DE2443979A1 - THIAMINE DISULFIDE OROTATE - Google Patents
THIAMINE DISULFIDE OROTATEInfo
- Publication number
- DE2443979A1 DE2443979A1 DE19742443979 DE2443979A DE2443979A1 DE 2443979 A1 DE2443979 A1 DE 2443979A1 DE 19742443979 DE19742443979 DE 19742443979 DE 2443979 A DE2443979 A DE 2443979A DE 2443979 A1 DE2443979 A1 DE 2443979A1
- Authority
- DE
- Germany
- Prior art keywords
- thiamine disulfide
- orotate
- thiamine
- water
- orotic acid
- 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
- PXQPEWDEAKTCGB-UHFFFAOYSA-N orotic acid Chemical compound OC(=O)C1=CC(=O)NC(=O)N1 PXQPEWDEAKTCGB-UHFFFAOYSA-N 0.000 title claims description 60
- 229960001385 thiamine disulfide Drugs 0.000 title claims description 35
- GFEGEDUIIYDMOX-BMJUYKDLSA-N n-[(4-amino-2-methylpyrimidin-5-yl)methyl]-n-[(z)-3-[[(z)-2-[(4-amino-2-methylpyrimidin-5-yl)methyl-formylamino]-5-hydroxypent-2-en-3-yl]disulfanyl]-5-hydroxypent-2-en-2-yl]formamide Chemical compound C=1N=C(C)N=C(N)C=1CN(C=O)C(\C)=C(CCO)/SSC(/CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N GFEGEDUIIYDMOX-BMJUYKDLSA-N 0.000 title claims description 34
- 229960005010 orotic acid Drugs 0.000 claims description 22
- 238000002360 preparation method Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 4
- 239000012876 carrier material Substances 0.000 claims 1
- 229940079593 drug Drugs 0.000 claims 1
- 239000003814 drug Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 19
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 8
- 150000003839 salts Chemical class 0.000 description 8
- 239000000126 substance Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229920002472 Starch Polymers 0.000 description 6
- 235000019270 ammonium chloride Nutrition 0.000 description 6
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 6
- 229940100445 wheat starch Drugs 0.000 description 6
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- 208000002193 Pain Diseases 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 239000004480 active ingredient Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- 208000005392 Spasm Diseases 0.000 description 3
- JZRWCGZRTZMZEH-UHFFFAOYSA-N Thiamine Natural products CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N JZRWCGZRTZMZEH-UHFFFAOYSA-N 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002920 convulsive effect Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 235000019359 magnesium stearate Nutrition 0.000 description 3
- 230000002887 neurotoxic effect Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 229960002895 phenylbutazone Drugs 0.000 description 3
- VYMDGNCVAMGZFE-UHFFFAOYSA-N phenylbutazonum Chemical compound O=C1C(CCCC)C(=O)N(C=2C=CC=CC=2)N1C1=CC=CC=C1 VYMDGNCVAMGZFE-UHFFFAOYSA-N 0.000 description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229960003495 thiamine Drugs 0.000 description 3
- 235000019157 thiamine Nutrition 0.000 description 3
- KYMBYSLLVAOCFI-UHFFFAOYSA-N thiamine Chemical compound CC1=C(CCO)SCN1CC1=CN=C(C)N=C1N KYMBYSLLVAOCFI-UHFFFAOYSA-N 0.000 description 3
- 239000011721 thiamine Substances 0.000 description 3
- -1 thiamine disulfide orotate Chemical class 0.000 description 3
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001413 amino acids Chemical class 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 239000006071 cream Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 231100000189 neurotoxic Toxicity 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 238000005245 sintering Methods 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 235000019640 taste Nutrition 0.000 description 2
- 230000009967 tasteless effect Effects 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000000094 Chronic Pain Diseases 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 208000010201 Exanthema Diseases 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 1
- 239000004472 Lysine Substances 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 208000007101 Muscle Cramp Diseases 0.000 description 1
- 206010052904 Musculoskeletal stiffness Diseases 0.000 description 1
- 239000005662 Paraffin oil Substances 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- UCKMPCXJQFINFW-UHFFFAOYSA-N Sulphide Chemical compound [S-2] UCKMPCXJQFINFW-UHFFFAOYSA-N 0.000 description 1
- NWGKJDSIEKMTRX-BFWOXRRGSA-N [(2r)-2-[(3r,4s)-3,4-dihydroxyoxolan-2-yl]-2-hydroxyethyl] (z)-octadec-9-enoate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)C1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-BFWOXRRGSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001447 alkali salts Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003124 biologic agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229960002887 deanol Drugs 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000007911 effervescent powder Substances 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 201000005884 exanthem Diseases 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 description 1
- 210000002200 mouth mucosa Anatomy 0.000 description 1
- APVPOHHVBBYQAV-UHFFFAOYSA-N n-(4-aminophenyl)sulfonyloctadecanamide Chemical compound CCCCCCCCCCCCCCCCCC(=O)NS(=O)(=O)C1=CC=C(N)C=C1 APVPOHHVBBYQAV-UHFFFAOYSA-N 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007530 organic bases Chemical class 0.000 description 1
- 229940124641 pain reliever Drugs 0.000 description 1
- 229940102708 phenylbutazone 100 mg Drugs 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 210000004761 scalp Anatomy 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- ZTHMWDSJKLNDTE-UHFFFAOYSA-M sodium orotate Chemical compound [Na+].[O-]C(=O)C1=CC(=O)NC(=O)N1 ZTHMWDSJKLNDTE-UHFFFAOYSA-M 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 229940079101 sodium sulfide Drugs 0.000 description 1
- 235000019614 sour taste Nutrition 0.000 description 1
- 208000026843 stiff neck Diseases 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000003440 toxic substance Substances 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000014101 wine Nutrition 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
- C07D415/00—Heterocyclic compounds containing the thiamine skeleton
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
- Indole Compounds (AREA)
Description
Die Erfindung umfaßt Thiaminäisulfid-Orotat der nachstehendenThe invention includes thiamine sulfide orotate of the following
Konstitution : £ 44 ο 9 /$Constitution: £ 44 ο 9 / $
f°f °
CH3-C C - CHx-CH 3 -CC - CHx-
CH3 CH0-CH0-OH CH-CH0OH CH 3 CH 0 -CH 0 -OH CH-CH 0 OH
COOH seine Herstellung, Zubereitung und Verwendung in pharmazeutischenCOOH its manufacture, formulation and use in pharmaceutical
Präparaten.Preparations.
Es wurde gefunden, daß slniewiwx Thiamindisulf id-Orotat durch Umsatz von Thi'jmiridisulfid mit Orotsäure in Molverhältnissen gegebenenfalls in einem Verdünnungs- und Lösungsmittel, wie Alkohol oder Wasser, gegebenenfalls bei normaler oder höherer Temperatur in kristallinerIt was found that thiamine disulfide orotate slniewiwx by conversion of thi'jmiridisulphide with orotic acid in molar ratios, if appropriate in a diluent and solvent, such as alcohol or water, optionally at normal or higher temperature in crystalline form
Beschaffenheit erhalten wird.Texture is preserved.
Das £rhaltenfn«*t Thiamindisulfid-Orotat ist in Wasser leicht löslich.The contained thiamine disulphide orotate is easily soluble in water.
Somit ist das wesentliche Kennzeichen der Erfindung, daß durch die Salzbildung mittels Thiamindisulfid die in Wasser praktisch unlöslicheThus, the essential feature of the invention is that by the Salt formation by means of thiamine disulfide which is practically insoluble in water
Orotsäure wasserlöslich wird.Orotic acid becomes water-soluble.
Es ist vorherzusehen gewesen, daß Thiamindisulfid zwei Salze bildenIt was foreseen that thiamine disulfide would form two salts
kann :can :
a) mit 2-Mol Orotsäurea) with 2 moles of orotic acid
b) mit einem Mol Orotsäure.b) with one mole of orotic acid.
Das Salz mit 2 Mol Orotsäure ist in Wasser praktisch unlöslich. Dasjenige mit einem Mol Orotsäure jedoch spielend leicht löslich. Es löeen sich von diesem erfindungsgemäßen Thiamindisulfid-Orotat A g in 2 ml Wasser bei gewöhnlicher Temperatur glatt auf.* durch Erwärmen OWttti 1 g Thiamindisulfidfin 1 ml Wasser. In 1 g Thiamindisulf id-Ürotat sind 217 mg Orotsäure, in 1 oo mjr folglieh 21,7 mg Orotsäure, welche vollständig in 2 ml Wasser gelöst vorliegen.The salt with 2 moles of orotic acid is practically insoluble in water. The one with one mole of orotic acid, however, is easily soluble. This thiamine disulfide orotate A g of this invention dissolves smoothly in 2 ml of water at ordinary temperature. * By heating OWttti 1 g of thiamine disulfide in 1 ml of water. In 1 g of thiamine disulfide urotate there are 217 mg of orotic acid, in 1 oo mjr there are 21.7 mg of orotic acid, which are completely dissolved in 2 ml of water.
PH einer solchen Lösung liegt bei 5-6, also praktisch neutral. Es lassen sich ata» ohne weitersagen in Wasser " ^ The pH of such a solution is 5-6, i.e. practically neutral. It can be ata »Tell i n without water" ^
609818/1036609818/1036
herstellen,welche mindestens 1o %,optimal 2o %, Orotsäure gelöst enthalten. Diese Lösungen lassen sich sterilisieren, sie sijfjj auch unbegrenzt haltbar. Es lassen sich auch verschiedene andere gelöste Zubereitungen herstellen, wie Wein, Safte und Sirup.. Damit sindProduce which contain at least 1o %, optimally 2o %, orotic acid dissolved. These solutions can be sterilized, and they can also be kept indefinitely. Various other dissolved preparations can also be made, such as wine, juice and syrup
.1.1
gänzlich unerwartete neue Zubereitungsformen für das erfindungsgemäße Salz, und damit auch für die Orotsäure gegeben. Es ist bekannt, daß die Orotsäure in Wasser praktisch unlöslich ist. A\uch die Alkalisalze, wie die Natrium- und Kaliumsalze, sind in Wasser schwer löslich und dann nur beschränkt bis zu 5 oder 1o %, dazu mit einem intensiv alkalischen p„ von 1o bis 12. Das gilt auch für solche Salze mit organischen Basen, wie z.B. ß-Dimethylaminoäthanol, piperazin u.a., welche vielfach beschrieben worden sind. 1 bis 2/oige wässrige Lösungen der Orotsäure, die nicht alkalisch reagieren, sind mit Hilfe bestimmter Aminosäuren erhalten worden, vorzugsweise mit Glykokol und Lysin (DBR/155 88o). Von kristallinen Salzen ist hier jedoch nicht die Rede.Completely unexpected new forms of preparation for the salt according to the invention, and thus also for orotic acid, are given. It is known that orotic acid is practically insoluble in water. The alkali salts, too, such as the sodium and potassium salts, are sparingly soluble in water and then only up to 5 or 10 % with an intensely alkaline ratio of 10 to 12. This also applies to salts with organic bases , such as ß-dimethylaminoethanol, piperazine and others, which have been described many times. 1 to 2% aqueous solutions of orotic acid, which do not react alkaline, have been obtained with the help of certain amino acids, preferably with glycol and lysine (DBR / 155 88o). However, there is no mention of crystalline salts here.
Umso überraschender ist, keineswegs vorhersehbar, daß das erfindungsgemäße Thiamindisulfid-Orotat eine solche ausgezeichnte Wasserlöslichkeit besitzt.It is all the more surprising, in no way predictable, that the inventive Thiamine disulfide orotate such excellent water solubility owns.
Demgemäß liegt das wesentlich Neue der Erfindung darin, daß mit Hilfe von Thiamindisulfid die Orotsäure sogar unterhalb des neutralen Punktes in saurem Medium in hohen Konzentrationen wasserlöslich ist. Solches ist noch nie erreicht worden, sondern erstmalig durch das erfindungsgemäße Verfahren.Accordingly, the essential novelty of the invention is that with the aid of thiamine disulfide the orotic acid is even below the neutral one Point is soluble in water in high concentrations in an acidic medium. This has never been achieved, but for the first time by the method according to the invention.
Die Herstellung dieses Salzes yfo. erfolgt in bekannter Weise durch Urnsatz von 1 Mol Thiamindisulf id mit 1 Mol Orotsäure. Zweckmäßig wird Thiamindisulfid in einem niederen Alkohol, wie Äthanol oder Methanol, vorher heiß gelöst. In dieser heißen Lösung wird Orotsäure aufgelöst. Es wird aonVerunreinigungen und evtl. gebildeten Biorotat filtiert. Das klare Filtrat wird entweder eingedampftThe manufacture of this salt yfo. takes place in a known manner by using 1 mole of thiamine disulfide with 1 mole of orotic acid. Thiamine disulfide is expediently dissolved in a lower alcohol such as ethanol or methanol in advance while hot. Orotic acid is dissolved in this hot solution. Ao n impurities and possibly formed bio-rotate are filtered out. The clear filtrate is either evaporated
609818/1036 -3 -609818/1036 - 3 -
gm Methanol zurück zu gewinnen, oder aus der erhaltenen Lösung wird das gebildete Salz durch Zusatz von Äther oder Aceton gefällt. Es fällt gewöhnlich zuerst ein gelblich-weißes Harz aus, welches fest wird, durch Kochen mit i ,ethanol oder Aceton in weißer Beschaffenheit erhalten wird.gm to recover methanol, or from the solution obtained the salt formed is precipitated by adding ether or acetone. A yellowish-white resin usually precipitates out first, which solidifies is made by boiling with i, ethanol or acetone in a white texture is obtained.
Das erfindungsgemäße neue Thiamindisulfid-Orotat hat auch einen überraschenden Wirkungseffekt. Es beseitigt den schädlichen Einfluß neujirotoxischer .Stoffe. Ein neurotoxischer Stoff ist z.B. Ammoniumchlorid, WJßßifUfa 4oo mg/pro kg Ammoniumchlorid intraperitoneal an weibliche Wistar-Albino-Ratten verabreicht werden, so triitt im Gehirn ein Krampf ein. Dieser kann als cerebrale Aktivität mittels Jwbringung von Silberelektroden unter der Kopfhaut der Tiere registriert werden (EEG). Es treten sprungartige Krampfphasen auf, die sich im EEG durch Ausschläge, die sog. "Spikis"-Wellen äußern. Otine Ammoniumchlorid tritt dieser Effekt nicht auf. Wird jedoch 3o Minuten vor der Einverleibung von Ammaniumchlorid den Tieren die erfindungsgemäße Substanz, das Thiamindisulfid-Orotat, gegeben, so tritt die neurotoxische Wirkung des Ammoniumchlorids nicht auf. Dagegen sind sowohl ThiamindisulfidVDrofcsäure in Form des Natriumsälzes ohne Einfluß/ auf die Ausbildung der Krampfphasen des Ammoniumchlorids.The novel thiamine disulfide orotate according to the invention also has a surprising effect. It eliminates the harmful influence of neo-jirotoxic substances. A neurotoxic substance is, for example, ammonium chloride, if 400 mg / per kg of ammonium chloride are administered intraperitoneally to female Wistar albino rats, then a spasm occurs in the brain. This can be registered as cerebral activity by placing silver electrodes under the scalp of the animals (EEG). Sudden spasm phases occur, which are expressed in the EEG by rashes, the so-called "spikis" waves. Otine ammonium chloride does not have this effect. However, if the substance according to the invention, the thiamine disulfide orotate, is given to the animals 30 minutes before the ammanium chloride is incorporated, the neurotoxic effect of the ammonium chloride does not occur. On the other hand, both thiamine disulphide and drofacic acid in the form of the sodium salt have no influence on the formation of the spasmodic phases of ammonium chloride.
Die Versuchsanordnung besteht nun darin, daß jeweils 1o Tiere, weibliche Wistar-Albino-Ratten von 13o bis 16ο g Durchschnittsgewicht die Krampftdosis von 4oo mg/kg Körpergewicht Ammoniumchlorid in Wasser gelöst intraperitoneal erhalten, IM EEG zeigt sich das typische Bild von Krampfphasen. Sa^dann wird von Tfciamindisulfid# Orotsäurenatrium sowie Thiamindisulfid-Orotat jene Dosis gesucht, die 3o Minuten vorher ebenfalls intraperitoneal zugeführt, die Krampferscheinungen des Gehirns verhütet.The experimental set-up now consists in that 1o animals, female Wistar albino rats of 13o to 16o g mean weight the convulsive dose of 400 mg / kg body weight ammonium chloride Received intraperitoneally dissolved in water, the EEG shows the typical picture of convulsive phases. Sa ^ then is of Tfciamindisulfid # Orotic acid sodium as well as thiamine disulfide orotate that dose sought, which are also administered intraperitoneally 30 minutes beforehand, which prevents spasms in the brain.
809816/1036 " ' "809816/1036 "'"
Thiamindisulfid war selbst in Dosen von 3oo mg/kg und Natriumorotat in Dosen von 800 mg/kg völlig wirkungslos. Thiamindisulfid-Orotat verhinderte in der Dosis von 5o mg zu 5o % die Krampfphasen, bei 80 mg/kg vollends, also bei einem jeden Tier.Thiamine disulfide was completely ineffective even at doses of 300 mg / kg and sodium orotate at doses of 800 mg / kg. Thiamine disulfide orotate prevented the convulsive phases in the dose of 50 mg to 50 % , at 80 mg / kg completely, i.e. in every animal.
Die DL . des erfindungsgemäßen Thiamindisulfid-ürotat wurde nach Kärber berechnet. Dabei wurde die Mortalitätsrate innerhalb von zehn Tagen zugrunde gelegt. Diese beträgt für weii3e Mäuse in mg pro kg :The DL. of the thiamine disulfide ürotat according to the invention calculated according to Kärber. The mortality rate within ten days was used as the basis. This is for white mice in mg per kg:
Substanz i. v. i. p. oral Substance ivip oral
IJfhiamindisulfid-Orotat hat also praktisch eine sehr geringe Toxizität und ist folglich ein ungiftiger biologischer Wirkstoff.Ijfhiamindisulfid-Orotat thus practically has a very low level Toxicity and is therefore a non-toxic biological agent.
Es gibt eine große Zahl manigfaltiger Leiden, welche durifh überhöhte Ablagerung von .toxischen Stoffen, zu denen auch Ammoniak gehört, bedingt sind. Dazu gehört auch die Abnahme des Gedächtnisses, eine zu rasche Ermüdung, dann Schmerzzustände im Rücken und Nacken, die auf unsere konventionellen Schmerzstillungsmittel, wie Acetylsalicylsäure, Phenylbutazon u.a. wenig oder gar nicht ansprechen. Die Schmerzen bei Nackenversteifung z.B. sind nur Itittels langdepwdauernder Massagen beeinflußbar, so daß angenommen wird, daß es eine durch die Massage bedingte erhöhte Durchblutung ist, welche die neurotoxischen Stoffe als Krankheitsursache zui/rascheren Eliminierung, also Ausschwemmung bringt, so daß die Schmerzen dann langsam verschwinden. Das Gleiche gilt auch für zu rasche Ermüdungen und das langsame Nachlassen des Gedächtnisses. Bei beiden Leidenserscheinungen sind Massigen eine wertvolle Hilfe. Demgegenüber wurde nun gefunden, daß Thiamindisulfid-ürotat in Dosen von 5o - 00 - -?oo mg vorzüglich 809818/1036 - 5 -There are a great number of manifold ailments which have been exaggerated Deposits of toxic substances, including ammonia, are conditional. This also includes the decrease in memory, fatigue too quickly, then pain in the back and neck that respond to our conventional pain relievers, such as acetylsalicylic acid, Phenylbutazone and others have little or no response. The pain in the case of a stiff neck, for example, is only longer-lasting Massages can be influenced, so that it is assumed that it is an increased blood flow caused by the massage, which accelerate the neurotoxic substances as the cause of the disease Elimination, i.e. flushing out, so that the pain then slowly disappears. The same applies to fatigue that is too rapid and the slow decline in memory. Massive people are a valuable help with both symptoms. In contrast it has now been found that thiamine disulfide urotate in doses of 5o - 00 - -? oo mg is excellent 809818/1036 - 5 -
jedoch schon bei 5o mg, rasche Ermüdung zu beseitigen vermag, das Gedächtnis stärkt, sowie endlich auch Schmerzzustünde des Nackens, des Rückens und ähnliche chronische Schmerzen rasch beseitigt. DemgemäiJ ist ein weiteres Kennzeichen der Erfindung die Verwendung des Thiamindisulfid-ürotats in pharmazeutischen Zubereitungen. Thiamindisulfid-urotat kann hierbei mit Vitaminen oder antiphlogistisch-wirksamen bekannten Körpern, wie Azetyl-Salicylsä<rre, Phenylbutazon .mit Aminosäuren, Hormonen, synthetischen oder natürlichen Wirkstoffen kombiniert werden. In diesen Kombinationsmöglichkeiten obliegt der erfindungsgemäUen Substanz keinerlei Beschränkung. Die pharmazeutischen Präparate gemäS der Erfindung können nach an sich bekannten Arbeitsweisen und Vorfahren hergestellt werden. Sie können aus Pillen, Tabletten, Dragees, Pulvern, Kapseln, Brausepulvern, Arznoigetränken, Sirups, Suppositorien, Cremes, Salben, Einreibungen und endlich Injektionsflüssigkeiten bestehen. Auch in der Wahl der pharmazeutischen Präparate obliegt der Erfindung keine Beschränkung. Es soll an einigen Beispielen die Herstellung der erfindungsgemäßen Substanzen, des Thiamindisulfidürotats, sowie Zubereitung desselben, gezeigt werden, ohne die Erfindung einzuschränken.However, even at 50 mg, it is able to remove rapid fatigue, strengthens the memory, and finally also painful conditions of the neck, the back and similar chronic pain are quickly eliminated. Accordingly, a further characteristic of the invention is the use of thiamine disulfide urotate in pharmaceutical preparations. Thiamine disulfide urotate can be combined with vitamins or known anti-inflammatory substances, such as acetyl salicylic acid, phenylbutazone, with amino acids, hormones, synthetic or natural active ingredients. The substance according to the invention is not subject to any restriction in these possible combinations. The pharmaceutical preparations according to the invention can be produced according to procedures and processes known per se. They can consist of pills, tablets, coated tablets, powders, capsules, effervescent powders, medicinal drinks, syrups, suppositories, creams, ointments, rubs and finally injection liquids. The invention is also not subject to any restriction in the choice of pharmaceutical preparations. The preparation of the substances according to the invention, the thiamine disulfide acid, as well as its preparation are to be shown using a few examples, without restricting the invention.
■|N'i 9 Thiamindisulf id werden in loo ml Methanol heiß gelöst „ In die heiße Lösung werden 7,8 g i/asserfreie Orotsäure (oder entspr. Menge einer Hydrat-Urotsaure) eingetragen. Es wird noch einmal bis zur vollständigen Lösung ku/rz gekocht. Die ungelöste Trübung wird heiß filtriert. Das klare gelbe Filtrat kann wie folgt aufgearbeitet werden :■ | N'i 9 thiamine disulfide are dissolved in 100 ml hot methanol " 7.8 g of i / ater-free orotic acid (or equivalent) are added to the hot solution. Amount of a hydrate urotic acid) entered. It'll be up one more time boiled briefly to a complete solution. The undissolved cloudiness becomes filtered hot. The clear yellow filtrate can be worked up as follows will :
A) Man fügt :.:o ml Äther dem Filtrat hinzu. Es fällt sofort ein harziger Niederschlag aus, der nach einigen Stunden Stehen erstarrt. Man dekantiert das Lösungsmittel ab. Methanol wird durch DestillationA) Add:.: O ml of ether to the filtrate. A resinous one falls immediately Precipitation from which solidifies after a few hours of standing. The solvent is decanted off. Methanol is made by distillation
609818/1036 ^ ommL -«-609818/1036 ^ ommL - «-
mit dem Äther vollständig zurückerhalten.fully recovered with the ether.
Der Rückstand wird mit Aceton verrieben, wobei sich alles in mikrofeinejrf Nadeln umwandelt. Ausbeute 3b" g.The residue is triturated with acetone, everything in converts microfine needles. Yield 3b "g.
.toh-Fp.: sintert ab 85 C und schmilzt bis I6o C..toh-Fp .: sinters from 85 C and melts to 16o C.
Diese Kristalle werden in ca 6o ml Methanol gekocht. Nach kurzer Auflösung- fallen sofort weiße^ farblose Nadeln aus. Es wird nach Erkalten Aceton zur Vervollständig der Kristallisation zugesetzt.These crystals are boiled in about 60 ml of methanol. After short Dissolution - white, colorless needles fall out immediately. It will be after Cooling acetone added to complete the crystallization.
Das Thiamindisulfid-Qrotat fällt in mikrofeinen farblosen Kristallen aus. Ausbeute ca 31 g.. Fp.: 16o bis 163 C Sinterung zu einer glasigen Masse, die bei 178 - Ί8o C unter Blasenbildung durchsichtig wird,The thiamine disulfide crystal falls in microfine, colorless crystals the end. Yield approx 31 g .. Mp .: 16o to 163 C sintering to a glassy one Mass that becomes transparent at 178 - Ί8o C with formation of bubbles,
B) Das klare P'iltrat wird im Vakurnm von Methanol befreit.
Der Rückstand wird mit Aceton verrieben, wodurch derselbe kristallin wird.
Anbeute 35 g. Fp.: sintert ab 85°C, bis 16o°C klare, gelbe
Schmelze."fckkristallisiert wird aus Methanol und Aceton auch wie
vorher beschrieben. Ausbeute 31,5 g, Fp.: I6o C unter Sinterung
zu einer glasigen Masse, die bei 178 bis Ί8o C unter Blasenbildung
klar wird.
1 g Host sich bei gewöhnlicher Temperatur in 2 ml Wasser mit einem
P11 von <;,5 bis 5,5 auf. Bei Erwärmen löst sich 1 g in einem mlB) The clear filtrate is freed from methanol in vacuo. The residue is triturated with acetone, making it crystalline.
Take 35 g. Melting point: sinters from 85 ° C. to 160 ° C., a clear, yellow melt. "It is also crystallized from methanol and acetone as described above. Yield 31.5 g, melting point: 160 ° C. with sintering to a vitreous mass which at 178 to Ί8o C becomes clear with formation of bubbles.
1 g of host dissolves in 2 ml of water with a P 11 of <;, 5 to 5.5 at normal temperature. When heated, 1 g dissolves in one ml
Wasser auf.Water on.
Thiamindisulfid-Orotat hat einen charakteristisch-bittersauren, fast fruchtsäureartigen Geschmack. Thiamindisulfid schmeckt nur bitter. Die Orotsäure ist geschmacklos, fade, liegt als mehlartiges Pulver auf Zunge und Mundschleimhaut.Thiamine disulfide orotate has a characteristic bitter-acidic, almost fruity-like taste. Thiamine disulfide only tastes bitter. Orotic acid is tasteless, bland, lies as flour-like Powder on tongue and oral mucosa.
Dor bittep-ffiitchtsaure Geschmack des Thiamindisulfid-Orotats dürfte als charakteristisches Kennzeichen für das Vorliegen der The bitterly sour taste of the thiamine disulfide orotate is likely to be a characteristic indicator for the presence of the
609818/1036 -7609818/1036 -7
IiDIiD
_ 7 —_ 7 -
Orotsäure in echter löslicher Form gelten, denn die ungelöste orotsäure ist auf der Zunge nur deswegen geschmacklos, und fade, weil sie gar nicht resorbiert wird, und das wird auch im Organismus so sein, daß nur ein kleiner Teil derselben wirklich resorbiert wird und damit zur biologischen Wirkung gelangt.Orotic acid in real soluble form apply for the undissolved Orotic acid is tasteless on the tongue because of that, and bland, because it is not absorbed at all, and that is also the case in the organism be such that only a small part of it is actually absorbed and thus has a biological effect.
Beispiel 2 : Tabletten:Example 2: tablets:
Thiamindisulfid-Orotsäure MannitThiamine disulfide orotic acid Mannitol
WeizenstärkeWheat starch
KolÜdale Kieselsäure Polyvinylpyrrolidon TalkKolÜdale Silicic Acid Polyvinylpyrrolidone Talk
MagnesiumstearatMagnesium stearate
3oo mg3oo mg
Herstellung :Manufacturing:
Der Wirkstoff wird mit dem Mannit, der kolloidalen Kieselsäure und einem Teil der Weizenstärke gemischt. Die Mischung wird durch ein Sieb getrieben und mit einer wässrig-äthanolischen Lösung von Polyvinylpyrrolidon geknetet, bis eine plastische Ma^se entstanden ist. Diese wird durch ein Sieb getrieben, getrocknet und das erhaltene trockene Granulat nochmals gesiebt. Darauf werden die restlichem Weizenstärke, Talk und Magnesiumstearat zugemischt und die Mischung zu Tabletten von 3oo mg Gewicht, gegebenenfalls mit BruchTille verpresst.The active ingredient is with the mannitol, the colloidal silica and mixed with a part of the wheat starch. The mixture is forced through a sieve and treated with an aqueous-ethanolic solution of Polyvinylpyrrolidone kneaded until a plastic mass was formed is. This is driven through a sieve, dried and the dry granules obtained are sieved again. The remaining wheat starch, talc and magnesium stearate mixed in and the mixture into tablets of 300 mg weight, optionally with BruchTille pressed.
609818/1D36609818 / 1D36
Beispiel 3 : Kombination mit Phenylbutazon.Example 3: Combination with phenylbutazone.
Thiamindisulfid-Orotat 5o mb|Thiamine disulfide orotate 50 mb |
Phenylbutazon 1oo mgPhenylbutazone 100 mg
Mannit 11ο mgMannitol 11ο mg
Weizenstärkfc 135 mgWheat starch 135 mg
Kolloidale Kieselsäure . 15 mgColloidal silica. 15 mg
Polyvinylpyrrolidon 15 mgPolyvinylpyrrolidone 15 mg
Talk 22 mgTalc 22 mg
Magnesiumstearat 3 mg Magnesium stearate 3 mg
'■;5o mg'■; 50 mg
Herstellung :Manufacturing:
Die beiden ^rkstoffe werden mit dem Mannit, der kolloidalen Kieselsäure und einem Teil der Weizenstärke gemischt. Daraufhin verfährt man wie nach Beispiel 2 und erhält Tabletten zu 45o mg nACH DEM Pressen.The two ingredients are combined with mannitol, the colloidal silicic acid and part of the wheat starch mixed. Then proceed as in Example 2 and get tablets of 45o mg AFTER pressing.
Bepsiel 4 : Kapseln Thiamindisulfid-Orotat LactoseBepsiel 4: Capsules thiamine disulfide orotate lactose
Weizenstärke TalkumWheat starch talc
3oo mg3oo mg
Herstellung : .Manufacture:.
Die Bestandteile werden gemischt und in Gelatinekapseln gefüllt.The ingredients are mixed and filled into gelatin capsules.
609818/1036609818/1036
Beispiel 5 : Ampullen.Example 5: ampoules.
Thiamindisulf id-Orotat 'i op mgThiamine disulfide orotate i op mg
Natriumchlorid "18 mgSodium chloride "18 mg
dest. Wasser ad. :-. mlleast. Water ad. : -. ml
Herstellung:Manufacturing:
Wirkstoff und Natriumchlorid werden in Wasser gelöst, die Lösung wird durch einen geeigneten Filter filtriert, buk Die erhaltene klare Lösung wird durch Erhitzen in Autoklaven sterilisiert und unter Stickstoff in Glasampullen abgefüllt.The active ingredient and sodium chloride are dissolved in water, the solution is filtered through a suitable filter, the obtained buk The clear solution is sterilized by heating in an autoclave and filled into glass ampoules under nitrogen.
Beispiel 6 : Suppositorien.Example 6: suppositories.
Thiamindisulf id-Orotat 'i 5o mgThiamine disulfide orotate 50 mg
Cacaobutter ad i.ooo mgCocoa butter ad iooo mg
Die Herstellung erfolgt in bekannter Weise.The production takes place in a known manner.
üeispiel 7 : Cremes.Example 7: Creams.
Thiamilldisulfid-ürotat 5,oo gThiamill disulfide urotate 5, oo g
Arlacel 6o L1oo gArlacel 6o L 1 oo g
Twecn 6o 6,oo gTwecn 6o 6, oo g
Paraffinöl 1o,oo gParaffin oil 1o, oo g
Mluminiumpentasilikat 8 , oo gAluminum pentasilicate 8, oo g
.p-Hydroxybenzoesäuremethylester ο,23 g.p-Hydroxybenzoic acid methyl ester ο, 23 g
Dest. Wasser ad. Ιοο,οο gDist. Water ad. Ιοο, οο g
Herstellung:Manufacturing:
Die Fettanteile werden zuscimmenrcschmol^n. BeP Wirkstoff uri^ Q'·-'^ Konservierungsmittel werden in Wasser gelöst und die beiden Mischungen unter gutem Rühren miteinander vermischt.The fat content will decrease. BeP active ingredient uri ^ Q '· -' ^ preservatives are dissolved in water and the two mixtures are mixed together with thorough stirring.
6098 18/10366098 18/1036
Claims (1)
Priority Applications (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742443979 DE2443979A1 (en) | 1974-09-12 | 1974-09-12 | THIAMINE DISULFIDE OROTATE |
| GB3662575A GB1477263A (en) | 1974-09-12 | 1975-09-05 | Thiamindisulphidemono-orotate and process for its preparation |
| SE7510137A SE7510137L (en) | 1974-09-12 | 1975-09-11 | THIAMIN DISULFIDOROTATE AND PROCEDURE FOR ITS PREPARATION |
| AU84723/75A AU8472375A (en) | 1974-09-12 | 1975-09-11 | Thiamindisulphide-orotate |
| ZA00755816A ZA755816B (en) | 1974-09-12 | 1975-09-11 | Thiamindisulphide-orotate and process for its preparation |
| NL7510703A NL7510703A (en) | 1974-09-12 | 1975-09-11 | THIAMINE DISULPHIDE ORROTATE AND THE PHARMACEUTICAL APPLICATION THEREOF. |
| FR7527952A FR2284328A1 (en) | 1974-09-12 | 1975-09-11 | THIAMINE DISULPHIDE OROTATE AND ITS PREPARATION PROCESS |
| JP50110836A JPS5161614A (en) | 1974-09-12 | 1975-09-11 | Orutosanno suiyoseijudotaino seizohoho |
| CH1177775A CH602666A5 (en) | 1974-09-12 | 1975-09-11 | |
| BE159985A BE833351A (en) | 1974-09-12 | 1975-09-12 | THIAMINE DISULPHIDE OROTATE AND ITS PREPARATION PROCESS |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19742443979 DE2443979A1 (en) | 1974-09-12 | 1974-09-12 | THIAMINE DISULFIDE OROTATE |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| DE2443979A1 true DE2443979A1 (en) | 1976-04-29 |
Family
ID=5925726
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DE19742443979 Pending DE2443979A1 (en) | 1974-09-12 | 1974-09-12 | THIAMINE DISULFIDE OROTATE |
Country Status (10)
| Country | Link |
|---|---|
| JP (1) | JPS5161614A (en) |
| AU (1) | AU8472375A (en) |
| BE (1) | BE833351A (en) |
| CH (1) | CH602666A5 (en) |
| DE (1) | DE2443979A1 (en) |
| FR (1) | FR2284328A1 (en) |
| GB (1) | GB1477263A (en) |
| NL (1) | NL7510703A (en) |
| SE (1) | SE7510137L (en) |
| ZA (1) | ZA755816B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8034823B2 (en) | 2005-02-22 | 2011-10-11 | Savvipharm Inc | Method of increasing drug oral bioavailability and compositions of less toxic orotate salts |
| DE102009025549A1 (en) * | 2009-06-15 | 2010-12-16 | Werth Akupunktur Center | Composition for the transport of orotic acid across the blood-brain barrier |
-
1974
- 1974-09-12 DE DE19742443979 patent/DE2443979A1/en active Pending
-
1975
- 1975-09-05 GB GB3662575A patent/GB1477263A/en not_active Expired
- 1975-09-11 AU AU84723/75A patent/AU8472375A/en not_active Expired
- 1975-09-11 CH CH1177775A patent/CH602666A5/xx not_active IP Right Cessation
- 1975-09-11 JP JP50110836A patent/JPS5161614A/en active Pending
- 1975-09-11 FR FR7527952A patent/FR2284328A1/en active Granted
- 1975-09-11 SE SE7510137A patent/SE7510137L/en unknown
- 1975-09-11 NL NL7510703A patent/NL7510703A/en not_active Application Discontinuation
- 1975-09-11 ZA ZA00755816A patent/ZA755816B/en unknown
- 1975-09-12 BE BE159985A patent/BE833351A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| ZA755816B (en) | 1976-08-25 |
| SE7510137L (en) | 1976-03-15 |
| FR2284328A1 (en) | 1976-04-09 |
| JPS5161614A (en) | 1976-05-28 |
| FR2284328B1 (en) | 1979-09-14 |
| BE833351A (en) | 1975-12-31 |
| NL7510703A (en) | 1976-03-16 |
| AU8472375A (en) | 1977-03-17 |
| GB1477263A (en) | 1977-06-22 |
| CH602666A5 (en) | 1978-07-31 |
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