SI23949A - The new crystalline salts of zofenopril, the procedure for obtaining them and their use in therapy - Google Patents

The new crystalline salts of zofenopril, the procedure for obtaining them and their use in therapy Download PDF

Info

Publication number
SI23949A
SI23949A SI201100472A SI201100472A SI23949A SI 23949 A SI23949 A SI 23949A SI 201100472 A SI201100472 A SI 201100472A SI 201100472 A SI201100472 A SI 201100472A SI 23949 A SI23949 A SI 23949A
Authority
SI
Slovenia
Prior art keywords
zofenopril
salt
theta
intensity
following
Prior art date
Application number
SI201100472A
Other languages
Slovenian (sl)
Inventor
Rudolf RuÄŤman
Pavel Zupet
Original Assignee
Silverstone Pharma
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Silverstone Pharma filed Critical Silverstone Pharma
Priority to SI201100472A priority Critical patent/SI23949A/en
Priority to PCT/SI2012/000040 priority patent/WO2013095307A1/en
Priority to EP12753265.3A priority patent/EP2794560A1/en
Publication of SI23949A publication Critical patent/SI23949A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Cardiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Patentna prijava opisuje nove soli zofenoprila v točno določeni kristalni obliki, postopke za njihovo pripravo in farmacevtske formulacije v trdni obliki za uporabo pri zdravljenju infarkta miokarda in arterijske hipertenzije.The patent application describes novel salts of zofenopril in a specific crystalline form, processes for their preparation and pharmaceutical formulations in solid form for use in the treatment of myocardial infarction and arterial hypertension.

Description

Nove kristalne soli zofenoprila, postopek za njihovo dobivanje in njihova uporaba v terapijiNew crystalline salts of zofenopril, a process for their preparation and their use in therapy

Področje tehnike, v katero spada izum.FIELD OF THE INVENTION

Predloženi izum je s področja farmacevtske kemije in se nanaša na nove soli zofenoprila in njihove polimorfne oblike.The present invention is in the field of pharmaceutical chemistry and relates to novel salts of zofenopril and their polymorphic forms.

Soli zofenoprila, kije kemijsko (4S)-1-[(2S)-3-benzoiltio-2-metilpropionil]-4-(feniltio)-Lprolin, imajo naslednjo splošno formulo I.:Sophenopril salts, which are chemically (4S) -1 - [(2S) -3-benzoylthio-2-methylpropionyl] -4- (phenylthio) -Lprolin, have the following general formula I:

. baza kjer n pomeni 1 ali 2, kjer je baza organska amino spojina s formulo II:. a base where n is 1 or 2, where the base is an organic amino compound of formula II:

H2N-CHH2N-CH

R1R1

R2 kjer je Ri lahko H, CH3 ali C2H5 skupina, R2 pa CH2OH skupina, ali kjer je baza organska diamino spojina s formulo III:R 2 is wherein R may be H, CH3 or C2H5 group, R 2 CH 2 OH group, or wherein the base is an organic diamino compound of formula III:

R NH CH2 (CH)m CH2-NH-RR NH CH2 (CH) m CH2-NH-R

X kjer je R lahko H, alkilna skupina z 1 do 6 ogljikovimi atomi ali benzilna skupina, m lahko pomeni 0 ali 1,X where R may be H, an alkyl group of 1 to 6 carbon atoms or a benzyl group, m may be 0 or 1,

X lahko pomeni OH ali H skupino.X may represent OH or H group.

• ·• ·

Tehnični problem.A technical problem.

Zofenopril se v farmacevtiki uporablja izključno v obliki kalcijeve soli. Pomanjkljivost te soli je zelo nizka topnost v vodi in predvsem njene številne polimorfne oblike . Dogaja se tudi, da ena polimorfna oblika v določenih pogojih prehaja v drugo tako, da nastane mešanica polimorfnih oblik. Te probleme bi bilo smiselno rešiti s pripravo nove soli, ki bi lepo kristalizirala v enotni, točno definirani kristalni obliki.Zofenopril is used solely in the form of calcium salts in the pharmaceutical industry. The disadvantage of this salt is its very low water solubility and, above all, its numerous polymorphic forms. It also happens that, under certain conditions, one polymorphic form passes into another to form a mixture of polymorphic forms. It would be wise to solve these problems by preparing a new salt that would crystallize beautifully in a single, well-defined crystalline form.

Stanje tehnike.The state of the art.

Zofenopril je ACE inhibitor (okr.: Angiotensin Converting Enzyme) in se uporablja za zdravljenje kardiovaskularnih bolezni, posebej za uravnavanje povišanega krvnega pritiska in miokardnega infarkta. Ima tudi lipofilne in antioksidativne lastnosti zaradi prisotne sulfidne funkcije.Zofenopril is an ACE inhibitor (aka: Angiotensin Converting Enzyme) and is used to treat cardiovascular disease, specifically to regulate high blood pressure and myocardial infarction. It also has lipophilic and antioxidant properties due to its sulfide function.

Zofenopril in drugi merkaptoacilni derivati substituiranih prolinov so bili opisani v patentih GB 2,028.327 in US 4,316.906 (firma Squib & Sons).Zofenopril and other mercaptoacyl derivatives of substituted proline have been described in patents GB 2,028,327 and US 4,316,906 (Squib & Sons).

V patentih US 6,521.760 in US 6,515.021 je firma Menarini zaščitila postopek za pripravo kalcijeve soli in sicer kot mešanico polimorfnih oblik A in B.In US Patent Nos. 6,521,760 and 6,515,021, Menarini protected the process for the preparation of calcium salts as a mixture of polymorphic forms A and B.

Patenti WO 2007/138352A1 in WO 2007/003963A1 opisujejo postopek za dobivanje kalcijeve soli zofenoprila, ki poleg polimorfne oblike A vsebuje še 6% drugih oblik s tem, da reagira raztopina topne kalcijeve soli, prednostno kalcijevega klorida, z raztopino zofenopril kisline ali druge soli zofenoprila.Patents WO 2007 / 138352A1 and WO 2007 / 003963A1 describe a process for the preparation of the calcium salt of zofenopril which, in addition to polymorph A, contains 6% of other forms by reacting a solution of a soluble calcium salt, preferably calcium chloride, with a solution of zofenopril acid or other salts zofenopril.

Dve novi polimorfni kristalni obliki E in F je zaščitila firma Generics Ltd. v patentni prijavi št. WO 2009/106894A1. V prijavi WO 2009/022168A1 pa navaja novo anhidro obliko D kalcijeve soli zofenoprila.Two new polymorphic crystals E and F are protected by Generics Ltd. in patent application no. WO 2009 / 106894A1. In WO 2009 / 022168A1, however, it mentions a new anhydrous form D of the calcium salt of zofenopril.

Patent firme Glenmark št. WO 2010/84515A2 opisuje sintezo zofenoprila in njegovih soli: amorfno in kristalno obliko kalcijeve soli, poleg tega tudi soli s terc. butilaminom in dicikloheksilaminom.Glenmark patent no. WO 2010 / 84515A2 describes the synthesis of zofenopril and its salts: the amorphous and crystalline forms of the calcium salt, in addition to the tertiary salts. butylamine and dicyclohexylamine.

Publikacija firme Menarini ΜΧΡΑ 05013701 A-2007-06,14.6 opisuje tudi farmacevtsko formulacijo zofenoprila z diuretikom hidroklortiazidom.Menarini Publication ΜΧΡΑ 05013701 A-2007-06,14.6 also describes a pharmaceutical formulation of zofenopril with a diuretic hydrochlorothiazide.

Ameriški patent US 4,316.906 izčrpno opisuje sintezo zofenoprila in sorodnih spojin. Navaja številne možne soli zofenoprila z raznimi anorganskimi in organskimi bazami, dokumentira pa le sinteze natrijeve, kalijeve, kalcijeve soli ter soli z adamantilaminom in 2-amino-2-hidroksimetil-1.3-propandiolom. Ne obravnava pa nobenih kristalnih struktur in polimorfnih modifikacij, pač pa navaja možnost kombinacije zofenoprila z diuretikom hidroklorotiazidom.U.S. Patent 4,316,906 exhaustively describes the synthesis of zofenopril and related compounds. He lists many possible salts of zofenopril with various inorganic and organic bases and documents only the syntheses of sodium, potassium, calcium salts and salts with adamantylamine and 2-amino-2-hydroxymethyl-1,3-propanediol. However, it does not address any crystal structures and polymorphic modifications, but does indicate the possibility of combining zofenopril with a diuretic hydrochlorothiazide.

Znani so tudi kitajski patenti: CN 101012192A 2008, CN 101372472A 2009 in CN 101053563A 2007, ki obsegajo zaščito sinteze, oralne farmacevtske formulacije in kombinacijo z diuretikom hidroklorotiazidom.Chinese patents are also known: CN 101012192A 2008, CN 101372472A 2009, and CN 101053563A 2007, comprising synthesis protection, oral pharmaceutical formulations, and a combination with a diuretic hydrochlorothiazide.

Opis rešitve tehničnega problema.Description of solution to a technical problem.

Pri soleh zofenoprila, zlasti pri kalcijevi soli, je zelo moteča nizka topnost in slaba resorptivnost, zlasti pa nagnjenost k tvorbi številnih polimorfnih oblik in nekontroliranih mešanic polimorfnih oblik.The solubility of zofenopril, especially in the calcium salt, is very disturbing due to its low solubility and poor resorptivity, and especially the tendency to form many polymorphic forms and uncontrolled mixtures of polymorphic forms.

V smislu našega izuma smo pripravili nove soli zofenoprila s točno definirano, enotno kristalno strukturo.In accordance with our invention, new salts of zofenopril with a well-defined, uniform crystalline structure have been prepared.

Predloženi izum se tako nanaša na nove soli zofenoprila, prikazane s prej navedeno splošno formulo I, in njihove hidrate z 1-3 molekulami vode.The present invention thus relates to novel salts of zofenopril shown by the aforementioned general formula I and their hydrates with 1-3 water molecules.

Nadalje se predloženi izum nanaša na postopek za pripravo soli zofenoprila v smislu izuma, ki obsega naslednje stopnje:The present invention further relates to a process for the preparation of a zofenopril salt of the invention comprising the following steps:

a) kombinacijo raztopine zofenoprila ali njegove topne soli z organskimi amino spojinami ali njihovimi solmi,a) the combination of a solution of zofenopril or its soluble salt with organic amino compounds or their salts,

b) mešanje te nastale raztopine in stanje pri znižani temperaturi, dokler sol ne kristalizira,b) stirring this resulting solution and condition under reduced temperature until the salt crystallizes,

c) separacijo nastale kristalne soli od raztopine,c) separation of the crystalline salt formed from the solution,

d) sušenje soli pri temperaturi do največ 50 °C v vakuumu.d) drying the salt at a temperature not exceeding 50 ° C in vacuo.

V ta namen izhajamo lahko iz čistega zofenoprila (ki je kislina) ali iz njegove topne soli, kot na primer natrijeve ali kalijeve, ter z reakcijo z drugo organsko bazo ali njeno soljo in kristalizacijo dobimo nove soli. Presenetljivo pri tem je, da imajo te nove soli dobro topnost v vodi, predvsem pa stabilno kristalno zgradbo. Kot organsko bazo uporabimo etilendiamin ali substituirani etilendiamin, kot na primer N,N'dibenziletilendiamin ali Ν,Ν'-dimetiletilendiamin, oziroma aminoalkohol, kot na primer 2-amino-1-butanol, 2-amino-1 -etanol ali 1,3-diamino-1-propanol. Pri tem uporabimo aminoalkohole v razmerju 1 mol na 1 mol zofenoprila, v slučaju reakcije z derivati etilendiamina pa v razmerju 2 mola zofenoprila na 1 mol etilendiamina.For this purpose, a pure zofenopril (which is an acid) or a soluble salt thereof, such as sodium or potassium, may be derived and new salts may be obtained by reaction with another organic base or its salt and crystallization. Surprisingly, these new salts have good water solubility and, above all, a stable crystalline structure. Ethylenediamine or substituted ethylenediamine such as N, N'dibenzylethylenediamine or Ν, Ν'-dimethylethylenediamine or amino alcohol, such as 2-amino-1-butanol, 2-amino-1-ethanol or 1,3, is used as the organic base. -Diamino-1-propanol. The use of amino alcohols in the ratio of 1 mol per 1 mole of zofenopril, and in the case of reaction with ethylenediamine derivatives in the ratio of 2 moles of zofenopril per 1 mole of ethylenediamine.

Reakcijo izvajamo pri sobni temperaturi v primernem topilu, na primer v metanolu, etanolu, etilacetatu, acetonitrilu, ali v mešanici teh topil z vodo. Za doseganjeThe reaction is carried out at room temperature in a suitable solvent, for example in methanol, ethanol, ethyl acetate, acetonitrile, or in a mixture of these solvents with water. To achieve

boljšega izkoristka pri kristalizaciji lahko dodajamo tudi tretje, manj polarno topilo kot dietileter, n-heksan ali metil-terc. butileter.For crystallization efficiency, a third, less polar solvent than diethyl ether, n-hexane or methyl-tert may also be added. butyl ether.

Identiteto in strukturo spojin smo določili z elementno analizo, z FTIR spektri (aparat Perkin Elmer 727B), z 1H-NMR spektri (aparat Bruker Advance DPX300), kristalno strukturo pa z praškovnimi rentgenskimi difraktogrami (difraktometer PANanalytica X' Pert, CuKa, območje Od 3 do 35° 2 theta).The identity and structure of the compounds were determined by elemental analysis, FTIR spectra (Perkin Elmer 727B apparatus), 1 H-NMR spectra (Bruker Advance DPX300 apparatus), and crystal structure by powder X-ray diffractometers (PANanalytica X 'Pert diffractometer, CuKa, range 3 to 35 ° 2 theta).

Topnost sintetiziranih soli zofenoprila v vodi pri 20 °C ustreza za pripravo farmacevtskih formulacij v trdni obliki.The solubility of the synthesized salts of zofenopril in water at 20 ° C is suitable for the preparation of pharmaceutical formulations in solid form.

Predloženi izum se nadalje nanaša na farmacevtske formulacije, ki vsebujejo soli zofenoprila v smislu predloženega izuma.The present invention further relates to pharmaceutical formulations containing the salts of zofenopril of the present invention.

V smislu izuma pripravljene soli zofenoprila uporabimo kot aktivno sestavino za pripravo tablet ali drugih trdnih oblik. Pri tem uporabimo snovi in postopke, ki so običajni pri izdelavi trdnih farmacevtskih formulacij, kot so polnila, razgrajevala, snovi za mazanje, drsila in druge.In accordance with the invention, the prepared salt of zofenopril is used as the active ingredient for the preparation of tablets or other solid forms. In doing so, we use substances and processes that are common in the manufacture of solid pharmaceutical formulations, such as fillers, decomposers, lubricants, gliders, and others.

V farmacevtski formulaciji lahko tudi kombiniramo soli zofenoprila z diuretiki, kot na primer z indapamidom ali z dodatkom zaviralcev kalcijevih ionov iz skupine dihidropiridinov (amlodipin, lacidipin).The pharmaceutical formulation may also combine zofenopril salts with diuretics, such as with indapamide or with the addition of dihydropyridine calcium ion inhibitors (amlodipine, lacidipine).

Predloženi izum se tako nadalje nanaša na uporabo soli zofenoprila v smislu izuma za izdelavo zdravila za zdravljenje arterijske hipertenzije in miokardnega infarkta.The present invention thus further relates to the use of the zofenopril salt of the invention for the manufacture of a medicament for the treatment of arterial hypertension and myocardial infarction.

Kratek opis slik.Short description of the pictures.

Fig. 1. 1H-NMR spekter soli zofenoprila z Ν,Ν'-etilendiaminom - trihidrat.FIG. 1. 1 H-NMR spectrum of the salt of zophenopril with N, N-ethylenediamine trihydrate.

Fig.2.1H-NMR spekter soli zofenoprila z Ν,Ν'-dimetiletilendiaminom.Fig.2. 1 H-NMR spectrum of zofenopril salt with N, N-dimethylethylenediamine.

Fig.3. 1H-NMR spekter soli zofenoprila z N,N'-dibenziletilendiaminom.Fig.3. 1 H-NMR spectrum of the salt of zophenopril with N, N'-dibenzylethylenediamine.

Fig.4. 1H-NMR spekter soli zofenoprila z 1,3-diamino-1-propanolom - trihidrat.Fig.4. 1 H-NMR spectrum of zofenopril salt with 1,3-diamino-1-propanol trihydrate.

Fig.5. 1H-NMR spekter soli zofenoprila z (R)-2-amino-1-butanolom.Fig.5. 1 H-NMR spectrum of zofenopril salt with (R) -2-amino-1-butanol.

Fig.6. 1H-NMR spekter soli zofenoprila z 2-amino-1 -etanolom - hidrat.Fig.6. 1 H-NMR spectrum of the salt of zofenopril with 2-amino-1-ethanol hydrate.

Izum pojasnjujejo naslednji izvedbeni primeri, ki ga v ničemer omejujejo.The invention is explained by the following embodiments, which in no way limit it.

PRIMER 1. Sol zofenoprila z N, N'- etilendiaminom - trihidrat.EXAMPLE 1. A salt of zofenopril with N, N'-ethylenediamine trihydrate.

V raztopino zofenoprila (2,0 g, 4,65 mmol) v 10 ml etanola med mešanjem pri °C počasi dodamo N,N'-etilendiamin (0,15 g, 2,49 mmol) raztopljen v 1 ml etanola. Med počasnim mešanjem dodamo 20 ml dietiletra. Preko noči nastale kristale odfiltriramo in osušimo v vakuumu. Dobimo 1,99 g (92,5 %) kristalne soli, ki se tali priN, N'-Ethylenediamine (0.15 g, 2.49 mmol) dissolved in 1 ml of ethanol was slowly added to a solution of zofenopril (2.0 g, 4.65 mmol) in 10 ml of ethanol while stirring at ° C. 20 ml of diethyl ether are added while slowly stirring. The crystals formed overnight were filtered off and dried in vacuo. 1.99 g (92.5%) of a crystalline salt are obtained which melt at

- 80 °C. Pri 20°C se v vodi topi 10 mg/100 ml.80 ° C. At 20 ° C, 10 mg / 100 ml is dissolved in water.

Elementna analiza odgovarja formuli: C46H54N4O8S4 . 3 H2O: izračunano: C: 56.77% H: 6,21% N: 5.67% najdeno: C: 56,32% H: 6,32% N: 5,70%Elemental analysis corresponds to the formula: C46H54N4O8S4. 3 H 2 O: calculated: C: 56.77% H: 6.21% N: 5.67% found: C: 56.32% H: 6.32% N: 5.70%

Določitev vode po K. Fischerju da 5,5 %, kar odgovarja trihidratu.The determination of water according to K. Fischer gives 5.5%, which corresponds to the trihydrate.

IR spekter (KBr) : u-cm’1 = 3309 (NH/OH/COOH); 3058, 2972, 2930, 2856 (=CH CH); 1653 1631 (C=O), 1560, 1580 (arom.).IR spectrum (KBr): in cm- 1 = 3309 (NH / OH / COOH); 3058, 2972, 2930, 2856 (= CH CH); 1653 1631 (C = O), 1560, 1580 (arom.).

1H-NMR spekter posnet v DMSO odgovarja zgornji strukturi (Fig. 1.) The 1 H-NMR spectrum recorded in DMSO corresponds to the structure above (Fig. 1)

Rentgenski praškovni difraktogram (navedeni so samo refleksi nad 10%):X-ray powder diffraction pattern (only reflexes above 10% are listed):

No. No. Položaj [2 theta/0]Position [2 theta / 0 ] Razdalja [d / A ] Distance [d / A] Relat. intenziteta [ % Relat. intensity [% 2 2 7,4968 7,4968 11,78268 11,78268 100 100 6 6 10,7666 10,7666 8,21056 8,21056 17,62 17,62 10 10 14,1756 14,1756 6,24279 6,24279 18,00 18,00 15 15 17,0633 17,0633 5,19225 5,19225 28,33 28.33 18 18 18,7849 18,7849 4,72009 4,72009 48,21 48.21 19 19 19,5573 19,5573 4,53539 4,53539 66,79 66.79 20 20 20,2753 20,2753 4,37635 4,37635 79,31 79.31 21 21 20,9658 20,9658 4,23375 4,23375 21,78 21,78 22 22 21,6467 21,6467 4,10210 4,10210 37,73 37.73 23 23 22,0162 22,0162 4,03408 4,03408 16,10 16.10 25 25 22,5757 22,5757 3,93535 3,93535 14,94 14,94 26 26 23,5248 23,5248 3,77869 3,77869 37,44 37.44 27 27 23,8932 23,8932 3,72126 3,72126 17,79 17,79 29 29 25,0202 25,0202 3,55612 3,55612 25,61 25.61 31 31 26,2286 26,2286 3,39497 3,39497 11,78 11,78

PRIMER 2. Sol zofenoprila z N,N'-dimetil-etilendiaminom.EXAMPLE 2. A salt of zofenopril with N, N'-dimethyl-ethylenediamine.

Raztopini zofenoprila (2,7 g, 6,28 mmol) v acetonitrilu (10 ml) med mešanjem pri 30 °C počasi dodamo Ν,Ν'-dimetil-etilendiamin (0,28 g, 3,17 mmol). Sol takoj kristalizira. Dobimo 2,90 g (97,3%) spojine s tališčem 177-178 °C. V vodi se topi 15 mg/100 ml pri 20 °C.To a solution of zofenopril (2.7 g, 6.28 mmol) in acetonitrile (10 ml), while stirring at 30 ° C, was slowly added N, N'-dimethyl-ethylenediamine (0.28 g, 3.17 mmol). The salt crystallizes immediately. 2.90 g (97.3%) of the compound are obtained with a melting point of 177-178 ° C. Dissolve 15 mg / 100 ml of water at 20 ° C.

Elementna analiza odgovarja formuli: C48H58N4O8S4:Elemental analysis corresponds to the formula: C4 8 H 5 8N4O 8 S4:

izračunano: C: 60,86% H: 6,17% N: 5,91% najdeno: C: 60,87% H: 5,82% N: 5,91%calculated: C: 60.86% H: 6.17% N: 5.91% found: C: 60.87% H: 5.82% N: 5.91%

IR spekter (KBr): v-cm'1 = 3060,2970,2929,2857 (=CH, CH); 1652,1633 (C=O), 1579 (arom.) 1H-NMR spekter (v DMSO) odgovarja zgornji strukturi.IR spectrum (KBr): in cm- 1 '= 3060,2970,2929,2857 (= CH, CH); 1652.1633 (C = O), 1579 (arom.) The 1 H-NMR spectrum (in DMSO) corresponds to the above structure.

Rentgenski praškovni difraktogram (navedeni so samo refleksi nad 10%):X-ray powder diffraction pattern (only reflexes above 10% are listed):

No: Položaj [2 theta/0] Razdalja [d / A ] Rel. intenziteta [%]No: Position [2 theta / 0 ] Distance [d / A] Rel. intensity [%]

8,9856 9,83350 14,048.9856 9.83350 14.04

5 5 12,3249 12,3249 7,17575 7,17575 20,41 20,41 7 7 13,7868 13,7868 6,41797 6,41797 42,89 42.89 8 8 15,7461 15,7461 5,62351 5,62351 17,67 17,67 9 9 16,5660 16.5660 5,34699 5,34699 38,23 38.23 10 10 17,5937 17.5937 5,03689 5,03689 100 100 11 11 18,5747 18,5747 4,77303 4,77303 27,06 27.06 12 12 18,7471 18,7471 4,72952 4,72952 57,09 57.09 13 13 19,2580 19,2580 4,60518 4,60518 52,26 52.26 14 14 19,9986 19,9986 4,43629 4,43629 16,01 16.01 15 15 20,4523 20,4523 4,33889 4,33889 26,37 26.37 16 16 21,3897 21,3897 4,15080 4,15080 84,69 84.69 17 17 22,7087 22,7087 3,91260 3,91260 96,05 96.05 19 19 23,7407 23,7407 3.74480 3.74480 42,06 42.06 20 20 24,3608 24,3608 3,65087 3,65087 71,72 71,72 21 21 24,8107 24,8107 3,58568 3,58568 23,08 23.08 22 22 26,3491 26,3491 3,37971 3,37971 14,98 14.98 24 24 27,2011 27,2011 3,27575 3,27575 34,98 34.98 27 27 28,9350 28,9350 3,08329 3,08329 21,25 21,25 28 28 29,8135 29,8135 2,99440 2,99440 18,81 18,81 29 29 30,8541 30,8541 2,89574 2,89574 17,46 17.46 32 32 33,4840 33,4840 2,67407 2,67407 17,88 17,88 33 33 34,0535 34,0535 2,63064 2,63064 11,28 11,28 35 35 35,2639 35,2639 2,54307 2,54307 20,78 20,78 36 36 35,8800 35.8800 2,50080 2,50080 33,21 33.21

PRIMER 3. Sol zofenoprila z N,N'-dibenziletilendiaminomEXAMPLE 3 A salt of zofenopril with N, N'-dibenzylethylenediamine

V raztopino kalijeve soli zofenoprila (16,33 g, 34,9 mmol) v 23-odstotnem etanolu med intenzivnim mešanjem pri 30 °C dodamo raztopino N,N'-dibenziletilendiamina diacetata (6,3 g, 17,47 mmol) v 5-odstotnem etanolu. Kristalno maso mešamo še 15 minut, nato jo filtriramo, dobro izperemo z vodo in posušimo v vakuumu pri 50 °C. Dobimo 19,20 g (100 %) brezbarvnih kristalov s tališčem pri 184 -187 °C. V vodi se topijo: 5 mg/100 ml.To a solution of the potassium salt of zofenopril (16.33 g, 34.9 mmol) in 23% ethanol was added a solution of N, N'-dibenzylethylenediamine diacetate (6.3 g, 17.47 mmol) in vigorous stirring at 30 ° C. - Percent ethanol. The crystalline mass was stirred for another 15 minutes, then filtered, washed well with water and dried in vacuo at 50 ° C. 19.20 g (100%) of colorless crystals were obtained with a melting point at 184 -187 ° C. Dissolve in water: 5 mg / 100 ml.

Elementna analiza odgovarja formuli: C60H66N4O8S4:Elemental analysis corresponds to the formula: C60H66N4O8S4:

izračunano: C: 65,55 % H: 5,98 % N: 5,04 % najdeno: C: 65,67 % H: 6,05 % N: 5,14%calculated: C: 65.55% H: 5.98% N: 5.04% found: C: 65.67% H: 6.05% N: 5.14%

IR spekter (KBr) = u cm'1 : 3062, 2968, 2927, 2869 (=CH, CH); 1652, 1637 (C = O); 1579 (arm.).IR spectrum (KBr) = in cm @ -1 : 3062, 2968, 2927, 2869 (= CH, CH); 1652, 1637 (C = O); 1579 (arm.).

1H-NMR spekter v DMSO odgovarja navedeni strukturi (Fig. 3.) The 1 H-NMR spectrum in DMSO corresponds to the structure indicated (Fig. 3)

Rentgenski praškovni difraktogram (navedeni so samo refleksi nad 10%):X-ray powder diffraction pattern (only reflexes above 10% are listed):

No.: Položaj [2 theta /°] Razdalja [ d /A ] Rel. intenziteta [ % ]No .: Position [2 theta / °] Distance [d / A] Rel. intensity [%]

4,8157 18,33508 22,744.8157 18.33508 22.74

9,0256 9,79002 22,909.0256 9.79002 22.90

9,3796 9,42134 17,149.3796 9.42134 17.14

7 7 9,6776 9,6776 9,13190 9,13190 51,15 51.15 9 9 12,9249 12,9249 6,84393 6,84393 46,23 46,23 10 10 14,0657 14,0657 6,29134 6,29134 15,53 15.53 11 11 14,5326 14,5326 6,09022 6,09022 66,81 66.81 12 12 14,9637 14,9637 5,91571 5,91571 26,78 26,78 13 13 16,6958 16,6958 5,30569 5,30569 56,96 56.96 14 14 17,4254 17,4254 5,08515 5,08515 17,78 17,78 15 15 18,4070 18,4070 4,81750 4,81750 54,70 54.70 16 16 18,7237 18,7237 4,73538 4,73538 100,00 100.00 17 17 19,3397 19,3397 4,58591 4,58591 40,38 40.38 19 19 21,0942 21.0942 4,20828 4,20828 23,32 23,32 20 20 21,2653 21,2653 4,17481 4,17481 18,77 18,77 21 21 21,9128 21,9128 4,05289 4,05289 66,84 66.84 24 24 24,3046 24,3046 3,65919 3,65919 24,39 24.39 25 25 25,0970 25.0970 3,54541 3,54541 19,41 19,41 26 26 26,0301 26.0301 3,42040 3,42040 23,43 23,43 27 27 26,8654 26,8654 3,31592 3,31592 25,28 25,28 28 28 28,2661 28,2661 3,15471 3,15471 21,79 21,79 29 29 28,6171 28,6171 3,11681 3,11681 18,52 18.52 30 30 29,2658 29,2658 3,04918 3,04918 47,43 47.43 31 31 30,0432 30.0432 2,97202 2,97202 15,22 15,22 33 33 31,6758 31,6758 2,82247 2,82247 31,67 31,67 34 34 32,7945 32,7945 2,72870 2,72870 24,48 24,48 35 35 34,2694 34,2694 2,61456 2,61456 20,43 20,43 36 36 35,1785 35,1785 2,54904 2,54904 16,26 16.26

PRIMER 4. Sol zofenoprila z 1,3-diamino-2-propanolom - trihidratEXAMPLE 4 A salt of zofenopril with 1,3-diamino-2-propanol - trihydrate

Zofenopril (2,55 g, 5,94 mmol) raztopimo v 7 ml etanola in med mešanjem počasi dodamo 1,3-diamino-2-propanol (0,28 g, 3,1 mmol), nato pa še 25 ml metilterc. butiletra, do rahle pomotnitve. Kristale, izpadle preko noči, odfiltriramo in osušimo v vakuumu. Dobimo 2,72 g (96,1 %) brezbarvnih kristalov s tališčem pri 104-106 °C. V vodi se topi 17,5 mg/100 ml vode.Zofenopril (2.55 g, 5.94 mmol) was dissolved in 7 ml of ethanol and 1,3-diamino-2-propanol (0.28 g, 3.1 mmol) was slowly added while stirring, followed by 25 ml of methyl tert. butylether, until slightly misty. The crystals which were removed overnight were filtered off and dried in vacuo. 2.72 g (96.1%) of colorless crystals were obtained with a melting point at 104-106 ° C. Dissolve 17.5 mg / 100 ml water in water.

Elementna analiza odgovarja formuli: C47H56N4O9S4.3 H2O : izračunano: C: 56,27 % H: 6,23 % N: 5,58 % najdeno: C: 56,49 % H: 6,10 % N: 5,59 %Elemental analysis corresponds to the formula: C47H56N4O9S4.3 H 2 O: calculated: C: 56.27% H: 6.23% N: 5.58% found: C: 56.49% H: 6.10% N: 5. 59%

Analiza po K. Fischerju da 5,65 % vode, kar odgovarja trihidratu.According to K. Fischer's analysis, 5.65% of water corresponds to trihydrate.

1H.NMR spekter v DMSO ustreza zgornji spojini (Fig. 4.) 1 The H. NMR spectrum in DMSO corresponds to the above compound (Fig. 4.)

Rentgenski praškovni difraktogram ( navedeni so samo refleksi nad 10 %):X-ray powder diffraction pattern (only reflexes above 10% are listed):

No.: No .: Položaj [ 2 theta/0 ]Position [2 theta / 0 ] Razdalja [ d / A ] Distance [d / A] Rel. intenziteta [%] Rel. intensity [%] 11 11 15,8829 15,8829 5,57536 5,57536 96,96 96.96 15 15 17,0655 17,0655 5,19158 5,19158 23,15 23.15 16 16 17,5637 17,5637 5,04541 5,04541 100,00 100.00 20 20 19,7596 19,7596 4,48941 No. 4,48941 19,34 19,34 22 22 20,5599 20,5599 4,31631 4,31631 13.23 13.23

23 23 20,9703 20,9703 4,23287 4,23287 28,25 28,25 24 24 21,3168 21,3168 4,16484 4,16484 18,90 18,90 25 25 22,1812 22,1812 4,00444 4,00444 37,54 37.54 26 26 22,6882 22,6882 3,91609 3,91609 54,02 54.02 27 27 23,0216 23,0216 3,86013 3,86013 15,15 15.15 29 29 24,2341 24,2341 3,66986 3,66986 41,93 41.93 30 30 24,6348 24,6348 3,61089 3,61089 14,65 14,65 32 32 25,8287 25,8287 3,44674 3,44674 44,30 44,30 33 33 26,3087 26,3087 3,38482 3,38482 17,48 17,48 34 34 27,1428 27,1428 3,28266 3,28266 31,07 31.07 35 35 27,4263 27,4263 3,24937 3,24937 14,17 14.17 36 36 28,7918 28,7918 3,09838 3,09838 28,09 28.09 39 39 30,9007 30,9007 2,89148 2,89148 21.24 21.24 40 40 31,2312 31,2312 2,86163 2,86163 14,83 14,83 42 42 32,1246 32,1246 2,78405 2,78405 17,73 17.73 43 43 32,7009 32,7009 2,73639 2,73639 19,84 19,84 44 44 33,8865 33,8865 2,64322 2,64322 25,59 25.59 45 45 34,7113 34,7113 2,58228 2,58228 10,98 10.98 46 46 35,4357 35.4357 2,53113 2,53113 29,09 29.09 47 47 36,2288 36,2288 2,47752 2,47752 12,21 12,21

PRIMER 5. Sol zofenoprila z (R)-2-amino-1-butanolomEXAMPLE 5. A salt of zofenopril with (R) -2-amino-1-butanol

Zofenoprilu (1 g, 2,32 mmol) v 15 ml etanola dodamo (R)-2-amino-1- butanol (0,21 g, 2,33 mmol), nato pa postopoma še 30 ml dietiletra. Kristaliziramo pri - 10 °CZofenopril (1 g, 2.32 mmol) in 15 ml of ethanol was added (R) -2-amino-1-butanol (0.21 g, 2.33 mmol) followed by a further 30 ml of diethyl ether. Crystallize at -10 ° C

preko noči. Dobimo 0,77 g (63,6 %) iglastih kristalov s tališčem pri 132- 135 °C. vodi se topi 300 mg/100 ml. Elementna analiza ustreza formuli: C26H34N2O5S2: izračunano: C: 60,20 % H: 6,61 % N: 5,40 % najdeno: C: 60,21 % H: 6,60 % N: 5,40 % 1H-NMR spekter v DMSO ustreza tej spojini (Fig. 5).overnight. 0.77 g (63.6%) of needle crystals were obtained with a melting point of 132-135 ° C. water is dissolved 300 mg / 100 ml. Elemental analysis corresponds to the formula: C26H34N2O5S2: calculated: C: 60.20% H: 6.61% N: 5.40% found: C: 60.21% H: 6.60% N: 5.40% 1 H- The NMR spectrum in DMSO corresponds to this compound (Fig. 5). Rentgenski praškovni difraktogram (navedeni so samo refleksi nad 10 %): X-ray powder diffraction pattern (only reflexes above 10% are listed): No.: No .: Položaj [ 2 theta /°] Position [2 theta / °] Razdalja [ d / A ] Rel. Distance [d / A] Rel. intenziteta [ % ] intensity [%] 3 3 9,0551 9,0551 9,75824 9,75824 15,16 15.16 13 13 18,9475 18.9475 4,67996 4,67996 9,96 9.96 14 14 20,0524 20.0524 4,42450 4,42450 14,74 14,74 16 16 21,5877 21,5877 4,11317 4,11317 100,00 100.00 18 18 23,4280 23,4280 3,79409 3,79409 18,35 18,35 22 22 25,2415 25,2415 3,52545 3,52545 10,04 10.04 24 24 27,2815 27,2815 3,26628 3,26628 12,99 12,99 25 25 27,9473 27,9473 3,18997 3.18997 11,62 11,62 29 29 31.3866 31.3866 2,84781 2,84781 13,11 13.11

PRIMER 6. Sol zofenoprila z 2-amino-1 -etanolom - hidratEXAMPLE 6 A salt of zofenopril with 2-amino-1-ethanol - hydrate

Raztopini zofenoprila (2,0 g, 4,65 mmola) v 12 ml etanola dodamo 2-amino-1 -etanol (0,285 g, 4,67 mmola), mešamo, ter dodamo postopoma še 30 ml dietiletra. Kristaliziramo pri - 10 °C 24 ur. Dobimo 2,04 g (89,3 %) kristalov s tališčem 105 107 °C. V vodi se topijo zelo dobro, 8,75 g/100 ml pri 20 °C.To a solution of zofenopril (2.0 g, 4.65 mmol) in 12 ml of ethanol was added 2-amino-1-ethanol (0.285 g, 4.67 mmol), stirred and 30 ml of diethyl ether was added gradually. Crystallize at - 10 ° C for 24 hours. 2.04 g (89.3%) of crystals were obtained with a melting point of 105 107 ° C. They dissolve very well in water, 8.75 g / 100 ml at 20 ° C.

Elementna analiza ustreza formuli: C24H30N2O5S2. H2O : izračunano: C: 56,67 % H: 6,34 % N: 5,50 % najdeno: C: 56,80 % H: 6,29 % N: 5,50 %Elemental analysis corresponds to the formula: C24H30N2O5S2. H 2 O: calculated: C: 56.67% H: 6.34% N: 5.50% found: C: 56.80% H: 6.29% N: 5.50%

Analiza po K. Fischerju da 3,18 % vode, kar ustreza hidratu.According to K. Fischer analysis 3.18% of water is equivalent to hydrate.

IR spekter (KBr) = v cm’1 : 3061, 2968, 2926, 2868 (=CH, CH), 1652, 1636 (C=O), 1579 (arom.) 1H-NMR spekter v DMSO ustreza navedeni strukturi (Fig. 6.).IR spectrum (KBr) = in cm -1 : 3061, 2968, 2926, 2868 (= CH, CH), 1652, 1636 (C = O), 1579 (arom.) The 1 H-NMR spectrum in DMSO corresponds to the indicated structure ( Fig. 6.).

Rentgenski praškovni dufraktogram (navedeni so samo refleksi nad 10 %):X-ray powder diffraction pattern (only reflexes above 10% are listed):

No.: No .: Položaj [ 2 theta /° ] Position [2 theta / °] Razdalja [ d/A ] Distance [d / A] Rel. intenziteta [ % ] Rel. intensity [%] 8 8 18,2813 18,2813 4,84895 4,84895 51,33 51.33 11 11 20,7644 20,7644 4,27437 4,27437 47,64 47.64 12 12 21,5219 21,5219 4,12560 4,12560 18,51 18,51 13 13 22,0849 22.0849 4,02169 4,02169 100,00 100.00 15 15 23,1722 23,1722 3,83537 3,83537 48,90 48.90 16 16 23,6163 23,6163 3,76425 3,76425 53,97 53.97 18 18 25,2647 25,2647 3,52226 3,52226 16,25 16,25 19 19 25,4502 25,4502 3,49702 3,49702 20,32 20,32 20 20 25,7698 25,7698 3,45436 3,45436 12,08 12.08 21 21 26,4076 26,4076 3,37236 3,37236 67,58 67.58 22 22 27,2237 27,2237 3,27309 3,27309 13,54 13,54 23 23 27,6248 27,6248 3,22647 3,22647 11,94 11,94 24 24 28,3944 28,3944 3,14074 3,14074 26,93 26.93 25 25 30,1998 30,1998 2,95697 2,95697 39,27 39.27 26 26 31,2466 31,2466 2,86025 2,86025 13,73 13,73 27 27 32,1108 32,1108 2,78522 2,78522 17,29 17,29 28 28 33,3411 33,3411 2,68520 2,68520 35,41 35.41 29 29 33,6594 33,6594 2,66054 2,66054 19,39 19,39 PRIMER 7. Sestava tablet. EXAMPLE 7. Composition of tablets.

Sestavina: Teža (mg):Ingredient: Weight (mg):

Ν,Ν'-dibenziletilendiamin zofenopril.....Ν, Ν'-dibenzylethylenediamine zofenopril .....

mikrokristalinična celuloza ...................microcrystalline cellulose ...................

laktoza monohidrat ..............................lactose monohydrate ..............................

koruzni škrob.........................................corn starch.........................................

hipromeloza ..........................................hypromellosis ..........................................

koloidni silicijev dioksid..........................colloidal silica ..........................

magnezijev stearat.................................magnesium stearate .................................

9,2* (* odgovarja: 7,2 mg zofenoprila)9,2 * (* replies: 7,2 mg zofenopril)

36.436.4

27.5 16,227.5 16,2

3,03.0

1,21,2

95,0 mg95.0 mg

Sestavine filmske obloge: hipromeloza, titan dioksid, makrogol 400, makrogol 6000, skupno 5 mg.Film coating components: hypromellose, titanium dioxide, macrogol 400, macrogol 6000, 5 mg total.

Končna teža tablete: 100 mgFinal tablet weight: 100 mg

PRIMER 8. Sestava tablet.EXAMPLE 8. Composition of tablets.

Sestavina: Teža (mg):Ingredient: Weight (mg):

Ν,Ν'-dimetiletilendiamin zofenopril .. 15,80* (* odgovarja: 14.33 mg zofenoprila indapamid.......................................... 1,25 cellactose.......................................... 83,65 kroskarmeloza................................... 2,50 koloidni silicijev dioksid ..................... 0,90 magnezijev stearat............................. 0,90Ν, Ν'-dimethylethylenediamine zofenopril .. 15.80 * (* replies: 14.33 mg zofenopril indapamide ............................. ............. 1,25 cellactose ................................. ......... 83.65 croscarmellose ................................... 2. 50 colloidal silica ..................... 0.90 magnesium stearate .................... ......... 0.90

105 mg105 mg

Filmska obloga: 5 mg, končna teža tablete: 110 mg.Film coating: 5 mg, final tablet weight: 110 mg.

PRIMER 9. Sestava tablet.EXAMPLE 9. Composition of tablets.

Sestavina: Ingredient: Teža (mg): Weight (mg): N,Ν'-etilendiamin zofenopril hidrat. N, N'-Ethylenediamine zophenopril hydrate. 34,00* ( 34.00 * ( amlodipin besilat ........................... amlodipine besylate ........................... .. 24,45 .. 24,45 manitol ........................................... mannitol ........................................... . 67,30 . 67.30 laktoza monohidrat......................... lactose monohydrate ......................... . 36,10 . 36,10 mikrokristalinična celuloza.............. microcrystalline cellulose .............. ... 57,50 ... 57,50 koruzni škrob.................................. corn starch.................................. .... 17,55 .... 17.55 magnezijev stearat ........................ magnesium stearate ........................ .... 3,00 .... 3,00

(‘odgovarja: 28,66 mg zofenoprila)('Replies: 28.66 mg zofenopril)

240 mg240 mg

Filmska obloga: 10 mg, končna teža tablete: 250 mgFilm coating: 10 mg, final tablet weight: 250 mg

Claims (11)

Patentni zahtevki.Patent claims. 1. Soli zofenoprila s splošno formulo I.:1. Salts of zophenopril of general formula I: O OO O COOH . baza kjer n pomeni 1 ali 2, kjer je baza organska amino spojina s formuloCOOH. a base wherein n is 1 or 2, wherein the base is an organic amino compound of formula H2N-CHH 2 N-CH R1R1 R2 kjer je Ri lahko H, CH3 ali C2H5 skupina, R2 pa CH2OH skupina, ali kjer je baza organska diamino spojina s formulo III:R 2 where R 1 can be H, CH 3 or C 2 H 5 group and R 2 is a CH 2 OH group, or where the base is an organic diamino compound of formula III: R-NH-CH2-(CH)m-CH2-NH-RR-NH-CH 2 - (CH) m -CH 2 -NH-R X kjer je R lahko H, alkilna skupina z 1 do 6 ogljikovimi atomi ali benzilna skupina, m lahko pomeni 0 ali 1,X where R may be H, an alkyl group of 1 to 6 carbon atoms or a benzyl group, m may be 0 or 1, X lahko pomeni OH ali H skupino.X may represent OH or H group. 2. Soli zofenoprila po zahtevku 1 v obliki hidratov z 1 do 3 molekulami vode.2. Zofenopril salts according to claim 1 in the form of hydrates with 1 to 3 water molecules. 3. Sol zofenoprila z Ν,Ν'-etilendiaminom po zahtevku 1 z naslednjim rentgenskim praškovnim difraktogramom:3. The salt of zophenopril with Ν, Ν-ethylenediamine according to claim 1 with the following X-ray powder diffraction pattern: No. No. Položaj [2 theta/0]Position [2 theta / 0 ] Razdalja [d / A ] Distance [d / A] Relat. intenziteta [ % ] Relat. intensity [%] 2 2 7,4968 7,4968 11,78268 11,78268 100 100 6 6 10,7666 10,7666 8,21056 8,21056 17,62 17,62 10 10 14,1756 14,1756 6,24279 6,24279 18,00 18,00 15 15 17,0633 17,0633 5,19225 5,19225 28,33 28.33 18 18 18,7849 18,7849 4,72009 4,72009 48,21 48.21 19 19 19,5573 19,5573 4,53539 4,53539 66,79 66.79 20 20 20,2753 20,2753 4,37635 4,37635 79,31 79.31 21 21 20,9658 20,9658 4,23375 4,23375 21,78 21,78
22 22 21,6467 21,6467 4,10210 4,10210 37,73 37.73 23 23 22,0162 22,0162 4,03408 4,03408 16,10 16.10 25 25 22,5757 22,5757 3,93535 3,93535 14,94 14,94 26 26 23,5248 23,5248 3,77869 3,77869 37,44 37.44 27 27 23,8932 23,8932 3,72126 3,72126 17,79 17,79 29 29 25,0202 25,0202 3,55612 3,55612 25,61 25.61 31 31 26,2286 26,2286 3,39497 3,39497 11,78 11,78
4. Sol zofenoprila z Ν,Ν'-dimetiletilendiaminom po zahtevku 1 z naslednjim rentgenskim difraktogramom:The salt of zophenopril with Ν, Ν'-dimethylethylenediamine according to claim 1 with the following X-ray diffractogram: No. No. Položaj [2 theta/0]Position [2 theta / 0 ] Razdalja [d / A ] Distance [d / A] Rel. intenziteta [ % ] Rel. intensity [%] 3 3 8,9856 8,9856 9,83350 9,83350 14,04 14.04 5 5 12,3249 12,3249 7,17575 7,17575 20,41 20,41 7 7 13,7868 13,7868 6,41797 6,41797 42,89 42.89 8 8 15,7461 15,7461 5,62351 5,62351 17,67 17,67 9 9 16,5660 16.5660 5,34699 5,34699 38,23 38.23 10 10 17,5937 17.5937 5,03689 5,03689 100 100 11 11 18,5747 18,5747 4,77303 4,77303 27,06 27.06 12 12 18,7471 18,7471 4,72952 4,72952 57,09 57.09 13 13 19,2580 19,2580 4,60518 4,60518 52,26 52.26 14 14 19,9986 19,9986 4,43629 4,43629 16,01 16.01 15 15 20,4523 20,4523 4,33889 4,33889 26,37 26.37 16 16 21,3897 21,3897 4,15080 4,15080 84,69 84.69 17 17 22,7087 22,7087 3,91260 3,91260 96,05 96.05 19 19 23,7407 23,7407 3.74480 3.74480 42,06 42.06 20 20 24,3608 24,3608 3,65087 3,65087 71,72 71,72 21 21 24,8107 24,8107 3,58568 3,58568 23,08 23.08 22 22 26,3491 26,3491 3,37971 3,37971 14,98 14.98 24 24 27,2011 27,2011 3,27575 3,27575 34,98 34.98 27 27 28,9350 28,9350 3,08329 3,08329 21,25 21,25 28 28 29,8135 29,8135 2,99440 2,99440 18,81 18,81 29 29 30,8541 30,8541 2,89574 2,89574 17,46 17.46 32 32 33,4840 33,4840 2,67407 2,67407 17,88 17,88 33 33 34,0535 34,0535 2,63064 2,63064 11,28 11,28 35 35 35,2639 35,2639 2,54307 2,54307 20,78 20,78 36 36 35,8800 35.8800 2,50080 2,50080 33,21 33.21
5. Sol zofenoprila z Ν,Ν'-dibenziletilendiaminom po zahtevku 1 z naslednjim5. The salt of zophenopril with Ν, Ν'-dibenzylethylenediamine according to claim 1 with the following rentgenskim difraktogramom: X-ray diffractogram: No. No. Položaj [ 2 theta /°] Position [2 theta / °] Razdalja [ d / A ] Distance [d / A] Rel. intenziteta [ % Rel. intensity [% 2 2 4,8157 4,8157 18,33508 18,33508 22,74 22,74 5 5 9,0256 9,0256 9,79002 9,79002 22,90 22,90 6 6 9,3796 9,3796 9,42134 9,42134 17,14 17.14 7 7 9,6776 9,6776 9,13190 9,13190 51,15 51.15 9 9 12,9249 12,9249 6,84393 6,84393 46,23 46,23 10 10 14,0657 14,0657 6,29134 6,29134 15,53 15.53 11 11 14,5326 14,5326 6,09022 6,09022 66,81 66.81 12 12 14,9637 14,9637 5,91571 5,91571 26,78 26,78
• ·• · 13 13 16,6958 16,6958 5,30569 5,30569 56,96 56.96 14 14 17,4254 17,4254 5,08515 5,08515 17,78 17,78 15 15 18,4070 18,4070 4,81750 4,81750 54,70 54.70 16 16 18,7237 18,7237 4,73538 4,73538 100,00 100.00 17 17 19,3397 19,3397 4,58591 4,58591 40,38 40.38 19 19 21,0942 21.0942 4,20828 4,20828 23,32 23,32 20 20 21,2653 21,2653 4,17481 4,17481 18,77 18,77 21 21 21,9128 21,9128 4,05289 4,05289 66,84 66.84 24 24 24,3046 24,3046 3,65919 3,65919 24,39 24.39 25 25 25,0970 25.0970 3,54541 3,54541 19,41 19,41 26 26 26,0301 26.0301 3,42040 3,42040 23,43 23,43 27 27 26,8654 26,8654 3,31592 3,31592 25,28 25,28 28 28 28,2661 28,2661 3,15471 3,15471 21,79 21,79 29 29 28,6171 28,6171 3,11681 3,11681 18,52 18.52 30 30 29,2658 29,2658 3,04918 3,04918 47,43 47.43 31 31 30,0432 30.0432 2,97202 2,97202 15,22 15,22 33 33 31,6758 31,6758 2,82247 2,82247 31,67 31,67 34 34 32,7945 32,7945 2,72870 2,72870 24,48 24,48 35 35 34,2694 34,2694 2,61456 2,61456 20,43 20,43 36 36 35,1785 35,1785 2,54904 2,54904 16,26 16.26
6. Sol zofenoprila z 1,3-diamino-1-propanolom po zahtevku 1 z naslednjim rentgenskim difraktogramom:The salt of zofenopril with 1,3-diamino-1-propanol according to claim 1 with the following X-ray diffraction pattern: No. No. Položaj [ 2 theta /°j Position [2 theta / ° j Razdalja [ d / A ] Distance [d / A] Rel. intenziteta [ % Rel. intensity [% 11 11 15,8829 15,8829 5,57536 5,57536 96,96 96.96 15 15 17,0655 17,0655 5,19158 5,19158 23,15 23.15 16 16 17,5637 17,5637 5,04541 5,04541 100,00 100.00 20 20 19,7596 19,7596 4,48941 No. 4,48941 19,34 19,34 22 22 20,5599 20,5599 4,31631 4,31631 13.23 13.23 23 23 20,9703 20,9703 4,23287 4,23287 28,25 28,25 24 24 21,3168 21,3168 4,16484 4,16484 18,90 18,90 25 25 22,1812 22,1812 4,00444 4,00444 37,54 37.54 26 26 22,6882 22,6882 3,91609 3,91609 54,02 54.02 27 27 23,0216 23,0216 3,86013 3,86013 15,15 15.15 29 29 24,2341 24,2341 3,66986 3,66986 41,93 41.93 30 30 24,6348 24,6348 3,61089 3,61089 14,65 14,65 32 32 25,8287 25,8287 3,44674 3,44674 44,30 44,30 33 33 26,3087 26,3087 3,38482 3,38482 17,48 17,48 34 34 27,1428 27,1428 3,28266 3,28266 31,07 31.07 35 35 27,4263 27,4263 3,24937 3,24937 14,17 14.17 36 36 28,7918 28,7918 3,09838 3,09838 28,09 28.09 39 39 30,9007 30,9007 2,89148 2,89148 21.24 21.24 40 40 31,2312 31,2312 2,86163 2,86163 14,83 14,83 42 42 32,1246 32,1246 2,78405 2,78405 17,73 17.73 43 43 32,7009 32,7009 2,73639 2,73639 19,84 19,84 44 44 33,8865 33,8865 2,64322 2,64322 25,59 25.59 45 45 34,7113 34,7113 2,58228 2,58228 10,98 10.98 46 46 35,4357 35.4357 2,53113 2,53113 29,09 29.09 47 47 36,2288 36,2288 2,47752 2,47752 12,21 12,21
7. Sol zofenoprila z (R)-2-amino-1-butanolom po zahtevku 1 z naslednjim rentgenskim difraktogramom:7. The salt of zofenopril with (R) -2-amino-1-butanol according to claim 1 with the following X-ray diffraction pattern: No.: No .: Položaj [ 2 theta /°] Position [2 theta / °] Razdalja [ d / A ] Distance [d / A] Rel. intenziteta [ % Rel. intensity [% 3 3 9,0551 9,0551 9,75824 9,75824 15,16 15.16 13 13 18,9475 18.9475 4,67996 4,67996 9,96 9.96 14 14 20,0524 20.0524 4,42450 4,42450 14,74 14,74 16 16 21,5877 21,5877 4,11317 4,11317 100,00 100.00 18 18 23,4280 23,4280 3,79409 3,79409 18,35 18,35 22 22 25,2415 25,2415 3,52545 3,52545 10,04 10.04 24 24 27,2815 27,2815 3,26628 3,26628 12,99 12,99 25 25 27,9473 27,9473 3,18997 3.18997 11,62 11,62 29 29 31.3866 31.3866 2,84781 2,84781 13,11 13.11
8. Sol zofenoprila z 2-amino-1 -etanolom po zahtevku 1 z naslednjim rentgenskim difraktogramom:The salt of zofenopril with 2-amino-1-ethanol according to claim 1 with the following X-ray diffractogram: No.: No .: Položaj [ 2 theta /° ] Position [2 theta / °] Razdalja [ d/A ] Distance [d / A] Rel. intenziteta [ % ] Rel. intensity [%] 8 8 18,2813 18,2813 4,84895 4,84895 51,33 51.33 11 11 20,7644 20,7644 4,27437 4,27437 47,64 47.64 12 12 21,5219 21,5219 4,12560 4,12560 18,51 18,51 13 13 22,0849 22.0849 4,02169 4,02169 100,00 100.00 15 15 23,1722 23,1722 3,83537 3,83537 48,90 48.90 16 16 23,6163 23,6163 3,76425 3,76425 53,97 53.97 18 18 25,2647 25,2647 3,52226 3,52226 16,25 16,25 19 19 25,4502 25,4502 3,49702 3,49702 20,32 20,32 20 20 25,7698 25,7698 3,45436 3,45436 12,08 12.08 21 21 26,4076 26,4076 3,37236 3,37236 67,58 67.58 22 22 27,2237 27,2237 3,27309 3,27309 13,54 13,54 23 23 27,6248 27,6248 3,22647 3,22647 11,94 11,94 24 24 28,3944 28,3944 3,14074 3,14074 26,93 26.93 25 25 30,1998 30,1998 2,95697 2,95697 39,27 39.27 26 26 31,2466 31,2466 2,86025 2,86025 13,73 13,73 27 27 32,1108 32,1108 2,78522 2,78522 17,29 17,29 28 28 33,3411 33,3411 2,68520 2,68520 35,41 35.41 29 29 33,6594 33,6594 2,66054 2,66054 19,39 19,39
9. Postopek za pripravo soli zofenoprila po zahtevkih od 1 do 8, ki obsega naslednje stopnje:A process for the preparation of a zofenopril salt according to claims 1 to 8, comprising the following steps: a) kombinacijo raztopine zofenoprila ali njegove topne soli z organskimi amino spojinami ali njihovimi solmi,a) the combination of a solution of zofenopril or its soluble salt with organic amino compounds or their salts, b) mešanje te nastale raztopine in stanje pri znižani temperaturi dokler sol ne kristalizira,b) stirring this resulting solution and the condition at reduced temperature until the salt crystallizes, c) separacijo nastale kristalne soli od raztopine,c) separation of the crystalline salt formed from the solution, d) sušenje soli pri temperaturi do največ 50 °C v vakuumu.d) drying the salt at a temperature not exceeding 50 ° C in vacuo. 10. Farmacevtska formulacija,ki vsebuje soli zofenoprila po zahtevkih od 1 do 8.A pharmaceutical formulation comprising zofenopril salts according to claims 1 to 8. 11. Uporaba soli zofenoprila po zahtevkih od 1 do 8, za izdelavo zdravila za zdravljenje arterijske hipertenzije in miokardnega infarkta.Use of the zofenopril salt according to claims 1 to 8 for the manufacture of a medicament for the treatment of arterial hypertension and myocardial infarction.
SI201100472A 2011-12-19 2011-12-19 The new crystalline salts of zofenopril, the procedure for obtaining them and their use in therapy SI23949A (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
SI201100472A SI23949A (en) 2011-12-19 2011-12-19 The new crystalline salts of zofenopril, the procedure for obtaining them and their use in therapy
PCT/SI2012/000040 WO2013095307A1 (en) 2011-12-19 2012-06-19 New crystal salts of zofenopril, process for obtaining them and their use in therapy
EP12753265.3A EP2794560A1 (en) 2011-12-19 2012-06-19 New crystal salts of zofenopril, process for obtaining them and their use in therapy

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
SI201100472A SI23949A (en) 2011-12-19 2011-12-19 The new crystalline salts of zofenopril, the procedure for obtaining them and their use in therapy

Publications (1)

Publication Number Publication Date
SI23949A true SI23949A (en) 2013-06-28

Family

ID=46759025

Family Applications (1)

Application Number Title Priority Date Filing Date
SI201100472A SI23949A (en) 2011-12-19 2011-12-19 The new crystalline salts of zofenopril, the procedure for obtaining them and their use in therapy

Country Status (3)

Country Link
EP (1) EP2794560A1 (en)
SI (1) SI23949A (en)
WO (1) WO2013095307A1 (en)

Family Cites Families (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US431690A (en) 1890-07-08 William z
US4316906A (en) 1978-08-11 1982-02-23 E. R. Squibb & Sons, Inc. Mercaptoacyl derivatives of substituted prolines
CA1144930A (en) 1978-08-11 1983-04-19 Miguel A. Ondetti Mercaptoacyl derivatives of substituted prolines
FR2746101B1 (en) 1996-03-14 1998-04-30 BICYCLIC-AROMATIC COMPOUNDS
IT1301993B1 (en) 1998-08-04 2000-07-20 Menarini Ricerche Spa PROCESS FOR THE PREPARATION OF ZOFENOPRIL CALCIUM SALT.
WO2007003963A1 (en) 2005-07-01 2007-01-11 Generics [Uk] Limited Zofenopril calcium in polymorph form c
CN101053563A (en) 2006-04-12 2007-10-17 北京德众万全药物技术开发有限公司 Zofenopril oral medicinal composition
EP2041083B1 (en) 2006-05-26 2014-11-05 Generics [UK] Limited Methods of preparing zofenopril calcium
CN101012192A (en) 2007-01-30 2007-08-08 广东邦民制药厂有限公司 Method of preparing zofenopril calcium
GB0715626D0 (en) 2007-08-10 2007-09-19 Generics Uk Ltd Crystalline form of zofenopril calcium
CN101372472A (en) 2007-08-24 2009-02-25 扬子江药业集团上海海尼药业有限公司 Method for synthesizing Zofenopril
EP2245007B1 (en) 2008-02-27 2020-08-19 Generics [UK] Limited Process for preparing a crystalline form of zofenopril calcium
WO2010084515A2 (en) 2009-01-23 2010-07-29 Glenmark Generics Limited A process for the preparation of zofenopril and its pharmaceutically acceptable salts thereof

Also Published As

Publication number Publication date
EP2794560A1 (en) 2014-10-29
WO2013095307A1 (en) 2013-06-27

Similar Documents

Publication Publication Date Title
EA009736B1 (en) 3-[(2-{[4-hexyloxycarbonylamino-imino-methyl)-phenylamino]-methyl}-1-methyl-1h-benzimidazol-5-carbonyl)-pyridine-2-yl-amino]-propionic acid ethyl ester methane sulphonate and use thereof as a medicament
KR101829706B1 (en) Acid addition salts of (S)-4-(5,7-difluorochroman-4-yloxy)-N,N,2-trimethyl-1H-benzo[d]imidazole-6-carboxamide
SK283394B6 (en) 4-phenylpiperidine compounds and its pharmaceutically acceptable salts, process for their preparation, medicament containing them and their use
KR20180030964A (en) The co-crystals of ibrutinib and carboxylic acid
NO335103B1 (en) Compound, pharmaceutical composition containing the compound, use of the compound and method of preparation thereof
EP2186809A1 (en) New crystal form of sunitinib malate
CZ342896A3 (en) Crystalline hydrochloride of (r)-(-)-2-{n-£4-(1,1-dioxido-3-oxo-2,3-dihydrobenzisothiazol-1-yl)-butyl|- -aminomethyl}-chroman, process of its preparation, pharmaceutical composition containing thereof and its use
WO2012051246A1 (en) Tapentadol hydrobromide and crystalline forms thereof
WO2010049449A2 (en) Novel salts of sunitinib
US20230028566A1 (en) Crystalline Form of a 7H-Benzo[7]Annulene-2-Carboxylic Acid Derivative
EP2601175A1 (en) A novel crystalline compound comprising saxagliptin and phosphoric acid
KR20090122218A (en) Acid addition salts, hydrates and polymorphs of 5-(2,4-dihydroxy-5-isopropyl-phenyl)-4-(4-morpholin-4-ylmethyl-phenyl)-isoxazole-3-carboxylic acid ethylamide and formulations comprising these forms
WO2012017029A1 (en) Novel salts of saxagrliptin with organic di-acids
TW200900392A (en) Novel crystalline bepotastine metal salt hydrate, method for preparing same, and pharmaceutical composition comprising same
AU2007309558B2 (en) Crystal modifications -3- (1H-indol-3-yl) -4- [2- (4-methyl-piperazin-1-yl) -quinazolin-4-yl] -pyrrole-2, 5-dione
US7915302B2 (en) Crystal forms of pyrrolylheptanoic acid derivatives
SI23949A (en) The new crystalline salts of zofenopril, the procedure for obtaining them and their use in therapy
US9034904B2 (en) Forms of dexlansoprazole and processes for the preparation thereof
KR20110095400A (en) Novel polymorphic forms of an azabicyclo-trifluoromethyl benzamide derivative
US9981912B2 (en) Cocrystal of lorcaserin, preparation methods, pharmaceutical compositions and uses thereof
US20050113309A1 (en) Crystalline forms(2s)-n-5[amino(imino)methyl]-2-thienylmethyl-1-(2r)-2[(carboxymethyl) amino]-3,3-diphenylpropanoyl-2-pyrrolidinecarboxamide nh2o
EP2773621B1 (en) A process for making crystalline delta-form of ivabradine hydrochloride
MXPA01012328A (en) Polymorphs of crystalline (2-benzhydryl-1-azabicyclo[2.2. 2]oct-3-yl)-(5-isopropyl-2-methoxybenzyl)-amine citrate as nk-1 receptor antagonists.
RU2487128C2 (en) 3-(1h-indol-3-yl)-4-[2-(4-methylpiperazin-1-yl)quinazolin-4-yl]pyrrole-2,5-dione salts
JPWO2020129876A1 (en) A novel form of isoquinoline sulfonamide

Legal Events

Date Code Title Description
OO00 Grant of patent

Effective date: 20130710

KO00 Lapse of patent

Effective date: 20170818