Phenyl pyrrolidine ether tachykinin receptor antagonists
View Patent ↗The present invention is directed to certain phenyl pyrrolidine ether compounds which are useful as neurokinin-1 (NK-1) receptor antagonists, and inhibitors of tachykinin and in particular substance P. The invention is also concerned with pharmaceutical formulations comprising these compounds as active ingredients and the use of the compounds and their formulations in the treatment of certain disorders, including emesis, depression, and anxiety.
1. A compound of the formula I:
wherein:
R 1 , R 1a and R 1b are independently selected from the group consisting of H, F, Cl, Br, I, CH 3 , CF 3 , OH, OCH 3 , NH 2 , NHCH 3 , SH, and SCH 3 ;
R 2 is selected from the group consisting of H, R 4 , COR 4 , and SO 2 R 4 ;
Y is a bond, CHCH 3 , or CH 2 ;
Z is selected from the group consisting of CH 2 , CHCH 3 , CO, and COCH 2 ;
R 4 is independently selected from the group consisting of H, C 1-6 alkyl, phenyl optionally substituted by R 6 , benzyl, O—C 1-6 alkyl, O-benzyl, N(R 5 )—C 1-6 alkyl, N(R 5 )-benzyl,
R 5 is H or C 1-6 alkyl;
R 6 , R 6a , and R 6b are independently selected from the group consisting of H, F, Cl, CF 3 , OCH 3 , CH 3 , COCH 3 , CO 2 CH 3 , CH 2 CONH 2 , CONH 2 , CONHCH 3 , and SO 2 CH 3 ;
and pharmaceutically acceptable salts thereof.
2. The compound of claim 1 of the formula Ia:
wherein Y, Z, R 1 , R 2 , and R 3 are as defined in claim 1 .
3. The compound of claim 2 wherein Y is a bond.
4. The compound of claim 3 wherein R 1 is H or F.
5. The compound of claim 4 wherein R 2 is R 4 .
6. The compound of claim 5 wherein R 4 is selected from the group consisting of:
wherein R 6 and R 6a are independently selected from the group consisting of H, F, Cl, CF 3 , OCH 3 , CH 3 , COCH 3 , CO 2 CH 3 , CH 2 CONH 2 , CONH 2 , CONHCH 3 , and SO 2 CH 3 .
7. The compound of claim 4 wherein R 2 is COR 4 .
8. The compound of claim 7 wherein R 4 is selected from the group consisting of:
—NHCH 3 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —OCH 3 , —OC(CH 3 ) 3 , —CH 3 , —CH 2 CH 3 , —CH(CH 3 ) 2 ,
wherein R 6 , R 6a , and R 6b are independently selected from the group consisting of H, F, Cl, CF 3 , OCH 3 , CH 3 , COCH 3 , CO 2 CH 3 , CH 2 CONH 2 , CONH 2 , CONHCH 3 , and SO 2 CH 3 .
9. A compound which is selected from the group consisting of:
wherein R 2 and R 1 are selected from the table below:
R 2
R 1
F
H
F
F
H
F
F
F
F
F
F
F
F
H
F
F
F
H
F
H
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
F
H
H
F
H
F
and
F;
and pharmaceutically acceptable salts thereof.
10. A compound which is selected from the group consisting of:
(3R,4S)-1-Acetyl-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidine;
(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)-N-methylpyrrolidine-1-carboxamide;
3-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one;
tert-Butyl 4-{[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidin-1-yl]carbonyl}-2,2-dimethyl-1,3-oxazolidine-3-carboxylate;
2-Amino-3-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidin-1-yl]-3-oxopropan-1-ol;
4-{[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-phenylpyrrolidin-1-yl]carbonyl}-1,3-oxazolidin-2-one;
3-[(3R,4R)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]cyclopent-2-en-1-one;
(5R)-3-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-methylcyclopent-2-en-1-one;
(5S)-3-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-methylcyclopent-2-en-1-one;
(5R)-3-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-hydroxycyclopent-2-en-1-one;
(5S)-3-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-hydroxycyclopent-2-en-1-one;
3-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-4-methylcyclopent-2-en-1-one;
(4R)-3-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]hydroxycyclopent-2-en-1-one;
2-{2-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-oxocyclopent-1-en-1-yl}acetamide;
Methyl 2-[(3R,4S)-3-({(1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-5-oxocyclopent-1-ene-1-carboxylate; and
2-[(3R,4S)-3-({(1R)-1-[3,5-Bis(trifluoromethyl)phenyl]ethyl}oxy)-4-(4-fluorophenyl)pyrrolidin-1-yl]-N-methyl-5-oxocyclopent-1-ene-1-carboxamide.
11. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of claim 1 .
12. A method for antagonizing the effect of substance P at its receptor site or for the blockade of neurokinin-1 receptors in a mammal which comprises the administration to the mammal of the compound of claim 1 in an amount that is effective for antagonizing the effect of substance P at its receptor site in the mammal.
13. A method for the treatment of emesis in a mammal in need thereof which comprises the administration to the mammal of a therapeutically effective amount of the compound of claim 1 .