CS201043B2 - Method of producing etherified hydroxy-benzo-diheterocyclic compounds - Google Patents

Description

The invention relates to a process for the preparation of etherified hydroxybenzodiheterocyclic compounds of the formula I

OH

R 1 -h ₂ -ch ₂ -ch ₂ -o

C = O in which

R 1 represents a C 3 -C 5 alkyl radical which is optionally branched on the carbon atom to which this radical is attached, optionally further C 1 -C 3 alkoxy groups having from 7 to 7 carbon atoms or a C 3 -C 5 phenylalkyl radical substituted by a methylenedioxy radical in the alkyl moiety and alkyl

AND

R ₂ represents one of the groups -NH-, -O-CHg-,-CH₂-O-, -N-, with up to 7 carbon atoms, -NH-CH₂, -CO-NH-, -O-, or -NH-CO or a salt thereof, in particular a pharmaceutically acceptable, non-toxic acid salt thereof. The alkyl radical R 1 preferably contains 3 to 5 carbon atoms and is primarily a isopropyl or tert-butyl radical, or also a sec-butyl or 2-methyl-2-butyl radical.

Substituted alkyl radical R ₁ is preferably an optionally substituted phenylalkyl radical. The substituted phenyl contains as lower substituents lower alkoxy or methylenedioxy, these substituents being present one to three times and may be the same or different.

Thus, the substituted alkyl radical R 1, in particular in the phenyl radical optionally, for example as mentioned above, is substituted on the carbon atom to which this radical is attached optionally branched phenylalkyl radical, as in the phenyl radical optionally, for example as mentioned, substituted 1-phenyl- 2-propyl or 4-phenyl-2-butyl, in addition also 2-phenylethyl, wherein the substituted phenyl may be substituted by alkoxy or methylenedioxy.

An alkyl radical, unless specifically defined above for R, is, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 1-methyl-2 radicals. -butyl or neopentyl.

Alkoxy is, for example, methoxy, ethoxy, n-propyloxy, n-butyloxy or isobutyloxy.

Salts of the compounds of formula I are in particular acid addition salts, and in particular pharmaceutically usable, non-toxic acid addition salts, which are suitable inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or phosphoric acid, or suitable organic aliphatic, cycloaliphatic, aromatic, araliphatic or heterocyclic carboxylic acids or sulfonic acids such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, fumaric acid, pyruvic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, salicylic acid, phenylacetic acid, embonic acid, methensulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, 4-chlorobenzene zensulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, sulfanilic acid or cyclohexylamine sulfonic acid.

Due to the close relationship between the novel compounds in the free form and in the form of their salts, the free compounds and the salts according to the meaning and suitably also the corresponding salts or the free compounds are also to be understood.

The novel compounds may exist in the form of racemates or in the form of antipodes.

The novel compounds have valuable pharmacological properties, in particular they have potent and long-lasting beta-receptor blocking effects which can be demonstrated by appropriate pharmacological experiments (see, for example, Meier et al., Arzneimittelforschung, Vol. 20, p. 1890 (1970)). Thus, the novel compounds exhibit isoproterenol-induced tachycardia inhibition on isolated guinea pig heart muscle (Langendorff) at a concentration ranging from about 0.001 µg / ml to about 1 µg / ml, and isoproterenol-induced tachycardia and vasodilation on anesthetized cat over a dose range of about 0.0003 mg / kg up to about 0.3 mg / kg when administered intravenously. The novel compounds may therefore be used as beta-receptor blockers, for example in the treatment of cardiac rhythm (arrhythmia) disorders and coronary heart diseases such as angina pectoris, as well as agents for lowering blood pressure in the treatment of hypertonia. In addition, these compounds also have cardiac pacing activity which can be demonstrated in the isolated guinea pig atrium in the form of an increase in heart rate and myokerdial counter-stroke in a concentration range of about 0.003 to about 3 µg / ml.

This type of effect can be further demonstrated in anesthetized cat by increasing heart rate and maximum rate of heart rate increase and maximum rate of blood pressure increase (dP / dt) in the left ventricle over a dose range of about 0.0003 to about 0.3 mg / kg intrávenízně. Compounds with such pacemaking activity therefore affect function less than substances which do not have these additional properties.

In addition, some of these compounds exhibit alpha-receptor blocking properties, which manifest themselves, for example, in an isolated blood-bearing mesenteric bed of a rat in a concentration range of about 0.03 to about 3 pg / ml by suppressing noradrenaline-induced vasoconstriction. For example, the blood pressure lowering effect may be favorably influenced by this component of action.

In particular, the invention relates to a process for the preparation of a compound of formula I in which R 1 represents a C 3 -C 4 alkyl group, or optionally 1 to 3 methoxy or methylenedioxy in the phenyl group substituted with a C 1 -C 3 phenylalkyl and alkyl group

R 8 represents one of the groups -NH-, -O-CH ₂ -, -CH 2 -O-, -J- with 4 carbon atoms, -CH ₂ -NH-, -CO-NH-, -O- or -NH- WHAT-.

In particular, the invention relates to a process for the preparation of a compound of formula I wherein R 1 is isopropyl, tert. butyl, 1-phenylprop-2-yl, 2- (3,4-dimethoxyphenyl) ethyl or 2- (3,4-methylenedioxyphenyl) ethyl and

CH, CH, -CH, -CH, -CH, 3 2 2 2 3

R ₂ represents one of the groups -NH-, -O-CH ₂ -, -CH ₂ -O-, -N-, -N-, -CH ₈ -NH-,

-CO-NH-, -O- or -NH-CO-.

The invention relates to the processes described in the Examples for the preparation of the compounds of formula I therein.

The novel compounds of formula (I) are prepared in a manner known per se, for example by the formation of a compound of formula (11)

wherein one of X; and X ₂ is an alkoxycarbonyl group having 8 to 7 carbon atoms in the alkoxy moiety, an aminocarbonyl group or a halocarbonyl group, the other of which is hydrogen, or cleaves the X residues in its salts, and X _{2 by a} cyclization condensation reaction to form a carbonyl group; optionally converting the obtained free compound into a salt, or converting the obtained salt into a free compound and / or, and optionally obtaining the racemate into antipodes.

The starting materials usable in the form of salts are, in particular, starting materials in the form of acid addition salts, in particular in the form of the corresponding salts with inorganic acids, for example mineral acids, as well as 3 organic acids.

The starting material of the formula II in the form of an acid addition salt is, for example, the corresponding compound in the form of a mineral acid salt.

Typically, one of X and Xg is hydrogen, while the other is an acyl radical of a carbonic acid derivative such as an ester, halide or amide, and is, for example, a lower alkoxycarbonyl radical such as a methoxycarbonyl radical or ethoxycarbonyl radical or a halocarbonyl radical such as chlorocarbonyl or aminocarbonyl.

The reaction is carried out in the presence or absence of a suitable solvent or diluent, such as an optionally substituted, for example, chlorinated, aliphatic, cycloaliphatic or aromatic hydrocarbon, such as benzene and, if necessary, with cooling or heating, e.g. ° C, in a closed vessel and / or in an inert gas atmosphere, for example under a nitrogen atmosphere. Optionally, and preferably when one of X or Xg is aminocarbonyl, the reaction is carried out in the presence of a basic condensing agent such as a metal alkoxide such as an alkali metal alkoxide, for example sodium ethoxide in a solvent such as a lower alkanol, for example ethanol . The process is carried out in a temperature range of from about 0 to 150 ° C, preferably from 10 to 120 ° C.

The starting materials of the formula II can be prepared in a manner known per se and optionally in situ.

Thus, advantageous starting materials can be obtained by converting, for example, in a 2,3-dinitrophenol, a phenolic hydroxy group, such as by treatment with an allyl halide such as allyl bromide in the presence of a base such as potassium carbonate to an allyloxy group. for example in the presence of potassium bicarbonate or by treatment with a suitable inorganic or organic percarboxylic acid, for example 3-chloroperbenzoic acid, is converted to a 2,3-epoxypropyloxy group and this group is converted, for example, by reaction of an intermediate with amine Rj-NHg to 3- (R, -amino) -2-hydroxypropyloxy. Then, both nitro groups in the 3- (3- (R, -amino) -2-hydroxypropyloxy) -1,2-dinitrobenzene thus obtained are reduced to amino groups, for example by treatment with catalytically activated hydrogen. Reaction with a suitable reactive carbonic acid derivative, for example a corresponding ester, such as di (lower) alkyl carbonate, for example dimethyl or diethyl carbonate, with a mixed anhydride such as carbonic dihalide, for example phosgene or an amide, for example urea or With Ν, Ν'-carbonyldiimidazole, a preferred starting material is obtained, which is preferably formed in situ and is directly converted to the compound of formula 1.

Depending on the process conditions and the starting materials used, the novel compounds are obtained in free form or in the form of their salts, which are also included within the scope of the invention, wherein the novel compounds or their salts may also be present as hemihydrates, sesquihydrates or polyhydrates. Salts of the novel compounds can be converted into the free compounds in a manner known per se. Thus, acid addition salts can be converted into the free compounds by, for example, treatment with acidic agents such as alkali metal hydroxides, carbonates or acidic alkali metal carbonates or by ion exchangers, and optionally metal salts such as alkali metal salts converted according to the invention as mineral acids to the free compounds. On the other hand, the free compounds obtained can be converted into acid addition salts in a manner known per se, for example by reaction with organic or inorganic acids, such as the abovementioned acids, in particular those which are suitable for the production of pharmaceutically usable acids. salts.

These or other salts, in particular the acid addition salts of these novel compounds, such as picrates or perchlorates, can also be used to purify the free bases obtained by converting the free compounds into salts, separating and purifying the salts and from the salts. again form the free compounds.

Depending on the choice of starting materials and processes, the novel compounds can be present as optical antipodes or racemates.

The racemates obtained can be decomposed into antipodes by methods known per se, for example by recrystallization from an optically active solvent, by treatment with suitable microorganisms or by reacting with an optically active compound which forms a salt with the racemic compound, in particular an appropriate acid. by different solubilities, to diastereomeric salts from which free antipodes can be released by treatment with suitable agents. Particularly useful as optically active acids are, for example, the D- and L-forms of tartaric, di-o-toluyltartaric, malic, mandelic, camphorsulfonic, glutamine, aspartic or quinic acids. Preferably, the more effective of both antipodes is isolated.

The invention also relates to those embodiments of the process in which the reactants are optionally used in the form of salts.

Suitably, for the reactions according to the invention, such starting materials are used which lead to the groups of fines mentioned in particular in the introductory part of the description and in particular to the specially described or emphasized fines.

The novel compounds can be used in the form of pharmaceutical preparations containing a pharmacologically effective amount of the active ingredient, optionally together with inorganic or organic, solid or liquid, pharmaceutically acceptable carriers which are suitable for enteral, for example oral or parenteral administration. Thus, tablets or gelatin capsules are used which contain the active ingredient together with diluents, for example lactose, dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine, and / or lubricants such as silica gel, talc, stearic acid or its salts. , such as the magnesium or calcium salt of stearic acid and / or polyethylene glycol. The tablets may also contain binding agents, for example magnesium aluminum silicate, starches such as corn starch, wheat starch, rice starch or marzipan starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidone and optionally together with tablet disintegrating agents such as starches, agar, alginic acid, or a salt thereof, such as sodium alginate and / or mixtures of effervescent agents, or adsorbents, colorants, flavorings, and sweeteners.

Furthermore, the novel pharmacologically active compounds can be used in the form of parenterally administrable preparations or infusion solutions. Such solutions are preferably isotonic aqueous solutions or suspensions, which, as in the case of lyophilized preparations which contain the active ingredient alone or together with a carrier such as mannitol, can be prepared before use. The pharmaceutical preparations may be sterilized and / or contain adjuvants such as preservatives, stabilizers, wetting agents and / or emulsifiers, co-solvents, salts for regulating the osmotic pressure and / or buffers. The present pharmaceutical compositions, which, if desired, may contain other pharmacologically active substances, are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, solvent or lyophilizing processes and contain from about 0.1% to 100%, in particular from about 1% to about 50%, lyophilizates up to 100% of active ingredient.

The dose may be dependent on various factors such as the mode of administration, the species, the age and / or the individual condition. Daily dosages for oral administration are between about 1 mg and about 15 mg for a warm-blooded weight of about 70 kg.

The following examples serve to illustrate the invention; temperatures are given in degrees Celsius.

He did

8.0 g of 2-aminomethyl-3- (3-tert-butylamino-2-hydroxypropoxy) aniline was reacted with 3.3 g of methyl chloroformate in a mixture of 28 ml of isopropanol and 28 ml of water with stirring and ice-cooling to < 5 DEG-20 DEG C. and then with 3.2 g of sodium methoxide in 30 ml of methanol. After working up, 5- (3-tert-butylamino-2-hydroxypropoxy) -3,4-dihydro-1H-quinazolin-2-one is obtained, m.p. 204-205 ° C.

201043 6

The starting material can be prepared as follows:

a) A mixture of 11.0 g of 2- (2,3-epoxypropoxy) -6-nitrobenzonitrile and 18.5 g of tert-butylamine in 300 ml of isopropanol was refluxed for 5-6 hours. Evaporation left a crystalline residue which is triturated with 20 ml of carbon tetrachloride and then filtered off to give 1-tert-butylamino-3- (2-cyen-3-nitrophenoxy) -2-propanol, m.p. 115-118 ° C. .

(b) 12.2 g of 1-tert-butylamino-3- (2-cyeno-3-nitrophenoxy) -2-propanol in 200 ml of ethanol are treated with 11 g of hydrazine hydrate and Raney nickel at boiling point and after filtration through diatomaceous earth; and evaporation of the filtrate gave crude 6- (3-tert-butylamino-2-hydroxypropoxy) anthranilamide as an oil which was further processed without further purification.

c) 12 g of crude 6- (3-tert-butylamino-2-hydroxypropoxy) anthranilamide are dissolved in 400 ml of tetrahydrofuran and this is reduced under nitrogen with 6.1 g of lithium aluminum hydride for 48 hours with stirring under reflux. After working up, 2-aminomethyl-3- (3-tert-butylamino-2-hydroxypropoxy) aniline is obtained in the form of an oil, which is further used as such. It forms the tri-hydrochloride, m.p. 250 DEG-260 DEG C. (sublimation).

Example 2

2- (3-tert-butylamino-2-hydroxypropoxy) -6-ureidobenzamide (3.24 g) was refluxed with a solution of 0.28 g of sodium in 150 ml of absolute ethanol for 1.5 hours, the reaction mixture was evaporated and the residue was evaporated. Dissolve in 50 ml of water. After neutralization of the aqueous solution with 2N hydrochloric acid, the mixture is filtered, the filtrate is evaporated and the residue is boiled in 100 ml of methanol. The undissolved material was filtered off and the filtrate was evaporated to give 5- (3-tert-butylamino-2-hydroxypropoxy) - (1H) (3H) -quinazoline-2,4-dione as the hydrochloride, m.p. 298-305 °. C (dec.).

The starting material can be prepared as follows:

a) 6.2 g of 2- (3- (N-benzyl-tert-butylemino) -2-hydroxypropoxy) -6-ureidobenzamide are hydrogenated in 500 ml of methanol in the presence of 0.6 g of palladium on carbon catalyst (5%) until the end of hydrogen consumption. Filtration, evaporation of the filtrate and addition of isopropanol to the residue gave 2- (3-tert-butylamino-2-hydroxypropoxy) -6-ureidobenzamide, m.p. 189-191 ° C.

Example 3

To 2.5 g of 1- (2,3-dlaminophenoxy) -2-hydroxy-3-tert-butylaminopropane was added 1.7 ml of concentrated hydrochloric acid, followed by 10 ml of a molar solution of phosgene in toluene, and the mixture was stirred at 20 ° C for 5 hours. Deň: 32 ° C. After the addition of 0 ml of phosgene solution, the mixture was stirred for an additional 8 hours. Then, the solvent was distilled off under reduced pressure. The residue was recrystallized from a mixture of methanol and acetone to give 4- (3-tert-butylamino-2-hydroxypropoyloxy) benzimidazol-2-one hydrochloride, m.p. 250 DEG-260 DEG C. (slow decomposition).

The 1- (2,3-dieminophenoxy) -2-hydroxy-3-tert-butylaminopropane used as starting material can be prepared as follows:

(a) A mixture of 65.1 g of 2,3-dinitrophenol, 300 ml of acetone and 47.1 g of potassium carbonate is heated to reflux while stirring, and 29 ml of allyl bromide are added dropwise over 1 hour. After an additional 16 hours of stirring and reflux, the inorganic salts are filtered off and the residue is washed with acetone. The filtrate is evaporated under reduced pressure, the residue is taken up in diethyl ether and petroleum ether is added, followed by crystallization of 1-allyloxy-2,3-dinitrobenzene, m.p. 51-52 ° C.

b) To a solution of 52.2 g of 1-allyloxy-2,3-dinitrobenzene in 450 ml of methanol was added 4.6 g of potassium bicarbonate, 36.0 benzonitrile and 60 ml of 30% hydrogen peroxide, and then the mixture was stirred at 22 DEG C. for 4 days. Deň: 32 ° C. The crystalline precipitate obtained is filtered off and recrystallized from methanol to give 1- (2,3-dinitrophenoxy) -2,3-epoxypropane, m.p. 98-100 ° C.

c) Dry carbon dioxide is introduced into a solution of 11.4 ml of tert-butylamine in 40 ml of diethyl ether to form a white crystalline precipitate. The introduction of carbon dioxide is continued until only a large portion of the ether flows. The residue is treated with 24.0 g of 1- (2,3-dinitrophenoxy) -2,3-epoxypropane and 300 ml of isopropanol and the mixture is heated under reflux for 1 hour while obtaining a clear solution. This solution was evaporated under reduced pressure and the crystalline residue was recrystallized from toluene to give 1- (2,3-dinitrophenoxy) -2-hydroxy-3-tert-butylaminopropane, m.p. 124-25 ° C.

d) A suspension of 0.5 g of Raney nickel in 20 ml of ethanol is heated with stirring to an internal temperature of 65-70 ° C. A solution of 2.3 g of 1- (2,3-dinitrophenoxy) -2-hydroxy-3-tert-butylaminopropane in 40 ml of tetrahydrofuran and a solution of 3.6 ml of hydrazine hydrate in 40 ml of ethanol are simultaneously added dropwise from two dropping funnels. The mixture is stirred at 65-70 ° C for 2 hours, the catalyst is filtered off, the filtrate is evaporated under reduced pressure, the residue is dissolved in diethyl ether, charcoal is added to the ether solution and the mixture is filtered. After concentration of the filtrate, 1- (2,3-diaminophenoxy) -2-hydroxy-3-tert-butylaminopropane is obtained after the addition of petroleum ether, m.p. 73-75 ° C.

Example 4

The following compounds were prepared in an analogous manner to that described in Examples 1 to 3 using the corresponding starting materials:

a) 8- (tert-Butylamino-2-hydroxypropyloxy) -2,3-dihydro- (4H) -benz [5,6] oxazin-3-one in the form of the hydrochloride, m.p. 82-83 ° C;

b) 7- (3-tert-butylamino-2-hydroxypropyloxy) -4H-1,3-benzoxazin-2 (1H) -one in the form of the hydrochloride, m.p. 243-244 ° C;

c) 4- (3-tert-butylamino-2-hydroxypropyloxy) -3-n-butylbenzimidazol-2-one in the form of the hydrochloride, m.p. 226-227 ° C;

d) 4- (3-isopropylamino-2-hydroxypropyloxy) benzimidazol-2-one in the form of the hydrochloride, m.p. 23-232 ° C;

e) 4- (tert-Butylamino-2-hydroxypropyloxy) -3-methylbenzimidazol-2-one in the form of the hydrochloride, m.p. 246 DEG-248 DEG C. (dec.);

f) 4- (3- (1-phenylpropyl-2-amino) -2-hydroxypropyloxy) benzimidazol-2-one in the form of a fumarate (1: 1), m.p. 186-188 ° C;

g) 4- (3- (2- (3,4-dimethoxyphenyl / ethylamino) -2-hydroxypropyloxy) benzimidazol-2-one in the form of the hydrochloride, m.p. 230-232 ° C;

h) 4- (3- (2- (3,4-methylenedioxyphenyl / ethylamino) -2-hydroxypropyloxy) benzimidazol-2-one in the form of the hydrochloride, m.p. 249-251 ° C, compound south at 243 ° C;

i) 7- (3-tert-butylamino-2-hydroxypropyloxy) -2 (3H) -benzoxazolone as its hydrochloride, m.p. 221-224 ° C;

β

k) 5- (3-Isopropylamino-2-hydroxypropyloxy) -1,2,3,4-tetrahydro-2,3-dioxoquinoxazoline as hydrochloride, m.p. 290-294 ° C (dec.).

Claims (8)

CLAIMS 1. A process for the preparation of ether-flocked hydroxybenzodiheterocyclic compounds of the general formula (1) in which: EMI2.0 [0016] OH fy-NH-CH _{2 -} <L-CH ₂ -O (I) R ₁ represents a C 3 -C 5 alkyl group optionally branched on the carbon atom to which it is bound, optionally in the phenyl moiety of 1 to 3 C 1 -C 7 alkoxy or a 3 to 5 phenylalkyl substituted methylenedioxy group carbon atoms in the alkyl moiety and alkyl R ₂ represents one of the groups -NH-, -O-GHg-, -GHg -O-, -R- having up to 7 carbon atoms-CH₂-NH-, -CO-NH-, -0- or -NH- CO- or a salt thereof, characterized in that in a compound of formula II wherein one of X and Xg is alkoxycarbonyl of up to 7 carbon atoms in the alkoxy moiety, aminocarbonyl or halocarbonyl group, and the other of hydrogen, or in a salt of such a compound, cleaves the X and X ₂ residues by cyclization condensation to form a carbonyl group, whereupon the optionally obtained free compound is converted into a salt or the resulting salt is converted into a free compound and / or the obtained racemate is resolved into optical antipodes . 2. The process of claim 1, wherein the reaction is carried out in the presence of a basic condensing agent and in the presence of a solvent. Process according to one of Claims 1 to 2, characterized in that the reaction is carried out in the presence of a metal alkoxide in a lower alkanol. Fourth pressurized feed vessels according to claim 1, wherein the compound of formula 11 wherein one of the radicals Xi and Xg represents a chlorocarbonyl group and the other is hydrogen, and R, and R ₂ have the above meanings, is subjected to condensation in cykllzační concentrated acid hydrochloric acid. Process according to one of Claims 1 to 4, characterized in that the compound of the formula (IX) in which R 1 represents a C 3 -C 4 alkyl group or in the phenyl part, optionally 1 to 3 methoxy or phenylalkyl substituted methylenedioxy groups C 1 -C 3 alkyl; and alkyl R 2 is one of the groups -NH-, -O-CH _{2 -} , -CH ₂ -O-, -N- with up to 4 carbon atoms, -CH 2 -NH-, -CO-NH-, -O- or -NH- CO- and X1 and X2 are as defined above, or a salt of this compound undergoes cyclization condensation to form a carbonyl group. 6. A process according to any one of Claims 1 to 4 wherein the compound of formula (II) wherein R @ 1 is isopropyl, tert-butyl, 1-phenyl-2-propyl, 2- (3,4 -dimethoxyphenylDiethyl or 2- (3,4-methylenedioxyphenyl) ethyl; and R ₂ represents one of the groups -NH-, -O-CH ₂ -, f ^H 3? ^H -i-, -Ah ₂ -ch ₂ -ch ₂ CH, -CO-NH-, -O- or -NH-CO-, or a salt of this compound, undergoes cyclization condensation to form a carbonyl group. 7. A process according to any one of claims 1 to 4, wherein 1- (2-amino-3-chlorocarbonylaminophenoxy) -2-hydroxy-3-tert-butylaminopropane is subjected to cyclization condensation to form a carbonyl group. 8. A process according to any one of claims 1 to 7, wherein the compound of formula I is converted to a pharmaceutically acceptable non-toxic acid addition salt.