Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-12-23
1999-06-15
Richter, Johann
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D28512
Patent
active
059123532
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to an industrially advantageous process for producing tetrazolylated biphenylmethane derivatives which have excellent angiotensin II antagonistic action and antihypertensive action and are useful as pharmaceuticals.
BACKGROUND ART
Angiotensin II is an active compound of the renin-angiotensin system, and has powerful vasopressor action and stimulating action for the synthesis and secretion of aldosterone in the adrenal cortex. It is also known to be a substance causing hypertension. Its action is considered to be caused through a specific receptor on various target organs such as adrenal cortex, kidneys, arterioles and the peripheries of sympathetic nerves. Because of such a technical background, a number of angiotensin II antagonists have been reported with a view to developing a therapeutic for hypertension.
Among them, a tetrazolylated biphenylmethane derivative on which the present inventors have previously filed an application (WO94/04516) and which is represented by the following formula (6): ##STR1## wherein R.sup.1 represents a lower alkyl group and ring A represents a cycloalkane, cycloalkene or benzene ring; or a salt thereof is known to have excellent angiotensin II antagonistic action and be useful as a therapeutic for circulatory diseases such as hypertension, heart diseases and cerebral apoplexy.
As a process for producing the above biphenylmethane derivative (6), described in the international publication WO94/04516 is a process to obtain the derivative, as described in the below-described reaction scheme, by reacting a 2-(protected amino)-1,3,4-thiadiazole (7) with a protected tetrazolylated biphenylmethylbromide (8), eliminating the protecting group from the tetrazolyl group, also eliminating the amino-protecting group and then reacting with an acid anhydride (5). ##STR2## wherein R.sup.3 represents an amino protecting group, R.sup.4 represents a tetrazolyl protecting group (for example, triphenylmethyl group) and R.sup.1 and ring A have the same meanings as defined above.
The above process is however accompanied with the drawback that the protection of a tetrazolyl group is essential so that an eliminating operation of the protecting group is required, which means increase of the steps and lowering of the yield.
Accordingly, an object of the present invention is to provide an industrially advantageous process of a tetrazolylated biphenylmethane derivatives (6) or salts thereof.
DISCLOSURE OF THE INVENTION
The present inventors therefore have carried out an extensive investigation on various production processes which do not require protection of a tetrazolyl group. As a result, it has been found that a tetrazolylated biphenylmethane derivative (6) can be obtained in a high yield without a step for the protection of a tetrazolyl group by tetrazolylation subsequent to the condensation between a cyanated biphenylmethane and a thiadiazole, leading to the completion of the present invention.
The process of the present invention is represented by the following reaction scheme. ##STR3## wherein R.sup.2 represents a hydrogen atom or an amino-protecting group, Z represents a halogen atom or a sulfonyloxy group and R.sup.1 and ring A have the same meanings as defined above.
The present invention therefore provides a process for producing a tetrazolylated biphenylmethane derivatives (6) or salts thereof, which comprises reacting a 2-(protected amino)-1,3,4-thiadiazole (1) with a cyanated biphenylmethane (2), reacting the resulting compound (3) with a metallic azide compound and an acid and, when there exists an amino protecting group, eliminating the protecting group and then reacting the resulting compound (4) with an acid anhydride (5).
BEST MODES FOR CARRYING OUT THE INVENTION
In the 2-amino-1,3,4-thiadiazole (1) used in the process of the present invention, examples of the lower alkyl group represented by R.sup.1 include linear or branched alkyl groups having 1 to 7 carbon atoms, with those having 1 to 5 carbon atoms being more preferred. Sp
REFERENCES:
patent: 5654322 (1997-08-01), Hirata et al.
Terukage Hirata, et al., Bioorganic and Medicinal Chemistry Letters, vol. 6, No. 13, pp. 1469 to 1474, "Acyliminothiadiazoline Derivatives: New, Highly Potent, and Orally Active Angiotensin II Receptor Antagonists", 1996.
Hirata Terukage
Inoue Satoshi
Nishimura Kouji
Sakae Nobuya
Yokomoto Masaharu
Richter Johann
Sackey Ebenezer
Wakunaga Seiyaku Kabushiki Kaisha
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