Therapeutic heterocyclic compounds

• US 5,863,935 A
• Filed: 06/06/1995
• Issued: 01/26/1999
• Est. Priority Date: 06/07/1990
• Status: Expired due to Term

• Current Assignee: Astrazeneca UK Limited (Astrazeneca PLC)
• Original Assignee: Zeneca Incorporated (Astrazeneca PLC)
• Inventors: Robertson, Alan D., Glen, Robert C., Hill, Alan P., Martin, Graeme R.
• Primary Examiner(s): CHANG, CELIA C
• Application Number:
  US08/471,229
• Time in Patent Office: 1,330 Days
• Field of Search: 546/201, 546/273, 548/181, 548/229, 548/490, 548/491, 548/504, 548/505, 548/517, 548/518, 514/414
• US Class Current: 514/414
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

##STR1## The present invention is concerned with compounds of formula (I), wherein n is an integer of from 0 to 3: W is a group of formula (i), (ii), or (iii), wherein R is hydrogen or C_1-4 alkyl, X is --O--, --S--, --NH--, or --CH₂ --, Y is oxygen or sulphur and the chiral center (*) in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions: and Z is a group of formula (iv), (v), or (vi), wherein R¹ and R² are independently selected from hydrogen and C_1-4 alkyl and R³ is hydrogen or C_1-4 alkyl; and their salts, solvates and physiologically functional derivatives, with processes for their preparation, with medicaments containing them and with their use as therapeutic agents, particularly in the prophylaxis and treatment of migraine.

Claims

1. A process for the preparation of a compound of formula (I) ##STR37## wherein n is an integer of from 0 to 3;

W is a group of formula (i), (ii), or (iii) ##STR38## wherein R is hydrogen or C_1-4 alkyl, X is --O--, --S--, --NH--, or --CH₂ --, Y is oxygen or sulphur and the chiral center * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions; and

Z is a group of the formula (iv)

space="preserve" listing-type="equation">CH.sub.2 CH.sub.2 NR.sup.1 R.sup.2 (iv)

wherein R¹ and R² are independently selected from hydrogen and C_1-4 alkyl;

which process comprises

reacting a compound of formula (II) ##STR39## wherein n and W are as hereinbefore defined, with a compound of formula (III) ##STR40## or a carbonyl-protected form thereof, wherein L is --NR¹ R² wherein R¹ and R² are as hereinbefore defined or halogen or a protected amino group which can be converted in situ to an amino group;

and optionally converting the compound of formula (I) so formed to a corresponding physiologically acceptable salt or solvate.

2. A process for the preparation of a compound of formula (I) ##STR41## wherein n is an integer of from 0 to 3;

W is a group of formula (i), (ii), or (iii) ##STR42## wherein R is hydrogen or C_1-4 alkyl, X is --O--, --S--, --NH--, or --CH₂ --, Y is oxygen or sulphur and the chiral center * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions; and

Z is a group of the formula (vi) ##STR43## wherein R³ is hydrogen or C_1-4 alkyl, which process comprises

(1) condensing a compound of the formula;

##STR44## where W and n are as defined above with a compound of the formula (XXVIII) ##STR45## wherein R³ is as defined above, and thereafter (2) reducing the reaction product of step (1) by catalytic hydrogenation to produce a compound of the formula;

##STR46## and optionally converting the compound of formula (I) so formed to a corresponding physiologically acceptable salt or solvate.

3. A process for the preparation of the compound N,N-dimethyl-2- 5-(2-oxo-1,3-oxazolidin-4-ylmethyl)-1H-indol-3-yl!ethylamine in either its (S) or (R) form or as a mixture thereof in any proportions;

which comprises reacting a compound of formula (II) ##STR47## wherein n is 1 and W is a group ##STR48## and the chiral center * is in its (S) or (R) form or is a mixture thereof with a compound of formula (III) ##STR49## or a carbonyl-protected form thereof, wherein L is --NR¹ R² wherein R¹ and R² are each methyl or protected amino group which can be converted in situ to a dimethyl amino group

and optionally converting said compound to a corresponding physiologically acceptable salt or solvate.

4. The compound N-methyl-2- 5-(2-oxo-1,3-oxazolidin-4-yl-methyl)-1H-indol-3-yl!ethylamine or a pharmaceutically acceptable salt and/or solvate thereof.

6. A method of treating or preventing migraine comprising administering to a patient in need of the same an effective amount of a compound of claim 4 or claim 5.

7. A pharmaceutical composition comprising an effective amount of a compound of claim 4 or claim 5 together with a pharmaceutically acceptable carrier.

8. A pharmaceutical composition according to claim 6 which is in the form of a tablet or capsule.

5. The compound (S)-N-methyl-2- 5-(2-oxo-1,3-oxazolidin-4-yl-methyl)-1H-indol-3-yl!ethylamine or a pharmaceutically acceptable salt and/or solvate thereof.

9. A process for the preparation of a compound of formula (I) ##STR50## wherein n is an integer of from 0 to 3;

W is a group of formula (i), (ii) ##STR51## wherein R is hydrogen or C_1-4 alkyl, X is --O--, --S--, --NH--, or --CH₂ --, Y is oxygen or sulfur and the chiral center * in formula (i) or (ii) is in its (S) or (R) form or is a mixture thereof in any proportions; and

Z is a group of the formula (iv) or (vi) ##STR52## wherein R¹ and R² are independently selected form hydrogen and C_1-4 alkyl;

and R³ is hydrogen or C_1-4 alkyl;

which process comprises

reacting a compound of formula (XV) ##STR53## wherein n, R and X are as hereinbefore defined and Z is a group of formula (iv) or (vi), with a compound of formula (VII) ##STR54## wherein Y is as hereinbefore defined and J and K, which may be the same or different, are independently selected from chlorine, ethoxy, trichloromethyl, trichloromethoxy or imidazoyl;

and optionally converting the compound of formula (I) so formed to a corresponding physiologically acceptable salt or solvate.