Carbamic acid derivatives

Details Carbamic acid derivatives Carbamic acid derivatives

2003-05-14

2004-10-12

Stockton, Laura L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C549S390000

Reexamination Certificate

active

06803381

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.


REFERENCES:
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patent: 849 263 (1998-06-01), None
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Hohenlohe-Oehringen,Reaktionen des 5,5-diphenyl-4-hydroxy-1,2,3-triaazols, Monatshefte Für Chemie, vol. 89, No. 4/5, pp. 588-596 (1958).
Casagrande etal.,Synthesis and antiarrhythmic activity of 5,5-disubstituted-3-aminoalkylhydantoins and some heterocyclic and noncyclic analogues, IL Farmaco-Edizione Scientifica, vol. 29, No. 10, pp. 757-785 (1974).
Chemical Abstract of Japanese Patent No. 39 012921 (Jul. 8, 1964).
Toms et al.,Latest eruptions in metabotropic glutamate receptors, Trends in Pharmacological Sciences, vol. 17, No. 12, pp. 429-435 (1996).
Abstract of Document C3, (Hohenlohe-Oehringen,Monatshefte Für Chemie, vol. 89, No. 4/5, pp. 588-596 (1958), CA 53: 218981, 1959.

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