Cyanopyrrole-containing cyclic carbamate and thiocarbamate biaryls and methods for preparing the same
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.
1. A method for producing 6-(cyanopyrrole)-cyclocarbamate or cyclothiocarbamate compounds comprising the steps of:
(a) reacting a cyanopyrrole with a coupling agent;
(b) reacting the product of step (a) with an anthranilic alcohol or anthranilic nitro alcohol to form a cyanopyrrole substituted anthranilic alcohol or a cyanopyrrole substituted anthranilic nitro alcohol; and
(c) optionally reducing the cyanopyrrole substituted anthranilic nitro alcohol to the cyanopyrrole substituted anthranilic alcohol; and
(d) converting the cyanopyrrole substituted anthranilic alcohol to said 6-(cyanopyrrole)-cyclocarbamate or cyclothiocarbamate compound.
2. The method according to claim 1 , wherein said anthranilic alcohol is bromoanthranilic alcohol.
3. The method according to claim 1 , wherein said anthranilic alcohol is 4-bromo-methylanthranilic alcohol.
4. The method according to claim 1 , wherein said anthranilic alcohol or nitro alcohol thereof 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, 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.
5. The method according to claim 1 , wherein the cyanopyrrole substituted anthranilic alcohol is formed by:
(i) reacting the product of (a) with an anthranilate or nitroester thereof to form a cyanopyrrole substituted anthranilate or nitroester thereof; and
(ii) reacting the cyanopyrrole substituted anthranilate or nitroester thereof with an organometallic nucleophile.
6. The method according to claim 5 , wherein the anthranilate is a bromoanthranilate.
7. The method according to claim 5 , wherein said anthranilate is 4-bromo-methylanthranilate.
8. The method according to claim 5 , wherein said anthranilate or nitroester 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;
R C is 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 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 step (d) 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.
10. 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.
11. The method according to claim 1 , wherein said cyanopyrrole is 1-methyl-2-cyanopyrrole.
12. The method according to claim 1 , wherein said coupling agent is a trialkyl borate.
13. 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.
14. The method according to claim 1 , wherein the product of step (a) is (5-cyano-1-methyl-1H-pyrrol-2-yl) boronic acid.
15. 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.
16. 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.
17. 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.