JPS5978194A - Novel derivative of 2-phenylimidazo(2,1-b)benzothiazole and its preparation - Google Patents

Abstract

NEW MATERIAL:The compound of formula I (A is lower alkylene or lower alkenylene; n is 0 or 1; R is lower alkyl) or its salt. EXAMPLE:2-[ m-( 3-Ethoxycarbonylpropionyloxy )phenyl ]imidazo[2,1-b]benzothiazole. USE:It is useful especially as an agent to suppress delayed allergy and an antirheumatic agent, and furthermore, as a remedy for autoimmune diseases and an agent to suppress the rejection reaction in the skin grafting. PROCESS:The objective compound can be prepared by reacting (acylating) 2-hydroxyphenylimidazo[2,1-b]benzothiazole of formula III with monoesterified dicarboxylic acid of formula HOOC-(A-)n-COOR or its reactive derivative preferably in an organic solvent such as pyridine.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel derivatives of 2-phenylimidazo[2,1-b]benozothiazole represented by the following general formula (I), salts thereof, and methods for producing them.

(In the formula, A means a lower alkylene group or a lower alkenylene group, n means 0 or 1, and R means a lower alkyl group.

Same below) In the definitions of groups of general formulas herein.

The term "2-lower" means a straight or branched carbon chain having 1 to 5 carbon atoms (2 to 5 carbon atoms for lower alkenylene groups). Therefore, the lower alkyl group represented by R is a methyl group, an ethyl group, a 2-propyl group, an isopropyl group, a butyl group, an isobutyl group, and a 5ee-butyl group.
er t-butyl group.

Examples include penotyl group, isoamyl group, neopentyl group, and the like. In addition, the lower alkylev group of A is a methylene group, a methylmethylene group, an ethylene group, a trimethylene group, a propyleno group, an ethylmethylene group, a tetramethylene group, a methyltrimethylene group, an ethylethylene group, a propylmethylene group, an isopropylmethylene group, Dimethylethylene group, ethylmethylmethylene group, pentamethylene group, methyltetramethylene group, ethyltrimethylene group, propylethylene group, butylmethylene group, dimethyltrimethylene group, isopropylethylene group, ethylmethylethylene group,
Diethylmethylene/group, methylpropylmethylene group, etc.
Furthermore, lower alkenylene groups include vinylene group, methylvinylene group, flopenylene group, butenylene group, methylgropenylene group, ethylvinylene group, dimethylvinylene group, pentenylene group, methylbutenylene group, ethylpropenylene group, propylvinylene group, dimethyl Examples include propenylene group and ethylmethylvinylene group.

The compounds of general formula (I) provided by the present invention form acid addition salts. The present invention also includes pharmacologically acceptable salts of the compound of general formula (I), such as mineral acids such as hydrochloric acid, hydrobromic acid, and sulfuric acid, and methanesulfonic acid. , Haratoruensur*7
Examples include acid addition salts with organic acids such as H.

Moreover, isomers such as geometric isomers exist in the compound represented by the above general formula (D). The present invention includes all of these isomers.

Compound (I) of the present invention acts on the immune system. For example, it suppresses the delayed allergic reaction that is typical of cell-mediated immunity against Tough Bacterial antigens, so it is useful as an anti-allergic agent, an anti-seumatic agent, a therapeutic agent for autoimmune diseases, and an agent to suppress rejection reactions during organ transplants and skin transplants. be. It is particularly useful as a delayed allergy suppressant and an antirheumatic agent. That is, conventionally, steroid drugs have been known as anti-allergy agents, especially delayed-acting allergy suppressants.
・. Resistance 2. - The same goes for gusset. However, when steroids are used continuously for a long period of time, they cause a serious side effect, so-called steroid dependence, so there is a desire for the development of non-steroidal anti-allergy, anti-IJ, and anti-inflammatory agents with fewer side effects. The compound of the present invention, which has a strong delayed allergy suppressing effect, can be used as a substitute for these steroids or in combination with steroids, thereby reducing the amount of steroids used.

Since the compound (I) of the present invention has extremely low toxicity, it can be used as a medicine for the various uses mentioned above.

The compound (1) of the present invention is a compound of 2-hydroxyphenylimidazo[2,1-b'3 benzothiazole] disclosed in two prior applications (Japanese Patent Application No. 106438/1982 and 30990/1983) of the present applicant. A novel derivative in which the hydroxyl group is acylated with a carboxylic acid having a lower alkoxycarbonyl group.

It is characterized by its pharmacological effects, such as delayed allergy suppressive effect, which are superior to those of its hydroxyl compounds.

The drug containing the compound (1) of the present invention or its acid addition salt as a main component may be carried using any conventional pharmaceutical carrier.

It is prepared in any conventional manner using excipients.

Administration may be in the form of oral administration such as tablets, gunpowders, capsules, or granules, or parenteral administration such as injections such as intravenous or intramuscular injections, aerosols, or semi-open forms. The dosage depends on the symptoms and the age of the recipient.

The dosage is determined as appropriate for each individual case, taking into account gender, etc., but the usual daily dose for adults is 5 to 500 mg for oral administration and 2 to 300 mg for parenteral administration.

This is administered in divided doses 2 to 3 times a day.

The present invention also includes a method for producing the compound represented by the above general formula (1) and a salt thereof, and typical production methods thereof are illustrated below.

First production method (II) The compound (I) of the present invention is a 2-hydroxyphenylimidazo[2,1-b]benzothiazole represented by the formula (TI) and a monoesterified dicarboxylic acid represented by the general formula (III). or by reaction (acylation) with a reactive derivative at its carboxy group.

Here, the reactive derivatives at the carboxy group of the starting compound (Il[) include acid chlorides, acid bromides, etc.; acid azides; acid anhydrides; alkyl carbonates,
Mixed acid anhydrides with alkylphosphoric acid, dialkylsulfurous acid, sulfuric acid, etc.; tonoic acids such as imidazole; and active esters such as p-nitrophenyl ester and 2,4-dinitrophenyl ester.

This reaction is preferably carried out using compound (n) and equimolar or excess molar amount of compound (I) or its reactive derivative in an organic solvent under cooling, at room temperature, or under heating. Examples of organic solvents are:

Examples include acetone, tetrahydrofurano, dichloromethane, chloroform, viridi, dimethylformamide, a mixture of tetrahydrofurano or dichloromethane and pyridine.

When compound (II) is used in the free state.

N,N'-dicyclohexylcarbodiimide, N,N
It is preferable to carry out the reaction using a condensing agent such as '-carbonylimidazole in the presence of a base such as pyridine or N,N-dimethylaniline. In this case, KN-hydroxybenztriazole may be used together with the condensing agent.

Second Production Method (TV) Derivative (V) (1) The compound (1) of the present invention is also a carboxylic acid compound represented by general formula (IV) or a reactive derivative thereof.

It can also be produced by reacting with a lower alcohol represented by general formula (V).

As in the first production method, examples of reactive derivatives of the carboxylic acid compound of general formula (IV) include acid halides such as acid chloride and acid bromide; acid azides; acid anhydrides; Examples include mixed acid anhydrides with acids, sulfuric acid, etc.; acid amides such as imidazole; and active esters such as p-nitrophenyl ester and 2,4-dinitrophenyl ester.

This reaction can be carried out under substantially the same conditions as in the first production method. That is, the compound of the present invention ( 1) can be manufactured.

When using the raw material compound (IV) in a free state, 2
The reaction is N,N'-dicyclohexylcarbodiimide,
It is preferable to use a condensing agent such as N,N'-carbonylimidazole in the presence of a base such as pyridine or N,N-dimethylaniline. In this case, it is possible to use N-hydroxybenztriazole together with the condensing agent.
.

Advantageous solvents used in these reactions include organic solvents such as acetone, tetrahydrol, dichloromethano, chloroform, pyridino, dimethylformamide, tetrahydrofurano or a mixture of dichloromethano and pyridine.

The compound (I) of the present invention produced by two different methods as described above, either as it is or as its salt, is subjected to P removal, solvent extraction, recrystallization, various chromatography, etc., taking into consideration its physical and chemical properties and reaction conditions. It is isolated and purified by applying any conventional means in the art, such as photography.

EXAMPLES The present invention will be described in further detail with reference to Examples below.

The two raw material compounds (II) and (IV) of the present invention are produced by the method described in the above-mentioned Japanese Patent Application No. 106438/1982 and Japanese Patent Application No. 208609/1989 filed by the present applicant.

Example 1゜2-(m-hydroxyphenyl)imidazo[2゜1-b
] In a solution of 10 g of benzothiazole and 9 g of succinic acid monoethyl ester dissolved in 100 ml of pyridine, 1 g of dicyclohexylcarbodiimide was dissolved in 10 ml of pyridine.
Add the dissolved solution at 15-25C while stirring, and
Stir at 20-25C for an hour. The precipitated urea is distributed door to door, and the P solution is concentrated under reduced pressure. The residue was dissolved in 100 ml of toluene, washed twice with 100 ml of water, dried over anhydrous magnesium sulfate, and the solvent was distilled off. The candy-like residue was subjected to silica gel column chromatography and benzene-
Elute with ethyl acetate (volume ratio 9:1) to give 2-[m-(3
8.9 g of -ethoxy13-dicarbonylpropionyloxy)phenyl]imidazo[2,1-b]benzothiazole was obtained.

Melting point 70-74C (hydrochloride 155-1s9C) Elemental analysis value (as C2, H,, N, O, S) C (chi)
H(chi) N(chil S(chi) theoretical value 63.9
5 4,60 7,10 8.13 Experimental value 64,0
3 4.43 7.16 8.11 Example 2゜2-(m-hydroxyphenyl)imidazo[2゜1-
b] 3.2 g of benozothiazole and 3.2 g of adipino acid monoethyl ester were treated in the same manner as in Example 1 at ℃ to obtain 2-(m-(5-ethoxycarbonylpentanoyloxy)phenyl]imidazo[2,1 -b] 18 g of benozothiazole was obtained.

Melting point 90-92D Elemental analysis value (as C23H22N204 S) 14- C (嗟) Hf CH) N (CH) S (CH) Theory 1 straight 65.39 5,25 6,63 7.
59 Experimental value 65.57 5,32 6,72 7.
41 Example 3゜2-(m-hydroxyphenyl)imidazo[2゜1-
b] Using 10 g of benzothiazole and 8.3 g of maleic acid monoethyl ester (treated in the same manner as in Example 1, 2-(m (cis-3-ethoxycarbonylpropenoyloxy)phenyl)imitaso[2, 1-
b] 7.2 g of benzothiazole was obtained.

Melting point 126-128C Elemental analysis value (as C21Hfa N204 S) C (
h) H (ch) N (ch) Sf h) Theoretical value
64,27 4,11 7,14 8.17 Experimental value
64.34 3.81 7.23 7.992- (
A mixture of 2.1 g of ethoxalyl chloride and 10 ml of tetrahydrofuran is added to a mixture of 4 g of m-hydroxyphenyl)imidazo[2<1-b]benzothiazole, 1.52 g of triethylamine, and 50 ml of tetrahydrofuran at a temperature below -10C. After completion of the dropwise addition, the two reaction solutions were stirred at room temperature overnight and then concentrated under reduced pressure. The residue is dissolved in 209 ml of toluene. The toluene solution is washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 80n+Z, eluent:
Toluene:ethyl acetate=9:1) to obtain 2.75 g of 2-(m-ethoxalyloxyphenyl)imidazo[2,1-b]benzothiazole.

Melting point 120-121C Elemental analysis value (as C,, T-1,, N20.S) C (
Chil H(chi) N(chi) S(chi) Theoretical value 62,29 3.85 7.65 8.75 Experimental value 62.48 3.76 7,50 8.74 Example 5゜2-(m -carboxyacetoxyphenyl)imidazo[
2,1-b]benzothiazole 4g, ethanol 052
g and 50 ml of tetrahydrofuran.

Add a mixture of 2.3 g of dicyclohexylcarbodiimide and 10 mt of tetrahydrofluff at 10C or less. After completion of the dropwise addition, the mixture was stirred overnight at room temperature, the dicyclohexylurea formed was removed, and the mother liquor was concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel 80ml, eluent: toluene:ethyl acetate - 9:1) to obtain an oily 2-(m-ethoxycarbonylacetoxyphenyl)imidazo[2,
1-b] Benozothiazole 17-2.0 g was obtained.

Nuclear magnetic resonance spectrum (CDCl5) δ (ppm): 1.33 (t, 3H, -CH2
Cul) 3.61 (S, 2H, coc3co) Example 6 2-(m-hydroxyphenyl)imidazo[2゜1-
b] 2-(m-(trans-3-ethoxycarbonylpropenoyloxy)phenyl)imidazo 7.3 g of [2,1-b]benzothiazole was obtained.

Melting point 130-130.5tl? 18- Elemental analysis value (as C21HI3 N204 S) C(
) H (chi) N (chi) S (chi) Theoretical value
64,27 4,11 7,14 8.17 Experimental value 6
4,38 3.95 7,19 8.21 Patent applicant
Yamanouchi Pharmaceutical Co., Ltd. Agent Akira Sasaki - -19=

Claims (1)

[Claims] 1 2-phenylimidazo[2, 1-b] A novel derivative of benzothiazole or a salt thereof. 2-hydroxyphenylimidazo [:2,1
-b] Benzothiazole and the general formula % (In the formula, A means a lower alkylene group or a lower alkenylene group, n means O or 1, and R means a lower alkyl group. The same applies hereinafter) A method for producing a novel 2-phenylimidazo[2,1-b]benzothiazole derivative or a salt thereof represented by the general formula, which comprises reacting a monoesterified dicarboxylic acid or a reactive derivative thereof. 3. A carboxylic acid compound or its reactive derivative represented by the general formula (wherein A represents a lower alkylene group or a lower alkenylene group, and n represents O or 1. The same applies hereinafter) and the general formula % formula % (R means a lower alkyl group (hereinafter the same applies) A novel derivative of 2-phenylimidazo[2,1,-b]benzothiazole represented by the general formula or a salt thereof, which is characterized by reacting with a lower alcohol represented by manufacturing method.