Method of reducing blood glucose

• US 5,741,791 A
• Filed: 12/13/1996
• Issued: 04/21/1998
• Est. Priority Date: 12/15/1995
• Status: Expired due to Fees

• Current Assignee: Novo Nordisk A/S
• Original Assignee: Novo Nordisk A/S
• Inventors: Olsen, Uffe Bang
• Primary Examiner(s): Cintins, Marianne M.
• Assistant Examiner(s): Jones, Dwayne C.
• Application Number:
  US08/766,839
• Time in Patent Office: 494 Days
• Field of Search: 514/212, 514/323, 514/324, 514/325, 514/454, 514/437
• US Class Current: 514/211.11
• CPC Class Codes: A61K 31/453 containing a six-membered ring with oxygen as a ring hetero atom
• CPC Class Codes: A61K 31/4535 containing a heterocyclic ring having sulfur as a ring hetero atom, e.g. pizotifen
• CPC Class Codes: A61K 31/454 containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
• CPC Class Codes: A61K 31/473 ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 31/5415 ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
• CPC Class Codes: A61K 31/551 having two nitrogen atoms, e.g. dilazep
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention relates to the use of compounds of the general formula ##STR1## for reducing blood glucose and/or inhibit the secretion, circulation or effect of insulin antagonizing peptides like CGRP or amylin. Hence the compound can be used in the treatment of insulin resistance related to NIDDM (non-insulin-dependent diabetes mellitus) or aging.

Claims

1. A method for reducing blood glucose and/or inhibiting the activity of CGRP comprising administering to a patient a clinically effective amount of a compound of formula I ##STR4## wherein R¹ and R² independently are hydrogen, halogen, trifluoromethyl, C_1-6 -alkyl or C_1-6 -alkoxy;

Y is >

N--CH₂ --, >

CH--CH₂ -- or >

C═

CH-- wherein only the underscored atom participates in the ring system;

X is --O--, --S--, CR⁷ R⁸, --CH₂ CH₂ --, --CH═

CH--CH₂ --, --CH₂ --CH═

CH--, --CH₂ CH₂ CH₂ --, --CH═

CH--, NR⁹ (C═

O)--, --O--CH₂ --, --(C═

O)-- or --(S═

O)-- wherein R⁷, R⁸ and R⁹ independently are hydrogen or C_1-6 -alkyl;

r is 1, 2, or 3;

m is 1 or 2;

n is 1 when m is 1 and n is 0 when m is 2;

R⁴ and R⁵ represents hydrogen or may--when m is 2--together represent a bond; and

R⁶ is OH or C_1-8 -alkoxy;

or

a pharmaceutically acceptable salt thereof.

2. The method according to claim 1 wherein R¹ and R² independently are hydrogen, halogen, triflouromethyl or methoxy.

3. The method according to claim 1 wherein Y is >

N--CH₂.

4. The method according to claim 3 wherein X is --O--, --S--, --(CH₂)₂ --, --(CH₂)₃ --, --CH═

CH--, --N(CH₃)(C═

O)--, --O--CH₂ --, --(C═

O)-- or --(S═

O)--.

5. The method according to claim 1 wherein Y is >

C═

CH--.

6. The method according to claim 5 wherein X is --O--, --S--, --(CH₂)₂ --, --(CH₂)₃ --, --CH═

CH--, --N(CH₃)(C═

O)--, --O--CH₂ --, --(C═

O)-- or --(S═

O)--.

7. The method according to claim 1 wherein X is --O--, --S--, --(CH₂)₂ --, --(CH₂)₃ --, --CH═

CH--, --N(CH₃)(C═

O)--, --O--CH₂ --, --(C═

O)-- or --(S═

O)--.

8. The method according to claim 1 wherein R⁶ is OH.

9. The method according to claim 1 wherein m is 1.

10. The method according to claim 1 wherein m is 2.

11. The method according to claim 1 wherein the compound is (R)-1-(3-(10,11-Dihydro-5H-dibenzo a,d!cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically salt.

12. The method according to claim 1 wherein the compound is in a form suitable for oral administration.

13. The method according to claim 1 wherein the compound is administered at a dose in a range from about 0.5 to 1000 mg/day.

14. The method according to claim 1 wherein the compound is

(R)-1-(3-(10,11-Dihydro-5H-dibenz b,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(4-(10,11-Dihydro-5H-dibenzo b,f!azepin-5-yl)-1-butyl)-3-piperidinecarboxylic acid;

(R)-1-(2-(10,11-Dihydro-5H-dibenzo b,f!azepin-5-yl)ethyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(3-chloro-10,11-dihydro-5H-dibenzo b,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

(S)-1-(3-(10,11-Dihydro-5H-dibenzo b,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

1-(3-(10,11-Dihydro-5H-dibenzo b,f!azepin-5-yl)-1-propyl)-3-pyrrolidinacetic acid;

1-(3-(10,11-Dihydro-5H-dibenzo b,f!azepin-5-yl)-1-propyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid;

(R)-1-(3-(6,7-Dihydro-5H-dibenzo b,g!azocin-12-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(3-Methoxy-10,11-dihydro-5H-dibenzo b,f!azepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

or

a pharmaceutically acceptable salt thereof.

15. The method according to claim 1 wherein the compound is

(R)-1-(3-(10-Methyl-11-oxo-10,11-dihydro-5H-dibenzo b,e! 1,4!diazepin-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(11H-10-Oxa-5-aza-5H -dibenzo a,d!cyclohepten-5-yl)-1-propyl)-3-piperidinecarboxylic acid;

or

a pharmaceutically acceptable salt thereof.

16. The method according to claim 1 wherein the compound is

(R)-1-(3-(5-Oxo-10H-phenothiazin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(10H-Phenoxazin-10-yl)-1-propyl)-3-piperidinecarboxylic acid;

or

a pharmaceutically acceptable salt thereof.

17. The method according to claim 1 wherein the compound is (R)-1-(3-(9(H)-Oxo-10H-acridin-10-yl)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof.

18. The method according to claim 1 wherein the compound is

(S)-1-(3-(10,11-Dihydro-5H-dibenzo a,d!cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid;

1-(3-(10,11-Dihydro-5H-dibenzo a,d!cyclohepten-5-ylidene)-1-propyl)-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid;

(R)-1-(3-Fluoren-9-ylidene)-1-propyl)-3-piperidinecarboxylic acid;

(R)-1-(3-(3-Methyl-10,11-dihydro-5H-dibenzo a,d!cyclohepten-5-ylidene)-1-propyl-3-piperidinecarboxylic acid;

1-(3-(5H-Dibenzo a,d!cyclohepten-5-ylidene)-1-propyl)-3-piperidinecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

19. The method according to claim 1 wherein the compound is 1-(3-(Thioxanthen-9-ylidene)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof.

20. The method according to claim 1 wherein the compound is (R)-1-(3-(6,7-Dihydro-5H-dibenzo b,g!azocin-12-yl)-1-propyl)-3-piperidinecarboxylic acid or a pharmaceutically acceptable salt thereof.