Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Patent
1998-10-14
2000-05-02
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
514274, 544297, 544316, A01N 4354, A61K 31505, C07D23902
Patent
active
060573325
DESCRIPTION:
BRIEF SUMMARY
FIELD OF INVENTION
This invention relates to novel 2-alkylheterodihydropyrimidine derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy. A further objective is to provide compounds which are potent ligands for N-type neuronal calcium channels.
BACKGROUND OF THE INVENTION
It is well known that there are several different types of voltage-gated calcium channels which can be distinguished on the basis of biophysical and pharmacological properties. These calcium channels are defined by differences in the amino acid sequence of the .alpha..sub.1 subunits ("Molecular Determinants of Ca.sup.2+ Channel Function and Drug Action" TiPS 1995, 16, 43-49), and by different sensitivities to various ligands ("Synthetic Organic Ligands Active at Voltage-Gated Calcium Channels", Ann. N.Y. Acad. Sci., 1991, 635, 123-138). These publications teach that the L-type calcium channel differs from the N-type calcium channel in regard to the amino acid sequence of the .alpha..sub.1 subunits and the sensitivity to dihydropyridines (L-channels are sensitive, N-channels are not) and the sensitivity to .omega.-Conotoxins GVIA and MVIIA (N-channels are sensitive, L-channels are not).
L-Type calcium channel antagonists are clinically proven compounds for the treatment of cardiovascular disease, particularly hypertension.
The use of compounds which bind to N-type neuronal calcium channels has been discussed with respect to the treatment of a range of disorders involving abnormal calcium flux in cells, including ischaemia, Alzheimer's disease, neuroprotection and analgesia ("Neuronal Voltage-Sensitive Calcium Channels" Drug News & Perspectives, 1994, 7, 261-268). N-Type neuronal calcium channels have also been found to be involved in the release of various neurotransmitters and therefore, compounds that bind to N-type calcium channels may also be useful in various disease states characterized by abnormal neurotransmitter release, for example, anxiety, schizophrenia, Parkinson's disease and migraine.
Patent application EP 0 202 654 discloses 5-carboxy-1,4-dihydropyrimidine derivatives of general structure: ##STR2## as cardiovascular agents, particularly, by virtue of their vasodilator activity, as antihypertensive agents. These compounds are distinguished from the scope of the present application by virtue of the definition of the group R.sup.2 and by their different pharmacological activity.
Patent application JP 62-267272 discloses dihydropyrimidines of general structure: ##STR3## as agents for the treatment of circulation disorders. These compounds are distinguished from the scope of the present application by virtue of the definitions of groups R.sup.3 and R.sup.4, and by their different pharmacological activity.
DISCLOSURE OF THE INVENTION
According to the invention we provide a compound of formula (I) ##STR4## wherein: R.sup.1 represents SR.sup.6, NR.sup.6 R.sup.7 or OR.sup.6 ; optionally including O or S, and which is substituted by a phenyl or a monocyclic heteroaryl ring, which aromatic ring is optionally substituted by one or more substituents independently selected from halogen, alkyl C 1 to 6 or alkoxy C 1 to 6; incorporating one heteroatom selected from N, O or S, optionally substituted by one or more substituents independently selected from halogen, alkyl C 1 to 6, alkoxy C 1 to 6, cyano, trifluoromethyl, amino, hydroxy, nitro or carbomethoxy; orbenzyl; or the group NR.sup.4 R.sup.5 together represents piperidinyl, morpholinyl, 3,4-dehydropiperidinyl, thiomorpholinyl, pyrrolidinyl, N-methylpiperidinium, piperazinyl or piperazinyl further substituted at N-4 by alkyl C 1 to 6; 3 to 6, or benzyl, optionally substituted on the phenyl ring by alkyl C 1 to 6, alkoxy C 1 to 6 or halogen; salts thereof.
Examples of said "monocyclic or bicyclic aromatic ring optionally incorporating one heteroatom selected from N, O or S" include, but are not limited to, phenyl; 1- and 2-naphthyl; 2-, 3- and 4-pyridyl; 2- and 3-thienyl; 2- and 3-furyl;quinolyl; isoquinolyl; indolyl; ben
REFERENCES:
Varadi et al, "Molecular determinants of Ca.sup.2+ channel . . . ," TiPS, vol. 16, pp. 43-49 (1995).
Triggle et al, "Synthetic Organic Ligands Active at . . . ," Ann. New York Acad. Sci., vol. 635, pp. 123-138 (1991).
Bowersox et al, "Neuronal Voltage-Sensitive Calcium Channels," DN&P, vol. 7, No. 5, pp. 261-268 (1994).
Pat. Abs. of Japan, vol. 12, No. 155 (C-494) 3002) (1988).
Cho et al, "Dihydropyrimidines: Novel Calcium . . . ," J. Med. Chem., vol. 32, pp. 2399-2406 (1989).
Michne William F.
Pierson, Jr. M. Edward
Astra Aktiebolag
Shah Mukund J.
Truong Tamthon N.
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