GB2159709A

GB2159709A - Pharmaceutical compositions of polyprenyl ketones

Info

Publication number: GB2159709A
Application number: GB08508215A
Authority: GB
Inventors: Masaichi Yamamoto; Seiichi Araki; Hiroshi Yamamoto; Isao Yamatsu; Takeshi Suzuki; Akiharu Kajiwara; Yoshikazu Suzuki; Haruyoshi Arai
Original assignee: Eisai Co Ltd
Current assignee: Eisai Co Ltd
Priority date: 1982-05-28
Filing date: 1985-03-29
Publication date: 1985-12-11
Also published as: GB2159709B; GB8508215D0

Abstract

Pharmaceutical compositions of compounds of the formula <IMAGE> where a=b=H or a+b is a bond and n is 1 to 10 are useful as prophylactic therapeutic agents for immuno-deficiency diseases and phylactic agents against infectious diseases.

Description

SPECIFICATION A polyprenyl compound and a pharmaceutical composition containing a polyprenyl compound This invention relates to polyprenpyl compounds.

According to the present invention there is provided a novel ,y-dihydropolyprenyl alcohol derivatives having the formula (I) below, a process for preparing the same and a pharamaceutical composition containing a polyprenyl compound having the formula Xl, XII or XIII below or another polyprenyl compound as defined hereinafter, which is useful as a prophylactic therapeuticagentforhuman and animal immunodeficiency diseases and a phylactic agent against human and animal infectious diseases.

Theformula (I) referred to above is

wherein n is an integer of 5 to 7 and R is a hydrogen atom,a loweralkyl group oran aliphaticoraromatic acyl group.

In this formula (I), the loweralkyl group in the definition of R normally means C1 to C6 straight-chain or branched alkyl groups such as methyl, ethyl n-propyl, isopropyl, n-butyl, isobutyl, 1-methyl-prop yl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl.

The novel compound having the formula (I) can be prepared by various methods and some typical examples will be given.

MethodofPreparation 1 (a) The compound represented by the following general formula [II] is reacted with an alkyl cyanoacetate in the presence of a base to obtain a compound represented by the following general formula [III]:

wherein n is an integer of 5 to 7;

wherein n is an integerof 5to 7 and R is a lower alkyl group.

(b) The resulting compound offormula [III] is reduced using a reducing agent such as sodium borohydrideto obtain a compound represented by thefollowing general formula [IV]:

wherein each of n and R has the meaning as defined above.

(c) The resulting compound of formula [IV] is subjected to ester and nitrile hydrolysis in the presence of a strong alkali such as potassium hydroxideto obtain a compound represented by the following general formula [V]:

wherein n has the same meaning as defined above.

(d) The resulting compound offormula [V] is decarboxylated in the presence of puridinelcopper, for example, to obtain a compound represented by the following general formula [VI]:

wherein n has the same meaning as defied above.

(e) The resulting compouna offormula [VI] is reduced using a reducing agent such as lithium aluminun hydride, vitrite, sodium bis(2-methoxyehtoxy)aluminum hydride or the like, providing one of the intended compounds of the general formula [I]:

wherein n has the same meaning as defined already.

(f) The alcoholic hydroxyl group of compound of formula [I] is converted into an active group such as a tosyl or mesyl group and the compound is reacted with a corresponding alkyl alcohol in the presence of a base such as caustic potash to give its alkyl ether. Its ester also can be derived by reacting the compound with a corresponding aliphatic or aromatic acyl chloride or acid anhydride.

Method of Preparation 2 Acompound represented by the following general formula [II] is subjected to the Wittig-Homer reaction together with triethylphosphonoacetic acid in the presence of a base to obtain a compound represented bythefollowing general formula [VII]:

wherein n is an integer of 5 to 7;

wherein n has the same meaning as defined already.

The resulting compound offormula [VII] is hydrolyzed using a base such as caustic potash to obtain a compound represented by the following general formula [VIII]:

wherein n has the same meaning as defined already.

The compound offormula [VIII] is then reduced using metallic sodium orthe like to obtain a compound represented by the following general formula [VI]:

The corresponding alcohol and its derivative can be derived by following the procedures of Method of Preparation 1.

Method of Preparation 3 Acompound represented bythefollowing general formula [lil is subjected to the Witting-Hormer reaction together with diethyl phosphonoacetonitrile in the presence of a base to obtain a compound represented bythefollowing general formula [IX]:

whereinnisan integer of 5 to 7;

wherein n has the same meaning as defined above.

The resulting compound offormula fIX] is reduced using a reducing agent such as metallic magnesium in a mixed solvent such as methanol/THFto obtan a compound represented by the following general formula W:

wherein n has the same meaning as defined above.

Next,the compound offormula [X] is hydrolyzed using caustic potash, for example, to obtain a compound represented by the following general formula [VIII]:

Thereafter, the procedures of Method of Preparation 1 are followed to derive the corresponding alcohol and its derivative.

The invention further provided a pharmaceutical composition which comprises a pharmaceuticaily acceptable carrier and a pharmaceutically effective amount of a polyprenyl compound selected from polyprenyl compounds having the following formulae:

wherein n is an integer or 5 to 7 and R is a loweralkyl group of an aliphatic or aromatic acyl group;

wherein each of aand b is hydrogen or a and bare combined togetherto form a bond, and n is an integer ofltol0;

wherein each ofaandbis hydrogen oraand bare combined togetherto form a bond and n is an integer ofl to 10; 3,7,11,15 -tetramethylhexadec- 1-en -3-ol; 3,7,11,15 -tetramethyl - 1,6,10,14 -hexadecatetraen - 3 -ol; docosanol; phytol and iso-phytol.

In other words, the above defined pharmaceutical composition contains as the effective ingredientthe novel ss,y-dihydropolyprenyl alcohol derivative as mentioned before or another polyprenyl compound.

The above defined pharmaceutical composition is effective as a prophylactic,therapeuticagentfor human and animal immuno-deficiency diseases.

More especially, the composition containing the polyprenylcompound having theformula XII orXIII is useful as a phylactic agent against human and animal infectious diseases.

Immunology has made remarkable progress in recent years and various diseases are now believed to originate from immunodeficiency. For example, cancer, microbism, asthma, rheumarthritis and autoimmune disease can be cited as the diseases resulting from immunodeficiency.

In addition to simple microbism due to mere invasion of pathogenic bacteria, the increase ofthe complicated microbism involving various fundamental troubles has become a serious problem.

The microbism induced by cancer, for example, is one of the mosttroublesome clinical problems.

Cancertriggersthe drop of general and local resistance and complicating and secondary diseases would occur in an easily infective state. Infection due to cancer mostly assumes the form of infection through a respirator, a urinary passage, a placental passage and a skin atthe initial stage and results mostly in pneumonia and sepsis atthe final stage.

The mechanism of coincidence of infection due to this tumortakesgenerallythefollowing form.

With the progress of leukemia, malignant lymphoma or cancer, the function of normal tissue and cells, especiallythatof lymphatic cells and granulocyte cells is reduced so that a patient is easily infected and infectious diseases occurcoincidently. In such a case, the dose of antibiotics does not result in radical cure but mostly in such problems as repeated infection, microbial substitution or refractory infection. Accordingly, radial cure can not be expected by use of the conventional antibiotics and chemotherapeutic agents butcan be cured onlyaftera biophylactic function is improved. Hence, development of drugs for improving the biophylacticfunction of organisms has been earnestly awaited.

On the other hand, antibiotics have been used primarilyto cure bacterial infection of animals such as livestock and poultry and, as a matter of fact, various antibiotics have reduced the number or kinds of serious infectious diseases due to pathogenic bacteria. In the livestock industry, however, the abuse of antibiotics has caused a serious sociai problem such as residual drugs in various products, increase of drug-resistant bacteria and microbial substitution.

In otherwords, the phylactic power of the host is reduce remarkably and a restorative function against infectious diseases is also impaired so that the microbism is difficu It to cure and the host is liable to sufferfrom reinfection. Furthermore, spontaneous infectious diseases (opportunistic infectional) reduce the producibility of livestock and the ioss is great.

Hence, the immunological competence ofthe host and the biophlacticfunction must be enhanced.

Underthese circumstances, the inventors ofthe present invention have made intensive studies in search ofdrugsthat normalize an immunological function and enhance a biophylacticfunction, and havefound unexpectedlythata polyprenyl compound as defined above is effective as a prophylactic/ therapeutic agent for human and animal immunodeficiency diseases and especially as a phylactic agent against human and animal infectious diseases:: In other words, the compound ofthe present invention is effective in normalizing human and animal immunological functions and enhancing re sistanceagainstthe infection. Hence,thecompound is useful as a prophylactic/therapeutic agent for human and animal immunodeficiency diseases and as a phylactic agent against a variety of infectious diseases.

For man, the compound of the present invention is effective for rheuma rth ritis, autoimmune disease, cancer, asthma, various infectious diseases such as sepsis, pneumonia, meningitis and otherviral infectious diseases.

For animals, the compound ofthe present invention is effective for swine diarrhea, pneumonia (SEP, AR. hemophilus, pasteurella) and TGE, avian pneumonia (microplasma, hemophilus) and Marek's diseases, and bovine diarrhea, pneumonia and mastitis.

In the curing human and animal infectious diseases by the compound of the present invention, the therapeutic effect can be improved remarkably by the use ofthe present compound in combination with antibiotics. This is significant because the aforementioned social problem of the abuse of antibiotics can also be solved.

In the case of animals such as livestock and poultry, the compound ofthe present invention enhances the resistance of organism against infection and hence the compound is effective as a basal drug forthe newborn. Furthermore, it is effective for mitigating the stress resulting from mass raising, transporta- tion, and the like and is also useful for improving the vaccinal effect.

Accordingly, it is another purpose ofthe present invention to provide a novel prophylactic/therapeutic composition for human and animal immunodeficiency.

It is afurther purpose ofthe present invention to provide a novel phylactic composition against hu man and animal infectious diseases.

The following compounds are typical examples of polyprenyl alcohols having the formulae (Xl) and (XII), but it is to be noted that they are merely illustrative but not limitative in any manner.

o 3,7,11,15,19,23,27,31 - octam ethyl - 2,6,10,14,18,22,26,30 - dotriacontaoctaen - 1 - ol o 3,7,11,15,19,23,27,31,35-nonamethyl 2,6,10,14,1 8,22,26,30,34 -hexatriacontanonaen -1 -ol o 3,7,11,15,19,23,27,31,35,39-decamethyl 2,6,10,14,18,22,26,30,34,38 -tetracontadecaen - 1-ol o 3,7,11,15,19,23,27,31,35,39,43-undecamethyl 2,6,10,14,18,22,26,30,34,38,42-tetraetracon tandecaen - 1 - ol o 3,711,15,19,23,27-heptamethyl- 2,6,10,14,18,22,26 - octacosaheptaen - 1 - ol o 3,7,11,15,19,23 -hexamethyl -2,6,10,14,18,22 - tetracosahexaen - 1 - ol o 3,7,11,15,19- pentamethyl -2,6,10,14,18-eico- sapentaen - 1 - ol o 3,7,11,15-tetramethyl-2,6,10,14-hexade catetraen - 1 - ol o 3,7,11 -trimethyl - 2,6,10 - dodecatrien - 1 - ol o 3,7 - dimethyl - 2,6 - octadien -1 - ol o 3,7,11,15,19,23,27,31,35 - nona methyl - 6,10,14,18,22,26,30,34 -hexatriacontaoctaen - 1 -ol o 3,7,11,15,19,23,27,31,35,39-decamethyl 6,10,14,18,22,26,30,34,38-tetracontanonaen-1 -ol o 3,7,11,15,19,23,27,31,35,39,43 - u ndecamethyl - 6,10,14,18,22,26,30,34,38,42-tetracontade caen-1 -ol o 3,7,11,15,19- pentamethyl -6,10,14,18-eico- satetraen - 1 - ol o 3,7,11,15-tetramethyl-6,10,14-hexadecatrien -1 -ol o 3,7,11 -trimethyl - 6,10 - dodecadien - 1 - ol o 3,7-dimethyl-6-octen -l-ol o 3,7,11,15,19,23-hexamethyl-6,10,14,18,22 tetracosapentan - 1 - ol o 3,7,11,15,19,23,27- heptamethyl 6,10,14,18,22,26 - octacosahexane - 1 - ol o 3,7,11,15,19,23,27,31 -octamethyl- 6,10,14,18,22,26,30 - dotriacontaheptaen - 1 -ol The compounds having the formulae [Xl] and [Xll] can be prepared by various methods. When a and bin the general formula [Xll] are combined togetherto form a bond, the compound can be prepared by those methods which are disclosed by Burrell et a I. in J.

Chem. Soc. (C), 1966,2144, Popjak et al. in d. Biol.

Chem., 237,56(1962), 0. Isler et al. in Helv. Chim.

Acta, 32,2616(1956), Japanese Patent Laid-Open No.

31610/1978, and Japanese Patent Laid-Open No.

55506/1979,for example.

When a and bare both hydrogen atoms in the formula [XII], the compound and the compound having the formula [Xl] can be prepared bythe method disclosed in Japanese Patent Laid-Open No.

76829/1980, for example. This method will be described more definitely.

(a) A lower alkyl cyanoacetate is reacted with a compound of the formula [II]

(wherein n is an integer of 1 to 10) in the presence of a base to obtain a compound represented by the formula [III]:

(wherein n has the same meaning as above and R is a loweralkyl group).

(b) The resulting compound offormuia [III] is reduced buy a reducing agent such as sodium borohydrideto obtain a compound represented by the formula [IV]:

(wherein n and R have the same meaning as above).

(c) The resulting compound oftheformula [IV] is decarboxylated in the presence of a strong alkali such as potassium hydride to obtain a compound represented bytheformula [XV]:

(wherein n has the same meaning as above).

(d) The resulting compound oftheformula [XV] is hydrolyzed in the presence of a strong alkali such as Potassium hydroxide to obtain a compound represented bytheformula [XVI]:

(e) The intended compound oftheformulae [Xl] and [XII] where a and bare hydrogen can be prepared by reducing the resulting compound of the formula [XVI] using a reducing agent such asvitrite, lithium aluminum hydride, orthe like:

(wherein n is an integer of 1 to 10).

The compound having the formula [XIII] is illustrated as follows: o 6,10,14 -trimethyl - 5,9,13 - pentadecatrien - 2 one o 6,10,14,18 -tetramethyl - 5,9,13,17 - nonadecatetraen -2 - one o 6,10,14,18,22-pentamethyl-5,9,13,17,21 tricosapentaen . 2 - one o 6,10,14,18,26-hexamethyl-5,9,13,17,21,25 heptacosahexaen - 2 - one o 6,10,14,18,22,26,30 - heptamethyl 5,9,13,17,21,25,29 - hentriacontaheptaen - 2 -one o 6,10,14,18,22,26,30,34 - octamethyl - 5,9,13,17,21,25,29,33 - pentatriacontaoctaen - 2 -one o 6,10,14,18,22,26,30,34,38 - nona methyl - 5,9,13,17,21 ,25,29,33,37 -nonatriacontanonaen -2-one o 6,10,14,1 8,22,26,30,34,38,42 - decamethyl 5,9,13,17,25,29,33,37,41-tritetracontade caen-2-one o 6,10 - dimethyl - 5,9 - undecadien - 2 - one o 6-methyl -5-hepten-2-one o 6,10,14,18,22,26,30,34,38,42-decamethyl tritetracontan - 2 - one o 6,10,14,1 8,22,26,30,34,38- nonamethylnonat- riacontan - 2 - one o 6,10,14,18,22,26,30,34 - octa methyl pentat- riacontan - 2 - one o 6,10,14,18,22,26,30 - heptamethylhentriacontan -2-one o 6,10,14,18,22,26- hexamethylheptacosan - 2 one o 6,10,14,18,22 - pentamethyltricosapentan - 2 one o 6,10,14,18 - tetramethylnonadecan - 2 - one o 6,10,14-trimethylpentadecan-2-one o 6,10 - dimethylundecan - 2 - one o 6 - methylheptan - 2 - one Though the compound oftheformula [XIII] can be prepared by various methods, one ofthe ordinary methods is as follows:

cH HH2-t-c-c2) n-i C2-C-CH-CH2X XCH3 II CH2~C~CH~CH2X II ab ab 0 CH C2H5-O-C-CH2-C=O [XVIII t condensation CH3 HCH2-C-C?!-CH2C'I-C=O Elxx a H5CH2-C-CH-CH2YCH-C=O b COOC a b COOC2H5 ester cleavage ii) decarboxylatioc (I) wherein each of a, band n has the same meaning as defined already, and Xis a halogen atom.

In otherwords, prenyl halide represented bythe general formula [XVII] and ethyl acetoacetate [XVIII] are reacted in the presence of a condensing agent such as metallic sodium, metallic potassium, sodium ethylate, sodium hydrate orthe like in a solvent such as ethanol, t-butanol, dioxane, benzene or the like, whenever necessary, to effect condensation. The resulting condensate is generally treated with an alkali reagent such as a dilute aqueous caustic soda solution, a dilute aqueous caustic potash solution or the like without isolating the condensate, so as to effect ester cleavage and decarboxylation and thus obtain the intended compound offormula [Xlil].

The following are examples ofthe novel compound according to the present invention. However, these examples are merely illustrative but not limitative in any manner.

Example 1 3,7,11,15,19,23 - Hexamethyl - 6,10,14,18,22 - tetra- cosapentaenol 40g of6,10,14,18,22,26-hexamethyl - 5,9,13,17,21,25 - heptacosahexaen - 2 - one, 15 g of ethyl cyanoacetate, 15 g of acetic acid and 500 ml of acetone were mixed, refluxed at 84 to 85"C and subjected to dehydro-condensation with stirring.

After reacted for 7 hours, the reaction product was washed with water and an organiclayerwas isolated.

While the residue was cooled by ice and stirred, 100 ml of an ethanol solution containing 13 g of sodium borohydride was added. After the reduction was completed, the excess reducing agent was decom posed by 10% acetic acid, washed with water and concentrated. The concentrate was dissolved in 200 ml of propylene glycol. After 26 g of caustic potash was added, the solution was stirred at 160"C for 3 hours. The reaction solution was cooled by ice and after 100 ml of 6N hydrochloric acid was added, itwas extracted with n-hexane.Afterthe organic layer was I washed with water and dried, the productwas concentrated.

42g of a dicarboxylicacid was obtained as the crude reaction product was dissolved in 200 ml of pyridine. After 1 g of copper powderwas added, the solution was heated under reflux for 2 hours for decarboxylation. Pyridine was vacuum - distilled and 100 ml of water and 300 ml of n-hexane were added.

The copper powder was vacuum-filtered and 200 ml of 1 N HCI was added to the filtrate. The organic layer was washed with water, then dried and thereafter concentrated.

The concentrate was refined into a colorless oily matter by silica gel column chromatography, provid ing 30 g of 3,7,1 1,1 5,1 9,23 - hexamethyl - 6,10,14,18,22-tetracosapentaenoic acid.

While being cooled by ice with stirring, the product was added dropwise to 300 ml of an ethereal suspension of of lithium aluminum hydride. After the suspension was continuously stirred for 30 minutes, 4 ml ofwaterwith 4 ml of a 15% caustic soda solution and 12 rnl | of water were sequentially added.

The precipitated crystal was filtered and washed twice with 200 ml of ether. The filtrate was concentrated and the concentrate was refined into a colorless oily matter by silica gel column chromatography, providing the captioned 3,7,11,15,19,23hexamethyl-6,10,14,18,22-tetracosapentaenol.

The physicochemical properties ofthe product were as follows: Elementarvanalysis: as C30H52O C H calculated(%): 84.04 12.23 found (%): 84.06 12.23 Infrared absorption spectrum (nujol): vmaxcm-1; 3,300,2,930, 1,650, 1,450,1,380 NMR spectrum: #(CDCl3): 5.07 (m, 5H), 3.65 (t, = 7 Hz,2 H), 1.8-2.2 (m, 18H), 1.67(s,3H), 1.59(s,15H), 1.1-18(m,6H), 0.90(d,J=7 Hz, 3H).

Mass (MIE): 428 Example2 3,7,11,15,19,23,27-Heptamethyl-6,10,14,18,22,26 - octacosahexasnol 82 g of 3,7,11,15,19,23,27 - heptamethyl 2,6,10,14,18,22,26 - octacosaheptaenoic acid was dissolved in 11 of n-amyl alcohol and 74 g of metallic sodium was added porticnwise whilethe solution was vigorously stirred. After metallic sodium was completely dissolved,the reaction solution was poured into iced water and was made acidic by adding 300 ml of 6N hydrochloric acid. It was then extracted with 11 of n-hexane, washed with water, dried and concentrated. 78 g of colorless, oily 3,7,11,15,19,23,27 - heptamethyl - 6,10,14,18,22,26 octacosahexaenoic acid was obtained as the crude product.The product was then added dropwise to 500 ml of an ethereal suspension of 10 g of lithium aluminum hydridewhile being cooled by ice and stirred. After stirring was continued for 30 minutes, 10 ml ofwaterwith 10 ml of a 15% caustic soda solution, and 30 ml | of water were sequentially added. The precipitated crystal was filtered and washed twice with 200 ml of ether. The filtrate was concentrated and the concentrate was defined by silica gel column chromatography, providing the captioned 3,7,11,15,19,23,27 - heptamethyl -6,10,14,18,22,26 octacosahexaenol as a colorless oily matter.

The physicochemical properties were as follows: Elementary analysis; as C35H60O C H calculated(%): 84.61 12.17 found(%): 84.60 12.18 Infrared absorption spectrum (nujol): vmaxcm1: 3,300,2,930,1,650,1,450,1,380.

NMRspectrum: o(CDCI3) 5.07 (m,6H), 3.65 (t, J = 7Hz, 2H), 1.8-2.2 (m, 22H), 1,67(s,3H), 1.59(s,18H), 1.1-1.8(m,6H), 0.90(d,J=7) Hz, 3H).

Mass (M/EJ: 496 Example 3 3,711,15,19,23,27,37 - Octamethyl - 6,10,14,18,22,26,30-dotriacontaheptaenol 21 g of 3,7,11,15,19,23,27,31 - octamethyl 2,6,10,14,18,22,26,30 -dotriaco ntaoctaenon itri le was dissolved in 250 ml of methanol and 100 ml of THF, and 24 g of metallic sodium was added. The reaction solution was stirred at room temperature for 30 minutes and was cooled with ice when foaming and heat generation were recognized. After the reaction solution was reacted for 2 hours, 500 ml of 6N hydrochloric acid was added and the reaction product was extracted by 500 ml of n-hexane.The organic layer was concentrated and the concentrate was refined by silica gel column chromatography, providing 16 g of 3,7,11,15,19,23,27,31-octamethyl 6,10,14,18,22,26,30 - dotriacontaheptaenon itrile.

The resulting compound was dissolved in 100 ml of propylene glycol and, after 12 g of caustic potash was added, the solution was stirred at 160 C for 3 hours.

The reaction solution was cooled with ice and, after 100 ml of 6N hydrochloric acid was added, extraction was effected using n-hexane. The organic layer was washed with water, dried and then concentrated, providing 16 g of 3,7,11,15,19,23,27,31 - octamethyl 6,10,14,18,22,26,30 - dotriacontaheptaenci:: acid as the crude reaction product. The product was added dropwise to 200 ml of an ethereal suspension of 2 g of lithium aluminum hydride. After stirring was con tinuedfor30 minutes, 2 ml of water with 2 ml of a 15% caustic soda solution, and 6 ml of water were sequentially added. The precipitated crystal was filtered and washed twice with 100 ml of ether.The filtrate was concentrated and the concentrate was refined by silica gel column chromatography, providing 14 g ofthe captioned 3,7,11,15,19,23,27,31 octamethyl - 6,10,14,18,22,26,30 - dotriacon taheptaenol in a white waxy form.

The physicochemical properties were as follows: Elementaryanalysis: as C40H68O C H calculated(%): 85.03 12.13 found(%): 85.04 12.12 Infrared absorption spectrum (nujol); Vmaxcm-1: 3,300,2,930,1,650,1,450,1,380.

NMR spectrum: #(CDCl3): 5.07 (m, 7H), 3.65 (t, J 7Hz, 2H), 1.8-2.2 (m, 26H), 1.67(s,3H), 1.59(s,18H), 1.1-1.8(m,6H), 0.90(d,J=7 Hz, 3H), Mass (M/E):564 Example 4 3,7,11,15,19,23- Hexamethyl - 6,10,14,18,22 - tetracosapentaenyl methyl ether 4 g of 3,7,1 1,15,19,23 - Hexamethyl - 6,10,14,18,22 tetracosapentaenol was dissolved in 20 ml of pyri dine, and 10g of p-toluenesulfonyl chloride was added. The solution was stirred at room temperature for 2 hours, 20 g of iced water was added and the solution was stirred for 30 minutes Extraction was then made using 100 ml of n-hexane.The extract was sequentially washed with 1 N hydrochloric acid and then with water, dried and concentrated. The concen trate was dissolved in 20 ml of dioxane. 10 ml of sodium methylate (a 28% methanolicsolution)was added and the solution was stirred and refluxed for 4 hours. The reaction solution was cooled with ice and 50 ml of 6N hvdrochloric acid was added. Extraction wasthen made using 200 ml of n-hexane. The organic layerwas washed with water, dried and concentrated. The concentrate was refined by silica gel column chromatography, providing 3 g of the cap- tioned 3,7,11,15,23 - hexamethyl -6,10,14,18,22 tetracosapentaenyl methyl ether in a colorless oily form.

The physicochemical properties were as follows: Elementary analysis: as C31H54O C H calculated(%): 84.09 12.29 found(%): 84.09 12.30 Infrared absorption spectrum (nujol): Vmaxcm-1: 2,930,2,830,1,650,1,450,1,380 NMR spectrum: #(CDCl3) 5.08 (m,5H), 3.37 (t, J = 7 Hz,2H), 3.30(s, 3H), 1.8-2.2(m,18H), 1,67(s,3H), 1.59(s,15H), 1.1-1.8(m, 5H), 0.90 (d,J=7Hz,3H).

Mass (M/E): 442 Example 5 3,711,15 19,23,27-Heptamethyl- 6,10,14,18,22,26 - octacosahexaenylacetate 3.5g of 3,7,11,15,19,23,27-heptamethyl 6,10,14,18,22,26 -octacosahexaenol was dissolved in 20 ml of pyridine, and 10 mi of acetic anhydride was added. After 20 g oficed water was added, the solution was stirred for one hour and extraction vvas then made using 100 ml of n-hexane. The extract was washed with 1 N hydrochloric acid and then with water, dried and concentrated. The concentrate was refined by silica gel column chromatography, providing 3 g of the captioned 3,7,11,15,19,23,27 - heptamethyl - 6,10,14,18,22,26 - octacosahexaenyl acetate in a colorless oily form.

The physicochemical properties were as follows: Elementary analysis: as C37H62O C H calculated(%): 82.46 11.60 found(%): 82.45 11.60 Infrared absorption spectrum (nujol): Vmaxcm-1: 2,930, 1.735, 1.650, 1.450, 1.380.

NMR spectrum: 6(CDCI3) 5.07 (m, 6H), 4.08 (t, J = 7 Hz,2H),2.02 (s,3H), 1.8-2.2(m,22H), 1.67(s,3H), 1.59(s,18H), 1.1-1.8(m, 5H), 0.90 (d,J = 7 Hz, 3H).

Mass (M/E): 538 Example 6 3,7,11,15,19,23,27,31-Octamethyl 6,10,14,18,22,26,30-dotriacontaheptaenyl benzoate 3,2 g of 3,7,11,15,19,23,27,31-Octamethyl - 6,10,14, 18,22,26,30 - dotriacontaheptanol was dissolved in 20 ml of pyridine, and 5 g of benzoyl chloride was added.

The solution was stirred at room temperature for 2 hours. 20 g of iced water was added and the solution was stirred for 30 minutes. Extraction was then made using 100 ml of n-hexane. The extract was washed with 1 N hydrochloric acid and then with water, dried and concentrated. The concentrate was refined by silica gel column chromatography, providing 2.7 g of the captioned 3,7,11,15,19,23,27,31 -octamethyl 6, 10,14.18.22.26,30- - dotriacontaheptaenyl benzoate in a white waxy form.

Elementary analysis: as C47H72O2 C H calculated(%): 84.37 10.85 found(%): 84.38 10.83 Infrared absorption spectrum (nujol): Vmaxcm-1: 3,030, 2,930, 1,720, 1,650, 1,450, 1,380.

NMR spectrum: #(CDCl3) 7.20-8.15(m,5H), 5.07(m,7H), 4.36(t, J=7Hz,2H), 1.8-2.2 (m, 26H), 1.67(s,3H), 1.59 (s,21 H), 1.1-1.8(m, 5H), û.90 (d, u =7Hz, 3K).

Mass (M/E): 668 Next, the effect of the compound ofthe present invention will be described in detail with reference to Experimental Examples.

Experimental Examples: 1. Phylatic effect (1) Method of experiment The following specimen compounds were intra muscularly administered to sIc: ICR male mice (6 to 7 weeks old, weighing 22 to 30 g) in the respective amounts tabulated in Table 1. After 24 hours, Escherichia coli obtained clinically was sub cutancoulsy innoculated at a rate of 2.8 x 1 Oalmouse.

The suivivai ratio was determined from the number of survivors on the seventh day from infection.

(2) Specimen compounds Compound A:

3,7,11 -trimethyl - 6,10- dodecadien - 1 - ol Compound B:

3,7,11,15 - tetramethyl - 2,6,10,14 - hexadecatetraen - 1 -ol Compound C:

3,7,11,15 -tetramethyl - 6,10,14 - hexadecatrien - 1 - ol CompoundD:

3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen -1-ol Compound E:

3,7,11,15,19,23,27 - heptamethyl - 2,6,10,14,18,22,26 - octacosaheptaen - 1- ol Compound F:

3,7- dimethyl - 2,6- octadien - 1 - ol Compound G:

3,7,11,15,19,23,27,31,35,39-decamethyl2,6,10,14,18,22,30,34,38 - tetracontadecaen - 1 -ol Compound H::

3,7,11,15,19,23,31,35,39,43 - undecamethyl 6,10,14,18,22,26,30,34,38,42-tetratetracontadecaen1 -ol Compound

3,7,11,15,19,23 - hexamethyl - 6,10,14,18,22 -tetraco- sapentaen - 1 - ol Compound J:

3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26octacosahexaen-1-ol Compound K:

3,7,11,15,19,23,27,31 - octamethyl 6,10,14,18,22,26,30 - dotriacontaheptaen - 1 - ol Control compound: MDP (AcMur- L-Ala-D-Glu) (3) Results The results are illustrated in Table 1.

Table 1 Survival ratio after one week, number of Specimen survivals/number of compound Dosage subjects compound A lOOmg/kg 6/10 . 60 (z) compound B 100 mg/kg 6/10 # 60 (%) compound C 100 mg/kg 7/10 # 70 (%) compound D 100 mg/kg 6/10 # 60 (%) compound E 50mg/kg 9/10 + 90 (z) 100mg/kg 10/10 100 (%) compound F 100 mg/kg 3/10 # 30 (%) compound G 100mg/kg 10/10 100 (t) compound H 100 mg/kg 7/10 # 70 (%) compound I 100 mg/kg 9/10 + 90 (%) compound J 50 mg/kg 6/100 # 60 (%) 100mg/kg 10/10 100 (81 compound K SOmg/kg 5/10 - 50 (%) 100 mg/kg 9/10 # 90 (%) blank 1/80 # 1.25 (%) (non-treated) control 3.5 mg/kg 4/10 # 40 (%) compound (MDP) 2. Phagocytosis-enhancing effect of macrophage (1) Method and results of experiment Each specimen compound was intramuscularly administered to slc; ICR male mice (8 weeks old, weighing 22 to 30 g) at a rate of 100 mg/kg. After 24 hours, the carbon clearance test was conducted to measure the phagocystosis-enhancing effect of mac rophages. The carbon clearance test was carried out in accordance with the method described by G.

Biozi, B. Benacerraf and B. N. Halpern in Brit. J. Exp.

Path.,24,441-4587.

The results are shown in Table 2.

In Table 2, the value ofthe changes in phagcytosis represents a relative value with respect to the half-value period ofthe blank which was set at 100.

Table 2 Number Half-value Changes in Specimen of period phagocytosis compound animal: (nin:sec) # blank (non- 48 8:D1 100 treated) compound .- 4 5:34 10 compound D 4 5:30 69 compound E 4 5:18 66 compound G 3 6:43 84 compound I 4 5:20 63 compound J 4 5:15 65 compound k 4 325 43 In Table 2, when the phagocytosis is enhanced, the half-value period drops. However, at 20 (% ) or more, that is, when its numeric value is smaller than 80, the phagocytosis is strongly promoted. Accordingly, among the compounds of the present invention, compounds A, D, El, l, J and K obviously have an extremely high phagocytosis-enhancing effect.

It is evident from the Experimental Examples described above that the compound of the present invention normalises the immunological function and enhances resistance against infection.

The compound having the formula [XIII] was examined in the same way as before described.

Specimen compounds Compound L:

6,10,14,18,22,26- hexamethyl - 5,9,13,17,21,25 heptacosahexaen-2-one Compound M:

6,10,14,18,22,26,30-heptamethyl-5,9,13,17,21,25,29 - hentriacontahepten - 2 - one Compound N:

6,10 - dimethyl - 5,9- undecadien -2 - one Compound 0:

6,10,14,18,22,26,30,34,38,42-decamethyl5,9,13,17,21,25,29,33,37,41-tetracontadecaen-2one Compound P:

6,10-dimethylundecan-2-one Compound Q:

6,10,14-trimethylpentadecan-2-one Compound R:

6,10,14,1 8,22,25,30,34,38,42 - decamethyltritetracon- tan-2-one Control compound: MDP (AcMur-L-Ala-D- Glu) Results of Experiment The results are illustrated in Table 3.

Table 3 Survival ratio after one Specimen week. number of survivors/ compound Dosage number of subjects compound If 50 m7 4/10 . 40 (t) 100 mg 9/10 # 90 (%) compound M 100 mg 8/10 # 80 (%) compound N 100 mg 4/10 # 40 (%) compound O 100 mg 4/10 # 40 (%) compound P 100 mg 8/10 # 80 (%) compound Q 100 mg 10/10 # 100 (%) compound H 100 mg 3/10 + 30 (8) blank (non- 1/80 1.25 (1) treated 4/10 # 1.25 (%) control compound 3.5 mg/kg 4/10 # 40 (%) (NDP) Table 4 Number Half-value Specimen of period Changes in compound animals (min:sec) phagocytosis(%) compound 1 4 6::00 75 compound N 4 7:00 87 blank (non- 48 8:01 100 treated) Accordingly, compounds Land M as the typical compounds of the present invention obviously have an extremely high effect of promoting phagocytosis.

The following compounds S, T, U and V were examined in the same way as before described.

Specimen compound Compound S:

3,7,11,15 -tetramethyl hexadec - 1 - en - 3 - ol Compound T:

3,7,11,15 - tetramethyl- 1,6,10,14 - hexadecatetraen 3-ol Compound U: docosanol

Compound V:

phytol Control compound: MDP(AcMur-L-Ala-D-Glu) Results of Experiments The results are illustrated in Table 5.

Table 5

Survival ratio after Specimen one week Dosage compound number of number of survivors subjects compound S 100 mg/kg 10/10 + 100 (%) compound T 100 mg/kg 10/10 + 100 (%) compound U 100 mg/kg 3/10 + 30 (%) compound V 100 mg/kg 10/10 + 100 (%) blank (non1/80 + 1.25 (%) treated) control com3.5 mg/kg 4/10 # 40 (%) pound (MDP) Table 6

Specimen Number Half-value Changes in compound of period phagocytosis animals (min:sec) (%) blank (non- 48 8:01 100 treated) compound T 3 7 : 41 96 ccmpound V 4 5: 48 72 In Table 6, when the phagocytosis is enhanced, the half-value period drops. However, at 20 (%) or more, that is, when its numeric value is smallerthan 80, the phagacytosis is strongly promoted. Accordingly, among the compounds of the present invention, compound V exhibited a particularly high phagocyto sis-enhancing effect.

The compound of the present invention has extremely low toxicity and extremely high safety and can be dosed continuously for an extended period of time. In this sense, too, the compound of the present invention is highly valuable.

When the compounds (A th rough K) described above were perorally administered to SD rats (weighing about 200 g) at a rage of 500 mg/kg, neither death ofthe subjects nor side reaction were observed atall.

The dosage of the compound ofthe present invention as a prophylactic/therapeutic agent against human immunodeficiency diseases or as a phylactic agent against human infectious diseases varies remarkably depending upon the kind and degree of the diseases and upon the kind ofthe compounds is not limitative, in particular. Generally, about 10 to 4,000 mg and preferably, 50 to 500 mg per adult per day is dosed either perorally or parenterally. When the compound is dosed as the phylactic agent against infectious diseases, it may be of course dosed in combination with antibiotics. Examples of dosage forms are powder, fine particles, granules, tablets, capsules, injection, and so forth. In the preparation of the compound, the drug is prepared in a customary mannerusing an ordinary support.

In preparing a peroral solid preparation, for example, an excipient and, if necessary, a binder, a disintegrator, a lubricant, a coloring agent, a flavoring agent and the like are added to the principal agent and the mixture is them prepared in the form of a tablet, a coated tablet, a granule, powder, a capsule, and the like in a customary manner.

Examples of excipients are lactose, corn starch, refined sugar, glucose, sorbitol, crystalline cellulose, and the like. Examples of binders are polyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl-starch, polyvinylpyrrolidone, and the like. Examples of disintegrators are starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin, pectin, and the like.

Examples of lubricants are magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil, and the like. Examples of coloring agents arethose whose use for pharmaceuticals are officially permitted. Examples offlavoring agents are cocoa powder, menthol, aromatic powder peppermint oil, borneoi, powdered cinnamon bark, and the like. Sugarcoating, gelatin coating or the like may be appropriately applied to theses tablets and granules.

In preparing an injection, a PH adjuster, a buffer, a stabilizer, a preserver, a solubilizer, and the like are added to the principal agent, whenever necessary, and the injection of subcutaneous, intramuscular or intravenous injection is prepared in a customary manner.

The drug ofthe present invention can also be dosed to the livestock and poutry either perorally or parenterally. Peroral administration is generally effected by adding the drug to the feed. Parenteral administration can be effected by preparing an injection in a customary manner and then dosing the injection parenterally, intramascularly or in travenousiy.

The following are examples of preparations using 3,7,11,15,19,23,27,31 - octamethyl -2,6,10,14,18,22,26,30 - dotriacontaoctaen - 1 - ol (hereinafter referred to as the "principal agent") which is one of the compounds ofthe present invention.

Example of Preparation 1 (capsule) principal agent 5 g microcrystalline cellulose 80 g cornstarch 20 g lactos 22 g polyvinylpyrrolidione 3 g total 130 g The components were granulated in a customary manner and were packed into 1,000 hard gelatin capsules. One capsule contained 5 mg of the principal drug.

Example of Preparation 2 (powder) principal agent 50 g microcrystalline cellulose 400 g cornstarch 550 g total 1,000 g The principle agentwasfirst dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafter dried.-itwas then mixed with corn starch and was prepared inthepowderform of 20-fold dilution.

Example of Preparation 3 (tablet) principal agent 5 g cornstarch 10 g lactose 20 g calcium carboxymethyl cellulose 10 g microcrystalline cellulose 40 g polyvinylpyrrolidone 5 g talc 10 g total 100 g The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafter dried. Itwasthen mixed with corn starch, lactose and calcium carboxymethylcellulose and an aqueous solution of polyvinylpyrrolidone was added as a binder. The mixed solution was then granulated in a customary manner. After talc as a lubricant was added and mixed, the mixture was prepared in 100 mg tablets. One tablet contained 5 mg ofthe principal agent.

Example of Preparation 4 (injection) principal agent 10 g Nikkoi HCO-60 (product of Nikko Chemical Co.) 37 g sesameoil 29 sodium chloride 9 g propyleneglycol 40 g phosphateuffer (0.1 M, pH 6.0) 100 Ml distilled water q.s. ad 1,000 ml The principal agent, Nikkol HCO-60, sesame oil and the halfofpropylene glycol were mixed and heat dissolvedatabout805C. Phosphate buffer and distilled water dissolving therein in advance sodium chloride and propylene glycol were heated to about 80"C and added to the solution described above to prepare 1,000 ml of an aqueous soiution. The resulting aqueous solution was dividedly charged into 2 ml ampoules. After heat-sealed, the ampoules were heat-sterilized.

One ampoule contained 20 mg of the principal agent.

Thefollowing are examples of preparations using 3,7,11,15,19,21,27,31 - octamethyl - 6, 10,14,18,22,26,30 - doctriacontaheptaen - 1 - ol (hereinafter referred to as the "principal agent") which is one ofthe compounds ofthe present invention.

Example of Preparation 5 (capsule) principal agent 5 g microcrystalline cellulose 80 g cornstarch 20 g lactose 22 g polyvinylpyrrolidone 3 9 total 130 g The components were granulated in a customary manner and were packed into 1,000 hard gelatin capsules. One capsule containing 5 mg ofthe principal drug.

Example of Preparation 6 (powder) principal drug 5G g m:=rocrystaliine cellulose 400 g corn starch 550 g total 1,000 g The principal agentwasfirst dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafterdried. Itwasthen mixed with corn starch and was prepared in the powderform of 20-fold dilution.

Example of Preparation 7 (tablet) principal agent 5 g cornstarch 10 g lactose 20 g calcium carboxymethyl cellulose 10 g microcrystalline cellulose 40 g polyvinylpyrrolidone 5 g talc 10 g total 100 g The principal agentwas first dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafter dried. It was then mixed with corn starch, lactose and calcium carboxymethylcellulose and an aqueous solution of polyvinylpyrrolidone was added as a binder. The mixed solution was then granulated in customary manner. Aftertalcas a lubricant was added and mixed, the mixture was prepared in 100 mg tablet. One tablet contained 5 mg ofthe principal agent.

Example of Preparation 8 (injection) principal agent 10 g Nikkol HCO-60 (product of Nikko Chemical Co.) 37 g sesame oil 29 sodium chloride 9 g propyleneglycol 40 g phosphoric acid buffer (0.1 M,pH6.0) 100 ml distilled water total 1,000 ml The principal agent, Nikkol HCO-60, sesame oil and the half of propylene glycol were mixed and heat dissolved at about 80'C. Phosphate buffer and distilled water dissolving therein in advance sodium chloride and propyleneglycol were heated to about 80"C and added to the solution described above to prepare 1,000 ml of an aqueous solution. The resulting aqueous solution was dividelycharged into 2 ml ampoules. After heat-sealed, the ampoules were heat-sterilized.

One ampoule contained 20 mg of the principal agent.

Preparations using 6,10,14,18,22,26- hexamethyl 5,9,13,17,21,25 - heptacosahexaen - 2 - one (hereinaf ter referred to as the "principal agent"),follow.

Example of Preparation 9 (capsule) principal agent 5 g microcrystallinecellulos 80 g cornstarch 20 g lactose 22 g polyvinylpyrrolidone 3 9 total 130 g Aftergranulated in a customary manner, these components were charged into 1,000 hard gelatin capsules. Each capsule contained 5 mg of the principal agent.

Example of Preparation 10 (powder) principal agent 50 g microcrystalline cellulose 400 g cornstarch 550 g total 1,000 g The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafter dried.

Afterthe dried matter was mixed with corn starch, the mixture was prepared in the powder form of 20-fold dilution of the principal agent in a customary manner.

Example of Preparation 11 (tablet) principal agent 5 g cornstarch 10 g lactose 20 g calcium carboxymethyl cellulose 10 g microcrystalline cellulose 40 g polyvinylpyrrniidone 5 9 talc 10 g total 100 g The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafter dried. Corn starch, lactose and calcium carboxymethylcellulose were then added and mixed with the dried matter. After an aqueous solution of polyvinylpyrrolidone was added as a binder, the mixture was granulated in a customary manner. After talc as the lubricant was added, 100 mg tablets were prepared. Each tablet contained 5 mg of the principal agent.

Example of Preparation 12 (injection) principal agent 10 g Nikkol HCO-60 (product of Nikko Chemical Co.,) 37 g sesameoil 2g sodium chloride 9 g propyleneglycol 40 g phosphate buffer (0.1 M,pH6.0) 100 ml distilled water q.s. ad 1,000 ml The principal agent, Nikkol HCO-60, sesame oil and the half of propylene glycol were mixed and heatdissolved at about 805C. Phosphate buffer and distilled water dissolving therein in advance sodium chloride and propylene glycol were heated to about 80"C and added to the solution described above to prepare 1,000 ml of an aqueous solution. The resulting aqueous solution was dividedly charged into 2 ml ampoules. After heat-sealed, the ampoules were heat-sterilized.

One ampoule contained 20 mg ofthe principal agent.

Claims

1. A ss,y-dihydropolyprenyl alcohol derivative having the formula:

wherein n is a integer of 5 to 7 and R is hydrogen, a loweralkyl group oran aliphatic oraromaticacyl group.

2. A composition as claimed in claim 1, and substantially as hereinbefroe described with refer encetoanyone of Preparations 9to 12.

2. A ss,y-dihydropolyprenyl alcohol derivative as claimed in claim 1, wherein said lower alkyl group is a straight chain or branched chain alkyl group having from 1 to 6 carbon atoms.

3. A I3,y-dihydrnpolyprenyl alcohol derivative as claimed in claim 1 or 2 wherein R is hydrogen.

4. A pharmacuetical composition which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a polyprenyl compound selected from polyprenyl compounds having the following formulae:

wherein n is an integer of 5 to 7 and R is a lower alkyl group or an aliphatic or aromatic acyl group;

wherein each of a and bis hydrogen or a and bare combined togetherto form a bond, and n is an integer of 1to10;

wherein each of a and bis hydrogen or a and bare combined together to form a bond, and n is an integer of 1to10; 3,7,11,15 -tetramethylhexadec 1-en -3-ol, 3,7,11,15 -tetramethyl - 1,6,10,14 -hexadecatetraen - 3 - ol, docosanol, phytol an iso-phytol.

5. A composition as claimed in claim 4, wherein the lower alkyl group in the compound XI is a straight chain or branched chain alkyl group having 1 to 6 carbon atoms.

6. A process for preparing a derivative as claimed in claim 1, which comprises the steps hereinbefore described under "Method of Preparation 1".

7. A process for preparing a derivitive as claimed in claim 1, which comprises the steps hereinbefore described under "Method Preparation 2"

8. A process for preparing a derivative as claimed in claim 1, which comprises the steps hereinbefore described under "Method of Preparation 3".

9. A derivative as claimed in claim 1, and substantially as herein before described with reference to any one of Examples 1 to 6.

10. A composition as claimed in claim 4, and substantially as hereinbefore described with refer ence to any one of Preparations 1 to 12.

Newclaimsoramendmentstoclaimsfiled on Superseded claims 1 to 10.

1. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of polyprenyl compound having the following formula:

wherein each of a and b is hydrogen or a and bare combined togetherto form a bond, and n is an integer of 1 to 10.