CS242898B2 - Process for preparing novel 1,4-dihydropyridine derivatives - Google Patents

Abstract

A method for producing new 1,4-dihydropyridine derivatives of the general formula IA H R 4 Rlooc^ XX/COOR2 CHj h CH2-O-Y~N__ NH in which R represents a phenyl radical, optionally substituted by one or two substituents selected from the group comprising a nitro group, halogen atoms, alkyl groups with 1 to 4 carbon atoms, an alkoxy group with 1 to 4 carbon atoms, a hydroxyl group, a trifluoromethyl group, alkoxycarbonyl groups with 1 to 4 carbon atoms in the alkoxy moiety, and a cyano group, further a 1-naphthyl or 2-naphthyl radical, a benzofuranyl group, a benzothienyl group, a pyridyl group, optionally monosubstituted by a methyl group or cyano group, a quinyl group, a benzoxazdlyl group, a benzothiazdlyl group, a furyl group, a pyrimidinyl group, a thiazolyl group, 2,1,3-benzoxadiazol-4-yl group, 2,1,3-benzothiadiazol-4-yl group or thienyl group, optionally monosubstituted by halogen or alkyl group with 1 to 4 carbon atoms, R1 and R2 independently of each other each represent an alkyl group with 1 to 4 carbon atoms or a 2-methoxyethyl group and Y represents a group -(CH2)2-, -(CH2)3-, -CH2CH(CH3)- or -CH2C(CH3)2, and their pharmaceutically usable acid addition salts. The compounds produced are useful as antiischemic and antihypertensive agents.

Description

The invention describes 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 antiischemic and antihypertensive agents.

The compounds of the invention inhibit the movement of calcium into cells and are therefore able to delay or prevent cardiac contracture. This contracture is believed to be caused by the accumulation of calcium inside the 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 utilization of oxygen for ATP production, activation of mitochondrial fatty acid oxidation, and possibly the induction of cellular necrosis.

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

Accordingly, the invention describes a process for the production of novel 1,4-dihydropyridine derivatives of general formula IA

- HR ROOC. χ COOR ² jf r (ία) ^H 3 ^C H CH ₂ -0 —Y —NN—H in which

R represents an aryl or heteroaryl group as defined below,

2

R and R independently of each other each represent an alkyl group with 1 to 4 carbon atoms or a 2-methoxyethyl group and

Y represents the group — (Cl^) 2'' -d^CH^CH^)- or (CH^) 2~ r and their pharmaceutically acceptable acid addition salts.

Compounds of the above general 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 can be separated by physical methods, for example fractional crystallization of the free bases or suitable salts or chromatography of the free bases. The invention includes a process for the preparation of both the separated pairs and mixtures thereof, such as racemic mixtures or separated d- and 1-optically active isomeric forms.

Pharmaceutically acceptable acid addition salts of _compounds of general formula IA are salts with acids forming non-toxic addition salts, such as hydrochlorides, hydrobromides, sulfates or hydrogen sulfates, phosphates or hydrogen phosphates, acetates, citrates, fumarates, gluconates, lactates, maleates, succinates 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, alkyl (C1-4), alkoxy (C1-4), hydroxyl, trifluoromethyl, alkoxycarbonyl (C1-4) and cyano. The above term also includes 1-naphthyl and 2-naphthyl.

The term heteroaryl, as used herein, means a benzofuranyl group, a benzothienyl group, a pyridyl group optionally monosubstituted with a methyl group or a cyano group, a quinolyl group, a benzoxazolyl group, a benzothiazolyl group, a furyl group, a pyridiminyl group, a thiazolyl group, a 2,1,3-benzo3 xadiazol-4-yl group, a 2,1,3-benzthiadiazol-4-yl group and a thienyl group optionally monosubstituted with a halogen atom or an alkyl group with 1 to 4 carbon atoms. A preferred heteroaryl radical is a pyridyl, furyl and thiazolyl radical.

The term halogen means fluorine, chlorine, bromine or iodine.

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

The symbol R preferably represents 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 the symbol R are 2-chlorophenyl, 2-trifluoromethylphenyl, 2,3-dichlorophenyl, 3,5-dichlorophenyl, 2,6-dichlorophenyl, 1-naphthyl, 3-chlorophenyl and 2-fluorophenyl.

The symbol R 1 preferably represents a methyl group.

The symbol R preferably represents an ethyl group.

Y preferably represents the group -(CH 2 )

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

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

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

H R

R ¹ OOC x/x5/ ^Coor2

CHj'}!} ch ₂ ovn nh

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

Nitrogen-protected piperazines are obtained in a conventional manner. The corresponding N-benzyl and N-(4-chlorobenzyl) derivatives are, for example, described and protected in our published European Patent Application No. 0060674.

These starting materials can be prepared by the following procedures:

a) Hantzsch synthesis:

^XCOOR

CH

RCHO + I warm-up

II

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

b) reaction according to the scheme

CH + »

-COO ² R warm-up

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

Acid addition salts of compounds of formula IA can be prepared in a 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 it precipitates from solution, or by evaporating the solution to dryness.

The ability of the compounds of the invention to inhibit calcium entry into cells is demonstrated by their efficacy in suppressing the response of isolated cardiac tissue to increases in calcium ion concentration in vitro. This test is performed by fixing spirally cut strips of rat aorta at one end and connecting the other end to a force transducer. The tissue is placed in a bath consisting of physiological saline containing 45 mmol of potassium ions and no calcium. Calcium chloride is then added to the bath by pipette until a final calcium ion concentration of 2 mmol is reached. '

The change in tension induced by the 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 the test compound required 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 ^ic jq values. The value 1 M means 1 grammol/liter. The lower the concentration given, the more effective the respective compound is.

Test substance

IC

Product from example 1 Product from example 2 Product from example 3

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

The antihypertensive efficacy of the compounds of the invention can also be assessed after their oral administration by measuring the decrease in blood pressure in spontaneously hypertensive rats or renally hypertensive dogs.

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

FROM

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

In human medicine, the compounds of formula IA may be administered as such, but are generally administered in admixture with a pharmaceutical carrier selected having regard to the intended route of administration and standard pharmaceutical practice. For example, these compounds may be administered orally in the form of tablets containing as carriers, for example, starch or lactose, or in the form of capsules or ovules containing the compounds described either alone or in admixture with carriers and/or excipients, or in the form of elixirs or suspensions containing aromatic additives or colorants.

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

The invention therefore 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 describes a method of protecting the heart from the harmful effects of ischemia, which comprises administering an effective amount of a compound of general 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, which comprises administering to the 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 examples, which are not intended to limit the scope of the invention in any way.

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 piperazine bis-oxalate C protected by a 4-chlorobenzyl group (2 = Cl) in 1,500 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 as catalyst under 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 is dried over sodium carbonate and, after filtration, evaporated to dryness. 3 g of the oily free base of the title compound are obtained. A sample of this base is converted in acetone to the bis-oxalate melting with decomposition at 170 °C.

Analysis: for C24H22CIN2O5.2 (100% C10H10) calculated: 51.03 C, 5.66 H, 6.38 N;

found: 51.72% C, 5.58% H, 6.54% N.

Method B.— 1 g of benzyl-protected piperazine C (Z = hydrogen) in 1500 ml of methanol and 9 ml of acetic acid are hydrogenated at 40 °C overnight at 0.35 MPa in the presence of 2 g of 5% palladium on carbon as a catalyst. By working up analogously to Method A, 19 g of the title compound are 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 38, respectively, of our published European Patent Application No. 0060674. These substances are prepared according to the following reaction scheme:

CHCOOC„H _c II 4 5

Examples2 to 8

In a manner analogous to the previous example, the following compounds characterized in the form given in the following overview are prepared from the appropriate starting materials.

/

The preparation of these substances is carried out according to the scheme

H R

CH ₃ OOC^^x^ _/ cooch ₂ ch ₃

_H2 /Pd/C

CH·

Μ' \ ΛΛ pj CH ₂ OYN NCH ₂ Ph

H R

C^OOC^jX^COOCH^Kj ^CH 3 pj CH ₂ OY-rC^H

Example Number . Method R Y Isolated form Melting point (°C) Analysis (%) found (calculated) C H N 2 A -CH,C(CH,),- “ci bis-oxalate 120 52.53 (52.51 5.77 5.88 5.77 6.12) 3 A _-CH2CH ( _CH3 )- mono-oxalate 225-227 55.29 (55.71 6.26 6.23 7.14 7.22)

Cl

Example Method R number

Isolated NMR (CDCl,, 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 t. 2H) , 3.70 (q, 2H), 4.71 (with, 2H) , 5.57 (s, 1H), 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, 1H), 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 (p. 1H) ; IR (nujol):

NH 3380 cm ^-1 , C=O 1685 cm'

free base

free base

1.06 (t, 3H) , 2.24 (with, 3H) , 2.58 (m, 10H) , 3.38 (t, . 2H) 3.52 (p. 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 to go, 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) : NH .3 300 cm \ C=O 1 685 cm

The starting piperazines protected by the benzyl group, used in the hydrogenations according to Examples 2 and 3, are prepared in an analogous manner to that described in the final part of the example of Example 1.

The starting piperazines protected by the benzyl group, used in the hydrogenations according to Examples 4 and 8, are 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 /—i II

PhCH ₂ N nch ₂ ch ₂ och ₂ cch ₂ co ₂ c ₂ h ₅ (ii) by the Hantzsch reaction (see for example published European 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\/COOC ₂ H ₅

ΛΑ γλ

CHj 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-(ethoxycarbonyl-ethylmethoxy)ethyl]-1-triphenylmethylpiperazine, 0.81 g

1-naphthaldehyde and 0.6 g of methyl-3-aminocrotonate in 50 ml of methanol are heated to 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 is stirred for 1 hour with 25 ml of 50% aqueous hydrochloric acid, then basified with concentrated aqueous sodium carbonate solution and extracted with methylene chloride. From the methylene chloride extract, 1.4 g of 3-ethoxycarbonyl-5-methoxycarbonyl-6-methyl-4-(1-naphthyl)-2-(2-(piperazin-1-yl)ethoxymethyl)-1,4-dihydropyridine are obtained in the form of an orange-colored oil.

NMR (deuterochloroform, ^f”) values:

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

Examples 10 and 11

Using a procedure analogous to the previous example, the following compounds are prepared from the corresponding starting materials:

H r

CH,OOC ^COOC 2 ^H 5

AA, ch ₂ och ₂ ch ₂ n nh

CH,

Example number

Isolated form

MNR (CDCl2, values / ):

10 ίιΊ free base 1.17 (t, 3H) , 2.34 is, 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 is, 2H) , 5.20 (p. 1H) , 7.07 (m, 5H) . 11 free base 1.23 (i.e. 3H) , 2.37 No. 3H) , New York 2.46 (m. 10H) , 3.47 (with, , 2H) 3.63 (p. 1H) , 3.70 (with , 3H) , 4.13 (q, 2H) , 4.75 (with , 2h) , 5.50 ( S , 1H) , 7.08 (p. 1H) , 7.59 (d, 1H) , 7.68 (m, 1H) . -

Example 12

The following ingredients are used to prepare tablets with the following composition:

Ingredient mg/tablet compound according to the invention 10 calcium monohydrogen phosphate 120 corn starch 20 magnesium stearate 1.8 sodium lauryl sulfate 0.2

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

Example 13

Capsules containing a mixture with the following composition are prepared from the following ingredients:

Ingredient 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 thoroughly mixed and the mixture is filled into hard gelatin capsules, the size of which corresponds to the desired content of the ingredients.

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

Preparation (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 while stirring at room temperature. After the addition is complete, the reaction solution is stirred for another 18 hours at room temperature and then evaporated to dryness. The residue is basified with 5% aqueous sodium bicarbonate solution and extracted with methylene chloride. The extract yields 4.0 g of 1-(2-hydroxyethyl)-4-triphenylmethylpiperazine with a melting point of 82 °C, which is used directly in the next step.

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

To 15 ml of dry tetrahydrofuran, 0.9 g of sodium hydride is added while 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 another 1 hour, after which a solution of 1.8 g of ethyl 4-chloroacetoacetate in 5 ml of dry tetrahydrofuran is added over 1 hour and the reaction mixture is stirred at room temperature for 18 hours.

After adding 5 drops of isopropanol, the resulting mixture is poured onto 100 g of ice and carefully neutralized with concentrated hydrochloric acid and extracted with ethyl acetate. The extract is evaporated, the oily residue is dissolved in acetonitrile, the solution is 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)

SUBJECT OF THE INVENTION 1. Process for the production of new 1,4-dihydropyridine derivatives of general formula IA ROOC COOR ² (IA) ch ₂ -oyn nh ^í \_/ in which R represents a phenyl radical, optionally substituted by one or two substituents selected from the group comprising a nitro group, halogen atoms, alkyl groups with 1 to 4 carbon atoms, alkoxy groups with 1 to 4 carbon atoms, hydroxyl group, trifluoromethyl group, alkoxycarbonyl groups with 1 to 4 carbon atoms in the alkoxy moiety and cyano group, further a 1-naphthyl or 2-naphthyl radical, benzofuranyl group, benzothienyl group, pyridyl group, optionally monosubstituted by methyl group or cyano group, quinolyl group, benzoxazolyl group, benzthiazolyl group, furyl group, pyrimidinyl group, thiazolyl group, 2,1,3-benzoxadiazol-4-yl group, 2,1,3-benzthiadiazol-4-yl group or thienyl group, optionally monosubstituted by halogen or an alkyl group with 1 to 4 carbon atoms, 1 2 R and R independently of each other each represent an alkyl group with 1 to 4 carbon atoms or a 2-methoxyethyl group and Y represents the group -(CH ₂ ) ₂ -, -(CH ₂ ) ₃ ~, -CH ₂ CH(CH ₃ >- or -CH ₂ C (CHp ₂ ~, and their pharmaceutically acceptable acid addition salts, characterized in that the protecting group Q is cleaved from the compound of the general formula II r'ooc ^R COOR ^{2 CH} 3 H .''cHjOYN NQ (II) in which 1 2 R, R, R and Y have the above meaning as in point 1 and Q represents a protecting group, and the resulting product is optionally converted into its pharmaceutically acceptable acid addition salt by reaction with a non-toxic acid. 2. The method according to item 1, characterized in that the starting material used is a compound of the general formula II, in which R, R, R and Y have the meaning as in item 1 and the protecting group Q is a benzyl or 4-chlorobenzyl group, which are removed by hydrogenation, or a trityl group, which is removed by the action of an acid. 3. The method according to any of items 1 and 2, characterized in that the corresponding starting materials are used to form products in which R represents a 2-chlorophenyl group, a 2-trifluoromethyl group, a 2,3-dichlorophenyl group, a 3,,5-dichlorophenyl group, 2,6-dichlorophenyl group, 1-naphthyl group, 3-chlorophenyl group or 2-chloro1 2 phenyl group, R represents a methyl group, R represents an ethyl group and Y has the above meaning. 4. The method according to any one of items 1 to 3, characterized in that corresponding starting materials are used to form products in which Y represents a group ^and the remaining general symbols have the meanings given above.