IT8322170A1 - Compounds suitable for the therapeutic treatment of biliary changes, in particular lithogenic bile and cholesterol stones, and pharmaceutical compositions containing them - Google Patents
Compounds suitable for the therapeutic treatment of biliary changes, in particular lithogenic bile and cholesterol stones, and pharmaceutical compositions containing them Download PDFInfo
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- IT8322170A1 IT8322170A1 IT1983A22170A IT2217083A IT8322170A1 IT 8322170 A1 IT8322170 A1 IT 8322170A1 IT 1983A22170 A IT1983A22170 A IT 1983A22170A IT 2217083 A IT2217083 A IT 2217083A IT 8322170 A1 IT8322170 A1 IT 8322170A1
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- bile
- biliary
- cholesterol
- changes
- lithogenic
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- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims description 22
- 150000001875 compounds Chemical class 0.000 title claims description 14
- 210000000941 bile Anatomy 0.000 title claims description 12
- 235000012000 cholesterol Nutrition 0.000 title claims description 11
- 238000011282 treatment Methods 0.000 title claims description 10
- 230000000927 lithogenic effect Effects 0.000 title claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title description 5
- RUDATBOHQWOJDD-UHFFFAOYSA-N (3beta,5beta,7alpha)-3,7-Dihydroxycholan-24-oic acid Natural products OC1CC2CC(O)CCC2(C)C2C1C1CCC(C(CCC(O)=O)C)C1(C)CC2 RUDATBOHQWOJDD-UHFFFAOYSA-N 0.000 claims description 21
- RUDATBOHQWOJDD-UZVSRGJWSA-N ursodeoxycholic acid Chemical compound C([C@H]1C[C@@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-UZVSRGJWSA-N 0.000 claims description 15
- 229960001661 ursodiol Drugs 0.000 claims description 15
- 239000003613 bile acid Substances 0.000 claims description 10
- 239000000203 mixture Substances 0.000 claims description 9
- 201000001883 cholelithiasis Diseases 0.000 claims description 6
- 230000004075 alteration Effects 0.000 claims description 5
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 claims description 4
- 239000011575 calcium Substances 0.000 claims description 4
- 229910052791 calcium Inorganic materials 0.000 claims description 4
- 208000001130 gallstones Diseases 0.000 claims description 4
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 3
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 150000002500 ions Chemical class 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- ZKGCEXPUCJDWMB-ZPMVHPDISA-N (4r)-4-[(8r,9s,10s,13r,14s,17r)-10,13-dimethyl-7-oxo-1,2,3,4,5,6,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C1CCCC2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)CC[C@@H]3[C@]21C ZKGCEXPUCJDWMB-ZPMVHPDISA-N 0.000 claims 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- 238000003756 stirring Methods 0.000 description 9
- 239000008367 deionised water Substances 0.000 description 8
- 229910021641 deionized water Inorganic materials 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- RUDATBOHQWOJDD-BSWAIDMHSA-N chenodeoxycholic acid Chemical compound C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)CC1 RUDATBOHQWOJDD-BSWAIDMHSA-N 0.000 description 6
- 229960001091 chenodeoxycholic acid Drugs 0.000 description 6
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 239000002253 acid Substances 0.000 description 4
- QHFQAJHNDKBRBO-UHFFFAOYSA-L calcium chloride hexahydrate Chemical compound O.O.O.O.O.O.[Cl-].[Cl-].[Ca+2] QHFQAJHNDKBRBO-UHFFFAOYSA-L 0.000 description 3
- 230000002440 hepatic effect Effects 0.000 description 3
- 241000735552 Erythroxylum Species 0.000 description 2
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 2
- ARLZGEXVMUDUQZ-UHFFFAOYSA-N O.O.[Ca] Chemical compound O.O.[Ca] ARLZGEXVMUDUQZ-UHFFFAOYSA-N 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036983 biotransformation Effects 0.000 description 2
- 235000008957 cocaer Nutrition 0.000 description 2
- ZPUCINDJVBIVPJ-LJISPDSOSA-N ***e Chemical compound O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- DCUGZOBNIZLALZ-UHFFFAOYSA-N magnesium;dihydrate Chemical compound O.O.[Mg] DCUGZOBNIZLALZ-UHFFFAOYSA-N 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- DXOCDBGWDZAYRQ-DVTFWNRPSA-N (4r)-4-[(3r,8r,9s,10s,13r,14s,17r)-3-hydroxy-10,13-dimethyl-7-oxo-1,2,3,4,5,6,8,9,11,12,14,15,16,17-tetradecahydrocyclopenta[a]phenanthren-17-yl]pentanoic acid Chemical compound C1C[C@@H](O)CC2CC(=O)[C@H]3[C@@H]4CC[C@H]([C@@H](CCC(O)=O)C)[C@@]4(C)CC[C@@H]3[C@]21C DXOCDBGWDZAYRQ-DVTFWNRPSA-N 0.000 description 1
- CSWRFCISTSMAHQ-VBTQOLOKSA-N (8S,9S,10R,13S,14S,17R)-16,16-dihydroxy-13-methyl-17-[(2R)-pentan-2-yl]-1,2,3,4,5,6,7,8,9,11,12,14,15,17-tetradecahydrocyclopenta[a]phenanthrene-10-carboxylic acid Chemical compound C1CC2CCCC[C@]2(C(O)=O)[C@@H]2[C@@H]1[C@@H]1CC(O)(O)[C@H]([C@H](C)CCC)[C@@]1(C)CC2 CSWRFCISTSMAHQ-VBTQOLOKSA-N 0.000 description 1
- 125000003907 chenodeoxycholic acid group Chemical group 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 150000004683 dihydrates Chemical class 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000004973 liquid crystal related substance Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- WRUGWIBCXHJTDG-UHFFFAOYSA-L magnesium sulfate heptahydrate Chemical compound O.O.O.O.O.O.O.[Mg+2].[O-]S([O-])(=O)=O WRUGWIBCXHJTDG-UHFFFAOYSA-L 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000001612 ursodeoxycholic acid group Chemical group 0.000 description 1
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Description
D E SCR IZ ION E DESCRIPTION
dell'invenzione "industriale dal titolo: of the "industrial invention entitled:
''Composti atti al trattamento terapeutico delle alterazioni biliari, in particolare della bile litogena e dei calcoli colesterolici, e composizioni farmaceutiche che li contengono" '' Compounds suitable for the therapeutic treatment of biliary alterations, in particular lithogenic bile and cholesterol stones, and pharmaceutical compositions containing them "
RIASSUNTO SUMMARY
La presente invenzione riguarda un composto atto al trattamento delle alterazioni biliari, in particolare della bile litogena e dei calcoli biliari da "colesterolo caratterizzato dal fatto di essere il prodotto di salificazione dell'acido ursodesossicolico e di un secondo acido biliare scelto tra i seguenti: acido 3?-idrossi-7-cheto colanico,'3?,7?-diidrossi-l2-cheto colanico, 3?,7?,12?-triidrossicolanico; con uno ione scelto tra calcio e magnesio, e le composizioni farmaceutiche che li contengono come principi attivi. The present invention relates to a compound suitable for the treatment of biliary alterations, in particular of lithogenic bile and gallstones from "cholesterol, characterized in that it is the salification product of ursodeoxycholic acid and of a second bile acid selected from the following: acid 3? -Hydroxy-7-ketocholanic, 3?, 7? -Dihydroxy-12-ketocholanic, 3?, 7?, 12? -Trioxycholanic; with an ion selected from calcium and magnesium, and the pharmaceutical compositions that contain as active ingredients.
DESCRIZIONE DESCRIPTION
E* noto che gli acidi biliari, principalmente l'acido ursodesossicolico (UDCA) e chenodesossicolico (CDCA), sono in grado di desaturare la bile litogena ed operare la dissoluzione dei calcoli biliari di colesterolo.^ Se si limita per semplicit? la discussione al caso dell'UDCA, si osserva che il meccanismo d'azione attraverso il quale tale composto desatura la bile so? vrasatura in colesterolo ? solo per certi aspetti chiarito; certamente giocano un ruolo importante la -riduzione della secrezione epatica di colesterolo e la formazione di cristalli liquidi di colesterolo in presenza di fosfalipidi. It is known that bile acids, mainly ursodeoxycholic acid (UDCA) and chenodeoxycholic acid (CDCA), are capable of desaturating lithogenic bile and dissolving cholesterol gallstones. the discussion to the case of the UDCA, it is observed that the mechanism of action through which this compound desaturates the bile I know? vrasatura in cholesterol? only in some respects clarified; certainly play an important role in the reduction of the hepatic secretion of cholesterol and the formation of liquid crystals of cholesterol in the presence of phoshalipids.
Di particolare rilievo ai fini dell'effetto terapeutico finale sono i processi metabolici, quali le hiotrasformazioni ad opera del fegato e della flora intestinale, a cui l'UDCA ? sottoposto.'Mediante la somministrazione di questa sostanza la dissoluzione dei calcoli biliari generalmente ? ottenuta in percentuali di pazienti oscillanti tra il 40 e il 60%.?La durata dei trattamenti ? in media di un anno.' Of particular importance for the purposes of the final therapeutic effect are the metabolic processes, such as hiotransformations by the liver and intestinal flora, to which the UDCA? subjected. 'By the administration of this substance the dissolution of gallstones generally? obtained in percentages of patients ranging from 40 to 60%.? The duration of the treatments? an average of one year. '
A sua volta, l'acido chetolitocolico (7KLCA) rappresenta un metabolita fisiologico negli interprocessi di biotrasformazione del CDCA e dell'UDCA.?La sua somministrazione nell'uomo d? luogo per biotrasformazione epatica a CDCA in larga prevalenza (ca.' 70-80%) 'ed in minor misura a UDCA.' In turn, ketolithocolic acid (7KLCA) represents a physiological metabolite in the biotransformation processes of CDCA and UDCA. place for hepatic biotransformation to CDCA in large prevalence (ca. '70-80%)' and to a lesser extent to UDCA. '
Recenti indagini cliniche condotte con questo derivato hanno dimostrato che esso ? in grado di desaturare la bile litogena anche quando usato a dosi di 400 mg/dj?/ Tale effetto pure se riconducibile certamente in parte alla produzione di COCA e UDCA sembra peraltro conseguenza anche di un effetto diretto consistente in una riduzione della sintesi epatica del colesterolo.' Recent clinical investigations conducted with this derivative have shown that it? able to desaturate lithogenic bile even when used at doses of 400 mg / dj? / This effect, although certainly partly attributable to the production of COCA and UDCA, seems to be a consequence of a direct effect consisting of a reduction in the hepatic synthesis of cholesterol . '
Secondo gli scopi della presente invenzione sarebbe desiderabile ottenere una combinazione degli effetti di tali acidi biliari.'A tale riguardo si pu? osservare che la combinazione di UDCA e COCA sembra assicurare maggiore percentuali di dissoluzione dei calcoli e quindi un effetto terapeutico pi? favorevole^ According to the purposes of the present invention it would be desirable to obtain a combination of the effects of such bile acids. observe that the combination of UDCA and COCA seems to ensure a higher percentage of dissolution of the stones and therefore a more therapeutic effect? favorable ^
UDCA e CDCA sembrano dotati di meccanismi d'azione in qualche modo differenti: UDCA forma mdcelle miste con colesterolo in minor misura di CDCA mentre ancora UDCA pi? che CDCA forma cristalli liquidi di colesterolo ed arricchisce in maggior misura la bile di acido biliare primario.? UDCA and CDCA seem to have somewhat different mechanisms of action: UDCA forms mixed cells with cholesterol to a lesser extent than CDCA while still UDCA more? that CDCA forms liquid cholesterol crystals and enriches bile to a greater extent with primary bile acid.
La combinazione dei due acidi biliari desatura la bile pi? del solo UDCA.' D'altra parte la combinazione di UDCA con 7KLCA sembra accentuare tale capacit?, aggiungendo anche l'attivit? propria del yKLCA.' The combination of the two bile acids desaturates the bile more. of the UDCA alone. ' On the other hand, the combination of UDCA with 7KLCA seems to accentuate this capacity, adding also the activity? proper to yKLCA. '
Secondo la presente invenzioni si desidera combinare gli effetti dei diversi acidi biliari nel campo del trattamento dei calcoli biliari soprattutto allo scopo di realizzare una desaturazione biliare pi? rapida e di maggiore entit? di quella ottenibile usando^ come previsto dalla tecnica nota, tali? acidi singolarmente/ According to the present invention, it is desired to combine the effects of the various bile acids in the field of gallstone treatment, above all in order to achieve a greater biliary desaturation. rapid and of greater entity? than that obtainable using as foreseen by the known art, such? acids individually /
Tuttavia, secondo l?invenzione, questo scopo vuole essere raggiunto disponendo sempre di un unico composto, e non somministrando insieme diversi acidi biliari noti presi singolarmente, ci? perch? potere disporre di un unico composto principalmente consentirebbe di dosare al meglio il principio attivo .nella somministrazione per l?ottenimento della specifica attivit? desiderata, e faciliterebbe in ogni caso in maniera considerevole il trattamento terapeutico/ However, according to the invention, this aim is to be achieved by always having a single compound, and not by administering together several known bile acids taken individually. why? being able to have a single compound mainly would allow to better dose the active ingredient. in the administration to obtain the specific activity? desired, and would in any case considerably facilitate the therapeutic treatment /
L?insieme degli scopi sopra detti secondo la presente invenzione ? realizzato con un composto atto al trattamento delle alterazioni biliari in particolare della bile litogena e dei calcoli biliari da colesterolo caratterizzato dal fatto di essere il prodotto di salificazione dell?acido ursodesossicolico ? di un secondo acido biliare scelto tra i seguenti: acido 3a-idrossi-7-cheto colanico; 3a,7?-diidrossi-12-cheto colanico; 3a,7?,12a-triidrossicolanico; con uno ione scelto tra calcio e magnesio/ The set of the above purposes according to the present invention? made with a compound suitable for the treatment of biliary alterations in particular of lithogenic bile and cholesterol gallstones characterized by the fact of being the salification product of ursodeoxycholic acid? a second bile acid selected from the following: 3a-hydroxy-7-ketocholanic acid; 3a, 7? -Dihydroxy-12-keto colanic; 3a, 7?, 12a-trihydroxycholan; with an ion chosen between calcium and magnesium /
Allo scopo di meglio comprendere caratteristiche e vantaggi dell1invenzione se ne descrivono di seguito esempi preparativi di alcuni dei composti da essa indicati; tali esempi non sono in alcun modo limitativi dell'invenzione/ In order to better understand the characteristics and advantages of the invention, preparatory examples of some of the compounds indicated therein are described below; these examples are in no way limiting of the invention /
Esempio 1 Example 1
3 alfa, 7 beta-diidrossi colanato, 3 alfa-idrossi-7-cheto colanato di magnesio diidrato/ 3 alpha, 7 beta-dihydroxycholanate, 3 alpha-hydroxy-7-ketocholanate of magnesium dihydrate /
In un pallone a 4 colli da mi 2000, caricare: In a 4-neck balloon of mi 2000, load:
aggiungere, sotto agitazione, sodio idrato 27% (p/v) q.lb/ a pH=l2 a soluzione limpida gocciolare una soluzione ottenuta sciogliendo g 75 di magnesio solfato eptaidrato RPE in mi 200 di acqua deionizzata.^ add, while stirring, sodium hydrate 27% (w / v) q.lb/ at pH = l2 to a clear solution drop a solution obtained by dissolving 75 g of magnesium sulphate heptahydrate RPE in 200 ml of deionized water.
Terminata l?aggiunta si porta a pH=8,5 con acido acetico 10%. si lascia in agitazione 2 ore; si filtra si lava il pannello con mi 200 di acqua deionizzata/ Si secca a 80?C/ At the end of the addition, bring to pH = 8.5 with 10% acetic acid. it is left under stirring for 2 hours; the panel is filtered and washed with 200 ml of deionized water / It is dried at 80 ° C /
Si ottengono g 105 con le seguenti caratteristiche: 105 g is obtained with the following characteristics:
Si riporta di seguito la formula strutturale del composto ottenuto: The structural formula of the compound obtained is shown below:
Esempio 2 Example 2
3 alfa, 7 beta-diidrossicolanato, 3 alfa-idrossi-7-cheto coianato di calcio biidrato 3 alpha, 7 beta-dihydroxycholanate, 3 alpha-hydroxy-7-keto coyanate of calcium dihydrate
In un pallone a 4 colli da mi 2000 si caricano: In a 4-package 2000 ml balloon, the following are loaded:
Si agita; si aggiunge sodio idrato 27% (p/v) q;b/ a pH = 12 (circa ml 36).' He agitates; 27% sodium hydrate (w / v) q is added; b / a pH = 12 (approximately ml 36).
Alla soluzione limpida cos? ottenuta si aggiunge, lentamente, una soluzione preparata sciogliendo g 58,6 di calcio cloruro esaidrato RP in mi 200 di acqua To the clear solution so? obtained, a solution prepared by dissolving 58.6 g of calcium chloride hexahydrate RP in 200 ml of water is added slowly
deionizzata.?!Terminata l'aggiunta si lascia in agitazione per 1 ora.? Si porta il pH a 10,5 ~ 11 con acido acetico 10% (p/v) e si lascia 1 ora in agitazione.' Once the addition is complete, the mixture is left under stirring for 1 hour. The pH is brought to 10.5 ~ 11 with 10% acetic acid (w / v) and the mixture is left under stirring for 1 hour.
Si filtra, si lava con mi 200 di acqua deionizzata It is filtered and washed with 200 ml of deionized water
e si secca in stufa a 8o?C.?: and dries in the stove at 8o? C.?:
Si ottengono g 104 con le seguenti caratteristiche: 104 g is obtained with the following characteristics:
Esempio 3 Example 3
3 alfa, 7 beta-diidrossicolanato, 3 alfa, 7 beta, 12 alfatriidrossico lanato di calcio biidrato 3 alpha, 7 beta-dihydroxycholanate, 3 alpha, 7 beta, 12 alpha-hydroxy calcium lanate dihydrate
In un pallone a 4 colli da mi 2000 si caricano: In a 4-package 2000 ml balloon, the following are loaded:
Si agita; si aggiunge sodio idrato 27% (p/v) q.b. a pH=12 (circa mi 36).1 He agitates; 27% sodium hydrate (w / v) is added to the taste. at pH = 12 (about 36 ml). 1
Alla soluzione limpida cos? ottenuta, si aggiunge, lentamente, una soluzione preparata sciogliendo g 58,6 di calcio cloruro esaidrato RP in mi 200 di acqua deionizzata.' Terminata l'aggiunta si lascia in agitazione per 1 ora.' Si porta il pH=10,5 - 11 con acido acetico 10% (p/v) e si lascia 1 ora in agitazione.' To the clear solution so? obtained, a solution prepared by dissolving 58.6 g of calcium chloride hexahydrate RP in 200 ml of deionized water is added slowly. At the end of the addition, the mixture is left under stirring for 1 hour. The pH is brought to 10.5 - 11 with 10% acetic acid (w / v) and the mixture is left under stirring for 1 hour.
Si filtra, si lava con mi 200 di acqua deionizzata e si secca in stufa a 80?C.' Si ottengono g 107 di prodotto con le seguenti caratteristiche: It is filtered, washed with 200 ml of deionized water and dried in an oven at 80 ° C. ' 107 g of product are obtained with the following characteristics:
Esempio 4 Example 4
3 alfa, 7 beta?diidrossicolanato, 3 alfa, 7 beta?diidrossi-12-cheto colanato di magnesio biidrato 3 alpha, 7 beta? Dihydroxycholanate, 3 alpha, 7 beta? Dihydroxy-12-keto colanate of magnesium dihydrate
In un pallone a 4 colli da mi 2000 si caricano: In a 4-package 2000 ml balloon, the following are loaded:
Si agita; si aggiunge sodio idrato 27% (p/v) q.b. He agitates; 27% sodium hydrate (w / v) is added to the taste.
a pH 12 (circa mi 36).? at pH 12 (about 36 mi).
Alla soluzione limpida cos? ottenuta, si aggiunge lentamente una soluzione preparata sciogliendo g 66 di To the clear solution so? obtained, a solution prepared by dissolving 66 g of
magnesio solfato estaidrato RF in mi 200 di acqua magnesium sulfate hestahydrate RF in 200 ml of water
deionizzata.'Terminata l'aggiunta si lascia in agitazione per 1 ora.' Si porta a pH = 8,5 con acido acetico 10% e si lascia 1 ora in agitazione.' Si filtra, deionized. 'At the end of the addition it is left under stirring for 1 hour.' The mixture is brought to pH = 8.5 with 10% acetic acid and is left under stirring for 1 hour. It filters,
si lava con mi 200 di acqua deionizzata e si secca it is washed with 200 ml of deionized water and dried
in stufa a 80?C.' in the stove at 80? C. '
Si ottengono g 105 di prodotto con le seguenti caratteristiche: 105 g of product are obtained with the following characteristics:
Esempio 5 Example 5
3 alfa, 12 beta-diidrossicolanato, 3 alfa, 7 beta-dii? drossi-12-cheto colanato di calcio biidrato 3 alpha, 12 beta-dihydroxycholanate, 3 alpha, 7 beta-dii? hydroxy-12-keto colanate of calcium dihydrate
In un pallone a 4 colli di mi 2000 si caricano: In a 4-necked balloon of mi 2000 the following are loaded:
Si agita, si aggiunge sodio idrato 27% (p/v) q.'b.' a pH=2 (circa mi 36).' The mixture is stirred, 27% sodium hydrate (w / v) q.'b. 'is added. at pH = 2 (about 36 mi). '
Alla soluzione limpida cos? ottenuta, si aggiunge lentamente una soluzione preparata sciogliendo g 58,6 di calcio cloruro esaidrato RP in mi 200 .di acqua deionizzata.1Terminata l'aggiunta si lascia in agitazione per 1 ora.' Si porta il pH=10,5 A 11 con acido acetico 10% e si lascia 1 ora in agitazione.' To the clear solution so? obtained, a solution prepared by dissolving 58.6 g of calcium chloride hexahydrate RP in 200 ml of deionized water is added slowly. The pH is brought to 10.5 to 11 with 10% acetic acid and the mixture is left under stirring for 1 hour.
Si filtra, si lava con mi 200 di acqua deionizzata e It is filtered, washed with 200 ml of deionized water and
si secca in stufa a 80?C.' it dries in the stove at 80? C. '
Si ottengono g 107 di prodotto con le seguenti caratteristiche: 107 g of product are obtained with the following characteristics:
I composti dell'invenzione,,preparati in opportune composizioni per uso farmaceutico, si dimostrano adatti The compounds of the invention, prepared in suitable compositions for pharmaceutical use, prove to be suitable
al trattamento delle alterazioni biliari, principalmente della bile litogena e dei calcoli colesterolici, in unit? farmaceutiche in?cui sono contenuti a dosi to the treatment of biliary alterations, mainly of lithogenic bile and cholesterol stones, in unit? pharmaceuticals in which they are contained in doses
varianti da circa 100 a 400 mg, da assumere fino a 2/3 volte al giorno/ varying from about 100 to 400 mg, to be taken up to 2/3 times a day /
In tal modo un composto dell'invenzione dimostra Thus a compound of the invention demonstrates
di potere efficacemente svolgere il ruolo di combinare in ma unico prodotto le diverse attivit? degli acidi biliari fondamentali, con azione pi? rapida ed efficace di quella degli stessi acidi presi singolarmente, to be able to effectively play the role of combining the different activities in a single product? of the fundamental bile acids, with action pi? quick and effective than that of the same acids taken individually,
Claims (4)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22170/83A IT1194332B (en) | 1983-07-21 | 1983-07-21 | Cholesterol impairment treatment compsn. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT22170/83A IT1194332B (en) | 1983-07-21 | 1983-07-21 | Cholesterol impairment treatment compsn. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IT8322170A0 IT8322170A0 (en) | 1983-07-21 |
| IT8322170A1 true IT8322170A1 (en) | 1985-01-21 |
| IT1194332B IT1194332B (en) | 1988-09-14 |
Family
ID=11192539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT22170/83A IT1194332B (en) | 1983-07-21 | 1983-07-21 | Cholesterol impairment treatment compsn. |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1194332B (en) |
-
1983
- 1983-07-21 IT IT22170/83A patent/IT1194332B/en active
Also Published As
| Publication number | Publication date |
|---|---|
| IT1194332B (en) | 1988-09-14 |
| IT8322170A0 (en) | 1983-07-21 |
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