CS242898B2 - Method of 1,4-dihydropyridine new derivatives production - Google Patents

Abstract

Process for preparing novel 1,4-dihydropyiidine derivatives of Formula IA H 4 R 4 ROCO 2 XX / COOR 2 CH2 is CH2-O-Y-NH in which R is phenyl optionally substituted one or two substituents selected from nitro, halogen, C 1 -C 4 alkyl, alkoxy C 1 -C 4 hydroxyl, trifluoromethyl, alkoxycarbonyl C 1 -C 4 alkoxy, and cyano, 1-naphthyl or 2-naphthyl, benzofuranyl, benzothienyl, pyridyl, optionally monosubstituted methyl or cyano; benzoxazdlyl, benzothiazdlyl furyl, pyrimidinyl thiazolyl, 2,1,3-benzoxadiazole- -4-yl, 2,1,3-benzothiadiazole-4-yl a group or thienyl group optionally monosubstituted halogen or alkyl with 1 to 4 carbon atoms, r! and R 2 are each independently alkyl C 1 -C 4 or 2-methoxyethyloMDU group a Y is - (CH 2) 2 - r - (CH 2) 3 - -CH 2 CH (CH 3) - or -CH 2 C (CH 3) 2, and pharmaceutically acceptable addition salts thereof with acids. The produced crosslinks are useful as anti-ischemic and antipertensive agents.

Description

The present invention provides a process for the preparation of certain dihydropyridines, particularly certain 1,4-dihydropyridines bearing a piperazinyl group in the side chain attached at the 2-position, which compounds are useful as anti-ischemic and anti-hypertensive agents.

The compounds of the invention inhibit the movement of calcium into cells and are thus capable of delaying or preventing cardiac contracts. This contracture is believed to be caused by the accumulation of calcium within cells under ischemic conditions. Excess calcium during ischemia can have a number of other deleterious effects that could further adversely affect the ischemic myocardium. These effects include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation, and possibly induction of cell necrosis.

Thus, the compounds of the invention are useful in the treatment or prevention of various cardiac conditions, such as angina, cardiac arrhythmias, heart attacks and cardiac hypertrophy. The disclosed compounds also exhibit vasodilatory activity because they can inhibit calcium entry into vascular tissue cells and are therefore useful as antihypertensive agents and for the treatment of coronary artery spasm.

Accordingly, the present invention provides a process for the preparation of the novel 1,4-dihydropyridine derivatives of formula IA

- HR ROOC. χ COOR ² jf r (ία) ^H 3 ^C H CH ₂ -O — Y —NN — H wherein

R is an aryl or heteroaryl group as defined below,

2

R @ 1 and R @ 2 are each independently C1 -C4 alkyl or 2-methoxyethyl;

Y is - (CH 2) 2 - (CH 2 CH 2) - or (CH 2) 2 - and their pharmaceutically acceptable acid addition salts.

Compounds of formula IA containing one or more centers of asymmetry exist in the form of one or more pairs of enantiomers, and these pairs or individual isomers may be separated by physical methods such as fractional crystallization of the free bases or suitable salts or chromatography of the free bases. The invention encompasses a process for making both separate pairs and mixtures thereof, as racemic mixtures, or separate d- and optically active isomeric forms.

Pharmaceutically acceptable acid addition salts of the compounds, ₄ wzorce IA are salts with acids which form nontoxic acid addition salts such as hydrochloride, hydrobromide, sulphate or bisulphate, phosphate or hydrogen phosphate, acetate, citrate, fumarate, gluconate, lactate, maleate, succinate and salts with tartaric acid.

The term aryl as used herein means a phenyl radical substituted with one or two substituents selected from the group consisting of nitro, halogen, C1-C4alkyl, C1-C4alkoxy, hydroxyl, trifluoromethyl, alkoxycarbonyl C 1 -C 4 alkoxy and cyano. The above-mentioned term also means a 1-naphthyl and a 2-naphthyl group.

The term heteroaryl as used herein means benzofuranyl, benzothienyl, pyridyl, optionally monosubstituted methyl or cyano, quinolyl, benzoxazolyl, benzothiazolyl, furyl, pyridiminyl, thiazolyl, 2,1,3-benzo3 xadiazol-4-yl, 2,1,3-benzthiadiazol-4-yl, and thienyl optionally monosubstituted with halogen or C 1 -C 4 alkyl. Preferred heteroaryl radicals are pyridyl, furyl and thiazolyl.

By halogen is meant fluorine, chlorine, bromine or iodine.

The alkyl and alkoxy groups containing 3 or more carbon atoms may be straight or branched.

R is preferably a phenyl group substituted by one or two halogen atoms or one trifluoromethyl group, or a 1- or 2-naphthyl group. Even more preferred aryl radicals in the meaning of R are 2-chlorophenyl, 2-trifluoromethylphenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 1-naphthyl, 3-chlorophenyl and 2-fluorophenyl.

R @ 1 is preferably methyl.

R is preferably ethyl.

Y is preferably - (CH3) -

In preferred individual compounds of the invention, R is 2,3-dichlorophenyl 1 2, R is methyl, R is ethyl, and Y is

In accordance with the invention, compounds of formula IA can be prepared by cleavage of a suitable protecting group from the corresponding nitrogen-protected piperazine derivative, i.e., according to the following reaction scheme:

R ¹ OOC ch ₃ coor ² ch ₂ oyn nq cleavage of protecting group Q

H R

R ¹ OOC X / X5 / ^COOR2

CH ₂ '}!} Ch ₂ ovn nh

Preferred protecting groups are benzyl, 4-chlorobenzyl (both cleavable by hydrogenation) and trityl (acid cleavable).

The nitrogen-protected piperazines are obtained in a conventional manner. For example, the corresponding N-benzyl- and N- (4-chlorobenzyl) derivatives are described and protected in our published European patent application 0060674.

These starting materials can be prepared by the following procedures:

a) Hantzsch synthesis:

^ XCOOR

CH

RCHO + I heating

II

^X ^ 0 \ CH., OYN ^/ NQ ² \ __ / at which, as is known in the art, either initially zhařeje ketoester with the aldehyde and then adding crotonate, or in which all three are heated reactants together, or

b) reactions according to the scheme

CH + »

-COO ² R heating

COOR ^c with ammonium acetate as known in the art.

Acid addition salts of compounds of formula IA may be prepared in conventional manner, for example by reacting a solution of the free base in a suitable organic solvent with a solution of the desired acid in a suitable solvent and isolating the resulting salt either by filtration if precipitated from the solution or by evaporating the solution to dryness. .

The ability of the compounds of the invention to inhibit the entry of calcium into cells demonstrates their efficacy in suppressing the response of isolated cardiac tissue to an increase in calcium ion concentration in vitro. This test is performed by fastening the spiral-cut strips of the rat aorta at one end and attaching it to the power transducer at the other end. The tissue is placed in a bath consisting of physiological saline containing 45 mmol potassium ions and no calcium. Calcium chloride is then added to the bath by pipette to a final calcium ion concentration of 2 mmol. '

The change in tension induced by tissue concentration is recorded. The bath is removed and replaced with fresh saline and after 45 minutes the test is repeated with the test compound present in the saline. The concentration of this test compound needed to suppress the response by 50% is determined.

The results obtained with the individual compounds of the invention in this test are summarized in the following table, where they are given in values of ^ic jq. 1 M means 1 grammol / liter. The lower the concentration, the more effective the compound is.

Test substance

IC

The product of Example 1 The product of Example 2 The product of Example 3

1.55 x 10 ^-7 M 3.4 × 10 ^_7 M 2.24 x 10 ^-7 M

The antihypertensive activity of the compounds of the invention can also be evaluated after their oral administration by measuring the blood pressure drop of spontaneously hypertensive rats or renally hypertensive dogs.

For administration in human medicine for curative or prophylactic treatment of cardiac disorders and hypertension, doses of the compounds when administered orally to an average adult patient (70 kg) will range from 2 to 100 mg per day. Thus, for a typical adult patient, a single tablet or capsule may generally contain 1 to 20 mg, in particular up to 10 mg, of the active ingredient in combination with a suitable pharmaceutically acceptable carrier. In the case of intravenous administration, the dosage will be in the range of 1 to 10 mg, as appropriate, for a single dose. In practice, the appropriate dose which will be most suitable for each patient and will vary depending on the age > weight and response of the particular patient to the drug administered will be determined by the attending physician.

OF

The above dosage is only an example of an average case and, of course, there may be individual cases where higher or lower doses are required. All such cases are within the scope of the invention.

In human meidcin, the compounds of formula IA may be administered as such, but are generally administered in admixture with a pharmaceutical carrier selected taking into account the intended route of administration and standard pharmaceutical practice. For example, the compounds may be administered orally in the form of tablets containing, for example, starch or lactose as carriers, or in the form of capsules or ovules in which the compounds are present either alone or in admixture with carriers and / or excipients, or in the form of elixirs. or a suspension containing flavoring or coloring agents.

The active compounds according to the invention can also be administered by parenteral injection, for example intravenously, intramuscularly or subcutaneously. For parenteral administration, the disclosed compounds are most preferably used in the form of a sterile aqueous solution which may contain other substances, for example, salts or glucose to render the solution isotonic.

Accordingly, the invention also provides a pharmaceutical composition comprising a compound of Formula IA or a pharmaceutically acceptable acid addition salt thereof, together with a pharmaceutically acceptable diluent or carrier.

The invention also provides a method of protecting the heart from the deleterious effects of ischemia, comprising administering an effective amount of a compound of Formula IA or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition as defined above.

The invention further provides a method of treating hypertension, comprising administering to said patient an antihypertensive amount of a compound of Formula IA or a pharmaceutically acceptable acid addition salt thereof, or a pharmaceutical composition as defined above.

The invention is illustrated by the following non-limiting examples.

Example 1

Preparation of 4- (2-chlorophenyl) -3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-2- [2- (piperazin-1-yl) ethoxymethyl] -1,4-dihydropyridine and its bis-oxalate

g of 4-chlorobenzyl-protected piperazine C bis-oxalate (2 = Cl) in 1500 ml of methanol is hydrogenated at room temperature overnight with stirring in the presence of 0.5 g

0.5 g of 5% palladium on carbon catalyst at a pressure of 0.35 MPA. The catalyst is filtered off, the solvent is evaporated and the residue is partitioned between 100 ml of methylene chloride and 100 ml of dilute aqueous ammonia. The organic phase was dried over sodium carbonate and evaporated to dryness after filtration. 3 g of the oily free base of the title compound are obtained. A sample of this base was converted in acetone to bis-oxalate melting at 170 ° C with decomposition.

For C 24 H 22 ClN 2 O 5.2 (1 H 2 O 2 O) calculated: 51.03 ° C, 5.66 S, H, 6.38%;

Found: C 51.72, H 5.58, N 6.54.

Method B. Benzyl-protected piperazine C (Z = hydrogen) in 1500 ml of methanol, and 9 ml of acetic acid are hydrogenated at 40 DEG C. overnight at 40 psi in the presence of 2 g of 5% palladium on carbon. as a catalyst. By analogous treatment to Method A, 19 g of the title compound is obtained in the form of the bis-oxalate, which is identical to the salt obtained by Method A.

The starting 4-chlorobenzyl and benzyl piperazines used are described in Examples 34 and 34, respectively. 38 of our published European patent application 0060674. These compounds are prepared according to the following reaction scheme:

CHCOOC 'H _c II 4 5

Examples2 to 8

The following compounds, characterized in the form shown in the following overview, were prepared from the appropriate starting materials in an analogous manner to the previous example.

/

The preparation of these compounds follows the scheme

H R

_CH3 OOC ^^ x ^ _/ Cooch ₂ CH ₃

H ₂ / Pd / C

CH ·

Μ '\ ΛΛ pj CH ₂ OYN NCH ₂ Ph

H R

C ^ jX ^ OOC-COO K ^ pj ^CH 3 CH ₂ OY-rC ^ H

Example Number . Method R Y Isolated form Melting point (° C) Analysis (%) found (calculated) C H N 2 AND -CH, C (CH 2), - "whose bis-oxalate 120 52.53 (52.51 5.77 5.88 5.77 6.12) 3 AND -CH ₂ CH (CH ₃ ) - mono-oxalate 225-227 55.29 (55.71 6.26 6.23 7.14 7.22)

Cl

Example Method R number

Isolated NMR (CDCl 3 values):

form

Cl

- <ch ₂ ).

free base

Cl

Cl

- (CH

2 '2 free base

Cl

- <ch ₂ ) ₂ free base

1,2 (t, 3H), 2.01 (m, 4H); 2.35 (with, 3H), 2.75 (m, 4H); 3.13 (m, 2H), 3.58 (s, 3H); 3.60 ťt. 2H), 3.70 (q, 2H). 4.71 (with, 2H), 5.57 (s, 1 H), 6.40 (m, 2H), 7.34 (m, 4H). 1.18 (t, 3H), 2.35 (s, 3H); 2.65 (m, kkH) 3.58 (s, 3H); 3.60 (i.e. 2H), 4.01 (q, 2H). 4.68 (with, 2H), 5.25 (s, 1 H), 7.14 (m, 4H). 1.18 (i.e. 3H, 2.38 (s, 3H); 2.85 (m, 11H) 3.60 (s, 3H). 3.60 (wide signal, 2H), 4.10 (q, 2H), 4.65 (s, 2H), 4.90 (with, 1H), 7.25 (m, 3H) 8.87 (with. 1H); IR (nujol):

NH 3380 cm ^-1 , C = O 1,685 cm -1

free base

free base

1.06 (t, 3H), 2.24 (with, 3H), 2.58 (m, 10H) , 3.38 (t, . 2H) 3.52 (with. 3H), 3.61 (m, 1H), 3.96 (<3, 2H), 4.64 (with, 2H), 5.93 <S, 1H), 7.12 (m. 3H), 7.46 (m, 1H). 1,21 ít, 3H), 2,38, (with, . 3H) 2.60 (m, 11H) , 3.60 (with, , 3H) 3.60 <t, 2H), 4.05 <q. 2H), 4.68 (with, 2H), 4.95 (with, 1H), 7.16 (m, 5H). iC (nujol): NH3, 300 cm @ -1 = C, 1685 cm @ -1

The benzyl-protected starting piperazines used in the hydrogenations of Examples 2 and 3 were prepared in an analogous manner to that described in the final section of Example 1.

The benzyl-protected starting piperazines used in the hydrogenations of Examples 4 and 8 were prepared by the Hantzsch reaction according to the following scheme:

(i) / - \

C1.CH ₂ C.CH ₂ CO ₂ C ₂ H ₅ + HOCH ₂ CH ₂ N N-CH ₂ Ph o

NaH (tetrahydrofuran) II

PhCH ₂ N, NCH ₂ CH ₂ OCH ₂ CCH _{2 CO2 C2 H5} (ii) Hantzsch reaction (see for example European Published Patent Application no. 0060674) according to the following scheme:

PhCH

NCH ₂ CH ₂ OCH ₂ CCH ₂ CO ₂ C ₂ H ₅ + R.CHO + CH ₃

C = CH.COOCH

I ^NH 2 ethanol, glacial acetic acid, heating

H R

CH ₃ OOC <X 1 / COOC ₂ H ₅

ΛΑ γλ

CH ₂ N CH ₂ OCH ₂ CH ₂ N NCH ₂ Ph

Example

3-Ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4- (1-naphthyl) -2- (2- (piperazin-1-yl) ethoxymethyl) -1,4-dihydropyridine

A mixture of 2.6 g of 1- [2- (ethoxycarbonylaoethylmethoxy) ethyl] -1-triphenylmethylpiperazine, 0.81 g

Of 1-naphthaldehyde and 0.6 g of methyl 3-aminocrotonate in 50 ml of methanol are heated under reflux for 5 hours. After evaporation of the solvent, the oily residue is dissolved in diisopropyl ether, the solution is filtered and evaporated. The oily residue was stirred with 25 ml of 50% aqueous hydrochloric acid for 1 hour, then basified with concentrated aqueous sodium carbonate solution and extracted with methylene chloride. 1.4 g of 3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4- (1-naphthyl) -2- (2- (piperazin-1-yl) ethoxymethyl) -1,4-dihydropyridine are obtained from methylene chloride extract. in the form of an orange-colored oil.

NMR (CDCl3):

0.92 (t, 3H), 2.42 (with, 3H), 2.73 (m, 10H) 3.41 (with, 3H>, 3.75 << 3r 2H), 4.10 (t, 2H), 4.76 (with, 2H), 5.80 (with. 1H), 7.50 (m, 7H), 8.55 (m, 2H).

Examples 10 and 11

The following compounds were prepared from the corresponding starting materials in an analogous manner to the previous example:

H r

CH, OOC ^COOC 2 ^H 5

AA, ch ₂ and ₂ ch ₂ nnh

CH,

Example number

Isolated form

MNR (CDCl3, values /):

10 ίιΊ free base 1.17 (t, 3H), 2.34 ís, 3H), vs 2.52 (m, 6H), 2.88 (m, 5H), 1 3.56 (with, 3H), 3.63 (t, 2H), 3.98 <q, 2H), 4.69 ís, 2H), 5.20 (with. 1H), 7.07 (m, 5H). 11 free base 1,23 (i.e. 3H), 2.37 no. 3H), NyS 2.46 (m. 10H) , 3.47 (with, , 2H) 3.63 (with. 1H), 3.70 (s, 3H), 4.13 (q, 2H), 4.75 (s, 2h), 5.50 (S, 1H), 7.08 (with. 1H), 7.59 (d, 1H), 7.68 (m, 1H). -

Example 12

Tablets having the following composition are prepared from the following ingredients:

Ingredient mg / tablet Compound of the invention 10 Calcium monohydrogen phosphate 120 Maize starch 20 Magnesium stearate 1,8 Sodium lauryl sulfate 0,2

The above ingredients are intimately mixed, compressed, granulated and processed into tablets of the desired size.

Example 13

Capsules containing the following composition are prepared from the following ingredients:

Component mg / capsule Compound of the invention 10 Corn starch 127 Microcrystalline cellulose 127 Magnesium stearate 5.4 Sodium lauryl sulfate 0.6

The above ingredients are mixed thoroughly and filled into hard gelatin capsules the size of which corresponds to the desired ingredient content.

The preparation of the new starting material used in Example 9 is illustrated by the following preparation.

Preparation of (A) 1- (2-hydroxyethyl) -4-triphenylmethylpiperazine

2.6 g of 1- (2-hydroxyethyl) piperazine are dissolved in a mixture of 20 ml of dry methylene chloride and 10 ml of trimethylamine, and a solution of 5.6 g of trityl chloride in 20 ml of dry methylene chloride is slowly added to the resulting solution. After the addition was complete, the reaction solution was stirred at room temperature for 18 hours and then evaporated to dryness. The residue was basified with 5% aqueous sodium bicarbonate solution and extracted with methylene chloride. The extract yielded 4.0 g of 1- (2-hydroxyethyl) -4-triphenylmethylpiperazine, m.p. 82 DEG C., which was used directly in the next step.

(B) 1- [2- (ethoxycarbonylacetylmethoxy) ethyl] -4-triphenylmethylpiperazine

To 15 ml of dry tetrahydrofuran, 0.9 g of sodium hydride is added under stirring at room temperature under nitrogen, then a solution of 1- (2-hydroxyethyl) -4-triphenylmethylpiperazine in 5 ml of dry tetrahydrofuranone is added dropwise and the mixture is stirred for 1 hour. A solution of 1.8 g of ethyl 4-chloroacetoacetate in 5 ml of dry tetrahydrofuran was added over 1 hour and the reaction mixture was stirred at room temperature for 18 hours.

After addition of 5 drops of isopropanol, the resulting mixture was poured onto 100 g of ice and carefully neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The extract was evaporated, the oily residue was dissolved in acetonitrile, washed three times with petroleum ether (40-60 ° C) and evaporated. 2.6 g of 1- [2- (ethoxycarbonylacetylmethoxy) ethyl] -4-triphenylmethylpiperazine are obtained in the form of an orange-red oil which is used without further purification.

Claims (4)

OBJECT OF THE INVENTION A process for the preparation of novel 1,4-dihydropyridine derivatives of the general formula IA ROOC COOR ² (IA) CH ₂ NH -oyn ^I \ _ / wherein R is a phenyl radical optionally substituted by one or two substituents selected from nitro, halogen, C1-C4alkyl, C1-C4alkoxy, hydroxyl, trifluoromethyl, C1-C4alkoxycarbonyl carbon in the alkoxy moiety and cyano, 1-naphthyl or 2-naphthyl, benzofuranyl, benzothienyl, pyridyl, optionally monosubstituted methyl or cyano, quinolyl, benzoxazolyl, benzthiazolyl, furyl, pyrimidinyl, thimidinyl a 2,1,3-benzoxadiazol-4-yl group, a 2,1,3-benzthiadiazol-4-yl group or a thienyl group, optionally monosubstituted by halogen or a (C1-C4) alkyl group, 1 2 R and R are each independently C1-C4alkyl or C1-C4alkyl; 2-methoxyethyl; and Y is - (CH ₂ ) ₂ -, - (CH ₂ ) ₃ -, -CH ₂ CH (CH ₃ -) - or -CH ₂ C (CH p ₂ -), and their pharmaceutically acceptable acid addition salts, characterized in that cleaving the protecting group Q from the compound of formula II ^R R'OOC COOR H ^{2 CH} 3. 'cHjOYN NQ (II) in which 1 2 R, R, R and Y are as previously defined as in 1a Q is a protecting group, and the resulting product is optionally converted to its pharmaceutically acceptable acid addition salt by reaction with a non-toxic acid. 2. A process according to claim 1, wherein the compound of formula (II) wherein R, R, R and Y are as defined in point 1 and the protecting group Q is benzyl or 4-chlorobenzyl is used as starting material. which are removed by hydrogenation, or a trityl group which is removed by treatment with an acid. 3. A process according to any one of Claims 1 and 2, wherein the corresponding starting materials are used to produce products in which R is 2-chlorophenyl, 2-trifluoromethyl, 2,3-dichlorophenyl, 3,5, 5 -dochlorophenyl group, 2,6-dichlorophenyl, 1-naphthyl, 3-chlorophenyl or 2-chloro-2-phenyl, R is methyl, R is ethyl and Y is as defined above. 4. A process according to any one of claims 1 to 3, wherein the corresponding starting materials are used to produce products in which Y is a group ^{and the} remaining general symbols are as defined above.