JPH03193785A - Pyrrolothiazole derivative - Google Patents

Abstract

NEW MATERIAL:The pyridyl-1H,3H-pyrrolo[1,2-c]thiazole derivative of formula I [R<1> is lower hydroxyalkyl, lower alkoxy-lower alkyl, aryloxy-lower alkyl, formyl (lower alkyl), etc.; R<2> is H or lower alkyl]. EXAMPLE:7-(Hydroxymethyl)-3-(3-pyridyl)-1H,3H-pyrrolo[1,2-c]thiazole of formula II. USE:Antagonist of platelet activation factor(PAF). PREPARATION:The objective compound can be produced by reducing a compound of formula III [A is single bond or 1-5C alkylene; R<3> is COOH, COOR<4> (R<4> is ester residue or anhydride-constituting residue), -COX (X is halogen) or -CONH2] with a reducing agent such as aluminum hydride optionally in an inert solvent such as ether.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel pyridylpyrrolothiazole derivatives and salts thereof having platelet activating factor (PAF) antagonistic activity.

Conventional oligolimb strain PAF is a chemical substance released from human and animal cells, and is acetylglyceryl ether of phosphorylcholine represented by the following formula.

CLO (CHJr CHs - (in the formula, l means 15 or 17) PAF is:
airway smooth muscle contraction, increased vascular permeability, platelet aggregation,
It has physiological activities such as lowering blood pressure, and is thought to be a factor that causes various symptoms such as asthma, inflammation, thrombosis, nephritis, and chronic illness. Therefore, research into substances that antagonize the physiological activity of PAF is underway, and several anti-PAF drugs have been reported (for example, JP-A-59-134798, JP-A-61
-93191, JP 60-116679, JP 60-142932, JP 59-134798,
JP 61-87684, JP 61-37726, JP 63-22588, JP 63-22589
issue).

The present inventors have found that a novel pyridylpyrrolothiazole derivative and its salt, which have a different chemical structure from conventional anti-PAF drugs, have excellent anti-PAF activity, and have completed the present invention.

The pyridylpyrrolothiazole derivative of the present invention for use in i''l is represented by the following general formula (I).

t (wherein R1 is a hydroxy lower alkyl group, a lower alkoxy lower alkyl group, an aralkyloxy lower alkyl group, an aryloxy lower alkyl group, a lower alkanoyloxy lower alkyl group, an aryl lower alkanoyloxy lower alkyl group, an arylcarbonyloxy lower Pyridyl-Il (,3H-pyrrolo (1,2-C)thiazole derivative or salt thereof.

A more detailed explanation of the compound of the present invention is as follows.

In the definition of the general formula herein, unless otherwise specified, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms.

The hydroxy lower alkyl group means a group in which any hydrogen of a lower alkyl group is substituted with a hydroxyl group,
Specifically, the lower alkyl group includes, for example, a methyl group,
Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, 5ec-butyl group, tert-butyl group,
Pentyl (amyl) 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, 13-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
-Methylpropyl group and the like. Therefore, examples of the hydroxy lower alkyl group include a hydroxymethyl group, a hydroxyethyl group, and a hydroxypropyl group.

The lower alkoxy lower alkyl group is a lower alkyl group in which any hydrogen atom of the above lower alkyl group is a methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, 5ec-butoxy group, tert-butoxy group, or pentyloxy group. , isopentyloxy group, neopentyloxy group, tert-pentyloxy group, pentyloxy group substituted with a linear or branched alkoxy group having 1 to 6 carbon atoms. Therefore, examples of the lower alkoxy lower alkyl group include, for example, a methoxy group, a methoxymethyl group, a methoxyethyl group, a methoxypropyl group, and the like.

The aralkyloxy lower alkyl group means a group in which any hydrogen atom of the above lower alkyl group is substituted with an aralkyloxy group.

The aralkyloxy group means a group in which any hydrogen atom of the lower alkoxy group is substituted with an aryl group described below. Examples of the aryl group include a phenyl group such as a benzyloxy group, a phenethyloxy group, and a 1-phenylethoxy group. , 3-phenylpropoxy group, 2-phenylpropoxy group, 1-phenylproboxy group, 1-methyl-2
-phenylethoxy group, 4-phenylbutoxy group, 3-
Phenylbutoxy group, 2-phenylbutoxy group, 1-phenylbutoxy group, 2-methyl-3-phenylpropoxy group, 2-methyl-2-phenylpropoxy group, 2-methyl-1-phenylpropoxy group, 1-methyl- 3-phenylpropoxy group, 1-methyl-2-phenylpropoxy group, ■Methyl-1-phenylpropoxy group, 1-ethyl-2-phenylethoxy group, 1,1-dimethyl-2-
phenylethoxy group, 5-phenylpentyloxy group,
Examples include 6-phenylhexyloxy group. Therefore, examples of the aralkyloxy lower alkyl group include a benzyloxymethyl group, a benzyloxyethyl group, a benzyloxypropyl group, and the like, for example, a henzyloxy group.

The aryloxy lower alkyl group means a lower alkyl group in which any hydrogen atom is substituted with an aryloxy group.

Unless otherwise specified, the aryl group means both a carbocyclic aryl group and a heterocyclic aryl group.

Specifically, the carbocyclic aryl group includes, for example, a phenyl group, a tolyl group, a xyl group, a biphenyl group, a naphthyl group,
There are groups such as anthryl group, phenanthryl group, lower alkoxyphenyl group, chlorphenyl group, nitrophenyl group, etc., and heterocyclic aryl group includes pyridyl group,
Suitable examples include a pyrimidyl group, a pyrrolyl group, a furyl group, and a thienyl group.

Therefore, examples of the aryloxy group include carbocyclic aryloxy groups such as phenyloxy, tolyloxy, xylyloxy, biphenyloxy, and naphthyloxy groups, and heterocyclic aryloxy groups such as pyridyloxy and pyrimidyloxy groups. It will be done.

Therefore, examples of aryloxy lower alkyl groups include phenyl and pyridyl groups, such as phenoxymethyl, phenoxyethyl, phenoxypropyl, pyridyloxymethyl, pyridyloxyethyl, and pyridyloxypropyl groups. I can do it.

A lower alkanoyloxy lower alkyl group means a lower alkyl group in which any hydrogen is substituted with a lower alkanoyloxy group. Examples of the lower alkanoyloxy group include a formyloxy group, an acetoxy group, a propionyloxy group, a butyryloxy group, and a valeryloxy group. Therefore, examples of the lower alkanoyloxy lower alkyl group include an acetyl group, such as an acetoxymethyl group, an acetoxyethyl group, and an acetoxypropyl group.

The aryl lower alkanoyloxy lower alkyl group means a group in which any hydrogen of the lower alkanoyl group in the above-mentioned lower alkanoyloxy lower alkyl group is substituted with an aryl group. Therefore, examples of the aryl lower alkanoyloxy lower alkyl group include, for example, a phenyl group as an aryl group, a benzylcarbonyloxymethyl group, a benzylcarbonyloxyethyl group, a benzylcarbonyloxyprobyl group, and the like.

The arylcarbonyloxy lower alkyl group means a lower alkyl group in which any hydrogen atom is substituted with an arylcarboxy group. Examples of such a group include, for example, a phenyl group as an aryl group, a benzoyloxymethyl group, a hendyloxyethyl group, a hendyloxypropyl group, and the like.

As the alkenyl group, it is preferable to use an alkenyl group having 2 to 12 carbon atoms, and examples of such groups include ethynyl group, 1-propenyl group, 2-propenyl group,
1-Butenyl L 2-phthynyl group, 2-methylpropenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 1-hexenyl group, 2-hexenyl group, 3-
hexenyl group, 4-hexenyl group, 1-hebutenyl group,
2-hebutenyl group, 3-hebutenyl group, 4-hebutenyl group, 5-hebutenyl group, 2-octenyl group, 3-octenyl group, 4-octenyl group, 5-octenyl group, 6-octenyl group, 3 -nonenyl group, 4-nonenyl group, 5-nonenyl group, 6-nonenyl group, 4-decenyl group, 5-dodecenyl group, 6-undecenyl group and the like.

The arylalkenyl group means a group in which any hydrogen atom of the alkenyl group having 2 to 6 carbon atoms is substituted with an aryl group. Taking a phenyl group as an example of an aryl group, phenylethynyl group, phenylpropenyl group , phenylbutenyl group, phenylmethylpropenyl group, and the like.

Further, formyl lower alkyl group means a group in which any hydrogen atom of a lower alkyl group is substituted with a formyl group, and examples of such groups include formylmethyl group, formylethyl group,
A formylpropyl group and the like can be exemplified.

The compound (1) of the present invention forms a salt. The present invention includes salts of compound (1). Examples of such salts include mineral acids such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and hydroiodic acid, as well as acetic acid, oxalic acid, succinic acid, citric acid, maleic acid, and apple acid. acids, acid addition salts with organic acids such as fumaric acid, tartaric acid, picric acid, methanesulfonic acid, ethanesulfonic acid, salts with amino acids such as glutamic acid and aspartic acid, methyl chloride, methyl bromide, methyl iodide, etc. Examples include quaternary ammonium salts formed by bonding with alkyl halides.

The compound of the present invention has various isomers such as optical isomers based on asymmetric carbon atoms and geometric isomers based on the presence of double bonds. The present invention includes separated versions of these isomers as well as mixtures of each isomer.

Compound (I) of the present invention can be produced by applying various synthetic methods utilizing the characteristics of the basic skeleton and various substituents.A typical method for producing the compound (I) will be exemplified below.

Examples of the first production method include groups such as a kyl group, and an aralkyl group such as hensyl, phenethyl, and trityl.

Examples of the anhydride-constituting residue include a group represented by the following formula, an alkyl carbonate residue, and an organic sulfonic acid residue.

2 (Ia) [In the formula, R2 is a hydrogen atom or a lower alkyl group, and A is a single bond or a lower alkylene group having 1 to 5 carbon atoms (methylene, ethylene, methylmethylene, trimethylene, 1-propylene, 2- propylene, tetramethylene,
1-methyltrimethylene, 2-methyltrimethylene, 3
- methyltrimethylene, pentamethylene, 1-methyltetramethylene, 2-methyltetramethylene, 3-methyltetramethylene, etc.).

In addition, R3 is a group such as -COOI (-COOR'-COX or -CONTo) (R' represents an ester residue or an anhydride-constituting residue. Indicates a halogen atom such as a chlorine atom or a bromine atom.) The reduction treatment can be performed using a reducing agent such as a metal hydride or a metal hydride complex.

The above reducing agents include aluminum hydride, lithium aluminum hydride, diisobutyl aluminum hydride, di(
(2-methoxyethoxy) sodium aluminum hydride, trimethoxy lithium aluminum hydride, diporan, etc. In some cases, sodium borohydride, sodium borohydride-aluminum chloride, etc. can also be used.

These reduction reactions are carried out by conventional methods without a solvent or, if necessary, in a solvent inert to the reaction such as ether, tetrahydrofuran, dioxane, diglyme, benzene, methanol, hexamethylphosphoric triamide, or the like.

It is desirable to perform the second manufacturing method treatment. As the oxidizing agent, pyridinium dichromate, pyridinium chromate, pyridinium chromate chloride, graphite chromate, dichromic acid-sulfuric acid, lead pyridinium tetraacetate, etc. are used. In particular, it is desirable to select an appropriate oxidizing agent in order to prevent carboxylic acid from being produced as a by-product due to excessive oxidation.

Third Production Method 2 (Ib) (In the formula, R2 and A are the same as defined above.) The compound represented by the formula (Ib) of the present invention can be synthesized by various methods. When the compound represented by 2Ha) is used as a starting material, it is preferable to synthesize it by oxidation treatment as shown in the second production method.

The oxidation treatment is carried out by oxidizing with an oxidizing agent and adding water 2 (Ic) (In the formula, R2 and A are the same as defined above.

R5 represents a phenyl group, a lower alkyl group, or a lower alkoxy group; R6 represents a phenyl group or a lower alkyl group; and XI represents a halogen such as an iodine atom, a bromine atom, or a chlorine atom). Ic) is the compound (
When Ib) is used as a raw material, it is added with a phosphonium salt (Ib).
II) is preferably synthesized by the Wittig reaction.

This reaction is carried out in an equimolar reaction in a solvent in the presence of a base at room temperature or at elevated temperature.

Solvents include dimethyl sulfoxide, dimethylformamide, benzene, toluene, xylene, dichloromethane,
Reaction-inert organic solvents such as chloroform, carbon tetrachloride, ether, and tetrahydrofuran, and water are used.

In addition, examples of the base include sodium hydride, sodium hydroxide, sodium carbonate, triethylamine, trimethylamine, 1,5-diazabicyclo(4,3,0
) nonene, alcoholades such as potassium t-butoxide, methyllithium, n-butyllithium, phenyllithium, and the like.

Moreover, the reaction was carried out in an inert gas atmosphere, and the compound (I
It is preferable to use more than equimolar amount of [I).

Fourth manufacturing method R2(Id) (wherein R″ and A are the same as defined above.

R7 represents a lower alkyl group, an aralkyl group, or an aryl group).

The ether compound (Id) in the present invention can be synthesized by the Mitsunobu reaction in which the hydroxyalkylpyrrolothiazole derivative (Ia) and alcohol or phenol (TV) are reacted in the presence of triphenylphosphine and diethyl azodicarboxylate. preferable.

This reaction uses equimolar amounts of compound (Ia) and compound (IV) to a slight excess of compound (■), and an inert organic solvent such as ether, tetrahydrofuran, dioxane, benzene, toluene, or xylene as a solvent. It is desirable to carry out the process under cooling or at room temperature.

Fifth manufacturing method (ra) R” (Ie) (In the formula, R2 and A are the same as defined above.

R11 represents a lower alkyl group, an aralkyl group, or an aryl group) Compound (Ie) in the present invention can be synthesized by a normal esterification reaction using approximately equal moles of compound (Ia) and compound (V). is preferred. As the reactive derivative of the metal compound (V), acid halides, acid anhydrides, and the like are used. When a free carboxylic acid (V) is used, it is reacted in the presence of a condensing agent such as dicyclocarbodiimide or in the presence of an acid catalyst, and when an acid halide or acid anhydride is used, it is reacted in the presence of a base. It is advantageous to react with Such acid catalysts include hydrochloric acid and trifluoroacetic acid, and bases include organic bases such as triethylamine and inorganic bases such as sodium hydroxide.

Further, the reaction is preferably carried out in an organic solvent inert to the reaction, such as benzene, toluene, xylene, methylene chloride, ethertetrahydrofuran, or the like.

The resulting reaction product is isolated and purified in its free form or as a salt thereof. Salts can be produced by subjecting them to commonly used salt-forming reactions.

Isolation and purification is performed by applying ordinary chemical operations such as extraction, concentration, crystallization, filtration, recrystallization, and various chromatography.

Compound (1) of the present invention and its salts have PAF antagonistic activity and are useful for the treatment and prevention of various diseases caused by PAF. Especially anti-asthmatic agents, anti-inflammatory agents, anti-tumor agents,
It can be used as a palliative agent for shock symptoms, a therapeutic agent for ischemic heart disease, liver disease, thrombosis and nephritis, and an agent to suppress rejection during organ transplantation.

The anti-PAF effect of the compound of the present invention was confirmed by the following method.

Test method for blood in PAF: 3.8 from the ear artery of a male Japanese white rabbit weighing 3 kg.
Nine volumes of blood were collected into a plastic syringe containing one volume of % sodium citrate aqueous solution. Platelet-rich plasma (PRP) was obtained by centrifuging the blood at 270”Xg for 10 minutes.
The remaining blood was further centrifuged at 1100 x g for 15 minutes to obtain platelet-poor plasma (P P P').
(poor plasma) was obtained. Dilute PRP with PPP to increase the platelet count to 500,000/μ! After preparation, PAF
Platelet aggregation by Born and Cross, Journal of Physiology, Vol. 168, pp. 178-195 (
1963).

That is, PRP with PAF (10-1 IM) using NBS hematotracer (binary bioscience)
The change in light transmittance was measured. The compound was added 2 minutes before the addition of PAF, and the IC5° value (50% inhibitory concentration) was determined from the inhibition rate of the maximum light transmittance by PAF in the control.
I asked for

The compound of the present invention is ADP (3μML arachidonic acid (1
00IIM) and collagen (10ug/m), PAF
It seems to be a specific antagonist.

Next, the present invention will be explained in more detail with reference to Reference Examples and Examples.

(Reference Example 1) 7-(carbomethoxy)-3-(3-pyridyl)-18
, 31+pyrrolo(L 2-C) Production of thiazole fumarate 3-(3-pyridyl)-18,311-pyrrolo(
1,2-C)thiazole-7-carboxylic acid (10,0g
, 40.6 m moj2) and methanol (300 In
Concentrated sulfuric acid (3.0 mj) was added dropwise to the mixture of 1) under water cooling. After stirring the resulting solution under heating and reflux for 12 hours,
It was cooled and concentrated to about half its volume under reduced pressure. After adding an excess amount of sodium hydrogen carbonate and stirring at room temperature for 30 minutes, the mixture was concentrated under reduced pressure. Water was added to the obtained residue, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure to give 7-(carbomethoxy)3-(
3-pyridi/L/) -IH,3H-biOt:l (1
,2-C) Thiazole (9.48g, 36.4mm
of, 90%) was obtained.

The obtained compound (61■) was purified by silica gel column chromatography (eluent: hexane: ethyl acetate - 2:1), and the obtained compound (61■) was dissolved in ethanol, and an ethanol solution of fumaric acid (26■) was added thereto. Ta.

After stirring at room temperature for 10 minutes, the solvent was distilled off under reduced pressure, and the resulting residue was crystallized from ethanol-diethyl ether, collected by filtration, and 7-(carbomethoxy)-3-(3-pyridyl)-
1H,38-pyrrolo(1,2-C)thiazole fumarate (30 .mu.) was obtained.

The physicochemical properties of this compound are as follows.

Nuclear magnetic resonance spectrum (DMSO-d, ・TMS internal standard) 7.56 (IH, ddd) 8.45-8.54 (2+1. m) Example 1 7-(Hydroxymethyl)-3-(3-pyridyl) )-1
L3) Preparation of 1-pyrrolo(1,2-C)thiazole 7-(carbomethoxy)-3-(3pyridyl)-11L 3H-pyrrolo[1,2-C)thiazole(
3,40g, 13.1m mon) of toluene (10
0I! dl)? IN-diisobutylaluminum hydride/hexane solution (27.5d) was added dropwise to liquid 8 at -70"C. After stirring at the same temperature for 6 hours, IN-diisobutylaluminum hydride/hexane solution (3 relative) was added. , and further stirred for 2 hours. To the resulting mixture, a solution of methanol (4d) in toluene (10Ii) was added, followed by a solution of water (2IIi) and methanol (51d), heated to room temperature, and stirred for 30 minutes. .Filter off insoluble matter,
The filtrate was dried over anhydrous sodium sulfate and concentrated under reduced pressure.

The resulting residue was subjected to silica gel column chromatography (
Eluent; Chloroform: Methanol: Concentrated ammonia water =
40:1:0.1) to give 7-(hydroxymethyl)-3-(3-pyridyl)-1H,3+1-pyrrolo[
1゜2-C]thiazole (2.27g, 9.77m
mof) was obtained.

The physical and chemical properties are as follows.

Melting point 60°C Elemental analysis value (as C,□H+zNzO3)C(χ)
H(χ) N(χ) S(χ) Theoretical value 62.04
5.21 12.06 13.80 Experimental value 61.6
5 5.20 11.90 13.79 Example 2 7-(formyl)-3-(3-pyridyl)-1H,31
Production mass spectrometry value of 1-pyrrolo[1°2-C]thiazole tm/z 230 (M”) nuclear magnetic resonance spectrum (CDCI!, 3, TMS internal standard)
Under an argon atmosphere, 7-(hydroxymethyl)-3(3
-pyridyl)-18,311-pyrrolo(1,2-C)thiazole (368■, 1.58 m mob), pyridinium dichromate (896 oi, 3.89 m mo
f) a mixture of dichloromethane (3d) at room temperature for 12
Stir for hours. The resulting mixture was diluted with diethyl ether and filtered. Water was added to the obtained crystals, the pH was adjusted to 10 with potassium carbonate, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and then combined with the filtrate and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (eluent;
Chloroform: Methanol::a Aqueous ammonia-40:
I:0.1) to give 7-(formyl)-3-(3pyridyl)-111,3H-pyrrolo(1,2-C)thiazole (149μ, 41%).

The physical and chemical properties are as follows.

9.77 (18,s) Example 3 7-(2-phenylethynyl)-3-(3-pyridyl)
-1H.

(The AAAV line indicates a mixture of geometric isomers) Under an argon atmosphere, 60% oily sodium hydride (100%, 2.
50m mof! ) and dimethyl sulfoxide (3m
) was stirred at 70°C for 30 minutes. Cool to room temperature and add benzyltriphenylphosphonium chloride (9
7-(formyl)-3-(3-pyridyl)-
1H,3H-pyrrolo(1,2-C)thiazole, (37
A solution of dimethyl sulfoxide (3 m) was added dropwise to the flask.

After stirring at room temperature for 5 hours, the reaction solution was diluted with ethyl acetate, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (elution 1nn-hexane:ethyl acetate-
3:1) to give 7-(2-phenylethynyl)
-3-(3-pyridyl)411゜3H-pyrrolo(1,2
-C) Thiazole (278■) was obtained.

Mass spectrometry value: mHz 304 (M') nuclear magnetic resonance spectrum (CDCI!, 3, TMS internal standard) 8
．． 44-8.61 (2H, m) Example 4 7-(phenoxymethyl)-3-(3-pyridyl)-1
Preparation of H,3H-pyrrolo(1,2-C)thiazole Under argon atmosphere, 7-(hydroxymethyl)-3(3
-Pyridyl)-1H,3H-pyrrolo(1,2-C)thiazole (205■, 0.8h +5offi) and tetrahydrofuran (Id) was added with phenol (91■) under water cooling.

0.97 mmoj2) and tetrahydrofuran (1
, 5d), triphenylphosphine (255■,
0.97 m mol> and tetrahydrofuran (1,5
d) solution of diethyl azodicarboxylate (170
■, 0.98 m mol> and tetrahydrofuran (
A solution of 1,5id) was sequentially added dropwise. The resulting mixture was stirred at room temperature for 12 hours, and then the solvent was distilled off under reduced pressure. The obtained residue was dissolved in ethyl acetate, washed successively with a saturated aqueous sodium bicarbonate solution, water, and saturated brine, and then dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate -2:1 to 1:1) to obtain 7(
phenoxymethyl)-3-(3-pyridyl)-Il+,
3B-pyrrolo[1,2-C)thiazole (53 mg) was obtained.

The physical and chemical properties are as follows.

Mass spectrometry value; m/z 308 (M”) Nuclear magnetic resonance spectrum (CDCf3, TMS internal standard) Example 5 7-(benzoyloxymethyl)-3-(3-pyridyl)IH,3)1-pyrrolo( 1,2-C) Production of thiazole 7-(hydroxymethyl)-3-(3-pyridyl)-
1H,3H pyrrolo(1,2-C)thiazole (102■
, 044 m mol2).

4-(N, N-dimethylamino)pyridine (6■,
0.049 m5of), benzoic acid (59■, 0.4
8+s mol2), methylene chloride (21d)
dicyclohexylcarbodiimide (
A solution of 100 μm, 0.48 mmol and methylene chloride (2d) was added dropwise. After stirring at room temperature for 12 hours,
It was diluted with ethyl acetate, and insoluble materials were filtered off. The filtrate was washed successively with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous sodium sulfate. The residue obtained by concentration under reduced pressure was subjected to silica gel column chromatography (eluent;
Chloroform: Methanol: Concentrated ammonia water = 100:
1:0.1) to give 7-(benzoyloxymethyl)3-(3-pyridyl)-II+, 3H-pyrrolo(1
, 2-C) thiazole (84■) was obtained.

The physical and chemical properties are as follows.

Claims (1)

[Claims] (1) General formula▲ Numerical formula, chemical formula, table, etc.▼ (In the formula, R^1 is hydroxy lower alkyl group, lower alkoxy lower alkyl group, aralkyloxy lower alkyl group, aryloxy lower alkyl group, lower alkanoyloxy a group selected from the group consisting of a lower alkyl group, an aryl lower alkanoyloxy lower alkyl group, an arylcarbonyloxy lower alkyl group, an alkenyl group, an aryl alkenyl group, a formyl group, and a formyl lower alkyl group, R^2 is a hydrogen atom or A pyridyl-1H,3H-pyrrolo[1,2-C]thiazole derivative or a salt thereof, each represented by a lower alkyl group.