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Compounds of general structural formula (1) are shown to have AMPA receptor enhancing properties. The compounds are useful for such therapeutic purposes as facilitating the learning of behaviors dependent upon AMPA receptors, and in treating conditions, such as memory impairment, in which AMPA receptors, or synapses utilizing these receptors, are reduced in numbers or efficiency. They may also be used to enhance excitatory synaptic activity in order to restore an imbalance between brain subregions, as in treatment of schizophrenia or schizophreniform behavior.

Inventors: Gary A. Rogers, Christopher M. Marrs
Original Assignee: The Regents of the University of California
Primary Examiner: Sabiha Qazi
Attorneys: Henry D. Coleman, R. Neil Sudol, William J. Sapone
Current U.S. Classification: 514/254.03; 514/231.2; 514/231.5; 514/249; 514/263.3; 514/315; 514/319; 514/320; 514/321; 514/322; 514/328; 514/338; 544/95; 544/106; 544/268; 544/336; 544/349; 546/159; 546/193; 546/194; 546/199
International Classification: C07D29500; A61K/31445; A61K/3143

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Citations

Cited PatentFiling dateIssue dateOriginal AssigneeTitle
US3981864Sep 5, 1974Sep 21, 1976Eisai Co., Ltd.1,3-Benzodioxol derivatives
US4420485Sep 29, 1982Dec 13, 1983Hoechst-Roussel Pharmaceuticals Inc.1'-[3-(1,2-Benzisoxazol-3-yl) proply]spiro[benzofuran-2(3H),3' or 4'-piperidines or 3'-pyrrolidines]
US4476135Feb 16, 1982Oct 9, 1984Sandoz Ltd.Amino-2,1,3-benzothiadiazole and -benzoxadiazole derivatives, their preparation and pharmaceutical compositions containing them
US5032604Dec 8, 1989Jul 16, 1991Merck & Co., Inc.Class III antiarrhythmic agents
US5112824Jul 15, 1991May 12, 1992Merck & Co., Inc.Benzofuran compounds as class III antiarrhythmic agents
US5650409Jun 2, 1995Jul 22, 1997Cortex Pharmaceuticals, Inc.Benzoyl piperidines/pyrrolidines for enhancing synaptic response
US5736543Apr 3, 1996Apr 7, 1998The Regents of the University of California
Cortex Pharmaceuticals, Inc.		Benzoxazines for enhancing synaptic response
US5985871Dec 24, 1997Nov 16, 1999Cortex Pharmaceuticals, Inc.Benzoxazine compounds for enhancing synaptic response

Referenced by

Citing PatentFiling dateIssue dateOriginal AssigneeTitle
US8039468Aug 30, 2007Oct 18, 2011The Governors of the University of AlbertaMethod of inhibition of respiratory depression using positive allosteric AMPA receptor modulators

Claims

1. A compound having the structure:

in which:

R1 is oxygen or sulfur;
R2 and R3 are independently selected from the group consisting of CR and CX;
M is CR4, wherein R4 and R8 are independently R or together form a single linking moiety linking M to the ring vertex 2, the linking moiety being selected from the group consisting of a single bond, CRR, CRCR, C(O), S(O)y, NR, and N; and
R5 and R7 are independently selected from the group consisting of (CRR)n, C(O), CRCR, CRCX, CRX, CXX, S, and O, and
R6 is selected from the group consisting of (CRR)m, C(O), CRCR, CRX, CXX, S, and O;
wherein
X and X are independently selected from Br, Cl, F, CN, NO2, OR, SR, NRR, C(O)R, CO2R, or CONRR, wherein two groups R or R on an individual group X, or on two adjacent groups X, may together form a ring; and
R and R are independently selected from (i) hydrogen, (ii) C1-C6 branched or unbranched alkyl or C3 to C6 cycloalkyl groups, which may be unsubstituted or substituted with one: or more functionalities selected from halogen, nitro, alkoxy, hydroxy, alkylthio, amino, keto, aldehyde, carboxylic acid, carboxylic ester, or carboxylic amide, and wherein two such alkyl groups on a single carbon or on adjacent carbons may together form a ring, and (iii) aryl, which may be unsubstituted or substituted with one or more functionalities selected from halogen, intro, alkoxy, hydroxy, aryloxy, alklcylthio, amino, keto, aldehyde, carboxylic acid, carboxylic ester, or carboxylic amide;
m and p are, independently, 0 or 1; and
n and y are, independently, 0, 1 or 2.

2. A compound in accordance with claim 1 in which R and R are independently selected from (i) hydrogen and (ii) C1-C6 branched or unbranched alkyl or C3 to C6 cycloalkyl, which may be unsubstituted or substituted with one or more functionalities selected from halogen, nitro, alkoxy, hydroxy, alkylthio, amino, keto, aldehyde, carboxylic acid, carboxylic ester, or carboxylic amide, and wherein two such alkyl groups on a single carbon or on adjacent carbons may together form a ring.

3. A compound in accordance with claim 1 in which R2 and R3 are CR.

4. A compound in accordance with claim 3 in which p is 0 and R4 and R8 are hydrogen.

5. A compound in accordance with claim 4 in which R5 and R7 are (CRR)n and R6 is (CRR)m.

6. A compound in accordance with claim 3 in which p is 0, R4, R8, R, and R are hydrogen, and mn1.

7. A compound in accordance with claim 4 in which R5 is CRCX, R6 is (CRR)m, R7 is (CRR)n, and m is 0.

8. A compound in accordance with claim 7 in which R and R are hydrogen.

9. A compound in accordance with claim 8 in which X is fluorine and n is 1, said compound being 1-(benzofurazan-5-ylcarbonyl)-4-fluoro-1,2,3,6-tetrahydropyridine.

10. A compound in accordance with claim 4 in which R5 is CRCR, R6 is (CRR)m, R7 is (CRR)n, and m is 0.

11. A compound in accordance with claim 10 in which R and R are hydrogen.

12. A compound in accordance with claim 11 in which n is 1, said compound being 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine.

13. A compound in accordance with claim 4 in which R5 and R7 are (CRR)n, and R6 is C(O), CRX, CXX, O, or S.

14. A compound in accordance with claim 13 in which R6 is CXX, R and R are hydrogen, n is 1, and X and X are fluorine, said compound being 1-(benzofurazan-5-ylcarbonyl)-4,4-difluoropiperidine.

15. A compound in accordance with claim 13 in which which R6 is CRX, R and R are hydrogen, and n is 1.

16. A compound in accordance with claim 13 in which R6 is S, or C(O), n is 1, and R and R are hydrogen, said compound being selected from 4-(benzofurazan-5-ylcarbonyl)thiomorpholine, and 4-(benzofurazan-5-ylcarbonyl)-4-piperidone.

17. A compound in accordance with claim 1 wherein R4 and R8 together form a single linking moiety linking M to the ring vertex 2, the linking moiety being a single bond, CRR, CRCR, C(O), S, NR, or N.

18. A compound in accordance with claim 17 in which R2 and R3 are CR.

19. A compound in accordance with claim 18 in which p is 0, R5 and R7 are (CRR)n, and R6 is (CRR)m.

20. A compound in accordance with claim 19 in which n1.

21. A compound in accordance with claim 19 in which the linking moiety is CRR, S, or N.

22. A compound in accordance with claim 21 in which the linking moiety is S or N.

23. A compound in accordance with claim 1 in which R6 is selected from the group consisting of (CRR)m, C(O), CRCR, CRX, CXX, and S, and R and R are independently selected from C1-C7 branched or unbranched alkyl or C3 to C6 cycloalkyl, which may be unsubstituted or substituted with one or more functionalities selected from halogen, nitro, alkoxy, hydroxy, alkylthio, amino, keto, aldehyde, carboxylic acid, carboxylic ester, or carboxylic amide, and wherein two such alkyl groups on a single carbon or on adjacent carbons may together form a ring.

24. A compound in accordance with claim 1 chosen from the from the group consisting of:

a. 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine
b. 1-(benzofurazan-5-ylcarbonyl)-4-fluoro-1,2,3,6-tetrahydropyridine
c. 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine
d. 1-(benzofurazan-5-ylcarbonyl)-4,4-difluoropiperidine
e. 4-(benzofurazan-5-ylcarbonyl)thiomorpholine
f. 4-(benzofurazan-5-ylcarbonyl)-4-piperidone.

25. A method for enhancing AMPA receptor function in a mammalian subject in need thereof, said method comprising administering to said subject a compound in accordance with any of claims 1-22, 23 or 24, in a pharmaceutically acceptable carrier.

26. A method for enhancing AMPA receptor function in a mammalian subject in need thereof, wherein said enhancing is effective to alleviate impairment of memory or other cognitive functions caused by a hypoglutamatergic condition or by deficiency in the number or strength of excitatory synapses or in the number of AMPA receptors, said method comprising administering to said subject a compound in accordance with any of claims 1-22, 23 or 24, in a pharmaceutically acceptable carrier.

27. A method for enhancing AMPA receptor function in a mammalian subject in need thereof, wherein said enhancing is effective to treat schizophrenia or schizophreniform behavior, said method comprising administering to said subject a compound in accordance with any of claims 1-22, 23 or 24, in a pharmaceutically acceptable carrier.

28. A method for enhancing AMPA receptor function in a mammalian subject in need thereof, wherein said enhancing is effective to facilitate learning of behaviors dependent on AMPA receptor functioning, said method comprising administering to said subject a compound in accordance with any of claims 1-22, 23 or 24, in a pharmaceutically acceptable carrier.

29. A method for enhancing AMPA receptor function in a mammalian subject in need thereof, said method comprising administering to said subject a compound selected from the group consisting of:

a. 1-(benzo-2,1,3-thiadiazole-5-ylcarbonyl)piperidine
b. 1-(benzofurazan-5-ylcarbonyl)-4-fluoro-1,2,3,6-tetrahydropyridine
c. 1-(benzofurazan-5-ylcarbonyl)-1,2,3,6-tetrahydropyridine
d. 1-(benzofurazan-5-ylcarbonyl)-4,4-difluoropiperidine
e. 4-(benzofurazan-5-ylcarbonyl)thiomorpholine
f. 4-(benzofurazan-5-ylcarbonyl)-4-piperidone
in a pharmaceutically acceptable carrier.

Drawings