JP2003531894A - Biphenylbutyric acid derivatives as matrix metalloprotease inhibitors - Google Patents

Abstract

  (57) [Summary] The present invention provides novel biphenylbutyric acid derivatives, isomers thereof, pharmaceutically acceptable salts thereof, and methods for producing them, which are useful as inhibitors of matrix metalloproteases (MMPs). The biphenylbutyric acid derivative compound of the present invention selectively inhibits the activity of MMP in vitro, and is useful for preventing and treating various diseases induced by overexpression and excessive activation of MMP.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD OF THE INVENTION

The present invention relates to biphenyl butyric acid derivatives. More specifically, it relates to a novel biphenylbutyric acid derivative represented by the following general formula (I), a pharmaceutically acceptable salt thereof, and a method for producing the same, which is useful as a matrix metalloprotease inhibitor.

[0002]

[Chemical 10]

[0003]

[Prior art]

Matrix metalloproteinase (hereinafter "MMP")
) Is a calcium (Ca ²⁺ ) dependent protease containing zinc (Zn ²⁺ ) in the active site. To date, about 18 species are known in the art, including the family of stromelysin, collagenase and gelatinase. Under biological conditions, MMP decomposes various extracellular matrix components such as collagen, laminin, proteoglycan, pibronectin, elastin, gelatin, and joint tissue,
Causes bone tissue, connective tissue growth and tissue remodeling. MMP is TIMP (t
It is secreted in the form of an inactive precursor enzyme, along with a natural inhibitor known as an issue inhibitor of metalloproteinase, and then activated outside the cell.

On the other hand, MMP inhibitors are useful for preventing and treating various diseases caused by overexpression and excessive activation of MMP. Examples of the diseases, rheumatism, osteoarthritis, abnormal bone resorption, osteoporosis, periodontitis, nephritis nephritis, arteriosclerosis, emphysema, liver cirrhosis, corneal damage, tumor cell metastasis, invasion, or Growth, autoimmune diseases, vascular migration, or diseases caused by infiltration of leukocytes, arterial hematopoiesis (see B
eeley et al. , Curr. Opin. Ther. Patents, 4 (1): 7-16, 1994). For example, it was reported that the synthesized MMP inhibitor has an anti-cancer effect in vivo with an inhibitory effect on basement membrane remodeling in a murine model of ovarian cancer (see Cancer Res.
, 53: 2087, 1993). In particular, it is known that MMP-2 and MMP-9 among the MMP enzymes play an indispensable role at the angiogenesis stage which is essential for cancer cell growth (see: Biochim. Biophys. Acta, 695). , 1983), and among MMP enzymes, MMP-1 and MMP-3 are synovium and cartilage of rheumatoid arthritis patients.
(cartilage) was observed at a concentration much higher than the normal value, and the MMP-1 / M
MP-3 is known to play an important role in the progression of arthritis (see Arthri).
tis Rheum. , 35: 35-42, 1992), it is considered that selectivity for MMP-1 / MMP-2 plays an important role in reducing side effects such as joint pain. Therefore, recent research has focused on the development of selective inhibitors, and such MMP inhibitors have been multifaceted designed and synthesized (see J. Enzyme Inhibitor, 2: 1-22).
, 1987; Current Medicinal Chemistry, 2: 743-762, 1995; Progress in Medici
nal 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
Drugs of the Future 2000, 25 (6), 551-557; Exp. Opin. Invest. Drugs, 20
00, 2167-2177).

Several compounds are known to have inhibitory activity against MMPs. Typically,
They are zinc-binding groups that coordinate to the zinc ion of the MMP enzyme at their active site.
(zinc binding group, ZBG). As such ZBG, hydroxamic acid, carboxylic acid, phosphoric acid, phosphinic acid, thiol and the like are known (see: WO 92/09564; WO 95/04033; WO 00/04030).
WO 00/43404; WO 95/13289; WO 96/11209; WO 95/09834; WO 95/09620; WO 0
0/40577; WO 00/40600; WO 98/03166; Chem. Rev. , 99: 2735-2776, 1999). In particular, various succinic acid derivatives have been synthesized as peptide-like inhibitors based on the substrate skeleton (see: WO 99/25693; WO 90/05719; WO 94/02446; WO 95/09841; WO 95
/ 19956; WO 95/19957; WO 95/19961; WO 96/06074; WO 96/16931; WO 98/43959;
WO 98/24759; WO 98/30551; WO 98/30541; WO 97/32846; WO 99/01428; EP 897
908; WO 98/38179; JP 95-002797; WO 99/18074; WO 99/19296; EP 641323). Such peptide-like inhibitors have hydroxamic acid as ZBG and show a broad spectrum for MMPs. However, some peptide-like inhibitors are known to cause joint pain as a side effect in clinical trials.
(Reference: Current Pharmaceutical Design, 5: 787-819, 1999; Current Opinion i
n Drug Discovery & Development, 3: 353-361, 2000). In addition, the above peptide-like inhibitors also have problems such as low oral absorption rate and low MMP-1 / MMP-2 selectivity (see: Drugs of the Future, 21 (12): 1215). -1220, 1996).

In 1994, a non-peptidic inhibitor was developed to solve the problems of the peptide-like inhibitor. These are completely different in chemical structure from the peptide-like inhibitors and are represented by simple sulfonyl amino acid derivatives as shown below (see USP 5,
506, 242; Med. Chem. , 40: 2525-2532, 1997).

[0007]

[Chemical 11] Small molecules of sulfonamide derivative MMP inhibitors exhibit MMP enzyme activity inhibitory activity in vitro and are considered to have various advantages as compared with the peptide analog inhibitors, and various sulfonamide inhibitors have been synthesized, Reported (Ref: WO 98/503
48; WO 97/20824; WO 00/09485; WO 99/58531; WO 99/51572; WO 99/52889; WO
99/52910; WO 99/37625; WO 98/32748; WO 99/18076; WO 99/06410; WO 99/0767
5; WO 98/27069; WO 97/22587; EP 979816; EP 895988; EP 878467; EP 1041072
). A novel sulfonamide derivative was devised by converting the P1 ′ portion of the sulfonamide inhibitor that binds to the S1 ′ subsite of the enzyme for the purpose of improving enzyme activity, selectivity and pharmacokinetic profile in vitro. , Synthesized.

The sulfonamide inhibitor has a relatively high MMP activity inhibitory effect in vitro, but the selectivity for MMP-1 / MMP-2 is not high as compared with conventional peptide analog inhibitors. Some of them have reported side effects of joint pain in clinical trials (see Current Pharmaceutical Design, 5: 787-819, 1999; Current Opi).
nion in Drug Discovery & Development, 3: 353-361, 2000; Exp. Opin. Invest
． Drugs, 9: 2159-2165, 2000; SCRIP, 2467: 19, 1999; Drugs of the Future, 2
4 (1): 16-21, 1999). Further, sulfonamide inhibitors having hydroxamic acid as ZBG generally show extremely strong in vitro inhibitory activity as compared with sulfonamide inhibitors having carboxylic acid as ZBG, but in vivo absorption and metabolic stability (metabolic stability) Due to its low stability, there is a limit to its use for oral use (Ref: J. Med. Chem., 41: 640-649, 1988; Investigational New Dru.
gs, 16: 303-313, 1999; Exp. Opin. Ther. Patents, 10: 111-115, 2000; WO 00
/ 63194; WO 00/27808; WO 99/18079; USP 6,117,869).

In order to solve the above-mentioned problems, 3-oxo-3-biphenylbutyric acid (3-oxo-3) containing a butyric acid group as described below is used as another non-peptidic inhibitor having enhanced selectivity. -
A derivative of biphenylbutyric acid) was found (see: WO 96/15096).

[0010]

[Chemical 12] The above-mentioned inhibitors have much lower in vitro MMP inhibitory activity than the peptide-like succinic acid derivatives and sulfonylamino acid derivatives, but the selectivity of MMP-1 / MMP-2 is extremely high, and the inhibitor is very effective in clinical experiments. Almost no side effects such as pain were observed
(Reference: Drugs of the Future, 24 (1): 16-21, 1999). In order to solve the problems of the inhibitors, various biphenylbutyric acid derivatives have been devised and reported as MMP inhibitors (see USP 5,789,434; USP 5,854,277; USP 5,859, 047; USP 5
, 861, 427; USP 5, 861, 428; USP 5, 874, 473; USP 5, 886, 022; USP 5, 88
6, 024; USP 5,886, 043).

Another butyric acid derivative having the following structural formula was also reported.
The P inhibitory activity was significantly inferior (Ref: WO 98/09940; WO 98/06711).

[0012]

[Chemical 13] Under these circumstances, it has been strongly desired to develop a surrogate compound that enhances MMP inhibitory activity and MMP-1 / MMP-2 selectivity to reduce side effects.

[0013]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The inventors of the present invention have conducted diligent research as a result of developing a novel compound having enhanced MMP inhibitory activity and selectivity for MMP-1 / MMP-2 to reduce side effects. It was found that the newly synthesized biphenylbutyric acid derivative selectively inhibits MMP activity in vitro.

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

[0015]   Another object of the present invention is to provide a method for producing said derivative.

[0016]

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a biphenylbutyric acid derivative compound which inhibits the action of MMP represented by the following general formula (I), isomers thereof and pharmaceutically acceptable salts thereof, and a method for producing the substance.

[0017]

[Chemical 14] In the formula, R ₁ is hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano, or
OCF ₃ , -OCH ₂ F,

[Chemical 15] -OR ₄ , -SR ₄ , -S (O) R ₄ or -S (O) ₂ (provided that R ₄ and R ₄ ^a may be the same or different, alkyl, allyl, allylalkyl, heteroaryl) R ₂ and R _{3, which} may be the same or different, are hydrogen, alkyl, allyl, allylalkyl, heteroaryl or cycloalkyl; and n is 1 or 2.

In the above formula, R ₂ and R ₃ may be connected to each other by carbon, nitrogen, oxygen or sulfur to form a C _5-6 ring, and include the following structures.

[0019]

[Chemical 16] Wherein R ₈ is hydrogen, alkyl, allyl, allylalkyl, heteroaryl, or cycloalkyl; and X is 0 or S. In addition, when R ₃ is hydrogen, R ₂ may further include a substituent represented by the following structural formula:

[Chemical 17] Wherein R ₅ is hydrogen, alkyl, allyl, allylalkyl, heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, allylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, allylsulfinylalkyl, allylsulfonylalkyl or cycloalkyl. And R ₆ and R _{7, which} may be the same or different, are hydrogen, alkyl, allyl, allylalkyl, heteroaryl or cycloalkyl.

When R ₃ is not hydrogen, R ₃ and R _{5 in} the above formula (I) can be linked with carbon, nitrogen, oxygen or sulfur to form a C _5-6 ring,

[Chemical 18] The portion shown by has the following structure.

[0021]

[Chemical 19] R ₆ and R ₇ are as defined above; R ₉ is hydrogen, hydroxy, alkoxy, allyloxy, thiol or alkylthio; R ₁₀ is oxo, hydroxyamine or hydrazone; R ₁₁ and R ₁₂ Is hydrogen or C _1-6 lower alkyl; and Y is CH ₂ , 0 or S.

In addition, R ₆ and R ₇ may be linked by carbon, nitrogen, oxygen or sulfur to form a C _5-6 ring, and specifically include the following structures.

[0023]

[Chemical 20] In the formula, R ₈ and X are as described above.

Unless otherwise stated, all isomers of the biphenylbutyric acid derivative compounds are included within the scope of the present invention.

The pharmaceutically acceptable salts of the present invention include acid addition salts and hydrated salts. The compound of the general formula (I) of the present invention can be converted into a corresponding salt, but an alkali metal salt (sodium, potassium etc.), an alkaline earth metal salt (calcium, magnesium etc.), an ammonium salt, a pharmaceutical organic amine Non-toxic salts and water-soluble salts of The compound of the general formula (I) of the present invention is a salt of an inorganic acid (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), a salt of an organic acid (acetate, lactate, It can be converted into the corresponding acid addition salt, such as tartarate, oxalate, fumarate, glucuronate, etc., but non-toxic and water-soluble salts are preferred. The compounds of general formula (I) and salts thereof of the present invention can be converted into the corresponding hydrates by methods known in the art.

Two processes for producing the compound of general formula (I) are shown by the following steps.
First, the compound can be prepared by the following step 1.

Manufacturing method 1:

[Chemical 21] In the formula, R ₁ , R ₂ and R ₃ are as described above.

Step 1: Synthesis of t-butyl ester (IV): Reaction of compound (II) with compound (III) to obtain t-butyl ester (IV): where:
Compound (II) may be a commercially available product or may be produced by a known method.
(III) can be produced by partially modifying a known method (see: BS Furniss, et al.,
VOGEL's Textbook of Practical Organic Chemistry, 5th ed. , Pp942-943, 19
88; WO 96/15096).

Second step: Synthesis of compound (V): Compound (V ) obtained by deprotecting the above t-butyl ester (IV) without a butyl ester group.
To get At this time, the deprotection group reaction is preferably performed using TFA or anhydrous HCl.

Step 3: Synthesis of compound (VI): The compound (V) is condensed with an amine compound to give a compound having a diethyl ester group (
VI). At this time, the amine compound contains the R ₂ and R ₃ groups defined above, and the condensation with the amine compound is carried out by the acid chloride method, the active ester (active ester) method.
ster method, mixed anhydride method and the like.

Fourth Step: Synthesis of Compound (I) The diethyl ester group of the compound (VI) is hydrolyzed to carboxylic acid and decarboxylated to produce compound (I).

[0032]   The compound of the general formula (I) can also be produced according to the following production method 2.

Process 2:

[Chemical formula 22] In the formula, R ₁ , R ₂ and R ₃ are as described above.

First step: Synthesis of t-butyl ester (IV) Compound (II) is reacted with compound (III) to obtain t-butyl ester (IV): Here, compound (II) is commercially available Compound (III) may be purchased or may be produced by a known method, and the compound (III) can be produced by partially modifying the known method (see: BS Furn
iss, et al. , VOGEL's Textbook of Practical Organic Chemistry, 5th ed.
, Pp942-943, 1988; WO 96/15096).

Second step: Synthesis of compound (VII) One ethyl ester in the above t-butyl ester (IV) is hydrolyzed to a carboxyl group and decarboxylated to obtain compound (VII): here The hydrolysis is carried out in the presence of a base, and the decarboxylation reaction is carried out in the presence of an organic solvent. The base is not particularly limited, but it is desirable to use 1 equivalent of KOH / EtOH. It is desirable to use 1,4-dioxane.

Third step: Synthesis of compound (VIII): The compound (VII) is deprotected to obtain a compound (VIII) having no butyl ester group:
Here, the deprotection group reaction is preferably performed using TFA or anhydrous HCl.

Step 4: Synthesis of compound (IX) The compound (VII) is condensed with an amine compound to obtain a compound (IX) having an ethyl ester group: where the amine compound is R as defined above. ₂ and R ₃ groups, the condensation method of the amine is an acid chloride method, an active ester method.
Although various methods such as the ster method and the mixed anhydride method can be used, it is most preferable to use the active ester method. Fifth step: Synthesis of compound (I) Compound (I) is produced by hydrolyzing the ethyl ester group of compound (IV) to a carboxyl group (see WO 96/15096).

[0038]

【Example】

Hereinafter, the present invention will be described in more detail with reference to Examples, but the scope of the present invention is not limited to these Examples.

Example 1: Preparation of 5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R ₁ = H) NaH (95 %, 505 mg, 20.0 mmol) and high-purity THF (15 m
L) was added and the mixture was cooled to -10 ° C. To this, diethyl t- dissolved in THF (10 mL)
Butoxycarbonylmethylmalonic acid (III, 4.9 g, 18.17 mmol) was added slowly and stirred for 30 minutes at room temperature. 4-Phenyl-α-bromoacetophenone (II, R ₁ = H, 5 g, 18.17 mmol) dissolved in THF (15 mL) was slowly added thereto, and the mixture was stirred at room temperature for 1 hour and a half, and then a 1N HCl solution ( It was extracted with 30 mL) and ethyl acetate (30 mL). The organic layer was washed with water (10 mL), anhydrous MgSO ₄ was added, the mixture was stirred for 5 min, filtered and distilled under reduced pressure to give the title compound (8.65 g, 95%).

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (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: 5- (4'-methoxybiphenyl Preparation of 4- (4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R ₁ = OMe) 4- (4′-methoxyphenyl) -α-bromoacetophenone (II, The title compound was prepared in the same manner as in Example 1, except that R ₁ = OMe) was used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 6H), 1.38 (s, 9H), 3.21 (s, 2H), 3.86 (s
, 3H), 3.94 (s, 2H), 4.24 (q, 4H), 7.0 (d, 2H), 7.58 (d, 2H), 7.65 (d, 2H), 8
.02 (d, 2H) Example 3: 5- (4'-Bromobiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid
Preparation of t-butyl ester (IV, R ₁ = Br) A method similar to that of Example 1 except using 4- (4′-bromophenyl) -α-bromoacetophenone (II, R ₁ = Br). The title compound was prepared in.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (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 4: 5- (4'-chlorobiphenyl -4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid
Preparation of t-butyl ester (IV, R ₁ = Cl) By the same method as in Example 1 except 4- (4′-chlorophenyl) -α-bromoacetophenone (II, R ₁ = Cl) was used. The title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.25 (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 5: 5- (biphenyl-4-yl) ) -5-Oxo-3,3-diethoxycarbonylvaleric acid (V, R ₁ = H)
Preparation of 5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R ₁ = H, 1.5 g, 3.2 mmol) in methylene chloride After dispersing in (20 mL), TFA (2 mL) was added, the mixture was stirred at room temperature for 24 hours, and then MC was removed under reduced pressure. To this, add ethyl acetic acid (20 mL), slowly add 1N NaOH solution,
After stirring for 10 minutes, it was extracted with water. A 1N HCl solution (30 mL) was added to this, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered and distilled under reduced pressure to give the title compound (1
． 2g, 91%) was produced.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 6H), 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 6: 5- (4'-methoxybiphenyl-4-yl) -5 Preparation of 5-oxo-3,3-diethoxycarbonylvaleric acid (V, R ₁ = OMe) 5- (4′-methoxybiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid t The title compound was prepared in a similar manner to Example 5 except using -butyl ester (IV, R ₁ = OMe).

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 6H), 3.21 (s, 2H), 3.86 (s, 3H), 3.94 (s
, 2H), 4.24 (q, 4H), 7.0 (d, 2H), 7.58 (d, 2H), 7.65 (d, 2H), 8.02 (d, 2H) Example 7: 5- (4'-bromobiphenyl l-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid
Preparation of (V, R ₁ = Br) 5- (4′-bromobiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R ₁ = Br) The title compound was prepared in the same manner as in Example 5 except that it was used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (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 8: N-phenyl-5- (biphenyl-4-yl) -5 Preparation of 5-oxo-3,3-diethoxycarbonylvaleric acid amide (VI, R ₁ = H) 5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid (V, R ₁ =
H, 0.5 g, 1.2 mmol), EDC (0.23 g, 1.2 mmol) and HOBt (0.16 g, 1.2)
mmol) was dissolved in MC (5 mL) and then cooled to 0 ° C. TEA (170mL, 1.2
(mmol) and stirred for 10 minutes, aniline (122 mL, 1.3 mmol) was added, and the mixture was stirred again at room temperature for 2 hours and a half. After adding 1N HCl solution to this and extracting with MC, it was dried with anhydrous MgSO ₄ , filtered and distilled under reduced pressure, and column chromatography (Hx / EA = 4/1).
The title compound (0.365 g, 62%) was prepared by purification.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 6H), 3.32 (s, 2H), 4.05 (s, 2H), 4.24 (q
, 4H), 7.07 (t, 1H), 7.26 (m, 1H), 7.45 (m, 5H), 7.65 (m, 5H), 8.04 (d, 2H) Example 9: N-cyclopropyl-5- ( Preparation of biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid (VI, R ₁ = H) 5- (biphenyl-4-yl) -5-oxo-3,3-diethoxy Carbonylvaleric acid (V, R ₁ =
The title compound was prepared in the same manner as in Example 8 except that H) and cyclopropylamine were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ0.41 (m, 2H), 0.69 (m, 2H), 2.62 (m, 1H), 3.08 (s
, 2H), 4.00 (s, 2H), 4.24 (q, 4H), 5.9 (s, 1H), 7.45 (m, 3H), 7.61 (d, 2H), 7
.69 (d, 2H), 8.04 (d, 2H) Example 10: N- (α-methylbenzyl) -5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid Preparation of amide (VI, R ₁ = H) (VI) 5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid (V, R ₁ =
The title compound was prepared in the same manner as in Example 8 except that H) and α-methylbenzylamine were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 6H), 1.41 (d, 3H), 3.17 (d, 2H), 3.97 (d
, 2H), 4.21 (q, 4H), 5.0 (m, 1H), 5.95 (d, 1H), 7.19 (m, 5H), 7.46 (m, 3H), 7
.61 (d, 2H), 7.67 (d, 2H), 8.04 (d, 2H) Example 11: N-phenyl-5- (4'-methoxybiphenyl-4-yl) -5-oxo-3,3 -Preparation of diethoxycarbonylvaleric acid amide (VI, R ₁ = OMe) 5- (4'-methoxybiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid (V, R ₁ = The title compound was prepared in the same manner as in Example 8 except that OMe) and aniline were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 6H), 3.34 (s, 2H), 3.86 (s, 3H), 4.04 (s
, 2H), 4.24 (q, 4H), 7.0 (d, 2H), 7.05 (t, 1H), 7.26 (t, 2H), 7.44 (d, 2H), 7
.54 (d, 2H), 7.62 (d, 2H), 8.02 (d, 2H) Example 12: N- [1,5-dioxo-5- (4'-methoxybiphenyl-4-yl) -3, Preparation of 3-diethoxycarbonylpentan-1-yl] -4-methylpiperazine (VI, R ₁ = OMe) (VI) 5- (4′-methoxybiphenyl-4-yl) -5-oxo-3,3 The title compound was prepared in the same manner as in Example 8 except that -diethoxycarbonylvaleric acid (V, R ₁ = OMe) and N-methylpiperazine were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 6H), 2.30 (s, 3H), 2.34 (br, 4H), 3.35 (
s, 2H), 3.55 (br, 4H), 3.86 (s, 3H), 4.10 (s, 2H), 4.24 (q, 4H), 7.0 (d, 2H),
7.58 (d, 2H), 7.65 (d, 2H), 8.02 (d, 2H) Example 13: N- [1,5-dioxo-5- (4'-bromobiphenyl-4-yl) -3,3 Preparation of -diethoxycarbonylpentan- ₁ -yl] piperazine (VI, R ₁ = Br) 5- (4′-bromobiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid (V , R ₁ = Br) and piperidine were used to produce the title compound in the same manner as in Example 8.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 6H), 2.85 (Br, 4H), 3.37 (s, 2H), 3.64 (
br, 4H), 4.00 (s, 2H), 4.26 (q, 4H), 7.48 (d, 2H), 7.59 (d, 2H), 7.66 (d, 2H)
, 8.04 (d, 2H) Example 14: N- [1,5-dioxo-5- (4'-bromobiphenyl-4-yl) -3,3-diethoxycarbonylpentan-1-yl] -4- Preparation of benzopiperazine (VI, R ₁ = Br) N-benzopiperazine (Ref: Kondo, K. et al, J. Chem. Soc, Perkin Trans 1
, 1998, 2973-2974) and 5- (4′-bromobiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid (V, R ₁ = Br), except that The title compound was prepared in the same manner as in Example 8.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 6H), 3.18 (s, 2H), 3.54 (br, 4H), 3.75 (
br, 4H), 4.00 (s, 2H), 4.24 (q, 4H), 7.40 (m, 4H), 7.42 (d, 2H), 7.62 (m, 4H)
, 7.86 (d, 1H), 8.02 (d, 2H) Example 15: 1,5-dioxo-1- (1-phenylcarbamoyl-1-ethylamino) -5- (4'-bromobiphenyl-4-yl ) -3,3-Diethoxycarbonylpentane (VI, R ₁ = Br) 5- (4′-bromobiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid (V, R ₁ = Br, 140 mg, 0.285 mmol), EDC (60 mg, 0.313 mmol) and HOBt
(42.4 mg, 0.313 mmol) was dissolved in MC (5 mL) and cooled to 0 ° C. TE
A (44.3 mL, 0.313 mmol) was added and the mixture was stirred for 10 minutes, then L-Ala-CONH-Ph (56 mg, 0.
(342 mmol) was added and the mixture was stirred 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, v / v) to give the title compound (120 mg , 69%
) Was manufactured.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (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, 1H), 6.15 (d, 1H), 7.07 (t, 1H),
7.27 (m, 1H), 7.45 (d, 2H), 7.58 (m, 6H), 7.97 (d, 2H), 8.60 (s, 1H) Example 16: N-phenyl-5- (biphenyl-4-yl) ) -5-Oxo-3-carboxyvaleramide (I, R
₁ = H) N-Phenyl-5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleramide (VI, R ₁ = H, 0.36 g, 0.74 mmol) Was dissolved in ethanol (10 mL), 1N NaOH (1.55 mL, 1.55 mmol) was added, and the mixture was stirred at room temperature for 2 hours. After removing ethanol under reduced pressure, water was added and the mixture was washed with ethyl acetate. Then 1 NH
Acidified with Cl solution and extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered,
It was distilled under reduced pressure. The obtained material was dissolved in 1,4-dioxane (dioxane, 10 mL) and then heated under reflux for 3 hours to remove the solvent under reduced pressure. The residue was added to MC / MeOH solution (19/1
, V / v) and hexane to give the title compound (0.17 g, 60%).

¹ H NMR (300 MHz, CDCl ₃ ): δ2.76 (dd, 1H), 2.90 (dd, 1H), 3.42 (dd, 1H), 3.4
9 (m, 1H), 3.58 (dd, 1H), 7.10 (t, 1H), 7.26 (m, 1H), 7.45 (m, 5H), 7.65 (m, 5
H), 8.07 (d, 2H) Example 17: Preparation of N-cyclopropyl-5- (biphenyl-4-yl) -5-oxo-3-carboxylic valeramide (I, R ₁ = H) N- By a method similar to that in Example 16 except that cyclopropyl-5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleramide (VI, R ₁ = H) was used. The title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ 0.47 (m, 2H), 0.73 (m, 2H), 2.48 (dd, 1H), 2.68 (
m, 2H), 3.39 (m, 2H), 3.54 (dd, 1H), 7.40 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H)
, 8.02 (d, 2H) Example 18: Preparation of N- (α-methylbenzyl) -5- (biphenyl-4-yl) -5-oxo-3-carboxyvaleric acid (I, R ₁ = H) N Example 16 except that-(α-methylbenzyl) -5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleramide (VI, R ₁ = H) was used. The title compound was prepared in a similar manner to.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.44 (d, 3H), 2.48 (dd, 1H), 2.68 (m, 2H), 3.39 (
m, 2H), 3.54 (dd, 1H), 4.98 (m, 1H), 7.40 (m, 3H), 7.61 (d, 2H), 7.69 (d, 2H)
, 8.02 (d, 2H) Example 19: Preparation of N-phenyl-5- (4'-methoxybiphenyl-4-yl) -5-oxo-3-carboxylic valeric acid (I, R ₁ = OMe) N- By a method similar to that in Example 16, except that phenyl-5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleramide (VI, R ₁ = OMe) was used. The compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ2.70 (dd, 1H), 2.91 (dd, 1H), 3.40 (dd, 1H), 3.4
9 (m, 1H), 3.55 (dd, 1H), 3.84 (s, 3H), 6.98 (d, 2H), 7.06 (t, 1H), 7.30 (m, 2
H), 7.50 (m, 4H), 7.62 (d, 2H), 8.01 (d, 2H) Example 20: N- [1,5-dioxo-5- (4'-methoxybiphenyl-4-yl)- 3-carboxypentane-1
-Yl] -4-Methylpiperazine (I, R ₁ = OMe) (VI) N- [1,5-dioxo-5- (4′-methoxybiphenyl-4-yl) -3,3-diethoxy The title compound was prepared in the same manner as in Example 16 except that carbonylpentan-1-yl] -4-methylpiperazine (VI, R ₁ = OMe) was used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.20 (s, 3H), 2.45 (s, 1H), 2.65 (m, 4H), 2.82 (d
d, 1H), 3.28 (dd, 1H), 3.39 (br, 4H), 3.65 (dd, 1H), 3.84 (s, 3H), 4.13 (m, 1
H), 6.98 (d, 2H), 7.54 (d, 2H), 7.62 (d, 2H), 8.00 (d, 2H) Example 21: N-phenyl-5- (4'-bromobiphenyl-4-yl) ) -5-Oxo-3-carboxyl valeric acid (
I, R ₁ = OMe) (I) N-phenyl-5- (4′-bromobiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleramide (VI, R ₁ = The title compound was prepared in the same manner as in Example 16 except that Br) was used.

¹ H NMR (300 MHz, CDCl ₃ + DMSO): δ2.73 (dd, 1H), 2.89 (dd, 1H), 3.33 (dd, 2H)
, 3.55 (m, 1H), 7.05 (t, 1H), 7.28 (t, 2H), 7.52 (m, 6H), 7.65 (d, 2H), 8.04 (
d, 2H) Example 22: N- [1,5-dioxo-5- (4'-bromobiphenyl-4-yl) -3-carboxylpentane-1
-Yl] Preparation of piperazine (I, R ₁ = Br) N- [1,5-dioxo-5- (4′-bromobiphenyl-4-yl) -3,3-diethoxycarbonylpentan-1-yl] Example 1 except using piperazine (VI, R ₁ = Br)
The title compound was prepared in a similar manner to 6.

¹ H NMR (300 MHz, CDCl ₃ ): δ2.85 (Br, 4H), 3.37 (m, 2H), 3.64 (br, 4H), 4.00
(m, 2H), 4.13 (m, 1H), 7.48 (d, 2H), 7.59 (d, 2H), 7.66 (d, 2H), 8.04 (d, 2H) Example 23: N- [1, 5 -Dioxo-5- (4'-bromobiphenyl-4-yl) -3-carboxylpentane-1
-Yl] -4-benzylpiperazine (I, R ₁ = Br) N- [1,5-dioxo-5- (4′-bromobiphenyl-4-yl) -3,3-diethoxycarbonylpentane-1- The title compound was prepared in the same manner as in Example 16 except that [Ill] -4-benzoylpiperazine (VI, R ₁ = Br) was used.

¹ H NMR (300 MHz, CDCl ₃ ): δ2.59 (dd, 1H), 2.86 (br, 4H), 3.10 (dd, 1H), 3.4
2 (dd, 2H), 3.62 (Br, 4H), 3.80 (m, 1H), 7.40 (m, 4H), 7.42 (d, 2H), 7.62 (m,
4H), 7.86 (d, 1H), 8.02 (d, 2H) Example 24: 1,5-dioxo-1- (1-phenylcarbamoyl-1-ethylamino) -5- (4'-bromobiphenyl-4 -Yl) -3-Carboxylpentane (I, R ₁ = Br) Preparation 1,5-dioxo-1- (1-phenylcarbamoyl-1-ethylamino) -5- (4′-bromobiphenyl-4-yl) ) -3,3-Diethoxycarbonylpentane (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, water was added, and the mixture was washed with ethyl acetate. This was acidified with a 1N HCl solution, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure. The obtained substance was dissolved in 1,4-dioxane (dioxane, 10 mL) and heated under reflux for 2 hours, and then the solvent was removed under reduced pressure. The obtained material was recrystallized from MC / MeOH solution (19/1, v / v) and hexane to give the title compound (64 mg, 60%).

¹ H NMR (300 MHz, CDCl ₃ ): δ1.43 (d, 3H), 3.06 (d, 1H), 3.17 (d, 1H), 3.40 (d
d, 1H), 3.53 (m, 3H), 4.56 (m, 1H), 6.15 (d, 1H), 7.07 (t, 1H), 7.27 (m, 1H), 7.45 (d, 2H), 7.58 (m , 6H), 7.97 (d, 2H), 8.60 (s, 1H) Example 25: 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid t-butyl ester ( VII, R ₁ = Cl) 5- (4′-chlorobiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R ₁ = Cl, 5. To ethanol (30 mL) in which 26 g, 10.46 mmol) was dissolved, ethanol (30 mL) in which KOH (85%, 0.72 g, 11.0 mmol) was dissolved was slowly added. The reaction mixture was stirred at room temperature for 6 hours, acidified with 1N HCl solution, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered and evaporated under reduced pressure. The obtained material was dissolved in 1,4-dioxane (10 mL), heated under reflux for 3 hours, and the solvent was removed under reduced pressure to give the title compound (3.51 g, 78%).

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (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, 2
H), 7.65 (m, 2H), 8.03 (d, 2H) Example 26: 5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid t-butyl ester (VII, R ₁ = Preparation of H) and Example 25 except that 5- (biphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R ₁ = H) was used. The title compound was prepared in a similar manner.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 3H), 1.45 (s, 9H), 2.66 (ddd, 2H), 3.2
4 (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 27: 5- (4'-bromobiphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid t-butyl ester (VII , R ₁ = Br) 5- (4′-bromobiphenyl-4-yl) -5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R ₁ = Br) is used The title compound was prepared in the same manner as in Example 25 except for the above.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (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), 7.48 (d, 2H), 7.60 (d, 2
H), 7.65 (d, 2H), 8.04 (d, 2H) Example 28: 5- (4'-chlorobiphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII
, R ₁ = Cl) 5- (4′-chlorobiphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid t-
Butyl ester (VII, R ₁ = Cl, 3.51 g, 8.14 mmol) was dispersed in MC (50 mL), TFA (7.4 mL) was added, and the mixture was stirred at room temperature for 24 hours. The MC was removed under reduced pressure, ethyl acetate (20 mL) was added, 1N NaOH solution was slowly added, and the mixture was stirred for 10 minutes and then extracted with water. A 1N HCl solution (30 mL) was added thereto, extracted with ethyl acetate, dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure. The residue was recrystallized from CHCl ₃ and hexane to give the title compound (2.7 g, 88%).

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H), 3.4
8 (m, 1H), 3.57 (dd, 1H), 4.18 (q, 2H), 7.42 (d, 2H), 7.55 (d, 2H), 7.65 (m, 2
H), 8.03 (d, 2H) Example 29: 5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ = H)
Preparation of 5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid t-butyl ester ((VII, R ₁ = H)) In a similar manner to that of Example 28 except for using. The title compound was prepared.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H), 3.4
8 (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 30: 5- (4'-bromobiphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII
, R ₁ = Br) 5- (4′-bromobiphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid t-
The title compound was prepared in a similar manner to Example 28, except that butyl ester ((VII, R ₁ = Br) was used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 3H), 2.84 (ddd, 2H), 3.30 (dd, 1H), 3.4
8 (m, 1H), 3.57 (dd, 1H), 4.18 (q, 2H), 7.48 (d, 2H), 7.60 (d, 2H), 7.65 (d, 2
H), 8.04 (d, 2H) Example 31: N- (3-cyanophenyl) -5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleramide (IX, R ₁ = H ) 5- (Biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ = H
, 50 mg, 0.147 mmol) was dissolved in THF (3 mL) and cooled to 0 ° C. To this was added N-methylmorpholine (35 mL, 0.323 mmol) and ethyl chloroformate (16 mL, 0
． (162 mmol) was added and the mixture was stirred for 30 minutes, THF (1 mL) in which 3-aminobenznitrile was dissolved was added, the mixture was stirred at room temperature for 3 hours and a half, filtered, and distilled under reduced pressure. This was diluted with chloroform, washed successively with 1N HCl solution, 10% NaHCO ₃ solution and water, dried over anhydrous MgSO ₄ , filtered and distilled under reduced pressure to give the title compound (55.5).
mg, 86%).

¹ H NMR (300 MHz, CDCl ₃ ): δ1.22 (t, 3H), 2.74 (dd, 1H), 3.01 (dd, 1H), 3.54
(m, 3H), 4.22 (q, 2H), 7.42 (m, 4H), 7.65 (m, 5H), 8.01 (m, 3H), 8.20 (s, 1H) Example 32: N- (3-acetyl Phenyl) -5-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleramide (IX, R ₁ = H) (IV) 5- (biphenyl-4-yl) -5 -Oxo-3-ethoxycarbonylvaleric acid ((VIII, R ₁ = H
) And 3-aminoacetophenone were used to prepare the title compound in the same manner as in Example 31.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.23 (t, 3H), 2.59 (s, 3H), 2.80 (dd, 1H), 3.00 (
dd, 1H), 3.56 (m, 3H), 4.20 (q, 2H), 7.40 (m, 4H), 7.60 (m, 5H), 8.03 (m, 3H)
, 8.20 (s, 1H) Example 33: N- (3-acetylphenyl) -5-[(4'-chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid (IX, R _{1 [} = Cl) 5-[(4'-chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid (V
III, R ₁ = Cl) and using 3-aminoacetophenone.
The title compound was prepared in the same manner as in 1.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 3H), 2.60 (s, 3H), 2.80 (dd, 1H), 2.94 (
dd, 1H), 3.56 (m, 3H), 4.20 (q, 2H), 7.44 (m, 3H), 7.54 (d, 2H), 7.66 (m, 3H)
, 7.82 (s, 1H), 8.04 (m, 3H) Example 34: N- (2-chlorophenyl) -5-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid (IX , R ₁ = H) 5-(-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid (VIII, R
_The title compound was prepared in the same manner as in Example 31, except that ₁ = H) and 2-chloroaniline were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.24 (t, 3H), 2.88 (dd, 1H), 3.03 (dd, 1H), 3.48
~ 3.66 (m, 3H), 4.24 (q, 2H), 7.05 (t, 1H), 7.43 (m, 4H), 7.62 (d, 2H), 7.70 (d
, 2H), 7.90 (s, 1H), 8.06 (d, 2H), 8.30 (s, 1H) Example 35: N- (3-chlorophenyl) -5-[(biphenyl-4-yl)]-5- Preparation of oxo-3-ethoxycarbonylvaleramide (IX, R ₁ = H) 5-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ = H)
The title compound was prepared in the same manner as in Example 31, except that H) and 3-chloroaniline were used.

¹ H NMR (300 MHz, MeOH-d ₄ ): δ1.24 (t, 3H), 2.88 (dd, 1H), 3.03 (dd, 1H), 3.
48 ~ 3.66 (m, 3H), 4.24 (q, 2H), 7.23 (d, 2H), 7.42 (m, 3H), 7.48 (d, 2H), 7.62
(d, 2H), 7.69 (d, 2H), 8.04 (d, 2H) Example 36: N- (4-chlorophenyl) -5-[(biphenyl-4-yl)]-5-oxo-3-ethoxy Preparation of carbonylvaleric acid amide (IX, R ₁ = H) (IX) 5-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ = H)
The title compound was prepared in the same manner as in Example 31, except that H) and 4-chloroaniline were used.

¹ H NMR (300 MHz, DMSO-d ₆ ): δ1.24 (t, 3H), 2.76 (dd, 1H), 2.90 (dd, 1H), 3.
53 (m, 3H), 4.20 (q, 2H), 7.06 (d, 2H), 7.21 (t, 1H), 7.44 (m, 4H), 7.62 (d, 2
H), 7.68 (d, 2H), 8.04 (d, 2H) Example 37: N- [3- (N, N-diethylcarbamoyl) phenyl] -5-[(4'-chlorobiphenyl-4-yl
)]-5-Oxo-3-ethoxycarbonyl valeramide (IX, R ₁ = Cl) (IX) 5-[(4′-chlorobiphenyl-4-yl)]-5-oxo-3-ethoxy Carbonyl valeric acid (V
The title compound was prepared in the same manner as in Example 31, except that III, R ₁ = Cl) and 3- (N, N-diethylcarbamoyl) aniline were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.11 (t, 3H), 1.23 (t, 6H), 2.73 (dd, 1H), 2.90 (
dd, 1H), 3.26 (br, 2H), 3.52 (m, 5H), 4.22 (q, 2H), 7.08 (d, 1H), 7.32 (t, 1H
), 7.44 (d, 2H), 7.54 (m, 3H), 7.65 (d, 2H), 7.80 (s, 1H), 8.03 (d, 2H) Example 38: N- [3- (N-phenylcarbonyl ) Phenyl] -5-[(4'-chlorobiphenyl-4-yl)]-5-
Preparation of oxo-3-ethoxycarbonylvaleric acid amide (IX, R ₁ = Cl) 5-[(4′-chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid (V
The title compound was prepared in the same manner as in Example 31, except that III, R ₁ = Cl) and 3- (N-phenylcarbamoyl) aniline were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.17 (t, 3H), 2.85 (dd, 1H), 3.10 (dd, 1H), 3.56
(d, 2H), 3.65 (m, 1H), 4.15 (q, 2H), 7.15 (t, 1H), 7.34 (m, 4H), 7.50 (d, 3H)
, 7.61 (d, 3H), 7.75 (d, 3H), 8.00 (d, 2H), 8.35 (s, 1H), 8.50 (s, 1H) Example 39: (L) -1,5-dioxo-1 Preparation of-(1-phenylcarbamoyl-1-ethylamino) -5- (biphenyl-4-yl) -3-ethoxycarbonylpentane (IX, R ₁ = H) 5- (biphenyl-4-yl) -5- Oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ = H
, 100 mg, 0.29 mmol) was dissolved in THF (5 mL) and cooled at 0 ° C. Then N-
Methylmorpholine (70 mL, 0.65 mmol) and ethyl chloroformate (31 mL,
(0.32 mmol) was added and the mixture was stirred for 30 minutes. L-Ala-CONH-Ph (see: Kruse, C.
H. et al, J. Org. Chem. 50: 2792, 1985; Fink, C.I. A. et al, Bioorg. Med
． Chem. Lett. , 9: 195-200, 1999) dissolved in THF (1 mL) and added at room temperature for 3
After stirring for half an hour, the mixture was filtered and distilled under reduced pressure. Dilute this with chloroform and add 1N
After washing sequentially with HCl solution, 10% NaHCO ₃ solution and water, anhydrous MgS
The extract was dried over O ₄ , filtered, and distilled under reduced pressure to give the title compound (105 mg, 73%).

¹ H NMR (300 MHz, CDCl ₃ ): δ1.20 (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, 1H), 6.15 (dd, 1H), 7.07 (t
, 1H), 7.27 (m, 1H), 7.45 (m, 3H), 7.58 (m, 6H), 7.97 (t, 2H), 8.40-8.60 (d,
1H) Example 40: (D) -1,5-dioxo-1- (1-phenylcarbamoyl-1-ethylamino) -5- (biphenyl-4-yl) -3-ethoxycarbonylpentane (IX, R ₁ = H) 5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid and D-Ala-CONH-
The title compound (105 mg, 73%) was prepared in the same manner as in Example 39 except that Ph was used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.20 (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, 1H), 6.15 (dd, 1H), 7.07 (t
, 1H), 7.27 (m, 1H), 7.45 (m, 3H), 7.58 (m, 6H), 7.97 (t, 2H), 8.40-8.60 (d,
1H) Example 41: 1,5-Dioxo-1- [1- (o-chlorophenyl) carbamoyl-1-ethylamino] -5- (biphenyl-4-yl) -3-ethoxycarbonylpentane (IX, R ₁ = H) (IX) 5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ = H)
The title compound was produced in the same manner as in Example 39 except that and L-Ala-CONH-o-ClPh were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.20 (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, 1H), 6.15 (dd, 1H), 7.07 (t
, 1H), 7.27 (m, 1H), 7.45 (m, 3H), 7.58 (m, 6H), 7.70 (d, 2H), 7.97 (t, 2H),
8.60 (d, 1H) Example 42: 1,5-dioxo-1- [1- (m-chlorophenyl) carbamoyl-1-ethylamino] -5- (biphenyl-4-yl) -3-ethoxycarbonylpentane ( IX, R ₁ = H) (IX) 5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ =
The title compound was prepared in the same manner as in Example 39 except that H) and L-Ala-CONH-m-ClPh were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.20 (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, 1H), 6.15 (dd, 1H), 7.07 (t
, 1H), 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 43: 1,5-dioxo-1- [1- (p-chlorophenyl) carbamoyl-1-ethylamino] -5- (biphenyl-4-yl) -3-ethoxycarbanylpentane Preparation of (IX, R ₁ = H) (IX) 5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ = H)
The title compound was produced in the same manner as in Example 39 except that and L-Ala-CONH-p-ClPh were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.20 (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, 1H), 6.15 (dd, 1H), 7.08 (t
, 1H), 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 44: N- {1,5-dioxo-5-[(biphenyl-4-yl)]-3-ethoxycarbonylpentane-1-
Ile} -2- (N-phenylcarbamoyl) pyrrolidine (IX, R ₁ = H) 5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ = H)
The title compound was prepared in the same manner as in Example 39 except that and L-Pro-CONH-Ph were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.17 (t, 3H), 1.90 (m, 1H), 2.06 (m, 1H), 2.58 (b
r, 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, 1H), 7.05 (t, 1H), 7.27 (m, 2H), 7.45 (m, 3H), 7.58 (m, 5H), 8
.03 (d, 2H), 9.2-9.4 (d, 1H) Example 45: 1,5-dioxo-1- [1-phenylcarbamoyl-2-phenyl-1-ethylamino] -5- (biphenyl-4 -Yl) -3-Ethoxycarbonylpentane (IX, R ₁ = H) 5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII, R ₁ = H)
The title compound was prepared in the same manner as in Example 39, except that and L-Phe-CONH-Ph were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.17 (dt, 3H), 2.38-2.55 (ddd, 1H), 2.70 (ddd, 1
H), 3.20 (m, 2H), 3.45 (m, 3H), 4.13 (dq, 2H), 4.75-4.90 (dq, 1H), 6.10-6.3
0 (dd, 1H), 7.08 (t, 1H), 7.24 (m, 6H), 7.42 (m, 4H), 7.63 (m, 5H), 8.00 (d, 2
H), 7.90 & 8.30 (d, 1H) Example 46: N- {1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl)]-3-ethoxycarbonylpentan-1-yl} Preparation of 2- (N-phenylcarbamoyl) pyrrolidine (IX, R ₁ = H) 5- (4′-chlorobiphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VII
I, R ₁ = Cl) and L-Pro-CONH-Ph were used to produce the title compound in the same manner as in Example 39.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.20 (t, 3H), 1.90 (m, 1H), 2.06 (m, 1H), 2.58 (b
r, 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, 1H), 7.05 (t, 1H), 7.27 (m, 2H), 7.45 (m, 2H), 7.58 (m, 5H), 8
.03 (d, 2H), 9.2-9.4 (d, 1H) Example 47: 1,5-dioxo-1- [1-phenylcarbamoyl-2-phenyl-1-ethylamino] -5- (4 ′
Preparation of 5-chlorobiphenyl-4-yl) -3-ethoxycarbonylpentane (IX, R ₁ = Cl) 5- (4′-chlorobiphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VII
The title compound was prepared in the same manner as in Example 39, except that I, R ₁ = Cl) and L-Phe-CONH-Ph were used.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.17 (dt, 3H), 2.38-2.55 (ddd, 1H), 2.70 (ddd, 1
H), 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, 1H) Example 48: N- (3-Cyanophenyl) -5-[(biphenyl-4-yl)]-5-oxo-3-carboxylic valeric acid amide (I, R ₁ = H) N- (3-Cyanophenyl) -5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleramide (IX, R ₁ = H, 11.8 mg, 0.0268 mmol Was dissolved in ethanol (2 mL), 1N NaOH (0.5 mL) was added, and the mixture was stirred at room temperature for 1.5 hours, water was added, and the mixture was washed with ethyl acetate. The resulting material was acidified with 1N HCl solution, extracted with MC and dried over anhydrous MgSO ₄ . Then, the obtained substance was filtered, distilled under reduced pressure, and recrystallized from CHCl ₃ / MeOH solution (19/1, v / v) and hexane to give the title compound (10
． 4 mg, 94%). ¹ H NMR (300 MHz, CDCl ₃ ): δ2.74 (dd, 1H), 3.01 (dd, 1H), 3.54 (m, 3H), 7.42
(m, 4H), 7.65 (m, 5H), 8.01 (m, 3H), 8.20 (s, 1H) Example 49: N- (3-acetylphenyl) -5-[(biphenyl-4-yl)] -Preparation of 5-oxo-3-carboxyvaleramide (I, R ₁ = H) N- (3-acetylphenyl) -5- (biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid The title compound was prepared in a similar manner to Example 48 except using the amide (IX, R ₁ = H).

¹ H NMR (300 MHz, CDCl ₃ ): δ2.59 (s, 3H), 2.80 (dd, 1H), 3.00 (dd, 1H), 3.56
(m, 3H), 7.40 (m, 4H), 7.60 (m, 5H), 8.03 (m, 3H), 8.20 (s, 1H) Example 50: N- (3-acetylphenyl) -5-[( 4'-Chlorobiphenyl-4-yl)]-5-oxo-3-carboxylic valeramide (I, R ₁ = H) Preparation N- (3-acetylphenyl) -5- (4'-chlorobiphenyl- The title compound was prepared in the same manner as in Example 48 except that 4-yl) -5-oxo-3-ethoxycarbonylvaleramide (IX, R ₁ = H) was used.

¹ H NMR (300 MHz, CDCl ₃ ): δ2.60 (s, 3H), 2.80 (dd, 1H), 2.94 (dd, 1H), 3.56
(m, 3H), 7.44 (m, 3H), 7.54 (d, 2H), 7.66 (m, 3H), 7.82 (s, 1H), 8.04 (m, 3H) Example 51: N- (3-chlorophenyl ) -5-[(Biphenyl-4-yl)]-5-oxo-3-carboxylvaleramide (I, R ₁ = H) Preparation N- (3-chlorophenyl) -5- (biphenyl-4-yl) ) -5-Oxo-3-ethoxycarbonylvaleramide (IX, R ₁ = H) was used to prepare the title compound in the same manner as in Example 48.

¹ H NMR (300 MHz, MeOH-d4): δ2.88 (dd, 1H), 3.03 (dd, 1H), 3.48-3.66 (m, 3H
), 7.23 (d, 2H), 7.42 (m, 3H), 7.48 (d, 2H), 7.62 (d, 2H), 7.69 (d, 2H), 8.04
(d, 2H) Example 52: 1,5-dioxo-1- (1-phenylcarbamoyl-1-ethylamino) -5- (biphenyl-4-
Yield) -3-carboxypentane (I, R ₁ = H) 1,5-dioxo-1- (1-phenylcarbamoyl-1-ethylamino) -5- (biphenyl-
4-yl) -3-ethoxycarbonylpentane (IX, R ₁ = H, 105 mg, 0.215 mmol) was dissolved in ethanol (5 mL), 1N NaOH (1 mL, 1 mmol) was added, and the mixture was stirred at room temperature for 90 minutes. Water was added and the mixture was washed with ethyl acetate. The obtained material was acidified with 1N HCl solution, extracted with MC, dried over anhydrous MgSO ₄ , filtered, and distilled under reduced pressure. The residue was recrystallized from CHCl ₃ / MeOH solution (19/1, v / v) and hexane to give 88 mg (89%) of the title compound.

¹ H NMR (300 MHz, CDCl ₃ ): δ1.47 (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, 1H), 7.27 (m, 1H), 7.45 (m,
3H), 7.58 (m, 6H), 7.97 (t, 2H), 8.40-8.60 (d, 1H) Example 53: N- {1,5-dioxo-5-[(4'-chlorobiphenyl-4- Ill)]-3-Carboxylpentane
-1-yl} -3- (N-phenylcarbamoyl) -1,2,3,4-tetrahydroisoquinoline (
Preparation of I, R ₁ = Cl) N- {1,5-dioxo-5-[(4′-chlorobiphenyl-4-yl)]-3-ethoxycarbonylpentan-1-yl} -3- (N- The title compound was prepared in the same manner as in Example 52, except that phenylcarbamoyl) -1,2,3,4-tetrahydroisoquinoline (IX, R ₁ = Cl) was used.

¹ H NMR (300 MHz, CDCl ₃ ): δ2.70-3.20 (m, 2H), 3.38-3.57 (m, 4H), 4.11 (m, 1
H), 4.66 (m, 2H), 5.33 (d, 1H), 6.92 (t, 1H), 7.15 (m, 4H), 7.45 (m, 7H), 7.9
3 (d, 2H), 8.66 (m, 1H) Example 54: Inhibition of gelatinase A (MMP-2) in vitro This test was performed using a fluorescent synthetic peptide substrate (7-methoxycoumarin-4-acetyl-proline-
Leucine-glycine-leucine-β- (2,4-dinitrophenylamino) alanine-alanine-arginine-NH ₂ , Sigma Chem. Co. , U. S. A. ) Is cleaved with gelatinase A (Boehringer Mannheim cat # 1782916, derived from human fibrosarcoma cells) to measure the fluorescence intensity of a fluorescent substance (7-methoxycoumarin-4-acetyl-Pro-Leu-Gly). went.

The enzyme reaction using the fluorescent synthetic substrate was performed by adding the test compound and TNB to a 96-well plate.
C buffer solution (25 mM Tris-HCl, pH 7.5, 0.1 M NaCl, 0.01% Brij-35, 5 mM CaCl
₂ ) Immediately before the enzymatic reaction, use 1 mM APMA (aminophenylmercuric acetate) at 37 ° C.
Gelatinase A (final concentration in the well: 4.17 nM) and the fluorescent synthetic peptide (final concentration in the well: 9.15 uM), which were activated for 30 minutes at 37 ° C, were added and reacted at 37 ° C for 30 minutes, followed by fluorescence. Excitation wavelength 328nm, emission wavelength 393nm using analyzer
The fluorescence intensity was measured with. The inhibition rate (%) was calculated from the following formula.

[0093]

[Equation 1] In the formula, A is the fluorescence intensity before the reaction with the inhibitor added; B is the fluorescence intensity after the reaction; C is the fluorescence intensity before the reaction without the inhibitor; and D is the fluorescence intensity after the reaction. is there.

Example 55: Inhibition of gelatinase B (MMP-9) in vitro Gelatinase B (MMP-9, Boehringer Mannheim cat # 1758896, from huma
n blood), and the concentration of gelatinase B (final concentration in well: 2.715 nM) and the concentration of the fluorescent synthetic peptide as a substrate (final concentration in well: 4.575 uM) are different from Example 54. In the same manner, in vitro gelatinase B (MMP-9
) Was measured.

Example 56: Inhibition of collagenase (MMP-1) in vitro Collagenase (manufactured by AngioLab) was used, except that the concentration of collagenase (final concentration in well: 7.25 nM) was different from that of Example 54. The inhibition rate of collagenase (MMP-1) in vitro was measured by the same method.

[0096]

[Chemical formula 23]

[Table 1]

[Chemical formula 24]

[Table 2]

[Chemical 25]

[Table 3]

[0097]

【The invention's effect】

As clearly described and demonstrated above, the present invention provides a novel biphenylbutyric acid derivative compound which inhibits the action of MMP, isomers thereof and pharmaceutically acceptable salts thereof, and a method for producing the compound. Is. Since the biphenylbutyric acid derivative compound of the present invention selectively inhibits the activity of MMP under in vitro conditions, an MMP inhibitor containing the biphenylbutyric acid derivative as an active ingredient is MMP.
It is usefully used for the prevention and treatment of various diseases induced by overexpression and excessive activation of the.

While the preferred embodiments of the present invention have been disclosed by way of illustration, those skilled in the art will appreciate various modifications, additions and substitutions without departing from the scope and spirit of the invention as set forth in the appended claims. It will be understood that is possible.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/495 A61K 31/495 31/5375 31/5375 A61P 1/02 A61P 1/02 1/16 1 / 16 9/10 101 9/10 101 11/00 11/00 19/02 19/02 19/08 19/08 29/00 29/00 101 101 35/04 35/04 37/02 37/02 43/00 111 43/00 111 C07C 231/02 C07C 231/02 237/04 237/04 Z C07D 207/16 C07D 207/16 217/26 217/26 295/18 295/18 AZ 317/50 317/50 (81 ) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, TR), OA (BF, BJ , CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AE , AG, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CR, CU, CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KZ, LC, LK, LR, LS, LT, LU, LV, MA , MD, MG, MK, MN, MW, MX, MZ, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW (72) Inventor Yeo Yeeuk Korean 305-390 Taeyeon, Yousung-gu, Yongmin-dong, Expo Apartment, 506-1501 (72) Inventor Chae, Myeong-youn Republic of Korea 305-390 Taeyeon, Yousung-gu, Youngmin-dong, Sejong Apartment, 110-304 ( 72) Inventor Paek, Sang Hyun Republic of Korea 305-390 Taeyeon, Yousung-gu, Youngmin-dong, Sejong Apartment, 111-902 (72) Inventor Kim, Yun-chul Republic of Korea 305-390 Taeyeon, Yousung-gu, Youngmin- Dong, Sejong Apartment, 111-501 (72) Inventor Lee, Young-Wook Republic of Korea 305-390 Taeyeon, Yousung, Youngmin-Don, Sejong Apartment, 101-701 (72) Inventor Min, Heeyun Republic of Korea 305-390 Taeyeon, Yousung, Youngmin-Dong, Sejong Apartment, 101-1304 (72) Inventor Bae Hae Yun Korea 305-390 Taeyeon, Yousung-gu, Yongmin-dong, Sejong Apartment, 111-607 (72) Inventor Oh, Yu-gen South Korea 305-390 Taeyeon, Yousung, Yeongmin-dong, Expo Apartment Ment, 306-403 F term (reference) 4C034 AN03 4C069 AA16 4C086 AA01 AA02 AA03 AA04 BA13 BC30 BC50 BC73 MA01 MA04 NA14 ZA33 ZA45 ZA59 ZA67 ZA75 ZA81 ZA96 ZA07 GA01 A01 A03 A01 A03 A04 A03 A01 A02 A03 A04 ZA45 ZA59 ZA67 ZA75 ZA81 ZA96 ZB11 ZB15 ZB26 4H006 AA01 AA02 AB22 AB23 AB26 AC53 AC80 BJ50 BR30 BT12 BV36 BV50

Claims (8)

[Claims] 1. A compound represented by the following general formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof: embedded image In the formula, R ₁ is hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano, or
OCF ₃ , —OCH ₂ F, embedded image -OR ₄ , -SR ₄ , -S (O) R ₄ or -S (O) ₂ (provided that R ₄ and R
₄ ^a may be the same or different and is alkyl, allyl, allylalkyl, heteroaryl or cycloalkyl); R ₂ and R ₃ may be the same or different and are hydrogen, alkyl, allyl, allylalkyl, heteroaryl. Or cycloalkyl; and n is 1 or 2. 2. The R ₂ and R ₃ are linked by carbon, nitrogen, oxygen or sulfur,
The compound according to claim 1, which forms the following C _5-6 ring compound,
Its isomers or their pharmaceutically acceptable salts: Wherein R ₈ is hydrogen, alkyl, allyl, allylalkyl, heteroaryl, or cycloalkyl; and X is 0 or S. 3. The compound, its isomer or a pharmaceutically acceptable salt thereof according to claim 1, wherein R ₂ further comprises a substituent represented by the following general formula: Chemical 4] Wherein R ₅ is hydrogen, alkyl, allyl, allylalkyl, heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, allylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, allylsulfinylalkyl, allylsulfonylalkyl or cycloalkyl. And R ₆ and R _{7, which} may be the same or different, are hydrogen, alkyl, allyl, allylalkyl, heteroaryl or cycloalkyl. Wherein said R ₃ is R ₂ in the case of hydrogen have the same substituent as claimed in claim 3, wherein R ₃ and R ₅ when R ₃ is not hydrogen carbon, nitrogen, oxygen or sulfur Are linked to form a C _5-6 ring and have the following formula: The compound of claim 3, the isomer thereof, or a pharmaceutically acceptable salt thereof, wherein the moiety represented by: has the structure: R ₆ and R ₇ are as defined in claim 3; R ₉ is hydrogen, hydroxy, alkoxy, allyloxy, thiol or alkylthio; R ₁₀ is oxo, hydroxyamine or hydrazone; R ₁₁ And R ₁₂ is hydrogen or C _1-6 lower alkyl; and Y is CH ₂ , O or S. 5. R ₆ and R ₇ are linked by carbon, nitrogen, oxygen or sulfur,
The compound according to claim 3 or 4, characterized by forming the following cyclic compound, an isomer thereof, or a pharmaceutically acceptable salt thereof. [Chemical 7] In the formula, R ₈ and X are as described above. 6. The compound according to any one of claims 1 to 5, an isomer thereof, or a pharmaceutically acceptable salt thereof, which exhibits a matrix metalloprotease inhibitory activity. 7. A method for producing a compound represented by the general formula (I), which comprises the following steps. i) a step of reacting compounds (II) and (III) to obtain t-butyl ester (IV); ii) a compound (V having no butyl ester group as a deprotecting group of t-butyl ester (IV) above
Iii) Condensing the above compound (V) with an amine compound to obtain a compound (VI) having a diethyl ester group; and iv) hydrolyzing the diethyl ester group of the above compound (VI) Carboxyl group,
A process for producing a compound of the general formula (I) by decarboxylating this: embedded image In the formula, R ₁ , R ₂ and R ₃ are as defined in claim 1. 8. A method for producing a compound represented by the general formula (I), which comprises the following steps. i) a step of reacting compounds (II) and (III) to obtain t-butyl ester (IV); ii) hydrolysis of one of the ethyl esters in t-butyl ester (IV) to give a carboxyl group A step of decarboxylating this to obtain a compound (VII); iii) a step of deprotecting the above compound (VII) to obtain a compound (VIII) having no butyl ester group; iv) converting the above compound (VIII) A compound that condenses with an amine compound and contains an ethyl ester group
And (v) hydrolyzing the ethyl ester group of the compound (IX) to obtain a carboxyl group,
Process for producing compound of general formula (I): In the formula, R ₁ , R ₂ and R ₃ are as defined in claim 1.