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CN103703011A - Platinum type compound with leaving group being hydroxy acid derivative containing amino group or alkyl amino, and preparation method and use thereof - Google Patents

Platinum type compound with leaving group being hydroxy acid derivative containing amino group or alkyl amino, and preparation method and use thereof Download PDF

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CN103703011A
CN103703011A CN201280023132.5A CN201280023132A CN103703011A CN 103703011 A CN103703011 A CN 103703011A CN 201280023132 A CN201280023132 A CN 201280023132A CN 103703011 A CN103703011 A CN 103703011A
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protective embankment
platinum
compound
cis
base
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CN103703011B (en
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陈小平
高泽军
孟小平
温守明
阎亚矢
赵锋
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Beijing Shuobai Pharmaceutical Technology Co.,Ltd.
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Beijing Shuobai Pharmaceutical Technology Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F15/00—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table
    • C07F15/0006—Compounds containing elements of Groups 8, 9, 10 or 18 of the Periodic Table compounds of the platinum group
    • C07F15/0086—Platinum compounds
    • C07F15/0093—Platinum compounds without a metal-carbon linkage
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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Abstract

Disclosed are a platinum type compound with leaving group being hydroxy acid derivative containing amino group or alkyl amino, pharmaceutically acceptable salt thereof, preparation method thereof and pharmaceutical composition containing the compound. Also disclosed are uses of the compound in treating cell proliferation diseases, especially in treating cancer. The platinum type compound of the present invention has high solubility in water and low toxicity and side effects.

Description

Platinum type compound with leaving group being hydroxy acid derivative containing amino group or alkyl amino, and preparation method and use thereof
The class leaving group of specification one is the platinum-like compounds of hydroxy-acid derivative containing amino or alkylamino and its preparation method and application technical field
The present invention relates to a kind of platinum-like compounds of suppressing cell reproduction disease, a more particularly to class leaving group contains amino, the platinum-like compounds of the hydroxy-acid derivative of alkylamino, preparation method and applications.Background technology
Cancer（Malignant tumour）It is one of topmost disease of current threat human life.The morbidity and mortality of tumour steeply rise in recent years, the tumor development trend that the World Health Organization once disclosed shows, the annual tumor patient newly made a definite diagnosis in the whole world is more than 10,000,000 since 1996, 40,000,000 people are exceeded to the end of the year 1999 global tumor patient sum, the whole world there are about 7,000,000 people and dies from various tumours every year, world's tumor incidences in 2001 and the death rate rise 22% than nineteen ninety, it is the 2nd big cause of the death for being only second to cardiovascular and cerebrovascular disease, most common cancer is lung cancer, breast cancer, colorectal cancer, stomach cancer, liver cancer, cervical carcinoma, cancer of the esophagus and carcinoma of urinary bladder.Tenth national Clinical Oncology conference is announced the authoritative survey datas such as the incidence and the death rate of the every tumour of China in 2006 and shown, 2,120,000 newly-increased tumor patients are there are about every year.In mortality of malignant tumors, lung cancer row malignant tumour first.Expert, it is expected that to the year two thousand twenty, year death toll will be more than 4,000,000；By 2025, tumour was by the first big cause of disease as global death toll.
Clinical treatment tumour mainly has operation, three kinds of approach of radiotherapy and chemotherapy, and antineoplastic is to apply most common therapeutic modality, and the global antineoplastic market sales revenue is 48,000,000,000 dollars within 2008.Clinically antineoplastic is broadly divided into several major classes such as protective embankment agent, antimetabolite, metal platinum class, plant alkaloid and other crude drugs, cytotoxin class antibiotic at present.Platinum antineoplastic medicine is the most important antineoplastic of a class, is the antineoplastic developed first 1960s.Important difference with traditional cell toxicant series antineoplastic medicament is that its mechanism of action is unique, and antineoplastic selectivity is good.Its main function target spot is DNA, is interlinked between DNA and in chain, forms platinum complex DNA compounds, disturbs DNA replication dna, or is combined with nucleoprotein and plasmosin, belongs to cycle non-specific medicine.Successfully develop CDDP i.e. cis-platinum in succession
(Cisplatin), cis-ammino platinum of 1,1- ring fourth protective embankments carboxylic acid two is carboplatin (Carboplatin), 254-S i.e. Nedaplatin（Nedaplatin), oxalic acid-(trans-L-1,2-l, 2- cyclohexanediamine）It is oxaliplatin to close platinum
(Oxal iplatin), cis-[double (the aminomethyl) -2- isopropyls 1 of (4R, 5R) -4,5-, 3- dioxanes] (bidentate）Platinum is Eptaplatin (Sunpla) and 1, it is lobaplatin (Lobaplatin) etc. that 2 diaminomethyls-ring fourth protective embankment-lactic acid, which closes platinum, platinum antineoplastic medical instrument has the features such as Antitumor test is wide, effect is strong, and platinum antineoplastic medicine also has good synergy with other antineoplastics, not only increase the inhibiting rate to existing tumour, and Antitumor test is expanded, thus consolidate status of the platinum antineoplastic medicine in clinical treatment.Nineteen ninety-five WHO carries out ranking to hundreds of antineoplastic, and cis-platinum is in terms of curative effect and market Specification overall merit is located at second.There is statistics to show, there are 70 % 80% based on platinum in all chemotherapy regimens of China or there is platinum medicine to participate in compatibility.
But it is larger that current platinum series antineoplastic medicament has toxicity, such as bone marrow suppression, Toxicity of Kidney, neurotrosis, solubility is bad, anticancer spectrum relative narrower and the shortcomings of drug resistance.Therefore, the platinum series antineoplastic medicament of design and synthesizing new is still one of the Main way of present anticarcinogen research (M A Jakuper, M. Galanski, B. K. Keppler. Tumour-inhibiting platinum complexes-state of art and future perspect ives, Rev. Physiol Biochem Pharmacol, 2003,146,1-53).
It is within nearly 2 years to reduce the toxic side effect of platinum-based chemotherapy medicine, improve curative effect, reduce tumor recurrence and avoid drug-fast generation, and improves the water solubility of platinum-like compounds, people has carried out substantial amounts of research.The solubility of such as cis-platinum is 2. 65mg/ml, and the solubility of the husky sharp platinum of later Austria is 7. 9mg/ml, and the solubility of Nedaplatin is 8mg/ml, and the solubility of carboplatin is 17. 8mg/ ml, the solubility of minoplatin is 27 1, and the toxic side effect of oxaliplatin and carboplatin etc. is compared with cis-platinum and decreased, between unfortunately the solubility of the so-called water-soluble platinum-like compounds of the above is still within slightly soluble or is slightly molten.Murray A. Plan etc. are prepared for the sodium alkoxide of platinum-like compounds, and solubility (US4322362A) is effectively improved in vitro, but its compound must could dissolve under conditions of more than pHIO, and toxicity problem is not also solved effectively.Giulia C etc. are also prepared for a series of platinum compounds, however the solubility of these compounds be also the failure to be improved significantly（Chem Med Chem, 2009, 4 (10) , 1677-1685).W02006091790A1 also discloses that a series of platinum compounds with specific structure, but equally fail solution solubility and toxicity problem.The content of the invention
It is used to treat proliferative diseases the invention provides a class, leaving group particularly in compound structure contains amino, the platinum-like compounds of the hydroxy-acid derivative of protective embankment amino, its pharmaceutically acceptable salt, solvate, stereoisomer or its pro-drug, compared with the antitumor platinum class of prior art, its inside and outside antitumor action is strong, solubility has great improvement, toxic side effect is substantially reduced, and generates unexpected technique effect.The structure of such compound is as shown in formula A：
Specification is wherein：R includes but is not limited to hydrogen, alkyl, cycloalkyl, alkoxy and washed base, protective embankment amino protective embankment base, heterocycle, alkenyl, alkynyl group, above alkyl, protective embankment epoxide protective embankment base, protective embankment amino protective embankment base and heterocycle can be unsubstituted, it can also be optionally substituted, preferably by halogen, hydroxyl, protective embankment epoxide, protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, protective embankment amino, amino, heterocyclic substituted.
R.There may be, can also be not present, work as R.In the presence of, the compounds of this invention is quaternary ammonium salt, it is necessary to have corresponding anion to exist simultaneously.Work as R.In the absence of when, the compounds of this invention be tertiary amine, secondary amine or primary amino-compound；Work as R.In the presence of, R.Protective embankment base, ring protective embankment base, alkoxyalkyl, protective embankment amino protective embankment base, heterocycle, alkenyl, alkynyl group can be but not limited to, above alkyl, alkoxy protective embankment base, alkylamino protective embankment base and heterocycle can be unsubstituted, it can also be optionally substituted, preferably by halogen, hydroxyl, protective embankment epoxide, protective embankment base, protective embankment epoxide alkyl, cycloalkyl, protective embankment amino, amino, heterocyclic substituted；^ and can be with identical or different, including but not limited to hydrogen, protective embankment base, ring protective embankment base, alkoxy protective embankment base, alkylamino protective embankment base, heterocycle, alkenyl, alkynyl group, above alkyl, protective embankment epoxide protective embankment base, protective embankment amino protective embankment base and heterocycle can be unsubstituted, it can also be optionally substituted, it is preferred that by halogen, hydroxyl, protective embankment epoxide, protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, protective embankment amino, amino, heterocyclic substituted, condition be no matter R.It whether there is, R.Or in if containing unsaturated bond, the atom of the unsaturated bond can not be joined directly together with nitrogen-atoms；
！^ and and its nitrogen-atoms that is connected can also form the saturation or unsaturated heterocycle of closure together, for example can be ternary, quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring, above ring can also be condensed optionally with other rings, and optionally it can be replaced by halogen, hydroxyl, protective embankment epoxide, protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, heterocycle, aryl, condition is that what is be connected with the nitrogen-atoms must be the carbon atom of saturation；
It can be but not limited to：Protective embankment base, cycloalkyl ,-R31-0-R32-, R31And R32Independently selected from key or alkyl, R31It is to be connected with the nitrogen-atoms in formula, condition is R31Such as contain unsaturated bond, the atom of unsaturated bond directly can not be connected with above-mentioned nitrogen-atoms;Protective embankment base or ring protective embankment base described above can be unsubstituted, can also be optionally substituted, preferably by halogen, hydroxyl, alkoxy, protective embankment base, the substitution such as protective embankment epoxide protective embankment base, ring protective embankment base, protective embankment amino, amino, heterocycle；
R3The atom being connected with R and its jointly can also form the saturation or unsaturation ring of closure together, for example can be ternary, quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring, above ring can also be condensed optionally with other rings, and optionally it can be replaced by halogen, hydroxyl, protective embankment epoxide, protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, heterocycle, aryl, the carbon atom that condition is connected in being with nitrogen-atoms must be the carbon atom of saturation；
！^ and it be able to can be but not limited to identical or different：Hydrogen, hydroxyl, protective embankment base, ring protective embankment base, protective embankment epoxide, protective embankment epoxide protective embankment base, heterocycle, alkenyl, alkynyl group, above protective embankment base, alkenyl, alkynyl group, ring protective embankment base, protective embankment epoxide protective embankment base, protective embankment amino protective embankment base and heterocycle can be unsubstituted, it can also be optionally substituted, it is preferred that by halogen, hydroxyl, protective embankment epoxide, straight or branched protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, protective embankment amino, amino, heterocyclic substituted；
With and its atom that is connected can also form the ring of closure together, for example can be quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring, above ring can also be condensed optionally with other rings, and can be optionally substituted.
Preferably, R is selected from oxygen, d-8Alkyl, cycloalkyl； R.And selected from hydrogen, d-8Alkyl, ring protective embankment base, protective embankment epoxide alkane Specification base, amino, alkyl amino alkyl, heterocycle；It can be but not limited to：D protective embankments base, cycloalkyl；With selected from hydrogen, hydroxyl, d-8Protective embankment base, ring protective embankment base, protective embankment epoxide, protective embankment epoxide protective embankment base, heterocycle.
R6Can be key or-CRaRb-;
Work as R6During for key, it has structure shown in formula A1：
Work as R6For-CRb- when, RaAnd RbCan be with identical or different, independently selected from key, hydrogen, saturation or unsaturated alkyl, and with and its atom that is connected can also together with form the saturation or unsaturation ring of closure, for example can be ternary, quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring, above ring can also be condensed optionally with other rings, and optionally it can be replaced by halogen, hydroxyl, protective embankment epoxide, alkyl, protective embankment epoxide alkyl, ring protective embankment base, heterocycle, aryl, the carbon atom that condition is connected in being with nitrogen-atoms must be the carbon atom of saturation.
It is highly preferred that the present invention is provided
Wherein n=0,1, R.、 R2 、 R3As described above.
Most preferably, R.For methyl, ethyl, propyl group or butyl, R and be hydrogen, methyl, ethyl, propyl group or butyl,！^ and its atom connected can also form the ring of closure, most preferably five yuan, hexatomic ring, i.e. nafoxidine base or piperidyl together；For-(CH2) 2- or-(CH2) 3- or-(CH2) 4- or-(CH2) 5- or-(CH2) 6 -。
Hai Jin mono- Walk of the present invention provide formula C compounds and its pharmaceutically-acceptable salts, i.e., with and its atom that is connected form the compound obtained during the ring of closure together, structural formula is as follows： Specification
(C) wherein, R, R., be selected from it is upper described, W is preferably but not limited to:
And above structure optionally can also be connected by various suitable substituents.
Formula（C platinum compounds), can be but not limited to（C¾)n, wherein n=0-3, preferably n=0-2, some of which-C-can be replaced by -0-,（CH2).One or more hydrogen can be replaced by halogen, protective embankment base, hydroxyl, hydroxyl protective embankment base or protective embankment epoxide etc..
With can be but not limited to：Hydrogen, halogen, hydroxyl, hydroxyl protective embankment base, protective embankment alkyl, protective embankment epoxide, heterocycle etc., and can be with identical or different, preferred methylol（F).
.It can be but not limited to Ru：Hydrogen, halogen, hydroxyl protective embankment base, alkyl, protective embankment epoxide, heterocycle etc.,.Can be with identical or different with Ru, preferred methylol.
R12It can be but not limited to（CH2) n, wherein n=2-4, some of which-CH2- can be replaced by -0-,（C¾)nOne or more hydrogen can be replaced by halogen, alkyl, hydroxyl or alkoxy etc..
R13Can be-C-or -0-, preferably-C -.
R14Can be hydrogen, halogen, protective embankment base, alkoxy, hydroxyl protective embankment base or hydroxyl, R14It is preferred that hydrogen.
R15(CH can be but not limited to2) n, whereinn=l- 3,-C -0- or -0-, (CH2) one or more hydrogen can be replaced by protective embankment base, protective embankment epoxide, hydroxyl or hydroxyl protective embankment base etc., preferably-c-o-c-.
R16It can be but not limited to（C¾)n, wherein n=l-6, preferably 3-5, most preferably 4, some of which-C-can be replaced by -0-.（C¾).One or more hydrogen can be replaced by halogen, protective embankment base, hydroxyl or protective embankment epoxide etc., compound preferably is（Scholar）Trans 1,2- oneself, penta, fourth and propane diamine close platinum（11).
It is preferred that compound structure it is as follows：
Specification
(H)
The most preferred compound of the present invention includes：
Compound 1:2- (2- methylamino second protective embankment bases）The cis two amminos platinum of -3- hydroxy-propionic acids（II) phosphate；Compound 2:2- (3- dimethylaminos the third protective embankment bases）The cis two amminos platinum of -3- hydroxy-propionic acids（II) acetate；Compound 3:2- (3- aminopropan protective embankment bases）The cis two amminos platinum of -3- hydroxy-propionic acids（II) phosphate；
Compound 4:2- (2- triithylamine base second protective embankment bases）The cis two amminos platinum of -3- hydroxy-propionic acids（II) mesylate；Compound 5:2- (5- (1- piperidyls）- penta protective embankment base）The cis two amminos platinum of -3- hydroxy-propionic acids（II) phosphate compounds 6:2- (6- (1- nafoxidine protective embankment bases）- own protective embankment base）The cis two amminos platinum of -3- hydroxy-propionic acids（II) phosphate cpd 7:2- (3- dimethylaminos the third protective embankment bases）- 3- hydroxy-propionic acids are cis-(1,2- trans-cyclohexanediamine）Close platinum (II) phosphate；
Compound 8:2- (3- dimethylamino propyls）- glycolic is cis-(1,2- trans-cyclohexanediamine）Close platinum（II) phosphate；
Compound 9:2- (2- ethylamino second protective embankment bases）- lactic acid is cis-(1,2- trans-cyclohexanediamine）Close platinum（II) phosphate;Compound 10:2- (3- (1- piperidyls）- the third protective embankment base）- glycolic * is cis-(1,2- trans-cyclohexanediamines）Close platinum（II) citrate
Compound 11:2- (3- lignocaines the third protective embankment bases）- 3- hydroxy-propionic acids are cis-(1,2- trans-ring pentanediamine）Close platinum (II) phosphate;
Compound 12:2- (3- dimethylamino propyls）- glycolic * is cis-and 1,2- ethylenediamines close platinum（II) p-methyl benzenesulfonic acid Specification compound 13:2- (2- lignocaine second protective embankment bases）- 3- hydroxy-propionic acids are cis-and 1,3- propane diamine closes platinum（II) phosphate cpd 14:2- (n-propylamine base the third protective embankment bases of 3- bis-）Cis -1,4- the dibutyl amine of -3- hydroxy-propionic acids closes platinum（II) phosphate；
Compound 15:2- (2- dimethylamino second protective embankment bases）- 3- hydroxy-propionic acids are cis -1,3- (2,2- methylols）- propane diamine closes platinum（II) phosphate；
Compound 16:2- (2- dimethylamino second protective embankment bases）- 3- hydroxy-propionic acids cis-Isosorbide-5-Nitrae-(trans -2,3- cyclobutyl）- butylamine closes platinum（Π) phosphate；
Compound 17:2- (2- lignocaine second protective embankment bases）- 3- hydroxy-propionic acids are cis -1,3- (2,2- (4- oxacyclohexyls））- propane diamine closes platinum（Π) Rocky hydrochlorates；
Compound 18:2- propyl group -2- (the dibutylamino fourth protective embankment bases of 4- propyl group -4）The cis ammonia cyclopentamine of -2- glycolics closes platinum phosphate；
Compound 19:2- butyl -2- (2- methyl -2- diamyl ammonia ethyl groups）Cis two cyclopentamine of -2- glycolics closes platinum phosphate cpd 20:2- amyl groups -2- (the own amino second protective embankment bases of 2- ethyls -2- two）The cis ammonia cyclohexylamine of -2- glycolics closes platinum phosphate；
Compound 21:2- methoxyl groups -2- (3- methyl -3- fourth aminopropan protective embankment bases）The cis dicyclohexyl amine of -2- glycolics closes platinum phosphate；
Compound 22:2- methoxies -2- (the aminopentane bases of 5- dimethyl -5- penta）The cis cyclopentamine * cyclohexylamine of -2- glycolics closes platinum Rocky hydrochlorates；
Compound 23:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis methylamine cyclopentamine of -2- glycolics closes platinum phosphate；
Compound 24:2- cyclohexyl -2- (2- dimethylamino second protective embankment bases）The cis methylamine ethamine of -2- glycolics closes platinum phosphate;Compound 25:2- cyclopenta -2- (dimethylaminos-first protective embankment base）The cis two amminos platinum phosphate of-glycolic；Compound 26:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis diamylamine of-glycolic closes platinum phosphate cpd 27:2- cyclohexyl -2- (2- dimethylamino second protective embankment bases）The cis dihexylamine of-glycolic closes platinum phosphate；Compound 28:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）- glycolic * cis two-(3- methoxyl group cyclopentamines）Close platinum phosphate；
Compound 29:2- propyl group -2- (the protective embankment bases of 5- dimethyl-own amino penta）- glycolic * cis two-(4- methoxycyclohexyl amine）Close platinum phosphate； Specification compound 30:2- propyl group -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis ammonia of-glycolic（4- methoxy cyclohexylamine）Close platinum Rocky hydrochlorates；
Compound 31:2- (2,4- dicyclopentenyls）- 2- (the own aminoethane bases of 2- ethyls -2- two）The cis ammonia * cyclohexylamine of-glycolic closes platinum phosphate；
Compound 32:2- (3- chloropropyls）- 2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis ammonia methoxycyclohexyl amine of-glycolic closes platinum phosphate；
Compound 33:The cis diamylamine of 2- butyl -2- (2- diamyl amino second protective embankments base) -3- hydroxy-propionic acids closes platinum and seen hydrochlorate；Compound 34:2- amyl groups -2- (the own aminoethane bases of 2- bis-）The cis ammonia cyclohexylamine of -3- hydroxy-propionic acids closes platinum phosphate cpd 35:2- methoxyl groups -2- (3- methyl -3- fourth aminopropan protective embankment bases）The cis dihexylamine of -3- hydroxy-propionic acids closes platinum phosphate；
Compound 36:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis diamylamine of -3- hydroxy-propionic acids closes platinum phosphate；
Compound 37:2- cyclohexyl -2- (2- dimethylamino second protective embankment bases）The cis dihexylamine of -3- hydroxy-propionic acids closes platinum phosphate;Compound 38:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- methyl -5-）- 3- hydroxy-propionic acids cis two-(3- hydroxycyclopent amine）Close platinum phosphate；
Compound 39:2- propyl group -2- (the own protective embankment bases of amino penta of 5- methyl -5-）- 3- hydroxy-propionic acids cis two-(4- methoxycyclohexyl amine）Close platinum phosphate；
Compound 40:2- (2,4- cinene）- 2- (the own aminoethane bases of 2- bis-）The cis ammonia cyclohexylamine of -3- hydroxy-propionic acids closes platinum phosphate；
Compound 41:2- (2- chloroethyls）- 2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis ammonia of -3- hydroxy-propionic acids（4- methoxycyclohexyl amine）Close platinum phosphate；
Compound 42:2- (2- methyl -3- diethylamino basic ring fourth protective embankment bases）The cis cyclopentamine nafoxidine of-glycolic closes platinum phosphate；
Compound 43:2- (2- methyl -3- diethylamino basic ring fourth protective embankment bases）The cis two amminos platinum phosphate of-glycolic；Compound 44:2- (3- dimethylamino -1,1- cyclobutyl）- glycolic cis trans -1,2- cyclohexanediamine closes platinum phosphate cpd 45:2- (2- methyl -3- lignocaine -1,1- cyclobutyl）- glycolic cis trans -1,2- cyclohexanediamine closes platinum phosphate；
Compound 46:4- piperidyl -1- hydroxyl -2- carboxylic acid cis trans -1,2- cyclohexanediamine closes platinum phosphate；Compound 47:4- (4 hydrogen piperidyls）- 1- hydroxyl -2- carboxylic acid cis trans -1,2- cyclohexanediamine closes platinum phosphate； Specification compound 48:4- dimethylamino -1- hydroxyl -2- carboxylic acid cis trans -1,2- cyclohexanediamine closes platinum phosphate；Compound 49:4- triithylamine base -1- hydroxyl -2- carboxylic acid cis trans -1,2- cyclohexanediamine closes platinum Rocky hydrochlorates.Following definition for being classified as the various terms for describing the present invention.In addition to limiting under special circumstances, following term is useful in entire disclosure and claim and used（Individually or as a part for big group）.
Term " protective embankment base " refers to the saturation univalence hydrocarbyl of straight or branched, specifically, protective embankment base be with 1-20 ((-2。)、 1-15 (( -15)、 1-10 ((： )、 l-7 (d-7) or 1-4 (CH) individual carbon atom straight chain saturation univalence hydrocarbyl, or 3-20 (C3-2.）、 3- 15 (C3— 15) , 3- 10 (C3— 3-7 ( C3— 7) or (C of 3- 43— 4) individual carbon atom side chain saturation univalence hydrocarbyl.The example of protective embankment base includes but is not limited to methyl, ethyl, n-propyl, isopropyl, normal-butyl, isobutyl group, sec-butyl, the tert-butyl group, amyl group (including all isomeric forms）, hexyl (including all isomeric forms）, heptyl (including all isomeric forms）, octyl group (including all isomeric forms）, nonyl (including all isomeric forms）, decyl (including all isomeric forms）, 11 protective embankment bases (including all isomeric forms）, 12 protective embankment bases (including all isomeric forms）, 13 protective embankment bases (including all isomeric forms）, myristyl (including all isomeric forms）, 15 protective embankment bases (including all isomeric forms）, 16 protective embankment bases (including all isomeric forms）, 17 protective embankment bases (including all isomeric forms）, octadecyl (including all isomeric forms）, 19 protective embankment bases (including all isomeric forms) and 20 protective embankment bases (including all isomeric forms）.For example,（ -7Institute's base refers to the saturation univalence hydrocarbyl of the saturation univalence hydrocarbyl of the straight chain of 1-7 carbon atom or the side chain of 3-7 carbon atom.
" protective embankment base " can optionally by one, two, three or four substituents replace：Such as halogen, trifluoromethyl, trifluoromethoxy, hydroxyl, protective embankment epoxide, ring protective embankment epoxide, heterocyclic oxy group, oxo, chain protective embankment acyl group, aryloxy group, chain protective embankment acyloxy, amino, protective embankment amino, arylamino, aryl alkyl amino, ring protective embankment base amino, heterocyclic amino group, the tertiary ammonia of substitution, (wherein 2 nitrogen substituents are selected from protective embankment base, aryl or fragrant protective embankment base）, chain protective embankment acyl amino, aroylamino, fragrant alkanoylamino, substitution chain protective embankment acyl amino, substitution fragrant amino, the fragrant alkanoyl of substitution, thiol base, protective embankment base sulfenyl, artyl sulfo, aromatic alkyl sulfurio, ring protective embankment base sulfenyl, heterocyclethio, protective embankment base thiocarbonyl group, arylthiono, aralkyl thiocarbonyl group, protective embankment base sulfonyl, aryl sulfonyl, arylalkyl sulfonyl, sulfonamido（Such as S02NH2), substitution sulfonamido, nitro, cyano group, carboxyl, carbamyl (such as C0N), substitution carbamyl（For example the fragrant protective embankment base of C0NH protective embankments base, C0NH aryl, C0NH or in the case of there are two substituents on nitrogen selected from protective embankment base, aryl or fragrant protective embankment base）, protective embankment Epoxide carbonyl, aryl, substituted aryl, guanidine radicals and heterocyclic radical（Such as indyl, imidazole radicals, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridine radicals, pyrimidine radicals）.Above-mentioned substituent further can be replaced by halogen, alkyl, protective embankment epoxide, aryl or fragrant protective embankment base.
Term " alkoxy " refer to 1-20 (d-2.）、 1-15 (d—15)、 1-10 .）, 1-7 (^ -7) or 1-4 (d -4) individual carbon atom straight chain saturation univalence hydrocarbyl or the (C of 3- 203-2.）、 3- 15 (C3— 15), (C of 3- 103— 10)、 3-7 ( C3— 7) or (C of 3- 43— 4) individual carbon atom side chain saturation univalence hydrocarbyl and oxygen atom link after generation group.The example of alkoxy includes but is not limited to methoxyl group, ethyoxyl, propoxyl group, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy（Bag Specification includes all isomeric forms）, hexyloxy (including all isomeric forms）, epoxide in heptan (including all isomeric forms）, octyloxy (including all isomeric forms）, nonyl epoxide (including all isomeric forms）, decyloxy (including all isomeric forms）, 11 protective embankment epoxides (including all isomeric forms）, dodecyloxy (including all isomeric forms）, 13 protective embankment epoxides (including all isomeric forms）, tetradecyloxyaniline (including all isomeric forms）, pentadecane epoxide (including all isomeric forms）, 16 protective embankment epoxides (including all isomeric forms）, 17 protective embankment epoxides (including all isomeric forms）, 18 protective embankment epoxides (including all isomeric forms）, 19 protective embankment epoxides (including all isomeric forms) and 20 protective embankment epoxides (including all isomeric forms）.Term " protective embankment amino " refers to-^121 or 2 H respectively by with 1-10 ((：), the straight chain protective embankment base or 3-10 (C of 1-6 (d -6) or 1-4 (C^) individual carbon atom3-1())、 3-6 (C3-6) or 3-4 (C3—4) individual carbon atom side chain protective embankment base substitution group；When above-mentioned 2 H are simultaneously substituted, substituent can be with identical or different.The example of protective embankment amino includes but is not limited to methylamino,Dimethylamino,Ethylamino,Lignocaine,Third amino,Dipropyl amino,Isopropylamino,Diisopropylaminoethyl,N-butyl amine base,I-butylamino,Tertiary fourth amino,Two n-butyl amine bases,Two i-butylaminos,Two tertiary fourth amino,Penta amino,Diamyl amino,Own amino,Two own amino,Heptan amino,Two heptan amino,Pungent amino,Two pungent amino,Nonyl amino,Two nonyl amino,Last of the ten Heavenly stems amino,Didecyl amino,N- methyl-N-ethylaminos,N- methyl-N-propylaminos,N- methyl-N-isoproylaminos,N- methyl-N- butylaminos,N- methyl-N-isopropyl butylaminos,N- methyl-N- tert-butylaminos,N- methyl-N-pentylaminos,N- methyl-N- hexylaminos,N- methyl-N- heptyl amino,N- methyl-N-octyl amino,N- methyl-N- nonylaminos,N- methyl-N- Decylaminos,N- ethyl-N- propylcarbamics,N- ethyl-N-iso-propylaminos,N- ethyl-N- butylaminos,N- ethyl-N- isobutylaminos,N- ethyl-N- tert-butylaminos,N- ethyl-N- pentyl aminos,N- ethyl-N- hexylaminos,N- ethyl-N- heptyl amino,N- ethyl-N- octyl aminos,N- ethyl-N- nonylaminos,N- ethyl-N- Decylaminos,N- propyl group-N- isopropylaminos,N- propyl group-N- butylaminos,N- propyl group-N- isobutylaminos,N- propyl group-N- tert-butylaminos,N- propyl group-N- pentyl aminos,N- propyl group-N- hexylaminos,N- propyl group-N- heptyl amino,N- propyl group-N- octyl aminos,N- propyl group-N- nonylaminos,N- propyl group-N- Decylaminos,N- isopropyl-N- butylaminos,N- isopropyl-N- isobutylaminos,N- isopropyl-N- tert-butylaminos,N- isopropyl-N- pentyl aminos,N- isopropyl-N- hexylaminos,N- isopropyl-N- heptyl amino,N- isopropyl-N- octyl aminos,N- isopropyl-N- nonylaminos,N- isopropyl-N- Decylaminos,N- butyl-N- isobutylaminos,N- butyl-N- tert-butylaminos,N- butyl-N- pentyl aminos,N- butyl-N- hexylaminos,N- butyl-N- heptyl amino,N- butyl-N- octyl aminos,N- butyl-N- nonylaminos,N- butyl-N- Decylaminos,N- iso-butyl-N-tert-butyl amino,N- isobutyl group-N- pentyl aminos,N- isobutyl group-N- hexylaminos,N- isobutyl group-N- heptyl amino,N- isobutyl group-N- octyl aminos,N- isobutyl group-N- nonylaminos,N- isobutyl group-N- Decylaminos,N- tert-butyl-n-pentyl aminos,N- tert-butyl-n-hexylaminos,N- tert-butyl-n-heptyl amino,N- tert-butyl-n-octyl aminos,N- tert-butyl-n-nonylaminos,N- tert-butyl-n-Decylaminos,N- amyl group-N- hexylaminos,N- amyl group-N- heptyl amino,N- amyl group-N- octyl aminos,N- amyl group-N- nonylaminos,N- amyl group-N- Decylaminos,N- hexyl-N- heptyl amino,N- hexyl-N- octyl aminos,N- hexyl-N- nonylaminos,N- hexyl-N- Decylaminos,N- heptyl-N- octyl aminos,N- heptyl nonylaminos,N- heptyl Decylaminos,N- octyl group nonylaminos,N- octyl-decyl amino,N_ nonyls _ N_ Specification Decylamino, and above-mentioned amino all isomeric forms etc..
Term " halogen " or " halo " refer to fluorine, chlorine, bromine and iodine.
Term " alkyl " refers to the functional group containing only carbon, two kinds of atoms of hydrogen.
Term " aryl " refers to the monocyclic or Bicyclic alkyl for having 6-12 carbon atom in loop section, and such as phenyl, naphthyl, xenyl and diphenyl can be each substituted.
" aryl " optionally can be replaced by substituents：Such as protective embankment base, halogen, trifluoromethoxy, trifluoromethyl, hydroxyl, protective embankment epoxide, ring protective embankment epoxide, heterocyclic oxy group, chain protective embankment acyl group, chain protective embankment acyloxy, amino, protective embankment base amino, aryl alkyl amino, ring protective embankment base amino, heterocyclic amino group, dialkyl amido, alkanoylamino, thiol base, protective embankment base is thio, cycloalkylthio, heterocyclic thio, urea groups, nitro, cyano group, carboxyl, carboxyl protective embankment base, carbamoyl, alkoxy carbonyl, protective embankment base thiocarbonyl group, arylthiono, alkyl sulphonyl, sulfonamido, aryloxy group etc..The substituent further can be replaced by halogen, hydroxyl, protective embankment base, protective embankment epoxide or aryl.
Term " aralkyl " refers to the aryl directly combined by alkyl group, such as benzyl, phenethyl, phenylpropyl.
Term " alkenyl " refers to containing 2-20 carbon atom, it is preferred that 10 carbon atoms of 2-, most preferably 2-6 carbon atom, straight or branched hydrocarbyl group with one to four double bond, also include the group with " cis " and " trans " configuration, or, " E " and " Z " configuration, it will be appreciated by those skilled in the art that.
" alkenyl " optionally can be replaced by substituents, for example halogen, hydroxyl, protective embankment epoxide, alkanoyl.Chain protective embankment acyloxy, amino, protective embankment base amino, dialkyl amido, chain protective embankment acyl group amido, thiol base, thio protective embankment base, protective embankment base thiocarbonyl group, protective embankment base sulfonyl, sulfonamido, nitro, cyano group, carboxyl, carbamoyl, carbamoyl, guanidine radicals and the heterocyclic group of substitution, such as indyl, imidazole radicals, furyl, thienyl, thiazolyl, pyrroles's protective embankment base, pyridine radicals, pyrimidine radicals.
Term " alkynyl " or " alkynyl group " refer to containing 2-20 carbon atom, it is preferred that 2-10 carbon atom, most preferably 2-6 carbon atom, straight or branched hydrocarbyl group with one to four three key, also include the group with " cis " and " trans " configuration, or, " E " and " Z " configuration, it will be appreciated by those skilled in the art that.
" alkynyl " optionally can be replaced by substituents：Halogen, hydroxyl, protective embankment epoxide, chain protective embankment acyl group, chain protective embankment acyloxy, amino, protective embankment base amino, two protective embankment base amino, chain protective embankment acyl group amido, thiol base, alkylthio, protective embankment base sulphur treasure base, protective embankment base sulfonyl, sulfonamido, nitro, cyano group, carboxyl, carbamoyl, carbamoyl, guanidine radicals and the heterocyclic radical of substitution, such as imidazole radicals, furyl, thienyl, thiazolyl, pyrrolidinyl, pyridine radicals, pyrimidine radicals.
Term " ring protective embankment base " refer to preferably comprise 1-3 ring and each ring (can further with undersaturated C3 -C7It is carbocyclic fused）Optionally substituted, saturation cyclic hydrocarbon ring system containing 3-7 carbon.Exemplary group includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, cyclooctyl, cyclodecyl, the protective embankment base of ring 12 and Buddha's warrior attendant protective embankment base.Exemplary substituents include one or more protective embankment base groups as described above, or one or more protective embankment base substituents as described above. Specification term " heterocycle ", " heterocycle " and " heterocyclic radical " refer to optionally substituted, fully saturated or undersaturated, fragrant or nonaromatic cyclic group, for example, the ring is 4-7 unit monocycles, 7-11 membered bicyclics or 10-15 membered tricyclic systems, contain at least one hetero atom on the ring at least containing a carbon atom.Can have 1 on each ring containing heteroatomic heterocyclic group, 2,3 or 4 be selected from nitrogen-atoms, oxygen atom and sulphur atom hetero atom, wherein the nitrogen and sulfur heteroatom also can be optionally oxidized and nitrogen heteroatom is also optional quaternized.The heterocyclic group can be connected on any hetero atom or carbon atom.
Exemplary monocyclic heterocyclic group includes pyrroles's protective embankment base, pyrrole radicals, indyl, pyrazolyl, oxa- fourth ring group, pyrazolinyl, imidazole radicals, imidazolinyl, imidazoles protective embankment base, oxazolyl, oxazole protective embankment base, isoxazoline-3-yl, isoxazolyl, thiazolyl, thiadiazolyl group, thiazole protective embankment base, isothiazolyl, isothiazole protective embankment base, furyl, tetrahydrofuran base, thienyl, oxadiazolyl, piperidyl, piperazinyl, 2- oxopiperazinyls, 2- oxo-piperidine bases, 2- oxo pyrroles's protective embankment bases, 2- oxo azepines bases, azepines base, 4- piperidone bases, pyridine radicals, N- oxo-pyridinyls, pyrazinyl, pyrimidine radicals, pyridazinyl, tetrahydrochysene thiopyranyl, THP trtrahydropyranyl, morpholinyl, thiomorpholine base, thiomorpholine base sulfoxide, tetrahydrochysene thiopyranyl sulfone, thiomorpholine base sulfone, DOX base and tetrahydrochysene -1,1- dioxythiophene base, dioxane base, isothiazole protective embankment base, trimethylene sulfide base, thiiranes group, triazine radical and triazolyl etc..
Exemplary bicyclic heterocyclic group includes benzothiazolyl, benzoxazolyl, benzothienyl, quininuclidinyl, quinolyl, quinolyl-N-oxide, tetrahydro isoquinolyl, isoquinolyl, benzimidazolyl, benzopyranyl, indolizine base, benzofuranyl, chromone base, cumarin base, 1, 2- phthalazinyls, quinoxalinyl, Yin mutters base, pyrrolopyridinyl, furopyridyl (such as furans simultaneously [2, 3-c] pyridine radicals, furans simultaneously [3, 1-b] pyridine radicals or furans simultaneously [2, 3-b] pyridine radicals）, dihydro-iso indolyl, dihydroquinazoline base (such as 3,4- dihydro -4- oxo-quinazolinyls）, benzisothia oxazolyl, benzoisoxazole base, benzodiazine base, benzofuranyl, benzothiopyran derivative base, BTA base, benzopyrazoles base, dihydro benzo furyl, dihydrobenzo thienyl, thiochroman base, thiochroman base sulfone, dihydrobenzopyrans base, indolinyl, isochroman base, iso-dihydro-indole-group, 1, 5- phthalazinyls, 2, 3- phthalazinyls, 3, 4- (methylenedioxy) benzyls, purine radicals, pyridopyridine base, quinazolyl, tetrahydric quinoline group, thienofuran base, thienopyridine base, thienothiophene base etc..
In less heterocycle, such as epoxides and aziridine are also included within.
Term " hetero atom " includes oxygen, sulphur and nitrogen.
Term " pharmaceutically acceptable salt " includes the salt for the reactive compound that the specified substituent according to present on compound specifically described herein is prepared using the acid or alkali of relative nontoxic.When the compounds of this invention is containing acid functional group relatively, can by make this compound of neutral form with it is enough the need for alkali it is independent or contacted in suitable atent solvent and obtain base addition salts.The example of salt includes aluminium, ammonium, calcium, copper, ferric iron, ferrous iron, lithium, magnesium, manganese, bivalent manganese, potassium, sodium, zinc etc. as derived from pharmaceutically acceptable inorganic base.Salt includes the salt of primary, secondary and tertiary amine as derived from pharmaceutically acceptable organic base, and they include amine, cyclammonium, natural amine of substitution etc., such as arginine, glycine betaine, caffeine, choline, N, N'- dibenzyl-ethylenediamins, two Specification ethylamino, 2- DEAE diethylaminoethanols, DMAE, monoethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, gucosamine, aminoglucose, histidine, Kazakhstan amine (hydrabamine), isopropylamine, lysine, methylglucosamine, morpholine, piperazine, piperidines, polyamino resin, procaine, fast cry of certain animals, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), tromethamine etc..When the compounds of this invention is containing alkaline functional group relatively, can by make this compound of neutral form with it is enough the need for acid it is independent or contacted in suitable atent solvent and obtain acid-addition salts.The example of pharmaceutically acceptable acid-addition salts includes those salt by inorganic acids, and inorganic acid salt is such as nitrate, carbonate, bicarbonate, phosphate, hydrophosphate, dihydric phosphate, sulfate, disulfate, phosphite, hydrochloride, hydrobromate, hydriodate；The salt as derived from the organic acid of relative nontoxic, the organic acid is such as acetic acid, propionic acid, isobutyric acid, malonic acid, benzoic acid, butanedioic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzene sulfonic acid, p-methyl benzenesulfonic acid, citric acid, tartaric acid, methanesulfonic acid.Also include the salt of salt and organic acids of the amino acid such as arginine such as glucose ferment acid or galactonic acid etc..Preferably nitrate, carbonate, bicarbonate, phosphate, hydrophosphate, dihydric phosphate, sulfate, disulfate, phosphite, acetate, propionate, isobutyrate, malonate, benzoate, succinate, suberate, fumarate, mandelate, Phthalate, benzene sulfonate, tosilate, citrate, tartrate, mesylate, arginine salt, glucuronate or galactolipin hydrochlorate.
In some embodiments provided by the present invention, compound leaving group of the invention contains basic group, can prepare platinum using method well-known to those skilled in the art with acid into salt（Π) the salt of compound.With inorganic acid, such as nitric acid, carbonic acid, sulfuric acid or phosphoric acid etc. can also form corresponding salt.Adoptable acid includes organic acid, inorganic acid etc..For example, with rudimentary protective embankment base sulfonic acid, such as methanesulfonic acid, trifluoromethanesulfonic acid etc. can form mesylate, fluoroform sulphonate；With aryl sulfonic acid, such as benzene sulfonic acid or p-methyl benzenesulfonic acid can form tosilate, benzene sulfonate, camsilate；With organic carboxyl acid, such as acetic acid, fumaric acid, tartaric acid, oxalic acid, maleic acid, malic acid, butanedioic acid, lactic acid or citric acid etc. can form corresponding salt；With amino acid, such as glutamic acid or aspartic acid can form glutamate or aspartate.
The compound of the present invention can mutually be changed with the form of its salt by the conventional method in this area, for example can be by making salt and alkali or acid contacts again the compound of isolated free form in the usual way, can also be by the way that compound be added into acid or alkali again using the form of its isolated salt of conventional method.The difference of solubility of some physical properties of compound free form for example in polar solvent and various salt forms, but for the object of the invention, the compound of salt and parent fo has same antineoplastic effect.
In addition to salt form, the present invention provides the compound of prodrug ester-formin." prodrug " of compound specifically described herein is that those compounds that chemical change obtains the compounds of this invention easily occur under physiological environment.In addition, can be by with chemistry or biochemical method by pro-drug conversion being the compounds of this invention in ex vivo environment.For example, when being placed in the transdermal patch reservoir containing suitable enzyme or chemical reagent, prodrug can be slowly converted into the compounds of this invention.Prodrug is often pharmacology inert compound before active medicine is converted into, but such case is not necessarily.Generally by by be probably in medicine active part need functional group use " precursor group "（Defined below）Cover, formation (such as can be cracked by conversion under specific use condition）Discharge functional group so as to Specification obtains " precursor portions " of active medicine, obtains prodrug.Can be to precursor portions for example by hydrolysis, or (for example temperature changes by another agent (such as enzyme, light, acid or alkali) or physics or ambient parameter change）Or be catalyzed or induced exposed to physics or ambient parameter, carry out spontaneous cracking.Agent can be endogenic relative to use environment, for example, be present in and give the intracellular enzyme of prodrug or the sour environment of stomach, or can be provided by external source.
" precursor group " refers to medicine can be converted into a class blocking group of prodrug when being used to cover the functional group in active medicine and forming " precursor portions ".Precursor group is generally connected by the functional group of key and medicine, key cleavable under specific use condition.Therefore, precursor group is a part for precursor portions, and the precursor portions are cracked under specific use condition, discharges functional group.It is used as particular instance, formula-NH-C (0) CH3Amide precursor part include precursor group-C (0) CH3。
It is adapted to cover functional group in reactive compound well known in the art with a variety of precursor groups for obtaining prodrug and obtained precursor portions.It is changed into sulphonic acid ester, ester (such as acetic acid esters or maleate) or carbonate precursor part for example, hydroxy functional group can be covered, the precursor portions can be hydrolyzed in vivo, obtain hydroxyl.Amido functional group can be covered and be changed into acid amides, carbamate, imines, urea, phosphenyl, phosphoryl or sulfhydryl precursor portions, they can be hydrolyzed in vivo, obtain amino.Carboxyl can be covered as ester (including methyl, ethyl, oxy acid methyl neopentyl, silyl ester and thioester）, acid amides or hydrazides precursor portions, they can in vivo hydrolyze and obtain carboxyl.The present invention includes those esters and acyl group as known in the art for being used to change solubility or hydrolysis properties, for use as sustained release or prodrug formulation.The particular instance of suitable precursor group and their corresponding precursor portions will be apparent to those skilled in the art.
The some compounds of the present invention can be with nonsolvated forms and including hydrated form solvation form exist." solvate " refers to the compound that molecule or ions binding by solvent molecule and solute are formed.Solvent can be organic compound, inorganic compound or the mixture of the two.Some examples of solvent include but is not limited to methanol, DMF, tetrahydrofuran, dimethyl sulfoxide and water.In general, solvation form is equal to nonsolvated forms, and it is included in the scope of the present invention.The some compounds of the present invention can exist with polymorph or amorphous form.Generally, for it is contemplated by the invention that purposes, all physical form all sames and within the scope of the present invention.
The some compounds of the present invention have asymmetric carbon atom (rotophore) or double bond；Its racemic modification, diastereomer, geometric isomer, region isomer and single isomers (enantiomer of such as separation) are included in the scope of the invention.Can be with conventional method by these separations or asymmetric syntheses, so that isomers " optically-active is pure ", i.e., other isomers substantially free of it.For example, if necessary to the specific enantiomeric of the compounds of this invention, can be prepared by asymmetric syntheses, or by using chiral auxiliary derivatization, wherein obtained diastereoisomeric mixture is separated, then agent groups are cracked obtain it is pure the need for enantiomer.Or, when molecule contains basic functionality such as amino or acidic functionality such as carboxyl, the salt of asymmetric isomery is formed with appropriate optically active acid or alkali, then the diastereomer being consequently formed is split by fractional crystallization or chromatographic process well known in the art, then reclaims pure enantiomer.
The compounds of this invention can also contain the atom isotope of improper ratio in the one or more atoms for constituting the compound.Example Specification such as, can by compound radio isotope such as tritium (；), iodine-125 (1251) or carbon-14 (14C) mark.Regardless of whether with radioactivity, all isotope forms of the compounds of this invention are included in the scope of the invention.
Another object of the present invention is provide a kind of preparation method of aforesaid compound.
First, formula（A preparation method) is as follows：
( 1 )：Take potassium chloroplatinite to add water, at room temperature stirring and dissolving, take KI to be put into after being dissolved in water in above-mentioned chloroplatinous acid potassium solution, lucifuge, water bath condition are reacted under nitrogen charging；
( 2 )：R4 is taken to be added drop-wise to after being dissolved in water（1) in reaction solution, reacted under water bath condition；
( 3 )：Reaction solution is cooled to below room temperature, R is taken5NH2It is added drop-wise to after being dissolved in water（2) in reaction solution, water-bath has a large amount of yellow mercury oxides to generate, temperature in reaction solution is cooled into the following suction filtration of room temperature, washs, and obtains diiodo- diamines and closes platinum（Π ).
(4)：Take Ag2S0jP, which enters in water, to be stirred, and takes above-mentioned diiodo- diamines to close platinum（I I) put into reaction solution, add under water, nitrogen charging and reacted under lucifuge water bath condition, suction filtration obtains two water diamines and closes platinum（Π) sulfate.
( 5 )：Take hydroxyl acetoacetic ester, and Br-R3- Br is placed in flask, adds K2C03, TBAB stirring, heating response, suction filtration removes solid and simultaneously washs, merging filtrate, wash organic layer, dry, leavened solvent is steamed in decompression, collect it is leavened go out thing.
(6 )：Take 2- Br-R3- hydroxyl acetoacetic ester is placed in flask, adds anhydrous K2C03, and acetonitrile stirring.
Separately take-R.Add in reaction solution, heating response filters out insoluble matter.Work as R.In the absence of when, after filtrate is drained add organic solvent dissolving, the aqueous solution washing, organic layer dry, decompression extract solvent, obtain product, purify.Work as R.In the presence of, can and R.In the absence of when equally operated, but obtain product contain bromo element, finally need to remove using ion exchange by the way of, after can also filtrate be drained add water dissolving, the aqueous solution addition Ag20, insoluble matter is filtered out, pH to 9-11 is adjusted, is extracted with ethyl acetate, organic layer is dried, decompression extracts solvent, obtains product.
(7 )：Take（6) product is placed in flask, is added NaOH solution, is stirred at room temperature.
(8 )：Take（7) product, adjusts pH with acid solution, adds above-mentioned（4) product, heating response produces the non-quaternary ammonium eka-platinium compound of racemic of the present invention（Work as R.In the presence of, in step（6) if not passing through Ag in20 processing, now products therefrom needs are by by filling anion exchange resin（0H types）Post carries out ion-exchange treatment）.Products therefrom is when pH is 9-11 into base, solubility is smaller in water, it is soluble in the small molecular alcohol such as organic solvent such as methanol, ethanol, its ethanol solution can generate corresponding salt from different acid reactions, such as add appropriate chiral mandelic acid's solution, chiral mandelic acid's salt is obtained, crystallization is separated out, and homochiral product can be obtained through operating repeatedly；
(9 )：(8) product, which can add water, makes dissolving, by filling anion exchange resin after cooling（0H types）Post, be converted into other anionic radicals all replaced by hydroxyl obtained by quaternary ammonium hydroxide, add acid produce corresponding salt.
It is preferred that preparation method it is as follows： Specification
(1)：Take potassium chloroplatinite to add water, at room temperature stirring and dissolving, take KI to be put into after being dissolved in water in above-mentioned chloroplatinous acid potassium solution, N2Protection, notes lucifuge, and 30 ~ 60min is reacted under 40 ~ 60 °C of water-bath;
(2)：Take R4 H2It is added drop-wise to after being dissolved in water（1) in reaction solution, 30 ~ 60min is reacted under 40 ~ 60 °C of water-bath;
(3)：Reaction solution is cooled to less than 20 °C, R is taken5NH2It is added drop-wise to after being dissolved in water（2) in reaction solution, 30 60min are reacted under 40 ~ 60 °C of water-bath, there are a large amount of yellow mercury oxides to generate, temperature in reaction solution is cooled to less than 20 °C suction filtrations, washed successively with water, absolute ethyl alcohol, ether, diiodo- diamines is obtained and closes platinum（11).
(4)：Take Ag2S04Enter in water and stir, take above-mentioned diiodo- diamines to close platinum（II) in input reaction solution, water is added, is protected, react 4 ~ 8h under lucifuge in 40 ~ 60 °C, suction filtration obtains two water diamines and closes platinum（II) sulfate.
(5)：Take hydroxyl acetoacetic ester, and Br--Br to be placed in flask, add K2C03, TBAB stirring, oil bath heating reaction, suction filtration, remove solid simultaneously washed with ether, merging filtrate, organic layer is washed with water, dry, vacuum distillation solvent, collect certain vacuum degree distillate.
(6)：Take 2- Br--hydroxyl acetoacetic ester to be placed in three-necked flask, add anhydrous K2C03, and acetonitrile stirring.
Separately takeR R =N_R.Add in reaction solution, oil bath heating reaction filters out insoluble matter.Work as R.In the absence of when, after filtrate is drained add ethyl acetate dissolving, wash with the saturation NaCl aqueous solution, organic layer dry, water pump decompression extract solvent, purifying.Work as R.In the presence of, can and R.In the absence of when equally operated, but obtain product contain bromo element, finally need to remove using ion exchange by the way of, after can also filtrate be drained add water dissolving, the aqueous solution addition Ag20, insoluble matter is filtered out, pH to 9-11 is adjusted, is extracted with ethyl acetate, organic layer is dried, decompression extracts solvent, obtains product.
(7)：Take（6) product is placed in flask, is added above-mentioned NaOH solution, is stirred at room temperature.
(8)：Take（7) product, is adjusted with acid solution, is added above-mentioned（4) product, heating response produces the non-quaternary ammonium eka-platinium compound of racemic of the present invention（Work as R.In the presence of, in step（6) if not passing through Ag in20 processing, now products therefrom needs to pass through carries out ion-exchange treatment by filling anion exchange resin (0H types) post）.Products therefrom is when pH is 9-11 into base, solubility is smaller in water, it is soluble in the small molecular alcohol such as organic solvent such as methanol, ethanol, its ethanol solution can generate corresponding salt from different acid reactions, such as add appropriate chiral mandelic acid's solution, chiral mandelic acid's salt is obtained, crystallization is separated out, and homochiral product can be obtained through operating repeatedly；
(9)：(8) product, which can also add water, makes dissolving, by filling anion exchange resin after cooling（0H types）Diaion SA-10A post, be converted into other anionic radicals all replaced by hydroxyl obtained by compound, add acid produce corresponding salt. Specification
R4H: .OH
HNR, Ag2S04 . ,、、、
Pt i Pt SO
H O ,
R4H2N^ 、NH2R5 OH
R5H
2nd, formula（C) preparation method is as follows：
(1)：Take potassium chloroplatinite to add water, at room temperature stirring and dissolving, take KI to be put into after being dissolved in water in above-mentioned chloroplatinous acid potassium solution, lucifuge water bath condition is reacted under nitrogen charging；
(2)：Bidentate ammonia N-X-N are taken to be added drop-wise to after being dissolved in water（1) in reaction solution, water-bath has a large amount of yellow mercury oxides to generate, temperature in reaction solution is cooled into the following suction filtration of room temperature, washs, and obtains bidentate diiodo- diamines and closes platinum（11).
(3)：Take Ag2S04Enter in water and stir, take above-mentioned diiodo- diamines to close platinum（II) in input reaction solution, add under water, nitrogen charging and reacted under lucifuge water bath condition, suction filtration obtains two water diamines and closes platinum（Π) sulfate.
(4)：Take hydroxyl acetoacetic ester, and Br-R3- Br is placed in flask, adds K2C03, TBAB stirring, heating response, suction filtration removes solid and simultaneously washs, merging filtrate, wash organic layer, dry, leavened solvent is steamed in decompression, collect distillate.
(5)：Take 2- Br-R3- hydroxyl acetoacetic ester is placed in flask, adds anhydrous K2C03, and acetonitrile stirring.
Another to take in addition reaction solution, heating response filters out insoluble matter.Work as R.In the absence of when, after filtrate is drained add ethyl acetate dissolving, wash with the saturation NaCl aqueous solution, organic layer dry, water pump decompression extract solvent, purifying.Work as R.In the presence of, can and R.In the absence of when equally operated, but obtain product contain bromo element, finally need to remove using ion exchange by the way of, after can also filtrate be drained add water dissolving, the aqueous solution addition Ag20, insoluble matter is filtered out, pH to 9-11 is adjusted, is extracted with ethyl acetate, organic layer is dried, decompression extracts solvent, obtains product.
(6)：Take（5) product is placed in flask, is added NaOH solution, is stirred at room temperature.
(7)：Take（6) product, is adjusted with acid solution, is added above-mentioned（3) product, heating response produces the present invention's Specification
The non-quaternary ammonium eka-platinium compound of racemic（Work as R.In the presence of, in step（5) if not passing through Ag in20 processing, now products therefrom needs to pass through carries out ion-exchange treatment by filling anion exchange resin (0H types) post）.Products therefrom is when pH is 9-11 into base, solubility is smaller in water, it is soluble in the small molecular alcohol such as organic solvent such as methanol, ethanol, its ethanol solution can generate corresponding salt from different acid reactions, such as add appropriate chiral mandelic acid's solution, chiral mandelic acid's salt is obtained, crystallization is separated out, and homochiral product can be obtained through operating repeatedly；
(8)：(7) product, which can also add water, makes dissolving, by filling anion exchange resin after cooling（0H types）Post, be converted into other anionic radicals all replaced by hydroxyl obtained by quaternary ammonium compound, add acid produce corresponding salt.
It is preferred that preparation method it is as follows：
( 1 )：Take potassium chloroplatinite to add water, at room temperature stirring and dissolving, take KI to be put into after being dissolved in water in above-mentioned chloroplatinous acid potassium solution, N2Protection, notes lucifuge, and 30 ~ 60min is reacted under 40 ~ 60 °C of water-bath;
( 2 )：Take bidentate ammonia NH2-X-NH2It is added drop-wise to after being dissolved in water（1) in reaction solution, 30 ~ 60min is reacted under 40 ~ 60 °C of water-bath, there are a large amount of yellow mercury oxides to generate, temperature in reaction solution is cooled to less than 20 °C suction filtrations, washed successively with water, absolute ethyl alcohol, ether, bidentate diiodo- diamines is obtained and closes platinum（11 ).
(3 )：Take Ag2S04Enter in water and stir, take above-mentioned diiodo- diamines to close platinum（I I) put into reaction solution, add water, N24 ~ 8h is reacted under protection, lucifuge in 40 ~ 60 °C, suction filtration obtains two water diamines and closes platinum（II) sulfate.
(4)：Take hydroxyl acetoacetic ester, and Br--Br to be placed in flask, add K2C03, TBAB stirring, oil bath heating reaction, suction filtration, remove solid simultaneously washed with ether, merging filtrate, organic layer is washed with water, dry, vacuum distillation solvent, collect certain vacuum degree distillate.
( 5 )：Take 2- Br-R3- hydroxyl acetoacetic ester is placed in three-necked flask, adds anhydrous K2C03, and acetonitrile stirring.Another to take in addition reaction solution, oil bath heating reaction filters out insoluble matter.Work as R.In the absence of when, after filtrate is drained add ethyl acetate dissolving, wash with the saturation NaCl aqueous solution, organic layer dry, water pump decompression extract solvent, purifying；Work as R.In the presence of, can and R.In the absence of when equally operated, but obtain product contain bromo element, finally need to remove using ion exchange by the way of, after can also filtrate be drained add water dissolving, the aqueous solution addition Ag20, insoluble matter is filtered out, pH to 9-11 is adjusted, is extracted with ethyl acetate, organic layer is dried, decompression extracts solvent, obtains product.
(6 )：Take（5) product is placed in flask, is added above-mentioned NaOH solution, is stirred at room temperature.
( 7 )：Take（6) product, adjusts pH with acid solution, adds（3) product, heating response produces the non-quaternary ammonium eka-platinium compound of racemic of the present invention（Work as R.In the presence of, in step（5) if not passing through Ag in20 processing, now products therefrom needs to pass through carries out ion-exchange treatment by filling anion exchange resin (0H types) post）.Products therefrom is when pH is 9-11 into base, solubility is smaller in water, it is soluble in the small molecular alcohol such as organic solvent such as methanol, ethanol, its ethanol solution can generate corresponding salt from different acid reactions, such as add appropriate chiral mandelic acid's solution, chiral mandelic acid's salt is obtained, crystallization is separated out, and homochiral product can be obtained through operating repeatedly； Specification
(8)：(7) product, which can also add water, makes dissolving, by filling anion exchange resin after cooling（0H types）Diaion SA-10A post, be converted into other anionic radicals all replaced by hydroxyl obtained by quaternary ammonium compound, add acid produce corresponding salt.
Present invention also offers the pharmaceutical composition containing above compound, its pharmaceutically acceptable salt, stereoisomer, medicine or its solvate and pharmaceutical acceptable carrier and/or excipient.Composition contains 0. 01 %-100 %, preferably 0. 1 %-100%, more preferably 1 %-100 %, even more preferably from 20%-100% (weight）One or more the compounds of this invention, remainder is made up of suitable pharmaceutical carrier and/or excipient.It can be made up of composition with method of administration to match with the compounds of this invention using suitable carrier and/or excipient method well known in the art.
The amount of reactive compound can be in 0. OOlmg between lOOOmg in unit dose formulations, and preferably 0. Olmg is between 500mg, and more preferably lmg is between lOOmg, and most preferably lOmg changes between 50mg.
Administration can be for example oral, local, intravenous, subcutaneous, percutaneous, transdermal, intramuscular, intra-articular, parenteral, intra-arterial, intracutaneous, intra-ventricle, encephalic, intraperitoneal, interior, intranasal damaging part, rectum, vagina, suction or by being implanted into bank.Term " parenteral " used herein is included in subcutaneous, intravenous, intramuscular, intra-articular, synovia, breastbone is interior, intrathecal, liver is interior, damaging part is interior and intracranial injection or infusion techniques.It is preferred that intravenous administration composition.Invention formulation can be designed as to quick-acting, quick-release or long-acting.Still further, compound can be given by part rather than systemic fashion, for example, gives and (for example inject) sustained release preparation.According to representative embodiment, the present composition can be formulated as giving the medicine of mammal, preferably people.
Repeatable to give the present compositions containing one or more, for example, at least 2,3,4,5,6,7,8 or more is secondary, or can give composition by continuous infusion.The proper site of administration includes but is not limited to blood vessel, muscle, skin, bronchus, stomach, anus, vagina, eyes and ear.Preparation can use liquid dosage form, freeze-dried powder form, solid or semisolid, for example Specification solution, suspension, emulsion, tablet, pill, capsule, powder, suppository, retention enema, creme, ointment, lotion, gel, aerosol etc., are preferably adapted for simply giving the unit dosage forms of correct dose.
For parenteral, composition can be aseptic parenteral solution and aseptic packaging powder form.It is preferred that, prepare parenteral solution in PH4. 5-7. 5.
The present composition of Sterile injectable forms is water or oil suspension.By techniques known in the art these suspensions can be prepared with suitable scattered or wetting agent and suspending agent.Aseptic injection preparation is alternatively the aseptic injectable solution or suspension for being dissolved in or being suspended in the acceptable diluent of nontoxic parenteral or solvent, for example, be dissolved in the solution of 1,3-BDO.Workable acceptable solvent and solvent include water, ringer's solution and isotonic sodium chlorrde solution.In addition, sterile non-volatile oils are also typically used as solvent or suspending medium.Therefore, the fixed oil of any brand including the monoglyceride or diester synthesized can be used.With natural pharmaceutically acceptable oily such as olive oil or castor oil, especially they polyoxyethylated versions it is identical, aliphatic acid such as oleic acid and its glyceride ester derivatives can be used for preparing ejection preparation.These oil solutions or suspension can also contain long-chain alcohol diluents or dispersant, for example, carboxymethyl cellulose or be generally used for including emulsion and the similar dispersant in the preparation of the pharmaceutically acceptable formulation including suspension.Other conventional surfactants such as tween, sapn and it is commonly used for preparing other emulsifying agents of pharmaceutically acceptable solid, liquid or other formulations or bioavilability accelerator can also be used for preparation purpose.Can prepare is used for the compound of parenteral by injecting such as large bolus injection or continuous infusion.Injection unit dosage forms can be in ampoule or multi-dose container.
The present composition of lyophilized form can be also provided.Such composition can redissolve comprising that can include buffer in the buffer such as bicarbonate, or freeze-dried composition for being used to redissolve before administration for such as water.Freeze-dried composition can also contain suitable vasoconstrictor, such as adrenaline.Freeze-dried composition can be provided by syringe, be optionally packaged together with the buffer for redissolution, so as to which patient can be given the redissolution composition immediately.
Pharmaceutical composition of the present invention can also be any oral acceptable formulation, and they include tablet, capsule, cachet, emulsion, suspension, solution, syrup, elixir, spray, pill, lozenge, powder, granule and sustained release preparation.Suitable excipient for oral administration includes pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, saccharin sodium, talcum powder, cellulose, glucose, gelatin, sucrose, magnesium carbonate etc..In the case of tablet for oral administration, conventional carrier includes lactose and cornstarch.Generally it is additionally added lubricant such as magnesium stearate.For capsule, useful diluent includes lactose and dried corn starch.When oral medication needs aqueous suspension, active component is mixed with emulsification and suspending agent.Also it can take the circumstances into consideration to add some sweeteners, flavouring or colouring agent.
Can be by by one or more the compounds of this invention and choosing any one kind of them or during a variety of pharmaceutically acceptable auxiliary materials are dissolved or dispersed in carrier such as saline solution, D/W, glycerine, ethanol, formed for example for oral, part or the solution or suspension of intravenous administration, prepare fluid composition.The pharmaceutical preparation of liquid suspension or solution form can be prepared with sterile liquid such as oil, water, ethanol and combinations thereof.For oral and parenteral administration, suitable surfactant on medicament can be added, hanged Specification floats agent or emulsifying agent.Suspension can oil-containing, such as peanut oil, sesame oil, cottonseed oil, corn oil and olive oil.Suspension formulations also can fatty acids ester, such as ethyl oleate, isopropyl myristate；Fatty glyceride and acetylated fatty acid glycerides.Suspension formulations can include alcohol, such as ethanol, isopropanol, hexadecanol, glycerine and propane diols.Ether for example gathers（Ethylene glycol）；Petroleum hydrocarbon such as mineral oil and vaseline, water can also be used for suspension formulations.
Composition can use pill, tablet or Capsule form, therefore, and composition can contain and one or more diluents, such as lactose, sucrose, dicalcium phosphate；Disintegrant, such as starch or derivatives thereof；Lubricant, such as magnesium stearate；And/or adhesive, such as starch, Arabic gum, polyvinyl pyrrole protective embankment ketone, gelatin, cellulose and its derivates.Tablet can be prepared by any compacting well known by persons skilled in the art or molding methods.Can by suppressed in suitable machine optionally with auxiliary element (such as adhesive, lubricant, diluent, disintegrant or dispersant）The compounds of this invention of the free-flowing form (such as powder or particle) of mixing, prepares compressed tablets.Molded tablets can be prepared by moulding the mixture of powders of the compounds of this invention and any suitable carrier in suitable machine.
Or Pharmaceutical composition of the present invention can be the suppository form for rectally.These suppositorys can be prepared by making medicine be at room temperature solid with suitable but be liquid under rectal temperature and thereby the suitable non-irritating excipient of release medicine is mixed in the rectum.Such material includes cocoa butter, beeswax, polyethylene glycol, tallow and/or hydrogenated coco-glyceride.Rectal enema unit can also be contained by being adapted to the composition of rectally, and the unit contains one or more the compounds of this invention and pharmaceutically acceptable solvent (such as 50 % ethanol waters or saline solution）, such solvent is with rectum and/or colon in physical compatibility.Rectal enema unit is preferably made up of containing the medicator tip protected by inert cover, the tip polyethylene, and with lubricator for example albolene lubricates, and is preferably protected by unidirectional pottery, to prevent the drug reflux sent.Rectal enema unit also has sufficient length, and preferably 2 inches, it is inserted into colon by anus.
Pharmaceutical composition of the present invention is alternatively Topical application forme, and especially when therapeutic targets include the region or the organ that are easily accessible by local application, the disease of these organs includes the disease of eyes, skin or lower intestinal tract.Easily prepare the suitable topical formulations for each region in these regions or organ or organ.For local administration, the composition containing one or more the compounds of this invention can be emulsion, lotion, gel, foam, creme, jelly, solution, suspension, ointment and transdermal patch form.
It can be realized by rectal suppository formulation or suitable enema preparation in lower intestinal tract local application.Topical transdermal patch can also be used.For local application, the Pharmaceutical composition of suitable ointment form can be prepared, the ointment contains the active component for being suspended in or being dissolved in one or more carriers.Include but is not limited to mineral oil, Albolene, albolene, propane diols, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water for administering locally to the carrier of the compounds of this invention.Or, suitable lotion or the Pharmaceutical composition of cream can be prepared, these lotions or creme contain the active component for being suspended in or being dissolved in one or more pharmaceutically acceptable carriers.Suitable carrier includes mineral oil, Arlacel-60, Tween-60, cetyl, wax, cetanol, 2- octyl dodecanols, phenmethylol and water.
Also Pharmaceutical composition of the present invention can be given by nasal aerosol or suction.For passing medicine by suction, it can be passed by sprayer Specification send the composition of dried powder or liquid form.Such composition is prepared according to known technology in field of pharmaceutical preparations, and can be in salt solution, with the composition of phenmethylol or other suitable preservatives, sorbefacient, fluorocarbons and/or the other conventional solubilizer of strengthening bioavilability or dispersant preparation solution form.
Pharmaceutically acceptable carrier available for these compositions includes ion-exchanger, aluminum oxide, aluminum stearate, lecithin;Haemocyanin such as human serum albumins；Buffer substance such as phosphate；Glycine, sorbic acid, potassium sorbate, the partial glyceride mixture of saturated vegetable fatty acid, water, salt or electrolyte such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt；Cataloid, magnesium trisilicate, polyvinyl pyrrole protective embankment ketone, cellulose substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and wool grease.
The example of suitable excipient includes but is not limited to water, salt solution, lactose, glucose, sucrose, sorbierite, mannitol, starch, Arabic gum, calcium phosphate, alginates, tragacanth, gelatin, calcium silicates, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, syrup, methylcellulose, ethyl cellulose, hydroxypropyl methyl cellulose and polyacrylic acid, such as carbopol.Composition can also contain lubricant such as talcum powder, magnesium stearate and mineral oil；Wetting agent；Emulsifying agent；Suspending agent；Preservative such as methyl-, ethyl-and propyl group-hydroxy-benzoic acid ester；For example inorganic and organic bronsted lowry acids and bases bronsted lowry of pH adjusting agent；Sweetener；And flavouring.
In addition to the representative formulation of those described above, those skilled in the art generally it is known that other pharmaceutically acceptable excipient and carrier and formulation, be included in the present invention.It should be understood that, the given dose and therapeutic scheme of any specific patient will depend on many factors, they including the use of the activity of particular compound, the age of patient, body weight, general health, sex, diet, administration time, drainage rate, combination medicine, the judgement for the treatment of physician and the disease specific treated seriousness.The amount of active component additionally depends on other medicines in particular compound and (if present) composition.
Above pharmaceutical composition can further include the active ingredient of other treatment or auxiliary treatment proliferative diseases, or be used with the drug regimen of other treatment or auxiliary treatment proliferative diseases.For example, anti-proliferative agent, immunomodulator, anticarcinogen, cytotoxic agent, the used as adjuvant drug for antitumor outside the present invention are applied in combination.
The example of these other therapeutic agents includes：Anti-proliferative agent, such as methotrexate (MTX), FK506 (fujimycin 506, Prograf), mycophenolic acid it is luxuriant and rich with fragrance for gram；Cytotoxic drugs, such as imuran and endoxan；TNF- alpha inhibitors, such as Tenidap；Anti-TNF antibodies or soluble TNF acceptor, such as etanerc print t (Enbrel)；Rapamycin, leflunimide, and cyclooxygenase-2 (C0X-2) inhibitor, such as celecoxib and rofecoxib, or their derivative；And the published ptk inhibitor of prior art.
Typical each kind anti-cancer drugs and cytotoxic agent include but is not limited to：Protective embankment base reagent, such as mustargen, protective embankment base sulphonic acid ester, nitrourea, aziridine and triazenes；Antimetabolite, such as folate antagonist, purine analogue and pyrimidine analogue；Antibioticses, such as anthracene nucleus element, bleomycin, mitomycin, dactinomycin D and fold mycin；Enzyme, such as L-ASP；Farnesyl protein transferase inhibitors；Hormone agents, for example, glucocorticoid, estrogen/antiestrogenic, androgen/antiandrogen, progesterone, luteinizing hormone releasing hormone antagonist, acetic acid Sandostatin LAR Depot；Microtubule disruption agent, such as ecteinascidin or its analog Specification and derivative；Microtubule stabilizer, such as taxol, Docetaxel and epothilone or its analog or derivative；Product from plant, such as vinca alkaloids, table ghost say toxin, Japanese yew protective embankment；Topoisomerase enzyme inhibitor；It is different to defend dialkylene protein transferase inhibitors；Miscellaneous agents, for example, hydroxycarbamide, procarbazine, the chloroethene protective embankment of chlorobenzene two, Altretamine, platinum coordination complex such as cis-platinum and carboplatin；And other medicaments and cytotoxic agent for anticancer, such as biological response conditioning agent, growth factor；Immunomodulator and monoclonal antibody.The compounds of this invention can also be used in combination with radiation-therapy.
The anticarcinogen of these classifications and the example of cytotoxic agent include but is not limited to：Mustine hydrochlcride, endoxan, Chlorambucil, chloramphenalan, ifosfamide, busulfan, carmustine, lomustine, A ring of nitrosourea, streptozotocin, Tespamin, Dacarbazine, methotrexate (MTX), sulphur guanopterin, purinethol, fludarabine, Pentastatin, leustatin, cytarabine, fluorouracil, doxorubicin hydrochloride, daunorubicin, darubicin, Bleomycin Sulphate, mitomycin (, actinomycin 0, safracins, Micronomicin, quinocarcins, discodermol ides, vincristine, vincaleukoblastinum, Vinorelbine tartrate, Etoposide, ghost says thiophene glycosides, taxol, TAM, estramustine, estradiol phosphate sodium salt, Flutan, Buserelin, Acetate, pteridine, two acetylenics, levamisol, aflaCON, interferon, interleukin, Aldesleukin, Fei Ersi pyridines, Sargramostim, Mabthera, BCG, vitamin A acid, CPT-11, betamethasone, GEMCITABINE HYDROCHLORIDE, hexamidine and TOPO, and their any analog or derivative.
Preferred member in these classifications includes but is not limited to：Talk endlessly cry of certain animals, methopterin, methyl of taxol, cis-platinum, carboplatin, adriamycin, carminomycin, daunorubicin, amino is talked endlessly cry of certain animals, mitomycin（, ecteinascidin, porfiromycin, 5 FU 5 fluorouracil, Ismipur, gemcitabine, cytarabine, podophyllotoxin or podophyllotoxin derivative, such as Etoposide, etoposide phosphate or the white thiophene glycosides of ghost, chloramphenalan, vincaleukoblastinum, vincristine, leurosidine, eldisine and leurosine.
The example of antineoplastic and other cytotoxic agents includes： US6262094、 DE4138042. W097/19086.
W098/2246K W098/25929、 W098/38192、 W099/01124, W099/02224, W099/02514, f 099/03848 W099/07692, W099/27890 W099/28324. W099/43653>Epothi lone derivatives in W099/54330 W099/54318, W099/54319, W099/65913, W099/67252, W099/67253, and W000/00485；The kinase inhibitor of cyclin dependent in W099/24416；And such as the Prenyl-protein inhibitors in TO97/30992 and W098/54966.
More than other therapeutic agents, when when the compounds of this invention is used together, pointed dosage for example in clinical application handbook can be used, or use according to dosage determined by those of ordinary skill in the art.
Finally, the method for cell proliferation disorders is treated present invention also offers a kind of, including gives the formula A compounds of bacterium in need.
" cell proliferation disorders " refer to the illness for being characterised by abnormal cell proliferation.Propagation disease does not indicate that any limitation of cell growth speed, but only represents to lose to influence growth and fissional normal control.Therefore, breeding the cell of disease can have Specification and normal cell identical cell splitting rate, but it is not responding to limit the signal of this growth." Cells proliferative disorders " in neoplasm or range of tumor, neoplasm or tumour are the misgrowth of tissue." cancer " refers to be characterised by any one in the various malignant tumours of cell propagation, and these tumours have intrusion surrounding tissue and/or are transferred to the ability at new colonization position.
Typically, any illness for being characterised by abnormal cell proliferation can be related to the Cells proliferative disorders of compounds for treating disclosed herein.These include various benign or pernicious, transfer or non-diverting tumour and cancer.Special nature of the method specifically described herein to anticancer, such as tissue invasion or metastatic can be used.Cells proliferative disorders include kinds cancer, and they include but is not limited to：Cancer：Including carcinoma of urinary bladder, breast cancer, colon cancer, kidney, liver cancer, lung cancer, ED-SCLC, oophoroma, prostate cancer, cancer of pancreas, cancer of the esophagus, stomach cancer, gallbladder cancer, cervical carcinoma, thyroid cancer, cutaneum carcinoma and squamous cell carcinoma；
The hematopoietic tumors of lymphatic system：Including leukaemia, acute lymphoblastic system leukaemia, Acute Lymphoblastic Leukemia, beta cell lymthoma, Τ-cell lymphoma, Hodgkins lymphomas, non-Hodgkins lymphomas, villus cell lymthoma and Burketts lymphomas；
The hematopoietic tumors of marrow system：Including acute and chronic myeloid leukemia, myelodysplastic syndromes and progranulocyte leukemia；
The tumour of maincenter and peripheral neverous system：Including astrocytoma, neuroblastoma, glioma and neurinoma；The knurl of mesenchymal derivation：Including fibrosarcoma, rhabdomyosarcoma and osteosarcoma；
Other tumours：Including melanoma, xenodema pigmentos and, amination acanthoma (acanthomata), seminoma, thyroid follcular carcinoma and teratocarcinoma.
Can be neoplastic hematologic disorder with the Cells proliferative disorders of the compounds for treating, the tumour grows for the cellular dysmorphology of hemopoietic system.Neoplastic hematologic disorder includes lymphocytoma, and wherein abnormal cell is derived from lymphoid cell lineage and/or shows the characteristic phenotypic of lymphoid cell lineage.Lymphoid cell knurl can be subdivided into B cell knurl, T and NK cytomas, and Hodgkin lymphoma.
B cell knurl can be sub-divided into first ancestor's B cell knurl and maturation/periphery B cell knurl.The B cell knurl of illustration is precursor B lymphatic leukemias/lymthoma（Precursor B cells acute lymphatic leukemia）, maturation/periphery B cell knurl is B cell chronic lymphatic leukemia/primary lymphedema lymthoma, the young lymphatic leukemia of B cell, lymph-plasma lymthoma, Pi Yuan areas B cell lymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma, the Fan Yuyuan areas B cell lymphoma of MALT types, Jie Yuan areas B cell lymphomas, follicular lymphoma, lymphoma mantle cell, dispersivity large B cell lymphoid tumor, mediastinum large B cell lymphoid tumor, primary permeability lymthoma and Burkitt lymphoma/leukemia Burkitt cell.T cell and Nk cytomas are sub-divided into precursor T cell cancers and maturation（Periphery）T cell knurl.Precursor T-cell knurl is precursor T- lymphocytic lympbomas/leukaemia（Precursor T-cell ALL）, ripe (periphery）T cell knurl is T cell prolymphocytic leukemia T cell granular lymphocyte leukemia, aggressive ware chronic myeloid leukemia, adult T cell lymphoma/leukaemia（HTLV-1), knot external nose type ware/t cell lymphoma；Nose type, pathological form t cell lymphoma, liver and spleen Y-δ Τ cell lymphomas, subcutaneous panniculitis-like Τ cell lymphomas, early sample granuloma/sezary syndrome, degeneration large celllymphoma；Τ/null cell, Primary dermal type periphery Τ Lymphocytes Specification knurl, Angioimmunoblast τ cell lymphomas, degeneration large celllymphoma, the T/ null cells not characterized in addition, primary whole body type.The third in lymphoid cell knurl is Hodgkin lymphoma, also known as Hodgkin's disease.The super advantage Hodgkin lymphoma of nodular lymphocyte and the Hodgkin's disease of various classical field formalisms, wherein nodular hardening Hodgkin lymphoma can be included but is not limited to the diagnosis of such disease of the compounds for treating（1 grade and 2 grades）, the classical Hodgkin lymphoma of lymphocyte-rich, mixed type cellularity Hodgkin lymphoma and lymphocyte exhaust Hodgkin lymphoma.
Neoplastic hematologic disorder also includes myelocytome.Such knurl includes being related to or showing a major class Cells proliferative disorders of the characteristic phenotypic of myelocyte lineage.Myelocytome can be subdivided into myeloproliferative disease, myeloproliferative disorder/myeloproliferative disorders, myelodysplastic syndrome and acute myelocytic leukemia.Myeloproliferative disorders are Chronic Myeloid granulocytic leukemia, chronic neutrophilic granulocytic leukemia, chronic eosinophilic leukemia/hypereosinophilic syndrome, Chronic Spontaneous myelofibrosis, polycythemia and primary thrombocytosis.Myeloproliferative disorder/myeloproliferative disorders are chronic monokaryon myelocytic leukemia, atypical Chronic Myeloid granulocytic leukemia and teenager's monokaryon myelocytic leukemia.Myelodysplastic syndrome is to have ring grain sideroblast and refractory anemia disease without ring grain sideroblast, with the hypogenetic intractable cytopenia (myelodysplastic syndrome of polyphyly）, with the sick (myelodysplastic syndrome of refractory anemia of excess blasts）, 5q- syndromes and myelodysplastic syndrome.The compounds of this invention treatment and related any myelocytome can be used.
The compounds for treating acute myelocytic leukemia (AML) can be used, the leukaemia, which represents to have, can subdivide a major class myelocytome of illness.These branches include but is not limited to AML, the companion hypogenetic AML of polyphyly and other non-classified AML with recurrent cytogenetic translocations.Include but is not limited to that there is t (8 with the AML of the hereditary transposition of regenerable cells； 21) (q22;Q22 AML), AMLl (CBF- a)/ET0. acute promyelocytic leukemias（With t (15; 17) (q22 ;Q l l- 12) AML and modification, PML/RAR- a), with abnormal marrow eosinophil（Inv (16) (p l3q22) or " 16; 16) (pl3；Q l l), CBFb/MYHl lX) AML and the AML abnormal with l lq23 (MLL).It is those AMLs relevant or unrelated with preceding myelodysplastic syndrome with the hypogenetic AML of polyphyly.Unallocated other acute myelocytic leukemias in any definable class include AML, immature AM the maturation AML of minimum differentiation, acute monokaryon myelocytic leukemia, acute monokaryon type leukaemia, acute class erythrocytic form leukaemia, acute megakaryoblastic type leukaemia, acute basophile leukecythemia and and with the acute panmyelosis leukemia of myelofibrosis.
The tumour of preferred therapeutic is breast cancer, lung cancer, colon cancer, stomach cancer, the cancer of the esophagus, oophoroma, osteosarcoma, cervical carcinoma, liver cancer, brain tumor, prostate cancer, melanoma.
" treatment " in text of the invention represents to alleviate the symptom relevant with illness or disease, or terminates the further development of those symptoms or deteriorate, or prevents or prevention disease or illness.
Term " pharmacy effective dose ", " therapeutically effective amount " or " treatment effective dose " refers to the amount of the motif compound for the biological or medical response for causing tissue, system, animal or people that researcher, animal doctor, doctor or other clinical technicians are look for.
Term " therapeutically effective amount " includes giving metapedes to prevent the one or more symptom developments for the disease or illness treated Specification is alleviated to the amount of compound to a certain degree.Therapeutically effective amount must become with age, body weight of compound, illness or state and its seriousness and the mammal treated etc..
" patient " being defined herein includes animal, and such as mammal, mammal includes but is not limited to primate (such as people）, cow, sheep, goat, horse, dog, cat, rabbit, rat, mouse etc..In preferred embodiments, patient behaves.The effective dose of the compounds of this invention can be determined that the dosage for adult is per daily 0. 001-1000m of kg body weight by those of ordinary skill in the artgReactive compound, can be administered in a single dose, or the medication in the form of each divided dose, such as daily 1-4 times.It should understand, for any specific object, specific dosage level and administration number of times can change, this depends on many factors, include the activity of particular compound used, the metabolic stability and action time length of the compound, the species of medication object, age, body weight, healthy overview, sex and eating habit, the mode of medication and time, drainage rate, the order of severity of the combination of medicine and specific illness.
Anti-tumor platinum compound of the free cpds relative to prior art of the present invention, solubility is significantly improved, there is more than 50mg/ml solubility in water, the compound of those particularly currently preferred embodiments is respectively provided with 90mg/ml even more than lOOmg/ml solubility.Moreover, the platinum compounds of prior art can not can be more beneficial for it and stable dosage form is made into salt, compound of the invention in the form of forming salt.
The above formulation of any compound containing effective dose is in normal experiment scope and the scope of the invention.Treatment effective dose can be adjusted according to administration path and formulation.Representative compound of the present invention is the preparation of display high therapeutic index.Therapeutic index is the dose ratio of toxicity and curative effect, can be by L.With internal antitumor activity（Ε .）Or vitro cytotoxicity（IC5.）Ratio represent the index. LD5.To make the dosage that 50 % populations are lethal, ED5.To reach therapeutically effective dosage in 50% population.By standard pharmaceutical procedures, LD is determined in Zooblast culture medium or experimental animal5.And ED5..Because the compounds of this invention represents the LD of toxicity50(the dosage mmol/kg for causing half animal dead) is significantly larger than platinum compounds cis-platinum and carboplatin of present technology etc., and the effective dose of antitumor activity and external suppression cytotoxic concentration IC in vivo5.Value is suitable or lower with carboplatin, therefore can be used for not being resistant to the patient that the existing platinum compounds such as carboplatin, cis-platinum is treated, and obtains good technique effect.The compounds of this invention can be used alone, or in combination with one another, and/or be used with other suitable therapeutic agents available for treatment proliferative disease.Embodiment：
The exploitativeness of the present invention can be described in more detail in the following examples, test example, but the invention is not limited in any way.It will be understood by those of skill in the art that according to the teaching of prior art, corresponding technical characteristic is modified or replaced, the scope of protection of present invention is still fallen within.As long as more than the raw materials used purity of the present invention reaches that chemistry is pure, source is commercially available.Compound obtained by lower example embodiment is the form of salt, the compound of these salt forms can obtain free cpds by adding alkali regulation pH, and it can be easy to change into the organic or inorganic salt of other species using the method for adding corresponding acid, nitrate, carbonate, bicarbonate, phosphate, hydrophosphate, biphosphate can be but not limited to Specification salt, sulfate, disulfate, phosphite, acetate, propionate, isobutyrate, malonate, benzoate, succinate, suberate, fumarate, mandelate, Phthalate, benzene sulfonate, tosilate, citrate, tartrate, mesylate, arginine salt, glucuronate or galactolipin hydrochlorate etc., are no longer illustrated one by one in following examples.
[embodiment 1]:2- (2- methylamino second protective embankment bases）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（II) phosphate；
Step 1:2- (2- bromoethyls）- 3--ethyl propionate
Take commercially available 3- hydroxy-propionic aad ethyl esters 11.82g (0. lmol), and 1,2- dibromo second protective embankment 47.49g (0.25mol) to be placed in 150ml three-necked flasks, add K2C03(15.3g 0. llmol), TBAB 155mg are stirred, oil bath heating reacts 16 ~ 24h to 65 ~ 85 °C, suction filtration, remove solid and wash paint with ether (30ml X 3 times), merging filtrate, organic layer is washed with water (40ml X 3 times), MgS0 is used44 ~ 8h, vacuum distillation solvent are dried, then uses oil pump vacuum distillation, vacuum 7mmHg, 13 Γ 〇 -14 Γ 〇 fraction 7.65g, yield 34.0% are collected.
Step 2:2- (2- methylamino second -3- hydroxy-propionic aad ethyl esters
Take 2- (2- bromoethyls）- 3- hydroxy-propionic aad ethyl esters 90.16g (0.4mol) is placed in three-necked flask, adds 55.85g (0.4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.It is another to take the lower methylamine solution 31.0g (l. Omol) preserved of freezing to add in reaction solution, oil bath heating is to reacting 2-6h under 40 ~ 60 °C, insoluble matter is filtered out, ethyl acetate 1000ml dissolvings are added after filtrate is drained, are washed with the saturation NaCl aqueous solution（250ml X 3 times）, the anhydrous M of organic layergS04It is dried overnight, water pump decompression extracts solvent, obtains pale yellow inclined red, transparent shape thing 80.7g, column chromatography method purifies to obtain sterling 26.51g, yield 37.87%.
Walk rapid 3:2- (2- methylamino ethane -3- hydroxy-propionic acid sodium salts
Take NaOH 215mg (5mmol) add water 2.5mL dissolving, produce 2M aOH solution, separately take 2- (2- methylamino second protective embankment bases）- 3- hydroxy-propionic aad ethyl esters 350mg (2mmol) is placed in 20mL three-necked flasks, is added above-mentioned NaOH solution, is stirred at room temperature Specification
45 ~ 60h, produces 2- (2- methylamino second protective embankment bases）- 3- hydroxy-propionic acid sodium salt solutions.
Iodine closes platinum（II)
Take Platinous Potassium Chloride (K2PtCl4) 2.075g (5mmol), add water 50ml, at room temperature stirring and dissolving, takes KI6.640g (40mmol) to be added after being dissolved with water 50ml in reaction solution, N2Protection, lucifuge, heating water bath to 0.5 ~ 2h of reaction under 40 ~ 60 °C.Ammoniacal liquor is taken again（Containing ammonia 5mmol) 50ml add reaction solution in, continue keep this under the conditions of react 0.5 ~ 2h.Suction filtration obtains faint yellow solid product, uses water（10mlX3 times）, ether（10ml X 3 times）Washing, obtains product 2.29g, yield 95.1%.Elementary analysis：HI.24% (theory 1.21%) N5.56% (theory 5.797%).
Step 5:Diamino two is hydrated platinum（Π) sulfate
Take Ag2S04625mg (2mmol) is placed in 100ml three-necked flasks, the 30ml that adds water stirrings, takes diamino diiodo- to close in platinum (11) 0.96g (2mmol) input reaction solutions, and add the reaction of 40ml water, N2Protection, lucifuge reacts 4 ~ 8h under 40 ~ 60 °C of water-bath.Suction filtration removes Agl precipitations, obtains the aqueous solution of filtrate, as product.
Step 6:(2- -3- hydroxy-propionic acids cis-diammine closes platinum to 2-（II) phosphate
Take containing 2 gangsters01 2- (2- methylamino second protective embankment bases）- 3- hydroxy-propionic acid sodium salt solutions H3P04(1M) regulation pH is hydrated platinum to 57, then by cis-diammine two（Π) sulfate solution is poured into reaction solution, N2Protection, heating water bath reacts 4-6h to 40 ~ 75 °C, static by reaction solution suction filtration Hou Nong Shrink to certain volume, obtains crystal type 2- (2- methylamino ethyl groups）The cis diaminourea of -3- hydroxyls-propionic acid closes platinum（Π) phosphate 102mg.
The compound is soluble in water, solubility is 168mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, phosphate, citrate, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C19.45% (theory 19.25%)； H4.63°/.（Theory is 4.55%)；N10.98% (theory 11.23%).
¾NMR (D20) (ppm)： δ 3.51 (m, 1H), δ 3.02(d, 2H), δ 2.86(s, 3H), δ 2.66(t, 2H), δ 1.74 (m, 2H). Specification
[embodiment 2] 2- (3- dimethylaminos the third protective embankment bases）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（II) acetate;
Step 1:2- (3- bromines the third protective embankment bases）- 3- hydroxy-propionic aad ethyl esters
Take 3- hydroxy-propionic aad ethyl esters 11.85g (0. lmol), and 1,3- dibromo the third protective embankment 50.4g (0.25mol) to be placed in 150ml three-necked flasks, add K2C0315. lg (0. llmol), TBAB 155mg is stirred, oil bath heating reacts 16 24h to 65 ~ 85 °C, suction filtration, remove solid and washed with ether (30ml X 3 times), merging filtrate, washs organic layer with water (40ml X 3 times), uses MgS044 ~ 8h, vacuum distillation solvent are dried, then steams leavened with oil pump decompression, vacuum 7mmH is collectedg, 132 °C of -142 °C of leavened part 7.98g, yield 33.39%0
Step 2:2- (3- dimethylaminos the third protective embankment bases）- 3- hydroxy-propionic aad ethyl esters
Take 2- (3- bromines the third protective embankment bases）- 3- hydroxy-propionic aad ethyl esters 95.6g (0. iOL) it is placed in three-necked flask, adds 55.6g (0. ol) anhydrous K2C03, and acetonitrile 500ml stirrings.The another dimethylamine solution 45.3g (l. Omol) for taking freezen protective is added in reaction solution, oil bath heating is to reacting 2-6h under 40 60 °C, insoluble matter is filtered out, ethyl acetate 1000ml dissolvings are added after filtrate is drained, are washed with the saturation NaCl aqueous solution（250ml X 3 times）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains pale yellow inclined red, transparent shape thing 92.5g, column chromatography method purifies to obtain sterling 25.6g, yield 31.52%.
Walk rapid 3:2- (3- dimethylaminos the third protective embankment bases）- 3- hydroxy-propionic acid sodium salts
Take NaOH 212.2mg (5 ol) add water 2.5m L dissolving, produce 2M NaOH solutions, separately take 2- (3- dimethylaminos the third protective embankment bases）- 3- hydroxy-propionic aad ethyl esters 407mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature, 2- (3- dimethylamino-propane bases are produced）- 3- hydroxy-propionic acid sodium salt solutions.
Step 4,5：With [embodiment 1] step 4,5. Specification
Step 6:2- (3- dimethylaminos the third protective embankment bases）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（II) acetate;
Take 2- (3- dimethylaminos the third protective embankment bases）- 3- hydroxy-propionic acids sodium salt solution adjusts pH with HAC (1M) and is hydrated platinum to 5 ~ 7, then by cis-diammine * bis-（Π) sulfate solution is poured into reaction solution, N2Protection, heating water bath will be concentrated to certain volume to 40 75 °C of reaction 4-6h after reaction solution suction filtration, static, obtain crystal type product 107mg.
The compound as its free base is soluble in water with salt, solubility is 152mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, Chinese holly Citron hydrochlorates, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C23.63% (theory 23.88%)；H5.13% (theory 5.22%)；N10.72% (theory 10.45%).
LHNMR (D20) (ppm)： δ 3.51 (m, 1H) , δ 2.92(d, 2H), δ 2.76(s,6H) , δ 2.68(t, 2Η), δ 1.76 (m, 2Η), δ 1.50 (m, 2Η) .
[embodiment 3]:2- (3- aminopropan protective embankment bases）The cis diaminourea of -3- hydroxy-propionic acids * closes platinum（Π) Pity hydrochlorates；
Step 1:With [embodiment 2] step 1.
Step 2:(3- aminopropans burn base to 2-）- 3- hydroxy-propionic aad ethyl esters
Take 2- bromopropyl -3- hydroxy-propionic aad ethyl esters 95.5g (0. ol) to be placed in three-necked flask, add 55 lg (0.4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.Excess of ammonia is passed through in reaction solution, oil bath heating filters out insoluble matter to 2-6h is reacted under 40 ~ 60 °C, ethyl acetate 1000ml dissolvings are added after filtrate is drained, are washed with the saturation NaCl aqueous solution（250ml X 3 times）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains pale yellow inclined red, transparent shape thing 77.9g, column chromatography method purifies to obtain sterling 24.3g, yield 34.7%.
Step 3:2- (3- aminopropan protective embankment bases）- 3- hydroxy-propionic acid sodium salts Specification
Take NaOH 213mg (5mmol) add water 2. 5mL dissolving, produce 2M NaOH solutions, separately take 2- (3- aminopropan protective embankment bases）- 3- hydroxy-propionic aad ethyl esters 351mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature, 2- (3- ammonia the third protective embankment bases are produced）- 3- hydroxy-propionic acid sodium salt solutions.
Step 4,5：With [embodiment 1] step 4,5.
Step 6:2- (3- aminopropan protective embankment bases）The cis diaminourea of -3- hydroxy-propionic acids * closes platinum（II) phosphate；
Take 2- (3- aminopropan protective embankment bases）- 3- hydroxy-propionic acid sodium salt solutions P04(1M) regulation pH is hydrated platinum to 5 ~ 7, then by cis-diamino two（II) sulfate solution is poured into reaction solution, N2Protection, heating water bath will be concentrated to certain volume to 40 ~ 75 °C of reaction 4-6h after reaction solution suction filtration, static, obtain crystal type product 101mg.
The compound as its free base is soluble in water with salt, solubility is 165mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis： C19. 47./.(theory 19. 25%)；H4. 45% (theory 4. 58%)；N10. 98% (theory 11. 23%).
1HNMR (D20) (ppm)： δ 3. 51 (m, 1H) , δ 2. 92 (d, 2H) , δ 2. 87 (t, 2Η) , δ 1. 79 (m, 2Η) , δ 1. 51 (m, 2Η) .
[embodiment 4]:2- (2- triithylamine Ji Yi institutes bases）The cis diaminourea of -3- hydroxy-propionic acids * closes platinum（II) mesylate；
Walk rapid 1:With [the] Walk rapid 1 of embodiment 1.
Walk rapid 2:2- (wash base by 2- triithylamine base second）- 3- hydroxy-propionic aad ethyl ester bromides
Specification takes 2- bromoethyl -3- hydroxy-propionic aad ethyl esters 95.7g (0.4mol) to be placed in three-necked flask, adds 55.6g (0.4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.Separately take triethylamine 40.5g (0. iOL) add in reaction solution, oil bath heating washes paint to reacting under 45 ~ 60 °C with ethyl acetate after 2-6h, drying precipitate（100ml X 3 times）, cross and filter out solvent, obtain Light yellow crystals solid 46.25g, yield 32.67/
Step 3:2- (second -3- hydroxy-propionic acid the sodium salts of 2- tri-
Take NaOH 215mg (5mmol) add water 2.5mL dissolving, produce 2M NaOH solutions, separately take 2- (2- triithylamine base second protective embankment bases）- 3- hydroxy-propionic aad ethyl esters 652mg(2 ol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature and produces 2- (2- triithylamine base second protective embankment bases）- 3- hydroxy-propionic acid sodium salt solutions.
Step 45：With [embodiment 1] step 45
Step 6:2- (2- triithylamine base base ethyl groups）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（II);
Take 2- (2- triithylamine base base ethyl groups）- 3- hydroxy-propionic acid sodium salt solutions H3P04(1M) adjusts pH to 5 ~ 7, then cis-diammine, two is hydrated into platinum（Π) sulfate solution is poured into reaction solution, protection, and heating water bath will be concentrated to certain volume to 45 ~ 75 °C of reaction 4-6h after reaction solution suction filtration, static, obtain crystal type product.
Walk rapid 7:2- (2- triithylamine base base ethyl groups）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（Π) hydroxide；
Step（6) product, which adds water, makes dissolving, by filling anion exchange resin after cooling（0H types）Diaion SA-10A post, obtains 2- (2- triithylamine base second protective embankment bases）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（II) hydroxide 107mg, the compound is soluble in water, solubility is 206mg/ml, acid adding can change into various organic or inorganic salt, can be but not limited to sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc.. Specification free alkali elementary analysis：C28.76% (theory 28.57%)；H6.25% (theory 6.28%)；N9.16% (theory 9.09%).
¾NMR (D20) (ppm)： δ 3.51 (m, 1H) , δ 2.98 (q, 6H) , δ 2.85 (d, 2H) , δ 2.69 (t, 2H) ' δ
1.70 (m, 2H), δ 1.18 (t, 9H).
Walk rapid 8:2- (2- triithylamine base ethyl groups）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（II) mesylate；
Step（7) pH is adjusted to 5 ~ 7 with 1M methanesulfonic acids after product dissolving, produces 2- (2- triithylamine base second protective embankment bases）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（Π) mesylate, solubility is 215 mg/ml.
[embodiment 5]:2- (5- (1- piperidyls）- penta protective embankment base）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（II) Pity hydrochlorates
Step 1:2- (5- bromine amyl groups）- 3- hydroxy-propionic aad ethyl esters
Take commercially available 3- hydroxy-propionic aad ethyl esters 11.8g (O. lmol), and the protective embankment 57.49g (0.25mol) of 1,5- dibromo penta to be placed in 150ml three-necked flasks, add K2C0315.2g (0. llmol), TBAB 156mg is stirred, oil bath heating reacts 16 ~ 24h to 65 ~ 85 °C, suction filtration, remove solid and wash paint with ether (30ml X 3 times), merging filtrate, washs organic layer with water (40ml X 3 times), uses MgS044 ~ 8h, vacuum distillation solvent are dried, then uses oil pump vacuum distillation, vacuum 7mmHg, 139 °C of -149 °C of fraction 8.61g, yield 32.25% are collected.
Step 2:2- (5- (1- piperidyls）- penta protective embankment base）- 3- hydroxy-propionic aad ethyl esters
Take 5- bromine amyl group -3- hydroxy-propionic aad ethyl esters 106.7g (0.4mol) to be placed in three-necked flask, add 55.5g (0. ol) anhydrous K2C03, and acetonitrile 500ml stirrings.It is another to take piperidine solution 85.0g (1.0mol) to add in reaction solution, oil bath heating to 40 ~ 60 Specification
2-6h is reacted under °C, insoluble matter is filtered out, ethyl acetate 1000ml dissolvings are added after filtrate is drained, (250ml X 3 times are washed with the saturation NaCl aqueous solution）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains pale yellow inclined red, transparent shape thing 101.5g, column chromatography method purifies to obtain sterling 32.38g, yield 29.87%
Step 3:2- (5- (1- piperazines-pentyl）- 3- hydroxy-propionic aad ethyl ester sodium salts
Take NaOH 212.3mg (5 ol) add water 2.5m L dissolving, produce 2M NaOH solutions, separately take 2- (5- (1- piperidyls）- penta protective embankment base）- 3- hydroxy-propionic aad ethyl esters 541mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature, 2- (5- (1- piperidyls are produced）- penta protective embankment base）- 3- hydroxy-propionic acid sodium salt solutions.
Step 45：With [embodiment 1] step 45
Step 6:2- (5- (1- piperidyls）- pentyl）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（II) phosphate；
Take 2- (5- (1- piperidyls）- penta protective embankment base）- 3- hydroxy-propionic acid sodium salt solutions H3P04Cis-diammine two is hydrated platinum by (1M) regulation pH to 5 ~ 7 again（Π) sulfate solution is poured into reaction solution, N2Protection, heating water bath will be concentrated to certain volume to 40 ~ 75 °C of reaction 4-6h after reaction solution suction filtration, static, obtain crystal type product 143mg
The compound as its free base is soluble in water with salt, solubility is 119mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：29.80% (theory 29.86%)；H5.73% (theory 5.70%)；N9.62% (theory 9.50%)
¾NMR (D20) (ppm) δ 3.51 (m, 1H), δ 2.92 (d, 2H), δ 2.82 (m, 4H) δ 2.71 (t, 2H) δ 1.83(m, 2H), δ 1.65(m, 2H), δ 1.37 (m, 2H) , δ 1.21 (m, 2H) , δ ΐ.05(m 2H)。
[embodiment 6]:2- (6- (1- nafoxidine protective embankment bases）- hexyl）The cis diaminourea of -3- hydroxy-propionic acids closes platinum（II) phosphoric acid step 1:2- (6- bromine hexyls）- 3- hydroxy-propionic aad ethyl esters Specification
Take commercially available 3- hydroxy-propionic aad ethyl esters 11.76g (0. lmol), and the own lg of protective embankment 61. (0.25mol) of 1,6- dibromo to be placed in 150ml three-necked flasks, add K2C0315.3g (0. llmol), TBAB 155mg is stirred, oil bath heating reacts 16 24h to 65 ~ 85 °C, suction filtration, remove solid and wash paint with ether (30ml X 3 times), merging filtrate, washs organic layer with water (40ml X 3 times), uses MgS044 ~ 8h, vacuum distillation solvent are dried, then steams leavened with oil pump decompression, vacuum 7mmHg, 143 °C of -153 °C of fraction 8.92g, yield 31.74% are collected.
Step 2:2- (6- (1- nafoxidine protective embankment bases）- own protective embankment base）- 3- hydroxy-propionic aad ethyl esters
Take 6- bromines hexyl-3-hydroxy-ethyl propionate 112.6g (0.4mol) to be placed in three-necked flask, add 55.7g (0. ol) it is anhydrous (：03, and acetonitrile 500ml stirrings.Another to take the lg (l.Omol) of nafoxidine protective embankment solution 71. to add in reaction solution, oil bath heating filters out insoluble matter, ethyl acetate 1000ml dissolvings is added after filtrate is drained, are washed with the saturation NaCl aqueous solution to 2-6h is reacted under 40 ~ 60 °C（250ml X 3 times）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains pale yellow inclined red, transparent shape thing 95.8g, column chromatography method purifies to obtain sterling 32.82g, yield 30.28%.
Step 3:2- (6- (1- nafoxidine alkyl）- own protective embankment base）- 3- hydroxy-propionic aad ethyl ester sodium salts
Take the lmg of aOH 212. (5mmol) add water 2.5m L dissolving, produce 2M NaOH solutions, separately take 2- (6- (1- nafoxidine alkyl）- hexyl）- 3- hydroxy-propionic aad ethyl esters 542mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, 45 60h are stirred at room temperature, 2- (6- (1- nafoxidine protective embankment bases are produced）- own protective embankment base）- 3- hydroxy-propionic acid sodium salt solutions.
Step 4,5：With [embodiment 1] step 4,5.
Step 6:2- (6- (1- nafoxidine protective embankment bases）- own protective embankment base）The cis diaminourea of -3- hydroxy-propionic acids * closes platinum（II) phosphoric acid Specification
Take 2- (6- (1- nafoxidine protective embankment bases）- hexyl）- 3- hydroxy-propionic acid sodium salt solutions H3P04(1M) regulation pH is hydrated platinum to 5-7, then by cis-diammine * bis-（II) sulfate solution is poured into reaction solution, N2Protection, heating water bath will be concentrated to certain volume to 40 ~ 75 °C of reaction 4-6h after reaction solution suction filtration, static, obtain crystal type product 113mg.
The compound as its free base is soluble in water with salt, solubility is 109mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, Chinese holly Citron hydrochlorates, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C33.25% (theory 33.19%)；H6.08% (theory 6.21%)；N8.88% (theory 8.93%).
¾NMR (D20) (ppm)： δ 3.52 (m, 1H) , δ 2.91 (d, 2H) , δ 2.8 Km, 4Η), δ 2.71 (m, 2Η), δ 1.82(m, 2Η), δ 1.79(m, 4Η), δ 1.37 (m, 2Η) , δ 1.21 (m, 2Η), δ 1.10 (m, 2Η) , δ 1.01 (m, 2Η)
[embodiment 7]:2- (3- dimethylaminos the third protective embankment bases）- 3- hydroxy-propionic acids are cis-(1,2- trans-cyclohexanediamine）Close platinum（II) phosphate;
Step 1,2,3：With [embodiment 2] step 1,2,3.
Rapid 4:Trans-cyclohexanediamine diiodo- closes platinum（II)
Take Platinous Potassium Chloride (K2PtCl4) 2.075g (5mmol), add water 50ml, at room temperature stirring and dissolving, takes KI6.640g (40mmol) to be added after being dissolved with water 50ml in reaction solution, N2Protection, lucifuge, heating water bath to 0.5 ~ 2h of reaction under 40 ~ 60 °C.Trans-cyclohexanediamine 571mg (5mmol) 50ml water is taken to dissolve again, it is rear to add in reaction solution, continue to keep to react 0.5 ~ 2h under the conditions of this.Suction filtration obtains yellow solid product, uses water（10ml X 3 times）, ether（10ml X 3 times）Washing, obtains product 2.709g, yield 96.2%.Elementary analysis：C12.68% (theory 12.80%)；H2.61% (theory 2.51%)；N4.99% (theory 4.98%).
Step 5:Trans-hydration platinum of hexamethylene two or two（II) sulfate
Specification takes Ag2S04625mg (2mmol) is placed in 100ml three-necked flasks, the 30ml that adds water stirrings, takes trans-cyclohexanediamine diiodo- to close in platinum (II) 1.126g (2mmol) input reaction solutions, and add the reaction of 40ml water, N2Protection, lucifuge reacts 4 ~ 8h under 40-60 °C of water-bath.Suction filtration removes Agl precipitations, obtains the aqueous solution of filtrate, as product.
Walk rapid 6:2- (3- dimethylamino-propane bases）- 3- hydroxy-propionic acids are cis-(1,2- trans-cyclohexanediamine）Close platinum（II) phosphate；
Take 2- (3- dimethylaminos the third protective embankment bases）- 3- hydroxy-propionic acid sodium salt solutions H3P04(1M) regulation ρ Η are hydrated platinum to 5 ~ 7, then by trans-cyclohexanediamine two（Π) sulfate solution is poured into reaction solution, Ν2Reaction solution is added 2.5g column chromatography silica gels by protection, heating water bath to 40 ~ 60 °C of 4 ~ 8h of reaction（200-300 mesh）Drained after stirring 15min, column chromatography processing obtains product 128mg.
The compound is soluble in water, solubility is 178mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C34.57% (theory 34.85%)；H5.83% (theory 6.02%);N8.95% (theory 8.71%).
¾NMR (D20) (ppm)：δ 3.51 (m, 1H), δ 2.91 (d, 2H), δ 2.82 (s, 6 Η), δ 2.78 (t, 2 Η), (br of δ 2.06,2 Η), δ 1.74 (m, 2 Η), δ 1.46 (m, 4 Η), (m of δ 1.21,2 Η), δ 1.11 (m, 4 Η).
[embodiment 8]:2- (3- dimethylaminos the third protective embankment bases）- glycolic is cis-(1,2- trans-cyclohexanediamine）Close platinum（II) phosphoric acid step 1:2- (3- bromines the third protective embankment bases）- ethyl glycolate
Take commercially available ethyl glycolate 10.5g (0. lmol), and 1,2- dibromopropane 49.4g (0.25mol) to be placed in 150ml three-necked flasks, add K2C0315. lg (0. llmol), TBAB 156mg are stirred, oil bath heating to 65 ~ 85 °C of 16 ~ 24h of reaction, suction filtration, removes solid and is washed, merging filtrate with ether (30ml X 3 times), organic layer is washed with water (40ml X 3 times) Specification MgS044 ~ 8h, vacuum distillation solvent are dried, then uses oil pump vacuum distillation, vacuum 7mmHg, 127 °C of -137 °C of fraction 7.19g, yield 32.1% are collected.
Walk rapid 2:2- (3- dimethylaminos the third protective embankment bases）- ethyl glycolate bromide
Take 2- (the third protective embankment of 3- bromines base)-ethyl glycolate 89.6g (0.4mol) to be placed in three-necked flask, add 55.8g (0.4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.Another to take trimethylamine solution 23.6g (1.0mol) to add in reaction solution, oil bath heating is washed with ethyl acetate to reacting under 40 ~ 60 °C after 2-6h, drying precipitate（100ml X 3 times）, cross and filter out solvent, obtain Light yellow crystals solid 31.2g, yield 27.47%.
Step 3:2- (3- dimethylaminos the third protective embankment bases）- glycolic sodium salt
+
Take NaOH 215mg (5mmol) add water 2.5mL dissolving, produce 2M NaOH solutions, separately take 2- (3- dimethylaminos the third protective embankment bases）- ethyl glycolate bromide 568mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature, 2- (3- dimethylamino propyls are produced）- sodium glycollate salting liquid.
Step 4,5：With [embodiment 7] step 4,5.
Step 6:2- (3- dimethylaminos the third protective embankment bases）- glycolic is cis-(1,2- trans-cyclohexanediamine）Close platinum（II);
Take 2- (3- dimethylaminos the third protective embankment bases）- sodium glycollate salting liquid P04(1M) regulation pH is hydrated platinum to 5 ~ 7, then by trans-cyclohexanediamine two（Π) sulfate solution is poured into reaction solution, N2Protection, heating water bath will be concentrated to certain volume to 40 ~ 60 °C of 4 ~ 8h of reaction after reaction solution suction filtration, static, obtain crystal type product.
Step 7:2- (3- dimethylaminos the third protective embankment bases）- glycolic is cis-(1,2- trans-cyclohexanediamine）Close platinum（II) hydrogen-oxygen Specification compound;
Step（6) product, which adds water, makes dissolving, by filling anion exchange resin after cooling（0H types）Diaion SA-10A post obtains 2- (3- dimethylaminos the third protective embankment bases）- glycolic is cis-(1,2- trans-cyclohexanediamine）Close platinum（Hydroxide 118mg Π), the compound is soluble in water, and solubility is 225mg/ ml, acid adding can change into various organic or inorganic salt, can be but not limited to sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc..Free alkali elementary analysis：C33. 71% (theory 33. 6%)；H6. 25% (theory 6. 20%)；N8. 26% (theory 8. 40%).
LHNMR (D20) (ppm)：δ 3. 51 (m, 1H), δ 2. 80 (s, 9H), δ 2. 71 (t, 2H), δ 2. 06 (br, 2H), δ 1. 74 (m, 2H), δ 1. 46 (m, 4H), (the m of δ 1. 21,2H), δ 1. 11 (m, 4H).
Walk rapid 8:2- (2- dimethylaminos the third protective embankment bases）The cis two amminos platinum of-glycolic（II) mesylate；
Step（7) pH is adjusted to 57 with 1M methanesulfonic acids after product dissolving, produces 2- (3- dimethylaminos the third protective embankment bases）- glycolic * is cis-(1,2- trans-cyclohexanediamine）Close platinum（I I) mesylate, solubility is 230mg/ml。
[embodiment 8] compound can also be prepared in the following manner：
Step 1 is ibid：
Step 2:2- (3- dimethylaminos the third protective embankment bases）- ethyl glycolate hydroxide
OH—
Take the 5g (0. 4mol) of 2- (the third protective embankment of 3- bromines base)-ethyl glycolate 89. to be placed in three-necked flask, add 55. 6g (0. 4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.Another to take the 6g of trimethylamine solution 23. (1. 0mol) to add in reaction solution, oil bath heating is washed with ethyl acetate to reacting under 40 ~ 60 °C after 2-6h, drying precipitate（100ml X 3 times）, cross and filter out solvent, obtain light yellow knot Specification crystalline substance solid, the 50ml that adds water makes dissolving, adds Ag20 50g, centrifugation, supernatant is extracted three times with 300ml ethyl acetate respectively, merges extract solution, and revolving removes ethyl acetate and obtains product 25.2g, yield 28.51%.
Step 3:2- (3- dimethylaminos the third protective embankment bases）- glycolic sodium salt
OH—
Take NaOH 215mg (5mmol) add water 2.5mL dissolving, produce 2M NaOH solutions, separately take 2- (3- dimethylaminos the third protective embankment bases）- ethyl glycolate hydroxide 442mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature, 2- (3- dimethylamino propyls are produced）- sodium glycollate salting liquid.
Walk rapid 4,5：With [the] Walk rapid 4,5 of embodiment 7.
Step 6:2- (3- dimethylaminos the third protective embankment bases）- glycolic is cis-(1,2- trans-cyclohexanediamine）Close platinum（II) mesylate；
Take step（3) compound solution methanesulfonic acid（1M) regulation pH is hydrated platinum to 5 ~ 7, then by trans-cyclohexanediamine two（II) sulfate solution is poured into reaction solution, N2Protection, heating water bath reacts 4 ~ 8h to 40 ~ 60 °C, static by reaction solution suction filtration Hou Nong Shrink to certain volume, produces 2- (3- dimethylaminos the third protective embankment bases）- glycolic * is cis-(1,2- trans-cyclohexanediamine）Close platinum（Π) mesylate.Must be by filling anion exchange resin during quaternary ammonium compoundses change acid ion of the present invention（0H types）Post carries out ion exchange, the salt needed for then being obtained with corresponding acid reaction.
[embodiment 9]:2- (2- ethylamino second protective embankments base)-lactic acid is cis-and (1,2- trans-cyclohexanediamine) close platinum（II) phosphoric acid step 1:2- (2- bromoethanes base)-ethyl lactate
Take commercially available ethyl lactate 11.8g (0. lmol), and the lg (0.25mol) of 1,2- dibromo second protective embankment 47. to be placed in 150ml three-necked flasks, add K2C0315. lg (0. llmol), TBAB 156mg are stirred, oil bath heating is taken out to 65 ~ 85 °C of 16 ~ 24h of reaction Specification is filtered, and is removed solid and is washed, merging filtrate with ether (30ml X 3 times), washs organic layer with water (40ml X 3 times), use MgS04Dry 4 ~ 8h, vacuum distillation solvent, then steam leavened with oil pump decompression, collect vacuum 132 °C of -142 °C of fraction 7.23g of 7mmHg, yield 32.13%
Step 2:2- (2- ethylamino second protective embankment bases）- ethyl lactate
Take 2- (2- bromine second protective embankments base)-ethyl lactate 90.2g (0. ol) to be placed in three-necked flask, add 55.0 g (0.4mol) water K2C03, and acetonitrile 500ml stirrings.Plus the ethylamino 44.2g (1.0mol) of freezen protective enters in reaction solution, oil bath heating filters out insoluble matter to 2-6h is reacted under 40 ~ 60 °C, and ethyl acetate 1000ml dissolvings are added after filtrate is drained, are washed with the saturation NaCl aqueous solution（250ml X 3 times）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains pale yellow inclined red, transparent shape thing 70.5g, column chromatography method purifies to obtain sterling 21.3g, yield 28.2%
Walk rapid 3:2- (2- ethylamino ethyl groups）- lactylate salt
Take NaOH 215mg (5 ol) add water 2.5mL dissolving, produce 2M NaOH solutions, separately take 2- (2- ethylamino second protective embankment bases）- ethyl lactate 378mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature, 2- is produced
(2- ethylamino second protective embankment bases）- lactylate salt solution.
Step 45：With [embodiment 7] step 45
Step 6:2- (2- ethylamino second protective embankment bases）- lactic acid is cis-(1 2- trans-cyclohexanediamines）Close platinum（II) phosphate
Take 2- (2- ethylamino ethyl groups）- lactic acid disodium salting liquid H3P04(1M) regulation pH is hydrated platinum to 5 ~ 7, then by trans-cyclohexanediamine two（Π) sulfate solution is poured into reaction solution, N2Reaction solution is added 2.5g column chromatography silica gels by protection, heating water bath to 40 ~ 60 °C of 4 ~ 8h of reaction（200-300 mesh）Drained after stirring 15min, column chromatography processing obtains product 123mg
¾NMR (D20) (ppm)： δ 2.81 (q, 2Η), δ 2.70 (t, 2Η), 2.06 (br, 2H) , 1.81(s, 3H), δ Specification
1.70 (t, 2H), 1.46 (m, 4H), 1.21 (br, 2H), δ 1.18 (t, 3H) 1.00 (m, 2H).
The compound is soluble in water, solubility is 132mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C33.53% (theory 33.33%)；H5.51% (theory 5.77%);N8.68% (theory 8.97%).
[embodiment 10] 2- (3- (1- piperidyls）- the third protective embankment base）- glycolic《Cis-(1,2- trans-cyclohexanediamine）Close platinum（Π) Chinese holly Citron hydrochlorates
Step 1:With [embodiment 8] step 1.
Step 2:2- (3- (1- piperidyls）- the third protective embankment base）- ethyl glycolate
Take the lg (0.4mol) of 2- (the third protective embankment of 3- bromines base)-ethyl glycolate 90. to be placed in three-necked flask, add 55.4g (0.4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.It is another to take the lg of piperidine solution 85. (l.Omol) to add in reaction solution, oil bath heating is to reacting 2-6h under 40 ~ 60 °C, insoluble matter is filtered out, ethyl acetate 1000ml dissolvings are added after filtrate is drained, (250ml X 3 times are washed with the saturation NaCl aqueous solution）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains pale yellow inclined red, transparent shape thing 80.5g, column chromatography method purifies to obtain sterling 26.35g, yield 28.77%.
Walk rapid 3:2- (3- (1- piperazines-propyl）- glycolic sodium salt
Take NaOH 212mg (5mmol) add water 2.5m L dissolving, produce 2M NaOH solutions, separately take 2- (3- (1- piperidyls）- propyl）- ethyl glycolate 458mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature, 2- (3- (1- piperidyls are produced）- the third protective embankment base）- sodium glycollate salting liquid.
Step 4,5：With [embodiment 7] step 4,5.
Walk rapid 6:2- (3- (1- piperidyls）- the third protective embankment base)-glycolic is cis-and (1,2- trans-cyclohexanediamine) close platinum（II) citrate Specification
Take 2- (3- (1- piperidyls）- propyl）- sodium glycollate salting liquid citric acid C6H807(1M) regulation pH is hydrated platinum to 5 ~ 7, then by trans-cyclohexanediamine two（Π) sulfate solution is poured into reaction solution, N2Reaction solution is added 2.5g column chromatography silica gels by protection, heating water bath to 40 ~ 60 °C of 4 ~ 8h of reaction（200-300 mesh）Drained after stirring 15min, column chromatography processing obtains product 137mg.
¾NMR (D20) (ppm)： δ 3.52 (m, 1Η) , δ 2.78 (m, 4Η) , δ 2.70(t, 2Η), δ 2.06 (br, 2Η) , δ 1.81(m, 2Η), δ 1.70(m, 2Η), δ 1.46 (m, 2Η) , δ 1.37 (m, 2Η) δ 1.21 (br, 2Η) , δ 1.15(m, 4Η), δ 1.08 (m, 2Η), δ 1·00(ιη, 2Η).
The compound is soluble in water, solubility is 120mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, phosphate, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C37.51% (theory 37.80%);H6.15% (theory 6.10%);N8.48% (theory 8.27%).
[embodiment 11]:2- (3- lignocaines the third protective embankment bases）- 3- hydroxy-propionic acids are cis-(1,2- trans-ring pentanediamine）Close platinum（II) phosphate；
Step 1:With [embodiment 2] step 1.
Step 2:2- (3- lignocaine propyls）- 3- hydroxy-propionic aad ethyl esters
Take 2- (3- bromopropyls）- 3- hydroxy-propionic aad ethyl esters 95.5g (0.4mol) is placed in three-necked flask, adds 55.6g (0.4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.The another diethylamine solution 73.0g (1.0mol) for taking freezen protective is added in reaction solution, oil bath heating is to reacting 2-6h under 40 60 °C, insoluble matter is filtered out, ethyl acetate 1000ml dissolvings are added after filtrate is drained, are washed with the saturation NaCl aqueous solution（250mlX3 times）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains the pale yellow inclined lg of red, transparent shape thing 80., column chromatography method purifies to obtain sterling 26.6g, yield 28.79%.
Walk rapid 3:2- (3- lignocaines the third protective embankment bases）- 3- hydroxy-propionic acid sodium Specification
Take NaOH 212.5mg (5mmol) add water 2.5mL dissolving, produce 2M NaOH solutions, separately 2- (the third protective embankment of 3- lignocaines base) -ol acetoacetic ester 462mg (2mmol) is taken to be placed in 20mL three-necked flasks, add above-mentioned NaOH solution, 45 ~ 60h is stirred at room temperature, produces 2- (3- lignocaines the third protective embankment bases）- 3- hydroxy-propionic acid sodium salt solutions.
Synthesis step 4:1,2- trans-ring pentanediamine
Cyclopentene 6.81g (100mmol) is taken to be placed in 100ml three-necked flasks, plus dichloromethane protective embankment 30ml stirring and dissolvings, Br is slowly added dropwise under the conditions of -5 ~ 10 ° of 〇216.5g (103mmol), stirs l 3h, uses saturated sodium bicarbonate solution（10ml X 3 times）Washing, the anhydrous MgS0 of organic layer42 ~ 3h being dried, water pump decompression extracts solvent, obtains light yellow clear shape thing 1,2- is trans-the protective embankment 20.56g of dibromo ring penta, yield 90.18%.Elementary analysis：C26.51% (theory 26.32%)；H3.62% (theory 3.51%).
Take 1,2- is trans-dibromo pentamethylene 11.5g (50mmol), it is placed in 100ml autoclave pressures, the ethanol solution 30ml of the ammonia of power Jie 30%, is heated to 40 ~ 60 °C, reacts 6 ~ 8 hours, solvent is evaporated off, light yellow clear shape thing 1,2- is trans-ring pentanediamine 4.015g, yield 79.6%o elementary analyses：C60.21% (theory 59.95%)；H12.12% (theory 12.08%) N28.21% (theory 27.97%).
Walk rapid 5:1,2- trans-ring pentanediamine diiodo- closes platinum（II)
Take Platinous Potassium Chloride（K2PtCl4) 2.073g (5mmol), add water 50ml, at room temperature stirring and dissolving, takes KI6.63g (40mmol) to be added after being dissolved with water 50ml in reaction solution, N2Protection, lucifuge, heating water bath to 0.5 ~ 2h of reaction under 40 ~ 60 °C.Take again 1,2- it is trans-ring pentanediamine 501mg (5mmol) 50ml water dissolves, rear to add in reaction solution, continue to keep to react 0.5 ~ 2h under the conditions of this.Suction filtration obtains yellow solid product, uses water（10mlX3 times）, ether（10ml X 3 times) washing, obtain product 2.561g, yield 93.3%.Elementary analysis：C10.78% (theory 10.93%)；H2.31% (theory 2.19%)；N4.98% (theory 5.10%) Specification rapid 6:1, the 2- trans hydration of a ring penta 22 platinum（II) sulfate
Take Ag2S04625mg (2mmol) is placed in 100ml three-necked flasks, the 30ml that adds water stirring, take 1,2- it is trans-ring pentanediamine diiodo- close platinum（Π) 1.10g (2mmol) is put into reaction solution, and adds the reaction of 40ml water, N2Protection, lucifuge reacts 4 ~ 8h under 40 ~ 60 °C of water-bath.Suction filtration removes Agl precipitations, obtains the aqueous solution of filtrate, as product.
Step 7:2- (3- lignocaines the third protective embankment bases）- 3- hydroxy-propionic acids are cis-(1,2- trans-ring pentanediamine）Close platinum（II) phosphate
Take 2- (3- lignocaines the third protective embankment bases）- 3- hydroxy-propionic acid sodium salt solutions H3P04(1M) adjusts pH and is hydrated platinum to 5 ~ 7, then by 1,2- trans-cyclohexanediamines two（II) sulfate solution is poured into reaction solution, N2Reaction solution is added 2.5g column chromatography silica gels by protection, heating water bath to 40 ~ 60 °C of 4 ~ 8h of reaction（200-300 mesh）Drained after stirring 15min, column chromatography processing obtains product 132mg.
LHNMR (D20) (ppm)：δ 3.52 (m, 1 Η), (d of δ 2.91,2 Η), δ 2.79 (q, 4 Η), δ 2.71 (t, 2 Η), (br of δ 2.09,2 Η), δ 1.82 (m, 2 Η), (the m of δ 1.71,2 Η), δ 1.48 (m, 2 Η), (the m of δ 1.43,2 Η), δ 1.21 (m, 1 Η), (the t of δ 1.09,6H), S 1.01 (m, lH).
The compound is soluble in water, solubility is 122mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C36.51% (theory 36.29%);H6.47% (theory 6.25%);N8.31% (theory 8.47%).
[embodiment 12] 2- (3- dimethylaminos the third protective embankment bases）- glycolic is cis-and 1,2- ethylenediamines close platinum（II) tosilate；Step 1,2,3：With [embodiment 8] step 1,2,3.
Step 4:1,2- ethylenediamine diiodo- closes platinum（II) Specification
Take Platinous Potassium Chloride（K2PtCl4) 2.076g (5mmol), add water 50ml, at room temperature stirring and dissolving, takes KI6.64g
(40mmol) is added in reaction solution after being dissolved with water 50ml, N2Protection, lucifuge, heating water bath to 0.5 ~ 2h of reaction under 40 ~ 60 °C.1, the 2- ethylenediamines of freezen protective are taken again（It is commercially available）301mg (5mmol) 50ml water dissolves, rear to add in reaction solution, continues to keep to react 0.5 ~ 2h under the conditions of this.Suction filtration obtains yellow solid product, uses water（10ml X 3 times）, ether（10ml X 3 times）Washing, obtains product 2.254g, yield 89.8%.Elementary analysis：C4.77% (theory 4.72%)；HI.41% (theory 1.57%)；
N5.41% (theory 5.50%).
Step 5:1,2- ethylenediamines two are hydrated platinum（II) sulfate
S04
Take Ag2S04625mg (2mmol) is placed in 100ml three-necked flasks, the 30ml that adds water stirrings, takes 1,2- ethylenediamines diiodo- to close in platinum (II) 1.020g (2mmol) input reaction solutions, and add the reaction of 40ml water, N2Protection, lucifuge reacts 4 ~ 8h under 40-60 °C of water-bath.Suction filtration removes Agl precipitations, obtains the aqueous solution of filtrate, as product.
Step 6:2- (3- dimethylaminos base the third protective embankment bases）- glycolic is cis-and 1,2- ethylenediamines close platinum（II);
+
Take 2- (3- dimethylaminos base the third protective embankment bases）- sodium glycollate salting liquid is used04( ）Adjust ^ and be hydrated platinum to 5 ~ 7, then by ethylenediamine ' two（II) sulfate solution is poured into reaction solution, N2Protection, heating water bath reacts 4 ~ 8h to 40 ~ 60 °C, static by reaction solution suction filtration Hou Nong Shrink to certain volume, obtains crystal type product.
Step 7:2- (3- dimethylaminos base the third protective embankment bases）- glycolic is cis-and 1,2- ethylenediamines close platinum（II) hydroxide；
Step（6) product, which adds water, makes dissolving, by filling anion exchange resin after cooling（0H types） Diaion SA-10A The post of specification obtains 2- (3- dimethylamino base propyls）- glycolic * is cis-(1,2- trans-cyclohexanediamine）Close platinum（II hydroxide 107mg), the compound is soluble in water when pH is less than 8, solubility is 200mg/ml, acid adding can change into various organic or inorganic salt, can be but not limited to sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc..Hydroxide elementary analysis：C26.71% (theory 26.91%)；H5.45% (theory 5.61%)；N9.26% (theory 9.42%).
¾NMR ( 0) (ppm)：δ 3.52 (m, 1H), δ 2.69 (s, 9 Η), δ 2.55 (t, 2 Η), δ 2.24-2.31 (br, 4 Η), δ 1.73 (m, 2 Η), δ 1.49 (m, 2 Η).
Step 8:2- (3- dimethylaminos base the third protective embankment bases）- glycolic is cis-and 1,2- ethylenediamines close platinum（II) tosilate;
Walk is rapid（7) pH is adjusted to 5 ~ 7 with 1M methanesulfonic acids after product dissolving, produces 2- (3- triithylamine base base the third protective embankment bases）- glycolic is cis-and 1,2- diethylamine closes platinum（II) tosilate, solubility is 235 mg/ml.
[embodiment 13] 2- (2- lignocaine second protective embankments base) -3- hydroxy-propionic acids are cis-and 1,3- propane diamine closes platinum（II) phosphate；Step 1:With [embodiment 1] step 1.
Step 2:2- (2- lignocaine ethyl groups）- 3- hydroxy-propionic aad ethyl esters
Take 2- (2- bromoethyls) -3- hydroxy-propionic aad ethyl esters 90g (0. ol) to be placed in three-necked flask, add 55.8g (0.4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.It is another to take the lower diethylamine solution 73.2g (l. Omol) preserved of freezing to add in reaction solution, oil bath heating is to reacting 2-6h under 40 60 °C, insoluble matter is filtered out, ethyl acetate 1000ml dissolvings are added after filtrate is drained, are washed with the saturation NaCl aqueous solution（250mlX3 times）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains pale yellow inclined red, transparent shape thing 82.7g, column chromatography method purifies to obtain sterling 26.51g, yield 30.54%.
Walk rapid 3:2- (2- lignocaine second protective embankment bases）- 3- hydroxy-propionic acid sodium salts Specification
Take NaOH 215mg (5 ol) add water 2.5mL dissolving, produce 2M aOH solution, separately take 2- (2- methylamino second protective embankment bases）- 3- hydroxy-propionic aad ethyl esters 435mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature, 2- (2- lignocaine second protective embankment bases are produced）- 3- hydroxy-propionic acid sodium salt solutions.
Step 4:1 3- propane diamine diiodo- closes platinum（II)
Take Platinous Potassium Chloride（K2PtCl4) 2.073g (5 ol), add water 50ml, at room temperature stirring and dissolving, takes KI6.63g (40mmol) to be added after being dissolved with water 50ml in reaction solution, N2Protection, lucifuge, heating water bath takes 1 3- propane diamine of freezen protective to 0.5 ~ 2h of reaction under 40 ~ 60 °C again（It is commercially available）372mg (5mmol) 50ml water dissolves, rear to add in reaction solution, continues to keep to react 0.5 ~ 2h under the conditions of this.Suction filtration obtains yellow solid product, uses water（10mlX3 times）, ether（10mlX3 times）Washing, obtains product 2.281g, yield 87.6%.Elementary analysis：C6.77% (theory 6.88%) HI.79% (theory 1.91%) N5.43% (theory 5.35%)
Step 5:1 3- propane diamine two
Take Ag2S04625mg (2mmol) is placed in 100ml three-necked flasks, the 30ml that adds water stirrings, takes 1 2- ethylenediamines diiodo- to close in platinum (II) 1.043g (2mmol) input reaction solutions, and add the reaction of 40ml water, N2Protection, lucifuge reacts 4 ~ 8h under 40-60 °C of water-bath.Suction filtration removes Agl precipitations, obtains the aqueous solution of filtrate, as product.
Step 6:2- (2- lignocaine second protective embankment bases）Cis -1 3- propane diamine of -3- hydroxy-propionic acids closes platinum（II) phosphate
Take 2- (2- lignocaine ethyl groups）- 3- hydroxy-propionic acid sodium salt solutions P04(1M) adjusts ρ Η to 5 ~ 7, then by 1 Specification
3- propane diamine《Two hydration platinum（II) sulfate solution is poured into reaction solution, N2Reaction solution is added 2.5g column chromatography silica gels by protection, heating water bath to 40 ~ 60 °C of 4 ~ 8h of reaction（200-300 mesh）Drained after stirring 15min, column chromatography processing obtains product 123mg.
¾NMR (D20) (ppm)：δ 3.51 (m, 1 Η), (d of δ 2.92,2 Η), δ 2.78 (q, 4 Η), δ 2.70 (m, 2 Η), (t of δ 2.26,4 Η), δ 1.70 (m, 2H), (the m of δ 1.45,2 Η), δ 1.08 (t, 6H).
The compound is soluble in water, solubility is 145mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C31.70% (theory 31.58%);H5.81% (theory 5.96%);N9.28% (theory 9.21%).
[embodiment 14] 2- (n-propylamine base the third protective embankment bases of 3- bis-）Cis-Isosorbide-5-Nitrae-the dibutyl amine of -3- hydroxy-propionic acids closes platinum（II) phosphate；Step 1:With [embodiment 3] step 1.
Step 2:Step 2:2- (3- dipropyl aminopropan alkyl）- 3- hydroxy-propionic aad ethyl esters
Take 2- (3- bromopropyls）- 3- hydroxy-propionic aad ethyl esters 95.6g (0.4mol) is placed in three-necked flask, adds 55.5g (0.4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.Another to take dipropyl amine aqueous solution 93.0g (1.0mol) to add in reaction solution, oil bath heating filters out insoluble matter, ethyl acetate 1000ml dissolvings is added after filtrate is drained, are washed with the saturation NaCl aqueous solution to 2-6h is reacted under 40 ~ 60 °C（250ml X 3 times）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains the pale yellow inclined lg of red, transparent shape thing 84., column chromatography method purifies to obtain the lg of sterling 27., yield 26.99%.
Step 3:2- (3- dipropyl aminopropan protective embankment bases）- 3- hydroxy-propionic acid sodium
Take NaOH 213mg (5mmol) add water 2.5mL dissolving, produce 2M NaOH solutions, separately take 2- (3- dipropyl aminopropan protective embankment bases）- 3- hydroxy-propionic aad ethyl esters 502mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, 45 60h are stirred at room temperature, 2- (3- dipropyl aminopropan alkyl is produced）- 3- hydroxy-propionic acid sodium salt solutions.
Step 4:Putriscine diiodo- closes platinum（II) Specification
Take Platinous Potassium Chloride (K2PtCl4) 2.071g (5mmol), add water 50ml, at room temperature stirring and dissolving, takes KI6.635g (40mmol) to be added after being dissolved with water 50ml in reaction solution, N2Protection, lucifuge, heating water bath to 0.5 ~ 2h of reaction under 40 ~ 60 °C.The Putriscine of freezen protective is taken again（It is commercially available）431mg (5mmol) 50ml water dissolves, rear to add in reaction solution, continues to keep to react 0.5 ~ 2h under the conditions of this.Suction filtration obtains yellow solid product, uses water（10ml X 3 times）, ether（10ml X 3 times）Washing, obtains product 2.365g, yield 88.1%.Elementary analysis：C8.69% (theory 8.94%)；H2.39% (theory 2.23%)；N5.44% (theory 5.21%).
Step 5:1,4- butanediamine two is hydrated platinum（II) sulfate
Take Ag2S04624mg (2mmol) is placed in 100ml three-necked flasks, the 30ml that adds water stirrings, takes Putriscine diiodo- to close in platinum (II) 1.072g (2mmol) input reaction solutions, and add the reaction of 40ml water, N2Protection, lucifuge, water-bath 40-60
4 8h are reacted under °C.Suction filtration removes Agl precipitations, obtains the aqueous solution of filtrate, as product.
Step 6:2- (n-propylamine base the third protective embankment bases of 3- bis-）- 3- hydroxy-propionic acids are cis-and Putriscine closes platinum（Π) phosphate
Take 2- (the n-propylamine base propyls of 3- bis-）- 3- hydroxy-propionic acid sodium salt solutions P04(1M) is adjustedPH is hydrated platinum to 5 ~ 7, then by Putriscine two（II) sulfate solution is poured into reaction solution, N2Reaction solution is added 2.5g column chromatography silica gels by protection, heating water bath to 40 ~ 60 °C of 4 ~ 8h of reaction（200-300 mesh）Drained after stirring 15min, column chromatography processing obtains product 137mg.
¾NMR (D20) (ppm)：δ 3.51 (m, 1 Η), δ 2.92 (d, 2 Η), δ 2.71 (m, 4 Η), δ 2.51 (m, 4 Η), δ 2.37 (t, 2 Η), (m of δ 2.14,2H), δ 1.83 (m, 2 Η), δ 1.53 (t, 4 Η), (m of δ 1.38,4 Η), δ 1.06 (t, 6 Η).
The compound is soluble in water, solubility is 142mg/ml, can be easy to change into the organic or inorganic salt of other species by free, can be but not limited to sulfate, mesylate, tartrate, succinate, acetate, citrate, to first Specification benzene sulfonate, fumarate etc..Free alkali elementary analysis：C37.32% (theory 37.50%);H6.62% (theory 6.84%);N7.98% (theory 8.20%)
[embodiment 15] 2- (2- dimethylamino second protective embankment bases）- 3- hydroxy-propionic acids cis -1 3- (2 2- methylols）- propane diamine closes platinum（II) phosphate；
Step 1:With [embodiment 1] step 1
Step 2:2- (2- dimethylaminoethane bases）- 3- hydroxy-propionic aad ethyl esters
Take 2- (2- bromoethyls）The lg of -3- hydroxy-propionic aad ethyl esters 90. (0.4mol) is placed in three-necked flask, adds 55.6g (0.4mol) anhydrous K2C03, and acetonitrile 500ml stirrings.It is another to take the lower lg of dimethylamine solution 45. (l. Omol) preserved of freezing to add in reaction solution, oil bath heating is to reacting 2-6h under 40 60 °C, insoluble matter is filtered out, ethyl acetate 1000ml dissolvings are added after filtrate is drained, are washed with the saturation NaCl aqueous solution（250mlX3 times）, the anhydrous MgS0 of organic layer4It is dried overnight, water pump decompression extracts solvent, obtains the pale yellow inclined lg of red, transparent shape thing 79., column chromatography method purifies to obtain sterling 23.4g, yield 30.95%
Walk rapid 3:2- (2- lignocaine second）- 3- hydroxy-propionic acid sodium salts
Take NaOH 215mg (5 ol) add water 2.5mL dissolving, produce 2M NaOH solutions, separately take 2- (2- dimethylamino second protective embankment bases）- 3- hydroxy-propionic aad ethyl esters 378mg (2mmol) is placed in 20mL three-necked flasks, adds above-mentioned NaOH solution, and 45 ~ 60h is stirred at room temperature, 2- (2- lignocaine ethyl groups are produced）- 3- hydroxy-propionic acid sodium salt solutions.
Step 4:(2 2- methylols-propane diamine diiodo- closes platinum to 1,3-（II)
Take Platinous Potassium Chloride（K2PtCl4) 2.074g (5mmol), add water 50ml, at room temperature stirring and dissolving, takes KI6.636g (40mmol) to be added after being dissolved with water 50ml in reaction solution, N2Protection, lucifuge, heating water bath to 0.5 ~ 2h of reaction under 40 ~ 60 °C Specification takes 1 3- (2 2- methylols again）- propane diamine 671mg (5 ol) 50ml water dissolves, rear to add in reaction solution, continues to keep to react 0.5 ~ 2h under the conditions of this.Suction filtration obtains yellow solid product, uses water（10mlX3 times）, ether（10mlX3 times) washing, obtain product 2.163g, the elementary analysis of yield 79.96%：C10.37% (theory 10.29%) H2.49% (theory 2.40%) N5.01% (theory 4.80%)
Step 5:(2 2--propane diamine two is hydrated platinum to 1,3-（II) sulfate
Take Ag2S04624mg (2mmol) is placed in 100ml three-necked flasks, the 30ml that adds water stirrings, takes 1 3- (2 2_ methylols）- propane diamine * diiodo-s close platinum（11) 1.162g (2 ol) is put into reaction solution, and adds the reaction of 40ml water, N2Protection, lucifuge reacts 4 ~ 8h under 40 ~ 60 °C of water-bath.Suction filtration removes Agl precipitations, obtains the aqueous solution of filtrate, as product.
Step 6:2- (2- dimethylamino second protective embankment bases）- 3- hydroxy-propionic acids cis -1 3- (2 2- methylols）- propane diamine closes platinum（Π) phosphate
Take 2- (2- dimethylaminoethane bases）- 3- hydroxy-propionic acid sodium salt solutions P04(1M) adjusts ρ Η to 5 ~ 7, then by 1 3- (2 2- methylols）- propane diamine two is hydrated platinum（II) sulfate solution is poured into reaction solution, Ν2Reaction solution is added 2.5g column chromatography silica gels by protection, heating water bath to 40 ~ 60 °C of 4 ~ 8h of reaction（200-300 mesh）Drained after stirring 15min, column chromatography processing obtains product 127mg
1Brain R (0) (ppm) δ 3.51 (m, 1H), (s of δ 3.47,4 Η), δ 2.92 (d, 2 Η), (s of δ 2.74,6 Η), δ 2.69 (t, 2 Η), (s of δ 2.55,4 Η), δ 1.68 (Η of m 2)
The compound is soluble in water, solubility is 145mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, Chinese holly Citron hydrochlorates, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C29.29% (theory 29.51%);H5.53% (theory 5.53%);N8.48% (theory 8.61%).
[embodiment 16]:2- (2- dimethylamino second protective embankment bases）- 3- hydroxy-propionic acids cis -1 4- (trans -2 3- cyclobutyl）- butylamine closes platinum（II) phosphate；
Step 123：With [embodiment 15] step 123 Specification step 4:Isosorbide-5-Nitrae-(trans -2,3- cyclobutyl）- butylamine * diiodo-s close platinum（II)
Take Platinous Potassium Chloride（K2PtCl4) 2.075g (5mmol), add water 50ml, at room temperature stirring and dissolving, takes KI6.64g (40mmol) to be added after being dissolved with water 50ml in reaction solution, N2Protection, lucifuge, heating water bath to 0.5 ~ 2h of reaction under 40 ~ 60 °C.Isosorbide-5-Nitrae-(trans -2,3- cyclobutyl is taken again）- butylamine 571mg (5mmol) 50ml water dissolves, rear to add in reaction solution, continues to keep to react 0.5 ~ 2h under the conditions of this.Suction filtration obtains yellow solid product, uses water（10ml X 3 times）, ether（10ml X 3 times) washing, obtain product 2.251g, yield 79.96%.Elementary analysis：C12.61% (theory 12.79%)；H2.45% (theory 2.49%)；N5.11% (theory 4.97%)
Step 5:Isosorbide-5-Nitrae-(trans -2,3- cyclobutyl）- butylamine two is hydrated platinum（II) sulfate
Take Ag2S04625mg (2 Wai ol) is placed in 100ml three-necked flasks, the 30ml that adds water stirrings, takes 1,3- (2,2-methylols）- propane diamine * diiodo-s close platinum（Π) 1.122g (2mmol) is put into reaction solution, and adds the reaction of 40ml water, N2Protection, lucifuge reacts 4 ~ 8h under 40 ~ 60 °C of water-bath.Suction filtration removes Agl precipitations, obtains the aqueous solution of filtrate, as product.
Step 6:2- (2- dimethylamino second protective embankment bases）- 3- hydroxy-propionic acids cis-Isosorbide-5-Nitrae-(trans -2,3- cyclobutyl）- butylamine closes platinum（II) phosphate
Take 2- (2- dimethylamino second protective embankment bases）- 3- hydroxy-propionic acid sodium salt solutions P04(1M) adjusts pH to 5 ~ 7, then by Isosorbide-5-Nitrae-(trans -2,3- cyclobutyl）- butylamine two is hydrated platinum（II) sulfate solution is poured into reaction solution, N2Reaction solution is added 2.5g column chromatography silica gels by protection, heating water bath to 40 ~ 60 °C of 4 ~ 8h of reaction（200-300 mesh）Drained after stirring 15min, column chromatography processing obtains product 136mg.
¾NMR (D20) (ppm)： δ 3.51 (m, 1Η) , δ 2.92 (d, 2Η), δ 2.76(s, 6Η) , δ 2.71 (t, 2Η) , δ 2.21(d, 4Η), δ 1.96 (m, 2Η) , δ 1.69 (m, 2Η) , δ 1.42(m, 4Η) The specification compound is soluble in water, and solubility is 105mg/mL, can be easy to change into the organic or inorganic salt of other species by free, can be but not limited to sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc..Free alkali elementary analysis：C33.57% (theory 33.33%)； H5.52°/.（Theory is 5.77%)：N8. 68% (theory 8.97%).
[embodiment 17] 2- (2- lignocaine second protective embankment bases）- 3- hydroxy-propionic acids are cis -1,3- (2,2- (4- oxacyclohexyls））- propane diamine closes platinum（Π) phosphate；
Step 1:With [embodiment 1] step 1.
Step 2,3：With [embodiment 13] step 2,3.
Step 4:1,3- (2,2- (4-）- propane diamine diiodo- closes platinum（II)
Take Platinous Potassium Chloride（K2PtCl4) 2.071g (5mmol), add water 50ml, at room temperature stirring and dissolving, takes KI6.64g (40mmol) to be added after being dissolved with water 50ml in reaction solution, N2Protection, lucifuge, heating water bath to 0.5 ~ 2h of reaction under 40 ~ 60 °C.1,3- (2,2- (4- oxacyclohexyls are taken again））- propane diamine 722mg (5mmol) 50ml water dissolves, rear to add in reaction solution, continues to keep to react 0.5 2h under the conditions of this.Suction filtration obtains yellow solid product, uses water（10ml X 3 times）, ether（10ml X3 times）Washing, obtains product 2.547g, yield 85.91%.Elementary analysis：C14.35% (theory 14.17%)；H2.75% (theory 2.70%)；N4.72% (theory 4.72%).
Step 5:1,3- (2,2- (4-）- propane diamine two is hydrated platinum（II) sulfate
Take Ag2S04623mg (2mmol) is placed in 100ml three-necked flasks, the 30ml that adds water stirrings, takes 1,3- (2,2- (4- oxacyclohexyls））- propane diamine * diiodo-s close platinum（11) 1.185g (2mmol) is put into reaction solution, and adds the reaction of 40ml water, N2Protection, lucifuge reacts 4 ~ 8h under 40 ~ 60 °C of water-bath.Suction filtration removes Agl precipitations, obtains the aqueous solution of filtrate, as product.
Walk rapid 6:2- (2- lignocaine second protective embankment bases）- 3- hydroxy-propionic acids are cis -1,3- (2,2- (4- oxacyclohexyls）)-propane diamine closes platinum（Π) phosphate Bright book
Take 2- (2- lignocaine second protective embankment bases）- 3- hydroxy-propionic acid sodium salt solutions H3P04(1M) adjusts pH to 5 ~ 7, then by 1,3- (2,2- (4- oxacyclohexyls））- propane diamine two is hydrated platinum（II) sulfate solution is poured into reaction solution, N2Reaction solution is added 2. 5g column chromatography silica gels by protection, heating water bath to 40 60 °C of 4 8h of reaction（200-300 mesh）Drained after stirring 15min, column chromatography processing obtains product 131mg.
LHNMR (D20) (ppm)： δ 3. 71 (t, 4Η) , δ 3. 42 (d, 2Η) , δ 2. 92 (m, 1Η) , δ 2. 77 (m, 4Η) , δ 2. 68 (t, 2Η) , δ 2. 10 (s, 4Η) , δ 1. 87 (m, 2Η) , δ 1. 51 (t, 4Η) , δ 1. 07 (t, 6Η).
The compound is soluble in water, solubility is 100mg/ml, it can be easy to change into the organic or inorganic salt of other species by free, sulfate, mesylate, tartrate, succinate, acetate, citrate, tosilate, fumarate etc. can be but not limited to.Free alkali elementary analysis：C36. 44% (theory 36. 50%);H6. 41% (theory 6. 32%);N8. 05% (theory 7. 98%).
[experimental example 1]:Acute Toxicity of the platinum class complex compound to normal mouse
The 22g of body weight 18,46 week old kunming mices are taken, male and female half and half, embodiment platinum-like compounds are dissolved with 5% glucose solution, single intravenous administration（Comparison medicine is carboplatin and cis-platinum）Various dose, to the observation post administration death rate and toxicity profile, observes 14 days, LD is calculated according to death rate application Bl iss methods altogether5.Value.It is shown in Table 1:Table 1, mouse mainline cis-platinum, carboplatin and embodiment platinum-like compounds LD5.As a result:
Specification compound 8 0. 549
Conclusion：Embodiment compound molar concentration acute toxicity is much smaller than cis-platinum and carboplatin.
[experimental example 2]：CDCC of the platinum-like compounds to tumor cell
By applying MTT colorimetric methods, toxic action of the observation embodiment platinum-like compounds to tumour cell.Take several tumour cells of exponential phase of growth that single cell suspension is made, be inoculated in the density in the holes of 4 X 107 on 96 orifice plates, with containing 10 °/.1640 culture mediums of hyclone（Complete medium）37 °C of cultures allow cell attachment for 24 hours, and culture final volume is 100 μ 1.Culture observes cellular morphology after 24 hours, and for platinum-like compounds consumption, because the IC50 of various cells is different, following concentration is determined by trial test：The g/ml of cis-platinum 200,60 20 62,0. 6 is given, the g/ml of carboplatin 200 60 20,6,2,0. 6, embodiment platinum-like compounds give ^ Shi Wins when adjustment according to its sensitiveness difference to every kind of cell, as a result see the table below 2-5:Wins Pine
Cell toxicant IC of the different tested platinum medicine compounds of table 2 to different cells5()
Ic of the different cell lines to chemotherapeutics5 (n =6)
IC5(mM) Rong
Cell line
Carboplatin cis-platinum
Pulmonary epithelial cells
0. 0,033 0. 005 0. 004 0. 007 0 Wins Suo 005 0. 005
BEAS-2B 0. 037
φ
Lung cancer Lewis
0. 038 0. 045 0. 018 0. 042 0. 034 0. 018 0. 021 colon cancer SW480 Wins
0. 087 0. 015 0. 021 0. 015 0. 016 0. 025 0. 022 lung cancer H292
Cell toxicant IC of the different tested platinum medicine compounds of 0. 055 0. 0,053 0. 006 0. 013 0. 026 0. 014 0. 008 table 3 to different cells5o
Ic of the different cell lines to chemotherapeutics5 (η =6)
IC5 (mM)
Cell line chemical combination
Carboplatin cis-platinum
The pulmonary epithelial cells of thing 10
The colon cancer SW480 of 0. 037 0. 0,033 0. 007 0. 005 0. 008 0. 011 0. 015 lung cancer Lewis of BEAS-2B 0. 038 0. 045 0. 039 0. 032 0. 031 0. 051 0. 033
0. 087 0. 015 0. 012 0. 025 0. 011 0. 022 0. 024 lung cancer H292
Cell toxicant ic of the different tested platinum medicine compounds of 0. 055 0. 0,053 0. 006 0. 007 0. 009 0. 015 0. 008 table 4 to different cells5()
Ic of the different cell lines to chemotherapeutics5 (n =6)
IC5 (mM)
The compound combination combination of cell line carboplatin cis-platinum chemical combination is closed Specification
The testicular cell ST of 14 thing of thing 11 thing, 12 thing, 13 thing 15
0. 195 0. 009 0. 011 0. 015 0. 012 0. 021 0. 043
0. 625 0. 0025 0. 003 0. 011 0. 007 0. 006 0. 019
MGC803
Colon cancer SW480
0. 087 0. 015 0. 022 0. 012 0. 008 0. 013 0. 014 lung cancer H292
Cell toxicant IC 50 of the 0. 055 0. 0,053 0. 007 0. 011 0. 012 0. 009 0. 011 different tested platinum medicine compounds to different cells
IC of the different cell lines to chemotherapeutics5。 (n =6)
IC60 (mM)
From table 2-5, embodiment 1-17 compounds have acts on the stronger Vitro Cytotoxicity suitable with cis-platinum than carboplatin(In addition, the present invention has also synthesized the phosphate of the compound of table 6：
Table 6, the other compounds of the invention synthesized, melting point compound, solubility and the external IC to H292 in water5。(mM)
Specification
Specification
The present invention has also synthesized the phosphate of following compound, its structure, melting point compound, solubility and the external IC to H292 in water5.(mM) it is as follows：
Wherein, R6For-CH2- , Specification
In addition, present invention also offers the phosphate of following compound, its structure and fusing point and the external IC to H2925.Value is as follows: Specification
[preparation example 1]:The preparation of parenteral solution
Prescription 1
The compounds acetic acid salt 10g of embodiment 2
Glucose 50g
Water for injection adds to 1000ml
It is made 1000
Technique：The compounds acetic acid salt 10g of embodiment 2 and glucose 50g is added in 2000ml glasswares, water for injection 1000ml is added at normal temperatures makes dissolving, after 0. 22 filtering with microporous membrane, it is distributed into lml ampoules, produces, specification is lOmg/ml o
Prescription 2
The compound methanesulfonic acid salt 10g of embodiment 4
Glucose 50g
Water for injection adds to 1000ml
It is made 1000
Technique：The compound methanesulfonic acid salt 10g of embodiment 4 and glucose 50g is added in 1000ml glasswares, water for injection 1000ml is added at normal temperatures makes dissolving, after 0. 22 filtering with microporous membrane, it is distributed into 2ml cillin bottles, produces, specification is 10mg/ bottles.
[preparation example 2]:The preparation of injection freeze-dried powder
Prescription 1
The compound phosphate 10g of embodiment 8
Mannitol 50g
Water for injection adds to 1000ml
It is made 1000
Technique：The compound 10g of embodiment 8 and mannitol 50g is added in 1000ml glasswares, note is added at normal temperatures Specification is penetrated makes dissolving with water 1000ml, after 0. 22 μ ω filtering with microporous membrane, is distributed into 2ml cillin bottles, every bottle of filling lml solution, freeze-drying, produces, and specification is 10mg/ bottles.
Prescription 2
The compound tosilate 20g of embodiment 12
Mannitol 50g
Water for injection adds to 1000ml
It is made 1000
Technique：By the compound tosilate 20g of embodiment 12 and mannitol 50g, add in 1000ml glasswares, adding water for injection 1000ml at normal temperatures makes dissolving, after 0. 22 filtering with microporous membrane, it is distributed into 2ml cillin bottles, every bottle of filling lml solution, is freeze-dried, produce, specification is 20mg/ bottles.
Prescription 3
The compound phosphate 50g of embodiment 15
Water for injection adds to 1000ml
It is made 1000
Technique：By the compound phosphate 50 of embodiment 15g, add in 1000ml glasswares, water for injection 1000ml is added at normal temperatures makes dissolving, with 0. 22 | after im filtering with microporous membrane, it is distributed into 2ml cillin bottles, every bottle of filling lml solution, is freeze-dried, produces, specification is 50mg/ bottles.

Claims (16)

  1. Claims
    1st, platinum compounds shown in formula A, its pharmaceutically acceptable salt, solvate, isomers or precursor,
    (A)
    R is selected from hydrogen, alkyl, ring protective embankment base, alkoxyalkyl, protective embankment aminoalkyl, heterocycle, alkenyl, alkynyl group, above alkyl, protective embankment epoxide protective embankment base, alkylamino protective embankment base and heterocycle can be unsubstituted, it can also be optionally substituted, preferably by halogen, hydroxyl, alkoxy, protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, protective embankment amino, amino, heterocyclic substituted；
    Ro may have, and can also be not present, work as R.In the presence of, the compounds of this invention is quaternary ammonium salt, it is necessary to have corresponding anion to exist simultaneously；Work as R.In the absence of when, the compounds of this invention be tertiary amine, secondary amine or primary amino-compound；Work as R.In the presence of, R.Protective embankment base, ring protective embankment base, protective embankment epoxide can be but not limited to and burn base, protective embankment amino protective embankment base, heterocycle, alkenyl, alkynyl group, it can be unsubstituted that above alkyl, protective embankment epoxide, which burn base, protective embankment amino protective embankment base and heterocycle, it can also be optionally substituted, preferably by halogen, hydroxyl, protective embankment epoxide, protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, alkylamino, amino, heterocyclic substituted；With can be with identical or different, including but not limited to hydrogen, alkyl, cycloalkyl, protective embankment epoxide alkyl, alkylamino protective embankment base, heterocycle, alkenyl, alkynyl group, above alkyl, protective embankment epoxide alkyl, protective embankment aminoalkyl and heterocycle can be unsubstituted, it can also be optionally substituted, it is preferred that by halogen, hydroxyl, protective embankment epoxide, protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, protective embankment amino, amino, heterocyclic substituted, condition be no matter R.It whether there is, R.Or in if containing unsaturated bond, the atom of the unsaturated bond can not be joined directly together with nitrogen-atoms in formula；
    With and its nitrogen-atoms that is connected can also form the saturation or unsaturated heterocycle of closure together, can be ternary, quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring, above ring can also be condensed optionally with other rings, and optionally it can be replaced by element, hydroxyl, protective embankment epoxide, protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, heterocycle, aryl, condition is that what is be connected with the nitrogen-atoms must be the carbon atom of saturation；
    Selected from protective embankment base, cycloalkyl ,-R31-0-R32-, R31And R32Independently selected from key or alkyl, R31It is and formula In nitrogen-atoms be connected, condition is R31Such as contain unsaturated bond, the atom of unsaturated bond directly can not be connected with above-mentioned nitrogen-atoms；Protective embankment base described above or cycloalkyl can be unsubstituted, can also be optionally substituted, preferably by halogen, hydroxyl, alkoxy, protective embankment base, the substitution such as protective embankment epoxide protective embankment base, cycloalkyl, alkylamino, amino, heterocycle；
    The atom being connected with R and its jointly can also form the saturation or unsaturation ring of closure together, for example can be ternary, quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring, above ring can also be condensed optionally with other rings, and optionally it can be replaced by halogen, hydroxyl, protective embankment epoxide, protective embankment base, protective embankment epoxide protective embankment base, ring protective embankment base, heterocycle, aryl, the carbon atom during nitrogen-atoms is connected in condition formula must be the carbon atom of saturation；With can be with identical or different, independently selected from hydrogen, hydroxyl, alkyl, ring protective embankment base, protective embankment epoxide, alkoxyalkyl, heterocycle, alkenyl, alkynyl group, above alkyl, alkenyl, alkynyl group, ring protective embankment base, protective embankment epoxide protective embankment base, protective embankment aminoalkyl and heterocycle can be unsubstituted, it can also be optionally substituted, it is preferred that by halogen, hydroxyl, protective embankment epoxide, straight or branched alkyl, alkoxyalkyl, ring protective embankment base, protective embankment amino, amino, heterocyclic substituted；
    With and its atom that is connected can also form the ring of closure together, can be quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring, above ring can also be condensed optionally with other rings, and can be optionally substituted；
    Can be key or-CRaRb-; RaAnd RbCan be with identical or different, selected from key, hydrogen, saturation or unsaturated alkyl, and with and its atom that is connected can also together with form the saturation or unsaturation ring of closure, for example can be ternary, quaternary, five yuan, hexa-atomic, seven yuan or octatomic ring, above ring can also be condensed optionally with other rings, and optionally it can be replaced by halogen, hydroxyl, protective embankment epoxide, alkyl, alkoxy protective embankment base, ring protective embankment base, heterocycle, aryl, the carbon atom that condition is connected in being with nitrogen-atoms in formula must be the carbon atom of saturation.
    2nd, platinum compounds according to claim 1, R Xuan Zi No, d-8Alkyl, cycloalkyl； R., standing grain mouthful R2Selected from hydrogen, d-8Protective embankment base, ring protective embankment base, alkoxyalkyl, amino, protective embankment aminoalkyl, heterocycle； R3It can be but not limited to： d-8Institute's base, cycloalkyl； R4And R5Selected from hydrogen, hydroxyl, d-8Protective embankment base, ring protective embankment base, protective embankment epoxide, protective embankment epoxide protective embankment base, heterocycle.
    3rd, according to the platinum compounds of claim 1 or 2, its structure is as shown in formula B：
    (B)
    4th, platinum compounds according to claim 3, R.Selected from methyl, ethyl, propyl group or butyl R,！^ and independently selected from hydrogen, methyl, ethyl, propyl group or butyl；Or and and its nitrogen-atoms that is connected form nafoxidine ring or piperidine ring together；Selected from-(CH2) 2-、 - ( CH2) 3-、 - ( CH2) 4-、 - (CH2) 5- or-（C¾)6-。
    5th, platinum compounds according to claim 1, its structure is as shown in formula C：
    (C)
    H2N、,
    ''''
    Wherein, R, R.、 、 R2 R3The group being selected from is as claimed in claim 1,
    And above structure optionally can also be replaced by various suitable substituents,
    Selected from (C)n, wherein n=0- 3, preferably n=0-2, some of which-C-can be replaced by -0-,（C¾ ).One or more hydrogen can be replaced by halogen, protective embankment base, hydroxyl, hydroxyl protective embankment base, protective embankment epoxide or heterocycle；
    With selected from：Hydrogen, halogen, hydroxyl, hydroxyl protective embankment base, protective embankment alkyl, alkoxy, heterocycle etc., and Can be with identical or different, preferred methylol；
    .With selected from：Hydrogen, halogen, hydroxyalkyl, protective embankment base, protective embankment epoxide, heterocycle etc.,.Can be with identical or different with Ru, preferred methylol；
    R12Selected from (C)n, wherein n=2- 4, some of which-CH2- can be replaced by -0-, (CH2).One or more hydrogen can be replaced by halogen, alkyl, hydroxyl, alkoxy or heterocycle；
    R13Can be-CH2- or -0-, preferably-CH2-;
    Ru can be hydrogen, halogen, alkyl, protective embankment epoxide, heterocycle, hydroxyl protective embankment base or hydroxyl, RMPreferably hydrogen； R15(CH can be but not limited to2) n, wherein n=l- 3 ,-CH2- 0- or -0-, (CH2).One or more hydrogen can be replaced by protective embankment base, protective embankment epoxide, heterocycle, hydroxyl or hydroxyl protective embankment base, preferably-C -0-CH2-;
    R16It is selected from（C) n, wherein n=l-6, preferably 3-5, most preferably 4, some of which-CH2- can be replaced by -0-,（CH2).One or more hydrogen can be replaced by halogen, protective embankment base, hydroxyl, protective embankment epoxide or heterocycle etc., compound preferably is（Scholar）Trans 1,2- oneself, penta, fourth and propane diamine close platinum（11).
    6th, platinum compounds according to claim 5, it has following structure：
    (D)
    (El )
    (E2)
    (E3)
    (H) 。
    7th, according to claim any of the above platinum compounds, wherein R.It is not present.
    8th, its pharmaceutically acceptable salt of platinum compounds according to claim 1, solvate, isomers or precursor, compound therein are selected from：
    Compound 1:2- (2- first ammonia second protective embankment bases）The cis two amminos platinum of -3- hydroxy-propionic acids（II) Rocky hydrochlorates；Compound 2:2- (3- diformazan ammonia propyls）The cis two amminos platinum of -3- hydroxy-propionic acids（II) acetate; Compound 3:2- (3- aminopropan protective embankment bases）The cis two amminos platinum of -3- hydroxy-propionic acids（II) phosphate；Compound 4:2- (2- triithylamine second protective embankment bases）The cis two amminos platinum of -3- hydroxy-propionic acids（II) mesylate compound 5:2- (5- (1- piperidyls）- pentyl）The cis two amminos platinum of -3- hydroxy-propionic acids（II) phosphate
    Compound 6:2- (6- (1- nafoxidine protective embankment bases）- own protective embankment base）The cis two amminos platinum of -3- hydroxy-propionic acids（Π) phosphate
    Compound 7:2- (3- diformazans ammonia the third protective embankment bases）- 3- hydroxy-propionic acids are cis-(1,2- trans-cyclohexanediamines）Close platinum（II) phosphate；
    Compound 8:2- (3- trimethylaminopropane bases）- glycolic is cis-(1,2- trans-cyclohexanediamine）Close platinum（Π) phosphate；
    Compound 9:2- (2- second ammonia second protective embankment bases）- lactic acid is cis-(1,2- trans-cyclohexanediamine）Close platinum (II) phosphate；
    Compound 10:2- (3- (1- piperidyls）- the third protective embankment base）- glycolic * is cis-(1,2- trans-cyclohexanediamine）Close platinum（Π) citrate
    Compound 11:2- (3- diethylaminos the third protective embankment bases）- 3- hydroxy-propionic acids are cis-(1,2- trans-ring pentanediamine）Close platinum（II) phosphate；
    Compound 12:2- (3- trimethylaminopropane bases）- glycolic is cis-and 1,2- ethylenediamines close platinum（II) tosilate；
    Compound 13:2- (2- diethylamino second protective embankment bases）- 3- hydroxy-propionic acids are cis-and 1,3- propane diamine closes platinum (II) phosphate；
    Compound 14:2- (n-propylamine the third protective embankment bases of 3- bis-）Cis -1,4- the dibutyl amine of -3- hydroxy-propionic acids closes platinum（Π) phosphate；
    Compound 15:2- (2- diformazan ammonia second protective embankment bases）- 3- hydroxy-propionic acids are cis -1,3- (2,2- methylols）- propane diamine closes platinum（Π) phosphate；
    Compound 16:2- (2- diformazan ammonia second protective embankment bases）- 3- hydroxy-propionic acids cis-Isosorbide-5-Nitrae-(trans -2,3- cyclobutyl）- butylamine closes platinum（Π) phosphate；
    Compound 17:2- (2- diethylamino second protective embankment bases）- 3- hydroxy-propionic acids are cis -1,3- (2,2- (4- oxacyclohexyls））- propane diamine closes platinum（Π) phosphate； Compound 18:2- propyl group -2- (the dibutylamino fourth protective embankment bases of 4- propyl group -4）The cis ammonia * cyclopentamines of -2- glycolics close platinum phosphate；
    Compound 19:2- butyl -2- (2- methyl -2- diamyl ammonia second protective embankment bases）Cis two cyclopentamine of -2- glycolics closes platinum phosphate；
    Compound 20:2- amyl groups -2- (the own aminoethane bases of 2- ethyls -2- two）The cis ammonia cyclohexylamine of -2- glycolics closes platinum phosphate；
    Compound 21:2- methoxyl groups -2- (3- methyl -3- fourth aminopropan protective embankment bases）The cis dicyclohexyl amines of -2- glycolics * close platinum phosphate；
    Compound 22:2- methoxies -2- (the protective embankment bases of penta amino of 5- dimethyl -5- penta）The cis cyclopentamine cyclohexylamine of -2- glycolics closes platinum phosphate；
    Compound 23:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis methylamine cyclopentamine of -2- glycolics closes platinum phosphate；
    Compound 24:2- cyclohexyl -2- (2- dimethylamino ethyl groups）The cis methylamine ethamine of -2- glycolics closes platinum phosphate；
    Compound 25:2- cyclopenta -2- (dimethylaminos-methyl）The cis two amminos platinum phosphate cpd 26 of-glycolic:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis diamylamines of-glycolic * close platinum phosphate；
    Compound 27:2- cyclohexyl -2- (2- dimethylamino second protective embankment bases）The cis dihexylamines of-glycolic * close platinum phosphate；
    Compound 28:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）- glycolic * cis two-(3- methoxyl group cyclopentamines）Close platinum phosphate；
    Compound 29:2- propyl group -2- (the protective embankment bases of 5- dimethyl-own amino penta）- glycolic * cis two-(4- methoxycyclohexyl amine）Close platinum phosphate；
    Compound 30:2- propyl group -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）- glycolic cis ammonia * (4- methoxy cyclohexylamine）Close platinum phosphate；
    Compound 31:2- (2,4- dicyclopentenyls）- 2- (the own amino second protective embankment bases of 2- ethyls -2- two）The cis ammonia cyclohexylamine of-glycolic closes platinum phosphate；
    Compound 32:2- (3- chloropropyls）- 2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）- glycolic is suitable Formula ammonia methoxycyclohexyl amine closes platinum phosphate；
    Compound 33:The cis diamylamine of 2- butyl -2- (2- diamyl amino second protective embankments base) -3- hydroxy-propionic acids closes platinum phosphate；
    Compound 34:2- amyl groups -2- (the own amino second protective embankment bases of 2- bis-）The cis ammonia cyclohexylamine of -3- hydroxy-propionic acids closes platinum phosphate；
    Compound 35:2- methoxyl groups -2- (3- methyl -3- fourth aminopropan protective embankment bases）The cis dihexylamine of -3- hydroxy-propionic acids closes platinum phosphate；
    Compound 36:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis diamylamines of -3- hydroxy-propionic acids * close platinum phosphate；
    Compound 37:2- cyclohexyl -2- (2- dimethylaminoethane bases）The cis dihexylamine of -3- hydroxy-propionic acids closes platinum phosphate；
    Compound 38:2- cyclopenta -2- (the own protective embankment bases of amino penta of 5- methyl -5-）- 3- hydroxy-propionic acids cis two-(3- hydroxycyclopent amine）Close platinum phosphate；
    Compound 39:2- propyl group -2- (the own protective embankment bases of amino penta of 5- methyl -5-）- 3- hydroxy-propionic acids cis two-(4- methoxycyclohexyl amine）Close platinum phosphate；
    Compound 40:2- (2,4- cinene）- 2- (the own amino second protective embankment bases of 2- bis-）The cis ammonia cyclohexylamine of -3- hydroxy-propionic acids * closes platinum phosphate；
    Compound 41:2- (2- chloroethyls）- 2- (the own protective embankment bases of amino penta of 5- dimethyl -5-）The cis ammonia of -3- hydroxy-propionic acids（4- methoxycyclohexyl amine）Close platinum phosphate；
    Compound 42:2- (2- methyl -3- diethylamino basic ring fourth protective embankment bases）The cis cyclopentamine nafoxidine of-glycolic closes platinum phosphate；
    Compound 43:2- (2- methyl -3- lignocaine cyclobutane bases）The cis two amminos platinum phosphate of-glycolic *；
    Compound 44:2- (3- dimethylamino -1,1- cyclobutyl）- glycolic cis trans -1,2- cyclohexanediamine closes platinum phosphate；
    Compound 45:2- (2- methyl -3- lignocaine -1,1- cyclobutyl）- glycolic * cis trans -1,2- cyclohexanediamine closes platinum phosphate；
    Compound 46:4- piperidyl -1- hydroxyl -2- carboxylic acids, cis trans -1,2- cyclohexanediamine closes platinum phosphate；Compound 47:4- (4 hydrogen piperidyls）- 1- hydroxyl -2- carboxylic acid * cis trans -1,2- cyclohexanediamine is closed Platinum phosphate；
    Compound 48:4- dimethylamino -1- hydroxyl -2- carboxylic acid cis trans -1,2- cyclohexanediamine closes platinum phosphate cpd 49:4- triithylamine base -1- hydroxyl -2- carboxylic acid cis trans -1,2- cyclohexanediamine closes platinum phosphate.
    9th, according to any one of claim 1-8 platinum compounds, it is the form of pharmaceutically-acceptable salts, and pharmaceutically acceptable salt preferably is nitrate, carbonate, sulfate, phosphate, mesylate, three width mesylates, tosilate, benzene sulfonate, acetate, fumarate, tartrate, oxalates, maleate, malate, succinate, lactate, citrate, glutamate, aspartate.
    10th, a kind of pharmaceutical composition, platinum compounds and pharmaceutically acceptable carrier and/or excipient containing any one of claim 1-9.
    11st, composition according to claim 10, it is the form of injection.
    12nd, composition according to claim 11, it can also the medicine containing one or more other treating cancers.
    13rd, in claim 1 platinum compounds preparation method, comprise the following steps：
    (1) take potassium chloroplatinite to add water, at room temperature stirring and dissolving, take KI to be put into after being dissolved in water in above-mentioned chloroplatinous acid potassium solution, lucifuge, water bath condition are reacted under nitrogen charging；
    (2) 1^ is taken to be added drop-wise to step after being dissolved in water（1) in reaction solution, reacted under water bath condition；
    (3) reaction solution is cooled to below room temperature, takes Ν Η2Step is added drop-wise to after water dissolving（2) in reaction solution, water-bath has a large amount of yellow mercury oxides to generate, temperature in reaction solution is cooled into the following suction filtration of room temperature, washs, and obtains diiodo- diamines and closes platinum（I I );
    (4) Ag is taken2S0jm, which enters in water, to be stirred, and takes above-mentioned diiodo- diamines to close platinum（II) in input reaction solution, add under water, nitrogen charging and reacted under lucifuge water bath condition, suction filtration obtains two water diamines and closes platinum（I I) sulfate；
    (5) hydroxyl acetoacetic ester, and Br-R are taken3_ Br is placed in flask, adds K2C03, TBAB stirring, heating response, suction filtration, remove solid simultaneously wash, merging filtrate, wash organic layer, dry, vacuum distillation solvent, collect it is leavened go out thing；
    (6) 2- Br-R are taken3- hydroxyl acetoacetic ester is placed in flask, adds anhydrous K2C03, and acetonitrile stirring, separately take ＞N— R.Add in reaction solution, heating response filters out insoluble matter, organic solvent dissolving is added after filtrate is drained, it is water-soluble Liquid is washed, and organic layer is dried, and decompression extracts solvent, obtains product, is purified；Work as R.In the presence of, can and R.In the absence of when equally operated, but obtain product contain bromo element, finally need to remove using ion exchange by the way of, after can also filtrate be drained add water dissolving, the aqueous solution addition Ag20, insoluble matter is filtered out, pH to 9-11 is adjusted, is extracted with ethyl acetate, organic layer is dried, decompression extracts solvent, obtains product；
    (7) Qu Walk are rapid（6) product is placed in flask, is added NaOH solution, is stirred at room temperature；
    (8) step is taken（7) product, adjusts pH with acid solution, adds above-mentioned steps（4) product, heating response.
    14th, in claim 5 platinum compounds preparation method, comprise the following steps：
    (1) take potassium chloroplatinite to add water, at room temperature stirring and dissolving, take KI to be put into after being dissolved in water in above-mentioned chloroplatinous acid potassium solution, lucifuge water bath condition is reacted under nitrogen charging；
    (2) bidentate ammonia N-X-NHjm water is taken to be added drop-wise to step after dissolving（1) in reaction solution, water-bath has a large amount of yellow mercury oxides to generate, temperature in reaction solution is cooled into the following suction filtration of room temperature, washs, and obtains bidentate diiodo- diamines and closes platinum（II);
    (3) Ag is taken2S0jjP, which enters in water, to be stirred, and takes above-mentioned diiodo- diamines to close platinum（II) in input reaction solution, add under water, nitrogen charging and reacted under lucifuge water bath condition, suction filtration obtains two water diamines and closes platinum（Π) sulfate；
    (4) hydroxyl acetoacetic ester, and Br-R are taken3- Br is placed in flask, adds K2C03, TBAB stirring, heating response, suction filtration, remove solid simultaneously wash, merging filtrate, wash organic layer, dry, vacuum distillation solvent, collect distillate；
    (5) 2- Br-R are taken3- hydroxyl acetoacetic ester is placed in flask, adds anhydrous K2C03, and acetonitrile stirring, separately take>N— R.Add in reaction solution, heating response filters out insoluble matter, organic solvent dissolving is added after filtrate is drained, aqueous solution washing, organic layer is dried, and decompression extracts solvent, obtains product, purifies；Work as R.In the presence of, can and R.In the absence of when equally operated, but obtain product contain bromo element, finally need to remove using ion exchange by the way of, after can also filtrate be drained add water dissolving, the aqueous solution addition Ag20, insoluble matter is filtered out, pH to 9-11 is adjusted, is extracted with ethyl acetate, organic layer is dried, decompression extracts solvent, obtains product；
    (6) step is taken（5) product is placed in flask, is added NaOH solution, is stirred at room temperature；
    (7) step is taken（6) product, adjusts pH with acid solution, adds above-mentioned steps（3) product, heating response.
    15th, claim 1-12 product prepare treatment cell proliferation disorders medicine in purposes, cell proliferation disorders therein are preferably cancer, particularly preferred cancer be breast cancer, lung cancer, colon cancer, stomach cancer, The cancer of the esophagus, oophoroma, osteosarcoma, cervical carcinoma, carcinoma of urinary bladder, liver cancer, brain tumor, prostate cancer, melanoma.
    16th, a kind of kit, includes claim 10-12 pharmaceutical composition and operation instruction.
    17th, a kind of method for treating cell proliferation disorders, kit including giving Patient libraries requirement 1-12 or claim 16, cell proliferation disorders are preferably cancer, and particularly preferred cancer is breast cancer, lung cancer, colon cancer, stomach cancer, the cancer of the esophagus, oophoroma, osteosarcoma, cervical carcinoma, carcinoma of urinary bladder, liver cancer, brain tumor, prostate cancer, melanoma.
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