SI9200409A - (+)-(1s,1r)-2-((n-(2-hydroxylamino-2-oxoethyl)-n-methyl-amino) carbonyl)cyclohexan-1-carboxylic acids stable salts, process for the preparation thereof and pharmaceutical preparations comprising the same - Google Patents

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

(57) New salts of (+) - (1S, 2R) -2 [[N- (2-hydroxylamino2-oxoethyl) -N-methyl-amino] carbonyl cyclohexane-1-carboxylic acid with metals and organic bases, represented by the general formula

COO

Sl 9200409 A

CO - N - CHa - CO - NH - o

I

CH _S wherein R and R, when taken together, are divalent cations selected from calcium, ethylene diamine and other pharmaceutically acceptable cations or organic bases, or R if R = H ⁺ , sodium, potassium, imidazole group, lysine , choline, diethanolamine, arginine, or histidine, which exhibit ACE-inhibitory activity and are therefore useful as active ingredients in anti-hypertension medicines. The process for preparing them preferably involves the reaction of a benzyl-protected starting acid with a suitable hydrate, carbonate or organic base and conditions for hydrogenation in the presence of a hydrogenation catalyst.

STABLE SALTS <+> - (1S, 2R) -2 - [[n- (2-HYDROXYLAMINO-2-OXOETHYL) N-METHYL-AM AND NO] K ARBONY l] CYCLOHEXANE-1-K ARBOXYLIC ACIDS.

PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICALS

THE INGREDIENTS CONTAINING THEM

san-1-carboxylic acids with metals and organic bases exhibiting hypertensive activity to a process for their preparation and their use in pharmaceutical preparations, ie salts represented by general formula (I)

COO

CQ - N - CH ^ - CO - NH - O

CH ₃ where R and R ', when taken together, is a divalent cation selected from calcium, ethylene diamine and other pharmaceutically acceptable cations or organic bases, or R if R' = H *, sodium, potassium, imidazole group , lysine, choline, diethylamine, arginine, histidine. (+) - (1S, 2R) -2- [N- (2-hydroxy 1 amino-2-oxoethyl) -N-methyl 1-amino-carbonylcyclohexane-1-carboxylic acid i, (DCI Idapril) is a compound disclosed in European patent application no. 89106304.2 as a new ACE inhibitory agent, which therefore exhibits activity against high blood pressure.

This acid *, if left standing in air under normal conditions of humidity and ambient temperature, undergoes self-degradation processes that lead to the formation of impurities that are clearly incompatible with regard to therapeutic use. Such degradation processes are also accelerated by an increase in the acid temperature which is allowed to stand under the aforementioned conditions.

We have now discovered, and it is a major object of the present invention, that the new salts of this invention, as defined above, are not subject to the self-degradation and degradation processes previously mentioned.

As will be seen from the experimental results that will be reported thereafter, the salts of the invention, especially when fully purified, are stable compounds under normal environmental conditions.

Furthermore, salts remain unchanged over time, or if left as such, or incorporated (in solid form) into a pharmaceutical preparation (tablets, pills, capsules,

1iofi1izirae compositions and the like) prepared for their therapeutic use.

The use of these salts and medicines allows us to avoid costly protective methods that are otherwise necessary for the storage and conversion of the aforementioned acids into pharmaceutical preparations.

The preparation of the compounds of the invention is based on a process characterized in that the compound selected from (+) - (1S, 2R) -2 - [[N- (2- (2-benzyl-hydroxyamino-2-oxoethyl)) N-methyl-amino carbonyl cyclohexane-1-carboxylic acid 2 and (+) - (1S, 2R) -2- N- (2-hydroxylamino-2-oxoethyl) -N-methyl-1-amino] carbonyl chlohexane ^- 1 —Carboxylic acid 1 is reacted with a compound selected from hydrates and carbonates or other suitable salts of alkali and alkaline earth metals as defined in the present invention, as well as with organic bases, in an organic solvent or in mixtures with water, the reaction is carried out in the case of starting product 2, with the simultaneous hydrogenolysis of the protecting benzyl group with hydrogen at atmospheric pressure, in the presence of a suitable hydrogenation catalyst, and the process is completed by isolating the desired acid salt.

The following synthesis schemes illustrate the process of the present invention wherein S is a hydroxide or an alkali metal salt or a calcium salt or an organic base.

In the process as previously defined, the preferred catalyst is Pd on charcoal, but we can also use

PtO ₂ , Rh / Al ₂ O _3, and Raneyev Ni.

As for the organic solvent, besides methanol and ethanol, propanol, tetrahydrofuran and dioxane are also suitable.

The following examples, which merely illustrate and do not limit the purpose of the invention, will explain the specific aspects and chemical-physical properties of the compounds of the invention.

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EXAMPLE 1

Calcium "ol (+) - (1S * 2R) -2 - [[N- (2-hydroxyl" ino-2-oxo • til) -N- "ati1 - *" inocarbonyl] cycloch "k" an-l- carboxylic acids.

To a suspension of 15.2 g of calcium hydroxide in water (152 mL) which was stirred vigorously * was added in a nitrogen atmosphere a solution of 75 g (+) - (1S, 2R) -2 - [[n-2-benzylhydroxyamino-2- oxoet1> Nmeti laminated carbonyl carbonyl cyclohexane-1-carboxylic acid 2 which was dissolved in methanol (1150 mL) and stirred continuously for 2 minutes under a nitrogen atmosphere at 2G ° C.

After the addition of 15 g of 10% Pd / agly * suspended in 152 n "L of water *, the product was hydrogenated at 20 ° C for 3 hours and the initial pressure of H _with 1

Atm.

When the absorption of hydrogen has stopped (approx

5000 mL) * was filtered off the catalyst and washed with a mixture (300 mL) of water / methanol (1/1) and the filtrate * to which was added the rinsing liquid * was concentrated in vacuo at

40 ° C until all methanol has been removed.

The suspension thus prepared was treated twice with 200 mL of methanol and then * still in vacuo at 40 ° C * all solvent removed.

The final suspension was cooled for 20 hours at 0-4 ° C and the precipitate was filtered and washed with 70 mL of pre-cooled water at 0-4 ° C on the filter.

We obtained 55 g 3 (85% yield) * as an ivory solid »having the following chemical · physical properties:

Melting point> 250 ° C [βτ] ο ^2θ = + 35,3 ° (c = l, HaO)

Heavy metals <30 ppm

Sulfur ash = 40.6% (2 by product as obtained)

Ca (EDTA) = 11.77.

K.F. = 7.87.

Ethanol = 400 ppm

TSK: Stationary - Phase of Merck F254 silica gel

Mobile Phase nBuOH / AcOH / HaO = 6/2/2

Single stain at Rf = 0.7

HPLC: Nucleosyl column C _xs 5 μ (250x4,6)

Eluent CHaCN / H-sPO ^ 0.17. = 20/80

Flow rate 0.8 mL / min.

Wavelength = 214 nm

Injection of 20 mL of 0.01% solution into CHaCN / HzO = 20/80

The chiral purity of the product was tested by HPLC on a chiral column: the AGP chiral column

Eluent CH3CN / buffer at pH = 4.1 = 1/99

Flow rate 0.7 mL / min

Wavelength = 214 nm

Injection of 20 μ L0.01% solution of CH 2 CN / HzO = 1/99

Chemical purity: total impurities = 0.5%

Optical purity> 98%

EXAMPLE 2

The calcium salt of (+) - (1S <2R) -2 - [[N- (2-hydroxylamino-2-oxo] ti 1) -N-methylamino] carbonyl cyclohexane-1-carboxylic acid.

To a suspension of 15.2 g of calcium hydroxide in 1500 mL of water, 50 g (+) - (IS, 2R) -2 - [[n- (2-hydroxylamino-2-oxoethyl)) -N were added with vigorous stirring and nitrogen flow. —Mintamino] carbonyl cyclohexane-1-carboxylic acid 1 and the mixture was further stirred vigorously for 60 minutes at 20 ° C.

The light suspension thus prepared was filtered (on paper) and the filtrate was concentrated in vacuo at 40 ° C to

200 mL.

After cooling at 0-4 ° C for 24 hours, the precipitate in which the product was filtered was washed with 50 mL of pre-cooled water at 0-4 ° C on the filter.

4S, 2 g of 3 (yield 847) was obtained as an ivory solid having the following characteristics:

Melting point> 250 ° C mflfjo ³⁰ = + 34.8 ° (c = l, HaO)

Ca (EDTA) = 10.17 (based on product as obtained)

K.F. 9,047.

TSK: Stationary phase of Merck F254 silica gel board

Mobile Phase nBuOH / AcOH / tbO - 6/2/2

A single stain

HPLC: Analytical and chiral chromatography were performed under the conditions explained in Example 1.

Chemical purity: total impurities = 1.07

Optical purity> 987

EXAMPLE 3

(+) - (1S, 2R) -2 - [[n- (2-hydroxylamino-2-oxoethyl) -N-methylamino] carbonyl] cyclohexane-1-carboxylic acid sodium salt.

g 2 at 20 ° C and stirring was added 7.6 g of sodium hydroxide, which was dissolved in 957 ethanol (1050 mL).

7 g of 107 was added to this solution under a nitrogen atmosphere

Pd / charcoal suspended in 35 mL of water and hydrogenated at

20 ° C and an initial pressure of H _a 1 Atm for 3 hours.

When hydrogen absorption ceased (4850 mL absorbed), the catalyst was filtered off and washed twice with 957

ethanol (150 mL). Filtrate, who we are Mrs combined with liquids with whom we are derived washing, we are pair in a vacuum at 30 ° C to small volume. Stay we are twice 200 mL was added acetone and again

concentrated to low volume, then diluted with acetone (200 mL) and the precipitated product filtered off and washed with acetone (100 mL) on the filter.

56 g of 4 were obtained as a hygroscopic white solid having the following characteristics:

[flt] o ³ ° C = + 26.0 ° (c = l, HzO)

Heavy metals <20 ppm

Sulfur ash = 197 (with respect to the product as it is

K. F. = 2.57

Ethanol = 1.17

^ .Acetone = 5.87 Age 1i)

TSK: Stationary phase of Merck F254 silica gel plate

Mobile phase nBuOH / AcOH / H ^ O = b / 2.f2

Rf uniform stain = O »7

HPLC; Analytical and chiral chromatography were performed under the conditions explained in Example 1Chemical purity: total impurities = 2) 0%

Optical purity> 95%

EXAMPLE 4

A salt of L-lysine and (+) - (1S »2R) -2 - [[N- (2-hydroxylamino-2-oxoethyl) -N-methylamino] carbonyl] cyclohecaan-1-carboxylic acid.

21 g of lysine were dissolved in water (33 mL) and added to a solution of 2 in 95% ethanol (725 mL) while stirring.

To this solution was added 5 g of 10% Pd / charcoal under a nitrogen atmosphere and hydrogenated at 20 ° C and an initial pressure of H ₃ 1 Atm for 3 hours.

When hydrogen absorption ceased (3600 mL of H ₃ absorbed), the catalyst was filtered on paper and washed twice with absolute ethanol (150 mL).

The filtrate was combined with the liquids by which the filter was washed and concentrated at 30 ° C, and acetone (200 mL) was added twice to the residue, and then the evaporated portion was removed in vacuo.

The residue thus obtained was again acetone (200 mL) filtered and washed with acetone (100 mL) on the filter.

49 g of 5 were obtained as a hygroscopic white solid.

HPLC analysis was performed under the conditions of Example 1: impurities =

4% overall.

EXAMPLE 3

(+) - (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 changes in the realctants, a very hygroscopic white solid was obtained, with the following chemical-physical properties:

TSK: Stationary phase of Merck F254 silica gel plate

Mobile-phase nBuOH / AcOH / HaO =

R-f single stain - 0.7

HPLC: Analytical and chiral chromatography was performed under the conditions of Example 1.

Chemical purity: total impurities = 4.0%

Optical purity> 90%

EXAMPLE 6

Imidazole salt of (+) - (1S, 2R) -2 - [[N- (2-hydroxylanino-2-oxoethyl] -N-methylamino] carbonyl] cyclohexane-1-carboxylic acid.

Following the same method as in Example 4, with appropriate modifications, a hygroscopic resinous product was obtained.

HPLC analysis was performed under the conditions of Example 1: impurities =

10%.

Compound 1 and compounds of Examples 1 and 3 were obtained in solid form so that they could therefore be weighed and characterized from a physical standpoint and their relative stability tested at 60 ° C in air, in accordance with the following method:

g of the substance was placed in a thermostated oven at 6 ° C and HPLC analysis was performed at predetermined times to determine both the purity and possible impurities of the compound.

Apparatus: Maters 600E multi-solvent delivery system

Adjustable Maters 484 absorbance detector

20 pL injection loop

Maters 745 Data Integration Module

Cie 5 P Nucleosyl Column (250 x 4.6)

CbbCN / HaPCU mobile phase 0.017. = 20/80

Flow rate 0.9 mL / min.

Detector: Wavelength = 214 nm

Sample preparation: Dissolve 20 mg of the sample substance in 100 mL

HaO / CHaCN 80/20 Injection 20 pL

The retention time, in these conditions, is a no. = 7.9 min.

Table 1 shows the results and the first column provides data for acid (1) tested in the same way.

The salts of the invention are also practically comparable in appropriate dose ratios both in terms of efficiency and duration of acid activity 1.

Such pharmacological equivalence was demonstrated experimentally by comparing the acid (s) with the calcium salt

TABLE 1

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The sample from Example 1 was constant as indicated by the experimental results given in Table 2.

TABLE 2

Inhibition of angiotensin I response responses in EDso collected rats (pmol units of Kg ^-l po) and

95% reliable limits

Pharmacokinetics in dogs at doses

8multiples Kg ^- lp.o.

AUC * (pg min / mL) F (%)

Acid 1

2.83 (0.12-8.13)

Compound pr. 1

3.06 (0.43-7.40) ± 12

189 ± 56 'Surface under curve (plasma drug concentrations)

The salts of the present invention present the active ingredients for the preparation of pharmaceutical compositions • for oral and parenteral use.

Such compositions and preparations have been made by well-known pharmaceutical techniques using conventional excipients, carriers and solvents.

As for oral administration, a dosage of 25 to 150 mg / day and 2.5-25 mg / day for parenteral administration is considered prudent.

GUIDOTTI LABORATORIES S.p.A

Italy

For:

E T M and C · ·

ΪΑ JANEŽIČ Resljeva 24 233

PATENT APPLICATIONS

Claims (9)

1. Stable salts of (+) - (IS, 2R) -2 - [[N- (2-hydroxyamino-2-oxoethyl) -N-methyl-aminocarbons 1J cyohexane-1-carboxylic acids not by represents the general formula (I) COO R R ' CO - N - CH ₃ - CO - NH - O I CH ₃ where R and R ', when taken together, is a divalent cation selected from calcium, ethylene diamine and pharmaceutically acceptable cations or organic bases, or R if R '= H *, sodium, potassium, imidazole group, lysine, choline, diethanolamine, arginine or histidine. Salts according to claim 1, characterized in that they exhibit ACE-inhibitory activity. Process for the preparation of salts of the formulas (I) according to claim 1, characterized in that the compound selected from (+> - (1S, 2R) -2 - [[n- (2-benzyl-hydroxy) amino -2-oxoethyl) N-methyl-1-amino carbonyl hexane-1-carboxylic acid 2 and (- * -> - (IS, 2R) -2-N- (2-hydroxyamino-2-oxoethyl) - N-methylamino-carbonylcyclohexane-1-carboxylic acid 1 reacts with a compound selected from hydrates and carbonates or other suitable salts of alkali and alkaline earth metals as defined in the present invention, as well as with organic bases, in an organic solvent or in mixtures thereof with water, the reaction is carried out in the case of initial product 2 with the simultaneous hydrogenolysis of the protective benzyl group with hydrogen at atmospheric pressure, in the presence of a suitable hydrogenation catalyst, and the process is completed by isolating the desired acid salt 1. Process according to claim 3, characterized in that a mixture of acid 2 with a compound selected from hydrate, alkali metal or alkaline earth metal carbonate or organic base, reacts with hydrogen at atmospheric pressure in the presence of a hydrogenation catalyst. C Process according to claim 3, characterized in that said alkaline earth metal is calcium. Process according to claim 3, characterized in that said alkali metal is selected from sodium and potassium. Process according to claim 3, characterized in that said catalyst is palladium on charcoal. Process according to claim 3, characterized in that said organic solvent is selected from propanol, tetrahydrofuran and dioxane. 9. A pharmaceutical composition comprising, as active ingredient, the salt of claim 1, as well as conventional excipients and carriers. Pharmaceutical composition according to claim 9, characterized in that it exhibits antihypertensive activity. GUIDOTTI LABORATORS S.p.A., Italy For: J. Summary STABLE SALTS (+) - (IS, 2R) -2 - [(n (2- + IIDR0XYLAMIN0-2-0KS0ETYL) N-METHYL-AMIΝθ] CARBONYL] CYCLOHEXAN-1-CARBOXYLIC ACIDS, PROCEDURE FOR THEIR PREPARATION AND PHARMACEUTICALS THE INGREDIENTS CONTAINING THEM New Salts (+) - (IS, 2R) -2- N - (2-hydroxy 1-amino-2-oxoethyl and 1) - N-Methyl 1-aminoCarbonyl cyclohexane-1-carboxylic acids with metals and organic bases represented by the general formula R R ' CH ₃ where R and R ', when taken together, is a divalent cation selected from calcium, ethylene diamine and other pharmaceutically acceptable cations or organic bases, or R if R * = H * is sodium, potassium, an imidazole group , lysine, choline, diethanolamine, arginine or histidine showing ACE — inhibitory activity and are therefore useful as active ingredients in anti-hypertension medicines. The process for preparing them preferably involves the reaction of a benzyl-protected starting acid with a suitable hydrate, carbonate or organic base and hydrogenation conditions in the presence of a catalyst for the preparation of a benzyl group.