Triazole derivatives

Details Triazole derivatives Triazole derivatives

2000-07-19

2001-07-24

McKane, Joseph K. (Department: 1626)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C548S266200, C548S267200

Reexamination Certificate

active

06265426

ABSTRACT:

This application claims priority to European Patent Office (EPO) 99114313.2 Jul. 21, 1999.
BACKGROUND OF THE INVENTION
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 pharmacological properties. Therapeutic indications for NMDA receptor subtype specific blockers include acute forms of neurodegeneration caused, e.g., by stroke or brain trauma; chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease or ALS (amyotrophic lateral sclerosis); neurodegeneration associated with bacterial or viral infections and associated with diseases such as schizophrenia, anxiety and depression and acute/chronic pain.
SUMMARY OF THE INVENTION
The compounds of the present invention are NMDA (N-methyl-D-aspartate)-receptor-subtype selective blockers. NMDA receptors have a key function in modulating neuronal activity and plasticity which makes them key players in mediating processes underlying development of CNS including learning and memory formation and function. However when overactive, NMDA receptors contribute to neurodegeneration. Therefore compounds which block NMDA receptor activation are therapeutically important. The compounds of this invention are NMDA receptor blockers, thus have activity in reducing neurodegeneration related to NMDA activity. Conditions such as stroke or brain trauma, Alzheimer's disease, Parkinson's disease, Huntington's disease or ALS (amyotrophic lateral sclerosis), bacterial or viral infections, and schizophrenia, anxiety, depression and acute/chronic pain can all result in NMDA mediated neurodegeneration which neurodegeration can be prevented or treated by compounds of this invention.
The present invention relates to compounds of the formula
wherein
R
1
R
4
signify independently hydrogen, —CF
3
, —OCF
3
, OCHF
2
, —OCH
2
F, lower alkyl, lower alkoxy, halogen, hydroxy, phenyl, benzyl, amino, nitro, pyrrol-1-yl, lower alkyl-sulfonyl, lower alkyl-sulfanyl, cyano or benzyloxy; or
R
2
and R
3
may be taken together to form —O—(CH
2
)
2
—O—, —O—CH
2
—O—, —O—(CH
2
)
2
—, —(CH
2
)
3
— or —CH═CH—CH═CH—;
X signifies —N═, —N(R
7
)— or —CH═;
Y signifies —N═, ═N—, —N(R
7
)— or —CH═; wherein at least one of X or Y has to be nitrogen;
R
5
and R
6
signify independently from each other hydrogen, lower alkyl, —C(O)-lower alkyl, hydroxy-lower alkyl, lower alkenyl, —C(O)CH
2
OH or
R
5
and R
6
may be taken together with the N-atom to form a substituted or unsubstituted ring structure —(CH
2
)
n
—, —(CH
2
)
2
—O—(CH
2
)
2
—, —CH
2
—CH[OC(O)CH
3
]—(CH
2
)
2
, —CH
2
—CH[NHC(O)CH
3
]—(CH
2
)
2
, —O—(CH
2
)
3
—, —CH
2
—CH(OCH
3
)—(CH
2
)
2
—, —CH
2
—CH(halogen)—(CH
2
)
2
—, —(CH
2
)
2
—CH(O-phenyl)—(CH
2
)
2
—, —(CH
2
—N(CHO)—(CH
2
)
2
—, —CH
2
—N(COCH
3
)—(CH
2
)
2
—, —CH
2
—CH(OH)—(CH
2
)
3
—, —(CH
2
)
2
—CH(OH)—(CH
2
)
2
—, —(CH
2
)
2
—N(benzyl)—CH
2
)
2
— or —CH
2
—CH═CH—CH
2
—;
n signifies 3 to 5; and
R
7
signifies hydrogen, lower alkyl, lower alkenyl, lower alkinyl, —(CH
2
)
m
—O-lower alkyl, —(CH
2
)
m
OH, —(CH
2
)
m
—CHF
2
, —(CH
2
)
m
—CH
2
F, —(CH
2
)
m
—C(O)-lower alkyl, —(CH
2
)
m
—C(O)O-lower alkyl, —(CH
2
)
m
—CH(OH)-lower alkyl, —(CH
2
)
m
—CH(OH)—(CH
2
)
m
OH, —(CH
2
)
m
—C
6
H
5
, which phenyl ring is optionally substituted by lower alkyl, lower alkoxy or hydroxy, —(CH
2
)
m
—C(═CH
2
)-lower alkyl, —(CH
2
)
m
-cycloalkyl, —(CH
2
)
m
—CN, —(CH
2
)
m
-pyridin-4-yl, —CH
2
)
m
-pyridin-3-yl or —(CH
2
)
m
-pyridin-2-yl;
m signifies 0 to 4;
and to the pharmaceutically acceptable acid addition salts and tautomers.
Object of the present invention are novel compounds of formular I and their tautomers and pharmaceutically acceptable acid addition salts thereof, the use of the compounds in the treatment or prophylaxis of diseases caused by overaction of respective NMDA receptor subtypes, which include acute forms of neurodegeneration caused, e.g., by stroke or brain trauma; chronic forms of neurodegeneration such as Alzheimer's disease, Parkinson's disease, Huntington's disease or ALS (amyotrophic lateral sclerosis); neurodegeneration associated with bacterial or viral infections, and associated with conditions such as schizophrenia, anxiety, depression and acute/chronic pain, the use of these compounds for manufacture of corresponding medicaments, processes for the manufacture of these novel compounds and medicaments, containing them.
DETAILED DESCRIPTION OF THE INVENTION
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 1-4 carbon atoms, for example, methyl, ethyl, propyl, isopropyl, butyl and the like. The term “cycloalkyl” means a saturated hydrocarbon ring having from 3 to 10 carbon atoms, preferable from 5 to 7 carbon atoms.
The term “lower alkyl sulfonyl” means a lower alkyl group as defined above bound to the rest of the molecule through the sulfur atom in the sulfonyl group. The term “lower alkyl sulfanyl” means a lower alkyl group as defined above bound to the rest of the molecule through the sulfer atom in the sulfanyl group.
The term “hydroxy lower alkyl” means a lower alkyl group as defined above where one of the hydrogens is replaced by a hydroxyl group.
The term “lower alkoxy” denotes an ether group wherein the alkyl residue is as defined above.
The term “lower alkenyl” means an alkylene group having from 2 to 10 carbon atoms with a double bond located between any two adjacent carbon atoms. The term “lower alkinyl” means an alkylene group having from 2 to 10 carbon atoms with a triple bond located between any two adjacent carbon atoms.
The term “halogen” denotes chlorine, bromine, fluorine or iodine.
The term “pharmaceutically acceptable acid addition salts” embraces salts with inorganic and organic acids, such as hydrochloric acid, nitric acid, sulfuric acid, lactic acid, phosphoric acid, citric acid, formic acid, fumaric acid, maleic acid, acetic acid, succinic acid, trataric acid, methane-sulfonic acid, p-toluenesulfonic acid and the like.
The term “tautomers” embraces the standard meaning of the term, e.g. a type of isomerism in which migration of a hydrogen atom results in two or more structures called tautomers. For example any compound of this invention where X is —N═ or —CH═ and Y is —N(R
7
)— includes the tautomer where Y is —N═ or —CH═ and X is —N(R
7
)—, where R
7
is a suitable group.
Thus the triazole or imidazole group of compounds of formula I represented by
may have the following structure:
In preferred compounds of formula I, R
1
is hydrogen, lower alkoxy, halogen, or hydroxy; R
2
is hydrogen, lower alkoxy, halogen, CF
3
, —OCF
3
, OCHF
2
, or may be taken together with R
3
to form —O—(CH
2
)
2
—O—, —O—CH
2
—O—, —O—(CH
2
)
2
—, —(CH
2
)
3
— or —CH═CH—CH═CH—; —OCH
3
, R
4
is hydrogen, halogen, lower alkoxy, or CF
3
, and R
3
, R
5
, R
6
and R
7
are all as in formula I. In especially preferred such compounds, R
1
is hydrogen, methoxy, ethoxy, chloro, or fluoro; R
2
is hydrogen, chioro, or fluoro, R
3
is —OCHF
2
, —OCH
2
F, —OCH
3
, —OCH
2
CH
3
, chloro, methyl or methyloxy; R
4
is hydrogen or fluoro, and R
5
and R
6
are hydrogen or lower alkyl or are together —(CH
2
)
4
—, —CH
2
CH(OH)(CH
2
)
2
— or —CH
2
CH[NHC(O)CH
3
](CH
2
)
2
—. Relevant tautoers, are included.
Exemplary especially preferred compounds of formula I, in which X is —N═, Y is —NH

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