Anti-emetic quinuclidinyl benzamides

• US 4,820,715 A
• Filed: 05/18/1987
• Issued: 04/11/1989
• Est. Priority Date: 06/28/1984
• Status: Expired due to Fees

• Current Assignee: Bristol-Myers Squibb Company
• Original Assignee: Bristol-Myers Squibb Company
• Inventors: Willner, David, Monkovic, Ivo
• Primary Examiner(s): Schwartz, Richard A.
• Application Number:
  US07/051,880
• Time in Patent Office: 694 Days
• Field of Search: 546/133, 514/305
• US Class Current: 514/305
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07C 237/44 having carbon atoms of carboxamide groups, amino groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
• CPC Class Codes: C07C 243/00 Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
• CPC Class Codes: C07C 255/00 Carboxylic acid nitriles cyanogen or compounds thereof C01C3/00
• CPC Class Codes: C07C 2601/14 The ring being saturated
• CPC Class Codes: C07D 209/48 with oxygen atoms in positions 1 and 3, e.g. phthalimide
• CPC Class Codes: C07D 211/42 attached in position 3 or 5
• CPC Class Codes: C07D 213/30 Oxygen atoms
• CPC Class Codes: C07D 233/22 Radicals substituted by oxygen atoms
• CPC Class Codes: C07D 261/08 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 263/24 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
• CPC Class Codes: C07D 295/185 from aliphatic carboxylic acids
• CPC Class Codes: C07D 317/22 etherified
• CPC Class Codes: C07D 333/16 by oxygen atoms
• CPC Class Codes: C07D 453/02 containing not further condensed quinuclidine ring systems

Abstract

Novel substituted benzamides of the formula ##STR1## wherein R¹, R², R³, R⁴, R⁵ and A are as defined herein are useful in the treatment of emesis, and particularly chemotherapy-induced emesis in cancer patients. Some of the compounds are also useful in disorders relating to impaired gastric motility.

Claims

1. A compound of the formula ##STR64## wherein R³ is hydrogen or, when R⁴ and R⁵ are each hydrogen, R³ may be (lower)alkoxy;

R⁴ is hydrogen, amino, lowerallylamino, acetamido or (lower)alkoxy;

R⁵ is hydrogen, chloro, bromo, fluoro, trifluoromethyl, (lower)alkylthio, (lower)alkanesulfinyl, (lower)alkanesulfonyl,

sulfamyl or ##STR65## , or R⁴ and R⁵, taken together, may be --HN--N═

N--;

R⁶ is (lower)alkyl, (lower)alkenyl or (lower)alkynyl;

R¹ is ##STR66## wherein A is oxygen or ##STR67## wherein X is oxygen, sulfur or ═

NOR¹⁶ ;

Z is --(CH₂)_p --, O, N or ##STR68## p is 0, 1 or 2;

q is an integer of from 0 to 4, inclusive;

R⁹ is hydrogen or (lower)alkyl;

R¹¹, R¹², R¹³, R¹⁵, and R¹⁶ are the same or different, and are hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkoxy(lower)alkyl, cycloalkyl containing from 5 to 7 carbon atoms, inclusive, or ##STR69## wherein R¹⁷ is hydrogen, halogen, hydroxy, (lower)alkyl or (lower)alkoxy;

provided that, when R¹¹, R¹⁵ or R¹⁶ is (lower)alkenyl or (lower)alkynyl, the unsaturated carbon atom may not be directly attached to an oxygen or nitrogen atom;

R¹⁵ can additionally be loweralkylcarbonyl;

R¹⁴ is hydrogen, halogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cycloalkyl containing from 5 to 7 carbon atoms, inclusive, hydroxy, (lower)alkoxy, (lower)alkenyloxy, (lower)alkoxycarbonyl(lower)alkenyl, hydrazino, acetylhydrazino, thienyl, phenyl, ##STR70## R²⁰ and R²¹ are each hydrogen or R¹² and R¹³, taken together with the carbon atom to which they are attached, may form a saturated ring of from 5 to 7 atoms, inclusive;

or R¹² and R¹⁴, taken together with the carbon atoms to which they are attached, may form a saturated or unsaturated ring of from 5 to 7 atoms, inclusive;

or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or quaternary ammonium salt thereof.

2. A compound of claim 1 having the formula ##STR71## wherein R¹ is ##STR72## and wherein R² is H, ##STR73## wherein X is oxygen, sulfur or ═

NOR¹⁶ ;

Z is --(CH₂)_p --, O, N or ##STR74## p is 0, 1 or 2;

q is an integer of from 0 to 4;

R⁹ is hydrogen or (lower)alkyl;

R¹¹, R¹², R¹³, R¹⁵ and R¹⁶ are the same or different, and are hydrogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, (lower)alkoxy(lower)alkyl or cycloalkyl containing from 5 to 7 carbon atoms, inclusive, provided that, when R¹¹, R¹⁵ or R¹⁶ is (lower)alkenyl or (lower)alkynyl, the unsaturated carbon atom may not be directly attached to an oxygen or nitrogen atom;

R¹⁵ can additionally be loweralkylcarbonyl;

R¹⁴ is hydrogen, halogen, (lower)alkyl, (lower)alkenyl, (lower)alkynyl, cycloalkyl containing from 5 to 7 carbon atoms, inclusive, (lower)alkoxy, hydroxy, (lower)alkenyloxy, hydrazino, (lower)alkoxycarbonyl(lower)alkenyl, acetylhydrazino, thienyl, phenyl or ##STR75## R²⁰ and R²¹ are each hydrogen or R¹² and R¹⁴, taken together with the carbon atoms to which they are attached, may form a saturated or unsaturated ring of from 5 to 7 atoms, inclusive;

or a nontoxic pharmaceutically acceptable salt, hydrate, solvate or quaternary ammonium salt thereof.

3. The compound of claim 1 wherein R² is loweralkenyl or loweralkynyl.

4. The compound of claim 1 wherein R² is butan-2-on-3-yl.

5. The compound of claim 1 which is 4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-hydroxybenzamide.

6. The compound of claim 1 which is 4-Amino-N-(1-azabicyclo[2.2.2.]oct-3-yl)-2-(butan-2-on-3-yl)oxy-5-chlorobenzamide.

7. The compound of claim 1 which is 2-Allyloxy-4-amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chlorobenzamide.

8. The compound of claim 1 which is 4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-propargyloxybenzamide

9. The compound of claim 1 which is 4-Amino-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-[2-(methylsulfinyl)ethoxy]benzamide.

10. The compound of claim 1 which is N-1-Azabicyclo[2.2.2]oct-3-yl)-5-chloro-4-methylamino-2-hydroxybenzamide.

11. A pharmaceutical composition for the alleviation of nausea and vomiting, which commprises an effective antiemitic amount of at least one compound of Formula XXI of claim 1, or a salt, hydrate or solvate thereof, plus a pharmaceutically acceptable carrier.

12. A pharmaceutical composition for the treatment of disorders related to impaired gastric motility, which comprises an effective gastric motility facilitating amount of at least one compound of Formula XXI of claim 1, or a salt, hydrate or solvate thereof, and a pharmaceutically acceptable carrier.

13. A method of alleviating nausea and vomiting in a warm-blooded mammal in need thereof, which comprises administering to said mammal an effective antiemetic amount of at least one compound of Formula XXI of claim 1, or a salt, hydrate or solvate thereof, in a pharmaceutically acceptable carrier.

14. A method of treating disorders related to impaired gastric motility in a warm-blooded mammal, which comprises administering to said mammal an effective gastric motility facilitating amount of at least one compound of Formula XXI of claim 1, or a salt, hydrate or solvate thereof, in a pharmaceutically acceptable carrier.