WO1993013056A1 - Stable salts of (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid, process for their preparation and pharmaceutical compositions containing them - Google Patents

Stable salts of (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid, process for their preparation and pharmaceutical compositions containing them Download PDF

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WO1993013056A1
WO1993013056A1 PCT/EP1992/002903 EP9202903W WO9313056A1 WO 1993013056 A1 WO1993013056 A1 WO 1993013056A1 EP 9202903 W EP9202903 W EP 9202903W WO 9313056 A1 WO9313056 A1 WO 9313056A1
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Prior art keywords
oxoethyl
carbonyl
carboxylic acid
salts
alkaline
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PCT/EP1992/002903
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French (fr)
Inventor
Raffaello Giorgi
Alessandro Subissi
Luigi Turbanti
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Laboratori Guidotti Spa
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Priority to JP5511398A priority Critical patent/JPH06506002A/en
Priority to AU30871/92A priority patent/AU657591B2/en
Priority to RU9293052414A priority patent/RU2079489C1/en
Priority to BR9205652A priority patent/BR9205652A/en
Publication of WO1993013056A1 publication Critical patent/WO1993013056A1/en
Priority to BG98050A priority patent/BG98050A/en
Priority to NO93932982A priority patent/NO932982L/en
Priority to FI933685A priority patent/FI933685A/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/26—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having more than one amino group bound to the carbon skeleton, e.g. lysine
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • This invention refers to novel salts of
  • (+)-(lS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane- 1-carboxylic acid 1, (D.C.I. Idrapril) is a compound disclosed in the European Patent Application No. 89106304.2 as a novel ACE- inhibitory agent and therefore having antihypertensive activity.
  • This acid when kept exposed to the air in the normal environmental conditions of humidity and temperature, is subject to autodecomposition processes which give rise to impurities obviously incompatible with regard to a therapeutical use. Such degradation processes are also accelerated by a temperature increase of the acid kept in the above conditions.
  • novel salts according to this invention do not undergo to the autodecomposition and degradation processes previously mentioned.
  • the salts of the invention are stable compounds in the normal environmental conditions. Further the salts remain unchanged with time either kept as such or included (in a solid state) in a pharmaceutical preparation (tablets, pills, capsules, lyophilized compositions and the like) provided for their therapeutical use.
  • a pharmaceutical preparation tablettes, pills, capsules, lyophilized compositions and the like
  • the preparation of the compounds of the invention is based on a process characterized in that a compound, selected between
  • (+)-(1S,2R)-2-[[N-(2-hydroxyIamino-2-oxoethyl)-N-methylam ⁇ no]carbonyllcyclohexane-1 -carboxylic acid 1, is reacted with a compound selected among hydrates and carbonates or other suitable salts of alkaline and alkaline-earth metals, as defined in the present invention, as well as with organic bases, in an organic solvent or mixtures thereof with water, the reaction taking place, in the case of the starting product 2, contemporaneous hydrogenalysis of the protecting benzyl group with hydrogen at atmospheric pressure, in the presence of a suitable hydrogenation catalyst, the process being completed by isolating the desired salt of the acid.
  • Q is said hydroxide, or alkaline salt or calcium salt or an organic base.
  • the preferred hydrogenation catalyst is charcoal-supported Pd, but PtO 2 ,Rh/Al 2 O 3 and Ni-Raney can also be used.
  • propanol, tetrahydrofuran and dioxane are also suitable besides methanol and ethanol.
  • the catalyst was filtered and washed with awater/methanol (1/1) mixture (300 ml) and the filtrate, combined with the washings, concentrated under vacuum at 40°C until all the methanol has been removed.
  • the final suspension was cooled for 20 hours at 0-4°C and the precipitate was filtered and washed on the filter with 70 ml precooled water at 0-4°C.
  • (+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyI)-N-methylamino ⁇ carbonyl]cyclohexane-1 -carboxylic acid 1 were added and the mixture was further vigorously stirred for 60 minutes at 20°C.
  • the light suspension thus obtained was filtered (on paper) and the filtrate was concentrated under vacuum at 40°C to 200 mL.
  • the precipitated product was filtered and washed on filter with 50 mL of precooled water at 0-4°C.
  • Sample preparation Dissolve 20 mg of sample substance in 100 ml H 2 O/CH 3 CN 80/20
  • Table 1 shows the results, and in the first column, the data for the acid 1, tested in the same way, are reported.
  • the salts of the invention are also, within the suitable dosage ratios, practically comparable either for potency and for the activity lasting time to the acid 1.
  • the salts of this invention constitute the active ingredients for preparing pharmaceutical compositions both for oral and parenteral use.
  • compositions and preparations are made with the well-known pharmaceutical techniques and employing conventional excipients, carriers and solvents.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The novel salts of (+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid with metals and organic bases, represented by general formula (I) wherein R and R' if taken together represent a bivalent cation selected from calcium, ethylene diamine and other pharmaceutically acceptable cations or organic bases, or if R' = H+, R represents sodium, potassium, an imidazole group, lysine, choline, diethanolamine, arginine, or histidine, possess ACE-inhibitory activity and are therefore useful as active ingredients of antihypertensive drugs. The process for their preparation preferably entails the reaction of the starting acid, protected with a benzyl group, with the suitable hydrate, carbonate or organic base in hydrogenation conditions in the presence of a hydrogenation catalyst.

Description

Stable salts of
(+)-(1S,2R)-2-[[N-(2-hydroxyIamino-2-oxoethyI)-N-methyl-aιnino]carbonyI]cyclohexan e-1-carboxylic acid, process for their preparation and pharmaceutical compositions containing therw
This invention refers to novel salts of
(+)-(1S,2R)-2-t[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane- 1 -carboxylic acid with metal and organic bases having hypertensive activity, the process for their preparation and their use in pharmaceuticals, said salts being represented by the general formula (I)
COO
++
R R '
Figure imgf000003_0002
CO - N - CH2 - CO - NH - O
Figure imgf000003_0003
CH3
Figure imgf000003_0001
Figure imgf000003_0004
wherein R and R', if taken together, represent a bivalent cation selected from calcium, ethylene diamine, and other pharmaceutically acceptable cations or organic bases, or, if R' = H+, R represents sodium, potassium, an imidazole group, lysine, choline, diethylamine, arginine, histidine.The
(+)-(lS,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane- 1-carboxylic acid 1, (D.C.I. Idrapril) is a compound disclosed in the European Patent Application No. 89106304.2 as a novel ACE- inhibitory agent and therefore having antihypertensive activity.
This acid, when kept exposed to the air in the normal environmental conditions of humidity and temperature, is subject to autodecomposition processes which give rise to impurities obviously incompatible with regard to a therapeutical use. Such degradation processes are also accelerated by a temperature increase of the acid kept in the above conditions.
It has now been found and it is the main object of the present invention that the novel salts according to this invention, as defined above, do not undergo to the autodecomposition and degradation processes previously mentioned.
As it will be noted from the experimental data hereinafter reported, the salts of the invention, particularly if perfectly purified, are stable compounds in the normal environmental conditions. Further the salts remain unchanged with time either kept as such or included (in a solid state) in a pharmaceutical preparation (tablets, pills, capsules, lyophilized compositions and the like) provided for their therapeutical use. The utilisation of these salts in drugs allows to avoid the costly protective methods otherwise necessary to store and transform into pharmaceutical preparations the aforementioned acid.
The preparation of the compounds of the invention is based on a process characterized in that a compound, selected between
(+)-(1S,2R)-2-[[N-(2-(2-benzyl-hydroxyamino-2-oxoethyl)N-methyI-amino]carbonyl]cyclo hexane-1-carboxylic acid 2 and
(+)-(1S,2R)-2-[[N-(2-hydroxyIamino-2-oxoethyl)-N-methylamϊno]carbonyllcyclohexane-1 -carboxylic acid 1, is reacted with a compound selected among hydrates and carbonates or other suitable salts of alkaline and alkaline-earth metals, as defined in the present invention, as well as with organic bases, in an organic solvent or mixtures thereof with water, the reaction taking place, in the case of the starting product 2, contemporaneous hydrogenalysis of the protecting benzyl group with hydrogen at atmospheric pressure, in the presence of a suitable hydrogenation catalyst, the process being completed by isolating the desired salt of the acid.
The following synthesis schemes illustrate the process of the present invention
Figure imgf000005_0001
where Q is said hydroxide, or alkaline salt or calcium salt or an organic base.
In the as above defined process, the preferred hydrogenation catalyst is charcoal-supported Pd, but PtO2,Rh/Al2O3 and Ni-Raney can also be used.
As to the organic solvent, propanol, tetrahydrofuran and dioxane are also suitable besides methanol and ethanol.
The following examples, that only illustrate and do not limit the scope of the invention, explain the specific aspects and the chemical-physical properties of the compounds of the invention.
EXAMPLE 1
(+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane-
1-carboxylic acid calcium salt.
To a vigorously stirred suspension of 15.2 g calcium hydroxide in water (152 ml), was added under nitrogen, a solution of 75 g of
(+)-(1S,2R)-2-[[N-2-benzylhydroxyamino-2-oxoethyl)N-methyIamino]carbonyl]cylcohexan e-1-carboxylic acid 2, dissolved in methanol (1150 ml) and stirring continued for 20 minutes under nitrogen at 20°C.
After an addition of 15 g 10% Pd/Charcoal suspended in 152 ml water, hydrogenation of the product at 20°C with an initial H2 pressure of 1 Atm, is carried out for 3 hours.
Once the hydrogen absorption ceased (about 5000 ml absorbed), the catalyst was filtered and washed with awater/methanol (1/1) mixture (300 ml) and the filtrate, combined with the washings, concentrated under vacuum at 40°C until all the methanol has been removed.
The suspension thus obtained was treated twice with 200 ml methanol, removing thereafter, still under vacuum at 40°C, all the solvent.
The final suspension was cooled for 20 hours at 0-4°C and the precipitate was filtered and washed on the filter with 70 ml precooled water at 0-4°C.
55 g of (3) (yield 85%) as an ivory solid, having the following chemical-physical characteristics, were obtained:
Melting point > 250°C
Figure imgf000006_0001
= + 35.3° (c=1, H2O)
Heavy metals < 30 ppm
Sulphuric ashes = 40.6% (on the product as obtained)
Ca (EDTA) = 11.7%
K.F. = 7.8% Ethanol = 400 ppm
TLC: Stationary phase Merck F254 silicagel plates
Mobile phase nBuOH/AcOH/H2O = 6/2/2
Unitary spot at Rf = 0.7
HPLC : Nucleosil Column C135 μ (250x4.6)
Eluent CH3CN/H3PO4 0.1% = 20/80
Flow rate 0.8 ml/min.
Wave lenght = 214 nm.
Injection of 20 ml 0.01% CH3CN/H2O solution = 20/80
The chiral purity of the product is assayed by HPLC on chiral column:
Kiral column AGP
Eluent CH3CN/buffer at pH = 4.1 = 1/99
Flow 0.7 ml/min
Wave lenght = 214 nm
Injection 20 μ of 0.01% CH3CN/H2O solution = 1/99
Chemical purity:total impurities = 0.5%
Optical purity > 98%
EXAMPLE 2
(+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-1 -carboxylic acid - calcium salt.
To a suspension of 15.2 g calcium hydroxide in 1500 ml water, under vigorous stirring and nitrogen flow, 50 g of
(+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyI)-N-methylamino}carbonyl]cyclohexane-1 -carboxylic acid 1 were added and the mixture was further vigorously stirred for 60 minutes at 20°C.
The light suspension thus obtained was filtered (on paper) and the filtrate was concentrated under vacuum at 40°C to 200 mL.
After cooling at 0-4°C for 24 hours, the precipitated product was filtered and washed on filter with 50 mL of precooled water at 0-4°C.
48.2 g of 3 (yield 84%) were obtained as ivory solid with the following characteristic:
Melting point > 250°C
> - +34.8° (c=1, H2O)
Ca (EDTA) = 10.1% (on the product as obtained)
K.F. = 9.04% TLC Stationary phase Merck F254 silicagel plates
Mobile phase nBuOH/AcOH/H2O = 6/2/2
Unitary spot
HPLC: Analytical and chiral chromatography was carried out in conditions set forth in Example 1.
Chemical purity: total impurities = 1.0%
Optical purity > 98%
EXAMPLE 3
(+)-(1S,2R)-2-{[N-(2-hydroxylamino-2-oxoethyl)-N-methylaminolcarbonyIlcyclohexane-1 -carboxylic acid sodium salt.
70 g of 2 were added, at 20°C under stirring, to 7.6 g sodium hydroxide dissolved in 95% ethanol (1050 mL).
This solution was added with 7g of 10% Pd charcoal suspended in 35 mL water under nitrogen and hydrogenated at 20°C with an initial H2 pressure of 1 Atm, for 3 hours.
Once the hydrogen absorption ceased (4850 mL absorbed), the catalyst was filtered and washed twice with 95% ethanol (150 mL).
The filtrate combined with the washings was evaporated under vacuum at 30°C to small volume. The residue was added twice with 200 mL acetone and again concentrated to small volume, then diluted with acetone (200 mL9 and the precipitated product was filtered and washed on filter with acetone (100 mL).
56 g of 4, were obtained as hygroscopic, white solid, with the following chemical-physical characteristics:
Figure imgf000008_0001
= + 26.0° (c=1, H2O)
Heavy metals < 20 ppm
Sulphuric ashes = 19% (on the product as obtained)
KJ. = 2.5%
Ethanol = 1.1%
Acetone = 5.8%
TLC: Stationary phase Merck F254 silicagel plates
Mobile phase nBuOH/AcOH/H2O = 6/2/2
Unitary spot R.f. = 0.7
HPLC: Analytical and chiral chromatography was carried out in the conditions set forth in Example 1.
Chemical purity: total impurities = 2.0 % Optical purity > 95%
EXAMPLE 4
(+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-1
-carboxylic acid L-lysine salt.
21 g lysine dissolved in water (38 mL) were added, under stirring, to a solution of
2 in 95% ethanol (725 mL).
Under nitrogen, this solution was added with 5g 10% Pd/Charcoal and hydrogenated at 20°C witt an initial H2 pressure of 1 Atm, for 3 hours.
Once the hydrogen absorption ceased (3600 mL H2 absorbed) the catalyst was filtered on paper and washed twice with absolute ethanol (150 mL).
The filtrate combined with the washings was concentrated to dryness under vacuum at 30°C and the residue was added twice with acetone (200 mL), thereafter removing the volatile portion under vacuum.
The resulting residue was added with acetone (200 mL) was filtered and washed on filter with acetone (100 mL).
49 g of 5 were obtained as hygroscopic, white solid.
HPLC analysis was effected in the conditions of Example 1: Impurities = 4% total
EXAMPLE 5
(+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino}carbonyl]cyclohexane-1
-carboxylic acid - potassium salt.
Following the same method as in example 4 with appropriate changings of reactants, a highly hygroscopic, white solid, with the following chemical-physical characteristics, was obtained:
TLC: Stationary phase Merck F254 silicagel plates
Mobile phase nBuOH/AcOH/H2O = 6/2/2
Unitary spot R.f. = 0.7
HPLC Analytical and chiral chromatography, was carried out in the conditions of
Example 1.
Chemical purity : total impurities = 4.0 %
Optical purity > 90%
EXAMPLE 6
(+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methylamino]carbonyl]cyclohexane-1
-carboxylic acid imidazole salt.
Following the same method as in Example 4, with appropriate changings, a hygroscopic, resinous product was obtained. HPLC analysis was effected in the conditions of Example 1: Impurities = 10%
The compound 1 and the compounds of Example 1 and 3 having been obtained in solid form, and thus weighable and characterizable from the physical viewpoint, have been tested as regards relative stability at 60°C in air, in accordance with the following method.
2 g of substance are placed in a thermostatic stove at 60°C and, at prefixed times, a HPLC analysis is carried out to determine both purity and possible impurities of the compound.
Apparatus: Waters 600E Multisolvent delivery systemn
Tunable absorbance detector Waters 484
Injection loop 20 μ
Integrato Waters 745 Data Module
Nucleosil Column C18 5 μ (250 x 4.6)
Mobile Phase Ch3CN/H3PO4 0.01%=20/80
Flow rate 0.9 ml/min.
Detector: Wave length = 214 nm
Sample preparation: Dissolve 20 mg of sample substance in 100 ml H2O/CH3CN 80/20
20 μ injection
Retention time, under these conditions, is r.t. = 7.9 min.
Table 1 shows the results, and in the first column, the data for the acid 1, tested in the same way, are reported.
Figure imgf000011_0001
The salts of the invention are also, within the suitable dosage ratios, practically comparable either for potency and for the activity lasting time to the acid 1.
Such pharmacological equivalence has been experimentally demonstrated by comparing acid (1) with the calcium salt of Example 1 as shown by the experimental results listed in Table 2.
Figure imgf000012_0001
The salts of this invention constitute the active ingredients for preparing pharmaceutical compositions both for oral and parenteral use.
Such compositions and preparations are made with the well-known pharmaceutical techniques and employing conventional excipients, carriers and solvents.
As regards the oral administration, dosages of from 25 to 150 mgs/day, and from
2.5-25 mgs/day for parenteral administration, are envisaged respectively.

Claims

1. Stable salts of
(+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)N-methylamino]carbonyl]cyclohexane -1-carboxylic acid, represented by the general formula (I)
COO
+ +
R R '
Figure imgf000013_0002
CO - N - CH2 - CO - NH - O
Figure imgf000013_0003
CH3
Figure imgf000013_0001
Figure imgf000013_0004
wherein R and R', if taken together, represent a bivalent cation selected from calcium, ethylene diamine and pharmaceutically acceptable cations or organic bases, or if R1 = H+, R represents sodium, potassium, an imidazole group, lysine, choline, diethanolamine, arginine or histidine.
2. Salts of claim 1, characterized in that they possess ACE-inhibitory activity.
3. Process for the preparation of salts according to formula (I) of claim 1, characterized by that a compound selected between (+)-(1S,2R)-2-[[N-(2-benzylhydroxyamino-2-oxoethyl)N-methylamino]carbonyl]cycloh exane-1 -carboxylic acid 2 and
(+)-(1S,2R)-2-[[N-(2-hydroxyIamino-2-oxoethyl)-N-methylamino]carbonyl}cyclohexan e-1 -carboxylic acid 1 is reacted with a compound selected among hydrates and carbonates or other suitable salts of alkaline and alkaline-earch metals, as defined in the present invention, as well as with organic bases, in an organic solvent or mixtures thereof with water, the reaction taking place, in the case of the starting product 2, with contemporaneous hydrogenolysis of protecting benzyl group hydrogen at atmospheric pressure, in the presence of a suitable hydrogenation catalyst, the process being completed by isolating the desired salt of the acid 1.
4. Process according to claim 3, characterized in that the mixture of acid 2 with the compound selected from hydrate, carbonate of alkali or alkaline-earth metal or organic base, undergoes a reaction with hydrogen at atmospheric pressure in the presence of a hydrogenation catalyst.
5. Process of claim 3, characterized in that said alkaline-earthmetal is calcium.
6. Process of claim 3, characterized in that said alkaline metal is selected between sodium and potassium.
7. Process of claim 3, characterized in that said hydrogenation catalyst is charcoal supported palladium.
8. Process of claim 3, whereby said organic solvent is selected from propanol, tetrahydrofuran and dioxane.
9. Pharmaceutical composition, characterized in that it contains as active ingredient a salt according to claim 1, as well as the usual excipients and carriers.
10. Pharmaceutical composition according to claim 9, characterized in that it possess antihypertensive activity.
PCT/EP1992/002903 1991-12-23 1992-12-12 Stable salts of (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid, process for their preparation and pharmaceutical compositions containing them WO1993013056A1 (en)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP5511398A JPH06506002A (en) 1991-12-23 1992-12-12 Stable salt of (+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid
AU30871/92A AU657591B2 (en) 1991-12-23 1992-12-12 Stable salts of (+)-(1S,2R)-2-((N-(2-hydroxylamino-2-oxoethyl)-N-methyl- amino)carbonyl)cyclohexane-1-carboxylic acid, process for their preparation and pharmaceutical compositions containing them
RU9293052414A RU2079489C1 (en) 1991-12-23 1992-12-12 (+)-(1s,2r)-2-[[n-(2-hydroxyamino-2-oxoethyl)-n-methylamino]- -carbonyl]-cyclohexane-1-carboxylic acid stable salts, method of their synthesis and pharmaceutical composition
BR9205652A BR9205652A (en) 1991-12-23 1992-12-12 Stable salts of (+) - (15,2R) -N- (2-hydroxylamine-2-oxoethyl) N-methylamino carbonyl cyclohexane-carboxylic acid, process of its preparation, and pharmaceutical composition
BG98050A BG98050A (en) 1991-12-23 1993-08-18 Salts resistant to (+)-(1s,2r)-2-[[n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino] carbonyl] cyclohexane-1-carbonic acid, method for their preparation and pharmaceutical compositions containing them
NO93932982A NO932982L (en) 1991-12-23 1993-08-20 STABLE SALTS OF (+) - (1S, 2R) -2 - ((N- (2-HYDROXYLAMINO-2-OXOETHYL) -N-METHYLAMINO) CARBONYL) CYCLOHEXAN-1-CARBOXYLIC ACID ACID AND PREPARING PROCESS FOR THE PREPARATION OF PREPARATION THEREOF
FI933685A FI933685A (en) 1991-12-23 1993-08-20 STABILA SALTER AV (+) - (1S, 2R) -2 - ((N- (2-HYDROXYLAMINO-2-OXOETHYL) -N-METHYLAMINO) CARBONYL) CYCLOHEXAN-1-CARBOXYL SYRIA,

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Application Number Priority Date Filing Date Title
ITMI91A003448 1991-12-23
ITMI913448A IT1252708B (en) 1991-12-23 1991-12-23 STABLE SALTS OF (+) - (1R, 2S) -2 ((N- (2-HYDROXYLAMINE-2-OSSOETHL) -N-METHYLAMINE) CARBONYL) CYCLOHEXAN-1-CARBOXYL, ACE INHIBITIVE ACTIVITY, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM.

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WO1993013056A1 true WO1993013056A1 (en) 1993-07-08

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EP (1) EP0575572A1 (en)
JP (1) JPH06506002A (en)
CN (1) CN1079474A (en)
AU (1) AU657591B2 (en)
BG (1) BG98050A (en)
BR (1) BR9205652A (en)
CA (1) CA2104372A1 (en)
CZ (1) CZ379692A3 (en)
EE (1) EE9400006A (en)
FI (1) FI933685A (en)
HR (1) HRP921454A2 (en)
HU (1) HUT69287A (en)
IT (1) IT1252708B (en)
LV (1) LV10426B (en)
MA (1) MA22749A1 (en)
MX (1) MX9207543A (en)
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PL (1) PL169086B1 (en)
PT (1) PT101156A (en)
RU (1) RU2079489C1 (en)
SI (1) SI9200409A (en)
SK (1) SK379692A3 (en)
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WO (1) WO1993013056A1 (en)
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2279345A (en) * 1993-06-21 1995-01-04 Guidotti & C Spa Labor Cyclohexanecarboxylic acid derivatives
WO1996020918A1 (en) * 1994-12-29 1996-07-11 The Procter & Gamble Company Hydroxamic acid-containing inhibitors of matrix metalloproteases
EP2079304A1 (en) * 2006-09-28 2009-07-22 Merck & Co., Inc. Amine base salts of saha and polymorphs thereof

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2817241B1 (en) 2000-11-30 2003-03-07 Cebal ALUMINUM TUBE WITH SPLITABLE END
AU2021263319B2 (en) * 2020-04-27 2022-12-01 Carter-Hoffmann, Llc Door movement system for cabinet

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0337348A2 (en) * 1988-04-12 1989-10-18 Laboratori Guidotti S.p.A. Amides of cyclomethylen-1,2-bicarboxylic acids having therapeutical activity, processes for their preparation and pharmaceutical compositions containing them

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0337348A2 (en) * 1988-04-12 1989-10-18 Laboratori Guidotti S.p.A. Amides of cyclomethylen-1,2-bicarboxylic acids having therapeutical activity, processes for their preparation and pharmaceutical compositions containing them

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2279345A (en) * 1993-06-21 1995-01-04 Guidotti & C Spa Labor Cyclohexanecarboxylic acid derivatives
WO1996020918A1 (en) * 1994-12-29 1996-07-11 The Procter & Gamble Company Hydroxamic acid-containing inhibitors of matrix metalloproteases
US5639746A (en) * 1994-12-29 1997-06-17 The Procter & Gamble Company Hydroxamic acid-containing inhibitors of matrix metalloproteases
AU706409B2 (en) * 1994-12-29 1999-06-17 Procter & Gamble Company, The Hydroxamic acid-containing inhibitors of matrix metalloproteases
EP2079304A1 (en) * 2006-09-28 2009-07-22 Merck & Co., Inc. Amine base salts of saha and polymorphs thereof
EP2079304A4 (en) * 2006-09-28 2010-01-06 Merck & Co Inc Amine base salts of saha and polymorphs thereof

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JPH06506002A (en) 1994-07-07
ZA9210004B (en) 1993-12-13
AU3087192A (en) 1993-07-28
CN1079474A (en) 1993-12-15
ITMI913448A1 (en) 1993-06-23
YU110892A (en) 1996-01-08
HUT69287A (en) 1995-09-28
BR9205652A (en) 1994-05-03
CA2104372A1 (en) 1993-06-24
MA22749A1 (en) 1993-07-01
RU2079489C1 (en) 1997-05-20
SI9200409A (en) 1993-09-30
HU9302389D0 (en) 1993-11-29
TNSN92117A1 (en) 1993-06-08
BG98050A (en) 1994-04-29
MX9207543A (en) 1993-08-01
IT1252708B (en) 1995-06-26
PT101156A (en) 1994-06-30
EE9400006A (en) 1995-12-15
ITMI913448A0 (en) 1991-12-23
LV10426A (en) 1995-02-20
HRP921454A2 (en) 1995-02-28
AU657591B2 (en) 1995-03-16
FI933685A0 (en) 1993-08-20
CZ379692A3 (en) 1993-09-15
PL297118A1 (en) 1993-09-06
SK379692A3 (en) 1995-04-12
FI933685A (en) 1993-08-20
LV10426B (en) 1995-08-20
NZ245547A (en) 1995-12-21
EP0575572A1 (en) 1993-12-29
PL169086B1 (en) 1996-05-31

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