US 7,094,895 B2 · Tyrosyl derivatives and their use as P2X7 receptor modulators

Abstract

The present invention relates to compounds of the formula wherein R1 and R2 are independently hydrogen, C1–C4 alkyl, C1–C4 substituted alkyl, C1–C4 alkoxy, C1–C4 substituted alkoxy, C1–C4 acyl, halogen, cyano, nitro, amino, alkylamino, or dialkylamino; R3, R4, R5, R6, R7, and R8 are independently CH or nitrogen; R9 is hydrogen or methyl; R10 is C═O or (CH2)n; where n is 0, 1, 2, 3, or 4; R11 and R12 are independently nitrogen or CH; X1 and X2 are independently hydrogen, deuterium, tritium or halogen; and X3 is N; and their pharmaceutically acceptable salts; compositions thereof. Methods of preparing the compounds are also described. The compounds are useful in the treatment of diseases in mammals that are mediated by the action of the P2X7 receptor.

Claims7

Dependent claims

A compound of the formula

wherein
R1 is methyl substituted at the ortho-position;
R2 is hydrogen;
R3 and R8 are each nitrogen;
R4, R5, R6, and R7, are each CH;
R9 is methyl;
R10 is (CH2)n where n is 0;
R11 and R12 are each CH;
X1 and X2 are each tritium;
and
X3 is nitrogen.

8 more elements

A compound selected from the group of tyrosyl piperazine derivatives consisting of:

a. (S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-nitrophenyl)-piperazine;
b. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(p-tolyl)-piperazine;
c. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-chlorophenyl)-piperazine;
d. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorophenyl)-piperazine;
e. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3,4-dichlorophenyl)-piperazine;
f. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-cyanophenyl)-piperazine;
g. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-chlorophenyl)-piperazine;
h. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-methoxyphenyl)-piperazine;
i. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-benzyl-piperazine;
j. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-iodophenyl)-piperazine;
k. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-acetylphenyl)-piperazine;
l. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzyl)-piperazine;
m. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzoyll)-piperazine;
n. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-nitrobenzyl)-piperazine;
o. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-fluorophenyl)-piperazine;
p. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine;
q. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-methoxyphenyl)-piperazine;
r. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3-chlorophenyl)-piperazine;
s. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3-trifluoromethylphenyl)-piperazine;
t. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2,3-dimethylphenyl)-piperazine;
u. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(pyridin-2-yl)-piperazine;
v. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(pyrimidin-2-yl)-piperazine;
w. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-benzyl-piperidine;
x. 1-[(S)—N-tert-butyloxycarbonyl-tyrosyl]-4-(4-fluorophenyl)-piperazine;
y. 1-[(S)—N-tert-butyloxycarbonyl-tyrosyl]-4-(o-tolyl)-piperazine;
z. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-aminophenyl)-piperazine;
and
aa. 1-[(S)—N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-bromo-2-methylphenyl)-piperazine.

25 more elements

A compound selected from the group of tyrosyl piperazine derivatives consisting of:

a. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-nitrophenyl)-piperazine];
b. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(p-tolyl)-piperazine;
c. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-chlorophenyl)-piperazine];
d. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorophenyl)-piperazine];
e. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl-4-(3,4-dichlorophenyl)-piperazine;
f. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-cyanophenyl)-piperazine];
g. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-chlorophenyl)-piperazine];
h. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-methoxyphenyl)-piperazine;
i. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-benzylpiperazine;
j. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-iodophenyl)-piperazine;
k. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-acetylphenyl)-piperazine;
l. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzyl)-piperazine;
m. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-fluorobenzoyl)-piperazine;
n. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-nitrobenzyl)-piperazine;
o. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-fluorophenyl)-piperazine;
p. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(o-tolyl)-piperazine;
q. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2-methoxyphenyl)-piperazine;
r. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]4-(3-chlorophenyl)-piperazine;
s. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(3-trifluoromethylphenyl)-piperazine;
t. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(2,3-dimethylphenyl)-piperazine;
u. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl-]-4-(pyridin-2-yl)-piperazine;
v. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(pyrimidin-2-yl)-piperazine;
w. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-benzylpiperazine;
x. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbony-1-tyrosyl]-4-(4-fluorophenyl)-piperidine;
y. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-tyrosyl]-4-(o-tolyl)-piperazine;
z. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(4-aminophenyl)-piperazine;
aa. 1-[(S)—O-(3-pyridinesulfonyl)-N-tert-butyloxycarbonyl-tyrosyl]-4-(o-tolyl)-piperazine;
bb. 1-[(S)—O-(3-pyridinesulfonyl)-N-tert-butyloxycarbonyl-N-methyl-tyrosyl]-4-(phenyl)-piperazine;
cc. 1-[(S)—O-(3-pyridinesulfonyl)-N-tert-butyloxycarbonyl-tyrosyl]-4-(2-methylphenyl)-piperazine;
and
dd. 1-[(S)—O-isoquinolinesulfonyl-N-tert-butyloxycarbonyl-tyrosyl]-4-(4-bromo-2-methylphenyl)-piperazine.

28 more elements

Dependencies are inferred from the claim text.

Facts

Application

10/329,094Filed 23 Dec 2002 · us provisional application

Priority

21 Dec 2001

Published

US 2003/0181452 A125 Sep 2003

Granted

22 Aug 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification17 codes

C07D 401/14
Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a…:…
A61K 31/496
Having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines: non-condensed piperazines…
A61K 45/06
Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00: mixtures of active ingredients without…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system

Tyrosyl derivatives and their use as P2X7 receptor modulators

Life of this patent

Tyrosyl derivatives and their use as P2X7 receptor modulators

Life of this patent

Abstract

Claims7