JPH09227539A - Oxime derivative, its production and medicinal composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound having excellent matrix metalloproteinase- inhibiting action, high oral activity, slow excretion into bile and long acting time and useful for treating and preventing articular disease, periodontal disease, etc. SOLUTION: This compound is represented by formula I (R<1> and R<2> are each phenyl, benzyl, phenethyl or thienyl which is unsubstituted or substituted with a lower alkyl, lower alkoxy and; R<3> is a lower alkyl or a benzyl which is unsaturated or substituted with a halogen, carboxyl, amino, acylamino or amide; R<4> is H, a lower alkyl or lower acyl) and its salt, e.g. [4-benzyl-1-(3,3- diphenyl-3-hydroxy-2-hydroxyimino)propyl]piperazine. The compound of formula I is obtained by reacting a compound of formula II with a compound of the formula, R<4> ONH2 . The compound is useful for treating and preventing articular diseases such as arthrorheumatism or hypertrophic arthritis, periodontal diseases, corneal ulcer, epidermolysis bullosa, neoplastic infiltration, tumor metastasis, bone resorption diseases, etc.

Description

Detailed Description of the Invention

[0001]

The present invention relates to matrix metalloproteinases (hereinafter, referred to as Matrix Metalloproteinases).
The present invention relates to an oxime derivative having an inhibitory action (referred to as MMPs) or a pharmaceutically acceptable salt thereof, a method for producing the same, and a pharmaceutical composition containing the oxime derivative or the salt as an active ingredient.

[0002]

2. Description of the Related Art MMPs are extracellular matrix (Extr
It is a proteolytic enzyme involved in the degradation of acellular matrix and has Zn ⁺⁺ and Ca ⁺⁺ in the active center. Arthritis is caused by the erosion of articular cartilage, which is thought to be caused by the deficiency of type 2 collagen, and the lack of stromelysin (Arthritis Rheu
m. 33, 388, 1990) and neutrophils (J. Clin. Immu
nol. 10, 19, 1990) MMPs are involved and it is considered that the destruction of extracellular matrix by these MMPs is the cause. Also, in cancer metastasis, MMPs are said to be required when cancer cells migrate through the vascular basement membrane (Curr. Op.
in. Invest. Drugs. 2 (6), 617, 1993).
It is effective to inhibit MMPs in the destruction of synovial membrane and cartilage of joints and the suppression of cancer metastasis / proliferation in the above arthritis, and many studies have been conducted on MMPs inhibitors therefor (for example, Curr). . Opin. Invest.
Drugs. 2 (6), 617, 1993; Curr. Opin. The
r. Patents. 4,7,1994; Bioorg. Med. Chem. L.
ett. 5,337, 1995; Biochemistry, 34, 6
602, 1995; Biochemistry, 34, 14012,
1995).

Furthermore, since heart failure involves the destruction of the collagen tissue in the interstitium of myocardial cells by MMP-1 (type I collagenase), inhibition of MMP-1 is expected to have a preventive effect on heart failure (J. . Mol. Cell. Cardio
l. 15, 261, 1983; Biochem. 265,2
33, 1990). In addition, MMP-1 was increased in the early stage of fibrosis due to the destruction of the extracellular matrix of the liver (Life Sci.
30, 1379, 1982) and an increase in MMP-2 (“liver / gall / pancreas” 31,433, 1995) are also known to occur, and the production of MMP-1 and MMP-2 (type IV collagenase). It is believed that the inhibition of liver damage can be expected to prevent liver damage. Therefore, various compounds having an inhibitory action on MMPs have been studied so far, and various peptide derivatives (JP-A-4-22907,
JP-A-4-352757) and various hydroxamic acid derivatives (JP-A-7-2797, JP-A-7-196598) have been proposed.

[0004]

However, these conventionally proposed peptide compounds and hydroxamic acid derivatives have a high MMPs inhibitory activity in vitro but low oral activity, and particularly hydroxamic acid derivatives have poor oral activity.
Further, in terms of pharmacokinetics, for example, excretion into bile is rapid, and some have long-term effects that cannot be expected. Therefore, peptide compounds and hydroxamic acid derivatives are administered intrapleurally (Drug News & Perspective).
s, 8 (4), 247, 1995) or administration by eye drops (Drug of the Future, 18, 1109, 1993), and oral administration has not been performed. The present invention
In view of the above circumstances, MM effective by oral administration
A highly safe compound having a Ps inhibitory activity and exhibiting a long-term activity, a method for producing the same, and treatment of a disease caused by the destruction of extracellular matrix by MMPs containing the compound as an active ingredient, and And / or to provide a pharmaceutical composition for prevention.

[0005]

The present invention provides a general formula (I) represented by the following formula.

[0006]

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(Wherein R ¹ and R ² represent the same or different groups selected from a phenyl group, a benzyl group, a phenethyl group or a thienyl group which is unsubstituted or substituted by a lower alkyl group or a lower alkoxy group, R ³ represents a lower alkyl group or a benzyl group which is unsubstituted or substituted by a halogen, a carboxyl group, an amino group, an acylamino group or an amide group, and R ⁴ represents a hydrogen atom, a lower alkyl group or a lower acyl group.) Is an oxime derivative or a pharmaceutically acceptable salt thereof. The present invention also provides a method for producing the oxime derivative or a pharmaceutically acceptable salt thereof, and further a pharmaceutical composition containing the oxime derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
The compounds represented by the above general formula (I) are novel compounds. The oxime compound is a non-peptidic compound and is a compound containing no hydroxamic acid,
It is a new family of compounds as MPs inhibitors.

In the general formula (I), R ¹ and R ² are the same or different groups selected from a phenyl group, a benzyl group, a phenethyl group or a thienyl group which is unsubstituted or substituted by a lower alkyl group or a lower alkoxy group. is there.
The position to be substituted may be any of the ortho, meta and para positions.
C1-C1 such as methoxy, ethoxy, and propoxy groups
5 is an alkyl group or an alkoxy group. Moreover, a phenyl group and a 2-thienyl group are mentioned as a particularly preferable group.

In the general formula (I), R ³ is a lower alkyl group, unsubstituted or halogen, a carboxyl group,
It is a benzyl group substituted with an amino group, an acylamino group or an amide group. Examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, a butyl group and a pentyl group. Further, as the benzyl group, an unsubstituted benzyl group, a chlorine atom at the para position, an amino group, an acetylamino group, and (N-tert-butoxycarbonyl-β
Examples of the benzyl group include a -alanyl) amino group, a carboxyl group, a methoxycarbonyl group, and a [2- (N-tert-butoxycarbonylamino) ethyl] aminocarbonyl group.

In the general formula (I), R ⁴ is a hydrogen atom,
A lower alkyl group or a lower acyl group. The lower alkyl group includes an alkyl group having 1 to 5 carbon atoms such as a methyl group, an ethyl group and a propyl group, and the lower acyl group includes an acyl group having 2 to 5 carbon atoms such as an acetyl group.

The compounds of general formula (I) can be used in free form or in the form of pharmaceutically acceptable acid addition salts. Preferred examples of pharmaceutically acceptable acid addition salts include salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid and phosphoric acid, and formic acid, acetic acid, oxalic acid, fumaric acid, citric acid, succinic acid and the like. It is a salt with an organic acid.

The oxime derivative represented by the general formula (I) can be produced, for example, by the following two methods. First Manufacturing Method The synthesis steps of the first manufacturing method are shown below.

[0013]

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(Wherein R ¹ and R ² represent the same or different groups selected from a phenyl group, a benzyl group, a phenethyl group or a thienyl group which is unsubstituted or substituted by a lower alkyl group or a lower alkoxy group, R ³ represents a lower alkyl group or a benzyl group which is unsubstituted or substituted with a halogen, a carboxyl group, an amino group, an acylamino group or an amide group, R ⁴ represents a hydrogen atom or a lower alkyl group, and TMS represents trimethylsilyl. Represents a group.)

That is, the ketone (2) was added to Rusty, E.
K. (J. Org. Chem. 45, 3994, 1980) and reacted with Horner-Emmons reagent to give formula (3).
Then, desilylation is carried out with a solution of tetra-n-butylammonium fluoride [(n-Bu) ₄ NF] in tetrahydrofuran (THF) to obtain α-hydroxyketone (4). Then, the α-hydroxyketone (4) is halogenated. For example, Carl, K. Etc. (J.
Med. Chem. 36, 610, 1993) and bromination with pyrrolidone hydrotribromide (PHT) to give compounds of formula (5). The bromine compound of formula (5) is reacted with a 1-substituted piperazine to give a compound of formula (6). The ketone of the formula (6) is reacted with hydroxylamine hydrochloride to obtain the oxime derivative of the present invention in which R ⁴ of the general formula (I) is a hydrogen atom. Further, the ketone of the formula (6) is reacted with O-methylhydroxylamine hydrochloride to obtain an oxime derivative of the present invention in which R ⁴ of the general formula (I) is a methyl group. In addition, an oxime derivative in which R ^{4 of} the general formula (I) is a lower acyl group, for example, an acetyl derivative can be produced by the process represented by the following formula.

[0016]

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(In the formula, R ¹ , R ² and R ³ have the same meaning as described above.) That is, the acetyl derivative (8) can be obtained by reacting the oxime (7) with acetyl chloride.

Second Manufacturing Method The synthesis process of the second manufacturing method will be described below.

[0019]

Embedded image

(Wherein R ¹ and R ² represent the same or different groups selected from a phenyl group, a benzyl group, a phenethyl group or a thienyl group which is unsubstituted or substituted by a lower alkyl group or a lower alkoxy group, R ³ represents a lower alkyl group or a benzyl group which is unsubstituted or substituted with a halogen, a carboxyl group, an amino group, an acylamino group or an amide group, and R ⁴ represents a hydrogen atom, a lower alkyl group or a lower acyl group. , NMO is N
-Methylmorpholine-N-oxide, DMSO represents dimethyl sulfoxide. )

That is, in this production step, the olefin (9) is obtained from the ketone (2) by the Wittig reaction.
The olefin (9) is reacted with osmium tetroxide (OsO ₄ ) to give a 1,2-dihydroxy compound (10).
1,2-dihydroxy compound (10) is a Doering-Pari
It is converted to α-hydroxyketone (4) by kh oxidation. The obtained α-hydroxyketone (4) is used as the oxime derivative (I) of the present invention according to the production process shown in the first production method.

The oxime derivative of the present invention obtained by the above method is shown below. (1) [4-Methyl-1- (3,3-diphenyl-3-
Hydroxy-2-hydroxyimino) propyl] piperazine (Compound 1) (2) [4-Ethyl-1- (3,3-diphenyl-3-
Hydroxy-2-hydroxyimino) propyl] piperazine (Compound 2) (3) [4-Propyl-1- (3,3-diphenyl-3)
-Hydroxy-2-hydroxyimino) propyl] piperazine (Compound 3) (4) [4-Butyl-1- (3,3-diphenyl-3-)
Hydroxy-2-hydroxyimino) propyl] piperazine (Compound 4) (5) [4-Pentyl-1- (3,3-diphenyl-3)
-Hydroxy-2-hydroxyimino) propyl] piperazine (Compound 5) (6) [4-Benzyl-1- (3,3-diphenyl-3)
-Hydroxy-2-hydroxyimino) propyl] piperazine (Compound 6) (7) [4-benzyl-1- (3,3-diphenyl-3)
-Hydroxy-2-methoxyimino) propyl] piperazine (Compound 7)

(8) [4-benzyl-1- (3,3-diphenyl-3-hydroxy-2-acetyloxyimino) propyl] piperazine (Compound 8) (9) [4- (4-chlorobenzyl)- 1- (3,3-
Diphenyl-3-hydroxy-2-hydroxyimino)
Propyl] piperazine (Compound 9) (10) [4- (4-methoxycarbonylbenzyl)-
1- (3,3-diphenyl-3-hydroxy-2-hydroxyimino) propyl] piperazine (Compound 10) (11) [4- (4-carboxybenzyl) -1-
(3,3-Diphenyl-3-hydroxy-2-hydroxyimino) propyl] piperazine (Compound 11) (12) [4- (4-aminobenzyl) -1- (3,3
-Diphenyl-3-hydroxy-2-hydroxyimino) propyl] piperazine (Compound 12) (13) [4- (4-acetylaminobenzyl) -1-
(3,3-Diphenyl-3-hydroxy-2-hydroxyimino) propyl] piperazine (Compound 13) (14) [4- (4-((2- (N-t-butoxycarbonylamino) ethyl) carbamoyl) benzyl ) -1
-(3,3-Diphenyl-3-hydroxy-2-hydroxyimino) propyl] piperazine (Compound 14)

(15) [4- (4- (N- (3- (N-
tert-butoxycarbonylamino) -1-oxo)
Propyl) aminobenzyl) -1- (3,3-diphenyl-3-hydroxy-2-hydroxyimino) propyl) piperazine (Compound 15) (16) [4-benzyl-1- (3,3-di (4- Tolyl) -3-hydroxy-2-hydroxyimino) propyl] piperazine (compound 16) (17) [4-benzyl-1- (3,3-di (4-tolyl) -3-hydroxy-2-methoxyimino) Propyl] piperazine (Compound 17) (18) [4-benzyl-1- (3,3-di (4-tolyl) -3-hydroxy-2-acetyloxyimino) propyl] piperazine (Compound 18) (19) [ 4-benzyl-1- (3-hydroxy-3-
Phenyl-3- (thiophen-2-yl) -2-hydroxyimino) propyl] piperazine (Compound 19) (20) [4-Methyl-1- (3-hydroxy-3-)
(2-Tolyl) -3- (thiophen-2-yl) -2-
Hydroxyimino) propyl] piperazine (Compound 2
0) (21) [4-methyl-1- (3-hydroxy-3-)
(3-Tolyl) -3- (thiophen-2-yl) -2-
Hydroxyimino) propyl] piperazine (Compound 2
1)

(22) [4-benzyl-1- (3-hydroxy-3- (2-tolyl) -3- (thiophen-2-
Iyl) -2-hydroxyimino) propyl] piperazine (Compound 22) (23) [4-benzyl-1- (3-hydroxy-3-)
(3-Tolyl) -3- (thiophen-2-yl) -2-
Hydroxyimino) propyl] piperazine (Compound 2
3) (24) [4-benzyl-1- (3-hydroxy-3-)
(4-Tolyl) -3- (thiophen-2-yl) -2-
Hydroxyimino) propyl] piperazine (Compound 2
4) (25) [4-benzyl-1- (3-hydroxy-3-)
(4-Tolyl) -3- (thiophen-2-yl) -2-
Methoxyimino) propyl] piperazine (Compound 25) (26) [4-benzyl-1- (3-hydroxy-3-)
(4-Tolyl) -3- (thiophen-2-yl) -2-
(Acetyloxy) propyl] piperazine (Compound 26) (27) [4-benzyl-1- (3-hydroxy-3-)
(4-Methoxyphenyl) -3- (thiophen-2-yl) -2-hydroxyimino) propyl] piperazine (Compound 27) (28) [4-methyl-1- (3,3-di (thiophen-2- Il) -3-hydroxy-2-hydroxyimino) propyl] piperazine (Compound 28)

(29) [4-benzyl-1- (3,3-
Di (thiophen-2-yl) -3-hydroxy-2-hydroxyimino) propyl] piperazine (Compound 29) (30) [4-methyl-1- (3-benzyl-3-hydroxy-4-phenyl-2- Hydroxyimino) butyl] piperazine (Compound 30) (31) [4-Benzyl-1- (3-benzyl-3-hydroxy-4-phenyl-2-hydroxyimino) butyl] piperazine (Compound 31) (32) [4 -Methyl-1- (3-hydroxy-5-phenyl-3- (2-phenylethyl) -2-hydroxyimino) pentyl] piperazine (Compound 32) (33) [4-benzyl-1- (3-hydroxy- 5-
Phenyl-3- (2-phenylethyl) -2-hydroxyimino) pentyl] piperazine (Compound 33)

The oxime derivative of the present invention is MMPs
It is used as a pharmaceutical composition for the treatment and / or prophylaxis of a disease caused by the destruction of extracellular matrix due to the administration of tablets, capsules, granules,
It can be orally administered as a syrup or the like, or can be parenterally administered in the form of a direct injection or the like. The dose varies depending on the patient's symptoms, age, and body weight, but is, for example, 1 per adult per day.
The effect is expected by administering 0 to 1000 mg in 1 to several divided doses.

[0028]

The compound of the present invention represented by the general formula (I) has an excellent inhibitory action on MMPs, as is clear from the pharmacological tests shown below. The pharmacological test results of the compound of the present invention are shown below. (MMP-1 inhibitory action) MMP-1 (type I collagenase) inhibitory activity is derived from human skin fibroblast-derived MMP-1.
And an enzyme assay using a type I collagenase activity measurement kit (Yagai Co., Ltd.) (Method Enzym
ol. 82, 423, 1982). That is, 0.010
U / ml MMP-1, 0.001-10 μM concentration of the compound of the present invention, and FITC fluorescence-labeled type I collagen (50 μg) were added to 200 mM NaCl and 500 mM C.
Incubated for 4 hours at 37 ° C. in 500 μl of 0.05 M Tris / HCl buffer (pH 7.5) containing aCl ₂ . MMP-1 cleaves collagen molecules at the Gly-Leu binding site into 3/4 and 1/4 fragments. Both fragments degenerate immediately under the present measurement conditions. 200m
The reaction was stopped using 200 μl of 0.05 M Tris / HCl buffer (pH 9.5) containing M NaCl, 50 mM o-phenanthroline and ethanol, and only the undenatured collagen was precipitated by centrifugation. The fluorescence intensity of the supernatant was read at an excitation wavelength of 495 mm and an emission wavelength of 520 mm, and the substrate decomposition rate was determined by comparing with the fluorescence intensity of the substrate denatured by heating. The rate of inhibition of substrate degradation by adding the compound of the present invention was calculated by comparing with the rate of substrate degradation of a control to which the compound of the present invention was not added, and the 50% inhibitory concentration (IC ₅₀
Value) was calculated. Table 1 shows the results.

(Inhibitory action of MMP-2 and MMP-9) M
MP-2 and MMP-9 (type IV collagenase) inhibitory activity was confirmed by MMP-2 and MMP- derived from human fibrosarcoma cells.
9 was evaluated by an enzyme assay using a type IV collagenase activity measurement kit (Yagai Co., Ltd.) (J. Cel.
l. Biochem. 28, 39, 1984). That is, 0.
010 U / ml of MMP-2 or MMP-9, a compound of the present invention in a specific concentration range, and FITC fluorescently labeled type IV collagen (from bovine placenta, about 25 μg) were added to 200 mM.
0.05 MT with NaCl and 5 mM CaCl ₂
Incubated for 4 hours at 42 ° C. in 100 μl of ris / HCl buffer (pH 7.5). MM
By the same operation as in the case of the enzyme assay using P-1, only undenatured type IV collagen was precipitated by centrifugation,
The substrate decomposition rate was determined from the fluorescence intensity of the supernatant. The rate of inhibition of substrate degradation by adding the compound of the present invention was determined by comparing with the rate of substrate degradation of a control to which the compound of the present invention was not added, and the 50% inhibitory concentration (IC ₅₀ value) was calculated. Table 1 shows the results.

[0030]

[Table 1]

[0031]

Examples are shown below. Example 1 Preparation of [4-benzyl-1- (3,3-diphenyl-3-hydroxy-2-hydroxyimino) propyl] piperazine (Compound 6). (A) Under an argon gas atmosphere, a 500 ml three-necked flask was charged with 8.50 ml (60.6 m) of diisopropylamine.
(mol) and tetrahydrofuran (50.0 ml) were taken and stirred. After cooling to -78 ° C with dry ice-acetone, 45.3 ml (72.5 mmol) of 1.60 Mn-hexane solution of n-butyllithium was added dropwise over 60 minutes, and after the addition, the mixture was stirred at -78 ° C for 60 minutes. did. 15.3 of (EtO) ₂ P (O) CH (OTMS) CH _{3 was} added to the reaction solution.
g (60.2 mmol) was added dropwise over 15 minutes, and after the addition, the mixture was stirred at -78 ° C for 90 minutes. Subsequently, 50.0 ml of a tetrahydrofuran solution containing 10.0 g (54.9 mmol) of benzophenone was added dropwise over 60 minutes. After dropping, −
The mixture was stirred at 78 ° C for 30 minutes and further at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give (1,1-diphenyl-1-trimethylsiloxy) propan-2-one.

The obtained (1,1-diphenyl-1-
Trimethylsiloxy) propan-2-one was dissolved in 100 ml of tetrahydrofuran and cooled to 0 ° C. To this, 1.0 of tetra-n-butylammonium fluoride was added.
5M of 0M tetrahydrofuran solution (55.0m
(mol) and then stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate.
The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (BW-200, ethyl acetate:
Purification with n-hexane = 1: 20) and the desired (1,1-diphenyl-1-hydroxy) propane-2
-On as pale yellow crystals, 6.30 g (27.8 mmo)
l) Got it. The yield was 50.6%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 2.27 (3H, S), 7.37 (10H,
S) Infrared absorption spectrum (cm ^-1 ): 3448, 1707,
1446, 1356, 1158, 1053, 753, 6
99 mass spectrum (M ⁺ ) = 226

(B) In a 100 ml eggplant-shaped flask, (1,1-diphenyl-1-hydroxy) propane-2 was added.
1.50 g (6.63 mmol) of -one, 30.0 ml of tetrahydrofuran and 4.27 g (8.62 mmol) of pyrrolidone trihydrobromide were taken, stirred and heated under reflux for 2 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (B
W-200, ethyl acetate: n-hexane = 1: 4), and the desired (1-bromo-3,3-diphenyl-3-hydroxy) propan-2-one as a pale yellow oily substance 1 0.81 g (5.93 mmol) was obtained. Yield 8
It was 9.6%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 3.97 (1H, S), 4.25 (2H,
S), 7.31 to 7.45 (10H, m) infrared absorption spectrum (cm ^-1 ): 3472, 1728,
1446, 1265, 1044, 759, 696, 61
5 Mass spectrum (M ⁺ ) = 306

(C) In a 100 ml eggplant-shaped flask (1
-Bromo-3,3-diphenyl-3-hydroxy) propan-2-one 1.81 g (5.93 mmol), tetrahydrofuran 30.0 ml, N-benzylpiperazine 2.09 g (11.9 mmol) were taken, and at room temperature. Thirty
Minutes. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (BW-2
00, ethyl acetate: n-hexane = 1: 3), and the desired [4-benzyl-1- (3,3-diphenyl-3-hydroxy-2-oxo) propyl] piperazine as colorless crystals. 2.16 g (5.39 mmol)
Obtained. The yield was 90.9%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 2.40 (8H, bs), 3.46 (4H,
S), 3.70 (1H, S), 7.20 to 7.46 (1
5H, m) infrared absorption spectrum (cm ^-1 ): 3052, 3016,
2812, 1719, 1596, 1491, 1449,
1290, 1248, 747, 696 Mass spectrum (M ⁺ ) = 354

(D) In a 25 ml eggplant-shaped flask, [4-
Benzyl-1- (3,3-diphenyl-3-hydroxy-2-oxo) propyl] piperazine 0.512 g
(1.28 mmol), ethanol 14.0 ml, triethylamine 2.14 ml (15.4 mmol), hydroxylamine hydrochloride 0.889 g (12.8 mmo).
1) was taken, stirred, and heated under reflux for 15 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (BW-200, chloroform:
Purify with methanol = 50: 1) to obtain the desired [4-
0.410 g (0.987 mm) of benzyl-1- (3,3-diphenyl-3-hydroxy-2-hydroxyimino) propyl] piperazine (Compound 6) as colorless crystals.
ol) obtained. The yield was 77.2%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 2.20 to 2.70 (8H, m), 3.43
(2H, s), 3.46 (2H, s), 3.69 (1
H, s), 7.20 to 7.42 (15H, m), 8.4
1 (1H, s) infrared absorption spectrum (cm ⁻¹ ): 3274, 3058,
3004, 2932, 2818, 1728, 1491,
1449, 1296, 1215 Mass spectrum (M ⁺ -OH) = 398

The compounds synthesized according to Example 1 are shown in Tables 2 and 3.

[0037]

[Table 2]

[0038]

[Table 3]

Example 2 Preparation of [4-benzyl-1- (3,3-diphenyl-3-hydroxy-2-methoxyimino) propyl] piperazine (Compound 7). (A) to (c) of Example 1 in a 25 ml eggplant-shaped flask.
[4-benzyl-1- (3,3-diphenyl-3-hydroxy-2-oxo) propyl] piperazine (0.334 g, 0.834 mmol), ethanol 10.0 ml, triethylamine 1.39 ml (9.
97 mmol), 0.696 g (8.34 mmol) of O-methylhydroxylamine hydrochloride, stirred and
Heated to reflux for an hour. After the reaction is completed, the reaction solution is poured into ice water,
It was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (B
Purify with W-200, chloroform: methanol = 50: 1, and obtain the desired [4-benzyl-1- (3,3-
Diphenyl-3-hydroxy-2-methoxyimino) propyl] piperazine (Compound 7) was obtained as colorless crystals.
124 g (0.289 mmol) was obtained. Yield 34.6
%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 2.46 (8H, bs), 3.47 (2H,
s), 3.48 (2H, s), 3.75 (3H, s),
7.21 to 7.50 (15H, m) infrared absorption spectrum (cm ^-1 ): 3260, 3052,
2960, 1448, 1370, 756, 698 Mass spectrum (M ⁺ ) = 429

The compounds synthesized according to Example 2 are shown in Table 4.

[0041]

[Table 4]

Example 3 Preparation of [4-benzyl-1- (3,3-diphenyl-3-hydroxy-2-acetyloxyxiimino) propyl] piperazine (Compound 8). [4-benzyl-1- (3,3-diphenyl-3-hydroxy-2-hydroxyimino) propyl obtained according to (a) to (d) of Example 1 in a 25 ml eggplant-shaped flask under an argon gas atmosphere. ] Piperazine (Compound 6)
0.480 g (1.16 mmol), dichloromethane 1
0.0 ml, triethylamine 0.200 ml (1.3
9 mmol) was taken and stirred. The mixture was cooled to 0 ° C, 0.100 ml (1.39 mmol) of acetyl chloride was added, and the mixture was stirred at 0 ° C for 30 minutes. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (BW-200, chloroform: methanol = 5).
Purify at 0: 1) to obtain the desired [4-benzyl-1-
(3,3-Diphenyl-3-hydroxy-2-acetyloxyxiimino) propyl] piperazine (Compound 8)
As a colorless oil, 0.410 g (0.896 mmo)
l) Got it. The yield was 77.6%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 2.03 (3H, s), 2.14 to 2.60
(8H, m), 3.47 (2H, s), 3.58 (2
H, s), 7.20 to 7.47 (15H, m) infrared absorption spectrum (cm ^-1 ): 3052, 3010,
2932, 2812, 1770, 1494, 1449,
1368, 1341, 1296, 1218, 1188,
1029 mass spectrum (M ⁺ ) = 457

The compounds synthesized according to Example 3 are shown in Table 5.

[0044]

[Table 5]

Example 4 Preparation of [4-benzyl-1- (5-phenyl-3- (2-phenyl) ethyl-3-hydroxy-2-hydroxyimino) pentyl] piperazine (Compound 33). (A) Triphenylethylphosphonium bromide 12.5 in a 200 ml eggplant-shaped flask under an argon gas atmosphere.
g (33.6 mmol), tetrahydrofuran 70.0
Take ml and stir. The suspension was cooled to 0 ° C., 3.77 g (33.6 mmol) of potassium t-butoxide was added, and the mixture was stirred at room temperature for 30 minutes. There, 4.00 g (16.8 mmo) of 1,5-diphenylpentan-3-one
10.0 ml of a tetrahydrofuran solution of 1) was added, and the mixture was heated under reflux for 60 minutes. After completion of the reaction, the reaction solution was poured into a saturated aqueous solution of ammonium chloride and extracted with diethyl ether. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (BW-200, ethyl acetate: n-hexane = 1: 9) to obtain the desired [5-phenyl-3- (2-phenyl) ethyl] -2-.
3.83 g (15.3 mm) of pentene as colorless oil
ol) obtained. The yield was 91.2%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 1.53 (3H, d, J = 6.8Hz),
2.29 to 2.39 (4H, m), 2.66 to 2.74
(4H, m), 5.29 (1H, q, J = 6.8H
z), 7.13 to 7.30 (10H, m) infrared absorption spectrum (cm ^-1 ): 3016, 2920,
2854, 1494, 1452, 744, 696 Mass spectrum (M ⁺ ) = 250

(B) 100 ml under argon gas atmosphere
[5-phenyl-3- (2-phenyl) ethyl] -2-pentene 3.81 g (15.2 mm)
ol), acetonitrile 15.0 ml, water 7.00 ml
Was taken and stirred. The reaction liquid was cooled to 0 ° C., and N−
Methylmorpholine-N-oxide 3.57 g (42.7
mmol), 4% osmium tetroxide aqueous solution 1.00 ml
Was added and the mixture was stirred at room temperature for 5 hours. After the reaction was completed, 50.0 ml of a saturated sodium sulfite aqueous solution was added to the reaction solution, and the mixture was stirred for 30 minutes. Then, the mixture was extracted with ethyl acetate, the organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is purified by silica gel column chromatography (BW-200, ethyl acetate: n-hexane = 1: 2) to obtain the desired [5-phenyl-2,3-dihydroxy-3- (2-phenyl) ethyl. ] 4.02 g (14.1 m) of propane as colorless crystals
mol) was obtained. The yield was 92.8%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 1.24 (3H, d, J = 6.4Hz),
1.69 to 2.05 (6H, m), 2.62 to 2.81
(4H, m), 3.88 (1H, q, J = 6.4H
z), 7.18 to 7.32 (10H, m) infrared absorption spectrum (cm ^-1 ): 3364, 3010,
2926, 1452, 1065, 1050, 957, 7
44, 729, 696 Mass spectrum (M ⁺ ) = 284

(C) Add [5] to a 200 ml eggplant-shaped flask.
-Phenyl-2,3-dihydroxy-3- (2-phenyl) ethyl] propane 2.00 g (7.03 mmo
1) and 20.0 ml of dichloromethane were taken and stirred.
The reaction solution was cooled to 0 ° C., and dimethyl sulfoxide 4.20 was added.
ml (59.2 mmol), triethylamine 2.90
ml (20.8 mmol) was added, and then 4.24 g (14.1 mmol) of pyridine sulfatrioxide was added to 4 ml.
Added in batches. Then, the mixture was stirred at room temperature for 75 minutes. After the reaction was completed, the reaction solution was poured into ice water and extracted with dichloromethane. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue is purified by silica gel column chromatography (BW-200, ethyl acetate: n-hexane = 1: 4) to obtain the desired [5-phenyl-3-hydroxy-3- (2-phenyl) ethyl] propane. 1.61 g (5.70 mmol) of 2-one was obtained as a colorless oil. Yield 81.1
%Met. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 1.97 to 2.14 (4H, m), 2.13
(3H, s), 2.27 to 2.35 (2H, m), 2.
74-2.82 (2H, m), 4.14 (1H, s),
7.14-7.30 (10H, m) Infrared absorption spectrum (cm ^-1 ): 3472, 3052,
3016, 2914, 1704, 1494, 1452,
1356, 1116, 747, 699 Mass spectrum (M ⁺ ) = 282

(D) [5]
-Phenyl-3-hydroxy-3- (2-phenyl) ethyl] propan-2-one 1.50 g (5.31 mmo
1), tetrahydrofuran 15.0 ml and pyrrolidone trihydrobromide 3.16 g (6.37 mmol) were taken, stirred and heated under reflux for 2 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (BW-200, ethyl acetate: n-hexane =
1: 4), and the target [1-bromo-5-phenyl-3- (2-phenyl) ethyl-3-hydroxy] pentan-2-one as a pale yellow oil was 1.79.
g (4.75 mmol) was obtained. The yield was 93.2%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 2.07 to 2.19 (4H, m), 2.39
Up to 2.47 (2H, m), 2.75 to 2.82 (2H,
m), 3.52 (1H, s), 4.02 (2H, s),
7.14 to 7.30 (10H, m) Infrared absorption spectrum (cm ^-1 ): 3490, 3052,
3016, 2926, 1722, 1494, 1452,
1377, 1248, 744, 696 Mass spectrum (M ⁺ ) = 361

(E) Add [1-
Bromo-5-phenyl-3- (2-phenyl) ethyl-
3-hydroxy] pentan-2-one 0.850 g
(2.35 mmol), tetrahydrofuran 10.0 m
l, N-benzylpiperazine 0.830 g (4.71 m)
(mol) and was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography (BW-200, ethyl acetate: n
-Hexane = 1: 1), and the desired [4-benzyl-1- (5-phenyl-3- (2-phenyl) ethyl-3-hydroxy-2-oxo) pentyl] piperazine was pale yellow. 0.820 g (1.80 mmo as crystals
l) Got it. The yield was 76.6%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 1.99 to 2.05 (4H, m), 2.37
~ 2.45 (2H, m), 2.58 (8H, bs),
2.72 to 2.80 (2H, m), 3.40 (2H,
s), 3.52 (2H, s), 7.14 to 7.32 (1
5H, m) infrared absorption spectrum (cm ^-1 ): 3442, 3016,
2932, 2800, 1710, 1452, 1002,
741,696 Mass spectrum (M ⁺ +1) = 457

(F) 0.300 g (0.657 mmol) of [4-benzyl-1- (5-phenyl-3- (2-phenyl) ethyl-3-hydroxy-2-oxo) pentyl] piperazine in a 25 ml round-bottomed flask. ), Ethanol 7.00 ml, triethylamine 1.10 ml (7.8
8 mmol), hydroxylamine hydrochloride 0.460 g
(6.57 mmol) was taken, stirred, and heated under reflux for 15 hours. After the reaction was completed, the reaction solution was poured into ice water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was recrystallized from ethyl acetate to obtain the desired [4-benzyl-1- (5-phenyl-3- (2-phenyl) ethyl-
0.210 g of 3-hydroxy-2-hydroxyimino) pentyl] piperazine (Compound 33) as colorless crystals
(0.445 mmol) was obtained. The yield was 68.0%. Nuclear magnetic resonance spectrum (400MHz, CDCl ₃ , δ
ppm): 1.85 to 2.04 (4H, m), 2.51
-2.58 (10H, m), 2.75-2.83 (2
H, m), 3.37 (2H, s), 3.51 (2H,
s), 7.15 to 7.34 (15H, m) infrared absorption spectrum (cm ^-1 ): 3412, 3016,
2938, 2818, 1452, 747, 699 Mass spectrum (M ⁺ -OH) = 455

The compounds synthesized according to Example 4 are shown in Table 6.

[0052]

[Table 6]

[0053]

INDUSTRIAL APPLICABILITY The compound represented by the general formula (I) of the present invention is an excellent matrix metalloproteinase (MM).
Ps) inhibitory action. Further, this compound has high oral activity, is slowly excreted in bile, and can be expected to have a long duration of action, and is represented by rheumatoid arthritis and osteoarthritis, which are considered to be mainly caused by the destruction of extracellular matrix by MMPs. It is useful for the treatment and / or prevention of diseases such as joint diseases, periodontal diseases, corneal ulcers, hydrocotylosis epidermis, neoplastic infiltration, cancer metastasis and bone resorption diseases.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07D 333/20 C07D 333/20 (72) Inventor Satoshi Takeuchi 6433 Sakajo, Sakajo, Hanashina-gun Nagano Prefecture Wakakusa Dormitory (72) Inventor Yasushi Okura 440-21 Nakanojo, Ueda City, Nagano Prefecture

Claims (5)

[Claims] 1. A general formula (I) represented by the following formula: (In the formula, R ¹ and R ² are each a phenyl group which is unsubstituted or substituted by a lower alkyl group or a lower alkoxy group,
Represents a same or different group selected from a benzyl group, a phenethyl group and a thienyl group, R ³ represents a lower alkyl group,
Or, it represents a benzyl group which is unsubstituted or substituted by a halogen, a carboxyl group, an amino group, an acylamino group or an amide group, and R ⁴ represents a hydrogen atom, a lower alkyl group or a lower acyl group. And a pharmaceutically acceptable salt thereof. 2. The following general formula (6): (In the formula, R ¹ and R ² are each a phenyl group which is unsubstituted or substituted by a lower alkyl group or a lower alkoxy group,
Represents a same or different group selected from a benzyl group, a phenethyl group and a thienyl group, R ³ represents a lower alkyl group,
Alternatively, it represents a benzyl group which is unsubstituted or substituted with a halogen, a carboxyl group, an amino group, an acylamino group or an amide group. ) Is a compound represented by the general formula R
⁴ ONH ₂ (wherein R ⁴ represents a hydrogen atom or a lower alkyl group) is reacted with a compound represented by the following general formula (I): A method for producing a compound represented by the formula (wherein R ¹ , R ² , R ³ and R ⁴ represent the same as above). 3. The following general formula (4): (In the formula, R ¹ and R ² are each a phenyl group which is unsubstituted or substituted by a lower alkyl group or a lower alkoxy group,
It represents the same or different groups selected from a benzyl group, a phenethyl group and a thienyl group. ) (1,1-
The halogenated substituted-1-hydroxy) propan-2-one is converted into (3,3-substituted-3-hydroxy-1-halogeno) propan-2-one to give 1 in the halide.
-Substituted piperazine is reacted to give the following general formula (6): (Wherein R ³ represents a lower alkyl group, or a benzyl group which is unsubstituted or substituted with a halogen, a carboxyl group, an amino group, an acylamino group or an amide group.), And then the general formula R ⁴ ON
H ₂ (provided that R ⁴ represents a hydrogen atom or a lower alkyl group)
A compound represented by the following general formula (I): A method for producing a compound represented by the formula (wherein R ¹ , R ² , R ³ and R ⁴ represent the same as above). 4. The following general formula (7): Wherein R ¹ and R ² represent the same or different groups selected from a phenyl group, a benzyl group, a phenethyl group or a thienyl group which is unsubstituted or substituted by a lower alkyl group or a lower alkoxy group. , R ³ is a lower alkyl group, or an unsubstituted or halogen, a carboxyl group, an amino group, a.) for a benzyl group substituted by an acylamino group or an amide group, the general formula R ⁴
Wherein a compound represented by Cl (wherein R ⁴ represents a lower acyl group) is reacted, and a compound represented by the following general formula (I): A method for producing a compound represented by the formula (wherein R ¹ , R ² , R ³ and R ⁴ represent the same as above). 5. The following general formula (I): (Provided that R ¹ , R ² , R ³ and R ⁴ in the formula have the same meanings as described in claim 1) and the oxime derivative and a pharmaceutically acceptable salt as active ingredients. A pharmaceutical composition for treating and / or preventing a disease caused by destruction of extracellular matrix by metalloproteinase.