WO2008125014A1 - Composés d'urée, leurs procédés de préparation et leurs utilisations pharmaceutiques - Google Patents

Composés d'urée, leurs procédés de préparation et leurs utilisations pharmaceutiques Download PDF

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WO2008125014A1
WO2008125014A1 PCT/CN2008/000760 CN2008000760W WO2008125014A1 WO 2008125014 A1 WO2008125014 A1 WO 2008125014A1 CN 2008000760 W CN2008000760 W CN 2008000760W WO 2008125014 A1 WO2008125014 A1 WO 2008125014A1
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tert
butyl
pyrazolyl
urea
alkenyl
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PCT/CN2008/000760
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English (en)
Chinese (zh)
Inventor
Song Li
Xinming Zhou
Wu Zhong
Zhibing Zheng
Junhai Xiao
Lili Wang
Hongying Liu
Yunde Xie
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Institute Of Pharmacology And Toxicology Academy Of Military Medical Sciences P.L.A.
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Priority to CN2008800089963A priority Critical patent/CN101636397B/zh
Publication of WO2008125014A1 publication Critical patent/WO2008125014A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole 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
    • C07D231/38—Nitrogen atoms
    • C07D231/40—Acylated on said nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two 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
    • C07D233/88—Nitrogen atoms, e.g. allantoin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D261/14—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole 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
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • C07D405/02—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 two hetero rings
    • C07D405/12—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 two hetero rings linked by a chain containing hetero atoms as chain links
    • 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
    • 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
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen 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

Definitions

  • the present invention relates to urea compounds which inhibit P38 protein kinase, pharmaceutical compositions containing them, methods for preparing these compounds and their medical use.
  • TNF and IL-1 are central players in the pathogenesis associated with many chronic inflammation and autoimmune diseases.
  • IL-1 is involved in mediating or worsening diseases such as rheumatoid arthritis (see, Arend, WP Arthritis & Rheumatism 38(2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, Tuberculosis, atherosclerosis, diabetes, Hodgkin's disease, (see, Benharroch, D. et al. Euro. Cytokine Network 7(1): 51-57) and Alzheimer's disease.
  • the kinase, MAPK) cascade is the main signal transduction system in the cell.
  • the extracellular stimulation signal is transmitted to the nucleus through this system, which leads to a series of physiological and pathological processes such as cell growth, development, division, cytokine secretion and malignant transformation.
  • threonine, T or tyrosine (y) residues are activated by phosphorylation.
  • activation of all MAPK family members requires two-site phosphorylation of threonine and tyrosine residues, and the MAPK double-site phosphorylation group has
  • T-X-Y Thr-Xaa-Tyr
  • MAPKKK MAPK kinase kinase
  • MAPKKK activates the phosphorylation of the serine and threonine sites of MAPKK; the activated MAPKK further activates the MAPK by phosphorylation of the serine and threonine sites.
  • the MAPK family includes at least four subfamilies, namely ERK (extracel luar regulated protein kinase), c-Jun N-terminal kinase, p38, ERK5. Different subfamilies are distinguished primarily by differences in Xaa and/or upstream kinase between the phosphorylation sites.
  • ERK extracel luar regulated protein kinase
  • c-Jun N-terminal kinase p38
  • ERK5 extracel luar regulated protein kinase
  • Different subfamilies are distinguished primarily by differences in Xaa and/or upstream kinase between the phosphorylation sites.
  • MAPKs have about 40-45% homology, and all four ⁇ 38 structures have a circular active center containing a TGY tripeptide module, which is a specific double phosphorylation site of the upstream molecule.
  • ⁇ 38 ⁇ , ⁇ 38 ⁇ is widely present in the human body.
  • ⁇ 38 ⁇ is mainly found in skeletal muscle, and ⁇ 3 ⁇ is mainly distributed in the lung, kidney, testis, pancreas and small intestine. Different subtypes of ⁇ 38 are distributed differently in different cells.
  • the unactivated ⁇ 38 is located in the cytosol, and the activated ⁇ 38 is expressed in both the cytoplasm and the nucleus.
  • o P 38 (Lee named it CSBP1 and 2) provides a mechanism for the action of a class of anti-inflammatory compounds, of which SK&F 86002 is a prototype. These compounds inhibit IL-1 and TNF synthesis in human monocytes at low ⁇ ⁇ concentrations [Lee et al., Int. J. I, nopharmac. 10 (7), 835 (1988)] and show up in animal models. Activity, these animal models are resistant to cyclooxygenase inhibitors [Lee et al, Annal s NY Acad. Sci., 696, 10 149 (1993)].
  • CSBP/p38 is one of several kinases involved in the stress response signaling pathway that is parallel and largely independent of the similar mitogen-activated protein kinase cascade.
  • Stress response signals including LPS, pro-inflammatory cytokines, oxidants, UV rays and osmotic pressure, activate the upstream kinase from CSBP/p38, which in turn phosphorylates CSBP/p38 at the sulphonic acid 180 and tyrosine 182 sites.
  • MAPKAP kinase-2 has been identified and MAPKAP kinase-3 is
  • a downstream substrate of CSBP/p38 which in turn phosphorylates the heat shock protein Hsp27.
  • Other downstream substrates known to be phosphorylated by p38 include kinases (Mnk 1/2, MSK1/2 and PRAK) and transcription factors (CHOP, MEF2, ATF2 and CREB).
  • kinases Mnk 1/2, MSK1/2 and PRAK
  • transcription factors CHOP, MEF2, ATF2 and CREB
  • p38 kinase inhibitors (SK&F86002 and SB 203580) also reduce a variety of pro-inflammatory proteins including IL-6, IL- 8. Synthesis of GM-CSF and C0X-2 It has also been shown that inhibitors of CSBP/p38 kinase inhibit TNF- ot-induced VCAM-1 expression on endothelial cells, TNF- ⁇ -induced phosphorylation of cellular cytoplasmic PLA2 And activation and synthesis of IL-1 stimulated collagenase and stromelysin.
  • the object of the present invention is to find and develop a small molecule compound having p38 MAPK inhibitory activity for treating a cytokine (TNF-o, IL-1, etc.) mediated disease, a risk factor or a condition, such as psoriatic arthritis.
  • cytokine TNF-o, IL-1, etc.
  • Lyttle's syndrome gout, traumatic arthritis, rubella arthritis, acute synovitis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, gouty arthritis and other joint diseases, sepsis , septic shock, endotoxic shock, Gram-negative, sepsis, toxic shock syndrome, cerebral malaria, meningitis, ischemic stroke and hemorrhagic stroke, neurological trauma/closed head injury, asthma , adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, pulmonary sarcoma, bone resorption, osteoporosis, restenosis, heart and brain and kidney reperfusion injury, congestive heart failure, coronary artery bypass Bypass (CABG) surgery, blood test formation, glomerulonephritis, chronic renal failure, diabetes, diabetic retinopathy, macular degeneration, Graft versus host response, allograft rejection, inflammatory bowel disease, Crohn's disease, ulcerative co
  • the invention provides a compound of formula (I), or a pharmaceutically acceptable salt or solvate thereof,
  • ⁇ is ⁇ - ⁇ .
  • Aromatic carbocyclic rings including but not limited to benzene rings, substituted benzene rings, cyclooctatetraene, cyclopentapentene, etc.; or C ⁇ .
  • a saturated or unsaturated non-aromatic carbocyclic ring including, but not limited to, cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.; C 5 -d.
  • An aromatic heterocyclic ring including one or more heteroatoms selected from 0, N, S, including but not limited to imidazole, pyrazole, phenazole, oxazole, oxazole, pyrocoat, morpholine pyridine, pyrimidine, hydrazine, carbazole and quinoline; or a C 5 - C 8 heteromonocyclic or C 8 -Cu double heterocycle, comprising one or more heteroatoms selected from 0, N, S heteroatoms, including but not limited to tetrahydrofuran, tetrahydrothiophene , piperidine, hexahydropyrimidine, octahydropurine, etc.; said A is independently and optionally substituted by one to more R 15 R 2 ;
  • Ar 2 is a benzo five- or six-membered heterocyclic ring.
  • the ring includes 1-3 heteroatoms selected from 0, N, S, including but not limited to benzofuran, benzothiophene, benzopyrrole, benzopyrazole, benzodiazepine Hydrofuran, benzodihydrothiophene, benzodihydropyrrole, benzodihydropyrazole, benzothiazole, benzodihydrothiazole, etc.;
  • one ring is selected from 0, S Heteroatoms or 2-4 heteroatoms selected from 0, N, S, including but not limited to benzopyran, benzothiopyran, benzopyrimidine, benzoxazine, benzo Dihydropyran, benzoin, benzopiperidin, benzodihydrothiazide, benzomorpholine, etc.; said Ar 2
  • n 0, 1 or 2;
  • P is phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzene Imidazolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2, 3 - b pyridine, pyrrolo[3,4- b]pyridinyl, 1, 3-oxathia[4,5-pyridinyl, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl,
  • R 1 is independent
  • a cycloalkyl or cycloalkenyl group the group may be partially or fully halogenated, or optionally substituted by 1 to 3 C-C 6 fluorenyl or (a wide alkoxy group; the above-mentioned cycloalkyl or ring)
  • the 1-3 methylene groups of the alkenyl group may be optionally substituted by 0, NH, S, SO, S0 2 , carbonyl, hydroxymethyl; the above cycloalkyl or cycloalkenyl group may be independently 0-5 or less Substituted: halogen, C 6 straight or branched fluorenyl, OC 6 straight or branched alkoxy;
  • aromatic ring, aromatic heterocyclic or fused aromatic ring including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, carbazolyl, iso Carbazolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazolyl , benzofuranyl, benzopyrazolyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3, 4-b Pyrimidinyl, pyrrolo[2,3-b]pyridinyl, pyrrolo[3,4-
  • (-.cycloalkyl or cycloalkenyl, the group may be partially or fully halogenated, or optionally substituted by 1-3 dC 6 alkyl or d-C 6 alkoxy;
  • a hydrogen atom a linear or branched fluorenyl group, a dC 6 straight or branched alkenyl group, a phenyl group, a naphthyl group, a mono or a double d-C 4 alkylamino C C 6 alkyl group; m is 0, 1 or 2;
  • halogen nitro, carboxy, d-linear or branched alkyl, dC 6 straight or branched alkenyl, C 3 - .
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I) according to the invention, which comprises at least one compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, and one or more Use a carrier or excipient.
  • the invention relates to a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof.
  • the invention relates to the use of a compound of formula (I) for the manufacture of a medicament for the treatment and/or prevention of a cytokine (TNF-ct, IL-1, etc.) mediated disease or condition.
  • a cytokine TNF-ct, IL-1, etc.
  • the invention provides methods of treating and/or preventing a cytokine (TNF-a, IL-1, etc.) mediated disease, risk factor or disorder, comprising administering to a subject in need thereof treatment and/or prevention An effective amount of a compound of the invention.
  • a cytokine TNF-a, IL-1, etc.
  • cytokine (TNF- ot, IL-1, etc.) mediated diseases, risk factors or conditions described in the present invention include psoriatic arthritis, Lyttle's syndrome, gout, traumatic arthritis, rubella arthritis , acute synovitis, rheumatoid arthritis, rheumatoid arthritis, osteoarthritis, gouty arthritis and other joint diseases, sepsis, septic shock, endotoxic shock, Gram-negative, sepsis, Toxic shock syndrome, cerebral malaria, meningitis, ischemic stroke and hemorrhagic stroke, neurological trauma/closed craniocerebral injury, asthma, adult respiratory distress syndrome, chronic pneumonia, chronic obstructive pulmonary disease, silicosis, Pulmonary sarcoma, bone resorption, osteoporosis, restenosis, heart and brain and kidney re-inflation injury, congestive heart failure, coronary artery bypass grafting (CABG), blood test, glomerulonep
  • the invention provides a compound of formula I, a pharmaceutically acceptable salt or solvate thereof,
  • Aromatic carbocyclic ring including but not limited to benzene ring, substituted benzene ring, cyclotetraene, cyclopentaene, etc.; or ⁇ - saturated or unsaturated non-aromatic carbocyclic ring, including but not limited to cyclopentane, cyclohexane , cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.;
  • Aromatic heterocycles including one or more heteroatoms selected from 0, N, S, including but not limited to imidazole, pyrazole, rongha, ? : azole, carbazole, pyrotherapy, morpholine pyridine, pyrimidine, hydrazine, oxazole, quinoline, etc.; or C 5 -C 8 monoheterocycle or Cs-Cu diheterocycle, including one or more Heteroatoms from 0, N, S, including but not limited to tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyrimidine, octahydropurine, etc.; said Ar! independently and selectively one to more, 11 2 Replaced
  • Ar 2 is a benzo five- or six-membered heterocyclic ring.
  • the ring includes 1-3 heteroatoms selected from 0, N, S, including but not limited to benzofuran, benzothiophene, benzopyrrole, benzopyrazole, benzodiazepine Hydrofuran, benzodihydrothiophene, benzodihydropyrrole, benzodihydropyrazole, benzothiazole, benzodihydrothiazole, etc.;
  • when it is a six-membered heterocyclic ring one ring selected from 0, S Heteroatoms or 2 to 4 heteroatoms selected from 0, N, S, including but not limited to benzopyran, benzothiopyran, benzopyrimidine, benzoxazine, chroman, Benzohydropyran, benzopiperidine, benzodihydrothiazide, benzo Morpholine or the like; the Ar 2
  • n 0, 1 or 2j
  • P is phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzene Imidazolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2, 3 - b] pyridyl, pyrrolo[3,4-b]pyridyl, 1, 3-oxathia[4,5-pyridinyl, 1, 2, 3-triazolyl, 1 , 2,4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydr
  • R 1 is independent
  • a straight or branched alkyl group, the alkyl group may be partially or fully halogenated, and may be substituted by 1-3 phenyl, naphthyl or a heterocyclic ring: quinolyl, isoquinolinyl, pyridyl , pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thiahaki, isoxazolyl, isothiazolyl; the above phenyl, tea or heterocyclic ring can be 0 - 5 of the following groups replaced: !
  • a cycloalkyl or cycloalkenyl group the group may be partially or fully halogenated, or substituted by 1-3 C-C 6 alkyl or Cr-C 6 alkoxy; the above cycloalkyl or cycloalkenyl
  • the 1-3 methylene groups of the group may be replaced by 0, NH, S, SO, S0 2 , carbonyl, hydroxymethyl; the above cycloalkyl or cycloalkenyl group may be independently substituted by 0-5 groups: Halogen, straight or branched chain base, d-Cs straight or branched alkoxy;
  • C 3 - a linear or branched alkenyl group which may be partially or fully halogenated, and may be substituted by 1 to 3 ( ⁇ -C 6 linear or branched alkyl, phenyl, naphthyl or the following heterocyclic ring)
  • Substituents quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, isothiazolyl;
  • the above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, dC 6 straight or branched alkyl, C 3 - cycloalkyl, -cycloalkenyl, hydroxy, nitrile , dC 6 straight or branched alkoxy, trifluoromethyl
  • phenyl ring, aromatic heterocyclic or fused aromatic ring including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, carbazolyl, iso Olezolyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thienyl, pyranyl, phylyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazolyl , benzofuranyl, benzopyrazolyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzothiazino, benzisothiazolyl, pyrazolo[3, 4- b]pyrimidinyl, pyrrolo[2,3-b]pyridyl, pyrrolo[
  • the above aromatic ring, aromatic heterocyclic ring or fused aromatic ring group may be independently substituted by 0-5 R 4 groups;
  • a cycloalkyl or cycloalkenyl group the group may be partially or fully halogenated, or substituted with 1-3 C-C 6 alkyl or dC 6 alkoxy;
  • Hydrogen atom d-C 6 straight or branched alkyl group, CrC fi straight or branched alkenyl group, phenyl, naphthyl group, mono or di C 4 alkylamino group ( ⁇ -( ⁇ alkyl; m is 0 , 1 or 2;
  • halogen nitro, carboxy, C-C 6 straight or branched alkyl, ( ⁇ - straight or branched alkenyl, CfC!.
  • cycloalkyl -(: 8 cycloalkenyl, hydroxy, nitrile , d-C 6 straight or branched alkoxy, trifluoromethyl, trifluoromethoxy;
  • Wide range R 3 NH-, R 3 2 N-, R 3 NCO-R 3 CONH-, R 3 C00 -, R 3 0C0 -, R 3 S (0) m , R 3 S (0) m NH, R 3 NHS (0) m - ;
  • the invention provides a compound represented by formula I, a pharmaceutically acceptable salt or solvate thereof,
  • Aromatic carbocyclic rings including but not limited to benzene rings, substituted benzene rings, cyclooctatetraene, cyclopentaene, etc., or . a saturated or unsaturated non-aromatic carbocyclic ring, including but not limited to cyclopentane, cyclohexane, cyclopentene, cyclohexene, cyclopentadiene, cyclohexadiene, etc.;
  • a C 5 -C 1Q aromatic heterocycle comprising one or more heteroatoms selected from 0, N, S, including but not limited to imidazole, pyrazole, thiophene, thiazole, oxazole, pyridinium, morpholinium pyridine, pyrimidine, An oxime, a carbazole, a quinoline or the like; or a monoheterocyclic ring of C-C s or a bi-heterocyclic ring of c 8 - c u , including one or more heteroatoms selected from 0, N, S, including but not limited to Tetrahydrofuran, tetrahydrothiophene, piperidine, hexahydropyrimidine, octahydropurine, etc.; said A is independently and selectively substituted by one to more R 2 ;
  • Ar 2 is a benzopyran or a chromanyl group; the Ar 2 may be substituted with from 1 to 4 substituents selected from C: C 6 straight or branched alkyl, C 2 - C 6 straight or branched alkenyl, dC 6 straight or branched alkoxy, C 2 -C 6 straight or branched alkenyloxy, trifluoromethyl, trifluoromethoxy, acetyl, aroyl , halogen, methoxyhistyl, ethoxycarbonyl, phenylsulfonyl, hydroxy, amino, mono- or di-d-C-alkyl substituted amino, mono- or bi- Substituted aminosulfonyl, nitrile, nitro, aminosulfonyl;
  • ( 2 ) ( ⁇ . Saturated or unsaturated, linear or branched carbon chain; one or more methylene groups independently replaced by 0, ⁇ , S ( 0 ) m or 0-2 And the linking group can be substituted by one or more halogen atoms;
  • n 0, 1 or 2;
  • P is phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrrolyl, benzene Imidazolyl, furyl, thienyl, pyranyl, naphthyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2, 3-b] pyridyl, pyrrolo[3,4-b]pyridinyl, 1, 3-oxaza-[4,5-pyridinyl, 1, 2, 3-triazolyl, 1, 2,4-triazolyl, tetrazolyl, tetrahydropyranyl, tetrahydrofuranyl, di
  • R 1 is independent
  • (1) d-. a linear or branched alkyl group the alkyl group may be partially or wholly halogenated And substituted by 1-3 phenyl, naphthyl or a heterocyclic ring: quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, fluorenyl, piperazinyl, pyrrolyl, imidazolyl, Pyrazolyl, furyl, thienyl, isotazolyl, isothiazolyl; the above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, CrC 6 straight or branched alkane , ( ⁇ -cycloalkyl, C 5 -cycloalkenyl, hydroxy, nitrile, d-Cs straight or branched alkoxy, trifluoromethyl, trifluoromethoxy, aminocarbonyl, bis (wide) Alkyl substituted aminocarbonyl
  • C factory d. a cycloalkyl or cycloalkenyl group, said group being partially or fully halogenated, or substituted by 1 to 3 d-C 6 alkyl or d-Ce alkoxy; above cycloalkyl or cycloalkenyl
  • the 3 methylene groups may be replaced by 0, NH, S, SO, S0 2 , carbonyl, hydroxymethyl; the above cycloalkyl or cycloalkenyl may be independently substituted by 0-5 groups: halogen, d-Cs straight or branched alkyl, d-C 6 straight or branched alkoxy;
  • C 3 - a linear or branched alkenyl group which may be partially or fully halogenated, and may be substituted by 1 to 3 ( ⁇ -C 6 linear or branched alkyl, phenyl, naphthyl or the following heterocyclic ring)
  • Substituents quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, piperazinyl, pyrrolyl, imidazolyl, pyrazolyl, furyl, thienyl, isoxazolyl, isothiazolyl;
  • the above phenyl, naphthyl or heterocyclic ring may be substituted by 0-5 groups: halogen, dC 6 straight or branched alkyl, C 3 - cycloalkyl, 0 5 -( 8 cycloalkenyl, a hydroxy group, a nitrile group, a CrCe linear or
  • a ring, an aromatic heterocyclic group or a fused aromatic ring including phenyl, naphthyl, quinolyl, isoquinolinyl, pyridyl, pyrimidinyl, pyridazinyl, imidazolyl, carbazolyl, isoindole Azyl, thiazolyl, isothiazolyl, pyrrolyl, furyl, thiol, pyranyl, ca Pyridyl, piperazinyl, pyrazolyl, thiazolyl, fluorenyl, fluorenyl, benzimidazolyl, benzofuranyl, benzopyrazolyl, benzothienyl, benzindenyl, benzo Isoxazolyl, benzothiazolyl, benzisothiazolyl, pyrazolo[3,4-b]pyrimidinyl, pyrrolo[2,3-b]pyridyl, pyrrol
  • C 3 -C le cycloalkyl or cycloalkenyl said group may be partially or fully halogenated, or substituted by 1-3 ( ⁇ -( ⁇ alkyl or d-C 6 alkoxy) ;
  • a hydrogen atom a straight or branched alkyl group of Ci-Cs, a linear or branched alkenyl group of d-Ce, a phenyl group, a naphthyl group, a mono or double dC 4 alkylamino dC 6 alkyl group; m is 0, 1 or 2;
  • halogen nitro, carboxy, dC 6 straight or branched chain, Cr straight or branched alkenyl, C 3 - C 1D cycloalkyl, C 5 - (: 8 cycloalkenyl, hydroxy, nitrile Base, d-c 6 straight or branched alkoxy, trifluoromethyl, trifluoromethoxy;
  • Preferred compounds of the invention include:
  • the compound of formula I can be prepared by several methods, preferably method 3. method 1
  • R 6 CCI 3 , C 6 H 4 N0 2 , OC 2 H 5 , imidiazole, Triazole
  • reaction sequence of the above three methods can be reversed, that is, phosgene, chloroformate or carbonate can be first reacted with PL-Ar 2 -NH 2 , and the resulting intermediate is further reacted with A ri NH 2 .
  • Ar 1 ? Ar 2 , L, P are as defined for Formula I.
  • a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroacetic acid, added with an aqueous solution of sodium hydrogencarbonate or carbonic acid, cooled in a water bath, added with phosgene, stirred for 5-30 minutes,
  • the intermediate is reacted with another heterocyclic amine in an anhydrous aprotic solvent (eg THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-45 ° C. 2-24
  • anhydrous aprotic solvent eg THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.
  • a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroethane, added with a suitable base (such as triethylamine, etc.), then added with a chloroformate, and reacted at 0-85 Torr. 2 - 24 hours, the obtained intermediate and another heterocyclic amine in an anhydrous non-porous solvent (such as THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-110
  • anhydrous non-porous solvent such as THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.
  • a heterocyclic amine is dissolved in dichloromethane, chloroform or dichloroethane, added with a suitable base (such as triethylamine, etc.), then carbonate is added, and the reaction is carried out at - 20-45 Torr.
  • a suitable base such as triethylamine, etc.
  • carbonate is added, and the reaction is carried out at - 20-45 Torr.
  • the obtained intermediate is reacted with another heterocyclic amine in an anhydrous aprotic solvent (such as THF, diethyl ether, toluene, dioxane, dichloromethane, ethyl acetate, etc.) at 0-110 Torr.
  • the compound of formula I is obtained in 240 hours.
  • Ar ⁇ I ⁇ is synthesized by the following routes according to the structure.
  • Rl, R2 are defined as the same formula I.
  • the amine is at -10-10.
  • C is subjected to heavy argonization to obtain a diazonium salt, and the diazonium salt is reduced by sodium sulfite or stannous chloride to obtain hydrazine.
  • Ethyl acetate is reacted with ⁇ -bromo ketone under the action of a strong base (sodium, sodium hydride, sodium ethoxide, etc.), and the obtained diketoester V is reacted with sulfuric acid or hydrochloric acid in a solvent such as ethanol to obtain 3-furancarboxylic acid B.
  • Ester VI, ethyl 3-furancarboxylate VI and hydrazine hydrate and formic acid are reacted to give 3-aminofuran compound VII.
  • the diketone and Lawesson's reagent are refluxed in an anhydrous aprotic solvent for 1-10 hours to obtain a substituted thiophene, which is then nitrated by concentrated nitric acid, iron/hydrochloric acid or catalytic hydrogenation to give 3-aminothiophene compound VIII.
  • nitrile aldehyde and the substituted amine are in the range of 50-90 in acetic acid/water.
  • acyl nitrile, aldehyde, and anhydrous ammonium acetate are refluxed in acetic acid for 3-6 hours to give 4-amino ⁇ azole compound XI.
  • the acid chloride is reacted with a nitrileamine at 0 ° C in a solvent such as tetrahydrofuran to obtain an amide oxime: hydrazine is dissolved in dry dichloromethane, ethanethiol is added, and dry hydrogen chloride gas is introduced. The reaction is carried out for 5-30 minutes, and the obtained product xm is at o. Hydrogen sulfide is introduced into the dried pyridine to saturation, and after 5 hours, the 5-aminocarbazole compound XIV is obtained.
  • ⁇ XXI is added to 11 chloroketone and phthalic acid imide potassium salt in DMF for 2 hours to obtain the compound ⁇ , XIX and ⁇ , ⁇ -dimethylformamide dimethyl acetal in DMF
  • the reaction was carried out at 100 ° C for 12 hours to give the compound XX.
  • XX and substituted hydrazine are refluxed in 90% ethanol for 12 hours to give compound XX I, XX I is decomposed in ethanol to give 4-aminopyrazole XX oxime.
  • the cyanoketone is reacted with 50% hydrazine under basic conditions with hydroxylamine hydrochloride to give 5-aminoisoxazole XX m.
  • Physiologically acceptable salts of the compounds of formula I include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or inorganic or organic bases, and quaternary ammonium acid addition salts. More specific examples of suitable acid salts include hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, perchloric acid, fumaric acid, acetic acid, propionic acid, succinic acid, glycolic acid, formic acid, lactic acid, maleic acid, tartaric acid.
  • citric acid citric acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, benzoic acid, water Salts of salicylic acid, fumaric acid, toluenesulfonic acid, methanesulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, hydroxynaphthoic acid, hydroiodic acid, malic acid, s teroic, citric acid and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates to obtain the compounds of the invention and their pharmaceutically acceptable salts.
  • Suitable base salts include sodium, hydrate, potassium, magnesium, aluminum, calcium, zinc, N,N,-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, B. Diamine, N-methylglucamine and procaine salts.
  • the present invention also encompasses prodrugs of the compounds of the invention which, upon administration, are chemically converted by metabolic processes and thereafter become active drugs.
  • prodrugs are functional derivatives of the compounds of the invention which are readily converted in vivo to the desired compound of formula (I).
  • conventional methods for selecting and preparing suitable prodrug derivatives are described in "Design Of Prodrugs", H Bund Saard, Elsevier, ed., 1985.
  • the invention also includes active metabolites of the compounds of the invention.
  • compositions comprising a compound of the invention and at least one pharmaceutically acceptable carrier which is useful for in vivo treatment and is biocompatible.
  • the pharmaceutical compositions can be prepared in a variety of forms depending on the route of administration.
  • the compounds referred to in the present invention can also be prepared into various pharmaceutically acceptable salts.
  • the agonistic effect of the compound of the present invention on PPAR can be measured by the following method.
  • the THP- 1 cells were suspended in fetal calf serum containing 15%, 0. 02 nM 2- RMPI medium-mercaptoethanol at a cell concentration of 1-2 106 cells / mL, and plated in 96 well plates (each The pores contain 0.2 mL).
  • the test compound was dissolved in DMS0 and then diluted with a medium to give a final concentration of DMSO of 5%. 25 test compound solutions or DMSO only medium (control) were added to each well.
  • composition of the compound of the present invention can be administered in any of the following ways: oral, spray inhalation, rectal administration, nasal administration, buccal administration, topical administration, parenteral administration, such as subcutaneous, intravenous, intramuscular, intraperitoneal, sheath Intra, intraventricular, intrasternal, and intracranial injection or input, or by means of an explant reservoir.
  • oral, intraperitoneal or intravenous administration is preferred.
  • the compounds of the invention may be formulated in any orally acceptable form including, but not limited to, tablets, gels, aqueous solutions or aqueous suspensions.
  • the carrier used for the tablet generally includes lactose and corn starch, and a lubricant such as magnesium stearate may also be added.
  • the diluent used in the gelatin preparation generally comprises lactose and dried corn starch.
  • Aqueous suspension preparations are usually prepared by mixing the active ingredient with suitable emulsifying and suspending agents Use. If desired, some of the above oral preparation forms may also contain some sweeteners, fragrances or colorants.
  • the compounds of the invention When applied topically, especially in the treatment of facial or organs easily accessible by topical application, such as eye, skin or lower intestinal neuropathy, the compounds of the invention may be made into different parts according to different affected faces or organs.
  • the form of the pharmaceutical preparation is specifically described as follows:
  • the compound of the present invention can be formulated into a preparation form of a micronized suspension or solution, and the carrier used is an isotonic pH-stabilized saline solution, which can be added thereto. There may be no preservatives such as benzyl chloride alkoxide.
  • the compound can also be formulated into a bone form such as vaseline.
  • the compounds of the invention When applied topically to the skin, the compounds of the invention may be formulated in a suitable cartilage, lotion or cream formulation wherein the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers for cartilage preparations include, but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; lotions or creams may be used including but not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl esters wax, hexadecene aryl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compounds of the present invention can also be administered in the form of a sterile injectable preparation, including sterile aqueous or oily suspension or sterile injection solutions.
  • a sterile injectable preparation including sterile aqueous or oily suspension or sterile injection solutions.
  • carriers and solvents which can be used include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized, fixed oils may be employed as a solvent or suspension medium such as a monoglyceride or a diglyceride.
  • the dosage and method of use of the compounds of the invention depends on a number of factors, including the age, weight, sex, natural health, nutritional status of the compound, the strength of the compound, the time of administration, the rate of metabolism, the severity of the condition, and Subjective judgment of the doctor.
  • a preferred dosage is from 0.01 to 100 mg/kg body weight per day, wherein the optimal dose is 5 mg/kg 10 mg/kg body weight per day.
  • the melting point of the compound was determined by a YRT-3 type melting point apparatus, and the temperature was not corrected.
  • NMR spectra were determined by a Bruker ARX 400 nuclear magnetic instrument.
  • FAB mass spectra were determined by a Zabspect high resolution magnetic mass spectrometer.
  • Aromatic amine (0.04 fflol) was added to 40 mL of concentrated hydrochloric acid, stirred, and cooled to -5 °C to precipitate white fine granular crystals.
  • sodium nitrite solution (2. 90g sodium nitrite dissolved in 20mL water), control the temperature does not exceed 0 °C, and react for 1 hour after the addition.
  • acyl acetonitrile (1.25 g, 0. Olmol) obtained in the step 3 and the aromatic hydrazine hydrochloride obtained in the step 2 are added to 50 mL of ethanol, and 2. OmL of concentrated hydrochloric acid is added dropwise, and the mixture is heated to reflux for 12-24 hours. The mixture was cooled, poured into 100 mL of water, adjusted to pH 12 with dilute sodium hydroxide, extracted with ethyl acetate and dried. The obtained crude product was subjected to silica gel column chromatography to afford white solid product.
  • the title compound is prepared by using p-butyl chloromethyl ester as a general material,
  • the title compound was obtained as a white solid using 3,4-dimethylaniline as a material.
  • the title compound was obtained as a white solid using 4-ethylaniline as a crude material.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound is based on intermediate 1 and p-bromophenyl hydrazine.
  • step 2 The product obtained in step 1 (0. Olmol) was dissolved in 20 mL of DMF, N,N-dimethylformamide dimethyl acetal (1.44 g, 0.012 mol) was added dropwise, 100 was reacted for 12 hours, and N was added. N-Dimethylformamide dimethyl acetal (1.44 g, 0.012 mol) was further reacted for 24 hours, cooled, poured into 100 mL of ice water, extracted with ethyl acetate, dried and then purified to afford white solid.
  • step 3 The product obtained in step 2 (0. Olmol) is dissolved in 100 mL of 90% ethanol, substituted hydrazine (0. Ollmol) is added, heated under reflux for 12 hours, cooled, solid is precipitated, filtered, and the filter cake is washed with anhydrous diethyl ether and dried. A white solid product was obtained.
  • step 3 The product obtained in step 3 (0. Olmol) was dissolved in 100 mL of ethanol, 85% hydrazine hydrate solution (0.04 mol) was added dropwise, and heated under reflux for 2 hours to precipitate a white solid, which was cooled, concentrated, and then added with 20 mL of diethyl ether, filtered and filtered. The cake was washed with anhydrous diethyl ether, and the filtrate was combined, concentrated, and purified to afford white powder.
  • Intermediate 29 The product obtained in step 3 (0. Olmol) was dissolved in 100 mL of ethanol, 85% hydrazine hydrate solution (0.04 mol) was added dropwise, and heated under reflux for 2 hours to precipitate a white solid, which was cooled, concentrated, and then added with 20 mL of diethyl ether, filtered and filtered. The cake was washed with anhydrous diethyl ether, and the filtrate was combined, concentrated, and purified to afford white powder.
  • the title compound is based on intermediate 29 and potassium phthalimide as a raw material.
  • step 2 The product obtained in step 1 (0, Olmol), cyanamide (4.23 g, 0.1 mol) was refluxed in 100 mL of ethanol for 12 hours. Concentrate, add the residue to water, extract three times with ethyl acetate, combine the organic layer, then dilute sodium hydroxide solution, water, saturated salt Water washing, drying, and column separation gave a white solid product.
  • the title compound is obtained as a white solid in a yield of 99.2%.
  • P - L-Ar 2 NH 2 can be synthesized by the following route depending on the structure.
  • Resorcinol 44. Og, 0.40 mol
  • anhydrous potassium carbonate 66.24 g, 0.48 mol
  • benzyl bromide 47.88 g, 0.28 mol
  • the reaction was carried out for 5 hours, poured into cold dilute hydrochloric acid to make acidity, and extracted with ethyl acetate three times. The ethyl acetate layer was combined, washed with saturated brine, and dried. It turned into a white solid with a yield of 46.9%.
  • the title compound is prepared from the intermediate 49 and morpholine as a general operation C.
  • Example 2 Using the preparation method of Example 1, the intermediate 11 was changed to the intermediate 15 and the intermediate 41 was changed to the intermediate 40 to give the title compound as white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • Example 2 200 mg of the product obtained in Example 2 was dissolved in 50 mL of absolute ethanol, 0.2 g of palladium on charcoal was added, and the mixture was heated to 60 ° C, and 1.0 mL of hydrazine hydrate was added dropwise, followed by heating under reflux for 6 hours, cooled, filtered, and the filtrate was concentrated.
  • the title compound 149 mg was obtained as a white solid.
  • Example 2 Using the preparation method of Example 1, the intermediate 41 was changed to an intermediate 40, the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a yellow solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • Example 14 Using the preparation method of Example 15, the intermediate 59 was changed to an intermediate. 54 The title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate. 16. The title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a yellow solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate.
  • Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate.
  • the title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.
  • Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate.
  • Example 36 Using the preparation method of Example 36, the intermediate 11 was changed to an intermediate.
  • Example 61 l-[4-tert-butyl-1-(4-methylphenyl)- 1 ⁇ 2-imidazole Benzyl]-3- ⁇ 8- ⁇ 5-[2-(4-morphinolinyl)ethoxy]-2 ⁇ enyl ⁇ urea
  • the preparation method of Example 36 was used to change the intermediate 11 The title compound was obtained as a white solid.
  • the title compound was obtained as a white solid.

Abstract

L'invention porte sur les composés d'urée de formule I, sur les sels pharmaceutiquement acceptables et les solvates de ces composés, sur leurs procédés de préparation, sur les compositions pharmaceutiques comprenant lesdits composés et sur leurs utilisations comme inhibiteurs de la p38 kinase. Les substituants sont définis dans la description.
PCT/CN2008/000760 2007-04-13 2008-04-14 Composés d'urée, leurs procédés de préparation et leurs utilisations pharmaceutiques WO2008125014A1 (fr)

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