4-(aroylamino)piperidine-butanimide derivatives

• US 4,990,521 A
• Filed: 09/08/1989
• Issued: 02/05/1991
• Est. Priority Date: 07/03/1986
• Status: Expired due to Fees

• Current Assignee: Janssen Pharmaceuticals, Inc. (Johnson & Johnson)
• Original Assignee: Janssen Pharmaceuticals, Inc. (Johnson & Johnson)
• Inventors: Van Daele, Georges H. P., Sommen, Francois M., De Cleyn, Michel A. J., Vlaeminck, Freddy F.
• Primary Examiner(s): Waddell, Frederick E.
• Application Number:
  US07/405,575
• Time in Patent Office: 515 Days
• Field of Search: 514/316, 514/327
• US Class Current: 514/327
• CPC Class Codes: C07D 211/58 attached in position 4
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 405/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 409/12 linked by a chain containing hetero atoms as chain links
• CPC Class Codes: C07D 417/12 linked by a chain containing hetero atoms as chain links

Abstract

A method of treating warm-blooded animals suffering from diarrhea, which method comprises the administration of particular 4-(aroylamino)piperidinebutanamide derivatives and compositions containing the same. Novel 4-(aroylamino)piperidinebutanamide derivatives.

Claims

1. A method of treating warm-blooded animals suffering from diarrhea, which method comprises the systemic administration to warm-blooded animals of an amount effective in treating diarrhea of a compound having the formula:

##STR22## an N-oxide form, a pharmaceutically acceptable acid-solution salt, or a possible stereoisomeric form thereof, wherein

R¹ is a member selected from the group consisting of hydrogen, C_1-6 alkyl, aryl C_1-6 alkyl;

C_1-6 alkylcarbonyl, aminoC_1-6 alkyl, and mono- and di(C_1-6 alkyl)aminoC_1-6 alkyl;

R² is a member selected from the group consisting of hydrogen and C_1-6 alkyl;

Ar is a radical of the formula;

##STR23## wherein R³, R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 alkyloxy, halo, hydroxy, cyano, nitro, amino, mono- and di(C_1-6 alkyl)amino, aminocarbonyl, arylcarbonylamino, C_1-6 alkylcarbonylamino, C_1-6 alkylcarbonyl, C_1-6 alkylcarbonyloxy, aminosulfonyl, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, CI-6 alkylthio, mercapto, C3-6 alkynyloxy, C3-6 alkenyloxy, aryl C_1-6 alkyloxy, aryloxy, and C_1-6 alkyl substituted with up to 4 halo atoms;

Alk is --CH₂ --CH₂ - or --CH₂ --CH(CH₃)--;

Ar¹ and Ar² are, each independently, phenyl or halophenyl;

R⁶ and R⁷ are each independently hydrogen, C_1-6 alkyl, phenylmethyl, or 2-propenyl;

wherein aryl is 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, C_1-6 alkyl, C_1-6 alkyloxy, aminosulfonyl, C_1-6 alkylcarbonyl, nitro, trifluoromethyl, amino, aminocarboxyl, and phenylcarbonyl, said phenylcarbonyl being optionally substituted with up to 3 halo atoms.

2. A method according to claim 1 wherein the active compound is a compound of formula (I) wherein the substituents in the 3- and 4-position of the piperidine ring have the trans configuration.

3. A method according to claim 2 wherein Ar is a radical of formula (a-1) wherein R³ is arylC_1-6 alkyloxy, aryloxy, C_3-6 alkenyloxy, C_3-6 alkynyloxy, and C_1-4 alkyl substituted with up to 4 halo atoms, and R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, C_1-6 alkylC_1-6 alkyloxy, halo, hydroxy, cyano, nitro, amino, mono- and di(C_1-6 alkyl)amino, aminocarbonyl, arylcarbonylamino, C_1-6 alkylcarbonylamino, C_1-6 alkylcarbonyl, C_1-6 alkylcarbonyloxy, aminosulfonyl, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_1-6 alkylthio, mercapto, aryl C_1-6 alkyloxy, aryloxy, C_3-6 alkenyloxy, C_3-6 alkynyloxy, and C_1-6 alkyl substituted with up to 4 halo atoms.

4. A method according to claim 2 wherein Ar is a radical of formula (a-1) wherein R³, R⁴, and R⁵ are each independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 alkyloxy, halo, hydroxy, cyano, nitro, amino, mono- and di((C_1-6 alkyl)amino, aminocarbonyl, arylcarbonylamino, C_1-6 alkylcarbonylamino C_1-6 alkycarbonyl, C_1-6 alkylcarbonyloxy, aminosulfonyl, C_1-6 alkylsulfinyl C_1-6 alkylsulfonyl C_1-6 alkylthio, and mercapto.

5. A method according to claim 3 wherein Ar is a radical of formula (a-1) wherein R³ is phenylmethoxy, phenyloxy, propenyloxy, or C_1-4 alkyl substituted with up to 4 halo substituents, and R⁴ and R⁵ are each independently hydrogen, C_1-4 alkyl, C_1-4 alkyloxy, halo, hydroxy, nitro, amino, phenylmethoxy, phenoxy, propenyloxy, or C_1-4 alkyl substituted with up to 4 halo atoms;

R¹ is hydrogen or C_1-4 alkyl; and

R⁶ and R⁷ are each independently hydrogen, C_1-4 alkyl, phenylmethyl, or 2-propenyl.

6. A method according to claim 5 wherein Ar is a radical of formula (a-1) wherein R³ is trifluoromethyl substituted on the meta position and R⁴ and R⁵ are each independently hydrogen, methyl, methoxy, halo, hydroxy, nitro, amino, trifluoromethyl, phenylmethoxy, phenoxy, or propenyloxy.

7. A method according to claim 1, wherein R³ is C_1-6 alkyl substituted with 1-4 halo atoms.

14. A method according to claim 1 wherein the compound is trans-3-hydroxy-N,N,γ

-trimethyl-α

α

-diphenyl-4-[[3-(trifluoromethyl)-benzoyl]amino]-1-piperidinebutanamide.

8. An anti-diarrheal composition comprising an inert carrier and as an active ingredient an anti-diarrheal amount of at least one compound having the formula:

##STR24## an N-oxide form, a pharmaceutically acceptable acid-addition salt, or a possible stereoisomeric form thereof, wherein

R¹ is a member selected from the group consisting of hydrogen, C_1-6 alkyl, acryl C_1-6 alkyl, C_1-6 alkylcarbonyl, amino C_1-6 alkyl, and mono- and di-(C_1-6 alkyl)amino C_1-6 alkyl;

R² is a member selected from the group consisting of hydrogen and C_1-6 alkyl;

Ar is a radical of the formula;

##STR25## wherein R³, is aryl C_1-6 alkyloxy, aryloxy, C_3-6 alkenyloxy, C_3-6 alkynyloxy, or C_1-5 alkyl substituted with 1-4 halo atoms, and R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 alkyloxy, halo, hydroxy, cyano, nitro, amino, mono- and di (C_1-6 alkyl)amino, aminocarbonyl, arylcarbonylamino, C_1-6 alkylcarbonylamino, C_1-6 alkylcarbonyl, C_1-6 alkylcarbonyloxy, aminosulfonyl, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_1-6 alkylthio, mercapto, C_3-6 alkylnyloxy, C_3-6 alkenyloxy, aryl C_1-6 alkyloxy, aryloxy, and C_1-6 alkyl substituted with up to 4 halo atoms;

Alk is --CH₂ --CH₂ --or --CH₂ --CH(CH₃)--;

Ar¹ and Ar² are each independently phenyl or halophenyl;

R⁶ and R⁷ are each independently hydrogen, C_1-6 alkyl, phenylmethyl, or 2-propenyl;

wherein aryl 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, C_1-6 alkyl, C_1-6 alkyloxy, aminosulfonyl, C_1-6 alkylcarbonyl, nitro, trifluoromethyl, amino, aminocarbonyl and phenylcarbonyl, said phenylcarbonyl being optionally substituted with up to 3 halo atoms.

9. An anti-diarrheal composition according to claim 8 wherein the active compound is a compound of formula (I) wherein the substituents in the 3- and 4-position of the piperidine ring have the trans configuration.

10. An anti-diarrheal composition according to claim 9 wherein Ar is a radical of formula (a-2) wherein R⁴ and R⁵ are each independently selected from the group consisting of hydrogen, C_1-6 alkyl, C_1-6 alkyloxy, halo, hydroxy, cyano, nitro, amino, mono- and di(C_1-6 alkyl) amino, aminocarbonyl, arylcarbonylamino, C_1-6 alkylcarbonylamino, C_1-6 aIkylcarbonyl, C_1-6 alkylcarbonyloxy, aminosulfonyl, C_1-6 alkylsulfinyl, C_1-6 alkylsulfonyl, C_1-6 alkylthio, and mercapto.

11. An anti-diarrheal composition according to claim 9 wherein Ar is a radical of formula (a-2) wherein R³ is phenylmethoxy, phenyloxy, propenyloxy, or C_1-4 alkyl substituted with up to 4 halo substituents;

R⁴ and R⁵ are each independently hydrogen, C_1-4 alkyl, C_1-4 alkyloxy, halo, hydroxy, nitro, amino, phenylmethoxy, phenoxy, propenyloxy, or C_1-4 alkyl substituted with up to 4 halo atoms;

R¹ is hydrogen or C_1-4 alkyl; and

R⁶ and R⁷ are each independently hydrogen, C_1-4 alkyl, phenylmethyl, or 2-propenyl.

12. An anti-diarrheal composition according to claim 11 wherein Ar is a radical of formula (a-2) wherein R³, is trifluoromethyl substituted on the meta position, and R⁴ and R⁵ are each independently hydrogen, methyl, methoxy, halo, hydroxy, nitro, amino, trifluoromethyl, phenylmethoxy, phenoxy, or propenyloxy.

13. An anti-diarrheal composition according to claim 8 wherein the compound is that wherein R^3'"'"' is C_1-6 alkyl substituted with 1-4 halo atoms.

15. An anti-diarrheal composition according to claim 8 wherein the compound is trans-3-hydroxy-N,N,γ

-trimethyl-α

,α

-diphenyl-4-[[3-(trifluoromethyl)benzoyl]amino]-1-piperidinebutanamide.