WO1998046593A1

WO1998046593A1 - Novel carbostyril derivative

Info

Publication number: WO1998046593A1
Application number: PCT/JP1998/001726
Authority: WO
Inventors: Tadaaki Ohtani; Kenji Otsubo; Jun Matsubara; Kazuyoshi Kitano; Seiji Morita; Yoshikazu Kawano; Minoru Uchida; Shuji Yamashita
Original assignee: Otsuka Pharmaceutical Co., Ltd.
Priority date: 1997-04-16
Filing date: 1998-04-15
Publication date: 1998-10-22
Also published as: AU6851798A

Abstract

The present invention provides a novel carbostyril derivative represented by general formula (1), wherein A is a lower alkylene group; R1 is a lower alkyl group which may have hydroxyl groups; R2 is a hydrogen atom or a hydroxyl group; l is 0, 1 or 2; and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is a single bond or double bond. The above-mentioned carbostyril derivative is useful as the effective ingredient for pharmaceutical preparation.

Description

DESCRIPTION

NOVEL CARBOSTYRIL DERIVATIVE

TECHNICAL FIELD

The present invention relates to a novel carbostyril derivative. More particularly, the invention provides a novel carbostyril derivative which is useful as an effective ingredient for pharmaceuticals.

The carbostyril derivative of the present invention is a novel compound which has not been known in any related prior art literature, and is represented by the following general formula (1),

[wherein A is a lower alkylene group; R¹ is a lower alkyl group which may have hydroxyl groups, a lower alkanoyloxy-lower alkyl group, a lower alkylsulfonyloxy- lower alkyl group, a lower alkenyloxy-lower alkyl group or a group of the formula,

(wherein A_{ is a lower alkylene group; R³ is a hydrogen atom or a lower alkyl group; R^ή , R⁵ and R⁶ are the same or different from each other and are hydrogen atoms or lower alkanoyl groups ) ; R² is a hydrogen atom or a hydroxyl group; _ is 0, 1 or 2; and the carbon-carbon bond between 3 and 4-poεitions in the carbostyril skeleton is a single or double bond; provided that when R¹ is a lower alkyl group, then R² is a hydroxyl group].

The carbostyril derivative of the present invention possesses strong platelet adhesion inhibiting activity, further possesses characteristics with less side-effects such as activity of cardiovascular circulation, thus the carbostyril derivative is useful for curing and preventing arteriosclerotic diseases and thro botic diseases .

RELATED ART STATEMENT

Arteriosclerosis is a lesion accompanied by hypertrophy, sclerosis and regression of arterial wall, and is frequently combined with thrombosis, which causes ischemic lesions in various organic tissues such as the brain, heart and peripheral organs due to the stenosis and occlusion of the arterial lumen. There has been well known that the platelets are regarded greatly in crisis and development of arteriosclerosis [cf.

Russell Ross et al . , Proc. Natl. Acad. Sci. U. S. A., Vol. 71, p. 1207, (1974); Russell Ross et al., New Engl . J. Med., Vol. 314, p. 488, (1986)]. The first step of crisis of arterioslcerosis is caused by adhesion of platlets to the blood vessel wall of which the endotheliu cell is disturbed and peeled off due to various derangement factors such as hypertension, hyperlipidemia, smoking, hormones, bacteria, serotonin and thromboxane A₂, etc. Further, this adhesion of platlets is the initial reaction for the thrombosis . The adhered platelets make further coagulation with other platelets mediated by fibrinogen, followed by physiologically active substances such as thromboxane A₂, serotonin, ADP, PDGF (platelet derived growth factor), etc. are released to outside of the cells from granules in the coagulated platelets . The released thromboxane A₂, serotonin and ADP disturb the intima of the blood vessel, further the released PDGF induces the migration of medial smooth muscle cell to the intima in the blood vessel, and causes proliferation and hypertrophy of the intima which will develop to arteriosclerosis. Therefore, platelet adhesion inhibitor inhibits hypertrophy of the intima of the blood vessel, thus arteriosclerosis and ischemic disease of thrombosis can be cured and prevented by inhibition of platelet adhesion.

Currently, a number of anti-coagulant agents as to curing ischemic diseases, are in developing stages .

However, it should be noted the fact that these agents are substances for inhibiting coagulation of platelets, and indeed these agents inhibit thrombo- poiesis in the blood flow, but they cannot inhibit hypertrophy of the intima of the blood vessel. Thus, an agent having abilities of both inhibiting thrombo- poiesis and hypertrophy of intima of the artery, also having abilities to keep and improve the blood flow is earnestly desired.

12-Hydroxyeicosatetraenoic acid (hereinafter referred to as 12-HETE) is one of the arachidonate metabolites, and its distribution _in_ vivo and physiological activities are getting apparent since last few years [cf. Yamamoto et al., J. Lipid Mediators

Cell Signaling, Vol. 12, p. 195, (1995)]. There are described clearly in this literature that 12-HETE exists in the tissues and cells such as central nervous system, leukocytes, platelets, blood vessel walls, etc. and its typical physiological activities are as follows. Thus, 12-HETE controls the functions of adhesion and coagulation of platelets [cf. Buchanan, M. R. et al, Prost. Leukot. and Med., Vol. 21, p. 157, (1986); Buchanan, M. R. et al., Prost. Leukot . and Essential Fatty Acid, Vol. 36, p. 171, (1989)]. Further, there is disclosed that 12-HETE plays an important role in controlling the activation of platelets by acting as an autoregulational mediator for the transformation of platelet reactivity from the step of initial stimulation induced by collagen to the next simulation induced by thrombin [cf. Sekiya, F. et al., BBRC, Vol. 179, No. 1, p. 345, (1991)], and is suggested the relativity to thrombosis. Additionally, there is pointed out that 12-HETE may have some possibilities of relation to crisis of ischemic heart disease [cf. Tada, M. et al., Cardiovascular Research, Vol. 21, No. 8, p. 551, (1987)], and is suggested that 12-HETE has a relation to crisis of thrombotic ischemic disease.

It is reported that 12-HETE relates to the development of arteriosclerosis lesion by accelerating migration of the smooth muscle cells of the blood vessel [cf. Murota Seiitsu et al., CHIRYO-GAKU (a Japanese journal of therapeutics), Vol. 13, No. 8, p. 785, (1984)]. Furthermore, there are reported that 12-HETE shows an effect on proliferation activity of cells via tyrosine kinase in culture smooth muscle cells in rabbit [cf. Huang, H. C. et al., Eur. J. Pharm., Vol. 237, No. 1, p. 39, (1993)]; 12-HETE accelerates transformation of the smooth muscle cells [cf . Ramboer, I. et al.: Kidney Int. Supple., Vol. 37, pp. 67, (1992)]; thus, it is suggested that 12-HETE relates to crisis and development of arteriosclerosis lesion, and to stenosis of the intima of the blood vessel.

There is pointed out that in a patient of non-insulin-dependent diabetes mellitus, the content of 12-HETE in the blood is increased as compared with that of shown in normal adult, and the content of prosta- glandin I₂ is decreased, and such increased 12-HETE become causes of diabetic vascular lesion [cf. Jost-Vu, E. et al., Clinical Research, Vol. 40, No. 1, p. 106A, (1992)].

In correlation with cerebrovascular contrac- ture, 12-HETE is presumably related to this disease for the reason that 12-HETE was detected in the hematoma accompanied with constriction of the basilar artery in the cerebrovascular spasm model, which was occurred by infusing autohemic of the test dog twice to its cerebellomedullaris [cf. Watanabe, T. et al . , J. Neurochem., Vol. 50, No. 4, p. 1145, (1988)].

Furthermore, at the diseased site in a patient of psoriasis vulgaris, 12-HETE is outstandingly increased together with free arachidonic acid as compared with the normal site. For this reason, it is suggested that 12-HETE is related to this disease [cf. Hammarstrom, S. et al . , Proc. Natl. Acad. Sci. U. S. A., Vol. 72, p. 5130, (1975)].

Recently, Murota et al . found the fact that 12-HETE, which is produced endogenously in the cultured mesangial cells of rat glomerule, accelerates the proliferation of mesangium. For this reason, it is suggested that 12-HETE is related to the crisis of nephrosis [cf. Murota, S. et al., Prost. Leukot . and Essential Fatty Acid, Vol. 51, No. 3, p. 177, (1994)]. Additionally, there have been found the facts that, 12-HETE accelerates the expression of adhesive protein of Vβ3 integrin on the surface of endothelium cell of the blood vessel, and also accelerates the adhesion of tumor cells [cf. Honn, K. V. et al . , Int. J. Cancer, Vol. 54, p. 102, (1993)]; 12-HETE derived from tumor cells retracts the endothelial cell of the blood vessel [cf. Honn, K. V. et al . , Cancer Res., Vol. 54, p. 565, (1994)] , thus it is suggested that 12-HETE plays an important role in metastasis of cancer. On the basis of the above-mentioned facts, there can be concluded that an agent which inhibit the production of 12-HETE is effective for curing and prevention of allergic diseases, inflammatory disease and metastasis of cancer, ischemic diseases such as arteriosclerosis and thrombosis; reconstriction after the percutaneous transluminal coronary anginoplasty (PCTA), myocardinal disturbance at reperfusion of ischemia; diabetogenous vascular lesion; diseases in the circulation system such as contracture of cerebro- vascular; psoriasis and nephritis.

Under the circumstances, the present inventor have conducted research and development works to find pharmaceuticals which will be useful for curing and preventing both arteriosclerotic diseases and thrombotic diseases. As the result, the present inventors have found that a carbostyril derivative represented by the general formula (1) of the present invention possess activity for inhibiting adhesion of platelets and activity for inhibiting production of 12-HETE, thus the carbostyril derivative (1) ia useful for curing and preventing arteriosclerotic diseases and thrombotic diseases, and finally the present invention was succe- ssfully completed.

There have been known some compounds, having chemical structure similar to that of the carbostyril derivative (1) of the present invention, and possess the platelet adhesion inhibiting activity are disclosed in U. S. Patent Nos. 5,008,274 and 5,541,198. However, these prior art literatures do not disclose at all that these similar compounds having the activity for inhibiting production of 12-HETE.

DISCLOSURE OF THE INVENTION The carbostyril derivative of the present invention is a novel compound which has not been reported in any prior art literature, and represented by the general formula (1),

(wherein A_: is a lower alkylene group; R³ is a hydrogen atom or a lower alkyl group; R* , R⁵ and R⁶ are the same or different from each other and are hydrogen atoms or lower alkanoyl groups); R² is a hydrogen atom or a hydroxyl group; jP_ is 0, 1 or 2; and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is a single or double bond; provided that when R¹ is a lower alkyl group, then R² is a hydroxyl group] . The carbostyril derivative of the present invention possesses strong activity for inhibiting adhesion of the platelets, further possesses advantageous features of less side-effects such as adverse influences cardiovascular circulation, thus the carbostyril derivative (1) is useful for curing and preventing arteriosclerotic diseases and thrombotic diseases .

The carbostyril derivative (1) of the present invention inhibits both thrombopoiesis and hypertrophy of the intima of the artery, and is capable to keep and improve the blood flow. Therefore the carbostyril derivative (1) is useful as an agent for inhibiting adhesion of platelets, an agent for anti-thrombopoiesis as well as an agent for inhibiting stenosis of the intima of the artery. As to clinical applications, the carbostyril derivatives ( 1 ) is usef l for curing and preventing cerebral disease such as cerebral infarction, ephemeral ischemic attack of the brain, cerebral arteriosclerosis, etc.; heart diseases such as myocardial infarction, angina pectoris, etc.; peripheral diseases such as chronic arteriosclerosis, Buerger's disease, etc.; renal diseases such as glomerular nephritis, renal hypertension, etc. Further, the carbo- styril derivative (1) of the present invention can be used for preventing re-constriction in the cases of artificial blood vessel transplantation, such as blood vessel re-construction, percutaneous angioplasty such as PTA (percutaneous transluminal angioplasty), PTCA (percutaneous transluminal coronary angioplasty), PTCR (percutaneous transluminal coronary recannalization ) ; for improvement of circulation in the cases of arti- ficial dialysis, artificial organ transplantation, intermittent claudication, collagenosis , diabetes mellitus, local vibration, etc.; and for improvement of neurosis symptoms.

Additionally, the carbostyril derivative (1) of the present invention possesses activity for inhibiting production of 12-HETE, thus it is useful for curing and preventing various diseases caused by excessive production of 12-HETE, for example arteriosclerotic and thrombotic ischemic diseases, re-constriction after PTCA (percutaneous transluminal coronary anginoplasty) , myocardial disturbance in the re-perfusion of ischemia, diabetogenous vascular lesion, diseases in the circulation system such as contracture of cerebrovascular lesion, allergic diseases and inflammatory diseases such as nephritis, psoriasis and the like, colonization of cancer, etc.

Concrete examples of each one of the substi- tuents shown in the general formula ( 1 ) are shown as follows . Examples of a lower alkylene group is a straight chain- or branched chain-alkylene group having 1 to 6 carbon atoms, such as methylene, ethylene, tri- methylene, 2-methyltrimethylene, 2, 2-dimethyltri- methylene 1-methyltrimethylene, methylmethylene, ethyl- methylene, tetramethylene, pentamethylene, hexamethylene groups and the like.

Examples of a lower alkyl group which may have hydroxyl groups is a straight chain- or branched chain- alkyl group having 1 to 6 carbon atoms and which may have 1 to 3 hydroxyl groups, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl , pentyl, hexyl, hydroxymethyl , 2-hydroxyethyl , 1-hydroxyeth l , 3-hydroxypropyl, 4-hydroxybutyl , 5-hydroxypentyl , 6- hydroxyhex 1 , 1 , 1-dimethy1-2-hydroxyethy1 , 2-methyl-3- hydroxypropyl , 2 , 3-dihydroxypropyl , 5 , 5 , 4-trihydroxy- pentyl , 1-hydroxyisopropyl groups and the like.

Examples of a lower alkanoyl group is a straight chain- or branched chain-alkanoyl group having 1 to 6 carbon atoms, such as formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl , tert.-butylcarbonyl , hexanoyl groups and the like.

Examples of a lower alkanoyloxy-lower alkyl group is a straight chain- or branched chain-alkyl group having 1 to 6 carbon atoms which is substituted with a straight chain- or branched chain-alkanoyloxy group having 2 to 6 carbon atoms, such as acetyloxymethyl , 2-propionyloxyethyl, 1-butyryloxyethyl , 3-acetyloxy- propyl, 4-acetyloxybutyl , 4-isobutyryloxybutyl, 5- pentanoyloxypentyl , 6-acetyloxyhexyl , 6-tert-butyl- carbonyloxyhexyl , 1 , l-dimethyl-2-hexanoyloxyethyl , 2-methyl-3-acetyloxypropyl groups and the like. Examples of a lower alkylsulfonyloxy-lower alkyl group is a straight chain- or branched chain- lower alkyl group having 1 to 6 carbon atoms which is substituted with a straight chain- or branched chain- alkylsulfonyloxy group having 1 to 6 carbon atoms, such as methylsulfonyloxymethyl, 1-ethylsulfonyloxy- ethyl, 2-propylsulfonyloxyethyl, 3-isopropylsulfonyl- oxypropyl, 4-butylsulfonyloxybutyl , 5-pentylsulfonyl- oxypentyl, 6-hexylsulfonyloxyhexyl, 1 , l-dimethyl-2- methylsulfonyloxyethyl , 2-methyl-3-ethylsulfonyloxy- propyl groups and the like .

Examples of a lower alkenyloxy-lower alkyl group is a straight chain- or branched chain-alkyl group having 1 to 6 carbon atoms which is substituted with a straight chain- or branched chain-alkenyloxy group having 2 to 6 carbon atoms, such as vinyloxymethyl , 2- allyloxyethyl, 1- ( 2-butenyloxy) ethyl , 3- ( 3-butenyloxy )- propyl, 4-( 1-methylallyloxy)butyl, 5-( 2-pentenyloxy) - pentyl, 6- ( 2-hexenyloxy) hexyl , ( 1-propenyloxy)methyl , 1 , l-dimethyl-2-( 1-propenyloxy) ethyl, 2-methyl-3- allyloxypropyl groups and the like.

The carbostyril derivative of the general formula ( 1 ) of the present invention involving various derivatives as shown below. In the following embodi- ments, the symbol A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are all the same as defined in the general formula (1). (1) A carbostyril derivative (1) or a salt thereof, wherein f. is 0; R¹ is a lower alkyl group which may have hydroxyl groups; and R² is a hydrogen atom.

(2) A carbostyril derivative (1) or a salt thereof, wherein __ is 0; R¹ is a lower alkanoyloxy-lower alkyl group; and R² is a hydrogen atom.

(3) A carbostyril derivative (1) or a salt thereof, wherein _£_ is 0; R¹ is a lower alkylsulfonyloxy-lower alkyl group; and R² is a hydrogen atom.

(4) A carbostyril derivative (1) or a salt thereof, wherein _ is 0; R¹ is a lower alkenyloxy-lower alkyl group; and R² is a hydrogen atom.

(5) A carbostyril derivative (1) or a salt thereof, wherein __ is 0; R¹ is a group of the formula,

[wherein R_{l r} R³, R^A , R⁵ and R⁶ are the same as defined in the above-mentioned general formula ( 1 ) ] ; and R² is a hydrogen atom.

(6) A carbostyril derivative (1) or a salt thereof, wherein £ is 0; R¹ is a lower alkyl group which may have hydroxyl group; and R² is a hydroxyl group.

(7) A carbostyril derivative (1) or a salt thereof, wherein |_ is 0; R¹ is a lower alkanoyloxy-lower alkyl group; and R² is a hydroxyl group. (8) A carbostyril derivative (1) or a salt thereof, wherein __ is 0; R^! is a lower alkylsulfonyloxy-lower alkyl group; and R² is a hydroxyl group.

(9) A carbostyril derivative (1) or a salt thereof, wherein _ is 0; R¹ is a lower alkenyloxy-lower alkyl group; and R² is a hydroxyl group.

(10) A carbostyril derivative (1) or a salt thereof, wherein t_ is 0; R¹ is a group of the formula,

[wherein _γ , R³ , R⁴ , R⁵ and R⁶ are the same as defined in the above-mentioned general formula ( 1 ) ] ; and R² is a hydroxyl group.

(11) A carbostyril derivative (1) or a salt thereof, wherein _£_ is 1; R¹ is a lower alkyl group which may have hydroxyl groups; and R² is a hydrogen atom.

(12) A carbostyril derivative (1) or a salt thereof, wherein £_ is 1; R¹ is a lower alkanoyloxy-lower alkyl group; and R² is a hydrogen atom.

(13) A carbostyril derivative (1) or a salt thereof, wherein t_ is 1; R¹ is a lower alkylsulfonyloxy-lower alkyl group; and R² is a hydrogen atom.

(14) A carbostyril derivative (1) or a salt thereof, wherein _ is 1; R^! is a lower alkenyloxy-lower alkyl group; and R² is a hydrogen atom.

(15) A carbostyril derivative (1) or a salt thereof, wherein As 1; R¹ is a group of the formula,

[wherein A,, R³, R* , R⁵ and R⁶ are the same as defined in the above-mentioned general formula ( 1 ) ] ; and R² is a hydrogen atom.

(16) A carbostyril derivative (1) or a salt thereof, wherein __ is 1; R¹ is a lower alkyl group which may have hydroxyl group; and R² is a hydroxyl group. (17) A carbostyril derivative (1) or a salt thereof, wherein _ is 1; R¹ is a lower alkanoyloxy-lower alkyl group; and R² is a hydroxyl group.

(18) A carbostyril derivative (1) or a salt thereof, wherein _£_ is 1; R¹ is a lower alkylsulfonyloxy-lower alkyl group; and R² is a hydroxyl group.

(19) A carbostyril derivative (1) or a salt thereof, wherein |_ is 1; R¹ is a lower alkenyloxy-lower alkyl group; and R² is a hydroxyl group.

(20) A carbostyril derivative (1) or a salt thereof, wherein i_ is 1; R¹ is a group of the formula,

[wherein A_{i r} R³, R , R⁵ and R⁶ are the same as defined in the above-mentioned general formula (1)]; and R² is a hydroxyl group .

(21) A carbostyril derivative (1) or a salt thereof, wherein _ is 2; R¹ is a lower alkyl group which may have hydroxyl groups; and R² is a hydrogen atom.

(22) A carbostyril derivative (1) or a salt thereof, wherein _ is 2; R¹ is a lower alkanoyloxy-lower alkyl group; and R² is a hydrogen atom.

(23) A carbostyril derivative (1) or a salt thereof, wherein _ is 2; R¹ is a lower alkylsulfonyloxy-lower alkyl group; and R² is a hydrogen atom.

(24) A carbostyril derivative (1) or a salt thereof, wherein _P_ is 2; R¹ is a lower alkenyloxy-lower alkyl group; and R² is a hydrogen atom.

(25) A carbostyril derivative (1) or a salt thereof, wherein C_ is 2; R¹ is a group of the formula,

[wherein A_! , R³, R^ή , R⁵ and R⁶ are the same as defined in the above-mentioned general formula (1)]; and R² is a hydroxyl group .

(26) A carbostyril derivative (1) or a salt thereof, wherein is 2; R¹ is a lower alkyl group which may have hydroxyl group; and R² is a hydroxyl group.

(27) A carbostyril derivative (1) or a salt thereof, wherein £ is 2; R¹ is a lower alkanoyloxy-lower alkyl group; and R² is a hydroxyl group.

(28) A carbostyril derivative (1) or a salt thereof, wherein JJ_ is 2; R¹ is a lower alkylsulfonyloxy-lower alkyl group; and R² is a hydroxyl group.

(29) A carbostyril derivative (1) or a salt thereof, wherein _£_ is 2; R¹ is a lower alkenyloxy-lower alkyl group; and R² is a hydroxyl group.

(30) A carbostyril derivative (1) or a salt thereof, wherein |_ is 2; R¹ is a group of the formula,

[wherein A,, R³, R , R³ and R⁶ are the same as defined in the above-mentioned general formula ( 1 ) ] ; and R² is a hydroxyl group.

( 31 ) 3 , 4-Dihydro-6-{3-[ 1- ( 2-hydroxymethylphenyl ) -2- ) imidazolyl ] sulfinylpropoxy}-2 ( IH) -quinolinone .

(32) (S)-(+ -3,4-Dihydro-6-{3-[l-(2-hydroxymethyl- phenyl -2-imidazolyl]sulfinylpropoxy}-2 ( 1H)- quinolinone.

(33) (R)-(- ι-3 ,4-Dihydro-6-{3-[ l-( 2-hydroxymethyl- phenyl -2-imidazolyl ] sulfinylpropoxy}-2 ( IH) - quinolinone.

( 34 ) 6-{ 3- [ 1- ( 2-Hydroxymethylphenyl ) -2-imidazolyl ] - sulfonylpropoxy}-2 ( IH) -quinolinone .

(35) 6-{3-[l-( 2-Hydroxymethylphenyl ) -2-imidazolyl ] - sulfinylpropoxy}-2 ( IH) -quinolinone .

(36) (S)-(+)-6-{3-[l-(2-Hydroxymethylphenyl)-2- imidazolyl ] sulfinylpropoxy}-2 ( IH ) -quinolinone .

(37) (R)-(-)_6-{3-[l-( 2-Hydroxymethylphenyl ) -2- imidazolyl ] sulfinylpropoxy}-2 ( IH) -quinolinone . (38) 3,4-Dihydro-4-hydroxy-6-{3-[l-(2-hydroxymethyl- phenyl )-2-imidazolyl ] sulfinylpropoxy}-2 ( IH) - quinolinone. ( 39 ) 3 , 4-Dihydro-3-hydroxy-6-{3- [ 1- ( 2-hydroxymethyl- phenyl ) -2-imidazolyl ] sulfonylpropoxy}-2 ( 1H)- quinolinone.

The carbostyril derivative represented by the general formula ( 1 ) of the present invention and intermediates therefor are prepared by various methods as shown in Reaction formula-1 through -14 as follows.

Reaction formula-1

(la

[wherein R¹ , R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined above; X is a halogen atom, a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group] .

As to the lower alkanesulfonyloxy group shown by X, concretely methanesulfonyloxy, ethanesulfonyloxy , propanesulfonyloxy, isopropanesulfonyloxy , butane- sulfonyloxy, tert-butanesulfonyloxy, pentanesulfonyloxy and hexanesulfonyloxy groups, etc. can be exemplified. As to the arylsulfonyloxy group shown by X, concretely phenylsulfonyloxy , 4-methylphenylsulfonyloxy, 2-methyl- phenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxy- phenylsulfonyloxy, 3-chlorophenylsulfonyloxy and - naphthylsulfonyloxy groups, etc. can be exemplified. As to the aralkylsulfonyloxy group shown by X, concretely benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy and ct-naphthylmethylsulfonyloxy groups, etc. can be exemplified. As to the halogen atom shown by X, concretely fluorine atom, chlorine atom, bromine atom and iodine atom can be exemplified.

The reaction of a compound of the general formula (2) with a compound of the general formula (3) can be carried out in the presence or absence of a suitable solvent and in the presence of a basic compound. As to the basic compound, those of widely known basic compounds can be used, thus inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, silver carbonate and the like; alkali metals such as metallic sodium, metallic potassium and the like; alcoholates such as sodium methylate, sodium ethylate, potassium t_-butoxide and the like; and organic basic compound such as triethylamine, pyridine, N , N-dimethylamine , N-methyl- morpholine, 4-dimethylaminopyridine, 1 , 5-diazabicyclo- [4.3.0]non-5-ene (DBN), 1 , 8-diazabicyclo[ 5.4.0 ]undec-7- ene (DBU), 1 , 4-diazabicyclo[ 2.2.2 ] octane (DABCO) and the like can be exemplified. As to the solvent, inert solvents which do not give adverse effects can be used, thus alcohols such as methanol, ethanol, propanol, isopropanol, butanol, ethylene glycol and the like; ethers such as diethyl ether, tetrahydrofuran, dioxane, monoglyme, diglyme and the like; ketones such as acetone, methyl ethyl ketone and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; esters such as methyl acetate, ethyl acetate and the like; aprotic polar solvents such as acetonitrile, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA) and the like can be exemplified. This reaction may also be carried out in the presence of a metal iodide such as sodium iodide, potassium iodide and the like. In the above-mentioned reaction, ratio of used amounts of a compound (2) to a compound (3) is not specifically restricted and can be selected from a wide range, and generally an equimolar quantity to 5 times the molar quantity, preferably an equimolar quantity to 3 times the molar quantity of the latter may be used to the former. Reaction temperature of the above-mentioned reaction is not specifically restricted, generally the reaction is carried out at room temperature to about 200°C, preferably at 50° to about 150 °C, and generally the reaction is finished in about 5 minutes to 30 hours. Reaction formula-2

[wherein R¹ , R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined above] .

The reaction of introducing a compound ( la ) to a compound (lb) is carried out in the presence of an oxidizing agent in a suitable solvent. As to the oxidizing agent used in this reaction, any oxidizing agent known in the art, which is capable to oxidize sulfide group to sulfoxide group, can be used, thus peracids such as performic acid, peracetic acid, pertrifluoroacetic acid, perbenzoic acid, m-chloro- perbenzoic acid, _-carbonylperbonzoic acid and the like; hydrogen peroxide; combinations of an alkylhydroperoxide such as _t-butylhydroperoxide , cumenehydroperoxide and the like with a titanium tetraalkoxide such as titanium tetraisopropoxide and the like; bichromic acid; bichromates such as sodium bichromate, potassium bichromate and the like; permanganic acid; permanganates such as sodium permanganate, potassium permanganate and the like can be exemplified. As to the solvent, water; organic acids such as formic acid, acetic acid, trifluoroacetic acid and the like; alcohols such as methanol, ethanol and the like; halogenated hydrocarbon such as chloro- form, dichloroethane, dichloromethane and the like; and mixtures of these solvents can be exemplified.

The above-mentioned reaction is generally proceeded at -20 to 40°C, preferably at -20°C to about room temperature, and generally finished in about 5 minutes to 70 hours. Used amount of the oxidizing agent is generally at least an equimolar quantity, preferably an equimolar to 1.5 times the molar quantity to a compound (la). In case of using alkylhydroperoxide and titanium tetraalkoxide as the oxidizing agent, preferably an equimolar to 5 times the molar quantity may be used.

In the above-mentioned reaction, an optically active compound (lb) can be obtained in high yield and high purity by adding into the reaction system an agent of asymetric induction such as an optically active dialkyl tartarate such as D- (-) -diethyl tartarate, L- (+) -diethyl tartarate and the like; naphthols for example binaphthol and the like. An optically active compound (lb) having higher purity can be introduced by subjecting the thus obtained optically active compound (lb) to usual method of recrystallization repeatedly. Used amount of the agent of asymetric induction may be an equimolar to 5 times the molar quantity to a compound (la). As to the oxidizing agent to be used for preparing the optically active compound (lb), a combination of an alkylhydroperoxide with a titanium tetraalkoxide is preferable. Furthermore, in case of using said oxidizing agent, the reaction is carried out advantageously by adding molecular sieves or 0.1 to 1 equivalent amount of water to a compound ( la ) .

Oxidation reaction for introducing a compound (la) to a compound (lc) is carried out under conditions similar to the oxidation reaction for introducing a compound (la) to a compound (lb), except that at least 2 times the molar quantity, preferably 2 to 4 times the molar quantity of the oxidizing agent to a compound (la) is used. Oxidation reaction for introducing a compound

(lb) to a compound (lc) is carried out under condition similar to the oxidation reaction for introducing a compound (la) to a compound (lb). Reaction formula-3

[wherein R², A, f_, A_! and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined above; R ^a is a lower alkyl group, R , R and R are the same or different, and are lower alkanoyl groups; and X_: is a halogen atom]. The reaction of a compound (Id) with a compound (4) is carried out in a suitable solvent and in the presence of a dehydrating agent such as a molecular sieves, and a protonic acid such as trifluoromethane- sulfonic acid, and the like or a lewis acid such as trimethylsilyl trifluoromethanesulfonate, and the like.

As to the solvent to be used in this reaction, examples are halogenated hydrocarbon such as chloroform, dichloromethane, dichloroethane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; aprotic polar solvents such as N,N-dimethyl- formamide (DMF), dimethyl sulfoxide (DMSO), hexamethyl- phosphoric triamide (HMPA) and the like; and mixtures of these solvents. This reaction is carried out at -30 to 50°C, preferably at -30°C to about room temperature, and generally finished in about 1 to 30 hours. A compound (4) may be used in an amount of at least an equimolar quantity, preferably an equimolar to 1.5 times the molar quantity to a compound (Id). The reaction for introducing a compound (le) to a compounds (If) can be carried out in a suitable solvent or without a solvent and in the presence of a basic compound. As to the solvent to be used in this reaction, examples are water; lower alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone and the like; and ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and the like. As to the basic compounds, examples are metal carbonates such as sodium carbonate, potassium carbonate and the like; metal hydroxide such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. The reaction is carried out generally at 0 to 60°C, preferably at 0°C to about room temperature, and is finished generally in 10 minutes to 80 hours.

Reaction formula-4

[wherein R¹, A and t_ are the same as defined above; R⁷ is a lower alkyl group] .

The reaction of a compound (5) with a compound ( 6 ) is carried out in a suitable solvent and in the presence of a basic compound. As to the basic compound examples are carbonates such as sodium carbonate, potassium carbonate and the like; hydrogen carbonates such as sodium hydrogen carbonate; metal hydroxide such as sodium hydroxide; sodium amide; sodium hydride; metal alcoholates such as sodium methylate, sodium ethylate, potassium t_-butoxide and the like; organic basic compound such as triethylamine, tripropylamine, piperidine, pyridine, quinoline, organic basic compounds of lithium or lithium amide such as lithium diisopropylamide, lithium 1 , 1 , 1 , 3 , 3 , 3-hexamethyldisilazane and the like. As to the solvents, examples are aromatic hydrocarbons such as benzene, toluene, xylene and the like; esters such as ethyl acetate, methyl acetate and the like; lower alcohols such as methanol, ethanol, isopropanol and the like; ethers such as dioxane, tetrahydrofuran

(THF), ethylene glycol dimethyl ether, diethyl ether and the like, polar solvents such as pyridine, N-methylpyr- rolidone, N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), hexamethylphosphoric triamide (HMPA) and the like; and mixtures of these solvents. A compound (6) may be used in an amount of generally at least an equimolar quantity, preferably 2 to 7 times the molar quantity to a compound (5). The reaction is carried out generally at -80 to 200°C, preferably at -80 to 150°C, and is finished in about 1 to 10 hours.

A compound (lg) is introduced by treating a compound (7) in a suitable solvent, in the presence of a reducing agent. Examples of solvents are water; alcohols such as methanol, ethanol, isopropanol and the like; hydrocarbons such as hexane, cyclohexane and the like; ethers such as diethylene glycol dimethyl ether, dioxane, tetrahydrofuran (THF), diethyl ether and the like; esters such as ethyl acetate, methyl acetate and the like; and mixtures of these solvents. Examples of reducing agents are ammonium salts such as ferrous sulfate-ammonium hydroxide, zinc-ammonium chloride, zinc-ammonium acetate, and the like. The reducing agent may be used generally in an excessively large amount. The reaction is carried out generally at 0° to 150°C, preferably 0° to 100°C, and is finished in about 5 minutes to 10 hours.

Reaction formula-5

( lh ) ( l i [wherein R², A, _C_ and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined above].

The reaction for introducing a compound (lh) to a compound (li) is carried out in a suitable solvent, and in the presence of an acid. As to the solvents to be used in this reaction, any solvent used in the reaction for introducing a compound (la) to a compound (lb) in above-mentioned Reaction formula-2 can also be used. As to the acid to be used in this reaction, mineral acids such as hydrochloric acid, sulfuric acid hydrobromic acid can be exemplified. This reaction is carried out generally at 0 to 150 °C, preferably at about 0 to 100°C, and is finished in about 1 to 15 hours.

Reaction formula-β

[wherein A, A, and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined above].

The reaction for introducing a compound (lj) to a compound (Ik) and a compound (If) is carried out in a suitable solvent or without solvent, and in the presence of lipase by adding vinyl acetate (8) to a compound ( 1 j ) .

As to the solvent to be used in this reaction, examples are aliphatic hydrocarbons such as cyclohexane, ri-hexane and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as diethyl ether, diisopropyl ether, dioxane, tetrahydro- furan and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and the like; esters such as methyl acetate, ethyl acetate and the like; acetonitrile and the like; and mixtures of these solvents .

As to the lipase to be used in this reaction, any one of upases obtained from various biological sources for example animals, yeasts, fungi, bacteria and the like can be used. Further, various commercial products of lipase can also be used. Examples of commercial products of lipase are Lipase QL (mfd. by Meito Sangyo Co., Ltd., a lipase prepared from a bacillus belonging to Alcaliσenes sp. ); Lipase AL (mfd. by Meito Sangyo Co., Ltd., a lipase prepared from a fungus belonging to Achromobacter sp.1 ; Lipase PL (mfd. by Meito Sangyo Co., Ltd., a lipase prepared from a bacillus belonging to Alcaliqenes sp. caligenes sp.); Lipase QLG (mfd. by Meito Sangyo Co., Ltd., a lipase prepared from a bacillus belonging to Alcaliqenes sp. ) ; Lipase OF (mfd. by Meito Sangyo Co., Ltd., a lipase prepared from a fungus belonging to Candida cylindracea ) ; Lipozyme IM (mfd. by Novo Nordisk Bioindustry, A/S; a lipase prepared from a fungus belonging to Mucor miehei ) ; Novozym 435, SP523, SP524, SP525, SP526 (mfd. by Novo Nordisk Bioindustry, A/S; upases prepared from fungi belonging to Asperqillus oryzael ; Subtilisin A (mfd. by Novo Nordisk A/S; a lipase prepared from a bacillus belonging to Bacillus licheniformis ) ; Toyozyme LIP (mfd. by Toyobo Co., Ltd.); PPL (mfd. by Sigma Chemical Co., Ltd.; a lipase prepared from a Porcine Pancreas); CCL (mfd. by Sigma Chemical Co., Ltd.; a lipase prepared from a fungus belonging to Candida cylindracea ) ; and Nacalai Lipase (mfd. by Nacalai Co., Ltd.: a lipase prepared from a bacillus belonging to Pseudomonas fluorescens . Among these commercial products of lipase, Novozym 435 is the most preferable. Amount of lipase used in this reaction is not specifically restricted, the amount can be selected from a wide range, generally, an equivalent amount to 1.5 times the amount of lipase, and preferably, an equivalent amount of lipase may be used to a compound

(lj)-

In the above-mentioned reaction, an amount of vinyl acetate (8) is not specifically restricted, generally an excessively large amount thereof may be used to a compound (lj). This reaction is generally carried out at 0°C to about 60°C, preferably at 0°C to about 50 °C, and finished in about 1 to 100 hours.

In the above-mentioned reaction, a compound (Ik) is also formed at the same time, however, this compound (Ik) and a compound ( li ) can be obtained separately by a usual method of separation such as a column chromatography, a preparative thin layer chromatography and the like.

The reaction for introducing a compound (Ik) to a compound (lm) is carried out in a suitable solvent or without solvent, and in the presence of an acid or basic compound. As to the solvent to be used, examples are water, alcohols such as methanol, ethanol, isopropanol and the like; ketones such as acetone, methyl ethyl ketone and the like; ethers such as diethyl ether, dioxane, tetrahydrofuran, ethylene glycol dimethyl ether and the like; fatty acids such as formic acid, acetic acid and the like; and mixtures of these solvents. As to the acid, examples are mineral acids such as hydrochloric acid, sulfuric acid, hydrobromic acid and the like; organic acids such as formic acid acetic acid, aromatic sulfonic acids and the like. As to the basic compounds , examples are metal carbonates such as sodium carbonate, potassium carbonate and the like; metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and the like. The reaction is carried out generally at 0°C to about 200°C, preferably at 0°C to about 150°C, and generally finished in about 0.05 to 25 hours.

By applying the above-mentioned reaction, optically active compounds of the general formulas (1.) and (lm) of the present invention, having high purities can be obtained in high yield.

Reaction foπτmla-7

[wherein R², A, χ_, A,, X, and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined above; R⁸ is a lower alkylsulfonyl group; and R⁹ is a lower alkyl group] .

In the above-mentioned reaction, optically active compounds (In) and (lo) having high purity can be obtained in high yield by using an optically active compound (Id). The optically active compound (In) is useful as an intermediate for introducing an optically active compound having the general formula,

[wherein R⁹ and A are the same as defined the above], which is known as useful platelet adhesion inhibitor.

The reaction of a compound (Id) with a compound (9) is carried out generally in an inert solvent in the presence or absence of a basic compound,

Examples of the solvent to be used in this reaction are, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethylene glycol dimethyl ether and the like; halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride and the like; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert-butanol and the like; acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethyl sulfoxide, N,N-dimethylformamide, hexamethylphosphoric triamide; and mixtures of these solvents and the like. Examples of the basic compounds are carbonates such as sodium carbonate, potassium hydrogencarbonate, potassium carbonate, sodium hydrogencarbonate and the like, metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; sodium hydride, metallic potassium, metallic sodium, sodium amide; metal alcoholates such as sodium methylate, sodium ethylate and the like; organic basic compounds such as pyridine, N-ethyldiisopropyl- a ine, dimethylaminopyridine , triethylamine, 1,5- diazabicyclo[4.3.0]non-5-ene (DBN), 1 , 8-diazabicyclo- [5.4.0]undec-7-ene (DBU), l,4-diazabicyclo[2.2.2]octane (DABCO) and the like.

Ratio of amounts of a compound (Id) and a compound (9) is not specifically restricted and can be selected from a wide range, generally at least an equimolar quantity, preferably an equimolar to 10 times the molar quantity of the latter may be used to the former. The reaction is generally carried out at about 0 to 200°C, preferably at about 0 to 170°C, and is finished in about 30 minutes to 30 hours. Into the reaction system, an alkali metal halide such as sodium iodide, potassium iodide and the like may be added . The reaction for introducing a compound (In) to a compound (lo) is carries out in a suitable solvent and in the presence of a hydrogenation reducing agent.

Examples of the solvent used in this reaction are halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; ethers such as tetrahydrofuran, diethyl ether, diisopropyl ether, diglyme and the like; and alcohols such as methanol, ethanol, isopropanol and the like. As to the hydrogenation reducing agent, lithium trialkylborohydride, such as lithium triethyl- borohydride, lithium tri-s-butylborohydride, lithium t-butylborohydride and the like can be exemplified. Amount of the hydrogenation reducing agent, at least an equimolar quantity, preferably an equimolar to 3 times the molar quantity may be used to a compound (In).

The reaction is carried out generally at -20°C to 150°C, preferably at 0° to about 100°C, and is finished in about 5 to 10 hours. Reaction formula-

(1)

[wherein R¹ , R², A, __ and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined the above; R¹⁰ is a hydrogen atom or an alkali metal such as sodium or potassium] .

The reaction of a compound (10) with a compound (11) is carried out under condition similar to that of the reaction of a compound (2) with a compound (3) in the above-mentioned Reaction formula-1, except that amount of compound (10) is used generally in an equimolar quantity to about 5 times the molar quantity, preferably an equimolar quantity to 2 times the molar quantity to a compound (11).

Compounds (3), (5), (10) and (11) which are used for the starting materials in the above-mentioned Reaction formulas-1, -4, and -8 are prepared by the following methods . Reaction formula-9

(12) (13)

[wherein R¹ is the same as defined the above; R^u and R¹² are the same or different and are lower alkyl groups] .

The reaction for introducing compound (12) to compound (13) can be carried out by method (a): in which compound (12) is reacted with thiophosgen in a suitable solvent, or by method (b): in which compound (12) is reacted with carbon disulfide in a suitable solvent and in the presence of a basic compound, then further reacting in the suitable solvent in the presence of a dehydrating agent such as dicyclohexylcarbodiimide , carbonyldiimidazole or the like.

As to the solvent used in method (a), any solvent which does not give adverse effect to the reaction can be used. Examples of the solvents are, alcohols such as ethanol, methanol, isopropanol and the like; halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride and the like; aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as dioxane, diethylene glycol dimethyl ether, diethyl ether, tetrahydrofuran and the like; and polar solvents such as dimethyl sulfoxide, hexamethylphosphoric triamide and the like. The reaction is generally carried out at room temperature to 150°C, preferably at room temperature to about 100°C, and is finished in 1 hour to about 10 hours. Amount of thiophosgen used may be at least an equimolar quantity, preferably an equimolar to 3 times the molar quantity to compound (12).

As to the solvent used in method (b), in addition to the solvents used in the above method (a), pyridine etc. can also be used. As to the basic compound used in this reaction, examples are inorganic basic compounds such as sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, potassium carbonate, sodium methoxide, sodium ethoxide, sodium hydride, metallic sodium, metallic potassium, sodium amide and the like; organic basic compounds such as N,N-dimethylaniline, piperidine, pyridine, triethylamine , sodium acetate, potassium acetate and the like. Reaction is carried out generally at -30°C to 100°C, preferably at -30°C to 70 °C, and is finished in 1 hour to about 15 hours. Amount of carbon disulfide used may be generally in an equimolar quantity to 20 times the molar quantity, preferably an equimolar quantity to 10 times the molar quantity to a compound (12).

As to the solvent used in the subsequent reaction with a dehydrating agent, any one of the solvents used in the above-mentioned reaction of compound (12) with carbon disulfide can also be used.

Said reaction is carried out generally at 0°C to 100°C, preferably at 0°C to 70°C, , and is generally finished in 1 hour to about 20 hours. Amount of the dehydrating agent used may be at least an equimolar quantity, preferably an equimolar to 2 times the molar quantity to a compound ( 12) .

Reaction of compound (13) with compound (14) is carried out in a suitable solvent or without solvent. As to the solvent used in this reaction, any one of the solvents as disclosed in the above-mentioned method (a) for introducing compound (12) to compound (13) can be used. Said reaction is carried out generally at 0°C to 200°C, preferably at 0°C to about 150°C, and is finished generally in 5 minutes to about 5 hours. Amount of compound (14) used may be at least an equimolar quantity, preferably about an equimolar quantity to 2 times the molar quantity to a compound (13).

Reaction for removal of alcohol is carried out in a suitable solvent or without solvent and in the presence of a mineral acid such as hydrochloric acid, sulfuric acid and the like, at room temperature to 150°C, preferably at room temperature to about 100°C and is finished in about 10 minutes to about 10 hours. Examples of the solvents are water; alcohols such as methanol, ethanol, isopropanol and the like; ethers such as diethyl ether, tetrahydrofuran and the like; and mixtures of these solvents .

^Reaction formula-10

19) (20) (21)

[wherein R¹ , A, X and X, are the same as defined the above; R³ is a lower alkoxy-lower alkoxy-lower alkyl group] .

Reaction formula-11

117) (lla)

20) (lib;

,21) (lie) [wherein R¹, A and X are the same as defined the above].

In the above-mentioned Reaction formula-10, the lower alkoxy-lower alkoxy-lower alkyl group is an alkoxyalkoxyalkyl group in which the alkoxy moiety is a straight chain- or branched chain-alkoxy group having 1 to 6 carbon atoms, and the alkyl moiety is a straight chain- or branched chain-alkyl group having 1 to 6 carbon atoms, for examples are ( 2-methoxyethoxy)- methyl , 3-methoxymethoxypropyl , ( 1-ethoxyethoxy)methyl , 3- ( 3-ethoxypropoxy)propyl, 4-( 4-ethoxybutoxy)butyl ,

5- ( 5-isopropoxypentyloxy)pentyl , 6- ( 6-propoxyhexyloxy) - hexyl, 1 , l-dimethyl-2- ( 2-butoxyethoxy) ethyl, 2-methyl-3- ( 3-tert-butoxypropoxy) propyl . 2-( 2-pentyloxyethoxy)- ethyl, hexyloxymethoxymethyl groups and the like. Reaction of compound (3) with compound (16) and the reaction of compound (3) with compound (16a) are carried out under the condition similar to that of used in the reaction of compound (2) with compound (3) in the above-mentioned Reaction formula-1. Reaction for introducing compound (17) to compound (20) and reaction for introducing compound (19) to compound (22) are carried out under the condition similar to that of the reaction for introducing compound (la) to compound (lb) in the above-mentioned Reaction formula-2.

Reaction for introducing compound (20) to compound (21) and reaction for introducing compound (22) to compound (23) are carried out under the condition similar to that of used in reaction for introducing compound (lb) to compound (lc) in the above-mentioned Reaction formula-2.

Reaction for introducing compound (19) to compound (23) and reaction for introducing compound (17) to compound (21) are carried out under the condition similar to that of used in reaction for introducing compound (la) to compound (lc) in the above-mentioned Reaction formula-2. Reaction for introducing compound (17) to compound (11a), reaction for introducing compound (21) to compound (lie) and reaction for introducing compound (20) to compound (lib) are carried out as follows. For example, when X in the general formula of compound (11a), (lib) or (lie) is a halogen atom, then reaction is carried out in the presence of a halogenating agent and in a suitable solvent or without solvent. As to the halogenating agent, examples are hydrogen halides such as hydrochloric acid, hydrobromic acid and the like; N,N-diethyl-l , 2, 2-trichlorovinylamide, phosphorus pentachloride, phosphorus pentabromide, phosphorus oxychloride, thionyl chloride and the like. Amount of the halogenating agent used may be at least an equimolar quantity, generally a large excess quantity to compound (17), (20) or (21). As to the solvent, examples are ethers such as dioxane, tetrahydrofuran, diethyl ether and the like; and halogenated hydrocarbons such as chloroform, methylene chloride, carbon tetra- chloride and the like. The above-mentioned reaction is carried out generally at -20 to 150°C, preferably -20 to 80°C, and is finished generally in 10 minutes to about 6 hours . When X in the general formula of compound

(11a), (lib) or (lie) is a lower alkanesulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group, then compound (17), (20) or (21) is reacted with a compound represented by a formula R¹X₂ (24) (wherein R is a lower alkanesulfonyl group, an arylsulfonyl group or an aralkylsulfonyl group; X₂ is a halogen atom or an arylsulfonyloxy group) in a suitable solvent and in the presence of a basic compound. As to the solvent and basic compound used in this reaction, any one of the solvents and basic compounds shown in the reaction of compound (2) with compound (3) in Reaction formula-1 can be also used. This reaction is carried out generally at 0°C to 200°C, preferably at 0°C to about 100°C, and is finished generally in 5 minutes to about 10 hours. Amount of compound (24) used may be at least an equimolar quantity, preferably an equimolar to 2 times the molar quantity to compound (17), (20) or (21).

The reaction of compound (17) with compound (18), reaction of compound (20) with compound (18) and reaction of compound (21) with (18) are generally carried out in a suitable inert solvent in the presence or absence of a basic compound.

As to the inert solvent used in this reaction, aromatic hydrocarbons such as benzene, toluene, xylene and the like; ethers such as tetrahydrofuran, dioxane, diethylene glycol dimethyl ether and the like; halogenated hydrocarbons such as dichloromethane, chloro- form, carbon tetrachloride and the like; lower alcohols such as methanol, ethanol, isopropanol, butanol, tert- butanol and the like; acetic acid, ethyl acetate, acetone, acetonitrile, pyridine, dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide and the like; and mixtures of these solvents can be exemplified. As to the basic compound, for examples, metal carbonates such as sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate and the like; metal hydroxides such as sodium hydroxide, potassium hydroxide and the like; sodium hydride, metallic potassium, metallic sodium, sodium amide, metal alcoholates such as sodium methylate, sodium ethylate and the like; organic basic compounds such as pyridine, N-ethyldiisopropylamine , dimethylaminopyridine , triethylamine, 1 , 5-diazabicyclo[ 4.3.0 ]non-5-ene (DBN), l,8-diazabicyclo[5.4.0 ]undec-7-ene (DBU), 1,4- diazabicyclof 2.2.2]octane (DABCO) and the like can be exemplified.

Ratio of used amounts of compound (17), (20) or (21) to compound (18) is not specifically restricted and may be selected from a wide range, and at least an equimolar quantity, preferably an equimolar to 10 times the molar quantity of the latter may be used to the former. The reaction is generally carried out at 0°C to about 200°C, preferably at 0°C to about 170°C, and is finished generally in 30 minutes to about 30 hours. Into the reaction system, alkali metal halogenide such as sodium iodide or potassium iodide may be added. When compound (20) is an optically active compound, then optically active compounds (22) and (lib) can be introduced by reacting similar to the above.

Reaction formula-12

H₃

( 20c ) [wherein A is the same as the above; R ^a is a lower alkyl group, a lower alkanoyloxy-lower alkyl group, a lower alkylsulfonyloxy-lower alkyl group or a lower alkenyloxy-lower alkyl group] . The reactions for introducing compound (20a) to compounds (25) and (20b) are carried out under the conditions similar to those of used in the reactions for introducing compound (lj) to compounds (Ik) and (It) in the above-mentioned Reaction formula-6. As to the lipase used in this reaction, Lipase AL and Lipase PL are particularly preferable among commercially available products of lipase.

The reaction for introducing compound (25) to compound (20c) is carried out under the condition similar to that of used in the reaction for introducing compound (Ik) to compound (lm) in Reaction formula-6.

Reaction formula-13

(22a)

(26) (22b)

22e) (22c (22d [wherein A, A_y and R¹³ are the same as defined the above] .

The reactions for introducing compound (22a) to compounds (26) and (22b) are carried out under the conditions similar to those of used in the reactions for introducing compound (lj) to compound (Ik) and (If) in Reaction formula-6. As to the lipase used in this reaction, Novozym 435 is particularly preferable among commercially available products of lipase. Reaction for introducing compound (26) to compound (22c) is carried out under the condition similar to that of used in the reaction for introducing compound (Ik) to compound (lm) in the above-mentioned Reaction formula-6. Reactions for introducing compound (22b) or

(22c) to compound (22d) or (22e) are carried out in a suitable solvent, and in the presence of a Lewis acid. As to the solvent used in the reaction, any one of the solvents used in the reaction for introducing compound (Ik) to compound (lm) in Reaction formula-6 can be used. Additionally, halogenated hydrocarbons such as chloroform, dichloromethane, carbon tetrachloride and the like can be exemplified. As to the Lewis acid, zinc bromide, titanium tetrachloride and the like can be exemplified. This reaction is carried out generally at room temperature to about 200°C, preferably the reaction is advantageously proceeded at room temperature to about 150°C, and is finished generally in about 0.05 to 25 hours. 8/46593

55 Under the condition similar to that of used in the reaction for introducing compound (20) to compound (lib), compounds (20b), (20c), (22d) and (22e) are introduced to compounds (lid), (lie), (llf) and (llg) as shown in the general formulas as follows:

lid' (lie)

(llf (iig)

1 =

[wherein R , A, A, and X are the same as defined the above] . These intermediate of (lid), (lie), (llf) and

(llg) can be introduced to an optically active compound (1) of the present invention having high purity and in high yield by applying the method of Reaction formula-8

Reaction formula-14

(2 (29)

(5a; [wherein X_lf A and R¹ are the same as defined the above; X₃ is a halogen atom] .

Reaction of compound (27) with compound (28) is carried out under the condition similar to that of used in the reaction of compound (17) with compound (18) in Reaction formula-10.

Reaction of compound (29) with compound (3) is carried out under the condition similar to that of used in the reaction of compound ( 2 ) with compound ( 3 ) in Reaction formula-1.

In compound (3) of Reaction formula-9; compounds (5) and (7) of Reaction formula-4; compound (11) of Reaction formula-8; compounds (17), (19), (20), (21), (22) and (23) of Reaction formula-10; and compounds (25), (20b) and (20c) of Reaction formula-12; when R¹ or R is 1-propenyloxymethyl group, then these compounds are introduced to other compounds, wherein the

1 F corresponding R¹ or R is converted into hydroxymethyl group by treating the former starting compounds under the condition similar to that of used in the reaction for introducing compound (lh) to compound (li) in

Reaction formula-5.

In compound (1), compounds (5) and (7) of

Reaction formula-4; compound (11) of Reaction formula-8; compound (3) of Reaction formula-9; compounds (17),

(19), (20), (21), (22) and (23) of Reaction formula-10; and compounds (25), (20b) and (20c) of Reaction formula-12; when R¹ or Rla is an aryloxymethyl group, then these compounds are introduced to other compounds , wherein the corresponding R¹ or R is converted into 1-propenyloxymethyl group by treating the former starting compounds with a basic compound in a suitable solvent. As to the solvent used in this reaction, any one of the solvents used in the reaction of compound (17) with compound (18) in Reaction formula-10 can be also used. As to the basic compound used, metal alcoholates such as potassium tert-butoxide and the like can be exemplified. The reaction is carried out generally at 0°C to 150°C, preferably at 0°C to about 100°C, and is finished in 1 hour to about 15 hours.

In compound (3) of Reaction formula-9, compounds (5) and (7) of Reaction formula-4; compound (11) of Reaction formula-8; compounds (17), (19), (20), (21), (22) and (23) of Reaction formula-10; and compounds (25), (20b) and (20c) of Reaction formula-12; when R¹ or R ^a is a lower alkylsulfonyloxy-lower alkyl group or a lower alkyl group having hydroxyl groups , then these compounds are introduced to other compounds, wherein the corresponding R¹ or R is converted into a lower alkyl group by treating the former starting compounds under the condition similar to that of used in the reaction for introducing compound (In) to compound (lo) in Reaction formula-7. When compounds (3), (5), (7), (11), (17), (19), (20), (21), (22), (23), (25), (20b) and (20c) are optically active compounds, the above-mentioned compounds can be introduced to optically active compounds wherein R¹ is a lower alkyl group.

In compound (3) of Reaction formula-9, compounds (5) and (7) of Reaction formula-4; compound (11) of Reaction formula-8; compounds (17), (19), (20), (21), (22) and (23) of Reaction formula-10; when R¹ is a lower alkyl group having hydroxyl groups, then those compounds are introduced to other compounds, wherein the corresponding R¹ is converted into a lower alkylsulfonyloxy-lower alkyl group by treating the former compounds under the condition similar to that of used in the reaction of compound (Id) with compound (9) in the above-mentioned Reaction formula-7. When compound (3), (5), (7), (11), (17), (19), (20), (21), (22) and (23) are optically active compounds, the corresponding optically active compound, wherein R¹ is a lower alkylsulfonyloxy-lower alkyl group can be obtained.

The objective compounds obtained in each one of the above-mentioned reaction processes can be easily isolated and purified from the reaction systems by means of common separating methods. As to methods for separation and purification, there can be exemplified, solvent extraction, dilution, recrystallization, a column chromatography, preparative thin layer chromatography and the like. Carbostyril derivatives of the present invention inevitably are involving optical isomers and stereo isomers .

A carbostyril derivative represented by the general formula is used generally in the form of pharma- ceutical preparations . The pharmaceutical preparations are generally formulated by using commonly used diluents, such as fillers, bulking agents, binders, wetting agents, disintegrating agents, surface active agents, lubricants and the like; or excipients. The pharmaceutical preparations can be selected from various administration forms in accordance with the therapeutic purposes . As to typical administration forms , there can be exemplified tablets, pills, powders, liquids, suspen- sion, emulsions, granules, capsules, suppositories, injection preparations (liquids, suspensions, etc.) and the like.

In case of shaping the administration unit form into tablets, various carriers which are well-known in this field can be selected from a wide range and used. Examples of the carriers are, excipients such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystallin cellulose, silicic acid and the like; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution; carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and the like; disintegrating agents such as dry starch, sodium alginate, agar powder, laminaran powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium laurylsulfate, monoglycerid of stearic acid, starch, lactose and the like; disintegration inhibitors such as white sugar, stearin, cacao butter, hydrogenated oils and the like; absorption accelerators such as quaternary ammonium salts, sodium laurylsulfate and the like; wetting agents such as glycerin, starch and the like; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid and the like; and lubricants such as refined talc, stearates, boric acid powder, polyethylene glycols and the like. The tablets preparations can be further shaped into tablets coated with usual tablet coating, for example sugar coated tablets, gelatin film coated tablets, tablets coated with enteric coating, tablets coated with film coating, or double layer tablets and multiple layers tablets . In case of shaping the administration unit form into pills, various carriers which are well-known in this field can be selected from a wide range and used. Examples of the carriers are, excipients such as glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and the like; binders such as powdered arabic gum, powdered tragacanth, gelatin, ethanol and the like; and disintegrating agents such as la inaran, agar and the like.

In case of shaping the administration unit form into suppositories, various carriers which are well-known in this field can be selected from a wide range and used. Examples of the carriers are, polyethylene glycols, cacao butter, higher alcohols esters of higher alcohols, gelatin, semi-synthesized glycerides and the like

In case of shaping the administration unit form into injecting preparations, liquid preparations, emulsion preparations and suspension preparations are sterilized, further these preparations may be preferably isotonic to the blood. In case of preparing these liquid preparations and suspension preparations, the all of diluents which are conventionally used in this field can also be used. For example water, lactic acid aqueous solution, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylenesorbitan fatty acid esters can be used. For the purpose to prepare isotonic injection preparations, an adequate amount of sodium chloride, glucose or glycerin may be added to the injection preparations, further, usual dissolving additives, buffering agents, local anesthetics and the like may be added . Moreover, of necessary, coloring agents, preservatives, spices, flavors, sweetening agents and other additive may be added to the pharmaceutical preparations .

In case of shaping the administration unit form into paste, creams and gels, as to diluents, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycols, silicones bentonite and the like can be used. Amount of a carbostyril derivative of the general formula (1) or salt thereof as the effective ingredient to be contained in pharmaceutical preparation of the present invention is not specifically restricted and can be suitably selected from a wide range, generally 1 to 70% by weight of the active ingredient may be contained in the whole composition of pharmaceutical preparation.

Methods for administering the pharmaceutical preparation of the present invention are not specially restricted, they can be administered in accordance with various forms of preparations, age of the patient, distinction of sex and other conditions, the degree of symptom, etc. For example, tablets, pills, liquids, suspensions, emulsions, granules and capsules are administered orally. While, injection preparations are intravenously administered singly or by mixing with common transfusions such as glucose or amino acid solutions, and if necessary, they are singly admini- stered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. Suppositories are administered to the rectum.

Dosage of pharmaceutical preparation of the present invention is suitable selected depend on the usage, age of the patient, difference of sex and other condition, the degree of symptom, etc., generally amount of a carbostyril derivative of the general formula (1) or a salt thereof as the effective ingredient may be about 0.06 to 100 mg/kg of the body weight per day. The pharmaceutical preparation can be administered dividedly in 2 to 4 timed a day.

EXAMPLES The present invention will be explained in detail by illustrating with Preparation examples, Reference examples, Examples and Pharmacological tests as follows.

Preparation example 1 [Preparation of tablets]

Ingredients Amount ( a )

6-{ 3- [ 1- ( 2-Hydroxymethylpheny1 ) -2- imidazolyl ] sulfonylpropoxy}carbostyril (Compound of the present invention) 5 Lactose (Japanese Pharmacopoeia grade) 50 Corn starch (Japanese Pharmacopoeia grade) 25 Crystalline cellulose

(Japanese Pharmacopoeia grade) 25

Methyl cellulose (Japanese Pharmacopoeia grade) 1.5

Magnesium stearate

(Japanese Pharmacopoeia grade) 1.0

The above-mentioned compound of the present invention, lactose, corn starch and crystalline cellulose are thoroughly mixed together, and the mixture is granulated with 5% queous solution of methyl cellulose, then the thus obtained granules are sieved through a sieve of 200 mesh, next the sieved granules are dried carefully, and the dried granules are pounded by means of usual method to prepare 1000 tables.

Preparation example 2

[Preparation of capsules]

Ingredients Amount ( g ) 6-{3-[l-(2-Hydroxyme hylpheny1 ) -2- imidazolyl ] sulfinylpropoxy}-3 , 4- dihydrocarbostyril

(Compound of the present invention) 10

Lactose (Japanese Pharmacopoeia grade) 80 Starch (Japanese Pharmacopoeia grade) 30

Talc (Japanese Pharmacopoeia grade) 5

Magnesium stearate

(Japanese Pharmacopoeia grade) 1

The above-mentioned ingredients are ground to fine powder and agitated thoroughly to make them as a uniform mixture. Then the thus obtained uniform mixture is filed in gelatin capsules for oral administration having desired size to prepare 1,000 capsules. Preparation example 3

[Preparation of injection preparation]

Ingredients Amount ( )

3-Hydroxy-6-{3-[ 1- ( 2-hydroxymethylphenyl )- 2-imidazolyl ] sulfonylpropoxy}-3 , 4- dihydrocarbostyril

(Compound of the present invention) 1 Polyethylene glycol (Molecular weight: 4000)

(Japanese Pharmacopoeia grade) 0.3 Sodium chloride (Japanese Pharmacopoeia grade) 0.9 Polyoxyethylenesorbitan monooleate

(Japanese Pharmacopoeia grade) 0.4

Sodium metabisulfite 0.1

Methyl-paraben (Japanese Pharmacopoeia grade) 0.18 Propyl-paraben (Japanese Pharmacopoeia grade) 0.02

Distilled water for injection 100 (ml)

The above-mentioned parabens , sodium metabi- sulfite and sodium chloride are dissolved in a half volume of the above-mentioned distilled water under stirring, then the solution was cooled to 40°C, next the compound of the present invention, polyethylene glycol and polyoxyethylenesorbitan monooleate are dissolved in the above solution, and the remaining half volume of distilled water is added to make them to the final volume. The thus obtained solution is sterilized by filtration to prepare the desired injection preparation.

Reference example 1

Into a mixed solution of 36.0 g of 2- (allyloxymethyl) aniline, 48 ml of pyridine and 63 ml of triethylamine, was added 91 ml of carbon disulfide at -20 °C, and the whole mixture was stirred at the same temperature for 3 hours . To this reaction mixture was added a pyridine solution (25 ml), containing 46.0 g of dicyclohexylcarbodiimide and was stirred for 18 hours by elevating the original temperature to room temperature. To this reaction mixture was added n-hexane and the solid matters being separated out were removed by filtration. The filtrate was concentrated, and the residue obtained was purified by means of a silica gel column chromatography (eluent: n-hexane/ethyl acetate = 98/2 - 95/5), there was obtained 44.8 g of 2-(allyloxy- methyl )phenylisocyanate as yellow oily product. -NMR (250MHz, CDC1₃) δ (ppm):

4.10-4.13 (m, 2H), 4.58 (s, 2H), 5.22-5.28 (m, IH) , 5.31-5.39 (m, IH), 5.91-6.07 (m, IH), 7.20-7.32 (m, 3H), 7.41-7.47 (m, IH) .

Reference example 2

Into a chloroform solution (350 ml), contain- ing 44.8 g of 2- (allyloxymethyl )phenylisocyanate, was added 35.0 ml of aminoacetaldehyde diethylacetal at 0°C and the mixture was refluxed for 1 hour. The solvent was removed and the residue thus obtained was purified by means of a silica gel column chromatography (eluent: dichloromethane/ethyl acetate = 90/10 - 85/15), there was obtained 72.7 g of N-[ 2- (allyloxymethyl )phenyl ]-N' - ( 2, 2-diethoxyethyl ) thiourea as yellow oily product. ^-NMR (250 MHz, CDC1₃) δ (ppm):

1.16 (t, J=7.0Hz, 6H), 3.53 (qd, J=7.0Hz, J=9.5Hz, 2H), 3.70 (qd, J=7.0Hz, J=9.5Hz, 2H) , 3.76-3.80 (m, 2H), 4.06-4.09 (m, 2H) , 4.49 (s, 2H), 4.64 (t, J=5.5Hz, IH), 5.22-5.28 (m, IH), 5.29-5.38 (m, IH), 5.91-6.07 (m, IH) , 6.32 (m, IH), 7.22-7.43 (m, 4H), 8.09 (br.s, IH).

Reference example 3

To 72.7 g of N-[ 2- (allyloxymethyl ) phenyl ] -N' - ( 2 , 2-diethoxyethyl ) thiourea was added 72 ml of 3N-hydro- chloric acid at 80 °C, and the mixture was stirred for 2 hours at the same temperature. After water was added to this reaction mixture, the solid matters precipitated was collected by filtration, then washed with water-n- hexane, there was obtained 31.1 of l-[ 2- (allyloxymethyl)phenyl ]-2-mercaptoimidazole as white powdery product.

^XH-NMR (250 MHz, CDC1₃) δ (ppm):

3.96-3.99 (m, 2H), 4.43 (s, 2H) , 5.14-5.20 (m, IH), 5.22-5.31 ( , IH) , 5.80-5.96 (m, IH) , 6.81 (s, 2H), 7.31-7.35 (m, IH) , 7.42-7.54

(m, 2H), 7.61-7.65 (m, IH) , 11.73 (brs, IH) .

Reference example 4

Into a dimethyl sulfoxide solution (350 ml) of 31.1 g of l-[ 2-(allyloxymethyl)phenyl]-2-mercapt- imidazole, was added 71.0 g of potassium t.-butoxide at room temperature, and the mixture was stirred for 7.5 hours at 60°C. Diluted hydrochloric acid was added to this reaction mixture, and solid matters sedimented were collected by filtration and washed with water and diethyl ether, there was obtained 19.6 g of l-{2-[l- ( trans-1-propeny1 ) oxymeth 1 ]phenyl}-2-mercaptoimidazole in yellow powdery product. ^XH-NMR (250 MHz, CDC1₃) δ (ppm): 1.56-1.59 (m, 3H), 4.35-4.46 (m, IH),

4.74 (br.s, 2H), 5.94-5.98 (m, IH) , 6.79 (d, J=2.4Hz, IH), 6.82 (d, J=2.4Hz, IH), 7.30-7.34 (m, IH), 7.43-7.56 (m, 2H), 7.60-7.64 (m, IH), 12.14 (br.s, IH) .

Reference example 5

Into an acetonitrile solution (200 ml), containing 10.0 g of 5-hydroxy-2-nitrobenzaldehyde and 30 ml of l-bromo-3-chloropropane was added 10.0 g of potassium carbonate at room temperature and the mixture was refluxed for 1 hour. The insoluble matters were removed by filtration, and the filtrate was concent- rated, the thus obtained residue was purified by means of a silica gel chromatography (eluent: n-hexane/ethyl acetate = 93/7 - 90/10), there was obtained 14.0 g of 5-( 3-chloropropoxy)-2-nitrobenzaldehyde as yellow oily product .

^-NMR (200 MHz, CDC1₃) δ (ppm):

2.31 (quint, J=6.0Hz, 2H), 3.76 (t, J=6.0Hz, 2H) , 4.28 (t, J=6.0Hz, 2H), 7.17 (dd, J=2.8Hz, J=9.0Hz, IH), 7.35 (d, J=2.8Hz, IH), 8.17 (d, J=9.0Hz, IH), 10.49 (s, IH).

Reference example 6

Into an acetonitrile solution (150 ml), containing 7.5 g of 5-(3-chloropropoxy)-2-nitrobenzal- dehyde and 5.9 g of l-( 2-methylphenyl)-2-mercapto- imidazole was addeed 6.4 g of potassium carbonate at room temperature, and refluxed for 7 hours. The insoluble matters being precipitated were removed by filtration, and the filtrate was concentrated and the residue was purified by means of a silica gel column chromatography (eluent: dichloromethane/ethyl acetate = 93/7 - 90/10), there was obtained 8.2 g of 2-nitro-5- { 3- [ 1- ( 2-methylphenyl ) -2-imidazolyl ]thiopropoxyj-benzal- dehyde as yellow oily product. tø-NMR (200 MHz, CDC1₃) δ (ppm): 2.08 (s, 3H), 2.16 - 2.29 ( , 2H) , 3.23

(t, J=6.8Hz,2H), 4.17 (t, J=6.0Hz, 2H) , 7.01

(d, J=1.3Hz, IH), 7.10 (dd, J=2.8Hz, J=9.0Hz, IH), 7.17-7.21 [m, 2H, containing 7.19 (d, J=1.3Hz)], 7.26-7.40 (m, 4H), 8.14 (d, J=9.0Hz, IH), 10.47 (ε, IH).

Reference example 7 Into a tetrahydrofuran solution (100 ml), containing lithium 1 , 1 , 1 , 3 , 3 , 3-hexamethyldisilazane (LiHMDS), which was prepared by reacting 11.6 ml of 1 , 1 , 1 , 3 , 3 , 3-hexamethyldisilazane with 38 ml of 1.6 M- ri-butyl lithium, was added 5.1 ml of ethyl acetate at -78 °C, and the reaction mixture was stirred at the same temperature for 1 hour. Into this reaction mixture was added a tetrahydrofuran solution (50 ml), containing 8.2 g of 2-nitro-5-{3-[ 1- ( 2-methylphenyl ) -2-imidazolyl ]- thiopropoxyj-benzaldehyde and the mixture was stirred for 30 minutes at -78°C, and for 1 hour by elevating the temperature from -78° to -40°C. Aqueous solution of ammonium chloride and ethyl acetate were added to the reaction mixture, then the whole mixture was subjected to separation, the organic layer was dried over anhydrous sodium sulfate. The solvent was removed by distillation, and the residue was purified by means of a silica gel column chromatography (eluent: dichloro- methane/ethyl acetate = 88/12 → 75/25), there was obtained 7.4 g of ethyl 3-hydroxy-3-[ 2-nitro-5-{3-[ 1- ( 2-methylphenyl ) -2-imidazolyl ] thiopropoxy}phenyl ]propion ate as brown oily product. ^JH- MR (200 MHz, CDC1₃) δ (ppm):

1.29 (t, J=7.2Hz, 3H), 2.08 (s, 3H), 2.13-2.26 (m, 2H), 2.57 (dd, J=9.2Hz, J=16.6Hz, IH), 2.97 (dd, J=2.6Hz, J=16.6Hz, IH) , 3.20 (t, J=6.8Hz, 2H), 3.96 (d, J=3.4Hz, IH),

4.15 (t, J=6.0Hz, 2H), 4.22 (q, J=7.2Hz, 2H), 5.76-5.84 (m, IH) , 6.83 (dd, J=2.8Hz, J=9.2Hz, IH), 7.00-7.01 (m, IH), 7.17 - 7.21 (m, 2H) , 7.26-7.40 (m, 4H), 8.07 (d, J=9.2Hz, IH) .

Reference example 8

By using suitable starting materials and by a method similar to that of used in Reference example 6, there was obtained the following compound. 2-Nitro-5-{3-[l-{2-[l-(trans_-l-propenyl)oxy- methyl]phenyl}-2-imidazoly]thiopropoxy}benzaldehyde as yellow oily product. -NMR (250 MHz, CDC1₃) 6 (ppm):

1.57-1.63 (m, 3H), 2.18-2.29 (m, 2H), 3.24 (t, J=6.8Hz, 2H), 4.18 (t, J=6.0Hz, 2H) , 4.37-4.48 (m, IH) , 4.51 (brs, 2H) , 5.83-5.89 (m, IH), 7.06 (d, J=1.4Hz, IH) , 7.11 (dd, J-2.8Hz, J=9.0Hz, IH) , 7.18 (d, J=1.4Hz, IH), 7.23-7.28 (m, 2H) , 7.39-7.64 (m, 3H) , 8.14 (d, J=9.0Hz, IH), 10.48 (d, J=3.3Hz, IH) . Reference example 9

By using suitable starting materials and by a method similar to that of used in Reference example 7, there was obtained the following compound as brown oily product.

Ethyl 3-hydroxy-3-[2-nitro-5-{3-[l-{2-[l- ( trans.-1-propeny1 )oxymethy1 ]phenyl}-2-imidazoly] - thiopropoxy}phenyl ]propionate . -NMR (200 MHz, CDC1₃) δ (ppm): 1.29 (t, J=7.2Hz, 3H), 1.59 (dd, J=1.7Hz, J=6.8Hz, 3H), 2.13-2.27 ( , 2H), 2.57 (dd, J=9.4Hz, J=16.6Hz, IH), 2.97 (dd, J=2.6Hz, J=16.6Hz, IH) , 3.22 (t, J=7.0Hz, 2H), 3.94 (d, J=3.4Hz, IH), 4.15 (t, J=6.0Hz, 2H), 4.22 (q, J=7.2Hz, 2H) , 4.35-4.51 ( , 3H), 5.67-5.88 (m, 2H), 6.83

(dd, J=2.8Hz, J=9.2Hz, IH) , 7.05 (d, J=1.4Hz, IH), 7.19 (d, J=1.4Hz, IH), 7.22-7.26 (m, IH), 7.37-7.66 (m, 4H) , 8.07 (d, J=9.2Hz, IH) .

Reference example 10 Into a methanol solution (70 ml), containing

6.4 g of ethyl 3-hydroxy-3-[2-nitro-5-{3-[ l-( 2-[ 1- ( trans.-1-propeny1 )oxymethy1 ]phenyl ) -2-imidazoly] thioprop oxy}phenyl ]propionate was added 24 ml of IN-hydrochloric acid at room temperature, and was stirred at 50°C for 2.5 hours. An aqueous solution of sodium hydrogencarbonate and ethyl acetate were added to the reaction mixture. The organic layer was separated and dried over anhydrous sodium sulfate . The solvent was removed by distillation and the residue was purified by means of a silica gel column chromatography (eluent: dichloro- methane/methanol=15/l) , there was obtained 3.9 g of ethyl 3-hydroxy-3-[ 2-nitro-5-{3-[ l-( 2-hydroxymethyl- phenyl)-2-imidazolyl]thiopropoxy}phenyl]propionate as brown oily product. ^XH-NMR (200 MHz, CDC1₃) δ (ppm):

1.28 (t, J=7.2Hz, 3H), 2.12-2.25 (m, 2H) , 2.37-2.42 ( , IH) , 2.57 (dd, J=9.2Hz, J=16.6Hz, IH), 2.96 (dd, J=2.6Hz, J=16.6Hz, IH) , 3.20 (t, J=6.8Hz, 2H), 4.10-4.26 [m, 5H, including 4.13 (t, J=5.4Hz) and 4.21 (q, J=7.2Hz)], 4.41-4.43 (m, 2H) , 5.76-5.83 (m, IH) , 6.83 (dd, J=2.8Hz, J=9.2Hz, IH) , 7.04 (d, J=1.3Hz, IH), 7.15 (d, J=1.3Hz, IH), 7.18-7.24 (m, IH), 7.35-7.57 (m, 3H), 7.64-7.69 (m, IH), 8.06 (d, J=9.2Hz, IH) .

Reference example 11 500 Milligrams of l--f2- r 1- . trans-1-propenyl ) - oxymethyl]phenyl}-2-mercaptoimidazole and 450 mg of 3- (2-methoxyethoxymethoxy)propyl chloride were dissolved in 30 ml of dimethylformamide . To this solution was added 0.4 ml of DBU and stirred at 50°C for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate solution was washed with water and dried over anhydrous sodium sulfate. The solvent was removed by distillation, the residue was purified by means of a silica gel column chromatography (eluent: n-hexane/ethyl acetate=l/l ) , there was obtained 680 mg of 2-[ 3-( 2-methoxyethoxy- methoxy)propylthio1-l--f2-fl-(trans-1-propenyl ) - oxymethyl]phenyl}imidazole as colorless oily product.

1.60 (dd, J=1.6Hz, J=6.8Hz, 3H), 1.90-2.00 (m, 2H), 3.16 (t, J=7.1Hz, 2H), 3.37 (s, 3H) , 3.40-3.70 (m, 6H) , 4.40-4.50 (m, IH) ,

4.52 (s, 2H), 4.67 (s, 2H), 5.87 (dd, J=1.6Hz, J=6.2Hz, IH), 7.03 (d, J=1.2Hz, IH), 7.18 (d, J=1.2Hz, IH), 7.20-7.70 (m, 4H) .

Reference example 12 670 Milligrams of 2-[ 3-( 2-methoxyethoxymethoxy)propylthio ] -l-{ 2- [ 1- ( trans-1-propenyl ) oxymethyl ] phenyl}imidazole was dissolved in 30 ml of ethanol. To this solution was added 2 ml of IN-hydrochloric acid and stirred at 60°C for 2 hours. Ethanol was removed by distillation, the residue was diluted with water and extracted with chloroform. The chloroform solution was dried over anhydrous sodium sulfate, the solvent was removed by distillation. The residue was purified by means of a silica gel column chromatography (eluent: methylene chloride/methanol=20/l ) , there was obtained 500 mg of l-( 2-hydroxymethylphenyl)-2-[ 3-( 2-methoxyethoxymethoxy)propylthio]imidazole as pale yellow oily product . H-NMR (CDCI₃) δ (ppm):

1.92 q, J=6.6Hz, 2H), 3.12 (t, J=6.8Hz, 2H), 3.36 s, 3H), 3.40-3.70 (m, 6H), 4.42 (s, 2H), 4.64 s, 2H), 7.03 (d, J=l.lHz, IH), 7.16 d, J=l.lHz, IH), 7.21 (d, J=7.6Hz, IH), 7.40 t, J=7.5Hz, IH), 7.52 (t, J=7.5Hz, IH), 7.69 d, J=7.6Hz, IH).

Reference example 13 400 Milligrams of 1- ( 2-hydroxymethylphenyl ) -

2-[ 3- ( 2-methoxyethoxymethoxy)propylthio ]imidazole was dissolved in 30 ml of chloroform. To this mixture was added 300 mg of metachloroperbenzoic acid (80%) under ice-cooling condition, and stirred at the same tempera- ture for 10 minutes. The reaction mixture was washed with a saturated aqueous solution of sodium hydrogencarbonate, then dried over anhydrous sodium sulfate. The solvent was removed by distillation and the residue was purified by means of a silica gel column chromato- graphy (eluent :methylene chloride/methanol=20/l ) , there was obtained 360 mg of 1- ( 2-hydroxymethylphenyl )-2- [ 3-( 2-methoxyethoxymethoxy)propylsulfinyl]imidazole as pale yellow oily product. ^-NMR (CDCI₃) δ (ppm): 1.90-2.10 (m, 2H) , 3.37 (s, 3H), 3.40-3.80 (m, 8H), 4.10-4.30 (m, 2H), 4.67 (s, 2H), 7.21 (d, J=0.7Hz, IH), 7.20-7.34 (m, IH) , 7.34 (d, J=0.7Hz, IH) , 7.34 (t, J=7.3Hz, IH) ,

7.57 (t, J=7.5Hz, IH), 7.67 (t, J=6.9Hz, IH).

Reference example 14 (a) 5 Grams of 1- ( 2-hydroxymethyIpheny1 ) -2-

[ 3-( 2-methoxyethoxymethoxy)propylsulfinyl ]imidazole was dissolved in 400 ml of methylene chloride-vinyl acetate (7:3), then 5 g of Novozym 435 was added thereto and stirred at room temperature for 6 hours. Novozym 435 was removed by filtration using Celite, the filtrate was concentrated under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent: methylene chloride/ethyl acetate/methanol= 9/9/2), there were obtained 2.5 g of (S ) - (+ ) -1- ( 2- acetoxymethyIpheny1 ) -2- [ 3- ( 2-methoxyethoxymethoxy) - propylsulfinyl] imidazole(acetoxy-form) (pale yellow oily product, optical purity: 96% e.e.) and 2.5 g of (R)-(-)- 1- ( 2-hydroxymethyIpheny1 ) -2- [ 3- ( 2-methoxyethoxymethoxy) p ropylsulfinyl]imidazole (hydroxy-form) (colorless oily product, optical purity: 88% e.e.). The optical purities of these products were measured by means of HPLC analysis under the conditions as follows, (i) For the hydroxy-form isomer

Column: Chiralcel OD (mfd. by Daicel Chemical Industries, Ltd.)

Eluent: n-Hexane/ethanol=4/l Detecting wave length: UV 254 nm Rate of flow: 1.0 ml/minute Retention time: 11.1 minutes [(S)-form enantiomer ]

13.6 minutes [(R)-form enantiomer] (ϋ) For the acetoxy-form isomer

Column: Chiralcel OD-R (mfd. Ibid.) Eluent: Acetonitrile/water=l/4 Detecting wave length: UN 254 nm Rate of flow: 0.5 ml/minute Retention time: 31.4 minutes [(S)-form enantiomer]

36.4 minutes [(R)-form enantiomer]

(b) To a methanol solution (25 ml) containing 2.5 g of the acetoxy-form isomer obtained in the above- mentioned process a) was added 1.7 g of potassium carbonate and stirred at 0°C for 20 minutes. Water and dichloromethane were added to the reaction mixture and subjected to separation. The organic layer was dried over anhydrous sodium sulfate, then the solvents were removed by distillation, the residue was purified by means of a silica gel column chromatography (eluent: methylene chloride/ethyl acetate/methanol=9/9/l ) , there was obtained 2.2 g of (S ) - (+ ) -l-[ 2- (hydroxymethyl )- phenyl] -2- [ 3-( 2-methoxyethoxymethoxy)propylsulfinyl] - imidazole (alcohol-form) (colorless oily product).

(c) 2.2 Grams of the alcohol-form enantiomer obtained in the above-mentioned process (b) was dis- solved in 200 ml of methylene chloride-vinyl acetate (7:3), 2.5 g of Novozym 435 was added thereto and stirred at room temperature for 3.5 hours . This reaction mixture was treated by the procedure similar to that of used in the above-mentioned process (a), there was obtained 1.6 g of (S)-(+)-l-( 2-acetoxymethylphenyl )- 2-[ 3-( 2-methoxyethoxymethoxy)propylsulfinyl]imidazole (colorless oily product, optical purity: 100% e.e.)

1.90-2.10 [m, 5H, including 2.03 (s)],

3.37-3.73 [m, 11H, including 3.37 (s)], 4.67 (s, 2H), 4.74-5.14 (m, 2H), 7.23 (br.s, IH), 7.36-7.64 (m, 5H) Angle of rotation: [ ]_D ²⁶ = +55.4° (c=l, chloroform) d) To a methanol solution (15 ml) containing

1.6 g of (S)-(+)-l-(2-acetoxymethylphenyl)-2-[3-(2- methoxyethoxymethoxy)propylsulfinyl ] imidazole obtained in the above-mentioned process c) was added 1.0 g of potassium carbonate, and stirred at 0°C for 30 minutes. The reaction mixture was treated by procedure similar to that of used in the above-mentioned process b), there was obtained 1.3 g of (S)-(+)-l-[2-(hydroxymethyl- phenyl ) ] -2- [ 3- ( 2-methoxyethoxymethoxy)propylsulfinyl ] - imidazole (colorless oily product, optical quantity: 100% e.e. ) .

^XH-NMR (CDC1₃) δ (ppm):

1.85-2.17 (m, 2H), 3.17-3.79 [ , 11H, including 3.42 (s)], 4.06-4.39 (m, 3H) , 4.68 (br.s, 2H), 7.19-7.31 (m, 2H), 7.35-7.36 ( , IH), 7.40-7.47 (m, IH), 7.55-7.61 (m, IH) , 7.68 - 7.73 (m. IH) Angle of rotation: [ ]_D ²⁶ = +45.6° (c=l, chloroform) (e) 2.5 Grams of the hydroxy-form enantiomer obtained in the above-mentioned process (a) was dissolved in 200 ml of methylene chloride-vinyl acetate (1:1), and 2.5 g of Novozym 435 was added thereto, and stirred at room temperature for 8 hours . The reaction mixture was treated by procedure similar to that of used in the above-mentioned process (a), there was obtained 1.8 g of (R)-(-)-l-[2-(hydroxymethyl)phenyl]-2-[3-(2- methoxyethoxy ethoxy)propylsulfinyl] imidazole (colorless oily product, optical purity: 100% e.e.). ^- MR (CDC1₃) δ (ppm):

1.85-2.17 (m, 2H), 3.17-3.79 [m, 11H, including 3.42 (s)], 4.06 - 4.39 (m, 3H) , 4.68 (br.s, 2H) , 7.19-7.31 (m, 2H) , 7.35-7.36 (m, IH) , 7.40-7.47 (m, IH), 7.55-7.61 (m, IH), 7.68-7.73 (m. IH)

Angle of rotation: [α]_D ²⁶ = -45.2° (c=l, chloroform)

Reference example 15

0.4 Gram of (S)-(+)-l-(2-hydrσxymethylphenyl)- 2-[ 3-( 2-methoxyethoxymethoxy)propylsulfinyl] imidazole and 0.24 g of triethylamine were dissolved in 30 ml of methylene chloride. Into this solution was added 0.31 g of methanesulfonyl chloride was added dropwise under an ice-cooling condition and stirred for 1 hour. The reaction mixture was diluted with methylene chloride, then washed with an aqueous solution of sodium hydrogencarbonate . The methylene chloride solution was dried over anhydrous sodium sulfate, then concentrated under reduced pressure, there was obtained 0.45 g of ( S ) -1- [ 2- (methanesulfonyloxy)phenyl ] -2- [ 3- ( 2-methoxyethoxymethoxy)propylsulfinyl]imidazole as pale yellow oily product.

1.90-2.10 (m, 2H), 2.90 (s, 3H) , 3.37 (s, 3H) , 3.49-3.70 (m, 8H), 4.67 (s, 2H) , 4.90-5.10 (m, 2H), 7.20-7.38 (m, 2H) , 7.39 (d, J=l.lHz, IH) 7.50 - 7.70 (m. 3H) .

Reference example 16

0.45 Gram of (S )-l-[ 2- (methanesulfonyloxy) - phenyl ] -2- [ 3- ( 2-methoxyethoxymethoxy)propylsulfinyl ] - imidazole was dissolved in 20 ml of methylene chloride. Under ice-cooling condition, to this solution was added dropwise 2 ml of lithium triethylborohydride ( 1M- tetrahydrof ran solution) and stirred for 1 hour. The reaction mixture was poured into an aqueous solution of ammonium chloride, then extracted with methylene chloride. The methylene chloride solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent: methylene chloride/methanol=300/l - 100/1), there was obtained 0. 2 g of (S)-l-(2-methylphenyl)-2-[3-( 2-methoxyethoxymethoxy )propylsulfinyl )imidazole as pale yellow oily product. H-NMR (CDC1₃) δ (ppm):

1.90-2.04 (m, 2H), 2.10 (s, 3H), 3.37 (s, 3H),

3.40-3.70 (m, 8H), 4.67 (s, 2H) ,

7.15 (d, J=l.lHz, IH), 7.30-7.50 (m, 5H).

Reference example 17 1.32 Grams of ( S ) -1- ( 2-methylphenyl ) -2- [ 3-

(hydroxypropyl ) sulfinyl ] imidazole and 0.97 g of N,N- diisopropylethylamine were dissolved in 50 ml of methylene chloride. Into this solution was added 0.75 g of methoxyethoxymethyl chloride and stirred at room temperature overnight. The reaction mixture was diluted with methylene chloride, and washed with water and an aqueous solution of 20%-citric acid. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent: methylene chloride/methanol=300/l - 100/1), there was obtained 0.25 g of (S)-l-( 2-methyIpheny1 ) -2- [ 3-( 2-methoxyethoxymethoxy) propylsulfinyl] imidazol as pale yellow oily product. ^:H-NMR (CDCI₃) δ (ppm):

1.90-2.04 (m, 2H) , 2.10 (s, 3H), 3.37 (s, 3H), 3.40-3.70 (m, 8H) , 4.67 (s, 2H), 7 . 15 ( d , J=l . lHz , IH ) , 7 . 30- 7 . 50 ( m , 5H ) .

Reference example 18

(a) A mixture consisting of 264 mg of 3-[l-(2- methylphenyl ) -2-imidazolyl ] sulfinylpropanol , 12 ml of ethyl acetate, 200 mg of isopropenyl acetate and 50 mg of Lipase AL, was stirred at 4°C for 4 days. Then Lipase AL was removed by filtration using High Flow Supercel (or Celite), the filtrate was concentrated under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluent: dichloromethane/methanol = 40/1), there were obtained 180 mg of (S)-3-[ 1- ( 2-methylphenyl ) -2-imidazolyl ]- sulfinylpropyl acetate (acetoxy-form) (optical purity: 59.8% e.e.) as colorless oily product, and 110 mg of

(R) -3-[ 1- ( 2-methylphenyl ) -2-imidazolyl ] sulfinylpropanol (hydroxy-form) (optical purity: 64.5% e.e.) as white powdery product. 110 Milligrams of this hydroxy-form enantiomer was recrystallized twice from ethyl acetate- n-hexane , there was obtained 42 mg of hydroxy-form enantiomer, having optical purity: 100% e.e.

Optical purity was measured by means of an HPLC analysis under the conditions as follows.

HPLC column: Chiralpak AD (0.46 cm x 25 cm) Eluent: n-Hexane/ethanol/diethylamine =

600/400/1 Rate of flow: 1.2 ml/minute Detecting wave length: UV 254 nm Retention time (minutes):

Hydroxy-form: 4- (R) -form enantiomer 5.5 min .

4-(S)-form enantiomer 6.7 min .

Acetoxy-form: 3-(S)-form enantiomer 8.3 min.

3- (R) -form enantiomer 10.0 min.

Physical properties of the acetoxy-form enantiomer are as follows:

Colorless oily product

2.00 (s, 3H), 2.00-2.20 (m, 2H), 2.11 (broad, 3H) , 3.30-3.60 (m, 2H), 4.17 (t, J=6.2Hz, 2H) , 7.15 (d, J=l.lHz, IH), 7.25-7.50 (m, 5H) .

Physical properties of the hydroxy-form enantiomer are as follows: Colorless needle-like crystals Melting point: 110-110.5°C.

Rotation angle: [ ]_D ²⁷: -66.4° (c=0.1, methanol) ^:H-NMR (CDCI₃) δ (ppm):

2.00-2.20 (m, 2H), 2.13 (s, 3H), 2.75 (broad, IH) , 3.40-3.60 (m, 2H), 3.60-3.85 (m, 2H) , 6.84 (d, J=1.0Hz, IH), 7.25-7.50 (m, 5H) .

(b) A mixture consisting of 180 mg of the acetoxy-form of enantiomer obtained in the above- mentioned process (a), 5 ml of methanol and 146 mg of potassium carbonate, was stirred at room temperature for 30 minutes. The reaction mixture was poured into water, and extracted with dichloromethane, the organic layer was dried and concentrated under reduced pressure, the residue was recrystallized twice from ethyl acetate- n-hexane , there was obtained 51 mg of hydroxy-form enantionmer (optical purity: 100% e.e. ) as colorless needle-like crystals . Melting point: 108°C.

Rotation angle: [ ]_D ²⁷= +64.4° (c=0.1, methanol) ^XH-NMR (CDC1₃) δ (ppm):

2.00 - 2.20 (m, 2H), 2.13 (s, 3H), 2.75 (broad, IH), 3.40 - 3.60 (m, 2H), 3.60 - 3.85 ( , 2H), 6.84 (d, J=1.0Hz, IH) , 7.25 - 7.50 (m, 5H).

Reference example 19

Into a dichloromethane solution (4 ml), containing 100 mg of (S)-3,4-dihydro-6-{3-[ l-(methane- sulfonyloxymethyl)phenyl ]-2-imidazolyl}sulfinylpropoxy]- 2 ( IH) -quinolinone was added 0.4 ml of lM-lithium tri- ethylborohydride-tetrahydrofuran solution under ice- cooling condition and this mixture was stirred at the same temperature for 1 hour. Water was added to the reaction mixture, the organic layer was separated and dried over anhydrous sodium sulfate, the solvent was removed by distillation under reduced pressure. The residue was treated by a preparative thin layer chromatography (eluent: dichloromethane/methanol = 20/1), then recrystallized from ethanol, there was obtained 50 mg of ( S )-3 , 4-dihydro-6-{3-[ 1- ( 2-methyl- phenyl ) -2-imidazolyl ] sulfinylpropoxy}-2 ( IH) -quinolinone (optical purity: 94% e.e.). White powdery product . Melting point: 124.5-126.5°C.

The optical purity of the product was measured by means of an HPLC analysis under the following conditions .

Column: ULTRON ES-OVM (mfd. by Shinwa Kako Co.) Eluent: acetonitrile/20 mM-KH₂P0_A aqueous solution = 9/91 Rate of flow: 1.0 ml/minute

Detecting wave length: UV 254 nm

Retention time: (S)-form enantiomer: 10.8 minutes

(R)-form enantiomer: 14.1 minutes

Reference example 20 By using suitable starting materials and by procedure similar to that of used in Reference example 19, there was obtained (S ) - (+ ) -6-{3-[ 1- ( 2-methylphenyl )- 2-imidazolyl] sulfinylpropoxy}-2- ( IH) -quinolinone . Colorless needle-like crystals Melting point: 126.5-129°C. (Recrystallized from ethyl acetate-dichloromethane ) Rotation angle: [ ]_D ²⁷ = +17.8° (c=l, chloroform) Optical purity: 95.1% e.e.

The optical purity of the product was measured by means of an HPLC analysis under the following conditions . Column: ULTRON ES-OVM (mfd. by Shinwa Kako Co.)

Eluent: Acetonitrile/20 mM-KH₂PO aqueous solution

= 10/90 Rate of flow: 1.0 ml/minute Detecting wave length: UV 254 nm Retention time: (S)-form enantiomer: 11.6 minutes

(R)-form enantiomer: 15.3 minutes

Reference example 21

(a) 470 Milligrams of ( S ) - (+ ) -1- ( 2- hydroxymethyIpheny1 ) -2- [ 3- ( 2-methoxyethoxymethoxy) propyl sulfinyl ] imidazole was dissolved in 5 ml of methylene chloride, then 0.4 ml of triethylamine and 0.15 ml of methanesulfonyl chloride were added thereto and stirred at 0°C for 30 minutes. Into the reaction mixture was added a saturated aqueous solution of sodium hydrogencarbonate and methylene chloride, the organic layer was separated and dried over anhydrous sodium sulfate, then the solvent was removed by distillation, the residue was purified by means of a silica gel column chromatography ( eluent :methylene chloride/methanol=30/l ) , there was obtained 566 mg of pale yellow oily product.

566 Milligrams of the thus obtained oily product was dissolved in 15 ml of tetrahydrofuran, then 2.5 ml of tetrahydrofuran solution of lM-lithium triethylborohydride was added thereto, this mixture was stirred at 0°C for 1.5 hours under nitrogen gas stream. To this reaction mixture was added an aqueous solution of 10%-citric acid and methylene chloride, and the organic layer was separated, and washed with a saturated aqueous solution of sodium hydrogencarbonate, and dried over anhydrous sodium sulfate. After removal of the solvents, the residue was purified by means of a silica gel column chromatography (eluent :methylene chloride/ methanol=25/l) , there was obtained 360 mg of (S)-(+)-l- ( 2-methylphenyl )-2-[ 3-( 2-methoxyethoxymethoxy) propyl- sulfinyl] imidazole (yellow oily product) (optical purity: 100% e.e.). ^XH-NMR (CDC1₃) δ (ppm):

1.92-2.04 (m, 2H) , 2.10 (br.s, 3H), 3.32-3.72 [m, 11H, including 3.38 (s)] 4.67 (s, 2H), 7.14 (d, J=1.0Hz, IH) , 7.22-7.47 [m, 5H, including 7.38 (d, J=1.0Hz)]. Rotation angle: [ ]_D ²⁶ = +50.3° (c=l, chloroform).

(b) Absolute structure of (S )-(+ )-l-( 2-methyl- phenyl ) -2- [ 3- ( 2-methoxyethoxymethoxy)propylsulfinyl ] - imidazole obtained from the above-mentioned process (a) was confirmed by means of an HPLC analysis, that the absolute structure of the above-mentioned compound was coincident with that of the compound derived from ( S ) - ( + ) -1- ( 2-methylphenyl ) -2- ( 3-hydroxypropylsulfinyl ) - imidazole, of which absolute structure was well known. Therefore, absolute structures of the all compounds obtained from the above-mentioned processes (a) to (d) in Reference example 14 were determined.

In this case, the HPLC analysis was carried out under the following conditions: Column: Chiralcel OJ

(mfd. by Daicel Chemical Co., Ltd.) Eluent: n-Hexane/ethanol/diethylamine=600/400/1 Detecting wave length: UV 254 nm Rate of flow: 1.0 ml/minute

Retention time: 19.9 minutes [(S)-form enamtiomer]

22.2 minutes [(R)-form enantiomer] .

Example 1 Into a dimethyl formamide solution (50 ml) containing 5.3 g of 1— -f 2— r l-( trans-1-propenyl ) - oxymethyl ]phenyl}-2-mercaptoimidazole was added 3.6 ml of 1 , 8-diazabicyclo[ 5.4.0 ]undec-7-ene and a N,N- dimethylformamide solution (50 ml) containing 5.2 g of 6- ( 3-chloropropoxy) -3 , 4-dihydro-2 ( IH) -quinolinone at room temperature and stirred at 60°C for 5.5 hours. Water and ethyl acetate were added to the reaction mixture, the organic layer was separated and dried with anhydrous sodium sulfate. The solvent was removed by distillation, the residue was purified by means of a silica gel column chromatography (eluent: dichloro- methane/methanol = 15/1 - 10/1). The crude product thus obtained was dissolved in 160 ml of ethanol, 40 ml of IN-hydrochloric acid was added at room temperature and refluxed for 2 hours . An aqueous solution of sodium hydrogencarbonate and ethyl acetate were added thereto, the organic layer was separated and dried over anhydrous sodium sulfate. The solvent was removed by distillation, the residue was purified by means of a silica gel column chromatography (eluent: dichloromethane/ methanol = 15/1 - 10/1), the product was recrystallized from ethyl acetate-methanol, there was obtained 7.5 g of 3 , 4-dihydro-6-{ 3- [ 1- ( 2-hydroxymethylpheny1 ) -2- imidazolyl ]thiopropoxy}-2- ( IH) -quinolinone as white powdery product. Melting point: 141.0-142.5°C.

Examples 2 - 26

By using suitable starting materials and by procedure similar to that of used in Example 1 , there were obtained the objective compounds as shown in the following Table 1.

Table 1

Example 2

A: -(CH₃)-, A 0, R¹: -CH₂OH ( 2-position ) , R²: H

Side-chain: Substituted at 6-position in the carbostyril skeleton

The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Double bond Crystal form: White powder Melting point: 161.5-163.0°C. Recrystallization solvent: Methanol-water

Example 3

A: -(CH₃)-, £.: 1, R¹ : -CH₃ (2-position) R²: -OH (substituted at 4-position in the carbostyril skeleton) Side chain: Substituted at 6-position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: Pale brown amorphous NMR data: (1)

Example 4

A: -(CH₂)₃-, A 1, R¹: -CH₂OH (2-Position) R²: H

Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: White amorphous NMR data: (2)

Example 5

A: -(CH₂)₃-, __ 1, R¹ : -CH₂OH (2-position) R²: H

Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Double bond

Crystal form: White amorphous NMR data: (3)

Example 6

A: -(CH₂)₃-, A 1, R¹: -CH₂OH (2-position) R²: -OH (3-position in the carbostyril skeleton)

Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: White powder Melting point: 174-177°C.

Recrystallization solvent: Ethanol-ethyl acetate

Example 7

A: -(CH₂)₃-, A 1. R¹: -CH₂OH (2-position) R²: -OH (4-position in the carbostyril skeleton) Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: Pale yellow amorphous NMR data: (4)

Example 8

A: -(CH₂)₃-, f_: 2, R¹ : -CH₂OH (2-position) R²: H

Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond

Crystal form: White powder Melting point: 156-157°C. Recrystallization solvent: Ethyl acetate-methanol

Example 9 A: -(CH₂)₃-, £_.: 2, R¹ : -CH₂0H (2-position)

R²: H

Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Double bond Crystal form: Pale yellow needle-like Melting point: 185-187°C. Recrystallization solvent: Ethanol-water

Example 10

A: -(CH₂)₃-, !_: 2, R¹ : -CH₂OH (2-position) R²: -OH (3-position in the carbostyril skeleton) Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: White powder Melting point: 173-175°C.

Recrystallization solvent: Ethanol-ethyl acetate

Example 11

A: -(CH₂)₃-, {_: 2, R¹ : -CH₂OH (2-position) R²: -OH (4-position in the carbostyril skeleton) Side chain: 6-Position in the carbostyril skeleton

The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: White amorphous NMR data : ( 5 )

Example 12

A: -(CH₂)₃-, A 1, R¹: OH

( 2-position ) Side chain: 6-Position in the carbostyril skeleton

The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: Pale yellow powder Melting point: Higher than 132°C. (decompd.) Recrystallization solvent: Methanol-water Example 13

( 2-position ) Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: Pale yellow powdery Melting point: Higher than 175°C. (decompd.) Recrystallization solvent: Methanol-water

Example 14

( 2-position) Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: White amorphous

NMR data : ( 6 ) Example 15

(2-position)

Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: White amorphous NMR data: (7)

Example 16 0

II

A: -(CH₂)₃-, __'• 1, R¹ : -CH₂0CCH₃ (2-position)

R²: H Side chain: 6-Position in the carbostyril skeleton

The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond

Crystal form: Colorless amorphous

NMR data: (8) (S)-(+)-form Optical purity: 100% e.e.

Rotation angle : [ ]_D ²⁸= +44.8° (c=0.1, chloroform)

Example 17

A: -(CH₂)₃-, £_: 1, R¹ : -CH₂0H (2-position) R²: H Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: Colorless amorphous NMR data : ( 9 ) (S)-(+)-form Optical purity: 100% e.e.

Rotation angle: [θ-]_D ²⁶⁼ +27° (c=0.1, chloroform)

Example 18

A: -(CH₂)₃-, f_: 1, R²: H, R¹ : -CH₂OH

( 2-position) Side chain: 6-Position in the carbostyril skeleton

The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: Colorless amorphous NMR data: (10) (R)-(-)-form Optical purity: 100% e.e.

[ ]_D ²⁶=-27° (c=0.1, chloroform) Rotation angle: [α]_D ²⁶ = -27° (c=0.1, chloroform)

Example 19 A: -(CH₂)₃-, i_: 1, R¹ : -CH₂OS0₂CH₃ (2-position)

R²: H

Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: Colorless amorphous

NMR data: (11) Example 20

A: -(CH₂)₃-, A 0, R¹ : -CH₃ (2-position) R²: -OH (4-position in the carbostyril skeleton) Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: pale yellow amorphous NMR data: (12)

Example 21 A: -(CH₂)₃-, 1: 0, R¹ : -CH₂OCH=CH-CH₃ (2-Position)

R²: -OH (3-position in the carbostyril skeleton)

Side chain: 6-Position in the carbostyril skeleton

Crystal form: White powder

NMR data: (13)

Recrystallization solvent: Ethyl acetate-n-hexane

Example 22 A: -(CH₂)₃-, 1: 0, R¹ : -CH₂OH (2-position)

R²: -OH (3-position in the carbostyril skeleton) Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: White powder

NMR data: (14) Recrystallization solvent: Ethanol-ethyl acetate

Example 23

A: -(CH₂)₃-, 1: 0, R¹ : -CH₂OH (2-position) R²: -OH (4-position in the carbostyril skeleton) Side chain: 6-Position in the carbostyril skeleton

The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Single bond Crystal form: Pale yellow amorphous NMR data: (15)

Example 24

0

A: -(CH₂)₃-, 1: 1, R¹ : -CH₂O ιrCCH₃ (2-position)

R²: H

Crystal form: White amorphous

NMR data: (16)

(S)-(+)-form Optical purity: 100% e.e.

Rotation angle: [c-]_D ²⁸⁼ +32.4° (c=l, chloroform)

Example 25

A: -(CH₂)₃-, 1: 1, R¹ : -CH₂OH (2-position) R²: H

Side chain: 6-Position in the carbostyril skeleton The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Double bond Crystal form: White amorphous NMR data: (17) (S)-(+ )-form

Optical purity: 100% e.e.

Rotation angle. [ ]_D ²⁸= +24.1° (c=l, chloroform)

Example 26

A: -(CH₂)₃-, 1: 1, R¹ : -CH₂OH (2-position) R²: H

Side chain: 6-Position in the carbostyril skeleton

The carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton: Double bond

Crystal form: White amorphous NMR data: (18)

(R)-(-)-form

Optical purity: 100% e.e.

Rotation angle: [ ]_D ²⁸= -24.8° (c=l, chloroform)

NMR data (1)-(18) of the compounds obtained in Examples 3-5, 7, 11, 14-26 are as follows. (1) ^XH-NMR (CDC1₃, 250MHz) δ (ppm):

2.05-2.20 [m, 5H, including 2.09 (br.s)], 2.73 (dd, J=5.0Hz, J=16.5Hz, IH), 2.80 (dd, J=5.5Hz, J=16.5Hz, IH),

3.36-3.47 (m, IH) , 3.56-3.68 (m, IH), 3.93-4.05 (m, 3H), 4.83 (br.s, IH) , 6.63-6.73 (m, 2H), 6.88 (m, IH), 7.15 (m, IH), 7.27-7.46 (m, 5H), 9.02 (s, IH) .

(2) -NMR (CDC1₃, 250MHz) δ (ppm):

2.09-2.35 (m, 2H), 2.55-2.61 (m, 2H), 2.87-2.93 (m, 2H), 3.25-4.43 (m, 7H) ,

6.63-6.74 (m, 3H) , 7.21-7.71 (m, 6H), 8.96 (s, IH).

(3) ^!H-NMR (DMSO-d₆ 250MHz ) δ (ppm):

1.91-2.16 (m, 2H), 3.27-3.59 (m, 2H), 4.07 (t, J=6.0Hz, 2H), 4.14-4.27 (m, 2H) ,

5.26 (t, J=5.3Hz, IH), 6.47 (d, J=9.5Hz, IH), 7.08-7.24 (m, 3H) , 7.36-7.50 (m, 3H), 7.54-7.66 (m, 3H), 7.81 (d, J=9.5Hz, IH), 11.63 (s, IH). (4) ^-N R (DMSO-d₆, 250MHz) δ (ppm):

1.88-2.13 (m, 2H), 2.45 (dd, J=6.3Hz, J=16.0Hz, IH), 2.61 (dd, J=4.8Hz, J=16.0Hz, IH) , 3.30-3.57 (m, 2H), 4.00 (t, J=6.0Hz, 2H), 4.10-4.26 (m, 2H), 4.68 (m, IH), 5.27 (br. IH), 5.41 (br, IH), 6.77-6.87 (m, 3H) ,

7.37 - 7.48 (m, 3H), 7.55-7.67 (m, 3H), 9.96 (s, IH). (5) ^XH-NMR (DMSO-d₆, 250MHz) δ (ppm):

1.98-2.09 (m, 2H) , 2.44 (dd, J=6.3Hz, J=16.0Hz, IH), 2.61 (dd, J=4.8Hz , J=16.0Hz, IH),

3.50-3.56 (m, 2H), 3.97 (t, J=6.0Hz, 2H), 4.14-4.30 (m, 2H) , 4.69 (m, IH) , 5.29 (br, IH), 5.41 (br, IH), 6.77-6.88 (m, 3H) , 7.36-7.43 (m, 3H), 7.51-7.57 (m, IH), 7.60-7.63 (m, 2H), 9.97 (s, IH).

(6) *H-NMR (CDC1₃, 250MHz) δ (ppm):

1.06-1.12 (m, 27H), 2.13-2.29 (m, 2H), 2.56-2.63 (m, 2H) , 2.89-2.95 (m, 2H),

3.41-3.79 [m, 5H, including 3.70 (s)] 3.98-4.11 (m, 3H), 4.29-4.34 (m, IH), 4.56-4.68 (m, 2H) , 5.05-5.37 (m, 3H) , 6.66-6.70 (m, 3H), 7.21-7.73 (m, 6H), 7.98 (br, IH) .

(7) ^XH-NMR (CDC1₃, 250MHz) δ (ppm):

1.09-1.12 (m, 27H), 2.23-2.34 (m, 2H) , 2.57-2.63 (m, 2H), 2.89-2.95 (m, 2H), 3.57-3.64 (m, 2H), 3.71 (s, 3H) , 3.93-4.05 (m, 3H) , 4.31-4.46 (m, IH),

4.53-4.68 (m, 2H), 5.01-5.38 (m, 3H) , 6.69 (s, 3H), 7.15 (br.s, IH) , 7.23-7.62 (m, 5H) , 7.86 (br.s, IH) .

(8) ^-NMR (DMSO-d₆, 250MHz) δ (ppm): 1.75-2.17 (m, 5H) , 2.26-2.44 (m, 2H) ,

2.69-2.91 (m, 2H) , 3.30-3.65 (m, 2H) , 3.99 (t, J=6.0Hz, 2H), 4.67-4.98 (m, 2H), 6.57-6.87 (m, 3H), 7.25-7.83 (m, 6H) , 9.89 (br.s, IH) . (9) ^-NMR (DMSO-d₆, 250MHz) δ (ppm):

1.80-2.10 ( , 2H), 2.30-2.44 (m, 2H), 2.72-2.87 (m, 2H), 3.16-3.61 (m, 2H) , 3.98 (t, J=6.2Hz, 2H), 4.06-4.32 (m, 2H) , 5.26 (t, J=5.3Hz, IH), 6.57-6.83 (m, 3H) , 7.23-7.53 (m, 3H) , 7.53-7.75 (m, 3H), 9.89 (brs, IH) .

(10) ^:H-NMR (DMSO-d₆, 250MHz) δ (ppm): 1.83-2.12 (m, 2H), 2.27-2.44 (m, 2H),

2.71-2.89 (m, 2H), 3.25-3.59 (m, 2H), 3.98 (t, J=6.2Hz,2H), 4.06 - 4.33 (m, 2H), 5.25 (t, J=5.3H, IH), 6.60 - 6.81 (m, 3H), 7.27-7.53 (m, 3H), 7.53-7.72 (m, 3H), 9.89 (brs, IH) .

(11) ^-NMR (CDC1₃, 250MHz) δ (ppm):

2.10-2.35 (m, 2H), 2.46-2.70 (m, 2H), 2.77-3.06 (m, 5H) , 3.35-3.81 (m, 2H) , 3.90-4.13 (m, 2H), 4.18-5.22 (m, 2H) , 6.47-6.84 (m, 3H) , 7.15-7.79 (m, 6H),

8.31-8.63 (m, IH) .

(12) ^:H-NMR (CDC1₃, 200MHz) δ (ppm):

1.96-2.17 [m, 5H, including 2.07 (s)], 2.82 (d, J=5.6Hz, 2H), 3.10 (t, J=6.8Hz, 2H), 3.90 - 4.02 [m, 3H, including 3.99 (t, J=6.0Hz)]

4.91 (m, IH), 6.70-6.71 (m, 2H) , 6.97-7.00 (m, 2H), 7.17-7.20 (m, 2H) , 7.26-7.44 (m, 3H) , 8.58 (s, IH) .

(13) ^:H-NMR (CDC1₃, 200MHz) δ (ppm): 1.57-1.61 (m, 3H), 2.07-2.21 (m, 2H) ,

2.89-3.04 (m, IH), 3.10-3.27 [m, 3H, including 3.23 (t, J=7.0Hz)], 3.76 (m, IH), 3.98 (t, J=6.0Hz, 2H), 4.26-4.52 (m, 4H), 5.82-5.90 (m, IH), 6.70 (m, 3H), 7.05 (d, J=1.4Hz, IH), 7.19-7.26 [m, 2H, including 7.20 (d, J=1.4Hz)], 7.38-7.64 (m, 3H) , 8.00 (s, IH) . (14) ^JH-NMR (CDC1₃, 200MHz) δ (ppm):

2.06-2.18 (m, 2H), 2.51-2.57 (m, IH), 2.88-3.24 [m, 4H, including 3.20 (t, J=7. OHz ) ] , 3.91-3.98 [m, 3H, including 3.95 (t, J=6.0Hz)] 4.25-4.44 (m, 3H), 6.64-6.74 (m, 3H), 7.05 (m, IH), 7.18-7.24 (m, 2H) ,

7.37-7.56 (m, 2H) , 7.66-7.69 (m, IH), 8.43 (s, IH).

(15) ^-NMR (DMSO-d₆, 200MHz) 8 (ppm):

1.92-2.05 (m, 2H) , 2.43 (dd, J=6.4Hz, J=16.0Hz, IH), 2.60 (dd, J=4.8Hz, J=16.0Hz, IH),

3.08 (t, J=7.0Hz, 2H), 3.92 (t, J=6.0Hz, 2H), 4.18 (d, J=5.4Hz, 2H), 4.62 - 4.71 (m, IH) , 5.26 (t, J=5.4Hz, IH), 5.37 (m, IH) , 6.76-6.86 (m, 3H) , 7.11 (m, IH), 7.21-7.25 (m, IH) , 7.35-7.43 (m, 2H) ,

7.49-7.56 (m, IH), 7.63-7.66 (m, IH),

9.93 (s, IH).

(16) ^-NMR (CDCI₃, 250MHz) δ (ppm):

2.01 (br.s, 3H), 2.19-2.34 (m, 2H), 3.52 (td, J=7.5Hz, J=13.3Hz, IH),

3.63-3.81 (m, IH) , 4.07-4.20 (m, 2H), 4.70-5.11 (m, 2H), 6.70 (d, J=9.5Hz, IH), 6.95 (d, J=2.5Hz, IH), 7.09 (dd, J=2.5Hz, J=9.0Hz, IH), 7.24 - 7.62 [m, 7H, including 7.37 (d, J=l. OHz) ] ,7.71 (d, J=9.5Hz, IH), 11.49 (s, IH).

(17) ^XH-NMR (CDC1₃, 250MHz) δ (ppm): 2.11-2.43 (m, 2H) , 3.33-4.39 (m, 7H),

6.69 (d, J=9.5Hz, IH), 6.93 (brs, IH), 7.06-7.09 (m, IH) , 7.20-7.45 [m, 5H, including 7.21 (d, J=1.0Hz) and 7.35 (d, J=1.0Hz)], 7.50-7.59 (m, IH) , 7.69-7.73 [m, 2H, including 7.71 (d, J=9.5Hz)], 12.42 (s, IH) .

(18) ^XH-NMR (CDC1₃, 250MHz) δ (ppm):

2.11-2.42 (m, 2H) , 3.32-4.39 (m, 7H), 6.69 (d, J=9.5Hz, IH), 6.93 (br.s, IH), 7.05-7.08 (m, IH), 7.20-7.44 [m, 5H, including 7.21 (d, J=1.0Hz) and 7.35 (d, J=1.0Hz)],

7.50-7.59 (m, IH) , 7.69-7.72 [m, 2H, including 7.71 (d, J=9.5Hz)], 12.56 (s, IH).

Example 27 Into a chloroform solution (20 ml), containing

849 mg of 3 , 4-dihydro-6- [ 3-{l-[ 2- (hydroxymethyl )phenyl ] - 2-imidazoly}thiopropoxy] -2 ( IH) -quinolinone, was added 438 mg of m-chloroperbenzoic acid at 0°C and stirred at the same temperature for 30 minutes. An aqueous solution of sodium hydrogensulfite and dichloromethane were added to this reaction mixture, the organic layer was separated, washed with an aqueous solution of sodium hydrogencarbonate and dried over anhydrous sodium sulfate. The solvent was removed by distillation, the residue was purified by means of a silica gel column chromatography (eluent: dichloromethane/methanol/ = 10/1), there was obtained 819 mg of 3 ,4-dihydro-6-<3-[ 1- ( 2-hydroxymethylphenyl)-2-imidazoly]sulfinylpropoxy}- 2 (IH) -quinolinone as white amorphous product. ^:H-NMR (CDC1₃, 250MHz) δ (ppm):

2.09-2.35 (m, 2H) , 2.55-2.61 (m, 2H) , 2.87-2.93 (m, 2H) , 3.25-4.43 (m, 7H), 6.63-6.74 (m, 3H) , 7.21-7.71 (m, 6H) ,

8.96 (s, IH).

By using suitable starting materials and by procedure similar to that of used in Example 27, there were prepared compounds of the above-mentioned Examples 3, 5-7, 12, 14, 16-19 and 24-26.

Example 28

Into a chloroform solution (500 ml), containing 20.0 g of 3, 4-dihydro-6-[ 3-{l-[ 2- (hydroxymethyl ) - phenyl ]-2-imidazolyl}thiopropoxy] -2 ( IH) -quinolinone was added 32.0 g of m-chloroperbenzoic acid at 0°C, and stirred at room temperature for 4.5 hours . An aqueous solution of sodium hydrogensulfate was added to this reaction mixture, the organic layer was separated, washed with an aqueous solution of sodium hydroxide and dried over anhydrous sodium sulfate. The solvent was removed by distillation, the residue was purified by means of a silica gel column chromatography (eluent: dichloromethane/methanol = 16/1), the product obtained was recrystallized from ethyl acetate-methanol, there was obtained 15.4 g of 3 , 4-dihydro-6-{3- [ 1- ( 2-hydroxy- methylphenyl ) -2-imidazolyl ] sulfonylpropoxy}-2- ( IH) - quinolinone, as white powdery product. Melting point: 156-157°C.

By using suitable starting materials and by procedure similar to that of used in Example 28, there were prepared compounds of the above-mentioned Examples 9-11, 13 and 15.

Example 29

Into an ethanol solution (20 ml), containing 808 mg of methyl 2-[ 2-{3-[ 3 , 4-dihydro-2 ( lH)-quinolinone- 6-yl ]oxypropylsulfonyl}-l-imidazolyl ] -l-benzyl-2 ,3,4- tri-O-pivaloyl-β-D-glucopyranosidouronate acid, was added 4.4 ml of an aqueous solution of lN-sodium hydroxide at 0°C and stirred for 3 days. To this reaction mixture was added Dowex 50wx8 to adjust the pH thereof to pH=4 , and the mixture was subjected to filtration. The filtrate was concentrated and dissolved by adding methanol and water, then concentrated. The residue was recrystallized from methanol-water , there was obtained 214 mg of 2-[ 2-{3-[ 3 , 4-dihydro-2-( 1H)- quinolinon-6-yl]oxypropylsulfonyl}-l-imidazolyl]-l- benzyl-β-D-glucopyranosidouronic acid as pale yellow powdery product . Melting point: Higher than 175°C (decomposed).

By using suitable starting materials and by procedure similar to that of used in Example 29, there was prepared the compound of the above-mentioned Example 12.

Example 30

Into an aqueous solution (720 ml), containing 76.8 g of ferrous sulfate heptahydrate were added an ethanol solution (240 ml), containing 8.2 g of ethyl 3-hydroxy-3-[2-nitro-5-{3-[l-(2-methylphenyl)-2- imidazolyl ] thiopropoxy}phenyl]propionate and 36 ml of ammonium hydroxide at room temperature, and stirred at the same temperature for 30 minutes then at 60°C for 2.5 hours. Water, dichloromethane and Celite were added to the reaction mixture and filtered. The filtrate was subjected to separation, the organic layer was dried over anhydrous sodium sulfate and concentrated . The residue was purified by means of a silica gel column chromatography (eluent: dichloromethane/methanol = 15/1 - 10/1), there was obtained 4.3 g of 3 , -dihydro-4- hydroxy-6-{3-[ 1- ( 2-methylphenyl ) -2-imidazolyl ] thiopropox y}-2 ( IH) -quinolinone as pale yellow amorphous. -NMR (CDC1₃, 200MHz) δ (ppm):

1.96-2.17 [m, 5H, including 2.07 (s)], 2.82 (d, J=5.6Hz, 2H) , 3.10 (t, J=6.8Hz, 2H) ,

3.90-4.02 [m, 3H, including 3.99 (t, J=6.0Hz)], 4.91 (m, IH), 6.70-6.71 (m, 2H), 6 . 97 -7 . 00 ( m, 2H ) , 7 . 17-7 . 20 (m, 2H ) , 7 . 26-7 . 44 (m, 3H ) , 8 . 58 ( s , IH ) .

By using suitable starting materials and by procedure similar to that of used in Example 30, there were obtained the compounds of the above-mentioned Examples 3, 7, 11 and 23.

Example 31

Into a solution of methanol (60 ml ) /dichloromethane (15 ml), containing 6.7 g of 3,4-dihydro-3- hydroxy-6- [ 3-{ 1- [ 2- ( 1-propenyloxymethyl )phenyl ] -2- imidazolyl}thiopropoxy] -2 ( IH) -quinolinone, was added 20 ml of IN-hydrochloric acid at room temperature, and stirred at the same temperature for 14 hours . An aqueous solution of sodium hydrogencarbonate and dichloromethane were added to the reaction mixture, and subjected to separation. The organic layer was dried over anhydrous sodium sulfate, the solvent was removed by distillation. The residue was recrystallized from ethanol-ethyl acetate, there was obtained 5.9 g of 3,4-dihydro-3-hydroxy-6-{3-[l-(2-hydroxymethylphenyl)-2- imidazolyl}thiopropoxy]-2( IH) -quinolinone as white powdery product. -NMR (CDC1₃, 200MHz) δ (ppm):

2.06-2.18 (m, 2H) , 2.51-2.57 (m, IH), 2.88-3.24 [m, 4H, including 3.20 (t, J=7.0Hz)],

3.91-3.98 [ , 3H, including 3.95 (t, J=6.0Hz)], 4.25-4.44 (m, 3H), 6.64 - 6.74 (m, 3H), 7 . 05 (m, IH ) , 7 . 18-7 . 24 ( m, 2H ) , 7 . 37 - 7 . 56 (m, 2H ) , 7 . 66-7 . 69 ( m, IH ) , 8 . 43 ( s , IH ) .

By using suitable starting materials and by procedure similar to that of used in Example 31, there were obtained the compounds of the above-mentioned Examples 1, 2, 4-11, 17, 18, 23, 25 and 26.

Example 32

Into a dichloromethane suspension (20 ml), containing 1.5 g of 3 , 4-dihydro-6-[ 3-{l-[ 2- ( hydroxy- methyl )phenyl]-2-imidazolyl}sulfonylpropoxy] -2 (1H)- quinolinone, 2.1 g of methyl 2 , 3 , 4-tri-O-pivaloyl-l-O- trichloroacetimidoyl- -D-glucopyranosidouronate and 0.5 g of molecular sieves 4A was added 0.89 ml of trimethylsilyl trifluoromethanesulfonate at -25°C, and stirred by elevating the temperature from same temperature to room temperature for 27 hours. An aqueous solution of sodium hydrogencarbonate and dichloromethane were added to the reaction mixture, the insoluble matters were removed by filtration, the filtrate was subjected to separation. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed by distillation. The residue was purified by means of a silica gel column chromatography (eluent: dichloromethane/ethyl acetate/ methanol = 20/20/1 - 15/15/1), there was obtained 1.1 g of methyl 2-[ 2-{3-[ 3,4-dihydro-2( lH)-quinolinon-6- yl ]oxypropylsulfonyl}-l-imidazolyl ] -l-benzyl-2 , 3 , 4-tri- O-pivaloyl-β-D-glucopyranosidouronate as white amorphous . H-NMR (CDC1₃, 250MHz) δ (ppm):

1.09-1.12 (m, 27H), 2.23-2.34 (m, 2H), 2.57-2.63 (m, 2H) , 2.89-2.95 (m, 2H) , 3.57-3.64 (m, 2H) , 3.71 (s, 3H) ,

3.93-4.05 (m, 3H) , 4.31-4.46 (m, IH) , 4.53-4.68 (m, 2H) , 5.01-5.38 (m, 3H), 6.69 (s, 3H), 7.15 (br.s, 3H), 7.23-7.62 (m, 5H) , 7.86 (br.s, IH) . By using suitable starting materials and by procedure similar to that of used in Example 32, there was obtained the compound of the above-mentioned Example 14.

Example 33 (a) Into a dichloromethane solution (140 ml), containing 1.94 g of ( ± ) -3 , 4-dihydro-6-[ 3-{ l-[ 2- ( hydroxymethyl ) phenyl ] -2-imidazolyl }sulfinylpropoxy] - 2 ( IH) -quinolinone , was added 60 ml of vinyl acetate and 1.94 g of Novozym 435 (mfd. by Novonordisk Bioindustry S/A) , and stirred at room temperature for 100 minutes. The insoluble matters were removed by filtration using Celite, the filtrated was concentrated. The residue was subjected to purification by means of a silica gel column chromatography (eluent: dichloromethane/methanol = 20/1), there were obtained 0.85 g of (S)-(+)-3,4- dihydro-6- [ 3-{ 1- [ 2- ( acetoxymethyl )phenyl ] -2-imidazoly1 }- sulfinylpropoxy] -2 (IH) -quinolinone (acetoxy-form) (optical purity: 94.6%, e.e.) and 1.02 g of (R)-(-)-3,4- dihydro-6- [ 3- { 1- [ 2- ( hydroxymethyl ) phenyl ] -2-imidazolyl }- sulfinylpropoxy] -2 ( IH) -quinolinone (hydroxy-form) (optical purity: 66.6%, e.e.) The optical purity was measured by means of

HPLC analysis under the conditions as follows .

Column: ULTRON ES-OVM (mfd. by Shinwa Kako, Co.,

Ltd. ) Eluent: Acetonitrile/20 mM-KH2P04 aqueous solution = 7/93

Rate of flow: 1.0 ml/minute Detecting wave length: UN 254 nm Retention time:

Hydroxy-form: (S)-form enantiomer: 8.0 minutes (R)-form enantiomer: 9.0 minutes

Acetoxy-form: (S)-form enantiomer: 15.9 minutes (R)-form enantiomer: 23.7 minutes By using suitable starting materials and by procedure similar to that of used in Example 33 a), there were obtained the compound of the above-mentioned Examples 24 and 26.

(b) Into a methanol solution (20 ml), containing 0.85 g of the acetoxy-form compound obtained in the above-mentioned process (a) was added 0.28 g of potassium carbonate, and stirred at room temperature for 6 hours. To this reaction mixture was added water (5 ml), then methanol was removed by distillation. The residue was extracted with dichloromethane and dried over anhydrous sodium sulfate, the solvent was removed by distillation, there was obtained 0.75 g of colorless amorphous solid product. A dichloromethane solution (35 ml), containing 0.50 g of this solid product, was added 15 ml of vinyl acetate and 0.50 g of Novozym 435 (mfd. by Novonordisk Bioindustry, S/A) and stirred at room temperature for 5 hours . The insoluble matters were remove by filtration using Celite, the filtrate was concentrated. The residue was subjected to purification by means of a silica gel column chromatography (eluent: dichloromethan/methanol = 20/1), there was obtained 0.47 g of (S)-(+)-3,4-dihydro-6-[3-{l-[2-(acetoxymethyl)- phenyl]-2-imidazolyl}sulfinylpropoxy] -2 (IH) -quinolinone (optical purity: 100%, e.e.). The optical purity of the product were conducted by means of HPLC analysis under the conditions as follows.

Column: ULTRON ES-OVM (mfd. by Shinwa Kako, Co., Ltd. ) Eluent: Acetonitrile/20 mM-KH2P04 aqueous solution

= 1/15 Rate of flow: 1.0 ml/minute Detecting wave length: UN 254 nm

Retention time: (S)-form enantiomer: 21.9 minutes (R)-form enantiomer: 34.8 minutes

Colorless amorphous Rotation angle: [ ]_D ²⁸= +44.8° (c=0.1, chloroform) ^!H-NMR (DMSO-d₆, 250MHz) δ (ppm):

1.75-2.17 (m, 5H), 2.26-2.44 (m, 2H), 2.69-2.91 (m, 2H), 3.30-3.65 (m, 2H) , 3.99 (t, J=6.0Hz, 2H), 4.67-4.98 (m, 2H) , 6.57-6.87 (m, 3H), 7.25-7.83 (m, 6H),

9.89 (br.s, IH) .

By using suitable starting material and by procedure similar to that of used in Example 33 b), there was obtained the compound of the above-mentioned Example 24.

(c) Into a dichloromethane solution (100 ml), containing 1.02 g of the hydroxy-form of compound obtained in the above-mentioned process (a) were added 100 ml of vinyl acetate and 1.00 g of Novozym 435 (mfd. by Novonordisk Bioindustry S/A) and stirred at room temperature for 6 hours . The insoluble matters were removed by filtration using Celite, the filtrate was concentrated. The residue was subjected to purification by means of a silica gel column chromatography (eluent :dichloromethane/methanol=20/l ) , there was obtianed 691 mg of (R) -( - ) -3 , 4-dihydro-6-[ 3-{l-[ 2- ( hydroxymethyl ) phenyl ] -2-imidazolyl}sulfinylpropoxy] - 2 ( IH) -quinolinone (optical purity: 100%, e.e.).

The optical purity of the product was measured by means of HPLC analysis under the conditions as follows.

Column: CHIRALCEL OJ (mfd. by Daicel Chemical

Industries, Ltd.) Rate of flow: 1.0 m. /minute

Eluent: ri-Hexane/ethanol/diethylamine = 500/500/1 Detecting wave length: UN 254 nm

Retention time: (S)-form enantiomer: 25.7 minutes (R)-form enantiomer: 20.5 minutes

Colorless amorphous

Rotation angle: [ ]_D ²⁶= -27° (c=0.1, chloroform) H-ΝMR (DMSO-d₆ 250MHz) δ (ppm):

1.83-2.12 (m, 2H), 2.27-2.44 (m, 2H), 2.71-2.89 (m, 2H) , 3.25-3.59 (m, 2H),

3.98 (t, J=6.2Hz, 2H), 4.06-4.33 (m, 2H), 5.25 (t, J=5.3Hz, IH), 6.60-6.81 (m, 3H), 7.27-7.53 ( , 3H) , 7.53-7.72 (m, 3H), 9.89 (br.s, IH) . By using suitable starting materials and by procedures similar to that of used in Example 33 c), there was obtained the compound of the above-mentioned Example 26.

Example 34 Into a methanol solution (20 ml), containing

0.41 g of (S)-(+) -3, 4-dihydro-6-[3-{l-[ 2- (acetoxymethyl )phenyl ] -2-imidazolyl}sulfinylpropoxy] -2 ( IH) -quino linone was added 0.13 g of potassium carbonate, and stirred at room temperature for 16 hours. Water (5 ml) was added to the reaction mixture, then methanol was removed by distillation. The residue was extracted with dichloromethane, dried over anhydrous sodium sulfate and the solvent was removed by distillation. The residue was subjected to purification by means of a silica gel column chromatography (eluent: dichloromethane/methanol = 20/1), there was obtained 0.32 g of (S)-(+)-3,4- dihydro-6-[3-{l-[ 2- (hydroxymethyl )phenyl ]-2-imidazolyl}- sulfinylpropoxy] -2- ( IH) -quinolinone (optical purity: 100% e.e. ) .

Column: CHIRALCEL OJ (mfd. by Daicel Chemical

Industries, Ltd.) Eluent: n-Hexane/ethanol/diethylamine = 500/500/1 Rate of flow: 1.0 ml/minute Detecting wave length: UN 254 nm

Retention time: (S)-form enantiomer: 25.7 minutes

(R)-form enantiomer: 20.5 minutes Colorless amorphous

Rotation angle: [ ]_D ²⁶= +27° (c=0.1, chloroform) ^:H-ΝMR (DMSO-d₆ 250MHz) δ (ppm):

1.80-2.10 (m, 2H), 2.30-2.44 (m, 2H), 2.72-2.87 (m, 2H), 3.16-3.61 (m, 2H) , 3.98 (t, J=6.2Hz, 2H), 4.06-4.32 (m, 2H), 5.26 (t, J=5.3Hz, IH), 6.57-6.83 (m, 3H), 7.23-7.53 (m, 3H) , 7.53-7.75 (m, 3H),

9.89 (brs, IH) .

By using suitable starting materials and by procedure similar to that of used in Example 34, there was obtained the compound of the above-mentioned Example 25.

Example 35 Into a dichloromethane solution (5 ml), containing 110 mg of ( S )- (+ ) -3 , 4-dihydro-6-[ 3-{l-[ 2- hydroxymethyl ) phenyl ] -2-imidazolyl} sulfinylpropoxy] - 2 ( IH) -quinolinone, was added 80 μl of triethylamine, then 50 μl of methanesulfonyl chloride was added dropwise under ice-cooling condition and stirred at the same temperature for 2 hours . The reaction mixture was washed with an aqueous saturated solution of sodium hydrogencarbonate, the organic layer was dried over anhydrous sodium sulfate. After removal of the solvent by distillation, the residue was subjected to purification by means of a silica gel column chromatography (eluent: dichloromethane/methanol=20/l ) , there was obtained 110 mg of ( S ) -3 , 4-dihydro-6- [ 3-{l-[ 2- (methanesulfonyloxymethyl )phenyl ] -2-imidazolyl}sulfinylpropoxy] - 2 ( IH) -quinolinone as colorless amorphous. *H-NMR (CDC1₃ 250MHz) δ (ppm):

2.10-2.35 (m, 2H), 2.46-2.70 (m, 2H), 2.77-3.06 (m, 5H), 3.35-3.81 (m, 2H), 3.90-4.13 (m, 2H), 4.18-5.22 ( , 2H), 6.47-6.84 ( , 3H) , 7.15-7.79 (m, 6H),

8.31-8.63 ( , IH) . Pharmacological test

[Inhibiting activity for 12-HETE production]

(1) Materials and apparatus used for the test

A blood was collected from a healthy volunteer, by a method of EDTA/saline, and washed platelet suspension was prepared using EDTA/Tyrode' s buffer. As to collagen, Collagen Reagent Form [mfd. by Nycomed Arzneimittel Co., Ltd. in (West) Germany] was used. The amount of 12-HETE was determined by using 12-HETE EIA-kit manufactured by PerSeptive Diagnostics Co., Ltd.

(2) Test method

Blood was collected from healthy volunteer, and washed platelet was prepared with EDTA/saline at a concentration of 3 x 10⁵/μl, in accordance with a usual procedure. In the 200 μl of the washed platelet suspension, 10^"8 to 10^"6 M of test compound were added and was incubated at 37 °C for 2 min. Then the platelets were stimulated by adding 30 μg/ml of collagen and this mixture was incubated at 37 °C for 5 min. The reaction mixture was stand in ice in order to stop the reaction. Then this platelet suspension was freeze and thawed twice to destroy the cells and eicosanoids in the sample was extracted using C18 column. The concentration of 12-HETE in the extracted sample was quantitatively measured by use of EIA-kit. The test was conducted in n=3. (3) Evaluation method

Effect of the test compounds for inhibiting production of 12-HETE per 3 x 10⁸ of platelets was discussed. IC₅₀ values for 12-HETE production were performed by the test compounds and the results are shown in Table 2 as follows.

Table 2 Test compound ICn value (μM

Compound of Example 4 0.07 Compound of Example 9 0.08

Claims

1. A carbostyril derivative represented by the general formula (1),

(wherein A_x is a lower alkylene group; R³ is a hydrogen atom or a lower alkyl group; R , R⁵ and R⁶ are the same or different from each other and are hydrogen atoms or lower alkanoyl groups); R² is a hydrogen atom or a hydroxyl group; 1 is 0, 1 or 2; and the carbon-carbon bond between 3 and 4-positions in the carbostyril skeleton is a single or double bond; provided that when R¹ is a lower alkyl group, then R² is a hydroxyl group] or salt thereof .

2. The carbostyril derivative or salt thereof according to Claim 1, wherein R¹ is a lower alkyl group which may have hydroxyl groups .

3. The carbostyril derivative or salt thereof according to Claim 1, wherein R¹ is a lower alkanoyloxy- lower alkyl group, a lower alkylsulfonyloxy-lower alkyl group or a lower alkenyloxy-lower alkyl group.

4. The carbostyril derivative or salt thereof according to Claim 1, wherein R¹ is a group of the formula,

(wherein A_{l r} R³, R^A, R⁵ and R⁶ are the same as defined the above .

5. The carbostyril derivative or salt thereof according to Claim 2, wherein 1 is 0; and R² is a hydrogen atom.

6. The carbostyril derivative or salt thereof according to Claim 2, wherein 1 is 1; and R² is a hydrogen atom .

7. The carbostyril derivative or salt thereof according to Claim 2, wherein 1 is 2; and R² is a hydrogen atom.

8. The carbostyril derivative or salt thereof according to Claim 2, wherein 1 is 0; and R² is a hydroxyl group .

9. The carbostyril derivative or salt thereof according to Claim 2, wherein 1 is 1; and R² is a hydroxyl group .

10. The carbostyril derivative or salt thereof according to Claim 2, wherein 1 is 2; and R² is a hydroxyl group.

11. The carbostyril derivative or salt thereof according to Claim 3, wherein 1 is 0; and R² is a hydrogen atom.

12. The carbostyril derivative or salt thereof according to Claim 3, wherein 1 is 1; and R² is a hydrogen atom.

13. The carbostyril derivative or salt thereof according to Claim 3, wherein 1 is 2; and R² is a hydrogen atom.

14. The carbostyril derivative or salt thereof according to Claim 3, wherein 1 is 0; and R² is a hydroxyl group .

15. The carbostyril derivative or salt thereof according to Claim 3, wherein 1 is 1; and R² is a hydroxyl group .

16. The carbostyril derivative or salt thereof according to Claim 3, wherein 1 is 2; and R² is a hydroxyl group .

17. The carbostyril derivative or salt thereof according to Claim 4, wherein 1 is 0; and R² is a hydrogen atom.

18. The carbostyril derivative or salt thereof according to Claim 4, wherein 1 is 1; and R² is a hydrogen atom.

19. The carbostyril derivative or salt thereof according to Claim 4, wherein 1 is 2; and R² is a hydrogen atom.

20. The carbostyril derivative or salt thereof according to Claim 4, wherein 1 is 0; and R² is a hydroxyl group .

21. The carbostyril derivative or salt thereof according to Claim 4, wherein 1 is 1; and R² is a hydroxyl group .

22. The carbostyril derivative or salt thereof according to Claim 4, wherein 1 is 2; and R² is a hydroxyl group.

23. The carbostyril derivative or salt thereof according to Claim 1 , wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a single bond.

24. The carbostyril derivative or salt thereof according to Claim 1, wherein the carbon-carbon bond between 3-and 4-positions in the carbostyril skeleton is a double bond.

25. 3 , 4-Dihydro-6-{ 3- [ 1- ( 2-hydroxymethyIpheny1 ) -2- imidazolyl ] sulfinylpropoxy}-2 ( IH) -quinolinone .

26. (S)-(+)-3, 4-Dihydro-6-{3- [ 1- ( 2-hydroxymethyl- phenyl ) -2-imidazolyl ] sulfinylpropoxy}-2 ( IH ) -quinolinone .

27. (R)-(-)-3,4-Dihydro-6-{3-[l-(2-hydroxymethyl- phenyl ) -2-imidazolyl ] sulfinylpropoxy}-2 ( IH) -quinolinone .

28. 6-{3-[l-(2-hydroxymethylphenyl)-2-imidazolyl]- sulfonylpropoxy}-2 ( IH) -quinolinone .

29. 6-{3-[l-(2-hydroxymethylphenyl)-2-imidazolyl]- sulfinylpropoxy}-2(lH) -quinolinone.

30. (S)-(+)-6-{3-[l-(2-Hydroxymethylphenyl)-2- imidazolyl ] sulfinylpropoxy}-2 ( IH ) -quinolinone .

31. (R) - ( - ) -6-{ 3- [ 1- ( 2-HydroxymethyIpheny1 ) -2- imidazolyl]sulfinylpropoxy}-2 ( IH) -quinolinone.

32. 3,4-Dihydro-4-hydroxy-6-{3-[l-(2-hydroxy- methylphenyl ) -2-imidazolyl ] sulfinylpropoxy}-2 ( IH) - quinolinone.

33. 3,4-Dihydro-3-hydroxy-6-{3-[l-(2-hydroxy- methylphenyl ) -2-imidazolyl ] sulfonylpropoxy}-2 ( IH) - quinolinone.

34. An agent for platelet adhesion inhibitor characterized by containing, as the effective ingredient, a carbostyril derivative or salt thereof as claimed in Claim 1.

35. Anti-thrombosis agent characterized by containing, as the effective ingredient, a carbostyril derivative or salt thereof as claimed in Claim 1.

36. An agent for inhibiting hyperplasia of the intima of the artery characterized by containing, as the effective ingredient, a carbostyril derivative or salt thereof as claimed in Claim 1.

37. An agent for platelet agglutination inhibitor characterized by containing, as the effective ingredient, a carbostyril derivative or salt thereof as claimed in Claim 1.

38. An agent for inhibiting production of 12- hydroxyeicosatetraenoic acid characterized by containing, as the effective ingredient, a carbostyril derivative or salt thereof as claimed in Claim 1.

39. Process for preparing a carbostyril derivative represented by the general formula (la),

(la)

(wherein A, is a lower alkylene group; R³ is a hydrogen atom or a lower alkyl group; R^╬¢, R⁵ and R⁶ are the same or different from each other and are hydrogen atoms or lower alkanoyl groups); R² is a hydrogen atom or a hydroxyl group; and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is a single bond or double bond; provided that when R¹ is a lower alkyl group, then R² is a hydroxyl group], by reacting a carbostyril derivative represented by the general formula ( 2 ) ,

[wherein R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined the above; X is a halogen atom, a lower alkane- sulfonyloxy group, an arylsulfonyloxy group or an aralkylsulfonyloxy group] , with a compound represented by the general formula (3),

[wherein R¹ is the same as defined the above].

40. Process for preparing a carbostyril derivative represented by the general formula (lb),

[wherein R¹, R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39], by oxidizing a carbostyril derivative represented by the general formula (la),

[wherein R¹ , R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39].

41. Process for preparing a carbostyril derivative represented by the general formula (lc),

[wherein R¹, R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39].

42. Process for preparing a carbostyril derivative represented by the general formula (lc),

[wherein R^! , R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39], by oxidizing a carbostyril derivative represented by the general formula (lb),

43. Process for preparing a carbostyril derivative represented by the general formula (If),

[wherein R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39; 1 is 0, 1 or 2; and A, is a lower alkylene group], by reacting a carbostyril derivative represented by the general formula (Id),

(Id)

[wherein R², A, A, and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, and is the same as defined above], with a compound represented by the general formula ( 4 ) ,

[wherein R is a lower alkyl group; R , R ^a and R are the same or different, and are lower alkanoyl groups; and Xi is a halogen atom] to obtain a carbostyril derivative represented by the general formula (le),.

[wherein R², A, A_: and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, and 1, R^3a, R^4a, R^5a and R^6a are the same as defined above], then reacting this carbostyril derivative (le) with a basic compound to obtain the desired carbostyril derivative represented by the general formula (If).

44. Process for preparing a carbostyril derivative represented by the general formula (lg),

[wherein A, and R¹ are the same as defined in Claim 39, and 1 is 0, 1 or 2; and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton is a single bond], by reducing a compound represented by the general formula (7)

[wherein A and R¹ are the same as defined in Claim 39, and 1 is the same as defined above; and R⁷ is a lower alkyl group], with a reducing agent.

45. Process for preparing a carbostyril derivative represented by the general formula (li),

(li)

[wherein R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, and 1 is 0, 1 or 2], by reacting a compound represented by the general formula (In),

( in ) [wherein R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, and 1 is the same as defined above], with an acid.

46. Process for preparing a carbostyril derivative represented by the formula (lm),

( -OH

[wherein A, A_╬│ and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39], by reacting a carbostyril derivative represented by the general formula (lj),

(ij) [wherein A, A_X and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39], with vinyl acetate (8) in the presence of a lipase to obtain a carbostyril derivative represented by the general formula (Ik),

[wherein A, A_: and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39], then reacting said carbostyril derivative (Ik) with an acid or basic compound to obtain the desired carbostyril derivative (lm).

47. Process for preparing a carbostyril derivative represented by the general formula (IC),

[wherein A, A_x and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39], by reacting a carbostyril derivative represented by the general formula (lj),

(lj)

[wherein A, A_x and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39], with vinyl acetate (8) in the presence of a lipase to obtain the desired carbostyril derivative ( 1C ) .

48. Process for preparing a carbostyril derivative represented by the general formula (In),.

(in)

[wherein R², A, A, and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, 1 is 0, 1 or 2; and R⁸ is a lower alkylsulfonyl group] , by reaction a carbostyril derivatives represented by the general formula (Id),

(Id) [wherein R², A, A, and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, and 1 is the same as defined above], with a compound represented by the general formula (9),

R (9)

[wherein R⁸ is the same as defined the above, and _x is the same as defined in Claim 43] in the presence or absence of a basic compound.

49. Process for preparing a carbostyril derivative represented by the general formula (lo),

(lo)

[wherein R², A and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, is 0, 1 or 2; and R⁹ is a lower alkyl group] , by reducing a carbostyril derivative represented by the general formula (In), 8/46593

140

(In)

[wherein R², A, A_: and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, 1 is 0, 1 or 2; and R⁸ is the same as defined in Claim 48], in the presence of a hydrogenation reducing agent.

50. Process for preparing a carbostyril derivative represented by the general formula (1),

(1) [wherein R², A, R¹ and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, and 1 is 0, 1 or 2], by reacting a carbostyril derivative represented by the general formula ( 10 ) ,

(10)

[wherein R² and the carbon-carbon bond between 3- and 4- positions in the carbostyril skeleton are the same as defined the in Claim 39; and R¹⁰ is a hydrogen atom or an alkali metal atom] , with a compound represented by the general formula (11),

[wherein A, X, R¹ and the carbon-carbon bond between 3- and 4-positions in the carbostyril skeleton are the same as defined in Claim 39, and 1 is the same as defined above ] .