Claims
- 1. A compound of the formula: ##STR16## wherein R.sub.1 is methyl;
- R.sub.2 is heteroaryl selected from the group consisting of thienyl, isoxazolyl, prazolyl and quinolinyl;
- each A is independently selected from the group consisting of hydrogen, alkyl or alkoxy of 1-4 carbon atoms and halogen; and n is 1 or 2.
- 2. The compound of claim 1, wherein R.sub.2 is thienyl.
- 3. The compound of claim 1, wherein R.sub.2 is isoxazolyl.
- 4. The compound of claim 1, wherein R.sub.2 is pyrazolyl.
- 5. The compound of claim 1, wherein R.sub.2 is quinolinyl.
- 6. The compound of claim 1, wherein A is a alkyl of 1-4 carbon atoms.
- 7. The compound of claim 1, wherein n is 2, one A is halogen and the other A is alkyl of 1-4 carbon atoms.
- 8. The compound of claim 1, wherein R.sub.1 is methyl, and R.sub.2 A.sub.n is 2-thienyl.
- 9. The compound of claim 1, wherein R.sub.1 is methyl, and R.sub.2 A.sub.n is 3,5-dimethylisoxazolyl.
- 10. The compound of claim 1, wherein R.sub.1 is methyl, and R.sub.2 A.sub.n is 5-chloro-1,3-dimethylpyrazolyl.
- 11. The compound of claim 1, wherein R.sub.1 is methyl, and R.sub.2 A.sub.n is 8-quinolinyl.
- 12. An antineoplastic composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
- 13. An antineoplastic composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier.
- 14. An antineoplastic composition comprising a compound of claim 9 and a pharmaceutically acceptable carrier.
- 15. An antineoplastic composition comprising a compound of claim 10 and a pharmaceutically acceptable carrier.
- 16. An antineoplastic composition comprising a compound of claim 11 and a pharmaceutically acceptable carrier.
- 17. A method of inhibiting the growth of B16 melanoma tumors in a host organism which comprises administering to said host organism a B16 melanoma tumor inhibiting amount of the compound of claim 1.
BACKGROUND OF THE INVENTION
This is a continuation-in-part of application Ser. No. 820,114 filed Jan. 21, 1986, now abandoned.
1. Field of the Invention
This invention relates to novel compounds having antineoplastic activity, i.e. activity for inhibiting the growth of malignant tumors More specifically, it relates to compounds of the class 1- alkyl-1 -sulfonyl-2-alkoxycarbonylsulfenylhydrazines and their use in inhibiting malignant tumors. These novel compounds constitute a new class of alkylating agents.
2. Prior Art and Other Information
Alkylating agents capable of methylation of biological molecules form a useful group of antineoplastic agents, with procarbazine, streptozotocin and dacarbazine being examples of clinically active agents of this type.
The assignee hereof has also discovered another class of N, N'-bis(sulfonyl)hydrazines useful for inhibiting the growth of malignant tumors. These compounds are described in U.S. Ser. No. 06/683,852 filed on Dec. 20, 1984, now abandoned and also in U.S. Ser. No. 06/810,644 filed on Dec. 18, 1985 now U.S. Pat. No. 4,684,747, which is a continuation-in-part of U.S. Ser. No. 06/683,852. See also Shyam et al., J. Med. Chem., 28, 525 (1985). The compounds described therein are of a different structure. A patent issuing from a division of said application 810,644 is U.S. Pat. No. 4,892,887. A patent issuing from a continuation of said application 820,114 is U.S. Pat. No. 4,849,563.
An object of this invention is to provide a new class of alkylating agents having antineoplastic activity.
A further object is to provide compositions containing such agents in a form suitable for administration to host organisms.
A still further object is to provide a method for preparing the novel alkylating agents.
A still further object is to provide novel compounds which have activity against malignant tumors.
This invention relates to compounds of the formula: ##STR2## wherein R.sub.1 is an alkyl of 1-6 carbon atoms, benzyl, phenyl, or phenyl substituted by halogen, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, amino or carbonyl substituents, or --RN(R').sub.2 wherein R and R' are each independently an alkyl of 1 to 4 carbon atoms, and R.sub.2 is an aromatic substituent, and each A is an aromatic substitution independently selected from the group consisting of hydrogen, alkyl of 1-4 carbon atoms, alkoxy of 1-4 carbon atoms, halogen, --NO.sub.2, --NH.sub.2, --COOH, and --NHCOCH.sub.3. The compounds have been found to be alkylating agents having antineoplastic activity for use in inhibiting the growth of malignant tumors, i.e. exhibit pronounced antitumor activity. In addition, they probably have low mammalian toxicity. The compounds may suitably be administered to a host organism internally in the form of conventional pharmaceutical preparations, for example, in conventional pharmaceutically acceptable enteral or parenteral excipients.
The compounds described above are a new class of antineoplastic agents. A number of them have been synthesized and tested with demonstrable effectiveness against the B16 melanoma and/or L1210 leukemia transplanted rodent tumors These compounds possess the capacity to generate an alkylating species under physiological conditions. As indicated above, the compounds have the general formula: ##STR3##
R.sub.1 is an alkyl of 1-6 carbon atoms. As used herein, the term "alkyl" represents straight or branched carbon chains Preferably, R.sub.1 is methyl, but may also be ethyl, isopropyl, or tert-butyl.
R.sub.1 may also be a benzyl or a phenyl substituent or a phenyl substituent substituted by halogen, alkoxy of 1 to 4 carbon atoms, alkyl of 1 to 4 carbon atoms, amino or carbonyl substituents.
R.sub.1 may also be --RN(R').sub.2 wherein R and R' may each independently be an alkyl of 1 to 4 carbon atoms, e.g. R is --CH.sub.2 CH.sub.2 and R' is CH.sub.3.
R.sub.2 is an aromatic substituent selected from the group consisting of: ##STR4## and heteroaryl, wherein the heteroatom is N, O and/or S, such as the unsaturated 5-member rings exemplified by ##STR5## and other heterocycles such as quinolinyl ##STR6##
Each A is an aromatic substitution which may be hydrogen. When this occurs, the aromatic substituents are considered unsubstituted. Otherwise, the aromatic substituents may be substituted by an A which is an alkyl or alkoxy of 1-4 carbon atoms, including straight or branched chain hydrocarbons or halogen. The term "halogen" is meant to include all four halogens, namely chlorine, bromine, iodine and fluorine. Chlorine and bromine are the preferred halogens. Additionally, the phenyl, benzyl and naphthyl substituents may be substituted by a --NO.sub.2, --NH.sub.2, --COOH, or --NHCOCH.sub.3 substituent.
The compounds of this invention may be made by the methodology shown in Scheme I:
The N-methyl-N-sulfonylhydrazides were prepared by reacting the appropriate sulfonyl chloride with methylhydrazine in a 1:2 molar ratio in tetrahydrofuran, see Friedman, et al., Org. Synth. Coll. Vol. 5, 1055 (1973), the entire disclosure of which is incorporated herein by reference. The appropriate sulfonyl chlorides may be obtained commercially. The 1-methyl-1-arylsulfonylhydrazines were prepared by reacting the appropriate sulfonyl chlorides with methylhydrazine in tetrahydrofuran. The reaction of these intermediates in diethyl ether with about one equivalent of pyridine and one equivalent of alkoxycarbonylsulfenyl chloride produce the claimed products herein. Other solvents may be used, e.g. methylene chloride, chloroform. Furthermore, other organic bases may also be incorporated, e.g. triethylamine, lutidine.
The compounds of this invention are preferably administered internally, in the form of conventional pharmaceutical preparations, for example, in conventional enteral or parenteral pharmaceutically acceptable excipients containing organic and/or inorganic inert carriers, such as water, gelatin, lactose, dimethylacetamide, starch, magnesium stearate, talc, plant oils, gums, alcohol, vaseline, or the like. The pharmaceutical preparations can be in solid forms, for example, tablets, dragees, suppositories, capsules, or the like or conventional liquid forms, such as suspensions, emulsions, or the like. If desired, they can be sterilized and/or contain conventional pharmaceutical adjuvants, such as preservatives, stabilizing agents, wetting agents, emulsifying agents, buffers, or salts used for the adjustment of osmotic pressure. The pharmaceutical preparations may also contain other therapeutically active materials.
The pharmaceutical preparation should include an amount of a compound of this invention effective for antineoplastic activity. The effective dosage will depend on the antineoplastic activity and toxicity of the particular compound employed, and is thus within the ordinary skill of the art to determine for any particular host mammal or other host organism. Suitable may be, for example, in the range of about 2-15 mg/kg for man.
Typical compounds of the present invention include:
The following is a theoretical mechanism by which the compounds of this invention are activated based on the examples shown herein and previous work. As previously demonstrated, a variety of 1-methyl-1,2-bis(arenesulfonyl)hydrazines (see U.S. Ser. No. 683,852 filed on Dec. 20, 1984 and the continuation-in-part thereof U.S. Ser. No. 06/810,644, filed Dec. 18, 1985 and Shyam, Cosby and Sartorelli, J. Med. Chem., 28, 525 (1985)) have been shown to be effective against the L1210 leukemia and B16 melanoma in mice. These compounds have the following formula: ##STR8## in which and Ar and Ar' are aromatic substituents.
The compounds break down under physiological conditions to generate the putative alkylating species which has the formula:
This was hypothesized to account for the observed biological activity of these compounds.
Replacement of the 2-arenesulfonyl group in the compound of Formula II by methoxycarbonylsulfenyl moiety to form a 1-methyl-1-arenesulfonyl-2-alkoxycarbonylsulfenylhydrazine of the following formula: ##STR9## provided a compound which was capable of decomposing by the same mechanism as the compounds of Formula II to give the methylating species shown below: ##STR10##
The compounds claimed herein also possess the ability to react directly with the sulphur atom of biological nucleophiles such as glutathione or various sulphur containing proteins to give methyldiazene, the postulated alkylating species derived from procarbazine (see Reed, "Procarbazine" in Antineoplastic and Immunosuppressive Agents, Part II ed. by Sartorelli and Johns. Berlin: Springer-Verlag, 1975, pp. 747-765) which can undergo further homolytic cleavage to generate the methyl radical, hydrogen radical and nitrogen. This is depicted in the Scheme II:
Government Interests
This research was supported in part by a U.S. Public Health Service Grant (Grant No. CA-02817) from the National Cancer Institute.
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Non-Patent Literature Citations (1)
| Entry |
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Continuation in Parts (1)
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Number |
Date |
Country |
| Parent |
820114 |
Jan 1986 |
|
Patent Grant
4962114
