Heterocyclic amines

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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514315, 514317, 514320, 514324, 5142388, 514422, 514428, 514468, 514443, 544173, 546248, 546202, 548525, 548574, 549 51, 549460, A61K 31435, A61K 31395

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055434223

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BRIEF SUMMARY
This application is a 371 of PCT/GB93/02048 filed Oct. 1, 1993.
This invention is in the field of heterocyclic amines and in particular it relates to N-(substituted-alkyl)-cyclic amines which possess calmodulin antagonist properties. Such a compound has a cardioprotective action and finds particular use in the treatment of myocardial ischaemia and hypertension.
Calmodulin is a protein containing 148 amino acids which is found in a wide variety of tissues, including the heart. It is a receptor for calcium ions and, when bound to calcium, regulates the activity of amongst others, the enzymes phosphodiesterase, adenylate cyclase and myosin light-chain kinase and thereby influences the contraction of smooth muscle. Calmodulin also modulates the intracellular concentration of calcium ions. It is believed that in many cell systems calcium can only play its role in the presence of calmodulin, and therefore an antagonist of calmodulin acts as a calcium antagonist. The role of calmodulin is fully discussed in reviews by Means and Dedman, Nature, 1980, 285, pages 73-77; Klee et al., Annual Reviews of Biochemistry, 1980, 49, pages 489-515; and Veigl et al., Pharmacology & Therapeutics, 1989, 44, pages 181-239.
Accordingly the invention provides the use of a heterocyclic amine of the formula: or which bears one or more substituents selected from halo, nitro and cyano groups and alkyl and alkoxy groups each of up to 4 carbon atoms; has the formula --C(R.sup.3).dbd.CH-- herein R.sup.3 is hydrogen or alkyl of up to 4 carbon atoms; atoms which may be interrupted by --O--, --S-- or --NH--; manufacture of a medicament for use in the treatment of a calmodulin-mediated disease or medical condition.
Numerous compounds have been described which incorporate a group of the formula --O--(CH.sub.2).sub.n -- linking an aromatic group to an amine group. In most of these compounds the linking group is only a minor part of the molecule and either the aromatic group, or the amino group, or both, are complex in nature. Furthermore, in most such compounds the linking group is --O--(CH.sub.2).sub.3 -- and there are relatively few examples of known compounds wherein n is greater than 3. Examples of known compounds wherein there is a suggestion of activity on the cardiovascular system are:--J. Medicinal Chem., 1981, 24, 159-167 and related patent specifications DE 2730593 and FR 2431491 (complex benzofuran derivatives); EP 303920 (complex benzofuran derivatives); and WO 8905289 (4-benzylpiperidine derivatives). There is no suggestion that any of these compounds are calmodulin antagonists.
A group of Czechoslovakian patents (the contents of which are described in abstract form in Chemical Abstracts, 1983, 100, 209437; 1983, 190, 22591 and 1983, 101, 23366) describe various N-(4-naphthyloxybutyl)-cyclic amines; the only indication of utility is that their N-oxides have potential use as antimicrobials. Naphthoxyalkylamines having anti-inflammatory activity and in particular N-8-(naphth-1-yloxy)octylpyrrolidine are described in EP 82005. Thimmaiah et al., 3. Medicinal Chem., 1992, 35, 3358-3364, describe N-substituted phenoxazines and in particular various N-[4-(phenoxazin-10-yl)propyl and butyl]-cyclic amines which were studied for their ability to reverse Vinca alkaloid resistance in multidrug-resistant cancer cells. There is no suggestion that any of these compounds are calmodulin antagonists.
The compounds of the formula Ar-X-A-NR.sup.1 R.sup.2 are heterocyclic amines, i.e. they incorporate a saturated nitrogen-containing heterocyclic ring system NR.sup.1 R.sup.2.
The group Ar is, for example, a carbocyclic aromatic group, preferably naphthyl, anthryl, phenanthryl or fluorenyl, or a benz-heterocyclic group wherein the heterocyclic group is a 5- or 6-membered group which contains 1 or 2 heteroatoms selected from nitrogen, oxygen or sulphur atoms, for example benzo[b]thienyl, benzo[b]furyl, indolyl, quinolyl, isoquinolyl, quinazolinyl, carbazolyl or dibenzofuryl. Ar is more preferably 1- or 2-naphthyl or especially benzo[b]thienyl, for example

REFERENCES:
CA 106: 169032e Derivatives . . . Properties, Val'dman et al., p. 70, 1987.
CA 110: 165948t Synthesis . . . Propanols. Borisova et al., p. 61, 1989.
CA 120: 244684p N-Aryloxy(thio)alkyl-. . . Compositions, and Intermediates, Brown et al., p. 1004, 1994.
Chemical Abstracts #6017k, vol. 97 No. 1, 5 Jul. 1982, Columbus, Ohio, USA, p. 580.
Chemical Abstracts #22591d, vol. 100 No. 3, 16 Jan. 1984, Columbus, Ohio USA, p. 488.
Chemical Abstracts #209437a, vol. 100 No. 25, 18 Jun. 1984, Columbus, Ohio, USA, p. 560.
Chemical Abstracts #23366s, vol. 101 No. 3, 16 Jul. 1984, Columbus, Ohio, USA, p. 591.

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