Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1991-04-22
1994-05-10
Robinson, Douglas W.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514247, 514248, 435119, 435122, 4352545, 435933, 544230, 544231, A01N 4358, A61K 31495, C07D23700, C12P 1712
Patent
active
053107411
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to a novel compound TAN-1251 (hereinafter sometimes referred to briefly as TAN-1251 which, unless otherwise indicated, means a series of TAN-1251 compounds) which is a muscarinic receptor blocking compound of value as a mydriatic or as an antispasmodic/antiulcer agent.
BACKGROUND OF THE INVENTION
The parasympathetic nerve inervates a diversity of peripheral tissues to manifest multi-facted activity. The receptors of acetylcholine, which is its neurotransmitter, are roughly classified into muscarinic receptors sensitive to muscarine which is an alkaloid of Amanita muscaria and nicotinic receptors sensitive to nicotine which is an alkaloid occurring in Nicotiana tabacum. Atropine and scopolamine, which are the alkaloids of the belladonna plants, have been utilized for centuries as nonspecific antimuscarinic drugs and are in use even today as mydriatics or antispasmodics [Goodman and Gilman's the Pharmacological Basis of Therapeutics, 7th ed., 130 (1985)].
It is known that muscarinic receptors can be classified into subtypes, i.e. M1 which has a high affinity for pirenzepine which is an antispasmodic/antiulcer agent and M2 which is low in that affinity [Nature 283, 90 (1980)]. Furthermore, a further ramification of muscarine M2 receptors according to their affinity for AF-DX 116 has been proposed [Life Sciences 38, 1653 (1986) and Clinical and Experimental Pharmacology and Physiology 16, 523 (1989)], and much research is in progress on methoctoramine and other compounds having subtype specificity [Trends in Pharmacological Science 9, 216 (1988)].
On the other hand, muscarinic receptor genes have been cloned by genetic engineering techniques [FEBS Letters, 235, 257 (1986)] and so far at least 5 kinds of genes have been reported to exist in man. While the pharmacologic correspondence of them to receptors remains yet to be elucidated, it will not be long before it is clarified [Trends in Pharmacological Science 12, 148 (1989)]. It is expected that muscarinic blockers having novel pharmacologic activity will be developed in this milieu.
Under the circumstances, search for muscarinic receptor blocking substances in microbial metabolites is also in progress. In fact, Eulissin, Argvalin, IJ2702-I & 2702-II and PF6766 [Journal of The Agricultural Chemical Society of Japan, 62, 338 (1988)] have already been reported but none of them have sufficiently potent activity.
In the above-mentioned situation, the inventors of the present invention explored microbial metabolites for novel compounds which would exhibit potent muscarinic blocking activity and discovered a TAN-1251 series of compounds having strong antimuscarinic activity. TAN-1251 is comprised of 4 species which the inventors designated TAN-1251A, B, C and D. Subsequent research revealed that these compounds have the following structures: ##STR2##
The inventors of the present invention further conducted degradation and derivatizing experiments using TAN-1251A, B, C and D as starting compounds and examined the biological activity of the degradation products and derivatives. As a result, they found that the following compounds were promising candidates for antispasmodic/antiulcer agents. The finding prompted further study which has resulted in the present invention.
SUMMARY OF THE INVENTION
Thus, the present invention is directed to:
1. A compound of the formula ##STR3## wherein R.sup.1 is hydrogen or a hydrocarbon residue which may be substituted; R.sup.2 is oxo or hydrogen and a hydroxy which may be acylated; R.sup.3 is hydrogen or hydroxy which may be acylated; at least one of the dotted lines represents a single bond, or a salt thereof.
2. A method of producing a compound of the formula ##STR4## wherein R.sup.3' is hydrogen or hydroxy; at least one of the dotted lines represents a single bond; provided that where R.sup.3' is hydroxy, the dotted line on the right-hand side represents a single bond and the one on the left-hand side represents a double bond, or a salt thereof, characterized by culturing a
Harada Setsuo
Ishimaru Takenori
Shirafuji Hideo
Tsubotani Shigetoshi
Robinson Douglas W.
Sevigny Jeffrey J.
Takeda Chemical Industries Ltd.
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