CA1229618A - Platinum-diamine complexes, a process for the preparation thereof, a process for the preparation of medical composition using a such platinum-diamine complex for the treatment of cancer, as well as the thus shaped composition - Google Patents
Platinum-diamine complexes, a process for the preparation thereof, a process for the preparation of medical composition using a such platinum-diamine complex for the treatment of cancer, as well as the thus shaped compositionInfo
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- CA1229618A CA1229618A CA000439308A CA439308A CA1229618A CA 1229618 A CA1229618 A CA 1229618A CA 000439308 A CA000439308 A CA 000439308A CA 439308 A CA439308 A CA 439308A CA 1229618 A CA1229618 A CA 1229618A
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- 238000000034 method Methods 0.000 title claims abstract description 41
- 206010028980 Neoplasm Diseases 0.000 title abstract description 14
- 201000011510 cancer Diseases 0.000 title abstract description 14
- 238000002360 preparation method Methods 0.000 title abstract description 9
- 239000000203 mixture Substances 0.000 title description 23
- 150000001875 compounds Chemical class 0.000 claims abstract description 38
- 229910052799 carbon Inorganic materials 0.000 claims abstract description 11
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 11
- 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 11
- ROBFUDYVXSDBQM-UHFFFAOYSA-N hydroxymalonic acid Chemical group OC(=O)C(O)C(O)=O ROBFUDYVXSDBQM-UHFFFAOYSA-N 0.000 claims abstract description 9
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical group OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 7
- 159000000000 sodium salts Chemical class 0.000 claims abstract description 6
- CCQPAEQGAVNNIA-UHFFFAOYSA-N cyclobutane-1,1-dicarboxylic acid Chemical group OC(=O)C1(C(O)=O)CCC1 CCQPAEQGAVNNIA-UHFFFAOYSA-N 0.000 claims abstract 5
- UKFXDFUAPNAMPJ-UHFFFAOYSA-N ethylmalonic acid Chemical group CCC(C(O)=O)C(O)=O UKFXDFUAPNAMPJ-UHFFFAOYSA-N 0.000 claims abstract 5
- 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 3
- 239000000126 substance Substances 0.000 claims description 15
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 claims description 2
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims 3
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 claims 3
- 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 claims 2
- 229910002651 NO3 Inorganic materials 0.000 claims 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 claims 1
- 150000007942 carboxylates Chemical class 0.000 claims 1
- 229940106681 chloroacetic acid Drugs 0.000 claims 1
- 235000006408 oxalic acid Nutrition 0.000 claims 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 abstract description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical group CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 abstract description 2
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical group OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 abstract description 2
- 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 29
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Substances [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 23
- 208000028018 Lymphocytic leukaemia Diseases 0.000 description 17
- 208000003747 lymphoid leukemia Diseases 0.000 description 17
- 229910052697 platinum Inorganic materials 0.000 description 16
- 239000000243 solution Substances 0.000 description 13
- 241001315286 Damon Species 0.000 description 10
- 239000000706 filtrate Substances 0.000 description 8
- 231100000417 nephrotoxicity Toxicity 0.000 description 8
- 229910052778 Plutonium Inorganic materials 0.000 description 7
- 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
- 235000018936 Vitellaria paradoxa Nutrition 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
- -1 platinum amine Chemical class 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
- 241000699666 Mus <mouse, genus> Species 0.000 description 3
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 3
- 150000001412 amines Chemical class 0.000 description 3
- 125000004202 aminomethyl group Chemical group [H]N([H])C([H])([H])* 0.000 description 3
- 150000003057 platinum Chemical class 0.000 description 3
- OYEHPCDNVJXUIW-UHFFFAOYSA-N plutonium atom Chemical compound [Pu] OYEHPCDNVJXUIW-UHFFFAOYSA-N 0.000 description 3
- 238000011160 research Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 201000009030 Carcinoma Diseases 0.000 description 2
- 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
- 241000699670 Mus sp. Species 0.000 description 2
- 229910021607 Silver chloride Inorganic materials 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 229920000180 alkyd Polymers 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
- 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
- 230000002611 ovarian Effects 0.000 description 2
- 208000029340 primitive neuroectodermal tumor Diseases 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- HKZLPVFGJNLROG-UHFFFAOYSA-M silver monochloride Chemical compound [Cl-].[Ag+] HKZLPVFGJNLROG-UHFFFAOYSA-M 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- AYTGUZPQPXGYFS-UHFFFAOYSA-N urea nitrate Chemical compound NC(N)=O.O[N+]([O-])=O AYTGUZPQPXGYFS-UHFFFAOYSA-N 0.000 description 2
- 101100084595 Caenorhabditis elegans pam-1 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- PMPVIKIVABFJJI-UHFFFAOYSA-N Cyclobutane Chemical compound C1CCC1 PMPVIKIVABFJJI-UHFFFAOYSA-N 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- 101100186820 Drosophila melanogaster sicily gene Proteins 0.000 description 1
- HGINADPHJQTSKN-UHFFFAOYSA-N Monoethyl malonic acid Chemical group CCOC(=O)CC(O)=O HGINADPHJQTSKN-UHFFFAOYSA-N 0.000 description 1
- 241000282320 Panthera leo Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010042674 Swelling Diseases 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-M chloroacetate Chemical compound [O-]C(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-M 0.000 description 1
- 229940089960 chloroacetate Drugs 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
- 150000003891 oxalate salts Chemical group 0.000 description 1
- LCCNCVORNKJIRZ-UHFFFAOYSA-N parathion Chemical compound CCOP(=S)(OCC)OC1=CC=C([N+]([O-])=O)C=C1 LCCNCVORNKJIRZ-UHFFFAOYSA-N 0.000 description 1
- 125000005498 phthalate group 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
Landscapes
- 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
A B S T R A C T
===============
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 charac-terized by the formula
===============
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 charac-terized by the formula
Description
~7~2~
Platinum-diamine complexes, a process for the preparation thereof, a process for the preparation of a medical compost-lion using such a platinum-diamine complex for the treatment of cancer, as well as the thus shaped composition.
The invention relates to novel platinum-diamine come plexus, 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.
Brief Description of the Drawings Figures 1-15 show chemical formulas of various compounds relating to the invention and this art.
Such platinum-diamine complexes are known from the article by ASP. Zip and SAG. Zippy Schemed 54 (12), (1977), page 739, which describes the application of is-platinum Damon dichlorides (POD) for the treatment of cancer.
It is mentioned that the platinum compounds have a broad spectrum of activity as anti tumor 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 Damon dichlorides 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.
Widely Medical bulletin, Vol. 7, No. 1, pp. 114-134, discloses a large number of platinum Damon complexes, including cis-platinum Damon dichlorides for the treatment of cancer. Here, too, the kidney toxicity is stated as the most important drawback of these compounds.
Chum. and Erg. News, Thea June 1977, pp. 29-30, also describes cis-platinum Damon chloride and its application for the treatment of cancer. Kidney toxicity is also I
mentioned as the most important drawback of these compounds.
In an article in Cancer Chemotherapy Reports Part 1, Vol. 59, No. 3, May/June 1975, pp. 629-641, the kidney toxicity of cis-platinum~ Damon dichlorides is also reported.
Because of the toxicity of POD 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-II-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 plutonium) 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.
In United States Patents No. 3,892,790, 3,904,663, and 4,119,653 and in French Patent No. 2,182,943, there are disclosed a large number of platinum Damon 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 two US. patents and the French patent were compared with cis-platinum Damon dichlorides and were found to have better effects. None of the above patents states anything about kidney toxicity.
Platinum Damon complexes have been described which are characterized by the formula 1 of the formula sheet, wherein Al and R2 are independently of each other a hydrogen atom or a substituted or unsubstituted alkyd, cycloalkyl, aureole or aralkyl group, while Al 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 alkyd, aureole or aralkyl group, and X is an anionic group.
Now novel platinum Damon complexes have been found, I
which are characterized by the formula 1 of the formula sheet, wherein Al 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 car boxy phthalate group, a bachelor acetate group, a cyclobutane~ 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 pro-parathion in a way known per so 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 Organize-lion for Research on the Treatment of Cancer, Brussels, Belgium, has shown that the compounds according to this invention disk play a high therapeutic activity against cancer in contradict lion to the platinum complexes known up to now and used iII
practice for the combat of cancer, like the cis-platinum dip amine dichlorides (POD), 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 (PUS), L-1210 lymphoid leukemia (LYE), ependymoblastoma and B16 Delano-carcinoma (By). The therapeutical activity of the relative novel compounds is higher than that of the cis-platinum dip amine dichlorides (POD) which is used as experimental clinical chemotherapeuticum.
A very serious drawback of the POD used in practice, 71 l as well of all other platinum-II-complexes with anti-cancer activity and known up to now (with the exception of those referred to above which were previously described) 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 POD 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, NUN).
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 LDlo amount as with the LD50 amount the urea-nitrogen contents in the blood are identical to the control values. The compound POD, on the contrary, gives at a LDlo 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.
Jo I
- Table A
Anti-cancerous activity in micra -Compendiums codebtumorC dose/injection T/C
mg/kg I) .
formula 406 LYE 36,00 246 LE/cis-PDD 24,00 500 (3/6) formula 5BDFl LYE 4û,00 200 formula 6BDFl LYE -6,00 207 formula 7BDFl LYE 128 229 (1/6) LE/cis-PDD 64 144 formula 8BDFl LYE 24 214 LE-cis-PDD 18 144 formula gBDFl LYE 128 643 (4/6) LE/cis-PDD 96 150 formula 10 BDFl LYE 128 >643 (3/6) LE/cis-PDD 96 188 formula 11 BDFl LYE R 229 formula 12 BDFl LYE 80 283 LE/cis-FDD 80 231 formula 13 BDFl LYE 30 217 LE/cis-PDD 15 188 formula 14 BDFl LYE 6 200 LE/cis-PDD 6 163 formula 15 BDFl LE/cis-PDD 16 230 a: More detailed information concerning the testing procedure and interpretation, vise Instruction 14, Screening data summary interpretation and outline of current screen, Maryland, 20014, 1977.
b: 02 = mouse code B6D2Fl (BDFl); 03 = mouse code C 57 BLUE;
06 = mouse code CD2Fl (CDFl).
c: PUS = P 388 lymphocytic leukemia; LYE = L 1210 Lymphoid leukemia;
EM - ependymoblastoma; By = B16 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/C 125.
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 SAC. Doria: Indian J.Chem. 8, 193 (1970).
Example I
Cis-dichloro-l l-di(aminometh 1) cyclohexane plutonium) Y _ -I having the formula 3 of the Formula sheet.
To a solution of 16 9 K2PtC14 in 16n ml of water a solution of 26.4 9 KIT in 20 ml of water were added and the mixture was heated for 5 min. in a water bath.
Hereupon 6.4 9 l,l-di(aminomethyl) cyclohexane were added and after the mixture had been stirred for 5 minutes, -I the precipitate was sucked and washed three times with hot water, twice with cold ethyl alcohol and twice with ether.
11.8 9 of this formed Dodd derivative were added to a solution of 6.6 9 Agony in 48 ml water.
After the mixture had been stirred for 10 minutes at 95-100C, the Ago was filtered off and washed with water.
To the clear filtrate 3.28 9 Clue were added and the mixture was stirred for 12 min. at 95-100C. After the mixture had been cooled, the precipitate was sucked and washed with water.
Yield: 6.0 9.
Analysis (percentage by weight):
Calculated: C: 23.53; H: 4.45; N: 6.87; PUT: 47.80 Found: 23.32; 4.46; 6.86; 47.63.
Example II
Preparation of cis-l,l-di(aminomethyl)-cyclohexane hydroxy-malonate plutonium) having the formula 4.
3û 1.6 9 of the dichloro derivative, prepared according to example I (formula 3) were added to a solution of 1.28 9 Agony in 25 ml of water.
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate a solution of 0.456 9 hydroxy-Masonic acid and 0.455 9 KOCH 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 JO.
Analysis (weight 0):
Calculated: C: 29.01; H: 4.43; N: 6.15; Pi: 42.84; 0: 17.58 Found: 2~.77; 4.3B; 6.18; 42.96; 17.54.
Melting point = 248C (decomposition).
Example III
~Cis-4-carboxvphthalato-1,1-di(aminomethyl)-cycloheexane-plutonium) having the formula 5.
1.2 9 of the dichloro derivative prepared according to example I (formula 3), were added to a solution of 1 9 Agony in 25 ml of water.
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate 0.63 9 1,2,4-tricarboxyben~ene 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 9 (45 weight JO) Analysis (weight 0):
Calculated: C: 36.24; H: 4.29; N: 4.97;
Found: 36.42; 4.13; 4.77.
Example It z5 Cis-l,l-di(aminomethyl)-cyclohexane-bis(chloro acetate?-plutonium), 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 9 Agony in 25 ml of water.
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate a solution of 0.73 g monochloro acetic acid and 0,45 9 KOCH in 25 ml water was added and the mixture was stirred during 2 hours at room temperature.
US The precipitate was sucked off and washed with water Yield 1.3 9 (65 weight JO).
Analysis (weight I):
~2;2~
Calculated: t: 27.49; H: 4.23; H: 5.34;
Found: 27.43; 4.21; 5.55.
Example V
Cis-l,l-di(aminomethyl)-cyclohexane-malonate-platiinum(II) having the formula 15.
This compound has already been mentioned in the Dutch Patent Application 79,04740, but its preparation is important for the following examples.
1.6 9 of the dichloro derivative prepared according to example I (formula 3) were added to a solution of 1.28 9 Agony in 25 ml water.
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate a solution of 0.4 9 Masonic acid and 0.455 9 KOCH in 10 ml water was added.
After stirring during 2 hours at room temperature the precipitate was filtered off and dried.
Yield: 1.0 9 (59 weight JO).
Analysis (weight 0):
Calculated: C: 30.07; H: 4.59; H: 6.38; Pi: 44.40; 0: 14.57;
Found: 29.98; 4.54; 6.32; 44.32; 14.57.
Example VI
Cis-2t?-diethyl-1,3-diaminopropane-2-eth~lmalonatee-platinum (II), having the formula 7, was prepared according to the z5 method of example V.
Yield: 65 weight JO.
Analysis (weight I):
Calculated + 2 H20: C: 29.33; H: 5.74; N: 5.70;
Found: 29.23; 5.64; 5.71.
Example VII
Cis-2,2-diethyl-1,3-diaminopropane-2-hydroxymalonaate-plutonium), having the formula 8 was prepared according to the method of example V.
Yield: 87 weight JO.
Analysis (weight 0):
Calculated 1/2 H20: 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
Sicily l-di(aminomethyl)cyclohexane-2-ethyl-malonate-plutonium) having the formula 10 was prepared according to the method of example V.
Yield: 64 weight JO.
Analysis (weight 0):
Cafe. + 1.5 H20: C:31.57; H:5.5n; 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-diethvl-1,3-diaminopropane-2-hvdroxymalonaate-platinum(II)-sodium salt having the formula 13.
- 0.5 9 of the hydroxymalonate derivative prepared accord ding to example VII (formula 8) were suspended in 25 ml water.
1.105 ml 0.1 N Noah were added and the mixture was stirred during 30 min. at room temperature.
The clear solution was evaporated to dryness and the remaining solid was dried.
Yield: 0.4 9 (72 weight OWE) Analysis (weight 0):
Calculated + 2 H20: C:23.91; H: 4,61; N: 5.5~;
Found: 23.75; 4.44; 5.52.
Example X
Cis-l~l-di(aminomethyl)cyclohexane-l~l-cyclobutaneedicarb late-platinum(II ? having the formula 12.
Platinum-diamine complexes, a process for the preparation thereof, a process for the preparation of a medical compost-lion using such a platinum-diamine complex for the treatment of cancer, as well as the thus shaped composition.
The invention relates to novel platinum-diamine come plexus, 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.
Brief Description of the Drawings Figures 1-15 show chemical formulas of various compounds relating to the invention and this art.
Such platinum-diamine complexes are known from the article by ASP. Zip and SAG. Zippy Schemed 54 (12), (1977), page 739, which describes the application of is-platinum Damon dichlorides (POD) for the treatment of cancer.
It is mentioned that the platinum compounds have a broad spectrum of activity as anti tumor 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 Damon dichlorides 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.
Widely Medical bulletin, Vol. 7, No. 1, pp. 114-134, discloses a large number of platinum Damon complexes, including cis-platinum Damon dichlorides for the treatment of cancer. Here, too, the kidney toxicity is stated as the most important drawback of these compounds.
Chum. and Erg. News, Thea June 1977, pp. 29-30, also describes cis-platinum Damon chloride and its application for the treatment of cancer. Kidney toxicity is also I
mentioned as the most important drawback of these compounds.
In an article in Cancer Chemotherapy Reports Part 1, Vol. 59, No. 3, May/June 1975, pp. 629-641, the kidney toxicity of cis-platinum~ Damon dichlorides is also reported.
Because of the toxicity of POD 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-II-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 plutonium) 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.
In United States Patents No. 3,892,790, 3,904,663, and 4,119,653 and in French Patent No. 2,182,943, there are disclosed a large number of platinum Damon 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 two US. patents and the French patent were compared with cis-platinum Damon dichlorides and were found to have better effects. None of the above patents states anything about kidney toxicity.
Platinum Damon complexes have been described which are characterized by the formula 1 of the formula sheet, wherein Al and R2 are independently of each other a hydrogen atom or a substituted or unsubstituted alkyd, cycloalkyl, aureole or aralkyl group, while Al 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 alkyd, aureole or aralkyl group, and X is an anionic group.
Now novel platinum Damon complexes have been found, I
which are characterized by the formula 1 of the formula sheet, wherein Al 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 car boxy phthalate group, a bachelor acetate group, a cyclobutane~ 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 pro-parathion in a way known per so 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 Organize-lion for Research on the Treatment of Cancer, Brussels, Belgium, has shown that the compounds according to this invention disk play a high therapeutic activity against cancer in contradict lion to the platinum complexes known up to now and used iII
practice for the combat of cancer, like the cis-platinum dip amine dichlorides (POD), 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 (PUS), L-1210 lymphoid leukemia (LYE), ependymoblastoma and B16 Delano-carcinoma (By). The therapeutical activity of the relative novel compounds is higher than that of the cis-platinum dip amine dichlorides (POD) which is used as experimental clinical chemotherapeuticum.
A very serious drawback of the POD used in practice, 71 l as well of all other platinum-II-complexes with anti-cancer activity and known up to now (with the exception of those referred to above which were previously described) 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 POD 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, NUN).
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 LDlo amount as with the LD50 amount the urea-nitrogen contents in the blood are identical to the control values. The compound POD, on the contrary, gives at a LDlo 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.
Jo I
- Table A
Anti-cancerous activity in micra -Compendiums codebtumorC dose/injection T/C
mg/kg I) .
formula 406 LYE 36,00 246 LE/cis-PDD 24,00 500 (3/6) formula 5BDFl LYE 4û,00 200 formula 6BDFl LYE -6,00 207 formula 7BDFl LYE 128 229 (1/6) LE/cis-PDD 64 144 formula 8BDFl LYE 24 214 LE-cis-PDD 18 144 formula gBDFl LYE 128 643 (4/6) LE/cis-PDD 96 150 formula 10 BDFl LYE 128 >643 (3/6) LE/cis-PDD 96 188 formula 11 BDFl LYE R 229 formula 12 BDFl LYE 80 283 LE/cis-FDD 80 231 formula 13 BDFl LYE 30 217 LE/cis-PDD 15 188 formula 14 BDFl LYE 6 200 LE/cis-PDD 6 163 formula 15 BDFl LE/cis-PDD 16 230 a: More detailed information concerning the testing procedure and interpretation, vise Instruction 14, Screening data summary interpretation and outline of current screen, Maryland, 20014, 1977.
b: 02 = mouse code B6D2Fl (BDFl); 03 = mouse code C 57 BLUE;
06 = mouse code CD2Fl (CDFl).
c: PUS = P 388 lymphocytic leukemia; LYE = L 1210 Lymphoid leukemia;
EM - ependymoblastoma; By = B16 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/C 125.
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 SAC. Doria: Indian J.Chem. 8, 193 (1970).
Example I
Cis-dichloro-l l-di(aminometh 1) cyclohexane plutonium) Y _ -I having the formula 3 of the Formula sheet.
To a solution of 16 9 K2PtC14 in 16n ml of water a solution of 26.4 9 KIT in 20 ml of water were added and the mixture was heated for 5 min. in a water bath.
Hereupon 6.4 9 l,l-di(aminomethyl) cyclohexane were added and after the mixture had been stirred for 5 minutes, -I the precipitate was sucked and washed three times with hot water, twice with cold ethyl alcohol and twice with ether.
11.8 9 of this formed Dodd derivative were added to a solution of 6.6 9 Agony in 48 ml water.
After the mixture had been stirred for 10 minutes at 95-100C, the Ago was filtered off and washed with water.
To the clear filtrate 3.28 9 Clue were added and the mixture was stirred for 12 min. at 95-100C. After the mixture had been cooled, the precipitate was sucked and washed with water.
Yield: 6.0 9.
Analysis (percentage by weight):
Calculated: C: 23.53; H: 4.45; N: 6.87; PUT: 47.80 Found: 23.32; 4.46; 6.86; 47.63.
Example II
Preparation of cis-l,l-di(aminomethyl)-cyclohexane hydroxy-malonate plutonium) having the formula 4.
3û 1.6 9 of the dichloro derivative, prepared according to example I (formula 3) were added to a solution of 1.28 9 Agony in 25 ml of water.
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate a solution of 0.456 9 hydroxy-Masonic acid and 0.455 9 KOCH 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 JO.
Analysis (weight 0):
Calculated: C: 29.01; H: 4.43; N: 6.15; Pi: 42.84; 0: 17.58 Found: 2~.77; 4.3B; 6.18; 42.96; 17.54.
Melting point = 248C (decomposition).
Example III
~Cis-4-carboxvphthalato-1,1-di(aminomethyl)-cycloheexane-plutonium) having the formula 5.
1.2 9 of the dichloro derivative prepared according to example I (formula 3), were added to a solution of 1 9 Agony in 25 ml of water.
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate 0.63 9 1,2,4-tricarboxyben~ene 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 9 (45 weight JO) Analysis (weight 0):
Calculated: C: 36.24; H: 4.29; N: 4.97;
Found: 36.42; 4.13; 4.77.
Example It z5 Cis-l,l-di(aminomethyl)-cyclohexane-bis(chloro acetate?-plutonium), 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 9 Agony in 25 ml of water.
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate a solution of 0.73 g monochloro acetic acid and 0,45 9 KOCH in 25 ml water was added and the mixture was stirred during 2 hours at room temperature.
US The precipitate was sucked off and washed with water Yield 1.3 9 (65 weight JO).
Analysis (weight I):
~2;2~
Calculated: t: 27.49; H: 4.23; H: 5.34;
Found: 27.43; 4.21; 5.55.
Example V
Cis-l,l-di(aminomethyl)-cyclohexane-malonate-platiinum(II) having the formula 15.
This compound has already been mentioned in the Dutch Patent Application 79,04740, but its preparation is important for the following examples.
1.6 9 of the dichloro derivative prepared according to example I (formula 3) were added to a solution of 1.28 9 Agony in 25 ml water.
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate a solution of 0.4 9 Masonic acid and 0.455 9 KOCH in 10 ml water was added.
After stirring during 2 hours at room temperature the precipitate was filtered off and dried.
Yield: 1.0 9 (59 weight JO).
Analysis (weight 0):
Calculated: C: 30.07; H: 4.59; H: 6.38; Pi: 44.40; 0: 14.57;
Found: 29.98; 4.54; 6.32; 44.32; 14.57.
Example VI
Cis-2t?-diethyl-1,3-diaminopropane-2-eth~lmalonatee-platinum (II), having the formula 7, was prepared according to the z5 method of example V.
Yield: 65 weight JO.
Analysis (weight I):
Calculated + 2 H20: C: 29.33; H: 5.74; N: 5.70;
Found: 29.23; 5.64; 5.71.
Example VII
Cis-2,2-diethyl-1,3-diaminopropane-2-hydroxymalonaate-plutonium), having the formula 8 was prepared according to the method of example V.
Yield: 87 weight JO.
Analysis (weight 0):
Calculated 1/2 H20: 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
Sicily l-di(aminomethyl)cyclohexane-2-ethyl-malonate-plutonium) having the formula 10 was prepared according to the method of example V.
Yield: 64 weight JO.
Analysis (weight 0):
Cafe. + 1.5 H20: C:31.57; H:5.5n; 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-diethvl-1,3-diaminopropane-2-hvdroxymalonaate-platinum(II)-sodium salt having the formula 13.
- 0.5 9 of the hydroxymalonate derivative prepared accord ding to example VII (formula 8) were suspended in 25 ml water.
1.105 ml 0.1 N Noah were added and the mixture was stirred during 30 min. at room temperature.
The clear solution was evaporated to dryness and the remaining solid was dried.
Yield: 0.4 9 (72 weight OWE) Analysis (weight 0):
Calculated + 2 H20: C:23.91; H: 4,61; N: 5.5~;
Found: 23.75; 4.44; 5.52.
Example X
Cis-l~l-di(aminomethyl)cyclohexane-l~l-cyclobutaneedicarb late-platinum(II ? having the formula 12.
2 9 of the dichloro compound, prepared according to example I (formula 3) were added to a solution of 1.6 9 Agony in 25 ml water.
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate a solution of 0.677 9 l.l-cyclo-butane dicarboxylic acid and 0.547 9 KOCH in 10 ml water was added.
After 2 hours at room temperature and 1 hour at 0C the white precipitate was Filtered off and dried.
- .3L2296~13 Yield: 1.4 9 (62 weight JO).
Analysis (weight 0):
Calculated + H20: C: 33.80; H: 5.27; N: 5.63;
Found: 33.98; 5.02 5.77.
Exam e XI
Cis-2,2-diethyl-1,3-diaminopropane-1,1-cyclobutanee dicarbo-zealot plutonium), having the formula 9, was prepared according to the method of example X.
Yield: 64 weight Do.
Analysis (weight 0):
Calculated + 2.5 H20: C: 30.46; H: 5.70; N: 5.47; Pi: 38.07;
Found: 30.40; 5.44; 5.37; 38.16.
Example XII
Cis-l~l-bis(aminomethyl)cyclohexane platinum(II)nltrat~
having the formula 11.
4 9 cis-dichloro-l,l-bis(aminomethyl)cyclohexane plait-Nemo) (0.0097 mole) were suspended in 30 ml distilled water.
To this 3.1 9 Agony (0.0182 mole) were added and sub-sequently the mixture was heated during 1 hour at Cole light was excluded.
The formed silver chloride was filtered off and washed with distilled water (10 ml).
The clear filtrate was evaporated under reduced pressure.
25 Weight solid substance: 4.17 9 (93.5 weight OWE).
Melting point : explodes at about 240C;
decomposes slowly at temperatures below 240C.
Analysis (weight JO) : calculi.: C:20.83; H:3.93; N:12.14 found : 20.9 ; 4.1 ; 11.9 .
I H-NMR-spectrum in DMS0-d6 ovarian T60) with respect to ITS:
SHEA (ring) : ].37 Pam SHEA (NH2) : 2.30 Pam NH2: 5.67 Pam 35 satellites : 5.20 Pam : 6.18 Pam J195Pt lo : 58 HO
fed ok :~22~6~1~
Example XIII
Cis-l,l-bis(i~minomethyl)cy~lohexane e~tinum(II)oxalate having the formula 14.
4.1 9 Cis-dichloro-l,l-bis(aminomPthyl)cyclohexane plutonium) (0.01 mole) were suspended in 30 ml distilled water.
To this 3.2 9 Agony (0,019 mole) were added and subset quaintly the mixture was heated during 1 hour at 40C while 'light was excluded.
The formed silver chloride was filtered off and washed with distilled water (50 ml).
To the filtrate 2.02 9 potassium oxalate (0.01 mole) were added, thereafter the mixture was stirred during 1 hour at room temperature.
Subsequently the formed solid was sucked off, washed with distilled water and dried.
jut dry : 3.7 9 (87 weight I
Analysis (weight Do) gala. + 1.5 H20: 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 DMS0-d6 ovarian T603 with respect to TAMS:
SHEA (ring) : 1.32 Pam SHEA (NH2) : 2.17 Pam NH2 : 5.45 Pam satellites : 4.83 Pam : 6.08 Pam 1 Pt-lH : 76 Ho
After stirring the mixture during 1 hour at 40C the Axle was filtered off and washed with water.
To the clear filtrate a solution of 0.677 9 l.l-cyclo-butane dicarboxylic acid and 0.547 9 KOCH in 10 ml water was added.
After 2 hours at room temperature and 1 hour at 0C the white precipitate was Filtered off and dried.
- .3L2296~13 Yield: 1.4 9 (62 weight JO).
Analysis (weight 0):
Calculated + H20: C: 33.80; H: 5.27; N: 5.63;
Found: 33.98; 5.02 5.77.
Exam e XI
Cis-2,2-diethyl-1,3-diaminopropane-1,1-cyclobutanee dicarbo-zealot plutonium), having the formula 9, was prepared according to the method of example X.
Yield: 64 weight Do.
Analysis (weight 0):
Calculated + 2.5 H20: C: 30.46; H: 5.70; N: 5.47; Pi: 38.07;
Found: 30.40; 5.44; 5.37; 38.16.
Example XII
Cis-l~l-bis(aminomethyl)cyclohexane platinum(II)nltrat~
having the formula 11.
4 9 cis-dichloro-l,l-bis(aminomethyl)cyclohexane plait-Nemo) (0.0097 mole) were suspended in 30 ml distilled water.
To this 3.1 9 Agony (0.0182 mole) were added and sub-sequently the mixture was heated during 1 hour at Cole light was excluded.
The formed silver chloride was filtered off and washed with distilled water (10 ml).
The clear filtrate was evaporated under reduced pressure.
25 Weight solid substance: 4.17 9 (93.5 weight OWE).
Melting point : explodes at about 240C;
decomposes slowly at temperatures below 240C.
Analysis (weight JO) : calculi.: C:20.83; H:3.93; N:12.14 found : 20.9 ; 4.1 ; 11.9 .
I H-NMR-spectrum in DMS0-d6 ovarian T60) with respect to ITS:
SHEA (ring) : ].37 Pam SHEA (NH2) : 2.30 Pam NH2: 5.67 Pam 35 satellites : 5.20 Pam : 6.18 Pam J195Pt lo : 58 HO
fed ok :~22~6~1~
Example XIII
Cis-l,l-bis(i~minomethyl)cy~lohexane e~tinum(II)oxalate having the formula 14.
4.1 9 Cis-dichloro-l,l-bis(aminomPthyl)cyclohexane plutonium) (0.01 mole) were suspended in 30 ml distilled water.
To this 3.2 9 Agony (0,019 mole) were added and subset quaintly the mixture was heated during 1 hour at 40C while 'light was excluded.
The formed silver chloride was filtered off and washed with distilled water (50 ml).
To the filtrate 2.02 9 potassium oxalate (0.01 mole) were added, thereafter the mixture was stirred during 1 hour at room temperature.
Subsequently the formed solid was sucked off, washed with distilled water and dried.
jut dry : 3.7 9 (87 weight I
Analysis (weight Do) gala. + 1.5 H20: 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 DMS0-d6 ovarian T603 with respect to TAMS:
SHEA (ring) : 1.32 Pam SHEA (NH2) : 2.17 Pam NH2 : 5.45 Pam satellites : 4.83 Pam : 6.08 Pam 1 Pt-lH : 76 Ho
Claims (24)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A method for preparing a compound of the formula A, A
wherein R1 and R2 are both ethyl or together with the carbon atom to which they are bonded, a cyclohexyl group, and both of X provide an ethylmalonate group, a hydroxy-malonate group, a carboxyphthalate group, a bischloroacetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate, an oxalate group or a sodium salt of these groups, comprising:
reacting a compound of the formula B
B
with AgNO3 to give which may be isolated as a dinitrate of formula A or which may be reacted further with X-H or its carboxylate or dicarboxylate thereof, X being other than nitrate as defined above, to give a compound of formula A.
wherein R1 and R2 are both ethyl or together with the carbon atom to which they are bonded, a cyclohexyl group, and both of X provide an ethylmalonate group, a hydroxy-malonate group, a carboxyphthalate group, a bischloroacetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate, an oxalate group or a sodium salt of these groups, comprising:
reacting a compound of the formula B
B
with AgNO3 to give which may be isolated as a dinitrate of formula A or which may be reacted further with X-H or its carboxylate or dicarboxylate thereof, X being other than nitrate as defined above, to give a compound of formula A.
2. A method as claimed in claim 1, wherein R1 and R2 together with the carbon atom to which they are bonded form a cyclohexyl group and X-H is hydroxymalonic acid.
3. A method as claimed in claim 1, wherein R1 and R2 together with the carbon atom to which they are bonded form a cyclohexyl group and X-H is 1,2,4-tricarboxybenzene.
4. A method as claimed in claim 1, wherein R1 and R2 together with the carbon atom to which they are bonded form a cyclohexyl group and X-H is chloroacetic acid.
5. A method as claimed in claim 1, wherein R1 and R2 are both ethyl and X-H is ethylmalonic acid.
6. A method as claimed in claim 1, wherein R1 and R2 are both ethyl and X-H is hydroxymalonic acid.
7. A method as claimed in claim 1, wherein R1 and R2 are both ethyl and X-H is 1,1-dicarboxycyclobutane.
8. A method as claimed in claim 1, wherein R1 and R2 together with the carbon atom to which they are bonded form a cyclohexyl group and X-H is ethylmalonic acid.
9. A method as claimed in claim 1, wherein R1 and R2 together with the carbon atom to which they are bonded form a cyclohexyl group and both of X provide a dinitrate.
10. A method as claimed in claim 1, wherein R1 and R2 together with the carbon atom to which they are bonded form a cyclohexyl group and X-H is 1,1-dicarboxycyclobutane.
11. A method as claimed in claim 6, further comprising the step of reacting the product with NaOH to form the sodium salt thereof.
12. A method as claimed in claim 1, wherein R1 and R2 together with the carbon atom to which they are bonded form a cyclohexyl group and X-H is oxalic acid.
13. A compound of the formula A
A
wherein R1 and R2 are both ethyl or together with the carbon atom to which they are bonded, a cyclohexyl group, and both of X provide an ethylmalonate group, a hydroxy-malonate group, a carboxyphthalate group, a bischloroacetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate, an oxalate group or a sodium salt of these groups, when prepared by the method of claim 1 or its obvious chemical equivalent.
A
wherein R1 and R2 are both ethyl or together with the carbon atom to which they are bonded, a cyclohexyl group, and both of X provide an ethylmalonate group, a hydroxy-malonate group, a carboxyphthalate group, a bischloroacetate group, a cyclobutane-1,1-dicarboxylate group, a dinitrate, an oxalate group or a sodium salt of these groups, when prepared by the method of claim 1 or its obvious chemical equivalent.
14. A compound of the formula whenever prepared by the process of claim 2 or its obvious chemical equivalent.
15. A compound of the formula whenever prepared by the process of claim 3 or its obvious chemical equivalent.
16. A compound of the formula whenever prepared by the process of claim 4 or its obvious chemical equivalent.
17. A compound of the formula whenever prepared by the process of claim 5 or its obvious chemical equivalent.
18. A compound of the formula whenever prepared by the process of claim 6 or its obvious chemical equivalent.
19. A compound of the formula whenever prepared by the process of claim 7 or its obvious chemical equivalent.
20. A compound of the formula whenever prepared by the process of claim 8 or its obvious chemical equivalent.
21. A compound of the formula whenever prepared by the process of claim 9 or its obvious chemical equivalent.
22. A compound of the formula whenever prepared by the process of claim 10 or its obvious chemical equivalent.
23. A compound of the formula whenever prepared by the process of claim 11 or its obvious chemical equivalent.
24. A compound of the formula whenever prepared by the process of claim 12 or its obvious chemical equivalent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NL8204067 | 1982-10-21 | ||
| 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 (1)
| Publication Number | Publication Date |
|---|---|
| CA1229618A true CA1229618A (en) | 1987-11-24 |
Family
ID=19840444
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000439308A Expired CA1229618A (en) | 1982-10-21 | 1983-10-19 | Platinum-diamine complexes, a process for the preparation thereof, a process for the preparation of medical composition using a such platinum-diamine complex for the treatment of cancer, as well as the thus shaped composition |
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| 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) |
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| 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) |
Families Citing this family (16)
| 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 |
| EP0169645A1 (en) * | 1984-06-27 | 1986-01-29 | Johnson Matthey Public Limited Company | Platinum co-ordination compounds |
| DE3432320A1 (en) * | 1984-09-03 | 1986-03-13 | Behringwerke Ag, 3550 Marburg | CIS-PLATINUM COMPLEXES WITH A PENTAERYTHRITE DERIVATIVE AS A LIGAND, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENT CONTAINING THESE COMPOUNDS |
| HU193809B (en) * | 1984-09-12 | 1987-12-28 | Chugai Pharmaceutical Co Ltd | Process for producing new platinum complexes |
| US4737589A (en) * | 1985-08-27 | 1988-04-12 | Nippon Kayaku Kabushiki Kaisha | Platinum Complexes |
| US4880790A (en) * | 1986-01-31 | 1989-11-14 | American Cyanamid Company | (Gem-heterocyclodimethanamine-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 |
| DE3630497A1 (en) * | 1986-09-08 | 1988-03-10 | Behringwerke Ag | CIS-PLATINUM COMPLEXES, METHOD FOR THE PRODUCTION THEREOF AND PHARMACEUTICAL AGENTS CONTAINING THESE COMPOUNDS |
| DE3762972D1 (en) * | 1986-10-03 | 1990-07-05 | Asta Pharma Ag | DIAMINE-PLATIN (II) COMPLEX COMPOUNDS WITH A HYDROXYLATED 2-PHENYL INDOLRING. |
| JPS63203692A (en) * | 1987-02-19 | 1988-08-23 | Nippon Kayaku Co Ltd | Novel platinum complex |
| AT390065B (en) * | 1987-10-08 | 1990-03-12 | Behringwerke Ag | cis-Platinum complexes, process for their preparation and pharmaceutical compositions containing these compounds |
| NL8802150A (en) * | 1988-08-31 | 1990-03-16 | Tno | PLATINUM (II) DIAMINE COMPLEX, PROCESS FOR PREPARING THIS COMPOUND, PREPARATION WITH ANTI-TUMOR EFFECT, CONTAINING THIS COMPOUND AND FORMED PREPARATIONS WITH ANTI-TUMOR EFFECT. |
| NL8802149A (en) * | 1988-08-31 | 1990-03-16 | Tno | PLATINUM (IV) DIAMINE COMPLEX, METHOD FOR PREPARING THIS COMPOUND, PREPARATION WITH ANTI-TUMOR EFFECT, CONTAINING AT LEAST A PLATINUM COMPOUND, AND FORMED PREPARATIONS WITH ANTI-TUMOR EFFECT. |
| 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 |
Family Cites Families (6)
| 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 |
| US4206226A (en) * | 1977-08-29 | 1980-06-03 | The United States Of America As Represented By The Department Of Health, Education And Welfare | Use of 4-carboxy-phthalato-(1,2-diaminocyclohexane)-platinum(II) and alkali metal salts thereof in alleviating L1210 murine leukemia |
| NL7807334A (en) * | 1978-07-06 | 1980-01-08 | Tno | PLATINUM DIAMINE COMPLEXES, METHOD FOR PREPARING THE SAME, METHOD FOR PREPARING A MEDICINAL PRODUCT USING SUCH A PLATINUM DIAMOND COMPLEX FOR THE TREATMENT OF CANCER, SO PREVENTLY DRIVED. |
| 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 |
| NZ197104A (en) * | 1980-05-27 | 1984-05-31 | Bristol Myers Co | Soluble ammonium and sodium salts of 2-hydroxymalonato platinum ii derivatives |
-
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 AT AT0373083A patent/AT390610B/en not_active IP Right Cessation
- 1983-10-20 SE SE8305783A patent/SE8305783L/en not_active Application Discontinuation
- 1983-10-20 FR FR8316715A patent/FR2534907B1/en not_active Expired
- 1983-10-20 YU YU2107/83A patent/YU43554B/en unknown
- 1983-10-20 NO NO833825A patent/NO171276C/en unknown
- 1983-10-20 IE IE2459/83A patent/IE56124B1/en not_active IP Right Cessation
- 1983-10-20 NZ NZ206018A patent/NZ206018A/en unknown
- 1983-10-20 GB GB08328084A patent/GB2128615B/en not_active Expired
- 1983-10-20 DK DK483083A patent/DK483083A/en not_active Application Discontinuation
- 1983-10-20 CH CH5718/83A patent/CH658244A5/en not_active IP Right Cessation
- 1983-10-20 HU HU833623A patent/HU188035B/en not_active IP Right Cessation
- 1983-10-20 GR GR72754A patent/GR79652B/el unknown
- 1983-10-20 FI FI833842A patent/FI76351C/en not_active IP Right Cessation
- 1983-10-20 DD DD83255826A patent/DD217522A5/en not_active IP Right Cessation
- 1983-10-20 LU LU85054A patent/LU85054A1/xx unknown
- 1983-10-20 PT PT77542A patent/PT77542B/en unknown
- 1983-10-21 ES ES526670A patent/ES526670A0/en active Granted
- 1983-10-21 ZA ZA837857A patent/ZA837857B/en unknown
- 1983-10-21 CS CS837752A patent/CS242888B2/en unknown
- 1983-10-21 PH PH29726A patent/PH24077A/en unknown
- 1983-10-21 BE BE0/211755A patent/BE898058A/en not_active IP Right Cessation
- 1983-10-21 KR KR1019830004987A patent/KR910002536B1/en not_active IP Right Cessation
- 1983-10-21 JP JP58196286A patent/JPS5993091A/en active Granted
-
1992
- 1992-06-09 DK DK92755A patent/DK75592D0/en not_active Application Discontinuation
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