EP2638018A1 - Composés de pyridine et leurs analogues aza en tant qu'inhibiteurs de tyk2 - Google Patents

Composés de pyridine et leurs analogues aza en tant qu'inhibiteurs de tyk2

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Publication number
EP2638018A1
EP2638018A1 EP11781515.9A EP11781515A EP2638018A1 EP 2638018 A1 EP2638018 A1 EP 2638018A1 EP 11781515 A EP11781515 A EP 11781515A EP 2638018 A1 EP2638018 A1 EP 2638018A1
Authority
EP
European Patent Office
Prior art keywords
methyl
pyrazol
pyrimidin
amino
amine
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Withdrawn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
EP11781515.9A
Other languages
German (de)
English (en)
Inventor
Katie Ellard
Jeremy Major
Alison Jones
Rosemary Lynch
Nigel Ramsden
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.)
Cellzome Ltd
Original Assignee
Cellzome Ltd
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Filing date
Publication date
Application filed by Cellzome Ltd filed Critical Cellzome Ltd
Priority to EP11781515.9A priority Critical patent/EP2638018A1/fr
Publication of EP2638018A1 publication Critical patent/EP2638018A1/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • 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
    • 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
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    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
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    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
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    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • A61P5/40—Mineralocorticosteroids, e.g. aldosterone; Drugs increasing or potentiating the activity of mineralocorticosteroids
    • A—HUMAN NECESSITIES
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    • A61P7/06—Antianaemics
    • 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
    • C07D401/14—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 three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • 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
    • C07D417/14—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 three or more hetero rings

Definitions

  • 26 29 are independently selected from the group consisting of halogen; CN; C(0)OR 30 ; OR 30 ; C(0)R 30 ; C(O)N(R 30 R 30a ); S(O) 2 N(R 30 R 30a ); S(O)N(R 30 R 30a ); S(0) 2 R 30 ; S(0)R 30 ; N(R 30 )S(O) 2 N(R 30a R 30b ); N(R 30 )S(O)N(R 30a R 30b ); SR 30 ; N(R 30 R 30a ); OC(0)R 3 °; N(R 30 )C(O)R 30a ; N(R 30 )S(O) 2 R 30a ; N(R 30 )S(O)R 30a ; N(R 30 )C(O)N(R 30a R 30b ); N(R 30 )C(O)OR 30a ; and OC(O)N(R 30 R 30a ); R , R 2 , R
  • R is defined as indicated above.
  • the invention also comprises their corresponding pharmaceutically or toxicologically acceptable salts, in particular their pharmaceutically utilizable salts.
  • the compounds of the formula (I) which contain acidic groups can be used according to the invention, for example, as alkali metal salts, alkaline earth metal salts or as ammonium salts. More precise examples of such salts include sodium salts, potassium salts, calcium salts, magnesium salts or salts with ammonia or organic amines such as, for example, ethylamine, ethanolamine, triethanolamine or amino acids.
  • Compounds of the formula (I) which contain one or more basic groups i.e.
  • the compounds of the present invention are selective TYK2 inhibitors.
  • carrier refers to a diluent, adjuvant, excipient, or vehicle with which the therapeutic is administered.
  • Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, including but not limited to peanut oil, soybean oil, mineral oil, sesame oil and the like. Water is a preferred carrier when the pharmaceutical composition is administered orally.
  • Saline and aqueous dextrose are preferred carriers when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions are preferably employed as liquid carriers for injectable solutions.
  • Oral formulation can include standard carriers such as pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by E.W. Martin. Such compositions will contain a therapeutically effective amount of the therapeutic, preferably in purified form, together with a suitable amount of carrier so as to provide the form for proper administration to the patient. The formulation should suit the mode of administration.
  • the diseases or disorder is associated with TYK2 is an immunological, inflammatory, autoimmune, or allergic disorder or disease of a transplant rejection or a Graft-versus host disease.
  • Inflammation of tissues and organs occurs in a wide range of disorders and diseases and in certain variations, results from activation of the cytokine family of receptors.
  • Exemplary inflammatory disorders associated with activation of TYK2 include, in a non-limiting manner, skin inflammation due radiation exposure, asthma, allergic inflammation and chronic inflammation.
  • Another aspect of the present invention is a compound or a pharmaceutically acceptable salt thereof of the present invention for use in a method of treating or preventing a proliferative disease, especially cancer.
  • Phenylchloroformate (209 mg, 1.3 mmol) was added dropwise to a stirred mixture of 4-(4- aminophenyl)-5-methyl-N-(l-methyl-lH-pyrazol-4-yl)pyrimidin-2-amine (250 mg, 0.89 mmol, prepared according to Procedure I(i)) and NaHC0 3 (224 mg, 2. 7 mmol) in THF (10 mL) and the mixture was stirred at rt for 3 h.
  • Step (ii) A mixture of perfluorophenyl 4-bromobenzenesulfonate (3.3 g, 8.2 mmol), bis(pinacolato)diboron (2.29 g, 9.0 mmol), Pd(dppf)Cl 2 (669 mg, 0.82 mmol), dppf (454 mg, 0.82 mmol), and sodium acetate (4.0 g, 49 mmol) in dioxane (116 mL) was heated to reflux under a nitrogen atmosphere for 16 h. The reaction was then cooled and the solid precipitate removed by filtration. The filtrate was concentrated to give a crude product which was boiled in hexane (40 mL).
  • Examples inhibited TYK2 with activity level A and JAK2 with activity level B 36, 37, 49, 50, 51, 53, 54, 58, 60, 61, 71, 72, 75, 76, 77, 79, 83, 84, 88, 89, 91, 93, 94, 95, 96, 106, 114, 116, 117, 118, 120, 124, 137, 144, 146, 152, 154, 158, 159, 166, 171, 175, 176, 178, 183, 184, 185, 187, 191, 192, 193, 195, 198, 202, 203, 204, 207, 208, 209, 216, 218, 219.

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  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Endocrinology (AREA)
  • Pulmonology (AREA)
  • Hematology (AREA)
  • Dermatology (AREA)
  • Oncology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Neurology (AREA)
  • Rheumatology (AREA)
  • Obesity (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Urology & Nephrology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Biomedical Technology (AREA)
  • Pain & Pain Management (AREA)
  • Neurosurgery (AREA)
  • Transplantation (AREA)
  • Emergency Medicine (AREA)
  • Reproductive Health (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne des composés de formule (I), dans laquelle R1 à R3, X1, X2 ont la signification telle que citée dans la description et les revendications. Lesdits composés sont utiles en tant qu'inhibiteurs de TYK2 pour le traitement ou la prophylaxie de troubles immunologiques, inflammatoires, auto-immuns, allergiques et de maladies à médiation immunologique. L'invention concerne également des compositions pharmaceutiques contenant lesdits composés ainsi que leur utilisation en tant que médicaments.
EP11781515.9A 2010-11-09 2011-11-07 Composés de pyridine et leurs analogues aza en tant qu'inhibiteurs de tyk2 Withdrawn EP2638018A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP11781515.9A EP2638018A1 (fr) 2010-11-09 2011-11-07 Composés de pyridine et leurs analogues aza en tant qu'inhibiteurs de tyk2

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP10190460 2010-11-09
PCT/EP2011/069553 WO2012062704A1 (fr) 2010-11-09 2011-11-07 Composés de pyridine et leurs analogues aza en tant qu'inhibiteurs de tyk2
EP11781515.9A EP2638018A1 (fr) 2010-11-09 2011-11-07 Composés de pyridine et leurs analogues aza en tant qu'inhibiteurs de tyk2

Publications (1)

Publication Number Publication Date
EP2638018A1 true EP2638018A1 (fr) 2013-09-18

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EP11781515.9A Withdrawn EP2638018A1 (fr) 2010-11-09 2011-11-07 Composés de pyridine et leurs analogues aza en tant qu'inhibiteurs de tyk2

Country Status (6)

Country Link
EP (1) EP2638018A1 (fr)
JP (1) JP2014500254A (fr)
CN (1) CN103298794A (fr)
AU (1) AU2011328237A1 (fr)
CA (1) CA2815330A1 (fr)
WO (1) WO2012062704A1 (fr)

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