BACKGROUND OF THE INVENTION Field of the Invention The present invention relates to novel thiazolidin-4-one derivatives having the following formula(I), which inhibit platelet-activating factor and/or 5-lipoxygenase for the prevention or treatment of inflammatory and allergic disorders mediated by platelet-activating factor and/or leukotrienes, and to pharmaceutical compositions containing these compounds, and to the use thereof to inhibit PAF and/or leukotriene. A process for preparing these compounds is also included in the present invention.

wherein, n, T, Q, R ¹ , R ² , R\ R ⁴ , R ⁵ , R ⁶ , R ⁷ and R ^s are respectively defined as the below.

Description of the Related Art

Benveniste et al. found a factor in 1972 which strongly induces platelet aggregation from rabbit basophils. This factor was named platelet-activating factor

(hereinafter referred to PAF). Hanahan et al. indentified the factor in 1980 as a phosphoglyceride of the alkyl ether type having an acetyl group in the 2-position, i. e.

1-O-hexadecyl or octadecyl-2-acetyl-sπ-glyceryl-3-phosphocholine.

The physiological roles of PAF have been intensively investigated, and it is known that PAF is an important factor acting on platelet aggregation, reduction in blood pressure, immediate allergic reaction, contraction of smooth muscle, inflammation, pain, edema, and alternation in the respiratory and circulatory systems.

Therefore, PAF-antagonistic activity-possessing compounds are very useful for

treating various PAF-induced diseases, such as inflammatory diseases, allergic diseases, anaphylatic shocks, septic shocks, vascular diseases as DIC, myocardinal diseases, asthma, pulmonary edema, and adult respiratory diseases.

Leukotrienes, like PAF, are potent lipid mediators of a variety of topical and systemic diseases and disorders. A 5-lipoxygenase in cytoplasm catalyzes the conversion of arachidonic acid to leukotriene A4 which is the precursor of leukotriene B4 and C4. Leukotriene B4 and C4 are oxygenated metabolites that contribute to the pathogenosis of such inflammatory disorders as arthritis, asthma, psoriasis, and thrombotic disease. Leukotrienes are released concomitantly from leukocytes with PAF from a common phospholipid precursor upon cellular activation and act synergistically with PAF in many biological models.

It has been demonstrated by O'Donnell and Lewis et al. that a physical combination of a PAF antagonist and leukotriene inhibitor is significantly more effective than either agent alone in treating athma in an animal model [Therapeutic Approaches to inflammatory Diseases, Lewis et al., Elsevier, New York, 1989, pp 169-193]. Shen et al. and Page et al. pointed out that single compounds which possess the dual inhibitory activity of PAF and leukotriene inhibition would have greater anti-inflammatory activities than a physical combination of a PAF and a leukotriene inhibitor. [PAF and Related Lipid Mediators, Plenum Pub., N.Y., 164 (1987) ; Trends in Pharmacol. Sci., 10(1989)].

Moreover, the chemical combination of PAF and 5-lipoxygenase inhibitory activities in one molicule has advantages over drug combinations in terms of optical pharmacokinetics, clinical applications and developmental costs.

Under these circumstances, various thiazolidin-4-one derivatives have been synthesized. But thiazolidin-4-one compounds simutaniously possessing PAF- antagonistic activity and leukotriene inhibition activity have not been known at this time.

Reports related to thiazolidin-4-one derivatives are as followings: JV-(phenyl,

pyridyl)-2-pyridyl-thiazoUdin-4-one derivatives for agricultural chemicals [Japanese Patent Kokai No. 145679/79]; JV-(phenyl, benzyl, cycloalkyl)-2-pyridyl-thiazolidin-4- one derivatives for agricultural chemicals [Japanese Patent Kokai No. 55184/80]; N- (carboxycyclohexylmethyl)-2-pyridyl-thiazolidin-4-one derivatives for anticomplementary acitvity [Japanese Patent Application Kokai No. 85380/82]; N- (carboxymethylphenyl)-2-pyridyl-thiazolidin-4-one derivatives having anti- inflammatory and analgesic activity [Japanese Patent Kokai No. 88170/82]; N- (pyrazinyl)-2-pyridyl-thiazolidin-4-one derivatives for agricultural chemicals [Japanese Patent Kokai No. 183689/83]; N-(phenyl)-2-pyridyl-thiazolidin-4-one derivatives for intermediates in synthesis [U.S. Patent No. 4,501 ,746]; iV- (carbamoyloxy)-2-pyridyl-thiazolidin-4-one derivatives for cardiotonic[Japanese Patent Kokai No. 103883/86]; JV-(alkyl, aminoalkyl)-2-ρyridyl-thiazolidin-4-one derivatives for PAF-antagonist [Japanese Patent Kokai No. 126391/87, 139304/87, 160481/87, 12379/88 and European Patent Application No. 292305/88] etc.. Because of the large number of diseases and disorders which are mediated by

PAF and leukotrienes, synthesis of new compounds which possess leukotriene or PAF inhibitory activity, and preferably compounds which possess both inhibitory activity will be very useful as active ingredients in the prevention and/or treatement of those diseases and disorders. Accordingly, the present inventors have conducted long term investigations and studies on thiazolidin-4-one derivatives which have PAF antagonistic acitvity and/ or leukotrienes inhibitory activity. The present invention has been accomplished based on these findings.

SUMMARY OF THE INVENTION

It is an object of this invention to provide novel thiazolidin-4-one derivatives which act as PAF antagonists and/or inhibit biosynthesis of leukotrienes via the 5- lipoxygenase pathway, the pharmaceutical uses of these derivatives, and a process for

preparing them.

The present invention relates to the novel thiazolidin-4-one derivatives having the following formula(I), which act as PAF antagonists and/or inhibit biosynthesis of leukotrienes via the 5-lipoxygenase pathway.

wherein, : n is (), 1, 2 or 3;

Q is C, - C _l alkyl group, phenyl group that is optionally substituted with one or more suitable substituents selected from methoxy group and nitro group, or pyridiyl group that is optionally substituted with one or more methyl group;

R ¹ , R ² and R ³ are independently hydrogen atom, C, ~ C ₁₀ alkyl group, C ₃ - C ₆ cycloalkyl group, or phenyl group that is optionally substituted with one or more methoxy group;

R ⁴ , R ⁵ , R ⁶ , R ⁷ and R" are independently hydrogen atom, hydroxyl group, halogen atom, C, - C _l0 alkyl group, C, - C ₁₀ alkoxy group, nitro group,

amino group that is optionally substituted with one or more suitable substituents

selected from C, - C ₁₀ alkyl group and C ₃ ~ C ₆ cycloalkyl group, phenyl group that is optionally substituted with one or more suitable substituents selected from methoxy

is 1, 2, 3 or 4 ); and

T is hydrogen atom, hydroxyl group, C, ~ C, ₀ alkyl group,

O O

- (CH^m-R ⁹ . - (CH ₂ ) _m -O- R ¹⁰ , - (CH ₂ ) _m -C-R ¹¹ , - (CH2) _m - NHC — R ¹² , O O O

- (CH _{2 m} - N(OH)C-R ¹⁶ - (CH ₂ ) _m - N(OH)CNH ₂ , - (CH2) _m - CN(OH) - R ¹⁶ ,

or — (CH ₂ ) _m -NR ¹³ R ¹⁴ (in which, m is 1, 2, 3 or 4; R ⁹ is hydrogen atom, phenyl group that is optionally substituted with one or more suitable substituents selected from C, ~ C ₆ alkyl group and C, ~ C ₆ alkoxy group, or a pyridyl group; R ¹⁰ is hydrogen atom, C, ~ C _]0 alkyl group, or C, - C ₄ alkanoyl group; R ⁿ is C, ~ C, ₀ alkyl group, C, - C ₁₀ alkoxy group, or amino group that is optionally substituted with one or more suitable substituents selected from C, ~ C , ₍₁ alkyl group and C ₃ ~ C ₆ cycloalkyl group; R ¹² is C, ~ C ₁₍₁ alkyl group or phenyl group; R ¹³ is hydrogen atom, C,

- C ₁₀ alkyl group, or C, ~ C _I alkanoyl group; R ¹⁴ is hydrogen atom or C, ~ C, ₀ alkyl group or when taken together, connecting R ¹³ and R ¹⁴ , a substituted or unsubstituted four- to seven-membered cycloamino group, or a cycloamino group having another hetero atoms; and R ¹⁶ is hydrogen atom or C, - C ₁₀ alkyl group.

The present invention also includes pharmaceutically acceptable salts of the formula(I), including, for example, salts with mineral acids such as, e.g., hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid, or salts with organic carboxylic acid such as, e.g., formic acid, acetic acid, malic acid, citric acid, maleinic acid, fumalic acid or tartaric acid.

And the compounds according to the invention, as well as the pharmacuetically acceptable salts thereof, may be existed geometrical or optical isomerism. Thus the present invention includes isomer in each case the isomerism and hydrate of the compounds.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description and the following detailed description are examplary and explanatory, and are intended to

provide further explanation of the invention as claimed.

Novel compounds(I) of the present invention can be prepared by reacting compound of formula(II)

wherein, T and Q are defined as in the formula(I); with compound of formula(III)

wherein, n, R\ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R" are defined as in the formual(I); in the presence of base and solvent at -78 "C to reflux temperature, via the formula (I- 1 ) as an intermidate

wherein, n, T, Q, R ¹ , R ² , R ³ , R ⁴ , R\ R ^fi , R ⁷ and R'are defined as in formula(I).

The reaction of compound(II) with compound(III) is preferably carried out in a suitable solvent which at least one selected from inert organic solvents such as, e.g., tetrahydrofuran, benzene, toluene, dichloromethane or dichloroethane, and polar organic solvents such as, e.g., methanol, ethanol, dimethylsulfoxide, N,N- dimethylformamide or acetic acid. The basic medium for the reaction of compound (II) and (III) is preferably metal hydride such as, e.g., sodium hydride, potassium hydride or calcium hydride, lithium diisopropylamide, methyl lithium, butyl lithium, phenyl lithium, sodium methoxide, sodium ethoxide, sodium acetate, sodium

hydroxide, potassium hydroxide, or organic base such as, e.g., trie thy 1 amine, piperidine or morpholine, etc..

Without isolation of the compound of formula(I-l) which is as an intermediate of the reaction mixtures, the reaction mixture can be reacted with an acid or alkali to immediately obtain compound of the formula(I).

wherein, n, T, Q, R ¹ , R ² , R ³ , R ⁴ , R ^s , R\ R ⁷ and R ^s are defined as the above.

Suitable preferred acids are inorganic acid such as, e.g., hydrochloric acid, hydrochloric acid methanol or hydrochloric acid/ethanol, or organic acid such as, e.g., acetic acid or p-toluenesulfonic acid, etc.. And suitable preferred alkalis are sodium hydroxide, potassium hydroxide, sodium methoxide or sodium ethoxide, etc..

If the reaction of compound(II) with compound(III) is carried out at -78 ^* C to 0 ∑, the formula(I-l) as intermidate may be isolated from the reaction mixture in a high yield. Also, according to the present invention the compound of formula(I) can be prepared by reacting compound of formula(II-l)

wherein, T and Q are defined as in the formula(I), and X is halogen atom; with compound of formula(πi)

wherein, n, R\ R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ and R* are defined as in the formula(I); in the presence of zinc and an organic solvent in which tetrahydrofuran, benzene, toluene or trimethoxyborane at -78 ^* C to reflux temperature, to obtain the formula (1-1) as intermidate

wherein, n, T, Q, R ¹ , R ² , R\ R ⁴ , R R\ R ⁷ and R" are defined as in the formulaQ); and reacting the compound of formula(I-l) with the said acid or alkali.

Also, the present invention relates to process for preparing compound of formula(II-l)

wherein, T and Q are as defined in formula(I), and X is halogen atom; reacting compound of formula(H)

wherein, T and Q are defined as in formula(I); with halide such as, e.g., bromine, iodine, chlorine, iVbromosuccinimide, N- bromophthalimide, -chlorosuccinimide or JV-chlorophthalimide in an organic solvents such as, e.g., ether, tetrahydrofuran, chloroform, carbon tetrachloride, dichloromethane, benzene, toluene, dimethyl form amide or etc. at 0 ^* C to reflux temperature.

Also, the present invention relates to process for preparing compound of formula(II)

wherein, T and Q are defined as in formula(I); by dehydrating the compound of Q-CHO( where in, Q is defined as in the formula(I)) with compound of T-NH ₂ ( wherein, T is defined in the formula(I)) and mercaptoacetic acid(HSCH ₂ CO ₂ H) in an organic solvent uch as, e.g., benzene, toluene, xylene and etc..

It is to be understood that application of the teaching of the present invention to a specific problem or environment will be within the capabilities of one having ordinary skill in the art in light of the teachings contained herein. Examples of the products of the present invention and a representative process for their preparation and recovery appear in the following examples. EXAMPLE 1. Preparation of 3-(2-dimelhylaminoethyl)-2-(3-pyridy])-thiazolidin-4-one

< Method A >

A solution of 3-pyridinecarboxaldehyde(1.0 g, 9.15 mmol) and N,N- dimethylethylenediamine(0.822 g, 9.15 mmol) in toluene(30mL ) was dehydrated under reflux for 1 h. The reaction mixture was allowed to cool to room temperature and evaporated to give 1.63 g(100 %) of N-nicotinylidene-./V',-V- dimethylethylenediamine.

Η NMR(300 MHZ, CDC1 _;I ) £ : 8.86(d, /=2.4Hz, 1H), 8.64(dd, /=4.8Hz, Δ v =

15Hz), 8.35(s, 1H), 8.1 l(m, 1H), 7.33(m, 1H), 3.78 (td, J^=6.9, 1.2Hz, 2H), 2.68(t, /=6.9Hz, 2H), 2.34 (s, 6H).

To a stirred solution of -nicotinylidene-iV',iV'-dimethylethylenediamine(1.63 g) in toluene(30mL ) was added mercaptoacetic acid(0.64 mL, 9.15 mmol) and dehydrated at reflux for 1 h. The reaction mixture was allowed to cool to room temperature and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 2.14 g (93 %) of 3-(2-dimethylaminoethyl)-2-(3- pyridyl)-thiazolidin-4-one.

¹ H NMR(30O MHz, CDCl ₃ ) £ : 8.63(m, 1H), 8.56(d, =2.1Hz, 1H), 7.68(m, 1H),

7.36(m, IH), 5.93(s, 1H), 3.85~3.77(m, 3H), 2.74~2.69(m, IH), 2.48~2.44(m, IH), 2.29~2.21(m, lH), 2.15(s, 6H).

< Method B >

A solution of 3-pyridinecarboxaldehyde(1.0 g, 9.15 mmol) and N,N- dimethylethylenediamine(0.822 g, 9.15 mmol) in toluene(3o mL) was dehydrated under reflux for 1 h. To reaction mixture was added mercaptoacetic acid(0.64 mL, 9.15 mmol) and dehydrated under reflux for 1 h. The reaction mixture was allowed to cool to room temperature and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 2.24 g(98 )of 3-(2- dimethylaminoethyl)-2-(3-pyridyl)-thiazolidin-4-one.

< Method C > A solution of 3-pyridinecarboxaldehyde(1.0 g, 9.15 mmol), N,N- dimethylethylenediamine(0.822 g, 9.15 mmol) and mercaptoacetic acid(0.64 mL, 9.15 mmol) in toluene(50 mL) was dehydrated under reflux for 2 h. The reaction mixture was allowed to cool to room temperature and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 2.22 g(97 %) of 3- (2-dimethylaminoethyl)-2-(3-pyridyl)-thiazolidin-4-one .

The intermediate compounds of formula(II) as shown in Table 1 were prepared in the same manner as described in EXAMPLE 1.

Table 1

Example 1H NMR(300 MHz, CDC1 ₃ ) *

8.63(m, IH), 8.56(d, J=2.1Hz, IH), 7.68 (m, IH), 7.36(m, IH), 5.93(s, IH),

1-1 3.85-3.77(m, 3H), 2.74- 2.69(m, IH), 2.48~2.44(m, IH), 2.29~2.21(m, IH), 2.15(s, 6H)

8.62(m, IH), 8.55(m, IH), 7.68(m, IH), 7.38(m, IH), 5.98(s, IH), 3.65 ~3.85(m,

2H), 2.60~2.79(m, 2H), 2.33~2.57(m, 5H), 0.97(t, J=7.2Hz, 6H)

8.62(m, IH), 8.60(m, IH), 7.66(m, IH), 7.35(m, IH), 5.94(s, IH), 3.84(m, IH), 3.78(m, 2H), 2.74(m, 2H), 2.4 l(m, 5H), 1.74(m, 4H)

8.62(m, IH), 8.55(m, IH), 7.67(m, IH), 7.35(m, IH), 5.98(s, IH), 3.72 ~3.88(m, 3H), 2.78(m, 1H), 2.51 (m, IH), 2.29(m, 5H), 1.54(m, 4H), 1.42(m, 2H)

Example ^! H NMR(300 MHz, CDCI3) *

8.63(m, IH), 8.55(m, IH), 7.68(m, IH), 7.36(m, IH), 5.89(s, IH), 3.74~3.87(m, 3H), 3.67(m, 4H), 2.78(m, IH), 2.48(m, IH), 2.37(m, 5H)

8.63(m, IH), 8.55(m, IH), 7.68(m, IH), 7.36(m, IH), 5,92(s. IH), 3.82(m, IH), 3.78(m, 2H), 2.87(m, 4H), 2.77(m, IH), 2.5()(m, IH), 2.35(m, 5H)

8.57(m, IH), 8.52(m, IH), 7.64(m, IH), 7.10-7.44(m, IH), 5.93(s, IH), 4.21(s, IH), 3.77(m, 3H), 2.73(m, IH). 2.55(m, lH), 2.39(m, 9H)

' ^"8 C°H?^ ⁰ ^ ^{N"CH2CH2" N}

8.63(m, IH), 8.56(m, IH), 7.67(m, IH), 7.35(m, IH), 5.71(s, IH), 3.77(m, 2H),

3.68(m, IH), 2.74(m, IH), 2.24(m, IH), 2.16(s, 6H), 1.70(m, IH), 1.58(m, IH)

Example Η NMR(300 MHZ, CDCb) δ

8.61(m, IH), 8.53(m, IH), 8.46(m, IH), 7.64(m, 2H), 7.34(m, IH), 7.19(m, 2H), 5.54(s, IH), 4.02(m, IH), 3.70(m, 2H), 2.80~3.20(m, 3H)

8.61(m, IH), 8.41(m, IH), 7.57(m, IH),

7.33(m, lH), 6.80(d, J=8.1Hz, IH), 6.64

1-1 1 H ₃ CO- VcH ₂ CH ₂ - ( , IH), 6.62(s, IH), 5.25(s, IH), 3.90 H ₃ CO ( , IH), 3.87(s, 3H), 3.85(s, 3H), 3.75 (m, 2H), 2.85(m, 2H), 2.68(m, IH)

8.63(m, IH), 8.44(d, J=1.8Hz, IH). 7.64 (m, IH), 7.34(m, IH), 6.70(d, J=7.8Hz, IH), 6.62(s, IH), 6.45(d, J=7.8Hz, IH), 5.95(s, 2H), 5.42(s, IH), 4.25(ABq, Δ v =467, J _AB = 15.0Hz, 2H), 3.84(ABq, Δ v =40.0, J _AB = 15.6Hz, 2H)

8.60(m, IH), 8.51(m, IH), 7.60- 7.76(m, 2H), 7.34(m, IH), 7.19(m, IH), 5.83(s, IH), 5.04(d, Jgem= 15.3Hz, IH), 3.90 (m, 2H), 3.81(d, Jgem=15.3Hz, IH)

Example 1H NMR(300 MHz, CDC1 ₃ ) *

8.63(m, IH), 8.49(m, IH), 7.34(m, IH), (s, IH), 4.25(ABq,

8.61(m, IH), 8.46(m, IH), 8.22(m, IH), 25

1-20 95 )

Example 1H NMR(300 MHz, CDC1 ₃ ) δ

8.52(m, IH), 8.40(m, IH), 7.52(m, IH), 7.51(s, IH), 7.18(m, IH), 5.45 (s, IH), 4.62(m, IH), 4.37(m, IH), 3.87(m, IH),

CH _a 3.80(dd, 2H), 3.60(s, 3H), 3.40(m, IH), 3.34(s, 3H)

8.57(s, 2H), 8.05(s, IH), 7.78(d, J=

1-22 OH 7.8Hz, IH), 7.33(m, 2H), 5.79(s, IH), 3.66(s, 2H)

8.64(m, IH). 8.55(m, IH), 7.68(m, IH), 7.37(m, lH), 5.65(d, J=1.5Hz, IH), 3.70 (m, IH), 2.64(m, IH), 1.44(m, 2H), 1.27 (m, 2H), 0.87(t, J=7.5Hz, 3H)

4.78(dd, J=6.3, 1.8Hz, IH), 3.82(td, J= 7.2, 7.2Hz, IH), 3.54(ABq, 2H), 3.07(td, CH ₃ -(CH ₂ ) ₇ - I=7.2Hz, 2H), 2.35(m, 2H), 2.26(s, 6H),

1.92(m, IH), 1.63(m, IH), 1.18~1.46(m, 12H), 0.89(t, J=6.6Hz, 3H)

Example 1H NMR(300 MHz, CDC1 ₃ ) *

4.57(m, IH), 3.56(dd, 2H), 2.90(s, 3H), 1-27 CH ₃ - CH ₃ -(CH ₂ ) ₇ ~ 1.84~1.99(m, IH), 1.57-1.80 (m, IH),

1.05~1.55(m, 12H), 0.89(t, J=6.6Hz, 3H)

4.58(m, IH), 3.57(ABq, 2H), 2.89 (s,

1-28 CH ₃ - CH ₃ - ⁽ CH ₂ ⁾ ₅ - 3H), 1.90(m, IH), 1.72(m, IH), 1.32(m,

8H), 0.89(t, J=6.6Hz, 3H)

4.58(m, IH), 3.54(ABq, Δ u =28, JAB= 15.6Hz, 2H), 2.90(s, 3H), 1.83-1.99(m,

1-29 CH ₃ - CH ₃ -(CH ₂ ) ₂ - IH), 1.61 ~1.79(m, IH), 1.32~1.52(m, 2H), 0.98(t, J=7.2Hz, 3H)

2H), 5.80(s, IH), 3.86(s, 9H), IH), 3.77(m, 2H), 2.86(m, IH), IH), 2.34(m, IH), 2.21(s, 6H)

Example IH NMR(300 MHz, CDC13) δ

8.6 l(m, 2H), 7.68(m, IH), 7.37(m, IH), 5.81(d, J=0.9Hz, IH), 3.76(m, 3H), 3.68 (s, 3H), 3.06(m, IH), 3.7 l(m, IH), 2.46 (m. IH)

8.63(m, 2H), 7.70(m, IH), 7.38(m, IH), i" ³⁷ H,Cθ 5.81(s, IH), 3.78(m, 3H), 3.67(s, 3H),

3.05(m, IH), 2.7 l(m, IH), 2.46(m, IH)

8.61(m, IH), 8.57(m, IH), 7.82(m, IH), 7.45(m, IH), 5.90(d, J=1.2Hz, IH), 4.02 (q, J=7.2Hz, 2H), 3.92 (dd, J=15.6, 1.2Hz, IH), 3.67(d, J=15.6Hz, IH), 3.61-3.73 (m, IH), 2.87(m, IH), 2.54(m, IH), 2.40(m, IH), 1.15(t, J=7.2Hz, 3H)

Example ^l H NMR(300 MHZ, CDC1 ₃ ) δ

8.47(dd, J=4.8, 1.2Hz, IH), 7.45 (dd, J= 7.8, 1.5Hz, IH), 7.2 l( , IH), 6.21 (s, 1-44 IH), 3.85(td, J=7.8, 1.8Hz, IH), 3.72(s, 2H), 2.72(m, IH), 2.59(s, 3H), 2.52(m, IH), 2.31(m, IH), 2.13(s, 3H)

8.63(m, IH), 8.56(d, J=2.1Hz, IH), 7.68 (m, IH), 7.36(m, IH), 5.93(s, IH),

1-46 3.85-3.77(m, 3H), 2.74-2.69 (m, IH), 2.48~2.44(m, IH), 2.15(s, 6H), 1.22(d, J=7.2Hz, 3H)

Example Η NMR(300 MHz, CDC1 ₃ ) δ

DMSO-d ; 8.60(d, J=1.8Hz, IH), 8.55 1.8Hz, IH), 7.85(m, IH),

1-47 , 5.85(s, IH), 3.85 (ABq, Δ 15.6Hz, 2H), 3.74(ABq, Δ * =219, J _AB = 17.Hz, 2H)

), 7.55(d, J=7.8Hz, IH), 7.25

1-48 CHv 79(m, IH), 3.17 (ABq, 2H),

8.47(m, 2H), 7.50(m, IH), 7.23(m, IH), 4.60(dd, J=1.8, 5.1Hz), 3.55 (m, 2H), 2.86(s, 3H), 2.68(t, J= 5.7Hz, 2H), 1.62~ 1.98(m, 4H)

12.34(brs, IH). 8.60(m, IH). 8.58 (m, IH), 7.83(m, IH), 7.45(m, IH), 5.91(d,

1-50 HO A C*H ₂ CCHH ₂ - J=1.2Hz, I H), 3.92 (dd, J=15.6, 1.2Hz, IH), 3.67(d, J=15.6Hz, IH), 3.63(m, IH), 2.83(m, IH), 2.54(m, IH), 2.29(m, IH)

Example T Q 'H NMR(300 MHz, CDCl ₃ ) δ

8.61(m, IH), 8.56(m, IH), 7.86(m, IH),

7.42(m, IH), 5.86(s, IH), 4.14(d, J=

9 ^ 17.4Hz, I H), 4.02(d, J= 15.6Hz, IH),

1-51 C ₂ H _G 0 CH ₂ - IT 5,

^- ^N 3.01(q, J=7.2Hz, 2H), 3.74(d, J=15.6Hz,

IH), 3.58(d, J= 17.4Hz, IH), 1.13(t, J=

7.2Hz, 3H)

10.51(s, IH), 8.80(s, IH), 8.59(m, 2H), 7.82(m, IH), 7.46(m, IH), 5.88(s, IH),

1-52 HO- ^■ 3.93(d, J=15.3Hz, I H), 3.63(m, IH), 3.67(d, J=15.3Hz, I H), 2.80(m, IH), 2.29(m, lH), 2.07(m, IH)

EXAMPLE 2.

Preparation of 3-(2-dimethylaminoethyl)-5-(α-hydroxybenzyl)-2-(3-pyridyl)- thiazolidin-4-one < Method A > To a solution of diisopropylamine (0.142 mL, 0.796 mmol) in tetrahydrofuran

(10 mL) was added » BuLi (1.6 M solution, 0.5 mL, 0.80 mmol) at -78 ^* C. After stirried for 1 h. To the reaction mixture was added 3-(2-dimethylaminoethyl)-2-(3- pyridyl)-thiazolidin-4-one(0.20 g, 0.796 mmol) dissolved in tetrahydrofuran(1.5 mL). After stirried for 30 min, to the reaction mixture was added benzaldehyde(98 fd, 0.950 mmol) and stirred for 1 h and allowed to warm to room temperature. The reaction mixture was poured into brine(2 mL) and it was then extracted by using ethyl acetate(30 L).

The ethyl acetate phase was dried over anhydrous magnesium sulfate and evaporated to dryness. The residure was purified by flash column chromatography on silica gel to give 0.253 g(89 %) of 3-(2-dimethylaminoethyl)-5-(α-hydroxybenzyl)- 2-(3-pyridyl)-thiazolidin-4-one.

'H NMR(30 MHz, CDCl ₃ ) £ : 8.62(m, 2H), 7.81(m, IH), 7.36(m, IH), 1.29-1.26

(m, 5H), 5.84(s, IH), 5.18(s, IH), 4.52(s, IH), 4.20 (m, IH), 2.75~2.35(m, 3H), 2.17(s, 6H). < Method B >

To a solution of 3-(2-dimethylaminoethyl)-2-(3-pyridyl)-thiazolidin-4-one (0.35 g, 1.39 mmol) in carbon tetrachloride (30 mL) was added .V-bromosuccinimide (0.260 g, 1.46 mmol) and benzoyl peroxide(l mg). The reaction mixture was heated under reflux for 5 h in the dark and filtered off precipitate. The filtrate was evaporated to give crude 5-bromo-3-(2-dimethylaminoethyl)-2-(3-pyridyl)-thiazolidin- 4-one.

¹ H NMR(300 MHz, CDCl ₃ ) ^ : 8.62~8.58(m, 2H), 7.70(d, J=8.1Hz, IH), 7.36-7.33

(m, IH), 5.94(s, IH), 5.21(s, IH), 4.68-4.80(m, IH),

2.82(m, IH), 2.61~2.43(m, 2H), 2.28(s, 6H). To a solution of Zn(0.136 g, 2.09 mmol), CuBr(15 mg, 0.670 mmol) and diethylaluminium chloride (0.184 mg, 1.53 mmol) in mixture of tetrahydrofuran and hexane (10 mL/10 mL) was slowly added 5-bromo-3-(2-dimethylaminoethyl)-2-(3- pyridyl)-thiazolidin-4-one and benzaldehyde (0.162 g, 1.53 mmol) dissolved in tetrahydrofuran at -20 "C for 5 min. After stirred for 2 h, to the reaction mixture was added pyridine (1 mL) warmed to room temperature, diluted with water (10 mL) and extracted with ethyl acetate(80 mL). The combined organic phase was dried over anhydrous magnesium sulfale, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 0.468 g (94 %) of 3-(2- dimethylaminoethyl)-5-(α-hydroxybenzyl)-2-(3-pyridyl)-thiaz olidin-4-one. EXAMPLE 3.

Preparation of 3-(2-dimethylaminoethyl)-5-phenylmethylene-2-(3-pyridyl)- thiazolidin-4-one. < Method A >

A solution of 3-(2-dimethylaminoethyl)-2-(3-pyridyl)-thiazoldin-4-one(0.13 0 g, 0.517 mmol) in tetrahydrofuran(K) mL) was cooled to 0 "C and added potassium hydride(51 mg, 1.29 mmol). After stirred for 5 min, to the reaction mixture was added benzaldehyde(64 l, 0.621 mmol) and warmed to room temperature. After stirred at room temperature for lh, the reaction mix-ture was cooled to 0 ^* C, poured into water(0.2 mL), and extrated with ethyl acetate(20 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 0.166 g (95 %) of 3-(2-dimethylaminoethyl)-5-phenylmethylene-2-(3-pyridyl)- thiazolidin-4-one.

¹ H NMR(300 MHz, CDCl ₃ ) <* : 8.65~8.61(m, 2H), 7.66(d, /=8.1Hz, IH), 7.53(s,

IH), 7.44~7.34(m, 5H), 6.18(s, IH), 4.08-3.97(m, IH). 2.78~2.82(m. IH). 2.63~2.53(m, IH),

2.40-2.35(m, IH), 2.19(s, 6H).

< Method B >

To a solution of 3-(2-dimethylaminoethyl)-2-(3-pyridyl)-thiazoldin-4-one (0.126 g, 0.501 mmol) in acetic acid(10 mL) was added sodium acetate (0.165 g, 20.1 mmol) and benzaldehyde(80 mg, 0.751 mmol). The reaction mixture was heated under reflux for 8 h and evaporated to dryness. The residue was dissolved in water(5 L) and extrated with ethyl acetate(30 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 0.144 g (85 %) of 3-(2-dimethylaminoethyl)-5-phenylmethylene-2-(3-pyridyl)-thi azolidin-4-one.

< Method C >

To a solution of 3-(2-dimethylaminoethyl)-5-(α-hydroxybenzyl)-2-(3-pyridyl)- thiazolidin-4-one(0.20 g) in toluene(K) mL) was added p-toluenesulfonic acid(10 mg).

The reaction mixture was dehydrated under reflux for 2 h, cooled to room temperature, and evaporated. The residue was purified by flash column chromatography on silica gel to give 0.188 g (99 %) of 3-(2-dimethylaminoethyl)-5- phenylmethylene-2-(3-pyridyl)-thiazolidin-4-one.

< Method D >

A solution of 3-(2-dimethylaminoethyl)-5-(α-hydroxybenzyl)-2-(3-pyridyl)- thiazoldin-4-one(0.40 g) dissolved in 28 % HCl-ethanol (5 mL) was stirred for 10 min at room temperature and evaporated. The residue was purified by flash column chromatography on silica gel to give 0.345 g (91 %) of 3-(2-dimethylaminoethyl)-5- phenylmethylene-2-(3-pyridyl)-thiazolidin-4-one.

EXAMPLE 4. Preparation of 3-(2-dimethylaminoethyl)-5-phenylmethylene-2-(3-pyridyl)- thiazolidin-4-one hydrochloride salt (Compound No. 1).

A solution of 3-(2-dimethylaminoethyl)-5-phenylmethylene-2-(3-pyridyl)-thi azolidin-

4-one (0.50g) dissolved in 28 % HCl-ethanol (2 L) was stirred for 3 h at room

temperature and filtered the precipitate. The precipitate was dried under vac. to give 0.537 g(97 %) of 3-(2-dimethylaminoethyl)-5-phenylmethylene-2-(3-pyridyl thiazolidin-4-one hydrochloride salt.

Η NMR(300 MHz, DMSO-d ₆ ) δ _: 9.70(s, IH), 8.79(s, IH), 8.69(d, /=4.5Hz, IH), 7.97(d, 7=8.1Hz, IH), 7.60~7.55(m, 6H), 6.39(s,

IH), 4.20~4.12(m, IH), 3.21~3.00(m, 3H), 2.82(d, /=3.9Hz, 6H). The compounds of formula(I), wherein R ⁴ , R ⁵ , R ⁶ , R ⁷ or R ⁸ is an hydroxyl group, can be prepared in the following EXAMPLE 5, introducing protecting group such as methoxyethoxymethyl group. EXAMPLE 5.

Preparation of 3-(2-iV, -dimethylaminoethyl)-5-(3,5-dimethyl-4-hydroxy- phenylmethylene)-2-(3-pyridyl)-tiιiazolidin-4-one hydrochloride salt (Compound No.

10) A solution of 3,5-dimethyl-4-hydroxybenzaldehyde (10.0 g, 66.6 mmol) in tetrahydrofuran (100 mL) was cooled to 0 "C and added 80 % NaH (2.40 g, 79.9 mmol). After stirred for 10 min at 0 "C, to the reaction mixture was added 2- methoxyethoxymethyl chloride ( 1 1.6 g, 93.2 mmol) and warmed to room temperature.

After stirred for 4 h, the reaction mixture was cooled to 0 "C and added methanol (10 mL). When no more evolution of hydrogen gas the reaction mixture was warmed to room temperature added water(2() L) and extracted with ethyl acetate(2 x 100 mL).

The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 13.6 g(86 ) of 3,5-dimethyl-4-(2- methoxyethoxymethyloxy)-benzaldehyde.

Η NMR(300 MHz, CDCl ₃ ) * : 9.87(s, IH), 7.55(s, 2H), 5.12(s, 2H), 3.95(t, /=

4.5Hz, 2H), 3.60(t, /=4.5Hz, 2H), 3.39(s, 3H), 2.35 (s, 6H)

To a solution of 3-(2- ,-V-dimethylaminoethyl)-2-(3-pyridyl)-thiazolidin-4-one

(1.00 g, 3.98 mmol) in tetrahydrofuran(50 mL) was added lithium diisopropylamide

(1.5M solution, 3.18 mL) at -78 ^* C and stirred for 10 min. To the reaction mixture was slowly added 3,5-dimethyl-4-(2-methoxyethoxymethyloxy)-benzaldehyde(1.13 g, 4.77 mmol) dissolved in tetrahydrofuran(5 mL). After stirred at -78 ^* C for 2 h, to the reaction mixture was added acetic acid(2 mL) and warmed to room temperature.

The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate(3 x 30 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was dissolved in 30% HCl-ethanol solution(5 mL), stirred for 3 h and then neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate

(2 x 50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 1.32 g(87 %) of 3-(2-N,N- dimethylaminoethyl)-5-(3,5-dimethyl-4-hydroxy-phenylemthylen e)-2-(3-ρyridyl)- thiazolidin-4-one.

¹ H NMR(30() MHz, CDCl ₁ ) 5 : 8.63~8.61(m, 2H), 7.75(m. IH), 7.54(s, IH), 7.35

(m, IH), 7.21(s, 2H), 6.17(s, IH), 4.15(m, IH), 2.85

(m, IH), 2.60(m, IH), 2.38(m, IH), 2.18(s, 6H) To a solution of 3-(2-/V,N-dimethylaminoethyl)-5-(3,5-dimethyl-4-hydroxy- phenylemthylene)-2-(3-pyridyl)-thiazolidin-4-one(1.32 g, 3.44 mmol) in ethanol(4 mL) was added 30 % HCl-ethanol solution(0.94 mL) and stirred at room temperature for 30 min. To the reaction mixture was added ethyl acetate(30 mL), filtered, and dried to give 1.49 g(95 %) of 3-(2-ΛT,iVdimethylaminoethyl)-5-(3,5-dimethyM- hydroxy-phenylemthylene)-2-(3-pyridyl)-thiazolidin-4-one hydrochloride salt. ^l H NMR(300 MHz, DMSO-d ₆ ) δ _: 9.60(brs, IH), 8.80(s, IH), 8.68(d, /=4.5Hz, IH),

8.01(m, IH), 7.61(m, IH), 7.38(s, IH), 7.16(s, 2H), 6.26(s, lH), 4.20(m, IH), 3.31~3.01(m, 3H), 2.82(d,

/=3.8Hz, 6H), 2.36(s, 6H) The thiazolidin-4-one derivatives of formula(I) as shown in Table 2 were prepared in the same manner as described in EXAMPLE 1 to EXAMPLE 5.

Table 2

Comp. No. R ¹ Ar Salt

Comp. No. Q R ¹ Ar Salt

»

Comp. No. Q R ¹ Ar Salt

OCH ₃

Comp. No. Q R ¹ Ar Salt

Comp. No. Q R ¹ Ar Salt

Comp. No. Q R ^l AT Salt

Comp. No. R ¹ Ar Salt

Comp. No. Q R ¹ Ar Salt

Comp. No. Q T R* Ar Salt

⁵⁹ C _C H ₅ ^{N N} - ^CH2CH2 - ^H Ij OH

OCH 3

Comp. No. Q T R ¹ Ar Salt

Comp. No. Q R ¹ Ar Salt

Comp. No. Q T R ¹ Ar Salt

Comp. No. R ¹ Ar Salt

Comp. No. Q T R ¹ Ar Salt

Comp. No. Q R ¹ Ar Salt

Comp. No. Q R ¹ Ar Salt

119 CH ₃ -(CH ₂ ) ₇

Comp. No. Q T R ^l Ar Salt

Comp. No. Q T R ¹ Ar Salt

EXAMPLE 6.

Preparation of 3-(2-N, _V-dimethylaminoethyl)-2-(3-pyridyl)-5-(4-hydroxy-3- methoxyphenylallyliden)-thiazolidine-4-one hydrochloride salt(Compound No. 148)

A solution of 4-hydroxy-3-methoxy-cinnamaldehyde(2.0 g, 11.2 mmol) in tetrahydrofuran(20 mL) was cooled to 0 ∑ and added 80 % NaH(0.404 g, 13.5 mmol).

After stirred for 10 min at 0 "C , to the reaction mixture was added 2- methoxyethoxymethyl chloride (1.68 g, 13.5 mmol) and warmed to room temperature.

After stirred for 3 h, the reaction mixture was cooled to 0 "C and added methanol(4 mL). When no more evolution of hydrogen gas the reaction mixture was warmed to room temperature added watei lO mL), and extracted with ethyl acetate(2 x 50 mL).

The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 2.74 g(92 %) of 3-methoxy-4-(2- methoxyethoxymethyloxy)-cinnamaldehyde. ¹ H NMR(30 MHz, CDCl,) ι5 : 9.66(d, 7=7.8Hz, IH), 7.42(d. _/=15.9Hz, IH), 7.24

(d, 7=8.4Hz, IH), 7.13(dd, 7=8.4, 2.1Hz, IH), 7.09

(d, 7=2.1Hz, IH), 6.62(dd, 7=15.9, 7.8Hz, IH),

5.3X(s, 2H), 3.89(s, 3H), 3.85(m, 2H), 3.55(m, 2H),

3.37(s, 3H) To a solution of 3-(2-N,N-dimethylaminoethyl)-2-(3-pyridyl)-thiazolidin-4-one

(l.OOg, 3.98 mmol) in tetrahydrofuran(30 mL) was added lithium diisopropylamide

(1.5M solution, 3.18 mL) at -78 ^* C and stirred for 10 min. To the reaction mixture was slowly added 3-methoxy-4-(2-methoxyethoxymethyloxy)-cinnamaldehyde(1.27 g,

4.77 mmol) dissolved in tetrahydrofuran(5 mL). After stirred at -78 "C for 3 h, the reaction mixture was added acetic acid(4 mL) and allowed to warm to room temperature. The reaction mixture was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate(2 x 50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to

dryness. The residue was dissolved in 30% HCl-ethanol solution(10 mL) stirred at room temperature for 3h and then neutralized with saturated sodium bicarbonate solution, extracted with ethyl acetate(2 x 50 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to give pale yellow solids. The residue was purified by flash column chromatography on silica gel to give 1.35 g (83 %) of 3-(2-iV,Λf-dimethylaminoethyl)-2-(3-pyridyl>5-(4-hydroxy -3- methoxyphenylallylidene) thiazolidin-4-one.

Η NMR(300 MHz, CDC],) £ : 8.62(m, 2H), 7.65(m, IH), 7.38(m, IH), 7.23(d, 7=

1 1,1Hz, IH), 6.98(d, 7=8.4Hz, IH), 6.92(s, IH), 6.85(d, 7=8.4Hz, IH), 6.75(d, 7=15.3Hz, IH), 6.58

(dd, 7=15.3, 11.1Hz, IH), 6.15(s, IH), 3.92(m, IH), 3.91(s, 3H), 2.83(m, I H), 2.59(m, IH), 2.28(m, IH), 2.2()(s, 6H) To a solution of 3-(2-N,ΛT-dimethylaminoethyl)-2-(3-pyridyl}-5-(4-hydroxy-3- methoxyphenylallylidene)thiazolidin-4-one(1.35 g, 3.28 mmol) in ethanol(4 mL) was added 30 % HCl-ethanol solution(0.98 mL) and stirred at room temperature for 1 h. To the reaction mixture was added ethyl aceiate(30 mL), filtered, and evaporated to give 1.53 g(97 % ) of 3-(2- , -dimethylaminoethyl)-2-(3-pyridyl)-5-(4-hydroxy-3- methoxyphenylallylidene)-lhiazolidine-4-one hydrochloride salt. EXAMPLE 7.

Preparation of 3-(2-N,N-dimethylaminoethyl)-2-(3-pyridyl>5-(3,5-diemthyl -4- hydroxyphenylallylidene)-thiazo!idine-4-one (Compound No. 150)

A solution of 3,5-dimethyl-4-hydroxycinnamaldehyde(2.0 g, 11.4 mmol) in tetrahydrofuran(25 mL) was cooled to 0 "C and added 80 % NaH(0.425 g, 14.2 mmol). After stirred for 15 min at 0 13 , to the reaction mixture was added 2- methoxyethoxymethyl chloride(2.12 g, 17.0 mmol) and warmed to room temperature.

After stirred for 4 h, the reaction mixture was cooled to 0 ^* C , added methanol(10 mL) and then warmed to room temperature, added water(20 mL), and extracted with ethyl

acetate(2 x 40 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 2.34 g(78 %) of 3,5-dimethyl-4-(2- methoxyethoxymethyloxy)-cinnamaldehyde. 5 Η NMR(300 MHZ, CDC1 ₃ ) £ : 9.65(d, 7=7.8Hz, IH), 7.36(d, 7=15.6Hz, IH), 7.24

(s, 2H), 6.02(dd, 7=15.6, 7.8Hz, IH), 5.09(s, 2H),

3.95(m, 2H), 3.62(m, 2H), 3.40(s, 3H), 2.3 l(s, 6H)

To a solution of 3-(2- ,Λ ^r -dimethylaminoethyl)-2-(3-pyridyl)-thiazolidin-4-one

(0.193g, 0.768 mmol) in tetrahydrofuran (8 mL) was added lithium diisopropylamide ι o (1.5M solution, 1.0 mL) at -78 ^* C and stirred for 5 min. To the reaction mixture was slowly added 3,5-dimethyl-4-(2-methoxyethoxymethyloxy cinnamaldehyde(0.225 g,

0.683 mmol) dissolved in tetrahydrofuran(l mL). After stirred at -35 ^* C ~ -40 t for

1 h, the reaction mixture was added acetic acid(l mL), allowed to warm to room temperature, and evaporated. To the residue was added 30 % HCl-ethanol solution(5

15 mL), stirred at room temperature for 2 h and it was then neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate(2 x 25 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 0.14 g (45 %) of 3-(2- , -dimethylaminoethyl)-2-(3-pyridyl 5- 0 (3,5-diemthyl-4-hydroxyphenylallylidene)-thiazolidine-4-one.

Η NMR(3(K) MHZ, CDC1 ₃ ) δ : 8.64~8.59(m, 2H), 7.69~7.66(m, IH), 7.37~7.33(m, lH), 7.22(d, 7=l l.lHz, IH), 7.09(s, 2H), 6.72(d, 7= 15.3Hz, IH), 6.55(dd, 7=15.3, 11.1Hz, 3.98-3.90 ( , IH), 2.86-2.77(m, IH), 2.60~2.51(m, IH), 5 2.37~2.28(m, IH), 2.24(s, 6H), 2.18(s, 6H)

EXAMPLE 8.

Preparation of 3-(2- ,jV-dimethylaminoethyl)-2-(3-pyridyl>5-(3,5-diemthyl-4- ethoxycarbonyloxyphenylallylidene)-thiazolidine-4-one (Compound No. 175)

To a solution of 3-(2-jV,-V-dimethylaminoethyl)-2-(3-pyridyl)-5-(3,5-diemthyl - 4-hydroxyphenylallylidene)-thiazolidine-4-one(0.537 g,1.31 mmol) in pyridine(5 mL) was added ethyl chloroform ate(0.284 g, 2.62 mmol), stirred at room temperature for 3 h, and evaporated. The residue was neutralized with saturated sodium bicarbonate solution and extracted with ethyl acetate(4 x 20 mL). The combined organic phase was dried over anhydrous magnesium sulfate, filtered, and evaporated to dryness. The residue was purified by flash column chromatography on silica gel to give 1.35 g (83 %) of3-(2- , Λf-dimethylaminoethyl)-2-(3-pyridyl>-5-(3,5-diemthyl-4- ethoxycarbonyloxyphenylallylidene)-thiazolidine-4-one. 'H NMR(300 MHz, CDC1,) * _: 8.65~8.61(m, 2H), 7.68(m, IH), 7.35(m, IH), 7.21

(d, 7=11.1Hz, IH), 7.10(s, 2H), 6.72(d, 7=15.3Hz, IH), 6.55(dd, 7=15.3, 11.1Hz, IH), 3.99(m, IH), 3.53(q, 7=7.6Hz, 2H), 2.83(m, IH), 2.65(m, IH), 2.30(m, IH), 2.24(s, 6H), 2.19(s, 6H), 1.25(t, 7= 7.6Hz, 3H)

The thiazolidin-4-one derivatives of formula(I) as shown in Table 3, Table 4, and Table 5 were prepared in the same manner as described in EXAMPLE 6 to EXAMPLE 8 using the intermediates of formula(II).

Table 3

Comp. No. Q Ar Salt

Comp. No. Q T R Ar Salt

Comp. No. Q R Ar Salt

Comp. No. Q R Ar Salt

Comp. No. Q R Ar Salt

177 N CHvCH. H

Comp. No. Q T R Ar Salt

Table 4

Comp. No. Ar Salt

196 N-CH ₂ CH ₂ CH ₃ CH ₂ CH ₂ -

197 NN--CCHH ₂₂ CCHH ₂₂ CCHH ₃₃ --

Comp. No. Q T R Ar Salt ^"

203 N-CH ₂ CH ₂ — CH ₃ CH ₂ CH ₂ - I I

CH,

Comp. No. Q R Ar Salt

Table 5

Comp. No. Ar

Also NMR datas of the compounds of formula(I) according to the present invention were listed as shown in Table 6. NMR solvent ; CDC1,

DMSO-d ₆ (Hydrochloride salts of formula(I))

Table 6

Comp. No. Η NMR(300 MHZ) δ

1 9.70(s, IH), 8.79(s, IH), 8.69(d, =4.5Hz, IH), 7.97(d, /=8.1Hz, IH),

7.60~7.55(m, 6H), 6.39(s, IH), 4.20~4.12(m, IH), 3.21~3.00(m, 3H), 2.82(d, /=3.9Hz, 6H)

2 8.65(m, 2H), 7.70(m, IH), 7.50(s, IH), 7.38(m, IH), 7.18(d, /=8.4Hz, IH), 7.05(s, IH), 6.85(d, /=8.4Hz, IH), 6.18(s, IH), 4.05(m, IH), 3.90 (s, 3H), 3.89(s, 3H), 2.82(m, IH), 2.59(m, IH), 2.38(m, IH), 2.18(s, 6H)

3 8.63(m, 2H), 7.66(m, IH), 7.50(s, IH), 7.36(m, IH), 6.74(s, 2H), 6.18(s, IH), 3.98(m, IH), 3.87(s, 3H), 3.86(s, 3H), 3.85(s, 3H), 2.82(m, IH), 2.69(m, IH), 2.38(m, IH), 2.18(s, 6H)

4 9.70(brs, IH), 8.74(s, IH), 8.64(m, IH), 7.84(m, IH), 7.80(m, IH), 7.66 (s, IH), 7.58(m, 2H), 7.49(m, IH), 6.38(s, I H), 4.15(m, IH), 3.38(m,

IH), 3.(K ⁾ ~3.20(m, 2H), 2.82(s, 6H)

6 I0.14(brs, IH), 9.95(s, IH), 8.79(d, /=4.5Hz, IH), 8.22(d, 7=8.1Hz, IH), 7.78(dd, 7=8.1, 4.5Hz, IH), 7.31(s, IH), 6.97(s, IH), 6.85(s, 2H), 6.46(s, IH), 4.15(m, IH), 3.65(m, IH), 3.40(m, IH), 3.15(m, IH), 2.87 (d, J=3.6Hz, 6H)

7 8.62(m, 2H), 7.68(m, IH), 7.50(s, IH), 7.37(d, /=9.0Hz, 2H), 7.35(m, lH), 6.67(d, J=9.0Hz, 2H), 6.1 l(s, IH), 3.97(m, IH), 3.38(q, J=7.2Hz, 4H), 2.85(m, IH), 2.55(m, IH), 2.14(m, IH), 2.18(s, 6H), 1.17(t, /= 7.2Hz, 6H) 8 8.60(m, 2H), 7.95(s, IH), 7.70(m, 2H), 7.54(m, 2H), 7.42(m, IH), 7.38

(m, IH), 6.17(s, IH), 4.10(m, IH), 2.85(m, IH), 2.60(m, IH), 2.37(m, lH), 2.18(s, 6H)

Comp. No. 'H NMR(300 MHz) δ

9 10.02(m, 2H), 8.88(brs, IH), 8.77(brs, IH), 8.13(m, IH), 7.74(s, 2H), 7.15(d, 7=8.7Hz, IH), 6.45(s, IH), 6.39(m, IH), 6.32(m, IH), 4.62(brs,

IH), 4.12(m, IH), 3.40(m, IH), 3.15(m, 2H), 2.80(s, 6H)

10 9.87(brs, IH), 8.86(d, 7=lHz, IH), 8.75(d, 7=4.5Hz, IH), 8.17(d, 7= 7.6Hz IH), 7.75(dd, 7=7.6, 4.5Hz, IH), 7.34(s, IH), 7.12(s, 2H), 6.39(s, IH), 4.05(m, IH), 3.15(m, 3H), 2.81(s, 6H), 2.17(s, 6H) 11 8.61(m, 2H), 7.75(m, IH), 7.54(s, IH), 7.41(s, 2H), 7.38(m, IH), 6.15(s,

IH), 4.20(m, IH), 2.85(m, IH), 2.62(m, IH), 2.38(m, IH), 2.19(s, 6H), 1.43(s, 18H)

12 8.62(m, 2H), 7.68(m, IH), 7.54(s, IH), 7.45(d, 7=9.0Hz, 2H), 7.27(m, IH), 6.94(d, 7=9.0Hz, 2H), 6.15(s, IH), 3.98(m, IH), 3.83(s, 3H), 2.85 (m, IH)

13 8.65(m, IH), 8.61(m, IH), 7.86(s, IH), 7.66(m, IH), 7.43-7.55(m, 2H), 7.3 ⁽⁾ (m, IH), 7.26(m, IH), 6.19(s, IH), 4. l(m, IH), 2.87(m, IH), 2.59 (m, IH), 2.36(m, IH), 2.19(s, 6H)

14 9.79(brs, IH), 8.82(s, IH). 8.72(m, IH), 8.03(m, IH), 7.83(s, IH), 7.65 (m, IH), 6.83(m, 2H), 6.72(m, IH), 6.35(s, IH), 4.14(m, IH), 3.42(m,

IH), 3.10(m, 2H), 2.82(m, 6H)

15 9.72(brs, IH), 9.43(brs, IH), 8.80(brs, IH), 8.70(brs, IH), 7.98(m, IH), 7.75(s, IH), 7.62(m, IH), 6.82(m, IH), 6.75(m, IH), 6.62(m, IH), 6.35(s, IH), 4.15(m, IH), 3.40(m, IH), 3.10(m, 2H), 2.82(m, 6H) 16 9.50(brs, IH), 9.00(brs, IH), 8.72(m, IH), 8.66(m, IH), 7.88(m, IH),

7.78(s, IH), 7.50(m, lH), 6.72(d, 7=8.7Hz, IH), 6.40(d, 7=8.7Hz, IH), 6.25(s, IH), 4.12(m, IH), 3.36(m, IH), 3.08(m, 2H), 2.80(m, 6H)

Comp. No. 'H NMR(300 MHZ) δ

17 8.65(m, IH), 8.60(m, IH), 7.66(m, IH), 7.39-7.49(m, 5H), 7.20-7.39 (m, 7H), 7.09(d, 7=1.8Hz, IH), 7.03(m, IH), 6.94(m, IH), 6.12(s, IH),

5.19(s, 2H), 5.17(s, 2H), 3.98(m, IH), 2.84(m, IH), 2.54(m, IH), 2.33(m, lH), 2.18(s, 6H)

22 10.09(brs, IH), 8.99(s, IH), 8.82(d, 7=4.8Hz, IH), 8.29(d, 7=8.1Hz, IH), 7.83(dd, 7=7.8, 5.4Hz, IH), 7.45(s, IH), 7.38(t, 7=7.8Hz, IH), 7.10 (d, 7=7.8Hz, IH), 7.06(s, lH), 6.94(dd, 7=8.4, 1.8Hz, IH), 6.52(s, IH),

4.15(m, IH), 3.82(s, 3H), 3.04~3.27(m, 2H), 2.81(s, 6H)

23 9.77(brs, IH), 8.82(m, IH), 8.74(m, IH), 8.02(m, IH), 7.64(m, IH), 7.43 (s, IH), 6.82(s, 2H), 6.38(s, IH), 4.15(m, IH), 3.93(t, 7=6.3Hz, 4H), 3.86(t, 7=6.3Hz, 2H), 2.96~3.37(m, 3H), 2.81(s, 6H), 1.73(m, 4H), 1.65 (m, 2H), 0.98(m, 9H)

38 8.59(m, 2H), 7.62(m, IH), 7.47(s, IH), 7.32(m, IH), 7.16(s, 2H), 6.21(s, IH), 3.82(m, IH), 2.85(m, 2H), 2.45(m, 5H), 2.29(s, 6H), 0.95(t, 7= 6.9Hz, 6H)

39 10.1(brs, IH), 8.93(s, IH), 8.81(m, IH), 8.24(m, IH), 7.79(m, IH), 7.31 (s, IH), 6.96(s, IH), 6.83(m, 2H), 6.24(s, IH), 4.04(m, IH), 3.24(m, 2H),

3.13(m, 4H), 1.17(t, 7=7.2Hz, 6H)

40 8.62(m, 2H), 7.68(m, 2H), 7.53(s, IH), 7.35(m, IH), 7.08(d, 7=8.2Hz, IH), 7.05(s, IH), 6.90(d, 7=8.2Hz, IH), 6.19(s, IH), 4.01(m, IH), 3.90 (s, 3H), 3.89(s, 3H), 2.80~3.02(m, 2H), 2.48(m, 5H), 1.77(m, 4H)

Comp. No. *H NMR(300 MHZ) δ

47 8.63(m, 2H), 7.67(m, IH), 7.53(s, IH), 7.35(m, IH), 7.08(d, 7=8.4Hz, IH), 7.05(s, IH). 6.90(d, 7=8.4Hz, IH), 6.21(s, IH), 3.95(m. IH), 3.90

(s, 6H). 2.91 (m, IH), 2.82(m, IH), 2.35(m, 5H). 1.57(m, IH). 1.44(m, 2H) 50 8.65(m, IH), 8.61(m, IH), 7.7 l(m, IH), 7.53(s, IH), 7.36(m, IH), 7.09

(d, 7=8.4Hz, IH), 7.05(s, IH), 6.91(d, 7=8.4Hz, IH), 6.14(s, IH), 3.96 (m, IH), 3.9( ⁾ (s, 3H), 3.89(s, 3H), 3.69(m, 4H), 2.93(m, IH), 2.61 (m, lH), 2.43(m, IH), 2.41(m, 4H) 67 8.8 l(s, IH), 8.76(d, 7=4.8Hz, IH), 8.08(d, 7=8.1Hz, IH), 7.73(m, IH),

7.16~7.29(m, 6H), 6.95(s, IH), 6.83(s, 2H), 6.22(s, IH), 3.92(m, IH), 3.05(m, IH), 2.95(m, IH), 2.89(m, IH) 69 8.60(s, IH), 8.59(s, IH), 7.72(d, 7=7.8Hz, IH), 7.45(m, IH), 7.40(s,

IH), 6.99~7.27(m, 8H), 6.03(s, IH), 3.95(m, IH), 3.80(s, 3H), 3.79(s, 3H), 2.80-3.05(m, 2H), 2.60-2.80(m, IH)

71 8.79(s, IH), 8.75(d, 7=4.8Hz, IH), 8.08(d, 7=8.1Hz, IH), 7.72(m, IH), 7.39(s, IH), 7.27(s, 2H), 7.17(m, 5H), 6.20(s, IH), 4.05(m, IH), 3.05(m, IH), 2.92(m, IH), 2.85(m, IH), 1.37(s. 18H)

72 8.62(d, 7=5.1Hz, IH), 8.39(s, IH), 7.61~7.51(m, 2H), 7.40~7.30(m, IH), 7.07(dd, 7=8.1, 2.1Hz, IH), 7.03(d, 7=2.1Hz, IH), 6.91(d, 7=8.1Hz, IH), 6.83(d, 7=8.1Hz, IH), 6.68(dd, 7=8.1, 1.5Hz, IH), 6.64(d, 7= 1.5Hz, IH), 5.26(s, H), 4.10(m, IH), 3.90(s, 3H), 3.89(s, 3H), 3.88(s, 3H), 3.82(s, 3H), 3.05~2.70(m, 3H)

Comp. No. Η NMR(300 MHZ) δ

74 8.76(m, 2H), 8.05(m, IH), 7.71(m, IH), 7.40(s, IH), 7.1 l(s, IH), 7.05(s, IH), 6.83(d, 7=8.4Hz), 6.73(s, IH), 6.65(d, 7=8.4Hz), 6.15(s, IH), 4.05

(m. IH). 3.78(s, 3H), 3.76(s, 3H). 3.05(m, I H), 2.80(m, IH), 2.65(m, lH), 2.17(s, 6H)

78 8.65(d, 7=3.9Hz, IH), 8.50(s, IH), 7.70(d, 7=8.1Hz, IH), 7.61(s, IH), 7.40(m, lH), 7.10(d, 7=6.9Hz, IH), 7.04(s, IH), 6.89(d, 7=8.1Hz, IH), 6.70(d, 7=7.8Hz, IH), 6.67(s, IH), 6.52(d, 7=7.8Hz), 5.96(s, 2H), 5.61

(s, IH), 4.44(ABq, Δ =411, 7 _AB =14.4Hz, 2H), 3.90(s, 3H), 3.89(s, 3H)

79 8.72(m, 2H), 8.06(d, 7=6.2Hz, IH), 7.71(m, IH), 7.36(s, IH), 6.95(s, IH), 6.79(m, 3H). 6.69(s, IH), 6.58(d, 7=7.8Hz, IH), 6.13(s, IH), 5.97 (s, 2H), 4.43(ABq, Δ v =228, 7 _AB =15.3Hz, 2H)

80 8.78-8.76(m, 2H), 8.15(d, 7=8.1Hz), 7.77(dd, 7=8.1, 5.4Hz, IH), 7.51(s, IH), 7.30(s, 2H), 6.78(d, 7=8.1Hz, IH), 6.70(s, IH), 6.58(d, 7=8.1Hz, IH), 6.17(s, IH), 5.99(s, 2H), 4.45(ABq, Δ v =205.5, 7 _AB =15Hz, 2H), 1.38(s, 18H) 81 8.60(m, 2H), 8.52(m, IH), 7.71(m, IH), 7.66(m, IH), 7.60(s, IH), 7.46

(d, 7=8.7Hz, 2H), 7.35(m, IH), 7.22(m, IH), 6.94(d, 7=8.7Hz, 2H), 6.04

(s, lH), 5.21(d, 7=15.3Hz, lH), 4.04(d, 7=15.3Hz, IH), 3.83(s, 3H)

82 8.56-8.67(m, 2H), 8.52(m, IH), 7.72(m, IH), 7.65(m, IH), 7.59(s, IH),

7.34(m, IH), 7.27(d, 7=6.6Hz, IH), 7.20(m, IH), 7.10(m, IH), 7.06(m, IH), 6.91(d, 7=6.6Hz, IH), 6.04(s, IH), 5.22(d, 7=15.3Hz, IH), 4.03(d,

7=15.3Hz, IH), 3.91(s, 3H), 3.90(s, 3H)

Comp. No. Η NMR(300 MHz) δ

83 8.62(m, 2H), 8.53(m, 2H), 7.73(m, IH), 7.66(m, IH), 7.56(s, IH), 7.35 (m, IH), 7.21(m, IH), 6.76(s, 2H), 6.07(s, IH), 5.22(d, 7=15.3Hz, IH),

4.04(d, 7=15.3Hz, IH). 3.87(s, 9H)

84 8.82(s, IH). 8.73(m, IH), 8.55(m, IH), 8.20(m. IH), 7.95(m, IH), 7.74 (m, IH), 7.43(m, 2H), 7.35(s, IH), 6.98(m, IH), 6.85(m, 2H), 6.36(s, lH), 5.01(d, 7=16.2Hz, lH), 4.36(d, 7=16.2Hz, IH) 85 8.70(m, 2H), 7.90(m, IH), 7.58(m, IH), 7.43(s, IH), 6.85(s, 2H), 6.30(s,

IH), 3.42(m, 1 IH), 1.42(m, 2H), 0.98(t, 7=7.6Hz, 3H)

86 8.62(m, IH), 8.53(m, IH), 8.49(m, IH), 7.61(m, 2H), 7.50(s, IH), 7.33 (m, IH), 7.19(m, 2H), 7.07(m, IH), 7.02(m, IH), 6.90(m, IH), 5.65(s, IH), 4.20(m, IH), 3.90(s, 3H), 3.89(s, 3H), 3.31(m, IH), 3.14(m, IH), 3.06(m, IH)

87 8.61(m, IH), 8.44~8.57(m, 2H), 7.60-7.74(m, 2H), 7.51(s, IH), 7.18~7.37(m, 4H), 7.07(d, 7=7.5Hz, IH), 7.01(s, IH), 6.90(m, IH), 5.73 (s, IH), 4,21(m, IH), 3.81(s, 3H), 3.3()(m, IH), 3.17(m, 2H)

88 8.62(m, IH), 8.53(m, IH), 8.48(m, IH), 7.56-7.70(m, 2H), 7.51(s, IH), 7.43(d, 7=8.7Hz, 2H), 7.29~7.37(m, IH), 7.12~7.23(m, 2H), 6.93(d, 7=

8.7Hz, 2H), 5.63(s, IH), 4.2 l(m, IH), 3.82(s, 3H), 3.30(m, IH), 3.15(m, IH), 3.05(m, IH)

89 8.72(m, 2H), 8.25(m, IH), 7.93(m, IH), 7.74(m, 2H), 7.60(m, H), 7.21(s, IH), 7.07(s, 2H), 6.33(s, IH), 4.12(m, IH), 3.20(m, 3H), 2.16(s, 6H)

Comp.No. Η NMR(300MHZ) δ

90 8.69(m, 2H), 8.37(s, IH), 7.78(d, 7=7.8Hz, IH), 7.50(s, IH).7.41(m, IH), 6.74(s, 2H), 5.99(s, IH), 4.40(m, IH), 4.13(m, IH), 3.87(s, 9H),

3.17(d, 7=14.4Hz, IH), 3.05(d, 7=14.4Hz, IH), 2.04(s, 3H)

91 9.90(brs, IH), 8.89(s, IH), 8.78(m, IH), 8.20(d, 7=7.6Hz, IH), 7.79(m, IH), 7.42(s, IH), 7.08(m, 3H), 6.35(s, IH), 3.89(m, IH), 3.85(m, IH), 3.78(s, 3H), 3.77(s, 3H), 3.61(m, IH), 3.00(m, IH), 1.94(s, 3H) 92 8.68(s, 2H), 8.42(s, IH).7.78(d, 7=7.6Hz, IH), 7.52(s, IH), 7.41(m, IH), 7.10(d, 7=8.4Hz, IH), 7.03(s, IH), 6.90(d, 7=8.4Hz, IH), 6.00(s, IH), 5,20(brs, 2H), 4.08(m, 2H), 3.91(s, 3H), 3.89(s, 3H), 3.14(m, 2H)

93 10.54(s, IH), 8.83(s, IH), 8.64(m, IH), 7.77(d, 7=7.8Hz, IH), 7.48(m, IH), 7.44(s, IH), 6.88(s, 2H), 6.24(s. IH).3.86(m, IH), 3.79(s, 6H), 3.69 (s, 3H), 3.02(m, IH), 2.38(m, IH), 2.15(m, IH)

94 8.64(s, IH), 8.49(d, 7=2.4Hz, IH), 7.74(d, 7=7.5Hz, IH), 7.42(s, IH), 6.96(d, 7=8.4Hz, IH), 6.93(s, IH), 6.78(d, 7=8.4Hz, IH), 6.12(s, IH), 4.38(d, 7=15.9Hz, IH), 3.89(s, 3H), 3.84(s, 3H), 3.54(d, 7=15.9Hz, IH)

95 8.71(s, IH), 8.50(m, IH), 8.32(d, 7=8.4Hz, IH), 8.24(s, IH), 7.72(m, 3H), 7.26(m, IH), 7.09(m, 4H), 6.92(d, 7=8.4Hz, IH), 3.92(s, 6H)

96 8.70(m, IH), 8.47(m, IH), 8.26(m, 2H), 7.69(m, 3H), 7.20(m, IH), 7.07 (s, IH), 7.05(m, IH), 6.79(s, 2H), 3.83(s, 3H), 3.82(s, 3H), 3.78(s, 3H)

97 8.72(m, IH), 8.43(m, IH), 8.24(m, IH), 8.09(m), 7.67(m, 2H), 7.39(d, 7=8.4Hz, 2H), 7.20(m, IH), 7.07(s, IH), 7.05(m, IH), 6.71(d, 7=8.4Hz, 2H), 6.49(s, IH).3.84(s, 3H)

Comp. No. 'H NMR(300 MHZ) δ

98 8.53(m, IH), 8.46(s, IH), 7.52(m, 3H), 7.17(m, IH), 7.07(d, 7=8.1Hz, IH), 7.02(s, IH), 6.91(d, 7=8.1Hz, IH), 5.62(s, IH), 4.79(m, IH), 4.40

(m, IH), 4.15(m, IH), 3.92(s, 3H), 3.90(s, 3H), 3.61(s, 3H),

99 8.62(m, 2H), 8.05(s, IH), 7.82(d, 7=7.8Hz, IH), 7.49(s, IH), 7.38(m, IH), 7.03(s, 2H), 6.00(s, IH), 3.90(s, 3H), 3.89(s, 3H), 3.88(s, 3H)

100 9.56(s, IH), 8.81(s, IH), 8.71(m, IH), 8.20(d, 7=8.1Hz, IH), 7.74(m, IH), 7.22(s, IH), 7.08(s, 2H), 6.26(s. IH), 2.17(s, 6H)

101 8.65(m, 2H), 8.06(s, IH), 7.82(m, IH), 7.50(s, IH), 7.39(m, IH), 7.09(d, 7=8.3Hz, 2H), 6.89(d, 7=8.3Hz, 2H), 6.01(s, IH), 3.91(s, 3H)

102 9.97 (s, IH), 8.83(s, IH), 8.73(d, 7=5.1Hz, IH), 8.20(d, 7=7.8Hz), 7.76 (s, IH), 7.74(m, IH), 7.56(s, 3H), 6.36(s, IH) 103 9.56(s, IH), 8.81(d, 7=1.5Hz, IH), 8.72(d, 7=4.8Hz), 8.19(d, 7=8.1Hz,

IH), 7.75(m, IH), 7.2()(s, IH), 6.93(s, IH), 6.81(s, 2H), 6.26(s, IH) 107 DMSO-d _Λ ; 9.56(s, IH), 8.80(d, 7=1.5Hz, IH), 8.7 l(d, 7=4.2Hz, IH),

8.15(d, 7=8.1Hz, IH), 7.73(dd, 7=7.8, 5.1Hz, IH), 7.33(s, IH), 7.27(s,

2H), 6.25(s, lH), 4.8(brs, IH), 1.38(s, 18H) 109 8.65(m, IH), 8.61(m, IH), 7.68(m, IH), 7.53(s, IH), 7.36(m, IH), 7.04

(m, 2H), 6.90(m, IH), 5.82(s, IH), 4.13(q, 7=6.9Hz, 2H), 3.89(s, 3H),

3.88(m, IH), 2.79(m, IH), 1.52(m, 2H), 1.47(t, 7=6.9Hz, 3H), 1.28(m,

2H), 0.89(t, 7=7.5Hz, 3H) 110 8.80(s, IH), 8.72(m, IH), 8.06(m, IH), 7.66(m, IH), 7.42(s, IH), 7.01~7.17(m, 3H), 6.33(s, IH), 3.78(s, 3H), 3.77(s, 3H), 3.68(m, IH),

2.79(m, IH), 1.42(m, 2H), 1.20(m, 2H), 0.83(t, 7=4.5Hz, 3H)

Comp. No. ^l H NMR(300 MHz) δ

111 8.83(s, IH), 8.74(s, IH), 8.10(brs, IH), 7.74(brs, IH), 7.28(s, IH), 6.95 (s, IH), 6.81(m, 2H), 6.32(s, IH), 4.25(brs, 2H), 3.75(m, IH), 2.78(m,

IH), 1.43(m, 2H), 1.22(m, 2H), 0.85(t. 7=6.3Hz, 3H)

112 8.63(m. 2H), 7.67(m, IH), 7.53(s, IH), 7.38(m, IH), 7.05(d, 7=8.4Hz, IH), 7.04(s, IH), 6.89(d, 7=8.4Hz, IH), 5.82(s, IH), 4.00(t, 7=6.9Hz, 2H), 3.92(m, IH), 3.88(s, 3H), 2.80(m, IH), 1.88(m, 2H), 1.52(m, 2H), 1.32(m, 2H), 1.01(t, 7=7.2Hz, 3H), 0.89(t, 7=7.5Hz, 3H)

115 8.66(d, 7=3.6Hz, IH), 8.62(d, 7=1.5Hz, IH), 7.68(d, 7=8.1Hz, IH), 7.54(s, IH), 7.37(dd, 7=8.1, 3.6Hz, IH), 7.10(dd, 7=8.4, 1.8Hz, IH), 7.05(s, IH), 6.91(d, 7=8.4Hz, IH), 5.72(s, IH), 3.90(s, 6H), 2.91(s, 3H)

116 9.39(s, IH), 9.18(s, IH), 8.61~8.60(m, 2H), 7.74(d, 7=8.1Hz, IH), 7.47 (dd, 7=8.1, 4.8Hz, IH), 7.27 (s, IH), 6.97(d, 7=1.5Hz), 6.85(dd, 7=8.4,

1.5Hz, IH), 6.80(d, 7=8.4Hz, IH), 6.12(s, IH), 3.34(s, 2H), 2.80(s, 3H)

117 8.92(d, 7= 1.2Hz, IH), 8.44(d, 7=4.8Hz, IH), 8.28(d, 7=8.1Hz, IH), 7.89(dd, 7=8.1, 4.8Hz, IH), 7.49(s, lH), 7.1 1(d, 7=1.8Hz, lH), 6.98(dd, 7=8.4, 1.8Hz, IH), 6.S8(d, 7=8.4Hz, IH), 6.28(s, IH), 5.40(brs, 3H), 3.78(s, 3H), 2.84(s, 3H)

118 7.26(s, IH), 6.99(s, IH), 6.87 (d, 7=8.4Hz, IH), 6.78(d, 7=8.4Hz, IH), 4.96(d, 7=6.3Hz, IH), 4.1(brs, 2H, 2OH), 3.25(m, IH), 2.66(m, 2H), 2.39(s, 6H), 1.87~2.05(m, IH), 1.56~1.79(m, IH), 1.31~1.50(m, 12H), 0.87(t, 7=6.6Hz, 3H)

Comp. No. Η NMR(300 MHZ) δ

119 7.42(s, IH), 7.14(d, 7=8.4Hz, IH), 7.09(s, IH), 6.92(d, 7=8.4Hz, IH), 5.05(dd, 7=8.1, 2.1Hz, IH), 3.98(m, IH), 3.93(s, 3H), 3.91(s, 3H), 3.30

(m, IH), 2.50(m, IH). 2.29(s, 6H), 1.92(m, IH), 1.74(m, IH), 1.14-1.53 (m, 12H), 0.88(t, 7=6.3Hz, 3H)

120 7.36(s, IH), 7.12(d, 7=1.8Hz, IH), 6.98(d, 7=1.8Hz, IH), 6.91(d, 7= 8.1Hz, lH), 4.77(dd, 7=8.4, 1.8Hz, IH), 3.06(s, 3H). 1.95~2.13(m, IH), 1.65~ 1.82(m, IH), 1.13~1.48(m, 12H), 0.88(t, 7=6.6Hz, 3H)

121 7.43(s, IH), 7.14(dd, 7=8.4, 1.5Hz, IH), 7.09(d, 7=1.5Hz, IH), 6.92(d, 7=8.4Hz, IH), 4.80(dd, 7=8.1, 1.8Hz, IH), 3.93(s, 3H), 3.91(s, 3H), 3.07 (s, 3H), 1.97~2.13(m, IH), 1.66-1.83(m, IH), 1.15-1.52(m, 12H), 0.88 (t, 7=6.6Hz, 3H) 122 7.36(s, IH), 7.12(d, 7=1.8Hz, IH), 7.98(dd, 7=8.4, 1.8Hz, IH), 6.91(d,

7=8.4Hz), 4.77(dd, 7=8.4, 2.7Hz, IH), 3.06(s, 3H), 1.91-2.12(m, IH), 1.63~1.81(m, IH), 1.09~1.52(m, 8H), ().88(t, 7=6.6Hz, 3H)

123 7.43(s, IH), 7.14(dd, 7=8.4, 1,8Hz, IH), 7.09(d, 7=1.8Hz, IH), 6.94(d, 7=8.4Hz, IH), 4.80(m, IH), 3.93(s, 3H), 3.91(s, 3H), 3.07(s, 3H), 2.05 (m, IH), 1.72(m, IH), 1.30(m, 8H), 0.89(t, 7=6.6Hz, 3H)

124 8.03(brs, 2H), 7.33(s. IH), 7.09(d, 7=1.8Hz, IH), 6.96(dd, 7=8.4, 1.8Hz, IH), 6.89(d, 7=8.4Hz, IH), 4.79(dd, 7=8.1, 2.7Hz, IH), 3.06(s, 3H), 1.95~2.12(m, IH), 1.65~1.82(m, IH), 1.32~1.55(m, 2H), 0.98(t, 7= 7.2Hz, 3H)

Comp. No. 1H NMR(300 MHz) δ

125 7.43(s, IH), 7.14(dd, 7=8.4, 1.8Hz, IH), 7.09(d, 7=1.8Hz, IH), 6.92(d, 7=8.4Hz, IH), 4.80(dd, 7=8.1, 2.7Hz, IH), 3.93(s, 3H), 3.91(s, 3H), 3.07

(s,3H), 1.83~2.11(m, IH), 1.64-1.84(m, IH), 1.34-1.55(m,2H), 0.99(t, 7=7.2Hz, 3H)

126 8.59(s, IH), 8.02(brs, IH), 7.31~7.52(m, 10H), 6.19(s, IH), 4.63(ABq, Δ v =224, 7 _AB =16.2Hz,2H), 1.38(s, 18H) 130 7.51(s, IH), 7.12(d, 7=8.4Hz, IH), 7.06(s, IH), 6.91(d, 7=8.4Hz, IH), 6.55(s, 2H), 6.01(s, IH), 4.01(m, IH), 3.90(s, 6H), 3.85(s, 9H), 3.00(m, IH), 2.58(m, IH), 2.47(m, IH), 2.26(s, 6H)

131 9.42(s, IH), 9.21(s, IH), 7.27(s, IH), 6.97(s, IH), 6.84(m, 2H), 6.76(s, 2H), 6.12(s, IH), 4.12(m, IH), 3.78(s, 6H), 3.67(s, 3H), 3.26(m, 3H), 2.81(s,6H)

132 12.37(brs, IH), 7.43(s, IH), 7.16(s, 2H), 6.70(s, 2H), 6.10(s, IH), 4.00 (m, IH), 3.87(s, 6H), 3.85(s, 3H), 3.68(m, IH), 3.08-3.13(m, 2H), 2.87 (d, 7=4.2Hz, 3H), 2.79(d, 7=3.9Hz, 3H), 2.26(s, 6H)

133 10.0(s, IH), 9.76(s, IH), 9.41(brs, IH), 7.71(s, IH), 7.18(d, 7=8.7Hz, IH), 6.75(s, 2H), 6.40(s, IH), 6.30(d, 7=8.7Hz, IH), 6.07(s, IH), 4.05

(m, IH), 3.78(s, 6H), 2.25(s, 6H) 138 8.63(m, 2H), 7.69(d, 7=7.8Hz, IH), 7.54(s, IH), 7.35(m, IH), 7.03-7.16 (m, 2H), 6.91(d, 7=8.4Hz, IH), 6.12(s, IH), 4.03(m, IH), 3.91(s, 3H), 3.90(s, 3H), 3.62(m, IH), 3.52(m, IH), 3.32(s, 3H), 2.94(m, IH)

Comp. No. ^l H NMR(300 MHz) δ

139 8.62(m, 2H), 7.69(d. 7=8.1Hz, IH), 7.54(s, IH), 7.35(m, IH), 7.03-7.16 (m, 2H), 6.91(d, 7=8.4Hz, IH), 6.17(s, IH). 4.05(m, IH), 3.91(s, 3H),

3.90(s, 3H), 3.67(m, IH), 3.40~3.58(m, 3H), 2.93(m, IH), 1.92(t, 7= 7.2Hz, 3H)

140 8.65(m, 2H), 7.68(d, 7=8.1Hz, IH), 7.54(s, IH), 7.37(m, IH), 7.09(d, 7= 8.4Hz, lH), 7.04(s, IH), 6.90(d, 7=8.4Hz, lH), 5.96(s, lH), 4.30(m, IH), 4.17(m, 2H), 3.91(s, 3H), 3.90(s, 3H), 3.05(m, IH), 2.05(s, 3H)

141 8.66(brs, 2H), 7.69(m, IH), 7.52(s, IH), 7.36(m, IH), 7.08(dd, 7=8.4, 1.8Hz, IH), 7.04(d, 7=1.8Hz, IH), 6.90(d, 7=8.4Hz, IH), 6.05(s, IH), 4.14(q, 7=7.2Hz, 2H), 3.91(m, IH), 3.90(s, 3H), 3.89(s, 3H), 3.19(m, lH), 2.82(m, lH), 2.50(m, IH), 1.25(t, 7=7.2Hz, 3H) 145 8.7 l(m, IH), 8.61(m, IH), 7.73(m, IH), 7.50(s, IH), 7.33(m, IH), 7.09

(d, 7=8.4Hz, IH), 7.05(s, IH), 6.90(d, 7=8.4Hz, IH), 6.27(s, IH), 3.90

(s, 3H), 3.89(s, 3H), 3.78(m, IH), 3.35(m, IH), 3.00(m, IH), 2.97(s, 3H),

2.94(s, 3H), 2.5()(m, IH)

146 DMSO-d _ή ; 8.64(m, IH), 8.60(m, IH), 7.75(m, IH), 7.44(m, IH), 7.41(s, IH), 7.12-7.05(m, 3H), 6.32(s, IH), 3.78(s, 3H), 3.77(s, 3H), 3.30-3.21

( , 5H), 3.05(m, IH), 2.67(m, IH), 2.39(m, IH), 1.77(m, 4H)

148 8.62(m, 2H), 7.65(m, IH), 7.38(m, IH), 7.23(d, 7=l l.lHz, IH), 6.98(d,

7=8.4Hz, IH), 6.92(s, IH), 6.85(d, 7=8.4Hz, IH), 6.75(d, 7=15.3Hz,

IH), 6.58(dd, 7=15.3, 11.1Hz, IH), 6.15(s, IH), 3.92(m, IH), 3.91(s, 3H), 2.83(m, IH), 2.59(m, IH), 2.28(m, IH), 2.20(s, 6H)

Comp. No. ΗNMR(300MHZ) δ

149 8.60(m, 2H), 7.70(d, 7=7.6Hz, IH), 7.67(s, IH),7.39(dd, 7=7.6,4.2Hz, IH), 7.14(d, 7=11.1Hz, IH), 6.97(s, IH), 6.78(s, 2H), 6.70(d, 7=15.3Hz,

IH), 6.48(dd, 7=15.3, 11.1Hz, IH), 6.17(s, IH), 3.90(m, IH), 2.80(m, IH), 2.50(m, IH), 2.35(m, IH), 2.17(s, 6H)

150 8.64~8.59(m, 2H), 7.69-7.66(m, IH).7.37~7.33(m, IH), 7.22(d, 7= 11.1Hz, IH), 7.09(s, 2H), 6.72(d, 7=15.3Hz, IH), 6.55(dd, 7=15.3, 11.1Hz, IH), 3.98~3.90(m, IH), 2.86-2.77(m, IH), 2.60~2.51(m, IH),

2.37-2.28(m, IH), 2.24(s, 6H), 2.18(s, 6H)

151 8.63(m, 2H),7.67(m, IH), 7.36(m, lH),7.23(d, 7=ll.lHz, IH), 6.75(d, 7=15.6Hz, IH), 6.68(s,2H), 6.59(dd, 7=15.6, 11.2Hz, IH), 6.16(s, IH), 3.97(m, IH), 3.91(s, 6H), 2.84(m, IH), 2.55(m, IH), 2.35(m, IH), 2.18(s, 6H)

152 8.62(m, 2H), 7.69(m, IH), 7.41(m, IH), 7.23(s, 2H), 7.08(d, 7=11.2Hz, IH), 6.91(d, 7=15.2Hz, lH),6.53(dd, 7=15.2, 11.2Hz, IH), 6.24(s, IH), 5.37(s, IH), 3.94(m, IH), 2.82(m, IH), 2.57(m, IH), 3.31(m, 2H), 2.31 (m, IH), 2.18(s,6H), 1.21(d, 7=7.2Hz, 12H) 153 8.6l(m, 2H), 7.69(dt, 7=7.8, 1.8Hz, IH), 7.38(m, IH), 7.25(s, 2H), 7.09 (d, 7=ll.lHz, lH),6.92(d, 7=15Hz, IH), 6.54(dd, 7=15.0, 11.1Hz, IH), 6.25(s, IH), 5.37(s, IH), 3.92(m, IH), 2.82(m, IH), 2.56(m, IH), 2.31(m, lH),2.18(s,6H), 1.45(s, 18H)

Comp. No. Η NMR(300 MHZ) δ

158 8.62(m, 2H), 7.65(m, IH), 7.38(m, IH), 7.23(d, 7=l l.lHz, IH), 7.1 Km, 5 10H), 6.98(d, 7=8.4Hz, IH), 6.92(s, IH), 6.85(d. 7=8.4Hz, IH), 6.75(d,

7=15.2Hz, IH), 6.58(dd, 7=15.2, ll.lHz, IH), 6.25(s, IH), 4.25(s, IH), 3.92(m, IH), 3.9 l(s, 3H), 2.83(m, 3H), 2.65(m, 8H)

159 8.62(m, 2H), 7.58(m, IH), 7.42(m, IH), 7.24(d, 7=11.2Hz, IH), 6.97(d, 7=8.4Hz, IH), 6.9 l(s, IH), 6.82(d, 7=8.4Hz, IH), 6.72(d, 7=15.3Hz, i o IH), 6.55(dd, 7=15.3, 1 1.2Hz, IH), 6.20(s, IH), 3.95(m, IH), 3.92(s,

3H), 2.83(m, IH), 2.59(m, 6H), 1.82(m, 4H), 0.98(m, 2H)

160 8.64(m, 2H), 7.62(m, IH), 7.40(m, IH), 7.24(d, 7=11.1Hz, IH), 6.98(d, 7=8.4Hz, IH), 6.92(s, H), 6.85(d, 7=8.4Hz, IH), 6.76(d, 7=15.3Hz, IH), 6.57(dd, 7=15.3, l l.lHz, IH), 6.15(s, IH), 3.95(m, 5H), 3.91(s, 3H),

15 3.62(m, 5H), 2.83(m, IH), 2.59(m, IH)

161 8.61(m, 2H), 7.68(m, IH), 7.34(m, IH), 7.22(d, 7=l l. lHz, lH), 6.71(d, 7=15.6Hz, IH), 6.68(s, 2H), 6.57(dd, 7=15.6, l l. lHz, IH), 5.93(s, IH), 3.92(s, 6H), 3.82(m, IH), 2.86(m, IH), 2.2()~2.40(m, 2H), 2.24(s, 6H), 1.5()-1.90(m, 2H) 0 162 8.63(m, 2H), 7.69(m, IH), 7.35(m, IH), 7.23(d, 7=11.2Hz, IH), 6.98(d,

7=8.2Hz, IH), 6.93(s, IH), 6.87(d, 7=8.2Hz, IH), 6.73(d, 7=15.6Hz, IH), 6.57(dd, 7=15.6, 11.2Hz, IH), 5.90(s, IH), 3.92(s, 3H), 3.79(m, IH), 2.88(m, IH), 2.26(m, 2H), 2.20(s, 6H), 1.55-1.95(m, 2H)

5

Comp. No. 'HNMR(300MHZ) δ

163 8.62(m, 2H), 7.65(m, IH), 7.45(d, 7=12.0Hz, IH), 7.33(m, IH), 6.98(d, 7=8.4Hz, IH), 6.85(d, 7=8.4Hz, IH), 6.73(s, IH), 6.18(d, 7=12Hz, IH),

6.12(s, IH),4.15(m, IH), 3.89(s, 3H), 2.79(m, 5H), 2.51(m,4H), 1.74(m, 4H), 1.07(t, 7=7.6Hz, 3H)

164 8.64(m, 2H), 7.75(m, IH), 7.33(m, IH), 7.25(m, 2H), 6.92(t, 7=8.4Hz, IH), 6.82(m, 4H), 6.49(t, IH), 6.12(s, IH), 3.89(m, IH), 3.79(s, 3H), 3.76(s, 3H), 2.82(m, IH), 2.52(m, IH), 2.31(m, IH), 2.16(s, 6H)

165 8.63(m, IH), 8.59(m, IH), 7.66(m, IH), 7.36(m, IH), 7.23(d, 7= 11.1Hz, IH), 6.75(d, 7=15.3Hz, IH), 6.67(s, 2H), 6.56(dd, 7=15.3, 11.1 Hz, IH), 6.17(s, IH), 3.98(m, IH), 3.91(s, 6H), 2.84(m, 2H), 2.45(m, 5H), 1.76(m, 4H) 166 8.64(m, IH), 8.59(m, IH), 7.66(m, IH), 7.37(m, lH),7.22(d, 7=10.5Hz, IH), 7.14(s, 2H), 6.6()~6.80(m, 2H), 6.22(s, IH), 4.32(q, 7=7.2Hz, 2H), 3.85(m, IH), 2.68-2.92(m, 2H), 2.16~2.63(m, 5H), 2.20(s, 6H), 1.38(t, 7=7.2Hz, 3H), 0.99(t, 7=7.2Hz, 6H)

168 8.61(m, 2H), 7.66(m, IH), 7.45(d, 7=12H, IH), 7.34(m, IH), 6.98(d, 7= 8.4Hz, IH), 6.89(d, 7=8.4Hz, IH), 6.73(s, IH), 6.19(d, 7=12Hz, IH),

6.13(s, IH), 3.90(s, 3H), 3.89(m, IH), 2.76(m, 3H), 2.57(m, IH), 2.21(m, IH), 2.18(s, 6H), 1.22(t, 7=7.6Hz, 3H)

169 8.63(m, IH), 8.57(m, IH), 7.64(m, IH), 7.38(m, lH),7.19(d, 7=11.4Hz, IH), 6.95(d, 7=8.4Hz, IH), 6.9l(s, IH), 6.83(d, 7=8.4Hz, IH), 6.73(d, 7=15.3Hz, IH), 6.52(dd, 7=15.3, 11.4Hz, IH), 6.15(s, IH), 4.05(m, IH),

3.90(s, 3H), 2.82(m, 2H), 2.45(m, 5H).1.76(m, 4H)

Comp. No. Η NMR(300 MHZ) δ

170 8.63(m, IH), 8.60(m, IH), 7.68(m, IH), 7.37(m, IH), 7.23(d, 7=l l.lHz, 5 IH), 7.08(s, 2H), 6.72(d, 7=15.3Hz, IH), 6.56(dd, 7=15.3, 11.1Hz, IH),

6.14(s, IH), 3.96(m, IH), 2.83(m, 2H), 2.44(m, 4H), 2.24(s, 6H), 1.75(m, 4H)

171 8.63(m, IH), 8.59(m, IH), 7.66(m, IH), 7.35(m, IH), 7.22(d, 7=10.8Hz, lH), 7.09(s, 2H), 6.72(d, 7=15.2Hz, IH), 6.58(dd, 7=15.2, 10.8Hz. IH), ι o 6.20(s, IH), 3.84(m, IH), 2.68-2.92(m, 2H), 2.33~2.60(m, 6H), 2.24(s,

6H), 0.99(t, 7=7.2Hz, 6H)

173 8.64(m, IH), 8.59(m, IH), 7.66(m, IH), 7.36(m, lH), 7.21(d, 7=11.2Hz,

IH), 6.93(d, 7=8.2Hz, IH), 6.93(s, IH), 6.86(d, 7=8.2Hz, IH), 6.75(d,

7=15.2Hz, IH). 6.57(dd, 7=15.2, 1 1.2Hz, IH), 6.22(s, IH), 3.91(s, 3H),

15 3.85(m, IH), 2.82(m, 2H), 2.52(m, 5H), 0.99(t, 7=7.2Hz, 6H)

175 8.65~8.61(m, 2H), 7.68(m, I H), 7.35(m, IH), 7.21(d, 7=11.1Hz, IH),

7.10(s, 2H), 6.72(d, 7=15.3Hz, lH), 6.55(dd, 7=15.3, l l.lHz, IH), 3.99 ( , IH), 6.21(s, IH), 4.32(q, 7=7.6Hz, 2H), 2.83(m, IH), 2.65(m, IH), 2.30(m, IH), 2.24(s, 6H), 2.19(s, 6H), 1.25(t, 7=7.6Hz, 3H) 0 176 8.64(m, IH), 8.61(m, IH), 7.65(m, IH), 7.36(m, lH), 7.22(d, 7=10.5Hz, lH), 7.14(s, IH), 6.75(d, 7=14.3Hz, IH), 6.64(dd, 7=14.3. 10.5Hz, IH), 6.16(s, IH), 4.32(q, 7=6.9Hz, 2H), 3.99(m, IH), 2.83(m, 2H), 2.43(m, 5H), 2.19(s, 6H), 1.75(m, 4H), 1.38(t, 7=6.9Hz, 3H)

5

Comp. No. 'H NMR(300MHZ) δ

177 8.64~8.59(m.2H), 7.70(m, IH), 7.35(m, IH), 7.23(d, 7=14.7Hz, IH), 7.21(s, IH), 7.14(s, IH), 6.77(d, 7=16.5Hz, IH), 6.51(dd, 7=16.5,

14.7Hz, IH), 6.13(s, IH), 3.94(m, IH).2.82(m, IH).2.55(m, IH), 2.33 (m, IH), 2.48(s, 3H), 2.18(s, 6H), 1.41(s, 9H)

178 8.61(m, 2H), 7.67(m, IH), 7.34(m, IH), 7.27(d, 7=10.8Hz, IH), 7.18(s, IH), 7.10(d, 7=15Hz, IH), 6.48(dd, 7=15, 10.8Hz, IH), 6.14(s, IH), 3.95(m, IH), 2.82(m, IH), 2.58(m, IH), 2.40(m, IH), 2.26(s, 3H), 2.22

(s, 3H), 2.2l(s, 3H), 2.18(s, 6H)

179 8.64(m, IH), 8.58(m, IH), 7.68(m, IH), 7.36(m, IH), 7.27(d, 7=11.2Hz, lH),6.89(d, 7=15.6Hz, IH), 6.50(s, lH),6.17(dd, 7=15.6, 11.2Hz, IH), 6.12(s, IH), 3.95(m, IH), 2.80(m, IH), 2.50(m, IH), 2.30(m, IH), 2.24(s, 3H), 2.28(s, 3H), 2.18(s, 6H), 2.15(s, 3H)

180 8.53~8.47(m, 2H), 7.64~7.73(m, IH), 7.36(dd, 7=7.8, 4.8Hz, IH), 7.21 (s, IH), 7.02-7.12(m, 2H), 6.64~6.71(m, IH), 6.63(s, IH), 6.40(dd, 7= 15.3, ll.lHz, IH), 6.1 l(s, IH), 3.96~4.08(m, IH), 2.72~2.87(m, IH), 2.49~2.60(m, IH), 2.3 -2.49(m, IH), 2.25(s, 9H) 181 8.65(m, IH), 8.60(m, IH), 7.68(m, IH), 7.44(m, 2H), 7.22-7.4l(m, 4H),

6.65~6.92(m, 2H), 6.16(s, IH), 3.94(m, IH), 2.82(m, IH), 2.53(m, IH),

2.32(m, lH),2.17(s,6H) 182 8.60-8.65(m, 2H), 7.67-7.69(m, IH), 7.35~7.41(m, IH), 7.24(d, 7=

11.4Hz, IH), 7.00(d, 7=8.1Hz), 6.82(d, 7=8.1Hz, IH), 6.78(d, 7= 15.1Hz), 6.59(dd.7=15.1, 11.4Hz, IH), 6.15(s, IH), 3.93(m, IH), 3.91(s,

3H), 3.90(s, 3H), 2.84(m, IH), 2.58(m, IH), 2.33(m, IH),2.20(s, 6H)

Comp. No. Η NMR(300MHZ) δ

183 9.10(brs, IH), 8.62(m, 2H), 7.67(m, IH), 7.38(m, IH), 7.30(d, 7=8.4Hz, 2H), 7.19(d, 7=11.2Hz, IH), 6.81(d. 7=8.4Hz, 2H), 6.76(d, 7=15.0Hz,

IH), 6.53(dd, 7=15.0, 11.2Hz, IH), 6.15(s, IH), 3.91(m, IH), 2.83(m, IH), 2.54(m, IH), 2.32(m, IH), 2.18(s, 6H)

184 8.65(dd, 7=4.8, 1.5Hz, IH), 8.60(d, 7=2.1Hz, IH), 7.68(td, 7=7.8, 1.8Hz, lH),7.40(m, lH),7.24(d, 7=11.4Hz, IH), 7.01(dd, 7=8.1, 1.5Hz, IH), 6.93(d, 7=1.5Hz, IH), 6.88(d, 7=8.1Hz, IH), 6.78(d, 7=15.3Hz,

IH), 6.55(dd, 7=15.3, 11.4Hz, IH), 5.70(s, IH), 3.92(s, 3H), 2.87(s, 3H)

185 8.55(m, 2H), 7.60(m, IH), 7.29(m, IH), 7.10(d, 7=11.4Hz, IH), 6.97(m, 2H), 6.93(m, IH), 6.87(d, 7=8.4Hz, IH), 6.7l(d, 7=15.3Hz, IH), 6.51 (dd, 7=15.3, 11.4Hz, IH), 5.74(s, lH),4.96(dd, 7=9.0, 3.6Hz, IH), 3.94 (s, 3H), 3.46(dd, 7=13.5, 3.6Hz, IH), 3.17(s, 3H), 2.90(dd, 7=13.5,

9.0Hz, IH)

188 8.46(m, 2H), 7.5l(m, IH), 7.24(m, IH), 7.14(d, 7=ll.lHz, lH),7.02(m, lH),6.95(s, lH),6.88(d, 7=8.1Hz, lH),6.73(d, 7=15.3Hz, lH),6.59(dd, 7=15.3, ll.lHz, IH), 5.81(s. IH), 4.80(m, IH), 3.94(s, 3H), 2.99(s, 3H), 2.69(m, 2H),2.01(m, IH), 1.82(m, 2H), 1.67(m, IH)

189 8.47(d, 7=3.3Hz, IH), 7.46(d, 7=7.8Hz, IH), 7.20(m, 2H), 7.07(s, 2H), 6.70(d, 7=15.3Hz, IH), 6.50(dd, 7=15.3, ll.lHz, lH),4.02(m, IH), 2.80 (m, IH), 2.62(s, 3H), 2.59(m, IH), 2.3(m, IH), 2.34(s, 6H), 2.15(s, 6H)

Comp. No. ^l H NMR(300 MHZ) δ

190 8.47(m, IH), 7.46(m, IH), 7.20(m, 2H), 7.07(s, 2H), 6.68(d, 7=15.3Hz, lH), 6.50(dd, 7=15.3, l l.lHz, IH), 4.31(q, 7=7.6Hz, 2H), 4.02(m. IH),

2.80(m, IH), 2.62(s, 3H). 2.59(m, IH), 2.30(m, IH), 2.34(s, 6H), 2.15(s, 6H), 1.25(t, 7=7.6Hz, 3H)

193 8.64(m, IH), 8.60(m, IH), 7.77(m, IH), 7.35(m, IH), 7.24(d, 7=l l.lHz, IH), 7.08~7.00(m, 3H), 6.81(d, 7=15.3Hz, IH), 6.67(dd, 7=15.3, l l. lHz, IH), 6.16(s, IH), 4.31(q, 7=7.2Hz, 2H), 3.94(m, IH), 3.87(s,

3H), 2.82(m, IH), 2.56(m, IH), 2.31(m, IH), 2.17(s, 6H), 1.38(1, 7= 7.2Hz, 3H)

194 8.63~8.58(m, 2H), 7.66(m, IH). 7.35(m. IH), 7.24(s, IH), 6.96(s, 2H), 6.65(s, IH), 6.07(s, IH), 3.95(m, IH), 2.83(m, IH), 2.55(m, IH), 2.30(m, IH), 2.24(s, 6H), 2.17(s, 6H), 2.15(s, 3H)

195 8.63(m, 2H), 7.69(m, I H), 7.34(m, IH), 7.19(s, IH), 6.95(s, 2H), 6.61(s, IH), 6.08(s, IH), 3.95(m, IH), 2.85(m, IH), 2.60~2.30(m, 2H), 2.95(m, IH), 2.24(s, 6H), 2.17(s, 6H), 1.18(1, 7=7.6Hz, 3H)

196 8.63~8.58(m, 2H), 7.68(m, IH), 7.35(m, IH), 7.20(s, IH), 6.93(s, 2H), 6.63(s, IH), 6.07(s, IH), 3.90(m, IH), 2.85(m, IH), 2.60-2.20(m, 4H),

2.24(s, 6H), 2.17(s, 6H), 1.69~1.22(m, 2H), 0.96(t, 7=8.7Hz, 3H)

197 8.57~8.67(m, 2H), 7.62~7.73(m, I H), 7.31~7.40(m, IH), 7.26(d, 7= 2.7Hz, IH), 6.82~6.96(m, 2H), 6.73(s, IH), 6.08(s, IH), 5.29(s, IH), 3.90~4.05(m, IH), 3.89(s, 3H), 3.88(s, 3H), 2.77~2.93(m, IH), 2.48~2.64(m, IH), 2.27~2.40(m, IH), 2.19(s, 6H), 2.22(d, 7=0.9Hz, 3H)

Comp. No. ^l H NMR(300 MHZ) δ

198 8.58~8.64(m, 2H), 7.65~7.68(m, I H). 7.34-7.37(m, IH), 7.24(d, 7= 7.5Hz, IH). 6.80~6.87(m, 4H), 6.69(s. IH), 6.07(s, IH), 3.98-4.01 (m,

IH), 3.88(s, 3H), 2.77-2.92(m, IH), 2.48~2.64(m, IH), 2.27-2.39 (m, lH), 0.21(s, 3H), 2.19(s, 6H)

199 8.59(m, 2H), 7.62(m, IH), 7.38(m, IH), 7.20(s, IH), 6.87(m, 2H), 6.85(s, IH), 6.09(s, IH), 5.29(s, IH), 3.88(s, 3H), 3.85(m, IH), 2.85(m, IH), 2.52(m, 3H), 2.25(m, IH), 2.17(s, 6H), 1.27(t, 7=6.8Hz, 3H)

200 8.62(m, 2H), 7.64(m, IH), 7.38(m, IH), 7.19(s, IH), 6.83(m, 3H), 6.66(s, IH), 6.08(s, I H), 3.98(m, IH), 3.87(s, 3H), 2.85(m, IH), 2.47(m, 4H), 2.19(s, 6H), 1.65(m, 2H), 0.94(t, 7=6.8Hz, 3H)

207 8.60(m, 2H), 7.68(m, IH), 7.35(m, IH), 7.20(s. IH), 6.65(s, IH), 6.55 (s, 2H), 6.10(s, IH), 3.95(m, IH), 3.87(s, 6H), 2.85(m, IH), 2.30-2.60 (m,

4H), 2.18(s, 6H), 1.21(t, 7=7.6Hz, 3H)

208 8.62(m, 2H), 7.65(m, IH), 7.38(m, IH), 7.20(s, IH), 6.65(s, IH), 6.55(s, 2H), 6.10(s, I H), 3.97(m, IH), 3.88(s, 6H), 2.80(m, IH), 2.54(m, 2H), 2.35(m, 2H), 2.19(s, 6H), 1.23(t, 7=7.6Hz, 3H) 21 1 8.63(d, 7=4.3Hz, IH), 8.59(d, 7=1.8Hz, IH), 7.62-7.73(m, IH), 7.36 dd,

7=7.8, 4.8Hz, IH), 7.13(d, 7=7.8Hz, IH), 7.06(s, 2H), 6.59(m, 3H), 6.21 (dd, 7=13.8, 1 1.7Hz, IH), 6.13(s, IH), 3.98(m, IH), 2.82(m, IH), 2.59 (m, IH), 2.38(m, IH), 2.23(s, 6H), 2.17(s, 6H)

The present invention further relates to pharmaceutical compositions containing these compounds or acceptable salts thereof and the use of these compounds as antagonist of the PAF and/or inhibitor of the leukotriene. As stated above, compounds of the present invention possess activity of PAF-antagonist and/or

leukotriene-inhibition. Thus compounds of the invention may be used for the treatment and prophylaxis of diseases mediated or effected by PAF and leukotriene. The typical diseases for which the compounds of the present invention may be used as a therapeutic and propylactic agent include inflammation (for example, arthritis, nephritis), circulatory diseases(for example, shock, thrombosis, transplant rejection, cerebral anemia, etc.) and allergic diseases (for example, asthma, psoriasis).

The compounds according to the invention, as well as the pharmaceutically acceptable salts thereof, have potent PAF-antagonistic and leukotriene-inhibitory activity. Accordingly the novel compounds may be used in pharmaceutical composition comprising a phar aceutically effective amount of one of the compounds defined above and a pharmaceutically acceptable carrier. The inventive compounds are particularly useful as anti-allergic agents, anti-asthmatic agents, anti-psoriasis agents, anti-anaphylact^c shock agents, anti-septic shock agents, anti-arthritic agents, anti-nephritic agents, anti-thromboplastic agents, anti-transplant rejection agents and anti-cerebral anemic agents.

The compounds accroding to the present invention, as well as the pharmaceutically acceptable salt thereof, may be incorporated into convenient dosage forms such as capsules, tablets, or injectable preparations. Solid or liquid pharmaceutically acceptable carriers may also be employed. Solid carriers include starch, lactose, calcium sulphate dihydrate, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate and stearic acid. Liquid carriers include syrup, peanut oil, olive oil, saline solution and water.

The carrier or diluent may include any prolonged release material, such as glyceryl monostearate or glyceryl distearate, alone or with wax. When a liquid carrier is used, the preparation may be in the form of a syrup, elixir, emulsion, soft gelatin capsule, sterile injectable liquid(e.g. solution) or a nonaqueous or aqueous liquid suspension.

The pharmaceutical preparations are prepared conventional techniques of the

pharmaceutical chemist.

Compounds according to the present invention may be administrated orally topically, parenterally, by inhalation spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles.

The term parenteral as used herein includes subcutaneous injections, intravenous injection, intramuscular injection, intrasternal injection or infusion techniques.

An examplary daily dosage employed depends on the type of disease, the degree of symptom and age. The dosage levels of the compound in the above- indicated compositions may, of course, be varied and may conveniently be between about 0.0 lmg to about 200 mg per kilogram of the weight.

Pharmaceutical compositions containing compounds according to the invention may be in any form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispensable powders or granules, emulsion, hard or soft capsules, syrups or elixirs.

The tablets, capsules and the like may also contain a binder such as, e.g., lactose, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose or gelatin; excipients such as, e.g., dicalcium phosphate; a disintegrating agent such as, e.g., co starch or potato starch; a lubricant such as, e.g., magnesium stearate, calcium stearate, sodium stearylfumalate or polyethylene glycol wax. When the dosage unit form is a capsule, it may further contain, in addition to the types of materials described above, a liquid carrier such as e.g., a fatty oil.

These active compounds according to the present invention may also be administered parenterally. A solution or suspension of the active compounds may be prepared in water, optionally mixed with stabilizer or buffering agents. The dosages for parenteral administration are preferably as ampule or vial type.

These active compounds according to the invention may also be administered

by any known process of administrating the dose including topically, for example, an ointment, cream, jelly, solution, suspension or pachydematous patch; rectally, for example, suppository; intranasally or intrathoracally by inhalation spray.

Accordingly, the present invention provides pharmaceutical compositions comprising a pharmaceutically effective amount of thiazolidin-4-one derivatives and a pharmaceutically acceptable salt thereof. The present invention also provides the pharmaceutical uses of these compounds and compositions, especially for the prevent or treatment of various PAF- and/or leukotriene- induced diseases, [pharmaceutical compositions] Orally administration(Tablet) :

Composition mg/Tablet rag Tablet

Active Ingredient 100 500

Lactose 122 113

Corn starch/water 30 40

Corn starch 45 40

Magnesium stearate 3 7

Total 300 700

X. Sterile water may be added to the above composition for intravenous injection.

The compounds of this invention were tested for pharmacological activity as described in the following pharmacology examples.

Pharmacology Example 1 : PAF-induced rabbit platelet aggregation.

Blood was collected from the ear artery of a male New Zealand white rabbit and mixed with 3.8 % sodium citrate in a 9:1 volume ratio. Platelet rich plasma(PRP) was obtained by centrifugation of blood at 150 g for 10 min at room temperature. The number of platelets was adjusted to 3 x 10* platelets/mL with platelet poor plasma. Platelet aggregation was monitored by continuous recording of light transmission in a dual-channel aggregometer(Chrono-Log 560-VS) coupled with a two channel recorder(Chrono-Log 707). Stirred PRP was treated with various concentration of test compounds or vehicle(0.5 % DMSO) for 2 min and then PAF(5 x l() ^'y M) was added to induce platelet aggregation.

Inhibition values were calculated by comparing the extent of aggregation obtainted in the presence of the vehicle alone(0.5 % DMSO) and in the presence of a test compound. Log concentration-response curves were generated and the IC^ values were determined by regression analysis. Pharmacology Example 2 : Inhibitory activity for LTB„ biosynthesis

A suspension of rat basophillic leukemia- 1 cell in phosphoric acid buffer solution with a concentration of 5 x 10 ^r '/mL was allowed at 37'C for 5 min and added the compound of thiazolidin-4-one. A ter allowed for 5 min, to the mixture was added arachidonic acid(25 l/mL) and calcium ionophoie A23187(1 / /mL). After allowed for 15 min, the reaction mixture was quenched with 0.1N cooled hydrochloric acid and centrifuged with 3,3(X) rpm for 5 min. The supernatant solution was extracted with ethyl acetate and concentrated under nitrogen gas. The residue was dissolved in mobile phase and a amount of LTB ₄ was determined with HPLC. Table 7 lists result from this assay for inhibition of PAF-induced rabbit platelet aggregation and of LTB ₄ biosynthesis for illustrative examples of the compounds of this invention.

Table 7 : Inhibitory activity of PAF-induced rabbit platelet aggregation and LTB _< biosynthesis

Compound PAF IC _5ϋ Inhibition of LTB ₄ biosynthesis

No. (μM) (%, lO μM)

_(I Inhibition of LTB ₄ biosynthesis (%, 10 μM)

41

57

92

99

42

39

47

100

100

65

75

67

17

KM)

100

45

100

65

25 30

_S0 Inhibition of LTB ₄ biosynthesis ( , 10 μM)

100 48

47

38

63

63

57

37

100

67

28

98

42

98

45

100

72

100

52 100

,, Inhibition of LTB ₄ biosynthesis (%, 10 μM)

60

59

40

45

75

63

1(X)

1(K)

65

100

100

50

10

30

100

100

100

100

100 80

₍₎ Inhibition of LTB ₄ biosynthesis (%, 10 μM)

100

80

54

100

100

100

100

100 100