FI90343B - Process for the preparation of antihypertensive and antiarrhythmic trans-2,2-dimethylchroman-3-parent derivatives - Google Patents

Description

90 343

The present invention relates to the preparation of chroman derivatives having antihypertensive and antiarrhythmic activity. The present invention relates to a process for the preparation of chroman derivatives having antihypertensive and antiarrhythmic activity.

BE Patent 829,611 discloses a complete series of chroman-3-ol derivatives having antihypertensive activity; these derivatives are characterized in that in the 4-position there is a group NR 1, R 2 in which R 1 is hydrogen or an optionally substituted hydrocarbon group and R 2 is hydrogen or alkyl, and NR [R 2 may be a heterocyclic group having 3 to 8 atoms and which is unsubstituted or the substituent is substituted with one or two methyl groups, and that the 6-position or the 7-position in some cases has a large number of possible substituents.

EP application 76 075 discloses chroman-3-ol derivatives having antihypertensive activity and characterized by a 2-oxopyrrolidin-1-yl group or a 2-oxopiperidin-1-yl group in the 4-position and in some cases a large number of possible substituents including a cyano group in the 6-position or the 7-position.

It has now been found that 2,2-dimethylchroman-3-ol derivative derivatives, characterized in that the 4-position has a nitrogen atom which forms part of a 6-membered heterocycle containing two double bonds conjugated to an oxo group, has excellent antihypertensive and antiarrhythmic activity and very low toxicity.

Thus, the present invention relates to a process for the preparation of antihypertensive and antiarrhythmic trans-2,2-dimethylchroman-3-ol derivatives of the formula 2 90 333 Π 5 ζ y \ J \ my \ / \ / (i) \ λλζ 10 wherein A between N and CO is a group -CH = CH-E = CH- or a group -n = CC = C-; R 1 R 2 R 3 Z is halogen or cyano, acetyl, trifluoroacetyl, nitro, alkylthio or dialkoxyphosphoryl, wherein the alkylthio and alkoxy groups contain 1 to 3 carbon atoms; E is a nitrogen atom or a group C (R4);

R 1 is a hydrogen atom or a methyl or hydroxyl group, and R 2 and R 3 are hydrogen or methyl groups, wherein only one of the substituents R 1, R 2 and R 3 is methyl; and R 4 is a hydrogen or halogen atom or a methyl or hydroxyl group, the process being characterized in that the chroman epoxide of formula yw 30 V \ A ™ 3 (II)

v / \ 0 / CH

3 wherein Z is as defined above is treated with a heterocyclic compound having one of the tautomeric forms 3 9 O 3 Ί 3 A -> (ΑΛ (III) Ν ^ νοη <-

5 H

where A is as defined above.

In the following description and the following claims, halogen means a fluorine, chlorine-10 or bromine atom.

The compounds of formula I have two asymmetric carbon atoms in the 3-position and in the 4-position of the chroman ring. The definition of formula I includes both stereoisomers as well as the racemate.

The reaction to open the epoxide (II) is carried out at a temperature of 10 to 100 ° C in an inert organic solvent such as dioxane, tetrahydrofuran, methyl tert-butyl ether, dimethyl sulfoxide or dimethylformamide, a basic condensing agent such as sodium hydroxide, sodium hydride or quaternary hydride. - in the presence of cyltrimethylammonium hydroxide. Under these working conditions, opening of the epoxide (II) results in compounds of formula I having the trans configuration.

When the reaction is complete, a compound is obtained which

is formula A

e \ 0 (Ia)

30 V \ A / H

wherein A and Z are as defined above, and the compound is isolated using conventional methods.

4; O3'r3

The capped starting epoxides of formula II are known or are prepared according to known methods. Thus, the epoxide (II) in which Z is a cyano group is disclosed in BE Patent 852,955; epoxides (II) in which Z is a nitro group or an acetyl group are disclosed in J. Med. Chem. 26, (1983), 1582-1589; epoxides (II) in which Z is an alkylthio group are prepared by an analogous method; and epoxides (II) in which Z is halogen are prepared from Tetrahedron, 37, (15), (1981) 2613-2616.

A compound of formula II wherein Z is a trifluoroacetyl group or a dialkoxyphosphoryl group is not disclosed in the literature. These compounds are prepared from the corresponding chromene of the following formula 'OOt-, n / CH3 20 with which N-bromosuccinimide is reacted in aqueous solution of dimethyl sulfoxide to give a bromine derivative of the formula

OH

This compound (V) is treated with an alkaline substance in a mixture of water 30 and an organic solvent, for example a water / dioxane mixture, preferably at room temperature for 8-20 hours, and the resulting epoxide of formula II is isolated by conventional methods, for example by concentrating the reaction mixture. , recovering the residue as a solvent, which removes impurities such as methylene chloride, washing with water and concentrating.

When Z is a dialoxyphosphoryl group, chromene IV can be prepared from 6-bromo-2,2-dimethylchrome (J. Chem. Soc. (1960), 3094-3098) of formula 5

Br. .

By reaction with trialkyl phosphite in the presence of nickel chloride at 180 ° C.

When Z is a trifluoroacetyl group, chromene (IV) can be prepared from 4-trifluoroacetylphenol (J. Med. Chem. 15 8, (1965), 229) by adding 3-chloro-3-methylbut-1-yne in a basic medium in the presence of a phase transfer catalyst.

Heterocyclic compounds of formula (III) are known and commercially available or are prepared according to known methods.

The compounds obtained according to the invention increase the polarization of smooth muscle fibers and have a vasodilating effect in the portal vein; their antihypertensive effect has been observed in animals.

In addition, it has been found that the compounds of the present invention accelerate the polarization of myocardial cells; their antiarrhythmic effect has also been observed in animal experiments.

No signs of toxicity were observed with these compounds at pharmaceutically active doses.

The compounds of the invention may thus be used in the treatment of hypertension and pathological conditions involving gastric and intestinal, respiratory and uterine and urinary smooth muscle fibers 6 i-; C-.V, 3 contractions such as ulcers, asthma, premature uterine contractions and incontinence, and in the treatment of other cardiovascular pathological conditions such as pain, heart failure, and cerebral or peripheral vascular diseases. In addition, the compounds of the invention may be used in the treatment of cardiac arrhythmias.

Finally, the compounds of formula I can be used topically in the treatment of baldness.

The compounds of formula I may be used in the form of pharmaceutical compositions containing an effective dose of a compound of formula I and suitable additives. These additives are selected according to the pharmaceutical form and the desired mode of administration.

15 The pharmaceutical compositions can be oral at the site to, sublingual, subcutaneous, intramuscular, intravenous, topical, administered via the skin or rectal administration of the active ingredient of the formula I as described hereinabove or a suitable salt thereof in animals and 20 human dosage unit forms, mixed with conventional pharmaceutical to prevent or treat the carriers above disorders or diseases. Suitable unit dosage forms for oral administration include oral forms such as tablets, gelatin capsules, powders, granules, and solutions or suspensions that can be administered orally; tongue and cheek forms; subcutaneously, through the muscle and vein forms for oral and rectal.

For topical administration, the compounds of formula I may be used in the form of creams, ointments, pomades or lotions.

In order to achieve the desired protective or therapeutic effect, the daily dose of the active ingredient may vary between 0.01 and 5 mg / kg.

Each unit dose may contain 0.5 to 200 mg, preferably 1 to 50 mg of active ingredients in association with a pharmaceutical carrier. This unit dose may be administered 1 to 5 times a day to give a daily dose of 0.5 to 1000 mg, preferably 1 to 250 mg.

When the solid composition is prepared in the form of tablets, the main active ingredient is mixed with a pharmaceutical carrier such as gelatin, starch, lactose, magnesium stearate, talc, acacia or the like. The tablets may be coated with sucrose 1a, a cellulose derivative or other suitable substance, or may be treated so as to have a delayed or prolonged action and to release a predetermined amount of the active ingredient continuously.

The preparation in the form of gelatin capsules is obtained by mixing the active ingredient with a diluent and pouring the resulting mixture into soft or hard chelating capsules.

The preparation, which is in the form of a syrup or elixir or is intended to be administered in the form of drops, may contain the active ingredient with a sweetener, preferably calorie-free, containing methyl paraben and propyl paraben as an antiseptic, a flavor enhancer and a suitable colorant.

Water-dispersible powders or granules may contain the active ingredient in admixture with a dispersing agent or in admixture with wetting or suspending agents, such as polyvinylpyrrolidone, and sweetening or flavoring agents.

for rectal administration of 30 to suppositories which are prepared with binders which melt at rectal temperature, for example, using cocoa butter or polyethylene glycols.

For parenteral administration, aqueous suspensions, isotonic saline solutions or injectable sterile solutions are used which contain pharmacologically acceptable dispersing and / or wetting agents, for example, propylene glycol or butylene glycol.

The active ingredient may also be formulated as microcapsules, and when appropriate with one or more excipients.

The compositions may contain, in addition to the product of formula I set forth above, other active ingredients, for example, sedatives or other drugs that may be useful in the treatment of the disorders or diseases set forth above.

The following examples illustrate the present invention without limiting it. In the examples as well as throughout the specification and claim, the products are designated as chroman derivatives. The present compounds of formula I are 2,2-dimethyl-3,4-dihydro-2H-chromene derivatives and thus the term "chromane" means "3,4-dihydro-2H-chromene".

Preparation I

20 a) 6-Diethylphosphono-2,2-dimethyl-2H-chromene 16 g of 6-bromo-2,2-dimethyl-2H-chromene are dissolved in 100 ml of triethylphosphite. 2 g of nickel chloride are added and the mixture is heated at 180 ° C for 24 hours in an autoclave. The remaining triethyl phosphite is concentrated and then the desired product is distilled at 130-140 ° C at 133.322 Pa. 11.5 g of product are collected.

b) Trans-3-bromo-6-diethylphosphono-2,2-dimethylchroman-4-ol 11 g of the above product are dissolved in 62 ml of dimethyl sulfoxide containing 1.35 ml of water. 12.2 g of N-bromosuccinimide are added in small portions while keeping the temperature below 20 ° C. The mixture is stirred at room temperature for 30 minutes, then 100 ml of water are added and the mixture is extracted with ethyl acetate. After drying over sodium sulfate, the organic phase is concentrated and the residue is taken up in 100 ml of acetone and 50 ml of water and then refluxed for 5 hours. The acetone is concentrated, the residue is extracted with ether and the extract is dried over sodium sulfate and concentrated.

5 The expected product crystallizes from isopropyl ether. The crystals are filtered off and dried, and the product is then recovered

3.2 g. Melting point: 124 ° C

c) 6-Diethylphosphono-2,2-dimethyl-3,4-epoxychroman 23 g of the compound obtained in the previous step are mixed with 12 g of sodium hydroxide in 900 ml of dioxane and 100 ml of water. After 24 hours at room temperature, the dioxane is concentrated and the residue is taken up in water and extracted with ethyl ether, and the extract is dried over sodium sulfate. After concentration, 16.2 g of the desired product are obtained.

Preparation II

a) 2,2-Dimethyl-6-trifluoroacetylchrome Reflux for 48 hours with stirring a mixture of the following composition: 8.4 g of 4-trifluoroacetylphenol (prepared as described in J. Med. Chem. 8, (1965), 229 1.8 g of sodium hydroxide pellets, 50 ml of methylene chloride, 30 ml of water, 11 g of a 3% solution of benzyltrimethylammonium hydroxide in methanol, 14 ml of 25 tri (3,6-dioxaheptyl) amine and 6.1 g of 3-chloro -3-methyl-libut-l-yne. 11 g of 3-chloro-3-methylbutyne are added and the mixture is kept under reflux for four days. 50 ml of water and 100 ml of methylene chloride are then added, the mixture is allowed to separate and the organic phase is washed with 1N sodium hydroxide solution and then with water, dried and then concentrated in vacuo to give 10 g of an oil which is used as a crude product in crystallization. 40 ml of 1,2-dichlorobenzene are added and the mixture is refluxed for two hours. The mixture is concentrated in vacuo and the residue is taken up in 40 ml of hexane: 3: 3 and chromatographed on a 300 g silica column, eluting with isopropyl ether. This gives 3.5 g of a yellow oil.

Yield: 40% TLC on silica (hexane / acetone 7/3): Rf = 0.66 IR and NMR spectra confirm the structure.

b) 3-Bromo-2,2-dimethyl-4-hydroxy-6-trifluoroacetylchroman 3.4 g of 2,2-dimethyl-6-trifluoroacetylchromene, prepared in the previous step, are mixed with 30 ml of dimethyl sulfoxide and 5 ml of to water at 15 ° C with stirring. 5 g of N-bromosuccinimide are added over 20 minutes and the mixture is stirred for two hours. The mixture is poured into ice water and the precipitate formed is filtered off, washed with water and dried. This is dissolved in 300 ml of hexane, after which the insoluble matter is filtered off and the filtrate is concentrated to give 3 g of a yellowish solid.

Yield: 68%

Melting point: 103 ° C

TLC on silica (hexane / acetone: 7/3): Rf = 0.55 IR and NMR spectra confirm the structure.

c) 2,2-Dimethyl-3,4-epoxy-6-trifluoroacetylchroman A mixture of 2.9 g of 3-bromo-2,2-dimethyl-4-hydroxy-6-trifluoroacetylchroman prepared in in the previous step, 25 ml of dioxane, 0.5 g of sodium hydroxide pellets and 5 ml of water are stirred at 20 ° C for 20 hours. Concentrate in vacuo at 40 ° C, then treat the residue four times with 100 ml of ethyl ether and then dry the extracts and concentrate in vacuo to give 2 g of a yellow oil.

Yield: 90% TLC on silica (methylene chloride): Rf = 0.80 35 IR and NMR spectra confirm the structure.

11 ", Γ '. 7 / V

- v. r J

Preparation III

4-Fluoropyrid-2-one is prepared according to Leznoff, C. C. et al., J. Het. Chem. , 22, (1985) 145, as follows: 5 a) 2-Methoxypyridine N-oxide hydrochloride This compound is obtained from 21.8 g of 2-methoxypyridine and 144.4 g of a 45% aqueous solution of metachloroperbenzoic acid. In 500 ml of methylene chloride.

Weight: 23.6 g Yield: 61%

Melting point: 123 ° C

(b) 2-methoxy-4-nitropyridine N-oxide 30 ml of concentrated sulfuric acid, cooled to 0 ° C, are added to 15.5 g of 2-methoxypyridine N-oxide-15 hydrochloride, followed by dropwise addition of 42 ml of fuming nitric acid, and 14 ml of concentrated sulfuric acid at 0 ° C. After allowing the temperature to rise, the reaction mixture is heated for three hours at 90 to 100 ° C, after which it is cooled and poured onto 50 g of ice. Mixture 20 is neutralized to pH 7 by the addition of concentrated aqueous ammonia at a temperature below 10 ° C. The aqueous phase is extracted six times with methylene chloride, the organic phase is then dried over sodium sulfate and concentrated, and 11 g of a yellow solid, 2-methoxy-4-nitropyridine N-oxide and 2-methoxy-5-nitropyridine N-oxide, are collected. mixture. The two products are chromatographed on silica using a methylene chloride / methanol mixture (95/5) as eluent. 6.3 g of 2-methoxy-4-nitropyridine N-oxide are recovered.

Melting point: 180 ° C

Yield: 46.3% c) 4-amino-2-methoxypyridine

A mixture of 6.3 g of 2-methoxy-4-nitropyridine N-oxide and 12.6 g of iron powder in 150 ml of acetic acid is heated at 100 ° C for one hour. The mixture is cooled and then sodium hydroxide is added and filtered and the material on the filter is washed with water. The aqueous phase is extracted with ethyl ether. Dry and concentrate, then recover 3.6 g of an oil which crystallizes to a white solid.

5 Yield: 78.4%

Melting point: 88 ° C

d) 4-fluoro-2-methoxypyridine

A solution of 3.6 g of 4-amino-2-methoxypyridine in 15 ml of 48% fluoroboric acid is cooled to 10 ° C. 3 g of sodium nitrite are added in small portions at a temperature below -5 ° C, and the mixture is then stirred for 45 minutes at 0 ° C. The mixture is slowly warmed to room temperature and then stirred in a water bath for 30 minutes. The mixture is cooled to -10 ° C and neutralized by the addition of 3 M sodium hydroxide solution while maintaining a low temperature. The mixture is extracted with 50 ml of ethyl ether and the organic phase is washed with 5 ml of cold water and dried over anhydrous potassium fluoride. The ether is distilled at atmospheric pressure. The oily residue is used as such in the next step.

e) 4-Fluoropyrid-2-one 5.85 g of iodotrimethylsilane in 3 ml of methylene chloride are added dropwise under argon to a solution of 3.3 g of the product obtained above in 13 ml of methylene chloride. The mixture is stirred at room temperature for four hours, then heated at 40 ° C for one hour and kept at room temperature overnight. The solvent is concentrated in vacuo, 10 ml of methylene chloride are added and the mixture is concentrated again in vacuo. The residue obtained is dissolved in methylene chloride, a few crystals of sodium thiosulfate are added and then the mixture is stirred until the brown color has disappeared. The mixture is filtered and the filtrate is dried over sodium sulfate. The inorganic residue is taken up in methanol and filtered. The inorganic residue is chromatographed on silica using methylene chloride (7/1) methylene chloride (9/1) as eluent. 0.590 g of a white solid is obtained.

Melting point: 172 ° C Example 1 trans-6-cyano-4- (1,2-dihydro-2-oxopyrid-1-yl) -2,2-dimethylchroman-3-ol; SR 44 709 1 g of 6-cyano-2,2-dimethyl-3,4-epoxychroman is heated under reflux for 40 hours together with 1 g of 2-hydroxypyridine in 10 ml of dioxane 10 in the presence of 0.20 ml of methanol solution with 35% benzyltrimethylammonium hydroxide. The mixture is taken up in 30 ml of water and the precipitate obtained is filtered off, washed with isopropyl ether and then recrystallized from 20 ml of absolute ethyl alcohol to give 0.9 g of the desired product.

Melting point: 243 ° C with decomposition (capillary tube) Example 2 trans-6-diethylphosphono-4- (1,2-dihydro-2-oxopyrid-1-yl) -2,2-dimethylchroman-3-ol: SR 44 745 20 A mixture of 5.6 g of 6-diethylphosphono-2,2-dimethyl-3,4-epoxychroman (Preparation I), 2.5 g of 2-hydroxypyridine and four drops of benzyltrimethylammonium hydroxide is heated under reflux. hours. The dioxane is concentrated, the residue is taken up in methylene chloride and the mixture is washed twice with water, then dried over sodium sulfate and concentrated to dryness. Ethyl ether is added and the product crystallizes. Recrystallize from ethyl acetate to give 1.5 g of the desired product.

30 Melting point: 130.5 ° C (capillary tube)

Example 3 trans-4- (1,2-dihydro-2-oxopyrid-1-yl) -2,2-dimethyl-6-trifluoroacetylchroman-3-ol: SR 45 160

A mixture of 1.9 g of 2,2-dimethyl-3,4-epoxy-6-trifluoroacetylchroman (Preparation II), 1.4 g of 2-hydroxy-14 9 P Vr 3 sipyridine, 5 ml of dioxane and 0 g of , 2 ml of a methanolic solution of 35% benzyltrimethylammonium hydroxide are heated under reflux for 20 hours. The residue obtained after concentration in vacuo is taken up in 20 ml of water and the insoluble residue is filtered off and washed with water and boiling isopropyl ether. The product is chromatographed on a 50 g silica column using methylene chloride / ethyl acetate (7/3) as eluent. This gives 0.3 g of dry product.

Yield: 12% IR spectrum: 1150 cm -1: C-O-C (chroman) 1665 cm -1: CO (pyridone) 1720 cm -1: CO (CF 3 CO)

3670 cm-1: OH

15

Example 4 Trans-6-cyano-4- (1,2-dihydro-4-hydroxy-2-oxopyrid-1-yl) -2,2-dimethylchroman-3-ol: SR 44 793 3 g of 6-cyano -2,2-Dimethyl-3,4-epoxychroman is heated under reflux for 20 hours together with 1.8 g of 2,4-dihydroxypyridine in 30 ml of dioxane and 20 ml of dimethylformamide in the presence of 0 , 6 ml of a methanolic solution of 35% benzyltrimethylammonium hydroxide. The solvents are evaporated in vacuo and the residue is then crystallized by adding isopropyl ether. The obtained crystals are collected in water, filtered and then washed with acetone to give 850 mg of the desired product.

Melting point: 248-250 ° C Example 5 trans-6-cyano-4- (1,6-dihydro-6-oxopyridazin-1-yl) -2,2-dimethylchroman-3-ol: SR 44 758 1 g 6 -cyano-2,2-dimethyl-3,4-epoxychroman and 1 g of 3-hydroxypyridazine are refluxed for 20 hours in 5 ml of 35 dioxanes in the presence of 0.20 ml of methanol solution, 9 Π X \ χ is y. containing 35% benzyltrimethylammonium hydroxide. The mixture is concentrated in vacuo and then the residue is triturated with 20 ml of water; the precipitate obtained is filtered, washed with water and isopropyl ether and then recrystallized from 10 ml of isopropyl alcohol to give 0.9 g of the desired product.

Melting point: 211-215 ° C - Rf / silica (ethyl acetate): 0.34

Example 6 trans-6-cyano- (1,6-dihydro-3-hydroxy-6-oxopyridazin-1-yl) -2,2-dimethylchroman-3-ol; SR 44 994

A mixture of 1 g of 6-cyano-2,2-dimethyl-3,4-epoxychroman, 1.1 g of 3,6-dihydroxypyridazine and 0.20 ml of a methanolic solution of 35% benzyltrimethylammonium hydroxide in 5 ml of dioxane and 5 mL of dime-formamide, heated to reflux for 50 hours. The product is concentrated in vacuo and then the residue is triturated with 15 ml of water. The precipitate formed is filtered off and washed with water and isopropyl ether.

The product is crystallized from 60 ml of 95% ethanol to give 0.7 g of the desired product.

Melting point: 251-252 ° C - Rf / silica (ethyl acetate / ethanol: 8/2): 0.63 Examples 7 and 8 2 5 trans-6-cyano-4- (1,6-dihydro-3-hydroxy- 5-methyl-6-oxopyridazin-1-yl) -2,2-dimethylchroman-3-ol: SR 45 209 (Ex. 7) and trans-6-cyano-4- (1,6-dihydro-3 -hydroxy-4-methyl-6-oxo-pyridazin-1-yl) -2,2-dimethylchroman-3-ol: SR 45 218 30 (Example 8)

A mixture of 2 g of 6-cyano-2,2-dimethyl-3,4-epoxychroman, 2.5 g of 3,6-dihydroxy-4-methylpyridazine, 30 ml of dimethylformamide and 0.4 ml of a methanol solution containing 35% benzyltrimethylammonium hydroxide, pi-15 is kept at 120 ° C for eight hours.

16 U 5 'r 0

The product is concentrated in vacuo and then the residue is triturated in 30 ml of water, filtered, washed with absolute ethanol and then crystallized from 40 ml of methanol to give 1.3 g of a mixture of the two products, which are separated by chromatography on a silica column. SR 45 209: Rf (ethyl acetate / ethyl alcohol: 8/2): 0.80 SR 45 218: Rf (ethyl acetate / ethyl alcohol: 8/2): 0.71 The structures of the two products are confirmed by their NMR spectra running at 250 MHz. : 11a in DMSO.

10 The following abbreviations have been used to describe the spectrum: s = singlet d = doublet m = multiplet or unresolved signals 15 J = coupling constant 17 9 0 3-: 3

NMR Spectrum

SR 45 209 aAa

\ A

XNX 0 Ha H'a "VW" 1 · 10 „A / aA ™ 3

He: Delta ppm: Occurrence: Protons: Interpretation: 15 ________________ne n________________________________: 1.25: 2s: 6 H: 2CH3: 1.40:::: 2.09: s: 3 H: CH2:. . . . (Pyridazine); 20 ::::::: d'n d; ··; :: 3.80: J = 6Hz,: 1H: H'b:: J = 8Hz::: 5.87: d, J = 8Hz: 1H: H'a: 25 :::::: 5 , 90: d, J = 6Hz: 1H: OH:: 6.95: d, J = 10Hz: 1H: He:: 7.19: s: 1H: Hd: 30; : d1 nd:::: 7.67: J = 10Hz,: 1H: Hb:: J = 2Hz::: 7.73: d, J = 2Hz: 1H: Ha: 3 5: 12: s: 1H: 0H2: 189 C ^ '3

NMR Spectrum

™ 3 .'JR 4 5 218 2H \ / ^ \ / Hd »[5 N l \ / ¾ N '0

If H 'a ”' νγΛ \ AA«; I ->

He: Delta ppm: Occurrence: Protonio: Interpretation: 1.29: 2s: 6 H: 2CH3:: 1.40:::: 2.09: s: 3 H: CH3:. (pyridazine) 20; · ·:.: D'n d::: 3.83: J = 4Hz, 1H: H'b:: J = 6Hz::: 5.78: d, J = 6Hz: 1H: H'a : 2 5:: 5.90: d, J = 4Hz: 1H: 0Ηχ: 6.80: s: 1H Hd 7.00: d, J = 8Hz 1H H: 30; 7.68 d, J = 8 Hz: 1H Hb:: 7.78 s: 1H: Ha:: 12.10 <: s: 1H OH2::> 11.8: broad: 35 ....

90 3 ', 3 19

Example 9 Trans-6-cyano-4- (1,6-dihydro-3-methyl-6-oxopyridazin-1-yl) -2,2-dimethylchroman-3-ol: SR 45 225

A mixture is prepared containing 1 g of 6 cyano-2,2-5 dimethyl-3,4-epoxychroman and 1.1 g of 6-methylpyridazin-3-one (prepared by the method described in J. Chem. Soc. (1947)). , 241, in which ethyl levulinate is incubated with hydrazine hydrate) in 10 ml of dioxane containing 0.1 ml of a 35% methanolic solution of benzyl-10-trimethylammonium hydroxide. The mixture is kept for two days at room temperature and then the mixture is diluted with water and filtered, the filter aid is dissolved in ethyl acetate, the water is decanted off and the organic phase is dried and concentrated. Recrystallize from ethyl acetate / isopropyl ether to give 0.6 g of the desired product.

Melting point:> 257 ° C

The product is characterized by its NMR spectrum running at 250 MHz.

20 r, η 7/7

^ J 'r J

NMR SPECTRUM He CH J Hd

5 W

II

N \ Λ N 0 Ha H’a

N = c I X OH

10 L 1 L-ch,

Hb θ 'CH_ I 3

He 15: Delta ppm: Occurrence: Protons: Interpretation: 20: .......................: ........... ...........:: 1.25: s: 6 H: 2CH3:: 1.46: s: 2.2: s: 3 H: CH3: 25: ::: (pyridicine) : 4.15: m: 1H: H'b:: 5.78: d, J = 8Hz: 1H: OH: 30:: 6: m: 1H: H'a:: 6.96-7, 68: m: 5 H: Ha, Hb, He,::: Hd, He: 35 21 is 7 '7

- '„r J

Example 10 Trans-6-cyano-4- (1,2-dihydro-4-fluoro-2-oxopyrid-1-yl) -2,2-dimethylchroman-3-ol: SR 45 311

A mixture of 460 mg of 6-cyano-2,2-dimethyl-5H-3,4-epoxychroman, 283 mg of 4-fluoropyrid-2-one (Preparation III) and 0.05 ml of a methanol solution containing 35% of benzyltrimethylammonium hydroxide, 5 in ml of tetrahydrofuran, reflux for 24 hours. The solvent is concentrated, the residue is taken up in ethyl acetate and the organic phase is then washed with water, dried over sodium sulfate and concentrated in vacuo. The residue obtained is chromatographed on silica using a methylene chloride / methanol mixture (97/3) as eluent. This gives 200 ml of a white solid.

Melting point: 235 ° C

The compounds of formula I summarized in Table 1 have also been prepared using a similar method.

22 90343

table 1

O

V \ Ar

Uk Λοη3 X / 0X CH3 10 15. Example-.Product. : A: Melting point.

No. No. Z '"\ (recrystallization-::: Z: (solvent: j):

V

:::: N 0:::::: Cl:: 20; | : 11: SR 45012: CN; / v; 260-261 ° C::::: PI: (AcOEt)::::: 0:: 25:::: N::: 12: SR 45067: CN: / 251-253 ° C::::: I]; (AcOEt - CH 2 Cl 2):::: N 2 O::

:::: CH

30. | .

: 13: SR 45135: CN:: 266-267 ° C:: 0 X: <thf>::: NX 0::::: 1 35 90 3 '3 23: 14: SR 45373: Br; / v; 248 ° C: 6::: l A '(<1Pt) 2 °>:::: O:: t: 15: SR 45434: Cl:: 250 ° C: 10:::: J: (AcOEt): : N 'O:: 16: SR 45484: CH 2 CO 2; a; 260 ° C::::: U! (THF):

15 \ A

:::: O::

:. . I

: 17: SR 45485: NO2: ./\v: 224-226 ° C::::: 1) 1 ·· (AcOEt): 20:::: X N '\>:: l

: 18: SR 45512: CH.S.:V, 154 ° C

• · (A

:::: iT O

25; ; I

When the product was recrystallized, the recrystallization solvent used is shown in parentheses. The meanings of the abbreviations 30 are as follows:

AcOEt: ethyl acetate THF: tetrahydrofuran (IPr) 20: isopropyl ether

Pharmaceutical compositions were prepared containing products prepared according to the invention.

24 903 43

Example 19 Coated tablet

Tablets can be prepared by wet granulation. Ethyl alcohol and purified water are used as co-solvents. After evaporation of these solvents, magnesium stearate is added as an external phase as a solvent. The tablets are then coated.

Composition SR 44 709 1 mg 10 95% ethyl alcohol 0.02 ml

Microcrystalline cellulose 48 mg

Lactose 69.8 mg

Magnesium stearate 1.2 mg

Purified water is added to a volume of 120 mg 15 Composition of the coating:

Methylhydroxypropylcellulose, 6 cps 0.14 mg

Titanium dioxide 0.04 mg

Polyoxyethylene glycol 6000 0.02 mg 20 Purified water 1.8 mg

To the film-coated tablets is added until the intended talc 122 mg coated tablet is obtained. Example 20

Injectable form SR 44 709 1 mg

Polyoxyethylene glycol 400 0.5 ml

Purified water for injections is added to a volume of 1 ml

Example 21 Injectable form SR 44 709 1 mg

Polysorbate 80R 0.1 ml 35 Propylene glycol 0.1 g

Purified water for injections is added to a volume of 1 ml 25 f ^ 7 '7 V ί .: 6 r 0

The products prepared according to the invention were tested in the following external and internal pharmacological experiments A), B) and C). Trans-6-cyano-4- (2-oxopyrrolidin-1-yl) -2,2-dimethyl-5-chroman-3-ol of the formula o 0 V \ A / *

Qa λ * 0 CH3 and disclosed in EP 76 075 and hereinafter referred to as "product A" was used as a reference compound and tested under the same conditions.

A) Isolated rat portal vein

Male Spraque Dawley rats (250-300 g) are anesthetized and bled after throat surgery. The portal vein bound at two sites 15 mm apart is isolated, cut lengthwise, and then attached vertically to a test vessel containing physiological saline having the following composition at 37 ° C (mmol / L): NaCl: 137; KCl: 5.4; MgCl 2: 1.05; CaCl 2: 1.8; NaH 2 PO 4: 1.2; NaHCO 3: 15.5; glucose: 11.5 and bubbling a gas mixture of 95% oxygen and 5% carbon dioxide.

A pressure of 500 mg is applied intravenously. After a stabilization time (about 1 h 30 min), the spontaneous contraction activities are recorded by means of an isometric detector. Each measurement is performed sequentially with four preparations.

The product is examined by successively increasing the concentrations (15 min per concentration) until spontaneous contractions are completely prevented. The results are presented as a 35 molar concentration that causes 50% 26 c n 7 * 7 inhibition of its spontaneous contractile activity (ie »).

The results obtained are summarized in the following Table 2. The result column shows IC50 values for spontaneous contraction activities in isolated rat portal veins.

Table 2

Prevention of spontaneous contractile activities 10 Ρςί

PRODUCT:. : ICcn M

mark 50: SR 44 709: 1: 9.0. 1θ "8: - 15: SR 44 758: 5: 1,3. 10 ~ 7:: SR 44 793: 4: 3,4. 10 ~ 8:: SR 44 994: 6: 9.0. 1Ö" 9 :: SR 45 012: 11: 2.6. 10 "8:: SR 45 067: 12: 7.7. 10" 8: 20: SR 45 135: 13: 8.0. 10 ~ 8:: SR 45 209: 7: 5.8. 10 "8:: SR 45 218: 8: 2,0. Ίο" 8:: SR 45 225: 9: 8,8. ίο "8:: SR 45 311: 10: 5,0 ίο" 8:25: Product A ·· -: 6.8. 10 8:

All of the compounds tested have essentially an inhibitory effect against spontaneous venous contraction and have at least the same effect as the reference product. Four of the compounds - SR 44 994, SR 44 793, SR 45 012 and SR 45 218 - with ICS0 values equal to or less than 3,4.1ο11 are at least five times more ak-Jb denser than product A in this test.

90 3 43 27 B) Guinea pig nvstvlihas

Male Albino Charles River guinea pigs (300-400 g) are anesthetized and bled. after The heart is isolated and opened, and the right humerus is removed and kept alive in a test vessel containing physiological saline at 36 ° C (composition shown above).

The preparation is stimulated by means of a bipolar electrode 1 connected to a stimulator (frequency = 60 10 beats per minute). The ventricular activity potential is measured by a conventional microelectrode method. Characteristic parameters were measured as potentials of action (AP) before and after the addition of test compounds at three consecutive ascending concentrations (30 minutes through -15 flows per concentration). Express the concentration that produces a 50% reduction in AP duration (IC *,) ·

The results are shown in Table 3 below.

Table 3 20 Duration of the impact potential: Product:. : ICcr. : mark 50 25: SR 44 709: 1: 2.0. 10 * 5:: SR 44 793: 4: 2.7. 10’6:: SR 44 994: 6: 4.0. 10 * 6:: Product A: -: 1.6. io ”5:30

The table shows that the duration of the impact potential is significantly reduced. In particular, the concentrations of SR 44 793 and SR 44 994, which cause a 50% reduction in this parameter, are 5-10 35 times lower than for product A and reflect a higher ο n 7 * 7

28 '"' 'J

electrophysiological activity to the membrane permeability responsible for this re-polarization phase.

The electrophysiological profiles of the three compounds studied are similar: no significant effect on the residual potential and the maximum depolarization rate; this means that the compounds tested do not have a local anesthetic effect.

C) Antihypertensive effect to be vigilant. spontaneously in hypertensive rats 10 (SHm

The experiment has been performed on male SHRs (Wistar species), age 11-12 weeks; in pentobarbital anesthesia, the catheter is placed in the carotid artery the day before the experiment. The experiment records diastolic pressure (DP) and 15 systolic pressure (SP) from awake animals one hour before the experiment and two hours after product administration. Heart rate (HR) is determined by pulse pressure and is continuously recorded simultaneously.

The products suspended in a 5% aqueous solution of gum arabic were administered orally in a volume of 2 ml per 100 g body weight.

The results are shown in Table 4 below.

90 3 (3 29

Table 4

Blood pressure reduction 5:: Pre-: Dose: Maximum decrease-:. Product. sign. mg / kg. medium.

‘Oral blood pressure:’ ·: through pressure:. . . mm Hg (+ s.e); : SR 44 709: 1: 0.06: 21 + 5:::: 0.10: .39 + 12:: SR 44 758: 5: 0.03: 12 + 2: 0.10: 33 + 5: 15: SR 44 793: 4: 0.03: 22 + 2:::: 0.06: 26 + 3::: 0.10 50 + 9:: SR 44 994: 6: 0.03: 14 + 0 : 20::: 0,10: 37 + 4:: Product A: -: 0,03: 16 + 5::: 0,10: 30 + 10: 25 se = standard error

The compounds according to the invention are effective antihypertensive agents having an activity of the same order of magnitude as that of product A.

30 On the other hand, it is noted that the two representative compounds, SR 44 793 and SR 44 994, have longer shelf lives than product A.

The products according to the invention were also tested for antiarrhythmic activity in the following experiment D).

90 343 30 D) Antiarrhythmic activity in fresh dogs The method used is Dupuis et al. (Br. J. Pharmacol., 58, (1976), 409), in which an acute 5 infarction is induced by placing a copper coil in the coronary circulation with the breast closed. The electric heart rate curve is measured with a telemetry and the excess heart contraction is analyzed and calculated automatically while the animal is observed with an internal television circuit. The products were administered orally to animals with at least 50% extra cardiac contraction.

Two compounds of the present invention - SR 44 709 orally at 1 mg / kg and SR 44 793 orally at 0.1 to 0.5 mg / kg - had substantial antiarrhythmic activity, and they reduced the amount of extra heart contractions or restored the sinus rhythm for a period ranging from 2 to 10 hours depending on the animal.

The above biological data indicate that the compounds of the invention are effective antihypertensive agents and potential antiarrhythmic agents.

The acute toxicity of one of the compounds of formula I -25 SR 44 709 of the invention was measured in a group of ten mice by oral administration at doses of 10, 50, 500 and 1000 mg / kg and compared to product A.

In the case of SR 44 709, all animals survived at a dose of 1,000 mg / kg, while with product A, all 10 30 animals died at a dose of 1,000 mg / kg.

Claims (6)

31 90343 A process for the preparation of antihypertensive and antiarrhythmic trans-2,2-dimethylchroman-3-5 ol derivatives of the formula O y \ A / H \ AoAj 15 wherein A between N and CO is a group -CH = CH-E = CH- or group -n = CC = C-; R 1 R 2 R 3 20. is a halogen or cyano, acetyl, trifluoroacetyl, nitro, alkylthio or dialoxyphosphoryl group, wherein the alkylthio and alkoxy groups contain 1 to 3 carbon atoms; E is a nitrogen atom or a group c (R 4); R 1 is a hydrogen atom or a methyl or hydroxyl group, and R 2 and R 3 are hydrogen or methyl groups, wherein only one of the substituents R 1, R 2 and R 3 is methyl; and R «is a hydrogen or halogen atom or a methyl or hydroxyl group, characterized in that the chroman epoxide of formula VW kA A“ s (ii> 3 5 χ0κ ch3 32 ~ rya 7 ^ L '0 r 3 where Z is as defined above) as defined, is treated with a heterocyclic compound having one of the tautomeric forms 5 ---> C 'j; (III) <- γ \ H wherein A is as defined above. Process according to Claim 1, characterized in that the treatment is carried out at a temperature of 10 to 100 ° C in an inert organic solvent in the presence of a basic condensing agent. Process according to Claim 1 or 2, characterized in that an epoxide of the formula II is treated in which Z is a cyano group. Process according to one of Claims 1 to 3, characterized in that the compound of the formula III is 2-hydroxypyridine and the compound obtained is trans-6-cyano-4- (1,2-dihydro-2-oxopyrid-1-yl) -2,2-dimethylchroman-3-ol. Process according to one of Claims 1 to 3, characterized in that the compound of the formula III is 2,4-dihydroxypyridine and the compound obtained is 2. trans-6-cyano-4- (1,2-dihydro-4-hydroxy-2 -oxopyrid-1-yl) -2,2-dimethylchroman-3-ol. Process according to one of Claims 1 to 3, characterized in that the compound of the formula III is 3,6-dihydroxypyridazine and the compound obtained is 3. trans-6-cyano-4- (1,6-dihydro-3-hydroxy-6 -oxopyridazin-1-yl) -2,2-dimethyl-5-chroman-3-ol. 33 90343