IP Library › Granted Patent US 7,074,805

Granted Patent B2

US 7,074,805 · App. 10/364,210 · Granted Jul 11, 2006

Fused azabicyclic compounds that inhibit vanilloid receptor subtype 1 (VR1) receptor

Assignee: Abbott Laboratories

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Quick Facts

Patent No.: US 7,074,805
App. No.: 10/364,210
Granted: Jul 11, 2006
Kind: B2

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Abstract

The isoquinoline compounds of formula (I) are VR1 antagonists that are useful in treating pain, inflammation, thermal hyperalgesia, urinary incontinence and bladder over activity. The “R”, “Z” and “L” variables are defined in the disclosure and the “X” variables are defined as follows: X 1 is CR 1 ; X 2 is selected from the group consisting of N and CR 2 ; X 3 is selected from the group consisting of N and CR 3 ; X 4 is CR 4 ; and X 5 is selected from the group consisting of N and C.

Claims (669)

1. A compound of formula (I)

or a pharmaceutically acceptable salt or prodrug thereof, wherein

- - - is absent or is a single bond;

X 1 is CR 1 ;

X 2 is selected from the group consisting of N and CR 2 ;

X 3 is selected from the group consisting of N and CR 3 ;

X 4 is CR 4 ;

X 5 is selected from the group consisting of N and C;

provided that only one of X 2 , and X 3 is N;

Z 1 is O;

Z 2 is a bond or selected from the group consisting of NH and O;

L is selected from the group consisting of alkenylene, alkylene, cycloalkylene,

—(CH 2 ) m O(CH 2 ) n —, and N(R Y ), wherein the left end of —(CH 2 ) m O(CH 2 ) n — is attached to Z 2 and the right end is attached to R 9 ;

m and n are each independently 1-6;

R Y is selected from the group consisting of hydrogen and alkyl;

R 1 , R 3 , R 5 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkyl, alkylcarbonyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, —NR A S(O) 2 R B , —S(O) 2 R B , —NZ A Z B , (NZ A Z B )alkyl, (NZ A Z B )carbonylalkyl and (NZ A Z B )sulfonyl, wherein Z A and Z B are each independently selected from the group consisting of hydrogen, alkyl, alkylcarbonyl, aryl, and arylalkyl;

R 2 and R 4 are each independently selected from the group consisting of hydrogen, alkoxy, alkoxyalkoxy, alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, alkyl, alkylcarbonyl, alkylcarbonylalkyl, alkylcarbonyloxy, carboxy, carboxyalkyl, cyano, cyanoalkyl, cycloalkyl, cycloalkylalkyl, haloalkoxy, haloalkyl, haloalkylthio, halogen, hydroxy, hydroxyalkyl, —NR A S(O) 2 R B , —S(O) 2 OR A , —S(O) 2 R B , —NZ A Z B , (NZ A Z B )alkyl, (NZ A Z B )alkylcarbonyl, (NZ A Z B )carbonyl, (NZ A Z B )carbonylalkyl, and (NZ A Z B )sulfonyl;

R A is selected from the group consisting of hydrogen and alkyl;

R B is selected from the group consisting of alkyl, aryl, and arylalkyl;

R 8a is selected from the group consisting of hydrogen and alkyl;

R 8b is absent when X 5 is N or R 8b is selected from the group consisting of hydrogen, alkoxy, alkoxycarbonylalkyl, alkyl, alkylcarbonyloxy, alkylsulfonyloxy, halogen, and hydroxy when X 5 is C; and

R 9 is selected from the group consisting of hydrogen, aryl, cycloalkyl, and heterocycle.

2. The compound according to claim 1 wherein

- - - is a single bond;

X 1 is CR 1 ;

X 2 is CR 2 ;

X 3 is N; and

X 4 is CR 4 .

3. The compound according to claim 2 wherein

X 5 is N;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene; and

R 9 is aryl.

4. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 6 and R 7 are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and halogen;

R 8a is hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene;

R 9 is aryl wherein said aryl is phenyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and —NZ C Z D ; and

Z A , Z B , Z C , and Z D are independently selected from the group consisting of hydrogen and alkyl.

5. The compound according to claim 4 selected from the group consisting of

N-[2-(3-fluorophenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-[2-(3-bromophenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-N′-[4-(trifluoromethyl)benzyl]urea;

N-[3-fluoro-5-(trifluoromethyl)benzyl]-N′-isoquinolin-5-ylurea;

N-(2,5-dichlorobenzyl)-N′-isoquinolin-5-ylurea;

N-(1,3-benzodioxol-5-ylmethyl)-N′-isoquinolin-5-ylurea;

N-[2-(4-fluorophenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-(3-bromobenzyl)-N′-isoquinolin-5-ylurea;

N-[2-(3,4-dimethylphenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-[1-(4-bromophenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-N′-[4-(trifluoromethoxy)benzyl]urea;

N-isoquinolin-5-yl-N′-(4-methylbenzyl)urea;

N-(4-fluorobenzyl)-N′-isoquinolin-5-ylurea;

N-[2-(3,4-dichlorophenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-[2-(3,5-dimethoxyphenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-(4-chlorobenzyl)-N′-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-N′-{2-[3-(trifluoromethyl)phenyl]ethyl}urea;

N-[2-(2,6-dichlorophenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-[2-(2,3-dichlorophenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-N′-[3-(trifluoromethoxy)benzyl]urea;

N-[2-(4-ethoxy-3-methoxyphenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-[2-(2,4-dichlorophenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-(3-bromo-4-fluorobenzyl)-N′-isoquinolin-5-ylurea;

N-(3,4-dimethylbenzyl)-N′-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-N′-(3-phenylpropyl)urea;

N-(3,5-dichlorobenzyl)-N′-isoquinolin-5-ylurea;

N-(3-chloro-4-methylbenzyl)-N′-isoquinolin-5-ylurea;

N-(3,4-dichlorobenzyl)-N′-isoquinolin-5-ylurea;

N-(3-fluorobenzyl)-N′-isoquinolin-5-ylurea;

N-(4-tert-butylbenzyl)-N′-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-N′-[2-(3-methylphenyl)ethyl]urea;

N-isoquinolin-5-yl-N′-[2-(4-methylphenyl)ethyl]urea;

N-[2-(2,4-dimethylphenyl)ethyl]-N′-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-N′-[2-(2-methylphenyl)ethyl]urea;

N-isoquinolin-5-yl-N′-{4-[(trifluoromethyl)thio]benzyl}urea;

N-isoquinolin-5-yl-N′-[3-(trifluoromethyl)benzyl]urea;

N-[4-chloro-3-(trifluoromethyl)benzyl]-N′-isoquinolin-5-ylurea;

N-(3,5-dimethylbenzyl)-N′-isoquinolin-5-ylurea;

N-(3,5-difluorobenzyl)-N′-isoquinolin-5-ylurea;

N-(4-bromobenzyl)-N′-isoquinolin-5-ylurea;

N-(3,5-dimethoxybenzyl)-N′-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-N′-(3,4,5-trimethoxybenzyl)urea;

N-isoquinolin-5-yl-N′-[4-(methylsulfonyl)benzyl]urea;

N-(3,4-dimethoxybenzyl)-N′-isoquinolin-5-ylurea;

N-isoquinolin-5-yl-N′-(1-naphthylmethyl)urea;

N-(2,4-dimethylbenzyl)-N′-isoquinolin-5-ylurea;

N-[4-(dimethylamino)benzyl]-N′-isoquinolin-5-ylurea;

N-(4-bromobenzyl)-N′-(3-chloroisoquinolin-5-yl)urea;

N-[(4-cyanophenyl)methyl]-N′-isoquinolin-5-ylurea;

N-[(4-bromophenyl)methyl]-N′-(3-methylisoquinolin-5-yl)urea;

N-[(4-bromophenyl)methyl]-N′-(1-chloroisoquinolin-5-yl)urea;

N-[(4-bromophenyl)methyl]-N′-(1-methylisoquinolin-5-yl)urea;

N-isoquinolin-5-yl-N′-[(4-morpholin-4-ylphenyl)methyl]urea;

N-{[4-(2,6-dimethylmorpholin-4-yl)phenyl]methyl}-N′isoquinolin-5ylurea

N-isoquinolin-5-yl-N′-[(4-thiomorpholin-4-ylphenyl)methyl]urea;

methyl 5-({[(4-bromobenzyl)amino]carbonyl}amino)isoquinoline-3-carboxylate;

methyl 5-({[(2,4-dichlorobenzyl)amino]carbonyl}amino)isoquinoline-3-carboxylate;

N-(8-bromoisoquinolin-5-yl)-N′-(2,4-dichlorobenzyl)urea;

N-(8-bromoisoquinolin-5-yl)-N′-(4-fluorobenzyl)urea;

N-(8-bromoisoquinolin-5-yl)-N′-(3-fluorobenzyl)urea;

N-[1-(4-chlorophenyl)-1-methylethyl]-N′-isoquinolin-5-ylurea;

N-(1,1′-biphenyl-4-ylmethyl)-N′-5-isoquinolinylurea;

N-[3-fluoro-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea;

N-5-isoquinolinyl-N′-(3-methylbenzyl)urea;

N-[4-fluoro-3-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea;

N-(3-chloro-4-fluorobenzyl)-N′-5-isoquinolinylurea;

N-5-isoquinolinyl-N′-[4-(1-pyrrolidinyl)benzyl]urea;

N-[4-(1-azepanyl)benzyl]-N′-5-isoquinolinylurea;

N-[3-fluoro-4-(1-pyrrolidinyl)benzyl]-N′-5-isoquinolinylurea;

N-[4-(1-azepanyl)-3-fluorobenzyl]-N′-5-isoquinolinylurea;

N-[4-(1-azocanyl)benzyl]-N′-5-isoquinolinylurea;

N-benzhydryl-N′-5-isoquinolinylurea;

N-[(1S)-1-(4-bromophenyl)ethyl]-N′-5-isoquinolinylurea;

N-[(1R)-1-(4-bromophenyl)ethyl]-N′-5-isoquinolinylurea;

N-5-isoquinolinyl-N′-{1-[4-(trifluoromethyl)phenyl]ethyl}urea;

(−) N-5-isoquinolinyl-N′-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}urea;

(+) N-5-isoquinolinyl-N′-{(1S)-1-[4-(trifluoromethyl)phenyl]ethyl}urea;

N-[1-(4-tert-butylphenyl)ethyl]-N′-5-isoquinolinylurea;

N-{cyclopropyl[4-(trifluoromethyl)phenyl]methyl}-N′-5-isoquinolinylurea;

N-(3-fluorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-(4-bromo-3-fluorobenzyl)-N′-5-isoquinolinylurea;

N-(3-amino-5-isoquinolinyl)-N′-[4-(1-piperidinyl)benzyl]urea;

N-(3-amino-5-isoquinolinyl)-N′-[4-(1-azepanyl)benzyl]urea;

N-(1,1′-biphenyl-3-ylmethyl)-N′-5-isoquinolinylurea;

N-5-isoquinolinyl-N′-[4-(2-pyridinyl)benzyl]urea;

N-(4-bromo-3-fluorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-[3-fluoro-4-(4-methyl-1-piperidinyl)benzyl]-N′-(3-methyl-5-isoqinolinyl)urea;

N-(3-methyl-5-isoquinolinyl)-N′-[4-(4-methyl-1-piperidinyl)benzyl]urea;

N-[3-fluoro-4-(1-piperidinyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-(3-methyl-5-isoquinolinyl)-N′-[4-(1-piperidinyl)benzyl]urea;

N-[4-(1-azepanyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-(3-methyl-5-isoquinolinyl)-N′-[4-(1-pyrrolidinyl)benzyl]urea;

N-[3-fluoro-4-(1-pyrrolidinyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-[4-(1-azepanyl)-3-fluorobenzyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-[4-(1-azocanyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-[4-(1-azocanyl)-3-fluorobenzyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-[(1S)-1-(4-bromophenyl)ethyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-{(1S)-1-[4-(1-azepanyl)phenyl]ethyl}-N′-(3-methyl-5-isoquinolinyl)urea;

N-benzyl-N′-(3-chloro-5-isoquinolinyl)urea;

N-(4-bromobenzyl)-N′-(1-chloro-5-isoquinolinyl)urea;

N-(4-cyanobenzyl)-N′-5-isoquinolinylurea;

N-(4-bromobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-(4-bromobenzyl)-N′-(1-methyl-5-isoquinolinyl)urea;

N-5-isoquinolinyl-N′-[4-(4-morpholinyl)benzyl]urea;

N-[4-(2,6-dimethyl-4-morpholinyl)benzyl]-N′-5-isoquinolinylurea;

N-5-isoquinolinyl-N′-[4-(4-thiomorpholinyl)benzyl]urea;

N-(4-bromobenzyl)-N′-(3-fluoro-5-isoquinolinyl)urea;

N-(3-chloro-5-isoquinolinyl)-N′-[4-(4-morpholinyl)benzyl]urea;

N-[3,5-difluoro-4-(4-morpholinyl)benzyl]-N′-5-isoquinolinylurea;

N-(4-bromobenzyl)-N′-(1,3-dimethyl-5-isoquinolinyl)urea;

N-(3,4-dimethylbenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-[3,5-bis(trifluoromethyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-(3-amino-5-isoquinolinyl)-N′-(4-bromobenzyl)urea;

N-(3-methyl-5-isoquinolinyl)-N′-[4-(trifluoromethyl)benzyl]urea;

N-(4-tert-butylbenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-(4-tert-butylbenzyl)-N′-(1,3-dimethyl-5-isoquinolinyl)urea;

N-[3-fluoro-4-(trifluoromethyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-[1-(4-bromophenyl)ethyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-(3,4-dichlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-(2,4-dichlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-(3-chlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-(3-methyl-5-isoquinolinyl)-N′-[4-(trifluoromethoxy)benzyl]urea;

N-[2-(3,4-dichlorophenyl)ethyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-(4-ethylbenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-(3-methyl-5-isoquinolinyl)-N′-{2-[4-(trifluoromethyl)phenyl]ethyl}urea;

N-(3-methyl-5-isoquinolinyl)-N′-{4-[(trifluoromethyl)thio]benzyl}urea;

N-(4-chlorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-(2,4-difluorobenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-(1,3-dimethyl-5-isoquinolinyl)-N′-[3-fluoro-4-(trifluoromethyl)benzyl]urea;

N-(4-isopropylbenzyl)-N′-(3-methyl-5-isoquinolinyl)urea;

N-[4-fluoro-3-(trifluoromethyl)benzyl]-N′-(3-methyl-5-isoquinolinyl)urea;

N-(3-amino-5-isoquinolinyl)-N′-{1-[4-(trifluoromethyl)phenyl]ethyl}urea;

N-(3-amino-5-isoquinolinyl)-N′-[3-fluoro-4-(trifluoromethyl)benzyl]urea;

N-(5-bromo-2-fluorobenzyl)-N′-5-isoquinolinylurea;

N-(4-chloro-2-fluorobenzyl)-N′-5-isoquinolinylurea;

N-(4-tert-butylbenzyl)-N′-5-isoquinolinylurea;

N-(3,4-difluorobenzyl)-N′-5-isoquinolinylurea;

N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-N′-5-isoquinolinylurea;

N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]propyl}-N′-5-isoquinolinylurea;

N-(8-bromo-5-isoquinolinyl)-N′-(2,4-dichlorobenzyl)urea;

N-(8-bromo-5-isoquinolinyl)-N′-(4-fluorobenzyl)urea;

N-(8-bromo-5-isoquinolinyl)-N′-(3-fluorobenzyl)urea;

N-[1-(4-chlorophenyl)-1-methylethyl]-N′-5-isoquinolinylurea;

N-(4-bromo-3-methylbenzyl)-N′-5-isoquinolinylurea;

N-[2-fluoro-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea;

N-(4-bromobenzyl)-N′-(3-hydroxy-5-isoquinolinyl)urea;

N-[3-bromo-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea;

N-[2,4-bis(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea;

N-[2,3-difluoro-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea;

N-[2-chloro-4-(trifluoromethyl)benzyl]-N′-5-isoquinolinylurea;

N-5-isoquinolinyl-N′-{1-methyl-1-[4-(trifluoromethyl)phenyl]ethyl}urea; and

N-[2-(4-bromophenyl)-2-hydroxyethyl]-N′-5-isoquinolinylurea.

6. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene; and

R 9 is aryl wherein said aryl is substituted with aryloxy.

7. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each hydrogen;

R 8a is hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene;

R 9 is aryl wherein said aryl is phenyl substituted with aryloxy wherein said aryloxy is phenoxy substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, methylenedioxy, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and —NZ C Z D ; and

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

8. The compound according to claim 7 selected from the group consisting of

N-isoquinolin-5-yl-N′-(4-phenoxybenzyl)urea; and

N-isoquinolin-5-yl-N′-(3-phenoxybenzyl)urea.

9. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each hydrogen;

R 8a is hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene; and

R 9 is aryl wherein said aryl is napthyl.

10. The compound according to claim 9 that is N-isoquinolin-5-yl-N′-(1-naphthylmethyl)urea.

11. The compound according to claim 2 wherein

X 5 is N;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene; and

R 9 is cycloalkyl.

12. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 6 and R 7 are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and alkyl;

R 8a is hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene;

R 9 is cycloalkyl wherein said cycloalkyl is selected from the group consisting of adamantyl, bicyclo[3.1.1]heptyl, and cyclohexyl, wherein the cycloalkyl is substituted with 0, 1 or 2 alkyl groups; and

Z A and Z B are independently selected from the group consisting of hydrogen and alkyl.

13. The compound according to claim 12 selected from the group consisting of

N-(1-adamantylmethyl)-N′-5-isoquinolinylurea;

N-(cyclohexylmethyl)-N′-5-isoquinolinylurea;

N-[(6,6-dimethylbicyclo[3.1.1]hept-2-yl)methyl]-N′-5-isoquinolinylurea;

N-[(4-tert-butylcyclohexyl)methyl]-N′-5-isoquinolinylurea; and

N-5-isoquinolinyl-N′-{[4-(trifluoromethyl)cyclohexyl]methyl}urea.

14. The compound according to claim 2 wherein

X 5 is N;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene; and

R 9 is heterocycle.

15. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 6 and R 7 are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and halogen;

R 8a is hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene;

R 9 is heterocycle wherein said heterocycle is pyridinyl substituted with 0, 1, 2, or 3 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and —NZ C Z D ; and

Z A , Z B , Z C , and Z D are independently selected from the group consisting of hydrogen and alkyl.

16. The compound according to claim 15 that is N-5-isoquinolinyl-N′-{[5-(trifluoromethyl)-2-pyridinyl]methyl}urea.

17. The compound according to claim 2 wherein

X 5 is N;

Z 1 is O;

Z 2 is NH;

R 8b is absent; and

R 9 is hydrogen.

18. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each hydrogen;

R 8a is hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene; and

R 9 is hydrogen.

19. The compound according to claim 18 selected from the group consisting of

N-hexyl-N′-isoquinolin-5-ylurea;

N-5-isoquinolinyl-N′-pentylurea; and

N-5-isoquinolinyl-N′-octylurea.

20. The compound according to claim 2 wherein

X 5 is N;

Z 1 is O;

Z 2 is NH;

L is cycloalkylene;

R 8b is absent; and

R 9 is aryl.

21. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each hydrogen;

R 8a is hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is cycloalkylene;

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

22. The compound according to claim 21 that is N-isoquinolin-5-yl-N′-[(trans)-2-phenylcyclopropyl]urea.

23. The compound according to claim 2 wherein

X 5 is N;

Z 1 is O;

Z 2 is a bond;

L is cycloalkylene;

R 8b is absent; and

R 9 is aryl.

24. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each hydrogen;

R 8a is hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is a bond;

L is cycloalkylene;

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

25. The compound according to claim 24 that is N-5-isoquinolinyl-2-phenylcyclopropanecarboxamide.

26. The compound according to claim 2 wherein

X 5 is N;

Z 1 is O;

Z 2 is NH;

L is —(CH 2 ) m O(CH 2 ) n — wherein the left end is attached to Z 2 and the right end is attached to R 9 ;

R 8b is absent; and

R 9 is aryl.

27. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8a are each hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is —(CH 2 ) m O(CH 2 ) n — wherein the left end is attached to Z 2 and the right end is attached to R 9 ;

m is 1-2;

n is 0-2;

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

28. The compound according to claim 27 selected from the group consisting of

N-isoquinolin-5-yl-N′-(2-phenoxyethyl)urea; and

N-[(2,4-dichlorobenzyl)oxy]-N′-5-isoquinolinylurea.

29. The compound according to claim 2 wherein

X 5 is N;

Z 1 is O;

Z 2 is NH;

L is N(R Y );

R 8b is absent; and

R 9 is aryl.

30. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8a are each hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is N(R Y );

m is 2-4;

n is 0;

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

31. The compound according to claim 30 that is N-5-isoquinolinyl-2-[4-(trifluoromethyl)phenyl]hydrazinecarboxamide.

32. The compound according to claim 2 wherein

X 5 is N;

Z 1 is O;

Z 2 is a bond;

R 8b is absent; and

R 9 is aryl.

33. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 5 , R 6 , R 7 , and R 8a are each hydrogen;

R 8b is absent;

R 2 is selected from the group consisting of hydrogen and alkyl;

Z 1 is O;

Z 2 is a bond;

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

34. The compound according to claim 33 that is selected from the group consisting of

4-(3,4-dichlorophenyl)-N-isoquinolin-5-ylpiperazine-1-carboxamide;

4-(3-chlorophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide;

4-(3,4-dimethylphenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide;

4-(4-chlorophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide;

N-5-isoquinolinyl-3-methyl-4-(4-methylphenyl)-1-piperazinecarboxamide;

4-(2,3-dimethylphenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide;

4-(2,3-dichlorophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide;

4-(3,4-dichlorophenyl)-N-(3-methyl-5-isoquinolinyl)-1-piperazinecarboxamide;

N-5-isoquinolinyl-4-[3-(trifluoromethyl)phenyl]-1-piperazinecarboxamide; and

4-(4-bromophenyl)-N-5-isoquinolinyl-1-piperazinecarboxamide.

35. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 and R 6 are each hydrogen;

R 7 is (CF 3 ) 2 (HO)C—;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene;

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

36. The compound according to claim 35 that is N-(4-bromobenzyl)-N′-{6-[2,2,2-trifluoro-1-hydroxy-1-(trifluoromethyl)ethyl]isoquinolin-5-yl}urea.

37. The compound according to claim 2 wherein

X 5 is N;

Z 1 is O;

Z 2 is O;

L is alkylene;

R 8b is absent; and

R 9 is aryl.

38. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , and R 8a are each hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is O;

L is alkylene;

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

39. The compound according to claim 38 selected from the group consisting of

4-(trifluoromethyl)benzyl isoquinolin-5-ylcarbamate;

2-(3-bromophenyl)ethyl isoquinolin-5-ylcarbamate;

4-cyanobenzyl isoquinolin-5-ylcarbamate;

4-methylbenzyl 5-isoquinolinylcarbamate;

4-bromobenzyl 5-isoquinolinylcarbamate;

2-(4-chlorophenyl)ethyl 5-isoquinolinylcarbamate; and

2-[2-(trifluoromethyl)phenyl]ethyl 5-isoquinolinylcarbamate.

40. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 2 , R 4 , R 5 , R 6 and R 7 are each hydrogen;

Z 1 is O;

Z 2 is O;

L is alkylene;

R 8b is absent; and

R 9 is aryl wherein said aryl is naphthyl.

41. The compound according to claim 40 that is 1-naphthylmethyl isoquinolin-5-ylcarbamate.

42. The compound according to claim 2 wherein

X 5 is N;

R 8b is absent;

Z 1 is O;

Z 2 is a bond;

L is alkenylene; and

R 9 is aryl.

43. The compound according to claim 2 wherein

X 5 is N;

R 1 , R 6 and R 7 are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and halogen;

R 8a is hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is a bond;

L is alkenylene;

Z A , Z B , Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

44. The compound according to claim 43 that is selected from the group consisting of

(2E)-N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-2-butenamide;

N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-3-butenamide;

(2Z)-N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]-2-butenamide;

(2E)-3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-5-isoquinolinyl-2-butenamide;

3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-5-isoquinolinyl-3-butenamide;

(2E)-N-5-isoquinolinyl-3-[4-(1-piperidinyl)phenyl]-2-butenamide;

N-5-isoquinolinyl-3-[4-(trifluoromethyl)phenyl]acrylamide;

N-5-isoquinolinyl-3-[3-(trifluoromethyl)phenyl]acrylamide;

3-(4-isopropylphenyl)-N-5-isoquinolinylacrylamide;

3-(3,4-dichlorophenyl)-N-5-isoquinolinylacrylamide;

3-(1,1′-biphenyl-4-yl)-N-5-isoquinolinylacrylamide;

3-(3-bromo-4-fluorophenyl)-N-5-isoquinolinylacrylamide;

3-(4-tert-butylphenyl)-N-5-isoquinolinylacrylamide; and

3-[3-fluoro-4-(trifluoromethyl)phenyl]-N-5-isoquinolinylacrylamide.

45. The compound according to claim 2 wherein

X 5 is C;

Z 1 is O;

Z 2 is NH;

L is alkylene; and

R 9 is heterocycle.

46. The compound according to claim 2 wherein

X 5 is C;

R 1 , R 6 and R 7 are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and halogen;

R 8a is hydrogen;

R 8b is hydrogen;

Z 1 is O;

Z 2 is NH;

L is alkylene;

R 9 is heterocycle wherein said heterocycle is selected from the group consisting of imidazolyl, pyridinyl, pyrrolidinyl, and thienyl, wherein the heterocycle is substituted with 0, 1 or 2 alternative substituents independently selected from the group consisting of alkoxy, alkyl, alkylsulfonyl, 1-azepanyl, 1-azocanyl, cyano, haloalkoxy, haloalkyl, haloalkylthio, halogen, oxo, 4-morpholinyl, 2,6,-dimethyl-4-morpholinyl, phenyl, 1-piperidinyl, 4-methyl-1-piperidinyl, pyridinyl, 1-pyrrolidinyl, 4-thiomorpholinyl, and —NZ C Z D ; and

Z A , Z B , Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

47. The compound according to claim 46 selected from the group consisting of

2-(5-isoquinolinyl)-N-[2-(2-thienyl)ethyl]acetamide;

N-[3-(1H-imidazol-1-yl)propyl]-2-(5-isoquinolinyl)acetamide;

2-(5-isoquinolinyl)-N-[3-(2-oxo-1-pyrrolidinyl)propyl]acetamide; and

2-(5-isoquinolinyl)-N-[2-(3-pyridinyl)ethyl]acetamide.

48. The compound according to claim 2 wherein

X 5 is C;

Z 1 is O;

Z 2 is NH;

L is —(CH 2 ) m O(CH 2 ) n — wherein the left end is attached to Z 2 and the right end is attached to R 9 ; and

R 9 is hydrogen.

49. The compound according to claim 2 wherein

X 5 is C;

R 1 , R 6 and R 7 are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and halogen;

R 8a is hydrogen;

R 8b is hydrogen;

Z 1 is O;

Z 2 is NH;

L is —(CH 2 ) m O(CH 2 ) n — wherein the left end is attached to Z 2 and the right end is attached to R 9 ;

m is 1-4;

n is 0-4;

R 9 is hydrogen; and

Z A and Z B are independently selected from the group consisting of hydrogen and alkyl.

50. The compound according to claim 49 that is N-(3-butoxypropyl)-2-(5-isoquinolinyl)acetamide.

51. The compound according to claim 2 wherein

X 5 is C;

Z 1 is O;

Z 2 is NH;

L is alkylene; and

R 9 is aryl.

52. The compound according to claim 2 wherein

X 5 is C;

R 1 , R 6 , R 7 , R 8a and R 8b are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and halogen;

Z 1 is O;

Z 2 is NH;

L is alkylene;

Z A , Z B , Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

53. The compound according to claim 52 selected from the group consisting of

2-isoquinolin-5-yl-N-[4-(trifluoromethyl)benzyl]acetamide;

N-(4-bromobenzyl)-2-(3-methyl-5-isoquinolinyl)acetamide;

N-(4-bromobenzyl)-2-(5-isoquinolinyl)acetamide;

N-[1-(4-bromophenyl)ethyl]-2-(5-isoquinolinyl)acetamide;

N-[1-(4-bromophenyl)ethyl]-2-(3-methyl-5-isoquinolinyl)acetamide;

2-(5-isoquinolinyl)-N-[4-(trifluoromethoxy)benzyl]acetamide;

N-(4-tert-butylbenzyl)-2-(5-isoquinolinyl)acetamide;

N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide;

N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]ethyl}-2-(5-isoquinolinyl)acetamide;

N-{1-[3-fluoro-4-(trifluoromethyl)phenyl]propyl}-2-(5-isoquinolinyl)acetamide;

2-(3-methyl-5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]acetamide;

N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(3-methyl-5-isoquinolinyl)acetamide;

2-(5-isoquinolinyl)-N-{2-[3-(trifluoromethyl)phenyl]ethyl}acetamide;

N-(3,3-diphenylpropyl)-2-(5-isoquinolinyl)acetamide;

2-(5-isoquinolinyl)-N-(3-phenylpropyl)acetamide;

N-(2,2-diphenylethyl)-2-(5-isoquinolinyl)acetamide;

N-benzyl-2-(5-isoquinolinyl)acetamide;

2-(5-isoquinolinyl)-N-{4-[(trifluoromethyl)thio]benzyl}acetamide;

2-(5-isoquinolinyl)-N-(2-phenylethyl)acetamide;

N-[3-bromo-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide;

N-(4-bromo-3-methylbenzyl)-2-(5-isoquinolinyl)acetamide;

N-[2,4-bis(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide;

N-[2-chloro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide;

N-[2,3-difluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)acetamide; and

N-[4-(1-azepanyl)-3-fluorobenzyl]-2-(5-isoquinolinyl)acetamide.

54. The compound according to claim 2 wherein

X 5 is C;

R 1 , R 6 , and R 7 are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and halogen;

R 8a is selected from the group consisting of hydrogen and alkyl;

R 8b is alkyl;

Z 1 is O;

Z 2 is NH;

L is alkylene;

Z A , Z B , Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

55. The compound according to claim 54 selected from the group consisting of

N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)propanamide;

2-(5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]propanamide;

2-(5-isoquinolinyl)-N-[3-(trifluoromethyl)benzyl]propanamide;

2-(5-isoquinolinyl)-N-{4-[(trifluoromethyl)thio]benzyl}propanamide;

N-(4-bromobenzyl)-2-(5-isoquinolinyl)propanamide;

N-(4-tert-butylbenzyl)-2-(5-isoquinolinyl)propanamide;

N-[3-fluoro-5-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)propanamide;

2-(5-isoquinolinyl)-N-[4-(trifluoromethoxy)benzyl]propanamide;

2-(5-isoquinolinyl)-N-[3-(trifluoromethoxy)benzyl]propanamide;

N-(2,4-dimethylbenzyl)-2-(5-isoquinolinyl)propanamide;

N-(2,5-dimethylbenzyl)-2-(5-isoquinolinyl)propanamide;

N-(2,3-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide;

N-(2,4-dichlorobenzyl)-2-(5-isoqinolinyl)propanamide;

N-(2,5-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide;

N-(3,4-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide;

N-(3,5-dichlorobenzyl)-2-(5-isoquinolinyl)propanamide;

N-[4-(1-azepanyl)benzyl]-2-(5-isoquinolinyl)propanamide;

N-[4-(1-azepanyl)-3-fluorobenzyl]-2-(5-isoquinolinyl)propanamide;

N-[3-fluoro-4-(trifluoromethyl)benzyl]-2-(5-isoquinolinyl)butanamide;

2-(5-isoquinolinyl)-N-[4-(trifluoromethyl)benzyl]butanamide;

N-(4-bromobenzyl)-2-(5-isoquinolinyl)butanamide;

2-(5-isoquinolinyl)-N-{4-[(trifluoromethyl)thio]benzyl}butanamide;

N-[4-(1-azepanyl)-3-fluorobenzyl]-2-(5-isoquinolinyl)butanamide; and

2-(5-isoquinolinyl)-2-methyl-N-{4-[(trifluoromethyl)thio]benzyl}propanamide.

56. The compound according to claim 2 wherein

X 5 is C;

R 1 , R 6 , and R 7 and are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and halogen;

R 8a is hydrogen;

R 8b is selected from the group consisting of alkoxy, alkoxycarbonylalkyl, alkylcarbonyloxy, alkylsulfonyl, halogen, and hydroxy;

Z 1 is O;

Z 2 is NH;

L is alkylene;

Z A , Z B , Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

57. The compound according to claim 56 selected from the group consisting of

N-(4-tert-butylbenzyl)-2-hydroxy-2-(5-isoquinolinyl)acetamide;

N-(4-tert-butyl-3-fluorobenzyl)-2-hydroxy-2-(5-isoquinolinyl)acetamide;

tert-butyl 4-[(4-tert-butylbenzyl)amino]-3-(5-isoquinolinyl)-4-oxobutanoate;

2-[(4-tert-butylbenzyl)amino]-1-(5-isoquinolinyl)-2-oxoethyl acetate;

2-[(4-tert-butylbenzyl)amino]-1-(5-isoquinolinyl)-2-oxoethyl methanesulfonate;

N-(4-tert-butylbenzyl)-2-(5-isoquinolinyl)-2-methoxyacetamide; and

N-(4-tert-butylbenzyl)-2-chloro-2-(5-isoquinolinyl)acetamide.

58. The compound according to claim 2 wherein

X 5 is C;

R 1 , R 6 , R 7 , and R 7 are each hydrogen;

R 2 and R 4 are independently selected from the group consisting of hydrogen, alkyl, halogen, hydroxy, and —NZ A Z B ;

R 5 is selected from the group consisting of hydrogen and halogen;

R 8a is selected from the group consisting of hydrogen and alkyl;

R 8b is selected from the group consisting of hydrogen, alkoxycarbonylalkyl, alkyl, and hydroxy;

Z 1 is O;

Z 2 is O;

L is alkylene;

R 9 is hydrogen; and

Z A and Z B are independently selected from the group consisting of hydrogen and alkyl.

59. The compound according to claim 58 selected from the group consisting of

ethyl 5-isoquinolinylacetate;

ethyl 2-(5-isoquinolinyl)propanoate;

ethyl 2-(5-isoquinolinyl)butanoate;

ethyl 2-(5-isoquinolinyl)-2-methylpropanoate;

ethyl hydroxy(5-isoquinolinyl)acetate; and

4-tert-butyl 1-ethyl 2-(5-isoquinolinyl)succinate.

60. The compound according to claim 1 wherein

- - - is a single bond;

X 1 is CR 1 ;

X 2 is N;

X 3 is CR 3 ; and

X 4 is CR 4 .

61. The compound according to claim 60 wherein

X 5 is N;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene; and

R 9 is aryl.

62. The compound according to claim 60 , wherein

X 5 is N;

R 1 , R 3 , R 4 , R 5 , R 6 and R 7 are each hydrogen;

R 8b is absent;

Z 1 is O;

Z 2 is NH;

L is alkylene;

Z C and Z D are independently selected from the group consisting of hydrogen and alkyl.

63. The compound according to claim 62 selected from the group consisting of

N-isoquinolin-8-yl-N′-[4-(trifluoromethyl)benzyl]urea; and

N-(4-bromobenzyl)-N′-isoquinolin-8-ylurea.

64. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a pharmaceutically acceptable carrier.

65. A method of treating a disorder wherein the disorder is ameliorated by inhibiting vanilloid receptor subtype 1 (VR1) receptor, and wherein the disorder is selected from the group comprising pain, bladder overactivity, urinary incontinence and inflammatory thermal hyperalgesia in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.

66. A method of treating bladder overactivity in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.

67. A method of treating urinary incontinence in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.

68. A method of treating pain in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.

69. A method of treating inflammatory thermal hyperalgesia in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof.

Assignments (2)

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 9, 2013

From: ABBOTT LABORATORIES

To: ABBVIE INC.

Reel/Frame 030176/0968 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Jan 19, 2005

From: LEE, CHIH-HUNG; BAYBURT, EROL K.; DIDOMENICO, STANLEY JR.; DRIZIN, IRENE; KOENIG, JOHN R.; SCHMIDT, ROBERT G. JR.; GOMTSYAN, ARTHUR R.; PERNER, RICHARD J.; TURNER, SEAN C.; JINKERSON, TAMMIE K. WHITE; ZHENG, GUO ZHU

To: ABBOTT LABORATORIES

Reel/Frame 015606/0542 →

Continuity (1)

Related Publication 20030158198A1 · Aug 21, 2003