Patent EA-001341-B1 (EA)
Title: Pyrrolidinyl and pyrrolinyl ethylamine compounds as kappa agonists
Inventor: ITO FUMITAKA
IPC: C07D/
Filed: 1997-08-21
Abstract: 1. A compound of the following formula    and the salts thereof, wherein  A is hydrogen, halo, hydroxy, C1-C6 alkyl, halo-C1-C6-alkyl, C1-C6-alkoxy, halo-C1-C6-alkoxy, oxo, OY, wherein Y is a hydroxy-protecting group, or is absent; the broken line represents an optional double bond with proviso that if the broken line is a double bond, then A is absent; Ar<1> is phenyl, optionally substituted by one or more substituents, selected from halo, hydroxy, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy-C1-C4-alkoxy, CF3, carboxy-C1-C4-alkoxy and C1-C4-alkoxycarbonyl-C1-C4-alkoxy; Ar<2> is aryl or heteroaryl selected from phenyl, naphthyl, pyridyl, thienyl, furyl, pyrrolyl and pyrimidyl, the aryl or heteroaryl being optionally substituted by one or more substituents selected from halo, hydroxy, amino, nitro, carboxy, C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylamino, di-C1-C4-alkylamino, halo-C1-C4-alkyl, C1-C4-alkylthio and sulfonylmethyl, R<1> is hydrogen, hydroxy, C1-C4-alkyl, C1-C4-alkoxy or OY wherein Y is a hydroxy-protecting group; and R<2> and R<3> are independently selected from hydrogen, hydroxy, C1-C7-alkyl optionally substituted by one or more hydroxy or halo, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C7-alkoxy, phenyl optionally substituted by halo, phenyl-C1-C7-alkyl, halo-substituted phenyl-C1-C7-alkyl, and (CH2)nX-R<4> wherein n is one or two, X is O, NH or S and R<4> is C1-C3-alkyl, or when Ar<2> is phenyl, -Ar<2>-C(=O)-N(R<2>)- is a phthalimide group and R<3> is C1-C7-alkyl, or R<2> and R<3>, together with the nitrogen atom to which they are attached, form a pyrrolidine, piperidine or morpholine ring, optionally substituted by C1-C3-alkyl or halo.  2. A compound according to claim 1, wherein  A is hydrogen, halo, hydroxy, oxo or OY; or if the broken line is a double bond, then A is absent;  Ar<1> is phenyl optionally substituted by one to three substituents selected from halo, hydroxy, C1-C4-alkoxy, carboxy-C1-C4-alkoxy and C1-C4-alkoxycarbonyl-C1-C4-alkoxy; Ar<2> is phenyl, pyridyl or thienyl, optionally substituted by one to two halo or C1-C4-alkoxy;  R<1> is hydrogen, hydroxy or C1-C4-alkyl; and R<2> and R<3> are independently selected from hydrogen, C1-C7-alkyl optionally substituted by one or more hydroxy or halo, C3-C6-cycloalkyl, C2-C6-alkenyl, C2-C6-alkynyl, C1-C4-alkoxyphenyl and halo-substituted C1-C7-alkyl, when Ar<2> is phenyl, -Ar<2>-C(=O)-N(R<2>)- is a phthalimide group and R<3> is C1-C7-alkyl, or R<2> and R<3>, together with the nitrogen atom to which they are attached, form a pyrrolidine or morpholine ring.  3. A compound according to claim 2, wherein A is hydrogen, fluorine, chlorine, hydroxy or OY wherein Y is methoxymethyl or tetrahydropyranyl; or if the broken line is a double bond, then A is absent; Ar<1> is phenyl optionally substituted by chlorine, hydroxy, methoxy or carboxymethoxy; Ar<2> is phenyl, pyridyl or thienyl, optionally substituted by chlorine, fluorine or methoxy;  R<1> is C1-C4-alkyl; R<2> is C1-C7-alkyl optionally substituted by hydroxy or fluorine, C2-C6-alkenyl, halo-substituted phenylmethyl or phenyl; and  R<3> is hydrogen or methyl; or  R<2> and R<3>, together with the nitrogen atom to which they are attached, form a pyrrolidine or morpholine ring.  4. A compound according to claim 3, wherein A is hydroxy, fluorine or chlorine; or if the broken line is a double bond, then  A is absent; Ar<1> is phenyl optionally substituted by carboxymethoxy; Ar<2> is phenyl optionally substituted by methoxy or pyridyl; R<1> is C1-C4-alkyl; R<2> is C1-C7-alkyl optionally substitute by hydroxy; and R<3> is hydrogen.  5. A compound according to claim 4 selected from  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-2-methoxy-N'-propylbenzamide;  6-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylnicotinamide;  4-{N-[1-(S)-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(2-(S)-hydroxypropyl)benzamide;  5-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylpicolinamide;  4-{N-methylamino-N-[2-(3-pyrrolin-1-yl)-1-(S)-phenylethyl]}-N'-propylbenzamide; and  4-{N-[2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'- (2-(S)-hydroxypropyl)benzamide.  6. A compound according to claim 3 selected from  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-isopropylbenzamide;  3-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;  2-chloro-4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-3-methoxy-N'-propylbenzamide;  3-chloro-4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[1-(S)-(3-hydroxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)ethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-(3-methoxyphenyl)ethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[1-(S)-phenyl-2-(pyrrolidin-1-yl)ethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[1-(S)-(3-chlorophenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)ethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-pyrrolidinebenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-morpholinebenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(2-(R)-hydroxypropyl)benzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-isobutylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-allylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(3,3,3-trifluoropropyl)benzamide;  3-fluoro-4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(2,2,3,3,3-pentafluoropropyl)benzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-tert-amylbenzamide;  5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylpicolinamide;  4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'- (2-(S)-hydroxypropyl)benzamide;  2-chloro-4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide; and  4-{N-[2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide.  7. A compound according to claim 2 selected from  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-methylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-ethylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-butylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-pentylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-phenylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(2-chlorobenzyl)benzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N',N'-dimethylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-methyl-N'-propylbenzamide;  5-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propyl-2-thiophenecarboxamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-amino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylphthalimide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-ethoxybenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(3-hydroxypropyl)benzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-cyclopropylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(S)-sec-butylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-(R)-sec-butylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propargylbenzamide;  4-{N-[1-(R)-(3-carboxymethoxyphenyl)-2-(3-(S)-hydroxypyrrolidin-1-yl)-ethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-tert-butylbenzamide;  4-{N-hydroxy-N-[2-(3-(S)-hydroxypyrrolidin-1-yl)-1-(S)-phenylethyl]amino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-hydroxyamino}-N'-propylbenzamide;  4-{N-[2-(3-(R)-fluoropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-fluoropyrrolidin-1-yl)-1-(R)-phenylethyl]-N-methylamino}-N'-propylbenzamide;  4-{N-[2-(3-(S)-chloropyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'- (2-(R)-hydroxypropyl)benzamide; and  4-{N-[2-(3-oxopyrrolidin-1-yl)-1-(S)-phenylethyl]-N-methylamino}-N'-propylbenzamide.  8. A pharmaceutical composition for the prevention or treatment of a medical condition for which agonist activity toward opioid kappa receptor is needed, in a mammalian subject, which comprises a therapeutically effective amount of a compound according to claim 1, and a pharmaceutically inert carrier.  9. A pharmaceutical composition according to claim 8, which is useful as an analgesic, anaesthetic, anti-inflammatory or neuroprotective agent, or useful in the treatment of arthritis, stroke or functional bowel disease.  10. A method for the treatment of a medical condition