WO2016155545A1 - 含氨磺酰基的1,2,5-噁二唑类衍生物、其制备方法及其在医药上的应用 - Google Patents
含氨磺酰基的1,2,5-噁二唑类衍生物、其制备方法及其在医药上的应用 Download PDFInfo
- Publication number
- WO2016155545A1 WO2016155545A1 PCT/CN2016/076975 CN2016076975W WO2016155545A1 WO 2016155545 A1 WO2016155545 A1 WO 2016155545A1 CN 2016076975 W CN2016076975 W CN 2016076975W WO 2016155545 A1 WO2016155545 A1 WO 2016155545A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- group
- compound
- formula
- cancer
- mixture
- Prior art date
Links
- 0 C(C1)C[C@]2[C@]1C*C2 Chemical compound C(C1)C[C@]2[C@]1C*C2 0.000 description 12
- SMTLVGBJNFIGET-VULFUBBASA-N CC(C)(C)OC(NCC1(CNC(/C(/C(N2c(cc3Br)ccc3F)=NOC2=O)=N\O)=N)CC1)=O Chemical compound CC(C)(C)OC(NCC1(CNC(/C(/C(N2c(cc3Br)ccc3F)=NOC2=O)=N\O)=N)CC1)=O SMTLVGBJNFIGET-VULFUBBASA-N 0.000 description 1
- GNBNXDHYPIBPFJ-MBTHVWNTSA-N CC(C)(C)OC(NCC1(CNC(/C(/C(Nc(cc2Br)ccc2F)=[IH]=C)=N\O)=N)CC1)=O Chemical compound CC(C)(C)OC(NCC1(CNC(/C(/C(Nc(cc2Br)ccc2F)=[IH]=C)=N\O)=N)CC1)=O GNBNXDHYPIBPFJ-MBTHVWNTSA-N 0.000 description 1
- FOECYGNKRZBEDD-UHFFFAOYSA-N CC(C)(C=C1)C=CC(O2)=C1NC2=O Chemical compound CC(C)(C=C1)C=CC(O2)=C1NC2=O FOECYGNKRZBEDD-UHFFFAOYSA-N 0.000 description 1
- XXQRKPKEVUDMDP-UHFFFAOYSA-N CC(C)(C=C1)C=CC2=C1NCO2 Chemical compound CC(C)(C=C1)C=CC2=C1NCO2 XXQRKPKEVUDMDP-UHFFFAOYSA-N 0.000 description 1
- FVDRGBSQLUTTAA-UHFFFAOYSA-N CC(C)(C=C1)C=Cc2c1[nH]cn2 Chemical compound CC(C)(C=C1)C=Cc2c1[nH]cn2 FVDRGBSQLUTTAA-UHFFFAOYSA-N 0.000 description 1
- RBSYDYCNDOXABE-UHFFFAOYSA-N CC(C)(C=C1)C=Cc2c1nc[s]2 Chemical compound CC(C)(C=C1)C=Cc2c1nc[s]2 RBSYDYCNDOXABE-UHFFFAOYSA-N 0.000 description 1
- DFFITIIHAPBRLZ-UHFFFAOYSA-N CC(C1)CN2C1COCC2 Chemical compound CC(C1)CN2C1COCC2 DFFITIIHAPBRLZ-UHFFFAOYSA-N 0.000 description 1
- CAXQEPUTRSXRFF-UHFFFAOYSA-N CC1(C)C=Cc([nH]nc2)c2C=C1 Chemical compound CC1(C)C=Cc([nH]nc2)c2C=C1 CAXQEPUTRSXRFF-UHFFFAOYSA-N 0.000 description 1
- VXCMFPWVADIDAL-UHFFFAOYSA-N CC1(C)C=Cc([o]cc2)c2C=C1 Chemical compound CC1(C)C=Cc([o]cc2)c2C=C1 VXCMFPWVADIDAL-UHFFFAOYSA-N 0.000 description 1
- LRBVKYINFBDQKR-UHFFFAOYSA-N C[N]=1(C)=CC=C2NC=CC2=CC=1 Chemical compound C[N]=1(C)=CC=C2NC=CC2=CC=1 LRBVKYINFBDQKR-UHFFFAOYSA-N 0.000 description 1
- GRUPAEWJLDLTPV-UHFFFAOYSA-N NC1C=C2OCC2C1 Chemical compound NC1C=C2OCC2C1 GRUPAEWJLDLTPV-UHFFFAOYSA-N 0.000 description 1
- OZCMOXMJLKFXQF-SRZZPIQSSA-O NCC1(CNC(/C(/C(N2c(cc3Br)ccc3F)=NOC2=O)=N\[OH2+])=N)CC1 Chemical compound NCC1(CNC(/C(/C(N2c(cc3Br)ccc3F)=NOC2=O)=N\[OH2+])=N)CC1 OZCMOXMJLKFXQF-SRZZPIQSSA-O 0.000 description 1
- SESWXEZRJJZGRD-UHFFFAOYSA-M NS(NCC1(CN/C(/C(C(Nc(cc2Br)ccc2F)=N)=N)=N/[O-])CC1)(=O)=O Chemical compound NS(NCC1(CN/C(/C(C(Nc(cc2Br)ccc2F)=N)=N)=N/[O-])CC1)(=O)=O SESWXEZRJJZGRD-UHFFFAOYSA-M 0.000 description 1
- PJPOUXZXHMBOTR-UHFFFAOYSA-N NS(NCC1(CNc2n[o]nc2C(N2c(cc3)cc(Br)c3F)=NOC2=O)CC1)(=O)=O Chemical compound NS(NCC1(CNc2n[o]nc2C(N2c(cc3)cc(Br)c3F)=NOC2=O)CC1)(=O)=O PJPOUXZXHMBOTR-UHFFFAOYSA-N 0.000 description 1
- QMLJLRAZXRXQDD-UHFFFAOYSA-N NS(NCC1(CNc2n[o]nc2C(Nc(cc2Br)ccc2F)=N)CC1)(=O)=O Chemical compound NS(NCC1(CNc2n[o]nc2C(Nc(cc2Br)ccc2F)=N)CC1)(=O)=O QMLJLRAZXRXQDD-UHFFFAOYSA-N 0.000 description 1
- RHYOUOZNAPENIN-UHFFFAOYSA-N [O-][N+](c1n[o]nc1C(N1c(cc2Br)ccc2F)=NOC1=O)=O Chemical compound [O-][N+](c1n[o]nc1C(N1c(cc2Br)ccc2F)=NOC1=O)=O RHYOUOZNAPENIN-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4245—Oxadiazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D271/00—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms
- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/08—1,2,5-Oxadiazoles; Hydrogenated 1,2,5-oxadiazoles
Definitions
- the invention belongs to the field of medicine and relates to a method for synthesizing a 1,2,5-oxadiazole derivative containing a sulfamoyl group and its application in medicine.
- the present invention discloses its use as an IDO inhibitor for the treatment of diseases having the pathological features of the IDO-mediated tryptophan metabolism pathway, including cancer, Alzheimer's disease, autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS.
- Tumors are one of the major diseases that seriously endanger human life, and more than half of them occur in developing countries.
- the incidence of malignant tumors in China is generally on the rise, and the incidence rate is increasing at an average annual rate of 3%-5%.
- Ageing, urbanization, industrialization and lifestyle changes In China's hospital drug market, the sales scale of anti-cancer drugs has been growing steadily in recent years. In 2012, it reached 66.42 billion yuan, an increase of 13.07% year-on-year. It is expected that by 2017, the market size of anti-cancer drugs will reach 105.57 billion yuan. The year-on-year growth was 7.57%.
- Tumor biotherapy is a new treatment for cancer prevention and treatment using modern biotechnology and related products. Because of its safety, effectiveness, and low adverse reactions, it has become the fourth mode of tumor treatment after surgery, radiotherapy and chemotherapy.
- the host's natural defense mechanisms such as inhibition of IDO-mediated tumor immune escape mechanisms) or the naturally occurring highly targeted substances to achieve anti-tumor effects.
- Indoleamine-pyrrole-2,3-dioxygenase is a heme-containing monomeric protein consisting of 403 amino acid residues, including two folds.
- the alpha-helical domain, the large domain contains a catalytic pocket, and the substrate can be hydrophobic with the IDO in the catalytic pocket.
- IDO is an enzyme that catalyzes the conversion of tryptophan to formyl kynurenine. It is widely distributed in tissues other than the liver of humans and other mammals (rabbits, mice) and is the only restriction outside the liver that catalyzes the catabolism of tryptophan.
- Fast enzyme which is an essential amino acid for cells to maintain activation and proliferation, is also an indispensable component of protein.
- IDO interferon
- IL interleukin
- tumor necrosis factor tumor necrosis factor
- IDO interferon
- IL interleukin
- tumor necrosis factor tumor necrosis factor
- other cytokines they can activate IDO under certain conditions.
- IDO In the cell cycle of T-cells, there is a regulation point that is very sensitive to tryptophan levels.
- IDO depletes local tryptophan, causing T-cells to arrest in the middle of G1 phase, thereby inhibiting the proliferation of T cells;
- IDO catalyzes the main product produced by the metabolism of tryptophan.
- Canine urea is induced by oxygen free radicals to induce changes in intracellular oxidants and antioxidants to induce T-cell apoptosis, which is an intrinsic immunosuppressive mechanism present in the body.
- IDO is highly expressed in leukemia cells, which inhibits the proliferation of local T cells, inhibits T-cell-mediated immune responses, and blocks T-cell activation signal transduction, thereby mediating tumor cell escape from the immune system. attack.
- 1-methyltryptophan is an oral small molecule IDO inhibitor developed by NewLink Genetics for the treatment of metastatic breast cancer and solid tumors and is currently in clinical phase II in the United States. Studies have shown that 1-methyltryptophan can enhance the sensitivity of tumor cells to T-cell immune stimulation in vitro, and can delay the growth of tumor cells and strengthen the anti-tumor effect of chemotherapy drugs in animal models in vivo, and almost All spontaneous tumors work.
- Incyte is developing a series of oral IDO small molecule inhibitors, INCB-24360 is also undergoing clinical phase II trials, mainly for the treatment of a variety of cancers including myelodysplastic syndrome.
- Inhibitors of the disclosed selective inhibitors of IDO include WO2004094409, WO2006122150, WO2007075598, WO2010005958 and WO2014066834, and the like.
- IDO inhibitors have good application prospects in the pharmaceutical industry as a drug, but no good IDO inhibitors have been found as marketable drugs. In order to achieve better tumor treatment effects and better meet market demand, we hope to Developed a new generation of highly efficient and low toxicity selective IDO inhibitors.
- the present invention will provide a novel structure of selective IDO inhibitors, and it has been found that compounds having such structures exhibit excellent effects and effects, particularly excellent pharmacogen absorption activities.
- the object of the present invention is to provide a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or a mixture form, or a pharmaceutically acceptable salt thereof, wherein the compound of the formula (I) has the following structure:
- a mixture selected from the group consisting of a cis isomer, a trans isomer or a cis and trans isomer;
- R 1 is selected from the group consisting of an alkyl group, a cycloalkyl group, and an alkoxy group, wherein the alkyl group, the cycloalkyl group, and the alkoxy group are each independently optionally further selected from the group consisting of a hydroxyl group, an alkyl group, an alkoxy group, and a halogenated alkyl group. Substituted by one or more substituents;
- R 2 is selected from the group consisting of a hydrogen atom, an alkyl group, a cycloalkyl group, and an alkoxy group, wherein the alkyl group, the cycloalkyl group, and the alkoxy group are each independently optionally further selected from the group consisting of a hydroxyl group, an alkyl group, an alkoxy group, and Substituting one or more substituents in the haloalkyl group;
- R 1 and R 2 together with the carbon atom to which they are attached form a cycloalkyl or heterocyclic group, wherein said cycloalkyl or heterocyclic group is optionally further selected from the group consisting of alkyl, halogen, cyano, cycloalkyl , heterocyclyl, aryl, heteroaryl, -NR 6 R 7 , -C(O)NR 6 R 7 , -NHS(O) m R 8 , -S(O) p R 8 , -NHC(O Substituting one or more substituents of R 8 , —OR 8 , —C(O)R 8 , —OC(O)R 8 and —C(O)OR 8 ;
- R 3 and R 4 are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a cyano group, an amino group, a halogen, an alkenyl group, an alkynyl group, a hydroxyl group, a nitro group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein The alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl are each independently optionally further selected from the group consisting of hydroxyl, halogen, amino, cyano, alkyl, alkoxy, cycloalkyl, hetero Substituting one or more substituents of a cyclic group, an aryl group, and a heteroaryl group;
- R 5 is selected from the group consisting of an alkyl group and an amino group, which are optionally further selected from the group consisting of a hydroxyl group, a halogen, an amino group, a cyano group, an alkyl group, an alkoxy group, a cycloalkyl group, a heterocyclic group, an aryl group and a hetero group.
- the alkyl group is preferably a C 1-4 alkyl group;
- R 6 and R 7 are each independently selected from a hydrogen atom, an alkyl group, a cycloalkyl group, a heterocyclic group, an aryl group and a heteroaryl group, wherein the alkyl group, cycloalkyl group, heterocyclic group, aryl group or hetero group
- the aryl groups are each independently optionally further substituted with one or more substituents selected from the group consisting of hydroxyl, halogen, alkyl, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
- R 8 is selected from the group consisting of a hydrogen atom, an alkyl group, an amino group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group, wherein the alkyl group, the cycloalkyl group, the heterocyclic group, the aryl group or the heteroaryl group are each independently Optionally optionally substituted with one or more substituents selected from the group consisting of alkyl, halo, hydroxy, amino, cyano, alkoxy, cycloalkyl, heterocyclyl, aryl and heteroaryl;
- n 0, 1, 2;
- n 0, 1, 2;
- p 0, 1, 2.
- the compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof wherein R 3 and R 4 are each independently selected from a hydrogen atom, a halogen, an alkyl group, or a halogenated alkyl group, and the halogen is preferably fluorine, chlorine or bromine, the alkyl group It is preferably a C 1-4 alkyl group, and the haloalkyl group is preferably a trifluoromethyl group.
- the compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer thereof, Or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (II) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer Isomers, or mixtures thereof, or pharmaceutically acceptable salts thereof:
- R 1 is an alkyl group or an alkoxy group, and the alkyl group or alkoxy group is further substituted by one or more hydroxyl groups or alkoxy groups; wherein preferably R 1 is an alkyl group substituted by a hydroxy group or an alkoxy group;
- R 3 to R 5 , m, n are as defined in the formula (I).
- R 1 is an alkyl group or an alkoxy group, and the alkyl group or alkoxy group is further substituted by one or more hydroxyl groups or alkoxy groups;
- R 3 is halogen, alkyl or haloalkyl, more preferably halogen
- R 4 is halogen, alkyl or haloalkyl, more preferably halogen
- R 5 is an amino group
- n is an integer of 0 to 2, more preferably 0;
- n is an integer of 0 to 2, and more preferably 1.
- the compound of the formula (I) or a tautomer, a mesogen, a racemate, an enantiomer or a diastereomer thereof 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 a conjugate, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
- A is a 3- to 8-membered ring, preferably a 3- to 6-membered ring, wherein the ring is selected from a carbocyclic or heterocyclic ring;
- R 3 to R 5 , m, n are as defined in the formula (I).
- A is a cycloalkyl group, more preferably a cyclopropyl group
- R 3 is halogen, alkyl or haloalkyl, more preferably halogen
- R 4 is halogen, alkyl or haloalkyl, more preferably halogen
- R 5 is an amino group
- n is an integer from 0 to 2;
- n is an integer of 1-2.
- the present invention also provides a compound of the formula (I) or a tautomer, a mesomer, a racemate, an enantiomer, a diastereomer thereof, or A method of the mixture, or a pharmaceutically acceptable salt thereof, the method comprising:
- the compound of the formula (IV) is ring-opened under basic conditions to give a compound of the formula (I), wherein the reagent of the basic condition is potassium carbonate or sodium hydroxide;
- R 1 to R 5 , m, n are as defined in the formula (I).
- the invention also relates to a compound of the formula (IV) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer, or a mixture thereof Or its pharmaceutically acceptable salt:
- R 1 to R 5 , m, n are as defined in the formula (I).
- a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (V) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
- R 1 , R 3 to R 5 , m, n are as defined in the formula (I).
- a compound of the formula (IV) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer a form, or a mixture thereof, or a pharmaceutically acceptable salt thereof which is a compound of the formula (VI) or a tautomer, a mesogen, a racemate, an enantiomer, a diastereomer, or a mixture thereof, or a pharmaceutically acceptable salt thereof:
- A is a 3- to 8-membered ring wherein the ring is selected from a carbocyclic or heterocyclic ring;
- R 3 to R 5 , m, n are as defined in the formula (I).
- the present invention synthesizes typical compounds of the general formula (I), (II), (III) by a series of reactions including, but not limited to:
- Another aspect of the invention relates to a pharmaceutical composition
- a pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula (I), (II) and (III) or a tautomer thereof, a mesogen, an external Racemates, enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts, and one or more pharmaceutically acceptable carriers, diluents or excipients.
- the present invention also relates to a process for the preparation of the above composition
- a process for the preparation of the above composition comprising the compounds of the formulae (I), (II) and (III) or tautomers, meso- and racemic forms thereof
- the enantiomers, diastereomers, or mixtures thereof, or pharmaceutically acceptable salts thereof are admixed with a pharmaceutically acceptable carrier, diluent or excipient.
- 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 the prevention and/or treatment of a disease having a pathological feature of an IDO-mediated tryptophan metabolism pathway.
- IDO inhibitors can be used for the inhibition of cardiac disorders as well as for the treatment of other pathological features of IDO-mediated tryptophan metabolism pathways, including infections of viruses such as AIDS, such as Lyme disease and streptococcal infections.
- neurodegenerative disorders eg Alzheimer's disease, Huntington's disease and Parkson's disease
- autoimmune diseases depression, anxiety, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer) , eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases
- cancer may be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, and brain cancer.
- skin cancer skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal swelling Tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, papillary renal tumor, head and neck tumor, leukemia, lymphoma, myeloma and non-small cell lung cancer.
- the present invention also relates to a compound of the formula (I) or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or A pharmaceutically acceptable salt, or a pharmaceutical composition comprising the same, for use in the prevention and/or treatment of a disease preventing the pathological features of the IDO-mediated tryptophan metabolism pathway.
- These diseases include infections of viruses such as AIDS, cellular infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (such as Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, solid tumors, gliomas, glioblastoma, hepatocellular carcinoma, papillary renal tumors, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
- the present invention also relates to a method of treating a disease preventing and/or treating a pathological feature having an IDO-mediated tryptophan metabolism pathway, comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) Or a tautomer, a mesophil, a racemate, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.
- These diseases include infections of viruses such as AIDS, cellular infections such as Lyme disease and streptococcal infection, neurodegenerative disorders (such as Alzheimer's disease, Huntington's disease and Parkson's disease), autoimmune diseases, depression, Anxiety disorders, cataracts, psychological disorders, AIDS, cancer (including T-cell leukemia and colon cancer), eye disease states (such as cataracts and age-related yellowing), and autoimmune diseases, wherein the cancer may be selected from the breast Cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, Peritoneal tumors, stage IV melanoma, solid tumors, gliomas, glioblastoma, hepatocellular carcinoma, papillary renal tumors, head and neck tumors, leukemia, lymphoma, myeloma, and non-small cell lung cancer.
- Another aspect of the invention relates to a method of treating cancer comprising administering to a patient a therapeutically effective amount of a compound of the formula (I) of the invention or a tautomer, a mesogen thereof, a foreign body A form of a rot, an enantiomer, a diastereomer or a mixture thereof, or a pharmaceutically acceptable salt thereof.
- the method exhibits outstanding efficacy and less side effects, wherein the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer, bone cancer, kidney cancer, ovarian cancer, bladder cancer, liver cancer, fallopian tube tumor, ovarian tumor, peritoneal tumor, stage IV melanoma, solid tumor, glioma, glioblastoma, hepatocellular carcinoma, mastoid Renal tumors, head and neck tumors, leukemias, lymphomas, myelomas and non-small cell lung cancers, preferably fallopian tube tumors, peritoneal tumors, stage IV melanoma, myeloma and breast cancer, more preferably breast cancer.
- the cancer can be selected from the group consisting of breast cancer, cervical cancer, colon cancer, lung cancer, stomach cancer, rectal cancer, pancreatic cancer, brain cancer, skin cancer, oral cancer, prostate Cancer
- the active ingredient-containing pharmaceutical composition may be in a form suitable for oral administration, such as tablets, dragees, 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 pharmaceutical compositions, 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 a tablet for admixture.
- 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 masking the taste of the drug or delaying disintegration and absorption in the gastrointestinal tract, thus providing a sustained release effect over a longer period of time.
- 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 acacia; dispersing or wetting agents may be naturally occurring a 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 ethylene oxide with a long chain fatty alcohol, such as heptadecylethyleneoxy cetyl alcohol (heptadecaethyleneoxy cetanol), or a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol, such as polyethylene oxide sorbitol monooleate, or ethylene oxide with derivatives derived from fatty acids and hexitols
- 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.
- preservatives such as ethylparaben or n-propylparaben
- coloring agents such as ethylparaben or n-propylparaben
- 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 oily 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 alpha-tocopherol.
- the dispersible powders and granules suitable for the preparation of aqueous suspensions can be provided by the addition of water to provide the active ingredient and dispersing or wetting agents, suspending agents 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 may 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 An oleate, and a condensation product of the partial ester and ethylene oxide, such as polyethylene 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 oily 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 bloodstream of the patient by a 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, such as a solution prepared in 1,3-butanediol, in a non-toxic parenterally acceptable diluent or solvent.
- sterile fixed oils may conveniently be 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 to be administered 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, and the behavior of the patient. , the patient's diet, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, etc.; in addition, the optimal treatment modality such as the mode of treatment, the daily dosage of the compound of the formula or the type of pharmaceutically acceptable salt may be Traditional treatment options to verify.
- alkyl refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing from 1 to 20 carbon atoms, preferably an alkyl group having from 1 to 12 carbon atoms, more preferably from 1 to 6 An alkyl group of a carbon atom.
- Non-limiting examples include 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-dimethylbutyl, 2,2-dimethylbutyl, 1,3 - dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2 -methylhexyl, 3-methylhexyl, 4-methylhexyl,
- lower alkyl groups having from 1 to 6 carbon atoms, non-limiting examples including methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl Base, 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 Base, 2,3-dimethylbutyl and the like.
- the alkyl 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 an alkane Base, alkenyl, alkynyl, alkoxy, alkylthio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, naphthenic Oxy, heterocycloalkoxy, cycloalkylthio, heterocycloalkylthio, oxo, -C(O)OR 7 , -OC(O)R 7 , -NHS(O) p R 7 ,- C(O)R 7 , -NHC(O)R 7 , -NHC(O)OR 7 , -NR 8 R 9 , -OC(O)NR 8 R 9 or -C(O)
- cycloalkyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 carbon atoms, preferably from 3 to 12 carbon atoms, more preferably from 3 to 10 carbon atoms.
- the carbon atoms further preferably contain 3 to 6 carbon atoms.
- Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatriene
- a polycycloalkyl group includes a spiro ring, a fused ring, and a cycloalkyl group.
- spirocycloalkyl refers to a polycyclic group that shares a carbon atom (referred to as a spiro atom) between 5 to 20 members of a single ring, which may contain one or more double bonds, but none of the rings have a fully conjugated ⁇ electronic system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- the spirocycloalkyl group is classified into a monospirocycloalkyl group, a bispirocycloalkyl group or a polyspirocycloalkyl group, preferably a monospirocycloalkyl group and a bispirocycloalkyl group, depending on the number of common spiro atoms between the rings.
- spirocycloalkyl groups include:
- fused cycloalkyl refers to 5 to 20 members, and each ring in the system shares an all-carbon polycyclic group of an adjacent pair of carbon atoms with other rings in the system, wherein one or more of the rings may contain one or Multiple double bonds, but none of the rings have a fully conjugated ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. According to the number of constituent rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, preferably bicyclic or tricyclic The ring is more preferably a 5- to 5- or 5-membered/6-membered bicycloalkyl group.
- fused cycloalkyl groups include:
- bridged cycloalkyl refers to an all-carbon polycyclic group of 5 to 20 members, any two rings sharing two carbon atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have complete Conjugate ⁇ -electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members. Depending on the number of constituent rings, it may be classified into a bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl group, preferably a bicyclic ring, a tricyclic ring or a tetracyclic ring, and more preferably a bicyclic ring or a tricyclic ring.
- bridged cycloalkyl groups include:
- the cycloalkyl ring may be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring to which the parent structure is attached is a cycloalkyl group, non-limiting examples include indanyl, tetrahydronaphthalene Base, benzocycloheptyl and the like.
- 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 alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, -C(O)OR 7 , -OC(O)R 7 , -NHS(O) p R 7 , -C(O)R 7 , -NHC(O)R 7 - -NHC(O)OR 7 , -NR 8 R 9 , -OC(O)NR 8 R 9 or -C(O)NR 8 R 9
- heterocyclyl refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent containing from 3 to 20 ring atoms wherein one or more ring atoms are selected from nitrogen, oxygen or S(O).
- a hetero atom of m (where m is an integer of 0 to 2), but excluding the ring moiety of -OO-, -OS- or -SS-, the remaining ring atoms being carbon. It preferably contains from 3 to 12 ring atoms, wherein from 1 to 4 are heteroatoms; more preferably from 3 to 10 ring atoms; more preferably from 3 to 8 ring atoms; more preferably from 3 to 6 ring atoms.
- Non-limiting examples of monocyclic heterocyclic groups include pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl and the like.
- Polycyclic heterocyclic groups include spiro, fused, and bridged heterocyclic groups.
- spiroheterocyclyl refers to a polycyclic heterocyclic group in which one atom (called a spiro atom) is shared between 5 to 20 members of a single ring, wherein one or more ring atoms are selected from nitrogen, oxygen or S (O). ) m (where m is an integer 0 to 2) heteroatoms, and the remaining ring atoms are carbon. It may contain one or more double bonds, but none of the rings have a fully conjugated pi-electron system. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- the spiroheterocyclyl group is classified into a monospiroheterocyclic group, a dispiroheterocyclic group or a polyspirocyclic group according to the number of the shared spiro atoms between the ring and the ring, and is preferably a monospiroheterocyclic group and a dispiroheterocyclic group. More preferably, it is 4 yuan / 4 yuan, 4 yuan / 5 yuan, 4 yuan / 6 yuan, 5 yuan / 5 yuan or 5 yuan / 6-membered monospiroheterocyclic group.
- Non-limiting examples of spiroheterocyclyl groups include:
- fused heterocyclyl refers to 5 to 20 members, and each ring in the system shares an adjacent pair of atomic polycyclic heterocyclic groups with other rings in the system, and one or more rings may contain one or more Double bond, but none of the rings have a fully conjugated ⁇ -electron system in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), and the remaining rings
- the atom is carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- fused heterocyclic groups include:
- bridge heterocyclyl refers to a polycyclic heterocyclic group of 5 to 14 members, any two rings sharing two atoms which are not directly bonded, which may contain one or more double bonds, but none of the rings have a total A ⁇ -electron system of a yoke in which one or more ring atoms are heteroatoms selected from nitrogen, oxygen or S(O) m (where m is an integer from 0 to 2), the remaining ring atoms being carbon. It is preferably 6 to 14 members, more preferably 7 to 10 members.
- bridge heterocyclic groups include:
- the heterocyclyl ring may be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heterocyclic group, non-limiting examples of which include:
- the heterocyclic group may be optionally substituted or unsubstituted, and when substituted, the substituent is preferably one or more of the following groups independently selected from alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, oxo, -C(O)OR 7 , -OC(O)R 7 , -NHS(O) p R 7 , -C(O)R 7 , -NHC(O)R 7 - -NHC(O)OR 7 , -NR 8 R 9 , -OC(O)NR 8 R 9 or -C(O)NR 8 R 9 .
- aryl refers to a 6 to 14 membered all-carbon monocyclic or fused polycyclic ring (ie, a ring that shares a pair of adjacent carbon atoms) having a conjugated ⁇ -electron system, preferably 6 to 10 members, such as benzene. Base and naphthyl.
- the aryl ring may be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring to which the parent structure is attached is an aryl ring, non-limiting examples of which include:
- 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 alkyl, alkenyl, alkynyl, alkoxy, alkylthio, Alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio, heterocycle Alkylthio, -C(O)OR 7 , -OC(O)R 7 , -NHS(O) p R 7 , -C(O)R 7 , -NHC(O)R 7 , -NHC(O) OR 7 , -NR 8 R 9 , -OC(O)NR 8 R 9 or -C(O)NR 8 R 9 .
- 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 furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetra Azolyl and the like.
- the heteroaryl ring may be fused to an aryl, heterocyclic or cycloalkyl ring, wherein the ring to which the parent structure is attached is a heteroaryl ring, non-limiting examples of which include:
- 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 alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)OR 7 , -OC(O)R 7 , -NHS(O) p R 7 , -C(O)R 7 , -NHC(O)R 7 , -NHC (O)OR 7 , -NR 8 R 9 , -OC(O)NR 8 R 9 or -C(O)NR 8 R 9 .
- alkoxy refers to -O-(alkyl) and -O-(unsubstituted cycloalkyl), wherein alkyl is as defined above.
- alkoxy groups include: methoxy, ethoxy, propoxy, butoxy, cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy.
- the alkoxy 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 alkyl, alkenyl, alkynyl, alkoxy, alkane Thio, alkylamino, halogen, fluorenyl, hydroxy, nitro, cyano, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, cycloalkoxy, heterocycloalkoxy, cycloalkylthio , heterocycloalkylthio, -C(O)OR 7 , -OC(O)R 7 , -NHS(O) p R 7 , -C(O)R 7 , -NHC(O)R 7 , -NHC (O)OR 7 , -NR 8 R 9 , -OC(O)NR 8 R 9 or -C(O)NR 8 R 9 .
- haloalkyl refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.
- hydroxyalkyl refers to an alkyl group substituted by a hydroxy group, wherein the alkyl group is as defined above.
- hydroxy refers to an -OH group.
- halogen means fluoro, chloro, bromo or iodo.
- amino means -NH 2.
- cyano refers to -CN.
- nitro refers to -NO 2 .
- carboxylate group refers to -C(O)O(alkyl) or -C(O)O(cycloalkyl), wherein alkyl is as defined above.
- acyl halide refers to a compound containing a -C(O)-halogen group.
- methylene refers to -CH 2 -.
- ethylene refers to -(CH 2 ) 2 -.
- propylene refers to -(CH 2 ) 3 -.
- butylene refers to -(CH 2 ) 4 -.
- alkynyl refers to -C ⁇ C-.
- X is selected from A, B, or C
- X is selected from A, B, and C
- X is A, B, or C
- X is A, B, and C
- heterocyclic group optionally substituted by alkyl means that an alkyl group may be, but is not necessarily, present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.
- Substituted refers to one or more hydrogen atoms in the group, preferably up to 5, more preferably 1 to 3, hydrogen atoms, independently of each other, substituted 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) substitutions that may or may not be possible 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., olefinic) 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 the administration of the organism, which facilitates the absorption of the active ingredient and thereby exerts biological activity.
- “Pharmaceutically acceptable salt” refers to a salt of a compound of the invention which is safe and effective for use in a mammal and which possesses the desired biological activity.
- the method for preparing the compound of the formula (I) or a salt thereof of the present invention comprises the following steps:
- the compound of the formula (Ia) is oxidized to a compound of the formula (Ib) under acidic conditions; the compound of the formula (Ib) is reacted with a compound of the formula (Ic) under basic conditions to give a compound of the formula (Id);
- the compound of the formula (Id) is ring-formed under heating and basic conditions, and the base is preferably N,N'-carbonyldiimidazole to give a compound of the formula (Ie); the compound of the formula (Ie) after ring formation is acidic
- the protecting group on the amino group is removed under the conditions to obtain a compound of the formula (If) or a salt thereof; an alkali solution of the compound of the formula (If) or a salt thereof is reacted with an alcohol solution of chlorosulfonyl isocyanate at a low temperature to obtain a formula (Ig).
- the alcohol solution is preferably a t-butanol solution
- the compound of the formula (Ig) is deprotected under acidic conditions to give a compound of the formula (IV); the obtained compound of the formula (IV) is obtained under basic conditions.
- the lower ring is opened to give the compound of the formula (I).
- the reagents providing basic conditions include organic bases and inorganic bases including, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, n-butyl Lithium lithium, potassium t-butoxide, tetrabutylammonium bromide, and the inorganic bases include, but are not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.
- the oxidizing agents used include, but are not limited to, hydrogen peroxide, potassium permanganate, and manganese dioxide.
- Solvents used include, but are not limited to, N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane or water.
- R 1 to R 4 , m, and n are as defined in the formula (I).
- the preparation method of the compound of the formula (II) of the present invention or a salt thereof comprises the following steps:
- the compound of the formula (Ia) is oxidized to a compound of the formula (Ib) under acidic conditions; the compound of the formula (Ib) is reacted with a compound of the formula (IIc) under basic conditions to give a compound of the formula (IId);
- the compound of the formula (IId) is ring-formed under heating and basic conditions, and the base under this condition is preferably N,N'-carbonyldiimidazole to give a compound of the formula (IIe); the compound of the formula (IIe) after ring formation is acidic
- the protective group on the amino group is removed to obtain a compound of the formula (IIf) or a salt thereof; an alkali solution of the compound of the formula (IIf) or a salt thereof is reacted with an alcohol solution of chlorosulfonyl isocyanate at a low temperature to obtain a formula (IIg).
- the alcohol solution is preferably a t-butanol solution
- the compound of the formula (IIg) is deprotected under acidic conditions to give a compound of the formula (V); and the obtained compound of the formula (V) is obtained under basic conditions.
- the lower ring is opened to give the compound of the formula (II).
- the alkaline conditions include organic bases and inorganic bases including, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, n-butyl.
- organic bases and inorganic bases including, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, n-butyl.
- Lithium, potassium t-butoxide, tetrabutylammonium bromide including, but not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.
- the oxidizing agents used include, but are not limited to, hydrogen peroxide, potassium permanganate, and manganese dioxide.
- Solvents used include, but are not limited to, N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane or water.
- R 1 , R 3 , R 4 , m, n are as defined in the general formula (I).
- the preparation method of the compound of the formula (III) of the present invention or a salt thereof comprises the following steps:
- the compound of the formula (Ia) is oxidized to a compound of the formula (Ib); the compound of the formula (Ib) is reacted with a compound of the formula (IIIc) under basic conditions to give a compound of the formula (IIId);
- the compound of the formula (IIId) is ring-formed under heating and basic conditions, and the base under this condition is preferably N,N'-carbonyldiimidazole to give a compound of the formula (IIIe);
- the compound of the formula (IIIe) after ring formation is acidic
- the protective group on the amino group is removed to obtain a compound of the formula (IIIf) or a salt thereof; an alkali solution of the compound of the formula (IIIf) or a salt thereof is reacted with an alcohol solution of chlorosulfonyl isocyanate at a low temperature to obtain a formula (IIIg) a compound, the alcohol solution is preferably a t-butanol solution; the compound of the formula (IIIg) is de
- the alkaline conditions include organic bases and inorganic bases including, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, n-butyl.
- organic bases and inorganic bases including, but not limited to, sodium hexamethyldisilazide, triethylamine, N,N-diisopropylethylamine, n-butyl.
- Lithium, potassium t-butoxide, tetrabutylammonium bromide including, but not limited to, sodium hydride, sodium carbonate, sodium hydrogencarbonate, potassium carbonate, potassium hydrogencarbonate or cesium carbonate.
- the oxidizing agents used include, but are not limited to, hydrogen peroxide, potassium permanganate, and manganese dioxide.
- Solvents used include, but are not limited to, N,N-dimethylformamide, toluene, acetic acid, methanol, ethanol, tetrahydrofuran, dichloromethane, dimethyl sulfoxide, 1,4-dioxane or water.
- A is a 3- to 8-membered ring wherein the ring is selected from a carbocyclic or heterocyclic ring;
- R 3 , R 4 , m, n are as defined in the general formula (I).
- the structure of the compound is determined by nuclear magnetic resonance (NMR) or mass spectrometry (MS).
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the NMR was measured by a Bruker AVANCE-400 nuclear magnetic apparatus, and the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated chloroform (CDCl 3 ), deuterated methanol (CD 3 OD), and the internal standard was four.
- DMSO-d 6 dimethyl sulfoxide
- CDCl 3 deuterated chloroform
- CD 3 OD deuterated methanol
- TMS Methylsilane
- chemical shifts are given in units of 10 -6 (ppm).
- the measurement of the MS was carried out 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 specification of silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm.
- the specification for separation and purification of thin layer chromatography is 0.4mm. ⁇ 0.5mm silica gel plate.
- 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 Organnics, Aldrich Chemical Company, Accela ChemBio Inc, Companies such as Dare Chemicals.
- 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 evacuated, charged with hydrogen, and operated three times.
- the microwave reaction used a CEM Discover-S Model 908860 microwave reactor.
- the solution in the reaction means an aqueous solution unless otherwise specified.
- the temperature of the reaction was room temperature unless otherwise specified.
- Room temperature is the most suitable reaction temperature, and the temperature range is from 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: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: petroleum ether And the ethyl acetate system, D: acetone, the volume ratio of the solvent is adjusted depending on the polarity of the compound.
- the system for the eluent of the column chromatography and the system for the thin layer chromatography of the developer used for the purification of the compound include: A: dichloromethane and methanol system, B: n-hexane and ethyl acetate system, C: n-hexane, acetic acid Ethyl ester and dichloromethane system, D: petroleum ether and ethyl acetate system, E: ethyl acetate, the volume ratio of the solvent is adjusted according to the polarity of the compound, and a small amount of triethylamine and acid or alkali may be added. The reagents and the like are adjusted.
- the crude product 1d (260 mg, 0.535 mmol) was dissolved in 20 mL of THF, and N,N'-carbonyldiimidazole (95 mg, 0.586 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals. The crude title product 1e (330 mg, yellow solid).
- Chlorosulfonyl isocyanate (0.793 g, 5.6 mmol, prepared by the well-known method "Organic Syntheses, 1966, 46, 23-7") was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, and tert-butanol was added ( 0.43 g, 5.8 mmol), and the reaction liquid was reacted at 0 ° C for 1 hour to obtain a reaction liquid A.
- the crude product 1f 400 mg, 1.0 mmol
- reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted at 0 ° C for 1 hour. After the reaction is completed, the reaction mixture is quenched with saturated sodium hydrogen carbonate solution, and the organic layer is washed with water, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated under reduced pressure. The obtained residue was purified to give titled product (1 g, m.
- the crude product 1 h (160 mg, 0.27 mmol) was dissolved in 20 mL of methanol, and potassium carbonate (230 mg, 1.67 mmol) was added and reacted at 50 ° C for 1 hour. After the reaction is completed, the reaction is neutralized by adding a saturated ammonium chloride solution, and the liquid is separated. The aqueous phase was extracted with EtOAc (EtOAc) EtOAc (EtOAc m. Solid), yield 7.5%.
- the crude product 2b (650 mg, 1.3 mmol) was dissolved in 30 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (222 mg, 1.37 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals.
- the crude title product 2c (715 mg, brown brown solid).
- the chlorosulfonyl isocyanate (509 mg, 3.59 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, tert-butanol (267 mg, 3.59 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction liquid A. .
- the crude product 2d (1.021 g, 2.4 mmol) was dissolved in 20 mL of dichloromethane, and 1 mL of triethylamine was added to obtain a reaction liquid B.
- the reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted at 0 ° C for 1 hour.
- the crude product 3b (370 mg, 0.74 mmol) was dissolved in 15 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (126 mg, 0.78 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals. The crude title product 3c (350 mg, yellow solid).
- the chlorosulfonyl isocyanate (145 mg, 1.024 mmol) was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, tert-butanol (76 mg, 1.025 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction solution A. .
- the crude product 3d (500 mg, 1.17 mmol) was dissolved in 20 mL of dichloromethane, and 1 mL of triethylamine was added to obtain a reaction liquid B.
- the reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted at 0 ° C for 1 hour.
- the crude product 4b (667 mg, 1.26 mmol) was dissolved in 20 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (225 mg, 1.38 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals.
- the crude title product 4c (710 mg, EtOAc) elute.
- the crude product 4e (300 mg, 0.538 mmol) was dissolved in dichloromethane (5 mL), and then, 3mL of trifluoroacetic acid was added, and the mixture was reacted at room temperature for 1 hour. After the reaction was completed, the reaction mixture was evaporated.
- Chlorosulfonyl isocyanate 120 mg, 0.848 mmol was dissolved in 10 mL of dichloromethane, cooled to 0 ° C, tert-butanol (63 mg, 0.849 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction liquid A.
- the crude product 4f 510 mg, 1.11 mmol was dissolved in 10 mL of dichloromethane, and 1 mL of triethylamine was added to obtain a reaction liquid B.
- the reaction liquid A was added to the reaction liquid B at room temperature, and reacted at room temperature for 1 hour.
- the crude product 5b (1 g, 1.99 mmol) was dissolved in 30 mL of tetrahydrofuran, and N,N'-carbonyldiimidazole (322 mg, 1.99 mmol) was added and reacted at 70 ° C for 1 hour. After the completion of the reaction, the reaction mixture was evaporated to dryness crystals.
- the crude title product 5c (1 g, yellow solid).
- the chlorosulfonyl isocyanate (400 mg, 2.83 mmol) was dissolved in 30 mL of dichloromethane, cooled to 0 ° C, tert-butanol (210 mg, 2.83 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction liquid A.
- the crude product 5d (1.55 g, 3.6 mmol) was dissolved in 20 mL of dichloromethane, cooled to 0 ° C, and 2.5 mL of triethylamine was added to obtain a reaction liquid B.
- the reaction liquid A was added dropwise to the reaction liquid B at room temperature, and reacted at room temperature for 1 hour.
- the crude product 5f (574 mg, 1.129 mmol) was dissolved in 10 mL of tetrahydrofuran, and 3 mL of 2N sodium hydroxide solution was added and reacted at room temperature for 15 minutes. After the completion of the reaction, the mixture was neutralized with a saturated aqueous solution of ammonium chloride, and the mixture was separated. The residue obtained was purified to afford title product 5 (150 mg, white solid).
- the chlorosulfonyl isocyanate (215 mg, 1.52 mmol) was dissolved in 15 mL of dichloromethane, cooled to 0 ° C, tert-butanol (113 mg, 1.52 mmol) was added, and the reaction mixture was reacted at 0 ° C for 15 minutes to obtain a reaction liquid A. .
- the crude 6f (900 mg, 2.48 mmol) was dissolved in 30 mL of dichloromethane, and 1 mL of triethylamine was added to obtain a reaction liquid B.
- the reaction liquid A was added to the reaction liquid B at 0 ° C, and reacted for 1 hour.
- the title material 12 (105 mg, white solid) was obtained from the title compound.
- the human IDO1 protease activity in vitro was tested by the following method.
- This method is used to determine the inhibitory effect of the compounds of the invention on the activity of human IDO1 protease.
- Microplate reader (Synergy HT, BIOTEK)
- Catalase is derived from bovine liver (C1345-1G, Sigma-Aldrich)
- Vortex mixer (6776, Corning)
- mini plate centrifuge mini-p25, ABSON life science equipment
- the IDO1 gene was transferred into the PET30a plasmid by gene cloning technology and then transferred into competent E. coli rosseta; in liquid LB (Luria-Bertani) medium [according to the Guide to Molecular Cloning (J. Sambrook DW La Selva) was prepared by enlarging culture in each liter of medium, collecting the cells, sonicating, and eluting the column to elute the purified IDO1 protease.
- liquid LB Lia-Bertani
- reaction plate 100 ul of enzyme (IDO1) was diluted 30 times with 3 mM of KPB to a concentration of 26 ng/ul of enzyme solution per well in a 96-well reaction plate (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as the reaction plate).
- reaction plate 100 ul of enzyme (IDO1) was diluted 30 times with 3 mM of KPB to a concentration of 26 ng/ul of enzyme solution per well in a 96-well reaction plate (AXYGEN, PCR-96-FLT-C) (hereinafter referred to as the reaction plate).
- KPB buffer preparation 50 mM
- KPB buffer preparation 50 mM
- the reaction plate was placed in a plate centrifuge for 15 seconds at the highest speed, and the reaction liquid was collected at the bottom.
- the shaker was mixed for 30 seconds, and incubated at 37 ° C for 1 h in a constant temperature incubator.
- 10 ul of 30% (w/v) trichloroacetic acid was added to each well, and incubated at 65 ° C for 15 minutes in an incubator.
- the plate was centrifuged at 4700 RPM on a centrifuge at room temperature for 5 minutes. 40 ul of supernatant was transferred from the reaction plate using a lance to a corresponding 96-well test plate (corning, #3599).
- protease inhibitory activity of the compound of the present invention against human IDO1 was measured by the above test, and the IC 50 values measured are shown in Table 1.
- the compounds of the present invention have a significant inhibitory effect on the activity of human IDO1 protease.
- Test Example 2 Determination of IDO protease inhibitory activity in Hela cells by the compound of the present invention
- the IDO protease activity in Hela cells was tested by the following method.
- Microplate reader (Synergy HT, BIOTEK)
- a HeLa cell suspension was prepared from fresh cell culture medium, and added to a 100-well culture system 96-well cell culture plate at 10,000 cells/well, and cultured at 5% carbon dioxide at 37 ° C for 24 hours. The supernatant was removed, and 90 ul of serum-free DMEM high glucose medium was added to each well; then 10 ul of each compound formulated in INF- ⁇ and tryptophan-containing medium was added to each well (the final concentration was: 100000, 10000, 1000).
- the IDO protease inhibitory activity of the compound of the present invention against HeLa cells was measured by the above test, and the IC 50 values measured are shown in Table 2.
- the compounds of the present invention have a significant inhibitory effect on IDO protease activity in Hela cells.
- SD rats were used as test animals, and the concentration of the drug in plasma at different times after intravenous administration of the compounds of Examples 3, 6 and 8 was measured by LC/MS/MS method.
- the pharmacokinetic behavior of the compounds of the invention in rats was investigated and their pharmacokinetic characteristics were evaluated.
- 0.1 ml of blood was collected from the eyelids before administration and 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, 24.0 h after administration, and placed in a heparinized test tube, and the plasma was separated by centrifugation at 3500 rpm for 10 minutes. Store at 20 ° C and eat 2 h after dosing.
- the content of the test compound in the plasma of rats after intragastric administration of different compounds was determined by LC/MS/MS method.
- the compound of the present invention has good absorption of the drug and has obvious pharmacological absorption effect.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种含氨磺酰基的1,2,5-噁二唑类衍生物、其制备方法及其在医药上的应用。具体而言,如通式(I)所示的含氨磺酰基的1,2,5-噁二唑类衍生物,其制备方法及含有该衍生物的药物组合物及其作为IDO抑制剂,可用于治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病,所述的疾病包括肿瘤、癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。其中通式(I)的各取代基与说明书中的定义相同。
Description
本发明属于医药领域,涉及一种含有氨磺酰基的1,2,5-噁二唑类衍生物的合成方法及其在医药上的应用。本发明公开了其作为IDO抑制剂,用于治疗具有IDO介导的色氨酸代谢途径病理学特征的疾病,所述的疾病包括癌症、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病。
肿瘤是严重危害人类生命的重大疾病之一,一半以上发生在发展中国家。我国恶性肿瘤发病率总体呈上升趋势,发病率以年均3%-5%的速度递增,预计到2020年,我国将有400万人发生癌症,300万人死于癌症,其主要原因是:老龄化、城镇化、工业化及生活习惯改变。在中国医院用药市场,抗肿瘤药物的销售规模近几年来一直稳步增长,2012年达到了664.2亿元,同比增长了13.07%,预计到2017年,抗肿瘤药物的市场规模将达到1055.7亿元,同比增长7.57%。
由于恶性肿瘤的无限制生长与浸润、转移,现今临床采用的三大常规治疗方法(手术、放疗和化疗)无法完全切除或彻底杀灭肿瘤细胞,因此常出现肿瘤转移或复发。肿瘤生物治疗是应用现代生物技术及其相关产品进行肿瘤防治的新疗法,因其安全、有效、不良反应低等特点,成为继手术、放疗、化疗之后肿瘤治疗的第四种模式,其通过调动宿主的天然防御机制(比如抑制IDO介导的肿瘤免疫逃逸机制)或给予天然产生的靶向性很强的物质来获得抗肿瘤的效应。
吲哚胺-吡咯-2,3-双加氧酶(Indoleamine-pyrrole-2,3-dioxygenase,IDO)是一种含铁血红素单体蛋白,由403个氨基酸残基组成,包括两个折叠的α-螺旋结构域,大结构域包含催化口袋,底物可在催化口袋内与IDO发生疏水等作用。IDO是催化色氨酸转化为甲酰犬尿氨酸的酶,广泛分布在人和其他哺乳动物(兔、鼠)除肝脏以外的组织中,是肝脏以外唯一可催化色氨酸分解代谢的限速酶,而色氨酸是细胞维持活化和增殖所必需的氨基酸,也是构成蛋白质不可缺少的重要成分。IDO与干扰素(interferon,IFN)、白细胞介素(interleukin,IL)、肿瘤坏死因子等多种细胞因子关系密切,它们在一定条件下可激活IDO。而T-细胞的细胞周期中存在一个对色氨酸水平非常敏感的调节点,一方面,IDO使局部色氨酸耗竭,致使T-细胞停滞于G1期中期,从而抑制了T细胞的增殖;另一方面,IDO催化色氨酸代谢产生的主要产物犬尿素由氧自由基介导引起细胞内氧化剂和抗氧化剂改变而诱导T-细胞凋亡,这是存在于机体的固有的免疫抑制机制。目前大量研究表明IDO在白血病细胞中较高表达,使局部T细胞增殖受抑,抑制T-细胞介导的免疫反应,使T-细胞活化信号转导受阻,从而介导肿瘤细胞逃逸免疫***的攻击。已经发现
大多数人类肿瘤组成性地表达IDO。因此,IDO是一个具潜力的癌症免疫治疗的靶标。
1-甲基色氨酸(1-methyltryptophan)是由NewLink Genetics公司开发的口服小分子IDO抑制剂,用于治疗转移性乳腺癌和实体瘤,目前在美国进入临床二期。研究表明1-甲基色氨酸在体外能增强肿瘤细胞对T-细胞的免疫刺激的敏感性,在体内的动物模型中能延缓肿瘤细胞的生长并强化化疗药物的抗肿瘤效果,而且几乎对所有的自发性肿瘤起作用。另外,Incyte公司正在研发的一系列口服IDO小分子抑制剂中INCB-24360也在进行临床二期试验,主要用于治疗包括骨髓增生异常综合症在内的多种癌症。
公开的选择性抑制IDO的抑制剂专利申请包括WO2004094409、WO2006122150、WO2007075598、WO2010005958和WO2014066834等。
IDO抑制剂作为药物在医药行业具有良好的应用前景,但是目前尚未找到很好的IDO抑制剂可作为上市药物,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IDO抑制剂。本发明将提供一种新型结构的选择性IDO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、或其可药用的盐,其中通式(I)所示的化合物结构如下:
其中:
R1选自烷基、环烷基和烷氧基,其中所述的烷基、环烷基、烷氧基各自独立地任选进一步被选自羟基、烷基、烷氧基和卤代烷基中的一个或多个取代基所取代;
R2选自氢原子、烷基、环烷基和烷氧基,其中所述的烷基、环烷基、烷氧基各自独立地任选进一步被选自羟基、烷基、烷氧基和卤代烷基中的一个或多个取代基所取代;
或R1和R2与它们连接的碳原子一起形成环烷基或杂环基,其中所述的环烷基、杂环基任选进一步被选自烷基、卤素、氰基、环烷基、杂环基、芳基、杂芳基、-NR6R7、
-C(O)NR6R7、-NHS(O)mR8、-S(O)pR8、-NHC(O)R8、-OR8、-C(O)R8、-OC(O)R8和-C(O)OR8中的一个或多个取代基所取代;
R3和R4各自独立地选自氢原子、烷基、氰基、氨基、卤素、烯基、炔基、羟基、硝基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被选自羟基、卤素、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;
R5选自烷基和氨基,所述的烷基和氨基任选进一步被选自羟基、卤素、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;所述烷基优选C1~4烷基;
R6和R7各自独立地选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;
R8选自氢原子、烷基、氨基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被选自烷基、卤素、羟基、氨基、氰基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;
m为0、1、2;
n为0、1、2;且
p为0、1、2。
在本发明一个优选的实施方案中,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和R4各自独立地选自氢原子、卤素、烷基、或卤代烷基,所述卤素优选为氟、氯或溴,所述烷基优选为C1~4烷基,所述卤代烷基优选为三氟甲基。
在本发明一个优选的实施方案中,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、或其可药用盐:
其中:
R1为烷基或烷氧基,所述的烷基或烷氧基进一步被一个或多个羟基或烷氧基取代;其中优选R1为被羟基或烷氧基取代的烷基;
本发明优选的通式(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:
其中:
R1为烷基或烷氧基,所述烷基或烷氧基进一步被一个或多个羟基或烷氧基取代;
R3为卤素、烷基或卤代烷基,更优选卤素;
R4为卤素、烷基或卤代烷基,更优选卤素;
R5为氨基;
m为0~2的整数,更优选为0;
n为0~2的整数,更优选为1。
在本发明的一个优选的实施方案中,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、或其可药用盐:
其中:
A为3~8元环,优选为3~6元环,其中所述的环选自碳环或杂环;
本发明优选的通式(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、或其可药用盐:
其中:
A为环烷基,更优选环丙基;
R3为卤素、烷基或卤代烷基,更优选卤素;
R4为卤素、烷基或卤代烷基,更优选卤素;
R5为氨基;
m为0~2的整数;
n为1~2的整数。
本发明还提供了一种制备通式(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(IV)化合物在碱性条件下开环得到通式(I)化合物,其中所述的碱性条件的试剂为碳酸钾或氢氧化钠;
其中:
本发明还涉及一种通式(IV)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~R5、m、n如通式(I)中所定义。
在本发明的一个优选的实施方案中,一种通式(IV)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(V)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、R3~R5、m、n如通式(I)中所定义。
在本发明的一个优选的实施方案中,一种通式(IV)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(VI)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:
A为3~8元环,其中所述的环选自碳环或杂环;
R3~R5、m、n如通式(I)中所定义。
本发明通过一系列的反应,合成了典型的通式(I)、(II)、(III)的化合物包括,但不限于:
本发明的另一方面涉及一种药物组合物,其含有治疗有效剂量的通式(I)、(II)和(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、或可药用的盐,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
本发明还涉及一种制备上述组合物的方法,其包括将通式(I)、(II)和(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、或其可药用的盐与药学上可接受的载体、稀释剂或赋形剂相混合。
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用于预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。IDO抑制剂可以用于心脏障碍的抑制以及治疗其他具有IDO介导的色氨酸代谢途径的病理学特征的疾病,这些疾病包括诸如AIDS等病毒的感染,诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性疾病,其中所述的癌症可以选自乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿
瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明还涉及通式(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,其用于预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病。这些疾病包括诸如AIDS等病毒的感染,诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性疾病,其中所述的癌症可以选自乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明还涉及一种治疗预防和/或治疗预防具有IDO介导的色氨酸代谢途径的病理学特征的疾病的方法,其包括向患者施用治疗有效剂量的通式(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。这些疾病包括诸如AIDS等病毒的感染,诸如莱姆病和链球菌感染等细胞感染、神经退行性病症(例如阿尔茨海默病、亨廷顿病和拍金森病)、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍、艾滋病、癌症(包括T细胞白血病和结肠癌)、眼睛疾病状态(例如白内障和与年龄相关的黄化)以及自身免疫性疾病,其中所述的癌症可以选自乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
本发明另一方面涉及一种治疗癌症的方法,该方法包括向患者施用治疗有效剂量的本发明的通式(I)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。该方法显示出突出的疗效和较少的副作用,其中所述的癌症可以选自乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、实体瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌,优选为输卵管肿瘤、腹膜肿瘤、IV期黑色素瘤、骨髓瘤和乳腺癌,更优选为乳腺癌。
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、聚乙烯吡咯烷酮或***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、聚乙烯吡咯烷酮和***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,或环氧乙烷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),或环氧乙烷与由脂肪酸和己糖醇衍生的部分酯的缩合产物,例如聚环氧乙烷山梨醇单油酸酯,或环氧乙烷与由脂肪酸和己糖醇酐衍生的偏酯的缩合产物,例如聚环氧乙烷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α-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也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烷的缩合产物,例如聚环氧乙烷山梨醇单油酸酯。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刺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,包括但并非限定于以下因素:所用具体化合物的活性、患者的年龄、患者的体重、患者的健康状况、患者的行被、患者的饮食、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。
发明的详细说明
除非有相反陈述,在说明书和权利要求书中使用的术语具有下述含义。
术语“烷基”指饱和脂肪族烃基团,其为包含1至20个碳原子的直链或支链基团,优选含有1至12个碳原子的烷基,更有选含有1至6个碳原子的烷基。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、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个碳原子的低级烷基,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、2,3-二甲基丁基等。烷基可以是取代的或非取代的,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,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、-C(O)OR7、-OC(O)R7、-NHS(O)pR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
术语“环烷基”指饱和或部分不饱和单环或多环环状烃取代基,环烷基环包含3至20个碳原子,优选包含3至12个碳原子,更优选包含3至10个碳原子,进一步优选包含3~6个碳原子。单环环烷基的非限制性实例包括环丙基、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;多环环烷基包括螺环、稠环和桥环的环烷基。
术语“螺环烷基”指5至20元的单环之间共用一个碳原子(称螺原子)的多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺环烷基分为单螺环烷基、双螺环烷基或多螺环烷基,优选为单螺环烷基和双螺环烷基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺环烷基。螺环烷基的非限制性实例包括:
术语“稠环烷基”指5至20元,***中的每个环与体系中的其他环共享毗邻的一对碳原子的全碳多环基团,其中一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠环烷基,优选为双环或三
环,更优选为5元/5元或5元/6元双环烷基。稠环烷基的非限制性实例包括:
术语“桥环烷基”指5至20元,任意两个环共用两个不直接连接的碳原子的全碳多环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥环烷基,优选为双环、三环或四环,更有选为双环或三环。桥环烷基的非限制性实例包括:
所述环烷基环可以稠合于芳基、杂芳基或杂环烷基环上,其中与母体结构连接在一起的环为环烷基,非限制性实例包括茚满基、四氢萘基、苯并环庚烷基等。环烷基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、-C(O)OR7、-OC(O)R7、-NHS(O)pR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
术语“杂环基”指饱和或部分不饱和单环或多环环状烃取代基,其包含3至20个环原子,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,但不包括-O-O-、-O-S-或-S-S-的环部分,其余环原子为碳。优选包含3至12个环原子,其中1~4个是杂原子;更优选包含3至10个环原子;更优选包含3至8个环原子;更优选包含3至6个环原子。单环杂环基的非限制性实例包括吡咯烷基、哌啶基、哌嗪基、吗啉基、硫代吗啉基、高哌嗪基等。多环杂环基包括螺环、稠环和桥环的杂环基。
术语“螺杂环基”指5至20元的单环之间共用一个原子(称螺原子)的多环杂环基团,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***。优选为6至14元,更优选为7至10元。根据环与环之间共用螺原子的数目将螺杂环基分为单螺杂环基、双螺杂环基或多螺杂环基,优选为单
螺杂环基和双螺杂环基。更优选为4元/4元、4元/5元、4元/6元、5元/5元或5元/6元单螺杂环基。螺杂环基的非限制性实例包括:
术语“稠杂环基”指5至20元,***中的每个环与体系中的其他环共享毗邻的一对原子的多环杂环基团,一个或多个环可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环稠杂环基,优选为双环或三环,更优选为5元/5元或5元/6元双环稠杂环基。稠杂环基的非限制性实例包括:
术语“桥杂环基”指5至14元,任意两个环共用两个不直接连接的原子的多环杂环基团,其可以含有一个或多个双键,但没有一个环具有完全共轭的π电子***,其中一个或多个环原子为选自氮、氧或S(O)m(其中m是整数0至2)的杂原子,其余环原子为碳。优选为6至14元,更优选为7至10元。根据组成环的数目可以分为双环、三环、四环或多环桥杂环基,优选为双环、三环或四环,更有选为双环或三环。桥杂环基的非限制性实例包括:
所述杂环基环可以稠合于芳基、杂芳基或环烷基环上,其中与母体结构连接在一起的环为杂环基,其非限制性实例包括:
杂环基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、氧代基、-C(O)OR7、-OC(O)R7、-NHS(O)pR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
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,例如苯基和萘基。所述芳基环可以稠合于杂芳基、杂环基或环烷基环上,其中与母体结构连接在一起的环为芳基环,其非限制性实例包括:
芳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,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-C(O)OR7、-OC(O)R7、-NHS(O)pR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
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,例如呋喃基、噻吩基、吡啶基、吡咯基、N-烷基吡咯基、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、杂环基或环烷基环上,其中与母体结构连接在一起的环为杂芳基环,其非限制性实例包括:
杂芳基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、
杂环烷氧基、环烷硫基、杂环烷硫基、-C(O)OR7、-OC(O)R7、-NHS(O)pR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
术语“烷氧基”指-O-(烷基)和-O-(非取代的环烷基),其中烷基的定义如上所述。烷氧基的非限制性实例包括: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。烷氧基可以是任选取代的或非取代的,当被取代时,取代基优选为一个或多个以下基团,其独立地选自烷基、烯基、炔基、烷氧基、烷硫基、烷基氨基、卤素、巯基、羟基、硝基、氰基、环烷基、杂环烷基、芳基、杂芳基、环烷氧基、杂环烷氧基、环烷硫基、杂环烷硫基、-C(O)OR7、-OC(O)R7、-NHS(O)pR7、-C(O)R7、-NHC(O)R7、-NHC(O)OR7、-NR8R9、-OC(O)NR8R9或-C(O)NR8R9。
术语“卤代烷基”指被一个或多个卤素取代的烷基,其中烷基的定义如上所述。
术语“羟烷基”指被羟基取代的烷基,其中烷基的定义如上所述。
术语“羟基”指-OH基团。
术语“卤素”指氟、氯、溴或碘。
术语“氨基”指-NH2。
术语“氰基”指-CN。
术语“硝基”指-NO2。
术语“氧代基”指=O。
术语“羧基”指-C(O)OH。
术语“羧酸酯基”指-C(O)O(烷基)或-C(O)O(环烷基),其中烷基的定义如上所述。
术语“酰卤”指含有-C(O)-卤素的基团的化合物。
术语“乙烯氧基”指CH2=CH-O-。
术语“亚甲基”指-CH2-。
术语“亚乙基”指-(CH2)2-。
术语“亚丙基”指-(CH2)3-。
术语“亚丁基”指-(CH2)4-。
术语“烯基”指-CH=CH-。
术语“炔基”指-C≡C-。
本发明中“X选自A、B、或C”、“X选自A、B和C”、“X为A、B或C”、“X为A、B和C”等不同用语均表达了相同的意义,即表示X可以是A、B、C中任意一种或几种。
“任选”或“任选地”意味着随后所描述的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,“任选被烷基取代的杂环基
团”意味着烷基可以但不必须存在,该说明包括杂环基团被烷基取代的情形和杂环基团不被烷基取代的情形。
“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(如烯属)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他化学组分的混合物,以及其他组分例如生理学/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。
“可药用盐”是指本发明化合物的盐,这类盐用于哺乳动物体内时具有安全性和有效性,且具有应有的生物活性。
本发明化合物的合成方法
为了完成本发明的目的,本发明采用如下技术方案:
本发明通式(I)所示的化合物或其盐的制备方法,包括以下步骤:
方案一
在酸性条件下,通式(Ia)化合物被氧化成通式(Ib)化合物;通式(Ib)化合物在碱性条件下与通式(Ic)化合物反应,得到通式(Id)化合物;通式(Id)化合物在加热、碱性条件下成环,该条件下的碱优选N,N’-羰基二咪唑,得到通式(Ie)化合物;成环后的通式(Ie)化合物在酸性条件下脱去氨基上的保护基,得到通式(If)化合物或其盐;通式(If)化合物或其盐的碱溶液与氯磺酰异氰酸酯的醇溶液在低温下反应得到通式(Ig)化合物,该醇溶液优选叔丁醇溶液;通式(Ig)化合物在酸性条件下脱去氨基上的保护基,得到通式(IV)化合物;得到的通式(IV)化合物在碱性条件下开环得到目标通式(I)化合物。
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氨基钠、三乙胺、N,N-二异丙基乙胺、正丁基锂、叔丁醇钾,四丁基溴化铵,所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾或碳酸铯。
所用的氧化剂包括但不限于:双氧水、高锰酸钾和二氧化锰。
所用溶剂包括但不限于:N,N-二甲基甲酰胺、甲苯、醋酸、甲醇、乙醇、四氢呋喃、二氯甲烷、二甲基亚砜、1,4-二氧六环或水。
其中:
本发明通式(II)所示的化合物或其盐的制备方法,包括以下步骤:
方案二
在酸性条件下,通式(Ia)化合物被氧化成通式(Ib)化合物;通式(Ib)化合物在碱性条件下与通式(IIc)化合物反应,得到通式(IId)化合物;通式(IId)化合物在加热、碱性条件下成环,该条件下的碱优选N,N’-羰基二咪唑,得到通式(IIe)化合物;成环后的通式(IIe)化合物在酸性条件下脱去氨基上的保护基,得到通式(IIf)化合物或其盐;通式(IIf)化合物或其盐的碱溶液与氯磺酰异氰酸酯的醇溶液在低温下反应得到通式(IIg)化合物,该醇溶液优选叔丁醇溶液;通式(IIg)化合物在酸性条件下脱去氨基上的保护基,得到通式(V)化合物;得到的通式(V)化合物在碱性条件下开环得到目标通式(II)化合物。
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氨基钠、三乙胺、N,N-二异丙基乙胺、正丁基锂、叔丁醇钾,四丁基溴化铵,所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾或碳酸铯。
所用的氧化剂包括但不限于:双氧水、高锰酸钾和二氧化锰。
所用溶剂包括但不限于:N,N-二甲基甲酰胺、甲苯、醋酸、甲醇、乙醇、四氢呋喃、二氯甲烷、二甲基亚砜、1,4-二氧六环或水。
其中:
本发明通式(III)所示的化合物或其盐的制备方法,包括以下步骤:
方案三
在酸性条件下,通式(Ia)化合物被氧化成通式(Ib)化合物;通式(Ib)化合物在碱性条件下与通式(IIIc)化合物反应,得到通式(IIId)化合物;通式(IIId)化合物在加热、碱性条件下成环,该条件下的碱优选N,N’-羰基二咪唑,得到通式(IIIe)化合物;成环后的通式(IIIe)化合物在酸性条件下脱去氨基上的保护基,得到通式(IIIf)化合物或其盐;通式(IIIf)化合物或其盐的碱溶液与氯磺酰异氰酸酯的醇溶液在低温下反应得到通式(IIIg)化合物,该醇溶液优选叔丁醇溶液;通式(IIIg)化合物在酸性条件下脱去氨基上的保护基,得到通式(VI)化合物;得到的通式(VI)化合物在碱性条件下开环得到目标通式(III)化合物。
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氨基钠、三乙胺、N,N-二异丙基乙胺、正丁基锂、叔丁醇钾,四丁基溴化铵,所述的无机碱类包括但不限于氢化钠、碳酸钠、碳酸氢钠、碳酸钾、碳酸氢钾或碳酸铯。
所用的氧化剂包括但不限于:双氧水、高锰酸钾和二氧化锰。
所用溶剂包括但不限于:N,N-二甲基甲酰胺、甲苯、醋酸、甲醇、乙醇、四氢呋喃、二氯甲烷、二甲基亚砜、1,4-二氧六环或水。
其中:
A为3~8元环,其中所述的环选自碳环或杂环;
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着本发明的范围。
实施例
化合物的结构是通过核磁共振(NMR)或质谱(MS)来确定的。NMR的测定是用Bruker AVANCE-400核磁仪,测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD),内标为四甲基硅烷(TMS),化学位移是以10-6(ppm)作为单位给出。
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 150×4.6mm色谱柱)和Waters 2695-2996高压液相色谱仪(Gimini C18 150×4.6mm色谱柱)。
激酶平均抑制率及IC50值的测定用NovoStar酶标仪(德国BMG公司)。
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0.15mm~0.2mm,薄层层析分离纯化产物采用的规格是0.4mm~0.5mm硅胶板。
柱层析一般使用烟台黄海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 Organnics,Aldrich Chemical Company,韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中如无特殊说明,反应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。
氢化反应通常抽真空,充入氢气,反复操作3次。
微波反应使用CEM Discover-S 908860型微波反应器。
实施例中如无特殊说明,反应中的溶液是指水溶液。
实施例中如无特殊说明,反应的温度为室温。
室温为最适宜的反应温度,温度范围是20℃~30℃。
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:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:石油醚和乙酸乙酯体系,D:丙酮,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的体系包括:A:二氯甲烷和甲醇体系,B:正己烷和乙酸乙酯体系,C:正己烷、乙酸乙酯和二氯甲烷体系,D:石油醚和乙酸乙酯体系,E:乙酸乙酯,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酸性或碱性试剂等进行调节。
实施例1
N-(3-溴-4-氟苯基)-N’-羟基-4-(((1-(氨磺酰基氨基)环丙基)甲基)氨基)-1,2,5-噁二唑-3-甲脒1
第一步
4-(3-溴-4-氟苯基)-3-(4-硝基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮1b
将3-(4-氨基-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮1a(264mg,2.23mmol,采用专利申请“WO2010005958”公开的方法制备而得)加入5mL三氟乙酸中,加入3mL双氧水(30%),于45℃反应16小时。反应结束后,加入饱和亚硫酸钠溶液淬灭反应,用乙酸乙酯萃取,合并有机相,用无水硫酸钠干燥,过滤,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1b(210mg,黄色油状物),产率78.6%。
MS m/z(LC-MS):342.9[M-1]
第二步
(1-(((4-(N-(3-溴-4-氟苯基)-N’-羟基甲脒基)-1,2,5-噁二唑-3-基)氨基)甲基)环丙基)氨基甲酸叔丁酯1d
将1b(210mg,0.56mmol)溶于15mL四氢呋喃中,加入(1-(氨甲基)环丙基)氨基甲酸叔丁酯1c(210mg,1.13mmol,采用专利申请“WO2013052394”公开的方法制备而得),加入1.5mL 2N的氢氧化钠溶液,于室温下反应30分钟。反应结束后,加入1N的盐酸调节反应液pH至2,用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题产物1d(260mg,黄色固体),产物不经纯化直接进行下一步反应。
MS m/z(LC-MS):485.2[M+1]
第三步
(1-(((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)甲基)环丙基)氨基甲酸叔丁酯1e
将粗品1d(260mg,0.535mmol)溶于20mL四氢呋喃中,加入N,N’-羰基二咪唑(95mg,0.586mmol),于70℃反应1小时。反应结束后,将反应液减压浓缩,用乙酸乙酯溶解残留物,依次用1N盐酸、水、饱和氯化钠溶液洗涤,用无水硫酸钠干燥有机相,过滤,滤液减压浓缩,得到粗品标题产物1e(330mg,黄色固体),产物不经纯化直接进行下一步反应。
MS m/z(LC-MS):455.3 [M+1-56]
第四步
3-(4-(((1-氨基环丙基)甲基)氨基)-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮三氟乙酸盐1f
将粗品1e(330mg,0.645mmol)溶于30mL二氯甲烷中,加入2mL三氟乙酸,于室温下反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物1f(400mg,黄褐色油状物),产品不经纯化直接进行下步反应。
第五步
N-(1-(((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)甲基)环丙基)氨磺酰基氨基甲酸叔丁酯1g
将氯磺酰异氰酸酯(0.793g,5.6mmol,采用公知的方法“Organic Syntheses,1966,46,23-7”制备而得)溶于10mL二氯甲烷中,冷却至0℃,加入叔丁醇(0.43g,5.8mmol),反应液在0℃下反应1小时,制得反应液A。将粗品1f(400mg,1.0mmol)溶于20mL二氯甲烷中,加入0.75mL三乙胺,制得反应液B。于0℃下,将反应液A加入反应液B中,于0℃反应1小时。反应结束后,加入饱和碳酸氢钠溶液将反应液淬灭,分液,有机相依次用水洗涤,饱和氯化钠溶液洗涤,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1g(120mg,白色固体),收率20%。
MS m/z(LC-MS):607.1 [M+18]
第六步
N-{1-[({4-[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]-1,2,5-噁二唑-3-基}氨基)甲基]环丙基}氨基磺酰胺1h
将1g(120mg,0.198mmol)溶于20mL二氯甲烷中,加入4mL三氟乙酸,于室温下反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物1h(160mg,褐色粘稠物),产品不经纯化直接进行下步反应。
MS m/z(LC-MS):490.0 [M+1]
第七步
N-(3-溴-4-氟苯基)-N’-羟基-4-(((1-(氨磺酰基氨基)环丙基)甲基)氨基)-1,2,5-噁二唑-3-甲脒1
将粗品1h(160mg,0.27mmol)溶于20mL甲醇中,加入碳酸钾(230mg,1.67mmol),于50℃反应1小时。反应结束后,加入饱和氯化铵溶液中和反应,分液,
水相用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,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1 (10mg,白色固体),收率7.5%。
MS m/z(ESI):466.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.54(s,1H),8.89(s,1H),7.11-7.25(m,3H),6.78-6.79(m,1H),6.68(s,2H),6.23(t,1H),3.44(d,2H),0.94(s,2H),0.68(s,2H).
实施例2
N-(3-溴-4-氟苯基)-N’-羟基-4-(((1-((氨磺酰基氨基)甲基)环丙基)甲基)氨基)-1,2,5-噁二唑-3-甲脒2
第一步
((1-(((4-(N-(3-溴-4-氟苯基)-N’-羟基甲脒基-1,2,5-噁二唑-3-基)氨基)甲基)环丙基)甲基)氨基甲酸叔丁酯2b
将1b(360mg,0.968mmol)溶于30mL四氢呋喃中,加入((1-(氨基甲基)环丙基)甲基)氨基甲酸叔丁酯2a(387mg,1.935mmol,采用专利申请“WO2009054468”公开的方法制备而得),加入2.9mL 2N的氢氧化钠溶液,于室温下反应30分钟。反应结束后,加入1N的盐酸调节反应液pH<7,用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题产物2b(650mg,黄褐色固体),产物不经纯化直接进行下一步反应。
第二步
((1-(((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)甲基)环丙基)甲基)氨基甲酸叔丁酯2c
将粗品2b(650mg,1.3mmol)溶于30mL四氢呋喃中,加入N,N’-羰基二咪唑(222mg,1.37mmol),于70℃反应1小时。反应结束后,将反应液减压浓缩,用乙酸乙酯溶解残留物,依次用1N盐酸、水、饱和氯化钠溶液洗涤,用无水硫酸钠干燥有机相,过滤,滤液减压浓缩,得到粗品标题产物2c(715mg,褐黄色固体),产物不经纯化直接进行下一步反应。
第三步
3-(4-(((1-(氨基甲基)环丙基)甲基)氨基)-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮2d
将粗品2c(715mg,1.36mmol)溶于5mL二氯甲烷中,加入5mL三氟乙酸,于室温下反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物2d(1.02g,红褐色油状物),产品不经纯化直接进行下一步反应。
MS m/z(LC-MS):427.0 [M+1]
第四步
N-((1-(((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)甲基)环丙基)甲基)氨磺酰基氨基甲酸叔丁酯2e
将氯磺酰异氰酸酯(509mg,3.59mmol)溶于10mL二氯甲烷中,冷却至0℃,加入叔丁醇(267mg,3.59mmol),反应液于0℃下反应15分钟,制得反应液A。将粗品2d(1.021g,2.4mmol)溶于20mL二氯甲烷,加入1mL三乙胺,制得反应液B。于0℃下将反应液A加入反应液B中,于0℃反应1小时。反应结束后,加入饱和碳酸氢钠溶液将反应液淬灭,分液,有机相依次用水洗涤,饱和氯化钠溶液洗涤,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2e(28mg,褐色固体),收率19%。
MS m/z(LC-MS):621.0[M+18]
第五步
N-({1-[({4-[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]-1,2,5-噁二唑-3-基}氨基)甲基]环丙基}甲基)氨基磺酰胺2f
将2e(282mg,0.466mmol)溶于10mL二氯甲烷中,加入5mL三氟乙酸,于室温下反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物2f(160mg,褐色粘稠物),产品不经纯化直接进行下步反应。
MS m/z(LC-MS):504.0[M+1]
第六步
N-(3-溴-4-氟苯基)-N’-羟基-4-(((1-((氨磺酰基氨基)甲基)环丙基)甲基)氨基)-1,2,5-噁二唑-3-甲脒2
将粗品2f(386mg,0.765mmol)溶于10mL甲醇中,加入碳酸钾(528mg,3.86mmol),于50℃反应1小时。反应结束后,加入饱和氯化铵溶液中和反应,分液,水相用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,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2(180mg,白色固体),收率49%。
MS m/z(ESI):478.2[M+1]
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.89(s,1H),7.19(t,1H),7.10-7.12(m,1H),6.78-6.79(m,1H),6.77(t,1H),6.49(s,2H),6.14(t,1H),3.23(d,2H),2.86(d,2H),0.48(s,4H).
实施例3
N-(3-溴-4-氟苯基)-N’-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-1,2,5-噁二唑-3-甲脒3
第一步
(1-(2-((4-(N-(3-溴-4-氟苯基)-N’-羟基甲脒基)-1,2,5-噁二唑-3-基)氨基)乙基)环丙基)氨基甲酸叔丁酯3b
将1b(210mg,0.564mmol)溶于20mL四氢呋喃中,加入叔丁酯(1-(2-氨基乙基)环丙基)氨基甲酸3a(240mg,1.19mmol,采用专利申请“WO2013020993”公开的方法制备而得),加入1.5mL 2N的氢氧化钠溶液,于室温下反应30分钟。反应结束后,加入1N的盐酸调节反应液pH<7,用乙酸乙酯萃取三次,合并有机相,
用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题产物3b(370mg,淡黄色固体),产物不经纯化直接进行下一步反应。
MS m/z(LC-MS):497.1 [M-1]
第二步
(1-(2-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基)环丙基)氨基甲酸叔丁酯3c
将粗品3b(370mg,0.74mmol)溶于15mL四氢呋喃中,加入N,N’-羰基二咪唑(126mg,0.78mmol),于70℃反应1小时。反应结束后,将反应液减压浓缩,用乙酸乙酯溶解残留物,依次用1N盐酸、水、饱和氯化钠溶液洗涤,用无水硫酸钠干燥有机相,过滤,滤液减压浓缩,得到粗品标题产物3c(350mg,黄色固体),产物不经纯化直接进行下一步反应。
MS m/z(LC-MS):523.0[M-1]
第三步
3-(4-((2-(1-氨基环丙基)乙基)氨基)-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮3d
将粗品3c(350mg,0.666mmol)溶于5mL二氯甲烷中,加入3mL三氟乙酸,于室温下反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物3d(300mg,黄褐色油状物),产品不经纯化直接进行下步反应。
第四步
N-(1-(2-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基)环丙基)氨磺酰基氨基甲酸叔丁酯3e
将氯磺酰异氰酸酯(145mg,1.024mmol)溶于10mL二氯甲烷中,冷却至0℃,加入叔丁醇(76mg,1.025mmol),反应液于0℃下反应15分钟,制得反应液A。将粗品3d(500mg,1.17mmol)溶于20mL二氯甲烷,加入1mL三乙胺,制得反应液B。于0℃下,将反应液A加入反应液B中,于0℃反应1小时。反应结束后,加入饱和碳酸氢钠溶液将反应液淬灭,分液,有机相依次用水洗涤,饱和氯化钠溶液洗涤,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3e(180mg,褐色固体),收率25%。
MS m/z(LC-MS):602.0[M-1]
第五步
N-{1-[2-({4-[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]-1,2,5-噁二唑-3-基}氨基)乙基]环丙基}氨基磺酰胺3f
将3e(180mg,0.298mmol)溶于40mL二氯甲烷中,加入2mL三氟乙酸,于室温下反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物3f(223mg,褐黄色粘稠物),产品不经纯化直接进行下步反应。
第六步
N-(3-溴-4-氟苯基)-N’-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-1,2,5-噁二唑-3-甲脒3
将粗品3f(223mg,0.44mmol)溶于15mL甲醇中,加入碳酸钾(380mg,2.75mmol),于50℃反应1小时。反应结束后,加入饱和氯化铵溶液中和反应,分液,水相用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,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3(70mg,白色固体),收率33%。
MS m/z(ESI):480.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.89(s,1H),7.19(t,1H),7.07-7.10(m,2H),6.77-6.78(m,1H),6.60(s,2H),6.13(t,1H),3.38-3.43(m,2H),1.82(t,2H),0.88(t,2H),0.46(t,2H).
实施例4
N-(3-溴-4-氟苯基)-N’-羟基-4-((3-羟基-2-(氨磺酰基氨基)丙基)氨基)-1,2,5-噁二唑-3-甲脒4
第一步
4-(((4-(N-(3-溴-4-氟苯基)-N’-羟基甲脒基)-1,2,5-噁二唑-3-基)氨基)甲基)-2,2-二甲基噁唑烷-3-羧酸叔丁酯4b
将1b(505mg,1.54mmol)溶于30mL四氢呋喃中,加入4-(氨基甲基)-2,2-二甲基噁唑烷-3-羧酸叔丁酯4a(630mg,2.73mmol,采用专利申请“WO2013020993”
公开的方法制备而得),加入4mL 2N的氢氧化钠溶液,于室温下反应30分钟。反应结束后,加入饱和氯化铵溶液调节溶液pH为9,用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题产物4b(667mg,褐色固体),产物不经纯化直接进行下一步反应。
MS m/z(LC-MS):529.1[M-1]
第二步
4-(((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)甲基)-2,2-二甲基噁唑烷-3-羧酸叔丁酯4c
将粗品4b(667mg,1.26mmol)溶于20mL四氢呋喃中,加入N,N’-羰基二咪唑(225mg,1.38mmol),于70℃反应1小时。反应结束后,将反应液减压浓缩,用乙酸乙酯溶解残留物,依次用1N盐酸、水、饱和氯化钠溶液洗涤,用无水硫酸钠干燥有机相,过滤,滤液减压浓缩,得到粗品标题产物4c(710mg,黄褐色油状物),产物不经纯化直接进行下一步反应。
MS m/z(LC-MS):555.1[M-1]
第三步
(1-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)-3-羟基丙烷-2-基)氨基甲酸叔丁酯4d
将粗品4c(710mg,1.28mmol)溶于20mL甲醇中,加入对甲苯磺酸一水合物(124mg,0.65mmol),于室温下反应12小时。反应结束后,加入饱和碳酸氢钠溶液中和反应,将反应液减压浓缩,用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,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4d(310mg,黄褐色油状物),收率47%。
MS m/z(LC-MS):513.0[M-1]
第四步
3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)-2-((叔丁氧羰基)氨基)丙基乙酸酯4e
将4d(310mg,0.60mmol)溶于30mL二氯甲烷中,加入0.18mL三乙胺,冷却至0℃,滴加乙酰氯(0.066mL,0.92mmol),于0℃反应1小时。反应结束后,加入饱和碳酸氢钠溶液,分液,有机相依次用水、饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题产物4e(510mg,褐色粘稠物),产品不经纯化直接进行下步反应。
MS m/z(LC-MS):556.0[M-1]
第五步
2-氨基-3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)丙基乙酸酯三氟乙酸盐4f
将粗品4e(300mg,0.538mmol)溶于5mL二氯甲烷,加入3mL三氟乙酸,于室温反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物4f(510mg,黄褐色油状物),产品不经纯化直接进行下一步。
第六步
3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)-2-((N-(叔丁氧羰基)氨磺酰基)氨基)丙基乙酸酯4g
将氯磺酰异氰酸酯(120mg,0.848mmol)溶于10mL二氯甲烷中,冷却至0℃,加入叔丁醇(63mg,0.849mmol),反应液于0℃反应15分钟,制得反应液A。将粗品4f(510mg,1.11mmol)溶于10mL二氯甲烷中,加入1mL三乙胺,制得反应液B。于室温将反应液A加入反应液B中,于室温反应1小时。反应结束后,加入饱和碳酸氢钠溶液将反应液淬灭,分液有机相依次用水、饱和氯化钠溶液洗涤,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4g(238mg,黄色固体),收率33%。
MS m/z(LC-MS):653.0[M+18]
第七步
3-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)-2-(氨磺酰基氨基)丙基乙酸酯4h
将4g(238mg,0.37mmol)溶于5mL二氯甲烷中,加入3mL三氟乙酸,于室温下反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物4h(250mg,淡褐色粘稠物),产品不经纯化直接进行下步反应。
第八步
N-(3-溴-4-氟苯基)-N’-羟基-4-((3-羟基-2-(氨磺酰基氨基)丙基)氨基)-1,2,5-噁二唑-3-甲脒4
将粗品4h(250mg,0.666mmol)溶于20mL甲醇中,加入碳酸钾(600mg,4.35mmol),于50℃反应1.5小时。反应结束后,将反应液减压浓缩,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(40mg,淡黄色固体),收率18%。
MS m/z(ESI):468.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.47(s,1H),8.87(s,1H),7.12-7.19(m,2H),6.77-6.78(m,2H),6.61(d,1H),6.56(s,1H),6.20-6.22(m,1H),4.82(t,1H),4.02-4.04(m,1H),3.44-3.57(m,3H),3.24-3.26(m,1H).
实施例5
N-(3-溴-4-氟苯基)-N’-羟基-4-((3-甲氧基-2-(氨磺酰基氨基)丙基)氨基)-1,2,5-噁二唑-3-甲脒5
第一步
(1-((4-(N-(3-溴-4-氟苯基)-N’-羟基甲脒基)-1,2,5-噁二唑-3-基)氨基)-3-甲氧基丙烷-2-基)氨基甲酸叔丁酯5b
将1b(756mg,2.03mmol)溶于50mL四氢呋喃中,加入(1-氨基-3-甲氧基丙烷-2-基)氨基甲酸叔丁酯5a(800mg,3.92mmol,采用专利申请“WO2012002577”公开的方法制备而得),加入6mL 2N的氢氧化钠溶液,于室温反应30分钟。反应结束后,加入1N的盐酸调节反应液至pH<7,用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题产物5b(1g,黄色固体),产物不经纯化直接进行下一步反应。
MS m/z(LC-MS):475.1 [M+1-28]
第二步
(1-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)-3-甲氧基丙烷-2-烷)氨基甲酸叔丁酯5c
将粗品5b(1g,1.99mmol)溶于30mL四氢呋喃中,加入N,N’-羰基二咪唑(322mg,1.99mmol),于70℃反应1小时。反应结束后,将反应液减压浓缩,用乙酸乙酯溶解残留物,依次用1N盐酸、水、饱和氯化钠溶液洗涤,用无水硫酸钠干燥有机相,过滤,滤液减压浓缩,得到粗品标题产物5c(1g,黄色固体),产物不经纯化直接进行下一步反应。
第三步
3-(4-((2-氨基-3-甲氧基丙基)氨基)-1,2,5-噁二唑-3-基)-4-(3-溴-4-氟苯基)-1,2,4-噁二唑-5(4H)-酮5d
将粗品5c(1g,1.89mmol)溶于10mL二氯甲烷中,加入10mL三氟乙酸,于室温反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物5d(1.55g,黄褐色油状物),产品不经纯化直接进行下步反应。
MS m/z(LC-MS):429.1[M+1]
第四步
N-(1-((4-(4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)-3-甲氧基丙烷-2-基)氨磺酰基氨基甲酸叔丁酯5e
将氯磺酰异氰酸酯(400mg,2.83mmol)溶于30mL二氯甲烷中,冷却至0℃,加入叔丁醇(210mg,2.83mmol),反应液于0℃反应15分钟制得反应液A。将粗品5d(1.55g,3.6mmol)溶于20mL二氯甲烷,冷却至0℃,加入2.5mL三乙胺,制得反应液B。于室温将反应液A滴加入反应液B中,于室温反应1小时。反应结束后,加入饱和碳酸氢钠溶液将反应液淬灭,分液,有机相依次用水、饱和氯化钠溶液洗涤,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5e(1.3g,黄褐色固体),收率59%。
MS m/z(LC-MS):625.0[M+18]
第五步
N-[1-({4-[4-(3-溴-4-氟苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]-1,2,5-噁二唑-3-基}氨基)-3-甲氧基丙烷-2-基]氨基磺酰胺5f
将5e(410mg,0.67mmol)溶于10mL二氯甲烷中,加入8mL三氟乙酸,于室温下反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物5f(574mg,褐色油状物),产品不经纯化直接进行下步反应。
第六步
N-(3-溴-4-氟苯基)-N’-羟基-4-((3-甲氧基-2-(氨磺酰基氨基)丙基)氨基)-1,2,5-噁二唑-3-甲脒5
将粗品5f(574mg,1.129mmol)溶于10mL四氢呋喃中,加入3mL 2N的氢氧化钠溶液,于室温反应15分钟。反应结束后,加入饱和氯化铵溶液中和反应,分液,水相用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,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5(150mg,白色固体),收率27%。
MS m/z(ESI):484.1[M+1]
1H NMR(400MHz,DMSO-d6)δ11.45(s,1H),8.88(s,1H),7.12-7.19(m,2H),6.74-6.78(m,2H),6.59(s,2H),6.20-6.2(m,1H),3.61-3.63(m,1H),3.43-3.46(m,2H),3.25-3.36(m,2H),3.28(s,3H).
实施例6
N-(3-氯苯基)-N'-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-1,2,5-噁二唑-3-甲脒6
第一步
4-氨基-N-(3-氯苯基)-N'-羟基-1,2,5-噁二唑-3-甲脒6b
将3-氯苯胺(4.7g,36.8mmol)溶于100mL乙醇,加入预制的50mL 4-氨基-N-羟基1,2,5-噁二唑-3-碳酰亚胺基氯6a(5g,30.8mmol,采用公知的方法“Journal of the American Chemical Society,2015,137(33),10532-10535”制备而得)的乙醇混悬液,滴加三乙胺(5.1mL,36.7mmol),搅拌反应12小时。反应结束后,将反应液减压浓缩,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6b(6.0g,淡黄色固体),产率76.9%。
第二步
3-(4-氨基-1,2,5-噁二唑-3-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮6c
将6b(5g,19mmol)溶于100mL四氢呋喃中,加入N,N'-羰基二咪唑(3.2g,19mmol),于70℃下反应1小时。反应结束后,将反应液冷却至室温,减压浓缩,加入乙酸乙酯和1N盐酸,分液,用饱和氯化钠溶液洗涤有机相,有机相用无水硫酸钠干燥,过滤除去干燥剂,滤液减压浓缩,用乙酸乙酯和正己烷打浆得粗品标题产物6c(3.7g,淡黄褐色固体),产品不经纯化直接进行下步反应。
第三步
4-(3-氯苯基)-3-(4-硝基-1,2,5-噁二唑-3-基)-1,2,4-噁二唑-5(4H)-酮6d
将粗品6c(800mg,2.86mmol)溶于15mL三氟乙酸中,加入7mL双氧水(30%),于50℃反应12小时。反应结束后,加入乙酸乙酯,再加入饱和亚硫酸钠溶液,分液,水相用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,过滤除去干燥剂,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6d(320mg,淡黄色固体),产率36%。
第四步
(1-(2-((4-(4-(3-氯苯基)-5-羰基-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基)环丙基)氨基甲酸叔丁酯6e
将6d(320mg,1.03mmol)和3a(227mg,1.135mmol)溶于20mL四氢呋喃中,加入1.1mL 1N的氢氧化钠溶液,搅拌反应30分钟。反应结束后,加入1N的盐酸调节反应液pH<7,加入乙酸乙酯,分液,水相用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,过滤,滤液减压浓缩,得到粗品标题产物6e(540mg,淡黄色固体),产物不经纯化直接进行下一步反应。
第五步
3-(4-((2-(1-氨基环丙基)乙基)氨基)-1,2,5-噁二唑-3-基)-4-(3-氯苯基)-1,2,4-噁二唑-5(4H)-酮6f
将粗品6e(540mg,1.17mmol)溶于15mL二氯甲烷中,加入10mL三氟乙酸搅拌反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物6f(900mg,褐色油状物),产品不经纯化直接进行下一步反应。
第六步
N-(1-(2-((4-(4-(3-氯苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基)-1,2,5-噁二唑-3-基)氨基)乙基)环丙基)氨磺酰基氨基甲酸叔丁酯6g
将氯磺酰异氰酸酯(215mg,1.52mmol)溶于15mL二氯甲烷中,冷却至0℃,加入叔丁醇(113mg,1.52mmol),反应液于0℃下反应15分钟,制得反应液A。将粗品6f(900mg,2.48mmol)溶于30mL二氯甲烷,加入1mL三乙胺,制得反应液B。于0℃下将反应液A加入反应液B中,反应1小时。反应结束后,加入饱和碳酸氢钠溶液将反应淬灭,分液,有机相依次用水洗涤,饱和氯化钠溶液洗涤,无水硫酸钠干燥,过滤,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6g(270mg,白色固体),收率20%。
第七步
N-{1-[2-({4-[4-(3-氯苯基)-5-氧代-4,5-二氢-1,2,4-噁二唑-3-基]-1,2,5-噁二唑-3-基}氨基)乙基]环丙基}氨基磺酰胺6h
将6g(270mg,0.498mmol)溶于10mL二氯甲烷中,加入5mL三氟乙酸,搅拌反应1小时。反应结束后,将反应液减压浓缩,得到粗品标题产物6h(264mg,淡黄色固体),产品不经纯化直接进行下步反应。
第八步
N-(3-氯苯基)-N'-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-1,2,5-噁二唑-3-甲脒6
将粗品6h(264mg,0.597mmol)溶于30mL四氢呋喃中,加入1.2mL 2.5M的氢氧化钠溶液,搅拌反应15分钟。反应结束后,加入饱和氯化铵溶液,分液,水相用乙酸乙酯萃取三次,合并有机相,用无水硫酸钠干燥,过滤,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(50mg,白色固体),收率20%。
MS m/z(ESI):414.3[M+1]
1H NMR(400MHz,CD3OD)δ7.17(t,1H),6.97-6.99(m,1H),6.86(t,1H),6.74-6.76(m,1H),3.56(t,2H),1.93(t,2H),1.00-1.03(m,2H),0.59-0.62(m,2H).
实施例7
N-(4-氟-3-(三氟甲基)苯基)-N'-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-1,2,5-噁二唑-3-甲脒7
采用实施例6的合成路线,将第一步原料替换为6a和4-氟-3-(三氟甲基)苯胺,制得标题产物7(170mg,白色固体)。
MS m/z(ESI):468.3[M+1]
1H NMR(400MHz,CD3OD)δ7.14-7.20(m,2H),7.10-7.12(m,1H),3.56(t,2H),1.94(t,2H),1.00-1.03(m,2H),0.60-0.63(m,2H).
实施例8
N-(4-氟-3-甲基苯基)-N'-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-1,2,5-噁二唑-3-甲脒8
采用实施例6的合成路线,将第一步原料替换为6a和4-氟-3-甲基苯胺,制得标题产物8(150mg,白色固体)。
MS m/z(ESI):414.3[M+1]
1H NMR(400MHz,CD3OD)δ6.87(t,1H),6.78-6.81(m,1H),6.68-6.72(m,1H),3.53(d,2H),2.20(d,3H),1.91(t,2H),0.99-1.02(m,2H),0.58-0.61(m,2H).
实施例9
N-(3-溴苯基)-N'-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-1,2,5-噁二唑-3-甲脒9
采用实施例6的合成路线,将第一步原料替换为6a和3-溴苯胺,制得标题产物9(50mg,白色固体)。
MS m/z(ESI):462.2[M+1]
1H NMR(400MHz,CD3OD)δ7.11-7.12(m,2H),7.01-7.02(m,1H),6.78-6.80(m,1H),3.55(t,2H),1.93(t,2H),1.00-1.03(m,2H),0.59-0.62(m,2H).
实施例10
N'-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-N-(m-甲苯基)-1,2,5-噁二唑-3-甲脒10
采用实施例6的合成路线,将第一步原料替换为6a和间甲苯胺,制得标题产物10(250mg,白色固体)。
MS m/z(ESI):396.3[M+1]
1H NMR(400MHz,CD3OD)δ7.08(t,1H),6.84(d,1H),6.64(s,1H),6.63(d,1H),3.52(t,2H),2.27(s,3H),1.90(t,2H),0.98-1.01(m,2H),0.57-0.60(m,2H).
实施例11
N-(3-氯-4-氟苯基)-N'-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-1,2,5-噁二唑-3-甲脒11
采用实施例6的合成路线,将第一步原料替换为6a和3-氯-4-氟苯胺,制得标题产物11(30mg,褐色固体)。
MS m/z(ESI):434.2[M+1]
1H NMR(400MHz,CD3OD)δ7.08(t,1H),6.98-6.99(m,1H),6.80-6.82(m,1H),3.55(t,2H),1.93(t,2H),1.01(s,2H),0.61(s,2H).
实施例12
N'-羟基-4-((2-(1-(氨磺酰基氨基)环丙基)乙基)氨基)-N-(3-(三氟甲基)苯基)-1,2,5-噁二唑-3-甲脒12
采用实施例6的合成路线,将第一步原料替换为6a和3-(三氟甲基)苯胺,制得标题产物12(105mg,白色固体)。
MS m/z(ESI):450.3[M+1]
1H NMR(400MHz,CD3OD)δ7.38(t,1H),7.25(d,1H),7.10(s,1H),7.05(d,1H),3.57(t,2H),1.94(t,2H),1.00-1.03(m,2H),0.59-0.62(m,2H).
生物学评价
以下结合测试例进一步描述解释本发明,但这些实施例并非意味着限制本发明的范围。
测试例1:
1、本发明化合物对人源IDO1蛋白酶抑制活性的测定
体外人源IDO1蛋白酶活性通过以下的方法进行测试。
该方法用来测定本发明中的化合物对人源IDO1蛋白酶活性的抑制作用。
一、实验材料及仪器
1、酶标仪(Synergy HT,BIOTEK)
2、色氨酸(T0254-5G,Sigma-Aldrich)
3、过氧化氢酶来源于牛肝脏(C1345-1G,Sigma-Aldrich))
4、亚甲蓝(M9140-25G,Sigma-Aldrich)
5、L-抗坏血酸钠(A7631-25G,Sigma-Aldrich)
6、4-(二甲基氨基)苯甲醛(D2004-25G,Sigma-Aldrich)
7、三氯乙酸(T9159-100G,Aigma-Aldrich)
8、IDO1基因(SC126221,Origene)
9、rosseta(CW0811A,北京康为世纪生物科技有限公司)
10、涡旋混合器(6776,Corning)
11、迷你板式离心机(mini-p25,ABSON life science equipment)
二、实验步骤
IDO1蛋白酶的自制
将IDO1基因通过基因克隆技术转入到PET30a质粒中,然后转入感受态的大肠杆菌rosseta;在液态LB(Luria-Bertani)培养基[根据《分子克隆实验指南》(J.萨姆布鲁克D.W.拉塞尔著)配制每升培养基]中放大培养,收集菌体,超声破碎,通过挂柱,洗脱得到纯化的IDO1蛋白酶。
化合物测试实验:
用50mM的KPB将100ul的酶(IDO1)30倍稀释至3ml,浓度为26ng/ul的酶溶液,在96孔反应板(AXYGEN,PCR-96-FLT-C)(以下简称反应板)每孔加入加入24ul酶溶液。空白孔加入24ul KPB缓冲液[KPB缓冲液的配制(50mM):用分析天平称取KH2PO4 6.805g放入1000ml的烧杯,用量筒加入去离子水至900ml,用1M的KOH调整pH至6.5,将其导入1L的量筒内,补水至1L即可。4℃储存]。在反应板加入1ul的化合物或DMSO到对应的反应孔中。准备A液:取250ul 500mM L-抗坏血酸钠加1437ul KPB,涡旋混合器最大速度混匀3秒。B液:125ul 10mM色氨的酸加100ul 100000单位/ml的过氧化氢酶,加5ul 10mM的亚甲蓝,最后加1437ul KPB,涡旋混合器最大速度混匀3秒。取1500ul A液与1500ul B液,在votex上最大速度混匀3秒。然后将此混合液以每孔24ul加入反应板中。将反应板放入板式离心机最高速度离心15秒,使反应液体都汇聚到底部,振荡器混匀30秒,在恒温孵育箱内,37℃,孵育1h。在反应板中,每孔加入10ul 30%(W/V)三氯乙酸,在孵育箱内65℃孵育15分钟。将反应板在离心机上4700RPM离心,室温,5分钟。用排枪从反应板中转移40ul上清液到对应96孔测试板(corning,#3599)中。每孔加入40ul 2%(W/V)的4-(二甲基氨基)苯甲醛/冰醋酸溶液,在振荡器上最大速度,混匀1分钟。在室温孵育2分钟后,在Synergy HT(BIOTEK)上读取480nm处的吸光值。
本发明中化合物对人源IDO1蛋白酶抑制活性通过以上的试验进行测定,测得的IC50值见表1。
表1 本发明中化合物对人源IDO1蛋白酶活性抑制IC50
实施例编号 | IC50(nM) |
2 | 78 |
3 | 18 |
4 | 57 |
5 | 68 |
6 | 28 |
7 | 98 |
8 | 15 |
9 | 9 |
11 | 77 |
12 | 70 |
结论:本发明化合物对人源IDO1蛋白酶活性具有明显的抑制作用。
测试例2、本发明化合物对Hela细胞内IDO蛋白酶抑制活性的测定
Hela细胞内IDO蛋白酶活性通过以下的方法进行测试。
该方法用来测定本发明中的化合物对Hela细胞内IDO蛋白酶活性的抑制作用。(注:HeLa细胞株在干扰素伽马(INF-γ)的诱导下表达吲哚胺2,3-双加氧酶(IDO))
一、实验材料及仪器
1、酶标仪(Synergy HT,BIOTEK)
2、色氨酸(T0254-5G,Sigma-Aldrich)
3、4-(二甲基氨基)苯甲醛(D2004-25G,Sigma-Aldrich)
4、三氯乙酸(T9159-100G,Aigma-Aldrich)
5、HeLa细胞株(CCL-2,ATCC)
二、实验步骤
用新鲜细胞培养基制取HeLa细胞悬液,以10000个细胞/孔加入100ul培养体系的96孔细胞培养板中,5%二氧化碳37℃培养24小时。去除上清,先每孔加入90ul无血清DMEM高糖培养基;然后每孔分别加入10ul配制在含INF-γ和色氨酸的培养基中的化合物(其终浓度为:100000,10000,1000,100,10,1nM),48小时5%二氧化碳37℃培养取出96孔细胞培养板中上清80ul至96孔圆底板中,每孔加入16ul 30%(W/V)三氯乙酸,在孵育箱内65℃孵育25分钟。将反应板在离心机上4700RPM离心,5分钟。用排枪从反应板中转移50ul上清液到96孔平底透明板中,然后每孔加入50ul 2%(W/V)的4-(二甲基氨基)苯甲醛/冰醋酸溶液,在振荡器上混匀1分钟。在室温孵育2分钟后,在Synergy HT Reader上读取480nm处的吸光值。
本发明中化合物对Hela细胞内IDO蛋白酶抑制活性通过以上的试验进行测定,测得的IC50值见表2。
表2 本发明中化合物对Hela细胞内IDO蛋白酶活性抑制IC50
实施例编号 | IC50(nM) |
1 | 73 |
3 | 3 |
4 | 16 |
5 | 73 |
6 | 7 |
7 | 24 |
8 | 6 |
9 | 5 |
10 | 59 |
11 | 14 |
12 | 15 |
结论:本发明化合物对Hela细胞内IDO蛋白酶活性具有明显的抑制作用。
药代动力学评价
测试例3、本发明实施例3、6和8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法测定了大鼠静脉注射给予实施例3、6和8化合物后不同时刻血浆中的药物浓度。研究本发明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
实施例3、6和8化合物
2.2试验动物
健康成年SD大鼠12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
称取适量药物,加入0.3ml二甲基乙酰胺使溶解,后加入10%2-羟丙基-β-环糊精至终体积,超声制成2.0mg/ml混悬液。
2.4给药
SD大鼠12只,雌雄各半,平均分成3组;禁食一夜后分别灌胃给药,给药体积10ml/kg。
3、操作
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、11.0、24.0h由眼眶采血0.1ml,置于肝素化试管中,3500rpm离心10min分离血浆,于-20℃保存,给药后2h进食。
用LC/MS/MS法测定不同化合物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
表3 本发明实施例3、6和8化合物的药代动力学参数
结论:本发明化合物的药代吸收良好,具有明显的药代吸收效果。
Claims (16)
- 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:R1选自烷基、环烷基和烷氧基,其中所述的烷基、环烷基、烷氧基各自独立地任选进一步被选自羟基、烷基、烷氧基和卤代烷基中的一个或多个取代基所取代;R2选自氢原子、烷基、环烷基和烷氧基,其中所述的烷基、环烷基、烷氧基各自独立地任选进一步被选自羟基、烷基、烷氧基和卤代烷基中的一个或多个取代基所取代;或R1和R2与它们连接的碳原子一起形成环烷基或杂环基,其中所述的环烷基、杂环基任选进一步被选自烷基、卤素、氰基、环烷基、杂环基、芳基、杂芳基、-NR6R7、-C(O)NR6R7、-NHS(O)mR8、-S(O)pR8、-NHC(O)R8、-OR8、-C(O)R8、-OC(O)R8和-C(O)OR8中的一个或多个取代基所取代;R3和R4各自独立地选自氢原子、烷基、氰基、氨基、卤素、烯基、炔基、羟基、硝基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被选自羟基、卤素、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;R5选自烷基和氨基,所述的烷基和氨基任选进一步被选自羟基、卤素、氨基、氰基、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;所述烷基优选C1~4烷基;R6和R7各自独立地选自氢原子、烷基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被选自羟基、卤素、烷基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;R8选自氢原子、烷基、氨基、环烷基、杂环基、芳基和杂芳基,其中所述的烷基、环烷基、杂环基、芳基或杂芳基各自独立地任选进一步被选自烷基、卤素、羟基、氨基、氰基、烷氧基、环烷基、杂环基、芳基和杂芳基中的一个或多个取代基所取代;m为0、1、2;n为0、1、2;且p为0、1、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R3和R4各自独立地选自氢原子、卤素、烷基、或卤代烷基,所述卤素优选为氟、氯或溴,所述烷基优选为C1~4烷基,所述卤代烷基优选为三氟甲基。
- 根据权利要求3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,m为0和/或n为1。
- 根据权利要求5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A为环烷基,优选为环丙基。
- 根据权利要求6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m为0或1和/或n为1或2。
- 一种药物组合物,其含有治疗有效量的根据权利要求1~8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,以及一种或多种药学上可接受的载体、稀释剂或赋形剂。
- 根据权利要求1~8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,或根据权利要求13所述的组合物在制备用于预防和/或治疗具有IDO介导的色氨酸代谢途径的病理学特征的疾病的药物中的用途。
- 根据权利要求14所述的用途,其中所述具有IDO介导的色氨酸代谢途径病理学特征的疾病选自癌症、骨髓增生异常综合征、阿尔茨海默病、自身免疫性疾病、抑郁症、焦虑症、白内障、心理障碍和艾滋病。
- 根据权利要求15所述的用途,其中所述癌症选自乳腺癌、***、结肠癌、肺癌、胃癌、直肠癌、胰腺癌、脑癌、皮肤癌、口腔癌、***癌、骨癌、肾癌、卵巢癌、膀胱癌、肝癌、输卵管肿瘤、卵巢瘤、腹膜肿瘤、IV期黑色素瘤、神经胶质瘤、神经胶母细胞瘤、肝细胞癌、乳突肾性瘤、头颈部肿瘤、白血病、淋巴瘤、骨髓瘤和非小细胞肺癌。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201680001854.9A CN106660974B (zh) | 2015-03-31 | 2016-03-22 | 含氨磺酰基的1,2,5-噁二唑类衍生物、其制备方法及其在医药上的应用 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510150668.9 | 2015-03-31 | ||
CN201510150668 | 2015-03-31 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2016155545A1 true WO2016155545A1 (zh) | 2016-10-06 |
Family
ID=57003875
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2016/076975 WO2016155545A1 (zh) | 2015-03-31 | 2016-03-22 | 含氨磺酰基的1,2,5-噁二唑类衍生物、其制备方法及其在医药上的应用 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN106660974B (zh) |
WO (1) | WO2016155545A1 (zh) |
Cited By (15)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN106967005A (zh) * | 2017-04-07 | 2017-07-21 | 钟燕 | 一种能抑制ido的化合物、其制备方法及其用途 |
WO2017129139A1 (zh) * | 2016-01-28 | 2017-08-03 | 中国科学院上海有机化学研究所 | 一种作为吲哚胺-2,3-双加氧酶抑制剂的氨基磺酸脂及其制备方法和用途 |
WO2017181849A1 (zh) * | 2016-04-20 | 2017-10-26 | 江苏豪森药业集团有限公司 | 吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用 |
CN107954999A (zh) * | 2016-10-17 | 2018-04-24 | 上海医药集团股份有限公司 | 含噁二唑环化合物、制备方法、中间体、组合物及应用 |
CN108689958A (zh) * | 2017-04-05 | 2018-10-23 | 南京华威医药科技开发有限公司 | 一种含有肼基的吲哚胺2,3-双加氧化酶抑制剂 |
WO2018196861A1 (zh) * | 2017-04-27 | 2018-11-01 | 鲁南制药集团股份有限公司 | 亚氨脲衍生物 |
CN108966651A (zh) * | 2016-04-20 | 2018-12-07 | 江苏豪森药业集团有限公司 | 吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用 |
WO2018228381A1 (zh) * | 2017-06-13 | 2018-12-20 | 山东绿叶制药有限公司 | 1,2,5-恶二唑化合物制备方法及其中间体 |
WO2018227886A1 (zh) * | 2017-06-14 | 2018-12-20 | 南京华威医药科技集团有限公司 | 新型吲哚胺2,3-双加氧化酶抑制剂 |
WO2019120237A1 (zh) | 2017-12-20 | 2019-06-27 | 成都海创药业有限公司 | 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途 |
WO2019149255A1 (zh) | 2018-02-02 | 2019-08-08 | 成都海创药业有限公司 | 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途 |
CN110248931A (zh) * | 2017-09-20 | 2019-09-17 | 上海翰森生物医药科技有限公司 | 一种双加氧酶抑制剂的盐及其制备方法和用途 |
CN110577501A (zh) * | 2018-06-07 | 2019-12-17 | 江苏柯菲平医药股份有限公司 | 吲哚胺2,3-双加氧酶调节剂,其制备方法及用途 |
US11214554B2 (en) | 2018-01-22 | 2022-01-04 | Nanjing Huawe Medicine Technology Group Co., Ltd. | Indoleamine 2,3-dioxygenase inhibitor, method for preparation and use thereof |
RU2780118C2 (ru) * | 2017-04-27 | 2022-09-19 | Лунэн Фармасьютикал Груп Корпорейшн | Производные иминомочевины |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110357831A (zh) * | 2018-04-11 | 2019-10-22 | 江苏恒瑞医药股份有限公司 | 一种ido抑制剂的晶型及其盐 |
CN108530444B (zh) * | 2018-06-11 | 2021-08-24 | 药康众拓(江苏)医药科技有限公司 | 一种新型nampt和ido双重抑制剂及其制备方法和医药用途 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070185165A1 (en) * | 2005-12-20 | 2007-08-09 | Combs Andrew P | N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
WO2008058178A1 (en) * | 2006-11-08 | 2008-05-15 | Incyte Corporation | N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
CN102164902A (zh) * | 2008-07-08 | 2011-08-24 | 因塞特公司 | 作为吲哚胺2,3-双加氧酶的抑制剂的1,2,5-二唑 |
-
2016
- 2016-03-22 WO PCT/CN2016/076975 patent/WO2016155545A1/zh active Application Filing
- 2016-03-22 CN CN201680001854.9A patent/CN106660974B/zh active Active
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20070185165A1 (en) * | 2005-12-20 | 2007-08-09 | Combs Andrew P | N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
WO2008058178A1 (en) * | 2006-11-08 | 2008-05-15 | Incyte Corporation | N-hydroxyamidinoheterocycles as modulators of indoleamine 2,3-dioxygenase |
CN102164902A (zh) * | 2008-07-08 | 2011-08-24 | 因塞特公司 | 作为吲哚胺2,3-双加氧酶的抑制剂的1,2,5-二唑 |
Cited By (31)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017129139A1 (zh) * | 2016-01-28 | 2017-08-03 | 中国科学院上海有机化学研究所 | 一种作为吲哚胺-2,3-双加氧酶抑制剂的氨基磺酸脂及其制备方法和用途 |
CN108966651A (zh) * | 2016-04-20 | 2018-12-07 | 江苏豪森药业集团有限公司 | 吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用 |
WO2017181849A1 (zh) * | 2016-04-20 | 2017-10-26 | 江苏豪森药业集团有限公司 | 吲哚胺2,3-双加氧酶抑制剂及其制备方法与应用 |
CN107954999B (zh) * | 2016-10-17 | 2023-01-24 | 上海医药集团股份有限公司 | 含噁二唑环化合物、制备方法、中间体、组合物及应用 |
CN107954999A (zh) * | 2016-10-17 | 2018-04-24 | 上海医药集团股份有限公司 | 含噁二唑环化合物、制备方法、中间体、组合物及应用 |
CN108689958B (zh) * | 2017-04-05 | 2021-09-17 | 南京华威医药科技集团有限公司 | 一种含有肼基的吲哚胺2,3-双加氧化酶抑制剂 |
CN108689958A (zh) * | 2017-04-05 | 2018-10-23 | 南京华威医药科技开发有限公司 | 一种含有肼基的吲哚胺2,3-双加氧化酶抑制剂 |
CN106967005A (zh) * | 2017-04-07 | 2017-07-21 | 钟燕 | 一种能抑制ido的化合物、其制备方法及其用途 |
WO2018184585A1 (zh) * | 2017-04-07 | 2018-10-11 | 上海肇钰医药科技有限公司 | 一种能抑制ido的化合物、其制备方法及其用途 |
CN106967005B (zh) * | 2017-04-07 | 2019-07-16 | 上海肇钰医药科技有限公司 | 一种能抑制ido的化合物、其制备方法及其用途 |
CN108794423A (zh) * | 2017-04-27 | 2018-11-13 | 鲁南制药集团股份有限公司 | 亚氨脲衍生物 |
JP7256130B2 (ja) | 2017-04-27 | 2023-04-11 | 魯南製薬集団股▲分▼有限公司 | グアニジン誘導体 |
KR102542904B1 (ko) | 2017-04-27 | 2023-06-13 | 루난 파마슈티컬 그룹 코퍼레이션 | 구아니딘 유도체 |
RU2780118C2 (ru) * | 2017-04-27 | 2022-09-19 | Лунэн Фармасьютикал Груп Корпорейшн | Производные иминомочевины |
CN108794423B (zh) * | 2017-04-27 | 2022-07-19 | 鲁南制药集团股份有限公司 | 亚氨脲衍生物 |
KR20220066176A (ko) * | 2017-04-27 | 2022-05-23 | 루난 파마슈티컬 그룹 코퍼레이션 | 구아니딘 유도체 |
WO2018196861A1 (zh) * | 2017-04-27 | 2018-11-01 | 鲁南制药集团股份有限公司 | 亚氨脲衍生物 |
JP2020517585A (ja) * | 2017-04-27 | 2020-06-18 | 魯南製薬集団股▲分▼有限公司 | グアニジン誘導体 |
WO2018228381A1 (zh) * | 2017-06-13 | 2018-12-20 | 山东绿叶制药有限公司 | 1,2,5-恶二唑化合物制备方法及其中间体 |
CN109081818B (zh) * | 2017-06-14 | 2022-04-22 | 南京华威医药科技集团有限公司 | 新型吲哚胺2,3-双加氧化酶抑制剂 |
CN109081818A (zh) * | 2017-06-14 | 2018-12-25 | 南京华威医药科技开发有限公司 | 新型吲哚胺2,3-双加氧化酶抑制剂 |
WO2018227886A1 (zh) * | 2017-06-14 | 2018-12-20 | 南京华威医药科技集团有限公司 | 新型吲哚胺2,3-双加氧化酶抑制剂 |
CN110248931A (zh) * | 2017-09-20 | 2019-09-17 | 上海翰森生物医药科技有限公司 | 一种双加氧酶抑制剂的盐及其制备方法和用途 |
CN110248931B (zh) * | 2017-09-20 | 2022-12-23 | 上海翰森生物医药科技有限公司 | 一种双加氧酶抑制剂的盐及其制备方法和用途 |
US11447477B2 (en) | 2017-12-20 | 2022-09-20 | Hinova Pharmaceuticals Inc. | Indoleamine-2,3-dioxygenase inhibitor, the preparative method and the use thereof |
WO2019120237A1 (zh) | 2017-12-20 | 2019-06-27 | 成都海创药业有限公司 | 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途 |
US11214554B2 (en) | 2018-01-22 | 2022-01-04 | Nanjing Huawe Medicine Technology Group Co., Ltd. | Indoleamine 2,3-dioxygenase inhibitor, method for preparation and use thereof |
CN110128367A (zh) * | 2018-02-02 | 2019-08-16 | 成都海创药业有限公司 | 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途 |
WO2019149255A1 (zh) | 2018-02-02 | 2019-08-08 | 成都海创药业有限公司 | 一种吲哚胺-2,3-双加氧酶抑制剂及其制备方法和用途 |
US11591301B2 (en) | 2018-02-02 | 2023-02-28 | Hinova Pharmaceuticals Inc. | Indoleamine-2,3-dioxygenase inhibitor, preparation method therefor and use thereof |
CN110577501A (zh) * | 2018-06-07 | 2019-12-17 | 江苏柯菲平医药股份有限公司 | 吲哚胺2,3-双加氧酶调节剂,其制备方法及用途 |
Also Published As
Publication number | Publication date |
---|---|
CN106660974B (zh) | 2019-08-30 |
CN106660974A (zh) | 2017-05-10 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WO2016155545A1 (zh) | 含氨磺酰基的1,2,5-噁二唑类衍生物、其制备方法及其在医药上的应用 | |
CN106536480B (zh) | 吡咯烷-2,5-二酮衍生物、药物组合物及用作ido1抑制剂的方法 | |
CN107759587B (zh) | [1,2,4]***并[1,5-a]吡啶类化合物及其制备方法和医药用途 | |
TWI710552B (zh) | 作為神經元組織胺受體-3拮抗劑之化合物及其用途 | |
CN106565696B (zh) | 噁二唑类衍生物、其制备方法及其在医药上的应用 | |
CN110256421A (zh) | Kras-g12c抑制剂 | |
WO2017084494A1 (zh) | 苯并呋喃类衍生物、其制备方法及其在医药上的应用 | |
CN107033097B (zh) | 噁二唑类衍生物、其制备方法及其在医药上的应用 | |
WO2016169421A1 (zh) | 咪唑并异吲哚类衍生物、其制备方法及其在医药上的应用 | |
AU2015336458B2 (en) | KCNQ2-5 channel activator | |
WO2001083456A1 (fr) | Derives d'heteroaryle condenses | |
JP2012504659A (ja) | カルバゾール化合物および当該化合物の治療用途 | |
EP3617195A1 (en) | Novel tetrahydronaphthyl urea derivatives | |
WO2018145525A1 (zh) | 吡咯并芳杂环类化合物及其制备方法和医药用途 | |
CN103502219A (zh) | 作为治疗剂的新型小分子 | |
JP2004529088A (ja) | IkBキナーゼ(IKK)のインヒビターを用いる炎症性および免疫疾患の処置法 | |
WO2019007382A1 (zh) | 吲哚甲酰胺类衍生物、其制备方法及其在医药上的应用 | |
CN111320633B (zh) | 吡咯/咪唑并六元杂芳环类化合物及其制备方法和医药用途 | |
CN117597341A (zh) | 磺酰胺衍生物、其制备方法及其在医药上的应用 | |
US20200277278A1 (en) | Deuterium Atom-Substituted Indole Formamide Derivative, Preparation Method Therefor, and Medical Applications Thereof | |
JP2011201777A (ja) | 光学活性なヘテロシクリデン−n−アリールアセトアミド誘導体 | |
CN111205309B (zh) | 吲哚类大环衍生物、其制备方法及其在医药上的应用 | |
CN103664734A (zh) | 杂环羟肟酸类化合物及其药用组合物和应用 | |
WO2013189241A1 (zh) | 嘧啶二胺类衍生物、其制备方法及其在医药上的应用 | |
CN107880038B (zh) | [1,2,4]***并[1,5-a]吡啶类化合物及其制备方法和医药用途 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 16771300 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 16771300 Country of ref document: EP Kind code of ref document: A1 |