KR100405913B1 - Biphenyl Butyric Acid Derivative as a Matrix Metalloproteinase Inhibitor - Google Patents

Abstract

The present invention relates to novel biphenyl butyric acid derivatives. The present invention provides novel biphenyl butyric acid derivatives of the general formula (I), pharmaceutically acceptable salts thereof, and methods for their preparation, which are useful as inhibitors of matrix metalloproteinases. The biphenyl butyric acid derivative compound of the present invention selectively inhibits the activity of matrix metalloproteinase (MMP) under in vitro conditions. The MMP inhibitor comprising the biphenyl butyric acid derivative as an active ingredient is an overexpression of MMP and It may be useful for the prevention and treatment of various diseases caused by excessive activation.

Description

Biphenyl Butyric Acid Derivative as a Matrix Metalloproteinase Inhibitor

The present invention relates to novel biphenyl butyric acid derivatives. More specifically, the present invention relates to novel biphenyl butyric acid derivatives of the general formula (I), pharmaceutically acceptable salts thereof, and methods for their preparation, useful as inhibitors of matrix metalloproteinases.

Matrix metalloproteinase (MMP) is a calcium (Ca ²⁺ ) dependent proteinase that contains zinc (Zn ²⁺ ) at its active sites and is a stromelysin and collagenase. About 18 are known, including families of agents and gelatinases. These MMP enzymes degrade the protein components of the connective tissue, namely collagen, laminin, proteoglycan, fibronectin, elastin, gelatin, etc., under biological conditions, leading to the growth and remodeling of joint tissue, bone tissue, connective tissue. These enzymes commonly contain zinc in their active sites and vary in activity depending on calcium, are secreted in the form of inactive preenzymes, activated outside of cells, and secreted with a natural inhibitor called TIMP (tissue inhibitor of metalloproteinase).

On the other hand, MMP inhibitors are useful for the prevention and treatment of various diseases caused by overexpression and excessive activation of MMP. Examples of the disease include rheumatoid, osteoarthritis, abnormal osteoporosis, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, emphysema, cirrhosis, corneal injury, tumor cell metastasis, invasion, or growth, autoimmune disease, vascular maintenance, Or diseases caused by invasion of leukocytes, arterialization (Beeley et al., Curr. Opin. Ther. Patents, 4 (1): 7-16, 1994). For example, it has been reported that the synthesized MMP inhibitor has an anti-cancer effect in vivo along with the inhibitory effect of substrate remodeling in a rat model of ovarian cancer (Cancer Res., 53: 2087, 1993). . In particular, it is known that MMP-2 and MMP-9 of the above MMP enzymes are essentially involved in the angiogenesis stage required for cancer cell growth (Biochim. Biophys. Acta, 695, 1983). In addition, MMP-1 and MMP-3 in the MMP enzymes were found to be higher than normal levels in synoviium and cartilage of rheumatoid arthritis patients. Since it is known to play an important role in progression (Arthritis Rheum., 35: 35-42, 1992), selectivity to MMP-1 / MMP-2 is believed to play an important role in reducing side effects such as joint pain. Thus, recent research has focused on the development of selective inhibitors, and the design and synthesis of such MMP inhibitors has been studied at various angles (J. Enzyme Inhibitor, 2: 1-22, 1987; Current Medicinal Chemistry, 2: 743-762, 1995; Progress in Medicinal Chemistry, 29: 271-334, 1992; Exp.Opin.Ther. Patents, 5: 1287-1296, 1995; Drug Discovery Today, 1: 16-26, 1996; Chem Rev. 99: 2735-2776, 1999).

In general, compounds having functional groups that coordinate well with zinc metal in the active site of MMP enzymes inhibit the catalytic activity of MMP. Such functional groups are known as hydroxamic acid, carboxylic acid, phosphoric acid, phosphinic acid, thiol, and the like, and MMP inhibitors designed and synthesized using such functional groups are already known. In particular, various succinic acid derivatives with peptide backbones, substrate migratory compounds, have been synthesized as early inhibitors (British Biotech, WO 9925693; Zeneca, WO 9843959, WO 9824759; Abbott, WO 9830551, WO9830541; PU, WO9732846; Roche, WO9901428, EP 897908; GW, WO 9838179; Sankyo, JP 95002797; DuPont, WO 9918074; Ono, WO 9919296; and, Otsuka, EP 641323), all of these substrate-like inhibitors use hydroxamic acids as Zn-coordinates. Although known to have, the electrical inhibitors have problems of low oral absorption and low selectivity of MMP-1 / MMP-2 possessed by the peptide derivative.

Since sulfonylamino acid derivatives were developed in 1996 as inhibitors to solve the aforementioned problems (see USP 5,506,242; J. Med. Chem., 40: 2525-2532, 1997), various sulfonylamino acid derivatives have been synthesized and reported. (See WO 9720824, JP 98316662, WO 9808825, EP 877018, JP 98204059, WO 9906410, JP 98204054, EP 895988, EP 9918076, WO 9832748, WO 9809934 and WO 9808823). The inhibitors have a relatively high inhibitory effect on MMP activity, but the selectivity of MMP-1 / MMP-2 was not high (Drugs of the Future, 24 (1): 16-21, 1999) and as a side effect in clinical trials. Since arthralgia has been reported, a multi-faceted study for solving the above-mentioned side effects has been reported as a biphenyl butyric acid compound (Bay12-9566) having the following structural formula as an inhibitor for solving the above-mentioned problems (WO: WO 9615096).

Bay12-9566 showed a significantly lower in vitro MMP inhibitory activity compared to the substrate-like succinic acid derivative or sulfonylamino acid derivative, but significantly improved the selectivity of MMP-1 / MMP-2 (see Drugs of the Future, 24 ( 1): 16-21, 1999), clinical trials showed little side effects such as joint pain. However, Bay 12-9566 has a problem of significantly lower activity against MMP-2 (IC ₅₀ : 11 nM) / MMP-9 (IC ₅₀ : 301 nM), and various biphenyl butyric acid derivatives have been reported as MMP inhibitors. (USP 5789434, USP 5854277, USP 5859047, USP 5861427, USP 5861428, USP 5874473, USP 5886022, USP 5886024 and USP 5886043).

In addition, butyric acid derivatives of the following structural formulas have been reported (see WO 9809940, WO 9806711), but the selectivity of MMP-1 / MMP-2 is increased, but in vitro compared to the above substrate-like succinic or sulfonylamino acid derivatives. MMP inhibitory activity had a problem of greatly falling.

Therefore, there is a constant need to develop new substances that can reduce side effects by increasing MMP inhibitory activity and selectivity to MMP-1 / MMP-2.

Accordingly, the present inventors have diligently researched to develop a new substance that can reduce side effects by increasing MMP inhibitory activity and selectivity to MMP-1 / MMP-2, and as a result, newly synthesized biphenyl butyric acid derivatives are in vitro. It was confirmed that selectively inhibiting the activity of MMP under the conditions, the present invention was completed.

After all, the main object of the present invention is to provide a biphenyl butyric acid derivative that inhibits the activity of MMP.

Another object of the present invention is to provide a method for producing an electrical derivative.

The present invention provides a method for preparing biphenyl butyric acid derivative compounds of the following general formula (I), their isomers, and their pharmaceutically acceptable salts and electrical substances which inhibit the action of MMP.

Where

R ₁ is hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano, -OCF ₃ ,

, -OCH ₂ F, -OCH ₂ F,

-OR ₁₀ , -SR ₁₀ , -S (O) R ₁₀ , or -S (O) _2, wherein R ₁₀ and R ₁₀ ^a

Are the same or different from each other, alkyl, aryl, arylalkyl, he

Teroaryl, or cycloalkyl);

R ₂ and R ₃ are the same as or different from each other, hydrogen, alkyl, aryl, arylal

Kiel, heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthioal

Kiel, Arylthioalkyl, Alkylsulfinylalkyl, Alkylsulfonylalkyl, Ah

Arylsulfinylalkyl, arylsulfonylalkyl or cycloalkyl;

R ₄ and R ₅ are the same as or different from each other, and hydrogen, alkyl, aryl, arylal

Ke, heteroaryl or cycloalkyl; And,

n is 1 or 2.

In addition, R ₂ and R ₃ may be connected to each other by carbon, nitrogen, oxygen or sulfur to form a ring of 5, 6, wherein The group specifically includes the following structure.

Where

R ₄ , R ₅ and n are the same as defined in general formula (I);

R ₆ is hydrogen, hydroxy, alkoxy, aryloxy, thiol or

Alkylthio;

R ₇ is oxo, hydroxyoxo or alkoxyoxo;

R ₈ and R ₉ are lower alkyl; And,

X is CH ₂ , O or S.

Unless otherwise noted, all isomers of the foregoing sulfonamide compounds are within the scope of the present invention. For example, in the case of alkyls, alkoxy alkenes, and alkynes, the straight and branched chains thereof, as well as isomers such as branched alkyls generated by asymmetric carbons, also belong to the invention.

Pharmaceutically acceptable salts of the present invention include acid addition salts, hydrate salts. Compounds of general formula (I) of the present invention can be converted to the corresponding salts, including salts of alkali metals (sodium, potassium, etc.), salts of alkaline earth metals (calcium, magnesium, etc.), ammonium salts, non-toxic organic amines Preferred salts and water soluble salts are preferred. Compounds of the general formula (I) of the present invention are salts of inorganic acids (hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate, nitrate, etc.), salts of organic acids (acetic acid, lactate, tartarate, oxalate, puma) Lysates, glucuronates, etc.), which can be converted to the corresponding acid addition salts, with non-toxic and water-soluble salts being preferred. The compounds of formula (I) and salts thereof of the present invention can also be converted to the corresponding hydrates by conventional methods in the art.

In particular, although various biphenyl butyric acid derivatives according to R ₂ and R ₃ as defined above among the compounds of general formula (I) are included, each biphenyl butyric acid derivative of the following general formula is preferred.

Where

R ₁ , R ₄ , R ₅ and n are the same as previously defined in general formula (I).

Below, the manufacturing method of the compound of general formula (I) is demonstrated according to process.

Preparation Method 1:

First step :

With some modification of the known methods, tertiary butyl ester (IV) is obtained from starting materials (II) and (III) (see WO 9615096): wherein starting material (II) is commercially available, It can be prepared by known methods (see BS Furniss, et al., VOGEL's Textbook of Practical Organic Chemistry, 5th, ed., Pp942-943, 1988), and starting material (III) has some modifications to known methods. It can be prepared by the reference (WO 9615096).

Second process :

Deprotective group reaction of the tertiary butyl ester (IV) affords compound (V).

Third process :

Condensation of compound (V) with an amine gives diethyl ester (VI): Condensation is preferably carried out using EDC / Et ₃ N.

4th process :

With some modification of the known methods, the compound (I) is prepared by hydrolysis and decarboxylation of diethyl ester (VI) (see WO 9615096).

Preparation Method 2:

The compound of general formula (I) can be manufactured by changing a manufacturing method mentioned above in part.

First step :

Compound (VII) is obtained by selectively hydrolyzing and decarboxylating only one ester in tertiary butyl ester (IV) obtained in the first step of Preparation Method 1 above.

Second process :

Compound (VII) is subjected to a deprotection group reaction in the same manner as in the second step of Preparation Method 1 to obtain compound (VII).

Third process :

Condensation reaction of compound (VII) with an amine yields ethyl ester (IV): At this time, the condensation reaction preferably uses an activated ester intermediate such as HOBT / DCC.

4th process :

Compound (I) is prepared by hydrolyzing ethyl ester (IV) with some modifications of known methods (see WO 9615096).

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention in more detail, it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples in accordance with the gist of the present invention. .

Example 1 : Preparation of 5- (biphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid t-butyl ester (IV, R ₁ = H)

NaH (95%, 505mg, 20.0mmol) and THF (15mL) were added to a 100ml flask and cooled to -10 ° C. Ethyl, t-butyl-2-ethylcarboxysuccinate (III) dissolved in THF (10mL) was added. , 4.9 g, 18.17 mmol) was added slowly, stirred at room temperature for 30 minutes, and then 2- (biphenyl-4-yl) -1-bromoethane (II, R ₁ = H, dissolved in THF (15 mL) 5 g, 18.17 mmol) was slowly added and stirred at room temperature for 1 hour 30 minutes. Then, 1N HCl solution (30 mL) and ethyl acetate (30 mL) were added thereto, and the organic layer was washed with water (10 mL), anhydrous MgSO ₄ was added thereto, stirred for 5 minutes, filtered and distilled under reduced pressure to obtain the title compound (8.65). g, 95%) was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.24 (t, 6H), 1.38 (s, 9H), 3.39 (s, 2H),

3.97 (s, 2H), 4.24 (q, 4H), 7.45 (m, 3H),

7.61 (d, 2H), 7.69 (d, 2H), 8.04 (d, 2H)

Example 2 Preparation of 5- (4'-Bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid t-butylester (IV, R ₁ = Br)

The title compound was prepared in the same manner as in Example 1 except for using 2- (4'-bromobiphenyl-4-yl) -1-bromoethane (II, R ₁ = Br).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.24 (t, 6H), 1.39 (s, 9H), 3.21 (s, 2H),

3.95 (s, 2H), 4.24 (q, 4H), 7.48 (d, 2H),

7.60 (d, 2H), 7.65 (d, 2H), 8.04 (d, 2H)

Example 3 Preparation of 5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid t-butylester (IV, R ₁ = Cl)

The title compound was prepared in the same manner as in Example 1 except for using 2- (4'-bromobiphenyl-4-yl) -1-bromoethane (II, R ₁ = Cl).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.25 (t, 6H), 1.39 (s, 9H), 3.21 (s, 2H),

3.95 (s, 2H), 4.24 (q, 4H), 7.44 (d, 2H),

7.56 (d, 2H), 7.65 (d, 2H), 8.06 (d, 2H)

Example 4 Preparation of 5- (4′-Bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R ₁ = Br)

5- (4'-Bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid t-butyl ester (IV, R ₁ = Br, 2.68 g, 4.9 mmol) was converted into MC ( 40 mL), TFA (4 mL) was added thereto, stirred at room temperature for 24 hours, and then the MC was removed under reduced pressure. Then, ethyl acetate (50 mL) was added, 1N NaOH solution was slowly added thereto, stirred for 10 minutes, and extracted with water. 1N HCl solution was added thereto, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure to obtain the title compound (1.47 g, 61%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.24 (t, 6H), 3.21 (s, 2H), 3.95 (s, 2H),

4.24 (q, 4H), 7.48 (d, 2H), 7.60 (d, 2H),

7.65 (d, 2H), 8.04 (d, 2H)

Example 5 N-[(N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(4'-bromobiphenyl-4-yl) -3,3-diethylcar Preparation of Vylvalerericamide (VI, R ₁ = Br)

5- (4'-Bromobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxyvaleric acid (V, R ₁ = Br, 140 mg, 0.285 mmol), EDC (60 mg, 0.313 mmol) And HOBt (42.4 mg, 0.313 mmol) were dissolved in MC (5 mL) and cooled to 0 ° C. After adding TEA (44.3 mL, 0.313 mmol) and stirring for 10 minutes, L-Ala-CONH-Ph (56 mg, 0.342 mmol) was added thereto, followed by stirring at room temperature for 12 hours. Then 1N HCl solution was added, extracted with MC, dried over anhydrous MgSO ₄ , filtered, distilled under reduced pressure, and purified by column chromatography (CHCl ₃ / MeOH = 19/1) to obtain 120 mg (69%) of the title compound. .

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.24 (t, 6H), 1.43 (d, 3H), 3.06 (d, 1H),

3.17 (d, 1H), 3.94 (s, 2H), 4.23 (q, 4H),

4.60 (m, 1 H), 6.15 (d, 1 H), 7.07 (t, 1 H),

7.27 (m, 1H), 7.45 (d, 2H), 7.58 (m, 6H),

7.97 (d, 2H), 8.60 (s, 1H)

Example 6 N-[(N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(4'-bromobiphenyl-4-yl) -3-carboxyvaleramide Preparation of (I, R ₁ = Br)

N-[(N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(4'-bromobiphenyl-4-yl) -3,3-diethylcarboxyvaleramideamide (VI, R ₁ = Br, 120 mg, 0.197 mmol) was dissolved in ethanol (5 mL), 1N NaOH (1 mL, 1 mmol) was added, and the mixture was stirred at room temperature for 5 hours. Then, ethanol was removed under reduced pressure, and water was added thereto and washed with ethyl acetate. The mixture was acidified with 1N HCl solution, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure. The synthesized material was dissolved in 1,4-dioxane (10 mL), heated to reflux for 2 hours, and then the solvent was removed under reduced pressure. The obtained material was recrystallized from MC / MeOH (19/1) solution (v / v) and hexane to give the title compound (64 mg, 60%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.43 (d, 3H), 3.06 (d, 1H), 3.17 (d, 1H),

3.40 (dd, 1H), 3.53 (m, 3H), 4.56 (m, 1H),

6.15 (d, 1 H), 7.07 (t, 1 H), 7.27 (m, 1 H),

7.45 (d, 2H), 7.58 (m, 6H), 7.97 (d, 2H),

8.60 (s, 1 H)

Example 7 Preparation of 5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid, t-butyl ester (VII, R ₁ = Cl)

A solution of KOH (85%, 0.72 g, 11.0 mmol) in ethanol (30 mL) was dissolved in 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid. , t-butyl ester (IV, R ₁ = Cl, 5.26 g, 10.46 mmol) was slowly added to the solution dissolved in ethanol (30 mL). It was stirred at room temperature for 6 hours, acidified with 1N HCl solution, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered and distilled under reduced pressure. The synthesized material was dissolved in 1,4-dihexane (dioxane, 10 mL), heated to reflux for 3 hours, and then the solvent was removed under reduced pressure to obtain the title compound (3.51 g, 78%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.24 (t, 3H), 1.45 (s, 9H), 2.66 (ddd, 2H),

3.24 (dd, 1H), 3.45 (m, 1H), 3.53 (dd, 1H),

4.16 (q, 2H), 7.42 (d, 2H), 7.55 (d, 2H),

7.65 (m, 2H), 8.03 (d, 2H)

Example 8 Preparation of 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid, t-butylether (VII, R ₁ = H)

Except for using 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3,3-diethylcarboxylic valeric acid, t-butyl ester (IV, R ₁ = H), The title compound was prepared in the same manner as in Example 7.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.24 (t, 3H), 1.45 (s, 9H), 2.66 (ddd, 2H),

3.24 (dd, 1H), 3.45 (m, 1H), 3.53 (dd, 1H),

4.16 (q, 2H), 7.45 (m, 3H), 7.61 (d, 2H),

7.69 (d, 2H), 8.04 (d, 2H)

Example 9 Preparation of 5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = Cl)

5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid, t-butyl ester (VII, R ₁ = Cl, 3.51 g, 8.14 mmol) in MC (50 mL) TFA (7.4 mL) was added thereto, stirred for 24 hours at room temperature, and the MC was removed under reduced pressure. Ethyl acetic acid (20 mL) was then added dropwise slowly to the 1N NaOH solution, then stirred for 10 minutes and extracted with water. Then, 1N HCl solution was added, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure, and recrystallized with CHCl ₃ and hexane to obtain 2.7 g (88%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H),

3.48 (m, 1 H), 3.57 (dd, 1 H), 4.18 (q, 2H),

7.42 (d, 2H), 7.55 (d, 2H), 7.65 (m, 2H),

8.03 (d, 2H)

Example 10 Preparation of 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = H)

In the same manner as in Example 1, except that 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid, t-butyl ester (VII, R ₁ = H) was used. The title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H),

`3.48 (m, 1H), 3.57 (dd, 1H), 4.18 (q, 2H),

7.45 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H),

8.04 (d, 2H)

Example 11 N-[((L) -N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxyvaleric Preparation of Amides (IX, R ₁ = H)

5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = H, 100 mg, 0.29 mmol) was dissolved in THF (5 mL) and cooled to 0 ° C., N-methylmorpholine (70 mL, 0.65 mmol) and ethyl chloroformate (31 mL, 0.32 mmol) were added and stirred for 30 minutes. To this was L-Ala-CONH-Ph ((a) Kruse, CH et al, J. Org . Chem. 1985, 50, 2792. (b) Fink, CA et al, Bioorg. Med. Chem. Lett. was added to a solution dissolving a 1999, 9, 195-200.) in THF (1mL) 3 hours at room temperature After stirring for 30 minutes, the filtrate was distilled under reduced pressure. It was diluted with chloroform, washed sequentially with 1N HCl solution, 10% NaHCO ₃ solution and water, and then dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure to obtain the title compound (105 mg, 73%).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd, 1H),

2.75 (ddd, 1H), 3.48 (m, 3H), 4.14 (m, 2H),

4.63 (m, 1 H), 6.15 (dd, 1 H), 7.07 (t, 1 H),

7.27 (m, 1 H), 7.45 (m, 3 H), 7.58 (m, 6 H),

7.97 (t, 2H), 8.40-8.60 (d, 1H)

Example 12 N-[((D) -N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxyvaleric Preparation of Amides (IX, R ₁ = H)

The title compound was prepared in the same manner as in Example 11 except for using 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = H). .

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd, 1H),

2.75 (ddd, 1H), 3.48 (m, 3H), 4.14 (m, 2H),

4.63 (m, 1 H), 6.15 (dd, 1 H), 7.07 (t, 1 H),

7.27 (m, 1 H), 7.45 (m, 3 H), 7.58 (m, 6 H),

7.97 (t, 2H), 8.40-8.60 (d, 1H)

Example 13 N-[((L) -No-Chlorophenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxyvalle Preparation of Ligamide (IX, R ₁ = H) (IX)

Example, except using 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = H) and L-Ala-CONH-o-ClPh In the same manner as in 11, the title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd, 1H),

2.75 (ddd, 1H), 3.48 (m, 3H), 4.14 (m, 2H),

4.63 (m, 1 H), 6.15 (dd, 1 H), 7.08 (t, 1 H),

7.29 (t, 2H), 7.45 (m, 3H), 7.58 (m, 4H),

7.70 (d, 2H), 7.97 (t, 2H), 8.60 (d, 1H)

Example 14 N-[((L) -Nm-chlorophenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxyvalle Preparation of Ligamide (IX, R ₁ = H) (IX)

Example, except using 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = H) and L-Ala-CONH-m-ClPh In the same manner as in 11, the title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd, 1H),

2.75 (ddd, 1H), 3.48 (m, 3H), 4.14 (m, 2H),

4.63 (m, 1 H), 6.15 (dd, 1 H), 7.07 (t, 1 H),

7.30 (t, 2H), 7.45 (m, 3H), 7.58 (m, 4H),

7.68 (d, 2H), 7.97 (t, 2H), 8.60 (d, 1H)

Example 15 N-[((L) -Np-chlorophenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxyvalle Preparation of Ligamide (IX, R ₁ = H) (IX)

Example, except using 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = H) and L-Ala-CONH-p-ClPh In the same manner as in 11, the title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.20 (dt, 3H), 1.47 (dd, 3H), 2.55 (ddd, 1H),

2.75 (ddd, 1H), 3.48 (m, 3H), 4.14 (m, 2H),

4.63 (m, 1 H), 6.15 (dd, 1 H), 7.08 (t, 1 H),

7.29 (t, 2H), 7.45 (m, 3H), 7.58 (m, 4H),

7.70 (d, 2H), 7.97 (t, 2H), 8.60 (d, 1H)

Example 16 : (IX) R1 = H, N- {1,5-dioxo-5-[(biphenyl-4-yl)]-3-ethylcarboxypentan-1-yl} -2- (N Preparation of -phenylaminocarboxyl) pyrrolidine (IX, R ₁ = H)

Example 11, except that 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid (VIII, R ₁ = H) and L-Pro-CONH-Ph were used. In the same manner, the title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.17 (t, 3H), 1.90 (m, 1H), 2.06 (m, 1H),

2.58 (br, 2H), 2.70-3.00 (m, 2H), 3.50 (m, 2H),

3.57 (m, 2H), 3.70 (m, 1H), 4.15 (m, 2H),

4.78 (m, 1 H), 7.05 (t, 1 H), 7.27 (m, 2 H),

7.45 (m, 3H), 7.58 (m, 5H), 8.03 (d, 2H),

9.2-9.4 (d, 1H)

Example 17 N-[((L) -N-phenyl-3-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethyl Preparation of Carboxylvaleramide (IX, R ₁ = H)

Example 11, except that 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid (VIII, R ₁ = H) and L-Phe-CONH-Ph were used. In the same manner, the title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.17 (dt, 3H), 2.38 to 2.55 (ddd, 1H),

2.70 (ddd, 1H), 3.20 (m, 2H), 3.45 (m, 3H),

4.13 (dq, 2H), 4.75-4.90 (dq, 1H),

6.10-6.30 (dd, 1H), 7.08 (t, 1H), 7.24 (m, 6H),

7.42 (m, 4H), 7.63 (m, 5H), 8.00 (d, 2H),

7.90 8.30 (d, 1 H)

Example 18 N-[((L) -N-phenyl-3-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethyl Preparation of Carboxylvaleramide (IX, R ₁ = H)

Example 11, except that 5- (biphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid (VIII, R ₁ = H) and L-Phe-CONH-Ph were used. In the same manner, the title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.20 (dt, 3H), 1.47 (dd, 2H), 2.55 (ddd, 1H),

2.74 (ddd, 1H), 3.48 (m, 3H), 3.57 (dd, 1H),

4.18 (dq, 2H), 4.65 (m, 1H), 6.25 (dd, 1H),

7.08 (t, 1 H), 7.27 (m, 1 H), 7.45 (d, 2 H),

7.61 (m, 6H), 8.01 (t, 2H), 8.60 (d, 1H)

Example 19 N- {1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl)]-3-ethylcarboxypentan-1-yl} -2- (N-phenylamino Preparation of carboxyl) pyrrolidine (IX, R ₁ = Cl)

Except for using 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = Cl) and L-Pro-CONH-Ph, In the same manner as in Example 11, the title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.20 (t, 3H), 1.90 (m, 1H), 2.06 (m, 1H),

2.58 (br, 2H), 2.70-3.00 (m, 2H), 3.50 (m, 2H),

3.57 (m, 2H), 3.70 (m, 1H), 4.15 (m, 2H),

4.78 (m, 1 H), 7.05 (t, 1 H), 7.27 (m, 2 H),

7.45 (m, 2H), 7.58 (m, 5H), 8.03 (d, 2H),

9.2-9.4 (d, 1H)

Example 20 N-[((L) -N-phenyl-3-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl) Preparation of 3-ethylcarboxyl valericamide (IX, R ₁ = Cl)

Except for using 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = Cl) and L-Phe-CONH-Ph, In the same manner as in Example 11, the title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.17 (dt, 3H), 2.38 to 2.55 (ddd, 1H),

2.70 (ddd, 1H), 3.20 (m, 2H), 3.45 (m, 3H),

4.13 (dq, 2H), 4.75-4.90 (dq, 1H),

6.10-6.30 (dd, 1H), 7.07 (t, 1H), 7.26 (m, 6H),

7.45 (m, 3H), 7.56 (m, 5H), 7.99 (d, 2H),

7.90 8.30 (d, 1 H)

Example 21 N-[((L) -N-phenyl-3- (3 ', 4'-dioxolanphenyl) propionamide-2-yl)]-1,5-dioxo-5-[( Preparation of 4'-Chlorobiphenyl-4-yl) -3-ethylcarboxylic valericamide (IX, R ₁ = Cl)

5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxylic valeric acid (VIII, R ₁ = Cl) and L-DOPA-CONH-Ph ((a) Kruse, CH et al, J. Org. Chem. 1985 , 50 , 2792. (b) Zelle, RE et al, Tetrahedron Lett. 1991 , 32 , 2461-2464. (c) Pink, CA et al, Bioorg. Med. Chem. Lett 1999, 9, 195-200.) to give the titled compound as and has the same procedures as in example 11 except for the use.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.18 (dt, 3H), 2.38-2.60 (ddd, 1H),

2.70 (ddd, 1H), 3.10-3.25 (m, 2H), 3.45 (m, 3H),

4.13 (dq, 2H), 4.60-4.80 (dq, 1H), 5.89 (s, 2H),

6.10-6.30 (dd, 1H), 6.74 (m, 3H). 7.10 (t, 1 H),

7.26 (m, 2H), 7.45 (m, 3H), 7.61 (m, 5H),

7.99 (m, 2 H)

Example 22 N- {1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl)]-3-ethylcarboxypentan-1-yl} -3- (N-phenylamino Preparation of carboxyl) -1,2,3,4-tetrahydroisoquinoline (IX, R ₁ = Cl)

5- (4'-Chlorobiphenyl-4-yl) -5-oxo-3-ethylcarboxyvaleric acid (VIII, R ₁ = Cl) and L-TIC-CONH-Ph ((a) Monsees, A. et al, Liebigs Ann / Recl. 1997 , 533-540. (b) Kruse, CH et al, J. Org. Chem. 1985 , 50 , 2792. (c) Pink, CA et al, Bioorg. Med. Chem. The title compound was prepared in the same manner as in Example 11 except for using Lett. 1999 , 9 , 195-200.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.17 (t, 3H), 2.70-3.20 (m, 2H),

3.38-3.57 (m, 4H), 4.11 (m, 1H), 4.16 (q, 2H),

4.66 (m, 2H), 5.33 (d, 1H), 6.92 (t, 1H),

7.15 (m, 4H), 7.45 (m, 7H), 7.93 (d, 2H),

8.66 (m, 1 H)

Example 23 N-[((L) -N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-carboxyvaleramideamide Preparation of (I, R ₁ = H)

N-[((L) -N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxylic valericamide (IX, R ₁ = H, 105 mg, 0.215 mmol) was dissolved in ethanol (5 mL), 1N NaOH (1 mL, 1 mmol) was added, the mixture was stirred at room temperature for 1 hour 30 minutes, and then water was added and washed with ethyl acetate, Acidified with 1N HCl solution. This was extracted with MC, dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure, and recrystallized with CHCl ₃ / MeOH (19/1) solution (v / v) and hexane to prepare 88 mg (89%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.47 (dd, 3H), 2.55 (ddd, 1H), 2.75 (ddd, 1H),

3.48 (m, 3H), 4.63 (m, 1H), 6.15 (dd, 1H),

7.07 (t, 1 H), 7.27 (m, 1 H), 7.45 (m, 3 H),

7.58 (m, 6H), 7.97 (t, 2H), 8.40-8.60 (d, 1H)

Example 24 N-[((D) -N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-carboxyvaleramide Preparation of (I, R ₁ = H) (I)

N-[((D) -N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxylic valericamide (IX, The title compound was prepared in the same manner as in Example 22, except for using R ₁ = H).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.47 (dd, 3H), 2.55 (ddd, 1H), 2.75 (ddd, 1H),

3.48 (m, 3H), 4.63 (m, 1H), 6.15 (dd, 1H),

7.07 (t, 1 H), 7.27 (m, 1 H), 7.45 (m, 3 H),

7.58 (m, 6H), 7.97 (t, 2H), 8.40-8.60 (d, 1H)

Example 25 N-[((L) -No-Chlorophenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-carboxybaleric Preparation of Amides (I, R ₁ = H)

N-[((L) -No-chlorophenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxyvaleramide (IX , The title compound was prepared in the same manner as in Example 22, except for using R ₁ = H).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.47 (dd, 3H), 2.55 (ddd, 1H), 2.75 (ddd, 1H),

3.48 (m, 3H), 4.63 (m, 1H), 6.15 (dd, 1H),

7.08 (t, 1 H), 7.29 (t, 2 H), 7.45 (m, 3 H),

7.58 (m, 4H), 7.70 (d, 2H), 7.97 (t, 2H),

8.60 (d, 1 H)

Example 26 N-[((L) -Nm-chlorophenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-carboxybaleric Preparation of Amides (I, R ₁ = H)

N-[((L) -Nm-chlorophenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxyvaleramide (IX , The title compound was prepared in the same manner as in Example 22, except for using R ₁ = H).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.47 (dd, 3H), 2.55 (ddd, 1H), 2.75 (ddd, 1H),

3.48 (m, 3H), 4.63 (m, 1H), 6.15 (dd, 1H),

7.07 (t, 1 H), 7.30 (t, 2 H), 7.45 (m, 3 H),

7.58 (m, 4H), 7.68 (d, 2H), 7.97 (t, 2H),

8.60 (d, 1 H)

Example 27 N-[((L) -Np-chlorophenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-carboxybaleric Preparation of Amides (I, R ₁ = H)

N-[((L) -No-chlorophenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxyvaleramide (IX , The title compound was prepared in the same manner as in Example 22, except for using R ₁ = H).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.47 (dd, 3H), 2.55 (ddd, 1H), 2.75 (ddd, 1H),

3.48 (m, 3H), 4.63 (m, 1H), 6.15 (dd, 1H),

7.08 (t, 1 H), 7.29 (t, 2 H), 7.45 (m, 3 H),

7.58 (m, 4H), 7.70 (d, 2H), 7.97 (t, 2H),

8.60 (d, 1 H)

Example 28 N- {1,5-dioxo-5-[(biphenyl-4-yl)]-3-carboxypentan-1-yl} -2- (N-phenylaminocarboxyl) pyrroli Preparation of Dean (IX, R ₁ = H)

N- {1,5-dioxo-5-[(biphenyl-4-yl)]-3-ethylcarboxypentan-1-yl} -2- (N-phenylaminocarboxy) pyrrolidine (IX , The title compound was prepared in the same manner as in Example 22, except for using R ₁ = H).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.90 (m, 1H), 2.06 (m, 1H), 2.58 (br, 2H),

2.70-3.00 (m, 2H), 3.50 (m, 2H), 3.57 (m, 2H),

3.70 (m, 1 H), 4.78 (m, 1 H), 7.05 (t, 1 H),

7.27 (m, 2H), 7.45 (m, 3H), 7.58 (m, 5H),

8.03 (d, 2H), 9.2 ~ 9.4 (d, 1H)

Example 29 N-[((L) -N-phenyl-3-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-car Preparation of Vacylvaleramide (IX, R ₁ = H)

N-[((L) -N-phenyl-3-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(biphenyl-4-yl) -3-ethylcarboxylic valeric The title compound was prepared in the same manner as in Example 22, except for using amide (IX, R ₁ = H).

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.38 to 2.55 (ddd, 1H), 2.70 (ddd, 1H),

3.20 (m, 2H), 3.45 (m, 3H), 4.75-4.90 (dq, 1H),

6.10-6.30 (dd, 1H), 7.08 (t, 1H), 7.24 (m, 6H),

7.42 (m, 4H), 7.63 (m, 5H), 8.00 (d, 2H),

7.90 8.30 (d, 1 H)

Example 30 N-[((L) -N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl) -3-car Preparation of Cyclovaleramide (I, R ₁ = Cl)

N-[((L) -N-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl) -3-ethylcarboxylic valeric The title compound was prepared in the same manner as in Example 22, except for using an amide (IX, R ₁ = Cl).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.47 (dd, 2H), 2.55 (ddd, 1H), 2.74 (ddd, 1H),

3.48 (m, 3H), 3.57 (dd, 1H), 4.65 (m, 1H),

6.25 (dd, 1H), 7.08 (t, 1H), 7.27 (m, 1H),

7.45 (d, 2H), 7.61 (m, 6H), 8.01 (t, 2H),

8.60 (d, 1 H)

Example 31 N- {1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl)]-3-carboxypentan-1-yl} -2- (N-phenylaminocar Preparation of Pyrrolidine (I, R ₁ = Cl)

N- {1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl)]-3-ethylcarboxypentan-1-yl} -2- (N-phenylaminocarboxyl) pi The title compound was prepared in the same manner as in Example 22, except using Ralidine (IX, R ₁ = Cl).

¹ H NMR (300 MHz, CDCl ₃ ): δ 1.90 (m, 1H), 2.06 (m, 1H), 2.58 (br, 2H),

2.70-3.00 (m, 2H), 3.50 (m, 2H), 3.57 (m, 2H),

3.70 (m, 1 H), 4.78 (m, 1 H), 7.05 (t, 1 H),

7.27 (m, 2H), 7.45 (m, 2H), 7.58 (m, 5H),

8.03 (d, 2H), 9.2 ~ 9.4 (d, 1H)

Example 32 N-[((L) -N-phenyl-3-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl) Preparation of -3-carboxyvaleramide (I, R ₁ = Cl)

N-[((L) -N-phenyl-3-phenylpropionamide-2-yl)]-1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl) -3-ethyl The title compound was prepared in the same manner as in Example 22, except for using carboxyvaleramide (IX, R ₁ = Cl).

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.38 to 2.55 (ddd, 1H), 2.70 (ddd, 1H),

3.20 (m, 2H), 3.45 (m, 3H), 4.75-4.90 (dq, 1H),

6.10-6.30 (dd, 1H), 7.07 (t, 1H), 7.26 (m, 6H),

7.45 (m, 3H), 7.56 (m, 5H), 7.99 (d, 2H),

7.90 8.30 (d, 1 H)

Example 33 N-[((L) -N-phenyl-3- (3 ', 4'-dioxolanphenyl) propionamide-2-yl)]-1,5-dioxo-5-[( Preparation of 4'-Chlorobiphenyl-4-yl) -3-carboxyvaleramide (I, R ₁ = Cl)

N-[((L) -N-phenyl-3- (3 ', 4'-dioxolanphenyl) propionamide-2-yl)]-1,5-dioxo-5-[(4'-chloro The title compound was prepared in the same manner as in Example 22, except for using rubiphenyl-4-yl) -3-ethylcarboxylic valericamide (IX, R ₁ = Cl).

¹ H NMR (300 MHz, CDCl ₃ ): δ 2.38-2.60 (ddd, 1H), 2.70 (ddd, 1H),

3.10-3.25 (m, 2H), 3.45 (m, 3H),

4.60-4.80 (dq, 1H), 5.89 (s, 2H),

6.10-6.30 (dd, 1H), 6.74 (m, 3H). 7.10 (t, 1 H),

7.26 (m, 2H), 7.45 (m, 3H), 7.61 (m, 5H),

7.99 (m, 2 H)

Example 34 N- {1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl)]-3-carboxypentan-1-yl} -3- (N-phenylaminocar Preparation of Compound) -1,2,3,4-tetrahydroisoquinoline (I, R ₁ = Cl)

N- {1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl)]-3-ethylcarboxypentan-1-yl} -3- (N-phenylaminocarboxyl)- The title compound was prepared in the same manner as in Example 22, except for using 1,2,3,4-tetrahydroisoquinoline (IX, R ₁ = Cl).

¹ H NMR (300 MHz, CDCl ₃ ): δ2.70 to 3.20 (m, 2H), 3.38 to 3.57 (m, 4H),

4.11 (m, 1 H), 4.66 (m, 2 H), 5.33 (d, 1 H),

6.92 (t, 1 H), 7.15 (m, 4 H), 7.45 (m, 7 H),

7.93 (d, 2 H), 8.66 (m, 1 H)

Example 35 Inhibition of Gelatinase A (MMP-2) in Vitro

This assay was performed using a fluoropeptide substrate ((7-methoxycoumarin-4-acetyl-Pro-Leu-Gly-Leu-β- (2,4-dinitrophenylamino) Ala-Ala-Arg-NH ₂ (Sigma Chem. Co., USA) )) Was performed by measuring the amount of fluorescence of the fluorescent substance (7-methoxycoumarin-4-acetyl-Pro-Leu-Gly) produced by cleaving gelatinase A (Boehringer Mannheim, cat # 1782916, from human fibrosarcoma cells). Enzyme reaction using fluorescence synthesis substrate was performed in 96-well plate with probe and TNBC (25 mM Tris-HCl, pH 7.5, 0.1M NaCl, 0.01% Brij-35, 5 mM CaCl ₂ ) buffer solution, 1 mM APMA ( gelatinase A (final concentration: 4.17 nM) activated with aminophenylmercuric acetate) at 37 ° C. for 30 minutes, and a fluorescent synthetic peptide (final concentration: 9.15 uM in a well) were added thereto, followed by reaction at 37 ° C. for 30 minutes. Fluorescence was measured at 328 nm of excitation and 393 nm of emission using a spectrofluorimeter (Fmax (molecular device)) equipped with a plate reader. From the reaction before the fluorescence amount (A) after the reaction and the fluorescence amount (B), after the reaction before the fluorescence amount (C) and the reaction raw unleavened an inhibitor fluorescence amount (D) of what put the inhibitor was calculated as:

Example 36 Inhibition of Gelatinase B (MMP-9) in Vitro

Using gelatinase B enzyme (Boehringer Mannheim cat # 1758896, From Human blood), the concentration of gelatinase B enzyme (final concentration in wells: 2.715 nM) and the concentration of the fluorescent fluorescent peptide as a substrate (final concentration in a well: 4.575 uM) Except for different), the inhibition rate of gelatinase B (MMP-9) in vitro was measured in the same manner as in Example 35.

Example 37 Inhibition of Collagenase (MMP-1) in Vitro

Using collagenase enzyme (AngioLab. Co.Ltd.) And collagenase enzyme concentration (final concentration in the well: 7.25nM), except collagen in vitro in the same manner as in Example 35 Inhibition rate of the first agent (MMP-1) was measured.

number R ₁ R ₂ R ₃ IC ₅₀ (μM) MMP-2 IC ₅₀ (μM) MMP-9 IC ₅₀ (μM) MMP-1 One Br (L) -Me Ph 0.018 0.3 2 H (D) -Me Ph 2.79 27.22 3 H (L) -Me Ph 0.08 3.21 4 H (L) -Me o-Cl-Ph 0.17 6.13 5 H (L) -Me m-Cl-Ph 0.13 3.65 6 H (L) -Me p-Cl-Ph 0.27 7.18 7 Cl (L) -Me Ph 0.015 0.22 8 H (L) -Ph Ph 0.037 0.28 9 Cl (L) -Ph Ph 0.007 0.099 80.31 10 Cl Ph 0.008 0.027

number R ₁ R ₂ IC ₅₀ (μM) MMP-2 IC ₅₀ (μM) MMP-9 IC ₅₀ (μM) MMP-1 One H 0.018 0.77 43.53 2 Cl 0.004 0.085 3 H 0.0062 0.11

The table compares substance is known to have inhibitory activity against MMP-2 as Bay12-9566 the IC ₅₀ 11nM, and the inhibitory activity against MMP-9 IC ₅₀ 301nM, selectivity 500 of MMP-1 / MMP-2 ( See Drugs of the Future, 24 (1): 16-21, 1999). Compared with the electrical comparative material which is reported to be the best so far, it can be seen that the compound of the present invention exhibits more excellent MMP inhibitory activity and exhibits MMP-1 / MMP-2 selectivity of 10000 times or more.

As described and demonstrated in detail above, the present invention provides a biphenyl butyric acid derivative compound, an isomer thereof, and a pharmaceutically acceptable salt thereof and a method for preparing the electrical substances that inhibit the action of MMP. The biphenyl butyric acid derivative compound of the present invention selectively inhibits the activity of MMP under in vitro conditions, and the MMP inhibitor containing the biphenyl butyric acid derivative as an active ingredient is characterized by overexpression and excessive activation of MMP. It may be useful for the prevention and treatment of various diseases caused.

Claims (6)

Compounds represented by the following general formula (I), isomers thereof and pharmaceutically acceptable salts thereof: Where R ₁ is hydrogen, C _1-12 alkyl, C _3-7 cycloalkyl, halogen, nitro, cyano, —OCF ₃ , , -OCH ₂ F, -OCH ₂ F, -OR ₁₀ , -SR ₁₀ , -S (O) R ₁₀ , or -S (O) _2, wherein R ₁₀ and R ₁₀ ^a Are the same or different from each other and are C _1-7 alkyl, C _1-7 aryl, C _1-7 arylalkyl, C _1-7 heteroaryl or C _3-7 cycloalkyl); R ₂ and R ₃ are the same as or different from each other, hydrogen, C _1-7 alkyl, C _1-7 aryl, C _1-7 arylalkyl, C _1-7 heteroaryl, C _1-7 hydroxyalkyl, C _{1 -7} alkoxyalkyl, C _1-7 alkylthioalkyl, C _1-7 arylthioalkyl, C _1-7 alkylsulfinylalkyl, C _1-7 alkylsulfonylalkyl, C _1-7 arylsulfinylalkyl, C _{1 -7} arylsulfonylalkyl or C _3-7 cycloalkyl; R ₄ and R ₅ are the same or different from each other and are hydrogen, C _1-7 alkyl, C _1-7 aryl, C _1-7 arylalkyl, C _1-7 heteroaryl or C _3-7 cycloalkyl; And, n is 1 or 2. The method of claim 1, R ₂ and R ₃ are connected to each other by carbon, nitrogen, oxygen or sulfur, When forming a ring, Creeper , , or Where R ₄ , R ₅ and n are defined by the general formula (I) Same as by; R ₆ is hydrogen, hydroxy, C _1-7 alkoxy, C _1-7 aryloxy, thiol or C _1-7 alkylthio; R ₇ is oxo, hydroxyoxo or C _1-7 alkoxyoxo; R ₈ and R ₉ are C _1-6 lower alkyl; And X is CH ₂ , O, or S). doing Compounds, isomers thereof and pharmaceutically acceptable salts thereof. The method of claim 1, To a compound represented by the following general formula (Ia), (Ib), (Ic) or (Id) Characterized in that it is selected from the configured group Compounds, Isomers thereof and their pharmaceutically acceptable salts: Where R ₁ , R ₄ , R ₅ and n are the same as defined in the general formula (I). delete (Iii) obtaining tertiary butyl ester (IV) from compounds (II) and (III); (Ii) a step of deprotecting the tert-butyl ester (IV) to obtain a compound (V); (Iii) condensation reaction of compound (V) with an amine to yield diethyl ester (VI); And, (Iii) hydrolyzing and decarboxylation of diethyl ester (VI) to produce compound (I). Method for preparing a compound of formula (I): Where R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as defined in the general formula (I). (Iii) selectively hydrolyzing only one ester in tert-butyl ester (IV) to decarboxylate to obtain compound (VII); (Ii) a step of deprotecting the compound (iii) to obtain the compound (iii); (Iv) condensation reaction of compound (iii) and amine to yield ethyl ester (iii); And, (Iii) hydrolyzing the ethyl ester (iii) to produce compound (I) Method for preparing a compound of formula (I): Where R ₁ , R ₂ , R ₃ , R ₄ and R ₅ are the same as defined in the general formula (I).