CN1010314B - Novel platinum complex production method - Google Patents
Novel platinum complex production methodInfo
- Publication number
- CN1010314B CN1010314B CN 86105441 CN86105441A CN1010314B CN 1010314 B CN1010314 B CN 1010314B CN 86105441 CN86105441 CN 86105441 CN 86105441 A CN86105441 A CN 86105441A CN 1010314 B CN1010314 B CN 1010314B
- Authority
- CN
- China
- Prior art keywords
- platinum
- butanediamine
- diamines
- closes
- milligrams
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 title claims description 270
- 229910052697 platinum Inorganic materials 0.000 title claims description 133
- 238000004519 manufacturing process Methods 0.000 title claims description 5
- 238000000034 method Methods 0.000 claims abstract description 53
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 10
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 9
- 125000005843 halogen group Chemical group 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 30
- 230000002378 acidificating effect Effects 0.000 claims description 27
- 150000004985 diamines Chemical class 0.000 claims description 20
- 238000006243 chemical reaction Methods 0.000 claims description 19
- -1 silver ions Chemical class 0.000 claims description 14
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 claims description 12
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 11
- 125000004429 atom Chemical group 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 229910052709 silver Inorganic materials 0.000 claims description 7
- 239000004332 silver Substances 0.000 claims description 7
- AIDLAEPHWROGFI-UHFFFAOYSA-N 2-methylbenzene-1,3-dicarboxylic acid Chemical compound CC1=C(C(O)=O)C=CC=C1C(O)=O AIDLAEPHWROGFI-UHFFFAOYSA-N 0.000 claims description 6
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 claims description 4
- 150000003839 salts Chemical class 0.000 claims description 4
- 229910052794 bromium Inorganic materials 0.000 claims description 3
- 150000001768 cations Chemical class 0.000 claims description 3
- 229910052801 chlorine Inorganic materials 0.000 claims description 3
- 229910052792 caesium Inorganic materials 0.000 claims description 2
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- XGJHPGPVESLKKD-UHFFFAOYSA-N 2-ethylbutane-1,4-diamine Chemical compound CCC(CN)CCN XGJHPGPVESLKKD-UHFFFAOYSA-N 0.000 claims 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-N carbonic acid Chemical compound OC(O)=O BVKZGUZCCUSVTD-UHFFFAOYSA-N 0.000 claims 1
- 239000000376 reactant Substances 0.000 claims 1
- 229910052739 hydrogen Inorganic materials 0.000 abstract description 4
- 239000001257 hydrogen Substances 0.000 abstract description 4
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 abstract 1
- 150000001875 compounds Chemical class 0.000 description 145
- 239000000243 solution Substances 0.000 description 73
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 54
- 238000004458 analytical method Methods 0.000 description 37
- 239000013078 crystal Substances 0.000 description 37
- 238000004992 fast atom bombardment mass spectroscopy Methods 0.000 description 35
- 239000000203 mixture Substances 0.000 description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 32
- 239000003643 water by type Substances 0.000 description 29
- 238000002474 experimental method Methods 0.000 description 18
- 238000005406 washing Methods 0.000 description 17
- DPDMMXDBJGCCQC-UHFFFAOYSA-N [Na].[Cl] Chemical compound [Na].[Cl] DPDMMXDBJGCCQC-UHFFFAOYSA-N 0.000 description 16
- 238000001291 vacuum drying Methods 0.000 description 16
- 238000001914 filtration Methods 0.000 description 15
- 210000004027 cell Anatomy 0.000 description 14
- 239000011541 reaction mixture Substances 0.000 description 14
- 210000004881 tumor cell Anatomy 0.000 description 14
- 230000000259 anti-tumor effect Effects 0.000 description 12
- 239000007864 aqueous solution Substances 0.000 description 12
- 125000003963 dichloro group Chemical group Cl* 0.000 description 12
- 231100000417 nephrotoxicity Toxicity 0.000 description 12
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 12
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 11
- 238000012360 testing method Methods 0.000 description 11
- 238000007912 intraperitoneal administration Methods 0.000 description 10
- 230000003287 optical effect Effects 0.000 description 10
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 9
- QCPTVXCMROGZOL-UHFFFAOYSA-L dipotassium;oxalate;hydrate Chemical compound O.[K+].[K+].[O-]C(=O)C([O-])=O QCPTVXCMROGZOL-UHFFFAOYSA-L 0.000 description 9
- LIAWOTKNAVAKCX-UHFFFAOYSA-N hydrazine;dihydrochloride Chemical class Cl.Cl.NN LIAWOTKNAVAKCX-UHFFFAOYSA-N 0.000 description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N oxalic acid Substances OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 9
- 229910001961 silver nitrate Inorganic materials 0.000 description 9
- 239000000047 product Substances 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- HCPOCMMGKBZWSJ-UHFFFAOYSA-N ethyl 3-hydrazinyl-3-oxopropanoate Chemical compound CCOC(=O)CC(=O)NN HCPOCMMGKBZWSJ-UHFFFAOYSA-N 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 230000004083 survival effect Effects 0.000 description 7
- 231100000419 toxicity Toxicity 0.000 description 7
- 230000001988 toxicity Effects 0.000 description 7
- 208000007093 Leukemia L1210 Diseases 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000002246 antineoplastic agent Substances 0.000 description 6
- 229940034982 antineoplastic agent Drugs 0.000 description 6
- QQVIHTHCMHWDBS-UHFFFAOYSA-N perisophthalic acid Natural products OC(=O)C1=CC=CC(C(O)=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-N 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- 206010028980 Neoplasm Diseases 0.000 description 5
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 5
- OREAFAJWWJHCOT-UHFFFAOYSA-N dimethylmalonic acid Chemical class OC(=O)C(C)(C)C(O)=O OREAFAJWWJHCOT-UHFFFAOYSA-N 0.000 description 5
- 239000003446 ligand Substances 0.000 description 5
- 239000011591 potassium Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 4
- 239000002895 emetic Substances 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 230000005764 inhibitory process Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 238000010998 test method Methods 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 3
- 210000000683 abdominal cavity Anatomy 0.000 description 3
- 238000000862 absorption spectrum Methods 0.000 description 3
- 230000000118 anti-neoplastic effect Effects 0.000 description 3
- 239000011260 aqueous acid Substances 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 230000035777 life prolongation Effects 0.000 description 3
- 229940095064 tartrate Drugs 0.000 description 3
- JKFYKCYQEWQPTM-UHFFFAOYSA-N 2-azaniumyl-2-(4-fluorophenyl)acetate Chemical compound OC(=O)C(N)C1=CC=C(F)C=C1 JKFYKCYQEWQPTM-UHFFFAOYSA-N 0.000 description 2
- 206010051779 Bone marrow toxicity Diseases 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- MJPHQJHHOLEQJJ-UHFFFAOYSA-N ClC1=C(C(=C(C(=O)O)C=C1)C)C(=O)O Chemical class ClC1=C(C(=C(C(=O)O)C=C1)C)C(=O)O MJPHQJHHOLEQJJ-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 2
- 231100000111 LD50 Toxicity 0.000 description 2
- 208000008342 Leukemia P388 Diseases 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- AYDQIZKZTQHYIY-UHFFFAOYSA-N OC(=O)C1(C)CC(C(O)=O)=CC=C1 Chemical compound OC(=O)C1(C)CC(C(O)=O)=CC=C1 AYDQIZKZTQHYIY-UHFFFAOYSA-N 0.000 description 2
- 229910021612 Silver iodide Inorganic materials 0.000 description 2
- 238000013019 agitation Methods 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 231100000366 bone marrow toxicity Toxicity 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical compound CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 230000000704 physical effect Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 229940045105 silver iodide Drugs 0.000 description 2
- YPNVIBVEFVRZPJ-UHFFFAOYSA-L silver sulfate Chemical compound [Ag+].[Ag+].[O-]S([O-])(=O)=O YPNVIBVEFVRZPJ-UHFFFAOYSA-L 0.000 description 2
- 229910052938 sodium sulfate Inorganic materials 0.000 description 2
- 235000011152 sodium sulphate Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- WHLFXPIYRPOHGB-UHFFFAOYSA-N 4-methylpentane-1,4-diamine Chemical compound CC(C)(N)CCCN WHLFXPIYRPOHGB-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- MODWLQTWCVEBNI-UHFFFAOYSA-N ClC1C(C(=O)O)=CC=CC1(C(=O)O)C Chemical class ClC1C(C(=O)O)=CC=CC1(C(=O)O)C MODWLQTWCVEBNI-UHFFFAOYSA-N 0.000 description 1
- 206010009944 Colon cancer Diseases 0.000 description 1
- DWSTUTXETNBCJK-UHFFFAOYSA-N IC1=C(C(=C(C(=O)O)C=C1)C)C(=O)O Chemical class IC1=C(C(=C(C(=O)O)C=C1)C)C(=O)O DWSTUTXETNBCJK-UHFFFAOYSA-N 0.000 description 1
- BIQXZOFITWJALD-UHFFFAOYSA-N IC1C(C(=O)O)(C=CC=C1C(=O)O)C Chemical class IC1C(C(=O)O)(C=CC=C1C(=O)O)C BIQXZOFITWJALD-UHFFFAOYSA-N 0.000 description 1
- 239000012980 RPMI-1640 medium Substances 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 210000000601 blood cell Anatomy 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309466 calf Species 0.000 description 1
- 150000001721 carbon Chemical group 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 208000029742 colonic neoplasm Diseases 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- IRXRGVFLQOSHOH-UHFFFAOYSA-L dipotassium;oxalate Chemical compound [K+].[K+].[O-]C(=O)C([O-])=O IRXRGVFLQOSHOH-UHFFFAOYSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 206010016629 fibroma Diseases 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 210000000265 leukocyte Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000002068 microbial inoculum Substances 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- ZDYUUBIMAGBMPY-UHFFFAOYSA-N oxalic acid;hydrate Chemical compound O.OC(=O)C(O)=O ZDYUUBIMAGBMPY-UHFFFAOYSA-N 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 238000000711 polarimetry Methods 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 239000012047 saturated solution Substances 0.000 description 1
- 238000005204 segregation Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- CQLFBEKRDQMJLZ-UHFFFAOYSA-M silver acetate Chemical compound [Ag+].CC([O-])=O CQLFBEKRDQMJLZ-UHFFFAOYSA-M 0.000 description 1
- SDLBJIZEEMKQKY-UHFFFAOYSA-M silver chlorate Chemical compound [Ag+].[O-]Cl(=O)=O SDLBJIZEEMKQKY-UHFFFAOYSA-M 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
Landscapes
- Catalysts (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A process for producing a diamineplatinum (II) complex represented by the general formula (1) wherein R is1、R2、R3And R4Are each hydrogen or lower alkyl; two X are each a halogen atom or together form a group represented by the formula (2) (wherein R is5And R6Independently a hydrogen atom or a lower alkyl group) or a group represented by the formula (3) (wherein m is 1 or 2).
Description
The invention relates to the production method of novel platinum complex with antitumor action.
Just have the platinum complex of antitumor action, it is commercially available that suitable-two hydrazine dichlorides close platinum, because it is evident in efficacy, just is applied in many cases at present.Other platinum complex with antitumor action is reported in several pieces of papers.Wherein, be confined to the ligand that those contain following general formula representative with the straight chained alkyl diamines as the platinum complex of ligand:
H
2N-CnR
2n-NH
2（Ⅰ）
R is hydrogen atom or substituting group in the formula, and as alkyl, hydroxyl and analogue, n are integer 1～3.(for example, Japanese Patent Application Publication (Laidopen) number 156416/1982 or 103192/1981).
As noted above, to close platinum commercially available as platinum complex system cancer microbial inoculum for suitable-two hydrazine dichlorides.Yet the renal toxicity that suitable-two hydrazine dichlorides close platinum is big, has the dose limitation factor.Therefore, when taking suitable-two hydrazine dichlorides and closing platinum, take suitable-two hydrazine dichlorides close platinum before and take and must drink a large amount of water in the process and the while is taken diuretic(s) for a long time.In addition, it is low and dissolution rate is slow that suitable-two hydrazine dichlorides close the solubleness of platinum in water, can only provide with low-down concentration.Moreover suitable-two hydrazine dichlorides close platinum and have very high emetic toxicity, and this also gives in the treatment and has brought difficulty.Because these shortcomings that suitable-two hydrazine dichlorides close platinum have been carried out many research work, so that find a kind of platinum complex, it has anti-tumor activity, has solubleness in the very high water, low renal toxicity and low emetic toxicity.But there is not platinum complex to be used for reality so far as yet.
When 1, the reaction of 4-butanediamine or derivatives thereof and pt atom when two nitrogen-atoms by diamines form coordination compoundes, has formed the ring texture of seven atoms that comprise pt atom, promptly as formula II seven meta structures shown in hereinafter.In general, the title complex with this seven-members ring structure is difficult to usual method synthetic.Through broad research, the inventor successfully synthesizes and has 1,4-butanediamine or derivatives thereof is as various platinum (II) title complex of ligand, and finds that these title complexs have antitumous effect, and their renal toxicity and emetic toxicity are starkly lower than suitable-two hydrazine dichlorides and close platinum.
Based on above-mentioned discovery, finished the present invention.
The diamines that the invention relates to logical formula II representative closes platinum complex:
R in the formula
1, R
2, R
3And R
4Be respectively hydrogen atom or low alkyl group; Two X are respectively halogen atom or form the represented base of following formula jointly:
(R wherein
5And R
6Be respectively hydrogen atom or low alkyl group) or the base represented of following formula
(wherein m is 1 or 2).
In the superincumbent logical formula II, R
1, R
2, R
3, R
4, R
5And R
6The low alkyl group of representative comprises the alkyl as 1～4 carbon atom, and that mentions particularly has methyl, ethyl, n-propyl, a sec.-propyl etc.
In logical formula II, the halogen atom of X representative comprises Cl, Br etc.
In the title complex of the present invention of logical formula II representative, the base that is expressed from the next with those, formed jointly by two X is for well,
Those are R wherein
1And R
2What represent hydrogen atom respectively also is good.
The exemplary of logical formula II representative shows below, but the present invention is not subjected to the restriction of these examples.
1. suitable-diamino-1, the 4-butanediamine closes platinum
2. suitable-tetramethylene-1,1-dicarboxyl acidic group-1, the 4-butanediamine closes platinum
3. suitable-4-amylene oxide-1,1-dicarboxyl acidic group-1, the 4-butanediamine closes platinum
4. suitable-diamino-the 1-methyl isophthalic acid, the 4-butanediamine closes platinum
5. suitable-oxalic acid base-1-methyl isophthalic acid, the 4-butanediamine closes platinum
6. suitable-propanedioic acid base-1-methyl isophthalic acid, the 4-butanediamine closes platinum
7. suitable-tetramethylene-1,1-dicarboxyl acidic group-1-methyl isophthalic acid, the 4-butanediamine closes platinum
8. suitable-dimethyl malonic acid base-1-methyl isophthalic acid, the 4-butanediamine closes platinum
9. suitable-ethyl malonic acid base-1-methyl isophthalic acid, the 4-butanediamine closes platinum
10. suitable-two chloro-1-ethyls-1, the 4-butanediamine closes platinum
11. suitable-tetramethylene-1,1-dicarboxyl acidic group-1-ethyl-1, the 4-butanediamine closes platinum
12. suitable-4-amylene oxide-1,1-dicarboxyl acidic group-1-ethyl-1, the 4-butanediamine closes platinum
13. suitable-two chloro-2-methyl isophthalic acids, the 4-butanediamine closes platinum
14. suitable-propanedioic acid base-2-methyl isophthalic acid, the 4-butanediamine closes platinum
15. suitable-tetramethylene-1,1-dicarboxyl acidic group-2-methyl isophthalic acid, the 4-butanediamine closes platinum
16. suitable-4-amylene oxide-1,1-dicarboxyl acidic group-2-methyl isophthalic acid, the 4-butanediamine closes platinum
17. suitable-dimethyl malonic acid base-2-methyl isophthalic acid, the 4-butanediamine closes platinum
18. suitable-malonic ester-the 2-methyl isophthalic acid, the 4-butanediamine closes platinum
19. suitable-two chloro-2,2-dimethyl-1, the 4-butanediamine closes platinum
20. suitable-oxalic acid base-2,2-dimethyl-1, the 4-butanediamine closes platinum
21. suitable-propanedioic acid base-2,2-dimethyl-1, the 4-butanediamine closes platinum
22. suitable-tetramethylene-1,1-dicarboxyl acidic group-2,2-dimethyl-1, the 4-butanediamine closes platinum
23. suitable-4-amylene oxide-1,1-dicarboxyl acidic group-2,2-dimethyl-1, the 4-butanediamine closes platinum
24. suitable-dimethyl malonic acid base-2,2-dimethyl-1, the 4-butanediamine closes platinum
25. suitable-two chloro-1,1-dimethyl-1, the 4-butanediamine closes platinum
26. suitable-oxalic acid base-1,1-dimethyl-1, the 4-butanediamine closes platinum
27. suitable-tetramethylene-1,1-dicarboxyl acidic group-1,1-dimethyl-1, the 4-butanediamine closes platinum
28. suitable-dimethyl malonic acid base-1,1-dimethyl-1, the 4-butanediamine closes platinum
29. suitable-two chloro-2-ethyls-1, the 4-butanediamine closes platinum
30. suitable-oxalic acid base-2-ethyl-1, the 4-butanediamine closes platinum
31. suitable-propanedioic acid base-2-ethyl-1, the 4-butanediamine closes platinum
32. suitable-tetramethylene-1,1-dicarboxyl acidic group-2-ethyl-1, the 4-butanediamine closes platinum
33. suitable-dimethyl malonic acid base-2-ethyl-1, the 4-butanediamine closes platinum
34. suitable-oxalic acid base-2-sec.-propyl-1, the 4-butanediamine closes platinum
35. suitable-two chloro-1,2-dimethyl-1, the 4-butanediamine closes platinum
Compound of the present invention can utilize known method production, for example at Indian JChem., and 8, the 193(1970) method described in, but must improve reaction method.
Compound of the present invention can be by the diamines of following general formula representative
(R wherein
1, R
2, R
3And R
4Have the same definition that provides previously respectively) with
M
2Pt（Hal）
4
(wherein M is the atom that can become monovalent cation, and Hal is a halogen atom) reaction obtains closing platinum complex with the dihalo-diamines that following general formula is expressed,
(R in the formula
1, R
2, R
3And R
4And Hal is identical with the definition that provides previously respectively), and must have under the situation of water, allow the dihalo-diamines close platinum complex and the silver ions reaction is transformed into two hydrated complexes, then, two hydrated complexes and dicarboxylic acid or dicarboxylate react.
The production method of compound of the present invention will give more detailed description.
(in above-mentioned reaction, M is the atom that can be transformed into monovalent cation, for example Na, K, Cs etc.; Hal is a halogen atom, for example Cl, Br, I etc.; R
1, R
2, R
3And R
4Respectively with top provide the definition identical.）
Shown in top reaction synoptic diagram, four halogen close platinum and diamines in liquid medium, preferably react in water, generate the dihalo-diamines and close platinum.The consumption of water is preferably every mole four halogen and closes 5～500 liters in platinum, is preferably 5～160 liters, and the best is 20～80 liters.The consumption of diamines is that every mole four halogen closes 0.5～4 mole in platinum, and the best is 0.9～1.2 mole.This is reflected at 0 °～100 ℃, is preferably in 50 °～70 ℃ and under agitation carries out.When reacting, preferably simultaneously four halogen are closed the platinum aqueous solution and two amine aqueous solutions little by little, add in the distilled water respectively.It is slow that adding speed is preferably wanted, generally will be with 1～6 hour.Reaction can be carried out in air, but is preferably in inert gas, for example carries out in nitrogen and the similar atmosphere.
Then, shown in following reaction synoptic diagram, make the dihalo-diamines close platinum (II a) be suspended in the water and with the silver ions reaction, by removing by filter the silver halide precipitation of gained, obtain the aqueous solution of two hydrated complexes (III).
（Ⅱa）+2Ag
++2H
2O
Can an amount of water being used to suspend, (II a), (II is 5～150 premium on currency a) but be preferably every mole of title complex for the dihalo-diamine complexes.Amount to silver ions is not particularly limited, but from an economic point of view, (II is 0.5～6 equivalent a) for preferably every normal dihalo-diamine complexes.For avoiding excessive adding, this amount the best is that (II is 1.9～2 equivalents a) whenever amount dihalo-diamine complexes.This reaction is at 0 °～100 ℃, and preferably 60 °～80 ℃ are carried out under stirring.Just produce the compound of silver ions, can use for example Silver Nitrate, Sulfuric acid disilver salt, mistake silver chlorate and Silver monoacetate.
At last, make two hydrated complexes (III) and dicarboxylate, dicarboxylic acid hydrogen salt or dicarboxylic acid reaction.For example, react by containing in the aqueous solution that an amount of dicarboxylate, dicarboxylic acid hydrogen salt or dicarboxyl aqueous acid be added to this two hydrated complexes (III).The consumption of described salt or acid, every mole two hydrated complexes (III) is preferably 0.5～10 mole, and the best is 0.9～6 mole.Reaction can be carried out under 0 ℃～100 ℃, but is preferably under 40 ℃～90 ℃, makes compound (II b).
(III) ten dicarboxylates or dicarboxylic acid hydrogen salt or dicarboxylic acid
(in the reaction, X ' is identical with X, is not halogen atom in the above)
The structure of compound of the present invention (II) is by various analytical procedures, for example ultimate analysis, infrared absorption spectrum, high speed atom bombardment mass spectrum (FAB-MS Pt
194) or the like be confirmed.
Compound of the present invention has low-down renal toxicity and low-down emetic toxicity; In water, have very high solubleness and the dissolution rate in water is fast, have good antitumor action, therefore can be used as antineoplastic agent.When they are used as antineoplastic agent, can adopt mode medications such as injection, medicinal preparation for oral administration.In addition, compound of the present invention is stable in atmosphere at room temperature, thereby does not need low temperature storage.
Below by embodiment embodiment of the present invention are described.But the present invention never is subjected to the restriction of these embodiment.
Embodiment 1 suitable-two chloro-1, the 4-butanediamine closes platinum (No. 1 compound)
10 gram potassium tetrachloroplatinates (II) are dissolved in the water of 350ml.Under agitation, add 16 to the inside and restrain the liquor kalii iodide that is dissolved in 50 ml waters.Under 35 ℃, continuously stirring 5 minutes, the tetraiodo that obtains black is closed the potassium platinate aqueous solution (II).With 2.12 grams 1, the 4-butanediamine is dissolved in 400 ml waters, obtains 1, the aqueous solution of 4-butanediamine separately.Put into 250 ml waters in flask, in this water, with constant speed, the tetraiodo for preparing on stirring drips is simultaneously closed potassium platinate (II) aqueous solution and 1, the 4-butanediamine aqueous solution, and the dropping time is 2 hours, temperature is 60 ℃.Collect resulting reddish-brown crystal and water, ethanol and ether washing in turn by filtering.Crystal is through vacuum-drying then, and (productive rate: suitable-two iodo-1 75.3%), the 4-butanediamine closes the crystal of platinum to obtain 9.74 grams.
1 this product of gram is suspended in 20 ml waters, then to wherein adding 620 milligrams of Silver Nitrates that are dissolved in 10 ml waters.For reaction is carried out, they were stirred 20 minutes at 60 ℃.Reaction mixture is cooled to room temperature and removes by filter Silver iodide.The Silver iodide of being removed wash with water.After leaching thing and washing lotion and being mixed together, add 653 milligrams of sodium chloride solutions that are dissolved in 5 ml waters.Under chambers temp, mixture was stirred 10 minutes.The yellow crystals of gained is collected by filtering, and with a small amount of 0 ℃ washing, washes with ethanol again, obtains compound after the vacuum-drying No. 1.
Output: 538mg
Ultimate analysis
Calculated value (%): C13.57, H3.42, N7.91, Pr55.09
Measured value (%): C13.44, H3.56, N8.04, Pr54.8
FAB-MS：（M+H）
+＝353
Embodiment 2 suitable-tetramethylene-1,1-dicarboxyl acidic group-1,4-butanediamine close platinum (No. 2 compounds)
Be dissolved in 7.26 milliliters the 1N aqueous sodium hydroxide solution 537 milligrams 1,1-tetramethylene-dicarboxyl aqueous acid replaces the 653 milligrams of sodium chloride aqueous solutions in 5 ml waters of being dissolved among the embodiment 1.The mixture of gained was 60 ℃ of following stirring reactions 2 hours behind this adding solution.This reaction mixture is concentrated 5 milliliters, be cooled to 0 ℃ then.Collect resulting white crystal by filtering,, wash with ethanol then, obtain compound after the vacuum-drying No. 2 with a small amount of 0 ℃ washing.
Output: 457 milliliters
Ultimate analysis
Calculated value (%): C28.24, H4.27, N6.59, Pt45.86
Measured value (%): C28.56, H4.41, N6.48, Pt45.2
FAB-MS：（M+H）
+＝425
Embodiment 3 suitable-4-amylene oxide-1,1-dicarboxyl acidic group-1,4-butanediamine close platinum (No. 3 compounds)
Be used in the 4-amylene oxide-1 of 324 milligrams of dissolvings in 7.26 milliliters the 1N aqueous sodium hydroxide solution, the aqueous solution of 1-carboxylic acid replaces in embodiment 1, the aqueous solution of 653 milligrams of sodium-chlor of dissolving in 5 ml waters.The mixture that adds gained behind the solution was 60 ℃ of following stirring reactions 2 hours.This reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then.Collect resulting white crystal by filtering,, wash with ethanol then, obtain compound after the vacuum-drying No. 3 with a small amount of 0 ℃ washing.
Output: 493 milligrams
Ultimate analysis
Calculated value (%): C29.01, H4.43, N6.15, Pt42.84
Measured value (%): C28.76, H4.62, N6.04, Pt42.4
FAB-MS：（M+H）
+＝455
Embodiment 4 suitable-two chloro-1-methyl isophthalic acids, the 4-butanediamine closes platinum (No. 4 compounds)
With the 1-methyl isophthalic acids of 2.46 grams, the 4-butanediamine replaces 2.12 grams 1 among the embodiment 1, the 4-butanediamine, and (productive rate: reddish-brown suitable-two iodo-1-methyl isophthalic acids 72.6%), the 4-butanediamine closes the platinum crystallization to obtain 9.64 grams.Identical with the working method of embodiment 1, the above-mentioned product except with 1 gram outside 604 milligrams of Silver Nitrates are different with 636 milligrams of sodium-chlor, obtains No. 4 compounds of yellow crystals.
Output: 400 milligrams
Ultimate analysis
Calculated value (%): C16.31, H3.83, N7.61, Pt52.99
Measured value (%): C16.57, H3.98, N7.81, Pt53.0
FAB-MS：（M+H）
+＝367
Embodiment 5 suitable-oxalic acid base-1-methyl isophthalic acids, the 4-butanediamine closes platinum (No. 5 compounds)
With 636 milligrams of sodium-chlor among 669 milligrams of potassium oxalates-hydrate replacement embodiment 4.After 669 milligrams of addings are dissolved in the solution of the above-mentioned potassium oxalate-hydrate in 5 ml waters, resulting mixture was stirred 2 hours down in 60 ℃.The mixture of gained is concentrated to 5 milliliters, is cooled to 0 ℃ then.By filtering the white crystal of collecting gained, with a spot of 0 ℃ of washing, wash with ethanol again, obtain compound after the vacuum-drying No. 5.
Output: 426 milligrams
Ultimate analysis
Calculated value (%): C21.82, H3.66, N7.27, Pt50.63
Measured value (%): C22.01, H3.71, N6.98, Pt52.0
FAB-MS：（M+H）
+＝385
Embodiment 6 suitable-propanedioic acid base-1-methyl isophthalic acids, the 4-butanediamine closes platinum (No. 6 compounds)
The solution that is used in 6.90 milliliters of 1N aqueous sodium hydroxide solutions the propanedioic acid of 378 milligrams of dissolvings replaces 636 milligrams of sodium chloride solutions that are dissolved in 5 ml waters among the embodiment 4.The mixture that adds behind the above-mentioned solution stirred 8 hours down in 50 ℃.This reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then.By filtering the white crystal of collecting gained, with a small amount of 0 ℃ of washing, wash with ethanol again, obtain compound after the vacuum-drying No. 6.
Output: 305 milligrams
Ultimate analysis
Calculated value (%): C24.06, H4.04, N7.02, Pt48.85
Measured value (%): C24.38, H4.27, N6.80, Pt48.4
FAB-MS：（M+H）
+＝399
Embodiment 7 suitable-tetramethylene-1,1-dicarboxyl acidic group-1-methyl isophthalic acid, 4-butanediamine close platinum (No. 7 compounds)
Be used in 523 milligrams of tetramethylene-1 of dissolving in 7.08 milliliters the 1N aqueous sodium hydroxide solution, the solution of 1-dicarboxylic acid replaces 636 milligrams of sodium-chlor among the embodiment 4 to be dissolved in solution in 5 ml waters.The gained mixture stirred 2 hours down in 60 ℃ after adding above-mentioned solution.Reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then by filtering the white crystal of collecting gained, with a small amount of 0 ℃ of washing, washes with ethanol again, obtains compound after the vacuum-drying No. 7.
Output: 608 milligrams
Ultimate analysis
Calculated value (%): C30.07, H4.59, N6.38, Pt44.40
Measured value (%): C29.88, H4.44, N6.53, Pt44.1
FAB-MS：（M+H）
+＝439
Embodiment 8 suitable-dimethyl malonic acid base-1-methyl isophthalic acids, the 4-butanediamine closes platinum (No. 8 compounds)
The solution that is used in 480 milligrams of dimethyl malonic acids of dissolving in 7.08 milliliters the 1N aqueous sodium hydroxide solution replaces 636 milligrams of sodium-chlor among the embodiment 4 to be dissolved in solution in 5 ml waters.The mixture that adds behind the above-mentioned solution stirred 6 hours in 50 ℃.Reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then.Collect resulting white crystal by filtering,, wash with ethanol again, obtain compound after the vacuum-drying No. 8 with a small amount of 0 ℃ of washing.
Output: 532 milligrams
Ultimate analysis
Calculated value (%): C28.11, H4.72, N6.55, Pt45.65
Measured value (%): C28.40, H4.91, N6.30, Pr46.4
FAB-MS：（M+H）
+＝427
Embodiment 9 suitable-ethyl malonic acid-1-methyl isophthalic acids, 4-butanediamine close platinum (No. 9 compounds)
The solution that is used in the ethyl malonic acid of 480 milligrams of dissolvings in 7.08 milliliters the 1N aqueous sodium hydroxide solution replaces 636 milligrams of sodium-chlor among the embodiment 4 to be dissolved in solution in 5 ml waters.The mixture that adds above-mentioned solution stirred 2 hours in 60 ℃.Reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then.By filtering the white crystal of collecting gained, with a small amount of 0 ℃ washing, wash with ethanol again, obtain compound after the vacuum-drying No. 9.
Output: 575 milligrams
Ultimate analysis
Calculated value (%): C28.11, H4.72, N6.55, Pr45.65
Measured value (%): C27.88, H4.65, N6.48, Pr46.1
FAB-MS：（M+H）
+＝427
Embodiment 10 suitable-two chloro-1-ethyls-1, the 4-butanediamine closes platinum (No. 10 compounds)
With the 1-ethyl-1 of 2.80 grams, 1 of 2.12 grams among the 4-butanediamine replacement embodiment 1, the 4-butanediamine, (productive rate: suitable-two iodo-1-ethyls-1 80.1%), the 4-butanediamine closes the reddish-brown crystal of platinum to obtain 10.90 grams.Except above-mentioned product with 1 gram, identical outside 589 milligrams Silver Nitrate and the 620 milligrams of sodium-chlor with the working method of embodiment 1, obtain No. 10 compounds of yellow crystals.
Output: 394 milligrams
Ultimate analysis
Calculated value (%): C18.86, H4.22, N7.33, Pr51.04
Measured value (%): C18.99, H4.50, N7.55, Pr50.1
FAB-MS：（M+H）
+＝381
Embodiment 11 suitable-tetramethylene-1,1-dicarboxyl acidic group-1-ethyl-1,4-butanediamine close platinum (No. 11 compounds)
The solution that is used in 510 milligrams of tetramethylene-dicarboxylic acid of dissolving in 6.90 milliliters the 1N aqueous sodium hydroxide solution replaces 620 milligrams of sodium-chlor among the embodiment 10 to be dissolved in solution in 5 ml waters.Adding the mixture that obtains behind the above-mentioned solution stirred 2 hours in 60 ℃.Reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then.Collect resulting white crystal by filtering,, wash with ethanol then, obtain compound after the vacuum-drying No. 11 with a small amount of 0 ℃ of washing.
Output: 342 milligrams
Ultimate analysis
Calculated value (%): C31.79, H4.89, N6.18, Pt43.03
Measured value (%): C31.53, H4.71, N6.36, Pt42.6
FAB-MS：（M+H）
+＝453
Embodiment 12 suitable-4-amylene oxide-1,1-dicarboxyl acidic group-1-ethyl-1,4-butanediamine close platinum (No. 12 compounds)
Be used in the 4-amylene oxide-1 of 616 milligrams of dissolvings in 7.08 milliliters the 1N aqueous sodium hydroxide solution, the solution of 1-dicarboxylic acid replaces 620 milligrams of sodium-chlor among the embodiment 10 to be dissolved in solution in 5 ml waters.The mixture that adds gained behind the above-mentioned solution stirred 2 hours in 60 ℃.Reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then.By filtering the white crystal of collecting gained, with a small amount of 0 ℃ washing, wash with ethanol again, obtain compound after the vacuum-drying No. 12.
Output: 321 milligrams
Ultimate analysis
Calculated value (%): C32.30, H5.00, N5.79, Pr40.35
Measured value (%): C32.51, H5.12, N6.01, Pt39.2
FAB-MS：（M+H）
+＝483
Embodiment 13 suitable-two chloro-2-methyl isophthalic acids, the 4-butanediamine closes platinum (No. 13 compounds)
With the 2-methyl isophthalic acid of 2.46 grams, 1 of 2.12 grams among the 4-butanediamine replacement embodiment 1, the 4-butanediamine, (productive rate: suitable-two iodo-2-methyl isophthalic acids 74.9%), the 4-butanediamine closes the reddish-brown crystal of platinum to obtain 9.94 grams.Except using the above-mentioned product of 1 gram, identical outside the sodium-chlor of 604 milligrams Silver Nitrate and 636 milligrams with working method among the embodiment 1, obtain No. 13 compounds of yellow crystals.
Output: 238 milligrams
Ultimate analysis
Calculated value (%): C16.31, H3.83, N7.61, Pt52.99
Measured value (%): C16.15, H3.70, N7.44, Pr53.1
FAB-MS：（M+H）
+＝367
Embodiment 14 suitable-propanedioic acid base-2-methyl isophthalic acids, the 4-butanediamine closes platinum (No. 14 compounds)
The propanedioic acid solution that is used in 227 milligrams of dissolvings in 4.36 milliliters the 1N aqueous sodium hydroxide solution replaces 636 milligrams of sodium-chlor among the embodiment 13 to be dissolved in solution in 5 ml waters.The mixture that adds gained behind this solution stirred 2 hours in 60 ℃.Reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then.By filtering the white crystal of collecting gained, with a small amount of 0 ℃ of washing, wash with ethanol again, obtain compound after the vacuum-drying No. 14.
Output: 125 milligrams
Ultimate analysis
Calculated value (%): C24.06, H4.04, N7.02, Pr48.85
Measured value (%): C24.22, H3.99, N7.41, Pr49.4
FAB-MS：（M+H）
+＝399
Embodiment 15 suitable-tetramethylene-1,1-dicarboxyl acidic group-2-methyl isophthalic acid, 4-butanediamine close platinum (No. 15 compounds)
Dissolve 523 milligrams tetramethylene-1 in 7.29 milliliters of 1N aqueous sodium hydroxide solutions except being used in, 1-dicarboxyl aqueous acid replaces outside the solution of 227 milligrams of propanedioic acid of dissolving in 436 milliliters of 1N aqueous sodium hydroxide solutions, identical with the working method among the embodiment 14, obtain No. 15 compounds of white crystal.
Output: 131 milligrams
Ultimate analysis
Calculated value (%): C30.07, H4.59, N6.38, Pr44.40
Measured value (%): C30.20, H4.31, N6.15, Pr44.5
FAB-MS：（M+H）
+＝439
Embodiment 16 suitable-4-amylene oxide-1,1-dicarboxyl acidic group-2-methyl isophthalic acid, 4-butanediamine close platinum (No. 16 compounds)
Except with 632 milligrams of 4-amylene oxide-1, the 1-dicarboxylic acid replaces 523 milligrams of tetramethylene-1, and is identical with working method among the embodiment 15 outside the 1-dicarboxylic acid, obtains compound No. 16.
Output: 171 milligrams
Ultimate analysis
Calculated value (%): C30.71, H4.72, N5.97, Pr41.56
Measured value (%): C30.28, H4.88, N6.10, Pr42.0
FAB-MS：（M+H）
+＝469
Embodiment 17 suitable-dimethyl malonic acid base-2-methyl isophthalic acids, the 4-butanediamine closes platinum (No. 17 compounds)
Except replacing 523 milligrams of tetramethylene-1 with 480 milligrams of dimethyl malonic acids, identical outside the 1-dicarboxylic acid with working method among the embodiment 15, obtain compound No. 17.
Output: 141 milligrams
Ultimate analysis
Calculated value (%): C28.11, H4.72, N6.56, Pr45.65
Measured value (%): C27.80, H4.52, N6.26, Pr45.4
FAB-MS：（M+H）
+＝427
Embodiment 18 suitable-ethyl malonic acid base-2-methyl isophthalic acids, the 4-butanediamine closes platinum (No. 18 compounds)
Except replacing 523 milligrams of tetramethylene-1 with 480 milligrams of ethyl malonic acids, outside the 1-dicarboxylic acid, the same quadrat method operation according among the embodiment 15 obtains compound No. 18.
Output: 124 milligrams
Ultimate analysis
Calculated value (%): C28.11, H4.72, N6.56, Pt45.65
Measured value (%): C27.60, H4.91, N6.10, Pt45.2
FAB-MS：（M+H）
+＝427
Embodiment 19 suitable-two chloro-2,2-dimethyl-1,4-butanediamine close platinum (No. 19 compounds)
With 2.80 grams 2,2-dimethyl-1, the 4-butanediamine replaces 2.12 grams 1 among the embodiment 1, and the 4-butanediamine obtains 11.20 gram (productive rates: suitable-two iodo-2 82.3%), 2-dimethyl-1, the 4-butanediamine closes the yellowish brown crystal of platinum, except with the above-mentioned product of 1 gram, outside 589 milligrams of Silver Nitrates and the 620 milligrams of sodium-chlor, operate according to the same quadrat method among the embodiment 1, obtain No. 19 compounds of yellow crystals.
Output: 283 milligrams
Ultimate analysis
Calculated value (%): C18.86, H4.22, N7.33, Pt51.04
Measured value (%): C19.12, H4.03, N7.01, Pt50.8
FAB-MS：（M+H）
+＝381
Embodiment 20 suitable-oxalic acid bases-2,2-dimethyl-1,4-butanediamine close platinum (No. 20 compounds)
Being dissolved in potassium oxalate in 5 ml waters-hydrates with 652 milligrams replaces 620 milligrams of sodium-chlor among the embodiment 19 to be dissolved in solution in 5 ml waters.Adding the mixture that obtains behind the above-mentioned solution stirred 2 hours in 60 ℃.Reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then.Collect resulting white crystal by filtering,, wash with ethanol again, obtain compound after the vacuum-drying No. 20 with a small amount of 0 ℃ of washing.
Output: 448 milligrams
Ultimate analysis
Calculated value (%): C24.06, H4.04, N7.02, Pt48.85
Measured value (%): C23.99, H4.11, N6.86, Pt49.3
FAB-MS：（M+H）
+＝339
Embodiment 21 suitable-propanedioic acid bases-2,2-dimethyl-1,4-butanediamine close platinum (No. 21 compounds)
The solution of 368 milligrams of propanedioic acid of dissolving replaces 652 milligrams of potassium oxalate-hydrates to be dissolved in the solution in 5 ml waters in being used in 6.90 milliliters of 1N aqueous sodium hydroxide solutions, according to the same quadrat method operation among the embodiment 20, obtain No. 21 compounds of white crystal.
Output: 331 milligrams
Ultimate analysis
Calculated value (%): C26.15, H4.39, N6.78, Pt47.20
Measured value (%): C26.51, H4.55, N6.41, Pt46.1
FAB-MS：（M+H）
+＝413
Embodiment 22 suitable-tetramethylene-1,1-dicarboxyl acidic group-2,2-dimethyl-1,4-butanediamine close platinum (No. 22 compounds)
Except being used in 510 milligrams of tetramethylene-1 of dissolving in 6.90 milliliters of 1N aqueous sodium hydroxide solutions, the solution of 1-dicarboxylic acid replaces 652 milligrams of potassium oxalate-hydrates to be dissolved in outside the solution in 5 ml waters, according to the same quadrat method operation in embodiment 20, obtain No. 22 compounds of white crystal.
Output: 375 milligrams
Ultimate analysis
Calculated value (%): C31.79, H4.89, N6.18, Pt43.03
Measured value (%): C31.81, H5.01, N6.36, Pt43.2
FAB-MS：（M+H）
+＝453
Embodiment 23 suitable-4-amylene oxide-1,1-dicarboxyl acidic group-2,2-dimethyl-1,4-butanediamine close platinum (No. 23 compounds)
Except being used in 616 milligrams of 4-amylene oxide-1 of dissolving in 6.90 milliliters of 1N aqueous sodium hydroxide solutions, the solution of 1-dicarboxylic acid replaces 652 milligrams of potassium oxalate-hydrates to be dissolved in outside the solution in 5 ml waters, according to the same quadrat method operation among the embodiment 20, obtain No. 23 compounds of white crystal.
Output: 326 milligrams
Ultimate analysis
Calculated value (%): C32.30, H5.00, N5.79, Pt40.35
Measured value (%): C33.11, H4.97, N6.01, Pt39.8
FAB-MS：（M+H）
+＝483
Embodiment 24 suitable-dimethyl malonic acid bases-2,2-dimethyl-1,4-butanediamine close platinum (No. 24 compounds)
467 milligrams of dimethyl malonic acid solution of dissolving replace 652 milligrams of potassium oxalate-hydrates to be dissolved in the solution in 5 ml waters in being used in 6.90 milliliters of 1N aqueous sodium hydroxide solutions, operate according to embodiment 20 same methods, obtain No. 24 compounds of white crystal.
Output: 407 milligrams
Ultimate analysis
Calculated value (%): C29.93, H5.02, N6.35, Pt44.20
Measured value (%): C30.14, H5.28, N6.19, Pt43.9
FAB-MS：（M+H）
+＝441
Embodiment 25 suitable-two chloro-1,1-dimethyl-1,4-butanediamine close platinum (No. 25 compounds)
With 2.80 grams 1,1-dimethyl-1,4-butanediamine replace 2.12 grams 1 among the embodiment 1, the 4-butanediamine, and (productive rate: suitable-two iodo-1 78.0%), 1-dimethyl-1,4-butanediamine close the reddish-brown crystal of platinum to obtain 10.62 grams.Except with this product of 1 gram, 589 milligrams of Silver Nitrates and the 620 milligrams of sodium hydrides, according in embodiment 1 with the quadrat method operation, obtain No. 25 compounds of yellow crystals.
Output: 264 milligrams
Ultimate analysis
Calculated value (%): C18.86, H4.22, N7.33, Pt51.04
Measured value (%): C18.77, H4.33, N7.58, Pt50.7
FAB-MS：（M+H）
+＝381
Embodiment 26 suitable-oxalic acid bases-1,1-dimethyl-1,4-butanediamine close platinum (No. 26 compounds)
In embodiment 25, be dissolved in solution in 5 ml waters with 652 milligrams of potassium oxalate-hydrates and replace 620 milligrams of sodium-chlor to be dissolved in solution in 5 ml waters.Mixed 2 hours in 60 ℃ adding the mixture that obtains behind this solution.Reaction mixture is concentrated to 5 milliliters, is cooled to 0 ℃ then.By filtering the white crystal of collecting gained, with a small amount of 0 ℃ washing, wash with ethanol then, obtain compound after the vacuum-drying No. 26.
Output: 433 milligrams
Ultimate analysis
Calculated value (%): C24.06, H4.04, N7.02, Pt48.85
Measured value (%): C24.31, H4.22, N7.01, Pt49.2
FAB-MS：（M+H）
+＝399
Embodiment 27 suitable-tetramethylene-1,1-dicarboxyl acidic group-1,1-dimethyl-1,4-butanediamine close platinum (No. 27 compounds)
Except being used in 510 milligrams of tetramethylene-1 of dissolving in 6.90 milliliters of 1N aqueous sodium hydroxide solutions, 1-dicarboxylic acid and the solution that obtains replace 652 milligrams of potassium oxalate-hydrates to be dissolved in outside the solution in 5 ml waters, according in embodiment 26, operating, obtain No. 27 compounds of white crystal with quadrat method.
Output: 207 milligrams
Ultimate analysis
Calculated value (%): C31.79, H4.89, N6.18, Pt43.03
Measured value (%): C32.02, H5.11, N6.01, Pt44.2
FAB-MS：（M+H）
+＝453
Embodiment 28 suitable-dimethyl malonic acid bases-1,1-dimethyl-1,4-butanediamine close platinum (No. 28 compounds)
Except replacing 510 milligrams of tetramethylene-1, beyond the 1-dicarboxylic acid,, obtain No. 28 compounds of white crystal according in embodiment 27, operating with quadrat method with 467 milligrams of dimethyl malonic acids.
Output: 337 milligrams
Ultimate analysis
Calculated value (%): C29.93, H5.02, N6.35, Pt44.20
Measured value (%): C30.22, H5.36, N6.10, Pt43.4
FAB-MS：（M+H）
+＝441
Embodiment 29 suitable-two chloro-2-ethyls-1, the 4-butanediamine closes platinum (No. 29 compounds)
With 2.80 gram 2-ethyls-1, the 4-butanediamine replaces 2.12 grams 1 among the embodiment 1, the 4-butanediamine, and (productive rate: suitable-two iodo-2-ethyls-1 75.8%), the 4-butanediamine closes the reddish-brown crystal of platinum to obtain 10.32 grams.Except with this product of 1 gram, 589 milligrams of Silver Nitrates and the 620 milligrams of sodium-chlor, according in embodiment 1 with the quadrat method operation, obtain No. 29 compounds of yellow crystals.
Output: 257 milligrams
Ultimate analysis
Calculated value (%): C18.86, H4.22, N7.33, Pt51.04
Measured value (%): C19.00, H4.35, N7.16, Pt51.0
FAB-MS：（M+H）
+＝381
Embodiment 30 suitable-oxalic acid base-2-ethyls-1, the 4-butanediamine closes platinum (No. 30 compounds)
Being dissolved in solution in 5 ml waters with 652 milligrams of potassium oxalate-hydrates replaces 620 milligrams of sodium-chlor in embodiment 29 to be dissolved in solution in 5 ml waters.Stirred 2 hours in 60 ℃ adding the mixture that obtains behind this solution.Reaction mixture is concentrated into 5 milliliters, is cooled to 0 ℃ then.Collect resulting white crystal by filtering,, wash with ethanol then, obtain compound after the vacuum-drying No. 30 with a spot of 0 ℃ of washing.
Output: 428 milligrams
Ultimate analysis
Calculated value (%): C24.06, H4.04, N7.02, Pt48.85
Measured value (%): C24.33, H4.17, N6.96, Pt48.5
FAB-MS：（M+H）
+＝399
Embodiment 31 suitable-propanedioic acid base-2-ethyls-1, the 4-butanediamine closes platinum (No. 31 compounds)
368 milligrams of propanedioic acid of dissolving in being used in 6.90 milliliters of 1N aqueous sodium hydroxide solutions and the solution that obtains replace 652 milligrams of potassium oxalate-hydrates to be dissolved in the solution in 5 ml waters, according in embodiment 30 with the quadrat method operation, obtain compound No. 31.
Output: 280 milligrams
Ultimate analysis
Calculated value (%): C26.15, H4.39, N6.78, Pt47.20
Measured value (%): C26.53, H4.50, N6.59, Pt46.1
FAB-MS：（M+H）
+＝413
Embodiment 32 suitable-tetramethylene-1,1-dicarboxyl acidic group-2-ethyl-1,4-butanediamine close platinum (No. 32 compounds)
Except with 510 milligrams of tetramethylene-1, beyond 368 milligrams of propanedioic acid of 1-dicarboxylic acid replacement,, obtain compound No. 32 according to the operation of the method in embodiment 31.
Output: 451 milligrams
Ultimate analysis
Calculated value (%): C31.79, H4.89, N6.18, Pt43.03
Measured value (%): C31.51, H4.67, N6.22, Pt42.1
FAB-MS：（M+H）
+＝453
Embodiment 33 suitable-dimethyl malonic acid base-2-ethyls-1, the 4-butanediamine closes platinum (No. 33 compounds)
Except replace 368 milligrams of propanedioic acid with 467 milligrams of dimethyl malonic acids,, obtain compound No. 33 according in embodiment 31, operating with quadrat method.
Output: 361 milligrams
Ultimate analysis
Calculated value (%): C29.93, H5.02, N6.35, Pt44.20
Measured value (%): C30.14, H5.18, N6.19, Pt45.2
FAB-MS：（M+H）
+＝441
The physical property of The compounds of this invention is shown in table 1(and sees the literary composition back) in.
In view of the suitable-solubleness of dichloro two ammino platinum in physiological saline is about 1.2mg/ml, the solubleness of obvious compound of the present invention in water is very high.In addition, compound of the present invention dissolves very fast in water.Therefore when the crystallization of The compounds of this invention is used to inject, before injection that it is soluble in water, can at once obtained aqueous solution be injected after the dissolving.
Then, the anti-tumor activity of The compounds of this invention will be by experiment example be illustrated.
Experiment embodiment 1 is about artificial culture mouse leukemia L1210 cell growth inhibition test (test method)
In containing the RPMI1640 medium of 10% foetal calf serum, cultivate mouse leukemia L1210 cell.The growth-inhibiting percentage can calculate from the cell count under the situation that adds and do not add every kind of compound.
Draw on logarithm probability paper compound concentration and suppress percentile graphic representation from graphic representation, can be obtained IC
50Value (concentration when 50% growth is suppressed).
The results are shown in table 2(and see the literary composition back) in.
Find out obviously that from table 2 compound of the present invention growth to cancer cells under the situation of lower concentration demonstrates the inhibition activity.
The growth that compound of the present invention also resists along dichloro two ammino platinum tumour cells demonstrates good inhibition activity, and this tumour cell obtains a kind of resistibility to suitable dichloro two ammino platinum owing to using along dichloro two ammino platinum.Relevant this active experiment embodiment is that example is described with No. 15 compounds.
Experiment embodiment 2 is along the growth inhibition test of dichloro two ammino platinum antineoplastic cells
(experimental technique)
1 * 10
5Individual mouse leukemia L1210 cell or 1 * 10
5Individual mouse leukemia P388 Transplanted cells is in CDF
1The intraperitoneal of female mouse.Transplanted back 2 days, and they were used suitable-dichloro two ammino platinum of 6mg/kg in the mode in interior abdominal cavity.After 5 days, with their cancer cell transplantation in other CDF
1Female mouse intraperitoneal is taked same treatment process.Repeat above-mentioned steps, can obtain along dichloro two ammino platinum antineoplastic cells.
Utilize the above-mentioned tumour cell that obtains, carry out the growth inhibitory activity test, can obtain anti-IC whereby along dichloro two ammino platinum tumour cells by the method identical with experiment embodiment 1
50(hereinafter claim IC
50R).Can calculate above-mentioned IC then
50R and the tumour cell IC that does not have suitable dichloro two ammino platinum resistibilitys
50Ratio, i.e. IC
50R/IC
50
The results are shown in table 3(and see the literary composition back) in.
Find out obviously that from table 3 The compounds of this invention also demonstrates inhibition to the growth along dichloro two ammino platinum antineoplastic cells under lower concentration active.
The anti-tumor activity test of 3 pairs of live body mouse of experiment embodiment leukemia L1210
(test method)
1 * 10
5The mouse blood cell is transplanted the female CDF in 6 weeks
1The intraperitoneal of mouse.From second day, imposed a kind of compound to their intraperitoneal in continuous once a day 5 days.One group of mouse (control group) mouse without the compound treatment group imposes normal saline solution in the same way.Measure compound treatment group and control group (being abbreviated as T and the C respectively) mean survival time, and calculate the percentage (T/C * 100) of T/C from following equation.
T/C=(mean survival time of compound treatment group)/(mean survival time of control group) * 100
When any mouse dies in implementation process owing to the violent toxicity of the compound that is applied, can calculate 50% lethal dose (LD according to ordinary method
50).
The results are shown in table 4(and see the literary composition back) in.In the table 4, max(T/C) mean the maximum value of T/C, optimal dose (Opt.dose) means the formulation rate of maximum (T/C) value, promptly best formulation rate.
Find out obviously that from table 4 compound of the present invention has life prolongation effect for the mouse of injecting mouse leukemia L1210 cell.
Compound of the present invention is not that the tumour cell of mouse leukemia L1210 cell also has life prolongation effect for transplanting.These effects are that example is illustrated with No. 15 compounds in experiment embodiment 4.
Experiment embodiment 4 is for various antitumor activity against various tumors tests in the body
(test method)
1 * 10
6Mouse leukemia P388 transplants the female CDF in 6 weeks
1The intraperitoneal of mouse from second day continuous once a day 5 days, imposes compound No. 15 to their intraperitoneal.Respectively, with 1 * 10
6Mouse lung cancer lewis lung cancer (LL) Transplanted cells in public BDF
1The intraperitoneal of mouse, from second day, the intraperitoneal to it imposed compound No. 15 in continuous once a day 5 days.Respectively, with 1 * 10
6Mouse fibroma M5076 cell through subcutaneous transplantation in female C57BL/
6The mouse side imposes on abdominal cavity in it from second day with No. 15 compounds.Respectively, with 1 * 10
6Mouse colon cancer (colon 26) Transplanted cells is in female CDF
1The intraperitoneal of mouse from second day once a day, imposes on abdominal cavity in it with No. 15 compounds.Each control group (without the compound treatment group) is imposed physiological saline.From the survival time of compound treatment group and control group, can calculate intermediate value (intermediate value survival time) separately.Utilize this value, can calculate the percentage of T/C from following method.
T/C=(the intermediate value survival time of compound treatment group)/(the intermediate value survival time of control group) * 100%
The results are shown in table 5(and see the literary composition back) in.
Find out obviously that from table 5 compound of the present invention has tangible life prolongation effect to the mouse of having transplanted various tumour cells.
Secondly, the renal toxicity of The compounds of this invention will be described in the experiment embodiment mode.
Experiment embodiment 5 renal toxicity tests
(test method)
With a kind of compound once the value of moving in 6 all public CDF
1The mouse intraperitoneal.After four days, collect their blood, measure blood urinary nitrogen concentration (BUN value).
The results are shown in the table 6, according to the method for example 3, the optimal dose of cis-platinum is 4mg/kg, but in above-mentioned renal toxicity test, though impose along dichloro two ammino platinum with 4 times when the optimal dose, the BUN value still is higher than normal value (30mg/dl or lower) far away.Based on the above-mentioned fact, just as shown in table 6, the amount of executing of the The compounds of this invention that is adopted in experiment embodiment 4 is 4 times or more is higher than experiment embodiment 3 resulting optimal doses.In the table 6 (see literary composition back), weight ratio is the body weight of dispenser after 4 days and the ratio of the body weight during dispenser.
From table 6, obviously find out, use BUN value that The compounds of this invention obtains be significantly less than use commercially available suitable-BUN value that dichloro two ammino platinum obtain, and approach to execute the resulting BUN value of normal saline solution.This shows that compound of the present invention has very low renal toxicity, thereby The compounds of this invention can be used as low renal toxicity antineoplastic agent.Because these characteristics and the high-dissolvability in water, in doing, can use discontinuously during abdominal injection compound of the present invention, but with the medication of pill mode.
The diamines as ligand in some The compounds of this invention has unsymmetrical carbon.Such amine decomposes the third contact of a total solar or lunar eclipse isomer that generates it through optics.Using these isomers can synthesize each title complex as ligand is also tested.These synthetic and tests will be example with No. 15 compounds, be illustrated in the mode of example and experiment embodiment.
Embodiment 34 R-2-methyl isophthalic acids, the 4-butanediamine
The R-2-methyl hexanodioic acid of 40g is added in the mixture of the 200g vitriol oil and 320 milliliters of benzene.Use heating in water bath mixture to 45 ℃, dissolving 3-methyl hexanodioic acid.Slowly add the 50g sodiumazide in above-mentioned solution, mixture is 45 ℃～50 ℃ reactions down then.After adding sodiumazide, continuously stirring 10 minutes.Drip the saturated solution that contains 200g sodium hydroxide then.By removing by filter the sodium sulfate precipitation, separate the benzene phase in the filtrate.Water in the filtrate then with 500 milliliters of ether extractings, is used 500 milliliters of chloroform extractings 4 times with 500 milliliters of benzene extractings at last.All extractivess are mixed, and use anhydrous sodium sulfate dehydration then.Removing by filter sodium sulfate leaches thing and concentrates with rotatory evaporator.Enriched material obtains the R-2-methyl isophthalic acid through vacuum distilling, the 4-butanediamine.
Output: 6.92 gram (productive rates: 27.1%)
Boiling point: 83 ℃/30 millimeters
Purity: 99.3%
Optical purity: 100%
In present embodiment and next embodiment, purity and optical purity are by measuring such as class methods such as gas-chromatography, polarimetries.
Embodiment 35 passes through the optics decomposition method, segregation 2-methyl isophthalic acid, the optical isomeric compound of 4-butanediamine
By using dibenzoic acid base tartrate with the 2-methyl isophthalic acid, the 4-butanediamine changes salify again with the method for this salt recrystallization (two kinds of optical isomeric compounds have different solubleness), and its optics is decomposed.Use (-)-dibenzoic acid base-tartrate system R-2-methyl isophthalic acid, the 4-butanediamine uses (+)-dibenzoic acid base tartrate system S-2-methyl isophthalic acid, the 4-butanediamine.Two kinds of 2-methyl isophthalic acids, decomposition productive rate, purity and the optical purity of the isomer of 4-butanediamine are shown in table 7(and see the literary composition back) in.
Utilize the optical isomeric compound that obtains in embodiment 34 and 35, take 15 identical operations methods with embodiment, obtain suitable-tetramethylene-1,1-dicarboxylic acid R-2-methyl isophthalic acid, the 4-butanediamine closes platinum (15R compound) and suitable-tetramethylene-1,1-dicarboxylic acid-S-2-methyl isophthalic acid, 4-butanediamine close platinum (15S compound).(see the literary composition back) in the table 8 and listed synthetic yield and ultimate analysis, (see the literary composition back) in the table 9 and list their physicals with the above-mentioned title complex of potassium tetrachloroplatinate (II) synthetic.(M+H) of the title complex that the FAB-MS method is measured
+Value all is 439.
Optical isomeric compound 15R and 15S will be through the tests identical with experiment embodiment 1 and experiment embodiment 3.The results are shown in table 10(and see the literary composition back) in.
Optical isomeric compound 15R and 15S are through the test identical with experiment embodiment 4.The results are shown in table 11(and see the literary composition back) in.
Optical isomeric compound 15R and 15S will be through the renal toxicity tests identical with experiment embodiment 5.The results are shown in table 12(and see the literary composition back) in.The dosage of each compound is four times in the optimal dose of listing in the table 10.
Find out obviously that from above experimental result 15R and 15S all have solubleness in the very high water, demonstrate the anti-tumor activity good, and have very low renal toxicity various tumour cells.
Embodiment 36 (No. 5 compounds)
Replace 639 milligrams the sodium chloride solution in the 5ml water of being dissolved among the embodiment 4 with the solution that is dissolved in 343 milligrams oxalic acid hydrate in the 5ml water.Stirred 24 hours down in 40 ℃ from adding the mixture that obtains behind the above-mentioned solution.Reaction mixture simmer down to 5ml is cooled to 0 ℃ then.Filter and collect the product white crystals, with a small amount of 0 ℃ of washing, wash with ethanol then, then vacuum-drying obtains compound No. 5.This compound have with embodiment 5 in No. 5 identical analytical values of compound.
Embodiment 37 (No. 4 compounds)
Being dissolved in solution in 150 ml waters with 560 milligrams of Sulfuric acid disilver salts replaces 604 milligrams of Silver Nitrates among the embodiment 4 to be dissolved in solution in 10 ml waters.Adding the mixture that above-mentioned solution obtains stirred 20 minutes down in 80 ℃.Remaining schedule of operation is identical with embodiment 4, obtains No. 4 compounds of yellow crystal whereby.This compound has and No. 4 identical analytical values of compound.
Compound of the present invention demonstrates for tumour cell under the lower concentration situation has growth inhibitory activity, therefore has extraordinary antitumor action for various tumours.Solubleness height in the water of compound of the present invention, and dissolving is very fast in water.The renal toxicity of compound of the present invention and vomiting poison are very low.Further with regard to bone marrow toxicity, the bone marrow toxicity of compound of the present invention is slight, and this toxicity can be seen at traditional platinum complex antineoplastic agent usually, promptly mainly is that white blood cell count reduces, and they are very slight to hematoblastic toxicity.Say that further when The compounds of this invention was used for antineoplastic agent, it was very fast returning to usual terms, therefore be easy to control.Substantially above-mentioned these facts, The compounds of this invention are very good antineoplastic agent.Again further, The compounds of this invention is stable in air at room temperature, need not low temperature storage like this.
Table 1
Compound in water the solubleness infrared absorption spectrum (centimetre
-1)
Numbering (mg/ml) N-H C=O
1 ＞2＊ 3250-3150 -
2 ＞5 3210-3130 1650-1610
3 ＞10 3230-3120 1670-1630
4 ＞2＊ 3240-3150 -
5 ＞3 3220-3140 1700-1685
6 ＞10 3260-3090 1640-1600
7 ＞5 3220-3110 1660-1600
8 ＞20 3230-3140 1640-1590
9 ＞10 3250-3110 1630-1590
10 ＞2＊ 3230-3120 -
11 ＞3 3210-3100 1650-1600
12 ＞5 3230-3090 1680-1620
13 ＞2＊ 3248-3225 -
14 ＞50 3200-3125 1730-1610
15 ＞8 3200-3125 1700-1620
16 ＞15 3200-3130 1690-1610
17 ＞20 3250-3125 1680-1640
18 ＞10 3190-3120 1710-1620
19 ＞2＊ 3220-3130 -
20 ＞3 3260-3140 1690-1660
21 ＞5 3190-3120 1680-1610
22 ＞3 3220-3130 1620-1600
23 ＞3 3230-3130 1650-1590
24 ＞10 3250-3140 1640-1590
25 ＞2 3210-3130 -
26 ＞3 3220-3140 1700-1660
27 ＞10 3220-3130 1640-1600
28 ＞10 3240-3140 1640-1590
29 ＞2＊ 3220-3130 -
30 ＞3 3240-3120 1690-1660
31 ＞10 3230-3130 1680-1600
32 ＞5 3220-3130 1630-1590
33 ＞10 3240-3150 1650-1600
* the solubleness in normal saline solution
Table 2
Compound number IC
50(μ g/ml)
1 0.33
2 0.88
3 0.65
4 0.20
5 0.29
6 0.76
7 2.80
8 0.90
9 2.40
10 0.35
11 4.70
12 1.05
13 0.10
14 0.74
15 1.20
16 0.43
17 0.50
18 0.84
19 0.20
20 0.37
21 0.72
22 2.20
23 0.44
24 0.78
25 0.25
26 0.30
28 4.50
29 0.05
30 0.06
31 0.66
32 0.67
33 0.23
Table 3
Compound number IC
50R/IC
50
Tumour cell L1210 tumour cell P388
Along dichloro two ammino platinum 11.4 10.7
15 3.19 3.26
Table 4
Compound maximum (T/C) optimal dose LD
50
Numbering (mg/kg) (mg/kg)
1 203 2 4.8
2 182 32 48.0
3 132 8 8.4
4 225 2 2.4
5 273 4 6.0
6 359 32 48.0
7 176 64 -
8 189 64 -
9 222 64 96.0
10 210 4 6.0
11 139 64 -
12 181 64 -
13 187 2 4.2
14 346 32 -
15 182 32 80.0
16 167 8 12.0
17 238 32 -
18 264 16 24.0
19 359 4 6.0
20 272 8 12.0
21 301 32 48.0
22 320 128 -
23 159 32 -
24 253 64 -
25 150 2 3.0
29 261 2 3.0
30 253 8 -
32 275 32 -
No. 15 compounds of table 5 are to the anti-tumor activity of various tumour cells
Tumour cell maximum (T/C) optimal dose (milligram/kilogram)
P388 260 32
LL 222 32
M5076 152 16
Colon 26 198 32
Table 6
Compound dosage weight ratio BUN value
Numbering (milligram/kilogram) (ml/min liter)
Physiological saline-1.05 22.7
Cis-platinum 16 0.72 92.9
1 8 0.83 11.4
2 128 0.73 16.2
4 8 0.75 28.4
5 16 0.76 12.9
6 128 0.75 24.6
7 256 0.85 13.1
8 256 0.71 25.4
10 16 0.74 21.3
11 256 1.09 23.2
12 256 0.94 16.8
13 20 0.74 22.6
14 128 0.72 15.9
15 240 0.74 19.8
17 128 0.73 16.7
18 64 0.74 19.6
19 16 0.76 15.7
20 32 0.75 13.5
21 128 0.76 16.7
22 512 0.74 14.4
23 128 0.89 15.0
24 256 0.79 19.7
25 8 0.79 16.8
29 8 0.72 18.1
30 32 0.87 18.2
32 128 0.74 19.7
Table 7
Decompose productive rate (%) purity (%) optical purity (%)
R-isomer 57.8 100 98.6
S-isomer 51.4 100 98.8
Table 8
Compound number synthetic yield ultimate analysis (%)
（%） C H N Pt
15R 24.6 29.98 4.43 6.22 44.8
15S 23.1 30.21 4.37 6.36 45.0
Table 9
Solubleness infrared absorption spectrum in the compound water (centimetre
-1)
Numbering (mg/ml) N-H C=O
15R ＞15 3200-3125 1700-1620
15S ＞15 3210-3130 1700-1620
Table 10
Compound I C
50Maximum optimal dose IC
50
Numbering microgram/ml T/C milligram/kilogram milligram/kilogram
15R 0.78 189 32 33.6
15S 1.08 206 32 48.0
Table 11
Compound number tumour cell maximum (T/C) optimal dose
(milligram/kilogram)
15R P388 253 20
15R LL 166 30
15S P388 253 40
15S LL 164 50
Table 12
Compound dosage weight ratio BUN value
Numbering (milligram/kilogram) (milligram/decilitre)
15R 128 0.71 10.6
15S 128 0.90 21.4
Claims (15)
1, a kind of production diamines closes the method for platinum (II) title complex, and this title complex is expressed by following general formula:
[(R in the formula
1, R
2, R
3And R
4Be respectively hydrogen atom or low alkyl group; Two X are connected to form the group of being expressed by following general formula;
(R in the formula
5And R
6Be respectively hydrogen atom or low alkyl group) or the group of expressing by following general formula;
(m is 1 or 2 in the formula)], this method comprises the diamines that following general formula is expressed
(R in the formula
1, R
2, R
3And R
4Respectively by aforementioned definitions) with
M
2Pt(Hal)
4
(M is for becoming the atom of monovalent cation in the formula, and Hal is a halogen atom) reaction generates the dihalo-diamines of being expressed by following general formula and closes platinum complex:
(R in the formula
1, R
2, R
3And R
4Be halogen atom, has the above-mentioned identical definition that provides respectively), and make the dihalo-diamines close platinum complex to exist under the situation with the silver ions reaction at water and generate two hydrated complexes, two hydrated complexes and dicarboxylic acid or its reactant salt then, wherein the consumption of diamines is 0.5～4 moles/mole M
2Pt (Hal)
4, the consumption of silver ions is that 0.5～6 equivalent/equivalent dihalo-diamines closes platinum complex, the consumption of two carbonic acid or its salt is 0.5～10 moles/mole, two water complexs.
2, method according to claim 1, wherein R
1And R
2Be respectively hydrogen atom.
3, method according to claim 1, common bases that form of two X wherein, express by following formula:
(in the formula, R
5And R
6Be respectively hydrogen atom or low alkyl group) or the base of expressing by following general formula:
4, according to claim 1,2 or 3 described method, wherein M
2Pt(Hal)
4In M be Na, K or Cs, Hal is Cl, Br or I.
5, according to claim 2 or 3 described methods, wherein diamines is 1,4-butanediamine, 2-methyl isophthalic acid, 4-butanediamine or 2-ethyl-1,4-butanediamine.
6, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-tetramethylene-1 to the gained diamines, 1-dicarboxyl acidic group-1, and the 4-butanediamine closes platinum.
7, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-propanedioic acid base-2-methyl isophthalic acid to the gained diamines, and the 4-butanediamine closes platinum.
8, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-tetramethylene-1 to the gained diamines, 1-dicarboxyl acidic group-2-methyl isophthalic acid, and the 4-butanediamine closes platinum.
9, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-dimethyl malonic acid base-2-methyl isophthalic acid to the gained diamines, and the 4-butanediamine closes platinum.
10, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-ethyl malonic acid base-2-methyl isophthalic acid to the gained diamines, and the 4-butanediamine closes platinum.
11, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-propanedioic acid base-2-ethyl-1 to the gained diamines, and the 4-butanediamine closes platinum.
12, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-tetramethylene-1 to the gained diamines, 1-dicarboxyl acidic group-2-ethyl-1, and the 4-butanediamine closes platinum.
13, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-dimethyl malonic acid base-2-ethyl-1 to the gained diamines, and the 4-butanediamine closes platinum.
14, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-tetramethylene-1 to the gained diamines, 1-dicarboxyl acidic group-R-2-methyl isophthalic acid, and the 4-butanediamine closes platinum.
15, according to the described method of claim 3, wherein to close platinum (II) title complex be suitable-tetramethylene-1 to the gained diamines, 1-dicarboxyl acidic group-S-2-methyl isophthalic acid, and the 4-butanediamine closes platinum.
Applications Claiming Priority (9)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP187710/85 | 1985-08-27 | ||
| JP26800/86 | 1986-02-12 | ||
| JP26799/86 | 1986-02-12 | ||
| JP2680086 | 1986-02-12 | ||
| JP2679986 | 1986-02-12 | ||
| JP94625/86 | 1986-04-25 | ||
| JP9462686 | 1986-04-25 | ||
| JP152635/86 | 1986-07-01 | ||
| JP61152635A JPS6345290A (en) | 1985-08-27 | 1986-07-01 | Novel platinum complex |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86105441A CN86105441A (en) | 1987-03-11 |
| CN1010314B true CN1010314B (en) | 1990-11-07 |
Family
ID=27458575
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 86105441 Expired CN1010314B (en) | 1985-08-27 | 1986-08-26 | Novel platinum complex production method |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1010314B (en) |
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| CN110099913B (en) * | 2016-12-21 | 2022-05-13 | 国立研究开发法人产业技术综合研究所 | Method for producing cyclometalated iridium complex |
-
1986
- 1986-08-26 CN CN 86105441 patent/CN1010314B/en not_active Expired
Also Published As
| Publication number | Publication date |
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| CN86105441A (en) | 1987-03-11 |
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