US3562273A - Tris (hydroxymethyl) aminomethane theophylline acetate - Google Patents

Tris (hydroxymethyl) aminomethane theophylline acetate Download PDF

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US3562273A
US3562273A US616780A US3562273DA US3562273A US 3562273 A US3562273 A US 3562273A US 616780 A US616780 A US 616780A US 3562273D A US3562273D A US 3562273DA US 3562273 A US3562273 A US 3562273A
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tris
hydroxymethyl
aminomethane
theophylline
alcohol
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US616780A
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Carlos Ferrer Salat
Jorge Ferrer Batlles
Juan Colome Riera
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Ferrer Internacional SA
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Laboratorios Ferrer SL
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C07D239/545—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/557—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals with other hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. orotic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H23/00—Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12

Definitions

  • the present invention concerns new compounds of antiacidotic action such as the derivatives of tris (hydroxymethyl) amiuomethane, of important therapeutic applications.
  • Nahas introduced the organic amines, among whichby its efficacy and non-toxicitythe tris (hydroxymethyl) aminomethane or THAM, which not only acts as a plasmatic buffer but also as an intracellular buffer.
  • the mixture is constantly and vigorously agitated until a limpid liquid is obtained which is dropped, still scalding, into steel trays and, finally, is subjected to vacuum desiccation to preserve from moisture.
  • the desiccated product must be manipulated rapidly and in a very dry medium as it is very hygroscopic. In this way are obtained some 145 g. of tris (hydroxymethyl) aminomethane theophylline acetate.
  • EXAMPLE 4 15.8 g. of tris (hydroxymethyl) aminomethane hydrochloride are dissolved in the smallest possible quantity of water and 22.8 g. of sodium thioctate are previously added, dissolved in the smallest possible quantity of water.
  • EXAMPLE 5 4 The product thus obtained is a microcrystalline powder, soluble in water and in alcohol and insoluble in ether.
  • the LD 50 of tris (hydroxymethyl) aminomethane theophylline acetate in albino mice by oral route is 4.05:0.174 g./kg. and 2.45 i0.145 g./kg. by intravenous route.
  • the LD 50 is 1600:168 mg./kg. by oral route, 345.2: 27.1 mg./kg. by intravenous route and 365:255 mg./ kg. by intraperitoneal route.
  • the tris (hydroxymethyl) aminomethane theophylline. acetate can be considered, by its characteristics, as a complete antiacidotic product since it acts not only on the blood factors that regulate the pH but also on the cellular pulmonary and renal factors.
  • the new compound acts as a proton acceptor neutralizing the intracellular hydrogen ions.
  • respiratory acidosis the depressant action of tris (hydroxymethyl) aminomethane on the respiratory centers is counter acted by the stimulant action exerted by the theophylline on them.
  • renal acidosis there is a synergism between the diuretic action of osmotic and tubular type of the tris (hydroxymethyl) aminomethane with that of glomerular type of the theophylline.
  • the tris (hydroxymethyl) aminomethane theophylline-acetate is indicated in all types of toxic, respiratory or metabolic acidosis of tissular, pulmonary, plasmatic, or renal origin. Also in intoxications of medicamental origin produced by barbiturates, salicylic derivatives and the like, in which it facilitates the quick elimination of the toxic substances by renal route.
  • the new compound can be administered, unlike the tris (hydroxymethyl) aminomethane, by oral route without producing digestive troubles, and by intravenous route without provoking irritations.

Abstract

THE PRESENT INVENTION RELATES TO COMPOSITIONS OF TRIS (HYDROXYMETHYL) AMINOMETHANE WITH MONOCARBOXYLIC AMINATED ORGANIC OACIDS SUCH AS THEOPHYLLINE-ACETIC ACID, THIOCTIC ACID, OROTIC ACID AND PANGAMIC ACID, THE METHOD OF MANUFACTURING THE SAME, AND THE METHOD OF TREATING ACIDOSIS BY ADMINSTRATION OF THE SAME.

Description

United States Patent Oflice 3,562,273 Patented Feb. 9, 1971 Int. or. (Jim 57/52 U.S. Cl. 260-253 1 Claim ABSTRACT OF THE DISCLOSURE The present invention relates to compositions of tris (hydroxymethyl) aminomethane with monocarboxylic aminated organic acids such as theophylline-acetic acid, thioctic acid, orotic acid and pangamic acid, the method of manufacturing the same, and the method of treating acidosis by administration of the same.
The present invention concerns new compounds of antiacidotic action such as the derivatives of tris (hydroxymethyl) amiuomethane, of important therapeutic applications.
Constant blood pH is essential for the development of vital processes of the human organism. However, the acidosis produced either by abnormal accumulation in blood of ketone groups originating from the abnormal catabolism of fatty. acids together with a deficiency in the metabolism of carbohydrates, either by failure in the mechanism regulating the blood and extra-blood pH.
In the first type of acidosis, the treatment can be directed to increase the pH and the alkali reserve, to promote the whole metabolism of the ketone bodies, or both, simultaneously.
In the second case, the treatment must be directed to increase the alkali reserve and to activate the extra-blood regulator mechanisms.
In general, the treatments used up to now were directed to normalize the pH by increasing the alkali reserve.
For instance, use was made of sodium bicarbonate which acts exclusively as a blood butter, but it shows the disadvantage of being contraindicated in the acidosis of respiratory or renal nature and being devoid of intracellular buffer action.
In 1959, Nahas introduced the organic amines, among whichby its efficacy and non-toxicitythe tris (hydroxymethyl) aminomethane or THAM, which not only acts as a plasmatic buffer but also as an intracellular buffer.
However, the THAM shows some disadvantages in relation to its administration since its solutions are too alkaline and may provoke digestive troubles. On the other hand, it is not active against the causes of the acidosis.
To correct such disadvantages in the treatment of acidosis we have directed our investigation towards the synthesis of THAM derivatives having more effective therapeutic properties and being better tolerated.
In this way we have synthesized a series of THAM derivatives with organic acids acting on acidosis. The mentioned compounds not only reestablish the pH but they are also active against the causes producing the changes, and they differentiate from the antiacidotic substances known so far.
The method of obtaining these compounds is essentially based on the direct reaction of the respective acid with tris (hydroxymethyl) aminomethane, either in the fusion state or in a suitable solvent.
These compounds can also be obtained by reacting the salts of the components by means of double replacement in a solvent that is suitable in each particular case.
The invention is illustrated, by the following examples:
EXAMPLE 1 200 g. of theophylline and 500 cc. of water are heated to ebullition and added to g. of chloroacetic acid and small portions of sodium hydroxide 30% without discontinuing agitation and heating strongly for 10 minutes. Then keep slow ebullition for another 30 minutes.
The solution is then cooled in a drier, then filtered, the resulting crystals are washed with slightly acidified water and, finally, desiccated. The crystals thus obtained correspond to theophylline acetic acid.
100 g. of theophylline acetic acid perfectly dried are pulverized with 50.9 g. of tris (hydroxymethyl) amino methane in a mortar until a homogenous mixture is obtained. The mixture is immediately transferred to a steel container in oil bath and heated to 150l75 C.
The mixture is constantly and vigorously agitated until a limpid liquid is obtained which is dropped, still scalding, into steel trays and, finally, is subjected to vacuum desiccation to preserve from moisture.
The desiccated product must be manipulated rapidly and in a very dry medium as it is very hygroscopic. In this way are obtained some 145 g. of tris (hydroxymethyl) aminomethane theophylline acetate.
EXAMPLE 2 26.0 g. of sodium theophylline acetate are dissolved in the smallest possible quantity of water, to which 15.8 g. of tris (hydroxymethyl) aminomethane hydrochloride is added.
Ebullition is maintained for 30 minutes; then 200 cc. of warm alcohol 96 are added, and the hot solution is filtered to separate the NaCl thus formed. The resulting solution is vacuum evaporated until a pasty mass of crystals is detached and then treated with absolute alcohol; the evaporation to dryness is repeated to eliminate the remaining water.
The efiiciency is 88%.
The product thus obtained has been identified as the tris (hydroxymethyl) aminomethane theophylline-acetate of molecular weight 359.3, empirical formula 13 21 5 'z and structural formula:
o int-00011 N H C-N F I I HOHzC-OCH2OH 0 N HzOH White powder, hygroscopic, melting at C., very soluble in water and warm alcohol, sparingly soluble in 3 cold alcohol, insoluble in chloroform, acetone, benzene and ether. In 0.05 M solution it has a pH of 6.4. Its absorption spectrum in ultraviolet in HCl 0.1 N shows a maximum at 272H1/1..
EXAMPLE 3 In a double opening 500 cc. matrass are placed 14.4 g. of tris (hydroxymethyl) aminomethane finely powdered and 125 cc. of absolute ethyl alcohol. The matrass is adjusted to a reflux cooler.
The mixture is heated in water-bath until the tris(hydroxyrnethyl) aminomethane is dissolved. In the free end of the matrass is adjusted a separatory funnel containing a solution of 25 g. of thioctic acid in 125 cc. alcohol.
This solution is slowly dropped in the matrass for 30 minutes always maintaining the matrass contents in ebullition. Then the ebullition is maintained for another 10 minutes to complete the reaction.
The solution being still hot, it is carefully vacuum concentrated to avoid sudden elimination of the alcohol. It is cooled in the refrigerator for 3 to 4 hours, with occasional agitation to obtain crystallization.
The mixture is vacuum filtered and dried in the drying chamber at 60 C. for 1 hour.
The product is re-crystallized in alcohol at the rate of 4 cc. alcohol/g, then the crystals are washed with anhydrous ether and dried in the drying chamber at 60 C. A tris (hydroxymethyl) aminoethane thioctate, crystalline yellowish powder of 120 C. melting point, is obtained.
The efiiciency is 87%.
EXAMPLE 4 15.8 g. of tris (hydroxymethyl) aminomethane hydrochloride are dissolved in the smallest possible quantity of water and 22.8 g. of sodium thioctate are previously added, dissolved in the smallest possible quantity of water.
The resulting solution is maintained in ebullition for 30 minutes and one part of the solvent is allowed to evaporate. Then it is allowed to cool, 200 cc. of alcohol are added and the mixture is heated again. The solution, still hot, is immediately filtered to separate the sodium chloride thus formed. The solution is slowly cooled in the refrigerator and the product becomes crystallized.
The product is vacuum filtered and dried, then recrystallized in alcohol as in Example 3. The efiiciency is in the range of 80% but the mother waters of crystallization can be used for a new obtention.
The product obtained, the tris (hydroxymethyl) aminomethane thioctate, has the empirical formula:
and it corresponds to the following structural formula:
CH2OH The molecular weight is 327.5 and its melting point is 120 C.
It is a yellow crystalline powder, very soluble in water and in hot alcohol. It is sparingly soluble in cold alcohol and in warm acetone. It is insoluble in chloroform, benzene and ether. In 0.1 M aqueous solution it has a pH of 6.5. Its ultraviolet spectrum shows a maximum absorption of 335m in ethanol.
EXAMPLE 5 4 The product thus obtained is a microcrystalline powder, soluble in water and in alcohol and insoluble in ether.
EXAMPLE 6 Small amounts of water are added to 15 g. of sodium pangamate until complete dissolution.
On the other hand, 7.6 g. of tris (hydroxymethyl) aminomethane hydrochloride are dissolved in the smallest possible amount of water. The solutions are mixed and heated to ebullition.
96 alcohol is added to the necessary amount until the sodium chloride starts becoming insoluble, then 10 cc. of 96 alcohol is added.
The solution is filtered and the residue is washed with 96 alcohol.
Both filtrates are joined. The solution is evaporated to dryness with vacuum aid.
Efiiciency is in the range of 96% A series of toxicologic, pharmacologic and clinical experiences have been carried out with the new compounds.
The LD 50 of tris (hydroxymethyl) aminomethane theophylline acetate in albino mice by oral route is 4.05:0.174 g./kg. and 2.45 i0.145 g./kg. by intravenous route.
The LD 50 of tris (hydroxymethyl) aminomethane thioctate in mice is 506:4.71 mg. by oral route, 126.4: 5.76 mg./kg. by intravenous route and 27815.69 mg./ kg. by intraperitoneal route.
This compound has also been experimented in rats. The LD 50 is 1600:168 mg./kg. by oral route, 345.2: 27.1 mg./kg. by intravenous route and 365:255 mg./ kg. by intraperitoneal route.
All results are expressed according to the Reed-Muench method.
The buffer capacity of these compounds has been verified in dogs anesthetized with pentothal with acute experimental acidosis induced by iv. injection of a solution of phosphates, ammonium chloride, lactic acid, etc. up to a pH of 7.2.
When the product is administered by intravenous route the pH return to normal values and the reserve expressed in bicarbonate is recuperated.
The study of the results of the administration of 50 mg./kg. of tris (hydroxymethyl) aminomethane thioctate to cats weighing 2 to 3 kg. showed no changes in blood pressure nor modification of the respiratory recording. The electrocardiogram was neither modified during or after administration.
The tris (hydroxymethyl) aminomethane theophylline. acetate can be considered, by its characteristics, as a complete antiacidotic product since it acts not only on the blood factors that regulate the pH but also on the cellular pulmonary and renal factors.
In acidosis of intracellular origin, the new compound acts as a proton acceptor neutralizing the intracellular hydrogen ions. In respiratory acidosis, the depressant action of tris (hydroxymethyl) aminomethane on the respiratory centers is counter acted by the stimulant action exerted by the theophylline on them. In renal acidosis, there is a synergism between the diuretic action of osmotic and tubular type of the tris (hydroxymethyl) aminomethane with that of glomerular type of the theophylline.
Clinically, the tris (hydroxymethyl) aminomethane theophylline-acetate is indicated in all types of toxic, respiratory or metabolic acidosis of tissular, pulmonary, plasmatic, or renal origin. Also in intoxications of medicamental origin produced by barbiturates, salicylic derivatives and the like, in which it facilitates the quick elimination of the toxic substances by renal route.
As it has a slightly alkaline pH, the new compound can be administered, unlike the tris (hydroxymethyl) aminomethane, by oral route without producing digestive troubles, and by intravenous route without provoking irritations.
6 Clinically, excellent results have been obtained with References Cited the tris (hydroxymethyl) aminomethane thioctate, oro- UNITED STATES PATENTS tate and pangamate by its buffer and eumetabolic action in acidosis of metabolic or toxic type related with troux 3: bles of the liver function or of the metabolism of glu- 5 v3098854 6/1963 Klosa 26O 253 cides. Likewise, in acidoketosis by fever, vomiting, ketonuria, dehydratations, denutrition, alcoholism, diabetic ALEX MAZEL, Primary Examiner acidosis, post-anesthetic acidosis, etc. TIGHE, Assistant Examiner We claim: 1. A composition of matter tris (hydroxymethyl) m aminomethane theophylline acetate. 260-460, 327, 482; 424-251, 253, 277, 311
US616780A 1966-02-17 1967-02-17 Tris (hydroxymethyl) aminomethane theophylline acetate Expired - Lifetime US3562273A (en)

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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4071517A (en) * 1974-09-10 1978-01-31 Claude Dufour Soluble salts containing sulphur
US4572811A (en) * 1978-06-29 1986-02-25 Yoshino Kogyosho Co., Ltd. Method for producing polyester containers
WO2003011852A1 (en) * 2001-07-31 2003-02-13 Viatris Gmbh & Co. Kg Novel modifications of the trometamol salt of r-thioctic acid and method for producing the same
US20070196442A1 (en) * 2006-02-10 2007-08-23 Heuer Marvin A Method for improving the oral administration of alpha-lipoic acid
US20090264651A1 (en) * 2008-04-17 2009-10-22 Thomas Daly Biological Buffers with Wide Buffering Ranges
US20100099868A1 (en) * 2008-04-17 2010-04-22 Thomas Daly Biological Buffers with Wide Buffering Ranges
US20100190993A1 (en) * 2008-04-17 2010-07-29 Thomas Daly Biological Buffers with Wide Buffering Ranges
US20110137076A1 (en) * 2008-04-17 2011-06-09 Thomas Daly Biological Buffers with Wide Buffering Ranges
US8519141B2 (en) 2008-04-17 2013-08-27 Thomas Daly Biological buffers with wide buffering ranges
US8541601B2 (en) 2009-06-24 2013-09-24 Celltrion Chemical Research Institute Piperazine dithioctate and pharmaceutical composition comprising the same
CN103360393A (en) * 2013-07-29 2013-10-23 上海万巷制药有限公司 Preparation method of theophylline-7-acetic acid
US8822728B2 (en) 2008-04-17 2014-09-02 Thomas Daly Biological buffers with wide buffering ranges
US9090638B2 (en) 2008-04-17 2015-07-28 Thomas Daly Biological buffers with wide buffering ranges
US9447310B2 (en) 2008-04-17 2016-09-20 Thomas P. Daly Biological buffers with wide buffering ranges
US9475754B2 (en) 2011-10-06 2016-10-25 Thomas P. Daly Biological buffers with wide buffering ranges
US10927279B2 (en) 2008-04-17 2021-02-23 Thomas Daly Biological buffers with wide buffering ranges
CN113200959A (en) * 2020-12-16 2021-08-03 南京海融制药有限公司 Lipoic acid tromethamine salt crystal form and preparation method thereof

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EP0318891B1 (en) * 1987-12-04 1992-01-02 ASTA Medica Aktiengesellschaft Injectable solution of thioctic acid containing trometamole and/or basic amino acids
US5136096A (en) * 1989-08-31 1992-08-04 University Of South Florida Multifunctional synthons as used in the preparation of cascade polymers or unimolecular micelles
DE4433764A1 (en) * 1994-09-22 1996-03-28 Asta Medica Ag Dosage forms containing alpha-lipoic acid, solid salts of R-thioctic acid with improved release and bioavailability

Cited By (29)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4071517A (en) * 1974-09-10 1978-01-31 Claude Dufour Soluble salts containing sulphur
US4572811A (en) * 1978-06-29 1986-02-25 Yoshino Kogyosho Co., Ltd. Method for producing polyester containers
US4590021A (en) * 1978-06-29 1986-05-20 Yoshino Kogyosho Co., Ltd. Method for producing polyester containers
WO2003011852A1 (en) * 2001-07-31 2003-02-13 Viatris Gmbh & Co. Kg Novel modifications of the trometamol salt of r-thioctic acid and method for producing the same
CN1309718C (en) * 2001-07-31 2007-04-11 维亚特里斯两合公司 Novel modifications of aminobutantriol salt of R-thioctic acid and method for producing the same
CN100410248C (en) * 2001-07-31 2008-08-13 维亚特里斯两合公司 Modifications of the trometamol salt of R-thioctic acid as well as a process for their production
KR100913684B1 (en) * 2001-07-31 2009-08-24 에보니크 데구사 게엠베하 Novel crystallization of the trometamol salt of R-thioctic acid, method for producing the same and medicament comprising the same
US20070196442A1 (en) * 2006-02-10 2007-08-23 Heuer Marvin A Method for improving the oral administration of alpha-lipoic acid
US7851652B2 (en) 2008-04-17 2010-12-14 Thomas Daly Biological buffers with wide buffering ranges
US8519141B2 (en) 2008-04-17 2013-08-27 Thomas Daly Biological buffers with wide buffering ranges
US10927279B2 (en) 2008-04-17 2021-02-23 Thomas Daly Biological buffers with wide buffering ranges
US7635791B2 (en) 2008-04-17 2009-12-22 Tpat Ip Llc Biological buffers with wide buffering ranges
US20100099868A1 (en) * 2008-04-17 2010-04-22 Thomas Daly Biological Buffers with Wide Buffering Ranges
US20100190993A1 (en) * 2008-04-17 2010-07-29 Thomas Daly Biological Buffers with Wide Buffering Ranges
US20090264651A1 (en) * 2008-04-17 2009-10-22 Thomas Daly Biological Buffers with Wide Buffering Ranges
US7939659B2 (en) 2008-04-17 2011-05-10 Thomas Daly Biological buffers with wide buffering ranges
US20110137076A1 (en) * 2008-04-17 2011-06-09 Thomas Daly Biological Buffers with Wide Buffering Ranges
US8034951B2 (en) 2008-04-17 2011-10-11 Thomas Daly Biological buffers with wide buffering ranges
US8334402B2 (en) 2008-04-17 2012-12-18 Thomas Daly Biological buffers with wide buffering ranges
US20090264675A1 (en) * 2008-04-17 2009-10-22 Thomas Daly Biological buffers with wide buffering ranges
US9447310B2 (en) 2008-04-17 2016-09-20 Thomas P. Daly Biological buffers with wide buffering ranges
US9090638B2 (en) 2008-04-17 2015-07-28 Thomas Daly Biological buffers with wide buffering ranges
US8822728B2 (en) 2008-04-17 2014-09-02 Thomas Daly Biological buffers with wide buffering ranges
WO2009137765A1 (en) * 2008-05-09 2009-11-12 Thomas Daly Biological buffers with wide buffering ranges
US8541601B2 (en) 2009-06-24 2013-09-24 Celltrion Chemical Research Institute Piperazine dithioctate and pharmaceutical composition comprising the same
US9475754B2 (en) 2011-10-06 2016-10-25 Thomas P. Daly Biological buffers with wide buffering ranges
CN103360393A (en) * 2013-07-29 2013-10-23 上海万巷制药有限公司 Preparation method of theophylline-7-acetic acid
CN103360393B (en) * 2013-07-29 2016-01-06 上海万巷制药有限公司 The preparation method of theophylline acetic acid
CN113200959A (en) * 2020-12-16 2021-08-03 南京海融制药有限公司 Lipoic acid tromethamine salt crystal form and preparation method thereof

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ES323195A1 (en) 1966-12-01
CH469659A (en) 1969-03-15
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FR1511911A (en) 1968-02-02
GB1113600A (en) 1968-05-15

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