PHARMACEUTICAL PREPARATIONS COMPRISING POLYPRENYL COMPOUNDS, ESPECIALLY AS ANTI-CANCER AGENTS, AND PHARMACEUTICAL COMPOSITIONS FOR THE PREVENTION AND TREATMENT OF CANCER AND SKIN DISEASES

Abstract: Pharmaceutical compositions which comprise a poly­ prenyl compound having the formula:

Description: Pharmaceutical preParations comprising polyprenyl compounds, especiallv as anti-cancer aqent, and method of application of them for the prevention and treatment of cancer and skin diseases. This invention relates to pharmaceutical preparations comprising a polyprenyl compound having the formula (I): EMI1.1 in which each of n and m is 0, 1 or 2, n + m is Cr 1 or 2, EMI1.2 lower alkpxy group, or EMI1.3 (wherein each of R1 and R2 is the hydrogen atom. a lower alkyl group or an aryl group)); provided that EMI1.4 n is 1, m is 0, A is especially as anti-cancer agent, and method of application of them for the prevention and treatment of cancer ans skin diseases. Examples of the lower alkoxy groups represented by R in the above-mentioned formula (I) include methoxy, ethoxy, I- propoxy, n-propoxy, t-butoxy and n-butoxy. Examples of the lower alkyl groups represented by R1 and R2 include methyl, ethyl, i-propyl, n-propyl, t-butyl and n-butyl, and examples of the aryl groups represented by R1 and R2 include phenyl and a phenyl group having substituent: groups such as hydroxyl, a lower alkyl group or halogen. If R in the formula (I) is hydroxyl, the compound may be in the form of a salt such as sodium or potassium salt. W. Bollag et al. reported in Europ. J. Cancer, Vql. 10, p 731 (1974) that retinoids such as ethyl 9-(2,3,6-trimethyl- 4-methoxyphenyl)-3,7-dimethyl-2,4,6,8-nonatetraenoate have anti-cancer activity, These retinoide compounds, however, are highly toxic, and further have problems such as causing hypervitanlnosis of Vitamin A when administered. The present invention provides an anti-cancer agent comprising the polyprenyl compound of the formula (I). The polyprenyl compounds of the formula (I)show remarkable anticancer activity and are highly safe compounds. For instance, these polyprenyl compounds do not cause hypervitaminosis of Vitamin A. Further , toxicities of the polyprenyl compounds of the formula (I) other than the hypervitaminosis are also at low level. Moreover, the polyprenyl compounds of the formula (I) are of value as therapeutic agents for treatment of skin diseases with keratinization or treatment of allergic S inflammatory skin diseases1 such as psoriasis, acne, acne vulgaris, Darier's disease, palmoplantar pustulosis, lichen plasnus, ichthyosis, erythroderma, pityriasis rubra pilasis, and keratosis senilis, as well as therapeutic agents for prevention and treatment of cancer and precancerous conditions. Some of the polyprenyl compounds of the formula (I) are already known. For instance, some polyprenyl compounds repre send by the formula (I) are described in Japanese Patent Provisional Publication 54 -5042, Helv. Chim. Acta., Vol. 35, p. 1649 (1952), Agr. Biol. Chem., Vol. 34, Nq. 8, p. 1184 (970), and J. Chem. Soc. (C) p. 2154 (1966)- However, these references do not describe - the anti-cancer activity of these cou- pounds. Examples of the known polyprenyl compounds represented by the formula (I) include: 6, 10, 14-trimethyl-3,5,9,13-pentadecatetraen-2-on 6, 10, 14-trimethyl-3,5-pentadecadien-2-on 6, 10, 14-18-tetramethyl-3,5,9,13,17-nonadecapentaen-2-on 6, 10, 14-18-tetramethyl-3,5,9,17-nonadecatetraen-2-on 6,10,11s,18-tetramethyl5,9,13,17nonadecatetraen-2-on 6,10,14,18-tetramethyl-3,5-nonadecadien-2 on 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid ethyl 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenate 3,7,11-trimethyl-2,4,6,10-dodecatetraenoic acid ethyl 3,7,11-trimethyl-2,4,6,10-dodecatetraenoate methyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecahexaenoate Examples of the novel polyprenyl compounds represented by the formula (I) include: : 3,7 11,15,19-pentamethyl-2,4,6,10,14,18-eicosahexaenoic acid 3,7,11,15-tetramethyl-2,4,6,14-hexadecatetraenoic acid 3,7,11,15-tetramethyl-2,4,6-hexadecatrienoic acid 3,7,11,15-tetramethyl.2,4,6,8,10,14-hexzdecahexaenoic acid 3,7,11,15-tetramethyl-2,4,6,10-hexadecatetraenoic acid 3,7,11,15,19-pentamethyl-2,4,6,8,1p,14,18-eicosahepta- enoic acid 3,7,11,15,19-tetramethyl-2,4,6,10,18-eicosapentaenoic acid ethyl 3,7,11,15-tetramethyl-2,4,6-hexadecatrienoate ethyl 3,7,11,t5,19-pentamethyl-2,4,6,10,14,18-eicosa- hexaenoate methyl 3,7,11,15,19-tetramethyl-2,4,6,10,14,18-eicosahexaenoate ethyl 3,7,11,15-tetramethyl-2,4,6,8,10,14-hexadecahexa enoate 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide N-(P-hydroxyphenyl)-3,7,11,15-tetramethyl-2,4,6,10,14hexadecapentaenoamide N-ethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide N,N-dimethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoamide N-ethyl-3,7,11,15-tetramethyl-2,4,6,8,10,14-hexadeca hexaenoamide N-ethyl-3,7, 11, 15,19-pentamethyl-2,4,6,10,14,18-eicosa- hexaenoamide ethyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapenta enoate propyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapenta- enoate 3,7,11,15-tetramethyl-6,10,14-hexadecapentaenoic acid N,N-dimethyl-3,7,11,15-tetramethyl-6,10,14-hexadecatri enoamide N-ethyl-3,7,11,15-tetramethyl-2,6,10,14-hexadecatrienoamide. The novel polyprenyl compounds represented by the formula (I) such as exemplified above can be prepared in the manner described in the aforementioned publications, in the process given hereinafter, or in a conventional manner. The results of the pharmacological tests and toxicity tests on the polyprenyl compounds of the formula (I) are set forth below. Pharmacological Tests (Anti-cancer Activist) (1) Test procedure A mouse (ICR strain, femaie, 50 days age) was shaved at the back of neck (to the extent of'S cm2). 7112-Di-ethylbenzo- t2]-anthracene was dissolved in acetone to give-75 mg /100 ml. solution. The so Drepared solution was applied to the mouse on the 60th day of age and further on the 75th day of aqe in the amount of 0.2 ml per mouse. Croton oil was dissolved in acetone to give 250 mg/ 100 ml solution, and the so prepared solution was applied to the mouse in the amount of 0.2 ml per mouse,-twice a week until the treatment was started. When 3 - 7 papillomata (diamether of 3 - 8 mm for each, and total diameter of 30 60 mm ) were produced for a mouse, the treatment was started. The compound to be tested (test compound) was dissolved in groundnut oil to give 20 mg /ml solution, and administered orally to the mouse. the solution was administered 10 times for 14 days (once a day), and the diameters of the papillomata were measured on the 14th day to determine the total diameter for each mouse. Ratio of increase or decrease of the papillomata was calculated from the total diameter on the 14th day and the total diameter measured prior to the starting of administration of the test compound. This value was adopted for evaluating the anti-cancer activity. (2) Results Table 1 EMI5.1 <tb> <SEP> Numbe <SEP> Ratio <SEP> of. <tb> <SEP> of <SEP> inareaseo <tb> <SEP> Test <SEP> Compound <SEP> decrease <SEP> o <tb> <SEP> mouse <SEP> U <tb> <SEP> Croundnut <SEP> onl; <SEP> .(Control) <SEP> +17,1 <tb> <SEP> ( <SEP> 1 <SEP> ) <SEP> , <tb> <SEP> 00Ii <SEP> 5 <SEP> --2 <SEP> 4-0 <tb> <SEP> (2)Q/J3/COOH' <SEP> 4--19.5 <tb> <SEP> > <SEP> OOH <SEP> 4 <SEP> - <SEP> l <SEP> 9.5 <tb> <SEP> 4 <SEP> O <SEP> O <SEP> Cs <SEP> Razz <SEP> 4 <SEP> -1o <tb> <SEP> (4) <tb> <SEP> OH <tb> <SEP> Co. <SEP> COOH <SEP> 5 <SEP> - <SEP> 2 <SEP> 63 <tb> <SEP> (5) <tb> <SEP> > <SEP> ONHC2H <SEP> 5 <SEP> 5 <SEP> --25.5 <tb> <SEP> (6) <tb> <SEP> > <SEP> COOC2B5 <SEP> 17 <SEP> -l <SEP> -1 <SEP> 7.5 <tb> <SEP> (7) <SEP> ¯ <SEP> &verbar; <tb> <SEP> (7) <SEP> -. <SEP> 5 <SEP> -12.7 <tb> <SEP> 7 <SEP> COOH <SEP> 7 <SEP> - <SEP> 6.5 <tb> , <SEP> . <SEP> l <tb> <SEP> 7 <SEP> - <SEP> 8.2 <tb> Remarks: The compounds identified by the structural formulae in Table 1 correspond to the following polyprenyl compounds. (1) 3,7,11,15-tetramethyl-2,4,6,10,14,18-eicosahexa enoic acid (2) 3,7,11,15-tetramethyl-2,4,6,14-hexadecatetraenoic acid (3) ethyl 3,7,11,15-tetramethyl-2,4,6,14-hexadecatetra- enoate (4) 3,7,11,15-tetramethyl-2,4,6,8,10,14-hexadecaeno ic acid (5) 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaeno amide (6) ethyl ,7,11,15-tetramethyl-2,4,6,10,14-hexadeca pentaenoate (7) 3,10,14,18-tetramethyl-3,5,9,13,17-nonadecapentaen 2-on (8) 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraenoic acid (9) 6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen 2-on As seen from the data in Table 1, the polyprenyl compounds of the formula (I) are effective against the papilloma. Toxicity Tests (1) Test procedure The test compound was administered repeatedly to a group of 6 mice (ICR'strain, female) for 14 days in the dosage of 200 mg /kg iday. In the course of the administration pro ceduresj increase or decrease of the weight of the mouse, oceurance, of death, etc. were obseryed. (2) Test compound The compounds set forth in the above Table 1 were employed. (3) Test results No death was observed. Decrease of the weight was not . observed, and a little increase of the weight was observed No symptoms indicating the effects of side actIons, such as falling-out df hair, cyanosis, etc., were observed. The decrease of the weight and the falling-out of hair are known as indicating the hypervitaminosis of Vitamin A. Accordingly, the results are considered to indicate that the polyprenyl compounds of the formula (I) do not cause the hypervitaminosis of Vitamin A. In view of the pharmacological test results and the toxicity test results Åas described hereinbefore, the polyprenyl compounds of the formula (I) are judged to be of high safety and to be of value as anti-cancer agents for prevention and treatment of cancer and precancerous conditions. It is well known that mouse papillomate as mentioned above are useful as a model for proliferous, allergic keratinization. Accordingly it is understood from the above shown data that the compound according to the invention is effective also against skin diseases with keratinization. For the application as anUt-cancer agent, the poly- prenyl compound of the formula (I) can be administered orally in the form of powder, granule, pellet, hard capsule, etc., or parenterally in the form of ointment, suppository, injec tion solution, etc. The dosage is generally set in the range of 40 mg to 4 g/day for an adult. If the polyprenyl compound of the formula (I) is applied in the form of an external preparation, the dosage can be varied depending on the largeness of area on the affected part. The above-mentioned preparations can be prepared from the polyprenyl compound and generally employable carriers for the medical use by utilizing the conventional methods. The following examples will illustrate processes for preparing the polyprenyl compounds of the formula (I) and the preparations comprisingRthe polyprenyl compounds, but these examples are not given to restrict the present invention. Preparation Example 1 Ethyl 3,7,11,15-tetramethyl-2,4,6,14-hexadecatetraenoate To a suspension of 2.5 g. of 55 % sodium hydride (in oil) in 30 ml. of n-hexane was added 13.6 g. of triethyl phosphonoacetate. The mixture was then heated under reflux, and 10 g. of 6,10,14-trimethyl-3,5,13-pentadecatrien-2-on was added dropwise to the mixture under stirring. After 30 minutes1 the reaction liquid was poured into 100 ml. of ice-water, and then 200 ml. of n-hexane was added for extraction. The n-hexane phase was separated, washed with two 50 ml. portions of a mixture of methanol and water (2 : 1), and concentrated. The so obtained concentrate was purified by' the silica gel column chromatography to give 9.0 g. of the desired product as an oil. Analysis for C22H36 02 C H Calculated (%) 79.46 10.92 Found (%) 79.74 11.04 NMR spectrum ( i,CDC13): 0.87 C3H, d, J = 6Hz), 1.28 (3H, t, J = 7Hz), 1.0 - 1.6 (7H), 1.61 (3H, s), 1.69 (3H, s), 1.85 (3H, s), 1.9 - 2.4 (4H), 23.4 (3H, d, J = 1Hz), 4.17 (2H, q, J = 7Hz), 5.10 (1H, t, J = 7Hz), 5.75 (1H, bs), 5.95 (1H, d, J = 11Hz), 6.16 (1H, d, J = t5Hz), 6.86 C1H, dd, J = 15Hz, 11Hz) Mass spectrum (m/e): : 332 (H+) Preparation Example 2 3,7,11,15-Tetramethyl-2,4,6,14-hexadecatetraenoic acid o 8.0 g. of the ethyl 3,7,11,15-tetramethyl-2,LI,6,14 hexadecatetraenoate obtained in the previous Preparation Example 1 was added to a solution of 3.2 g. of potassium hydroxide in 20 ml. of isopropyl alcohol, and the mixture was stirred at 50 C for T hour. The reaction liquid was then poured into ice-water, made acidic by addition of hydrochloric acid, and extracted with 50 ml. of diethyl ether. The ether phase was washed with water, dried over magnesium sulfate, and concentrated to give 7. g. of an oil. The oil was dissolved in 40 ml. of n-hexane and crystallized at - 200C to give 3.1 g. of the desired product as white crystals. M.p. : 60 - 62 OC Analysis for C20H3202 C H Calculated tZ) 78.89 10.59 Found (%) 78.77 10.63 NMR spectrum (Z, CDCl3): 0.87 (3H, d, J = 6Hz), 1.0 1.6 (7H), 1.60 (3H, s), 1.69 (3H, s), 1.85 (3H,'s) 1.9 - 2.3 (4H), 2.34 (3H, d, J = 1Hz)-, 5.10 (1H, t, J = 7Hz), 5.77 (1H, bs), 5.97 (1H, d, J = 11Hz), 6.20 (1H, d, J = @15Hz). 6.91 (1H, dd, J : 15Hz, 11Hz), 9.6 (1H, b) Mass spectrum (m/e): 304 (M+) Preparation Example 3 3,7,11,15-Tetramethyl-2,4,6,14-hexadecatetraenoic acid To a suspension of 30.3 g. of sodium ethoxide in 300 ml. of tetrahydrofuran was added 118 g. of diethyl 3-ethoxycarbo- nyl-2-methyl-2-propenylphosphonate. To the mixture was added 67 g. of 3,7,11-tetramethyl-2,4,6,10-dodecatetraen-1-al under stirring, chilling with ice and shielding from the light. After 1 hour, the reaction liquid was poured into 1 liter of water, and 1 liter of n-hexane was added for extraction. The n-hexane phase was separated, washed with two 100 ml. portions of a mixture of methanol and water (2 : 1), and concentrated to give 99 g. of a concentrate. To a refluxing solution of 8. 2 g. of potassium hydroxide and 80 ml. of isopropyl alcohol was added 21 g. of the concentrate under shielding from the light. After 15 minutes, the reaction liquid was poured into 300 ml. -of-ice-water, made acidic by addition of hydrochloric acid; and extracted with 300 ml. of diethyl ether. The extract was washed with three 100 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue was dissolved in 200 ml. of n-hexane and chilled to - 20 C to crystallize. There was obtained 9.8 g. of the desired product as ,pale yellow crystals. Analysis for C20H2802 C H Calculated (%) 79.95 9.39 Found (%) 80.22 9.47 NMR spectrum C , CDCl3): 1.63 (3H, s), 1.69 (3H, s), 1.84 (3H, s), 1.99 (3H, s), 2.0 - 2.3 (4H), 2.36 (3H, s), 5.15 (1H, m), 5.6 - 7.2 (7H, m), 1.04 (1H, b) Mass spectrum (m/e): 300 (M+) Preparation- Example 4 3,7,11,15,19-Pentamethyl-2,4,6,10,14,18-eincosahexaenoic acid In 100 ml. of tetrahydrofuran was dissolved 12 g. of 1-p-tolylsulfonyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecatetraene, and the solution was chilled to - 50 OC, To the solution was added dropwise 18,5 ml. of 15 !. n-butyllithium - n-hexane solution under stirring and in a stresm of nitrogen, maintaining the temperature of the solution at - 50 OC. Then, 300 ml. of tetrahydrofuan solution containing 5.7 g. of ethyl 4-bromo-3-meFhyl-2-butenate was added dropwise to the so produced solution. After 30 minutes, '100 ml. of 10 % aqueous ammonium chloride solution was added, and then the mixture was allowed to stand to reach room temperature. The mixture was subsequently extracted with two 200 ml. portions of n-hexane. The n-hexane phase was washed with three 100 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the sdlvent. There was obtained 14 g. of ethyl 3,7,11,15,19-pentamethyl-5-p-tolylsulfonyl-2,6,10,14,18 eicosapentaenoate. To 4.1 g. of potassium hydroxide in 50 ml. of isopropyl alcohol was added 12 g. of the above-obtained ethyl 3;7,11,15, 19-pentamethyl-5-p-tolylsulfonyl-2,6,10,14,18-eicosapentaenoate, and the mixture was stirred at 50 C for 3 hours. The reaction liquid was poured into ice-water, made acidic by addition of hydrochloric acid, and extracted with 100 ml of diethyl ether. The extract was washed with water, dried over magnesium sulfate and evaporated to remove the solvent. There was obtrained 8.5 g. of an oil. The so obtained oil was dissolved in 40 ml. of--n-hexane and chilled to - 20 OC to crystallize. There was obtained 2.3 g. of the desired product as white crystals. M.p.: 45.5 - 46.5 C Analysis for C25H3802 C H Calculated (%) 81.03 10.34 Found (%) 80,89 10.52 NMR spectrum ( f, CDCl ) 1.60 (9H, s), 1.68 C3H, s), 1.86 (3H, s), 1.9 - 2.3 (12H), 2.33 (3H, s), 5.09 (3H, b), 5.76 (1H, bs), 5.96 (1H, d, J = 10Hz), 6.18 (1H, d, J = 15Hz), 6.89 C'1H, dd, J = 15Hz, 10Hz), 10.2 (1H, b) Mass spectrum (m/e): 370 (M+) Preparation Example 5 Ethyl 3,7,11,15-tetramethyl-2,4,6,14-hexadecate The procedures described in Preparation Example 1 were repeated using 6,10,14-trimethyl-3,5-pentadecadien-2-on to obtain the desired product as an oil. Analysis for C22H3802 C H Calculated (%) 78,98 11.45 Found (%) 79.16 11.56 NMR spectrum ( # , CDCl3): 0.87 (9H,'d, J = 7Hz), 1.27 (3H, t, J = 7Hz), 0.9 - 1.6 (12H), 1.84 (3H, s), 2.08 (2H, t, J = 7Hz), 2.34 C3H, s), 4.16 (2H, q, J = 7Hz), 5.74 (1d, bs), 5.95 C1.H, d, J = 11Hz), 6.16 (1H, d, J = 15Hz), 6.85 (1H, dd, J = 15Hz, 11 Hz) Mass spectrum (m/e): 334 (H+) Preparation Example 6 3,7,11,15-Tetramethyl-2,4,6-hexadecatrienoic acid The procedures described in Preparation Example 2 were repeated using the ethyl 3,7,11,15-tetramethyl-2,4,6-hexadecatrienoate obrained in Preparation Example 5 to carry out the hydrolysis. There was obtained the desired product as white crystals. H.p.: 84.5 - 85.5 C Analysis, for C20H3402 C H Calculated (%) 78.38 11.18 Found (%) 78.35 11.21 NMR spectrum ( #, CDCl3): 0.87 (9H, d, J = 7Hz), 0.5 1.6 (12H), 1.84 (3H, s), 2.09 (2H, t, J = 7Hz), 2.35 (3H, s), 5.76 (1H, bs), 5.96 (1H, d, J = 11Hz), 6.19 (1H, d, J = 15Hz), 6.90 C1H, dd, J = 15Hz, 11Hz), 11.5 (1H, b) Mass spectrum (m/e); 306 (M+) Preparation Example 7 ..... Ethyl 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapenta enoate To a suspension of 5.0 g. of 55 % sodium hydride (in oil) in 60 ml. of n-hexane was added 28.6 g. of triethyl phosphonoacetate. The mixture was then heated under reflux, and 20 g. of 6,10,14-trimethyl-3,5,9,13-pentadencatetraen-2-on was added dropwise to the mixture under stirring. After 30 minutes, the reaction liquid was poured into 200 ml. of icewater, and then 500 ml. of n-hexane was added for extraction. The n-hexane phase was separated, washed with two 100 ml. portions of a mixture of methanol and water (2 e 1), and concentrated. The so obtained concentrate was purified by silica gel column chromatography to give 18 g. of the desired product as an oil. Analysis for C22H3402 C H Calculated (%) 79.95 10.37 Found (%) 80.11 10.26 NMR spectrum ( 5 , CDCl3): 1.28 (3H, t, J = 7Hz), 1.60 3. (6H, s); 1.68 (3H, s), 1.85 C3H, s), 1.9 - 2.3 (8H), 2.33 (3H, d, J = 1Hz), 4.16 (2H, q, J 7Hz); 5.09 C2H, b), 5.73 (1H, bs), 5.96 (1H, d, J = 11Hz), 6.16 (1H, d, J = 15Hz), 6.85 (1H, dd, J = 15Hz, 11Hz) Mass spectrum (m/e): 330 (M+) Preparation Example 8 3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoamide To 3.9 g. of potassium hydroxide in 30 ml. of isopropyl alcohol was added 10 g. of the ethyl 3,7,11,15-tetramethyl- 2,4,6,10,14-hexadecapentaenoate obtained in Preparation Example 7, and the mixture was stirred at 50 0C for 1 hour. The reaction liquid was poured into ice-water, made acidic by addition of hydrochloric acid, and extracted with 100 ml. of diethyl ether. The ether phase was washed with water, dried over magnesium sulfate and concentrated to give 9.0 g. of an oil. The so obtained oil was dissolved in 50 ml. of n-hexane and chilled to - 20 C to crystallize. There was obtained 4.0 g. of 3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid as pale yellow needles. In 20 ml. of diethyl ether was dissolved 3. g. of the above-obtained 3,7, 11,15-tetramethyl-2,4,6,10, 14-hexadeca- pentaenoic acid. To this solution was added 1 g. of triethylamine, and further added 1.1 g. of ethyl chlorocarbonate under stirring at room-temperature. After 10 minutes, gaseous ammonia was introduced into the solution. The reaction liquid was washed with three 10 ml. portions of water, dried over magnesium sulfate, and evaporated to remove the solvent. The residue was purified by almina column chromatography and crystallized from a mixture of acetone and n-hexane (1 : 2). There was obtained 1.7 g. of the desired product as pale yellow crystals. M.p.: 63 - 65 C Analysis for C20H31N0 C H N Calculated (%) 79.67 10.37 4.65 Found (%) 79.48 10.59 4.73 NMR spectrum ( ; , CDC13): 1.60 C6H, s), 1.68 (3H, s), 1.84 C3H, d, J = 1Hz), 1.9 - 2.3 (8H), 2:33 (3H, d, J = lHz), 5.08 (2H, m), 5,70 (1H, bs), 5.4 6.1 (2H, b), 5.95 (1H, d', J = 11Hz), 6.15 (1H, d, J = 15Hz), 6.82 (1H, dd, J = 15Hz, 11Hz) Mass spectrum (m/ej: 301 (M+) Preparation Example 9 N-(p-Hydroxyphenyl)-3,7,11,15-tetramethyl-2,46,10.14- hexadecapentaenoamide In 30 ml. of tetrahydrofuran was dissolved 3 gP of 3,7, 11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid. To this solution was added 1 g. of triethylamine, and further added 1.1 g. of ethyl chldrocarbonate under stirring at room temperature. After 10 minutes, the reaction liquid was poured into 100 ml. of water, and extracted with 100 ml. of n-hexane. The extract was washed with 50 ml. of water and evaporated to remove the solvent. The residue was dissolved in 30 ml. of tetrahydrofuran. To this solution was added 1.1 g. of paminophenol, and the mixture was stirred at room temperature for 30 minutes. To the reaction liquid was added 200 ml. of diethyl ether, and the mixture was washed successively with two 50 ml. portions of dilute hydrochloric acid and two 50 ml. portions of water. The ether phase was dried over magnesium sulfate and evaporated to remove the solvent. The residue was crystallized from ethanol to obtain 3.2 g. of the desired product as pale yellow crystals. M.p. 163 - 164 C Analysis for C26H35NO2 C H N Calculated (%) 79.34 8.96 3.56 Found (%) 79.61 8.78 3.62 NMR spectrum ( # , CDCl3): 1.61 (6H, s), 1.68 (3H, s), 1.85 (3H, s), 1.9 - 2.3 (8H), 2.38 (3H, s), 5.09 (2H, m), 5.76 (1H, bs), 5.96 (1H, d, J = 11Hz), 6.15 (1H, d, J = 15Hz), 6.42 (1H, b), 6.74 (2H, d, J = 8Hz), 6.82 (1H, d, J = 15Hz, 11Hz), 7.22 (1H, bs), 7.32 (2H, d, J - 8Hz) Mass spectrum (m/e): 393 (M+) Preparation Example 10 N-Ethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapenta enoamide 3,7,11,15-Tetramethyl2,4,6,10,14-hexadecapentaenoic acid and ethylamine were reacted in the same manner as in Preparation Example 9 to obtain the desired product as an oil. Analysis for C22H35N C H N Calculated (%) 80.19 10.71 4.25 Found (%) 80.44 10.79 4.38 NMR spectrum ( S, CDCl3): 1.15 (3H, t, J = 7Hz), 1.60 (6H, s), 1.67 (3H, s), 1.83 (3H, s), 1.9 - 2.3 (8H), 2.33 (3H, d, J = 1Hz), 3.27 (2H, qd, J = 7Hz, 6Hz), 5.10 (2H, m), 5.65 (1H, bs), 5.82 (1H, t, J = 6Hz), 5.94 (1H, d, J = 11Hz), 6.10 (1H, d, J = 15Hz); 6.77 (1H, dd, J 15 Hz, 11Hz) Mass spectrum (m/e): 329 (M+) Preparation Example 11 N,N-Dimethyl-3,7,11,15-tetramethyl-2,4,6,10,14-hexadeca- pentaenoate 3,7,11,15-Tetramethyl-2,4,6,10,14-hexadecapentaenoic acid and dimethylamine were reacted in the same manner as in Preparation Example 9 to obtain the desired product as pale yellow crystals. M.P.: 39 - 39.5 C Analysis for C22H35NO C H N Calculated (%) 80.19 10.71 4.25 Found (%) 80.26 10.83 4.32 NMR spectrum ( T CDCl3): 1.60 (6H, s), 1.68 (3H, s), 1.76 (3H, s), 2.09 (3H, d, J = 1Hz), 1.9 - 2.3 (8H), 3.00 (3H, s), 3.01 (3H, s), 5.10 (2H, m), 5.93 (1H, bs), 5.94 (1H, d, J = 10Hz), 6.18 (1H, d, J = 15Hz), 6.68 (1H, dd, J = 15Hz, 10Hz) Mass spectrum (m/e): 329 (M+) Example 1 Tablet Preparation N-Ethyl-3,7,11,15-tetramethyl 2,4,6,10,14-hexadecapentaenoamide 50 g. Silicic anhydride 30 g Crystalline cellulose .50 g. Corn starch 36 g. Hydroxypropylcellulose 10 g. Magnesium stearate 4 g. The above-described composition was processed in the conventional manner to produce tablets (180 mg. per one tablet).

Claims: Claims: 1. A pharmaceutical composition which comprises a poly prenyl compound having the formula (I): EMI17.1 in which each of n and m is 0, 1 or 2, n + m is 0, 1 or 2, A is # , # , or # , and B is # COR, # COR, # COR, #O, or #O, wherein R represents a hydroxy group, a lower alkoxy group, or EMI17.2 in which each of R1 and R2 is a hydrogen ato ower alkyl group or an aryl group; provided that R is a lower alkoxy or EMI17.3 if n is 1, m is 0, A is EMI17.4 and B is EMI17.5 2. A pharmaceutical composition according to claim 1 as anti-cancer agent. 3. A pharmaceutical composition as claimed in claim 2, which comprises 3,7,11,15,19-pentamethyl-2,4,6,10,14,18-- eicosahexaenoic acid. 4. A pharmaceutical composition as claimed in claim 2, which comprises 3,7,11 ,15-tetramethyl-2,4,6-14- hexadecatetraenoic acid. 5. A pharmaceutical composition as claimed in claim 2, which comprises ethyl 3,7,11 ,15-tetramethyl-2,4,6-14- hexadecatetraenate. 6. A pharmaceutical composition as claimed in claim 2, which comprises 3,7,1 1i5-tetramethyl-2,4,6,8,10, 14- hexadecahexaenoic acid. 7. A pharmaceutical composition as claimed in claim 2, which comprises 3,7,11,15-tetramethyl-2,4,6,8,10,14- hexadecapentaeno-amide 8. A pharmaceutical composition as claimed in claim 2, which comprises ethyl 3,7,11 ,15-tetramethyl-2,4,6,10, 14- hexadecapentaenoate. 9. A pharmaceutical composition as claimed in claim 2,: which comprises 6,10,14,18-tetrametyhl-3,5,9,13,17- nonadecapentaen-2-on. 10. A pharmaceutical composition as claimed in claim 2, which comprises 3,7,11,15-tetramethyl-2,6,10,14- hexadecatetraenoic acid. 11. A pharmaceutical composition as claimed in claim 2, which comprises 6,10,14,18-tetramethyl-5,9,13,17 nonadecatetraen-2-on. 12. A method of application of a pharmaceutical preparation, which comprises a polyprenyl compound having the formula (I): EMI18.1 in which each of n and m is 0, 1 or 2, n + m is 0, 1 or 2, EMI19.1 alkoxy group, or EMI19.2 in which each of R1 and R2 is trie hydrogen atom, a lower alkyl group or an aryl group; provided that R is a lower alkoxy or if n is1, m is 0, A EMI19.3 is EMI19.4 and B is EMI19.5 for prevention or treatment of cancer or precancerous conditions by administering to patient orally or parenterally above preparation, which comprises the active ingredient in a dosage ranging from 40 mg to 4 g/day for an adult. 13. A method of application of a pharmaceutical preparation which comprises a polyprenyl compound having the formula (I): EMI19.6 in which each of n and m is 0, 1 or 2; n + m is 0, 1 or 2, EMI19.7 alkoxy group, or EMI19.8 in which each of R1 and R2 is a hydrogen atom, a lkyl group or an aryl group; provided that R is a lower alkoxy or EMI19.9 n is 1, m is 0, A is EMI19.10 and 8 is EMI19.11 for treatment skin diseases with keratinization and allergic or. inflamatory skin diseases by administering to a patient orally or parenterally above preparation, which comprises the above ingredient in a dosage ranging from 40 mg to 4 g/day for an adult.

Inventors: ABE, KOUICHI, ABE, SHINYA, INAI, YUICHI, SUZUKI, KOUICHI, SUZUKI, TAKESHI, SUZUKI, YOSHIKAZU, TAGAYA, OSAMU, YAMADA, KOUJI, YAMATSU, ISAO
Applicants: EISAI CO., LTD.
Application year: 1981
Main classification: C07C57
IPC codes: C07C57, C07C49, A61K31