Anti-neoplastic, anti-viral or anti-retroviral spermine derivatives

Abstract: The present invention provides a compound having one of the formulae: Wherein: R₁ and R₆ may be the same or different and are H, alkyl or aralkyl having from 1 to 12 carbon atoms, provided that R₁ and R₆ are not H; R₇ is H, alkyl, aryl or aralkyl having from 1 to 12 carbon atoms; m is an integer from 3 to 6, inclusive; and n is an integer from 3 to 6, inclusive, or (IV), a salt thereof especially for anti-neoplastic, anti-psoriasis, anti-viral or anti-retroviral therapy or for controlling the growth of insects.

Description: BACKGROUND OF THE INVENTION This invention was made with U.S. Government support under Grant NCDDG-CA37606, awarded by the National Cancer Institute. The U.S. Government has certain rights in this invention. Field of the Invention The present invention relates to anti-neoplastic and anti-psoriasis pharmaceutical compositions and to insecticidal compositions and methods of controlling the growth of insects. In recent years a great deal of attention has been focused on the polyamines, e.g., spermidine, norspermidine, homospermidine, 1,4-diaminobutane (putrescine), and spermine. These studies have been directed largely at the biological properties of the polyamines probably because of the role they play in proliferative processes. It was shown early on that the polyamine levels in dividing cells,e.g., cancer cells, are much higher than in resting cells. See Janne et al, A. Biochim. Biophys. Acta. 473, 241 (1978); Fillingame et al, Proc. Natl. Acad. Sci. U.S.A. 72:4042 (1975); Metcalf et al, J. Am. Chem. Soc. 100:2551 (1978); Flink et al, Nature (London) 253:62 (1975); and Pegg et al, Polyamine Metabolism and Function, Am. J. Cell. Physiol. 243:212-221 (1982). Several lines of evidence indicate that polyamines, particularly spermidine, are required for cell proliferation: (i) they are found in greater amounts in growing than in non-growing tissues; (ii) prokaryotic and eukaryotic mutants deficient in polyamine biosynthesis are auxotrophic for polyamines; and (iii) inhibitors specific for polyamine biosynthesis also inhibit cell growth. Despite this evidence, the precise biological role of polyamines in cell proliferation is uncertain. It has been suggested that polyamines, by virtue of their charged nature under physiological conditions and their conformational flexibility, might serve to stabilize macromolecules such as nucleic acids by anion neutralization. See Dkystra et al, Science, 149:48 (1965); Russell et al, Polyamines as Biochemical Markers of Normal and Malignant Growth (Raven, New York, 1978); Hirschfield et al, J. Bacteriol., 101:725 (1970); Morris et al, ibid, p. 731; Whitney et al, ibid, 134:214 (1978); Hafner et al, J. Biol. Chem., 254:12419 (1979); Cohn et al, J. Bacteriol. 134:208 (1978); Pohjatipelto et al, Nature (London), 293:475 (1981); Mamont et al, Biochem. Biophys. Res. Commun. 81:58 (1978); Bloomfield et al, Polyamines in Biology and Medicine (D.R. Morris and L.J.. Morton, Eds. - Dekker, New York, 1981) pp. 183-205; Gosule et al, Nature, 259:333 (1976); Gabbay et al, Ann. N.Y. Acad. Sci., 171:810 (1970); Suwalsky et al, J. Mol. Biol., 42:363 (1969) and Liquori et al., J. Mol. Biol., 24:113 (1968). However, regardless of the reason for increased polyamine levels the phenomenon can be and has been exploited in chemotherapy. See Sjoerdsma et al, Butterworths Int. Med. Rev.: Clin. Pharmacol. Ther. 35:287 (1984); Israel et al, J. Med. Chem., 16:1 (1973); Morris et al, Polyamines in Biology and Medicine; Dekker, New York, p. 223 (1981) and Wang et al, Biochem. Biophys. Res. Commun., 94:85 (1980). J Med. Chem. 1988, 31, 1183-1190 (Bergeran et al) discloses the synthesis and biological activity of N-alkylated spermine compounds, especially diethylspermine and dimethylspermine. Advances in Experimental Medicine and Biology, vo. 250, 717 to 726 (Bitonti et al) discloses the growth inhibition of malaria bacteria by polyamine analogs, particularly spermine and analogues thereof having more than 4 carbon atoms in the central alkylene group. EP-0311068 discloses a polyamine for treating neoplastic disease states, the polyamine having a central alkylene group with 6 to 9 carbon atoms. It is an object of the present invention to provide novel anti-neoplastic, - viral, and -retroviral compounds, pharmaceutical compositions and methods of treatment. SUMMARY OF THE INVENTION The foregoing and other objects are realized by the present invention, as defined in the accompanying claims. According to one embodiment, the invention provides a pharmaceutical composition comprising: an anti-neoplastic, an anti-viral, an anti-psoriasis or an anti-retroviral effective amount of a compound of the formula: wherein: R 1 and R 6 may be the same or different and are alkyl or aralkyl having from 1 to 12 carbon atoms; R 2 - R 5 may be the same or different and are H, R 1 or R 6 ; m and n are 3, or m and n are 4; or a salt thereof with a pharmaceutically acceptable acid and a pharmaceutically acceptable carrier therefor. DETAILED DESCRIPTION OF THE INVENTION In compounds of the invention, R 1 and R 6 are preferably methyl, ethyl, propyl, benzyl, etc., it being understood that the term "aralkyl" is intended to embrace any aromatic group the chemical and physical properties of which do not adversely affect the efficacy and safety of the compound for therapeutic applications. Preferred, however, are the hydrocarbyl aralkyl groups, i.e., comprised only of C and H atoms. R 2 -R 5 preferably are H, methyl, ethyl, propyl or benzyl. Compounds of formula (I) are preferably synthesized by first forming a sulfonamide of the polyamine at all of the amino nitrogens (1) to activate the primary amines for monoalkylation, and (2) to protect any secondary nitrogens from alkylation. Suitable sulfonating agents include alkyl, aryl and arylalkyl sulfonating agents of the general structure RSO 2 X wherein R is alkyl, aryl or arylalkyl and X is a leaving group, e.g., Cl - , Br - , etc. The sulfonation is accomplished by reacting the polyamine with 1.0 equivalent of sulfonating agent per nitrogen in the presence of a base, e..g., tertiary amine or a hydroxide. The reaction is best accomplished using aqueous sodium hydroxide as the base and p -toluenesulfonyl chloride (TsCl) as the sulfonating agent in a biphasic solvent system consisting of an organic solvent, e.g., methylene chloride and water. The sulfonating agent is added in methylene chloride to an aqueous solution of the amine and sodium hydroxide and the reaction proceeds according to the following equation, using spermine as the base compound: Wherein: Ts = p -toluenesulfonyl. After purification the sulfonamide is next alkylated. The alkylations involve formation of N-anions on the primary amino sulfonamides with a base such as NaH followed by reaction of the N-anion with an alkylating agent RX wherein R is as defined above and X is a leaving group such as I - , CI - , Br - , p -CH 3 C 6 H 4 SO 3 - , CH 3 SO 3 - . The alkylation can be carried out in a variety of dipolar aprotic solvents, preferably, N, N-dimethylformamide (DMF). The reaction proceeds according to the following equation: After alkylation of the sulfonamide, the sulfonyl protecting groups are next removed under reducing conditions. Although a variety of standard reducing conditions can be utilized (LiAlH 4 , Li/NH 3 , catalytic reduction), Na and NH 3 function optimally. The reduction proceeds according to the following equation: The compounds are isolated as the free amines and then may be converted to and utilized as the corresponding hydrochloride salts by treatment with concentrated HCl. However, they may also be used as salts with any pharmaceutically acceptable acid, e.g., HBr, CH 3 CO 2 H, CH 3 SO 3 H, etc. The alkylating agent is formed by treatment of N-alkyl- p -toluenesulfonamide with excess 1,3 dichloropropane under the aforementioned conditions according to the following scheme: After purification of the dialkylated hexatosylated hexaamine, the sulfonyl protecting groups are removed reductively with sodium in liquid ammonia and THF as follows: The final product is isolated as the free amine and may be converted to the hydrochloride salt. Compounds of formula (III) may be prepared by reacting a tetraamine of formula (I) in which R 2 -R 5 =H and R 1 ,R 6 =alkyl or aralkyl with two equivalents of an aldehyde R 7 CHO, wherein R 7 =H, alkyl or aralkyl. Specifically, to N 1 ,N 4 -diethylspermine tetrahydrochloride is added aqueous NaOH and formalin (two equivalents) to generate the bis-hexahydropyrimidine as follows: The invention is illustrated by the following non-limiting examples. EXAMPLE 1 Preparation of N 1 ,N 4 -diethylspermine (N 1 ,N 4 - diethylspermine is not in accordance with the claims) N 1 ,N 2 ,N 3 ,N 4 -Tetra-p-tosylspermine. To spermine tetrahydrochloride (4.53 g, 13.0 mmol) and 10% aqueous NaOH (200 mL, 132 mmol) at 0° is added dropwise p -toluenesulfonyl chloride (9.98 g, 52.3 mmol) in CH 2 Cl 2 with rapid stirring. After 1 hr the mixture is allowed to warm to room temperature and to stir for 2 days. The organic phase is separated and washed with 0.5 N HCl, H 2 O, and brine, dried over Na 2 SO 4 and purified on silica gel (450 g, 3% MeOH/CHCl 3 ) to give 9.69 g, 91% yield of tetratosylspermine. NMR (CDCl 3 ) δ 7.2-7.9 (m, 16H), 5.34 (t, 2H, J=7), 2.9-3.3 (m, 12H), 2.43 (s, 12H), 1.5-2.0 (m, 8H). N 1 ,N 4 -Diethyl-N 1 ,N 2 ,N 3 ,N 4 -Tetra-p-tosylspermine. To the tetratosylspermine prepared above (1.75 g, 2.14 mmol) in dry DMF (12 mL) was cautiously added 80% sodium hydride (0.25 g, 8.33 mmol) and then ethyl iodide (1.0 mL, 12.5 mmol). After heating under nitrogen (10 h, 55°), the mixture was quenched with ice water and extracted with chloroform (3 x). The organic phase was washed with 5% Na 2 SO 3 , 5% NaOH, 1 N HCl, and water, then dried with Na 2 SO 4 . Removal of DMF by flash distillation and purification of the crude product on silica gel (4% EtOH/CHCl 3 ) produced 1.63 g (87%) of the desired product. NMR (CDCl 3 ) δ 7.2-7.8 (m, 16H), 3.03-3.3 (m, 16H), 2.43 (s, 12H),1.5-2.1 (m, 8H), 1.08 (t, 6H, J=7). Anal. Calcd. for C 24 H 58 N 4 O 8 S 4 ; C, 57.64; H, 6.68; N, 6.40. Found: C, 57.69; H, 6.74; N, 6.20. N 1 ,N 4 -diethylspermine (DES). Into a solution of the N 1 ,N 4 -diethyl-N 1 ,N 2 ,N 3 ,N 4 -tetratosylspermine prepared above (2.78 g, 3.18 mmoles) in dry, distilled THF (200 mL) at -78°C was condensed 300 mL NH 3 , using a dry ice condenser. Sodium spheres (3.0 g, 0.13 mol) were then added in small portions and the reaction mixture was stirred at -78°C for 4 h. The reaction mixture was allowed to warm to room temperature overnight and the NH 3 boiled off. Diethyl ether was added to the mixture. Ethanol was then cautiously added, then H 2 O was added to finally quench the reaction. The solvents were evaporated and the product extracted with diethyl ether and then chloroform. The extracts were dried over Na 2 SO 4 , filtered and the extracts concentrated. The resultant liquid was distilled in a Kugelrohr apparatus (150°C, 0.1 mm). Concentrated hydrochloric acid was added to an ether/ethanol (1:1) solution of the distillate to form the hydrochloride salt, which was recrystallized from hot aqueous ethanol to give 790 mg (63%) DES. NMR (D 2 O) δ 1.4 (t, 6H); 1.9 (m, 4H); 2.25 (m, 4H); 3.25 (m, 16H); 4.80 (s, HOD, reference). The following protocols were followed to determine the IC 50 values for DES against cultured L1210 cells, Daudi cells and HL-60 cells. Cell Culture. Murine L1210 leukemia cells, human Burkitt lymphoma cells (Daudi) and human promyelocytic leukemia cells (HL-60) were maintained in logarithmic growth as suspension cultures in RPMI-1640 medium containing 2% 4-(1-hydroxyethyl)-1-piperazineethanesulfonic acid/3-(N-morpholino)propanesulfonic acid, 100 µM aminoguanidine, and 10% fetal bovine serum. Cells were grown in 25 sq cm tissue culture flasks in a total volume of 10 mL under a humidified 5% CO 2 atmosphere at 37°C. The cells were treated while in logarithmic growth (L1210 cells 0.3x10 5 cells/mL; Daudi and HL-60 1x10 5 cells/mL) with the polyamine derivatives diluted in sterile water and filtered through a 0.2 micron filter immediately prior to use. Following a 48 h incubation with L1210 cells and a 72 h incubation with Daudi or HL-60 cells, L1210 cells were reseeded at 0.3x10 5 cells/mL, Daudi and HL-60 cells were reseeded at 1x10 5 cells/mL and all cells were incubated in the presence of the polyamine derivative for an additional 48 h or 72 h. Cell samples at the indicated time periods were removed for counting. Cell number was determined by electronic particle counting and confirmed periodically with hemocytometer measurements. Cell viability was assessed by trypan blue dye exclusion. The percentage of control growth was determined as follows: % of control growth = Final treated cell no. - initial inoculum Final untreated cell no. - initial inoculum x 100 The IC 50 is defined as the concentration of compound necessary to reduce cell growth to 50% of control growth. The results are set forth in Tables 1 and 2. L1210 Cells 48 H 96 H IC 50 IC 50 DES 10 µM 0.10 µM Daudi Cells HL-60 Cells 72 H 144 H 72 H 144 H IC 50 IC 50 IC 50 IC 50 DES > 40 µM 0.5 µM 10 µM 0.3 µM Animal Studies. The murine L1210 leukemia cells were maintained in DBA/2J mice. L1210 cells, from a single mouse which was injected i.p. with 10 6 cells 5 days earlier, were harvested and diluted with cold saline so that there were 10 5 or 10 6 cells in 0.25 cc. For each study, mice were injected i.p. with 10 6 L1210 cells or 10 5 L1210 cells (See Table 3) on day O. The polyamine analogues were diluted in sterile saline within 24 h of use and the unused portion stored at 5°C. DES was administered by i.p. injection 15 mg/kg or 20 mg/kg every 8 h for 3 days (days 1-3), 4 days (days 1-4), or 6 days (days 1-6) (see Table 3). Mice which were treated with saline injections served as controls. The parameter used for treatment evaluation was mean survival time. (Percent increased life span, % ILS). % ILS = mean survival time treated animals-mean survival time controls mean survival controls x 100 The murine Lewis lung carcinoma was maintained as s.c. tumor in C57B1/6 mice. The line was propagated every 14 days. A 2-4 mm fragment of s.c. donor tumor was implanted s.c. in the axillary region with a puncture in the inguinal region on day 0. DES was administered by i.p. injection 20 mg/kg every 8 h for 5 days beginning on day 5 (days 5-9). Equal numbers of mice treated with saline injections served as controls. The parameter used for treatment evaluation was mean survival time (% ILS). The parameters of the animal tests and results are set forth below in Tables 3 and 4. Evaluation of N 1 , N 4 -Di-ethylspermine (DES) in C57B1/6J Male Mice with Lewis Lung Carcinoma (s.c.) Drug Dose (mg/kg) Schedule Survival Values (Days) Mean ± S.D. % ILS DES 20 (i.p.) Every 8 h, days 5-9 43.7 ± 7.1 24 Control (Saline) - - 35.2 ± 2.6 0 EXAMPLE 2 The % ILS value for various dosages of N 1 ,N 4 -diethylhomospermine were determined according to the procedure of Example 1. The results are set forth in Table 6. L1210 i.p. Leukemia in DBA/2J female mice given 10 5 cells on day 0. No. Dosing Schedule # Animals Day of Death Mean Survival + S.D.(days) ILS (%) 1. 2.5 mg/kg q8hr days 1-6 (i.p.) 5 20.5, 32 23, 22, 60 31.5 + 16.6 242 Control 9.2 ± 0.3 2. 5 mg/kg q8hr days 1-6 (i.p.) 10 25, 9x60 56.5 ± 11.1 524 Control 9.1 ± 0.6 3. 10 mg/kg q12hr days 1-6 (i.p.) 6 31, 5x60 55.2 ± 11.8 441 Control 10.2 ± 1.1 4. 10 mg/kg once daily days (1-6 (i.p.) 5 12, 17, 24, 24, 27 20.8 ± 6.1 115 Control 9.3 ± 0.4 5. 15 mg/kg once daily days (i.p.) 5 21, 27, 3x60 45.6 ± 19.8 390 Control 9.3 ± 0.3 Unexpectedly, and for reasons as not yet understood, the compounds have been found to be effective anti-viral, and most surprisingly, anti-retroviral agents. The development of compounds useful for the prophylaxis and therapy of viral disease has presented more difficult problems than those encountered in the search for drugs effective in disorders produced by other microorganisms. This is primarily because, in contrast to most other infectious agents, viruses are obligate intracellular parasites that require the active participation of the metabolic processes of the invaded cell. Thus, agents that may inhibit or cause the death of viruses are also very likely to injure the host cells that harbor them. Although the search for substances that might be of use in the management of viral infections has been long and intensive, very few agents have been found to have clinical applicability. Indeed, even these have exhibited very narrow activity, limited to one or only a few specific viruses. The retroviruses have presented an even greater challenge due to their even more complex intracellular metabolic activity. The following examples illustrate the utilization of the compounds as anti-retrovirus agents. EXAMPLE 3 Embryonic chicken fibroblasts were grown to near confluence in cell culture media. The fibroblasts were next exposed to avian sarcoma virus for five hours. The cells were next washed with buffer to remove excess virus. The virus infected cells were then treated with 10 µM or 100 µM, N 1 ,N 4 -diethylspermine, (DES), in culture media for 18 hours. N 1 ,N 4 -diethylspermine is not in accordance with the accompanying claims. The cell culture media was next removed and the cells were overlaid with soft agar growth media. The cells were then allowed to grow at 37°C for 6-8 days. The culture plates were evaluated for foci (transformed cells) utilizing an inverted microscope. The results of these measurements are indicated below. NUMBER OF FOCI AT 6-DAYS 8-DAYS CONTROL (ASV+FIBROBLASTS) 300 300 ASV+FIBROBLASTS+10µM DES 20 300 ASV+FIBROBLASTS+100µM DES 0 110 In a second experiment the virus was first treated with DES at 10µM or 100µM for three hours and then added to the fibroblast monolayer for 18 hours at 37°C. The excess virus was then removed by washing and the monolayer overlaid with soft agar culture media. The plates were allowed to incubate at 37°C for 8 days and the plates were examined for foci. The results are indicated as follows. NUMBER OF FOCI AT 8 DAYS ASV+FIBROBLASTS (CONTROL) 300 ASV+FIBROBLASTS+10µM DES 200 ASV+FIBROBLASTS+100µM DES 16 Inasmuch as the compounds described herein are anti-proliferation agents, they are also useful as anti-psoriasis agents. The following example illustrates the transdermal penetration characteristics of the compounds. EXAMPLE 4 Hairless mice were sacrificed by cervical dislocation and their skin removed. The skin was denuded of fatty tissue and stretched over a drug diffusion cell. The diffusion cell contained a phosphate receptor phase at pH 7.4. The donor phase contained the drug DES dissolved in glycine buffer at pH 8.0 at a concentration of 10 mg/mL. DES is not in accordance with the present invention Samples of the receptor phase (3 mL) were taken at 48 hours. After each sample was withdrawn, an equal volume of fresh receptor phase was added back. The samples removed from the diffusion cell were assayed for polyamine utilizing a liquid chromatography-C-18 reverse system. The samples were first acidified with perchloric acid and then reacted with dansyl chloride to produce the corresponding dansylated polyamines. The experiment revealed that DES did indeed cross the skin at the dermal barrier. For each of the utilities mentioned herein, the amount required of active agent and the frequency of its administration will vary with the identity of the agent concerned and with the nature and severity of the condition being treated and is of course ultimately at the discretion of the physician or veterinarian. In general, however, a suitable dose of agent will lie in the range of 1 mg to 200 mg per kilogram mammal body weight being treated. Administration by the parenteral route (intravenously, intradermally, intraperitoneally, intramuscularly or subcutaneously is preferred for a period of time of from 1 to 20 days. While it is possible for the agents to be administered as the raw substances it is preferable, in view of their potency, to present them as a pharmaceutical formulation. The formulations, both veterinary and for human use, of the present invention comprise the agent, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. Desirably, the formulations should not include oxidizing agents and other substances with which the agents are known to be incompatible. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association the agent with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the agent with the carrier(s) and then, if necessary, dividing the product into unit dosages thereof. Formulations suitable for parenteral administration conveniently comprise sterile aqueous preparations of the agents which are preferably isotonic with the blood of the recipient. Suitable such carrier solutions include phosphate buffered saline, saline, water, lactated ringers or dextrose (5% in water). Such formulations may be conveniently prepared by admixing the agent with water to produce a solution or suspension which is filled into a sterile container and sealed against bacterial contamination. Preferably sterile materials are used under aseptic manufacturing conditions to avoid the need for terminal sterilization. Such formulations may optionally contain one or more additional ingredients among which may be mentioned preservatives, such as methyl hydroxybenzoate, chlorocresol, metacresol, phenol and benzalkonium chloride. Such materials are of especial value when the formulations are presented in multi-dose containers. Buffers may also be included to provide a suitable pH value for the formulation and suitable materials include sodium phosphate and acetate. Sodium chloride or glycerin may be used to render a formulation isotonic with the blood. If desired, the formulation may be filled into the containers under an inert atmosphere such as nitrogen or may contain an antioxidant, and are conveniently presented in unit dose or multidose form, for example, in a sealed ampoule. It will be appreciated that while the agents described herein form acid addition salts and carboxy acid salts the biological activity thereof will reside in the agent itself. These salts may be used in human and in veterinary medicine and presented as pharmaceutical formulations in the manner and in the amounts (calculated as the base) described hereinabove, and it is then preferable that the acid moiety be pharmacologically and pharmaceutically acceptable to the recipient. Examples of such suitable acids include (a) mineral acids: hydrochloric, hydrobromic, phosphoric, metaphosphoric, and sulphuric acids; (b) organic acids: tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycollic, gluconic, gulonic, succinic and aryl-sulphonic, for example, p-toluenesulphonic acids. Surprisingly, the compounds have also demonstrated insecticidal properties. The compounds have been found to be particularly effective against mosquitoes. EXAMPLE 5 Mosquito eggs (1,000) were hatched at 25°C in a cultured media consisting of well water (500 mL), baker's yeast (200 mg) and liver extract (300 mg). The eggs were maintained under these conditions for 4 to 5 days. The larvae were next transferred to test tubes containing 3 mL of culture media. Each test tube contained 10 mosquito larvae. In each experiment, 23 test tubes, each with 10 mosquitos in it, served as controls. The cidal activity of each of the polyamine analogues against the mosquito larvae was tested at, 1, 3, 10, and 30 ppm. Each compound was tested at each concentration in triplicate again in test tubes containing 10 mosquito larvae in 3 mL of culture media, maintained at 25°C. The control and test larvae were examined for insect death at 24 and 48 hour intervals. Table 9 includes representative examples of the cidal activity of the polyamine analogues against mosquito larvae. The data is reported as the LD 50 values for each compound, i.e., the concentration of polyamine required to kill 50% of the larvae. Furthermore, the data is reported at 48 and 96 hours. Compound 48 Hr. LD 50 96 Hr. LD 50 N 1 ,N 4 -Diethyl homospermine 7ppm 5ppm The insecticidal compounds may be dissolved or dispersed in any suitable carrier medium adapted for spraying insecticides, e.g., water or other aqueous media and sprayed on an insect infested area or areas subject to potential infestation. The concentration of polyamines applied to an area would depend on the species of insect and its accessibility, however, solutions containing from 10 to 10,000 ppm per 3.8 l (gallon) broadcast over 9.3 m 2 (100 ft 2 .)

Claims: Claims for the following Contracting States : AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE A pharmaceutical composition comprising: an anti-neoplastic, an anti-viral, an anti-psoriasis or an anti-retroviral effective amount of a compound of the formula: wherein: R 1 and R 6 may be the same or different and are alkyl or aralkyl having from 1 to 12 carbon atoms; R 2 - R 5 may be the same or different and are H, R 1 or R 6 ; m and n are 3, or m and n are 4; or a salt thereof with a pharmaceutically acceptable acid and a pharmaceutically acceptable carrier therefor. A composition according to claim 1, wherein m is 3 and n is 3. A composition according to claim 1 or claim 2, wherein R 1 and R 6 are alkyl, or wherein R 1 and R 6 are aralkyl, or wherein R 1 and R 6 are ethyl, or wherein R 1 and R 6 are propyl, or wherein R 1 and R 6 are benzyl. A compound having the formula: wherein R 1 - R 6 may be the same or different and are methyl, propyl, butyl, pentyl, benzyl or β,β,β-trifluoroethyl; m and n are 3, or m and n are 4 or a salt thereof with an acid, but subject to the provisos that R 1 and R 6 do not both stand for methyl when R 3 and R 4 each stands for methyl, m equals 3 and n equals 3. A compound according to claim 4, wherein R 1 and R 6 are propyl or wherein R 1 and R 6 are benzyl. A compound according to claim 4 or claim 5, wherein m and n are 3. A compound of the formula: wherein: R 1 and R 6 may be the same or different and are alkyl having from 1 to 12 carbon atoms; R 2 - R 5 may be the same or different and are H, R 1 or R 6 ; m and n are 3, or m and n are 4; or a salt thereof with a pharmaceutically acceptable acid but subject to the proviso that R 1 and R 6 do not both stand for methyl or ethyl when R 3 and R 4 each stands for methyl, m equals 3 and n equals 3. A compound according to claim 7, wherein m and n are 3. A compound according to claim 7 or claim 8, wherein R 1 and R 6 are ethyl, or wherein R 1 and R 1 are propyl. A compound: (i) of the general formula I as defined in any one of claims 1 to 3, or (ii) of any one of claims 4 to 9, or a salt of any one of the said compounds with a pharmaceutically acceptable acid for use in therapy. Use of: (i) a compound of the general formula I as defined in any one of claims 1 to 3 or (ii) a compound of any one of claims 4 to 9 or a salt of any one of the said compounds with a pharmaceutically acceptable acid in the manufacture of a medicament for anti-neoplastic therapy, anti-psoriasis therapy, anti-viral therapy or anti-retroviral therapy. A pharmaceutical composition comprising an anti-neoplastic, an anti-viral, an antipsoriasis or an anti-retroviral effective amount of a compound or salt as claimed in any one of claims 4 to 9. An insecticidal composition comprising an insecticidally effective amount of a compound as defined in any one of claims 4 to 9 or a salt thereof with an acid; and a carrier therefor. A method of controlling the growth of insects comprising administering to said insects an insecticidal effective amount of a compound as defined in any one of claims 1 to 9 or a salt thereof with an acid. Claims for the following Contracting State : ES A method of making a pharmaceutical composition comprising mixing: an anti-neoplastic, an anti-viral, an anti-psoriasis or an anti-retroviral effective amount of a compound of the formula: wherein: R 1 and R 6 may be the same or different and are alkyl or aralkyl having from 1 to 12 carbon atoms; R 2 - R 5 may be the same or different and are H, R 1 or R 6 ; m and n are 3, or m and n are 4; or a salt thereof with a pharmaceutically acceptable acid, and a pharmaceutically acceptable carrier therefor. A method according to claim 1, wherein m is 3 and n is 3. A method according to claim 1 or claim 2, wherein R 1 and R 6 are alkyl, or wherein R 1 and R 6 are aralkyl, or wherein R 1 and R 6 are ethyl, or wherein R 1 and R 6 are propyl, or wherein R 1 and R 6 are benzyl. A method of making a pharmaceutical composition comprising mixing a compound having the formula: wherein R 1 - R 6 may be the same or different and are methyl, propyl, butyl, pentyl, benzyl or β,β,β-trifluoroethyl; m and n are 3, or m and n are 4 or a salt thereof with an acid, but subject to the provisos that R 1 and R 6 do not both stand for methyl when R 3 and R 4 each stands for methyl, m equals 3 and n equals 3 and a pharmaceutically acceptable carrier therefor. A method according to claim 4, wherein R 1 and R 6 are propyl or wherein R 1 and R 6 are benzyl. A method according to claim 4 or claim 5, wherein m and n are 3. A method of making a pharmaceutical composition comprising mixing a compound of the formula: wherein: R 1 and R 6 may be the same or different and are alkyl having from 1 to 12 carbon atoms; R 2 - R 5 may be the same or different and are H, R 1 or R 6 ; m and n are 3, or m and n are 4; or a salt thereof with a pharmaceutically acceptable acid but subject to the proviso that R 1 and R 6 do not both stand for methyl or ethyl when R 3 and R 4 each stands for methyl, m equals 3 and n equals 3, and a pharmaceutically acceptable carrier therefor. A method according to claim 7, wherein m and n are 3. A method according to claim 7 or claim 8, wherein R 1 and R 6 are ethyl, or wherein R 1 and R 1 are propyl. Use of: (i) a compound of the general formula I as defined in any one of claims 1 to 3 or (ii) a compound as defined in any one of claims 4 to 9 or a salt of any one of the said compounds with a pharmaceutically acceptable acid in the manufacture of a medicament for anti-neoplastic therapy, anti-psoriasis therapy, anti-viral therapy or anti-retroviral therapy. A method of making an insecticidal composition comprising mixing an insecticidally effective amount of a compound as defined in any one of claims 4 to 9 or a salt thereof with an acid; with a carrier therefor. A method of controlling the growth of insects comprising administering to said insects an insecticidal effective amount of a compound as defined in any one of claims 1 to 9 or a salt thereof with an acid. Claims for the following Contracting State : GR A method of making a pharmaceutical composition comprising mixing: an anti-neoplastic, an anti-viral, an anti-psoriasis or an anti-retroviral effective amount of a compound of the formula: wherein: R 1 and R 6 may be the same or different and are alkyl or aralkyl having from 1 to 12 carbon atoms; R 2 - R 5 may be the same or different and are H, R 1 or R 6; m and n are 3, or m and n are 4; or a salt thereof with a pharmaceutically acceptable acid, and a pharmaceutically acceptable carrier therefor. A method according to claim 1, wherein m is 3 and n is 3. A method according to claim 1 or claim 2, wherein R 1 and R 6 are alkyl, or wherein R 1 and R 6 are aralkyl, or wherein R 1 and R 6 are ethyl, or wherein R 1 and R 6 are propyl or wherein R 1 and R 6 are benzyl. A method of making a pharmaceutical composition comprising mixing a compound having the formula: wherein R 1 - R 6 may be the same or different and are methyl, propyl, butyl, pentyl, benzyl or β,β,β-trifluoroethyl; m and n are 3, or m and n are 4 or a salt thereof with an acid, but subject to the provisos that R 1 and R 6 do not both stand for methyl when R 3 and R 4 each stands for methyl, m equals 3 and n equals 3 and a pharmaceutically acceptable carrier therefor. A method according to claim 4, wherein R 1 and R 6 are propyl or wherein R 1 and R 6 are benzyl. A method according to claim 4 or claim 5, wherein m and n are 3. A method of making a pharmaceutical composition comprising mixing a compound of the formula: wherein: R 1 and R 6 may be the same or different and are alkyl having from 1 to 12 carbon atoms; R 2 - R 5 may be the same or different and are H, R 1 or R 6 ; m and n are 3, or m and n are 4; or a salt thereof with a pharmaceutically acceptable acid but subject to the proviso that R 1 and R 6 do not both stand for methyl or ethyl when R 3 and R 4 each stands for methyl, m equals 3 and n equals 3, and a pharmaceutically acceptable carrier therefor. A method according to claim 7, wherein m and n are 3. A method according to claim 7 or claim 8, wherein R 1 and R 6 are ethyl, or wherein R 1 and R 1 are propyl. Use of: (i) a compound of the general formula I as defined in any one of claims 1 to 3 or (ii) a compound as defined in any one of claims 4 to 9 or a salt of any one of the said compounds with a pharmaceutically acceptable acid in the manufacture of a medicament for anti-neoplastic therapy, anti-psoriasis therapy, anti-viral therapy or anti-retroviral therapy. An insecticidal composition comprising mixing an insecticidally effective amount of a compound as defined in any one of claims 4 to 9 or a salt thereof with an acid; and a carrier therefor. A method of controlling the growth of insects comprising administering to said insects an insecticidal effective amount of a compound as defined in any one of claims 1 to 9 or a salt thereof with an acid.

Inventors: BERGERON RAYMOND J, BERGERON, RAYMOND J.
Applicants: UNIV FLORIDA, THE UNIVERSITY OF FLORIDA
Application year: 1989
Main classification: A61K31
IPC codes: A01N33, A61K31, A61P31, A01N43, C07C211, A61P35, C07C209, C07D239, A61P17