2-substituted-1-piperidyl benzimidazole compounds as ORL1-receptor agonists
First Claim
Patent Images
1. A compound of the following formula:
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or a salt thereof, whereinR is selected from the group consisting of (C3-C11)cycloalkyl, (C6-C16)bicycloalkyl, (C6-C16)tricycloalkyl and (C8-C16)tetracyclyoalkyl, wherein said groups are partially saturated, fully saturated or fully unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5)alkyl and (C3-C7)cycloalkyl;
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, mono-, di, or tri-halo (C1-C7)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, phenyl-(C1-C5)alkyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms, and said phenyl moiety in phenyl-(C1-C5)alkyl, aryl, or aromatic or non-aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, halo (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
N—
OH;
Y is selected from the group consisting of hydrogen, halo, amino, mercapto, (C1-C12)alky-M—
, (C3-C7)cycloalkyl-M—
, (C2-C6)alkenyl-M—
, aryl-M—
, aromatic or non-aromatic heterocyclic-M—
, aryl-(C1-C5)alkyl-M—
, aromatic or non-aromatic heterocyclic-(C1-C5)alkyl-M—
, said aromatic or non-aromatic heterocyclic moiety of said groups comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms, and M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO, NQ, NQCO, and CONQ, wherein Q is selected from the group consisting of hydrogen and (C1-C6)alkyl, said (C1-C12)alkyl, (C3-C7)cycloalkyl or (C2-C6)alkenyl moiety in said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, amino, (C1-C4)alkyl-NH—
, di-(C1-C4)alkyl-N—
, hydrazino, azido, ureido, amidino, guanidino, (C1-C4)alkoxy, (C1-C4)alkyl-S—
, (C1-C4)alkyl-SO— and
(C1-C4)alkyl-SO2—
, and said aryl, or aromatic or non-aromatic heterocyclic moiety of said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, halo (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di(C1-C4 alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
N—
OH; and
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylsulfonyl, (C1-C4)alkyl-CO—
, carboxy, (C1-C4)alkyl-COO—
, amino, NH2CO—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-SO2—
NH—
, phenyl and naphthyl.
1 Assignment
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Accused Products
Abstract
A compound of the formula:
or a pharmaceutically acceptable salt thereof, wherein R is unsubstituted, mono-, di- or tri-substituted (C3-C11)cycloalkyl or (C3-C11)cycloalkenyl or the like, A is unsubstituted (C1-C7)alkyl or (C2-C5 )alkenyl, or unsubstituted, mono-, di- or tri-substituted aryl, or aromatic-heterocyclic or the like, Y is hydrogen, halo, amino or mercapto, or unsubstituted, mono-, di- or tri- substituted (C1-C10)alkyl-M—, (C3-C7)cycloalkyl-M—, (C2-C6)alkenyl-M—, (C1-C4)alkyl-NH-((C1-C4)alkyl)-M—, di(C1-C4)alkyl-N-((C1-C4)alkyl)-M—, aryl-M—, aromatic or non-aromatic heterocyclic-M—, aryl-(C1-C5)alkyl-M— or aromatic non-aromatic heterocyclic-(C1-C5)alkyl-M—, wherein M is a covalent bond O, S, NH or the like, or the like; Z1, Z2, Z3 and Z4 are hydrogen or the like, has ORL1-receptor agonist activity, and are useful as analgesics or the like in mammalian subjects.
69 Citations
22 Claims
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1. A compound of the following formula:
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or a salt thereof, wherein R is selected from the group consisting of (C3-C11)cycloalkyl, (C6-C16)bicycloalkyl, (C6-C16)tricycloalkyl and (C8-C16)tetracyclyoalkyl, wherein said groups are partially saturated, fully saturated or fully unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5)alkyl and (C3-C7)cycloalkyl;
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, mono-, di, or tri-halo (C1-C7)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, phenyl-(C1-C5)alkyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms, and said phenyl moiety in phenyl-(C1-C5)alkyl, aryl, or aromatic or non-aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, halo (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
N—
OH;
Y is selected from the group consisting of hydrogen, halo, amino, mercapto, (C1-C12)alky-M—
, (C3-C7)cycloalkyl-M—
, (C2-C6)alkenyl-M—
, aryl-M—
, aromatic or non-aromatic heterocyclic-M—
, aryl-(C1-C5)alkyl-M—
, aromatic or non-aromatic heterocyclic-(C1-C5)alkyl-M—
, said aromatic or non-aromatic heterocyclic moiety of said groups comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms, and M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO, NQ, NQCO, and CONQ, wherein Q is selected from the group consisting of hydrogen and (C1-C6)alkyl, said (C1-C12)alkyl, (C3-C7)cycloalkyl or (C2-C6)alkenyl moiety in said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, amino, (C1-C4)alkyl-NH—
, di-(C1-C4)alkyl-N—
, hydrazino, azido, ureido, amidino, guanidino, (C1-C4)alkoxy, (C1-C4)alkyl-S—
, (C1-C4)alkyl-SO— and
(C1-C4)alkyl-SO2—
, andsaid aryl, or aromatic or non-aromatic heterocyclic moiety of said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, halo (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di(C1-C4 alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
N—
OH; and
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylsulfonyl, (C1-C4)alkyl-CO—
, carboxy, (C1-C4)alkyl-COO—
, amino, NH2CO—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-SO2—
NH—
, phenyl and naphthyl.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12)
R is selected from the group consisting of (C3-C11)cycloalkyl and (C3-C11)cycloalkenyl, said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5)alkyl and (C3-C7)cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, mono-, di- or tri-halo (C1-C7)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to six ring atoms wherein one to two ring atoms are independently selected from heteroatoms, and aryl, or aromatic or non-aromatic heterocyclic wherein each of said aforementioned groups is optionally substituted with up to three substituents independently selected from halo, (C1-C4)alkyl , halo (C1-C4)alkyl, (C1-C4)alkoxy, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH— and
(C1-C4)alkyl-NH—
CO—
;
Y is selected from the group consisting of hydrogen, halo, amino, mercapto, (C1-C10)alkyl-M—
, (C3-C7)cycloalkyl-M—
, (C2-C6)alkenyl-M—
, aryl-M—
, aromatic or non-aromatic heterocyclic-M—
, aryl-(C1-C5)alkyl-M—
, and aromatic or non-aromatic heterocyclic-(C1-C5)alkyl-M—
, said aromatic or non-aromatic heterocyclic moiety of said groups comprising four to six ring atoms wherein one to two ring atoms are independently selected from heteroatoms, M is selected from group consisting of a covalent bond, O, S, SO, SO2, CO, NH, N((C1-C6)alkyl), CONH and NHCO,said (C1-C10)alkyl, (C3-C7)cycloalkyl and (C2-C6)alkenyl moiety of said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, amino, (C1-C4)alkyl-NH—
, di(C1-C4)alkyl-N—
, hydrazino, azido, ureido, amidino, guanidino, (C1-C4)alkyl-S—
, (C1-C4)alkyl-SO— and
(C1-C4)alkyl-SO2—
, andsaid aryl, or aromatic or non-aromatic heterocyclic moiety of said groups being optionally substituted with substituents independently selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, NH2—
CO—
, (C1-C4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
NOH; and
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen and halo.
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3. A compound according to claim 2 or a salt thereof, wherein
R is selected from the group consisting of (C3-C11)cycloalkyl, (C3-C11)cycloalkenyl, mono-, di- or tri-halo (C3-C11)cycloalkyl, mono-, di- or tri-halo (C3-C11)cycloalkenyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, (C2-C5)alkenyl, aryl selected from the group consisting of phenyl and naphthyl, and aromatic-heterocyclic selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, pyridyl, oxazinyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, said aryl or aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, (C1-C4)alkyl, halo (C1-C4)alkyl and (C1-C4)alkoxy;
Y is selected from the group consisting of hydrogen, halo, amino, mercapto, (C1-C10)alkyl-M—
, (C3-C7)cycloalkyl-M—
, (C2-C6)alkenyl-M—
, aryl-M—
, aromatic or non-aromatic heterocyclic-M—
, aryl-(C1-C5)alkyl-M—
, and aromatic or non-aromatic heterocyclic-(C1-C5)alkyl-M—
, said aryl moiety of said groups being selected from the group consisting of phenyl and naphthyl, said aromatic or non-aromatic heterocyclic moiety of said groups being selected from the group consisting of azetidinyl, furyl, pyrrolidinyl, thienyl, pyridyl, piperidyl, piperidino, morpholinyl, morphorino, pyrazinyl, pyridazinyl, aziridinyl, pyrrolidinyl, piperazinyl and thiamorpholino, M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO, NH, CONH, N((C1-C6)alkyl) and NHCO,said (C1-C10)alkyl, (C3-C7)cycloalkyl and (C2-C6)alkenyl moiety of said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, amino, (C1-C4)alkyl-NH—
, di(C1-C4)alkyl-N—
, hydrazino, azido, ureido, amidino, guanidino, (C1-C4)alkyl-S—
, (C1-C4)alkyl-SO— and
(C1-C4)alkyl-SO2—
, andsaid aryl, or aromatic or non-aromatic heterocyclic moiety of said groups being optionally substituted with up to three substituents selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, NH2—
CO—
, (C1-C4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
NOH; and
Z1 and Z2 are independently selected from the group consisting of hydrogen and halo;
and Z3 and Z4 are both hydrogen.
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4. A compound according to claim 3 or a salt thereof, wherein
R is (C6-C10)cycloalkyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of (C1-C7)alkyl and (C2-C5)alkenyl, phenyl and naphthyl;
Y is selected from the group consisting of hydrogen, amino, (C1-C6)alkyl-M—
, piperidyl, piperidino and piperazinyl, M is selected from group consisting of a covalent bond, O, SO2, CO, NH, CONH and NHCO,said alkyl moiety of (C1-C6)alkyl-M—
being optionally substituted with up to three substituents independently selected from the group consisting of amino and guanidino, andsaid piperidyl, piperidino or piperazinyl being optionally substituted with up to three substituents independently selected from (C1-C4)alkyl; and
Z1, Z2, Z3 and Z4 are all hydrogen.
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5. A compound according to claim 4 or a salt thereof, wherein
R is (C7-C9)cycloalkyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and is selected from the group consisting of methyl and phenyl;
Y is selected from the group consisting of amino, (C1-C6)alkyl-NH—
, amino-(C1-C6)alkyl-O—
, amino-(C1-C6)alkyl-CONH—
, amino-(C1-C6)alkyl-SO2— and
piperazinyl substituted by (C1-C4)alkyl; and
Z1, Z2, Z3 and Z4 are all hydrogen.
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6. A compound according to claim 1 selected from the group consisting of
N-methyl-1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-amine; -
2-(4-methylpiperazino)-1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole;
1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole;
2-(4-methylpiperazino)-1-[1-(1-phenylcyclooctyl)-4-piperidinyl]-1H-benzimidazole;
1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-2-(4-piperidinyl)-1H-benzimidazole;
N-methyl-1-[1-(1-methylcyclononyl)-4-piperidinyl]-1H-benzimidazol-2-amine;
1-[1-(1-phenylcyclononyl)-4-piperidinyl]-1H-benzimidazol-2-amine;
N-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}acetamide;
2-(4-methylpiperazino)-1-[1-(1-methylcyclooctyl)-4-piperidinyl]-1H-benzimidazole;
3-amino-1-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}-1-propanone;
N-methyl-1-[1-(1-methylcyclooctyl)-4-piperidinyl]-1H-benzimidazol-2-amine;
4-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}-1-piperidinecarboximidamide;
4-{1-[1-(1-methylcyclooctyl)-4-piperidinyl]-1H-benzimidazol-2-yl}1-piperazinecarboximidamide;
2-amino-N-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}acetamide;
2-({1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}oxy)-1-ethanamine;
3-({1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl }sulfonyl)-1-propanamine;
1-[1-(1-phenylcyclooctyl)-4-piperidinyl]-1H-benzimidazol-2-amine;
2-amino-N-{1-[1-(1-phenylcyclooctyl)-4-piperidinyl]-1H-benzimidazol-2-yl}acetamide; and
(2S)-2-amino-N-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}propanamide;
or a salt thereof.
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7. A compound according to claim 6 selected from the group consisting of
2-(4-methylpiperazino)-1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazole; -
1-[1-(1-phenylcyclononyl)-4-piperidinyl]-1H-benzimidazol-2-amine;
N-methyl-1-[1-(1-methylcyclooctyl)-4-piperidinyl]-1H-benzimidazol-2-amine;
2-amino-N-{1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}acetamide;
2-({1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}oxy)-1-ethanamine;
3-({1-[1-(1-phenylcycloheptyl)-4-piperidinyl]-1H-benzimidazol-2-yl}sulfonyl)-1-propanamine; and
2-amino-N-{1-[1-(1-phenylcyclooctyl)-4-piperidinyl]-1H-benzimidazol-2-yl}acetamide;
or a salt thereof.
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8. A pharmaceutical composition for the treatment of a disorder or condition mediated by ORL1-receptor and its endogenous ligands in a mammal, or for anesthetizing a mammal, which comprises an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
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9. A method of treating a disorder or condition, or anesthetizing a mammal, the treatment and anesthetization of which can be effected or facilitated by activating ORL1-receptor in a mammal, comprising administering to a mammal in need of such treatment an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof.
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10. A process for preparing a compound of formula (I) according to claim 1 wherein
R is selected from the group consisting of (C3-C11)cycloalkyl, (C6-C16)bicycloalkyl, (C6-C16)tricycloalkyl and (C8-C16)tetracyclyoalkyl, wherein said groups are partially saturated, fully saturated or fully unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5)alkyl and (C3-C7)cycloalkyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, mono-, di, or tri-halo (C1-C7)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, phenyl-(C1-C5)alkyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms, and said phenyl moiety in phenyl-(C1-C5)alkyl, aryl, or aromatic or non-aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1C4)alkyl, (C1-C4)alkoxy, halo (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, (C1-4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
N—
OH;
Y is selected from the group consisting of hydrogen, halo, amino, mercapto, (C1-C12)alkyl-M—
, (C3-C7)cycloalkyl-M—
, (C2-C6)alkenyl-M—
, aryl-M—
, aromatic or non-aromatic heterocyclic-M—
, aryl-(C1-C5)alkyl-M—
, aromatic or non-aromatic heterocyclic-(C1-C5)alkyl-M—
, said aromatic or non-aromatic heterocyclic moiety of said groups comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms, and M is selected from the group consisting of a covalent bond, O, S, SO, SO2, CO, NQ, NQCO, and CONQ, wherein Q is selected from the group consisting of hydrogen and (C1-C6)alkyl,said (C1-C12)alkyl, (C3-C7)cycloalkyl or (C2-C6)alkenyl moiety in said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, amino, (C1-C4)alkyl-NH—
, di-(C1-C4)alkyl-N—
, hydrazino, azido, ureido, amidino, guanidino, (C1-C4)alkoxy, (C1-C4)alkyl-S—
, (C1-C4)alkyl-SO— and
(C1-C4)alkyl-SO2—
, andsaid aryl, or aromatic or non-aromatic heterocyclic moiety of said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, halo (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di(C1-C4 alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
N—
OH; and
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylsulfonyl, (C1-C4)alkyl-CO—
, carboxy, (C1-C4)alkyl-COO—
, amino, NH2CO—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-SO2—
NH—
, phenyl and naphthyl, which comprises(a) coupling compounds of formulae
wherein R, A and Z1 to Z4 are defined as above, and L is halo to give the compound of formula(b) reducing the compound of formula (IX) to the compound of formula (X)
by either reduction or hydrogenation; and
(c) subjecting the resulting compound of formula (X) to benzimidazole formation to give the compound of formula (I).
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11. A process of claim 10 wherein
in step (a), the coupling reaction is carried out in the presence of a base in a reaction inert solvent at a temperature in the range from room temperature to the reflux temperature of the reaction mixture for from 0.5 to 48 hours; -
in step (b), the reduction is carried out in the presence of a reducing reagent in a reaction inert solvent at a temperature in the range from room temperature to the reflux temperature of the reaction mixture for from 0.5 to 48 hours, and the hydrogenation is carried out in the presence of a metal catalyst at a temperature in the range from 0°
to 100°
C. under hydrogen atmosphere in a reaction inert solvent for from 0.5 to 48 hours; and
in step (c), benzimidazole formation is carried out with a coupling reagent selected from the group consisting of carboxylic acids, amino carboxylic acids, acid anhydrides, formamides, alkylcarbonyl halides, aryl carbonyl halides, aryl alkyl carbonyl halides, heteroaryl carboxylic acids, carbon disulfides, cyanogen halides, cyanamide and trialkyl orthoformates, in the presence of a peptide coupling reagent in a reaction inert solvent at a temperature in the range from 0°
C. to the reflux temperature of the reaction mixture for from 1 minutes to 120 hours.
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12. A process of claim 11 wherein,
in step (a), the base is selected from the group consisting of K2CO3, and amines; -
in step (b), the reducing reagent is selected from the group consisting of SnCl2, zinc catalysts and iron catalysts, and the metal catalyst used in the hydrogenation is selected from the group consisting of Raney nickel catalysts, palladium catalysts and platinum catalysts; and
in step (c), the peptide coupling reagent used in the benzimidazole formation is selected from the group consisting of dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIPC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (WSC), benzotriazole-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP) and diphenylphosphorylazide (DPPA).
-
-
13. A compound of formula
wherein R is selected from the group consisting of (C3-C11)cycloalkyl, (C6-C16)bicycloalkyl, (C6-C16)tricycloalkyl and (C8-C16)tetracyclyoalkyl, wherein said groups are partially saturated, fully saturated or fully unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5)alkyl and (C3-C7)cycloalkyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, mono-, di, or tri-halo (C1-C7)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, phenyl-(C1-C5)alkyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms, and said phenyl moiety in phenyl-(C1-C5)alkyl, aryl, or aromatic or non-aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, halo (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, (C1-4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
N—
OH; and
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-4)alkoxy, (C1-4)alkylsulfonyl, (C1-C4)alkyl-CO—
, carboxy, (C1-C4)alkyl-COO—
, amino, NH2CO—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-SO2—
NH—
, phenyl and naphthyl.- View Dependent Claims (14, 15, 16, 17)
R is selected from the group consisting of (C3-C11)cycloalkyl and (C3-C11)cycloalkenyl, said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5)alkyl and (C3-C7)cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, mono-, di- or tri-halo (C1-C7)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to six ring atoms wherein one to two ring atoms are independently selected from heteroatoms, and aryl, or aromatic or non-aromatic heterocyclic wherein each of said aforementioned groups is optionally substituted with up to three substituents independently selected from halo, (C1-C4)alkyl , halo (C1-C4)alkyl, (C1-C4)alkoxy, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH— and
(C1-C4)alkyl-NH—
CO—
; and
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen and halo.
-
-
15. A compound according to claim 14, wherein
R is selected from the group consisting of (C3-C11)cycloalkyl, (C3-C11)cycloalkenyl, mono-, di- or tri-halo (C3-C11)cycloalkyl, mono-, di- or tri-halo (C3-C11)cycloalkenyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, (C2-C5)alkenyl, aryl selected from the group consisting of phenyl and naphthyl, and aromatic-heterocyclic selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, pyridyl, oxazinyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, said aryl or aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, (C1-C4)alkyl, halo (C1-C4)alkyl and (C1-C4)alkoxy; and
Z1 and Z2 are independently selected from the group consisting of hydrogen and halo;
and Z3 and Z4 are both hydrogen.
-
-
16. A compound according to claim 15 wherein
R is (C6-C10)cycloalkyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl and (C2-C5)alkenyl, phenyl and naphthyl; and
Z1, Z2, Z3 and Z4 are all hydrogen.
-
-
17. A compound according to claim 16 wherein
R is (C7-C9)cycloalkyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of methyl and phenyl; and
Z1, Z2, Z3 and Z4 are all hydrogen.
-
-
18. A compound of formula
wherein R is selected from the group consisting of (C3-C11)cycloalkyl, (C6-C16)bicycloalkyl, (C6-C16)tricycloalkyl and (C8-C16)tetracyclyoalkyl, wherein said groups are partially saturated, fully saturated or fully unsaturated and are optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5)alkyl and (C3-C7)cycloalkyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, mono-, di, or tri-halo (C1-C7)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, phenyl-(C1-C5)alkyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to ten ring atoms wherein one to four ring atoms are independently selected from heteroatoms, and said phenyl moiety in phenyl-(C1-C5)alkyl, aryl, or aromatic or non-aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, halo (C1-C4)alkoxy, (C1-C4)alkyl-CO—
, phenyl, benzyl, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-NH—
CO—
, hydrazino, azido, ureido, amidino, guanidino, oxo and ═
N—
OH; and
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen, halo, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylsulfonyl, (C1-C4)alkyl-CO—
, carboxy, (C1-C4)alkyl-COO—
, amino, NH2CO—
, (C1-C4)alkyl-CO—
NH—
, (C1-C4)alkyl-SO2—
NH—
, phenyl and naphthyl.- View Dependent Claims (19, 20, 21, 22)
R is selected from the group consisting of (C3-C11)cycloalkyl and (C3-C11)cycloalkenyl, said groups being optionally substituted with up to three substituents independently selected from the group consisting of halo, hydroxy, (C1-C5)alkyl and (C3-C7)cycloalkyl; A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, mono-, di- or tri-halo (C1-C7)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, aryl, and aromatic or non-aromatic heterocyclic comprising four to six ring atoms wherein one to two ring atoms are independently selected from heteroatoms, and aryl, or aromatic or non-aromatic heterocyclic wherein each of said aforementioned groups is optionally substituted with up to three substituents independently selected from halo, (C1-C4)alkyl, halo (C1-C4)alkyl, (C1-C4)alkoxy, —
CHO, cyano, (C1-C4)alkyl-CO—
, NH2—
CO—
, NH2—
CH2—
, amino, (C1-C4)alkyl-NH—
, di((C1-C4)alkyl)-N—
, (C1-C4)alkyl-CO—
NH— and
(C1-C4)alkyl-NH—
CO—
; and
Z1, Z2, Z3 and Z4 are independently selected from the group consisting of hydrogen and halo.
-
-
20. A compound according to claim 19, wherein
R is selected from the group consisting of (C3-C11)cycloalkyl, (C3-C11)cycloalkenyl, mono-, di- or tri-halo (C3-C11)cycloalkyl, mono-, di- or tri-halo (C3-C11)cycloalkenyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl, (C2-C5)alkenyl, aryl selected from the group consisting of phenyl and naphthyl, and aromatic-heterocyclic selected from the group consisting of furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, furazanyl, tetrazolyl, pyranyl, pyridyl, oxazinyl, thiazinyl, pyridazinyl, pyrimidinyl, pyrazinyl and triazinyl, said aryl or aromatic heterocyclic being optionally substituted with up to three substituents independently selected from the group consisting of halo, (C1-C4)alkyl, halo (C1-C4)alkyl and (C1-C4)alkoxy; and
Z1 and Z2 are independently selected from the group consisting of hydrogen and halo;
and Z3 and Z4 are both hydrogen.
-
-
21. A compound according to claim 20 wherein
R is (C6-C10)cycloalkyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of (C1-C7)alkyl and (C2-C5)alkenyl, phenyl and naphthyl; and
Z1, Z2, Z3 and Z4 are all hydrogen.
-
-
22. A compound according to claim 21 wherein
R is (C7-C9)cycloalkyl; -
A is attached to the carbon atom of R with which R is attached to the nitrogen atom of the piperidine ring, and selected from the group consisting of methyl and phenyl; and
Z1, Z2, Z3 and Z4 are all hydrogen.
-
Specification
-
- Resources
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Current AssigneePfizer Pharmaceuticals LLC (Pfizer Inc.)
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Original AssigneePfizer Inc.
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InventorsKondo, Hiroshi, Noguchi, Hirohide, Ito, Fumitaka
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Primary Examiner(s)Huang, Evelyn Mei
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Application NumberUS09/369,208Time in Patent Office523 DaysField of Search546/187, 546/199, 544/364, 544/124, 514/254, 514/316, 514/322, 514/252.13, 514/235.8US Class Current514/252.13CPC Class CodesA61P 1/00 Drugs for disorders of the ...A61P 23/00 AnaestheticsA61P 25/00 Drugs for disorders of the ...A61P 25/16 Anti-Parkinson drugsA61P 25/18 Antipsychotics, i.e. neurol...A61P 25/20 Hypnotics; SedativesA61P 25/22 AnxiolyticsA61P 25/28 for treating neurodegenerat...A61P 25/30 for treating abuse or depen...A61P 29/00 Non-central analgesic, anti...A61P 3/12 for electrolyte homeostasisA61P 39/02 AntidotesA61P 9/12 AntihypertensivesC07D 211/58 attached in position 4C07D 401/04 directly linked by a ring-m...C07D 401/14 containing three or more he...
