DE1695358A1 - Derivatives of tris (hydroxymethyl) aminomethane - Google Patents
Derivatives of tris (hydroxymethyl) aminomethaneInfo
- Publication number
- DE1695358A1 DE1695358A1 DE19671695358 DE1695358A DE1695358A1 DE 1695358 A1 DE1695358 A1 DE 1695358A1 DE 19671695358 DE19671695358 DE 19671695358 DE 1695358 A DE1695358 A DE 1695358A DE 1695358 A1 DE1695358 A1 DE 1695358A1
- Authority
- DE
- Germany
- Prior art keywords
- tris
- acid
- hydroxymethyl
- aminomethane
- salt
- 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.)
- Pending
Links
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical class OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 title claims description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 150000003839 salts Chemical class 0.000 claims description 22
- 238000000034 method Methods 0.000 claims description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 19
- 239000000243 solution Substances 0.000 claims description 17
- 235000019136 lipoic acid Nutrition 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 229960002663 thioctic acid Drugs 0.000 claims description 14
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- 239000007983 Tris buffer Substances 0.000 claims description 12
- 230000008569 process Effects 0.000 claims description 12
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 claims description 11
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 8
- 238000009835 boiling Methods 0.000 claims description 7
- 238000002360 preparation method Methods 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims 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 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- 229960005010 orotic acid Drugs 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 4
- BAVYZALUXZFZLV-UHFFFAOYSA-N Methylamine Chemical compound NC BAVYZALUXZFZLV-UHFFFAOYSA-N 0.000 claims description 3
- 125000000896 monocarboxylic acid group Chemical group 0.000 claims description 3
- 230000015572 biosynthetic process Effects 0.000 claims description 2
- 229940106978 pangamate Drugs 0.000 claims description 2
- 239000002798 polar solvent Substances 0.000 claims 9
- AGBQKNBQESQNJD-UHFFFAOYSA-N lipoic acid Chemical compound OC(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-N 0.000 claims 6
- RVSTWRHIGKXTLG-WCXIOVBPSA-N Pangamic acid Chemical compound CC(C)N(C(C)C)C(N(C(C)C)C(C)C)C(=O)OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RVSTWRHIGKXTLG-WCXIOVBPSA-N 0.000 claims 5
- RVSTWRHIGKXTLG-UHFFFAOYSA-N Pangamic acid Natural products CC(C)N(C(C)C)C(N(C(C)C)C(C)C)C(=O)OCC(O)C(O)C(O)C(O)C(O)=O RVSTWRHIGKXTLG-UHFFFAOYSA-N 0.000 claims 5
- 238000001914 filtration Methods 0.000 claims 5
- 229940055705 pangamic acid Drugs 0.000 claims 5
- 108700024047 pangamic acid Proteins 0.000 claims 5
- 229910017053 inorganic salt Inorganic materials 0.000 claims 4
- 150000002763 monocarboxylic acids Chemical class 0.000 claims 2
- 150000007513 acids Chemical class 0.000 claims 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 1
- 230000000630 rising effect Effects 0.000 claims 1
- 238000001291 vacuum drying Methods 0.000 claims 1
- 238000005406 washing Methods 0.000 claims 1
- 235000019441 ethanol Nutrition 0.000 description 17
- 208000010444 Acidosis Diseases 0.000 description 13
- 230000007950 acidosis Effects 0.000 description 12
- 208000026545 acidosis disease Diseases 0.000 description 12
- 239000000047 product Substances 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 6
- AGBQKNBQESQNJD-UHFFFAOYSA-M lipoate Chemical compound [O-]C(=O)CCCCC1CCSS1 AGBQKNBQESQNJD-UHFFFAOYSA-M 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
- 239000008280 blood Substances 0.000 description 5
- 238000001990 intravenous administration Methods 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000000872 buffer Substances 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 239000003513 alkali Substances 0.000 description 3
- -1 hydroxy- Chemical class 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 229960000278 theophylline Drugs 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 206010027417 Metabolic acidosis Diseases 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
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 230000003139 buffering effect Effects 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
- 230000001079 digestive effect Effects 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 230000001788 irregular Effects 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 230000000241 respiratory effect Effects 0.000 description 2
- 239000010959 steel Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 208000007848 Alcoholism Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- 208000002720 Malnutrition 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
- 206010047700 Vomiting Diseases 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
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 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
- 229960000182 blood factors Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 230000001914 calming effect 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
- 230000008859 change 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
- 230000002950 deficient Effects 0.000 description 1
- 230000018044 dehydration Effects 0.000 description 1
- 238000006297 dehydration reaction Methods 0.000 description 1
- 230000000994 depressogenic effect Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 238000000605 extraction 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
- 230000001434 glomerular Effects 0.000 description 1
- 230000010224 hepatic metabolism Effects 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
- 231100000566 intoxication Toxicity 0.000 description 1
- 230000035987 intoxication Effects 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000007794 irritation Effects 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
- 230000003908 liver function Effects 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- VNWKTOKETHGBQD-UHFFFAOYSA-N methane Chemical class C VNWKTOKETHGBQD-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- NQMRYBIKMRVZLB-UHFFFAOYSA-N methylamine hydrochloride Chemical compound [Cl-].[NH3+]C NQMRYBIKMRVZLB-UHFFFAOYSA-N 0.000 description 1
- IZXGZAJMDLJLMF-UHFFFAOYSA-N methylaminomethanol Chemical compound CNCO IZXGZAJMDLJLMF-UHFFFAOYSA-N 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 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
- 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
- 230000002685 pulmonary effect Effects 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008844 regulatory mechanism Effects 0.000 description 1
- 210000001034 respiratory center Anatomy 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 229940058287 salicylic acid derivative anticestodals Drugs 0.000 description 1
- 150000003872 salicylic acid derivatives Chemical class 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 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
- 230000004936 stimulating effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229940068511 thioctate Drugs 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
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
- 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 or vitamin B12
Landscapes
- 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)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Description
Die Erfindung bezieht sich auf Derivate des Tris(hydroxymethyl)aminomethans und ein Verfahren zu ihrer Herstellung. Die neuen Verbindungen besitzen wertvolle therapeutische Eigenschaften, die sie insbesondere als Mittel gegen Acidose geeignet machen.The invention relates to derivatives of tris (hydroxymethyl) aminomethane and a method for their production. The new compounds have valuable therapeutic properties Properties that make them particularly useful as a remedy for acidosis make suitable.
Ein konstanter pH-Wert des Blutes ist für die Entwicklung lebenswichtiger Vorgänge des menschlichen Organismus wesentlich. Die Acidose wird jedoch entweder durch unregelmäßige Anhäufung von Ketongruppen im Blut, welche durch den unregelmäßigen Katabolismus von Fettsäuren und einen mangelhaften Metabolismus von Kohlenhydraten entstehen, oder durch eine Schwäche des den pH-Wert des Blutes und der Körpersäfte (extra-blood) regulierenden Mechanismus verursacht.A constant pH of the blood is essential for development vital processes of the human organism. The acidosis, however, is either due to irregular Accumulation of ketone groups in the blood caused by the irregular catabolism of fatty acids and a deficient Metabolism of carbohydrates arise or from a weakness in the pH of the blood and the body fluids (extra-blood) regulating mechanism.
Bei der ersten Art der Acidose kann die Behandlung auf eine Erhöhung des pH und der Alkalireserve, eine Unterstützung des gesamten Metabolismus der Ketonkörper oder beide gleichzeitig abgestellt werden.For the first type of acidosis , treatment can be directed towards increasing the pH and the alkali reserve, supporting the overall metabolism of the ketone bodies, or both at the same time.
209816/166 5209816/166 5
Im zweiten Fall muß die Behandlung auf eine Erhöhung der Alkalireserve und eine Aktiyierung des Regulationsmechanismus der Körpersäfte abgestellt werden.In the second case, the treatment must aim to increase the Alkali reserve and an activation of the regulation mechanism of the body fluids are turned off.
Im allgemeinen waren bisher die angewandten Behandlungen auf eine Normalisierung des pH durch Erhöhung der Alkalireserve gerichtet.In general, the treatments used so far have been to normalize the pH by increasing the alkali reserve directed.
Es wurde beispielsweise Natriumbicarbonat verwendet, das ausschließlich als Blutpuffer wirkt, jedoch den Nachteil der Kontraindikation bei Acidose respiratorischer oder renaler Natur hat und keine interzellulare Pufferwirkung zeigt.For example, sodium bicarbonate was used exclusively acts as a blood buffer, but has the disadvantage of contraindication in respiratory or renal acidosis Nature and shows no intercellular buffer effect.
1959 wurden durch Nahas die organischen Amine bekannt und unter anderem aufrund seiner Wirksamkeit und Ungiftigkeit das Tris(hydroxymethyl)aminomethan oder THAM, das nicht nur als Plasmapuffer, sondern auch als interzellularer Puffer wirkt.In 1959, the organic amines became known through Nahas and among other things due to its effectiveness and non-toxicity Tris (hydroxymethyl) aminomethane or THAM, which is not only available as Plasma buffer, but also acts as an intercellular buffer.
Jedoch zeigt Tr±s(hydroxymethyl)aminomethan einige Nachteile hinsichtlich seiner Verabreichung, da seine Lösungen zu alkalisch sind und Verdauungsschwierigkeiten hervorrufen. Andererseits ist es gegenüber den Ursachen der Acidose nicht wirksam. However, Tr ± s (hydroxymethyl) aminomethane has some disadvantages regarding its administration, since its solutions are too alkaline and cause digestive difficulties. on the other hand it is not effective against the causes of acidosis.
Um derartige Nachteile bei der Behandlung von Acidose zu korrigieren, wurde das Augenmerk bei der vorliegenden Erfindung auf die Synthese von Tris(hydroxymethyl)aminomethanderivaten gerichtet, die wirksamere therapeutische Eigenschaften haben und besser vertragen werden.In order to correct such drawbacks in the treatment of acidosis, attention has been paid to the present invention on the synthesis of tris (hydroxymethyl) aminomethane derivatives directed to the more effective therapeutic properties and are better tolerated.
Auf diese Weise wurde erfindungsgemäß eine Anzahl von Tris-(hydroxymethyl)aminomethanderivaten mit auf Acidose wirkenden organischen Säuren synthetisch hergestellt, nie erwähnten Ver-In this way a number of tris (hydroxymethyl) aminomethane derivatives have been made in accordance with the invention synthetically produced with organic acids that act on acidosis, never mentioned
209816/1665209816/1665
BAD ORIGINAL BATH ORIGINAL
bindungen stellen nicht nur den pH-¥ert wieder her, sondern sie sind auch gegen die die Veränderungen hervorrufenden Ursachen wirksam und sie unterscheiden sich von den bisher bekannten Substanzen gegen Acidose.Bonds not only restore the pH value, they are also against the causes that cause the changes effective and they differ from the previously known substances against acidosis.
Das Verfahren zur Herstellung dieser Verbindungen basiert im wesentlichen auf der direkten Umsetzung der jeweiligen Säure mit Tris(hydroxymethyl)aminomethan entweder im schmelzflüssigen Zustand oder in einem geeigneten Lösungmittel. ™The process for the preparation of these compounds is essentially based on the direct conversion of the respective acid with tris (hydroxymethyl) aminomethane either in the molten liquid Condition or in a suitable solvent. ™
Diese Verbindungen können auch durch Umsetzung der Salze der Komponenten durch zweifache Substitution in einem Lösungsmittel, das jeweils in dem besonderen Fall geeignet ist, erhalten werden. These compounds can also be prepared by reacting the salts of the components by double substitution in a solvent, which is appropriate in each particular case, can be obtained.
Die Erfindung wird nachstehend durch Beispiele erläutert»The invention is illustrated below by means of examples »
3
2oo g Theophyllin und 5oo cm Wasser werden zum Sieden erhitzt
und zu loo g Chloressigsäure und kleinen Anteilen Natriumhydroxyd
(30 $) gegeben, ohne das Rühren zu unterbrechen, wobei
1o Minuten lang stark erhitzt wird. Dann wird weitere 3o Minuten langsam gekocht.3
200 g of theophylline and 500 cm of water are heated to the boil and added to 100 g of chloroacetic acid and small portions of sodium hydroxide ($ 30) without interrupting the stirring, during which time the mixture is heated vigorously for 10 minutes. Then cook slowly for another 30 minutes.
Anschließend wird die Lösung in einem Trockner gekühlt, dann filtriert, die erhaltenen Kristalle werden mit leicht angesäuertem Wasser gewaschen und schließlich getrocknet. Die so erhaltenen Kristalle entsprechen Theophyllinessigsäure.Subsequently, the solution is cooled in a dryer, then filtered, the crystals obtained are acidified with slightly acidic Water washed and finally dried. The crystals obtained in this way correspond to theophyllinetic acid.
1oo g vollkommen getrocknete Theophyllinessigsäure werden mit 5o,9 g Tris(hydroxymethyl)aminomethan in einem Mörser pulveri-100 g of completely dried theophyllinetic acid are with 5o, 9 g of tris (hydroxymethyl) aminomethane in a mortar powder
209816/1665209816/1665
siert, bis eine homogene Mischung erhalten wird. Die Mischung wird sofort in einen Stahlbehälter in einem Ölbad übergeführt und auf 15o bis 175°C erhitzt.sated until a homogeneous mixture is obtained. The mixture is immediately transferred to a steel container in an oil bath and heated to 15o to 175 ° C.
Die Mischung wird konstant kräftig gerührt, bis eine klare Flüssigkeit erhalten wird, welche unter ständigem Kochen in Stahlschalen getropft wird und schließlich einer Vakuumtrocknung unterworfen wird, um sie vor Feuchtigkeit zu schützen.The mixture is constantly stirred vigorously until a clear liquid is obtained, which under constant boiling in Steel trays are dripped and finally vacuum-dried to protect them from moisture.
Das getrocknete Produkt muß rasch gehandhabt werden, und zwar in einem sehr trockenen Medium, da es sehr hygroskopisch ist. Auf diese Weise werden etwa 145 g Tris(hydroxymethyl)aminomethantheophyllinacetat erhalten.The dried product must be handled quickly, namely in a very dry medium as it is very hygroscopic. In this way, about 145 g of tris (hydroxymethyl) aminomethane theophylline acetate are obtained obtain.
B ei s- .ρ i elB ei s- .ρ i el
26,ο g Natriumtheophyllinacetat werden in der kleinstmöglichen Wassermenge gelöst; hierzu werden 15»8 g Tris(hydroxymethyl) äminomethanhydrochlorid gegeben.26, ο g of sodium theophylline acetate are used in the smallest possible Amount of water dissolved; 15 »8 g of tris (hydroxymethyl) given aminomethane hydrochloride.
Das Sieden wird 3ö Minuten lang beibehalten; danach werden 2oo cm warmer 96 $iger Alkohol zugegeben und die heiße Lösung zur Abtrennung des auf diese Weise gebildeten NaCl filtriert. Die erhaltene Lösung wird im Vakumm eingedampft, bis eine pastenartige Kristallmasse abgesondert wird, die dann mit reinem Alkohol behandelt wird j zur Entfernung des restlichen Wassers wird abermals zur Trockene eingedampft. Die Wirksamkeit beträgt 88 #.The boiling is maintained for 30 minutes; after that 200 cm of warm 96% alcohol was added and the hot solution filtered to separate the NaCl formed in this way. The resulting solution is evaporated in vacuo until a paste-like crystal mass is secreted, which then with pure alcohol is treated j to remove the remaining water, it is again evaporated to dryness. The effectiveness is 88 #.
Das so erhaltene Produkt wurde als Tris(hydroxymethyl)aminomethantheophyllinacetat mit einem Molekulargewicht von 359,3, der empirischen Formel Cir.H21N_07 und der StrukturforinelThe product obtained in this way was identified as tris (hydroxymethyl) aminomethane theophylline acetate with a molecular weight of 359.3, the empirical formula C ir .H 21 N_0 7 and the structural formula
2098167168S2098167168S
CH2-CQOHCH 2 -CQOH
-SsS-SsS
H3CH 3 C
Qe^ J -N . HOH^C- -C- -GH2OHQe ^ J -N. HOH ^ C- -C- -GH 2 OH
CH2OHCH 2 OH
identifiziert. Weißes Pulver, hygroskopisch } P = 115°C, in Wasser und warmem Alkohol stark löslich, kaum löslich in kaltem Alkohol, unlöslich in Chloroform, Aceton, Benzol und Äther. In einer o,o5 M-LSsung hat es einen pH-Wert von 6,4. Sein Ültraviolett-Absorptionsspektrum in o,l N-HCl zeigt ein Maximum bei 272 mu. -"--■"..-.identified. White powder, hygroscopic } P = 115 ° C, highly soluble in water and warm alcohol, hardly soluble in cold alcohol, insoluble in chloroform, acetone, benzene and ether. In a 0.05 M solution it has a pH value of 6.4. Its ultraviolet absorption spectrum in 0.1 N-HCl shows a maximum at 272 mu. - "- ■" ..-.
B e i s pi e 1Example 1
In einen 5oo cm -Destillierkolben mit doppelter Öffnung werden Τ4,4 g Tris(hydroxymethyl)aminomethan in fein pulverisier-Be placed in a 5oo cm double-ended still Τ4.4 g tris (hydroxymethyl) aminomethane in finely powdered
3 -■■"-■3 - ■■ "- ■
ter Form und 125 cm absoluter Äthylalkohol eingebracht. Der Destillierkolben wird an einem Rückflußkühler angeschlossen.ter form and 125 cm of absolute ethyl alcohol introduced. Of the The still is connected to a reflux condenser.
Die Mischung wird im Wasserbad erhitzt, bis das Tris(hydroxy- . methyl)aminomethan gelöst ist» Am freien Ende des Destillier- :The mixture is heated in a water bath until the tris (hydroxy-. methyl) aminomethane is dissolved »At the free end of the distillation:
3 kolbens wird ein eine Lösung von 25 g Liponsäure in 125 cm3 flasks become a solution of 25 g of lipoic acid in 125 cm
Alkohol enthaltender Scheidetrichter angeschlossen. iSeparating funnel containing alcohol connected. i
Diese Lösung wird während 3o Minuten langsam in den Destillierr kolben getropft, wobei der Inhalt des Destillierkolbens stets am Sieden gehalten wird. Danach wird weitere 1o Minuten zur Beendigung der Reaktion gekocht. jThis solution is slowly, with the contents of the distilling is always kept boiling dropped into the distilling flask while r 3o minutes. Then boil for a further 10 minutes to end the reaction. j
0 9 8 16/18680 9 8 16/1868
Während die Lösung noch heiß ist, wird sie vorsichtig unter einem Vakuum konzentriert, um eine plötzliche Ausscheidung des Alkohols zu vermeiden, Sie wird in einem Kühlapparat ; 3 bis 4 Stunden gekühlt, wobei man zur Erzielung der Kristallisation gelegentlich rührt. While the solution is still hot, it is carefully concentrated under a vacuum to avoid sudden excretion of the alcohol; it is placed in a refrigerator ; Cooled for 3 to 4 hours, stirring occasionally to achieve crystallization.
Die Mischung wird unter Vakuum filtriert und in der Trockenkammer bei 6o C 1 Stunde lang getrocknet«The mixture is filtered under vacuum and dried in the drying chamber at 6o C for 1 hour «
Das Produkt wird mit einer Geschwindigkeit Von k cm Alkohol/g
in Alkohol umkristallisiert, anschließend werden die Kristalle
mit wasserfreiem Äther gewaschen und in der Trockenkammer bei 6o C getrocknet. Es wird ein Tris(hydroxymethyl)aminomethanderivat
der Liponsäure ( tris (hydroxymethyl )aminoinethane
thioctate) in Form eines kristallinen, gelblichen Pulvers,
Fp = 120°C, erhalten.
Ausbeuter 87 $The product is recrystallized in alcohol at a rate of k cm alcohol / g, then the crystals are washed with anhydrous ether and dried in the drying chamber at 6 ° C. A tris (hydroxymethyl) aminomethane derivative of lipoic acid (tris (hydroxymethyl) aminoinethane thioctate) is obtained in the form of a crystalline, yellowish powder, mp = 120.degree.
Exploiter $ 87
15,8 g Tris (hydroxymethyl ) aminome tlianhydro chi or id werden in der kleinstmöglichen Wassermenge gelöst und zuvor 22,8 g Natriumsalz der Liponsäure gelöst in der kleinstmöglichen Wassermenge zugegeben.15.8 g of tris (hydroxymethyl) aminome tlianhydro chi or id are in dissolved in the smallest possible amount of water and previously dissolved 22.8 g of the sodium salt of lipoic acid in the smallest possible Amount of water added.
Die erhaltene Lösung wird 3o Minuten am Sieden gehalten; einen Teil des Lösungsmittels läßt man verdampfen. Danach läßt manThe solution obtained is kept boiling for 30 minutes; part of the solvent is allowed to evaporate. Then you let
3
sie abkühlen, 200 cm Alkohol werden zugegeben und die Mischung wieder erhitzt. Die noch heiße Lösung wird sofort filtriert,
um das so gebildete Natriumchlorid abzutrennen. Die Lösung wird in der Kühlmaschine langsam gekühlt und das Produkt
kristallisiert.3
they cool, 200 cm of alcohol are added and the mixture is reheated. The still hot solution is filtered immediately in order to separate off the sodium chloride thus formed. The solution is slowly cooled in the refrigerator and the product crystallizes.
209816/1665209816/1665
Das Produkt wird im Vakuum filtriert und getrocknet und anschließend wie in Beispiel 3 in Alkohol umkristallisiert. Die Ausbeute ist ungefähr 80 $, jedoch können die Mutterlaugen ! oder das Mutterwasser der Kristallisation für eine neue Ge- ; winnung verwend e t werden.The product is filtered and dried in vacuo and then recrystallized from alcohol as in Example 3. The yield is about $ 80, however the mother liquors can! or the mother water of crystallization for a new plant; extraction can be used.
Das erhaltene Produkt, das Tris(hydroxymethyl)aminomethanderivat der Liponsäure hat die empirische Formel C12H2-O-N S2 und Λ The product obtained, the tris (hydroxymethyl) aminomethane derivative of lipoic acid, has the empirical formula C 12 H 2 -ON S 2 and Λ
entspricht der nachstehenden Strukturformel ■corresponds to the following structural formula ■
CH2OHCH 2 OH
. H2N —C— -CH2OH. H 2 N —C— —CH 2 OH
(CH2)^COOH(CH 2 ) ^ COOH
c:c:
H2OHH 2 OH
Das Molekulargewicht beträgt 327,5» Fp = 120°C.The molecular weight is 327.5 »mp = 120 ° C.
Es ist ein gelbes kristallines Pulver, das in Wasser und heißem Alkohol stark löslich ist. Es ist in kaltem Alkohol und warmem Aceton kaum löslich. Es ist in Chloroform, Benzol und Äther unlöslich. In einer o,1 M-wässerigen Lösung hat es einen pH-Wert von 6,5. Sein Ultraviolettspektrum zeigt eine maximale Absorption bei 335 mu in Äthanol.It is a yellow crystalline powder that dissolves in water and is highly soluble in hot alcohol. It is hardly soluble in cold alcohol and warm acetone. It's in chloroform, benzene and ether insoluble. In a 0.1 M aqueous solution, it has a pH value of 6.5. Its ultraviolet spectrum shows one maximum absorption at 335 mu in ethanol.
Beispiel 5Example 5
7,8 g {λ/Zo Mol) Orotsäure werden in kleinen Anteilen zu einer ° £T (1/2Ό- Mol) Tris (hydroxymethyl)aminomethan in 100 cm Wasser enthaltenden Lösung gegeben.7.8 g (λ / zo mol) of orotic acid are added in small portions to a solution containing ° £ T (1 / 2Ό mol) tris (hydroxymethyl) aminomethane in 100 cm of water.
Die Temperatur wird unter ständigem Rühren langsam auf 80°C er-' höht.The temperature is slowly increased to 80 ° C with constant stirring. increases.
2 09816/16652 09816/1665
Das Lösungsmittel wird zur Trockene eingedampft t das Produkt mit Äther gewaschen und im Vakuum abermals getrocknet. Die Ausbeute liegt im Bereich von 94 #.The solvent is evaporated to dryness t the product washed with ether and dried again under vacuum. The yield is in the range of # 94.
Das so erhaltene Produkt ist ein mikrokristallines Pulver, das in Wasser und Alkohol löslich und in Äther unlöslich ist.The product thus obtained is a microcrystalline powder, which is soluble in water and alcohol and insoluble in ether.
Kleine Mengen Wasser werden bis zur vollständigen Lösung zu i 15 g Natriumpangamat gegeben.Small amounts of water are added to 15 g of sodium pangamate until completely dissolved.
Außerdem werden 7f6 g Tris(hydroxymethyl)aminomethanhydro- ' Chlorid in der kleinstmöglichen Menge Wasser gelöst. Die Lö- ί sungen werden vermischt und zum Sieden gebracht· 96 $igerAlkohol wird in der erforderlichen Menge zugegeben, I bis das Natriumchlorid unlöslich zu werden beginnt; anschlies- ; send werd'en 10 cm 96 $iger Alkohol zugegeben.Moreover, are dissolved in the smallest possible amount of water 7 f 6 g tris (hydroxymethyl) aminomethanhydro- 'chloride. The solutions are mixed and brought to the boil. 96% alcohol is added in the required amount until the sodium chloride begins to become insoluble; connecting; 10 cm of 96 % alcohol are then added.
Die Lösung wird filtriert und der Rückstand mit 96 %igem Alkohol gewaschen. , Beide Filtrate werden vereinigt. Die Lösung wird mit Hilfe eines Vakuums zur Trockene eingedampft.The solution is filtered and the residue is washed with 96% alcohol. , Both filtrates are combined. The solution is evaporated to dryness using a vacuum.
Die Ausbeute oder Leistung liegt im Bereich von 96 $.The yield or performance is in the range of $ 96.
Mit den Verbindungen nach dem Verfahren der Erfindung wurden eine Reihe von toxikologischen, pharmakologischen und klinischen Versuchen angestellt. Using the compounds according to the method of the invention were made a number of toxicological, pharmacological and clinical trials.
INSPBCTHD 2 0 9 8 16/1665INSPBCTHD 2 0 9 8 16/1665
> Der LD 5o von Tris (hydroxymethyl )aminoniethantheophyllinacetat bei Albinomäusen ist bei oraler Verabreichung 4,o5 + o,1?4 g/kg ! und bei intravenöser. Verabreichung 2,45 + Oti45 k/kg.'> The LD 50 of tris (hydroxymethyl) aminoniethantheophylline acetate in albino mice is 4.05 + 0.1-4 g / kg after oral administration! and intravenous. Administration 2.45 + O t i45 k / kg. '
Der LD 5Q von Tris(hydroxymethyl)aminomethansalz der Liponsäure bei Mäusen beträgt bei oraler Verabreichung 5o6 + 4,71 mg bei intravenöser Verabreichung 126,4 +5,?6 mg/kg und bei intra ; peritonealer Verabreichung 278 + 5»69 mg/kg.The LD 5Q of the tris (hydroxymethyl) aminomethane salt of lipoic acid in mice, when administered orally, is 506 + 4.71 mg with intravenous administration 126.4 +5,? 6 mg / kg and with intra ; peritoneal administration 278 + 5 »69 mg / kg.
Diese Verbindung wurde auch bei Ratten untersucht. Der LD 5o . beträgt bei oraler Verabreichung I600 +168 Eig/kg, bei intravenöser Verabreichung 345*2 + 27,1 mg/kg und bei intricperitοι nealea? Verabreichung 365 + 25*5 mg/kg*This connection has also been studied in rats. The LD 5o . is with oral administration I600 +168 egg / kg, with intravenous administration 345 * 2 + 27.1 mg / kg and with intricperitοι nealea? Administration 365 + 25 * 5 mg / kg *
ι Sämtliche Ergebnisse sind gemäß der Reed-Muench-Methode ausgedrückt. All results are expressed according to the Reed-Muench method.
Die Puffereigenschaft dieser Verbindungen wurde bei mit Pentothai betäubten Hunden bestätigt, die eine akute experimentelle Acidose aufwiesen, die durch intravenöse injektion einer Lösung von Phosphaten, Ammoniumchlorid, Milchsäure usw. bis zu einem pH-Weyt von 7*2 hervorgerufen wurde.The buffering property of these compounds was found with Pentothai anesthetized dogs with acute experimental acidosis confirmed by intravenous injection of a solution by phosphates, ammonium chloride, lactic acid etc. up to a pH value of 7 * 2.
Wenn das Produkt auf intravenösem Tfeg verabreicht wird, kehrt der pH-Wert auf normale Werte zurück und die in Bioarbonat aus gedrückte Reserve wird wiederhergestellt.If the product is administered on intravenous Tfeg, it reverses the pH returns to normal values and that in bio carbonate off depressed reserve is restored.
Eine Untersuchung der Ergebnisse der Verabreichung von 5o mg/kg Tris(hydroxymethyl)aminomethansälz der Liponsäure an Katzen mit einem Gewicht von 2 bia 3 kg zeigte weder Veränderungen im Blutdruck noch eine Änderung der Atmungsgeräusche. Das Elektrokardiogramm war weder während noch nach der Verabreichung verändert.An investigation into the results of the administration of 50 mg / kg tris (hydroxymethyl) aminomethane salt of lipoic acid in cats with a weight of 2 to 3 kg showed neither changes There is still a change in the sounds of breathing in the blood pressure. The electrocardiogram was not changed either during or after the administration.
209818/1665209818/1665
- 1ο -- 1ο -
Das Tris(hydroxymethyljaminomethantheophylinacetat kann aufgrund seiner Merkmale oder Eigenschaften als ein vollkommenes antiacidotisch.es Produkt angesehen werden, da es nicht nur auf die Blutfaktoren einwirkt, die den pH-Wert regulieren, sondern auch auf die zellularen, pulmonalen und renalen Faktoren.The tris (hydroxymethyljaminomethane theophylin acetate can be due to its characteristics or properties as a perfect one antiacidotic.es product can be considered as it is not only based on acts on blood factors that regulate pH, but also on cellular, pulmonary and renal factors.
Bei Acidose mit intrazellularem Ursprung wirkt die neue Verbindung als Protonenakzeptor, der die interzellularen Wasserstoff ionen neutralisiert. Bei Atmungsacidose wird der beruhigenden Wirkung von Tris(hydroxymethyl)aminomethan auf die Atmungszentren, durch die anregende Wirkung, die durch Theophyllin auf diese ausgeübt wird, entgegengewirkt. Bei renaler Acidose besteht ein Synergismus zwischen der Diuresewirkung osmotischer und tubulärer Art des Tris (hydroxymethyl)aminomethans unu derjenigen glomüerulärer Art des Theophylline.The new compound works for acidosis of intracellular origin as a proton acceptor that neutralizes the intercellular hydrogen ions. In the case of respiratory acidosis, it is calming Effect of tris (hydroxymethyl) aminomethane on the Respiratory centers, counteracted by the stimulating effect that theophylline has on them. With renal Acidosis there is a synergism between the action of the diuretic osmotic and tubular type of tris (hydroxymethyl) aminomethane unu of the glomerular kind of theophylline.
Klinisch ist Tris(hydroxymethyl)aminomethantheophyllinacetat bei allen Arten toxischer, Atmungs- oder metabolischer Acidose von Gewebs-, oulmonalem, Plasma- oder renalem Ursprung, indiziert. Ebenso bei Intoxikationen aufgrund von Medikamenten, die durch Barbiturate, Salicylsäurederivate oder dergl. hervorgerufen wurden, wobei es die rasche Eliminierung der toxischen Substanzen auf renalem Weg erleichtert.Clinical is tris (hydroxymethyl) aminomethane theophylline acetate in all types of toxic, respiratory or metabolic acidosis of tissue, oulmonary, plasma, or renal origin. Likewise in the case of intoxication due to drugs caused by barbiturates, salicylic acid derivatives or the like have been, with the rapid elimination of the toxic Substances facilitated by the renal route.
Da sie einen leicht alkalischen pH besitzt, kann die Verbindung nach dem Verfahren gemäß der Erfindung im Gegensatz zu Tris(hydroxymethyl·)aminomethan auf oralem Weg ohne Verdauungsschwierigkeiten und auf intravenösem Weg ohne Hervorrufung irgendwelcher Reizungen verabreicht werden. .Since it has a slightly alkaline pH, the compound can according to the method according to the invention in contrast to tris (hydroxymethyl ·) aminomethane by the oral route without digestive difficulties and by the intravenous route without evocation any irritation. .
Klinisch wurden aufgrund der Puffer- und eumetabolischen Wirkung ausgezeichnete Ergebnisse mit Tris(hydroxymethyl)amino- ·Clinical have been due to the buffering and eumetabolic effects excellent results with tris (hydroxymethyl) amino- ·
2088167166520881671665
methansalz der Liponsäure, -orotat und -pangamat bei Acidose metabolischer oder toxischer Art verbunden mit Schwierigkeiten der Leberfunktion oder des Metabolismus von Gluciden erzielt. Ebenso bei Acidoketosis durch Fieber, Erbrechen, Ketonurie, Wasserentziehung, Unterernährung, Alkoholismus, diabetischer Acidose, post-anästhetischer Acidose usw.Methane salt of lipoic acid, lipoic orotate and pangamate in acidosis metabolic or toxic in nature with difficulties liver function or metabolism of glucides. Likewise with acidoketosis due to fever, vomiting, ketonuria, Dehydration, malnutrition, alcoholism, diabetic Acidosis, post-anesthetic acidosis, etc.
209 816/ 166B209 816 / 166B
Claims (1)
ι 1
ι
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ES0323195A ES323195A1 (en) | 1966-02-17 | 1966-02-17 | Tris (hydroxymethyl) aminomethane theophylline acetate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE1695358A1 true DE1695358A1 (en) | 1972-04-13 |
Family
ID=8442738
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19671695358 Pending DE1695358A1 (en) | 1966-02-17 | 1967-02-16 | Derivatives of tris (hydroxymethyl) aminomethane |
Country Status (7)
| Country | Link |
|---|---|
| US (1) | US3562273A (en) |
| BE (1) | BE694127A (en) |
| CH (1) | CH469659A (en) |
| DE (1) | DE1695358A1 (en) |
| ES (1) | ES323195A1 (en) |
| FR (1) | FR1511911A (en) |
| GB (1) | GB1113600A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0318891A1 (en) * | 1987-12-04 | 1989-06-07 | ASTA Medica Aktiengesellschaft | Injectable solution of thioctic acid containing trometamole and/or basic amino acids |
| EP0702953A2 (en) | 1994-09-22 | 1996-03-27 | ASTA Medica Aktiengesellschaft | Dosage form comprising alpha-lipoic acid or solid salts thereof with improved bioavailability |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NL162361C (en) * | 1974-09-10 | Dufour Claude Etude | PROCESS FOR PREPARING A SALT OF THEOPHYLLINACETIC ACID AND OF A PHARMACEUTICAL PREPARATION WITH MUCOLYTIC ACTION CONTAINING THIS SALT, AND PHARMACEUTICAL OBJECTS. | |
| GB2024087B (en) * | 1978-06-29 | 1982-08-25 | Yoshino Kogyosho Co Ltd | Blow moulding polyester container |
| 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 |
| DE10137381A1 (en) * | 2001-07-31 | 2003-02-13 | Viatris Gmbh | New crystalline modifications of R-thioctic acid trometamol salt, useful as antiinflammatory agent, for treating diabetes mellitus or as appetite suppressant |
| US20070196442A1 (en) * | 2006-02-10 | 2007-08-23 | Heuer Marvin A | Method for improving the oral administration of alpha-lipoic acid |
| US8334402B2 (en) * | 2008-04-17 | 2012-12-18 | Thomas Daly | Biological buffers with wide buffering ranges |
| US8519141B2 (en) | 2008-04-17 | 2013-08-27 | Thomas Daly | Biological buffers with wide buffering ranges |
| US8822728B2 (en) | 2008-04-17 | 2014-09-02 | Thomas Daly | Biological buffers with wide buffering ranges |
| US7939659B2 (en) * | 2008-04-17 | 2011-05-10 | 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 |
| 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 |
| US20170313920A1 (en) | 2010-10-06 | 2017-11-02 | Thomas P. Daly | Biological Buffers with Wide Buffering Ranges |
| US8034951B2 (en) * | 2008-04-17 | 2011-10-11 | Thomas Daly | Biological buffers with wide buffering ranges |
| KR100935554B1 (en) | 2009-06-24 | 2010-01-07 | 주식회사 셀트리온제약 | Piperazine dithioctate and pharmaceutical composition including the same |
| US9475754B2 (en) | 2011-10-06 | 2016-10-25 | Thomas P. Daly | Biological buffers with wide buffering ranges |
| 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 |
-
1966
- 1966-02-17 ES ES0323195A patent/ES323195A1/en not_active Expired
-
1967
- 1967-02-15 GB GB7186/67A patent/GB1113600A/en not_active Expired
- 1967-02-16 BE BE694127D patent/BE694127A/xx unknown
- 1967-02-16 DE DE19671695358 patent/DE1695358A1/en active Pending
- 1967-02-17 CH CH240367A patent/CH469659A/en unknown
- 1967-02-17 FR FR95468A patent/FR1511911A/en not_active Expired
- 1967-02-17 US US616780A patent/US3562273A/en not_active Expired - Lifetime
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0318891A1 (en) * | 1987-12-04 | 1989-06-07 | ASTA Medica Aktiengesellschaft | Injectable solution of thioctic acid containing trometamole and/or basic amino acids |
| EP0702953A2 (en) | 1994-09-22 | 1996-03-27 | ASTA Medica Aktiengesellschaft | Dosage form comprising alpha-lipoic acid or solid salts thereof with improved bioavailability |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| GB1113600A (en) | 1968-05-15 |
| ES323195A1 (en) | 1966-12-01 |
| FR1511911A (en) | 1968-02-02 |
| US3562273A (en) | 1971-02-09 |
| BE694127A (en) | 1967-07-31 |
| CH469659A (en) | 1969-03-15 |
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