CS222698B2 - Method of preparation of the new indolizine derivatives - Google Patents

Description

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

The indolysin derivatives of the general formula (I) are prepared by the process according to the invention

from ^R i (I)

CAO- (CH _{2 n} -N 6)

And their pharmaceutically acceptable acid addition salts, such as oxalate or hydro-chloride, wherein:

R represents a branched or linear alkyl group having 1 to 6 carbon atoms, or a phenyl group, monofluorophenyl, monochlorophenyl, monobromophenyl, monomethylphenyl or monomethoxyphenyl, difluorophenyl, dichlorophenyl, dibromophenyl or methylphenyl substituted on the aromatic ring by a fluorine atom,

A is hydrogen, chlorine, bromine, iodine, methyl or methoxy, is

222696 where

Xg is hydrogen, chlorine, bromine, iodine, methyl or methoxy;

X ^ represents a hydrogen, bromine, chlorine, iodine or methyl group,

R ₁ represents a methyl group, a stylish group, an n-propyl or an n-butyl group, n represents an integer from 2 to 6 inclusive, provided that when X 8 and X 6 represent a hydrogen atom or a methyl group, then X j represents a group other than an atom hydrogen.

The indolizine derivatives prepared by the process of 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 pharmacological activity 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 process of the invention by condensing 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 indolysine derivative of formula II

O (II) where

R, A and Q have the meaning given for formula I with an alkylamine derivative of formula III

(III) 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 in formula (I) to give the desired indolizine derivative which is optionally reacted with with a suitable organic or inorganic acid to form a pharmaceutically acceptable acid addition salt.

Compounds of formula II wherein A is R 8 are either the compounds described in British Patent Specification No. 2051812 A or compounds which may be according to the methods described in said patent application.

Other compounds of formula II, i.e. compounds wherein A is R-p, may be obtained by reacting the corresponding 2-substituted indolizine with 2,3-dichloro-4-acetyloxy or 4-tosyloxybenzoyl 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-tosyloxybenzoic acid and the corresponding acid chloride is subsequently formed by methods known per se, for example by reaction with thionyl chloride.

The following examples illustrate the process of the invention:

EXAMPLE 11 1-Bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indoline and its salts.

To a 1 liter flask with stirring is transferred a mixture of 180 mL of water, 180 mL of toluene, 73 g (0.178 mol) of 1-bromo-2-methyl-3- (3-bromo-4-hydroxybenzoyl) indoleZine, 42.7 g (0.21 mol) of 1-di-n-butylamino-3-chloropropane and 34.5 g of potassium carbonate.

The reaction medium is heated to reflux for 20 hours. After cooling to room temperature, the aqueous phase was decanted and the toluene layer was washed three times with 200 ml of water each. The toluene solution is transferred to a flask and toluene is distilled to dryness under ambient pressure. The residue thus obtained is cooled.

This procedure gives crude 1-bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indolizine as the free base.

The following salts of this compound are then prepared:

(a) hydrochloride:

8 g of hydrochloric acid in 61 ml of ethyl acetate are added to the free base obtained as described above. 104 g of the precipitate thus formed are filtered off, washed with ethyl acetate and recrystallized from 500 ml of isopropanol. 93 g of 1-bromo-2-methyl-3- [4- (3-dl-n-butylaminopropyl) oxy-3-bromobenzoyl] indolizine are obtained in the form of the hydrochloride.

Yield: 84.7%, melting point: 172 ° C.

b) addition salt 8 with oxalic acid

To an ether solution of the base obtained above is added a solution of an equimolar amount of acetic acid in ethyl ether. The salt thus formed is recrystallized from isopropanol. There was thus obtained 1-oxo-2-methyl-3- [tert-3-di-n-butylaminopropyl] oxy-3-bromobenzoyl] indolizine addition salt 8 with oxalic acid.

Melting point: 89-90 ° C.

Example 2

Oxalic acid 2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] indolizine addition salt.

A mixture of 4 g (0.01 mol) of 2-methyl-3- (3,5-dibromo-4-hydroxybenzoyl) indolizine and 150 ml of acetone is transferred to a 250 ml flask. After indolizine is dissolved, 4 g of anhydrous potassium carbonate and 2.2 g of di-n-butylaminopropyl chloride are added. While stirring, the reaction mixture was refluxed for 16 hours. After cooling to room temperature, the solid salts were filtered off and washed on the filter with acetone. The acetone is then distilled off under reduced pressure using a rotary evaporator and the oily residue is dissolved in approximately 100 ml of ethyl acetate. The medium is filtered on a filter and 1.5 £ of anhydrous scalic acid is added to the filtrate. The reaction medium is allowed to stand and the oxalate which crystallizes is filtered off, washed with ethyl acetate and dried under vacuum. 6.2 g of 2-methyl-3- [4- (3-dl-n-butylaminopropyl) oxy-3,5-dibromobenzoyl] indolizine 8 addition salt with acetic acid are obtained.

822698 prepares the following merger:. at 92.7%, mp 96 ° C.

In a stable manner, using the appropriate starting materials, the meat is:

Servant

Temperature (° ^C)

Acidic ělavelan Broome-1 ~ 2-eeyl --- £ 4- / 3 - ^DD-n-p toUylanino ^of PRP l / ^s oxybenzoyl indd ^of IZI nu

An acidic šlavel-toon ^ ^ - ^ - Bromophenyl ¹ / - ^ - ⁴ 4- / ^3-di-n-b in ^T1L aminoppop ^p1 / oxybbnoZ ^b1] indoPizinu

Krselý áťavelan 1-chloro-2-rneet1-3 g of 4- / 3-di-n-butyl ^{p t1} lamlnp rρpyl ^of pχb snzpyl ^b] IO ^ Iízízu

1-Methyl-1-oxo-2-ethyl-4- [3- (4-dihydro-oxo-benzoyl) -indolizine]

1-Chloro-4-n-propyl-4- [3- (4-t-butylamino) propenyl] indolizole acid 1-chloro-2-n-tert-butyl-3- [4-03-dl- n-butylamino-propyl / oxybenzoyl] indizizine 1-chloro-4-chloro-1-chloro-4-chloro-1-chloro-3-oxo-3-oxo-3-oxo-benzoic acid fA - ^ - di-n-butylamine

1-chPpг-2-n -: bUt1-3- [4- / 6] -di-o-butyPaιninoPleχ1 / ooK1bnzpyP1 lindool zine

1-br (»- 2-ethyl-3- [4- / 3-di-n-propylamino-propyl] oxy-3-brp [n-biphenyl] indoline)

Acidic acid 2-γneSt1-3- [4'0 03dlo _n -Ultpaalinpprρp ^: Ly ^ d3 ^ 1 ^ - ^ 3 ^ * ^ t ^] ^ o ^ mb4 ^] ^ n ^ (^ of1.] Indole zinc ⁴ tysteous 2зst1l-3-43- · 33-di-n-ppr1Laβlinpз prpyl / pχy-3bbppmbsnzp1l] indolizine

Acid šlavelan 2 ^^ 13- (44 - ^ - di-ruttyty lani no pro. Pyl0ρχ1з3-brρmbbnoop1LinddPizinu

Yellowish-2-n-r-prprl-3 - [4- (3-d-3-propyl-propyl) -dilf-Zrpdlbsnz opl] indole zine tartaric acid 2-isproppl-3-r4- (3-dion-bulllp-propy1) -3зbrolbbPOpyl] inddPlzine 2-n-3mtt1lZ--4- / 3-d3o3-rPppylallooproprl / oxy-3bbpolbenzp1l] indpline

2-n-Butyl-3- (3-d) -3-d3o3-Ullyyylapropp-acid scalalane. pollen / ρχy-ЗbbrplbsnzoylIndolizine

2-Phenyl-3- [4- (4-dione-propyl-isopropyl) -3-bromobenzyl] iodine zinc acid violet 2-phenyl-3-44o / di-n-tertiylllt.n-chloro-3-bromo-3-bromo nu

2-Acidophosphoric acid - 3-4-o / 3-dione-Utylbliopз propp1 / pχ1-3-brPlbenooyl / 0iidoPizine

Acidic acid 2-04-cllprfez110з3зr4з / 3-di-n-propyl acrylonitrone · rpp1 / pχy-3зbrolonozaylJindolizine 2- (4-sllPгfslιo1 / з3- £4з03зdi-n-ωbislamin-3-ol)] n-o-ombutylamine

2-03-brolfeso1 / -3-44- / 3-di-n-rrprylз amine pop (^ 1 / pχ1-3зbrpmbbnoep1l indpli zine)

107 to 108 (iso ^ opa ^ l) to 94 (iso) and 93 (iso) 162 (iso)

111 and 112 (izpprpranal)

106 to 108 (isopropanol)

161 and 162 (izpprpranpl)

158 ai 159 (methanol) 160 ai 161 (methanol)

- ai 82 (benzene) 139 and 140 (isopropanol)

141 ai 143 (10) 1 ethyl acetate / propanol)

163 (isopropanol) 98 and 99 (isopropanol)

113 to 115 (isopropanol)

105 to 107 (benzene) 136 to 137 (isopropanol) and 87 (isopropanol)

148 to 149 (isopropanol)

129 and 130 (isopropane)

110 (isopropanol)

163 · ai · 164 (methanol) 139 ai 140 (isopropanol)

142 - and 143. (isopropanol)

222696

2- (4-Bromo-phenylene) -3- [4- (3-di-n-Uitylaminopropyl) oxy-3-bromoenzoyl] indolizine acid hydrochloride (3-Oi-n-butylamino) propyl-3-bromobenzol

2-isopropyl-3-η 4 -O-n-butylaminopentyl] (> γ-3-bromobenzyl) indole zinc 2-Isoyrooyl acid-3- [4- (3-O-n-yrlyyl) Aminopyols // pχy-3'-bromobenzoyl / IndoPizine

2-Methyl-3- [4- (Zodi-n-butylamino) -propyl] -yl-3-chloro-benzoyl] -inolizine acid hydrochloride

Acid šlavelan 2-ethyl / l-3- 4- £ / Зodi-n-PPy / yIaminoyropy // oxy-3-chlorbenzop /] inOolizinu acidic šlavelan 2 · t / L-3- ^[> 4- / n-Зodi -bu (plaminlpropp) oxp-3-chlorobβezzpl] indolizine

2-Islyrlyl-3- [4- (3-OiL-n-butylaminoyl)] -pyridyl-3-chlorobenzylic acid

2-Loyoyroyyl-3-η 4 - (3-dypypypylaminopropyl) -yl-3-chloro-biphenyl-1,1-acid oxalate. nOolizine

Acidic šlavelan 2-i-butyl-3-44-3-ODI-n BT / ylaminoyro yl ^{p /} oy ^/ c ^H -3-lor ^b enzo ^{P /} S | intoli ztau

2-i-Btyl-3-44-33-di-n-ppyyl-ylailyilylpolyol-3-chlorobenzyl] -indoline

2-Phenyl-1- [3- (4-3-di-n-t-ylamino) -pyrrolidin-3-yl] -3-chloro-4-oxoic acid hydrochloride

2-Phenyl-3-44-33-di-p-pry / ylamino-pyrrolylic acid / l '/ 3' Chlorobenzopropanol

2- (4-acetyl) furo [1- [4- (3-O-n-prlyylaainippopropyl) py] 3-chlorobenzyl] indoline

2- (4-Bromophenil) -3-44- (3-O-1-ylyl-alayla-propyl) -ol (3-chlorobenzopentyl) -isooliziil acid hydrochloride

2- (4-bromophenyl) - 44- (3-O-i-butylaainippopropyl) -1H-3-chlorobenzyl] indmizine acid hydrochloride

2- (3-Biphenylphenyl) - (4-) - (3-O-i-butylamino-propyl) opy (3-chlorobenzop)] inololizine acid

2- (3-Brlaphenil) -3-44- / 3-Oi-n-yrlyyllainilPoppl // py / ЗзcChopbbnioplJindmizine

2- (4-CWLMrfein-4-yl) -3- (4- (3-diinobutyl) ylaryl) 116- 116

147 to 146.5 (methanol) 169 (isopropanol) to 62 (benzene)

179 (isopropanol)

141 to 143 (isopropanol) 161 to 162 (methanol) 116 to 117 (isopropanol)

115 to 117 (isopropanol)

168 to 169 '(methanol) to 85 and 107 to 109 (isopropanol)

130 ’to 131 (isopropanol)

121 to 122 (isopropanol)

157-159 (methanol) 134-135 (isopropanol)

154-155 (methanol) 134-135 (isopropanol)

92 ”to 93 (isopropanol)

146-150 (isopropanol) ppl / o] -3-chloro benzoinolizine

2- / 4-Chlorofluoric acid ₍ / l / -3-44-3Зod-i-yplУy / llminoppopyLlopy / 3-chloggbenizpl) lndolizine

Acid oxalate ^: 1-bPla-2-methyl-4- (3-diinobutyl) ylamino-propyl / pyrimidin-3-bromobenzyl

1-Broca-2-matic acid -3-E44 / 3-O-1-yrlyyl (isoprlpanol) 159-160 (methanol) to 90 (isopropanol)

164-165 amino-3-ynyl-3-bromobenzyl / L-10-zinc

Acyl šlavelan 1-b: y-α-ethyl --- ---4- (2-O-L-methylaminpetylPo:-зЗbrlmbenz0O) .L [.inOmi zine]

1-Brln-2-ethyl-3- [44-73-dimethylamino] -yl] -yl-3-bromobenzyl] -indo-pizine acid hydrochloride.

1-Brop-2-ethyl acid / 13-44- / 2-O-ethyl-ethylalethyl / lPoxy-ЗbbP (mbenzol / lindmizine)

1-Brln-22-ey / -3-Γ44 / 3-Oi-ethylaainol-3-yl-1-bromo-3-bromobenzoyl acid

Acidic acid 1 - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - -

Acidic šlavelan-1 ta _'(^ Жe- -ey / _з- [4 -. / 3-D-inyppyp / llai.nlpropy // ωy / -3-brlmbbnioyl / inioPl zine (iz opгoppnm / maeanmZ

164-165 (Oichloroethane)

150 to 151 (Oichloroethane)

166 to 169 (Oichloroethane)

140-141.5 (isoyroyine) 163-164 (isproyanol)

139 to 140 (isoprlpanol)

Acidic sorrel -brlш ¹ ^ n-2-eeyl ^{Γ4--3/2-di-O-butyl} [ninolrolpУ / исууЗ-zine ЬпттепгоуЦ indoH ^K Yssel ^STA Velan ¹ -brol 2-eeyl ЗЧ-4- / 3 ^{with a} di- -butyl ylет о ^ ^ ^ о У / LXY 3-brombbпozlУ1 iodllizinu Yssel rfav ^K ^ ^{0 1} - ^{b RLM-lp} 22noppо У - з [4- / з_zi ^-o - ^u t ^y У ~ aminolrоlpУ / lx ^p- 3-bоomm-пozlУ] in0zlУzlnu

Acidic ^Avelana-1 - ^B-гlm 22nopr ^оo ylyЗ-ΓO- / 3 · di -p ^{on оl} PXlamlnolP0lχУ / oxχyЗ ^{brlmm-K-nzoyOУin0zlУzinu} Yssel ^Y t ^{ave 1} y ⁿ - ^^ - 2 - ^^ ^ 1 - ^^ - / ^^ - ^ 0-р руУ minolrоlyУ ^and / oxyyЗ ^{bгlmmbпooyУУlndoOizinu-K} ^^ ysey ^{characterized} Elan ¹ - ^b-rlIl 22nobbtyУ í'4--3/3-d ¹ - ^o - ^butyl LAI ^oiol propyl / oxy-3-brombenozoyJioZoyiziou ^Ky Sey ^{characterized} rteveyan ¹ - ^'b гo □: L-2-feп ^of L-3- [4- / 3-d ⁱ -np ^оo У ^y p ^{and y} шinolP0l У / LXY 3 -brombbnozlУ1iodoУizine

Kyseyý ^STA veyan ^{1-bromo-2-fβп about} У-3- [4- / 3-di-01-b ^u t ^y ^ УемУх pr ^o p ^yy / ^L xy-3- оlmbbпoz ^{b y} y] indz ^of nisin

Sour. ^št ave1an 1 - ROL-22/4-mmtexl yrп ^{χ 0} / -3- ^[4- / 3- butyУaminoρropχУ ^Z IO / oxy-3-boombenz о ^ уУ-НпО narrows nu

Acid oxalate 1 - rlΠl-22 // 4πmtпtУ4n ^y 0У13- [4- / 3-Zi-o-butyy 8010 ^ □ руУ / юх-У-Ьо ипО-по 0 ^p o / in4Zoizi nu

Acid oxalate 1 - (-) - [24 - (-) - [3- [4- (3-Z-O-butylamino) propyl] oxy-3-benzoyl] ioZoУizinu

Acidic acid 1 - оom - 2/3-bmlmm4пoУ-) · 3- £ 4- / 3-01-04 -butylaminopropyl / oxy-34-br zoyzio zoyizine zmben

Acid oxalate 1 - ^rzl-2-b ut n ^y tyЗз [4- / 4-di4n - ut aminolutχУ 14 ^y / LXY 3-zine brombenoolУ1JioZoУi

1-Cholyl4 - пtУyЗ-4 - “/ 3-Zi-04-utyУaminlprlpy1 / oxy-3-lhloτbenoolУ] oxalate]

Acacia juice 1-chУooо2-eпyУ-3- [4- / 3-Zi-n-prlpyУ4 aminolP0lpУ / oxχyЗ-chУórbпnzl ^y У] ioZoliziou

Kyseyý .. 1-c1h.or-2- / 3 - оlmm4пol / -3- [4- / 3-Zi-o - uty1aminzprolpУ / o} χyЗ-chhlrbeпozlУ] inZzlizlnu

Kyseyý 1-chУooо2- / 34-rlmpheny0У-Зз [4- / 3-Zi40-ppylpylaminolP0lpУ / exχyЗ-chУlrbenoolУ1inZzlizine

Kxseyý juiceAao 14chУlr-2-пtχУ43-4 - / 3-Zi-n-prlpyУ4 and [-inooгooχУ // lχyЗз4Zihhzlb-пozlУ] inZz01zine

Kxsey's State Yao 1-chyor-2-ethyl-34- / 3-Zi-o-b

Kyseyy juice 1-chУooо2-eпχУ-3-f4- / 3-Zi404-utχУ- ^and minO0POlpУ / olχyЗ, 5-ZichУoо-пnzolУ1ioZzOizine

Kyseyý shlayeyen 1-chУoo-2-4пoyУ-3-C4- / 3-Zi-04pоopχУaшinolrzoχУ // lχy-, 5-ZichУorbeпozlУ] ioZoOizine

Acid oxalate 1 -chУlr-2-: 4пopУ43--4-3ЗzZion-buУyУ ^and mi0l4 proppy / oxy-3,5-ZichУlоbп] 050lУУioZoУizine

Acid juice 1 - rom-22m-t tlyЗ- [4- / 3-Zi-o-pоlppУaminolPOlpУ / zlχyЗ-cl'h.zrbenozlУ1in0z0izine

Kyseyý štavelao 1-bromo-3- ^^^ 22 £ 4 - // 34Z n ^{-but-p and} y minolPоopУ / olχyЗ-chУlrbenozlУ1ioZzУizinu

Kyseyý štaveyan 1 - rzm-22eepУ-3-4 - “/ 3“ Oiτn-pI »lppУ4 йminolP0lpУ / oxp-3-ch1lrbeozoy1JioZoyizine

Kyseyý šlavelao 1-Brzom - 2tпl-Зз44- / 3-Zi40 - utpУ ^and minolPOPpl / ⁰ lχyЗ-chУlrbenozlУ1ioZzУiziou

Kyseyý Štaveyan 1 - оlm - 2noprоoyУ --- [4- / 3-Zi-o-butyУεmiolprelpУ / zxχyЗ-chУor-enzzoУ] ioZzУiziou

Acidic acid 1 - rol-221iZlroplУyЗ- [4- / 3-Zi-o-butylamiooppoopy / ozxy 3-chУυг-пozolУ1 ioZoyizine

Kyseyy oxalate 1 - rolm2-nobbtuУ - з-4- / 3-Zi-o-pоlpχУaminolrоlpУ / ox, yyЗ 'ChУlrbпnzoyУJ ioZoyizine

164-165 (Lisopropanol) 101-101.5 (isopropanol) (benzene)

132 to 136 (isoprppanol)

151 to 152 (2/1 isopropanol / methanol)

101 to 103.

(isopropanol)

169 to 170 (1/1 maeanol / 1 zoproDanol)

167. to 169 '(isopropanol) 17; 8 to 179 (methanol)

169 to 170.5 '(1/1 ømeanol / isopoopanoУ)

170-171 (methanol)

172 to 173 (methanol)

118 to 120 • (isopropanol)

115 to 117 (isopropanol)

137 to 138 (isopropanol)

171 to 172 (mm)

194-195 (mmtanol). 141 (ethyl acetate)

,. 129 (ethyl acetate) 156 (isopropanol) 136 (isopropanol / heptane)

110 to 112 (isopropanol)

108 to 110 (isopropanol) 136.5 to 138 (isopropanol)

103-105 (isopropanol) -1. 96 (isopropanol)

116 (isopropanol)

159 to 160 (meeanol)

1-Bromo-2-n-butyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-chlorobenzoyl] indolizine acid oxalate,

1-Brop-2-phenyllЗ- / 4- (3-dL) n-butyl / atliilopro- ryl / oyl / - / hlbbbnooplJinddPioin

Acid oxalate 1 / boom-2- / erol-3-C4- (3-di-n-roorylaininoproprole) ox-3-cyclobenzyl iodolioin

Acid oxalate 1-eropropanol- (34зhl1o0etol) -3-Γ4- (3-di-nebutplafimopooppl) oyy / 3зChlorobenzophyl] indolioia Acid oxalate 1-brop-i- / 4-chloropfeeo0l - / - / 4- / 3-di-n poopllafiooprpppl (o: yy-3-chlooetnooplindoleol) Acid oxalate 1-ery-22/4-bbpofirgin.l-3з34433-di-o-poopylaflnppppppl (o: yy-3-chlooetnoopljonolioiourea) 4ьОро1пTenyy L ^^ - A-dL (O) / bylil ^ e ^ m ^ ny ^ r ^ t ^ I ^ rl / yX ^ -S-ch ^^ oobe ^ a ^ c ^ O ^ 11l iodplioin Acid oxalate 1-bro-2- / 3-bboferol-3- [4- (3-dioloroorilinylpropyl) (5X-3-chlorobenzyl) -polium] Oxalic acid oxalate 1-brpp-2- / 3- / bopferol-3-L4- / 3-di / 0 / bulylamiooprpppl / oyp-3-chloobeozopl

1-chhaoo2-etll-3-04- [3-di-o-bytlafinpppo rrl] oxy-3-brpphenoxy] iodplioin oxalate oxalate

Acid oxalate 1-chloro-2-eeyl-3- [4- (3-di-n-β-pylaminoproprole) doyl 3,5-dibooffenooylindole] oine

Acid oxalic acid 1-chloro-2-elll-3-C4з3З-di-n-butylbutylphosphoric / 0X7-3,5 / 01brpbenzpyl iodolioin

1-Chloro-2-felmyl acid 3-η 4 - [3- (3-di-n-poopylamino) propyl] -3-dibenzobenzyl iodolioium acid oxalate

Acid oxalate 1-chhPOo2-feeol-3- [4-73-di-o-wasollaphorphoroforiline / 3,5odolOoffbeoooyl iodolioin 3,5-dibromobenzoyl iodolioin

Acid oxalate 2- (11-Z-f) - (4-iilyl) monopoopyoyl] / (3,5) 01-bromobenzene opioiodo

Acid oxalate of 2-α-3-f4з-23-dttytyliminothyl / α-α-3,5-dibooffetoopl] indoline.

2-Zetyl-3-43-33-diethyll 10o-propl / oyyз / 3,5 / dibrofbeemopl

2- ^ 11-3-4 / - / 3- / 0-ρ-ογρ ^ 1οπιΟnopooppl / oχy-з, 5з.dibгpmetnzoyl] iodolioin hydropohhpride

2-elll-3-44- (3-d0-e-Uutalaminopropylpropyl) -3- (dibromobenzoyl) hydrochloride hydrochloride

2-o-proppl-3- [4-3 / -dio] p -polplaninopropyl / oyy-3,5-dibromoenzool1] iodolioin hydrochloride

Acid oxalate 2-isoproopl-3- [4- / 3-di-o-oplo [iinoopoopl] 2-isoproopl-3- [4- / 3зdi-n-poopyll [iinoopoopl] about _yy-3) 5-deboofetozoylJ iodolioiou

Acid oxalate '2-isoproppl-3-04з / 3-d3o3e'Уutylafinoз proprl / oyp-3,5-dibrofbetooolJiodoOizlny

Acid oxalate 2-o-eutyl [3- [4-d-dl-n-polyplaphio-propyl] -yy (3,5) di-benzoyl] -o-olefin

2-o-Eutyl / 3 / [4/3-d-3-d-butyutyl-3,5-diol-3,5-diol of oetool] indole oxo

2-Feoll / 3-з4з3З-d0-p-oгplylim0nopooз pollen / oyy-3,5-dibooinyenooyy] iodpli oiou

2-phtoylз3з [4-3з_d3on-Уut1lloioo / proppl / oyy-3,5 / dibrof Ub ^ ec ^] hdpOi oine

Sulfate oxo 2- / 4з / fluooftoyl / з3-C4 - / (iз-n-propyl-)

101 to 103.

(ioopoopanal)

157.5 to 169

169 to 170 (fftappl)

160 to 161 (izppoopanpl)

184 to 185 (rnftanpl)

176 to 177 (fetappl)

168 to 169 (ioopropaopl)

200 to 201 (ffeanoC)) 170.5 · to 172 (fetappl)

104 to 105 (prppropanpl)

157 (izppropanpl) * 140 (izppropanpl)

172 (isopropappl)

146 (izppoopanpl)

136 (elilacetate)

148 (elil ^ acrla-1)

171 (elancl)

191 (50) 50 (acetate / ellool)

166 (^ ιΙ ^ βΙάΊ)

157 (elil ^ acetate)

145 (elil ^ acetate)

107 (elilacetate)

126 (e lil ^ acel letance) (^ ιanci ^ βίάν ^ ιΐ ^ βΐ ^)

146 (ethyl acetate)

110 (elilacetal)

142 (eluting with t / elanOH) (ell1lethate)

166 aninopropyl / oxy-3,5-dibroabenzoyl indelizine (ethyl acetate / ethanol)

2- (4-Fluoro-phenyl) -3- [4- (3-dl-n-butylamino-propyl) -1H-oxy-3,5-di-benzoyl] indolizine acid oxalate 2- (4-Chloophenyl) -3- [4- / 3-di-n-poopylaninoppo [o] 3 '- 5-dlobenzobinzoyl iinddoisine 2- (4-chlorophenyl) - (C 4 -) - di-o-butylanine oxo acid oxalate 3-di-benzobenzoyl iinddoizine ] Ofero1 / '3- [4- / 3-di-o-poopylebinoppoppУ / oзд 3 »5-iibopbbinooylJinddPizinu ^Kp 1elý rtaveten 2- / 3,4-d ⁱ c ^h lPг ^f er ^O1 / -3- [4- / 3-di-o-3,5-butylabinopPopp1loэχ dibopbbinozpl] inddPiziou acidic aveteo-2- / 3- ⁱ oo fn ^{b n} l / -3- [4- / 4-di-n-ρoppylaminopPoppУ / o: χ1- 3,5-d: ibrpbbenzoyl indolizine Kreelý ftaaoao 2- / 3-bopbonyl] -3-Γ4- (3-difo-butylabinoppopp) / pPφ13,5-dl.boobbinoopУJinddPizine Kršý 'šlavelao 2- / 4- ^ μ ^ 13 ^ 11 [3- [4- (3-di-n-poppylamino) piperidine] -5- [1,3-di-n-poppylamino] piperidine-2-thiophenol (4-betplfenpiperidine) - / - --4 - // - ii-O (iutpl) allnoppoppy / plsy-3,5-dibP <mbenzdyl] indelizine K1 <RTIgt; ssl </RTI> 2/4-bbt <RTI ID = 0.0> pplφflol-3-f4- / 3-di-n-poppy </RTI> Lami NOPRO e JP1 / o3qr-3>5'-di bromobenzyl oyl] i from olizinu acidic šlavelan 2- / 4-oetPp1fenylL - / - // 3- 44 ^d ln-the-t1laminoppop11 / oэpг 3> 5 diboobbbnopp1linddPiziou Acid šlavelan 2-bθty1-3 Γ4- / 3-diol - opeρyaabinppropp1 / pχ1-3,5-dichloobθnzep1] indolizine acidic šlavelan шony1-3-44-2 - / - idion -BU1 ^p lom0no1oopyl / ox1-3,5-dichlρobeozop1 2-Ethyl-3- [4- (4-oxo-OPO-aminobenzyl) indole] iodine lysine Acidic acid 2-ethyl-3'-C4 '- / 3'-oxo acid ^-iЪu, tyaabinppгopp1 / pзд З _{L-5-dichlooienzop1]} lndolizinu tyselý šlavelan 2-n-poρpp1-3-4- / 3-in - oppρyaabinpprop ^P1 / pэχr 3 »5- ^d ic ^h LPO ^and enoo ^P1L indol- z ⁱ nu 2-n-pгppp1 - / - f4- / 3-d-onibu1 ^[ aabinop] op1] / pJq1 · 3,5-dichloobenooo1] indpOizine 2-isppooppl-3-O4-73ddio-- oppppaabioppre pLZ ^ / ^ drunk -dichloobenzopl indoliziou Acid šlavelan izopoop ^2-p-L-3 4- / 3-di-n-butplabinopz ^ o l ^pp / op ^y - / 5-dic ^h lpobeozopli iotollzlou Kpselý šlavelan 2-feoyУ -3-Γ4- // dd / on-oP11yaabino / ppopp1 / o3p1-3, S-dichloobenzopl] fhdoli ziou 2-Feoyl - / - C4 - // - dl-nibu1 ^p aabinoprppp1 / op ^ 3,5-dlchlooienzpp1] indelizine 2- / 4-Iopropanol - / - f 4 - // - di-n-poppylabineproppy / pppi · 3,5-di-chlorophenoxy] iodole ziou i 2- (4-boombinyl) -3- ^ 4 / 3- di-n-butplaninoppopplepep13,5-ddc hlopberno z ^^ c ^ liz! 1-Bis-2-m-methyl-1- [4- / 3-di-o-butylaminopropanol / exyl-3'-dlboombenzepl] iodole ziourea acidic acid 1-b ^ <^ D ^ - ^ 1? ' ^ n -]? p <^] ^ 3 ^ 11 l ^ '^ | F4 - ^ - ^ (^ ^L-O-P poop lablnoppopp1 / eзpr 3,5-di bo * obbeiozoylL indolizine šlavelan Acid 1- bгpm-22-ey1-3-C4- (3-ii-n-butllablnopogppp1 / op ^p - [5-dibopbbinopp1] indidine) Zinc acid 1-breo-b 2 ^ 01--3-44 / 3- (11 -0- ^ 171aimminop1Op11 / p2p1-3,5 / iiboobЪinoop1JindoPi ziou Acidic acid 1-iгoo-0-24-m-tnlУel'n0-1l - // f - // - di / n / -butylabinopгopp1 / o: Q-3,5-Chloro (indolizine) indelizine

152 (izppoopaoel)

190 · (П0118СП040) (п011всп040) 114 (Ethyl Acetate Piano!) 95 (Ethyl acetate / iP10oGoIpl) 136 (Ethanol)

122 (п0118Сп040) 126 (nt1lacntatllP1oгo1aopl) 90 (1Ο1 ^^ Ο4Ο)

167 (acetone) pasty. at about 70 ° C (ntancP / ntlLiet)

145 (nt1lattát / ntaocl) (it11ac e té ^ пО ^^ Ою)

100 (pasty) ^ 1 ^^ 140) (ι01 ^ βι040) 142 (i zapo ^ yes!) 144) (isopoopanol) (ι01 ^ βι000) (nt1lacntét) 146 (ethano ^) pasty at about 90 ° C ( ι01 ^ βι040)

174 (ι01 ^ βι040)

133 (п011всп040) 141 to 143 (isopoao) 138 to 139 (isopoopanol) 131 to 132.5 (isopoopanel) 160 to 161 (isopoopanol) 105 to 106 (isopoopaool)

1-tara-2- (4-bromo-tert-butyl) -> 3- [4- (3-t-butylaminopropyl) oxy] -3,5-dibromobeenoyl] indole zoline acid 3- [4- (3-Oi-n-tuitylaminoproopio) -1x-3,5-oiboombeeooyl] indolePioin 1-eoop-2- (Zizchlop-3-ylethyl) ethyl oxalate / -3-? 1-bromo-2-eey / -3-04з / 3- (f3o3ebu / ylmminpз propp) / oxp-3,5-0ichloobenzoo / JinOoli oine

Acid oxalate 1-eoom-2 / feen / LZ- £ 4з / 3-d3oз-rPopylaeioopropp / ZoK / - ») 5з0ichlobobenzpp /] iodp01oin

Acid oxalate 1-pg (P1-2-: 3een / -3- ~ 4- / 3-dio-3butplaminepos after op) V oxy-3,5-Oi chlorobeno op) H 2 -piperidine 2-n-but / 1- 3-C4з3-di-untytylbminoproppl / pχy-3зbrombenmop /] indo oinhpOrochhori O

148 to 149 (isopoopanol)

196 to 197 (isopoopanol)

168 to 169 (isopropanol) 134 (isopropanol)

145 (et / lacetate)

106 (et / lacetate) 113 to 113.5 (et / lacetate)

HptOrochhoriO 2-n-eutplз3 - [‘4-3Зo (13on-Uutlaaminopropз ppl / oxy-3,5з0ibr) (» benoopllindoPiino tydreclihoriO 2-et-1-3-43- / 3-d0-b-butylemopopopyl / ppoeenzin)

154 (89) 20 ethyl acetate / acetone)

132 to 133 (et / lacetate / ipppporanpl)

HrdoocchoriO 2-o-eutylз3з. [4- / 3d (: 3L-n-Uutplaπ10nppoppyl / oxyз3зhhloobenzop / lolOoli oin)

HydroohholrL0 1 зerpm-3-febo / -3-r4з / 3-d3o3eUu · -ylaeiopз prppy1 / ρзqr-3-chloro-renoopl] IndoPioin ·

Acid oxalate 1-chlppr2- / 4-chlpopheno - / - 3- £ 4- / 3-0iзOз зpoopplaminpprrppl / ρpy-3enooplJindoPioin

Acid oxalate 1-metppy --- fetyl-3з34- / 3з0i-o-prpylз aminpprppyl O2χbetooyl] iddpPioin

Acid oxalate 1-metPc ---- fety0-Зз [ ^, 4- / 3-0iro-btytyl-amioppropyl / oзφbenooyl] indoPioin

Acid oxalate 1-methyl-2-phenyl-3- [4- (4-methyl-3-ylamino) -propyl] -pyridine-3-eno-3-one

1-Eettpy-2-fetyl-3з34- / 3-di-n-brtylз aminopprppl / opp-3ззhhppbetoopl]

Acid oxalate 1-eetopy-2-fetol-3-C4- / 3-diisopropylaminopropylpeptide / pχy-3-bromomethylpyridine-isoZizine,

Acid oxalate. 1зeettpy-2-ethyl-ЗзΓe-33-diзo-eutylamiзppprpy / 7pJq - 3-eromЪeзzoyP / iзOoPiziou

Acid oxalate 1-ethoxy-2-phenyP-3з34- / 3з0i-n-ρrppyPз aminpppppy- / pχy-3зmetp: χ-benoop-1'oOpoole oin

Acid oxalate 1- ^ DetP: p ---- phenyla-3-phe-33-di-o-e-butylamineeppoppl / py O / ndOOi oine

1-Ethoxy-oxalate oxalic acid - [(4-phenoxyethanol) -3- [4-] - 3-iodo [beta] -prop-lamlnpproppl / pχy-3-methyl-ethanoic acid

2-Meep-3-44- (Zodone-Uu-paamyl) propyl / oxy-3-methyl-ethyl-indizoline oxalate oxalate

KfMlý · 2-eeeyl-3з £ 4з / Зod3oз-ppp / yleeiзopooз pollen / ox-з3-metpχ-betooplJindpPioin

2-Et-1-3- [4- (4-dihydro-Uu-yl) -isopropyl] ox-α-3-methoxypetoxy] indizizine acid oxalate

Acid oxalate 2-et-1-3- [4-33-dl-n-ppp / ylaeiopprp] io / oχ-з3зme toxybetooyl] indoPioiou

1-bгpnз2-mettl-3з34- / 3з0i-з-1Uttyaaeiooprppyl / ox-з3-methpentyl benzoate

Acid oxalate 1-bromo-2-methyl-3- [4- (3-dihydro-3-propylamino) -P-1 / pχ-3-mt toχ-tamoopindine] oine

Acidic acid 1-bromo-2 / зey - 3з £ 4з / 3-d3oз-Ut-yleminopopз pollen / pχyз3-mβ to: —betoopljindePi oinu

104 (tt / lacttate) 156-157

168-169 (me e-ianol)

117 (tt / liter) 80 (et / 1 acetate) 172 (et / lacetate)

120

160 (tt / lactate) (tt-lactate)

148 (et / l acetate) 78 (tt-lactate) (tt / lacttate)

159 (isopoopanol)

171 (mmtanol) 88 (et. Lac.) 121-122 (tt / lacttate) 87-90 (beno) 139-141 (isopoppanol)

111 (beno ^)

1-Bromo-2-ethyl-3- [4- (3-di-n-propylaminopropyl) oxy-3-ethoxy-benzoyl] indolizine acidic šlavelan

Acid 2- (4-fluorophenyl) -3-C4 / 3eodl-e-Uityaaainiproppl / oxy-3-mmto3QrlenzoylIndolioin

2-Netyl-3- [4-3- ω-1-n-bulmilino-aminopropyl] oxy-3-methyl-benzoyl-indole-diol

2-Ethyl-3- [3- (3-di-n-bulyl-1-propyl) oxy] -4-methylenenol-1-ol indole lineate

Acidic acid 1-enyeny2-n-ppolpl - / - 4-73-0i-z-bxbyllminzlгPlyУ / oxy-3-ethoxymenzoyl izZoldoi nu

/ Acidic acid / -iooppop-1 - / - [4- / 3-ddn-eb: ttya-dnopp opy1 / lxyl / - methyleneenooyl

2-n-Butyl-3- [4- (3-desbutyl) -poly-1-oxy-3-methyl-ethylenedioic acid oxalate]

1-Methyl-4-n-1-methyl-3- (4- [3- (1-butylamino) propyl] -xy-3-epi-benzoyl] -innololine acid hydrochloride

Acyl šlavelan 1-1 ^^ 1 --- ^^ 1-3- (4- / 3-01- ^ 1 ^ 11 ^^ propyl / l - / - erlmmenzol) JinZolioin

Acyl šlavelan 1--17011-2-1 ^^ 1 -3r4- (3-0i-n-tuitylaminoproppl) oxy-3,5-01-propylene] z]

1-Joyl-2-ethyl-3-E4- [3- (3-d) -butytylamino] -oxy- [ _1,5] methylmethylene azole] indoleol

2-ethyl-3- / 2, -dichloro-4 / -O-z-1-propylene (di-n-propylene / 1-oxyene-o-11-indole)

2-Ethyl-3- [2, 3-oxo-4-propyl-amino-3-propylamino] -oxyl-oxo-phenyl-phenyl-3-oxyl-3-ol-4-yl 3 - nn ά- pipiyamniinoppopry / oxy-BZ-oillindolioin / -Feln1ιЗ - // 3-01ihlop 4- / 3-d-znebu1yameinoppopyУ / oxyethylene -eznoiylindoOicin ^{// 4 //} nyУ -flu1PΪ ⁿ - ^{E /} _J 3- ⁰ lih ^l ope ⁴ -3-d ^- z - p1-ρyУaelnopгop-У / 1xyЪenzo1УllndoYloln /-/4-H.bαprnnrl)-/-//, / -0iihУ1P-4- / Зod-zeebu1yaamin1ppopp ^y / oxy ^- ezzzyl] Jntoliota

Acid Slavel-an 1-igom --- θtyУ --- [t, 2-d-c0Уoop4- / 3-0i-n-ebtyllmlzop-P1-У / o: χгbenzo1УJlndoO1oinb

1-Eromo-β-phenoic acid hydrochloride - / - 2,3 / -0,11,11β-4-3-cod-n - P1-yУаmizz1-P1-Y / o1χУenzoyУJizdoisin

-C-yzop-z-zz-Ii 3- / 2, / -0iihУ1P-4- / 3 · -d-z - pm-γ-yla-in-1-rzp-1 / oЪЪЪenzom1lin0zYlzine

2-n-Bityl-3- [4- (3o) -d-z-bbl1yaa-inoppm polyl / oxy-3-yloxy-o-ezzon-111-zylzi acid hydrochloride

149 (dzz-pm-lzel) 85 (ethyl acetate) 149 (isz-po-lzl) 133 (ethyl acetate) 127 (п ^ 11спЬ0О.

(dzo-po-lzole) 89 ζ ζ ^ ((ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety ety -tlz) (Уп ^ ш) 119 (Уп ^ ш) 95 to 96 (Уп ^ ш)

164 (ize-pmp)

171 (izzppopazzl) 136 (Уп ^ ш) 90-92 (п1111сп1 ^^)

Claims (10)

SUBJECT OF THE INVENTION 1.Zpil8Ob of the preparation of inOoliz-newiy OerZvátd тЬеепёУт yzop ^ I (I) And pharmaceutically acceptable acid addition salts thereof, wherein where is A branched or linear alkyl group having 1 to 8 carbon atoms, or a phenyl group, a monofluorophenyl, monochlorophenyl, monobromophenyl, monomethylphenylphenyl or monomethoxyphenyl, difluorophenyl, dichlorophenyl, dibromophenyl or methylphenyl group substituted on a bromine atom with a fluorine atom, Xj represents a hydrogen atom, A represents a chlorine, bromine, iodine, methyl or methoxy group, or R a chlorine, bromine, iodine, methyl or methoxy group and X 1 of a bromine, chlorine, iodine or methyl group, wherein X ₂ is hydrogen, is hydrogen, is methyl, ethyl, n-propyl or n-butyl, n is an integer from 2 to 6 inclusive, provided that when X ₂ and X ₃ are hydrogen or methyl then X ^ represents a group other than a hydrogen atom, characterized in that the alkali metal salt of the indolysine derivative of the general formula II (II) is condensed wherein: Are as defined above, in an aprotic solvent with an alkylamino derivative of formula III (III) or an acid addition salt thereof, wherein Z is a halogen atom, or p-toluenesulfonyloxy and n and b are as defined above, to give the desired an indolizine derivative which is optionally reacted with a pharmaceutically acceptable organic or inorganic acid. 2. A process as claimed in claim 1, wherein the sodium or potassium salt of the indolizine derivative of formula (II) is condensed, wherein the individual symbols are as defined in (1) with an alkyl amine derivative of formula (III) wherein Z is chlorine or bromine. as defined in 1, in acetone, methyl ethyl ketone or toluene. 3. A process according to claim 1 for the preparation of 1-bromo-2-methyl-3- [4- (3-di-n-butylaminopropyl) oxy-3-bromobenzoyl] indolizine and pharmaceutically acceptable acid addition salts thereof, characterized in that: is condensed with 1-bromo-2-methyl-3- (3-bromo-4-hydroxybenzoyl) indolizine with 1-di-n-butylamino-3-chloropropane in an aprotic solvent. 4. The process of item 1 for preparing 2-n-butyl-3- [1- (1-di-n-butylaminopropyl) oxy-1-bromobenzoyl] indolizine ⁱ . ^{its fl} imaceutickt vhotoé idiční sellnimi ^y sk salts, ^you destroyed by snškondenzujn 2-yl-bbttl-3 / n-bloan4 hydrlxybbnyool // nddlizlУ with Lidl buttlamino-n-3-chloropropane in iprotickém rozpoubtědle. 5. A process as claimed in claim 1 for the preparation of 2-ethyl-3- [4- (3-d-b-butilai-o-propyl) -ox-lichloro-benzoyl-indolizine and a pharmaceutically acceptable acid addition salt thereof, characterized in that tert-3- (n-halo-4-hydroxybenyol) iodole with lidl-n-buttliaino-1-chloropropine in an iprotic solvent. ^6. pŮBob according boto příprivu ¹ to 2 n ^b ut ln ^{y /} -. | ⁴ i / ^{/ ndd} in- utylamino ^{b p} ro ^p yl ^/ oxy - / - i ^{h b} llΓi mzzyJintíoHzlnu his firaiceuticky VTO ^ Ne idiční SOH s ^ ^^^ εβί ^{characterized} marks ^and prices tm, ^Z e is condensed with 2- N -butyl-N-chloro-4-hydroxybenzyl alcohol with 1-di-ylbutyl-3-pyrrolidine in an iptotic solvent. 7. The process of item 1 for the preparation of 2-isopropyl-N- [4- (2-di-n-butylaminopropyl) oxy] -, 5'-di-pyrrolidin-1-one, and its pharmaceutically acceptable acid addition salt, which is destroyed by condensation. 5-dichloro-4-hydroxybenzoyl] indole with imidium-1-chloropentanil in an IPC solvent. ^6. Pusl podle.bodu ^b 1 to ^b RLM příprivu 1- 2- ^{yl n} en L3- [4i / ^{3-di-n-but yl} mminoprlp ^y · l / ^t ox in / -ihllrbnnzootlJindoOizlnb his fiímiceuticky suitable acid addition salt, destroyed by condensation of 1-bromo-1-phenyl- [1- (3-chloro-4-hydroxybenzyl)] -disulfide with M 2 -butyl; with lmino- / n-chlorolploline in an iprotic solvent. ^9. P ⁱⁿ accordance with ^b BHU pMprivu ¹ to ¹ II ^H lori2ietpl / i- [4 / ^/ 3-d-b ^{y-but l} lamУloproppl / ox ^t i - / - cihorbbnzzllt] inddllzinu its pharmaceutically acceptable salts idičbí kysellnimi, vyzničený by condensation of 1-chloro-2-et ^yl-3 / n-hhlon 4-tddloxtben-0L1 / indolizln 1-diyne-butdli imino - / - ihlorplolanem in iprotickém solvent. • 10. ^The processes according to b. ¹ for ^{EXAMPLE 1} -ihllr Riva ^{beta.-2i.nib 8j} p ^t -3- [4 - // - ^l dУyybbutp aalУoprop ^Pt / lXdbbn-odlЗinddllzlnu his firmiceutlcky suitable idiční SOH with kysellnimi, vyzničený by condensing 1- N-Hydroxybenzoyl-indolizine with 1-di-n-butylamino-3-chloropropane in an iprotic solvent. 11. The process according to clause 1 for the preparation of 1-methyl-n-n-4-chlorophenyl [4- (3-dn-n-butylaminone propyl) (1-p-hexylbenzoyl) indole] - a pharmaceutically acceptable acid addition salt thereof. by condensation of 1-benzyl-2- (4-chlorophenyl) -hexyl-4-hydroxybenzyl-1-benzyl-2-methylbenzyl / methylphosphine in an aprotic solvent.