JPH07149745A - New 2-aminothiazole derivative - Google Patents

Abstract

PURPOSE:To obtain the new derivative useful as a medicine having inhibiting actions on a serine protease, especially the inhibiting actions on an elastase. CONSTITUTION:This compound is expressed by formula I [R1 and R2 are each p-pivaloyloxyphenyl, H, a halogen, an alkyl, a substitutive phenyl, a substitutive benzyl or CH2COOR5 (R5 is H, an alkyl or a substitutive benzyl), with the proviso that at least one is p-pivaloyloxyphenyl; R3 and R4 are each H, an alkyl, an (halo)alkylsulfonyl, a substitutive phenylsulfonyl, amidino, CO-R6 {R6 is an alkyl, a substitutive phenyl, (CH2)m-COOH [(m) is 1-5], (CH2)n-NHR7 [(n) is 1-5; R7 is H, tert-butoxycarbonyl, etc.] or (CH2)Q-R8 (Q is 0-5; R8 is an alkoxy, phenyl, etc.}], e.g. 2-(2-methoxyphenyl)amino-5-methyl-4-(4-pivaloyloxyphenyl) thiazole. The compound is obtained by reacting a compound expressed by formula II with a compound expressed by formula III.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel 2-aminothiazole derivative useful for the use of a drug having a serine protease inhibitory action, particularly an elastase inhibitory action.

[0002]

BACKGROUND ART When elastase released from neutrophils reaches the extracellular space, α, a common inhibitor of serine enzymes,
It is normally rapidly captured and inactivated by ₁ -proteinase inhibitors. However, when the enzyme-inhibitor system is unbalanced, it causes connective tissue destruction by elastase, which causes serious pathological conditions such as rheumatoid arthritis, emphysema, acute respiratory distress syndrome (ARDS), bronchitis, sepsis, shock. , Periodontitis, osteomyelitis, psoriasis, atherosclerosis, kidney and liver failure.

The present invention provides a novel thiazole derivative useful for suppressing the tissue destruction and various inflammation or degeneration symptoms caused by the action of elastase.

[0004]

DISCLOSURE OF THE INVENTION The present invention provides a novel 2-aminothiazole derivative represented by the following general formula (I).

[Chemical 3] [In the formula, R ₁ and R ₂ are each a p-pivaloyloxyphenyl group, a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, and —CH ₂ COOR. ₅ (in the formula, R ₅ is a hydrogen atom, a lower alkyl group, a benzyl group or a substituted benzyl group). However, at least one of R ₁ and R ₂ is a p-pivaloyloxyphenyl group. R ₃ and R ₄ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a halo lower alkylsulfonyl group, a phenylsulfonyl group or a substituted phenylsulfonyl group, an amidino group, —CO—R.
₆ {in the formula, R ₆ is a lower alkyl group, a phenyl group or a substituted phenyl group,-(CH ₂ ) _m -COOH (in the formula, m
Is an integer of from 1 to _{5), - (CH 2) n} -NH-R 7 ( wherein, n an integer of 1 to 5, _{R 7} is a hydrogen atom, tert.
- butoxycarbonyl group, a benzyloxycarbonyl group)} and _{- (CH 2) Q -R 8} ( wherein, Q is 0
An integer of 5, R ₈ is a lower alkoxy group, a phenyl group or a substituted phenyl group, a pyridyl group or a substituted pyridyl group,
Or a cyclic amino group) or R ₃ and R ₄ may combine with each other to form a cyclic amino group].

The present invention will be described in more detail below. In the above general formula (I), the halogen atom is a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and the lower alkyl group is methyl, ethyl, n-propyl or iso.
-Propyl, n-butyl, iso-butyl, tert.
-Butyl, n-pentyl, n-hexyl and the like having 1 to 1 carbon atoms
6 alkyl groups. In addition, examples of the cycloalkyl group include cycloalkyl groups having 3 to 7 carbon atoms such as cyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl, and examples of the lower alkylsulfonyl group include
Examples thereof include alkylsulfonyl groups having 1 to 6 carbon atoms such as methylsulfonyl, ethylsulfonyl, propylsulfonyl and butylsulfonyl groups. The halo lower alkylsulfonyl group is a lower alkylsulfonyl group substituted with one or more halogen atoms. And lower alkoxy groups include methoxy, ethoxy, propoxy and iso.
-Propoxy, n-butoxy, iso-butoxy, te
rt. An alkoxy group having 2 to 6 carbon atoms such as butoxy. Further, as the cyclic amino group, a 5- or 6-membered cyclic amino group containing a nitrogen atom or an oxygen atom such as piperidino, pyrrolidino, morpholino, piperazino, pipecolino (this group is substituted with a halogen atom, a lower alkyl group, etc. Which may be present), and examples of the substituent in the substituted phenyl, the substituted benzyl, the substituted pyridyl group and the substituted phenylsulfonyl group include a lower alkyl group,
Halogen atom, hydroxyl group, nitro group, phenyl group, trifluoromethyl group, lower alkoxy group, halo lower alkoxy group substituted with one or more halogen atoms,
Methylsulfenyl, ethylsulfenyl, n-propylsulfenyl, iso-propylsulfenyl, n-
Butylsulfenyl, tert. A lower alkylsulfenyl group having 1 to 6 carbon atoms such as butylsulfenyl, a dilower alkylamino group having 1 to 6 carbon atoms such as dimethylamino, diethylamino, di-n-propylamino, di-n-butylamino, A lower alkanoylamino group having 2 to 6 carbon atoms such as acetylamino, propionylamino, butyrylamino, iso-butyrylamino, valerylamino, pivaloylamino, -COOR ₅ , -CH ₂ COOR.
₅ (in the formula, R ₅ has the same meaning as described above).

The salts of the novel 2-aminothiazole derivative represented by the formula (I) according to the present invention include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid and phosphoric acid, and maleic acid, fumaric acid, oxalic acid and succinic acid. Acid, malonic acid, lactic acid, citric acid,
Salts with organic acids such as methanesulfonic acid, benzenesulfonic acid and acetic acid, alkali metal salts such as lithium salt, sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, inorganic such as ammonium salt Salts and organic salts such as triethylamine salt, ethanolamine salt, triethanolamine salt, and dicyclohexylamine salt.

When the compound represented by the general formula (I) or a salt thereof is used as a medicine, tablets, capsules, injections, suppositories, ointments, creams, gels, as they are or together with known excipients, It can be usually administered systemically or topically, orally or parenterally in a suitable pharmaceutical dosage form such as lotion, aerosol, oral preparation, plaster, ship, eye drop and the like. The dosage is
It may be appropriately determined according to the symptoms of the subject, the age of the recipient, the sex, etc. When normally administered orally to an adult, the compound of formula (I) or a salt thereof is used as a single dose of 10 to 10 times. It is preferable to administer about 500 mg about once to several times a day.

Next, a method for producing the compound of the present invention will be described. The compound of the present invention can be obtained in high yield by the methods exemplified below, but the production method is not limited to these examples.

[0009]

[Manufacturing method]

 Manufacturing method 1

[Chemical 4] (In the formula, R ₁ , R ₂ , R ₃ , and R ₄ have the above-mentioned meanings. Hal means a halogen atom)

By mixing the compound represented by the general formula (II) and the compound represented by the general formula (III) in a suitable solvent at room temperature or under heating, the compound represented by the general formula (I) is obtained. Compounds can be prepared. Examples of the reaction solvent include, but are not limited to, methanol, ethanol, acetone, tetrahydrofuran, N, N-dimethylformamide, and dimethylsulfoxide.

Manufacturing method 2

[Chemical 5] (In the formula, R ₁ , R ₂ , R ₃ , and R ₄ have the above-mentioned meanings, and Hal means a halogen atom.)

The compound represented by the general formula (Ia) and the compound represented by the general formula (IV) or the compound represented by (V) are used without solvent or in a suitable solvent in the presence of a base catalyst. Then, the compound represented by the general formula (I) can be produced by reacting under cooling, at room temperature, or under heating. As a reaction solvent, dichloromethane,
Chloroform, carbon tetrachloride, tetrahydrofuran, N,
Organic solvents that do not participate in the above reaction, such as N-dimethylacetetamide, N, N-dimethylformamide, and dimethylsulfoxide, are used. As the base catalyst, a basic substance that promotes the deoxidation reaction such as pyridine, collidine, triethylamine, tri-n-propylamine, and tri-n-butylamine is used, but the base catalyst is not limited thereto. General formulas (Ia) and (II) used in the above production method
Each compound represented by (V) can be produced by a known combination of reactions (JP-A-64-40474, etc.).

[0013]

The present invention will be described in more detail with reference to the following examples. However, the present invention is not limited to these examples. Example 1 α-Bromo- (p-pivaloyloxy) propiophenone (1.00 g) and N- (2-methoxyphenyl)
Thiourea (0.70 g) was added in ethanol (50 ml) and then refluxed for 2 hours. The reaction solvent was concentrated under reduced pressure, 10% NaHCO ₃ was added, the product was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration and recrystallized from ether-petroleum ether to give 2-
(2-Methoxyphenyl) amino-5-methyl-4-
(4-pivaloyloxyphenyl) thiazole (0.7
9 g) was obtained. The melting point was 112-114 ° C. IR: 2967, 1742, 1569, 1501, 11
27 cm ⁻¹ MASS (m / e): 396 (M ⁺ ) Elemental analysis value (as C ₂₂ H ₂₄ N ₂ O ₃ S) Calculated value C: 66.64 H: 6.10 N: 7.07 Measured value C : 66.76 H: 6.16 N: 7.14

Example 2 α-Bromo- (p-pivaloyloxy) propiophenone (0.50 g) and N- (3-morpholinopropyl) thiourea (0.35 g) were added to ethanol (25 ml).
It was added to the inside and then refluxed for 1 hour. The reaction solvent was concentrated under reduced pressure, 10% NaOH was added, the product was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting crystals were collected by filtration and recrystallized from isopropyl ether to give 5-methyl-2- (3-morpholinopropyl) amino-4- (4
-Pivaloyloxyphenyl) thiazole (0.34
g) was obtained. The melting point was 125 to 126 ° C. The melting point of the methanesulfonate salt was 168 to 169 ° C. IR: 2962, 1744, 1584, 1199, 11
22 cm ⁻¹ MASS (m / e): 417 (M ⁺ ) Elemental analysis value (as C ₂₂ H ₃₁ N ₃ O ₃ S) Calculated value C: 63.28 H: 7.48 N: 10.0
6 Found C: 63.35 H: 7.69 N: 10.1
Three

Example 3 2-Amino-5-phenyl-4- (4-pivaloyloxyphenyl) thiazole (1.00 g) and triethylamine (0.90 g) in chloroform (25 ml) under nitrogen atmosphere- While stirring at 20 to -15 ° C, trifluoromethanesulfonic anhydride (2.4 g) was slowly added dropwise, and the mixture was stirred as it was for 5 hours and then at room temperature overnight. The reaction solvent was washed with diluted hydrochloric acid and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (chloroform: methanol = 30: 1), and the obtained crystals were collected by filtration and recrystallized from isopropyl ether-hexane to give 5-phenyl-4. -(4-Pivaloyloxyphenyl) -2-trifluoromethanesulfonylaminothiazole (0.34g) was obtained. Melting point is 210-212 ° C
Met. IR: 1746, 1555, 1334, 1209, 11
16 cm ^-1 MASS (m / e): 484 (M ⁺ ) Elemental analysis value (as C ₂₁ H ₁₉ F ₃ N ₂ O ₄ S ₂ ) Calculated value C: 52.06 H: 3.95 N: 5.78 Found C: 52.10 H: 4.05 N: 5.62

Example 4 2-Amino-5-phenyl-4- (4-pivaloyloxyphenyl) thiazole (0.50 g) in pyridine (5
ml) solution, benzenesulfonic acid chloride (0.3
8 g) was added at room temperature and stirred for 1 hour. Ice water was poured into the reaction solution, which was extracted with ethyl acetate, washed with diluted hydrochloric acid, water and saturated saline in this order, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography (isopropyl ether), and the obtained crystals were collected by filtration and recrystallized from isopropyl ether-petroleum ether to give 2-benzenesulfonylamino-5-phenyl. -4- (4-Pivaloyloxyphenyl) thiazole (0.21 g) was obtained. Melting point is 222
Was 223 ° C. IR: 2988, 1754, 1688, 1205, 11
00 cm ⁻¹ MASS (m / e): 492 (M ⁺ ) Elemental analysis value (calculated value as C ₂₆ H ₂₄ N ₂ O ₄ S ₂ C: 63.39 H: 4.91 N: 5.69 measured value C : 63.40 H: 4.91 N: 5.54

Example 5 2-Amino-5-methyl-4- (4-pivaloyloxyphenyl) thiazole (3.00 g) in pyridine (30)
ml) solution, add succinic anhydride (1.24 g) to
Reflux for hours. Dilute hydrochloric acid was added to the reaction solution, which was extracted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were collected by filtration and recrystallized from isopropyl ether-acetone to give 3- {N- [5-methyl-4- (4-pivaloyloxyphenyl)). Thiazol-2-yl] carbamoyl}
Propionic acid (0.21 g) was obtained. Melting point is 222-
It was 223 ° C. IR: 2980, 1752, 1688, 1168, 11
16 cm ⁻¹ MASS (m / e): 390 (M ⁺ ) Elemental analysis value (as C ₁₉ H ₂₂ N ₂ O ₅ S.1 / 4H ₂ O) Calculated value C: 57.78 H: 5.74 N: 7.09 measured value C: 57.61 H: 5.81 N: 7.01

Example 6 N-benzyloxycarbonylglycine (0.42 g)
Of anhydrous tetrahydrofuran (10 ml) was stirred at -20 to -15 ° C under nitrogen atmosphere, ethyl chlorocarbonate (0.19 ml) and N-methylmorpholine (0.22 ml) were added, and the mixture was stirred for 5 minutes as it was. . 2-amino-5-methyl-4- (4-pivaloyloxyphenyl) thiazole (0.58 g) was added to the reaction solution,
After stirring for 2 hours as it was, the mixture was stirred at room temperature overnight. The obtained reaction solution was concentrated under reduced pressure, extracted with ethyl acetate, and then extracted with 5%.
Washed with NaHCO ₃ , water, 10% citric acid, water in this order,
It was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were collected by filtration and recrystallized from isopropyl ether to give 2- (2-benzyloxycarbonylaminoacetyl) amino-5-methyl-4- (4
-Pivaloyloxyphenyl) thiazole (0.62
g) was obtained. The melting point was 207 to 209 ° C. IR: 3234, 1754, 1713, 1686, 15
66 cm ⁻¹ MASS (m / e): 481 (M ⁺ ) Elemental analysis value (as C ₂₅ H ₂₇ N ₃ O ₅ S) Calculated value C: 62.36 H: 5.65 N: 8.73 Measured value C : 62.24 H: 5.73 N: 8.73

Examples 7 to 57 Based on the methods described in Examples 1 to 6, the compounds shown in the following Table 1 were synthesized. Indications of compounds in the table are those of Example No. 7-No. 57 in the general formula (I)

[Chemical 6] Is shown in the table.

[0020]

[Table 1]

[0021]

[Table 2]

[0022]

[Table 3]

[0023]

[Table 4]

[Action] The enzyme inhibition test conducted for the elastase inhibitory action of the compound of the present invention and the result thereof will be shown below. Test method The enzyme inhibition test was performed using human leukocyte elastase and succinyl-Ala-Pro-Ala-7-amido-4-methylcoumarin. That is, the sample is DMSO
(For fluorescence analysis) 0.1 M Tris-HCl buffer (0.2
(Including M NaCl) to various concentrations. In addition, the enzyme solution was prepared with the above buffer solution, and the reaction mixture solution
Incubated at 0 ° C for 30 minutes. The reaction was stopped by adding 15% acetic acid, and the excitation wavelength was 380 nm.
The fluorescence intensity of m was measured. The test results are expressed as a 50% inhibitory concentration (IC ₅₀ ).

Results The elastase inhibitory activity (IC ₅₀ ) is shown in Table 2 below.

[Table 5]

As is clear from the results of these tests,
The compound of the present invention has an elastase inhibitory action, and the compound of the present invention is a therapeutic agent for tissue destruction and various inflammations or degenerative symptoms caused by the action of elastase,
Alternatively, it is expected to be used as a prophylactic agent and is a very useful substance in the pharmaceutical industry.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI technical display location C07D 277/44 417/04 207 211 417/12 213 // (C07D 417/04 207: 40 277: 42) (C07D 417/04 211: 10 277: 42) (C07D 417/12 213: 74 277: 42) (C07D 417/12 213: 38 277: 42) (72) Inventor Shigenori Yahiro Tashiro, Tosu City, Saga Prefecture Daikanmachi 408 Hisamitsu Pharmaceutical Co., Ltd. (72) Inventor Kazuhisa Takeda Daishiro Tashiro, Tosu City, Saga Prefecture 408 Hisamitsu Pharmaceutical Co., Ltd. (72) Inventor Kazunori Nakamura Koshokucho, Chiba City Midori-ku, Chiba Prefecture 1170-10 4-509

Claims (2)

[Claims] 1. A compound represented by the general formula (I): [In the formula, R ₁ and R ₂ are each a p-pivaloyloxyphenyl group, a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, and —CH ₂ COOR. ₅ (in the formula, R ₅ is a hydrogen atom, a lower alkyl group, a benzyl group or a substituted benzyl group). However, at least one of R ₁ and R ₂ is a p-pivaloyloxyphenyl group. R ₃ and R ₄ are the same or different and each is a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, a halo lower alkylsulfonyl group, a phenylsulfonyl group or a substituted phenylsulfonyl group, an amidino group, —CO—R.
₆ {in the formula, R ₆ is a lower alkyl group, a phenyl group or a substituted phenyl group,-(CH ₂ ) _m -COOH (in the formula, m
Is an integer of from 1 to _{5), - (CH 2) n} -NH-R 7 ( wherein, n an integer of 1 to 5, _{R 7} is a hydrogen atom, tert.
- butoxycarbonyl group, a benzyloxycarbonyl group)} and _{- (CH 2) Q -R 8} ( wherein, Q is 0
An integer of 5, R ₈ is a lower alkoxy group, a phenyl group or a substituted phenyl group, a pyridyl group or a substituted pyridyl group,
A cyclic amino group) or R ₃ and R ₄ may combine with each other to form a cyclic amino group] or a salt thereof. 2. A compound represented by the general formula (I): [In the formula, R ₁ and R ₂ are each a p-pivaloyloxyphenyl group, a hydrogen atom, a halogen atom, a lower alkyl group, a phenyl group, a substituted phenyl group, a benzyl group, a substituted benzyl group, and —CH ₂ COOR. ₅ (in the formula, R ₅ represents a hydrogen source, a lower alkyl group, a benzyl group or a substituted benzyl group). However, at least one of R ₁ and R ₂ is a p-pivaloyloxyphenyl group. R ₃ and R ₄ are the same or different and each is a hydrogen atom,
Lower alkyl group, lower alkylsulfonyl group, halo lower alkylsulfonyl group, phenylsulfonyl group or substituted phenylsulfonyl group, amidino group, -CO-R
₆ {in the formula, R ₆ is a lower alkyl group, a phenyl group or a substituted phenyl group,-(CH ₂ ) _m -COOH (in the formula, m
Is an integer of from 1 to _{5), - (CH 2) n} -NH-R 7 ( wherein, n an integer of 1 to 5, _{R 7} is a hydrogen atom, tert.
- butoxycarbonyl group, a benzyloxycarbonyl group)} and _{- (CH 2) Q -R 8} ( wherein, Q is 0
An integer of 5, R ₈ is a lower alkoxy group, a phenyl group or a substituted phenyl group, a pyridyl group or a substituted pyridyl group,
A cyclic amino group) or R ₃ and R ₄ may combine with each other to form a cyclic amino group] or an elastase inhibitor containing a 2-aminothiazole derivative or a salt thereof as an active ingredient. Agent.