CA1310660C - B, -dihydropolyprenyl alcohol derivatives and pharmaceutical composition containing a polyprenyl compound - Google Patents
B, -dihydropolyprenyl alcohol derivatives and pharmaceutical composition containing a polyprenyl compoundInfo
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- CA1310660C CA1310660C CA000429108A CA429108A CA1310660C CA 1310660 C CA1310660 C CA 1310660C CA 000429108 A CA000429108 A CA 000429108A CA 429108 A CA429108 A CA 429108A CA 1310660 C CA1310660 C CA 1310660C
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C255/00—Carboxylic acid nitriles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/765—Polymers containing oxygen
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- C07—ORGANIC CHEMISTRY
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- C07C29/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
- C07C29/132—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group
- C07C29/136—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH
- C07C29/147—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring by reduction of an oxygen containing functional group of >C=O containing groups, e.g. —COOH of carboxylic acids or derivatives thereof
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- C07C33/02—Acyclic alcohols with carbon-to-carbon double bonds
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C43/00—Ethers; Compounds having groups, groups or groups
- C07C43/02—Ethers
- C07C43/03—Ethers having all ether-oxygen atoms bound to acyclic carbon atoms
- C07C43/14—Unsaturated ethers
- C07C43/15—Unsaturated ethers containing only non-aromatic carbon-to-carbon double bonds
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- C07C49/20—Unsaturated compounds containing keto groups bound to acyclic carbon atoms
- C07C49/203—Unsaturated compounds containing keto groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/08—Preparation of carboxylic acids or their salts, halides or anhydrides from nitriles
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
- C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/03—Monocarboxylic acids
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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- C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
- C07C69/12—Acetic acid esters
- C07C69/14—Acetic acid esters of monohydroxylic compounds
- C07C69/145—Acetic acid esters of monohydroxylic compounds of unsaturated alcohols
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- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/76—Esters of carboxylic acids having a carboxyl group bound to a carbon atom of a six-membered aromatic ring
- C07C69/78—Benzoic acid esters
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12C—BEER; PREPARATION OF BEER BY FERMENTATION; PREPARATION OF MALT FOR MAKING BEER; PREPARATION OF HOPS FOR MAKING BEER
- C12C11/00—Fermentation processes for beer
- C12C11/02—Pitching yeast
Abstract
Abstract of the Disclosure A .beta.,.gamma.-dihydropolyprenyl alcohol derivative having the formula:
Description
~3~0~
~,'f-DIHYDROPOLYPRENYL ALCOHOL DERIVATIVES AND
PHAR~ACEUTICAL COMPOSITION CONTAINING A POLYPRENYL
COMPOUND
This invention relates to a novel ~,~f-dihydro-polyprenyl alcohol derivatives having the formula (I), a process for preparing the same and a pharmaceutical composition containing a polyprenyl compound having the formula XI, XII or XIII or another polyprenyl compound, which is useful as a =prophylactic therapeutie agent for human and animal immuno-deficieney diseases and a phylaetic agent against human and animal infectious diseases.
( 2 C CH-CH2 ~ CH2-CH-CH2-CH OR (I) wherein n is an integer of 5 to 7 and R is a hydrogen atom, a lower alkyl group or an aliphatie or aromatic acyl group.
In this formula (I), the lower alkyl group in the definition of R means Cl to C6 straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, l-methyl-propyl, tert-butyl, n-pentyl, l-ethylpropyl, iso-amyl and n-hexyl.
13~6~
The novel compound having the formula (I) can be prepared by various methods and some typical examples will be given.
Method of Preparation 1 (a) The compound represented by the following general formula [II] is reacted with an alkyl cyano-acetate in the presence of a base to obtain a com-pound represented by the following general formula [III]:
CH
1 3 ll H-(CH2-C=CH-CH2 ~ CH2-C-CH3 [II]
wherein n is an integer of 5 to 7;
-(CH2-C=~H-CH2 ~ cH2-c = C-COORI [III]
wherein n is an integer of 5 to 7 and R'is a lower alkyl group.
(b) The resulting compound of formula [III] is reduced using a reducing agent such as sodium boro-hydride to obtain a compound represented by the following general formula [IV]:
H-(CH2-C=CH-CH2 ~ CH2-CH-CH-COOR [IV]
wherein each of n and R has the meaning as defined above.
(c3 The resulting compound of formula [IV]
is subjected to ester and nitrile hydrolysis in the presence of a strong alkali such as potassium hydroxide to obtain a compound represented by the following general formula [V]:
H-(CH2-C=CH-CH2 ~ CH2-CH- CH-COOH [V3 o/e~/
wherein n has the same meaning as ~ef ned above.
(d) The resulting compound of formula [V] is decarboxylated in the presence of pyridine/copper, for example, to obtain a compound represented by the following general formula [VI]:
( H2C CH-CH2 ~ CH2-CH-CH2-COOH [VI]
wherein n has the same meaning as defined above.
(e) The resulting compound of formula [VI] is reduced using a reducing agent such as lithium aluminum hydride, vitrite, sodium bis(2-methoxyethoxy)aluminum hydride or the like, providing one of the intended compounds of the general formula [I]:
ICH3 fH3 ( H2 C CH-CH2 ~ CH2-CH-CH2-CH OH [I]
wherein n has the same meaning as defined already.
(f) The alcoholic hydroxyl group of the compound of formula [I] is converted into an active group such as a tosyl or mesyl group and the com-pound 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 correspond-ing aliphatic or aromatic acyl chloride or acid anhydride.
Method of Preparation 2 A compound represented by the following general formula [II] is subjected to the Wittig-Homer reac-tion together with triethylphosphonoacetic acid in 131~0 the presence of a base to obtain a compound represented by the following general formula [VII]:
CH3 o H-(CH2-C=CH-CH2 ~ CH2-C-CH3 [II]
wherein n is an integer of 5 to 7;
H-(CH2-C=CH-CH2 ~ CH2-C=CH-COOC2H5[VII]
wherein n has the same meaning as defined already.
The resulting compound of formula [VII] is hydrolyzed using a base such as caustic potash to obtain a compound represented by the following general formula [VIII]:
H-(CH2-C=CH-CH2 ~ CH2-C=CH-COOH [VIII]
wherein n has the same meaning as defined already.
The compound of formula lVIII] is then reduced using metallic sodium or the like to obtain a com-pound represented by the following general formula [VI]:
~,'f-DIHYDROPOLYPRENYL ALCOHOL DERIVATIVES AND
PHAR~ACEUTICAL COMPOSITION CONTAINING A POLYPRENYL
COMPOUND
This invention relates to a novel ~,~f-dihydro-polyprenyl alcohol derivatives having the formula (I), a process for preparing the same and a pharmaceutical composition containing a polyprenyl compound having the formula XI, XII or XIII or another polyprenyl compound, which is useful as a =prophylactic therapeutie agent for human and animal immuno-deficieney diseases and a phylaetic agent against human and animal infectious diseases.
( 2 C CH-CH2 ~ CH2-CH-CH2-CH OR (I) wherein n is an integer of 5 to 7 and R is a hydrogen atom, a lower alkyl group or an aliphatie or aromatic acyl group.
In this formula (I), the lower alkyl group in the definition of R means Cl to C6 straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, l-methyl-propyl, tert-butyl, n-pentyl, l-ethylpropyl, iso-amyl and n-hexyl.
13~6~
The novel compound having the formula (I) can be prepared by various methods and some typical examples will be given.
Method of Preparation 1 (a) The compound represented by the following general formula [II] is reacted with an alkyl cyano-acetate in the presence of a base to obtain a com-pound represented by the following general formula [III]:
CH
1 3 ll H-(CH2-C=CH-CH2 ~ CH2-C-CH3 [II]
wherein n is an integer of 5 to 7;
-(CH2-C=~H-CH2 ~ cH2-c = C-COORI [III]
wherein n is an integer of 5 to 7 and R'is a lower alkyl group.
(b) The resulting compound of formula [III] is reduced using a reducing agent such as sodium boro-hydride to obtain a compound represented by the following general formula [IV]:
H-(CH2-C=CH-CH2 ~ CH2-CH-CH-COOR [IV]
wherein each of n and R has the meaning as defined above.
(c3 The resulting compound of formula [IV]
is subjected to ester and nitrile hydrolysis in the presence of a strong alkali such as potassium hydroxide to obtain a compound represented by the following general formula [V]:
H-(CH2-C=CH-CH2 ~ CH2-CH- CH-COOH [V3 o/e~/
wherein n has the same meaning as ~ef ned above.
(d) The resulting compound of formula [V] is decarboxylated in the presence of pyridine/copper, for example, to obtain a compound represented by the following general formula [VI]:
( H2C CH-CH2 ~ CH2-CH-CH2-COOH [VI]
wherein n has the same meaning as defined above.
(e) The resulting compound of formula [VI] is reduced using a reducing agent such as lithium aluminum hydride, vitrite, sodium bis(2-methoxyethoxy)aluminum hydride or the like, providing one of the intended compounds of the general formula [I]:
ICH3 fH3 ( H2 C CH-CH2 ~ CH2-CH-CH2-CH OH [I]
wherein n has the same meaning as defined already.
(f) The alcoholic hydroxyl group of the compound of formula [I] is converted into an active group such as a tosyl or mesyl group and the com-pound 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 correspond-ing aliphatic or aromatic acyl chloride or acid anhydride.
Method of Preparation 2 A compound represented by the following general formula [II] is subjected to the Wittig-Homer reac-tion together with triethylphosphonoacetic acid in 131~0 the presence of a base to obtain a compound represented by the following general formula [VII]:
CH3 o H-(CH2-C=CH-CH2 ~ CH2-C-CH3 [II]
wherein n is an integer of 5 to 7;
H-(CH2-C=CH-CH2 ~ CH2-C=CH-COOC2H5[VII]
wherein n has the same meaning as defined already.
The resulting compound of formula [VII] is hydrolyzed using a base such as caustic potash to obtain a compound represented by the following general formula [VIII]:
H-(CH2-C=CH-CH2 ~ CH2-C=CH-COOH [VIII]
wherein n has the same meaning as defined already.
The compound of formula lVIII] is then reduced using metallic sodium or the like to obtain a com-pound represented by the following general formula [VI]:
2 C CH-C~2 ~ CH2-C~CH2-COOH [VI]
The corresponding alcohol and its derivative can be derived by following the procedures of Method of Preparation 1.
Method of Preparation 3 A compound represented by the following general formula [II] is subjected to the Witting-Hormer - reaction together with diethylphosphonoacetonitrile in the presence or a base to obtain a compound 1310~0 represented by the following general formula [IX]:
CH O
1 3 ll H-(CH2-C=CH-CH2 ~ CH2-C-CH3 [II]
wherein n is an integer of 5 to 7;
H-(CH2-C=CH-CH2 ~ CH2-C=CH-CN [IX]
wherein n has the same meaning as defined above.
The resulting compound of formula [IX] is reduced using a reducing agent such as metallic magnesium in a mixed solvent such as methanol/THF
to obtain a compound represented by the following general formula [X]:
fH3 ICH3 2 2 ~ CH2 CH CH2 CN [X]
wherein n has the same meaning as defined above.
Next, the compound of formula [X] is hydro-lyzed using caustic potash, for example, to obtain a compound represented by the following general C formula [VI~]:
fH3 ICH3 ( 2 C CH-CH2 ~ CH2-CH-CH2-cooH [VI~]
Thereafter, the procedures of Example of Preparation 1 are followed to derive the corre-sponding alcohol and its derivative.
The invention further provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a pharmaceutically ~ffective amount of a polyprenyl compound selected foEm the group consisting of polyprenyl compounds having ~310v~
the ~ollowing formulae:
Cl~3 fH3 ( 2 C CH CH2 ~ CH2-CH-CH2-CH OR" [XI]
wherein n is an integer of 5 to 7 and R"is a lower alkyl group or an allphatic or aromatic acyl group;
f H3 CIH3 H-(CH2-C=CH-CH2 ~ CH2-C-CH-CH20~ [XII]
a b wherein each of _ and b is hydrogen or a and b are combined together to form a bond, and n is an integer of l to l0;
H 'C~l2-C-CH-CH2 ~ C~2-C=o [XIII]
a b 2~ wherein each of a and _ is hydrogen or a and b are combined together to form a bond and n is an integer of l to l0;
The corresponding alcohol and its derivative can be derived by following the procedures of Method of Preparation 1.
Method of Preparation 3 A compound represented by the following general formula [II] is subjected to the Witting-Hormer - reaction together with diethylphosphonoacetonitrile in the presence or a base to obtain a compound 1310~0 represented by the following general formula [IX]:
CH O
1 3 ll H-(CH2-C=CH-CH2 ~ CH2-C-CH3 [II]
wherein n is an integer of 5 to 7;
H-(CH2-C=CH-CH2 ~ CH2-C=CH-CN [IX]
wherein n has the same meaning as defined above.
The resulting compound of formula [IX] is reduced using a reducing agent such as metallic magnesium in a mixed solvent such as methanol/THF
to obtain a compound represented by the following general formula [X]:
fH3 ICH3 2 2 ~ CH2 CH CH2 CN [X]
wherein n has the same meaning as defined above.
Next, the compound of formula [X] is hydro-lyzed using caustic potash, for example, to obtain a compound represented by the following general C formula [VI~]:
fH3 ICH3 ( 2 C CH-CH2 ~ CH2-CH-CH2-cooH [VI~]
Thereafter, the procedures of Example of Preparation 1 are followed to derive the corre-sponding alcohol and its derivative.
The invention further provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a pharmaceutically ~ffective amount of a polyprenyl compound selected foEm the group consisting of polyprenyl compounds having ~310v~
the ~ollowing formulae:
Cl~3 fH3 ( 2 C CH CH2 ~ CH2-CH-CH2-CH OR" [XI]
wherein n is an integer of 5 to 7 and R"is a lower alkyl group or an allphatic or aromatic acyl group;
f H3 CIH3 H-(CH2-C=CH-CH2 ~ CH2-C-CH-CH20~ [XII]
a b wherein each of _ and b is hydrogen or a and b are combined together to form a bond, and n is an integer of l to l0;
H 'C~l2-C-CH-CH2 ~ C~2-C=o [XIII]
a b 2~ wherein each of a and _ is hydrogen or a and b are combined together to form a bond and n is an integer of l to l0;
3,7,11,15-tetramethylhexadeca-1-en-3-ol:3,7,11,15-tetramethyl-l,6,l0,l~-hexadecatetraen-3-ol;
docosanol; phytol and iso-phytol.
In other words, the above defined pharmaceutical composition contains as the effective ingredient the novel ~ ,~-dihydropolyprenyl alcohol derivative as mentioned before or another polyprenyl compound.
Among those compounds of formula [XII], the following are not included in the compound of formula (I).
~.'' J
- 6a - 65702-174 H--~CH2-C=CH-CH2 )n CH2-CH C 2 2 (wherein n is an integer of 1 to 4 or 8 to 10), and ,CH3 iCH3 H--~ CH2-C=CH-CH2 ~ CH2-C=CH-CH20H
(wherein n is an integer of 1 to 10).
All the above defined pharmaceutical composition is effective as a prophylactic, therapeutic agent for human and animal immuno-deficiency diseases. Morevover, especially the composition containing the polyprenyl compound having the formula XII or XIII is useful as a phylactic agent . ~
1 3 ~
against human and animal infectious deseases.
Immunology has made a 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 of the complicated microbism involving various fundamental troubles has become a serious problem. The microbism induced by cancer, for example, is one of the most troublesome clinical problems. Cancer triggers the drop of general and local resistance and complicating and secondary diseases would occur in an easily in-fective state. Infection due to cancer mostly assumes the form of infection through a respirator, a urinary passage, a placental passage and a skin at the initial stage and results mostly in pneumonia and sepsis at the final stage. The mechanism of coincidence of infection due to this tumor takes generally the following process.
With the progress of leukemia, malignant lymphoma or cancer, the function of normal tissue and cells, especially that of lymphatic cells and granulocyte cells is reduced so that a patient is easily infected and infectious diseases occur coincidently. In such a case, the dose of anti-biotics does not result in radical cure but mostly 3~ in such problems as repeated infection, microbial substitution or refractory infection. Accordingly, radical cure can not be expected by use of the conventional antibiotics and chemotherapeutic agents but can be cured only after a biophylactic function is improved. Hence, development of drugs for 1310~
improving the biophylactic function of organism has been earnestly awaited.
On the other hand, antibiotics have been used primarily to 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 social problem such as residual drugs in various products, increase of drug-resistant bacteria and microbial substitution. In other words, the phylactic power of host is reduced remarkably and a restorative function against infectious diseases is also impaired so that the microbism is difficult to cure and the host is liable to suffer from reinfection. Furthermore,~
spontaneous infectious diseases topportunistic infection) reduce the producibility of livestock and its loss is great. Hence~ the immunological compe-tence of the host and the biophylactic function mustbe enhanced.
Under these circumstances, the inventors of the present invention have made intensive studies in search of drugs that normalize an immunological function and enhance a biophylactic function, and have found unexpectedly that a polyprenyl compound as defined above is effective as a prophylactic/
therapeutic agent for human and animal immuno-deficiency diseases and especially as a phylactic agent against human and animal infectious diseases:
In other words, the compound of the present invention is effective in normalizing human and animal immunological functions and enhancing resistance against the infection. Hence, the com-pound is useful as a prophylactic/therapeutic agent ~3~6~
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 rheumarthritis, autoimmune disease, cancer, asthma, various infectious diseases such as sepsis, pneumonia, meningitis and other viral infec-tious diseases.
For animals, the compound of the present inven-tion is effective for swine diarrhea, pneumonia (SEP,AR, haemophilus, pasteurella) and TGE, avian pneumonia (mycoplasma, haemophilus) and Marek's diseases, and bovine diarrhea, pneumonia and mastitis.
In curing human and animal infectious diseases by the compound of the present invention, the thera-peutic effect can be improved remarkably by the use o~ the present compound in combination with anti-biotics. This is significant because the afore-mentioned social problem of the abuse of antibiotics can also be solved.
In the case of animals such as the livestock and poultry, the compound of the present invention enhances the resistance of organism against infec-tion and hence the compound is effective as a basal drug for newborn. Furthermore, it is effective for mitigating the stress resulting from mass raising, transportation, and the like and is also useful for improving the vaccinal effect.
Accordingly, it is another purpose of the present invention to provide a novel prophylactic/
therapeutic composition for human and animal immunodeficiency.
It is further purpose of the present invention - to provide a novel phylactic composition against human and animal infectious diseases.
1 3 ~ 0 The following compounds are typical examples of polyprenyl alcohols having the formulae (XI) 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-octamethyl-2,6,10,14,18, 22,26,30-dotriacontaoctaen-1-ol o 3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18, 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-tetratetraconta-undecaen-l-ol o 3,7,11,15,19,23,27-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-l-ol o 3,7,11,15,19-pentamethyl-2,6,10,14,18-eicosapen-taen-1-ol o 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-l-ol o 3,7,11-trimethyl-2,6,10~dodecatrien-1-ol o 3,7-dimethyl-2,6-octadien-1-ol o 3,7,1].,15,19,23,27,31,35-nonamethyl-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-undecamethyl-6,10,14,18,22,26,30,34,38,42-tetratetraconta-decaen-l-ol o 3,7,11,15,19-pentamethyl-6,10,14,18-eicosa-tetraen-1-ol o 3,7,11,15-tetramethyl-6,10,14-hexadecatrien-l-ol o 3,7,11-trimethyl-6,10-dodecadien-1-ol ~310~fi~
o 3,7-dimethyl-6-octen-1-ol o 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaen-l-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 compound having the formulae [XI] and [~II]
can be prepared by various methods. When _ and b in the general formula [XII] are combined together to form a bond, the compound can be prepared by those methods which are disclosed by Burrell et al.
in J. Chem. Soc. (C), 1966, 2144, Popjak et al. in J. Biol. Chem., 237, 56 (1962), O. 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 _ and b are both hydro~en atoms in the formula [XII], the compound and the compound having the formula [XI] can be prepared by the.method disclosed in Japanese Patent Laid-Gpen 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~
CH3 o H-(cH2-c=cH-cH2 ~ CH2-C-CH3 [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]:
H-(CH2-C=CH-CH2 ~ CH2-C=- C-COOR' [III]
~ 3~&~a (wherein n has the same meaning as above and R~is a lower alkyl group).
~ b) The resulting compound of formula [III] is reduced by a reducing agent such as sodium boro-hydride to obtain a compound represented by the formula [IV]:
CIH3 clH3 ICN
H-(CH2-C=CH-CH2 ~ CH2-CH--CH-COOR' [IV]
(wherein n and R'have the same meaning as above).
(c) The resulting compound of the formula [IV]
is decarboxylated in the presence of a strong alkali such as potassium hydride to obtain a compound represented by the formula [XV]:
CIH3 lH3 ( 2 2 ~ C 2 CH CH2 CN [XV]
(wherein n has the same meaning as above).
(d) The resulting compound of the formula [XV]
is hydrolyzed in the presence of a strong alkali such as potassium hydroxide to obtain a compound represented by the formula [XVI]:
( 2 C CH-CH2 ~ CH2-CH-CH2-COOH [XVI]
(e) The intended compound of the formulae [XI] and [XII] where a and b are hydrogen can be prepared by reducing the resulting compound of the formu].a [XVI] using a reducing agent such as vitrite, lithium aluminum hydride, or the like:
( 2 C CH CH2~ CH2-CH-CH2-CH2OH
(wherein n is an integer of 1 to 10).
131~g60 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-nonadeca-tetraen-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-nonamethyl-5,9,13,17, 21,25,29,33,37-nonatriacontanonaen-2-one o 6,10,14,18,22,26,30,34,38,42-decamethyl-5,9,13, 17,21,25,29,33,37,41-tritetracontadecaen-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-decamethyltri-tetracontan-2-one o 6,10,14,18,22,26,30,34,38-nonamethylnonatri-acontan-2-one o 6,10,].4,18,22,26,30,34-octamethylpentatri-acontan-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 of the formula [XIII] can be prepared by various methods, one of the ordinary methods is as follows:
--~CH2 lC CIH-CHz)n-l CH2-f-CH-CH2X [XVII3 a b a b .
+
Il I
C2H5-O-C-CH -C=o[XVIII]
condensation , ~ , H--~CH2_C_C~_CH2 ~ CH-C=O[IXX]
a b COOC2H5 i) ester cleava e ~ , ii) decarboxylation (I) wherein each of a, b and n has the same meaning as defined already, and X is a halogen atom.
In other words, prenyl halide represented by the general formula [XVII] and ethyl acetoacetate [~VIII] are reacted in the presence of a condensing agent such as metallic sodium, metallic potassium, sodium ethylate, sodium hydrate or the iike in a solvent such as ethanol, t-butanol, dioxane, benzene or the like, whenever necessary, to effect conden-sation. The resulting condensate is generally treated with an alkali reagent such as a dilute aqueous caustic soda solu~ion, a dilute aqueous caustic potash solution or the like without isolat-ing the condensate, so as to effect ester cleavage and decarboxylation and thus obtain the intended ~31~
compound of formula [XIII].
The following are examples of the 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-tetracosapentaenol 40 g of 6,10,14,18,22,26-hexamethyl-5,9,13,17,21, 25-heptacosahexaen-2-one, 15 g of ethyl cyanoacetate, 15 g of acetic acid and 500 mQ of acetone were mixed, refluxed at 84 to 85C and subjected to dehydro-condensation with stirring. After reacted for 7 hours, the reaction product was washed with water and an organic layer was isolated. While the residue was cooled by ice and stirred, 100 mQ of an ethanol solution containing 13 g of sodium borohydride was added. After the reduction was completed, the exces-sive reducing agent was decomposed by 10% acetic acid, washed with water and concentrated. The con-centrate was dissolved in 200 mQ of propylene glyco~.
After 26 g of caustic potash was added, the solution was stirred at 160C for 3 hours. The reaction solution was cooled by ice and after 100 mQ of 6N
hydrochloric acid was added, it was extracted with n-hexane. After the organic layer was washed with water and dried, the product was concentrated.
42 g of a dicarboxylic acid obtained as the crude reaction product was dissolved in 200 mQ of pyridine. After 1 g of copper powder was added, the solution was heated under reflux for 2 hours for decarboxylation. Pyridine was vacuum-distilled, and 100 mQ of water and 300 mQ of n-hexane were added. The copper powder was vacuum-filtered and 200 mQ of lN HCQ was added to the filtrate.
131~6~
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, providing 30 g of 3,7,11,15,19,23-hexamethyl-6,10, 14,18,22-tetracosapentaenoic acid.
While being cooled by ice with stirring, the product was added dropwise to 300 mQ of an ethereal suspension of 4 g of lithium aluminum hydride.
After the suspension was continuously stirred for 30 minutes, 4 mQ of water with 4 mQ of a 15% caustic soda solution and 12 mQ of water were sequentially added. The precipitated crystal was filtered and washed twice with 200 mQ of ether. The filtrate was concentrated and the concentrate was refined into a colorless oily matter by silica gel column chromato-graphy, providing the captioned 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaenol.
The physicochemical properties of the product 20 were as follows:
Elementary analysis: as C30H52O
C H
calculated (~): 84.04 12.23 found (~): 84.06 12.23 Infrared ahsorption spectrum (nujol~: v cm 1 max 3,300, 2,930, 1,650, 1,450, 1,380 NMR spectrum: ~(CDCQ3):
5.07 (m, 5H), 3.65 (t, J = 7 Hz, 2H), 1.8 - 2.2 (m, 18H), 1.67 (s, 3H), 1.59 (s, 15H), 1.1 - 1.8 (m, 6H), 0.90 (d, J = 7 Hz, 3H).
Mass (M/E): 428 Example 2 3,7,11,15,19,23~27-Heptamethyl-6,10,14,18,22, 26-octacosahexaenol 82 g of 3,7,11,15,19,23,27-heptamethyl-2,6,10,14, rc~ /'1Q rk ~310~6~
18,22,26-octacosaheptaenoic acid was dissolved in 1 Q of n-amyl alcohol and 74 g of metallic sodium was added portionwise while the 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 mQ of 6N hydrochloric acid. It was then extracted with 1 Q 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 mQ of an ethereal suspension of 10 g of lithium aluminum hydride while being cooled by ice and stirred. After stirring was continued for 30 minutes, 10 mQ of water with 10 mQ of a 15% caustic soda solution, and 30 m~ of water were sequentially added. The precipitated crystal was filtered and washed twice with 200 mQ 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, 22,2~-octacosahexaenol as a colorless oily matter.
The physicochemical properties were as follows:
Elementary analysis: as C H O
C H
calculated (%): 84.6112.17 found ~%): 84.60 12.18 Infrared absorption spectrum (nujol~ vmaxcm 1 3,300, 2,930, 1,65~, 1,450, 1,380.
NMR spectrum: ~(CDCQ3) 5.07 (m, 6H), 3.65 (t, J = 7 Hz, 2H), 108 - 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/E): 496 ~ 'r~^~c~/~ ~R rk 1310~
Example 3 3,7,11,15,19,23,27,31-Octamethyl-6,10,14,18,22, 26,30-dotriacontaheptaenol 21 g of 3,7,11,15,19,23,27,31-octamethyl-2,6,10, 14,18,22j26,30-dotriacontaoctaenonitrile was dissolved in250 mQ of methanol and 100 mQ 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 mQ of 6N
hydrochloric acid was added and the reaction product was extracted by 500 mQ of n-hexane. The organic layer was concentrated and the concentrate was refined by silica gel column chromatography, provid-ing 16 g of 3,7,11,15,19,23,27,31-octamethyl-6,10, 14,18,22,26,30-dotriacontaheptaenonitrile.
The resulting compound was dissolved in 100 mQ
of propylene glycol and, after 12 g of caustic potash was added, the solution was stirred at 160C
for 3 hours. The reaction solution was cooled with ice and, after 100 mQ 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-dotriaconta~
heptaenoic acid as the crude reaction product. The product was added dropwise to 200 mQ of an ethereal suspension of 2 g of lithium aluminum hydride.
After stirring was continued for 30 minutes, 2 mQ of water with 2 mQ of a 15% caustic soda solution, and 6 mQ of water were sequentially added. The precipi-tated crystal was filtered and washed twice with 100 mQ of ether. The filtrate was concentrated and the concentrate was refined by silica gel column 1310~60 chromatography, providing 14 g of the captioned 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26, 30-dotriacontaheptaenol in a white waxy form.
The physicochemical properties were as follows:
EIementary analysis: as C40H~8O
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: ~(CDCQ3):
5.07 (m, 7H), 3.65 (t, J = 7 Hz, 2H), 1.8 - 2.2 (m, 26H), 1.67 (s, 3H), l.S9 (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 3,7,11,15,19,23-Hexamethyl-6,10,14,18, 22-tetracosapentaenol was dissolved in 20 mQ of pyridine, and 10 g of p-toluenesulfonyl chloride was added. The solution was stirred at room tem-perature for 2 hours. 20 g of iced water was added and the solution was stirred for 30 minutes.
Extraction was then made using 100 mQ of n-hexane.
The extract was sequentially washed with lN hydro-chloric acid and then with water, dried and concentrated. The concentrate was dissolved in 20 mQ of dioxane. 10 mQ of sodium methylate (a 28% methanolic solution) was added and the solu-tion was stirred and refluxed for 4 hours. The reaction solution was cooled with ice and 50 mQ of 6N hydrochloric acid was added. Extraction was then made using 200 mQ of n-hexane. The organic .
~ r~ k ~310~60 layer was washed with water, dried and concentrated.
The concentrate was refined by silica gel column chromatography, providing 3 g of the captioned 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 ~ f lO found (%): 84.09 12.30 Infrared absorption spectrum (nujol). vmaxcm 1 2,930, 2,830, 1,650, 1,450, 1,380.
NMR spectrum: ~(CDCQ3) 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), l.S9 (s, lSH), 1.1 - 1.8 (m, SH), n.go (d, J = 7 Hz, 3H).
Mass (M/E): 442 Example 5 3,7,11,15,19,23,27-Heptamethyl-6,10,14,18,22, 26-octacosahexaenyl acetate 3.5 g of 3,7,11,15,19,23,27-heptamethyl-6,10,14, 18,22,26-octacosahexaenol was dissolved in 20 mQ of pyridine, and 10 mQ of acetic anhydride was added.
After 20 g of iced water was added, the solution was stirred for one hour and extraction was then made using 100 mQ of n-hexane. The extract was washed with lN 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:
~ f~ k l3la~0 Elementary analysis: as C37H~2O
C H
calculated (~): 82.4611.60 found (%): 82.45 11.60 ~' Infrared absorption spectrum (nujol~: vmaxcm ` 2,930, 1,735, 1,650, 1,450, 1,380.
NMR spectrum: ~(CDCQ3) 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, h~P~nvi 14,18,22,26,30-dotriacontah~tanol was dissolved in 20 mQ 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 mQ of n-hexane. The extract was washed with lN 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 ~enzoate in a white waxy form.
Elementary analysis: as C H O
C H
calculated (%): 84.37 10.85 found (~): 84.38 10.83 Infrared absorption spectrum (nujol ~ v cm 1 max 3,030, 2,930, 1,720, 1,650, 1,450, 1,380.
~Gr~ l~a~k 1310~
NMR spectrum: ~(CDCQ3) 7.20 - 8.15 (m, 5H), 5.07 (m, 7H), 4.36 (t, J =
7 Hz, 2H), 1.8 - 2.2 (m, 26H), 1.67 (s, 3H), 1.59 (5, 21H), 1.1 - 1.8 (m, 5H), 0.90 (d, J =
7 Hz, 3H) .
Mass (M/E): 668 Next, the effect of the compound of the present invention will be described in detail with reference to Experimental Examples.
Experimental Examples:
1. Phylactic effect (1) Method of experiment The following specimen compounds were intra-muscularly administered to slc: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 subcuta-neously innoculated at a rate of 2. 8 x 108/mouse .
The survival ratio was determined from the number of survivors on the seventh day from infection.
(2) Specimen compounds Co~pound A:
H ~
OH
3,7,11-trimethyl-6,10-dodecadien-1-ol Compound B:
H~
OH
131~0 3,7,11,15-tetramethyl-2,6,10,14-hexadeca-tetraen-l-ol Compound C:
H ¦
~\\/~/V\
OH
3,7,11,15-tetramethyl-5,10,14-hexadecatrien-l-ol Compound D:
H ~ ~
OH
3,7,11,15,19-pentamethyl-6,10,14,18-eicosa-tetraen-l-ol Compound E:
~0 3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18, 22,26 octacosaheptaen-l-ol Compound F:
H~V~OH
3,7-dimethyl-2,6-octadien-1-ol - Compound G:
- , ~ . -. . ~
~ 3 ~
OH
3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10, 14,18,22,26,30,34,38-tetracontadecaen-1-ol Compound H:
\/ \OH
3,7,11,15,19,23,27,31,35,39,43-undecamethyl-6,10,14,18,22,26,30,34,38,42-tetratetra contadecaen~l-ol Compound I:
H OH
3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaen-l-ol Compound J:
~OH
3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22, 26-octacosahexaen-1-ol Compound K:
1310~60 ~//~// \OH
3,7~11,15,19,23,27,31-octamethyl-6,10,14,18,22, 26,30-dotriacontaheptaen-1-ol Control compound: MDP (Ac~ur-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 compoundDosage subjects compound A lOOmg/kg6/10 ~ 60 (%) compound B lOOmg/kg6/10 ~ 6~ (%) compound C lO~mg/kg7/10 > 70 (%) compound D lOOmg/kg6/10 ~ 60 (%) 2 compound E 5Omg/kg9/10 90 (%) lOOmg/kg 10/10 ~lOn (%) compound F lOOmg/kg3/10 ~ 30 (%) compound G lOOmg/kg10/10 ~100 (%) compound H 10 Omg/kg7/10 ~ 70 (%) compound I lOOmg/kg9/10 ~ 90 (%) compound J5~mg/kg6/10 ~ 60 (%) lOOmg/kg 10/10 ~100 (%) compound ~50mg/kg5/10 ~ 50 (%) lOOmg/kg 9/10 ~ 90 (%) blank .1/80 ~ 1.25 (%) (non-treated) 30control 3.5mg/kg4/10 ~ 40 (%) compound(MDP) 2. Phagocytosis-enhancing effect of macrophage (1) Method and results of e~Periment -Each specimen compound was intramuscularly 131~60 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 phagocytosis-enhancing effect of macro-phages. The carbon clearance test was carried out in accordance with the method described by G. Biozzi, B. Benacerraf and B. N. Halpern in Brit. J. Exp.
Path., 24, 441-457.
The results are shown in Table 2.
In Table 2, the value of the changes in phago-cytosis represents a relative value with respect to the half-value period of the blank which was set at 100 .
Table 2 Number Half-value Changes in Specimen of periodphagocytosis compound animals (min:sec)~) blank (non- 48 8:01 100 treated) compound A 4 5:34 70 compound D 4 5:30 69 compound E 4 5:18 66 compound G 3 6:43 84 compound I 4 5:20 67 compound J 4 5:15 65 compound K 4 3:25 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, E, I, J and K obviously have an extremely high phagocytosis-enhancing effect.
131~60 It is evident from the Experimental Examples described above that the compound of the present invention normalizes 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:
H ~
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-hentriacontahepaten-2-one Compound N:
H
6,10-dimethyl-5,9-undecadien-2-one Compound o:
~\0 1310~60 6,10,14,18,22,26,30,34,38,42-decamethyl-5,9,13, 17,21,25,29,33,37,41-tritetracontadecaen-2-one Compound P:
6,10-dimethylundecan-2-one Compound Q:
6,10,14-trimethylpentadecan-2-one Compound R:
6,10,14,18,22,26,30,34,38,42-decamethyltri-tetracontan-2-one Control compound: MDP (AcMur-L-Ala-D-Glu) R~sults of Experiment The results are illustrated in Table 3.
131066û
Table 3 Survival ratio after one Specimen week, number of survivors/
compound ~osage number of subjects compound L 50 mg 4/10 ~ 40 (%) 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 (%) 10 compound P 100 mg 8/10 ~ 80 (%) compound Q 100 mg 10/10 ~ 100 (%) compound R 100 mg 3/10 ~ 30 (%) blank (non- 1/80 ~ 1.25 (%) control compound3.5 mg/kg 4/10 ~ 40 (%) (NDP) Table 4 Number Half-value 20 Specimen of period Changes in compound animals (min:sec) phagocytosis(%) compound L 4 6:00 75 compound M - 4 7:00 87 blank (non- 48 8:01 100 .
Accordingly, compounds L and 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:
t310~0 -3~-3,7,11,15~etramethylhexadeca-1-en-3-ol Comnound T:
H ~
3,7,11,15-tetramethyl-1,6,10,14-hexadeca-tetraen-3-ol Compound U:
~ ~ / ~ OH
docosanol Compound V:
~3 OH
phytol Control compound: MDP (AcMur-L-Ala-D-Glu) R_ ults of Experiments The results are illustrated in Table 5.
131~gO
~31~
Table 5 . Survival ratio after Specimen one week compound Dosage number of /number of . survivors/ subjects compound S lO0 mg/kg lO/10 ~ 100 (%) compound T 100 mg/kg lO/lO ~ lO0 (%) compound U lO0 mg/kg 3/10 ~ 30 (%) compound V 100 mg/kg lO/lO ~ lO0 (%) . .
blank (non- l/80 ~ 1.25 (%) __ pound (MDP) 3.5 mg/kg 4/lO ~ 40 (%) Table 6 Specimen Number Half-value ¦Changes in compoundof period phagocytosis animals (min:sec) (%) _. ~
blank (non-~ 8 : 01 lO0 compound T3 7 : 41 96 compound V. 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 smaller than 80, the phagocytosis is strongly promoted.
Accordingly, among the compounds of the present invention, compound V exhibited a particularly high phagocytosis-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 1310~60 of time. In this sense, too, the compound of the present invention is highly valuable.
When the compounds (A through K) described above were perorally administered to SD rats (weighing about 200 g) at a rate of 500 mg/kg, neither death of the subjects nor side reaction were observed at all.
The dosage of the compound of the 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 of the 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 paren-terally. 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 manner using 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 fla-voring agent and the like are added to the principal agent and the mixture is then 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 cellu-lose, and the like. Examples of binders are poly-vinyl alcohol, polyvinyl ether, ethylcellulose, 1310~60 methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl-starch, polyvinylpyrrolidone, and the like.
E~amples 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, poly-ethylene glycol, silica, hardened vegetable oil, and the like. Examples of coloring agents are those whose use for pharmaceuticals are officially permitted. Examples of flavoring agents are cocoa powder, menthol, aromatic powder, peppermint oil, borneol, powdered cinnamon bark, and the like.
Sugar coating, gelatin coating or the like may be appropriately applied to these tablets and granules.
In ~reparing an injection, a pH adjuster, a buffer, a stabilizer, a preserver, a solubilizer, and the like are added to the principal agent, ~henever necessary, and the injection for subcuta-neous, intramuscular or intravenous injection is prepared in a customary manner.
The drug of the 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 injec-tion in a customary manner and then dosing the injection parenterally, intramascularly or intraveously.
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 ~310660 compounds of the present invention.
Example of Preparation 1 (capsule) principal agent 5 g microcrystalline cellulose 80 g corn starch 20 g ` lactose 22 g polyvinylpyrrolidone 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 drug 50 g microcrystalline cellulose 400 g corn starch 550 g ~ . .
total 1,000 g The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellu-lose and thereafter dried. It was then mixed with corn starch and was prepared in the powder form of 20-fold dilution.
Example of Preparation 3 (tablet) principal agent 5 g corn starch 10 g lactose 20 g calcium carboxymethylcellulose 10 g microcrystalline cellulose 40 g polyvinylpyrrolidone 5 g talc 10 g total 100 g 131~0 The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellu- -lose and thereafter dried. It was then mixed with corn starch, lactose and calcium carboxymethyl-cellulose and a~ aqueous solution of polyvinyl-pyrrolidone 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 of the principal agent.
Example of Preparation 4 ~injection) -principal agent 10 g Nikkol HCO-60~(product of 37 g Nikko Chemical Co.~
sesame oil 2 g sodium chloride 9 g propylene glycol 40 g phosphate buffer (0.1 M, 100 mQ
pH 6.0) 0 distilled water q.s. ad 1,000 mQ
The principal agent, Nikkol HCO-60, sesame oil and the half of propylene glycol were mixed and heat-dissolved at about 80C. Phosphate buffer and distilled water dissolving therein in advance sodium chloride and propylene glycol were heated to about 80C and added to the solution described above to prepare 1,000 mQ of an aqueous solution. The resulting aqueous solution was dividedly charged into 2 mQ ampoules. After heat-sealed, the ampoules were heat-sterilized.
One ampoule contained 20 mg of the principal agent.
The following are examples of preparations using 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-k 1310~60 dotriacontaheptaen-l-ol (hereinafter referred to as the "principal agent") which is one of the compounds of the present invention.
Example of Preparation 5 (capsule) .
principal agent 5 g microcrystalline cellulose 80 g corn starch 20 g lactose 22 g polyvinylpyrrolidone3 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 6 (powder) principal drug 50 g microcrystalline cellulose 400 g corn starch 550 g total 1,000 g The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafter dried. It was then mixed with corn starch and was prepared in the powder form of 20-fold dilution.
Example of Preparation 7 (tablet) principal agent 5 g corn starch 10 g lactose 20 g calcium carboxymethylcellulose 10 g microcrystalline cellulose 40 g polyvinylpyrrolidone5 g talc 10 g ~ .
total 100 g l3l0~a The principal agent was 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 a customary manner. After talc as a lubricant was added and mixed, the mixture was prepared in 100 mg tablets. One tablet contained 10 5 mg of the principal agent.
Exam~le of Preparation 8 (injection) principal agent 10 g Nikkol HCO-60 (product of 37 g ` Nikko Chemical Co.) sesame oil 2 g sodium chloride 9 g propylene glycol 40 g phosphoric acid buffer 100 m2 (0.1 M, pH 6.0) .
distilled water total 1,000 mQ
The principal agent, Nikkol HCO-60, sesame oil and the half of propylene glycol were mixed and heat-dissolved at about 80C. Phosphate buffer and distilled water dissolving therein in advance sodium chloride and propylene glycol were heated to about 80C and added to the solution described above to prepare 1,000 mQ of an aqueous solution. The result-ing aqueous solution was dividedly charged into 2 mQ
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 (hereinafter referred to as the "principal agent"), follow.
rr ~
131B~
Example of Preparation 9 (capsule) principal agent 5 g microcrystalline cellulose 80 g corn starch 20 g lactose 22 g ~ polyvinylpyrrolidone 3 g total 130 g After granulated 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 corn starch 550 g total 1,000 g The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafter dried.
After the 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 corn starch 10 g lactose 20 g calcium carboxymethylcellulose 10 g microcrystalline cellulose 40 g polyvinylpyrrolidone 5 g talc 10 g -total 100 g 1310~
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 solu-tion 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 HC0-60 (product of 37 g Nikko Chemical Co~) sesame oil 2 g sodium chloride 9 g propylene glycol 40 g phosphate buffer 100 mQ
(0.1 M, pH 6.0) distilled water q.s. ad 1,000 mQ
The principal agent, Nikkol HCO-60, sesame oil and the half of propylene glycol were mixed and heat-dissolved at about 80C. Phosphate buffer and distilled water dissolving therein in advance sodium chloride and propylene glycol were heated to about 80C and added to the solution described above to prepare 1,000 mQ of an aqueous solution. The result-ing aqueous solution was dividedly charged into 2 mQ
ampoules. After heat-sealed, the ampoules were heat-sterilized.
One ampoule contained 20 mg of the principal agent.
~ f~ k
docosanol; phytol and iso-phytol.
In other words, the above defined pharmaceutical composition contains as the effective ingredient the novel ~ ,~-dihydropolyprenyl alcohol derivative as mentioned before or another polyprenyl compound.
Among those compounds of formula [XII], the following are not included in the compound of formula (I).
~.'' J
- 6a - 65702-174 H--~CH2-C=CH-CH2 )n CH2-CH C 2 2 (wherein n is an integer of 1 to 4 or 8 to 10), and ,CH3 iCH3 H--~ CH2-C=CH-CH2 ~ CH2-C=CH-CH20H
(wherein n is an integer of 1 to 10).
All the above defined pharmaceutical composition is effective as a prophylactic, therapeutic agent for human and animal immuno-deficiency diseases. Morevover, especially the composition containing the polyprenyl compound having the formula XII or XIII is useful as a phylactic agent . ~
1 3 ~
against human and animal infectious deseases.
Immunology has made a 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 of the complicated microbism involving various fundamental troubles has become a serious problem. The microbism induced by cancer, for example, is one of the most troublesome clinical problems. Cancer triggers the drop of general and local resistance and complicating and secondary diseases would occur in an easily in-fective state. Infection due to cancer mostly assumes the form of infection through a respirator, a urinary passage, a placental passage and a skin at the initial stage and results mostly in pneumonia and sepsis at the final stage. The mechanism of coincidence of infection due to this tumor takes generally the following process.
With the progress of leukemia, malignant lymphoma or cancer, the function of normal tissue and cells, especially that of lymphatic cells and granulocyte cells is reduced so that a patient is easily infected and infectious diseases occur coincidently. In such a case, the dose of anti-biotics does not result in radical cure but mostly 3~ in such problems as repeated infection, microbial substitution or refractory infection. Accordingly, radical cure can not be expected by use of the conventional antibiotics and chemotherapeutic agents but can be cured only after a biophylactic function is improved. Hence, development of drugs for 1310~
improving the biophylactic function of organism has been earnestly awaited.
On the other hand, antibiotics have been used primarily to 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 social problem such as residual drugs in various products, increase of drug-resistant bacteria and microbial substitution. In other words, the phylactic power of host is reduced remarkably and a restorative function against infectious diseases is also impaired so that the microbism is difficult to cure and the host is liable to suffer from reinfection. Furthermore,~
spontaneous infectious diseases topportunistic infection) reduce the producibility of livestock and its loss is great. Hence~ the immunological compe-tence of the host and the biophylactic function mustbe enhanced.
Under these circumstances, the inventors of the present invention have made intensive studies in search of drugs that normalize an immunological function and enhance a biophylactic function, and have found unexpectedly that a polyprenyl compound as defined above is effective as a prophylactic/
therapeutic agent for human and animal immuno-deficiency diseases and especially as a phylactic agent against human and animal infectious diseases:
In other words, the compound of the present invention is effective in normalizing human and animal immunological functions and enhancing resistance against the infection. Hence, the com-pound is useful as a prophylactic/therapeutic agent ~3~6~
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 rheumarthritis, autoimmune disease, cancer, asthma, various infectious diseases such as sepsis, pneumonia, meningitis and other viral infec-tious diseases.
For animals, the compound of the present inven-tion is effective for swine diarrhea, pneumonia (SEP,AR, haemophilus, pasteurella) and TGE, avian pneumonia (mycoplasma, haemophilus) and Marek's diseases, and bovine diarrhea, pneumonia and mastitis.
In curing human and animal infectious diseases by the compound of the present invention, the thera-peutic effect can be improved remarkably by the use o~ the present compound in combination with anti-biotics. This is significant because the afore-mentioned social problem of the abuse of antibiotics can also be solved.
In the case of animals such as the livestock and poultry, the compound of the present invention enhances the resistance of organism against infec-tion and hence the compound is effective as a basal drug for newborn. Furthermore, it is effective for mitigating the stress resulting from mass raising, transportation, and the like and is also useful for improving the vaccinal effect.
Accordingly, it is another purpose of the present invention to provide a novel prophylactic/
therapeutic composition for human and animal immunodeficiency.
It is further purpose of the present invention - to provide a novel phylactic composition against human and animal infectious diseases.
1 3 ~ 0 The following compounds are typical examples of polyprenyl alcohols having the formulae (XI) 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-octamethyl-2,6,10,14,18, 22,26,30-dotriacontaoctaen-1-ol o 3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18, 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-tetratetraconta-undecaen-l-ol o 3,7,11,15,19,23,27-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-l-ol o 3,7,11,15,19-pentamethyl-2,6,10,14,18-eicosapen-taen-1-ol o 3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-l-ol o 3,7,11-trimethyl-2,6,10~dodecatrien-1-ol o 3,7-dimethyl-2,6-octadien-1-ol o 3,7,1].,15,19,23,27,31,35-nonamethyl-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-undecamethyl-6,10,14,18,22,26,30,34,38,42-tetratetraconta-decaen-l-ol o 3,7,11,15,19-pentamethyl-6,10,14,18-eicosa-tetraen-1-ol o 3,7,11,15-tetramethyl-6,10,14-hexadecatrien-l-ol o 3,7,11-trimethyl-6,10-dodecadien-1-ol ~310~fi~
o 3,7-dimethyl-6-octen-1-ol o 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaen-l-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 compound having the formulae [XI] and [~II]
can be prepared by various methods. When _ and b in the general formula [XII] are combined together to form a bond, the compound can be prepared by those methods which are disclosed by Burrell et al.
in J. Chem. Soc. (C), 1966, 2144, Popjak et al. in J. Biol. Chem., 237, 56 (1962), O. 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 _ and b are both hydro~en atoms in the formula [XII], the compound and the compound having the formula [XI] can be prepared by the.method disclosed in Japanese Patent Laid-Gpen 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~
CH3 o H-(cH2-c=cH-cH2 ~ CH2-C-CH3 [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]:
H-(CH2-C=CH-CH2 ~ CH2-C=- C-COOR' [III]
~ 3~&~a (wherein n has the same meaning as above and R~is a lower alkyl group).
~ b) The resulting compound of formula [III] is reduced by a reducing agent such as sodium boro-hydride to obtain a compound represented by the formula [IV]:
CIH3 clH3 ICN
H-(CH2-C=CH-CH2 ~ CH2-CH--CH-COOR' [IV]
(wherein n and R'have the same meaning as above).
(c) The resulting compound of the formula [IV]
is decarboxylated in the presence of a strong alkali such as potassium hydride to obtain a compound represented by the formula [XV]:
CIH3 lH3 ( 2 2 ~ C 2 CH CH2 CN [XV]
(wherein n has the same meaning as above).
(d) The resulting compound of the formula [XV]
is hydrolyzed in the presence of a strong alkali such as potassium hydroxide to obtain a compound represented by the formula [XVI]:
( 2 C CH-CH2 ~ CH2-CH-CH2-COOH [XVI]
(e) The intended compound of the formulae [XI] and [XII] where a and b are hydrogen can be prepared by reducing the resulting compound of the formu].a [XVI] using a reducing agent such as vitrite, lithium aluminum hydride, or the like:
( 2 C CH CH2~ CH2-CH-CH2-CH2OH
(wherein n is an integer of 1 to 10).
131~g60 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-nonadeca-tetraen-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-nonamethyl-5,9,13,17, 21,25,29,33,37-nonatriacontanonaen-2-one o 6,10,14,18,22,26,30,34,38,42-decamethyl-5,9,13, 17,21,25,29,33,37,41-tritetracontadecaen-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-decamethyltri-tetracontan-2-one o 6,10,14,18,22,26,30,34,38-nonamethylnonatri-acontan-2-one o 6,10,].4,18,22,26,30,34-octamethylpentatri-acontan-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 of the formula [XIII] can be prepared by various methods, one of the ordinary methods is as follows:
--~CH2 lC CIH-CHz)n-l CH2-f-CH-CH2X [XVII3 a b a b .
+
Il I
C2H5-O-C-CH -C=o[XVIII]
condensation , ~ , H--~CH2_C_C~_CH2 ~ CH-C=O[IXX]
a b COOC2H5 i) ester cleava e ~ , ii) decarboxylation (I) wherein each of a, b and n has the same meaning as defined already, and X is a halogen atom.
In other words, prenyl halide represented by the general formula [XVII] and ethyl acetoacetate [~VIII] are reacted in the presence of a condensing agent such as metallic sodium, metallic potassium, sodium ethylate, sodium hydrate or the iike in a solvent such as ethanol, t-butanol, dioxane, benzene or the like, whenever necessary, to effect conden-sation. The resulting condensate is generally treated with an alkali reagent such as a dilute aqueous caustic soda solu~ion, a dilute aqueous caustic potash solution or the like without isolat-ing the condensate, so as to effect ester cleavage and decarboxylation and thus obtain the intended ~31~
compound of formula [XIII].
The following are examples of the 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-tetracosapentaenol 40 g of 6,10,14,18,22,26-hexamethyl-5,9,13,17,21, 25-heptacosahexaen-2-one, 15 g of ethyl cyanoacetate, 15 g of acetic acid and 500 mQ of acetone were mixed, refluxed at 84 to 85C and subjected to dehydro-condensation with stirring. After reacted for 7 hours, the reaction product was washed with water and an organic layer was isolated. While the residue was cooled by ice and stirred, 100 mQ of an ethanol solution containing 13 g of sodium borohydride was added. After the reduction was completed, the exces-sive reducing agent was decomposed by 10% acetic acid, washed with water and concentrated. The con-centrate was dissolved in 200 mQ of propylene glyco~.
After 26 g of caustic potash was added, the solution was stirred at 160C for 3 hours. The reaction solution was cooled by ice and after 100 mQ of 6N
hydrochloric acid was added, it was extracted with n-hexane. After the organic layer was washed with water and dried, the product was concentrated.
42 g of a dicarboxylic acid obtained as the crude reaction product was dissolved in 200 mQ of pyridine. After 1 g of copper powder was added, the solution was heated under reflux for 2 hours for decarboxylation. Pyridine was vacuum-distilled, and 100 mQ of water and 300 mQ of n-hexane were added. The copper powder was vacuum-filtered and 200 mQ of lN HCQ was added to the filtrate.
131~6~
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, providing 30 g of 3,7,11,15,19,23-hexamethyl-6,10, 14,18,22-tetracosapentaenoic acid.
While being cooled by ice with stirring, the product was added dropwise to 300 mQ of an ethereal suspension of 4 g of lithium aluminum hydride.
After the suspension was continuously stirred for 30 minutes, 4 mQ of water with 4 mQ of a 15% caustic soda solution and 12 mQ of water were sequentially added. The precipitated crystal was filtered and washed twice with 200 mQ of ether. The filtrate was concentrated and the concentrate was refined into a colorless oily matter by silica gel column chromato-graphy, providing the captioned 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaenol.
The physicochemical properties of the product 20 were as follows:
Elementary analysis: as C30H52O
C H
calculated (~): 84.04 12.23 found (~): 84.06 12.23 Infrared ahsorption spectrum (nujol~: v cm 1 max 3,300, 2,930, 1,650, 1,450, 1,380 NMR spectrum: ~(CDCQ3):
5.07 (m, 5H), 3.65 (t, J = 7 Hz, 2H), 1.8 - 2.2 (m, 18H), 1.67 (s, 3H), 1.59 (s, 15H), 1.1 - 1.8 (m, 6H), 0.90 (d, J = 7 Hz, 3H).
Mass (M/E): 428 Example 2 3,7,11,15,19,23~27-Heptamethyl-6,10,14,18,22, 26-octacosahexaenol 82 g of 3,7,11,15,19,23,27-heptamethyl-2,6,10,14, rc~ /'1Q rk ~310~6~
18,22,26-octacosaheptaenoic acid was dissolved in 1 Q of n-amyl alcohol and 74 g of metallic sodium was added portionwise while the 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 mQ of 6N hydrochloric acid. It was then extracted with 1 Q 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 mQ of an ethereal suspension of 10 g of lithium aluminum hydride while being cooled by ice and stirred. After stirring was continued for 30 minutes, 10 mQ of water with 10 mQ of a 15% caustic soda solution, and 30 m~ of water were sequentially added. The precipitated crystal was filtered and washed twice with 200 mQ 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, 22,2~-octacosahexaenol as a colorless oily matter.
The physicochemical properties were as follows:
Elementary analysis: as C H O
C H
calculated (%): 84.6112.17 found ~%): 84.60 12.18 Infrared absorption spectrum (nujol~ vmaxcm 1 3,300, 2,930, 1,65~, 1,450, 1,380.
NMR spectrum: ~(CDCQ3) 5.07 (m, 6H), 3.65 (t, J = 7 Hz, 2H), 108 - 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/E): 496 ~ 'r~^~c~/~ ~R rk 1310~
Example 3 3,7,11,15,19,23,27,31-Octamethyl-6,10,14,18,22, 26,30-dotriacontaheptaenol 21 g of 3,7,11,15,19,23,27,31-octamethyl-2,6,10, 14,18,22j26,30-dotriacontaoctaenonitrile was dissolved in250 mQ of methanol and 100 mQ 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 mQ of 6N
hydrochloric acid was added and the reaction product was extracted by 500 mQ of n-hexane. The organic layer was concentrated and the concentrate was refined by silica gel column chromatography, provid-ing 16 g of 3,7,11,15,19,23,27,31-octamethyl-6,10, 14,18,22,26,30-dotriacontaheptaenonitrile.
The resulting compound was dissolved in 100 mQ
of propylene glycol and, after 12 g of caustic potash was added, the solution was stirred at 160C
for 3 hours. The reaction solution was cooled with ice and, after 100 mQ 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-dotriaconta~
heptaenoic acid as the crude reaction product. The product was added dropwise to 200 mQ of an ethereal suspension of 2 g of lithium aluminum hydride.
After stirring was continued for 30 minutes, 2 mQ of water with 2 mQ of a 15% caustic soda solution, and 6 mQ of water were sequentially added. The precipi-tated crystal was filtered and washed twice with 100 mQ of ether. The filtrate was concentrated and the concentrate was refined by silica gel column 1310~60 chromatography, providing 14 g of the captioned 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26, 30-dotriacontaheptaenol in a white waxy form.
The physicochemical properties were as follows:
EIementary analysis: as C40H~8O
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: ~(CDCQ3):
5.07 (m, 7H), 3.65 (t, J = 7 Hz, 2H), 1.8 - 2.2 (m, 26H), 1.67 (s, 3H), l.S9 (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 3,7,11,15,19,23-Hexamethyl-6,10,14,18, 22-tetracosapentaenol was dissolved in 20 mQ of pyridine, and 10 g of p-toluenesulfonyl chloride was added. The solution was stirred at room tem-perature for 2 hours. 20 g of iced water was added and the solution was stirred for 30 minutes.
Extraction was then made using 100 mQ of n-hexane.
The extract was sequentially washed with lN hydro-chloric acid and then with water, dried and concentrated. The concentrate was dissolved in 20 mQ of dioxane. 10 mQ of sodium methylate (a 28% methanolic solution) was added and the solu-tion was stirred and refluxed for 4 hours. The reaction solution was cooled with ice and 50 mQ of 6N hydrochloric acid was added. Extraction was then made using 200 mQ of n-hexane. The organic .
~ r~ k ~310~60 layer was washed with water, dried and concentrated.
The concentrate was refined by silica gel column chromatography, providing 3 g of the captioned 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 ~ f lO found (%): 84.09 12.30 Infrared absorption spectrum (nujol). vmaxcm 1 2,930, 2,830, 1,650, 1,450, 1,380.
NMR spectrum: ~(CDCQ3) 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), l.S9 (s, lSH), 1.1 - 1.8 (m, SH), n.go (d, J = 7 Hz, 3H).
Mass (M/E): 442 Example 5 3,7,11,15,19,23,27-Heptamethyl-6,10,14,18,22, 26-octacosahexaenyl acetate 3.5 g of 3,7,11,15,19,23,27-heptamethyl-6,10,14, 18,22,26-octacosahexaenol was dissolved in 20 mQ of pyridine, and 10 mQ of acetic anhydride was added.
After 20 g of iced water was added, the solution was stirred for one hour and extraction was then made using 100 mQ of n-hexane. The extract was washed with lN 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:
~ f~ k l3la~0 Elementary analysis: as C37H~2O
C H
calculated (~): 82.4611.60 found (%): 82.45 11.60 ~' Infrared absorption spectrum (nujol~: vmaxcm ` 2,930, 1,735, 1,650, 1,450, 1,380.
NMR spectrum: ~(CDCQ3) 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, h~P~nvi 14,18,22,26,30-dotriacontah~tanol was dissolved in 20 mQ 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 mQ of n-hexane. The extract was washed with lN 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 ~enzoate in a white waxy form.
Elementary analysis: as C H O
C H
calculated (%): 84.37 10.85 found (~): 84.38 10.83 Infrared absorption spectrum (nujol ~ v cm 1 max 3,030, 2,930, 1,720, 1,650, 1,450, 1,380.
~Gr~ l~a~k 1310~
NMR spectrum: ~(CDCQ3) 7.20 - 8.15 (m, 5H), 5.07 (m, 7H), 4.36 (t, J =
7 Hz, 2H), 1.8 - 2.2 (m, 26H), 1.67 (s, 3H), 1.59 (5, 21H), 1.1 - 1.8 (m, 5H), 0.90 (d, J =
7 Hz, 3H) .
Mass (M/E): 668 Next, the effect of the compound of the present invention will be described in detail with reference to Experimental Examples.
Experimental Examples:
1. Phylactic effect (1) Method of experiment The following specimen compounds were intra-muscularly administered to slc: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 subcuta-neously innoculated at a rate of 2. 8 x 108/mouse .
The survival ratio was determined from the number of survivors on the seventh day from infection.
(2) Specimen compounds Co~pound A:
H ~
OH
3,7,11-trimethyl-6,10-dodecadien-1-ol Compound B:
H~
OH
131~0 3,7,11,15-tetramethyl-2,6,10,14-hexadeca-tetraen-l-ol Compound C:
H ¦
~\\/~/V\
OH
3,7,11,15-tetramethyl-5,10,14-hexadecatrien-l-ol Compound D:
H ~ ~
OH
3,7,11,15,19-pentamethyl-6,10,14,18-eicosa-tetraen-l-ol Compound E:
~0 3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18, 22,26 octacosaheptaen-l-ol Compound F:
H~V~OH
3,7-dimethyl-2,6-octadien-1-ol - Compound G:
- , ~ . -. . ~
~ 3 ~
OH
3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10, 14,18,22,26,30,34,38-tetracontadecaen-1-ol Compound H:
\/ \OH
3,7,11,15,19,23,27,31,35,39,43-undecamethyl-6,10,14,18,22,26,30,34,38,42-tetratetra contadecaen~l-ol Compound I:
H OH
3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaen-l-ol Compound J:
~OH
3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22, 26-octacosahexaen-1-ol Compound K:
1310~60 ~//~// \OH
3,7~11,15,19,23,27,31-octamethyl-6,10,14,18,22, 26,30-dotriacontaheptaen-1-ol Control compound: MDP (Ac~ur-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 compoundDosage subjects compound A lOOmg/kg6/10 ~ 60 (%) compound B lOOmg/kg6/10 ~ 6~ (%) compound C lO~mg/kg7/10 > 70 (%) compound D lOOmg/kg6/10 ~ 60 (%) 2 compound E 5Omg/kg9/10 90 (%) lOOmg/kg 10/10 ~lOn (%) compound F lOOmg/kg3/10 ~ 30 (%) compound G lOOmg/kg10/10 ~100 (%) compound H 10 Omg/kg7/10 ~ 70 (%) compound I lOOmg/kg9/10 ~ 90 (%) compound J5~mg/kg6/10 ~ 60 (%) lOOmg/kg 10/10 ~100 (%) compound ~50mg/kg5/10 ~ 50 (%) lOOmg/kg 9/10 ~ 90 (%) blank .1/80 ~ 1.25 (%) (non-treated) 30control 3.5mg/kg4/10 ~ 40 (%) compound(MDP) 2. Phagocytosis-enhancing effect of macrophage (1) Method and results of e~Periment -Each specimen compound was intramuscularly 131~60 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 phagocytosis-enhancing effect of macro-phages. The carbon clearance test was carried out in accordance with the method described by G. Biozzi, B. Benacerraf and B. N. Halpern in Brit. J. Exp.
Path., 24, 441-457.
The results are shown in Table 2.
In Table 2, the value of the changes in phago-cytosis represents a relative value with respect to the half-value period of the blank which was set at 100 .
Table 2 Number Half-value Changes in Specimen of periodphagocytosis compound animals (min:sec)~) blank (non- 48 8:01 100 treated) compound A 4 5:34 70 compound D 4 5:30 69 compound E 4 5:18 66 compound G 3 6:43 84 compound I 4 5:20 67 compound J 4 5:15 65 compound K 4 3:25 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, E, I, J and K obviously have an extremely high phagocytosis-enhancing effect.
131~60 It is evident from the Experimental Examples described above that the compound of the present invention normalizes 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:
H ~
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-hentriacontahepaten-2-one Compound N:
H
6,10-dimethyl-5,9-undecadien-2-one Compound o:
~\0 1310~60 6,10,14,18,22,26,30,34,38,42-decamethyl-5,9,13, 17,21,25,29,33,37,41-tritetracontadecaen-2-one Compound P:
6,10-dimethylundecan-2-one Compound Q:
6,10,14-trimethylpentadecan-2-one Compound R:
6,10,14,18,22,26,30,34,38,42-decamethyltri-tetracontan-2-one Control compound: MDP (AcMur-L-Ala-D-Glu) R~sults of Experiment The results are illustrated in Table 3.
131066û
Table 3 Survival ratio after one Specimen week, number of survivors/
compound ~osage number of subjects compound L 50 mg 4/10 ~ 40 (%) 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 (%) 10 compound P 100 mg 8/10 ~ 80 (%) compound Q 100 mg 10/10 ~ 100 (%) compound R 100 mg 3/10 ~ 30 (%) blank (non- 1/80 ~ 1.25 (%) control compound3.5 mg/kg 4/10 ~ 40 (%) (NDP) Table 4 Number Half-value 20 Specimen of period Changes in compound animals (min:sec) phagocytosis(%) compound L 4 6:00 75 compound M - 4 7:00 87 blank (non- 48 8:01 100 .
Accordingly, compounds L and 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:
t310~0 -3~-3,7,11,15~etramethylhexadeca-1-en-3-ol Comnound T:
H ~
3,7,11,15-tetramethyl-1,6,10,14-hexadeca-tetraen-3-ol Compound U:
~ ~ / ~ OH
docosanol Compound V:
~3 OH
phytol Control compound: MDP (AcMur-L-Ala-D-Glu) R_ ults of Experiments The results are illustrated in Table 5.
131~gO
~31~
Table 5 . Survival ratio after Specimen one week compound Dosage number of /number of . survivors/ subjects compound S lO0 mg/kg lO/10 ~ 100 (%) compound T 100 mg/kg lO/lO ~ lO0 (%) compound U lO0 mg/kg 3/10 ~ 30 (%) compound V 100 mg/kg lO/lO ~ lO0 (%) . .
blank (non- l/80 ~ 1.25 (%) __ pound (MDP) 3.5 mg/kg 4/lO ~ 40 (%) Table 6 Specimen Number Half-value ¦Changes in compoundof period phagocytosis animals (min:sec) (%) _. ~
blank (non-~ 8 : 01 lO0 compound T3 7 : 41 96 compound V. 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 smaller than 80, the phagocytosis is strongly promoted.
Accordingly, among the compounds of the present invention, compound V exhibited a particularly high phagocytosis-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 1310~60 of time. In this sense, too, the compound of the present invention is highly valuable.
When the compounds (A through K) described above were perorally administered to SD rats (weighing about 200 g) at a rate of 500 mg/kg, neither death of the subjects nor side reaction were observed at all.
The dosage of the compound of the 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 of the 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 paren-terally. 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 manner using 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 fla-voring agent and the like are added to the principal agent and the mixture is then 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 cellu-lose, and the like. Examples of binders are poly-vinyl alcohol, polyvinyl ether, ethylcellulose, 1310~60 methylcellulose, gum arabic, tragacanth, gelatin, shellac, hydroxypropylcellulose, hydroxypropyl-starch, polyvinylpyrrolidone, and the like.
E~amples 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, poly-ethylene glycol, silica, hardened vegetable oil, and the like. Examples of coloring agents are those whose use for pharmaceuticals are officially permitted. Examples of flavoring agents are cocoa powder, menthol, aromatic powder, peppermint oil, borneol, powdered cinnamon bark, and the like.
Sugar coating, gelatin coating or the like may be appropriately applied to these tablets and granules.
In ~reparing an injection, a pH adjuster, a buffer, a stabilizer, a preserver, a solubilizer, and the like are added to the principal agent, ~henever necessary, and the injection for subcuta-neous, intramuscular or intravenous injection is prepared in a customary manner.
The drug of the 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 injec-tion in a customary manner and then dosing the injection parenterally, intramascularly or intraveously.
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 ~310660 compounds of the present invention.
Example of Preparation 1 (capsule) principal agent 5 g microcrystalline cellulose 80 g corn starch 20 g ` lactose 22 g polyvinylpyrrolidone 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 drug 50 g microcrystalline cellulose 400 g corn starch 550 g ~ . .
total 1,000 g The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellu-lose and thereafter dried. It was then mixed with corn starch and was prepared in the powder form of 20-fold dilution.
Example of Preparation 3 (tablet) principal agent 5 g corn starch 10 g lactose 20 g calcium carboxymethylcellulose 10 g microcrystalline cellulose 40 g polyvinylpyrrolidone 5 g talc 10 g total 100 g 131~0 The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellu- -lose and thereafter dried. It was then mixed with corn starch, lactose and calcium carboxymethyl-cellulose and a~ aqueous solution of polyvinyl-pyrrolidone 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 of the principal agent.
Example of Preparation 4 ~injection) -principal agent 10 g Nikkol HCO-60~(product of 37 g Nikko Chemical Co.~
sesame oil 2 g sodium chloride 9 g propylene glycol 40 g phosphate buffer (0.1 M, 100 mQ
pH 6.0) 0 distilled water q.s. ad 1,000 mQ
The principal agent, Nikkol HCO-60, sesame oil and the half of propylene glycol were mixed and heat-dissolved at about 80C. Phosphate buffer and distilled water dissolving therein in advance sodium chloride and propylene glycol were heated to about 80C and added to the solution described above to prepare 1,000 mQ of an aqueous solution. The resulting aqueous solution was dividedly charged into 2 mQ ampoules. After heat-sealed, the ampoules were heat-sterilized.
One ampoule contained 20 mg of the principal agent.
The following are examples of preparations using 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-k 1310~60 dotriacontaheptaen-l-ol (hereinafter referred to as the "principal agent") which is one of the compounds of the present invention.
Example of Preparation 5 (capsule) .
principal agent 5 g microcrystalline cellulose 80 g corn starch 20 g lactose 22 g polyvinylpyrrolidone3 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 6 (powder) principal drug 50 g microcrystalline cellulose 400 g corn starch 550 g total 1,000 g The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafter dried. It was then mixed with corn starch and was prepared in the powder form of 20-fold dilution.
Example of Preparation 7 (tablet) principal agent 5 g corn starch 10 g lactose 20 g calcium carboxymethylcellulose 10 g microcrystalline cellulose 40 g polyvinylpyrrolidone5 g talc 10 g ~ .
total 100 g l3l0~a The principal agent was 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 a customary manner. After talc as a lubricant was added and mixed, the mixture was prepared in 100 mg tablets. One tablet contained 10 5 mg of the principal agent.
Exam~le of Preparation 8 (injection) principal agent 10 g Nikkol HCO-60 (product of 37 g ` Nikko Chemical Co.) sesame oil 2 g sodium chloride 9 g propylene glycol 40 g phosphoric acid buffer 100 m2 (0.1 M, pH 6.0) .
distilled water total 1,000 mQ
The principal agent, Nikkol HCO-60, sesame oil and the half of propylene glycol were mixed and heat-dissolved at about 80C. Phosphate buffer and distilled water dissolving therein in advance sodium chloride and propylene glycol were heated to about 80C and added to the solution described above to prepare 1,000 mQ of an aqueous solution. The result-ing aqueous solution was dividedly charged into 2 mQ
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 (hereinafter referred to as the "principal agent"), follow.
rr ~
131B~
Example of Preparation 9 (capsule) principal agent 5 g microcrystalline cellulose 80 g corn starch 20 g lactose 22 g ~ polyvinylpyrrolidone 3 g total 130 g After granulated 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 corn starch 550 g total 1,000 g The principal agent was first dissolved in acetone, then adsorbed by microcrystalline cellulose and thereafter dried.
After the 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 corn starch 10 g lactose 20 g calcium carboxymethylcellulose 10 g microcrystalline cellulose 40 g polyvinylpyrrolidone 5 g talc 10 g -total 100 g 1310~
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 solu-tion 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 HC0-60 (product of 37 g Nikko Chemical Co~) sesame oil 2 g sodium chloride 9 g propylene glycol 40 g phosphate buffer 100 mQ
(0.1 M, pH 6.0) distilled water q.s. ad 1,000 mQ
The principal agent, Nikkol HCO-60, sesame oil and the half of propylene glycol were mixed and heat-dissolved at about 80C. Phosphate buffer and distilled water dissolving therein in advance sodium chloride and propylene glycol were heated to about 80C and added to the solution described above to prepare 1,000 mQ of an aqueous solution. The result-ing aqueous solution was dividedly charged into 2 mQ
ampoules. After heat-sealed, the ampoules were heat-sterilized.
One ampoule contained 20 mg of the principal agent.
~ f~ k
Claims (50)
1. A process for preparing a .beta.,.gamma.-dihydropolyprenyl alcohol derivative of the formula I:
[I]
wherein n is an integer of 5 to 7 and R is hydrogen, a lower alkyl group or an aliphatic or aromatic acyl group, which comprises (i) for a compound of formula I in which R is hydrogen reducing a compound of formula VI
[VI]
wherein n has the same meaning as defined above, and (ii) for a compound of formula I in which R is a lower alkyl group, converting the alcoholic hydroxyl group of a com-pound of formula I obtained by step (i) above into an active group and reacting the compound so obtained with the corresponding alkyl alcohol, or (iii) for a compound of formula I in which R is an aliphatic or aromatic acyl group, reacting a compound of formula I obtained by step (i) above with the corresponding aliphatic or aromatic acyl chloride or acid anhydride.
[I]
wherein n is an integer of 5 to 7 and R is hydrogen, a lower alkyl group or an aliphatic or aromatic acyl group, which comprises (i) for a compound of formula I in which R is hydrogen reducing a compound of formula VI
[VI]
wherein n has the same meaning as defined above, and (ii) for a compound of formula I in which R is a lower alkyl group, converting the alcoholic hydroxyl group of a com-pound of formula I obtained by step (i) above into an active group and reacting the compound so obtained with the corresponding alkyl alcohol, or (iii) for a compound of formula I in which R is an aliphatic or aromatic acyl group, reacting a compound of formula I obtained by step (i) above with the corresponding aliphatic or aromatic acyl chloride or acid anhydride.
2. A process according to claim 1 wherein the compound of formula VI is prepared by one of the following reaction sequences:
method 1 (a) reacting a compound of formula II
[II]
wherein n is an integer of 5 to 7; with an alkyl cyano-acetate in contact with a base to obtain a compound of formula III
[III]
wherein n is an integer of 5 to 7 and R' is a lower alkyl group (b) reducing the above compound of formula III to obtain a compound of formula IV
[IV]
wherein each of n and R' has the meaning as defined above (c) subjecting the above compound of formula IV to ester and nitrile hydrolysis in contact with a strong alkali to obtain a compound of formula V
[V]
wherein n has the same meaning as defined above and (d) decarboxylating the above compound of formula V to ob-tain a compound of formula VI; or method 2 reacting a compound of formula II as defined above with triethylphosphonoacetic acid in contact with a base to obtain a compound of formula VII
[VII]
wherein n has the same meaning as defined above, hydrolyzing the above compound of formula VII with a base to obtain a compound of formula VIII
[VIII]
wherein n has the same meaning as defined above and reducing the above compound to obtain the compound of formula VI; or method 3 reacting a compound of formula II as defined above with triethylphosphonoacetic acid in contact with a base to obtain a compound of the formula IX
[IX]
wherein n has the same meaning as defined above, reducing the above compound of formula IX to obtain a compound of formula X
[X]
wherein n has the same meaning as defined above hydrolyzing the above compound of formula X to obtain the compound of formula VI.
method 1 (a) reacting a compound of formula II
[II]
wherein n is an integer of 5 to 7; with an alkyl cyano-acetate in contact with a base to obtain a compound of formula III
[III]
wherein n is an integer of 5 to 7 and R' is a lower alkyl group (b) reducing the above compound of formula III to obtain a compound of formula IV
[IV]
wherein each of n and R' has the meaning as defined above (c) subjecting the above compound of formula IV to ester and nitrile hydrolysis in contact with a strong alkali to obtain a compound of formula V
[V]
wherein n has the same meaning as defined above and (d) decarboxylating the above compound of formula V to ob-tain a compound of formula VI; or method 2 reacting a compound of formula II as defined above with triethylphosphonoacetic acid in contact with a base to obtain a compound of formula VII
[VII]
wherein n has the same meaning as defined above, hydrolyzing the above compound of formula VII with a base to obtain a compound of formula VIII
[VIII]
wherein n has the same meaning as defined above and reducing the above compound to obtain the compound of formula VI; or method 3 reacting a compound of formula II as defined above with triethylphosphonoacetic acid in contact with a base to obtain a compound of the formula IX
[IX]
wherein n has the same meaning as defined above, reducing the above compound of formula IX to obtain a compound of formula X
[X]
wherein n has the same meaning as defined above hydrolyzing the above compound of formula X to obtain the compound of formula VI.
3. A process according to claim 2 wherein in method 1 the reducing agent in step (b) is sodium borohydride, the strong alkali in step (c) is potassium hydroxide, the decarboxylation in step (d) is effected with pyridine/copper, in method 2 the base in the hydrolysis step is caustic potash, the reduction is effect-ed with metallic sodium and in method 3 the reduction is effected with metallic magnesium in a mixed solvent of methanol/THF and the hydrolysis is effected with caustic potash.
4. A process according to claim 1 wherein R is hydrogen.
5. A process according to claim 2, wherein R is hydrogen.
6. A .beta.,.gamma.-dihydropolyprenyl alcohol derivative of the formula I:
[I]
wherein n is an integer of 5 to 7 and R is hydrogen, a lower alkyl group or an aliphatic or aromatic acyl group.
[I]
wherein n is an integer of 5 to 7 and R is hydrogen, a lower alkyl group or an aliphatic or aromatic acyl group.
7. A compound according to claim 6, wherein R is hydrogen.
8. A process for preparing 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaenol which comprises reducing 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaenoic acid with lithium aluminum hydride.
9. A process according to claim 8, wherein the 3,7,11,15,19, 23-hexamethyl-6,10,14,18,22-tetracosapentaenoic acid is obtained by reacting 6,10,14,18,22,26-hexamethyl-5,9,13,17,21,25-heptacosahexaen-2-one with ethyl cyanoacetate, reducing the reaction product with sodium borohydride, hydrolysing the product of the reduction with caustic potash and decarboxylating the product of the hydrolysis with copper in pyridine.
10. The compound 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaenol.
11. A process for preparing 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol which comprises reducing 3,7,11,15,19,23,27 heptamethyl-6,10,14,18,22,26-octacosahexaenoic acid with lithium aluminum hydride.
12. A process according to claim 11, wherein the 3,7,11,15, 19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenoic acid is obtained by reducing 3,7,11,15,19,23,27-heptamethyl-2,6,10,14, 18,22,26-octacosaheptaenoic acid with metallic sodium.
13. The compound 3,7,11,15,19,23,27-heptamethyl-6,10,14,18, 22,26-octacosahexaenol.
14. A process for preparing 3,7,11,15,19,23,27,31-octa-methyl-6,10,14,18,22,26,30-dotriacontaheptaenol which comprises reducing 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenoic acid with lithium aluminum hydride.
15. A process according to claim 14, wherein the 3,7,11,15,19, 23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenoic acid is obtained by reducing 3,7,11,15,19,23,27,31-octamethyl-2,6,10,14,18,22,26,30-dotriacontaoctaenonitrile with metallic sodium is methanol and THF, and hydrolysing the 3,7,11,15,19,23, 27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenonitrile so obtained with caustic potash.
16. The compound 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18, 22,26,30-dotriacontaheptaenol.
17. A process for preparing 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaenyl methyl ether which comprises reacting 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosa-pentaenol with p-toluenesulfonyl chloride followed by reaction with sodium methylate.
18. A process according to claim 8 further comprising the step of reacting the 3,7,11,15,19,23-hexamethyl-6,10,14,18,22 tetracosapentaenol so formed with p-toluenesulfonyl chloride followed by reaction with sodium methylate.
19. A process according to claim 9 further comprising the step of reacting the 3,7,11,15,19,23-hexamethyl-6,10,14,18,22 tetracosapentaenol so formed with p-toluenesulfonyl chloride followed by reaction with sodium methylate.
20. The compound 3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaenyl methyl ether.
21. A process for preparing 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenyl acetate which comprises reacting 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol with acetic anhydride.
22. A process according to claim 11 further comprising the step of reacting the 3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol so obtained with acetic anhydride.
23. A process according to claim 12, further comprising the step of reacting the 3,7,11,15,19,23,27-heptamethyl-6,10,14,18, 22,26-octacosahexaenol so obtained with acetic anhydride.
24. The compound 3,7,11,15,19,23,27-heptamethyl-6,10,14,18, 22,26-octacosahexaenyl acetate.
25. A process for preparing 3,7,11,15,19,23,27,31-octa-methyl-6,10,14,18,22,26,30-dotriacontaheptaenyl benzoate which comprises reacting 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18, 22,26,30-dotriacontaheptaenol with benzoyl chloride.
26. A process according to claim 14 further comprising the step of reacting the 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenol so obtained with benzoyl chloride.
27. A process according to claim 15 further comprising the step of reacting the 3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenol so obtained with benzoyl chloride.
28. The compound 3,7,11,15,19,23,27,31-octamethyl-6,10,14, 18,22,26,30-dotriacontaheptaenyl benzoate.
29. A compound according to claim 6, wherein R is C1 to C6 straight-chain or branched alkyl group.
30. A compound according to claim 6, wherein R is acetyl.
31. A compound according to claim 6, wherein R is benzoyl.
32. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a .beta.,.gamma.-dihydropolyprenyl alcohol derivative as claimed in claim 6 in an prophylactic or therapeutic effective amount against human or animal immuno-deficiency diseases.
33. A pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a .beta.,.gamma.-dihydropolyprenyl alcohol as claimed in claim 7 in a phylactic effective amount against human or animal infectious diseases.
34. A composition according to claim 32, wherein such compound is as claimed in claim 7 or 10.
35. A composition according to claim 32, wherein such compound is as claimed in claim 13 or 16.
36. A composition according to claim 32, wherein such compound is as claimed in claim 20 or 24.
37. A composition according to claim 32, wherein such compound is as claimed in claim 28.
38. A composition according to claim 33, wherein such compound is as claimed in claim 10 or 13.
39. A composition according to claim 33, wherein such compound is as claimed in claim 16.
40. A pharmaceutical composition for preventing or treating human and animal immuno-deficiency diseases, which comprises a pharmaceutically acceptable carrier and a polyprenyl compound selected from a group consisting of:
(a) a compound of the formula:
[XI]
(wherein n is an integer of 5 to 7 and R" is a lower alkyl group or an aliphatic or aromatic acyl group);
(b) a compound of the formula:
[XII]
(wherein n is an integer of 1 to 10, and each of a and b is hydrogen or a and b together form a bond);
(c) a compound of the formula:
[XIII]
(wherein n is an integer of 1 to 10, and each of a and b is hydrogen or a and b together form a bond);
(d) 3,7,11,15-tetramethylhexadeca-1-en-3-ol;
(e) 3,7,11,15-tetramethyl-1,6,10 ,14-hexadecatetraen-3-ol;
(f) docosanol; and (g) phytol or isophytol, in a prophylactic or therapeutic effective amount against human or animal immuno-deficiency diseases.
(a) a compound of the formula:
[XI]
(wherein n is an integer of 5 to 7 and R" is a lower alkyl group or an aliphatic or aromatic acyl group);
(b) a compound of the formula:
[XII]
(wherein n is an integer of 1 to 10, and each of a and b is hydrogen or a and b together form a bond);
(c) a compound of the formula:
[XIII]
(wherein n is an integer of 1 to 10, and each of a and b is hydrogen or a and b together form a bond);
(d) 3,7,11,15-tetramethylhexadeca-1-en-3-ol;
(e) 3,7,11,15-tetramethyl-1,6,10 ,14-hexadecatetraen-3-ol;
(f) docosanol; and (g) phytol or isophytol, in a prophylactic or therapeutic effective amount against human or animal immuno-deficiency diseases.
41. A pharmaceutical composition for treating human or animal infectious diseases, which comprises a compound of the formula [XII] or [XIII] as defined in claim 40 in a phylactic effective amount against human or animal infectious diseases, in admixture with a pharmaceutically acceptable carrier.
42. A pharmaceutical composition for preventing or treating human and animal immuno-deficiency diseases, which comprises a pharmaceutically acceptable carrier and, in a prophylactic or therapeutic effective amount against human or animal immuno-deficiency diseases, a polyprenyl compound selected from the group consisting of polyprenyl compounds having the following formulae:
(wherein n is an integer of 1 to 4 or 8 to 10);
(wherein n is an integer of 1 to 10);
[XIII]
(wherein each of a and b is hydrogen or a and b together form a bond, and n is an integer of 1 to 10);
3,7,11,15-tetramethylhexadeca-1-en-3-ol; 3,7,11,15-tetramethyl-1,6,10,14-hexadecatetraen-3-ol ; docosanol; phytol; and isophytol.
(wherein n is an integer of 1 to 4 or 8 to 10);
(wherein n is an integer of 1 to 10);
[XIII]
(wherein each of a and b is hydrogen or a and b together form a bond, and n is an integer of 1 to 10);
3,7,11,15-tetramethylhexadeca-1-en-3-ol; 3,7,11,15-tetramethyl-1,6,10,14-hexadecatetraen-3-ol ; docosanol; phytol; and isophytol.
43. A pharmaceutical composition according to claim 42, wherein the polyprenyl compound is 3,7,11-trimethyl-6,10-dodecadien-1-ol.
44. A pharmaceutical composition according to claim 42, wherein the polyprenyl compound is 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-1-ol.
45. A pharmaceutical composition according to claim 42, wherein the polyprenyl compound is 6,10,14,18,22,26-hexamethyl-5,9,13,17,21,25-heptacosahexaen-2-one.
46. A pharmaceutical composition according to claim 42, wherein the polyprenyl compound is 6,10,14,18,22,26,30-heptamethyl-5,9,13,17,21,25,29-hentriacontahepaen-2-one.
47. A pharmaceutical composition according to claim 42, wherein the polyprenyl compound is phytol.
48. A pharmaceutical composition according to claim 42, 43 or 44, which comprises the polyprenyl compound in a phylactic effective amount against human or animal infectious diseases.
49. Use of a polyprenyl compound of (a) through (g) according to claim 40 for the preparation of a pharmaceutical composition for preventing or treating human and animal immuno-deficiency diseases.
50. Use of a polyprenyl compound of the formula [XII] or [XIII] as defined in claim 40 for the preparation of a pharma-ceutical composition for treating human or animal infectious diseases.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP57089806A JPS58206517A (en) | 1982-05-28 | 1982-05-28 | Preventive and remedy for disease caused by immunoinsufficiency |
| JP89806/82 | 1982-05-28 | ||
| JP10620382A JPS58225014A (en) | 1982-06-22 | 1982-06-22 | Preventive and remedy for disease caused by incompetence of immune function |
| JP106203/82 | 1982-06-22 | ||
| JP18364282A JPS5973513A (en) | 1982-10-21 | 1982-10-21 | Preventive and remedy for disease caused by immunological function insufficiency |
| JP18364382A JPS5973533A (en) | 1982-10-21 | 1982-10-21 | Beta,gamma-dihydropolyprenyl alcohol derivative |
| JP183642/82 | 1982-10-21 | ||
| JP183643/82 | 1982-10-21 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1310660C true CA1310660C (en) | 1992-11-24 |
Family
ID=27467677
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000429108A Expired - Fee Related CA1310660C (en) | 1982-05-28 | 1983-05-27 | B, -dihydropolyprenyl alcohol derivatives and pharmaceutical composition containing a polyprenyl compound |
Country Status (12)
| Country | Link |
|---|---|
| US (3) | US4624966A (en) |
| AT (1) | AT389871B (en) |
| CA (1) | CA1310660C (en) |
| CH (1) | CH654823A5 (en) |
| DE (2) | DE3348500C2 (en) |
| DK (1) | DK171640B1 (en) |
| ES (3) | ES8406992A1 (en) |
| FR (5) | FR2527597B1 (en) |
| GB (7) | GB2122610B (en) |
| IT (1) | IT1164256B (en) |
| NL (1) | NL194300C (en) |
| SE (4) | SE461650B (en) |
Families Citing this family (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3348500C2 (en) * | 1982-05-28 | 1998-10-22 | Eisai Co Ltd | beta, gamma-dihydropolyprenyl alcohol derivative |
| JPS6112622A (en) * | 1984-06-29 | 1986-01-21 | Kuraray Co Ltd | Agent for promoting differentiation and proliferation of hemopoietic stem cell |
| JPH0759504B2 (en) * | 1986-01-23 | 1995-06-28 | エーザイ株式会社 | Injection containing polyprenyl alcohol |
| US5071879A (en) * | 1989-04-28 | 1991-12-10 | Lidak Pharmaceuticals | Systemic antiviral treatment |
| US5070107A (en) * | 1989-04-28 | 1991-12-03 | Lidak Pharmaceuticals | Systemic antiviral treatment |
| JP3166991B2 (en) * | 1992-08-17 | 2001-05-14 | 日清製粉株式会社 | (S) -2,3-dihydropolyprenol compound as an active ingredient for suppressing cancer growth and / or inhibiting cancer metastasis |
| US5602184A (en) * | 1993-03-03 | 1997-02-11 | The United States Of America As Represented By Department Of Health And Human Services | Monoterpenes, sesquiterpenes and diterpenes as cancer therapy |
| CN1103586C (en) * | 1993-12-13 | 2003-03-26 | 里达克药品公司 | Sucrose ester C-zo to C-28 alcohol formulations |
| TW338042B (en) * | 1995-10-31 | 1998-08-11 | Clary Kk | Process for producing all trans-form polyprenols |
| GB2310138A (en) * | 1996-02-19 | 1997-08-20 | Juris Rubens | Immunomodulating plant polyprenols |
| US5952392A (en) * | 1996-09-17 | 1999-09-14 | Avanir Pharmaceuticals | Long-chain alcohols, alkanes, fatty acids and amides in the treatment of burns and viral inhibition |
| US6440980B1 (en) * | 1996-09-17 | 2002-08-27 | Avanir Pharmaceuticals | Synergistic inhibition of viral replication by long-chain hydrocarbons and nucleoside analogs |
| WO1998025599A1 (en) * | 1996-12-12 | 1998-06-18 | Pharmacia & Upjohn Company | An oil composition of dihydropolyprenols |
| CA2234326C (en) * | 1997-04-25 | 2001-07-31 | Yoshin Tamai | Process for preparing polyprenols |
| US6784207B2 (en) * | 2000-08-04 | 2004-08-31 | Roche Vitamins Inc. | Phytanic acid derivative compositions |
| HUP0402624A3 (en) * | 2001-10-16 | 2008-04-28 | Avanir Pharmaceuticals | Viral inhibition by n-docosanol |
| US7015022B2 (en) * | 2002-06-07 | 2006-03-21 | University Of Medicine & Dentistry Of New Jersey | Mammalian catalase-dependent oxidation processes and methods for stimulating oxidative activities |
| US20050158329A1 (en) | 2004-01-21 | 2005-07-21 | Ghosh Swapan K. | Novel phytol derived immunoadjuvants and their use in vaccine formulations |
| WO2017087539A1 (en) | 2015-11-16 | 2017-05-26 | O'neil Gregory W | Alkenone-based formulations for topical applications |
Family Cites Families (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS53145922A (en) * | 1977-05-26 | 1978-12-19 | Eisai Co Ltd | Remedy for peptic ulcer containing prenyl ketone compound |
| FR4055M (en) * | 1964-01-20 | 1966-04-04 | ||
| GB1459233A (en) | 1973-08-29 | 1976-12-22 | Inst Rech Chim Biolog | Medicament containing a higher alkanol |
| US4059641A (en) * | 1975-11-18 | 1977-11-22 | Sankyo Company Limited | Polyprenyl derivatives |
| JPS5391137A (en) * | 1977-01-19 | 1978-08-10 | Sumitomo Chem Co Ltd | Stabilization of agrichemicals |
| GB2002231B (en) * | 1977-08-10 | 1982-03-17 | Eisai Co Ltd | Hypertension treating agent |
| US4199587A (en) * | 1977-08-10 | 1980-04-22 | Eisai Co., Ltd. | Method of treating hypertension with polyprenyl alcohol ester |
| JPS6058209B2 (en) * | 1978-12-01 | 1985-12-19 | エーザイ株式会社 | β,γ-dihydropolyprenyl alcohol and antihypertensive agents consisting of it |
| FR2443245A1 (en) * | 1978-12-07 | 1980-07-04 | Nisshin Flour Milling Co | Antiulcer compsns. contg. carboxylic acids, esters or alcohols - including new terpenoid cpds. |
| EP0041235B1 (en) * | 1980-05-30 | 1985-02-13 | Eisai Co., Ltd. | Alpha,beta-dihydropolyprenyl derivatives for treating liver diseases |
| CA1165240A (en) * | 1980-07-09 | 1984-04-10 | The Procter & Gamble Company | Penetrating topical pharmaceutical compositions |
| JPS5791932A (en) * | 1980-11-28 | 1982-06-08 | Kuraray Co Ltd | Polyprenyl compound |
| JPS57106618A (en) * | 1980-12-24 | 1982-07-02 | Eisai Co Ltd | Anticancer agent consisting of polyprenyl compound |
| DE3163920D1 (en) * | 1980-12-24 | 1984-07-05 | Eisai Co Ltd | Pharmaceutical preparations comprising polyprenyl compounds, especially as anti-cancer agents, and pharmaceutical compositions for the prevention and treatment of cancer and skin diseases |
| DE3348500C2 (en) * | 1982-05-28 | 1998-10-22 | Eisai Co Ltd | beta, gamma-dihydropolyprenyl alcohol derivative |
| DE69325935T2 (en) * | 1992-03-17 | 2000-01-20 | Eisai Co Ltd | Skin bleaching agent containing teprenone |
-
1983
- 1983-05-25 DE DE3348500A patent/DE3348500C2/en not_active Expired - Fee Related
- 1983-05-25 DE DE3318989A patent/DE3318989C2/en not_active Expired - Fee Related
- 1983-05-25 GB GB08314419A patent/GB2122610B/en not_active Expired
- 1983-05-27 NL NL8301892A patent/NL194300C/en not_active IP Right Cessation
- 1983-05-27 CA CA000429108A patent/CA1310660C/en not_active Expired - Fee Related
- 1983-05-27 CH CH2902/83A patent/CH654823A5/en not_active IP Right Cessation
- 1983-05-27 DK DK239483A patent/DK171640B1/en not_active IP Right Cessation
- 1983-05-27 SE SE8303013A patent/SE461650B/en unknown
- 1983-05-27 ES ES522789A patent/ES8406992A1/en not_active Expired
- 1983-05-30 AT AT0197283A patent/AT389871B/en not_active IP Right Cessation
- 1983-05-30 IT IT21364/83A patent/IT1164256B/en active
- 1983-05-30 FR FR838308941A patent/FR2527597B1/en not_active Expired
- 1983-10-27 FR FR8317169A patent/FR2532843A1/en active Pending
- 1983-10-27 FR FR8317170A patent/FR2532848B1/en not_active Expired
- 1983-10-27 FR FR8317171A patent/FR2532844B1/en not_active Expired
-
1984
- 1984-02-15 ES ES529753A patent/ES8506567A1/en not_active Expired
- 1984-02-15 ES ES529754A patent/ES8507444A1/en not_active Expired
-
1985
- 1985-03-29 GB GB08508219A patent/GB2159712B/en not_active Expired
- 1985-03-29 GB GB08508216A patent/GB2159055B/en not_active Expired
- 1985-03-29 GB GB08508220A patent/GB2159713A/en not_active Withdrawn
- 1985-03-29 GB GB08508217A patent/GB2159710B/en not_active Expired
- 1985-03-29 GB GB08508214A patent/GB2159054B/en not_active Expired
- 1985-03-29 GB GB08508218A patent/GB2159711B/en not_active Expired
- 1985-07-29 US US06/760,221 patent/US4624966A/en not_active Expired - Lifetime
- 1985-09-02 FR FR858513026A patent/FR2569108B1/en not_active Expired - Lifetime
-
1988
- 1988-04-22 SE SE8801515A patent/SE502924C2/en unknown
- 1988-04-22 SE SE8801514A patent/SE502923C2/en unknown
- 1988-04-22 SE SE8801513A patent/SE502922C2/en unknown
-
1996
- 1996-01-11 US US08/584,145 patent/US6111131A/en not_active Expired - Fee Related
- 1996-02-14 US US08/601,489 patent/US6288128B1/en not_active Expired - Fee Related
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