Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-08-09
2001-02-06
Jarvis, William R. A. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S452000, C514S603000, C514S605000, C514S647000
Reexamination Certificate
active
06184236
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the treatment of neurodegenerative diseases.
BACKGROUND OF THE INVENTION
The present invention involves treatment with a compound of the general formula
wherein
Ar
1
is phenyl, naphthyl or tetrahydronaphthyl, optionally substituted by hydroxy, lower alkoxy, nitro, amino or methanesulfonamide;
Ar
2
is phenyl, naphthyl or tetrahydronaphthyl, optionally substituted by lower alkyl or halogen;
X is C, CH, C(OH) or N;
Y is —CH
2
—, CH or O
Z —CH
2
—, —CH(CH
3
)— or —C(CH
3
)
2
—;
R
1
is hydrogen, lower alkyl or acetyl;
A is C═O or —(CHR
2
)
n
—, wherein R
2
is hydrogen, lower alkyl or hydroxy-lower alkyl;
B is —(CH
2
)
n
—, O, —CH(OH)(CH
2
)
n
—, —CH(CH
2
OH)(CH
2
)
n
—, —(CH
2
)
n
CH(OH)— or —CH(CH
2
OH)—;
- - - may be a bond and
n is 0-4
and to pharmaceutically acceptable acid addition salts thereof.
Most of the described aryl derivatives are known compounds. In EP 503 411 and EP 481 299 are described N-phenyl-4-amino-piperidines with antiarrythmic and psychotropic activities. In WO 9715549 are described compounds of the present of formula I, which have a potent effect of stimulating beta-3 adrenaline receptors. These compounds were known to be useful for the treatment of urinary disorders such as frequent urination and urinary incontinence, convulsion and exasperation of the function of digestive tract movement, obesity and diabetes.
SUMMARY OF THE INVENTION
The present invention is a method of treatment of a neurodegenerative disease comprising administering a therapeutically effective amount of a compound of the general formula
wherein
Ar
1
is phenyl, naphthyl or tetrahydronaphthyl, optionally substituted by hydroxy, lower alkoxy, nitro, amino or methanesulfonamide;
Ar
2
is phenyl, naphthyl or tetrahydronaphthyl, optionally substituted by lower alkyl or halogen;
X is C, CH, C(OH) or N;
Y is —CH
2
—, CH or O;
Z —CH
2
—, —CH(CH
3
)— or —C(CH
3
)
2
—;
R
1
is hydrogen, lower alkyl or acetyl;
A is C═O or —(CHR
2
)
n
—, wherein R
2
is hydrogen, lower alkyl or hydroxy-lower alkyl;
B is —(CH
2
)
n
—, O, —CH(OH)(CH
2
)
n
—, —CH(CH
2
OH)(CH
2
)
n
—, —(CH
2
)
n
CH(OH)— or —CH(CH
2
OH)—;
- - - may be a bond; and
n is 0-4,
or pharmaceutically acceptable acid addition salts thereof. The diseases that may be treated in accordance with the present invention include stroke, brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, neurodegeneration associated with bacterial sclerosis and neurodegeneration associated with bacterial or viral infection.
Moreover, the present invention relates to the method of treatment wherein the compound is administered in an amount from about 0.1 mg to about 1000 mg per day.
Detailed Description of the Invention It has now surprisingly been found that compounds of the present invention are NMDA(N-methyl-D-aspartate)-receptor subtype selective blockers, which have a key function in modulating neuronal activity and plasticity. These therepeutic properties make the compounds of formula I and their salts key players in mediating processes underlying development of CNS as well as learning and memory formation.
Under pathological conditions of acute and chronic forms of neurodegeneration, overactivation of NMDA receptors is a key event for triggering neuronal cell death. NMDA receptors are composed of members from two subunit families, namely NR-1 (8 different splice variants) and NR-2 (A to D) originating from different genes. Members from the two subunit families show a distinct distribution in different brain areas. Heteromeric combinations of NR-1 members with different NR-2 subunits result in NMDA receptors displaying different pharmaceutical properties. Possible therapeutic indications for NMDA receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke and brain trauma, and chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease, ALS (amyotrophic lateral sclerosis), neurodegeneration associated with bacterial sclerosis and neurodegeneration associated with bacterial or viral infections.
In accordance with the present invention, the use of compounds of formula I and pharmaceutically acceptable acid addition salts thereof are administered in the treatment or prophylaxis of diseases, caused by overactivation of respective NMDA receptor subtype. Also encompassed by the present invention are methods of treatment by administering a compound of formula I or a pharmaceutically acceptable acid addition salt thereof or a pharmaceutical composition containing such compound.
The present invention embraces treatment with racemic mixtures and all their corresponding enantiomers of the compounds of formula I.
Referring to X as position 1 of the ring, the —N(R
1
)—A—B—Ar
2
group can be a subsituent at ring position 2 (where 4 is not 0), 3 or 4.
The following definitions of the general terms used in the present description apply irrespective of whether the terms in question appear alone or in combination.
As used herein, the term “lower alkyl” denotes a straight- or branched-chain alkyl group containing from 1 to 4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like.
The term “halogen” denotes chlorine, iodine, fluorine and bromine.
The term “lower alkoxy” denotes a group wherein the alkyl residue is as defined above for “lower alkyl”.
The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
The term “leaving group” has the meaning conventionally used, and refers to, for example, halogen, alkylsulfonyloxy, arylsulfonyloxy and the like. The most preferred leaving group in the present case is a halogen.
The compounds of the present invention may be subdivided in the following subgroups:
wherein Z is —CH(CH
3
)— or C(CH
3
)
2
—, Ar
1
, Ar
2
, X, A, B, the dotted line and R
1
have the significances given above and X
1
is C(OH) or N.
Preferred compounds of formula Ia in the scope of the present invention are the following:
trans-4-[4-(3-phenyl-propylamino)-cyclohexyl]-phenol,
trans-4-[4-[methyl-(3-phenyl-propyl)-amino]-cyclohexyl]-phenol,
trans-4-[4-[ethyl-(3-phenyl-propyl)-amino]-cyclohexyl]-phenol,
trans-4-[4-(4-phenyl-butylamino)-cyclohexyl]-phenol,
trans-4-[4-[3-(4-fluoro-phenyl)-propylamino]-cyclohexyl]phenol,
trans-4-(4-[[3-(4-fluoro-phenyl)-propyl ]-methyl-amino]-cyclohexyl)-phenol,
trans-4-[4-[methyl-(2-p-tolyloxy-ethyl)-amino]-cyclohexyl]-phenol,
(RS)-4-[trans-4-(1-hydroxymethyl-3-phenyl-propylamino)-cyclohexyl]-phenol,
(RS)-4-[trans-4-(2-hydroxymethyl-3-phenyl-propylamino)-cyclohexyl]-phenol,
and
trans-N-(4-[4-[methyl-(3-phenyl-propyl)-amino]-cyclohexyl]-phenyl)-methanesulfonamide.
The following examples are preferred compounds of formula Ib:
cis-4-[1-hydroxy-4-(3-phenyl-propylamino)-cyclohexyl]-phenol,
4-[4-[methyl-(3-phenyl-propyl)-amino]-piperidin-1-yl]-phenol and
4-[4-(3-phenyl-propylamino)-piperidin-1-yl]-phenol.
A preferred compound of formula Ic is
(1RS, 3RS, 4RS)-4-[3-methyl-4-[methyl-(3-phenyl-propyl)-amino]-cyclohexyl]-phenol.
Further preferred is a compound of formula Id, which is
trans-4-[5-(3-phenyl-propylamino)-[1,3]dioxan-2-yl]-phenol.
The afore-mentioned compounds of formula I and their subgroups (Ia-Id) can be manufactured in accordance with known methods, for example by
a) reacting a compound of formula
with an amine of formula
wherein Ar
1
, Ar
2
, X, Y, Z, A, B and R
1
have the significances given above, or
b) reacting a compound of formula
with
Alanine Alexander
Buttelmann Bernd
Heitz Neidhart Marie-Paule
Pinard Emmanuel
Wyler Rene
Ebel Eileen M.
Hoffmann-La Roche Inc.
Jarvis William R. A.
Johnston George W.
Rocha-Tramaloni Patricia S.
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