Claims
- 1. A compound of the formula I ##STR10## in which: R.sup.1 represents a hydrogen atom or an alkyl group of the formula CH.sub.3 (CH.sub.2).sub.n --where n [=] is 0, 1, 2, 3, 4 or 5;
- R.sup.2 represents a hydrogen atom when X is a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, a group of the formula R.sup.3 --O--CH.sub.2 --(CHR.sup.4).sub.m --CH.sub.2 --in which:
- R.sup.3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
- R.sup.4 is a hydroxyl group or an alkyloxy group having 1 to 3 carbon atoms, and
- m is 0, 1 or 2,
- a group of the formula H--(CH.sub.2).sub.a --(0--(CH.sub.2).sub.b).sub.c --where a is 0, 1, 2, 3 or 4, b is 1, 2, 3 or 4 and c is 1, 2, 3, 4, 5, 6 or 7, or a radical of the formula ##STR11## in which: R.sup.5, R.sup.6 and R.sup.7, independently of one another, are a hydrogen atom or a hydroxyl group, and
- R.sup.8 is a hydrogen atom, a methyl group or a hydroxy methyl group; p1 X represents a methylene group, a carbamoyl group or a covalent bond between R.sup.1 and the 2-carbon atom; and
- A.sup.1 and A.sup.2 are identical and represent a hydroxyl group, chloride, bromide, iodide, nitrate, acetate or trifluoroacetate, or A.sup.1 represents sulfate or carbonate and A.sup.2 represents H.sub.2 O, or A.sup.1 and A.sup.2 together represent the dianion of an organic acid.
- 2. A compound of the formula II, which is useful as a precursor for the preparation of a compound as claimed in claim 1, ##STR12## in which: R.sup.1 is a hydrogen atom or an alkyl group of the formula CH.sub.3 (CH.sub.2).sub.n where n is 0, 1, 2, 3, 4 or 5,
- R.sup.2 is a hydrogen atom,
- R.sup.9 is an azide group, and
- X is a methylene group, a carbamoyl group or a covalent bond between R.sup.1 and the 2-carbon atom.
- 3. A compound of the formula II, which is useful as an intermediate for the preparation of a compound as claimed in claim 1, ##STR13## in which: R1 represents a hydrogen atom or an alkyl group of the formula CH.sub.3 (CH.sub.2)n--where n is 0, 1, 2, 3, 4 or 5;
- R2 represents a hydrogen atom when X is a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, a group of the formula R.sup.3 --O--CH.sub.2 --(CHR.sup.4).sub.m -CH.sub.2 --in which:
- R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
- R4 is a hydroxyl group or an alkyloxy group having 1 to 3 carbon atoms, and
- m is 0, 1 or 2,
- a group of the formula H--(CH.sub.2).sub.a --(0--(CH.sub.2).sub.b).sub.c --where a is 0, 1, 2, 3 or 4, b is 1, 2, 3 or 4, and c is 1, 2, 3, 4, 5, 6 or 7, or a radical of the formula ##STR14## in which: R5, R6 and R7, independently of one another, are a hydrogen atom or a hydroxyl group, and
- R8 is a hydrogen atom, a methyl group or a hydroxy methyl group;
- X represents a methylene group, a carbamoyl group or a covalent bond between R.sup.1 and the 2-carbon atom; and
- R.sup.9 denotes an azido group, an amino group, or an ammonium salt.
- 4. A process for the preparation of a compound as claimed in claim 1, comprising reacting K.sub.2 PtCl.sub.4 with a diamino compound of the formula II ##STR15## in which: R1 represents a hydrogen atom or an alkyl group of the formula CH.sub.3 (CH.sub.2)n--where n is 0, 1, 2, 3, 4 or 5;
- R2 represents a hydrogen atom when X is a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, a group of the formula R.sup.3 --O--CH.sub.2 --(CHR.sup.4).sub.m --CH.sub.2 --in which:
- R3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
- R4 is a hydroxyl group or an alkyloxy group having 1 to 3 carbon atoms, and
- m is 0, 1 or 2,
- a group of the formula H--(CH.sub.2).sub.a --(0--(CH.sub.2).sub.b).sub.c --where a is 0, 1, 2, 3 or 4, b is 1, 2, 3 or 4, and c is 1, 2, 3, 4, 5, 6 or 7, or a radical of the formula ##STR16## in which: R5, R6 and R7, independently of one another, are a hydrogen atom or a hydroxyl group, and
- R8 is a hydrogen atom, a methyl group or a hydroxy methyl group;
- X represents a methylene group, a carbamoyl group or a covalent bond between R.sup.1 and the 2-carbon atom; and
- R.sup.9 denotes an azido group, an amino group, or an ammonium salt.
- 5. A compound as recited in claim 1, wherein A.sup.1 and A.sup.2 together represent the dianion of an organic acid selected from the group consisting of oxalic, malonic, hydroxymalonic, ethylmalonic, 1,1-cyclobutanedicarboxylic, 1,2-cyclobutanedicarboxylic, phthalic, 3-carboxyphthalic, 4-carboxyphthalic, 3,4-dicarboxyphthalic, and n-(carboylmethyl)-iminodiacetic acid.
- 6. A compound as recited in claim 1, wherein:
- R.sup.1 is a methyl or ethyl group;
- R.sup.2 is a methyl or ethyl group, a group of the formula ##STR17## or a group of the formula R.sup.3 --(OCH.sub.2 CH.sub.2).sub.C --where R.sup.3 is a hydrogen atom or a methyl radical, and c is 1, 2, 3, or 6, or a radical of the formula ##STR18## where: R.sup.5 and R.sup.6, independently of one another, are a hydrogen atom or a hydroxyl group, and
- R.sup.8 is a hydrogen atom, a methyl group or a hydroxymethyl group;
- X is a covalent bond; and
- A.sup.1 and A.sup.2 are identical and are a hydroxyl group, chloride or nitrate, or together are the dianion of malonic, 1,1-cyclobutanedicarboxylic or N-(carbamoylmethyl)-iminodiacetic acid.
- 7. A compound as recited in claim 1, wherein
- R.sup.1 --X is an acetamido group;
- R.sup.2 is a hydrogen atom; and
- A.sup.1 and A.sup.2 are identical and are a hydroxyl group, chloride, or nitrate, or together are the dianion of malonic, 1,1-cyclobutanedicarboxylic or N-(carbamoylmethyl)iminodiacetic acids.
- 8. A medicament useful in the treatment of tumors comprising, a compound of the formula ##STR19## in which: R.sup.1 represents a hydrogen atom or an alkyl group of the formula CH.sub.3 (CH.sub.2).sub.n - where n is 0, 1, 2, 3, 4 or 5;
- R.sup.2 represents a hydrogen atom when X is a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, a group of the formula R.sup.3 --O--CH.sub.2 --(CHR.sup.4).sub.m --CH.sub. --in which:
- R.sup.3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
- R.sup.4 is a hydroxyl group or an alkyloxy group having 1 to 3 carbon atoms, and
- m is 0, 1 or 2,
- a group of the formula H--(CH.sub.2).sub.a --(0--(CH.sub.2).sub.b).sub.c --where a is 0, 1, 2, 3 or 4, b is 1, 2, 3 or 4 and c is 1, 2, 3, 4, 5, 6 or 7, or a radical of the formula ##STR20## in which: R.sup.5, R.sup.6 and R.sup.7, independently of one another, are a hydrogen atom or a hydroxyl group, and
- R.sup.8 is a hydrogen atom, a methyl group or a hydroxy methyl group;
- X represents a methylene group, a carbamoyl group or a covalent bond between R.sup.1 and the 2-carbon atom; and
- A.sup.1 and A.sup.2 are identical and represent a hydroxyl group, chloride, bromide, iodide, nitrate, acetate or trifluoroacetate, or A.sup.1 represents sulfate or carbonate and A.sup.2 represents H.sub.2 O, or A.sup.1 and A.sup.2 together represent the dianion of an organic acid;
- together with a pharmaceutically acceptable diluent or carrier.
- 9. A medicament for the treatment of tumors as recited in claim 8, wherein A.sub.1 and A.sub.2, together represent the dianion of an organic acid selected from the group consisting of oxalic, malonic, hydroxymalonic, ethylmalonic, 1,1-cyclobutanedicarboxylic, 1,2-cyclobutanedicarboxylic, phthalic, 3-carboxyphthalic, 4-carboxyphthalic, 3,4-dicarboxyphthalic, and n-(carbamoylmethyl)-iminodiacetic acid.
- 10. A medicament for the treatment of tumors as recited in claim 8, wherein:
- R.sup.1 is a methyl or ethyl group;
- R.sup.2 is a methyl or ethyl group, a group of the formula ##STR21## or a group of the formula R.sup.3 --(OCH.sub.2 CH.sub.2).sub.C --where R.sup.3 is a hydrogen atom or a methyl radical, and c is 1, 2, 3, or 6, or a radical of the formula ##STR22## where: R.sup.5 and R.sup.6, independently of one another, are a hydrogen atom or a hydroxyl group, and
- R.sup.8 is a hydrogen atom, a methyl group or a hydroxylmethyl group;
- X is a covalent bond; and
- A.sup.1 and A.sup.2 are identical and are a hydroxyl group, chloride or nitrate, or together are the dianion of malonic, 1,1-cyclobutanedicarboxylic or N-(carbamoylmethyl)-iminodiacetic acid.
- 11. A method for the treatment of tumors comprising administering to a patient having tumors an effective amount of a compound of the formula ##STR23## in which: R.sup.1 represents a hydrogen atom or an alkyl group of the formula CH.sub.3 (CH.sub.2).sub.n --where n is 0, 1, 2, 3, 4 or 5;
- R.sup.2 represents a hydrogen atom when X is a carbamoyl group, an alkyl group having 1 to 6 carbon atoms, a group of the formula R.sup.3 --O--CH.sub.2 --(CHR.sup.4).sub.m --CH.sub.2 --in which:
- R.sup.3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms,
- R.sup.4 is a hydroxyl group or an alkyloxy group having 1 to 3 carbon atoms, and
- m is 0, 1 or 2,
- a group of the formula H--(CH.sub.2).sub.a --(0--(CH.sub.2).sub.b).sub.c --where a is 0, 1, 2, 3 or 4, b is 1, 2, 3 or 4 and c is 1, 2, 3, 4, 5, 6 or 7, or a radical of the formula ##STR24## in which: R.sup.5, R.sup.6 and R.sup.7, independently of one another, are a hydrogen atom or a hydroxyl group, and
- R.sup.8 is a hydrogen atom, a methyl group or a hydroxy methyl group;
- X represents a methylene group, a carbamoyl group or a covalent bond between R.sup.1 and the 2-carbon atom; and
- A.sup.1 and A.sup.2 are identical and represent a hydroxyl group, chloride, bromide, iodide, nitrate, acetate or trifluoroacetate, or A.sup.1 represents sulfate or carbonate and A.sup.2 represents H.sub.2 O, or A.sup.1 and A.sup.2 together represent the dianion of an organic acid.
- 12. A method for the treatment of tumors as recited in claim 11, wherein A.sup.1 and A.sup.2 together represent the dianion of an organic acid selected from the group consisting of oxalic, malonic, hydroxymalonic, ethylmalonic, 1,1-cyclobutanedicarboxylic, 1,2-cyclobutanedicarboxylic, phthalic, 3-carboxyphthalic, 4-carboxyphthalic, 3,4-dicarboxyphthalic, and n-(carbamoylmethyl)-iminodiacetic acid.
- 13. A method for the treatment of tumors as recited in claim 11, wherein:
- R.sup.1 is a methyl or ethyl group;
- R.sup.2 is a methyl or ethyl group, a group of the formula ##STR25## or a group of the formula R.sup.3 --(OCH.sub.2 CH.sub.2).sub.C --where R.sup.3 is a hydrogen atom or a methyl radical, and c is 1, 2, 3, or 6, or a radical of the formula ##STR26## where: R.sup.5 and .sup.6, independently of one another, are a hydrogen atom or a hydroxyl group, and
- R.sup.8 is a hydrogen atom, a methyl group or a hydroxymethyl group;
- X is a covalent bond; and
- A.sup.1 and A.sup.2 are identical and are a hydroxyl group, chloride or nitrate, or together are the dianion of malonic, 1,1-cyclobutanedicarboxylic or N-(carbamoylmethyl)-iminodiacetic acid.
Priority Claims (1)
Number |
Date |
Country |
Kind |
3630497 |
Sep 1986 |
DEX |
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Parent Case Info
This application is a continuation of application Ser. No. 07/467,276, filed Jan. 24, 1990, which is a continuation of application Ser. No. 07/093,207, filed Sept. 4, 1987, both now abandoned.
The invention relates to novel cis-platinum complex compounds containing a propane-1,3-diamine derivative as ligand, a process for the preparation thereof, and a pharmaceutical containing these novel compounds.
Cis-platinum complexes of the general formula cis-L.sub.2 PtX.sub.2 where L is a neutral ligand, such as NH.sub.3 or an organic amine, and X is an anionic ligand, such as chloride or an anion of an organic acid, have an antitumoral activity (Cisplatin; Current Status and New Developments, eds. A. W. Prestayko, S. T. Crooke and S. K. Carter, Academic Press, 1980, 149-191).
Cis-diamminedichloroplatinum(II) has been introduced as a medicament.
EPA 0,098,135 (A2) describes cis-platinum complexes which contain, as ligands, alkyl- or hydroxyalkyl-substituted propane-1,3-diamine derivatives. DE 3,337,333 (A1) and GB 2,024,823 (A) likewise describe (alkyl-, aryl- or aryl-alkylpropane-1,3-diamine)platinum complexes.
DE 3,432,320 (A1) describes symmetrical (propane-1,3-diamine)platinum complexes which carry two alkyloxymethyl substituents on carbon 2.
The kidney and bone marrow toxicity of alkyldiaminoplatinum complexes and their low solubility are disadvantageous.
Surprisingly, it became apparent that the previously unobtainable synthetic compounds N,N-(2-ethyl-2-methoxymethylpropane-1,3-diamine)dichloroplatinum(II) and the corresponding malonate derivative have a high cytostatic activity in the "in vivo" test using the L1210 tumor cell line, and that these compounds are only partially cross resistant in vitro to the medicament cis-diamminedichloroplatinum(II) which has been introduced for hospital use.
Proceeding from this knowledge, the object of the present invention was to prepare novel (propane-1,3-diamine)platinum complexes which are asymmetrically substituted at the 2-carbon atom, and to investigate the pharmacological utility thereof as cytostatics.
This object was achieved by the compounds of the formula I, which were conspicuous in the test for cytostatic activity.
The invention relates to cis-diamineplatinum(II) complexes of the formula I ##STR3## in which R.sup.1 represents a hydrogen atom or an alkyl group of the formula CH.sub.3 (CH.sub.2).sub.n --where n=0 to 5,
In the context of the invention, preferred compounds of general formula I are those in which the radicals
The compounds of the formula I according to the invention can be prepared, starting from a compound of the formula II ##STR7## in which R.sup.1 is a hydrogen atom or an alkyl group of the formula CH.sub.3 (CH.sub.2).sub.n, where n=0 to 5,
covalent bond between R.sup.1 and the 2-carbon atom, in a fashion which is known per se by preparing an ether or glycoside derivative of the formula II in which R.sup.1, R.sup.9 and X retain their abovementioned meaning and R.sup.2 is an alkyl group having 1 to 6 carbon atoms, a group, bonded in an ether-like fashion, of the formula R.sup.3 --O--CH.sub.2 --(CHR.sup.4).sub.m --CH.sub.2 --in which R.sup.3 is a hydrogen atom or an alkyl group having 1 to 6 carbon atoms, R.sup.4 is a hydroxyl group or an alkyloxy group and m is 0 to 2, or a group, bonded in an ether-like fashion, of the formula H--(CH.sub.2).sub.a --(O--(CH.sub.2).sub.b).sub.c --where a=0 to 4, b=1 to 4 and c=1 to 7, or R.sup.2 is a radical, bonded in an O-glycoside fashion, of the formula ##STR8## in which R.sup.5, R.sup.6 and R.sup.7, independently of one another, are a hydrogen atom or a hydroxyl group, or R.sup.5 and R.sup.6 represent an electron pair, and
The preparation of a compound of the general formula I is based on the use of processes which were described, for example in German Offenlegungsschrift 3,432,320 or are customary in carbohydrate chemistry.
Their cytostatic activity was determined in vitro on L1210 leukemia cells of the mouse or in vivo on L1210 leukemia, B16 melanoma and Lewis lung adenocarcinoma. The acute toxicity of the compounds was determined on NMRI mice. Taking into account the low acute toxicity (H. P. Kraemer, H. H. Sedlacek, Behring Institute Mitt. 74, 301-328, 1984), the compounds according to the invention proved to be superior to cisplatin with respect to cytotoxicity, solubility and activity on L1210 leukemia. In addition, the compounds according to the invention are also active in the case of tumor cells which are resistant towards cis-platin.
The invention also relates to medicaments, preferably for tumor therapy, which contain an active amount of one or more of the compounds of the formula I as active ingredient.
The manner of dosage and administration essentially corresponds to that which is known for cis-(NH.sub.3).sub.2 PtCl.sub.2, and higher dosages and/or more frequent administration are also suitable due to the favorable therapeutic index of the compounds according to the invention.
Besides conventional pharmaceutical formulation agents and/ or diluents, these medicaments can also contain, if appropriate, further active ingredients, besides the compounds of the formula I, for supplementing the therapy, so long as these do not exhibit any undesired side effects together with the compounds of the formula I according to the invention.
US Referenced Citations (1)
Number |
Name |
Date |
Kind |
4659810 |
Thiem et al. |
Apr 1987 |
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Foreign Referenced Citations (7)
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Date |
Country |
0098135A2 |
Jan 1984 |
EPX |
3337333A1 |
Apr 1984 |
DEX |
3432320A1 |
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DEX |
62-59294 |
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JPX |
856695 |
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GBX |
2128615A |
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GBX |
Non-Patent Literature Citations (2)
Entry |
Prestayko et al., Cisplatin; Current Status and New Developments, Academic Press, 1980, pp. 149-191. |
Kraemer et al., A Modified Screening System to Select New Cytostatic Drugs, Behring Inst. Mitt., No. 74, (1984), pp. 301-328. |
Continuations (2)
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Number |
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Parent |
467276 |
Jan 1990 |
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Parent |
93207 |
Sep 1987 |
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