Claims
- 1. A thiazole derivative represented by the following formula and a pharmaceutically acceptable salt thereof: ##STR331## wherein R.sub.1 and R.sub.2 each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a lower alkoxycarbonyl group or a phenyl group which is unsubstituted or substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkyl group of 1 to 3 carbon atoms or wherein R.sub.1 and R.sub.2 cooperate to represent a tetramethylene group corresponding to a fused cyclohexane ring or a butadienylene group which is unsubstituted or substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkyl group having 1 to 3 carbon atoms corresponding to a fused benzene ring; R.sub.3, R.sub.4, R.sub.5 and R.sub.6 each independently represent a hydrogen atom, a hydroxyl group, a lower alkoxy group, an alkyl group having 1 to 3 carbon atoms or a halogen atom; A is a linking group selected from the group consisting of --CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CH.dbd.CHCONH-- and -- CH.sub.2 OCH.sub.2 --; B is a group selected from the group consisting of (a) --(CH.sub.2).sub.n --CONH--, wherein n is an integer of 0-3, (b) --(CH.sub.2).sub.n --NH--, wherein n is an integer of 1-4, (c) --(CH.sub.2).sub.n --O--, wherein n is an integer of 1-4, (d) --(CH.sub.2).sub.n --, wherein n is an integer of 2-5, ##STR332## wherein R.sub.7 and R.sub.8 each independently represents a hydrogen atom or an alkyl group having 1 to 3 carbon atoms as defined above, ##STR333## wherein R.sub.7 and R.sub.8 have the same meanings as defined above, ##STR334## wherein R.sub.7 and R.sub.8 have the same meanings as defined above, ##STR335## wherein R.sub.9, R.sub.10, R.sub.11 and R.sub.12 each independently represent a hydrogen atom, a phenyl group or an alkyl group having 1 to 6 carbon atoms, ##STR336## wherein R.sub.9, R.sub.10, R.sub.11 and R.sub.12 have the same meanings as defined above, ##STR337## wherein R.sub.9, R.sub.10, R.sub.11 and R.sub.12 have the same meanings as defined above and m ranges from 0 to 3, ##STR338## wherein R.sub.9 and R.sub.11 have the same meanings as defined above, ##STR339## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR340## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR341## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR342## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR343## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR344## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR345## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR346## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR347## wherein R.sub.11 and R.sub.12 have the same meanings as defined above, and ##STR348## wherein R.sub.11 and R.sub.12 have the same meanings as defined above and Q represents a carboxyl group, a lower alkoxy group, a hydroxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms or a 5-tetrazolyl group.
- 2. The thiazole derivative and the pharmaceutically acceptable salt thereof according to claim 1, wherein said group B has the formkla: ##STR349## wherein R.sub.9 and R.sub.10 each independently represent an alkyl group of 1 to 6 carbon atoms.
- 3. A leukotriene antagonist composition comprising:
- a pharmaceutically effective amount of a thiazole derivative represented by the following formula or a pharmaceutically acceptable salt thereof as the active ingredient: ##STR350## wherein R.sub.1 and R.sub.2 each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a lower alkoxycarbonyl group or a phenyl group which is unsubstituted or substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkyl group having 1 to 3 carbon atoms or wherein R.sub.1 and R.sub.2 cooperate to represent a tetramethylene group corresponding to a fused cyclohexane ring or a butadienylene group which is unsubstituted or substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkyl group having 1 to 3 carbon atoms corresponding to a fused benzene ring; R.sub.3, R.sub.4, R.sub.5 and R.sub.6 each independently represent a hydrogen atom, a hydroxyl group, a lower alkoxy group, an alkyl group having 1 to 3 carbon atoms or a halogen atom; A is a linking group selected from the group consisting of --CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, --CH.dbd.CHCONH-- and --CH.sub.2 OCH.sub.2 --; B is a group selected from the group consisting of (a) --(CH.sub.2).sub.n --CONH--, wherein n is an integer of 1-3, (b) --(CH.sub.2).sub.n --NH--, wherein n is an integer of 1-4, (c) --(CH.sub.2).sub.n --O--, wherein n is an integer of 1-4, (d) --(CH.sub.2).sub.n --, wherein n is an integer of 2-5, ##STR351## wherein R.sub.7 and R.sub.8 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms as defined above, ##STR352## wherein R.sub.7 and R.sub.8 have the same meanings as defined above, ##STR353## wherein R.sub.7 and R.sub.8 have the same meanings as defined above, ##STR354## wherein R.sub.9, R.sub.10, R.sub.11 and R.sub.12 each independently represent a hydrogen atom, a phenyl group or an alkyl group having 1 to 6 carbon atoms, ##STR355## wherein R.sub.9, R.sub.10, R.sub.11 and R.sub.12 have the same meanings as defined above, ##STR356## wherein R.sub.9, R.sub.10, R.sub.11 and R.sub.12 have the same meanings as defined above and m ranges from 0 to 3, ##STR357## wherein R.sub.9 and R.sub.11 have the same meanings as defined above, ##STR358## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR359## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR360## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR361## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR362## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR363## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR364## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR365## wherein R.sub.10 and R.sub.12 have the same meanings as defined above, ##STR366## wherein R.sub.11 and R.sub.12 have the same meanings as defined above, and ##STR367## wherein R.sub.11 and R.sub.12 have the same meanings as defined above; and Q represents a carboxyl group, a lower alkoxy group, a hydroxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms or a 5-tetrazolyl group, in combination with a pharmaceutically acceptable excipient.
- 4. The leukotriene antagonist composition of claim 3, wherein said group B has the formula: ##STR368## wherein R.sub.9 and R.sub.10 each independently represent an alkyl group of 1 to 6 carbon atoms.
- 5. A leukotriene antagonist composition, comprising:
- a pharmaceutically effective amount of a thiazole derivative represented by the following formula or a pharmaceutically acceptable salt thereof as the active ingredient: ##STR369## wherein R.sub.7 and R.sub.8 each independently represent a hydrogen atom, an alkyl group having 1-8 carbon atoms or cooperatively represent a butadienylene group which is unsubstituted or substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkyl group having 1-3 carbon atoms corresponding to a fused benzene ring; and R.sub.9 and R.sub.10 each independently represent a hydrogen atom or an alkyl group having 1-6 carbon atoms.
- 6. A method of therapeutically treating an allergic disorder in which leukotriene is released, comprising: administering to a host subject a leukotriene antagonistic effective amount of the thiazole derivative of claim 1.
Priority Claims (1)
| Number |
Date |
Country |
Kind |
| 60-228912 |
Oct 1985 |
JPX |
|
BACKGROUND OF THE INVENTION
This application is a Continuation of application Ser. No. 06/919,497, filed on Oct. 16, 1986, now abandoned.
This invention relates to a novel thiazole derivative having leukotriene antagonistic action and a leukotriene antagonist containing the same as the active ingredient.
For prophylaxis or therapy of allergic diseases, there are the method which inhibits liberation of the mediator of anaphylaxis and the method which permits an antagonist to act on the mediator liberated. Disodium cromoglycate [The Merck Index, ninth edition 2585 (1976)] and Tranirast [Journal of Japanese Pharmacology, 74, 699 (1978)] are typical drugs belonging to the former and those belonging to the latter may include drugs antagonistic to hystamine which is one of the mediators of alllergic reactions such as diphenehydramine, chlorophenylamine, astemizole, terfenadine, clemastine, etc., as well known drugs. However, a substance which cannot be antagonized with an anti-hystamine agent, namely SRS (Slow Reacting Substance) has been suggested to be liberated from the lung of a bronchial asthma patient [Progr. Allergy, 6, 539 (1962)], and recently these SRS [leukotriene C.sub.4 (LTC.sub.4), leukotriene D.sub.4 (LTD.sub.4) and leukotriene E.sub.4 (LTE.sub.4)] are comprehensively called SRS [Proc. Natl. Acad. Sci. U.S.A., 76, 4275 (1979) and 77, 2014 (1980); Nature, 285, 104 (1980)] and considered as the important factor participating in human asthma attack [Proc. Natl. Acad. Sci. U.S.A., 80, 1712 (1983)].
Some leukotriene antagonists have been known in patents or literatures. For example, there have been known FPL-55712 [Agents and Actions, 9, 133 (1979)] represented by the following formula: ##STR2## KC-404 [Jap. J. Pharm., 33, 267 (1983)] represented by the following formula: ##STR3## KZ-111 [Chem. Abst, registration number 72637-30-0] represented by the following formula: ##STR4## and the compound represented by the following formula (U.S. Pat. No. 4,296,129): ##STR5## wherein R.sub.1 represents a hydrogen atom, an alkyl group having 1 to 4 carbon atoms or a group represented by represented by the following formula: ##STR6## (wherein R.sub.3 and R.sub.4 each represent an alkyl group having 1 to 3 carbon atoms); R.sub.2 represents an alkyl group having 8 to 15 carbon atoms or a cycloalkyl group having 6 to 12 carbon atoms; R.sub.5 and R.sub.6 each represent a hydrogen atom or a methyl group. However, none of these have been clinically applied.
On the other hand, of the thiazole derivatives, as the compounds in which the 2-position of thiazole and the phenyl group are bonded through 2 to 4 atoms, there have been known a large number of compounds such as the compound (Japanese Unexamine Patent Publication No. 22460/1973) represented by the formula: ##STR7## the compound represented by the following formula [Farmaco. Ed. Sci, 21, 740 (1966)]: ##STR8## the compound represented by the following formula (German Pat. No. 31 48 291): ##STR9## and the compound represented by the following formula (Japanese Unexamined Patent Publication No. 16871/1984): ##STR10## However, in any of these literatures or patents, nothing is mentioned about the leukotriene antagonistic action.
The present inventors have sought after compounds having antagonistic action to leukotriene and effective as the therapeutical medicine for various diseases caused by leukotriene, and consequently found that a novel thiazole derivative has excellent leukotriene antagonistic action to accomplish the present invention.
The thiazole derivative of the present invention is a compound represented by the following formula (I): ##STR11## wherein R.sub.1 and R.sub.2 each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, a lower alkoxycarbonyl group or a substituted or unsubstituted phenyl group or taken together represent a tetramethylene group corresponding to a fused cyclohexane ring or a butadienylene group which is unsubstituted or substituted with a halogen atom, a lower alkoxy group, a lower alkoxycarbonyl group or an alkyl group having 1 to 3 carbon atoms corresponding to a fused benzene ring; R.sub.3, R.sub.4, R.sub.5 and R.sub.6 each independently represent a hydrogen atom, a hydroxyl group, a lower alkoxy group, an alkyl group having 1 to 3 carbon atoms or a halogen atom; A represents a linking group having 2 to 4 chain members; B represents a linking group having 2 to 5 chain members; and Q represents a carboxyl group, a lower alkoxy group, a hydroxyl group, an alkoxycarbonyl group having 2 to 6 carbon atoms or a 5-tetrazolyl group.
In the above formula (I), the alkyl group having 1 to 3 carbon atoms may include methyl, ethyl, propyl and isopropyl. The alkyl group having 1 to 8 carbon atoms may include, in addition to the alkyl groups having 1 to 3 carbon atoms as mentioned above, straight and branched aliphatic groups having 4 to 8 carbon atoms such as butyl, isobutyl, sec-butyl, t-butyl, amyl, isoamyl, sec-amyl, sec-isoamyl (1,2-dimethylpropyl), t-amyl (1,1-dimethylpropyl), hexyl, isohexyl (4-methylpentyl), sec-hexyl (1-methylpentyl), 2-methylpentyl, 3-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethylpropyl, heptyl, isoheptyl (5-methylhexyl), 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl, octyl, isooctyl (6-methylheptyl), sec-octyl (1-methylheptyl) and t-octyl (1,1,3,3-tetramethylbutyl) group, etc. The lower alkoxy group may include straight and branched alkoxy groups having 1 to 3 carbon atoms such as methoxy, ethoxy, propoxy and isopropoxy group, etc. The lower alkoxy carbonyl group may include straight and branched alkoxycarbonyl groups having 2 to 4 carbon atoms such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl and isopropoxycarbonyl group. The alkoxy carbonyl group having 2 to 6 carbon atoms may include, in addition to the lower alkoxycarbonyl group as mentioned above, alkoxycarbonyl groups having 5 to 6 carbon atoms such as butoxycarbonyl group and amyloxycarbonyl group and isomer-substituted groups of these. Examples of the halogen atom may include fluorine atom, chlorine atom, bromine atom and iodine atom. As the substituent on the substituted phenyl group in the definition of R.sub.1 and R.sub.2, there may be employed, for example, the alkyl group having 1 to 3 carbon atoms, lower alkoxy group, lower alkoxycarbonyl group and halogen atom as mentioned above. As the linking group in the definition of A, any group having 2 to 4 atoms as the chain member constituting the linking group may be used, but it should particularly preferably contain carbon atom, oxygen atom, and nitrogen atom. Examples of such a linking group may include --CH.dbd.CH--, --CH.sub.2 CH.sub.2 --, --OCH.sub.2 --, --NHCH.sub.2 --, --CONH--, --CH.dbd.CH--CONH--, --CH.sub.2 OCH.sub.2 --, more preferably --CH.dbd.CH--, --CH.sub.2 CH.sub.2 --. As the linking group in the definition of B, any group having 2 to 5 atoms in the chain group constituting the linking group may be used, but it should particularly preferably contain carbon atom, oxygen atom and nitrogen atom. Examples of such a linking group may include --(CH.sub.2).sub.n --CONH-- (wherein n represents an integer of 0-3), --(CH.sub.2).sub.n --NH-- (wherein n represents an integer of 1-4), --(CH.sub.2).sub.n --O-- (wherein n represents an integer of 1-4), --(CH.sub.2).sub.n -- (wherein n represents an integer of 2-5), ##STR12## wherein R.sub.7 and R.sub.8 each independently represent a hydrogen atom or an alkyl group having 1 to 3 carbon atoms as defined above), ##STR13## (wherein R.sub.7 and R.sub.8 have the same meanings as defined above), ##STR14## (wherein R.sub.7 and R.sub.8 have the same meanings as defined above), ##STR15## (wherein R.sub.9, R.sub.10, R.sub.11 and R.sub.12 each independently represent a hydrogen atom, a phenyl group or an alkyl group having 1 to 6 carbon atoms), ##STR16## (wherein R.sub.9, R.sub.10, R.sub.11 and R.sub.12 have the same meanings as defined above), ##STR17## (wherein R.sub.9 and R.sub.11 have the same meanings as defined above), ##STR18## (wherein R.sub.10 and R.sub.12 have the same meanings as defined above), ##STR19## (wherein R.sub.10 and R.sub.12 have the same meanings as defined above), ##STR20## (wherein R.sub.10 and R.sub.12 have the same meanings as defined above), ##STR21## (wherein R.sub.10 and R.sub.12 have the same meanings as defined above), ##STR22## (wherein R.sub.10 and R.sub.12 have the same meanings as defined above), ##STR23## (wherein R.sub.10 and R.sub.12 have the same meanings as defined above), ##STR24## (wherein R.sub.10 and R.sub.12 have the same meanings as defined above), ##STR25## (wherein R.sub.10 and R.sub.12 have the same meanings as defined above), ##STR26## (wherein R.sub.11 and R.sub.12 have the same meanings as defined above), ##STR27## (wherein R.sub.11 and R.sub.12 have the same meanings as defined above), more preferably ##STR28## (wherein R.sub.11 and R.sub.12 each represent a hydrogen atom and R.sub.9 and R.sub.10 each independently represent an alkyl group having 1 to 6 carbon atoms).
The thiazole derivative of the present invention is not limited to a specific isomer, but includes all of geometric isomers, steric isomers, optical isomers and their mixtures such as racemic mixture.
The thiazole derivative of the present invention can be synthesized according to various methods.
For example, in the above formula (I), the compound wherein the linking group B is bonded through a nitrogen atom to the benzene ring can be synthesized according to the synthetic routes [A]-[C]. ##STR29##
In the synthetic routes, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6 and A have the same meanings as defined above, B.sub.3 represents a direct bond or a linking group having 1 to 3 chain members, B.sub.4 represents a linking group having 1 to 4 chain members, M represents an alkali metal atom, X represents a halogen atom and R.sub.13 represents an alkyl group having 1 to 5 carbon atoms.
The aniline derivative (II) used as the starting material can be synthesized according to the known method [Tetrahedron Letters, 25, 839 (1984)].
In the synthetic route [A], the aniline derivative (II) is allowed to react with 0.8 to 2 equal amounts of a cyclic acid anhydride to obtain the compound (Ia) (step [A-1]). As the reaction solvent, there may be employed aromatic hydrocarbons such as toluene, benzene, etc.; ether type solvent such as ethyl ether, dioxane, tetrahydrofuran, etc.; halogenated hydrocarbons such as chloroform, dichloromethane, etc. This reaction may be practiced at a temperature from under ice-cooling to the boiling point of the solvent, particularly preferably from room temperature to 60.degree. C. The compound (Ia) can be converted to an alkali metal salt (Ib) by the reaction with a carbonate, a hydrogen carbonate or a hydroxide of the corresponding alkali metal in a hydrous alcoholic solvent (step [A-2]). Further, the compound (Ib) can be allowed to react with 1 to 3 equivalents of an alkylating agent such as an alkyl halide or an alkyl sulfonate, etc., in a non-protonic polar solvent such as dimethyl sulfoxide, dimethylformamide, hexamethylphosphoramide triamide, etc., at 0.degree. to 100.degree. C. to be alkylated and converted to a carboxylic acid ester (Ic) (step [A-3]).
In the synthetic route [B], the compound (II) can be acylated by the reaction with a carboxylic acid monoester monohalide in the presence of an organic base such as pyridine, triethylamine, etc., or an inorganic base such as potassium carbonate, sodium hydrogen carbonate, etc., at 0.degree.-100.degree. C. to synthesize the compound (Ic) (step [B-1]). As the reaction solvent, there may be used aromatic hydrocarbons, ether type solvents, halogenated hydrocarbons or non-protonic polar solvents. The compound (Ic) can be hydrolyzed in a conventional manner in a hydrous alcoholic solvent with an alkali metal type inorganic base such as sodium hydroxide, potassium carbonate, etc., to be readily converted to the compound (Ib) (step [B-2]). Also, after the above hydrolysis, the product can be treated with a mineral acid to obtain a free carboxylic acid (Ia) (step [B-3]).
In the synthetic route [C], the compound (II) can be allowed to react with a .omega.-halocarboxylic acid ester in the presence of an organic base such as triethylamine, pyridine, etc., in an aromatic hydrocarbon type, ether type or halogenated hydrocarbon type solvent at a temperature from 0.degree. C. to the boiling point of the solvent to effect N-alkylation and result in synthesis of the compound (Id) (step [C-1]). The compound (Ie) can be synthesized according to the same method as in the step [B-3] (step [C-2]), and the compound (If) can be synthesized in the same manner as in the step [A-2] or the step [B-2] (step [C-3], step [C-4]).
In the above formula (I), the compound wherein the linking group B is bonded through an oxygen atom to the benzene ring can be synthesized according to the synthetic route [D] shown below. ##STR30##
In the above synthetic route, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.13, A, B.sub.4, M and X have the same meaning as defined above.
The phenol derivative (III) used as the starting material can be synthesized according to the known method [Journal of Medicinal Chemistry, 25, 1378 (1982)].
By O-alkylation of the compound (III) with a .omega.-halocarboxylic acid ester in a solvent of ketone type such as acetone, methyl ethyl ketone, etc., or alcohol type, in the presence of an inorganic base such as potassium carbonate, sodium hydrogen carbonate, etc., at a temperature from 0.degree. C. to the boiling point of the solvent, the phenylether compound (Ig) can be synthesized (step [D-1]). The compound (Ih) can be obtained from the compound (Ig) similarly as in the step [B-2] (step [D-2]), and the compound (Ii) can be obtained from the compound (Ih) according to the same method as in the step [A-2] (step [D-3]), or from the compound (Ig) in the same manner as in the step [B-2] (step [D-4]).
In the above formula (I), the compound when the linking group A is a vinylene group can be synthesized according to the synthetic route [E] shown below. ##STR31##
In the above synthetic route, R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.13 B and M have the same meanings as defined above. The benzaldehyde derivative [IV] used as the starting material can be synthesized according to the known method [Journal of Medicinal Chemistry, 25, 1378 (1982)].
The compound (Ij) can be obtained according to the dehydrating condensation reaction by heating the benzaldehyde derivative (IV) and a 2-methylthiazole in acetic anhydride under nitrogen gas stream to 100.degree.-200.degree. C. (step [E-1]). Hydrolysis of the compound (Ij) in the same manner as in the step [B-3] gives the compound (Ik) (step [E-2]). From the compound (Ik), an alkali metal salt (Il) can be obtained in the same manner as in the step [A-2] (step [E-3]). The alkali metal salt (Il) can be obtained also by treating similarly the compound (Ij) as in the step [B-2] (step [E-4]).
The compound (I) of the present invention is characterized by having a marked leukotriene antagonistic action.
More specifically, when the antagonistic action to SRS was tested in vitro by use of an extirpated ileum of a guinea pig for the compound of the present invention, it has been found to have a selective antagonistic action for SRS even at an extremely low concentration. When further detailed LTD.sub.4 antagonistic test was conducted by use of a guinea pig for some of the compounds of the present invention which have exhibited strong action in vitro test, it has been found that they can inhibit remarkably the asthmatic symptoms induced by LTD.sub.4.
The leukotriene antagonist of the present invention contains the compound represented by the above formkla (I) or its pharmaceutically acceptable salt as the active ingredient together with a solid or liquid carrier or diluent for medicine, namely additives such as excepients, stabilizers, etc. When the compound (I) has a carboxylic group, preferable salts are non-toxic salts which are pharmaceutically acceptable such as alkali metal salts and alkaline earth metal salts such as sodium salts, potassium salts, magnesium salts, calcium salts or aluminum salts. It is similarly preferable to use adequate non-toxic amine salts such as ammonium salts, lower-alkylamine [e.g. triethylamine] salts, hydroxy lower-alkylamine [e.g. 2-hydroxyethylamine, bis-(2-hydroxyethyl)amine, tris(hydroxymethyl)aminomethane or N-methyl-D-glucamine] salts, cycloalkylamine [e.g. dicyclohexylamine] salts, benzylamine [e.g. N,N'-dibenzylethylenediamine] salts and dibenzylamine salts. In view of the basicity of the thiazole ring of the compound (I) of the present invention, preferable salts may include non-toxic salts such as hydrochlorides, methanesulfonates, hydrobromides, sulfates, phosphates, fumarates, succinates, etc. These salts are water-soluble and hence most preferable when used for injections. In said leukotriene antagonist, the proportion of the active ingredient to the carrier component in therapy may be variable between 1 wt. % to 90 wt. %. The leukotriene antagonist may be administered orally in the dosage form such as granules, fine particles, powders, tablets, hard capsules, soft capsules, syrup, emulsion, suspension or solution, or alternatively administered intravenously, intramascularly or subcutaneously as injections. Also, it can be used as topical administration preparation to rectum, nose, eye, lung in the dosage form such as suppository, collunarium, eye drops or inhalent. Further, it can be used in the form of powder for injection which is to be formulated when used. It is possible to use an organic or inorganic, solid or liquid carrier or diluent for medicine suitable for oral, rectal, parenteral or local administration for preparation of the leukotriene antagonist of the present invention. Examples of the excepient to be used in preparation of a solid preparation may include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate, etc. Liquid preparations for oral administration, namely, emulsion, syrup, suspension, solution, etc., contain inert diluents generally employed such as water or vegetable oils, etc. These preparations can contain auxiliary agents other than inert diluents such as humectants, suspension aids, sweeteners, aromatics, colorants or preservatives. It may also be formulated into a liquid preparation which is contained in capsules of absorbable substances such as gelatin. As the solvent or suspending agent to be used for production of preparations for parentheral administration, namely injections, suppositories, collunarium, eye drops, inhalent, etc., there may be employed, for example, water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin, etc. As the base to be used for suppository, there may be included, for example, cacao fat, emulsified cacao fat, laurine fat, Witepp sol, etc. The preparations can be prepared according to conventional methods.
The clinical dose, when used by oral administration, may be generally 0.01 to 1000 mg/day as the compound of the present invention for human adult, preferably 0.01 to 100 mg, but it is more preferable to increase or decrease suitably the dose depending on the age, condition of disease and symptoms. The above mentioned dose per day of the leukotriene antagonist may be administered once per day or in 2 or 3 divided doses per day at suitable intervals, or intermittently.
On the other hand, when used as an injection, it is preferable to administer continuously or intermittently 0.001 to 100 mg/administration as the compound of the present invention to human adult.
According to the present invention, a novel thiazole derivative having remarkable leukotriene antagonistic action can be provided. Said thiazole derivative is useful as the leukotriene antagonist for prophylaxis and therapy of various diseases in which leukotriene participates.
The present invention is described in more detail by referring to Synthesis examples, Examples and Test examples, but these are not intended to limit the scope of the present invention at all. In Synthesis examples and Examples, the symbols of "IR", "TLC", "NMR" and "MS" represent "infrared-absorption spectrum", "thin layer chromatography", "nuclear magnetic resonance spectrum" and "mass analysis", respectively, the proportion of the solvent written at the site of separation by chromatography indicating volume ratio, the solvent in the parenthesis of "TLC" indicating a developing solvent, "IR" being measured according to the KBr tablet method unless otherwise specifically noted, and the solvent in the parenthesis of "NMR" indicating the measurement solvent.
To a solution of 25 g of 3-methyl-2-butanone dissolved in 174 ml of methanol, 15.8 ml of bromine was added dropwise while temperature of the reaction mixture was maintained within the range of 0.degree. to 5.degree. C., and further the mixture was stirred at 10.degree. C. for 1 hour. Then, 87 ml of water was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction mixture was extracted with ethyl ether, the extract was washed with 10% aqueous potassium carbonate solution and dried over calcium chloride, followed by evaporation of the solvent to give 53.2 g of a crude product of 1-bromo-3-methyl-4-butanone as colorless liquid. Further, without purification, 43.2 g of the above bromoketone was dissolved in 100 ml of ethanol and the solution was added at room temperature to a solution of 19.7 g of thioacetamide dissolved in 150 ml of ethanol. After the reaction was completed by refluxing for 2.5 hours, ethanol was evaporated under reduced pressure and the residue was ice-cooled to precipitate crystals. The crystals are washed with ethyl ether, poured into 250 ml of an aqueous saturated sodium hydrogen carbonate solution, free bases were extracted with n-hexane, followed by drying over anhydrous magnesium sulfate and concentration under reduced pressure to give 27.1 g (yield 73%) of the title compound as pale brown liquid.
IR (film): .nu.=2950, 1510, 1450, 1165, 730 cm.sup.-1.
NMR (CDCl.sub.3): .delta.=1.30(6H,d), 2.68(3H,s),
3.07(1H,m), 6.67(1H,s).
To 11.3 ml of acetic anhydride were added 29.0 g of 3-nitrobenzaldehyde and 27.1 g of 4-isopropyl-2-methylthiazole and the reaction was carried out under nitrogen gas stream at 170.degree. C. for 23 hours. After completion of the reaction, low boiling materials were evaporated under reduced pressure and the residue was recrystallized from ethyl ether-n-hexane to give 16.8 g (yield 32%) of the title compound as yellowish white crystals.
NMR (CDCl.sub.3): .delta.=1.34(6H,d), 3.12(1H,m),
6.86(1H,s), 7.2-8.4(6H,m).
IR: .nu.=1625, 1590, 1435, 1305, 1210, 945,
770 cm.sup.-1.
A mixture of 1.60 g of 3-nitrobenzyl chloride, 1.3 g of 2-hydroxymethylbenzothiazole and 0.54 of potassium carbonate in 20 ml of acetone was stirred at room temperature for 1.5 hours and then refluxed for 30 minutes. After evaporation of acetone under reduced pressure, the residue was dissolved in ethyl acetate, washed with water and dried over magnesium sulfate, followed by evaporation of the solvent under reduced pressure. The residue was purified through a silica gel column chromatography by use of ethyl ether-n-hexane to obtain 1.7 g (yield 73%) of the title compound.
IR: .nu.=1520, 1340, 1090, 800, 766, 725 cm.sup.-1.
NMR (CDCl.sub.3): .delta.=4.65(2H,s), 4.90(2H,s), 7.1-8.2
(8H,m).
A mixture of 6.0 g of 2-(trans-3-hydroxystyryl) benzothiazole and 0.5 g of 5% palladium-carbon in 80 ml of ethanol was stirred under hydrogen gas stream under normal pressure at 50.degree. to 60.degree. C. for 3 hours. After completion of the reaction, the catalyst was filtered off and the filtrate was evaporated under reduced pressure to obtain 5.5 g (yield 92%) of the title compound as pale gray crystals.
IR: .nu.=3050, 1580, 1480, 1280, 760 cm.sup.-1.
m.p.: 129.degree.-130.degree. C.
An amount of 3.0 g of 2-(trans-3-aminostyryl)-4-ethyl-5-methylthiazole was added to 18 ml of 20% hydrochloric acid and to the mixture was added dropwise slowly 3 ml of an aqueous solution of 0.86 g of sodium nitrite while maintaining the inner temperature at 4.degree. to 5.degree. C. After the mixture was stirred at the above temperature for 1.5 hours, the reaction mixture was added into 50 ml of boiling water over 20 minutes. After the mixture was cooled to room temperature, the precipitates formed were collected by filtration, washed with aqueous saturated sodium hydrogen carbonate solution and with water, followed by drying under reduced pressure. The crude product was washed with toluene and dried under reduced pressure to obtain 2.1 g (yield 70%) of the title compound.
m.p.: 161.degree.-162.degree. C.
IR: .nu.=1620, 1598, 1575, 1215, 950, 778 cm.sup.-1.
A mixture of 25 g of 3-hydroxybenzaldehyde, 36.6 g of 2-methylbenzothiazole, 38.8 ml of acetic anhydride and 7.7 ml of formic acid was heated at 120.degree. C. for 25 hours. The low boiling materials were evaporated together with toluene under reduced pressure, and the residue was added to 150 ml of methanol and refluxed with addition of 3 g of potassium carbonate for 1 hour. After cooled to room temperature, the mixture was filtered and filtrate was concentrated. The crude product formed was washed with methanol and ethyl ether and dried under reduced pressure to obtain 20.6 g (yield 40%) of the title compound.
m.p.: 210.degree.-211.degree. C.
IR: .nu.=1620, 1570, 1190, 1145, 935, 750 cm.sup.-1.
The operation similar to (1) was conducted to obtain 2-(trans-3-hydroxystyryl)-4-phenylthiazole (yield 21%).
m.p.: 150.degree.-151.degree. C.
IR: .nu.=3450, 1580, 1280, 950, 730 cm.sup.-1.
An amount of 0.66 g of 60% sodium hydride was added to 14 ml of anhydrous dimethyl sulfoxide and the mixture was heated under nitrogen gas stream to 75.degree. to 80.degree. C. to form dimsyl anions. After cooled to room temperature, the mixture was added to a solution of 6.3 g of 3-ethoxycarbonylpropyltriphenylphosphonium bromide in 20 ml of anhydrous dimethyl sulfoxide. The mixture was stirred at room temperature for 5 minutes and a solution of 1.5 g of 3-cyanobenzaldehyde in 4 ml of anhydrous dimethyl sulfoxide, followed by stirring at room temperature for 1.5 hours. After completion of the reaction, 5% hydrochloric acid was added to stop the reaction, and the reaction mixture was extracted with toluene. After evaporation of the solvent under reduced pressure, the residue was purified through silica gel column chromatography by use of ethyl ether-n-hexane to obtain 0.94 g (yield 36%) of the title compound as colorless oily product.
IR (film): .nu.=1725, 1245, 1180, 1150, 960,
785 cm.sup.-1.
NMR (CCl.sub.4): .delta.=1.25(3H,t), 2.2-2.8(4H,m),
4.09(2H,q), 6.2-6.6(2H,m),
7.3-7.7(4H,m).
An amount of 660 mg of ethyl 5-(3-cyanophenyl)-4-pentenoate and 60 mg of 5% palladium-carbon were added into 6 ml of ethanol and catalytic reduction was carried out under hydrogen gas stream at room temperature for 18 hours. After the catalyst was filtered off, the filtrate was evaporated under reduced pressure and 600 mg of the crude product was used for the subsequent reaction.
Into a suspension of 986 mg of anhydrous stannous chloride in anhydrous ethyl ether was introduced hydrogen chloride gas for 2 minutes to provide a uniform solution. Next, 600 mg of the above saturated carboxylic acid ester dissolved in 4 ml of ethyl ether was added and hydrogen chloride gas was introduced again for 1 minute, followed by stirring at room temperature for 5 hours. Subsequently, each 5 ml of ethyl ether and water was added and after stirred at room temperature for 1 hour, the organic layer was extracted with toluene. After drying over magnesium sulfate, the solvent was evaporated under reduced pressure and the residue was purified through silica gel column chromatography by use of ethyl ether-n-hexane to give 460 mg (yield 68%) of the title compound as colorless oily product.
IR (film): .nu.=1725, 1690, 1440, 1365, 1235, 1180,
1020, 790 cm.sup.-1.
NMR (CCl.sub.4): .delta.=1.20(3H,t), 1.4-1.9(4H,m),
2.0-2.9(4H,m), 4.5(2H,q),
7.2-7.8(4H,m), 9.88(1H,s).
To 50 ml of toluene were added 2.02 g of triethylamine and 5.04 g of 2-(trans-3-aminostyryl)benzothiazole at room temperature, and then 2.96 g of 4-bromobutyronitrile was added to carry out the reaction at 110.degree. C. for 7 hours. After completion of the reaction, the reaction mixture was extracted with ethyl acetate. After evaporation of the solvent under reduced pressure, the residue was purified through silica gel column chromatography by use of ethyl acetate-ethyl ether-n-hexane (2:5:5) to give 2.55 g (yield 40%) of the title compound as colorless oily product.
m.p.: 97.degree.-98.degree. C.
IR: .nu.=3400, 2250, 1600, 950, 760 cm.sup.-1.
To a solution of 16.8 g of 4-isopropyl-2-(trans-3-nitrostyryl)thiazole dissolved in 60 ml of ethanol was added a solution of 48.4 g of stannous chloride dihydrate in 60 ml of ethanol and the mixture was refluxed for 1.5 hours. After the reaction mixture was cooled to room temperature, the mixture was adjusted to pH 13 with addition of 30% aqueous sodium hydroxide solution and then the basic portion was extracted with the use of ethyl acetate and dried over magnesium sulfate, followed by evaporation of the solvent under reduced pressure. The solid residue formed was recrystallized from ethyl ether-n-hexane to obtain 7.1 g (yield 47%) of the pale yellowish white title compound.
m.p.: 62.degree.-63.degree. C.
IR: .nu.=3430, 3300, 1600, 1580, 960, 780, 740 cm.sup.-1.
NMR (CDCl.sub.3): .delta.=1.32(6H,d), 2.90-3.4(1H,m), 3.70(2H,s), 6.5-7.3(7H,m).
By carrying out the treatment similarly as in Synthesis example 10, various thiazole derivatives shown as Nos. 1-32 and 36-38 in Table 1 were obtained.
An amount of 1.0 g of 2-(3-aminostyryl)-4-ethyl-5-methylthiazole and 200 mg of 5% palladium-carbon were added to 20 ml of ethanol and catalytic reduction was carried out in a hydrogen gas atmosphere at room temperature and normal pressure for 12 hours. After the reaction mixture was filtered, the solvent was evaporated under reduced pressure to give 0.90 g (yield 90%) of the title compound as pale yellow crystals.
m.p.: 64.degree.-65.degree. C.
IR: .nu.=3410, 1590, 1300, 1120, 950, 760 cm.sup.-1.
By carrying out the treatment similarly as in Synthesis example 12, various 2-[2-(3-aminophenyl)ethyl]thiazoles shown as Nos. 34 and 35 in Table 1 were obtained.
To a solution of 282 mg of 2-(trans-3-amino-4-methoxystyryl)benzothiazole dissolved in 30 ml of dichloromethane was added 380 mg of phosphorous tribromide at 70.degree. C., and the mixture was gradually returned to room temperature and stirred overnight. After an aqueous saturated sodium hydrogen carbonate solution was added to the reaction mixture to make it weakly alkaline, the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was evaporated under reduced pressure to give 260 mg (yield 97%) of the title compound.
m.p.: 192.degree.-193.degree. C.
IR: .nu.=3400, 1590, 1510, 1290, 800, 760 cm.sup.-1.
By carrying out the treatment similarly as in Synthesis example 14, the title compound shown as No. 33 in Table 1 was obtained.
To a solvent mixture of 50 ml of dioxane and 30 ml of methanol, 2.0 g of 5-methoxycarbonyl-2-(trans-3-nitrostyryl)benzothiazole was added and, under vigorous stirring, a solution of 0.37 g of calcium chloride in 55 ml of water and 9.8 g of zinc powder were added, followed by refluxing for 2 hours. After cooled to room temperature, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure, and the solid residue formed was washed with toluene to give 1.4 g (yield 77%) of the title compound.
m.p.: 165.degree.-167.degree. C.
IR: .nu.=1710, 1630, 1305, 1100, 755 cm.sup.-1.
US Referenced Citations (2)
Continuations (1)
|
Number |
Date |
Country |
| Parent |
919497 |
Oct 1986 |
|
Patent Grant
4902700
