IE940268L - Aminophenyl derivatives - Google Patents

Description

74959 DESCRIPTION AMINQPHENYL DERIVATIVES Summary This invention relates to amijiophenyl derivatives.

More particularly, this invention is related to novel (fused) benz(thio)amides having an inhibitory activity on 5ot-Reductase; processes for the preparation of them; and pharmaceutical agents containing them as active ingredient.

Background In the study of prostaglandins (abbreviated as PG hereafter), many important discoveries have been made continuously in recent years. And so it was found a large change in the direction of the research and development of PG. In the compounds which have been newly found or newly confirmed their structure in PG family, it can be said that PG endoperoxides, (i.e. PGGj and PGH^), thromboxane (abbreviated as TXA2 hereafter), prostacyclin (i.e. PGI^) and leukotriene , D4 and E4 (abbreviated as LTC4, LTD^ and LTE4, respectively, hereafter) etc. have especially strong and unique biological activities.

All the compounds of PG family containing various PG previously known well in addition to the above compounds, are biosynthesized from the same mother compound, i.e. arachidonic acid in a living body and, therefore, the metabolic routes starting from arachidonic acid is called "Arachidonate cascade" as a whole. The detailed explanation of each route and the pharmacological character of each metabolite are described in Igaku No Ayumi, 114_, 378 (1980) , ibid, 114 , 462 (1980) , ibid, 114, 866 (1980), ibid, 114, 929 (1980), Gendai Iryo, 12, 909 (1980), ibid, 12, 1029 (1980), ibid, 12, 1065 (1980) and ibid, 12, 1105 (1980) etc.

The arachiaonate cascade can be largely divided into two routes; one is the route that cyclooxygenase acts on arachidonic acid to convert, into various PGs, e.g. prostaglandin (abbreviated PGF^ hereafter), prostaglandin E-, (abbreviated PGE_ hereafter), PGI-,, TXA_, via PGG_ and further PG^ and the other is the route that lipoxygenase acts on arachidonic acid to convert, in hydroxyeicosatetraenoic acid (abbreviated as HETE hereafter) or leukotrienes, via hvaroperoxyeicosatetraenoic acid (abbreviated HPETE hereafter) .

As the former route is well known, it is not described in the present specification in detail. See Prostaglandin (1978), edited by Makoto Katori et al., published by Kohdan-sha.

Concerning the latter route, it has been known that various compounds are produced according to the following scheme I.

Scheme I U U 16 18 Arachidonic acid lipoxygenase r peroxvdase 15 5-HETS COOH 8-HPETE, 9-HPETE, 11 —HPETE, 12-HPETE or 15-HPETE peroxydase 8-HETE, 9-HETE, 11-HETE, 12-HETE or 15-HETE LTA liAj glutathion-S-transferase LTC, LTB, COOH CHCONHCH-COOH I NHCOCH-CH-CHCOOH I T 1 4. 1 NH2 7 -glutamyl. 2 transpeptidase QH H COOH CHCONHCH2 COOH COOH LTE Besides being metabolized through a well known route, i.e. the route via PG endoperoxides, arachidonic acid is also metabolized through another route by the action of lipoxygenase. That is to say, arachidonic acid is metabolized by the action of lipoxygenase, e.g. 5-lipoxygenase, 12-lipoxygenase and 15-lipoxygenase, to 5-HPETE, 12-HPETE and 15-HPETE, respectively.

These HPETE are converted into 5-HETE, 12-HETE and 15-HETE, respectively, by the action of peroxidase converting a hydroperoxy group into a hydroxy group. Furthermore, LTA^ is also produced from 5-HPETE by dehydration. LTA^ is converted into leukotriene B^ (abbreviated as LTB^ hereafter) or LTC4 enzymatically . Further, LTC^ is converted into LTD4 by the action of jf-glutamyl transpeptidase.

Moreover, it was recently defined that LTD4 is metabolized to LTE4 (see Biochem. Biophys. Res. Commun., 91, 1266 (1979) and Prostaglandins, 19.(5), 645 (1980)).

Besides, SRS is an abbreviation of Slow Reacting Substance and it was named by Feldberg et al. for the substance released when perfusing cobra venom through isolated lung or incubating cobra venom with vitellus. And it was reported that the substance constricted ilem isolated from guinea pig slowly and continually (see J. Physiol., SA_, 187 (1938)).

Moreover, Kellaway et al. showed the relation between SRS-A and allergic reaction from the fact that SRS-A is released when an antigen is sensitized to perfusing lung isolated from guinea pig (see Quant. J. Exp. Physiol. , 30^, 121 (1940)) .

Brocklehurst reported that when the anticen is sensitized to a lung fragment isolated from a bronchial asthmatic whose specific antigen is defined, by an operation, histamine and SRS-A are released and strongly constrict the bronchial muscxe. Since such constriction can not be prevented by an antihistamine agent, he suggested that SRS-A is an important bronchoconstrictor in an asthmatic paroxysm (see Progr. Allergy, 6, 539 (1962)).

Since then, many reports were published, fcr instance, SRS-A prepared from human lung slice constrict a tracheal spiral of normal human (see Int. Arch. Allercv Acpl.

Immunol., 38, 217 (1970)); when SRS-A prepared from rats is injected intravenously to guinea pig, significant increase of pulmonary resistance is observed (see J. Clin. Invest., 53., 1679 (1974)); in addition, a subcutaneous injection of SRS-A to guinea pig, rat and monkey enhances vascular permeability (see Advances in Immunology, .10, 105 (1969), J. Allergy Clin. Immunol., 621, 371 (1978), Prostaglandins, 1^(5), 779 (19S0) etc.).

Generally, the substance released by immunological reaction is called SRS-A. On the other hand, the substance released by non-immunological reaction such as calcium ionophore is called SRS. However, the above two substances have many similarities each other and, therefore, it is considered they would probably be the same substance.

Further, it was confirmed that SRS or SRS-A is a mixture of LTC. and LTD,. So it can be understood that the 4 4 pharmacological characters of these leukotrienes are the same as those of SRS or SRS-A (see ?roc. Natl. Acad. Sci. USA, 76, 4275 (1979), Bicchem. Biopnys. Res. Commun., 91^, 1266 (1979), Proc. Natl. Acad. Sci. USA, 21, 2014 (1980) and Nature, 285 , 104 (1980)).

Based or. result of these studies, various leukotrienes (LTC^, LTD^ and LTE^, and further other ieukotrienes which may be confirmed their structures in future) biosynthesired frca arachidonic acid via LTA^, are considered to be important factors relating to the appearance of allergic tracheal and bronchial diseases, allergic lung diseases, allergic shock and various allergic inflaminaticns.

The suppression of leukotrienes is useful for the prevention and/or treatment of tracheal, bronchial or lung diseases such as asthma, allergic lung diseases, allergic shock or various allergic diseases.

On the other hand, arachidonic acid is released frcm phospholipids by the action of phospholipase, and two routes were generally accepted, namely (1) the action of phospholipase A2 on phosphatidyl choline, and (2) the action of phospholipase C on phosphatidyl inositol to produce the 1,2-diglyceride, and the action of diglyceridelipase followed by monoglyceridelipase on it to release arachidonic acic (see Kagaku to Seibutsu (Chemistry and Biology), 21^, 154 (1983)).

Also it was known that the arachidonic acid released is metabolized through two different routes i.e. (1) a metabolic route to bioactive substances e.g. prostaglandins (PGs), thromboxane A2 (TXA2) by cyclooxygenase, and (2) a metabolic route to bioactive substances e.g. SRS-A (Slow Reacting Substances of Anaphylaxis), hydroxyeicosatetraenoic acid (HETE) and leukotriene (LTB^) by lipoxygenase (see Kagaku to Seibutsu (Chemistry and Biology), 2jL, 154 (1983)). for example, TXA2 is a compound which has a potent activity of platelet aggregation and aorta contraction, SRS-A is a chemical mediator on asthma, LTB^ is a chemical mediator on various inflammations (e.g. gout) , and PGs are also chemical mediators on various inflammations which enhance a vascular permeability and pain, and have a vasoailative action, pvrogenetic action ana chemotactic action (see Prostaglandin (1978) , edited by Makoto Xatori et al, published by Kohdan-sha). various chemical mediators which play an important physiological part in the living body. And it was known that ill-balances of those chemical mediators induce various disorders.

As antagonists of SRS, the groups of the compounds of general formula: hydroxy group, an alkyl group of from 1 to 6 carbon atom(s) , an alkoxv group of from 1 to 6 carbon atom(s) , an amino group, an acyl group, an acylamino group of from 2 to 6 carbon atoms, an alkenvl group of from 2 to 6 carbon atoms, a halogen atom or a These metabolites are known as chemical mediators; Arachidonic acid is converted and metabolized to (A) (wherein from R1 to R5 and R7 each represent a hydrogen atom, a phenylalkoxy group in which alkoxv have from 1 to 6 carbon atom(s) ; X represents a hydrocarbvl group of frem 1 to 10 carbon atom(s) being optionally substituted by hydroxy group(s); A represents an oxygen atom or absense; C represents an alkylene, alkenylene or alkynvlene group of from 2 to 6 carbon atoms which may be branched; D represents a carboxy group, a 5-tetrazolyl group or carbamico-5-tetrazolyl group.) form the subject of patent applications by Fisons Co., Ltd. (see Japanese Patent Application No. 55-1273841 i.e. European Patent Publication No. 17332 or United States Patent No. 4281008.).

The following compounds form the subject of patent applications by Kissei Pharmaceutical Co., Ltd, as anti-allergic agents, of the general formula: (wherein KJ" and R each represent a hydrogen atom or ar. alkyl 3 4 croup with 1-4 carbon atoms; R ana R eacn represent a hydrogen atom or -nav be combined tcgecher to form an additional chemical bond; X represents a hydroxy1 croup, a halogen atom, a straight or branched chain saturated or unsaturated alkyl group with 1-4 carbon atoms, a straight or branched chain saturated or unsaturated alkoxv group with 1-4 carbon atoms, an acyloxv group with 1-4 carbon atoms, or a cycloalkyl group with up to 6 carbon atoms; n is zero or an integer of 1-3 with the proviso that when n is 2 or 3; X's may be the same or different and that when two X's are commonly the alkyl or alkoxv croup, both X's may be combined together to form a ring; and Y represents a straight or branched chain alkylene group or a straight or branched chain oxyalkyiene group connected to the benzene nucleus through an oxygen atom.) as well as physiologically acceptable salts thereof. (see United States Patent No. 4,026,896.) And benzamides, i.e. compounds represented by the general formula (I) depicted hereafter, wherein the symbol B is 4 opened and R is a group of the formula: -OCl^COOR, were patent-applicatea by the present inventors. (see Japanese Patent Application Nos. 58-203632, 58-224067, 58-245531 and 59-1855.) Disclosure of the Invention The present inventors have been synthesized novel compounds of the general formula (I) depicted hereafter, which have a structure characterized as (thio)amiao group being substituted on fused benzene ring or benzene ring and have been found the compounds nave potent antagonistic activity on leukotrienes (SRS), and then achieved the present invention.

And, the compounds of the present invention also inhibit phospholipase, so inhibit release of arachidonic acid from phospholipids, and therefore be useful for prevention and/or treatment of diseases induced by arachidonate metabolites e.g. TXA^/ PGs, leukotrienes in mammals including human beings, especially human beings.

Examples of the diseases to the subject are various allergic diseases induced by leukotrienes described above, thrombosis e.g. one induced by injury (damage) or cerebral or coronary, endothelium or intima ana inflammations e.g. arthritis, rheumatism (see Junkan Kagaku (Cardiovascular Science) _3 , 484 (1983) Yakkvoku (Pharmacy) 2A' (1983)).

It was found that the compounds of the present invention also have an inhibitory activity on 5c*-reductase described below, besides the activity of leukotriene antagonist and phospholipase inhibitor described above. 5o<-Reductase presents in endoplasmic reticulum and nucleic acid, and it converts teststerone which is taken into a target tissue, into active 5c^-dihydrotestosterone. The activated 5o<-dihydrotestosterone induces cell proliferaction by binding to an intracelluar receptor. Activation of this enzyme is considered to cause some diseases such as prostatic hypertrophy, make pattern badness and acne.

As a matter of course, the compounds of the present invention have no activity peculiar like hormones, and inhibit 5oi-reductase, so surpress increasing of 5o^-dihvdrotestcsterone, therefore surpress cell proliferaction, and therefore be useful for the prevention ana/or treatment of prostatic hypertrophy, male pattern badness and acne in mammals including human beings especially human beings.

Furthermore, it was found that the compounds of the present invention also have an inhibitory activity on aldose reductases.

An aldose reductase is an enzyme which reduces an aldose (e.g. glucose, galactose) into the corresponding polvol (e.g. sorbitol, galactitol) in human beings or other animals.

The sorbitol and galactitol produced by the action of this enzyme are accumulated in the crystalline lenses, the peripheral nerves, the kidney, etc of diabetics including galactosemiacs thus causing the above described 5 complications e.g. retinopathy, diabetic cateract, nerve disturbances or renal disorders (see Jap. J. Opthamol., 20, 399 (1976), Int. Congr. Ser. Excepta Med., 403, 584 (1977) and Metabolism, 28, 456 (1979)).

The compounds of the present invention have 10 inhibitory activity in an aldose reductase and are therefore effective for the prevention and/or treatment of diabetic complications described above in mammals especially human beings.

According to the present invention, there is 15 provided an aminophenyl derivative of the general formula: (I) [wherein symbol A represents a single bond or a group of methylene, ethylene, trimethylene, tetramethylene, 20 vinylene, propenylene, butenylene, butadienylene or ethylene group optionally being substituted by one, two or three straight or branched alkyl group(s) of from 1 to 10 carbon atom(s) and/or phenyl group(s), symbol B represents a divalent group of formula: I I 0 or S , V- ^ symbol T represents an oxygen atom or a sulphur atom, R1 represents a group of formula: iii) JrtJ R6 or (iv) a straight or branched alkyl, alkenyl or 5 alkynyl group of from 1 to 20 carbon atom(s), (wherein R5 and R6 independently represent a hydrogen atom or a halogen atom or a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s) wherein one, two, three, four or five of the 10 carbon atom(s) may be replaced by oxygen atom(s), sulphur atom(s), halogen atom(s), nitrogen atom(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy 15 group(s), carboxy group(s), azido group(s) and/or nitro group(s)), R2 represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s), R3 represents a hydrogen atom, a halogen atom, a 20 hydroxy group, a nitro group, a group of general formula: -C00R7 (wherein R7 represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon atom(s)) or a straight or branched alkyl or branched alkyl, alkoxy or alkylthio group of from 1 to 6 carbon 25 atom(s), and R4 represents a group of general formula: —(CH2)s-COOR8 1 s or N-N —(CH2)q-< II N-N (wherein R8 represents a hydrogen atom or a straight or branched chain alkyl group of from 1 to 6 carbon atoms, s represents an integer of from 1 to 10, and q represents zero or an integer of from 1 to 10), ; or a non-toxic salt thereof, (1) with the proviso that compounds wherein symbol A is a single bond, symbol B is a divalent of general formula: ■ [wherein (a) R3 is a hydrogen atom and R6 is a straight or branched alkyl group of from 1 to 4 carbon atom(s), halogen atom or trifluoromethyl group or (b) R3 is a halogen atom and R6 is a halogen atom] R3 is a hydrogen atom, straight alkyl or alkoxy group of from 1 to 4 carbon atom(s) or halogen atom are excluded, O symbol T is an oxygen atom, Q is 0, R' is a group of the formula: R2 is a hydrogen atom, and and (2) with the proviso that compounds of the following general formula are exluded: Rl'-A" IJQr H O^.R4 ( I" ) [wherein the symbol A' is a single bond or a vinylene or ethylene group optionally substituted by straight or branched chain alkyl group(s) of from 1 to 4 carbon atoms, R4 is -(CH2)n-COOR8 (wherein R8 is as defined above and n is an integer of from 1 to 10), R3 is a hydrogen atom, halogen atom or straight or branched alkyl or alkoxyl group of from 1 to 4 carbon atoms, and (wherein R3 and R6 are hydrogen atom(s), hydroxy group(s), halogen atom(s), trifluoromethyl group(s), straight or branched alkyl, alkenyl, alkynyl, alkoxy, alkenyloxy, alkynyloxy or acyloxy group(s) of from 1 to 4 carbon atoms(s) or cycloalkyi group(s) of from 3 to 6 carbon atoms, independently), R1 is (i) a group of the general formula - 13a - (ii) a group of the general formula: (wherein R5 and R6 are as defined above), or (iii) an unsubstituted naphthyl group].

The compounds of the general formula ( I ) are also novel compounds having first found to have inhibitory activities on -5a- reductase.

In the general formula (I), example of the groups represented by R^ and R^ are as follows:- o a hydrogen atom, a halogen atom o an alkyl group of from 1 to 20 carbon atom(s) o an alkenyl or alkynyl group of from 2 to 20 carbon atoms o an alkoxy or alkylthio group of from 1 to 19 carbon atom(s) o an alkenyloxy, alkenylthio, alkynyloxv or alkynylthio group of from 3 to 19 carbon atoms o an alkyl group of from 1 to 19 carbon atom(s) being substituted by halogen atom(s) and/or hydroxy group(s) o an alkenyl or alkynyl group of from 2 to 19 carbon atoms being substituted by halogen atom(s) ana/or hydroxy group(s) o an alkoxy or alkylthio group of from 1 to 18 carbon atom(s) being substituted by halogen atom(s) and/or hydroxy group(s) o an alkenyloxy, alkenylthio, alkynylthio or alkynyloxv group of from 3 to 18 carbon atoms being substituted by halogen atom(s) and/or hydroxy group(s) o an alkvloxyalkyl, alkenvloxyalkyl or aIkyloxyalkenyl group of from 2 to 19 carbon atoms o a cycloalkyi, cycloalkvloxy or cycloalkvlthio group of from 4 to 7 carbon atoms o a phenyl, phenoxv or phenvithio group o an alkyl group of from 1 to 19 carbon atom(s) which has carbocvclic ring(s) of from 4 to 7 carbon atoms, benzene ring(s), naphthalene ring(s) or thiophene ring(s) in the middle or at the terminal thereof o an alkoxy, alkylthio, alkenyloxy, alkenylthio, alkynyloxv or alkynylthio group of from 1 to 18 carbon atom(s) which have carbocvclic ring(s) of from 4 to 7 carbon atoms, benzene ring(s), naphthalene ring(s) or thiophene ring(s) in the middle or at the terminal thereof o a phenylthioalkoxy or phenyloxyalkyloxy group wherein alkyl moiety is a group from 1 to 17 carbon atom(s) o a carboxyalkyioxv, alkoxvcarbonylalkvloxy group of from 2 to 19 carbon atoms o an alkoxycarbonyloxyalkvloxy group of from 3 to 19 carbon atoms o an alkenylcarbonyloxy group of from 3 to 20 carbon atoms o an alkylcarbonyl group of from 2 to 20 carbon atoms o an azidoalkyl, nitroalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl group of from 1 to 19 carbon atom(s) o en aziaoalkyloxy, nitroalkvloxv, aminoaIkyloxy, alkylaminoalkyloxy, dialkvlaminoalkyloxy group of from 1 to 18 carbon atom(s) o an alkenylcarbonylamino group of frcm 3 to 19 5 carbon atoms o an alkylamino group of from i to 19 carbon etora(s) o groups described above being further substituted by halogen atom(s), hydroxy group(s) , azido group(s), nitro group(s) and/or carboxv croup(s) 1Q Among the groups described above, preferable croups as R"' and R^ are the following groups: o a hydrogen atom o a halogen atom o a straight or branched alkyl group of from 1 to 20 carbon atom(s) o a straight or branched alkoxy group of from 1 to 19 carbon atom(s) o a straight or branched alkenyloxy group of from j to 19 carbon atoms o a straight or branched alkvnvloxy group of from j to 19 carbon atoms o a straight or branched alkylthio group of from 1 to 19 carbon atom(s) o a straight or branched alkyl group of from 1 to 18 carbon atom(s) being substituted by halogen atom(s) o a straight or branched alkyloxyalkyl group of from 2 to 19 carbon atom(s) o a cycloalkyi, cvcioalkylalkyl (wherein alkyl moiety is a group of from 1 to 8 carbon atom(s) ) or cycloalkylalkyloxy (wherein alkyl moiety is a group of from 1 to 8 carbon atom (s) ) group optionally being substituted by straight or branched alkyl group(s) of from 1 to 8 carbon atom(s), hydroxy group(s) halogen atom(s) and/or nitro gruop(s) o a phenyl, phenvlalkyl (wherein alkyl moiety is a group of from 1 to 8 carbon atom(s) ) , pnenvlalkyloxy (wherein alkyl moiety is a croup of from 1 to 8 carbon atom(s)) or phenylalkenvloxy (wherein alkenyl moiety is a group of from 2 to 8 carbon atom(s)) group optionally being substituted by straight or branched alkyl group(s) of from 1 15 to 8 carbon atom(s),hydroxy group(s), halogen atom(s) and/or nitro group(s) o a naphthyl, naphthylalkyl (wherein alkyl moiety is a croup from i to 8 carbon atom(s).), napnthylalkoxy (wherein alkyl moiety is a croup 20 from 1 to 8 carbon atom(s).) or naphthylalkenvloxy (wherein alkenyl moiety is a group from 2 to 8 carbon atoms.) group optionally being substituted by straight or branched alkyl group(s), hydroxy group, halogen atom(s) and/or nitro group(s) o a straight or branched alkoxy, alkenyloxy or alkyloxyalkyloxy group of from 1 to 18 carbon " 18 ~ atom(s) being substituted by carbonyl, carbonvloxy ana/or hydroxy group(s) o a straight or branched alkoxy group of from 1 to 17 carbon atora(s) being substituted by phenoxy or phenvlthio group(s) o a straight or branched alkoxy group of from 1 to 18 carbon atom(s) being substituted by thiophene ring(s) o a straight or branched alkyl, alkenyl, alkoxy or alkenyloxy group of from 1 to 18 carbon atom(s) being substituted by aziao or nitro group(s) or amino group(s) being optionally substituted by an alkyl group of from 1 to 6 carbon atom(s) (including dialkylamino group(s)) o a straight or branched alkyl, alkenyl, alkoxv or alkenyloxy group of from 1 to 18 carbon atcm(s) being replaced by two kinds groups which are carbonyl group(s) and amino group(s) An alkyl group of from 1 to 20 carbon atom(s) in the present invention means a group of methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecvl, dodecyl, triaecyl, tetradecyl, pentadecyl, nexadecyl, heptaaecyl, octadecyl, nonadecyl, eicocyl group and an isomeric group thereof.

And an alkenyl and alkynyl group of from 1 to 20 carbon atom(s) mean corresponding groups described above.

An alkyl group of from 1 to 6 carbon atom(s) in the present invention means a group of methyl, ethyl, propyl, butyl, pentvl, hexyl group and isomeric group thereof.

A cycloalkyi group of from 4 to 7 carbon atoms in the present invention means a group of cvclobutyl, cvclopentyl, cvclohexyl and cycloheptyl group.

A halogen atom in the present invention means an atom of chlorine, bromine, iodine and fluorine atom.

In the present invention, when a certain carbon atom is replaced by another atom, a ring or a group, any carbon atom(s) can be replaced, so far as the replacement per se can be acceptable in chemical or physical. For example, "an isobutyl group replaced by a benzene ring in the middle or at the terminal" means a group of isopropvlpnenyl, cimethylpnenylmethyl or 2-phenylpropyl group. When the replacement, hydrogen atom(s) may be added or removed suitably. For example, "a pentyl group replaced by a nitrogen atom at the 2nd position" means N-propvlaminomethvl group.

And, for example, 2-(phenoxy)ethoxy group and 5 — (2 — chloro-4-nitrophenylthio)-5-methylpent-2-envloxv groups are induced by replacing five times or not more of them from pentyl group and 6,8-dimethylnon-3-enyl group, respectively, and therefore they are included in the present invention.

Apprently, these examples do not limit the present invention.

-C-C-C-C-C gentvl group (1) replacement by an oxygen atom I V -O-C-C-C-C butoxy group (2) replacement by an oxygen atom 1' -O-C-C-O-C 2-(methoxy)ethoxy group (3) replacement by a benzene ring -O-C-C-O-^Q) 2-(phenoxy)ethoxy group - 21 ~ c -c-c-c=c-c-c—c-c-c I c (1) replacement by an oxygen atom ' C I -o-c-c=c-c—c-c-c-c I c (2) replacement by a benzene ring C C (3) replacement by a sulphur atom C \ C (4) replacement by a halogen atom CI \ C (5) replacement by a nitro group CI C _ 22 _ Process for the Preparation (1) The present invention includes not only the compounds oer se, non-toxic salts thereof, use or method, but also process for the preparation.

According to the present invention, the compounds of the present invention of the general formula (I) may be prepared by reacting a compound of general formula: R1—A-COOH (II) (wherein all the symbols have the same meanings as described hereinbefore.) or a corresponding dithioic acid and a compound of general formula: R3 R (wherein all the symbols'are the same meaning as described hereinbefore.) to form amide-bond, and further subjecting saponification or 5 and/or esterification, if desired.

Reactions to form amide-bond are well known, it may be carried out, for example; (A) by the method with using mixed acid anhydride (B) by the method with using acid halide 10 (C) bv the method with using DCC Concrete description of the methods described above are as follows: (A) method with using mixed acid anhydride may be carried out, for example; an acid of the general formula (II) is reacted 15 with an acid halide (pivaloyl chloride, thionyl chloride, tosvl chloride, mesvl chloride, oxalyl chloride etc.) or an acid derivative (ethyl chloroformate, isobutyl chlorofornate etc.) in an inert organic solvent (chloroform, methylene chloride, diethyl ether, THF etc.) or without solvents, in the presence 20 of tertiary amine (pyridine, triethylamine, picoline etc.), at from 0°C to 40°C to give a mixed acid anhydride. The obtained acid mixed anhydride and an amine of the general formula (III) are reacted in an inert organic solvent (described above), at from 0°C to 40°C. _ 24 - (B) method with using acid halide may be carried out, for example; an acid of the general formula (II) is reacted with an acid halide (described above.) in an inert organic solvent (described above) or without solvents at from -20°C to a 5 refluxing temperature of the solvent used to give an acid halide. The obtained acid halide and an amine of the general formula (III) are reacted in an inert organic solvent (described above) in the presence or absence of tertiary amine (described above) at from 0°C to 40°C.

(C) method with using DCC may be carried out, for example; an acid of the general formula (II) and an amine of the general formula (III) are reacted in an inert organic solvent (described above) or without solvents in the presence or absence of tertiary amine (described above) using with DCC at 15 from 0°C to 40°C.

Preferably, the reactions (A), (B) and (C) described above are carried out in an atmosphere of inert gas (argon, nitrogen, etc.) on anhydrous condition.

Process for the Preparation (2) Among the compounds of the present invention, compounds of the general formula: R3 R2 R A N-N (la) 1 — H "?0 (wherein R~ represents methylene group or a single bond, and the other symbols are the same meaning as described hereinbefore.) may be prepared by reacting a compound of the general formula: ,3 (iv) R20-CN (wherein all the symbols are the same meaning as described hereinbefore.) with an azide.

Reactions to induce a 2-tetrazolyl group from a cvano group with an azide are known, it may be carried out, for example; on anhydrous condition, using with azide (sodium azide, lithium azide, potassium azide etc.), in the presence of weak acid (pyricium chloride, ammonium chloride, cimethvlaniline hydrochloride etc.) in an inert organic solvent (dimethylformamide, N-methylpyrroliaone etc.) with heating. _ 26 - Process for the preparation (3) Among the compounds of the present invention, compounds of the general formula: ,3 R1 — ; ro 121 40 (IB'; 1 21 (wherein R" represents a group of general formula: -(CH2)_- (wherein r represents zero or an integer of from 1 to 9.). 140 8 8 R represents a group of general formula: -COOR (wherein R has the same meaning as described hereinbefore.) or a group of formula: ,N N j| N N H and the other symbols have the same meanings as described hereinbefore.) may be prepared by reacting a compound of general formula: R3 T RX-A^ ,2 UH J(XXXXV) RJ (wherein all the symbols have the same meaningsas described hereinbefore.) and a compound of general formula: X 110 -ch2-r 121 -R 140 (xxxxvi) (wherein X1^"0 represents a halogen atom, and the other, symbols are the same meaning as described hereinbefore.) and further ecting saponification and/or esterification, if presence of a base (sodium hydride, potassium carbonate, sodium carbonate etc.), in a polar aprotic solvent (diethyl ether, tetrahydropvran, acetone etc.) at from 0°C to 100°C.

Process for the Preparation (4) Among the compounds of the present invention of the general formula (I) , certain compounds may be prepared from tr.e corresponding compounds of the present invention.

For example, it may be carried out in the following reaction formula and reaction scheme £Kj . reduction (I <0 _ 28 _ (Id.) (in the above case, butaaienvlene and butenvlene groups, or groups being substituted by an alkyl or phenyl groups may also be carried out similary, instead of vinylene group.) -R- o- uo H0- saponification CI/) (wherein the symbol represents whole group of the (1 R* and groups in R^" have the same meanings as ,30 substituent R and symbols therein are included in R respectively. described above in the following schemes. R~"~ represents an alkyl, alkenyl or alkynyl group of from 1 to 18 carbon atom(s).) _ 29 _ Scheme (A) w o UJ R 41' rRLi I (&) w"a B «' \ (11) ll,/Pd-C I rRl x J@) HjN- \ R NftNO, or iS^oX -A-^M (U) ( U) <7 Each symbol in the scheme fAj represents the following meanings or as defined.hereinbefore respectively. 40 a 1 R , R~ - an alkyl, alkenyl or alkynyl group of from 1 to 18 carbon atom(s) 45 R - a hyarogen atom or an alkyl, alkenyl or alkynyl group of from I to 18 carbon atom(s) - an oxygen atom or a sulphur atom, or an imido group - a lithium, potassium or sodium atom X1 - a halogen atom Processes for the Preparation of Intermediates Intermediates described hereinbefore of the general formula (III), (IV), (V) and (XXXXV) may be prepared by the processes described in the following reaction schemes, respectively.

Each symbols in the schemes represent the following meanings or as described hereinbefore, respectively. 21 R - a straight or branched al.p- (wherein all the symbols are the same meaning as described hereinbefore-) R^° - a trifluoroacetyl group v120 „130 v140 v150 . .

X , X ,X ,X - a halogen atom When imino group(s) are included in the symbol B, it is preferable to protect by trifluoro group (s) etc., and to remove the protect group(s) in a suitable step.

And compounds of the general formula (Illj) nay be prepared by the same procedure as the method to obtain compounds of general formula (Illh) from compounds of general formula (Illg).

Scheme |D) Scheme [FT (i)reduca 3n (i i) (saponi fication) /Is (iii) (HC1 ) 12i D—It -COOH1 J) —Jt' —coon® II1 K/ai-X (II.) II II* ^"4 t.''? trif luoroacet-ic anhydride • 2 u!r , (UCt) (Hig) u—u -cootr liS 11— h -coniij n' -N (L) /:'21 iin (li) ./» T h'-AV# n'-A^ (iil) I (i) Oil Hj (ii) (esteri-^^Tk^ (J£-ficat'ionT^ (OJ,B—-n -coon8 UN (11 Hi) -11 2 0 'j 12-2 "n —— T • it' -CONll, R'-A^l (LII) X'22 ^ Dv I'i" ^lt R3 it» (IVC) jio It —CONIIj (liii) — lljO 110 ii— ii — cn 11 (i■)' reduction N-N - 'ii ) (!!C1) H» no j (liv) no, (lv) , 120 ^N - N II Nil, (l'lC/j ft4 (IIIi) UN km 0 -,1°%?N ~ N V* (Illj) li1 (i) reduction (ii) (HC1 ) II4 NOj u — Ult • 1^1 (LVI) (xxxxvii) lt'-A^N H4 (IVCO H V»CN It4 y (LUX) "i1 (LIX) ft/" ll' j^n x°-ii^-cn . i \ ►-r'-a^n UH (LX) (IVe) r /21 D \ at U-il -CN ll4 it* t , r »'-aax"- _ ,„.axn ''N UH ll2 L/" jin r (XXXXV) "2 (LXII) Intermediates of 1,4-dithianaphthalene skelton also may be prepared using with a compound of general formula: ,3 (xxxii) (Wherein all the symbols are as the same meaning as described hereinbefore.) which may be obtained by hydrolizing a compound of general formula: r3 >' no2 (xxxd (wherein all the symbols are as the same meaning as described hereinbefore.) instead of the compound of the general formula (XIII).

In the processes for the preparation of the compounds of the present invention, esterification and saponification may be carried out as follows.

Conversion of a certain acid into a corresponding ester (i.e. esterif ication) is known reaction per se, and it may be carried out, for example; (1) by the method using a diazoalkane (2) by the method using an alkyl halide (3) by the method using DMF-alkylacetal and (4) by the method reacting with a corresponding alkanol _ 36 _ Concrete descriptions of the reactions above mentioned are as follows:- (1) the method using a diazoalkane may be carried out, for example, in an inert organic solvent (diethyl ether, ethyl acetate, methylene chloride, acetone, methanol, ethanol etc.) using with corresponding diazoalkane. (2) the method using an alkyl halide may be carried out, for example, in an organic solvent (acetone, N,N-dimethylformamide, DMSO etc.), in the presence of a base (potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium oxide etc.) using with a corresponding alkyl halide. (3) the method using DMF-dialkylacetal may be carried out, for example, in an inert organic solvent (benzene, toluene etc.) using with a corresponding DMF-dialkylacetal. (4) the method reacting with a corresponding alkanol may be carried out, for example, in a corresponding alkanol, using with an acid (hydrochloric acid, sulphuric acid, p-toluenesulphonic acid, hydrochloride gas etc.) or condensing agent (DCC, pivalovl chloride, arylsulphonyl halide, alkvlsulphonyl halide etc.).

Reactions mentioned above are carried out generally at from -10°C to 100°C; and they may be carried out further addition of inert organic solvent(s) (THF, methylene chloride etc.) not related to the reactions.

Conversion of a certain ester into corresponding acid (i.e. saponification) is known reaction per se, and it may be carried out, for example; (1) using with an aqueous solution of an alkali (potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate etc.) in a water-miscible organic solvent (THF, dioxane, ethanol, methanol etc.). (2) using an alkali mentioned above, in an alkanol (methanol, ethanol etc.) in anhydrous condition.

The reactions above are carried out generally at from -10°C to 100°C.

In each reaction in the present invention, products may be purified by conventional manner. For example, it may be carried out by distillation at atmospheric or reduced pressure, high performance liquid chromatography, thin layer chromatography or column chromatography using silica gel or magnesium silicate, washing or recrystallization. Purification may be carried out after each reactions, or after a series of reactions.

Starting Materials Starting materials and reagents in the present invention are known compounds per se or may be prepared by known methods per se.

For example, acids of the general formula (II) may be prepared by the methods described in the specification of Japanese Patent Application Nos. 58-203632, 58-224067, 58-245531, 58-245532 or 59-1855.

A certain compound of the general formula (VIII) wherein R"* is a hydrogen atom is_described in J. Med. Chem., £, 446 (1965).

A certain compound of the general formula (XIII) wherein is a hydrogen' atom is described in J. Am. Chem. Soc., 75 , 3277 (1953).

The compounds of the general formula (XV) may be prepared by the method described in J. Med. Chem., 2Q_, 371 (1977) .

A certain compound of the general formula (XXXI) wherein R^ is a hydrogen atom is described in J. Org. Chem., 42, 1925 (1977) .

The compounds of the general formula (XXXXVIII) may be prepared from the compounds of the general formula (II).

Compounds of the general formula (XXXXVI), (XXXXVII) and (XXXXVIII) are known compounds per se, or may be prepared by known methods per se.

For example, compounds wherein the symbol B is a morpholine ring, compounds wherein the symbol B is 2,3,4,5-tetrahydrofuran, compounds wherein the symbol B is a hydroxypyridine ring, compounds wherein the symbol B is 3,4,5,6-tetrahydro-2H-pyran ring may be prepared by the methods described in J. O. Chem-, 32^ 4155 (1967), Chem. Abst. 98, 179352 q (1983), J. 0. Chem., 32, 4155 (1967), and Chem. Abst., 84, 58747z, respectively or similar methods thereof. _ 39 _ Salts The compounds of the present invention of the general formula (I) may be formed salts at the carboxy or tetrazolyl moiety.

By converting'into salts, solubility of the compounds of the present invention against water can be increased, and therefore be useful at the administration as pharmaceuticals.

The compounds of the present invention may easily be converted into corresponding salts by the methods known per se, e.g. methods described hereafter.

The salts in the present invention are preferably non-toxic ones. The non-toxic salts herein referred mean salts of cations such that it is relatively innoxious to living body (animals including human beings) tissues and that the effective pharmacological properties of the compounds of the general formula (I) are not impaired by side effect(s) resulting from the cations when used in an amount required for the prevention and/or treatment. And water-soluble salts are preferable.

Suitable salts include, for example, a salt of an alkali metal such as sodium, potassium, a salt of an alkaline metal such as calcium, magnesium, an ammonium salt and a pharmaceutically acceptable (non-toxic) amine salt.

Amines suitable for forming such salts with carboxylie acid or tetrazolyl group are well known and include, for example, those amines which are theoretically obtained by substituting one or more of hydrogen atom(s) of ammonia by other group(s) . These groups, which may be the same or different when one or more hydrogen atom(s) are substituted. _ 40 _ are selected from, for example, alkyl group(s) of from 1 to 6 carbon atom(s) and hydroxyalkyl group(s) of from 1 to 3 carbon atom(s). Suitable non-toxic amine salts include salts of a tetraalkylammonium group, such as tetramethylammonium salt and salts of an organic amine, such as methylamine, dimethylamine, cvclopentylamine, benzylamine, phenetylamine, piperidine, monoethanolamine, diethanolamine, lysine and alginine.

Salts can be obtained from the compounds of the present invention of the general formula (I), by methods known per se, for example, by reacting the compound of the general formula (I) and a suitable base such as a hydroxide or carbonate of an alkali metal or alkaline earth metal, ammonium hydroxide, ammonia or an organic amine in theoretical amounts in an appropriate solvent.

The salts can be isolated by freeze-drying the solution, or by filtration if the salts are sufficiently insoluble to the reaction solution, or if necessary, by removing part of the solvent followed by filtration.

Pharmaceutical Activities The compounds of the present invention possess an inhibitory activity on In a standard laboratory test, for example, the compounds of the present invention showed the pharmaceutical activity in the following tables. (1) Inhibitory activity on 5a-reductase in vitro The compounds of the present invention showed an inhibitory activity on 5tf-reauctase in vitro (method is described hereafter) , shown in the following table.

Table VII: Inhibitory activity on 5a-reductase Example No. IC50 Kl) 1(2} ) Inhibitory activity of the compounds of the present invention on 5o(-reductase were measured by the following method.

Inhibitory activity of the compounds of the present invention on So^-reductase (IC..Q)_in vitro were measured by the following method.

Compounds tested were incubated with radioactive 14 -3 Z~4- Cj testosterone (5 _jiM) and NADPH (5 x 10 M) in the meaium containing 5^-reauctase, 0.09M Hepes (pH 7.4) and 0.22M sucrose at 37°C for 60 mins. The reaction was stopped by adding solution of chloroform-methanol (1:2). The reaction mixtuere was centrifuged and the supernatant was separated by thin layer chromatography on silica gel using chloroform-methanol-acetic acid (99.2:0.6:0.2) as a developing solvent. Radioactivity of formed 5«*-dihydrotestosterone was measured by TLC scanner. The values of were determined by the inhibition percents of 5C- reductase activity measeured by the above procedure (see Enaocrinal, Japon., 18, 179 (1971).).

Toxicity On the other hand, it was confirmed that the acute toxicity (LD,q) of all extent of the present invention were more than 500 mg/kg animal body weight by intravenous 20 administration. Therefore, the compounds of the present invention may be considered to be sufficiently safe and suitable for pharmaceutical use.

Application for Pharmaceuticals The present invention is also related to a pharmaceutical agent which is a 5£*-reductase inhibitor To inhibit 5 For the purpose hereinbefore described, the compounds of the present invention of the general formula or non-toxic salts thereof may normally be administered svstemicallv or partially; usually by oral or parenteral administration.

The doses to be administered is determined depending upon age, body weight, symptom, the desired therapeutic effect, 5 the route of administration, and the duration of the treatment etc. In the human adult, the doses per person per dose are generally between 0.1 mg and lOOmg, preferably between 2 mg and 20 mg, by oral administration, up to several times per cav, ana between 10 ug ana 10 mg, preferably between 0.1 mg and 1 mg, by 10 parenteral administration up to several times per day.

As mentioned above, the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.

Solid compositions according to the present invention for oral administration include compressed tablets, dispersibie powders and granules. In such solid compositions, one or more of the active compound(s) is or are, admixed with at least one inert diluent such as lactose, mannitoi, glucose, 20 hydroxypropylcellulose, micrccrvstalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate aluminate. The compositions may also comprise, as is normal practice, additional substances other than inert diluents e.g. lubricating agents such as magnesium stearate, disintegrating 25 agents such as cellulose calcium gluconate, and assistant for dissolving e.g. arginine, glutamic acid or amino-acid such as aspartic acid. The tablets or pills may, if desired, be made into gastric film-coated or enteric film-coated tablets or pills, such as sugar-coated, gelatin-coated, hvdroxypropyl cellulose-coated or hyaroxypropy line thy 1 cellulose phthalate-coated tablets or pills; two or more of layers may be used. The compositions for oral administration also include capsules of absorbable material such as gelatin.

Liquid compositions for oral administration include pharmaceutically-acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as distilled water or ethanol. Besides inert diluents such compositions may also comprise adjuvants such as wetting and suspending agents, and sweetening, flavouring, perfuming and preserving agents.

Other compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s).

Preparations for injection according to the present invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Example o: aqueous solvents or suspending media are distilled water for injection and physiological salt solution. Examples of non-aqueous solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, POLYSORBATE 80 (registered Trade Mark). These compositions may also include adjuvants such as preserving, wetting, emulsifying, despersing agents and assistant agent for dissolving (e.g. arginine, glutamic acid or araino-acid such as aspartic acid). They may be sterilized, for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately 5 before use.

Other compositions for parenteral administration include liquids for external use, and enaermic liniments such as ointments, suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by known - 4 7 - Throughout the specification including claims, isomers generated by the existence of stereo configuration unlimited (e.g. asymmetric carbon, double bond) are included in the corresponding formula, respectively. with proviso that, compounds which cannot exist per se in a chemical or physical sense (e.g. ones having a multiple bond next to an oxygen, nitrogen or sulphur atom \ are excluded from the present invention.

Reference Examples and Examples The following reference examples and examples are illustrate the present invention, but not limit the present invention.

In the reference examples and examples, "TLC", "NMR", "IR" and "Mass" represent "Thin layer chromatography", "Nuclear magnetic resonance spectrum", "Infrared absorption spectrum" and "Mass spectrum", respectively.

The solvents in the parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations.

Unless otherwise specified, "IR" was measured by the KBr tablet method and "NMR" was measured in a mixture of chloroform-d and ethanol-d^ respectively. - 49 " Reference Example 1 Synthesis of 8-(p-pentylcinnamoyl)amino-4-oxo-4H-l-benzopyran-2-carboxylic acid ethyl ester p-pentvlcinnamic acid (327 mg) , and the mixture was stirred for 30 min at room temperature. Excess oxyalyl chloride was removed from the mixture under reduced pressure. The residue was dissolved to methylene chloride (5 ml). In an atmosphere of argon, a solution of 8-amino-4-oxo-4H-l-benzopyran-2-carboxvlic acid ethyl ester (420 mg) in a mixture of methylene chloride (5 ml) and triethvlamine (0.6 mi) was added slowly. The reaction solution was stirred for 1 hr at room temperature, and then poured into 0.IN hydrochloric acid. The mixture was extracted with ethyl acetate. The extract was washed with water, a saturated aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride, successively, dried, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate: hexane =1:3) to give the title compound (140 mg) having the following physical data: COOEt Oxalvl chloride (3.4 ml) was added to -49a - TLC : Rf 0.6 0 (ethyl acetate: hexane = 1:1); NMR (CDC13): & 8.76(1H, ad), 8.23(1H, s), 7.72(1K, dc) 7.65(1H, d) , 7.38(2H, d), 7.27(1H, t), 7.07(2H, d), 7.00(1H, s), 6.52(1H, d); IR : 3270, 2930, 1730, 1660, 1630, 1530, 1430, 1290, 1260, 1180, 770 cm"1; Mass: m/e 433 Reference Example 2 Synthesis of 8-(p-pentvlcinnamoyl)amino-4-oxo-4H-l-benzcpvran-2-carboxvlic acic carboxvlic acid ethyl ester (132 mg; synthesized in Reference example was dissolved intc ethanol (10 ml). To the solution, an aqueous solution (1 ml) of sodium bicarbonate (126 mg) was added. The mixture was refluxea for 15 min. To the reaction solution mixture cooled to room temperature, water (20 ml) and IN hydrochloric acid (2 ml) were added. The mixture was extracted with ethyl acetate. The extract was washed with water and a saturated aqueous solution of sodium chloride, COOK 8- (p-per.tylcinnamov 1) amino-4-oxo-4H-l-benzopvran-2- - 49b - dried, and concentrated under reduced pressure. The residue was washed with a mixture of ethyl acetate and hexane (1:1), and dried to give the title compound (62 mg) having the following physical data: TLC : Rf 0.25 (ethyl acetate: methanol = 5:1); NMR : /" 8.66(1H, ad), 7.86(1H, da), 7.73(1H, a), 7.53 (2H, d) , 7.43(1H, t) , 7.22(2H, d) , 7.15(1H, s), 7.08(1H, d); IR : v7 3400, 2930, 1635, 1520, 1430, 1360 cm"1; 0 Mass: m/e 405 Examples 1(1) -1(3) By the same procedure as Reference examples 1 and 2, using with a corresponding carboxylic acid and 8-amino-4-oxo-4H-l-benzopyran-2-carboxylie acid ethyl ester which have corresponding substituent R"^, following compounds having the following physical data, shown in table Zx were given. - 49c - Table XVI Example No.

Formula HE vol no in tj.C (develop! n). 1.3 5 (4ll,o). 7.50(111,4). 7.20(211,4). 2Bll(2ll, t). 1.88(2lt,n), 000(311, t) 330Q 295Q 286a 164Ql 148(1 1 71 a i2S(n*)l 30$ 215, 211 white powder 0 0.30 (CDC/,) white im ^ (etKoiCetate: 7^0-r'/olTSMin"x ri'o-r30 ,70Q 1855 1615 157a <1,(o+\ P°Wder ' r ri I » 1-1) (211,n), 7.00(111,dt). 656(111,4). 2112 1520 292 211. / . (2ll,t), 2.63(2'!,t). 2.48(211,t). 1.80- 201 COOH 2.00 (211,») Examsie 1(1011-1(118) By the same procedure as Reference example 2, using a corresponding carboxylic acid and a corresponding amine, following compounds having the following physical cata, shown in table ZXVIl/ were ci'ven.

V.ililu XVII i:xiui\|>i c No.

I'oi inn I 1 (ln3) . ror « Y 'in,, v1 (doll fpr (h ' ' N ' S X " I ■ (''' 11 . , ;i iHi ioi x 11 1 ■ Itf vuliii; in TI.C (dove 1 op i IK] so) ven l.) M Korinu I a Rf value in (deve 1 opi ikj sol vcnl.) TT.C Mill Appea nmcc I 1104) ( >>Ut | 0 . 24 (cyclohexanc: ethyl acetate = 1:2) 13 1(H ), 312, 221, 2)1, 125, 9) wh i tc powder \(105) ("ill,,- = Xso- " T ( Poll 0.26 (cyclohexane: ethyl acetate -1:2) -165 (M ) , 3 4 6, 255, 245 , 211, 147 p<\ 1 e ye 11ow powder ui •> 1(106) Cil li 0.34 (ethyl acetate) 4 I 9(M ) , 225 pn 1 e brown ' crysta1 1 (112) On for ^ s 0) (Qfl rr v—COptf 0.23 (ethyl acetate: hex/ine - 1:1) 515(M ), 355, 321, 161 whi te powder U113) c HO •i6 S;> 9 0.30 (ethyl acotnle: hexano «■ 1:1) 415 (M ) , 221 whi te cry9tu1 ■ (coll 'I'dli I <; XVII (con t I mioil) Example "5 va],,e 'n 11,c f)o lorimila (developing Mass Appearance uolvontl 0 . 06 549 (M+), white 0 (ethyl acctate: 515, 463, crystal 1U14» hexane = 1 : 3) 355 , 1 95 , <"•" » 11115 Oil,,' JOO'u 0.22 (ethyl acetate: hexane = 1:1) 4 99(M ), 394, 305 whi te crysta1 line r>"„ 0 ''vv 0.22 (ethyl acetate; hexane * 1:1) 4 35 (Mt) , 241 pa) e ycllow powder , C.foll lul7' @U-..igr^r9 mi 0.10 (ethyl acetate; hexane ° 1:1) 503 (M ) , 417, 4 00, 399, 390, 309 wli I te powder 1 '118' ?"• (Or^r? I Of n!/ sCCOll 0.21 (ethyl acetate: hexane = 1:1) 515(H), 429, 355, 321 whi te crysta1 Reference Example 3 Synthesis of 8-Z~p- (4-phenvlbutoxy) benzoylamino/-2-(5-tetrazolyl)-2,3-dihydrobenzoxazin I I N = N In an atmosphere of argon, a mixture of 8-/fp- (4-phenylbutoxv) benzovlaminoJ-N-trif luoroacetyl-2 ,2-dihvdrobenzoxazin-2-nitrile (316 mg), sodium azide (196 mg), ammonium chloride (161 mg) and dimethylformamiae (2.5 mi) was stirred for 1 hr at 100°C. After reaction, the reaction solution was poured into a mixture of ice and dil. hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed, cried over magnesium sulphate, and conaenced under reduced pressure. The residue was dissolved into ethanol which was saturated with ammonia (50 ml). The solution was stirred for 20 hrs ar room temperature and then concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (chloroform: methanol = 3:1) to give the title compound (207 mc) having the following physical data: TLC : Rf 0.36 (chloroform: methanol = 3:1); IR : x? 3600-2300, 1630, 1600, 1500, 1465, 1250, 1170 cm"1; Mass: m/e 470(MT), 376, 358, 253; Appearance: brown powder.

Example 2fH - 2(2\ By the same procedure as Reference example 3, using a corresponding nitrile, following compounds having the following physical data, shown in table ZXVIII7 were given.

Tab)e XVIIT _ , tlf viilnu In TI.C f- , m6 t'orimilu (developing NMH (,>ppm) IN (l cn\ ) Mass Appearance' NO' solvent) 2d) \ ■ i M IIII 0. 30 (met liy leno chloride: methanol - 5:1) fl09(lll.dd), 7.118(211^), 7.40-7.00 (811,m), 6.95(21/,d), 5.54(2tl,»)s 40J(2lI,t), 2.71(211,t), 1.05-1.75 (-III,in) 335Q 3100-23UQ 161ft 443 (ni+), white 1600 156a 153Q ISia 361 313 powder 14 5(1 126(1 253 ' 2(2) 0.30 (me thy 1 one chloride: methanol - 5:1) (CDC/,) 8.10(111,#), 7.6U(2ll,d), 7.76-7. G4(|II. d), 7.05 (lH,t), 6.92(111, t). 682(211, d), 6.72(lll,<0> 600-558(211,m). 5.46(211/4). 4.-17(211,d) 320Q 3I0()-230QI600 1 69a 1560 1525, I Sllft 1250 wh 1 to 421 (n+), powde i" 331, 31 L 301 231 Example 3 Synthesis of 4-/"2-(p-pentyl-2-methylcinnamoyl) -aminophenoxy_7-butanoic acid and ethyl ester thereof.

CODE (C00C2HS) A mixture of 2-(p-pentyl-2-methvlcinnamoyl)-aminophenol (267 mg), 4-bromobutanoic acid ethyl ester (322 ng), potassium carbonate (135 mg) and acetone (2 ml) was refluxed overnight. After cooling, the reaction solution was diluted with ethyl acetate, precipitation was removed by filtration from the solution. The solution was concentrated under reduced pressure to give the title compound (ester) having the following physical data: TLC : Rf 0.66 (toluene: ethyl acetate = 10:1) ; Mass: m/e 4 37(M).

Ester obtained was dissolved into methanol (3.2 nil).

Tc the solution, a 2N aqueous solution of sodium hydroxide (1.64 ml), and the solution was stirred for 1.5 hrs at 40CC. After reaction, the solution was acidified with dil. hydrochloric acid. The mixture was extracted with ethyl 20 acetate. The extract was washed with water, dried and concentrated under reduced pressure to give the title compound (acid; 285 mg) having the following physical data: TLC : Rf 0.60 (methylene chloride: methanol = 5:1); IR : V 3470, 3200-2300, 1710, 1670, 1620, 25 1600, 1530, 1450, 750 cm"1; ~ 60 " NMR (CDC13): f 8.44(1H, dd), 8.28 (1H, s), 7.45(1H, s), 7 .30(2H, d) , 7.18 (1H, dd) , 4.11(2H, t); Mass: n/e 409(M), 215, 187; Appearance: white powder.

Example 3(1) - 3(2) Ey the same procedure as Example , using a corresponding phenol, following compounds were given. 3(1) COOH TLC : Rf 0.48 (ethyl acetate); IR : v/ 3320, 3200-2300, 1700, 1660, 16 30 , 1610 , 1540 cttt1; N'MR (CDC13) : cT 8.40(1H, c) , 8 . 22(1H, s), 7.60(1H, d) , 7.34 (2K, s) , 7 . 04 (2H , c) , 6.85(11-:, dd) , 6.76(1H, c), 6.69(1H, dd) ; Mass: ra/e 395(M), 201, 195; Appearance: white powder. 3(2) 61 _ H TLC : 0.4 (methylene chloride: methanol = 5:1); IR : \J 1655, 1600, 1520 , 1445 cm Mass: m/e 445 (M~) , 363, 345 , 255 , 191 , 147; Appearance: pale yellow powder.

Attention is drawn to Parent Irish Application No. 2035/85. - 62

Claims (5)

CLAIMS: 1) An aminophenyl derivative of the general formula: .. R3 r'-AAJ^S di R2 \ < R [wherein symbol A represents a single bond or a 5 methylene, ethylene, trimethylene, tetramethylene, vinylene, propenylene, butenylene, butadienylene or ethylene group optionally substituted by one, two or three straight or branched alkyl group(s) of from 1 to 10 carbon atom(s) and/or phenyl group(s), 10 symbol B represents a divalent group of formula:

1. 1 0 or S , symbol T represents an oxygen atom or a sulphur atom, R1 represents a group of formula: 15 (i) (ii) (iii) R5 R or - 63 - (iv) a straight or branched alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s), (wherein R5 and R6 independently represent a hydrogen atom or a halogen atom or a straight or branched 5 alkyl, alkenyl or alkynyl group of from 1 to 20 carbon atom(s) wherein one, two, three, four or five of the carbon atom(s) may be replaced by oxygen atom(s), sulphur atom(s) halogen atom(s), nitrogen atOTn(s), benzene ring(s), thiophene ring(s), naphthalene ring(s), 10 carbocyclic ring(s) of from 4 to 7 carbon atom(s), carbonyl group(s), carbonyloxy group(s), hydroxy group(s), carboxy group(s), azido group(s) and/or nitro group(s)), R2 represents a hydrogen atom or"a straight or 15 branched alkyl group of from 1 to 6 carbon atom(s), R3 represents a hydrogen atom, a halogen atom, a hydroxy group, a nitro group, a group of general formula: -C00R7 (wherein R7 represents a hydrogen atom or a straight or branched alkyl group of from 1 to 6 carbon 20 atom(s)) or a straight or branched alkyl or branched alkyl, alkoxy or alkylthio group of from 1 to 6 carbon atorn( s ) , and R* represents a group of general formula: 25 -(CH2)s-COOR8 or ^ N-N H g (wherein R represents a hydrogen atom or a straight or 30 branched chain alkyl group of from 1 to 6 carbon atoms, s represents an integer of from 1 to 10, and q represents zero or an integer of from 1 to 10), 35 ; or a non-toxic salt thereof, (1) with the proviso that compounds wherein symbol - 64 - A is a single bond, symbol B is a divalent of general formula: symbol T is an oxygen atom, q is 0, R1 is a group of the formula : [wherein (a) R5 is a hydrogen atom and R6 is a straight or branched alkyl group of from 1 to 4 carbon atom(s), halogen atom or trifluoromethy1 group or (b) R5 is a halogen atom and R6 is a halogen atom] R2 is a hydrogen atom, and R3 is a hydrogen atom, straight alkyl or alkoxy group of from 1 to 4 carbon atom(s) or halogen atom are excluded, and (2) with the proviso that compounds of the following - 65 - general formula are excluded: si i 4 • O ^ ^ R [wherein the symbol A' is a single bond or a vinylene or ethylene group optionally substituted by straight or branched chain alkyl group(s) of from 1 to 4 carbon atoms, R4 is - (CE2) n-COOR8 (wherein R8 is as defined above and n is an integer of from 1 to 10), R3 is a hydrogen atom, halogen atom or. straight or branched alkyl or alkoxyl group of from 1 to 4 carbon atoms, and R1 is (i) a group of the general formula: (wherein R2 and R6 are hydrogen atom(s), hydroxy group(s), halogen atom(s), trifluoromethyl group(s), straight cr branched alkyl, alkenyl"-, alkynyl, alkoxy, alkenyloxy, alkynyloxy or acyloxy group(s) of from 1 to 4 carbon atom(s) or cycloalkyi group(s) of from 3 to 6 carbon atoms, independently), (ii) a group of the general formula: (wherein R5 and R6 are as defined above), or (iii) an unsubstituted nap'nthyl group]. - 66 -

2. A compound according to claim 1, wherein the symbol B is a divalent group of formula 0 3. A compound according to claim 2, wherein the symbol A is a single bond or a vinylene group which is optionally substituted by straight or branched alkyl group(s) of from 1 to 6 carbons atom(s) or phenyl group(s), and the symbol T is an oxygen atom. 4. A compound according to claim 3, wherein FT is a group of the general formula: (wherein R5 and R~ are as defined in claim 1). 5. A compound according to claim 1, which is N- [p- (4-phenylbutoxy) benzoyl ] -2 - ( 5-tetrazolyl) - methoxyaniliae, N- [p- (2E-octenyloxy)benzoyl]-2-(5-tetrazolyl)-methoxyaniliae, 4 - [ 2 - (p-pentylcinnamoyl) aminophenoxy ] butanoic acid, 4 - [ 2 - (p-pentyl-2-methylcinnamoy 1) aminophenoxy ] -butanoic acid, N- (p-pentylcinnamoyl )-2-(5-tetrazolyl)-methoxyanilide, N- [p - (2-octynyi)cinnamoyl]-2-(5-tetrazolyl)-methoxyaniliae, 4- [2 - (p-pentylcinnamoyl) amino-4-chloropnenoxy ] -butanoic acid, 4 - [ 2 - [N-(p-isohexyl-2-phenylcir.namoyl) -N- methylamino]-phenoxy]butanoic acid, 4- [2-(p-pentyloxy-2 , 3-aimethylcinnamoyl) - aminophenoxyjbutanoic acid, 4—[2—[p—( 2E-octenyloxy) -m-chlorobenzoyl] - aminophenoxy]butanoic acid, - 67 - 4- [ 2- i.p- ( 3-pheny1thiopcope?y)benzoyl ] -aminophenoxy]butanoic acid, 4-[2-[p-(5-chloropentyloxy)benzoyl]aminophenoxy]-butanoic acid, 5 4-[2-[p-(p-pentylphenylmethoxy)-2- methylcinnamoyl]aminophenoxy]butanoic acid, 4-[2-(m-pentyloxy-o-methoxybenzoyl)aminophenoxy]- butanoic acid, 4-[2-[p-(p-pentylphenylmethoxy)-2-^ methylcinnamoyl]aminophenoxy]butanoic acid, 4-[2-[p-(p-pentylphenyl) -2-methylcinnamoyl]-aminophenoxy]butanoic acid, 4-[2-[5-(p-pentylphenyl)-2,4-pentadienoyi]-aminophenoxy]butanoic acid, ^ 4- [ 2- (p-phenylbutylthio-2-methylcinnamoyl )'- aminophenoxy]butanoic acid, or 4-[2-[p-(m-pentylphenylmethoxy)-2-met'nylcinnamoyl]aminophenoxy]butanoic acid; or a sodium salt thereof. 20 6. A compound according to claim 1, wherein -he symbol 3 is a divalent group of the formula: I S 25 7. A compound according to claim 6, wherein zr.e symbol A is a single bond or a vinylene group which is optionally substituted by straight or branched alkyl group(s) of from 1 to 6 carbon atoms(s) or phenyl 30 group(s), and the symbol T is an oxygen atom. 8. A compound according to claim 7, wherein ?.* is a group of the general formula: 35 (wherein R5 and R~ are as defined in claim 1) . - 68 - g. A compound according to claim 1, which is 4- [ 2- (p-pentyl-2-methvlcinnamoyl) aminophenylthio ] -butanoic acid, 4-[2-(p-pentyl-3-methylcinnamoyl) aminophenylthio ] -butanoic acid, 4- [2- (p-pentylcinnamoyl) aminophenylthio] butanoic acid, N-(p-pentylcinnamoyl)-2-(5-tetrazolyl)-methylthioanilide,

3. - [2 - (p-pentylcinnamoyl) aminophenylthio] -propionic acid, 4- [ 2- (p-isopropylcinnamoyl) aminophenylthio ] -butanoic acid, 4-[2-(p-cyclohexylcinnamoyl )aminophenylthio]-butanoic acid, 4- [ 2- (p-phenylmethylcinnamoyl ) aminophenylthio] -butanoic acid, or

4. -[2-[p-(2-octynyloxy)cinnamoyl]aminophenylthio]- butanoic acid; or a sodium salt thereof. 10. A process for the preparation of an aminophenyl derivative of the general formula: R- (wherein A, B, T, R*, R2, R3 and R" are as defined in claim 1, and subject to the provisosin claim 1), or a non-toxic salt thereof; said process being characterized by reacting an acid of general formula: R1—A-COOH (II) (wherein R" and A are as defined in claim 1), or a corresponding dithioic acid, with a compound of ceneral formula: - 69 - \ a4 (wherein all the symbols are as defined in claim 1), to form an amide-bond; and further, effecting saponification and/or esterification, if desired. 11. A process for the preparation of an aminophenyl derivative of general formula: ,3 (wherein R2" represents a methylene group or a single bond, and the other symbols are as defined in claim 1); or a non-toxic salt thereof; which process is characterized by reacting a compound of general formula: - 3 - 2C ~ —cn (wherein R2j is as defined above, and the other symbols are as defined in claim 1) and an azide; and, further, effecting salt formation, if desired. 12. A process for the preparation of an aminophenyl derivative of the general formula: R2 ?." - A / - N ■ ^ • U R;21_r'+° - 70 - wherein U represents an oxygen or a sulfur atom, R*21 represents a group of general formula: -(CH2)r- (wherein r 140 represents zero or an integer from 1 to 9), R represents a group of the general formula: -C00R3 (wherein Re is as defined in claim 1) or a group of formula: . N-N ^N-IJ H and the other symbols are as defined in claim 1), or a non-toxic salt thereof; which process is characterized by reacting a compound of general formula: ; xxxxv) (wherein U is as defined above and the other symbols are as defined in claim 1) with a compound of general formula: X:i°-CH2-R:21-RiiSO (XXXXVI) (wherein X*10 represents a halogen atom, and the other symbols are as defined above); and further effecting ; saponification and/or esterification, if desired. 13. A pharmaceutical composition characterised by comprising as active ingredient at least one compound c: the general formula (I) defined in claim 1, wherein various symbols are as defined in claim i, or non-toxic salt thereof, together with a pharmaceutical carrier and/or coating. 14. The use of a compound of general formula (I), as aefirved in claim 1 or a non-to.xic salt thereof, for the manufacture of a medicament, for the treatment of the human body by therapy. - 71 - 1

5. . The use of a compound of general f oriuula ^ I) , as defined in claim 1 of a non toxic salt thereof for the manufacture of a medicament for the prevention ana/or treatment of diseases such as prostatic hypertrophy, male pattern baldness or acne. TOMKINS & CO. c - 12 -