JPH02149524A - Treating agent for human immunodeficiency viral disease - Google Patents

Abstract

PURPOSE:To obtain a treating agent for human immunodeficiency viral diseases useful for AIDS or AIDS-related syndromes, having low toxicity, containing a specific compound, an ester or a salt thereof as an active ingredient. CONSTITUTION:The title treating agent containing a compound shown by formula I (R1 to R4 are lower alkylene; X is H or halogen and bonded to arbitrary bondable position of two benzene rings), an ester (e.g. acetyl or propionyl) or a salt (e.g. HCl or H2SO4) thereof. A dose of the compound shown by formula I is usually 1-100mg, preferably 2-50mg and administered dividedly twicefour times daily or preferably administered as a sustained release preparation. The compound shown by containing I, for example, is obtained by reacting a compound shown by formula II with a compound shown by formula III (Y and Z are halogen or alkyl) in the presence of an alkali condensation agent such as sodium amide to give a compound shown by formula IV and then reacting this compound with a compound shown by formula V.

Description

[Detailed Description of the Invention] [Industrial Application Field] The present invention relates to human immunodeficiency virus (Human Immunodeficiency Virus).
The present invention relates to agents for treating various diseases caused by munodeficiency V 1rus (hereinafter abbreviated as 1-11 V).

[Prior art] HIV is an AIDS (acquired immunodeficiency group 1, AI)
D S , Acquired Immunoder
It is known as the virus that causes the virus. AIDS is a viral disease in which T4 lymphocytes are attacked and the immune system is directly destroyed. As a result of the destruction of the immune system, opportunistic infections such as Pneumocystis carinii pneumonia and candidiasis, malignant tumors such as Kaposi's sarcoma, and mental disorders appear, and once AIDS develops, it can last for up to six months unless effective treatment is taken. It is feared as a disease with a poor prognosis, as it can lead to death within a short period of time, such as one year.

If such a dangerous AIDS epidemic were to occur, it would cause social unrest and inconvenient situations such as discrimination against patients, posing a major public health problem. Therefore, the development of therapeutic drugs for AIDS is currently an extremely important and urgent issue.

Currently, andothymidine (AZT) is a drug known to have antiviral effects against HIV.
Nucleic acid antiviral agents such as and glycyrrhizin C1
There are special plant ingredients such as

[Problems to be Solved by the Invention] However, nucleic acid antiviral agents such as AZT are highly toxic, and plant components such as glycyrrhizin are not sufficiently effective. Therefore, it has been desired to develop an anti-HIV agent that is sufficiently effective and has few side effects.

[Means for Solving the Problem] As a result of searching for highly safe substances that have anti-HIV effects, the inventor found that they are already commercially available as therapeutic agents for schizophrenia, Meniere's syndrome, etc. Therefore, perphenazine, which has been confirmed to be safe, is a strong anti-HI
It was discovered that it has a V effect, and that its analogs also have a similar effect, and based on this knowledge, the present invention was completed.

That is, the present invention is based on the general formula [where R, R2, R1 and R4 are lower alkylene groups, X is hydrogen or halogen, and X is at any bondable position of two benzene rings. The object of the present invention is to provide an agent for treating human immunodeficiency virus disease, which contains a compound represented by the following formula or a physiologically acceptable and hydrolyzable ester or physiologically acceptable salt thereof as an active ingredient.

[Dear deaf person] In the above formula, the lower alkylene group is methylene, ethylene,! -Methylethylene, 2-methylethylene, trimethylene, tetramethylene, 3-methyltetramethylene,
Included are alkylene groups having 1-6 carbon atoms such as 2-ethyltetramethylene.

Preferred groups for R1 and R4 are ethylene or trimethylene, and preferred groups for R and R8 are ethylene. Halogens include fluorine, chlorine and bromine.

The compound of the above formula (1) is, for example, a corresponding skeleton compound (
! 1) ■ [In the formula, halogen or an alkyl or arylsulfonyloxy group] to form the intermediate (IV) R, -Z [wherein , R3 and R4 have the above meanings].

Preferred Y is Br, and preferred Z is CI. Amine (V) is a compound Y'-R, -0H (VIIX
(Y' has the same meaning as Y) is reacted, and then hydrolyzed and decarboxylated.

Alternatively, compound (IV) can be reacted with compound (1), hydrolyzed, and then reacted with compound (V++).
No. 3 and No. 35-2380.

The physiologically acceptable salt of the above compound (1) means a salt that does not exhibit significant toxicity at the dosage level and does not have physical or chemical properties that make administration difficult. Such salts include salts with inorganic acids (mineral acids) such as hydrochloric acid, sulfuric acid, and phosphoric acid, as well as carboxylic acids such as acetic acid, tartaric acid, citric acid, succinic acid, and fumaric acid, and methanesulfonic acid and ethanesulfonic acid. , salts with organic acids such as sulfonic acids such as toluenesulfonic acid.

Physiologically acceptable and hydrolyzable esters are esters that do not exhibit significant toxicity at the dosage level and do not have physical or chemical properties that make administration difficult, and that do not occur under physiological conditions, e.g. in the animal body. It means an ester that can be hydrolyzed under the conditions of (1) to yield compound (1) and an acid that does not exhibit significant toxicity in the amount produced. Such esters include lower alkanoyl such as acetyl, propionyl, pivaloyl, lower aroyl such as benzoyl, p-methoxybenzoyl, lower alkoxycarbonyl such as ethoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, benzyloxycarbonyl, p- Includes lower aralkyloxycarbonyl such as methoxybenzyloxycarbonyl.

1-11 V is for lymphadenopathy-related diseases (L ymp
Hadenopathy As5ociated Vi
rus: LAV), Human T-L lymphotropic virus I [I (Human T-L lymphotropic virus I)
ic Virus Type III: HTLV-I
II), AIDS-associated retroviruses (AIDs)
-As5ociated Retrovirus:
ARV), etc., and there are mutant strains with different properties such as infectivity to cultured cells, but all of these are included.

As an HIV virus disease, AIDS (AIDS)
, AIDS-related syndrome (ARC), persistent acid lymphadenopathy (PGL), and lymphoadenopathy syndrome (LA
S), and according to another classification, acute symptoms due to ToIIV infection, generalized lymphadenopathy, persistent fever, diarrhea,
These include weight loss, dementia, medullary dysfunction, peripheral neuropathy, carinii pneumonia, toxoplasmosis, candidiasis, herpesvirus infection, Kaposi's sarcoma, non-Hodgkin's lymphoma, and cancer.

Treatment includes all kinds of prevention and treatment, such as prevention of infection, prevention of disease onset in cases where the person is infected but does not become ill, prevention of worsening of the disease (w, continuation), alleviation of symptoms, elimination of symptoms, complete recovery, etc. shall be taken as a thing.

The dosage of compound (1), its ester, or its salt for carrying out the above treatment varies depending on the age, condition, and intended treatment of the patient, but is usually 1-100rI9,
The dose is preferably 2 to 50 B, and it is suitable to administer this in divided doses 2 to 4 times a day or as a sustained-release preparation.

For administration, the drug is mixed with a pharmaceutical carrier such as an organic or inorganic solid or liquid excipient suitable for oral administration, rectal administration, injection, etc., and administered in the form of a conventional pharmaceutical preparation. can do.

Such formulations include solids such as tablets, granules, powders, and capsules, and liquids such as solutions, suspensions, and emulsions.

As the carrier, starch, lactose, glucose, sucrose, dextrin, cellulose and its derivatives, paraffin, fatty acid glyceride, water, alcohol, etc. are used.

Also, if necessary, auxiliaries, stabilizers, wetting agents, emulsifiers, lubricants, binders and other conventional additives can be added.

The toxicity of the representative compound (1) used in this invention is known to be extremely low. - As an example, the values for velphenazine are as follows.

[Example] This invention will be explained below by examples, and the effects of this invention will be clarified by test examples.

In addition, in each example, the active ingredient is compound (1)
, a salt thereof or an ester thereof.

Example! Active Ingredients 4 Shoulders 9 Micrograde Cellulose 40H Hydroxypropyl Cellulose 1m9 Synthetic Aluminum Silicate
2j! 9 hydroxypropyl starch
511g Magnesium stearate 2
In addition to an appropriate amount of Mg-lactose, the total amount is 100319.

The above ingredients are mixed, granulated by a wet method, compressed into tablets, and coated with sugar by a conventional method.

Test example! (Preparation of sample) The sample was RP with 10% fetal calf serum (FCS) ia.
It was diluted with Ml-1640 to a predetermined concentration.

(Assay of anti-HIV activity) MT-4 cells (MT-4) were injected with HIV LAVII (1
0”T CI D so/ mQ) to moi O,00
01TCID. /cell (or width oi O,001T
CIDs. /cell), after infection with an adsorption time of 1 hour,
In the presence of the drug, there was a cytopathic effect (C
After culturing until PE) appeared, the amount of HIV produced was measured. The measurements were carried out as follows. Microplate (
96 wells) were inoculated with MT-4 at 2XIO'10.1r+Q/well, then the virus solution obtained above was inoculated at 0,
The cells were inoculated at 1 mQ/well, the appearance of CPE was observed for 7 days, and the I-11V output was adjusted to 50% tissue culture infectious concentration (50
%tissue culture 1nfectius
d.

se: T CI D so/m (indicated by ri).

When the amount of HIV produced was suppressed compared to the control, it was determined that there was anti-HIV activity.

Belphenazine was used as the drug.

(Results) The results are shown in the table below, and the numbers in the table are TCID,
. /IIIQ is shown. Additionally, Tox exhibits cytotoxicity.

Drug concentration (μg/silence) 0 (control) 100 IQ 1 Cytotoxicity
TOX 0.001 10” To+[10”
10"

[Brief explanation of the drawing]

FIG. 1 is a graph showing the results of cell proliferation measured in Test Example 2. From the above results, it was found that the therapeutic agent of the present invention has antiviral activity against l~NV. Test Example 2 (Measurement of cytotoxicity) Cells (MT
-4) was cultured in a microtiter plate in 100 μρ portions. 3. After 4 and 5 days, the number of viable cells was compared with a control (no drug added) using trypan blue dye excretion method (only dead cells are stained blue), and cell proliferation was observed. The results are shown in Figure 1. In Figure 1, the black circle is the control, and the Sanno angle is the drug lOμ9/R (in the case of l, the white angle of view is 1μ9/R).
This is the case for RQ.

Claims (2)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ (I) [In the formula, R_1, R_2, R_3 and R_4 are lower alkylene groups, X means hydrogen or halogen,
A human immunodeficiency virus containing as an active ingredient a compound represented by the following formula, or a physiologically acceptable and hydrolyzable ester or physiologically acceptable salt thereof. Disease treatment agent. (2) The disease is AIDS (AIDS), AIDS-related syndrome (
2. The therapeutic agent according to claim 1, which is ARC), persistent generalized lymphadenopathy (PGL), or lymphadenopathy syndrome (LAS).