BG98050A - Salts resistant to (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino] carbonyl] cyclohexane-1-carbonic acid, method for their preparation and pharmaceutical compositions containing them - Google Patents
Salts resistant to (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino] carbonyl] cyclohexane-1-carbonic acid, method for their preparation and pharmaceutical compositions containing them Download PDFInfo
- Publication number
- BG98050A BG98050A BG98050A BG9805093A BG98050A BG 98050 A BG98050 A BG 98050A BG 98050 A BG98050 A BG 98050A BG 9805093 A BG9805093 A BG 9805093A BG 98050 A BG98050 A BG 98050A
- Authority
- BG
- Bulgaria
- Prior art keywords
- salts
- oxoethyl
- cyclohexane
- carboxylic acid
- carbonyl
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
- C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
- C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Landscapes
- Organic Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Peptides Or Proteins (AREA)
Abstract
Солите на (+)-(1s,2r)-2-[[n-(2-хидроксиламино-2-оксоетил)-n-метил-амин о]карбонил]циклохексан-1-карбонова киселина с метали и органични основи имат асе-инхибиращо действие и са полезни като активни съставки в антихипертонични лекарства. Имат обща формула в която r и r', взети заедно, представляват двувалентен катион, избран от калций, етилендиамин и други фармацевтично приемливи катиони или органични основи, а когато r' = н+, r представлява натрий, калий, имидазолова група, лизин, холин, диетаноламин, аргинин или хистидин. Получават се при реакция на изходната киселина, защитена с бензилова група, с подходящ хидрат, карбонат или органична основа в условия на хидрогениране в присъствието на катализатор за хидрогениране. 10 претенцииThe salts of (+) - (1S, 2R) -2 - [[N- (2-hydroxyamino-2-oxoethyl) -methanamine] carbonyl] cyclohexane-1 -carboxylic acid with metals and organic bases -inhibiting action and are useful as active ingredients in antihypertensive drugs. Have the general formula wherein r and r 'taken together represent a divalent cation selected from calcium, ethylenediamine and other pharmaceutically acceptable cations or organic bases and when r' = n +, r represents sodium, potassium, imidazole, lysine, choline, diethanolamine, arginine or histidine. They are obtained by reacting the benzyl-protected starting acid with a suitable hydrate, carbonate or organic base under hydrogenation conditions in the presence of a hydrogenation catalyst. 10 claims
Description
Настоялото ивобретеиие се отнася до довя сояи яа (*)-(1S,2R)-2-[|м-(2-хикроксижа>ап1о-2-охсоот)*Н-меткя-»миио карбояия цикяохексаи-1-карбонова кисенииа е мотах и оргажмяжх основи, имаци хидертонмчно действие, метода ва тяхното пояучаваие н ивпожвуваието им във фармацевтични проивведеиня, като от овцата формужа (I) споменатите сожн са представениThe present invention relates to the addition of soya ia (*) - (1S, 2R) -2- [| m- (2-hydroxyl> apo-2-oxoate) * N-methyl-carboxylic acid cyclohexa-1-carboxylic acid e moto and cut off the basics, having a hypertonic effect, the method of their appearance and their enjoyment in pharmaceutical science, with the formula (I) mentioned by the sheep mentioned
R R» ** където R и R*, ако са booth ваодие, представяният двуванантан нагнои, набран от каяци·, етижея джамия, и други фармацевтично прнем•ивн катионк нжя органични основи, ияи, ако R* · н*, R предстанжява натриева, хажнева, нмидавожова група, живия, хожнк, диетнжамнн, аршини, хистидии. (♦)-(18,2Я)-2-([м-(2-хидрокскяамнио-2-охсоотия)-Иметяя-амт01 карвони|цикжохоксая-1-карбояова кисежияа 1, (D.C.I.RR »** where R and R *, if they are booth vaodi, the represented dvuhanthane suppositories recruited from kayaks, mosque etiquette, and other pharmaceutically acceptable organic bases, if, if R * · n *, R precedes sodium , Khazhnev, Nmivozhiv group, live, Khozhn, diet, arshine, histidy. (♦) - (18,2J) -2 - ([m- (2-hydroxyamino-2-oxoethiol) -imethoxy-am01 carvoni | cyclohexane-1-carboxylic acid 1, (D.C.I.
Idraprll) е съединение, описано в ВвропеЖсха патентна заявка*W106304.2 • · · · като Аб>*юхибжтереи агент и следователно притежаван аитихипорто янчна аитжвяост.Idraprll) is a compound disclosed in the European Patent Application * W106304.2 as an OU * jubbterial agent, and therefore possesses aichiporticosity.
Tan кнсоиииа, жегата · наложена ва влиянието на въздуха жря яармаяня усяовжя на вяажяост н температура на ваобихаяяната среда, е предмет на процеси ва саморавяагаио, което увоничаза примесите, и което на свой род е несъвместимо с терапевтичното изпоязуваие. Такива процеси на разграждано се ускоряват сме при понижавано на температурата ка киселината, поддържана при споменатите по-горе условия*Tan ksoiiaia, the heat caused by the air of the yaramayanya devouring the vjajayäjä and the temperature of the vaobihaäya environment, is the subject of processes of self-rajayahai that dislodge impurities and which is, in a way, incompatible with therapeutic absorption. Such degradation processes are accelerated at a lower temperature than the acid maintained under the above conditions *
Сега бе открито и това е основната цол на настоялото изобретение, че новите сени съгласно изобретението, както са опродовеии по-горе, но преминават през процесите на саморазяагаио и разпадане, споменати по-гора.It has now been discovered, and it is a major object of the present invention, that the new shadows according to the invention, like the proclamations above, but undergo the processes of self-scattering and decay mentioned above.
Както мехе да се вади от посочените по-долу ехспориментании данни содите съгласно настоялото изобретение, особено когато се съвърноняо прочистени, са устойчиви съединения при нормални условия иа ваобикаляжата среда. По-иататък, сените остават непроменени с течение на времето, независимо дали се съхраняват като такива ияи са вкяжчеии (в твърдо състояние) въз фармацевтичен препарат (таблети, прахове, капсули, диофиякзираяи състави и подобия) предназначени за тяхното терапевтично използуване. Използуването иа този cohi в лекарства позволява да се избегнат скъпо стрували предпазни метили, необходими в друг случай, за съхранявано ка гореспоменатата киселина и трансформирането й във фармацевтични препарати.As the bag is to be extracted from the data below, the sodas of the present invention, especially when thoroughly purified, are stable compounds under normal conditions and in the surrounding environment. Furthermore, the haystack remains unchanged over time, whether stored as such and is a solid (in solid) form on a pharmaceutical preparation (tablets, powders, capsules, diophysics and similarities) intended for their therapeutic use. The use of this cohi in medicines makes it possible to avoid the expensive costly methyls needed in the other case for storing the aforementioned acid and transforming it into pharmaceuticals.
Получаването иа съединенията съгласно настолното изобретение е базирано на метод, характеризиран C0zj «ва, че иа съединение, избрано между (+)-(1S,2J()-2-f [к-(2-(2-вф1Ц|^-хмдроксиамино-2-оксоβτηβ)-Ν-μοτμη-βμηηο]карбонил]циклохексам-1-карболова киселина 2 и (+)-(18,2R)-2-[(W-(2-хкдрохсиламино-2-охсоотия)-И-мотиламии^карбеинц}шжлохожсаи-1-карболова киселина 1, сс взаимодойствува със съединение, избрано между хидрати и карбонати ияи други подходящ соли на аииаянн и миаяо-воми мотали, както е определено в настоявето изобретение, както и е органични основи, в органичен разтворител или негови смеси с вода,като се извърнва реакция, в случая с изходен продукт 2, едновременна хидрогояаинва на зенитната бонзиова група е водород при атмосферно наляган^ в ндеъетвнвто иаThe preparation of ia compounds according to the present invention is based on a method characterized by C0zj3aa that a compound selected from (+) - (1S, 2J () - 2-f [k- (2- (2-bnC 1 H -hydroxyamino) -2-oxoβτηβ) -Ν-μοτμη-βμηηο] carbonyl] cyclohexam-1-carboxylic acid 2 and (+) - (18,2R) -2 - [(W- (2-hydroxysilamino-2-oxoothio)) -I- 1-carboxylic acid 1-copolymer interacts with a compound selected from hydrates and carbonates and other suitable salts of ayaiyan and miayao motifs as defined in the present invention, and is an organic base in organic solvent or mixtures thereof with water, by reaction, in the case of starting product 2, the simultaneous hydrocarbons of the zenith bonsium group are hydrogen at atmospheric pressure
• ·• ·
• · • · · · където Q · споменатата основа, иян ажмама сол иян калциева соя яжя органична основа. При метода, както е дефиниран по-горе, предпочнтаинят хндрогенираи катализатор е паяаднй-на-въгжм,ио може см» така да ее използуват ?tO2,Rh/Al2Oj м Nl/Raney (радейликов). Яо се отнася до органкчният разтворител пропаиол, тетрвхкдрофурая я диоксан са съжо подходяин, наред е метанол и етанол.Where Q · said base, yian azhama salt salt jiang calcium soybean meal organic base. In the method as defined above, the preferred hydrogenated catalyst is a solder-on-carbon catalyst, which can be used to use tO 2 , Rh / Al 2 Oj m Nl / Raney. Yao refers to the organic solvent propiol, tetrahydrofuran dioxane are also suitable, methanol and ethanol, respectively.
Сяодважнто примери, която само поясняват, но яе ограничават обхвата яа изобретението, обясняват конкретни аспекти я хнмикофкзкчосхито свойства яа съединенията съгласно настоящото изобретения.Only examples which merely clarify but limit the scope of the invention will explain specific aspects of the chemical properties of the compounds according to the present invention.
ПРИМВР 1 (♦) - (1S, 2R) -2-Ц N- (2-*идрокеияампо- 2-охсоотяя) -N-мотия-амияо} Q кабМгаяДцихяохохсаи-1-карбоиова киселина - калциева сояEXAMPLE 1 (♦) - (1S, 2R) -2-C N- (2- * hydroxyamino-2-oxoacetate) -N-mothia-ammio} Q cabbage-cyclohexa-1-carboxylic acid - calcium soybean
Към енергийно разбърквана суспензия от 15.2 г. калциев хидроокис във вода (152 мж) се прибавя под азот разтвор яа 7S г. (♦)-(1S,2R)-2 -Цм-боязияхидроксиамияо-2 -океоетия) Н -метиламин©] карбояия)цикнохексах-1-карбонова киселина 2, разтворена в метаяож (1150 ми) и разбъркването продължава 20 минути в азотна атмосфера при температура 20°С.To a stirred slurry of 15.2 g, calcium hydroxide in water (152 m) was added under nitrogen a solution of 7S g. (♦) - (1S, 2R) -2-Cm-dye-hydroxyamio-2-oxoethyl) N-methylamine ©] carboxylic acid) cyclohexax-1-carboxylic acid 2 dissolved in methanol (1150 mi) and stirring was continued for 20 minutes in a nitrogen atmosphere at 20 ° C.
Сяед прибавяне жа 15 г. 105 Pd/въглед, суспендирай вSayyad added 15 g 105 Pd / view, suspend at
152 мж. вода, се осъиествява хидрогениране на продукта при 20°С е първоначално Н2 налягане 1 атмосфера.152 m. water, hydrogenation of the product is carried out at 20 ° C is initially H 2 pressure 1 atmosphere.
Сяед като се преустанови абсорбираното иа водорода (окожо 5000 мл се абсорбират), катализатора се филтрира и ивмива с яж смес от вода/метакол (1/1) (300 мж) я филтрата, комбиниран с промивките, се концентрира под вакуум п^г ПС, докато се отстрани метанояа изцяло.After discontinuing the absorbed hydrogen (about 5000 ml were absorbed), the catalyst was filtered and washed with water with a mixture of water / methanol (1/1) (300 m), the filtrate combined with the washes was concentrated in vacuo. P C until the methane is completely removed.
Така получената суспоявия се третира два пъти с 200 яж метанол, като сяед това, все one под вакуум п,р 40°С, се отстранява изцяло разтворителят.The resulting slurry was then treated twice with 200 ml of methanol, whereby the solvent was removed completely under vacuum n, p 40 ° C.
Крайната суспензия се охлажда в продъжхеяяе иа 20 часа при 0-4°С и утайката се филтрира и ивмива жа филтър със 70 мл предварително охладена вода пря 0-4°С.The final suspension was cooled for 20 hours at 0-4 ° C and the precipitate was filtered off and washed with 70 ml of pre-cooled water at 0-4 ° C.
Получават се 55 г. (3) (добив 151) като твърдо веаюство е цвят на слонова кост, имано еяодиито химико-физически харантерИСТИХЯ!55 years (3) (yield 151) are obtained as a solid ivory, ivory having a chemical-physical guarantee.
• ·• ·
Точка на топене> 250®с · ♦ 35.3® (с - 1, Н2О)Melting point> 250®C · 35.3® (c - 1, H 2 O)
Тежки мотани 30 мижионин частиHeavy motan 30 mijinin parts
Сараи останки 40.61 ( върху така пожучоинж продукт)Sheds remnants 40.61 (on such a yummy product)
Са (ВОТА) - 11.71Ca (VOTE) - 11.71
I.F. · 7.81 **ttoai 400 мнаиоми части.I.F. · 7.81 ** ttoai 400 pieces.
TLC (Тъжко-сжоНжа хроматографнж):TLC (Hard-chromatography):
Стадионариа Фаза Merck F254 сижихагож ласкиThe Merck F254 Stage is a sitting caress
ПодвВжжа фава nBuOH/AcOH/H2O 5/2/2Fava nBuOH / AcOH / H 2 O 5/2/2
Уиитарно потно при Rf · 0.7Vital sweat at Rf · 0.7
НМХ (’ВфеиДОЬа точка. хроматографкяН <»*-)*NMX ('Vfeid point. Chromatograph <* * -) *
- i *- i *
Нукжоозиж хожожа C^jS у (250 х 4.5)Nozzozhizh of the C ^ jS j (250 x 4.5)
В1ЖОИТ CHjCN/HjPO* 0.11 » 20/,80 Скорост иа потока 0.8 мж/мик.CH1CIT CHjCN / HjPO * 0.11 »20 /, 80 Flow rate 0.8 mJ / mic.
Двжжнка иа мъжката - 214 пи.The whisker and the male - 214 pi.
Иккектираке иа 20 мл. 0.011 разтвор « 20/80Iksektirake ia 20 ml. 0.011 solution «20/80
Хиралиа чистота иа продукта се опредмя чрез HPLC иа хиралиа козова: Тмрджиа у>ятца АПРChiralia purity is determined by HPLC and chiralia goat:
Вввзнт CBjCN/Оуфер при pH · 4.1 * 1/99CBjCN / Offer at pH · 4.1 * 1/99
Поток 0.7 мж/мии.Flow 0.7 mJ / mi.
Движиха иа ваяната «214 па №шоктираие 20 у 0.011 CHjCN/H2O разтвор · 1/99The motors were stirred in a 0.011 CHjCN / H 2 O solution · 1/99
Химическа чистота: обвю примеси « 0.51Chemical purity: impurity blend «0.51
Оптична чистота > 981 (♦)·(1S,2R)-[Гм-(2-Скдрокскиамнио-2-оксоотия)-М-мстиЖймюму харбоняж|цккжохохеан-1-карбоиова кисояика - каянима сояOptical Purity> 981 (♦) · (1S, 2R) - [Hm- (2-Skrokkiamnio-2-oxoothio) -M-vmJjummu Harbonage | ckjohochean-1-carboxylic soybean
Към суспензия от 15.2 г. кажциов хидроокис в 1500 мж. вода, при енергично разбърквано и азотен поток, са прибавят 50 г. (♦)-(1S,2R)-j ^-(2-хидрокснжамнио-2-оксоетил)-К«метинамино| * карбониж|цихяохоксан-1-карбонова киселмиа 1 и сместа продължава да се разбърква енергично око 60 минути при температура 20°С.To a suspension of 15.2 g each hydroxide in 1500 m. of water, with vigorous stirring and nitrogen flow, were added 50 g. (♦) - (1S, 2R) -J ^ - (2-hydroxyamino-2-oxoethyl) -N 'methinoamino | * carbonyl | cihaoxane-1-carboxylic acid 1 and the mixture was continued stirring vigorously for 60 minutes at 20 ° C.
• · • ·· ·• · · · ·
Така пояучената светва суспвквия се филтрира (върху хартия) я филтрата е· концентрира под вакуум при 40°С до 200 мж.The resulting flask was filtered (on paper) and the filtrate was concentrated in vacuo at 40 ° C to 200 m.
Сжод охлаждаже пои» 0-4°C в продъжжоиио жа 24 часа, утаожижт продукт са филтрира и измива жа филтър е S0 мж. от предварително охладена вода до С-4°С.Sozh cooled poi »0-4 ° C for 24 hours, the product was filtered off and the filter was washed with S0 mJ. from pre-cooled water to C-4 ° C.
Получават са 48.2 г. от съединение 3 (добив 841) като твърдо вшоства с цвят на слонова кост, имажо следните характеристики: Точка жа топене 250®С48.2 g of compound 3 (yield 841) were obtained as a solid ivory-colored solid having the following characteristics: Melting point 250®C
Са (ВОТА) « Г .. > (за така получения продукт)Ca (VOTA) «D ..> (for the product thus obtained)
K.F. « ?.О4 IK.F. «? .O4 I
ILC (Тънкослойна хроматография):ILC (Thin Layer Chromatography):
Стационарна фаза Merck F2S4 плаки силикагелStationary phase Merck F2S4 silica gel plates
Подвижна фаза nBuOH/AcOH/HjO* 6/2/2Mobile phase nBuOH / AcOH / HjO * 6/2/2
Хнитарно петноStool spot
HPLC (Вфектязха течна хроматография):HPLC (Liquid Chromatography):
Аналитична я хнражжа хроматография се извършват съгласно условията, посочени в пример 1.Analytical culture chromatography was performed according to the conditions indicated in Example 1.
Химическа чистота: общо примеси «1.01 Оптична чистота: >881Chemical purity: total impurities «1.01 Optical purity:> 881
ПРИМЕР S (♦) - (1S, 2R) - 2-|_ £ν· (2-хидрохсиламяяо- 2-оксоетяя) -N-метияамино^карeoHHxj цикяохексан-1-карбонова киселина - натриева сояEXAMPLE S (♦) - (1S, 2R) -2- (2-hydroxylamino-2-oxoethyl) -N-methylamino-carboxylic acid cyclohexane-1-carboxylic acid - sodium soy
г. от съединение 2 се прибавят, при 20*С с разбъркване, към 7.6 г. натриева основа, равтФореиа в 951 отаиож (10S0 мл).of compound 2 was added, at 20 * C with stirring, to 7.6 g of sodium hydroxide solution in 951 volumes (10S0 ml).
Към този разтвор се прибави 7 г. 101 Pd/въгпен суспендиран в 3S мл вода в азот н се хидрогеяира при 20°С е първоначално Н2 налягане 1 атмосфера, в продължение иа 3 часа.To this solution was added 7 g. 101 Pd / charcoal suspended in 3S ml of water in nitrogen and hydrogenated at 20 ° C was initially H 2 pressure 1 atmosphere for 3 hours.
Веднага сяед като престане абсорбираното иа водород (4850 мл се абсорбират), катализатора се филтрира и измива дуе пъти с 951 етанол (150 мж).Immediately after stopping absorption of hydrogen (4850 ml were absorbed), the catalyst was filtered off and washed twice with 951 ethanol (150 mg).
Филтрата се комбинира с промивките и се ивпарява под вакуум при 30°С до малък обем. Към утайката се добавя два пъти 200 мя ацетон и отново се концентрира до малък обем, сяед което се разрежда с ацетон (200 мж> и утаеният продукт се филтрира и измива яз филтър с ацетон (100 мж).The filtrate was combined with the washes and evaporated in vacuo at 30 ° C to low volume. 200 mg of acetone were added to the precipitate twice and concentrated again to a small volume, which was diluted with acetone (200 m> and the precipitated product was filtered and washed with a filter of acetone (100 m).
Claims (8)
Applications Claiming Priority (2)
| 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. |
| PCT/EP1992/002903 WO1993013056A1 (en) | 1991-12-23 | 1992-12-12 | Stable salts of (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid, process for their preparation and pharmaceutical compositions containing them |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| BG98050A true BG98050A (en) | 1994-04-29 |
Family
ID=11361409
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| BG98050A BG98050A (en) | 1991-12-23 | 1993-08-18 | Salts resistant to (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino] carbonyl] cyclohexane-1-carbonic acid, method for their preparation and pharmaceutical compositions containing them |
Country Status (26)
| 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) | FI933685A0 (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) |
| YU (1) | YU110892A (en) |
| ZA (1) | ZA9210004B (en) |
Families Citing this family (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CA2663614A1 (en) * | 2006-09-28 | 2008-04-10 | Merck And Co., Inc. | Amine base salts of saha and polymorphs thereof |
| CA3212302A1 (en) * | 2020-04-27 | 2021-11-04 | Carter Hoffmann, Llc | Door movement system for cabinet |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1224627B (en) * | 1988-04-12 | 1990-10-04 | Guidotti & C Spa Labor | ACID STARCHES CYCLOMETHYLEN_1,2_DICARBOSSILS THERAPEUTIC ADAPTIVITY, PROCEDURES FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM. |
-
1991
- 1991-12-23 IT ITMI913448A patent/IT1252708B/en active IP Right Grant
-
1992
- 1992-12-12 RU RU9293052414A patent/RU2079489C1/en active
- 1992-12-12 WO PCT/EP1992/002903 patent/WO1993013056A1/en not_active Application Discontinuation
- 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 HU HU9302389A patent/HUT69287A/en unknown
- 1992-12-12 AU AU30871/92A patent/AU657591B2/en not_active Ceased
- 1992-12-12 CA CA002104372A patent/CA2104372A1/en not_active Abandoned
- 1992-12-12 EP EP92924726A patent/EP0575572A1/en not_active Withdrawn
- 1992-12-21 SK SK3796-92A patent/SK379692A3/en unknown
- 1992-12-21 CZ CS923796A patent/CZ379692A3/en unknown
- 1992-12-21 NZ NZ245547A patent/NZ245547A/en unknown
- 1992-12-22 HR HR921454A patent/HRP921454A2/en not_active Application Discontinuation
- 1992-12-22 SI SI9200409A patent/SI9200409A/en unknown
- 1992-12-22 MA MA23040A patent/MA22749A1/en unknown
- 1992-12-23 LV LVP-92-358A patent/LV10426B/en unknown
- 1992-12-23 YU YU110892A patent/YU110892A/en unknown
- 1992-12-23 MX MX9207543A patent/MX9207543A/en unknown
- 1992-12-23 CN CN92113839A patent/CN1079474A/en active Pending
- 1992-12-23 PL PL92297118A patent/PL169086B1/en unknown
- 1992-12-23 PT PT101156A patent/PT101156A/en not_active Application Discontinuation
- 1992-12-23 ZA ZA9210004A patent/ZA9210004B/en unknown
- 1992-12-23 TN TNTNSN92117A patent/TNSN92117A1/en unknown
-
1993
- 1993-08-18 BG BG98050A patent/BG98050A/en unknown
- 1993-08-20 FI FI933685A patent/FI933685A0/en not_active Application Discontinuation
-
1994
- 1994-05-23 EE EE9400006A patent/EE9400006A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| HU9302389D0 (en) | 1993-11-29 |
| HRP921454A2 (en) | 1995-02-28 |
| FI933685A (en) | 1993-08-20 |
| IT1252708B (en) | 1995-06-26 |
| ZA9210004B (en) | 1993-12-13 |
| ITMI913448A1 (en) | 1993-06-23 |
| FI933685A0 (en) | 1993-08-20 |
| EE9400006A (en) | 1995-12-15 |
| NZ245547A (en) | 1995-12-21 |
| CZ379692A3 (en) | 1993-09-15 |
| WO1993013056A1 (en) | 1993-07-08 |
| SI9200409A (en) | 1993-09-30 |
| MA22749A1 (en) | 1993-07-01 |
| HUT69287A (en) | 1995-09-28 |
| YU110892A (en) | 1996-01-08 |
| ITMI913448A0 (en) | 1991-12-23 |
| SK379692A3 (en) | 1995-04-12 |
| RU2079489C1 (en) | 1997-05-20 |
| PL169086B1 (en) | 1996-05-31 |
| BR9205652A (en) | 1994-05-03 |
| PL297118A1 (en) | 1993-09-06 |
| EP0575572A1 (en) | 1993-12-29 |
| AU3087192A (en) | 1993-07-28 |
| CA2104372A1 (en) | 1993-06-24 |
| JPH06506002A (en) | 1994-07-07 |
| AU657591B2 (en) | 1995-03-16 |
| LV10426A (en) | 1995-02-20 |
| LV10426B (en) | 1995-08-20 |
| TNSN92117A1 (en) | 1993-06-08 |
| PT101156A (en) | 1994-06-30 |
| CN1079474A (en) | 1993-12-15 |
| MX9207543A (en) | 1993-08-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU634319B2 (en) | Amino acid derivatives | |
| AU2009202389B2 (en) | Perindopril | |
| NZ206236A (en) | 3-(4-(1-carboxyalk-3-yl)-alpha-aminoalkanoyl)-3-azatricyclo-(5.2.1.0 2-6 ) decan-4-ylcarboxylic acids | |
| IE60128B1 (en) | Hydroxylamine derivatives,their preparation and use as medicaments | |
| WO1989007610A1 (en) | RENIN INHIBITORS CONTAINING alpha-HETEROATOM AMINO ACIDS | |
| NZ206574A (en) | 1-(n-(1-carboxyalkyl)-alpha-aminoalkanoyl)-octahydro2s,3as,8as-cyclohepta(b)pyrrol-2-ylcarboxylic acid derivatives | |
| DE60221508T2 (en) | Amino acid derivatives as HIV protease inhibitors | |
| FR2758328A1 (en) | NOVEL AROMATIC AMINES DERIVED FROM CYCLIC AMINES USEFUL AS MEDICAMENTS | |
| US4216209A (en) | Tripeptide angiotensin converting enzyme inhibitors | |
| DE69510338T2 (en) | AZIRDINE DERIVATIVES, THEIR PRODUCTION AND USE | |
| BG98050A (en) | Salts resistant to (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino] carbonyl] cyclohexane-1-carbonic acid, method for their preparation and pharmaceutical compositions containing them | |
| KR100209118B1 (en) | Benzamide derivatives | |
| US4322436A (en) | Novel substituted phenylacetic acid amide compounds | |
| FR2471972A1 (en) | TETRAPEPTIDES APPROVED FOR ENKEPHALINES, THEIR PREPARATION AND THEIR THERAPEUTIC USE | |
| CA2164296C (en) | Heterocyclic chemistry | |
| GB2077719A (en) | (N-(Cycloalkyl)amino acid compounds and compositions containing same | |
| US5420283A (en) | Resolution of (R)-2-benzylsuccinic acid 4-[4-(N-t-butoxycarbonylmethylamino)-piperidine] amide | |
| EP0712838B1 (en) | Acylphenylglycine derivative and preventive and remedy for diseases caused by increased collagenase activity containing said compound as active ingredient | |
| JP3254238B2 (en) | Diastereoselective reductive pinacol coupling method for homochiral α-aminoaldehyde | |
| US4370494A (en) | Converting enzyme inhibitors | |
| US4386075A (en) | Renally active tetrapeptides | |
| JP2013528214A (en) | Preparation of crystalline ezatiostat hydrochloride non-solvate form D | |
| US20060019951A1 (en) | Vacuolins | |
| JPH0662671B2 (en) | Proline derivative | |
| EP0103927B1 (en) | Converting enzyme inhibitors |