Phenyl-oxo-alkyl-(4-piperidinyl)benzoate derivatives

• US 5,872,131 A
• Filed: 03/24/1997
• Issued: 02/16/1999
• Est. Priority Date: 09/27/1994
• Status: Expired due to Term

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Verdonck, Marc Gustaaf Celine, Bosmans, Jean-Paul Rene Marie Andre, Van Daele, Peter Jules Victor, Hendrickx, Marie-Louise, Van Daele, Glenn Kurt Ludo, Van Daele, Kurt Godfried Cornelius Emile
• Primary Examiner(s): Kight, John
• Assistant Examiner(s): SEAMAN, D MARGARET M
• Application Number:
  US08/809,502
• Time in Patent Office: 694 Days
• Field of Search: 546/196, 546/218, 514/320, 514/327
• US Class Current: 514/320
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: C07D 211/46 having a hydrogen atom as the second substituent in position 4
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/14 containing three or more hetero rings

Abstract

The present invention is concerned with novel benzoate derivatives having the formula ##STR1## the N-oxide forms, the pharmaceutically acceptable acid addition salts and the stereochemically isomeric forms thereof, wherein R¹ is halo or C_1-6 alkylsulfonylamino; either R² is hydrogen and R³ is C_1-6 alkyl, C_2-6 alkenyl or C_2-6 alkynyl; or R² and R³ taken together form a bivalent radical of formula --CH═CH-- (a), --(CH₂)₂ -- (b), or --(CH₂)₃ -- (c); in the bivalent radicals of formula (a), (b) or (c) one or two hydrogen atoms may be replaced by C_1-6 alkyl; Alk is C_1-6 alkanediyl; R⁴ is hydrogen or C_1-6 alkyloxy; R⁵, R⁶ and R⁷ each independently are hydrogen, halo, C_1-6 alkyl, C_1-6 alkyloxy; or R⁵ and R⁶ taken together may also form a bivalent radical of formula: --NR⁸ C(O)NR⁹ --, --NH--C(NHR¹⁰)═N--, --O--(CH₂)_m --O--; R⁸ and R⁹ each independently are hydrogen or C_1-6 alkyl; R¹⁰ is hydrogen, C_1-6 alkylcarbonyl, C_1-6 alkyloxycarbonyl; m is 1 or 2. Pharmaceutical compositions comprising said compounds, processes for preparing compounds and compositions as well as the use as a medicine, in particular for the treatment of intestinal disorders involving a decreased colon motility are described.

Claims

1. A compound of formula (I) ##STR14## a N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein:

R¹ is halo or C_1-6 alkylsulfonylamino;

either R² is hydrogen and R³ is C_1-6 alkyl, C_2-6 alkenyl or C_2-6 alkynyl;

or

R² and R³ taken together form a bivalent radical of formula;

space="preserve" listing-type="equation">--CH═

CH-- (a),

space="preserve" listing-type="equation">--(CH.sub.2).sub.2 -- (b),

or

space="preserve" listing-type="equation">--(CH.sub.2).sub.3 -- (c);

in the bivalent radicals of formula (a), (b) or (c) one or two hydrogen atoms may be replaced by C_1-6 alkyl;

Alk is C_1-6 alkanediyl;

R⁴ is hydrogen or C_1-6 alkyloxy;

R⁵, R⁶ and R⁷ each independently are hydrogen, halo, C_1-6 alkyl, C_1-6 alkyloxy;

or R⁵ and R⁶ taken together may also form a bivalent radical of formula;

##STR15## R⁸ and R⁹ each independently are hydrogen or C_1-6 alkyl;

R¹⁰ is hydrogen, C_1-6 alkylcarbonyl, C_1-6 alkyloxycarbonyl;

m is 1 or 2.

2. A compound as claimed in claim 1 wherein R¹ is chloro.

3. A compound as claimed in claim 1 wherein R² and R³ taken together form a bivalent radical of formula (b).

4. A compound as claimed in claim 1 wherein Alk is 1,3-propanediyl.

5. A compound as claimed in claim 1 wherein the compound is

cis-3-methoxy-1- 4-oxo-4-(3,4,5-trimethoxyphenyl)butyl!-4-piperidinyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate;

1- 4-oxo-4-(3,4,5-trimethoxyphenyl)butyl!-4-piperidinyl-4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate;

1- 4(2,3-dihydro-2-oxo-1H-benzimidazol-5-yl)-4-oxobutyl!-4-piperidinyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate;

1- 4-(4-methoxy-3,5-dimethylphenyl)-4-oxobutyl!-4-piperidinyl 4-amino-5-chloro-2,3-dihydro-7-benzofurancarboxylate;

a stereoisomeric form thereof or a pharmaceutically acceptable acid addition salt thereof.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound as claimed in claim 1 and a pharmaceutically acceptable carrier.

7. An intermediate of formula ##STR16## a N-oxide form, a pharmaceutically acceptable acid addition salt or a stereochemically isomeric form thereof, wherein R¹ to R⁴, R⁷ and Alk are defined as in claim 1.

8. A method for stimulating intestinal motility in warm-blooded mammals which comprises administering to warm-blooded mammals a therapeutically effective amount of a compound as defined in claim 1.

9. A method for stimulating intestinal motility in warm-blooded mammals which comprises administering to warm-blooded mammals a therapeutically effective amount of a compound as defined in claim 2.

10. A method for stimulating intestinal motility in warm-blooded mammals which comprises administering to warm-blooded mammals a therapeutically effective amount of a compound as defined in claim 3.

11. A method for stimulating intestinal motility in warm-blooded mammals which comprises administering to warm-blooded mammals a therapeutically effective amount of a compound as defined in claim 4.

12. A method for stimulating intestinal motility in warm-blooded mammals which comprises administering to warm-blooded mammals a therapeutically effective amount of a compound as defined in claim 5.

13. A compound as claimed in claim 1, wherein R¹ is fluoro, chloro or bromo;

R³ is C_1-6 alkyl or R² and R³ taken together are a bivalent radical of formula (b);

Alk is 1,2 ethanediyl, 1,3-propanediyl or 1,4 butanediyl;

R⁴ is hydrogen or methoxy;

R⁵, R⁶ and R⁷ are hydrogen, C_1-6 alkyl, C_1-6 alkyloxy or R⁵ and R⁶ taken together are a bivalent radical of formula (d) or (e).

14. A compound according to claim 1, wherein R⁵, R⁶ and R⁷ are methoxy.

15. A compound according to claim 1, wherein R⁷ is hydrogen and R⁵ and R⁶ taken together form a radical of formula (d) wherein R⁸ and R⁹ are hydrogen.

16. A compound according to claim 1, wherein R⁵ and R⁷ are methyl and R⁶ is methoxy.