DE2138865A1 - 3-INDOLYLPIPERAZINE, THE PROCESS FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS - Google Patents

Description

SUMITOMO CHEMICAL COMPANY, LIMIiCED. Osaka, Japan

"3-Indolylpiperazine, process for their preparation by means of ^Yl __________" ____

Priority: August 15, 1970, Japan, ITr. 71 611/70 August 24, 1970, Japan, Mr. 74 404/70

September 8, 1970, Japan, No. 79 141/70

November 9, 1970, Japan, No. 98 942/70

and medicinal

I) he invention relates to new ones
3-Indolylpiperazines of the general formula I

R ₁

R,

(D

in the E, and

, which are identical or different, a hydrogen or halogen atom, an alkyl radical with 1 to 5 carbon atoms, an alkoxy radical with 1 to 3 carbon atoms or * a trifluoromethyl group or R- ^ and H ₂ together with the Benzollcera a 5- or 6- membered heterocyclic ring, iU a hydrogen atom, an alkyl radical with 1 to 5 carbon atoms »an aryl radical or an aryl-lower-alkyl radical, B ^ a hydrogen or halogen atom ·, an alkyl radical with 1 to 5 carbon atoms, an alkoxy radical with 1 to 3 carbon

30980B / 13 & 9

OR) GiNAL INSPECTED

atomen.oder a trifluoromothyl group and Y an alkylene radical with means up to 5 carbon atoms, and their salts with acids.

The invention also relates to a method for producing these Compounds, which is characterized by the fact that one either

(A) a nitro compound of the general formula III

R ₂

in the R ^ and IL? have the above meaning and X is a cyano group, an alkanoyl radical with 1 to 6 carbon atoms or an aryl-lower-alkyl radical, with a pipera zinc derivative of the general formula IY

Civ)

in which R ^ and Y have the meaning given above and Z is a halogen atom or a T o sjl oxy group, or the salt thereof is condensed or
(b) a nitro compound of the general formula V

(V)

in which R ^, R ₂ * ^x * ^Y ^ ¹ ^ · ^{z have} the meaning given above, with a Pxperazine derivative of the general formula VI

(VI)

309808/1359

in the S, the meaning given above has _g or its salt condensed and

[c) the resulting piperazine compound of the general formula II

X ■ ·

R ₁

-CH -Y-

\ f ^ uU tb £

^ NO ₂

in which B ^ * R ₂ *% » ^{x 1} ^ ^ have ^the meaning given above, reduced.

Specific examples of the halogen atoms are fluorine chlorine _{9 s} bromine and iodine. The alkyl radicals with 1 to 5 carbon atoms can be unbranched or branched. Specific examples of the alkoxy groups having 1 to 3 carbon atoms are methoxy, ethoxy, n-propoxy, and isepropoxy.

The salts may be derived from inorganic or organic acids, such as sulfuric acid, nitric acid, phosphoric acid _P hydrochloric acid, hydrobromic acid, citric acid, acetic acid, lactic acid, tartaric acid, succinic acid, fumaric acid, glycolic acid, _a cinnamic acid, benzoic acid, oxalic acid and methanesulfonic acid. The salts are prepared by customary processes.

The implementation of the nitro compound of general formula III with the piperazine derivative of the general formula IV is preferably in the presence of a condensing agent and., in a solvent carried out. Examples of suitable solvents are alcohols such as methanol, ethanol, propanol, isopropanol, butanol, sec-butanol, tert-butane oil, sec-amyl alcohol, tert-amy alcohol or cyclohexanol, or other organic solvents such as

309 8.0 8/1359

Mäthyläther ”, Tetrahydrofuran Bioxane _? Benaol, toluene, xylene, dimethylformamide «, dimethyl sulfate!?! or liquid ammonia.

Examples of suitable condensate solvents are. Alkali metal hydrides such as ₉ Matriurahydridp Alfelinetsiliallcoliolate as Uafeiumlaethylatj, JSTatEiraaäthylat j> MstriiiraisopEOpylat, latriiaaeycloiiexanolats lairira-seka-asjlats E ^ JLiiisäthylat or EaliiiM-tertcbutylatj or HkalimetallaEiide _s. such as liafeiusaEid, EslIiisafiiieL and Lithiumasiid _o Preferably ivirä Eali »JSi = -ter-t _e -T3ut; rlat la tert-butanol« ad toluene irerMeElei; ,, DI® condensate! onsreslr-ion is generallyii "at temperatures of 0 0 Ms leads to the sieving of the solvent used, preferably ir; ird

the Umsetsung hot Semperaturea ¥ © a 10 Isis 30 ° C dureligefiüar-t "

The condensation of the 'HitroiriSrTbindimg the general for-Eiel ¥ is with the piperazine derivative of the general iOriael VI top case preferably! Onsmittels and in a solvent in the presence of a condensate "Examples of suitable solvents are AIkOhOIe _5, such as methanol, Äthssiol or isopropanol _s or other organic solvents such as tetrahydrofuran, Diozaa _s diethyl ether, dimethylformamide and disethyl sulfoxide. Examples of suitable condensing agents are sodium carbonate and potassium carbonate. The reaction is generally carried out at a temperature from room temperature to the boiling point of the solvent used

be.

As a decisive intermediate product in general inventions are obtained in this way in a smooth reaction fiis P compounds of the general 10Ezasl II _O Specific examples of? the bipsrazine compounds produced according to the invention on? cS.l common 1Όϊ? μ © 1 II are; .

308808/1 3.5 p

1- / 3 '-aetyl-3' - (2 "-nitro-4 ^M , 5" -dime thoxyphenyl) -pr opyl / -4-

phenylpiperazine,
1- / 3 '-Cyan-3' - (2 "-nitrQ-4" * 5 "-methylenedioxyphenyl) -propyl / -4-

^ phenylpiperazine,
1- / 3 »-acetyl-3 '- (2" -nitro-4 ", 5" -methylenedioxyphenyl) -propyl7-

4- (2-methoxyphenyl) -piperazine,
1_ ^ 31 -Benzoyl-3 '- (2 «-nitr o-5" -f luophenyl) -butyl / -4- (4 ^! -Chlor-

phenyl) -piperaz in,
1- / 3 · -Propionyl-3 · - (2 "-nitro-5" -chiorphenyl) -2 · -methylpropyl7-4-

(3 ¹ -trifluoromethylphenyl) -piperazine, a

1- / 3-phenylacetyl-3 '- (2 "-nitr o-4" -trifluoromethyl) -propyl7-4-

phenylpiperazine,
1- / 3 '-Butyryl-3 »- (2 ^lf -nitro-4", 5 "-äthylenedioxyphenyl) -propyl7-4-

(2'-ethoxyphenyl) -piperazine,
1- / 3 '-acetyl-3 ^f - (2 "-nitro-4" -methoxy-5 "-ethoxyphenyl) -propyl7-

4- (4 * -hromphenyl) -piperazine,
1/31 _ (4 "-chlorophenyl) -acetyl-3 '- (2" -nitro-5 "-propoxyphenyl) -

propyl7-4- (4'-propoxyphenyl) -piperazine and 1- / 3 · - (4 "-Luobenzoyl) -3 '-' {2" -nitr o -5 "-methoxyphenyl) -propyl7-4- (41-ethoxyphenyl) -piperazine.

The piperazine compounds of the general formula II or their Salts can be converted into the corresponding 3-indolylpiperazines of the general formula I smoothly and in high yield and purity when treated with a suitable reducing agent that effects the reductive cyclization. The reductive Cyclization can be by electrolytic reduction or catalytic Reduction can be effected in a suitable solvent. Furthermore, this reduction can also be carried out with a metal in acidic or acidic

3Ö9SQ8 / 13S9

■ - 6 -

alkaline medium in a suitable solvent. Examples of suitable solvents for these Implementation are water, "alcohols such as methanol, ethanol or isopropanol, and organic solvents such as tetrahydrofuran, dioxane, ethyl acetate, benzene and acetic acid. For reductive cyclization are preferably palladium-on-carbon or Raney nickel in suitable solvents such as methanol, ethanol or acetic acid, used at temperatures from room temperature to 40 ° C.

Preferably the reductive cyclization is carried out in the presence of metals such as zinc or iron in an acidic medium, e.g., aqueous Hydrochloric acid, aqueous "sulfuric acid, or acetic acid, at temperatures carried out from 70 to 130 C. The reaction in the presence of iron in aqueous acetic acid at 85 is particularly preferred up to 95 ° 0.

According to the method according to the invention, for example, the following can be used 3-Indolylpiperazines of the general formula I are prepared:

l-Z2 ^I - (2 "-Hethyl-5 ^tf -chlor-3" -indolyl) -äthyl7-4- (2 ¹ -ethoxyphenyl) -

piperazine,
1- / 2 »- (4», 5 »-Methylenedioxy-3 ⁿ -indolyl) -propyl7-4- (4 ^f -fluorophenyl)

piperazine,
1- / 2 '- (2 "-Phenyl-5" -fluoro-3 »-indolyl) -propyl7-4- (4 * -chlorophenyl) -

piperazine, - *

1- / 2 ^f - (2 «-Ethyl-5« -chlor-3 »-indolyl) -2 · -methylethyl7-4- (3 ^l -tr i-

fluoromethy! phenyl) piperazine,
1- / 2 »- (2" -Benzyl-6 »-trifluoromethyl-3" -indolyl) -äthyl7-4 ~ phenylpiperazine,

3098Q8 / 1359

1/2 ^! - (2 "-Propyl-4", 5 "-äthylendiosy-3" -indolyl) -propyl / -4- (2 · -

ethoxyplieny 1) -piperazine,
1/2 ^! - (2 ^ll -Methyl-4 ^B -methoxy-5 ^M -etho3cy-3 ^ll -indolyl) - = propyl7-4-

(4 '-bromophenyl) -piperazine and
1- / 2 · - (4 "-Chlorophenyl-5 ⁿ -propo2y-3 ^rt - ± ndolyl) -butyl7-4- (4 '-propoxyphenyl) -piperazine.

Oh. The inventive method wimen "well-known and new 3-Indolylpiperazine the general formula I Made werdenο These compounds are zneimittel valuable Mx a dampening Viirkung on the central and autonomr: Nervous System" exercise the cardiovascular system and the skeletal muscular system "The compounds are potent ü ? rang.uilizer ₂ muscle relaxants and hypotonics. Some of these compounds are used to treat schizophrenia

Some of the 3-Indolylpiperazine AESX general Eormel I are described in British Patent bites described 944,445 Tsrbindungen can by several methods produced iieT & © n _s, for example, by reduction of a - / B-indolyl-lower-alkanoyl / -piperazinderivats to the corresponding L-- / 3 = ^> indolyl-lower-alkyl7- "piperazine.

The inventive method differs from the known methods, since it allows the production of 3-Indolylpiperäzi- NEN of the general formula I in allows smoother and-'wirtschaftlicher manner and in high yield and purity.

The examples explain the invention

.8th/

example 1

A mixture of 3 g of l- (2'-chloroethyl) -! - (2'-nitro-4 ', 5 ^s -dimetho :: yphenyl) -propan-2-one, 1.8 g of bienylpiperazine and 1.5 gv / Water-free potassium carbonate in 10 ml of 99% -5% ethanol is heated to 85 ° C. under reflux for 5 hours and stirred. Compartment cooling, the mixture is filtered and the residue washed with ethanol washed-β The FiItrat and Waschiösungen ρ are combined and the solvent is distilled off under reduced pressure. The Hüekstand is recrystallized in 5 ml of methanol. There are 0 _s 5 g of 1- (4 '~ 5henylpiperazxno) -ethyl-1- (2'-nitro-4 ", 5'-dimethoxyphenyl) propan-2-one obtained from 1 114 to 115 ° C",

Example p

A "mixture of 4 _S 2 g X» (2 ^ Sss ^ oxyäükjl) -! - (> ^ -nitro-4 ¹ , 5'-diraethoxyphenyl ^ acetonitrile, I ₃ S g Kisaylpigsrasin and 1.5 g potassium carbonate in 10 si dimethylformamide heated ^ ird'4 hours under reflux at 70 G · UaeL fieia AöKililea the mixture in 30 ml of cold Masser poured mid ± m 'b BiaiLyllatiier extracted. the Itherestralste ¥ eroi7ilgt _c via Hi-'irimasulfat dried vnä evaporated "DER Itlcksi'-arid ii ± vü εζι Sillkagel chromatographed raid with eineia Semisefe of benzene and ethyl acetate (3: 1). elui-ert "are 1 ₉ 5 g of l- (4 -Phenylpiperazino ³⁾ -äthyll" (2 "-nitro - = 4 ⁸ _a 5 ^t ~ äiiaetb.ozy) -ac®tsinitrll ice pale yellow oil frosted »-

B eis pi s 1 3 30 ml 5prosentig® lafeoalaugs ~ msü®n si'ö S ₅ 5 g ^ -PlaSva ^ IpipDi-a ^ I-

100 ml of benzene extracted, the benzene extract is washed with water and dried over anhydrous potassium carbonate »

A solution of 4 g 4 _r 2 Uitro-4 _s 5-dimethoxyphenylacetone in 30 ml of dimethylformamide (60 percent) was added to 8 g 0 _P latriumhydrid in 50 ml of toluene. The mixture obtained is heated to 110 ° C. for 90 minutes and stirred. Thereafter, the mixture is "added to the benzene extract of 4-bienylpiperazinoethyl bromide at room temperature within 90 minutes" The resulting mixture is heated for 4 hours to 70 ° C. After cooling, the mixture is poured into water and extracted with diethyl ether The solvent is then distilled off under reduced pressure and the residue is digested with methanol. 5 g of ^{1- (4 l} -phenylpiperazino) -ethyl-l- (2'-nitro-4 ' _S 5 ^l dimethoxyphenyl) -propan-2-one obtained from ¥ _e 114 to 115 ° C.

Example 4

According to Example 3, a benzene solution of 4-phenylpiperazinoethyl bromide is used manufactured. |

A solution of 4 »4 g of 2-Mtro-4p5-dimethoxyphenylacetonitrile in 30 ml of dimethylformamide is added to 0.8 g of sodium hydride (60 percent) in 30 ml of toluene, and the mixture is heated to 40 g for 90 minutes while stirring the mixture at 40 ⁰ C over 90 minutes Aiit offset of Ben & Qllösung of 4-Phenylpiperazinoätliylteöraid thereto and heated for 4 hours at 70 ⁰ C. IJaefa ßeai Abl: ülil © n is the resultant mixture poured into cold water & UJA extracted with diethyl ether The combined XTS records, with fesser washed _ff over sodium sulfate

% ^ i ^ f? Π P '/ 1 * b K Q

'^ ^ f Q / Kl ^% 3 ^l -tä ä- ti tc5 tei c ^ J

2138885

- ίο -

dried and evaporated under reduced pressure. The residue is purified on silica gel or omatograplii sofc. A mixture of benzene and ethyl acetate (5si) is used as the solvent. There are obtained 4-6 g of 1- ^ -'- phenylpiperazino) -ethyl-1- (2'-nitro-4 ¹ , 5 ^l -dimethoxyphenyl) -aoetonitrile as a pale yellow oil.

Example 5

A mixture of 28 g of phenylpiperazine quathyl bromide hydrobromide in 100 ml of 20 percent aqueous sodium carbonate solution is extracted with 150 ml of toluene. The toluene extract is washed and dried over 15 g of anhydrous potassium carbonate for 1 hour. A solution of 50 ml of tert-butanol and 15 ml of ^τ © Ιΐ * ο1 is mixed with 2 g of potassium and heated under a flow of faeces for 1 hour. The resulting potassium tert-butylate solution * mg is mixed with 12 g of l- (2 * -mitro-4 ^l , 5'-dimethoxyphenyl) propan-2-one at 25 ° C., and the mixture is Stirred for 30 minutes at 25 ° C. The toluene solution of the phenylpiperazinoethyl bromide is then added to the tert-butanol solution of 1- (2 · -Ηΐ ^ ο-4 ', 5' -dimethoxyphenyl) propan-2-one at 25.degree. The mixture obtained is stirred at 25 ° C. for 24 hours and then poured into 15 percent hydrochloric acid. The hydrochloric acid solution is made alkaline with 10 percent sodium hydroxide solution and extracted with methylene chloride. The methylene chloride extract is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is digested with 10 ml of methanol. There are 14.3 g of l- (2'-Iiitro-4 ^I »5 '-dime thoxyphenyl) -! - (4' -phenylpiperazinoätfcyl) -pr opan-2-one vom] ?. 115 Ms 117 ° C received «

309803/1359

Example β

A solution of 2 g of ^{1- (4 8} -hienylpiperazinoät] iyl) -l - (2 ^! ~ Nitro = 4 ^s ^ -methylenedioxyphenylj-aeetonitrile in 20 ml of ethanol is mixed with 0.5 g of Raney-ITickel (¥ -6) with hydrogen 'Shaken at atmospheric pressure and room temperature »Haeh uptake of 430 ml of hydrogen, the Raney nickel is filtered off and the filtrate is evaporated under reduced pressure» The residue is recrystallized from 5 ml of methanol. «1 g of 3- (4" = phenylpiperazino- . Ethyl) -5,6-methylenedioxyindole obtained from E, 141 to 143 ° C «

According to example 6 v / are the following connections established?

3- / 4 '~ (o-Tolyl) -piperazinoäthyl7-indole _s F ° 124 to 126 ⁰ C; . 3_ / 4 '- (o-methoxyphenyl) -piperazinoäthyl7-indol _i7 F _0111-114 ° G; 5 "^ 4 s - ~ (o-methoxyphenyl) -piper azinoethyl / -6 ~ methoxyind oil ;,

p _o 98 to 10O ⁰ C; 3 - ^. '- (o-Tolyl) -piperazinoäthyiy. "5", 6-methylenedioxyindole _s

Io 159 to 160 ⁰ C; 3_ Q ι _ (m-tolyl) -piperazinoäthyl7-5,6-dimethoxyindole,

137 to 139 ° O; 3_ ^ 41_ (o-Ethoxyphenyl) -piperazinoäthyl7-5 _s 6-dimethoxyindole, S ¹ . 120 to 124 ° C;

3/4 "_ (o-Chlorphenyi) -piperazinoäthyl7-indole ₉ Po 141 to 143 ⁰ C; 3- / J '- (o-methoxyphenyl) piperazinoethyl / -5 _s 6-dimethoxyindole ₉

P. 116 to 117 ° C.

s "

example

A solution of 2 g of l- (4 ^t -I ^> henylpiperazinoäthyl) -l- (2 ⁰ -nitro-4 ^S p5 ^l -dimethoxyphenyl) acetone in 50 ml of ethanol is mixed with 2 g of 10 percent palladium-on-carbon and 3 ml more focused

Hydrochloric acid is added and the mixture is shaken with hydrogen at room temperature and atmospheric pressure. Once 350 ml of hydrogen have been absorbed, the reduction is complete, the catalyst is filtered off and the piltrate is evaporated under reduced pressure. 15 g of sodium hydroxide solution are added to the residue and extracted with 20 ml of chloroform. The chloroform extract is dried over sodium sulphate and then under reduced pressure The pressure is evaporated. The residue is digested with methanol. "1 g of 2-methyl <= 3- (4'-phenylpiperazinoethyl) -5» 6-dimethoxyindole. Obtained from IL 138 Ms 140 ⁰ C,

Example 3

A solution of 5 g of i- (4 ⁰ -Pl3.enylpiperazinoä.thyl) -l- (2 ^l -nitro-4 ^S £) 5'-diBietiio3Q ^r piienyl) -aoetone-hydrochloride in 30 ml of acetic acid and 5 ml of water is Iron powder is added to the solution for a period of 30 minutes at 85 ° C. while stirring. The solution is then stirred for a further 30 minutes "at 85 to 95 ° C. In the case of the AbMsfolen", 200 ml of chloroform are added to the solution and 40% strength to the mixture caustic soda allüaliseii gsüiaoht _e Then t / ith the mixture filtered ₀ üio CiiIorGfO2 ialoEu: ig AUgstseaatj Ε - *; "'* laessr gei-msGhen and üfeer sodium sulfate gstrocloi3-io T ^ s iösuagamittel% ifird uater verniinaerte® HJZ-uqIz abdastilliert MiÄ? 3.sr Eiisicstand digested with methanol Es: ws ^ DLEA 2 ₃ 2 g of 2-l-i3'i "kr?" l = 5 = "(4 ° ^Sc.

For example 7 or 8 lieräsn aoola Followsaäs

ia produced

1 ^ ß oil

S ί5 tu SU

2-methyl-3 ~ (4'-phenylpiperazinoethyl) indole, F. 153 to 155 ⁰ Cj 2-methyl-3- / 4 ^f - (4 "-methoxyphenyl) -piperazinoäthy 37-5,6-methy-

lendioxyindole, mp 160-163 ° C;
2-Methy 1-3- / 3 -'- (4 "-meth oxyphenyl) -piperazinoäthyl7-5,6-dimeth-

oxyindole hydrochloride, m.p. 215 to 218 ⁰ C; 2-Methy1-3- / 4 '- (2 "-methylphenyl) -piperazinoäthyl7-5,6-dimeth-

oxyindole, F. 120 Ms 122 ⁰ C;
2-methyl-3- / 4 '- (3 "-methylphenyl) -piperazinoäthyl7-5,6-dimeth-

oxyindole hydrochloride, mp 210-215 ° C; 2-Methy 1-3- / 4 '- (3 "-DIe ^ OXy phenyl) -piper az in oäthyl7-5,6-dimeth-

oxyindole hydrochloride, mp 181-185 ° C; 2-methyl-3- / 4 ^f - (2 "-methoxyphenyl) -piperazinoäthyl7-5,6-methylen

dioxyindole, F. .137 ^to ^ 3 ⁰ C ₁ '
2-methyl-3- (4'-phenylpiperazinoethyl) -6-methoxyindole-hydro-

chloride, m.p. 253-257 ° C;
2-phenyl-3- (4'-phenylpiperazinoethyl) -6-methoxyindole,

M.p. 147 to 149 ° C;
2-ethyl-3- (4'-phenylpiperazinoethyl) -5,6-dimethoxyindole-hydro-

hydrochloride, m.p. 236 to 24O ⁰ C;
2-methyl-3- (4 ^f -phenylpiperazinopropyl) -5,6-dimethoxyindole,

M.p. 117 to 119 ° C;
2-methyl-3- (4'-phenylpiperazinoethyl) -5,6-methylenedi bxyindole,

M.p. 151 to 153 ^° C

309808/1359

Claims (1)

Claims 3-Indolylpiperazine der
general formula I. (D in which R- and Rp, which are identical or different, represent a hydrogen or halogen atom, an alkyl radical having 1 to 5 carbon atoms, an alkoxy radical having 1 to 3 carbon atoms or a trifluoromethyl group, or R- and Rp together with the benzene nucleus represent one 5- or 6-membered heterocyclic ring, Rz is a hydrogen atom, an alkyl radical with 1 to 5 carbon atoms, an aryl radical or an aryl-lower-alkyl radical, R * is a hydrogen or halogen atom, an alkyl radical with 1 to 5 carbon atoms, a Alkoxy radical with 1 to 3 carbon atoms or a trifluoromethyl group and Y an alkylene radical Acids, with 1 to 5 carbon atoms, and their salts with / 2. Process for the preparation of the compounds Remäß.Anspruch 1, characterized in that one either a) an nitro compound of the general formula III " ^X (III) in the R-, and Rp the. the above meaning habsn and X is a cyano group _P an alkanoyl radical from I to 6 carbon atoms or an aryl-lower-alkyl radical, rail il-sin Pipera zinc derivative of the general formula IV 309808/1359 in which R. and Y have the meanings given and Z is a halogen atom or a tosyloxy group ₅ or its salt is condensed or
b) a nitro compound of the general formula ¥ in which R- ,, Rp, X, Y and Z have the meaning given above with a piperazine derivative of the general formula TI in the R, which has the meaning given before, or its salt condenses luiö,
c) _the obtained piperasine compound of the general formula II (H) in dor R- _{,, Rg 9} R ^ p Σ imd Y the meaning given above have ρ reduced Jo method according to ibiapruch 2 a) j characterized ₉ that the condensation is carried out in the presence of an AllcalinietallhydridSp -alkoholate or.-Anixäs » 309808/1359 4. The method according to claim 2b), characterized in that the condensation is carried out in the presence of sodium carbonate or potassium carbonate. 5. * The method according to claim 2 c), characterized in that the reduction with hydrogen in the presence of palladium on carbon, Raney nickel or with nascent hydrogen made of iron or zinc and an acid. 6. Medicaments consisting of a compound according to claim 1 and customary carriers, diluents and / or auxiliaries. 09008/1369