PL161234B1 - Method of obtaining derivatives of bezo- and theine-3,4-dihydropyridine - Google Patents

Abstract

Fused bis(3,4-dihydro-1-pyridyl)methanes of the general formula <IMAGE> in which A and B denote a benzo or thieno radical; R1 denotes hydrogen, (C1-C10)alkyl, phenyl, phenyl=(C1-C5)alkyl, (C1-C4)alkoxy or -NHCOX(in which X is (C1-C5)alkyl); R5 denotes hydrogen, (C1-C4)alkyl or hydroxymethyl; R2, R3, R6 and R7 denote hydrogen or (C1-C5)alkyl, or R2 with R3 and/or R6 with R7 and the respective carbon atom to which they are bonded denote a 5- or 6-membered carbocycle; their tautomeric forms and their pharmacologically acceptable salts. The compounds have cardioprotective action and are suitable as active compounds for the production of medicaments for the treatment of coronary heart disease and acute myocardial infarct.

Description

The subject of the invention is a process for the preparation of new benzo and thieno-3,4-dihydropyridine derivatives.

The new compounds correspond to the general formula I, in which A is a benzo or thieno group, R2 and Rj represent a hydrogen atom, or together with the carbon atom to which they are attached represent a 5- or 6-membered carbocyclic group, Rpp is a Cp- group C4-alkyl, halogen, such as fluorine, chlorine, bromine or iodine, hydroxyl, Cp-Cp-alkoxy, amino, thiomethyl, methanesulfonyloxy or methanesulfonamide, or two adjacent Rpp substituents together represent a group of formula -O-CH2 -0 or 0- ^ 2- ^ 2-0-, m is 0, 1, 2 or 3 when A is benzo and m is 0, 1 or 2 when A

161 234 represents the thieno group, and 0 represents the group of the general formula Ia where in the general formula Ia B represents the benzo or oxygen group, Rj represents the hydrogen atom, the Cj-Cpg-alkyl group, the phenyl group or the group of the formula -NHCOX in which X represents a C 1 -C 6 -alkyl group, Rj is a hydrogen atom, a C 1 -C 6 -alkyl or hydroxymethyl group, Rg 1 R " represent a hydrogen atom or a C1-C8 -alkyl group, or together with the carbon atom to which they are attached, are a 5- or a f-membered carbocyclic group, Rij is a C1-C8-alkyl group, halogen as fluorine, chlorine, bromine or iodine, hydroxyl, C1-C8-alkoxy, amino, thymethyl, methanesulfonyloxy or methanesulfonamide, or two adjacent Rj together they represent a group of formula -O-CHj-O- or -0- ^ 2 ^ Η--0- and n is 0, 1, 2 or 3 when B is benzo and n is 0, 1 or 2 , when B is an oxygen moiety, and pharmaceutically available salts thereof, with inorganic or organic acids, with the exception of a compound of general formula I in which 0 is the group of formula Ia and Rj, R ', Rj, Rj, Rg and R' represent a hydrogen atom and A and B represent a group of formula 4.

As carbocyclic compounds that form the substituents R? and Rj or Rg 1 R? in each case the carbon to which they are attached are understood to mean in particular 5-membered saturated or 6-membered carbocyclic rings.

Compounds of formula 1 in which O is the group of formula Ia are hereinafter referred to as compounds of general formula 3. Compounds of formula 5 in which Rj is hydrogen form tautomers of formula 5a and 5b in which Rj is also hydrogen. The definition of formula 1 or 5 also includes the mentioned tautomers. By Kober, Jeno has been featured in Szeged! Tanarkepzo Foiskola Tud. Goat. 1975, pages 145-153 (cf. Chem. Abstr. B7, 1349802) the compound of the general formula 5 and its preparation, wherein Rj, R ', Rp Rj, Rg 1 R' represent hydrogen and the substituted groups A and B represent the residue of formula 4. No data on physiological effects are given in this publication.

It has surprisingly been found that the new compounds of general formula I and the above-mentioned compound and the necessary intermediate of general formula II both as bases and in the form of salts thereof have valuable therapeutic properties.

Among the compounds of formula 5, the following are particularly interesting:

- / compounds of general formula 5 in which Rj represents a hydrogen atom, a Cj-Cj-alkyl group or a group of the formula -NHCOX in which X is a CjCC group - alkyl, Rjj and Rj independently of each other represent a C1-8 alkyl, hydroxy, C1-8 alkoxy, methanesulfonyloxy or methanesulfonyloxy group, or two adjacent Rjj or Rj substituents. together they represent a group of formula -O- ^ 2-O- or -0 - (^ - ^ 2-O-) compounds of general formula 5 in which Rj is hydrogen, Cp-Cp-aalkyl group or a group of formula - NHCOX, where X is Cj-Ccca1l-a; R2, Rp Rg and R 'are each independently hydrogen or R2 with Rj and Or Rg with R' and each carbon atom to which they are attached are lαrbocyk- Found about 5 or 6 members; jj ^{R and} R? are each independently hydroxy, C - g aakoksylową, a methanesulfonyloxy group or a metanosulfonamldową, or two adjacent substituents R RJJ or together represent a group of the formula -0-CH2-0 or -O-CH2-CH2-O;

- / especially compounds of the general formula 5 in which Rj represents a hydrogen atom, a -j-Cg-a1kyl group or a -NHCOCHj group and / or Rj represents a hydrogen atom, a methyl or hydroxymethyl group and / or ^R 2, Rp Rg and R? each independently represent a hydrogen atom or ^R2 with Rj and / or Rg with R? and the each carbon atom to which they are attached represent a 5-membered carbocycle and / or Rjj and Rj independently from each other are hydroxy, methoxy, methanesulfonyloxy or methanesulfonamldo, or two adjacent substituents Rjj or Rj? once ^em denote the group -O-CH2-0-.

161 234

There are compounds □ of the general formula 5 in which mu / or n represent the number 2, especially those in which A and / or Θ represent a benzo group, where predominantly both Rjj and / or R | 2 in the benzo group are present in positions meta or para to functional points of group A or B.

Characterized by compounds wherein RJJ R and _Z are methoxy.

Examples of specific compounds according to the invention are shown in the tables below, distinguishing between 1- (3, A-dihydro-6,7-dl-methoxyisoquinolin-1-yl) -1- (3, A-dihydro-6.7-). d-methoxyisoquinolin-1-ylidene) -ethane and the compound of formula 13 and their physiologically tolerable salts.

The production process according to the invention of formula 1 (hereinafter referred to as compound of formula 3) comprises the fact that an amide of general formula 2, optionally obtained under reaction conditions by condensation from a compound of formula 3, optionally without isolation thereof, wherein A, Rj, R ?, R, R * Ry * ^R II · ^R J2 ^or with m are as defined above, Ar is phenyl or thienyl and n 'represents a number 0, 1, 2 or 3, where Ar is a phenyl group, and n' is the number 0, 1 or 2, when Ar is a thienyl group, whereby for a compound of formula 2 Rj is a hydrogen atom or a Cj-Cj-alkyl group and for a compound of formula 3 Rj is a hydrogen atom, it is cyclized in the presence of a condensation agent to the corresponding compound of general formula 5.

Strong Lewis acids, such as, for example, phosphorus oxychloride, phosphorus pentachloride, phosphorus trichloride, phosphorus pentoxide, titanium tetrachloride, boron trifluoride or tin tetrachloride, or also inorganic acids, such as, for example, polyphosphoric acid, sulfuric acid, fluorosulfuric acid, are suitable as condensation agents. and hydrofluoric acid, or mixtures of condensing agents, such as, for example, a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of phosphorus pentoxide and C1-C8-alkanesulfonic acid, for example with a proportion of phosphorus pentoxide of about 10% by weight.

If a compound of general formula II in which Rj is hydrogen is cyclized in the presence of a mixture of phosphorus pentoxide and Cj-Cj-alkanesulfonic acid, then in addition to the corresponding compound of general formula III in which Rj is hydrogen, an analogous compound is obtained Formula 3 in which Rj is Cj-Cj-alkyl.

This variant of the process is preferably carried out with methanesulfonic acid.

Cyclization is performed in the presence or absence of a solvent. All inert solvents are suitable which have sufficient solubility of the reaction components and have a sufficiently high boiling point, for example benzene, alkylbenzenes, such as toluene or xylene, chlorobenzenes, chloroform, acetonitrile or decalin. A distinctive variant of the process is that a condensation agent is used, for example phosphorus oxychloride or a mixture of phosphorus pentoxide and C1-C8-alkanesulfonic acid, without the addition of a solvent. The cyclization is preferably carried out with phosphorus oxychloride or, in severe cases, with a mixture of phosphorus pentoxide and a C1-C8 alkanesulfonic acid, preferably methanesulfonic acid.

The cyclization reaction is carried out over a wide temperature range, typically with heating or heating to a temperature from 50 ° C to about the boiling point of the reaction mixture.

The required reaction time is from several days to several hours depending on the starting compound of the general formula 2.

The compounds of the above-defined general formula 2 are novel compounds. They can be prepared by cyclization of the corresponding malonic acid diamide of general formula III wherein Rj is hydrogen and Rp, R ', Rj, Rg, R7, Rp and Rj2 are as defined above, Ar is a phenyl or thienyl group and m' and n 'independently of each other represent 0, 1, 2 or 3 when Ar is phenyl and are 0, 1 or 2 when Ar is thienyl. The cyclization reaction is carried out analogously to the cyclization of a compound of general formula 2 to

If the reaction is carried out with mixtures of phosphorus pentoxide and C1-C6-alkanesulfonic acid, then in addition to the corresponding compound of general formula II in which R1 is hydrogen, an analogous compound of general formula II is also obtained wherein Rj is C1-C6alkyl.

Optionally, the compound of general formula 5 is prepared from the compound of general formula 3 in situ without isolation of the intermediate of general formula 2.

Due to the fact that in such compounds it is very difficult to close the lzoquinoline or the oxopyridine ring, it is possibly necessary or desirable to isolate the compound of general formula II or its tautomer formed during the cyclization reaction, release the base and subject it to a second cyclization reaction. . In this case, phosphorus oxychloride is preferably used in the first step with gentle heating. In the second step, the ring is closed with phosphorus pentachloride, a mixture of phosphorus oxychloride and phosphorus pentachloride, or a mixture of methanesulfonic acid and phosphorus pentoxide.

In principle, compounds of general formula III are known compounds and can be prepared by known methods.

Compounds of general formula I in which R5 is hydrogen are optionally alkylated on nitrogen. In principle, all known alkylating agents are suitable for this alkylation, provided that they have sufficient reactivity, e.g. active alkyl esters such as dialkyl sulfate, alkyl toluenesulfonic acid esters or alkyl fluoromethanesulfonic acid esters, the alkyls here being C1-C6 - alkyls. The reaction is carried out at temperatures up to the boiling point of the reaction mixture.

The N-hydroxymethylation reaction is carried out under the aminoalkylation conditions according to Leuckart-Wallach / Ber. Ltsch. Chem. Goose. 18, (1985) 8341 / or according to Eschweiler-Clark (Teilheimer 2 (1948) No. 352, 4. (1950) No. 370). Generally the substance is treated at room temperature with, for example, a 30¾ formalin solution in the presence of formic acid.

The free bases of general formula I are converted into acid addition salts in known manner.

Suitable acids for salt formation are, for example, hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, acetic, propionic, butyric, oxalic, malonic, succinic, maleic, fumaric, lactic, tartaric, citric, malic, benzoic, cinnamic, ascorbic acid and acid. methanesulfonic acid.

The new bis- (3,4-dihydro-1-pyridinyl) -methanes of the general formula I, both as bases and in the form of their salts, have valuable therapeutic properties.

These substances have particularly pronounced heart-protective effects, which have been labeled as follows:

Myocardial Ca (2 +) is known to be a measure of hypoxic or toxic doses of catecholamine induced damage to the heart (Higgins et al., Hol.Coli. Cardiol. 10, 427-438,184; Nakanishi et al., Am. J. Physiol. 242,437-449,1982; Flechenstein A. Vortrage der Erlanger Physiol. Tagang 1970, Edit. Keidel, Springer Verlag Berlin, Heidelberg, New York 1971 /. Conversely, inhibition of hypoxic or isoprenaline-induced calcium uptake by the myocardium is a measure of the cardioprotective effect of calcium antagonists (Flechenstein A. Vortrage der Erlanger Physiol). Tagang 1970, Edit. Keidel, Springer Verlag Berlin, Heidelberg, New York, 1971), calcium inhibitors (Sliggins) and other pharmaceutical agents, e.g. beta blockers (Arndts, Arzneimittelforschung 25, 1279-1284, 1975). The cardioprotective effect was found by the method described by

Arndts'a / Arzneimittelforschung 25, 1279-1284, 1975 / on sleepy rats after subcutaneous or oral administration of the active substance, and the strength of the test substances was given as

^Η value 161 234 50 · This value corresponds to the dose that inhibits the intake of radioactive calcium 50¾ myocardial conditioned by a subcutaneous dose of isoprenaline 30 mg / kg.

The new compounds tested turned out to be up to five times more effective than the well-known commercial product Propanolol:

Table 1

Relationship Hj0 value for oral administration AND 1.25

If kept for a long time under ischemic conditions, the isolated heart perfuses normally again, and there is no immediate normalization of heart function. There are multiple transient periods characterized by contractures and arrhythmias. This phase of arrhythmias is conditioned by changes in the function and structure of myocardial cells with intercellular calcium overload / Hess and Manson, J.Mol.Celi.Cardiol. 16, 969, 1984 /. Heart protective compounds like Verapamil 1 Olttiazem Reduce Calcium Overload 1 Improve Contraction Behavior / Watts et al., Am. J. Physiol. 238, H908, 1980; Meno et al., Am. J. Physiol. 247, H 380, 1984). The protective effect of the heart was tested on isolated rat hearts, with ischemia and subsequent re-refusion. Under control conditions, with 1-hour ischaemia (flow 0.15 ml / min), there is a period of irregular heart rate of 10-15 minutes. The infusion of compounds protecting the heart significantly shortens this period.

Table 2

Relationship Concentration Shortening the arrhythmia phase from 11-13 minutes AND 3.3 4.0 minutes

determination of compound A (compound from Table 3)

^R 11 : CHjO R5 = H. Rll : CHjO ^R 12 ' ^: CHjO R1 : H. ^R 12 ^: CHjO ^R 2 ^R 3 : - (CH ₂ ) ₄ - R ₆ -R ₇ : - / CH _2/4 temp. top salt 119 / rule

In vitro studies on smooth muscles (sorta strands) have shown that the compounds according to the invention are calcium antagonists with a new mechanism of action:

Calcium antagonists inhibit the transmembrane flow of calcium ions into the cell. This inhibition relates to the voltage dependent (slow) flow of calcium into the cell membrane. Determination of the transmembrane flux of calcium ions on tissue bands by the potassium dopolarization according to the method described by van Breemen clearly shows calcium antagonists (van Breemen et al., Chest. 78, 1575-1655, 1980; van Breemen et al. Am. 7. Cardiol 49 , 507-510, 1982; Casteels et al., Plagers Arch. 392, 139145, 1981; Doth. Van Breemen, 7. Membrans 8iol. 30, 363-380, 1977).

161 234

These studies show that the compounds according to the invention are not classic calcium antagonists.

On the basis of this finding, the compounds of the general formula-1 or their acid addition salts according to the invention are included as active ingredients in medicaments for the treatment of coronary heart diseases and acute myocardial infarction.

When testing the survival of animals in a closed chamber (hypoxia tolerance test), through which a gas mixture consisting of 95.6% nitrogen and 3.5% oxygen was flowing, the animals pretreated with the substances according to the invention showed a statistically highly significant higher survival ability than control animals or animals pretreated with substances such as Oiltiazem, Nfodipin or Verapamil. The brain-protective effect reported by this method was already evident at 5 mg / kg orally. Hence, the compounds according to the invention, both in terms of the effective dose and the improvement in performance obtained in animal experiments, are clearly superior to the substances mentioned.

On the basis of these findings, the compounds of general formula I or their acid addition salts are used as active substances for medicaments against heart failure and against cerebral metabolic disorders or cerebral psychosyndrome and traumatic and alcoholic brain injuries.

Medicinal products containing, as active ingredient, the compounds of the general formula I according to the invention and their salts with inorganic or organic acids are suitable for oral or parenteral administration. These remedies are mostly in the form of tablets, dragees, ampoules and juices. The unit dose of these forms is 1.0-200 mg, usually 20-50 mg per 75 kg body weight. Depending on the severity of the case, generally 1-3 unit doses are administered daily.

The examples below illustrate the invention in more detail.

Example 1 1- (3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl) -1 (1,2,3,4-tetrahydro-6,7-dimethoxyisoquinolin-1-ylldene) pentane and - (3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl) -1- (1,2,3,4-tetrahydro-6,7-dimethoxy-2-methylisoquinolin-1-ylidene) -pentane

4.9 g of n-butylmalonic acid di-N- (2- (3,4-dimethoxyphenyl) -ethyl) -amide in 20 ml of methanesulfonic acid-PjOj mixture (proportion of PjO ^ 10% by weight) is heated for 1-2 hours up to a temperature of 100 * C. After completion of the reaction, as verified by thin layer chromatography, the reaction mixture is poured onto ice, made basic with saturated sodium hydroxide solution, and extracted with methylene chloride. The organic phase is washed with water, dried over sodium sulfate, concentrated under reduced pressure and the residue is partitioned on silica gel using methylene chloride as eluent: methanol = 100: 5 parts by volume. The compound N-H is eluted first. Compound N-H: mp = 158-159 ° C (hydrochloride).

Compound N-CHj: mp = 136-137 'C (hydrochloride).

Example II. 1- (3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl) -1- (3,4-dihydro-6,7-dimethoxy-2-N-methyl-isoquinolin-1-vlidene) -pentane hydrochloride g prepared as in the example: I 1- (3,4-dihydro-6,7-dimethoxyisoquinolin-1-yl) -1- (1,2,3,4-tetrahydro-6,7-d-methoxylzoquinolin-1-ylidene) -pentane it is placed in 2 ml of freshly distilled dimethyl sulphate and heated to reflux for 6 hours. After the usual work-up, chromatography is carried out on silica gel, eluting with methylene chloride, unethanol = 100: 5 parts by volume. A hydrochloride is formed which crystallizes from ethanol / ether.

The product is identical to that produced according to Example I.

161 236

Example III. 1- (3,6-dlhydro-6,7-dl (Betoxyisquinolin-1-yl) -1- (JA-dihydro-e.T-dimethoxy-1-N-hydroxyeethylolzochlnolin-1-ylideneZ-ethene hydrochloride.

g of 1- / 3,4-dihydro-6,7-dimetoksylzochlnolin-l ^^ l ^ / - l- / _{3,4-dihydro-6-1} dlraetoksylzochlnolln-7-ylidene / -ethane allowed to stand at room temperature for 20 hours in a mixture consisting of 20 ml of 30¾ formalin solution and 10 ml of 90¾ formic acid. It is then concentrated to dryness under reduced pressure generated by a water jet pump. The reaction product is taken up in methylene chloride, washed with dilute soda solution and then with water. The organic phase is dried over sodium sulphate, the solvent is stripped off under reduced pressure, the residue is taken up in a sufficient quantity of ethanol and, with the addition of ethereal hydrogen chloride, the hydrochloride is precipitated. Melting point: 155 ° C.

Example IV. «Æ // 3 ₁ 4-Dihydro-6l7-dl-methoxylzochlnolin-1-yl) -ll2l3l4-tetrahydro-6,7-dimethoxy-1-benzylldenoisoquinoline

4.9 gl ^^^ - tetrahydro ^^ - dimethoxy-l- ° C 2 - / 3,4-dimethoxyphenyl / ethyl J-aminokarbonyloj-benz ^ oizochinoHny um ^and eszcza t ^o in ²⁰ ml of St ^ Zo ^d es ^{so much} Comm ^The content of phosphorus 1 is heated to reflux for 4 hours. After completion of the reaction as judged by thin layer chromatography, excess phosphorus oxychloride was distilled off, the residue was partitioned between methylene chloride and a dilute sodium hydroxide solution. The organic phase is washed with water, dried over sodium sulfate and concentrated. The residue is chromatographed on silica gel using methylene chloride: methanol 100: 10 parts by volume as eluent. S ^s current soon to ^g n ^a whole yellow fralccja ^d ostarcza o6 - ^{/ 3,} 6-dih ^y of Road ^6,7 -dimetoks ^{yi leaves} no ZOC ^high-yl nl ^/ -1l2l3l4-tetrahydΓO-6l7-dimethoxy-l-benzylidene- 2-N-phosphonolzoquinoline (mp:> 270 ° C (hydrochloride));

The next red zone provides the title N-H compound mp 95-100 ° C.

Example V. / 4l5-dihydrothieno / 2l3-cZplridin-1-yl / -4l5l6l7-tetrahydro-1-methyl ^^^^^^ l ^ enc ^> ^ 2 ^^ - ^^ iplridine g di-N-Z2- Z3-thieno-ethyl) -amldium melonic acid in 25 ml of phosphorus oxychloride is heated to reflux for 3 hours. When the starting material is no longer detectable, the reaction mixture is worked up in the usual manner. The reaction product is purified over neutral AljOj activity stage III (by Hoelm) using methylene chloride as eluent and then forms the hydrochloride.

Melting point: 233 - 235 ° C.

Examples of the preparation of starting compounds

Example VI. "6-isobutylamlnocarbonyl-1-pentyl-dl-methoxy ^^ - dihydroisoquinoline

3.8 g (10 mmol) of 6-isobutylamlncarbonyl valeric acid 2- (3,4-dimethoxyphenyl) -ethyl-7-amldium are dissolved in 120 ml of acetonitrile and mixed with 18 ml of phosphorus oxychloride. The reaction mixture is heated for about 2 hours to reflux temperature. Then it is concentrated, the residue is taken up in 200 ml of methylene chloride and made alkaline by stirring it into a solution of potassium in ice water. After the usual work-up, i.e. shaking with methylene chloride, drying the organic phase over sodium sulphate, stripping off the solvent, etc., the product is purified on a silica gel column using methylene chloride: methanol - 100: 2 as eluent. Melting point: 158-160 ° C.

Example VII. Methyl 2-ethyl-2- / 3L4-dlhydro-5l6-dimethoxy-l-lzochi nolinylo / ^g -butanokarboksytowego es ^t ru me ^{so much} detailed ^g of 2- / 2- ^{2 Z 3, 4} -dime ^t ox ^yf en ^yl o ^/ s ^{from you} lq selected ^and nokarbony ^l o ^ ^{- 2-et} y ^l ojutanokarboksylowego placed in a mixture of 100 ml of acetonitrile and 12 ml

161,234 phosphorus oxychloride, 1 is refluxed until the substance is completely reacted (about an hour). The reaction mixture is then worked up in the usual manner and the reaction product is purified on silica gel, eluting with methylene chloride: methanol = 100: 2, and the hydrochloride is formed. Melting point: 141-143 ° C (ethanol / ether).

The compounds shown in the following tables are prepared analogously to the examples described above.

Table 3 Compound of formula 6

^R 11 Rii R1 R2 R3 R5 ^R 12 Rl2 R6 ^R 7 Melting point / * C / salt form CHjO CHjO H. - / CH24- H. CHjO CHjO - / 0 119 / rule CH2SO4H CHjO H. H. H. H. CHjO CHOSOR H. H. 233-238 / decomposition / rule CHjO CHjO -C4H9 H. H. CHj CHjO CHjO H. H. 136-137 / chloride CHjO CHjO -CAH9 H. H. H. CHjO CHjO H. H. 158-159 / chloride CHjO CHjO CHj H. H. H. CHjO CHjO H. Η 180 / chloride CHjO CHjO CHj H. H. CHj CHjO CHjO H. H. 177 / rule CHjO CHjO H. H. H. H. CHjS0 ₂ 0 HO H. H. 182-186 / rule CHjO CHjO H. H. H. CHj CHjO CHjO H. H. 138-140 / rule CHjO CHjSO ₂ H. H. H. CHj SO CHjO H. H. 222-225 / base CHjO CHjO CHj H. H. CHjOH CHjO CHjO H. H. 155 / chloride CHjO CHjO ^nc 5 ^H ll H. H. CHj CHjO CHjO H. H. 75-79 / amorphous principle CHjO CHjO c ^2H 5 H. H. CHj CHjO CHjO H. H. 80 / amorphous principle CHjO CHjO CHj H. H. H. -O-CH2— -0- H. H. 156-158 / chloride CHjO CHjO c ^2H 5 H. H. H. -O-CH2-- -0- H. H. 148-155 / chloride CHjO CHjO ^C 2 ^H 5 H. H. H. CHjO CHjO H. Η 177-179 / chloride CHjO CHjO H. H. H. H. -O — CH2- —0- H. H. 251-253 / chloride -0 ---- * 2—0 H. H. H. H. -O — CH2- —0- H. H. 251-253 / decomposition / chloride CHjO CHjO CHjCONH H. H. H. CHjO CHjO H. H. 171-172 / chloride -o — ch ₂ - ----- Q. C6H ₅ H. H. H. -o-ch ₂ - —0- H. H. 191-195 / rule

161 234

Table 4 Compound of formula 7

R Salt form Melting temperature compound of formula B chloride 218 - 222 compound of formula 9 chloride. 239 - 235

Table 5 Compound of formula 10

R Salt form Melting temperature compound of formula 11 chloride 162 - 172 compound of formula 9 chloride 237 - 239 compound of formula 12 chloride 250 - 253

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Claims (1)

Patent claim A method for the preparation of benzo and thieno-3,4-dihydropyridine derivatives of the general formula I, in which A is benzo or thieno, R2 and Rj represent a hydrogen atom, or together with the carbon atom to which they are attached represent a carbocyclic group of 5 or 6 members, Rn is Cp-Cp-alkyl, halogen, hydroxyl, C 1-6 alkoxy, amino, thiomethy, methanesulfonyloxy or methanesulfonamide, or two adjacent Rjp groups together represent a -O- group CHj-O- or -O-CH2-CH2-O-, m is 0, 1, 2 or '3 when A is benzo and m is 0, 1 or 2 when A is thieno, 0 represents a group of the general formula Ia, in which B is a benzo or thieno group, Rj is a hydrogen atom, a Cp-Cp-alkyl group, a phenyl group, or a group of the formula -NHCOX in which X is a Cj-Cj-alkyl group, Rj is a hydrogen atom, a Cp-Cp-alkyl or hydroxymethyl group, R &lt; each independently represent a hydrogen atom or a C1-C5-alkyl, or together with the carbon atom to which they are attached, represent a 5- or 6 for human new carbocyclic group, R ₂ is a C ^ -C ^ alkyl, halogen halogen, hydroxyl, Cp-Cp-alkoxy, amino, thiomethyl, methanesulfonyloxy or methanesulfonamide, or two adjacent Rp ₂ substituents together represent a group of formula -O-CHj-O- or -O-CHj-CH ₂ -O-, and n is 0, 1, 2 or 3 when B is benzo and n is 0, 1 or 2 when B is thieno and their pharmaceutically available salts, with inorganic or organic acids, except for the compound of general formula I where 0 is the group of formula Ia and Rj, R2, Rj, Rj, Rp and R7 are hydrogen, and A and B are the group of formula 4, characterized in that the compound of general formula 2, optionally obtained under the conditions reaction by condensation from a compound of formula 3, optionally without isolating it, wherein A, R p, R 2, R, R _fi, R7, Rpp, R 12 and m are as defined above, Ar is phenyl or thienyl and n 'represents a number 0, 1, 2 or 3, where Ar is a phenyl group, while n 'is 0, 1 or 2, when Ar is thienyl group, whereby for the compound of formula 2 Rj is a hydrogen atom or a Cp-Cp-alkyl group, and for a compound of formula 3 Rj is a hydrogen atom, it is cyclized in the presence of a condensation agent, and that the optionally obtained compound of general formula 1 in which R2 is hydrogen is optionally alkylated to a compound of general formula 1 in which Rj is a Cp-C6-alkyl group, or the obtained compound of general formula 1 where 0 is a group of general formula Ia and Rj is a hydrogen atom is optionally subjected to hydroxymethylation to a compound in which Rj is a hydroxymethyl group or individual tautomers included in general formula 1 are isolated or the free compound of general formula 1 is isolated from the obtained salt 1 or receive any compound of formula I is converted to its pharmaceutically digestible sdl. ···