IT9020829A1 - DIOSMINE DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM - Google Patents
DIOSMINE DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM Download PDFInfo
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- IT9020829A1 IT9020829A1 IT020829A IT2082990A IT9020829A1 IT 9020829 A1 IT9020829 A1 IT 9020829A1 IT 020829 A IT020829 A IT 020829A IT 2082990 A IT2082990 A IT 2082990A IT 9020829 A1 IT9020829 A1 IT 9020829A1
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- GZSOSUNBTXMUFQ-YFAPSIMESA-N diosmin Chemical class C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)O1 GZSOSUNBTXMUFQ-YFAPSIMESA-N 0.000 title claims description 17
- 238000000034 method Methods 0.000 title claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 4
- 150000001875 compounds Chemical class 0.000 claims description 18
- GZSOSUNBTXMUFQ-NJGQXECBSA-N 5,7,3'-Trihydroxy-4'-methoxyflavone 7-O-rutinoside Natural products O(C[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](Oc2cc(O)c3C(=O)C=C(c4cc(O)c(OC)cc4)Oc3c2)O1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 GZSOSUNBTXMUFQ-NJGQXECBSA-N 0.000 claims description 14
- 229960004352 diosmin Drugs 0.000 claims description 14
- IGBKNLGEMMEWKD-UHFFFAOYSA-N diosmin Natural products COc1ccc(cc1)C2=C(O)C(=O)c3c(O)cc(OC4OC(COC5OC(C)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 IGBKNLGEMMEWKD-UHFFFAOYSA-N 0.000 claims description 14
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 claims description 14
- 150000001768 cations Chemical class 0.000 claims description 9
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 claims description 6
- 238000006243 chemical reaction Methods 0.000 claims description 5
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- CKDWPUIZGOQOOM-UHFFFAOYSA-N Carbamyl chloride Chemical compound NC(Cl)=O CKDWPUIZGOQOOM-UHFFFAOYSA-N 0.000 claims description 3
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical group 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 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- 229910052708 sodium Inorganic materials 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- PVOAHINGSUIXLS-UHFFFAOYSA-N 1-Methylpiperazine Chemical group CN1CCNCC1 PVOAHINGSUIXLS-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O Ammonium Chemical compound [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 2
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical group [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical group [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical group [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical group [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 239000011575 calcium Chemical group 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- 125000005842 heteroatom Chemical group 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 239000011777 magnesium Chemical group 0.000 claims description 2
- 229910052749 magnesium Inorganic materials 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 2
- 150000007530 organic bases Chemical class 0.000 claims description 2
- 239000011591 potassium Chemical group 0.000 claims description 2
- 229910052700 potassium Inorganic materials 0.000 claims description 2
- 238000005670 sulfation reaction Methods 0.000 claims description 2
- GETQZCLCWQTVFV-UHFFFAOYSA-O trimethylammonium Chemical compound C[NH+](C)C GETQZCLCWQTVFV-UHFFFAOYSA-O 0.000 claims description 2
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 239000003880 polar aprotic solvent Substances 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 4
- 229910000104 sodium hydride Inorganic materials 0.000 description 4
- 239000012312 sodium hydride Substances 0.000 description 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- -1 diosmin glycoside Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 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
- 239000004480 active ingredient Substances 0.000 description 1
- AZDRQVAHHNSJOQ-UHFFFAOYSA-N alumane Chemical class [AlH3] AZDRQVAHHNSJOQ-UHFFFAOYSA-N 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000002364 anti-haemorrhagic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical class OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- RTZKZFJDLAIYFH-UHFFFAOYSA-N ether Substances CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 229930182470 glycoside Natural products 0.000 description 1
- 150000004678 hydrides Chemical class 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- QTPUQXFLUMJEDT-UHFFFAOYSA-N n-pyrrolidin-1-ylcarbamoyl chloride Chemical compound ClC(=O)NN1CCCC1 QTPUQXFLUMJEDT-UHFFFAOYSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000004962 physiological condition Effects 0.000 description 1
- 235000011056 potassium acetate Nutrition 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- VYPDUQYOLCLEGS-UHFFFAOYSA-M sodium;2-ethylhexanoate Chemical compound [Na+].CCCCC(CC)C([O-])=O VYPDUQYOLCLEGS-UHFFFAOYSA-M 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000019635 sulfation Effects 0.000 description 1
- GETQZCLCWQTVFV-UHFFFAOYSA-N trimethylamine Chemical class CN(C)C GETQZCLCWQTVFV-UHFFFAOYSA-N 0.000 description 1
- 230000001643 venotonic effect Effects 0.000 description 1
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
Descrizione dell'invenzione industriale avente per titolo: "DERIVATI DELLA DIOSMINA, PROCEDIMENTO PER LA LORO PREPARA-ZIONE E COMPOSIZIONI FARMACEUTICHE CHE LI CONTENGONO" Description of the industrial invention entitled: "DIOSMINE DERIVATIVES, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM"
La presente invenzione riguarda composti della formula generale (I) The present invention relates to compounds of the general formula (I)
nella quale Rrappresenta idrogeno, un gruppo o un gruppo in which it represents hydrogen, a group or a group
dove indipendentemente l'uno dall'altro, rappresentano gruppi alchilici oppure formano, con l'atomo d'azoto cui sono legati, un anello a 5-7 membri, eventualmente contenente un altro eteroatomo, mentre X rappresenta l'equivalente d'un metallo alcalino, alcalino-terroso o terroso, il catione ammonio o il catione d'unabase organica farmaceuticamente compatibile, almeno uno degli R dovendo rappresentare un gruppo e almeno un altro degli R dovendo rappresentare un gruppo where independently of each other, they represent alkyl groups or form, with the nitrogen atom to which they are bonded, a 5-7 membered ring, possibly containing another heteroatom, while X represents the equivalent of a metal alkaline, alkaline-earth or earthy, the ammonium cation or the cation of a pharmaceutically compatible organic base, at least one of the R having to represent a group and at least another of the R having to represent a group
Di preferenza, nella predetta formula rappresentano residui alchilici (uguali o diversi) eppure l'aggruppamento rappresenta un residuo pirrolidinico, piperidinico o 4-metilpiperazinico; mentre X rappresenta di preferenza sodio, potassio, magnesio, calcio, alluminio o il catione d'un anminoacido basico, per esempio lisina. Ancora, si preferiscono composti (I) nei quali R assume il significato Preferably, in the above formula they represent alkyl residues (the same or different) and yet the grouping represents a pyrrolidine, piperidine or 4-methylpiperazine residue; while X preferably represents sodium, potassium, magnesium, calcium, aluminum or the cation of a basic amino acid, for example lysine. Again, compounds (I) are preferred in which R takes on the meaning
in corrispondenza di uno o di entrambi gli idrossili fenolici. at one or both of the phenolic hydroxyls.
L'invenzione riguarda inoltre un processo per l'ottenimento dei ccrrposti della formula I. Fanno parte dell'invenzione anche composizioni farmaceutiche contenenti uno o più dei composti I come principio attivo. The invention also relates to a process for obtaining the compounds of formula I. Also part of the invention are pharmaceutical compositions containing one or more of the compounds I as active principle.
I composti I oggetto dell'invenzione sono derivati del glicoside diosmina . Tale sostanza, della formula (II): The compounds I object of the invention are derivatives of the diosmin glycoside. This substance, of the formula (II):
è di grande importanza farmaceutica perché ne sono ben note e sfruttate le caratteristiche antiemorragiche e venotoniche. it is of great pharmaceutical importance because its anti-haemorrhagic and venotonic characteristics are well known and exploited.
Un grave inconveniente che caratterizza l'uso della diosmina è la scarsissima solubilità del composto. Ciò da un lato determina difficoltà di formulazione e dall'altro crea nell'organismo problemi di biodisponibilità del farmaco. A serious drawback that characterizes the use of diosmin is the very poor solubility of the compound. On the one hand, this causes difficulties in formulation and on the other creates problems in the body regarding the bioavailability of the drug.
Esisteva quindi il problema di mettere a disposizione dell'industria farmaceutica derivati della diosmina che presentassero buone caratteristiche di solubilità e nello stesso tempo garantissero una buona biodisponibilità del principio attivo nell'organismo. There was therefore the problem of making diosmin derivatives available to the pharmaceutical industry which had good solubility characteristics and at the same time guaranteed a good bioavailability of the active ingredient in the body.
Un tentativo in tal senso è stato fatto con la domanda di brevetto spagnolo 469.101 (C.A. 90, 168459p, 1979) nella quale sono descritti eteri β-idrossietilici della diosmina. Benché tali eteri siano in grado di soddisfare il principio della idrosolubilità, essi non soddisfano il principio della biodisponibilità: è infatti noto che il legame etereo non è facilmente scindibile in condizioni fisiologiche. An attempt in this sense has been made with the Spanish patent application 469.101 (C.A. 90, 168459p, 1979) in which β-hydroxyethyl ethers of diosmin are described. Although these ethers are able to satisfy the principle of water solubility, they do not satisfy the principle of bioavailability: it is in fact known that the ether bond is not easily divisible under physiological conditions.
Un altro tentativo è stato fatto tramite la preparazione di composti derivati dalla diosmina nei quali uno o due degli idrossili fenolici di essa sono esterificati con acido solforico ed eventualmente trasformati nei sali corrispondenti. Benché ciò realizzi un miglioramento della solubilità, l'instabilità di questi prodotti rende difficile la formulazione farmaceutica . Another attempt has been made through the preparation of compounds derived from diosmin in which one or two of the phenolic hydroxyls thereof are esterified with sulfuric acid and possibly transformed into the corresponding salts. While this achieves an improvement in solubility, the instability of these products makes pharmaceutical formulation difficult.
É stato ora trovato sorprendentemente che si possono ottenere derivati idrosolubili e stabili della diosmina della formula generale I precedentemente definita facendo reagire la diosmina II con un cloruro di carbammoile della formula (III): It has now been surprisingly found that water-soluble and stable derivatives of the diosmin of the general formula I previously defined can be obtained by reacting the diosmin II with a carbamoyl chloride of the formula (III):
nella quale hanno i significati sopra definiti, per ottenere un intermedio in cui uno o più (ma comunque non tutti gli) idrossili della diosmina sono stati sostituiti da gruppi (dove hanno i significati sopra definiti), facendo poi reagire tale intermedio con il complesso anidride solforica-trimetilammina della formula (IV): in which they have the meanings defined above, to obtain an intermediate in which one or more (but in any case not all) hydroxyls of the diosmin have been replaced by groups (where they have the meanings defined above), then causing this intermediate to react with the anhydride complex sulfuric-trimethylamine of the formula (IV):
così da ottenere un composto solfatato in cui almeno un idrossile della diosmina è stato sostituito ccn un gruppo il catione trimetriarmonio essendo poi opzionalmente sostituito, secondo metodi di per sè noti, con altri cationi corrispondenti al significato di X, per esempio attraverso la reazione del predetto conposto solfatato con un alcanoato di formula generale (V) so as to obtain a sulphated compound in which at least one hydroxyl of the diosmin has been substituted with one group, the trimetriaronium cation being then optionally substituted, according to methods per se known, with other cations corresponding to the meaning of X, for example through the reaction of the aforesaid compound sulphated with an alkanoate of general formula (V)
dove X ha il significato indicato in precedenza e significa un alchile lineare o ramificato É inoltre possibile sostituire, con metodi tradizionali, un qualunque catione X con un altro. where X has the meaning indicated above and means a linear or branched alkyl. It is also possible to replace, with traditional methods, any cation X with another.
La sequenza di reazioni dell'invenzione viene eseguita secondo tecniche convenzionali facendo reagire la diosmina II con il cloruro di carbammoile III in un solvente inerte, preferibilmente polare aprotico, come per esempio dìmetìlformammide o dimetilacetammide , di preferenza dopo aver salificato gli idrossili ccn una adatta base, per esempio un idruro alcalino, preferibilmente idruro di sodio. La successiva reazione di solfstazione può essere effettuata direttamente, senza isolare l'intermedio carbammoilato, nello stesso solvente usato per il passaggio precedente. The sequence of reactions of the invention is carried out according to conventional techniques by reacting the diosmin II with the carbamoyl chloride III in an inert solvent, preferably polar aprotic, such as for example dimethylformamide or dimethylacetamide, preferably after having salified the hydroxyls with a suitable base. , for example an alkaline hydride, preferably sodium hydride. The subsequent sulfstation reaction can be carried out directly, without isolating the carbamoylate intermediate, in the same solvent used for the previous step.
La solfatazione è condotta preferibilmente scaldando a temperatura moderata per alcune ore. Il composto solfatato viene isolato dalla miscela di reazione, ma, nel caso in cui il catione trimetilammonio debba essere sostituito con altro catione, non necessita di purificazione. Esso viene allora trattato direttamente con l'alcanoato V per ottenere il sale voluto. Si opera di preferenza in un solvente alcanolico come etanolo o, meglio, metanolo, nel quale il prodotto finale è poco solubile e precipita direttamente in condizioni di elevata purezza. The sulfation is preferably carried out by heating at a moderate temperature for a few hours. The sulphated compound is isolated from the reaction mixture, but, in the event that the trimethylammonium cation has to be replaced with another cation, it does not require purification. It is then treated directly with the alkanoate V to obtain the desired salt. It is preferable to operate in an alkanolic solvent such as ethanol or, better, methanol, in which the final product is not very soluble and precipitates directly under conditions of high purity.
I prodotti dell'invenzione sono estremamente stabili, mostrano una soddisfacente idrosolubilità e hanno una buona biocompatibilità. Prove farmacologiche hanno dimostrato che la loro attività è dello stesso tipo di quella della diosmina, ma è più elevata a causa della migliare biodisponibilità. The products of the invention are extremely stable, show satisfactory water solubility and have good biocompatibility. Pharmacological tests have shown that their activity is of the same type as that of diosmin, but is higher due to the great bioavailability.
Gli esempi seguenti illustrano l'invenzione senza limitarla in alcun modo. The following examples illustrate the invention without limiting it in any way.
ESEMPIO 1 EXAMPLE 1
60,85 mg (0,10 nmoli) di diosmina II sono sospesi in 10 ml di dimetilacetammide. Si aggiungono 6 mg (0,25 nmoli) di sodioidruro a temperatura ambiente e dopo 3 ore si aggiungono 26,9 mg (0,25 limoli) di N,N-dimetilcarbannoileloruro . 60.85 mg (0.10 nmoles) of diosmin II are suspended in 10 ml of dimethylacetamide. 6 mg (0.25 nmoles) of sodium hydride at room temperature are added and after 3 hours 26.9 mg (0.25 limols) of N, N-dimethylcarbannoyleloride are added.
Alla fine della reazione (2 ore circa) si aggiungono 50 ml di dimetilacetammide e 208,65 mg (1,5 mmoli) di complesso si scalda a 60-70°C per 3 ore. Si distilla sotto vuoto la dimetilacetammide e si riprende il residuo (sale di trimetilammonio) con metanolo. La soluzione metanolica (eventualmente filtrata su carbone) viene trattata con una soluzione satura di acetato di potassio in metanolo. Si ha così la precipitazione del sale potassico che si lava con metanolo e si essicca a 40°C sotto vuoto. Per ottenere il sede sodico si tratta invece il sale di trimetilammonio, sciolto in metanolo, con una soluzione satura di 2-etil-esanoato sodico in metanolo. At the end of the reaction (about 2 hours), 50 ml of dimethylacetamide are added and 208.65 mg (1.5 mmoles) of the complex are heated at 60-70 ° C for 3 hours. The dimethylacetamide is distilled under vacuum and the residue (trimethylammonium salt) is taken up with methanol. The methanolic solution (possibly filtered on charcoal) is treated with a saturated solution of potassium acetate in methanol. Thus the potassium salt precipitates, which is washed with methanol and dried at 40 ° C under vacuum. To obtain the sodium site, the trimethylammonium salt, dissolved in methanol, is treated with a saturated solution of sodium 2-ethyl-hexanoate in methanol.
Analisi elementare per Elementary analysis for
ESEMPIO 2 EXAMPLE 2
60,85 mg (0,10 mmoli) di diosmina sono sospesi in 10 ml di dimetilacetammide . si aggiungono 6,00 mg (0,25 mmoli) di sodio idruro a temperatura ambiente e dopo 3 ore si aggiungono 33,40 mg (0,25 mmoli ) di N-pirrolidil-carbammoilcloruro. Si procede come nell'esempio 1. 60.85 mg (0.10 mmol) of diosmin are suspended in 10 ml of dimethylacetamide. 6.00 mg (0.25 mmoles) of sodium hydride at room temperature are added and after 3 hours 33.40 mg (0.25 mmoles) of N-pyrrolidyl-carbamoyl chloride are added. Proceed as in example 1.
Analisi elementare per Elementary analysis for
Il sale sodico ottenuto, sciolto in acqua e trattato con una soluzione acquosa di ossicloruro di allumminio, dà il sale di alluminio corrispondente . The sodium salt obtained, dissolved in water and treated with an aqueous solution of aluminum oxychloride, gives the corresponding aluminum salt.
ESEMPIO 3 EXAMPLE 3
60,85 mg (0,10 ntnoli) di diosmina sono sospesi in 10 ml di dimetilacetammide. Si aggiungono 6,00 mg (0,25 mmoli ) di sodio idruro a temperatura ambiente e dopo 3 ore si aggiungono 37,16 mg (0,25 mmoli ) di N'-metil -N-piperazil-carbammoilcloruro. 60.85 mg (0.10 ntnoles) of diosmin are suspended in 10 ml of dimethylacetamide. 6.00 mg (0.25 mmoles) of sodium hydride are added at room temperature and after 3 hours 37.16 mg (0.25 mmoles) of N'-methyl -N-piperazil-carbammoyl chloride are added.
Si procede come nell'esempio 1. Proceed as in example 1.
Analisi elementare per<r > Elementary analysis for <r>
Claims (10)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02082990A IT1249041B (en) | 1990-06-29 | 1990-06-29 | Derivatives of diosmin, process for their preparation and pharmaceutical compositions which contain them |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT02082990A IT1249041B (en) | 1990-06-29 | 1990-06-29 | Derivatives of diosmin, process for their preparation and pharmaceutical compositions which contain them |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| IT9020829A0 IT9020829A0 (en) | 1990-06-29 |
| IT9020829A1 true IT9020829A1 (en) | 1991-12-29 |
| IT1249041B IT1249041B (en) | 1995-02-11 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| IT02082990A IT1249041B (en) | 1990-06-29 | 1990-06-29 | Derivatives of diosmin, process for their preparation and pharmaceutical compositions which contain them |
Country Status (1)
| Country | Link |
|---|---|
| IT (1) | IT1249041B (en) |
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1990
- 1990-06-29 IT IT02082990A patent/IT1249041B/en active IP Right Grant
Also Published As
| Publication number | Publication date |
|---|---|
| IT9020829A0 (en) | 1990-06-29 |
| IT1249041B (en) | 1995-02-11 |
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