Substituted bis aryl and heteroaryl compounds as selective 5HT
View Patent ↗The present invention relates to a series of substituted bis aryl and heteroaryl compounds of formula (I): Wherein X, Y, Z, A, B, D, Ar, R 1 and R 2 are as defined herein. The compounds of this invention are selective 5HT 2A antagonists, and are therefore, useful in treating a variety of diseases including but not limited to a wide variety of sleep disorders as disclosed and claimed herein.
1. A compound, including enantiomers, stereoisomers, and tautomers of said compound and pharmaceutically acceptable salts thereof, with said compound having the general structure shown in formula I:
wherein:
denotes a single bond between X and Y;
X is O or S;
Y is CHR or CO;
Z is NR;
A, B and E are the same or different and independently from each other are CR;
D is either CH 2 or CO;
Ar is selected from the group consisting of substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, furanyl and thiophenyl wherein the substituents are selected from the group consisting of fluorine, chlorine, C 1-4 alkyl, C 1-4 alkoxy and —CF 3;
each R is independently chosen from hydrogen, halogen, CN, C(O)NR 3 R 4 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkenyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1; wherein
R 3 and R 4 are hydrogen or C 1 alkyl; and
R 1 and R 2 taken together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted piperazine or diazepane; and wherein
the substituents are selected from the group consisting of phenyl, fluorophenyl, trifluoromethylphenyl, pyridinyl, thiophenyl, furanyl C 3-8 cycloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkenyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1, —NO 2 , —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —C(O)R 5 , —NHC(O)(C 1-4 alkyl), —SO 2 Cl, —SO 2 (C 1-4 alkyl), halogen and hydroxy; wherein
R 5 is hydroxy, C 1-3 alkoxy, —O-phenyl, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 or phenyl.
2. The compound as set forth in claim 1 , wherein:
D is CH 2 ;
Ar is substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, furanyl or thiophenyl; wherein the substituents are selected from the group consisting of fluorine, chlorine, C 1-4 alkyl, C 1-4 alkoxy and —CF 3 ;
each R is independently chosen from hydrogen, CN or C 1-4 alkyl; and
R 1 and R 2 taken together with the nitrogen atom to which they are attached form a unsubstituted or at least monosubstituted piperazine or diazepane; wherein the substituents are selected from the group consisting of phenyl, fluorophenyl, trifluoromethylphenyl, pyridinyl, thiophenyl, furanyl and C 1-4 alkyl.
3. The compound as set forth in claim 2 , wherein:
denotes a single bond between X and Y;
X is O or S;
Y is CO;
Z is NR;
A, B and E are CH;
Ar is phenyl, fluorophenyl, chlorophenyl, pyridinyl, pyrazinyl, furanyl or thiophenyl;
each R is independently chosen from hydrogen, methyl or ethyl;
R 1 and R 2 taken together with the nitrogen atom to which they are attached form a unsubstituted or at least monosubstituted piperazine or diazepane; wherein the substituents are selected from the group consisting of phenyl, fluorophenyl, trifluoromethylphenyl, pyridinyl, thiophenyl, furanyl and methyl.
4. The compound as set forth in claim 3 selected from the group consisting of:
6-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3H-benzooxazol-2-one;
6-{5-[2R-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-furan-3-yl}-3H-benzooxazol-2-one;
6-{5-[2S-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-furan-2-yl}-3H-benzooxazol-2-one;
6-{5-[2S-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-thiophen-3-yl}-3H-benzooxazol-2-one;
6-[4-fluoro-3-(2-thiophen-2-yl-piperazin-1-ylmethyl)-phenyl]-3H-benzooxazol-2-one;
6-{5-[2S-(4-fluorophenyl)-4-methylpiperazine-1-ylmethyl]-furan-3-yl}-3H-benzoxazol-2-one;
6-{5-[2S-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-furan-3-yl}-3H-benzooxazol-2-one acetate;
6-{4-fluoro-3-[2S-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-phenyl}-3H-benzooxazol-2-one; and
6-{5-[2S-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-pyridin-3-yl}-3H -benzooxazol-2-one acetate;
or a pharmaceutically acceptable salt thereof or an optical or stereoisomer thereof.
5. A pharmaceutical composition comprising one or more compounds of formula I, including enantiomers, stereoisomers, and tautomers of said compound and pharmaceutically acceptable salts thereof, in combination with one or more pharmaceutically acceptable carriers, diluents or excipients:
wherein:
denotes a single bond between X and Y;
X is O or S;
Y is CHR or CO;
Z is NR;
A, B and E are the same or different and independently from each other are CR;
D is either CH 2 or CO;
Ar is selected from the group consisting of substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, furanyl and thiophenyl wherein the substituents are selected from the group consisting of fluorine, chlorine, C 1-4 alkyl, C 1-4 alkoxy and —CF 3 ;
each R is independently chosen from hydrogen, halogen, CN, C(O)NR 3 R 4 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkenyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1; wherein R 3 and R 4 are hydrogen or C 1-4 alkyl;
R 1 and R 2 taken together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted piperazine or diazepane; and wherein
the substituents are selected from the group consisting of phenyl, fluorophenyl, trifluoromethylphenyl, pyridinyl, thiophenyl, furanyl C 3-8 cycloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkenyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H y F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1, —NO 2 , —NH 2 , —NH(C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —C(O)R 5 , —NHC(O)(C 1-4 alkyl), —SO 2 Cl, —SO 2 (C 1-4 alkyl), halogen and hydroxy; wherein
R 5 is hydroxy, C 1-3 alkoxy, —O-phenyl, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 or phenyl.
6. The composition as set forth in claim 5 , wherein the compound of formula (I) is having:
D is CH 2 ;
Ar is substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, furanyl or thiophenyl; wherein the substituents are selected from the group consisting of fluorine, chlorine, C 1-4 alkyl, C 1-4 alkoxy and —CF 3 ;
each R is independently chosen from hydrogen, CN or C 1-4 alkyl; and
R 1 and R 2 taken together with the nitrogen atom to which they are attached form a unsubstituted or at least monosubstituted piperazine or diazepane; wherein the substituents are selected from the group consisting of phenyl, fluorophenyl, trifluoromethylphenyl, pyridinyl, thiophenyl, furanyl and C 1-4 alkyl.
7. The composition as set forth in claim 5 , wherein the compound of formula (I) is selected from the group consisting of:
6-[3-(4-methyl-piperazin-1-ylmethyl)-phenyl]-3H-benzooxazol-2-one;
6-{5-[2R-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-furan-3-yl}-3H-benzooxazol-2-one;
6-{5-[2S-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-furan-2-yl}-3H -benzooxazol-2-one;
6-{5-[2S-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-thiophen-3-yl}-3H-benzooxazol-2-one;
6-[4-fluoro-3-(2-thiophen-2-yl-piperazin-1-ylmethyl)-phenyl]-3H-benzooxazol-2-one;
6-{5-[2S-(4-fluorophenyl)-4-methylpiperazine-1-ylmethyl]-furan-3-yl}-3H-benzoxazol-2-one;
6-{5-[2S-(4-fluoro-phenyl)-piperazin-1-ylmethyl]-furan-3-yl}-3H -benzooxazol-2-one acetate;
6-{4-fluoro-3-[2S-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-phenyl}-3H -benzooxazol-2-one; and
6-{5-[2S-(4-fluoro-phenyl)-4-methyl-piperazin-1-ylmethyl]-pyridin-3-yl}-3H-benzooxazol-2-one acetate;
or a pharmaceutically acceptable salt thereof or an optical or stereoisomer thereof.
8. A method of treating a sleep disorder selected from the group consisting of insomnia, primary insomnia and obstructive sleep apnea in a patient comprising administering to said patient a therapeutically effective amount of a compound of formula I, including enantiomers, stereoisomers, and tautomers of said compound and pharmaceutically acceptable salts thereof, optionally in combination with one or more pharmaceutically acceptable carriers, diluents or excipients:
wherein:
denotes a single bond between X and Y;
X is O or S;
Y is CHR or CO;
Z is NR;
A, B and E are the same or different and independently from each other are CR;
D is either CH 2 or CO;
Ar is selected from the group consisting of substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, furanyl and thiophenyl wherein the substituents are selected from the group consisting of fluorine, chlorine, C 1-4 alkyl, C 1-4 alkoxy and —CF 3 ;
each R is independently chosen from hydrogen, halogen, CN, C(O)NR 3 R 4 , C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkenyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1; wherein R 3 and R 4 are hydrogen or C 1 alkyl; and
R 1 and R 2 taken together with the nitrogen atom to which they are attached form an unsubstituted or at least monosubstituted piperazine or diazepane; and wherein
the substituents are selected from the group consisting of phenyl, fluorophenyl, trifluoromethylphenyl, pyridinyl, thiophenyl, furanyl C 3-8 cycloalkyl, C 1-4 alkyl, C 1-4 alkoxy, C 1-4 alkenyl, fluoroalkyl or fluoroalkoxy of the formula C n H x F y or OC n H x F y wherein n is an integer from 1 to 4, x is an integer from 0 to 8, y is an integer from 1 to 9 and sum of x and y is 2n+1, —NO2, —NH 2 , —NH (C 1-4 alkyl), —N(C 1-4 alkyl) 2 , —CN, —C(O)R 5 , —NHC(O)(C 1-4 alkyl), —SO 2 Cl, —SO 2 (C 1-4 alkyl), halogen and hydroxy; wherein
R 5 is hydroxy, C 1-3 alkoxy, —O-phenyl, —NH 2 , —NH(C 1-3 alkyl), —N(C 1-3 alkyl) 2 or phenyl.
9. The method as set forth in claim 8 , wherein the compound of formula (I) is having:
D is CH 2 ;
Ar is substituted or unsubstituted phenyl, pyridinyl, pyrazinyl, furanyl or thiophenyl; wherein the substituents are selected from the group consisting of fluorine, chlorine, C 1-4 alkyl, C 1-4 alkoxy and —CF 3 ;
each R is independently chosen from hydrogen, CN or C 1-4 alkyl; and
R 1 and R 2 taken together with the nitrogen atom to which they are attached form a unsubstituted or at least monosubstituted piperazine or diazepane; wherein the substituents are selected from the group consisting of phenyl, fluorophenyl, trifluoromethylphenyl, pyridinyl, thiophenyl, furanyl and C 1-4 alkyl.
10. The method as set forth in claim 8 , wherein the sleep disorder is insomma.
11. The method as set forth in claim 8 , wherein the sleep disorder is primary insomnia.
12. The method set forth in claim 8 , wherein the sleep disorder is an obstructive sleep apnea.