IP Library › Granted Patent US 8,003,784
Granted Patent B2
US 8,003,784 · App. 12/508,679 · Granted Aug 23, 2011

Cyanopyrrole containing cyclic carbamate and thiocarbamate biaryls and methods for preparing the same

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Quick Facts
Patent No.
US 8,003,784
App. No.
12/508,679
Granted
Aug 23, 2011
Kind
B2
Abstract

Methods for preparing cyclic carbamates and thiocarbamates containing cyanopyrrole moieties and of the formula are provided. Z are the same or different and are H, optionally substituted C 1 to C 6 alkyl, or COR A ; R A is H, optionally substituted C 1 to C 6 alkyl, optionally substituted C 1 to C 6 alkoxy, or optionally substituted C 1 to C 6 aminoalkyl; Q are the same or different and are H, OH, NH 2 , CN, halogen, optionally substituted C 1 to C 6 alkyl, optionally substituted C 2 to C 6 alkenyl, optionally substituted C 1 to C 6 alkynyl, optionally substituted C 1 to C 6 alkoxy, optionally substituted C 1 to C 6 aminoalkyl, or COR B ; and R B is H, optionally substituted C 1 to C 6 alkyl, optionally substituted C 1 to C 6 alkoxy, or optionally substituted C 1 to C 6 aminoalkyl. Compounds including 2-amino-5-(5-cyano-1-methyl-1H-pyrrol-2-yl)benzoic acid methyl ester, 5-[4-amino-3-(1-hydroxy-1-methyl-ethyl)-phenyl]-1-methyl-1H-pyrrole-2-carbonitrile, and 2-amino-5-(5-cyano-1-methyl-1H-pyrrol-2-yl)-phenyl-ethanone, or pharmaceutically acceptable salts thereof, and the uses thereof are also provided.

Claims (58)

1. A method for producing 6-(cyanopyrrole)-cyclocarbamate or cyclothiocarbamate compounds comprising:

(a) reacting a cyanopyrrole with a coupling agent;

(b) reacting the product of step (a) with an anthranilic ketone or nitro ketone thereof to form a cyanopyrrole substituted anthranilic ketone or nitro ketone thereof;

(c) reacting the cyanopyrrole substituted anthranilic ketone or nitro ketone thereof with an organometallic nucleophile to form cyanopyrrole substituted anthranilic alcohol or nitro alcohol thereof;

(d) optionally reducing the cyanopyrrole substituted anthranilic nitro alcohol to the cyanopyrrole substituted anthranilic alcohol; and

(e) converting the cyanopyrrole substituted anthranilic alcohol to said 6-(cyanopyrrole)-cyclocarbamate or cyclothiocarbamate compound.

2. The method according to claim 1 , wherein said cyanopyrrole is:

wherein:

Z is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or COR A ;

R A is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;

Q is H, OH, NH 2 , CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ; and

R B is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl.

3. The method according to claim 1 , wherein said cyanopyrrole is 1-methyl-2-cyanopyrrole.

4. The method according to claim 1 , wherein said coupling agent is a trialkyl borate.

5. The method according to claim 1 , wherein the product of step (a) is:

wherein:

M′ is a boron, zinc, magnesium or silicon containing coupling group;

Z is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or COR A ;

R A is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;

Q is H, OH, NH 2 , CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ; and

R B is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl.

6. The method according to claim 1 , wherein the product of step (a) is:

wherein, R is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, aryl, and substituted aryl.

7. The method according to claim 1 , wherein the product of step (a) is (5-cyano-1-methyl-1H-pyrrol-2-yl)boronic acid.

8. The method according to claim 1 , wherein said anthranilic ketone or nitro ketone thereof is:

wherein:

Q are, independently, H, OH, NH 2 , CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ;

R B is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;

L is halogen or OSO 2 R 1 ; and

R 1 is H, C 1 to C 6 alkyl, or substituted C 1 to C 6 alkyl.

9. The method according to claim 1 , wherein said anthranilic ketone is 1-(2-amino-5-bromo-phenyl)-ethanone.

10. The method according to claim 1 , wherein the product of step (b) is:

wherein:

Z are, independently, H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or COR A ;

R A is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;

Q are, independently, H, OH, NH 2 , CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ; and

R B is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl.

11. The method according to claim 1 , wherein the product of step (c) is:

wherein:

Z are, independently, H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or COR A ;

R A is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;

Q are, independently, H, OH, NH 2 , CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ; and

R B is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl.

12. The method according to claim 1 , wherein said anthranilic alcohol is 5-[4-amino-3-(1-hydroxy-1-methyl-ethyl)-phenyl]-1-methyl-1H-pyrrole-2-carbonitrile.

13. The method according to claim 1 , wherein step (e) is performed using phosgene, thiophosgene, triphosgene, 1,1′-carbonyldiimidazole (CDI), 1,1′-thiocarbonyldiimidazole (TCDI), carbon disulfide, or carbon disulfide in the presence of a base.

14. The method according to claim 1 , wherein said 6-(cyanopyrrole)-cyclocarbamate compound is:

wherein:

Z are, independently, H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or COR A ;

R A is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;

Q are, independently, H, OH, NH 2 , CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ; and

R B is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl.

15. The method according to claim 1 , wherein said 6-(cyanopyrrole)-cyclothiocarbamate compound is:

wherein:

Z are, independently, H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, or COR A ;

R A is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl;

Q are, independently, H, OH, NH 2 , CN, halogen, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 2 to C 6 alkenyl, substituted C 2 to C 6 alkenyl, C 2 to C 6 alkynyl, substituted C 2 to C 6 alkynyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, substituted C 1 to C 6 aminoalkyl, or COR B ; and

R B is H, C 1 to C 6 alkyl, substituted C 1 to C 6 alkyl, C 1 to C 6 alkoxy, substituted C 1 to C 6 alkoxy, C 1 to C 6 aminoalkyl, or substituted C 1 to C 6 aminoalkyl.

16. The method according to claim 1 , wherein said 6-(cyanopyrrole)-cyclothiocarbamate compound is 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-benzooxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile, or a pharmaceutically acceptable salt thereof and said 6-(cyanopyrrole)-cyclocarbamate compound is 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-benzooxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile, or a pharmaceutically acceptable salt thereof.