WO2016045598A1 - Composé pyrrolo[2,3-d]pyrimidine substitué en position 4 et utilisation dudit composé - Google Patents

Composé pyrrolo[2,3-d]pyrimidine substitué en position 4 et utilisation dudit composé Download PDF

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Publication number
WO2016045598A1
WO2016045598A1 PCT/CN2015/090497 CN2015090497W WO2016045598A1 WO 2016045598 A1 WO2016045598 A1 WO 2016045598A1 CN 2015090497 W CN2015090497 W CN 2015090497W WO 2016045598 A1 WO2016045598 A1 WO 2016045598A1
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Prior art keywords
compound
pharmaceutically acceptable
group
tautomer
pyrrole
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PCT/CN2015/090497
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English (en)
Chinese (zh)
Inventor
秦引林
苏梅
金秋
陈涛
伍贤志
蒋建华
Original Assignee
江苏柯菲平医药股份有限公司
南京柯菲平盛辉制药有限公司
南京柯菲平制药有限公司
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Publication of WO2016045598A1 publication Critical patent/WO2016045598A1/fr

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    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a 4-substituted pyrrolo[2,3-d]pyrimidine compound and its use in the preparation of a medicament for the treatment of diseases of the immune system, treatment of rheumatoid diseases such as rheumatoid, tumors and the like.
  • Protein kinases also known as protein phosphakinase, are a class of enzymes that catalyze the phosphorylation of proteins. It can transfer the ⁇ -phosphate on adenosine triphosphate (ATP) to the amino acid residues of protein molecules, thereby changing the conformation and activity of proteins and enzymes. Phosphorylation of proteins is an important part of many signaling pathways, and most important life processes in cells are inseparable from protein phosphorylation. These enzymes are key factors in regulating cellular signaling, including cell proliferation and cell differentiation.
  • ATP adenosine triphosphate
  • Protein kinase signaling plays a major role in transduction: one is to regulate protein activity through phosphorylation. Phosphorylation and dephosphorylation are common mechanisms for reversible activation of most signaling pathway components. Some proteins are phosphorylated. It has activity, some is active after dephosphorylation; the other is to gradually amplify the signal through the stepwise phosphorylation of the protein, causing cell reaction.
  • Janus-activated kinase Singal transducers and activators of transcriprion is a newly discovered intracellular signaling pathway closely related to cytokines, which is involved in cell proliferation and differentiation. Many important biological processes such as apoptosis and immune regulation.
  • Janus kinase is a non-receptor tyrosine protein kinase.
  • JAK1, JAK2, TYK2 and JAK3 There are 4 family members, namely JAK1, JAK2, TYK2 and JAK3.
  • JAK is a very important drug target
  • JAK inhibitors While JAK is a very important drug target, JAK inhibitors have been proven to be useful in the treatment of blood system diseases, tumors, rheumatoid arthritis and psoriasis. Because JAK inhibitors have significant medical uses and can be used in a variety of related disease drugs, the research and discovery of such compounds is extremely beneficial.
  • JAK inhibitor of a related disease Its mother core structure is shown in the following chemical formula.
  • As an effective JAK inhibitor it can be used as a drug substance for the preparation of a medicament for treating diseases such as rheumatoid arthritis, skin diseases, cancer, and myeloproliferative diseases.
  • JAK inhibitors which is marketed as a typical JAK inhibitor, is used for rheumatoid arthritis (rheumatoid). Arthritis). The first drug to treat.
  • JAK inhibitors involves a wide range of applications, and it is an effort in the field to seek new, more active, and more highly compounded compounds.
  • a first technical object of the present invention is to provide a novel JAK inhibitor compound; a second technical object of the present invention is to provide a JAK inhibitor compound of the present invention in the preparation of a medicament for treating a disease associated with a JAK inhibitor application.
  • R 1 is selected from the group consisting of hydrogen, halogen, and alkyl.
  • R 2 is selected from: Wherein R 4 , R 5 , R 6 , and R 7 are each independently selected from the group consisting of hydrogen, halogen, alkyl, nitro, amino, and hydroxy; and X is selected from O, N or S. Further, in R 2 , R 4 , R 5 , R 6 and R 7 are each independently selected from the group consisting of hydrogen, halogen and alkyl.
  • R 3 is selected from: Wherein R 8 is selected from the group consisting of alkyl, cycloalkyl and heterocycloalkyl.
  • R 3 is selected from
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of any one of formula (I), a stereoisomer, tautomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier , adjuvant or solvent.
  • a compound represented by the formula (I), a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt thereof is used as a medicament.
  • a compound of the formula (I), a stereoisomer, a tautomer, a prodrug or a pharmaceutically acceptable salt thereof which is used as a medicament for treating an immune disease; and a treatment selected from rheumatoid sex Drugs for arthritis, asthma, systemic lupus erythematosus, psoriasis, IBD, and transplant rejection of immune diseases.
  • JAK1 kinase activity for inhibiting a responsive disease, particularly an immune disease, more particularly selected from the group consisting of rheumatoid arthritis, asthma, systemic lupus erythematosus, psoriasis, IBD, and transplant rejection Immune disease.
  • a responsive disease particularly an immune disease, more particularly selected from the group consisting of rheumatoid arthritis, asthma, systemic lupus erythematosus, psoriasis, IBD, and transplant rejection Immune disease.
  • Alkyl means a saturated aliphatic hydrocarbon group. A straight or branched chain group of 1 to 20 carbon atoms is included. Preference is given to medium-sized alkyl groups having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. More preferred are lower alkyl groups having 1 to 4 carbon atoms such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl or t-butyl groups and the like.
  • the alkyl group may be substituted or unsubstituted, and when substituted, preferred groups are: halogen, C 2 -C 6 alkenyl, C 6 -C 10 aryl, C 5 -C 10 heteroaryl, halogen C 1 -C 6 alkyl, 4 to 8 membered heteroalicyclic, hydroxy, C 1 -C 6 alkoxy, C 6 -C 10 aryloxy.
  • Cycloalkyl means a 3 to 8 membered all-carbon monocyclic, all-carbon 5/6 or 6/6-membered fused or polycyclic fused ring ("thickened” ring means each in the system The ring shares an adjacent pair of carbon atoms) groups with other rings in the system, wherein one or more of the rings have a fully linked pi-electron system, and examples of cycloalkyl groups (not limited to) are cyclopropane, cyclobutane, Cyclopentane, cyclopentene, cyclohexane, adamantane, cyclohexadiene, cycloheptane and cycloheptatriene.
  • Cycloalkyl groups are substitutable and substituted.
  • the substituent is preferably one or more groups each selected from the group consisting of: hydrogen, hydroxy, thiol, oxo, lower alkyl, lower alkoxy, lower cycloalkyl, lower heteroalicyclic , lower haloalkoxy, alkylthio, halogen, lower haloalkyl, lower hydroxyalkyl, lower cycloalkylalkylene, lower heteroalicyclic alkylene, aryl, heteroaryl, alkoxycarbonyl, Amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, Alkylcarbonylamino, arylcarbonylamino,
  • Heterocycloalkyl means a monocyclic or fused ring radical having from 5 to 9 ring atoms in the ring wherein one or both of the ring atoms are selected from N, O or S(O) p (where p is A hetero atom of 0 to 2 integers, and the remaining ring atoms are C. These rings may have one or more double bonds, but these rings do not have a fully conjugated pi-electron system.
  • Non-limiting examples of unsubstituted heteroalicyclic groups are pyrrolidinyl, piperidino, piperazino, morpholino, thiomorpholino, homopiperazino and the like.
  • the heteroalicyclic group can be substituted or unsubstituted.
  • the substituent is preferably one or more, more preferably one, two or three, and even more preferably one or two, said substituent being selected from the group consisting of hydrogen, hydroxy, thiol, oxygen a lower alkyl group, a lower alkoxy group, a lower cycloalkyl group, a lower heteroalicyclic group, a lower haloalkoxy group, an alkylthio group, a halogen, a lower haloalkyl group, a lower hydroxyalkyl group, a lower cycloalkylalkylene group, Lower heteroalicyclic alkylene, aryl, heteroaryl, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkyl Sulfonylamino, arylsulfonylamino, alkylaminocarbony
  • heteroalicyclic groups include, but are not limited to, morpholinyl, piperazinyl, piperidinyl, azetidinyl, pyrrolidinyl, hexahydroazepine, oxetanyl, tetrahydrofuranyl , tetrahydrothiophenyl, oxazolidinyl, thiazolidinyl, isoxazolidinyl, tetrahydropyranyl, thiomorphinyl, quinuclidinyl and imidazolinyl, each group as described above, Examples may also be bicyclic, such as, for example, 3,8-diaza-bicyclo[3.2.1]octane, 2,5-diazabicyclo[2.2.2]octane or octahydro-pyrazine. [2,1-c][1,4]oxazine. Its heteroalicyclic group (and derivatives).
  • Haldroxy means an -OH group.
  • Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or chloro.
  • Amino means a -NH 2 group.
  • substituted by one or more groups means that one, two, three or four hydrogen atoms in a given atom or group are each selected from a specified range of groups. Replace the same or different groups.
  • “Pharmaceutically acceptable salt” means those salts which retain the biological effectiveness and properties of the parent compound. Such salts include:
  • a salt with an acid obtained by a reaction of a free base of a parent compound with an inorganic or organic acid includes hydrochloric acid, hydrobromic acid, nitric acid, phosphoric acid, metaphosphoric acid, sulfuric acid, sulfurous acid, perchloric acid, etc.
  • Organic acids include acetic acid, propionic acid, acrylic acid, oxalic acid, (D) or (L) malic acid, fumaric acid, maleic acid, hydroxybenzoic acid, ⁇ -hydroxybutyric acid, methoxybenzoic acid, ortho-benzene Formic acid, methanesulfonic acid, ethanesulfonic acid, naphthalene-1-sulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid, salicylic acid, tartaric acid, citric acid, lactic acid, mandelic acid, succinic acid or malonic acid .
  • an organic base such as ethanolamine, diethanolamine, or the like. Ethanolamine, tromethamine, N-methylglucamine, and the like.
  • “Pharmaceutical composition” means that one or more of the compounds of the invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is mixed with another chemical component, such as a pharmaceutically acceptable carrier. .
  • the purpose of the pharmaceutical composition is to facilitate the administration to the animal.
  • “Pharmaceutically acceptable carrier” refers to an inactive ingredient in a pharmaceutical composition that does not cause significant irritation to the organism and does not interfere with the biological activity and properties of the administered compound, such as, but not limited to, calcium carbonate, calcium phosphate, various Sugar (eg lactose, mannitol, etc.), starch, cyclodextrin, magnesium stearate, cellulose, magnesium carbonate, acrylic polymer or methacrylic acid polymer, gel, water, polyethylene glycol, propylene glycol, B Glycol, castor oil or hydrogenated castor oil or polyethoxylated hydrogenated castor oil, sesame oil, corn oil, peanut oil and the like.
  • the aforementioned pharmaceutical composition may include, in addition to a pharmaceutically acceptable carrier, an adjuvant which is commonly used in medicine, for example, an antibacterial agent, an antifungal agent, an antimicrobial agent, a quality agent, a tone.
  • an adjuvant which is commonly used in medicine, for example, an antibacterial agent, an antifungal agent, an antimicrobial agent, a quality agent, a tone.
  • Tin reagent (Compound B, 1.0 g, 1.57 mmol), 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H--pyrrolo[2,3- d]pyrimidine (Compound A, 540 mg, 1.90 mmol), tetrakis(triphenylphosphine)palladium (183 mg, 0.16 mmol), CuI (0.031 g, 0.16 mmol) in anhydrous DMF (10 mL). The reaction was carried out at ° C for 14 hours. After the reaction was completed, it was poured into water (10 mL), ethyl acetate (100 mL*3), and the organic phase was dried over anhydrous magnesium sulfate. 1) 0.7 g of the target compound was obtained in a yield of 75%.
  • Diisopropylamine was added dropwise to butyllithium (160 mL, 0.4 mol, 10 eq) at 0 ° C, stirred for 1 h, cooled to -78 ° C, and cyclohexanone (40.0 g, 0.4 mol, 10 eq) was added dropwise. Stir for 2 hours with heat.
  • a solution of Compound A (12.0 g, 0.04 mol, 1.0 eq) in THF (100 mL) was added dropwise, and the mixture was warmed to room temperature and stirred for 15 h. Add saturated ammonium chloride solution (50 mL) to the reaction solution, extract with EA (100 mL * 3), combined organic phase spin directly into the next step.
  • the Km value of the different adenosine triphosphate (ATP) concentrations was examined by the Caliper Mobility Shift Assay method to examine the effects of the following enumerated compounds of the invention on inhibitors of the Janus series of kinases.
  • the inhibitory effect of the compounds of the invention on the JAK-STAT pathway was found to be very pronounced.
  • the inhibition of IL-3 and IL-4 induced proliferation of TF-1 cells by the compounds was examined by the MTS method, and the IC 50 value was calculated.
  • TF-1 cells were resuspended in 10 ng/ml IL-3, IL-4 RPMI-1640 medium (containing 10% FBS), and inserted into 96 wells at a density of 15000 cells/well. In the board. Two control groups were set up in the experiment. Negative control group: containing cells, but not containing IL-3 or IL-4 factor, containing 10% serum; positive control group (compound 0 concentration well): cells without compound action, but containing IL-3 or IL-4 Child and serum. Gradiently diluted compounds were added to the cells to a final concentration of 20,000 nM, diluted 3 times, a total of 10 concentrations (containing 0 concentration wells), 3 replicates per concentration.
  • the DMSO content in the medium was 0.1%.
  • the cells were cultured in an incubator at 37 ° C, 5% CO 2 , and the compounds were allowed to act on the cells for 72 h.
  • CCK8 was added, containing 10% (V/V) per well, and incubated at 37 °C for 3 h.
  • the microplate reader detects the absorbance at 450 nM.
  • the compound of the present invention inhibits the action of rheumatoid arthritis, selects DBA/1J mice, and 50 ug of bovine type II collagen with an equal volume of complete Freund's
  • the agent (CFA) was completely emulsified and injected subcutaneously. After 21 days, 50 ug of the same antigen and incomplete Freund's adjuvant (IFA fully emulsified, boosted once. The observation was started from the 45th day. Using 1-4 scoring method: 1 point, normal; 2 points, 1 Joint swelling; 3 points, more than 1 joint swelling, but did not accumulate all joints; 4 points, the entire paw was severely swollen or stiff. The score of each claw was added to obtain the total score of joint inflammation in mice.
  • mice greater than 1 were successfully established in the model. After successfully establishing a mouse model of rheumatoid arthritis, the mice of the present invention were intragastrically administered with the compound of the present invention, and the joint inflammation of the mice was scored after 2 weeks of administration, and the result showed that the product was displayed. It has obvious therapeutic effects on rheumatoid arthritis in mice.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un composé pyrrolo[2,3-d]pyrimidine substitué en position 4 et l'utilisation dudit composé pour préparer des médicaments destinés à traiter des maladies associées à JAK, telles que la polyarthrite rhumatoïde, les maladies du système immunitaire, les tumeurs etc. Ledit composé pyrrolo[2,3-d]pyrimidine susbtitué en position 4 est tel que représenté dans la formule structurale (I). Les résultats relatifs à l'activité montrent que certains des composés représentés par la formule (I) ont un puissant effet inhibiteur sur les Janus kinases.
PCT/CN2015/090497 2014-09-28 2015-09-24 Composé pyrrolo[2,3-d]pyrimidine substitué en position 4 et utilisation dudit composé WO2016045598A1 (fr)

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CN201410505760.8 2014-09-28
CN201410505760.8A CN105524067A (zh) 2014-09-28 2014-09-28 4-取代吡咯并[2,3-d]嘧啶化合物及其用途

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11014941B2 (en) 2017-04-24 2021-05-25 Cocrystal Pharma, Inc. Pyrrolopyrimidine derivatives useful as inhibitors of influenza virus replication
US11661419B2 (en) 2019-12-20 2023-05-30 Pfizer Inc. Benzimidazole derivative compounds and uses thereof

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107573364A (zh) * 2017-10-31 2018-01-12 无锡福祈制药有限公司 一种jak激酶抑制剂
KR20200129099A (ko) * 2018-01-30 2020-11-17 인사이트 코포레이션 (1-(3-플루오로-2-(트리플루오로메틸)이소니코티닐)피페리딘-4-온)의 제조 방법
CN110028509B (zh) * 2019-05-27 2020-10-09 上海勋和医药科技有限公司 作为选择性jak2抑制剂的吡咯并嘧啶类化合物、其合成方法及用途

Citations (4)

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CN1305479A (zh) * 1998-06-19 2001-07-25 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
CN101142218A (zh) * 2005-02-03 2008-03-12 沃泰克斯药物股份有限公司 可用作蛋白激酶抑制剂的吡咯并嘧啶
CN101448826A (zh) * 2005-12-13 2009-06-03 因塞特公司 作为两面神激酶抑制剂的杂芳基取代的吡咯并[2,3-b]吡咯和吡咯并[2,3-b]嘧啶
CN102026999A (zh) * 2008-03-11 2011-04-20 因塞特公司 作为jak抑制剂的氮杂环丁烷和环丁烷衍生物

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1305479A (zh) * 1998-06-19 2001-07-25 辉瑞产品公司 吡咯并[2,3－d]嘧啶化合物
CN101142218A (zh) * 2005-02-03 2008-03-12 沃泰克斯药物股份有限公司 可用作蛋白激酶抑制剂的吡咯并嘧啶
CN101448826A (zh) * 2005-12-13 2009-06-03 因塞特公司 作为两面神激酶抑制剂的杂芳基取代的吡咯并[2,3-b]吡咯和吡咯并[2,3-b]嘧啶
CN102026999A (zh) * 2008-03-11 2011-04-20 因塞特公司 作为jak抑制剂的氮杂环丁烷和环丁烷衍生物

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11014941B2 (en) 2017-04-24 2021-05-25 Cocrystal Pharma, Inc. Pyrrolopyrimidine derivatives useful as inhibitors of influenza virus replication
US11661419B2 (en) 2019-12-20 2023-05-30 Pfizer Inc. Benzimidazole derivative compounds and uses thereof

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