FR2654103A1 - 4-Amidinochroman derivatives, process of production and pharmaceutical compositions containing them - Google Patents

Abstract

The present invention relates to 4-amidinochroman derivatives of formula in which: . A + B = either -CH=CH-CH=X1, with X1 = N or CH, or -(CH2)n-X2, with X2 = NH or CH2 and n = 2 or 3 . X = N or C-Z . Z = H, Cl, Br, F, CN, NO2, CH3CO or CF3CO . R1 = H, CN or NO2 . R2 = H; R3 = OH or R2 and R3 together form a bond. Another subject of the invention is a process for the preparation of the said derivatives and pharmaceutical compositions containing them. The said derivatives have antihypertensive and antiarrhythmic activities.

Description

 The present invention relates to amidino4 chroman derivatives, a process for obtaining them and pharmaceutical compositions containing them. Said derivatives have antihypertensive and antiarrhythmic activities.

 Belgian patent 829,611 mentions a whole series of chromannol-3 derivatives with antihypertensive activity; these derivatives are characterized by the presence in position 4 of a group NR1R2 in which R1 is hydrogen or an optionally substituted hydrocarbon group, R2 is hydrogen or an alkyl, NR1R2 being able to be a heterocyclic group comprising from 3 to 8 atoms , unsubstituted or substituted by one or two methyl groups and by the possible presence of a large number of possible substituents in position 6 or in position 7.

dans laquelle notamment - R'5 désigne un groupe hétérocyclique tel que pyridone-2 yL-1,
pyridazinone-2 yl-1, pyrimidone-2 yl--1, pyrimidone--6 yl--1,
pyrazinone-2 yl-1, thiopyridone-2 yl-1 ; ce groupe peut être par
tiellement hydraté, et non substitué ou substitué ; - R'3 représente OH ou OCOCH3 ; - R'4 représente L'hydrogène ou bien R'3 et R'4 ensemble forment
une liaison.
o
European patent application No. 273,262 describes the chroman derivatives of the formula:

in which in particular - R'5 denotes a heterocyclic group such as pyridone-2 yL-1,
pyridazinone-2 yl-1, pyrimidone-2 yl - 1, pyrimidone - 6 yl - 1,
pyrazinone-2 yl-1, thiopyridone-2 yl-1; this group can be by
partially hydrated, and unsubstituted or substituted; - R'3 represents OH or OCOCH3; - R'4 represents Hydrogen or R'3 and R'4 together form
a relationship.

 European patent applications 296 975 and 312 432 describe similar compounds.

dans laquelle X" représente O ou S et R"5 et R6 peuvent former un hétérocycle.Finally, European patent application 205 292 describes pyranoC3,2-cApyridine derivatives of formula:

in which X "represents O or S and R" 5 and R6 can form a heterocycle.

 We have now found new compounds, chroman derivatives or pyranoC3,2-c3pyridine which exhibit activity as antihypertensives and antiarrhythmics.

dans laquelle : - A et B sont unis entre N et C = NR1 et représentent
soit un groupe - CH = CH - CH = X1 - dans lequel X1 repré
sente un atome d'azote ou le groupe CH,
soit un groupe -(CH2)n X2 dans lequel X2 représente un
groupe NH ou un groupe CH2 et n est égal à 2 ou 3 ; - X représente un atome d'azote ou le groupe C-Z ; - Z représente l'hydrogène, un halogène, un groupe cyano, un groupe
nitro, un groupe acétyle ou un groupe trifluoroacétyle ; - R1 représente un atome dthydrogène, un groupe cyano ou un groupe
nitro ; - R2 représente un atome d'hydrogène ; - R3 représente un groupe hydroxyle ou R2 et R3 forment ensemble
une liaison.Thus the present invention relates according to one of its aspects to the compounds of formula:

in which: - A and B are united between N and C = NR1 and represent
or a group - CH = CH - CH = X1 - in which X1 represents
smells of a nitrogen atom or the CH group,
either a group - (CH2) n X2 in which X2 represents a
NH group or CH2 group and n is 2 or 3; - X represents a nitrogen atom or the group CZ; - Z represents hydrogen, a halogen, a cyano group, a group
nitro, an acetyl group or a trifluoroacetyl group; - R1 represents a hydrogen atom, a cyano group or a group
nitro; - R2 represents a hydrogen atom; - R3 represents a hydroxyl group or R2 and R3 form together
a relationship.

 In your present description and in the claims which will follow, by halogen is meant a chlorine, bromine or fluorine atom.

The compounds of formula (I) in which R2 = H and
R3 = OH have the trans configuration. They can have two asymmetric carbons. The present invention comprises each of the optical isomers of (I) as well as the racemic.

 The present invention also relates to a process for the preparation of the compounds (I).

dans laquelle X a Les significations données ci-dessus pour (I) avec un hétérocycle III répondant à L'une des formes tautomères suivantes :

dans lesquelles A, B et R1 ont les significations indiquées précédemment pour (I)
b) on déshydrate éventueLlement Le composé ainsi obtenu de formule (I) dans laquelle R2 = H et R3 = OH en un composé de formule (I) dans laquelle R2 et R3 forment ensemble une liaison.Said process is characterized in that:
a) treating an epoxide II of formula:

in which X has the meanings given above for (I) with a heterocycle III corresponding to one of the following tautomeric forms:

in which A, B and R1 have the meanings indicated above for (I)
b) optionally dehydrating The compound thus obtained of formula (I) in which R2 = H and R3 = OH into a compound of formula (I) in which R2 and R3 together form a bond.

 In step a), the opening reaction of the epoxide (II) oo is carried out at a temperature of between 10 ° C. and 100 ° C. in an inert organic solvent such as dioxane, tetrahydrofuran, methyl tert-butyl ether , dimethylsulfoxide or dimethylformamide in the presence of a basic condensing agent such as sodium hydride, triethylamine, a quaternary ammonium hydroxide such as benzyltrimethylammonium hydroxide. Under these operating conditions, the opening of the epoxide (II) leads to compounds of formula (I) in which R2 = H and R3 = OH having the trans configuration.

 In step b), dehydration is obtained by the action of an alkaline hydride, for example sodium hydride or lithium hydride, in an inert solvent at a temperature between 200C and 1000C.

 The epoxides of formula (II) are known or prepared according to known methods.

 The epoxide (II) in which X represents a nitrogen atom is described in European patent application 205 292. The epoxides (II) in which X represents the group C-Z are described in various publications.

 Thus The epoxide (II) in which Z represents the cyano group is described in Belgian patent 852 955; the epoxide (II) in which Z represents the nitro group or an acetyl group is described in J. Med. Chem., 1983, 23, 1582-1589; the epoxides (II) in which Z represents a halogen are prepared according to Tetrahedron, 1981, 37 (15), 2613-2616. The epoxide (II) in which Z represents trifluoroacetyl is described in European patent application 296 975. The epoxide (II) in which Z represents hydrogen is described in J. Chem. Soc. 1962, p 76-79.

 The heterocyclic compounds (III) are known or are prepared by known methods.

 The compounds according to the invention increase the polarization of the smooth muscle fibers and have a vasodilator effect on the portal vein, according to the test described in European patent application 296 975. Their antihypertensive effect has been observed in animals.

 Furthermore, it has been observed that the compounds according to the invention accelerate the repolarization of myocardial cells; at the same time, their antiarrhythmic effect was observed in an animal model.

 No signs of toxicity are observed with these compounds at pharmacologically active doses.

 Thus the compounds according to the invention can be used in the treatment of hypertension, pathological disorders associated with contractions of the smooth muscle fibers of the gastrointestinal, respiratory, uterine and urinary tracts, for example: ulcer, asthma, premature uterine contraction, incontinence , and in the treatment of other cardiovascular pathological disorders such as: angina, heart failure, cerebral and peripheral vascular diseases. In addition, the compounds according to the invention can be used in the treatment of cardiac arrhythmia as well as in the treatment of glaucoma. Furthermore, the compounds according to the invention can be used in the treatment of depression or other diseases of the central nervous system.

 Finally, the compounds of the present invention can be used for the topical treatment of aLopecia.

 The present invention therefore also relates to pharmaceutical compositions containing an effective dose of a compound according to the invention and suitable excipients. Said excipients are chosen according to the pharmaceutical form and the desired mode of administration.

 In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, transdermal or rectal administration, the active principles of formula (I) above can be administered in unit administration forms , mixed with conventional pharmaceutical carriers, to animals and humans for the prophylaxis or treatment of the above disorders or diseases. Suitable unit administration forms include oral forms such as tablets, capsules, powders, granules and oral solutions or suspensions, sublingual and oral administration forms, subcutaneous administration forms , intramuscular or intravenous and forms of rectal administration. For topical application, the compounds according to the invention can be used in creams, ointments or lotions.

 In order to obtain the desired prophylactic or therapeutic effect, the dose of active principle can vary between 0.01 and 5 mg per kg of body weight per day.

 Each unit dose can contain from 0.5 to 100 mg, preferably from 1 to 50 mg of active ingredients in combination with a pharmaceutical carrier. This unit dose can be administered 1 to 5 times a day so as to administer a daily dosage of 1 to 500 mg, preferably from 1 to 250 mg.

 When preparing a solid composition in tablet form, the main active ingredient is mixed with a pharmaceutical vehicle such as gelatin, starch, lactose, magnesium stearate, talc, gum arabic or the like. The tablets can be coated with sucrose, a cellulose derivative, or other suitable materials or they can be treated so that they have a prolonged or delayed activity and that they continuously release a quantity predetermined active ingredient.

 A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture obtained into soft or hard capsules.

 A preparation in the form of a syrup or elixir or for administration in the form of drops may contain the active ingredient together with a sweetener, preferably calorie-free, methylparaben and propylparaben as antiseptics, as well as a flavoring agent and an appropriate dye.

 The powders or granules dispersible in water can contain the active ingredient in mixture with dispersing agents or wetting agents, or suspending agents, like polyvinylpyrrolidone, as well as with sweeteners or correctors taste.

 Suppositories are used for rectal administration which are prepared with binders which melt at rectal temperature, for example cocoa butter or polyethylene glycols.

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

 The active principle can also be formulated in the form of microcapsules, optionally with one or more carriers or additives.

 The compositions of the present invention may contain, in addition to the products of formula (I) above or of a pharmaceutically acceptable salt, other active principles such as, for example, tranquilizers, p-blockers or d other medicines which may be useful in the treatment of the disorders or diseases indicated above.

 The following examples illustrate the invention without, however, limiting it. In the examples, as well as in the descriptive part and in the claims, the products are designated as derivatives of chroman. It is understood that the products of the present invention are derivatives of 2,2-dimethyl-3,4-dihydro-2Hchromene and that the term "chroman" denotes "dihydro-3,4-2H-chromene".

 Melting points (Fc) are given in degrees Celsius.

Example 1
Trans (cyanamido-2 dihydro - 1,2 pyridyl - 1) - 4 cyano - 6 dimethyl-2,2 hydroxy-3 chromanne: SR 47023
Cyanamido-2 pyridine is prepared according to the method described in Ann. Pharm. Fr., 1968, 26 (6), 469-472.

 A solution containing 1 g of cyano-6 dimethyl-2,2 epoxy-4,4 chromanne, 0.8 g of cyanamido-2 pyridine in 50 ml of dimethoxyethane and 0.2 ml with ethyl acetate. It is dried over sodium sulfate and then concentrated. The residue is taken up in ethyl ether, filtered and then washed with dichloromethane. 110 mg of the expected product are obtained.

o
Fc = 284 C.

Example 2
Trans (2-cyanamido-1,2 dihydro-1,2 pyridyl-1) -4 dimethyl-2,2 hydroxy-3 nitro-6 chroman: SR 47025.

 A solution containing 2.7 g of 2-cyanamido-pyridine, 3 g of 2,2-dimethyl-2,2-epoxy3,4-nitro-6 chroman in 50 ml of tetrahydrofuran and 0.2 ml of triethylamine is heated at reflux for 96 hours. It is allowed to cool and then filtered. The precipitate is washed with ethyl ether, then with water and with acetone and dried. 250 mg of the expected product are obtained.

o
Fc = 253 C.

Example 3
(Cyanamido-2 dihydro-1,2 pyridyl-1) -4 dimethyl-2,2 nitro6 chromene: SR 47063.

 This compound is prepared from the chromannol obtained in Example 2.

 To 400 mg of SR 47025 placed in 50 ml of tetrahydrofuran, 30 mg of sodium hydride are added in small portions.

After 96 hours at room temperature, the reaction medium is concentrated to dryness and then taken up in 50 ml of water. Extraction is carried out twice with methylene chloride, then it is dried and concentrated. 250 mg of product are obtained which are purified by chromatography on a silica column, eluting with a methylene methanol chloride mixture (99.5 / 0.5 - v / v).

 80 mg of the expected product are collected.

o
Fc = 251 C.

Example 4
Trans (2-cyanamido-imidazolidinyl-1) -4 2,2-dimethyl-3-hydroxy-6-nitro-chroman: SR 46798.

 The synthesis of 1,3-dimethylene cyano guanidine is carried out according to the method described by H.W. MOORE and W.G. DUNCAN in J. Org. Chem., 1973, 38 (1), 155-156.

 A solution of 1.5 g of dimethytene-1,3 cyanoguanidine in 30 ml of dimethylsulfoxide is prepared, to which 305 mg of sodium hydride are added in small fractions. After 30 minutes at room temperature, 2.2 g of 2,2-dimethyl-3,4-epoxy-6-nitro-chroman are added and the mixture is left stirring for 12 hours at room temperature. Poured onto 200 ml of water and then extracted with methylene chloride, dried over sodium sulfate and concentrated.

1.5 g of product are obtained which are purified by chromatography on a silica column, eluting with a methylene chloride-methanol mixture (96-4, v / v).

 1.2 g of the expected product are obtained.

 Fc = 2740C.

Example 5
Trans acetyl (2-cyanamido-1,2 dihydro-1,2 pyrimidyl-1) -4 dimethyl-2,2 hydroxy-3 chroman: SR 47141
Cyanamido-2 pyrimidine is prepared according to British patent 860,423.

 SR 47141 is obtained according to the method described in Example 1.

 Fc = 2540C.

Example 6
Trans (2-cyanamido-1,2 dihydro-1,2 pyridyl-1) -4 2,2-dimethyl-3-hydroxy-6-trifluorocetyl chroman: SR 47140
This compound is prepared according to the method described in Example 1.

o
Fc = 218 C.

Example 7
Trans cyano-6 (1,2-dihydro-2 nitramido-2 pyridyl 1) -4 dimethyl-2,2 hydroxy-3 chroman: SR 47159
Pyridylnitramine is prepared according to the method described in J. Am. Chem. Soc., 1955, 77, 3154.

 The compound of Example 7 is obtained by following the method of Example 2.

o
Fc = 279 C.

Example 8
Trans (2-cyanamido-1,2 dihydro-1,2 pyridyl-1) -4 dimethyl-2,2 hydroxy-3 pyranoE3,2-cpyridine: SR 47142
This compound is obtained from the epoxide (II) in which X = N and 2-cyanamido-pyridine by following the procedure described in Example 1.

 Fc = 171 0C.

Claims (3)

1. Amidino-4 chroman derivatives of formula:

 in which: - A and B are united between N and C = NR1 and represent  - either a group - CH = CH - CH = X1 - in which X1 represents  smells of a nitrogen atom or the CH group,  . either a group (CH2) n - X2 - in which X2 represents a  NH group or CH2 group and n is 2 or 3, - X represents a nitrogen atom or the C-Z group; - Z represents hydrogen, a halogen, a cyano group, a group  nitro, an acetyl group or a trifluoroacetyl group; - R1 represents a hydrogen atom, a cyano group, or a group  nitro; - R2 represents a hydrogen atom; - R3 represents a hydroxyl group or R2 and R3 form together  a relationship.  2. Process for the preparation of a compound according to claim 1 characterized in that: a) an epoxide (II) of formula is treated

  in which X has the meaning given in claim 1 with a heterocycle (III) corresponding to one of the following tautomeric forms:

 in which A, B and R1 have the meanings given in claim 1  b) optionally dehydrating the compound thus obtained of formula (I) in which R2 = H and R3 = OH into a compound of formula (I) in which R2 and R3 together form a bond.  3. Pharmaceutical composition characterized in that it contains, as active principle, a 4-amidino-chroman derivative according to claim 1.