Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
1996-02-14
2001-09-11
Aulakh, C. S. (Department: 1625)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C514S722000, C514S675000, C514S546000, C514S544000
Reexamination Certificate
active
06288128
ABSTRACT:
This invention relates to a novel &bgr;,&ggr;-dihydropolyprenyl 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 therapeutic agent for human and animal immuno-deficiency diseases and a phylactic agent against human and animal infectious diseases.
wherein n is an integer of 5 to 7 and R is a hydrogen atom, a lower alkyl group or an aliphatic or aromatic acyl group.
In this formula (I), the lower alkyl group in the definition of R means C
1
to C
6
straight-chain or branched alkyl groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl, n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl.
The novel compound having the formula (I) can be prepared by various methods and some typical examples will be given.
Method of Preparation 1
(a) The compound represented by the following general formula [II] is reacted with an alkyl cyanoacetate in the presence of a base to obtain a compound represented by the following general formula [III]:
wherein n is an integer of 5 to 7;
wherein n is an 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 borohydride to obtain a compound represented by the following general formula [IV]:
wherein each of n and R has the meaning as defined above.
(c) The resulting compound of formula [IV] is subjected to ester and nitrile hydrolysis in the presence of a strong alkali such as potassium hydroxide to obtain a compound represented by the following general formula [V]:
wherein n has the same meaning as defined 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]:
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]:
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 compound is reacted with a corresponding alkyl alcohol in the presence of a base such as caustic potash to give its alkyl ether. Its ester also can be derived by reacting the compound with a corresponding aliphatic or aromatic acyl chloride or acid anhydride.
Method of Preparation 2
A compound represented by the following general formula [II] is subjected to the Wittig-Homer reaction together with triethylphosphonoacetic acid in the presence of a base to obtain a compound represented by the following general formula [VII]:
wherein n is an integer of 5 to 7;
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]:
wherein n has the same meaning as defined already.
The compound of formula [VIII] is then reduced using metallic sodium or the like to obtain a compound represented by the following general formula [VI]:
The corresponding alcohol and its derivative can be derived by following the procedures of Method of Preparation 1.
Method of Preparation 3
A compound represented by the following general formula [II] is subjected to the Witting-Hormer reaction together with diethylphosphonoacetonitrile in the presence of a base to obtain a compound represented by the following general formula [IX]:
wherein n is an integer of 5 to 7;
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]:
wherein n has the same meaning as defined above.
Next, the compound of formula [X] is hydrolyzed using caustic potash, for example, to obtain a compound represented by the following general formula [VIII]:
Thereafter, the procedures of Example of Preparation 1 are followed to derive the corresponding alcohol and its derivative.
The invention further provides a pharmaceutical composition which comprises a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a polyprenyl compound selected from the group consisting of polyprenyl compounds having the following formulae:
wherein n is an integer of 5 to 7 and R is a lower alkyl group or an aliphatic or aromatic acyl group;
wherein each of a and b is hydrogen or a and b are combined together to form a bond, and n is an integer of 1 to 10;
wherein each of a and b is hydrogen or a and b are combined together to 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 iso-phytol.
In other words, the above defined pharmaceutical composition contains as the effective ingredient the novel &bgr;,&ggr;-dihydropolyprenyl alcohol derivative as mentioned before or another polyprenyl compound.
All the above defined pharmaceutical compositions are effective as a prophylactic, therapeutic agent for human and animal immuno-deficiency diseases. Moreover, especially the composition containing the polyprenyl compound having the formula XII or XIII is useful as a phylactic agent against human and animal infectious diseases.
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 occur in an easily infective state. Infection due to cancer mostly, assumes the form of infection through a respirator, a urinary passage, a placental passage and a skin 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 antibiotics does not result in radical cure but mostly 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 obtained only after a biophylactic function is improved. Hence, development of drugs for 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 substit
Arai Haruyoshi
Araki Seiichi
Kajiwara Akiharu
Suzuki Takeshi
Suzuki Yoshikazu
Aulakh C. S.
Eisai Co. Ltd.
Flynn ,Thiel, Boutell & Tanis, P.C.
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