in
U.S. Pat. No. 3,262,852; trolnitrate phosphate, which may be
prepared by nitration of triethanolamine followed by precipitation
with phosphoric acid according to methods well-known to those
skilled in the art; visnadine, which may be prepared as disclosed
in U.S. Pat. Nos. 2,816,118 and 2,980,699. The disclosures thereof
are incorporated herein by reference.
[0031] Peripheral vasodilators within the scope of this invention
include, but are not limited to: aluminum nicotinate, which may be
prepared as disclosed in U.S. Pat. No. 2,970,082; bamethan, which
may be prepared as disclosed in Corrigan et al., Journal of the
American Chemical Society, 1945, 67, 1894; bencyclane, which may be
prepared as disclosed above; betahistine, which may be prepared as
disclosed in Walter et al.; Journal of the American Chemical
Society, 1941, 63, 2771; bradykinin, which may be prepared as
disclosed in Hamburg et al., Arch. Biochem. Biophys., 1958, 76,
252; brovincamine, which may be prepared as disclosed in U.S. Pat.
No. 4,146,643; bufeniode, which may be prepared as disclosed in
U.S. Pat. No. 3,542,870; buflomedil, which may be prepared as
disclosed in U.S. Pat. No. 3,895,030; butalamine, which may be
prepared as disclosed in U.S. Pat. No. 3,338,899; cetiedil, which
may be prepared as disclosed in French Patent Nos. 1,460,571;
ciclonicate, which may be prepared as disclosed in German Patent
No. 1,910,481; cinepazide, which may be prepared as disclosed in
Belgian Patent No. 730,345; cinnarizine, which may be prepared as
disclosed above; cyclandelate, which may be prepared as disclosed
above; diisopropylamine dichloroacetate, which may be prepared as
disclosed above; eledoisin, which may be prepared as disclosed in
British Patent No. 984,810; fenoxedil, which may be prepared as
disclosed above; flunarizine, which may be prepared as disclosed
above; hepronicate, which may be prepared as disclosed in U.S. Pat.
No. 3,384,642; ifenprodil, which may be prepared as disclosed
above; iloprost, which may be prepared as disclosed in U.S. Pat.
No. 4,692,464; inositol niacinate, which may be prepared as
disclosed in Badgett et al., Journal of the American Chemical
Society, 1947, 69, 2907; isoxsuprine, which may be prepared as
disclosed in U.S. Pat. No. 3,056,836; kallidin, which may be
prepared as disclosed in Biochem. Biophys. Res. Commun., 1961, 6,
210; kallikrein, which may be prepared as disclosed in German
Patent No. 1,102,973; moxisylyte, which may be prepared as
disclosed in German Patent No. 905,738; nafronyl, which may be
prepared as disclosed above; nicametate, which may be prepared as
disclosed above; nicergoline, which may be prepared as disclosed
above; nicofuranose, which may be prepared as disclosed in Swiss
Patent No. 366,523; nylidrin, which may be prepared as disclosed in
U.S. Pat. Nos. 2,661,372 and 2,661,373; pentifylline, which may be
prepared as disclosed above; pentoxifylline, which may be prepared
as disclosed in U.S. Pat. No. 3,422,107; piribedil, which may be
prepared as disclosed in U.S. Pat. No. 3,299,067; prostaglandin
E.sub.1, which may be prepared by any of the methods referenced in
the Merck Index, Twelfth Edition, Budaveri, Ed., New Jersey, 1996,
p. 1353; suloctidil, which may be prepared as disclosed in German
Patent No. 2,334,404; tolazoline, which may be prepared as
disclosed in U.S. Pat. No. 2,161,938; and xanthinol niacinate,
which may be prepared as disclosed in German Patent No. 1,102,750
or Korbonits et al., Acta. Pharm. Hung., 1968, 38, 98. The
disclosures thereof are incorporated herein by reference.
[0032] The term "diuretic," within the scope of this invention, is
meant to include diuretic benzothiadiazine derivatives, diuretic
organomercurials, diuretic purines, diuretic steroids, diuretic
sulfonamide derivatives, diuretic uracils and other diuretics such
as amanozine, which may be prepared as disclosed in Austrian Patent
No. 168,063; amiloride, which may be prepared as disclosed in
Belgian Patent No. 639,386; arbutin, which may be prepared as
disclosed in Tschitschibabin, Annalen, 1930, 479, 303; chlorazanil,
which may be prepared as disclosed in Austrian Patent No. 168,063;
ethacrynic acid, which may be prepared as disclosed in U.S. Pat.
No. 3,255,241; etozolin, which may be prepared as disclosed in U.S.
Pat. No. 3,072,653; hydracarbazine, which may be prepared as
disclosed in British Patent No. 856,409; isosorbide, which may be
prepared as disclosed in U.S. Pat. No. 3,160,641; mannitol;
metochalcone, which may be prepared as disclosed in Freudenberg et
al., Ber., 1957, 90, 957; muzolimine, which may be prepared as
disclosed in U.S. Pat. No. 4,018,890; perhexiline, which may be
prepared as disclosed above; ticrynafen, which may be prepared as
disclosed in U.S. Pat. No. 3,758,506; triamterene which may be
prepared as disclosed in U.S. Pat. No. 3,081,230; and urea. The
disclosures thereof are incorporated herein by reference.
[0033] Diuretic benzothiadiazine derivatives within the scope of
this invention include, but are not limited to: althiazide, which
may be prepared as disclosed in British Patent No. 902,658;
bendroflumethiazide, which may be prepared as disclosed in U.S.
Pat. No. 3,265,573; benzthiazide, McManus et al., 136th Am. Soc.
Meeting (Atlantic City, September 1959), Abstract of papers, pp
13-O; benzylhydrochlorothiazide, which may be prepared as disclosed
in U.S. Pat. No. 3,108,097; buthiazide, which may be prepared as
disclosed in British Patent Nos. 861,367 and 885,078;
chlorothiazide, which may be prepared as disclosed in U.S. Pat.
Nos. 2,809,194 and 2,937,169; chlorthalidone, which may be prepared
as disclosed in U.S. Pat. No. 3,055,904; cyclopenthiazide, which
may be prepared as disclosed in Belgian Patent No. 587,225;
cyclothiazide, which may be prepared as disclosed in Whitehead et
al., Journal of Organic Chemistry, 1961, 26, 2814; epithiazide,
which may be prepared as disclosed in U.S. Pat. No. 3,009,911;
ethiazide, which may be prepared as disclosed in British Patent No.
861,367; fenquizone, which may be prepared as disclosed in U.S.
Pat. No. 3,870,720; indapamide, which may be prepared as disclosed
in U.S. Pat. No. 3,565,911; hydrochlorothiazide, which may be
prepared as disclosed in U.S. Pat. No. 3,164,588;
hydroflumethiazide, which may be prepared as disclosed in U.S. Pat.
No. 3,254,076; methyclothiazide, which may be prepared as disclosed
in Close et al., Journal of the American Chemical Society, 1960,
82, 1132; meticrane, which may be prepared as disclosed in French
Patent Nos. M2790 and 1,365,504; metolazone, which may be prepared
as disclosed in U.S. Pat. No. 3,360,518; paraflutizide, which may
be prepared as disclosed in Belgian Patent No. 620,829;
polythiazide, which may be prepared as disclosed in U.S. Pat. No.
3,009,911; quinethazone, which may be prepared as disclosed in U.S.
Pat. No. 2,976,289; teclothiazide, which may be prepared as
disclosed in Close et al., Journal of the American Chemical
Society, 1960, 82, 1132; and trichlormethiazide, which may be
prepared as dislcosed in deStevens et al., Experientia, 1960, 16,
113. The disclosures thereof are incorporated herein by
reference.
[0034] Diuretic sulfonamide derivatives within the scope of this
invention include, but are not limited to: acetazolamide, which may
be prepared as disclosed in U.S. Pat. No. 2,980,679; ambuside,
which may be prepared as disclosed in U.S. Pat. No. 3,188,329;
azosemide, which may be prepared as disclosed in U.S. Pat. No.
3,665,002; bumetamide, which may be prepared as disclosed in U.S.
Pat. No. 3,634,583; butazolamide, which may be prepared as
disclosed in British Patent No. 769,757; chloraminophenamide, which
may be prepared as disclosed in U.S. Pat. Nos. 2,809,194, 2,965,655
and 2,965,656; clofenamide, which may be prepared as disclosed in
Olivier, Rec. Trav. Chim., 1918, 37, 307; clopamide, which may be
prepared as disclosed in U.S. Pat. No. 3,459,756; clorexolone,
which may be prepared as disclosed in U.S. Pat. No. 3,183,243;
disulfamide, which may be prepared as disclosed in British Patent
No. 851,287; ethoxolamide, which may be prepared as disclosed in
British Patent No. 795,174; furosemide, which may be prepared as
disclosed in U.S. Pat. No. 3,058,882; mefruside, which may be
prepared as disclosed in U.S. Pat. No. 3,356,692; methazolamide,
which may be prepared as disclosed in U.S. Pat. No. 2,783,241;
piretamide, which may be prepared as disclosed in U.S. Pat. No.
4,010,273; torasemide, which may be prepared as disclosed in U.S.
Pat. No. 4,018,929; tripamide, which may be prepared as disclosed
in Japanese Patent No. 73 05,585; and xipamide, which may be
prepared as disclosed in U.S. Pat. No. 3,567,777. The disclosures
thereof are incorporated herein by reference.
[0035] Any NHE-1 inhibitor may be used as the second pharmaceutical
agent in the pharmaceutical compositions, methods and kits of this
invention. The term NHE-1 inhibitor refers to compounds which
inhibit the sodium/proton (Na.sup.+/H.sup.+) exchange transport
system and hence are useful as a therapeutic or prophylactic agent
for diseases caused or aggravated by the acceleration of the
sodium/proton (Na.sup.+/H.sup.+) exchange transport system, for
example, cardiovascular diseases [e.g., arteriosclerosis,
hypertension, arrhythmia (e.g. ischemic arrhythmia, arrhythmia due
to myocardial infarction, myocardial stunning, myocardial
dysfunction, arrhythmia after PTCA or after thrombolysis, etc.),
angina pectoris, cardiac hypertrophy, myocardial infarction, heart
failure (e.g. congestive heart failure, acute heart failure,
cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock
(e.g. hemorrhagic shock, endotoxin shock, etc.)], renal diseases
(e.g. diabetes mellitus, diabetic nephropathy, ischemic acute renal
failure, etc.) organ disorders associated with ischemia or ischemic
reperfusion [e.g. heart muscle ischemic reperfusion associated
disorders, acute renal failure, or disorders induced by surgical
treatment such as coronary artery bypass grafting (CABG) surgeries,
vascular surgeries, organ transplantation, non-cardiac surgeries or
percutaneous transluminal coronary angioplasty (PTCA)],
cerebrovascular diseases (e.g. ischemic stroke, hemorrhagic stroke,
etc.), cerebro ischemic disorders (e.g. disorders associated with
cerebral infarction, disorders caused after cerebral apoplexy as
sequelae, or cerebral edema. NHE-1 inhibitors can also be used as
an agent for myocardial protection during coronary artery bypass
grafting (CABG) surgeries, vascular surgeries, percutaneous
transluminal coronary angioplasty (PTCA), PTCI, organ
transplantation, or non-cardiac surgeries. The utility of NHE-1
inhibitors as medical agents in the treatment of diseases, such as
are detailed herein in mammals (e.g. humans) for example,
myocardial protection during surgery or mycardial protection in
patients presenting with ongoing cardiac or cerebral ischemic
events or chronic cardioprotection in patients with diagnosed
coronary heart disease, or at risk for coronary heart disease,
cardiac dysfunction or myocardial stunning is demonstrated by the
activity of the compounds of formula I of this invention in
conventional preclinical cardioprotection assays [see the in vivo
assay in Klein, H. et al., Circulation 92:912-917 (1995); the
isolated heart assay in Scholz, W. et al., Cardiovascular Research
29:260-268 (1995); the antiarrhythmic assay in Yasutake M. et al.,
Am. J. Physiol., 36:H2430-H2440 (1994); the NMR assay in Kolke et
al., J. Thorac. Cardiovasc. Surg. 112: 765-775 (1996)] and the
additional in vitro and in vivo assays described below. Such assays
also provide a means whereby the activities of the compounds of
formula I of this invention can be compared with the activities of
other known compounds. The results of these comparisons are useful
for determining dosage levels in mammals, including humans, for the
treatment of such diseases.
[0036] NHE-1 inhibitors are disclosed in U.S. Pat. No. 5,698,581,
European Patent Application Publication No. EP 803 501 A1,
International Patent Application Publication Nos. WO 94/26709 and
PCT/JP97/04650, each of which is incorporated herein by reference.
The NHE-1 inhibitors disclosed therein have utility in the
combination of this invention. Said NHE-1 inhibitors can be
prepared as disclosed therein.
[0037] Preferred NHE-1 inhibitors include compounds of the formula
NHE, 2
[0038] a prodrug thereof or a pharmaceutically acceptable salt of
said compound or of said prodrug, wherein
[0039] Z in the compound of formula NHE is carbon connected and is
a five-membered, diaza, diunsaturated ring having two contiguous
nitrogens, said ring optionally mono-, di-, or tri-substituted with
up to three substituents independently selected from R.sup.1,
R.sup.2 and R.sup.3; or
[0040] Z in the compound of formula NHE carbon connected and is a
five-membered, triaza, diunsaturated ring, said ring optionally
mono- or di-substituted with up to two substituents independently
selected from R.sup.4 and R.sup.5;
[0041] wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 in
the compound of formula NHE are each independently hydrogen,
hydroxy-(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkylthio, (C.sub.3-C.sub.4)cycloalkyl,
(C.sub.3-C.sub.7)cycloalkyl(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxy(C.sub.1-C.sub.4)alkyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylcarbamoyl, M or
M(C.sub.1-C.sub.4)alkyl, any of said previous
(C.sub.1-C.sub.4)alkyl moieties optionally having from one to nine
fluorines; said (C.sub.1-C.sub.4)alkyl or
(C.sub.3-C.sub.4)cycloalkyl optionally mono-or di-substituted
independently with hydroxy, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, (C.sub.1-C.sub.4)alkyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylcarbamoyl or mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylaminosulfonyl; and said
(C.sub.3-C.sub.4)cycloalkyl optionally having from one to seven
fluorines;
[0042] wherein M in the compound of formula NHE is a partially
saturated, fully saturated or fully unsaturated five to eight
membered ring optionally having one to three heteroatoms selected
independently from oxygen, sulfur and nitrogen, or, a bicyclic ring
consisting of two fused partially saturated, fully saturated or
fully unsaturated three to six membered rings, taken independently,
optionally having one to four heteroatoms selected independently
from nitrogen, sulfur and oxygen;
[0043] said M in the compound of formula NHE is optionally
substituted, on one ring if the moiety is monocyclic, or one or
both rings if the moiety is bicyclic, on carbon or nitrogen with up
to three substituents independently selected from R.sup.6, R.sup.7
and R.sup.8, wherein one of R.sup.6, R.sup.7 and R.sup.8 is
optionally a partially saturated, fully saturated, or fully
unsaturated three to seven membered ring optionally having one to
three heteroatoms selected independently from oxygen, sulfur and
nitrogen optionally substituted with (C.sub.1-C.sub.4)alkyl and
additionally R.sup.6, R.sup.7 and R.sup.8 are optionally hydroxy,
nitro, halo, (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkoxycarbonyl, (C.sub.1-C.sub.4)alkyl, formyl,
(C.sub.1-C.sub.4)alkanoyl, (C.sub.1-C.sub.4)alkanoyloxy,
(C.sub.1-C.sub.4)alkanoylamino,
(C.sub.1-C.sub.4)alkoxycarbonylamino, sulfonamido,
(C.sub.1-C.sub.4)alkylsulfonamido, amino, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylamino, carbamoyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylcarbamoyl, cyano, thiol,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkyla- minosulfonyl,
(C.sub.2-C.sub.4)alkenyl, (C.sub.2-C.sub.4)alkynyl or
(C.sub.5-C.sub.7)cycloalkenyl,
[0044] wherein said (C.sub.1-C.sub.4)alkoxy,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.7)alkanoyl,
(C.sub.1-C.sub.4)alkylthio, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylamino or (C.sub.3-C.sub.7)cycloalkyl
R.sup.6, R.sup.7 and R.sup.8 substituents are optionally
mono-substituted independently with hydroxy,
(C.sub.1-C.sub.4)alkoxycarbonyl, (C.sub.3-C.sub.7)cycloalkyl,
(C.sub.1-C.sub.4)alkanoyl, (C.sub.1-C.sub.4)alkanoylamino,
(C.sub.1-C.sub.4)alkanoyloxy, (C.sub.1-C.sub.4)alkoxycarbonylamino,
sulfonamido, (C.sub.1-C.sub.4)alkylsulfonamido, amino, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylamino, carbamoyl, mono-N- or
di-N,N-(C.sub.1-C.sub.4)alkylcarbamoyl, cyano, thiol, nitro,
(C.sub.1-C.sub.4)alkylthio, (C.sub.1-C.sub.4)alkylsulfinyl,
(C.sub.1-C.sub.4)alkylsulfonyl or mono-N-or
di-N,N-(C.sub.1-C.sub.4)alkyl- aminosulfonyl or optionally
substituted with one to nine fluorines.
[0045] Especially preferred NHE-1 inhibitors include
[1-(8-bromoquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(6-chloroquinolin-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine-
; [1-(indazol-7-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(benzimidazol-5-yl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(1-isoquinolyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(4-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(quinolin-5-yl)-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(quinolin-8-yl)-1H-pyrazole-4-carbonyl]guanidine;
[1-(indazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(indazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(benzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(1-methylbenzimidazol-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
1-(5-quinolinyl)-5-n-propyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(5-quinolinyl)-5-isopropyl-1H-pyrazole-4-carbonyl]guanidine;
[5-ethyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-methylbenzimidazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(1,4-benzodioxan-6-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(benzotriazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(3-chloroindazol-5-yl)-5-ethyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(5-quinolinyl)-5-butyl-1H-pyrazole-4-carbonyl]guanidine;
[5-propyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[5-isopropyl-1-(6-quinolinyl)-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-4-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl-
]guanidine;
[1-(2-chlorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guani-
dine;
[1-(2-trifluoromethyl-4-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-ca-
rbonyl]guanidine;
[1-(2-bromophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]-
guanidine;
[1-(2-fluorophenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanid-
ine;
[1-(2-chloro-5-methoxyphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]gu-
anidine;
[1-(2-chloro-4-methylaminosulfonylphenyl)-5-cyclopropyl-1H-pyrazo-
le-4-carbonyl]guanidine;
[1-(2,5-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-
-4-carbonyl]guanidine;
[1-(2,3-dichlorophenyl)-5-cyclopropyl-1H-pyrazole-4-
-carbonyl]guanidine;
[1-(2-chloro-5-aminocarbonylphenyl)-5-cyclopropyl-1H--
pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-5-aminosulfonylphenyl)-5-cyclo-
propyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-fluoro-6-trifluoromethylphe-
nyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chloro-5-methylsulfonylphenyl)-5-cyclopropyl-1H-pyrazole-4-carbonyl-
]guanidine;
[1-(2-chloro-5-dimethylaminosulfonylphenyl)-5-cyclopropyl-1H-p-
yrazole-4-carbonyl]guanidine;
[1-(2-trifluoromethyl-4-chlorophenyl)-5-cycl-
opropyl-1H-pyrazole-4-carbonyl]guanidine;
[1-(2-chlorophenyl)-5-methyl-1H-- pyrazole-4-carbonyl]guanidine;
[5-methyl-1-(2-trifluoromethylphenyl)-1H-py-
razole-4-carbonyl]guanidine;
[5-ethyl-1-phenyl-1H-pyrazole-4-carbonyl]guan- idine;
[5-cyclopropyl-1-(2-trifluoromethylphenyl)-1H-pyrazole-4-carbonyl]g-
uanidine; [5-cyclopropyl-1-phenyl-1H-pyrazole-4-carbonyl]guanidine;
[5-cyclopropyl-1-(2,6-dichlorophenyl)-1H-pyrazole-4-carbonyl]guanidine
or or a pharmaceutically acceptable salt thereof.
[0046] The preferred and especially preferred NHE-1 inhibitors
disclosed in the above two paragraphs can be prepared according to
methods set forth in International Patent Application No.
PCT/IB99/00206 or as set forth below, where the variables in the
following schemes and description refer only to the NHE-1
compounds. 3 4 5 6 7 8 9 10
[0047] According to Scheme I, the Formula I-a compound, wherein
R.sup.4 is as described above for the compound of formula NHE, is
dissolved or suspended in an aqueous alkali metal hydroxide
solution (e.g. 1 N sodium hydroxide) along with sodium nitrite and
the mixture is added to an aqueous acidic solution (e.g. 10% v/v
sulfuric acid) at a pH of about 0 at a temperature of about
0.degree. C. to about 5.degree. C. for about 30 min to about 1
hour. The resulting mixture is filtered to yield the Formula I-b
oxime. Alternatively, the Formula I-a compound is dissolved in 1:1
acetic acid/propionic acid and solid sodium nitrite is added at
about 0.degree. C. The reaction mixture is stirred at about
0.degree. C. for about 2 hours, then poured into ice water and the
Formula I-b oxime is obtained by filtration.
[0048] The Formula I-b compound is reacted with a Formula I-c
compound, wherein R.sup.5 is as described above for the compound of
formula NHE in a protic solvent such as ethanol at a temperature of
about 50.degree. C. to about 110.degree. C. for about 10 min to
about 1 hour to form the Formula I-d hydrazone.
[0049] The Formula I-d hydrazone is cyclized and hydrolyzed to the
Formula I-e triazole in an alcoholic solvent such as
2-ethoxyethanol under basic conditions (e.g., potassium hydroxide)
at a temperature of about 100.degree. C. to about 175.degree. C.
for about 1/2 hour to about 2 hours followed by acidification to
yield the Formula I-e triazole acid.
[0050] The Formula I-e acid is coupled with guanidine in the
presence of a suitable coupling agent. A suitable coupling agent is
one which transforms a carboxylic acid into a reactive species
which forms an amide linkage on reaction with an amine.
[0051] The coupling agent may be a reagent which effects this
condensation in a one pot process when mixed together with the
carboxylic acid and guanidine. Exemplary coupling reagents are
1-(3-dimethylaminopropyl)-3-et- hylcarbodiimide
hydrochloride-hydroxybenzotriazole (EDC/HBT),
dicyclohexylcarbodiimide/hydroxybenzotriazole(HBT),
2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), and
diethylphosphorylcyanide. The coupling is performed in an inert
solvent, preferably an aprotic solvent at a temperature of about
-20.degree. C. to about 50.degree. C. for about 1 to about 48
hours, in the presence of excess guanidine as base. Exemplary
solvents include acetonitrile, dichloromethane, dimethylformamide
and chloroform or mixtures thereof.
[0052] The coupling agent may also be that agent which converts the
carboxylic acid to an activated intermediate which is isolated
and/or formed in a first step and allowed to react with guanidine
in a second step. Examples of such coupling agents and activated
intermediates are thionyl chloride or oxalyl chloride to form the
acid chloride, cyanuric fluoride to form an acid fluoride or an
alkyl chloroformate such as isobutyl or isopropenyl chloroformate
or propanephosphonic anhydride (propanephosphonic acid anhydride,
PPA) (with a tertiary amine base) to form a mixed anhydride of the
carboxylic acid, or carbonyldiimidazole to form an acylimidazole.
If the coupling agent is oxalyl chloride, it is advantageous to
employ a small amount of dimethylformamide as cosolvent with
another solvent (such as dichloromethane) to catalyze the formation
of the acid chloride. This activated acid derivative may be coupled
by mixing with excess guanidine in an appropriate solvent together
with an appropriate base. Appropriate solvent/base combinations are
for example, dichloromethane, dimethylformamide or acetonitrile or
mixtures thereof in the presence of excess guanidine as base. Other
appropriate solvent/base combinations include water or a
(C.sub.1-C.sub.5)alcohol or a mixture thereof together with a
cosolvent such as dichloromethane, tetrahydrofuran or dioxane and a
base such as sodium, potassium or lithium hydroxide in sufficient
quantity to consume the acid liberated in the reaction. Use of
these coupling agents and appropriate selection of solvents and
temperatures are known to those skilled in the art or can be
readily determined from the literature. These and other exemplary
conditions useful for coupling carboxylic acids are described in
Houben-Weyl, Vol XV, part II, E. Wunsch, Ed., G. Theime Verlag,
1974, Stuttgart; M. Bodansky, Principles of Peptide Synthesis,
Springer-Verlag, Berlin 1984; and The Peptides, Analysis, Synthesis
and Biology (ed. E. Gross and J. Meienhofer), vols 1-5 (Academic
Press, NY 1979-1983).
[0053] According to Scheme II, the Formula II-a primary amine
wherein R.sup.5 is as described above for the compound of formula
NHE is reacted with a Formula II-b .alpha.-diazo-.beta.-keto-ester
wherein R.sup.4 is as described above for the compound of formula
NHE, and R is lower alkyl, in the presence of titanium
tetrachloride analogously to the method described in Eguchi S. et
al. Synthesis 1993, 793 to form the Formula II-c triazole
carboxylic acid ester. The Formula II-c ester is converted directly
to the acylguanidine II-d by reaction with guanidine in an
alcoholic solvent at a temperature of about 60 to about 110.degree.
C., preferably refluxing methanol, for a period of 8 to 20
hours.
[0054] According to Scheme III, the Formula II-a compound wherein
R.sup.4 and R.sup.5 are as described above for the compound of
formula NHE is treated with Lawesson's reagent (i.e.,
2,4-bis(4-methoxyphenyl)-1,3-dithi-
a-2,4-diphosphetane-2,4-disulfide) in an aprotic solvent such as
dimethoxyethane at a temperature of about 20.degree. C. to about
120.degree. C. for about one to eight hours. The resulting
thioamide is treated with an alkylating agent such as methyl iodide
in a polar, inert solvent such as acetone, conveniently at ambient
temperature for about eight hours to about forty-eight hours. The
resulting compound is reacted with anhydrous hydrazine in an
alcoholic solvent at a temperature of about 0.degree. C. to about
25.degree. C. for about one to eight hours to provide the Formula
III-b compound (analogously as described in Doyle and Kurzer,
Synthesis 1974, 583).
[0055] The Formula III-b compound is treated with a monoalkyloxalyl
chloride in an aprotic solvent at a temperature of about 25.degree.
C. to about 50.degree. C. for about one to eight hours to provide
the Formula III-c carboxylic ester compound wherein R is lower
alkyl. The Formula III-c ester is directly coupled with guanidine
in an alcoholic solvent at a temperature of about 60.degree. C. to
about 110.degree. C., preferably refluxing methanol, for a period
of eight to twenty hours, to prepare the Formula III-d triazole
carbonyl guanidines.
[0056] According to Scheme IV the Formula IV-a compound wherein
R.sup.5 is as described above for the compound of formula NHE is
treated with methyl iodide in an inert solvent, conveniently at
ambient temperature for about four to twenty-four hours. The
resulting compound is reacted with anhydrous R.sup.4-hydrazine
(wherein R.sup.4 is as described above for the compound of formula
NHE) in an alcoholic solvent at a temperature of about 0.degree. C.
to about 25.degree. C. for about one to eight hours to provide the
Formula IV-b amidrazone compound (analogously as described in Doyle
and Kurzer, Synthesis 1974, 583).
[0057] The Formula IV-b compound is treated with a monoalkyloxalyl
chloride in an aprotic solvent at a temperature of about 25.degree.
C. to about 50.degree. C. for about one to eight hours to provide
the Formula IV-c carboxylic ester compound wherein R is lower
alkyl. The Formula IV-c ester is directly coupled with guanidine in
an alcoholic solvent at a temperature of about 60.degree. C. to
about 110.degree. C., preferably refluxing methanol, for a period
of eight to twenty hours to prepare the Formula IV-d triazole
carbonyl guanidines.
[0058] According to Scheme V the Formula V-a compound wherein
R.sup.1 is as described above for the compound of formula NHE is
combined with excess (CH.sub.3O).sub.2C(R.sup.3)N(CH.sub.3).sub.2
(N,N-dimethyl amide dimethyl acetal) wherein R.sup.3 is as
described above for the compound of formula NHE, optionally in the
presence of an acid catalyst such as p-toluenesulfonic acid at a
temperature of about 90.degree. C. to about 110.degree. C. for
about one to about two hours to prepare the Formula V-c compound
above.
[0059] The Formula V-c compound is cyclized with a Formula V-d
compound, wherein R.sup.2 is as described above for the compound of
formula NHE, in an inert solvent such as ethanol at a temperature
of about 20.degree. C. to about 30.degree. C. for about 5 minutes
to about one hour followed by heating to a temperature of about
70.degree. C. to about 110.degree. C. for about two hours to about
four hours to form the Formula V-f pyrazole.
[0060] Alternatively, according to Scheme V the Formula V-a
compound, wherein R.sup.1 is as described above for the compound of
formula NHE, is combined with a triethylorthoester (i.e.,
R.sup.3C(OEt).sub.3 wherein R.sup.3 is as described above for the
compound of formula NHE) and acetic anhydride at a temperature of
about 120.degree. C. to about 150.degree. C. for about two to about
five hours to prepare the Formula V-b compound.
[0061] The Formula V-b compound is cyclized with a Formula V-d
compound, wherein R.sup.2 is as described above for the compound of
formula NHE, to form the Formula V-c pyrazole.
[0062] The Formula V-c pyrazole is hydrolyzed with a base such as
sodium hydroxide or lithium hydroxide in a solvent such as water
and/or methanol and/or THF conveniently at ambient temperature or
at elevated temperature (e.g., reflux) for about one hour to about
five hours to prepare the Formula V-f acid.
[0063] The Formula V-f acid is coupled with guanidine in the
presence of a suitable coupling agent as described for the above
coupling of the Formula I-e acid and guanidine. In one embodiment,
the Formula V-f acid is activated with thionyl chloride at a
temperature of about 60.degree. C. to about 90.degree. C. for about
fifteen minutes to about two hours. The resulting activated acid
chloride is combined with guanidine hydrochloride and an inorganic
base (e.g., sodium hydroxide) in anhydrous tetrahydrofuran and
optionally methanol and/or water. The solution is heated,
conveniently at reflux, for about one hour to about eight hours to
prepare the Formula V-g compound.
[0064] Alternatively according to Scheme V the Formula V-e compound
can be directly converted to the Formula V-g compound by several
methods. For example, the Formula V-e compound can be heated in the
presence of excess guanidine, in a polar protic solvent for
example, methanol or isopropanol at a suitable temperature
conveniently, at reflux for about one to about seventy-two hours.
This transformation may also be performed by repeatedly removing
the solvent, for example removing ethanol or toluene about four
times, from a mixture of the Formula V-e compound and excess
guanidine at a pressure of about one to about 100 mmHg and at a
temperature of about 25.degree. C. to about 95.degree. C. This
reaction may also be performed in the absence of solvent by heating
the mixture of the Formula V-e compound and excess guanidine at a
temperature of about 100.degree. C. to about 180.degree. C.,
optionally at about a pressure of about 1 to about 100 mmHg for
about five minutes to about eight hours.
[0065] According to Scheme VI, the Formula VI-a compound, wherein
R.sup.3 is as described above for the compound of formula NHE, is
reacted with the Formula VI-b compound, wherein R.sup.1 and R.sup.2
are as described above for the compound of formula NHE, in an
aprotic solvent at a temperature of about 0.degree. C. to about
25.degree. C. for about two hours to about twenty-four hours in the
presence of an appropriate amine base, such as triethylamine, to
form the Formula VI-c compound.
[0066] The resulting Formula VI-c compound is hydrolyzed and
coupled with guanidine using one of the methods described in
earlier Schemes, such as the method employing carbonyldiimidazole,
to form the Formula VI-d compound.
[0067] According to Scheme VII, the Formula VII-a hydrazine,
wherein R.sup.2 is as described above for the compound of formula
NHE, is reacted with the appropriate Formula VII-b compound to form
the Formula VII-c pyrazole ester wherein R is lower alkyl according
to the method of Bajnati, A. and Hubert-Habart, M. Bull. Soc. Chim.
France 1988, 540. The resulting pyrazole ester is converted to the
Formula VII-d acyl guanidine using the hydrolysis and coupling
methods described above.
[0068] According to Scheme VIII, the Formula VIII-a compound
wherein R.sup.2 and R.sup.1 are as described above for the compound
of formula NHE is transformed to the Formula VIII-b lithium salt
where R is lower alkyl according to the method described in J. Het.
Chem. 1989, 26,1389. The Formula VIII-b lithium salt is combined
with the Formula VIII-c hydrazine, wherein R.sup.3 is as described
above for the compound of formula NHE, in an inert solvent such as
ethanol, in the presence of a mineral acid, at a temperature of
about 20.degree. C. to about 30.degree. C. for about five minutes
to about one hour followed by heating to a temperature of about
70.degree. C. to about 110.degree. C. for two hours to about four
hours to form both the Formula VIII-d and VIII-e pyrazoles. The
Formula VIII-d and VIII-e pyrazoles are converted to the Formula
VIII-f and VIII-g acyl guanidines respectively using the hydrolysis
and coupling methods described above. Some of the methods useful
for the preparation of the compounds described herein may require
protection of remote functionality (e.g., primary amine, secondary
amine, carboxyl in Formula I precursors). The need for such
protection will vary depending on the nature of the remote
functionality and the conditions of the preparation methods. The
need for such protection is readily determined by one skilled in
the art. The use of such protection/deprotection methods is also
within the skill in the art. For a general description of
protecting groups and their use, see T. W. Greene, Protective
Groups in Organic Synthesis, John Wiley & Sons, New York,
1991.
[0069] The compounds of formula I of the present invention, when
used in combination with NHE-1 inhibitors, inhibit the
sodium/proton (Na.sup.+/H.sup.+) exchange transport system and
hence are useful as a therapeutic or prophylactic agent for
diseases caused or aggravated by the acceleration of the
sodium/proton (Na.sup.+/H.sup.+) exchange transport system, for
example, cardiovascular diseases [e.g., arteriosclerosis,
hypertension, arrhythmia (e.g. ischemic arrhythmia, arrhythmia due
to myocardial infarction, myocardial stunning, myocardial
dysfunction, arrhythmia after PTCA or after thrombolysis, etc.),
angina pectoris, cardiac hypertrophy, myocardial infarction, heart
failure (e.g. congestive heart failure, acute heart failure,
cardiac hypertrophy, etc.), restenosis after PTCA, PTCI, shock
(e.g. hemorrhagic shock, endotoxin shock, etc.)], renal diseases
(e.g. diabetes mellitus, diabetic nephropathy, ischemic acute renal
failure, etc.) organ disorders associated with ischemia or ischemic
reperfusion [e.g. heart muscle ischemic reperfusion associated
disorders, acute renal failure, or disorders induced by surgical
treatment such as coronary artery bypass grafting (CABG) surgeries,
vascular surgeries, organ transplantation, non-cardiac surgeries or
percutaneous transluminal coronary angioplasty (PTCA)],
cerebrovascular diseases (e.g. ischemic stroke, hemorrhagic stroke,
etc.), cerebro ischemic disorders (e.g. disorders associated with
cerebral infarction, disorders caused after cerebral apoplexy as
sequelae, or cerebral edema.
[0070] Preferably, the compounds of formula I of this invention can
be used in combination with NHE-1 inhibitors as agents for
myocardial protection before, during, or after coronary artery
bypass grafting (CABG) surgeries, vascular surgeries, percutaneous
transluminal coronary angioplasty (PTCA), organ transplantation, or
non-cardiac surgeries.
[0071] Preferably, the compounds of formula I of this invention can
be used in combination with NHE-1 inhibitors as agents for
myocardial protection in patients presenting with ongoing cardiac
(acute coronary syndromes, e.g. myocardial infarction or unstable
angina) or cerebral ischemic events (e.g. stroke).
[0072] Preferably, the compounds of formula I of this invention can
be used in combination with NHE-1 inhibitors as agents for chronic
myocardial protection in patients with diagnosed coronary heart
disease (e.g. previous myocardial infarction or unstable angina) or
patients who are at high risk for myocardial infarction (age
greater than 65 and two or more risk factors for coronary heart
disease).
[0073] In addition, a combination of the compounds of formula I of
this invention with NHE-1 inhibitors has a strong inhibitory effect
on the proliferation of cells, for example the proliferation of
fibroblast cells and the proliferation of the smooth muscle cells
of the blood vessels. For this reason, the combination of the
compounds of formula I of this invention with NHE-1 inhibitors of
this invention is a valuable therapeutic agent for use in diseases
in which cell proliferation represents a primary or secondary cause
and may, therefore, be used as antiatherosclerotic agents, and as
agents against diabetic late complications, cancerous diseases,
fibrotic diseases such as pulmonary fibrosis, hepatic fibrosis or
renal fibrosis, glomerular nephrosclerosis, organ hypertrophies or
hyperplasias, in particular hyperplasia or hypertrophy of the
prostate, pulmonary fibrosis, diabetic complications or recurrent
stricture after PTCA, or diseases caused by endothelial cell
injury.
[0074] The utility of the combination of compounds of the present
invention with NHE-1 inhibitors as medical agents in the treatment
of diseases, such as are detailed herein in mammals (e.g. humans)
for example, myocardial protection during surgery or mycardial
protection in patients presenting with ongoing cardiac or cerebral
ischemic events or chronic cardioprotection in patients with
diagnosed coronary heart disease, or at risk for coronary heart
disease, cardiac dysfunction or myocardial stunning is demonstrated
by the activity of said combination in conventional preclinical
cardioprotection assays [see the in vivo assay in Klein, H. et al.,
Circulation 92:912-917 (1995); the isolated heart assay in Scholz,
W. et al., Cardiovascular Research 29:260-268 (1995); the
antiarrhythmic assay in Yasutake M. et al., Am. J. Physiol.,
36:H2430-H2440 (1994); the NMR assay in Kolke et al., J. Thorac.
Cardiovasc. Surg. 112: 765-775 (1996)] and the additional in vitro
and in vivo assays described below. Such assays also provide a
means whereby the activities of the compounds of formula I of this
invention can be compared with the activities of other known
compounds. The results of these comparisons are useful for
determining dosage levels in mammals, including humans, for the
treatment of such diseases.
[0075] Measurement of Human NHE-1 Inhibitory Activity
[0076] Methodologies for measurement of human NHE-1 activity and
inhibitor potency are based on those published by Watson et al.,
Am. J. Physiol., 24:G229-G238, 1991), where NHE-mediated recovery
of intracellular pH is measured following intracellular
acidification. Thus, fibroblasts stably expressing human NHE-1
(Counillon, L. et al., Mol. Pharmacol., 44:1041-1045 (1993) are
plated onto collagen coated 96 well plates (50,000/well) and grown
to confluence in growth media (DMEM high glucose, 10% fetal bovine
serum, 50 u/ml penicillin and streptomycin). Confluent plates are
incubated for 30 minutes at 37.degree. C. with the pH sensitive
fluorescent probe BCECF (5 .mu.M; Molecular Probes, Eugene, Oreg.).
BCECF loaded cells are incubated for 30 minutes at 37.degree. C. in
acid loading media (70 mM choline chloride, 50 mM NHCl.sub.4, 5 mM
KCl, 1 mM MgCl.sub.2, 1.8 mM CaCl.sub.2, 5 mM glucose, 10 mM HEPES,
pH 7.5), and then placed in a Fluorescent Imaging Plate Reader
(Molecular Devices, CA). BCECF fluorescence is monitored using
excitation and emission wavelengths of 485 nM and 525 nM,
respectively. Intracellular acidification is initiated via rapid
replacement of acid loading media with recovery media (120 mM NaCl,
5 mM KCl, 1 mM MgCl.sub.2, 1.8 mM CaCl.sub.2, 5 mM glucose, 10 mM
HEPES, pH 7.5).+-.test combination, and NHE-mediated recovery of
intracellular pH is monitored as the subsequent time-dependent
increase BCECF fluorescence. The potency of the combinations of the
compounds of formula I of this invention with NHE-1 inhibitors is
calculated as the concentration that reduces recovery of
intracellular pH by 50% (IC.sub.50). Under these conditions
reference NHE inhibitors amiloride and HOE-642 had IC.sub.50 values
for human NHE-1 of 50 .mu.M and 0.5 .mu.M, respectively.
[0077] As background information, it is noted that brief periods of
myocardial ischemia followed by coronary artery reperfusion
protects the heart from subsequent severe myocardial ischemia
(Murry et al., Circulation 74:1124-1136, 1986).
[0078] The therapeutic effects of the combination of the compounds
of formula I of this invention with NHE-1 inhibitors in preventing
heart tissue damage resulting from an ischemic insult can be
demonstrated in vitro along lines presented in Liu et al.
(Cardiovasc. Res., 28:1057-1061, 1994), as described specifically
herein. Cardioprotection, as indicated by a reduction in infarcted
myocardium, can be induced pharmacologically using adenosine
receptor agonists in isolated, retrogradely perfused rabbit hearts
as an in vitro model of myocardial ischemic preconditioning (Liu et
al., Cardiovasc. Res., 28:1057-1061, 1994). The in vitro test
described below demonstrates that a test compound or, in this case
a test combination (i.e., a combination of a compound of formula I
with an NHE-1 antagonist) can also pharmacologically induce
cardioprotection, i.e., reduced myocardial infarct size, when
administered to a rabbit isolated heart. The effects of the test
combination are compared to ischemic preconditioning and the A1/A3
adenosine agonist, APNEA
(N.sup.6-[2-(4-aminophenyl)ethyl]adenosine- ), that has been shown
to pharmacologically induce cardioprotection in the rabbit isolated
heart (Liu et al., Cardiovasc. Res., 28:1057-1061, 1994). The exact
methodology is described below.
[0079] The protocol used for these experiments closely follows that
described by Liu et al., Cardiovasc. Res., 28:1057-1061, 1994. Male
New Zealand White rabbits (3-4 kg) are anesthetized with sodium
pentobarbital (30 mg/kg, i.v.). After deep anesthesia is achieved
(determined by the absence of an ocular blink reflex) the animal is
intubated and ventilated with 100% O.sub.2 using a positive
pressure ventilator. A left thoracotomy is performed, the heart
exposed, and a snare (2-0 silk) is placed loosely around a
prominent branch of the left coronary artery, approximately 2/3 of
the distance towards the apex of the heart. The heart is removed
from the chest and rapidly (<30 sec) mounted on a Langendorff
apparatus. The heart is retrogradely perfused in a
non-recirculating manner with a modified Krebs solution (NaCl 118.5
mM, KCl 4.7 mM, Mg SO.sub.4 1.2 mM, KH.sub.2PO.sub.41.2 mM,
NaHCO.sub.3 24.8 mM, CaCl.sub.2 2.5 mM, and glucose 10 mM), at a
constant pressure of 80 mmHg and a temperature of 37.degree. C.
Perfusate pH is maintained at 7.4-7.5 by bubbling with 95%
O.sub.2/5% CO.sub.2. Heart temperature is tightly controlled by
using heated reservoirs for the physiological solution and water
jacketing around both the perfusion tubing and the isolated heart.
Heart rate and left ventricular pressures are determined via a
latex balloon which is inserted in the left ventricle and connected
by stainless steel tubing to a pressure transducer. The
intraventricular balloon is inflated to provide a systolic pressure
of 80-100 mmHg, and a diastolic pressure .ltoreq.10 mmHg. Total
coronary flow is also continuously monitored using an in-line flow
probe and normalized for heart weight.
[0080] The heart is allowed to equilibrate for 30 minutes, over
which time the heart must show stable left ventricular pressures
within the parameters outlined above. If the heart rate falls below
180 bpm at any time prior to the 30 minutes period of regional
ischemia, the heart is paced at about 200 bpm for the remainder of
the experiment. Ischemic preconditioning is induced by total
cessation of cardiac perfusion (global ischemia) for 5 minutes,
followed by reperfusion for 10 minutes. The regional ischemia is
provided by tightening the snare around the coronary artery branch.
Following the 30 minutes regional ischemia, the snare is released
and the heart reperfused for an additional 120 minutes.
[0081] Pharmacological cardioprotection is induced by infusing the
test combination, i.e., a combination of a compound of formula I
with an NHE-1 inhibitor, at predetermined concentrations, starting
30 minutes prior to the 30 minutes regional ischemia, and
continuing until the end of the 120 minutes reperfusion period.
Hearts which receive the test combination do not undergo the period
of ischemic preconditioning. The reference compound, APNEA (500 nM)
is perfused through hearts (which do not receive the test compound)
for a 5 minutes period which ends 10 minutes before the 30 minutes
regional ischemia.
[0082] At the end of the 120 minutes reperfusion period, the
coronary artery snare is tightened, and a 0.5% suspension of
fluorescent zinc cadmium sulfate particles (1-10 .mu.M) Duke
Scientific Corp.(Palo Alto, Calif.) is perfused through the heart;
this stains all of the myocardium, except that area-at-risk for
infarct development (area-at-risk). The heart is removed from the
Langendorff apparatus, blotted dry, wrapped in aluminum foil and
stored overnight at -20.degree. C. The next day, the heart is
sliced into 2 mm transverse sections from the apex to the top of
the ventricles. The slices are stained with 1% triphenyl
tetrazolium chloride (TTC) in phosphate-buffered saline for 20
minutes at 37.degree. C. Since TTC reacts with living tissue
(containing NAD-dependent dehydrogenases), this stain
differentiates between living (red stained) tissue, and dead tissue
(unstained infarcted tissue). The infarcted area (no stain) and the
area-at-risk (no fluorescent particles) are calculated for each
slice of left ventricle using a precalibrated image analyzer. To
normalize the ischemic injury for differences in the area-at-risk
between hearts, the data is expressed as the ratio of infarct area
vs. area-at-risk (%IA/AAR). All data are expressed as mean.+-.SE
and compared statistically using a Mann-Whitney non-parametric test
with a Bonferroni correction for multiple comparisons. Significance
is considered as p<0.05.
[0083] The results from the above in vitro test demonstrate that a
combination of a compound of this invention with an NHE-1 inhibitor
induce significant cardioprotection relative to the control
group.
[0084] The therapeutic effects of a combination of a compound of
formula I of this invention with an NHE-1 inhibitor in preventing
heart tissue damage otherwise resulting from an ischemic insult can
also be demonstrated in vivo along lines presented in Liu et al.
(Circulation, Vol. 84:350-356, 1991) as described specifically
herein. The in vivo assay tests the cardioprotection of the test
combination, i.e., a compound of formula I together with an NHE-1
inhibitor, relative to the control group which receives saline
vehicle. Cardioprotection, as indicated by a reduction in infarcted
myocardium, can be induced pharmacologically using intravenously
administered adenosine receptor agonists in intact, anesthetized
rabbits studied as an in situ model of myocardial ischemic
preconditioning (Liu et al., Circulation 84:350-356, 1991). The in
vivo assay tests whether the instant combination of a compound of
formula I with an NHE-1 inhibitor can pharmacologically induce
cardioprotection, i.e., reduced myocardial infarct size, when
parenterally administered to intact, anesthetized rabbits. The
effects of the combination of a compound of formula I of this
invention with an NHE-11 inhibitor can be compared to ischemic
preconditioning using the A1 adenosine agonist,
N.sup.6-1-(phenyl-2R-isopropyl) adenosine (PIA) that has been shown
to pharmacologically induce cardioprotection in intact anesthetized
rabbits studied in situ (Liu et al., Circulation 84:350-356, 1991).
The methodology is described below.
[0085] Surgery: New Zealand White mate rabbits (3-4 kg) are
anesthetized with sodium pentobarbital (30 mg/kg, i.v.). A
tracheotomy is performed via a ventral midline cervical incision
and the rabbits are ventilated with 100% oxygen using a positive
pressure ventilator. Catheters are placed in the left jugular vein
for drug administration and in the left carotid artery for blood
pressure measurements. The hearts are then exposed through a left
thoracotomy and a snare (00 silk) placed around a prominent branch
of the left coronary artery. Ischemia is induced by pulling the
snare tight and clamping it in place. Releasing the snare allows
the affected area to reperfuse. Myocardial ischemia is evidenced by
regional cyanosis; reperfusion is evidenced by reactive
hyperemia.
[0086] Protocol: Once arterial pressure and heart rate have been
stable for at least 30 minutes the test is started. Ischemic
preconditioning is induced by occluding the coronary artery for 5
minutes followed by a 10 minutes reperfusion. Pharmacological
preconditioning is induced by infusing the test combination, i.e.,
a combination of a compound of formula I of this invention with an
NHE-1 inhibitor, over, for example, 5 minutes and allowing 10
minutes before further intervention or by infusing the adenosine
agonist, PIA (0.25 mg/kg). Following ischemic preconditioning,
pharmacological preconditioning or no conditioning (unconditioned,
vehicle control) the artery is occluded for 30 minutes and then
reperfused for two hours to induce myocardial infarction. The test
combination and PIA are dissolved in saline or other suitable
vehicle and delivered at 1 to 5 mg/kg, respectively.
[0087] Staining (Liu et al., Circulation 84:350-356, 1991): At the
end of the 2 hour reperfusion period, the hearts are quickly
removed, hung on a Langendorff apparatus, and flushed for 1 minute
with normal saline heated to body temperature (38.degree. C.). The
silk suture used as the snare is then tied tightly to reocclude the
artery and a 0.5% suspension of fluorescent zinc cadmium sulphate
particles (1-10 .mu.m) Duke Scientific Corp. (Palo Alto, Calif.) is
infused with the perfusate to stain all of the myocardium except
the area at risk (nonfluorescent ventricle). The hearts are then
quickly frozen and stored overnight at -20.degree. C. On the
following day, the hearts are cut into 2 mm slices and stained with
1% triphenyl tetrazolium chloride (TTC). Since TTC reacts with
living tissue, this stain differentiates between living (red
stained) tissue, and dead tissue (unstained infarcted tissue). The
infarcted area (no stain) and the area at risk (no fluorescent
particles) are calculated for each slice of left ventricle using a
pre-calibrated image analyzer. To normalize the ischemic injury for
differences in the area at risk between hearts, the data is
expressed as the ratio of infarct area vs. area at risk (%IA/AAR).
All data are expressed as Mean.+-.SEM and compared statistically
using single factor ANOVA or Mann Whitney non parametric test.
Significance is considered as p<0.05.
[0088] Any glycogen phosphorylase inhibitor (GPI) may be used as
the second pharmacetical agent in the pharmaceutical compositions,
methods and kits of this invention. The term glycogen phosphorylase
inhibitor refers to any substance or agent or any combination of
substances and/or agents which reduces, retards, or eliminates the
enzymatic action of glycogen phosphorylase. The currently known
enzymatic action of glycogen phosphorylase is the degradation of
glycogen by catalysis of the reversible reaction of a glycogen
macromolecule and inorganic phosphate to glucose-1-phosphate and a
glycogen macromolecule which is one glucosyl residue shorter than
the original glycogen macromolecule (forward direction of
glycogenolysis). Such actions are readily determined by those
skilled in the art according to standard assays as described in the
following published PCT applications: PCT application publication
WO 96/39384 and PCT application publication WO96/39385. A variety
of these compounds are included in those applications. However,
other glycogen phosphorylase inhibitors will be known to those
skilled in the art.
[0089] Any sorbitol dehydrogenase inhibitor (SDI) may be used as
the second pharmaceutical agent in the pharmaceutical compositions,
methods and kits of this invention. The term sorbitol dehydrogenase
inhibitor refers to any substance or agent or any combination of
substances and/or agents which reduces, retards, or eliminates the
enzymatic action of sorbitol dehydrogenase. The currently known
enzymatic action of sorbitol dehydrogenase is the catalysis of the
oxidation of sorbitol to fructose.
[0090] Preferred SDI compounds include compounds of the formula
11
[0091] a prodrug thereof or a pharmaceutically acceptable salt of
said compound or said prodrug, wherein:
[0092] R.sup.1 in the compound of formula SDI is formyl, acetyl,
propionyl, carbamoyl or --C(OH)R.sup.4R.sup.5;
[0093] R.sup.4 and R.sup.5 in the compound of formula SDI are each
independently hydrogen, methyl, ethyl or
hydroxy-(C.sub.1-C.sub.3)alkyl;
[0094] R.sup.2 in the compound of formula SDI is hydrogen,
(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkoxy;
[0095] R.sup.3 in the compound of formula SDI is a radical of the
formula 1213
[0096] wherein said radical of formula R.sup.3a is additionally
substituted on the ring by R.sup.6, R.sup.7 and R.sup.8;
[0097] said radical of formula R.sup.3b is additionally substituted
on the ring by R.sup.18, R.sup.19 and R.sup.20
[0098] G, G.sup.1 and G.sup.2 are taken separately and are each
hydrogen and R.sup.6 is hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxyc- arbonyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
hydroxy-(C.sub.1-C.sub.4)alkyl or phenyl optionally independently
substituted with up to three hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alky- l,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkoxy, wherein said
(C.sub.1-C.sub.4)alkyl in the definition of R.sup.6 and said
(C.sub.1-C.sub.4)alkoxy in the definition of R.sup.6 are optionally
and independently substituted with up to five fluoro; R.sup.7 and
R.sup.8 are each independently hydrogen or (C.sub.1-C.sub.4)alkyl;
or
[0099] G and G.sup.1 in the compound of formula SDI are taken
together and are (C.sub.1-C.sub.3)alkylene and R.sup.6, R.sup.7,
R.sup.8 and G.sup.2 are hydrogen; or
[0100] G.sup.1 and G.sup.2 in the compound of formula SDI are taken
together and are (C.sub.1-C.sub.3)alkylene and R.sup.6, R.sup.7,
R.sup.8 and G are hydrogen;
[0101] q in the compound of formula SDI is 0 or 1;
[0102] X in the compound of formula SDI is a covalent bond,
--(C.dbd.NR.sup.10)--, oxycarbonyl, vinylenylcarbonyl,
oxy(C.sub.1-C.sub.4)alkylenylcarbonyl,
(C.sub.1-C.sub.4)alkylenylcarbonyl- ,
(C.sub.3-C.sub.4)alkenylcarbonyl,
thio(C.sub.1-C.sub.4)alkylenylcarbonyl- , vinylenylsulfonyl,
sulfinyl-(C.sub.1-C.sub.4)alkylenylcarbonyl,
sulfonyl-(C.sub.1-C.sub.4)alkylenylcarbonyl or
carbonyl(C.sub.0-C.sub.4)a- lkylenylcarbonyl; wherein said
oxy(C.sub.1-C.sub.4)alkylenylcarbonyl,
(C.sub.1-C.sub.4)alkylenylcarbonyl,
(C.sub.3-C.sub.4)alkenylcarbonyl and
thio(C.sub.1-C.sub.4)alkylenylcarbonyl in the definition of X are
each optionally and independently substituted with up to two
(C.sub.1-C.sub.4)alkyl, benzyl or Ar; said vinylenylsulfonyl and
said vinylenylcarbonyl in the definition of X are optionally
substituted independently on one or two vinylenyl carbons with
(C.sub.1-C.sub.4)alkyl, benzyl or Ar; and said
carbonyl(C.sub.0-C.sub.4)a- lkylenylcarbonyl in the definition of X
is optionally substituted indepedently with up to three
(C.sub.1-C.sub.4)alkyl, benzyl or Ar;
[0103] R.sup.10 in the compound of formula SDI is hydrogen or
(C.sub.1-C.sub.4)alkyl;
[0104] R.sup.9 in the compound of formula SDI is
(C.sub.3-C.sub.7)cycloalk- yl, Ar.sup.1--(C.sub.0-C.sub.3)alkylenyl
or (C.sub.1-C.sub.6)alkyl optionally substituted with up to five
fluoro; provided that when q=0 and X is a covalent bond,
oxycarbonyl or (C.sub.1-C.sub.4)alkylenylcarbonyl, then R.sup.9 is
not (C.sub.1-C.sub.6)alkyl; Ar and Ar.sup.1 in the compound of
formula SDI are independently a fully saturated, partially
saturated or fully unsaturated five- to eight-membered ring
optionally having up to four heteroatoms selected independently
from oxygen, sulfur and nitrogen, or a bicyclic ring consisting of
two fused independently partially saturated, fully saturated or
fully unsaturated five- to seven-membered rings, taken
independently, optionally having up to four heteroatoms selected
independently from nitrogen, sulfur and oxygen, or a tricyclic ring
consisting of three fused independently partially saturated, fully
saturated or fully unsaturated five to seven membered rings, taken
independently, optionally having up to four heteroatoms selected
independently from nitrogen, sulfur and oxygen, said partially
saturated, fully saturated ring or fully unsaturated monocyclic
ring, bicyclic ring or tricyclic ring optionally having one or two
oxo groups substituted on carbon or one or two oxo groups
substituted on sulfur; Ar and Ar.sup.1 in the compound of formula
SDI are optionally independently substituted on carbon or nitrogen,
on one ring if the moiety is monocyclic, on one or both rings if
the moiety is bicyclic, or on one, two or three rings if the moiety
is tricyclic, with up to a total of four substituents independently
selected from R.sup.11, R.sup.12, R.sup.13 and R.sup.14; wherein
R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are each taken separately
and are each independently halo, formyl,
(C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkylenyloxycarbonyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
C(OH)R.sup.15R.sup.16, naphthyl, phenyl, imidazolyl, pyridyl,
triazolyl, morpholinyl, (C.sub.0-C.sub.4)alkylsulfamoyl,
N-(C.sub.0-C.sub.4)alkylcarbamoyl,
N,N-di-(C.sub.1-C.sub.4)alkylcarbamoyl, N-phenylcarbamoyl,
N-(C.sub.1-C.sub.4)alkyl-N-phenylcarbamoyl, N,N-diphenyl carbamoyl,
(C.sub.1-C.sub.4)alkylcarbonylamido,
(C.sub.3-C.sub.7)cycloalkylcarbonyla- mido, phenylcarbonylamido,
piperidinyl, pyrrolidinyl, piperazinyl, cyano, benzimidazolyl,
amino, anilino, pyrimidyl, oxazolyl, isoxazolyl, tetrazolyl,
thienyl, thiazolyl, benzothiazolyl, pyrrolyl, pyrazolyl,
tetrahydroquinolyl, tetrahydroisoquinolyl, benzoxazolyl,
pyridazinyl, pyridyloxy, pyridylsulfanyl, furanyl,
8-(C.sub.1-C.sub.4)alkyl-3,8-diaza[- 3.2.1]bicyclooctyl,
3,5-dioxo-1,2,4-triazinyl, phenoxy, thiophenoxy,
(C.sub.1-C.sub.4)alkylsulfanyl, (C.sub.1-C.sub.4)alkylsulfonyl,
(C.sub.3-C.sub.7)cycloalkyl, (C.sub.1-C.sub.4)alkyl optionally
substituted with up to five fluoro or (C.sub.1-C.sub.4)alkoxy
optionally substituted with up to five fluoro; said naphthyl,
phenyl, pyridyl, piperidinyl, benzimidazolyl, pyrimidyl, thienyl,
benzothiazolyl, pyrrolyl, tetrahydroquinolyl,
tetrahydroisoquinolyl, benzoxazolyl, pyridazinyl, pyridyloxy,
pyridylsulfanyl, furanyl, thiophenoxy, anilino and phenoxy in the
definition of R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are
optionally substituted with up to three substituents independently
selected from hydroxy, halo, hydroxy-(C.sub.1-C.sub.4)alkyl- ,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; said imidazolyl, oxazolyl, isoxazolyl, thiazolyl
and pyrazolyl in the definition of R.sup.11, R.sup.12, R.sup.13 and
R.sup.14 are optionally substituted with up to two substituents
independently selected from hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; said morpholinyl in the definition of R.sup.11,
R.sup.12, R.sup.13 and R.sup.14 is optionally substituted with up
to two substituents independently selected from
(C.sub.1-C.sub.4)alkyl; said pyrrolidinyl in the definition of
R.sup.11, R.sup.12, R.sup.13 and R.sup.14 is optionally substituted
with up to two substituents independently selected from hydroxy,
hydroxy-(C.sub.1-C.sub.3)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; said piperazinyl in the definition of R.sup.11,
R.sup.12, R.sup.13 and R.sup.14 is optionally substituted with up
to three substituents independently selected from
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
hydroxy-(C.sub.1-C.sub.3)- alkyl, phenyl, pyridyl,
(C.sub.0-C.sub.4)alkylsulfamoyl, (C.sub.1-C.sub.4)alkyl optionally
substituted with up to five fluoro and (C.sub.1-C.sub.4)alkoxy
optionally substituted with up to five fluoro; said triazolyl in
the definition of R.sup.11, R.sup.12, R.sup.13 and R.sup.14 is
optionally substituted with hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; said tetrazolyl in the definition of R.sup.11,
R.sup.12, R.sup.13 and R.sup.14 is optionally substituted with
hydroxy-(C.sub.2-C.sub.3)alky- l or (C.sub.1-C.sub.4)alkyl
optionally substituted with up to five fluoro; and said phenyl and
pyridyl which are optionally substituted on piperazine in the
definition of R.sup.11, R.sup.12, R.sup.13 and R.sup.14 are
optionally substituted with up to three hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; or
[0105] R.sup.11 and R.sup.12 in the compound of formula SDI are
taken together on adjacent carbon atoms and are
[0106] --CH.sub.2OC(CH.sub.3).sub.2OCH.sub.2-- or
--O--(CH.sub.2).sub.p--O- --, and R.sup.13 and R.sup.14 are taken
separately and are each independently hydrogen or
(C.sub.1-C.sub.4)alkyl;
[0107] p in the compound of formula SDI is 1, 2 or 3;
[0108] R.sup.15 and R.sup.16 in the compound of formula SDI are
taken separately and are each independently hydrogen,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro; or
[0109] R.sup.15 and R.sup.16 are taken separately and R.sup.15 is
hydrogen and R.sup.16 is (C.sub.3-C.sub.6)cycloalkyl,
hydroxy-(C.sub.1-C.sub.3)alk- yl, phenyl, pyridyl, pyrimidyl,
thienyl, furanyl, thiazolyl, oxazolyl, imidazolyl, benzothiazolyl
or benzoxazolyl; or R.sup.15 and R.sup.16 are taken together and
are (C.sub.3-C.sub.6)alkylene;
[0110] G.sup.3, G.sup.4 and G.sup.5 in the compound of formula SDI
are taken separately and are each hydrogen; r is 0; R.sup.18 is
hydrogen, (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
hydroxy-(C.sub.1-C.sub.4)- alkyl or phenyl optionally independently
substituted with up to three hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy-(C-
.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl or
(C.sub.1-C.sub.4)alkoxy, wherein said (C.sub.1-C.sub.4)alkyl in the
definition of R.sup.6 and said (C.sub.1-C.sub.4)alkoxy in the
definition of R.sup.6 are optionally and independently substituted
with up to five fluoro; and R.sup.19 and R.sup.20 are each
independently (C.sub.1-C.sub.4)alkyl; or
[0111] G.sup.3, G.sup.4 and G.sup.5 are taken separately and are
each hydrogen; r is 1; R.sup.18 is hydrogen,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4- )alkyl,
hydroxy-(C.sub.1-C.sub.4)alkyl or phenyl optionally independently
substituted with up to three hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alky- l,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl or (C.sub.1-C.sub.4)alkoxy, wherein said
(C.sub.1-C.sub.4)alkyl in the definition of R.sup.6 and said
(C.sub.1-C.sub.4)alkoxy in the definition of R.sup.6 are optionally
and independently substituted with up to five fluoro; and R.sup.19
and R.sup.20 are each independently hydrogen or
(C.sub.1-C.sub.4)alkyl; or
[0112] G.sup.3 and G.sup.4 in the compound of formula SDI are taken
together and are (C.sub.1-C.sub.3)alkylene; r is 0 or 1; and
R.sup.18, R.sup.19, R.sup.20 and G.sup.5 are hydrogen; or
[0113] G.sup.4 and G.sup.5 are taken together and are
(C.sub.1-C.sub.3)alkylene; r is 0 or 1; and R.sup.18, R.sup.19,
R.sup.20 and G.sup.3 are hydrogen;
[0114] R.sup.17 in the compound of formula SDI is
SO.sub.2NR.sup.21R.sup.2- 2, CONR.sup.21R.sup.22,
(C.sub.1-C.sub.6)alkoxycarbonyl, (C.sub.1-C.sub.6)alkylcarbonyl,
Ar.sup.2-carbonyl, (C.sub.1-C.sub.6)alkylsulfonyl,
(C.sub.1-C.sub.6)alkylsulfinyl, Ar.sup.2-sulfonyl, Ar.sup.2-sufinyl
and (C.sub.1-C.sub.6)alkyl;
[0115] R.sup.21 and R.sup.22 in the compound of formula SDI are
taken separately and are each independently selected from hydrogen,
(C.sub.1-C.sub.6)alkyl, (C.sub.3-C.sub.7)cycloalkyl and
Ar.sup.2--(C.sub.0-C.sub.4)alkylenyl; or
[0116] R.sup.21 and R.sup.22 in the compound of formula SDI are
taken together with the nitrogen atom to which they are attached to
form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,
azabicyclo[2.2.1]heptyl, 6,7-dihydro-5H-dibenzo[c,e]azepinyl,
1,2,3,4-tetrahydro-isoquinolyl or
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the
definition of R.sup.21 and R.sup.22 is optionally substituted
independently with one substituent selected from hydroxy, amino,
hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; said pyrrolidinyl, piperidinyl, azepinyl in the
definition of R.sup.21 and R.sup.22 are optionally substituted
independently with up to two substituents independently selected
from hydroxy, amino, hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; said morpholinyl in the definition of R.sup.21 and
R.sup.22 is optionally substituted with up to two substituents
independently selected from hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.s- ub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; said piperazinyl in the definition of R.sup.21 and
R.sup.22 is optionally substituted independently with up to three
substituents independently selected from phenyl, pyridyl,
pyrimidyl, (C.sub.1-C.sub.4)alkoxycarbonyl and
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro; said 1,2,3,4-tetrahydro-isoquinolyl and said
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl in the definition of
R.sup.21 and R.sup.22 are optionally substituted independently with
up to three substituents independently selected from hydroxy,
amino, halo, hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the
definition of R.sup.21 and R.sup.22 is optionally substituted with
up to four substituents independently selected from hydroxy, amino,
halo, hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; said pyrimidyl, pyridyl and phenyl which are
optionally substituted on said piperazine in the definition of
R.sup.21 and R.sup.22 is optionally substituted with up to three
substituents selected from hydroxy, amino,
hydroxy-(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy-(-
C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl optionally
substituted with up to five fluoro and (C.sub.1-C.sub.4)alkoxy
optionally substituted with up to five fluoro;
[0117] Ar.sup.2 in the compound of formula SDI is independently
defined as set forth for Ar and Ar.sup.1 above;
[0118] said Ar.sup.2 is optionally independently substituted as set
forth for Ar and Ar.sup.1 above;
[0119] R.sup.23 in the compound of formula SDI is
CONR.sup.25R.sup.26 or SO.sub.2R.sup.25R.sup.26, wherein R.sup.25
is hydrogen (C.sub.1-C.sub.4)alkyl or
Ar.sup.3--(C.sub.0-C.sub.4)alkylenyl and R.sup.26 is
Ar.sup.3--(C.sub.0-C.sub.4)alkylenyl; provided that when Ar.sup.3
is phenyl, naphthyl or biphenyl, then R.sup.23 cannot be
CONR.sup.25R.sup.26 where R.sup.25 in the compound of formula SDI
is hydrogen or Ar.sup.3 and R.sup.26 is Ar.sup.3;
[0120] R.sup.24 in the compound of formula SDI is hydrogen,
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxycarbonyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
hydroxy-(C.sub.1-C.sub.4)- alkyl or phenyl optionally independently
substituted with up to three hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy-(C-
.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl or
(C.sub.1-C.sub.4)alkoxy, wherein said (C.sub.1-C.sub.4)alkyl in the
definition of R.sup.6 and said (C.sub.1-C.sub.4)alkoxy in the
definition of R.sup.6 are optionally and independently substituted
with up to five fluoro;
[0121] Ar.sup.3 in the compound of formula SDI is independently
defined as set forth for Ar and Ar.sup.1 above;
[0122] said Ar.sup.3 is optionally independently substituted as set
forth for Ar and Ar.sup.1 above;
[0123] R.sup.27 in the compound of formula SDI is hydrogen or
(C.sub.1-C.sub.4)alkyl;
[0124] R.sup.28 and R.sup.29 in the compound of formula SDI are
each independently hydrogen, hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro, (C.sub.1-C.sub.4)alkoxy optionally substituted with up to
five fluoro, phenyl, pyridyl, pyrimidyl, thienyl, furanyl,
thiazolyl, oxazolyl, phenoxy, thiophenoxy,
SO.sub.2NR.sup.30R.sup.31, CONR.sup.30R.sup.31 or
NR.sup.30R.sup.31; said thienyl, pyrimidyl, furanyl, thiazolyl and
oxazolyl in the definition of R.sup.28 and R.sup.29 are optionally
substituted by up to two hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.- sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro or (C.sub.1-C.sub.4)alkoxy optionally substituted with up to
five fluoro; said phenyl, pyridyl, phenoxy and thiophenoxy in the
definition of R.sup.28 and R.sup.29 are optionally substituted by
up to three hydroxy, halo, hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C- .sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro or (C.sub.1-C.sub.4)alkoxy optionally substituted with up to
five fluoro;
[0125] R.sup.30 and R.sup.31 in the compound of formula SDI are
each independently hydrogen, (C.sub.1-C.sub.4)alkyl,
(C.sub.3-C.sub.7)cycloalk- yl or phenyl, said phenyl is optionally
substituted with up to three hydroxy, halo,
hydroxy-(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkoxy-(C-
.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl optionally substituted
with up to five fluoro or (C.sub.1-C.sub.4)alkoxy optionally
substituted with up to five fluoro; or
[0126] R.sup.30 and R.sup.31 in the compound of formula SDI are
taken together with the nitrogen to which they are attached to form
indolinyl, pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
said pyrrolidinyl and piperidinyl in the definition of R.sup.30 and
R.sup.31 are optionally substituted with up to two hydroxy, amino,
hydroxy-(C.sub.1-C.sub.4)alkyl- ,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro or (C.sub.1-C.sub.4)alkoxy optionally substituted with up to
five fluoro; said indolinyl and piperazinyl in the definition of
R.sup.30 and R.sup.31 are optionally substituted with up to three
hydroxy, amino, hydroxy-(C.sub.1-C.sub.4)alk- yl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxycarbonyl, (C.sub.1-C.sub.4)alkyl optionally
substituted with up to five fluoro or (C.sub.1-C.sub.4)alkoxy
optionally substituted with up to five fluoro; said morpholinyl in
the definition of R.sup.30 and R.sup.31 is optionally substituted
with up to two substituents independently selected from
hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro;
[0127] A in the compound of formula SDI is N optionally substituted
with hydrogen or (C.sub.1-C.sub.4)alkyl and B is carbonyl; or
[0128] A in the compound of formula SDI is carbonyl and B is N
optionally substituted with hydrogen or (C.sub.1-C.sub.4)alkyl;
[0129] R.sup.32 in the compound of formula SDI is hydrogen or
(C.sub.1-C.sub.4)alkyl;
[0130] R.sup.33 in the compound of formula SDI is phenyl, pyridyl,
pyrimidyl, thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl,
phthalizinyl, quinoxanlyl, benzothiazoyl, benzoxazolyl,
benzofuranyl or benzothienyl; said phenyl, pyridyl, pyrimidyl,
thiazolyl, oxazolyl, benzyl, quinolyl, isoquinolyl, phthalizinyl,
quinoxanlyl, benzothiazoyl, benzoxazolyl, benzofuranyl and
benzothienyl in the definition of R.sup.33 are optionally
substituted with up to three phenyl, phenoxy, NR.sup.34R.sup.35,
halo, hydroxy, hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro or (C.sub.1-C.sub.4)alkoxy optionally substituted with up to
five fluoro;
[0131] R.sup.34 and R.sup.35 in the compound of formula SDI are
each independently hydrogen, (C.sub.1-C.sub.4 alkyl), phenyl or
phenylsulfonyl; said phenyl and phenylsulfonyl in the definition of
R.sup.34 and R.sup.35 are optionally substituted with up to three
halo, hydroxy, (C.sub.1-C.sub.4)alkyl optionally substituted with
up to five fluoro or (C.sub.1-C.sub.4)alkoxy optionally substituted
with up to five fluoro;
[0132] D in the compound of formula SDI is CO, CHOH or
CH.sub.2;
[0133] E in the compound of formula SDI is O, NH or S;
[0134] R.sup.36 and R.sup.37 in the compound of formula SDI are
taken separately and are each independently hydrogen, halo, cyano,
hydroxy, amino, (C.sub.1-C.sub.6)alkylamino,
di-(C.sub.1-C.sub.6)alkylamino, pyrrolidino, piperidino,
morpholino, (C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.s- ub.4)alkyl,
hydroxy-(C.sub.1-C.sub.4)alkyl, Ar.sup.4, (C.sub.1-C.sub.4)alkyl
optionally substituted with up to five fluoro or
(C.sub.1-C.sub.4)alkoxy optionally substituted with up to five
fluoro;
[0135] R.sup.38, R.sup.39 and R.sup.40 in the compound of formula
SDI are each independently hydrogen or (C.sub.1-C.sub.4)-alkyl;
[0136] Ar.sup.4 in the compound of formula SDI is phenyl, furanyl,
thienyl, pyridyl, pyrimidyl, pyrazinyl or pyridazinyl; said
Ar.sup.4 being optionally substituted with up to three hydroxy,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl, halo,
hydroxy-(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)alkyl optionally
substituted with up to five fluoro or (C.sub.1-C.sub.4)alkoxy
optionally substituted with up to five fluoro; or
[0137] R.sup.36 and R.sup.37 in the compound of formula SDI are
taken together on adjacent carbon atoms and are
--O--(CH.sub.2).sub.t--O--;
[0138] t in the compound of formula SDI is 1, 2 or 3;
[0139] Y in the compound of formula SDI is
(C.sub.2-C.sub.6)alkylene;
[0140] R.sup.44, R.sup.45 and R.sup.46 in the compound of formula
SDI are each independently hydrogen or (C.sub.1-C.sub.4)alkyl;
[0141] m and n in the compound of formula SDI are each
independently 1, 2 or 3, provided that the sum of m and n is 2, 3
or 4;
[0142] k in the compound of formula SDI is 0, 1, 2, 3 or 4;
[0143] Y.sup.1 in the compound of formula SDI is a covalent bond,
carbonyl, sulfonyl or oxycarbonyl;
[0144] R.sup.43 in the compound of formula SDI is
(C.sub.3-C.sub.7)cycloal- kyl,
Ar.sup.5--(C.sub.0-C.sub.4)alkylenyl, NR.sup.47R.sup.48 or
(C.sub.1-C.sub.6)alkyl optionally substituted with one to five
fluoro; provided that when Y.sup.1 is a covalent bond or
oxycarbonyl, then R.sup.43 is not NR.sup.47R.sup.48;
[0145] R.sup.47 and R.sup.48 in the compound of formula SDI are
taken separately and are each independently selected from hydrogen,
Ar.sup.5, (C.sub.1-C.sub.6)alkyl and
Ar.sup.5--(C.sub.0-C.sub.4)alkylenyl; or
[0146] R.sup.47 and R.sup.48 in the compound of formula SDI are
taken together with the nitrogen atom to which they are attached to
form azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl,
morpholinyl, azepinyl, azabicyclo[3.2.2]nonanyl,
azabicyclo[2.2.1]heptyl, 1,2,3,4-tetrahydroisoquinolyl,
6,7-dihydro-5H-dibenzo[c,e]azepinyl or
5,6,7,8-tetrahydropyrido[4,3-d]pyrimidyl; said azetidinyl in the
definition of R.sup.47 and R.sup.48 are optionally substituted with
one hydroxy, amino, hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(- C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro or (C.sub.1-C.sub.4)alkoxy optionally substituted with up to
five fluoro; said pyrrolidinyl, piperidinyl and azepinyl in the
definition of R.sup.47 and R.sup.48 are optionally substituted with
up to two hydroxy, amino, hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro or (C.sub.1-C.sub.4)alkoxy optionally substituted with up to
five fluoro; said morpholinyl in the definition of R.sup.47 and
R.sup.48 is optionally substituted with up to two substituents
independently selected from hydroxy-(C.sub.1-C.sub.4)alk- yl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro and (C.sub.1-C.sub.4)alkoxy optionally substituted with up
to five fluoro; said piperazinyl, 1,2,3,4-tetrahydroisoquinolyl and
5,6,7,8-tetrahydro[4,3-d]pyrimidyl in the definition of R.sup.47
and R.sup.48 are optionally substituted with up to three hydroxy,
amino, halo, hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro or (C.sub.1-C.sub.4)alkoxy optionally substituted with up to
five fluoro; and said 6,7-dihydro-5H-dibenzo[c,e]azepinyl in the
definition of R.sup.47 and R.sup.48 are optionally substituted with
up to four hydroxy, amino, halo, hydroxy-(C.sub.1-C.sub.4)alkyl,
(C.sub.1-C.sub.4)alkoxy-(C.sub.1-C.sub.4)- alkyl,
(C.sub.1-C.sub.4)alkyl optionally substituted with up to five
fluoro or (C.sub.1-C.sub.4)alkoxy optionally substituted with up to
five fluoro;
[0147] Ar.sup.5 in the compound of formula SDI is independently
defined as set forth for Ar and Ar.sup.1 above;
[0148] Ar.sup.5 in the compound of formula SDI is optionally
independently substituted as set forth for Ar and Ar.sup.1
above;
[0149] R.sup.42 and R.sup.42a in the compound of formula SDI are
independently hydrogen, (C.sub.3-C.sub.7)cycloalkyl,
Ar.sup.6--(C.sub.0-C.sub.3)alkylenyl,
Ar.sup.6--(C.sub.2-C.sub.4)alkenyl, Ar.sup.6-carbonyl or
(C.sub.1-C.sub.6)alkyl optionally substituted with up to five
fluoro;
[0150] Ar.sup.6 in the compound of formula SDI is independently
defined as set forth for Ar and Ar.sup.1 above;
[0151] Ar.sup.6 in the compound of formula SDI is optionally
independently substituted as set forth for Ar and Ar.sup.1 above;
and
[0152] R.sup.41 and R.sup.41a in the compound of formula SDI are
each independently hydrogen or (C.sub.1-C.sub.4)alkyl.
[0153] Especially preferred SDI compounds include
1R-(4-{1'-[2-(1R-hydroxy-
-ethyl)-pyrimidin-4-yl]-[4,4]bipiperidinyl-1-yl}-pyrimidin-2-yl)-ethanol;
furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-di-
methyl-piperazin-1-yl}-methanone;
(4-chloro-furo[3,2-c]pyridin-2-yl)-{4-[2-
-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-methano-
ne;
{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl-
}-(4-pyrrolidin-1-yl-furo[3,2-c]pyridin-2-yl)-methanone;
{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-(-
4-morpholin-4-yl-furo[3,2-c]pyridin-2-yl)-methanone;
{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-i-
midazo[1,2-a]pyridin-2-yl-methanone;
furo[3,2-c]pyridin-2-yl-{4-[2-(1R-hyd-
roxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-methanone;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carbo-
xylic acid pyridin-3-yl ester;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,-
6S-dimethyl-piperazine-1-carboxylic acid 2-methyl-pyridin-3-yl
ester;
4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazine-1-carbo-
xylic acid 5-chloro-pyridin-3-yl ester;
4-[2-(1R-hydroxy-ethyl)-pyrimidin--
4-yl]-2R,6S-dimethyl-piperazine-1-carboxylic acid
6-methyl-pyridin-3-yl ester;
(E)-1-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-pipe-
razin-1-yl}-3-thiophen-2-yl-propenone;
1R-{4-[4-(4,6-dimethyl-pyrimidin-2--
yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-methoxymethyl-6-methyl-pyrimidin-2-yl)-3R,5S-dimethyl-piperaz-
in-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrim-
idin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-piperazin-1-yl)-pyrimidin-4-yl]-pipe-
razin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)--
pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{3R,5S-dimethyl-4-[2-(4-methyl-imidazol-1-yl)-pyrimidin-4-yl]-piper-
azin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{3R,5S-dimethyl-4-[2-(2-methyl-i-
midazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-p-
iperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(4-isopropyl-piperazin-
-1-yl)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-etha-
nol;
1R-(4-{3R,5S-dimethyl-4-[4-methyl-6-(4-methyl-piperazin-1-yl)-[1,3,5]-
triazin-2-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazi-
n-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2--
yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-ethoxy-6-methyl-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-
-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-isopropoxy-6-methyl-[1,3,5]tri-
azin-2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[3R,5S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-py-
rimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methoxy-[1,3,5]triazin--
2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-isopropoxy-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-pipe-
razin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-isopropyl-[1,3,5]triazin--
2-yl)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-ethyl-6-methoxy-[1,3,5]triazin-2-yl)-3R,5S-dimethyl-piperazin-
-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethyl-pyrimidin-2-yl)-2R,-
6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)-2R,6S-dimethyl-piperaz-
in-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-[1,2,4]triazo-
l-1-yl-pyrimidin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(2,6-dimethyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyr-
imidin-2-yl}-ethanol;
1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-
-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[4-(2-hydroxymeth-
yl-6-methyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-
-ethanol;
1R-(4-{4-[2-(1S-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-dimethyl-pi-
perazin-1-yl}-pyrimidin-2-yl)-ethanol;
1S-(4-{4-[2-(1R-hydroxy-ethyl)-pyri-
midin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidi-
n-2-yl}-ethanone;
1RS-(4-{4-[2-(1RS-hydroxy-ethyl)-pyrimidin-4-yl]-2R,6S-d-
imethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
(4-{4-[2-(1R-hydroxy-ethy-
l)-pyrimidin-4-yl]-3R,5S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone-
;
1R-{4-[2R,6S-dimethyl-4-(2-morpholin-4-yl-pyrimidin-4-yl)-piperazin-1-yl-
]-pyrimidin-2-yl}-ethanol;
1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-piperazin--
1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[2R,6S-dimethyl-4-(2-[1,2,4]triazol-1-yl-pyrimidin-4-yl)-piperazin--
1-yl]-pyrimidin-2-yl}-ethanol;
1R-(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4--
yl]-2R,6R-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(4-ethyl-piperazin-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-piper-
azin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{2R,6S-dimethyl-4-[2-(4-methyl-i-
midazol-1-yl)-pyrimidin-4-yl]-piperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-(4-{4-[2-(2,4-dimethyl-imidazol-1-yl)-pyrimidin-4-yl]-2R,6S-dimethyl-p-
iperazin-1-yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-morphol-
in-4-yl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-methoxy-6-methyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazi-
n-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethoxy-[1,3,5]triazin-2--
yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[2R,6S-dimethyl-4-(4-phenyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-py-
rimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-methyl-pyrimidin-2-yl)--
3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(2-hydroxymeth-
yl-pyrimidin-4-yl)-3S-methyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(2-hydroxymethyl-6-methyl-pyrimidin-4-yl)-3S-methyl-piperazin-1--
yl]-py-rimidin-2-yl}-ethanol;
1R-[4-(3S-methyl-4-oxazolo[5,4-b]pyridin-2-y-
l-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;
1R-[4-(3S-methyl-4-oxazolo[4,5--
b]pyridin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethanol;
1R-[4-(3S-methyl-4-quinoxalin-2-yl-piperazin-1-yl)-pyrimidin-2-yl]-ethano-
l;
(4-{4-[2-(1R-hydroxy-ethyl)-pyrimidin-4-yl]-2R,5S-dimethyl-piperazin-1--
yl}-pyrimidin-2-yl)-ethanol;
1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-3-
R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[3R,5S-dimethyl-4-(4-methyl-6-phenyl-[1,3,5]triazin-2-yl)-piperazin-
-1-yl]pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl-
)-3R,5S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-cyclopropyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-y-
l]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4,6-dimethyl-[1,3,5]triazin-2-yl)-2R-
,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-hydroxymethyl-6-phenyl-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-pi-
perazin-1-yl]-pyrimidin-2-yl}-ethanol;
1R-{4-[4-(4-methoxy-6-methoxymethyl-
-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl]-pyrimidin-2-yl}-ethan-
ol;
1R-{4-[2R,6S-dimethyl-4-(4-methyl-[1,3,5]triazin-2-yl)-piperazin-1-yl]-
-pyrimidin-2-yl-ethanol;
1-{4-[4-(2-acetyl-pyrimidin-4-yl)-2R*,6S*-dimethy-
l-piperazin-1-yl]-pyrimidin-2-yl}-ethanone;
1-(-4-{4-[2-(1R-hydroxy-ethyl)-
-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanone;
1R-{4-[4-(4-methoxymethyl-6-phenyl-[1,3,5]-triazin-2-yl)-2R,6S-dimethyl-p-
iperazin-1-yl]-pyrimidin-2-yl}-ethanol; and 1
S-(4-{4-[2-(1R-hydroxy-ethyl-
)-pyrimidin-4-yl]-2R,6S-dimethyl-piperazin-1-yl}-pyrimidin-2-yl)-ethanol.
An even more especially preferred SDI compound is
1R-(4-(4-(4,6-dimethyl)-
-[1,3,5]triazin-2-yl)-2R,6S-dimethyl-piperazin-1-yl)-pyrimidin-2-yl)-ethan-
ol.
[0154] The preferred and especially preferred SDIs disclosed in the
above two paragraphs can be prepared according to methods set forth
in U.S. Provisional Patent Application No. 60/127,437, filed on
Apr. 1, 1999, or as set forth below, where the variables in the
following schemes and description refer only to the SDI compounds.
14
[0155] Compounds of formula 1-3 (i.e., formula I) are prepared as
set forth in Scheme 1, particularly as described below.
[0156] Compounds of formula 1-3 are prepared by the displacement
reaction of a pyrimidine of the formula 1-1 where R.sup.1 and
R.sup.2 are defined herein. Lv is a leaving group preferably
selected from fluoro, chloro, bromo, iodo, thiomethyl,
methylsulfone, or OSO.sub.2J wherein J is (C.sub.1-C.sub.6)-lower
alkyl, trifluoromethyl, pentafluoroethyl, phenyl optionally
substituted with up to three (C.sub.1-C.sub.4)alkyl, nitro or halo.
The leaving group Lv is displaced by an amine of the formula 1-2
where R.sup.3 is defined above. The reaction is conducted in the
presence of a non-aqueous base, preferably an organic amine or an
inorganic base. Preferred organic amines include triethylamine,
pyridine, dimethylaminopyridine and N,N'-diisopropylethylamine
(Hunig's base). Preferred inorganic bases include alkaline metal
carbonates and bicarbonates such as sodium or potassium carbonate
and sodium or potassium bicarbonate. An especially preferred
inorganic base is potassium carbonate. An especially preferred
organic amine is triethylamine. Alternatively, an excess of the
reacting amine 1-2 can be used as the base for this reaction. The
reaction can be conducted in the absence of solvent or in a
reaction inert solvent. Where used herein, "reaction inert solvent"
refers to a solvent which does not interact with starting
materials, reagents, intermediates or products in a manner which
adversely affects the yield of the desired product. Preferred
reaction inert solvents include aqueous media, pyridine,
(C.sub.1-C.sub.4)alcohol, (C.sub.2-C.sub.6)glycol, halocarbon,
aliphatic/aromatic hydrocarbon, ethereal solvent, polar aprotic
solvent, ketonic solvent, or combinations thereof. The reaction
time ranges from 15 minutes to 3 days and the reaction temperature
ranges from 0.degree. C. to 180.degree. C. Conveniently, the
reaction may be conducted at the reflux temperature of the solvent
being used. The reaction is preferably conducted at ambient
pressure. The term ambient pressure, where used herein, refers to
the pressure of the room in which the reaction is being conducted.
The term ambient temperature, where used herein, refers to the
temperature of the room in which the reaction is being
conducted.
[0157] When R.sup.1 contains a hydroxy group, the hydroxyl group
may or may not be protected. When the hydroxyl group is protected,
the protecting group may be any suitable hydroxyl protecting group.
The conditions used to remove such optional hydroxyl protecting
groups contained in R.sup.1 in compounds of formula 1-3 are as
follows. When the protecting group is an ester, removal of such
ester protecting groups is conducted under basic conditions using
inorganic hydroxides or carbonates, preferably lithium hydroxide,
sodium hydroxide, potassium hydroxide or potassium carbonate. The
reaction is carried out in a reaction inert solvent, preferably an
alcoholic solvent. Especially preferred is methanol or methanol in
combination with co-solvents such as water, tetrahydrofuran, or
dioxane. The reaction time ranges from 15 minutes to 24 hours and
the reaction temperature ranges from 0.degree. C. to 100.degree. C.
or to the reflux temperature of the solvent(s) of use.
Alternatively, ester cleavage may be accomplished under acidic
conditions. It is preferred to utilize aqueous hydrochloric acid,
generally 2 N to concentrated, with or without a co-solvent. When a
co-solvent is used, dioxane or methanol are preferred. The reaction
time ranges from 4 hours to 3 days and the reaction temperature
ranges from 0.degree. C. to 60.degree. C.
[0158] When the protecting group is an alkyl ether, removal of such
alkyl ether protecting groups is conducted using well known
dealkylative conditions. For example, the alkyl ether may be
cleaved by reaction with boron tribromide or diethylboron bromide
in a reaction inert solvent, preferably a halocarbon solvent. It
will be recognized by those skilled in the art that a buffer such
as triethylamine may facilitate the reaction. The reaction times
range from 15 minutes to 24 hours and the reaction temperature
ranges from 0.degree. C. to 60.degree. C. In addition, a benzyl
ether protecting group can be removed via standard or transfer
hydrogenolysis using a palladium catalyst such as palladium on
carbon. The hydrogenolysis reaction is conducted under a hydrogen
atmosphere at ambient pressure to 50 psi in a reaction inert
solvent, preferably methanol. The hydrogen source may be hydrogen
gas, ammonium formate or trialkylammonium formate or cyclohexene.
The reaction temperature ranges from room temperature to the reflux
temperature of the solvent employed. The reaction time ranges from
15 minutes to 24 hours.
[0159] When a silyl ether protecting group is employed, removal of
such silyl ether protecting groups is conducted under acidic
conditions, preferably with aqueous hydrochloric acid such as 1 N
to 6 N hydrochloric acid. The de-protection may be carried out in
the presence of a co-solvent such as methanol or tetrahydrofuran.
The reaction time ranges from 2 hours to 48 hours and the reaction
temperature ranges from 0.degree. C. to 100.degree. C.
Alternatively, the silyl ether protecting group may be removed via
fluoride-mediated deprotection. In this case, deprotection is
conducted using tetrabutylammonium fluoride or one of a variety of
hydrofluoric acid sources in a reaction inert solvent. It is
preferred to use ethereal solvents such as diethyl ether, dioxane
or tetrahydrofuran, with tetrahydrofuran being especially
preferred. The reaction time ranges from 2 hours to 48 hours and
the reaction temperatures range from 0.degree. C. to the reflux
temperature of the solvent being used. Other methods for removal of
the aforementioned protecting groups are well known to those
skilled in the art or can be found in Greene, T. W.; Wuts, P. G.
M., Protective Groups in Organic Synthesis, 2.sup.nd ed.; John
Wiley and Sons Inc.: New York, 1991. Other suitable hydroxyl
protecting groups and methods for their removal may be found also
be found therein. The method of Scheme I is preferred when R.sup.3
is R.sup.3k, l, m, n, o, p and q. Thus, compounds of formula 1-2
are reacted with compounds of formula 1-1. Compounds of formula 1-2
where R is R.sup.3k, l, m, n, o, p or q are commercially available
or can be prepared by methods well known to those skilled in the
art. 15
[0160] Compounds of formula 2-7 are prepared as set forth in Scheme
2, particularly as described below.
[0161] Where R.sup.27 is H, ethyl
1-benzyl-3-oxo-4-piperidine-carboxylate hydrochloride, the compound
of formula 2-1, which is available from Aldrich, is condensed with
compounds of formula 2-2 to give compounds of formula 2-3. The
compounds of formula 2-1 where R.sup.27 is not H can be prepared
according to methods well known to those skilled in the art. The
reaction is conducted in the presence of excess base including
non-aqueous bases, organic amines and inorganic bases. Preferred
organic amines include triethylamine and pyridine. Preferred
non-aqueous bases include alkaline metal
(C.sub.1-C.sub.4)alkoxides. Preferred inorganic bases include
potassium carbonate. The reaction is conducted in a reaction inert
solvent. Preferred such solvents include (C.sub.1-C.sub.4)alcohols,
aromatic or aliphatic hydrocarbons, polar aprotic solvents,
halocarbons, and ethereal solvents. (C.sub.1-C.sub.4)Alcohols are
especially preferred. The reaction time ranges from 2 hours to 3
days. The reaction temperature ranges from ambient temperature to
the reflux temperature of the solvent being employed. The reaction
is preferably run at ambient pressure but may be conducted at
pressures up to 250 psi.
[0162] Compounds of formula 2-4 are prepared from compounds of
formula 2-3 by converting a compound of formula 2-3 into an
activated compound of formula 2-4 where Lv.sup.1 is selected from
fluoro, chloro, bromo, iodo, trifluoromethanesulfonate,
(C.sub.1-C.sub.6)alkylsulfonate, or phenylsulfonate, wherein said
phenyl is optionally substituted with up to three
(C.sub.1-C.sub.4)alkyl, halo or nitro. This reaction is
accomplished by reacting compounds of formula 2-3 with a
chlorinating agent such as phosphorus oxychloride and/or phosphorus
pentachloride to provide compounds of formula 2-4 where Lv.sup.1 is
chloro. This reaction is conducted at ambient pressure in the
absence of solvent or in a reaction inert solvent, preferably a
halocarbon solvent at temperatures ranging from ambient temperature
to 180.degree. C. Treatment of the chloro compound thus formed with
the requisite mineral acid provides a compound of formula 2-4 where
Lv.sup.1 is bromo or iodo. A sulfonate of formula 2-4 is prepared
by reaction of a compound of formula 2-3 with a sulfonic acid
chloride or anhydride in the presence of an organic amine base,
preferably triethylamine or pyridine. In certain cases recognized
by those skilled in the art, it may be necessary to add a catalyst
to the reaction. In those cases, a preferred catalyst is
4-dimethylaminopyridine- . This reaction is conducted at ambient
pressure in a reaction inert solvent, preferably pyridine, a
halocarbon such as chloroform, dichloromethane or carbon
tetrachloride, an aromatic or aliphatic hydrocarbon, an ethereal
solvent, or combinations thereof. The reaction temperature ranges
from -20.degree. C. to 100.degree. C. and the reaction time ranges
from 15 minutes to 1 day.
[0163] Compounds of formula 2-5 wherein R.sup.29 is defined above
are prepared from compounds of formula 2-4 by a reduction reaction
or by displacement of Lv.sup.1 with a nucleophile. The reduction is
conducted with a reducing agent, preferably ammonium formate or
hydrogen gas, in a reaction inert solvent. The reduction is
conducted in the presence of a palladium catalyst at ambient
pressure or under a hydrogen pressure of up to 50 psi. Preferred
solvents include (C.sub.1-C.sub.4)alcohols such as methanol and
ethanol, and ether solvents such as diethyl ether, dioxane and
tetrahydrofuran. The nucleophilic displacement reaction may be
conducted by adding the nucleophile directly or by pre-forming the
nucleophile separately or in situ from a nucleophile precursor.
Preferred nucleophiles include organoaluminum, organoboron,
organocopper, organotin, organozinc or Grignard reagent;
R.sup.29--H; or, where R.sup.29 contains a hydroxyl or thiol group,
the anion of R.sup.29. The term "organo" in the terms
organoaluminum, organoboron, organocopper, organotin and organozinc
refers to an organic radical selected from R.sup.29. It will be
recognized by those skilled in the art that transition-metal
catalysts may be required to effect reaction in certain
displacement reactions. When required, such transition metal
catalysts may include palladium(0), palladium(II), nickel(0), and
nickel(II) complexes. Palladium(II) bis(diphenylphosphinobutane)
dichloride is a preferred such catalyst. Additionally, an aqueous
or non-aqueous base may be required in the displacement reaction.
Preferred such bases include sodium carbonate, sodium hydride,
triethylamine and sodium tert-butoxide. The reaction is conducted
at ambient pressure in a reaction inert solvent such as a
halocarbon, an aromatic or aliphatic hydrocarbon, an ether or a
polar aprotic solvent or a combination thereof. In certain cases, a
(C.sub.1-C.sub.4)alcohol is used as a solvent or co-solvent. The
reaction temperature ranges from -20.degree. C. to the reflux
temperature of the solvent employed. The reaction time ranges from
1 hour to 3 days.
[0164] Compounds of formula 2-6 are prepared by removal of the
benzyl protecting group from compounds of formula 2-3 or 2-5. This
transformation is accomplished using the freebase, or preferably
the pre-formed hydrochloride or similar salt, under standard or
transfer hydrogenolysis conditions. The catalysts which may be used
in the hydrogenolysis reaction include, but are not limited to,
palladium on carbon, palladium hydroxide on carbon and platinum(IV)
oxide. The reaction is conducted in a reaction inert solvent,
preferably methanol or ethanol and the reaction temperature ranges
from room temperature to the reflux temperature of the solvent
being employed. The hydrogen source is hydrogen gas, ammonium
formate, trialkylammonium formate, or cyclohexene. The reaction
time ranges from 15 minutes to 3 days. Generally the reaction is
conducted at ambient pressure but pressures of up to 50 psi of
hydrogen may be employed. Alternatively, if appropriate, the benzyl
protecting group is removed in two steps via chloroformate-induced
acylative dealkylation. This involves reaction with a chloroformate
derivative to form a carbamate followed by cleavage of the
carbamate. While this reaction is preferably conducted with
1-chloroethyl chloroformate and sodium iodide catalysis, it will be
recognized by those skilled in the art that catalysis may not be
required in certain cases. The reaction is conducted at ambient
temperature in a reaction inert solvent such as a halocarbon, an
aromatic or aliphatic hydrocarbon, a ketone, an ether or a polar
aprotic solvent. The reaction temperature ranges from -78.degree.
C. to the reflux temperature of the solvent being employed and the
reaction time ranges from 15 minutes to 1 day. Cleavage of the
carbamate formed by reaction with 1-chloroethyl chloroformate is
accomplished upon exposure to methanol or ethanol at ambient
pressure to give compounds of formula 2-6 as a hydrochloride salt.
The reaction proceeds at temperatures from room temperature to the
reflux temperature of the solvent being employed and the reaction
time ranges from 15 minutes to 1 day. Deprotection conditions for
other carbamates can be found in Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 2.sup.nd ed.; John Wiley
and Sons Inc.: New York, 1991, pp 315-348.
[0165] Compounds of formula 2-7 are prepared from the displacement
reaction of amine 2-6 as described in Scheme 1, where the amine 2-6
is equivalent to R.sup.3--NH.
[0166] Alternatively, compounds of formula 2-7 where R.sup.29 is as
defined above are prepared from compounds of formula 2-3 wherein
R.sup.29 is OH according to the sequence outlined in Scheme 2a
below, wherein the conditions are as set forth as described for
Scheme 2. 16
[0167] Compounds of formula 2-2 which are used in Schemes 2 and 2a
above are commercially available or are prepared according to
methods well known to those skilled in the art, such as those
described in March, J. Advanced Organic Chemistry, 3.sup.rd ed.;
John Wiley and Sons.: New York, 1985, p 359, 374. 17
[0168] Compounds of formula 3-5 are prepared as set forth in Scheme
3 above and more particularly as described below.
[0169] Compounds of formula 3-3 are prepared by condensing a
compound of formula 3-1 with a compound of formula 3-2. Where
R.sup.38 and R.sup.39 are each H, the compound of formula 3-1 is
1-benzyl-4-piperidone, which is commercially available from
Aldrich. Compounds of formula 3-2 are either commercially available
or can be prepared according to methods well known to those skilled
in the art, particularly according to methods set forth in March,
J. Advanced Organic Chemistry, 3.sup.rd ed.; John Wiley and Sons
Inc.: New York, 1985, pp 499-500. The reaction is conducted at
ambient pressure in the presence of a secondary amine. Generally an
excess of the secondary amine, preferably pyrrolidine, piperidine,
morpholine or diethylamine, is used. An especially preferred
secondary amine is pyrrolidine. The reaction is conducted in a
reaction inert solvent, preferably a (C.sub.1-C.sub.4)alcohol, an
aromatic or aliphatic hydrocarbon, a polar aprotic solvent, a
halocarbon or an ether. An especially preferred solvent is ethanol.
The reaction time ranges from 2 hours to 3 days and the reaction
temperature ranges from ambient temperature to the reflux
temperature of the solvent being employed.
[0170] Compounds of the formula 3-4 are prepared by removal of the
benzyl protecting group from compounds of formula 3-3. This
transformation is conducted in a manner analogous to the procedure
set forth for the preparation of compounds of formula 2-6
above.
[0171] Compounds of formula 3-5 are prepared from the displacement
reaction of amine 3-4 as described in Scheme 1, where the amine 3-4
is equivalent to R.sup.3--NH. 18
[0172] Compounds of formulas 3a-1 and 3a-2 are prepared as shown in
Scheme 3a from compounds of formula 3-5. Thus, to prepare a
compound of 3a-1, a compound of formula 3-5 is reduced with a
common reducing agent, such as, for example, sodium borohydride,
lithium aluminum hydride or diisobutylaluminum hydride. Other
reducing agents capable of effecting the reduction of a ketone to
an alcohol are well known to those skilled in the art (e.g.,
Larock, R. D. Comprehensive Organic Transformations, VCH
Publishers, Inc.: New York, 1989, pp 527-547). Likewise, compounds
of formula 3a-2 are prepared from compounds of formula 3-5 by
reduction with reducing agents capable of reducing a ketone
completely to a methylene group. A preferred such reducing agent is
aluminum trichloride/borane-tert-butylamine complex. Other such
reducing agents are well known to those skilled in the art (e.g.,
J. Org. Chem. 1989, 54, 4350; Larock, R. D. Comprehensive Organic
Transformations, VCH Publishers, Inc.: New York, 1989, pp 35-37).
It will be recognized by those skilled in the art that the
transformation of 3-5 to 3a-1 or 3a-2 can be conducted at different
points in Scheme 3, depending upon the dynamics of the particular
system.
[0173] Alternatively, compounds of formula 3-5 wherein R.sup.38 and
R.sup.39 are hydrogen can be prepared from 4-piperidone monohydrate
monochloride in a manner analogous to the procedure described in
Scheme 1, where the amine 3-6 is equivalent to R.sup.3--NH to give
compounds of formula 3-7. Compounds of formula 3-7 can be reacted
with compounds of formula 3-2 in a manner analogous to the
procedure set forth for the synthesis of compounds of formula 3-3
to afford compounds of formula 3-5. 19
[0174] Compounds of formula 4-5 are prepared according to Scheme 4
and more particularly as described below.
[0175] Compounds of formula 4-3 are prepared by reacting a compound
of formula 4-2 with a compound of formula 4-1 or 4-1a. Compounds of
formula 4-1 and 4-1a are prepared according to methods well known
to those skilled in the art. Where R.sup.32 is hydrogen,
4-oxo-piperidine-1,3-dica- rboxylic acid 1-tert-butyl ester 3-ethyl
ester is condensed with a compound of formula 4-2 to afford a
compound of formula 4-3. Said compounds of formula 4-2 are readily
available from well known commercial vendors, known in the
literature, or are synthesized under standard conditions well known
to those skilled in the art. Preferred conditions to prepare
compounds of formula 4-3 from a compound of formula 4-1 where A is
CO and B is NH or from a compound of formula 4-1a where A is NH and
B is CO can be found in March, J. Advanced Organic Chemistry,
3.sup.rd ed.; John Wiley and Sons Inc.: New York, 1985, p 1163. The
reaction is conducted at ambient pressure in a reaction inert
solvent. Preferred such solvents include aqueous media, a
(C.sub.1-C.sub.4)alcohol, glacial acetic acid, an aromatic or
aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and
ethers or combinations thereof. The reaction time ranges from 2
hours to 3 days and the reaction temperature ranges from ambient
temperature to the reflux temperature of the solvent being used. An
optional second step using aqueous or non-aqueous base may be
employed in certain cases which will be recognized by those skilled
in the art. This second step is conducted at ambient pressure in a
reaction inert solvent. Preferred such solvents include aqueous
media, a (C.sub.1-C.sub.4)alcohol, glacial acetic acid, an aromatic
or aliphatic hydrocarbon, a polar aprotic solvent, a halocarbon and
ethers or combinations thereof. The reaction time ranges from 2
hours to 3 days and the reaction temperature ranges from ambient
temperature to the reflux temperature of the solvent being
used.
[0176] Compounds of formula 4-3 wherein B is CO and A is N-alkyl or
wherein B is N-alkyl and A is CO are prepared by alkylation of
compounds of formula 4-3 where B is CO and A is NH or wherein B is
NH and A is CO, respectively. The anion of those compounds of
formula 4-3 is formed by reaction with an appropriate base.
Preferred such bases include sodium hydride and sodium
hexamethyldisilazide, although other bases may be used where
conditions warrant, as determined by the skilled person. The
reaction is conducted in a reaction inert solvent, preferably an
ether such as tetrahydrofuran, diethyl ether, dioxane or diglyme or
polar aprotic solvent such as dimethylformamide. The reaction
proceeds at ambient pressure and at temperatures ranging from
-100.degree. C. to ambient temperature. The reaction times are from
10 minutes to 2 hours. Addition of (C.sub.1-C.sub.4)alkyl halides
or (C.sub.1-C.sub.4)alkylsulfo- nates such as mesylate, tosylate or
nosylate to the anion of 4-3 proceeds at ambient pressure and at
temperatures ranging from -20.degree. C. to 50.degree. C. The
reaction times range from 10 minutes to 1 day.
[0177] Compounds of formula 4-4 are prepared form compounds of
formula 4-3 wherein A is N-alkyl and B is CO or A is CO and B is
N-alkyl via acid-catalyzed deprotection of the Boc carbamate under
standard conditions, for example, hydrochloric acid or
trifluoroacetic acid in a reaction inert solvent or in the absence
of solvent. Such conditions are known to those skilled in the art.
Exemplary conditions are disclosed in Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 2nd ed.; John Wiley and
Sons Inc.: New York, 1991, pp 327-330.
[0178] Compounds of formula 4-5 are prepared by the displacement
reaction of amine 4-4 as described in Scheme 1, where the amine 4-4
is equivalent to R.sup.3--H. 20
[0179] Compounds of formula 5-4 where X is a covalent bond and G,
G.sup.1, G.sup.2, q, R.sup.2, R.sup.6, R.sup.7 and R.sup.8 are as
defined above are prepared according to Scheme 5 above and
particularly as described below.
[0180] Compounds of formula 5-3 are prepared by reaction of a
compound of formula 5-1 with a compound of formula 5-2 where Prt is
an optional amine protecting group selected from benzyl and
CO.sub.2R.sup.90, where R.sup.90 is selected from
(C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)allyl, trichloroethyl and
benzyl substitutedby up to two (C.sub.1-C.sub.4)alkoxy- . Compounds
of formula 5-1 where R.sup.9 is Ar.sup.1 and Lv.sup.3 is halo,
(C.sub.1-C.sub.4)alkylsulfide, (C.sub.1-C.sub.4)alkylsulfone,
trifluoromethanesulfonate, (C.sub.1-C.sub.6)alkylsulfonate or
phenylsulfonate, where said phenyl is optionally substituted with
up to three halo, nitro or (C.sub.1-C.sub.4)alkyl are commercially
available or are readily prepared according to methods well known
to those skilled in the art. For example, to prepare compounds of
formula 5-1 wherein Lv.sup.3 is chloro, a compound of formula
Ar.sup.1--OH, or the Ar.sup.1--(.dbd.O) tautomer thereof, is
reacted with a chlorinating agent such as phosphorus oxychloride
and/or phosphorus pentachloride. This chlorinating reaction is
conducted at ambient pressure in the absence of solvent or in a
reaction inert solvent, preferably a halocarbon solvent, at
temperatures ranging from ambient temperature to 180.degree. C.
Treatment of the chloro compound with the requisite mineral acid
provides compounds of formula 5-1 where Lv.sup.3 is bromo or iodo.
Compounds of formula 5-1 wherein Lv.sup.3 is
trifluoromethanesulfonate, (C.sub.1-C.sub.6)alkylsulfonate or
phenylsulfonate are prepared from a compound of formula
Ar.sup.1--OH, or the Ar.sup.1--(.dbd.O) tautomer thereof, by
reaction with a sulfonic acid chloride or anhydride in the presence
of a base, preferably an organic amine such as triethylamine,
N,N'-diisopropylethylamine, dimethylaminopyridine or pyridine. In
certain cases it will be recognized by those skilled in the art
that a catalyst will be required to effect reaction. In those
cases, a preferred catalyst is 4-dimethylaminopyridine. This
reaction is conducted at ambient pressure in a reaction inert
solvent such as pyridine, a halocarbon, an aromatic or aliphatic
hydrocarbon, an ether, or a combination thereof. The reaction
temperature ranges from -20.degree. C. to 100.degree. C. and the
reaction time ranges from 15 minutes to 1 day. Compounds of formula
5-1 where Lv.sup.3 is thiomethyl are prepared by reacting a
compound of formula Ar.sup.1--SH, or the Ar.sup.1--(.dbd.S)
tautomer thereof, with methyl iodide or dimethylsulfate in the
presence of an inorganic base, preferably potassium carbonate.
These reactions are conducted at ambient pressure in a reaction
inert solvent, preferably an ether or a polar aprotic solvent. An
especially preferred polar aprotic solvent is dimethylformamide at
a temperature ranging from 0.degree. C. to 100.degree. C. Compounds
of formula 5-1 where Lv.sup.3 is methylsulfone are prepared from a
compound of formula 5-1 where Lv.sup.3 is thiomethyl by oxidation
thereof according to procedures well known to those skilled in the
art, specifically as set forth in March, J. Advanced Organic
Chemistry, 3.sup.rd ed.; John Wiley and Sons.: New York, 1985, pp
1089-1090.
[0181] A representative set of compounds of formula 5-1 which are
commercially available or which can be prepared according to
methods analogous to a literature procedure include
4-chloropyridine (Aldrich, P.O. Box 355, Milwaukee, Wis. 53201,
USA), 3-chloro-6-methyl-pyridazine (Maybridge, c/o Ryan Scientific,
443 Long Point Road, Suite D, Mount Pleasant, S.C. 29464, USA),
2-chloro-pyrazine (Aldrich), 2,6-dichloro-pyrazine (Aldrich),
3-chloro-2,5-dimethylpyrazine (Aldrich), 2,4-dichloro-pyrimidine
(Aldrich), 4,6-dichloro-pyrimidine (Aldrich),
4-chloro-2-methyl-pyrimidine (Chem. Ber. 1904, 37, 3641),
4-chloro-6-methyl-pyrimidine (Chem. Ber. 1899, 32, 2931),
4-chloro-2,6-dimethyl-pyrimidine (J. Am. Chem. Soc. 1946, 68,
1299), 4-chloro-2,6-bis(trifluoromethyl)-pyrimidine (J. Org. Chem.
1961, 26, 4504), 4-chloro-2-methylsulfanyl-pyrimidine (Aldrich),
4-chloro-2-methoxymethyl-pyrimidine (U.S. Pat. No. 5,215,990),
1-chloro-isoquinoline (J. Am. Chem. Soc. 1946, 68, 1299),
2-chloro-quinoline (Aldrich), 4-chloro-quinazoline (J. Am. Chem.
Soc. 1909, 31, 509), 2-chloro-quinoxaline (U.S. Pat. No.
2,537,870), 2-chloro-3-methyl-quinoxaline (Aldrich),
2,6,7-trichloro-quinoxaline (J. Chem. Soc., Chem. Commun.
1956,4731), 4-chloro-pteridine (J. Chem. Soc., Chem. Commun. 1954,
3832), 7-chloro-pteridine (J. Chem. Soc., Chem. Commun. 1954,
3832), and 6-chloro-9H-purine (Aldrich). Other compounds of formula
5-1 can be prepared using methods well known to those skilled in
the art or by using methods analogous to those described in the
foregoing references.
[0182] Compounds of formula 5-3 are prepared by the displacement
reaction of a compound of formula 5-1 with an amine of the formula
5-2. The reaction is conducted in the presence of a non-aqueous
base, prefeably an organic amine such as pyridine,
4-dimethylaminopyridine, triethylamine or
N,N'-diisopropylethylamine; an inorganic base such as potassium or
sodium carbonate or bicarbonate; or an alkaline metal alkoxide such
as potassium t-butoxide. Alternatively, an excess of the reacting
amine 5-2 can be used in lieu of the added base. In cases where the
leaving group Lv.sup.3 is unactivated, or in specific cases which
will be recognized by those skilled in the art, the use of a
transition-metal catalyst such as palladium(0), palladium (II),
nickel(0) or nickel(II), along with phosphine-based ligands, such
as 2,2'-bis(diphenylphosphino)-1,1'-binapht- hyl (BINAP), may be
required to effect reaction. More specific details concerning this
reaction are available in the following references: J. Org. Chem.
1997, 62, 1264; J. Org. Chem. 1997, 62,1568; Syn Lett 1997, 329.
The reaction can be conducted in the absence of solvent or in a
reaction inert solvent. Preferable reaction inert solvents include
aqueous media, (C.sub.1-C.sub.4)alcohol, (C.sub.2-C.sub.6)glycol, a
halocarbon, an aliphatic or aromatic hydrocarbon, an ether, a polar
aprotic solvent, a ketone, or combinations thereof. The reaction
time ranges from 15 minutes to 3 days and the reaction temperature
ranges from 0.degree. C. to 180.degree. C. or to the reflux
temperature of the solvent being used. The reactions are preferably
conducted at ambient pressure.
[0183] In certain cases which will be recognized by those skilled
in the art, transformations of existing functionality in Ar.sup.1
of compound 5-3 may be necessary to produce compounds of formula
5-4. This pertains in particular to those cases where, for example,
R.sup.9 in 5-3 contains an aromatic or heteroaromatic halide,
(C.sub.1-C.sub.4)alkylsulfonate or triflate. Said compounds of
formula 5-3 wherein Ar.sup.1 contains up to two substituents
selected from halide, (C.sub.1-C.sub.4)alkylsulfonate or triflate,
may be converted to a compound of formula Ar.sup.1 where said
halide, (C.sub.1-C.sub.4)alkylsulfonate or triflate is transformed
into another functional group by a reduction reaction or by a
displacement reaction of said halide,
(C.sub.1-C.sub.4)alkylsulfonate or triflate with a nucleophile. The
reduction reaction is conducted with a reducing agent, preferably
ammonium formate or hydrogen gas, in a reaction inert solvent. The
reduction is conducted in the presence of a palladium catalyst at
ambient pressure or under a hydrogen pressure of up to 50 psi.
Preferred solvents include (C.sub.1-C.sub.4)alcohols such as
methanol and ethanol, and ether solvents such as diethyl ether,
dioxane and tetrahydrofuran. The nucleophilic displacement reaction
may be conducted by adding the nucleophile directly or by
pre-forming the nucleophile separately or in situ from a
nucleophile precursor. Preferred nucleophiles include
organoaluminum, organoboron, organocopper, organotin, organozinc or
Grignard reagent; R.sup.11-oxide or R.sup.11-thioxide; or anilino
where anilino is within the scope of R.sup.11. It will be
recognized by those skilled in the art that transition-metal
catalysts may be required to effect reaction in certain
displacement reactions. When required, such transition metal
catalysts may include palladium(0), palladium(II), nickel(0), and
nickel(II) complexes. Palladium(II) bis(diphenylphosphinobutane)
dichloride is a preferred such catalyst. Additionally, an aqueous
or non-aqueous base may be required in the displacement reaction.
Preferred such bases include sodium carbonate, sodium hydride,
triethylamine and sodium tert-butoxide. The reaction is conducted
at ambient pressure in a reaction inert solvent such as a
halocarbon, an aromatic or aliphatic hydrocarbon, an ether or a
polar aprotic solvent or a combination thereof. In certain cases, a
(C.sub.1-C.sub.4)alcohol is used as a solvent or co-solvent. The
reaction temperature ranges from -20.degree. C. to the reflux
temperature of the solvent employed. The reaction time ranges from
1 hour to 3 days.
[0184] Optional protecting groups which may be present in compounds
of formula 5-3 are removed according to methods set forth above, or
according to methods well known to those skilled in the art,
particularly as set forth in: Greene, T. W.; Wuts, P. G. M.
Protective Groups in Organic Synthesis, 2.sup.nd ed.; John Wiley
and Sons Inc.: New York, 1991.
[0185] Compounds of formula 5-4 are prepared from the displacement
reaction of amine 5-3 as described in Scheme 1, where the amine 5-3
is equivalent to R.sup.3--NH. A representative set of amines of
formula 5-3 which are commercially available or which can be
prepared by a literature procedure include 1-phenyl-piperazine
(Aldrich), 1-pyridin-2-yl-piperazin- e (Aldrich),
3-piperazin-1-yl-benzo[d]isoxazole (J. Med. Chem. 1986, 29, 359),
3-piperazin-1-yl-benzo[d]isothiazole (J. Med. Chem. 1986, 29, 359),
2-piperazin-1-yl-quinoxaline (J. Med. Chem. 1981, 24, 93),
1-naphthalen-2-yl-piperazine (cf. Tetrahedron Lett. 1994, 35,
7331), and 1-(3,5-dimethylphenyl)-piperazine (cf. Tetrahedron Lett.
1994, 35, 7331). Other compounds of formula 5-3 can be prepared
using methods well known to those skilled in the art or by using
methods analogous to those described in the foregoing
references.
[0186] Alternatively, compounds of formula 5-4 can be prepared from
reaction with compounds of formula 5-1 with compounds of formula
5-5 using conditions set forth above to prepare 5-3. Compounds of
formula 5-5 can be prepared in a manner analogous to the method
used to prepare compounds of formula 1-3.
[0187] Compounds of formula 5-4 wherein X is oxycarbonyl,
vinylenylcarbonyl, oxy(C.sub.1-C.sub.4)alkylenylcarbonyl,
(C.sub.1-C.sub.4)alkylenylcarbonyl,
(C.sub.3-C.sub.4)alkenylcarbonyl,
thio(C.sub.1-C.sub.4)alkenylcarbonyl, vinylenylsulfonyl or
carbonyl(C.sub.0-C.sub.4)alkylenylcarbonyl; wherein said
oxy(C.sub.1-C.sub.4)alkylenylcarbonyl,
(C.sub.1-C.sub.4)alkylenylcarbonyl- ,
(C.sub.3-C.sub.4)alkenylcarbonyl, and
thio(C.sub.3-C.sub.4)alkenylcarbon- yl in the definition of X are
each optionally and independently substituted with up to two
(C.sub.1-C.sub.4)alkyl, benzyl, or Ar; said vinylenylsulfonyl and
said vinylenylcarbonyl in the definition of X are each optionally
and independently substituted with up to three
(C.sub.1-C.sub.4)alkyl, benzyl, or Ar are also prepared according
to Scheme 5 above and particularly as described below.
[0188] Compounds of formula 5-4 where X is as defined in the
immediately preceding paragraph are prepared by reacting a compound
of formula 5-5 with a compound of formula 5-1 where R.sup.9 is
described above, X is as defined in the immediately preceding
paragraph and Lv.sup.3 is chloro. The reaction is conducted under
anhydrous conditions in the presence of a non-aqueous base, which
includes organic amines such as triethylamine,
N,N'-diisopropylethylamine and pyridine and derivatives thereof.
The reaction is generally conducted in a reaction inert solvent.
Preferred solvents include halocarbon, aliphatic or aromatic
hydrocarbon, ethers, ethyl acetate, pyridine and combinations
thereof. The reaction time ranges from 15 minutes to 24 hours and
the reaction temperature ranges from 0.degree. C. to 80.degree. C.
or to the reflux temperature of the solvent being used. The
reactions are preferably conducted at from 0.degree. C. to ambient
temperature and at ambient pressure. Removal of optional protecting
groups is carried out as described in Scheme I.
[0189] Compounds of formula 5-4 wherein X is vinylenylcarbonyl,
oxy(C.sub.1-C.sub.4)alkylenylcarbonyl,
(C.sub.1-C.sub.4)alkylenylcarbonyl- ,
(C.sub.3-C.sub.4)alkenylcarbonyl,
thio(C.sub.2-C.sub.4)alkenylcarbonyl, or
carbonyl(C.sub.0-C.sub.4)alkylenylcarbonyl,; wherein said
oxy(C.sub.1-C.sub.4)alkylenylcarbonyl,
(C.sub.1-C.sub.4)alkylenylcarbonyl- ,
(C.sub.3-C.sub.4)alkenylcarbonyl, and
thio(C.sub.2-C.sub.4)alkenylcarbon- yl in the definition of X are
each optionally and independently substituted with up to two
(C.sub.1-C.sub.4)alkyl, benzyl, or Ar; and said vinylenylcarbonyl
in the definition of X are each optionally and independently
substituted with up to three (C.sub.1-C.sub.4)alkyl, benzyl, or Ar
are also prepared according to Scheme 5 avove and particularly as
described below.
[0190] Compounds of formula 5-4 are prepared by reacting a compound
of formula 5-5 with a compound of formula R.sup.9--X-Lv.sup.3 where
R.sup.9 is described above, X is as defined in the immediately
preceding paragraph and Lv.sup.3 is OH. The reaction is conducted
in the presence of coupling agents, preferably
dicyclohexylcarbodiimide or
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride as
described in J. Amer. Chem. Soc. 1996, 118, 4952. The reaction is
conducted in a reaction inert solvent. Preferred solvents include
halocarbon, aliphatic or aromatic hydrocarbon and ethers.
Especially preferred solvents include dichloromethane and
chloroform. Other coupling agents that can be used are well known
to those skilled in the art and include, but are not limited to,
various phosphine reagents, ethyl chloroformate, and
N-hydroxysuccinimide. These reagents and procedures are described
in "Compendium of Organic Synthetic Methods" (Ed., I. T. Harrison
and S. Harrison, John Wiley & Sons). Specific references
include the following: J. Org. Chem, 1971, 36,1305; Bull. Soc.
Chim. Fr., 1971, 3034; Bull. Chem. Soc. Japan, 1971, 44, 1373;
Tetrahedron Lett., 1973, 28, 1595; Tetrahedron Lett., 1971, 26,
2967, and J. Med. Chem., 1968, 11, 534. Removal of optional
protecting groups is carried out as described in Scheme I.
[0191] Compounds of formula 5-4 wherein X is a covalent bond and
R.sup.9 is (C.sub.3-C.sub.7)cycloalkyl or
Ar.sup.1--(C.sub.1-C.sub.3)alkylenyl are also prepared according to
Scheme 5 above and particularly as described below.
[0192] Compounds of formula 5-4 wherein X is a covalent bond and
R.sup.9 is (C.sub.3-C.sub.7)cycloalkyl or
Ar.sup.1--(C.sub.1-C.sub.3)alkylenyl are prepared by reacting a
compound of formula 5-1 wherein X is a covalent bond, R.sup.9 is
(C.sub.3-C.sub.7)cycloalkyl or Ar.sup.2--(C.sub.1-C.sub.3)alkylenyl
and Lv.sup.3 is halo, methanesulfonate, p-toluenesulfonate or
trifluoromethanesulfonate. The reaction is conducted under
anhydrous conditions in the presence of a non-aqueous base, which
includes organic amines such as triethylamine,
N,N'-diisopropylethylamine and pyridine and derivatives thereof.
The reaction is conducted in a reaction inert solvent. Preferred
solvents for the reaction include halocarbons, aliphatic or
aromatic hydrocarbons, ethers, ethyl acetate, pyridine and
combinations thereof. The reaction time ranges from 15 minutes to
24 hours and the reaction temperature ranges from -20.degree. C. to
80.degree. C. or to the reflux temperature of the solvent being
used. The reactions are preferably conducted at ambient temperature
of the solvent being used and at ambient pressure. Removal of
optional protecting groups is conducted as set forth in Scheme I.
21
[0193] Compounds of formula 6-5 wherein G, G.sup.1, G.sup.2, q,
R.sup.1, R.sup.2, R.sup.6, R.sup.7 and R.sup.8 are as defined above
are prepared as set forth in Scheme 6 above and particularly as
described below.
[0194] Compounds of formula 6-1 are prepared from an amine of the
formula 5-2 where Prt is an optional amine protecting group
selected from benzyl and CO.sub.2R.sup.90, where R.sup.90 is
selected from (C.sub.1-C.sub.4)alkyl, (C.sub.1-C.sub.4)allyl,
trichloroethyl and benzyl substituted with up to two
(C.sub.1-C.sub.4)alkoxy. The preferred procedure for preparing
compounds of formula 6-1 can be found in Tetrahedron Lett. 1993,
48, 7767 or J. Org. Chem 1997, 62, 1540.
[0195] Compounds of formula 6-3 are prepared by condensation of
.beta.-diketones or .beta.-ketoesters of the formula 6-2b, where
R.sup.11 and R.sup.12 are independently substituted as set forth
above, or compounds of the formula 6-2a Where Lv.sup.4 is, for
example, hydroxy, chloro or dimethylamino with guanidines of the
formula 6-1. The reaction is conducted in the presence of an
aqueous or non-aqueous base, preferably potassium or sodium
hydroxide, potassium or sodium (C.sub.1-C.sub.4)-alkoxide,
triethylamine, pyridine, 4-dimethylaminopyridine, potassium or
sodium carbonate or potassium or sodium bicarbonate. The reaction
is conducted in a reaction inert solvent, preferably aqueous media,
a (C.sub.1-C.sub.4)alcohol, a (C.sub.2-C.sub.6)dialcohol, an
aromatic hydrocarbon, a polar aprotic solvent, or combinations
thereof. The reaction time ranges from 2 hours to 3 days and the
reaction temperature ranges from room temperature to reflux of the
solvent employed. The reaction is preferably run at ambient
pressure, but may be conducted at pressures up to 250 psi.
[0196] Removal of of optional protecting groups in compounds of
formula 6-3 to afford compounds of formula 6-4 is accomplished as
set forth above.
[0197] Compounds of formula 6-5 are prepared from the displacement
reaction of amine 6-4 as described in Scheme 1, where the amine 6-4
is equivalent to R.sup.3--NH.
[0198] Alternatively, compounds of formula 6-5 are prepared from
compounds of formula 5-5 by formation of a compound of formula 6-6,
or by reaction with compounds of formula 6-2a or 6-2b under the
conditions outlined above in Scheme 6. Removal of optional
protecting groups is conducted as described in Scheme 1. Compounds
of formula 5-5 are prepared as set forth above. 22
[0199] Compounds of formula 7-4 wherein G.sup.3, G.sup.4, G.sup.5,
r, R.sup.1, R.sup.2, R.sup.18, R.sup.19 and R.sup.20 are defined as
set forth above are prepared as set forth in Scheme 7 and
particularly as described below.
[0200] Compounds of formula 7-1 are prepared by reaction of an
amine of the formula 7-0 with phosgene or a phosgene equivalent
such as triphosgene. Compounds of 7-1 wherein the chloro group is
replaced by an imidazolyl group are also useful in this reaction.
Such compounds are prepared by reaction of an amine of formula 7-0
with carbonyl diimidazole. The reaction is conducted under
anhydrous conditions in the presence of a nonaqueous base.
Preferred such bases include triethylamine and other tertiary
amines and pyridine and derivatives thereof. The reaction is
conducted in a reaction inert solvent at -78.degree. C. to
80.degree. C. or at the reflux temperature of the solvent being
used for 15 minutes to 24 hours. Preferred solvents for this
reaction include a halocarbon, an aliphatic or aromatic
hydrocarbon, an ether, ethyl acetate, pyridine and combinations
thereof. The reactions are preferably conducted at from 0.degree.
C. to ambient temperature and at ambient pressure.
[0201] Compounds of formula 7-4 are prepared by reaction of
carbamoyl chlorides of the formula 7-1 with amines of the formula
7-3, where R.sup.21 and R.sup.22 are defined above. The reaction
can be conducted in the absence of solvent, or in a reaction inert
solvent. Preferred such solvents include aqueous media, a
(C.sub.1-C.sub.4)alcohol, a (C.sub.2-C.sub.6)dialcohol, an aromatic
or aliphatic hydrocarbon, a halocarbon, an ether, a polar aprotic
solvent, a ketone, pyridine or combinations thereof. The reaction
time ranges from 15 minutes to 3 days and the reaction temperature
ranges from 0.degree. C. to the reflux temperature of the solvent
being used. The reaction is preferably conducted at ambient
pressure. It will be recognized by those skilled in the art that
addition of a base may be required to effect reaction. In those
cases, preferred bases include potassium or sodium hydroxide,
triethylamine and other tertiary amines, pyridine and its
derivatives and inorganic bases such as sodium or potassium
carbonate and sodium or potassium bicarbonate. Removal of optional
hydroxyl protecting groups contained in R.sup.1 is carried out
according to methods set forth in Scheme 1.
[0202] Alternatively, compounds of formula 7-4 are prepared from
compounds of formula 7-0 by reaction with isocyanates of the
formula 7-6 or with carbamoyl chlorides of the formula 7-8. Said
isocyanates are commercially available, known in the literature, or
synthesized under standard conditions known to those skilled in the
art, particularly as described in March, J. Advanced Organic
Chemistry, 3.sup.rd ed.; John Wiley and Sons Inc.: New York, 1985,
p 1166. A preferred method of forming such isocyanates is the
Curtius rearrangement of a suitable acyl azide. Said carbamoyl
chlorides are synthesized using methods analogous to that described
for the preparation of compounds of formula 7-1 in Scheme 7.
Removal of optional hydroxyl protecting groups contained in R.sup.1
is carried out according to methods set forth in Scheme 1.
[0203] Compounds of formula I containing the radical R.sup.3c are
prepared according to the procedures set forth in Scheme 7 using
the corresponding starting materials and reagents. 23
[0204] Compounds of formula 8-5 are prepared as set forth in Scheme
8 and particularly as described below.
[0205] Compounds of formula 8-2 are readily prepared from
commercially available phenethylamines of formula 8-1a and
formaldehyde or an aldehyde of the formula R.sup.27--CHO under
Pictet-Spengler conditions. The Pictet-Spengler reaction is
reviewed in Chem. Rev. 1995, 95, 1797. A similar route route to
1,2,3,4-tetrahydroisoquinolines using the Bischler-Napieralski
reaction, as disclosed in March, J. Advanced Organic Chemistry,
3.sup.rd ed.; John Wiley and Sons.: New York, 1985, 495, followed
by standard reduction of the imine formed may also be employed.
[0206] Compounds of formula 8-4 are prepared from compounds of
formula 8-3 by aromatic electrophilic substitution using the
appropriate electrophile. A general reference for this type of
reaction can be found in March, J. Advanced Organic Chemistry,
3.sup.rd ed.; John Wiley and Sons.: New York, 1985, 447-511.
[0207] Compounds of formula 8-2 are also prepared by removal of the
protecting group from a compound of formula 8-4. Preferably the
protecting group is trifluoroacetamide which may be removed under
basic conditions using inorganic hydroxides or carbonates in a
reaction inert solvent. Suitable such solvents include
(C.sub.1-C.sub.4)alcohols and preferably methanol. Optionally, one
or more co-solvents, preferably selected from water,
tetrahydrofuran and dioxane may be employed. The reaction time
ranges from 15 minutes to 24 hours and the reaction temperature
ranges from 0.degree. C. to 100.degree. C. or to the reflux
temperature of the solvent or solvent system being used. The
reaction is preferably conducted at ambient temperature. Other
conditions for deprotection of trifluoroacetamides and deprotection
conditions for other suitable protecting groups can be found in
Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2.sup.nd ed.; John Wiley and Sons Inc.: New York,
1991.
[0208] Compounds of formula 8-4 are prepared by adding a protecting
group to compounds of formula 8-2. Preferably the protecting group
is trifluoroacetamide or tert-butoxycarbonyl (BOC). The protecting
group is attached by reaction of a compound of formula 8-2 with
trifluoroacetyl chloride or di-tert-butyl dicarbonate or an
equivalent thereof in the presence of a base, preferably
triethylamine or pyridine. The reaction is conducted in a reaction
inert solvent. Preferred such solvents include ethers such as
tetrahydrofuran, diethyl ether, dioxane or dimethoxyethane; a
halocarbon such as dichloromethane, chloroform or carbon
tetrachloride; and aromatic or aliphatic hydrocarbons such as
benzene, toluene or hexanes. The reaction time ranges from 15
minutes to 3 days and the reaction temperature ranges from
0.degree. C. to the reflux temperature of the solvent being used.
The reaction is preferably conducted at ambient pressure. Other
conditions for protection of amines with trifluoroacetamides or
tert-butoxycarbonyl groups as well as other suitable protecting
groups can be found in Greene, T. W.; Wuts, P. G. M. Protective
Groups in Organic Synthesis, 2.sup.nd ed.; John Wiley and Sons
Inc.: New York, 1991.
[0209] Manipulation of the substituents R.sup.28 and R.sup.29 is
carried out to provide isoquinolines with altered substitution.
Preferably, transition metal-catalyzed cross-coupling of a compound
of formula 8-4 where R.sup.28 or R.sup.29 is bromide or triflate is
employed to afford compounds of formula 8-4 wherein R.sup.28 or
R.sup.29 are as set forth above. This reaction is conducted
according to methods well known to those skilled in the art,
particularly as set forth in Tetrahedron, 1998, 54, 263 for Stille
and Suzuki Reactions and in Acc. Chem. Res. 1998, 31, 805 for
Buchwald Amination Reactions.
[0210] Compounds of formula 8-5 are prepared from the displacement
reaction of amine 8-2 as described in Scheme 1, where the amine 8-2
is equivalent to R.sup.3--NH. 24
[0211] Compounds of formula 9-3 are prepared according to the
general procedures set forth in Scheme 2 starting from ethyl
1-benzyl-4-oxo-3-piperidine carboxylate hydrochloride (9-1). In
certain cases, where R.sup.29 is H,
N-tertbutoxycarbonyl-3-(dimethylaminomethylen- e)-4-piperidone
(9-2, Chemical Abstracts 121:157661) is used as the starting
material. 25
[0212] Compounds of formula 10-6 wherein R.sup.1, R.sup.2, R.sup.32
and R.sup.33 are as defined above are prepared as set forth in
Scheme 10 and more particularly as described below.
[0213] Compounds of formula 10-2 where R.sup.91 is
(C.sub.1-C.sub.4)alkyl are prepared by reacting a compound of
formula 10-1, where Cbz is benzyloxycarbonyl, with an O-alkylating
agent. A preferred compound of formula 10-1 is
3-oxo-piperazine-1-carboxylic acid benzyl ester. A preferred
O-alkylating agent is triethyloxonium tetrafluoroborate. The
reaction is conducted at ambient pressure in a reaction inert
solvent. Preferred solvents include an aromatic or aliphatic
hydrocarbons, halocarbons and ethers. Dichloromethane is especially
preferred. The reaction time ranges from 2 hours to 3 days and the
reaction temperature ranges from -100.degree. C. to ambient
temperature.
[0214] Compounds of formula 10-4 are prepared by condensation of a
compound of formula 10-2 with a compound of formula 10-3. Said
compounds of formula 10-3 are commercially available, are known in
the literature, or are readily prepared via standard amidation of
hydrazine and an activated carboxylic acid, such as a carboxylic
acid chloride. Such reactions are well known by those skilled in
the art. The condensation reaction is preferably run at ambient
pressure, although higher pressures up to 250 psi may be employed
if necessary. The reaction is conducted in a reaction inert
solvent, preferably selected from (C.sub.1-C.sub.4)alcohols,
aromatic or aliphatic hydrocarbons, polar aprotic media,
halocarbons and ethers, or combinations thereof. The reaction is
conducted at temperatures ranging from ambient temperature to
180.degree. C. The reaction times are from 2 hours to 3 days.
[0215] Compounds of formula 10-5 are prepared form compounds of
formula 10-4 via Lewis acid-catalyzed cleavage or hydrogenolysis of
the Cbz carbamate under standard conditions which are well known to
those skilled in the art, particularly as set forth in Greene, T.
W.; Wuts, P. G. M. Protective Groups in Organic Synthesis, 2.sup.nd
ed.; John Wiley and Sons Inc.: New York, 1991, pp 335-338.
[0216] Compounds of formula 10-6 are prepared from the displacement
reaction of an amine of the formula 10-5 as described in Scheme 1,
where the amine 10-5 is equivalent to R.sup.3--NH. 26
[0217] Compounds of formula 11-4, wherein R.sup.1, R.sup.2,
R.sup.36, R.sup.37, R.sup.38, R.sup.39 and R.sup.40 are as defined
above are prepared as set forth in Scheme 11 and more particularly
as described below.
[0218] Where R.sup.38 and R.sup.39 are hydrogen,
1-benzyl-4-piperidone (3-1), available from Aldrich, is condensed
with a compound of formula 11-1, which are either commercially
available or well known to those skilled in the art, to give
compounds of formula 11-2. Where R.sup.38 and R.sup.39 are not
hydrogen, compounds of formula 3-1 can be prepared according to
methods well known to those skilled in the art. The reaction is
conducted at ambient pressure in the absence of solvent or in a
reaction inert solvent. Preferred solvents include
(C.sub.1-C.sub.4)alcohols, aromatic or aliphatic hydrocarbons,
polar aprotic solvents, halocarbons and ethers. The reaction time
ranges from 2 hours to 3 days and the reaction temperature ranges
from ambient temperature to the reflux temperature of the solvent
being employed. More specific conditions can be found in Indian J.
Chem. 1976, 14B, 984 and J. Chem. Soc., Perkin Trans. 1 1984,
2465.
[0219] Compounds of formula 11-3 are prepared by removal of the
benzyl protecting group from a compound of formula 11-2 in a manner
analogous to the method employed for the preparation of compounds
of 2-6 described above.
[0220] Compounds of formula 11-4 are prepared by the displacement
reaction of an amine of the formula 11-3 as described in Scheme 1,
where the amine 11-3 is equivalent to R.sup.3--H. 27
[0221] Compounds of formula 12-3 and 12-3a where R.sup.17 and
R.sup.23 are (C.sub.1-C.sub.6)alkoxycarbonyl,
(C.sub.1-C.sub.6)alkylcarbonyl, Ar.sup.2-carbonyl,
(C.sub.1-C.sub.6)alkylsulfonyl, Ar.sup.2-sulfonyl, or
Ar.sup.2-sulfinyl are prepared according to Scheme 12 above and
particularly as set forth below.
[0222] Compounds of formula 12-3 and 12-3a where R.sup.17 and
R.sup.23 are as defined in the immediately preceding paragraph are
prepared by condensation with a compound of formula 12-2 and 12-2a,
wherein Lv.sup.4 is chloro, respectively. Examples of compounds of
formula 12-2 and 12-2a include (C.sub.1-C.sub.6)alkoxyCOCl,
(C.sub.1-C.sub.6)alkylCOCl, Ar.sup.2--COCl,
(C.sub.1-C.sub.6)alkylSO.sub.2Cl, Ar.sup.2--SO.sub.2Cl, or
Ar.sup.2--SOCl. The reaction is conducted under anhydrous
conditions in the presence of a non-aqueous base, which includes
organic amines such as triethylamine, N,N'-diisopropylethylamine
and pyridine and derivatives thereof. The reaction is conducted in
a reaction inert solvent. Preferred solvents for the reaction
include halocarbon, aliphatic or aromatic hydrocarbon, ethers,
ethyl acetate, pyridine and combinations thereof. The reaction time
ranges from 15 minutes to 24 hours and the reaction temperature
ranges from 0.degree. C. to 80.degree. C. or to the reflux
temperature of the solvent being used. The reactions are preferably
conducted at from 0.degree. C. to ambient temperature and at
ambient pressure. Removal of optional protecting groups is carried
out as described in Scheme I.
[0223] Compounds of formula 12-3 and 12-3a wherein R.sup.17 and
R.sup.23 are (C.sub.1-C.sub.6)alkylcarbonyl or Ar.sup.2-carbonyl
are also prepared according to Scheme 12 above and particularly as
described below.
[0224] Compounds of formula 12-3 and 12-3a wherein R.sup.17 and
R.sup.23 are (C.sub.1-C.sub.6)alkylcarbonyl or Ar.sup.2-carbonyl
are prepared by a condensation reaction with a compound of formula
12-2 or 12-2a, respectively, wherein Lv.sup.4 is hydroxy in the
presence of coupling agents such as dicyclohexylcarbodiimide or
1-(3-dimethylaminopropyl)-3-et- hylcarbodiimide hydrochloride. The
reaction is conducted in a reaction inert solvent. Preferred
solvents include halocarbon, aliphatic/aromatic hydrocarbons and
ethers. Especially preferred solvents include dichloromethane and
chloroform. Other coupling agents that can be used are well known
to those skilled in the art and include, but are not limited to,
various phosphine reagents, ethyl chloroformate, and
N-hydroxysuccinimide. Removal of optional protecting groups is
carried out as described in Scheme I.
[0225] Compounds of formula 12-3 where R.sup.17 is
(C.sub.1-C.sub.6)alkyyl are also prepared according to Scheme 12
and particularly as described below.
[0226] Compounds of formula 12-3 where R.sup.17 is
(C.sub.1-C.sub.6)alkyl are prepared by reacting a compound of
formula 12-1 with a compound of formula 12-2 where R.sup.17 is
(C.sub.1-C.sub.4)alkyl and Lv.sup.4 is Cl, Br, I,
methanesulfonyloxy, p-toluenesulfonyloxy or
trifluoromethanesulfonyloxy. The reaction is conducted under
anhydrous conditions in the presence of a nonaqueous base, which
includes organic amines such as triethylamine, Hunig's base and
pyridine and derivatives thereof. The reaction is conducted in a
reaction inert solvent. Preferred solvents for the reaction include
halocarbons, aliphatic or aromatic hydrocarbons, ethers, ethyl
acetate, pyridine and combinations thereof. The reaction time
ranges from 15 minutes to 24 hours and the reaction temperature
ranges from ambient temperature to 80.degree. C. or to the reflux
temperature of the solvent being used. The reactions are preferably
conducted at ambient temperature and pressure.
[0227] The starting materials and reagents for the above described
compounds are also readily available or can be easily synthesized
by those skilled in the art using conventional methods of organic
synthesis. For example, many of the compounds used herein are
related to, or are derived from, compounds found in nature, in
which there is a large scientific interest and commercial need, and
accordingly many such compounds are commercially available or are
reported in the literature or are easily prepared from other
commonly available substances by methods which are reported in the
literature.
[0228] The compounds of the instant invention inhibit the formation
of sorbitol dehydrogenase and as such have utility in the treatment
of diabetic complications including but not limited to such
complications as diabetic nephropathy, diabetic neuropathy,
diabetic retinopathy, diabetic microangiopathy and diabetic
macroangiopathy and diabetic cardiomyopathy. The utility of the
compounds of the present invention as medical agents in the
treatment of diseases, such as are detailed herein in mammals
(e.g., humans) for example, diabetic complications such as diabetic
cardiomyopathy, diabetic neuropathy, diabetic nephropathy, diabetic
retinopathy, diabetic microangiopathy and diabetic macroangiopathy
is demonstrated by the activity of the compounds of formula I of
this invention in conventional assays. Such assays also provide a
means whereby the activities of the compounds of formula I of this
invention can be compared with the activities of other known
compounds. The results of these comparisons are useful for
determining dosage levels in mammals, including humans, for the
treatment of such diseases.
Measurement of SDH Activity
[0229] Male Sprague-Dawley rats (350-400 g) are used for these
experiments. Diabetes is induced in some of the rats by a tail vein
injection of streptozocin, 85 mg/kg. Twenty-four hours later, 4
groups of diabetic rats are given a single dose of the test
compound of formula I of this invention (0.001 to 100 mg/kg) by
oral gavage. Animals are sacrificed 4-6 hours after dosing and
blood and sciatic nerves are harvested. Tissues and cells are
extracted with 6% perchloric acid.
[0230] Sorbitol in erythrocytes and nerves is measured by a
modification of the method of R. S. Clements et al. (Science, 166:
1007-8, 1969). Aliquots of tissue extracts are added to an assay
system which has final concentrations of reagents of 0.033 M
glycine, pH 9.4, 800 mM .beta.-nicotine adenine dinucleotide, and 4
units/ml of sorbitol dehydrogenase. After incubation for 30 minutes
at room temperature, sample fluorescence is determined on a
fluorescence spectrophotometer with excitation at 366 nm and
emission at 452 nm. After subtracting appropriate blanks, the
amount of sorbitol in each sample is determined from a linear
regression of sorbitol standards processed in the same manner as
the tissue extracts.
[0231] Fructose is determined by a modification of the method
described by M. Ameyama, Methods in Enzymology, 89: 20-25 (1982).
Resazurin is substituted for ferricyanide. Aliquots of tissue
extracts are added to the assay system, which has final
concentrations of reagents of 1.2 M citric acid, pH 4.5, 13 mM
resazurin, 3.3 units/ml of fructose dehydrogenase and 0.068% Triton
X-100. After incubation for 60 minutes at room temperature, sample
fluorescence is determined on a fluorescence spectrophotometer with
excitation at 560 nm and emission at 580 nm. After subtracting
appropriate blanks, the amount of fructose in each sample is
determined from a linear regression of fructose standards processed
in the same manner as the tissue extracts.
[0232] SDH activity is measured by a modification of the method
described by U. Gerlach, Methodology of Enzymatic Analyses, edited
by H. U. Bergmeyer, 3, 112-117 (1983). Aliquots of sera or urine
are added to the assay system, which has final concentrations of
reagents of 0.1 M potassium phosphate buffer, pH 7.4, 5 mM NAD, 20
mM sorbitol, and 0.7 units/ml of sorbitol dehydrogenase. After
incubation for 10 minutes at room temperature, the average change
in sample absorbance is determined at 340 nm. SDH activity was
presented as milliOD.sub.340 units/minute (OD.sub.340=optical
density at 340 nm).
[0233] The expression "pharmaceutically acceptable salts" includes
both pharmaceutically acceptable acid addition salts and
pharmaceutically acceptable cationic salts, where appropriate. The
expression "pharmaceutically-acceptable cationic salts" is intended
to define but is not limited to such salts as the alkali metal
salts, (e.g., sodium and potassium), alkaline earth metal salts
(e.g., calcium and magnesium), aluminum salts, ammonium salts, and
salts with organic amines such as benzathine
(N,N'-dibenzylethylenediamine), choline, ethanolamine,
ethylenediamine, meglumine (N-methylglucamine), benethamine
(N-benzylphenethylamine), diethylamine, piperazine, tromethamine
(2-amino-2-hydroxymethyl-1,3-propanediol) and procaine. The
expression "pharmaceutically-acceptable acid addition salts" is
intended to define but is not limited to such salts as the
hydrochloride, hydrobromide, sulfate, hydrogen sulfate, phosphate,
hydrogen phosphate, dihydrogenphosphate, acetate, succinate,
citrate, methanesulfonate (mesylate) and p-toluenesulfonate
(tosylate) salts.
[0234] Pharmaceutically acceptable salts of the second
pharmaceutical agents of this invention may be readily prepared by
reacting the free acid form of said second pharmaceutical agent
with an appropriate base, usually one equivalent, in a co-solvent.
Typical bases are sodium hydroxide, sodium methoxide, sodium
ethoxide, sodium hydride, potassium methoxide, magnesium hydroxide,
calcium hydroxide, benzathine, choline, ethanolamine, piperazine
and tromethamine. The salt is isolated by concentration to dryness
or by addition of a non-solvent. In many cases, salts are
preferably prepared by mixing a solution of the acid with a
solution of a different salt of the cation (sodium or potassium
ethylhexanoate, magnesium oleate), and employing a solvent (e.g.,
ethyl acetate) from which the desired cationic salt precipitates,
or can be otherwise isolated by concentration and/or addition of a
non-solvent.
[0235] The acid addition salts of the second pharmaceutical agents
of this invention may be readily prepared by reacting the free base
form of said second pharmaceutical agent with the appropriate acid.
When the salt is of a monobasic acid (e.g., the hydrochloride, the
hydrobromide, the p-toluenesulfonate, the acetate), the hydrogen
form of a dibasic acid (e.g., the hydrogen sulfate, the succinate)
or the dihydrogen form of a tribasic acid (e.g., the dihydrogen
phosphate, the citrate), at least one molar equivalent and usually
a molar excess of the acid is employed. However when such salts as
the sulfate, the hemisuccinate, the hydrogen phosphate or the
phosphate are desired, the appropriate and exact chemical
equivalents of acid will generally be used. The free base and the
acid are usually combined in a co-solvent from which the desired
salt precipitates, or can be otherwise isolated by concentration
and/or addition of a non-solvent.
[0236] In addition, zopolrestat ethanolamine, zopolrestat
diethanolamine, zopolrestat triethanolamine and the second
pharmaceutical agents which may be used in accordance with this
invention, prodrugs of said second pharmaceutical agents and
pharmaceutically acceptable salts of said second pharmaceutical
agents or of said prodrugs, may occur as hydrates or solvates. Said
hydrates and solvates are also within the scope of the
invention.
[0237] This invention relates to methods of treating diabetic
complications in which zopolrestat ethanolamine, zopolrestat
diethanoalamine or zopolrestat triethanolamine is administered.
Generally, in carrying out the methods of this invention, an
effective dosage for zopolrestat ethanolamine, zopolrestat
diethanolamine or zopolrestat triethanolamine is in the range of
about 0.1 mg/kg/day to about 100 mg/kg/day in single or divided
doses, preferably 0.1 mg/kg/day to about 20 mg/kg/day in single or
divided doses.
[0238] This invention also relates both to methods of treating
diabetic complications in which zopoirestat ethanolamine,
zopolrestat diethanolamine or zopolrestat triethanolamine and the
second pharmaceutical agent are administered together, as part of
the same pharmaceutical composition, and to methods in which these
two agents are administered separately, in any order, as part of an
appropriate dosage regimen designed to obtain the benefits of the
combination therapy. The appropriate dosage regimen, the amount of
each dose administered and the intervals between doses of the
active agents will depend upon the second pharmaceutical agent
being used, the type of pharmaceutical formulations being used, the
characteristics of the subject being treated and the severity of
the complications. Generally, in carrying out the methods of this
invention, an effective dosage for zopolrestat ethanolamine,
zopolrestat diethanolamine or zopolrestat triethanolamine is in the
range of about 0.1 mg/kg/day to about 100 mg/kg/day in single or
divided doses, preferably 0.1 mg/kg/day to 20 mg/kg/day in single
or divided doses.
[0239] When the second pharmaceutical agent is a SSRI, the SSRI
will be administered in single or divided doses. SSRIs will
generally be administered in amounts ranging from about 0.01
mg/kg/day to about 500 mg/kg/day in single or divided doses,
preferably 10 mg/kg to about 300 mg/kg per day for an average
subject, depending upon the SSRI and the route of administration.
However, some variation in dosage will necessarily occur depending
on the condition of the subject being treated. The prescribing
physician will, in any event, determine the appropriate dose for
the individual subject.
[0240] When the second pharmaceutical agent is a NHE-1 inhibitor,
the NHE-1 inhibitor will be administered in single or divided
doses. NHE-1 inhibitors will generally be administered in amounts
ranging from about 0.001 mg/kg/day to about 100 mg/kg/day in single
or divided doses, preferably 0.01 mg/kg to about 50 mg/kg per day
for an average subject, depending upon the NHE-1 inhibitor and the
route of administration. However, some variation in dosage will
necessarily occur depending on the condition of the subject being
treated. The prescribing physician will, in any event, determine
the appropriate dose for the individual subject.
[0241] When the second pharmaceutical agent is a GPI, the GPI will
be administered in single or divided doses. GPI s will generally be
administered in amounts ranging from about 0.005 mg/kg/day to about
50 mg/kg/day in single or divided doses, preferably 0.01 mg/kg to
about 25 mg/kg per day for an average subject and most preferably
0.1 mg/kg to about 15 mg/kg per day for an average subject,
depending upon the GPI and the route of administration. However,
some variation in dosage will necessarily occur depending on the
condition of the subject being treated. The prescribing physician
will, in any event, determine the appropriate dose for the
individual subject.
[0242] When the second pharmaceutical agent is a SDI, the SDI will
be administered in single or divided doses. SDIs will generally be
administered in amounts ranging from about 0.001 mg/kg/day to about
100 mg/kg/day in single or divided doses, preferably 0.01 mg/kg to
about 10 mg/kg per day for an average subject, depending upon the
SDI and the route of administration. However, some variation in
dosage will necessarily occur depending on the condition of the
subject being treated. The prescribing physician will, in any
event, determine the appropriate dose for the individual
subject.
[0243] When the second pharmaceutical agent is an antihypertensive
agent, the antihypertensive agent will be administered in single or
divided doses. Antihypertensive agents will generally be
administered in amounts ranging from about 0.01 mg/kg/day to about
500 mg/kg/day in single or divided doses, preferably 10 mg to about
300 mg per day for an average subject, depending upon the
antihypertensive agent and the route of administration. However,
some variation in dosage will necessarily occur depending on the
condition of the subject being treated. The prescribing physician
will, in any event, determine the appropriate dose for the
individual subject.
[0244] Administration of zopolrestat ethanolamine, zopolrestat
diethanolamine or zopolrestat triethanolamine and of the
combination of one of said salts of zopolrestat and the second
pharmaceutical agents of this invention can be via any method which
delivers said zopolrestat ethanolamine, zopolrestat diethanolamine,
zopolrestat triethanolamine or said combinations of this invention
preferentially to the desired tissue (e.g., nerve, kidney, retina
and/or cardiac tissues). These methods include oral routes,
parenteral, intraduodenal routes, etc. Generally, zopolrestat
ethanolamine, zopolrestat diethanolamine or zopolrestat
triethanolamine and the combinations of the present invention are
administered in single (e.g., once daily) or multiple doses or via
constant infusion.
[0245] Pharmaceutical compositions comprising zopolrestat
ethanolamine, zopolrestat diethanolamine, zopolrestat
triethanolamine or a combination of one of said salts of
zopolrestat and a second pharmaceutical agent of this invention are
hereinafter referred to, collectively, as "the active compositions
of this invention."
[0246] The active compositions of this invention may be
administered to a subject in need of treatment by a variety of
conventional routes of administration, including orally, topically,
parenterally, e.g., intravenously, subcutaneously or
intramedullary. Further, the active compositions of this invention
may be administered intranasally, as a rectal suppository or using
a "flash" formulation, i.e., allowing the medication to dissolve in
the mouth without the need to use water.
[0247] The active compositions of this invention may be
administered alone or in combination with pharmaceutically
acceptable carriers, vehicles or diluents, in either single or
multiple doses. Suitable pharmaceutical carriers, vehicles and
diluents include inert solid diluents or fillers, sterile aqueous
solutions and various organic solvents. The pharmaceutical
compositions formed by combining the active compositions of this
invention and the pharmaceutically acceptable carriers, vehicles or
diluents are then readily administered in a variety of dosage forms
such as tablets, powders, lozenges, syrups, injectable solutions
and the like. These pharmaceutical compositions can, if desired,
contain additional ingredients such as flavorings, binders,
excipients and the like. Thus, for purposes of oral administration,
tablets containing various excipients such as sodium citrate,
calcium carbonate and calcium phosphate may be employed along with
various disintegrants such as starch, alginic acid and certain
complex silicates, together with binding agents such as
polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally,
lubricating agents such as magnesium stearate, sodium lauryl
sulfate and talc are often useful for tabletting purposes. Solid
compositions of a similar type may also be employed as fillers in
soft and hard filled gelatin capsules. Preferred materials for this
include lactose or milk sugar and high molecular weight
polyethylene glycols. When aqueous suspensions or elixirs are
desired for oral administration, the essential active ingredient
therein may be combined with various sweetening or flavoring
agents, coloring matter or dyes and, if desired, emulsifying or
suspending agents, together with diluents such as water, ethanol,
propylene glycol, glycerin and combinations thereof.
[0248] For parenteral administration, solutions of the active
compositions of this invention in sesame or peanut oil, aqueous
propylene glycol, or in sterile aqueous solutions may be employed.
Such aqueous solutions should be suitably buffered if necessary and
the liquid diluent first rendered isotonic with sufficient saline
or glucose. These particular aqueous solutions are especially
suitable for intravenous, intramuscular, subcutaneous and
intraperitoneal administration. In this connection, the sterile
aqueous media employed are all readily available by standard
techniques known to those skilled in the art.
[0249] Generally, an active composition of this invention is
administered orally, or parenterally (e.g., intravenous,
intramuscular, subcutaneous or intramedullary). Topical
administration may also be indicated, for example, where the
patient is suffering from gastrointestinal disorders or Whenever
the medication is best applied to the surface of a tissue or organ
as determined by the attending physician.
[0250] For buccal administration the active composition of this
invention (two active agents administered together or separately)
may take the form of tablets or lozenges formulated in a
conventional manner.
[0251] For intranasal administration or administration by
inhalation, the active compositions of the invention (two active
agents administered together or separately) are conveniently
delivered in the form of a solution or suspension from a pump spray
container that is squeezed or pumped by the patient or as an
aerosol spray presentation from a pressurized container or a
nebulizer, with the use of a suitable propellant, e.g.,
dichlorodifluoromethane, trichlorofluoromethane,
dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In
the case of a pressurized aerosol, the dosage unit may be
determined by providing a valve to deliver a metered amount. The
pressurized container or nebulizer may contain a solution or
suspension of the active compound or combination of compounds.
Capsules and cartridges (made, for example, from gelatin) for use
in an inhaler or insufflator may be formulated containing a powder
mix of a compound or compounds of the invention and a suitable
powder base such as lactose or starch.
[0252] For purposes of transdermal (e.g., topical) administration,
dilute sterile, aqueous or partially aqueous solutions (usually in
about 0.1% to 5% concentration), otherwise similar to the above
parenteral solutions, are prepared.
[0253] Methods of preparing various pharmaceutical compositions
with a certain amount of active ingredient are known, or will be
apparent in light of this disclosure, to those skilled in this art.
For examples of methods of preparing pharmaceutical compositions,
see Remington's Pharmaceutical Sciences, Mack Publishing Company,
Easton, Pa., 19th Edition (1995).
[0254] The active compositions of this invention contain an amount
of both zopolrestat ethanolamine, zopolrestat diethanolamine or
zopolrestat triethanolamine or an amount of one of said salts of
zopolrestat and a second pharmaceutical agent of this invention.
The amount of each of those ingredients may independently be, for
example, 0.0001%-95% of the total amount of the composition, where
the total amount may not, of course, exceed 100%. In any event, the
composition or formulation to be administered will contain a
quantity of each of the components of the composition according to
the invention in an amount effective to treat the disease/condition
of the subject being treated.
[0255] Since the present invention has an aspect that relates to
the treatment of the disease/conditions described herein with a
combination of active ingredients which may be administered
separately, the invention also relates to combining separate
pharmaceutical compositions in kit form. The kit comprises two
separate pharmaceutical compositions: zopolrestat ethanolamine,
zopolrestat diethanolamine or zopolrestat triethanolamine; and a
second pharmaceutical agent, a prodrug thereof or a
pharmaceutically acceptable salt thereof or of said prodrug as
described above. The kit comprises a container for containing the
separate compositions such as a divided bottle or a divided foil
packet. Typically the kit comprises directions for the
administration of the separate components. The kit form is
particularly advantageous when the separate components are
preferably administered in different dosage forms (e.g., oral and
parenteral), are administered at different dosage intervals, or
when titration of the individual components of the combination is
desired by the prescribing physician.
[0256] An example of such a kit is a so-called blister pack.
Blister packs are well known in the packaging industry and are
being widely used for the packaging of pharmaceutical unit dosage
forms (tablets, capsules, and the like). Blister packs generally
consist of a sheet of relatively stiff material covered with a foil
of a preferably transparent plastic material. During the packaging
process recesses are formed in the plastic foil. The recesses have
the size and shape of the tablets or capsules to be packed. Next,
the tablets or capsules are placed in the recesses and the sheet of
relatively stiff material is sealed against the plastic foil at the
face of the foil which is opposite from the direction in which the
recesses were formed. As a result, the tablets or capsules are
sealed in the recesses between the plastic toil and the sheet.
Preferably the strength of the sheet is such that the tablets or
capsules can be removed from the blister pack by manually applying
pressure on the recesses whereby an opening is formed in the sheet
at the place of the recess. The tablet or capsule can then be
removed via said opening.
[0257] It may be desirable to provide a memory aid on the kit,
e.g., in the form of numbers next to the tablets or capsules
whereby the numbers correspond with the days of the regimen which
the tablets or capsules so specified should be ingested. Another
example of such a memory aid is a calendar printed on a card, e.g.,
as follows "First Week, Monday, Tuesday, . . . etc. . . . Second
Week, Monday, Tuesday, . . . " etc. Other variations of memory aids
will be readily apparent. A "daily dose" can be a single tablet or
capsule or several pills or capsules to be taken on a given day.
Also, a daily dose of the salt of zopolrestat can consist of one
tablet or capsule while a daily dose of the second pharmaceutical
agent can consist of several tablets or capsules and vice versa.
The memory aid should reflect this.
[0258] In another specific embodiment of the invention, a dispenser
designed to dispense the daily doses one at a time in the order of
their intended use is provided. Preferably, the dispenser is
equipped with a memory-aid, so as to further facilitate compliance
with the regimen. An example of such a memory-aid is a mechanical
counter which indicates the number of daily doses that has been
dispensed. Another example of such a memory-aid is a
battery-powered micro-chip memory coupled with a liquid crystal
readout, or audible reminder signal which, for example, reads out
the date that the last daily dose has been taken and/or reminds one
when the next dose is to be taken.
[0259] Other features and advantages will be apparent from the
specification and claims which describe the invention.
EXAMPLE ONE
[0260]
[4-Oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phth-
alazin-1-yl]-acetic acid ethanolamine salt. To a solution of
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-
-1-yl]-acetic acid (419 mg, 1.0 mmol) in acetone (20 mL) was added
ethanolamine (611 mg, 10.0 mmol). After stirring at ambient
temperature for 1.0 hour, the mixture was evaporated to a
semi-solid, which was crystallized from ethanol:diethyl ether (1:4)
to afford the title compound as a white crystalline solid (460 mg,
95%). mp: 119-121.degree. C.; .sup.1H NMR (D.sub.2O, 350 MHz):
.delta. 3.30 (m, 2H), 3.66 (s, 2H), 3.79 (s, 6H), 5.47 (s, 2H),
7.19 (m, 1H), 7.48-7.71 (m, 5H), 7.99 (m, 1H).
EXAMPLE TWO
[0261]
[4-Oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phth-
alazin-1-yl]-acetic acid diethanolamine salt. To a solution of
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-
-1-yl]-acetic acid (2.09 g, 5.0 mmol) in acetone (200 mL) was added
diethanolamine (1.05 g, 10.0 mmol). After stirring at ambient
temperature for 2.0 hours, the mixture was evaporated to a
semi-solid, which was crystallized from ethanol:acetone (1:5) to
afford the title compound as a white crystalline solid (2.12 g,
81%). mp: 163-164.degree. C.; .sup.1H NMR (D.sub.2O, 350 MHz):
.delta. 3.05 (m, 4H), 3.61 (s, 2H), 3.69 (m, 4H), 5.42 (s, 2H),
7.03 (m, 1H), 7.35 (m, 1H), 7.48-7.65 (m, 4H), 7.92 (m, 1H); MS
(Cl) 419 (MH.sup.+).
EXAMPLE THREE
[0262]
[4-Oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phth-
alazin-1-yl]-acetic acid triethanolamine salt. To a solution of
[4-oxo-(5-trifluoromethyl-benzothiazol-2-ylmethyl)-3,4-dihydro-phthalazin-
-1-yl]-acetic acid (419 mg, 1.0 mmol) in acetone (20 mL) was added
triethanolamine (1.49 g, 10.0 mmol). After stirring at ambient
temperature for 1.0 hours, the mixture was evaporated to a
semi-solid, which was crystallized from ethanol:acetone (1:4) to
afford the title compound as a white crystalline solid (494 mg,
86%). mp: 83-84.degree. C.; .sup.1H NMR (D.sub.2O, 350 MHz):
.delta. 3.30 (m, 6H), 3.67 (s, 2H), 3.79 (m, 6H), 5.47 (s, 2H),
7.17 (m, 1H), 7.48-7.71 (m, 5H), 8.01 (m,1H); MS (Cl) 419 (MH).
[0263] It should be understood that the invention is not limited to
the particular embodiments described herein, but that various
changes and modifications may be made without departing from the
spirit and scope of this invention as defined by the following
claims.
* * * * *