IP Library › Granted Patent US 7,868,003

Granted Patent B2

US 7,868,003 · App. 11/776,041 · Granted Jan 11, 2011

Substituted 4-phenyltetrahydroisoquinolines, pharmaceutical compositions comprising them and therapeutic methods for their use

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Quick Facts

Patent No.: US 7,868,003
App. No.: 11/776,041
Granted: Jan 11, 2011
Kind: B2

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Abstract

The invention relates to substituted 4-phenyltetrahydroisoquinolines of formula I wherein R1-R8, N, W, X and Z are defined herein. These compounds and pharmaceutical compositions comprising them are useful in the treatment of respiratory disorders, sleep apnea, kidney disorders, high blood pressure, hypertension, disorders of the central nervous system and the like.

Claims (225)

1. A compound of formula I

wherein:

R1, R2, R3 and R4

are each independently hydrogen, F, Cl, Br, I, CN, NO 2 or R11—(C m H 2m )—A n —;

m is zero, 1, 2, 3 or 4;

n is zero or 1;

R11 is hydrogen, methyl or C p F 2p+1 ;

A is oxygen, NH, N(CH 3 ) or S(O) q ;

p is 1, 2 or 3;

q is zero, 1 or 2;

R5 is hydrogen, alkyl having 1, 2, 3, 4, 5 or 6 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

R6 is hydrogen, OH, F, CF 3 , alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

R7 and R8 are each independently hydrogen, F, Cl, Br, CN, CO 2 R12, NR13R14 or R16—(C mm H 2mm )—B nn —;

R12 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

R13 and R14 are each independently hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms; or

R13 and R14, which, including the nitrogen atom to which they are bonded, form a 4-, 5-, 6- or 7-membered ring in which one CH 2 group may be replaced by NR15, S or oxygen;

R15 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

mm is zero, 1, 2, 3 or 4;

nn is zero or 1;

R16 is hydrogen, methyl or C pp F 2pp+1 ;

B is oxygen or S(O) qq ;

pp is 1, 2 or 3;

qq is zero, 1 or 2;

W is C r H 2r or C s H 2s−2 ; wherein one or more CH 2 groups in C r H 2r and C s H 2s−2 may be replaced by NR17, oxygen or S;

R17 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

r is 1, 2, 3, 4, 5, 6, 7 or 8;

s is 2, 3, 4, 5, 6, 7 or 8;

X is —C(O)— or —S(O) 2 —; and

Z is —C(O)— or a bond;

or a pharmaceutically acceptable salt or trifluoroacetate thereof.

2. The compound according to claim 1 wherein

R1, R2, R3 and R4 are each independently hydrogen, F, Cl, Br, CN or R11—(C m H 2m )—A n —;

m is zero or 1;

n is zero or 1;

R11 is hydrogen, methyl or C p F 2p+1 ;

A is oxygen, NCH 3 or S(O) q ;

p is 1 or 2;

q is zero, 1 or 2;

R5 is hydrogen, methyl, ethyl or cyclopropyl;

R6 is hydrogen or methyl;

R7 and R8 are each independently hydrogen, F, Cl, CN, CO 2 R12, NR13R14 or R16—(C mm H 2mm )—B nn —;

R12 is hydrogen, methyl or ethyl;

R13 and R14 are each independently hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms; or

R13 and R14, which, including the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered ring in which one CH 2 group may be replaced by NR15, S or oxygen;

R15 is hydrogen, alkyl having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

mm is zero, 1 or 2;

nn is zero or 1;

R16 is hydrogen, methyl or C pp F 2pp+1 ;

B is oxygen or S(O) qq ;

pp is 1 or 2;

qq is zero, 1 or 2;

W is C r H 2r or C s H 2s−2 wherein one or more CH 2 groups in C r H 2r and C s H 2s−2 may be replaced by NR17, oxygen or S;

R17 is selected from the group consisting of hydrogen, an alkyl group having 1, 2, 3 or 4 carbon atoms or cycloalkyl having 3, 4, 5 or 6 carbon atoms;

r is 2, 3, 4, 5, 6, 7 or 8;

s is 2, 3, 4, 5, 6, 7 or 8;

X is —C(O)— or —S(O) 2 —; and

Z is —C(O)—;

or a pharmaceutically acceptable salt or trifluoroacetate thereof.

3. The compound according to claim 1 wherein

R1 and R3 are each hydrogen;

R2 and R4 are each independently hydrogen, F, Cl, Br, NH 2 , NHCH 3 or N(CH 3 ) 2 ;

R5 is hydrogen, methyl, ethyl or cyclopropyl;

R6 is hydrogen or methyl;

R7 and R8 are each hydrogen;

W is C r H 2r or C s H 2s−2 wherein one or more CH 2 groups in C r H 2r and C s H 2s−2 may be replaced by NR17, oxygen or S;

R17 is hydrogen or methyl;

r is 2, 3, 4, 5 or 6;

s is 2, 3, 4, 5 or 6;

X is —C(O)— or —S(O) 2 —; and

Z is —C(O)—;

or a pharmaceutically acceptable salt or trifluoroacetate thereof.

4. The compound according to claim 1 , which is:

1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1-methylimidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1-methyl-imidazolidine-2,4-dione

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-imidazolidine-2,4-dione

(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisochinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

4-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]morpholine-3,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]oxazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]thiazolidine-2,4-dione,

1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrolidine-2,5-dione,

(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-piperidine-2,6-dione,

(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-piperidine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,5-dimethyl-piperidine-2,6-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methyl-pyrrolidine-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,3-dimethyl-pyrrolidine-2,5-dione,

1-[2-(6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidine-2,6-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidine-2,6-dione,

1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidine-2,6-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrole-2,5-dione,

1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,

3-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,

3-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,

3-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,

3-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-oxazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-methyl-imidazolidine-2,4-dione,

(3R,4S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,4-dimethylpyrrolidine-2,5-dione,

1-[4-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-pyrrole-2,5-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidine-2,6-dione,

1-[3-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]piperidine-2,6-dione,

3-[3-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]imidazolidine-2,4-dione,

1-[2-((R)-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-isopropyl-imidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-isobutyl-imidazolidine-2,4-dione,

(R and S)-3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5-(2-methylsulfanylethyl)imidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-5,5-dimethyl-imidazolidine-2,4-dione,

1-[2-((R)-6,8-dichloro-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-thiazolidine-2,4-dione,

1-[2-((S)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

1-[2-((S)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)-phenyl]-pyrrolidine-2,5-dione,

1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3,3,4,4-tetra-methylpyrrolidine-2,5-dione,

(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-methylpiperidine-2,6-dione,

1-[4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-4,4-dimethyl-piperidine-2,6-dione or

1-[2-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrole-2,5-dione,

or a pharmaceutically acceptable salt or trifluoroacetate thereof.

5. The compound according to claim 1 , which is:

1-[2-(8-bromo-6-chloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]pyrrolidine-2,5-dione,

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisochinolin-4-yl)phenyl]-1-methyl-imidazolidine-2,4-dione,

3-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-1-methyl-imidazolidine-2,4-dione

3-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-imidazolidine-2,4-dione

(S)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-cyclopropyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(R)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidine-2,5-dione,

(S)-1-[2-((R)-6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)phenyl]-3-hydroxypyrrolidin-2,5-dione,