US 2006/0052406 A1 · Methods and compositions for treatment of central and peripheral nervous system disorders and novel compounds useful therefor

Abstract

There are provided methods for the treatment of diseases involving dysfunction of the peripheral and central nervous system comprising administering one or more spiro compounds. Also provided are pharmaceutical compositions useful in such methods, compounds for use in the preparation of such pharmaceutical compositions, processes for preparing compounds useful in the practice of such methods, and some novel such compounds per se.

Claims80

Dependent claims

A compound of the formula (I):

wherein:
C denotes a spiro carbon atom shared by ring A and the ring containing a, b, d and e;
A is selected from the group consisting of:
R is selected from H, C1-C8 straight- or branched-chain alkyl, or —CH2—P(═O)(OH)2;
a is —O— or —S—;
b is —CR1R2— or —C(R1)═;
d is selected from the group consisting of ═N—, —C(═O)—, —C(═S)— and ═N(R3)═O;
e is selected from the group consisting of —CH2—, —CHR4—, —NH—, —NR5—, —N(SO2R6)— and —N(C(═O)R6)—;
R, R1, R2, R3, R4 are each independently selected from the group consisting of H, C1-6 alkoxy, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkyl optionally substituted by one to three phenyls;
R5 is independently selected from the group consisting of H, C1-6 alkyl optionally substituted by one, two or three phenyls, C1-6 alkoxy, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, optionally substituted phenyl, heteroaryl, and C1-6 alkyl optionally substituted by one to three phenyls;
or, when the compound of formula (I) is a dimer, in which both halves of the dimer share a single R5, R5 is selected from the group consisting of —(CH2)n— and —(CH2O)n—, wherein n is 1 to 6;
and
R6 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl, each optionally substituted by from 1-6 halogen atoms, hydroxy-C1-6-alkyl, aryl substituted with a halogen, nitro, amino, hydroxyl, or CF3 group, C1-6 alkyl substituted by one to three aryl groups, and Cm alkyl-X, wherein m=0 to 6 and X is selected from the group consisting of indole, C1-6 alkyl indole, isoindolyl, 3-pyridinyl, 3-piperidinyl, benzimidazolyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, and pteridinyl;
or an enantiomer, diastereomer, racemate, tautomer, geometrical isomer, dimer, metabolite or pharmaceutically acceptable salt thereof,
with the proviso that when A is
R is —CH3, a is S, b is —CH(CH2CH3)— and d is —C(═O)—, then e is not —NH— (AF267 or an enantiomer thereof), and
with the further proviso that when A is
R is —CH3, a is S, b is —C(CH3)═ and d is ═N—, then e is not —CH2— (AF150(S)).

15 more elements

Dependencies are inferred from the claim text.

Facts

Application

10/512,673Filed 1 May 2003

Priority

3 May 2002

Published

9 Mar 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification39 codes

C07D 513/10
In which the condensed system contains two hetero rings: spiro-condensed systems
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system
A61P 1/04
Drugs for disorders of the alimentary tract or the digestive system: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of…
A61P 1/10
Drugs for disorders of the alimentary tract or the digestive system: laxatives

Abstract

Claims80

Dependent claims

A compound of the formula (I):

wherein:
C denotes a spiro carbon atom shared by ring A and the ring containing a, b, d and e;
A is selected from the group consisting of:
R is selected from H, C1-C8 straight- or branched-chain alkyl, or —CH2—P(═O)(OH)2;
a is —O— or —S—;
b is —CR1R2— or —C(R1)═;
d is selected from the group consisting of ═N—, —C(═O)—, —C(═S)— and ═N(R3)═O;
e is selected from the group consisting of —CH2—, —CHR4—, —NH—, —NR5—, —N(SO2R6)— and —N(C(═O)R6)—;
R, R1, R2, R3, R4 are each independently selected from the group consisting of H, C1-6 alkoxy, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, and C1-6 alkyl optionally substituted by one to three phenyls;
R5 is independently selected from the group consisting of H, C1-6 alkyl optionally substituted by one, two or three phenyls, C1-6 alkoxy, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, optionally substituted phenyl, heteroaryl, and C1-6 alkyl optionally substituted by one to three phenyls;
or, when the compound of formula (I) is a dimer, in which both halves of the dimer share a single R5, R5 is selected from the group consisting of —(CH2)n— and —(CH2O)n—, wherein n is 1 to 6;
and
R6 is selected from the group consisting of C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C2-6 hydroxyalkyl, C2-6 alkenyl, C2-6 alkynyl, and C3-7 cycloalkyl, each optionally substituted by from 1-6 halogen atoms, hydroxy-C1-6-alkyl, aryl substituted with a halogen, nitro, amino, hydroxyl, or CF3 group, C1-6 alkyl substituted by one to three aryl groups, and Cm alkyl-X, wherein m=0 to 6 and X is selected from the group consisting of indole, C1-6 alkyl indole, isoindolyl, 3-pyridinyl, 3-piperidinyl, benzimidazolyl, thienyl, isothiazolyl, imidazolyl, pyrazinyl, benzofuranyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,5-thiadiazolyl, isooxazolyl, pyrrolyl, pyrazolyl, quinazolinyl, pyridazinyl, pyrazinyl, cinnolinyl, phthalazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, and pteridinyl;
or an enantiomer, diastereomer, racemate, tautomer, geometrical isomer, dimer, metabolite or pharmaceutically acceptable salt thereof,
with the proviso that when A is
R is —CH3, a is S, b is —CH(CH2CH3)— and d is —C(═O)—, then e is not —NH— (AF267 or an enantiomer thereof), and
with the further proviso that when A is
R is —CH3, a is S, b is —C(CH3)═ and d is ═N—, then e is not —CH2— (AF150(S)).

15 more elements

Dependencies are inferred from the claim text.

Methods and compositions for treatment of central and peripheral nervous system disorders and novel compounds useful therefor

Life of this patent

Abstract

Claims80

Methods and compositions for treatment of central and peripheral nervous system disorders and novel compounds useful therefor

Life of this patent

Abstract

Claims80