Tyrosyl derivatives and their use as P2X7 receptor modulators
View Patent ↗The present invention relates to compounds of the formula wherein R 1 and R 2 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; R 3 , R 4 , R 5 , R 6 , R 7 , and R 8 are independently CH or nitrogen; R 9 is hydrogen or methyl; R 10 is C═O or (CH 2 ) n ; where n is 0, 1, 2, 3, or 4; R 11 and R 12 are independently nitrogen or CH; X 1 and X 2 are independently hydrogen, deuterium, tritium or halogen; and X 3 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 P2X 7 receptor.
1. A compound of the formula
wherein
R 1 is methyl substituted at the ortho-position;
R 2 is hydrogen;
R 3 and R 8 are each nitrogen;
R 4 , R 5 , R 6 , and R 7 , are each CH;
R 9 is methyl;
R 10 is (CH 2 ) n where n is 0;
R 11 and R 12 are each CH;
X 1 and X 2 are each tritium; and
X 3 is nitrogen.
2. A compound of the formula
wherein
wherein R 1 and R 2 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;
R 3 , R 5 , R 6 , and R 8 are independently CH;
R 4 and R 7 are independently nitrogen;
R 9 is hydrogen or methyl;
R 10 is C═O or (CH 2 ) n where n is 0 or 1;
R 11 and R 12 are independently nitrogen or CH; X 1 and X 2 are independently hydrogen, deuterium, tritium or halogen; and X 3 is nitrogen;
with the proviso that when n is 0, and R 11 and R 12 are CH, either R 1 or R 2 is C1–C4 alkyl, C1–C4 alkoxy, C1–C4 acyl, halogen, cyano, nitro or amino.
3. A compound of the formula
wherein;
R 1 and R 2 are independently hydrogen, C1–C4 alkyl, C1–C4 alkoxy, C1–C4 acyl, halogen, cyano, nitro, amino, alkylamino, or dialkylamino; R 9 is hydrogen or methyl; X 1 and X 2 are independently hydrogen, deuterium, tritium, or halogen; and X 3 is nitrogen.
4. The pharmaceutically acceptable salts of a compound of claim 3 .
5. A compounds of the formula
wherein
R 1 and R 2 are independently hydrogen, C1–C4 alkyl, C1–C4 alkoxy, halogen, cyano, nitro, or amino;
R 3 , R 5 , R 6 , and R 8 are independently CH, and where R 4 and R 7 are independently nitrogen; and
n is 0 or 1;
with the proviso that when n is 0 either R 1 or R 2 is not hydrogen.
6. 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.
7. 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.