JPH06506002A - Stable salt of (+)-(1S,2R)-2-[[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] (+)-, (IS, 2R)-2-[[N-(2-hydroxylamino-2-ox soethyl)-N-methyl-amino]carbonyl]cyclohexane-1-carvone stable salts of acids The present invention provides (+)-(Is, 2R)-2-[[N-(2-hypertensive) Droxylamino-2-oxoethyl)-N-methyl-amino]carbonyl]sil Novel salts of clohexane-1-carboxylic acid with metals and organic bases, their production process, and With regard to its use in drugs and medicines, the salt has the general formula (I) [wherein R and R′ taken together represent calcium, ethylenediamine and other pharmaceutical indicates a divalent cation or organic base selected from cations that are acceptable for Or in the case of R'=H"", R is sodium, potassium, imidazole group, lysine , choline, diethylamine, arginine, histidine] It is shown by. (+)-(Is, 2R)-2-[[N-(2-hydroxyl Amino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexa N-cho-carboxylic acid l, (D, C, 1, Idrapril) is In European Patent Application No. 89106304.2, as novel ACE-inhibitors: Therefore, it is disclosed as a compound having antihypertensive activity.

This acid self-decomposes when stored exposed to air under normal environmental conditions of humidity and temperature. The process inevitably produces impurities that are clearly unsuitable for pharmaceutical use. above Such a decay process of acids stored at conditions is also accelerated by an increase in temperature . .

The novel salt of the present invention as defined above herein does not undergo the above-mentioned autolysis and disintegration process. It has been found that there is no such thing, and that is the main objective of the present invention.

As can be seen from the experimental data reported later, the salts of the present invention are particularly completely purified. and is a stable compound under normal environmental conditions. Additionally, salt can be used as is or for therapeutic purposes. For pharmaceutical preparations (tablets, pills, capsules, lyophilized compositions, etc.) provided to Even when contained and stored (in a solid state), it does not change over time. In medicine These salts can be used to preserve the acids and convert them into pharmaceutical compositions when they are not used. This avoids the costly protection laws that would otherwise be required.

The preparation of the compounds of the present invention involves (+)-(Is, 2R)-2-[[N-(2-(2- benzyl-hydroxylamino-2-oxoethyl)N-methyl-amino]car [bonyl]cyclohexane-1-carboxylic acid 2, and (+)-(Is, 2R)-2 -[[N-(2-hydroxylamino-2-oxoethyl)-N-methyl-amino [carbonyl]cyclohexane-1-carboxylic acid 1, Alkali and alkaline earths defined in the present invention in organic solvents or their mixtures with water. selected from metal hydrates and carbonates or other suitable salts, and organic bases. The method is based on a method characterized in that the starting compound 2 is reacted with In this case, the reaction is performed using atmospheric hydrogen in the presence of a suitable hydrogenation catalyst. occurs with simultaneous hydrogenolysis of the acid, and the process is completed by isolating the desired salt of the acid. Complete. The following reaction scheme illustrates the process of the invention.

In the formula, Q is the hydroxide, an alkali salt, a calcium salt, or an organic base. .

In the process defined above, the preferred hydrogenation catalyst is charcoal-supported Pd. However, PtO2, Rh/AI□03 and Ni-Raney can also be used.

Regarding organic solvents, in addition to methanol and ethanol, propatool and tetrahydrogen Dorofuran and dioxane are also suitable.

The following examples illustrate specific characteristics and chemico-physical properties of the compounds of the invention. These are merely illustrative of the present invention and are not intended to limit its scope.

monooxoethyl)-N-methyl-amino]carbonyl]cyclohexane-1-carboxylic acid Rubonic acid calcium salt In a vigorously stirred suspension of 15.2 g of calcium hydroxide in water (152 ml) , 75 g of (+)-(Is,2R)-2 dissolved in methanol (1150 ml) -[[N-(2-(2-benzylhydroxylamino-2-oxoethyl)N- A solution of methyl-amino]carbonyl]cyclohexane-1-carboxylic acid 2 was heated with nitrogen. and stirring continued for 20 minutes under nitrogen at 20°C.

After adding 15 g of 10% Pd/charcoal suspended in 152 ml of water, 1 Atmospheric H! Hydrogenation of the compound is carried out for 3 hours at 20° C. using initial pressure.

After hydrogen absorption has stopped (approximately 5000 ml absorption), filter the catalyst and add water/methanol. The filtrate was combined with the washing solution and heated to 40°C. Concentrate under vacuum until all methanol is removed. The suspension thus obtained was treated twice with 200 ml of methanol, also under vacuum at 40°C, and then all of the solvent was removed.

The final suspension was cooled to 0-4°C for 20 hours, the precipitate was filtered, and the precipitate was filtered at 0-4°C. - Washed with 70 ml of pre-chilled water.

55 g of (3) (85% yield) was converted into an ivory colored solid with the following chemical-physical properties: Got as body: Melting point〉250℃ [α]”o=+35.3° (C=1, HzO) Heavy metals <30ppm based on things) Ca (EDTA) = 11.7% ,F, =7. 8% Ethanol = 400ppm TLC: Stationary phase Merk F254 silica gel plate Mobile phase nBuOH Single spot at /AcOH/HzO=6/2/2Rf=0.7 HPLC: Nucleosil column C+s5μ (250x4.6) eluent CH3CN / Hs P O40, 1% = 20/80 flow rate 8ml/min Wavelength = 214nm 20ml of 0.01% CHsCN/HzO solution = 20/80 injection Analyzing the xyl purity of the product by HPLC on a chiral column: xyl column A G.P. Eluent CH3CN/buffer at pH 4.1 = 1/99 flow rate 0.7ml / minute Wavelength = 214nm 20 μ of 0.01% CHs CN/H20 solution = 1/99 injection chemical purity :Total impurities=0.5% Optical purity〉98% Example 2 (+)-(Is, 2R)-2-[[N-(2-hydroxylamino-2-oxo ethyl)廿N-methylamino]carbonyl]cyclohexane-1-carboxylic acid- calcium salt 15.2 g of calcium hydroxide in 1500 ml of water with vigorous stirring under a stream of nitrogen 50 g of (+)-(Is,2R)-2-[[N-(2-hydroxy cylamino-2-oxoethyl)-N-methylaminococarbonylcocyclohexyl San-1-carboxylic acid 1 was added and the mixture was stirred vigorously for an additional 60 min at 20°C. did.

The light suspension thus obtained was filtered (on filter paper), and the filtrate was heated at 40° C. under vacuum for 200 min. Concentrated to mL. After cooling to 0-4°C for 24 hours, the precipitated product was filtered and Washed on the filter with 50 mL of pre-chilled water at °C.

Obtained 48.2 g of 3 (84% yield) as a brown solid with the following properties: Melting point〉250℃ [α] “o-+34.8’ (c=1, H20) Ca (EDTA)-10, 1% (based on the product obtained) K, F, = 9. 04% TLC: Stationary phase Merk F254 silica gel plate Mobile phase nBuOH /AcOH/HtO=6/2/2 single spot HPLC: Analysis and xyl chromatography were performed under the conditions shown in Example 1. Ta.

Chemical purity Two total impurities = 1.0% Optical purity〉98% (+)-(IS, 2R)-2-[[N-(2-hydroxylamino-2-oxo ethyl)-N-methylamino]carbonyl]cyclohexane-1-carboxylic acid sodium salt 70 g of 2 was dissolved in 95% ethanol (1050 mL) under stirring at 20 °C. 7.6 g of sodium hydroxide.

To this solution was added 7 g of 10% Pd charcoal suspended in 35 mL of water under nitrogen. The mixture was then hydrogenated at 20° C. for 3 hours using an initial H1 pressure of 1 atm.

After hydrogen absorption has stopped (4850 mL absorption), filter the catalyst and add 95% ethanol. The solution was washed twice with water (150 mL).

The filtrate was combined with the washings and evaporated to a small volume under vacuum at 30°C.

Add two 200 mL portions of acetone to the residue, reconcentrate to a small volume, and then add Dilute with setone (200 mL), filter the precipitated product and place on the filter with acetone. (100 mL). 56 g of 4 with the following chemical-physical properties Obtained as a hygroscopic white solid: [α]!・o=+26.0" (c=1, H IO) Heavy metals <20ppm Sulfur ash content 2+19% (based on the product obtained) K, F, = 2.　5% Ethanol = 1.1% Acetone = 5.8% TLC: Stationary phase Merk F254 silica gel plate Mobile phase nBuOH /AcOH/HzO=6/2/2 single spot top R,f,=0. 7 HPLC: Analysis and xyl chromatography were performed under the conditions described in Example 11i*. It was.

Chemical purity 2 total impurities = 2.0% Optical purity〉95% Example 4 (+)-(Is, 2R)-2-[[N-(2-hydroxylamino-2-oxo ethyl)-N-methylamino]carbonyl]cyclohexane-1-carboxylic acid L-lysine salt 21 g of seaweed dissolved in water (38 mL) was stirred in 95% ethanol (725 mL). 2 in mL).

To this solution was added 5 g of 10% Pd/charcoal under nitrogen and 1 atm H1 initial Hydrogenation was carried out using pressure at 20° C. for 3 hours.

After hydrogen absorption has stopped (3600 mL of H1 absorption), filter the catalyst on filter paper and remove the Washed twice with water and ethanol (150 mL).

The filtrate was combined with the washing solution and evaporated to dryness under vacuum at 30°C, and the residue was diluted with acetone (20°C). 0 mL) were added twice and then the volatile portions were removed under vacuum.

Acetone (200 mL) was added to the resulting residue, filtered, and acetone was added on the filter. (100 mL).

Obtained 49 g of 5 as a hygroscopic white solid.

HPLC analysis was carried out under the conditions of Example 1: Impurities = 4% total Example 5 (+)-(Is, 2R)-2-[[N-(2-hydroxylamino-2-oxo ethyl)-N-methylamino]carbonyl]cyclohexane-1-carboxylic acid potassium salt In the same manner as in Example 4, with appropriate changes in the reactants, the following chemical-physical properties were prepared: A highly hygroscopic white solid was obtained: TLC: Stationary phase: Merc F254 silica Gel plate mobile phase nBuOH/AcOH/HzO=6/2/2 single spot R, f, = 0. 7 HPLC: Analysis and xyl chromatography optical purity under the conditions shown in Example 1. degree〉90% Example 6 (+)-(Is, 2R)-2-[[N-(2-hydroxylamino-2-oxo ethyl)-N-methylamino]carbonyl]cyclohexane-1-carboxylic acid imidazole salt A hygroscopic resinous product was obtained in the same manner as in Example 4 by changing the reactants appropriately.

HPLC analysis was carried out under the conditions of Example 1: impurities = obtained in the form of 10% solids, Compound 1 and Example 1, which can therefore be weighed and characterized from a physical point of view, and The compounds of No. 3 were tested for their relative stability in air at 60°C according to the following method: It was tested.

2g of the substance was placed in a thermostatically controlled heating furnace at 60°C and heated to a predetermined temperature. Perform HPLC analysis on time to determine both compound purity and possible impurities did.

Equipment: Waters 600E multisolvent delivery system delivery system) Injection loop 20μ Integration Waters 745 Data Module Nucleostl Ram Cps 5μ (250x4.6) Mobile phase CHICN/H3PO40,0 1% = 20/80 flow rate 0.9ml/min Detector: Wavelength = 214nm Sample preparation + 20 mg sample material in 100 ml HtO/CHsCN 80/20 Dissolve.

20μ injection Under these conditions, the retention time is t, =7. It was 9 minutes.

Table 1 shows the results and reports data for acid 1 tested in a similar manner in No. do.

Table 1 The salts of the invention are also virtually identical to acid 1 with respect to potency and duration of activity, within suitable dosage rates. That's about it. As shown in the experimental results listed in Table 2, the acid (1) and the calcium of Example 1 Such pharmacological equivalence is demonstrated experimentally by comparing sia salts. .

Table 2 The salts of the invention are suitable for the preparation of pharmaceutical compositions for both oral and parenteral use. Becomes the active ingredient.

Such compositions and preparations may be made using well known pharmaceutical techniques and using conventional excipients, carriers and solvents. It can be made using

For oral administration, the dosage is 25-150 mg/day, and for parenteral administration, respectively. A dosage of 2.5-25 mg/day is good.

Continuation of front page (81) Designated countries EP (AT, BE, CH, DE.

DK, ES, FR, GB, GR, IE, IT, LU, MC, NL, PT, S E), 0A (BF, BJ, CF, CG, CI, CM, GA, GN, M L, MR, SN, TD.

TG), AU, BB, BG, BR, CA, FI, HU.

JP, KP, KR, LK, MG, MW, No, RO, RU, SD, UA, US

Claims (10)

[Claims] 1. General formula (I) ▲Contains mathematical formulas, chemical formulas, tables, etc.▼ [wherein R and R′ taken together represent calcium, ethylenediamine and pharmaceutical represents a divalent cation or organic base selected from acceptable cations, or When R'=H+, R is sodium, potassium, imidazole group, lysine, choline , diethanolamine, arginine, histidine] (+)-(1S,2R)-2-[[N-(2-hydroxylamide) -2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane- 1-Stable salts of carboxylic acids. 2. The salt according to claim 1, characterized in that it has ACE-inhibiting activity. 3. (+)-(1S.2R)-2-[[N-(2-benzylhydroxylamino -2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexane-f -carboxylic acid 2 and (+)-(1S,2R)-2-[[N-(2-hydroxyl Amino-2-oxoethyl)-N-methyl-amino]carbonyl]cyclohexa A compound selected from 1-carboxylic acids 1 in an organic solvent or a mixture thereof with water. Hydrates and carbonates of alkali and alkaline earth metals as defined in the present invention are or other suitable salts, as well as organic bases, to form the starting compound. In the case of product 2, the reaction is carried out in a protected atmosphere using atmospheric hydrogen in the presence of a suitable hydrogenation catalyst. occurs with simultaneous hydrogenolysis of the unzyl group, leading to the isolation of the desired salt of acid 1. Preparation of a salt of formula (I) according to claim 1, characterized in that the process is completed by Construction method. 4. selected from acids 2 and alkali or alkaline earth metal hydrates, carbonates or organic bases. Characterized by the reaction of a mixture of chemical compounds with hydrogen at atmospheric pressure in the presence of a hydrogenation catalyst The method according to claim 3, wherein: 5. Claim 3, characterized in that the alkaline earth metal is calcium. Method described. 6. Claim characterized in that the alkali metal is selected from sodium and potassium. The method described in Scope 3 of the request. 7. The claimed hydrogenation catalyst is characterized in that the hydrogenation catalyst is palladium supported on charcoal. The method described in scope 3. 8. the organic solvent is selected from propanol, tetrahydrofuran and dioxane; The method according to claim 3. 9. Salts according to claim 1 as active ingredients and customary excipients and carriers A pharmaceutical composition comprising: 10. Pharmaceutical composition according to claim 9, characterized in that it has antihypertensive activity. Composition.