Phthalimido derivatives and a process for their preparation

Details Phthalimido derivatives and a process for their preparation Phthalimido derivatives and a process for their preparation

2003-03-13

2003-12-09

Rotman, Alan L. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S378000, C514S320000, C514S417000, C548S240000, C548S247000, C548S465000, C548S476000, C548S477000, C548S478000, C546S201000, C544S144000

Reexamination Certificate

active

06660736

ABSTRACT:

FIELD OF THE INVENTION
This invention relates to phthalimido derivatives and a process for preparing these compounds.
BACKGROUND OF THE INVENTION
This invention relates to phthalimido derivatives of the formula
wherein
X is —N═ or —CH═;
R
1
is —CO—NR
5
R
6
;
—CHR
7
—(CH
2
)
n
—CO—NR
5
R
6
;
—(CH
2
)
n
—NR
5
R
6
;
—(CH
2
)
n
—COOR
8
;
—(CH
2
)
n
—CN;
—CHR
7
—(CH
2
)
n
—CF
3
;
—(CH
2
)
n
—NH—COR
9
;
—(CH
2
)
n
—NH—COOR
8
;
—(CH
2
)
n
-piperidinyl, —(CH
2
)
n
-morpholinyl, —(CH
2
)
n
-tetrahydrofuranyl; —(CH
2
)
n
-thiophenyl or —(CH
2
)
n
-isoxazolyl, wherein the heterocyclic ring may be substituted by C
1
-C
6
-alkyl;
—(CH
2
)
n
-phenyl, wherein the phenyl ring may be substituted by halogen or halogen-(C
1
-C
6
)-alkyl;
—(CH
2
)
p
—OR
8
;
—(CH
2
)
p
—SR
8
;
—(CH
2
)
p
—SO—R
9
; or
—(CH
2
)
n
—CS—NR
5
R
6
;
R
2
is hydrogen;
C
1
-C
6
-alkyl;
—(CH
2
)
p
—OR
10
;
—(CH
2
)
p
—SR
10
; or benzyl;
R
3
is hydrogen or C
1
-C
6
-alkyl;
R
4
is halogen, halogen-(C
1
-C
6
)-alkyl, cyano, C
1
-C
6
-alkoxy or halogen-(C
1
-C
6
)-alkoxy;
R
5
and R
6
are independently from each other hydrogen or C
1
-C
6
-alkyl;
R
7
is hydrogen, hydroxy or C
1
-C
6
-alkoxy;
R
8
is hydrogen or C
1
-C
6
-alkyl;
R
9
is C
1
-C
6
-alkyl;
R
10
is hydrogen or C
1
-C
6
-alkyl;
m is 1, 2 or 3;
n is 0, 1 or 2; and
p is 1 or 2;
or a pharmaceutically acceptable salt thereof.
It has now been found that the compounds of formula I are selective monoamine oxidase B inhibitors.
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. phenylethylamine, 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
This invention is directed to phthalimido derivatives of the formula
wherein
X is —N═ or —CH═;
R
1
is —CO—NR
5
R
6
;
—CHR
7
—(CH
2
)
n
—CO—NR
5
R
6
;
—(CH
2
)
n
—NR
5
R
6
;
—(CH
2
)
n
—COOR
8
;
—(CH
2
)
n
—CN;
—CHR
7
—(CH
2
)
n
—CF
3
;
—(CH
2
)
n
—NH—COR
9
;
—(CH
2
)
n
—NH—COOR
8
;
—(CH
2
)
n
—piperidinyl, —(CH
2
)
n
-morpholinyl, —(CH
2
)
n
-tetrahydrofuranyl; —(CH
2
)
n
-thiophenyl or —(CH
2
)
n
-isoxazolyl, wherein the heterocyclic ring may be substituted by C
1
-C
6
-alkyl;
—(CH
2
)
n
-phenyl, wherein the phenyl ring may be substituted by halogen or halogen-(C
1
-C
6
)-alkyl;
—(CH
2
)
p
—OR
8
;
—(CH
2
)
p
—SR
8
;
—(CH
2
)
p
—SO—R
9
; or
—(CH
2
)
n
—CS—NR
5
R
6
;
R
2
is hydrogen;
C
1
-C
6
-alkyl;
—(CH
2
)
p
—OR
10
;
—(CH
2
)
p
—SR
10
; or benzyl;
R
3
is hydrogen or C
1
-C
6
-alkyl;
R
4
is halogen, halogen-(C
1
-C
6
)-alkyl, cyano, C
1
-C
6
-alkoxy or halogen-(C
1
-C
6
)-alkoxy;
R
5
and R
6
are independently from each other hydrogen or C
1
-C
6
-alkyl;
R
7
is hydrogen, hydroxy or C
1
-C
6
-alkoxy;
R
8
is hydrogen or C
1
-C
6
-alkyl;
R
9
is C
1
-C
6
-alkyl;
R
10
is hydrogen or C
1
-C
6
-alkyl;
m is 1, 2 or 3;
n is 0, 1 or 2; and
p is 1 or 2;
or a pharmaceutically acceptable salt thereof.
The compounds of this invention have the advantageous properties mentioned above. It has been found that the compounds of formula I of the present invention and their pharmaceutically acceptable salts show the potential to be highly selective MAO-B inhibitors. Subjects of the present invention are further pharmaceutical compositions based on a compound of formula I in accordance with the invention, a method of treating a disease mediated by monoamine oxidase B inhibitors by administering a therapeutically effective amount of at least one of these compounds, and a process for preparing these compounds.
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 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.
“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.
“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 de

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