Substituted imidazo[1,2-A] pyridine derivatives

Details Substituted imidazo[1,2-A] pyridine derivatives Substituted imidazo[1,2-A] pyridine derivatives

2002-03-08

2003-07-22

Aulakh, Charanjit S. (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C546S121000

Reexamination Certificate

active

06596731

ABSTRACT:

BACKGROUND
The synthesis of some imidazo[1,2-a]pyridine derivatives is described in
Recl. Trav. Chim. Pays
-
Bas
1949, 68, 441-470, in
J. Org. Chem.
1954, 19, 1370-1374, in
J. Heterocyclic Chem.
1988, 25, 129-137, in International patent application WO 00/08021 or in
J. Org. Chem.
2000, 65, 9201-9205. According to
J. Prakt. Chem
1971, 313, 977-985, imidazo[1,2-a]-pyridines bearing a benzothienyl, thienyl or benzofuranyl group have been prepared by condensation of &agr;-haloketones or &agr;-hydroxyketones with amidines. The synthesis and antimicrobial action of furyl derivatives of imidazo[1,2-a]pyrimidine is reported in
Khim.
-
Farm. Zh.
1970, 4, 20-26.
Different uses have been described for imidazo[1,2-a]pyridine derivatives. The preparation of 2-[p-(dimethylamino)phenyl]-imidazo[1,2-a]pyridine as an azo dye and its evaluation as disperse dye on synthetic fibers, cellulose acetate, and cotton is described in
Boll. Sci. Fac. Chim. Ind. Bologna
1966, 24, 205-214. Fluorescent properties of imidazo[1,2-a]-pyridine-based compounds are described in
Bull. Chem. Soc. Jpn.
1999, 72(6), 1327-1334. Japanese patent applications JP 50-140477, JP 51-004194 and JP 51-125095 report the analgesic, antiinflammatory, antipyretic, and local anesthetic activities of certain phenyl-imidazo[1,2-a]pyridines wherein the phenyl ring is substituted by —CR
1
R
2
COOH, —CR
1
R
2
COOR, —CR
1
R
2
CONH
2
, —CR
1
R
2
CSNH
2
, —CR
1
R
2
CN, —CO
2
—(CH
2
)
1-4
—NR
3
R
4
or —CH
2
OH and R, R
1
, R
2
, R
3
and R
4
are hydrogen or alkyl. According to
Arzneim.
-
Forsch.
1981, 31(7), 1111-1118, the most preferred compound thereof, viz. 4-imidazo[1,2-a]pyridin-2-yl-&agr;-methyl-benzeneacetic acid (miroprofen) is effective in suppressing pain responses and acute inflammation accompanied by increased vascular permeability. The use of imidazo[1,2-a] pyridines substituted at the 2 and 6 positions as anthelmintic and fungicidal agents is disclosed in U.S. Pat. No. 3,701,780. Isothiocyanato derivatives like 2-(4-isothiocyanato-phenyl) -6-methyl-imidazo[1,2-a]pyridine are described as antihelmintics in Swiss patent No. CH 590 862.
The use of imidazo[1,2-a]pyridine derivatives as inhibitors for STAT6 6 transcription factor activation and IL 4 antagonists for treatment of allergic, autoimmune, parasital, viral, and bacterial diseases, tumors, host-vs. graft syndrome, systemic lupus erythematosus, and AIDS is disclosed in Japanese patent application No. JP 11-116481.
According to
Eur. J. Med. Chem.
1994, 29(5), 339-342, aryl- or pyridyl-substituted fused imidazoles such as 2-(4-pyridinyl)-imidazo[1,2-a]pyridine, possess cardiotonic activity. N-(4-imidazo[1,2-a]pyridin-2-yl-phenyl)-methanesulfonamide has been prepared and is reported as an antithrombotic and cardiovascular agent in European patent application EP 0 185 345. According to
Eur. J. Med. Chem.
1987, 22(5), 457-462, certain imidazo[1,2-a]pyrimidines, e.g. 2-(2-furanyl)-imidazo[1,2-a]pyridine, were tested for bronchodilator activity and for inhibition of a cardiac phosphodiesterase. Phosphonic acid derivatives of imidazo[1,2-a]pyridines, e.g. [5-(6-chloroimidazo[1,2-a]pyridin-2-yl)-2-furanyl]-phosphonic acid, are described as human liver fructose-1,6-bisphosphatase inhibitors in International patent application WO 98/39342.
N,N,6-trimethyl-2-(4-methylphenyl)-imidazo[1,2-a] pyridine-3-acetamide (Zolpidem) and its use as anticonvulsant and hypnotic was first disclosed in European patent application EP 0 050 563. Further imidazo[1,2-a]pyridine derivatives with anticonvulsant, hypnotic and anxiolytic activity are also described in the patent applications EP 0 092 458, EP 0 092 459, EP 0 172 096, FR 25 81 646, EP 0 234 970, EP 0 251 859 and EP 0 267 111
. Eur. J. Pharmacol.
1986, 130(3), 257-263, reports that Zolpidem possesses agonist properties at central benzodiazepine receptors and according to
Br. J. Pharmacol.
2000, 131(7), 1251-1254 the mechanism of action of Zolpidem in vivo is based on its high affinity to the &agr;1-GABAA receptor benzodiazepine site.
SUMMARY
The present invention is a method of treating a disease responsive to mediating the mGluR5 receptor by administering, to a person in need of such treatment, a therapeutically effective amount of a compound of formula
wherein
R
1
is selected from the group consisting of hydrogen, (C
1-6
)-alkyl, halogen, hydroxy and (C
1-6
)-alkoxy;
R
2
is selected from the group consisting of hydrogen, (C
1-6
)-alkyl, halogen, hydroxy and (C
1-6
)-alkoxy; and
A is unsubstituted aryl or aryl substituted with at least one substituent selected from the group consisting of (C
1-6
)-alkyl, halogen, halogen-(C
1-6
)-alkyl, hydroxy, (C
1-6
)-alkoxy, benzyloxy, amino, (C
1-6
)-alkylamino, di-(C
1-6
)-alkyl-amino, arylamino, diarylamino and nitro, or is unsubstituted heteroaryl or heteroaryl substituted with at least one substituent selected from the group consisting of (C
1-6
)-alkyl, halogen, halogen-(C
1-6
)-alkyl, hydroxy, (C
1-6
)-alkoxy, benzyloxy, amino, (C
1-6
)-alkylamino, di-(C
1-6
)-alkyl-amino, arylamino, diarylamino and nitro or signifies the group
 wherein
X
a
, X
b
are, independently from each other, selected from the group consisting of CH
2
— and —O—; and
n is 1 or 2;
or a pharmaceutically acceptable salt thereof.
It has now surprisingly been found that the compounds of formula I are metabotropic glutamate receptor antagonists. Compounds of formula I are distinguished by having valuable therapeutic properties. These compounds can be used in the treatment or prevention of mGluR5 receptor mediated disorders.
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.
Glutamate is the major excitatory neurotransmitter in the brain and plays a unique role in a variety of central nervous system (CNS) functions. The glutamate-dependent stimulus receptors are divided into two main groups. The first main group, namely the ionotropic receptors, 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 receptors are known and some of these even have sub-types. According to their sequence homology, signal transduction mechanisms and agonist selectivity, 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, epilepsy, 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 ischemia, 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 depressions.
Disorders mediated full or in part by mGluR5 are for example acute, traumatic and chronic degenerative processes of the nervous system, such as Alzheimer's disease, senile dementia, Parkinson's disease, Huntington's chorea, amyotrophic lateral sclerosi

Affiliated with

Also associated with

Rating

Substituted imidazo[1,2-A] pyridine derivatives does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Substituted imidazo[1,2-A] pyridine derivatives, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Substituted imidazo[1,2-A] pyridine derivatives will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3051181