2,3-bis(aziridinyl)-1,4-naphthoquinone sulfonate derivatives having antineoplastic activity

Information

  • Patent Grant
  • 4806531
  • Patent Number
    4,806,531
  • Date Filed
    Thursday, February 20, 1986
    38 years ago
  • Date Issued
    Tuesday, February 21, 1989
    35 years ago
Abstract
The compounds of the formula: ##STR1## wherein R is selected from the group consisting of: (a) a substituent having the formula: ##STR2## wherein R.sub.1, R.sub.2 and R.sub.3 are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen and --NO.sub.2,(b) a substituent having the formula: ##STR3## wherein R.sub.4 is hydrogen or an N(R').sub.2 substituent, wherein R' is an alkyl of 1 to 4 carbon atoms and R.sub.5 is CH or N,(c) alkyl of 1 to 18 carbon atoms,(d) halo-substituted alkyl of 1 to 6 carbon atoms,(e) styrenyl,(f) toluenyl, or(g) camphoryl.The compounds have been found to have anti-neoplastic activity for use in inhibiting the growth of tumors.
Description

BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to compounds having antineoplastic activity, i.e., activity for inhibiting the growth of malignant tumors. More specifically it relates to compounds of the class 2,3-bis(aziridinyl)-1,4-naphthoquinone sulfonate derivatives, an intermediate therefor, and the use of these compounds in inhibiting malignant tumors.
2. Prior Art and Other Information
Assignee herein has discovered other classes of compounds 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, and now abandoned, and also in U.S. Ser. No. 06/810,644 now U.S. Pat. No. 4,684,747, filed on Dec. 18, 1985, which is a continuation-in-part of U.S. Ser. No. 06/683,852. The compounds described in this application are also described in Shyam et al. J. Med. Chem., 28, 525 (1985). These compounds are N,N'-bis(sulfonyl)hydrazines and are particularly active against both L1210 leukemia and B16 melanoma. Additionally, Assignee herein has also discovered 1-alkyl-2-arenesulfonyl-2-methoxycarbonyl sulfenyl hydrazines which are also useful for inhibiting the growth of malignant tumors. These compounds are described in U.S. Ser. No. 820,114 filed on Jan. 21, 1986, now abandoned and refiled in U.S. Ser. No. 142,354 on Dec. 28, 1987 and have significant activity against mice bearing the B16 melanoma.
Additionally, Applicant is aware of several references which describe compounds which might be considered relevant to the invention described and claimed herein.
In particular, U.S. Pat. No. 2,868,782 to Gauss describes polyhydro-2-aziridino-1,4-naphthoquinones. These compounds have the formula: ##STR4## wherein R is a divalent radical selected from the group consisting of --CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 --, --CH.dbd.CHCH.sub.2 CH.sub.2 -- or --CH.sub.2 CH.dbd.CHCH.sub.2 -- and R' may be hydrogen or methyl. The compounds are described as useful in chemotherapy and more particularly possessing cytostatic properties useful in the study and treatment of cancer.
U.S. Pat. No. 3,631,026 to Nakao describes 2,5-bis(1-aziridinyl)-1,4-benzoquinone derivatives of the formula: ##STR5## The compounds are said to exert an antileukemic activity and may be used on human beings as a drug for the remission and treatment of leukemia.
U.S. Pat. No. 4,146,622 to Driscoll describes aziridinyl quinone type compounds of the formula: ##STR6##
The preferred compounds are 2,5-diaziridinyl-1,4-benzoquinone derivatives.
U.S. Pat. Nos. 4,418,078 and 4,540,519 both to Murdock describes 1,4-bis(substituted-amino)-5,8-dihydroxyanthraquinone compounds of the type: ##STR7## an aziridinyl substituent may be formed by R.sub.1 and R.sub.2. The compounds are said to be useful in inhibiting the growth of transplanted mouse tumors.
British Pat. No. 864,747 describes "alkyleneimino-quinones" of the formula: ##STR8## wherein X and Y may represent an "annelated pyridine or benzene nucleus" and R may be a hydrogen or methyl group. More specifically this reference describes "2,3-di-(ethylene-imino)-naphthoquinone-(1,4)". The compounds are described are capable of inhibiting the growth of animal tumor cells.
None of the foregoing references teach or suggest the compounds described and claimed herein.
OBJECTS AND SUMMARY OF THE INVENTION
An object of this invention is to provide a new class of compounds having antineoplastic activity.
A further object of this invention is to provide compositions containing such agents in a form suitable for administration to host organisms.
Still another object is to provide a method for preparing the novel compounds.
A further object is to provide novel compounds which have activity against malignant tumors.
The compounds of this invention have the formula: ##STR9## wherein R is selected from the group consisting of: (a) a substituent having the formula: ##STR10## wherein R.sub.1, R.sub.2, and R.sub.3 are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen and --NO.sub.2,
(b) a substituent having the formula: ##STR11## wherein R.sub.4 is hydrogen or an N(R').sub.2 substituent, wherein R' is an alkyl of 1 to 4 carbon atoms, and R.sub.5 is CH or N,
(c) alkyl of 1 to 18 carbon atoms,
(d) halo-substituted alkyl of 1 to 6 carbon atoms,
(e) styrenyl,
(f) toluenyl, or
(g) camphoryl.
The compounds have been found to have pronounced antitumor activity. The compounds are particularly active against the L1210 leukemia and the B16 melanoma in tumor-bearing CDF.sub.1 mice. In addition, they probably have low mammalian toxicity. The compounds may suitably be administered to host organisms internally in the form of conventional pharmaceutical preparations, for example, in conventional pharmaceutically acceptable enteral or parenteral excipients.
DETAILED DESCRIPTION OF THE INVENTION
The compounds described above are a new class of antineoplastic agents which have demonstrable effectiveness against the rodent tumors L1210 leukemia and B16 melanoma in CDF.sub.1 mice.
As indicated above, the compounds have the general formula: ##STR12## R may be selected from several substituents. The preferred substituents have the general formula: ##STR13## R.sub.1, R.sub.2 and R.sub.3 may each be independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen and --NO.sub.2. As used herein, and throughout the specification, the term "alkyl" represents straight or branched chain carbon atoms. Preferred alkyl substituents are methyl, ethyl, isopropyl and butyl.
Additionally as used herein and throughout the specification, the term "halogen" is meant to include all four halogens, namely, chlorine, bromine, iodine and fluorine. Chlorine and bromine are the preferred halogens.
The alkoxy substituent of 1 to 4 carbon atoms, includes straight or branched chain hydrocarbons thereon. A preferred alkoxy is methoxy.
Preferred compounds falling within the foregoing formula are:
(4) 2,3-Bis(aziridinyl)-5-(O-benzenesulfonyl)-1,4-naphthoquinone
(5) 2,3-Bis(aziridinyl)-5-[O-(p-toluenesulfonyl)]-1,4-naphthoquinone
(6) 2,3-Bis(aziridinyl)-5-[O-(p-methoxybenzenesulfonyl)]-1,4-naphthoquinone
(7) 2,3-Bis(aziridinyl)-5-[O-(p-t-butylbenzenesulfonyl)]-1,4-naphthoquinone
(8) 2,3-Bis(aziridinyl)-5-[O-(2',4',6'-trimethylbenzenesulfonyl)]-1,4-naphthoquinone
(9) 2,3-Bis(aziridinyl)-5-[O-(2', 4', 6'-tri-isopropylbenzenesulfonyl)]-1,4-naphthoquinone
(10) 2,3-Bis(aziridinyl)-5-[O-(p-chlorobenzenesulfonyl)]-1,4-naphthoquinone
(11) 2,3-Bis(aziridinyl)-5-[O-(p-nitrobenzenesulfonyl)]-1,4-naphthoquinone
(12) 2,3-Bis(aziridinyl)-5-[O-(2,4-dinitrobenzenesulfonyl)]-1,4-naphthoquinone
In the foregoing formula, R may also be a substituent of the formula: ##STR14## Preferred compounds of this formula are wherein R.sub.4 is hydrogen or a N(R').sub.2 substituent, wherein R' is an alkyl of 1 to 4 carbon atoms, and R.sub.5 is CH or N. Preferred compounds of this type are the following:
(13) 2,3-Bis(aziridinyl)-5-[O-(naphthalene-1-sulfonyl)]-1,4-naphthoquinone
(14) 2,3-Bis(aziridinyl)-5-[O-(8-quinolenesulfonyl)]-1,4-naphthoquinone
(15) 2,3-Bis(aziridinyl)-5-[O-(5'-dimethylamino-1'-naphthalenesulfonyl)]-1,4-naphthoquinone.
Additionally preferred compounds are wherein R is a straight or branched chain alkyl of 1 to 18 carbon atoms, a halo-substituted alkyl of 1 to 6 carbon atoms, styrene, toluene, or camphor.
Preferred compounds of this type are:
(16) 2,3-Bis(aziridinyl)-5-(O-methanesulfonyl)-1,4-naphthoquinone
(17) 2,3-Bis(aziridinyl)-5-O-(butanesulfonyl)-1,4-naphthoquinone
(18) 2,3-Bis(aziridinyl)-5-[O-(1'-hexadecanesulfonyl)]-1,4-naphthoquinone
(19) 2,3-Bis(aziridinyl)-5-[O-(3-chloropropanesulfonyl)]-1,4-naphthoquinone
(20) 2,3-Bis(aziridinyl)-5-[O-(beta-styrenesulfonyl)]-1,4-naphthoquinone
(21) 2,3-Bis(aziridinyl)-5-[O-(alpha-toluenesulfonyl)]-1,4-naphthoquinone
(22) 2,3-Bis(aziridinyl)-5-[O-(d-10-camphorsulfonyl)]-1,4-naphthoquinone
The compounds of this invention of the formula: ##STR15## may be formed by reacting a compound of the formula: ##STR16## with a compound of the formula: ##STR17## wherein R is as previously defined. More particularly, the appropriate sulfonylchloride is reacted with 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (Compound 2) in a solvent such as CH.sub.2 Cl.sub.2, and further in the presence of a base, such as triethylamine. The resultant solution is then concentrated to a small volume and preferably chromatographed on a silica gel column to obtain the purified desired compound.
The 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (Compound 2) is obtained by adding 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (Compound 1) having the formula: ##STR18## to ethylenimine with stirring. The excess ethylenimine is then removed by evaporation and the solid dissolved in CH.sub.2 Cl.sub.2, washed and evaporated to dryness.
The 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (compound 1) is produced by reacting 5-hydroxy-1,4-naphthoquinone with ethylenimine in an alcohol solvent, concentrated by evaporating the solvent, and then chromatographed on a silica gel column.
Optionally, instead of producing 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (Compound 2) sequentially, 5-hydroxy-1,4-naphthoquinone may be reacted with at least 2 moles of ethylenimine to produce the 2,3-bis(aziridinyl)derivative. (See, British Pat. No. 864,747, incorporated herein by reference).
In producing compounds 1 and 2 herein, the reaction with ethylenimine may desirably be conducted by intimately contacting the starting naphthoquinone with ethylenimine in a suitable inert solvent. Any of those solvents that are inert and do not adversely affect the reaction of the process may be used. Suitable examples of such solvents which may be employed, include lower alkanols, e.g., methanol, ethanol, or isopropanol; di-lower alkyl ketones, e.g., acetone or methyl ketone. Preferred solvents are the lower alkanols, e.g., ethanol. The reaction temperature is not critical in the process, but it is usual and preferable to conduct the reaction at room temperature or below. Higher temperatures, may, of course, be applied although these do not result in any further advantages. The reaction period is not critical and may vary over a wide range mainly depending upon the kind of starting material employed. Usually it requires from several hours to several days to bring the reaction to completion.
To Applicant's knowledge the 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (Compound 2) of the formula: ##STR19## which is employed as an intermediate in the process for making the active claimed compounds, is a new chemical substance.
The compounds of this invention are preferably administered internally, in the form of conventional pharmaceutical preparations using a pharmaceutically acceptable carrier.
As used herein "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art.
Supplementary active ingredients can also be incorporated into the compositions, for example, conventional enteral or parenteral pharmaceutically acceptable excipients containing organic and/or inorganic inert carriers, such as water, gelatin, lactose, 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, lotions, or the like. If desired, they can be sterilized and/or contain conventional pharmaceutical additives 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 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 in the art to determine for any particular host mammal or other host organism. Suitable dosages may be, for example, in the range of about 0.5-15 mg/kg for man.





The tests herein indicate that the claimed Compounds of this invention possess excellent anti-tumor activity, resulting in a prolonged survival of test animals and curative effect on tumors.
SYNTHESIS AND PHYSICAL PROPERTIES 2-AZIRIDINYL-5-HYDROXY-1,4-NAPHTHOQUINONE
Compound 1
Ethylenimine (5.0 g, 115.7 mmol, 6 mL) in 60 mL of ethanol was added slowly to a stirred solution of 5-hydroxy-1,4-naphthoquinone (5.0 g, 28.7 mmol) in 940 mL of ethanol at 0.degree. C. (ice-water bath) over a period of 0.5 hours. The solution was stirred for another 4 hours at the same temperature, and then concentrated in vacuo. The residue was chromatographed on a silica gel column (EtOAc-C.sub.6 H.sub.14 -CH.sub.2 Cl.sub.2, 3:4:5, v/v) to afford 3.2 g (44%) of product.
The product physical properties were as follows:
mp 170.degree.-172.degree. C.; R.sub.f 0.57 (EtOAC-C.sub.6 -H.sub.14 -CH.sub.2 Cl.sub.2, 3:4:5, v/v); NMR (CDCl.sub.3) .delta.2.31 (s, 4H, 2-aziridinyl), 6.27 (s, 1H, 3-H), 7.23 (m, 1H, 6-H), 7.60 (m, 2H, 7- and 8-H), 11.92 (s, 1H, 5-OH, D.sub.2 O exchangeable). The product C.sub.12 H.sub.9 NO.sub.3 should have C, 66.97; H, 4.22; N, 6.51. The product was found to have C, 67.21; H, 3.89; N, 6.18.
2,3-BIS(AZIRIDINYL)-5-HYDROXY-1,4-NAPHTHOQUINONE
Compound 2 ##STR20##
2-Aziridinyl-5-hydroxy-1,4-naphthoquinone (Compound 1) (1.0 g, 4.7 mmol) was added in small portions to 5.8 g (7 mL, 134.9 mmol) of ethylenimine at 0.degree. C. with stirring. The reaction mixture was stirred at the same temperature for an additional 20 hours. The excess ethylenimine was removed in vacuo, and the resulting solid residue was redissolved in 150 mL of CH.sub.2 Cl.sub.2. The solution was washed with water (3.times.20 mL) and dried (anhydrous Na.sub.2 SO.sub.4). The drying agent was removed by filtration. The filtrate was evaporated to dryness under reduced pressure to give 1.1 g (92%) of product.
The product physical properties were as follows:
mp 181.degree.-183.degree. C.; R.sub.f 0.38 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.42 (s, 8H, 2- and 3-aziridinyl), 7.26 (d, 1H, 6-H), 7.48-7.54 (m, 1H, 7-H), 7.55 (d, 1H, 8-H), 12.16 (s, 1H, 5-OH, D.sub.2 O exchangeable). The product C.sub.14 H.sub.12 N.sub.2 O.sub.3 should have C, 65.61; H, 4.72; N, 10.93. The product was found to have C, 65.40; H, 4.45; N, 11.26.
2-AZIRIDINYL-5-[O-(p-TOLUENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 3 ##STR21##
A solution of triethylamine (1.45 g, 14.4 mmol, 2 mL) and 1.20 g (6.30 mmol) of p-toluenesulfonyl chloride in 10 mL of CH.sub.2 Cl.sub.2 was added to a solution of 0.70 g (3.25 mmol) of 2-aziridinyl-5-hydroxy-1,4-naphthoquinone (Compound 1) in 30 mL of CH.sub.2 Cl.sub.2. The reaction mixture was stirred for 2 hours at room temperature. The solution was concentrated to a small volume and chromatographed on a silica gel column (EtOAc-C.sub.6 H.sub.14 -CH.sub.2 Cl.sub.2, 2:3:5, v/v) to give 0.5 g (42%) of the desired product.
The product physical properties were as follows: mp 152.degree.-154.degree. C.; R.sub.f 0.48 (EtOAc-C.sub.6 H.sub.14 -CH.sub.2 Cl.sub.2, 2:3:5, v/v); NMR (CDCl.sub.3) .delta.2.26 (s, 4H, 2-aziridinyl), 2.47 (s, 3H, 4'-CH.sub.3), 6.23 (s, 1H, 3-H), 7.36 (d, 2H, 3'- and 5'-H), 7.41 (d, 1H, 6-H), 7.66 (m, 1H , 7-H), 7.87 (d, 2H, 2'- and 6'-H), 8.07 (d, 1H, 8-H). The product, C.sub.19 H.sub.15 NO.sub.5 S.EtOAc should have C, 60.38; H, 4.63; N, 3.06. The product was found to have C, 60.74; H, 3.95; N, 3.02.
All of the compounds of the formula: ##STR22## were synthesized in a manner similar to Compound 5 hereinafter, i.e., the R-sulfonyl chloride was reacted with 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (Compound 2) in methylene chloride in the presence of triethylamine.
Synthesis of compounds of the formula: ##STR23## wherein R is: ##STR24##
2,3-BIS(AZIRIDINYL)-5-[O-(p-TOLUENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 5
R.sub.1 =CH.sub.3 ; R.sub.2 and R.sub.3 =H
A solution of p-toluenesulfonyl chloride (0.50 g, 2.60 mmol) and triethylamine (0.73 g, 7.20 mmol, 1 mL) in 10 mL of CH.sub.2 Cl.sub.2 was added to a stirred solution of 2,3-bis(aziridinyl)-5-hydroxy-1,4-naphthoquinone (Compound 2) in 10 mL of CH.sub.2 Cl.sub.2. The reaction mixture was stirred for another 20 hours at room temperature. The solution was then concentrated to a small volume and chromatographed on a silica gel column (EtOAc-C.sub.6 H.sub.14, 1:1, v/v; and followed by EtOAc) to afford 0.2 g (41%) of product. The product had the following physical properties:
mp 157.degree.-159.degree. C.; R.sub.f 0.2 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.35 and 2.37 (two s, 8H, 2- and 3-aziridinyl), 2.45 (s, 3H, 4'-CH.sub.3), 7.33 (d, 1H, 6-H), 7.35 (d, 2H, 3'- and 5'-H), 7.54 (dd, 1H, 7-H), 7.88 (d, 2H, 2'- and 6'-H), 8.01 (d, 1H, 8-H). The product C.sub.21 H.sub.18 N.sub.2 O.sub.5 S.0.5 EtOAc should have C, 60.78; H, 4.88; N, 6.16. The product was found to have: C, 60.29; H, 4.48; N, 5.99.
2,3-BIS(AZIRIDINYL)-5-(O-BENZENESULFONYL)-1,4-NAPHTHOQUINONE
Compound 4
R.sub.1 =R.sub.2 =R.sub.3 =H
Physical Properties:
mp 154.degree.-156.degree. C.; R.sub.f 0.12 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.36 (two s, 8H, 2- and 3-aziridinyl), 7.32 (d, 1H, 6-H), 7.54-7.58 (m, 3H, 3'-, 5'- and 7-H), 7.69 (m, 1H, 5'-H), 8.01 (m, 3H, 2'-, 6'- and 8-H). The product C.sub.20 H.sub.16 N.sub.2 O.sub.5 S.0.25 CH.sub.2 Cl.sub.2 should have C, 58.23; H, 3.98; N, 6.71. The product was found to have: C, 58.08; H, 3.92; N, 6.10.
2,3-BIS(AZIRIDINYL)-5-[O-(p-METHOXYBENZENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 6
R.sub.1 =OCH.sub.3 ; R.sub.2 =R.sub.3 =H
Physical properties:
mp 143.degree.-145.degree. C.; R.sub.f 0.47 (EtOAc-CH.sub.2 Cl.sub.2, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.38 (s, 8H, 2- and 3-aziridinyl), 3.90 (s, 3H, 4'-CH.sub.3 O-), 7.01 (d, 2H, 3'- and 5'-H), 7.35 (d, 1H, 6-H), 7.57 (M, 1H, 7-H), 7.95 (d, 2H, 2'- and 6'-H), 8.02 (d, 1H, 8-H). The product C.sub.21 H.sub.18 N.sub.2 O.sub.6 S should have C, 59.14; H, 4.25; N, 6.57. The product was found to have: C, 59.37; H, 4.25; N, 6.63.
2,3-BIS(AZIRIDINYL)-5-[O-(p-t-BUTYLBENZENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 7
R.sub.1 =C(CH.sub.3).sub.3 ; R.sub.2 =R.sub.3 =H
Physical properties:
mp 139.degree.-141.degree. C.; R.sub.f 0.39 (EtOAc-C.sub.6 H.sub.14 -CH.sub.2 Cl.sub.2, 3:4:5, v/v); NMR (CDCl.sub.3) .delta.1.36 (s, 9H, 4'-t-butyl), 2.36 (two s, 8H, 2- and 3-aziridinyl), 7.36 (d, 1H, 6-H), 7.58 (m, 3H, 3'-, 5'- and 7-H), 7.93 (d, 2H, 2'- and 6'-H), 8.02 (d, 1H, 8-H). The product C.sub.24 H.sub.24 N.sub.2 O.sub.5 S should have C, 63.70; H, 5.35; N, 6.19. The product was found to have: C, 63.40; H, 5.53; N, 5.92.
2,3-BIS(AZIRIDINYL)-5-[O-(2',4',6'-TRIMETHYLBENZENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 8
R.sub.1 =R.sub.2 =R.sub.3 =CH.sub.3
Physical properties:
mp 125.degree.-127.degree. C.; R.sub.f 0.39 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.36 (s, 3H, 4'-CH.sub.3), 2.39 (s, 8H, 2- and 3-aziridinyl), 2.61 (s, 6H, 2'- and 6'-CH.sub.3), 7.02 (m, 3H, 3'-, 5'- and 6-H), 7.50 (t, 1H, 7-H), 8.00 (d, 1H, 8-H). The product C.sub.23 H.sub.22 N.sub.2 O.sub.5 S should have C, 62.99; H, 5.06; N, 6.39. The product was found to have C, 62.69; H, 5.24; N, 6.04.
2,3-BIS(AZIRIDINYL)-5-[O-(2',4',6'-TRIISOPROPYLBENZENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 9
R.sub.1 =R.sub.2 =R.sub.3 =CH(CH.sub.3).sub.2
Physical properties:
mp 74.degree.-76.degree. C.; R.sub.f 0.37 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.1.22 (two s, 12H, 2'- and 6'-methyl of isopropyl), 1.30 (d, 6H, 4'-methyl of isopropyl), 2.38 (two s, 8H, 2- and 3-aziridinyl), 2.95 (m, 1H, 4'-CH of isopropyl), 4.08 (m, 2H, 2'- and 6'-CH of isopropyl), 6.96 (d, 1H, 6-H), 7.24 (s, 2H, 3'- and 5'-H), 7.50 (t, 1H, 7-H), 8.00 (d, 1H, 8-H). The product should have C.sub.29 H.sub.34 N.sub.2 O.sub.5 S.EtOAC: C, 64.89; H, 6.93; N, 4.59. The product was found to have C, 64.46; H, 7.06; N, 4.16.
2,3-BIS(AZIRIDINYL)-5-[O-(p-CHLOROBENZENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 10
R.sub.1 =Cl; R.sub.2 =R.sub.3 =H
Physical properties:
mp 159.degree.-161.degree. C. dec; R.sub.f 0.57 (EtOAc-CH.sub.2 Cl.sub.2, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.38 (two s, 8H, 2- and 3-aziridinyl), 7.38 (d, 1H, 6-H), 7.56 (d, 2H, 3'- and 5'-H), 7.61 (m, 1H, 7-H), 7.98 (d, 2H, 2'- and 6'-H), 8.04 (d, 1H, 8-H). The product C.sub.20 H.sub.15 ClN.sub.2 O.sub.5 S should have C, 55.75; H, 3.51; N, 6.50. The product was found to have C, 56.60; H, 3.49; N, 5.99.
2,3-BIS(AZIRIDINYL)-5-[O-(p-NITROBENZENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 11
R.sub.1 =NO.sub.2 ; R.sub.2 =R.sub.3 =H
Physical properties:
mp 150.degree.-151.degree. C. dec; R.sub.f 0.34 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v; NMR (CDCl.sub.3) .delta.2.38 (two s, 8H, 2- and 3-aziridinyl), 7.45 (d, 1H, 6-H), 7.64 (t, 1H, 7-H), 8.08 (d, 1H, 8-H), 8.31 (d, 2H, 2'- and 6'-H), 8.44 (d, 2H, 3'- and 5'-H). The product C.sub.20 H.sub.15 N.sub.3 O.sub.7 S.0.5 EtOAc should have C, 54.43; H, 3.45; N, 8.66. The product was found to have C, 54.67; H, 3.31; N, 8.20.
2,3-BIS(AZIRIDINYL)-5-[O-(2,4-DINITROBENZENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 12
R.sub.1 =R.sub.2 =NO.sub.2 ; R.sub.3 =H
Physical properties:
mp 164.degree.-166.degree. C. dec; R.sub.f 0.26 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.30 (s, 4H, 2-aziridinyl), 2.39 (s, 4H, 3-aziridinyl), 7.53 (d, 1H, 6-H), 7.69 (t, 1H, 7-H), 8.10 (d, 1H, 8-H), 8.59 (d, 1H, 6'-H), 8.63 (d, 1H, 5'-H), 8.72 (s, 1H, 3'-H). The product C.sub.20 H.sub.14 N.sub.4 O.sub.9 S.0.5 EtOAC should have C, 49.80; H, 3.42; N, 10.56. The product was found to have C, 50.20; H, 2.66; N, 10.24.
Synthesis and physical properties of Compounds: ##STR25## wherein R is: ##STR26##
2,3-BIS(AZIRIDINYL)-5-[O-NAPHTHALENE-1-SULFONYL)]-1,4-NAPHTHOQUINONE
Compound 13
R.sub.4 =H; R.sub.5 =CH
Physical properties:
mp 118.degree.-120.degree. C.; R.sub.f 0.25 (EtOAc-C.sub.6 H.sub.14 -CH.sub.2 Cl.sub.2, 3:4:5, v/v); NMR (CDCl.sub.3) .delta.2.35 (s, 4H, 2-aziridinyl), 2.38 (s, 4H, 3-aziridinyl), 6.74 (d, 1H, 5'-H), 7.34 (m, 1H, 6'-H), 7.54 (m, 1H, 7'-H), 7.67 (m, 1H, 7-H), 7.78 (m, 1H, 3'-H), 7.95 (d, 1H, 6-H), 8.01 (d, 1H, 8-H), 8.13 (d, 1H, 4'-H), 8.18 (d, 1H, 8'-H), 8.90 (d, 1H, 1'-H). The product C.sub.24 H.sub.18 N.sub.2 O.sub.5 S should have C, 64.56; H, 4.06; N, 6.28. The product was found to have C, 64.27; H, 4.07; N, 5.96.
2,3 BIS(AZIRIDINYL)-5-[O-8-QUINOLELESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 14
R.sub.4 =H; R.sub.5 =N
Physical properties:
mp 161.degree.-163.degree. C.; R.sub.f 0.30 (EtOAc); NMR (CDCl.sub.3) .delta.2.22 (s, 4H, 2-aziridinyl), 2.36 (s, 4H, 3-aziridinyl), 7.29 (d, 1H, 6-H), 7.51 (m, 1H, 3'-H), 7.57 (m, 1H, 6'-H), 7.70 (m, 1H, 7-H), 8.01 (d, 1H, 8-H), 8.19 (d, 1H, 4'-H), 8.31 (d, 1H, 5'-H), 8.55 (d, 1H, 2'-H), 9.05 (d, 1H, 7'-H). The product C.sub.23 H.sub.17 N.sub.3 O.sub.5 S should have C, 61.73; H, 3.83; N, 9.39. The product was found to have C, 61.51; H, 3.74; N, 8.96.
2,3-BIS(AZIRIDINYL)-5-[O-(5'-DIMETHYLAMINO-1'-NAPHTHALENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 15
R.sub.4 =N(CH.sub.3).sub.2 ; R.sub.5 =CH
Physical properties:
mp 79.degree.-81.degree. C. dec; R.sub.f 0.29 (EtOAc-C.sub.6 H.sub.14 ; 7:3 v/v); NMR (CDCl.sub.3) .delta.2.38 (two s, 8H, 2- and 3-aziridinyl), 2.92 [s, 6H, 5'-N(CH.sub.3).sub.2 ], 6.71 (d, 1H, 6'-H). 7.26 (d, 1H, 6-H), 7.35 (dd, 1H, 7'-H), 7.51 (dd, 1H, 7-H), 7.66 (dd, 1H, 3'-H), 7.95 (d, 1H, 8'-H), 8.10 (d, 1H, 8-H), 8.54 (d, 1H, 4'-H), 8.65 (d, 1H, 2'-H). The product C.sub.26 H.sub.23 N.sub.3 O.sub.5 S.0.5 EtOAc should have C, 63.06; H, 5.10; N, 7.88. The product was found to have C, 62.64; H, 5.36; N, 8.64.
Synthesis and physical properties of Compounds of the formula: ##STR27## wherein R is: alkyl
2,3-BIS(AZIRIDINYL)-5-(O-METHANESULFONYL)-1,4-NAPHTHOQUINONE
Compound 16 R=CH.sub.3
mp 171.degree.-173.degree. C.; R.sub.f 0.53 (EtOAc-CH.sub.2 Cl.sub.2, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.42 (d, 8H, 2- and 3-aziridinyl), 3.45 (s, 3H, --SO.sub.3 CH.sub.3), 7.59 (c, 1H, 6-H), 7.66 (m, 1H, 7-H), 8.06 (d, 1H, 8-H). The product C.sub.15 H.sub.14 N.sub.2 O.sub.5 S should have C, 53.88; H, 4.22; N, 8.38. The product was found to have C, 53.59; H, 4.30; N, 8.27.
2,3-BIS(AZIRIDINYL)-5-O-(BUTANESULFONYL)-1,4-NAPHTHOQUINONE
Compound 17
R=CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3
Physical properties:
Isolated as a glass, NMR (CDCl.sub.3) .delta.1.02 (t, 3H, 4'-CH.sub.3), 1.59 (m, 2H, 3'-CH.sub.3), 2.05 (m, 2H, 2'-CH.sub.2), 2.38-2.39 (two s, 8H, 2- and 3-aziridinyl), 3.59 (m, 2H, 1'-CH.sub.2), 7.57 (d, 1H, 6-H), 7.62 (m, 1H, 7-H), 8.02 (d, 1H, 8-H). The product C.sub.18 H.sub.20 N.sub.2 O.sub.5 S.0.5 EtOAc should have C, 57.13; H, 5.75; N, 6.66. The product was found to have C, 57.26; H, 5.43; N, 6.22.
2,3-BIS(AZIRIDINYL)-5-[O-(1'-HEXADECANESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 18
R=CH.sub.2 (CH.sub.2).sub.14 CH.sub.3
Physical properties:
mp 71.degree.-73.degree. C.; R.sub.f 0.49 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.0.89 (t, 3H, 16'-CH.sub.3), 1.27-1.30 (m, 22H, 5'- to 15'-CH.sub.2), 1.40 (m, 2H, 4'-CH.sub.2), 1.54 (m, 2H, 3'-CH.sub.2), 2.07 (m, 2H, 2'-CH.sub.2), 2.40 (s, 4H, 2-aziridinyl), 2.41 (s, 4H, 3-aziridinyl), 3.60 (t, 2H, 1'-CH.sub.2), 7.60 (d, 1H, 6-H), 7.64 (t, 1H, 7-H), 8.04 (d, 1H, 8-H). The product C.sub.30 H.sub.44 N.sub.2 O.sub.5 S should have C, 66.61; H, 8.14; N, 5.14. The product was found to have C, 66.76; H, 8.38; N, 5.00.
2,3-BIS(AZIRIDINYL)-5-[O-(3-CHLOROPROPANESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 19
R=CH.sub.2 CH.sub.2 CH.sub.2 Cl
mp 115.degree.-117.degree. C.; R.sub.f 0.22 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.41 (s, 8H, 2- and 3-aziridinyl), 2.61 (m, 2H, 2'-CH.sub.2), 3.81 (m, 4H, 1'- and 3'-CH.sub.2), 7.60 (d, 1H, 6-H), 7.65 (t, 1H, 7-H), 8.06 (d, 1H, 8-H). The product C.sub.17 H.sub.17 ClN.sub.2 O.sub.5 S.0.5 EtOAc should have been C, 51.76; H, 4.80; N, 6.36. The product was found to have C, 52.41; H, 4.58; N, 6.82.
2,3-BIS(AZIRIDINYL)-5-[O-(BETA-STYRENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 20
R=CH.dbd.CH--C.sub.6 H.sub.5
mp 171.degree.-173.degree. C. dec; R.sub.f 0.24 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.37 (two s, 8H, 2- and 3-aziridinyl), 7.21 (d, 1H, styrene-H.sub.alpha), 7.43-7.47 (m, 3H, 6-, 3'- and 5'-H), 7.25-7.56 (m, 3H, 2'-, 6'- and styrene-H.sub.beta), 7.62-7.65 (m, 3H, 4'- and 7-H), 8.03 (q, 1H, 8-H). The product C.sub.22 H.sub.18 N.sub.2 O.sub.5 S.0.5CH.sub.2 Cl.sub.2 : C, 58.12; H, 4.12; N, 6.03. The product was found to have C, 57.76; H, 4.48; N, 5.71.
2,3-BIS(AZIRIDINYL)-5-[O-(alpha-TOLUENESULFONYL)]-1,4-NAPHTHOQUINONE
Compound 21
R=CH.sub.2 C.sub.6 H.sub.5
isolated as a glass; R.sub.f 0.24 (EtOAc-C.sub.6 H.sub.14, 1:1, v/v); NMR (CDCl.sub.3) .delta.2.42 (s, 4H, 2-aziridinyl), 2.45 (s, 4H, 3-aziridinyl), 4.91 (s, 2H, alpha-CH.sub.2), 7.43 (m, 3H, 3'-, 4'- and 5'-H), 7.51 (d, 1H, 6-H), 7.60 (m, 2H, 2'- and 6'-H), 7.61 (t, 1H, 7-H), 8.02 (d, 1H, 8-H). The product C.sub.21 H.sub.18 N.sub.2 O.sub.5 S should have C, 61.45; H, 4.42; N, 6.83. The product was found to have C, 61.17; H, 4.30; N, 6.53.
2,3-BIS(AZIRIDINYL)-5-[O-(d-10-CAMPHORSULFONYL)]-1,4-NAPHTHOQUINONE
Compound 22 ##STR28##
mp 121.degree.-123.degree. C.; R.sub.f 0.33 (EtOAc-C.sub.6 H.sub.14 ; 1:1, v/v); NMR (CDCl.sub.3) .delta.1.00 (s, 3H, 9'-CH.sub.3), 1.21 (s, 3H, 8'-CH.sub.3), 1.47 (m, 1H, 4'-H, a or e), 1.77 (m, 1H, 4'-H, a or e), 1.97 (m, 1H, 5'-H, a or e), 2.11 (m, 1H, 2'-H, a or e), 2.16 (m, 1H, 3'-H), 2.41 (s, 8H, 2- and 3-aziridinyl), 2.47 (m, 1H, 5'-H, a or e), 2.55 (m, 1H, 2'-H, a or e), 3.78 (d, 1H, 10'-H.sub.A or H.sub.B), 4.05 (d, 1H, 10'-H.sub.A or H.sub.B), 7.60 (d, 1H, 6-H), 7.65 (m, 1H, 7-H), 8.04 (d, 1H, 8-H). The product C.sub.24 H.sub.24 N.sub.2 O.sub.6 S should have C, 61.52; H, 5.16; N, 5.98. The product was found to have C, 61.80; H, 5.42; N, 5.89.
SUMMARY TABLE I__________________________________________________________________________Compound Formula Melting Point (.degree.C.) Analysis__________________________________________________________________________ ##STR29## 170-172 C.sub.12 H.sub.9 NO.sub.32 ##STR30## 181-183 C.sub.14 H.sub.12 N.sub.2 O.sub.33 ##STR31## 152-154 C.sub.19 H.sub.15 NO.sub.5__________________________________________________________________________ S.EtOAc ##STR32##Compound R.sub.1 R.sub.2 R.sub.3 Melting Point (.degree.C.) Analysis__________________________________________________________________________4 H H H 54-156 C.sub.20 H.sub.16 N.sub.2 O.sub.5.O.25 CH.sub.2 Cl.sub.25 CH.sub.3 H H 157-159 C.sub.21 H.sub.18 N.sub.2 O.sub.5 S.O.5 EtOAc6 OCH.sub.3 H H 143-145 C.sub.21 H.sub.18 N.sub.2 O.sub.6 S7 C(CH.sub.3).sub.3 H H 139-141 C.sub.24 H.sub.24 N.sub.2 O.sub.5 S8 CH.sub.3 CH.sub.3 CH.sub.3 125-127 C.sub.23 H.sub.22 N.sub.2 O.sub.5 S9 CH(CH.sub.3).sub.2 CH(CH.sub.3).sub.2 CH(CH.sub.3).sub.2 74-76 C.sub.29 H.sub.34 N.sub.2 O.sub.5 S.EtOAc10 Cl H H 159-161 C.sub.20 H.sub.15 ClN.sub.2 O.sub.5 S11 NO.sub.2 H H 150-151 C.sub.20 H.sub.15 N.sub.3 O.sub.7 S.O.5 EtOAc12 NO.sub.2 NO.sub.2 H 164-166 C.sub. 20 H.sub.14 N.sub.4 O.sub.9 S.O.5 EtOAc__________________________________________________________________________ ##STR33##Compound R.sub.4 R.sub.5 Melting Point (.degree.C.) Analysis__________________________________________________________________________13 H CH 118-120 C.sub.24 H.sub.18 N.sub.2 O.sub.5 S14 H N 161-163 C.sub.23 H.sub.17 N.sub.3 O.sub.5 S15 N(CH.sub.3).sub.2 CH 79-81 C.sub.26 H.sub.23 N.sub.3 O.sub.5 S.O.5 EtOAc__________________________________________________________________________ ##STR34##Compound R Melting Point (.degree.C.) Analysis__________________________________________________________________________16 CH.sub.3 171-173 C.sub.15 H.sub.14 N.sub.2 O.sub.5 S17 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3 glass C.sub.18 H.sub.20 N.sub.2 O.sub.5 S.O.5 EtOAc18 CH.sub.2 (CH.sub.2).sub.14 CH.sub.3 71-73 C.sub.30 H.sub.44 N.sub.2 O.sub.5 S19 CH.sub.2 CH.sub.2 CH.sub.2 Cl 115-117 C.sub.17 H.sub.17 ClN.sub.2 O.sub.5 S.O.5 EtOAc20 CHCHC.sub.6 H.sub.5 171-173 C.sub.22 H.sub.18 N.sub.2 O.sub.5 S.O.5 CH.sub.2 Cl.sub.221 CH.sub.2 C.sub.6 H.sub.5 171-173 C.sub.21 H.sub.18 N.sub.2 O.sub.5 S22 camphoryl 121-123 C.sub.24 H.sub.24 N.sub.2 O.sub.6 S__________________________________________________________________________
BIOLOGICAL ACTIVITY OF COMPOUNDS
Transplantation of L1210 ascites cells was carried out by withdrawing peritoneal fluid from donor CDF.sub.1 female mice bearing 7-day growths. The suspension was centrifuged for 2 minutes (1600 g), the supernatant peritoneal fluid was decanted, and a 10-fold dilution with isotonic saline was made. The cell number was determined with a Coulter particle counter and the cell population was adjusted to 10.sup.6 cells/mL. One-tenth mL of the resulting cell suspension (containing approximately 10.sup.5 cells) was injected intraperitoneally into each animal. The drug was administered by intraperitoneal injection beginning 24 hours after tumor implantation, once daily for 6 consecutive days. Test compounds were injected intraperitoneally as suspensions in isotonic saline in a volume of 0.25 mL. For any one experiment, animals were distributed into groups of five mice of comparable weight and maintained throughout the course of the experiment on Laboratory Chow pellets and water ad libitum. Controls given injections of a comparable volume of vehicle (saline) were included in each experiment. Mice were weighed during the course of the experiments, and the percentage change in body weight from onset to termination of therapy was used as an indication of drug toxicity. The results of these experiments are summarized in Table II.
TABLE II______________________________________THE EFFECTS OF 2,3-BIS(AZIRIDINYL)-1,4-NAPH-THOQUINONE SULFONATE DERIVATIVES ON THESURVIVAL TIME OF MICE BEARINGTHE L1210 LUEKEMIA Daily dosage.sup.a Avg. Change inCompound (mg/kg) body wt. (%) T/C .times. 100.sup.b______________________________________1 5 +12.7 94 (0/5) 10 +5.1 90 (0/5) 15 +2.1 94 (0/5)2 5 +6.3 114 (0/5) 10 -3.2 96 (0/5) 15 -0.8 104 (0/5)3 20 +7.3 102 (0/5) 25 +5.1 103 (0/5) 30 +1.2 111 (0/5)4 20 -6.2 -- (5/5) 25 -8.3 -- (5/5) 30 -7.0 359 (4/5)5 20 -2.2 155 (7/10) 25 -3.5 490 (9/10) 30 -7.4 248 (7/10)6 20 -0.1 175 (1/5) 25 -2.4 222 (3/4) 30 -1.3 193 (2/5)7 20 +12.0 104 (0/5) 25 +11.8 98 (0/5) 30 +6.7 98 (0/5)8 20 -0.4 113 (0/5) 25 -2.5 113 (0/5) 30 -2.6 124 (0/5)10 20 + 4.2 161 (0/5) 25 +1.7 200 (0/5) 30 -2.7 167 (3/5)11 20 -11.1 402 (4/5) 25 -12.9 293 (3/5) 30 -13.1 152 (4/5)15 20 +2.2 110 (0/5) 25 +3.8 115 (0/5) 30 +3.9 117 (0/5)16 5 +3.3 130 (0/5) 10 -7.1 185 (4/5) 15 -10.5 295 (2/5)______________________________________ .sup.a Drugs were administered by intraperitoneal injection, beginning 24 hr after tumor implantation, once daily for 6 oonsecutive days. .sup.b T/C .times. 100 represents the ratio of the survival time of treated animals that died to control animals .times. 100. The average survival time of the untreated tumorbearing control animals was 9.2 .+-. 0.4 days. The values in parentheses represent the number of mice that survived for greater than 50 days relative to the number of mice treated.
TABLE III______________________________________THE EFFECTS OF 2,3-BIS(AZIRIDINYL)-1,4-NAPH-THOQUINONE SULFONATE DERIVATIVES ON THESURVIVAL TIME OF MICE BEARINGTHE B16 MELANOMA Daily dosage.sup.a Avg. Change inCompound (mg/kg) body wt. (%) T/C .times. 100.sup.b______________________________________4 50 -1.3 156 100 -12.3 180 150 -13.5 1485 50 +4.5 144 100 -1.9 153 150 -9.8 141______________________________________ .sup.a Drugs were administered by intraperitoneal injection, beginning 24 hr after tumor implantation, once daily for 6 consecutive days. .sup.b T/C .times. 100 represents the ratio of the survival time of treated to control animals .times. 100. The average survival time of the untreated tumorbearing control animals was 13.2 .+-. 1.2 days.
DISCUSSION OF EXAMPLES
The tumor-inhibitory properties of compounds 1-8, 10, 11, 15 and 16 were determined by measuring their effects on the survival time of mice bearing the L1210 leukemia. The results of tests conducted are summarized in Table II. Compounds 1-3 are not included within the claimed compounds which are active and, as indicated therein, did not display any substantial activity against the L1210 leukemia.
The inactivity of Compound 3 compared to the activity of Compound 5, indicates the criticality of the 2,3-bisaziridinyl substituents for providing antineoplastic activity.
Compounds 4 and 5 were also evaluated for anticancer activity against mice bearing the B16 melanoma. The results of these tests are summarized in Table III. Both of these compounds were found to be active against this tumor.
Although the invention has been specifically described with reference to particular embodiments, it is to be understood that the invention is not limited to the particulars disclosed and extends to all equivalents within the scope of the claims.
Claims
  • 1. A compound of the formula: ##STR35## wherein R is selected from the group consisting of: (a) a substituent of the formula: ##STR36## wherein R.sub.1, R.sub.2 and R.sub.3 are each independently selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 4 carbon atoms, halogen and --NO.sub.2,
  • (b) a substituent of the formula: ##STR37## wherein R is hydrogen or an N(R').sub.2 substituent, wherein R' is an alkyl of 1 to 4 carbon atoms, and R.sub.5 is CH or N,
  • (c) alkyl of 1 to 18 carbon atoms,
  • (d) halo substituent alkyl of 1 to 6 carbon atoms,
  • (e) styrenyl,
  • (f) toluenyl, or
  • (g) camphoryl.
  • 2. The compound of claim 1, wherein R is substituent (a) and R.sub.1, R.sub.2, and R.sub.3 are hydrogen.
  • 3. The compound of claim 1, wherein R is substituent (a) and R.sub.1 is alkyl of 1 to 6 carbon atoms and R.sub.2 and R.sub.3 are hydrogen.
  • 4. The compound of claim 3, wherein R.sub.1 is methyl.
  • 5. The compound of claim 3, wherein R.sub.1 is tert-butyl.
  • 6. The compound of claim 1, wherein R is substituent (a) and R.sub.1 is alkoxy of 1 to 4 carbon atoms and R.sub.2 and R.sub.3 are hydrogen.
  • 7. The compound of claim 6, wherein R.sub.1 is methoxy.
  • 8. The compound of claim 1, wherein R is substituent (a) and R.sub.1, R.sub.2 and R.sub.3 are alkyl of 1 to 6 carbon atoms.
  • 9. The compound of claim 8, wherein R.sub.1, R.sub.2 and R.sub.3 are methyl.
  • 10. The compound of claim 8, wherein R.sub.1, R.sub.2 and R.sub.3 are isopropyl.
  • 11. The compound of claim 1, wherein R is substituent (a) and R.sub.2 and R.sub.3 are hydrogen.
  • 12. The compound of claim 11, wherein R.sub.1 is NO.sub.2.
  • 13. The compound of claim 11, wherein R.sub.1 is chlorine.
  • 14. The compound of claim 1, wherein R is substituent (a) and R.sub.1 and R.sub.2 are --NO.sub.2 and R.sub.3 is hydrogen.
  • 15. The compound of claim 1, wherein R is substituent (b) and R.sub.4 is hydrogen and R.sub.5 is CH or N.
  • 16. The compound of claim 1, wherein R is substituent (b) and R.sub.4 is dimethylamino and R.sub.5 is CH.
  • 17. The compound of claim 1, wherein R is a methyl substituent.
  • 18. The compound of claim 1, wherein R is a butyl substituent.
  • 19. The compound of claim 1, wherein R a hexadecyl substituent.
  • 20. The compound of claim 1, wherein R is a 3-chloropropyl substituent.
  • 21. The compound of claim 1, wherein R is a styrenyl substituent.
  • 22. The compound of claim 1, wherein R is a toluenyl substituent.
  • 23. The compound of claim 1, wherein R is a camphoryl substituent.
  • 24. An antineoplastic composition comprising an antineoplastically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.
  • 25. A method of inhibiting the growth of L1210 leukemia and B16 melanoma tumors in host organisms which comprises administering to said host organism a tumor inhibitory amount of the compound of claim 1.
  • 26. A compound of the formula: ##STR38##
Government Interests

This research was supported in part by a grant (No. CH-211) from the American Cancer Society.

US Referenced Citations (1)
Number Name Date Kind
4233215 Driscoll et al. Nov 1980
Foreign Referenced Citations (1)
Number Date Country
1809762 Nov 1958 DEX
Non-Patent Literature Citations (1)
Entry
Wurm et al., Chem. Abstracts, vol. 101 (1984), entry 130363k.