EP0199400A2 — Substituted N-[(4-piperidinyl)alkyl] bicyclic con…

Claim 1

Independent Claim 335 words

A chemical compound having the formula a pharmaceutically acceptable acid addition salt or a possible stereochemically isomeric form thereof, wherein -A 1 =A 2 -A 3 =A 4 -is a bivalent radical having the formula -CH = CH-CH = CH-(a), -N = CH-CH = CH-(b), -CH = N-CH = CH-(c), -CH = CH-N = CH-(d), -CH = CH-CH = N-(e), -N = CH-N = CH-(f) or -CH = N-CH = N-(g), wherein one or two hydrogen atoms in said radicals (f) -(g) and up to three hydrogen atoms in said radicals (a) -(e), may each independently from each other be replaced by halo, hydroxy, amino, trifluoromethyl, c 1-6 alkyl or C 1-6 alkyloxy, or two hydrogen atoms in said radicals (a) -(e) substituted on adjacent carbon atoms may be replaced by a bivalent radical of formula -O-CH 2 -O-or=O-CH 2 -CH 2 -O-; Z is -0-or -S-; R' is a member selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, aryl G 1- 6 alkyl, arylcarbonyl and C 1-6 alkyloxycarbonyl; Q is G 1-6 alkanediyl; R is a member selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy and C 1-6 alkyloxy; L is a member selected from the group consisting of a radical of formula and a radical of formula Alk is C 1-4 alkanediyl; X is -0-or -CH 2 -; R 2 is hydrogen or G 1-6 alkyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen, halo, trifluoromethyl, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy and phenyl C 1-6 alkyloxy; wherein aryl is a member selected from the group consisting of phenyl, susbtituted phenyl, pyridinyl, mono-and di(C 1-6 alkyloxy)pyridinyl, thienyl, halothienyl, C 1-6 alkylthienyl, pyrrolyl, C 1- 6 alkylpyrrolyl, furanyl, furanyl substituted with C 1- 6 alkyl, pyrazinyl, thiazolyl and imidazolyl; said substituted phenyl being phenyl substituted with up to 3 substituents each independently selected from the group consisting of halo, hydroxy, trifluoromethyl, C 1-6 alkyl and C 1-6 alkyloxy.

Claim 2

Dependent Claim 335 words

A chemical compound having the formula a pharmaceutically acceptable acid addition salt or a possible stereochemically isomeric form thereof, wherein -A 1 =A 2 -A 3 =A 4 -is a bivalent radical having the formula -CH = CH-CH = CH-(a), -N = CH-CH = CH-(b), -CH = N-CH = CH-(c), -CH = CH-N = CH-(d), -CH = CH-CH = N-(e), -N = CH-N = CH-(f) or -CH = N-CH = N-(g), wherein one or two hydrogen atoms in said radicals (f) -(g) and up to three hydrogen atoms in said radicals (a) -(e), may each independently from each other be replaced by halo, hydroxy, amino, trifluoromethyl, c 1-6 alkyl or C 1-6 alkyloxy, or two hydrogen atoms in said radicals (a) -(e) substituted on adjacent carbon atoms may be replaced by a bivalent radical of formula -O-CH 2 -O-or=O-CH 2 -CH 2 -O-; Z is -0-or -S-; R' is a member selected from the group consisting of hydrogen, C 1-6 alkyl, C 1-6 alkylcarbonyl, aryl G 1- 6 alkyl, arylcarbonyl and C 1-6 alkyloxycarbonyl; Q is G 1-6 alkanediyl; R is a member selected from the group consisting of hydrogen, C 1-6 alkyl, hydroxy and C 1-6 alkyloxy; L is a member selected from the group consisting of a radical of formula and a radical of formula Alk is C 1-4 alkanediyl; X is -0-or -CH 2 -; R 2 is hydrogen or G 1-6 alkyl; R 3 and R 4 are each independently selected from the group consisting of hydrogen, halo, trifluoromethyl, hydroxy, C 1-6 alkyl, C 1-6 alkyloxy and phenyl C 1-6 alkyloxy; wherein aryl is a member selected from the group consisting of phenyl, susbtituted phenyl, pyridinyl, mono-and di(C 1-6 alkyloxy)pyridinyl, thienyl, halothienyl, C 1-6 alkylthienyl, pyrrolyl, C 1- 6 alkylpyrrolyl, furanyl, furanyl substituted with C 1- 6 alkyl, pyrazinyl, thiazolyl and imidazolyl; said substituted phenyl being phenyl substituted with up to 3 substituents each independently selected from the group consisting of halo, hydroxy, trifluoromethyl, C 1-6 alkyl and C 1-6 alkyloxy.

Claim 3

Dependent Claim 62 words

A chemical compound according to claim 1, wherein L is a radical of formula (h) wherein R 3 and R 4 are both hydrogen; or L is a radical of formula - (i) wherein R 3 is hydrogen, halo, C 1-6 alkyl, C 1 - 6 alkyloxy or phenyl C 1-6 alkyloxy and R 4 is hydrogen, halo or C 1-6 alkyloxy.

Claim 4

Dependent Claim 68 words

A chemical compound according to claim 2, wherein R is hydrogen, L is a radical of formula (h) wherein R 2 is hydrogen, or L is a radical of formula (i) wherein R' is hydrogen or halo and R 4 is hydrogen; and R' is a member selected from the group consisting of hydrogen, C 1-6 alkyl, C i . 6 alkylcarbonyl, aryl C 1-6 alkyl and arylcarbonyl.

Claim 5

Dependent Claim 87 words

A chemical compound according to claim 3, wherein Q is C 1-3 alkanediyl; L is a radical of formula (h) wherein Alk is methylene; and R' is a member selected from the group consisting of hydrogen, C 1-4 alkyl, aryl C 1-2 alkyl and arylcarbonyl, wherein aryl is a member selected from the group consisting of phenyl, substituted phenyl, furanyl and thiazolyl; said substituted phenyl being phenyl substituted with up to 2 substituents each independently selected from the group consisting of halo, hydroxy, trifluoromethyl, methyl and methoxy.

Claim 6

Dependent Claim 34 words

A chemical compound according to claim 4 wherein A 1 =A 2 -A 3 =A 4 is a bivalent radical of formula (a) being optionally substituted with up to three C 1-6 alkyloxy radicals.

Claim 7

Dependent Claim 12 words

A chemical compound according to claim 1, wherein the compound is N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-2-benzothiazolamine.

Claim 8

Dependent Claim 12 words

A chemical compound according to claim 1, wherein the compound is (S)-(-)-N-[[1-[(2,3-dihydro-1,4-benzodioxin-2-yl)methyl]-4-piperidinyl]methyl]-2-benzothiazolamine.

Claim 9

Dependent Claim 29 words

A pharmaceutical composition comprising a suitable pharmaceutical carrier and as active ingredient a therapeutically effective amount of a compound as claimed in any one of claims 1 to 7.

Claim 10

Dependent Claim 40 words

An anti-depressive or anti-Parkinson or en- terokenetically effective composition comprising a suitable pharmaceutical carrier and as active ingredient an effective anti-depressive or anti-Parkinson or enterokinetically effective amount of a compound as claimed in any one of claims 1 to 7.

Claim 11

Independent Claim 33 words

A method of preparing a pharmaceutical composition, characterized in that a therapeutically effective amount of a compound as defined in any of claims 1 to 7 is intimately mixed with suitable pharmaceutical carriers.

Claim 12

Dependent Claim 17 words

A compound as claimed in any one of claims 1 to 7 for use as a medicine.

Claim 13

Dependent Claim 21 words

A compound as claimed in any one of claims 1 to 7 for use as an anti-depressive, anti-Parkinson or enterokinetic medicine.

Claim 14

Dependent Claim 319 words

A process for preparing a chemical compound as claimed in any of claims 1 to 7, characterized by a) N-alkylating a piperidine of formula H-D (III), with a reagent of formula L-W (II), wherein W represents a reactive leaving group, in a reaction-inert solvent; b) reductively N-alkylating a piperidine of formula - (III) with a carbonyl-compound of formula L'=C=O (IV), said L' =C = O being a compound of a formula L-H wherein a -CH2-radical is oxidated to a carbonyl radical, in an reaction-inert solvent; c) cyclizing an urea or thiourea derivative of formula in a reaction-inert solvent, in the presence of an oxidant; d) reacting a piperidine of formula with a bicyclic condensed oxazol-or thiazol derivative of formula in a reaction-inert solvent; wherein i) E is a radical of formula -NR'H and E 2 is a radical of formula -W', wherein W' represents a reactive leaving group; or ii) E' is a radical of formula -W and E 2 is a radical of formula -NR'H, said -W having the previously defined meaning; e) cyclodesulfurizing a thiourea derivative of formula which in situ may be prepared by condensing an isothiocyanate of formula with an aromatic aminoalcohol of formula thus preparing a compound of formula f) cyclizing an urea or thiourea derivative of formula which in situ may be formed by reacting an isocyanate or isothiocyanate of formula with an aromatic amine of formula wherein W 2 represents a leaving group, thus preparing a compound of formula g) reacting a piperidine of formula (III) with an alkene derivative of formula or respectively, in a reaction-inert solvent, thus preparing a compound of formula or respectively; wherein D represents a radical of formula wherein -A 1 =A 2 A 3 =A 4 -, Z, R', Q and R are as defined hereinabove; or, optionally converting the compounds of formula (I) into each other following art-known group transformation procedures, and, if desired, converting

Claim 15

Dependent Claim 40 words

the compounds of formula (1) into a therapeutically active non-toxic acid addition salt form by treatment with an appropriate acid or, conversely, converting the acid addition salt into the free base form with alkali; and/or preparing stereochemically isomeric forms thereof.

Claim 16

Dependent Claim 40 words

the compounds of formula (1) into a therapeutically active non-toxic acid addition salt form by treatment with an appropriate acid or, conversely, converting the acid addition salt into the free base form with alkali; and/or preparing stereochemically isomeric forms thereof.

Substituted N-[(4-piperidinyl)alkyl] bicyclic condensed ozazol- and thiazolamines

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