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US 5,668,148 AGranted
Alpha1a adrenergic receptor antagonists
AssigneeMerck & Co., Inc.
InventorsLinda S. Payne, Steven D. Young, Mary Jo L. Zaborowski
Life of this patent
Estimating the term…
Abstract
Compounds that specifically bind to the human alpha1a adrenergic receptor, including compounds effective to reduce symptoms of benign prostatic hypertrophy include compounds of formula: ##STR1## wherein: Ar1 and Ar2 can be independantly aromatic, heteroaromatic, or condensed heteroaromatic unsubstituted or substituted with amino, alkoxy, sulfonamido, alkyl, heteroalkyl, halo; m is 0 or 1; n is 0, 1, or 2; het is an aromatic or nonaromatic heterocyclic ring, substituted with alkyl, halo, or alkoxy substituents; and X is a branched or straight chain aliphatic or halogen substituent.
Claims12
A method of treating benign prostatic hypertrophy in a subject in need thereof which comprises administering to the subject a therapeutically effective amount of a compound of formula I ##STR28## wherein the broken lines represent two non-adjacent double bonds in any position within the five-membered ring;
- one of X and Y represents nitrogen, and the other of X and Y represents oxygen, sulphur or N--R.sup.2 ;
- Q represents a substituted five- or six-membered monocyclic heteroaliphatic ring selected from Qa to Qe ##STR29## and is linked to the five-membered heteroatomic ring containing the moieties X and Y via a carbon atom;
- wherein R.sup.6 is C.sub.0-6 alkyl substituted with a monocyclic or polycyclic aromatic or heteroaromatic group selected from:
- phenyl;
- 1-naphthyl;
- 2-naphthyl;
- benzothiophene;
- benzofuran;
- indole;
- quinoline;
- isoquinoline;
- indazole;
- benzisoxazole;
- benzimidazol(on)e;
- thiophene;
- furan;
- or pyridine;
- each of which may or may not be substituted with one or more of C.sub.1-6 alkyl;
- C.sub.1-6 alkoxy(C.sub.1-6)alkyl;
- C.sub.1-6 alkoxy;
- cyano;
- nitro;
- carboxamido;
- amidino;
- amino;
- halogen;
- sulfonamido;
- amidosulfonyl;
- or hydroxy;
- R.sup.7 represents hydrogen, hydrocarbon, an ether or a heterocyclic group;
- R.sup.1 represents hydrogen, halogen, C.sub.1-6 alkyl, hydroxy or C.sub.1-6 alkoxy;
- R.sup.2 represents hydrogen or C.sub.1-6 alkyl;
- A represents a group of formula (iv):
- ##STR30## R.sup.3, R.sup.4 and R.sup.5 are each independently selected from hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a or --CO.sub.2 NR.sup.a R.sup.b ;
- R.sup.a and R.sup.b independently represent hydrogen, hydrocarbon or a heterocyclic group;
- the ring M is optionally an additional ring or ring system such that the entire structure (iv) is dicyclic, or polycyclic aromatic or heteroaromatic ring system, selected from:
- benzodioxane;
- methylenedioxyphenyl;
- indane;
- 2,3-dihydrobenzofuran;
- 2,7-dihydroizobenzofuran;
- 1-naphthyl;
- 2-naphthyl;
- benzothiophene;
- benzofuran;
- indole;
- quinoline;
- isoquinoline;
- indazole;
- benzisoxazole;
- benzthiazole;
- or benzimidazol(on)e;
- each of which may be substituted with R.sup.3, R.sup.4 and R.sup.5, as described above and, in addition, with R.sup.18, and R.sup.19, each of which may be independently:
- C.sub.1-6 alkyl;
- C.sub.1-6 alkoxy-C.sub.1-6 alkyl;
- C.sub.1-6 alkoxy;
- cyano;
- nitro;
- carboxamido;
- amidino;
- amino;
- halo;
- sulfonamido;
- amidosulfonyl;
- hydrogen or hydroxy;
- the heterocyclic group, at each occurrence, is independently selected from azetidinyl, pyrrolidyl, piperidyl, pyridyl, quinolyl, isoquinolyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, indolyl, imidazolyl, oxadiazolyl, thiadiazolyl, azetidinyl(C.sub.1-6)alkyl, pyrrolidyl(C.sub.1-6)alkyl, piperidyl(C.sub.1-6)alkyl, pyridyl(C.sub.1-6)alkyl, quinolyl(C.sub.1-6)alkyl, isoquinolyl(C.sub.1-6)alkyl, pyranyl(C.sub.1-6)alkyl, furyl(C.sub.1-6)alkyl, benzofuryl(C.sub.1-6)alkyl, dibenzofuryl(C.sub.1-6)alkyl, thienyl(C.sub.1-6)alkyl, benzothienyl(C.sub.1-6)alkyl, indolyl(C.sub.1-6)alkyl, imidazolyl(C.sub.1-6)alkyl, oxadiazolyl(C.sub.1-6)alkyl, or thiadiazolyl(C.sub.1-6)alkyl;
- and the pharmaceutically acceptable salts thereof.
64 more elements
A compound represented by formula I ##STR32## wherein the broken lines represent two non-adjacent double bonds in any position within the five-membered ring;
- one of X and Y represents nitrogen, and the other of X and Y represents oxygen, sulphur or N--R.sup.2 ;
- Q represents a substituted five- or six-membered monocyclic heteroaliphatic ring selected from Qa to Qe ##STR33## and is linked to the five-membered heteroatomic ring containing the moieties X and Y via a carbon atom;
- wherein R.sup.6 is C.sub.0-6 alkyl substituted with a monocyclic or polycyclic aromatic or heteroaromatic group selected from:
- phenyl;
- 1-naphthyl;
- 2-naphthyl;
- benzothiophene;
- benzofuran;
- indole;
- quinoline;
- isoquinoline;
- indazole;
- benzisoxazole;
- benzimidazol(on)e;
- thiophene;
- furan or pyridine;
- each of which may or may not be substituted with one or more of C.sub.1-6 alkyl;
- C.sub.1-6 alkoxy(C.sub.1-6)alkyl;
- C.sub.1-6 alkoxy;
- cyano;
- nitro;
- carboxamido;
- amidino;
- amino;
- halogen;
- sulfonamido;
- amidosulfonyl;
- or hydroxy;
- R.sup.7 represents hydrogen, hydrocarbon, an ether or a heterocyclic group;
- R.sup.1 is selected from hydrogen, halogen, C.sub.1-6 alkyl, hydroxy or C.sub.1-6 alkoxy;
- R.sup.2 is selected from hydrogen or C.sub.1-6 alkyl;
- and
- A represents a group of formula (iv):
- ##STR34## in which R.sup.3, R.sup.4 and R.sup.5 are each independently selected from hydrogen, hydrocarbon, a heterocyclic group, halogen, cyano, trifluoromethyl, nitro, --OR.sup.a, --SR.sup.a, --SOR.sup.a, --SO.sub.2 R.sup.a, --SO.sub.2 NR.sup.a R.sup.b, --NR.sup.a R.sup.b, --NR.sup.a COR.sup.b, --NR.sup.a CO.sub.2 R.sup.b, --COR.sup.a, --CO.sub.2 R.sup.a or --CO.sub.2 NR.sup.a R.sup.b ;
- R.sup.a and R.sup.b are each independently selected from hydrogen, hydrocarbon or a heterocyclic group;
- the ring M is optionally an additional ring or ring system such that the entire structure (iv) is a dicyclic, or polycyclic aromatic or heteroaromatic ring system, selected from:
- benzodioxane;
- dioxane;
- methylenedioxyphenyl;
- indane;
- 2,3-dihydrobenzofuran;
- 2,7-dihydroizobenzofuran;
- 1-naphthyl;
- 2-naphthyl;
- benzothiophene;
- benzofuran;
- indole;
- quinoline;
- isoquinoline;
- indazole;
- benzisoxazole;
- benzthiazole;
- or benzimidazol(on)e;
- each of which may be substituted with R.sup.3, R.sup.4 and R.sup.5, as described above and, in addition, with R.sup.18, and R.sup.19, each of which may be independently:
- C.sub.1-6 alkyl;
- C.sub.1-6 alkoxy (C.sub.1-6)alkyl;
- C.sub.1-6 alkoxy;
- cyano;
- nitro;
- carboxamido;
- amidino;
- amino;
- halo;
- sulfonamido;
- amidosulfonyl;
- hydrogen or hydroxy;
- the heterocyclic group, at each occurrence, is independently selected from azetidinyl, pyrrolidyl, piperidyl, pyridyl, quinolyl, isoquinolyl, pyranyl, furyl, benzofuryl, dibenzofuryl, thienyl, benzothienyl, indolyl, imidazolyl, oxadiazolyl, thiadiazolyl, azetidinyl(C.sub.1-6)alkyl, pyrrolidyl(C.sub.1-6)alkyl, piperidyl(C.sub.1-6)alkyl, pyridyl(C.sub.1-6)alkyl, quinolyl(C.sub.1-6)alkyl, isoquinolyl(C.sub.1-6)alkyl, pyranyl(C.sub.1-6)alkyl, furyl(C.sub.1-6)alkyl, benzofuryl(C.sub.1-6)alkyl, dibenzofuryl(C.sub.1-6)alkyl, thienyl(C.sub.1-6)alkyl, benzothienyl(C.sub.1-6)alkyl, indolyl(C.sub.1-6)alkyl, imidazolyl(C.sub.1-6)alkyl, oxadiazolyl(C.sub.1-6)alkyl, or thiadiazolyl(C.sub.1-6)alkyl;
- and the pharmaceutically acceptable salts thereof.
65 more elements
A compound selected from:
- 1-(2-(1--Naphthyl)ethyl)-4-(5-(benzodioxan-6-yl)pyrazol-3-yl)piperdine;
- 1-(2-(1--Naphthyl)ethyl)-4-(5-(3,4-methylenedioxyphenyl)pyrazol-3-yl)-piper dine;
- 1-(2-(1--Naphthyl)ethyl)-4-(5-(6-quinolinyl)pyrazol-3-yl)piperdine;
- 1-(2-(3-Indolyl)ethyl)-4-(5-(benzodioxan-6-yl)pyrazol-3-yl)piperdine;
- 1-(2-(3-Benzofuryl)ethyl)-4-(5-(benzodioxan-6-yl)pyrazol-3-yl)piperdine;
- 1-(2-(1--Naphthyl)ethyl)-4-(3-(1,4-benzodioxan-6-yl)isoxazol-5-yl)piperdine ;
- and
- 1-(2-(1--Naphthyl)ethyl)-4-(5-(1,4-benzodioxan-6-yl)isoxazol-3-yl)piperdine
- and the pharmaceutically acceptable salts thereof.
6 more elements
Dependencies are inferred from the claim text.