[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

EP1189882A1 - Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle - Google Patents

Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle

Info

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Withdrawn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)
English (en)
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
Original Assignee
Samsung Electronics Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from KR10-2000-0021835A external-priority patent/KR100405914B1/ko
Priority claimed from KR10-2000-0021834A external-priority patent/KR100405913B1/ko
Application filed by Samsung Electronics Co Ltd filed Critical Samsung Electronics Co Ltd
Publication of EP1189882A1 publication Critical patent/EP1189882A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—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
    • 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
    • C07C235/76—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—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
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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. .

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Vascular Medicine (AREA)
  • Oncology (AREA)
  • Pain & Pain Management (AREA)
  • Cardiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pulmonology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Cette invention, qui a trait à de nouveaux dérivés d'acide diphénylbutirique, à leurs isomères ainsi qu'à leurs sels admissibles du point de vue pharmaceutique, lesquels dérivés se révèlent des plus utiles en tant qu'inhibiteurs de la métalloprotéinase matricielle (MMP), concerne également un procédé de production de ces composés. Dans la mesure où ces dérivés d'acide diphénylbutirique inhibent, de manière sélective, l'activité des MMP in vitro, ils sont administrés dans le cadre du traitement et de la prévention de différents états pathologiques dus à une surexpression et à une suractivation de MMP.
EP01926225A 2000-04-25 2001-04-24 Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle Withdrawn EP1189882A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
KR10-2000-0021835A KR100405914B1 (ko) 2000-04-25 2000-04-25 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
KR2000021835 2000-04-25
KR2000021834 2000-04-25
KR10-2000-0021834A KR100405913B1 (ko) 2000-04-25 2000-04-25 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
PCT/KR2001/000687 WO2001083445A1 (fr) 2000-04-25 2001-04-24 Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle

Publications (1)

Publication Number Publication Date
EP1189882A1 true EP1189882A1 (fr) 2002-03-27

Family

ID=26637911

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01926225A Withdrawn EP1189882A1 (fr) 2000-04-25 2001-04-24 Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle

Country Status (6)

Country Link
EP (1) EP1189882A1 (fr)
JP (1) JP2003531894A (fr)
CN (1) CN1366518A (fr)
AU (1) AU5275901A (fr)
CA (1) CA2377629A1 (fr)
WO (1) WO2001083445A1 (fr)

Families Citing this family (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100405913B1 (ko) * 2000-04-25 2003-11-14 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
KR100405914B1 (ko) * 2000-04-25 2003-11-15 삼성전자주식회사 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
US20100022582A1 (en) * 2005-03-10 2010-01-28 Kenji Takahashi Tetrahydroisoquinoline Compound and Medicinal Use Thereof
RU2436768C2 (ru) * 2005-07-11 2011-12-20 Вайет Глютаматы в качестве ингибиторов аггреканазы
CN101282927A (zh) 2005-10-13 2008-10-08 惠氏公司 制备谷氨酸衍生物的方法
WO2008058278A2 (fr) * 2006-11-09 2008-05-15 Wyeth Polymorphes de la n2-(1,1'-biphényl-4-ylcarbonyl)-n1-[2-(4-fluorophényl)-1,1-diméthyléthyl]-l-α-glutamine
CN101353320A (zh) * 2007-07-24 2009-01-28 中国人民解放军军事医学科学院毒物药物研究所 基质金属蛋白酶抑制剂、含有它们的药物组合物及其制备方法和用途
CN104955806B (zh) * 2013-02-06 2018-09-14 默克专利股份公司 用于治疗骨关节炎的作为聚蛋白聚糖酶抑制剂的取代羧酸衍生物
KR102408261B1 (ko) 2014-02-03 2022-06-10 비타이 파마슈티컬즈, 엘엘씨 Ror-감마의 디하이드로피롤로피리딘 저해제
PL3207043T6 (pl) 2014-10-14 2020-11-02 Vitae Pharmaceuticals, Llc Inhibitory dihydropirolopirydynowe ror-gamma
US9845308B2 (en) 2014-11-05 2017-12-19 Vitae Pharmaceuticals, Inc. Isoindoline inhibitors of ROR-gamma
US9663515B2 (en) 2014-11-05 2017-05-30 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
DK3331876T3 (da) 2015-08-05 2021-01-11 Vitae Pharmaceuticals Llc Modulators of ror-gamma
KR20180086221A (ko) 2015-11-20 2018-07-30 비타이 파마슈티컬즈, 인코포레이티드 Ror-감마의 조절물질
TWI757266B (zh) 2016-01-29 2022-03-11 美商維它藥物有限責任公司 ＲＯＲ－γ調節劑
US9481674B1 (en) 2016-06-10 2016-11-01 Vitae Pharmaceuticals, Inc. Dihydropyrrolopyridine inhibitors of ROR-gamma
WO2019018975A1 (fr) 2017-07-24 2019-01-31 Vitae Pharmaceuticals, Inc. Inhibiteurs de ror gamma
CN111225914B (zh) 2017-07-24 2022-10-11 生命医药有限责任公司 RORγ的抑制剂

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
HUT71401A (en) * 1992-05-07 1995-11-28 Merck & Co Inc New quinazolines as inhibitors of hiv reverse transcriptase
ATE195530T1 (de) * 1992-05-20 2000-09-15 Merck & Co Inc 17-ether und thioether von 4-aza-steroiden
AU4159197A (en) * 1996-09-04 1998-03-26 Warner-Lambert Company Biphenyl butyric acids and their derivatives as inhibitors of matrix metalloproteinases
AU9663798A (en) * 1997-10-06 1999-04-27 Warner-Lambert Company Heteroaryl butyric acids and their derivatives as inhibitors of matrix metalloproteinases

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0183445A1 *

Also Published As

Publication number Publication date
WO2001083445A1 (fr) 2001-11-08
JP2003531894A (ja) 2003-10-28
CN1366518A (zh) 2002-08-28
CA2377629A1 (fr) 2001-11-08
AU5275901A (en) 2001-11-12

Similar Documents

Publication Publication Date Title
EP1189882A1 (fr) Derives d'acide diphenylbutyrique inhibiteurs de metalloproteinase matricielle
ES2236829T3 (es) Acidos beta-sulfonil hidroxamicos como inhibidores de las metaloproteinas de la matriz.
SK284127B6 (sk) Cyklické deriváty amidov acylaminokyselín substituované tioskupinou a spôsob ich prípravy
JP2006503019A (ja) メタロプロテイナーゼｍｍｐ１２のインヒビターとしての２，５−ジオキソイミダゾリジン−４−イルアセトアミドおよび類似体
SK172004A3 (en) Aromatic hydroxamic acid derivatives useful as HDAC inhibitors
JP4008708B2 (ja) マトリックスメタロプロテイナーゼの阻害剤としてのスルホンアミド誘導体
WO2007138242A1 (fr) Dérivés de biphényle et leur utilisation pour le traitement de l'hépatite c
KR20080046716A (ko) 4-페닐-6-치환-피리미딘-2-카르보니트릴 유도체
WO2007135106A1 (fr) Derives de piperidine comme inhibiteurs du virus du papillome humain
EP1525193B1 (fr) Derives d'acylaminothiazole et leur utilisation comme inhibiteurs de beta-amyloide
US6689785B2 (en) Epoxysuccinamide derivatives
AU2007347428A1 (en) Substituted carboxamides
PL198827B1 (pl) ω-Amidy N-arylosulfonyloaminokwasów, sposób ich wytwarzania, środek farmaceutyczny i zastosowanie ω-amidów N-arylosulfonyloaminokwasów
US5684152A (en) Preparation of carboxyalkyl derivatives as inhibitors of matrix metalloproteinases
KR100405914B1 (ko) 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
CA2317502A1 (fr) Inhibiteurs de metalloprotease matricielle
KR100405913B1 (ko) 메트릭스 메탈로프로테이나제의 저해제로서의 비페닐부티릭산 유도체
WO2009139438A1 (fr) Procédé de production d'un acide carboxylique optiquement actif
FR2755438A1 (fr) Compose, procede pour sa preparation et composition pharmaceutique le contenant
KR100384693B1 (ko) 메트릭스 메탈로프로테이나제의 저해제로서의 설폰아미드유도체
KR100372757B1 (ko) 메트릭스 메탈로프로테이나제의 저해제로서의 설폰아미드유도체
KR20000016815A (ko) 칼륨 채널 조절제로서 사이클로부텐-3,4-디온의헤테로사이클릴메틸아미노 유도체
KR100432928B1 (ko) 신규한 하이드록스아믹산 유도체, 신규한 그의 중간체화합물 및 그들의 제조방법
WO1997011936A1 (fr) Preparation de derives de carboxyalkyle
KR20060116552A (ko) 매트릭스 메탈로프로테이나제 저해제로서 엔-포르밀히드록실아민 유도체

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20011227

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU MC NL PT SE TR

AX Request for extension of the european patent

Free format text: AL;LT;LV;MK;RO;SI

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION HAS BEEN WITHDRAWN

18W Application withdrawn

Withdrawal date: 20020626