Patent EA-001133-B1 (EA)
Title: 4-substituted piperidine analogs and their use as subtype selective nmda receptor antagonists
Inventor: BIGGE CHRISTOPHER F
IPC: C07D211/54
Filed: 1996-12-20
Abstract: 1. A compound represented by the formula (I)   or a pharmaceutically acceptable salt thereof wherein Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; z is a single bond; X is -(CHR<2>)m-, wherein each R<2> is independently hydrogen, and m is 1,  R<1> is hydrogen or hydroxy; n is 1 or 2; Q is -CH [triple bond] CH-; and R<4> is hydrogen or hydroxy. 2. A compound according to claim1, wherein Ar<1> is substituted or unsubstituted phenyl. 3. A compound according to claim 1, wherein Ar<1> is a halophenyl group. 4. A compound according to claim 1, said compound selected from the group consisting of: N-4-(1-(4-(3-aminophenyl)butyn-3-yl)piperidinyl)-2-oxobenzimidazol; 1-(4-benzo[l,3]dioxol-5-yl-but-3-ynyl)-4-benzyl-piperidine; 4-benzyl-1-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-but-3-ynyl]-piperidine; 5-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-lH-indole; 5-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-lH-indazole; 5-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-1,3-dihydrobenzoimidazol-2-one; 5-[4-(4-benzyl-piperidin-1-yl)-but-l-ynyl)-lH-indole- 2,3-dione; and  a pharmaceutically acceptable salt thereof. 5. A pharmaceutical composition useful for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes such as stroke, cerebral ischemia, central nervous systems, trauma, hypoglycemia, neurodegenerative disorders, anxiety, migraine headaches, convulsions, aminoglycoside antibiotics-induced hearing loss, chronic pain, psychosis, glaucoma, CMV retinitis, opioid tolerance or withdrawal or urinary incontinence, said compositions comprising a pharmaceutically acceptable carrier or diluent and a therapeutically effective amount of at least one compound of claim 1. 6. A compound represented by the formula: 6.   or a pharmaceutically acceptable salt thereof wherein: Ar1 is an aryl substituted with halogen and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  Q is -CH [triple bond] CH-. 7. A compound represented by the formula:   or a pharmaceutically acceptable salt thereof wherein: Ar1 is an aryl substituted with halogen and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  Q is -CH [triple bond] CH-. 8. A compound represented by the formula:   or a pharmaceutically acceptable salt thereof wherein: Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  Q is -CH [triple bond] CH-. 9. A compound represented by the formula:   or a pharmaceutically acceptable salt thereof wherein: Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  Q is -CH [triple bond] CH-. 10. A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:   or a pharmaceutically acceptable salt thereof wherein Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; z is a single bond; X is -(CHR<2>)m-, wherein each R<2> is independently hydrogen, and m is 1,  R<1> is hydrogen or hydroxy; n is 1 or 2; Q is -CH [triple bond] CH-; and R<4> is hydrogen or hydroxy. 11. A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:   or a pharmaceutically acceptable salt thereof wherein: Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and   Q is -CH [triple bond] CH-. 12. A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:   or a pharmaceutically acceptable salt thereof wherein: Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  Q is -CH [triple bond] CH-. 13. A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:   or a pharmaceutically acceptable salt thereof wherein: Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  Q is -CH [triple bond] CH-. 14. A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound represented by the formula:   or a pharmaceutically acceptable salt thereof wherein: Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; and  Q is -CH [triple bond] CH-. 15. A method for treating disorders responsive to the selective blockade of N-methyl-D-aspartate receptor subtypes in an animal suffering thereof which comprises administering in unit dosage form of at least one compound selected from the group consisting of: N-4-(1-(4-(3-aminophenyl)butyn-3-yl)piperidinyl)-2-oxobenzimidazol; 1-(4-benzo[l,3]dioxol-5-yl-but-3-ynyl)-4-benzyl-piperidine; 4-benzyl-1-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-but-3-ynyl]-piperidine; 5-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-lH-indole; 5-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-lH-indazole; 5-[4-(4-benzyl-piperidin-1-yl)-but-1-ynyl]-1,3-dihydrobenzoimidazol-2-one; 5-[4-(4-benzyl-piperidin-1-yl)-but-l-ynyl)-lH-indole- 2,3-dione; and  a pharmaceutically acceptable salt thereof. 16. A method for preparing the compound represented by formula I:   or a pharmaceutically acceptable salt thereof wherein Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; z is a single bond; X is -(CHR<2>)m-, wherein each R<2> is independently hydrogen, and m is 1,  R<1> is hydrogen or hydroxy; n is 1 or 2; Q is -CH [triple bond] CH-; and R<4> is hydrogen or hydroxy, said method comprising the steps of: (a) reacting, in the presence of a base, a compound of formula VII   wherein Ar<1>, X, R<1>, R<4> and z are as previously described, with a compound of formula IX: L-CH2-(CH2)n-Q-	IX wherein n and Q are as previously described and L is a leaving group to afford a compound of formula X:   wherein Ar<1>, X, R<1>, R<4>, z, n and Q are as previously described; and (b) reacting the compound of formula X with Ar<2>Y, wherein Ar<2> is as previously defined and Y is a transmetalation group, in the presence of a palladium catalyst to afford the compound of formula I. 17. A method according to claim 16, wherein said transmetalation group is selected from the group consisting of Br, I, B(OH)2 and HgCl. 18. A method for preparing the compound represented by formula I:   or a pharmaceutically acceptable salt thereof wherein Ar1 is an aryl group and Ar2 is a bicyclic heteroaryl group, either of which may be independently substituted by hydrogen, hydroxy, alkyl, halogen, nitro, aryl, aralkyl, amino, a halogenated alkyl group, -NHAc, -NHSO2Me, -N(SO2Me)2, -CONHalkyl, -SO2NH2, an alkylguanidine group, a lower alkyl amino group or a lower alkoxy group; z is a single