WO2012136111A1 - Composé phénylproponiate, son procédé de préparation et ses applications médicales - Google Patents

Composé phénylproponiate, son procédé de préparation et ses applications médicales Download PDF

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Publication number
WO2012136111A1
WO2012136111A1 PCT/CN2012/073192 CN2012073192W WO2012136111A1 WO 2012136111 A1 WO2012136111 A1 WO 2012136111A1 CN 2012073192 W CN2012073192 W CN 2012073192W WO 2012136111 A1 WO2012136111 A1 WO 2012136111A1
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phenyl
alkyl
group
thiazole
compound
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PCT/CN2012/073192
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English (en)
Chinese (zh)
Inventor
李松
钟武
林忠宝
王晓奎
刘洪英
谢云德
赵国明
郑志兵
肖军海
李行舟
Original Assignee
中国人民解放军军事医学科学院毒物药物研究所
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Priority to CN201280002759.2A priority Critical patent/CN103097367B/zh
Publication of WO2012136111A1 publication Critical patent/WO2012136111A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/30—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals

Definitions

  • Phenylpropionic acid compound preparation method thereof and medical use thereof
  • the present invention relates to the field of pharmaceutical and chemical engineering, and relates to a phenylpropionic acid compound or a pharmaceutically acceptable salt thereof, a pharmaceutical composition comprising the same, a process for the preparation thereof, and a pharmaceutical use thereof.
  • These compounds are S1P EDG1 receptor agonists, which regulate lymphocyte transport, regulate lymphocyte cell transport, accumulate lymphocytes in secondary lymphoid tissues, and enhance vascular integrity to exert immunosuppressive, anti-inflammatory and hemostatic effects.
  • Immunosuppressive and anti-inflammatory drugs have been shown to be useful in many autoimmune and chronic inflammatory diseases (including systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, grapes) Membrane inflammation, multiple sclerosis, and other diseases such as Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis , ichthyosis, Graves' eye disease, atopic dermatitis and asthma, chronic lung disease, acute lung injury, acute respiratory distress syndrome and sepsis. They have also been shown to be useful in the treatment of cancer, lymphoma and leukemia chemotherapy regimens.
  • Anti-inflammatory drugs act primarily by blocking the action or secretion of the above mediators, but do not improve the immune basis of the disease.
  • cytotoxic drugs such as cyclophosphamide
  • cytotoxic drugs act in a non-specific manner such that both normal and autoimmune responses are blocked. In fact, with death Like autoimmune diseases, patients treated with such non-specific immunosuppressive drugs are likely to die from infection.
  • Cyclosporin A is a drug that prevents rejection of transplanted organs.
  • FK-506 is another drug approved for the prevention of rejection in transplanted organs, especially liver transplants.
  • the body's immune system mobilizes its vast pool of natural protective factors to reject transplanted foreign proteins, and cyclosporin A and FK-506 act by suppressing the immune system.
  • Cyclosporin A is approved for the treatment of severe psoriasis and has been approved by European regulatory agencies for the treatment of atopic dermatitis.
  • cyclosporin A and FK-506 are effective in delaying or inhibiting transplant rejection, they can cause a variety of adverse side effects including nephrotoxicity, neurotoxicity and gastrointestinal discomfort. Therefore, there is still a need to develop immunosuppressive agents which do not have the above-mentioned side effects, and such immunosuppressive agents are also highly desirable.
  • the immunosuppressant FTY720 is currently marketed for the treatment of multiple sclerosis.
  • FTY720 is metabolized in mammals to an effective agonist compound of the sphingosine-1-phosphate receptor.
  • the sphingosine 1-phosphate receptor regulates leukocyte trafficking, induces lymphocytes (T cells and B cells) to accumulate in lymph nodes without causing lymphocyte deficiency, and does not destroy the spleen structure, thereby interfering with T cell-dependent antibodies.
  • S1P receptor agonist traces have anti-inflammatory properties by enhancing endothelial integrity and inhibiting vascular damage caused by activation of the immune system.
  • Such immunosuppressive and anti-inflammatory effects are required to prevent rejection after organ transplantation, to treat autoimmune diseases, and to treat diseases whose major defects are vascular integrity, such as acute lung injury, acute respiratory distress syndrome, and sepsis.
  • Sphingosine 1-phosphate is a biologically active sphingolipid metabolite secreted by hematopoietic cells, stored in platelets and released from living platelets. It acts as an agonist on the G protein-coupled receptor family to regulate cell proliferation, differentiation, survival, and movement.
  • sphingosine 1-phosphate administered to the animal induces the accumulation of lymphocytes in the peripheral blood to the secondary lymphoid organs, thereby producing a useful therapeutic immunosuppressive effect.
  • sphingosine 1-phosphate also has cardiovascular and bronchoconstrictive effects, and such effects limit its use as a therapeutic drug.
  • Intravenous administration of sphingosine 1-phosphate will reduce heart rate, ventricular contraction, and blood pressure in rats.
  • sphingosine 1 -phosphate regulates bronchial growth Contraction, airway inflammation, and contraction of airway remodeling in asthma, cell growth, and cytokine production.
  • the adverse effects of sphingosine 1-phosphate are related to its non-selective potent agonist activity on all S1P receptors.
  • SlP Edgl receptor selective agonists have advantages over existing therapies, broadening the therapeutic window of lymphocyte aggregation drugs and vascular intact drugs, resulting in better tolerance at higher doses, thus increasing monotherapy efficacy.
  • immunosuppressants and anti-inflammatory agents are mainly used to treat bone marrow, organs and graft rejection
  • other uses of these compounds include the treatment of arthritis (especially rheumatoid arthritis), insulin-dependent diabetes, non-insulin dependence. Diabetes, multiple sclerosis, psoriasis, inflammatory bowel disease, Crohn's disease, lupus erythematosus, asthma, allergies, chronic lung disease, acute lung injury, acute respiratory disease, sepsis, etc.
  • the present inventors have unexpectedly discovered in the study that the following compound of formula I is a SlPi/EDG1 receptor agonist which regulates lymphocyte transport by regulating leukocyte trafficking, allowing lymphocytes to accumulate in secondary lymphoid tissues and improving vascular integrity. It exerts immunosuppressive effects, anti-inflammatory activity and hemostasis. Therefore, this issue:
  • K is independently selected from - C00H, -P0 3 H, -P0 2 H 2 , - S0 3 H, -0 (P0 3 ) H;
  • U, V, W and J are independently selected from -C(R 2 ) - and -N-, and constitute a substituted or unsubstituted six-membered aromatic ring;
  • R 2 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -OH, d- 4 alkyl,
  • CH alkyl, CH alkenyl, CH alkynyl and CH alkoxy groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - C l, -Br, -1, -OH and d - 8 alkoxy;
  • the A ring and the B ring may be directly linked or connected via G;
  • d- 3 alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group are each optionally selected from -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkane Oxygen substitution;
  • R 3 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein the d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each Optionally substituted with -F, -C1, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
  • the Q and T thus obtained constitute a heterocyclic ring;
  • R ⁇ R 5 and R 6 are each independently selected from - H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl, and d- 6 alkoxy, d- 6 alkyl group described above, C 2 -6 alkenyl, C 2 -6 alkynyl and d- 6 alkoxy are each optionally -F, -Cl, -Br, -1, -OH, -CN, d- 4 alkyl and d- 4 alkoxy substituted;
  • R 1 is selected from the group consisting of phenyl, pyrimidinyl, pyridyl, pyrazinyl, pyridazinyl, thienyl and thiazolyl, wherein each of the groups is optionally substituted with the following substituents: - F, - Cl, -Br, -1, -0H, - CN, - NR 7 R 8, - N0 2, phenyl, benzyl, benzyloxy, d- 6 alkyl, (3 - 6 cycloalkyl group, C 2 - 6 women group, .2-6 block group, Ci- burning 3 ⁇ 4 ⁇ , C3-6 cycloalkyl group burning, C2-6 women oxo group, C2-6 block ⁇ ⁇ , d- 6 alkylthio, C 3 - 6 cycloalkylthio And C 2 -6 acyloxy, the above phenyl, benzyl and benzyloxy may
  • R 7 and R 8 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C
  • the 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, - Br, -1, -OH, - CN and d- 6 alkoxy;
  • R 7 and R 8 may together with the nitrogen atom to which they are attached form a saturated monocyclic ring of from 3 to 8 atoms, optionally containing from 1 to 2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
  • a compound of formula I wherein U, V, J and W are -CH-.
  • the compound of formula I is a compound of formula la or a pharmaceutically acceptable salt thereof:
  • J and W are independently selected from -C(R 4 )- and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;
  • R 4 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0 ⁇ , CH alkyl,
  • CH alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group and CH alkoxy group are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1. -OH and d- 8 alkoxy;
  • the A ring and the B ring can be directly connected or connected through G;
  • d- 3 alkyl group, C 2 -4 alkenyl group, C 2 -4 alkynyl group are each optionally selected from the group consisting of -F, -C1, -Br, -1, -OH, -CN, d- Substituted with a 4- alkyl and CH alkoxy group;
  • R 4 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein said d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each optionally substituted by -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
  • R 5 , R 6 and R 7 are each independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl, C 2 -6 alkynyl and ( ⁇ -6 alkoxy, above d- 6 alkyl , C 2 -6 alkenyl, C 2 -6 alkynyl and d- 6 alkoxy are each optionally -F, -Cl, -Br, -1, -OH, -CN, d- 4 alkyl and d - 4 alkoxy substituted;
  • Each of U and V is optionally independently selected from C and N;
  • Each of R 1 , R 2 and R 3 is optionally independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN, -NR 8 R 9 , - N0 2 , phenyl , benzyl, benzyloxy, d- 6 alkyl, C 3 - 6 cycloalkyl group burning.
  • 2-6 women's base In 2-6 women's base,. 2-6 blocks, Cl-alkyl, C3-6 ring base. 2-6 women's base ⁇ ⁇ ,
  • R 8 and R 9 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C
  • the 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy;
  • R 8 and R 9 may, together with the nitrogen atom to which they are attached, form a saturated monocyclic ring of 3-8 atoms, optionally containing 1-2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
  • the above C ring may be a six-membered aromatic heterocyclic ring or a benzene ring, and the broken line represents 1-3 double bonds.
  • the compound of formula I is a compound of formula I b or is pharmaceutically acceptable
  • J and W are independently selected from -C(R 4 )- and -N -, and constitute a substituted or unsubstituted six-membered aromatic ring;
  • R 4 is independently selected from the group consisting of -H, -F, -Cl, -Br, -1, -CN, -0H, CH alkyl,
  • CH alkyl, CH alkenyl, C 2 -4 alkynyl and CH alkoxy groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH and D- 8 alkoxy;
  • a ring and B ring are linked by G;
  • R 4 may be H, d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl, wherein the d- 3 alkyl, C 2 -4 alkenyl, C 2 -4 alkynyl are each Optionally substituted with -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy;
  • R 5 may be selected from the group consisting of: - H, d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 alkynyl and d- 6 alkoxy, the above-mentioned d- 6 alkyl, C 2 - 6 alkenyl, C 2 - 6 block and ( ⁇ 6 alkoxy are each optionally substituted by -F, -Cl, -Br, -1, -OH, -CN, CH alkyl and CH alkoxy ;
  • Each of R 1 , R 2 and R 3 is optionally independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN, - NR 6 R 7 , - N0 2 , phenyl , benzyl, benzyloxy, d- 6 alkyl, C 3 - 6 cycloalkyl group burning.
  • C 2 -6 alkynyloxy, ( ⁇ 6 alkylthio, C 3 - 6 cycloalkylthio and C 2 - 6 acyloxy, the above phenyl, benzyl and benzyloxy may be 1 - 3 or less Substituent substitution: - F, - Cl, -Br, -1, -CN, -NR 7 R 8 , -N0 2 ;
  • R 6 and R 7 are independently selected from -H, d- 6 alkyl, C 2 -6 alkenyl and C 2 -6 alkynyl, wherein said d- 6 alkyl, C 2 - 6 alkenyl and C
  • the 2 - 6 alkynyl groups are each optionally substituted with a substituent independently selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy;
  • R 6 and R 7 may together with the nitrogen atom to which they are attached form a saturated monocyclic ring of 3-8 atoms, optionally containing 1-2 oxygen atoms, optionally substituted with a substituent selected from the group consisting of: - F, - Cl, -Br, -1, -OH, - CN and d- 6 alkoxy.
  • the compound of the formula I of the present invention or a pharmaceutically acceptable salt thereof is further preferably selected from the following specific compounds or pharmaceutically acceptable salts of these compounds, as shown in Table 1 below. Show:
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, or a compound of formula la or a pharmaceutically acceptable salt thereof, or a compound of formula lb, or a pharmaceutically acceptable salt thereof, or a specific compound thereof , and a pharmaceutically acceptable carrier or excipient.
  • the invention further relates to a compound of formula I, or a pharmaceutically acceptable salt thereof, or a compound of formula la, or a pharmaceutically acceptable salt thereof, or a compound of formula lb, or a pharmaceutically acceptable salt thereof, or a specific compound thereof, for use in the treatment of immunity Use in the regulation of abnormal drugs.
  • the invention further relates to a method of treating an immunomodulatory abnormality in a mammalian subject, the method comprising administering to the patient an immunosuppressively effective amount of a compound of formula I.
  • the immunomodulatory abnormality is selected from the group consisting of an autoimmune disease or a chronic inflammatory disease: systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, Uveitis, multiple sclerosis, Crohn's disease, Ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' eye disease and asthma.
  • an autoimmune disease or a chronic inflammatory disease systemic lupus erythematosus, chronic rheumatoid arthritis, type I diabetes, inflammatory bowel disease, biliary cirrhosis, Uveitis, multiple sclerosis, Crohn's disease, Ulcerative colitis, bullous pemphigoid, sarcoidosis, psoria
  • the immunomodulatory abnormality is bone marrow or organ transplant rejection or graft versus host disease.
  • the immunomodulatory abnormality is selected from the group consisting of organ or tissue transplantation, graft-versus-host disease caused by transplantation, autoimmune syndrome, including rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple Sclerotherapy, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, post-infectious autoimmune diseases (including rheumatic fever and post-infectious glomerulonephritis) , inflammatory and hyperproliferative skin diseases, psoriasis, atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous Epidermolysis, urticaria, angioedema, vasculitis,
  • the immunomodulatory abnormality is selected from
  • the invention further relates to a compound of formula I or a pharmaceutically acceptable salt thereof for use in the treatment of immunomodulatory disorders, organ transplant rejection, respiratory diseases or disorders, inflammation, vascular related diseases or disorders in a mammalian patient.
  • the invention also encompasses a method of treating a respiratory disease or condition in a mammalian patient in need of such treatment, the method comprising administering to the patient an effective amount of a compound of formula I or a therapeutic agent for the respiratory disease or condition.
  • the respiratory disease or condition is selected from the group consisting of asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, eosinophilic granuloma, respiratory tract Syncytial bronchiolitis, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury, and obliterative bronchiolitis with organizing pneumonia.
  • the invention also includes a method of treating an vascular integrity-related disease or condition in a patient in need of such treatment, wherein the disease or condition is selected from the group consisting of angioedema, vasculitis, ischemic disease, and vascular injury caused by thrombosis , ischemic bowel disease, inflammatory bowel disease, necrotizing enterocolitis, thermal burn-related intestinal damage, arteriosclerosis, atherosclerosis, aortitis syndrome, preservation, transplantation or ischemic Organ ischemia after re-injection injury, endotoxin shock, pseudomembranous colitis, colitis caused by drugs or radiation, ischemic acute renal insufficiency, chronic renal insufficiency, pulmonary oxygen or drug-induced a disease caused by poisoning, sepsis, pancreatitis, histamine or leukotriene-C4 release, necrosis caused by toxins, viral hepatitis, shock or hypoxia, senile dementia and trauma, the method comprising administering the said
  • the invention also encompasses a method of treating a cerebral edema or pulmonary edema-associated disease or condition in a patient in need of such treatment, the method comprising administering to the patient an effective amount of a compound of the formula I or the disease.
  • a disease or condition selected from the group consisting of shock, sepsis, acute respiratory distress syndrome, and cerebral edema is included.
  • This embodiment is also included in the above method, wherein the patient also has a respiratory disease or condition.
  • compositions claimed in the present invention also include pharmaceutically acceptable salts and hydrates thereof.
  • Pharmaceutically acceptable salts include metal (inorganic) salts and organic salts, and it is well known to those skilled in the art to select suitable salt forms based on physicochemical stability, fluidity, hygroscopicity and solubility.
  • pharmaceutically acceptable salts include, but are not limited to, salts of inorganic acids such as hydrochlorides, sulfates, phosphates, diphosphates, hydrobromides and nitrates, or salts of organic acids.
  • pharmaceutically acceptable cations include, but are not limited to, sodium, potassium, calcium, aluminum, lithium, and ammonium (especially ammonium salts of secondary amines).
  • Preferred salts of the invention include potassium, sodium, calcium and ammonium salts for the reasons indicated above. Crystal forms, hydrates and solvates of the compounds of formula I are also included within the scope of the invention.
  • pharmaceutically acceptable hydrate refers to a hydrated form of the compound of the invention formed by crystallisation of one or more water molecules.
  • the compounds of the formula I according to the invention may comprise one or more asymmetric centers, thereby enabling racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and diastereomers Form exists.
  • the invention includes all of the above isomeric forms of the compounds of formula I.
  • Some of the compounds of the present invention contain olefinic double bonds, and unless otherwise stated, these double bonds include E and Z geometric isomers.
  • Some of the compounds of the invention may have different hydrogen attachment points, referred to as tautomers.
  • Such an example may be a ketone known as a keto-enol tautomer and its enol form.
  • the compounds of formula I include the individual tautomers and mixtures thereof.
  • the compound of formula I can be isolated as a diastereomeric pair of enantiomers, for example by fractional crystallization using a suitable solvent such as methanol, ethyl acetate or a mixture thereof.
  • a suitable solvent such as methanol, ethyl acetate or a mixture thereof.
  • the enantiomer pair thus obtained can be separated into individual stereoisomers by a conventional method (e.g., using an optically active acid as a resolving agent).
  • the enantiomers of the compounds of formula I can be obtained by stereospecific synthesis using neat optically active starting materials or reagents of known configuration.
  • the invention also includes substantially pure forms or mixtures of stereoisomers of one or more stereoisomers of formula I.
  • the invention includes all such isomers. Since the compound of the present invention has SIP Edgl agonist activity, it is an immunomodulator useful for treating or preventing autoimmune or chronic inflammatory diseases.
  • the compounds of the invention may be used to inhibit the immune system, for example, for bone marrow, organ or graft rejection, autoimmune or chronic inflammatory diseases, including systemic lupus erythematosus, chronic rheumatoid arthritis , type I diabetes, inflammatory bowel disease, biliary cirrhosis, uveitis, multiple sclerosis, Crohn's disease, ulcerative colitis, bullous pemphigoid, sarcoidosis, psoriasis, Autoimmune myositis, Wegener's granulomatosis, ichthyosis, Graves' eye disease, and asthma.
  • the compounds of the invention are also useful for enhancing vascular integrity.
  • the compounds of the invention are useful for the treatment or prevention of a disease or condition selected from the group consisting of organ or tissue transplantation, graft versus host disease caused by transplantation, autoimmune syndrome, including rheumatoid arthritis, systemic erythema Lupus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, posterior uveitis, allergic encephalomyelitis, glomerulonephritis, autoimmune diseases after infection (including rheumatic fever) And post-infection glomerulonephritis, inflammatory and hyperproliferative skin diseases, rickets, atopic dermatitis, contact dermatitis, eczema dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous Pemphigus, bullous epidermolysis, urticaria, angioedema, vasculitis, erythem
  • the compounds of the invention are also useful in the treatment or prevention of Alzheimer's sdi sease.
  • Embodiments of the invention also include a method of preventing or treating graft resistance or transplant rejection of an organ or tissue in a mammalian subject in need of such treatment, the method comprising administering a therapeutically effective amount of a compound of formula I.
  • Another embodiment of the invention is a method of inhibiting the immune system in a mammalian patient in need of such inhibition, the method comprising administering to the patient an effective amount of an immune system a compound of formula I.
  • the methods described herein include a method of treating or preventing bone marrow or organ transplant rejection comprising administering to a mammalian patient in need of such treatment or prevention an effective amount of a bone marrow or organ transplant rejection treatment Formula I or their pharmaceutically acceptable salts or hydrates.
  • the compounds of the invention are also useful in the treatment of respiratory diseases or conditions, such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, eosinophilic granuloma, respiratory syncytial virus bronchioles Inflammation, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury, and obliterative bronchiolitis with organizing pneumonia.
  • respiratory diseases or conditions such as asthma, chronic bronchitis, chronic obstructive pulmonary disease, adult respiratory distress syndrome, infant respiratory distress syndrome, cough, eosinophilic granuloma, respiratory syncytial virus bronchioles Inflammation, bronchiectasis, idiopathic pulmonary fibrosis, acute lung injury, and obliterative bronchiolitis with organizing pneumonia.
  • the compounds of the invention are selective agonists of the SIP Edgl receptor with selectivity superior to the SIP 3 /Edg3 receptor.
  • Edgl selective agonists are superior to existing therapies, broadening the therapeutic window of lymphocyte aggregating agents, resulting in better tolerance at higher doses, thus increasing the efficacy of monotherapy.
  • the pharmaceutical composition of the present invention can be used in various pharmaceutical preparation forms, and comprises a pharmaceutically acceptable carrier and Formula I or a pharmaceutically acceptable salt or hydrate thereof.
  • a second immunosuppressive agent can also be included in the formulation.
  • other immunosuppressive agents include, but are not limited to, azathioprine, buquina sodium, deoxyspermectin, mizar ibine, mycophenolate mofetil, cyclosporin, FK-506, rapamycin , FTY720 and ISAtx247 (Isotechnika), methods of administering a compound of formula I in combination with other immunosuppressive agents, including one or more immunosuppressive agents as described above, are also included in the present invention.
  • the compounds of the invention are useful in the treatment of autoimmune diseases, including prevention of bone marrow transplantation, rejection of foreign organ transplants, and/or related conditions and diseases.
  • the compound of the present invention can be administered by any means as long as the active ingredient compound is in effective contact with the site of action in the warm-blooded animal.
  • it can be administered orally, topically (including transdermal administration), ocular, buccal, intranasal, inhaled, intravaginal, rectal, intracisternal, and parenteral.
  • parenteral is intended to include the following Mode of drug: subcutaneous, intravenous, intramuscular, intra-articular injection or infusion, sternal flesh and intraperitoneal administration.
  • the compounds of the present invention can be administered in a separate preparation or a combined therapeutic agent by any conventional method for combination therapy.
  • These therapeutic agents may be administered alone, but are usually administered in combination with a pharmaceutically acceptable carrier which is selected according to the chosen route of administration and standard pharmaceutical practice.
  • the dosage will depend on the age, health and weight of the recipient, the severity of the disease, the type of combination therapy (if any), the frequency of treatment, and the nature of the desired effect.
  • the daily dose of the active ingredient compound is from about 0.1 to 2000 g/day. Usually, 1-100 grams per day or more can be effectively obtained to achieve the desired effect.
  • These doses are effective amounts for the treatment of autoimmune diseases, prevention of exogenous organ transplant rejection and/or related conditions and diseases.
  • the active ingredient can be administered orally in a solid dosage form (e.g., capsules, tablets, troches, lozenges, granules, and powders) or in liquid form (such as elixirs, syrups, emulsions, dispersions and suspensions).
  • a solid dosage form e.g., capsules, tablets, troches, lozenges, granules, and powders
  • liquid form such as elixirs, syrups, emulsions, dispersions and suspensions.
  • the active ingredient can also be administered parenterally in a sterile liquid form such as a dispersion, suspension or solution.
  • dosage forms may also be used for the administration of active ingredients, such as ointments, creams, drops, transdermal patches or powders for topical administration, ophthalmic solutions or suspensions for ophthalmic administration (ie drops) Eye drops), an aerosol or powder composition for inhaled or intranasal administration, or a cream, ointment, spray or suppository for rectal or vaginal administration.
  • active ingredients such as ointments, creams, drops, transdermal patches or powders for topical administration, ophthalmic solutions or suspensions for ophthalmic administration (ie drops) Eye drops), an aerosol or powder composition for inhaled or intranasal administration, or a cream, ointment, spray or suppository for rectal or vaginal administration.
  • Gelatin capsules contain the active ingredient and a powder carrier, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be prepared as sustained release products for continuous release of the drug over a period of hours. Compressed tablets are sugar coated or film coated to mask any unpleasant taste and to isolate the tablet from the air, or enteric coated for selective disintegration in the gastrointestinal tract.
  • a powder carrier such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similar diluents can be used to prepare compressed tablets. Both tablets and capsules can be prepared as sustained release products for continuous release of the drug over a period of hours. Compressed tablets are sugar coated or film coated to mask any unpleasant taste and to isolate the tablet from the air, or enteric coated for selective disintegration in the gastrointestinal tract.
  • Oral liquid dosage forms can contain coloring and flavoring to increase patient acceptance.
  • water, a suitable oil, saline, aqueous dextrose and related sugar solutions and glycols such as propylene glycol or polyethylene glycol are suitable carriers for parenteral solutions.
  • the solution for parenteral administration preferably comprises a water-soluble salt of the active ingredient, a suitable stabilizer, and if necessary, a buffer substance.
  • Antioxidant eg hydrogen bisulfite alone
  • Sodium, sodium sulfite, ascorbic acid or a combination thereof is a suitable stabilizer.
  • Citric acid and its salts and sodium edetate can also be used.
  • Parenteral solutions may also contain preservatives such as benzalkonium chloride, methyl paraben, propyl paraben and chlorobutanol.
  • the compounds of the invention may conveniently be administered by aerosol spray, which is produced by a pressure pack or nebulizer.
  • the compounds of the invention may also be administered in powder form, the powder may be formulated, and the powder composition may be inhaled by means of a powder inhaler.
  • a preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol which can be formulated as a suspension or solution of a compound of formula I in a suitable propellant such as a fluorocarbon or hydrocarbon.
  • MDI metered dose inhalation
  • the ophthalmic preparation can be formulated as a solution or suspension of the compound of formula I in a suitable ophthalmic vehicle in a suitable ophthalmic vehicle such that contact of the compound with the ocular surface is maintained for a sufficient period of time to allow for the compound Penetrate the cornea and inner area of the eye.
  • the present invention also includes any one of the following items (1) to (4):
  • a method for treating and/or preventing immunomodulatory abnormalities, respiratory diseases or symptoms, vascular phase integrity diseases or symptoms, cerebral edema or pulmonary edema-related diseases, or anti-inflammatory or hemostasis in a mammalian patient including administration An effective amount of a compound of the invention or a pharmaceutically acceptable salt thereof.
  • a method of modulating the activity of an S1P EDG1 receptor in vivo or in vitro comprising the step of using an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof.
  • Methods of preparing the compounds of the invention are illustrated by the following description, and one skilled in the art can prepare the compounds of the invention in accordance with the teachings below.
  • a solvent such as N, N-dimethylformamide, dimethyl sulfoxide or dichloromethane, by using carbonic acid clock, sodium carbonate, sodium hydrogencarbonate.
  • the acid produced during the neutralization reaction of triethylamine, the compound ii is prepared by heating or at room temperature; the thio group is thiolated by sodium hydrosulfide to obtain the thioamide compound iii; the thioamide and the bromo ketone compound in methanol .
  • Compound v can be prepared in a suitable solvent using reagents such as thionyl chloride, oxalyl chloride, phosphorus oxychloride and phosphorus pentoxide.
  • Compound V can also be prepared using a condensing agent such as DCC, DIEA, DBU, EDCI or the like; Vi-Pd-C catalytic hydrogenation debenzylation method commonly used by workers in the chemical field to prepare vi, which can be prepared by using cyclohexene, hydrogen or ammonium formate as a hydrogen donor under suitable pressure conditions; a base reaction (the method is similar to the preparation of compound ii); the last use of the compound;
  • a condensing agent such as DCC, DIEA, DBU, EDCI or the like
  • Vi-Pd-C catalytic hydrogenation debenzylation method commonly used by workers in the chemical field to prepare vi, which can be prepared by using cyclohexene, hydrogen or ammonium formate as a hydrogen donor under suitable pressure conditions
  • a base reaction the method is similar to the preparation of compound ii); the last use of the compound;
  • Scheme 2 shows that G is a -NH-formula compound I b (corresponding to Scheme 2)
  • the preparation method of the compound of the formula X firstly, the compound 1 is obtained by using an amino-substituted arylpropionic acid with a thiocyanate clock or ammonium thiocyanate in methanol, ethanol or water; the compound viii and 2-bromo-4, The hydroxyacetophenone is refluxed with various short-chain low-boiling alcohols to obtain the compound ix; the compound ix is obtained by a similar method in the reaction scheme 1, to obtain the final product.
  • alkyl means a straight or branched alkyl group having 1 to 4 carbon atoms, such as methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. Base, etc. d- 6 alkyl can also be similarly understood.
  • alkoxy refers to a straight or branched alkoxy group having from 1 to 4 carbon atoms, such as methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy Alkyl, tert-butoxy, etc. Alkoxy or d- 6 alkoxy can also be similarly understood.
  • C 2 -4 alkenyl refers to a straight or branched alkenyl group having 2 to 4 carbon atoms, such as ethenyl, propenyl, butenyl and the like. - 6 alkenyl can also be similarly understood.
  • C 2 -4 alkynyl refers to a straight or branched alkynyl group having 2 to 4 carbon atoms, such as ethynyl, propynyl, butynyl and the like. A similar understanding can also be made for the C 2 -6 alkynyl group.
  • C 3 - 6 cycloalkyl group means a cyclic alkoxy group having 3-6 carbon atoms, for example, each having 3, 4, 5, or cycloalkyl group having 6 carbon atoms.
  • the C 2 -6 alkenyloxy group means an alkenyloxy group having 2 to 6 carbon atoms, for example, an alkenyloxy group having 2, 3, 4, 5, or 6 carbon atoms, respectively.
  • the C 2 -6 alkynyloxy group means an alkynyloxy group having 2 to 6 carbon atoms, for example, an alkynyloxy group having 2, 3, 4, 5, or 6 carbon atoms, respectively.
  • the d- 6 alkylthio group means a linear or branched alkylthio group having 1 to 6 carbon atoms, for example, an alkylthio group having 1, 2, 3, 4, 5, or 6 carbon atoms, respectively.
  • C 3 - 6 cycloalkylthio refers to a cycloalkylthio group having 3 to 6 carbon atoms, for example, a cycloalkylthio group having 3, 4, 5, or 6 carbon atoms, respectively.
  • the C 2 -6 acyloxy group means an acyloxy group having 2 to 6 carbon atoms, for example, an acyloxy group having 2, 3, 4, 5, or 6 carbon atoms, respectively.
  • the melting point was determined by YRT-3 melting point apparatus (temperature uncorrected); mass spectrometry was determined by American ABI API 3000 triple quadrupole tandem mass spectrometer; nuclear magnetic resonance spectrum was determined by JEOL-ECA-400 superconducting instrument 11 (operating frequency) : NMR 400 MHz ) • High resolution mass spectrometry by Buker Hybrid Quadrupole Fourier Transform Ion Cyclotron Resonance Mass Spectrometer (Q-FT-MS). The reagents used in the experiment are chemically pure or analytically pure, and the boiling point of the petroleum ether used. Both are 60 to 90.
  • Example 1 Preparation of 4-benzyloxybenzonitrile
  • the compound iv4. 16g was hydrolyzed with 2M aqueous NaOH solution and heated to 50 for 5 hours. Then, the reaction solution was directly added with concentrated hydrochloric acid to adjust the solution pH 2, and a white solid was precipitated. After filtering off the solid, the filter cake was washed with about 200 ml of water to wash. 0% ⁇ The yield of 95.0%, the yield of 95.0%.
  • 1-24-(4-Benzyloxyphenyl)-4-thiazole acid 1.24g was added to a 50ml eggplant-shaped bottle, and then 10 times the amount of thionyl chloride and 30 ml of anhydrous THF were added, and the reflux condenser was placed above. Dry the tube, heat and reflux for 4 h, then distill off the solvent under reduced pressure and excess thionyl chloride. The dried solid was dissolved in anhydrous THF.
  • the compound v 4.38 g was first added, and then 3.32 g of 10% Pd-C was added slowly, and finally 150 ml of anhydrous methanol was added, and then reacted at 3 atm in a hydrogenation apparatus at room temperature for 24 hours, TLC monitoring. It shows that there is no raw material, there is a new point with a larger polarity. After filtering 10% Pd-C, after concentrating the reaction solution to 50ml, after adding 100ml of water, a large amount of solid is precipitated. After filtering out the solid, use a small amount of water. The product is 3. 15g, yield 88. 2 ° /. .
  • 5 ⁇ PEG-400 ⁇ 40ml ⁇ Add 0. 37g ( 2. 52mmol) of compound vi to a 50m three-necked bottle, add acid-breaking clock 0. 7g (about 2 times the amount), then add a 'j, granules, 0. 5ml PEG-400 and 40ml DMF, After heating to 80 ° C, the reaction is carried out for 30 min, 2 times the amount of RX is added, the reaction time is 2-10 ml, 2 times the amount of water is added to the reaction solution, and then extracted with ethyl acetate (3 ⁇ 50 ml), and the acetic acid is combined. After the ester layer, the organic layer was washed with water and saturated brine, and the solvent was evaporated to dryness under reduced pressure.
  • the mixture was stirred with 2M of LiOH water and tetrahydrofuran solvent, and then reacted for 5 h, TLC monitoring, substantially no starting point, finally added 5% ⁇
  • the yield of the final product is 0. 15g, the yield is 40. 5%.
  • the final product is 0. 15g, the yield is 40. 5%.
  • This compound was prepared according to the preparation method of Example 6, to give 0.46 g of compound vi and bromoisobutane in a yield of 37.1%.
  • the product is obtained by the preparation of the compound 3-(4-((5-(4-isopropoxyphenyl)thiazol-2)amino)phenyl)propanoic acid and bromoisopropane. , yield 12.6%.
  • the temperature of the low temperature reaction tank is lowered to -78. 5.27g ( 21. 96mmo l ) of dried 5-bromo-2-isopropoxybenzonitrile and 50ml of anhydrous THF were added to a 100ml three-necked flask, cooled and protected by nitrogen for about 15 minutes. The needle was pipetted with 13. 2 ml of n-BuLi, and slowly injected into a three-necked bottle. It took about 1 hour to complete the addition, and -78: stirred for 2 hours. After adding 11. Olg (47.83mmo l) tributyl borate reaction 1.
  • Example 39 Preparation of ethyl 3-methyl-4-(5-bromothiazol-2-yl)benzenepropanoate 7.03 g (25.52 mmol) 3-methyl-4-(thiazol-2-yl)benzene Ethyl propionate was added to a 100 ml three-necked flask, and then 4.31 g (52.54 mmol) of sodium acetate, 50 ml of glacial acetic acid was added, and stirred. A 1.5 ml (about 29.29 mmol) bromine was pipetted into a 50 ml dropping funnel, diluted with 20 ml of glacial acetic acid, and bromine was slowly added dropwise.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazol-2-imino)phenyl)propanoic acid and bromopropane. Rate: 14.6%.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromocyclopentane. Yield: 9. 12%.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromoisobutane. Yield: 11.3%.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared from the compound 3-(4-(4-(3-bromo-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromobutane. Rate: 19. 43°/. .
  • Example 53 Preparation of 2-bromo-1-(4-chloro-3-methoxyphenyl)ethanone The reaction procedure was similar to that of Example 42, using the compound 2-chloroanisole and bromoacetyl bromide. Yield: 98. 6°/o 0
  • Example 59 Preparation of 3-(4-(4-(3-chloro-4-isobutoxyphenyl)thiazole-2-imino)phenyl)propanoic acid
  • the reaction procedure was similar to that of Example 47, which was prepared from the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromoisobutane. , Yield: 11.9%.
  • Example 47 The reaction procedure was similar to that of Example 47, which was prepared from the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromocyclopentane. , Yield: 11. 2%.
  • Example 47 The reaction procedure was similar to that of Example 47, which was prepared from the compound 3-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imino)phenyl)propanoic acid and bromoisopentane. , Yield: 20. 0%.
  • Example 47 The reaction procedure is similar to that of Example 47, which is prepared by using the compound 2-(4-(4-(3-chloro-4-hydroxyphenyl)thiazole-2-imide)phenyl)acetic acid and bromocyclopentane. Rate: 24.8%.
  • Cell culture medium DMEM high glucose medium containing 0.5 mg/ml G418 and 10%
  • FBS Analytical medium F12 medium containing lOmM HEPES, 0.1% defatting BSA
  • the analytical medium of DMS0 was used as a 4 Control control working solution at a final concentration of 1%.
  • the sieved compound was formulated into a 30 mM mother liquor by DMS0, and diluted to a continuous concentration gradient of 1000 X mother liquor by DMS0 ratio, and then analyzed to prepare a 4 X working solution.
  • the final concentration of ⁇ and 3 ⁇ was selected for the initial selection.
  • the final concentration of 30 ⁇ , ⁇ , 300 ⁇ , 1 ⁇ , 3nM, 10nM, 30nM, 100nM, 300nM, 1 ⁇ , 3 ⁇ , 10 ⁇ was selected according to the gradient of the compound activity.
  • a dose-effect relationship is made for six to eight consecutive concentrations.
  • U20S cells stably expressing the EGFP-SPiPi fusion protein, 5% CO 2 were cultured in DMEM high glucose medium containing 0.5 mg/ml G418 and 10% FBS.
  • the cells were seeded in a 96-well black-bottomed cell culture plate according to the cells at 0.8x10 4 ⁇ /well, and cultured in 5% CO 2 for 18-24 hours.
  • the cells were washed once with 200 ⁇ l/well assay medium, and 150 ⁇ l/well assay medium was added and incubated for 37 min at 37 5% CO 2 .
  • Compound agonistic intensity (the total area of particles per cell contained in the compound-treated group - the total area of particles per cell contained in the Control control treatment group) I Control The total area of particles per cell contained in the control treatment group.
  • the excitation intensity was calculated by taking the average of 15 fields (5 per well) in 3 wells measured in parallel for each test concentration point of the compound.
  • the first initial screening was carried out at two final concentrations of ⁇ and 3 ⁇ M.
  • the experimental results are shown in Table 2.
  • the preliminary screening results show that the embodiment 6, the embodiment 12, the embodiment 21, the embodiment 22, the embodiment 45, the embodiment 47, the embodiment 48, the embodiment 49, the embodiment 50, the embodiment 52, the embodiment 56, and the implementation In Example 59 and Example 70, respectively, the agonistic activity reached 3 or more standard deviations at 3 ⁇ , and further screening was possible.
  • the EGFP-S1P!_U20S cell is a commercial cell strain of a compound used by the American company to screen for the S1P1 receptor, and the SIP receptor is activated after endocytosis, which is represented by the aggregation of the green fluorescent protein reporter gene in the cytoplasmic granule. Therefore, a compound having an agonistic activity on the SI receptor can cause a change in the reporter molecule £0??-31? 1 .
  • the agonist S1P activates S1 and causes its endocytic formation of particle aggregation, which is about 2- to 3-fold at 10 nM and about 5-6 times at 250 nM.
  • the agonistic activity at 1 ⁇ is approximately 7-8 times its EC 5 .
  • the value is approximately 25 nM.

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Abstract

L'invention concerne un composé de formule I ou son sel pharmaceutiquement acceptable. Le composé ou son sel pharmaceutiquement acceptable de cette invention peut tenir lieu d'immunosuppresseur permettant de réguler le transport des leucocytes et le transport cellulaire des lymphocytes de façon à ce que ces derniers se rassemblent sur les tissus lymphoïdes secondaires afin d'augmenter l'intégrité des vaisseaux sanguins et exercer une action immunosuppressive, une activité anti-inflammatoire et hémostatique.
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CN106810513A (zh) * 2017-01-10 2017-06-09 湖南华腾制药有限公司 一种哌嗪衍生物的制备方法
CN106854174A (zh) * 2015-12-08 2017-06-16 湖南华腾制药有限公司 一种4位取代哌啶衍生物的制备方法
CN107400082A (zh) * 2016-05-19 2017-11-28 湖南华腾制药有限公司 一种取代哌啶衍生物的制备方法
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
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CN109912414B (zh) * 2019-04-11 2021-09-17 荆门医药工业技术研究院 一种4-甲醛肟基苯甲酸乙酯的制备方法和应用

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KR20160014975A (ko) * 2014-07-30 2016-02-12 한국생명공학연구원 페닐 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 세포증식성 질병의 예방 또는 치료용 약학적 조성물
KR101721490B1 (ko) 2014-07-30 2017-03-30 한국생명공학연구원 페닐 유도체, 이의 제조방법 및 이를 유효성분으로 함유하는 세포증식성 질병의 예방 또는 치료용 약학적 조성물
CN106854174A (zh) * 2015-12-08 2017-06-16 湖南华腾制药有限公司 一种4位取代哌啶衍生物的制备方法
CN107400082A (zh) * 2016-05-19 2017-11-28 湖南华腾制药有限公司 一种取代哌啶衍生物的制备方法
CN106810513A (zh) * 2017-01-10 2017-06-09 湖南华腾制药有限公司 一种哌嗪衍生物的制备方法
US11938134B2 (en) 2017-03-10 2024-03-26 Eikonizo Therapeutics, Inc. Metalloenzyme inhibitor compounds
US11926616B2 (en) 2018-03-08 2024-03-12 Incyte Corporation Aminopyrazine diol compounds as PI3K-γ inhibitors
US11046658B2 (en) 2018-07-02 2021-06-29 Incyte Corporation Aminopyrazine derivatives as PI3K-γ inhibitors

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