CS222697B2 - Method of preparation of the new indoline derivatives - Google Patents

Description

(54) A process for preparing novel indolizine derivatives

Process for the preparation of the novel indolizino derivatives of the general formula (I)

wherein R, X, A, R. and n are as defined in item 1, and suitable acid addition salts thereof.

The process according to the invention consists in reacting a derivative of the general formula (II), wherein the general formula (II) and the meaning of the individual substituents are given in (1), with a halogenating agent selected from succinic acid N-chloroimide, iodine. and bromine. Using N-chloro succinic acid, the reaction is carried out at a temperature of from 0 ° C to room temperature. When iodine or bromine is ingested. the reaction is carried out in the presence of an alkali metal acetate. The free base of the indoline derivative thus obtained. of Formula I is optionally reacted with an organic or inorganic acid to form a pharmaceutically acceptable acid addition salt.

The compounds of formula I prepared are effective in the treatment of pathological syndromes of the heart and in particular angina and cardiac arrhythmias.

The invention relates to a process for the preparation of heterocyclic compounds, in particular to a process for the preparation of novel indolizine derivatives.

The indolizbium compounds are prepared according to the invention. derivatives of formula I

(X) and pharmaceutically acceptable acid addition salts thereof, such as, for example, cachel or hydrohalide, wherein:

R represents a branched or linear alkyl group having from 1 'to 8 carbon uh.íku, or phenyl, _{monnfluorfenylovou,>} monnlhholfenyllvou, monobronďfnyyovou, monnmethhyfenylovou or mblOllethhbyУenylovou group dilUmг оУ ^ ^ и, dihhllrfθnylfvlu, dibromophenyl group or iethylfenyllvou group substituted on the aromatic ring fluorine, chlorine or bromine, means chlorine, bromine, iodine,

A represents a group

wherein ^X 8 ^X 3 ' ¹ⁿ means means bromine, chlorine, bromine, chlorine, methyl, integers from 2 to 6 inclusive.

an iodine, methyl or methorium group, and an iodine or methyl group, ethyl group, o-propine or o-butyl group,

The iodolizone derivatives prepared by the process according to the invention have advantageous pharmacological properties which can be used in the treatment of certain pathological heart syndromes, in particular in the treatment of angina pectoris and auricular and ventricular cardiac arrhythmias of various origins

A detailed description of the collagen active efficacy and use of the compounds prepared by the process of the invention is given in the basic patent specification No. 222692.

The compounds of formula (I) are prepared by the method of the invention by reacting an indole compound of formula (II)

R

CAO- (CH ₂ ) _n -hT

O ^R 1 ^R 1 (IX) wherein A, R, R, is as defined for Formula I, with a halogenating agent selected from the group consisting of succinic acid N-chloroimide, iodine and bromine. Ex pouHtí chllrimidu N-succinic acid, the reaction is conducted in a suitable prostředd as Ыи ^? E and ^t and te ^ rpm at 0 °, ^and the temperature showing a section ^P s ^ i. When ^{p u} ou APPLICATION Joto ^b ROM or the reaction is performed at a temperature ηο ^^ ^ Ι · rozpouutčdle in an appropriate such as dioxan and in the presence of acetate alkaltokého metal, e.g. přítomnooto tfiného acetate. The free base of the oleillisin derivative of formula (I) thus obtained is optionally reacted with an organic or inorganic acid to form a pharmaceutically acceptable acid addition salt.

Compounds of formula (II) may be obtained either by condensation, which is preferably carried out in an inert solvent such as benzene or toluene, bromo-alkoxybenzzoliodolizine of the formula:

(III) wherein R, A and n are as defined for Formula I, with a secondary amine of Formula IV

(IV) wherein R ^ is as defined for formula I, or by condensation and preferably in an aprotic solvent such as acetone, methyl ethyl ketone or toluene, an alkali metal salt, preferably a potassium or sodium salt of a suitably substituted indolizine derivative of formula V

(V) wherein R and A are as defined for Formula I, with an alkylamine derivative of Formula VI

Z- ( ^CH 2) _n -N

(VI) or an acid addition salt thereof, wherein Z is a halogen atom such as chlorine or bromine or a p-toluenesulfonyloxy group and n and are as defined for formula (I).

Compounds of formula III may be prepared by condensation in an inert medium such as acetone or methyl ethyl ketone, alkali metal salts, preferably the potassium or sodium salt of a compound of formula V with a dibromoalkane of formula VII

Br- _{(CH2) n} -Br (VII) wherein n has the same meaning as defined for formula I.

Compounds of formula V wherein A is R ₂ are either compounds described in British Patent Specification No. 2051812 A or compounds that can be prepared according to the methods described in said patent specification.

Other compounds of formula V, i.e. compounds wherein A is Rp, may be obtained by reacting the corresponding 2-substituted indolizine with 2,3-dichloro-4-acetyloxy or 4-totyloxybenzoyl chloride. This benzoyl chloride derivative can itself be prepared by acetylation of 1,2-dichloroanisole under Friedel-Crafts conditions, oxidation of the acetyl derivative thus obtained with sodium hypochlorite to form the corresponding benzoic acid derivative and demethylation with hydroiodic acid to give 2,3-dichloro. -4-hydroxybenzoic acid. 2,3-Dichloro-4-hydroxybenzoic acid is then reacted with acetyl chloride or tosyl chloride to form the desired 2,3-dichloro-4-acetyloxy- or 4-toeyloxybenzoic acid and the corresponding acid chloride is subsequently formed in a manner known per se, for example by reaction with thionyl chloride.

A method according to the invention illustrating the following examples:

Example 1

1-Bromo-2-ethyl-3- [4- (3-di-n-propylminopropyl) oxy-3,5-dichlorobenzoyl} indolizine addition salt with tartaric acid.

2.8 g (0.005 mol) of 2-ethyl-3-Q- (3-di'-n-polyminopropp) oxy-3,5-dichlorobenzyl] indolizine-2-ethyl-3,5-dichloro-2-ethyl-2-ethyl-3,5-dichloro-indolizine are added to a 250 milliliter flask. 80 milliliters of dloxin. The reaction mixture was stirred after dissolution of the indolizine and 0.8 g of anhydrous sodium acetate was added. Using a dropping funnel, a solution of 0.8 grams of bromine in 20 ml of dioxin is added dropwise from the vigorous drawing. A temperature of 20 ° C was maintained during the introduction of the bromine solution.

The medium is stirred at room temperature for 2 hours and then the dioxin is distilled off in a rotary evaporator. The solid residue was dissolved in water, made alkaline with sodium hydroxide solution and extracted with chloroform. The chloroform solution was washed three times with water and the chloroform was distilled off from reduced pressure. The oily residue obtained in this manner is dissolved in dry ethyl ether, and after filtering on a filter, the addition salt with plumic acid is formed. By this procedure, after recrystallization from ethyl acetate, 1.8 grams of the addition salt of 1-bromo-2- [eta] < 3 > -3- [] 4- (3-di-n-propylminopropyl) o, 1,5-eichlorobenzoyl is obtained. ) indolizine with oxalic acid.

Yield: 55.8%, m.p. 135 ° C

In the same manner, the following compounds are prepared using suitable starting materials;

Compounds

1-chloro-2-ethyl-3- [4- (3-i-i-propyliminiminopropyl) oxyl-3,5-eichlorobenzoyl] -indolizine acid Štivelin

1-Chloro-2-ethyl-3-C4- (3-el-1-butyl) -inoliorroyl-oxo-1,5-eichlorobenzyl-11-indolizine

1-Chloro-2-phenyl-3-04-O-di-n-piopropyliminopropyl taxy-3,5-dichlo-benzol-indolizine acid Štivelin

Acidic štivelin-1 -chloro-2-fluoro-enyy -] 4- (3-di-n-butylilíini) OPooylLoэχ-3,5-eichllrbeniOllLiidelizirш Yssel ^{K W} tivelin of ⁰ ^ 1 ^ -2 1-3-0 ⁴ O - (-) - n-propyl (R) - (R) -3,5-dibro-benzoyl indolizine

Acidic štivelin-1-ohhoor2 eShh1lЗ- [Ϊ4 "(3-ei-i-butyllImilipropyl) lX1-3 _l 5ddbrloπlbsnzlyl7 indolizine

1-Hydroxy-2-phenyl-3- [4- (3-el-n-propylpiperidinyl) ollyl-3,5-di bromobenzool] indolizine acid

1-chloro-2-phenyl-3 - [[4- (4-di-n-shonylopropyl ⁾ acid tartrate ^]] . ^χ ^ - ^3,5 - ^d and ^b roíbeeiZ ^l1l in ^the nisin ^and d

Acidic štivelin bгom-one-2-míthyh1l-34- (n-Ззde buUyliminópropyltaxy- ^{3, 5} - ^d Ibrom benzoylj intolizinu

1-Brlm-2-n-prooyl-1-zz [44O-di-n-propyliminopropyl) oxy-3,5-dibro-benzoyl indolizine acid

Tivelin acidic ^with a ¹ - ^{b h ROM-s} -θth 1133f4 (3-d ^{e b} utyliminipropy -n i): IXI-3,5-1 dibrombenzoy indoH zine

1-Chloro- ⁴ -enyl-3-0 ^4- (3-di-n-butyliminopropyl-taxy-3,5-dibro-benzoyl) -indolizine acid Štivelin

Acidic štivelin 1-Bromo-l- (4-mmteyhfefel) -3-0 - (3-di-n-butylmllnlpropyl) o xy-3,5-dibroíbenzoyl] indole from ^{N ins} Yssel tive ^L ^ .in toom ^{- 2} - ^ - ^b ro ^m * e ^L1) -3-0 ^{4- (3- i} i-1 tax totylamino-dipropyl-l ^^ ibombenzoyl] · tatolteinu

Melting point (° C)

141 (ethyl acetate)

129 (ethyl acetate)

156 (isopropinol)

136 (iioprop inolhepine)

157 (isopropno)

140 (isopropinol)

172 (izlprlpllno)

146 (from prop)

141 to 143 (isopropinol)

138 to 139 (isopropyl) l) 131 to 132.5 (petroleum)

160 to 161 (isopropnol)

105 to 106 (isopropnol)

148 to 149 (isopropinol)

Compound Melting point (° C) Acid oxalate 1-1οο - 2 - (- ^ - dichloroenol) -3- ^ 4- - (3-di-o-butylaminoopoyl) -n: η 1 -3,5-dibenzimidoyl] indolizine Oxalic acid 1-ddom-2- (3-chloro- ⁴ -methylphenyl) --- ⁴ 4 - (- di-n-but ^and laminpprp íoyy ^l -yl - ^^ - ^ díhrom nzoý ^ iodoliziou acid oxalate ^1-bromo-2-6 ^ 11 ^ 1 - ^^ - ^^ - ^^ 1171aninojiropyl ^ ζ ^ - ^^ - ^^ ^ Ιο βοζο / Ι ^ ^- ο &> 1 ^- ζ1 ^ο υ Acid oxalate ¹ - ^ 0001-2 ^ 6 ^ 1-21 - ^ - 0 - ^ - 0- ^ 01 ^ anmnopropyl ^ xy ^^^--chlorobbme-zblJ i Acid--otolí Zint šťavelao ¹ - ^{d 3} dom- -fee ^AD - ^- - ⁴ 4- ^{(3-di-O- d-Butyl з μοΙπ φρο-1)} 02 ^ - 1,5- ^di lor c ^{h d} enzoyl ^J intollzinu acid oxalate 1-bdoom2 eehhl-3- (l, ^3--ά1 ι1οο 4з-- ^d-in- uιty ^{d i n} ιi NB ^p: oopy ^{l) of} yЪeeezy ^ol inddMzint acid oxalate Ьго- ^ ³ - ^^ ----? IL-ddchlor --- (- · di-NP: ropylιiinnponpyl) noydnnzonU ^indolizine-1 -CH ^ r ^^ ny ¹ --- ^{4-chloio-di-O-} ^^ - ^ n ^o after ^the oopylanine yl) ^ol online dnzo ^marks lin ⁿ d ⁿ izio 196 to 197 (iznponpaeol) 168 to 169 (iznponpaeol) 134 (isopoic) 145 (ethyl acetate) 106 (ethyl acetate) 164 (iznponpaeol) 171 (isoponpaeeb) 136 (heptane)

Claims (2)

OBJECT OF THE INVENTION * A process for the preparation of the novel indolizine derivatives of the general formula I (I) and their fairly acceptable addition salts with acids, where it represents. R is a branched or linear alkyl group having 1 to 8 telephony atoms, or a phenyl group, a mono-fluorophenyl group, a mono-anhophenyl group, a monobromophenyl group, a monomethylphenenyl group or a monoethenylphenyl group, a difluoroenyl, dichlororeenyl, X! means chlorine, bromine, iodine, A represents a group wherein X ₂ ^R 1 n X is a bromine, chlorine, iodine or methyl group, and the methyl skipine, ethyl, o-propyl or n-butyl group is an integer from 2 to 2; 6 inclusive, characterized in that an indolizine derivative of the general formula II R / ^R 1 is reacted CAO- (CH ₂ ) _n -N O R, (II) б wherein A, R, R, and n are as defined for formula I with a halogenating agent selected from the group consisting of N-chloroimide of succinic acid, iodine and bromine, using N-chloroimide of succinic acid, the reaction is carried out at 0 ° C and at room temperature, using iodine or bromine, the reaction is carried out in the presence of an alkali metal acetate, and the free base of the compound of formula I thus obtained is optionally reacted with an organic or inorganic acid to form a pharmaceutically acceptable acid addition salt. 2. The process according to claim 1, wherein the alkali metal acetate is sodium acetate.