EP1189882A1 - Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor - Google Patents

Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor

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Publication number
EP1189882A1
EP1189882A1 EP01926225A EP01926225A EP1189882A1 EP 1189882 A1 EP1189882 A1 EP 1189882A1 EP 01926225 A EP01926225 A EP 01926225A EP 01926225 A EP01926225 A EP 01926225A EP 1189882 A1 EP1189882 A1 EP 1189882A1
Authority
EP
European Patent Office
Prior art keywords
compound
oxo
hydrogen
biphenyl
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01926225A
Other languages
German (de)
French (fr)
Inventor
Young-Jun Park
Choon-Ho Ryu
Ji-Uk Yoo
Myeong-Yun Chae
Sang-Hyun Paek
Kyung-Chul Kim
Jeoung-Wook Lee
Hye-Kyung Min
Hae-Young Bae
Eu-Gene Oh
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Samsung Electronics Co Ltd
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Samsung Electronics Co Ltd
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Filing date
Publication date
Priority claimed from KR10-2000-0021835A external-priority patent/KR100405914B1/en
Priority claimed from KR10-2000-0021834A external-priority patent/KR100405913B1/en
Application filed by Samsung Electronics Co Ltd filed Critical Samsung Electronics Co Ltd
Publication of EP1189882A1 publication Critical patent/EP1189882A1/en
Withdrawn legal-status Critical Current

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    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
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    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
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    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
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    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
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    • C07C255/58—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton
    • C07C255/60—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and singly-bound nitrogen atoms, not being further bound to other hetero atoms, bound to the carbon skeleton at least one of the singly-bound nitrogen atoms being acylated
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    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
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    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/50—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to atoms of the carbocyclic ring
    • C07D317/60—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to biphenyl butyric 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.
  • Matrix metalloproteinase is a Ca 2+ -dependent proteinase containing zinc ion(Zn 2+ ) at its active site.
  • matrix metalloproteinases including stromelycin, collagenase and a family of gelatinase 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 activated in extracellular side, together with a naturally occuring inhibitor, TIMP (tissue inhibitor of metalloproteinase) .
  • TIMP tissue inhibitor of metalloproteinase
  • MMP inhibitor is useful to prevention and treatment of all sorts of diseases caused by overexpression or overactivation of MMP.
  • 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 (s_e_e_: Beeley et al., Curr. Opin. Ther. Patents, 4(1):7-16, 1994).
  • 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).
  • 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 .
  • MMP-1 and MMP- 3 among MMP enzymes play an important role in the progress of arthritis as observed in much higher concentration than normal in the synovium and cartilage of a patient of rheumatoid arthritis ( ⁇ e_£: Arthritis Rheum., 35:35-42, 1992), the selectivity to MMP-l/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 ( ⁇ e ⁇ : J.
  • 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.
  • ZBGs include hydroxamic acid, carboxylic acid, phosphoric acid, phosphinic acid, thiol and so forth ( ⁇ e_ ⁇ : WO 92/09564; WO
  • the peptide-mimic inhibitors are known to contain a hydroxamic acid as a ZBG and display a broad spectrum for MMP enzymes.
  • 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_e_e_: USP 5,506,242; J. Med. Chem., 40:2525-2532, 1997).
  • new sulfonamide derivatives have been designed and synthesized, by changing PI' of the above sulfonamide inhibitor which binds to SI' 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-l/MMP-2 as compared with previous peptide-mimic inhibitors. Some of them have also side effect of arthralgia in clinical trials (s_e_e_: Current Pharmaceutical Design, 5:787-819, 1999; Current Opinion in Drug Discovery & Development, 3:353-361, 2000; Exp. Opin. Invest.
  • biphenyl butyric acid derivatives as MMP inhibitors have been designed and reported (s_e_e_: 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) .
  • the present inventors have made an effort to develop novel compounds whose inhibitory action on MMP and selectivity to MMP-l/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.
  • the other object of the invention is to provide a process for preparing the said compounds.
  • 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 for preparing the said compounds.
  • R_ is hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano, -OCF 3 , -OCH 2 F,
  • R 4 and R 4 a which may be the same or different, are alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl
  • R 2 and R 3 which may be the same or different, are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl
  • n is 1 or 2
  • R 2 and R 3 are taken together with carbon, nitrogen, oxygen or sulfur to form C 5 _ 6 ring, which includes the followings:
  • R 8 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; and, X is 0 or S.
  • R 2 may further include a substituent represented as the following structural formula:
  • R 5 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl, hydroxyalkyl, alkoxyalkyl, alkylthioalkyl, arylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, arylsulfinylalkyl, arylsulfonylalkyl or cycloalkyl; and,
  • R 6 and R 7 which may be the same or different, are hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl.
  • R 3 is not hydrogen
  • R 3 and R 5 of the above formula (I) are taken together with carbon, nitrogen, oxygen or sulfur to form C 5 _ 6 ring in which
  • R 6 and R 7 are the same as above;
  • R 9 is hydrogen, hydroxy, alkoxy, aryloxy, thiol or alkylthio
  • R 10 is oxo, hydroxyamine or hydrazone
  • R u and R 12 are hydrogen or C**_ 6 lower alkyl
  • Y is CH 2 , 0 or S.
  • R 6 and R 7 are taken together with carbon, nitrogen, oxygen or sulfur to form C 5 _ 6 ring, which includes the followings:
  • the pharmaceutically acceptable salts of the invention include acid-added salts and hydrates.
  • 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.
  • inorganic acid salts hydrochloride, hydrogen bromide, hydrogen iodide, sulfate, phosphate, nitrate, etc.
  • organic acid salts acetate, lactate, tartarate, oxalate, fumarate, glucuronate, etc.
  • 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.
  • Step 1 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 commercially available or prepared by the conventionally known methods and the compound (III) may be prepared by partial modification of the conventionally known methods (sj ⁇ e.: B.S. Furniss, et al., VOGEL' s Textbook of Practical Organic Chemistry, 5 th ed., pp942-943, 1988; WO 96/15096) .
  • 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 HC1.
  • the compound (V) is condensed with an amine compound to give a compound (VI) containing diethylester group: the amine compound comprises R 2 and R 3 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.
  • Step 4 Synthesis of a compound (I)
  • the compounds of the general formula (I) may also be prepared by the following Process 2.
  • R- L , R 2 and R 3 are the same as above.
  • a compound (II) is reacted with a compound (III) to 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 (s_e_e: B.S. Furniss, et al . , VOGEL' s Textbook of Practical Organic Chemistry, 5 th ed. , pp942-943, 1988; WO 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.
  • the compound (VII) is deprotected to give a butylester group-free compound (VIII) : the deprotection is preferably carried out by using TFA or anhydrous HC1.
  • the compound (VIII) is condensed with an amine compound to give a compound (IX) containing ethylester group: the amine compound comprises R 2 and R 3 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.
  • Ethylester group of the compound (IX) is hydrolyzed to a carboxylic group to prepare a compound (I) (see: WO 96/15096) .
  • the titled compound was prepared in a similar manner as in Example 1, except for employing 4- (4 ' -bromophenyl) - ⁇ -bromoacetophenone (II, R ⁇ Br)
  • the titled compound was prepared in a similar manner as in Example 1, except for employing 4- (4 ' -chlorophenyl) - ⁇ -bromoacetophenone (II, R- ⁇ Cl) .
  • 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, R ⁇ 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, R- ⁇ Br) and piperidine.
  • the titled compound was prepared in a similar manner as in Example 8, except for employing N- benzoylpiperazine (see,: Kondo, K. et al, J. Chem. Soc,
  • 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,
  • the titled compound was prepared in a similar manner as in Example 16, except for employing N-phenyl-5- (biphenyl-4-yl ) -5-oxo-3 , 3-diethoxycarbonylvaleramide (VI , R ⁇ OMe) .
  • 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-l-yl] -4- methylpiperazine (VI, R- ⁇ OMe) .
  • 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,
  • 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, R ⁇ Br) .
  • 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, R- ⁇ H) and 2- chloroaniline .
  • 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, 73%) .
  • 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, R-
  • H) and L-Ala- CONH-m-ClPh.
  • Example 54 In vi tro 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- ⁇ -(2,4- dinitrophenylamino) Ala-Ala-Arg-NH 2 (Sigma Chem. Co., 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, 0.01% Brij-35, 5mM CaCl 2 ) , 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: 9.15uM) in 96 well plate and then reacting for 30 minutes at 37 °C, and the fluorescence intensity was measured at excitation 328nm and emission 393nm by spectrofluorimeter (Fma (molecular device)).
  • the inhibition rate(%) was calculated from the following equation:
  • A represents fluorescence intensity before the reaction with an inhibitor
  • B represents fluorescence intensity after the reaction with an inhibitor
  • C represents fluorescence intensity before the reaction without an inhibitor
  • D represents fluorescence intensity after the reaction without an inhibitor.
  • 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.
  • 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 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 overexpression and overactivation of MMP. .

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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 selectively inhibits the activity of MMP in vitro, it can be practically applied to the treatment and prevention of diseases caused by overexpression of MMP.

Description

BIPHENYL BUTYRIC ACID DERIVATIVE AS A MATRIX METALLOPROTEINASE INHIBITOR
BACKGROUND OF THE INVENTION
Field of the Invention
The present invention relates to biphenyl butyric 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.
Description of the 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 gelatinase 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 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 (s_e_e_: Beeley et al., Curr. Opin. Ther. Patents, 4(1):7-16, 1994). For 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 normal in the synovium and cartilage of a patient of rheumatoid arthritis (≤e_£: Arthritis Rheum., 35:35-42, 1992), the selectivity to MMP-l/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 (≤e≤: 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 (≤e_≤: 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 O 98/24759 O 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 (s_e_e_: 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 (≤e_e: 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_e_e_: USP 5,506,242; J. Med. Chem., 40:2525-2532, 1997).
CGS-27023A{Movarfe) Under a consideration that the small -molecule of sulfonamide-derived MMP inhibitors have activities in vi tro 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 (sss.: 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; EP8-95988; EP 878467; EP 1041072) . To improve in vi tro enzymatic activity, selectivity, and pharmacokinetic profiles, new sulfonamide derivatives have been designed and synthesized, by changing PI' of the above sulfonamide inhibitor which binds to SI' 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-l/MMP-2 as compared with previous peptide-mimic inhibitors. Some of them have also side effect of arthralgia in clinical trials (s_e_e_: 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 vi tro 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(.se_e_: 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 belo (see: WO 96/15096).
While the above inhibitors have a very low in vi tro inhibitory activity against MMP as compared with peptide- mimic succinic acid derivatives or sulfonyl amino acid derivatives, they have a far higher selectivity to MMP- l/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 variety of biphenyl butyric acid derivatives as MMP inhibitors have been designed and reported (s_e_e_: 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(£^e_: WO 98/09940; WO 98/06711).
Under the circumstance, there are strong reasons for developing alternative compounds whose inhibitory action on MMP and selectivity to MMP-l/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-l/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.
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 for preparing the said compounds.
wherein,
R_ is hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano, -OCF3, -OCH2F,
-S(0)R4 or -S(0)2 where R4 and R4 a, 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,
In the above formula, R2 and R3 are taken together with carbon, nitrogen, oxygen or sulfur to form C5_6 ring, which includes the followings:
wherein,
R8 is hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; and, X is 0 or S.
Also, in case that R3 is hydrogen, R2 may further include a substituent represented as the following structural formula:
wherein,
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.
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
-fjh-R2 R3 moiety includes the followings:
wherein,
R6 and R7 are the same as above;
R9 is hydrogen, hydroxy, alkoxy, aryloxy, thiol or alkylthio;
R10 is oxo, hydroxyamine or hydrazone;
Ru and R12 are hydrogen or C**_6 lower alkyl; and,
Y is CH2, 0 or S.
Also, R6 and R7 are taken together with carbon, nitrogen, oxygen or sulfur to form C5_6 ring, which includes the followings:
wherein,
Ro and X are the same as above.
Otherwise mentioned, all kinds of isomers of the biphenyl butyric acid derivatives are fallen within the 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.
Process 1:
wherein,
R_, R2 and R3 are the same as above. Step 1: 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 commercially available or prepared by the conventionally known methods and the compound (III) may be prepared by partial modification of the conventionally known methods (sj≥e.: B.S. Furniss, et al., VOGEL' s Textbook of 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 HC1.
Step 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 R2 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.
Step 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: deprotection
wherein,
R-L, R2 and R3 are the same as above.
Step 1: 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 commercially available or prepared by the conventionally known methods and the compound (III) may be prepared by partial modification of the conventionally known methods (s_e_e: B.S. Furniss, et al . , VOGEL' s Textbook of Practical Organic Chemistry, 5th ed. , pp942-943, 1988; WO 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.
Step 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 HC1.
Step 4 : Synthesis of a compound (IX)
The compound (VIII) is condensed with an amine compound to give a compound (IX) containing ethylester group: the amine compound comprises R2 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: WO 96/15096) .
The present invention is further illustrated in the following examples, which should not be taken to limit the scope of the invention.
Example 1 : Preparation of 5- (Biphenyl-4-yl) -5-oxo-3, 3- diethoxycarbonylvaleric acid t-butyl ester (IV,
To 100ml flask were added NaH(95%, 505mg, 20.0mmol) and high-purity THF(15mL), and cooled to a temperature of -10°C. Then, diethyl t-butoxycarbonylmethylmalonate (III, 4.9g, 18.17mmol) dissolved in THF(lOmL) was added slowly, and stirred for 30min at room temperature. And then, 4- phenyl-α -bromoacetophenone (II, Rι=H, 5g, 18.17mmol) dissolved in THF(15mL) was added slowly, and stirred for lhr and 30min at room temperature, and extracted with IN 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, 95%).
λE NMR(300MHz, CDC13) : δ l.24(t, 6H) , 1.38(s, 9H) , 3.39(s, 2H), 3.97(s, 2H) , 4.24(q, 4H) , 7.45(m, 3H) , 7.61(d, 2H) , 7.69(d, 2H) , 8.04(d, 2H)
Example 2 : Preparation of 5- (4 ' -methoxybiphenyl-4-yl) -5- oxo-3, 3-diethoxycarbonylvaleric acid t-butyl ester (IV, Rx=OMe)
The titled compound was prepared in a similar manner as in Example 1, except for employing 4- (4 ' -methoxyphenyl) - α -bromoacetophenone (II, R1=OMe) .
XH NMR(300MHz, CDC13) : δ l.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, R-=Br)
The titled compound was prepared in a similar manner as in Example 1, except for employing 4- (4 ' -bromophenyl) -α -bromoacetophenone (II, R^Br)
XH NMR(300MHz, CDC13) : δ l.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, RX=C1)
The titled compound was prepared in a similar manner as in Example 1, except for employing 4- (4 ' -chlorophenyl) - α -bromoacetophenone (II, R-^Cl) .
'H NMR(300MHz, CDC13) : δ l.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- diethoxycarbonyl aleric acid(V,
To 5- (biphenyl-4-yl) -5-oxo-3, 3-diethoxycarbonylvaleric acid t-butyl ester (IV, RX=H, 1.5g, 3.2mmol) 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 IN NaOH were added slowly, and the separated organic layer was extracted with water. And then, the aqueous solution was collected, treated with IN 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, 91%).
XH NMR(300MHz, CDC13) : δ l.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, R.-OMe)
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=0Me) .
αH NMR(300MHz, CDC13) : δ l.24(t, 6H) , 3.21(s, 2H) , 3.86(s, 3H), 3.94(3, 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- 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, R^Br) .
λE NMR(300MHz, CDC13) : δ l.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, RX=H)
5- (Biphenyl-4-yl) -5-oxo-3, 3-diethoxycarbonylvaleric acid(V, R1=H, 0.5g, 1.2mmol), EDC(0.23g, 1.2mmol) and HOBt(0.16g, 1.2mmol) were dissolved in MC(5mL) and cooled to a temperature of 0°C. And, TEA(170mL, 1.2mmol) was added and stirred for lOmin, followed by addition of aniline (122mL, 1.3mmol) and stirring for 2hr and 30min at room temperature. And then, IN 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=4/1, v/v) to give the titled compound (0.365g, 62%).
XH NMR(300MHz, CDC13) : δ l.24(t, 6H) , 3.32(s, 2H) , 4.05(s, 2H) , 4.24(q, 4H) , 7.07(t, IH) , 7.26(m, IH) , 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, RX=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, RX=H) and cyclopropylamine .
lR NMR(300MHz, CDC13) : δ 0.41(m, 2H) , 0.69(m, 2H) , 2.62 (m, IH) , 3.08(s, 2H) , 4.00(s, 2H),, 4.24(q, 4H) , 5.9(s, IH) , 7.45 (m, 3H) , 7.61(d, 2H) , 7.69(d, 2H) , 8.04(d, 2H)
Example 10: Preparation of N- (α -methylbenzyl) -5- (biphenyl-
4-yl) -5-OXO-3, 3-diethoxycarbonylvaleramide (VI, Rι=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 α - methylbenzylamine .
XH NMR(300MHz, CDC13) : δ l.24(t, 6H) , 1.41 (d, 3H) , 3.17(d, 2H) , 3.97(d, 2H) , 4.21(q, 4H) , 5.0 (m, IH) , 5.95(d, IH) , 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, 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, Rx=OMe) and aniline.
XH NMR(300MHz, CDC13) : δ l.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, IH), 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.
H NMR(300MHz, CDC13) : δ l.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, R-.=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, R-^Br) and piperidine.
lH NMR (300MHz, CDC13) : δ l.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- benzoylpiperazine (see,: 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*,=Br) .
XH NMR(300MHz, CDC13) : δ l.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, IH) , 8.02(d, 2H)
Example 15: Preparation of 1, 5-dioxo-l- (1-phenylcarbamoyl- 1-ethylamino) -5- (4 ' -bromobiphenyl-4-yl) -3, 3- diethoxycarbonylpentane (VI, Rx=Br)
5- (4 ' -bromobiphenyl-4-yl) -5-oxo-3, 3- diethoxycarbonylvaleric acid(V, R^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 lOmin, followed by addition of L-Ala-CONH-Ph (56mg, 0.342mmol) and stirring for 12hrs at room temperature. And then, IN HC1 was added and extracted with MC, and dried over anhydrous MgS04, filtered, and distilled under reduced pressure, and subjected to a column chromatography (CHCl3/MeOH=19/l, v/v) to give the titled compound (12Omg, 69%).
XH NMR(300MHz, CDC13) : δ l.24(t, 6H) , 1.43(d, 3H) , 3.06(d, IH) , 3.17(d, IH) , 3.94(s, 2H) , 4.23(q, 4H) , 4.60(m, IH), 6.15(d, IH) , 7.07(t, IH) , 7.27 (m, IH) , 7.45(d, 2H) , 7 . 58 (m, 6H) , 7 . 97 (d, 2H) , 8 . 60 ( s, IH)
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, R.,=H, 0.36g, 0.74mmol) dissolved in ethanol (lOmL) was added IN NaOH(1.55mL, 1.55mmol) and stirred for 2hr at room temperature. Ethanol was removed under reduced pressure, added water and washed with ethylacetate, and then, acidified by adding IN 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, 60%).
XH NMR (300MHz, CDC13) : δ 2.76(dd, IH) , 2.90 (dd, IH) , 3.42(dd, IH) , 3.49(m, IH) , 3.58(dd, IH) , 7.10(t, IH) , 7.26(m, IH) , 7.45(m, 5H) , 7.65 (m, 5H) , 8.07(d, 2H)
Example 17: Preparation of N-cyclopropyl-5- (biphenyl-4-yl) - 5-oxo-3-carboxylvaleramide (I, R-^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,
XH NMR(300MHz, CDC13) : δ 0.47(m, 2H) , 0.73(m, 2H) , 2.48(dd, IH) , 2.68 (m, 2H) , 3.39(m, 2H) , 3.54(dd, IH) , 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-carboxylvaleramide (I, -^H) The titled compound was prepared in a similar manner as in Example 16, except for employing N-(α -methylbenzyl) - 5- (biphenyl-4-yl) -5-oxo-3, 3-diethoxycarbonylvaleramide (VI, Rι=H) .
XH NMR(300MHz, CDC13) : δ l.44(d, 3H) , 2.48(dd, IH) , 2.68(m, 2H), 3.39(m, 2H) , 3.54(dd, IH) , 4.98(m, IH) , 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-carboxylvaleramide (I, R.*=OMe)
The titled compound was prepared in a similar manner as in Example 16, except for employing N-phenyl-5- (biphenyl-4-yl ) -5-oxo-3 , 3-diethoxycarbonylvaleramide (VI , R^OMe) .
XH NMR (300MHz, CDC13) : δ 2.70(dd, IH) , 2.91 (dd, IH) , 3.40(dd, IH) , 3.49(m, IH) , 3.55(dd, IH) , 3.84(s, 3H) , 6.98(d, 2H) , 7.06(t, IH) , 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-l-yl] - 4-methylpiperazine (I, R^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-l-yl] -4- methylpiperazine (VI, R-^OMe) .
XH NMR(300MHz, CDC13) : δ 1.20(s, 3H) , 2.45(s, IH) , 2.65(m, 4H) , 2.82(dd, IH) , 3.28(dd, IH) , 3.39(br, 4H) , 3.65(dd, IH) , 3.84(s, 3H) , 4.13 (m, IH) , 6.98(d, 2H) , 7.54(d, 2H) , 7.62(d, 2H) , 8.00(d, 2H)
Example 21: Preparation of N-phenyl-5- (4 ' -bromobiphenyl-4- yl) -5-oxo-3-carboxylvaleramide (I, R-^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,
lE NMR(300MHz, CDC13+DMS0) : δ2.73(dd, IH) , 2.89(dd, IH) , 3.33(dd, 2H) , 3.55 (m, IH) , 7.05(t, IH) , 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-l-yl] piperidine (I, Rx=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-l-yl] piperidine (VI, R.*=Br) .
λE NMR(300MHz, CDC13) : δ2.85(Br, 4H) , 3.37 (m, 2H) , 3.64(br, 4H) , 4.00 (m, 2H) , 4.13(m, IH) , 7.48(d, 2H) , 7.59(d, 2H) , 7.66(d, 2H) , 8.04(d, 2H)
Example 23: Preparation of N- [1, 5-dioxo-5- (4 ' - bromobiphenyl-4-yl) -3-carboxylpentane-l-yl] -4- benzoylpiperazine (I, R-^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-l-yl] -4- benzoylpiperazine (VI, R]=Br) .
XH NMR (300MHz, CDC13) : δ2.59(dd, IH) , 2.86(br, 4H) , 3.10(dd, IH) , 3.42(dd, 2H) , 3.62(Br, 4H) , 3.80(m, IH) , 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-l- (1-phenylcarbamoyl- 1-ethylamino) -5- (4 ' -bromobiphenyl-4-yl) -3- carboxylpentane (I, R1=Br)
To 1, 5-dioxo-l- (1-phenylcarbamoyl-l-ethylamino) -5- (4 ' -bromobiphenyl-4-yl) -3, 3-diethoxycarbonylpentane (VI, R-^Br, 120mg, 0.197mmol) dissolved in ethanol (5mL) was added IN NaOH(lmL, lmmol) and stirred for 5hr at room temperature. Ethanol was removed under reduced pressure, added water and washed with ethylacetate, and then, acidified by adding IN HC1, 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/l, v/v) and hexane to give the titled compound (64mg, 60%).
XH NMR(300MHz, CDC13) : δ l.43(d, 3H) , 3.06(d, IH) , 3.17(d, IH) , 3.40(dd, IH) , 3.53(m, 3H) , 4.56(m, IH) , 6.15(d, IH) , 7.07(t, IH) , 7.27(m, IH) , 7.45(d, 2H) , 7.58 (m, 6H) , 7.97(d, 2H) , 8.60(s, IH)
Example 25: Preparation of 5- (4 ' -chlorobiphenyl-4-yl) -5- oxo-3-ethoxycarbonylvaleric acid t-butyl ester (VII, R^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=C1, 5.26g, 10.46mmol) dissolved in ethanol (30mL) . The reaction mixture was stirred for 6hr at room temperature, and acidified by adding IN HC1, 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 to give the titled compound (3.5lg, 78%).
XH NMR(300MHz, CDC13) : δ l.24(t, 3H) , 1.45(s, 9H) , 2.66(ddd, 2H) , 3.24(dd, IH) , 3.45(m, IH) , 3.53(dd, IH) , 4.16(q, 2H) , 7.42(d, 2H) , 7.55(d, 2H) , 7.65 (m, 2H) , 8.03(d, 2H)
Example 26: Preparation of 5- (biphenyl-4-yl) -5-oxo-3- ethoxycarbonylvaleric acid t-butyl ester (VII,
Rι=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, Rι=H) .
XR NMR(300MHz, CDC13) : δ l.24(t, 3H) , 1.45(3, 9H) , 2.66(ddd, 2H) , 3.24(dd, IH) , 3.45(m, IH) , 3.53(dd, IH) , 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, R-^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, R^Br) .
XH NMR(300MHz, CDC13) : δ l.24(t, 3H) , 1.45 (s, 9H) , 2.66(ddd, 2H) , 3.24(dd, IH) , 3.45 (m, IH) , 3.53(dd, IH) , 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-ethoxycarbonyl aleric acid (VIII, R-*=C1)
To 5- (4 ' -chlorobiphenyl-4-yl) -5-oxo-3- ethoxycarbonyl aleric acid t-butyl ester (VII, RX=C1, 3.51g, 8.14mmol) 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, IN NaOH was added slowly and stirred for lOmin, and the separated organic layer was extracted with water. And then, the aqueous solution was collected, treated with IN HCl(30mL) and extracted with ethylacetate. The separated organic layer was dried over anhydrous MgS04f filtered and distilled under reduced pressure. The residue was recrystallized with CHC13 and hexane to give the titled compound (2.7g, 88%).
XH NMR(300MHz, CDC13) : δ l.24(t, 3H) , 2.84(ddd, 2H) , 3.30(dd, IH), 3.48(m, IH) , 3.57(dd, IH) , 4.18(q, 2H) , 7.42(d, 2H) , 7.55(d, 2H) , 7.65 (m, 2H) , 8.03(d, 2H)
Example 29: Preparation of 5- (biphenyl-4-yl) -5-oxo-3- ethoxycarbonylvaleric acid (VIII, R-*=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, RX=H) .
λR NMR(300MHz, CDC13) : δ l.24(t, 3H) , 2.84(ddd, 2H) , 3.30(dd, IH), 3.48 (m,lH), 3.57(dd, IH) , 4.18(q, 2H) , 7.45(m, 3H) , 7.61(d, 2H) , 7.69(d, 2H) , 8.04(d, 2H)
Example 30: Preparation of 5- (4 ' -bromobiphenyl-4-yl) -5-oxo- 3-ethoxycarbonylvaleric acid (VIII, Rx=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, Rx=Br)
XH NMR(300MHz, CDC13) : δ l.24(t, 3H) , 2.84(ddd, 2H) , 3.30(dd, IH), 3.48(m, IH) , 3.57(dd, IH) , 4.18(q, 2H) , 7.48(d, 2H), 7.60(d, 2H) , 7.65(d, 2H) , 8.04(d, 2H)
Example 31: Preparation of N- (3-cyanophenyl) -5- (biphenyl-4- yl) -5-oxo-3-ethoxycarbonylvaleramide (IX, R-^H)
5- (Biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid
(VIII, RX=H, 50mg, 0.147mmol) was dissolved in THF(3mL) and cooled to a temperature of 0°C. And, N- methylmorpholine (35mL, 0.323mmol) and ethylchloroformate
(16mL, 0.162mmol) were added slowly, and stirred for 30 min at room temperature. And then, 3-aminόbenznitrile dissolved in THF(lmL) was added, stirred for 3hr and 30min, filtered and distilled under reduced pressure. After diluting with chloroform, washing with IN HC1, 10% NaHC03 and water in a sequential order, the resultant was dried over anhydrous MgS04, filtered and distilled under reduced pressure to give the titled compound (55.5mg, 86%).
λE NMR(300MHz, CDC13) : δ l.22(t, 3H) , 2.74(dd, IH) , 3.01 (dd, IH) , 3.54(m, 3H) , 4.22(q, 2H) , 7.42 (m, 4H) , 7.65(m, 5H) , 8.01 (m, 3H) , 8.20(s, IH)
Example 32 : Preparation of N- (3-acetylphenyl) -5- [ (biphenyl- 4-yl) ] -5-oxo-3-ethoxycarbonylvaleramide (IX, Rι=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-ethoxycarbonyl aleric acid ((VIII, R*ι=H) and 3- aminoacetophenone .
H NMR(300MHz, CDC13) : δ l.23(t, 3H) , 2.59 (s, 3H) , 2.80(dd, IH) , 3.00(dd, IH) , 3.56(m, 3H) , 4.20(q, 2H) , 7 . 40 (m, 4H) , 7 . 60 (m, 5H) , 8 . 03 (m, 3H) , 8 . 20 ( s , IH)
Example 33: Preparation of N- (3-acetylphenyl) -5- [ (4 '- chlorobiphenyl-4-yl) ] -5-oxo-3- ethoxycarbonylvaleramide (IX, R-^Cl)
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=C1) and 3-aminoacetophenone.
XH NMR(300MHz, CDC13) : δ l.24(t, 3H) , 2.60(s, 3H) , 2.80(dd, IH) , 2.94(dd, IH) , 3.56(m, 3H) , 4.20(q, 2H) , 7.44 (m, 3H), 7.54(d, 2H) , 7.66(m, 3H) , 7.82(s, IH) , 8.04(m, 3H)
Example 34: Preparation of N- (2-chlorophenyl) -5- [ (biphenyl- 4-yl) ] -5-oxo-3-ethoxycarbonylvaleramide (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, R-^H) and 2- chloroaniline .
E NMR(300MHz, CDC13) : δ l.24(t, 3H) , 2.88(dd, IH) , 3.03(dd, IH) , 3.48-3.66 (m, 3H) , 4.24(q, 2H) , 7.05(t, IH) , 7.43(m, 4H) , 7.62(d, 2H) , 7.70(d, 2H) , 7.90(s, IH) , 8.06(d, 2H) , 8.30(s, IH)
Example 35: Preparation of N- (3-chlorophenyl) -5- [ (biphenyl- 4-yl) ] - 5-oxo-3-ethoxycarbonylvaleramide (IX, Rχ=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, Rχ=H) and 3- chloroaniline .
X NMR(300MHz, MeOH-d4) : δ l.24(t, 3H) , 2.88(dd, IH) , 3.03(dd, IH), 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, Rι=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, Rι=H) and 4- chloroaniline.
XH NMR(300MHz, DMS0-d6) : δl.24(t, 3H) , 2.76(dd, IH) , 2.90(dd, IH), 3.53(m, 3H) , 4.20(q, 2H) , 7.06(d, 2H) , 7.21(t, IH) , 7.44(m, 4H) , 7.62(d, 2H) , 7.68(d, 2H) , 8.04(d, 2H)
Example 37: Preparation of N-[3-(N,N- diethylcarbamoyl)phenyl] -5- [ (4 ' - chlorobiphenyl-4-yl) ]-5-oxo-3- ethoxycarbonylvaleramide (IX, R^Cl) (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, R.*=C1) and 3- (N,N-diethylcarbamoyl) aniline .
XH NMR(300MHz, CDC13) : δ l.ll(t, 3H) , 1.23(t, 6H) , 2.73(dd, IH) , 2.90(dd, IH) , 3.26(br, 2H) , 3.52 (m, 5H) , 4.22(q, 2H) , 7.08(d, IH) , 7.32(t, IH) , 7.44(d, 2H) , 7.54(m, 3H), 7.65(d, 2H), 7.80(s, IH) , 8.03(d, 2H)
Example 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, RX=C1) and 3- (N-phenylcarbamoyl) aniline.
XH NMR(300MHz, CDC13) : δl.l7(t, 3H) , 2.85(dd, IH) , 3.10(dd, IH) , 3.56(d, 2H) , 3.65(m, IH) , 4.15(q, 2H) , 7.15(t, IH) , 7.34 (m, 4H) , 7.50(d, 3H) , 7.61(d, 3H) , 7.75(d, 3H) , 8.00(d, 2H) , 8.35(3, IH) , 8.50(s, IH)
Example 39: Preparation of (L) -1, 5-dioxo-l- (1- phenylcarbamoyl-1-ethylamino) -5- (biphenyl-4- yl) -3-ethoxycarbonylpentane (IX, R-^H)
5- (Biphenyl-4-yl) -5-oxo-3-ethoxycarbonylvaleric acid (VIII, R**=H, lOOmg, 0.29mmol) was dissolved in THF(5mL) and cooled to a temperature of 0°C. And, N- methylmorpholine (70mL, 0.65mmol) and ethyl chloroformate (31mL, 0.32mmol) were added and stirred for 30 min. And then, L-Ala-CONH-Ph (s^≤.: 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(lmL) was added, stirred for 3hr and 30min, filtered and distilled under reduced pressure. After diluting with chloroform, washing with IN HCl, 10% NaHC03 and water in a sequential order, the resultant was dried over anhydrous MgS04, filtered and distilled under reduced pressure to give the titled compound (105mg, 73%).
*H NMR(300MHz, CDC13) : δ l.20(dt, 3H) , 1.47(dd, 3H) , 2.55 (ddd, IH) , 2.75 (ddd, IH) , 3.48 (m, 3H) , 4.14 (m, 2H) , 4.63(m, IH) , 6.15(dd, IH) , 7.07(t, IH) , 7.27 (m, IH) , 7.45 (m, 3H) , 7.58 ( , 6H) , 7.97 (t, 2H) , 8.40~8.60(d, IH)
Example 40: Preparation of (D) -1, 5-dioxo-l- (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, 73%) .
XH NMR(300MHz, CDC13) : δ l.20(dt, 3H) , 1.47(dd, 3H) , 2.55 (ddd, IH) , 2.75 (ddd, IH) , 3.48 (m, 3H) , 4.14 (m, 2H) , 4.63 (m, IH) , 6.15(dd, IH) , 7.07(t, IH) , 7.27 (m, IH) , 7.45(m, 3H), 7.58 (m, 6H) , 7.97(t, 2H) , 8.40~8.60(d, IH)
Example 41: Preparation of 1, 5-dioxo-l- [1- (o- chlorophenyl) carbamoyl-1-ethylamino] -5-
(biphenyl-4-yl) -3-ethoxycarbonylpentane (IX, Rι=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-ethoxycarbonyl aleric acid (VIII, RX=H) and L-Ala- CONH-o-ClPh.
XH NMR(300MHz, CDC13) : δ l.20(dt, 3H) , 1.47(dd, 3H) , 2.55(ddd, IH) , 2.75(ddd, IH) , 3.48(m, 3H) , 4.1 (m, 2H) , 4.63(m, IH) , 6.15(dd, IH) , 7.08(t, IH) , 7.29(t, 2H) , 7.45(m, 3H) , 7.58 (m, 4H) , 7.70(d, 2H) , 7.97(t, 2H) , 8.60(d, IH)
Example 42: Preparation of 1, 5-dioxo-l- [1- (m- chlorophenyl) carbamoyl-1-ethylamino] -5-
(biphenyl-4-yl) -3-ethoxycarbonylpentane (IX, RX=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, R-|=H) and L-Ala- CONH-m-ClPh. XH NMR(300MHz, CDC13) : δ l.20(dt, 3H) , 1.47 (dd, 3H) , 2.55 (ddd, IH) , 2.75 (ddd, IH) , 3.48 (m, 3H) , 4.14 (m, 2H) , 4.63(m, IH), 6.15(dd, IH) , 7.07(t, IH) , 7.30(t, 2H) , 7.45(m, 3H) , 7.58 ( , 4H) , 7.68(d, 2H) , 7.97(t, 2H) , 8.60(d, IH)
Example 43: Preparation of 1, 5-dioxo-l- [1- (p- chlorophenyl) carbamoyl-1-ethylamino] -5- (biphenyl-4-yl) -3-ethoxycarbonylpentane (IX, RX=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, RX=H) and L-Ala- CONH-p-ClPh.
XH NMR(300MHz, CDC13) : δ l.20(dt, 3H) , 1.47 (dd, 3H) , 2.55 (ddd, IH), 2.75 (ddd, IH) , 3.48 (m, 3H) , 4.1 (m, 2H) , 4.63(m, IH) , 6.15(dd, IH) , 7.08(t, IH) , 7.29(t, 2H) , 7.45 ( , 3H) , 7.58 (m, 4H) , 7.70(d, 2H) , 7.97(t, 2H) , 8.60(d, IH)
Example 44: Preparation of N-{ 1, 5-dioxo-5- [ (biphenyl-4- yl) ] -3-ethoxylcarbonylpentane-l-yl}-2- (N- phenylcarbamoyl)pyrrolidine (IX, RX=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, RX=H) and L-Pro- CONH-Ph.
XE NMR(300MHz, CDC13) : δ l.l7(t, 3H) , 1.90(m, IH) ,
2.06(m, IH) , 2.58(br, 2H) , 2.70~3.00(m, 2H) , 3.50 (m, 2H) ,
3.57 (m, 2H) , 3.70(m, IH) , 4.15 (m, 2H) , 4.78 (m, IH) , 7.05(t,
IH) , 7.27 (m, 2H) , 7.45 (m, 3H) , 7.58 (m, 5H) , 8.03(d, 2H) , 9.2~9.4(d, IH)
Example 45: Preparation of 1, 5-dioxo-l- [1-phenylcarbamoyl- 2-phenyl-l-ethylamino] -5- (biphenyl-4-yl) -3- ethoxycarbonylpentane (IX, RX=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, RX=H) and L-Phe- CONH-Ph.
2H NMR (300MHz, CDC13) : δ l.l7(dt, 3H) , 2.38-2.55 (ddd, IH), 2.70(ddd, IH) , 3.20 (m, 2H) , 3.45(m, 3H) , 4.13(dq, 2H) , 4.75~4.90(dq, IH) , 6.10-6.30 (dd, IH) , 7.08 (t, IH) , 7.24(m, 6H), 7.42 (m, 4H) , 7.63 (m, 5H) , 8.00(d, 2H) , 7.90 & 8.30(d, IH)
Example 46: Preparation of N-{1, 5-dioxo-5- [ (4 ' - chlorobiphenyl-4-yl) ]-3- ethoxylcarbonylpentane-1-yl } -2- (N- phenylcarbamoyl) pyrrolidine (IX, RX=H)
The titled compound was prepared in a similar manner as in Example 39, except for employing 5-(4'- chlorobiphenyl-4-yl) -5-oxo-3-ethoxycarbonyl aleric acid (VIII, RX=C1) and L-Pro-CONH-Ph.
XE NMR(300MHz, CDC13) : δ l.20(t, 3H) , 1.90(m, IH) , 2.06(m, IH) , 2.58(br, 2H) , 2.70~3.00(m, 2H) , 3.50 ( , 2H) , 3.57 ( , 2H) , 3.70(m, IH) , 4.15 (m, 2H) , 4.78(m, IH) , 7.05 (t, IH) , 7.27 ( , 2H) , 7.45 (m, 2H) , 7.58 (m, 5H) , 8.03(d, 2H) , 9.2~9.4(d, IH)
Example 47: Preparation of 1, 5-dioxo-l- [1-phenylcarbamoyl- 2-phenyl-l-ethylamino] -5- (4 ' -chlorobiphenyl-4- yl) -3-ethoxycarbonylpentane (IX, RX=C1)
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, RX=C1) and L-Phe-CONH-Ph.
λE NMR(300MHz, CDC13) : δ l.l7(dt, 3H) , 2.38-2.55 (ddd,
IH) , 2.70(ddd, IH) , 3.20 ( , 2H) , 3.45 (m, 3H) , 4.13 (dq, 2H) , 4.75-4.90(dq, IH) , 6.10-6.30 (dd, IH) , 7.07(t, IH) , 7.26(m,
6H), 7.45 (m, 3H) , 7.56 (m, 5H) , 7.99(d, 2H) , 7.90 & 8.30(d,
IH)
Example 48: Preparation of N- (3-cyanophenyl) -5- [ (biphenyl- 4-yl) ] -5-oxo-3-carboxylvaleramide (I, RX=H)
To N- (3-cyanophenyl) -5- (biρhenyl-4-yl) -5-oxo-3- ethoxycarbonylvaleramide (IX, RX=H, 11.8mg, 0.0268mmol) dissolved in ethanol (2mL) was added IN 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 IN HCl, and extracted by employing MC, and dried over anhydrous MgS04. And then, the resultant was filtered and distilled under reduced pressure, and, recrystallized with CHCl3/MeOH (19/1, v/v) and hexane to give the titled compound (10.4mg, 94%).
XH NMR(300MHz, CDC13) : δ 2.74(dd, IH) , 3.01(dd, IH) , 3.54 ( , 3H) , 7.42 (m, 4H) , 7.65 (m, 5H) , 8.01(m, 3H) , 8.20(s, IH)
Example 49: Preparation of N- (3-acetylphenyl) -5- [ (biphenyl- 4-yl) ] -5-oxo-3-carboxylvaleramide (I, RX=H)
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, RX=H) .
E NMR(300MHz, CDC13) : δ 2.59(s, 3H) , 2.80 (dd, IH) , 3.00(dd, IH) , 3.56 (m, 3H) , 7.40 (m, 4H) , 7.60 (m, 5H) , 8.03 (m, 3H) , 8.20(s, IH) Example 50: Preparation of N- (3-acetylphenyl) -5- [ (4 ' - chlorobiphenyl-4-yl) ] -5-oxo-3- carboxylvaleramide (I, RX=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, RX=H) .
XH NMR(300MHz, CDC13) : δ 2.60(s, 3H) , 2.80 (dd, IH) , 2.94(dd, IH) , 3.56(m, 3H) , 7.44 (m, 3H) , 7.54(d, 2H) , 7.66(m, 3H) , 7.82(s, IH) , 8.04 (m, 3H)
Example 51: Preparation of N- (3-chlorophenyl) -5- [ (biphenyl- 4-yl) ] -5-oxo-3-carboxylvaleramide (I, RX=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, RX=H) .
XH NMR(300MHz, MeOH-d4): δ 2.88(dd, IH) , 3.03(dd, IH) , 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-l- (1-phenylcarbamoyl-
1-ethylamino) -5- (biphenyl-4-yl) -3- carboxylpentane (I, RX=H)
To 1, 5-dioxo-l- (1-phenylcarbamoyl-l-ethylamino) -5- (biphenyl-4-yl) -3-ethoxycarbonylpentane (IX, RX=H, 105mg, 0.215mmol) dissolved in ethanol (5mL) was added IN NaOH(lmL, lmmol) and stirred for 90min at room temperature, added water and washed with ethylacetate. And then, the resultant was acidified by adding IN HCl, and extracted with MC, and dried over anhydrous MgS04, filtered and distilled under reduced pressure. The residue was recrystallized with CHCl3/MeOH (19/1, v/v) and hexane to give the titled compound (88mg, 89%).
XH NMR(300MHz, CDC13) : δ l.47(dd, 3H) , 2.55(ddd, IH) ,
2.75(ddd, IH) , 3.48 ( , 3H) , 4.63(m, IH) , 6.15(dd, IH) , 7.07(t, IH), 7.27 (m, IH) , 7.45 (m, 3H) , 7.58 (m, 6H) , 7.97(t, 2H) , 8.40~8.60(d, IH)
Example 53: Preparation of N-{1, 5-dioxo-5- [ (4 ' - chlorobiphenyl-4-yl) ] -3-carboxylpentane-l-yl }- 3- (N-phenylcarbamoyl) -1, 2 , 3, 4- tetrahydroisoquinoline (I, RX=C1)
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-l-yl}-3- (N- phenylcarbamoyl) -1,2,3, 4-tetrahydroisoquinoline (IX, RX=C1) .
λE NMR(300MHz, CDC13) : δ 2.70-3.20 (m, 2H) , 3.38-3.57(m, 4H) , 4.11 (m, IH) , 4.66(m, 2H) , 5.33(d, IH) , 6.92(t, IH) , 7.15 (m, 4H) , 7.45 ( , 7H) , 7.93(d, 2H) , 8.66(m, IH)
Example 54: In vi tro 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-β -(2,4- dinitrophenylamino) Ala-Ala-Arg-NH2 (Sigma Chem. Co., 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, 0.01% 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: 9.15uM) in 96 well plate and then reacting for 30 minutes at 37 °C, and the fluorescence intensity was measured at excitation 328nm and emission 393nm by spectrofluorimeter (Fma (molecular device)). The inhibition rate(%) was calculated from the following equation:
Inhibition Rate(%) =
wherein,
A represents fluorescence intensity before the reaction with an inhibitor;
B represents fluorescence intensity after the reaction with an inhibitor; C represents fluorescence intensity before the reaction without an inhibitor; and,
D represents fluorescence intensity after the reaction without an inhibitor.
Example 55: In vi tro inhibition on gelatinase B(MMP-9)
In vi tro 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, from human blood) with a different concentratio (final concentration in well: 2.715nM) and a different concentration of the substrate, fluorescent synthetic peptide (final concentration in well: 4.575uM).
Example 56: 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.
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 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 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 TS:
1. A compound represented as the following general formula (I), its isomers and pharmaceutically acceptable salts thereof:
wherein,
Rx is hydrogen, alkyl, cycloalkyl, halogen, nitro, cyano, -OCF3, -OCH2F,
, , , -0R4, -SR4,
-S(0)R4 or -S(0)2 where R4 and R4 a, 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,
Rβ is hydrogen, alkyl, aryl, arylalkyl, heteroaryl or cycloalkyl; and, X is 0 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;
Rlx and RX2 are hydrogen or Cx_6 lower alkyl; and, Y is CH2, 0 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,
Rx, 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 compoun (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 group; and, (v) hydrolyzing ethylester group of the compound (IX) to a carboxylic group to prepare a compound ( I) : wherein,
Rx, R2 and R3 are the same as defined in claim 1,
deprotection
hydrolysis
EP01926225A 2000-04-25 2001-04-24 Biphenyl butyric acid derivative as a matrix metalloproteinase inhibitor Withdrawn EP1189882A1 (en)

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KR2000021834 2000-04-25
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KR20080058436A (en) 2005-10-13 2008-06-25 와이어쓰 Methods for preparing glutamic acid derivatives
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