Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2000-09-26
2003-04-15
Criares, Theordore J. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S351000, C514S649000
Reexamination Certificate
active
06548522
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 the use of carbonylamino derivatives of the formula
wherein
R signifies lower alkyl, lower alkenyl, lower alkinyl, cycloalkyl, lower alkoxy or CF
3
;
R
1
signifies hydrogen or lower alkyl;
R
2
and R
3
signify, independently from each other, hydrogen, halogen or nitro;
Y signifies CH or N;
n is 0-6;
m is 0-2;
as well as with their pharmaceutically acceptable salts.
Encompassed by the present formula I are the following chemical structures:
wherein the substituents R
1
-R
3
, R and n and m are given above.
These compounds and their salts are known compounds and they are described per se or with similar structures in the following documents:
WO 9728005; J. Org. Chem., 62(8), 2594, (1997); Tetrahedron Letters, 38(12), 2113, 1997; EP 0 474 589; J. Med. Chem., 32(10), 2318, (1989) and U.S. Pat. No. 3,534,041.
The use as mentioned below is not described in these documents.
It has now surprisingly been found that the compounds of formula I are metabotropic glutamate receptor antagonists or agonists.
DETAILED DESCRIPTION OF THE INVENTION
Objects of the present invention are the use of compounds of formula I and their pharmaceutically acceptable salts in the treatment or prophylaxis of diseases, caused by activation of metabotropic glutamate receptors ligands, medicaments, containing a compound of formula I or a pharmaceutically acceptable acid addition salt thereof, and the use of compounds of formula I for the manufacture of corresponding medicaments.
Preferred compounds of formula I-1 in the scope of the present invention are those, in which Y is CH.
The following are examples of such compounds:
N-pentyl-2,2-diphenyl-acetamide,
N-hexyl-2,2-diphenyl-acetamide,
N-cyclopropylmethyl-2,2-diphenyl-acetamide and
N-hex-2-enyl-2,2-diphenyl-acetamide.
Further preferred are compounds of formula I-2, wherein Y is N, for example the following compounds:
(RS)-N-cyclopropylmethyl-2-phenyl-2-pyridin-2-yl-acetamide,
(RS)-2-(3,4-difluoro-phenyl)-N-hexyl-2-pyridin-2-yl-acetamide and
(RS)-N-hexyl-2-(4-nitrophenyl)-2-pyridin-3-yl-acetamide.
The invention embraces all stereoisomeric forms in addition to the racemates.
Accordingly, this invention is directed to a method of treating or preventing a condition related to group I metabotropic glutamate receptor activation which comprises administering a compound of the formula
wherein
R signifies lower alkyl, lower alkenyl, lower alkinyl, cycloalkyl, lower alkoxy or CF
3
;
R
1
signifies hydrogen or lower alkyl;
R
2
and R
3
signify, independently from each other, hydrogen, halogen or nitro;
Y signifies CH or N;
n is 0-6 and
m is 0-2
as well as pharmaceutically acceptable salts in an amount effective to alleviate or to prevent said condition
Preferably the method of treating or preventing involves administering a compound of formula
especially a compound selected from the group of
N-pentyl-2,2-diphenyl-acetamide,
N-hexyl-2,2-diphenyl-acetamide,
N-cyclopropylmethyl-2,2-diphenyl-acetamide and
N-hex-2-enyl-2,2-diphenyl-acetamide, or a compound of formula
especially a compound selected from the group of
(RS)-N-cyclopropylmethyl-2-phenyl-2-pyridin-2-yl-acetamide,
(RS)-2-(3,4-difluoro-phenyl)-N-hexyl-2-pyridin-2-yl-acetamide and
(RS)-N-hexyl-2-(4-nitrophenyl)-2-pyridin-3-yl-acetamide.
Preferred conditions for treatment or prevention are psychosis, schizophrenia, Alzheimer's disease, cognitive disorders, memory deficits, chronic and acute pain, 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, Huntington's chorea, amyotrophic lateral sclerosis (ALS), dementia caused by AIDS, eye injuries, retinopathy, idiopathic Parkinsonism or Parkinsonism caused by medicaments, muscle spasms, convulsions, migraine, urinary incontinence, nicotine addiction, opiate addiction, anxiety, vomiting, dyskinesia and depression.
This invention also includes pharmaceutical compositions which contain one or more compounds of the formula
wherein
R signifies lower alkyl, lower alkenyl, lower alkinyl, cycloalkyl, lower alkoxy or CF
3
;
R
1
signifies hydrogen or lower alkyl;
R
2
and R
3
signify, independently from each other, hydrogen, halogen or nitro;
Y signifies CH or N;
n is 0-6 and
m is 0-2
as well as pharmaceutically acceptable salts; and a pharmaceutically acceptable carrier.
Preferred compositions comprise a compound of formula
especially one or more of
N-pentyl-2,2-diphenyl-acetamide,
N-hexyl-2,2-diphenyl-acetamide,
N-cyclopropylmethyl-2,2-diphenyl-acetamide and
N-hex-2-enyl-2,2-diphenyl-acetamide,
or a compound of the formula
especially one or more of
(RS)-N-cyclopropylmethyl-2-phenyl-2-pyridin-2-yl-acetamide,
(RS)-2-(3,4-difluoro-phenyl)-N-hexyl-2-pyridin-2-yl-acetamide and
(RS)-N-hexyl-2-(4-nitrophenyl)-2-pyridin-3-yl-acetamide.
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 alkenyl” denotes an alkylene group having from 2 to 7 carbon atoms with a double bond between any two adjacent carbon atoms, preferably with 1 ot 4 carbon atoms.
The term “lower alkinyl” denotes an alkylene group having from 2 to 7 carbon atoms with a triple bond located between any two adjacent carbon atoms, preferably with 1 to 4 carbon atoms.
The term “cycloalkyl” denotes a saturated hydrocarbon ring having from 3 to 8 carbon atoms, preferably from 3 to 5 carbon atoms.
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 phrase “condition related to group I metabotropic glutamate receptor activation” denotes conditions such as those listed above which produce undesirable physiological symptoms relat
Mutel Vincent
Vieira Eric
Wichmann Juergen
Criares Theordore J.
Hoffmann-La Roche Inc.
Johnston George W.
Rocha-Tramaloni Patricia S.
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