Acetamides

• US 5,472,961 A
• Filed: 03/02/1995
• Issued: 12/05/1995
• Est. Priority Date: 03/03/1994
• Status: Expired due to Fees

• Current Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Original Assignee: Merck Patent GmbH (Merck & Co., Inc.)
• Inventors: Seyfried, Christoph, Bartoszyk, Gerd, Greiner, Hartmut, Ackermann, Karl-August, Gottschlich, Rudolf, Barber, Andrew
• Primary Examiner(s): Ivy, C. Warren
• Assistant Examiner(s): NORTHINGTON DAVIS, ZINNA
• Application Number:
  US08/397,758
• Time in Patent Office: 278 Days
• Field of Search: 544/105, 548/321, 548/306.1, 514/230.5, 514/375, 514/387
• US Class Current: 514/230.5
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 235/26 Oxygen atoms
• CPC Class Codes: C07D 263/58 with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
• CPC Class Codes: C07D 265/36 condensed with one six-membered ring
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 401/14 containing three or more hetero rings
• CPC Class Codes: C07D 403/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 413/14 containing three or more hetero rings

Abstract

Novel acetamides of the formula I ##STR1## in which Q, R, X and Y have the meanings defined herein, have analgesic and neuroprotective properties and bind with high affinity to kappa receptors.

Claims

1. An acetamide compound according to formula I ##STR6## wherein Q is R₁ --CH(CH₂ Z)--NA--,

R is H, A or Ar

X and Y are each, independently of one another, --O--, --NH--,

--NA--, --CH₂ --O--, --CH₂ --NH-- or --CH₂ --NA--,

R¹ is A or Ar,

A is alkyl having 1 to 6 C atoms,

Z is 1-pyrrolidinyl or 3-hydroxy-1-pyrrolidinyl,

Ar is phenyl, unsubstituted or substituted once or twice

by A, OA or Hal,

Hal is F, Cl, Br or I and

n is 1 or 2, or

a physiologically acceptable salt thereof.

2. A compound according to claim 1, wherein said compound is:

(a) N-methyl-N-[(1S)-1phenyl-2-((3S)-3-hydroxypyrrolidino)ethyl]-2-(2,3-dihydro-2-oxobenzoxazol-5-yl)acetamide or a physiologically acceptable salt thereof;

(b) N-methyl-N-(2S)-[1-((3S)-3-hydroxypyrrolidino-3-methyl-2-butyl]-2-(2,3-dihydro-2-oxobenzoxazol-5-yl)acetamide or a physiologically

acceptable salt thereof;

(c) N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidino)ethyl]-2-(2,3-dihydro-2-oxobenzimidazol-5-yl)acetamide or a physiologically acceptable salt thereof;

(d) N-methyl-N-[(1S)-1-phenyl-2-((3S)-3-hydroxypyrrolidino)ethyl]-2-(2,3-dihydro-1-methyl-2-oxobenzimidazol-5-yl)acetamide or a physiologically acceptable salt thereof;

or

(e) N-methyl-N-[(1S)-1-phenyl-2-pyrrolidinoethyl ]-2 (2,3-dihydro-1-methyl-2-oxobenzimidazol-5-yl) acetamide or a physiologically acceptable salt thereof.

3. A compound according to claim 1, wherein

R is H, X is --O--CH₂ -- and Y is --NH--;

R is H, X=Y and are --NH-- or --NA--;

R is H, X is --O-- and Y is --NH--;

R is H, X is --NH-- and Y is --NA--;

or

R is H, X is --NA-- and Y is --NH--.

4. A compound according to claim 3, where Q is

(a) N-methyl-N-(1-phenyl-2-pyrrolidinoethyl)amino;

(b) N-methyl-N-[1-phenyl-2-(3-hydroxypyrrolidino)ethyl]amino;

(c) N-methyl-N-(1-pyrrolidino-3-methyl-2-butyl)amino;

(d) N-methyl-N-[1-(3-hydroxypyrrolidino)-3-methyl-2-butyl]amino; and

(e) N-(1-phenyl-2-pyrrolidinoethyl)amino.

5. A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable vehicle.

6. A pharmaceutical composition, comprising a compound of claim 2 and a pharmaceutically acceptable vehicle.

7. A pharmaceutical composition, comprising a compound of claim 3 and a pharmaceutically acceptable vehicle.

8. A pharmaceutical composition, comprising a compound of claim 4 and a pharmaceutically acceptable vehicle.

9. A pharmaceutical composition according to claim 5, wherein the composition is a solid, liquid, or semi-liquid.

10. A pharmaceutical composition according to claim 5, further comprising an additional active ingredient.

11. A method of relieving pain or producing analgesia, comprising administering an effective amount of a compound according to claim 1.

12. A method of relieving pain or producing analgesia, comprising administering an effective amount of a compound according to claim 2.

13. A method of reducing secondary damage after ischaemia, comprising administering an effective amount of a compound according to claim 1.

14. A method for reducing secondary damage after ischaemia, comprising administering an effective amount of a compound according to claim 2.

15. A method of binding a compound according to formula I of claim 1 to a kappa receptor, comprising administering an effective amount of said compound, wherein said amount is effective in producing analgesia or reducing secondary damage after ischaemia.