Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-02-12
2000-10-31
Rotman, Alan L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
546 17, C07D48710, A61K 3144
Patent
active
061403369
DESCRIPTION:
BRIEF SUMMARY
SPECIFICATION
The invention relates to novel spiro[2H-1-benzopyran-2,4'-piperidine]4(3H)-one derivatives of formula (I), ##STR3## wherein R stands for halogen, nitro group or a straight or branched chain C.sub.1-6 alkyl group, and their acid addition salts, ##STR4## wherein R and R' are the same or different and are identical to the meaning of said (above) R or can mean also hydrogen; and
The above compounds and salts exert a favorably influencing effect on dementias of various pathological origin or associated (accompanying) symptoms, respectively, thereof.
The invention also relates to pharmaceutical compositions containing and to methods of treatment employing as active ingredients novel or, wherein R means hydrogen, known spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one derivatives of formula (I) and/or pharmaceutically acceptable salts, and/or quaternary salts thereof of formula (Ia). These compositions favorably influence the dementias of various pathological origin or accompanying symptoms respectively, thereof.
Furthermore, the invention relates to the process of preparation of compounds of the formulas (I) and (Ia).
The invention relates also to a method of treatment, which comprises administering to a mammal, including man to be treated one or more effective dose(s) of a compound of formula (I) and/or pharmaceutically acceptable salts, and/or quaternary salts thereof of formula (Ia) for alleviating dementias of various pathological origin or the accompanying (associated) symptoms thereof.
Disturbances of various degree and progression of mental and cognitive functions (such as learning, memory, faculty of judgement and abstraction) are common characteristics of the dementias of various pathological origin, e.g.: Alzheimer's disease, multiinfarct dementias, states following stroke, dementias associated with Parkinson's disease or Huntington's chorea; or dementias occurring as sequels of hypoxia or poisonings. Since the life quality of both the patient and his surroundings are decisively determined by the integrity of psychic, mental and cognitive functions (learning, memory), one of the most important targets of the therapy of dementias of various aetiology is to prevent the impairment of the cognitive functions and to reverse the disturbances established and their sequels.
It has surprisingly been found that the spiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one derivatives of formulas (I) and (Ia) possess a significant antiamnesic effect.
1'-Benzylspiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one of formula (I) where R is hydrogen as well as some of its derivatives were described in Chem. Pharm. Bull. 29, 3494-3497 (1981). These compounds were investigated as inhibitors of the release of histamine from mast cells in comparison to disodium chromoglycate [chemically 1,3-bis(2-carboxy-4-oxochromen-5-yloxy)propan-2-ol disodium salt]. 1'-Benzylspiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one was prepared by boiling 1-benzyl-4-piperidone with 2-hydroxy-acetophenone under reflux in a methanolic medium in the presence of pyrrolidine. A reaction of similar type had previously been carried out between certain ketones and 2-hydroxyacetophenone in toluene by the addition of pyrrolidine [Synthesis 886 (1978)]. An advantageous feature of the method resides in that the water formed during the cyclocondensation may azeotropically be distilled off.
According to the Chem. Pharm. Bull. publication cited above, the melting point of 1'-benzylspiro[2H-1-benzopyran-2,4'-piperidine]-4(3H)-one of formula (I) where R is hydrogen is at 91-93.degree. C. However, it has been shown in our reproduced experiments directed to the preparation of this compound, that its melting point was about 10.degree. C. higher (103-104.degree. C.) in each case and independently thereof whether it was prepared by process a) or b). This observation may only be explained by either a high degree of contamination or by a chemical structure different from the published one of the compound described in the literature.
A much wide scope of sprio[2H-1-b
REFERENCES:
Chem. Pharm. Bull., 29(12), pp. 3494 to 3498 (1981).
J. Med. Chem., 1992, 35, pp. 3973 to 3976.
Chem. Abstracts, vol. 95, No. 9, Aug. 31, 1981, 95:80736u; XP002048516.
H. J. Kabbe, Synthesis, Dec. 1978, pp. 886-887.
J. Med. Exp., 10, 93 to 102 (1964); M. Fekete and J. Borsy.
Orvostudomany 33, 347 to 361 (1982).
Helv. Chim. Acta., 41, 1188 (1958).
J. Amer. Che. Soc., 68, 2108 (1946).
Synth. Comm. 20, 3537 (1990).
Borza Istvan
Csomor Katalin
Farkas Sandor
Gere Aniko
Harsanyi Kalman
Dubno Herbert
Myers Jonathan
Richter Gedeon Vegyeszeti Gyar Rt.
Rotman Alan L.
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