Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-05-04
2001-06-19
Morris, Patricia L. (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06248901
ABSTRACT:
BACKGROUND
In the central nervous system (CNS) the transmission of stimuli takes place by the interaction of a neurotransmitter, which is sent out by a neuron, with a neuroreceptor.
L-Glutamic acid, the most commonly occurring neurotransmitter in the CNS, plays a critical role in a large number of physiological processes. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group forms ligand-controlled ion channels. The metabotropic glutamate receptors (mGluR) belong to the second main group and, furthermore, belong to the family of G-protein-coupled receptors.
At present eight different members of these mGluR are known and of these some even have sub-types. On the basis of structural parameters, the different influences on the synthesis of secondary metabolites and the different affinity to low-molecular weight chemical compounds, these eight receptors can be sub-divided into three sub-groups:
mGluR1 and mGluR5 belong to group I, mGluR2 and mGluR3 belong to group II and mGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.
The ligands of the metabotropic glutamate receptors belonging to the second group are useful for treating Alzheimer's disease.
Other treatable indications in this connection are, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, cognitive disorders, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as for example muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, psychoses, opiate addiction, anxiety, vomiting, chronic pain, dyskinesia, depressions and pains.
The ligands can also be used for the treatment or prevention of acute and/or chronic neurological disorders such as restricted brain function caused by bypass operations or transplants, poor blood supply to the brain, spinal cord injuries, head injuries, hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia.
Objects of the present invention are the use of compounds of formula I and of their pharmaceutically acceptable salts as therapeutically active substances, as well as medicaments based on these compounds and their production, and novel compounds of formula I and their pharmacuetically acceptable salts per se and as pharmaceutically active substances for the control or prevention of illnesses of the aforementioned kind.
BRIEF SUMMARY OF THE INVENTION
In one aspect, the invention relates to a compound of the formula
wherein
R is halogen or lower alkyl;
n is 0-3;
R
1
is lower alkyl; cycloalkyl; benzyl unsubstituted or substituted by hydroxy, halogen, lower alkoxy or lower alkyl; benzoyl unsubstituted or substituted by amino, lower alkylamino or di-lower alkylamino; acetyl or cycloalkyl-carbonyl; and
is an aromatic 5-membered residue which is bonded via a N-atom and which contains further 1 or 3 N atoms in addition to the linking N atom,
or a pharmaceutically acceptable salt thereof.
In another aspect, the invention relates to a compound of the formula
wherein
R is halogen or lower alkyl;
n is 0-3
R
1
is cycloalkyl; and
is an aromatic 5-membered residue which is bonded via a N atom and which contains further 3 N atoms in addition to the linking N atom, or a pharmaceutically acceptable salt thereof.
In another aspect, the invention relates to a pharmaceutical composition comprising
(a) a compound of the formula I
wherein
R is halogen or lower alkyl;
n is 0-3;
R
1
is lower alkyl; cycloalkyl; benzyl unsubstituted or substituted by hydroxy, halogen, lower alkoxy or lower alkyl; benzoyl unsubstituted or substituted by amino, lower alkylamino or di-lower alkylamino; acetyl or cycloalkyl-carbonyl; and
is an aromatic 5-membered residue which is bonded via a N-atom and which contains further 1-3 N atoms in addition to the linking N atom,
or a pharmaceutically acceptable salts as thereof, and
(b) a pharmaceutically inert carrier.
DETAILED DESCRIPTION OF THE INVENTION
The invention is concerned with heterocyclic vinyl ethers of the formula
wherein
R is halogen or lower alkyl;
n is 0-3;
R
1
is lower alkyl; cycloalkyl; benzyl unsubstituted or substituted by hydroxy, halogen, lower alkoxy or lower alkyl; benzoyl unsubstituted or substituted by amino, lower alkylamino or di-lower alkylamino; acetyl or cycloalkyl-carbonyl; and
 is an aromatic 5-membered residue which is bonded via a N-atom and which contains further 1-3 N atoms in addition to the linking N atom, as well as their pharmaceutically acceptable salts.
Some triazole derivatives which fall under formula I have been known for a long time. They are described in European Application No. 079 856 for use as active substances for agrochemical pest control, preferably for the control or prevention of an attack by microorganisms.
It has surprisingly been found that the compounds of formula I are metabotropic glutamate receptor antagonists.
Novel compounds of formula I are especially those in which R and R
1
have the significance given above and  signifies an aromatic 5-membered ring which is bonded via a N atom and which contains further 1 or 3 N atoms in addition to the linking N atom or wherein R has the significance given above,  signifies an aromatic 5-membered ring which is bonded via a N atom and which contains a further 1-3 N atoms in addition to the linking N atom and R
1
signifies cycloalkyl.
The term “lower alkyl” used in the present description denotes straight-chain or branched saturated hydrocarbon residues with 1-7 carbon atoms, preferably with 1-4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl and the like.
The term “cycloalkyl” denotes cyclic saturated hydrocarbon residues with 3-7 carbon atoms in the ring, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
The term “lower alkoxy” denotes lower alkyl residues in the sense of the foregoing definition which are bonded via an oxygen atom.
The term “halogen” embraces fluorine, chlorine, bromine and iodine.
In the scope of the present invention those compounds of formula I in which R signifies chlorine, n is 1 or 2, R
1
signifies lower alkyl, cyclohexyl or benzyl and
 signifies an aromatic 5-membered ring which is bonded via a N atom and which contains further 2 or 3 N atoms in addition to the linking N atom are preferred for use as therapeutically active substances.
The following are examples of preferred compounds of formula I:
1-[2-(2,4-dichloro-phenyl)-2-cyclohexyloxy-vinyl]-1H[1,2,4]triazole,
1-[2-(2,4-dichloro-phenyl)-2-benzyloxy-vinyl]-1H-tetrazole,
2-[2-(4-chloro-phenyl)-2-butoxy-vinyl]-2H-tetrazole,
1-[2-(4-chloro-phenyl)-2-butoxy-vinyl]-1H-[1,2,4]-triazole and
1-[2-(2,6-dichloro-phenyl)-2-butoxy-vinyl]-1H-[1,2,4]triazole.
The novel compounds of formula I can be manufactured by alkylating or acylating a compound of the formula
wherein R, n and
have the significances given earlier, and, if desired, converting a compound of formula I obtained into a pharmaceutically acceptable salt.
If desired, a functional group in a compound of formula I can be converted into a different functional group; in particular, amino groups can be alkylated to lower alkylamino or di-lower alkylamino groups or hydroxy groups can be alkylated. These procedures will be familiar to any person skilled in the art.
In the alkylation or acylation an acetophenone derivative of formula II is reacted with a suitable alkylating or acylating agent, preferably with benzyl bromide, benzoyl chloride, acetyl chloride, cyclohexyl triflate, cyclopropyl chloride, isopropyl bromide, n-butyl bromide, 4-methoxybenzyl chloride, isopropyl triflate, 4-dimethylaminobenzoyl chloride, benzyl chloride or the like. This reaction is effected according to known methods, preferably in the presence of sodium hydride. THF (tetrahydrofuran) and DMPU (1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone) in the ratio 3:1 is especially suitable as the solvent.
This manufacturing variant is de
Adam Geo
Kolczewski Sabine
Mutel Vincent
Stadler Heinz
Wichmann Jurgen
Hoffman-La Roche Inc.
Johnston George W.
Morris Patricia L.
Rocha-Tramaloni Patricia S.
Silverman Robert A.
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