Carbamic acid derivatives

Details Carbamic acid derivatives Carbamic acid derivatives

2000-04-10

2002-10-08

Gerstl, Robert (Department: 1626)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C514S377000, C548S133000, C548S143000, C548S233000

Reexamination Certificate

active

06462198

ABSTRACT:

BACKGROUND OF THE INVENTION
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 mGluRs' are known and of these some even have sub-types. On the basis of structural parameters, the different second messager signalling pathways 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.
Ligands of metabotropic glutamate receptors belonging to the first group can be used for the treatment or prevention of acute and/or chronic neurological disorders such as psychosis, schizophrenia, Alzheimer's disease, cognitive disorders and memory deficits, as well as chronic and acute pain.
Other treatable indications in this connection are 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. Further treatable indications are Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic parkinsonism or parkinsonism caused by medicaments as well as conditions which lead to glutamate-deficiency functions, such as e.g. muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
SUMMARY OF THE INVENTION
The present invention is concerned with carbamic acid ester derivatives of the formula
wherein
R
1
signifies hydrogen or lower alkyl;
R
2
, R
2′
signify, independently from each other, hydrogen, lower alkyl, lower alkoxy, halogen or trifluoromethyl;
X signifies O, S or two hydrogen atoms not forming a bridge;
A
1
/A
2
signify, independently from each other, phenyl or a 6-membered heterocycle containing 1 or 2 nitrogen atoms;
B is a group of formula
 wherein
R
3
signifies lower alkyl, lower alkenyl, lower alkinyl, benzyl, lower alkyl-cycloalkyl, lower alkyl-cyano, lower alkyl-pyridinyl, lower alkyl-lower alkoxy-phenyl, lower alkyl-phenyl, which is optionally substituted by lower alkoxy, or phenyl, which is optionally substituted by lower alkoxy, or lower alkyl-thienyl, cycloalkyl, lower alkyl-trifluoromethyl or lower alkyl-morpholinyl;
Y signifies —O—, —S— or a bond;
Z signifies —O— or —S—;
or B is a 5-membered heterocyclic group of formulas
 wherein
R
4
and R
5
signifies hydrogen, lower alkyl, lower alkoxy, cyclohexyl, lower alkyl-cyclohexyl or trifluoromethyl, with the proviso that at least one of R
4
or R
5
has to be hydrogen;
as well as with their pharmaceutically acceptable salts.
In particular, the invention relates to compounds of the following structures:
wherein the definition of substituents is given above.
These compounds and their salts are novel and are distinguished by valuable therapeutic properties.
It has surprisingly been found that the compounds of formula I are metabotropic glutamate receptor modulators, acting as antagonists or agonists.
Objects of the present invention are compounds of formula I and their pharmaceutically acceptable salts per se and as pharmaceutically active substances, their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of the compounds in accordance with the invention in the control or prevention of illnesses of the aforementioned kind, and, respectively, for the production of corresponding medicaments.
DETAILED DESCRIPTION OF THE INVENTION
Preferred compounds of formula I in the scope of the present invention are those, in which A signifies phenyl, X signifies 2 hydrogen atoms not forming a bridge and B signifies the group
wherein Z is O and R
3
and Y are described above
The following are examples of such compounds:
diphenylacetyl-carbamic acid butyl ester,
diphenylacetyl-carbamic acid ethyl ester or
diphenylacetyl-carbamic acid pent-4-ynyl ester.
Compounds of formula I, wherein A signifies phenyl, X signifies —O— or —S— and B signifies the group
are further preferred, wherein Z is O and R
3
and Y are described above
Examples of such compounds are:
(9H-xanthene-9-carbonyl)-carbamic acid ethyl ester,
(9H-xanthene-9-carbonyl)-carbamic acid butyl ester or
(9H-thioxanthene-9-carbonyl)-carbamic acid butyl ester.
Preferred compounds of formula I in the scope of the present invention are those, in which A signifies phenyl, X signifies 2 hydrogen atoms not forming a bridge and B signifies a heterocyclic group of the formulas
wherein R
4
and R
5
have the significances given above.
Examples of such compounds are:
N-(5-ethyl-oxazol-2-yl)-2,2-diphenyl-acetamide,
N-(5-methyl-oxazol-2-yl)-2,2-diphenyl-acetamide,
2,2-diphenyl-N-(5-propyl-[1,3,4]oxadiazol-2-yl)-acetamide.
N-[5-(2-methoxy-ethyl)-[1,3,4]oxadiazol-2-yl]-2,2-diphenyl-acetamide,
N-(3-methyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenyl-acetamide,
N-(3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-2,2-diphenyl-acetamide or
N-(5-methyl-[1,2,4]oxadiazol-3-yl)-2,2-diphenyl-acetamide
Preferred are further compounds of formula I, in which A signifies phenyl, X signifies —O— or —S—; and B signifies a heterocyclic group of the formulas
for example the following compounds:
9H-xanthene-9-carboxylic acid oxazol-2-yl-amide,
9H-xanthene-9-carboxylic acid (5-propyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-ethyl-oxazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-methyl-oxazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-propyl-oxazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-ethyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (5-cyclopropylmethyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (4-methyl-oxazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (3-methyl-[1,2,4]oxadiazol-5-yl)-amide,
9H-Xanthene-9-carboxylic acid (5-trifluoromethyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-Xanthene-9-carboxylic acid (5-methoxymethyl-[1,3,4]oxadiazol-2-yl)-amide,
9H-xanthene-9-carboxylic acid (3-cyclopropyl-[1,2,4]oxadiazol-5-yl)-amide or
9H-xanthene-9-carboxylic acid (5-methyl-[1,2,4]oxadiazol-3-yl)-amide.
The invention embraces all stereoisomeric forms in addition to the racemates.
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 “lower alkoxy” denotes a lower alkyl residue in the sense of the foregoing definition bonded via an oxygen atom.
The term “halogen” embraces fluorine, chlorine, bromine and iodine.
The compounds of formula I and their pharmaceutically acceptable salts can be manufactured by processes, which comprises
a) reacting a compound of the formula
 with a compound of the formula
 to a compound of formula
 wherein the substituents have the significances given above, or
b) reacting a compound of formula
 with a compound of the formula
 to a compound of formula
 in which G is a suitable leaving group, such as Cl, Br or acyloxy, or a carbonyl chloride equivalent such as a carbonyl-pyrazolide, carbonyl imidazole, carbonyl benzotriazole, carbonyloxysuccinimide, or activated esters such as p-nitrophenylester, pentachlorophenylester and the like,

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