Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-02-26
2001-05-15
Fan, Jane (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S340000, C514S343000, C546S272400, C546S273400, C546S272700, C546S275400, C546S276400
Reexamination Certificate
active
06232329
ABSTRACT:
The present invention relates to new 4-aryltetra-hydropyridines and 4-arylpiperidinols linked to alkyl-azoles of general formula (I)
and to their physiologically acceptable salts, to the processes for their preparation, to their application as medicaments and to the pharmaceutical compositions which contain them.
The compounds which are the subjects of the invention can also be used in the pharmaceutical industry as intermediates and for the preparation of medicaments.
These compounds possess a powerful affinity for sigma and/or 5-HT
1A
receptors and are therefore potentially useful in the treatment of certain psychic and neurological disorders of human beings and other mammals.
Phenomena exist which involve sigma receptors in the treatment of psychosis. Many atypical antipsychotics, such as rimcazole (Schwarcz, G. et al., Drug Dev. Res., 1985, 5, 387), remoxipride (Wadworth, A. B. et al., Drugs 1990, 40, 863) or thiospirone (Jain, A. K. et al., Int. Clin. Psychopharmacol. 1987, 2, 129), show a significant affinity for sigma receptors.
Moreover, studies of the biology and function of sigma receptors indicate that ligands for the sigma receptor can be effective in the treatment of certain motor disorders, in particular Huntington's chorea, dystonia and Tourette's syndrome. The presence of sigma receptors in the substantia nigra makes it possible to use them in the treatment of Parkinson's disease (Walker, J. M. et al., Pharmacological Reviews, 1990, 42, 355).
Certain ligands for sigma receptors are involved in the modulation of the effects produced by the intervention of the NMDA receptor and act as antiischemic agents in in vivo tests (Rao, T. S. et al., Molecular Pharmacology, 1990, 37, 978), with the possibility of use as neuroprotectors and in the treatment of epilepsy and of convulsion (Kaiser C., Neurotransmissions VII, 1991).
It has been said that ligands for sigma receptors exhibit antiamnesic effects in animal models (Early et al., Brain Research, 1991, 546, 281).
Sigma ligands influence the levels of acetylcholine in animal models (Matsuno et al., Brain Research 1992, 575, 315) and can consequently be used in the treatment of senile dementia, for example of Alzheimer type.
Ligands for 5-HT
1A
receptors, in particular agonists or partial agonists for 5-HT
1A
, show a proven anxiolytic and antidepressant activity (Glitz, D. A., Drugs, 1991, 41, 11).
Consequently, agents having a powerful affinity for sigma and/or 5-HT
1A
receptors can be used in one or a number of the treatments indicated.
Examples of 4-aryl-1,2,3,6-tetrahydropyridines and of 4-aryl-4-hydroxypiperidines are found in the bibliography; however, compounds in which these sub-structures are joined to the nitrogen of an azole ring by means of an unsubstituted alkyl chain are not found to be described:
Davis L. Temple et al., U.S. Pat. No. 4,320,131; 16 March 1982.
Richard A. Glennon et al., J. Med. Chem., 1991, 34, 3360-65.
Jean-Luc Malleron et al., J. Med. Chem., 1991, 34; 8, 2477-83.
Henning Böttcher et al., J. Med. Chem., 1992, 35, 4020-26.
Zhuihua Sui et al., Synthesis, 1993, 803-8.
David I. Schuster et al., J. Med. Chem., 1993, 36, 3923-28.
David J. Wustrow et al., BioMed. Chem. Lett., 1993, 3, 277-80.
Shimazaki Norihiko et al., Can. Pat. App., CA 2053475 AA.
The Inventors have previously described a series of N-alkylazoles joined to the nitrogen of various heterocycles which are useful as non-benzodiazepine agents in the treatment of anxiety (European Patents No. EP 382637, EP 497659 and EP 502786) and in the treatment of other behavioral disorders (European Patents EP 429360 and EP 497658). Descriptions are given in the cited patents of the compounds of general formula (I) in which A represents, in all cases, a nitrogen atom and it consequently concerns a piperazine ring. In the present invention, the piperazine ring is replaced by a piperidine or a tetrahydropyridine.
The compounds which are the subjects of the invention correspond to the general formula (I)
in which
R
1
, R
2
and R
3
, which are identical or different, each represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, an aryl or substituted aryl radical or an alkoxyl radical. Moreover, two adjacent radicals can form a saturated or aromatic ring.
A represents a carbon atom and the dotted line represents an additional bond or else A represents a carbon atom bonded to a hydroxyl group (C—OH) and the dotted line represents the absence of an additional bond.
n can have values ranging from 2 to 6
Z
1
represents a nitrogen atom or a substituted carbon atom which can be represented by C—R
4
Z
2
represents a nitrogen atom or a substituted carbon atom which can be represented by C—R
5
Z
4
represents a nitrogen atom or a substituted carbon atom which can be represented by C—R
7
R
4
, R
5
, R
6
and R
7
, which are identical or different, represent a hydrogen atom, a halogen atom, a linear or branched alkyl radical, a hydroxyl radical, an alkoxyl radical, a carboxyl radical, a carboxamide radical, an alkyl carboxylate radical or an aryl or substituted aryl radical or else two adjacent radicals can form part of another ring, which may or may not be aromatic.
The invention also relates to the physiologically acceptable salts of the compounds of general formula (I), in particular the salts of hydrochloric, hydrobromic, sulfuric, phosphoric, acetic, lactic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, benzoic, phenylacetic, cinnamic and salicylic acids and of alkane-, cycloalkane- or arenesulfonic acids.
The new derivatives of general formula (I) can be prepared according to the following processes:
Process A:
By reaction of a spiran derivative of general formula (II)
in which
R
1
, R
2
, R
3
and A have the meaning indicated above, m can have values ranging from 0 to 4 and X represents a leaving group, such as chloro, bromo, mesyloxy or tosyloxy,
with a nitrogenous heterocycle of general formula (III)
in which
Z
1
, Z
2
, Z
4
and R
6
have the meaning indicated above.
The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene or an aliphatic hydrocarbon such as hexane or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.
The reaction temperature varies between room temperature and the reflux temperature of the solvent used.
The reaction times vary between 1 and 24 hours.
Process B:
By simultaneous “one pot” reaction between a derivative of general formula (IV), an alkylating agent of general formula (V) and a nitrogenous heterocycle of general formula (III).
where
R
1
, R
2
, R
3
, A, X, n, Z
1
, Z
2
, Z
4
and R
6
have the meaning given above.
The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene or an aliphatic hydrocarbon such as hexane or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.
The reaction temperature varies between room temperature and the ref lux temperature of the solvent used.
The reaction times vary between 1 and 24 hours.
Process C:
The preparation of the compounds of general formula (I) can be carried out by reaction, under alkylation conditions, of the amines of general formula (IV)
in which
R
1
, R
2
, R
3
and A have the meaning given above, with compounds of general formula (VI)
in which
X, n, Z
1
, Z
2
, Z
4
and R
6
have the meaning indicated above.
The reaction is carried out in a solution of dimethyl sulfoxide, dimethylformamide, an alcohol such as ethanol, an aromatic hydrocarbon such as toluene or an aliphatic hydrocarbon such as hexane or an ether such as dioxane. This reaction is preferably carried out in the presence of a base such as potassium carbonate or triethylamine.
The reaction temperature varies between room temperature and the ref lux temperature of the solve
Frigola-Constansa Jordi
Merce-Vidal Ramon
Fan Jane
Laboratorios Del Dr. Esteve, S.A.
Rockey Milnamow & Katz Ltd.
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