WO2014183520A1 - 吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用 - Google Patents
吡啶并嘧啶类衍生物、其制备方法及其在医药上的应用 Download PDFInfo
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- WO2014183520A1 WO2014183520A1 PCT/CN2014/075387 CN2014075387W WO2014183520A1 WO 2014183520 A1 WO2014183520 A1 WO 2014183520A1 CN 2014075387 W CN2014075387 W CN 2014075387W WO 2014183520 A1 WO2014183520 A1 WO 2014183520A1
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- QJRHXEISZSWULH-UHFFFAOYSA-N tert-butyl 4-(6-chloropyridin-3-yl)-4-hydroxypiperidine-1-carboxylate Chemical compound C1CN(C(=O)OC(C)(C)C)CCC1(O)C1=CC=C(Cl)N=C1 QJRHXEISZSWULH-UHFFFAOYSA-N 0.000 description 1
- UCTKRHACHNKUPB-UHFFFAOYSA-N tert-butyl 4-(oxomethylidene)piperidine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(=C=O)CC1 UCTKRHACHNKUPB-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to a novel pyridopyrimidine derivative, a process for the preparation thereof, and a pharmaceutical composition containing the same, and its use as a cancer therapeutic agent, particularly as a CDK4 and/or CDK6 inhibitor.
- CDKs cyclin-dependent kinases
- Cyclin B/CDK1, Cyclin A/CDK2 Cyclin E/CDK2, Cyclin D/CDK4, Cyclin D/CDK6 and other heterodimers are important regulators of cell cycle progression. Additional functions of the Cyclin/CDK heterodimer include regulation of transcription, DNA repair, differentiation, and programmed cell death.
- CDK4 and CDK6 are highly homologous, CDK4 single knockout mice have diabetes signs and cell defects, and CDK6 single knockout mice have mild anemia symptoms due to defects in hematopoietic cell proliferation, while CDK4 and CDK6 (CDK4/6) pairs Gene knockout impairs the proliferative capacity of hematopoietic precursor cells, leading to double knockout of mouse embryonic death.
- CDK4 and CDK6 (CDK4/6) pairs Gene knockout impairs the proliferative capacity of hematopoietic precursor cells, leading to double knockout of mouse embryonic death.
- Superactivation of the CDK4/6- C ydin D/Rb signaling pathway is commonly found in tumor cells. Under the stimulation of various mitotic signals inside and outside the cell, cyclin D is highly expressed, regulating the interaction of CDK4/6 protein with cyclin D, promoting CDK4/6 localization and kinase activity.
- Activated CDK4/6 inhibits the activity of Rb tumor suppressor protein by phosphorylation, dissociates the Rb-E2F complex, releases free E2F into the nucleus, regulates protein transcription, and initiates cell cycle progression.
- Superactivation of CDK4 is often found in epithelial malignancies, whereas superactivation of CDK6 is often found in stromal cell tumors such as sarcomas and hematological cancers. Construction of a breast cancer-bearing mouse model revealed that wild-type nude mice all formed tumors, while CDK4 knockout nude mice could not form tumors completely; while anti-CDK4 siRNA interfered with CDK4 expression, tumor growth in nude mice was found to be significantly inhibited.
- CDK inhibitors can also be used to treat cardiovascular disorders such as restenosis and atherosclerosis and other vascular disorders caused by abnormal cell proliferation; for the treatment of diseases caused by various infectious agents , including fungi, protozoan parasites (such as Plasmodium falciparum) and DNA and RNA viruses; can also be used to improve various autoimmune disorders, studies have found that in the rat model of arthritis, joint swelling is basically expressed by pl6 Inhibited by viral treatment, CDK inhibitors can effectively fight other cells Proliferative disorders, including psoriasis (characterized by hyperproliferation of keratinocytes), glomerulonephritis, and lupus.
- G1/S transition phase and G2/M phase cells are extremely sensitive to DNA damaging agents such as ionizing radiation (IR), and the process of cell transition from G1 to S phase requires at least 3 cell cycles.
- IR ionizing radiation
- Protein-dependent kinases (CDK2, CDK4, and CDK6) and their regulatory subunit cyclins co-phosphorylate Rb family proteins for regulation.
- Selective CDK4/6 inhibitors can induce G1 arrest in cells, thereby increasing the tolerance of hematopoietic stem/progenitor cells to DNA damaging agents such as IR, and effectively reducing various hematopoietic toxicities caused by radiation, including myelosuppression, hooliganism.
- CDK inhibitors are difficult to identify compounds that specifically inhibit CDK proteins but not other enzymes. Thus, despite the potential to treat a variety of diseases, CDK inhibitors have not yet been approved for commercial use.
- PD-0332991 inhibits the phosphorylation of Rb by inhibiting the activity of CDK4 and CDK6, leaving the E2F-Rb complex in the cytosol and blocking the initiation of the cell cycle.
- Clinical trials showed that patients with letrozole monotherapy had a progression-free survival (PFS) of 7.5 months, whereas patients with letrozole and PD-0332991 were treated with progression-free survival. Extended to 26.1 months.
- PFS progression-free survival
- CDK4 and CDK6 include WO2003062236, WO2006008874, WO2009126584, WO2010075074, WO2011101409, and WO2012129344.
- the present invention will provide a novel structure of selective CDK4 and CDK6 inhibitors, and find that compounds having such structures exhibit excellent effects and effects, particularly excellent pharmacogen absorption activities. Summary of the invention
- the object of the present invention is to provide a compound represented by the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof.
- ⁇ is a single key or double key
- a 1 or A 2 are each independently selected from -CR' or N;
- R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, a fluorenyl group, a halogenated fluorenyl group, a hydroxy group or a decyloxy group;
- Y is selected from S or 0;
- R 1 is selected from a hydrogen atom, a halogen, a fluorenyl group, a halogenated fluorenyl group, a hydroxy fluorenyl group or a cyclodecyl group;
- R 2 is selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, -0R 7 , -C(0)R 7 , -C(0)OR 7 , or -OC(0)R 7 , wherein said fluorenyl, alkenyl, alkynyl, cyclodecyl, heterocycloalkyl, aryl or heteroaryl are each independently Optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, 3, 4, decyl, hydroxy, decyl, cyclodecyl, heterocycloalkyl Substituted with a substituent of an
- R 3 is selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the cycloalkyl group, the heterocyclic fluorenyl group, the aryl group or the heteroaryl group are each independently Optionally optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, 3 ⁇ 4 hydrazino, hydroxy fluorenyl, decyloxy, cyclodecyl, heterocyclic hydrazine Substituted by a substituent of a aryl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
- R 4 is selected from a hydrogen atom, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, -OR 7 , -C(0)R 7 or -C(0)OR.
- fluorenyl, alkenyl, alkynyl, cyclodecyl, heterocycloalkyl, aryl or heteroaryl group is each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, and nitro a substituent of an amino group, a hydroxyl group, an oxo group, a decyl group, a 3 ⁇ 4 fluorenyl group, a hydroxy group, a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group Replaced
- R 5 or R 6 are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR 7 , -C(0)R 7 -CCC OR 7 or -OCCC R 7 , wherein each of the indenyl, alkenyl, alkynyl, cyclodecyl, heterocycloalkyl, aryl or heteroaryl groups Optionally optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, halohydrazino, hydroxydecyl, decyloxy, cyclodecyl, heterocycle Substituted
- R 7 is selected from a hydrogen atom, a fluorenyl group, a hydroxyl group, a halogen, a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a hetero An aryl group, wherein said fluorenyl, decyloxy, cyclodecyl, heterocycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, a substituent of an amino group, a hydroxyl group, an oxo group, a decyl group, a halogenated fluorenyl group, a hydroxymethyl group, a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate
- a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein each of A 1 or A 2 is independently -CH.
- a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 5 or R 6 are each independently selected from a hydrogen atom, a halogen, a thiol group or a hydroxy group.
- a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 4 is selected from a hydrogen atom or a fluorenyl group, wherein the thiol group is further optionally further substituted by one or more substituents selected from halogen, hydroxy or cyclodecyl Replaced.
- a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula ( ⁇ ) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair Isomer or its mixed salt:
- RR 6 is as defined in the general formula (I).
- a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (III) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair Isomer or its mixed salt:
- RR 6 is as defined in the general formula (I).
- Typical compounds of the invention include, but are not limited to:
- the present invention also provides a compound of the formula (IC) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, It can be used for the synthesis or further synthesis of the compound of the formula (I) or its tautomer, mesogen, racemate, enantiomer, diastereomer Intermediates for isomers:
- ⁇ is a single key or double key
- Boc is a tert-butoxycarbonyl group
- R is a sulfhydryl group
- a 1 or A 2 are each independently selected from -CR' or N;
- R' is selected from a hydrogen atom, a halogen, a cyano group, a nitro group, a fluorenyl group, a halogenated fluorenyl group, a hydroxy group or a decyloxy group;
- Y is selected from S or 0;
- R 1 is selected from a hydrogen atom, a halogen, a fluorenyl group, a halogenated fluorenyl group, a hydroxy fluorenyl group or a cyclodecyl group;
- R 3 is selected from a hydrogen atom, a fluorenyl group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the cycloalkyl group, the heterocyclic fluorenyl group, the aryl group or the heteroaryl group are each independently Optionally optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, 3 ⁇ 4 hydrazino, hydroxy fluorenyl, decyloxy, cyclodecyl, heterocyclic hydrazine Substituted by a substituent of a aryl group, an aryl group, a heteroaryl group, a carboxyl group or a carboxylate group;
- R 5 or R 6 are each independently selected from the group consisting of a hydrogen atom, a halogen, a cyano group, a nitro group, an oxo group, a decyl group, an alkenyl group, an alkynyl group, a cyclodecyl group, a heterocycloalkyl group, an aryl group, a heteroaryl group, -OR 7 , -C(0)R 7 -CCC OR 7 or -OCCC R 7 , wherein each of the indenyl, alkenyl, alkynyl, cyclodecyl, heterocycloalkyl, aryl or heteroaryl groups Optionally optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, halohydrazino, hydroxydecyl, decyloxy, cyclodecyl, heterocycle Substituted
- R 7 is selected from a hydrogen atom, a fluorenyl group, a hydroxyl group, a halogen, a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group or a heteroaryl group, wherein the fluorenyl group, the decyloxy group, the cyclodecyl group, and the hetero aryl group
- the cycloalkyl, aryl or heteroaryl are each independently optionally further selected from one or more selected from the group consisting of halogen, cyano, nitro, amino, hydroxy, oxo, decyl, halodecyl, hydroxy fluorenyl Substituted by a substituent of a decyloxy group, a cyclodecyl group, a heterocyclic fluorenyl group, an aryl group, a heteroaryl group, a carboxyl group or a
- a compound of the formula (IC) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Body or a mixture thereof, or A pharmaceutically acceptable salt, wherein R is a butyl group the present invention also provides a compound of the formula (I) or a tautomer thereof, a mesogen, an oxime, an enantiomer, a non- a method of enantiomers or mixtures thereof, or a pharmaceutically acceptable salt thereof,
- the compound of the formula (IA) and the compound of the formula (IB) are subjected to a substitution reaction under basic conditions, optionally under the action of a catalyst to obtain a compound of the formula (IC); a compound of the formula (IC) in a solvent, under acidic conditions, Performing a deprotection reaction, optionally further performing a substitution reaction to obtain a compound of the formula (I);
- X is a halogen
- Boc is a tert-butoxycarbonyl group
- R 4 is preferably a hydrogen atom or a fluorenyl group, wherein the fluorenyl group is optionally further substituted with one or more substituents selected from a halogen, a hydroxyl group or a cyclodecyl group.
- the invention further relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer thereof A form, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents or excipients.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for inhibiting CDK4 and/or CDK6.
- the invention further relates to a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the treatment of abnormal cell proliferative diseases, infections (eg, viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg, rheumatoid arthritis, bone and joint) Inflammation, etc., autoimmune diseases (eg psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, surgery) Use in a medicament for a posterior vessel stenosis, restenosis, or the like, or a neurodegenerative disease (e.g., Alzheimer's disease, Parkinson's disease, etc.), where
- the invention further relates to a compound of the formula (I) or a tautomer thereof, a mesogen, a racemic form Use of a body, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for the preparation of a medicament for treating cancer, wherein the cancer is selected from the group consisting of breast Cancer, ovarian cancer, prostate cancer, melanoma, brain tumors (such as gliomas with malignant astroglia and oligodendroglioma), esophageal cancer, stomach cancer, liver cancer, pancreatic cancer, Colorectal cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, skin cancer, glioblastoma, neuromuscular Cell tumor, sarcoma, liposarcoma, osteochond
- the present invention relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer or a mixture thereof, or Use of a pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for the manufacture of a medicament for preventing or treating a hematopoietic toxic disease caused by radiation, wherein said radiation-induced hematopoietic toxic diseases include, but are not limited to, myelosuppression, neutrophils Reduced, leukopenia, anemia.
- the invention also relates to a method of inhibiting the activity of CDK4 and/or CDK6 comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, exosome thereof A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
- the present invention relates to the treatment of abnormal cell proliferative diseases, infections (eg, viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg, rheumatoid arthritis, osteoarthritis, etc.), autoimmune Diseases (eg psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc.) Or a method of a neurodegenerative disease (eg, Alzheimer's disease, Parkinson's disease, etc.) comprising administering to a patient in need thereof a therapeutically effective amount of a compound of the formula (I) or a tautomer thereof, a racemate, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt
- infections
- the invention further relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate, enantiomer thereof Is a form of an isomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, glioblastoma with malignant astroglia and oligodendroglioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (eg colon cancer, rectal cancer, etc.), Lung cancer (eg non-small cell lung cancer, small cell lung cancer, primary or metastatic squamous cell carcinoma, etc.), kidney cancer, skin cancer, glioblastoma, neuroblasto
- the invention also relates to a method of treating cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or a tautomer, mesogen, racemate, enantiomer thereof An isomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in combination with one or more other anticancer agents, the anticancer agent being selected from the group consisting of Deuterated agents (eg cyclophosphamide, ifosfamide, melphalan, busulfan, nimodin, ramustine, dacarbazine, temozolomide, nitrogen mustard, dibromomannitol, etc.), platinum Complexing agents (eg cisplatin, carboplatin, oxaliplatin, etc.), metabolic antagonists (eg methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine,
- the present invention also relates to a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a non-pair thereof, which is a drug which inhibits the activity of CDK4 and/or CDK6. Or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
- the invention also relates to the treatment of abnormal cell proliferative diseases, infections (eg viral infections such as herpes, HIV, fungal infections, etc.), inflammatory conditions (eg rheumatoid arthritis, osteoarthritis, etc.), autoimmune diseases (such as psoriasis, lupus, type I diabetes, diabetic nephropathy, multiple sclerosis, glomerulonephritis, etc.), cardiovascular disease (eg myocardial infarction, stroke, atherosclerosis, postoperative vascular stenosis, restenosis, etc.) or a compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer of a drug for a neurodegenerative disease (for example, Alzheimer's disease, Parkinson's disease, etc.)
- infections eg viral infections such as herpes, HIV, fungal infections, etc.
- inflammatory conditions eg rheumatoid arthritis, osteoarthritis
- the present invention further relates to a compound represented by the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or a drug for treating cancer. a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, wherein the cancer is selected from the group consisting of breast cancer, ovarian cancer, prostate cancer, melanoma, brain tumor (eg, malignant astrocyte and Glioma of oligodendroglioma, etc.), esophageal cancer, gastric cancer, liver cancer, pancreatic cancer, colorectal cancer (eg colon cancer, rectal cancer, etc.), lung cancer (eg non-small cell lung cancer, small cell lung cancer) , primary or metastatic squamous cell carcinoma, etc., kidney cancer, skin cancer, glioblastoma, neuroblastoma, sarcoma, liposarcoma, osteochondroma
- the present invention also relates to a compound represented by the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer thereof or a drug for treating cancer. a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, and one or more anticancer agents selected from the group consisting of oximation agents (eg, cyclophosphamide, ifosfamide) , melphalan, busulfan, nimodin, ramustine, dacarbazine, temozolomide, hydrochloric acid mustard, dibromomannitol, etc.), platinum complexing agents (eg cisplatin, carboplatin, oxa Lipoplatin, etc., metabolic antagonists (eg methotrexate, 5-fluorouracil, tegafur, gemcitabine, capecitabine, fluoride Vesicle, pemetrexed, etc
- the pharmaceutical composition containing the active ingredient may be in a form suitable for oral administration, such as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules, or syrups or Tincture.
- Oral compositions can be prepared according to any method known in the art for preparing a pharmaceutical composition, such compositions may contain one or more ingredients selected from the group consisting of sweeteners, flavoring agents, coloring agents, and preservatives, To provide a pleasing and tasty pharmaceutical preparation. Tablets contain the active ingredient and non-toxic pharmaceutically acceptable excipients suitable for the preparation of tablets for mixing.
- excipients may be inert excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating agents and disintegrating agents such as microcrystalline cellulose, croscarmellose sodium, corn Starch or alginic acid; a binder such as starch, gelatin, polyvinylpyrrolidone or gum arabic; and a lubricant such as magnesium stearate, stearic acid or talc.
- These tablets may be uncoated or may be coated by a known technique which provides a sustained release effect over a long period of time by masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract.
- water-soluble taste masking materials such as hydroxypropylmethylcellulose or hydroxypropylcellulose, or extended-time materials such as ethylcellulose, cellulose acetate butyrate may be used.
- hard gelatin capsules in which the active ingredient is mixed with an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin, or in which the active ingredient is mixed with a water-soluble carrier such as polyethylene glycol or an oil vehicle such as peanut oil, liquid paraffin or olive oil.
- Soft gelatin capsules provide oral preparations.
- the aqueous suspension contains the active substance and excipients suitable for the preparation of the aqueous suspension for mixing.
- excipients are suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone and gum arabic; dispersing or wetting agents can be a naturally occurring phospholipid such as lecithin, or a condensation product of an alkylene oxide with a fatty acid such as polyoxyethylene stearate, or a condensation product of an epoxy oxime with a long chain fatty alcohol, such as a heptadecylethyleneoxy whale Heptadecaethyleneoxy cetanol, or a condensation product of epoxy oxime with a partial ester derived from a fatty acid and a hexitol, such as polyepoxide sorbitan monooleate, or oxirane with a fatty acid and hexitol
- the aqueous suspensions may also contain one or more preservatives such as ethylparaben or n-propylparaben, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents. Flavoring agents such as sucrose, saccharin or aspartame.
- the oil suspension can be formulated by suspending the active ingredient in a vegetable oil such as peanut oil, olive oil, sesame oil or coconut oil, or a mineral oil such as liquid paraffin.
- the oil suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol.
- the above sweeteners and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an anti-oxidant such as butylated hydroxyanisole or (X-tocopherol).
- Dispersible powders and granules suitable for use in the preparation of aqueous suspensions may be employed in the preparation of aqueous dispersions in the presence of a dispersible or wetting agent, a suspending agent or one or more preservatives. Suitable dispersing or wetting agents and suspending agents can be used to illustrate the above examples. Other excipients such as sweetening, flavoring, and coloring agents can also be added. These compositions are preserved by the addition of an anti-oxidant such as ascorbic acid.
- the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsion.
- the oil phase may be a vegetable oil such as olive oil or peanut oil, or a mineral oil such as liquid paraffin or a mixture thereof.
- Suitable emulsifiers may be naturally occurring phospholipids, such as soy lecithin and esters or partial esters derived from fatty acids and hexitol anhydrides such as sorbitan monooleate, and condensation products of the partial esters and oxirane, For example, poly(ethylene oxide sorbitol monooleate).
- the emulsions may also contain sweeteners, flavoring agents, preservatives, and antioxidants.
- Syrups and elixirs may be formulated with sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
- sweetening agents such as glycerol, propylene glycol, sorbitol or sucrose.
- Such formulations may also contain a demulcent, a preservative, a colorant, and an antioxidant.
- the pharmaceutical composition may be in the form of a sterile injectable aqueous solution.
- acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
- the sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in the oil phase.
- the active ingredient is dissolved in a mixture of soybean oil and lecithin.
- the oil solution is then added to a mixture of water and glycerin to form a microemulsion.
- the injection or microemulsion can be injected into the patient's bloodstream by local injection.
- the solution and microemulsion are preferably administered in a manner that maintains a constant circulating concentration of the compound of the invention.
- a continuous intravenous delivery device can be used.
- An example of such a device is the Deltec CADD-PLUS. TM. 5400 intravenous pump.
- the pharmaceutical composition may be in the form of a sterile injectable aqueous or oily suspension for intramuscular and subcutaneous administration.
- the suspension may be formulated according to known techniques using those suitable dispersing or wetting agents and suspending agents.
- the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example, a solution prepared in 1,3-butanediol.
- sterile fixed oils can be conveniently employed as a solvent or suspension medium. For this purpose, any blended fixed oil including synthetic mono- or diglycerides can be used.
- fatty acids such as oleic acid can also be prepared as an injection.
- the compounds of the invention may be administered in the form of a suppository for rectal administration.
- These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and thus dissolves in the rectum to release the drug.
- suitable non-irritating excipient include a mixture of cocoa butter, glycerin gelatin, hydrogenated vegetable oil, polyethylene glycols of various molecular weights, and fatty acid esters of polyethylene glycol.
- the dosage of the drug depends on a variety of factors including, but not limited to, the following factors: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the performance of the patient, the patient Diet, time of administration, mode of administration, rate of excretion, combination of drugs, etc.; alternatively, the preferred mode of treatment, such as the mode of treatment, the daily amount of the compound of formula (I) or a pharmaceutically acceptable salt
- the preferred mode of treatment such as the mode of treatment, the daily amount of the compound of formula (I) or a pharmaceutically acceptable salt
- mercapto refers to a saturated aliphatic hydrocarbon group, including straight chain and branched chain groups of 1 to 20 carbon atoms.
- fluorenyl groups having 1 to 10 carbon atoms more preferably fluorenyl groups having 1 to 6 carbon atoms, most preferably fluorenyl groups having 1 to 4 carbon atoms, most preferably methyl groups.
- Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1, 1-dimethylpropyl,
- n-heptyl 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylpentyl, 2,4- Dimethylpentyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 2-ethylpentyl, 3-ethylpentyl, n-octyl, 2,3-dimethyl Hexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2- Ethylhexyl, 3-ethylhexyl, 4-ethylhexyl,
- lower fluorenyl groups having 1 to 6 carbon atoms non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl , n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3 -methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl , 2,3-dimethylbutyl and the like.
- the thiol group may be substituted or unsubstituted, and when substituted, the substituent may be substituted at any available point of attachment, preferably one or more of the following groups, independently selected from the group consisting of fluorenyl groups. , alkenyl, alkynyl, decyloxy, sulfonylthio, decylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclooxy A heterocyclic methoxy group, a cyclodecylthio group, a heterocyclic thiol group, an oxo group, an amino group, a 3 ⁇ 4 alkyl group, a hydroxy group, a carboxyl group or a carboxylate group.
- fluorenyl groups alkenyl, alkynyl, decyloxy, sulfonylthio,
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably the cyclodecyl ring comprises from 3 to The 10 carbon atoms, most preferably the cyclodecyl ring contains 3 to 6 carbon atoms, most preferably a cyclopropyl or cyclopentyl group.
- Non-limiting examples of monocyclic cyclodecyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
- the group, the cyclooctyl group and the like are preferably a cyclopropyl group or a cyclopentyl group.
- Polycyclic fluorenyl groups include spiro, fused, and cyclic fluorenyl groups.
- the cycloalkyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, a hydrazine sulfonium group.
- Base mercaptoamino, 3 ⁇ 4, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio , heterocyclic thiol, oxo, amino, halogen Mercapto, hydroxymethyl, carboxyl or carboxylate groups.
- alkenyl refers to a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, such as ethenyl, 1-propenyl, 2-propenyl, 1-, 2- or -butenyl and the like.
- Preferred is a C 2 .1Q alkenyl group, more preferably a C 2 . 6 alkenyl group, most preferably a C 2 . 4 alkenyl group, most preferably a vinyl group.
- the alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a fluorenyl group, an alkenyl group, an alkynyl group, a decyloxy group, a thiol group, Mercaptoamino, 3 ⁇ 4, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio, hetero Cyclodecylthio, oxo, amino, halodecyl, hydroxydecyl, carboxy or carboxylate.
- the substituent is preferably one or more of the following groups independently selected from the group consisting of a fluorenyl group, an alkenyl group, an alkynyl group, a decyloxy group,
- alkynyl refers to a fluorenyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, for example ethynyl, 1-propynyl, 2-propynyl, 1-, 2- Or 3-butynyl and the like.
- C 2. 1Q alkynyl group more preferably C 2. 6 alkynyl group, most preferably C 2. 4 alkynyl group.
- the alkynyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, a thiol group, Mercaptoamino, 3 ⁇ 4, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio, hetero Cyclodecylthio, oxo, amino, halodecyl, hydroxydecyl, carboxy or carboxylate.
- the substituent is preferably one or more of the following groups independently selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group
- heterocyclic fluorenyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent comprising from 3 to 20 ring atoms, wherein one or more ring atoms are selected from nitrogen, oxygen or S(0) A hetero atom of m (wherein m is an integer of 0 to 2), but does not include a ring moiety of -0-0-, -0-S- or -SS-, and the remaining ring atoms are carbon.
- It preferably comprises from 3 to 12 ring atoms, wherein 1 to 4 are hetero atoms, more preferably the heterocyclic indenyl ring contains 3 to 10 ring atoms, and more preferably the heterocyclic indenyl ring contains 5 to 6 ring atoms.
- monocyclic heterocyclic fluorenyl groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, pyranyl, tetrahydrofuranyl and the like.
- the polycyclic heterocyclic fluorenyl group includes a spiro ring, a fused ring, and a heterocyclic fluorenyl group of a bridged ring.
- the heterocyclic fluorenyl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of a fluorenyl group, an alkenyl group, an alkynyl group, a decyloxy group, and an anthracene group.
- aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring sharing a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, more preferably Phenyl and naphthyl are most preferred.
- the aryl ring may be fused to a heteroaryl, heterocycloalkyl or cyclodecyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples comprising:
- the aryl group may be substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups. Independently selected from the group consisting of fluorenyl, alkenyl, alkynyl, decyloxy, sulfonylthio, decylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, hetero Aryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio, heterocyclic thiol, amino, 3 ⁇ 4 fluorenyl, hydroxydecyl, carboxy or carboxylate.
- heteroaryl refers to a heteroaromatic system containing from 1 to 4 heteroatoms, from 5 to 14 ring atoms, wherein the heteroatoms are selected from the group consisting of oxygen, sulfur and nitrogen.
- the heteroaryl group is preferably 5 to 10 members, more preferably 5 or 6 members, such as thiadiazolyl, pyrazolyl, oxazolyl, oxadiazolyl, imidazolyl, triazolyl, thiazolyl, furyl , thienyl, pyridyl, pyrrolyl, fluorenyl-fluorenyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
- the heteroaryl ring may be fused to an aryl, heterocycloalkyl or cyclodecyl ring, wherein the parent structure is attached to one:
- the heteroaryl group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups, independently selected from the group consisting of fluorenyl, alkenyl, alkynyl, decyloxy, sulfonium sulfide Base, mercaptoamino, halogen, fluorenyl, hydroxy, nitro, cyano, cyclodecyl, heterocycloalkyl, aryl, heteroaryl, cyclodecyloxy, heterocyclomethoxy, cyclodecylthio, A heterocyclic thiol group, an amino group, a 3 ⁇ 4 fluorenyl group, a hydroxy group, a carboxyl group or a carboxylate group.
- decyloxy refers to -0-(fluorenyl) and -0-(unsubstituted cycloalkyl), wherein the fluorenyl and cyclodecyl are as defined above.
- Non-limiting examples include methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
- the decyloxy group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from the group consisting of an anthracenyl group, an alkenyl group, an alkynyl group, a decyloxy group, and an anthracene group.
- Haloalkyl means that the fluorenyl group is substituted by one or more halogens, wherein the fluorenyl group is as defined above.
- Hydrolysis means a hydrazine group.
- Haldroxycarbonyl refers to a fluorenyl group substituted with a hydroxy group, wherein the fluorenyl group is as defined above.
- Halogen means fluoro, chloro, bromo or iodo, preferably fluoro or iodo.
- Amino means - ⁇ 2 .
- Neitro means -N0 2 .
- Carboxy means -C(0)OH.
- Carboxylic acid ester group means -C(0)0(fluorenyl) or (cycloalkyl), wherein the indenyl or cyclodecyl group is as defined above.
- “Optional” or “optionally” means that the event or environment described subsequently may, but need not, occur, including where the event or environment occurs or does not occur.
- “heterocyclic fluorenyl group optionally substituted by thiol” means that fluorenyl may be, but not necessarily, present, including the case where the heterocyclic fluorene group is substituted by a thiol group and the heterocyclic fluorenyl group is not decyl The situation of substitution.
- Substituted means that one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms are independently substituted with each other by a corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, and those skilled in the art will be able to determine (by experiment or theory;) possible or impossible substitutions without undue effort. For example, an amino group or a hydroxyl group having a free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., a registered) bond.
- “Pharmaceutical composition” means a mixture comprising one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, and other chemical components, as well as other components such as physiological/pharmaceutically acceptable carriers. And excipients.
- the purpose of the pharmaceutical composition is to promote administration to an organism, to facilitate absorption of the active ingredient and to exert biological activity. Synthetic method of the present invention
- the compound of the formula (IA) and the compound of the formula (IB) are subjected to a substitution reaction under basic conditions, optionally under the action of a catalyst to obtain a compound of the formula (IC); a compound of the formula (IC) in a solvent, under acidic conditions, Performing a deprotection reaction, optionally further performing a substitution reaction to obtain a compound of the formula (I);
- X is a halogen
- Boc is a tert-butoxycarbonyl group
- R 4 is preferably a hydrogen atom or a fluorenyl group, wherein the fluorenyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy or cycloalkyl;
- R 2 is preferably -C(0)R 7 And R 7 is a fluorenyl group.
- a method of medicinal salt comprising:
- the compound of the formula (II-C) is obtained by a substitution reaction of a compound of the formula ( ⁇ - ⁇ ) with a compound of the formula ( ⁇ - ⁇ ) under basic conditions, optionally under the action of a catalyst; a compound of the formula (II-C); Deprotection reaction in a solvent under acidic conditions, optionally further performing a substitution reaction to obtain a compound of the formula ( ⁇ );
- X is a halogen
- Boc is a tert-butoxycarbonyl group
- R 4 is preferably a hydrogen atom or a fluorenyl group, wherein the fluorenyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy or cycloalkyl;
- R 2 is preferably -C(0)R 7 And R 7 is a fluorenyl group.
- the compound of the formula (III-C) is obtained by substituting a compound of the formula (III-C) with a compound of the formula (IB) under basic conditions, optionally under a catalyst; a compound of the formula (III-C) in a solvent a deprotection reaction under acidic conditions, optionally further performing a substitution reaction to obtain a compound of the formula (III);
- X is a halogen
- Boc is a tert-butoxycarbonyl group
- R 4 is preferably a hydrogen atom or a fluorenyl group, wherein the fluorenyl group is optionally further substituted by one or more substituents selected from halogen, hydroxy or cycloalkyl;
- R 2 is preferably -C(0)R 7 And R 7 is a fluorenyl group.
- the reagents providing basic conditions include organic bases including, but not limited to, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and diisopropylamino groups.
- organic bases including, but not limited to, lithium hexamethyldisilazide, sodium hexamethyldisilazide, and diisopropylamino groups.
- Inorganic bases include, but are not limited to, cesium carbonate, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide or sodium hydride.
- Conditions which provide acidity include, but are not limited to, formic acid, acetic acid, hydrochloric acid, sulfuric acid, methanesulfonic acid, trifluoroacetic acid, and hydroxyethanesulfonic acid, preferably trifluoroacetic acid or hydroxyethanesulfonic acid.
- Catalysts include, but are not limited to, 4,5-bisdiphenylphosphino-9,9-dimethyloxaxime, tris(dibenzylideneacetone)dipalladium, anthracene, fluorene-binaphthyl-2,2'-di Phenylphosphine, [ ⁇ , ⁇ -bis(diphenylphosphino)ferrocene] palladium dichloride, bis(triphenylphosphine)palladium dichloride, triphenylphosphine, palladium dichloride, palladium acetate, iodine Cuprous, palladium/carbon or Raney nickel.
- Solvents used include, but are not limited to, 1,4-dioxane, toluene, water, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, methanol, ethanol, n-butanol, dimethyl Sulfone or N,N-dimethylformamide. detailed description
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or/and mass spectrometry (MS).
- the MR displacement ( ⁇ ) is given in units of 10 ⁇ 6 (ppm).
- the MR was measured using a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-i3 ⁇ 4, deuterated chloroform (CDC1 3 ), and the internal standard was tetramethylsilyl (TMS)).
- the MS was assayed using a FINNIGAN LCQAd (ESI) mass spectrometer (manufacturer: Thermo, model: Finnigan LCQ advantage MAX).
- ESI FINNIGAN LCQAd
- the HPLC was measured using an Agilent 1200 DAD high pressure liquid chromatograph (Sunfire C18 150 x 4.6 mm column;) and a Waters 2695-2996 high pressure liquid chromatograph (Gimini C18 150 x 4.6 mm column;).
- the thin layer chromatography silica gel plate uses Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate.
- the silica gel plate used for thin layer chromatography (TLC) has a specification of 0.15 mm ⁇ 0.2 mm, and the thin layer chromatography separation and purification product adopts the specification of 0.4 mm. ⁇ 0.5 mm.
- the known starting materials of the present invention may be synthesized by or according to methods known in the art, or may be purchased from ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc. Companies such as chemicals.
- reaction can be carried out under an argon atmosphere or a nitrogen atmosphere.
- An argon atmosphere or a nitrogen atmosphere means that the reaction flask is connected to an argon or nitrogen balloon having a volume of about 1 L.
- the hydrogen atmosphere means that the reaction flask is connected to a hydrogen balloon of about 1 L volume.
- the pressurized hydrogenation reaction was carried out using a Parr Model 3916EKX hydrogenation apparatus and a clear blue QL-500 type hydrogen generator or a HC2-SS type hydrogenation apparatus.
- the hydrogenation reaction is usually carried out, charged with hydrogen, and operated three times.
- the solution means an aqueous solution.
- reaction temperature is room temperature and is 20 ° C to 30 ° C.
- the progress of the reaction in the examples was monitored by thin layer chromatography (TLC).
- TLC thin layer chromatography
- the system used for the reaction was: A: chloroform and methanol system, B: n-hexane and ethyl acetate system, C: petroleum In the ether and ethyl acetate systems, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
- the system of the eluent for column chromatography and the developer system for thin layer chromatography using the purified compound include:
- A dichloromethane and methanol system
- B n-hexane and ethyl acetate system
- C dichloromethane, methanol and ethyl acetate system
- the volume ratio of the solvent is adjusted according to the polarity of the compound, or Adjust with a small amount of alkaline or acidic reagent such as triethylamine and acetic acid.
- EtOAc (EtOAc m.) Cyclopentyl-5-methyl-2-((1',2',3',6'-tetrahydro-[3,4'-bipyridyl]-6-yl;)amino;)pyridino[2 , 3- ⁇ /]pyrimidin-7 (8H; >-keto 1 (750 mg, yellow solid;). 150 mg of the title product was purified using EtOAc (EtOAc)
- 6-Acetyl-8-cyclopentyl-2-((5-(4-hydroxypiperidin-4-yl)pyridin-2-yl)amino)-5-methylpyrido[2,3-0 Pyrimidine-7(8H)-one 3 (20 mg, 0.043 mmol) 36% aqueous formaldehyde (6.5 mg, 0.065 mmol) and 10 mL of dichloromethane were added to a 25 mL eggplant-shaped flask and stirred at room temperature 2 After an hour, sodium borohydride (27 mg, 0.129 mmol) was added, and stirring was continued at room temperature for 16 hours, the reaction was stopped, 1 mL of aqueous ammonia was added, and concentrated under reduced pressure to dryness.
- 6-Acetyl-8-cyclopentyl-2-((5-(4-hydroxy-1-methylpiperidin-4-yl)pyridin-2-yl)amino)-5-methylpyridino[ 2,3- ⁇ /]pyrimidine-7(8H)-one 4 (10 mg, 0.021 mmol) was dissolved in 5 mL of dichloromethane, then dimethylamino trifluoride was added under cooling in dry ice-acetone bath. Sulfur (2 drops), after stirring for 30 minutes, the reaction was monitored by TLC. Most of the starting materials were unreacted, and 2 drops of dimethylaminosulfur trifluoride were added. After stirring for 1 hour, the reaction was terminated.
- 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridino[2,3-0-pyrimidine- 7(8H)-one 6 (20 mg, 0.047 mmol), acetic acid (20 mg, 0.45 mmol), 4 mL of 1,2-dichloroacetone and sodium borohydride (25 mg, 0.11 mmol). , react at room temperature for 12 hours. The reaction was stopped, 3 mL of methanol was added, and the mixture was stirred for 5 min.
- 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridino[2,3-0-pyrimidine- 7(8H)-one 6 (15 mg, 0.033 mmol) cyclopropyl bromide (8.37 mg, 0.062 mmol), potassium carbonate (20.7 mg, 0.15 mmol) and 3 mL acetonitrile were added to the reaction flask and heated to 80 ° C, the reaction was stopped for 2 hours.
- 6-Acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-pyrimidine-7 ( 8H)-keto 6 (15 mg, 0.033 mmol) was dissolved in 4 mL of acetonitrile and heated with 1-bromo-2,2-difluoroethane (24.36 mg, 0.168 mmol) and potassium carbonate (30 mg, 0.22 mmol) The reaction was stopped at 80 ° C for 6 hours. After cooling to room temperature, the mixture was filtered, and the filtered cake was washed with methylene chloride (3 mL?), and the filtrate was concentrated under reduced pressure.
- Test Example 1 Determination of CDK kinase activity by the compounds of the present invention
- CDK4 In vitro CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase activities were tested by the following methods.
- CDK kinase used in this experiment CDK4/human cyclin Dl (Invitrogen, Cat. No. PV4400) or CDK4/CycD3 (Carna biosciences, Cat. No. 04-105); CDK6 human cyclin D1 (Invitrogen, Cat. No. PV4401) or CDK6/CycD3 (Carna biosciences, Cat. No. 04-107); CDKl/human cyclin B (Invitrogen, Cat. No. PV3292); CDK2 human cyclin A (Invitrogen, Cat. No. PV3267) or CDK2/CycA2 (Carna biosciences, Cat. No. 04-103); CDK9/human cyclin Tl (Invitrogen, Cat. No. PR7541B) or CDK9/CycTl (Cama biosciences, Cat. No. 04-110).
- CDK4/human cyclin Dl Invitrogen, Cat. No. PV4400
- the in vitro kinase assay described below can determine the inhibitory activity of a test compound against CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase.
- kit '-LYTETM Ser/Thr 12 Phosphorylated Peptide Substrate (Invitrogen, Cat. No. PV3675) and lx Buffer A are formulated as a phosphorylated peptide mixture to be used; 2.5 ⁇ L of the configured test compound solution is added to the well, 2.5 ⁇ 400 ⁇ ⁇ solution and 5 ⁇ L of enzyme and substrate mixture; control well 1 plus 5 ⁇ L ⁇ enzyme and substrate mixture, 2.5 ⁇ 4% dimethyl sulfoxide solution and 2.5 ⁇ ⁇ buffer ⁇ ; control well 2 Add 5 ⁇ L of enzyme and substrate mixture, 2.5 ⁇ 4% dimethyl sulfoxide solution and 2.5 ⁇ 400 ⁇ solution; add 5 ⁇ phosphorylated peptide mixture to control well 3, 2.5 ⁇ 4% dimethyl Sulfone solution and 2.5 ⁇ lx Flush A.
- Reagent A Invitrogen, Cat. No. PV3295
- Buffer BC Invitrogen Cat. No. P3127
- CDK4 and CDK6 The CDK (CDK4, CDK6, CDK1, CDK2, CDK9) kinase biochemical inhibitory activity of the compounds of the present invention was determined by the above test, and the IC 5Q values measured are shown in Table 1 for CCDK4 and CDK6), and Table 2 (CDK1, CDK2, and CDK9).
- the compounds of the present invention have a significant inhibitory effect on the activity of CDK kinase (CDK4, CDK6), and the inhibition of CDK kinase (CDK4, CDK6) by the compounds of the present invention compared to the inhibition of the activity of CDK kinase (CDK1, CDK2, CDK9).
- Selective. Test Example 2 Inhibition of proliferation of the human colon cancer cell line Colo205 by the compound of the present invention The following in vitro test was conducted to determine the proliferation inhibitory activity of the compound of the present invention against the human colon cancer cell line Colo205.
- the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound against a human colon cancer cell line, and its activity can be expressed by an IC 5Q value.
- the general protocol for this type of trial is as follows: First, Colo205 cells (Chinese Academy of Sciences cell bank, article number TCHul02) were seeded on a 384-well culture plate at a suitable cell concentration of 500 cells/well, and then the cells were cultured in a carbon dioxide incubator at 37 °C.
- test compound solution a medium with a range of concentration (1000 nM, 250 nM, 62.5 nM, 15.62 nM, 3.91 nM, 0.98 nM, 0.24 nM, 0.06 nM, 0.02 nM) test compound solution , return the plate to the incubator and continue to culture for 72 hours. After 72 hours, the test compound was tested for inhibition of cell proliferation activity by CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical). The IC 5Q value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
- the preferred compounds of the present invention have significant proliferation inhibitory activity against Colo205 cells.
- Test Example 3 The inhibition of proliferation of human breast cancer cell line MCF-7 by the compound of the present invention
- the following in vitro assay was used to determine the proliferation inhibitory activity of the compounds of the invention against human breast cancer cell line MCF-7.
- the in vitro cell assay described below can determine the proliferation inhibitory activity of a test compound on a human breast cancer cell line, and its activity can be expressed by an IC 5Q value.
- the general protocol for such an experiment is as follows: First, MCF-7 cells (purchased in Institute of biochemistry and cell biology) are seeded on a 96-well culture plate at a suitable cell concentration of 4000 cells/mL, and then the cells are placed in a carbon dioxide incubator. Incubate at 37 ° C, grow to overnight, and change the medium to a medium supplemented with a series of concentration (10000 nM, 1000 nM, 100 nM, 10 nM, 1 nM, 0.1 nM) test compound solution. Return to the incubator and continue to culture for 72 hours.
- test compound was assayed for inhibition of cell proliferation activity using CCK8 (Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical;).
- CCK8 Cell Counting Kit-8, Cat. No.: CK04, purchased from Tongren Chemical;
- the IC 5 o value can be calculated from the inhibition values of the test compound for the cells at a range of different concentrations.
- SD rats were used as test animals, and the concentration of the drug in plasma at different times after the administration of the compound of Example 7 by intragastric administration was determined by LC/MS/MS.
- the pharmacokinetic behavior of the compounds of the present invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
- Test plan 2.1 Test drug: PD-0332991, Example 6 and Example 7 compounds.
- Blood was collected before administration and 0.5, 1, 2, 4, 6, 8, 11, 24 hours after administration, placed in heparinized anticoagulation tubes, centrifuged at 3500 rpm for 10 minutes, plasma was separated, and stored at -20 °C. . Eat 2 hours after administration.
- the content of the test compound in the plasma of rats after intragastric administration was determined by LC/MS/MS method.
- the analytical method has a linear range of 1.00-500 ng/mL and a lower limit of quantification of 1.00 ng/mL.
- Plasma samples are pretreated with precipitated proteins for analysis.
- the pharmacokinetic parameters of the compounds of the invention are as follows:
- the Beagle dog was used as the test animal, and the concentration of the drug in plasma was measured by LC/MS/MS method in dogs after administration of PD-0332991 and the compounds of Examples 6 and 7.
- the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
- Test drug PD-0332991, Example 6 and Example 7 compound.
- the intravenous administration group received 1.0 mL of blood from the forelimb vein before and 5 minutes after administration, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 24.0 hours, placed in heparinized tubes, centrifuged at 3500 rpm. Plasma was separated in minutes and stored at -20 °C.
- the rats in the gavage administration group were subjected to blood collection before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 hours after administration, and the treatment method was the same as that of the intravenous administration group. Eat 3 hours after administration.
- the content of the test compound in the plasma of rats after intravenous and intragastric administration was determined by LC/MS/MS.
- the pharmacokinetic parameters of the compounds of the invention are as follows:
- Test Example 6 Test of the ability of the compound of Example 6 of the present invention to produce a reactive metabolite in comparison with PD-0332991
- liver microsomes protein concentration 20 mg/mL, purchased from BD GentestTM in the United States; male rat liver microsomes, protein concentration 20 mg/mL, purchased from BD GentestTM, USA; ⁇ -NADPH, chemical purity 93 -100%, purchased from Sigma, USA. L-reduced glutathione, purity >98%, was purchased from Sigma, USA.
- the total hatching system was 100 ⁇ and the medium was 100 mM phosphate buffer (PBS, pH 7.4).
- PBS phosphate buffer
- the precursor GX scan was used to detect the possible GSH adducts, and the peak area of the total GSH adduct formed by the test compound and the total GSH adduct peak formed by clozapine.
- the area ratio (Ratio) evaluates the ability of a compound to generate a reactive metabolite.
- Inventive Example 6 showed no significant GSH adduct production in both human and rat liver microsome incubation systems, and had a low ability to generate reactive metabolites.
- PD-0332991 has a human liver microsome ratio of 0.76 and is capable of generating reactive metabolites in a moderately strong manner.
- Example 6 of the present invention has low ability to generate reactive metabolites in human and rat liver microsomes, and PD-0332991 has a moderately strong ability to generate reactive metabolites in human liver microsomes.
Abstract
提供一种通式(I)所示吡啶并嘧啶类衍生物及其可药用盐,其制备方法以及它们作为癌症治疗剂特别是作为CDK4和/或CDK6抑制剂的用途,其中通式(I)中的各取代基的定义与说明书中的定义相同。
Description
吡啶并嘧啶类衍生物、 其制备方法及其在医药上的应用
技术领域
本发明涉及一种新型吡啶并嘧啶类衍生物、 其制备方法及含有该衍生物的药 物组合物, 以及其作为癌症治疗剂特别是作为 CDK4和 /或 CDK6抑制剂的用途。 背景技术
大量研究发现肿瘤与细胞周期反常相关, 大部分肿瘤都存在有丝***信号蛋 白的大量突变 /抗有丝***信号蛋白缺陷,基因组不稳定性 (GIN)和染色体组不稳定 性 (CIN), 这三种基本的细胞周期缺陷都直接或间接由细胞周期蛋白依赖性激酶 (CDKs)的失控引起。 CDK通过与其调节性亚单元 cyclins (细胞周期蛋白) 结合发 挥作用, 而 4大类 cydinS(A-, B-, D-, E-型 cyclins)在整个细胞周期的不同阶段发挥其 不同的作用, 至少有 16 种哺乳动物细胞周期蛋白已被鉴别。 细胞周期蛋白 Cyclin B/CDK1、 Cyclin A/CDK2 Cyclin E/CDK2、 Cyclin D/CDK4、 Cyclin D/CDK6和其 它杂二聚物 (包括 CDK3和 CDK7)是细胞周期进展的重要调节剂。 Cyclin/CDK杂二 聚物的另外功能包括对转录、 DNA修复、 分化和细胞程序性死亡的调节。
研究显示细胞周期蛋白依赖性激酶的活性增加或者活化异常会导致人类肿瘤 的形成。 事实上, 人类肿瘤的形成普遍与 CDK蛋白本身或其调节剂的改变有关。 体外实验发现天然存在的 CDK的蛋白质抑制剂例如 pl6和 p27能够抑制肺癌细胞系 的生长。
研究发现, CDK4和 CDK6高度同源, CDK4单基因敲除老鼠存在糖尿病征和细 胞缺陷, CDK6单基因敲除老鼠因造血细胞增值缺陷导致轻微的贫血症状,而 CDK4 和 CDK6(CDK4/6)双基因敲除则会使造血前体细胞增殖能力受损,导致双敲除老鼠 胚胎晚期的死亡。在肿瘤细胞中,普遍发现 CDK4/6-Cydin D/Rb信号通路的超活化。 在胞内外各种有丝***信号剌激下, cyclin D高表达, 调节 CDK4/6蛋白与 cyclin D 的相互作用, 促进 CDK4/6的定位和激酶活性。 激活的 CDK4/6通过磷酸化抑制 Rb 肿瘤抑制蛋白的活性,使 Rb-E2F复合物解离,释放游离的 E2F入核,调节蛋白转录, 启动细胞周期的进行。 在上皮细胞恶性肿瘤中常发现 CDK4的超活化, 而*** 肿瘤如肉瘤和血液性癌症中常发现 CDK6的超活化。 构建乳腺癌荷瘤鼠模型发现, 野生型裸鼠全部成瘤, 而 CDK4敲除裸鼠完全无法成瘤; 而用 anti-CDK4 siRNA干 扰 CDK4的表达, 则发现裸鼠的肿瘤生长显著受抑制。
除了抑制肿瘤的生长, 小分子 CDK抑制剂也可以用于治疗心血管障碍, 例如 再狭窄和动脉粥样硬化和其它由异常细胞增殖引起的血管障碍; 用于治疗由多种 感染剂导致的疾病, 包括真菌、 原生动物寄生虫 (例如恶性疟原虫)和 DNA与 RNA 病毒; 还可用于改善各种自身免疫障碍, 研究发现, 在关节炎的大鼠模型中, 关 节肿胀基本上被 pl6表达性腺病毒处理所抑制, CDK抑制剂可以有效对抗其它细胞
增殖障碍, 包括牛皮癖 (以角质形成细胞过度增殖为特征)、 肾小球性肾炎和狼疮。 研究发现, 在细胞周期中, G1/S转换期和 G2/M期细胞对 DNA损伤剂如电离辐 射 (IR)极为敏感, 而细胞从 G1期向 S期转换的过程至少需要通过 3种细胞周期蛋白 依赖性激酶 (CDK2、 CDK4和 CDK6)及其调节性亚单元 cyclins共同磷酸化 Rb家族蛋 白进行调节。选择性 CDK4/6抑制剂可以诱导细胞 G1期阻滞,进而提高造血干 /祖细 胞对 DNA损伤剂如 IR的耐受性, 有效减少由辐射引起的各种造血毒性,包括骨髓抑 制、 嗜中性白血球减少症、 白细胞减少症、 贫血等。
目前, 小分子 CDK抑制剂很难鉴别只特异性抑制 CDK蛋白而不抑制其它酶的 化合物。 因而, 尽管具有治疗多种疾病的潜力, CDK抑制剂目前尚未获得批准用 于商业目的。
近几年各大公司分别鉴定发现了一系列选择性抑制 CDK4和 CDK6的抑制剂, 用于治疗癌症, 心血管障碍及炎症等疾病。 目前有 3个特异性抑制 CDK4和 CDK6 的小分子化合物进入临床,分别是 Pfizer和 Onyx制药公司的 PD-0332991(临床三期)、 Eli Lilly的 LY-2835219(临床二期)和 Novartis的 LEE-011(临床一期)。 PD-0332991通过 抑制 CDK4和 CDK6的活性, 抑制 Rb的磷酸化, 使 E2F-Rb复合物留滞在胞浆中, 阻 断细胞周期的启动。 临床试验结果显示, 来曲唑单药治疗的患者的无进展存活期 (Progression-free survival, PFS)为 7.5月, 而来曲唑和 PD-0332991药物联用治疗的患 者其无进展存活期则延长至 26.1月。
公开的选择性抑制 CDK4和 CDK6的抑制剂专利申请包括 WO2003062236、 WO2006008874 、 WO2009126584 、 WO2010075074 、 WO2011101409 、 和 WO2012129344等。
为了达到更好的肿瘤治疗效果的目的, 更好的满足市场需求, 我们希望能开 发出新一代的高效低毒的选择性 CDK4和 CDK6抑制剂。 本发明将提供一种新型 结构的选择性 CDK4和 CDK6抑制剂, 并发现具有此类结构的化合物表现出优异 的效果和作用, 特别是优异的药代吸收活性。 发明内容
本发明的目的在于提供一种通式( I )所示的化合物或其互变异构体、 内消旋 体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐:
―为单键或双键;
A1或 A2各自独立地选自 -CR'或 N;
R'选自氢原子、 卤素、 氰基、 硝基、 垸基、 卤代垸基、 羟垸基或垸氧基; Y选自 S或 0;
R1选自氢原子、 卤素、 垸基、 卤代垸基、 羟垸基或环垸基;
R2选自氢原子、 卤素、 氰基、 硝基、 垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基、 杂芳基、 -0R7、 -C(0)R7, -C(0)OR7, 或 -OC(0)R7, 其中所述的垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任选进一步被一个或多个选 自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 ¾代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代;
R3选自氢原子、 垸基、 环垸基、 杂环垸基、 芳基或杂芳基, 其中所述的垸基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 ¾代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代;
R4选自氢原子、垸基、烯基、炔基、环垸基、杂环垸基、芳基、 杂芳基、 -OR7、 -C(0)R7或 -C(0)OR7, 其中所述的垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基或 杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 ¾代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代;
R5或 R6各自独立地选自氢原子、 卤素、 氰基、 硝基、 氧代基、 垸基、 烯基、 炔基、环垸基、 杂环垸基、芳基、 杂芳基、 -OR7、 -C(0)R7 -CCC OR7或 -OCCC R7, 其中所述的垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任 选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 卤 代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基 的取代基所取代;
R7选自氢原子、 垸基、 羟基、 卤素、 垸氧基、 环垸基、 杂环垸基、 芳基或杂
芳基, 其中所述的垸基、 垸氧基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地 任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 卤代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯 基的取代基所取代。 在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 A1或 A2各自独立地为 -CH。 在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 Y为 0。 在本发明一个优选的实施方案中, - -种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 R1为垸基。 在本发明一个优选的实施方案中, - -种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 R1为甲基。 在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 R2为 -C(0)R7; 且 R7为垸基。 在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 R2为 -C(0)R7; 且 R7为甲基。 在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 R3为环垸基。 在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 R3为环戊基。
在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 R5或 R6各自独立地选自氢原子、 卤素、 垸基或羟基。 在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其中 R4选自氢原子或垸基, 其中所述的垸基任选进一步被一个或多个选 自卤素、 羟基或环垸基的取代基所取代。 在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其为通式 (Π)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映 异构体、 非对映异构体或其混 用盐:
其中 :
二 , R R6的定义如通式(I )中所定义。 在本发明一个优选的实施方案中, 一种通式( I )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可 药用盐, 其为通式 (III)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映 异构体、 非对映异构体或其混 用盐:
其中, R R6的定义如通式(I )中所定义。
本发明典型的化合物包括, 但不限于:
形式, 或其可药用盐。 本发明还提供一种通式 (I-C)所示的化合物或其互变异构体、 内消旋体、 外消 旋体、 对映异构体、 非对映异构体或其混合物形式, 可用作合成或进一步合成通 式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映
异构体的中间体:
其中:
―为单键或双键;
Boc为叔丁氧羰基;
R为垸基;
A1或 A2各自独立地选自 -CR'或 N;
R'选自氢原子、 卤素、 氰基、 硝基、 垸基、 卤代垸基、 羟垸基或垸氧基; Y选自 S或 0;
R1选自氢原子、 卤素、 垸基、 卤代垸基、 羟垸基或环垸基;
R3选自氢原子、 垸基、 环垸基、 杂环垸基、 芳基或杂芳基, 其中所述的垸基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 ¾代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代;
R5或 R6各自独立地选自氢原子、 卤素、 氰基、 硝基、 氧代基、 垸基、 烯基、 炔基、环垸基、 杂环垸基、芳基、 杂芳基、 -OR7、 -C(0)R7 -CCC OR7或 -OCCC R7, 其中所述的垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任 选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 卤 代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基 的取代基所取代;
R7选自氢原子、 垸基、 羟基、 卤素、 垸氧基、 环垸基、 杂环垸基、 芳基或杂 芳基, 其中所述的垸基、 垸氧基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地 任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 卤代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯 基的取代基所取代。 在本发明一个优选的实施方案中, 一种通式(I-C )所示的化合物或其互变异构 体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可
药用盐, 其中 R为丁基 本发明还提供一种制备通式 (I)所示的化合物或其互变异构体、 内消旋体、 夕卜 消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐的方法, 该
( I - A ) (卜 B :
( I - C ) ( I )
通式 (I-A)化合物与通式 (I-B)化合物在碱性条件下, 任选在催化剂作用下进行 取代反应得到通式( I-C )化合物; 通式(I-C )化合物在溶剂中, 酸性条件下, 进行 脱保护反应, 任选进一步进行取代反应, 得到通式(I )化合物;
其中: X为卤素; Boc为叔丁氧羰基; R如通式(I-C)中所定义; =, A1, A2, Υ, Ι^〜Ι 6的定义如通式(I )中所定义; R4优选为氢原子或垸基, 其中所述的垸基 任选进一步被一个或多个选自卤素、 羟基或环垸基的取代基所取代。 本发明进一步涉及一种药物组合物, 所述药物组合物含有治疗有效量的通式 ( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异 构体或其混合物形式, 或其可药用盐, 以及一种或多种药学上可接受的载体、 稀 释剂或赋形剂。
本发明进一步涉及通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋 体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或包含其的药 物组合物在制备抑制 CDK4和 /或 CDK6的药物中的用途。
本发明进一步涉及通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋 体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或包含其的药 物组合物在制备治疗异常细胞增殖性疾病、 感染(例如病毒感染, 如疱疹、 HIV, 真菌感染等)、 炎性病症 (例如类风湿性关节炎、 骨关节炎等)、 自身免疫性疾病 (例 如牛皮癣、 狼疮、 I 型糖尿病、 糖尿病性肾病、 多发性硬化、 肾小球性肾炎等)、 心血管疾病 (例如心肌梗塞、 中风、 动脉粥样硬化、 手术后血管狭窄、 再狭窄等) 或神经变性疾病 (例如阿尔茨海默氏病、 帕金森病等)的药物中的用途, 其中所述 的异常细胞增殖性疾病可以为癌症 (如下所定义)。
本发明进一步涉及通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋
体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或包含其的药 物组合物在制备治疗癌症的药物中的用途, 其中所述癌症选自乳腺癌、 卵巢癌、 ***癌、 黑色素瘤、 脑瘤 (例如具有恶性的星形神经胶质和少突神经胶质细胞瘤 成分的神经胶质瘤等)、 食管癌、 胃癌、 肝癌、 胰腺癌、 结肠直肠癌 (例如结肠癌、 直肠癌等)、 肺癌 (例如非小细胞肺癌、 小细胞肺癌、 原发或转移性鳞状癌等)、 肾 癌、 皮肤癌、 成胶质细胞瘤、 神经母细胞瘤、 肉瘤、 脂肪肉瘤、 骨软骨瘤、 骨瘤、 骨肉瘤、 ***瘤、 睾丸肿瘤、 子宫癌 (例如子***、 子宫内膜癌等)、 头颈肿 瘤 (例如上颌骨癌、 喉癌、 咽癌、 舌癌、 口内癌等)、 多发性骨髓瘤、 恶性淋巴瘤 (例 如网状细胞肉瘤、 淋巴肉瘤、 霍奇金淋巴瘤、 套细胞淋巴瘤等;)、 真性红细胞增多 症、 白血病 (例如急性粒细胞白血病、 慢性粒细胞白血病、 急性淋巴细胞白血病、 慢性淋巴细胞白血病等)、 甲状腺肿瘤、 输尿管肿瘤、 ***、 胆囊癌、 胆管癌、 绒毛膜上皮癌或儿科肿瘤 (例如尤因家族性肉瘤、 维尔姆斯肉瘤、 横纹肌肉瘤、 血 管肉瘤、 胚胎睾丸癌、 成神经细胞瘤、 视网膜母细胞瘤、 肝胚细胞瘤、 肾母细胞 瘤等)等; 其中所述的药物可以进一步与另外一种或多种抗癌剂联合应用, 所述抗 癌剂选自垸化剂 (例如环磷酰胺、 异环磷酰胺、 美法仑、 白消安、 尼莫司丁、 雷莫 司汀、 达卡巴嗪、 替莫唑胺、 盐酸氮芥、 二溴甘露醇等)、 铂络合剂 (例如顺铂、 卡 铂、 奥沙利铂等)、 代谢拮抗剂 (例如甲氨蝶吟、 5-氟尿嘧啶、 替加氟、 吉西他滨、 卡培他滨、 氟维司群、 培美曲塞等)、 植物生物碱 (例如长春新碱、 长春碱、 长春地 辛、 依托泊苷、 多西他赛、 紫杉醇、 伊立替康、 长春瑞滨、 米托蒽醌、 长春氟宁、 拓扑替康等)、 抗体药物 (例如曲妥单抗、 帕妥珠单抗、 利妥昔单抗、 西妥昔单抗、 帕尼单抗、 贝伐单抗等)、 激素抗癌剂 (例如亮丙瑞林、 戈舍瑞林、 度他雄胺、 地塞 米松、 他莫昔芬等)、 蛋白酶体抑制剂 (例如硼替佐米、 来那度胺等)、 芳香化酶抑 制剂 (例如依西美坦、 来曲唑、 阿那曲唑等)、 VEGFR或 EGFR抑制剂 (例如舒尼替 尼、 索拉非尼、 伊马替尼、 吉非替尼、 埃罗替尼、 凡德他尼、 帕唑帕尼、 拉帕替 尼等)、 mTOR抑制剂 (例如依维莫司、西罗莫司、佐他莫司等)、 PI3K激酶抑制剂 (例 如 BKM-120、 XL-147、 BEZ-235等)、 B-Raf抑制剂 (例如威罗菲尼、 GSK-2118436 等)或 AKT抑制剂 (例如哌立福新、 MK-2206等)等; 优选为芳香化酶抑制剂, 更优 选来曲唑或阿那曲唑。
本发明涉及通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或包含其的药物组合 物在制备预防或治疗由辐射引起的造血毒性疾病的药物中的用途, 其中所述的辐 射引起的造血毒性疾病包括但不限于骨髓抑制、 嗜中性白血球减少症、 白细胞减 少症、 贫血。
本发明还涉及一种抑制 CDK4和 /或 CDK6活性的方法, 其包括给予所需患者 治疗有效量的通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映 异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或包含其的药物组合物。
换言之, 本发明涉及一种治疗异常细胞增殖性疾病、 感染 (例如病毒感染, 如 疱疹、 HIV, 真菌感染等)、 炎性病症 (例如类风湿性关节炎、 骨关节炎等)、 自身 免疫性疾病 (例如牛皮癣、 狼疮、 I 型糖尿病、 糖尿病性肾病、 多发性硬化、 肾小 球性肾炎等)、心血管疾病 (例如心肌梗塞、中风、动脉粥样硬化、手术后血管狭窄、 再狭窄等)或神经变性疾病 (例如阿尔茨海默氏病、 帕金森病等)的方法, 其包括给 予所需患者治疗有效量的通式(I )所示的化合物或其互变异构体、 内消旋体、 外消 旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或包含其的 药物组合物, 其中所述的异常细胞增殖性疾病可以是癌症 (如下所定义)。
本发明进一步涉及一种治疗癌症的方法, 其包括给予所需患者治疗有效量的 通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对 映异构体或其混合物形式, 或其可药用盐, 或包含其的药物组合物, 其中所述癌 症选自乳腺癌、 卵巢癌、 ***癌、 黑色素瘤、 脑瘤 (例如具有恶性的星形神经胶 质和少突神经胶质细胞瘤成分的神经胶质瘤等)、 食管癌、 胃癌、 肝癌、 胰腺癌、 结肠直肠癌 (例如结肠癌、 直肠癌等)、 肺癌 (例如非小细胞肺癌、 小细胞肺癌、 原 发或转移性鳞状癌等)、 肾癌、 皮肤癌、 成胶质细胞瘤、 神经母细胞瘤、 肉瘤、 脂 肪肉瘤、 骨软骨瘤、 骨瘤、 骨肉瘤、 ***瘤、 睾丸肿瘤、 子宫癌 (例如子宫颈 癌、 子宫内膜癌等)、 头颈肿瘤 (例如上颌骨癌、 喉癌、 咽癌、 舌癌、 口内癌等)、 多发性骨髓瘤、 恶性淋巴瘤 (例如网状细胞肉瘤、 淋巴肉瘤、 霍奇金淋巴瘤、 套细 胞淋巴瘤等;)、 真性红细胞增多症、 白血病 (例如急性粒细胞白血病、 慢性粒细胞白 血病、 急性淋巴细胞白血病、 慢性淋巴细胞白血病等;)、 甲状腺肿瘤、 输尿管肿瘤、 ***、 胆囊癌、 胆管癌、 绒毛膜上皮癌或儿科肿瘤 (例如尤因家族性肉瘤、 维 尔姆斯肉瘤、 横纹肌肉瘤、 血管肉瘤、 胚胎睾丸癌、 成神经细胞瘤、 视网膜母细 胞瘤、 肝胚细胞瘤、 肾母细胞瘤等)等。
本发明还涉及一种治疗癌症的方法, 其包括给予所需患者治疗有效量的通式 ( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异 构体或其混合物形式, 或其可药用盐, 或包含其的药物组合物, 与另外一种或多 种抗癌剂联合应用, 所述抗癌剂选自垸化剂 (例如环磷酰胺、异环磷酰胺、美法仑、 白消安、 尼莫司丁、 雷莫司汀、 达卡巴嗪、 替莫唑胺、 盐酸氮芥、 二溴甘露醇等)、 铂络合剂 (例如顺铂、卡铂、奥沙利铂等)、代谢拮抗剂 (例如甲氨蝶吟、 5-氟尿嘧啶、 替加氟、 吉西他滨、 卡培他滨、 氟维司群、 培美曲塞等)、 植物生物碱 (例如长春新 碱、 长春碱、 长春地辛、 依托泊苷、 多西他赛、 紫杉醇、 伊立替康、 长春瑞滨、 米托蒽醌、 长春氟宁、 拓扑替康等)、 抗体药物 (例如曲妥单抗、 帕妥珠单抗、 利妥 昔单抗、 西妥昔单抗、 帕尼单抗、 贝伐单抗等)、 激素抗癌剂 (例如亮丙瑞林、 戈舍 瑞林、 度他雄胺、 ***、 他莫昔芬等)、 蛋白酶体抑制剂 (例如硼替佐米、 来那 度胺等)、芳香化酶抑制剂 (例如依西美坦、来曲唑、阿那曲唑等)、 VEGFR或 EGFR 抑制剂 (例如舒尼替尼、 索拉非尼、 伊马替尼、 吉非替尼、 埃罗替尼、 凡德他尼、
帕唑帕尼、 拉帕替尼等)、 mTOR抑制剂 (例如依维莫司、 西罗莫司、 佐他莫司等)、 PI3K激酶抑制剂 (;例如 BKM-120 XL-147 BEZ-235等;)、 B-Raf抑制剂 (;例如威罗 菲尼、 GSK-2118436等)或 AKT抑制剂 (例如哌立福新、 MK-2206等)等; 优选为芳 香化酶抑制剂, 更优选来曲唑或阿那曲唑。
本发明还涉及作为抑制 CDK4和 /或 CDK6活性的药物的通式( I )所示的化合 物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合 物形式, 或其可药用盐, 或包含其的药物组合物。
本发明还涉及作为治疗异常细胞增殖性疾病、 感染 (例如病毒感染, 如疱疹、 HIV, 真菌感染等)、 炎性病症 (例如类风湿性关节炎、 骨关节炎等)、 自身免疫性 疾病 (例如牛皮癣、 狼疮、 I 型糖尿病、 糖尿病性肾病、 多发性硬化、 肾小球性肾 炎等)、 心血管疾病 (例如心肌梗塞、 中风、 动脉粥样硬化、 手术后血管狭窄、 再狭 窄等)或神经变性疾病 (例如阿尔茨海默氏病、 帕金森病等)的药物的通式( I )所示 的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或 其混合物形式, 或其可药用盐, 或包含其的药物组合物, 其中所述的异常细胞增 殖性疾病可以是癌症 (如下所定义)。
本发明进一步涉及作为治疗癌症的药物的通式( I )所示的化合物或其互变异 构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其 可药用盐, 或包含其的药物组合物, 其中所述癌症选自乳腺癌、 卵巢癌、 *** 癌、 黑色素瘤、 脑瘤 (例如具有恶性的星形神经胶质和少突神经胶质细胞瘤成分的 神经胶质瘤等)、 食管癌、 胃癌、 肝癌、 胰腺癌、 结肠直肠癌 (例如结肠癌、 直肠癌 等)、 肺癌 (例如非小细胞肺癌、 小细胞肺癌、 原发或转移性鳞状癌等)、 肾癌、 皮 肤癌、 成胶质细胞瘤、 神经母细胞瘤、 肉瘤、 脂肪肉瘤、 骨软骨瘤、 骨瘤、 骨肉 瘤、***瘤、 睾丸肿瘤、 子宫癌 (例如子***、 子宫内膜癌等)、 头颈肿瘤 (例 如上颌骨癌、 喉癌、 咽癌、 舌癌、 口内癌等)、 多发性骨髓瘤、 恶性淋巴瘤 (例如网 状细胞肉瘤、 淋巴肉瘤、 霍奇金淋巴瘤、 套细胞淋巴瘤等;)、 真性红细胞增多症、 白血病 (例如急性粒细胞白血病、 慢性粒细胞白血病、 急性淋巴细胞白血病、 慢性 淋巴细胞白血病等)、 甲状腺肿瘤、 输尿管肿瘤、 ***、 胆囊癌、 胆管癌、 绒 毛膜上皮癌或儿科肿瘤 (例如尤因家族性肉瘤、 维尔姆斯肉瘤、 横纹肌肉瘤、 血管 肉瘤、 胚胎睾丸癌、 成神经细胞瘤、 视网膜母细胞瘤、 肝胚细胞瘤、 肾母细胞瘤 J
本发明还涉及作为治疗癌症的药物的通式( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用 盐, 或包含其的药物组合物, 以及另外一种或多种抗癌剂, 所述抗癌剂选自垸化 剂 (例如环磷酰胺、 异环磷酰胺、 美法仑、 白消安、 尼莫司丁、 雷莫司汀、 达卡巴 嗪、 替莫唑胺、 盐酸氮芥、 二溴甘露醇等)、 铂络合剂 (例如顺铂、 卡铂、 奥沙利铂 等)、 代谢拮抗剂 (例如甲氨蝶吟、 5-氟尿嘧啶、 替加氟、 吉西他滨、 卡培他滨、 氟
维司群、培美曲塞等)、植物生物碱 (例如长春新碱、长春碱、长春地辛、依托泊苷、 多西他赛、 紫杉醇、 伊立替康、 长春瑞滨、 米托蒽醌、 长春氟宁、 拓扑替康等)、 抗体药物 (例如曲妥单抗、 帕妥珠单抗、 利妥昔单抗、 西妥昔单抗、 帕尼单抗、 贝 伐单抗等)、 激素抗癌剂 (例如亮丙瑞林、 戈舍瑞林、 度他雄胺、 ***、 他莫昔 芬等)、 蛋白酶体抑制剂 (例如硼替佐米、 来那度胺等)、 芳香化酶抑制剂 (例如依西 美坦、 来曲唑、 阿那曲唑等)、 VEGFR或 EGFR抑制剂 (例如舒尼替尼、 索拉非尼、 伊马替尼、 吉非替尼、 埃罗替尼、 凡德他尼、 帕唑帕尼、 拉帕替尼等)、 mTOR抑 制剂 (例如依维莫司、 西罗莫司、 佐他莫司等)、 PI3K激酶抑制剂 (例如 BKM-120、 XL-147、 BEZ-235等;)、 B-Raf抑制剂 (例如威罗菲尼、 GSK-2118436等;)或 AKT抑 制剂 (例如哌立福新、 MK-2206等)等; 优选为芳香化酶抑制剂, 更优选来曲唑或阿 那曲唑。
含活性成分的药物组合物可以是适用于口服的形式, 例如片剂、 糖锭剂、 锭 剂、 水或油混悬液、 可分散粉末或颗粒、 乳液、 硬或软胶囊, 或糖浆剂或酏剂。 可按照本领域任何已知制备药用组合物的方法制备口服组合物, 此类组合物可含 有一种或多种选自以下的成分: 甜味剂、 矫味剂、 着色剂和防腐剂, 以提供悦目 和可口的药用制剂。 片剂含有活性成分和用于混合的适宜制备片剂的无毒的可药 用的赋形剂。 这些赋形剂可以是惰性赋形剂, 如碳酸钙、 碳酸钠、 乳糖、 磷酸钙 或磷酸钠; 造粒剂和崩解剂, 例如微晶纤维素、 交联羧甲基纤维素钠、 玉米淀粉 或藻酸; 粘合剂, 例如淀粉、 明胶、 聚乙烯吡咯垸酮或***胶; 和润滑剂, 例 如硬脂酸镁、 硬脂酸或滑石粉。 这些片剂可以不包衣或可通过掩盖药物的味道或 在胃肠道中延迟崩解和吸收, 因而在较长时间内提供缓释作用的已知技术将其包 衣。 例如, 可使用水溶性味道掩蔽物质, 例如羟丙基甲基纤维素或羟丙基纤维素, 或延长时间物质例如乙基纤维素、 醋酸丁酸纤维素。
也可用其中活性成分与惰性固体稀释剂例如碳酸钙、 磷酸钙或高岭土混合的 硬明胶胶囊, 或其中活性成分与水溶性载体例如聚乙二醇或油溶媒例如花生油、 液体石蜡或橄榄油混合的软明胶胶囊提供口服制剂。
水悬浮液含有活性物质和用于混合的适宜制备水悬浮液的赋形剂。 此类赋形 剂是悬浮剂, 例如羧基甲基纤维素钠、 甲基纤维素、 羟丙基甲基纤维素、 藻酸钠、 聚乙烯吡咯垸酮和***胶; 分散剂或湿润剂可以是天然产生的磷脂例如卵磷脂, 或烯化氧与脂肪酸的缩合产物例如聚氧乙烯硬脂酸酯, 或环氧乙垸与长链脂肪醇 的缩合产物, 例如十七碳亚乙基氧基鲸蜡醇 (heptadecaethyleneoxy cetanol), 或环氧 乙垸与由脂肪酸和己糖醇衍生的部分酯的缩合产物, 例如聚环氧乙垸山梨醇单油 酸酯, 或环氧乙垸与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物, 例如聚环氧乙 垸脱水山梨醇单油酸酯。 水混悬液也可以含有一种或多种防腐剂例如尼泊金乙酯 或尼泊金正丙酯、 一种或多种着色剂、 一种或多种矫味剂和一种或多种甜味剂, 例如蔗糖、 糖精或阿司帕坦。
油混悬液可通过使活性成分悬浮于植物油如花生油、 橄榄油、 芝麻油或椰子 油, 或矿物油例如液体石蜡中配制而成。 油悬浮液可含有增稠剂, 例如蜂蜡、 硬 石蜡或鲸蜡醇。 可加入上述的甜味剂和矫味剂, 以提供可口的制剂。 可通过加入 抗氧化剂例如丁羟茴醚或 (X-生育酚保存这些组合物。
通过加入水可使适用于制备水混悬液的可分散粉末和颗粒提供活性成分和用 于混合的分散剂或湿润剂、 悬浮剂或一种或多种防腐剂。 适宜的分散剂或湿润剂 和悬浮剂可说明上述的例子。 也可加入其他赋形剂例如甜味剂、 矫味剂和着色剂。 通过加入抗氧化剂例如抗坏血酸保存这些组合物。
本发明的药物组合物也可以是水包油乳剂的形式。 油相可以是植物油例如橄 榄油或花生油, 或矿物油例如液体石蜡或其混合物。 适宜的乳化剂可以是天然产 生的磷脂, 例如大豆卵磷脂和由脂肪酸和己糖醇酐衍生的酯或偏酯例如山梨坦单 油酸酯, 和所述偏酯和环氧乙垸的缩合产物, 例如聚环氧乙垸山梨醇单油酸酯。 乳剂也可以含有甜味剂、 矫味剂、 防腐剂和抗氧剂。 可用甜味剂例如甘油、 丙二 醇、 山梨醇或蔗糖配制糖浆和酏剂。 此类制剂也可含有缓和剂、 防腐剂、 着色剂 和抗氧剂。
药物组合物可以是无菌注射水溶液形式。 可在使用的可接受的溶媒和溶剂中 有水、 林格氏液和等渗氯化钠溶液。 无菌注射制剂可以是其中活性成分溶于油相 的无菌注射水包油微乳。 例如将活性成分溶于大豆油和卵磷脂的混合物中。 然后 将油溶液加入水和甘油的混合物中处理形成微乳。 可通过局部大量注射, 将注射 液或微乳注入患者的血流中。 或者, 最好按可保持本发明化合物恒定循环浓度的 方式给予溶液和微乳。 为保持这种恒定浓度, 可使用连续静脉内递药装置。 这种 装置的实例是 Deltec CADD-PLUS. TM. 5400型静脉注射泵。
药物组合物可以是用于肌内和皮下给药的无菌注射水或油混悬液的形式。 可 按已知技术, 用上述那些适宜的分散剂或湿润剂和悬浮剂配制该混悬液。 无菌注 射制剂也可以是在无毒肠胃外可接受的稀释剂或溶剂中制备的无菌注射溶液或混 悬液, 例如 1,3-丁二醇中制备的溶液。此外, 可方便地用无菌固定油作为溶剂或悬 浮介质。 为此目的, 可使用包括合成甘油单或二酯在内的任何调和固定油。 此外, 脂肪酸例如油酸也可以制备注射剂。
可按用于直肠给药的栓剂形式给予本发明化合物。 可通过将药物与在普通温 度下为固体但在直肠中为液体, 因而在直肠中会溶化而释放药物的适宜的无剌激 性赋形剂混合来制备这些药物组合物。 此类物质包括可可脂、 甘油明胶、 氢化植 物油、 各种分子量的聚乙二醇和聚乙二醇的脂肪酸酯的混合物。
本领域技术人员所熟知的, 药物的给药剂量依赖于多种因素, 包括但并非限 定以下因素: 所用特定化合物的活性、 病人的年龄、 病人的体重、 病人的健康状 况、 病人的表现、 病人的饮食、 给药时间、 给药方式、 ***的速率、 药物的组合 等; 另外, 最佳的治疗方式如治疗的模式、 通式化合物 (I)的日用量或可药用的盐
的种类可以根据传统的治疗方案来验证。 发明详述
除非有相反陈述, 否则下列用在说明书和权利要求书中的术语具有下述含义。 术语 "垸基"指饱和的脂肪族烃基团, 包括 1至 20个碳原子的直链和支链基 团。 优选含有 1至 10个碳原子的垸基, 更优选含有 1至 6个碳原子的垸基, 最优 选含有 1至 4个碳原子的垸基, 最佳为甲基。 非限制性实施例包括甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 仲丁基、 正戊基、 1, 1-二甲基丙基、
1.2-二甲基丙基、 2,2-二甲基丙基、 1-乙基丙基、 2-甲基丁基、 3-甲基丁基、 正己基、
1-乙基 -2-甲基丙基、 1, 1,2-三甲基丙基、 1, 1-二甲基丁基、 1,2-二甲基丁基、 2,2-二 甲基丁基、 1,3-二甲基丁基、 2-乙基丁基、 2-甲基戊基、 3-甲基戊基、 4-甲基戊基、
2.3-二甲基丁基、正庚基、 2-甲基己基、 3-甲基己基、 4-甲基己基、 5-甲基己基、 2,3- 二甲基戊基、 2,4-二甲基戊基、 2,2-二甲基戊基、 3,3-二甲基戊基、 2-乙基戊基、 3- 乙基戊基、 正辛基、 2,3-二甲基己基、 2,4-二甲基己基、 2,5-二甲基己基、 2,2-二甲 基己基、 3,3-二甲基己基、 4,4-二甲基己基、 2-乙基己基、 3-乙基己基、 4-乙基己基、
2-甲基 -2-乙基戊基、 2-甲基 -3-乙基戊基、 正壬基、 2-甲基 -2-乙基己基、 2-甲基 -3- 乙基己基、 2,2-二乙基戊基、 正癸基、 3,3-二乙基己基、 2,2-二乙基己基, 及其各种 支链异构体等。 更优选的是含有 1至 6个碳原子的低级垸基, 非限制性实例包括 甲基、 乙基、 正丙基、 异丙基、 正丁基、 异丁基、 叔丁基、 仲丁基、 正戊基、 1,1- 二甲基丙基、 1,2-二甲基丙基、 2,2-二甲基丙基、 1-乙基丙基、 2-甲基丁基、 3-甲基 丁基、 正己基、 1-乙基 -2-甲基丙基、 1, 1,2-三甲基丙基、 1, 1-二甲基丁基、 1,2-二甲 基丁基、 2,2-二甲基丁基、 1,3-二甲基丁基、 2-乙基丁基、 2-甲基戊基、 3-甲基戊基、 4-甲基戊基、 2,3-二甲基丁基等。 垸基可以是取代的或未取代的, 当被取代时, 取 代基可以在任何可使用的连接点上被取代, 所述取代基优选为一个或多个以下基 团, 独立地选自垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 卤素、 巯基、 羟基、 硝基、 氰基、 环垸基、 杂环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸硫基、 杂环垸硫基、 氧代基、 氨基、 ¾代垸基、 羟垸基、 羧基或羧酸酯基。
术语 "环垸基"指饱和或部分不饱和单环或多环环状烃取代基, 其包括 3至 20个碳原子, 优选包括 3至 12个碳原子, 更优选环垸基环包含 3至 10个碳原子, 最优选环垸基环包含 3至 6个碳原子, 最佳为环丙基或环戊基。 单环环垸基的非 限制性实例包含环丙基、 环丁基、 环戊基、 环戊烯基、 环己基、 环己烯基、 环己 二烯基、 环庚基、 环庚三烯基、 环辛基等, 优选环丙基、 环戊基。 多环环垸基包 括螺环、 稠环和桥环的环垸基。 环垸基可以是任选取代的或未取代的, 当被取代 时, 取代基优选为一个或多个以下基团, 独立地选自垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 ¾素、 巯基、 羟基、 硝基、 氰基、 环垸基、 杂环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸硫基、 杂环垸硫基、 氧代基、 氨基、 卤代
垸基、 羟垸基、 羧基或羧酸酯基。
术语 "烯基"指由至少由两个碳原子和至少一个碳 -碳双键组成的如上定义的 垸基, 例如乙烯基、 1-丙烯基、 2-丙烯基、 1-、 2-或 3-丁烯基等。 优选 C2.1Q烯基, 更优选 C2.6烯基, 最优选 C2.4烯基, 最佳为乙烯基。 烯基可以是取代的或非取代 的, 当被取代时, 取代基优选为一个或多个以下基团, 其独立地选自垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 ¾素、 巯基、 羟基、 硝基、 氰基、 环垸基、 杂环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸硫基、 杂环垸硫基、 氧 代基、 氨基、 卤代垸基、 羟垸基、 羧基或羧酸酯基。
术语 "炔基"指至少由两个碳原子和至少一个碳-碳三键组成的如上所定义的 垸基, 例如乙炔基、 1-丙炔基、 2-丙炔基、 1-、 2-或 3-丁炔基等。 优选 C2.1Q炔基, 更优选 C2.6炔基, 最优选 C2.4炔基。 炔基可以是取代的或非取代的, 当被取代时, 取代基优选为一个或多个以下基团, 其独立地选自垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 ¾素、 巯基、 羟基、 硝基、 氰基、 环垸基、 杂环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸硫基、 杂环垸硫基、 氧代基、 氨基、 卤代 垸基、 羟垸基、 羧基或羧酸酯基。
术语 "杂环垸基"指饱和或部分不饱和单环或多环环状烃取代基, 其包括 3 至 20个环原子, 其中一个或多个环原子选自氮、 氧或 S(0)m (其中 m是 0至2的 整数)的杂原子, 但不包括 -0-0-、 -0-S-或 -S-S-的环部分, 其余环原子为碳。 优选 包括 3至 12个环原子, 其中 1〜4个是杂原子, 更优选杂环垸基环包含 3至 10个 环原子, 更优选杂环垸基环包含 5至 6个环原子。 单环杂环垸基的非限制性实例 包含吡咯垸基、 哌啶基、 哌嗪基、 吗啉基、 硫代吗啉基、 高哌嗪基、 吡喃基、 四 氢呋喃基等。 多环杂环垸基包括螺环、 稠环和桥环的杂环垸基。 杂环垸基可以是 任选取代的或未取代的, 当被取代时, 取代基优选为一个或多个以下基团, 独立 地选自垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 ¾素、 巯基、 羟基、 硝 基、 氰基、 环垸基、 杂环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸硫 基、 杂环垸硫基、 氧代基、 氨基、 ¾代垸基、 羟垸基、 羧基或羧酸酯基。
术语 "芳基"指具有共轭的 π电子体系的 6至 14元全碳单环或稠合多环 (也就 是共享毗邻碳原子对的环)基团, 优选为 6至 10元, 更优选苯基和萘基, 最优选苯 基。 所述芳基环可以稠合于杂芳基、 杂环垸基或环垸基环上, 其中与母体结构连 一起的环为芳基环, 非限制性实例包含:
芳基可以是取代的或未取代的, 当被取代时, 取代基优选为一个或多个以下基团,
独立地选自垸基、 烯基、 炔基、 垸氧基、 焼硫基、 垸基氨基、 卤素、 巯基、 羟基、 硝基、 氰基、 环垸基、 杂环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸 硫基、 杂环垸硫基、 氨基、 ¾代垸基、 羟垸基、 羧基或羧酸酯基。
术语 "杂芳基"指包含 1至 4个杂原子、 5至 14个环原子的杂芳族体系, 其 中杂原子选自氧、 硫和氮。 杂芳基优选为 5至 10元, 更优选为 5元或 6元, 例如 噻二唑基、 吡唑基、 噁唑基、 噁二唑基、 咪唑基、 ***基、 噻唑基、 呋喃基、 噻 吩基、 吡啶基、 吡咯基、 Ν-垸基吡咯基、 嘧啶基、 吡嗪基、 咪唑基、 四唑基等。 所述杂芳基环可以稠合于芳基、 杂环垸基或环垸基环上, 其中与母体结构连接在 一 :
杂芳基可以是任选取代的或未取代的, 当被取代时, 取代基优选为一个或多个以 下基团, 独立地选自垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 卤素、 巯 基、 羟基、 硝基、 氰基、 环垸基、 杂环垸基、 芳基、 杂芳基、 环垸氧基、 杂环垸 氧基、 环垸硫基、 杂环垸硫基、 氨基、 ¾代垸基、 羟垸基、 羧基或羧酸酯基。
术语 "垸氧基" 指 -0- (焼基)和 -0- (未取代的环垸基), 其中垸基、 环垸基的定 义如上所述。 非限制性实例包含甲氧基、 乙氧基、 丙氧基、 丁氧基、 环丙氧基、 环丁氧基、 环戊氧基、 环己氧基等。 垸氧基可以是任选取代的或未取代的, 当被 取代时, 取代基优选为一个或多个以下基团, 独立地选自为垸基、 烯基、 炔基、 垸氧基、 垸硫基、 垸基氨基、 ¾素、 巯基、 羟基、 硝基、 氰基、 环垸基、 杂环垸 基、 芳基、 杂芳基、 环垸氧基、 杂环垸氧基、 环垸硫基、 杂环垸硫基、 氨基、 卤 代垸基、 羟垸基、 羧基或羧酸酯基。
"卤代垸基"指垸基被一个或多个卤素取代, 其中垸基的定义如上所述。
"羟基"指 -ΟΗ基团。
"羟垸基"指被羟基取代的垸基, 其中垸基的定义如上所述。
"卤素"指氟、 氯、 溴或碘, 优选氟或碘。
"氨基"指 -ΝΗ2。
"氰基"指 -CN。
"硝基"指 -N02。
"氧代基"指 =0。
"羧基"指 -C(0)OH。
"羧酸酯基"指 -C(0)0(焼基)或 (环垸基), 其中垸基、环垸基的定义如上所述。
"任选"或 "任选地"意味着随后所描述地事件或环境可以但不必发生, 该 说明包括该事件或环境发生或不发生的场合。 例如, "任选被垸基取代的杂环垸基 团"意味着垸基可以但不必须存在, 该说明包括杂环垸基团被垸基取代的情形和 杂环垸基团不被垸基取代的情形。
"取代的"指基团中的一个或多个氢原子, 优选为最多 5个, 更优选为 1〜3 个氢原子彼此独立地被相应数目的取代基取代。 不言而喻, 取代基仅处在它们的 可能的化学位置, 本领域技术人员能够在不付出过多努力的情况下确定 (通过实验 或理论;)可能或不可能的取代。 例如, 具有游离氢的氨基或羟基与具有不饱和 (如録 属)键的碳原子结合时可能是不稳定的。
"药物组合物"表示含有一种或多种本文所述化合物或其生理学上 /可药用的 盐或前体药物与其它化学组分的混合物, 以及其它组分例如生理学 /可药用的载体 和赋形剂。 药物组合物的目的是促进对生物体的给药, 利于活性成分的吸收进而 发挥生物活性。 本发明的合成方法
为了完成本发明的合成目的, 本发明采用如下的合成技术方案:
一种制备通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映
( I - A ) (卜 B :
( l - C ) ( I )
通式 (I-A)化合物与通式( I-B)化合物在碱性条件下, 任选在催化剂作用下进行 取代反应得到通式( I-C )化合物; 通式(I-C )化合物在溶剂中, 酸性条件下, 进行 脱保护反应, 任选进一步进行取代反应得到通式( I )化合物;
其中: X为卤素; Boc为叔丁氧羰基; R为垸基, 优选为丁基; =, A1, A2, Υ, Ι^〜Ι 6的定义如通式(I )中所定义; R4优选为氢原子或垸基, 其中所述的垸基 任选进一步被一个或多个选自卤素、 羟基或环垸基的取代基所取代; R2优选为 -C(0)R7; 且 R7为垸基。 一种制备通式 (II)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映 异构体、 非对映异构体或其混合物形式, 或其可药用盐的方法, 该方法包括:
通式 (Π-Α)化合物与通式( Ι-Β)化合物在碱性条件下,任选在催化剂作用下进行 取代反应得到通式 (II-C )化合物; 通式 (II-C )化合物在溶剂中, 酸性条件下, 进行 脱保护反应, 任选进一步进行取代反应得到通式 (Π )化合物;
其中: X为卤素; Boc为叔丁氧羰基; R为垸基, 优选为丁基; =, A1, A2, Υ, Ι^〜Ι 6的定义如通式( I )中所定义; R4优选为氢原子或垸基, 其中所述的垸 基任选进一步被一个或多个选自卤素、 羟基或环垸基的取代基所取代; R2优选为 -C(0)R7; 且 R7为垸基。 一种制备通式( III )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对
通式 (ΙΠ-Α)化合物与通式( I-B)化合物在碱性条件下, 任选在催化剂作用下进 行取代反应得到通式 (III-C )化合物; 通式 (III-C )化合物在溶剂中, 酸性条件下, 进 行脱保护反应, 任选进一步进行取代反应得到通式 (III )化合物;
其中: X为卤素; Boc为叔丁氧羰基; R为垸基, 优选为丁基; =, A1, A2, Υ, Ι^〜Ι 6的定义如通式( I )中所定义; R4优选为氢原子或垸基, 其中所述的垸 基任选进一步被一个或多个选自卤素、 羟基或环垸基的取代基所取代; R2优选为 -C(0)R7; 且 R7为垸基。 提供碱性条件的试剂包括有机碱和无机碱类, 所述的有机碱类包括但不限于 六甲基二硅基胺基锂、 六甲基二硅基胺基钠、 二异丙基胺基锂、 三乙胺、 吡啶、 2,6-二甲基吡啶、 N,N-二异丙基乙基胺、 正丁基锂、 叔丁醇钾或四丁基溴化铵, 所
述的无机碱类包括但不限于碳酸铯、 碳酸钠、 碳酸氢钠、 碳酸钾、 碳酸氢钾、 氢 氧化锂、 氢氧化钠、 氢氧化钾或氢化钠。
提供酸性的条件包括但不限于甲酸、 乙酸、 盐酸、 硫酸、 甲磺酸、 三氟乙酸和 羟基乙磺酸, 优选三氟乙酸或羟基乙磺酸。
催化剂包括但不限于 4,5-双二苯基膦 -9,9-二甲基氧杂蒽、 三 (二亚苄基丙酮)二 钯、 Ι,Γ-联萘 -2,2'-二苯膦、 [Ι,Γ-双 (二苯基磷)二茂铁]二氯化钯、 二 (三苯基膦)二氯 化钯、 三苯基膦、 二氯化钯、 醋酸钯、 碘化亚铜、 钯 /碳或兰尼镍。
所用溶剂包括但不限于: 1,4-二氧六环、 甲苯、 水、 乙腈、 四氢呋喃、 二氯甲 垸、 1,2-二氯乙垸、 甲醇、 乙醇、 正丁醇、 二甲基亚砜或 N,N-二甲基甲酰胺。 具体实施方式
以下结合实施例进一步描述本发明, 但这些实施例并非限制本发明的范围。 本发明实施例中未注明具体条件的实验方法, 通常按照常规条件, 或按照原 料或商品制造厂商所建议的条件。 未注明具体来源的试剂, 为市场购买的常规试 剂。 实施例
化合物的结构是通过核磁共振 (NMR)或 /和质谱 (MS)来确定的。 MR位移 (δ) 以 10·6 (ppm)的单位给出。 MR的测定是用 Bruker AVANCE-400核磁仪, 测定溶 剂为氘代二甲基亚砜 (DMSO-i¾, 氘代氯仿 (CDC13), 内标为四甲基硅垸 (TMS;)。
MS的测定用 FINNIGAN LCQAd (ESI)质谱仪 (生产商: Thermo,型号: Finnigan LCQ advantage MAX)。
HPLC的测定使用安捷伦 1200DAD高压液相色谱仪 (Sunfire C18 150x4.6mm 色谱柱;)和 Waters 2695-2996高压液相色谱仪 (Gimini C18 150x4.6mm色谱柱;)。
薄层层析硅胶板使用烟台黄海 HSGF254或青岛 GF254硅胶板, 薄层色谱法 (TLC)使用的硅胶板采用的规格是 0.15 mm〜0.2 mm, 薄层层析分离纯化产品采用 的规格是 0.4 mm〜0.5 mm。
柱层析一般使用烟台黄海硅胶 200 300目硅胶为载体。
本发明的已知的起始原料可以采用或按照本领域已知的方法来合成, 或可购 买自 ABCR GmbH & Co. KG、 Acros Organics、 Aldrich Chemical Company 韶远化 学科技 (Accela ChemBio Inc) 达瑞化学品等公司。
实施例中无特殊说明, 反应能够均在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约 1L容积的氩气或氮气气球。
氢气氛是指反应瓶连接一个约 1L容积的氢气气球。
加压氢化反应使用 Parr 3916EKX型氢化仪和清蓝 QL-500 型氢气发生器或 HC2-SS型氢化仪。
氢化反应通常抽真 , 充入氢气, 反复操作 3次。
实施例中无特殊说明, 溶液是指水溶液。
实施例中无特殊说明, 反应的温度为室温, 为 20°C〜30°C。
实施例中的反应进程的监测采用薄层色谱法 (TLC), 反应所使用的展开剂的体 系有: A: 二氯甲垸和甲醇体系, B : 正己垸和乙酸乙酯体系, C : 石油醚和乙酸 乙酯体系, 溶剂的体积比根据化合物的极性不同而进行调节。
纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括:
A: 二氯甲垸和甲醇体系, B : 正己垸和乙酸乙酯体系, C : 二氯甲垸、 甲醇和乙 酸乙酯体系, 溶剂的体积比根据化合物的极性不同而进行调节, 也可以加入少量 的三乙胺和醋酸等碱性或酸性试剂进行调节。 实施例 1
6-乙酰基 -8-环戊基 -5-甲基 -2-((1',2',3',6'-四氢 -[3,4'-联吡 ®]-6-基)氨基)吡啶并 [2,3-
2-氨基 -6-溴 -8-环戊基 -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 依次将 6-溴 -2-氯 -8-环戊基 -5-甲基吡啶并 [2,3-ί/]嘧啶 -7(8H)-酮 la (5 g, 14.59 mmol ,采用"专利申请 WO2008032157 "公开的方法制备而得)、 2 mL氨水和 20 mL N,N-二甲基甲酰胺加入 50 mL茄形瓶中, 70°C下搅拌反应 1小时。 冷却至室温, 白色晶体析出, 加入 50 mL正己垸, 搅拌 5分钟, 抽滤, 滤饼用乙酸乙酯和正己 垸 (V/V = 1 : 10)的混合溶液洗涤, 固体直接干燥, 得到粗品标题产物 2-氨基 -6-溴 -8- 环戊基 -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 lb (5.0 g, 浅黄色固体)。
MS m/z (ESI): 324.9 [M+l]
第二步
2-氨基 -6-(l-丁氧基乙烯基 )-8-环戊基 -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 氩气氛下, 依次将粗品 2-氨基 -6-溴 -8-环戊基 -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)- 酮 lb (4.7 g, 14.54 mmol)、 乙烯基丁醚 (3.76 mL, 29.20 mmol) [Ι, Γ-双 (二苯基磷) 二茂铁]二氯化钯 (1.10 g, 1.50 mmol)、 N,N-二异丙基乙基胺 (5 mL, 29.2 mmol)和 30 mL正丁醇加入 100 mL茄形瓶中, 95 °C下搅拌反应 12小时。 冷却至室温, 减 压浓缩, 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物, 得到标题产物 2-氨基 -6 1-丁氧基乙烯基 )-8-环戊基 -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 lc (3.0 g, 浅黄色 固体), 产率 60.0%。
MS m/z (ESI): 343.2 [M+l]
第三步
6-氯 -5',6'-二氢 -[3,4'-联吡啶 ]-l'(2'H;)-羧酸叔丁酯 依次将 5-溴 -2-氯吡啶 Id (6.20 g, 0.032 mol)、 4-(4,4,5,5-四甲基 -1,3,2-二氧杂 戊硼垸 -2-基;) -5,6-二氢吡啶 -lpH)-羧酸叔丁酯 le (10 g, 0.032 mol) 碳酸钠 (6.86 g, 0.068 mol)和 102.3 mL二氧六环和水 (V/V = 10: 1)的混合溶剂加入 250 mL反应瓶 中, 氩气氛下, 加入 [Ι, Γ-双 (二苯基膦)二茂铁]二氯化钯二氯甲垸络合物 (1.89 g, 0.027 mol), 108°C反应 7小时。 冷却至室温, 过滤, 滤饼用二氯甲垸 (30 mL><3)洗 涤, 滤液减压浓缩, 用硅胶柱色谱法以洗脱剂体系 B纯化所得残余物, 得到标题 产物 6-氯 -5',6'-二氢 -[3,4'-联吡啶 ]-l'C2'H;)-羧酸叔丁酯 If (8.11 g, 黄色液体;), 产率 86.2%。
MS m/z (ESI): 295.3 [M+l]
第四步
6-((6-(l-丁氧基乙烯基 )-8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶并 [2,3- 嘧啶 -2-基) 氨基; )-5',6'-二氢 -[3,4'-联吡啶 ]-r(2'H)-羧酸叔丁酯 依次将 6-氯 -5',6'-二氢 -[3,4'-联吡啶 ]-l'(2'H)-羧酸叔丁酯 If (500 mg, 1.70 mmol)、 2-氨基 -6-(1-丁氧基乙烯基 )-8-环戊基 -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 lc (586 mg, 1.70 mmol)、 碳酸铯(1.10 g, 3.40 mmol)和 4,5-双二苯基膦 -9,9-二甲基氧
杂蒽 C156 mg, 0.27 mmol)加入装有 15 mL二氧六环的反应瓶中。 氩气氛下, 加入 三 (二亚苄基丙酮;)二钯 (125 mg, 0.14 mmol), 104°C反应 15小时。 停止反应, 冷却 至室温, 过滤, 滤饼用二氯甲垸洗涤 (15 mLx3), 滤液减压浓缩, 用薄层色谱法以 展开剂体系 C纯化所得残余物, 得到粗品标题产物 6-((6-(1-丁氧基乙烯基 )-8-环戊 基 -5-甲基 -7-氧代 -7,8-二氢吡啶并 [2,3- 嘧啶 -2-基)氨基 )-5',6'-二氢 -[3,4'-联吡 啶] -rp'H)-羧酸叔丁酯 lg (1.12 g, 黄色固体;)。
MS m/z (ESI): 601.2[M+1]
第五步
6-乙酰基 -8-环戊基 -5-甲基 -2-((Γ,2',3',6'-四氢 -[3,4'-联吡 ®]-6-基)氨基)吡啶并 [2,3- 嘧啶 -7(8H)-酮
将粗品 6-((6-(1-丁氧基乙烯基 )-8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶并 [2,3- 嘧啶 -2-基)氨基) -5',6'-二氢 -[3,4'-联吡啶 ]-l'(2'H)-羧酸叔丁酯 lg (750 mg, 1.25 mmol) 溶于 6 mL二氯甲垸中, 加入 2 mL三氟乙酸, 室温反应 1.5小时。 减压浓缩除去 溶剂, 加入 10 mL二氯甲垸和 2 mL甲醇, 滴加氨水调节 ρΗ为 8。 减压浓缩除去 溶剂, 加入二氯甲垸和甲醇 (V/V = 10: 1)的混合溶剂 (lO mLx l)洗涤, 过滤, 滤液减 压浓缩, 得到粗品标题产物 6-乙酰基 -8-环戊基 -5-甲基 -2-((1',2',3',6'-四氢 -[3,4'-联吡 啶] -6-基;)氨基;)吡啶并 [2,3-ί/]嘧啶 -7(8H;>-酮 1 (750 mg, 黄色固体;)。 取 150 mg标题 产物, 用薄层色谱法以展开剂体系 A纯化, 得到 70 mg产物。
MS m/z (ESI): 445.3 [M+l]
1H MR (400 MHz, DMSO- 6) δ 10.38 (s, IH), 9.01 (s, IH), 8.40 (s, IH), 8.05 (d, IH), 7.87 (d, IH), 6.27 (s, IH), 5.88-5.85 (m, IH), 2.94-2.91 (m, 2H), 2.40 (s, 3H), 2.36 (s, IH), 2.32 (s, 3H), 2.27-2.24 (m, 3H), 1.94-1.90 (m, 2H), 1.82-1.79 (m, 2H), 1.62-1.60 (m, 2H), 1.25-1.22 (m, 3H) 实施例 2
6-乙酰基 -8-环戊基- -甲基 -2-((Γ-甲基 -Γ,2',3',6'-四氢 -[3,4'-联吡 ®]-6-基)氨基)吡啶 并 [ -酮
1 2
依次将 6-乙酰基 -8-环戊基 -5-甲基 -2-((Γ,2',3',6'-四氢 -[3,4'-联吡 ®]-6-基)氨基) 吡啶并 [2,3-ί/]嘧啶 -7(8H)-酮 1 (100 mg, 0.22 mmol) 37%甲醛水溶液 (120mg, 1.48 mmol)和 10 mL 1,2-二氯乙垸加入到反应瓶中, 加入醋酸硼氢化钠 (;95 mg, 1.48 mmol) o 室温反应 15小时, 停止反应, 加入 4 mL甲醇, 滴加氨水调节 ρΗ至 8~9, 减压蒸熘浓缩, 得到标题产物 6-乙酰基 -8-环戊基 -5-甲基 -2-((1'-甲基 -1',2',3',6'-四氢 -[3,4'-联吡 ®]-6-基)氨基)吡啶并 [2,3- 嘧啶 -7(8H)-酮 2 (35 mg, 黄色固体), 产率: 34.7%。
MS m/z (ESI): 459.3 [M+l]
1H MR (400 MHz, DMSO- 6) δ 10.49 (s, IH), 9.02 (s, IH), 8.48 (s, IH), 8.12 (d, IH), 7.96 (d, IH), 6.27 (s, IH), 5.88-5.85 (m, IH), 3.73(s, 2H), 2.77 (s, 4H), 2.33 (s, 3H), 2.26 (s, 3H), 2.27-2.24 (m, 2H), 1.97-1.95 (m, 2H), 1.84-1.81 (m, 2H), 1.64-1.61 (m, 2H), 1.25-1.22 (m, 3H) 实施例 3
6-乙酰基 -8-环戊基 -2-((5-(4-羟基哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基吡啶并 [2,3- 嘧
4-(6-氯吡啶 -3-基) -4-羟基哌啶 -1-羧酸叔丁酯 在氩气保护下, 将 5-溴 -2-氯吡啶 Id (500 mg, 2.60 mmol)和 20 mL四氢呋喃 加入 100 mL茄形瓶中, 干冰-丙酮浴冷却至 -70°C, 往反应液中加入 1.6 M的正丁 基锂 C1.8 mL, 2.86 mmol), 并在此温度下搅拌 30分钟, 然后往反应物中加入预制 的 4-羰基哌啶 -1-羧酸叔丁酯 (570 mg, 2.86 mmol)的四氢呋喃溶液, 然后在干冰- 丙酮浴保护下反应 1小时。 加入 20 mL饱和氯化铵溶液淬灭反应, 用乙酸乙酯萃 取 (50 mLx3), 合并有机相, 无水硫酸钠干燥, 过滤, 滤液减压浓缩, 用薄层色谱 法以展开剂体系 A纯化所得残余物, 得到标题产物 4-(6-氯吡啶 -3-基) -4-羟基哌啶 -1-羧酸叔丁酯 3a (80 mg, 黄色固体;), 产率: 10%。
MS m/z (ESI): 313.1 [M+1]
第二步
4-(6-((6-(l-丁氧基乙烯基 )-8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶并 [2,3- 嘧啶 -2-基) 氨基)吡啶 -3-基 )-4-羟基哌啶 -1-羧酸叔丁酯
依次将 4-(6-氯吡啶 -3-基) -4-羟基哌啶 -1-羧酸叔丁酯 3a (80 mg, 0.26 mmol)、 2-氨基 -6-(1-丁氧基乙烯基 )-8-环戊基 -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 lc (80 mg, 0.26 mmol) 三 (二亚苄基丙酮)二钯 (24 mg, 0.026 mmol)、 Ι, Γ-联萘 -2,2'-二苯膦 (32 mg, 0.052 mmol)和碳酸铯 (170 mg, 0.52mmol)分别加入 50 mL的茄形瓶中, 然后 加入 20 mL的二氧六环, 氩气氛下, 在 90°C条件下搅拌反应 16小时, 将反应液减 压蒸熘,用薄层色谱法以展开剂体系 A纯化所得残余物,得到标题产物 4-(6-((6-(1- 丁氧基乙烯基 )-8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶并 [2,3- 嘧啶 -2-基;)氨基)吡啶 -3-基) -4-羟基哌啶 -1-羧酸叔丁酯 3b (60 mg, 黄色固体), 产率 37.3%。
MS m/z (ESI): 619.2[M+1]
第三步
6-乙酰基 -8-环戊基 -2-((5-(4-羟基哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基吡啶并 [2,3- 嘧 啶 -7(8H)-酮
将 4-(6-((6-(1-丁氧基乙烯基 )-8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶并 [2,3- 嘧 啶 -2-基)氨基)吡啶 -3-基 )-4-羟基哌啶 -1-羧酸叔丁酯 3b (60 mg, 0.097 mmol)和羟基 乙磺酸 (50 mg, 0.387 mmol)加入 25 mL茄形瓶中, 然后加入 2 mL 30%的甲醇水溶 液, 搅拌均匀, 在 60°C条件下反应 1小时, 然后往反应液中加入 10 mL的饱和碳 酸氢钠水溶液, 用乙酸乙酯萃取 (15 mLx3), 合并有机相, 无水硫酸钠干燥, 过滤, 滤液减压浓缩, 用薄层色谱法以展开剂体系 A纯化所得残余物, 得到标题产物 6- 乙酰基 -8-环戊基 -2-((5-(4-羟基哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 3 (30 mg, 浅黄色固体), 产率 66.8%。
MS m/z (ESI): 463.1 [M+1]
1H MR (400MHz, DMSO- 6) δ 10.38 (s, 1H), 8.97 (s, 1H), 8.42 (s, 1H), 8.06 (d, 1H), 7.87 (d, 1H), 5.83-5.82 (m, 1H), 5.60-5.58 (m, 1H), 2.82 (s, 3H), 2.54-2.52 (m, 1H),
2.42 (s, 3H), 2.35-2.32 (m, 2H), 2.28-2.26 (m, 2H), 2.20-2.17 (m, IH), 1.92-1.90 (m: 5H), 1.80-1.77 (m, 2H), 1.60-1.58 (m, 2H), 1.25-1.23 (m, 2H) 实施例 4
6-乙酰基 -8-环戊基 -2-((5-(4-羟基 -1-甲基哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基吡啶并
[2,3- 嘧啶 -7(8H)-酮
将 6-乙酰基 -8-环戊基 -2-((5-(4-羟基哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基吡啶并 [2,3-0嘧啶 -7(8H)-酮 3 (20 mg, 0.043 mmol) 36%甲醛水溶液 (6.5 mg, 0.065 mmol) 和 10 mL二氯甲垸加入到 25 mL的茄形瓶中, 在室温条件下搅拌 2小时后, 加入 醋酸硼氢化钠 (27 mg, 0.129 mmol), 并在室温条件下继续搅拌 16小时,停止反应, 加入 l mL氨水, 减压浓缩蒸干, 用薄层色谱法以展开剂体系 A纯化所得残余物, 得到标题产物 6-乙酰基 -8-环戊基 -2-((5-(4-羟基 -1-甲基哌啶 -4-基)吡啶 -2-基;)氨 基) -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 4 (10 mg, 黄色固体), 产率: 50.0%。
MS m/z (ESI): 477.3 [M+1]
1H MR (400MHz, DMSO- 6) δ 10.42 (s, IH), 9.02 (s, IH), 8.46 (s, IH), 8.09 (d, IH), 7.90 (d, IH), 5.88-5.86 (m, IH), 5.69-5.64 (m, IH), 2.80 (s, 3H), 2.55-2.53 (m, IH), 2.44 (s, 3H), 2.38-2.36 (m, 2H), 2.33 (s, 3H), 2.27-2.25 (m, 2H), 2.19-2.17 (m, IH), 1.91-1.88 (m, 4H), 1.82-1.79 (m, 2H), 1.61-1.59 (m, 2H), 1.26-1.24 (m, 2H) 实施例 5
6-乙酰基 -8-环戊基 -2-((5-(4-氟 -1-甲基哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基吡啶并
[2,3- 嘧啶 -7(8H)-酮
将 6-乙酰基 -8-环戊基 -2-((5-(4-羟基 -1-甲基哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基 吡啶并 [2,3-ί/]嘧啶 -7(8H)-酮 4 (10 mg, 0.021 mmol)溶于 5 mL的二氯甲垸中, 然后 在干冰-丙酮浴冷却下, 加入二甲氨基三氟化硫 (2滴), 搅拌 30分钟后 TLC监测反 应的进行, 大部分原料未反应, 补加 2 滴二甲氨基三氟化硫, 搅拌 1小时后, 终 止反应。 加入 15 mL水淬灭反应, 搅拌 10分钟后, 分液分离出有机相, 减压浓缩 蒸干, 用薄层色谱法以展开剂体系 A纯化所得残余物, 得到标题产物 6-乙酰基 -8- 环戊基 -2- 5-(4-氟 -1-甲基哌啶 -4-基)吡啶 -2-基;)氨基) -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 5 (6 mg, 黄色固体), 产率 60%。
MS m/z (ESI): 479.3 [M+l]
1H MR (400 MHz, DMSO- 6) δ 10.28 (s, 1H), 9.02 (s, 1H), 8.42 (s, 1H), 8.12(d, 1H), 7.69-7.66 (m, 3H), 5.87-5.84 (m, 1H), 2.42 (s, 3H), 2.32 (s, 1H), 2.24-2.21 (m, 3H), 1.99-1.96 (m, 4H), 1.96-1.93 (m, 3H), 1.92-1.89 (m, 3H), 1.78 (s, 3H), 1.60 (s, 3H) 实施例 6
6-乙酰基 -8-环戊基 -5-甲基 -2-((5- (哌啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3- 嘧啶
6-硝基 -5',6'-二氢 -[3,4'-联吡啶 ]-l'(2'H;>-羧酸叔丁酯 依次将 5-溴 -2-硝基吡啶 6a (720 mg, 3.56 mmol)、 4-(4,4,5,5-四甲基 -1,3,2-二氧 杂戊硼垸 -2-基;) -5,6-二氢吡啶 -1(2H)-羧酸叔丁酯 le (1 g, 3.24 mmol)、碳酸铯 (2.12 g, 6.50 mmol)和 17 mL二氧六环和水 CV/V = 16: 1)的混合溶剂加入封管中, 氩气氛下, 加入 [Ι,Γ-双 (;二苯基膦;)二茂铁]二氯化钯二氯甲垸络合物 (230 mg, 0.32 mmol), 85 °C反应 12小时。 冷却至室温, 减压浓缩, 用硅胶柱色谱法以洗脱剂体系 B纯化所 得残余物,得到标题产物 6-硝基 -5',6'-二氢 -[3,4'-联吡啶 ]-l'(2'H)-羧酸叔丁酯 6b (677 mg, 淡黄色固体;), 产率 67.7%。
MS m/z (ESI): 306.2 [M+l]
第二步
4-(6-氨基吡啶 -3-基;)哌啶 -1-羧酸叔丁酯
将 6-硝基 -5',6'-二氢 -[3,4'-联吡啶 ]-1'(2 )-羧酸叔丁酯 6b (650 mg, 2.13 mmol) 溶于 45 mL甲醇中, 加入 10%钯碳 (250 mg, cat), 氢气置换三次, 3个大气压下室 温反应 12小时。 停止反应, 少量硅藻土过滤, 滤饼用二氯甲垸和甲醇 (V/V = 10: 1) 的混合溶剂洗涤 (20 mLx l), 收集滤液, 减压浓缩, 得到粗品标题产物 4-(6-氨基吡 啶 -3-基)哌啶 -1-羧酸叔丁酯 6c (595 mg, 透明稠状物), 直接用于下一步。
MS m/z (ESI): 278.3 [M+l]
第三步
4-(6-((6-溴 -8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶并 [2,3- 嘧啶 -2-基)氨基)吡啶 -3- 基)哌啶 -1-羧酸叔丁酯
将粗品 4-C6-氨基吡啶 -3-基;)哌啶 -1-羧酸叔丁酯 6c (480 mg, 1.73 mmol)溶于 8 mL甲苯中, 加热溶解后, 加入六甲基二硅基胺基锂 (1.7 mL, 1.73 mmol), 室温反 应 20分钟, 加入溶于 3 mL 甲苯的 6-溴 -2-氯 -8-环戊基 -5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-S la (540 mg, 1.57 mmol), 室温反应 1.5小时。 加入 20 mL饱和氯化铵溶
液淬灭反应, 用乙酸乙酯萃取 (20 mLx3), 用饱和氯化钠溶液洗涤 (30 mLx2), 无水 硫酸钠干燥, 过滤, 滤液减压浓缩, 用薄层色谱法以展开剂体系 A纯化所得残余 物, 得到标题产物 4-(6-((6-溴 -8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶并 [2,3- 嘧啶 -2-基)氨基)吡啶 -3-基)哌啶 -1-羧酸叔丁酯 6d (HO mg, 淡黄色固体), 产率: 12.1%。 MS m/z (ESI): 583.3 [M+l]
第四步
4-(6-((6-(l-丁氧基乙烯基 )-8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶 [2,3- 嘧啶 -2-基) 氨基)吡啶 -3-基)哌啶 -1-羧酸叔丁酯
依次将 4-(6-((6-溴 -8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶并 [2,3- 嘧啶 -2-基)氨 基)吡啶 -3-基)哌啶 -1-羧酸叔丁酯 6d (100 mg, 0.17 mmol)、 [Ι, Γ-双(二苯基磷)二 茂铁]二氯化钯 (10 mg, 0.015 mmol)、 N,N-二异丙基乙基胺(105 mg, 0.73 mmol)和 4 mL正丁醇加入反应瓶中, 氩气氛下, 加入乙烯基丁醚 (160 mg, 1.36 mmol), 加 热至 95 °C, 反应 12小时。 冷却至室温, 减压浓缩, 得到粗品标题产物 4-(6-((6-(1- 丁氧基乙烯基 )-8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶 [2,3- 嘧啶 -2-基;)氨基)吡啶
-3-基)哌啶 -1-羧酸叔丁酯 6e (152mg, 褐色稠状物, 粗产率 >100%), 直接用于下一 止
少。
MS m/z (ESI): 603.2 [M+l]
第五步
6-乙酰基 -8-环戊基 -5-甲基 -2-((5- (哌啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3- 嘧啶
-7(8H)-酮
将粗品 4-(6-((6-(1-丁氧基乙烯基 )-8-环戊基 -5-甲基 -7-氧代 -7,8-二氢吡啶 [2,3- 嘧啶 -2-基;)氨基;)吡啶 -3-基;)哌啶 -1-羧酸叔丁酯 6e (25 mg, 0.041 mmol)溶于 2 mL甲 醇和水 (V/V = 40: 1)的混合溶剂中, 加入羟基乙磺酸 (20 mg, 0.16 mmol), 加热至 60°C, 反应 1小时。 依次加入 15 mL二氯甲垸、 2 mL甲醇和 2滴水, 搅拌均匀, 加入碳酸钠固体 (150 mg), 搅拌 20分钟, 过滤, 滤液减压浓缩, 用薄层色谱法以 展开剂体系 A纯化所得残余物,得到标题产物 6-乙酰基 -8-环戊基 -5-甲基 -2-((5- (哌 啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3- 嘧啶 -7(8H)-酮 6 (8 mg, 土黄色固体), 产率: 50.0%。
MS m/z (ESI): 447.3 [M+l]
1H MR (400 MHz, DMSO- 6) δ 10.38 (s, 1H), 8.99 (s, 1H), 8.24 (s, 1H), 8.02 (d, 1H), 7.69 (d, 1H), 5.87-5.83 (m, 1H), 2.97-2.94 (m, 2H), 2.94-2.91 (m, 1H), 2.42 (s, 3H), 2.32 (s, 3H), 2.27-2.24 (m, 4H), 1.93-1.88 (m, 4H), 1.81-1.77 (m, 4H), 1.58 (s, 2H), 1.25 (s, 1H) 实施例 7
6-乙酰基 -8-环戊基 -5-甲基 -2-((5-(l-甲基哌啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3- 嘧 啶 -7(8H)-酮
6 7
将 6-乙酰基 -8-环戊基 -5-甲基 -2-((5- (哌啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3- 嘧 啶 -7(8H)-酮 6 (25 mg, 0.056 mmol)禾口 37%甲醛溶液 (6.8 mg, 0.084 mmol)溶于 4 mL 1,2-二氯乙垸中, 反应 10分钟, 加入醋酸硼氢化钠 (35 mg, 0.17 mmol), 室温反应 12小时。 停止反应, 加入 2 mL甲醇, 搅拌 10分钟, 减压浓缩, 用薄层色谱法以 展开剂体系 A纯化所得残余物, 得到标题产物 6-乙酰基 -8-环戊基 -5-甲基 -2-((5-(1- 甲基哌啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3- 嘧啶 -7(8H)-酮 7 (20 mg,淡黄色固体), 产率: 77.8%。
MS m/z (ESI): 461.3 [M+l]
1H MR (400 MHz, DMSO- 6) δ 10.34 (s, 1H), 9.00 (s, 1H), 8.26 (s, 1H), 8.03 (d, 1H), 7.72 (d, 1H), 5.87-5.83 (m, 1H), 2.96 (s, 2H), 2.70 (s, 3H), 2.42 (s, 3H), 2.32 (s, 3H), 2.26 (s, 2H), 1.99 (s, 4H), 1.90 (s, 2H), 1.78 (s, 2H), 1.59 (s, 2H), 1.25 (s, 3H) 实施例 8
6-乙酰基 -8-环戊基 -2-((5-(l-乙基哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基吡啶并 [2,3- 嘧
依次将 6-乙酰基 -8-环戊基 -5-甲基 -2-((5- (哌啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3-0嘧啶 -7(8H)-酮 6 (20 mg, 0.047 mmol)、 乙酸 (20 mg, 0.45 mmol)、 4 mL 1,2- 二氯乙垸和醋酸硼氢化钠 (25 mg, 0.11 mmol)加入反应瓶中, 室温反应 12小时。 停止反应, 加入 3 mL甲醇, 搅拌 5分钟, 减压浓缩, 用薄层色谱法以展开剂体系 A纯化所得残余物, 得到标题产物 6-乙酰基 -8-环戊基 -2-((5-(1-乙基哌啶 -4-基)吡啶 -2-基;)氨基; )-5-甲基吡啶并 [2,3- 嘧啶 -7(8H)-酮 8 (10 mg,黄色固体;),产率: 45.4%。 MS m/z (ESI): 475.2 [M+l]
1H MR (400 MHz, DMSO- 6) δ 10.32 (s, 1H), 9.00 (s, 1H), 8.24 (s, 1H), 8.01 (d, 1H), 7.71 (d, 1H), 5.87-5.83 (m, 1H), 2.85 (s, 3H), 2.75 (s, 1H), 2.69-2.65 (m, 4H), 2.42 (s, 3H), 2.31 (s, 3H), 2.25 (s, 2H), 1.94-1.90 (m, 4H), 1.78 (s, 3H), 1.58 (s, 4H), 1.45 (s, 1H) 实施例 9
6-乙酰基 -8-环戊基 -2-((5-(l-(2-羟乙基)哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基吡啶并
得 6-乙酰基 -8-环戊基 -5-甲基 -2-((5- (哌啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3- 嘧
啶 -7(8H)-酮 6 (15 mg, 0.033 mmol)溶于 2.5 mL N,N-二甲基甲酰胺中, 加入 2-溴乙 醇 (10 mg, 0.080 mmol)和碳酸钾(12.5 mg, 0.091 mmol), 室温反应 12小时, TLC 检测反应, 原料没有反应完, 补加 1滴 2-溴乙醇, 加热至 70°C, 反应 2.5小时, TLC检测反应, 原料没有反应完, 加热至 90°C, 补加碳酸钾 15 mg, 反应 3小时, 停止反应。 冷却至室温, 过滤, 滤液减压浓缩, 用薄层色谱法以展开剂体系 A纯 化所得残余物, 得到标题产物 6-乙酰基 -8-环戊基 -2-((5-(1-(2-羟乙基)哌啶 -4-基)吡 啶 -2-基;)氨基; )-5-甲基吡啶并 [2,3- 嘧啶 -7(8H;>-酮 9 (10 mg, 淡黄色固体;), 产率: 62.5%。
MS m/z (ESI): 491.3 [M+l]
1H MR (400 MHz, DMSO- 6) δ 10.34 (s, 1H), 8.99 (s, 1H), 8.23 (s, 1H), 7.98 (d, 1H), 7.72 (d, 1H), 7.68 (s, 1H), 5.87-5.83 (m, 1H), 2.98 (d, 2H), 2.42 (s, 3H), 2.32 (s, 3H), 2.27-2.22 (m, 2H), 2.02-1.98 (m, 3H), 1.98-1.95 (m, 3H), 1.90 (s, 2H), 1.74-1.70 (m, 4H), 1.69-1.63 (m, 3H), 1.45 (s, 2H) 实施例 10
6-乙酰基 -8-环戊基 -2-((5-(l- (环丙基甲基)哌啶 -4-基;)吡啶 -2-基;)氨基) -5-甲基吡啶并
[2 酮
依次将 6-乙酰基 -8-环戊基 -5-甲基 -2-((5- (哌啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3-0嘧啶 -7(8H)-酮 6 (15 mg, 0.033 mmol) 环丙基溴甲垸 (8.37 mg, 0.062 mmol)、 碳酸钾 (20.7 mg, 0.15 mmol)和 3 mL乙腈加入反应瓶中, 加热至 80°C, 反应 2小 时, 停止反应。 冷却至室温, 过滤, 滤液减压浓缩, 用薄层色谱法以展开剂体系 A 纯化所得残余物, 得到标题产物 6-乙酰基 -8-环戊基 -2-((5-(1- (环丙基甲基)哌啶 -4-
基;)吡啶 -2-基;)氨基; )-5-甲基吡啶并 [2,3- 嘧啶 -7(8H;>-酮 10 (6 mg,黄色固体;),产率: 40.0%。
MS m/z (ESI): 501.2 [M+l]
1H MR (400 MHz, DMSO- 6) δ 10.28 (s, 1H), 8.99 (s, 1H), 8.24 (s, 1H), 7.97 (d, 1H), 7.74 (d, 1H), 5.87-5.83 (m, 1H), 3.22-3.18 (m, 3H),2.42 (s, 3H), 2.36 (s, 2H), 2.31 (s, 3H), 2.27-2.22 (m, 5H), 2.01-1.97 (m, 1H), 1.90 (s, 3H), 1.79 (s, 6H), 1.59 (s, 3H), 1.45 (s, 1H) 实施例 11
将 6-乙酰基 -8-环戊基 -5-甲基 -2-((5- (哌啶 -4-基)吡啶 -2-基)氨基)吡啶并 [2,3- 嘧 啶 -7(8H)-酮 6 (15 mg, 0.033 mmol)溶于 4 mL乙腈中,加入 1-溴 -2,2-二氟乙垸 (24.36 mg, 0.168 mmol)和碳酸钾 (30 mg, 0.22 mmol)加热至 80°C, 反应 6小时, 停止反 应。 冷却至室温, 过滤, 滤饼用二氯甲垸洗涤 (3 mLx2), 滤液减压浓缩, 用薄层色 谱法以展开剂体系 A 纯化所得残余物, 得到标题产物 6-乙酰基 -8-环戊基 -2-((5-(1-(2,2-二氟乙基)哌啶 -4-基)吡啶 -2-基)氨基) -5-甲基吡啶 [2,3-ί/]嘧啶 -7(8H 酮 11 (6 mg, 淡黄色固体;), 产率: 35.7%。
MS m/z (ESI): 511.2 [M+l]
1H MR (400 MHz, DMSO- 6) δ 10.28 (s, 1H), 8.99 (s, 1H), 8.24 (s, 1H), 7.99 (d, 1H), 7.74 (d, 1H), 5.87-5.83 (m, 1H), 3.28 (m, 2H), 2.77-2.73 (m, 2H), 2.42 (s, 3H), 2.30-2.24 (m, 3H), 2.01-1.97 (m, 4H), 1.90 (s, 2H), 1.75-1.71 (m, 4H), 1.61-1.58 (m, 3H), 1.50-1.45 (m, 3H)
测试例:
生物学评价
测试例 1、 本发明化合物对 CDK激酶活性的测定
体外 CDK(CDK4、 CDK6、 CDK1、 CDK2、 CDK9)激酶活性通过以下的方法 进行测试。
本实验使用的 CDK激酶: CDK4/人细胞周期蛋白 Dl (Invitrogen,货号 PV4400) 或 CDK4/CycD3(Carna biosciences , 货号 04-105) ; CDK6人细胞周期蛋白 D1 (Invitrogen,货号 PV4401)或 CDK6/CycD3(Carna biosciences,货号 04-107); CDKl/ 人细胞周期蛋白 B(Invitrogen,货号 PV3292); CDK2人细胞周期蛋白 A (Invitrogen, 货号 PV3267)或 CDK2/CycA2 (Carna biosciences,货号 04-103); CDK9/人细胞周期 蛋白 Tl (Invitrogen,货号 PR7541B)或 CDK9/CycTl(Cama biosciences,货号 04-110)。
使用试剂盒: Z'-LYTE™ Kinase Assay Kit-Ser/Thr 12 Peptide (Invitrogen, 货号 PV3673)0
以下所述的体外激酶实验可测定受试化合物对 CDK(CDK4、 CDK6、 CDK1、 CDK2、 CDK9)激酶的抑制活性。 配制 l x缓冲液 ACInvitrogen, 货号 PV3189); 将 测试化合物溶解于二甲亚砜中, 并根据试验需要稀释至各浓度梯度, 加入 I X缓冲 液 A配制成 4% 二甲亚砜溶液; 用 1 X缓冲液 A稀释 ATP得到 400 μΜ ATP溶液; 将适量试剂盒中的 Z'-LYTE™ Ser/Thr 12多肽底物 (Invitrogen,货号 PV3674), CDK 激酶与 l x缓冲液 A混合; 适量试剂盒中的 Z'-LYTETM Ser/Thr 12 磷酸化多肽底物 (Invitrogen, 货号 PV3675)和 l x缓冲液 A配成磷酸化多肽混合液待用; 在反应孔 中加上 2.5 μL配置好的测试化合物溶液, 2.5 μί 400 μΜ ΑΤΡ溶液和 5 μL酶和底物 混合液;对照孔 1中加上 5 μL·酶和底物混合液, 2.5 ^ 4% 二甲亚砜溶液和 2.5 μίΐ χ 缓冲液 Α; 对照孔 2中加上 5 μL·酶和底物混合液, 2.5 μί 4% 二甲亚砜溶液和 2.5 μί 400 μΜ ΑΤΡ溶液; 对照孔 3中加上 5μί磷酸化多肽混合液, 2.5 μί 4% 二甲亚 砜溶液和 2.5μί l x缓冲液 A。 25 °C孵育 24小时 (CDK4、 CDK6、 CDK9)或 25 °C孵 育 1小时 (CDK1、CDK2)后,在反应孔中加入 5 μL·试剂 A(Invitrogen,货号 PV3295) 和缓冲液 BCInvitrogen, 货号 P3127)的混合液 (;试剂 A: 缓冲液 B=l : 4095), 25 °C孵 育 60分钟后, 使用 NovoStar酶标仪读荧光 (激发波长: 400nm, 发射波长: 445nm 禾口 520nm)。
本发明化合物的 CDK(CDK4、 CDK6、 CDK1、 CDK2、 CDK9)激酶生化抑制 活性通过以上的试验进行测定,测得的 IC5Q值见表 1CCDK4、 CDK6),表 2(CDK1、 CDK2、 CDK9)。
3 32 28
4 28 24
5 52 43
6 12 12
7 5 6
8 12 9
9 15 13
10 20 13 表 2 本发明化合物对 CDK激酶 (CDK1、 CDK2、 CDK9)的活性抑制的 IC
结论: 本发明化合物对 CDK激酶 (CDK4、 CDK6)活性具有明显的抑制作用, 相比对 CDK激酶 (CDK1、 CDK2、 CDK9)活性的抑制作用, 本发明化合物对 CDK 激酶 (CDK4、 CDK6)的抑制具有选择性。 测试例 2、 本发明化合物对人结肠癌细胞株 Colo205的增殖抑制测定 下面的体外试验是用来测定本发明化合物对人结肠癌细胞株 Colo205 的增殖 抑制活性。
以下所述的体外细胞试验可测定受试化合物对人结肠癌细胞株的增殖抑制活 性,其活性可用 IC5Q值来表示。此类试验的一般方案如下:首先将 Colo205细胞 (中 科院细胞库,货号 TCHul02)以适宜细胞浓度 500个细胞 /孔接种在 384孔培养板上, 然后将细胞在二氧化碳恒温箱内 37°C进行培养, 生长至过夜, 更换培养基为加有 一系列浓度递度(1000 nM、 250 nM、 62.5 nM、 15.62 nM、 3.91 nM、 0.98 nM、 0.24nM、 0.06nM、 0.02nM)受试化合物溶液的培养基, 将培养板重新放回培养箱, 连续培养 72个小时。 72小时后, 可用 CCK8(Cell Counting Kit-8, 货号: CK04, 购于同仁 化学)方法进行测试化合物对于抑制细胞增殖活性。 IC5Q值可通过一系列不同浓度 下, 受试化合物对于细胞的抑制数值进行计算。
本发明化合物活性本发明化合物生物活性由上述分析所得, 计算所得的 IC50 值如下表 3 :
表 3本发明化合物对 Colo205细胞的增殖抑制的 IC 50
结论: 本发明优选化合物均对 Colo205细胞具有明显的增殖抑制活性 测试例 3、 本发明化合物对人乳腺癌细胞株 MCF-7的增殖抑制测定
下面的体外试验是用来测定本发明化合物对人乳腺癌细胞株 MCF-7的增殖抑 制活性。
以下所述的体外细胞试验可测定受试化合物对人乳腺癌细胞株的增殖抑制活 性, 其活性可用 IC5Q值来表示。此类试验的一般方案如下: 首先将 MCF-7细胞 (购 于 Institute of biochemistry and cell biology)以适宜细胞浓度 4000 个细胞 /mL 介质 接种在 96孔培养板上, 然后将细胞在二氧化碳恒温箱内 37°C进行培养, 生长至过 夜,更换培养基为加有一系列浓度递度(10000 nM、 1000 nM、 100 nM、 10 nM、 1 nM、 0.1 nM)受试化合物溶液的培养基,将培养板重新放回培养箱,连续培养 72个小时。 72小时后, 可用 CCK8(Cell Counting Kit-8, 货号: CK04, 购于同仁化学;)方法进 行测试化合物对于抑制细胞增殖活性。 IC5o值可通过一系列不同浓度下, 受试化合 物对于细胞的抑制数值进行计算。
本发明化合物生物活性由上述分析所得, 计算所得的 1。5()值如下表 4:
表 4本发明化合物对 MCF-7细胞的增殖抑制的 IC:
结论: 本发明优选化合物均对 MCF-7细胞具有明显的增殖抑制活性。 药代动力学评价
测试例 4、 本发明实施例 6和实施例 7化合物的药代动力学测试
1、 摘要
以 SD大鼠为受试动物, 应用 LC/MS/MS法测定了大鼠灌胃给予实施例 7化合物 后不同时刻血浆中的药物浓度。 研究本发明的化合物在大鼠体内的药代动力学行 为, 评价其药动学特征。
2、 试验方案
2.1 试验药品: PD-0332991 , 实施例 6和实施例 7化合物。
2.2 试验动物
健康成年 SD大鼠 4只, 雌雄各半, 购自上海西普尔 -必凯实验动物有限公司, 动物生产许可证号: SCXK (沪) 2008-0016。
2.3 药物配制
称取适量样品, 加入 0.5% CMC-Na至终体积, 超声制成 0.5 mg/mL混悬液。 2.4 给药
SD大鼠 4只, 雌雄各半, 禁食一夜后分别灌胃给药, 剂量为 5.0 mg/kg, 给药体 积 10 ml/kg。
3、 操作
于给药前及给药后 0.5、 1、 2、 4、 6、 8、 11、 24小时采血, 置于肝素化抗凝 试管中, 3500 rpm离心 10分钟, 分离血浆, 于 -20°C保存。 给药后 2小时进食。
用 LC/MS/MS法测定灌胃给药后大鼠血浆中的待测化合物含量。 分析方法的 线性范围为 1.00-500 ng/mL, 定量下限为 1.00 ng/mL; 血浆样品经沉淀蛋白预处理 后进行分析。
4、 药代动力学参数结果
本发明化合物的药代动力学参数如下:
结论: 本发明优选化合物的给药剂量为 5 mg/kg时, 与 PD-0332991比较, 大 鼠药代吸收良好, 半衰期长, 具有明显的口服吸收效果。 测试例 5、 本发明实施例 6和 7化合物的犬药代动力学测试
1、 摘要
以 Beagle犬为受试动物, 应用 LC/MS/MS法测定了犬灌胃给予 PD-0332991 , 实 施例 6和 7化合物后不同时刻血浆中的药物浓度。 研究本发明的化合物在大鼠体内 的药代动力学行为, 评价其药动学特征。
2、 试验方案
2.1 试验药品: PD-0332991 , 实施例 6和实施例 7化合物。
2.2 试验动物
健康成年 Beagle犬 20只, 雌雄各半, 购自苏州西山中科实验动物有限公司。 2.3 药物配制
称取适量样品, 加入二甲基乙酰胺和丙二醇使溶解, 后加入生理盐水至终体 积, 制成 1.0 mg/mL溶液。
称取适量样品, 加入 0.5% 吐温 80, 柠檬酸和 0.5% CMC-Na至终体积, 制成 1.0 mg/mL溶液。
2.4 给药
Beagle犬 20只, 雌雄各半, 平均分成 5组; 禁食一夜后分别静脉注射及灌胃给 药, 静脉注射给药剂量为 2.0 mg/kg, 灌胃给药剂量为 5.0 mg/kg。 静脉注射给药体 积为 2.0 mL/kg, 灌胃给药体积为 5.0 mL/kg。
3、 操作
静脉注射给药组于给药前及给药后 5分钟, 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 12.0, 24.0 小时由前肢静脉采血 1.0 mL, 置于肝素化试管中, 3500 rpm离心 10分钟分离血浆, 于 -20°C保存。 灌胃给药组于给药前及给药后 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 12.0, 24.0 小 时采血, 处理方法同静脉注射给药组。 给药后 3 小时进食。
用 LC/MS/MS法测定静脉注射及灌胃给药后大鼠血浆中的待测化合物含量。
4、 药代动力学参数结果
本发明化合物的药代动力学参数如下:
1、 摘要
以人和大鼠肝微粒体, 利用谷胱甘肽 (GSH)捕获反应性代谢物, 利用 LC-MS/MS***, 采用前体离子扫描筛选各类型的 GSH加合物。 研究实施例 6化合 物与 PD-0332991生成反应性代谢物的能力。
2、 试验方案
2.1 试验药品: PD-0332991 , 实施例 6化合物。
2.2 试验试剂
男性受试者肝微粒体, 蛋白浓度 20 mg/mL, 购于美国 BD Gentest™; 雄性大鼠 肝微粒体, 蛋白浓度 20 mg/mL, 购于美国 BD Gentest™; β-NADPH, 化学纯度 93-100%, 购于美国 Sigma公司。 L-还原型谷胱甘肽, 纯度 >98%, 购于美国 Sigma 公司。
2.3 药物配制
称取适量样品, 采用 DMSO溶解至终体积, 超声制成 50 mM储备液, 采用 100 mM磷酸缓冲液 (PBS, pH7.4)稀释上述储备液至 100 μΜ 。
2.4 体外孵化体系
孵化体系总体积为 100 μΐ,介质为 100 mM磷酸缓冲液 (PBS, pH7.4)。于 1 mL 96 孔板中, 加入人或大鼠肝微粒体溶液 (PBS配制), 待测化合物, 和 GSH溶液, 使其 终浓度为 10 μΜ的待测化合物, 5 mM GSH溶液和 1.0 mg/mL肝微粒体蛋白, 采用 热混仪于 37 °C进行孵育。 孵育 3分钟后, 加入 NADPH启始反应, NADPH终浓度为 2 mM。 反应 60分钟后加入 200 μΐ^冰冷乙腈终止反应, 3200 rpm离心 10分钟, 去上 清液进行 LC-MS/MS分析。
3、 操作
利用 Qtrap API4000 LC-MS/MS***, 采用前体离子扫描检测可能的 GSH加 合物, 以待测化合物生成的总 GSH加合物色谱峰面积与氯氮平生成的总 GSH加 合物色谱峰面积比值 (Ratio)评价化合物生成反应性代谢物的能力。
4、 实验结果
本发明例 6在人和大鼠肝微粒体孵化***均未见明显的 GSH加合物产生, 具 有低的生成反应性代谢物的能力。
PD-0332991在人肝微粒体 Ratio为 0.76,具有中强程度生成反应性代谢物的能 力。
结论:本发明例 6化合物在人和大鼠肝微粒体具有低的生成反应性代谢物的能 力, PD-0332991在人肝微粒体具有中强程度的生成反应性代谢物的能力。
Claims
1、 一种通式( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映 异构体、 非对映异构体或其混合物形式, 或其可药用盐:
其中:
―为单键或双键;
A1或 A2各自独立地选自 -CR,或 N;
R'选自氢原子、 卤素、 氰基、 硝基、 垸基、 卤代垸基、 羟垸基或垸氧基; Y选自 S或 0;
R1选自氢原子、 卤素、 垸基、 卤代垸基、 羟垸基或环垸基;
R2选自氢原子、 卤素、 氰基、 硝基、 垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基、 杂芳基、 -OR7, -C(0)R7、 -C(0)OR7、 或 -OC(0)R7, 其中所述的垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任选进一步被一个或多个选 自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 ¾代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代;
R3选自氢原子、 垸基、 环垸基、 杂环垸基、 芳基或杂芳基, 其中所述的垸基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 ¾代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代;
R4选自氢原子、垸基、烯基、炔基、环垸基、杂环垸基、芳基、 杂芳基、 -OR7、 -C(0)R7或 -C(0)OR7, 其中所述的垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基或 杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 ¾代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代;
R5或 R6各自独立地选自氢原子、 卤素、 氰基、 硝基、 氧代基、 垸基、 烯基、 炔基、环垸基、 杂环垸基、芳基、 杂芳基、 -OR7、 -C(0)R7、 -C(0)OR7或 -OC(0)R7, 其中所述的垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任
选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 卤 代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基 的取代基所取代;
R7选自氢原子、 垸基、 羟基、 卤素、 垸氧基、 环垸基、 杂环垸基、 芳基或杂 芳基, 其中所述的垸基、 垸氧基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地 任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 卤代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯 基的取代基所取代。
2、 根据权利要求 1所述的通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 其中 A1 或 A2各自独立地为 -CH。
3、根据权利要求 1〜2任意一项所述的通式( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用 盐, 其中 Y为 0。
4、根据权利要求 1〜3任意一项所述的通式( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用 盐, 其中 R1为垸基。
5、根据权利要求 1〜4任意一项所述的通式( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用 盐, 其中 R2为 -C(0)R7; 且 R7为垸基。
6、根据权利要求 1〜5任意一项所述的通式( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用 盐, 其中 R3为环垸基。
7、根据权利要求 1〜6任意一项所述的通式( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用 盐, 其中 R5或 R6各自独立地选自氢原子、 卤素、 垸基或羟基。
8、根据权利要求 1〜7任意一项所述的通式( I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用 盐, 其中 R4选自氢原子或垸基, 其中所述的垸基任选进一步被一个或多个选自卤 素、 羟基或环垸基的取代基所取代。
9、 根据权利要求 1所述的通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 其为通 式 (II)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映 异构体或其混合物形式, 或其
其中: , 1^〜1 6的定义如权利要求 1中所定义。
10、根据权利要求 1所述的通式(I )所示的化合物或其互变异构体、内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 其为通 式 (III)所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映 异构体或其混合物形式, 或其
其中: 1^〜1 6的定义如权利要求 1中所定义。
11、 根据权利要求 1〜10任意一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 其中所 述化合物选自:
12、 一种通式(I-C )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对 映异构体、 非对映异构体 盐:
其中:
―为单键或双键;
Boc为叔丁氧羰基;
R为垸基;
A1或 A2各自独立地选自 -CR,或 N;
R'选自氢原子、 卤素、 氰基、 硝基、 垸基、 卤代垸基、 羟垸基或垸氧基;
Y选自 S或 0;
R1选自氢原子、 卤素、 垸基、 卤代垸基、 羟垸基或环垸基;
R3选自氢原子、 垸基、 环垸基、 杂环垸基、 芳基或杂芳基, 其中所述的垸基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 ¾代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基的取代基所取代;
R5或 R6各自独立地选自氢原子、 卤素、 氰基、 硝基、 氧代基、 垸基、 烯基、 炔基、环垸基、 杂环垸基、芳基、 杂芳基、 -OR7、 -C(0)R7、 -C(0)OR7或 -OC(0)R7, 其中所述的垸基、 烯基、 炔基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地任 选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 卤 代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯基 的取代基所取代;
R7选自氢原子、 垸基、 羟基、 卤素、 垸氧基、 环垸基、 杂环垸基、 芳基或杂 芳基, 其中所述的垸基、 垸氧基、 环垸基、 杂环垸基、 芳基或杂芳基各自独立地 任选进一步被一个或多个选自卤素、 氰基、 硝基、 氨基、 羟基、 氧代基、 垸基、 卤代垸基、 羟垸基、 垸氧基、 环垸基、 杂环垸基、 芳基、 杂芳基、 羧基或羧酸酯 基的取代基所取代。
13、 一种制备根据权利要求 1 所述的化合物或其互变异构体、 内消旋体、 外 消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐的方法, 该
通式 (I-A)化合物与通式( I-B)化合物在碱性条件下, 任选在催化剂作用下进行 取代反应得到通式( I-C )化合物; 通式( I-C )化合物在溶剂中, 酸性条件下, 进行 脱保护反应, 任选进一步进行取代反应, 得到通式(I )化合物;
其中: X为卤素; Boc为叔丁氧羰基; R为垸基; =, A1, Α2, Υ, Ι^〜Ι 6 的定义如权利要求 1 中所述; R4优选为氢原子或垸基, 其中所述的垸基任选进一
步被一个或多个选自卤素、 羟基或环垸基的取代基所取代。
14、一种药物组合物, 所述药物组合物含有治疗有效量的根据权利要求 1〜12 任意一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非 对映异构体或其混合物形式, 或其可药用盐, 以及一种或多种药学上可接受的载 体、 稀释剂或赋形剂。
15、 根据权利要求 1〜12任意一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或根据 权利要求 14所述的药物组合物在制备抑制 CDK4和 /或 CDK6的药物中的用途。
16、 根据权利要求 1〜12任意一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或根据 权利要求 14所述的药物组合物在制备治疗异常细胞增殖性疾病、感染、炎性病症、 自身免疫性疾病、 心血管疾病或神经变性疾病的药物中的用途。
17、 根据权利要求 1〜12任意一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或根据 权利要求 14所述的药物组合物在制备治疗癌症的药物中的用途, 其中所述的癌症 选自乳腺癌、 卵巢癌、 ***癌、 黑色素瘤、 脑瘤、 食管癌、 胃癌、 肝癌、 胰腺 癌、 结肠直肠癌、 肺癌、 肾癌、 皮肤癌、 成胶质细胞瘤、 神经母细胞瘤、 肉瘤、 脂肪肉瘤、 骨软骨瘤、 骨瘤、 骨肉瘤、 ***瘤、 睾丸肿瘤、 子宫癌、 头颈肿 瘤、 多发性骨髓瘤、 恶性淋巴瘤、 真性红细胞增多症、 白血病、 甲状腺肿瘤、 输 尿管肿瘤、 ***、 胆囊癌、 胆管癌、 绒毛膜上皮癌或儿科肿瘤。
18、 根据权利要求 17所述的用途, 其中所述的药物进一步与另外一种或多种 抗癌剂联合应用, 所述的抗癌剂优选为芳香化酶抑制剂, 更优选来曲唑或阿那曲 唑。
19、 根据权利要求 1〜12任意一项所述的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其混合物形式, 或其可药用盐, 或根据 权利要求 14所述的药物组合物在制备预防或治疗由辐射引起的造血毒性疾病的药 物中的用途, 其中所述的辐射引起的造血毒性疾病包括但不限于骨髓抑制、 嗜中 性白血球减少症、 白细胞减少症、 贫血。
20、 一种抑制 CDK4和 /或 CDK6活性的方法, 其包括给予所需患者治疗有效 量的通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、
非对映异构体或其混合物形式, 或其可药用盐, 或包含其的药物组合物。
21、 一种治疗异常细胞增殖性疾病、 感染(例如病毒感染, 如疱疹、 HIV, 真 菌感染等)、 炎性病症 (例如类风湿性关节炎、 骨关节炎等)、 自身免疫性疾病 (例如 牛皮癣、 狼疮、 I 型糖尿病、 糖尿病性肾病、 多发性硬化、 肾小球性肾炎等)、 心 血管疾病 (例如心肌梗塞、 中风、 动脉粥样硬化、 手术后血管狭窄、 再狭窄等)或神 经变性疾病 (例如阿尔茨海默氏病、 帕金森病等)的方法, 其包括给予所需患者治 疗有效量的通式(I )所示的化合物或其互变异构体、 内消旋体、 外消旋体、 对映异 构体、 非对映异构体或其混合物形式, 或其可药用盐, 或包含其的药物组合物, 其中所述的异常细胞增殖性疾病可以是癌症。
22、 一种治疗癌症的方法, 其包括给予所需患者治疗有效量的通式( I )所示的 化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其 混合物形式, 或其可药用盐, 或包含其的药物组合物, 其中所述癌症选自乳腺癌、 卵巢癌、***癌、 黑色素瘤、脑瘤 (例如具有恶性的星形神经胶质和少突神经胶 质细胞瘤成分的神经胶质瘤等)、 食管癌、 胃癌、 肝癌、 胰腺癌、 结肠直肠癌 (例如 结肠癌、 直肠癌等)、 肺癌 (例如非小细胞肺癌、 小细胞肺癌、 原发或转移性鳞状癌 等)、 肾癌、 皮肤癌、 成胶质细胞瘤、 神经母细胞瘤、 肉瘤、 脂肪肉瘤、 骨软骨瘤、 骨瘤、 骨肉瘤、 ***瘤、 睾丸肿瘤、 子宫癌 (例如子***、 子宫内膜癌等)、 头颈肿瘤 (例如上颌骨癌、 喉癌、 咽癌、 舌癌、 口内癌等)、 多发性骨髓瘤、 恶性淋 巴瘤 (例如网状细胞肉瘤、 淋巴肉瘤、 霍奇金淋巴瘤、 套细胞淋巴瘤等)、 真性红细 胞增多症、 白血病 (例如急性粒细胞白血病、 慢性粒细胞白血病、 急性淋巴细胞白 血病、 慢性淋巴细胞白血病等)、 甲状腺肿瘤、 输尿管肿瘤、 ***、 胆囊癌、 胆管癌、 绒毛膜上皮癌或儿科肿瘤 (例如尤因家族性肉瘤、 维尔姆斯肉瘤、 横纹肌 肉瘤、 血管肉瘤、 胚胎睾丸癌、 成神经细胞瘤、 视网膜母细胞瘤、 肝胚细胞瘤、 肾母细胞瘤等)等。
23、 一种治疗癌症的方法, 其包括给予所需患者治疗有效量的通式(I )所示的 化合物或其互变异构体、 内消旋体、 外消旋体、 对映异构体、 非对映异构体或其 混合物形式, 或其可药用盐, 或包含其的药物组合物, 与另外一种或多种抗癌剂 联合应用, 所述抗癌剂选自垸化剂 (例如环磷酰胺、 异环磷酰胺、 美法仑、 白消安、 尼莫司丁、 雷莫司汀、 达卡巴嗪、 替莫唑胺、 盐酸氮芥、 二溴甘露醇等)、 铂络合 剂 (例如顺铂、 卡铂、 奥沙利铂等)、 代谢拮抗剂 (例如甲氨蝶吟、 5-氟尿嘧啶、 替加 氟、 吉西他滨、 卡培他滨、 氟维司群、 培美曲塞等)、 植物生物碱 (例如长春新碱、 长春碱、 长春地辛、 依托泊苷、 多西他赛、 紫杉醇、 伊立替康、 长春瑞滨、 米托 蒽醌、 长春氟宁、 拓扑替康等)、 抗体药物 (例如曲妥单抗、 帕妥珠单抗、 利妥昔单
抗、西妥昔单抗、 帕尼单抗、 贝伐单抗等)、激素抗癌剂 (例如亮丙瑞林、戈舍瑞林、 度他雄胺、***、他莫昔芬等)、蛋白酶体抑制剂 (例如硼替佐米、来那度胺等)、 芳香化酶抑制剂 (例如依西美坦、来曲唑、阿那曲唑等)、 VEGFR或 EGFR抑制剂 (例 如舒尼替尼、 索拉非尼、 伊马替尼、 吉非替尼、 埃罗替尼、 凡德他尼、 帕唑帕尼、 拉帕替尼等)、 mTOR抑制剂 (例如依维莫司、 西罗莫司、 佐他莫司等)、 PI3K激酶 抑制剂 (例如 BKM-120、 XL- 147 BEZ-235 等)、 B-Raf 抑制剂 (例如威罗菲尼、 GSK-2118436等)或 AKT抑制剂 (例如哌立福新、 MK-2206等)等; 优选为芳香化酶 抑制剂, 更优选来曲唑或阿那曲唑。
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