CA2377629A1

CA2377629A1 - Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor

Info

Publication number: CA2377629A1
Application number: CA002377629A
Authority: CA
Inventors: Hae-Young Bae; Young-Jun Park; Eu-Gene Oh; Ji-Uk Yoo; Choon-Ho Ryu; Hye-Kyung Min; Myeong-Yun Chae; Jeoung-Wook Lee; Sang-Hyun Paek; Kyung-Chul Kim
Original assignee: Individual
Current assignee: Samsung Electronics Co Ltd
Priority date: 2000-04-25
Filing date: 2001-04-24
Publication date: 2001-11-08
Also published as: JP2003531894A; EP1189882A1; WO2001083445A1; AU5275901A; CN1366518A

Abstract

The present invention provides a novel biphenyl butyric acid derivative, isomer and pharmaceutically acceptable salts thereof which are useful as an inhibitor of matrix metalloproteinase (MMP) and a process for preparing the same. Since the biphenyl butyric acid derivative of the invention selectivel y inhibits the activity of MMP in vitro, it can be practically applied to the treatment and prevention of diseases caused by overexpression of MMP.</SDOAB >

Description

BIPHENYL BUTYRTC ACID DERIVATIVE AS A MATRIX
METALLOPROTEINASE INHIBITOR
BACKGROUND OF THE TNVENTION
Field of the Invention The present invention relates to biphenyl butyric to acid derivatives, more specifically, to novel biphenyl butyric acid derivatives represented as the following general formula (I), useful as matrix metalloproteinase inhibitor and pharmaceutically acceptable salts thereof and a process for preparing the compounds.
O, OH
R 1 n~ ~ (~J
~3 DPSCr~ption of t~h Prior Art Matrix metalloproteinase("MMP") is a Ca2+-dependent proteinase containing zinc ion(Zn2+) at its active site. To the present, at least 18 matrix metalloproteinases including stromelycin, collagenase and a family of gelatinise have been identified in the art. MMP degrades various extracellular matrix components of collagen, laminin, proteoglycan, fibronectin, elastin and gelatin under biological conditions, which, in turn, leads to growth of articulation tissue, bone tissue and connective tissue, and remodeling of the tissues. MMP is secreted as an inactive form of proenzyme, which is subsequently 3o activated in extracellular side, together with a naturally occuring inhibitor, TIMP(tissue inhibitor of metalloproteinase).
Meanwhile, MMP inhibitor is useful to prevention and treatment of all sorts of diseases caused by overexpression or overactivation of MMP. Such diseases are, for example, rheumatoid, arthrosteitis, unusual bone resorption, osteoporosis, periodontitis, interstitial nephritis, arteriosclerosis, pulmonary emphysema, cirrhosis, cornea injury, metastasis, invasion or growth of tumor cell, autoimmune disease, disease caused by Vascular emigration or infiltration of leukocytes, arterialization(see: Beeley et al., Curr. Opin. Ther. Patents, 4(1):7-16, 1994). For 1o instance, it was reported that synthetic MMP inhibitor has an anti-cancer activity in vivo along with inhibition of basement membrane remodeling in the mouse model bearing ovarian cancer(see: Cancer Res., 53:2087, 1993).
Particularly, considering the fact that MMP-2 and MMP-9 among the above MMP enzymes play an essential role in angiogenesis required for the growth of cancer cells (see:
Biochim. Biophys. Acta, 695, 1983), and that MMP-1 and MMP-3 among MMP enzymes play an important role in the progress of arthritis as observed in much higher concentration than 2o normal in the synovium and cartilage of a patient of rheumatoid arthritis(see: Arthritis Rheum., 35:35-42, 1992), the selectivity to MMP-1/MMP-2 is considered to play a crucial role in reducing side effects such as arthralgia.
Therefore, researches have been made while focusing on the development of selective inhibitors, and many MMP
inhibitors have been designed and synthesized in many aspects(,~ee 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; Drugs of the Future 2000, 25(6), 551-557; Exp. Opin. Invest. Drugs, 2000, 2167-2177).
Some compounds possessing inhibitory activity against MMP are known. In general, they have a zinc binding group("ZBG"), which is coordinated to the zinc ion of MMP
enzymes at the active site of them. Such ZBGs include hydroxamic acid, carboxylic acid, phosphoric acid, phosphinic acid, thiol and so forth(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 00/40577; WO
00/40600; WO 98/03166; Chem. Rev. 99:2735-2776, 1999).
Especially, several kinds of succinic acid derivatives based on substrate backbone have been designed and synthesized as a peptide-mimic inhibitor. (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 98124759; WO 98/30551; WO
98/30541; WO 97/32846; WO 99/01428; EP 897908; WO 98/38179;
JP 95002797; WO 99/18074; WO 99/19296; EP 641323). The peptide-mimic inhibitors are known to contain a hydroxamic acid as a ZBG and display a broad spectrum for MMP enzymes.
However, some of the above peptide-mimic inhibitors induce the side effect of arthralgia in clinical trial(see:
Current Pharmaceutical Design, 5:787-819, 1999; Current Opinion in Drug Discovery & Development, 3:353-361, 2000).
They are also often poorly absorbed, exhibiting low oral bioavailability and furthermore, possess lower selectivity to MMP-1/MMP-2(see:Drugs of the Future, 21(12):1215-1220, 1996) .
In 1994, non-peptide inhibitors were developed to solve the said problems which are substantially distinguished in terms of chemical structure from the above peptide-mimic inhibitors having simple sulfonyl amino acid derivative represented as a chemical formula below(s_ee: USP
5,506,242; J. Med. Chem., 40:2525-2532, 1997).
~~~"~~.~~~~

Under a consideration that the small molecule of sulfonamide-derived MMP inhibitors have activities in vitro against MMP enzymes, and have advantages over the said peptide-mimic inhibitors, a variety of sulfonamide inhibitors have been synthesized and reported in the literature(see: WO 98/50348; 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
99/07675; WO 98/27069; WO 97/22587; EP 979816; EP895988; EP
878467; EP 1041072). To improve in vitro enzymatic activity, selectivity, and pharmacokinetic profiles, new sulfonamide derivatives have been designed and synthesized, by changing P1' of the above sulfonamide inhibitor which binds to S1' sub-site of the enzymes.
While the above sulfonamide inhibitors have relatively high inhibitory activity against MMP, they do not have a higher selectivity to MMP-1/MMP-2 as compared with previous peptide-mimic inhibitors. Some of them have also side effect of arthralgia in clinical trials(see:
2o Current Pharmaceutical Design, 5:787-819, 1999; Current Opinion in Drug Discovery & Development, 3:353-361, 2000;
Exp. Opin. Invest. Drugs, 9:2159-2165, 2000; SCRIP, 2467:19, 1999; Drugs of the Future, 24(1):16-21, 1999). Although the sulfonamide inhibitors containing a hydroxamic acid as a ZBG typically showed a very strong in vitro inhibitory activity as compared with those containing a carboxylic acid as a ZBG, they also have revealed a limitation in oral administration due to their lower bioavailability and lower metabolic stability in vivo(see: J. Med. Chem., 41:640-649, 1988; Investigational New Drugs 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).
Other non-peptide inhibitors, 3-oxo-3-biphenylbutyric acid derivatives, were found to solve the said problems and increase the selectivity which contain a butyric acid group represented as a chemical formula below(see WO 96/15096).

~H
~I ~''~--~
While the above inhibitors have a very low in vitro inhibitory activity against MMP as compared with peptide-s mimic succinic acid derivatives or sulfonyl amino acid derivatives, they have a far higher selectivity to MMP-1/MMP-2 and also little side effect of arthralgia in clinical trials(see: Drugs of the Future, 24(1):16-21, 1999). To improve the problem of said inhibitors, a 1o variety of biphenyl butyric acid derivatives as MMP
inhibitors have been designed and reported(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 5,886,024; USP
5, 886, 043) .
Another butyric acid derivatives represented as the following formula have been reported, however, they also have still the drawback of a low inhibitory activity against MMP(see: WO 98/09940; WO 98/06711).
~H
~H
I ~ ~'-~

Under the circumstance, there are strong reasons for developing alternative compounds whose inhibitory action on MMP and selectivity to MMP-1/MMP-2 are increased to reduce side effects.
SUMMARY OF THE INVENTION
The present inventors have made an effort to develop novel compounds whose inhibitory action on MMP and selectivity to MMP-1/MMP-2 are increased to reduce side effects, and finally found that novel synthetic inhibitors of biphenyl butyric acid derivatives selectively inhibit MMP activity in vitro.
A primary object of the present invention is, therefore, to provide biphenyl butyric acid derivatives inhibiting MMP activity.
to The other object of the invention is to provide a process for preparing the said compounds.
DETAILED DESCRIPTION OF THE INENTION
The present invention provides biphenyl butyric acid derivatives which inhibit the activity of MMP, represented as the following general formula(I), the isomers and the pharmaceutically acceptable salts thereof, and a process 2o for preparing the said compounds.
p ~H
n~ ~--~~J
O ~-Ra ~3 wherein, R1 is hydrogen, alkyl, cycloalkyl, halogen, vitro, cyano, -OCF3, -OCHZF, -I~-R.4 ~~4 -ORS, -SR4, -S (0) RQ or -S (O) 2 where RQ and RQa, which may be the same or different, are alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl;
3o R2 and R3, which may be the same or different, are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; and, n is 1 or 2.
In the above formula, RZ and R3 are taken together with carbon, nitrogen, oxygen or sulfur to form CS-6 ring, which includes the followings:
t~ t~ I~ I~ J-R ~
wherein, Rg is hydrogen, alkyl, aryl, arylalkyl, 1o heteroaryl or cycloalkyl; and, X is 0 or S.
Also, in case that R3 is hydrogen, R~ may further include a substituent represented as the following 25 structural formula:
R~
wherein, R5 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, 2o arylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylsulfinylalkyl, arylsulfonylalkyl or cycloalkyl; and, R6 and R7, which may be the same or different, are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl.
o In case that R3 is not hydrogen, R3 and R5 of the above formula(I) are taken together with carbon, nitrogen, oxygen or sulfur to form C5-6 ring in which 3o moiety includes the followings:

~I~ '10 ~1~
~ ~~
wherein, R6 and R, are the same as above;
R9 is hydrogen, hydroxy, alkoxy, aryloxy, thiol or alkylthio;
Rlo is oxo, hydroxyamine or hydrazone;
R11 and Rl~ are hydrogen or C1_6 lower alkyl; and, Y is CHz, 0 or S.
Also, R6 and R~ are taken together with carbon, nitrogen, oxygen or sulfur to form CS_6 ring, which includes the followings:
hJ f~ ~I f~ !-F~,~
wherein, Re and X are the same as above.
Otherwise mentioned, all kinds of isomers of the biphenyl butyric acid derivatives are fallen within the 2o scope of the invention.
The pharmaceutically acceptable salts of the invention include acid-added salts and hydrates. In general formula(I), the compound of the invention can be converted to the salts corresponding to them, preferably alkali metal salts(sodium, potassium, etc.), alkaline earth metal salts(calcium, magnesium, etc.), ammonium salts, non-toxic salts of pharmaceutical organic amine and water-soluble salts. The compound of the general formula(I) can be converted to inorganic acid salts(hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate, nitrate, etc.) and organic acid salts(acetate, lactate, tartarate, oxalate, fumarate, glucuronate, etc.), preferably non-toxic salts and water-soluble salts. The compound of the general formula(I) and its salts can be also converted to the hydrates corresponding to them by the conventionally known method in the art.
Two processes for preparing the compounds of the general formula(I) are illustrated by the following steps.
First, the above compounds may be prepared by the following Process 1.
Proces3s l:
~ 0~ OEt Br ~ Et feet ---~. I ~,.i -~t-Bu0 OEt OBu-t ~~
R ~ (a7 (n~ R 1 ~I'~
~ O OEt ~ 0 OEt ~Et d epratectia n O Et H~~s ~ I ~ O
r I ~H I R ~'R
R~ f~ R~ (~I) 3 hydrolysis decarba~tvlati~ a R
L~J
2o wherein, R1, R~ and R3 are the same as above .

t~~l: Synthesis of t-butylester compound(IV) A compound(II) is reacted with a compound(III) to 5 give t-butylester compound(IV): the compound(II) may be commercially available or prepared by the conventionally known methods and the compound(III) may be prepared by partial modification of the conventionally known methods(see: B.S. Furniss, et al., VOGEL's Textbook of so Practical Organic Chemistry, 5th ed., pp942-943, 1988; WO
96/15096). ' Step 2: Synthesis of a compound(V) The t-butylester compound(IV) is deprotected to give a butylester group-free compound(V): the deprotection is preferably accomplished by using TFA or anhydrous HCl.
_~p 3: Synthesis of a compound(VI) The compound(V) is condensed with an amine compound to give a compound(VI) containing diethylester group: the amine compound comprises R~ and R3 defined in the above and condensation with the amine compound can be carried out by a variety of methods such as acid chloride method, active ester method, mixed anhydride method, etc.
Ste~4: Synthesis of a compound(I) Diethylester groups of the compound(VI) are hydrolyzed to carboxylic groups and then the compound is decarboxylated to give a compound(I).
The compounds of the general formula(I) may also be prepared by the following Process 2.
Process 2:

gr Et +t-goo oEt (B~
a ~,.~Et ~ o h~rdralysis ~~~~,,.f",. dePratectian decarbouylatian ~. ~ O~W-t OBu~t ~ 1 Cl'q5 ~ 1 f ~~
HN
~H ~3 '~~

~1'R
l~J
0~
h~dral~sis ~ '1 ~1 wherein, R1, RZ and R3 are the same as above .
S~_ep l: Synthesis of t-butylester compound(IV) A compound(II) is reacted with a compound(III) to give t-butylester compound(IV): the compound(II) may be l0 commercially available or prepared by the conventionally known methods and the compound(III) may be prepared by partial modification of the conventionally known methods(see: B.S. Furniss, et al., VOGEL's Textbook of Practical Organic Chemistry, 5t'' ed., pp942-943, 1988; WO
i5 96/15096) .
Step 2: Synthesis of a compound(VII) One of ethylester groups of t-butylester compound(IV) is hydrolyzed to a carboxylic group and then decarboxylating the compound to give a compound(VII): the hydrolysis is carried out in the presence of a base and decarboxylation in the presence of an organic solvent; and, the base includes, but not limited to, preferably 1 equi.
of KOH/EtOH and the organic solvent includes preferably 1,4-dioxane.
Ste~~ 3 Synthesis of a compound(VIII) The compound(VII) is deprotected to give a butylester group-free compound(VIII): the deprotection is preferably carried out by using TFA or anhydrous HCl.
Step 4: Synthesis of a compound(TX) The compound(VIII) is condensed with an amine 2o compound to give a compound(IX) containing ethylester group: the amine compound comprises RZ and R3 defined in the above and condensation with the amine compound can be carried. out by a variety of methods such as acid chloride method, active ester method, mixed anhydride method, etc., most preferably, active ester method.
Step 5: Synthesis of a compound(I) Ethylester group of the compound(IX) is hydrolyzed to a carboxylic group to prepare a compound ( I ) ( see : V~10 96/15096).
The present invention is further illustrated in the following examples, which should not be taken to limit the scope of the invention.
Exampl~l_: Preparation of 5-(Biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester(IV, R1=H ) To 100m1 flask were added NaH(95o, 505mg, 20.0mmo1) and high-purity THF(l5mL), and cooled to a temperature of -10'C. Then, diethyl t-butoxycarbonylmethylmalonate(III, 4.9g, 18.17mmo1) dissolved in THF(lOmL) was added slowly, and stirred for 30min at room temperature. And then, 4-phenyl-a -bromoacetophenone(II, R1=H, 5g, 18.17mmol) 1o dissolved in THF(l5mL) was added slowly, and stirred for 1hr and 30min at room temperature, and extracted with 1N
HCl(30mL) and ethylacetate(30mL). The organic phase was washed with water(lOmL), and added anhydrous MgS04, stirred for 5 min, filtered and distilled under reduced pressure to give the titled compound(8.65g, 950).
1H NMR(300MHz, CDC13) : S 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) 2o Example 2: Preparation of 5-(4'-methoxybiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R1=OMe) The titled compound was prepared in a similar manner as in Example 1, except for employing 4-(4'-methoxyphenyl)-a -bromoacetophenone(II, R1=OMe).
1H NMR(300MHz, CDC13) : 8 1.24 (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: Preparation of 5-(4'-bromobiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester ( IV, R1=Br ) The titled compound was prepared in a similar manner as in Example 1, except for employing 4-(4'-bromophenyl)-a -bromoacetophenone (II, R1=Br) 1H NMR(300MHz, CDC13) : S 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 4: Preparation of 5-(4'-chlorobiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R1=Cl) The titled compound was prepared in a similar manner as in Example 1, except for employing 4- ( 4' -chlorophenyl ) -a -bromoacetophenone(II, Rl=Cl).
1H NMR(300MHz, CDC13) : 8 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 5: Preparation of 5-(Biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=H) To 5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonyl-valeric acid t-butyl ester(IV, R1=H, 1.5g, 3.2mmo1) dispersed in methylene chloride(MC)(20mL) was added TFA(2mL) and stirred for 24hr at room temperature. After MC was removed under reduced pressure, ethylacetate(20mL) and 1N NaOH were added slowly, and the separated organic layer was extracted with water. And then, the aqueous solution was collected, treated with 1N HCl(30mL) and extracted with ethylacetate. The separated organic layer was dried over anhydrous MgS04,filtered and distilled under reduced pressure to give the titled compound(1.2g, 910).
1H NMR (300MHz, CDC13) : s 1. 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: Preparation of 5-(4'-methoxybiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=OMe) 5 The titled compound was prepared in a similar manner as in Example 5, except for employing 5-(4'-methoxybiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester(IV, R1=OMe).
10 1H NMR (300MHz, CDC13) : s 1. 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: Preparation of 5-(4'-bromobiphenyl-4-yl)-5-oxo-15 3, 3-diethoxycarbonylvaleric acid (V, R1=Br) The titled compound was prepared in a similar manner as in Example 5, except for employing 5-(4'-bromobiphenyl 4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R1=Br) .
1H NMR (300MHz, CDC13) : S 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 8: Preparation of N-phenyl-5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI, R1=H) 5-(Biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric 3o acid(V, Rl=H, 0.5g, l.2mmol), EDC(0.23g, l.2mmol) and HOBt(0.16g, l,2mmol) were dissolved in MC(5mL) and cooled to a temperature of 0'C. And, TEA(170mL, l.2mmo1) was added and stirred for l0min, followed by addition of aniline(122mL, l.3mmol) and stirring for 2hr and 30min at room temperature. And then, 1N HCl was added and extracted by employing MC, and dried over anhydrous MgS04, filtered, and distilled under reduced pressure, and subjected to a column chromatography(Hx/EA=411, v/v) to give the titled compound ( 0 . 365g, 62 0 ) .
1H NMR (300MHz, CDC13) : s 1. 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: Preparation of N-cyclopropyl-5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI, R1=H) The titled compound was prepared in a similar manner as in Example 8, except for employing 5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=H) and cyclopropylamine.
1H NMR (300MHz, CDC13) : s 0. 41 (m, 2H) , 0. 69 (m, 2H) , 2.62(m, 1H), 3.08(x, 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) 2o Example 10: Preparation of N-(a -methylbenzyl)-5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI, Ri=H ) ( VI ) The titled compound was prepared in a similar manner as in Example 8, except for employing 5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=H) and a -methylbenzylamine.
1H NMR(300MHz, CDC13) : ~ 1.24 (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: Preparation of N-phenyl-5-(4'-methoxybiphenyl 4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI, R1=OMe ) The titled compound was prepared in a similar manner as in Example 8, except for employing 5-(4'-methoxybiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=OMe) and aniline.
1H NMR (300MHz, CDC13) : s 1.24 (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: Preparation of N-[1,5-dioxo-5-(4'-methoxybiphenyl-4-yl)-3,3-diethoxycarbonylpentane-1-yl]-4-methylpiperazine (VI, R1=OMe) (VI) The titled compound was prepared in a similar manner as in Example 8, except for employing 5-(4'-methoxybiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=OMe) and N-methylpiperazine.
1H NMR(300MHz, CDC13) : s 1.24 (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: Preparation of N-[1,5-dioxo-5-(4'-bromobiphenyl-4-yl)-3,3-diethoxycarbonylpentane-1-yl]piperidine(VI, R1=Br ) The titled compound was prepared in a similar manner as in Example 8, except for employing 5-(4'-bromobiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=Br) and piperidine.
1H NMR (300MHz, CDC13) : s 1. 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: Preparation of N-[1,5-dioxo-5-(4'-bromobiphenyl-4-yl)-3,3-diethoxycarbonylpentane-1-yl]-4-benzoylpiperazine (VI, R1=Br) The titled compound was prepared in a similar manner as in Example 8, except for employing N-L0 benzoylpiperazine(s~e ,: 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, R1=Br).
1H NMR(300MHz, CDC13) : S 1.24 (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: Preparation of 1,5-dioxo-1-(1-phenylcarbamoyl-1-ethylamino)-5-(4'-bromobiphenyl-4-yl)-3,3-diethoxycarbonylpentane(VI, R1=Br) 5-(4'-bromobiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid(V, R1=Br, 140mg, 0.285mmol), EDC(60mg, 0.313mmol) and HOBt(42.4mg, 0.313mmol) were dissolved in MC(5mL) and cooled to a temperature of 0'C.
And, TEA(44.3mL, 0.313mmol) was added and stirred for l0min, followed by addition of L-Ala-CONH-Ph(56mg, 0.342mmol) and stirring for l2hrs at room temperature. And then, 1N HC1 3o was added and extracted with MC, and dried over anhydrous MgS04, filtered, and distilled under reduced pressure, and subjected to a column chromatography(CHC13/MeOH=19/1, v/v) to give the titled compound(120mg, 69%).
1H NMR (300MHz, CDC13) : S 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, 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: Preparation of N-phenyl-5-(biphenyl-4-yl)-5-oxo-3-carboxylvaleramide(I, R1=H) To N-phenyl-5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI, R1=H,0.36g, 0.74mmol) dissolved in ethanol (lOmL) was added 1N NaOH(1.55mL, 1.55mmo1) and stirred for 2hr at room temperature. Ethanol to was removed under reduced pressure, added water and washed with ethylacetate, and then, acidified by adding 1N HCl, extracted with ethylacetate, and dried over anhydrous MgS04, filtered and distilled under reduced pressure. The resultant was dissolved in 1,4-dioxane(lOmL), refluxed for 3hr and solvent was evaporated under reduced pressure. The residue was recrystallized with MC/MeOH(19/1, v/v) and hexane to give the titled compound(0.17g, 600).
zH NMR (300MHz, CDC13) : 6 2. 76 (dd, 1H) , 2. 90 (dd, 1H) , 3. 42 (dd, 1H) , 3. 49 (m, 1H) , 3. 58 (dd, 1H) , 7. 10 (t, 1H) , 7.26(m, 1H), 7.45(m, 5H), 7.65(m, 5H), 8.07(d, 2H) Example 17: Preparation of N-cyclopropyl-5-(biphenyl-4-yI) 5-oxo-3-carboxylvaleramide(I, R1=H) The titled compound was prepared in a similar manner as in Example 16, except for employing N-cyclopropyl-5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI, R1=H ) .
1H NMR(300MHz, CDC13) : S 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), 7.62(d, 2H), 7.69(d, 2H), 8.02(d, 2H) example 18: Preparation of N-(a -methylbenzyl)-5-(biphenyl-4-yl)-5-oxo-3-carboxylvaleramide(I, R1=H) The titled compound was prepared in a similar manner as in Example 16, except for employing N-(a -methylbenzyl)-5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI, R1-H ) .

1H NMR(300MHz, CDC13) : s 1.44 (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) 1o Exanl~le 19: Preparation of N-phenyl-5-(4'-methoxybiphenyl-4-yl ) -5-oxo-3-carboxylvaleramide ( I, R1=OMe ) The titled compound was prepared in a similar manner as i.n Example 16, except for employing N-phenyl-5 15 (biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI, R1=OMe ) .
1H NMR (300MHz, CDC13) : 8 2. 70 (dd, 1H) , 2. 91 (dd, 1H) , 3.40(dd, 1H), 3.49(m, 1H), 3.55(dd, 1H), 3.84(s, 3H), 20 6.98(d, 2H), 7.06(t, 1H), 7.30(m, 2H), 7.50(m, 4H), 7.62(d, 2H), 8.01(d, 2H) Example 20: Preparation of N-[1,5-dioxo-5-(4'-methoxybiphenyl-4-yl)-3-carboxylpentane-1-yl]-4-methylpiperazine(I, R1=OMe)(VI) The titled compound was prepared in a similar manner as in Example 16, except for employing N-[1,5-dioxo-5-(4'-methoxybiphenyl-4-yl)-3,3-diethoxycarbonylpentane-1-yl]-4-3o methylpiperazine (VI, R1=OMe) .
1H NMR(300MHz, CDC13) : S 1.20 (s,' 3H) , 2.45 (s, 1H) , 2.65(m, 4H), 2.82(dd, 1H), 3.28(dd, 1H), 3.39(br, 4H), 3. 65 (dd, 1H) , 3. 84 (s, 3H) , 4 . 23 (m, 1H) , 6. 98 (d, 2H) , 7. 54 (d, 2H) , 7 . 62 (d, 2H) , 8 . 00 (d, 2H) Example 2 Preparation of N-phenyl-5-(4'-bromobiphenyl-4-y1 ) -5-oxo-3-carboxylvaleramide ( I, R1=OMe ) ( I ) The titled compound was prepared in a similar manner as in Example 16, except for employing N-phenyl-5-(4'-bromobiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleramide(VI, R1=Br ) .
1H NMR (300MHz, CDC13+DMSO) : s 2. 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: Preparation of N-[1,5-dioxo-5-(4'-bromobiphenyl-4-yl)-3-carboxylpentane-1-yl]
piperidine (I, R1=Br) The titled compound was prepared in a similar manner as in Example 16, except for employing N-[1,5-dioxo-5-(4'-bromobiphenyl-4-yl)-3,3-diethoxycarbonylpentane-1-yl]
piperidine (VI, R1=Br) .
1H NMR(300MHz, CDC13) : S 2.85 (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) Example23: Preparation of N-[1,5-dioxo-5-(4'-bromobiphenyl-4-yl)-3-carboxylpentane-1-yl]-4-benzoylpiperazine(I, R1=Br) The titled compound was prepared in a similar manner as in Example 16, except for employing N-[1,5-dioxo-5-(4'-bromobiphenyl-4-yl)-3,3-diethoxycarbonylpentane-1-yl]-4-benzoylpiperazine (VI, R1=Br) .
1H NMR (300MHz, CDC13) : s 2. 59 (dd, 1H) , 2. 86 (br, 4H) , 3.10(dd, 1H), 3.42(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, IH) , 8 . 02 (d, 2H) Example 24: Preparation of 1,5-dioxo-1-(1-phenylcarbamoyl-1-ethylamino)-5-(4'-bromobiphenyl-4-yl)-3-carboxylpentane(I, Rz=Br) To 1,5-dioxo-1-(1-phenylcarbamoyl-1-ethylamino)-5-(4'-bromobiphenyl-4-yl)-3,3-diethoxycarbonylpentane(VI, R1=Br, 120mg, 0.197mmol) dissolved in ethanol(5mL) was added 1N NaOH(lmL, lmmol) and stirred for 5hr at room 1o temperature. Ethanol was removed under reduced pressure, added water and washed with ethylacetate, and then, acidified by adding 1N HCl, extracted with ethylacetate, and dried over anhydrous MgS04, filtered and distilled under reduced pressure. The resultant was dissolved in 1,4-dioxane(lOmL), refluxed for 2hr and solvent was evaporated under reduced pressure. The residue was recrystallized with MC/MeOH(19/1, v/v) and hexane to give the titled compound(64mg, 60%).
1H NMR (300MHz, CDC13) : s 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, 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: Preparation of 5-(4'-chlorobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid t-butyl ester(VII, R1=Cl) KOH(85%, 0.72g, ll.Ommol) dissolved in ethanol(30mL) was added slowly to 5-(4'-chlorobiphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester(IV, R1=Cl, 5.26g, 10.46mmol) dissolved in ethanol(30mL). The reaction mixture was stirred for 6hr at room temperature, and acidified by adding 1N HCl, extracted with ethylacetate, and dried over anhydrous MgSOa, filtered and distilled under reduced pressure. The resultant was dissolved in 1,4-dioxane(lOmZ), refluxed for 3hr and solvent was evaporated under reduced pressure to give the titled compound(3.51g, 780).
1H NMR (300MHz, CDC13) : 6 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) Examz~le 26: Preparation of 5-(biphenyl-4-yl)-5-oxo-3-1o ethoxycarbonylvaleric acid t-butyl ester(VII, Ri-H ) The titled compound was prepared in a similar manner as in Example 25, except for employing 5-(biphenyl-4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester(IV, R1=H ) .
1H NMR(300MHz, CDC13) : S 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 27: Preparation of 5-(4'-bromobiphenyl-4-yl)-5-oxo 3-ethoxycarbonylvaleric acid t-butyl ester(VII, R1=Br ) The titled compound was prepared in a similar manner as in Example 25, except for employing 5-(4'-bromobiphenyl 4-yl)-5-oxo-3,3-diethoxycarbonylvaleric acid t-butyl ester (IV, R1=Br) .
1H NMR(300MHz, CDC13) : 8 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 . 48 (d, 2H) , 7. 60 (d, 2H) , 7 . 65 (d, 2H) , 8 . 04 (d, 2H) example 28: Preparation of 5-(4'-chlorobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=C1) To 5-(4'-chlorobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid t-butyl ester(VII, R1=Cl, 3.518, 8.14mmo1) dispersed in MC(50mL) was,added TFA(7.4mL) and stirred for 24hr at room temperature. MC was removed under reduced pressure, and added ethylacetate(20mL). Then, 1N
NaOH was added slowly and stirred for l0min, and the separated organic layer was extracted with water. And then, to the aqueous solution was collected, treated with 1N
HCl(30mL) and extracted with ethylacetate. The separated organic layer was dried over anhydrous MgS04, filtered and distilled under reduced pressure. The residue was recrystallized with CHC13 and hexane to give the titled compound(2.7g, 88%).
1H NMR (300MHz, CDC13) : S 1.24 (t, 3H) , 2. 84 (ddd, 2H) , 3.30(dd, 1H), 3.48(m, 1H), 3.57(dd, 1H), 4.18(q, 2H), 7.42(d, 2H), 7.55(d, 2H), 7.65(m, 2H), 8.03(d, 2H) 2o Example 29: Preparation of 5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) The titled compound was prepared in a similar manner as in Example 28, except for employing 5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid t-butyl ester((VII, R1=H).
1H NMR (300MHz, C.DC13) : S 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) Example30: Preparation of 5-(4'-bromobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=Br) The titled compound was prepared in a similar manner as in Example 28, except for employing 5-(4'-bromobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid t-butyl ester((VII, R1=Br ) .
1H NMR(300MHz, CDC13) : S 1.24 (t, 3H) , 2. 84 (ddd, 2H) , 3.30(dd, 1H), 3.48(m, 1H), 3.57(dd, 1H), 4.18(q, 2H), 5 7.48(d, 2H), 7.60(d, 2H), 7.65(d, 2H), 8.04(d, 2H) Examx~le 31: Preparation of N-(3-cyanophenyl)-5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleramide~(IX, R1=H) 10 5-(Biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid (VIII, R1=H, 50mg, 0.147mmo1) was dissolved in THF(3mL) and cooled to a temperature of OC. And, N-methylmorpholine(35mL, 0.323mmo1) and ethylchloroformate (l6mL, 0.162mmo1) were added slowly, and stirred for 30 min 15 at room temperature. And then, 3-aminbbenznitrile dissolved in THF(1mL) was added, stirred for 3hr and 30min, filtered and distilled under reduced pressure. After diluting with chloroform, washing with 1N HCl, 10o NaHC03 and water in a sequential order, the resultant was dried 20 over anhydrous MgS04, filtered and distilled under reduced pressure to give the titled compound(55.5mg, 860).
1H NMR (300MHz, CDC13) : s 1. 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, 25 5H) ., 8. 01 (m, 3H) , 8.20 (s, 1H) Example 32: Preparation of N-(3-acetylphenyl)-5-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleramide(IX, R1=H ) ( IX ) The titled compound was prepared in a similar manner as in Example 31, except for employing 5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid((VIII, R1=H) and 3-aminoacetophenone.
1H NMR (300MHz, CDC13) : S 1. 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) xample 3333: Preparation of N-(3-acetylphenyl)-5-[(4' chlorobiphenyl-4-yl)]-5-oxo-3 ethoxycarbonylvaleramide(IX, R1=C1) The titled compound was prepared in a similar manner as in Example 31, except for employing 5-[(4' chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvalerio acid (VIII, R1=Cl) and 3-aminoacetophenone.
1H NMR(300MHz, CDC13) : S 1.24 (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: Preparation of N-(2-chlorophenyl)-5-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleramide(IX, R1=H ) The titled compound was prepared in a similar manner as in Example 31, except for employing 5-(-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and 2-chloroaniline.
1H NMR (300MHz, CDC13) : 8 1.24 (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: Preparation of N-(3-chlorophenyl)-5-[(biphenyl-4-yl)]- 5-oxo-3-ethoxycarbonylvaleramide(IX, R1=H ) The titled compound was prepared in a similar manner as in Example 31, except for employing 5-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and 3-chloroaniline.
1H NMR(300MHz, MeOH-d4) : s 1.24 (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: Preparation of N-(4-chlorophenyl)-5-[(biphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleramide(IX, R1=H)(IX) The titled compound was prepared in a similar manner as in Example 31, except for employing 5-[(biphenyl-4-yl)]
5-oxo-3-ethoxycarbonylvaleric acid(VIII, Rl=H) and 4 chloroaniline.
1H NMR(300MHz, DMSO-d6) : s 1.24 (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, 2H) , 7 . 68 (d, 2H) , 8 . 04 (d, 2H) ao Example 37: Preparation of N-[3-(N,N-diethylcarbamoyl)phenyl]-5-[(4'-chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleramide(IX, R1=C1)(IX) The titled compound was prepared in a similar manner as in Example 31, except for employing 5-[(4'-chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid (VIII, R1=Cl) and 3-(N,N-diethylcarbamoyl)aniline.
1H NMR ( 300MHz, CDC13) : 8 1. 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) Examble 38: Preparation of N-[3-(N-phenylcarbamoyl)phenyl]-5-[(4'-chlorobiphenyl-4-yl)]-5-oxo-3-thoxycarbonylvaleramide(IX, R1=C1) The titled compound was prepared in a similar manner as in Example 31, except for employing 5-[(4'-chlorobiphenyl-4-yl)]-5-oxo-3-ethoxycarbonylvaleric acid (VIII, R1=Cl) and 3-(N-phenylcarbamoyl)aniline.
1H NMR(300MHz, CDC13) : s 1.17 (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: Preparation of (L)-1,5-dioxo-1-(1-phenylcarbamoyl-1-ethylamino)-5-(biphenyl-4-yl)-3-ethoxycarbonylpentane(IX, R1=H) 5-(Biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H, 100mg, 0.29mmo1) was dissolved in THF(5mL) and cooled to a temperature of 0°C. And, N-2o methylmorpholine(70mL, 0.65mmol) and ethyl chloroformate(3lmL, 0.32mmo1) were added and stirred for 30 min. And then, L-Ala-CONH-Ph(see: Kruse, C. H, et al, J.
Org. Chem., 50:2792, 1985; Fink, C. A, et al, Bioorg. Med.
Chem. Lett., 9:195-200, 1999) dissolved in THF(1mL) was added, stirred for 3hr and 30min, filtered and distilled under reduced pressure. After diluting with chloroform, washing with 1N HCl, 10% NaHC03 and water in a sequential order, the resultant was dried over anhydrous MgS09, filtered and distilled under reduced pressure to give the 3o titled compound(105mg, 73%).
1H NMR (300MHz, CDC13) : s 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, 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: Preparation of (D)-1,5-dioxo-1-(1-phenylcarbamoyl-1-ethylamino)-5-(biphenyl-4-yl)-3-ethoxycarbonylpentane(IX, R1=H) The titled compound was prepared in a similar manner as in Example 39, except for employing 5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid and D-Ala-CONH-Ph(105mg, 730) .
1H NMR (300MHz, CDC13) : 8 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, 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) Examp a 41: Preparation of 1,5-dioxo-1-[1-(0-chlorophenyl)carbamoyl-1-ethylamino]-5-(biphenyl-4-yl)-3-ethoxycarbonylpentane (IX, R1=H ) ( IX ) The titled compound was prepared in a similar manner 2o as in Example 39, except for employing 5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and L-Ala-CONH-o-ClPh.
1H NMR (300MHz, CDC13) : s 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, 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 42: Preparation of 1,5-dioxo-1-[1-(m-3o chlorophenyl)carbamoyl-1-ethylamino]-5-(biphenyl-4-yl)-3-ethoxycarbonylpentane(IX, R1=H ) ( IX ) The titled compound was prepared in a similar manner as in Example 39, except for employing 5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and L-Ala-~CONH-m-ClPh.

1H NMR (300MHz, CDC13) : 8 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, 1H) , 6. 15 (dd, 1H) , 7. 07 (t, 1H) , 7. 30 (t, 2H) , 7. 45 (m, 5 3H), 7.58(m, 4H), 7.68(d, 2H), 7.97(t, 2H), 8.60(d, 1H) Example 43: Preparation of 1,5-dioxo-1-[1-(p-chlorophenyl)carbamoyl-1-ethylamino]-5-(biphenyl-4-yl)-3-ethoxycarbonylpentane(IX, 10 R1=H ) ( IX ) The titled compound was prepared in a similar manner as in Example 39, except for employing 5-(biphenyl-4-yl)-5 oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and L-Ala 15 CONH-p-ClPh.
1H NMR (300MHz, CDC13) : s 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, 1H), 6.15(dd, 1H), 7.08(t, 1H), 7.29(t, 2H), 7.45(m, 20 3H) , 7 . 58 (m, 4H) , 7. 70 (d, 2H) , 7. 97 (t, 2H) , 8 . 60 (d, 1H) Example 44: Preparation of N-X1,5-dioxo-5-[(biphenyl-4-yl)]-3-ethoxylcarbonylpentane-1-yl}-2-(N-phenylcarbamoyl)pyrrolidine(IX, R1=H) The titled compound was prepared in a similar manner as in Example 39, except for employing 5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and L-Pro-CONH-Ph.
1H NMR (300MHz, CDC13) : S 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, 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) ~xamx~le 45: Preparation of 1,5-dioxo-1-[1-phenylcarbamoyl-2-phenyl-1-ethylamino]-5-(biphenyl-4-yl)-3-ethoxycarbonylpentane(TX, R1=H) The titled compound was prepared in a similar manner as in Example 39, except for employing 5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid(VIII, R1=H) and Z-Phe-CONH-Ph.
1H NMR (300MHz, CDC13) : S 1. 17 (dt, 3H) , 2. 382. 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, 1H) Examble 46: Preparation of N-X1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl)]-3-ethoxylcarbonylpentane-1-yl}-2-(N-phenylcarbamoyl)pyrrolidine(IX, R1=H) 2o The titled compound was prepared in a similar manner as in Example 39, except for employing 5-(4'-chlorobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid (VIII, R1=C1) and Z-Pro-CONH-Ph.
1H NMR (300MHz, CDCl3) : 8 1. 20 (t, 3H) , 1. 90 (m, 1H) ;
2 . 06 (m, 1H) , 2 . 58 (br, 2H) , 2. 703. 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), 9.29.4 (d, 1H) Example 47: Preparation of 1,5-dioxo-1-[1-phenylcarbamoyl-2-phenyl-1-ethylamino]-5-(4'-chlorobiphenyl-4-yl)-3-ethoxycarbonylpentane(IX, R1=Cl) The titled compound was prepared in a similar manner as in Example 39, except for employing 5-(4'-chlorobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleric acid (VIII, R1=C1) and L-Phe-CONH-Ph.
1H NMR(300MHz, CDC13).: 8 1.17 (dt, 3H) , 2.382.55 (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, 1H) Example 48: Preparation of N-(3-cyanophenyl)-5-[(biphenyl-4-yl)]-5-oxo-3-carboxylvaleramide(I, R1=H) To N-(3-cyanophenyl)-5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleramide(IX, R1=H, 11.8mg, 0.0268mmo1) dissolved in ethanol(2mL) was added 1N NaOH(0.5 mL) and stirred for lhr and 30min at room temperature, added water and washed with ethylacetate. And, the resultant was acidified by adding 1N HCl, and extracted by employing MC, and dried over anhydrous MgS04. And then, the resultant was filtered and distilled under reduced pressure, and, 2o recrystallized with CHC13/MeOH(19/l, v/v) and hexane to give the titled compound(10.4mg, 940).
1H NMR (300MHz, CDC13) : S 2. 74 (dd, 1H) , 3. O1 (dd, 1H) , 3.54(m, 3H), 7.42(m, 4H), 7.65(m, 5H), 8.01(m, 3H), 8.20(s, lH) Example 49: Preparation of N-(3-acetylphenyl)-5-[(biphenyl-4-yl)]-5-oxo-3-carboxylvaleramide(I, R1=H) 3o The titled compound was prepared in a similar manner as in Example 48, except for employing N-(3-acetylphenyl)-5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleramide(IX,R1=H).
1H NMR(300MHz, CDC13) : 8 2.59 (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: Preparation of N-(3-acetylphenyl)-5-[(4'-chlorobiphenyl-4-yl)]-5-oxo-3-carboxylvaleramide(I, R1=H) The titled compound was prepared in a similar manner as in Example 48, except for employing N-(3-acetylphenyl)-5-(4'-chlorobiphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleramide (IX, R1=H) .
l0 1H NMR(300MHz, CDC13) : 8 2. 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: Preparation of N-(3-chlorophenyl)-5-[(biphenyl-4-yl) ] -5-oxo-3-carboxylvaleramide (I, R1=H) The titled compound was prepared in a similar manner as in Example 48, except for employing N-(3-chlorophenyl)-5-(biphenyl-4-yl)-5-oxo-3-ethoxycarbonylvaleramide(IX,R1=H).
1H NMR (300MHz, MeOH-d4) : s 2. 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: Preparation of 1,5-dioxo-1-(1-phenylcarbamoyl-1-ethylamino) -5- (biphenyl-4-yl) -3-carboxylpentane (I, Rl=H) To 1,5-dioxo-1-(1-phenylcarbamoyl-1-ethylamino)-5-(biphenyl-4-yl)-3-ethoxycarbonylpentane(IX, R1=H, 105mg, 0.215mmol) dissolved in ethanol(5mL) was added 1N NaOH(lmL, lmmol) and stirred for 90min at room temperature, added water and washed with ethylacetate. And then, the resultant was acidified by adding 1N HCl, and extracted with MC, and dried over anhydrous MgS04, filtered and distilled under reduced pressure. The residue was recrystallized with CHC13/MeOH(19/1, v/v) and hexane to give the titled compound(88mg, 890).
1H NMR(300MHz, CDC13) : s 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, 1H) , 7 . 27 (m, 1H) , 7. 45 (m, 3H) , 7 . 58 (m, 6H) , 7. 97 (t, 2H) , 8. 408. 60 (d, 1H) Examx~le 53: Preparation of N-{1,5-dioxo-5-[(4'-chlorobiphenyl-4-yl)]-3-carboxylpentane-1-yl}-Lo 3-(N-phenylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline(I, R1=Cl) The titled compound was prepared in a similar manner as in Example 52, except for employing N-{1,5-dioxo-.5-[(4'-chlorobiphenyl-4-yl)]-3-ethoxycarbonylpentane-1-yl}-3-(N-phenylcarbamoyl)-1,2,3,4-tetrahydroisoquinoline(IX, R~=C1).
1H NMR (300MHz, CDC13) : 6 2. 703.20 (m, 2H) , 3. 383. 57 (m, 4H), 4.11(m, 1H), 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, 1H) Examx~le 54: In vitro inhibition on gelatinase A(MMP-2) The present test was accomplished by measuring the fluorescence intensity of a fluorescent material(7-methoxycoumarin-4-acetyl-Pro-Leu-Gly) produced from the cleavage of a fluorescent synthetic peptide substrate((7-methoxycoumarin-4-acetyl-Pro-Leu-Gly-Leu-j3 -(2,4-dinitrophenylamino)Ala-Ala-Arg-NHz(Sigma Chem. Co., 3o U.S.A.)) by gelatinase A(Boehringer Manneheim cat# 1782916, from human fibrosarcoma cells).
Enzymatic reaction employing a fluorescent synthetic substrate was accomplished by leaving test compounds, TNBC
buffer solution(25mM Tris-HCl, pH 7.5, 0.1M NaCl, 0.010 Brij-35, 5mM CaCl2), gelatinase A(final concentration in well: 4.17nM) activated with 1 mM of APMA(aminophenylmercuric acetate) for 30 minutes at 37°C

just before the enzymatic reaction, and the substrate, fluorescent synthetic peptide(final concentration in well:
9.25uM) in 96 well plate and then reacting for 30 minutes at 37°C, and the fluorescence intensity was measured at 5 excitation 328nm and emission 393nm by spectrofluorimeter(Fmax(molecular device)). The inhibition rate(o) was calculated from the following equation:
~11~1~1t3~1. .~,~~~~,~o~ _ 1o wherein, A represents fluorescence intensity before the reaction with an inhibitor;
B represents fluorescence intensity after the reaction with an inhibitor 15 C represents fluorescence intensity before the reaction without an inhibitor; and, D represents fluorescence intensity after the reaction without an inhibitor.
2o Example 55: In vitro inhibition on gelatinase B(MMP-9) In vitro inhibition rate on gelatinase B(MMP-9) was measured in a similar manner as in Example 54, except for employing gelatinase B(Boehringer Manneheim cat# 1758896, 25 from human blood) with a different concentration(final concentration in well: 2.715nM) and a different concentration of the substrate, fluorescent synthetic peptide(final concentration in well: 4.575uM).
3o Example 5~: In vitro inhibition on collagenase(MMP-1) In vitro inhibition rate on collagenase(MMP-1) was measured in a similar manner as in Example 54, except for employing collagenase(AngioLab. Co., Ltd) with a final concentration in well of 7.25nM.
ht O
i Hhf -w~1 No R1 R~ R3 ICSO (u ICso (~1 . M) M) 1 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 H (L) -Me m-C1-Ph 0 .13 3. 65 6 H (L)-Me p-C1-Ph 0.27 7.18 7 C1 (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 Cl Ph 0.008 0.027 No. R1 Rz ICSO (u ICSO (~L
M) M) 1 H ~~~ 0 . 018 0 . 7 7 2 C1 ~ ~ 0.004 0.085 .~t~

3 H a N~ 0.0062 0.11 H
D hi~R~
R
No. R1 RZ R3 ICso (~i ICso (1~ ICso (u M) M) M) 1 H Ph H 2.68 2 H Cyclopropyl H 3.22 3 H (+) -a -MeanH 1.16 4 Me0 Ph H 0.29 Me0 1.30 lil~rf.~

6 Br Ph H 0.17 6.2 7 Br 0.98 16.5 8 Br ~' 0 . 7 9 . 6 9 Cl Ph H 0.11 3.39 H o-Cl-Ph H 1.25 2.16 11 H m-Cl-Ph H 0.57 10.46 12 H p-Cl-Ph H 1.03 12.10 13 H m-CN-Ph H 2.82 76.61 14 H m-acetyl-Ph H 0.99 36.25 C1 m-acetyl-Ph H 0.14 1.61 16 Cl ~~ H 0.0081 0.09 137.97 5 As clearly illustrated and demonstrated as above, the present invention provides novel biphenylbutyric acid derivatives which inhibit MMP activity, their isomers and the pharmaceutically acceptable salts thereof, and a process for preparing the compounds. Since the to biphenylbutyric acid derivatives of the present invention selectively inhibit MMP activity in vitro, the MMP
inhibitors comprising the biphenylbutyric acid derivatives as an active ingredient can be practically applied for the prevention and treatment of diseases caused by 15 overexpression and overactivation of MMP.

.Although the preferred embodiments of the present invention have been disclosed for illustrative purpose, those who are skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as described in the accompanying claims.

Claims

WHAT IS CLAIMED IS:

1. A compound represented as the following general formula(I), its isomers and pharmaceutically acceptable salts thereof:

wherein, R1 is hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano, -OCF3, -OCH2F, -OR4, -SR4, -S(O)R4 or -S(O)2 where R4 and R4a, which may be the same or different, are alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl;
R2 and R3, which may be the same or different, are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; and, n is 1 or 2.

2. The compound, its isomers and pharmaceutically acceptable salts thereof according to claim 1, wherein R2 and R3 are taken together with carbon, nitrogen, oxygen or sulfur to form C5-6 ring, which includes the followings:

where, R8 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; and, X is O or S.

3. The compound, its isomers and pharmaceutically acceptable salts thereof according to claim 1, wherein R2 further includes a substituent represented as a general formula below:

where, R5 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylsulfinylalkyl, arylsulfonylalkyl or cycloalkyl; and, R6 and R7 which may be the same or different, are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl.

4. The compound, its isomers and pharmaceutically acceptable salts thereof according to claim 3, wherein R2 is the same as defined in claim 3, provided that R3 is hydrogen; and, provided that R3 is not hydrogen, R3 and R5 are taken together with carbon, nitrogen, oxygen or sulfur to form C5-6 ring in which moiety includes the followings:

where, R6 and R7 are the same as above;
R9 is hydrogen, hydroxy, alkoxy, aryloxy, thiol or alkylthio;
R10 is oxo, hydroxyamine or hydrazone;
R11 and R12 are hydrogen or C1-6 lower alkyl; and, Y is CH2, O or S.

5. The compound, its isomers and pharmaceutically acceptable salts thereof according to claim 3 or claim 4, wherein R6 and R7 are taken together with carbon, nitrogen, oxygen or sulfur to form cyclic compounds which include the followings:
Where, R8 and X are the same as above.

6. The compound, its isomers and pharmaceutically acceptable salts thereof according to one of claims 1 to 5 which have an inhibitory activity against matrix metalloproteinase.

7. A process for preparing a compound represented as the general formula(I), which comprises:
(i) reacting a compound(II) with a compound(III) to obtain t-butylester compound(IV);
(ii) deprotecting t-butylester compound(IV) to obtain a butylester group-free compound(V);
(iii) condensing the compound(V) with an amine compound to obtain a compound(VI) containing diethylester group; and, (iv) hydrolyzing diethylester groups of the compound(VI) into carboxylic groups and then decarboxylating, to prepare a compound(I):

wherein, R1, R2 and R3 are the same as defined in claim 1.

8. A process for preparing a compound represented as the general formula(I), which comprises:
(i) reacting a compound(II) with a compound(III) to obtain t-butylester compound(IV);
(ii) hydrolyzing one of ethylester groups in t-butylester compound(IV) to a carboxylic group and then decarboxylating, to obtain a compound(VII);
(iii) deprotecting the compound(VII) to obtain a butylester group-free compound(VIII);
(iv) condensing the compound(VIII) with an amine compound to obtain a compound(IX) containing ethylester groups; and, (v) hydrolyzing ethylester group of the compound(IX) to a carboxylic group to prepare a compound(I):

wherein, R1, R2 and R3 are the same as defined in claim 1.