N-acylamino benzyl ether derivatives

Details N-acylamino benzyl ether derivatives N-acylamino benzyl ether derivatives

2003-05-27

2004-07-13

Kumar, Shailendra (Department: 1621)

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

Organic compounds

Amino nitrogen containing

C564S158000, C562S455000, C558S392000, C514S520000, C514S521000, C514S535000, C514S616000

Reexamination Certificate

active

06762320

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new N-acylamino aryl derivatives, to processes and intermediates for their preparation, and to pharmaceutical compositions containing them. These compounds are selective monoamine oxidase inhibitors and, therefore, are useful for treating or preventing diseases mediated by monoamine oxidase B.
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.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide compounds having the following formula
in which X is —CHRO, —OCHR—, —CH
2
S—, —SCH
2
—, —CH
2
CH
2
—, —CH═CH— or —C≡C—, and the other variables are defined herein. The invention also provides for pharmaceutically acceptable salts of these compounds.
It has been found that the compounds of the invention are highly selective MAO-B inhibitors. Therefore, it is another object of the invention to provide compositions containing one or more compounds of formula I and a pharmaceutically acceptable carrier. It a further object of the invention to provide methods for the treatment or prevention of diseases mediated by monoamine oxidase B inhibitors. It is also an object of the present invention to provide a process for the manufacture of compounds of the invention, for example, compounds of formula I.
DETAILED DESCRIPTION OF THE INVENTION
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 3 carbon atoms, such as methyl, ethyl, n-propyl, i-propyl, n-butyl, sec-butyl, t-butyl, and the like. Accordingly, the term “(C
1
-C
3
)-alkyl” means a straight-chain or branched saturated hydrocarbon residue with 1 to 3 carbon atoms.
The term “halogen” denotes fluorine, chlorine, bromine and iodine.
“Halogen-(C
1
-C
6
)-alkyl” or “halogen-(C
1
-C
6
)-alkoxy” means the lower alkyl residue or lower alkoxy residue, respectively, 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. “
Halogenalkoxy” includes trifluoromethyloxy.
“(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.
The term “(C
3
-C
7
)-cycloalkyl” denotes a saturated carbocyclic group, containing 3 to 7 carbon atoms. For example, a cycloalkyl group is cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl, and these groups may optionally be substituted by one or two (C
1
-C
4
)-alkyl substituents, for example methyl or ethyl.
“Pharmaceutically acceptable,” such as pharmaceutically acceptable carrier, excipient, etc., means pharmacologically acceptable and substantially non-toxic to the subject to which the particular compound is administered.
“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. If possible, compounds of formula I may be converted into pharmaceutically salts. It should be understood that pharmaceutically acceptable salts are included in the present invention.
“Therapeutically effective amount” means an amount that is effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated.
It is an object of the present invention to provide compounds having the following formula
wherein
R
1
is halogen, halogen-(C
1
-C
6
)-alkyl, cyano, (C
1
-C
6
)-alkoxy or halogen-(C
1
-C
6
)-alkoxy;
R
21
, R
22
, R
23
and R
24
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)-alkyl, halogen, halogen-(C
1
-C
6
)-alkyl, hydroxy, (C
1
-C
6
)-alkoxy and —CHO;
R
3
is hydrogen or (C
1
-C
3
)-alkyl;
R
4
, R
5
are each independently selected from the group consisting of hydrogen, (C
1
-C
6
)-alkyl, (C
1
-C
6
)-alkoxy or —COO(C
1
-C
6
)alkyl;
or, alternatively, R
4
and R
5
, together with the C-atom to which they are attached, form a (C
3
-C
7
)-cycloalkyl ring;
R
6
is —CO—NR
7
R
8
; —COO(C
1
-C
6
)-alkyl, —CN, —N(R)
2
or —NHC(O)R;
R
7
and R
8
are each independently selected from the group consisting of hydrogen,
(C
1
-C
6
)-alkyl, NH
2
or

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