Pyridine amido derivatives

Details Pyridine amido derivatives Pyridine amido derivatives

2003-01-14

2003-12-23

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...

C546S298000, C546S292000, C546S291000, C546S290000, C514S346000, C514S345000

Reexamination Certificate

active

06667327

ABSTRACT:

BRIEF SUMMARY OF THE INVENTION
This invention relates to novel pyridine amido derivatives that are selective monoamine oxidase B (“MAO-B”) inhibitors. This invention also relates to pharmaceutical compositions containing these compounds and methods of treatment of diseases that are mediated by monoamine oxidase B inhibitors, such as, for example, Alzheimer's disease and senile dementia.
BACKGROUND OF THE INVENTION
Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-containing enzyme responsible for the oxidative deamination of endogenous monoamine neurotransmitters such as dopamine, serotonin, adrenaline, or noradrenaline, and trace amines, e.g. phenylethyl-amine, as well as a number of amine xenobiotics. The enzyme exists in two forms, MAO-A and MAO-B, encoded by different genes (A. W. Bach et al.,
Proc. Natl. Acad. Sci. USA
1988, 85, 4934-4938) and differing in tissue distribution, structure and substrate specificity. MAO-A has higher affinity for serotonin, octopamine, adrenaline, and noradrenaline; whereas the natural substrates for MAO-B are phenylethylamine and tyramine. Dopamine is thought to be oxidised by both isoforms. MAO-B is widely distributed in several organs including brain (A. M. Cesura and A. Pletscher, Prog. Drug Research 1992, 38, 171-297). Brain MAO-B activity appears to increase with age. This increase has been attributed to the gliosis associated with aging (C. J. Fowler et al.,
J. Neural. Transm
. 1980, 49, 1-20). Additionally, MAO-B activity is significantly higher in the brains of patients with Alzheimer's disease (P. Dostert et al.,
Biochem. Pharmacol
. 1989, 38, 555-561) and it has been found to be highly expressed in astrocytes around senile plaques (Saura et al.,
Neuroscience
1994, 70, 755-774). In this context, since oxidative deamination of primary monoamines by MAO produces NH
3
, aldehydes and H
2
O
2
, agents with established or potential toxicity, it is suggested that there is a rationale for the use of selective MAO-B inhibitors for the treatment of dementia and Parkinson's disease. Inhibition of MAO-B causes a reduction in the enzymatic inactivation of dopamine and thus prolongation of the availability of the neurotransmitter in dopaminergic neurons. The degeneration processes associated with age and Alzheimer's and Parkinson's diseases may also be attributed to oxidative stress due to increased MAO activity and consequent increased formation of H
2
O
2
by MAO-B. Therefore, MAO-B inhibitors may act by both reducing the formation of oxygen radicals and elevating the levels of monoamines in the brain.
Given the implication of MAO-B in the neurological disorders mentioned above, there is considerable interest to obtain potent and selective inhibitors that would permit control over this enzymatic activity. The pharmacology of some known MAO-B inhibitors is for example discussed by D. Bentué-Ferrer et al. in
CNS Drugs
1996, 6, 217-236. Whereas a major limitation of irreversible and non-selective MAO inhibitor activity is the need to observe dietary precautions due to the risk of inducing a hypertensive crisis when dietary tyramine is ingested, as well as the potential for interactions with other medications (D. M. Gardner et al.,
J. Clin. Psychiatry
1996, 57, 99-104), these adverse events are of less concern with reversible and selective MAO inhibitors, in particular of MAO-B. Thus, there is a need for MAO-B inhibitors with a high selectivity and without the adverse side-effects typical of irreversible MAO inhibitors with low selectivity for the enzyme.
DETAILED DESCRIPTION OF THE INVENTION
Definitions
The following definitions of general terms used in the present patent application apply irrespective of whether the terms in question appear alone or in combination. It must be noted that, as used in the specification and the appended claims, the singular forms “a”, “an,” and “the” include plural forms unless the context clearly dictates otherwise.
The term “C
1
-C
6
-alkyl” (“lower alkyl”) used in the present application denotes straight-chain or branched saturated hydrocarbon residues with 1 to 6 carbon atoms, preferably with 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and the like.
The term “halogen” denotes fluorine, chlorine, bromine and iodine.
“Halogenalkyl” or “halogen-(C
1
-C
6
)-alkyl” means the lower alkyl residue as defined herein substituted in any position with one or more halogen atoms as defined herein.
Examples of halogenalkyl residues include, but are not limited to, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and 1,1,1-trifluoropropyl, and the like.
“Alkoxy” or “(C
1
-C
6
)-alkoxy” means the residue —O—R, wherein R is a lower alkyl residue as defined herein. Examples of alkoxy radicals include, but are not limited to, methoxy, ethoxy, isopropoxy, and the like.
“Aryl” represents an aromatic carbocyclic group consisting of one individual ring, or one or more fused rings in which at least one ring is aromatic in nature. Preferred aryl groups are phenyl or naphthyl. Especially preferred is phenyl.
“Pharmaceutically acceptable salts” of a compound means salts that are pharmaceutically acceptable, which are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and that possess the desired pharmacological activity of the parent compound. These salts are derived from an inorganic or organic acid or base.
Such salts include:
(1) acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, benzenesulfonic acid, benzoic, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glutamic acid, glycolic acid, hydroxynaphthoic acid, 2-hydroxyethanesulfonic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, muconic acid, 2-naphthalenesulfonic acid, propionic acid, salicylic acid, succinic acid, dibenzoyl-L-tartaric acid, tartaric acid, p-toluene-sulfonic acid, trimethylacetic acid, 2,2,2-trifluoroacetic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic or inorganic base. Acceptable organic bases include diethanolamine, ethanolamine, N-methylglucamine, triethanolamine, tromethamine, and the like. Acceptable inorganic bases include aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide.
It should be understood that all references to pharmaceutically acceptable salts include solvent addition forms (solvates) or crystal forms (polymorphs) of the same acid addition salt.
Similarly, a “pharmaceutically acceptable carrier” or “excipient” means a pharmacologically acceptable and substantially non-toxic, inert, carrier or excipient. Such carriers and excipients are further discussed infra.
Preferred Embodiments
In one embodiment, this invention relates to pyridine amido derivatives of the formula
wherein
one of X or Y is —N═ and the other one is —CR
7
═;
R
1
is hydrogen or C
1
-C
6
-alkyl;
R
2
is hydrogen or C
1
-C
6
-alkyl;
R
3
is hydrogen or C
1
-C
6
-alkyl;
R
4
is selected from the group halogen-(C
1
-C
6
)-alkyl, unsubstituted aryl, and aryl substituted by one or more substituents selected from the group C
1
-C
6
-alkyl, halogen, halogen-(C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy and cyano;
R
5
is hydrogen or C
1
-C
6
-alkyl;
R
6
is hydrogen or C
1
-C
6
-alkyl; and
R
7
is hydrogen or C
1
-C
6
-alkyl;
or the pharmaceutically acceptable salts of said compounds.
The compounds of formula I of the present invention and their pharmaceutically acceptable salts are highly selective MAO-B inhibitors.
The present invention also relates to pharmaceutical compositions comprising a pharmaceutically effective amount of any one or more compound of formula I

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