Use of 5-substituted pyridine and hexahydroquinoline-3...

Details Use of 5-substituted pyridine and hexahydroquinoline-3... Use of 5-substituted pyridine and hexahydroquinoline-3...

1999-01-28

2001-02-27

Huang, Evelyn Mei (Department: 1625)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

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

C514S302000, C514S311000, C514S314000, C546S113000, C546S116000, C546S122000, C546S167000, C546S168000

Reexamination Certificate

active

06194428

ABSTRACT:

The present invention relates to the use of 5-substituted pyridine- and hexahydroquinoline-3-carboxylic acid derivatives for the production of medicaments, novel active compounds, a process for their preparation and their use, in particular as cerebrally active agents.
4-(2,3-Dichlorophenyl)-5,7-dihydro-2-methyl-5-oxo-ethyl furo[3,4-b]pyridine-3-carboxylate is already known from the publications J. Chromatogr., 565 (1-2), 237-46, 1991; J. Pharmacol. Exp. Ther. 250 (2), 632-6, 1989; Drug Metab. Dispos. 14 (5), 613-18, 1986 and Acta Pharm. Suec., 21 (6), 331-44, 1984.
It has now been found that the 5-substituted pyridine- and hexahydroquinoline-3-carboxylic acid derivatives of the general formula (I)
in which
A represents aryl having 6 to 10 carbon atoms or pyridyl, each of which is optionally substituted up to 3 times by identical or different substituents from the group consisting of nitro, cyano, halogen and trifluoromethyl or straight-chain or branched alkyl, alkoxy or alkylthio having up to 6 carbon atoms,
R
1
represents hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms,
D and E together represent
—CO—O—CH
2
—[CR
2
R
3
]
a
—,
—CO—NR
4
—[CR
2
R
3
]
a
—CH
2
—,
—CO—CH
2
—[CR
2
R
3
]
a
—CH
2
—
or
—CH
2
—[CR
2
R
3
]
a
—O—CO—,
 wherein
R
2
, R
3
and R
4
are identical or different and denote hydrogen or methyl,
a denotes a number 0 or 1
and their salts,
surprisingly have a modulating action on potassium channels and are thus suitable for the control of cerebral disorders.
In the context of the invention, physiologically acceptable salts are preferred. Physiologically acceptable salts are in general salts of the compounds according to the invention with inorganic or organic acids. Preferred salts are those with inorganic acids such as, for example, hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid, or salts with organic carboxylic or sulphonic acids such as, for example, acetic acid, maleic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid or methanesulphonic acid, ethanesulphonic acid, phenylsulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid.
The compounds according to the invention can exist in stereoisomeric forms which either behave as image and mirror image (enantiomers), or which do not behave as image and mirror image (diastereomers). The invention relates both to the antipodes and to the racemic forms as well as the diastereomer mixtures.
Preferably used are those compounds of the general formula (I) in which
A represents phenyl, naphthyl or pyridyl, each of which is optionally substituted up to 3 times by identical or different substituents from the group consisting of nitro, cyano, fluorine, chlorine, bromine, iodine and trifluoromethyl or straight-chain or branched alkyl, alkoxy or alkylthio having up to 4 carbon atoms,
R
1
represents hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms,
D and E together represent
—CO—O—CH
2
—[CR
2
R
3
]
a
—,
—CO—NR
4
—[CR
2
R
3
]
a
—CH
2
—,
—CO—CH
2
—[CR
2
R
3
]
a
—CH
2
—
or
—CH
2
—[CR
2
R
3
]
a
—O—CO—,
 wherein
R
2
, R
3
and R
4
are identical or different and denote hydrogen or methyl,
a denotes a number 0 or 1,
and their salts,
in the control of cerebral disorders.
Particularly preferably used are those compounds of the general formula (I) in which
A represents phenyl or pyridyl, each of which is optionally substituted up to 2 times by identical or different substituents from the group consisting of nitro, cyano, fluorine, chlorine, bromine, iodine and trifluoromethyl or methyl, methoxy or methylthio,
R
1
represents hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms,
D and E together represent
—CO—O—CH
2
—[CR
2
R
3
]
a
—,
—CO—NR
4
—[CR
2
R
3
]
a
—CH
2
—,
—CO—CH
2
—[CR
2
R
3
]
a
—CH
2
—
or
—CH
2
—[CR
2
R
3
]
a
—O—CO—,
 wherein
R
2
, R
3
and R
4
are identical or different and denote hydrogen or methyl,
a denotes a number 0 or 1,
and their salts,
in the control of cerebral disorders.
The compounds of the general formula (I) according to the invention show an unforeseeable, useful spectrum of pharmacological action.
They are modulators of channels having selectivity for calcium-dependent potassium channels of high conductivity (BK(Ca) channels), in particular of the central nervous system.
On account of their pharmacological properties, they can be employed for the production of medicaments for the treatment of degenerative central nervous system disorders, such as e.g. on occurrence of dementias such as multiinfarct dementia (MID), primary degenerative dementia (PDD), presenile and senile dementia of the Alzheimer's disease type, HIV dementia and other forms of dementia, and also for the treatment of Parkinson's disease or amyotrophic lateral sclerosis and also multiple sclerosis.
The active compounds are furthermore suitable for the treatment of brain function disorders in old age, of organic brain syndrome (OBS) and of age-related memory disorders (age-associated memory impairment, AAMI).
They are suitable for the prophylaxis, for the treatment and for the control of the sequelae of cerebral circulatory disorders such as cerebral ischaemias, strokes, craniocerebral traumata and subarachnoid haemorrhages.
They are useful for the treatment of depressions and psychoses, e.g. schizophrenia. They are additionally suitable for the treatment of disorders of neuroendocrine secretion and of neurotransmitter secretion and health disorders connected therewith such as mania, alcoholism, drug abuse, dependence or abnormal eating behaviour. Other application areas are the treatment of migraine, sleep disorders and neuropathies. They are moreover suitable as analgaesics.
The active compounds are further suitable for the treatment of disorders of the immune system, in particular of T-lymphocyte proliferation and for affecting the smooth musculature, in particular of uterus, urinary bladder and bronchial tract and for the treatment of diseases connected therewith such as e.g. asthma and urinary incontinence and for the treatment of high blood pressure, arrhythmia, angina and diabetes.
The invention additionally relates to new compounds of the general formula (Ia)
and their salts, having the substituent meanings indicated in the following table:
R
1
L
T
D-E
—CH
3
4-Cl
H
—CO—O—CH
2
—
—CH(CH
3
)
2
4-Cl
H
—CO—O—CH
2
—
—CH(CH
3
)
2
2-Cl
3-Cl
—CO—O—CH
2
—
—CH
3
4-Cl
H
—CO—NH—CH
2
—
—CH(CH
3
)
2
4-Cl
H
—CO—NH—CH
2
—
—CH
3
2-Cl
3-Cl
—CO—NH—CH
2
—
—CH(CH
3
)
2
2-Cl
3-Cl
—CO—NH—CH
2
—
—CH
3
4-Cl
H
—CO—CH
2
—CH
2
—CH
2
—
—CH(CH
3
)
2
4-Cl
H
—CO—CH
2
—CH
2
—CH
2
—
—CH
3
2-Cl
3-Cl
—CO—CH
2
—CH
2
—CH
2
—
—CH(CH
3
)
2
2-Cl
3-Cl
—CO—CH
2
—CH
2
—CH
2
—
—CH(CH
3
)
2
2-Cl
3-Cl
—CO—CH
2
—C(CH
3
)
2
—CH
2
—
—CH
3
3-H
4-Cl
—CO—CH
2
—C(CH
3
)
2
—CH
2
—
—CH
3
2-Cl
3-Cl
—CO—CH
2
—C(CH
3
)
2
—CH
2
—
—CH(CH
3
)
2
3-Cl
4-Cl
—CO—O—CH
2
—
—CH
3
2-F
3-F
—CO—O—CH
2
—
—CH
3
4-F
3-H
—CO—O—CH
2
—
—CH
3
2-F
6-Cl
—CO—O—CH
2
—
—CH
3
3-H
4-Cl
—CH
2
—O—CO—
—CH(CH
3
)
2
2-Cl
3-Cl
—CH
2
—O—CO—
—CH(CH
3
)
2
3-H
4-Cl
—CH
2
—O—CO—
—CH
3
2-Cl
3-Cl
—CH
2
—O—CO—
The compounds of the general formulae (I) and (Ia) are prepared by
[A] in the case where D and E together represent —CO—NR
4
—[CR
2
R
3
]
a
—CH
2
—, oxidizing the dihydropyridines of the formula (II)
 wherein
R
1
and A have the meaning indicated and
R
5
represents C
1
-C
4
-alkyl,
in inert solvents to give the corresponding pyridine and then closing this with hydrazine hydrate to give the lactam and optionally alkylating the nitrogen, or
[B] in the case where D and E together represent —CO—O—CH
2
—[CR
2
R
3
]
a
—, —CO—CH
2
—[CR
2
R
3
]
a
—CH
2
— or —CH
2
—[CR
2
R
3
]
a
—O—CO,
oxidizing the corresponding dihydropyridines.
The processes according to the invention can be illustrated by way of example by the following equations:
Suitable solvents for the process here are all i

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