# US 5,703,099 A · Phenoxyacetic acid derivatives

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- Number: US 5,703,099 A
- Document ID: US5703099A
- Status: Granted
- Kind: A
- Application number: 08/642,598
- Filed: 1996-05-03
- Granted: 1997-12-30
- Earliest claimed: 1992-02-28
- Assignees: Ono Pharmaceutical Co., Ltd.
- Inventors: Nobuyuki Hamanaka; Kanji Takahashi; Hidekado Tokumoto
- Web page: https://patentgrep.com/patent/US5703099A

## CPC

- C07D 213/53: Nitrogen atoms
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- A61P 9/08: Vasodilators for multiple indications
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 59/68: the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
- C07C 69/712: the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
- C07C 69/734: Ethers
- C07C 235/34: having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 235/38: having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
- C07C 239/20: having oxygen atoms of hydroxylamino groups etherified
- C07C 243/32: the carbon skeleton containing rings
- C07C 251/16: containing six-membered aromatic rings
- C07C 251/40: to carbon atoms of an unsaturated carbon skeleton
- C07C 251/86: having doubly-bound carbon atoms of hydrazone groups bound to carbon atoms of six-membered aromatic rings
- C07C 255/37: the carbon skeleton being further substituted by etherified hydroxy groups
- C07C 259/06: having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 259/14: having carbon atoms of hydroxamidine groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C 311/27: of an unsaturated carbon skeleton containing rings
- C07D 231/12: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D 263/32: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D 271/06: 1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
- C07D 275/02: not condensed with other rings
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

We proposed a novel compound having an activity of PGI.sub.2 receptor agonist. A phenoxyacetic acid derivative of the formula ##STR1## A is --C(R.sup.1).dbd.N.about.OR.sup.2, --CH(R)NH--OR.sup.2, --COE, --SO.sub.2 E, --CH.sub.2 --NR.sup.3 --Y, --Z--NR.sup.3 --CONR.sup.4 R.sup.5, --CH.sub.2 --OR.sup.6, --CO.sub.2 R.sup.6, --CH.sub.2 --O.about.N.dbd.CR.sup.7 R.sup.8, --CH.sub.2 --O--NHCHR.sup.7 R.sup.8, substituted by imidazolyl(methyl), pyrazolylmethyl, oxazolyl(methyl), thioxazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolylmethyl; T is alkylene, alkenylene, etc.; D is --CO.sub.2 R.sup.10, --CONR.sup.11 R.sup.12 ; E is (substitution) amino, hydradino; Y is substituted (thio) carbonyl, substituted sulfonyl; Z is --CH.dbd.N--, --CH.sub.2 NR.sup.3 --; R.sup.1, R.sup.3, R.sup.10 -R.sup.13 is each H or alkyl, etc.; R.sup.2, R.sup.4 -R.sup.9 is each H, alkyl or alkyl substituted by phenyl or hetero ring, etc. and non-toxic salts thereof, non-toxic acid addition salts thereof, possess an agonistic on PGI.sub.2 receptor, so it is useful for prevention and/or treatment of thrombosis, arteriosclerosis, ischemic heart diseases, gastric ulcer and hypertension.

## Claims

### Claim 1

A phenoxyacetic acid compound of the formula (I): ##STR153## wherein A is ##STR154## T is i) single bond,
ii) C1-6 alkylene,
iii) C2-6 alkenylene or
iv) --O--(CH.sub.2).sub.s --;
D is
i) --CO.sub.2 R.sup.10 or
ii) --CONR.sup.11 R.sup.12 ;
R.sup.9 is
i) hydrogen,
ii) phenyl,
iii) C1-4 alkyl or
iv) C1-4 alkyl substituted by one or two of phenyl or 4-7 membered monocyclic hetero ring containing one nitrogen;
R.sup.10 is hydrogen or C1-12 alkyl;
R.sup.11 and R.sup.12 each, independently, is hydrogen or C1-4 alkyl or
R.sup.11 and R.sup.12, taken together with nitrogen bond to R.sup.11 and R.sup.12 is the residue of an amino acid;
R.sup.13 is hydrogen, C1-4 alkyl, C1-4 alkoxy or nitro;
n is 1-2,
s is 2-4;
and the rings of the phenyl or the hetero ring of R.sup.9 may also be substituted by one to three of C1-C4 alkyl, C1-C4 alkoxy, halogen, nitro or trihalomethyl;
or a non-toxic salt thereof or a non-toxic acid addition salt thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein D is carboxy.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein D is C1-12 alkoxycarbonyl.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein D is CONR.sup.11 R.sup.12, wherein R.sup.11 and R.sup.12 each, independently, is hydrogen or C1-4 alkyl or R.sup.11 and R.sup.12, taken together with nitrogen bond to R.sup.11 and R.sup.12 is the residue of an amino acid.

### Claim 5 (depends on 1)

A compound according to claim 1, which is
3-›3-(5-Diphenylmethylisoxazol-3-yl)propyl!phenoxyacetic acid,
3-›3-(3-Diphenylmethylisoxazol-5-yl)propyl!phenoxyacetic acid,
3-›3-(Oxazol-2-yl)propyl!phenoxyacetic acid,
3-›3-(5-Ethyloxazol-4-yl)propyl!phenoxyacetic acid,
3-›3-›5-Di(3-pyridyl)methylisoxazol-3-yl!propyl!phenoxyacetic acid,
3-›3-›5-›1-Phenyl-1-(3-pyridyl)methyl!isoxazol-3-yl!propyl!phenoxyacetic acid,
or its methyl ester, or its octyl ester, or its acetamide, or its amide with glycine.

### Claim 6 (depends on 1)

A pharmaceutical composition which comprises, as active ingredient, an effective amount of a phenoxyacetic acid derivative of the formula (I) depicted in claim 1 or a non-toxic salt thereof, or a non-toxic acid addition salt thereof, with a pharmaceutical carrier or coating.

### Claim 7 (depends on 1)

A method for the treatment of thrombosis, arteriosclerosis, ischemic heart diseases, gastric ulcer or hypertension, which comprises the administration of an effective amount of a phenoxyacetic acid compound of the formula (I) depicted in claim 1 or a non-toxic salt thereof, or a non-toxic acid addition salt thereof.