CS273180B2 - Method of dihydropyridine derivatives production - Google Patents

Abstract

Method of production of dihydropyridine derivatives of formula I; where R<1> and R<2> always mean C1-4-alkyl, Ar is phenyl, possibly bearing one or two substituents selected from a group including atoms of halogens, the hydroxy group, nitro group, cyano group, alkyl, alkenyl, alkoxyl, alkenyloxy and alkanoyl groups also containing 6 carbon atoms, or Ar means 1,4-benzodioxan-5-yl-benzo-(b)fur-7-yl or 4-morpholino-1,2,5-thiadiazol-3-yl residue; X is the group -O- or -S- and Y is direct or branched C2-l2-alkylene, possibly interrupted by one or two groups selected from oxygen, the imino group and phenylene group and their additive salts with oxygen, based on the reaction of the compound of formula VII with amine of general formula VIII and possible conversion of the product into salt. The compounds either block adrenergic β-receptors or calcium ions, or have both these effects, and they can be used to treat hypertension.<IMAGE>

Description

The invention aa relates to a process for the preparation of novel alkanolamine derivatives; in particular, novel dihydropyridine derivatives having antihypertaneive properties.

Numerous 2,6-dialkyl-4-aryl-1,4-dihydropyridine-3,5-dicarboxylates are known to inhibit calcium ion movement in the cardiovascular system of warm-blooded animals and thereby exhibit an antihypartensive effect. The most widely used of these is the preparation of dipodipine, i.e. domethyl-1,4-dihydro-2,6-dirasthyl-4-o-nitrophenylpyridine-3,5-dicarboxylate,

Numerous 1-aryloxy-3-aminopropan-2-ol derivatives are also known which block adrenargic β-raceptors, and which also have an antihypartensive effect. Two of the most commonly used compounds of this type are propanolol and atenolol, which are 1- (1-naphthyloxy) - and 1-p-carbamoylmethylphanoxy-3-8-propylaminopropan-2-ol.

So far, the only attempt described to combine these two types of chemical structure into a single molecule is reported by Merck's staff in the Journal of Medicinal Chemistry; 1981; St. 24, pp. 628-631, wherein a 3-amino-2-hydroxypropoxyl substituent is introduced into the 4-aryl radical of the 4-aryl-1,4-dihydropyridine derivative. In this case, however, the authors' efforts to obtain a compound exhibiting antihypertensive activity have not met with great success.

Recently, after the priority date of the present application, U.S. Pat. No. 4,500,527 has been published; which discloses similar compounds wherein the 3-amino-2-hydroxypropoxyl substituent is attached to the 4-aryl moiety through the -CHbN- moiety. These compounds are protected as having antihypsrtansive activity and blocking adronergic β-receptors.

It has now been found that compounds that truly exhibit useful antihypertene activity can be obtained by appropriately combining a 3-aryl-oxy-2-hydroxypropylamine moiety with a 1,4-dihydropyridine moiety.

Accordingly, the invention provides a process for the preparation of dihydropyridine derivatives of the general formula I.

HIM.

X-r-HHCHgCHOHCHgOAr

IOGR ', 2

Ξ

CH.

in which 1 2

R and R; which may be the same or different (each represents an alkyl group containing up to 4 carbon atoms)

Ar represents a phenyl group; which is either unsubstituted or bears one or two substituents selected from the group consisting of halogen atoms, 'hydroxy,' nitro, cyano, alkyl; alkanyl; alkoxy; alkenyloxy and alkanoyl groups each containing up to 5 carbon atoms;

or Ar is a 1,4-banzodioxan-5-yl (banzo) b] fur-7-yl or 4-morpholino-1,2,5-thiadiazol-3-yl residue)

CS 273 ISO B2

X is -O- or -S- and

Y represents a straight or branched alkylene chain of 2 to 12 carbon atoms, optionally interrupted by one or two groups selected from -O-, imino -NH-, and phenylone, and their acid addition salts.

The dihydropyridine derivatives produced by the process of the present invention may contain at least two asymmetric carbon atoms (namely the carbon atom of the -CHOH- group in the alkanolamine chain and, if R and R are different), the carbon atom at the 4-position of the dihydropyridine nucleus. or in optically active forms. It will be appreciated that the invention encompasses both the racemic form of the dihydropyridine derivatives of Formula I and all optically active forms exhibiting antihypertaneive activity, and it is well known how a racamic compound can be resolved into optically active forms and how the antihypsynthetic activity of these forms can be determined. It should further be pointed out that the blocking activity of adrenergic δ-racaptors is usually predominant in the optically active form with an absolute S-configuration of the -CHOH- group in the alkanolamine chain.

2

Suitable radicals R and R and suitable substituents of the phenyl radical Ar are, for example, methyl, ethyl, isopropyl or isobutyl groups in the case of alkyl groups.

A suitable alkenyl substituent for Ar is, for example, allyl.

A suitable halogen substituent for Ar is, for example, a fluorine, chlorine or bromine atom.

A suitable alkoxy or alkenyloxy substituent for Ar is, for example, methoxy, alkoxy, propoxy, isopropoxy or allyloxy.

A suitable alkanoyl substituent for Ar is, for example, a formyl or acetyl group.

A particular value for Y is for example a straight chain alkylene of the formula "(CH ₂₎ -, where r» is an integer from 2 to 12 / or a residue of formula

- (CH ₂ ) m C (CH ₃ ) ₂ -,

- (CH _{2) m} -N _H - (CH _{2) n} -.

- (C ^H 2) _m N ^HCH 2 ^c ( ^CH 3) ₂ - or - (CH ₂ ) _m -O (CH ₂ ) _n where man is equal or different and is always 2, 3/4 or 5, or the rest of the formula

where m and n are the same or different and are always 1, 2, 3 or 4.

Suitable acid addition salts of the dihydropyridine derivative according to the invention (produced by the process according to the invention) are, for example, a salt with an inorganic acid, for example a hydrochloride, hydrobromide, phosphate or sulfate / or an organic acid-derived salt.

Examples of oxalate, lactate, euccinate, tartrate, acetate, salicylate, citrate, banzoate, β-naphthoate or adipate.

Preferred dihydropyridine derivatives prepared by the process according to the invention are the compounds of the above general formula (I), in which i 2

R and R, which are the same or different, each represent an alkyl group containing up to 4 carbon atoms.

Ar is a phenyl radical which is either unsubstituted or carries one or two substituents selected from the group consisting of fluorine, chlorine or bromine atoms, hydroxyl, nitro, cyano, alkyl, alkenyl and alkanoyl, each containing up to 4 carbon atoms, or Ar is 1,4-benzodioxan-5-yl, benzo / h-fur-7-yl or 4-morpholino-1,2,5-thladiszol-3-yl,

X is -O- or -S- and

Y represents a straight or branched alkylene chain of up to 8 carbon atoms, optionally interrupted by one or two groups selected from oxygen, imino and phenylene;

and their addition of salts and acids.

Particularly suitable dihydropyridines produced by the process of the present invention are the compounds of formula (I) above, wherein i

R and R, which may be the same or different / each represent a methyl or ethyl group, * the benzene ring A carries a nitro group at the 5-position and the side chain is attached to the benzene course A at the 2-position,

Ar is a phenyl radical which is either unsubstituted or substituted in the 2-position by fluorine, chlorine, bromine / nitro, cyano, allyl, methoxy, ethoxy, propoxy, isopropoxy, allyloxy or acetyl, or Ar is 1,4-benzodine -5-yl group,

X is -O- and

Y represents a straight or branched alkylene chain of up to 8 carbon atoms, optionally interrupted by oxygen, 'amino,' phenylene or phenyleneoxy, and their acid addition salts.

Specific dihydropyridine derivatives produced by the process of the invention are described in the Examples below. Among these, the following compounds are preferred:

diethyl 4- / 2- [4- (3-o-cyanophenoxy-2-hydroxypropylamino) -butoxy-3,5-nitrophenyl] -1,4-dihydro-2,6-dimethylpyridine-3,5-dicarboxylate, dimethyl-1 4-dihydro-4- [2- [4- (2-hydroxy-3-phenoxypropylamino) butoxy] -5-nitrophenyl] -2,6-dimethylpyridine-3,5-dicarboxylate and the corresponding salts thereof; (2-hydroxy-3-methoxyphenoxypropylamino) -, (3-o-ethoxyphenoxy-2-hydroxypropylamino) - and (2-hydroxy-3-o-propoxyphenoxypropylamino) analogs.

dimathyl-1,4-dihydro-4- [2- [3- (2-hydroxy-3-phenoxypropylamino) -3-methylbutoxy] -3-nitrophenyl] -2,6-dimethylpyridine-3,5-dicarboxylate, dimathyl-1 4-dihydro-4- (2- [3- (2-hydroxy-3-o-methoxyphanoxypropylamino) ethoxy] benzzyloxy) -5-nitrophanyl) -2,6-dimethylpyridine-3,5-dicarboxylate and ethylmethyl-1,4- dihydro-4- [2- {4- (2-hydroxy-3-o-methoxyphenoxypropylamino) butoxy] -5-nitrophenyl] -2,6-dimathylpyridine-3,5-dicarboxylate,

CS 273 180 S2, and in particular the (S) -antanomers of the aforementioned compounds with respect to the asymmetric carbon atom in the 2-position of the (2-hydroxy-3- (and optionally substituted) phenoxypropylamino) groups.

The object of the present invention is to provide a process for the preparation of dihydropyridine derivatives of the general formula Ϊ and their acid addition salts; indicating ee tlm; wherein the compound of formula (VII)

in which 1 2

R, R, X and Y are as defined above and Z is a displaceable group, reacted with an amine of formula VIII

HgNCHgCHOHCHgO-Ar in which

Ar is as defined above and the resulting product is optionally converted into an acid addition salt.

A suitable radical Z is, for example, a halogen atom, such as bromine or chlorine, or a sulfonyloxy group, for example a methanesulfonyloxy group or a p-toluenesulfonyloxy group.

As stated above (showing the dihydropyridine derivatives produced by the method of the invention antihypertene activity) which can demonstrate the ability of these compounds to lower the blood pressure of spontaneously hypersensitive rats or rats induced by hypertension by deoxycorticosterone acetate or dogs induced by hypertenae by the Goldblatt technique, consisting of a one-sided naphrectomy and a clamp on the other kidney. These are all standard tests used to prove the antihypertene properties of drugs.

Some of the dihydropyridines produced by the process of the invention block adrenergic β-receptors / some block calcium ions, and some show both of these types of action. Preferred dihydropyridines produced by the process of the present invention have both these types of action. Efficacy in blocking adrenergic S-receptors The in vitro ability of the compound to inhibit iaoprenaline-induced tachycardia in rat or cat, or by shifting the response curve of the isolated atrium of the guinea pig to isoprenaline to the right, can be prolonged. Calcium Ion Blocking Activity The in vitro ability of a test compound to reduce the spontaneous contraction of a rat portal vein preparation can be demonstrated. Again, these are all standard tests used to prove the above effects.

Since the dihydropyridines produced by the process of the present invention block the adre5

CS 273 ISO B2 nargniβ-receptors and / or calcium ions are also useful in the treatment of heart disease; like jaou angina pactoria and cardiac arrhythmia.

The following describes the performance and results of pharmacological tests demonstrating the efficacy of the compounds of the invention.

a) Spontaneously hypertensive rat (SHR)

Rat anemones (Okomoto - spontaneously hypertenaive strain) about 5 months old and weighing 200 to 250 g are divided into groups of 4/5 or 6 animals. All rats are anaesthetized with halothane (2%); by cutting under the throat and isolating their carotid artery into which a non-swollen catheter filled with saline solution (50 units / ml) is inserted and fixed to the optic. The animals are allowed to recover for 24 hours after surgery and then ground into open plastic tubes. A pressure transducer and a recording device are connected to the catheter to allow for! continuous recording of heart rate and blood pressure.

The test compound was administered orally to each animal in a single dose of 10 mg / kg body weight, dissolved in 1 ml of a 5: 4 ι 1 (v / v) mixture of polyethylene glycol / saline and ethanol. Blood pressure is recorded prior to administration of the test substance and after 1; 3 and 5 hours after administration.

During a five-hour observation period, aa reveals a maximum decrease (mean compared to pre-test substance) mean arterial pressure (MAP). The test substance is considered to be an antihypertensive agent when the decrease is at least Torr (2.666 kPa).

b) Spinal cord rat preparation

Female rats (Wistar - normotenaive strain) weighing about 250 g and divided into groups of 4 animals. All rats are anesthetized with halothane (2%) and, following insertion of the tracheal cannula, are rapidly sacrificed by breaking the spinal cord with a steel needle through the orbital according to the method described by Gillespie and Mulr (1967). The rats are then immediately converted to artificial respiration using a Palmar pump (3: 2 nitrogen / oxygen mixture, * 3 ml tidal volume; 53 cycles per minute).

The right throat vein ea introduces a cannula for injection of the test substance, and a cannula connected via a pressure transducer to a recording device allowing continuous recording of heart rate and blood pressure is also introduced into the left carotid artery. Both wagons were also separated.

Using isoprsnaline in doses of 0.003; 0.01, 0.03 and 0/1 µg / kg body weight is plotted against the dose of ieoprenaline and then the test compound dissolved in 0.5 ml of polyethylene glycol / saline / ethanol mixture is administered intravenously over 3 minutes. in a volume ratio of 5: 4: 1. The test substance is administered at a dose of 1 mg / kg body weight. 30 minutes after the end of dosing, the heart rate-isoprenaline dose-response curve is plotted. The doses of Ieoprenaline required to increase the heart rate by 50 beats per minute are then read from the curves. If the test substance has blocking activity on adrenergic beta-receptors, then the dose of leoprenaline required to increase the heart rate by 50 bpm is in the animals to which the test substance is administered; than the control animals. The ratio of the average isoprenaline dose required to increase the heart rate by 50 beats / min in treated and untreated control animals is calculated. A test substance is considered to be effective in blocking adrenergic β-receptors when this ratio is at least 15.

The following tables show the results obtained in the above tests with a wide variety of alkanolamine derivatives according to the invention. All compounds were tested in spontaneously hypsrtensive rats (SHR). Only some of these compounds were tested on a spinal cord rat preparation. Thus, if there is no value in the given column of the table, no compound was tested in this case.

Table 1

H

R Y Ar SHR max. MAP decrease (Torr / kPa) rat and spinal cord (ratio) et (CHgJg phenyl 25; 2/3 * 36 Et _{(CH2) 4} phenyl 52.3 / 6/97 35 isobutyl _{(CH2) 4} phenyl 23/3/3/11 Me W * 2-fluorophenyl 27.5 / 3/67 Me. . <ch ₂ ) ₄ 2-chlorophenyl 54/5/7/27 103 Me _{(CH2) 4} 2-bromophenyl 24/4/3/25 Me (° ₂ ) ₄ 2, ‘4-dichlorophenyl 1 20.4 / 2/72 Me (θΗ _{2) 4} 4-Hydroxyphenyl 20/1/2/68 Me _{(CH2) 4} 2-nitrophenyl 32.1 / 4/28 112 Et _{(CH2) 4} 2-cyanophenyl 42/7/5/69 96 Me <ch ₂ ) ₄ 3-tolyl 20.8 / 2/77 Me (™ ₂ > 4 2-allylphenyl 24/6/3/28 Me <ch ₂ ) ₄ 2-methoxyphenyl 81.5 / 10/87 79 Me (C _{2 2} > 4 4-methoxyphenyl 37/6/5/01 Me _{(CH2) 4} 2-ethoxyphenyl 45/6/6/08 95/2 Me _{(CH2) 4} 2-propoxyphenyl 91/4 / 12.19 62/7 Me _{(CH2) 4} 2-isopropoxyphenyl 25/2/3/36 75/1 Ms _{(CH2) 4} 2-allyloxyphenyl 34/7 / 4.63 53/4 Me _{(CH2) 4} 2-acetylphenyl 22.3 / 2/97

CS 273 180 B2

R Y Ar SHR max · decrease MAP (Torr / kPa) rat with scrambled spinal cord (ratio) Me C ^CH 2> 4 1,4-benzodioxan-5-yl 28, '8/3, '84 23/2 Me ( ^CH 2> 4 4-Borfolino-1,2,5- -thiadiazol-3-yl 23/5 / 3.13 Ms _{(CH2) 4} benzofuran-7-yl 40/0/5/33 7.9 Et (ch ₂ > phenyl 37 * 1 / 4- / 95 12/4 Ma ₂ ) ₅ 2-chlorophenyl 24.6 / 3.28 Me (C ^H 2) ₅ 2-cyanophenyl 24.8 / 3.31 Me (“2) 5 2-methoxyphenyl 20.5 / 2.73 Me _{(CH2) 6} phenyl 23/6/3/15 Me (CHgJg 2-cyanophenyl 45.3 / 6/04 4.7 Me _{(CH2) 6} 2-methoxyethoxy 26/7 / 3.56 Me ^(C H _{2) 6} 1/4-Benzodioxan-5-yl 20/7/2/76 Me (CH ₂ ) ₇ phenyl 54/3/7/24 3/3 Me (^ 2) 7 2-chlorophenyl 45/6/6/08 1/8 Et (CH ₂ ) ₇ 2-cyanophenyl 31/5/4/20 Me _{(CH2) 7} 2-Bethoxyphenyl 32/9 / 4.39 3/9 Me 4 phenyl (S-isomer) 30/0/4/00 160 Me _{(CH2) 4} phenyl (R-isomer) 20.0 / 2.67 3

Table 2

H

CS 273 180 B2

R Υ Ar SHR max. MAP decrease (Torr / kPa) spinal cord rat (ratio) Μβ -0Η ₂ (1'4-ίβηγ1βη) - och ₂ ch ₂ - 2-cyanophenyl 82/1 / 10.94 3/5 Me -CH ₂ (1/3-phenylsn) - and ₂ ch ₂ - phenyl 61.3 / 8, 17 3/3 Μθ -CH ₂ (1/3-phenylene ₂ ch ₂ - 2-cyanophenyl 80/1 / 10.68 10.2 Me -CH ₂ (1,3-phenylene ₂ ch ₂ - 2-methoxyphenyl 44/5 / 5.93 11/9 Me -CH ₂ (1,3-phenylene- _2- ch _2- ch ₂ - 2-cyanophenyl 57/1/7/61 2/1 Μβ -CH ₂ (1,4-phenylene- _2- ch ₂ - phenyl 33.3 / 4.44 12 Μβ -CH ₂ (1/4-phenylene- ₂ ch ₂ - 2-cyanophenyl 32.1 / 4.28 Μβ -CH ₂ (1,4-phenylene ₂ ch ₂ - 2-methoxyphenyl 28.6 / 3.81 * Μθ -CH ₂ (1/3-phonylene- CH ₂ CH ₂ - 2-cyanophenyl 70/3/9/37 12.9 Μθ _-CH2 (l, 2-phenylene- CH ₂ CH ₂ - phenyl 22/5/3/00 Μθ ch ₂ conch ₂ conhch ₂ ch ₂ 2-cyanophenyl 31/3/4/17 Et ch ₂ ch ₂ ch ₂ conhch ₂ ch ₂ 1,4-benzodioxan-5-yl 20.6 / 2/75 Μβ (CH _{2) 4} 0 (CH _{2) 4} phenyl 23/4/3/12 Μβ (CH _{2) 4} 0 (CH _{2) 4} 2-methoxyphenyl 22.0 / 2/93

Η

CS 273 180 B2

R AND Y ¹ Ar SHR max · MAP MAP (Torr / kPa) rat with broken spinal cord (ratio) Ma no _{2 (CH2) 3} 2-methoxyphanyl 33/4/40 507 Ha no _{2 (CH2) 3} 2-ethoxyphanyl 22/2/93 928 Ka no ₂ (CH ₂ ) ₃ 2-allyloxyphanyl 32 / 4.27 547/5 Ma no _{2 (CH2) 3} 2-chlorophanyl 41 / 5.47 1416/6 Ma no ₂ (CH ₂ ) ₃ 2-cyanophanyl 30/4/00 p-3000 Et no ₂ (CH ₂ > 3 22-cyanophenyl 23/3/10 Ma N0 ₂ (CH ₂ ) ₃ 2-nitrophenyl 21/2/80 846 Ma CN ₂ ) ₃ phenyl 29 / 3.87 Ma CN _{(CH2) 3} 2-methoxyphanyl 42/5/60 Ma CN CCH ₂ > 3 2-cyanophanyl 20/2/67 Ma no ₂ -CH ₂ (1,3-phenylan) OCH 8 - phenyl 44/5, '87 21 Ma no ₂ -CH ₂ (1,3-phenylan) OCH ₂ - 2-methoxyphenyl 25/3/33 Me no ₂ -CH ₂ (1,3-phenylene) -CH ₂ - 2-cyanophanyl 33/4/40

Note: all compounds in this table have the (-CH) configuration on the labeled -CHOH group.

Table 4

XY-KHCH ₂ CHOHCU ₂ OAr

CH ₃ 0 ₂ -

.co ₂ ch ₃

H

ISO 273

substitution circle A and side position chain X Y Ar SHR mac. decrease MAP (Torr / kPa) rat with interrupted spinal cord (ratio) 3-Nitro-4- 0 _{(CH2) 3} 2-methoxyphenyl 20.6 / 2; 3-Nitro-4- 0 _{(CH2) 4} 2-methoxyethoxy 22.6 / 3, '01 5-nitro-2- with _{(CH2) 4} 2-chlorophenyl 26, * 8 / 3.67

In the tables above, the abbreviations used have the following meanings:

Me methyl Et ethyl

Dihydropyridine derivatives produced by the process of the invention in batches; in which they produce an effective antihypertene response in the rat or dog, 'show no apparent signs of toxicity.

The dihydropyridine derivatives produced by the method of the invention may be administered to a warm-blooded animal, including a human, in the form of pharmaceutical compositions comprising as active ingredient at least one dihydropyridine derivative of the invention; or an acid addition salt thereof; in combination with a β pharmaceutically acceptable diluent or carrier.

A suitable composition is, for example, a tablet; a band, aqueous or oily solution or suspension; dispersible powder; spray or aerosol formulation.

The pharmaceutical compositions may contain, in addition to the dihydropyridine derivative produced by the process of the invention, one or more other drugs selected from the group consisting of sedatives, e.g. -tatranltrate, isoaorbid dinitrate and hydralazine, diuretics such as chlorthalidone, bendrofuazide, hydrochlorothiazide and chlorothiazide; Other antihypartanal agents, for example, reserpine bethanidine and guanathidine, cardiac membrane stabilizing agents; for example, quinidine, agents used to treat Parkinson's disease and other tremors; for example banzhaxol, cardlotonics such as digltisal preparations, and adrenergnioc receptor blocking agents such as phentolamine.

It is believed that ^one in the treatment of heart diseases, for example angina * pactoric and cardiac arrhythmias; or in the treatment of hypartenae in human medicine, the dihydropyridine derivatives produced by the method of the invention will be administered when administered orally in a total daily dose of between 20 mg and 600 mg, and in intravenous administration in a total daily dose of between 1 mg and 20 mg.

Preferred oral dosage forms are tablets or liquid containing between 10 and 100 mg; and preferably 10 mg or 50 mg of active ingredient. Preferred dosage forms for intravenous administration are sterile solutions of the dihydropyridine derivatives produced by the process of the invention or their non-toxic acid addition salts. containing between 0.05% and 1% (w / v) of active ingredient, in particular containing 0.1% (w / v) of active ingredient.

The following Examples illustrate the invention. However, it is not intended to limit the scope of the invention in any way.

CS 273 180 B2

Example 1

A molten mixture of 6/68 g of 1-amino-3-phanoxypropan-2-ol and 9,05 g of dimathyl-4- [2- (4-chlorobutoxy) -5-nitrophenyl] -1,4-dihydro-2; Dimethylpyridine-3,5-dicarboxylate and stirred at 125-135 ° C for 30 minutes, cooled and dissolved in 100 ml of warm methylene chloride. The mixture was filtered, and the filtrate was washed successively with 2 x 50 ml of 10% aqueous sodium bicarbonate solution and once with 50 ml of water, dried and evaporated to dryness. The residue was purified by flash column chromatography on 800 g of silica gel using a 90: 10: 3 (v / v) mixture of ethyl acetate / methanol and an aqueous ammonia solution (90:10: 3 by volume) as eluent. After crystallization from a mixture of ethyl acetate and petroleum ether (b.p. 60-80 ° C), the product gives dimathyl-1,4-dihydro-4- [2- [4- (2-hydroxy-3-phenoxypropylamino) butoxy] -5-nitrophanyl]. -2,6-dimathylpyridine-3,5-dicarboxylate, m.p. 122-124 ° C.

204 DEG-206 DEG C. Dimethyl pyridine-3/5-dicarboxylate; used as starting material, was prepared using 16.7 g of 5-nitroalkylaldehyde 13, 8 g of potassium carbonate (25/4 g of 1,4-dichlorobutane and 300 ml of dimethylformamide) as starting materials and following reactions 3, 0 g of the obtained 2- (4-chlorobutoxy) -5-nitrobenzaldehyde (m.p. 51-52 ° C) with 2/7 g of methylacetate, 0.1 g of ammonium acetate and 30 ml of ethanol (ammonium acetate and part of ethyl acetate are equivalent to methyl 3-aminocrotonate).

The procedure described above was repeated using the appropriate pyridine-3,5-dicarboxylic acid salt and 1-amino-3-aryloxypropan-2-ol as starting materials. The compounds are summarized in the following table according to the general formula

H

R ¹ R ² Y Ar melting point (° C) note methyl methyl < ^ch 2> 4 phenyl 168-163 1 methyl methyl < ^c h ₂ ) ₄ phenyl 162-165 2 methyl methyl _{(CH2) 4} 2-raethoxy- phenyl 130-132.5 methyl ethyl (Cn ₂ ) 4 phenyl oil 3 methyl ethyl _{(CH2) 4} 2-chlorophenyl 111-112 3

CS 273 180 B2

R ^{* 1} R ^{2 3 4} Y Ar melting point (° C) note methyl ethyl ( ^CH 2> 4 2-cyanfsnyl 160-163 3 methyl ethyl _{(CH2) 4} 2-methoxyphenyl oil 3 isobutyl Isobutyl _{(CH2) 4} fsnyl 122-125 allyl allyl Cch ₂ ) ₄ phenyl 142-143 allyl allyl _{(CH2) 4} 2-cyanfsnyl 141-145 allyl allyl _(CH2) 4 2-methoxyphenyl 116-118 methyl methyl (CH _{Z) 2} 0 _{(CH2) 2} phenyl oil 4 methyl methyl (CH _{2) 4} 0 (CH _{2) 4} phenyl oil 5 methyl methyl (CH _{2) 4} 0 (CH _{2) 4} 2-methoxyphenyl oil 6 methyl methyl (ch ₂ ) ₄ nh (ch ₂ ) ₂ phenyl oil 6

Note:

(-) - ispmer / / «ό / ⁶ -8/3 θ ^{5 0} (2% solution in methanol hydrochloride» $ 25 · (+) - isomer // I / Q +9/6 (2% solution in HCl methanol, (-) - enomar e is obtained using (+) - 1-amino-3-phanoxypropan-2-ol as the starting material;

The (+) - 18oraer is obtained using (-) - 1-amino-3-phenoxypropan-2-ol as the starting material ethyl-4- ₍ [2- (4-chlorobutoxy) -5-nitrophenyl) -1,4-dihydro] -5-methoxycarbonyl-2,6-dimethylpyridine-3-carboxylate (m.p. 157-158 ° C), used as starting material, was prepared from 0.6 g of 2- (4-chlorobutoxy) -5-nitrobenzaldehyde; 0.3 g of ethyl 3-aminocrotonate and 40 ml of ethanol, the reaction is carried out in dimethylformamide solution at 100 DEG C. for 3 hours, the starting pyridine derivative being dimathyl-1,4-dihydro- 2/6-Dinethyl-4- (5-nitro-2 - [(2-toloxyloxyethoxy) ethoxy] phenyl (pyridine-3) -5-dicarboxylate) prepared from 0.83 g of 5-nitroeallcylaldehyde, * 1/1 g of carbonate potassium, 2/28 g of bis-2-tosyloxyethylethar and 20 ml of dimethylformamide, followed by 0/56 g of the thus formed aldehyde β 3.5 g of methyl acetate, 0/12 g of ammonium acetate and 10 ml of iopropanol;

starting dimethyl 4- [2- [1- (4-chlorobutoxy) -7-5-nitrophenyl] -1,4-dihydro-2,6-dimathylpyridine-3,5-dicarboxylate, melting after crystallization from ethanol at 143-144 ° C C e prepared according to the procedure of the second paragraph of Example 1, using bis-4-chlorobutyl sthsr instead of 1,4-dichlorobutane,

1- (2-Aminosthylamino) -3-phenoxypropan-2-ol is used as the starting propanol derivative.

The other starting pyridine derivatives were prepared as described in Example 1, second paragraph, using the appropriate acetic acid ester instead of methyl acetyl acetate.

The compounds of the following Tables are also prepared in an analogous manner to Example 1. If non-crystalline compounds were obtained which could not be characterized by melting point / their structures were confirmed by elemental analysis, mass spectroscopy and proton magnetic resonance spectroscopy ·

CS 273 180 B2

R Y Ar melting point ( ethyl _{(CH2) 3} phenyl 117-20 ethyl _{(CH2) 4} phenyl 122-126 methyl _{(CH2) 4} 2-fluorophenyl 129-132 methyl ( ^CH 2> 4 2-chlorophenyl 144-146 ethyl (CH ₂ > 4 2-chlorophenyl 128-131 methyl _{(CH2) 4} 2-bromophenyl 127-130 methyl _{(CH2) 4} 2,4-dichlorophenyl oil methyl _{(CH2) 4} 4-hydroxyphenyl 162-163, methyl _{(CH2) 4} 2-nitrophenyl 74-77 ethyl _{(CH2) 4} 2-nitrophenyl 163-166 methyl ( ^CH 2> 4 2-cyanophenyl oil ethyl 4 2-cyanophanyl 185-188 methyl _{(CH2) 4} 3-tolyl 142-144 methyl (CH ₂ > 4 2-allylphenyl oil methyl _{(CH2) 4} 2smethoxyfanyl 130-132.5 ethyl _{(CH2) 4} 2-methoxyphenyl 135-138 methyl (CH ₂ > 4 4-methoxyphenyl 153,5-156 methyl _{(CH2) 4} 2-ethoxyphenyl 116-119 methyl _{(CH2) 4} 2-propoxyphenyl 121-122 methyl _{(CH2) 4} 2-isopropoxyphenyl 81-83 methyl _{(CH2) 4} 2-allyloxyphenyl 132-134I5 ethyl _{(CH2) 4} 2-allyloxyphenyl 109-112 methyl _{(CH2) 4} 2-benzyloxyphenyl 149-150.5 methyl _{(CH2) 4} 2-acetylphenyl oil methyl _{(CH2) 4} 1,4-benzodioxan-5-yl 144-147

CS 273 180 B2

R Y Ar melting point ethyl ( ^CH 2> 4 1,4-benzodioxan-5-yl 148-151 methyl 4 4-morpholino-1,2,5- -thiadiazol-3-yl oil methyl _{(CH2) 4} benzofuran-7-yl 161-162.5 methyl ( ^CH 2> 5 phenyl oil ethyl _{(CH2) 5} phenyl oil methyl ( ^CH2 ^ 5 2-chlorophanyl oil methyl ( ^CH2 ^ 5 2-cyanophenyl oil ethyl (¾ 2-cyanophanyl 175-178.5 methyl ( ^ch 2) _p 2-methoxyphenyl 107-110 ethyl ^(CH2) ₅ 2-methoxyphenyl oil methyl _{(CH2) 6} phenyl 101-104 methyl ( ^CH2 ^ 6 2-cyanophenyl 104-107 ethyl ^ ^CH2 ^ 6 2-cyanophenyl 152-156 methyl (CH ₂ ) _e 2-methoxyphenyl oil methyl ( ^CH2 ^ 6 1,4-benzodioxan-5-yl oil methyl _{(CH2) 7} phenyl 113-117 methyl _{(CH2) 7} 2-chlorophenyl 121-124 methyl _{(CH2) 7} 2-cyanophenyl 118-122 ethyl _{(CH2) 7} 2-cyanophenyl 161-164 methyl _{(CH2) 7} 2-methoxyphenyl oil methyl -CH ₂ CH ₂ C (CH ₃ - ₂ - phenyl oil methyl - (ch ₂ ) ₃ c (ch ₃ ) ₂ - 2-methoxyphenyl 124-127 methyl -CH ₂ ) (1,4-phenylene) -CH ₈ CH 8 - phenyl 114-118 methyl -CHg) 1,4-phenylene) -CH ₂ CH ₂ - 2-cyanophenyl 156-157 methyl -CH ₂ (1,4'-phenylene) -ch ₂ ch ₂ - 2-methoxyphenyl 119-121 methyl -CH ₂ ) 1,3-phenylene) -CH ₂ CH ₂ - 2-cyanophenyl oil methyl _-CH2) 1,2-phenylene) -CH ₂ CH ₂ - phenyl oil methyl -CH ₂ ) (1,4-phenylene) -OCH ₂ CH ₂ - 2-cyanophenyl oil methyl -CH ₂ ) (1-phenylene) -OCH ₂ CH ₂ - phenyl oil methyl (CH3) 1,3-phenylene) 2-cyanophenyl oil

-OCHgCHg15

CS 273 180 82

R Y Ar melting point (° C) methyl -CH ₂ (1,3-phenylene) -och ₂ ch ₂ - 2-methoxyphenyl oil methyl -CH ₂ (1, 3-phenylene) -oxh ₂ ch ₂ ch ₂ - 3-cyanophenyl oil methyl - {ch ₂ ) ₃ nhch ₂ - phenyl oil

c (ch ₃ , ₂ Table 2

AA

- X-Y-KHCEgCHflHClIgOAi

^CH 3 ° ₃ \ / H / ^CO 2 ^CC 3 HgC / A xCcH, II circle subetituent A and side chain position ' X Y Ar melting point (° C)

3-nitro-4- 0 2-methoxyphenyl oil 3-Nitro-4- 0 < ^CH 2> 4 2-methoxyphenyl 77-82 5-nitro-2 WITH ^(CH2) ₃ 2-chlorophenyl 149-152 5-nitro-2- WITH _{(CH2) 3} 2-methoxyphenyl 126-130

Example 2

Column for liquid chromatography and high resolution (25 cm x x 2; 12 cm); containing silicagal (Zorbax®), which was previously equilibrated with a mixture of isopropanol and hexane (58:42 by volume); in which tartaric acid (0.01 mol) and pyridine (0.05% by volume) were dissolved, 0.01 g of (+) - dimethyl-1,4-dihydro-4- [2- (2,4-dimethoxy) -4- [eta] &lt; 4 &gt; (2-hydroxy-3-phenoxypropylamino) butoxy] -5-nitrophenyl] -2,6-dimethylpyridine-3,5-dicarboxylate dissolved in 1 ml of methanol. The column is eluted with a peanut solvent used to quilibrate the product by UV absorption at 300 nm. The two separated products from two such elutions were individually combined and shaken and partitioned between 15 ml of ethyl acetate and 20 ml of saturated aqueous sodium bicarbonate solution. Organic

CS 273 180 B2 layer ββ was separated, washed twice with saturated aqueous sodium chloride solution and evaporated to dryness! * The following oily products are obtained:

(a) the first eluted, less polar isomer, which is (-) - dimathyl-1,4-dihydro-4- [2- / 3- (2-hydroxy-3-phenoxypropylamino) butoxy] -5-nitrophenyl] -2; 6-dimethylpyridine-3,5-dicarboxylate having an optical rotation of <= C / g ° -11 / 1 ° (c 0.87% in a 0 / 26N solution of hydrochloric acid in methanol, and

b) a more polar iaomer, eluted second; The corresponding (+) - isomar with an optical rotation of [.alpha.] D @ 20 = + 11.6 DEG (c 0/47% in a 0/26N solution of hydrochloric acid in methanol).

The above procedure repeats to separate the individual (_ +) - dimethyl-1,4-dlhydro-4- [2- [4- (2-hydroxy-3-o-methoxyphenoxypropylamino) butoxy] -5-nitrophenyl] -2 isomer, S-dimathylpyridine-3/5-dicarboxylate. The obtained (-) - isomer has an optical rotation of < 3Υ / θ ° -7 / 2 ° (c »0/6% in a 0.26N solution of hydrochloric acid in methanol) and the (+) - isomer has an optic90 optical rotation. / q * 6/1 (c 0/35 in the same solution).

Claims (4)

OBJECT OF THE INVENTION 1 O R and R; which may be the same or different (each being a methyl or ethyl group) the benzene ring A carries the nitro group at the 5-position and the side chain is attached to the benzene ring A at the 2-position * CS 273 180 B2 18 Ar represents a phenyl radical which is either unsubstituted or substituted in the 2-position by fluorine, chlorine, bromine, nitro; cyano, allyl, methoxy; ethoxy / propoxy; isopropoxy, allyloxy or acetyl; or Ar is 1,4-benzodioxan-5-yl, X is -O- and Y represents a straight or branched alkylene chain containing up to 8 carbon atoms; optionally interrupted by oxygen, imino, phenylene, or phenyleneoxy, and their acid addition salts. 1 2 R 1 and R 1 which are the same or different (each represent an alkyl group containing up to 4 carbon atoms) Ar is a phenyl moiety; unsubstituted or carries one or two substituents selected from the group consisting of fluorine atoms; chloro or bromo, hydroxyl, nitro (cyano, alkyl, alkenyl and alkanoyl) (each containing up to 4 carbon atoms) or Ar is 1/4-benzodioxan-5-yl, benzo / b-fur-7- or 4-morpholino-1,2,5-thiadiazol-3-yl; X is -O- or -S- and Y represents a straight or branched alkyl chain containing up to 8 carbon atoms, optionally interrupted by one or two groups selected from oxygen; imino and phenylene groups and their acid addition salts. A process for the preparation of dihydropyridine derivatives of the general formula X H in which 1 2 R and R, which may be the same or different; always represent an alkyl group containing up to 4 carbon atoms) Ar is phenyl which is either unsubstituted or carries one or two substituents selected from halogen, hydroxy, nitro, cyano / alkyl / alkenyl / alkoxy, alkenyloxy and alkanoyl groups each containing up to 6 carbon atoms; or Ar is a 1,4-benzodioxan-5-yl-, benzo [b] fur-7-yl or 4-morpholino-1,2,5-thiadiazol-3-yl residue; X is -O- or -S- and Y represents a straight or branched alkylene chain and is 2 to 12 carbon atoms / optionally interrupted by one or two groups selected from -O-, 1-amino-NH- and phenynyl; and the acid addition salts thereof (characterized in that the compound of formula VII) CS 273 180 B2 wherein 1 2R, 1R; X and Y are as defined above and. Z is a replaceable radical selected from the group consisting of halogen atoms, and sulfonyloxy, reacted with an amine of formula VIII HjNOHgCHOHCH2-Ar (VII) wherein Ar is as hereinbefore defined, and the resulting product is optionally converted into an β acid addition salt · 2. A process according to claim 1, wherein the corresponding starting materials are used; to form compounds of the above formula (X) wherein: 3. A process according to claim 1, wherein the corresponding starting materials are used to form compounds of the above general formula (1): 4. A process according to claim 1, wherein the corresponding starting materials are used to form the compounds of formula (1) above wherein: Y stands for the remainder of the formula '( ^CH 2 ^ m ^C ( ^CH 3 ^ 2 ^- ' ^kd ® - 3 ^Θ was 2; 3/4 or 5 and the remaining general symbols are as in 1) and their addition salts e acids.