GB2128615A - Platinum 1,3-propane-diamine complexes - Google Patents
Platinum 1,3-propane-diamine complexes Download PDFInfo
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- GB2128615A GB2128615A GB08328084A GB8328084A GB2128615A GB 2128615 A GB2128615 A GB 2128615A GB 08328084 A GB08328084 A GB 08328084A GB 8328084 A GB8328084 A GB 8328084A GB 2128615 A GB2128615 A GB 2128615A
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- VUWSEQPFJJGURL-UHFFFAOYSA-N platinum;propane-1,3-diamine Chemical class [Pt].NCCCN VUWSEQPFJJGURL-UHFFFAOYSA-N 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 46
- 238000000034 method Methods 0.000 claims abstract description 39
- 206010028980 Neoplasm Diseases 0.000 claims abstract description 15
- 201000011510 cancer Diseases 0.000 claims abstract description 14
- 238000002360 preparation method Methods 0.000 claims abstract description 8
- ROBFUDYVXSDBQM-UHFFFAOYSA-N hydroxymalonic acid Chemical group OC(=O)C(O)C(O)=O ROBFUDYVXSDBQM-UHFFFAOYSA-N 0.000 claims abstract description 7
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical group OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims abstract description 5
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 4
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 4
- DDRVFRXYTKAZHH-UHFFFAOYSA-N 2-carboxyoxycarbonylbenzoic acid Chemical group OC(=O)OC(=O)C1=CC=CC=C1C(O)=O DDRVFRXYTKAZHH-UHFFFAOYSA-N 0.000 claims abstract description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical group OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 3
- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical group OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims abstract description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract 2
- UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical group CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 claims abstract 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 claims description 46
- 229910052697 platinum Inorganic materials 0.000 claims description 37
- 239000000203 mixture Substances 0.000 claims description 21
- -1 Platinum diamine Chemical class 0.000 claims description 20
- 239000003085 diluting agent Substances 0.000 claims 1
- 229940045985 antineoplastic platinum compound Drugs 0.000 abstract description 2
- 150000003058 platinum compounds Chemical class 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 34
- 229910001868 water Inorganic materials 0.000 description 31
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 24
- 208000032839 leukemia Diseases 0.000 description 23
- 239000000243 solution Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 8
- 231100000417 nephrotoxicity Toxicity 0.000 description 8
- 210000003734 kidney Anatomy 0.000 description 7
- 239000002244 precipitate Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- 239000012153 distilled water Substances 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 4
- 241000699666 Mus <mouse, genus> Species 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 125000003963 dichloro group Chemical group Cl* 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 208000003747 lymphoid leukemia Diseases 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 150000003057 platinum Chemical class 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- AYTGUZPQPXGYFS-UHFFFAOYSA-N urea nitrate Chemical compound NC(N)=O.O[N+]([O-])=O AYTGUZPQPXGYFS-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 201000008228 Ependymoblastoma Diseases 0.000 description 2
- 206010014968 Ependymoma malignant Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 229910021607 Silver chloride Inorganic materials 0.000 description 2
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 2
- 125000000217 alkyl group Chemical group 0.000 description 2
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000003710 aryl alkyl group Chemical group 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 2
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- ARCGXLSVLAOJQL-UHFFFAOYSA-N trimellitic acid Chemical compound OC(=O)C1=CC=C(C(O)=O)C(C(O)=O)=C1 ARCGXLSVLAOJQL-UHFFFAOYSA-N 0.000 description 2
- 201000009030 Carcinoma Diseases 0.000 description 1
- 229910020427 K2PtCl4 Inorganic materials 0.000 description 1
- HGINADPHJQTSKN-UHFFFAOYSA-N Monoethyl malonic acid Chemical group CCOC(=O)CC(O)=O HGINADPHJQTSKN-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- XZAHJRZBUWYCBM-UHFFFAOYSA-N [1-(aminomethyl)cyclohexyl]methanamine Chemical compound NCC1(CN)CCCCC1 XZAHJRZBUWYCBM-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000001627 detrimental effect Effects 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
- 235000019441 ethanol Nutrition 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 231100000086 high toxicity Toxicity 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003211 malignant effect Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 150000003891 oxalate salts Chemical group 0.000 description 1
- HRGDZIGMBDGFTC-UHFFFAOYSA-N platinum(2+) Chemical compound [Pt+2] HRGDZIGMBDGFTC-UHFFFAOYSA-N 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000012956 testing procedure Methods 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
- 231100000816 toxic dose Toxicity 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
Classifications
-
- 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
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/28—Compounds containing heavy metals
-
- 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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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
This invention relates to novel platinum compounds, a method for the preparation thereof, a pharmaceutical composition using the novel compounds and a method for the treatment of cancer using the pharmaceutical composition, wherein the platinum-(II)-diamine complexes are characterized by the formula <IMAGE> wherein R1 and R2 are both ethyl or together with the carbon atom, to which they are bonded, a cyclohexyl group, R3 and R4 are both a hydrogen atom and X is a malonate group, an ethylmalonate group, a hydroxymalonate group, a carboxyphthalate group, a bischloro acetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate group or an oxalate group or a sodium salt of these groups.
Description
SPECIFICATION
Platinum diamine complexes
The invention relates to novel platinum-diamine complexes, and to a pharmaceutical composition using such a platinum-diamine complex for the treatment of cancer, for example, malignant swellings and malignant tumors, as well as to a shaped composition obtained by using this process.
Such platinum-diamine complexes are known from the article by A. P. Zipp and S. G. Zipp, J.
Chem. Ed., 54 (12), (1977), page 739, which describes the application of cis-platinum diamine dichloride (PDD) for the treatment of cancer. It is mentioned that the platinum compounds have a broad spectrum of activity as antitumor agents, but also that they have serious drawbacks, in particular that they are toxic to the kidneys. As method for counteracting the kidney toxicity a cis-platinum diamine dichloride is often used in combination with another substance or administered with large quantities of liquid or other techniques are used to bring about an adequate flow-through of the kidneys. A number of other platinum amine complexes are known including compounds having the formula 2 of the formula sheet.
Wadley Medical Bulletin, Vol. 7, No. 1, pp. 114-1 34, discloses a large number of platinum diamine complexes, including cis-platinum diamine dichloride, for the treatment of cancer. Here, too, the kidney toxicity is stated as the most important drawback of these compounds.
Chem. and Eng. News, 6th June 1977, pp. 29-30, also describes cis-platinum diamine chloride and its application for the treatment of cancer. Kidney toxicity is also mentioned as the most important drawback of these compounds.
In an article in Cancer Chemotherapy Reports Part 1,viol. 59, No. 3, May/June 1975, pp. 629641 , the kidney toxicity of cis-platinum-ll-diamine dichloride is also reported. Because of the toxicity of
PDD to the kidney and its low therapeutic index, other platinum complexes for the treatment of cancer have been sought. For this purpose combinations of cis-platinum diamine-ll-dichloride with other chemotherapeutic agents were tested; novel platinum complexes were also tried, but they were found to be toxic. It was found, for instance, that although cis-dichloro-biscyclopentyl amine platinum (II) is only slightly toxic to the kidneys, it is toxic to the spleen. So-called "platinum blues", a mixture of different amounts of five or more inseparable components have also been disclosed for the treatment of cancer.
Dutch Patent Applications 73,04880; 73,04881; 73,04882 and 77,03752 disclose a large number of platinum diamine complexes, including the compound having formula 2 of the formula sheet. In all of these compounds with a nucleus, nitrogen atoms are linked directly to the nucleus. The compounds of the first three Dutch applications were compared with cis-platinum diamine dichloride and were found to have better effects. None of the patent applications states anything about kidney toxicity.
In Dutch Patent Application 79,04740 platinum diamine complexes are described, which are characterized by the formula 1 of the formula sheet, wherein R1 and R2 are independently of each other a hydrogen atom or a substituted or unsubstituted alkyl, cycloalkyl, aryl or aralkyl group, while R, and
R2 may be together a substituted or unsubstituted cycloalkyl group, R3 and R4 independently of each other are a hydrogen atom or a substituted or unsubstituted alkyl, aryl or aralkyl group, and X is an anionic group.
Now novel platinum diamine complexes have been found, which are characterized by the formula 1 of the formula sheet, wherein R1 and R2 are both an ethyl group or together with the carbon atom, to which they are bonded, a cyclohexyl group, R3 and R4 are both a hydrogen atom and X is a malonate group, an ethyl malonate group, a hydroxy malonate group, a carboxy phthalate group, a bis-chloro acetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate group or an oxalate group, or a sodium salt of one of these groups.
The invention further relates to a process for the preparation in a way known per se of these compounds, to a process for the preparation of a medical composition, wherein these compounds are used as active substance, as well as to the so-obtained shaped medical composition.
An extensive research program carried out by the National Cancer Institute, Bethesda, U.S.A., and the European Organization for Research on the Treatment of Cancer, Brussels, Belgium, has shown that the compounds according to this invention display a high therapeutic activity against cancer in contradiction to the platinum complexes known up to now and used in practice for the combat of cancer, like the cis-platinum diamine dichloride (PDD), therein it also appeared that the compounds according to the invention show little or none kidney toxicity.
As it appears from the therapeutical activity values, mentioned in table A, the novel compounds show an important anti-tumor activity against a large number of different types of tumors, such as
P388 lymphocytic leukemia (PS), L-1210 lymphoid leukemia (LE), ependymoblastoma and B 16 melanocarcinoma (Bl). The therapeutical activity of the relative novel compounds is higher than that of the cis-platinum diamine dichloride (PDD) which is used as experimental clinical chemotherapeuticum.
A very serious drawback of the PDD used in practice, as well of all other platinum-ll-complexes with anti-cancer activity and known up to now (with the exception of those, which are described in the
Dutch Patent Application 79,04740) is as already mentioned the high toxicity of these compounds, of which the kidney toxicity is the most dangerous and in fact limiting for the dose, which can be used in practice.
Surprisingly the compounds according to the invention do not show detrimental side effects on the kidneys. This was demonstrated by means of histological research of rats after treatment of toxic doses of the compounds described herein below, while in a similar research with PDD serious kidney damages were found.
The new complexes also have no prejudicial influence on the activity of the kidneys. A generally recognized, significant method for the determination of kidney toxicity relates to the evaluation of the percentage urea nitrogen in the blood (blood urea nitrogen, BUN), also indicated as non-protein nitrogen (non protein nitrogen, NPN).
It further appears that the compounds according to the invention have no single influence on the urea-nitrogen contents in the blood. As well for doses corresponding with the LD10 amount as with the LDso amount the urea-nitrogen contents in the blood are identical to the control values. The compound
PDD, on the contrary, gives at a LD,o dose after the indicated times already a four times increase of the urea-nitrogen contents, while this at a LD50 dose is increased with a factor of not less than 11.
Table A
Anti-cancerous activity in mice a dose/injection
Compound mouse codeb tumor mg/kg T/C {%) formula 4 06 LE 36,00 246
LE/cis-PDD 24,00 > 500 (3/6)
formula 5 BDFr LE 40,00 200 formula 6 BDF, LE 6,00 207
formula 7 BDF1 LE 128 229 (1/6)
LE/cis-PDD 64 144
formula 8 BDF, LE 24 214
LE/cis-PDD 18 144
formula 9 BDF1 LE 128 > 643 (4/6)
LE/cis-PDD 96 1 50
formula 10 BDF, LE 128 > 643 (3/6)
LE/cis-PDD 96 1 88 formula 11 BDF, LE 8 229
formula 12 BDF, LE 80 283
LE/cis-PDD 80 231
formula 13 BDF, LE 30 217
LE/cis-PDD 1 5 1 88 formula 14 BDF, LE 6 200
LE/cis-PDD 6 163
formula 15 BDF, LE/cis-PDD 16 230
a:More detailed information concerning the testing procedure and interpretation, vide Instruction 14,
Screening data summary interpretation and outline of current screen, Maryland, 20014, 1977.
b: 02=mouse code B6D2F, (BDF); 03=mouse code C 57 BL/6; 06=mouse code CD2F, (CDF,).
c: PS=P 388 lymphocytic leukemia; LE=L 1210 Lymphoid leukemia; EM=ependymoblastoma; B,=Bf6 melano-carcinoma.
d: Period of survival is the ratio of survival times of the treated mice (T) to untreated mice (C); the
therapeutic activity is significant at T/Cz125.
LE/cis-PDD means resistant to cis-PDD.
The preparation of the above mentioned compounds is illustrated in the following examples.
The compounds were prepared according to the method of S. C. Dhara: Indian J. Chem. 8,193 (1970).
Example I Cis-dichloro-1 1 -di(aminomethyl) cyclohexane platinum(ll) having the formula 3 of the formula sheet.
To a solution of 16 g K2PtCl4 in 160 ml of water a solution of 26.4 g Kl in 20 ml of water were added and the mixture was heated for 5 min. in a water bath.
Hereupon 6.4 g 1,1 -di(aminomethyl) cyclohexane were added and after the mixture had been stirred for 5 minutes, the precipitate was sucked and washed three times with hot water, twice with cold ethyl alcohol and twice with ether.
11.8 g of this formed diiodo derivative were added to a solution of 6.6 g AgNO3 in 48 ml water.
After the mixture had been stirred for 10 minutes at 95--1000C, the Agl was filtered off and washed with water. To the clear filtrate 3.28 g KCI were added and the mixture was stirred for 1 2 min.
at 95-1 000C. After the mixture had been cooled, the precipitate was sucked and washed with water.
Yield: 6.0 g.
Analysis (percentage by weight):
Calculated: C: 23.53; H: 4.45; N: 6.87; Pt: 47.80.
Found: 23.32; 4.46; 6.86; 47.63.
Example II
Preparation of cis-1 1 -di(aminomethyl)-cyclohexane hydroxymalonate platinum(ll) having the formula 4.
1.6 g of the dichloro derivative, prepared according to example I (formula 3) were added to a solution of 1.28 g AgNO3 in 25 ml of water.
After stirring the mixture during 1 hour at 400C the AgCI was filtered off and washed with water.
To the clear filtrate a solution of 0.456 g hydroxymalonic acid and 0.455 g KOH in 10 ml of water was added.
After stirring during 2 hours at room temperature the precipitate was filtered off and dried.
Yield: 77 weight %.
Analysis (weight %):
Calculated: C: 29.01; H: 4.43; N: 6.15; Pt: 42.84; 0: 17.58.
Found: 28.77; 4.38; 6.18; 42.96; 17.54.
Melting point=2480 C (decomposition).
Example Ill
Cis-4-carboxyphthalato-1 1 -di(aminomethyl)-cyclohexane-platinum(ll) having the formula 5.
1.2 g of the dichloro derivative prepared according to example I (formula 3), were added to a solution of 1 g AgNO3 in 25 ml of water.
After stirring the mixture during 1 hour at 400C the AgCI was filtered off and washed with water.
To the clear filtrate 0.63 g 1 ,2,4-tricarboxybenzene was added and the mixture was stirred during 2 hours at room temperature. The precipitate was sucked off and washed with water.
Yield: 0.8 g (45 weight %)
Analysis (weight %):
Calculated: C: 36.24; H: 4.29; N: 4.97;
Found: 36.42; 4.13; 4.77.
Example IV Cis-1 1 di(aminomethyI)cyclohexane-bis(chlornacetate)-platinum(ll) having the formula 6.
1.6 g of the dichloro derivative prepared according to example I (formula 3), were added to a solution of 1.28 g AgNO3 in 25 ml of water.
After stirring the mixture during 1 hour at 4O0C the AgCI was filtered off and washed with water.
To the clear filtrate a solution of 0.73 g monochloro acetic acid and 0.45 g KOH in 25 ml water was added and the mixture was stirred during 2 hours at room temperature. The precipitate was sucked off and washed with water.
Yield: 1.3 g (65 weight %).
Analysis (weight %):
Calculated: C: 27.49; H: 4.23; H: 5.34;
Found: 27.43; 4.21; 5.55.
Example V Cis-1 1 di(aminomethyl)-cyclohexane-malonate-platinum(ll) having the formula 1 5.
This compound has already been mentioned in the Dutch Patent Application 79,04740, but its preparation is important for the following examples.
1.6 g of the dichloro derivative prepared according to example I (formula 3) were added to a solution of 1.28 g AgNO3 in 25 ml water.
After stirring the mixture during 1 hour at 400C the AgCI was filtered off and washed with water.
To the clear filtrate a solution of 0.4 g malonic acid and 0.455 g KOH in 10 ml water was added.
After stirring during 2 hours at room temperature the precipitate was filtered off and dried.
Yield: 1.0 g (59 weight %).
Analysis (weight %):
Calculated: C: 30.07; H: 4.59; H: 6.38; Pt: 44.40; 0: 14.57;
Found: 29.98; 4.54; 6.32; 44.32; 14.57.
Example VI Cis-2,2-diethyl-1,3-diaminopropane-2-ethylmalonate-platinum(ll), having the formula 7, was prepared according to the method of example V.
Yield: 65 weight %.
Analysis (weight %):
Calculated+2 H2O: C: 29.33; H: 5.74; N: 5.70;
Found: 29.23; 5.64; 5.71.
Example VII Cis-2,2-diethyl-i ,3-diaminopropane-2-hydroxymalonate-platinum(ll), having the formula 8 was prepared according to the method of example V.
Yield: 87 weight %.
Analysis (weight %):
Calculated+1/2 H2O: C: 26.55; H: 4.68; N: 6.19;
Found: 26.67; 4.56; 6.23.
The sodium salt of this compound having the formula 13 was prepared according to example IX.
Example VIII Cis-l 1 -di(aminomethyl)cyclohexane-2-ethyl-malonate-platinum(Il) having the formula 10 was prepared according to the method of example V.
Yield: 64 weight %.
Analysis (weight /0): Calculated+1.5 H20: C: 31.57; H: 5.50; N: 5.67; 0: 17.79; Pt: 39.43;
Found: 31.36; 5.47; 5.69; 18.02; 39.58.
Example IX Cis-2,2-diethyl-1,3-diaminopropane-2-hydroxymalonate-platinum(ll)-sodium salt having the formula 13.
0.5 g of the hydroxymalonate derivative prepared according to example VII (formula 8) were suspended in 25 ml water.
1.105 ml 0.1 N NaOH were added and the mixtures was stirred during 30 min. at room temperature.
The clear solution was evaporated to dryness and the remaining solid was dried.
Yield: 0.4 g (72 weight %)
Analysis (weight %):
Calculated+2 H20: C: 23.91; H: 4.61; N: 5.58;
Found: 23.75; 4.44; 5.52.
Example X Cis-i 1 -di(aminomethyl)cyclohexane-l 1 -cyclobutanedicarboxylate-platinum(ll) having the formula 12.
2 g of the dichloro compound, prepared according to example I (formula 3) were added to a solution of 1.6 g AgNO3 in 25 ml water.
After stirring the mixture during 1 hour at 400C the AgCI was filtered off and washed with water.
To the clear filtrate a solution of 0.677 g 1.1-cyclobutane dicarboxylic acid and 0.547 g KOH in 10 ml water was added.
After 2 hours at room temperature and 1 hour at OOC the white precipitate was filtered off and dried.
Yield: 1.4 g (62 weight %).
Analysis (weight %):
Calculated+H2O: C: 33.80; H: 5.27; N: 5.63;
Found: 33.98; 5.02 5.77.
Example XI Cis-2,2-diethyl-i ,3-diaminopropane-l 1 -cyclobutane dicarboxylate platinum(ll), having the formula 9, was prepared according to the method of example X.
Yield: 64 weight %.
Analysis (weight %):
Calculated+2.5 H2O: C: 30.46; H: 5.70; N: 5.47; Pt: 38.07;
Found: 30.40; 5.44; 5.37; 38.16.
Example XII Cis-i 1 -bis(aminomethyl)cyclohexane platinum(ll)nitrate, having the formula 11.
4 g cis-dichloro-1 ,1-bis(aminomethyl)cyclohexane platinum(ll) (0.0097 mole) were suspended in 30 ml distilled water.
To this 3.1 g AgNO3 (0.0182 mole) were added and subsequently the mixture was heated during
1 hour at 400C while light was excluded.
The formed silverchloride was filtered off and washed with distilled water (10 ml).
The clear filtrate was evaporated under reduced pressure.
Weight solid substance: 4.1 7 g (93.5 weight %).
Melting point: explodes at about 2400 C; decomposes slowly at temperatures below 2400 C.
Analysis (weight %):
Calculated: C: 20.83; H: 3.93; N: 12.14;
Found: 20.9 ; 4.1 ; 11.9
'H-NMR-spectrum in DMSO-d6 (Varian T60) with respect to TMS:
CH2 (ring): 1.37 ppm
CH2 (NH2): 2.30 ppm
NH2: 5.67 ppm
satellites: 5.20 ppm
6.18 ppm J1ssPt 1H 58 Hz Example XIII Cis-i 1 -bis(aminomethyl)cyclohexane platinum(ll)oxalate having the formula 14.
4.1 g Cis-dichloro-l,l -bis(aminomethyl)cyclohexane platinum(ll) (0.01 mole) were suspended in 30 ml distilled water.
To this 3.2 g AgNO3 (0.019 mole) was added and subsequently the mixture was heated during 1 hour at 400C while light was excluded.
The formed silver chloride was filtered off and washed with distilled water (50 ml).
To the filtrate 2.02 g potassium oxalate (0.01 mole) were added, whereafter the mixture was stirred during 1 hour at room temperature.
Subsequently the formed solid was sucked off, washed with distilled water and dried.
Weight dry: 3.7 g (87 weight %)
Analysis (weight %):
Calculated+1.5 H2O: C: 26.55; H: 4.68; N: 6.19; Pt: 43.13; 0: 19.45;
Found: 26.6 ; 4.6 ; 6.2 ; 43.4 ; 19.2 H-NMR-spectrum in DMSO-d6 (Varian T60) with respect to TMS:
CH2 (ring): 1.32 ppm CH2(NH2): 2.17ppm NH2: 5.45 ppm
satellites: 4.83 ppm
6.08 ppm 19sPt-1H: 76 Hz
Claims (38)
1. Platinum-(ll)-diamine complexes, characterized by the formula 1 of the formula sheet, wherein
R1 and R2 are both ethyl or together with the carbon atom, to which they are bonded, a cyclohexyl
group,
R3 and R4 are both a hydrogen atom and
X is a malonate group, an ethylmalonate group, a hydroxymalonate group, a carboxyphthalate
group, a bischloro acetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate group or
an oxalate group or a sodium salt of these groups.
2. Platinum diamine complex according to claim 1, characterized by the formula 4 of the formula sheet.
3. Platinum diamine complex according to claim 1, characterized by the formula 5 of the formula sheet.
4. Platinum diamine complex according to claim 1, characterized by the formula 6 bf the formula sheet.
5. Platinum diamine complex according to claim 1, characterized by the formula 7 of the formula sheet.
6. Platinum diamine complex according to claim 1, characterized by the formula 8 of the formula sheet.
7. Platinum diamine complex according to claim 1, characterized by the formula 9 of the formula sheet.
8. Platinum diamine complex according to claim 1, characterized by the formula 10 of the formula sheet.
9. Platinum diamine complex according to claim 1, characterized by the formula 11 of the formula sheet.
10. Platinum diamine complex according to claim 1, characterized by the formula 12 of the formula sheet.
11. Platinum diamine complex according to claim 1, characterized by the formula 13 of the formula sheet.
1 2. Platinum diamine complex according to claim 1, characterized by the formula 14 of the formula sheet.
1 3. A process for the preparation of a medical composition for the treatment of cancer while
14. The process according to claim 13, characterized in that as platinum-(ll)-diamine complex the compound having the formula 4 is used.
1 5. The process according to claim 13, characterized in that as platinum-(ll)-diamine complex the compound having the formula 5 is used.
1 6. The process according to claim 13, characterized in that as platinum-(ll)-diamine complex the using a platinum-(ll)-diarnine complex, characterized in that as platinum-(ll)-diamine complex a compound having the formula 1, wherein R1, R2, R3, R4and X have the meaning mentioned in claim 1, is used.
compound having the formula 6 is used.
17. The process according to claim 13, characterized in that as platinum-(ll)-diamine complex the compound having the formula 7 is used.
1 8. The process according to claim 1 3, characterized in that as platinum-(ll)-diamine complex the compound having the formula 8 is used.
1 9. The process according to claim 13, characterized in that as platinum-(ll)-diamine complex the compound having the formula 9 is used.
20. The process according to claim 13, characterized in that as platinum-(ll)-diamine complex the compound having the formula 10 is used.
21. The process according to claim 13, characterized in that as platinum-(ll)-diamine complex the compound having the formula 11 is used.
22. The process according to claim 13, characterized in that as platinum-(ll)-diamine complex the compound having the formula 12 is used.
23. The process according to claim 13, characterized in that as platinum-(ll)-diamine complex the compound having the formula 13 is used.
24. The process according to claim 13, characterized in that as platinum-(ll!-diamine complex the compound having the formula 14 is used.
25. A process for the preparation of platinum-(ll)-diamine complexes to be used in the process according to claims 14-24, characterized in that a platinum-(ll)-diamine complex having the formula 1, wherein R,, R2, R3, R4 and X have the meaning mentioned in claim 1, is prepared in a way known per se.
26. The process according to claim 25, characterized in that a compound having the formula 4 of the formula sheet is prepared.
27. The process according to claim 25, characterized in that a compound having the formula 5 of the formula sheet is prepared.
28. The process according to claim 25, characterized in that a compound having the formula 6 of the formula sheet is prepared.
29. The process according to claim 25, characterized in that a compound having the formula 7 of the formula sheet is prepared.
30. The process according to claim 25, characterized in that a compound having the formula 8 of the formula sheet is prepared.
31. The process according to claim 25, characterized in that a compound having the formula 9 of the formula sheet is prepared.
32. The process according to claim 25, characterized in that a compound having the formula 10 of the formula sheet is prepared.
33. The process according to claim 25, characterized in that a compound having the formula 11 of the formula sheet is prepared.
34. The process according to claim 25, characterized in that a compound having the formula 12 of the formula sheet is prepared.
35. The process according to claim 25, characterized in that a compound having the formula 13 of the formula sheet is prepared.
36. The process according to claim 25, characterized in that a compound having the formula 14 of the formula sheet is prepared.
37. A pharmaceutical composition for the treatment of cancer which comprises a platinum (II) diamine complex as claimed in any one of Claims 1 to 13, together with a pharmaceutically acceptable diluent or carrier.
38. A process as claimed in Claim 25 substantially as hereinbefore described with reference to any one of the Examples.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8204067A NL8204067A (en) | 1982-10-21 | 1982-10-21 | PLATINUM DIAMINE COMPLEXES, METHOD FOR PREPARING THE SAME, METHOD FOR PREPARING A MEDICINAL PRODUCT USING SUCH PLATINADIAMINE COMPLEX FOR THE TREATMENT OF CANCER, PREVENTLY PREVENTED. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| GB8328084D0 GB8328084D0 (en) | 1983-11-23 |
| GB2128615A true GB2128615A (en) | 1984-05-02 |
| GB2128615B GB2128615B (en) | 1986-07-16 |
Family
ID=19840444
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| GB08328084A Expired GB2128615B (en) | 1982-10-21 | 1983-10-20 | Platinum 1,3-propane diamine complexes |
Country Status (28)
| Country | Link |
|---|---|
| JP (1) | JPS5993091A (en) |
| KR (1) | KR910002536B1 (en) |
| AT (1) | AT390610B (en) |
| AU (1) | AU562964B2 (en) |
| BE (1) | BE898058A (en) |
| CA (1) | CA1229618A (en) |
| CH (1) | CH658244A5 (en) |
| CS (1) | CS242888B2 (en) |
| DD (1) | DD217522A5 (en) |
| DE (1) | DE3337333A1 (en) |
| DK (2) | DK483083A (en) |
| ES (1) | ES526670A0 (en) |
| FI (1) | FI76351C (en) |
| FR (1) | FR2534907B1 (en) |
| GB (1) | GB2128615B (en) |
| GR (1) | GR79652B (en) |
| HU (1) | HU188035B (en) |
| IE (1) | IE56124B1 (en) |
| IT (1) | IT1169858B (en) |
| LU (1) | LU85054A1 (en) |
| NL (1) | NL8204067A (en) |
| NO (1) | NO171276C (en) |
| NZ (1) | NZ206018A (en) |
| PH (1) | PH24077A (en) |
| PT (1) | PT77542B (en) |
| SE (1) | SE8305783L (en) |
| YU (1) | YU43554B (en) |
| ZA (1) | ZA837857B (en) |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0176005A1 (en) * | 1984-09-12 | 1986-04-02 | Chugai Seiyaku Kabushiki Kaisha | Novel platinum complexes |
| US4661516A (en) * | 1983-06-20 | 1987-04-28 | Research Corporation | Diaminocyclohexane platinum complexes |
| EP0174542A3 (en) * | 1984-09-03 | 1987-05-06 | Behringwerke Aktiengesellschaft | Cis-platinum-complexes having a pentaerythritol derivative as ligand, process for their preparation and pharmaceutical agent containing these compounds |
| US4758588A (en) * | 1983-06-20 | 1988-07-19 | Research Corporation Technologies | Diaminocyclohexane platinum complexes |
| US4760157A (en) * | 1986-01-31 | 1988-07-26 | American Cyanamid Company | (2,2,-bis(aminomethyl)-1,3-propanediol-N,N')platinum complexes |
| US4786725A (en) * | 1982-06-28 | 1988-11-22 | Engelhard Corporation | Solubilized platinum (II) complexes |
| US4880790A (en) * | 1986-01-31 | 1989-11-14 | American Cyanamid Company | (Gem-heterocyclodimethanamine-N,N')platinum complexes |
| EP0357109A3 (en) * | 1988-08-31 | 1990-12-19 | Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno | Platinum-(ii)-diamine complex, method for the preparation of this compound, preparation with an anti-tumour action which contains this compound and also shaped preparations with an anti-tumour action |
| US4987246A (en) * | 1987-02-19 | 1991-01-22 | Nippon Kayaku Kabushiki Kaisha | Novel platinum complexes |
| US4992553A (en) * | 1986-10-03 | 1991-02-12 | Asta Pharma Aktiengesellschaft | Diamine-platinum (II) complex compounds |
| US5028727A (en) * | 1988-08-31 | 1991-07-02 | Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno | Platinum-(IV)-diamine complex |
| US5068376A (en) * | 1985-08-27 | 1991-11-26 | Nippon Kayaku Kabushiki Kaisha | Novel platinum complexes |
| US5091521A (en) * | 1986-09-08 | 1992-02-25 | Behringwerke Aktiengesellschaft | Cis-platinum complexes, a process for the preparation thereof, and pharmaceuticals containing these compounds |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0169645A1 (en) * | 1984-06-27 | 1986-01-29 | Johnson Matthey Public Limited Company | Platinum co-ordination compounds |
| AT390065B (en) * | 1987-10-08 | 1990-03-12 | Behringwerke Ag | cis-Platinum complexes, process for their preparation and pharmaceutical compositions containing these compounds |
| CN102924528B (en) * | 2012-10-29 | 2015-04-15 | 东南大学 | Anti-tumor bivalent platinum complex and preparation method for complex and ligand of complex |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4115418A (en) * | 1976-09-02 | 1978-09-19 | Government Of The United States Of America | 1,2-diaminocyclohexane platinum (ii) complexes having antineoplastic activity |
| GB2003468A (en) * | 1977-08-29 | 1979-03-14 | Us Commerce | 4-carboxyphthalato(1,2-diaminocyclohexane)platinum(ii)and alkali metal salts thereof and its use in alleviating murine leukemia |
| GB2024823A (en) * | 1978-07-06 | 1980-01-16 | Netherlands Centralorganisatio | Platinum-diamine complexes for use in the treatment of cancer |
| EP0041644A2 (en) * | 1980-05-27 | 1981-12-16 | Bristol-Myers Company | Salts of 2-hydroxymalonato diammine platinum (II) compounds, process for preparing said compounds and pharmaceutical compositions containing said compounds |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL189358C (en) * | 1978-07-06 | 1993-03-16 | Tno | PROCESS FOR PREPARING A MEDICINE FOR THE TREATMENT OF CANCER, AND AN PLATINUM-DIAMMINE COMPLEX DERIVED FROM A 1,3-ALKANE DIAMINE. |
| US4322362A (en) * | 1980-07-28 | 1982-03-30 | Bristol-Myers Company | Salts of 2-hydroxymalonate platinum complexes |
-
1982
- 1982-10-21 NL NL8204067A patent/NL8204067A/en not_active Application Discontinuation
-
1983
- 1983-10-13 DE DE19833337333 patent/DE3337333A1/en not_active Ceased
- 1983-10-18 AU AU20275/83A patent/AU562964B2/en not_active Ceased
- 1983-10-19 IT IT23359/83A patent/IT1169858B/en active
- 1983-10-19 CA CA000439308A patent/CA1229618A/en not_active Expired
- 1983-10-20 NO NO833825A patent/NO171276C/en unknown
- 1983-10-20 GR GR72754A patent/GR79652B/el unknown
- 1983-10-20 NZ NZ206018A patent/NZ206018A/en unknown
- 1983-10-20 SE SE8305783A patent/SE8305783L/en not_active Application Discontinuation
- 1983-10-20 CH CH5718/83A patent/CH658244A5/en not_active IP Right Cessation
- 1983-10-20 GB GB08328084A patent/GB2128615B/en not_active Expired
- 1983-10-20 AT AT0373083A patent/AT390610B/en not_active IP Right Cessation
- 1983-10-20 DD DD83255826A patent/DD217522A5/en not_active IP Right Cessation
- 1983-10-20 DK DK483083A patent/DK483083A/en not_active Application Discontinuation
- 1983-10-20 IE IE2459/83A patent/IE56124B1/en not_active IP Right Cessation
- 1983-10-20 YU YU2107/83A patent/YU43554B/en unknown
- 1983-10-20 FI FI833842A patent/FI76351C/en not_active IP Right Cessation
- 1983-10-20 LU LU85054A patent/LU85054A1/xx unknown
- 1983-10-20 HU HU833623A patent/HU188035B/en not_active IP Right Cessation
- 1983-10-20 PT PT77542A patent/PT77542B/en unknown
- 1983-10-20 FR FR8316715A patent/FR2534907B1/en not_active Expired
- 1983-10-21 BE BE0/211755A patent/BE898058A/en not_active IP Right Cessation
- 1983-10-21 PH PH29726A patent/PH24077A/en unknown
- 1983-10-21 ES ES526670A patent/ES526670A0/en active Granted
- 1983-10-21 KR KR1019830004987A patent/KR910002536B1/en not_active Expired
- 1983-10-21 JP JP58196286A patent/JPS5993091A/en active Granted
- 1983-10-21 CS CS837752A patent/CS242888B2/en unknown
- 1983-10-21 ZA ZA837857A patent/ZA837857B/en unknown
-
1992
- 1992-06-09 DK DK92755A patent/DK75592D0/en not_active Application Discontinuation
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|---|---|---|---|---|
| US4115418A (en) * | 1976-09-02 | 1978-09-19 | Government Of The United States Of America | 1,2-diaminocyclohexane platinum (ii) complexes having antineoplastic activity |
| GB2003468A (en) * | 1977-08-29 | 1979-03-14 | Us Commerce | 4-carboxyphthalato(1,2-diaminocyclohexane)platinum(ii)and alkali metal salts thereof and its use in alleviating murine leukemia |
| GB2024823A (en) * | 1978-07-06 | 1980-01-16 | Netherlands Centralorganisatio | Platinum-diamine complexes for use in the treatment of cancer |
| EP0041644A2 (en) * | 1980-05-27 | 1981-12-16 | Bristol-Myers Company | Salts of 2-hydroxymalonato diammine platinum (II) compounds, process for preparing said compounds and pharmaceutical compositions containing said compounds |
Cited By (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4786725A (en) * | 1982-06-28 | 1988-11-22 | Engelhard Corporation | Solubilized platinum (II) complexes |
| US4661516A (en) * | 1983-06-20 | 1987-04-28 | Research Corporation | Diaminocyclohexane platinum complexes |
| US4758588A (en) * | 1983-06-20 | 1988-07-19 | Research Corporation Technologies | Diaminocyclohexane platinum complexes |
| EP0174542A3 (en) * | 1984-09-03 | 1987-05-06 | Behringwerke Aktiengesellschaft | Cis-platinum-complexes having a pentaerythritol derivative as ligand, process for their preparation and pharmaceutical agent containing these compounds |
| US4730069A (en) * | 1984-09-03 | 1988-03-08 | Behringwerke Aktiengesellschaft | Cis-platinum complexes with a pentaerythritol derivative as the ligand, a process for their preparation and a pharmaceutical agent containing these compounds |
| EP0176005A1 (en) * | 1984-09-12 | 1986-04-02 | Chugai Seiyaku Kabushiki Kaisha | Novel platinum complexes |
| US4822892A (en) * | 1984-09-12 | 1989-04-18 | Chugai Seiyaku Kabushiki Kaisha | N-heterocyclic platinum complexes |
| US5068376A (en) * | 1985-08-27 | 1991-11-26 | Nippon Kayaku Kabushiki Kaisha | Novel platinum complexes |
| US4880790A (en) * | 1986-01-31 | 1989-11-14 | American Cyanamid Company | (Gem-heterocyclodimethanamine-N,N')platinum complexes |
| US4900756A (en) * | 1986-01-31 | 1990-02-13 | American Cyanamid Company | (2,2-bis(aminomethyl)-1,3-propranediol-N,N')platinum complexes |
| US4760157A (en) * | 1986-01-31 | 1988-07-26 | American Cyanamid Company | (2,2,-bis(aminomethyl)-1,3-propanediol-N,N')platinum complexes |
| US5091521A (en) * | 1986-09-08 | 1992-02-25 | Behringwerke Aktiengesellschaft | Cis-platinum complexes, a process for the preparation thereof, and pharmaceuticals containing these compounds |
| US4992553A (en) * | 1986-10-03 | 1991-02-12 | Asta Pharma Aktiengesellschaft | Diamine-platinum (II) complex compounds |
| US5130308A (en) * | 1986-10-03 | 1992-07-14 | Asta Pharma | Method of treating hormone dependent tumors with diamine-platinum (ii) complex compounds |
| US4987246A (en) * | 1987-02-19 | 1991-01-22 | Nippon Kayaku Kabushiki Kaisha | Novel platinum complexes |
| US5128493A (en) * | 1987-02-19 | 1992-07-07 | Nippon Kayaku Kabushiki Kaisha | Platinum complexes |
| EP0357109A3 (en) * | 1988-08-31 | 1990-12-19 | Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno | Platinum-(ii)-diamine complex, method for the preparation of this compound, preparation with an anti-tumour action which contains this compound and also shaped preparations with an anti-tumour action |
| US5028727A (en) * | 1988-08-31 | 1991-07-02 | Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek Tno | Platinum-(IV)-diamine complex |
| US5034553A (en) * | 1988-08-31 | 1991-07-23 | Nederlandse Organisatie Voor Toegepast-Natuurwetenschappelijk Onderzoek | Platinum-(II)-diamine complex, method for the preparation of this compound, preparation with an anti-tumour action which contains this compound and also shaped preparations with an anti-tumour action |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PCNP | Patent ceased through non-payment of renewal fee |
Effective date: 19931020 |