US3718664A - Tris (hydroxymethyl) aminomethane salt of thioctic acid - Google Patents
Tris (hydroxymethyl) aminomethane salt of thioctic acid Download PDFInfo
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- US3718664A US3718664A US00069225A US3718664DA US3718664A US 3718664 A US3718664 A US 3718664A US 00069225 A US00069225 A US 00069225A US 3718664D A US3718664D A US 3718664DA US 3718664 A US3718664 A US 3718664A
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- hydroxymethyl
- tris
- aminomethane
- alcohol
- acidosis
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- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 title abstract description 24
- AGBQKNBQESQNJD-UHFFFAOYSA-N alpha-Lipoic acid Natural products OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 title description 8
- AGBQKNBQESQNJD-SSDOTTSWSA-N (R)-lipoic acid Chemical compound OC(=O)CCCC[C@@H]1CCSS1 AGBQKNBQESQNJD-SSDOTTSWSA-N 0.000 title description 5
- 235000019136 lipoic acid Nutrition 0.000 title description 4
- 229960002663 thioctic acid Drugs 0.000 title description 4
- 150000001875 compounds Chemical class 0.000 abstract description 9
- 230000009471 action Effects 0.000 abstract description 5
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 21
- 235000019441 ethanol Nutrition 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 208000010444 Acidosis Diseases 0.000 description 11
- 230000007950 acidosis Effects 0.000 description 10
- 208000026545 acidosis disease Diseases 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 6
- VYEYJCBEXFTGBN-UHFFFAOYSA-N acetic acid;1,3-dimethyl-7h-purine-2,6-dione Chemical compound CC(O)=O.O=C1N(C)C(=O)N(C)C2=C1NC=N2 VYEYJCBEXFTGBN-UHFFFAOYSA-N 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000000872 buffer Substances 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000013078 crystal Substances 0.000 description 4
- 230000003834 intracellular effect Effects 0.000 description 4
- 238000001990 intravenous administration Methods 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 229940068511 thioctate Drugs 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000013019 agitation Methods 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000000241 respiratory effect Effects 0.000 description 3
- 229960000278 theophylline Drugs 0.000 description 3
- HCYFGRCYSCXKNQ-UHFFFAOYSA-N 2-(1,3-dimethyl-2,6-dioxo-7-purinyl)acetic acid Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CC(O)=O)C=N2 HCYFGRCYSCXKNQ-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 208000003826 Respiratory Acidosis Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229910000831 Steel Inorganic materials 0.000 description 2
- 230000002159 abnormal effect Effects 0.000 description 2
- 229950003769 acefylline Drugs 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000008030 elimination Effects 0.000 description 2
- 238000003379 elimination reaction Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- -1 tris (hydroxymethyl) aminomethane orotate Chemical compound 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-M Bicarbonate Chemical compound OC([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-M 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 208000005156 Dehydration Diseases 0.000 description 1
- 208000001380 Diabetic Ketoacidosis Diseases 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- 206010023388 Ketonuria Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 206010027417 Metabolic acidosis Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010037660 Pyrexia Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 231100000645 Reed–Muench method Toxicity 0.000 description 1
- IUJDSEJGGMCXSG-UHFFFAOYSA-N Thiopental Chemical compound CCCC(C)C1(CC)C(=O)NC(=S)NC1=O IUJDSEJGGMCXSG-UHFFFAOYSA-N 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- ITBPIKUGMIZTJR-UHFFFAOYSA-N [bis(hydroxymethyl)amino]methanol Chemical compound OCN(CO)CO ITBPIKUGMIZTJR-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000000862 absorption spectrum Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 229940125717 barbiturate Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 229960000182 blood factors Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- FOCAUTSVDIKZOP-UHFFFAOYSA-N chloroacetic acid Chemical compound OC(=O)CCl FOCAUTSVDIKZOP-UHFFFAOYSA-N 0.000 description 1
- 229940106681 chloroacetic acid Drugs 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 238000010573 double replacement reaction Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 230000001434 glomerular Effects 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 231100000566 intoxication Toxicity 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000000468 ketone group Chemical group 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000003908 liver function Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 235000011837 pasties Nutrition 0.000 description 1
- 229940043200 pentothal Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000001034 respiratory center Anatomy 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- MKVDFFROCUECAJ-CKDSBIORSA-M sodium;(2r,3s,4r,5r)-6-[2-(dimethylamino)acetyl]oxy-2,3,4,5-tetrahydroxyhexanoate Chemical compound [Na+].CN(C)CC(=O)OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O MKVDFFROCUECAJ-CKDSBIORSA-M 0.000 description 1
- QVGLHVDBDYLFON-UHFFFAOYSA-M sodium;1,3-dimethylpurin-7-ide-2,6-dione Chemical compound [Na+].O=C1N(C)C(=O)N(C)C2=C1[N-]C=N2 QVGLHVDBDYLFON-UHFFFAOYSA-M 0.000 description 1
- UUDFBRWLHZIIQX-UHFFFAOYSA-M sodium;5-(dithiolan-3-yl)pentanoate Chemical compound [Na+].[O-]C(=O)CCCCC1CCSS1 UUDFBRWLHZIIQX-UHFFFAOYSA-M 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 230000002110 toxicologic effect Effects 0.000 description 1
- 231100000027 toxicology Toxicity 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- 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
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H23/00—Compounds containing boron, silicon or a metal, e.g. chelates or vitamin B12
Definitions
- ABSTRACT The present invention concerns new compounds of anti-acidotic action such as the derivatives of tris (hydroxymethyl) aminomethane, of important therapeutic application.
- Constant blood pH is essential for the development of vital processes of the human organism.
- 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 P
- 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.
- the treatment must be directed to increase the alkali reserve and to activate the extrablood regulator mechanisms.
- Nahas introduced the organic amines, among which by its efficacy and non-toxicity the tris (hydroxymethyl) aminomethane or THAM, which not only acts as a plasmatic buffer but also as an intracellular buffer.
- 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.
- the method of obtaining these compounds is essentially based on the direct reaction of the respective acid with tris (hydroxymethyl)amin'omethane, either in the fusion state or in a suitable solvent.
- EXAMPLE 1 200 g. of theophylline and 500 cc. of water are heated to ebullition and added to 100 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.
- 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.
- 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.
- the efficiency is 88 percent.
- EXAMPLE 3 In a double opening 500 cc. matrass are placed 14.4 g. of tris (hydroxymethyl) aminomethane finely powdered and cc. of absolute ethyl alcohol. The matrass is adjusted to a reflux cooler.
- the mixture is heated in water-bath until the tris (hydroxymethyl) aminomethane is dissolvedv
- a separatory funnel containing a solution of 25 g. of thioctic acid in 125 cc. alcohol.
- 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.
- the efficiency is 87 percent.
- 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 in 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 efficiency is in the range of 80 percent but the mother waters of crystallization can be used for a new obtention.
- the molecular weight is 327.5 and its melting point is 120 C.
- the temperature is raised slowly to 80 C, with continuous agitation.
- the efficiency is in the range of 94 percent.
- 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 g. of sodium pangamate until complete dissolution.
- 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.
- the LD 50 of tris (hydroxymethyl) aminomethane theophylline acetate in albino mice by oral route is 4.05 i 0.174 g./kg. and 2.45 i 0.145 g./kg. by intravenous route.
- mice The LD 50 of tris (hydroxymethyl) aminomethane thioctate in mice is 506 i 4.71 mg. by oral route, 126.4 1 5.76 mg./kg. by intravenous route and 278 i 5.69 mg./kg. by intraperitoneal route.
- the LD 50 is 1600 i 168 mg./kg. by oral route, 345.2 i 27.1 mg./kg. by intravenous route and 365: 25.5 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 counteracted by the stimulant action exerted by 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 emanatamental origin produced by barbiturates, salicylic derivatives and the like, in which it facilitates the quick elimination of the toxic substances by renal route.
- composition of matter tris(hydroxymethyl)aminomethane salt of thiocticacid.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- General Health & Medical Sciences (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention concerns new compounds of anti-acidotic action such as the derivatives of tris (hydroxymethyl) aminomethane, of important therapeutic application.
Description
United States Patent ['19] Salat et al.
[ 1 Feb. 27, 1973 [54] TRIS (HYDROXYMETHYL) AMINOMETHANE SALT OF THIOCTIC ACID [75] Inventors: Carlos Ferrer Salat, Jorge Ferrer Batlles, Juan Colome Riera, all of Barcelona, Spain [73] Assignee: Laboratorios Ferrer, S. L., Barcelona, Spain [22] Filed: Sept. 3, 1970 [21] Appl. No.: 69,225
Related U.S. Application Data [62] Division of Ser. No. 616,780, Dec. 17, 1967, Pat. No.
[30] Foreign Application Priority Data Feb. I7, 1966 Spain ..323,l95
[52] U.S. Cl. ..260/327 A, 260/251 R, 260/253,
424/250, 424/277 [51] Int. Cl. ..A6lk 27/00, C07d 7l/00 [58] Field of Search ..260/3 27 A [56] References Cited UNITED STATES PATENTS [57] ABSTRACT The present invention concerns new compounds of anti-acidotic action such as the derivatives of tris (hydroxymethyl) aminomethane, of important therapeutic application.
1 Claim, No Drawings TRIS (HYDROXYMETHYL) AMINOMETHANE SALT OF TIIIOCTIC ACID This application is a divisional application of applicants US. Patent application, Ser. No. 616,780, filed Feb. 17, 1967, now US. Pat. No. 3,562,273, patented Feb. 9, 1971.
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 P 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. 1
In the second case, the treatment must be directed to increase the alkali reserve and to activate the extrablood 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 buffer, 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 which by its efficacy and non-toxicity the 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)amin'omethane, 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 way of examination, by the following examples:
EXAMPLE 1 200 g. of theophylline and 500 cc. of water are heated to ebullition and added to 100 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.
g. of theophylline acetic acid perfectly dried are pulverized with 50.9 g. of tris (hydroxymethyl) aminomethane in a mortar until a homogenous mixture is obtained. The mixture is immediately transferred to a steel container in oil bathand heated to l50-l75 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 Na Cl 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 efficiency is 88 percent.
The product thus obtained has been identified as the trist (hydroxymethyl) aminomethane theophyllineacetate of molecular weight 359.3, empirical formula C H N O and structural formula:
0 I! l N NH? l l i HOHzC-C-CHzOH 0 N N 1......
White powder, hygroscopic, melting at C, very soluble in water and warm alcohol, sparingly soluble in cold alcohol, insoluble in chloroform, acetone, bencene and ether. In 0.05 M solution it has a pH of 6.4. Its absorption spectrum in ultraviolet in H Cl 0.1 N shows a maximum at 272 Mg.
EXAMPLE 3 In a double opening 500 cc. matrass are placed 14.4 g. of tris (hydroxymethyl) aminomethane finely powdered and cc. of absolute ethyl alcohol. The matrass is adjusted to a reflux cooler.
The mixture is heated in water-bath until the tris (hydroxymethyl) aminomethane is dissolvedv 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) aminomethane thioctate, crystalline yellowish powder of 120 C. metling point, is obtained.
The efficiency is 87 percent.
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 in 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 efficiency is in the range of 80 percent 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: C 2H25O5NSz and it corresponds to the following structural formula:
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 335 my. in ethanol.
EXAMPLES 7.8 g. (1/20 mol) of tris (hydroxymethyl) aminomethane orotate is added in small portions to a solution containing 6 g. (1/20 mol) of THAM in 100 cc. of water.
The temperature is raised slowly to 80 C, with continuous agitation.
The solvent is evaporated to dryness, the product is washed with ether and vacuum dried again.
The efficiency is in the range of 94 percent.
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 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.
Efficiency is in the range of 96 percent.
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 i 0.174 g./kg. and 2.45 i 0.145 g./kg. by intravenous route.
The LD 50 of tris (hydroxymethyl) aminomethane thioctate in mice is 506 i 4.71 mg. by oral route, 126.4 1 5.76 mg./kg. by intravenous route and 278 i 5.69 mg./kg. by intraperitoneal route.
This compound has also been experimented in rats. The LD 50 is 1600 i 168 mg./kg. by oral route, 345.2 i 27.1 mg./kg. by intravenous route and 365: 25.5 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 counteracted by the stimulant action exerted by 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 medieamental origin produced by barbiturates, salicylic derivatives and the like, in which it facilitates the quick elimination of the toxic substances by renal route.
with troubles of the liver function or of the metabolism of glucides. Likewise, in acidoketosis by fever, vomiting, ketonuria, dehydratations, denutrition, alcoholism, diabetic acidosis, post-anesthetic acidosis, etc.
We claim:
1. A composition of matter, tris(hydroxymethyl)aminomethane salt of thiocticacid.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES0323195A ES323195A1 (en) | 1966-02-17 | 1966-02-17 | Tris (hydroxymethyl) aminomethane theophylline acetate |
| US61678067A | 1967-12-17 | 1967-12-17 | |
| US6922570A | 1970-09-03 | 1970-09-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US3718664A true US3718664A (en) | 1973-02-27 |
Family
ID=27240694
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US00069225A Expired - Lifetime US3718664A (en) | 1966-02-17 | 1970-09-03 | Tris (hydroxymethyl) aminomethane salt of thioctic acid |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US3718664A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5990152A (en) * | 1994-09-22 | 1999-11-23 | Asta Medica Aktiengesellschaft | Dosage forms containing thioctic acid or solid salts of thioctic acid with improved release and bioavailability |
| US8541601B2 (en) | 2009-06-24 | 2013-09-24 | Celltrion Chemical Research Institute | Piperazine dithioctate and pharmaceutical composition comprising the same |
| WO2017124045A1 (en) * | 2016-01-15 | 2017-07-20 | Ming Zhao | Composition containing artesunate |
| 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 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3128186A (en) * | 1960-07-15 | 1964-04-07 | Gen Foods Corp | Stabilized photographic silver halide emulsions |
-
1970
- 1970-09-03 US US00069225A patent/US3718664A/en not_active Expired - Lifetime
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3128186A (en) * | 1960-07-15 | 1964-04-07 | Gen Foods Corp | Stabilized photographic silver halide emulsions |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5990152A (en) * | 1994-09-22 | 1999-11-23 | Asta Medica Aktiengesellschaft | Dosage forms containing thioctic acid or solid salts of thioctic acid with improved release and bioavailability |
| US6348490B1 (en) * | 1994-09-22 | 2002-02-19 | Asta Medica Aktiengesellschaft | Dosage forms containing thioctic acid or solid salts of thioctic acid with improved release and bioavailability |
| US8541601B2 (en) | 2009-06-24 | 2013-09-24 | Celltrion Chemical Research Institute | Piperazine dithioctate and pharmaceutical composition comprising the same |
| WO2017124045A1 (en) * | 2016-01-15 | 2017-07-20 | Ming Zhao | Composition containing artesunate |
| US10471042B2 (en) | 2016-01-15 | 2019-11-12 | Ming Zhao | Composition containing artesunate |
| US10987338B2 (en) | 2016-01-15 | 2021-04-27 | Ming Zhao | Composition containing artesunate |
| US12083096B2 (en) | 2016-01-15 | 2024-09-10 | Ming Zhao | Composition containing artesunate |
| 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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