EP2794560A1 - New crystal salts of zofenopril, process for obtaining them and their use in therapy - Google Patents

New crystal salts of zofenopril, process for obtaining them and their use in therapy

Info

Publication number
EP2794560A1
EP2794560A1 EP12753265.3A EP12753265A EP2794560A1 EP 2794560 A1 EP2794560 A1 EP 2794560A1 EP 12753265 A EP12753265 A EP 12753265A EP 2794560 A1 EP2794560 A1 EP 2794560A1
Authority
EP
European Patent Office
Prior art keywords
zofenopril
salt
salts
following
spacing
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP12753265.3A
Other languages
German (de)
French (fr)
Inventor
Rudolf RU MAN
Pavel Zupet
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Silverstone Pharma AG
Original Assignee
Silverstone Pharma AG
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 AG filed Critical Silverstone Pharma AG
Publication of EP2794560A1 publication Critical patent/EP2794560A1/en
Withdrawn legal-status Critical Current

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

Definitions

  • the present invention belongs to the field of pharmaceutical chemistry and relates to new salts of zofenopril and polymorph forms thereof.
  • n 1 or 2
  • Ri can be H, a CH 3 or C 2 H 5 group and R 2 is a CH 2 OH group, or
  • the base is an organic diamino compound of formula III:
  • R can be H, an alkyl group having 1 to 6 carbon atoms or a benzyl group
  • m can represent 0 or 1 ,
  • X can represent an OH group or H.
  • zofenopril is used exclusively in the form of a calcium salt.
  • a drawback of this salt is its very low solubility in water and especially its numerous polymorph forms. Under certain conditions, it also happens that one polymorph form turns into another and a mixture of polymorph forms is obtained.
  • Zofenopril is an ACE inhibitor (abr.: Angiotensin Converting Enzyme) and is used in the treatment of cardiovascular diseases, especially for regulating high blood pressure and myocardial infarction. It further has lipophilic and antioxidative properties due to the presence of sulfide function.
  • Patent applications WO 2007/138352A1 and WO 2007/003963A1 disclose a process for producing a calcium salt of zofenopril, which in addition to polymorph form A also contains 6 % of other forms, wherein the solution of a soluble calcium salt, preferably calcium chloride is reacted with a solution of zofenopril acid or other salt of zofenopril.
  • the company Generics Ltd. protected two new polymorph crystal forms E in F in their patent application WO 2009/106894 Al, whereas patent application WO 2009/022168 Al discloses a new anhydrous form D of a calcium salt of zofenopril.
  • Patent application WO 2010/84515 A2 owned by Glenmark discloses a synthesis of zofenopril and its salts: amorphous and crystal forms of a calcium salt and in addition also salts with tert-butyl amine and dicyclohexylamine.
  • Publication MXPA 05013701 A-2007-06,14,6 of the company Menarini describes a pharmaceutical formulation of zofenopril with the diuretic hydrochlorotiazide.
  • Patent US 4,316,906 provides an exhaustive description of a synthesis of zofenopril and related compounds.
  • salts of zofenopril particularly calcium salt
  • their low solubility and bad resorption and in particular their tendency to form numerous polymorph forms as well as uncontrolled mixtures of polymorphic forms.
  • the present invention therefore relates to new salts of zofenopril represented with the above-stated general formula I and their hydrates having 1 to 3 molecules of water.
  • the present invention further relates to a process for the preparation of salts of zofenopril according to the present invention, said method comprising the following steps: a) combining a solution of zofenopril or its soluble salt with organic amino compounds or their salts,
  • pure zofenopril which is an acid
  • its soluble salt such as sodium or potassium salt
  • Ethylenediamine or a substituted ethylenediamine such as ⁇ , ⁇ '- dibenzylethylenediamine or ⁇ , ⁇ '-dimethylethylenediamine, or an amino alcohol such as 2-amino-l-butanol, 2-amino-l ethanol or l,3-diamino-2-propanol are used as organic bases.
  • Amino alcohols are used in a ratio of 1 mol to 1 mol of zofenopril and in case of a reaction with ethylene diamine derivatives in a ratio of 2 mol of zofenopril to 1 mol of ethylenediamine.
  • the reaction is performed at room temperature in a suitable solvent, such as methanol, ethanol, ethyl acetate, acetonitrile or in a mixture of these solvents with water.
  • a suitable solvent such as methanol, ethanol, ethyl acetate, acetonitrile or in a mixture of these solvents with water.
  • a third less polar solvent such as diethyl ether, n- hexane or methyl tert-butyl ether may be added in crystallization.
  • the present invention further relates to pharmaceutical formulations containing salts of zofenopril according to the present invention.
  • Salts of zofenopril prepared according to the present invention are used as active ingredients in the preparation of tablets or other solid forms by use of substances and processes which are common in manufacturing of solid pharmaceutical formulations, such as fillers, disintegrants, lubricants, glidants etc.
  • the salts of zofenopril in a pharmaceutical formulation may also be combined with diuretics such as indapamide, or with calcium ion inhibitors form the group of dihydropiridines (amlodipine, lacidipine).
  • the present invention thus further relates to the use of salts of zofenopril according to the present invention for manufacturing of a medicament for the treatment of arterial hipertension and miocardial infarction.
  • Fig. 1 ⁇ -NMR spectrum of salt of zofenopril with ⁇ , ⁇ '-ethylenediamine - trihydrate
  • Fig. 2 ⁇ -NMR spectrum of salt of zofenopril with N,N'-dimethylethylenediamine
  • Fig. 3 ⁇ -NMR spectrum of salt of zofenopril with N,N'-dibenzylethylenediamine
  • Fig. 4 ⁇ -NMR spectrum of salt of zofenopril with 1,3-diamino-l-propanol - trihydrate
  • Fig. 5 ⁇ -NMR spectrum of salt of zofenopril with (R)-2-amino-l-butanol
  • the X-ray powder diffractogram represented by the following 2 values and relative intensities (only reflexes above 10 % are indicated):
  • the X-ray powder diffractogram represented by the following 2 ⁇ -values and relative intensities (only reflexes above 10 % are indicated):
  • the X-ray powder diffractogram represented by the following 2 lvalues and relative intensities (only reflexes above 10 % are indicated): Position [2 ⁇ °] Spacing [d/A] Relative intensity [%]
  • the X-ray powder diffractogram represented by the following 2(9-values and relative intensities (only reflexes above 10 % are indicated):
  • the X-ray powder diffractogram represented by the following 2 ⁇ -values and relative intensities (only reflexes above 10 % are indicated):
  • the X-ray powder diffractogram represented by the following 2 ⁇ -values and relative intensities (only reflexes above 10 % are indicated):
  • Film coating ingredients hypromellose, titanium dioxide, macrogol 400, macrogol

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

The patent application describes new salts of zofenopril in an exactly defined crystal form, processes for their preparation and pharmaceutical formulations in solid form for use in the treatment of miocardial infarction and arterial hypertension.

Description

New crystal salts of zofenopril, process for obtaining them and their use in therapy
Technical Field
The present invention belongs to the field of pharmaceutical chemistry and relates to new salts of zofenopril and polymorph forms thereof.
The salts of zofenopril, which is chemically (4S)-l-[(2S)-3-benzoylthio-2- methylpropionyl]-4-(phenylthio)-L-proline, have the following general formula I:
wherein
n represents 1 or 2,
base is an organic amino compound of formula II:
wherein
Ri can be H, a CH3 or C2H5 group and R2 is a CH2OH group, or
the base is an organic diamino compound of formula III:
R N H CH2 ( CH ) m CH2 NH R
X wherein
R can be H, an alkyl group having 1 to 6 carbon atoms or a benzyl group;
m can represent 0 or 1 ,
X can represent an OH group or H.
Technical Problem
In pharmaceutics, zofenopril is used exclusively in the form of a calcium salt. A drawback of this salt is its very low solubility in water and especially its numerous polymorph forms. Under certain conditions, it also happens that one polymorph form turns into another and a mixture of polymorph forms is obtained. These problems could be reasonably solved by a preparation of a new salt that would crystallize in a unique, exactly defined crystal form.
Prior Art
Zofenopril is an ACE inhibitor (abr.: Angiotensin Converting Enzyme) and is used in the treatment of cardiovascular diseases, especially for regulating high blood pressure and myocardial infarction. It further has lipophilic and antioxidative properties due to the presence of sulfide function.
Zofenopril and other mercaptoacyl derivatives of substituted prolines were described in GB 2,028,327 and US 4,316,90 (Squibb & Sons company). Patents US 6,521 ,760 and US 6,515,021 owned by Menarini protected a process for the preparation of a calcium salt as a mixture of polymorph forms A in B. Patent applications WO 2007/138352A1 and WO 2007/003963A1 disclose a process for producing a calcium salt of zofenopril, which in addition to polymorph form A also contains 6 % of other forms, wherein the solution of a soluble calcium salt, preferably calcium chloride is reacted with a solution of zofenopril acid or other salt of zofenopril. The company Generics Ltd. protected two new polymorph crystal forms E in F in their patent application WO 2009/106894 Al, whereas patent application WO 2009/022168 Al discloses a new anhydrous form D of a calcium salt of zofenopril. Patent application WO 2010/84515 A2 owned by Glenmark discloses a synthesis of zofenopril and its salts: amorphous and crystal forms of a calcium salt and in addition also salts with tert-butyl amine and dicyclohexylamine. Publication MXPA 05013701 A-2007-06,14,6 of the company Menarini describes a pharmaceutical formulation of zofenopril with the diuretic hydrochlorotiazide. Patent US 4,316,906 provides an exhaustive description of a synthesis of zofenopril and related compounds. Numerous possible salts of zofenopril with several inorganic and organic bases are listed, however only the syntheses of sodium, potassium, calcium salts and salts with adamantylamine and 2-amino-2-hydroxymethyl- l,3-propanediol are documented. No crystal structures and polymorph modifications are mentioned, only a possibility of a combination of zofenopril with the diuretic hydrochlorotiazide. There are also known Chinese patents: CN 101012192A 2008, CN 101372472A 2009 and CN 101053563A 2007 which protect syntheses, oral pharmaceutical formulations and a combination with the diuretic hydrochlorotiazide.
Technical Solution
A considerable disadvantage of salts of zofenopril, particularly calcium salt, is their low solubility and bad resorption, and in particular their tendency to form numerous polymorph forms as well as uncontrolled mixtures of polymorphic forms.
According to the present invention new salts of zofenopril with an exactly defined uniform crystal structure have been prepared.
The present invention therefore relates to new salts of zofenopril represented with the above-stated general formula I and their hydrates having 1 to 3 molecules of water. The present invention further relates to a process for the preparation of salts of zofenopril according to the present invention, said method comprising the following steps: a) combining a solution of zofenopril or its soluble salt with organic amino compounds or their salts,
b) stirring the obtained solution and keeping it at a low temperature until the salt crystallizes,
c) separating the resulting crystal salt from the solution,
d) vacuum drying the salt at a temperature not exceeding 50 °C.
To this purpose, pure zofenopril (which is an acid) or its soluble salt, such as sodium or potassium salt, is used and subjected to a reaction with another organic base or a salt thereof and further crystallization to obtain new salts.
Surprisingly, these new salts possess good solubility in water and even more importantly, a stable crystal structure.
Ethylenediamine or a substituted ethylenediamine such as Ν,Ν'- dibenzylethylenediamine or Ν,Ν'-dimethylethylenediamine, or an amino alcohol such as 2-amino-l-butanol, 2-amino-l ethanol or l,3-diamino-2-propanol are used as organic bases. Amino alcohols are used in a ratio of 1 mol to 1 mol of zofenopril and in case of a reaction with ethylene diamine derivatives in a ratio of 2 mol of zofenopril to 1 mol of ethylenediamine.
The reaction is performed at room temperature in a suitable solvent, such as methanol, ethanol, ethyl acetate, acetonitrile or in a mixture of these solvents with water. In order to achieve a better yield, also a third less polar solvent such as diethyl ether, n- hexane or methyl tert-butyl ether may be added in crystallization. The identity and structure of the compounds were determined by an elemental anlysis, by FTIR spectra (apparatus Perkin Elmer 727B), by Ή-NMR spectra (apparatus Bruker Advance DPX300), and the crystal structure by powder X-ray diffractograms (diffractometer PANanalytica X'Pert, CuKa, range 3-35° 2 theta). The solubility of synthesized salts of zofenopril in water at 20 °C is suitable for the preparation of pharmaceutical formulations in a solid form.
The present invention further relates to pharmaceutical formulations containing salts of zofenopril according to the present invention.
Salts of zofenopril prepared according to the present invention are used as active ingredients in the preparation of tablets or other solid forms by use of substances and processes which are common in manufacturing of solid pharmaceutical formulations, such as fillers, disintegrants, lubricants, glidants etc.
The salts of zofenopril in a pharmaceutical formulation may also be combined with diuretics such as indapamide, or with calcium ion inhibitors form the group of dihydropiridines (amlodipine, lacidipine).
The present invention thus further relates to the use of salts of zofenopril according to the present invention for manufacturing of a medicament for the treatment of arterial hipertension and miocardial infarction.
Brief Description of Figures
Fig. 1 Ή-NMR spectrum of salt of zofenopril with Ν,Ν'-ethylenediamine - trihydrate Fig. 2 Ή-NMR spectrum of salt of zofenopril with N,N'-dimethylethylenediamine Fig. 3 Ή-NMR spectrum of salt of zofenopril with N,N'-dibenzylethylenediamine Fig. 4 Ή-NMR spectrum of salt of zofenopril with 1,3-diamino-l-propanol - trihydrate Fig. 5 Ή-NMR spectrum of salt of zofenopril with (R)-2-amino-l-butanol
Fig. 6 'H-NMR spectrum of salt of zofenopril with 2-amino-l -ethanol - hydrate.
The present invention is illustrated by the following non-limiting Examples.
Example 1. Salt of zofenopril with Λ N ' -ethylenediamine - trihydrate
To a solution of zofenopril (2.0 g, 4.65 mmol) in 10 ml of ethanol Ν,Ν'- ethylenediamine (0.15 g, 2.49 mmol) dissolved in 1 ml of ethanol was slowly added at 30 °C while stirring. While slowly stirring, 20 ml of diethyl ether were added. The crystals formed overnight were filtered off and vacuum dried. 1.99 g (92.5 %) of a crystal salt which melts at 78-80 °C were obtained. At 20 °C, 10 mg/100 ml dissolve in water.
The elemental analysis corresponds to formula: C46H54N4O8S4 · 3 H2O:
calculated: C: 56.77 % H: 6.21 % N: 5.67 %
found: C: 56.32 % H: 6.32 % N: 5.70 %
Water determination according to K. Fischer gives 5.5 %, which corresponds to a trihydrate.
IR spectrum (KBr): vlcm { = 3309 (NH/OH/COOH); 3058, 2972, 2930, 2856 (=CH, CH); 1653, 1631 (CO), 1560, 1580 (arom.).
Ή-NMR spectrum recorded in DMSO corresponds to the above structure (Fig. 1).
The X-ray powder diffractogram represented by the following 2 values and relative intensities (only reflexes above 10 % are indicated):
No. Position [2< /°] Spacing [d/A] Relative intensity [%]
2 7.4968 1 1.78268 100.00
6 10.7666 8.21056 17.62
10 14.1756 6.24279 18.00
15 17.0633 5.19225 28.33
18 18.7849 4.72009 48.21 19 19.5573 4.53539 66.79
20 20.2753 4.37635 79.31
21 20.9658 4.23375 21.78
22 21.6467 4.10210 37.73
23 22.0162 4.03408 16.10
25 22.5757 3.93535 14.94
26 23.5248 3.77869 37.44
27 23.8932 3.72126 17.79
29 25.0202 3.55612 25.61
31 26.2286 3.39497 1 1.78
Example 2. Salt of zofenopril with N,N'-dimethylethylenediamine
To the solution of zofenopril (2.7 g, 6.28 mmol) in acetonitrile (10 ml) N,N'-dimethyl- ethylenediamine (0.28 g, 3.17 mmol) was slowly added at 30 °C while stirring. A salt crystallized immediately. 2.90 g (97.3 %) of a compound with the melting point at 177-178 °C were obtained. 15 mg/100 ml dissolve in water at 20 °C.
Elemental analysis corresponds to formula: C48H58N4O8S4:
calculated: C: 60.86 % H: 6.17 % N: 5.91 %
found: C: 60.87 % H: 5.82 % N: 5.91 %
IR spectrum (KBr): v/cnf 1 = 3060, 2970, 2929, 2857 (=CH, CH); 1652, 1633 (CO),
1579 (arom.)
Ή-NMR spectrum (in DMSO) corresponds to the above structure.
The X-ray powder diffractogram represented by the following 2 ^-values and relative intensities (only reflexes above 10 % are indicated):
No. Position [2θ/°] Spacing [d/A] Relative intensity [%]
3 8.9856 9.83350 14.04
5 12.3249 7.17575 20.41
7 13.7868 6.41797 42.89
8 15.7461 5.62351 17.67
9 16.5660 5.34699 38.23
10 17.5937 5.03689 100.00
1 1 18.5747 4.77303 27.06 12 18.7471 4.72952 57.09
13 19.2580 4.60518 52.26
14 19.9986 4.43629 16.01
15 20.4523 4.33889 26.37
16 21.3897 4.15080 84.69
17 22.7087 3.91260 96.05
19 23.7407 3.74480 42.06
20 24.3608 3.65087 71.72
21 24.8107 3.58568 23.08
22 26.3491 3.37971 14.98
24 27.201 1 3.27575 34.98
27 . 28.9350 3.08329 21.25
28 29.8135 2.99440 18.81
29 30.8541 2.89574 17.46
32 33.4840 2.67407 17.88
33 34.0535 2.63064 1 1.28
35 35.2639 2.54307 20.78
36 35.8800 2.50080 33.21
Example 3. Salt of zofenopril with N ,Ν' -dibenzylethylenediamine
To the solution of a potassium salt of zofenopril (16.33 g, 34.9 mmol) in 23 % ethanol a solution of Ν,Ν'-dibenzylethylenediamine diacetate (6.3 g, 17.47 mmol) in 5 % ethanol was added while vigorously stirring at 30 °C. The crystal mass was stirred for another 15 min, then filtered, well washed with water and vacuum dried at 50 °C. 19.20 g (100 %) of colourless crystals with a melting point at 184-187 °C were obtained. 5 mg/100 ml dissolve in water.
Elemental analysis corresponds to formula: C60H66N4O8S :
calculated: C: 65.55 % H: 5.98 % N: 5.04 %
found: C: 65.67 % H: 6.05 % N: 5.14 %
IR spectrum (KBr): v/cm"1 = 3062, 2968, 2927, 2869 (=CH, CH); 1652, 1637 (C =
O); 1579 (arom.).
Ή-NMR spectrum in DMSO corresponds to the stated structure (Fig. 3).
The X-ray powder diffractogram represented by the following 2 lvalues and relative intensities (only reflexes above 10 % are indicated): Position [2 ΘΙ°] Spacing [d/A] Relative intensity [%]
2 4.8157 18.33508 22.74
5 9.0256 9.79002 22.90
6 9.3796 9.42134 17.14
7 9.6776 9.13190 51.15
9 12.9249 6.84393 46.23
10 14.0657 6.29134 15.53
1 1 14.5326 6.09022 66.81
12 14.9637 5.91571 26.78
13 16.6958 5.30569 56.96
14 17.4254 5.08515 17.78
15 18.4070 4.81750 54.70
16 18.7237 4.73538 100.00
17 19.3397 4.58591 40.38
19 21.0942 4.20828 23.32
20 21.2653 4.17481 18.77
21 21.9128 4.05289 66.84
24 24.3046 3.65919 24.39
25 25.0970 3.54541 19.41
26 26.0301 3.42040 23.43
27 26.8654 3.31592 25.28
28 28.2661 3.15471 21.79
29 28.6171 3.1 1681 18.52
30 29.2658 3.04918 47.43
31 30.0432 2.97202 15.22
33 31.6758 2.82247 31.67
34 32.7945 2.72870 24.48
35 34.2694 2.61456 20.43
36 35.1785 2.54904 16.26
Example 4. Salt of zofenopril with 1 , 3 -diamino-2 -propanol - trihydrate
Zofenopril (2.55 g, 5.94 mmol) was dissolved in 7 ml of ethanol and l ,3-diamino-2- propanol (0.28 g, 3.1 mmol) was slowly added while stirring and subsequently also 25 ml of methyl tert-butyl ether was added until slight turbidity was reached. The crystals that were precipitated overnight, were filtered off and vacuum dried. 2.72 g (96.1 %) of colourless crystals with a melting point at 104-106 °C were obtained. 17.5 mg/100 ml dissolve in water. Elemental analysis corresponds to formula: C 7H56N409S
calculated: C: 56.27 % H: 6.23 % N: 5.58 %
found: C: 56.49 % H: 6.10 % N: 5.59 %
An analysis according to K. Fischer gives 5.65 % of water which corresponds to trihydrate.
Ή-NM spectrum in DMSO corresponds to the above compound (Fig. 4).
The X-ray powder diffractogram represented by the following 2(9-values and relative intensities (only reflexes above 10 % are indicated):
No. Position [2< /°] Spacing [d/A] Relative intensity [%]
1 1 15.8829 5.57536 96.96
15 17.0655 5.19158 23.15
16 17.5637 5.04541 100.00
20 19.7596 4.48941 19.34
22 20.5599 4.31631 13.23
23 20.9703 4.23287 28.25
24 21.3168 4.16484 18.90
25 22.1812 4.00444 37.54
26 22.6882 3.91609 54.02
27 23.0216 3.86013 15.15
29 24.2341 3.66986 41.93
30 24.6348 3.61089 14.65
32 25.8287 3.44674 44.30
33 26.3087 3.38482 17.48
34 27.1428 3.28266 31.07
35 27.4263 3.24937 14.17
36 28.7918 3.09838 28.09
39 30.9007 2.89148 21.24
40 31.2312 2.86163 14.83
42 32.1246 2.78405 17.73
43 32.7009 2.73639 19.84
44 33.8865 2.64322 25.59
45 34.7113 2.58228 10.98
46 35.4357 2.531 13 29.09
47 36.2288 2.47752 12.21 Example 5. Salt of zofenopril with (R)-2-amino-l -butanol
To zofenopril (1 g, 2.32 mmol) in 15 ml of ethanol, (R)-2-amino- 1 -butanol (0.21 g, 2.33 mmol) was added and subsequently also 30 ml of diethyl ether were gradually added. Crystallization was carried out at -10 °C overnight. 0.77 g (63.6 %) of needle-shaped crystals with a melting point at 132-135 °C were obtained. 300 mg/100 ml dissolve in water.
Elemental analysis corresponds to formula: C26H34N2O5S2:
calculated: C: 60.20 % H: 6.61 % N: 5.40 %
found: C: 60.21 % H: 6.60 % N: 5.40 %
'H-NMR spectrum in DMSO corresponds to this compound (Fig. 5).
The X-ray powder diffractogram represented by the following 2 ^-values and relative intensities (only reflexes above 10 % are indicated):
No. Position [26>/°] Spacing [d/A] Relative intensity [%]
3 9.0551 9.75824 15.16
13 18.9475 4.67996 9.96
14 20.0524 4.42450 14.74
16 21.5877 4.1 1317 100.00
18 23.4280 3.79409 18.35
22 25.2415 3.52545 10.04
24 27.2815 3.26628 12.99
25 27.9473 3.18997 11.62
29 31.3866 2.84781 13.1 1
Example 6. Salt of zofenopril with 2 -amino- 1 -ethanol - hydrate
To the solution of zofenopril (2.0 g, 4.65 mmol) in 12 ml of ethanol, 2-amino-l- ethanol (0.285 g, 4.67 mmol) was added and stirred, subsequently also 30 ml of diethyl ether were gradually added. Crystallization was carried out at -10 °C for 24 hours. 2.04 g (89.3 %) of crystals with a melting point at 105-107 °C were obtained. They are well soluble in water: 8,75 g/100 ml at 20 °C. The elemental analysis corresponds to formula: C24H3oN2O5S2 · H20 :
calculated: C: 56.67 % H: 6.34 % N: 5.50 %
found: C: 56.80 % H: 6.29 % N: 5.50 %
An analysis according to . Fischer gives 3.18 % of water which corresponds to hydrate.
IR spectrum (KBr): v/cnf1 = 3061 , 2968, 2926, 2868 (=CH, CH), 1652, 1636 (C=0),
1579 (arom.)
1 H-NMR spectrum in DMSO corresponds to the stated structure (Fig. 6).
The X-ray powder diffractogram represented by the following 2 ^-values and relative intensities (only reflexes above 10 % are indicated):
No. Position [2 <9/°] Spacing [d/A] Relative intensity [%]
8 18.2813 4.84895 51.33
1 1 20.7644 4.27437 47.64
12 21.5219 4.12560 18.51
13 22.0849 4.02169 100.00
15 23.1722 3.83537 48.90
16 23.6163 3.76425 53.97
18 25.2647 3.52226 16.25
19 25.4502 3.49702 20.32
20 25.7698 3.45436 12.08
21 26.4076 3.37236 67.58
22 27.2237 3.27309 13.54
23 27.6248 3.22647 1 1.94
24 28.3944 3.14074 26.93
25 30.1998 2.95697 39.27
26 31.2466 2.86025 13.73
27 32.1 108 2.78522 17.29
28 33.341 1 2.68520 35.41
29 33.6594 2.66054 19.39 Example 7. Tablet composition
Ingredient Mass
(mg)
N,N'-dibenzylethylenediamine 9.2* (^corresponds to 7.2 mg of zofenopril) zofenopril
microcrystalline cellulose 36.4
lactose monohydrate 27.5
corn starch 16.2
hypromellose 3.0
colloidal silica 1.2
magnesium stearate 1.5
95.0 mg
Film coating ingredients: hypromellose, titanium dioxide, macrogol 400, macrogol
6000; total 5 mg.
Final tablet mass: 100 mg
Example 8. Tablet composition
Ingredient Mass
(mg)
N,N'-dimethylethylenediamine 15,80* (*corresponds to 14.33 mg of zofenopril) zofenopril
indapamide 1.25
cellactose 83.65
croscarmellose 2.50
colloidal silica 0.90
magnesium stearate 0.90
105 mg Film coating: 5 mg, final tablet mass: 1 10 mg.
Example 9. Tablet composition
Ingredient Mass
(mg)
N,N'-ethylenediamine 34.00* (Corresponds to 28.66 mg of zofenopril) zofenopril hydrate
amlodipine besylate 24.45
mannitol 67.30
lactose monohydrate 36.10
microcrystalline cellulose 57.50
corn starch 17.55
magnesium stearate 3.00
240 mg
Film coating: 10 mg, final tablet mass: 250 mg

Claims

Claims
1. Salts of zofenopril of general formula I:
wherein
n represents 1 or 2,
base is an organic amino compound of formula II:
wherein
Ri can be H, a CH3 or C2H5 group and R2 is a CH2OH group, or the base is an organic diamino compound of formula III:
R NH CH2 ( CH ) m CH2 NH - R
wherein
R can be H, an alkyl group having 1 to 6 carbon atoms or a benzyl group; m can represent 0 or 1 ,
X can represent an OH group or H.
2. Salts of zofenopril according to claim 1 in the form of hydrates having 1 to 3 molecules of water.
3. Salt of zofenopril with Ν,Ν'-ethylenediamine according to claim 1 with an X-ray powder diffractogram represented by the following 2 values and relative intensities:
No. Position [2θ/°] Spacing [d/A] Relative intensity [%]
2 7.4968 1 1.78268 100.00
6 10.7666 8.21056 17.62
10 14.1756 6.24279 18.00
15 17.0633 5.19225 28.33
18 18.7849 4.72009 48.21
19 19.5573 4.53539 66.79
20 20.2753 4.37635 79.31
21 20.9658 4.23375 21.78
22 21.6467 4.10210 37.73
23 22.0162 4.03408 16.10
25 22.5757 3.93535 14.94
26 23.5248 3.77869 37.44
27 23.8932 3.72126 17.79
29 25.0202 3.55612 25.61
31 26.2286 3.39497 1 1.78
4. Salt of zofenopril with Ν,Ν'-dimethylethylenediamine according to claim 1 with an X-ray powder diffractogram represented by the following 2 values and relative intensities:
Position [26·/°] Spacing [d/A] Relative intensity [%]
3 8.9856 9.83350 14.04
5 12.3249 7.17575 20.41
7 13.7868 6.41797 42.89
8 15.7461 5.62351 17.67
9 16.5660 5.34699 38.23
10 17.5937 5.03689 100.00
1 1 18.5747 4.77303 27.06
12 18.7471 4.72952 57.09
13 19.2580 4.60518 52.26
14 19.9986 4.43629 16.01
15 20.4523 4.33889 26.37
16 21.3897 4.15080 84.69
17 22.7087 3.91260 96.05
19 23.7407 3.74480 42.06
20 24.3608 3.65087 71.72
21 24.8107 3.58568 23.08
22 26.3491 3.37971 14.98
24 27.201 1 3.27575 34.98
27 28.9350 3.08329 21.25
28 29.8135 2.99440 18.81
29 30.8541 2.89574 17.46
32 33.4840 2.67407 17.88
33 34.0535 2.63064 1 1.28
35 35.2639 2.54307 20.78
36 35.8800 2.50080 33.21
5. Salt of zofenopril with Ν,Ν'-dibenzylethylenediamine according to claim 1 with an X-ray powder diffractogram represented by the following 2 lvalues and relative intensities:
No. Position [26P] Spacing [d/A] Relative intensity [%]
2 4.8157 18.33508 22.74
5 9.0256 9.79002 22.90
6 9.3796 9.42134 17.14
7 9.6776 9.13190 51.15
9 12.9249 6.84393 46.23
10 14.0657 6.29134 15.53
1 1 14.5326 6.09022 66.81
12 14.9637 5.91571 26.78
13 16.6958 5.30569 56.96
14 17.4254 5.08515 17.78
15 18.4070 4.81750 54.70
16 18.7237 4.73538 100.00
17 19.3397 4.58591 40.38
19 21.0942 4.20828 23.32
20 21.2653 4.17481 18.77
21 21.9128 4.05289 66.84
24 24.3046 3.65919 24.39
25 25.0970 3.54541 19.41
26 26.0301 3.42040 23.43
27 26.8654 3.31592 25.28
28 28.2661 3.15471 21.79
29 28.6171 3.1 1681 18.52
30 29.2658 3.04918 47.43
31 30.0432 2.97202 15.22
33 31.6758 2.82247 31.67
34 32.7945 2.72870 24.48
35 34.2694 2.61456 20.43
36 35.1785 2.54904 16.26
6. Salt of zofenopril with 1,3-diamino-l-propanol according to claim 1 with an X-ray powder diffractogram represented by the following 2 values and relative intensities:
No. Position [26>/°] Spacing [d/A] Relative inte
11 15.8829 5.57536 96.96
15 17.0655 5.19158 23.15
16 17.5637 5.04541 100.00
20 19.7596 4.48941 19.34
22 20.5599 4.31631 13.23
23 20.9703 4.23287 28.25
24 21.3168 4.16484 18.90
25 22.1812 4.00444 37.54
26 22.6882 3.91609 54.02
27 23.0216 3.86013 15.15
29 24.2341 3.66986 41.93
30 24.6348 3.61089 14.65
32 25.8287 3.44674 44.30
33 26.3087 3.38482 17.48
34 27.1428 3.28266 31.07
35 27.4263 3.24937 14.17
36 28.7918 3.09838 28.09
39 30.9007 2.89148 21.24
40 31.2312 2.86163 14.83
42 32.1246 2.78405 17.73
43 32.7009 2.73639 19.84
44 33.8865 2.64322 25.59
45 34.71 13 2.58228 10.98
46 35.4357 2.531 13 29.09
47 36.2288 2.47752 12.21
7. Salt of zofenopril with (R)-2-amino-l-butanol according to claim 1 with an X-ray powder diffractogram represented by the following 2 values and relative intensities: No. Position [26>/°] Spacing [d/A] Relative intensity [%
3 9.0551 9.75824 15.16
13 18.9475 4.67996 9.96
14 20.0524 4.42450 14.74
16 21.5877 4.1 1317 100.00
18 23.4280 3.79409 18.35
22 25.2415 3.52545 10.04
24 27.2815 3.26628 12.99
25 27.9473 3.18997 1 1.62
29 31.3866 2.84781 13.1 1
8. Salt of zofenopril with 2-amino-l-ethanol according to claim 1 with an X-ray powder diffractogram represented by the following 2 #- values and relative intensities:
No. Position [26P] Spacing [d/A] Relative intensity [%]
8 18.2813 4.84895 51.33
1 1 20.7644 4.27437 47.64
12 21.5219 4.12560 18.51
13 22.0849 4.02169 100.00
15 23.1722 3.83537 48.90
16 23.6163 3.76425 53.97
18 25.2647 3.52226 16.25
19 25.4502 3.49702 20.32
20 25.7698 3.45436 12.08
21 26.4076 3.37236 67.58
22 27.2237 3.27309 13.54
23 27.6248 3.22647 1 1.94
24 28.3944 3.14074 26.93
25 30.1998 2.95697 39.27
26 31.2466 2.86025 13.73
27 32.1 108 2.78522 17.29
28 33.341 1 2.68520 35.41
29 33.6594 2.66054 19.39
9. A process for the preparation of salts of zofenopril according to claims 1-8 comprising the following steps: a) combining a solution of zofenopril or its soluble salt with organic amino compounds or their salts,
b) stirring the obtained solution and keeping it at a low temperature until the salt crystallizes,
c) separating the resulting crystal salt from the solution,
d) vacuum drying the salt at a temperature not exceeding 50 °C.
10. A pharmaceutical formulation containing salts of zofenopril according to claims 1 to 8.
1 1. Use of salts of zofenopril according to claims 1 to 8 used in the manufacture of a medicament for the treatment of arterial hipertension and miocardial infarction.
EP12753265.3A 2011-12-19 2012-06-19 New crystal salts of zofenopril, process for obtaining them and their use in therapy Withdrawn EP2794560A1 (en)

Applications Claiming Priority (2)

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

Publications (1)

Publication Number Publication Date
EP2794560A1 true EP2794560A1 (en) 2014-10-29

Family

ID=46759025

Family Applications (1)

Application Number Title Priority Date Filing Date
EP12753265.3A Withdrawn EP2794560A1 (en) 2011-12-19 2012-06-19 New crystal salts of zofenopril, process 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.
AU2006264650B2 (en) 2005-07-01 2012-08-23 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
HRP20150046T1 (en) 2006-05-26 2015-03-13 Generics PROCEDURES FOR PREPARATION OF 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
JP5530369B2 (en) 2008-02-27 2014-06-25 ジェネリクス・［ユーケー］・リミテッド New crystal form
WO2010084515A2 (en) 2009-01-23 2010-07-29 Glenmark Generics Limited A process for the preparation of zofenopril and its pharmaceutically acceptable salts thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO2013095307A1 *

Also Published As

Publication number Publication date
WO2013095307A1 (en) 2013-06-27
SI23949A (en) 2013-06-28

Similar Documents

Publication Publication Date Title
US12221417B2 (en) Salt of omecamtiv mecarbil and process for preparing salt
JP7407740B2 (en) Crystal forms of TLR7/TLR8 inhibitors
US8410288B2 (en) Polymorphs of Saxagliptin hydrochloride and processes for preparing them
US7989494B2 (en) Polymorphs of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide
WO2017009784A1 (en) Solid state forms of trisodium salt of valsartan/sacubitril complex and sacubitril
EP2601175A1 (en) A novel crystalline compound comprising saxagliptin and phosphoric acid
WO2016189486A1 (en) An improved process for preparation of apremilast and novel polymorphs thereof
US20080269315A1 (en) Crystalline form
CN101652358A (en) Novel crystalline bepotastine metal salt hydrate, method for preparing same, and pharmaceutical composition comprising same
US12384784B2 (en) Polymorphs of Acalabrutinib, a Bruton&#39;s tyrosine kinase inhibitor
TW201412745A (en) Crystal of N-[2-({2-[(2S)-2-cyanopyrrolidin-1-YL]-2- oxoethyl}amino)-2-methylpropyl]-2-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide
EP2794560A1 (en) New crystal salts of zofenopril, process for obtaining them and their use in therapy
WO2022232060A1 (en) Processes for the synthesis of valbenazine
EP2787998B1 (en) Crystalline forms of 2-(2-methylamino-pyrimidin-4-yl)-1h-indole-5-carboxylic acid [(s)-1-carbamoyl-2-(phenyl-pyrimidin-2-yl-amino)-ethyl]-amide
JP5530369B2 (en) New crystal form
US20110281928A1 (en) Process for the preparation of zofenopril and its pharmaceutically acceptable salts thereof
WO2006048894A1 (en) Novel crystalline forms of atorvastatin calcium and processes for preparing them.
CA2902436C (en) Salt of omecamtiv mecarbil and process for preparing salt
CA3268861A1 (en) Novel co-crystal of enavogliflozin
WO2012044189A1 (en) A new hydrated crystalline form of perindopril erbumine, methods for its preparation and its use in pharmaceutical preparations
HK1141290A (en) Novel crystalline bepotastine metal salt hydrate, method for preparing same, and pharmaceutical composition comprising same
HK1218544B (en) Salt of omecamtiv mecarbil and process for preparing salt
WO2013054146A1 (en) New co crystals useful in the preparation of pharmaceutical compositions

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 20140717

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

DAX Request for extension of the european patent (deleted)
17Q First examination report despatched

Effective date: 20151102

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20160312