Heterocyclic compounds and their use

• US 5,773,452 A
• Filed: 10/31/1995
• Issued: 06/30/1998
• Est. Priority Date: 03/05/1993
• Status: Expired due to Fees

• Current Assignee: NOVO Nordisk Biotech Incorporated (Novo Nordisk A/S)
• Original Assignee: NOVO Nordisk Biotech Incorporated (Novo Nordisk A/S)
• Inventors: Mitch, Charles H., Olesen, Preben H., Sauerberg, Per
• Primary Examiner(s): FAN, JANE T
• Application Number:
  US08/513,851
• Time in Patent Office: 973 Days
• Field of Search: 546/268.7, 546/269.4, 546/257, 514/340, 514/342, 514/334
• US Class Current: 514/340
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/20 Hypnotics; Sedatives
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07D 413/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 417/14 containing three or more hetero rings

Abstract

The present invention relates to therapeutically active azabicyclic compounds of formula (1), wherein Z1 is oxygen or sulphur, a method of preparing the same and to pharmaceutical compositions comprising the compounds. The novel compounds are useful as stimulants of the cognitive function of forebrain and hippocampus of mammals and especially in the treatment of Alzheimer'"'"'s disease, severe painful conditions and glaucoma. ##STR1##

Claims

1. A compound of formula I ##STR7## wherein Z¹ is oxygen or sulphur;

R is --Z² --C_3-7 -cycloalkyl optionally substituted with C_1-6 -alkyl, --Z² --C_4-10 -(cycloalkylalkyl), --Z² --C_4-10 -(cycloalkenylalkyl), or --Z² --C_4-10 -(methylenecycloalkylalkyl), wherein Z² is oxygen or sulfur;

R⁵ and R⁶ may be present at any appropriate position and independently are (1) hydrogen, (2) straight or branched C_1-5 -alkyl, (3) straight or branched C_2-5 -alkenyl, (4) straight or branched C_2-5 -alkynyl, (5) straight or branched C_1-10 -alkoxy, (6 straight or branched C_1-5 -alkyl substituted with --OH, (7) --OH, (8) halogen, (9) --NH₂ or (10) carboxy; and

R¹ is hydrogen, straight or branched C_1-5 -alkyl, straight or branched C_2-5 -alkenyl or straight or branched C_2-5 -alkynyl;

or

a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 which is:

3-(3-(4-Cyclohexylbutoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(4-Methylenecyclohexylmethyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(3-Cyclohexenylmethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(2-Methylcyclopropylmethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(3-Cyclohexylpropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(2-Cyclohexylethoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(1-Cyclopropylmethylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-Cyclopentylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-Cyclohexylmethylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising a compound according to claim 1 together with a pharmaceutically acceptable carrier or diluent.

4. The pharmaceutical composition according to claim 3 in the form of an oral dosage unit or a parenteral dosage unit.

5. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof an effective amount of a compound according to claim 1.

6. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof a pharmaceutical composition according to claim 3.

7. A compound of formula I ##STR8## wherein Z¹ is oxygen or sulphur;

R is --Z² R², wherein Z² is oxygen or sulphur, and R² is straight or branched C_1-15 -alkyl, straight or branched C_2-15 -alkenyl, or straight or branched C_2-15 -alkynyl, each of which is substituted with --SH, --COOH, --NH--R², or --NR² R³ wherein R³ is straight or branched C_1-15 -alkyl, straight or branched C_2-15 -alkenyl, or straight or branched C_2-15 -alkynyl;

R⁵ and R⁶ may be present at any appropriate position and independently are (1) hydrogen, (2) straight or branched C_1-5 -alkyl, (3) straight or branched C_2-5 -alkenyl, (4) straight or branched C_2-5 -alkynyl, (5) straight or branched C_1-10 -alkoxy, (6) straight or branched C_1-5 -alkyl substituted with --OH, (7) --OH, (8) halogen, (9) --NH₂ or (10) carboxy; and

R¹ is hydrogen, straight or branched C_1-5 -alkyl, straight or branched C_2-5 -alkenyl or straight or branched C_2-5 -alkynyl;

or

a pharmaceutically acceptable salt thereof.

8. The compound according to claim 7 which is:

3-(3-Dimethylaminoethoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-Dimethylaminopropoxy-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(3-Carboxypropylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(5-Carboxypentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(5-Mercaptopentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(6-Mercaptohexylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(4-Mercaptobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 7 which is:

3-(3-(3-Carboxypropoxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

or a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising a compound according to claim 7 together with a pharmaceutically acceptable carrier or diluent.

11. The pharmaceutical composition according to claim 10 in the form of an oral dosage unit or a parenteral dosage unit.

12. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof an effective amount of a compound according to claim 7.

13. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof a pharmaceutical composition according to claim 10.

14. A compound of formula I ##STR9## wherein Z¹ is oxygen or sulphur;

R is --Z² --X, wherein Z² is oxygen or sulphur and X is a heterocyclic group selected from the group consisting of 1,3-dioxolanyl, pyridyl, thienyl, pyrrolidonyl, oxazolidonyl, thiazolidonyl, pyrrolidinyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, tetrazolyl, thiazolyl and oxazolyl, which heterocyclic group is optionally substituted at carbon or nitrogen atom(s) with straight or branched C_1-6 -alkyl, C_1-6 -alkoxy, C_1-6 -alkylthio, phenyl, benzyl or pyridine; and

R⁵ and R⁶ may be present at any appropriate position and independently are (1) hydrogen, (2) straight or branched C_1-5 -alkyl, (3) straight or branched C_2-5 -alkenyl, (4) straight or branched C_2-5 -alkynyl, (5) straight or branched C_1-10 -alkoxy, (6) straight or branched C_1-5 -alkyl substituted with --OH, (7) --OH, (8) halogen, (9) --NH₂ or (10) carboxy;

R¹ is hydrogen, straight or branched C_1-5 -alkyl, straight or branched C_2-5 alkenyl or straight or branched C_2-5 -alkynyl;

or

a pharmaceutically acceptable salt thereof.

15. The compound according to claim 14 wherein X is 1,2,5-thiadiazolyl which is substituted with C_1-6 -alkoxy.

16. The compound according to claim 14 which is:

3-(3-(4-Ethoxy-1,2,5-thiadiazol-3-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(4-Ethylthio-1,2,5-thiadiazol-3-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(4-Butylthio-1,2,5-thiadiazol-3-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(4-Propoxy-1,2,5-thiadiazol-3-ylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

or

a pharmaceutically acceptable salt thereof.

17. A pharmaceutical composition comprising a compound according to claim 14 together with a pharmaceutically acceptable carrier or diluent.

18. The pharmaceutical composition according to claim 17 in the form of an oral dosage unit or a parenteral dosage unit.

19. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof an effective amount of a compound according to claim 14.

20. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof a pharmaceutical composition according to claim 17.

21. A compound of formula I ##STR10## wherein Z¹ is oxygen or sulphur;

R is --Z² R², wherein Z² is oxygen or sulphur and R² is an indenyl or naphthalylyl group;

R⁵ and R⁶ may be present at any appropriate position and independently are (1) hydrogen, (2) straight or branched C_1-5 -alkyl, (3) straight or branched C_2-5 -alkenyl, (4) straight or branched C_2-5 -alkynyl, (5) straight or branched C_1-10 -alkoxy, (6) straight or branched C_1-5 -alkyl substituted with --OH, (7) --OH, (8) halogen, (9) --NH₂ or (10) carboxy;

R¹ is hydrogen, straight or branched C_1-5 -alkyl, straight or branched C_2-5 -alkenyl or straight or branched C_2-5 -alkynyl;

or

a pharmaceutically acceptable salt thereof.

22. The compound according to claim 21 which is:

3-(3-(2,3-Dihydro-1-indenyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(1,2,3,4-Tetrahydro-2-naphtalyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

or

a pharmaceutically acceptable salt thereof.

23. A pharmaceutical composition comprising a compound according to claim 21 together with a pharmaceutically acceptable carrier or diluent.

24. The pharmaceutical composition according to claim 23 in the form of an oral dosage unit or a parenteral dosage unit.

25. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof an effective amount of a compound according to claim 21.

26. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof a pharmaceutical composition according to claim 23.

27. A compound of formula I ##STR11## wherein Z¹ is oxygen or sulphur;

R is --Z² --R² CO--R³, --Z² --R² --CO₂ --R³ or --Z² --R² --O₂ C--R³, wherein Z² is oxygen or sulphur, and R² and R³ independently are unsubstituted, straight or branched C_1-5 -alkyl, unsubstituted, straight or branched C_2-5 -alkenyl, or unsubstituted, straight or branched C_2-5 -alkynyl; and

R⁵ and R⁶ may be present at any appropriate position and independently are (1) hydrogen, (2) straight or branched C_1-5 -alkyl, (3) straight or branched C_2-5 -alkenyl, (4) straight or branched C_2-5 -alkynyl, (5) straight or branched C_1-10 -alkoxy, (6) straight or branched C_1-5 -alkyl substituted with --OH, (7) --OH, (8) halogen, (9) --NH₂ or (10) carboxy;

R¹ is hydrogen, straight or branched C_1-5 -alkyl, straight or branched C_2-5 -alkenyl or straight or branched C_2-5 -alkynyl;

or

a pharmaceutically acceptable salt thereof.

28. The compound according to claim 27 which is:

3-(3-(5-Oxyhexyloxy)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-Ethoxycarbonylpropylthio-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

3-(3-(1-Ethoxycarbonylpentylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

or

a pharmaceutically acceptable salt thereof.

29. A pharmaceutical composition comprising a compound according to claim 27 together with a pharmaceutically acceptable carrier or diluent.

30. The pharmaceutical composition according to claim 29 in the form of an oral dosage unit or a parenteral dosage unit.

31. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof an effective amount of a compound according to claim 27.

32. A method of treating Alzheimer'"'"'s disease comprising administering to a subject in need thereof a pharmaceutical composition according to claim 29.

33. A compound which is:

3-(3-(4-Phenylthiobutylthio)-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine;

or a pharmaceutically acceptable salt thereof.

34. A compound which is:

3-(3-1,2,5-thiadiazol-4-yl)-1,2,5,6-tetrahydro-1-methylpyridine or a pharmaceutically acceptable salt thereof.