Novel N-(3-hydroxy-4-piperidinyl)benzamide derivatives

• US 4,962,115 A
• Filed: 11/28/1989
• Issued: 10/09/1990
• Est. Priority Date: 10/01/1981
• Status: Expired due to Term

• Current Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceutica NV (Johnson & Johnson)
• Inventors: Van Daele, Georges
• Primary Examiner(s): Raymond, Richard L.
• Assistant Examiner(s): Trinh, Ba K.
• Application Number:
  US07/443,060
• Time in Patent Office: 315 Days
• Field of Search: 514/326, 514/329, 546/213, 546/221, 546/224
• US Class Current: 514/326
• CPC Class Codes: C07C 45/63 by introduction of halogen; by substitution of halogen atoms by other halogen atoms
• CPC Class Codes: C07C 49/83 polycyclic
• CPC Class Codes: C07D 211/44 attached in position 4
• CPC Class Codes: C07D 211/56 Nitrogen atoms nitro radicals C07D211/38
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 211/72 with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
• CPC Class Codes: C07D 211/74 Oxygen atoms
• CPC Class Codes: C07D 213/75 Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
• CPC Class Codes: C07D 231/12 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 233/56 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
• CPC Class Codes: C07D 235/26 Oxygen atoms
• CPC Class Codes: C07D 249/08 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
• CPC Class Codes: C07D 303/14 by free hydroxyl radicals
• CPC Class Codes: C07D 303/22 with monohydroxy compounds
• CPC Class Codes: C07D 307/87 Benzo [c] furans; Hydrogenated benzo [c] furans
• CPC Class Codes: C07D 309/30 Oxygen atoms, e.g. delta-lactones
• CPC Class Codes: C07D 317/16 Radicals substituted by halogen atoms or nitro radicals
• CPC Class Codes: C07D 401/04 directly linked by a ring-member-to-ring-member bond
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 405/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 407/12 : linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/06 : 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 471/04 : Ortho-condensed systems

Abstract

Novel N-(3-hydroxy-4-piperidinyl)benzamides and derivatives thereof, said compounds being useful as stimulators of the motility of the gastro-intestinal system.

Claims

1. A compound of the formula:

##STR60## the pharmaceutically acceptable acid addition salts thereof, the stereochemically isomeric forms, and the pharmaceutically acceptable quaternary ammonium salts thereof, wherein;

the substituents in the 3 and 4 positions in the piperidine ring have the cis configuration;

R¹ is a member selected from the group consisting of hydrogen, lower alkyl, (Ar¹) lower alkyl, lower alkylcarbonyl, aminolower alkyl, and mono- and di(lower alkyl)aminolower alkyl;

R² is hydrogen or lower alkyl;

R³, R⁴, and R⁵ each independently are hydrogen, lower alkyl, lower alkyloxy, halo, hydroxy, cyano, nitro, amino, mono- or di(lower alkyl)amino, aminocarbonyl, (Ar¹)carbonylamino, lower alkylcarbonylamino, lower alkylcarbonyl, lower alkylcarbonyloxy, aminosulfonyl, lower alkylsulfinyl, lower alkylsulfonyl, lower alkylthio or mercapto; and

L is a group of the formula;

space="preserve" listing-type="equation">Q--Y--C.sub.n H.sub.2n -- (b)

wherein;

n is an integer having a value of from 1 to 4 inclusive;

Y is a direct bond or a bivalent radical selected from the group consisting of --CO--, --NHCO--, --CONH--, --CH═

CH--, CR⁸ (Q)--, --C(OR⁶)(R⁷)--, --O--, --S--, --SO² --, and --NR⁹ --, wherein;

R⁶ is hydrogen or lower alkyl;

R⁷ is hydrogen, cycloalkyl, lower alkyloxy, or lower alkyl;

R⁸ is lower alkyloxycarbonyl, cyano, aminocarbonyl, or mono- or di(lower alkyl) aminocarbonyl; and

R⁹ is hydrogen, lower alkyl, Ar¹, (Ar¹) lower alkyl, (Ar¹)carbonyl, or (Arl)sulfonyl; and

Q is hydrogen, cycloalkyl, Ar¹, di(Ar¹)methyl, tri(Ar¹)methyl, and when Y is other than a direct bond Q may also be lower alkyl or (Ar¹)lower alkyl; and

wherein Ar¹ is a member selected from the group consisting of phenyl being optionally substituted with up to 3 substituents each independently selected from the group consisting of halo, hydroxy, lower alkyl, lower alkyloxy, aminosulfonyl, lower alkylcarbonyl, nitro, trifluoromethyl, amino, aminocarbonyl, phenylcarbonyl wherein said phenyl may be optionally substituted with up to 3 halo atoms, and thienyl substituted with halo or lower alkyl,

provided that L is other than benzyl or substituted benzyl.

2. A chemical compound according to claim 1 wherein R³, R⁴ and R⁵ are, each independently, selected from the group consisting of halo, amino, mono- and di(lower alkyl)amino and lower alkyloxy.

3. A chemical compound according to claim 1 wherein R³ is methoxy, R⁴ is amino or methylamino and R⁵ is chloro, said R³, R⁴ and R⁵ being attached to the phenyl ring in the 2-, respectively 4- and 5-positions.

5. A pharmaceutical composition in unit dosage form comprising per dosage unit an effective gastro-intestinal motility stimulating amount of a compound as described in claim 1, the pharmaceutically acceptable acid addition salts thereof, the stereochemically isomeric forms, and the pharmaceutically acceptable quaternary ammonium salts thereof.

6. A pharmaceutical composition according to claim 5 wherein R³, R⁴ and R⁵ are, each independently, selected from the group consisting of halo, amino, mono- and di-(lower alkyl)amino and lower alkyloxy.

7. A pharmaceutical composition according to claim 5 wherein R³ is methoxy, R⁴ is amino or methylamino and R⁵ is chloro, said R³, R⁴ and R⁵ being attached to the phenyl ring in the 2-, respectively 4- and 5-positions.

9. A method of stimulating the motility of the gastro-intestinal system which comprises the systemic administration to vertebrates of an effective gastro-intestinal motility stimulating amount of the compound as described in claim 1, the pharmaceutically acceptable acid addition salts thereof, the stereochemically isomeric forms, and the pharmaceutically acceptable quaternary ammonium salts thereof.

10. A method according to claim 9 wherein R³, R⁴ and R⁵ are, each independently, selected from the group consisting of halo, amino, mono- and di(lower alkyl)amino and lower alkyloxy.

11. A method according to claim 9 wherein R³ is methoxy, R⁴ is amino or methylamino and R⁵ is chloro, said R³, R⁴ and R⁵ being attached to the phenyl ring in the 2-, respectively 4- and 5-positions.

13. A compound according to claim 1 wherein Y is a direct bond, CO, NHCO, CONH, --CH═

CH--, O, S, or SO₂.

14. A pharmaceutical composition according to claim 5 wherein Y is a direct bond, CO, NHCO, CONH, --CH═

CH--, O, S, or SO₂.

15. A method according to claim 9 wherein Y is a direct bond, CO, NHCO, CONH, --CH═

CH--, O, S, or SO₂.

16. A chemical compound according to claim 2 or 3 wherein L is Ar¹ OC_n H_2n --.

17. A chemical compound according to claim 1 wherein L is Ar¹ OC_n H_2n --.

18. A chemical compound according to claim 2 or 3 wherein L is Ar¹ OC_n H₂ n-- and R₁ is H, lower alkyl, or CO-(lower alkyl).

19. A chemical compound according to claim 1 wherein L is Ar¹ OC_n H_2n -- nd R₁ is H, lower alkyl, or CO-(lower alkyl).

20. A chemical compound according to claim 2 or 3 wherein L is Ar¹ OC₃ H₆ --.

21. A chemical compound according to claim 1 wherein L is Ar¹ OC₃ H₆ --.

22. A chemical compound according to claim 2 or 3 wherein L is Ar¹ OC₃ H₆ -- and R₁ is H, lower alkyl, or CO-(lower alkyl).

23. A chemical compound according to claim 1 wherein L is Ar¹ OC₃ H₆ -- and R₁ is H, lower alkyl, or CO-(lower alkyl).

24. A pharmaceutical composition according to claim 6 or 7 wherein l is Ar¹ OC_n H_2n --.

25. A pharmaceutical composition according to claim 5 wherein I is Ar¹ OC_n H_2n --.

26. A pharmaceutical composition according to claim 6 or 7 wherein L is Ar¹ OC_n H_2n -- and R¹ is H, lower alkyl, or CO-(lower alkyl).

27. A pharmaceutical composition according to claim 5 wherein 1 is Ar¹ OC_n H_2n --and R¹ is H, lower alkyl, or CO-(lower alkyl).

28. A pharmaceutical composition according to claim 6 or 7 wherein L is Ar¹ OC₃ H₆ --.

29. A pharmaceutical composition according to claim 5 wherein L is Ar¹ OC₃ H₆ --.

30. A pharmaceutical composition according to claim 6 or 7 wherein L is Ar¹ OC₃ H₆ -- and R₁ is H, lower alkyl, or CO-(lower alkyl).

31. A pharmaceutical composition according to claim 5 wherein L is Ar¹ OC₃ H₆ - and R₁ is H, lower alkyl, or CO-(lower alkyl).

32. A method according to claim 10 or 11 wherein L is Ar¹ OC_n H_2n -.

33. A method according to claim 9 wherein L is Ar¹ OC_n H_2n.

34. A method according to claim 10 or 11 wherein L is Ar¹ OC_n H_2n --and R₁ is H, lower alkyl, or CO-(lower alkyl).

35. A pharmaceutical composition according to claim 9 wherein L is Ar¹ OC_n H_2n -- and R₁ is H, lower alkyl, or CO-(lower alkyl).

36. A method according to claim 10 or 11 wherein L is Ar¹ OC₃ H₆ --.

37. A method according to claim 9 wherein L is Ar¹ OC₃ H₆ --.

38. A method according to claim 10 or 11 wherein L is Ar¹ OC₃ H₆ and R₁ is H, lower alkyl, or CO-(lower alkyl).

39. A method according to claim 9 wherein L is Ar¹ OC₃ H₆ -- and R₁ is H, lower alkyl, or CO-(lower alkyl).

4. A chemical compound selected from the group consisting of 4-amino-5-chloro-N-2-methoxybenzamide, the pharmaceutically acceptable acid addition salts, the stereochemically isomeric forms and the pharmaceutically acceptable quaternary ammonium salts thereof.

8. A pharmaceutical composition in unit dosage form comprising per dosage unit an effective gastro-intestinal motility stimulating amount of a compound selected from the group consisting of 4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide, the pharmaceutically acceptable acid addition salts, the stereochemically isomeric forms and the pharmaceutically acceptable quaternary ammonium salts thereof.

12. A method of stimulating the motility of the gastrointestinal system which comprises the systemic administration to vertebrates of an effective gastro-intestinal motility stimulating amount of a compound selected from the group consisting of 4-amino-5-chloro-N-[1-[3-(4-fluorophenoxy)propyl]-3-methoxy-4-piperidinyl]-2-methoxybenzamide, the pharmaceutically acceptable acid addition salts, the stereochemically isomeric forms and the pharmaceutically acceptable quaternary ammonium salts thereof.