WO2019001342A1 - 氨基醇衍生物、其药物组合物和用途 - Google Patents

氨基醇衍生物、其药物组合物和用途 Download PDF

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WO2019001342A1
WO2019001342A1 PCT/CN2018/092233 CN2018092233W WO2019001342A1 WO 2019001342 A1 WO2019001342 A1 WO 2019001342A1 CN 2018092233 W CN2018092233 W CN 2018092233W WO 2019001342 A1 WO2019001342 A1 WO 2019001342A1
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group
alkyl
membered
mmol
cycloalkyl
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PCT/CN2018/092233
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English (en)
French (fr)
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季奇
张兴民
杜镇建
巩龙龙
王磊
高聪敏
杜美静
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北京富龙康泰生物技术有限公司
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Priority to EP18822870.4A priority Critical patent/EP3647309A4/en
Priority to US16/625,151 priority patent/US11584726B2/en
Priority to JP2019559065A priority patent/JP6837578B2/ja
Publication of WO2019001342A1 publication Critical patent/WO2019001342A1/zh

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4245Oxadiazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D271/00Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/061,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D271/00Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
    • C07D271/02Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
    • C07D271/101,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
    • C07D271/1071,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles with two aryl or substituted aryl radicals attached in positions 2 and 5
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00Drugs for dermatological disorders
    • A61P17/06Antipsoriatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00Drugs for skeletal disorders
    • A61P19/02Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00Drugs for disorders of the metabolism
    • A61P3/08Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • A61P37/02Immunomodulators
    • A61P37/06Immunosuppressants, e.g. drugs for graft rejection
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00Drugs for disorders of the endocrine system
    • A61P5/14Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A61P5/16Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4 for decreasing, blocking or antagonising the activity of the thyroid hormones
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic 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
    • C07D413/04Heterocyclic 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 directly linked by a ring-member-to-ring-member bond

Definitions

  • This application belongs to the field of medicine, and in particular relates to amino alcohol derivatives, pharmaceutical compositions thereof and uses thereof.
  • the immune system is the defensive structure of the body to protect itself. It is mainly composed of lymphoid organs (thymus, lymph nodes, spleen, tonsils), lymphoid tissues in other organs, lymphocytes and antigen-presenting cells throughout the body, and other blood. Plasma cells and mast cells in white blood cells and connective tissue.
  • the core component of the immune system is lymphocytes, which give the immune system the ability to recognize and remember. Lymphocytes travel throughout the body through the blood and lymph, from one lymphoid or lymphoid tissue to another lymphoid or lymphoid tissue, allowing the lymphatic and lymphoid tissues scattered throughout to form a functional whole. T cells and B cells are the most important immune cells in the human body. The normal function of each component of the immune system is to ensure that the immune function of the body is relatively stable. Any defect or function of any component will cause damage to the body.
  • the components of the immune system are widespread and complex, especially the immune cells and immune molecules are constantly produced, circulated and renewed in the body.
  • the immune system has a high degree of discrimination, can accurately identify itself and non-self substances to maintain the relative stability of the body; at the same time, it can accept, transmit, expand, store and memorize information about immunity, and positive and negative responses to immune information. And constantly adjust its responsiveness.
  • the imbalance of immune system function is also extremely unfavorable to the human body: the abnormal recognition ability of the human body can easily lead to allergic phenomena, and vice versa, causing repeated infections; the abnormal self-stabilizing ability of the human body will cause the immune system to respond to its own cells. , triggering autoimmune diseases.
  • Immunosuppressive agents are a new class of drugs developed on the basis of multidisciplinary research such as tumor chemotherapy, organ transplantation, immunopathology and clinical immunology. They have immunosuppressive effects and can inhibit abnormal immune responses in the body. For the treatment of organ transplant anti-rejection and autoimmune diseases. Common immunosuppressive agents are: cyclophosphamide (CTX), glucocorticoids, azathioprine, cyclosporine A (CsA), rapamycin, mycophenolate mofetil and the like.
  • CX cyclophosphamide
  • CsA azathioprine
  • CsA cyclosporine A
  • rapamycin mycophenolate mofetil and the like.
  • the above-mentioned immunosuppressive agents inevitably damage the immune defense ability of patients at the same time of treatment, resulting in decreased anti-infective ability, increased risk of malignant lesions, damage to hematopoiesis, immune system and liver and kidney.
  • the function of the digestive tract causes neurological and endocrine dysfunction and triggers certain allergic reactions. Therefore, the development and optimization of new immunosuppressants is an important direction for the development of new drugs.
  • S1P1 sphingosine-1-phosphate receptor 1
  • GPCR a GPCR
  • FTY720 sphingosine-1-phosphate receptor 1
  • S1P1 a GPCR
  • FTY720 sphingosine-1-phosphate receptor 1
  • S1P1 a GPCR
  • Amino alcohol derivatives have some structural similarities to endogenous hemolytic lipid sphingosine. Sphingosine forms 1-phospho-sphingosine via sphingosine-induced phosphorylation, and activation of its receptor results in cell differentiation and growth as well as regulation of cell adhesion and cell morphology.
  • T and B lymphocytes proliferate in lymph nodes.
  • they down-regulate S1P1 expression, and if activated, up-regulate the amount of S1P1 on the cell surface, which allows T and B cells to leave the lymph nodes.
  • S1P1 on the surface of lymphocytes can bind to the drug, thereby down-regulating the expression of S1P1, so that the lymphocytes no longer have the function of detaching from the lymph nodes and adhere to the lymph nodes.
  • the amino alcohol derivative does not destroy the immune function of lymphocytes, but achieves an effect of suppressing the immune response by allowing lymphocytes to remain in the lymphatic system and not entering the blood circulation system.
  • the sphingosine-1-phosphate receptor 1 agonist FTY720 has been successfully developed by Novartis. However, FTY720 acts not only on sphingosine-1-phosphate receptor 1 (S1P1) but also on sphingosine-1-phosphate receptor 3 (S1P3), which has side effects such as a sudden heart rate. Therefore, the development of S1P1 agonists with better receptor selectivity has become an important research direction in the field.
  • the present invention provides an amino alcohol derivative represented by the following formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, an isotope label, a solvate, a polymorph or a former medicine:
  • R 1 and R 2 are the same or different and are independently selected from H, -F, -Cl, -Br, -I, -OH, -SH, -CN, -COOH, -NO 2 , unsubstituted or
  • the following groups substituted by one or more R a are selected: C 1-40 alkyl, C 1 - 40 alkoxy, C 2 - 40 alkenyl, C 2 - 40 alkynyl, C 3 - 20 cycloalkyl , C 3 - 20 cycloalkyloxy, 3-20 membered heterocyclic, 3-20 membered heterocyclyloxy, C 6 - 20 aryl, C 6 - 20 aryloxy, 5-20 membered Aryl, 5-20 membered heteroaryloxy, H[(CH 2 ) n O] m -, -NR d R e , -CONR d R e or -C(O)Y 1 R d ;
  • R 3 is selected from the group consisting of unsubstituted or optionally substituted by one or more R b : C 3 - 20 cycloalkyl, 3-20 membered heterocyclyl, C 6 - 20 aryl, 5-20 membered Aryl;
  • Each R b is the same or different and is independently selected from -F, -Cl, -Br, -I, -SH, -OH, -CN, -COOH, unsubstituted or optionally by one or more R a Substituted groups: C 1-40 alkyl, C 1 - 40 alkoxy, C 2 - 40 alkenyl, C 2 - 40 alkynyl, C 3 - 20 cycloalkyl, 3-20 membered heterocyclic , C 6 - 20 aryl, 5-20 membered heteroaryl, C 3 - 20 cycloalkyloxy, 3-20 membered heterocyclyloxy, C 6 - 20 aryloxy, 5-20 membered Aryloxy, C 3 - 20 cycloalkyl C 1-40 alkyl, 3-20 membered heterocyclic C 1-40 alkyl, C 6 - 20 aryl C 1-40 alkyl, 5-20 Heteroaryl C 1-40 alkyl,
  • R 3 when R 3 is substituted by two or more of the same or different R b , two of the R b may each decouple the respective H or other group and form a R 3 together with the carbon atom to which they are attached a fused ring system R s , wherein R s is selected from C 3 - 20 cycloalkyl, 3-20 membered heterocyclyl, C 6 - 20 aryl, 5-20 membered heteroaryl fused to R 3 ;
  • R c , R d , R e are the same or different and are independently selected from H, or the following groups which are unsubstituted or optionally substituted by one or more R a : C 1 - 40 alkyl, C 2 - 40 ene , C 2 - 40 alkynyl, C 3 - 20 cycloalkyl, 3-20 membered heterocyclyl, C 6 - 20 aryl, 5-20 membered heteroaryl or CONH 2 ;
  • Y 1 is selected from a chemical bond, -O-, -S-, unsubstituted or optionally substituted by one or more R a -NH-, C 1 -40 alkyl, C 1 - 40 alkoxy, C 3- 20 cycloalkyl, 3-20 membered heterocyclyl, C 6 - 20 aryl, 5-20 membered heteroaryl or (CH 2 CH 2 O) j -;
  • n, j may be the same or different and are independently selected from an integer of 1 or more, for example, an integer of 1 to 20, such as 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • R 1 and R 2 may be the same or different and are independently selected from H, -F, -Cl, -Br, -I, -OH, -SH, -CN, -COOH or C 1-40 alkyl, for example R 1 , R 2 is selected from H or C 1-40 alkyl;
  • R 3 may be selected from the group consisting of unsubstituted or optionally substituted by one or more R b : C 3 -8 cycloalkyl, 3-8 membered heterocyclic, C 6 - 10 aryl, 5-6 Heteroaryl
  • Each R b is the same or different and is independently selected from -F, -Cl, -Br, -I, -SH, -OH, -CN, -COOH, unsubstituted or optionally by one or more R a Substituted the following groups: C 1-6 alkyl, C 1 -6 alkoxy, C 3 -8 cycloalkyl, 3-8 membered heterocyclic, C 6 - 10 aryl, 5-6-membered heteroaryl , C 3 -8 cycloalkyloxy, 3-8 membered heterocyclyloxy, C 6 - 10 aryloxy, 5-6 membered heteroaryloxy, C 3 -8 cycloalkyl C 1 -6 alkyl, 3-8 membered heterocyclic C 1-6 alkyl, C 6 - 10 aryl C 1-6 alkyl, 5-6 membered heteroaryl C 1-6 alkyl, H[(CH 2 ) n O] n -, -NR
  • R 3 when R 3 is substituted by two or more of the same or different R b , two of the R b may each decouple the respective H or other group and form a R 3 together with the carbon atom to which they are attached a fused ring system R s , wherein R s is selected from C 3 -8 cycloalkyl, 3-8 membered heterocyclyl, C 6 - 10 aryl, 5-6 membered heteroaryl fused to R 3 ;
  • R 3 may be selected from the group consisting of phenyl, pyridyl, pyrazinyl, cyclohexyl, piperidinyl, piperazinyl;
  • R 3 may be selected from the group consisting of phenyl, pyridin-1-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, piperidin-1-yl, piperidin-2-yl, piperidine Pyridin-3-yl, piperidin-4-yl;
  • each R b may be substituted at any suitable position on the R & lt 3, R 1,2,3 e.g. substituted at the 3 or 4-position;
  • each R b may be the same or different and independently selected from -F, -Cl, -Br, -I, -SH, -OH, -CN, -COOH, unsubstituted or optionally One or more of the following groups substituted by R a : C 1-6 alkyl (eg methyl, ethyl, propyl, isopropyl, tert-butyl), C 1-6 alkoxy (eg A Oxy, ethoxy, propoxy, isopropoxy, tert-butoxy), C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 1-6 alkylcarbonylamino, C 1-6 alkyloxycarbonyl, C 1-6 alkylcarbonyloxy, 3-6 membered heterocyclic C 1-6 alkyl, -CONH 2 , -NHCOCH 3 ;
  • C 1-6 alkyl eg methyl, ethyl, propyl, isoprop
  • each R b may be the same or different and independently selected from -F, -OH, -CN, -CF 3 , -COOH, -CONH 2 , methoxy, ethoxy, propoxy, iso Propyloxy, -NHCOCH 3 , cyclopentyl, -C(O)OCH 3 , azetidin-1-ylmethyl, pyrrolidin-1-ylmethyl, piperidin-1-ylmethyl;
  • R 3 when R 3 is substituted by two or more of the same or different R b , two of the R b may each decouple the respective H or other group and form a R 3 together with the carbon atom to which they are attached
  • R 3 when R 3 is phenyl, R 3 is preferably substituted by R b3 at least at the 3-position, wherein R b3 is a pull-electron substituent;
  • R 3 when R 3 is phenyl, R 3 is preferably substituted by R b4 at least at the 4-position, wherein R b4 is an electron-donating substituent.
  • R b3 may be selected from -Cl, -Br, -I, -SH, -OH, -CN, -COOH, -CONH 2 , -COC 1-6 alkyl, -COC 3-6 cycloalkyl, -CF 3 ;
  • R b4 may be selected from C 1-6 alkyl (eg methyl, ethyl, propyl, isopropyl, tert-butyl), C 1-6 alkoxy (eg methoxy, ethoxy) , propoxy, isopropoxy, tert-butoxy), C 3-6 cycloalkyl, C 3-6 cycloalkyloxy, C 1-6 alkylcarbonylamino.
  • the amino alcohol derivative of the formula I according to the present invention may have the structure represented by the following formula I':
  • the compound of formula I of the invention may be selected from the group consisting of:
  • the present invention also provides a process for the preparation of the amino alcohol derivative of the above formula I, comprising one or more of the following steps a to f:
  • R 1 , R 2 , R 3 have the definitions as described above;
  • X is selected from halogen
  • PG 1 is selected from a hydroxy protecting group
  • PG 2 is selected from an amino protecting group
  • PG 1 and PG 2 may be bonded to each other to simultaneously protect the hydroxyl group and the carbonyl group.
  • step a D-tartaric acid can be used as a resolving agent to obtain compound 7;
  • step b compound 7 can be protected with an amino group in the presence of PhCHO and NaBH(OAc) 3 , and then compound 8 can be obtained in the presence of CH 3 OC(CH 3 ) 2 OCH 3 and an acid;
  • step c compound 8 is reacted in the presence of n-BuLi, CO 2 at -78 ° C to obtain compound 9;
  • step d compound 9 can be first reacted with oxalyl chloride, and then reacted with compound 10 of the following formula in the presence of triethylamine to obtain compound 11;
  • step e compound 11 is reacted in the presence of TsCl and triethylamine to give compound 12;
  • step f) the protective groups PG 1 and PG 2 of the amino group and the hydroxy group are removed under deprotection conditions, for example, the hydroxy protecting group is removed in the presence of an acid; and the amino protecting group is removed under reducing conditions.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the amino alcohol derivative of the formula I of the present invention, a pharmaceutically acceptable salt, a stereoisomer, an isotopic label, a solvate, a polymorph or a prodrug thereof, and A pharmaceutically acceptable carrier.
  • the pharmaceutical composition may be in the form of, but not limited to, an oral dosage form, a parenteral administration dosage form, an external dosage form, and a rectal administration dosage form.
  • the pharmaceutical composition may be an oral tablet, capsule, pill, powder, sustained release formulation, solution and suspension, sterile solution, suspension or emulsion for parenteral injection, A topical ointment or cream, or a suppository for rectal administration.
  • the pharmaceutical composition is in a unit dosage form suitable for single administration of precise dosages.
  • the amount of the compound ranges from about 0.001 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • the amount of the compound ranges from about 0.5 mg/kg body weight/day to about 50 mg/kg body weight/day.
  • the amount of the compound is from about 0.001 g/day to about 7 g/day.
  • the amount of the compound is from about 0.002 g/day to about 6 g/day.
  • the amount of the compound is from about 0.005 g/day to about 5 g/day.
  • the amount of the compound is from about 0.01 g/day to about 5 g/day.
  • the amount of the compound is from about 0.02 g/day to about 5 g/day.
  • the amount of the compound is from about 0.05 g/day to about 2.5 g/day.
  • the amount of the compound is from about 0.1 g/day to about 1 g/day.
  • dosage levels below the lower end of the above range may already be sufficient.
  • dosage levels above the upper limit of the above range may be required.
  • the compound is administered in a single dose once daily.
  • the compound is administered in multiple doses more than once a day.
  • the compound is administered twice daily.
  • the compound is administered three times a day.
  • the compound is administered four times a day.
  • the compound is administered more than four times a day.
  • the individual to which the pharmaceutical composition is administered is a mammal.
  • the mammal is a human.
  • the pharmaceutical composition further comprises at least one additional therapeutic agent (ie, made into a dosage form).
  • the pharmaceutical composition and the at least one therapeutic agent are each combined in a separate dosage form into a combined product, such as a kit of parts.
  • the present invention also provides an amino alcohol derivative represented by the above formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic label, a solvate, a polymorph or a prodrug thereof, in the preparation of a medicament for down-regulating the expression of S1P1 application.
  • the present invention also provides an amino alcohol derivative of the above formula I, a pharmaceutically acceptable salt, stereoisomer, isotope label, solvate, polymorph or prodrug thereof for down-regulating the expression of S1P1.
  • the present application also provides a method of modulating (as follows) S1P1 activity, which comprises administering S1P1 with an effective amount of the above compound or a pharmaceutically acceptable salt, stereoisomer, isotopic label, solvate, polymorph thereof Or contact with the prodrug.
  • the method can be used in vivo as well as in vitro.
  • the present invention also provides an amino alcohol derivative represented by the above formula I, a pharmaceutically acceptable salt thereof, a stereoisomer, an isotopic label, a solvate, a polymorph or a prodrug thereof for preparation for prevention and treatment and immune inflammation Application in related disease drugs.
  • the present application also provides an amino alcohol derivative, a pharmaceutically acceptable salt, a stereoisomer, an isotope label, a solvate, a polymorph or a prodrug thereof, as shown in Formula I above, for use in the treatment or prophylaxis of an immune inflammation. Disease or condition.
  • the present application also provides an amino alcohol derivative, a pharmaceutically acceptable salt, a stereoisomer, an isotopic label, a solvate, a polymorph or a prodrug thereof, as shown in Formula I above, for the preparation of a therapeutic or prophylactic treatment and immunity. Use in medicines for activity-related diseases or conditions.
  • the present application also provides a method of treating a disease or condition associated with immunological activity, comprising administering an effective amount of an amino alcohol derivative of the above formula I or a pharmaceutically acceptable salt, stereoisomer, or isotope thereof. Labels, solvates, polymorphs or prodrugs are administered to an individual in need thereof.
  • the individual can be a mammal, such as a human.
  • the immune activity-related disease or condition may be multiple sclerosis, gradual freezing, chronic inflammatory demyelinating polyneuropathy (CIDP), systemic lupus erythematosus, class One or more of rheumatoid arthritis, ulcerative colitis, psoriasis, polymyositis, type I diabetes, hyperthyroidism, scleroderma, myasthenia gravis, and the like.
  • CIDP chronic inflammatory demyelinating polyneuropathy
  • systemic lupus erythematosus class One or more of rheumatoid arthritis, ulcerative colitis, psoriasis, polymyositis, type I diabetes, hyperthyroidism, scleroderma, myasthenia gravis, and the like.
  • the manufacturer's instructions for use of the kit can be utilized, or the reaction can be carried out and purified according to methods well known in the art or as described in the present application.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • the substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • CH 2 O is equivalent to OCH 2 .
  • halogen refers to F, Cl, Br and I. In other words, F, Cl, Br, and I can be described as “halogen" in this specification.
  • C 1-40 alkyl is understood to preferably denote a straight or branched saturated monovalent hydrocarbon radical having from 1 to 40 carbon atoms, preferably a C 1-10 alkyl group.
  • C 1-10 alkyl is understood to preferably denote a straight or branched saturated monovalent hydrocarbon radical having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the alkyl group is, for example, methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, isopentyl, 2-methylbutyl, 1-methylbutyl, 1-ethylpropyl, 1,2-dimethylpropyl, neopentyl, 1,1-dimethylpropyl, 4-methylpentyl, 3-methylpentyl Base, 2-methylpentyl, 1-methylpentyl, 2-ethylbutyl, 1-ethylbutyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 2,3-dimethylbutyl, 1,3-dimethylbutyl or 1,2-dimethylbutyl, or the like, or isomers thereof.
  • the group has 1, 2, 3, 4, 5, 6, carbon atoms ("C 1-6 alkyl”), such as methyl, ethyl, propyl, butyl, isopropyl , isobutyl, sec-butyl, tert-butyl, more particularly, the group has 1, 2 or 3 carbon atoms ("C 1-3 alkyl”), such as methyl, ethyl, n-propyl Base or isopropyl.
  • C 1-6 alkyl such as methyl, ethyl, propyl, butyl, isopropyl , isobutyl, sec-butyl, tert-butyl
  • C 1-3 alkyl such as methyl, ethyl, n-propyl Base or isopropyl.
  • C 2-40 alkenyl is understood to preferably denote a straight or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2 to 40 carbon atoms, preferably "C 2-10 alkenyl”.
  • C 2-10 alkenyl is understood to preferably denote a straight or branched monovalent hydrocarbon radical which contains one or more double bonds and has 2, 3, 4, 5, 6, 7, 8, 9 or 10 a carbon atom, especially 2 or 3 carbon atoms ("C 2-3 alkenyl”), it being understood that where the alkenyl group contains more than one double bond, the double bonds may be separated from each other or yoke.
  • the alkenyl group is, for example, a vinyl group, an allyl group, (E)-2-methylvinyl group, (Z)-2-methylvinyl group, (E)-but-2-alkenyl group, (Z)- But-2-enyl, (E)-but-1-enyl, (Z)-but-1-enyl, pent-4-enyl, (E)-pent-3-enyl, (Z) -pent-3-enyl, (E)-pent-2-enyl, (Z)-pent-2-enyl, (E)-pent-1-enyl, (Z)-pent-1-ene , hex-5-alkenyl, (E)-hex-4-enyl, (Z)-hex-4-enyl, (E)-hex-3-enyl, (Z)-hex-3- Alkenyl, (E)-hex-2-enyl, (Z)-hex-2-enyl,
  • C 2-40 alkynyl is understood to mean a straight or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2 to 40 carbon atoms, preferably "C 2 -C 10 alkynyl".
  • C 2 -C 10 alkynyl is understood to preferably denote a straight or branched monovalent hydrocarbon radical which contains one or more triple bonds and has 2, 3, 4, 5, 6, 7, 8, 9 Or 10 carbon atoms, especially 2 or 3 carbon atoms ("C 2 -C 3 -alkynyl").
  • the alkynyl group is, for example, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, pent-1-ynyl , pent-2-ynyl, pent-3-ynyl, pent-4-ynyl, hex-1-ynyl, hex-2-ynyl, hex-3-ynyl, hex-4-ynyl, Hex-5-alkynyl, 1-methylprop-2-ynyl, 2-methylbut-3-ynyl, 1-methylbut-3-ynyl, 1-methylbut-2-ynyl , 3-methylbut-1-ynyl, 1-ethylprop-2-ynyl, 3-methylpent-4-ynyl, 2-methylpent-4-ynyl, 1-methylpentyl 4-ynyl, 2-methylpent-3-yny
  • C 3-20 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having from 3 to 20 carbon atoms, preferably “C 3-10 cycloalkyl”.
  • C 3-10 cycloalkyl is understood to mean a saturated monovalent monocyclic or bicyclic hydrocarbon ring having 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms.
  • the C 3-10 cycloalkyl group may be a monocyclic hydrocarbon group such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclodecyl group or a cyclodecyl group, or a bicyclic ring.
  • a hydrocarbon group such as a decalin ring.
  • 3-20 membered heterocyclyl means a saturated monovalent monocyclic or bicyclic hydrocarbon ring comprising from 1 to 5 heteroatoms independently selected from N, O and S, preferably “3-10 membered heterocyclyl” ".
  • the term “3-10 membered heterocyclyl” means a saturated monovalent monocyclic or bicyclic hydrocarbon ring containing from 1 to 5, preferably from 1 to 3, heteroatoms selected from N, O and S.
  • the heterocyclic group can be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom, if present.
  • the heterocyclic group may include, but is not limited to, a 4-membered ring such as azetidinyl, oxetanyl; a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl; or 6-membered ring, such as tetrahydropyranyl, piperidinyl, morpholinyl, dithiaalkyl, thiomorpholinyl, piperazinyl Or a trithiaalkyl group; or a 7-membered ring such as a diazepanyl group.
  • a 4-membered ring such as azetidinyl, oxetanyl
  • a 5-membered ring such as tetrahydrofuranyl, dioxolyl, pyrrole Alkyl, imidazolidin
  • the heterocyclic group can be benzofused.
  • the heterocyclic group may be bicyclic, such as but not limited to a 5,5 membered ring such as a hexahydrocyclopenta[c]pyrrole-2(1H)-yl ring, or a 5,6 membered bicyclic ring such as hexahydropyrrole.
  • [1,2-a]pyrazine-2(1H)-yl ring [1,2-a]pyrazine-2(1H)-yl ring.
  • the ring containing a nitrogen atom may be partially unsaturated, that is, it may contain one or more double bonds such as, but not limited to, 2,5-dihydro-1H-pyrrolyl, 4H-[1,3,4]thiadiene.
  • the heterocyclic group is non-aromatic.
  • C 6-20 aryl is understood to mean preferably a monovalent, aromatic or partially aromatic monocyclic, bicyclic or tricyclic hydrocarbon ring having 6 to 20 carbon atoms, preferably “C 6-14 aryl”.
  • C 6-14 aryl is understood to mean preferably a monovalent, bicyclic or monovalent aromatic or partially aromatic having 6, 7, 8, 9, 10, 11, 12, 13 or 14 carbon atoms.
  • C 6-14 aryl a tricyclic hydrocarbon ring
  • C 6 aryl a ring having 6 carbon atoms
  • C 9 aryl such as indanyl or fluorenyl
  • C 10 aryl a ring having 10 carbon atoms
  • C13 aryl such as a fluorenyl group
  • C14 aryl a ring having 14 carbon atoms
  • 5-20 membered heteroaryl is understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having from 5 to 20 ring atoms and containing from 1 to 5 independently selected from N, O. And a hetero atom of S, such as “5-14 membered heteroaryl”.
  • the term “5-14 membered heteroaryl” is understood to include a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 7, 8, 9, 10, 11, 12, 13 or 14 ring atoms, especially 5 or 6 or 9 or 10 carbon atoms, and which contain 1-5, preferably 1-3, each independently selected from N, O and S heteroatoms and, in each case The benzo can be fused.
  • the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thia Diazolyl, thia-4H-pyrazolyl, and the like, and benzo derivatives thereof, such as benzofuranyl, benzothienyl, benzoxazolyl, benzisoxazolyl, benzimidazolyl, benzene And a triazolyl group, a carbazolyl group, a fluorenyl group, an isodecyl group, etc.; or a pyridyl group, a pyridazinyl group, a pyrimidinyl group, a pyrazinyl group, a triazinyl group, etc., and a benzo derivative thereof
  • a heterocyclyl, heteroaryl or heteroarylene includes all possible isomeric forms thereof, such as positional isomers thereof.
  • pyridyl or pyridinyl includes pyridin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-3-yl, pyridin-4-yl And pyridin-4-yl;
  • thienyl or thienylene includes thiophen-2-yl, thiophen-2-yl, thiophen-3-yl and thiophen-3-yl.
  • alkyl such as “C 1-40 alkyl”
  • C 1-40 alkyl refers to other terms containing “C 1-40 alkyl”, such as the term “C 1-40 alkyloxy”, “C. 1-40 alkoxy”, “C 1-40 alkylsilyl” and “C 1-40 alkylsilyloxy” and the like.
  • protecting group refers to a temporary substituent that protects a potentially reactive functional group from undesired chemical transformation.
  • any method for preparing a compound of the invention it may be necessary and/or desirable to protect any sensitive or reactive groups on the molecule. This can be achieved by known protecting groups, such as the protecting groups described in textbooks or reference books in the field.
  • the protecting group can be removed at a convenient subsequent stage using methods known in the art.
  • subject refers to an individual, including a mammal, and a non-mammal, having a disease, disorder, condition, or the like.
  • mammals include, but are not limited to, any member of the mammalian class: humans, non-human primates (eg, chimpanzees and other mites and monkeys); livestock, such as cattle, horses, sheep, goats, pigs; domesticated Animals such as rabbits, dogs and cats; laboratory animals, including rodents such as rats, mice and guinea pigs.
  • non-human mammals include, but are not limited to, birds and fish.
  • the mammal is a human.
  • treatment includes alleviating, alleviating or ameliorating the symptoms of a disease or condition, preventing other symptoms, ameliorating or preventing a potential metabolic cause of the symptoms, inhibiting the disease or condition, such as preventing the progression of the disease or condition, Ameliorating a disease or condition, ameliorating the disease or condition, alleviating the symptoms caused by the disease or condition, or terminating the symptoms of the disease or condition, and further, the term includes the purpose of prevention.
  • the term also includes obtaining a therapeutic effect and/or a preventive effect.
  • the therapeutic effect refers to curing or ameliorating the underlying disease to be treated.
  • the healing or amelioration of one or more physiological symptoms associated with a underlying disease is also a therapeutic effect, for example, although the patient may still be affected by the underlying disease, an improvement in the patient's condition is observed.
  • the composition can be administered to a patient at risk of developing a particular disease, or even if a diagnosis of the disease has not been made, the composition is administered to a patient who develops one or more physiological symptoms of the disease.
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is the amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical and rectal administration topical and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present application, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • composition refers to a biologically active compound, optionally in admixture with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, stabilizers, diluents. , dispersing agents, suspending agents, thickening agents and/or excipients.
  • carrier refers to a relatively non-toxic chemical compound or agent that facilitates the introduction of a compound into a cell or tissue.
  • pharmaceutically acceptable salt refers to a salt that retains the biological effectiveness of the free acid and free base of the specified compound, and which has no adverse effects biologically or otherwise.
  • the compounds of the present application also include pharmaceutically acceptable salts.
  • a pharmaceutically acceptable salt refers to a form in which a base group in a parent compound is converted into a salt.
  • Pharmaceutically acceptable salts include, but are not limited to, base or group of inorganic or organic acid salts of amine (amino) groups.
  • the pharmaceutically acceptable salts of the present application can be synthesized from the parent compound, i.e., the basic group in the parent compound is reacted with from 1 to 4 equivalents of acid in a solvent system.
  • Suitable salts include the Remingtong's Pharmaceutical Scicences, 17 th ed ., Mack Publishing Company, Easton, Pa., 1985, p.1418 , and Journal of Pharmaceutical Science, (1977) 66, 2 of, for example, hydrochloride.
  • the salt in the present application refers to an acid salt formed with an organic acid/inorganic acid, and a basic salt formed with an organic base/inorganic base.
  • the basic functional group of the compound of formula I is pyridine or imidazole (but not limited to pyridine or imidazole)
  • the acidic functional group is a carboxylic acid (but not limited to a carboxylic acid)
  • a zwitterion internal salt
  • the inner salt Also included in the salt in this application.
  • solvate refers to a combination of a compound of the present application and a solvent molecule formed by solvation.
  • a solvate refers to a hydrate, i.e., the solvent molecule is a water molecule, and the combination of the compound of the present application and water forms a hydrate.
  • One or more compounds in the present application may exist in the form of a solvate, as in the form of a solvate formed with a pharmaceutically acceptable solvent such as water, ethanol, etc., therefore, the present application includes both solvates and unsolvates. Forms.
  • Solvate refers to a physical agglomerate of a compound of the present application with one or more solvent molecules that includes varying degrees of ionic and covalent bonds, such as hydrogen bonds. This solvate has been shown to be isolated, for example, when one or more solvent molecules are mixed in the crystal lattice of the crystal. "Solvate” includes both a solvent phase and a separable solvate. There are many examples of corresponding solvates, including ethanol solvates, methanol solvates, and the like. "Hydrate” is a solvate with a water (H 2 O) molecule as a solvent.
  • One or more compounds of the present application can be prepared as solvates at will.
  • the preparation of solvates is well known.
  • the preparation of the solvate of the antifungal fluconazole i.e., prepared with ethyl acetate and water, is described, for example, in M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004). Similar preparation of solvates, hydrates is also described in ECvan Tonder et al, AAPS PharmSciTech., 5(1), article 12 (2004); and AL Bingham et al, Chem. Commun., 603-604 (2001). method.
  • a typical, non-limiting preparation process is to dissolve the inventive compound in a desired amount of an ideal solvent (organic solvent or water or a mixed solvent thereof) at a temperature higher than normal temperature, to cool down, to deposit crystallization, The crystals are then separated by standard methods. The presence of a solvent (water) which forms a solvate (hydrate) in the crystal can be confirmed by I.R. spectroscopy.
  • an ideal solvent organic solvent or water or a mixed solvent thereof
  • polymorph or “polymorph” as used herein, refers to a compound of the present application that exists in a different lattice form.
  • isotopic label refers to a compound of the present application that is isotopically labeled.
  • isotopes in the compounds of the present application include various isotopes of H, C, N, O, P, F, S, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F and 36 S.
  • pharmaceutically acceptable prodrug refers to any pharmaceutically acceptable salt, ester, ester salt or other derivative of a compound of the present application which can be provided, directly or indirectly, after administration to a recipient.
  • Particularly preferred derivatives or prodrugs are those compounds which, when administered to a patient, increase the bioavailability of the compounds of the present application (for example, may allow oral compounds to be more readily absorbed into the blood), or promote the parent compound to a biological organ or Those compounds that are delivered by a site of action, such as the brain or lymphatic system.
  • prodrug forms are well known in the art. See, Pro-drugs as Novel Delivery Systems by T. Higuchi and V. Stella (1987) Vol. 14 of the ACSSymposium Series, Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical The Association and the discussion on prodrugs are available in Pergamon Press. Design of Prodrugs, Bundgaard, A. Ed., Elseview, 1985 and Method in Enzymology, Widder, K. et al., Ed.; Academic, 1985, vol. 42, p. 309-396; Bundgaard, H.
  • stereoisomer refers to an isomer produced by the different arrangement of atoms in a molecule in space.
  • the compounds of formula I contain asymmetric or chiral centers and, therefore, exist in different stereoisomeric forms. All stereostructures and mixtures of Formula I, including racemic mixtures, are part of the current application.
  • the mixture of diastereomers can be separated into individual diastereomers, based on their different physicochemical properties, using well-known means, for example, resolution of the enantiomers can be carried out with appropriate optically active substances (eg chirality)
  • the alcohol or Mosher ⁇ s molyl chloride reaction is converted to a diastereomer which is separated and converted (e.g., hydrolyzed) to the corresponding single isomer.
  • Some of the compounds of Formula 1 may be atropisomers (e.g., substituted aryl groups) are also part of this application.
  • Enantiomers can also be separated using a chiral column.
  • the compounds of formula I may exist in different tautomeric forms, and such forms are embraced within the scope of the present application. For example, compounds in the form of keto-enol and imine-enamine.
  • immunological activity-related diseases refers to diseases caused by immune problems, including the following diseases: multiple sclerosis, gradual freezing, CIDP, systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis , psoriasis, polymyositis, type I diabetes, hyperthyroidism, scleroderma, myasthenia gravis and other diseases.
  • the compound of the present invention can act preferably on the sphingosine-1-phosphate receptor 1 (S1P1), and when it acts on the sphingosine-1-phosphate receptor 3 (S1P3), side effects such as a slow heart rate are improved.
  • the preparation method of the invention is simple, the reaction conditions are mild, and the product yield is high.
  • the racemic intermediate 6 was resolved by multiple crystallization from D-tartaric acid until the specific optical rotation of the product was no longer increased, and the chiral intermediate 7-1 was obtained.
  • LC-MS: 256,258 [M + 1] +, t R 1.143min.
  • the compound used in the test was synthesized by Beijing Fulong Kangtai Chemical Department.
  • Route of administration intragastric administration, once a day, for 4 consecutive days.
  • the eyelids of the mice were collected into 1.5 ml EP tubes containing anticoagulant and placed on ice; then transferred to a flow tube and centrifuged at 1200 rpm/min for 5 min at 4 ° C; the supernatant was discarded and lysed.
  • Example 16 ⁇ -arrestin test (PathHunter ⁇ -arrestin detection system)
  • the PathHunter beta-arrestin detection system is used to detect the biological activity of a compound.
  • ⁇ -arrestin engineered cells were cultured in a 386-well culture plate and placed in a 37 ° C incubator.
  • the chemiluminescence signal generated in the assay can be detected by a multi-function microplate reader (PerkinElmer EnvisionTM).
  • the DMSO was dissolved in the sample to be tested, and then the sample to be tested was diluted 3 times with the test buffer.
  • the reagent and the positive control were diluted in the same manner.
  • the FLIPRTETRA instrument was used to detect agonist, reagent and positive control reactions.
  • the detection time was 180 seconds in total and was used to evaluate the ability of each compound to activate each compound to activate the GPCR (S1P5).
  • the results are shown in Table 3.
  • the HEK293 engineered cell line stably expressing the hERG potassium channel was used to detect the compound.
  • Patch-clamp detection Cells isolated using TrypLE TM Express Prior to the experiment, the cells were plated 3x10 3 to the cover sheet, cultured in 24-well plates, were detected after 18 hours. Electrophysiological recording of the signal generated by the voltage stimulation of the cellular potassium current.

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Abstract

本发明属于医药领域,具体公开了式I所示的氨基醇衍生物、其药学可接受的盐、溶剂化物、多晶形物或前药。此外,还公开了包含上述物质的药物组合物,及所述物质在制备用于预防和治疗免疫炎症疾病或与免疫活性相关的疾病或病症如多发性硬化症、渐冻症、CIDP、系统性红斑狼疮、类风湿关节炎、溃疡性结肠炎、银屑病、多发性肌炎等中的用途。

Description

氨基醇衍生物、其药物组合物和用途 技术领域
本申请属于医药领域,具体涉及氨基醇衍生物、其药物组合物和用途。
背景技术
免疫系统是机体保护自身的防御性结构,主要由淋巴器官(胸腺、淋巴结、脾、扁桃体)、其它器官内的淋巴组织和全身各处的淋巴细胞、抗原呈递细胞等组成,也包括血液中其它白细胞及结缔组织中的浆细胞和肥大细胞。构成免疫系统的核心成分是淋巴细胞,它使免疫系统具备识别能力和记忆能力。淋巴细胞经血液和淋巴周游全身,从一处的淋巴器官或淋巴组织至另一处的淋巴器官或淋巴组织,使分散各处的淋巴器官和淋巴组织连成一个功能整体。T细胞和B细胞是人体最重要的免疫细胞。免疫系统各组分功能的正常是维持机体免疫功能相对稳定的保证,任何组分的缺陷或功能的亢进都会给机体带来损害。
免疫系统各组分广布全身,错综复杂,特别是免疫细胞和免疫分子在机体内不断地产生、循环和更新。免疫系统具有高度的辨别力,能精确识别自己和非己物质,以维持机体的相对稳定性;同时还能接受、传递、扩大、储存和记忆有关免疫的信息,针对免疫信息发生正和负的应答并不断调整其应答性。然而,免疫系统功能的失调也会对人体极为不利:人体的识别能力异常容易导致过敏现象的发生,反之则会引起反复感染;人体的自我稳定能力异常,会使免疫系统对自身的细胞作出反应,引发自身免疫疾病。
免疫抑制剂是一类在肿瘤化疗、器官移植、免疫病理学和临床免疫学等多学科研究基础上发展起来的新的药剂类别,具有免疫抑制作用,可抑制机体异常的免疫反应,目前广泛应用于器官移植抗排斥反应和自身免疫性疾病的治疗。常见的免疫抑制剂有:环磷酰胺(CTX)、糖皮质激素、硫唑嘌呤、环孢霉素A(CsA)、雷帕霉素、霉酚酸酯等。上述免疫抑制剂由于选择性和特异性的限制,在治疗的同时不可避免地会损伤患者的免疫防卫能力,致使患者抗感染能力下降,恶性病变的危险增加,损伤造血、免疫系统及肝、肾、消化道功能,造成神经和内分泌功能紊乱,并引发某些过敏反应等。因此开发和优化新的免疫抑制剂是新药开发的重要方向。
鞘氨醇-1-磷酸受体1(sphingosine-1-phosphate receptor 1,S1P1,一种GPCR)的激动剂(如FTY720)与靶分子S1P1结合后,使S1P1受体内化,下调S1P1在T细胞表面的表达,抑制靶分子的信号传导途径,从而抑制由激活的T细胞介导的免疫炎症反应。氨基醇衍生物与内生性溶血脂质鞘氨醇具有一些结构上的相似之处。鞘氨醇经由鞘氨醇酶诱导的磷酸化作用形成1-磷酸-鞘氨醇,其受体的激活导致细胞分化和生长以及调整细胞粘附和细胞形态。在正常的免疫反应中,T和B淋巴细胞在淋巴结中增殖。当它们处于淋巴结中时,它们下调S1P1表达,如被激活,就会上调细胞表面S1P1数量,这样可以使T和B 细胞离开淋巴结。淋巴细胞表面的S1P1可以与药物结合,从而下调S1P1的表达,使得淋巴细胞不再具有脱离淋巴结的功能,并粘附于淋巴结内。氨基醇衍生物并没有破坏淋巴细胞的免疫功能,而是通过使淋巴细胞滞留在淋巴系统不能进入血液循环系统,达到抑制免疫反应的效果。
鞘氨醇-1-磷酸受体1激动剂FTY720已由诺华公司研制成功。然而,FTY720不仅作用于鞘氨醇-1-磷酸受体1(S1P1),而且作用于鞘氨醇-1-磷酸受体3(S1P3),具有导致心率过缓等副作用。因此,需要开发受体选择性更好的S1P1激动剂成为本领域的一个重要研究方向。
发明内容
为了改善现有技术中存在的上述问题,本发明提供如下式I所示的氨基醇衍生物、其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药:
Figure PCTCN2018092233-appb-000001
其中,R 1、R 2相同或不同,彼此独立地选自H、-F、-Cl、-Br、-I、-OH、-SH、-CN、-COOH、-NO 2,无取代或任选被一个或多个R a取代的下列基团:C 1-40烷基、C 1- 40烷氧基、C 2- 40烯基、C 2- 40炔基、C 3- 20环烷基、C 3- 20环烷基氧基、3-20元杂环基、3-20元杂环基氧基、C 6- 20芳基、C 6- 20芳基氧基、5-20元杂芳基、5-20元杂芳基氧基、H[(CH 2) nO] m-、-NR dR e、-CONR dR e或-C(O)Y 1R d
R 3选自无取代或任选被一个或多个R b取代的下列基团:C 3- 20环烷基、3-20元杂环基、C 6- 20芳基、5-20元杂芳基;
每一个R a相同或不同,彼此独立地选自C 1- 40烷基、C 1- 40烷氧基、C 2- 40烯基、C 2- 40炔基、C 3- 20环烷基、-F、-Cl、-Br、-I、-OH、-NH、-SH、-CN、=O或-COOH;
每一个R b相同或不同,彼此独立地选自-F、-Cl、-Br、-I、-SH、-OH、-CN、-COOH、无取代或任选被一个或多个被R a取代的下列基团:C 1-40烷基、C 1- 40烷氧基、C 2- 40烯基、C 2- 40炔基、C 3- 20环烷基、3-20元杂环基、C 6- 20芳基、5-20元杂芳基、C 3- 20环烷基氧基、3-20元杂环基氧基、C 6- 20芳基氧基、5-20元杂芳基氧基、C 3- 20环烷基C 1-40烷基、3-20元杂环基C 1-40烷基、C 6- 20芳基C 1-40烷基、5-20元杂芳基C 1-40烷基、H[(CH 2) nO] n-、-NR cR d、-C(O)NR cR d、-Y 1C(O)R e或-C(O)Y 1R e
或者,当R 3被两个或更多个相同或不同的R b取代时,其中两个R b可以分别脱去各自的H或其他基团,并与其所连接的碳原子一起形成与R 3稠合的环系R s,其中R s选自与R 3稠合的C 3- 20环烷基、3-20元杂环基、C 6- 20芳基、5-20元杂芳基;
R c、R d、R e相同或不同,彼此独立地选自H,或无取代或任选被一个或多个R a取代的下列基团:C 1- 40烷基、C 2- 40烯基、C 2- 40炔基、C 3- 20环烷基、3-20元杂环基、C 6- 20芳基、5-20元杂芳基或CONH 2
Y 1选自化学键、-O-、-S-,无取代或任选被一个或多个R a取代的-NH-、C 1- 40烷基、C 1- 40烷氧基、C 3-20环烷基、3-20元杂环基、C 6- 20芳基、5-20元杂芳基或(CH 2CH 2O) j-;
m、n、j可以相同或不同,彼此独立地选自1以上的整数,例如1~20的整数,如1、2、3、4、5、6、7、8、9或10。
根据本发明的实施方案,其中,R 1、R 2可以相同或不同,彼此独立地选自H、-F、-Cl、-Br、-I、-OH、-SH、-CN、-COOH或C 1-40烷基,例如R 1、R 2选自H或C 1-40烷基;
R 3可以选自无取代或任选被一个或多个R b取代的下列基团:C 3- 8环烷基、3-8元杂环基、C 6- 10芳基、5-6元杂芳基;
每一个R b相同或不同,彼此独立地选自-F、-Cl、-Br、-I、-SH、-OH、-CN、-COOH、无取代或任选被一个或多个被R a取代的下列基团:C 1-6烷基、C 1- 6烷氧基、C 3- 8环烷基、3-8元杂环基、C 6- 10芳基、5-6元杂芳基、C 3- 8环烷基氧基、3-8元杂环基氧基、C 6- 10芳基氧基、5-6元杂芳基氧基、C 3- 8环烷基C 1-6烷基、3-8元杂环基C 1-6烷基、C 6- 10芳基C 1-6烷基、5-6元杂芳基C 1-6烷基、H[(CH 2) nO] n-、-NR cR d、-C(O)NR cR d、-Y 1C(O)R e或-C(O)Y 1R e
或者,当R 3被两个或更多个相同或不同的R b取代时,其中两个R b可以分别脱去各自的H或其他基团,并与其所连接的碳原子一起形成与R 3稠合的环系R s,其中R s选自与R 3稠合的C 3- 8环烷基、3-8元杂环基、C 6- 10芳基、5-6元杂芳基;
根据本发明的实施方案,R 3可以选自苯基、吡啶基、吡嗪基、环己基、哌啶基、哌嗪基;
作为实例,R 3可以选自苯基、吡啶-1-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基;
根据本发明的实施方案,每一个R b可以在R 3上的任何适宜位置取代,例如在R 3的1、2、3或4-位取代;
根据本发明的实施方案,每一个R b可以相同或不同,彼此独立地选自-F、-Cl、-Br、-I、-SH、-OH、-CN、-COOH、无取代或任选被一个或多个被R a取代的下列基团:C 1-6烷基(如甲基、乙基、丙基、异丙基、叔丁基)、C 1-6烷氧基(如甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基)、C 3-6环烷基、C 3-6环烷基氧基、C 1-6烷基羰基氨基、C 1-6烷基氧基羰基、C 1-6烷基羰基氧基、3-6元杂环基C 1-6烷基、-CONH 2、-NHCOCH 3
作为实例,每一个R b可以相同或不同,彼此独立地选自-F、-OH、-CN、-CF 3、-COOH、-CONH 2、甲氧基、乙氧基、丙氧基、异丙氧基、-NHCOCH 3、环戊基、-C(O)OCH 3、氮杂环丁烷-1-基甲基、吡咯烷-1-基甲基、哌啶-1-基甲基;
或者,当R 3被两个或更多个相同或不同的R b取代时,其中两个R b可以分别脱去各自的H或其他基团,并与其所连接的碳原子一起形成与R 3稠合的环系R s,其中R s选自与 R 3稠合的二氧杂环戊烯环系。
根据本发明的实施方案,其中当R 3为苯基时,R 3优选至少在3-位被R b3取代,其中R b3为拉电子取代基;
根据本发明进一步的实施方案,其中当R 3为苯基时,R 3优选至少在4-位被R b4取代,其中R b4为给电子取代基。
作为实例,R b3可以选自-Cl、-Br、-I、-SH、-OH、-CN、-COOH、-CONH 2、-COC 1-6烷基、-COC 3-6环烷基、-CF 3
作为实例,R b4可以选自C 1-6烷基(如甲基、乙基、丙基、异丙基、叔丁基)、C 1-6烷氧基(如甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基)、C 3-6环烷基、C 3-6环烷基氧基、C 1-6烷基羰基氨基。
根据本发明式I所示的氨基醇衍生物,其可具有如下式I’所示的结构:
Figure PCTCN2018092233-appb-000002
作为一个实施方案,本发明的式I化合物可以选自如下化合物:
Figure PCTCN2018092233-appb-000003
Figure PCTCN2018092233-appb-000004
本发明还提供如上式I所示氨基醇衍生物的制备方法,包括如下步骤a至f中的一步或多步:
Figure PCTCN2018092233-appb-000005
其中,R 1、R 2、R 3具有如上所述的定义;
X选自卤素;
PG 1选自羟基保护基;
PG 2选自氨基保护基;
或者,PG 1和PG 2可以彼此键合以对羟基和羰基同时进行保护。
根据本发明制备方法的实施方案,其中:
步骤a中,可以使用D-酒石酸作为拆分试剂,得到化合物7;
步骤b中,化合物7可以先在PhCHO和NaBH(OAc) 3的存在下对氨基进行保护,然后在CH 3OC(CH 3) 2OCH 3和酸的存在下得到化合物8;
步骤c中,化合物8在n-BuLi、CO 2的存在下,在-78℃下反应,得到化合物9;
步骤d中,化合物9可以先与草酰氯反应,然后与下式所示的化合物10在三乙胺的存在下反应,得到化合物11;
Figure PCTCN2018092233-appb-000006
步骤e中,化合物11在TsCl和三乙胺的存在下反应,得到化合物12;
步骤f)中,在脱保护的条件下脱去氨基和羟基的保护基PG 1和PG 2,例如在酸的存 在下脱去羟基保护基;以及在还原条件下脱去氨基保护基。
根据本发明制备方法的一个实施方案,可包括如下步骤:
Figure PCTCN2018092233-appb-000007
本发明还提供一种药物组合物,包含本发明式I所示的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药,以及药学上可接受的载体。
根据本发明,所述药物组合物可以为包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型的形式。
在一些实施方案中,所述药物组合物可以是口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液,用于胃肠外注射的无菌溶液、悬浮液或乳液,用于外用的软膏或乳膏,或者用于直肠给药的栓剂。
在其它实施方案中,所述药物组合物为适合单次施予精确剂量的单位剂型。
在其它实施方案中,所述化合物的量在约0.001mg/kg体重/天-约1000mg/kg体重/天的范围内。
在其它实施方案中,所述化合物的量的范围为约0.5mg/kg体重/天-约50mg/kg体重/天。
在一些实施方案中,所述化合物的量为约0.001g/天-约7g/天。
在其它实施方案中,所述化合物的量为约0.002g/天-约6g/天。
在其它实施方案中,所述化合物的量为约0.005g/天-约5g/天。
在其它实施方案中,所述化合物的量为约0.01g/天-约5g/天。
在其它实施方案中,所述化合物的量为约0.02g/天-约5g/天。
在其它实施方案中,所述化合物的量为约0.05g/天-约2.5g/天。
在其它实施方案中,所述化合物的量为约0.1g/天-约1g/天。
在其它实施方案中,低于上述范围下限的剂量水平可能已经是足够的。
在其它实施方案中,可能需要高于上述范围上限的剂量水平。
在一些实施方案中,以单剂量施用所述化合物,每天一次。
在其它实施方案中,以多剂量施用所述化合物,每天不止一次。
在一些实施方案中,每天施用两次所述化合物。
在其它实施方案中,每天施用三次所述化合物。
在其它实施方案中,每天施用四次所述化合物。
在其它实施方案中,每天施用四次以上的所述化合物。
在一些实施方案中,所述药物组合物施用于的个体为哺乳动物。
在其它实施方案中,所述哺乳动物是人。
在其它实施方案中,所述药物组合物还包含至少另一种治疗剂(即制成一种剂型)。
在一些实施方案中,所述药物组合物和至少一种治疗剂分别以独立的剂型组合成组合产品,如套装药品(kit of part)。
本发明还提供如上式I所示的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药在制备下调S1P1的表达的药物中的应用。
本发明还提供如上式I所示的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药用于下调S1P1的表达。
本申请还提供了一种调节(如下调)S1P1活性的方法,其中包括将S1P1与有效量的上述化合物或其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药接触。
优选地,该方法可以用于体内,也可以用于体外。
本发明还提供如上式I所示的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药在制备用于预防和治疗与免疫炎症相关的疾病药物中的应用。
本申请还提供如上式I所示的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药用于治疗或预防治疗与免疫炎症相关的疾病或病症。
本申请还提供如上式I所示的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药在制备用于治疗或预防治疗与免疫活性相关的疾病或病症的药物中的用途。
本申请还提供一种治疗与免疫活性相关的疾病或病症的方法,所述方法包括将有效量的如上式I所示的氨基醇衍生物或其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药施用于有此需求的个体。
根据本发明,所述个体可以为哺乳动物,如人类。
根据本发明的实施方案,所述与免疫活性相关的疾病或病症可以为多发性硬化症、渐冻症、慢性炎性脱髓鞘性多发性神经根神经病(CIDP)、系统性红斑狼疮、类风湿关节炎、溃疡性结肠炎、银屑病、多发性肌炎、I型糖尿病、甲状腺机能亢进、硬皮病、重症 肌无力等疾病中的一种或多种。
术语定义和说明
除非另有定义,否则本文所有科技术语具有的涵义与权利要求主题所属领域技术人员通常理解的涵义相同。除非另有说明,本文全文引用的所有专利、专利申请、公开材料通过引用方式整体并入本文。如果本文对术语有多个定义,以本章的定义为准。
应理解,上述简述和下文的详述为示例性且仅用于解释,而不对本申请主题作任何限制。在本申请中,除非另有具体说明,否则使用单数时也包括复数。还应注意,除非另有说明,否则所用“或”、“或者”表示“和/或”。此外,所用术语“包括”以及其它形式,例如“包含”、“含”和“含有”并非限制性。
本申请说明书和权利要求书记载的数值范围,当该数值范围被定义为“整数”时,应当理解为记载了该范围的两个端点以及该范围内的每一个整数。例如,“0~10的整数”应当理解为记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数。当该数值范围被定义为“数”时,应当理解为记载了该范围的两个端点、该范围内的每一个整数以及该范围内的每一个小数。例如,“0~10的数”应当理解为不仅记载了0、1、2、3、4、5、6、7、8、9和10的每一个整数,还至少记载了其中每一个整数分别与0.1、0.2、0.3、0.4、0.5、0.6、0.7、0.8、0.9的和。
应当理解,可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4 TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明,否则采用本领域技术范围内的常规方法,如质谱、NMR、IR和UV/Vis光谱法和药理学方法。除非提出具体定义,否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送,以及对患者的治疗中使用标准技术。例如,可利用厂商对试剂盒的使用说明,或者按照本领域公知的方式或本申请的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述,按照本领域熟知的常规方法实施上述技术和方法。在本说明书中,可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。当通过从左向右书写的常规化学式描述取代基时,该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言,CH 2O等同于OCH 2
术语“任选/任意”或“任选地/任意地”是指随后描述的事件或情况可能发生或可能不发生,该描述包括发生所述事件或情况和不发生所述事件或情况。
术语“卤素”指F、Cl、Br和I。换言之,F、Cl、Br和I在本说明书中可描述为“卤素”。
术语“C 1-40烷基”应理解为优选表示具有1~40个碳原子的直连或支链饱和一价烃基,优选为C 1-10烷基。“C 1-10烷基”应理解为优选表示具有1、2、3、4、5、6、7、8、9或10个碳原子的直连或支链饱和一价烃基。所述烷基是例如甲基、乙基、丙基、丁基、戊基、 己基、异丙基、异丁基、仲丁基、叔丁基、异戊基、2-甲基丁基、1-甲基丁基、1-乙基丙基、1,2-二甲基丙基、新戊基、1,1-二甲基丙基、4-甲基戊基、3-甲基戊基、2-甲基戊基、1-甲基戊基、2-乙基丁基、1-乙基丁基、3,3-二甲基丁基、2,2-二甲基丁基、1,1-二甲基丁基、2,3-二甲基丁基、1,3-二甲基丁基或1,2-二甲基丁基等或它们的异构体。特别地,所述基团具有1、2、3、4、5、6、个碳原子(“C 1-6烷基”),例如甲基、乙基、丙基、丁基、异丙基、异丁基、仲丁基、叔丁基,更特别地,所述基团具有1、2或3个碳原子(“C 1-3烷基”),例如甲基、乙基、正丙基或异丙基。
术语“C 2-40烯基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个双键并且具有2~40个碳原子,优选“C 2-10烯基”。“C 2-10烯基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个双键并且具有2、3、4、5、6、7、8、9或10个碳原子,特别是2或3个碳原子(“C 2-3烯基”),应理解,在所述烯基包含多于一个双键的情况下,所述双键可相互分离或者共轭。所述烯基是例如乙烯基、烯丙基、(E)-2-甲基乙烯基、(Z)-2-甲基乙烯基、(E)-丁-2-烯基、(Z)-丁-2-烯基、(E)-丁-1-烯基、(Z)-丁-1-烯基、戊-4-烯基、(E)-戊-3-烯基、(Z)-戊-3-烯基、(E)-戊-2-烯基、(Z)-戊-2-烯基、(E)-戊-1-烯基、(Z)-戊-1-烯基、己-5-烯基、(E)-己-4-烯基、(Z)-己-4-烯基、(E)-己-3-烯基、(Z)-己-3-烯基、(E)-己-2-烯基、(Z)-己-2-烯基、(E)-己-1-烯基、(Z)-己-1-烯基、异丙烯基、2-甲基丙-2-烯基、1-甲基丙-2-烯基、2-甲基丙-1-烯基、(E)-1-甲基丙-1-烯基、(Z)-1-甲基丙-1-烯基、3-甲基丁-3-烯基、2-甲基丁-3-烯基、1-甲基丁-3-烯基、3-甲基丁-2-烯基、(E)-2-甲基丁-2-烯基、(Z)-2-甲基丁-2-烯基、(E)-1-甲基丁-2-烯基、(Z)-1-甲基丁-2-烯基、(E)-3-甲基丁-1-烯基、(Z)-3-甲基丁-1-烯基、(E)-2-甲基丁-1-烯基、(Z)-2-甲基丁-1-烯基、(E)-1-甲基丁-1-烯基、(Z)-1-甲基丁-1-烯基、1,1-二甲基丙-2-烯基、1-乙基丙-1-烯基、1-丙基乙烯基、1-异丙基乙烯基。
术语“C 2-40炔基”应理解为表示直连或支链的一价烃基,其包含一个或多个三键并且具有2~40个碳原子,优选“C 2-C 10炔基”。术语“C 2-C 10炔基”应理解为优选表示直连或支链的一价烃基,其包含一个或多个三键并且具有2、3、4、5、6、7、8、9或10个碳原子,特别是2或3个碳原子(“C 2-C 3-炔基”)。所述炔基是例如乙炔基、丙-1-炔基、丙-2-炔基、丁-1-炔基、丁-2-炔基、丁-3-炔基、戊-1-炔基、戊-2-炔基、戊-3-炔基、戊-4-炔基、己-1-炔基、己-2-炔基、己-3-炔基、己-4-炔基、己-5-炔基、1-甲基丙-2-炔基、2-甲基丁-3-炔基、1-甲基丁-3-炔基、1-甲基丁-2-炔基、3-甲基丁-1-炔基、1-乙基丙-2-炔基、3-甲基戊-4-炔基、2-甲基戊-4-炔基、1-甲基戊-4-炔基、2-甲基戊-3-炔基、1-甲基戊-3-炔基、4-甲基戊-2-炔基、1-甲基戊-2-炔基、4-甲基戊-1-炔基、3-甲基戊-1-炔基、2-乙基丁-3-炔基、1-乙基丁-3-炔基、1-乙基丁-2-炔基、1-丙基丙-2-炔基、1-异丙基丙-2-炔基、2,2-二甲基丁-3-炔基、1,1-二甲基丁-3-炔基、1,1-二甲基丁-2-炔基或3,3-二甲基丁-1-炔基。特别地,所述炔基是乙炔基、丙-1-炔基或丙-2-炔基。
术语“C 3-20环烷基”应理解为表示饱和的一价单环或双环烃环,其具有3~20个碳原子,优选“C 3-10环烷基”。术语“C 3-10环烷基”应理解为表示饱和的一价单环或双环烃环,其具有 3、4、5、6、7、8、9或10个碳原子。所述C 3-10环烷基可以是单环烃基,如环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基或环癸基,或者是双环烃基如十氢化萘环。
术语“3-20元杂环基”意指饱和的一价单环或双环烃环,其包含1-5个独立选自N、O和S的杂原子,优选“3-10元杂环基”。术语“3-10元杂环基”意指饱和的一价单环或双环烃环,其包含1-5个,优选1-3个选自N、O和S的杂原子。所述杂环基可以通过所述碳原子中的任一个或氮原子(如果存在的话)与分子的其余部分连接。特别地,所述杂环基可以包括但不限于:4元环,如氮杂环丁烷基、氧杂环丁烷基;5元环,如四氢呋喃基、二氧杂环戊烯基、吡咯烷基、咪唑烷基、吡唑烷基、吡咯啉基;或6元环,如四氢吡喃基、哌啶基、吗啉基、二噻烷基、硫代吗啉基、哌嗪基或三噻烷基;或7元环,如二氮杂环庚烷基。任选地,所述杂环基可以是苯并稠合的。所述杂环基可以是双环的,例如但不限于5,5元环,如六氢环戊并[c]吡咯-2(1H)-基环,或者5,6元双环,如六氢吡咯并[1,2-a]吡嗪-2(1H)-基环。含氮原子的环可以是部分不饱和的,即它可以包含一个或多个双键,例如但不限于2,5-二氢-1H-吡咯基、4H-[1,3,4]噻二嗪基、4,5-二氢噁唑基或4H-[1,4]噻嗪基,或者,它可以是苯并稠合的,例如但不限于二氢异喹啉基、1,3-苯并噁唑基、1,3-苯并二氧杂环戊烯基。根据本发明,所述杂环基是无芳香性的。
术语“C 6-20芳基”应理解为优选表示具有6~20个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环,优选“C 6-14芳基”。术语“C 6-14芳基”应理解为优选表示具有6、7、8、9、10、11、12、13或14个碳原子的一价芳香性或部分芳香性的单环、双环或三环烃环(“C 6-14芳基”),特别是具有6个碳原子的环(“C 6芳基”),例如苯基;或联苯基,或者是具有9个碳原子的环(“C 9芳基”),例如茚满基或茚基,或者是具有10个碳原子的环(“C 10芳基”),例如四氢化萘基、二氢萘基或萘基,或者是具有13个碳原子的环(“C 13芳基”),例如芴基,或者是具有14个碳原子的环(“C 14芳基”),例如蒽基。
术语“5-20元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5~20个环原子且包含1-5个独立选自N、O和S的杂原子,例如“5-14元杂芳基”。术语“5-14元杂芳基”应理解为包括这样的一价单环、双环或三环芳族环系:其具有5、6、7、8、9、10、11、12、13或14个环原子,特别是5或6或9或10个碳原子,且其包含1-5个,优选1-3各独立选自N、O和S的杂原子并且,另外在每一种情况下可为苯并稠合的。特别地,杂芳基选自噻吩基、呋喃基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、异噁唑基、异噻唑基、噁二唑基、三唑基、噻二唑基、噻-4H-吡唑基等以及它们的苯并衍生物,例如苯并呋喃基、苯并噻吩基、苯并噁唑基、苯并异噁唑基、苯并咪唑基、苯并三唑基、吲唑基、吲哚基、异吲哚基等;或吡啶基、哒嗪基、嘧啶基、吡嗪基、三嗪基等,以及它们的苯并衍生物,例如喹啉基、喹唑啉基、异喹啉基等;或吖辛因基、吲嗪基、嘌呤基等以及它们的苯并衍生物;或噌啉基、酞嗪基、喹唑啉基、喹喔啉基、萘啶基、蝶啶基、咔唑基、吖啶基、吩嗪基、吩噻嗪基、吩噁嗪基等。
除非另有说明,杂环基、杂芳基或亚杂芳基包括其所有可能的异构形式,例如其位置异构体。因此,对于一些说明性的非限制性实例,吡啶基或亚吡啶基包括吡啶-2-基、亚吡啶-2-基、吡啶-3-基、亚吡啶-3-基、吡啶-4-基和亚吡啶-4-基;噻吩基或亚噻吩基包括噻吩-2-基、亚噻吩-2-基、噻吩-3-基和亚噻吩-3-基。
上述对术语“烷基”,如“C 1-40烷基”的定义同样适用于含有“C 1-40烷基”的其他术语,例如术语“C 1-40烷基氧基”、“C 1-40烷氧基”、“C 1-40烷基硅基”和“C 1-40烷基硅基氧基”等。同样地,上述对术语“C 2-40烯基”、“C 2- 40炔基”、“C 3-20环烷基”、“C 5-20环烯基”、“3-20元杂环基”、“C 6-20芳基”和“5-20元杂芳基”的定义相应地同样适用于含有其的其他术语,如术语“C 2-40烯基氧基”、C 2-40炔基氧基”、“C 3-20环烷基氧基”、“3-20元杂环基”、“3-20元杂环基氧基”、“C 6-20芳基氧基”、“C 6-20芳基烷基”和“5-20元杂芳基烷基”等。
本发明使用的术语“保护基”指临时的取代基,其保护具有潜在反应性的官能团而使之不会发生不期望的化学转化。在任何用于制备本发明化合物的方法中,可能必需和/或期望保护任何有关分子上的敏感或反应性基团。这可通过已知的保护基来实现,如本领域教科书或工具书描述的保护基。可使用本领域已知的方法在方便的后续阶段移除保护基团。本领域技术人员将认识到,取决于具体的保护基团,可将其他试剂用于该去保护步骤,包括但不限于Pd/C、Pd(OH) 2、PdCl 2、Pd(OAc) 2/Et 3SiH、兰尼镍、适当选择的酸、适当选择的碱、氟化物等等。
本文所用的有关术语“受试者”、“患者”或“个体”是指患有疾病、病症或病况等的个体,包括哺乳动物和非哺乳动物。哺乳动物的实施例包括但不限于哺乳动物纲的任何成员:人,非人的灵长类动物(例如黑猩猩和其它猿类和猴);家畜,例如牛、马、绵羊、山羊、猪;家养动物,例如兔、狗和猫;实验室动物,包括啮齿类动物,例如大鼠、小鼠和豚鼠等。非人哺乳动物的实施例包括但不限于鸟类和鱼类等。在本文提供的一个有关方法和组合物的实施方式中,所述哺乳动物为人。
本文所用的术语“治疗”和其它类似的同义词包括缓解、减轻或改善疾病或病症症状,预防其它症状,改善或预防导致症状的潜在代谢原因,抑制疾病或病症,例如阻止疾病或病症的发展,缓解疾病或病症,使疾病或病症好转,缓解由疾病或病症导致的症状,或者中止疾病或病症的症状,此外,该术语包含预防的目的。该术语还包括获得治疗效果和/或预防效果。所述治疗效果是指治愈或改善所治疗的潜在疾病。此外,对与潜在疾病相关的一种或多种生理症状的治愈或改善也是治疗效果,例如尽管患者可能仍然受到潜在疾病的影响,但观察到患者情况改善。就预防效果而言,可向具有患特定疾病风险的患者施用所述组合物,或者即便尚未做出疾病诊断,但向出现该疾病的一个或多个生理症状的患者施用所述组合物。
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解,或生物系统的任何其它所需变化。例如,用于治 疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、外用和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术,例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.;Pergamon;and Remington's,Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方式中,本文讨论的化合物和组合物通过口服施用。
本文针对制剂、组合物或成分所用术语“可接受的”是指对接受治疗的受试者的一般健康情况没有长期的有害影响。
本文所用术语“药学上可接受的”是指不影响本申请化合物的生物活性或性质的物质(如载体或稀释剂),并且相对无毒,即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。
本文所用术语“药物组合物”是指任选地混合有至少一种药学上可接受的化学成分的生物活性化合物,所述药学上可接受的化学成分包括但不限于载体、稳定剂、稀释剂、分散剂、悬浮剂、增稠剂和/或赋形剂。
本文所用术语“载体”是指相对无毒的化学化合物或试剂,其有助于将化合物引入到细胞或组织中。
本文所用术语“药学上可接受的盐”是指保留了指定化合物的游离酸和游离碱的生物效力,并且在生物学或其它方面上没有不良作用的盐。本申请化合物还包括药学上可以接受的盐。药学上可接受的盐是指把母体化合物中的碱基基团转换成盐的形式。药学上可接受的盐包括,但不仅限于,碱基基团例如胺(氨)基的无机或有机酸盐类。本申请药学上可接受的盐可以由母体化合物合成,即母体化合物中的碱性基团与1-4当量的酸在一个溶剂系统中反应。合适的盐列举在Remingtong’s Pharmaceutical Scicences,17 thed.,Mack Publishing Company,Easton,Pa.,1985,p.1418和Journal of Pharmaceutical Science,66,2(1977)中,例如盐酸盐。
除特别指示外,本申请中的盐指用有机酸/无机酸形成的酸式盐,以及用有机碱/无机碱形成的碱式盐。另外,当式I化合物的碱性官能团是吡啶或咪唑(但不限制于吡啶或咪唑),酸性官能团是羧酸(但不限制于羧酸)时就会形成两性离子(内盐),内盐也包括在本申请中的盐内。
本文所用术语“溶剂化物”是指通过溶剂化作用形成的本申请化合物与溶剂分子的组合。在某些情况下,溶剂化物指水合物,即溶剂分子为水分子,本申请化合物与水的组合形成水合物。本申请中的一个或多个化合物可能以溶剂化物的形式存在,就像与医药学上可接受的水、乙醇等溶剂形成的溶剂化物形式一样,因此,本申请包括溶剂化物和非溶剂 化物两种形式。“溶剂化物”指本申请中的一个化合物与一个或多个溶剂分子形成的物理聚集体,这个物理聚集体包括离子的不同程度和共价键,例如氢键。已证实这个溶剂化物可以被分离,例如,当晶体的晶格中混有一个或多个溶剂分子时。“溶剂化物”包括溶剂相和可分离的溶剂化物两部分。相应的溶剂化物例子有很多,包括乙醇溶剂化物、甲醇溶剂化物等。“水合物”是一种以水(H 2O)分子为溶剂的溶剂化物。
本申请中的一个或多个化合物都可以随意的制备成溶剂化物。溶剂化物的制备众所周知。例如M.Caira et al,J.Pharmaceutical Sci.,93(3),601-611(2004)中描述了抗真菌药氟康唑的溶剂化物的制备,即用乙酸乙酯和水制备。E.C.van Tonder et al,AAPS PharmSciTech.,5(1),article 12(2004);和A.L.Bingham et al,Chem.Commun.,603-604(2001)中也描述了溶剂化物、水合物的类似制备方法。一种典型的、非限制性的制备过程是在高于常温的温度时将发明的化合物溶解于所需要量的理想溶剂中(有机溶剂或水或它们的混合溶剂),降温,放置析晶,然后用标准的方法分离挑出晶体。用I.R.光谱学分析技术可以证实结晶中形成溶剂化物(水合物)的溶剂(水)的存在。
本文所用术语“多晶型物”或“多晶形”是指以不同的晶格形式存在的本申请化合物。
本文所使用的术语“同位素标记物”是指有同位素标记的本申请化合物。例如本申请的化合物中的同位素包括H,C,N,O,P,F,S的各种同位素,如 2H, 3H, 13C, 14C, 15N, 18O, 17O, 31P, 32P, 35S, 18F和 36S。
本文所使用术语“药学上可接受的前药”是指本申请化合物的任何药学上可接受的盐、酯、酯的盐或其它衍生物,其在向受体施用后能够直接或间接地提供本申请的化合物或其具有药学活性的代谢物或残基。特别优选的衍生物或前药是在施用于患者时可以提高本申请化合物生物利用度的那些化合物(例如,可以使口服的化合物更易于被吸收到血液中),或者促进母体化合物向生物器官或作用位点(例如脑部或淋巴系统)递送的那些化合物。
各种前药形式是本领域熟知的。参见,在T.Higuchi和V.Stella所著的Pro-drugs as Novel Delivery Systems(1987)Vol.14of the A.C.S.Symposium Series,Bioreversible Carriers in Drug Design,(1987)Edward B.Roche,ed.,American Pharmaceutical Association和在Pergamon Press中提供了有关前药的讨论。Design of Prodrugs,Bundgaard,A.Ed.,Elseview,1985and Method in Enzymology,Widder,K.et al.,Ed.;Academic,1985,vol.42,p.309-396;Bundgaard,H."Design and Application of Prodrugs"in A Textbook of Drug Design and Development,Krosgaard-Larsen and H.Bundgaard,Ed.,1991,第五章,113-191页;以及Bundgaard,H.,Advanced Drug Delivery Review,1992,8,1-38,以上文献通过引用并入本文。
本文使用的“立体异构体”是指由分子中原子在空间上排列方式不同所产生的异构体。式I化合物含有不对称或手性中心,因此,存在不同的立体异构形式。分子式I的所有立体结构和混合物一样,包括外消旋混合物,作为目前申请的一部分。非对映体混合物能够分离成单独的非对映体,基于它们不同的物理化学性质,采用众所周知的手段,例如,对映异构体的拆分可通过与适当的光学活性物质(例如手性醇或Mosher`s莫氏酰氯)反应 转换为非对映异构体,将其分离并转化(如水解)为相对应的单一的异构体。式1中的一些化合物可能是阻转异构体(如取代芳基)也是本申请中的一部分。对映异构体也可利用手性色谱柱分离。式I中的化合物可能存在着不同的互变异构形式,这些形式都包含在本申请范围内。例如,酮-烯醇和亚胺-烯胺形式的化合物。
本文所用的“免疫活性相关的疾病”是指因免疫问题引起的疾病,主要包括以下这些疾病:多发性硬化症、渐冻症、CIDP、系统性红斑狼疮、类风湿关节炎、溃疡性结肠炎、银屑病、多发性肌炎、I型糖尿病、甲状腺机能亢进、硬皮病、重症肌无力等疾病。
本发明的有益效果:
本发明的化合物可较好作用于鞘氨醇-1-磷酸受体1(S1P1),而且作用于鞘氨醇-1-磷酸受体3(S1P3)时,心率过缓等副作用得到改善。并且,本发明的制备方法简单,反应条件温和,产品收率较高。
具体实施方式
下文将结合具体实施例对本发明的通式化合物及其制备方法和应用做更进一步的详细说明。应当理解,下列实施例仅为示例性地说明和解释本发明,而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明,以下实施例中使用的原料和试剂均为市售商品,或者可以通过已知方法制备。
合成过程中的LC-MS分析条件如下:
仪器:Agilent LCMS1260/MSD6120
色谱柱:Agilent SB-C18,2.1*50mm,1.8μm,SN:USWEY07289
流动相:A:H 2O(0.1%FA)90%,B:乙腈10%,0.400mL/min,45.00℃
时间表
时间 函数               参数
2.24 更改溶剂组分       溶剂组分 A:0.0% B:100.0%
3.00 更改溶剂组分       溶剂组分 A:0.0% B:100.0%
3.01 更改流量           流量:0.5mL/min
3.01 更改溶剂组分       溶剂组分 A:90.0% B:10.0%
5.00 更改溶剂组分       溶剂组分 A:90.0% B:10.0%
5.01 更改流量           流量:0.4mL/min
5.01 更改溶剂组分       溶剂组分 A:90.0% B:10.0%。
仪器参数:
电离模式                :API-ES
极性                     :正
碰撞诱导解离阶升         :已禁用
循环时间百分比           :50.00%。
制备例1
Figure PCTCN2018092233-appb-000008
中间体2的合成:
将100g(465mmol)化合物1溶于500mL二氯甲烷中,冰盐浴冷却至0℃,滴加120g(930mmol)草酰氯,滴毕,加热至回流反应2小时。TLC检测反应结束后,蒸干溶剂,加入二氯甲烷再次蒸干,获得黄色液体中间体112g,直接用于下一步反应。将210g(1410mmol)三氯化铝悬浮于400mL二氯甲烷中,冷却至-10℃~-5℃,滴加上述所得的112g中间体溶于100mL二氯甲烷的溶液,滴毕向反应体系通入乙烯气约2小时,保持-10℃~-5℃。TLC检测反应结束后,将反应液倒入冰水混合液中,用二氯甲烷萃取,合并有机相,用饱和碳酸氢钠洗涤2次,饱和氯化钠洗涤1次,干燥,蒸干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=5/1,V/V)获得产品85g,橙红色液体,产率81.7%。LC-MS:225,227[M+1] +,t R=2.153min。
中间体3的合成:
在氮气保护下,将25.5g(113mmol)中间体2溶于20mL二氯甲烷中,加入1.78g(5.6mmol)碘化锌,水浴冷却下滴加20.7mL(167mmol)三甲基硅氰,室温搅拌反应3小时,TLC检测反应结束后,加入80mL 20%氨气甲醇溶液,室温搅拌3天。停止反应,蒸干反应液,剩余物中加入100mL 11%氯化氢甲醇溶液,搅拌30分钟,加入甲基叔丁基醚400mL,搅拌30分钟,过滤,获得产品27.9g,浅黄白色固体,产率85.5%。LC-MS:251,253[M+1] +,t R=1.731min。
中间体4的合成:
将30g(102mmol)中间体3悬浮于150mL 50%硫酸(V:V)中,加热至150℃反应3小时。HPLC检测反应完全,冷却至室温,放入4℃冰箱过夜,过滤,滤饼用浓盐酸洗涤,在干燥器中抽干,获得产品32g,浅棕色固体,产率100%。LC-MS:270,272[M+1] +,t R=1.382min。
中间体5的合成:
在0℃下,将12.1g(102mmol)氯化亚砜滴加到200mL甲醇中,搅拌1小时后,加入25g(34mmol)中间体4,加热至回流反应15小时。HPLC检测,反应结束后,蒸干反应液,用饱和碳酸氢钠调节pH=8,水层用二氯甲烷萃取,合并有机相,干燥,蒸干,获得产品9g,红棕色油状物,产率91.1%。LC-MS:284,286[M+1] +,t R=1.507min。
中间体6的制备:(2-氨基-7-溴-1,2,3,4-四氢萘-2-基)甲醇
将4.8g(126mmol)氢化铝锂悬浮200mL四氢呋喃中,冷却至-10℃,滴加18g(63mmol)中间体5溶于100mL四氢呋喃的溶液,滴毕,-10℃下反应30分钟。TLC检测,反应结束后,向反应体系依次加入4.8mL水、14.4mL 10%氢氧化钠溶液、24mL水,搅拌20分钟,加入70g无水硫酸钠,搅拌30分钟,静置过夜。过滤,干燥,蒸干,获得产品17g,黑色油状物,产率100%。LC-MS:256,258[M+1] +,t R=1.143min。
中间体7-1的制备:(S)-(2-氨基-7-溴-1,2,3,4-四氢萘-2-基)甲醇
将消旋的中间体6用D-酒石酸多次结晶拆分,直至产品的比旋光度不再提高,得到手性中间体7-1,比旋光度[α] D 20=27(C=1,MeOH)。LC-MS:256,258[M+1] +,t R=1.143min。
中间体8-1的合成:
将17g(66.mmol)中间体7-1和7.75g(73mmol)苯甲醛溶于200mL二氯甲烷中,加入6g(99.6mmol)乙酸,搅拌1小时,在冰盐浴下,分批加入21.1g(99.6mmol)三乙酰氧基硼氢化钠,加毕,室温反应2小时。TLC检测,反应结束后,向反应体系加入饱和碳酸氢钠调节pH=8,水层用二氯甲烷萃取,合并有机相,干燥,蒸干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=10/1,V/V)获得产品15.6g,黑色油状物,产率73%。LC-MS:346,348[M+1] +,t R=1.821min。
中间体8-2的合成:
将15.6g(45mmol)中间体8-1溶于120mL 2,2-二甲氧基丙烷中,加入1g(5.8mmol)对甲苯磺酸一水合物,10g分子筛,封闭加热至135℃,反应16小时。TLC检测,反应结束后,过滤,蒸干溶剂,加入饱和碳酸氢钠溶液,用二氯甲烷萃取,合并有机相,干燥,蒸干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=30/1,V/V)获得产品13g,淡黄色固体,产率75.1%。LC-MS:386,388[M+1] +,t R=3.352min。
中间体9-1的合成:
将14g(36mmol)中间体8-2溶于100mL四氢呋喃中,氮气保护下降温至-78℃,滴加17mL(43.5mmol)正丁基锂,在-78℃下搅拌30分钟后,通入二氧化碳气体30分钟,自然升至室温。TLC检测,反应结束后,加入醋酸调节pH至5-6,蒸干反应液,获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=30/1,V/V)获得产品9.1g,黄白色固体,产率71.9%。LC-MS:352[M+1] +,t R=2.415min。
中间体17的合成:
Figure PCTCN2018092233-appb-000009
将0.8g(4.7mmol)原料16、2.6g(18.8mmol)碳酸钾和1.8mL(18.8mmol)异丙基溴悬浮于8mL DMF中,在100℃反应1h。TLC(PE/EA=3:1)监测,反应完全。加入30mL饱和碳酸氢钠和30mL乙酸乙酯,搅拌,静置,分液,有机相用2×30mL水洗,有机相干燥,蒸干,获得粗品棕色液体0.94g,产率93.7%。
中间体19的合成:
Figure PCTCN2018092233-appb-000010
在氮气保护下,将0.94g(4.4mmol)中间体17悬于3.2g(52.9mmol)85%水合肼中,在85℃下反应500min。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,冷却至室温,过滤,水洗,抽干,获得0.86g,白色固体,产率91.7%。LC-MS:213[M+1] +,t R=2.441min。
中间体21的合成:
Figure PCTCN2018092233-appb-000011
将0.9g(2.56mmol)中间体9-1溶于36mL二氯甲烷中,加入0.015mL(cat.)N,N-二甲基甲酰胺,降温至0℃,滴加0.65mL(7.68mmol)草酰氯,滴毕,自然升至室温反应1小时。反应结束后,浓缩反应液,加入16mL二氯甲烷待用。将0.82g(3.84mmol)化合物19和1.1mL(7.68mmol)三乙胺溶于16mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应过夜。TLC(PE/EA=3:1+AcOH)检测,反应结束后,加入40mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品1.2g,黄色固体,产率84.8%。LC-MS:546[M+1] +,t R=4.125min。
中间体22的合成:
Figure PCTCN2018092233-appb-000012
将1.2g(2.16mmol)中间体21和1mL(6.49mmol)三乙胺溶于24mL乙腈中,降温至0℃,加入0.62g(3.24mmol)对甲苯磺酰氯,室温搅拌过夜。TLC(PE/EA=1:1)检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=10/1,V/V)获得产品0.7g,白色固体,产率61.4%。LC-MS:528[M+1] +,t R=5.226min。
中间体23的合成:
Figure PCTCN2018092233-appb-000013
将0.7g(1.33mmol)中间体22溶于3.7mL1M盐酸和21mL甲醇中,在80℃下反应120min。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,旋蒸浓缩,加入20mL饱和碳酸氢钠溶液,20mL二氯甲烷,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/2+1%Et 3N,V/V)共获得产品0.6g,白色固体,产率94.0%。
实施例1(S)-(2-氨基-7-(5-(3-氟-4-异丙氧基苯基)-1,3,4-噁二唑-2-基)-1,2,3,4-四氢萘-2-基)甲
Figure PCTCN2018092233-appb-000014
将0.6g(1.24mmol)中间体23溶于13mL甲醇中,加入0.01mL浓盐酸,置换氮气后加入0.122g(20%m/m)10%钯碳,置换氢气后,在95℃下反应240min。TLC(DCM:MeOH=10:1)检测,反应结束后,过滤,滤饼用大量甲醇洗涤,旋蒸浓缩滤液,加入30mL饱和碳酸钠溶液,30mL二氯甲烷,搅拌静置分液,水相用二氯甲烷萃取,合并有机相,干燥。过滤,旋蒸,粗品过硅胶柱纯化(洗脱液:DCM:MeOH=10/1+1%Et 3N V/V)获得实施例1目标化合物,白色固体0.3g,产率61.89%。LC-MS:398[M+1] +,t R=3.090min。此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。
制备例2
中间体27的合成:
Figure PCTCN2018092233-appb-000015
将2.0g(12mmol)中间体26溶于20mL甲醇中,冷却至0℃,滴加2.6mL(36mmol)氯化亚砜,升至室温,搅拌反应过夜。TLC检测,反应结束后,向反应体系加入饱和碳酸氢钠调节pH=8,旋干甲醇,水相用二氯甲烷萃取,合并有机相,干燥,旋干获得产品1.9g白色固体,产率81.67%。
中间体28的合成:
Figure PCTCN2018092233-appb-000016
氮气保护下,1.911g(9.8mmol)中间体27溶于7g(118.7mmol)85%水合肼中,加热至85℃,反应7小时。TLC检测,反应结束后,冷却至室温,过滤,抽干获得产品1.728g白色固体,产率81.67%。
中间体29的合成:
Figure PCTCN2018092233-appb-000017
将1.0g(2.84mmol)中间体9-1溶于40mL二氯甲烷中,加入5滴N,N-二甲基甲酰胺,降温至0℃,滴加0.72mL(8.52mmol)草酰氯,滴毕,自然升至室温反应1小时。反应结束后,浓缩反应液,加入30mL二氯甲烷待用。将0.823g(8.52mmol)化合物28和1.19mL(8.52mmol)三乙胺溶于30mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应过夜。TLC(PE/EA=3:1+AcOH)检测,反应结束后,加入500mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品1.3g黄色固体,产率89.08%。LC-MS:514[M+1] +,t R=8.349min。
中间体30的合成:
Figure PCTCN2018092233-appb-000018
将1.3g(2.53mmol)中间体29和1.06mL(7.60mmol)三乙胺溶于30mL乙腈中,降温至0℃,加入0.73g(3.80mmol)对甲苯磺酰氯,室温搅拌过夜。TLC(PE/EA=1:1)检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品1.2g黄色固体,产率 95.65%。
中间体31的合成:
Figure PCTCN2018092233-appb-000019
将1.2g(2.42mmol)中间体30溶于5.2mL 1M盐酸和30mL甲醇中,在80℃下反应30min。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,旋蒸浓缩,加入30mL饱和碳酸氢钠溶液,30mL二氯甲烷,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1+1%Et 3N,V/V)共获得产品0.7g黄色固体,产率63.64%。
实施例2(S)-(2-氨基-7-(5-(3-氟-4-异丙氧基苯基)-1,3,4-噁二唑-2-基)-1,2,3,4-四氢萘-2-基)甲
Figure PCTCN2018092233-appb-000020
将0.7g(1.54mmol)中间体31溶于30mL甲醇中,加入4滴浓盐酸,置换氮气后加入0.14g(20%m/m)10%钯碳,置换氢气后,在95℃下反应5h。TLC(DCM:MeOH=10:1)检测,反应结束后,过滤,滤饼用大量甲醇洗涤,旋蒸浓缩滤液,加入30mL饱和碳酸钠溶液,30mL乙酸乙酯,搅拌静置分液,水相用乙酸乙酯萃取,合并有机相,干燥。过滤,旋蒸,粗品过硅胶柱纯化(洗脱液:DCM:MeOH=10/1V/V)获得实施例2目标化合物,淡黄色固体0.514g,产率91.35%。LC-MS:366[M+1] +,t R=2.64min。此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。 1H NMR(400MHz,DMSO)δ8.31(s,3H),7.89(d,J=6.8Hz,2H),7.77–7.68(m,1H),7.63(d,J=1.6Hz,1H),7.37(d,J=8.6Hz,1H),7.15(d,J=8.1Hz,1H),6.18(s,2H),3.17(s,2H),3.08(s,2H),3.02–2.81(m,3H),2.11–1.90(m,2H)。
制备例3
中间体35的合成:
Figure PCTCN2018092233-appb-000021
在氮气保护下,将5.5g(23.8mmol)中间体34和2.3g(26.1mmol)氰化亚铜悬浮于30mL N-甲基吡咯烷酮中,在200℃下反应5小时。TLC检测,反应结束后,加入60 mL水和60mL乙酸乙酯搅拌30分钟,过滤,滤饼用乙酸乙酯洗涤,母液用乙酸乙酯萃取,合并,干燥,旋干,获得粗品。粗品经硅胶柱层析(洗脱液:乙酸乙酯/石油醚=1/1,V/V)获得产品3.6g,黄色油状物,产率85.3%。LC-MS:178[M+1] +,t R=3.251min。
中间体36的合成:
Figure PCTCN2018092233-appb-000022
将3.6g(20.3mmol)中间体35、9.9g(81.3mmol)2-溴丙烷和11.2g(81.3mmol)碳酸钾悬浮于36mL N,N-二甲基甲酰胺中,在90℃下反应2小时。TLC检测,反应结束后,加入30mL水和30mL乙酸乙酯,分层,有机相用30mL水洗涤3次,干燥,旋干,获得粗品2.6g,黄色油状物,产率58.1%。
中间体37的合成:
Figure PCTCN2018092233-appb-000023
在氮气保护下,将2.6g中间体36(11.8mmol)溶于5.9g(110mmol)85%水合肼中,在60℃下反应1小时。TLC检测,反应结束后,冷却至室温,过滤,水洗,抽干,获得粗品2g,白色固体,产率77.1%。
中间体38的合成:
Figure PCTCN2018092233-appb-000024
将2.6g(7.6mmol)中间体9-1溶于120mL二氯甲烷中,加入0.01g(cat.)N,N-二甲基甲酰胺,降温至0℃,滴加2.9g(22.8mmol)草酰氯,滴毕,自然升至室温反应3小时。TLC检测,反应结束后,浓缩反应液,加入50mL二氯甲烷待用。将2g(9.1mmol)化合物37和7.9g(22.8mmol)三乙胺溶于50mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应过夜。TLC检测,反应结束后,加入100mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品4.1g,黄色固体,产率97.3%。
中间体39的合成:
Figure PCTCN2018092233-appb-000025
将4.1g(7.4mmol)中间体38和2.2g(22.2mmol)三乙胺溶于120mL乙腈中,加入2.1g(11.1mmol)对甲苯磺酰氯,室温搅拌过夜。TLC检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。获得粗品4.3g,棕黄色固体,产率100%。
中间体40的合成:
Figure PCTCN2018092233-appb-000026
将4.3g(8mmol)中间体39溶于20.1mL 1M盐酸和120mL甲醇中,在80℃下反应2小时。TLC检测,反应结束后,加入50mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品1.5g,白色固体,产率37.5%。
实施例3(S)-5-(5-(7-氨基-7-(羟甲基)-5,6,7,8-四氢萘-2-基)-1,3,4-噁二唑-2-基)-2-异丙氧基苯 甲腈
Figure PCTCN2018092233-appb-000027
将1.5g(3.0mmol)中间体40溶于45mL甲醇中,加入0.5mL浓盐酸,置换氮气后加入0.3g(20%m/m)10%钯碳,置换氢气后,在80℃下反应8小时。TLC检测,反应结束后,过滤,滤饼用热甲醇洗涤,旋干滤液,获得粗品1.5g。粗品在15mL甲醇中重结晶,过滤,洗涤,获得实施例3目标化合物0.65g,白色固体,产率54.1%。LC-MS:405[M+1] +,t R=3.002min。此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。 1H NMR(400MHz,DMSO)δ8.51(d,J=2.2Hz,1H),8.37(dd,J=9.0,2.2Hz,1H),8.12(s,3H),7.96(d,J=6.6Hz,2H),7.54(d,J=9.2Hz,1H),7.40(d,J=8.6Hz,1H),5.62(t,J=5.1Hz,1H),5.01–4.87(m,1H),3.47(d,J=4.9Hz,2H),3.22–2.83(m,5H),2.06–1.89(m,2H),1.38(d,J=6.0Hz,6H)。
实施例4(S)-5-(5-(7-氨基-7-(羟甲基)-5,6,7,8-四氢萘-2-基)-1,3,4-噁二唑-2-基)-2-异丙氧基本 甲酰胺
Figure PCTCN2018092233-appb-000028
将0.2g(0.49mmol)实施例3目标化合物溶于5mL二甲基亚砜中,加入0.25g(1.8mmol)碳酸钾,冷却至0℃下,滴加2mL 30%双氧水,室温搅拌2小时。TLC检测,反应结束后,加入30mL水搅拌10分钟,过滤,水洗,抽干,获得粗品。粗品在20mL甲醇中重结晶,过滤,洗涤,抽干,获得实施例4目标化合物110mg,白色固体,产率53.4%。此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。 1H NMR(400MHz,DMSO)δ8.50(d,J=2.3Hz,1H),8.26(s,3H),8.19(dd,J=8.8,2.3Hz,1H),7.90(s,2H),7.79(s,1H),7.65(s,1H),7.40(t,J=9.5Hz,2H),6.11–5.14(br s,1H),5.01–4.85(m,1H),3.48(s,3H),3.19–2.76(m,4H),2.00(t,J=6.4Hz,2H),1.40(d,J=6.0Hz,6H)。
实施例5(S)-5-(5-(7-氨基-7-(羟甲基)-5,6,7,8-四氢萘-2-基)-1,3,4-噁二唑-2-基)-2-羟基苯甲腈
Figure PCTCN2018092233-appb-000029
将100mg(0.24mmol)实施例3目标化合物溶于50%硫酸中,在90℃下反应1小时。TLC检测,反应结束后,加入饱和碳酸氢钠溶液调节pH=2-3,过滤,水洗,抽干,获得实施例5目标化合物,白色固体35mg,收率34.3%。LC-MS:363[M+1] +,t R=1.142min。此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。
制备例4
中间体46的合成:
Figure PCTCN2018092233-appb-000030
将2.0g(9.08mmol)原料45、0.98g(18.17mmol)甲醇钠和少量TBAB悬浮于40mL THF中,在室温下搅拌30min后,加入1.7mL碘甲烷室温搅拌反应,TLC(PE/EA=3:1)监测,并补加碘甲烷至原料反应完全。旋蒸浓缩,加入40mL饱和碳酸氢钠和40mL二氯甲烷,搅拌,静置,分液,水相用2×40mL二氯甲烷萃取,合并,干燥,旋干,获得粗品2.1g,黄色固体,产率100%。LC-MS:235[M+1] +,t R=4.457min。
中间体47的合成:
Figure PCTCN2018092233-appb-000031
在氮气保护下,将2.12g(9.08mmol)中间体46悬于6.4mL(108.96mmol)85%水合肼中,在85℃下反应100min。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,冷却至室温,过滤,水洗,抽干,获得粗品1.96g,白色固体,产率92.4%。LC-MS:235[M+1] +,t R=3.005min。
中间体48的合成:
Figure PCTCN2018092233-appb-000032
将2.9g(8.25mmol)中间体9-1溶于60mL二氯甲烷中,加入0.01g(cat.)N’N-二甲基甲酰胺,降温至0℃,滴加2.1mL(24.75mmol)草酰氯,滴毕,自然升至室温反应1小时。反应结束后,浓缩反应液,加入30mL二氯甲烷待用。将2.32g(9.9mmol)化合物47和3.5mL(24.75mmol)三乙胺溶于30mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应3h。TLC(PE/EA=1:1+AcOH)检测,反应结束后,加入70mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品3.1g,棕色固体,产率66.2%。LC-MS:568[M+1] +,t R=4.678min。
中间体49的合成:
Figure PCTCN2018092233-appb-000033
将3.1g(5.46mmol)中间体48和2.3mL(16.38mmol)三乙胺溶于124mL乙腈中,降温至0℃,加入1.56g(8.19mmol)对甲苯磺酰氯,室温搅拌过夜。TLC(PE/EA=1:1)检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=3/1,V/V)获得产品1.9g,淡黄色固体,产率63.3%。LC-MS:550[M+1] +,t R=6.464min。
中间体50的合成:
Figure PCTCN2018092233-appb-000034
将1.0g(1.82mmol)中间体49溶于4.55mL 1M盐酸和30mL甲醇中,在80℃下反应100min。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,旋蒸浓缩,加入50mL饱和碳酸氢钠溶液,50mL二氯甲烷,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/2+1%Et 3N,V/V)获得产品0.8g,白色固体,产率86.32%。
实施例6(S)-(2-氨基-7-(5-(4-甲氧基-3-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)-1,2,3,4-四氢萘 -2-基)甲醇
Figure PCTCN2018092233-appb-000035
将0.8g(1.57mmol)中间体50溶于16mL甲醇中,加入0.1mL浓盐酸,置换氮气后加入0.16g(20%m/m)10%钯碳,置换氢气后,在95℃下反应5小时。TLC(DCM:MeOH=10:1)检测,反应结束后,过滤,滤饼用热甲醇洗涤,旋干滤液,获得粗品。粗品在24mL甲醇中重结晶,过滤,洗涤,获得实施例6目标化合物0.36g,白色固体,产率54.67%。LC-MS:420[M+1] +,t R=3.002min。此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。
制备例5
中间体54的合成:
Figure PCTCN2018092233-appb-000036
在氮气保护下,将2.0g(11.62mmol)原料53溶于20mL甲醇,加入8.2mL(139.44mmol)85%水合肼中,在室温下反应1.5小时。TLC(PE/EA=3:1)检测,反应结束后,加入50mL水搅拌析出固体,过滤,水洗,抽干。水相用EA萃取,干燥,旋蒸浓缩,真空抽干后得2g白色固体,产率100%。LC-MS:173[M+1] +,t R=2.528min。
中间体56的合成:
Figure PCTCN2018092233-appb-000037
将1g(2.84mmol)中间体9-1溶于40mL二氯甲烷中,加入0.01g(cat.)N’N-二甲基甲酰胺,降温至0℃,滴加0.72mL(8.52mmol)草酰氯,滴毕,自然升至室温反应1小时。反应结束后,浓缩反应液,加入20mL二氯甲烷待用。将0.54g(3.13mmol)化合物54和1.2mL(8.52mmol)三乙胺溶于20mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应过夜。TLC(PE/EA=3:1+AcOH)检测,反应结束后,加入40mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品0.7g,黄色固体,产率48.8%。LC-MS:506[M+1] +,t R=4.587min。
中间体57的合成:
Figure PCTCN2018092233-appb-000038
将0.7g(1.38mmol)中间体56和0.6mL(4.14mmol)三乙胺溶于38mL乙腈中,降温至0℃,加入0.32g(1.66mmol)对甲苯磺酰氯,室温搅拌反应5h。TLC(PE/EA=1:1)检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=10/1,V/V)得产品0.43g,白色固体,产率63.9%。LC-MS:488[M+1] +,t R=6.464min。
中间体58的合成:
Figure PCTCN2018092233-appb-000039
将0.4g(0.82mmol)中间体57溶于2.1mL 1M盐酸和16mL甲醇中,在80℃下反应1小时。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,加入40mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1+1%Et 3N,V/V)获得产品0.242g,白色固体,产率66.0%。
实施例7(S)-(2-氨基-7-(5-(3,4-二氟苯基)-1,3,4-噁二唑-2-基)-1,2,3,4-四氢萘-2-基)甲醇
Figure PCTCN2018092233-appb-000040
将0.24g(0.54mmol)中间体58溶于8mL甲醇中,加入0.01mL浓盐酸,置换氮气后加入0.048g 10%钯碳,置换氢气后,在95℃下反应5小时。TLC(DCM:MeOH=10:1)检测,反应结束后,过滤,滤饼用热甲醇洗涤,旋干滤液,获得粗品1.5g。硅胶制备板纯化(洗脱液:二氯甲烷:甲醇=10/1),获得实施例7目标化合物0.18g,白色固体,产率93.3%。LC-MS:358[M+1] +,t R=3.717min.此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。 1H NMR(400MHz,DMSO)δ8.30–8.16(m,1H),8.09–7.96(m,1H),7.87(d,J=6.7Hz,2H),7.79–7.64(m,1H),7.34(d,J=8.4Hz,1H),5.38–4.14(br,3H),3.74–3.16(m,5H),3.05–2.65(m,4H),1.91–1.60(m,2H)。
制备例6
中间体62的合成:
Figure PCTCN2018092233-appb-000041
氮气保护下,0.928g(5.04mmol)中间体61溶于3.56g(60.48mmol)85%水合肼中,加热至85℃,反应2小时。TLC检测,反应结束后,冷却至室温,过滤,抽干获得产品0.369g白色固体,产率39.68%。
中间体63的合成:
Figure PCTCN2018092233-appb-000042
将0.47g(1.34mmol)中间体9-1溶于20mL二氯甲烷中,加入3滴N,N-二甲基甲酰胺,降温至0℃,滴加0.34mL(4mmol)草酰氯,滴毕,自然升至室温反应1小时。反应结束后,浓缩反应液,加入20mL二氯甲烷待用。将0.369g(2mmol)化合物62和0.56mL(4mmol)三乙胺溶于20mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应过夜。TLC(PE/EA=3:1+AcOH)检测,反应结束后,加入30mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品0.302g黄色固体,产率43.28%。LC-MS:518[M+1] +,t R=5.462min。
中间体64的合成:
Figure PCTCN2018092233-appb-000043
将0.302g(0.58mmol)中间体63和0.24mL(1.74mmol)三乙胺溶于10mL乙腈中,降温至0℃,加入0.166g(0.87mmol)对甲苯磺酰氯,室温搅拌过夜。TLC(PE/EA=1:1)检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品0.332g黄色固体,产率100%。
中间体65的合成:
Figure PCTCN2018092233-appb-000044
将0.332g(0.58mmol)中间体64溶于1.25mL 1M盐酸和10mL甲醇中,在80℃下反应30min。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,旋蒸浓缩,加入10mL饱和碳酸氢钠溶液,10mL二氯甲烷,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1+1%Et 3N,V/V)共获得产品0.214g黄色固体,产率81.03%。
实施例8(S)-(2-氨基-7-(5-(3-氟-4-甲氧基苯基)-1,3,4-噁二唑-2-基)-1,2,3,4-四氢萘-2-基)甲醇
Figure PCTCN2018092233-appb-000045
将0.214g(0.47mmol)中间体65溶于10mL甲醇中,加入2滴浓盐酸,置换氮气后加入0.04g(20%m/m)10%钯碳,置换氢气后,在95℃下反应4h。TLC(DCM:MeOH=10:1)检测,反应结束后,过滤,滤饼用大量甲醇洗涤,旋蒸浓缩滤液,加入10mL饱和碳酸钠溶液,10mL乙酸乙酯,搅拌静置分液,水相用乙酸乙酯萃取,合并有机相,干燥。过滤,旋蒸,粗品过硅胶柱纯化(洗脱液:DCM:MeOH=10/1V/V)获得实施例8目标化合物,淡黄色固体0.138g,产率79.49%。LC-MS:370[M+1] +,t R=1.334min。此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。
制备例7
中间体69的合成:
Figure PCTCN2018092233-appb-000046
将1.0g(5.6mmol)中间体68溶于10mL N,N-二甲基甲酰胺中,加入2.34mL(16.8mmol)三乙胺,冷却至0℃,加入2.51g(6.16mmol)四甲基脲六氟磷酸酯,搅拌30min,将上述溶液滴入2.8g(56mmol)水合肼溶于10mL N’N-二甲基甲酰胺的溶液中,反应过夜。TLC检测,反应结束后,旋干反应液,加入10mL饱和碳酸氢钠溶液,10mL二氯甲烷,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:DCM:MeOH=10/1V/V)获得产品0.24g白色固体,产率22.18%。LC-MS:194[M+1] +,t R=1.435min。
中间体70的合成:
Figure PCTCN2018092233-appb-000047
将2.1g(5.97mmol)中间体9-1溶于80mL二氯甲烷中,加入10滴N,N-二甲基甲酰胺,降温至0℃,滴加1.52mL(17.92mmol)草酰氯,滴毕,自然升至室温反应1小时。反应结束后,浓缩反应液,加入80mL二氯甲烷待用。将1.732g(8.96mmol)化合物69和2.5mL(17.92mmol)三乙胺溶于80mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应过夜。TLC(PE/EA=3:1+AcOH)检测,反应结束后,加入120mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1,V/V)获得产品2.0g黄色固体,产率63.61%。LC-MS:527[M+1] +,t R=2.457min。
中间体71的合成:
Figure PCTCN2018092233-appb-000048
将2.0g(3.8mmol)中间体70和1.59mL(11.4mmol)三乙胺溶于50mL乙腈中, 降温至0℃,加入1.087g(5.7mmol)对甲苯磺酰氯,室温搅拌过夜。TLC(PE/EA=1:1)检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=5/1,V/V)获得产品2.2g黄色固体,产率100%。
中间体72的合成:
Figure PCTCN2018092233-appb-000049
将2.2g(3.8mmol)中间体71溶于8.17mL 1M盐酸和50mL甲醇中,在80℃下反应30min。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,旋蒸浓缩,加入50mL饱和碳酸氢钠溶液,50mL二氯甲烷,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1+1%Et 3N,V/V)共获得产品0.8g黄色固体,产率45.0%。
实施例9(S)-N-(4-(5-(7-氨基-7-(羟甲基)-5,6,7,8-四氢萘-2- yl)-1,3,4-噁二唑-2-基)苯基)乙酰
Figure PCTCN2018092233-appb-000050
将0.8g(1.71mmol)中间体72溶于30mL甲醇中,加入5滴浓盐酸,置换氮气后加入0.16g(20%m/m)10%钯碳,置换氢气后,在95℃下反应4h。TLC(DCM:MeOH=10:1)检测,反应结束后,过滤,滤饼用大量甲醇洗涤,旋蒸浓缩滤液,加入30mL饱和碳酸钠溶液,30mL乙酸乙酯,搅拌静置分液,水相用乙酸乙酯萃取,合并有机相,干燥。过滤,旋蒸,粗品过硅胶柱纯化(洗脱液:DCM:MeOH=10/1V/V)获得实施例9目标化合物,淡黄色固体0.326g,产率50.38%。LC-MS:379[M+1] +,t R=1.103min。此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。
制备例8
中间体76的合成:
Figure PCTCN2018092233-appb-000051
将1.0g(4.54mmol)原料75、1.9g(13.62mmol)碳酸钾和2.6mL(27.00mmol)苄氯悬浮于40mL丙酮中,回流反应过夜。TLC(PE/EA=3:1)监测原料75反应完全。旋蒸浓缩,加入40mL饱和碳酸氢钠和40mL二氯甲烷,搅拌,静置,分液,水相用40mL二氯甲烷萃取,合并,干燥,旋干,粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=20/1,V/V),获得白色固体1.4g,产率100%。
中间体77的合成:
Figure PCTCN2018092233-appb-000052
在氮气保护下,将1.4g(4.54mmol)中间体76悬浮于40mL甲醇和6.4mL(108.96mmol)85%水合肼中,在85℃下反应180min。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,旋蒸浓缩,冷却至室温,加入20mL水搅拌析出固体,过滤,水洗,抽干,获得粗品1.4g,白色固体,产率100%。LC-MS:311[M+1] +,t R=1.799min。
中间体78的合成:
Figure PCTCN2018092233-appb-000053
将1.36g(3.87mmol)中间体9-1溶于27mL二氯甲烷中,加入0.01g(cat.)N,N-二甲基甲酰胺,降温至0℃,滴加1.0mL(11.61mmol)草酰氯,滴毕,自然升至室温反应1小时。反应结束后,浓缩反应液,加入30mL二氯甲烷待用。将1.2g(3.87mmol)中间体77和1.62mL(11.61mmol)三乙胺溶于30mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应过夜。TLC(PE/EA=3:1+AcOH)检测,反应结束后,加入60mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=2/1,V/V)获得产品1.4g,黄色固体,产率56.2%。LC-MS:644[M+1] +,t R=2.396min。
中间体79的合成:
Figure PCTCN2018092233-appb-000054
将1.4g(2.17mmol)中间体78和1.0mL(6.51mmol)三乙胺溶于56mL乙腈中,降温至0℃,加入0.5g(2.61mmol)对甲苯磺酰氯,室温搅拌过夜。TLC(PE/EA=1:1)检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。粗 品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=3/1,V/V)获得产品0.6g,淡黄色固体,产率44.2%。
中间体80的合成:
Figure PCTCN2018092233-appb-000055
将0.6g(0.95mmol)中间体79溶于2.4mL 1M盐酸和30mL甲醇中,在80℃下反应120min,析出固体。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,抽滤,母液旋蒸浓缩,加入30mL饱和碳酸氢钠溶液,30mL二氯甲烷,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/2+1%Et 3N,V/V)共获得产品0.426g,白色固体,产率76.57%。
实施例10(S)-4-(5-(7-氨基-7-(羟甲基)-5,6,7,8-四氢萘-2-基)-1,3,4-噁二唑-2-基)-2-(三氟甲基) 苯酚
Figure PCTCN2018092233-appb-000056
将0.426g(0.727mmol)中间体80溶于16mL甲醇中,加入0.01mL浓盐酸,置换氮气后加入0.09g 10%钯碳,置换氢气后,在95℃下反应过夜。TLC(DCM:MeOH=10:1)检测,反应结束后,过滤,滤饼用热甲醇洗涤,旋蒸浓缩滤液,1%NaOH调溶液pH 9-10,用二氯甲烷萃取水相后,再用1M盐酸调水相pH 5.8-6.2析出白色固体,室温搅拌30min后,抽滤得白色固体(空气中容易氧化变质,氮气保护下低温放置)。得到实施例10目标化合物25mg,类白色固体,产率8.5%。LC-MS:406[M+1] +,t R=1.328min.此固体与氯化氢甲醇溶液混合搅拌可得到相应的盐酸盐。
制备例9
中间体84的合成:
Figure PCTCN2018092233-appb-000057
1.0mL(14.4mmol)二氯亚砜低温下加入到20mL甲醇中,冰水浴条件下搅拌反应1h后再向反应瓶中加入1.0g原料83,自然升温,后加热至55℃搅拌反应1h。TLC(PE/EA=3:1+AcOH)监测原料83反应完全。旋蒸浓缩,加入20mL饱和碳酸氢钠和20mL 乙酸乙酯,搅拌,静置,分液,水相用40mL乙酸乙酯萃取两次,合并干燥,旋干,获得粗品油状物0.7g,产率65.7%。
中间体85的合成:
Figure PCTCN2018092233-appb-000058
在氮气保护下,将0.7g(3.2mmol)中间体84悬于7mL甲醇和1.9mL(32mmol)85%水合肼中,在室温下反应过夜。TLC(PE/EA=3:1)检测,反应结束后,加入20mL水、20mL DCM搅拌分液,DCM萃取两次,合并干燥有机相,过滤,减压浓缩,抽干,得白色固体0.7g,产率100%。LC-MS:223[M+1] +,t R=1.879min。
中间体86的合成:
Figure PCTCN2018092233-appb-000059
将1.0g(3.1mmol)中间体9-1溶于40mL二氯甲烷中,加入0.01g(cat.)N,N-二甲基甲酰胺,降温至0℃,滴加0.8mL(9.3mmol)草酰氯,滴毕,自然升至室温反应1小时。反应结束后,浓缩反应液,加入20mL二氯甲烷待用。将0.7g(3.87mmol)中间体85和1.3mL(9.3mmol)三乙胺溶于20mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应过夜。TLC(PE/EA=3:1+AcOH)检测,反应结束后,加入40mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品1.5g,产率87.1%。
中间体87的合成:
Figure PCTCN2018092233-appb-000060
将1.5g(3.1mmol)中间体86和1.3mL(9.3mmol)三乙胺溶于60mL乙腈中,降温至0℃,加入0.88g(4.65mmol)对甲苯磺酰氯,室温搅拌过夜。TLC(PE/EA=1:1)检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=3/1,V/V)获得产品1.3g,淡黄色固体,产率78.0%。LC-MS:538[M+1] +,t R=3.251min。
中间体88的合成:
Figure PCTCN2018092233-appb-000061
将1.3g(2.4mmol)中间体87溶于6mL 1M盐酸和40mL甲醇中,在80℃下反应3h。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,减压浓缩,用10%NaOH和饱和NaHCO 3溶液调pH 8左右,用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1+1%Et 3N,V/V)共获得产品0.6g,白色固体,产率50.2%。
实施例11(S)-(2-氨基-7-(5-(3-氟-4-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)-1,2,3,4-四氢萘-2-基) 甲醇
Figure PCTCN2018092233-appb-000062
将0.6g(1.2mmol)中间体88溶于20mL甲醇中,加入0.01mL浓盐酸,置换氮气后加入0.12g(20%m/m)10%湿钯碳,置换氢气后,在85℃下反应6h。TLC(DCM:MeOH=10:1)检测,反应结束后,趁热过滤,滤饼用热甲醇洗涤,旋蒸浓缩滤液。向浓缩液中加入6mL甲醇,1mL 10%氯化氢甲醇溶液,升温回流,搅拌30min后自然降至室温,抽滤得白色固体获得白色固体0.1g,将滤液旋干并重复上述操作得到白色固体0.076g。所得两批白色固体合并共得到实施例11目标化合物(盐酸盐)0.176g,产率33.0%。LC-MS:408[M+1] +,t R=1.936min。
制备例10
中间体92的合成:
Figure PCTCN2018092233-appb-000063
1.7mL(23.1mmol)二氯亚砜低温下加入到40mL甲醇中,冰水浴条件下搅拌反应1h后再向反应瓶中加入2.0g原料91,自然升温,后加热至80℃搅拌反应1h。TLC(PE/EA=3:1+AcOH)监测原料91反应完全。旋蒸浓缩,加入20mL饱和碳酸氢钠和20mL乙酸乙酯,搅拌,静置,分液,水相用40mL乙酸乙酯萃取两次,合并干燥,旋干,获得粗品油状物1.5g,产率71.6%。
中间体93的合成:
Figure PCTCN2018092233-appb-000064
在氮气保护下,将1.5g(5.5mmol)中间体92悬于30mL甲醇,3.2mL(55mmol)85%水合肼中,在室温下反应过夜。TLC(PE/EA=3:1)检测,反应结束后,加入20mL水、20mL DCM搅拌分液,DCM萃取两次,合并干燥有机相,过滤,减压浓缩,抽干,得白色固体1.5g,产率100%。LC-MS:273[M+1] +,t R=2.034min。
中间体94的合成:
Figure PCTCN2018092233-appb-000065
将1.7g(5mmol)中间体9-1溶于68mL二氯甲烷中,加入0.02g(cat.)N,N-二甲基甲酰胺,降温至0℃,滴加1.3mL(15mmol)草酰氯,滴毕,自然升至室温反应1小时。反应结束后,浓缩反应液,加入34mL二氯甲烷待用。将1.5g(5.5mmol)中间体93和2.1mL(15mmol)三乙胺溶于40mL二氯甲烷中,降温至0℃,滴加上述制备好的酰氯的二氯甲烷溶液,滴毕,自然升至室温反应过夜。TLC(PE/EA=3:1+AcOH)检测,反应结束后,加入40mL饱和碳酸氢钠溶液,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品3.0g,产率100%。
中间体95的合成:
Figure PCTCN2018092233-appb-000066
将3.0g(5mmol)中间体94粗品和2.1mL(15mmol)三乙胺溶于120mL乙腈中,降温至0℃,加入1.1g(6mmol)对甲苯磺酰氯,室温搅拌过夜。TLC(PE/EA=1:1)检测,反应结束后,加入水,分层,水层用二氯甲烷萃取,合并有机相,干燥,旋干。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=10/1,V/V)获得产品1.3g,泡沫状固体,产率44.2%。LC-MS:588.5[M+1] +,t R=3.300min。
中间体96的合成:
Figure PCTCN2018092233-appb-000067
将1.3g(2.2mmol)中间体95溶于5.5mL 1M盐酸和50mL甲醇中,在90℃下反应2h。TLC(PE/EA=1:1+Et 3N)检测,反应结束后,减压浓缩,用10%NaOH和饱和NaHCO 3溶液调pH 8左右,用二氯甲烷萃取,合并有机相,干燥,旋干获得粗品。粗品经硅胶柱层析(洗脱液:石油醚/乙酸乙酯=1/1+1%Et 3N,V/V)共获得产品0.6g,白色固体,产率49.8%。
实施例12(S)-(2-氨基-7-(5-(3,5-双(三氟甲基)苯基)-1,3,4-噁二唑-2-基)-1,2,3,4-四氢萘-2-基) 甲醇
Figure PCTCN2018092233-appb-000068
将0.6g(1.1mmol)中间体96溶于34mL甲醇中,加入0.01mL浓盐酸,置换氮气后加入0.12g(20%m/m)10%湿钯碳,置换氢气后,在90℃下反应6h。TLC(DCM:MeOH=10:1)检测,反应结束后,趁热过滤,滤饼用热甲醇洗涤,旋蒸浓缩滤液得粗品白色固体经硅胶柱层析(洗脱液:二氯甲烷/甲醇=5/1,V/V)后溶于20mL DCM(含少量甲醇)、20mL水搅拌分液,DCM萃取水相,DCM相合并干燥,过滤,滤液中加入适量氯化氢甲醇溶液,旋干,真空抽干得实施例12目标化合物(盐酸盐)0.126g,收率33%,纯度96.1%。LC-MS:458[M+1] +,t R=1.961min。
实施例13(S)-(2-氨基-7-(5-(3,4-二乙氧基苯基)-1,3,4-噁二唑-2-基)-1,2,3,4-四氢萘-2-基)甲醇
Figure PCTCN2018092233-appb-000069
以手性中间体7-1为起始原料,重复专利WO2013181840上实例20化合物的合成方法,得到本实施例的手性化合物。LC-MS:410.2[M+1] +,t R=1.757min. 1H NMR(400MHz,DMSO)δ7.90–7.77(m,2H),7.68(dd,J=8.4,1.9Hz,1H),7.59(d,J=1.9Hz,1H),7.33(d,J=7.9Hz,1H),7.17(d,J=8.5Hz,1H),4.98(br s,1H),4.14(p,J=6.8Hz,5H),3.29(s,2H),3.04–2.60(m,5H),1.88–1.59(m,2H),1.43–1.30(m,6H)用少量氯化氢/甲醇溶液处理得到盐酸盐。
实施例14:(S)-(2-氨基-7-(5-(4-异丙氧基-3-(三氟甲基)苯基)-1,3,4-噁二唑-2-基)-1,2,3,4-四氢 萘-2-基)甲醇
Figure PCTCN2018092233-appb-000070
以手性中间体7-1为起始原料,重复专利WO2013181840上实例11化合物的合成方法,得到本实施例的手性化合物,用少量氯化氢/甲醇溶液处理得到盐酸盐。LC-MS:448.5[M+1] +,t R=3.183min. 1H NMR(400MHz,DMSO)δ8.43–8.31(m,1H),8.27(s,1H),8.13(s,3H),7.94(d,J=5.5Hz,2H),7.56(d,J=9.0Hz,1H),7.40(d,J=8.6Hz,1H),5.61(t,J=5.1Hz,1H),5.03–4.87(m,1H),3.47(d,J=5.0Hz,2H),3.17–2.79(m,4H),2.07–1.86(m,2H),1.35(d,J=6.0Hz,6H).
生物活性实验
以下对本发明的化合物进行生物活性检测:
实施例15氨基醇类化合物对小鼠外周血细胞CD4,CD8,及CD19表达的影响
1.试验材料:
小鼠(C57BL/6,8周龄)
FITC Rat Anti-Mouse CD8a:BD,Cat.#553030
PE Rat Anti-Mouse CD4:BD,Cat.#557308
APC Rat Anti-Mouse CD19:BD,Cat.#561738
试验所用化合物由北京富龙康泰化学部合成
2.试验方法:
给药途径:灌胃,每天1次,连续给药4天。
给药结束后小鼠眼眶采血至含有抗凝剂的1.5ml EP管中,放于冰上;再转移至流式管中,于4℃,1200rpm/min离心5min;弃掉上清,加入裂解液,冰上裂解5min;裂解结束后,预染;然后加入稀释过的抗体,避光孵育30min;孵育结束后加入清洗;弃掉上清,加入固定液,避光保存在4℃冰箱,准备上机进行流式检测。
3.试验结果
表1.氨基醇类对小鼠外周血细胞CD4,CD8,及CD19表达的影响
Figure PCTCN2018092233-appb-000071
Figure PCTCN2018092233-appb-000072
实施例16 β-arrestin检测试验(PathHunter β-arrestin检测系统)
实验方法
1.PathHunterβ-arrestin检测系统被用来检测化合物的生物活性。
2.β-arrestin工程细胞培养在386孔培养板中,放置在37℃孵箱中。
3.用反应液把待测物按5倍稀释。
4.将稀释过的待测物加入工程细胞中,诱导并观测反应。
5.试验中产生的化学发光信号可被多功能酶标仪(PerkinElmer EnvisionTM)检测到。
实验分析及结果
6.用CBIS数据分析软件(ChemInnovation,CA)分析所获得的数据,获得EC 50,实验结果如表2所示。
表2 实施例3、实施例13化合物的生物活性
β-arrestin试验
EC 50(nM)
Figure PCTCN2018092233-appb-000073
实施例17荧光检测试验(FLIPR assay)
试验方法及结果
把DMSO溶解待测样品,然后用试验缓冲液按3倍稀释待测样品。试剂和阳性对照用同样方法稀释。
用FLIPRTETRA仪器来检测激动剂,试剂和阳性对照反应。检测时间总共180秒,用于评估每个化合物激活每个化合物激活GPCR(S1P5)的能力,结果如表3所示。
表3 实施例3、实施例13化合物的生物活性
FLIPR试验
EC 50(nM)
Figure PCTCN2018092233-appb-000074
实施例18
试验方法
1.hERG钾离子通道稳定表达的HEK293工程细胞系被用来检测化合物。
2.膜片钳检测:实验之前细胞用TrypLE TM Express分离,将3x10 3细胞铺到盖片上,在24孔板中培养,18个小时后进行检测。电生理记录细胞钾电流的电压刺激所产生的信号。
数据分析及结果
首先将每一个药物浓度作用后的电流和空白对照电流标准化
Figure PCTCN2018092233-appb-000075
然后计算每一个药物浓度对应的抑制率
Figure PCTCN2018092233-appb-000076
对每一个浓度计算平均数和标准误,并用以下的方程计算每种化合物的半抑制浓度:
Figure PCTCN2018092233-appb-000077
用以上方程对剂量依赖效应进行非线性拟合,其中c代表药物浓度,IC50为的半抑制浓度,h代表希尔系数。曲线拟合以及IC 50的计算利用IGOR软件完成,结果如表4所示。
表4 实施例3、实施例13、实施例14的hERG检测
hERG检测试验
Figure PCTCN2018092233-appb-000078
以上,对本发明的实施方式进行了说明。但是,本发明不限定于上述实施方式。凡在本发明的精神和原则之内,所做的任何修改、等同替换、改进等,均应包含在本发明的保护范围之内。

Claims (10)

  1. 下式I所示的氨基醇衍生物、其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药:
    Figure PCTCN2018092233-appb-100001
    其中,R 1、R 2相同或不同,彼此独立地选自H、-F、-Cl、-Br、-I、-OH、-SH、-CN、-COOH、-NO 2,无取代或任选被一个或多个R a取代的下列基团:C 1-40烷基、C 1-40烷氧基、C 2-40烯基、C 2-40炔基、C 3-20环烷基、C 3-20环烷基氧基、3-20元杂环基、3-20元杂环基氧基、C 6-20芳基、C 6-20芳基氧基、5-20元杂芳基、5-20元杂芳基氧基、H[(CH 2) nO] m-、-NR dR e、-CONR dR e或-C(O)Y 1R d
    R 3选自无取代或任选被一个或多个R b取代的下列基团:C 3-20环烷基、3-20元杂环基、C 6-20芳基、5-20元杂芳基;
    每一个R a相同或不同,彼此独立地选自C 1-40烷基、C 1-40烷氧基、C 2-40烯基、C 2-40炔基、C 3-20环烷基、-F、-Cl、-Br、-I、-OH、-NH、-SH、-CN、=O或-COOH;
    每一个R b相同或不同,彼此独立地选自-F、-Cl、-Br、-I、-SH、-OH、-CN、-COOH、无取代或任选被一个或多个被R a取代的下列基团:C 1-40烷基、C 1-40烷氧基、C 2-40烯基、C 2-40炔基、C 3-20环烷基、3-20元杂环基、C 6-20芳基、5-20元杂芳基、C 3-20环烷基氧基、3-20元杂环基氧基、C 6-20芳基氧基、5-20元杂芳基氧基、C 3-20环烷基C 1-40烷基、3-20元杂环基C 1-40烷基、C 6-20芳基C 1-40烷基、5-20元杂芳基C 1-40烷基、H[(CH 2) nO] n-、-NR cR d、-C(O)NR cR d、-Y 1C(O)R e或-C(O)Y 1R e
    或者,当R 3被两个或更多个相同或不同的R b取代时,其中两个R b可以分别脱去各自的H或其他基团,并与其所连接的碳原子一起形成与R 3稠合的环系R s,其中R s选自与R 3稠合的C 3-20环烷基、3-20元杂环基、C 6-20芳基、5-20元杂芳基;
    R c、R d、R e相同或不同,彼此独立地选自H,或无取代或任选被一个或多个R a取代的下列基团:C 1-40烷基、C 2-40烯基、C 2-40炔基、C 3-20环烷基、3-20元杂环基、C 6-20芳基、5-20元杂芳基或CONH 2
    Y 1选自化学键、-O-、-S-,无取代或任选被一个或多个R a取代的-NH-、C 1-40烷基、C 1-40烷氧基、C 3-20环烷基、3-20元杂环基、C 6-20芳基、5-20元杂芳基或(CH 2CH 2O) j-;
    m、n、j可以相同或不同,彼此独立地选自1以上的整数,例如1~20的整数,如1、2、3、4、5、6、7、8、9或10;
    优选地,R 1、R 2可以相同或不同,彼此独立地选自H、F、Cl、Br、I、OH、SH、CN、 COOH或C 1-40烷基,例如R 1、R 2选自H或C 1-40烷基;
    R 3可以选自无取代或任选被一个或多个R b取代的下列基团:C 3-8环烷基、3-8元杂环基、C 6-10芳基、5-6元杂芳基;
    每一个R b相同或不同,彼此独立地选自F、Cl、Br、I、SH、OH、CN、COOH、无取代或任选被一个或多个被R a取代的下列基团:C 1-6烷基、C 1-6烷氧基、C 3-8环烷基、3-8元杂环基、C 6-10芳基、5-6元杂芳基、C 3-8环烷基氧基、3-8元杂环基氧基、C 6-10芳基氧基、5-6元杂芳基氧基、C 3-8环烷基C 1-6烷基、3-8元杂环基C 1-6烷基、C 6-10芳基C 1-6烷基、5-6元杂芳基C 1-6烷基、H[(CH 2) nO] n-、-NR cR d、-C(O)NR cR d、-Y 1C(O)R e或-C(O)Y 1R e
    或者,当R 3被两个或更多个相同或不同的R b取代时,其中两个R b可以分别脱去各自的H或其他基团,并与其所连接的碳原子一起形成与R 3稠合的环系R s,其中R s选自与R 3稠合的C 3-8环烷基、3-8元杂环基、C 6-10芳基、5-6元杂芳基。
  2. 如权利要求1所述的氨基醇衍生物、其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药,其中R 3可以选自苯基、吡啶基、吡嗪基、环己基、哌啶基、哌嗪基;
    例如,R 3可以选自苯基、吡啶-1-基、吡啶-2-基、吡啶-3-基、吡啶-4-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基;
    优选地,每一个R b可以相同或不同,彼此独立地选自F、Cl、Br、I、SH、OH、CN、COOH、无取代或任选被一个或多个被R a取代的下列基团:C 1-6烷基(如甲基、乙基、丙基、异丙基、叔丁基)、C 1-6烷氧基(如甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基)、C 3-6环烷基、C 3-6环烷基氧基、C 1-6烷基羰基氨基、C 1-6烷基氧基羰基、C 1-6烷基羰基氧基、3-6元杂环基C 1-6烷基、-CONH 2、-NHCOCH 3
    例如,每一个R b可以相同或不同,彼此独立地选自-F、-OH、-CN、-CF 3、-COOH、-CONH 2、甲氧基、乙氧基、丙氧基、异丙氧基、-NHCOCH 3、环戊基、-C(O)OCH 3、氮杂环丁烷-1-基甲基、吡咯烷-1-基甲基、哌啶-1-基甲基;
    或者,当R 3被两个或更多个相同或不同的R b取代时,其中两个R b可以分别脱去各自的H或其他基团,并与其所连接的碳原子一起形成与R 3稠合的环系R s,其中R s选自与R 3稠合的二氧杂环戊烯环系;
    优选地,当R 3为苯基时,R 3优选至少在3-位被R b3取代,其中R b3为拉电子取代基;
    优选地,当R 3为苯基时,R 3优选至少在4-位被R b4取代,其中R b4为给电子取代基;
    优选地,R b3可以选自-Cl、-Br、-I、-SH、-OH、-CN、-COOH、-CONH 2、-COC 1-6烷基、-COC 3-6环烷基、-CF 3
    优选地,R b4可以选自C 1-6烷基(如甲基、乙基、丙基、异丙基、叔丁基)、C 1-6烷氧基(如甲氧基、乙氧基、丙氧基、异丙氧基、叔丁氧基)、C 3-6环烷基、C 3-6环烷基氧基、C 1-6烷基羰基氨基。
  3. 如权利要求1或2所述的氨基醇衍生物、其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药,其中:
    式I所示的氨基醇衍生物具有如下式I’所示的结构:
    Figure PCTCN2018092233-appb-100002
  4. 如权利要求1-3任一项所述的氨基醇衍生物、其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药,其中式I化合物选自如下化合物:
    Figure PCTCN2018092233-appb-100003
    Figure PCTCN2018092233-appb-100004
  5. 权利要求1-4任一项所述氨基醇衍生物、其药学上可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药的制备方法,包括如下步骤a至f中的一步或多步:
    Figure PCTCN2018092233-appb-100005
    其中,R 1、R 2、R 3具有权利要求1-4任一项所述的定义;
    X选自卤素;
    PG 1选自羟基保护基;
    PG 2选自氨基保护基;
    或者,PG 1和PG 2可以彼此键合以对羟基和羰基同时进行保护。
  6. 如权利要求5所述的制备方法,其中:
    步骤a中,可以使用D-酒石酸作为拆分试剂,得到化合物7;
    步骤b中,化合物7可以先在PhCHO和NaBH(OAc) 3的存在下对氨基进行保护,然后在CH 3OC(CH 3) 2OCH 3(如2,2-二甲氧基丙烷)和酸的存在下得到化合物8;
    步骤c中,化合物8在n-BuLi、CO 2的存在下,在-78℃下反应,得到化合物9;
    步骤d中,化合物9可以先与草酰氯反应,然后与下式所示的化合物10在三乙胺的存在下反应,得到化合物11;
    Figure PCTCN2018092233-appb-100006
    步骤e中,化合物11在TsCl和三乙胺的存在下反应,得到化合物12;
    步骤f)中,在脱保护的条件下脱去氨基和羟基的保护基PG 1和PG 2,例如在酸的存在下脱去羟基保护基;以及在还原条件下脱去氨基保护基;
    优选地,所述制备方法可包括如下步骤:
    Figure PCTCN2018092233-appb-100007
  7. 一种药物组合物,包含权利要求1-4任一项所述的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药,以及药学上可接受的载体;
    所述药物组合物可以为包括但不限于口服剂型、胃肠外给药剂型、外用剂型和直肠给药剂型的形式;
    优选地,所述药物组合物为口服的片剂、胶囊、丸剂、粉剂、缓释制剂、溶液和悬浮液,用于胃肠外注射的无菌溶液、悬浮液或乳液,用于外用的软膏或乳膏,或者用于直肠给药的栓剂;
    优选地,所述药物组合物为适合单次施予精确剂量的单位剂型;
    优选地,所述药物组合物还包含至少另一种治疗剂;
    优选地,所述药物组合物和至少一种治疗剂分别以独立的剂型组合成组合产品,如套装药品。
  8. 权利要求1-4任一项所述的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药在制备下调S1P1的表达的药物中的应用。
  9. 权利要求1-4任一项所述的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药在制备用于预防和治疗与免疫炎症相关的疾病药物中的应用。
  10. 权利要求1-4任一项所述的氨基醇衍生物、其药学可接受的盐、立体异构体、同位素标记物、溶剂化物、多晶形物或前药在制备用于治疗或预防治疗与免疫活性相关的疾病或病症的药物中的用途;
    所述与免疫活性相关的疾病或病症可以为多发性硬化症、渐冻症、CIDP、系统性红斑狼疮、类风湿关节炎、溃疡性结肠炎、银屑病、多发性肌炎、I型糖尿病、甲状腺机能亢进、硬皮病、重症肌无力等疾病中的一种或多种。
PCT/CN2018/092233 2017-06-30 2018-06-21 氨基醇衍生物、其药物组合物和用途 WO2019001342A1 (zh)

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