Therapeutic compounds

Patent metadata

Field	Value
Publication number	US-12006294-B2
Application number	US-201916429507-A
Country	US
Kind code	B2
Filing date	Jun 3, 2019
Priority date	Jan 13, 2017
Publication date	Jun 11, 2024
Grant date	Jun 11, 2024

Abstract

The invention provides methods for producing analgesia in an animal comprising administering to the animal a compound of the formula Ia′, Ib′, Ic′, and Id′:

and pharmaceutically acceptable salts thereof, wherein the variables A, R 6 , R 7 , R 8 , R 9 , R x , L, X, Y, and Z have the meaning as described herein.

First claim

What is claimed is:

1. A method for producing analgesia in an animal comprising administering to the animal a compound, wherein the compound is selected from the group consisting of:

or a pharmaceutically acceptable salt thereof.

2. The method of claim 1 , wherein the compound is

3. The method of claim 1 , further comprising administering morphine to the animal.

4. The method of claim 1 , wherein the analgesia is produced for synergy in antinociception with reduced sedation or cardiovascular effects.

5. The method of claim 1 , further comprising administering acetaminophen to the animal.

6. A method for producing analgesia in an animal comprising administering to the animal a compound of formula Ia′:

or a pharmaceutically acceptable salt thereof and further comprising administering acetaminophen to the animal;
i) wherein the compound of formula Ia′:
ring A is phenyl, wherein the phenyl, is optionally substituted with one or more groups independently selected from the group consisting of C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, —F, —Cl, —Br, —I, —OR a , —SR a , —N(R a ) 2 , —NO 2 and —CN;
L is selected from the group consisting of:

R L is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl or C 3-8 cycloalkyl;
R 6 is hydrogen, or C 1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR f , —SR f , —N(R f ) 2 , oxo, —NO 2 or —CN; or R 6 and R 8 taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2 or —CN;
R 7 is hydrogen, or C 1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR g , —SR g , —N(R g ) 2 , oxo, —NO 2 or —CN;
R 8 is hydrogen, or C 1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR h , —SR h , —N(R h ) 2 , oxo, —NO 2 or —CN; or R 6 and R 8 taken together with the atoms to which they are attached form a heterocycle that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2 or —CN;
X is ═O, ═S or ═N—R x ; wherein R x is hydrogen, or C 1-6 alkyl that is optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2 or —CN; or R x and R 8 taken together with the nitrogen atoms to which they are attached form a heteroaryl or an unsaturated heterocycle; wherein the heteroaryl and hetrocycle are optionally substituted with one or more groups selected from —F, —Cl, —Br, —I, —OR i , —SR i , —N(R i ) 2 , —NO 2 or —CN;
each R a is independently hydrogen, C 1-4 alkyl or C 1-4 haloalkyl, wherein the C 1-4 alkyl and C 1-4 haloalkyl are optionally substituted with aryl or heteroaryl; or two R a groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each R f is independently hydrogen, C 1-4 alkyl or C 1-4 haloalkyl; or two R f groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each R g is independently hydrogen, C 1-4 alkyl or C 1-4 haloalkyl; or two R g groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
each R h is independently hydrogen, C 1-4 alkyl or C 1-4 haloalkyl; or two R h groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl; and
each R i is independently hydrogen, C 1-4 alkyl or C 1-4 haloalkyl; or two R i groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piperidinyl, piperazinyl or morpholinyl;
wherein the analgesia is produced for synergy in antinociception with reduced sedation or cardiovascular effects.

7. The method of claim 6 , wherein the compound is selected from the group consisting of:

8. The method of claim 6 , wherein the compound is

9. The method of claim 6 , further comprising administering morphine to the animal.

10. The method of claim 6 , wherein the compound is a compound of formula Ia:

or a pharmaceutically acceptable salt thereof, wherein:
ring A is phenyl;
R 1 is C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, —F, —Cl, —Br, —I, —OR a , —SR a , —N(R a ) 2 , —NO 2 or —CN;
R 2 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, —F, —Cl, —Br, —I, —OR b , —SR b , —N(R b ) 2 , —NO 2 or —CN;
R 3 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, —F, —Cl, —Br, —I, —OR c , —SR c , —N(R c ) 2 , —NO 2 or —CN;
R 4 is hydrogen, C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, —F, —Cl, —Br, —I, —OR d , —SR d , N(R d ) 2 , —NO 2 or —CN;
R 5 is C 1-4 alkyl, C 1-4 haloalkyl, C 3-8 cycloalkyl, —F, —Cl, —Br, —I, —OR e , —SR e , —N(R e ) 2 , —NO 2 or —CN;
the group

R b is independently hydrogen, C 1-4 alkyl or C 1-4 haloalkyl, wherein the C 1-4 alkyl and C 1-4 haloalkyl are optionally substituted with aryl or heteroaryl; or two R b groups taken together with the nitrogen to which they are attached form pyrrolidinyl, piper

Assignees

• Univ Minnesota

Inventors

• More Swati S
• Vince Robert

Classifications

• C07D239/06

  having one double bond between ring members or between a ring member and a non-ring member · CPC title

• C07D213/61

  Halogen atoms or nitro radicals · CPC title

• C07C281/18

  the other nitrogen atom being further doubly-bound to a carbon atom, e.g. guanylhydrazones · CPC title

• C07C279/22

  Y being a hydrogen or a carbon atom, e.g. benzoylguanidines · CPC title

• C07C279/18

  having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings · CPC title