CN103819471A - Derivative of pyridine and (4,3-d) pyrimidine-1(2H)-base phenyl acetamide and application thereof - Google Patents
Derivative of pyridine and (4,3-d) pyrimidine-1(2H)-base phenyl acetamide and application thereof Download PDFInfo
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- CN103819471A CN103819471A CN201310606201.1A CN201310606201A CN103819471A CN 103819471 A CN103819471 A CN 103819471A CN 201310606201 A CN201310606201 A CN 201310606201A CN 103819471 A CN103819471 A CN 103819471A
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- pyrimidine
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- LSBDFXRDZJMBSC-UHFFFAOYSA-N 2-phenylacetamide Chemical compound NC(=O)CC1=CC=CC=C1 LSBDFXRDZJMBSC-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 150000003222 pyridines Chemical class 0.000 title abstract 2
- 239000003814 drug Substances 0.000 claims abstract description 34
- 238000002360 preparation method Methods 0.000 claims description 16
- XUMBMVFBXHLACL-UHFFFAOYSA-N Melanin Chemical compound O=C1C(=O)C(C2=CNC3=C(C(C(=O)C4=C32)=O)C)=C2C4=CNC2=C1C XUMBMVFBXHLACL-UHFFFAOYSA-N 0.000 claims description 10
- 229910052731 fluorine Inorganic materials 0.000 claims description 9
- 239000011737 fluorine Substances 0.000 claims description 9
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 claims description 8
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 8
- 229910052805 deuterium Inorganic materials 0.000 claims description 8
- 201000001441 melanoma Diseases 0.000 claims description 8
- 206010027476 Metastases Diseases 0.000 claims description 6
- 206010028980 Neoplasm Diseases 0.000 claims description 6
- 230000009401 metastasis Effects 0.000 claims description 6
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 14
- 229940079593 drug Drugs 0.000 abstract description 11
- 239000008280 blood Substances 0.000 abstract description 4
- 210000004369 blood Anatomy 0.000 abstract description 4
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 abstract description 2
- 206010070863 Toxicity to various agents Diseases 0.000 abstract description 2
- 230000004060 metabolic process Effects 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 230000008569 process Effects 0.000 abstract description 2
- 230000014759 maintenance of location Effects 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- -1 fluoro-4-iodophenyl Chemical group 0.000 description 24
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 15
- UWAOJIWUVCMBAZ-UHFFFAOYSA-N [1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-dimethylazanium;chloride Chemical compound Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UWAOJIWUVCMBAZ-UHFFFAOYSA-N 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 8
- 229960003466 sibutramine hydrochloride Drugs 0.000 description 8
- 235000002639 sodium chloride Nutrition 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 5
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229960001701 chloroform Drugs 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 239000002547 new drug Substances 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
- 102000007665 Extracellular Signal-Regulated MAP Kinases Human genes 0.000 description 2
- 108010007457 Extracellular Signal-Regulated MAP Kinases Proteins 0.000 description 2
- KRHYYFGTRYWZRS-UHFFFAOYSA-N Fluorane Chemical compound F KRHYYFGTRYWZRS-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 2
- 229940124647 MEK inhibitor Drugs 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 229910052786 argon Inorganic materials 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 description 2
- 229940043355 kinase inhibitor Drugs 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000006241 metabolic reaction Methods 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 2
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 2
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 208000002874 Acne Vulgaris Diseases 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 229920000858 Cyclodextrin Polymers 0.000 description 1
- 206010048768 Dermatosis Diseases 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 206010035664 Pneumonia Diseases 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 1
- 206010039491 Sarcoma Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 206010000496 acne Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229940024606 amino acid Drugs 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- HNYOPLTXPVRDBG-UHFFFAOYSA-N barbituric acid Chemical compound O=C1CC(=O)NC(=O)N1 HNYOPLTXPVRDBG-UHFFFAOYSA-N 0.000 description 1
- SRSXLGNVWSONIS-UHFFFAOYSA-N benzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-N 0.000 description 1
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 1
- 210000003754 fetus Anatomy 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002989 glutamic acid Drugs 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 208000021267 infertility disease Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 229910017053 inorganic salt Inorganic materials 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 230000036210 malignancy Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000000684 melanotic effect Effects 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000003226 mitogen Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 210000003928 nasal cavity Anatomy 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000012074 organic phase Substances 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- NIXKBAZVOQAHGC-UHFFFAOYSA-N phenylmethanesulfonic acid Chemical compound OS(=O)(=O)CC1=CC=CC=C1 NIXKBAZVOQAHGC-UHFFFAOYSA-N 0.000 description 1
- OXNIZHLAWKMVMX-UHFFFAOYSA-N picric acid Chemical compound OC1=C([N+]([O-])=O)C=C([N+]([O-])=O)C=C1[N+]([O-])=O OXNIZHLAWKMVMX-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 230000035935 pregnancy Effects 0.000 description 1
- 235000019260 propionic acid Nutrition 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000008299 semisolid dosage form Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 208000017520 skin disease Diseases 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 description 1
- 229960004066 trametinib Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Substances FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a derivative of pyridine and (4,3-d) pyrimidine-1(2H)-base phenyl acetamide and an application thereof. The derivative has good pharmaceutical activity, can greatly prolong the half-life periods of drugs, prolongs the retention time of drugs in the human body, and meanwhile increases the drug concentration in the blood. Therefore, a better curative effect is achieved. As the half-life periods of drugs are greatly prolonged, the drugs can keep activity concentration for a longer time in the blood. Under the cure condition with dose limiting, the curative effect can be kept and the recommended dosage of drugs can be reduced at the same time, therefore the bad metabolism of drugs is eliminated, the drug toxicity is reduced, and the toxic and side effects in the drug using process are small.
Description
Technical field
The present invention relates to a kind of derivative and application thereof of compound, belong to technical field of pharmaceuticals.
Background technology
Melanoma is the malignant tumour that a kind of grade malignancy is quite high, claims again melanotic sarcoma, is mostly primary in skin, also can originate from eye, nasal cavity etc. and locate, and can shift in early days the common lung of metastasis site, brain.Melanoma is in dermatosis, to cause dead topmost sick kind.National Cancer Institute estimates to have for 2013 nearly 76690 Americans to be diagnosed as melanoma, and has 9480 to die from this kind of disease.On May 29th, 2013, U.S. food Drug Administration (FDA) has ratified a kind of new drug and has been used for the treatment of metastasis melanin tumor and melanoma patient that can not row operative treatment, and whether the use of this new drug simultaneously also can be used for diagnosing this patient to be applicable to receiving treatment.The chemical name of this new drug is: the fluoro-4-iodophenyl of N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide.Trade name: Sibutramine Hydrochloride is for Buddhist nun (Trametinib).This medicine is a kind of extracellular signal-regulated kinase inhibitor (mek inhibitor).Be used for the treatment of metastasis melanin tumor and melanoma patient that can not row operative treatment.Sibutramine Hydrochloride is to promote mitogen activation for Buddhist nun's mechanism of action, is a kind of extracellular signal-regulated kinase inhibitor (mek inhibitor).Find in Buddhist nun's clinical experimental study at Sibutramine Hydrochloride, compared with chemotherapy, Sibutramine Hydrochloride has significantly improved patient's Progression free survival phase and Overall survival for Buddhist nun.Due in the time using Sibutramine Hydrochloride to treat for Buddhist nun; conventionally strengthen dosage in order to reach result for the treatment of; cause producing a lot of poor metabolism problems; the active metabolite producing by bad metabolic reaction due to medicine normally medicine produces the important factor of toxicity and other side effects; thereby can produce a lot of toxic side effect to human body in therapeutic process; patient in treatment there will be untoward reaction in various degree conventionally, and the most serious untoward reaction comprises: cardiac failure, pneumonia, skin infections, blind.Modal untoward reaction comprises: fash, diarrhoea, swollen tissue (PE), acne sample skin dermexanthesis.Simultaneously FDA points out that Women of Childbearing Age uses Sibutramine Hydrochloride to have the risk that causes fetus infringement for Buddhist nun, and male patient and female patients use this kind of medicine to have to cause infertile risk.Women should be confirmed whether gestation for before Buddhist nun treatment accepting Sibutramine Hydrochloride, and men and women patient all should be warned these risks and need to take birth-control measures.
Summary of the invention
The object of the invention is to overcome defect of the prior art, pyrido (4,3-d) pyrimidine-1(2H is provided) derivative and the application thereof of-Ji phenyl-acetamides, the pharmaceutical activity of described derivative is good, the bad metabolic problems that can solve medicine simultaneously, the toxic side effect in medication process is little.
The present invention is achieved by the following technical programs.
Pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, there is the following chemical structure general formula:
R in formula
1, R
2, R
3be hydrogen or deuterium or fluorine independently, wherein have one at least for deuterium or fluorine.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, wherein, R
1, R
2, R
3in one or several is fluorine.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, wherein, R
1, R
2, R
3be fluorine.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, wherein, R
1, R
2, R
3in one or several is deuterium.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, wherein, R
1, R
2, R
3be deuterium.
Above-mentioned pyrido (4,3-d) pyrimidine-1(2H) application of derivative of-Ji phenyl-acetamides, the application of described derivative in the medicine of preparation treatment metastasis melanin tumor and melanoma disease that can not row operative treatment.
Pyrido (4 of the present invention, 3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides can be used as the activeconstituents of the medicine for the treatment of metastasis melanin tumor and melanoma disease that can not row operative treatment, in this medicine, also can contain described derivative and pharmaceutically acceptable carrier or the figuration body of significant quantity, make the formulation that is applicable to use.Drug delivery system can be albumin bound type injection liquid, liposome, powder pin, nanoparticle and cyclodextrin inclusion compound etc., form of administration can be injection liquid, also can be solid dosage or semisolid dosage form, as being injection, tablet, wafer, pill, powder or granule etc.
Pyrido (4 of the present invention, 3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides can be made into the pharmaceutically acceptable salt that is suitable as medicine, the pharmaceutically acceptable salt that is suitable as medicine refers to the salt that is suitable as medicine that compound of the present invention and acid or alkali form, and comprises inorganic salt and organic salt.The preferred salt of one class is compound of the present invention and the sour salt forming.The acid that is applicable to formation salt includes, but are not limited to: the mineral acids such as hydrochloric acid, Hydrogen bromide, hydrofluoric acid, sulfuric acid, nitric acid and phosphoric acid, the organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, propanedioic acid, succsinic acid, fumaric acid, toxilic acid, lactic acid, oxysuccinic acid, tartrate, citric acid, picric acid, methylsulfonic acid, benzene methanesulfonic acid and Phenylsulfonic acid; And the acidic amino acid such as aspartic acid, L-glutamic acid.
Pyrido of the present invention (4,3-d) pyrimidine-1(2H) derivative and the Sibutramine Hydrochloride of the prior art of-Ji phenyl-acetamides is for compared with Buddhist nun, and tool has the following advantages:
(1) better efficacy of derivative of the present invention, it can increase the transformation period of medicine greatly, the time that prolong drug is detained at human body Inner, improves the concentration of blood Chinese traditional medicine simultaneously, thereby reaches better curative effect.
(2) the drug use dosage of derivative of the present invention is less, thereby can eliminate the bad metabolic problems of medicine, because the transformation period of medicine greatly increases and makes medicine can keep for more time active concentration in blood, make under the treatment condition that has dose limitation, the using dosage that can reduce medicine in keeping curative effect, reduces drug toxicity.
(3) toxicity of derivative of the present invention, side effect are still less, the active metabolite producing by bad metabolic reaction due to medicine normally medicine produces the important factor of toxicity and other side effects, eliminate the bad metabolic problems of medicine, greatly reduced toxicity and other side effects of medicine.
Embodiment
By specific embodiment, the specific embodiment of the present invention is described in further detail below.
Embodiment 1
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1,1,1-d3.
Synthetic reduction and 2 steps of acetylize of comprising of derivative of the present invention:
Preparation process is as follows:
(1) reduction step
Preparation [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6,8-dimethyl-1-(3-aminophenyl)-pyrido [4,3-d] pyrimidine-2,4,7 (1H, 3H, 6H)-triketone 1-2, reaction equation is as follows:
Under anhydrous and oxygen-free argon shield; in dry three-necked flask, add [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6 of 3.78 grams; 8-dimethyl-1-(3-nitrophenyl)-pyrido [4; 3-d] pyrimidine-2; 4; the methylene dichloride of 7 (1H, 3H, 6H)-triketone 1-1 and 40ml.Under stirring at room temperature, add the sodium bisulfite of 3.27 grams and the water of 2 milliliters, stirring reaction 3-5 hour, temperature of reaction 80-95 ℃, then adds the water of 120 milliliters.Precipitation, separates, and washing can obtain [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6,8-dimethyl-1-(3-aminophenyl)-pyrido [4,3-d] pyrimidine-2,4,7 (1H, 3H, 6H)-triketone 1-2.
(2) acetylize step
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1,1,1-d3.
Under anhydrous and oxygen-free argon shield; in dry flask, incite somebody to action [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6; 8-dimethyl-1-(3-aminophenyl)-pyrido [4; 3-d] pyrimidine-2,4,7 (1H; 3H; 6H)-triketone 1-2 is suspended in pyridine and trichloromethane, adds acetic acid-d3 acid anhydride, stirring reaction 1-3 hour under stirring at room temperature.With the hydrochloric acid soln cancellation reaction of 1 volumetric molar concentration, then add trichloromethane.Organic phase is used respectively saturated common salt water washing.Anhydrous sodium sulfate drying.Filter, concentrated.Thick product obtains the fluoro-4-iodophenyl of target product N-[3-[3-cyclopropyl-5-[(2-through purification by silica gel column chromatography) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1,1,1-d3.[the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6,8-dimethyl-1-(3-aminophenyl)-pyrido [4,3-d] pyrimidine-2,4, the mole ratio of 7 (1H, 3H, 6H)-triketone 1-2 and acetic acid-d3 acid anhydride is 1 ︰ 1-1.2.1 molar [the fluoro-4-iodophenyl of 3-cyclopropyl-5-[(2-) amino]-6,8-dimethyl-1-(3-aminophenyl)-pyrido [4,3-d] pyrimidine-2,4,7 (1H, 3H, 6H)-triketone 1-2 uses hydrochloric acid, the trichloromethane of 5-10L and the saturated aqueous common salt of 10-40L of 1 volumetric molar concentration of pyridine, the 20-40L of 2-5L.
Embodiment 2
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1-d1.
Preparation method, with embodiment 1, replaces with acetic acid-d2 acid anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Embodiment 3
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl) ethanamide-1,1-d2.
Preparation method, with embodiment 1, replaces with acetic acid-d1 acid anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Embodiment 4
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl)-1,1,1-trifluoroacetamide.
Preparation method, with embodiment 1, replaces with 1,1,1-trifluoro-acetic anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Embodiment 5
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl)-1,1-bis-monofluoroacetamides.
Preparation method, with embodiment 1, replaces with 1,1-difluoro acetic anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Embodiment 6
The fluoro-4-iodophenyl of preparation N-[3-[3-cyclopropyl-5-[(2-) amino]-3,4,6,7-tetrahydrochysene-6,8-dimethyl-2,4,7-, tri-oxygen-pyrido [4,3-d] pyrimidine-1(2H)-yl } phenyl)-1-monofluoroacetamide.
Preparation method, with embodiment 1, replaces with 1-fluorine acetic anhydride by the acetic acid-d3 acid anhydride in embodiment 1.
Here description of the invention and application is illustrative, not wants scope of the present invention to limit in the above-described embodiments, and therefore, the present invention is not subject to the restriction of the present embodiment, and the technical scheme that any employing equivalence replacement obtains is all in the scope of protection of the invention.
Claims (6)
1. pyrido (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that thering is the following chemical structure general formula:
R in formula
1, R
2, R
3be hydrogen or deuterium or fluorine independently, wherein have one at least for deuterium or fluorine.
2. pyrido as claimed in claim 1 (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that R
1, R
2, R
3in one or several is fluorine.
3. pyrido as claimed in claim 2 (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that R
1, R
2, R
3be fluorine.
4. pyrido as claimed in claim 1 (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that R
1, R
2, R
3in one or several is deuterium.
5. pyrido as claimed in claim 4 (4,3-d) pyrimidine-1(2H) derivative of-Ji phenyl-acetamides, it is characterized in that R
1, R
2, R
3be deuterium.
6. the pyrido (4 as described in any one in claim 1-5,3-d) pyrimidine-1(2H) application of derivative of-Ji phenyl-acetamides, it is characterized in that the application of described derivative in the medicine of preparation treatment metastasis melanin tumor and melanoma disease that can not row operative treatment.
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|---|---|---|---|---|
| CN109320513A (en) * | 2018-11-09 | 2019-02-12 | 安庆奇创药业有限公司 | A method of synthesis Trimetinib |
| EP4087868A4 (en) * | 2020-01-08 | 2024-03-20 | Icahn School of Medicine at Mount Sinai | Small molecule modulators ksr-bound mek |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012088033A2 (en) * | 2010-12-20 | 2012-06-28 | Glaxosmithkline Llc | Novel pharmaceutical composition |
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2013
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012088033A2 (en) * | 2010-12-20 | 2012-06-28 | Glaxosmithkline Llc | Novel pharmaceutical composition |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109320513A (en) * | 2018-11-09 | 2019-02-12 | 安庆奇创药业有限公司 | A method of synthesis Trimetinib |
| CN109320513B (en) * | 2018-11-09 | 2021-03-16 | 安庆奇创药业有限公司 | Method for synthesizing trametinib |
| EP4087868A4 (en) * | 2020-01-08 | 2024-03-20 | Icahn School of Medicine at Mount Sinai | Small molecule modulators ksr-bound mek |
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