Naphthyloxyacetic acid derivatives and drugs comprising the same

Details Naphthyloxyacetic acid derivatives and drugs comprising the same Naphthyloxyacetic acid derivatives and drugs comprising the same

1998-01-26

2000-01-25

Geist, Gary

Organic compounds -- part of the class 532-570 series

Organic compounds

Carboxylic acid esters

560 9, 560 11, 562426, 562427, 562429, C07C32112, C07C31700

Patent

active

060180684

DESCRIPTION:

BRIEF SUMMARY
FIELD OF TECHNOLOGY

This invention is related to the naphthyloxyacetic acid derivatives. More particularly, this invention is related to ##STR2## wherein all symbols are the same meaning as hereafter defined, or non-toxic salts thereof, acid addition salts thereof or their hydrates and antagonists or agonists) which comprises them as an active ingredient.


BACKGROUND

PGE.sub.2 has been known as metabolite in the arachidonate cascade. In addition, the recent progress in the molecule biological technology makes the existence of three PGE.sub.2 receptors clear as shown in the following and have been making the relationship between each receptor and appearance of biological activity clear. For example, EP, receptor may cause contraction of the smooth muscle of digestive canal or bronchus etc. and promote the release of neurotransmitter. The representative activity of EP.sub.2 receptor is relaxation of smooth muscle of bronchus or ileum etc. or vasodilatation and reduce of the blood pressure due to relaxation of vascular smooth muscle. As the activity of EP.sub.3 receptor, uterine muscle contraction, suppression of gastric acid secretion, inhibition of reabsorption of water and ion by vasopressin in renes, inhibition of fat decomposition in fat tissue, inhibition of release of neurotransmitter and glucose-decomposition by gulcagon in liver cell etc. have been known. In addition, recently, the existence of fourth receptor is suggested. (Biochemistry Vol. 66, No. 3, pp. 218-231 (1994))
Therefor, to antagonize PGE.sub.2 receptor means to suppress the effects above mentioned, so such an activity is linked to inhibit diuretic, to inhibit hyperlipemia, to inhibit reduce of blood sugar, to inhibit uterine contraction, to have analgesic action, to inhibit digestive peristalsis, to induce sleep. Therefor, PGE.sub.2 receptor antagonists are considered to be useful as anti-hyperlipemia, for the prevention of abortion, for analgesics, or as antidiarrheals or sleep inducer.
To agonize for PGE.sub.2 receptor means to promote the effects above mentioned, so such an activity is linked to have diuretic, to promote hyperlipemia, to promote reduce of blood sugar, to contractile uterine, to promote digestive peristalsis, to suppress gastric acid secretion or to reduce blood pressure. Therefor, PGE.sub.2 receptor agonists are considered to be useful for diuretic, anti-diabetes, abortient, cathartics, antiulcer, anti-gastritis or antihypertensive.
In such a background, a lot of compounds which agonize or antagonize for PGE.sub.2 receptors have been proposed.
For example, in the specification of EP-0657422, it is disclosed that the compounds of the formula (A) ##STR3## wherein R.sup.1A is --COOR.sup.4 A in which R.sup.4A is hydrogen or C1-4 alkyl, --CONR.sup.5A R.sup.8A in which R.sup.5A and R.sup.6A each, independently, is hydrogen, C1-4 alkyl or C1-4 alkyl substituted by 1 of hydroxy or --CH.sub.2 OH, ##STR4## in which A.sup.A is single bond or C1-4 alkylene or ##STR5## in which A.sup.A is ##STR6## in which mA is 0, 1, 2, 3, 4, nA is 0, 1, 2, 3, 4, and mA+nA is 2, 3, 4, B.sup.A is --NR.sup.3A SO.sub.2 -- or --SO.sub.2 NR.sup.3A --in which R.sup.3A is hydrogen, C1-4 alkyl or --CH.sub.2 COOR.sup.7A in which R.sup.7A is hydrogen or R.sup.4aA, in which R.sup.4aA is C1-4 alkyl, phenyl, C4-7 cycloalkyl or phenyl substituted by 1, 2 or 3 substituents selected from C1-4 alkyl, C1-4 alkoxy or halogen or ##STR7## or non-toxic salts thereof, are useful as PGE.sub.2 antagonist or agonist.
As for different activity case, in the specification of EP-0578847 (corresponding to JP Patent Application Kokai Hei 6-25074), it is disclosed that the compounds of the formula (B) ##STR8## R.sup.1B is hydrogen or C1-4 alkyl, R.sup.2B is hydrogen, C1-6 alkyl or phenyl, 4-7 membered monocyclic ring containing one nitrogen, ##STR9## is (iii) or (iv), --(CH.sub.2)p.sup.B - and =CH--(CH.sub.2)s.sup.B -- is bonded at the position a or b on the ring, and the ring in R.sup.3B may be substituted by one to three of C1-4 alkyl, C1-4 alkoxy, halogen, nitro or trihalo

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