Chemistry of carbon compounds – Miscellaneous organic carbon compounds – C-metal
Patent
1983-11-17
1986-09-02
Roberts, Elbert L.
Chemistry of carbon compounds
Miscellaneous organic carbon compounds
C-metal
26039745, 26039747, 2603975, 2609982, 530331, 530330, 530329, C07J 100
Patent
active
046094962
DESCRIPTION:
BRIEF SUMMARY
DESCRIPTION
N-(2-ethyl chloride)-N-nitrosoureas ("CNU"), such as 1,3-bis-(2-ethyl chloride)-1-nitrosourea (BCNU), 1-(2-ethyl chloride)-3-cyclohexyl-1-nitrosourea (CCNU) and 1-(2-ethyl chloride)-3-(4-methyl)cyclohexyl-1-nitrosourea (MeCCNU) are important antineoplastic chemotherapeutic agents, from the clinical standpoint as well. (Nitrosoureas in Cancer Treatment, B. Serrou, P. S. Schein and J.-L. Imbach, editors, Elsevier/North-Holland Biomedicals Press, 1981; Nitrosoureas: current status and new developments, Academic Press, New York, 1981).
Along with their therapeutic efficacy, however, these substances also have a long-lasting cumulative toxicity (Eisenbrand et al., in: Nitrosoureas in Cancer Treatment, Elsevier 1981).
In order to obtain substances having a better therapeutic index, nitrosoureas have lately been synthesized with various substitutions (for instance, sugar, peptides, DNA bases) and experimentally tested.
It has been found that a series of tumors contain hormone receptors or are hormone-dependent. The attempt has already been made several times to improve the chemotherapy of such tumors by chemically bonding alkylanes, for example, to hormones in order to exploit the receptor affinity of the hormones for attaining target-specific transporting of the cytostatic alkylane into the tumor tissue. Some examples of substances of this type are Prednimustin.RTM., an ester of prednisolone and the alkylane chlorambucil (a phenylbutyric acid-mechlorethamine hydrochloride derivative), or Estracyt.RTM., an N,N-bis(2-ethyl chloride)-3-carbamate of the estradiol-17-.beta.-phosphate. (Cancer Chemotherapy, edited by H. M. Pinedo, Excerpta Medica, Amsterdam-Oxford, 1979 and 1980.)
In contrast to these directly alkylating mechlorethamine hydrochloride derivatives, the present case relates to 2-halogen-alkylnitrosourea derivatives, which release a cross-linking alkylane only upon their decomposition in vivo. The CNU grouping must therefore be evaluated differently in both chemical and biological terms from the mechlorethamine hydrochloride grouping. As a rule, the CNU derivatives have a wider therapeutic range than the mechlorethamine hydrochloride derivatives. In the compounds described herein, a steroid molecule or a stilbene derivative acting pharmacologically similarly is bonded via an ester bond with an N-(2-halogen ethyl)-N-nitroso-carbamoyl-amino acid or with a peptide chain, the terminal amino acids of which carry the N-(2-halogen ethyl)-N-nitroso-carbamoyl group. The term "steroid" here also encompasses pharmacologically similarly acting stilbene derivatives having at least one OH group without steric hindrance. The steroids are preferably of the estrane, androstane or pregnane series, or corticosteroids. The OH groups used for the purpose of esterification are preferably located in positions 3, 6, 7, 15, 16, 17 and 21 of the pregnane structure. Additionally present OH groups may be free or else etherified (for instance, with methyl or ethyl) or esterified (for instance, with acetate or propenate).
The stilbene derivatives are preferably those having the following structures: ##STR2## R' is accordingly the radical for supplementing the ethyl chloride nitrosourea, with R.sub.1 and R.sub.2 retaining their meaning given above; that is, they are radicals of amino acids. R"=H or R' or a low alkyl, in particular methyl or ethyl or acyl, in particular acetyl or benzoyl. The OR' or OR" substitutions are located at identical or different positions on the benzene rings, in particular in positions 3,3'; 4,4' and 3,4'. The ethylene double bond of the stilbene body may also be hydrogenated, as is evident from the formulas above.
To prepare these compounds, a CNU amino acid, a CNU di-, tri- or oligopeptide (up to hexapeptide), synthesized in accordance with W. Tang, G. Eisenbrand, Arch. Pharm. 314, 910-917 (1981) and with German Patent Application No. P 31 34 923.4, is put into an activated form, such as the imidazolide or a mixed acid anhydride (such as the paratoluolsulfonic acid) and converted with a steroid
REFERENCES:
patent: 4177269 (1979-12-01), Fex et al.
patent: 4181669 (1980-01-01), Hansen et al.
Journal of Medicinal Chemistry (1972) vol. 15, No. 11, pp. 1158-1161.
Journal of Medicinal Chemistry, 1979, vol. 22, No. 2, pp. 200-202, "Synthesis of Steroidal nitrosoureas with Antitumor Activity" Hing-Yat P. Lam et al.
Chemical Abstract #96:69391C, "Synthesis of Potentially Antineoplastic Derivatives of N-[N-(2-Chloroethyl)-N-nitrosocarbamoyl]Amino Acids," Tang et al.
Eisenbrand Gerhard
Schreiber Joachim
Roberts Elbert L.
Stiftung Deutsches Krebsforshungszentrum
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