JPS63307821A - Pharmaceutical preparation for treating aids virus infection - Google Patents

Abstract

PURPOSE:To obtain a preparation for treating AIDS virus infections, by adding organogermanium sesquioxide, thus having immunization accelerating and controlling action to increase host protection. CONSTITUTION:The object preparation is obtained by using an organogermanium sesquioxide of the formula [R1-R3 are H, lower alkyl, phenyl; X is -OH, -Metal (Na or K), -NH2, -O-alkyl] in a usual manner. It can be given orally or parenterally such as intramuscularly or intravenously and the dose is 1,000-6,000 mg/day. The compound of the formula is obtained by allowing germanium trichloride to react with acrylonitrile, hydrolyzing the product into carboxyethyltrichlorogermanium, treating the compound with thionyl chloride followed by hydrolysis to give the compound of the formula where X is -OH.

Description

DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to a drug for treating AIDS virus infection.

[Prior art] Acquired Immune Deficiency
AIDS, an acronym for Acquired Immune Deficiency Syndrome (AIDS), is an acute viral disease that disrupts the body's immune system, allowing normally controllable infections to enter the body. It allows people to do this, thereby causing disease.

The most common types of opportunistic infections, named to take advantage of reduced resistance to infection and decay, are carinii pneumonia (CPC), tuberculosis,
as well as types of cancer such as Kaboji's sarcoma.

In the long term, what we now know is that AIDS also attacks the nervous system and damages the brain.

This damage takes several years to develop, and symptoms may include memory loss, loss of coordination, partial paralysis, or mental impairment.

Infected people who have not yet developed fully overt AIDS develop AIDS-related syndrome (AIDS Re), which is milder than AIDS.
Patients may contract a disease called 1ated complex (ARC). This is a condition resulting from the AIDS virus, and the patient in this case tests positive for AIDS infection. However, the symptoms are milder than those of fully overt AIDS, and symptoms in a typical ARC patient include loss of appetite, fever, night sweats, skin rash, diarrhea, fatigue,
These include reduced resistance to infection and/or lymphatic swelling.

AIDS is a contagious disease in which the virus is transmitted from an infected person to an uninfected person primarily through blood, semen, and possibly vaginal fluids, during sexual activity and by sharing needles associated with intravenous drug abuse. be. Transmission of the virus that causes AIDS is difficult, and there is no evidence that it can be transmitted through casual casual contact such as coughing, hugging, kissing, shaking hands, or simply sharing eating, drinking, and toiletry utensils.

Exposure to the AIDS virus can be detected with a blood test that confirms the presence of antibodies to the virus, but as there is currently no cure or vaccine, this knowledge is limited to the current understanding of how the AIDS virus is transmitted. It only serves to warn people infected with AIDS, with the hope that this, together with the warning, will help prevent the spread of AIDS.

It is estimated that over 25,000 people in the United States have a fully overt AIDS infection, and that at least 1.5 million people in the United States are infected with the AIDS virus. It is said that one-third of these people will eventually become fully overt AIDS patients, and the same number or more will develop ARC.

Half of those found to have fully overt AIDS die from the disease. And since there is no cure, it is assumed that others will eventually die as well. Some experts believe that half of these people infected with AIDS will eventually die from AIDS. The official forecast for the next five years of epidemic disease is 179,000 deaths.
0 people, and the cumulative number of fully overt AIDS patients is 270.
The figure of 000 people is undoubtedly low because the estimated number of deaths by the ARC is not included at all, and the published figures are distorted by under-reporting as usual. .

By any analysis, the AIDS epidemic in the United States is a tremendous social and medical crisis, a national catastrophe for which no remedy has yet been found.

The virus that causes AIDS was identified in 1984, and the human T-cell leukemia virus old type (HTLV-m
) / lymphoma-associated virus (LAY), i.e. (H
It was named TLV-III/LAV). And this knowledge has provided us with a useful, if perhaps superficial, understanding of the mechanisms by which this virus affects, weakens, and immobilizes the human immune system.

Unlike many viruses, which are composed of segments of double-stranded DNA surrounded by a protein membrane, the AIDS virus is a pathogenic retrovirus composed of single-stranded RNA. On its own, RNA does not have the ability to take over a cell's genetic machinery, but retroviruses contain an enzyme called reverse transcriptase, which allows the AIDS virus to attack T cells of the immune system. Sometimes viral RNA is DNA
The virus then takes over the cell's genetic machinery, instructs the cell to make copies of the virus, and eventually leaves the host cell and infects other cells. More specifically, once in the bloodstream, the AIDS virus seeks out white blood cells, or T-4 cells, that control the immune system's complex responses. The AIDS virus binds to receptors on the surface of T-4 cells and then enters the cell, removing its protective protein coat and exposing the RNA-containing group. Reverse transcriptase converts the invading RNA into DNA, which is processed by host T-4 cells.
It is then inserted into the chromosome. Weeks and months after the invasion,
Once activated over a few years, the AIDS DNA instructs T-4 cells to make copies of the AIDS virus, which then leaves the host cell. Unlike most retroviruses, the AIDS virus has trans-transcriptional control. (TAT)
This property causes the growth of the AIDS virus to be extremely accelerated, and this explains the destructive effect of the AIDS virus on the body's immune system.

Therefore, a distinguishing feature of ITLV-m/LAY virus infection is the continued depletion of T-4 helper-inducer T cells and the decrease in T-helper-inducer T-cells and suppressor-cytotoxic T-8 cells.
-The ratio of 4 cells is low.

With this knowledge, HTLV-m/
The development of screening tests for drugs effective against the LAY virus has become easier.

But to date, even with these tests available, countless compounds and drugs have been tried in an effort to limit or stop the explosive spread of the deadly virus and its growing morbidity. However, no cure has been found,
No vaccine has been found either.

Only one drug, azidothymidine (AZT), has been shown to alleviate the symptoms, but AZT is not a therapeutic drug; it does not destroy the AIDS virus but stops its replication. AZT has severe side effects and is the only drug approved to be given to people with AIDS, even though it has been tested primarily in patients with pneumonia carinii pneumonia (PCP).

However, to date, HTLV-III/
There is no safe, effective, or even encouraging treatment for LAY; in fact, there is no guaranteed treatment that can safely alleviate symptoms or help prolong the lives of people with AIDS. No laws or drugs have appeared.

[Problem to be solved by the invention] In view of the above circumstances, the problem to be solved by the present invention is to
/ To provide effective and safe therapeutic agents for the treatment and control of LAY virus infection (AIDS).

[Means for Solving the Problems] The main means adopted by the present invention to solve the above problems is that in the general formula, R1 to R3 are each a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted phenyl group. X is -OH, -0 metal (this metal is Na or K), -
NH, and -0-alkyl group.

A drug for the treatment of AIDS virus infection characterized by containing a pharmacologically effective amount of an organogermanium sesquioxide compound represented by, or +1TLV-II[/L
A pharmacologically effective amount of an antiviral agent that is effective against AV viruses, and where R1 to R1 are each selected from the group consisting of a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted phenyl group. X is selected from the group consisting of -0 metal (the metal is Na or Ni), -NHz, and -0-alkyl group.

A drug for treating AIDS virus infection characterized by comprising a pharmacologically effective amount of an organogermanium sesquioxide compound having is a general formula in which R1 to R5 are each selected from the group consisting of a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted phenyl group, and X is -0)I, -0 metal ( This metal is Na or Ni),
-NH, and -0-alkyl group.

It contains an organic germanium sesquioxide compound having the following.

These organogermanium sesquioxide compounds are I(TL
It is twice as effective as an AIDS treatment drug compared to antiviral drugs against V-/LAV, and compared to immunomodulators that restore the human immune system function deteriorated by AIDS to recognize foreign substances and effectively fight infections. It is believed to be effective.

Organogermanium sesquioxide compounds and methods for their production are well known. Similarly, this compound is well known for the following points. Ehrlich Ascites Tumor Cell Proliferation Inhibition (U.S. Pat. No. 3.6119.5)
No. 13); Treatment of Hypertension (U.S. Pat. No. 3,793.
No. 455) 1 Efficacy as a topical skin treatment (U.S. Pat. No. 455)
No. 4.229.468); Treatment by inducing interferon production in animals (U.S. Pat. No. 4.279.892 and No. 4.473.581); the disclosures of these patents are incorporated herein by reference. . Furthermore, examples of the therapeutic effects of organogermanium sesquioxide compounds on human diseases other than those mentioned above can be found in Asai's "Miracle Cure Organic
c Ger-maniuml 1980j.

An example of a useful organogermanium sesquioxide compound in the present invention is a compound of formula [I], in which X
is a compound with -OH group, that is, carboxyethylgermanium sesquioxide, but this compound is trichlorogermane (trichlorogermane) according to the formula shown in the universal selection method.
rmane) with acrylonitrile to produce β-cyanoethyltrichlorogermane [II], which is further hydrolyzed in an acidic solution to obtain carboxyethyltrichlorogermane [III]. This product [ml] was treated with thionyl chloride to produce trichlorogermylpropionyl chloride (trichlo
ro-germyl propionyl c
hloridel [rV], which is then hydrolyzed with water to give the desired sesquioxide [V], i.e. X in formula [II
A product is obtained in which is -(It() group.

Ge1(C1s+ CH2=CHCN -C15Ge-
C) l*cHicN [H] hydrolyzed C15Ge-CLCLCNCIs GeCLCHiCOOH[III] Cl5GeC) IaCHaCOOB+5OC1a=C1
sGeC)licHacOcl [rV] Hydrolyzed C15GeC)IaCHzCOCl (Ge-CHxCHxCOOH) Js [V] Alternatively, carboxyethyl germanium sesquioxide [
V] can be produced by reacting trichlorogermane with acrylic acid to obtain carboxyethyltrichlorogermanium which can be hydrolyzed to give the desired sesquioxide.

The preferred compound for use, namely carboxyethylgermanium sesquioxide, is an odorless crystalline powder that is soluble in water but insoluble or only slightly soluble in almost all organic solvents. This compound has a temperature (270
℃), is very stable to humidity and light and therefore can be stored for long periods of time without causing problems.

The agent of the present invention containing organogermanium sesquioxide of formula [II] can be administered orally or parenterally by intramuscular or intravenous injection. For oral administration, the carrier can be a solid and the composition can be presented as a powder, capsule or tablet. The solid carrier may be any carrier that is commonly used in pharmaceutical formulations and is pharmacologically acceptable; when administered parenterally, preferably the organogermanium sesquioxide compound is pyrogen-free. A sterile solution in water may be used, in which case any pharmacologically acceptable carrier may be used.

One of the specific properties of the organogermanium compounds of formula II is that they are extremely safe, virtually non-toxic and have no harmful effects on reproductive or other functions. This is evidenced by acute, subacute, chronic and specific toxicity data obtained as a result of studies conducted in mice, rats and dogs.

For example, in the case of carboxyethylgermanium sesquioxide, L D s upon oral administration. is 10.000 mg or more per gram of body weight for mice, and 10.000 mg or more per gram of body weight for rats. In the case of intravenous injection, both mice and rats have LDs. is 40 per gram of body weight
00mg or more. In further long-term toxicity tests,
The organic germanium sesquioxide of the present invention was administered orally at a dose of 30 mg per kg of body weight per day for 6 months.
No death of rats occurred in any of the test groups administered 0 mg or 3000 mg. Also, no pathological damage was observed. and 500 mg of organogermanium sesquioxide compound per gram of body weight per day.
No toxicity was found when administered intravenously to dogs over a period of 6 months.

An effective antiviral agent ideally has sufficient power to completely block the infectivity and replication of the virus, resulting in the virus being suppressed. At the same time, the human immune system is stimulated to eliminate or suppress the virus. However, the AIDS virus, HTLV-
In the case of m/LAY, the patient's immune system cannot be trusted to suppress the infectivity and replication of the virus that escapes the antiviral drugs, and if infection and replication continue, Lysle will continue to spread. This results in progressive immunodeficiency. Therefore, in cases such as AIDS, where the human immune system is compromised and there are no antiviral drugs available to prevent infection and replication, it is important to restore the immune capacity of the human immune system to a normal level.

The organogermanium sesquioxide compounds useful in the present invention not only have excellent antiviral properties, but are also known as gamma interferon inducers. Thus, an important property for the use of the present organogermanium sesquioxide compounds in the treatment of AIDS HTLV-I[1/LAY virus infection is their immunostimulatory or immunomodulatory effects that enhance host defenses.

Interferon first attracted attention for its excellent antiviral properties, and more recently its role as a defense mechanism has been evaluated.
y) Defense mechanisms have been revealed by clinical trials.

According to the present invention, interferon production induced by an organogermanium sesquioxide compound of formula [I]
It is believed that it not only has a direct antiviral effect against TLI/-III/LAI/, but also contributes to a significant immunomodulatory effect and enhances the antiviral action of immunocompetent cells of the human immune system. .

Therefore, in the present invention, not only an effective therapeutic agent for the AIDS virus containing the organogermanium compound described herein as an active ingredient, but also a combination of drugs is administered to the patient. Although it is not known, there is a fact that a synergistic effect occurs and provides an antiviral effect and/or an immunomodulatory effect. Other antiviral agents (alone, HTLV-m/
The present invention contemplates the administration of a therapeutic agent that may or may not be effective against LAV. Drugs that may be combined with these organic germanium compounds include AZT, suramin, and acyclovir (acy-
clovir (ACV), 9-[f2-hydroxyethoxy)methylcoguanine), deoxycytidine, other adenosine and cytidine analogs, and similar antiviral agents. Furthermore, the present invention contemplates therapeutic agents containing the organogermanium sesquioxide compound of formula [I] and other immunomodulators when treating AIDS-infected patients.

The ability of an organogermanium sesquioxide compound to induce an antiviral response or the magnitude of its superior ability to inhibit viral infection is dependent on the dosage; the higher the dosage, the higher the potency of the organogermanium compound in the circulation. 1 In the context of the present invention, the term "pharmacologically effective amount" refers to ITLV-m
/ For effective treatment of LAV virus infection, refers to the amount of organogermanium sesquioxide sufficient to alleviate symptoms, hasten treatment, and delay or eliminate recurrence, ie, to provide the desired effect.

) The dosage of organogermanium sesquioxide as a pharmacologically effective amount for the treatment of ITLV-III/LAY virus infections will depend, at least in part, on the method and frequency of administration, the health status of the patient, and the virulence of the disease.
) or stage. The pharmacologically effective dosage level of organogermanium sesquioxide compounds for effectively treating patients infected with the AIDS virus is a relatively low dosage of approximately 1000 mg/day, whether administered orally or parenterally. Approximately 60%, which is a relatively high dosage from
00 mg/day, more typically 22
It is believed to be 50 mg/day. A typical example of oral administration of an anti-AIDS therapeutic agent containing an organogermanium sesquioxide compound is 250 m2 per capsule.
3 capsules containing the above compound after each meal, 3 capsules per day.
Give times. For parenteral administration, use an injection solution with an equivalent dose.

Organogermanium sesquioxide of formula [I], when administered to a host in a pharmacologically effective amount, promotes interferon production and activates macrophages if macrophages are present, and enhances the activity of N cells or CTt. do.

The enhanced activity of NK cells is particularly noteworthy, indicating excellent proliferative properties.

Furthermore, activated N cells exhibit superior killing ability against virus-infected cells, and activated N cells cooperate with macrophages and/or CTLs.
Regarding cells infected with retroviruses such as ITLV-III/LAV (7), it exhibits high level and highly effective cytotoxicity and destroys the virus.

The interferons obtained as a result of these inducing effects of organogermanium sesquioxide induce T in lymphocyte subsets.
-4 produced by helper cells, HTLV-I
The II/LAY virus attacks T-4 cells, takes over the cell's genetic machinery, and instructs the T-4 cells to make copies of the virus, resulting in active proliferation of the virus cells. HTLV-m/L by the organogermanium compound-induced interferon
Any spread of AY virus infection is prevented, thereby slowing the proliferation of viral cells, as uninfected T-4 cells are rendered resistant to the virus;
It is probably an anti-ITLV-III/LA that blocks virus invasion by making the chromosomes of T-4 cells produce messenger RNA.
This is probably because Y protein is prepared.

Furthermore, at least in tests on mice with reduced immunity, the organogermanium sesquioxide compound not only inhibits the increase in the production of immunoglobulins such as IgM, but also
It prevents the decline of the host's immune response or strengthens the immune response by its immunomodulatory effect. However, in this case, the ADCC activity of the virus-infected host is functionally enhanced and the appearance of suppressor macrophages is prevented.

Regarding the drug for treating AIDS virus infection of the present invention,
It will be more clearly understood from the following examples, ie, the description of the clinical efficacy for the treatment of HTLV-m/LAV virus infection.

[Example] When carboxyethyl germanium sesquioxide is administered,
Anticipating that cellular activity would be clearly enhanced by N, sesquioxide was administered orally to three patients with HTLV-m/LAV virus antibodies at a dose of 2,250 m
g/day/person) 9 capsules (250 mg each capsule)
administered. Then, 14 days after the start of administration, it was examined whether the NK activity in peripheral blood was clearly enhanced.

Method for measuring N activity Similar to the target cells, 1562 cells were labeled with CrIII and used as effector cells. buffycoat
It was created using atsl J. And these cells are treated with Ficoll Iypa
que) was used to give the centrifugal specific gravity. The ratio of effector cells to target cells was maintained at 20:1 and incubated at 37°C for 4 hours. After incubation, the % cytotoxicity was calculated based on the percentage of free CrS 1 in the supernatant.

Result 1 (As a result of daily administration of 9 capsules of carboxyethyl germanium sesquioxide per day to 3 patients with TLV-m/LA'/virus antibodies, 1 of the 3 patients (adult, male) showed an increase in N. There was a clear 23% increase in activity.

Claims (1)

[Claims] 1. General formula: ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, R_1 to R_3 are each selected from the group consisting of a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted phenyl group. and X is selected from the group consisting of -OH, -O metal (wherein the metal is Na or K), -NH_2 and -0-alkyl group. 1. A drug for treating AIDS virus infection, characterized by containing a pharmacologically effective amount of an organogermanium sesquioxide compound represented by: 2. The drug for treating AIDS virus infection according to claim 1, wherein R_1 to R_3 are all hydrogen atoms. 3. The drug for treating AIDS virus infection according to claim 1, wherein X is -OH. 4. The drug for treating AIDS virus infection according to claim 1, wherein X is -O metal. 5. The drug for treating AIDS virus infection according to claim 1, wherein X is -O-alkyl. 6. The drug for treating AIDS virus infection according to claim 1, wherein X is -NH_2. 7. A pharmacologically effective amount of antiviral agent that is effective against the HTLV-III/LAV virus and the formula ▲ Numerical formula, chemical formula, table, etc. ▼ In the formula, R_1 to R_3 are each a hydrogen atom, a lower alkyl group, or a substituted or unsubstituted phenyl group; X is a group consisting of -OH, -O metal (this metal is Na or K), -NH_2 and -O-alkyl group; Indicates what was selected from. and a pharmacologically effective amount of an organic germanium sesquioxide compound having the following properties: 8. The drug for treating AIDS virus infection according to claim 7, wherein R_1 to R_3 are all hydrogen atoms. 9. The drug for treating AIDS virus infection according to claim 7, wherein X is -OH. 10. The drug for treating AIDS virus infection according to claim 7, wherein X is -O metal. 11. The drug for treating AIDS virus infection according to claim 7, wherein X is -O-alkyl. 12. The drug for treating AIDS virus infection according to claim 7, wherein X is -NH_2.