WO2002030873A1 - Mmp inhibitor - Google Patents

Mmp inhibitor

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Publication number
WO2002030873A1
WO2002030873A1 PCT/JP2001/008325 JP0108325W WO0230873A1 WO 2002030873 A1 WO2002030873 A1 WO 2002030873A1 JP 0108325 W JP0108325 W JP 0108325W WO 0230873 A1 WO0230873 A1 WO 0230873A1
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WO
Grant status
Application
Patent type
Prior art keywords
group
lower
ariru
compound
lower alkyl
Prior art date
Application number
PCT/JP2001/008325
Other languages
French (fr)
Japanese (ja)
Inventor
Akihiko Sawada
Masahiro Neya
Original Assignee
Fujisawa Pharmaceutical 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

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulfur
    • C07D333/26Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulfur 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
    • C07D333/38Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D333/40Thiophene-2-carboxylic acid [2]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/16Amides, e.g. hydroxamic acids
    • A61K31/165Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/38Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/381Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D333/00Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulfur
    • C07D333/26Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulfur 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
    • C07D333/38Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K38/00Medicinal preparations containing peptides

Abstract

A novel MMP inhibitor. It is a compound represented by the formula (I) or a salt thereof: (I) wherein R?1 and R2¿ each means optionally substituted aryl, optionally substituted lower arylalkyl, lower arylalkenyl, lower aryloxyalkyl, or an optionally substituted heterocyclic group. The compound is useful as an MMP inhibitor.

Description

Specification

MM P inhibitor technology field

The present invention relates acceptable salt Contact Yopi their pharmaceutically novel compounds.

More particularly, the present invention is a matrix meta port protease (parts hereinafter MMP and call) or (hereinafter referred to as TNF Monument I) tumor necrosis factor α pharmaceutically acceptable salt thereof useful new compound and as an inhibitor of production , pharmaceutical compositions containing them, use as a medicament of that, and ΜΜΡ- or methods of using them therapeutically in the treatment you Yopi Ζ or prevention of TNF alpha-mediated diseases.

BACKGROUND

ΜΜΡ Inhibition useful piperidines Rajin compound as agent is known (WO97 / 20824, etc.).

Salts object to be acceptable new and useful compounds and their pharmaceutical that have a pharmacological activity such as MM .rho. or TNF non-producing one inhibitory activity of the present invention and the novel of compounds and their salts, to provide a method of manufacturing.

Another object of the present invention, as an active ingredient, is to provide a pharmaceutical composition containing acceptable salt the compound or its pharmaceutically.

Further object of the present invention, M in acceptable salt the compound and their pharmaceutically

MP- or to provide a use of the pharmaceutical and to for preventive and Z or therapeutic treatment of TNF a- mediated diseases.

Furthermore, object of the present invention is to provide a method for using them mammals, particularly for the treatment and Z or prevention of MMP- or TNF monument one mediated diseases, human.

The compounds of the invention have an inhibitory activity on MMP or TNF a production, seizures, arthritis, cancer, tissue ulceration, decubitus ulcer, restenosis, periodontal disease, epidermolysis bullosa, scleritis, psoriasis and matrix meta other diseases characterized by mouth protease activity are useful in the treatment and / or prevention of diseases such as other diseases caused in parallel beauty Aids, sepsis, by the production of septic shock and TNF alpha.

Numerous exist structurally related meta port proteases, they affect the degradation of structural proteins. Matrix degrading meth port proteases, for example, Zerah Chinaze (ΜΜ Ρ _ 2, ΜΜ Ρ - 9), be sampled port melissic (ΜΜ Ρ- 3) and co Ragenaze (MM P- 1, MM P- 8, MM P - 1 3) is involved in decomposition of tissue matrix, many conditions abnormal connective tissue and basement membrane matrix metabolism is involved, such as arthritis (e.g., osteoarthritis and rheumatoid arthritis), cerebral disease (e.g., stroke, etc.), tissue ulceration (e.g., corneal ulcers of skin and stomach), abnormal wound healing, periodontal disease, bone disease (e.g., Paget's disease Contact Yopi osteoporosis), the tumor metastasis or invasion, as well as It is to be related to HIV infection.

Tumor necrosis factor, that has been recognized to be involved in a number of infectious diseases and autoimmune diseases. Furthermore, it has been shown that TNF is a major mediator of the inflammatory response seen in sepsis and septic shock.

Disclosure of the Invention

The object compound of the present invention are new and can be represented by the following formula (I).

In "wherein each R 1 and R 2 are substituted they may be Ariru group, optionally substituted Ariru lower alkyl group, Ariru lower alkenyl group, Ariru Okishi lower alkyl group, or optionally substituted It means a heterocyclic group. or a salt thereof represented by ".

The object compound of the present invention may be by connexion produced in the following steps. -OH ☆ -Cl

(II) (III)

Chiron Technologies Pty:. Ltd - manufactured Tr it yl Linker Crown (100 pieces) and 100ml wide-mouth meal "Yoo - placed in a beam bottles, 2 0% chloride Asechiru methylene chloride solution was added 50ml After standing the reaction mixture 3 hours crown was filtered off. crown was washed with methylene chloride (50 ml x 5 minutes x2 times). preparation 2

(III) (IV)

100ml wide Romeshi ,, Interview - take the arm bottle N- arsenide Dorokishifuta one Louis Mi de (660 mg), was added N, N- diisopropyl E chill § Min a (2.8 ml) to the mixture suspended in methylene chloride 20ml . To the reaction mixture, while handling crown prepared in Production Method 1 (100), it was filtered off crown After standing 1 8 hours. The crown was washed with methylene chloride (50 ml X 5 minutes x3 times). The resulting crown dried.

(IV) (V)

2.2 arsenide 'hydrazine hydrate Roh the crown prepared in Production Method 2> Chirusuruokishi (50ml) was added and filtered off the crown after standing 20 hours. The N, N-dimethyl-phosphono REM ami de crown (50 ml X 5 minutes X 3 times), washed with Shioi匕 methylene (50 ml x 5 minutes x 3 times), dried and the resulting crown. Process 4

100ml wide-mouth mesylate ,, Yumu bottle N- a-Fmoc- β-1- (4, 4 _ Jimechinore _ 2, 6 Jiokiso 1 - to consequent opening cyclohexylidene) Echiru L- di § amino acid (1. 4 7 g ), HOB t (1-hydroxycarboxylic benzotriazole) (4 5 0 mg), di-isopropyl carbo di imide a (4 5 0 / i L) was added, and allowed to stand 2 0 minutes. The crown obtained by the production method 3 in reaction mixture, and the mixture was filtered off crown was allowed to stand 4 5 hours. The crown N, N-dimethyl formamidine de (50 ml x 5 minutes x 3 times), washed with salt methylene (50mlx 5 minutes x3 times), dried and the resulting crown c

Production, Chiron Technologies Pty the obtained crown by law 4; after wearing Ltd- made Transtem, 200 ml wide-mouth mesylate ,, Yumu Karoe bottle, 20 piperidine / N, the N-dimethylformamidine de solution 100ml was added, It was filtered off-out with Transtem crown was allowed to stand for 30 minutes. Transtem with crown ¾r Ν, Ν _ Nmechi / Rehonore ^ Da ^ de (50mlx 5 minutes χ3 times): was washed with methylene chloride (50mlx 5 minutes χ3 times), and dried the resulting ranstem attached crown. Production Method 6

Carboxylic acid (VIII) 100 ml wide Romeshi ,, Interview - was added to the arm bottles. 1. 5% HOB tZN, N- dimethylformamidine de solution (20 ml), Ka卩E diisopropyl carboxamide di imide (300 L), and allowed to stand for 20 minutes. 1 0 minutes split by Transtem with crown ¾Γ Chiron Technologies Pty Ltd. Ltd. TranSort system obtained in Process 5 was 18:00 HazamaShizu置 added Transtem with crown (1 0 pieces) to each reaction mixture. After filtering off the Transtem with crown subsequent 1 0 or mixing, NN- dimethylformamidine de (50 ml X 5 minutes x3 times), washed with methylene chloride (50 ml x 5 minutes x3 times), resulting Transtem the attached crown and dried. 200ml wide-mouth menu Interview the Transtem with crown obtained in Process 6 -. In addition to the arm bottle 2% hydrazine hydrate ZN, N-dimethylformamidine de solution 100ml were added, with Transtem allowed to stand for 15 minutes crown It was 爐另 IJ. The Transtem with crown N, N-dimethyl formamidine de (50 ml X 5 minutes X 3 times), washed with Shioi匕 methylene (50 ml 5 minutes 3 times), dried and the resulting Transtem with crown. Production Method 8

Carboxylic acid (XI) 100 ml wide-mouth mesylate "Interview -. Were added to the arm bottle 1. 5% HOB t / N, N- dimethylformamidine de solution (20 ml), diisopropyl carbo di imide (300 iL) was added, 2 and allowed to stand for 10 minutes. the Transtem with crown obtained by the production method 7 1 0 divided by TranSort system was 1 8 hours standing added Transtem with crown (1 0 pieces) to each reaction mixture. After that 1 after filtering off a mixture of 0 one-out with Transtem crown, N, N- dimethylformamidine de (50mlx 5 minutes x3 times), washed with methylene chloride (50 ml X 5 minutes x 3 times), resulting

The Transtem with crown and dried.

And Installation to the identified position of the pin holder of Chiron Technologies Pty Ltd. Ltd. using ranSort system Transtem with crown obtained by the production method 8.

Each 5% Torifuruoro acetic Z methylene chloride solution to immersion 1 hour (1. 5m l), was cut out of the objective compound 'from Transtem with crown. The resulting solution was dried by nitrogen stream to obtain the desired compound. The target compound was determined respective structures at L CZMS device (ESI + or ESI I).

"Wherein the same meaning as R 1 and R 2 are the, Fmoc is 9-Furuorenirume butoxy carbonyl, DDE means one chromatography (4, 4 one Jimechinore one 2, 6 Jiokiso one 1-cyclohexylene cyclohexylidene) Echiru"

Well target compound as a salt or a pharmaceutically acceptable salt conventional non-toxic salts of the present invention, an organic acid salt (e.g., acetate, Torifuruoro acetate, maleate, tartrate, fumarate , methanesulfonate, benzenesulfonate, formate, toluene sulfonate, etc.), inorganic acid salts (e.g., hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate acid addition salts of the salt) and the like, or amino acids (e.g., § arginine, Asuparagin acid, glutamic acid), alkali metal salts (e.g., sodium salt, potassium salt, etc.), alkaline earth metal salts (e.g., calcium salt, Mag Neshiumu salts), Anmoniumu salts, organic base salts (e.g., carboxymethyl Torimechiruamin salts, Toryechiruamin salt, pyridine salt, picoline salt, dicyclohexyl Ruamin including salts, N, N, the salts with bases over dibenzylethylenediammonium § amine salts, etc.) and the like.

Objective compounds and their pharmaceutically acceptable salts are inclusion compounds (e.g., hydrate etc.), solvates of such free, the invention encompasses within its scope the above and following descriptions of the present specification description of the illustrated have that suitable examples and various defined are as follows.

"Ariru group" and suitable in the "optionally substituted Ariru group" refers "Ariru", for example, phenyl, preparative Lil, xylyl, cumenyl, mesityl, carbon atoms naphthyl 6-1 0 Ariru, preferably phenyl, which may have one or more substituents. Examples of substituted Ariru substituents, halogen, Shiano, nitro, Amino, Ashiruamino, lower Arukiruamino force Rubamoi Le, human Dorokishi, lower alkoxy, Ariruokishi, Aroiru lower alkyl, good Mashiku the Ariruokishi (e.g. phenoxy, etc. ), a nitro your Yopi Aroiru (for example Benzoiru, etc.).

Suitable Aroiru, include Aroiru carbon number 6-1 0, especially rather preferably can be mentioned Benzoiru.

The suitable "heterocyclic group" of the "optionally substituted heterocyclic group optionally" refers, acid atom, a sulfur atom, at least a heteroatom of such a nitrogen atom containing one saturated or unsaturated 3 refers to 8-membered monocyclic or polycyclic heterocyclic group.

More preferred heterocyclic group:

one:! Unsaturated 3 to 8-membered containing to 4 nitrogen atoms, preferably 5 or 6-membered multi-containing monocyclic group, for example, pyrrolyl, pyrrolinyl, Imidazoriru, pyrazolyl, pyrid Le and N- Okishido, pyrimidyl; Pirajuru, pyridazinyl, Toriazo Lil (e.g. 4 H- 1, 2, 4-Toriazoriru, 1 H- 1, 2, 3- Toriazori Le, 2 H- 1, 2, 3- Toriazoriru etc.), tetrazolyl (e.g., 1 H- Tet Razoriru, 2 H- tetrazolyl, etc.), dihydric mud triazinyl (e.g., 4, 5 dihydric draw 1, 2, 4 _ triazinyl, 2, 5-dihydrazide mud one 1, 2, 4-thoria Jiniru etc.) and the like;

one:! Saturated 3 to 8-membered containing to 4 nitrogen atoms, preferably 5 or 6-membered heteromonocyclic group, for example, Azechijiniru, pyrrolidinyl, Imidazorijiniru, piperidin Le, pin piperidylpiperidine, Birazorijiniru, such piperazinyl;

One 1-5 pieces unsaturated condensed 7-1 3- containing nitrogen atoms, preferably 9 or 1 0-membered bicyclic heterocyclic group, for example, indolyl, isoindolyl, indolizinyl, benzimidazolyl, quinolyl, isoquinolyl, indazolyl , benzotriazole Lil, tetrazo port pyridyl, tetrazolo pyridazinyl (e.g., tetrazolo [1, 5-b] pyridazinyl, etc.), dihydric mud tri § Zorro pyridazinyl and the like;

One 1 or 2 unsaturations 3-8 membered containing oxygen atoms and 1 to 3 nitrogen atoms, preferably 5 or 6-membered heteromonocyclic group, for example, Okisazoriru, Isookisazori Le, Okisajiazoriru (e.g., 1, 2, 4-Okisajiazoriru, 1, 3, 4 Okisajiazoriru, 1, 2, 5-Okisajiazoriru etc.) and the like;

One one or two saturated 3-8 membered containing oxygen atoms and 1 to 3 nitrogen atoms, preferably 5 or 6-membered heteromonocyclic group, for example, morpholinyl, morpholino and the like;

One one or two unsaturated condensed containing oxygen atoms and 1 to 3 nitrogen atoms 7

~ 1 3-membered, preferably 9- or 1 0-membered bicyclic heterocyclic group, e.g., Benzuokisazori Le, benz O hexa di § benzisoxazolyl and the like;

One 1 or 2 unsaturations 3-8 membered containing sulfur atoms and 1 to 3 nitrogen atoms, preferably 5 or 6-membered heteromonocyclic group, for example, thiazolyl, 1, 2-thiazol Le, thiazolinyl, thiadiazolyl (e.g., 1, 2, 4-thiadiazolyl, 1, 3, 4-thiadiazolyl, 1, 2, 5-thiadiazolyl, 1, 2, 3 Chiajia Zoriru etc.) and the like;

One one or two saturated 3-8 membered containing sulfur atoms and 1 to 3 nitrogen atoms, preferably 5 or 6-membered heteromonocyclic group, for example, thiazolidinyl or the like;

Unsaturated 3 to 8-membered containing one sulfur atom, preferably 5 or 6-membered heteromonocyclic group, for example, thienyl, etc .;

Unsaturated 3 to 8-membered containing one oxygen atom, preferably 5 or 6-membered heteromonocyclic group such as furyl or the like;

Saturated 3 to 8-membered containing one oxygen atom, preferably 5 or 6-membered heteromonocyclic group, if example embodiment, Okisoraniru like:

One one or two unsaturated condensed 7-1 3-membered containing sulfur atoms and 1 to 3 nitrogen atoms, preferably 9 or 1 0-membered bicyclic heterocyclic group, for example, benzothiazolyl, benzothiadiazole azide § sled Le etc.; - one or two unsaturated condensed 7-1 3- containing oxygen atoms, preferably 9 or 1 0-membered bicyclic heterocyclic group, e.g., Benzojihi Dorofuraniru, Benzojiokisore sulfonyl and the like; a.

Most preferred heterocyclic groups include unsaturated 5 or 6-membered heteromonocyclic group containing a sulfur atom. '

These heterocyclic groups may have one or more substituents. Examples of substituents of substituted heterocyclic group, halogen, Shiano, nitro, Amino, Ashiruamino, lower Arukiruamino force Rubamoiru, human Dorokishi, lower alkoxy, Ariruo alkoxy, lower alkyl, Ariru, optionally substituted heterocyclic group, haloaryl, human Dorokishiariru, lower alkoxy § reel, lower alkyl § reel, nitro Arinore, biphenyl, Ryo reel O carboxymethyl § reel, trihaloalkyl § reel, Shiano (lower) alkoxy § reel, Shianoariru, Shiano (lower) alkyl Ariru, lower alkanoyloxy Noi Ruo carboxymethyl § reel, lower alkanoyloxy Noi Ruo carboxy (lower) alkyl § reel, di (lower) alkylaminosulfonyl § reel, human Dorokishi (lower) alkyl § reel, lower alkoxycarbonyl two Ariru, lower alkoxy Shikarubo two Honoré (lower) alkoxy § reel, lower alkoxysulfonyl Nino les oxy § reel, Ariru substituted by halogen Contact Yopihi Dorokishi, Ariru substituted with halogen Contact Yopi al Kanoiruokishi, halogen and lower alkoxy in substituted Ariru, lower alkyl - a heterocyclic group and a lower alkoxy substituted § Li Lumpur, lower alkyl one heterocyclic group and Ariru one heterocyclic group, preferably a halogen; phenylene Honoré; Harofueniru; human Dorokishifueniru; lower Arukokishifue two Honoré; lower alkylphenyl; Nitorofue two Honoré; Bifue two Rinore; Fuenokishifue sulfonyl; Turin, mouth (lower) alkylphenyl; Shiano (lower) Arukokishifue two Le; Shianofueniru; Shiano ( Lower) alkylphenyl; lower alkanoyl Honoré Oki Shifuweniru; lower alkanoyloxy Noi Ruo carboxy (lower) alkylphenyl; di (lower) Ryo Le Kill aminosulfonyl phenylalanine; lower § Roh record alkoxycarbonyl (lower) Anorekoki Shifueniru; lower alkoxy sulfonyl O carboxymethyl phenylalanine; phenyl substituted by halogen and lower alkoxy; halogen and hydroxycarboxylic with been phenyl substituted; halogen and lower alk Noi Ruo carboxymethyl with substituted phenyl is. Suitable in becomes "substituted also more Ariru lower alkyl" term "Ari Le lower alkyl" is a straight-chain or branched alkyl which has been from 1 6 carbon substituted by the above Ariru, methyl, Echinore, propyl , isopropyl, heptyl, Isobuchi Le, t ert - heptyl, pentyl, hexyl or the like to, and examples of the preferred Ariru lower alkyl is phenylmethyl and naphthylmethyl. The Ariru group may be substituted by one or more substituents, examples of substituents include halo gen, Shiano, nitro, Ashiruamino force Rubamoiru, human Dorokishi, lower alkoxy, lower Arukiru force Rubamoiru, carboxy , protected Karupokishi, di (lower grade) Arukiruamino, lower Arukiruamino, protected amino, Arirukarubo Niruamino, lower alkanoyloxy Noi Rua amino, lower alkylsulfonyl § amino, di (lower grade) alkylaminosulfonyl - there is Ruamino like. Preferably, it includes naphthylmethyl or chloro off We methylpropenylmethyl group as a 1 1 or 1 ^ 2.

Suitable in "Ariru lower alkenyl" refers "Ariru lower alkenyl" is a straight-chain or branched alkenyl of been 2 to 6 carbon atoms substituted by the above Ariru, Biel, 1 one propenyl, 2-propenyl cycloalkenyl, 1 Puteniru, 2 Buteyuru, 1 - pentenyl, 2-pentenyl and the like are exemplified, preferably Bulle. Preferred examples of Ariru lower alkenyl include Fuenirubyuru.

Preferable examples of the "Ariruokishi lower alkyl", Fuenokishimechiru, Fuenokishechiru naphthoquinone Tokishimechiru naphthoquinone Tokishechiru and the like, rather preferably can be mentioned Fuenokishechiru.

"Lower" refers to particular number of carbon atoms unless otherwise specified 1-6, preferably means from 1 to 4 carbon atoms.

Suitable "Nono androgenic" refers to fluorine, bromine, chlorine you Yopi iodine. Among the best mode target compound for carrying out the invention (I),

(1) preference is given,

"Each wherein, R 1 and R 2, § reel O carboxymethyl § aryl group, Aroiruari Lumpur group, Two Toroariru group, Ariru lower alkyl group, a haloaryl lower alkyl group, Ariru lower alkenyl group, Ariruokishi lower alkyl group, or 1 or unsaturated 3 to contain 2 sulfur atoms to means 8 membered heteromonocyclic group. compounds represented by "

(2) Preferred More,

R 1 and R 2 are each, Fuenokishifue group, benzo I Ruff enyl, Two Torofueniru group, a naphthyl lower alkyl group, Harofuweniru lower alkyl group, Hue sulfonyl lower alkenyl group, on a phenoxy-lower alkyl group or thienyl group, 'it is a compound according to SL (1),

(3) Most preferred are

R 1 and R 2 are each, 3- or 4-Fuenokishifue two Honoré group, 4-Benzo Irufueniru group, 4-nitrophenyl group, 1-naphthylmethyl group, 2-chlorophyll Enirumechiru group, 2-phenylene Rubiniru group, 1- or a compound according to the above (2) 2-Fuenokishechiru or 2-thienyl group.

The compound obtained in Process a conventional method, for example, grinding, recrystallization, column chromatography, reprecipitation, etc., can be separated and purified. Object compound in a customary manner, it is possible to convert the salts thereof.

The target compound may comprise one or more stereoisomers due to asymmetric carbon, they isomers and mixtures thereof are intended to be included within the scope of the present invention.

Collagenase starts the degradation of vertebrate collagen, in addition to their normal function in metabolism and wound healing connective tissue, a number of conditions, e.g., joints in chronic rheumatoid Umachi Yabu壌, periodontal disease, corneal ulceration , tumor metastasis, osteoarthritis, decubitus, percutaneous transluminal coronary extended postoperative restenosis, osteoporosis, psoriasis, chronic active hepatitis, because they are to be associated with autoimmune keratitis etc., the present invention the compounds are useful in the treatment and Z or prophylaxis of such conditions.

For therapeutic purposes, the compounds and their pharmaceutically acceptable salts of the present invention, acceptable carrier pharmaceuticals, for example, organic or inorganic solid or liquid, oral, parenteral or suitable for topical administration was blended with excipients, can be used in the form of preparations you containing one of said compounds as an active ingredient. Formulations, capsules, tablets, dragees, granules, solutions, suspensions, emulsifiers, sublingual tablets, suppositories, or ointments, and the like. If necessary, in these preparations, auxiliary substances, stabilizing agents, wetting agents, emulsifiers, buffers, and other may include additives usually used.

The dosage of the compound will vary by the patient's age and condition, etc., the daily dose per 1 kg body weight of the human in the case of intravenous administration 0. 0 1 to 1 200 mg, in the case of intramuscular administration arsenide bets 1 kg body weight per daily dose 0. 0 5~1 00mg, daily dose 0. 1 to 1 00 mg active ingredient MMP or TNF alpha mediated per 1 kg body weight of the human in the case of oral administration It is generally administered for the treatment of diseases.

Industrial Applicability

To demonstrate the utility of the object compound, it shows a data pharmacological testing of representative compounds as follows.

MM P inhibitory activity: -

1. Test Method

The inhibitory activity of MMP- 13 is Arthrogen - using the CIA MMP-13 Kit (Chondrex, Inc.), were measured by the following procedure according to the formulation of Chondrex Corporation. Human recombinant was activated at Activator_l MMP-13 solution 100 .mu.1, Buffer B solution 10 .mu.1 containing test material of various concentrations, was diluted 10-fold with Oyopi Buffer A solution † Substrate Stock Solution 100 μΐ after standing at room temperature for 2 hours the reaction initiated Te Caro immune, stop Solution and (10 mM o-phenanthroline) was stopped 10 Mi added the reaction. Fluorescent light meter the amount of Substrate liberated by the enzyme reaction (SPECTRAFLUOR PLUS: TECA, Inc.) excitation wavelength 360 nm was measured with a with a fluorescent wave length 465 nm. IC 5. Values ​​were shown as the concentration of each analyte required for 50% inhibition. 2. test compound

The compound of Example 1 9

3. Test Results

The following examples are intended to be mentioned for the purpose of illustrating the present invention in detail, it is in no way intended to limit the invention to these.

By the method shown in the Production Method 9, the object compound having the following structural formula were synthesized.

The combination of R 1 and R 2 in the structural formula, set forth in the table below.

Claims

The scope of the claims
formula:
(Wherein, R 1 and R 2 are substituted it may be Ariru group, optionally substituted Ariru lower alkyl group, Ariru lower alkenyl group, Ariru Okishi lower alkyl group, or optionally substituted It means a heterocyclic group.) a compound or its salt represented by.
. Two formulas:
(Respectively wherein, R 1 and R 2, § reel O carboxymethyl § aryl group, Aroiruari Lumpur groups, two Toroariru group, Ariru lower alkyl group, a haloaryl lower alkyl group, Ariru lower alkenyl group, Ariruokishi lower alkyl group, or 1 or compound of claim 1 represented by unsaturated 3 to contain 2 sulfur atoms to means 8 membered heteromonocyclic group.).
3 in. The formula, R 1 and R 2 are full enoki Schiff enyl, Benzoirufu Eniru group, nitrophenyl group, a naphthyl lower alkyl group, Harofueniru lower alk kill group, phenyl lower alkenyl group, phenoxy lower alkyl group or Choi two, It means a group, in a compound according to claim 2 represented.
4 in formula, R 1 and R 2 is 3- or 4 monounsaturated enoki shift enyl -. 4 one benzo I Ruff enyl, 4 twelve Torofueniru group, 1 one naphthylmethyl group, 2 one black hole phenylmethyl group , 2-phenylene Rubiniru group, 1 one or 2-phenoxy Echiru group or a 2 Choi meant a double group, in compound of claim 3 represented.
5. Compounds or pharmaceutical compositions containing the salt thereof according to claim 1.
6. Compounds or MMP- or TNF alpha production a salt thereof according to claim 1 - inhibitors.
7. for the manufacture of a medicament for the treatment of MM .rho. or TNF alpha-mediated diseases, compound or a salt thereof according to claim 1.
8. mammals including humans, comprising administering a compound or salt thereof according to claim 1, Myumyuro- or method of treating TNF a one-mediated diseases.
PCT/JP2001/008325 2000-10-10 2001-09-25 Mmp inhibitor WO2002030873A1 (en)

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EP1577302A1 (en) * 2002-12-24 2005-09-21 Daiichi Pharmaceutical Co., Ltd. Novel ethylenediamine derivatives
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FR2950056A1 (en) * 2009-09-17 2011-03-18 Galderma Res & Dev New compounds benzene-carboxamides, their process of synthesis and their use in medicine and in cosmetics
FR2950057A1 (en) * 2009-09-17 2011-03-18 Galderma Res & Dev New compounds benzene-carboxamides, their process of synthesis and their use in medicine and in cosmetics
EP2295402A3 (en) * 2003-01-08 2011-08-03 The University of Washington Antibacterial agents
WO2011132712A1 (en) * 2010-04-20 2011-10-27 大正製薬株式会社 Novel hydroxamic acid derivative
US9403758B2 (en) 2012-05-10 2016-08-02 Achaogen, Inc. Antibacterial agents
US9617256B2 (en) 2007-06-12 2017-04-11 Achaogen, Inc. Antibacterial agents

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EP1577302A1 (en) * 2002-12-24 2005-09-21 Daiichi Pharmaceutical Co., Ltd. Novel ethylenediamine derivatives
EP1577302A4 (en) * 2002-12-24 2010-09-01 Daiichi Seiyaku Co Novel ethylenediamine derivatives
EP2295402A3 (en) * 2003-01-08 2011-08-03 The University of Washington Antibacterial agents
US8101640B2 (en) 2003-01-08 2012-01-24 Novartis Vaccines And Diagnostics, Inc. Antibacterial agents
US8084615B2 (en) 2003-01-08 2011-12-27 University Of Washington Antibacterial agents
US8153843B2 (en) 2003-01-08 2012-04-10 University Of Washington Antibacterial agents
US7348437B2 (en) * 2004-06-01 2008-03-25 The Scripps Research Institute Proteomic analysis
US9617256B2 (en) 2007-06-12 2017-04-11 Achaogen, Inc. Antibacterial agents
US9115102B2 (en) 2009-09-17 2015-08-25 Galderma Research & Development N-[2-hydroxycarbamoyl-2-(piperazinyl) ethyl] benzamide compounds, their preparation and their use as TACE inhibitors
WO2011033010A1 (en) 2009-09-17 2011-03-24 Galderma Research & Development 4-alkoxy-n- (2-hydroxycarbamoyl-2-piperidinyl-ethyl) -benzamide compounds as selective tace-inhibitors for the treatment of inflammatory diseases
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FR2950056A1 (en) * 2009-09-17 2011-03-18 Galderma Res & Dev New compounds benzene-carboxamides, their process of synthesis and their use in medicine and in cosmetics
JP2013505215A (en) * 2009-09-17 2013-02-14 ガルデルマ・リサーチ・アンド・デヴェロップメント N- [2- hydroxy-carbamoyl-2- (piperazinyl) ethyl] benzamide, their use as their preparation and tace inhibitor
JP2013505216A (en) * 2009-09-17 2013-02-14 ガルデルマ・リサーチ・アンド・デヴェロップメント As selective tace inhibitors for inflammatory disease 4- alkoxy-n-(2-hydroxy-carbamoyl-2-piperidinyl-ethyl) - benzamide
WO2011033009A1 (en) 2009-09-17 2011-03-24 Galderma Research & Development N- [2-hydroxycarbamoyl-2- (piperazinyl) ethyl] benzamide compounds, their preparation and their use as tace inhibitors
US9266848B2 (en) 2009-09-17 2016-02-23 Galderma Research & Development 4-alkoxy-N-(2-hydroxycarbamoyl-2-piperidinyl-ethyl)-benzamide compounds as selective TACE-inhibitors for the treatment of inflammatory diseases
CN103003233A (en) * 2010-04-20 2013-03-27 大正制药株式会社 Novel hydroxamic acid derivative
US9073821B2 (en) 2010-04-20 2015-07-07 Taisho Pharmaceutical Co., Ltd Hydroxamic acid derivative
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WO2011132712A1 (en) * 2010-04-20 2011-10-27 大正製薬株式会社 Novel hydroxamic acid derivative
US9499477B2 (en) 2010-04-20 2016-11-22 Toyama Chemical Co., Ltd. Hydroxamic acid derivative
US9403758B2 (en) 2012-05-10 2016-08-02 Achaogen, Inc. Antibacterial agents
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