SK379692A3 - Stable salts of (+)-(1s,2r)-2-//n-(2-hydroxylamino-2- -oxoethyl)-n-methyl-amino/carbonyl/cyclohexan-1-carboxylic acid, method of their preparation and pharmaceutical agents containing these salts - Google Patents
Stable salts of (+)-(1s,2r)-2-//n-(2-hydroxylamino-2- -oxoethyl)-n-methyl-amino/carbonyl/cyclohexan-1-carboxylic acid, method of their preparation and pharmaceutical agents containing these salts Download PDFInfo
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Abstract
Description
Stabilní soli kyseliny (+)-(lS,2R)-2-//N-(2-h.vdroxyleir.ino2-oxoethyl)-N-methyl-amino/korbony1/cyklohexan-l-kerboxylové, zpúsob jejich prípravy a farmaceutické korapozice tyto stabilní soli obsahující *(+) - (1S, 2R) -2- [N- (2-Hydroxylamino-2-oxoethyl) -N-methylamino] carbonyl] cyclohexane-1-carboxylic acid stable salts, processes for their preparation and pharmaceuticals correction of these stable salts containing *
Oblast technikyTechnical field
Vynález se týká nových solí kyseliny (*)-(lS,2R)-2//N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino/karbony1/ cyk.lohexan-1-karboxylové s kovem a organickými bázemi, mající antihypertenzní účinnosť, zpúsob jejich prípravy p jejich použití ve farmaceutických kompozicích.The invention relates to novel salts of (*) - (1S, 2R) -2 H- N- (2-hydroxylamino-2-oxoethyl) -N-methylamino / carbonyl / cyclohexane-1-carboxylic acid with metal and organic bases having antihypertensive activity, a process for their preparation for use in pharmaceutical compositions.
Dosavadní _stav technikyBACKGROUND OF THE INVENTION
Evropská patentová prihláška 89106304.2 popisuje kyselinu (+)—(1S,2R)-2-//N-(2-hydroxylemino-2-oxoethyl)-Nmethyl-amino/karbonyl/cyklohexan-l-karboxylovou (1), (D.C.I. Idrapril) jako nové ACE-innibiční činidlo, mající antihypertenzní účinnost.European Patent Application 89106304.2 discloses (+) - (1S, 2R) -2- [N- (2-hydroxylemino-2-oxoethyl) -N-methylamino] carbonyl / cyclohexane-1-carboxylic acid (1), (DCI Idrapril) ) as a novel ACE-innovator having antihypertensive activity.
Tato kyselina v prípade, že je vystavená účinku vzduchu za normálni vlhkosti a teploty okolí, podléhá samorozkladným procesúm, pŕičemž vznikají nečistoty, které jsou samozrejmé neslučitelné s terapeutickým použitím této kyseliny. Tyto degradační procesy mohou být dále urýchlený zvýšenou teplotou pri zachovéní ostatních výše uvedených podmínek.This acid, when exposed to air at normal humidity and ambient temperature, undergoes self-degrading processes, producing impurities which are obviously incompatible with the therapeutic use of the acid. These degradation processes can be further accelerated by elevated temperature while maintaining the other conditions mentioned above.
Nyní bylo nové zjišténo, že nové soli podie vynálezu nepodléhají výše zmĺnéným samorozkladným a degradačním procesúm.It has now been found that the novel salts of the invention are not subject to the above-mentioned self-degrading and degradation processes.
Podstata vynálezuSUMMARY OF THE INVENTION
Podstatou vynálezu jsou nové soli (+)-(IS,2R)-2-//N(2-hydrox,ylemino-2-oxoethyl) -N-methyl-amino/karbonyl/cyklohexan-l-karboxylové kyseliny s kovem p. organickou bází mející antihypertenzní účinr.ost, zpúsob její pŕíprevy a je jich použití ve farmaceutických kompozicích, pričemž uvede ná súl nr.á obecný vzorec (1)SUMMARY OF THE INVENTION The present invention provides novel (+) - (1S, 2R) -2- [N (2-hydroxylmethyl-2-oxoethyl) -N-methylamino] carbonyl / cyclohexane-1-carboxylic acid salts of p. organic base having antihypertensive activity, process for its preparation and use in pharmaceutical compositions, the general formula (1)
» n r· ve kterém R a K spoleené znamenejí bivalentní ketiont zvolený ze skupiny zahrnující vápnik, ethylendiarain a další farmaceutický pŕijatelné ketionty nebo organické báze, nebo pokud R*znamená H , potom R znamená sodík, draslík, imidazolovou skupinu, lysin, cholin, dietnylemin, arginin nebo histidin.Wherein R and K taken together are a bivalent ketone selected from the group consisting of calcium, ethylenediamine and other pharmaceutically acceptable ketones or organic bases, or, if R * is H, then R is sodium, potassium, imidazole, lysine, choline, dietnylemin , arginine or histidine.
Jak bude zrejmé z dále uvedených experimenLélních dat, jsou soli podie vynálezu, zejména pokud jsou dokonale vyčištény, za normálních okolních podmínek stebilními sloučeninami. Kromé toho, jak v prípade samotných solí, tak i v pŕípadé, kdy jsou tyto soli (v pevném stavu) součástí fermaceutické kompozice (tablet, piiulek, kapslí, lyofilizovaných kompozic a dalších kompozic) pripravené za účelem jejich terapeutickoho použití, zústávají uvedené soli stabilní i v prúbéhu nezbytné dlouhé časové periódy. Použití téchto solí v léčivech umožňuje vyloučit finančné nákladné ochranné metódy, které jsou jinak nezbytné nutné ze účelem skladování a transformace uvedené kyseliny do farmaceutických preparátu.As will be apparent from the experimental data set forth below, the salts of the present invention, especially when thoroughly purified, are stable compounds under normal ambient conditions. In addition, both in the case of the salts themselves and when these salts (in the solid state) form part of a pharmaceutical composition (tablets, pills, capsules, lyophilized compositions and other compositions) prepared for their therapeutic use, said salts remain stable in the iv state. during the necessary long period of time. The use of these salts in pharmaceuticals makes it possible to avoid the costly protective methods which are otherwise necessary for the storage and transformation of the acid into pharmaceutical preparations.
Podstatou príprav;/ sloučenin podie vynálezu je postup, který je charakterizován tím, že se sloučenina zvolená z množiny obsnhující kyselinu (+)-(lS,2R)-2-//N-(2-benzylhydroxylamino-2-oxoethyl)N-methy1-emino/karbonyl/cyklchexan-l kyrobylovou (2) a kyselinu (+)-(lS,2H)-2-//N-(2-hydroxylamino-2-oxoethyl)-N-methylamino/karbony1/cyklohexan-l-karbox.ylovou (1) uvede v reakci se sloučeninou, zvolenou z množiny obsahující hydráty, karbonáty a další vhodné soli alkalických kovu a kovú alkalických zemin, jak byly definovány v predchozí části popisu, jakož i organické báze, v organickém rozpouštédle nebo ve smésích organického rozpouštédla s vodou, pŕičemž pri použití počátečníhp produktu (2) probíhá současne s touto reakci hydrogenolýza ochrané benzylové skupiny vodíkem pri atmosferickém tlaku v prítomnosti vhodného hydrogenačního katalytického činidla, pŕičemž izolací požadované soli uvedené kyseliny je popsaný proces ukončen.The present invention provides a process which is characterized in that the compound is selected from the group consisting of (+) - (1S, 2R) -2- [N- (2-benzylhydroxylamino-2-oxoethyl) N-] acid. methyl-emino / carbonyl / cyclchexane-1-cyrobylic acid (2) and (+) - (1S, 2H) -2- [N- (2-hydroxylamino-2-oxoethyl) -N-methylamino] carbonyl] cyclohexane-1 -carboxyl (1) reacts with a compound selected from the group consisting of hydrates, carbonates and other suitable alkali metal and alkaline earth metal salts as defined above, as well as an organic base, in an organic solvent or in mixtures of an organic solvent with water, wherein, using the starting product (2), hydrogenolysis of the benzyl protecting group by hydrogen at atmospheric pressure in the presence of a suitable hydrogenation catalyst is carried out simultaneously with the reaction, and isolating the desired salt of said acid en.
Popsaný zpúsob prípravy podie vynálezu ilustruje následující reakční schémaThe process described above is illustrated by the following reaction scheme
COOHCOOH
kde Q. znamená uvedený hydroxid, súl alkalického kovu, vápenatou sul a nebo organickou bázi.wherein Q. represents said hydroxide, alkali metal salt, calcium salt and / or organic base.
Výhodným katsl.yzátorem ve výše uvedcném postupu je aktivní uhlí na pnllsdiovém nosiči, ale lze použít i PtC>2 , Rh/AlgO^ a Raneyúv nikl.A preferred catalyst in the above process is activated carbon on a supported carrier, but PtC2, Rh / AlgO4 and Raney nickel may also be used.
Jako organické rozpouštédlo lze použít propsnol, tetrahydrofurán nebo dioxan, pŕičemž výhodnými rozpouštédl.v jsou methanol a ethanol.Propsol, tetrahydrofuran or dioxane may be used as the organic solvent, with methanol and ethanol being the preferred solvents.
V následující časti popisu bude vynález blíže objasnén pomoci konkrétníc'n pŕíkladú jeho provedeni, pŕičemž tyto príklady mají pouze ilustrativní cnarakter a nikterek neomezují rozsah vynálezu, který je jednoznačné vymezen formulací patentových nárokú.In the following, the invention will be further elucidated by means of specific embodiments thereof, which examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.
Príklady provedeni vynálezuDETAILED DESCRIPTION OF THE INVENTION
Príklad 1Example 1
Vápenatá súl kyseliny (+)-(lS,2R)-2-//N-(2-hydroxylamino2-oxoethyl)-N-methyl-amino/karbonyl/cyklohexsn-l-karboxylové(+) - (1S, 2R) -2- [N- (2-hydroxylamino-2-oxoethyl) -N-methylamino] carbonyl / cyclohexene-1-carboxylic acid calcium salt
Do intenzívne míchané suspenze 15,2 g hydroxidu vápenatého ve vodé (152 ml) byl pod dusíkem pŕidán roztok 75 g kyseliny (+)-(lS,2R)-2-//N-(2-benzylhydroxylamino-2oxoethyl)N-methylamino/karbonyl/cyklohexan-l-karboxylové (2) rozpušténé v methenolu (1150 ml) a míchání této smesi probíhalo dalších 20 minút pod dusíkem pri teploté 20°C.To a vigorously stirred suspension of 15.2 g calcium hydroxide in water (152 mL) was added a solution of 75 g of (+) - (1S, 2R) -2- [N- (2-benzylhydroxylamino-2-oxoethyl) N-methylamino] under nitrogen. (carbonyl) cyclohexane-1-carboxylic acid (2) dissolved in methanol (1150 mL) was stirred under nitrogen at 20 ° C for a further 20 minutes.
Pŕidóním 15 g 1056 Pd na aktivním uhlí suspendovaného v 152 ml vody je vyvolána hydrogenace produktu pri teplote 20 °C s počátečním tlakem H2 0,1 MPa, která probíhá po dobu tŕí hodin.Addition of 15 g of 1056 Pd on activated carbon suspended in 152 ml of water induced hydrogenation of the product at 20 ° C with an initial H 2 pressure of 3 bar for three hours.
Po ukončení absorpce vodíku (byle sbsorbováno asi 5 000 ml) je katalyzátor odfiltrován e propláchnut smési vody a methanolu v pomeru 1:1 (300 ml) 9 z filtrátu, který byl pŕipojen k promývací fázi, byl. pod vakuem pri teplote 40 °C odstrsnén všechen methanol.After completion of the hydrogen uptake (about 5000 ml was absorbed), the catalyst is filtered off and rinsed with a 1: 1 mixture of water and methanol (300 ml) 9 from the filtrate which was connected to the wash phase. all methanol was stripped off under vacuum at 40 ° C.
K takto získané suspenzi byl dvakrát pŕidén methanol (200 ml), pričemž veškeré rozpouštôdlo bylo následné pod vakuem pri teplote 40 °C odstranéno.Methanol (200 ml) was added twice to the suspension thus obtained, and all solvent was then removed under vacuum at 40 ° C.
Finálni suspenze byla chlazena po dobu 20 hodin pri teploté 0 až 4 °C a sraženina byla odfiltrovaná s na filtru promyta 70 ml vody ochlazené na 0 až 4 cC.The final suspension was cooled for 20 hours at 0-4 DEG C. and the precipitate was filtered washed on the filter with 70 ml of water, cooled to 0-4 C C
Bylo získáno 55 g produktu (3) (výtéžek 85 %) ve forme pevného produktu, který mel zbarvení slonové kosti a následující fyzikálné-chemické vlastnosti:55 g of product (3) (85% yield) were obtained as a solid product having an ivory coloring and the following physicochemical properties:
teplota tání: vyšší než 250 0 M 2° = +35,3° (c=1,H20)melting point: greater than 250 ° M 2 ° = + 35.3 ° (c = 1, H 2 0)
0bs8h téžkých kovú<3O ppmHeavy metals <30 ppm
Sulfurický zbytek= 40,6% (vztaženo na získaný produkt)Sulfuric residue = 40,6% (based on product obtained)
Ca (EDTA) = 11,7%Ca (EDTA) = 11.7%
K.F. = 7,8%KF = 7,8%
Ethanol = 400 ppm Chromatografie na tenké vrstve:Ethanol = 400 ppm Thin layer chromatography:
Stacionárni fáze - silikagelové desky Merck F254 Mobilní fáze - h3u0H/Ac0H/H20 = 6/2/2 Jediná skvrna,Rf =0,7Stationary phase - silica gel plates Merck F254 Mobile phase - h3u0H / Ac0H / H 2 0 = 6/2/2 Single spot, Rf = 0,7
Vysokotlská kapalinová chromatografie :High performance liquid chromatography:
Nukleosilní sloupec C-^5 pm (250x4,6)Nucleosil column C- ^ 5 pm (250x4.6)
Eluční soustava CH.jCN/H3PO4 0,1% = 20/80Elution system CH.jCN / H 3 PO 4 0.1% = 20/80
Prútok 0,8 ml/minFlow rate 0.8 ml / min
Vlnová délka - 214 nmWavelength - 214 nm
Injekce 20 ml 0,01% roztoku CH^CN/Í^O (20/80) Chirální čistota produktu je stanovená vysokotlakou kapalinovou chroma tografi í na chirálním sloupci:Injection 20 ml of a 0.01% solution of CH 2 CN / I 2 O (20/80) The chiral purity of the product is determined by high pressure liquid chromatography on a chiral column:
chirální sloupec AGP eluční soustava CH^CN/puŕr pri pH = 4,1 = 1/99 prútok 0,7 ml/min vlnová délka = 214 nm injekce 20 μ 0,01% CH3CN/H2O roztoku (1/99) chemická Čistota:celkové množství nečistôt = 0,5% optická čistota>98%chiral column AGP elution system CH 2 CN / buffer at pH = 4.1 = 1/99 flow 0.7 ml / min wavelength = 214 nm injection 20 µ 0.01% CH 3 CN / H 2 O solution (1 / 99) chemical Purity: total impurity = 0,5% optical purity> 98%
Príklad 2Example 2
Vápenatá súl kyseliny (+)-(lS ,2R)-2-//N-(2-hydroxylaInino2-oxoethyl J-N-methylamino/karbonyl/cyklohexan-l-karboxylové g (+)-(lS,2R)-2-//N-(2-hydroxylamino-2-oxoethyl)N-meth.ylemino/karbonyl/cyklohexan-l-karboxylové kyseliny (1) se pridalo do suspenze 15,2 g hydroxidu vápenatého v 1 500 ml vody ze stáleho míchání e pod proudem dusíku, pŕičemž byle uvedená smés dále po dobu 60 minút pri teploté 20°C intenzivné míchána.(+) - (1S, 2R) -2- [N- (2-Hydroxylamino) -2-oxoethyl] -N-methylamino / carbonyl / cyclohexane-1-carboxylic acid calcium salt of (+) - (1S, 2R) -2-] (N) - (2-Hydroxylamino-2-oxoethyl) - N -methylemino/carbonyl/cyclohexane-1-carboxylic acid (1) was added to a suspension of 15.2 g of calcium hydroxide in 1500 ml of water while stirring under a stream. The mixture was further stirred for 60 minutes at 20 ° C.
Takto získaná ŕídká suspenze byla filtrovaná pŕes papírový filtr a uvedený filtrát byl zahuštén pod vakuem pri teplote 40°C na 200 ml.The slurry thus obtained was filtered through a paper filter and the filtrate was concentrated under vacuum at 40 ° C to 200 ml.
Potom,co byl vysrážený produkt chlazen po dobu 24 hodin pri teploté 0 až 4 °C, byl tento produkt filtrován a na filtru promyt 50 ml vody ochlazené na teplotu 0 až 4°C.After cooling the precipitated product for 24 hours at 0 to 4 ° C, the product was filtered and washed on the filter with 50 ml of water cooled to 0 to 4 ° C.
Bylo získáno 48,2 g produktu 3 (výtežek 84%) ve forme pevné látky se zbarvením slonové kosti, který mél následující vlastnosti:48.2 g of product 3 (84% yield) was obtained as an ivory-colored solid having the following characteristics:
teplota tání: vyšší než 250 °C [Κΐξθ = +34,8° (c=1,H20)Melting point: greater than 250 ° C [Κΐξθ = + 34.8 ° (c = 1, H 2 0)
Ca (EDTA) = 10,1% (vztaženo na získaný produkt)Ca (EDTA) = 10.1% (based on product obtained)
K.F. = 9,04% chromatografie na tenké vrstve:KF = 9.04% thin layer chromatography:
stacionárni fáze - silikagelové desky Merck F254 mobilní fáze - nBuOH/AcOH/^O = 6/2/2 jediná škvrna vysokotleká kapalinová chromatografie byla provedena za stejných podmínek jako v pŕedcházejícím príkladu 1. Chemická čistota: celkové nečistoty = 1,0%stationary phase - Merck silica gel plates F254 mobile phase - nBuOH / AcOH /? O = 6/2/2 single spot high pressure liquid chromatography was performed under the same conditions as in the previous example 1. Chemical purity: total impurities = 1.0%
Optická čistota > 98%Optical purity> 98%
Príklad 3Example 3
Sodná sôl kyseliny (+)-(lS,2R)-2-//N-(2-hydroxylamino-2oxoethyl)-N-methylamino/karbonyl/cyklohexen-l-karboxylové(+) - (1S, 2R) -2- [N- (2-hydroxylamino-2-oxoethyl) -N-methylamino] carbonyl / cyclohexene-1-carboxylic acid sodium salt
Do 7,6 g hydroxidu sodného rozpušténého v 95% ethenolu (1 050 ml) bylo pri teploté 20 °C za stálého míchání pŕidáno 70 g produktu (2).To 7.6 g of sodium hydroxide dissolved in 95% ethanol (1050 ml) was added 70 g of product (2) at 20 ° C with stirring.
Tento roztok byl pŕidán k 7 g 10% Pd na aktivním uhlí suspendovaném v 35 ml vody pod dusíkem a hydrogenován pri teploté 20°C a počátečním tlaku H2 0,1 MPa po dobu tŕí hodin.This solution was added to 7 g of 10% Pd on activated carbon suspended in 35 ml of water under nitrogen and hydrogenated at 20 ° C and an initial H 2 pressure of 1 bar for three hours.
Po ukončení adsorbce vodíku ( bylo absorbováno 4 850 ml) byl katalyzátor odfiltrován a promyt dvakrát 95% ethanolem (150 ml).After hydrogen adsorption was complete (4850 ml was absorbed), the catalyst was filtered off and washed twice with 95% ethanol (150 ml).
Filtrát byl pripojen k promývecí fázi a následné pod vakuem pri teploté 30°C odpsren ne malý objem. Získaný zbytek byl dvakrát doplnén 200 ml acetónu e opét zahuštén na malý objem, nečež byl produkt neŕedéný acetonem (200 ml) a vysrážený filtrován a promyt na filtru acetonem (100 ml).The filtrate was connected to the wash phase and subsequently dried to a small volume under vacuum at 30 ° C. The residue was taken up twice with 200 ml of acetone and concentrated again to a small volume before the product undiluted with acetone (200 ml) and precipitated by filtration and washed on the filter with acetone (100 ml).
Bylo získéno 56 g produktu (4) ve forme bílé hygroskopické pevné látky s následujícími fyzikálné-chemickými vlastnostmi :56 g of product (4) were obtained in the form of a white hygroscopic solid having the following physical-chemical properties:
l^D° = +26,0° (c=1,H20) obsah téžkých kovú 20 ppm sulfurický zbytek - 19% (vztaženo na získaný produkt) D = + 26.0 ° (c = 1, H 2 0) heavy metal content 20 ppm Sulfur residue - 19% (based on product obtained)
K .F. = 2,5% ethanol = 1,1% acetón = 5,8% chromatografie na tenké vrstve:K .F. = 2.5% ethanol = 1.1% acetone = 5.8% thin layer chromatography:
stacionárni fáze - silikagelové desky Merck F254 mobilní fáze-nSuOH/AcOH/í^O = 6/2/2 jediné škvrna R.f. = 0,7 vysokotleká kapalinová chromatografie: analytická a chirální chromatografie byla provedena za stejných podmínek jako u príkladu 1.stationary phase - Merck silica gel plates F254 mobile phase-nSuOH / AcOH / ^O = 6/2/2 single spot R.f. = 0.7 HPLC: analytical and chiral chromatography was performed under the same conditions as Example 1.
chemická Čistota:celkové nečistoty = 2,0 % optická čistota > 35%chemical purity: total impurities = 2.0% optical purity> 35%
Príklad 4Example 4
L-lysinová súl kyseliny (+)-(13,2R)-2-//N-(2-hydroxylamino-2-oxoeth.yl)-N-methylamino/karbonyl/c.yklohexan-l-karboxylové.(+) - (13,2R) -2- N - (2-Hydroxylamino-2-oxoethyl) -N-methylamino (carbonyl) -cyclohexane-1-carboxylic acid L-lysine salt.
Do roztoku produktu (2) v 95% ethanolu (725 ml) bylo za stélého míchání'pŕidáno 21 g lysinu rozpušténého ve vodé (38 ml).To a solution of the product (2) in 95% ethanol (725 mL) was added, with stirring, 21 g of lysine dissolved in water (38 mL).
Tento roztok byl pŕidán k 5 g 10% Pd na ektivním uhlí pod dusíkem a pri teplote 20 °C a počátečním tlaku 0,1 MPa byl hydrogenován po dobu 3 hodin.This solution was added to 5 g of 10% Pd on charcoal under nitrogen and hydrogenated for 3 hours at 20 ° C and an initial pressure of 1 bar.
Po spotŕebování teoretického množství vodíku (bylo ebsorbovéno 3600 ml H^) byl katalyzátor filtrován pŕes papírový filtr a následné dvakrát na tomto filtru promyt bezvodým ethanolem (150 ml).After the theoretical amount of hydrogen had been consumed (3600 ml of H ^ was absorbed), the catalyst was filtered through a paper filter and washed twice with anhydrous ethanol (150 ml) on the filter.
Získaný filtrát byl pŕipojen k promývací fázi a následné pod vakuem pri teploté 30°C zanuštén do sucha a tento zbytek byl dvakrát doplnen. 200 ml acetónu, načež byly pod vakuem odstránený všechny tékavé složky.The resulting filtrate was connected to the wash phase and subsequently dried under vacuum at 30 ° C to dryness and the residue was refilled twice. 200 ml of acetone, after which all volatiles were removed under vacuum.
K výslednému zbytku bylo opet pŕidáno 200 ml acetónu, uvedený zbytek byl filtrován a ne filtru promyt 100 ml acetónu.Again, 200 ml of acetone was added to the resulting residue, which residue was filtered and not washed with 100 ml of acetone.
Bylo získéno 49 g produktu (5) ve formé hygroskopické pevné látky.49 g of product (5) were obtained as a hygroscopic solid.
Vysokotlaká kapalinová chromatografie byla provedena za podmínek použitých v príkladu 1 : nečistoty tvorí 4 % získaného produktuHigh pressure liquid chromatography was carried out under the conditions used in Example 1: impurities represented 4% of the obtained product
Príklad 5Example 5
Dreselná súl kyseliny (+)-(lS,2R)-2-//N-(2-nydroxylamino2-oxoethyl)-N-methylamino/kerbonyl/cyklohexan-1- karboxylové(+) - (1S, 2R) -2- [N- (2-Nydroxylamino-2-oxoethyl) -N-methylamino] carbonyl / cyclohexane-1-carboxylic acid jersey
Následuje stejný postup jako v príkladu 4 s použitím príslušných reakčních látek odpovídajících príkladu 5, pŕičemž byla získára vysoce hygroskopická bílá pevné látke s následujícími fyzikálné-chemickými vlastnostmi: Chromatogrefie na tenké vrstvé: silikagelové deok.y Merck F254 mobilní fázenSuOH/AcCH/K-O = 6/2/2 jediná škvrne,R.ľ. = 0,7Following the same procedure as in Example 4, using the appropriate reagents corresponding to Example 5, a highly hygroscopic white solid was obtained with the following physicochemical properties: Thin Layer Chromatography: Merck F254 silica gel mobile phaseSuOH / AcCH / KO = 6 / 2/2 single stain, R.ľ. = 0.7
Vysokotlaké kapalinová chromatograrie: analytická a chirélní chromatografie byla provedena za podmínek použitých v príkladu 1.High pressure liquid chromatography: analytical and chiral chromatography was carried out under the conditions used in Example 1.
Chemická čistota:celkové nečistoty = 4,0 %Chemical purity: total impurities = 4.0%
Optické čistota j>90%Optical purity j> 90%
Príklad 6Example 6
Imidazolová súl kyseliny ( + )- (13,2R)-2-//N- (2-hydrox.ylami no-2-oxoe thyl) -ľí-me thylamino/karbonyl/cyklohexan-l-korboxylové(+) - (13,2R) -2- [N- (2-Hydroxylamino-2-oxoethyl) -1H-thylamino / carbonyl] cyclohexane-1-carboxylic acid imidazole salt
Následuje stejný postup jako v príkladu 4 s použitím príslušných reakčních látek odpovídajících príkladu 6, pŕičemž byl získán hygroskopický pr.yskvŕičný produkt.Following the same procedure as in Example 4, using the appropriate reagents corresponding to Example 6, a hygroscopic glazing product was obtained.
Vysokotlaká kapalynová chromatografie byla provedena za podmínek použitých v príkladu 1: nečistoty tvorí 10 % získaného produktu.High pressure liquid chromatography was carried out under the conditions used in Example 1: impurities constituted 10% of the product obtained.
Uvedená sloučenina (1) a sloučeniny príkladu 1 a 3 byly získány ve formé pevné látky a tety ve fáme vážitelré a charakterizovatelné z fyzikálního hlediska. U téchto látek byla testována relatívni stabilita na vzduohu pri teploté 60 °C podie následujícího postupu.Said compound (1) and the compounds of Examples 1 and 3 were obtained in the form of a solid and aunt in a phase which is physically acceptable and characterized. These materials were tested for relative air stability at 60 ° C according to the following procedure.
Do termostatické sušárny vyhráte na 60 °Č jsou na pŕedem stanovenou dobu umístény 2 g uvedené látky, načež je pomoci vysokotlaké kapolinové chromatografie provedena analýza jak čistoty uvedené látky tak obsah možných nečistôt. Zaŕizeni: Multirozpouštôdlový nepájecí systém Woters600E leditelný ebsorbanční detektor Waters484 nástŕiková smyčkn 20 jiIn a thermostatic oven at 60 ° C, 2 g of the substance are placed for a predetermined period of time, and then the purity of the substance and the content of possible impurities are analyzed by means of HPLC. Equipment: Woters600E Multi-solvent Solder System Wettable Loop Detector Waters484 20 Loop
Data- modul Integra Lo V/aters 745Data module Integra Lo V / aters 745
Nukleosilní sloupec Clg 5 ja (250 x 4,6) mobilní fáze CH^CN/H-jK^ 0,01% (20/80) prutok 0,9 ml/minColumn Nucleosil C 5 and g (250 * 4.6) mobile phase CH? CN / H ^ jk 0.01% (20/80) Flow 0.9 ml / min
Detektor: vlnová délka = 214 nmDetector: wavelength = 214 nm
Príprava vzorku: ve 100 ml H^O/CH^CN (80/20) se rozpustí 20 mg testované látky 20 μ injekceSample preparation: dissolve 20 mg of the test substance in 20 ml of H ^ O / CH ^ CN (80/20) 20 μ injection
Retenční čas za téchto podmínek je 7,9 min.The retention time under these conditions is 7.9 min.
V tabulce 1 jsou zaznamenány výsledky výše uvedených testňTable 1 shows the results of the above tests
II
TabulkeTable
—-ar>í p—->> p
o·about·
PP
H W <3 -H <0 xj. l Φ (0 C O .H W <3 -H <0 xj. l Φ (0 ° C.
Ό (0 r-4 34 Ή >p XJ (ú0 (0 r-4 34 Ή> p XJ)
ÄÄ
PP
OABOUT
PP
Oi •HOi • H
mininmininininininm ooooooooooomininmininininininm ooooooooooooo
inmoo'í’íco^rooo^· OOr->CM(Q(0OOO o co co o p oinmoo'í’co ^ rooo ^ · OOr-> CM (Q (0OOO o what o o o)
C\J Tí σι <o * * * * ro <o (O n <o <n oo o p* ’í OIOIOIOICDOIOOOO oi to tí p~ oj oo <o σι o tíC \ J T o o * o * o * o (o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o o
JZ X £ £ σι tí oo .. σι 3 pJZ X £ £ σι t oo oo σι 3 p
3ä φ3ä φ
oabout
N >N>
>5> 5
CC
Φ >Φ>
BJ pBJ p
NN
OABOUT
- 14 Uvedené soli podie vynálezu, pokud jsou použitý ve vhodném dávkovacím poméru, jsou prakticky srovnatelné jak potencíj tak délkou trvaní účinku s uvedenou kyselinou (1)·Said salts according to the invention, when used in a suitable dosage ratio, are practically comparable in terms of both potency and duration of action to said acid (1).
Tato farmakologická ekvivalence byla experimentálné demonštrovaná srovnáním kyseliny (1) s vápenatou solí z príkladu 1, a je prokázéna experimentálními výsledky uvedenými v následující tsbulce 2This pharmacological equivalence has been experimentally demonstrated by comparing acid (1) with the calcium salt of Example 1, and is demonstrated by the experimental results presented in the following Table 2.
Tabulka 2Table 2
Soli podie vynálezu tvorí účinné látky pro prípravu farmaceutických kompozic vhodných pro perorální a parenterální použití.The salts of the invention form the active ingredients for the preparation of pharmaceutical compositions suitable for oral and parenteral use.
Takové kompozice a prípravky se ziskávejí za použití velmi dobre známých farmaceutickým technik za použitíSuch compositions and preparations are obtained using well known pharmaceutical techniques using
- 15 vhodných pomocných látek, nosičú e rozpouštédel.- 15 suitable excipients, solvent carriers.
Pokud jde o peroŕální podaní, používá se dávek 25 ažFor oral administration, doses of 25 to 25 are used
150 mg/den, zatímco v prípade parenterélního podání se po užívají dávky 2,5 až 25 mg/den.150 mg / day, while for parenteral administration doses of 2.5 to 25 mg / day are used.
Claims (10)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI913448A IT1252708B (en) | 1991-12-23 | 1991-12-23 | STABLE SALTS OF (+) - (1R, 2S) -2 ((N- (2-HYDROXYLAMINE-2-OSSOETHL) -N-METHYLAMINE) CARBONYL) CYCLOHEXAN-1-CARBOXYL, ACE INHIBITIVE ACTIVITY, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. |
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| Publication Number | Publication Date |
|---|---|
| SK379692A3 true SK379692A3 (en) | 1995-04-12 |
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|---|---|---|---|
| SK3796-92A SK379692A3 (en) | 1991-12-23 | 1992-12-21 | Stable salts of (+)-(1s,2r)-2-//n-(2-hydroxylamino-2- -oxoethyl)-n-methyl-amino/carbonyl/cyclohexan-1-carboxylic acid, method of their preparation and pharmaceutical agents containing these salts |
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| Country | Link |
|---|---|
| EP (1) | EP0575572A1 (en) |
| JP (1) | JPH06506002A (en) |
| CN (1) | CN1079474A (en) |
| AU (1) | AU657591B2 (en) |
| BG (1) | BG98050A (en) |
| BR (1) | BR9205652A (en) |
| CA (1) | CA2104372A1 (en) |
| CZ (1) | CZ379692A3 (en) |
| EE (1) | EE9400006A (en) |
| FI (1) | FI933685A (en) |
| HR (1) | HRP921454A2 (en) |
| HU (1) | HUT69287A (en) |
| IT (1) | IT1252708B (en) |
| LV (1) | LV10426B (en) |
| MA (1) | MA22749A1 (en) |
| MX (1) | MX9207543A (en) |
| NZ (1) | NZ245547A (en) |
| PL (1) | PL169086B1 (en) |
| PT (1) | PT101156A (en) |
| RU (1) | RU2079489C1 (en) |
| SI (1) | SI9200409A (en) |
| SK (1) | SK379692A3 (en) |
| TN (1) | TNSN92117A1 (en) |
| WO (1) | WO1993013056A1 (en) |
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| IT1264860B1 (en) * | 1993-06-21 | 1996-10-17 | Guidotti & C Spa Labor | DERIVATIVES OF CIS- AND TRANS-2(((2-(HYDROXYAMINO)-2-OXOETHYL)- ALKYLAMINO)CARBONYL)CYCLOHEXINECARBOXYLIC ACIDS |
| US5639746A (en) * | 1994-12-29 | 1997-06-17 | The Procter & Gamble Company | Hydroxamic acid-containing inhibitors of matrix metalloproteases |
| FR2817241B1 (en) | 2000-11-30 | 2003-03-07 | Cebal | ALUMINUM TUBE WITH SPLITABLE END |
| JP2010504969A (en) * | 2006-09-28 | 2010-02-18 | メルク エンド カムパニー インコーポレーテッド | SAHA amine base salts and polymorphs thereof |
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-
1991
- 1991-12-23 IT ITMI913448A patent/IT1252708B/en active IP Right Grant
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1992
- 1992-12-12 CA CA002104372A patent/CA2104372A1/en not_active Abandoned
- 1992-12-12 EP EP92924726A patent/EP0575572A1/en not_active Withdrawn
- 1992-12-12 RU RU9293052414A patent/RU2079489C1/en active
- 1992-12-12 BR BR9205652A patent/BR9205652A/en not_active Application Discontinuation
- 1992-12-12 JP JP5511398A patent/JPH06506002A/en active Pending
- 1992-12-12 WO PCT/EP1992/002903 patent/WO1993013056A1/en not_active Application Discontinuation
- 1992-12-12 HU HU9302389A patent/HUT69287A/en unknown
- 1992-12-12 AU AU30871/92A patent/AU657591B2/en not_active Ceased
- 1992-12-21 NZ NZ245547A patent/NZ245547A/en unknown
- 1992-12-21 SK SK3796-92A patent/SK379692A3/en unknown
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- 1992-12-22 MA MA23040A patent/MA22749A1/en unknown
- 1992-12-22 HR HR921454A patent/HRP921454A2/en not_active Application Discontinuation
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- 1992-12-23 PL PL92297118A patent/PL169086B1/en unknown
- 1992-12-23 YU YU110892A patent/YU110892A/en unknown
- 1992-12-23 ZA ZA9210004A patent/ZA9210004B/en unknown
- 1992-12-23 CN CN92113839A patent/CN1079474A/en active Pending
- 1992-12-23 MX MX9207543A patent/MX9207543A/en unknown
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- 1992-12-23 TN TNTNSN92117A patent/TNSN92117A1/en unknown
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1993
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Also Published As
| Publication number | Publication date |
|---|---|
| WO1993013056A1 (en) | 1993-07-08 |
| HRP921454A2 (en) | 1995-02-28 |
| BR9205652A (en) | 1994-05-03 |
| CN1079474A (en) | 1993-12-15 |
| LV10426B (en) | 1995-08-20 |
| MA22749A1 (en) | 1993-07-01 |
| EP0575572A1 (en) | 1993-12-29 |
| EE9400006A (en) | 1995-12-15 |
| FI933685A0 (en) | 1993-08-20 |
| AU3087192A (en) | 1993-07-28 |
| IT1252708B (en) | 1995-06-26 |
| RU2079489C1 (en) | 1997-05-20 |
| ITMI913448A0 (en) | 1991-12-23 |
| ZA9210004B (en) | 1993-12-13 |
| PT101156A (en) | 1994-06-30 |
| LV10426A (en) | 1995-02-20 |
| MX9207543A (en) | 1993-08-01 |
| FI933685A (en) | 1993-08-20 |
| YU110892A (en) | 1996-01-08 |
| CA2104372A1 (en) | 1993-06-24 |
| BG98050A (en) | 1994-04-29 |
| HUT69287A (en) | 1995-09-28 |
| NZ245547A (en) | 1995-12-21 |
| ITMI913448A1 (en) | 1993-06-23 |
| PL297118A1 (en) | 1993-09-06 |
| AU657591B2 (en) | 1995-03-16 |
| CZ379692A3 (en) | 1993-09-15 |
| JPH06506002A (en) | 1994-07-07 |
| TNSN92117A1 (en) | 1993-06-08 |
| SI9200409A (en) | 1993-09-30 |
| HU9302389D0 (en) | 1993-11-29 |
| PL169086B1 (en) | 1996-05-31 |
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