PT822186E - L-tert-leucina-2-piridilamida - Google Patents

L-tert-leucina-2-piridilamida Download PDF

Info

Publication number
PT822186E
PT822186E PT97117543T PT97117543T PT822186E PT 822186 E PT822186 E PT 822186E PT 97117543 T PT97117543 T PT 97117543T PT 97117543 T PT97117543 T PT 97117543T PT 822186 E PT822186 E PT 822186E
Authority
PT
Portugal
Prior art keywords
alkyl
pyridylamide
leucine
tert
preparation
Prior art date
Application number
PT97117543T
Other languages
English (en)
Inventor
Raymond Paul Beckett
Fionna Mitchell Martin
Mark Whittaker
Andrew Miller
Original Assignee
British Biotech Pharm
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 GB9401034A external-priority patent/GB9401034D0/en
Priority claimed from GB9415619A external-priority patent/GB9415619D0/en
Application filed by British Biotech Pharm filed Critical British Biotech Pharm
Publication of PT822186E publication Critical patent/PT822186E/pt

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • 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
    • A61P17/00—Drugs for dermatological disorders
    • 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
    • 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
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/14—Decongestants or antiallergics
    • 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
    • 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
    • A61P37/08—Antiallergic agents
    • 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
    • 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
    • C07C259/00—Compounds 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
    • C07C259/04—Compounds 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
    • C07C259/06—Compounds 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three 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
    • C07D277/38—Nitrogen atoms
    • C07D277/44—Acylated amino or imino radicals
    • C07D277/46—Acylated amino or imino radicals by carboxylic acids, or sulfur or nitrogen analogues thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D285/00—Heterocyclic compounds containing rings having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by groups C07D275/00 - C07D283/00
    • C07D285/01—Five-membered rings
    • C07D285/02—Thiadiazoles; Hydrogenated thiadiazoles
    • C07D285/04—Thiadiazoles; Hydrogenated thiadiazoles not condensed with other rings
    • C07D285/12—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles
    • C07D285/125—1,3,4-Thiadiazoles; Hydrogenated 1,3,4-thiadiazoles with oxygen, sulfur or nitrogen atoms, directly attached to ring carbon atoms, the nitrogen atoms not forming part of a nitro radical
    • C07D285/135—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic 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 sulphur atom
    • C07D333/26—Heterocyclic 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 sulphur atom 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
    • C07D333/30—Hetero atoms other than halogen
    • C07D333/34—Sulfur atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Immunology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Cardiology (AREA)
  • Epidemiology (AREA)
  • Pain & Pain Management (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Lubricants (AREA)
  • Pyridine Compounds (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Description

%ΙΖ \2&
- 1 -
DESCRIÇÃO •T-re/fr-LEUCINA-Z-PIRIDILAMIDA" [0001] A presente invenção relaciona-se com L-terí-leucina-2-piridil-amida, que é útil como um intermediário na preparação de derivados de ácidos hidroxâmicos e de ácidos carboxílicos, que são inibidores de metaloproteinase envolvida na degradação dos tecidos.
[0002] O nosso Pedido de Patente Europeia n° 95906396.7 (WO 95/19956) descreve e reivindica compostos inibidores da metaloproteinase de matriz de fórmula geral I.'
em que X é um grupo -C02H ou -CONHOH; R.! é hidrogénio; (Ci-C6)alquilo; (C2-C6)alcenilo; fenilo; fenilo substituído; fenil-(Ci-C6)alquilo; fenil substituído-(Ci-C6)alquilo; heterociclilo; hetero-ciclilo substituído; heterociclil-(Ci-C6)alquilo; heterociclil-(Ci-C6)alquilo -2- substituído; um grupo BSOnA- em que n é 0, 1 ou 2 e B é hidrogénio ou um (CrC6)alquilo, fenilo, fenilo substituído, heterociclilo, (Ci-C6)acilo, fenacilo ou grupo fenacilo substituído, e A representa (Ci-Cg)alquilo; ami-no; amino protegido; acilamino; OH; SH; (CrC6)alcoxi; (Ci-C6)alquil-amino; di-(Ci-C6)alquilamino; (CrC6)alquiltio; aril-(Ci-C6)alquilo; ami-no-(CrC6)alquilo; hidroxi-(Ci-C6)alquilo, mercapto-(Ci-C6)alquilo ou carboxi-(Ci-C6)alquilo em que os grupos amino, hidroxi, mercapto ou carboxilo são opcionalmente protegidos ou o grupo carboxilo amidado; alquilo inferior substituído por carbamoílo, mono(alquilo infe-rior)-carbamoílo, di(alquil inferior)-carbamoílo, di(alquil inferior)-amino, ou carboxi-alcanoil inferior-amino; R2 é um (C]-C6)alquilo, (C2-C6)alcenilo, (C2-C6)alquinilo, fenil-(Ci-C6)al-quilo, heteroaril-(CrC6)alquilo, cicloalquil-(Ci-C6)alquilo ou grupo cicloalcenil-(Ci-C6)alquilo, qualquer dos quais pode ser opcionalmente substituído por um ou mais substituentes seleccionados a partir de (Ci-C6)alquilo, -0-(Ci-C6)alquilo, -S-(Ci-C6)alquilo, halo e ciano (-CN); R3 é o grupo caracterizador de um amino ácido natural ou não natural no qual quaisquer grupos funcionais podem estar protegidos; R4 é um anel de fenilo ou heteroarilo de 5 ou 6 membros em que qualquer átomo de azoto do anel pode ser oxidado como um N-óxido, que pode ser opcionalmente condensado com um anel de benzeno ou com um anel heterocíclico de 5, 6 ou 7 membros, e em que qualquer dos anéis pode ser opcionalmente substituído por: -3- (a) um ou mais substituentes seleccionados independentemente de hidroxilo, halogéneo, -CN, -CO2H, -C02-(Ci-C6)alquilo, -(Ci-Có) alquilo-C02-(CrC6)alquilo, -CONH2, -CONH-(Ci-C6)alquilo, -CON-((CrC6)alquilo)2, -CHO, -CH2OH, -perfluoro-(CrC4)alqui-lo, -0-(CrC6) alquilo, -S-(Ci-C6)alquilo, -SO-(Ci-C6)alquilo, -S02-(C1-C6)alquilo, -N02, -NH2, -NH-(CrC6)alquilo, -N-((CrC6)-alquilo)2, e -NHCO-(Ci-C6)alquilo, ou (b) um grupo seleccionado de (Ci-C6)alquilo, (C2-C6)alcenilo, (C2-C6)-alquinilo, (C3-C8)cicloalquilo, (C4-C8)cicloalcenil, fenilo, benzilo, heteroarilo ou heteroarilmetilo, qualquer destes grupos podendo ser opcionalmente substituído por um ou mais substituentes seleccionados de halogéneo, hidroxilo, amino, carboxilo, perfluoro-(Ci-C4)-alquilo, (Ci-C6)alquilo, -0-(Ci-C6)alquilo ou -S-(Ci-C6)alquilo; R5 é hidrogénio ou um grupo (Ci-C6)alquilo; ou um seu sal, hidrato ou solvato, DESDE QUE R* não seja 2-piridilo ou 2-tia-zolilo quando Ri é hidrogénio, R2 é n-pentilo, R3 é iso-propilo, e R5 é hidrogénio.
[0003] Exemplos de tais compostos incluem aqueles em que R3 é tert-bu-tilo, R4 é 2-piridilo, e R5 é hidrogénio. A presente invenção relaciona-se com um intermediário para a preparação de tais compostos, nomeadamente L-terí-leu-cina-2-piridilamida, ou um seu sal de adição de ácido. Por exemplo, o Exemplo 23 do Pedido de Patente Europeia n° 95906396.7 (WO 95/19956) descreve a preparação do composto inibidor da metaloproteinase de matriz ácido R-(2,2-di- -4-
metil-lS-piridina-2-ilcarbamoil-propilcarbamoil)-5-metil-2S-propeno-2-il-hexano -hidroxâmico, de fórmula:
usando L-íert-leucina-2-piridilamida como um intermediário.
[0004] Preparações A e B abaixo, tomadas em conjunto descrevem a preparação de L-fórMeucina-2-piridilamida.
[0005] As abreviaturas seguintes foram usadas na Preparação A TLC Cromatografia de camada fina EDC Hidrocloreto de N-Etil-N’-(3-dimetilaminopropil)carbodi-imida
Os espectros NMR de *H e 13C foram registados usando um espectómetro Bruker AC 250E a 250.1 e 62.9 MHz, respectivamente. As microanálises elementares foram realizadas pela CHN Analysis Ltd. (Alpha House, Countesthorpe Road, South Wigston, Leicester LE8 2PJ, Reino Unido) ou Medac Ltd. (Department of Chemistry, Brunel University, Uxbridge, Middlesex UB8 3PH). -5-
Preparacão A
Passo A
Na‘ Benziloxicarbonil-L-fenilalanina-N-fenilamida [0006] Na'Benziloxicarbonil-L-fenilalanina (4,95 g, 16,5 mmol) foi dissolvida em diclorometano (70 ml) e a solução foi arrefecida para 0°C e agitada durante a adição de pentafluorofenol (3,35 g, 18,2 mmol), seguida por EDC (3,49 g, 18,2 mmol). A mistura foi deixada a aquecer até à temperatura ambiente, agitada por mais 1 hora e depois arrefecida de novo para 0°C. Foi adicionada, gota a gota, anilina (3,85 g, 41,4 mmol) e a mistura foi aquecida até à temperatura ambiente e depois agitada de um dia para o outro. A solução foi lavada duas vezes com carbonato de sódio 1 M, duas vezes com ácido clorídrico 1 M e finalmente com salmoura antes de secar sobre sulfato de magnésio anidro. A solução foi filtrada e evaporada até um sólido branco, que foi recristalizado a partir de acetato de etilo-hexano. Rendimento: 2,57 g (41 %). *H-NMR; δ (CDC13), 7,87 (1H, s lg), 7,43-7,03 (15 H, br m), 5,62 (1H, m), 5,08 (2H, s), 4,59 (1H, s) e 3,15 (2H, s). PASSO B: L-fenilalanina-N-fenilamida [0007] Na-Benziloxicarbonil-L-fenilalanina-N-fenilamida (2,50 g, 6,68 mmol) foi dissolvida em etanol (20 ml) e ciclo-hexano (5 ml) e foi adicionado paládio a 10% sobre carvão vegetal (250 mg). A mistura foi aquecida à temperatura de refluxo durante 1 hora após o que não foi detectado qualquer material de partida (como indicado por análise TLC). O catalisador foi removido -6- por filtração e o solvente evaporado para deixar o composto do título contaminado com etanol residual (1,74 g). 'H- NMR; d (CD3OD), 7,45 (2H, m), 7,18 (7H, m), 7,04 (1H, m), 3,56 (1H, m), 3,04 (1H, dd, J = 6,4, 13,3 Hz) e 2,85 (1H, dd, J = 7,2,13,3 Hz).
Preparação B L-fórí-leucina-2-piridilamida [0008] O composto do título foi preparado a partir de N^benziloxi-carbonil-L-férMeucina através de métodos análogos àqueles que são descritos na Preparação A. 'H-NMR; δ (CDC13), 8,26 (1H, m), 8,10 (1H, m), 7,74 (1H, m), 7,06 (1H, m), 3,25 (1H, s), 1,00 (9H, s).
Lisboa, 17 de Maio de 2000
JORGE CRUZ
Agente Oficial da Propriedade Industrial RUA VtCTOR CORDON, 14 1200 USBOA

Claims (1)

  1. - 1 - ácido. REIVINDICAÇÕES 1. L-férí-leucina-2-piridilamida ou um seu sal de adição de Lisboa, 17 de Maio de 2000 JORGE CRUZ Agente Oficial da Propriedade Industrial RUA VICTOR CORDON, 14 1200 USBOA
PT97117543T 1994-01-20 1995-01-20 L-tert-leucina-2-piridilamida PT822186E (pt)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9401034A GB9401034D0 (en) 1994-01-20 1994-01-20 Metalloproteinase inhibitors
GB9415619A GB9415619D0 (en) 1994-08-02 1994-08-02 Metalloprotease inhibitors

Publications (1)

Publication Number Publication Date
PT822186E true PT822186E (pt) 2000-08-31

Family

ID=26304192

Family Applications (1)

Application Number Title Priority Date Filing Date
PT97117543T PT822186E (pt) 1994-01-20 1995-01-20 L-tert-leucina-2-piridilamida

Country Status (22)

Country Link
US (2) US5747514A (pt)
EP (2) EP0822186B1 (pt)
JP (1) JP3297053B2 (pt)
KR (1) KR100418808B1 (pt)
CN (1) CN1049651C (pt)
AT (2) ATE165817T1 (pt)
AU (1) AU682920B2 (pt)
BR (1) BR9506535A (pt)
CZ (1) CZ290145B6 (pt)
DE (3) DE19581347T1 (pt)
DK (2) DK0740652T3 (pt)
ES (2) ES2144819T3 (pt)
FI (1) FI962904A0 (pt)
GR (1) GR3033209T3 (pt)
HU (1) HUT75059A (pt)
NO (1) NO306396B1 (pt)
NZ (1) NZ278627A (pt)
PL (1) PL179997B1 (pt)
PT (1) PT822186E (pt)
SK (1) SK281544B6 (pt)
UA (1) UA43358C2 (pt)
WO (1) WO1995019956A1 (pt)

Families Citing this family (60)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6037472A (en) * 1993-11-04 2000-03-14 Syntex (U.S.A.) Inc. Matrix metalloprotease inhibitors
GB9414157D0 (en) * 1994-07-13 1994-08-31 Smithkline Beecham Plc Medical use
GB9601042D0 (en) * 1996-01-17 1996-03-20 Smithkline Beecham Plc Medical use
GB9507799D0 (en) * 1995-04-18 1995-05-31 British Biotech Pharm Metalloproteinase inhibitors
EP0832875B1 (en) * 1995-04-25 2004-06-30 Daiichi Fine Chemical Co., Ltd. Highly water-soluble metalloproteinase inhibitor
US5677282A (en) * 1995-06-07 1997-10-14 Proscript, Inc. Amino acid amides of 1,3,4-thiadiazoles as matrix metalloproteinase
US6548084B2 (en) 1995-07-20 2003-04-15 Smithkline Beecham Plc Controlled release compositions
US6022893A (en) * 1995-08-08 2000-02-08 Ono Pharmaceutical Co., Ltd. Hydroxamic acid derivatives
PL326700A1 (en) * 1995-11-17 1998-10-26 Warner Lambert Co Sulphonamide-based inhibitors of intercellular substance metaloproteinases
CZ292617B6 (cs) 1995-11-23 2003-11-12 British Biotech Pharmaceuticals Limited Inhibitory metaloproteinázy a farmaceutický prostředek
JP2000509039A (ja) * 1996-04-23 2000-07-18 ファルマシア・アンド・アップジョン・カンパニー マトリックスメタロプロテイナーゼ・インヒビターとして有用なチアジアゾリル（チオ）尿素
GB9609794D0 (en) * 1996-05-10 1996-07-17 Smithkline Beecham Plc Novel compounds
AUPO048296A0 (en) * 1996-06-14 1996-07-11 Fujisawa Pharmaceutical Co., Ltd. New compound and its preparation
PT1021424E (pt) * 1996-06-21 2003-06-30 Upjohn Co Amidas de tiadiazolo como inibidores da metaloproteinase de matriz
CA2265666C (en) 1996-09-10 2008-01-15 British Biotech Pharmaceuticals Limited Cytostatic hydroxamic acid derivatives
US6462023B1 (en) 1996-09-10 2002-10-08 British Biotech Pharmaceuticals, Ltd. Cytostatic agents
ES2178759T3 (es) * 1996-10-02 2003-01-01 Novartis Ag Derivados de acido hidroxamico.
US6500983B2 (en) 1996-10-02 2002-12-31 Novartis Ag Hydroxamic acid derivatives
US5840974A (en) * 1996-12-04 1998-11-24 Britisch Biotech Pharmaceuticals, Ltd. Metalloproteinase inhibitors
US5952320A (en) * 1997-01-07 1999-09-14 Abbott Laboratories Macrocyclic inhibitors of matrix metalloproteinases and TNFα secretion
ZA9818B (en) * 1997-01-07 1998-07-02 Abbott Lab C-terminal ketone inhibitors of matrix metalloproteinases and tnf alpha secretion
US5985911A (en) * 1997-01-07 1999-11-16 Abbott Laboratories C-terminal ketone inhibitors of matrix metalloproteinases and TNFα secretion
US6376506B1 (en) 1997-01-23 2002-04-23 Syntex (U.S.A.) Llc Sulfamide-metalloprotease inhibitors
ZA98376B (en) * 1997-01-23 1998-07-23 Hoffmann La Roche Sulfamide-metalloprotease inhibitors
GB9702088D0 (en) * 1997-01-31 1997-03-19 Pharmacia & Upjohn Spa Matrix metalloproteinase inhibitors
CA2281664A1 (en) * 1997-02-26 1998-09-03 Robert William Wiethe Reverse hydroxamate derivatives as metalloprotease inhibitors
US6197791B1 (en) 1997-02-27 2001-03-06 American Cyanamid Company N-hdroxy-2-(alkyl, aryl, or heteroaryl, sulfanyl, sulfinyl or sulfonyl)-3-substituted alkyl, aryl or heteroarylamides as matrix metalloproteinase inhibitors
US5847148A (en) * 1997-04-10 1998-12-08 Pharmacia & Upjohn Company Thiadiazole derivatives useful for the treatment of diseases related to connective tissue degradation
EP0897908A1 (de) * 1997-08-19 1999-02-24 Roche Diagnostics GmbH 3-Aryl-Succinamido-Hydroxamsäuren, Prozesse zu ihrer Herstellung und diese Substanzen enthaltende Medikamente
US6130220A (en) * 1997-10-16 2000-10-10 Syntex (Usa) Inc. Sulfamide-metalloprotease inhibitors
ES2195122T3 (es) * 1997-11-13 2003-12-01 British Biotech Pharm Inhibidores de metaloproteinasa.
CN1125050C (zh) * 1997-11-13 2003-10-22 英国生物技术药物有限公司 金属蛋白酶抑制剂
JP3621884B2 (ja) 1998-01-09 2005-02-16 ファイザー・インク マトリックスメタロプロテアーゼ阻害剤
US6329418B1 (en) 1998-04-14 2001-12-11 The Procter & Gamble Company Substituted pyrrolidine hydroxamate metalloprotease inhibitors
US6172064B1 (en) 1998-08-26 2001-01-09 Glaxo Wellcome Inc. Formamides as therapeutic agents
GB9818605D0 (en) 1998-08-26 1998-10-21 Glaxo Group Ltd Formamide compounds as therepeutic agents
US6329400B1 (en) 1998-08-26 2001-12-11 Glaxo Wellcome Inc. Formamide compounds as therapeutic agents
US6288261B1 (en) 1998-12-18 2001-09-11 Abbott Laboratories Inhibitors of matrix metalloproteinases
US6329550B1 (en) 1998-12-31 2001-12-11 Aventis Pharmaceuticals Inc. Amidomalonamides useful as inhibitors of MMP of matrix metalloproteinase
US20040220103A1 (en) * 1999-04-19 2004-11-04 Immunex Corporation Soluble tumor necrosis factor receptor treatment of medical disorders
US6297337B1 (en) 1999-05-19 2001-10-02 Pmd Holdings Corp. Bioadhesive polymer compositions
JP2003508028A (ja) * 1999-07-28 2003-03-04 ジェネンテック・インコーポレーテッド 腫瘍治療のための組成物と方法
US6696456B1 (en) * 1999-10-14 2004-02-24 The Procter & Gamble Company Beta disubstituted metalloprotease inhibitors
US6797820B2 (en) * 1999-12-17 2004-09-28 Vicuron Pharmaceuticals Inc. Succinate compounds, compositions and methods of use and preparation
JP2003528082A (ja) * 2000-03-21 2003-09-24 ザ プロクター アンド ギャンブル カンパニー ニフッ化酪酸メタロプロテアーゼ阻害物質
IL151126A0 (en) * 2000-03-21 2003-04-10 Procter & Gamble Carbocyclic side chain containing metalloprotease inhibitors
EP1265864A1 (en) * 2000-03-21 2002-12-18 The Procter & Gamble Company Heterocyclic side chain containing, n-substituted metalloprotease inhibitors
US6803383B2 (en) * 2000-03-27 2004-10-12 The Scripps Research Institute Inhibition of angiogenesis and tumor growth
EP1712239A3 (en) * 2000-05-12 2007-08-22 Immunex Corporation Interleukin-1 inhibitors in the treatment of diseases
AR028606A1 (es) * 2000-05-24 2003-05-14 Smithkline Beecham Corp Nuevos inhibidores de mmp-2/mmp-9
US6458552B1 (en) * 2000-06-06 2002-10-01 Ortho-Mcneil Pharmaceutical, Inc. Metalloprotease peptide substrates and methods
JP4825375B2 (ja) * 2001-08-28 2011-11-30 株式会社 資生堂 ジチアゾール化合物及びマトリックスメタロプロテアーゼ活性阻害剤、皮膚外用剤
CN1732023A (zh) * 2002-12-27 2006-02-08 血管技术国际股份公司 组合物和使用collajolie的方法
US7892563B2 (en) * 2003-05-20 2011-02-22 Wyeth Holdings Corporation Methods for treatment of severe acute respiratory syndrome (SARS)
CA2560889A1 (en) * 2004-03-23 2005-10-13 Sanjay D. Khare Monoclonal antibodies specific for human ox40l (cd 134l)
EP2402435A3 (en) 2005-10-14 2012-03-28 MUSC Foundation For Research Development Targeting PAX2 for the induction of DEFB1-mediated tumor immunity and cancer therapy
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
CA2710683A1 (en) 2008-01-03 2009-07-16 Verenium Corporation Transferases and oxidoreductases, nucleic acids encoding them and methods for making and using them
GB0807139D0 (en) * 2008-04-18 2008-05-21 Syngenta Participations Ag Novel microbiocides
AU2009262199B2 (en) 2008-06-27 2012-08-09 Amgen Inc. Ang-2 inhibition to treat multiple sclerosis

Family Cites Families (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4599361A (en) * 1985-09-10 1986-07-08 G. D. Searle & Co. Hydroxamic acid based collagenase inhibitors
DK77487A (da) * 1986-03-11 1987-09-12 Hoffmann La Roche Hydroxylaminderivater
FR2609289B1 (fr) * 1987-01-06 1991-03-29 Bellon Labor Sa Roger Nouveaux composes a activite d'inhibiteurs de collagenase, procede pour les preparer et compositions pharmaceutiques contenant ces composes
GB8827305D0 (en) * 1988-11-23 1988-12-29 British Bio Technology Compounds
GB8827308D0 (en) * 1988-11-23 1988-12-29 British Bio Technology Compounds
GB8919251D0 (en) * 1989-08-24 1989-10-04 British Bio Technology Compounds
JPH05503720A (ja) * 1990-12-03 1993-06-17 セルテック　リミテッド ペプチジル誘導体
CA2058797A1 (en) * 1991-02-01 1992-08-02 Michael John Broadhurst Amino acid derivatives
GB9102635D0 (en) * 1991-02-07 1991-03-27 British Bio Technology Compounds
GB9107368D0 (en) * 1991-04-08 1991-05-22 Smithkline Beecham Plc Novel compounds
JPH06508135A (ja) * 1991-05-28 1994-09-14 メルク　エンド　カンパニー　インコーポレーテッド 抗変性活性剤としての置換ｎ−カルボキシアルキルペプチジル誘導体
AU2228292A (en) * 1991-06-14 1993-01-12 Research Corporation Technologies, Inc. Peptide derivatives of collagenase inhibitor
JPH05125029A (ja) * 1991-11-06 1993-05-21 Yamanouchi Pharmaceut Co Ltd 新規なアミド化合物又はその塩
HUT67374A (en) * 1991-11-08 1995-03-28 Sankyo Co Process for producing hexahydropyridazine carboxylic acid derivatives and pharmaceutical compositions containing them
AU3475393A (en) * 1992-01-15 1993-08-03 Merck & Co., Inc. Substituted phosphinic acid-containing peptidyl derivatives as antidegenerative agents
DE69309047T2 (de) * 1992-04-07 1997-09-11 British Biotech Pharm Hydroxamsäure enthaltende collagenase-inhibitoren und cytokinaktivitätsinhibitoren
GB9211707D0 (en) * 1992-06-03 1992-07-15 Celltech Ltd Peptidyl derivatives
GB9211706D0 (en) * 1992-06-03 1992-07-15 Celltech Ltd Peptidyl derivatives
US5318964A (en) * 1992-06-11 1994-06-07 Hoffmann-La Roche Inc. Hydroxamic derivatives and pharmaceutical compositions
US5672583A (en) * 1992-11-25 1997-09-30 Merck & Co., Inc. Carboxy-peptidyl derivatives as antidegenerative active agents
GB9307956D0 (en) * 1993-04-17 1993-06-02 Walls Alan J Hydroxamic acid derivatives

Also Published As

Publication number Publication date
US5859253A (en) 1999-01-12
UA43358C2 (uk) 2001-12-17
NO963030D0 (no) 1996-07-19
KR970700649A (ko) 1997-02-12
NO306396B1 (no) 1999-11-01
KR100418808B1 (ko) 2004-07-23
CZ211596A3 (cs) 1998-04-15
BR9506535A (pt) 1997-09-16
FI962904A (fi) 1996-07-19
DE69515702D1 (de) 2000-04-20
NZ278627A (en) 1997-04-24
ATE165817T1 (de) 1998-05-15
EP0822186A2 (en) 1998-02-04
AU682920B2 (en) 1997-10-23
ES2117400T3 (es) 1998-08-01
HUT75059A (en) 1997-03-28
GR3033209T3 (en) 2000-08-31
DE69502378D1 (en) 1998-06-10
DE19581347T1 (de) 1996-12-05
CN1138851A (zh) 1996-12-25
HU9601991D0 (en) 1996-09-30
DE69502378T2 (de) 1998-10-01
ES2144819T3 (es) 2000-06-16
EP0740652B1 (en) 1998-05-06
SK281544B6 (sk) 2001-04-09
EP0822186A3 (en) 1998-03-04
FI962904A0 (fi) 1996-07-19
SK94196A3 (en) 1997-03-05
DK0822186T3 (da) 2000-06-26
ATE190609T1 (de) 2000-04-15
EP0822186B1 (en) 2000-03-15
US5747514A (en) 1998-05-05
CZ290145B6 (cs) 2002-06-12
AU1459795A (en) 1995-08-08
EP0740652A1 (en) 1996-11-06
WO1995019956A1 (en) 1995-07-27
NO963030L (no) 1996-09-19
PL315745A1 (en) 1996-11-25
DK0740652T3 (da) 1999-02-01
JP3297053B2 (ja) 2002-07-02
PL179997B1 (pl) 2000-11-30
DE69515702T2 (de) 2000-08-10
CN1049651C (zh) 2000-02-23
JPH09508361A (ja) 1997-08-26

Similar Documents

Publication Publication Date Title
PT822186E (pt) L-tert-leucina-2-piridilamida
AP1204A (en) Nitric oxide synthase inhibitors.
AU2010251967B2 (en) Substituted aminopropionic derivatives as neprilysin inhibitors
US5412145A (en) P2'-modified hydroxamic acid collagenase inhibitors
ES2224604T3 (es) Bococñp(2.2. 1)heptanos y compuestos relacionados.
EP0457163B1 (de) Verwendung von Oxalyl-Aminosäurederivaten als Arzneimittel zur Inhibierung der Prolyl-Hydroxylase
CA2728756A1 (en) Modulators of the prostacyclin (pgi2) receptor useful for the treatment of disorders related thereto
WO2000039077A2 (en) Thyroid receptor ligands
OA13362A (en) Sulfonamide derivatives for the treatment of diseases.
WO1995032944A1 (en) Succinyl hydroxamic acid, n-formyl-n-hydroxy amino carboxylic acid and succinic acid amide derivatives as metalloprotease inhibitors
WO2018154118A2 (en) Novel aromatic compounds
Shiina et al. The effective use of substituted benzoic anhydrides for the synthesis of carboxamides
WO2022207935A1 (en) 2-(3-ethynylbenzyl)-substituted heterocycle derivatives as orexin-2 agonists
CA3109419A1 (en) Novel compounds
KR20090008441A (ko) 신경원인성 통증을 억제하는 피롤리딘 유사체 및 그 제조 방법
ES2555031T3 (es) Ácidos y análogos 4-((fenoxialquilo)tio)-fenoxiacéticos
AU2017356911A1 (en) Tricyclic sulfones as ROR gamma modulators
RU2512591C2 (ru) Способ получения плевромутилинов
GB2316078A (en) L-Tert.-Leucine-2-pyridylamide
Pan et al. Conformationally-restricted vigabatrin analogs as irreversible and reversible inhibitors of γ-aminobutyric acid aminotransferase
AU2018223177B2 (en) Aromatic compounds which enhance notch signaling, for use in therapy
JPH0692358B2 (ja) アミノ酸誘導体および該誘導体を有効成分として含有するエンケファリナーゼ阻害剤
SK287934B6 (sk) Prodrugs of excitatory amino acids
US6054595A (en) Method for synthesis of N-homocysteine thiolactonyl retinamide
KR0179459B1 (ko) 디페록사민 제조에 사용된 중간체