JPH05230069A - New pyrrolothiazole derivative - Google Patents

Abstract

PURPOSE:To obtain a new compound useful for therapeutic agent for antiasthmatic and nephritis and a relieving agent, etc., of ischemic heat and brain diseases, thrombosis and shock disorder by conbinedly using antagonism of a platelet-activating factor and action for preventing synthesis of thromboxane A2. CONSTITUTION:A compound of formula I [Z is formula II (R<1> and R<3> are H, halogen, lower alkyl, OH, cyano, nitro, etc.; A is halogen, halogeno-lower alkyl, OH, lower alkoxy, etc.), etc.], e.g. 2,4-decadiene amide of 2-cyano-5-(4- methoxyphenyl)-N-[3-(3-pyridin)-1H,3H-pyrrolo[1,2-C]thiazol-7-yl]. Furthermore, the compound of formula I is obtained by reacting a compound of formula III with a compound of formula IV in an organic solvent such as THF in the presence of a base such as triethylamine.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to pharmaceuticals, especially platelet activating factor (PAF) antagonism, and thromboxane A ₂ (TX).
A ₂ ) A novel pyrrolothiazole derivative, a salt thereof, a stereoisomer thereof, a solvate thereof and the like having a synthetic inhibitory action and useful as a preventive / therapeutic agent for diseases associated with these mediators ..

[0002]

2. Description of the Related Art RAF is a chemical substance produced and released from human and animal cells, and is acetylglyceryl ether of phosphorylcholine represented by the following formula.

[0003]

[Chemical 4]

(In the formula, 1 means 15 or 17.) PAF has pharmacological activities such as airway smooth muscle contraction, vascular permeability enhancement, platelet aggregation, and blood pressure reduction, and asthma, inflammation,
It is considered to be a factor that causes various symptoms such as thrombosis, nephritis, and shock.

On the other hand, TXA ₂ is an arachidonic acid caustic
It is the following unsaturated fatty acid that is biosynthesized from prostaglandin H ₂ by TXA ₂ synthase in the metabolic process.

[0006]

[Chemical 5]

[0007] TXA ₂ has pharmacological activities such as platelet aggregation, arterial contraction, bronchoconstriction, and is considered to be one of the factors involved in thrombosis, angina, bronchial asthma and the like.

Therefore, research on substances that antagonize the pharmacological activity of these mediators has been conducted. However, in actual clinical practice, it is difficult to obtain a sufficient therapeutic effect even if the pharmacological activity of one mediator is suppressed.
The combined use of various mediator inhibitors is practiced.

[0009]

However, the combined use of two or more drugs controls the pharmacokinetics of each drug because absorption, metabolism and excretion of each drug are unique. It's difficult. Moreover, the side effects may not occur unexpectedly due to the interaction between the drugs when used in combination. Therefore, there is a demand for the development of a pharmaceutical compound having the action of suppressing the pharmacological activity of each mediator with a single compound.

Conventionally, compounds having a pyridylpyrrolo [1,2-c] thiazole skeleton and having an anti-PAF activity are disclosed in JP-A-59-134798 and 63-2258.
The compounds described in JP-A-9-287875 and JP-A-3-287587 are known. However, these documents do not disclose or suggest that the compounds included therein have a TXA ₂ synthesis inhibitory action.

An object of the present invention is to provide a novel compound having both excellent anti-PAF activity and TXA ₂ synthesis inhibitory activity.

[0012]

The inventors of the present invention have synthesized various novel compounds, and have conducted extensive research into compounds having both anti-PAF activity and TXA ₂ synthesis inhibitory activity. As a result, the following general formula (I) The indicated pyridylpyrrolo [1,2-c]
The inventors have found that the thiazole derivative has both excellent anti-PAF activity and TXA ₂ synthesis inhibitory activity, and completed the present invention.

[0013]

[Chemical 6]

(The symbols in the formulas have the following meanings: Z: formula

[0015]

[Chemical 7]

A group represented by: R ¹ , R ² and R ^{3 are the} same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, cyano. Group or nitro group. A: halogen atom, halogeno lower alkyl group, hydroxyl group,
Lower alkoxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, cyano group, nitro group and formula

[0017]

[Chemical 8] And an optionally substituted alkylene group, alkenylene group or alkynylene group, which is a substituent selected from the group consisting of However, when A represents an unsubstituted alkylene group, at least one of R ¹ , R ² and R ³ represents a group other than a hydrogen atom)

The compound of the present invention will be described in more detail as follows. In the definitions of general formulas in this specification, the term “lower” means a carbon number of 1 to 6 unless otherwise specified.
Means straight or branched carbon chains. Therefore,
Specific examples of the “lower alkyl group” include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group,
tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1 -Dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1,2,2-trimethylpropyl group,
1-ethyl-1-methylpropyl group, 1-ethyl-2-
A methylpropyl group is mentioned.

The "lower alkoxy group" includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy (amyloxy), iso- Examples thereof include a pentyloxy group, a tert-pentyloxy group, a neopentyloxy group, a 2-methylbutoxy group, a 1,2-dimethylpropoxy group, a 1-ethylpropoxy group and a hexyloxy group.

The "lower alkylthio group" is a compound in which the oxygen atom of the above "lower alkoxy group" has become a sulfur atom, and specifically, methylthio group, ethylthio group, propylthio group, isopropylthio group, butylthio group. , S
Examples thereof include ec-butylthio group, tert-butylthio group, pentylthio group, neopentylthio group, 2-methylbutylthio group, 1,2-dimethylpropylthio group, 1-ethylpropylthio group and hexylthio group.

The "lower alkylsulfinyl group" and "lower alkylsulfonyl group" are groups obtained by oxidizing the above "lower alkylthio group", and specifically, for example, methyl-sulfinyl (or -sulfonyl) group, ethyl- Sulfinyl (or -sulfonyl group), propyl-sulfinyl (or -sulfonyl) group, isopropyl-sulfinyl (or -sulfonyl) group, butyl-sulfinyl (or -sulfonyl) group, sec-butyl-sulfinyl (or -sulfonyl) group, tert-butyl-sulfinyl (or -sulfonyl) group, pentyl-sulfinyl (sulfonyl) group, neopentyl-sulfinyl (or -sulfonyl) group, 2-methylbutyl-sulfinyl (or sulfonyl) group, 1,2-dimethylpropyl-sulfinyl ( Or Honiru) group, 1-ethylpropyl - sulfinyl (or - sulfonyl) group, hexyl -
Examples thereof include a sulfinyl (or -sulfonyl) group.

The alkylene group has 1 to 1 carbon atoms.
Two alkylene groups are preferable, and specifically, methylene group, ethylene group, methylmethylene group, trimethylene group, propylene group, 2-propylene group, dimethylmethylene group, tetramethylene group, 1-methyltrimethylene group. ，
2-methyltrimethylene group, 3-methyltrimethylene group, 1-ethylethylene group, 2-ethylethylene group,
2,2-dimethylethylene group, 1,1-dimethylethylene group, ethylmethylmethylene group, pentamethylene group, 1
-Methyltetramethylene group, 2-methyltetramethylene group, 3-methyltetramethylene group, 4-methyltetramethylene group, 1,1-dimethyltrimethylene group, 3,3-
Dimethyltrimethylene group, hexamethylene group, 1-methylpentamethylene group, 1,1-dimethyltetramethylene group, 4,4-dimethyltetramethylene group, heptamethylene group, 1-methylhexamethylene group, 1,1-dimethyl Pentamethylene group, 5,5-dimethylpentamethylene group, octamethylene group, 1-methylheptamethylene group,
1,1-dimethylhexamethylene group, nonamethylene group,
1-methyloctamethylene group, 1,1-dimethylheptamethylene group, decamethylene group, 1-methylnonamethylene group, 1,1-dimethyloctamethylene group, undecamethylene group, 1-methyldecamethylene group, 1,1 Examples thereof include linear or branched ones such as dimethylnonamethylene group, dodecamethylene group, and 1,1-dimethyldecamethylene group.

The alkenylene group is preferably a straight chain or branched chain having 1 to 4 double bonds and having 2 to 12 carbon atoms, and specifically, for example, vinylene group, propenylene group, 2- Propenylene group, 1-methylvinylene group, 2-methylvinylene group, butenylene group, 2-butenylene group, 3-butenylene group, 1,3-butadiene-
1,4-diyl group, pentenylene group, 1,3-pentadiene-1,5-diyl group, 1-methylbutenylene group, 1
-Methyl-1,3-butadiene-1,4-diyl group, hexenylene group, 1,3-hexadiene-1,6-diyl group, 1,3-hexadiene-1,4-diyl group, 1-methylpentenyl Ren group, 1,3,5-hexatriene-
1,4-diyl group, 1-methyl-1,3-pentadiene-1,5-diyl group, heptenylene group, 1,3-heptadiene-1,7-diyl group, 1,3-heptadiene-
1,4-diyl group, 1-methylhexenylene group, 1-methyl-1,3-hexadiene-1,6-diyl group, octenylene group, 1,3-octadiene-1,8-diyl group, 1, 3-octadiene-1,4-diyl group, 1-methylheptenylene group, 1-methyl-1,3-heptadiene-1,7-diyl group, nonenylene group, 1,3-nonadiene-1,9-diyl group Group, 1,3-nonadiene-1,4
-Diyl group, 1-methyloctenylene group, 1-methyl-
1,3-octadiene-1,8-diyl group, decenylene group, 1,3-decadiene-1,10-diyl group, 1,3
-Decadiene-1,4-diyl group, undecenylene group,
1,3-undecadiene-1,11-diyl group, 1,3
-Undecadiene-1,4-diyl group, dodecenylene group, 1,3-dodecadiene-1,12-diyl group, 1,
A 3-dodecadien-1,4-diyl group and the like can be mentioned.

Further, the alkynylene group is preferably a linear or branched one having 2 to 12 carbon atoms, specifically, for example, ethynylene group, propynylene group, 2-propynylene group, butynylene group, 2-butynylene group. Group, 3-
Butynylene group, 1,3-butadiyne-1,4-diyl group, pentynylene group, 2-pentynylene group, 3-pentynylene group, 4-pentynylene group, 1,3-pentadiyne-1,5-diyl group, hexynylene group, 2-hexynylene group, 3-hexynylene group, 1,3-hexadiyne-
1,6-diyl group, heptynylene group, 2-heptynylene group, 3-heptynylene group, 1,3-heptadiyne-1,
7-diyl group, octynylene group, 3-octynylene group,
Nonynylene group, 3-nonynylene group, decynylene group, 3-
Examples include decynylene group, undecynylene group, 3-undecynylene group, dodecynylene group and the like.

The "halogen atom" is not particularly specified and includes fluorine atom, chlorine atom, bromine atom and iodine atom. "Halogeno lower alkyl group"
Means a group in which any one of the hydrogen atoms of the above "lower alkyl group" is substituted with 1 to 3 of the above "halogen atom",
Specifically, when the fluorine atom is used as the halogen atom, for example, a fluoromethyl group, a trifluoromethyl group, a 2-fluoroethyl group, a 3-fluoropropyl group, a 2-fluoro-1-methylethyl group, a 4-fluorobutyl group. , 3-
Fluoro-2-methylpropyl group, 5-fluoropentyl group, 4-fluoro-3-methylbutyl group, 6-fluorohexyl group and the like can be mentioned.

The compound of the present invention represented by the general formula (I) forms a salt. The present invention includes salts of compound (I), and specific examples of such salts include mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid and phosphoric acid, formic acid, Acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid and aspartic acid, and acidic amino acids such as glutamic acid Examples thereof include acid addition salts with organic acids. Further, the compound (I) of the present invention has an asymmetric carbon atom and may have a double bond and the like, and stereoisomers such as optical isomers and geometric isomers based on the presence thereof exist. The present invention includes isolated stereoisomers and mixtures of these stereoisomers. further,
The present invention also includes various solvates of the compound (I) of the present invention and polymorphic substances.

The compound (I) of the present invention can be produced by applying various synthetic methods utilizing the characteristics of the basic skeleton and various substituents. Next, the typical manufacturing method is illustrated. First manufacturing method

[0028]

[Chemical 9]

(In the formula, Z represents the above meaning.) In the compound of the present invention, the amide compound represented by the general formula (I) is an amine (II) or a salt thereof and a carboxylic acid represented by the general formula (III). Alternatively, it can be produced by condensation with its reactive derivative according to a conventional method. Compound (I
Examples of the reactive derivative of II) are acid halides such as acid chloride and acid bromide; acid azides; active esters with N-hydroxybenzotriazole and N-hydroxysuccinimide; symmetrical acid anhydrides; alkyl carbonic acid, p -Mixed acid anhydrides with toluene sulfonic acid and the like can be mentioned. When the compound (III) is reacted with a free carboxylic acid, dicyclohexylcarbodiimide, 1-ethyl-3- (3
-Dimethylaminopropyl) carbodiimide, 1,1 '
It is advantageous to work in the presence of a condensing agent such as -carbonyldiimidazole, diphenylphosphoryl azide (DPPA).

The reaction conditions are the starting compounds, especially the compound (III)
Pyridine, tetrahydrofuran, dioxane, ether, N, depending on the kind of the reactive derivative of
N-dimethylformamide, benzene, toluene, xylene, methylene chloride, dichloroethane, chloroform, ethyl acetate, acetonitrile and the like in an organic solvent inert to the reaction, starting materials (II) and (III) are equimolar to starting materials (III) It is advantageous to react with a molar excess of. Depending on the kind of the reactive derivative or when using the salt of the starting compound (II), in the reaction, an organic base such as trimethylamine, triethylamine, pyridine, picoline, lutidine, dimethylaniline, N-methylmorpholine, potassium carbonate, sodium carbonate. , It may be advantageous to carry out in the presence of a base such as an inorganic base such as sodium hydrogen carbonate, sodium hydroxide, potassium hydroxide.
Pyridine can also serve as a solvent. The reaction temperature varies depending on the type of reactive derivative and is set appropriately. Second manufacturing method

[0031]

[Chemical 10]

(In the formula, R ¹ , R ² and R ³ have the above meanings, R ⁴ is a fluorine atom, a trifluoromethyl group,
A lower alkylsulfonyl group, a cyano group or a nitro group,
A ¹ is a single bond or a halogen atom, a halogeno lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylthio group,
Lower alkylsulfinyl group, lower alkylsulfonyl group, cyano group, nitro group and formula

[0033]

[Chemical 11]

A substituent selected from the group consisting of the groups represented by: 1 to 10 carbon atoms, each of which may be substituted.
The compound having a double bond of the formula (Ia) in the compound of the present invention is a general condensation reaction (Knoevenagel reaction) between the compound (IV) and the aldehyde compound (V). Can be synthesized by
This method consists of acetic acid-piperidine mixture, β-alanine, alumina, titanium tetrachloride, tin tetrachloride, boron trifluoride,
Potassium fluoride, sodium hydroxide, potassium hydroxide,
In the presence of an alkali metal alcoholate such as sodium carbonate, ammonium acetate, sodium ethoxide and potassium t-butoxide, a catalyst such as diethylamine, triethylamine, pentylamine and pyridine, an alcohol such as ethanol and methanol, Compound (IV) and an equimolar to excess molar amount of Compound (V) in an organic solvent such as tetrahydrofuran, diethyl ether, methylene chloride, chloroform, benzene, toluene, acetonitrile and the like, water or a mixed solvent thereof, It is suitable to carry out the reaction at room temperature or under heating, preferably under heating. Third manufacturing method

[0035]

[Chemical 12]

(Wherein Z represents the above meaning and R ⁵ represents an ester residue) The compound (I) of the present invention can be obtained from the carbamic acid ester of the formula (VI) by the following reaction. That is, the compound (III) is hydrolyzed (preferably treated with an acid such as trifluoroacetic acid, hydrochloric acid, acetic acid, hydrobromic acid-hydrochloric acid, hydrobromic acid-acetic acid or a mixture of these acids with anisole or dioxane. It can be produced by reacting the corresponding amino acid (II) obtained by acid hydrolysis) with the corresponding carboxylic acid or its reactive derivative according to the first production method without purification. Here, as the ester residue of R ⁵ , a methyl group,
Lower alkyl groups such as ethyl group and tert-butyl group,
An aralkyl group such as a benzyl group is preferable. The type of reactive derivative, the conditions of the condensation reaction, and the like are almost the same as in the first production method.

The reaction products obtained by the above respective production methods are
It is isolated and purified as a free compound, its salt or various solvates. The salt can be produced by subjecting it to a usual salt-forming reaction. Isolation and purification are carried out by applying ordinary chemical operations such as extraction, concentration, evaporation, crystallization, filtration, recrystallization and various chromatographies.

Geometric isomers can be easily separated by utilizing the difference in physicochemical properties between cis-trans isomers. In addition, the racemic compound can be obtained by using an appropriate starting material compound or by a general racemic resolution method [for example, a method of leading to a diastereomer salt with a general optically active acid (tartaric acid, etc. and performing optical resolution)] It can lead to chemically pure isomers. The diastereomer mixture can be separated by a conventional method such as fractional crystallization or chromatography.

[0039]

INDUSTRIAL APPLICABILITY The compound (I) of the present invention, its salt, its stereoisomer and its solvate have excellent PAF antagonistic activity and T
It also has an inhibitory effect on XA ₂ synthesis, PAF and T
A preventive and / or therapeutic agent for a disease caused by XA ₂ , particularly a disease involving both PAF and TXA ₂ mediators, which is effective by combining both effects of antagonizing these mediators and synthetically inhibiting them Is useful as Therefore,
The compound (I) of the present invention can be clinically useful as an anti-asthma agent, a therapeutic agent for nephritis, a relieving agent for ischemic heart, brain disease, thrombosis, shock symptom and the like.

The compounds of the present invention also include compounds having an active oxygen production inhibitory action and / or an endothelin action inhibitory action. These compounds are further clinically treated against the above diseases. Expected as a useful drug.

[0041]

EXAMPLES The present invention will be described in more detail with reference to the following examples. The starting material compounds of the present invention include new compounds and can be obtained by the method of Reference Examples or according to the method. In the reference examples and examples, NMR is TM
MS represents a nuclear magnetic resonance spectrum with S as an internal standard, and MS represents a mass spectrum.

Reference Example 1 (2E) -3- (4-methoxyphenyl) -2-octenal (494 mg), cyanoacetic acid ethyl ester (2
To a mixture of 40 mg) and ethanol (4 ml) was added a 3: 1 mixture of piperidine and acetic acid (3 drops) under heating under reflux, and the mixture was stirred under heating under reflux for 5 hours. After cooling, the mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 10: 1) to give (4E) -2-cyano-5- (4-methoxyphenyl). ) -2,4-decadienoic acid ethyl ester was obtained.
This compound was dissolved in methanol (10 ml) to give 10%
Aqueous sodium hydroxide solution (6 ml) was added, and the mixture was stirred with heating under reflux for 1 hr. After cooling, the mixture was concentrated under reduced pressure, water and diethyl ether were added to the obtained residue, the aqueous layer was separated, washed with diethyl ether, and adjusted to pH = 1 with concentrated hydrochloric acid. It was extracted with methylene chloride, and the organic layer was dried over anhydrous sodium sulfate. Concentrate under reduced pressure to (4E) -2-
Cyano-5- (4-methoxyphenyl) -2,4-decadienoic acid (400 mg) was obtained.

NMR (CDCl ₃ ) δ: 0.79-0.92 (3H, m), 1.15-1.
56 (6H, m), 2.55-2.92 (2H, m),
3.84 (3H, s), 6.63-7.20 (3H,
m), 7.55 (2H, d (J = 10Hz)), 7.9
1,8.31 (1H in total, d (J = 12H
z), d (J = 13 Hz))

Reference Example 2 Cyanoacetic acid (268 mg), dimethylformamide (1 drop), methylene chloride (3 m) under an argon atmosphere.
l) to the mixture of oxalyl chloride (480
(mg) was added dropwise, the mixture was stirred at the same temperature for 5 minutes, warmed to room temperature and stirred for 1 hour, and concentrated under reduced pressure to give cyanoacetic acid chloride. Under ice-cooling, (3R) -7-tert-butoxycarbonylamino-3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole (1 g) was added to trifluoroacetic acid (2 ml). Was added, and the mixture was stirred for 5 minutes, further heated to room temperature and stirred for 1 hour, concentrated under reduced pressure, neutralized by adding methylene chloride and saturated aqueous sodium hydrogen carbonate solution, and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give (3R) -7-amino-3- (3-pyridyl) -1H,
3H-pyrrolo [1,2-c] thiazole was obtained. This compound was dissolved in methylene chloride (2 ml), triethylamine (1.5 ml) was added, and under argon atmosphere,
Cyanoacetic acid chloride and dichloromethane (2m
The mixture of l) was added dropwise. The mixture was stirred at the same temperature for 5 minutes and further at room temperature for 1 hour. Methylene chloride and saturated aqueous ammonium chloride solution were added to the reaction mixture, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent;
Purify with methylene chloride: ethyl acetate = 1: 1),
N-[(3R) -3- (3-pyridyl) -1H, 3H-
Pyrrolo [1,2-c] thiazol-7-yl] cyanoacetamide (348 mg) was obtained.

NMR (CDCl ₃ ) δ: 3.52 (2H, s), 4.27 (2H, s),
6.21 (2H, d-d (J = 6.7, 4.9H
z)), 6.34 (1H, s) 7.26-7.64 (2H, m), 7.53-8.35.
(2H, m) MS: m / z 284 (M ⁺ ).

Reference Example 3 1.65 M n-butyllithium-under an argon atmosphere
A mixture of lithium diisopropylamide and tetrahydrofuran (5 ml) prepared from a hexane solution (0.49 ml) and diisopropylamine (81 mg) was -78.
After cooling to ° C, triethyl-2-fluoro-2-phosphonoacetate (202 mg) was added dropwise thereto, and the mixture was stirred for 30 minutes. At the same temperature, a mixture of 3,3-bis (4-methoxyphenyl) propenal (165 mg) and tetrahydrofuran (0.75 ml) was added dropwise, and the mixture was stirred for 3 hours.
A saturated ammonium chloride aqueous solution was added to the reaction mixture, the temperature was raised to room temperature, and the mixture was extracted with a mixed solvent of ether-hexane (1: 1). Wash the extract with saturated saline,
It was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 6: 1), and (2E) -ethyl-5,5-bis (4-methoxyphenyl) -2-fluoro-2,4-pentadiene. -To (185 mg) was obtained. Potassium hydroxide (370 mg) was added to a mixture of the compound (168 mg) obtained above, ethanol (4 ml) and water (0.2 ml), and the mixture was stirred for 2 hours. The reaction mixture was adjusted to pH 1-2 with 1N hydrochloric acid and extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated under reduced pressure,
(2E) -5,5-bis (4-methoxyphenyl) -2
-Fluoro-2,4-pentadienoic acid (160 mg) was obtained.

NMR (CDCl ₃ ) δ: 3.82 (3H, s), 3.87 (3H, s),
6.57 (1H, dd (J = 12, 21Hz)),
7.79-7.41 (8H, m), 7.54 (1H, d
(J = 12 Hz)) MS: m / z 328 (M ⁺ ).

Reference Examples 4 to 6 In the same manner as in Reference Example 3, the following compounds were obtained. Reference Example 4, 3,3-bis (4-methoxyphenyl) -2-fluoropropenoic acid NMR: (CDCl ₃ ) δ: 3.81 (3H, s), 3.83 (3H, s),
6.79-6.93 (4H, m), 7.03-7.33
(4H, m) MS: m / z 302 (M ⁺ )

Reference Example 5 5,5-bis (4-methoxyphenyl) -4-fluoro
-2,4-pentadienoic acid NMR: (CDCl₃ ) Δ: 3.83 (3H, s), 3.86 (3H, s),
6.21 (1H, d (J = 15Hz)), 6.86 (2
H, d (J = 9.0 Hz), 6.92 (2H, d (J
= 9.0H z)), 7.12 (2H, d (J = 7.0H
z)), 7.20-7.32 (3H, m) MS: m / z 328 (M⁺ )

Reference Example 6 5,5-bis (4-methoxyphenyl) -2,4-difluoro-2,4-pentadienoic acid NMR: (CDCl ₃ ) δ: 3.81 (3H, s), 3.85 (3H, s),
6.33 (1H, dd (J = 12, 24Hz)),
6.78-6.95 (4H, m), 7.08-7.33
(4H, m) MS: m / z 346 (M ⁺ ).

Reference Example 7 Ethyl-3,3-bis (4-methoxyphenyl) -2-fluoropropeneate (461 m under argon atmosphere)
g), hexane (2.6 ml), toluene (1.3 m)
To the mixture of 1), 0.95M diisobutylaluminum hydride-hexane solution (3 ml) was added dropwise at 0 ° C.,
Stir for hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture to decompose excess hydride, and 1N hydrochloric acid was added to adjust the liquidity to pH 1 to 2, followed by extraction with ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to obtain 3,3-bis (4-methoxyphenyl) -2-fluoro-2-propen-1-o-. To give (38 mg). Under an argon atmosphere, oxalyl chloride (174 mg) and methylene chloride (2 m
Dimethyl sulfoxide (214 mg) was added dropwise to the mixture of 1) at -78 ° C, and the mixture was stirred for 5 minutes, then, at the same temperature,
A mixture of 3,3-bis (4-methoxyphenyl) -2-fluoro-2-propen-1-ol (328 mg) and methylene chloride (1 ml) was added dropwise, and the mixture was stirred for 15 minutes. Triethylamine (693 mg) was added dropwise at the same temperature, and the mixture was stirred for 5 minutes. The reaction solution is warmed up to room temperature and water 10
After adding ml, the mixture was stirred for 5 minutes and extracted with methylene chloride. The extract was washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; hexane: ethyl acetate = 5:
Purified in 1), 3,3-bis (4-methoxyphenyl)
2-Fluoropropenal (285 mg) was obtained.

NMR (CDCl ₃ ) δ: 3.84 (3H, s), 3.87 (3H, s),
6.81-7.03 (4H, m), 7.15-7.44
(4H, m), 9.24 (1H, d (J = 19Hz)) MS: m / z 286 (M ⁺ )

Reference Example 8 3,3-bis (4-methoxyphenyl) -2-cyanopropenoic acid (928 mg), methylene chloride (5 m
In a mixture of 1), under argon atmosphere, under ice cooling, dimethylformamide (2 drops), oxalyl chloride (1.3
8 ml) was successively added dropwise, the mixture was stirred at the same temperature for 5 minutes, warmed to room temperature and further stirred for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain 3,3-bis (4-methoxyphenyl) -2-cyanopropenoyl chloride. 3, obtained above
Tetrahydrofuran (20 ml) was added to 3-bis (4-methoxyphenyl) -2-cyanopropenoyl chloride.
Was added and the mixture was cooled to −78 ° C. under an argon atmosphere, lithium aluminum hydride (76 mg) was added, and the mixture was stirred for 30 minutes. Sodium sulfate decahydrate was added to the reaction mixture to decompose unreacted hydride, the temperature was raised to room temperature, and anhydrous sodium sulfate was further added. Methylene chloride was added to this mixture, the mixture was filtered, washed with ethyl acetate, the washing solution and the filtrate were combined, and the residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (elution solvent; hexane: ethyl acetate = 3: 1). After purification, 3,3-bis (4-methoxyphenyl) -2-cyano-2-propenol (4
95 mg) was obtained. Under an argon atmosphere, oxalyl chloride (307 mg), methylene chloride (10 m
1) to a mixture of dimethyl sulfoxide (3
78 mg) was added dropwise and the mixture was stirred for 5 minutes. To this reaction mixture, at the same temperature, 3,3-bis (4-methoxyphenyl) -2-cyano-2-propenol (476) synthesized above was added.
mg) and methylene chloride (2 ml) were added dropwise and the mixture was stirred for 15 minutes, then triethylamine (1.22
g) was added dropwise and stirred for 5 minutes. Water (20 ml) was added, the temperature was raised to room temperature, and the mixture was extracted with a mixed solvent of methylene chloride and ether (1: 2). The extract was washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 4: 1) to obtain 3,3-bis (4-methoxyphenyl) -2-cyanopropenal (424 mg). It was

NMR (CDCl ₃ ) δ: 3.88 (3H, s), 3.89 (3H, s),
6.91-7.03 (4H, m), 7.14-7.28
(2H, m), 7.41-7.55 (2H, m), 9.
36 (1H, s) MS: m / z 293 (M ⁺ ).

Reference Example 9 Diisopropylamine (601 m
g) and a 1.65 M solution of n-butyllithium-hexane (3.65 ml) in a mixture of lithium diisopropylamide and tetrahydrofuran (4 ml),
Acetonitrile (256 mg) was added dropwise at -78 ° C to give 1
Stir for 5 minutes. A mixture of 1,2-bis (4-methoxyphenyl) ethanone (1.28 g) and tetrahydrofuran (12 ml) was added dropwise to this mixture, and the mixture was stirred for 5 minutes. Saturated aqueous ammonium chloride solution (15 ml) at the same temperature
After adding, the mixture was heated to room temperature and extracted with methylene chloride. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was recrystallized from ethyl acetate-hexane (1: 5) to give 2,3-
Bis (4-methoxyphenyl) -1-cyano-2-propanol (1.40 g) was obtained. 2,3 obtained above
-Bis (4-methoxyphenyl) -1-cyano-2-propanol (1.19 g), trifluoroacetic acid (670
mg) and methylene chloride (10 ml),
The mixture was heated under reflux for 2 hours. After cooling, methylene chloride (70 ml) was added to the obtained reaction mixture, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluting solvent: hexane: ethyl acetate = 6: 1),
3,4-bis (4-methoxyphenyl) -2-butenonitrile (1.11 g) (Compound A) was obtained. A mixture of 3,4-bis (4-methoxyphenyl) -2-butenonitrile (940 mg) and toluene (10 ml) obtained above under an argon atmosphere was added to 0.95 M diisobutylaluminum hydride-hexane at -40 ° C. Solution (4.7
5 ml) was added dropwise and the mixture was stirred for 1 hour. The temperature was raised to -10 ° C, 10% sulfuric acid (10 ml) was added, and the mixture was further heated at 40 ° C for 30 minutes.
Stir for minutes. After cooling, the reaction solution was extracted with toluene. The extract was washed successively with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 5: 1) to give 3,4-bis (4
-Methoxyphenyl) -2-butenal (492 mg)
(Compound B) was obtained.

(1) Compound A NMR (CDCl ₃ ) δ: 3.73-3.84 (6H, m), 4.13 (3)
H, s), 5.61 (1H, s), 6.77-7.54.
(8H, m) MS: m / z 279 (M ⁺ ) (2) Compound B NMR (CDCl ₃ ) δ: 3.75 (3H, s), 3.80 (3H, s),
4.32 (2H, s), 6.51 (1H, d (J = 8.
0 Hz)), 6.73-6.91 (4H, m), 7.0
5-7.54 (4H, m), 9.15 (1H, d (J =
8.0 Hz)) MS: m / z 282 (M ⁺ ).

Reference Example 10 3,4-bis (4-methoxyphenyl) -2-butenal (490 mg), methyltriphenylphosphoranylidene acetate (702 mg), methylene chloride (6)
ml) was heated to reflux for 2 hours. After cooling, the reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (elution solvent; hexane: ethyl acetate = 6: 1) and methyl 5,6-bis (4-
Methoxyphenyl) -2,4-hexadienate (50
5 mg) was obtained. Methyl 5,6-bis (4-methoxyphenyl) -2,4-hexadienate (282 mg) obtained above, 1N aqueous lithium hydroxide solution (2.8
ml) and tetrahydrofuran (3 ml),
Heated to reflux for hours. After cooling, the reaction mixture was adjusted to pH 1-2 with 5N hydrochloric acid and extracted with methylene chloride. The extract was washed successively with water and 10% brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained compound was recrystallized from ethyl acetate to give 5,6-bis (4-
Methoxyphenyl) -2,4-hexadienoic acid (354
mg) was obtained.

NMR (DMSO-d ₆) Δ: 3.67 (3H, s), 3.74 (3H, s),
4.03 (2H, s), 6.09 (1H, d (J = 15
Hz)), 6.74-7.24 (8H, m), 7.47
-7.19 (2H, m) MS: m / z 324 (M⁺)

Reference Example 11 In the same manner as in Reference Example 10, the following compound was obtained. 5,5-bis (4-methoxyphenyl) -4-cyano-
2,4-Pentadienoic acid NMR (CDCl ₃ ) δ: 3.86 (3H, s), 3.88 (3H, s),
6.42 (1H, d (J = 15Hz)), 6.86-
7.44 (8H, m), 7.53 (1H, d (J = 15
Hz)), MS: m / z 336 (M ⁺ +1)

Reference Example 12 1.65 M n-butyllithium-under an argon atmosphere
To a mixture of lithium diisopropylamide and tetrahydrofuran (2 ml) prepared from a hexane solution (0.67 ml) and diisopropylamine (111 mg),
Triethyl-2-phosphonopropionate (2
(62 mg) was added dropwise, and the mixture was stirred for 10 minutes. At the same temperature, 3,3-bis (4-methoxyphenyl) propenal (250 mg) and tetrahydrofuran (1 m) were added to this reaction mixture.
The mixture of 1) was added dropwise, and the mixture was stirred for 1 hour and a half, warmed to room temperature and stirred for 2 hours. A saturated ammonium chloride aqueous solution was added to the reaction mixture, and an ether-hexane mixed solvent (1: 2) was added.
It was extracted with. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent;
Purified with hexane: ethyl acetate = 6: 1), (2Z)-
Ethyl-5,5-bis (4-methoxyphenyl) -2-
Methyl-2,4-pentadienate (180 mg) was obtained. (2Z) -Ethyl-5,5-bis (4- obtained above
A mixture of methoxyphenyl) -2-methyl-2,4-pentadienate (328 mg), ethanol (18 ml) and water (0.5 ml) was added with potassium hydroxide (6) under ice cooling.
85 mg) was added and dissolved, and then the temperature was raised to room temperature.
Stir for hours. The mixture was acidified with hydrochloric acid and concentrated under reduced pressure. The resulting residue was extracted by adding a mixed solvent of water and methylene chloride-ethyl acetate (1: 2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained compound was washed successively with a mixed solvent of ether and hexane-methylene chloride (5: 1), (2E).
-5,5-bis (4-methoxyphenyl) -2-methyl-2,4-pentadienoic acid (263 mg) was obtained.

NMR (DMSO-d ₆ ) δ: 1.98 (3H, s), 3.77 (3H, s),
3.82 (3H, s), 6.79-7.32 (10H,
m) MS: m / z 324 (M ⁺ ).

Under an argon atmosphere, bis- (2,2,2-
Trifluoroethyl) -1-ethoxycarbonylethylphosphonate (698 mg), 18-crown-6-ether (1.32 g), tetrahydrofuran (15 m
The mixture of l) was added to a mixture of 0.5M-potassium hexamethyldisilazide-toluene solution at -78 ° C (4.04 ml).
Was added dropwise and stirred for 10 minutes. Then 3,3-bis (4
A mixture of -methoxyphenyl) propenal (541 mg) and tetrahydrofuran (2 ml) was added dropwise at the same temperature, and the mixture was stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction mixture at the same temperature, the temperature was raised to room temperature, and the mixture was extracted with ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent;
Purified with hexane: ethyl acetate = 7: 1), (2Z)-
Ethyl-5,5-bis (4-methoxyphenyl) -2-
Methyl-2,4-pentadienate (521 mg) was obtained. A 1N aqueous potassium hydroxide solution (3 ml) was added to a mixture of this compound (519 mg), tetrahydrofuran (5 ml) and methanol (2 ml), and the mixture was stirred for 45 hours for 12 hours.
Stir at ℃. After cooling, adjust the pH to 1-2 with 1N hydrochloric acid.
And extracted with methylene chloride. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give (2Z) -5,5-bis (4-methoxyphenyl) -2-methyl-2,4-pentadienoic acid ( 432m
g) was obtained.

NMR (CDCl ₃ ) δ: 1.95 (3H, d (J = 0.9Hz)), 3.8
0 (3H, s), 3.87 (3H, s), 6.66 (1
H, dd (J = 0.9, 1.2 Hz)), 6.77-
7.32 (8H, m), 7.74 (1H, d (J = 12
H, z) MS: m / z 324 (M ⁺ ).

Reference Example 14 3,3-bis (4-methoxyphenyl) propenal (385 mg), ethyl-2-methylsulfonylacetic acid (239 mg) and toluene (5 ml) were added to a mixture of piperidine and acetic acid (3: 1). ) Was added dropwise, Molecular Sieves 4A (100 mg) was added, and the mixture was heated under reflux for 18 hours. After cooling, methylene chloride was added to the reaction mixture, washed successively with saturated aqueous ammonium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (elution solvent; methylene chloride: ethyl acetate =).
It was purified by 50: 1) to obtain ethyl 5,5-bis (4-methoxyphenyl) -2-methylsulfonyl-2,4-pentadienate (313 mg).

NMR (CDCl ₃ ) δ: 1.41 (3H, t (J = 7.1Hz)), 3.1
7 (3H, s), 3.84 (3H, s), 3.87 (3
H, s), 4.41 (2H, q (J = 7.1 Hz)),
6.82-7.38 (8H, m), 7.57 (1H, d
(J = 12 Hz), 7.88 (1H, d (J = 12H)
z)) MS: m / z 416 (M ⁺ ).

Example 1 2-Cyano-5- (4-methoxyphenyl) -2,4-
To a mixture of decadienoic acid (372 mg), dimethylformamide (2 drops) and methylene chloride (4 ml)-
Oxalyl chloride (120 ml) was added dropwise at 78 ° C. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure to give 2-cyano-5- (4-methoxyphenyl) -2,4-decadienoic acid chloride. 7-t-butoxycarbonylamino-3- (3-pyridyl) -1H, 3H-pyrrolo [1,
Trifluoroacetic acid (3 ml) was added to 2-c] thiazole (400 mg) under ice cooling. After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the obtained residue, the mixture was extracted with methylene chloride, and the extract was dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was dissolved in methylene chloride (4 ml), triethylamine (530 ml) was added under ice cooling, and then 2-cyano-5- (4-methoxyphenyl) -obtained above was obtained.
A mixture of 2,4-decadienoic acid chloride and methylene chloride (4 ml) was added dropwise. After stirring at room temperature for 12 hours, the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, the obtained residue was subjected to silica gel column chromatography (elution solvent; methylene chloride: ethyl acetate = 3 :).
Purified in 1), 2-cyano-5- (4-methoxyphenyl) -N- [3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazol-7-yl]- 2,4-
Decadienamide (191 mg) was obtained.

Elemental analysis value (as C ₂₉ H ₃₀ N ₄ O ₂ S) C (%) H (%) N (%) S (%) Theoretical value 69.85 6.06 11.24 6.43 Experimental value _{69.47 6.06 11.06 6.38 NMR (CDCl 3} ) δ: 0.82-0.87 (3H, m), 1.22-1.
49 (6H, m), 2.63, 2.85 (total 2
H, each t (J = 8.1 Hz)), 3.84, 3.87
(3H in total, each s), 4.21-4.42 (2H,
m), 6.18-6.28 (2H, m), 6.33,
6.37 (1H in total, each s), 6.68, 6.88
-6.97 (3H in total, d (J = 10.8
Hz), m), 7.30-7.37 (1H, m), 7.
53-7.63 (2H, m), 8.03, 8.43 (1H in total, d (J = 10.8 Hz) d (J = 10.8 Hz)), 8.54-8.63 ( Two
H, m)

Examples 2 to 14 The following compounds were obtained in the same manner as in Example 1. Example 2 3,3-bis (4-methoxyphenyl) -2-cyano-
N- [3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazol-7-yl] -2-propenamide Melting point 190 ° C Elemental analysis value (C ₂₉ H ₂₄ N ₄ O ₃ S As) C (%) H (%) N (%) S (%) Theoretical value 68.49 4.76 11.02 6.30 Experimental value 68.27 4.83 10.77 6.13

Example 3 (2E, 4E) -5- (4-methoxyphenyl) -N-
[3- (3-pyridyl) -1H, 3H-pyrrolo [1,2
-C] thiazol-7-yl] -2,4-decadiene
Mido NMR (CDCl₃) Δ: 0.84 (3H, t (J = 6.7Hz)), 1.2
0-1.44 (6H, m), 2.74 (2H, t (J =
8.1 Hz)), 3.85 (3H, s), 4.36 (1
H, d (J = 14 Hz)), 4.43 (1 H, d (J =
14Hz)), 6.06 (1H, d (J = 14H
z)), 6.19 (1H, d (J = 4 Hz)), 6.2.
4 (1H, d (J = 4Hz)), 6.34 (1H,
s), 6.45 (1H, d (J = 11 Hz)), 6.9
0 (2H, d (J = 9.5Hz)), 7.27-7.3
4 (1H, m), 7.41 (2H, d (J = 9.5H
z)), 7.58-7.63 (1H, m), 7.76.
(1H, dd (J = 14Hz, 11Hz) 8.56-8.62 (2H, m) MS: m / z 473 (M⁺ )

Example 4 (2E) -5,5-bis (4-methoxyphenyl-N-)
[3- (pyridyl) -1H, 3H-pyrrolo [1,2-
c] thiazol-7-yl] -2,4-pentadienamide NMR (CDCl ₃ ) δ: 3.82 (3H, s), 3.85 (3H, s),
4.31 (1H, d (J = 13Hz)), 4.37 (1
H, d (J = 13 Hz)), 6.09-6.20 (3
H, m), 6.31 (1H, s), 6.68 (1H, d
(J = 11 Hz)), 6.84 (2H, d (J = 8.8)
Hz)), 6.92 (2H, d (J = 8.8Hz)),
7.14 (2H, d (J = 8.8Hz)), 7.25
(2H, d (J = 8.8Hz)), 7.28-7.30
(1H, m), 7.43 (1H, dd (J = 12Hz,
12 Hz)), 7.56-7.59 (1 H, m), 8.
53-8.58 (2H, m) MS: m / z 509 (M ⁺ ).

Example 5 5,6-bis (4-methoxyphenyl) -N-[(3
R) -3- (3-Pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazol-7-yl] -2,4-hexadienamide NMR (CDCl ₃ ) δ: 3.72-3.73 (3H, m), 3.79 (3
H, s), 4.05 (2H, s), 4.41 (1H, d
(J = 14 Hz)), 6.13 (1H, d (J = 14.
Hz)), 6.17 (1H, d (J = 3.1 Hz)),
6.22 (1H, d (J = 3.1 Hz)), 6.32
(1H, s), 6.71 (1H, d (J = 12H
z)), 6.74-6.76 (2H, m), 6.81-
6.83 (2H, m), 7.04-7.07 (3H,
m), 7.26-7.31 (1H, m), 7.39-
7.41 (2H, m), 7.59 (1H, d (J = 7.
9Hz)), 7.81 (1H, dd (J = 14, 13H
z)), 8.55 (1H, s), 8.59 (1H, d
(J = 4.0 Hz) MS: m / z 524 (M ⁺⁺ 1)

Example 6 7-Methoxy-N-[(3R) -3- (3-pyridyl)
-1H, 3H-pyrrolo [1,2-c] thiazole-7-
Yl] coumarin-3-carboxamide Elemental analysis _{(C 22 H 17 N 3 O} 4 S As) C (%) H (% ) N (%) S (%) Theoretical values 63.00 4.09 10.02 7 .64 experimental value 62.89 4.15 9.82 7.55 NMR (CDCl ₃ ) δ: 3.93 (3H, s), 4.42 (2H, s),
6.26 (1H, d (J = 2.9Hz)), 6.36-
6.42 (2H, m), 6.91 (1H, s), 6.9
9-7.03 (1H, m), 7.26-7.37 (1
H, m), 7.56-7.59 (2H, m), 8.56
-8.62 (2H, m), 8.91 (1H, s), 1
0.36 (1H, s),

Example 7 (2Z) -5,5-bis (4-methoxyphenyl) -2
-Fluoro-N-[(3R) -3- (3-pyridyl)-
1H, 3H-pyrrolo [1,2-c] thiazol-7-yl] -2,4-pentadiene amide Melting point 76-77 ° C NMR (CDCl ₃ ) δ: 3.80-3.87 (6H, m), 4.32-4.
42 (2H, m), 6.21-6.26 (2H, m),
6.34 (1H, s), 6.47 (1H, dd (J =
12, 24 Hz)), 6.82 (2H, d, (J = 9.
1Hz)), 6.95 (2H, d (J = 8.5H
z)), 7.15 (2H, d (J = 8.5 Hz)),
7.26-7.36 (4H, m), 7.85 (1H, d
(J = 12 Hz)), 8.50-8.80 (2H, m)

Example 8 3,3-bis (4-methoxyphenyl) -2-fluoro-N-[(3R) -3- (3-pyridyl) -1H, 3H
- pyrrolo [1, 2-c] thiazole-7-yl] propenamide mp _{78-80 ℃ NMR (CDCl 3) δ} : 3.825 (3H, s), 3.828 (3H,
s), 4.17 (1H, d, (J = 13Hz)), 4.
22 (1H, d (J = 13Hz)), 6.07 (1H,
d (J = 3.0 Hz), 6.18 (1H, d (J =
3.0 Hz)), 6.29 (1H, s), 6.85-
6.93 (4H, m), 7.20 (2H, d (J = 8.
8 Hz)), 7.26 (2H, d (J = 8.8H
z)), 7.30-7.33 (1H, m), 7.58.
(1H, d (J = 8.3Hz)), 8.56 (2H, d
(J = 29Hz))

Example 9 5,5-bis (4-methoxyphenyl) -2,4-difluoro-N-[(3R) -3- (3-pyridyl) -1
H, 3H-pyrrolo [1,2-c] thiazol-7-yl] -2,4-pentadiene amide NMR (CDCl ₃ ) δ: 3.80 (3H, s), 3.85 (3H, s),
4.35 (1H, d (J = 13Hz)), 4.41 (1
H, d, (J = 13 Hz)), 6.17-6.24 (3
H, m), 6.33 (1H, s), 6.83 (1H, d
(J = 8.8 Hz)), 6.91 (1H, d, (J =
8.8 Hz)), 7.12-7.16 (2H, m),
7.24-7.27 (2H, m), 7.30-7.36
(1H, m), 7.62-7.68 (2H, m), 8.
46-8.81 (2H, m) MS: m / z 546 (M ⁺ ).

Example 10 (2E) -5,5-bis (4-methoxyphenyl) -4
-Fluoro-N-[(3R) -3- (3-pyridyl)-
1H, 3H-pyrrolo [1,2-c] thiazol-7-yl] -2,4-pentadiene amide Melting point 97-98 ° C

Example 11 5,5-bis (4-methoxyphenyl) -4-cyano-
N-[(3R) -3- (3-pyridyl) -1H, 3H-
Pyrrolo [1,2-c] thiazol-7-yl] -2,4
-Pentadienamide Melting point 129-130 ° C NMR (CDCl ₃ ) δ: 3.82 (3H, s), 3.85 (3H, s),
4.21 (1H, d (J = 13Hz)), 4.28 (1
H, d, (J = 13 Hz), 6.27 (1H, d (J
= 2.9 Hz)), 6.30 (1H, s), 6.59
(1H, d (J = 16Hz)), 6.90-6.93
(4H, m), 7.12 (2H, d (J = 8.9H
z)), 7.26-7.32 (1H, m), 7.36-
7.39 (2H, m), 7.60 (1H, d (J = 4.
4Hz)), 7.72 (1H, s), 8.55 (1H,
s), 8.57-8.63 (1H, m)

Example 12 (2E) -5,5-bis (4-methoxyphenyl) -2
-Methyl-N-[(3R) -3- (3-pyridyl) -1
H, 3H-pyrrolo [1,2-c] thiazol-7-yl] -2,4-pentadiene amide Melting point 83-84 ° C NMR (CDCl ₃ ) δ: 2.17 (3H, d (J = 1.2Hz ), 3.83
(3H, s), 3.85 (3H, s), 4.30 (1
H, d (J = 14 Hz)), 4.31 (1H, d (J =
14Hz)), 6.13 (1H, d, (J = 3.0H
z)), 6.21 (1H, d (J = 3.0 Hz)),
6.32 (1H, s), 6.80 (1H, d (J = 12
Hz)), 6.86 (1H, d (J = 9.0 Hz),
6.93 (1 H, d (J = 9.0 Hz)), 7.04
(1H, d (J = 12Hz)), 7.11-7.27
(6H, m), 7.35 (1H, m), 7.63 (1
H, d (J = 8.0 Hz), 8.54-8.60 (2
H, m),

Example 13 (2Z) -5,5-bis (4-methoxyphenyl) -2
-Methyl-N-[(3R) -3- (3-pyridyl) -1
H, 3H-pyrrolo [1, 2-c] thiazole-7-yl] -2,4-pentadiene amide _{NMR (CDCl 3) δ: 2.04,2.17} ( together 3H, each s), 3.
80-3.89 (6H, m), 4.26-4.41 (2
H, m), 6.12-6.25 (2H, m), 6.34.
-6.37 (1H, m), 6.78-6.97 (4H,
m), 7.03-7.30 (5H, m), 7.38-
7.42 (1H, m), 7.67-7.73 (1H,
m), 8.54-8.61 (2H, m) MS: m / z 523 (M ⁺ ).

Example 14 5,5-bis (4-methoxyphenyl) -N-[(3
R) -3- (3-Pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazol-7-yl] pentanamide NMR (CDCl ₃ ) δ: 1.63-1.71 (2H, m) , 2.03-2.
09 (2H, m), 2.32 (2H, t (J = 7.2H
z)), 3.76 (6H, s), 3.83 (1H, t
(J = 7.6 Hz), 4.24 (1H, d (J = 13)
Hz)), 4.26 (1H, d (J = 13Hz)),
6.09 (1H, d (J = 2.8Hz)), 6.18
(1H, d (J = 2.8Hz)), 6.29 (1H,
s), 6.81 (4H, d (J = 8.8Hz)), 7.
13 (4H, d (J = 8.8Hz)), 7.28-7.
32 (1H, m), 7.57-7.59 (1H, m),
8.52-8.59 (2H, m) MS: m / z 512 (M ⁺ -1).

Example 15 3,3-Bis (4-methoxyphenyl) -2-fluoropropenal (158 mg), N-[(3R) -3-
(3-Pyridyl) -1H, 3H-pyrrolo [1,2-c]
Thiazol-7-yl] -2-cyanoacetamide (1
72 mg) and ethanol (2 ml) were added dropwise with 3 drops of a mixture of piperidine and acetic acid (3: 1). After heating under reflux for 3 hours, the mixture was concentrated under reduced pressure, saturated aqueous ammonium chloride solution was added to the residue, and the mixture was extracted with methylene chloride. The extract was washed with saturated brine and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (elution solvent; methylene chloride: ethyl acetate = 5: 1) to give 5,5-bis (4-methoxyphenyl) -2-cyano-4. -Fluoro-N-[(3R) -3- (3-pyridyl) -1H, 3
H, -pyrrolo [1,2-c] thiazol-7-yl]-
2,4-Pentadienamide (283 mg) was obtained.

Melting point 152-153 ° C.

Examples 16 to 17 The following compounds were obtained in the same manner as in Example 15. Example 16 5,5-bis (4-methoxyphenyl) -2,4-dicyano-N-[(3R) -3- (3-pyridyl) -1H,
3H-pyrrolo [1,2-c] thiazol-7-yl]-
2,4-pentadiene amide Melting point 122-123 ° C NMR (CDCl ₃ ) δ: 3.88 (3H, s), 3.89 (3H, s),
4.25 (1H, d (J = 14Hz)), 4.32 (1
H, d (J = 14 Hz), 6.26 (2H, dd (J
= 2.9, 8.0 Hz), 6.34 (1H, d (J =
2.9 Hz)), 6.94-7.00 (4H, m),
7.11 (2H, d (J = 8.8Hz)), 7.48
(2H, d (J = 8.8Hz)), 7.57-7.60
(1H, m), 7.89 (1H, s), 7.99 (1
H, s), 8.48-8.73 (2H, m) MS: m / z 560 (M ⁺ +1).

Example 17 5,5-bis (4-methoxyphenyl) -2-cyano-
N-[(3R) -3- (3-pyridyl) -1H, 3H-
Pyrrolo [1,2-c] thiazol-7-yl] -2,4
- pentadiene amide mp _{118-119 ℃ NMR (CDCl 3) δ} : 3.86 (3H, s), 3.87 (3H, s),
4.27 (1H, d, (J = 14Hz)), 4.33
(1H, d (J = 14Hz), 6.22 (1H, d (J
= 3.0 Hz)), 6.24 (1H, d (J = 3.0H)
z)), 6.33 (1H, s), 6.90 (2H, d
(J = 9.2 Hz)), 6.96 (2H, d (J = 9.
2Hz)), 7.09 (1H, d (J = 12Hz)),
7.16 (2H, d (J = 8.5Hz)), 7.30
(1H, m), 7.36 (2H, d (J = 8.5H
z)), 7.56 (1 H, d (J = 7.9 Hz)),
7.60 (1H, s), 8.07 (1H, d (J = 12
Hz)), 8.55 (1H, s), 8.59 (1H,
s)

Example 18 7-t-Butoxycarbonylamino-3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole (429 mg) was added trifluoroacetic acid (3 ml) under ice cooling. It was After stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the obtained residue, the mixture was extracted with methylene chloride, and the extract was dried over anhydrous sodium sulfate. After concentration under reduced pressure and under ice cooling, chromone-2-carboxylic acid (254 mg), 1-hydroxybenzotriazole (183 mg), dimethylformamide (6 ml) and triethylamine (190 μl) were added, and 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide hydrochloride (259 ml) and dimethylformamide (10 m
The mixture of l) was added dropwise. After stirring at room temperature for 12 hours, ethyl acetate was added, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous sodium sulfate. After concentration under reduced pressure, ethanol was added to the obtained residue,
It melted under heating and activated carbon was added. After cooling, the mixture was filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (elution solvent; chloroform: methanol =
100: 1) and N-[(3R) -3- (3-
Pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazol-7-yl] chromone-2-carboxamide.
The heptahydrate (169 mg) was obtained.

Melting point 95 ° C. Elemental analysis value (as C ₂₁ H ₁₅ N ₃ O ₃ S.0.7H ₂ O) C (%) H (%) N (%) S (%) Theoretical value 62.74 4. 11 10.45 7.98 Experimental value 62.64 3.98 10.65 8.06

Example 19 Ethyl 3,3-bis (4-methoxyphenyl) -2,
4-pentadienate (313 mg), ethanol (2
ml), water (0.3 ml), tetrahydrofuran (1 m
Potassium hydroxide (530 mg) was added to the mixture of l), and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with saturated aqueous ammonium chloride solution and concentrated under reduced pressure. The resulting residue was adjusted to pH 1-2 with 1N hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained compound was recrystallized from ethyl acetate to give 5,5-bis (4-
Methoxyphenyl) -2-methylsulfonyl-2,4-
Pentadienoic acid (292 mg) was obtained. This compound (2
92 mg) from (3R) -7-t-butoxycarbonylamino-3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazole (239 mg) and trifluoroacetic acid (2 ml) as a reference example. (3R) -7-amino-3- (3-pyridyl) -1H, obtained in the same manner as in 2.
A mixture of 3H-pyrrolo [1,2-c] thiazole, 1-hydroxybenzotriazole (152 mg) and tetrahydrofuran (5 ml) was added under cooling and then a mixture of dicyclohexylcarbodiimide (171 mg) and tetrahydrofuran (1 ml) at the same temperature. , And at room temperature, 1
Stir for 2 hours. Ethyl acetate (10 m
l) was added, the resulting insoluble material was filtered off, the filtrate was diluted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent; chloroform: methanol = 19: 1).
Purified with 5,5-bis (4-methoxyphenyl) -2
-Methylsulfonyl-N-[(3R) -3- (3-pyridyl) -1H, 3H-pyrrolo [1,2-c] thiazol-7-yl] -2,4-pentadienamide (51m
g) was obtained.

NMR (CDCl ₃ ) δ: 3.10 (3H, s), 3.83 (3H, s) 3.
87 (3H, s), 4.34 (1H, d (J = 13H
z)), 4.38 (1H, d (J = 13 Hz)), 6.
26 (1H, s), 6.33-6.35 (2H, m),
6.86 (2H, d (J = 7.5Hz)), 6.96
(2H, d (J = 7.5Hz)), 7.16 (2H, d
(J = 6.8 Hz)), 7.26-7.33 (3H,
m), 7.50 (1H, d (J = 11.7Hz)),
7.62-7.20 (2H, m), 8.56-8.60
(2H, m) MS: m / z 588 (M ⁺ +1)

[0089]

[Table 1]

[0090]

[Table 2]

[0091]

[Table 3]

[0092]

[Table 4]

[0093]

[Table 5]

[0094]

[Table 6]

[0095]

[Table 7]

[0096]

[Table 8]

[0097]

[Table 9]

[0098]

[Table 10]

[0099]

[Table 11]

[0100]

[Table 12]

─────────────────────────────────────────────────── ───

[Procedure amendment]

[Submission date] August 4, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

[Name of item to be corrected] Claim 1

[Correction method] Change

[Correction content]

[Chemical 1] (The symbols in the formulas have the following meanings. Z: Formula

[Chemical 2] Group represented by. R ¹ , R ² and R ^{3 are the} same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, cyano. Group or nitro group. A: halogen atom, halogeno lower alkyl group, hydroxyl group,
Lower alkoxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, cyano group, nitro group and formula

[Chemical 3] And an optionally substituted alkylene group, alkenylene group or alkynylene group, which is a substituent selected from the group consisting of Provided that when A represents an unsubstituted alkylene group, at least one of R ¹ , R ² and R ³ represents a group other than a hydrogen atom), a pyrrolothiazole derivative, a salt thereof, or a stereoisomer thereof. Or a solvate thereof.

Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 31/425 ACV 7252-4C

Claims (1)

[Claims] 1. The following general formula: (The symbols in the formulas have the following meanings. Z: Formula Group represented by. R ¹ , R ² and R ^{3 are the} same or different and are a hydrogen atom, a halogen atom, a lower alkyl group, a halogeno lower alkyl group, a hydroxyl group, a lower alkoxy group, a lower alkylthio group, a lower alkylsulfinyl group, a lower alkylsulfonyl group, cyano. Group or nitro group. A: halogen atom, halogeno lower alkyl group, hydroxyl group,
Lower alkoxy group, lower alkylthio group, lower alkylsulfinyl group, lower alkylsulfonyl group, cyano group, nitro group and the formula: And an optionally substituted alkylene group, alkenylene group or alkynylene group, which is a substituent selected from the group consisting of Provided that when A represents an unsubstituted alkylene group, at least one of R ¹ , R ² and R ³ represents a group other than a hydrogen atom), a pyrrolothiazole derivative, a salt thereof, or a stereoisomer thereof. Body or solvate thereof.