JPH09104680A - 4-alkylthiazoline derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a 4-alkylthiazoline derivative which has excellent blood platelet coagulation inhibiting action with good oral activity and is useful for prevention and therapy of ischemic diseases such as thrombosis or cerebral infarction and arteriosclerosis. SOLUTION: This 4-alkylthiazoline is represented by formula I (R<1> is a group represented by formula II; R<11> and R<12> are H, a 1-6C alkyl, a 2-7C alkoxycarbonyl; R<2> is a 2-6C alkyl, a 3-6C cycloalkyl, R<3> is H, a 1-6C alkyl; R<4> is a 1-4C alkyl), typically N-(2-methoxycarbonylethyl)-2-(4- amidinobenzoylimino)-3-methyl-4-ethyl-3H-thiazoline-5-carboxamide. The compound of formula I is prepared by condensation reaction of a compound of formula III (R<5> is an alkyl; X is a halogen), as a starting substance, with thiourea, alkylation of the resultant thiazoline ring, hydrolysis and amidation.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

FIELD OF THE INVENTION The present invention relates to a novel thiazoline derivative having an inhibitory effect on platelet aggregation.

[0002]

2. Description of the Related Art Platelet aggregation is said to occur when a fibrinogen binding site is expressed on the platelet membrane glycoprotein GPIIb / IIIa complex by the stimulation of various platelet aggregation-inducing substances. Therefore, a compound having an antagonistic effect on the fibrinogen receptor may have an inhibitory effect on platelet aggregation. As a thiazoline derivative having an inhibitory action on platelet aggregation by having an antagonistic action on a fibrinogen receptor, WO94 / 02
There are compounds disclosed in No. 472.

[0003]

However, the action is still not sufficient. An object of the present invention is to provide a compound which has an excellent inhibitory effect on platelet aggregation and further exhibits good oral activity.

[0004]

As a result of intensive studies, the present inventors have found a novel thiazoline derivative useful as a platelet aggregation inhibitor and having good oral activity, and completed the present invention.

That is, the present invention provides the following formula [I]:

[0006]

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[Wherein R ¹ is the formula (i)

[0008]

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(Wherein R ¹¹ and R ¹² are each a hydrogen atom,
An alkyl group having 1 to 6 carbon atoms, an alkoxycarbonyl group having 2 to 7 carbon atoms, a cycloalkyl group having 4 to 8 carbon atoms, a phenyl group, "an alkyl group having 1 to 4 carbon atoms, Phenyl group, aralkyl group or "alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, trifluoromethyl" substituted with an alkoxy group or halogen atom having 1 to 4 carbon atoms Group or haloalkyl group-substituted aralkyl group. )
A group represented by the formula (ii)

[0010]

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(In the formula, R ²¹ and R ²² each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, m and n each represent an integer of 1 to 3, and A represents a methylene group or a carbonyl group. , Ethylenedioxymethylene group, oxygen atom,
Sulfur atom, sulfinyl group, sulfonyl group or formula

[0012]

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(In the formula, R ³¹ is a hydrogen atom or a carbon atom number 1 to
6 alkyl groups, formyl groups, alkanoyl groups having 2 to 7 carbon atoms, phenyl groups, "alkyl groups having 1 to 6 carbon atoms, alkoxy groups having 1 to 6 carbon atoms, nitro groups, carbon And an alkanoyl group having 2 to 7 atoms, a phenyl group substituted with a halogen atom or a trifluoromethyl group, a pyridyl group or a benzyl group. ) Represents a group represented by. ) Or a group represented by (iii) imidazolin-2-yl group, R ² represents an alkyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms, or a phenyl group, R ³ represents a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, and R ⁴ represents 1 to 4 carbon atoms.
Alkyl groups. ] It is a thiazoline derivative and its salt represented by these.

In the present invention, the “alkyl group” used by itself or as a part of a certain group is a straight chain or branched chain group, and those having 1 to 4 carbon atoms include methyl group and ethyl group. Group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tertiary butyl group and the like. Examples of those having 1 to 6 carbon atoms include a pentyl group, an isopentyl group, a hexyl group, and 2 in addition to the above. −
A methyl pentyl group etc. can be mentioned. Also,
The cycloalkyl group having 4 to 8 carbon atoms is a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group and a cyclooctyl group. The halogen atom is a fluorine atom, a chlorine atom and a bromine atom. The aralkyl group is an alkyl group having 1 to 3 carbon atoms whose terminal is substituted with an aryl group (eg, phenyl group, naphthyl group, toluyl group), and examples thereof include benzyl group, phenethyl group, naphthylmethyl group, etc. Is.

The pharmaceutically acceptable salts of the compound of formula (I) are salts with alkali metals, alkaline earth metals, ammonium, alkylammonium, etc., or mineral acids, carboxylic acids, sulfonic acids, etc. And salt. They are, for example, sodium salt, potassium salt, calcium salt, ammonium salt, aluminum salt, triethylammonium salt, hydrochloride, hydrobromide, hydroiodide,
Sulfate, nitrate, phosphate, monomethyl sulfate, acetate,
Propionate, butyrate, succinate, tartrate, citrate, tannate, malate, capronate, valerate, fumarate, maleate, methanesulfonate, tosylate And so on. In the present invention, in formula (I), R ³ is a hydrogen atom, preferably compounds wherein R ⁴ is a methyl group, furthermore R ³ is a hydrogen atom, R ⁴ is a methyl group, R ² Most preferred is a compound in which is an isopropyl group.

The compound of the present invention can be produced, for example, by the method shown below. That is, first, for example, Org. Synth. Coll. , Vol. 7,359
The following formula (a) obtained by the method described on page

[0017]

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(In the formula, R ² has the same meaning as described above, X represents a halogen atom, and R ⁵ represents a lower alkyl group.)
The following formula (b) obtained by the condensation reaction of thiourea with

[0019]

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(Wherein R ² and R ⁵ are as defined above) or a salt thereof, for example, 4
-Cyanobenzoyl chloride is reacted to obtain the following formula (c):

[0021]

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A compound represented by the formula (wherein R ² and R ⁵ are as defined above) is obtained.

Then, the compound of the formula (c) is treated with WO94 / 0.
No. 2472, pages 3 to 4 [Formula (III)]
The method of alkylating the 3-position of the thiazoline ring of the compound of 5] and hydrolyzing and amidating the 5-position of the compound of formula (f)

[0024]

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(In the formula, R ² and R ⁴ have the same meanings as described above, and R ⁷ represents R ³ other than a hydrogen atom.) Further, the compound of formula (f) is disclosed in JP-A-8-99.
It can also be produced by converting the substituent at the 5-position of the thiazoline ring, if necessary, using the method described in Japanese Patent No. 966.

Further, a method of reacting the compound of formula (f) with hydrogen sulfide using, for example, a base as a catalyst, Na
Depending on the method of reacting with BH ₂ S ₃ , the formula (g)

[0027]

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(Wherein R ² , R ⁴ and R ⁷ have the same meanings as defined above), and the compound is represented by the formula
A lower alkyl halide represented by R ⁸ —X (wherein R ⁸ is an alkyl group having 1 to 6 carbon atoms, and X has the same meaning as defined above) or a compound represented by the formula R ⁸ ₂ SO ₄ (wherein , R ⁸ has the same meaning as defined above, and is treated with a compound represented by the formula (h)

[0029]

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The compound represented by the formula (wherein R ² , R ⁴ , R ⁷ and R ⁸ are as defined above) or a salt thereof is derived.

Then, this compound is represented by the formula (i)

[0032]

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(Wherein R ¹¹ and R ¹² have the same meanings as described above) or a compound of formula (j)

[0034]

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(Wherein R ²¹ , R ²² , m, n and A have the same meanings as defined above) or a salt thereof, in the presence or absence of an acid or a base. Can lead to the compound of the present invention.

When the compound of the present invention in which R ³ is a hydrogen atom or a salt thereof is produced, it is obtained by hydrolyzing the ester moiety from the compound of the present invention in which R ³ is an alkyl group having 1 to 6 carbon atoms. You can also For the hydrolysis of the ester, a general method such as an alkali treatment, a mineral acid treatment or an organic acid treatment can be used. R ³ has 1 carbon atom
The compounds of the invention which are ~ 6 alkyl groups can be exchanged with each other, for example by an acid catalyzed transesterification reaction.

When a base is used in the above reaction, examples of the base include sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, sodium hydroxide, potassium hydroxide, sodium zymcil, sodium hydride,
Alkali metal salts such as sodium amide and tertiary butyl potassium, amines such as triethylamine, diisopropylethylamine and pyridine, sodium acetate, potassium acetate and the like can be used. Examples of the mineral acid include hydrochloric acid, hydrobromic acid and iodide. Examples of the acid include hydrogen acid, nitric acid and sulfuric acid, and examples of the organic acid include acetic acid, methanesulfonic acid and p-toluenesulfonic acid. As a reaction solvent, water, alcohols such as methanol, ethanol, isopropyl alcohol and tert-butyl alcohol, ethers such as dioxane and tetrahydrofuran, dimethylformamide, dimethylsulfoxide, pyridine, methylene chloride, chloroform, acetone, acetic acid and the like An inert solvent can be used.

[0038]

INDUSTRIAL APPLICABILITY The compound of formula (I) thus obtained is a fibrinogen receptor (GpIIb / II) on platelets.
Fibrinogen, fibronectin against Ia),
It inhibits the binding of various adhesive proteins such as von Willebrand factor and has an inhibitory effect on platelet aggregation and adhesion. Therefore, the compound of the present invention can be used as a prophylactic and therapeutic agent for ischemic diseases such as thrombosis, cerebral infarction, myocardial infarction, and diseases such as arteriosclerosis.

For this purpose, the compound of formula (I) is added with conventional fillers, binders, disintegrants, pH adjusters, solubilizers, etc., and tablets, pills, capsules are prepared by conventional formulation techniques. It can be prepared into a drug, a granule, a powder, a liquid, an emulsion, a suspension and the like. The compound of formula (I) can be administered to an adult patient at 1 to 100 mg / day in several divided doses. This dose can be appropriately increased or decreased depending on the type of disease, age, weight, and symptoms of the patient. Hereinafter, the inhibitory action on the platelet aggregation of the compound of formula (I) will be described with reference to test examples.

Test Example [Oral administration of guinea pigs ex viv
o Platelet aggregation inhibitory effect] In the experiment, an overnight fasted Hartley male guinea pig 4 was used.
Four-week-old mice with a body weight of 250 to 300 g were used. The test drug was suspended in a 10% Tween 80 solution and orally administered at 1 mg / kg. Only the solvent was administered to the control group. Thirty minutes after oral administration, after laparotomy under anesthesia with pentobarbital (30 mg / kg ip), 3.8% was obtained from the abdominal aorta using a plastic syringe.
9 volumes of blood were collected for 1 volume of sodium citrate. The supernatant obtained by centrifuging blood at 120 g for 10 minutes was used as platelet rich plasma (PRP). 1 more of the remaining blood
After centrifugation at 100 g for 10 minutes, platelet poor plasma (PP
P) was obtained. PRP prepared by diluting with PPP to have a platelet count of 4 to 6 × 10 ⁵ cells / mm ³ was used.

Platelet aggregation is measured by the method of Born [Bor
n, G. V. R. , Nature, Vol. 194, Vol. 92
7 (1962)], adenosine diphosphate (manufactured by Sigma: hereinafter referred to as ADP) is used as an aggregation-inducing substance. That is, the formula (I) as a test drug
25 μl of a solution prepared by dissolving the compound of Example 1 in dimethylsulfoxide and adjusting the required concentration with physiological saline to 250 μl of PRP and incubating at 37 ° C. for 3 minutes. 10 μM) 25 μl was added, and measurement was performed for 5 minutes by a platelet aggregation measuring apparatus (Aglycoda TM PA-3210, manufactured by Kyoto Daiichi Kagaku), and the solution administration group was used as a control group.
The aggregation inhibition rate of the test drug administration group relative to the maximum aggregation rate was calculated by the following formula.

[0042]

(Equation 1)

As a comparative drug, N- (2-carboxyethyl) -2- (4-amidinobenzoylimino)-
3-Butyl-4-methyl-3H-thiazoline-5-carboxamide hydrobromide (compound described in WO94 / 02472, hereinafter referred to as comparative drug 1) and N-
(2-Carboxyethyl) -2- (4-amidinobenzoylimino) -3-isopropyl-4-methyl-3H-
Thiazoline-5-carboxamide hydrobromide (WO
Compounds described in Japanese Patent No. 94/02472, hereinafter comparative drug 2
The test liquid was prepared in the same manner as above, and the same test as above was performed. Table 1 shows the results.

[0044]

[Table 1]

[0045]

EXAMPLES The present invention will be described in more detail with reference to examples. In addition, Tables 2 to 5 below show a list of compounds synthesized in this example.

[0046]

[Table 2]

[0047]

[Table 3]

[0048]

[Table 4]

[0049]

[Table 5]

Example 1 (1) Sulfuryl chloride (7.4 ml) was added dropwise to ethyl 3-oxovalerate (10 g) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ethanol (200 ml) and thiourea (7.3 g) were added thereto, and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was cooled to room temperature, ethyl acetate was added, the precipitated crystals were collected by filtration, and the obtained crude crystals were dissolved in water. 25% aqueous ammonia was added until it became basic, and the precipitated crystals were collected by filtration and treated with 2-amino-
Ethyl 4-ethylthiazole-5-carboxylate (10.
5 g) were obtained. Melting point 167-170 [deg.] C.

(2) Ethyl 2-amino-4-ethylthiazole-5-carboxylate obtained in (1) (10 g), 4
A mixture of -cyanobenzoyl chloride (7.9 g) and pyridine (100 ml) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, 3% hydrochloric acid was added to the residue, and the precipitated crystals were collected by filtration, washed with water and dried to give ethyl 2- (4-cyanobenzoylamino) -4-ethylthiazole-5-carboxylate ( 15.5 g) was obtained. Melting point 250-253 [deg.] C (decomposition).

(3) 60% oily sodium hydride (2.
2- (4-cyanobenzoylamino) -4-ethylthiazole-5 obtained in (2) was added to a suspension of 2 g) of N, N-dimethylformamide (hereinafter abbreviated as DMF) (150 ml) under ice cooling. -Ethyl carboxylate (15 g) was added and stirred at room temperature for 1 hour. After ice cooling again, methyl iodide (3.
4 ml) was added and the mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into 3% hydrochloric acid, and the precipitated crystals were collected by filtration, washed with water and dried to give 2- (4-cyanobenzoylimino) -3-methyl-4-ethyl-3H-thiazoline-5-carboxylic acid. Obtained ethyl (14.8 g). Melting point 214-215.5 [deg.] C.

(4) Ethyl 2- (4-cyanobenzoylimino) -3-methyl-4-ethylthiazole-5-carboxylate obtained in (3) (14 g), 10% aqueous sodium hydroxide solution (32.6 ml) ), Acetone (200m
A mixture of l) and methylene chloride (50 ml) was stirred with heating under reflux for 4.5 hours. The reaction mixture was cooled to room temperature and the precipitated crystals were collected by filtration. This crystal, β-alanine methyl ester hydrochloride (5.7 g), 1-hydroxybenzotriazole hydrate (hereinafter abbreviated as HOBt · H ₂ O) (9.4 g), 1-ethyl-3- ( Dimethylaminopropyl) carbodiimide / hydrochloride (hereinafter WSC / H
Abbreviated as Cl. ) (7.8 g) and DMF (100 ml) were stirred at room temperature for 3 hours. The reaction mixture was washed with water (40
0 ml), the precipitated crystals were collected by filtration, and the obtained crude crystals were dissolved in methylene chloride. The extract was washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure, and the obtained crude crystals were recrystallized from methylene chloride-hexane to give N- (2-methoxycarbonyl). Ethyl) -2- (4-cyanobenzoylimino)
-3-Methyl-4-ethyl-3H-thiazoline-5-carboxamide (12.8 g) was obtained. Melting point 174-175.5 [deg.] C.

(5) N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoimino) -3-methyl-4-ethyl-3H-thiazoline-5 obtained in (4).
-Carboxamide (12 g), 70% sodium hydrosulfide (5.6 g), magnesium chloride hexahydrate (6.1
A mixture of g) and DMF (120 ml) was stirred at room temperature for 1 hour. The reaction mixture was poured into water (250 ml), and the precipitated crystals were collected by filtration. The obtained crude crystals were washed with 3% hydrochloric acid and N- (2-methoxycarbonylethyl) -2- (4-
Thiocarbamoylbenzoylimino) -3-methyl-4
-Ethyl-3H-thiazoline-5-carboxamide (1
1.8 g) was obtained. Melting point 208.5-209 [deg.] C.

(6) N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-ethyl-3H-thiazoline-5-carboxamide (11 g) obtained in (5) ), Dimethylsulfate (7.2 ml) and DMF (50 ml) were stirred at room temperature for 2.5 hours. The reaction mixture was charged with acetone (200
ml) was added, and the precipitated crystals were collected by filtration, dried and N- (2
-Methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-
Ethyl-3H-thiazoline-5-carboxamide methylsulfate (13.1 g) was obtained. Melting point 154-158 [deg.] C.

(7) N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-ethyl-3 obtained in (6)
A mixture of H-thiazoline-5-carboxamide methylsulfate (1 g), ammonium acetate (0.55 g) and methanol (10 ml) was stirred with heating under reflux for 1.5 hours. The reaction mixture was cooled to room temperature and the precipitated crystals were collected by filtration, washed with methylene chloride and N- (2-methoxycarbonylethyl) -2- (4-amidinobenzoylimino).
-3-Methyl-4-ethyl-3H-thiazoline-5-carboxamide acetic acid salt (Compound 1) was obtained. Melting point 227.5-228.5 [deg.] C.

Example 2 N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-ethyl-3H-thiazoline obtained in Example 1 (6) -5-carboxamide methyl sulfate (1 g), 1-
A mixture of (pyridin-2-yl) piperazine (0.44 g), acetic acid (0.15 ml) and methanol (10 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solution of acetone-ethyl acetate to obtain N 2.
-(2-Methoxycarbonylethyl) -2- {4-
{[4- (Pyridin-2-yl) piperazin-1-yl] imidoyl} benzoylimino} -3-methyl-4
-Ethyl-3H-thiazoline-5-carboxamide methylsulfate (Compound 2) was obtained. Melting point 200-202 ° C (decomposition).

Example 3 Compound 1 (0.5 g), methanesulfonic acid (1 ml),
A mixture of water (10 ml) was stirred at 80 ° C. for 1 hour. The reaction mixture was cooled to room temperature and the precipitated crystals were collected by filtration, washed with acetone and N- (2-carboxyethyl) -2-.
(4-Amidinobenzoylimino) -3-methyl-4-
Ethyl-3H-thiazoline-5-carboxamide methanesulfonate (Compound 3) was obtained. Melting point 254-24.5 <0> C (decomposition).

Example 4 A mixture of compound 2 (0.5 g), 5% aqueous sodium hydroxide solution (1.5 ml) and 2-propanol (5 ml) was stirred at room temperature for 1 hour. Add 1% phosphoric acid aqueous solution to pH
The crystals precipitated after adjusting to 7 were collected by filtration, washed with acetone and N- (2-carboxyethyl) -2- {4-{[4-
(Pyridin-2-yl) piperazin-1-yl] imidoyl} benzoylimino} -3-methyl-4-ethyl-
3H-thiazoline-5-carboxamide (compound 4) was obtained. Melting point 237-238 [deg.] C (decomposition).

Example 5 (1) 2,2-Dimethyl-1,3-dioxane-4,6
-In a solution of dione (8 g) in methylene chloride (50 ml),
After adding pyridine (10.9 ml) at -5 ° C, a solution of cyclopropylcarboxylic acid chloride (4.9 ml) in methylene chloride (50 ml) was added dropwise over 1 hour, and the mixture was stirred at -5 ° C for 1.5 hours. did. The reaction mixture was poured into a mixture of 6% hydrochloric acid and ice, and the organic layer was washed with 6% hydrochloric acid and saturated saline and dried over anhydrous magnesium sulfate. The residue obtained after concentration under reduced pressure was heated under reflux in methanol for 4 hours, and the reaction mixture was concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (methylene chloride: ethyl acetate = 7:
It was attached to 1) to obtain methyl 3-cyclopropyl-3-oxopropionate (5.9 g). 3-cyclopropyl-
Sulfuryl chloride (3.6 ml) was added dropwise to methyl 3-oxopropionate (5.8 g) under ice cooling, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ethanol (100 ml) and thiourea (3.4 g) were added to the residue, and the mixture was stirred with heating under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure until the amount of the solvent was reduced to about half, cooled with ice, and the precipitated crystals were collected by filtration.
Obtained methyl-amino-4-cyclopropylthiazole-5-carboxylate hydrochloride (8.0 g). 195-196 ° C.

(2) Using 2-amino-4-cyclopropylthiazole-5-carboxylate methyl hydrochloride obtained in (1) as a starting material and carrying out the same operation as in Example 1 (2), 2- Methyl (4-cyanobenzoylamino) -4-cyclopropylthiazole-5-carboxylate was obtained. Melting point 272-274 [deg.] C (decomposition).

(3) 2- (4-cyanobenzoylamino) -4-cyclopropylthiazole-5 obtained in (2)
-Using methyl carboxylate as a raw material, the same operation as in Example 1 (3) was performed. The obtained crystals were subjected to silica gel column chromatography (methylene chloride: ethyl acetate = 9:
Purification according to 1) gave methyl 2- (4-cyanobenzoylimino) -3-methyl-4-cyclopropyl-3H-thiazoline-5-carboxylate. Melting point 230-231 [deg.] C.

(4) 2- (4-cyanobenzoylimino) -3-methyl-4-cyclopropyl-obtained in (3)
Using methyl 3H-thiazoline-5-carboxylate as a starting material and performing the same operation as in Example 1 (4), N- (2-
Methoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3-methyl-4-cyclopropyl-3H
-Thiazoline-5-carboxamide was obtained. Melting point 189-189.5 [deg.] C.

(5) The raw material was N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3-methyl-4-cyclopropyl-3H-thiazoline-5-carboxamide obtained in (4). Used in Example 1
By performing the same operation as in (5), N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-cyclopropyl-3H-.
Thiazoline-5-carboxamide was obtained. Melting point 214-216 [deg.] C.

(6) N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-cyclopropyl-3 obtained in (5)
Using H-thiazoline-5-carboxamide as a starting material and performing the same operation as in Example 1 (6), N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3. -Methyl-4-cyclopropyl-3H-thiazoline-5-carboxamide methylsulfate was obtained. Melting point 186-187 [deg.] C.

(7) N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-cyclopropyl-3H-thiazoline-5 obtained in (6) Using N- (2-methoxycarbonylethyl) -2-carboxamide methylsulfate as a starting material, the same procedure as in Example 1 (7) was performed.
(4-Amidinobenzoylimino) -3-methyl-4-
Cyclopropyl-3H-thiazoline-5-carboxamide methylsulfate (Compound 5) was obtained. Melting point 249-251 [deg.] C (decomposition).

Example 6 N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-cyclopropyl-3H-obtained in Example 5 (6)
Thiazoline-5-carboxamide methyl sulfate (0.
A mixture of 45 g), 1- (pyridin-2-yl) piperazine (0.19 g), acetic acid (0.07 ml) and methanol (5 ml) was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from methylene chloride-ethyl acetate to give N- (2-methoxycarbonylethyl).
-2- {4-{[4- (pyridin-2-yl) piperazin-1-yl] imidoyl} benzoylimino} -3-
Methyl-4-cyclopropyl-3H-thiazoline-5-
A carboxamide methylsulfate (compound 6) was obtained. Melting point 70-73 ° C (decomposition).

Example 7 N- (2-carboxyethyl) -2- (4-amidinobenzoylimino) -3-methyl-4-cyclopropyl was prepared in the same manner as in Example 3 except that compound 5 was used as a starting material. -3H-thiazoline-5-carboxamide methanesulfonate (Compound 7) was obtained. Melting point 246-249 [deg.] C (decomposition).

Example 8 Using compound 6 as a starting material and repeating the same procedure as in example 4, N- (2-carboxyethyl) -2- {4-{[4-
(Pyridin-2-yl) piperazin-1-yl] imidoyl} benzoylimino} -3-methyl-4-cyclopropyl-3H-thiazoline-5-carboxamide (Compound 8) was obtained. Melting point 155-158 [deg.] C.

Example 9 (1) To ethyl 3-isopropyl-3-oxopropionate (10.34 g) was added sulfuryl chloride (5.5) under ice cooling.
ml) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, ethanol (100 ml) and thiourea (5.5 g) were added to the residue, and the mixture was stirred with heating under reflux for 2 hr. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in water. 25% aqueous ammonia was added until it became basic, and the precipitated crystals were collected by filtration, washed with water and dried to obtain ethyl 2-amino-4-isopropylthiazole-5-carboxylate. Melting point 173-175 [deg.] C.

(2) Using ethyl 2-amino-4-isopropylthiazole-5-carboxylate obtained in (1) as a starting material, the same operation as in Example 1 (2) was carried out to give 2- (4
-Ethyl-cyanobenzoylamino) -4-isopropylthiazole-5-carboxylate was obtained. Melting point 174-175 [deg.] C.

(3) 2- (4-cyanobenzoylamino) -4-isopropylthiazole-5-obtained in (2)
Using ethyl carboxylate as a starting material and performing the same operation as in Example 1 (3), 2- (4-cyanobenzoylimino) was obtained.
-3-Methyl-4-isopropyl-3H-thiazoline-
Obtained ethyl 5-carboxylate. 204-205 ° C.

(4) 2- (4-cyanobenzoylimino) -3-methyl-4-isopropyl-3 obtained in (3)
Using methyl H-thiazoline-5-carboxylate as a raw material,
The same operation as in Example 1 (4) was performed to obtain N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide. It was Melting point 100-103 [deg.] C.

(5) Using N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoimino) -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide obtained in (4) as a starting material Use, Example 1 (5)
The same operation was performed to obtain N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide. Melting point 186-190 [deg.] C.

(6) N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-isopropyl-3H obtained in (5)
Using thiazolin-5-carboxamide as a starting material and performing the same operation as in Example 1 (6), N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3- Methyl-4-isopropyl-3H-thiazoline-5-carboxamide methylsulfate was obtained. Melting point 158-160.5 [deg.] C.

(7) N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-isopropyl-3H-thiazoline-5 obtained in (6) Carboxamide methylsulfate was used as a starting material and the same operation as in Example 1 (7) was performed to carry out N- (2-methoxycarbonylethyl) -2- (4).
-Amidinobenzoylimino) -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide methylsulfate (compound 9) was obtained. Melting point 247-249 [deg.] C (decomposition).

Example 10 N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-isopropyl-3H-thiazoline obtained in Example 9 (6) N- (2-methoxycarbonylethyl) -2- {4-{[4- (pyridin-2-yl) piperazine] was prepared in the same manner as in Example 2, except that -5-carboxamide methylsulfate was used as the starting material. -1-yl] imidoyl} benzoylimino} -3-methyl-4-isopropyl-3
H-thiazoline-5-carboxamide methylsulfate (Compound 10) was obtained. Melting point 189-190 [deg.] C.

Example 11 Using compound 9 as a starting material and performing the same operation as in example 3, N- (2-carboxyethyl) -2- (4-amidinobenzoylimino) -3-methyl-4-isopropyl-
3H-thiazoline-5-carboxamide methanesulfonate (Compound 11) was obtained. Melting point 220-222 [deg.] C.

Example 12 Using compound 10 as a starting material and performing the same operation as in example 4, N- (2-carboxyethyl) -2- {4-{[4
-(Pyridin-2-yl) piperazin-1-yl] imidoyl} benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide (Compound 12) was obtained. Melting point 204-206 ° C (decomposition).

Example 13 (1) Using 2-ethyl-4-oxoenanthate as a starting material, the same procedure as in Example 9 (1) was repeated to give 2-amino-4-n.
-Ethyl butylthiazole-5-carboxylate was obtained. Melting point 121-122.5 [deg.] C.

(2) 2-amino-4-n obtained in (1)
2-Butylthiazole-5-carboxylate was used as a raw material and the same operation as in Example 1 (2) was performed to give 2- (4-
Obtained ethyl cyanobenzoylamino) -4-n-butylthiazole-5-carboxylate. Melting point 200-202 ° C (decomposition).

(3) Using ethyl 2- (4-cyanobenzoylamino) -4-n-butylthiazole-5-carboxylate obtained in (2) as a starting material, the same procedure as in Example 1 (3) was performed. 2- (4-cyanobenzoylimino)-
3-Methyl-4-n-butyl-3H-thiazoline-5-
Obtained ethyl carboxylate. Melting point 184-15.5 [deg.] C.

(4) 2- (4-cyanobenzoylimino) -3-methyl-4-n-butyl-3H obtained in (3)
Using N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3-methyl- by the same procedure as in Example 1 (4), but using methyl thiazoline-5-carboxylate as a starting material. 4-n-butyl-3H-thiazoline-5-carboxamide was obtained. Melting point 147-149 [deg.] C.

(5) N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3-methyl-4-n-butyl-3H-thiazoline-5-carboxamide obtained in (4) Using N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-n-butyl-3H-in the same manner as in Example 1 (5), used as a starting material. Thiazoline-5-carboxamide was obtained. Melting point 211-213 [deg.] C.

(6) N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-n-butyl-3H-obtained in (5)
Using thiazoline-5-carboxamide as a starting material and performing the same operation as in Example 1 (6), N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl was obtained. -4-n-Butyl-3H-thiazoline-5-carboxamide methylsulfate was obtained. Melting point 128-131 [deg.] C.

(7) N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-n-butyl-3H-thiazoline-obtained in (6) Using 5-carboxamide methylsulfate as a starting material and performing the same operation as in Example 1 (7), N- (2-methoxycarbonylethyl) -2- (4-
Amidinobenzoylimino) -3-methyl-4-n-butyl-3H-thiazoline-5-carboxamide methylsulfate (Compound 13) was obtained. Melting point 240-242 [deg.] C (decomposition).

Example 14 N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-n-butyl-3H obtained in Example 13 (6) -Thiazoline-5-carboxamide methyl sulfate (1
g), 1- (pyridin-21-yl) piperazine (0.
42 g), acetic acid (0.15 ml), methanol (10 m
The mixture of l) was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from acetone to give N- (2
-Methoxycarbonylethyl) -2- {4-{[4-
(Pyridin-2-yl) piperazinyl] imidoyl} benzoylimino} -3-methyl-4-n-butyl-3H
-Thiazoline-5-carboxamide acetic acid salt (compound 1
4) was obtained. Melting point 149-152 [deg.] C.

Example 15 Using compound 13 as a starting material and performing the same operation as in example 3, N- (2-carboxyethyl) -2- (4-amidinobenzoylimino) -3-methyl-4-n- Butyl-
3H-thiazoline-5-carboxamide methanesulfonate (Compound 15) was obtained. Melting point 228-230 <0> C (decomposition).

Example 16 Using compound 14 as a starting material and repeating the same procedure as in example 4, N- (2-carboxyethyl) -2- {4-{[4
-(Pyridin-2-yl) piperazinyl] imidoyl}
Benzoylimino} -3-methyl-4-n-butyl-3
H-thiazoline-5-carboxamide (Compound 16) was obtained. Melting point 224-226 [deg.] C (decomposition).

Example 17 (1) Example 9 using ethyl benzoyl acetate as a raw material
The same operation as in (1) was performed to obtain ethyl 2-amino-4-phenylthiazole-5-carboxylate. Melting point 166-168 [deg.] C.

(2) By using ethyl 2-amino-4-phenylthiazole-5-carboxylate obtained in (1) as a starting material and performing the same operation as in Example 1 (2), 2- (4-
Cyanobenzoylamino) -4-phenylthiazole-
Obtained ethyl 5-carboxylate. Melting point 262-264 [deg.] C (decomposition).

(3) Using ethyl 2- (4-cyanobenzoylamino) -4-phenylthiazole-5-carboxylate obtained in (2) as a starting material, the same procedure as in Example 1 (3) was performed. 2- (4-cyanobenzoylimino) -3
Obtained ethyl-methyl-4-phenyl-3H-thiazoline-5-carboxylate. Melting point 269-270 [deg.] C.

(4) 2- (4-Cyanobenzoylimino) -3-methyl-4-phenyl-3H-obtained in (3)
Using methyl thiazoline-5-carboxylate as a starting material and performing the same operation as in Example 1 (4), N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3-methyl-4 was prepared. -Phenyl-3H-thiazoline-
5-carboxamide was obtained. Melting point 225-228 [deg.] C.

(5) N- (2-methoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3-methyl-4-phenyl-3H-thiazoline-obtained in (4)
Using 5-carboxamide as a starting material and performing the same operation as in Example 1 (5), N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) was obtained.
-3-Methyl-4-phenyl-3H-thiazoline-5-
A carboxamide was obtained. Melting point 228-229 [deg.] C.

(6) The raw material was N- (2-methoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-phenyl-3H-thiazoline-5-carboxamide obtained in (5). Used in Example 1
By performing the same operation as in (6), N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl))
Benzoylimino] -3-methyl-4-phenyl-3H
-Thiazoline-5-carboxamide methylsulfate was obtained. Melting point 120-124 [deg.] C.

(7) N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-phenyl-obtained in (6)
Using 3H-thiazoline-5-carboxamide methylsulfate as a starting material and performing the same operation as in Example 1 (7), N- (2-methoxycarbonylethyl) -2- (4-amidinobenzoylimino) -3 was obtained. -Methyl-4-phenyl-3H-thiazoline-5-carboxamide acetic acid salt (Compound 17) was obtained. Melting point 218-219 [deg.] C.

Example 18 N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-phenyl-3H-thiazoline obtained in Example 17 (6) N- (2-methoxycarbonylethyl) -2- {4-{[4- (pyridin-2-yl) piperazinyl] was prepared by the same procedure as in Example 14, using -5-carboxamide methylsulfate as a starting material. ] Imidoyl} benzoylimino} -3-methyl-4-phenyl-3H-thiazoline-5-carboxamide methylsulfate (Compound 18)
I got Melting point 221-223 [deg.] C. (decomposition).

Example 19 N- (2-Methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-phenyl-3H-thiazoline obtained in Example 17 (6) -5-carboxamide methyl sulfate (1 g),
A mixture of morpholine (0.22 g), acetic acid (0.15 ml) and methanol (10 ml) was stirred with heating under reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure and the residue was dissolved in a mixture of water and saturated brine. A saturated aqueous sodium hydrogencarbonate solution was added to adjust the pH to 8, and the mixture was allowed to stand overnight, and the precipitated crystals were collected by filtration to obtain a crudely purified product. This is heated under reflux in ethyl acetate for 20 minutes, allowed to cool to room temperature, the crystals are filtered off, dried and N-
(2-Methoxycarbonylethyl) -2- [4- (morpholinimidoyl) benzoylimino] -3-methyl-
4-Phenyl-3H-thiazoline-5-carboxamide (Compound 19) was obtained. Melting point 237-239 [deg.] C (decomposition).

Example 20 N- (2-Methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-phenyl-3H-thiazoline obtained in Example 17 (6) -5-carboxamide methyl sulfate (1 g),
1-ethylpiperazine (0.28 g), acetic acid (0.14
(ml) and methanol (10 ml) were stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure to give an oily crude product. This was washed with toluene by a decantation method. The same operation was performed using a mixed solution of ethyl acetate and methylene chloride-ethyl acetate (1: 1), followed by crystallization with petroleum ether and N- (2-methoxycarbonylethyl) -2- {4-[(4 -Ethylpiperazin-1-yl) imidoyl] benzoylimino} -3-methyl-4-phenyl-3H-thiazoline-5-carboxamide methylsulfate (Compound 20) was obtained. Melting point 107-109 [deg.] C.

Example 21 N- (2-Methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-phenyl-3H-thiazoline obtained in Example 17 (6) N- (2-methoxycarbonylethyl) was prepared in the same manner as in Example 14, using -5-carboxamide methylsulfate and 4-fluorobenzylamine as starting materials.
-2- {4- [N- (4-fluorobenzyl) amidino] benzoylimino} -3-methyl-4-phenyl-
3H-thiazoline-5-carboxamide acetic acid salt (Compound 21) was obtained. Melting point 183-185 [deg.] C.

Example 22 N- (2-Methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-phenyl-3H-thiazoline obtained in Example 17 (6) -5-carboxamide methyl sulfate (1 g),
4-fluoroaniline (0.2 g), methanol (10
The mixture (ml) was stirred with heating under reflux for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from acetone to give N-
(2-Methoxycarbonylethyl) -2- {4- [N-
(4-Fluorophenyl) amidino] benzoylimino} -3-methyl-4-phenyl-3H-thiazoline-
5-Carboxamide methylsulfate (Compound 22) was obtained. Melting point 213-215 [deg.] C.

Example 23 N- (2-methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-phenyl-3H-thiazoline obtained in Example 17 (6) Using 5-carboxamide methylsulfate and 4-anisidine as raw materials, and performing the same operation as in Example 22, N- (2-methoxycarbonylethyl) -2- {4-
[N- (4-Methoxyphenyl) amidino] benzoylimino} -3-methyl-4-phenyl-3H-thiazoline-5-carboxamide methylsulfate (Compound 23)
I got ¹ H-NMR (DMSO-d ₆ ) δ (ppm); 2.3
6 (2H, t, J = 6Hz), 3.28 (2H, q, J
= 6 Hz), 3.32 (3H, s), 3.54 (3H,
s), 3.56 (3H, s), 3.73 (3H, s),
6.32 (2H, br), 6.76 to 7.00 (4H,
m), 7.29 (1H, t, J = 6Hz), 7.5-
7.7 (5H, m), 8.06 (2H, d, J = 8H
z), 8.28 (2H, d, J = 8Hz).

Example 24 N- (2-carboxyethyl) -2- (4-amidinobenzoylimino) -3-methyl-4-phenyl- was prepared by the same procedure as in Example 3 using compound 17 as a starting material. Three
H-thiazoline-5-carboxamide methanesulfonate (Compound 24) was obtained. Melting point 278.5-279 [deg.] C (decomposition).

Example 25 Compound 18 was subjected to the same procedure as in Example 4 to obtain N.
-(2-Carboxyethyl) -2- {4-{[4- (pyridin-2-yl) piperazinyl] imidoyl} benzoylimino} -3-methyl-4-phenyl-3H-thiazoline-5-carboxamide (Compound 25 ) Got. Melting point 224.5-225 [deg.] C (decomposition).

Example 26 Compound 19 (0.4 g), methanesulfonic acid (0.8 m
A mixture of l) and water (8 ml) was stirred at 80 ° C. for 50 minutes. The reaction mixture was cooled to room temperature, made basic with 10% aqueous sodium hydroxide solution (5 ml), and adjusted to pH 7 with 1% aqueous phosphoric acid solution. 2-propanol (10m
l) was added and the mixture was allowed to stand under ice cooling, and the precipitated crystals were collected by filtration, washed with acetone and N- (2-carboxyethyl) -2- [4
-(Morpholinoimidoyl) benzoylimino] -3-
Methyl-4-phenyl-3H-thiazoline-5-carboxamide (Compound 26) was obtained. Melting point 177-179 [deg.] C.

Example 27 A mixture of compound 20 (0.4 g), 5% aqueous sodium hydroxide solution (1.18 ml) and 2-propanol (3 ml) was stirred at room temperature for 40 minutes. Add 1% phosphoric acid aqueous solution p
The mixture was set to H7, 2-propanol was concentrated under reduced pressure, and the mixture was left under ice cooling. The precipitated crystals were collected by filtration and dried to give N- (2-carboxylethyl) -2- {4-[(4-ethylpiperazin-1-yl) imidoyl] benzoylimino} -3-methyl-4-phenyl-3H. -Thiazoline-5-carboxamide (compound 27) was obtained. Melting point 176-179 [deg.] C.

Example 28 Compounds 21 to 23 were used as starting materials and the same operation as in Example 3 was carried out to obtain the following compound. N- (2-carboxyethyl) -2- {4- [N- (4
-Fluorobenzyl) amidino] benzoylimino}-
3-Methyl-4-phenyl-3H-thiazoline-5-carboxamide methanesulfonate (Compound 28) Melting point 146-150 ° C. N- (2-carboxyethyl) -2- {4- [N- (4
-Fluorophenyl) amidino] benzoylimino}-
3-Methyl-4-phenyl-3H-thiazoline-5-carboxamide methanesulfonate (Compound 29) Melting point 246.5-247.5 ° C. N- (2-carboxyethyl) -2- {4- [N- (4
-Methoxyphenyl) amidino] benzoylimino}-
3-Methyl-4-phenyl-3H-thiazoline-5-carboxamide methanesulfonate (Compound 30) ¹ H-NMR (DMSO-d ₆ ) δ (ppm); 2.2
7 (2H, t, J = 6Hz), 2.28 (3H, s),
3.24 (2H, q, J = 6Hz), 3.57 (3H,
s), 3.83 (3H, s), 7.13 (2H, d, J
= 8 Hz), 7.22 (1H, t, J = 6 Hz), 7.
41 (2H, d, J = 8 Hz), 7.50 to 7.70
(5H, m), 8.01 (2H, d, J = 8Hz),
8.46 (2H, d, J = 8Hz), 12.23 (1
H. br).

Example 29 (1) Starting from methyl 2- (4-cyanobenzoylimino) -3-methyl-4-isopropyl-3H-thiazoline-5-carboxylate and β-alanine t-butyl ester hydrochloride. Using N- (2-t-butoxycarbonylethyl) -2- (4-), the same procedure as in Example 1 (4) was performed.
Cyanobenzoylimino) -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide was obtained. 128-129 ° C.

(2) N- (2-t-butoxycarbonylethyl) -2- (4-cyanobenzoylimino) -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide obtained in (1) Used as a raw material, Example 1
The same operation as in (5) was performed to carry out N- (2-t-butoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-isopropyl-3H-.
Thiazoline-5-carboxamide hydrochloride was obtained. Melting point 219.5-220 <0> C (decomposition).

(3) N- (2-t-butoxycarbonylethyl) -2- (4-thiocarbamoylbenzoylimino) -3-methyl-4-isopropyl-3 obtained in (2)
17 g of H-thiazoline-5-carboxamide (34.6
mmol), 22 ml of methyl iodide (346 mmo
l), a mixture of 280 ml of acetone was heated under reflux for 30
For a minute. The reaction mixture was allowed to cool to room temperature, the precipitated crystals were collected by filtration, washed with acetone, and N- (2-t-butoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3- Methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide was obtained. Melting point 165-15.5 [deg.] C (decomposition).

(4) N- (2-t-butoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-isopropyl-3H-thiazoline-obtained in (3) 5-carboxamide hydroiodide 1 g (1.58 mmol), aniline 0.22
A mixture of ml (2.37 mmol) and 10 ml of methanol was stirred with heating under reflux for 1.5 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was recrystallized from a mixed solvent of acetone-diethyl ether to give N- (2-t-butoxycarbonylethyl) -2- [4- (N-phenylamidino) benzoylimino]. -3-Methyl-4-isopropyl-3H
-0.44 g of thiazoline-5-carboxamide hydroiodide (Compound 31) was obtained. Melting point 221.5-222 [deg.] C (decomposition).

Example 30 Using the compound obtained in Example 29 (3) and 4-anisidine as starting materials, the same procedure as in Example 29 (4) was repeated to obtain N.
-(2-t-Butoxycarbonylethyl) -2- {4-
[N- (4-Methoxyphenyl) amidino] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 32) was obtained. Melting point 196.5-197.5 [deg.] C.

Example 31 N- (2-t-butoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-isopropyl-3H obtained in Example 29 (3)
-Thiazoline-5-carboxamide / hydroiodide 1
g (1.58 mmol), n-butylamine 0.173
A mixture of g (2.37 mmol) and 10 ml of acetone was stirred with heating under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, the residue was crystallized from an acetone-diethyl ether mixed solution, and N- (2-t-butoxycarbonylethyl) -2-
[4- (N-n-butylamidino) benzoylimino]
-3-Methyl-4-isopropyl-3H-thiazoline-
5-carboxamide hydroiodide (Compound 33)
0.60 g was obtained. Melting point 161-163 [deg.] C.

Example 32 N- (2-t-butoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-isopropyl-3H obtained in Example 29 (3)
-The thiazoline-5-carboxamide hydroiodide and the corresponding amine were used as raw materials and the same operation as in Example 31 was performed to obtain the following compounds. ○ N- (2-t-butoxycarbonylethyl) -2- [4
-(N-benzylamidino) benzoylimino] -3-
Methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 34) Melting point 101-103.5 ° C. ○ N- (2-t-butoxycarbonylethyl) -2- {4
-[N- (4-Fluorobenzyl) amidino] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 35) Melting point 137-138.5 ° C. ○ N- (2-t-butoxycarbonylethyl) -2- [4
-(N-Cyclohexylamidino) benzoylimino]
-3-Methyl-4-isopropyl-3H-thiazoline-
5-Carboxamide hydroiodide (Compound 36) Melting point 191.5-193.5 ° C.

N- (2-t-butoxycarbonylethyl) -2- [4- (N-benzyl-N-methylamidino) benzoylimino] -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide -Hydroiodide salt (Compound 37) Melting point 107-110 ° C. ○ N- (2-t-butoxycarbonylethyl) -2- {4
-[(Pyrrolidin-1-yl) imidoyl] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 38) melting point 210-212 ° C. ○ N- (2-t-butoxycarbonylethyl) -2- {4
-[(4-Ethylpiperazin-1-yl) imidoyl]
Benzoylimino} -3-methyl-4-isopropyl-
3H-thiazoline-5-carboxamide hydroiodide (Compound 39) Melting point 207-208.5 ° C.

N- (2-t-butoxycarbonylethyl) -2- {4-[(4-benzylpiperazin-1-yl) imidoyl] benzoylimino} -3-methyl-4
-Isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 40) Melting point 195-196 ° C. ○ N- (2-t-butoxycarbonylethyl) -2- {4
-[(4-Phenylpiperazin-1-yl) imidoyl] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 41) Melting point 193-194 ° C. ○ N- (2-t-butoxycarbonylethyl) -2- {4
-{[4- (4-acetylphenyl) piperazine-1-
Ill] imidoyl} benzoylimino} -3-methyl-
4-Isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 42) Melting point 161-163 ° C.

N- (2-t-butoxycarbonylethyl) -2- {4-[(4-formylpiperazin-1-yl) imidoyl] benzoylimino} -3-methyl-4
-Isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 43) Melting point 156-160 ° C. ○ N- (2-t-butoxycarbonylethyl) -2- [4
-(Morpholinoimidoyl) benzoylimino] -3-
Methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 44) Melting point 181-183 ° C.

Example 33 N- (2-t-butoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-isopropyl-3H obtained in Example 29 (3)
-Thiazoline-5-carboxamide hydroiodide 0.8 g (1.26 mmol), dimethylamine hydrochloride 0.16 g (1.90 mmol), sodium acetate 0.
A mixture of 16 g (1.90 mmol), methanol 1 ml, and acetone 9 ml was stirred with heating under reflux for 1 hour. The reaction mixture was concentrated under reduced pressure, acetone was added to the residue, the insoluble material was filtered off using Celite, and the mixture was concentrated under reduced pressure. The residue was crystallized from an acetone-diethyl ether mixture to give N.
-(2-t-Butoxycarbonylethyl) -2- [4-
(N, N-Dimethylamidino) benzoylimino] -3
-Methyl-4-isopropyl-3H-thiazoline-5-
Carboxamide hydroiodide (Compound 45) 0.2
g was obtained. Melting point 206.5-208.5 [deg.] C.

Example 34 N- (2-t-butoxycarbonylethyl) -2- [4-
(Methylthioimidoyl) benzoylimino] -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide and the corresponding amine hydrochloride were used as starting materials and the same procedure as in Example 33 was performed. Then, the following compound was obtained. ○ N- (2-t-butoxycarbonylethyl) -2- [4
-(4-oxopiperidinoimidoyl) benzoylimino] -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 4
6) Melting point 179-181 ° C. ○ N- (2-t-butoxycarbonylethyl) -2- {4
-[N- (3-methoxycarbonylpropyl) amidino] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydroiodide (Compound 47) Melting point 134.5-136 ° C.

Example 35 A mixture of 0.15 g (0.22 mmol) of compound 31 and 2 ml of trifluoroacetic acid was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure and crystallized from diethyl ether to give N- (2-carboxyethyl) -2- [4- (N-
Phenylamidino) benzoylimino] -3-methyl-
4-Isopropyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 48) was obtained. Melting point 100-101.5 ° C.

Example 36 Compounds 32 to 46 were used as starting materials and the same operation as in Example 35 was carried out to obtain the following compound. ○ N- (2-carboxyethyl) -2- {4- [N-
(4-Methoxyphenyl) amidino] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 49) Melting point 101-103 ° C. ○ N- (2-carboxyethyl) -2- [4- (N-n
-Butylamidino) benzoylimino] -3-methyl-
4-Isopropyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 50) Melting point 111-111.5 ° C (decomposition). ○ N- (2-carboxyethyl) -2- [4- (N-benzylamidino) benzoylimino] -3-methyl-4
-Isopropyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 51) Melting point 239.5-240 ° C (decomposition).

○ N- (2-carboxyethyl) -2-
{4- [N- (4-Fluorobenzyl) amidino] benzoylimino} -3-methyl-4-isopropyl-3H
-Thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 52) Melting point 220.5-221.5 ° C. ○ N- (2-carboxyethyl) -2- [4- (N-cyclohexylamidino) benzoylimino] -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 53) Melting point 111.5-116 ° C. ○ N- (2-carboxyethyl) -2- [4- (N-benzyl-N-methylamidino) benzoylimino] -3
-Methyl-4-isopropyl-3H-thiazoline-5-
Carboxamide trifluoroacetate salt (Compound 54) Melting point 115-117 ° C.

○ N- (2-carboxyethyl) -2-
{4-[(Pyrrolidin-1-yl) imidoyl] benzoylimino} -3-methyl-4-isopropyl-3H-
Thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 55) Melting point 201-202 ° C. ○ N- (2-carboxyethyl) -2- {4-[(4-
Ethylpiperazin-1-yl) imidoyl] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 56) Melting point 146-151 ° C. ○ N- (2-carboxyethyl) -2- {4-[(4-
Benzylpiperazin-1-yl) imidoyl] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 57) Melting point 157-160 ° C.

○ N- (2-carboxyethyl) -2-
{4-[(4-phenylpiperazin-1-yl) imidoyl] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide trifluoroacetate (Compound 58) Melting point 140-143 ° C. ○ N- (2-carboxyethyl) -2- {4-{[4-
(4-Acetylphenyl) piperazin-1-yl] imidoyl} benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide trifluoroacetate (Compound 59) Melting point 142-144 ° C. ○ N- (2-carboxyethyl) -2- {4-[(4-
Formylpiperazin-1-yl) imidoyl] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 60) Melting point 150-155 ° C.

○ N- (2-carboxyethyl) -2-
[4- (morpholininoimidoyl) benzoylimino]-
3-Methyl-4-isopropyl-3H-thiazoline-5
-Carboxamide trifluoroacetate salt (Compound 61) Melting point 122-124.5 ° C. ○ N- (2-carboxyethyl) -2- [4- (N, N
-Dimethylamidino) benzoylimino] -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide trifluoroacetic acid salt (Compound 62) ¹ H-NMR (DMSO-d ₆ ) δ (ppm); 1.3
4 (6H, d, J = 6Hz), 2.50 (2H, t, J
= 6 Hz), 2.99 (3H, s), 3.25 (3H,
s), 3.41 (2H, q, J = 6Hz), 3.69
(1H, septet, J = 6HZ), 3.94 (3
H, s), 7.71 (2H, d, J = 8Hz), 8.3
9 (2H, d, J = 8Hz), 8.54 (1H, t, J
= 6 Hz), 9.10 (1H, br), 9.42 (1
H, br), 12.33 (1H, br). ○ N- (2-carboxyethyl) -2- {4-[(4-
Oxopiperidino) imidoyl] benzoylimino}-
3-Methyl-4-isopropyl-3H-thiazoline-5
-Carboxamide trifluoroacetate salt (Compound 63) Melting point 153-154 ° C.

Example 37 A mixture of 0.3 g (0.14 mmol) of compound 47, 0.3 ml of methanesulfonic acid and 2.7 ml of water was added at 80 ° C.
For 2 hours. The reaction mixture was allowed to cool to room temperature, concentrated under reduced pressure, the residue was dissolved in 1 ml of water, and then 5% aqueous sodium hydroxide solution was added to adjust the pH to 11, and further 1% phosphoric acid aqueous solution was added to adjust the pH to 6. This solution is Diaion HP
Purification by -20 column chromatography (eluent: water then methanol) gave the crude product. This is 4N
-Hydrochloric acid / dioxane solution to form a hydrochloride, and recrystallized from acetone to give N- (2-carboxyethyl) -2- {4-
[N- (3-carboxypropyl) amidino] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide hydrochloride (Compound 64)
I got Melting point 230.5-232 [deg.] C (decomposition).

Example 38 N- (2-Methoxycarbonylethyl) -2- [4- (methylthioimidoyl) benzoylimino] -3-methyl-4-isopropyl-3H-obtained in Example 9 (6)
Thiazoline-5-carboxamide methylsulfate 0.8
g (1.39 mmol), 0.3 g of 1,4-dioxa-8-azabicyclo [4,5] decane (2.09 mmo)
A mixture of 1), acetic acid 0.12 ml (2.09 mmol) and acetone 10 ml was stirred for 1.5 hours while heating under reflux. The reaction mixture was allowed to cool to room temperature and then concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution and neutralized, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was crystallized from diethyl ether and N- (2-methoxycarbonylethyl) -2-
0.12 g of {4-[(4,4-ethylenedioxypiperidino) imidoyl] benzoylimino} -3-methyl-4-isopropyl-3H-thiazoline-5-carboxamide methylsulfate (Compound 65) was obtained. It was

¹ H-NMR (DMSO-d ₆ ) δ (pp
m): 1.33 (6H, d, J = 6Hz), 1.71
(4H, m), 2.58 (2H, t, J = 6Hz),
3.44 (2H, q, J = 6Hz), 3.2 to 3.6
(4H, m), 3.62 (3H, s), 3.69 (1
H, septet, J = 6 Hz), 3.92 (4H,
s), 3.93 (3H, s), 7.59 (2H, d, J
= 8 Hz), 8.30 (2H, d, J = 8 Hz), 8.
55 (1H, t, J = 6Hz), 8.6 (1H, b
r).

Example 39 0.1 g (0.18 mmol) of Compound 65, 0.16 ml (0.2 mmol) of 5% sodium hydroxide aqueous solution,
A mixture of 1 ml of 2-propanol was stirred at room temperature for 2 hours. A 1% phosphoric acid aqueous solution was added to adjust the pH to 7, the resulting aqueous solution was purified by Diaion HP-20 column chromatography (eluent: water, then methanol), concentrated under reduced pressure, and the obtained crude crystals were washed with acetone. N- (2-carboxyethyl) -2- {4-[(4,4-ethylenedioxypiperidino) imidoyl] benzoylimino}-
3-Methyl-4-isopropyl-3H-thiazoline-5
-0.1 g of carboxamide (compound 66) was obtained. Melting point 193-194 [deg.] C.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display area A61K 31/495 A61K 31/495 31/535 31/535 31/54 31/54 C07D 417/12 211 C07D 417/12 211 213 213 233 233 491/113 491/113 // (C07D 417/12 213: 16 277: 56) (C07D 417/12 233: 56 277: 56) (C07D 417/12 211: 74 277 : 56) (72) Inventor Yutaka Kawashima 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. (72) Inventor Katsuo Hatayama 3-24-1 Takada, Toshima-ku, Tokyo Taisho Pharmaceutical Co., Ltd. Within

Claims (1)

[Claims] (1) Formula (1) [Wherein R ¹ is the formula (i) (In the formula, R ¹¹ and R ¹² are a hydrogen atom and a carbon atom, respectively.
~ 6 alkyl groups, C2-7 alkoxycarbonyl groups, C4-8 cycloalkyl groups, phenyl groups, "C1-4 alkyl groups,
Phenyl group, aralkyl group or "alkyl group having 1 to 4 carbon atoms, alkoxy group having 1 to 4 carbon atoms, trifluoromethyl" substituted with an alkoxy group or halogen atom having 1 to 4 carbon atoms Group or haloalkyl group-substituted aralkyl group. ), A group represented by the formula (ii): (In the formula, R ²¹ and R ²² each represent a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, m and n each represent an integer of 1 to 3, A represents a methylene group, a carbonyl group,
An ethylenedioxymethylene group, an oxygen atom, a sulfur atom, a sulfinyl group, a sulfonyl group or a compound of the formula: (In the formula, R ³¹ represents a hydrogen atom, an alkyl group having 1 to 6 carbon atoms, a formyl group, an alkanoyl group having 2 to 7 carbon atoms, a phenyl group, and an “alkyl group having 1 to 6 carbon atoms,
A phenyl group, a pyridyl group or a benzyl group substituted with an alkoxy group having 1 to 6 carbon atoms, a nitro group, an alkanoyl group having 2 to 7 carbon atoms, a halogen atom or a trifluoromethyl group. ) Represents a group represented by. ) Or a group represented by (iii) imidazoline-2-
Represents an yl group, R ² represents an alkyl group having 2 to 6 carbon atoms, a cycloalkyl group having 3 to 6 carbon atoms or a phenyl group, and R ³ represents a hydrogen atom or 1 to 6 carbon atoms.
R ⁴ represents an alkyl group having 1 to 4 carbon atoms. ] The thiazoline derivative and its salt represented by these.