CS236679B2 - Manufacturing process of new benzoheterocyclic compounds - Google Patents

Abstract

Compounds of the formula <IMAGE> (A represents a single bond, -CH2-CH2-or <IMAGE> R4 represents hydrogen or alkyl, and R5 represents hydrogen or alkyl or, when R4 represents hydrogen, phenyl; R1 represents hydroxy, acyloxy, chlorine or hydrogen; R2 represents hydrogen, methyl or ethyl; R3 represents <IMAGE> m represents 2, 3 or 4, n represents 1,2, or 3, R6-8 represent hydrogen or methyl, R9 represents hydrogen, Ar, OAr, or -NH-CO-Ar <IMAGE> R10, R11, R12 are hydrogen, hydroxy, methyl, methoxy, halogen, -CONH2 or NH-R13, R13 is hydrogen, acyl or alkylsulfonyl, or any two of R10, R11, and R12 represent methylenedioxy), their acid addition salts, and corresponding compounds in which the CHOH group is replaced by CO (phenolic groups may be protected) are suitable for treating asthma, bronchitis, hay fever, cardiovascular disorders, for relaxation of the muscles of the uterus, and for improving flesh production and fodder utilisation in animals.

Description

(54) A method for producing novel benzoheterocyclic compounds

The present invention relates to a process for the production of novel benzoheterocyclic compounds having valuable pharmacological properties and which can be used as active ingredients of medicaments.

The novel compounds correspond to the general formula I

in which

A represents a single bond, R 5

- - / ·· · -.

= C \

Ri or —СНг — CH2—,

R 1 represents hydroxy, chlorine or hydrogen,

R2 is hydrogen, methyl or ethyl,

R 3 is a group of formula II or III

238679 'lili

»3 m stands for 2, 3 or 4, n stands for 1, 2 or 3, • R <stands for hydrogen or methyl,

R 5 is hydrogen, methyl, and in addition, when R 1 is hydrogen, also phenyl,

Re is hydrogen or methyl,

R 7 is hydrogen or methyl,

Re is hydrogen or methyl,

R 9 is hydrogen, Ar, -OAa, -NH-CO-Ar, wherein A is a group of formula or R 10

W (iv) wherein

R 10, R 11 and R 12, which may be the same or different, represent hydrogen, hydroxy, methyl, methoxy, halogen, methylenedioxy, -NH-R 13 or-CONH 2,

R 13 is hydrogen, СООН, or SG SG 2 CH 3.

Said compounds may exist in the form of racemates, enantiomers and, optionally, diastereomeric pairs of antipodes in the form of free bases or in the form of acid addition salts.

For the purposes of this invention, "halogen" means fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

». .

In a preferred embodiment of the invention, the general symbols in formula I have the following meanings:

A represents a single bond, = CH 2, = СН (СНз), = С (СНз) 2 or = СН (СгН5),

R 1 represents a hydroxy group at the m- or β-position to the side chain,

R2 is hydrogen, methyl or ethyl,

R3 represents the above radicals of formula II and III, m represents 2 or 3, n represents 1, 2 or 3,

R6, R7 and R6 are hydrogen or methyl,

R 9 is hydrogen, Ar, NH-CO-Ar,

Ar represents a radical of formula IV, a 2-pyridyl group or a 4-pyridyl group,

R10 represents hydrogen, hydroxy, methyl and, together with R11, methylenedioxy,

R11 represents hydrogen, hydroxy, methyl and, together with R10, methylenedioxy,

R12 is hydrogen,

R13 is acetyl or methanesulfonyl.

Particularly preferred are those compounds in which

A represents the group = С (СНз) г or · —CH2—,

R 1 represents a hydroxy group in the p- or m-position to the side chain,

R2 is hydrogen, methyl or ethyl,

R3 is isopropyl, tert-butyl, cyclopentyl, 1-methylcyclopentyl or the radical of formula III, n is 1 or 2,

R7 and R6 are hydrogen or methyl,

R 9 represents a phenyl group, a 4-hydroxyphenyl group, a 2-pyridyl group, a 4-pyridyl group or a 2-hydroxyphenyl group, a group of the formula

CH ₃

According to the invention, the novel compounds of the formula I are prepared by reducing the compounds of the formula V (V 1

238679 • - 5 in which

A, R 1 and R 2 are as defined above, but phenolic OH groups are optionally present, also in the form protected by a hydroigenolytically cleavable group,

R &^lt; 3 &gt; has the meaning of R &lt; 3 &gt;, but the OH group optionally present in R &lt; 3 &gt; is optionally protected by a hydrogenolytically cleavable group,

R 'is hydrogen or a hydrogenolytically cleavable protecting group, and optionally the protecting groups still present are cleaved, whereupon the optionally obtained compounds are separated into enantiomers, optionally into diastereomeric pairs, antipodes, or the obtained bases are converted into acid addition salts or the addition salts obtained the acid salts are optionally converted into bases or salts with other acids.

The reduction is carried out in a solvent which is sufficiently stable under the reaction conditions, such as in a lower alcohol such as ethanol. Hydrogen and hydrogenation catalysts (such as palladium, platinum, Raney nickel) or hydrides (such as sodium borohydride or diborane) are used as reducing agents. By the suitable choice of a reducing agent (catalytic reduction or reduction by hydrides), the formation of predominantly erythro-form or threo form can be achieved.

Hydrogenolytically cleavable protecting groups which are optionally present on the central amino group or on the phenolic hydroxyl group, for example benzyl or substituted benzyl, are removed in the usual manner during or after the reduction.

The novel compounds of formula (V) which serve as starting materials can be prepared by methods known per se, for example as shown in the following reaction scheme:

lion (Viti

Bz = benzyl P11 = phenyl

The corresponding bromo-ketones with an (protected) OH group in the m-position to the side chain can be obtained as follows:

& 'O (vin) PO

Thus, or according to other methods, the bromoketones of general formula X obtained

A, R1 and R2 are as defined above, but the phenolic-OH groups may be present in the form protected by hydrogenolytically cleavable groups, such as the benzyl group, are reacted with amines of formula XI

R *

AND

HN — R3 němž in which

R 3 ‘is as defined above and

R‘ represents hydrogen or a hydrogenolytically cleavable residue, such as a benzyl residue or a substituted benzyl residue.

This reaction is carried out in suitable solvents, for example acetonitrile, ethyl acetate, in the presence of an acid binder such as sodium carbonate or an amine in excess. Protecting groups present in the reaction. The product is then or, if appropriate, subsequently removed.

If appropriate, the compounds obtained according to the invention are separated according to conventional methods into enantiomers, optionally also into diastereomeric fifth antipodes, and the bases initially obtained are optionally converted into acid addition salts, or the initially obtained acid addition salts are optionally converted into bases or salts with other acids.

The compounds produced according to the invention are useful as pharmaceuticals. These compounds have, inter alia, broncholytic, spasmolytic (XI) polyvinylpyrrolidone 6 mg sodium cellulose glycolate 4 mg magnesium stearate 2 mg and an antiallergic effect and increase ciliary activity and reduce inflammatory-exudative reactions. They are therefore applicable to all forms of asthma and bronchitis, in urticaria, urticaria, conjunctivitis, hay fever and colds. Furthermore, they are suitable as uterine muscle relaxants to prevent prenatal problems. These compounds can also be used to treat cardiovascular disorders such as high blood pressure, peripheral vascular disease and arrhythmias. The following effects were observed: inhibition of gastric juice secretion and central nervous system antidepressant effects.

The therapeutic and prophylactic dose depends on the nature and severity of the disease state and the mode of administration.

For adult patients, the following daily doses may be considered for the following indications:

As broncholytics, doses of 0.05 to 5 mg, inhaled 0.01 to 1.0 mg and subcutaneous 0.02 to 0.5 mg are administered orally.

Doses of 10 to 50 mg orally or ampoules of 10 ml solution containing 0.1 to 1 mg are administered as uterine muscle relaxants.

10-100 mg ampoules for intramuscular injection of 20-40 mg are used for oral vascular expansion.

Doses of 200 mg to 1.8 g are used as oral blood pressure lowering agents.

The pharmaceutical preparations contain the active ingredients, pharmaceutically acceptable carriers and optionally other therapeutic ingredients.

Thus, broncholyitis is combined with theophylins, parasympatholytics (e.g. ipratropimbromidero], secrolytics (e.g. bromhexin), muscotropic spasmolytics (e.g. papaverine), corticosteroids and antiallergics. For uterine muscle relaxants, combination with corticoids is possible.

Capsules, tablets, solutions and suspensions are suitable for oral administration. For pulmonary application, preferably dry powders with a particle diameter of 0.5 to 7 μα are used, which are applied to the bronchial area by means of propellants.

Parenteral administration is conveniently carried out in the form of sterile isotonic aqueous solutions.

Lotions, creams, ointments, emulsions and sprays are used for topical application.

Example illustrating the composition of preparations:

Tablets:

Composition for one tablet: active ingredient according to the invention colloidal silicic acid lactose potato starch mg mg

118 mg me

220 mg

Ampoule: Solution composition for 1 ampoule active ingredient according to the invention 10 mg sorbitol 40 mg distilled water to 10 ml Suppositories: Composition for 1 suppository: active ingredient according to the invention 100 mig matrix for preparation suppositories (cocoa butter) 1600 mg 1700 mg

Inhalation powder:

0.5 mg of the active ingredient according to the invention and 19.5 mg of lactose having a particle diameter of between 0.5 and 7 μτη are filled into one hard-filled, gelatin capsule.

For pharmacological experiments, conventional tests and experimental animals or organs are used. What? The compounds of the present invention, to the pharmacological effects, differ greatly from the products of the same indication on the market. In addition to good duration of action, for example, there is a particularly pronounced selectivity in comparison to broncholysis for increasing heart rate. For example, for a compound of Example 1 in guinea pigs, the ED50 i. V. [.Mu.g / kg] is an increase in heart rate more than ten times higher than the ED50 i. V. [.Mu.g / kg] broncholysis, which is only 0.045 pg / k-g. Resorption ratios are generally also favorable. This is what the resorption quotient does

EDso p. EDso i. V.

for example; Compound 7 of Table III only 1.1, so that the effect when administered orally is practically the same as when administered intravenously. LD 50 values, for example, for a mouse, exceed the therapeutic dose so that there is a favorable therapeutic breadth.

The following examples are intended to illustrate the present invention in more detail without limiting it in any way, since the reaction conditions may vary considerably when a similar result is obtained.

Depending on the solvent from which the following substances crystallize, these substances partly still contain the crystalline substances, these substances partly contain a defined amount of the solvent which is bound in the crystal. The melting points indicated are not corrected.

Example 1 ^ СН ^ СНз

CH-X-Q-Ho HCtx ^x _H NHCH (CH _{3) 2}

16.1 g of 5'-benzylO'Xy-8 '- (1-O'XO-2-bromobutyl) -2H-1,4-benzoxazin-3- (4H) -one and 7.5 g of isopropylamine are stirred in 100 ml of acetonitrile at 60 ° C for 4 hours. After acidification with concentrated hydrochloric acid and - after addition to 100 ml of water, 5'-benzyloxy-8'1 (1-oxo-4-isopropylaminobutyl) -1H-benzoxazine-4 (4H) -one hydrochloride crystallizes, m.p. 229-232 ° C. .

g of this compound is debenzylated in methanol with the addition of palladium on carbon catalyst to give 5'-hydroxy-8 '- (1-oxo-2-isopropyl-1-aminobutyl) -2H-1,4-benzoxazin-3- (4H) 242 DEG-245 DEG C. 1-Hydrochloride 1-hydrate.

Hydrogenation of 3.3 g of this compound in methanol using platinum as the catalyst afforded 3 g of erythro-5-hydroxy-4- (1-hydroxyl-2-isopropylaminobutyl) -2H11,4-benzoxazine-5-1H-on-hydrochloride hydrate ( 90% yield, melting at 208-210 ° C.

Example 1a

HIM

OH

32.4 g of 5‘-benzyloxy-8 ‘- (1-oxo-2-bromobutyl) -2H-11,4-benzoxazin-13- (4H) -one and 72 g of benzylisopropylamine are stirred at 100 ° C for 15 hours. After addition of water, the precipitated oil was taken up in ether and diluted with petroleum ether. Crystallize 5‘-benzyioxy-8 *) (l)

-oxo-2-benzylisopropylaminobutyl) -2H-1,4-benzoxazin-13 (4H) -one.

To 11.6 g of this compound in a mixture of 60 ml of ethanol and 60 ml of acetonitrile was added 1 g of sodium borohydride and the reaction mixture was stirred for 3 hours. 250 ml of ice water and 100 ml of ethyl acetate are then added, after decomposition of sodium borohydride with concentrated acetic acid with stirring, the reaction mixture is made alkaline by addition of concentrated ammonia solution, the ethyl acetate phase is separated, dried and concentrated on a rotary evaporator. The oily residue was dissolved in ether, cooled and the precipitated ^{threo-5'-benzyloxy-1} - (L-2-hydroxy) butyl-amino benzylisopropylamil L2H L-l, 4) benzoxazin-3- (4H) -one of melting mp 89-92 ° C.

4.8 g of this compound are hydrogenated in 100 ml of methanol in the presence of palladium on carbon catalyst. After the hydrogen uptake is complete, the catalyst is filtered off, the mother liquor is concentrated on a rotary evaporator, the oily residue is dissolved in a mixture of acetone and ethanol and the solution is acidified with the calculated amount of hydrochloric acid. The solution was diluted with ether and the precipitated ^{threo-5'-hydroxy-1} - (l-hydroxy-2-isopropylaminobutyl) - -. -2H-1,4-benzoxazine-3- (4H) -one hydrochloride (74% yield) was filtered off. After recrystallization from methanol / ether, the product melts at 202-205 ° C.

Example 2

^ 3

CH-CH 2 NH-C-CH- X HCt II ³

OH CH ₃ g of 5'-benzyloxy-8 '- (1-oxo) 2-bromoethyl) -1H-1,4-benzoxazin-3- (4H) -one and 8.75 g of benzyl-tert-butylamine are boiled in 100 ml of acetonitrile under reflux for 3 hours. After cooling, the precipitated crystals are filtered off and washed with 200 ml of warm water. The crystals were acidified in acetonitrile with ethereal hydrogen chloride. After dilution with ethyl acetate, 5'-benzyloxy-8'1 (1-oxo-4-benzyl-tert-butylaminoethyl) -2H-1,4-benzoxazine-3I precipitates.

- (4H) -one-hydrochloride having an ice temperature of 185 to 185 ° C

189 ° C. .

g of this compound is debenzylated in 100 ml of methanol at 0.5 MPa at 50 DEG C. with the addition of palladium on carbon catalyst to give 5'-hydroxy-8 '- (1-oxo-2-tert-butylaminoethyl) 237 DEG-240 DEG C. -2H-1,4-benzoxazin-3- (4H) -one hydrochloride.

Catalytic hydrogenation of 2.2 g of this compound in methanol in the presence of platinum gives 1.6 g of 5‘-hydroxy-8 8- (1-hydroxy-2-tert-butylamino) -2H-1,4-benzoxazine. -3- (4H) -one hydrochloride (yield; 72.5% of theory) melting at 185-187 ° C.

The compounds listed in Table I are synthesized accordingly:

Number

TABLE I

Formula

Yield Salt s Melting point% theory ° C

4-NH-C (CH ₃ I ₃

CH ₃ CH ₃ inh-ch (ch ₃ ) ₂

CM _Z CH ₃

NH-CH 2 Cl 2

HCl x 2 HZO 230 (decomposition)

HCl x H2O 163-165

HCl 259-261

HCl 230-232

HCl x H2O 256-259

^ C ^ CH CH _{3 0H-CM} ^l NH-CH _{(CH3} 3} OH

H 'ch ₃

Ηθ-θ-CH-CH-NHCH (CH) _from

OH;

244

HCl x x 1/2 H2O

238679

Number

Formula

Yield Salt with ° / teorie theory

Melting point ° C

73.5

HCl x x 1/2 H 2 O

243 to 245

HCl

HCl

206 to 209

170-173 _ctt _t -NH-C _H = _CH-S 0 O

OH WNH _Z

IN

HN O

HC3SO3H x X H2O

197 let 201 «OA //

CH3SO3H

187 to 190

OH

208 to 211

_NH-C-CH3

OH

HCl

155 to 159

HNO

H О- У ^ CH-C H CHgNH -С- ^^ - _S NH ATI _'CH3

Number

Formula

Yield Salt s Melting point% theory ° C

HCl

CH 3 SO 3 H x x H 2 O

234 to 236 to 94

HCl

CH 3 SO 5 H X x H 2 O

234 to 236 to 94

The following compounds are also prepared in an analogous manner:

-2-methylbutylamino) ethyl] -2H-1,4-benzoxazta-3- (4H) -one hydrochloride

Example 3

5'-Hydroxy-8‘- [1-hydroxy-2- (4-phenyl-

M.p. 159-161 ° C.

HCt

Example 4

6‘-chloro-8‘- [1-hydroxy-2- (tert-butylamino) ethyl] -2H-1,4-benzoxazin-3- (4H) -one hydrochloride;

CH ₃ CH-CH-NH-C-CHn X on I ² I ^- OH CH ₃

The hydrochloride melts above 300

Melting point 173-177 ° C.

The compounds listed in Table II are also prepared in an analogous manner:

TABLE II

Number

Formula

Salt with

Melting point ° C

HCl

HCl

252 to 255

185 to 187

HCl x C2H5OH

205 to 208

OH.

HCl x 1/2 HzO

155 to 160 o

X _HN o _H0 -QOH o i

7¾

CH _Z

HCl

226 to 229

Formula

GH

Salt with

HCl

HCl x 1 acetonitrile

HC1 x СНзОН

HCOOH x H2O

CH3SO3H

Number

Melting point

206-209 fuzzy (195 ° C (decomposition)

130 to 133

120 to 124

192 to 195

HCl

205 to 208

CONH2.

Example 5

ОН

CH-CH 2 NHC ₂ H _with x HCl о

4.3 g of 5‘-benzyloxy-8‘- (1-hydroxy-2-benzylethylaminoethyl) -2H-1,4-benzoxazine-3- (4H)

The hydrochloride (m.p. 232 DEG-235 DEG C.) was hydrogenated in 125 ml of methanol with the addition of 0.5 g of 5% palladium on carbon. After the calculated amount of hydrogen had been consumed, the catalyst was filtered off and the solution was distilled off under reduced pressure. Trituration of the residue with acetonitrile gave 2.5 g of 5'-hydroxy-8'- (1-hydroxy-2-ethylaminoethyl) -2H-1,4-benzoxazin-3- (4H) -one hydrochloride (yield: 86.7% of theory) which melts after recrystallization from methanol / ether at 240-242 ° C.

Example 6

6.3 g of 4'-benzyloxy-7 '- [1-hydroxy-2- (4-picolinamido-2-methyl-2-butylamino) ethyl) -2-benzoxazoline (m.p. 130-133 ° C) were added and the resulting mixture was stirred at room temperature for 2 hours. hydrogenated in 125 ml of methanol with the addition of 1 g of 5% palladium on carbon. After the hydrogen uptake is complete, the catalyst is filtered off and the clear solution is evaporated on a rotary evaporator under reduced pressure. The oily residue is dissolved in 10 ml of alcohol and 0.58 g of formic acid is added to the obtained solution. After 5 hours, the precipitated 4'-hydroxy-7 '- [1-hydroxy-2- (4-picolinamido-2-methyl-2-butylamino) -2-benzoxazolinone] formate (• yield: 78.5 °) 166 DEG-168 DEG C.).

Accordingly, the following compounds were synthesized as described in the above examples:

Number Formula

TABLE III

Yield Melting point% theory Salt with AC

HCl x 205 to 208 x C2H5OH

HCl x 246 to 247 x C2H5OH

HCl x 120 to 123 x C2H5OH formic 189 to 192 acid x x H2O

OH

HCl 226-229

78.5 HCl 206-209

2366 79

Number

Formula

Yield% of theory

Salt

Melting point ° C

HCl 174-175

HCl x 155 to 160 x 1/2 H2O

1/2 fumaric 175 to 178 acids (170 to 173 bases)

HCl 143-146

HCl x fuzzy x 1 aceto- 195 nltril (decomposition)

CH 3 SO 3 H x 252 to 254 x IH 2 O

CH 3 SO 3 H x 178 to 180 x 1/2 H 2 O

Yield Salt with% theory

Formula

O

HCl x 159 to 162 x 1.5 H2O

OH

NH-SO _Z CH ₃ other

The melting point ° C of the intermediate is indicated

These compounds can also be used as medicaments themselves, since they have similar pharmacological properties to the end products of formula I.

in formula V, which can be obtained correspondingly according to the scheme outlined above.

TABLE IV

Salt with

Formula

Melting point, ° C

HIM

L <5> C-CH II

C-CH-N ^{H 'CH} (C ^H 3 R 2

I ^NH - ^C H ^{(CH 3)}

HC1 x. x 2 H2O

HCl

HCl

240 to 242

218 to 222

250 to 254

HIM

C-CH

OH O

HCl

HCl

HCl

HCl

250 to 253

217 to 223

156 to 161

243 to 247

2'3 6'9'79 «3

Formula

Salt with

Melting point ° C

ЭД

HCl 254-258

HC1 250

Claims (2)

I will invent the object A process for the preparation of novel benzohetero-cyclic compounds of the general formula I wherein: A represents a single bond, a group or a group --NG - CH2 -, R 1 represents hydroxy, chlorine or hydrogen, R2 is hydrogen, methyl or ethyl, R 3 is a group of formula II or III C HfTiCHzJfn ----— frebo I * 6 -C- (Cty _and -R ₉ ^R & (III) m is 2, 3 or 4, n is 1, 2 or 3, R4 represents a hydrogen atom, a methyl group, R 5 represents a hydrogen atom, a methyl group, and in addition, when R 4 represents a hydrogen atom, it also represents a phenyl group, Re is hydrogen or methyl, R 7 is hydrogen or methyl, Re is hydrogen or methyl, R 9 is hydrogen, Ar, -OAr, -NH-CO-Ar, Ar represents a group or (/ V) 236879 R 10, R 11 and R 12 may be the same or different from each other and are hydrogen, hydroxy, methyl, methoxy, halogen, methylenedioxy, -NH-R 13, or - CONH 2, R13 is hydrogen, -COCH3 or -SO2CH3, in the form of racemates, enantiomers and, optionally, diastereomeric pairs of antipodes, in each case in the form of free bases or in the form of acid addition salts, characterized in that the compound of formula V A, R1 and R2 have the meanings given above, however, the phenolic OH groups are optionally present in the form protected by a hydrogenolytically cleavable group, R 3 ‘has the meaning of R 3, but wherein the hydroxyl group is. optionally present in the residue R 3, is optionally protected by a hydrogenolytically cleavable group, and R 'represents hydrogen or a hydrogenolytically cleavable protecting group, is reduced and, if appropriate, the protecting groups still present are cleaved, whereupon any compounds obtained are separated into enantiomers or diastereomeric pairs of antipodes, or the obtained bases are converted into acid addition salts or obtained acid addition salts are optionally converted into bases or salts with other acids. 2. A process according to claim 1, wherein the corresponding compound of formula V is used as the starting material to give 5'-hydroxy-8'- (1-hydroxy-2-isopropylaminobutyl) -2H-1,4-benzoxazine- 3- (4H) -one and its salts.