CA1036618A - Process for the manufacture of tris (2-hydroxyethyl) ammonium-ortho-cresosyacetate - Google Patents

Process for the manufacture of tris (2-hydroxyethyl) ammonium-ortho-cresosyacetate

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Publication number
CA1036618A
CA1036618A CA204,161A CA204161A CA1036618A CA 1036618 A CA1036618 A CA 1036618A CA 204161 A CA204161 A CA 204161A CA 1036618 A CA1036618 A CA 1036618A
Authority
CA
Canada
Prior art keywords
preparation
tris
ammonium
ortho
desired product
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA204,161A
Other languages
French (fr)
Inventor
Mikhail G. Voronkov
Valery M. Dyakov
Nina V. Semenova
Nikolai A. Stetsenko
Evgeny F. Prokhoda
Ada T. Platonova
Nikolai L. Simbirtsev
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
IRKUTSKY INSTITUT ORGANICHESKOI KHIMII SIBIRSKOGO OTDELENIA AKADEMII NAU K SSSR
Original Assignee
IRKUTSKY INSTITUT ORGANICHESKOI KHIMII SIBIRSKOGO OTDELENIA AKADEMII NAU K SSSR
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SU1954859A external-priority patent/SU515742A1/en
Application filed by IRKUTSKY INSTITUT ORGANICHESKOI KHIMII SIBIRSKOGO OTDELENIA AKADEMII NAU K SSSR filed Critical IRKUTSKY INSTITUT ORGANICHESKOI KHIMII SIBIRSKOGO OTDELENIA AKADEMII NAU K SSSR
Application granted granted Critical
Publication of CA1036618A publication Critical patent/CA1036618A/en
Expired legal-status Critical Current

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Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40Unsaturated compounds
    • C07C59/58Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C07C59/70Ethers of hydroxy-acetic acid, e.g. substitutes on the ring

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicinal Preparation (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE

Tris(2-hydroxyethyl)ammonium-ortho-cresoxyacetate, has the following formula:
[o-CH3C6H4OCH2COO] - [NH(CH2CH2OH)3]+, useful for treating malignant neoplasms. A process for the manufacture of said substance, in accordance with the invention, comprises reacting triethanolamine with o-cresoxy-acetic acid at a temperature of up to 100°C and subsequently recovering the desired product. The invention also includes medicinal preparation for treating malignant neoplasms, which comprises an active principle, tris(2-hydroxyethyl)ammonium-ortho-cresoxyacetate of the following formula:

[o-CH3C6H4OCH2COO] - [NH(CH2CH2OH)3]+, or said active principle combined with a pharmaceutical solvent for injections or a pharmaceutical filler for tablets.

Description

~)36618 The present invention relates to the novel substance, tris(2-hydroxyethyl)ammonium-ortho-cresoxyacetate its prepa-ration and pharmaceutical preparations containing the same.
The novel substance, tris(2-hydroxyethyl)ammonium-ortho-cresoxyacetate, has the following formula:

[o-CH3C6H4OCH2COOl [NH(CH2CH2 )3~ .

The novel substance of this invention exhibits antitumorigenic activity and as such is employed in medicine as the active principle of a medicinal preparation for treating malignant neoplasms.
The proposed substance is a white crystalline powder, soft to the touch, devoid of smell, having a melting point of 80 to 82C, with a pungent bitter-turning-sweet taste, readily soluble in water and ethanol, and slightly soluble in ether, benzene and carbon tetrachloride.
The antitumorigenic activity of the proposed preparation was tested on spontaneous and induced tumors (strains of sarcoma 37, 45 and 180, Pliss lymphosarcoma; Guérin-Passy carcinoma; Brown-Pearce tumor; Walker carcinoma; and cancer of the hepatic mucosa). 120 non-pedigree white mice, 400 albino rats and 24 rabbits were used in the experiment. Some of the animals were allowed to live a natural span, a sure indication of the practically total resolution of the tumors and metastases (Brown-Pearce tumor and spontaneous tumors).
The preparation was admistered per os for 10 days starting 48 hours after the inoculation. The degree of suppression of tumor growth was calculated in percentage as compared with the control group of animals.

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The activity of the proposed preparation is illustrated by the following table.

Tumor suppression in ~ caused by the following doses, mg/kg Strain mg/kg mg/kg mg/kg mg/kg mg/kg mg/kg . . .
Sarcoma 37 43 58 91 98 Sarcoma 45 80 90 Sarcoma 180 51 64 86 92 95 98 , "~ ' Guerin carcinoma 51 60 Pliss lymphosarcoma 90 95 Walker carcinoma 95 98 Hepatic mucosa cancer 9o The most effective therapeutic doses of the prepara- --tion were found to be 300 to 400 mg/kg. At these doses, all ~ , the tumors studied were suppressed in their growth by 86 to 98 percent (except Guérin-Passy carcinoma which is suppressed in its growth by more than 50 percent).
- 20 ~' The therapeutic effectiveness of the preparation was ~-tested on spontaneous tumors of mice and induced Pliss lympho- :
sarcoma (rats) and Brown-Pearce tumor (rabbits). The course of treatment was initiated 10 to 20 days after the strain inoculation, during a period of intensive malignant growth. ;
The preparation in a dose of 400 mg/kg was administered per os daily for 25 to 45 days. The results obtained are given in the following table.
.' .
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103661~ ~ ~
~, Duration of the Number of cured Animal speeies Type of tumor course ofanimals,~
treatment, days i Mice Spontaneous tumor 30-40 75 Rats Pliss lympho-sarcoma 25-35 100 Rabbits Brown-Pearce tumor 45 100 The preparation exhibits a low level of toxicity. The maximum toleranee dose of the preparation is 2,600 mg/kg;
LD50= 2,800 mg/kg; LDloo= 3,600 mg/kg (for white mice, per os).
In accordanee with the invention, the process for the manufacture of said compound comprises reacting triethanolamine with o-cresoxyacetic acid at a temperature of up to 100 C.
and subsequently recovering the desired product.
It is preferred that the process be effected in a water-miscible organic solvent, preferably ethanol, acetone or dioxane. The process is preferably carried out at a temperature of from 50 to 80 C. In order that the desired product may be pure enough for medical applieations, the proeess is earried out in ethanol, and the desired product is reeovered by the addition of diethyl ether to the reaction mixture cooled down to -20 or -30C.
The proeess proeeeds as follows:

( 2CH2H)3 + o-cH3c6H4ocH2cooH -~
[ 3 6H4~CH2COO] - [NH(CH2cH2OH)3]+-Triethanolamine is dissolved in a water-miscible organic solvent, e.g. ethanol, acetone, dioxane, etc., mixed 103661~
with ortho-cresoxyacetic acid and heated to the point of boiling. The process may be effected in the absence of a solvent. In such a case the mixture of the parent components is melted down (m.p. 78 to 83C).
The desired product is recovered by cooling the reaction mixture and recrystallizing same. In order to obtain a high-purity desired product fit for medical applications, the process is effected in ethanol, and the desired product is recovered by adding diethyl ether to the reaction mixture cooled down to -20 or -30C. The yield of the desired product constitutes up to 98 percent by weight of the theoretical. ~-Practice of the novel process of this invention may be `
further understood by reference to the following examples of manufacturing tris(2-hydroxyethyl)ammonium-ortho-cresoxyacetate.
Example 1 A solution of 149.2g (l.OM) of triethanolamine in 150 ml of ethanol is added to a solution of 174.5 g (1.05 M) of o-cresoxyacetic acid in 500 ml of ethanolO The reaction mixture is heated to the point of boiling, then cooled to -a temperature of -20 or -30C, and 100 to 150 ml of diethyl ether is added thereto. The white crystalline precipitate is sucked off, washed with ether and dried in a vacuum. The ; yield of the desired product amounts to 295 g (93.6 percent by weight); m.p. 82 to 83C. An additional 2.5 g of the desired product is recovered from the mother liquor by concentration in a hot-water bath.

Example 2 ;
149.2 g (l.OM) of triethanolamine is added to 166.2 g (l.OM) of o-cresoxyacetic acid. As the reaction mixture is ' ~-`', .

.. -~03661~1 agitated, intensive, evolution of heat takes place. The resultant viscous desired product is melted down (m.p. 78 to 80C) and rapidly cooled. The crystals are washed with ether and dried. The yield is 315 to 317 g (100 percent by weight) of the desired product with m.p. 80 to 81C.
Actual composition, wt.%: C, 58.83; 57.14; H, 8.18;
8.20; N, 4.46; 4.26. C15H25NO6 Estimated composition, wt.%: C, 57.12; H,8.00; N,4.44.
The present invention also provides a novel medicinal preparation for treating malignant neoplasms.
In accordance with the invention, the medicinal preparation comprises an active principle, tris(2-hydroxyethyl) ammonium-orthocresoxyacetate of the following formula:

[ 3 6 4OCH2COOl ~H(CH2cH2oH)3~+

or said active principle combined with a pharmaceutical solvent for injections or a pharmaceutical filler for tablets.
The preparation has a marked antineoplastic effect and can be employed for the treatment of cancer of the stomach, -~
of the rectum, of the mammary gland, of the lungs, and of other localizations.
The preparation has a peculiar effect on neoplastic tissues: there appear therein collagenous fibres which rapidly grow in number so that, with the neoplastic tissue intergrown with connective tissue, its cells no longer receive nutrition, cease dividing and degenerate.
The preparation of this invention is practically atoxic and fails to suppress the growth of normal tissues having a high level of proliferative activity, which favourably distinguishes -. . ~ .

.. :
- 5 - ~

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103661~ :
it from the currently used antineoplastic preparations.
The preparation was studied for acute toxicity on white mice, albino rats and rabbits, weighing 17 to 20 g, 150 to 200 g, and 2 to 2.5 kg, respectively. In all animal groups, the breakdown by sex was fifty-fifty. The animals were kept under normal conditions and last fed 24 hours before the experiment. The mice and rats were kept in the laboratory for the entire observation period, whereas the rabbits were returned, after 6 hours in the laboratory, to the vivarium where they were observed twice a day. The animals were fed for the first time six hours after the ~
preparation had been administered, subsequently they were -put on a normal feeding routine. The preparation was administered in three ways: orally, intraperitoneally and ;
intravenously. The effect of a single dose of the prepara- ~
tion was assessed according to Berence on 48 non-pedigree -white mice. It was found that LDlo~=2,800 mg/kg and LD50= -~
2,600 mg/kg. The maximum tolerance dose was determined by ~ -selection on 50 white mice to be equal to 2,400 mg/kg 40 albino rats received the preparation intraperitoneally according to Kerber: LDloo=2,400 mg/kg; LD50=2,000 mg/kg-; Intravenous administration tests were carried out on white mice with the following results: at doses from 200 to 1,250 mg/kg, all the animals survived; LDloo--1,500 mg/kg;
LD50=1,300 mg/kg; the maximum tolerance dose = 1,250 mg/kg.
For rats which received the preparation orally according to Kerber, LDloo=5,000 mg/kg; LD50=4,500 mg/kg; the maximum tolerance dose = 4,000 mg/kg. For rabbits which received the preparation intravenously, LDloo=1,500 mg/kg i LD50~ 1,250 mg/kg; the maximum tolerance dose = 1,000 mg/kg The clinical picture of the effect of the preparation :

~.03661~

administered orally in a maximum tolerance dose of 2,400 mg/kg developed in the following way: after the administration of the preparation the latency period lasted for 5 to 20 minutes, testifying to the rapidity of its inhibition, after which a marked reduction in motor activity was observed which lasted for 8 to 20 hours. A day later the behaviour patterns of the animals showed no abnormality. In doses of 800 mg/kg and less, the preparation had no pronounced clinical manifesta-tions. The antineoplastic activity of the preparation was studied on induced and spontaneous tumours in mice, rats and rabbits. The preparation was administered orally. Each experimental group was made up of 6 to 12 animals. The experiments were repeated two or three times. In determining the suppressive effect of the preparation on tumour growth, -;
i~ was administered 48 hours after induction and then for 10 straight days. The inhibition process was evaluated by the results of tumour growth in the control and experimental animals. The results are given in Table 1.
' No. of Tumour Animal No. of No. of Percentage suppres-series strain species animals experi- sion in the ments group100 200 300 400 600 800 mg/kg 1.Sarcoma- Mice 10 2 51 64 86 92 95 99 2.Sarcoma- Mice 10 2 43 58 91 98
3.Sarcoma- Rats 10 3 80 90
4. Guerin Rats 10 3 51 60 sarcoma
5. LIO-l Rats 10 3 90 95
6. Walker Rats 10 3 95 98 carcinosar-coma
7. Cancer of Rats 10 3 90 the hepatic ~
mucosa ~-' .:
:

- . .. . . . .....

~)36618 In the course of treatment the general health status of the animals improved; they gained 5 to 7 percent of weight. The percentage suppression of tumour growth caused by 300 to 400 mg/kg was 80 to 98, except for the Guerin tumour which was suppressed by only 50 to 60 percent.
The therapeutic effectiveness of the preparation was studied on the following tumorigenic strains: Sarcoma-45, LIO-l, Walker carcinosarcoma, cancer of the hepatic mucosa in rats, and Brown-Pearce tumour in rabbits. The treatment was initiated 10 to 18 days after tumour induction, at the time of its intensive growth. The control animals with induced tumours underwent no treatment. The preparation was administered per os in daily doses of 400 mg/kg until total reso-lution of the tumour in most animals of the group occurred. At regular intervals during the course of treatment individual animals were butchered. The tumours were subjected to histological examination during the treatment. Blood samples were taken from rabbits with Brown-Pearce tumours. In the control groups with induced tumours, the animals lost weight in spite of the growing large tumours. Spontaneous resolution ~ was not observed. All the animals of the control groups died -~ within 20 to 35 days. The results of the treatment are given - in Table 2.
., No. of Tumour Animal No. of Duration Wt. Wt. % of series strain species animals of treat- prior after ani-ment, days to treat- mals treat- ment,g with ment, g resolved tumours . .

1. Sponta- Mice 8 35 27 32 75 neous tumour , .
. .
' , 1036618 : ~

2. Sarcoma- Mice 10 30 25 30 100 ~ -3. Sarcoma- Rats 10 35 190 210 100 4. LIO-45 Rats 10 30 230 242 100 5.Brown- Rabbits 12 45 2,550 2,620 100 Pearce tumour The tumours were completely resolved in all animals within 30 to 45 days. In the follow-up lasting for 2 to 4 months, no relapses were observed, as confirmed histologically.

The blood picture of the rabbits with Brown-Pearce sarcoma treated with the proposed preparation is given in Table 3.

Blood counts Time of sampling Before treatment, 30 days after on the 18th day the beginning after tumourof the course inductionof treatment (48 days after induction) Erythrocytes 4,300,000 4,900,000 Leucocytes 20,000 10,000 Thrombocytes 330,000 300,000 The chronic effect of the preparation was tested on intact rabbits which received the preparation daily in a dose of 150 mg/kg administered per os. Prior to the experi-ment as well as on the 10th, 20th, 30th, 60th and 90th days of study the animals were weighed and blood samples were taken and analyzed for hemoglobin, erythrocyte count, leucocyte count, thrombocyte count, residual nitrogen, sugar, total protein, protein fractions and bilirubin. Throughout the :.

g 103661~3 entire course of treatment no abnormal behaviour patterns were observed. The results of the study indicate that on no count was there any appreciable deviation from normalcy during the three months of observation. The wglght of the animals remained stable. On expiration of the three months the animals were butchered. The autopsy revealed no macrosco-pic abnormalities. Neither were any abnormalities found in the histological studies of the tissues of various organs.
The preparation is atoxic in prolonged application.

The preparation was put to clinical trials on 32 patients suffering from oncological diseases of the 4th degree (cancer of the stomach,Of the rectum, of the mammary ;~` gland, of the uterus and of the lungs; osseous and visceral sarcomas) with metastases. The preparation was prescribed per os in doses of from 0.1 to 0.5 g three times a day half an hour before meals every day for a month, then the treatment was discontinued for 5 to 10 days, whereupon the course of treatment was repeated. In spite of the grave initial -i~ condition, having been put on the preparation, the patients ~ 20 registered general improvement, alleviation or total ; disappearance of pain. The patients often gave up narcotics;
~' their sleep and appetite improved. In some patients, the tumours diminished and lost in density. The blood picture `
likewise improved.
In accordance with the invention, the preparation preferably comprises Ringer's solution or physiological solution as the pharmaceutical solvent for injections. The ;` preparation for injections preferably comprises 5 to 10 percent : ':
- 30 by weight of the active principle. Applied as tablets, the preparation comprises 0.1 to 0.5 g of the active principle per tablet.

10 - ~' '' 1~)366~
The injection preparation is slowly administered once a day; in the form of tablets, the preparation is taken 3 to 4 times a day half an hour before meals.
The preparation is atoxic, has no side effects and is easily tolerated by the patients, whatever the route of administration.
The active principle of the preparation, tris-2(hydro-xyethyl)-ammonium-orthocresoxyacetate, is produced as follows.
Triethanolamine is reacted with o-cresoxyacetic acid ; 10 at a temperature of up to 100C., and the desired product is subsequently recovered.
The process is effected in an organic solvent miscible with water.
~ Ethanol, acetone or dioxane are employed as the organic ;~ solvent miscible with water.
In order that the desired product may be of high ~- order of purity, the process is effected in ethanol, and the desired product is recovered by adding diethyl ether to the reaction mixture cooled to a temperature of 20 to 30C.

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Claims (6)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the manufacture of tris(2-hydroxy-ethyl)ammonium-ortho-cresoxyacetate which comprises reacting triethanolamine with o-cresoxyacetic acid at a temperature of up to 100°C and subsequently recovering the desired product.
2. A process as set forth in Claim 1, which is effected in an organic solvent miscible with water.
3. A process as set forth in Claim 2, wherein the water-miscible organic solvent is one selected from the group comprising ethanol, acetone and dioxane.
4. A process as set forth in Claim 1, which is effected at a temperature of 50 to 80°C.
5. A process as set forth in Claim 1, which in order to obtain a high-purity desired product fit for medical applic-ations, is effected in ethanol, with the desired product recovered by adding diethyl ether to the reaction mixture cooled down to a temperature of -20 or -30°C.
6. Tris(2-hydroxyethyl)ammonium-ortho-cresoxyacetate of the following formula:

[o-CH3C6H4OCH2COO] - [NH(CH2CH2OH)3]+

when prepared by the process as claimed in claim 1, 2 or 3 or an obvious chemical equivalent thereof.
CA204,161A 1973-07-05 1974-07-05 Process for the manufacture of tris (2-hydroxyethyl) ammonium-ortho-cresosyacetate Expired CA1036618A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
SU1946758 1973-07-05
SU1954859A SU515742A1 (en) 1973-08-06 1973-08-06 The method of obtaining tris (2-hydroxyethyl) ammonium-0-kresoxyacetate

Publications (1)

Publication Number Publication Date
CA1036618A true CA1036618A (en) 1978-08-15

Family

ID=26665493

Family Applications (1)

Application Number Title Priority Date Filing Date
CA204,161A Expired CA1036618A (en) 1973-07-05 1974-07-05 Process for the manufacture of tris (2-hydroxyethyl) ammonium-ortho-cresosyacetate

Country Status (6)

Country Link
CA (1) CA1036618A (en)
CH (1) CH599918A5 (en)
DE (2) DE2432392C3 (en)
FR (2) FR2235682B1 (en)
GB (2) GB1452339A (en)
SE (1) SE399250B (en)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4283419A (en) * 1978-11-01 1981-08-11 Voronkov Mikhail G Preparation for raising the fertility of animals
RU2098088C1 (en) * 1996-04-10 1997-12-10 Валерий Михайлович Дьяков Method for synthesis of medicinal agent (trecresan) showing immunotropic action
RU2623034C1 (en) * 2016-07-28 2017-06-21 Федеральное государственное бюджетное учреждение науки Иркутский институт химии им. А.Е. Фаворского Сибирского отделения Российской академии наук Antineoplastic agent
RU2700941C1 (en) * 2019-07-05 2019-09-24 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр реабилитации и курортологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ РК" Минздрава России) Method for preventing development of corneal opacity in case of mechanical injuries
RU2703302C1 (en) * 2019-07-05 2019-10-16 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр реабилитации и курортологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ РК" Минздрава России) Use of oxyethylammonium solution of methylphenoxyacetate
RU2701178C1 (en) * 2019-07-10 2019-09-25 Федеральное государственное бюджетное учреждение "Национальный медицинский исследовательский центр реабилитации и курортологии" Министерства здравоохранения Российской Федерации (ФГБУ "НМИЦ РК" Минздрава России) Method of accelerating corneal healing accompanying mechanical injuries

Also Published As

Publication number Publication date
DE2432393B2 (en) 1978-06-01
CH599918A5 (en) 1978-06-15
DE2432392C3 (en) 1978-04-27
DE2432393A1 (en) 1975-01-30
GB1452339A (en) 1976-10-13
DE2432392A1 (en) 1975-01-30
SE7408836L (en) 1975-01-07
DE2432393C3 (en) 1979-01-25
FR2235682A1 (en) 1975-01-31
FR2235681A1 (en) 1975-01-31
GB1452340A (en) 1976-10-13
SE399250B (en) 1978-02-06
FR2235682B1 (en) 1977-06-03
FR2235681B1 (en) 1977-06-03
DE2432392B2 (en) 1977-09-01

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