CA1193606A

CA1193606A - Substituted phenylpyrazole derivatives, process for their preparation, medicaments based therein, and their use

Info

Publication number: CA1193606A
Application number: CA000421424A
Authority: CA
Inventors: Rudolf Kunstmann; Martin Bickel
Original assignee: Hoechst AG
Current assignee: Hoechst AG
Priority date: 1982-02-13
Filing date: 1983-02-11
Publication date: 1985-09-17
Also published as: EP0086450B1; EP0086450A2; ES519727A0; ATE20057T1; EP0086450A3; DE3205187A1; ES8401475A1; DE3363640D1; JPS58148862A

Abstract

Abstract of the disclosure:
Substituted phenylpyrazole derivatives of the formula

Description

~9;~

- 2 - ilOE 82/F 025 The invention provides substituted phenylpyrazole deri~atives of the formula I

~1 ~ . 11 (I) ~"~,~ /Y~R3 and their salts with physiologically acceptable acids, which due to their pharmacoloyical properties cal1 be used as medicaments.
In the formula I, R1 and R2, which may be identical or different, are hydrogen, halogen, alkyl or alkoxy having from 1 to 4 carbon atoms, nitro or amino, R3 is hydrogen, a saturated or unsaturated, linear or branched a].kyl radical having from 1 to 8 carbon atoms, or a cycloalkyl radical having from 5 to 8 ca~.bon atoms;
the alkyl or cycloalkyl radical in turn may be substituted by a phenyl radical or a phenyl radical which may be mono~
or disubstituted by halogen, nitro, ami.no or alkyl or alkoxy having from 1 to 4 carbon atoms.
Preferred are those compounds of the formula I, in which R1 and R2 are identical or different and represent hydrogen, chlorine, fluorine, methyl or methoxy, and R3 is hydrogen or an alkyl chain having from 1 to 4 carbon atoms, which in turn may be substituted by phenyl optionally mono- or disubstituted by ch]orine, fluori.ne, methyl, methoxy, nitro or amino.
30- Especially preferred are those compounds of the formula I, in which R1 is hydrogen and R2 is chlorine, fluorine, me-thyl or me-thoxy,or R1 and R2 each are metl1oxy, and R3 is hydrogen or an al~yl chaill having from 1 to 4 carbon atoms, which in turn may be suhstituted by phenyl optionally mono- or dlsubstituted by chlol^irle, fluorine, methyl or methoxy .
.,, , , ~

~93~06

- 3- OE 8?/F 025 The compounds of the formula I according to the in-ven-tion are novel substances. In animal tests, they inhibit the secretion of ~astri..c acid stimulated by penta~astrin and are therefore medi.caments for the prevention and therapy of gastric ulcers. Furthermore, they serve as intermediates for the synthesis of novel medicaments.
Subject of the invention is also a process for the preparation of compounds of the formula I, which comprises reacting an aminopyrroline of the formula II with hydrazine or its hydrate to give a compound of the formula I

~R3 ~ ~ ~ }~
R1 ~ L ~ ~ R 1~
~\1~ ~\~/ '1~\ R3 O NH2 ~ N-l (II) (I~
in ~hich formulae R1 throu~h R3 are as defined ahove sub formula I, and if desired, converting a compound of the formula I in which R3 i.s benzyl to a compound of the formula I in which R3 is hydrogen by splitting off the benzyl group.
Generally, 1,3-di.carbonyl compounds or the derivatives thereof~ e.g. B-aminovinylketones, are smoothly cyclized to the corresponding pyrazole derivatives (A.N. Kost, I.I.
Grandberg, Advances in ~leterocycli.c Chemistry, Edited by A.R. Katritzky, A.J. Boulton, Vol. 6, p. 358 et seq .
Academic Press, New York, London 1966). In the present case, therefore, pyrrolo-/ 3,~~c_7-pyrazoles (IIa~ would be expected to be formed. However, it was surprising to obser.ve that on reaction of II with a hydrazine compound I
are obtained which difer from those initi.ally expected by an additionai reduction step in which the pyrroline ring of the starting material is opened.

3~
~ 4 - HOE 8?/F 025_ R1 ~ IIa The starting substances of the formula II are novel eompounds, and they are synthetized according to the following methods:
By reaction with substituted 3-aminopropionic acid nitri]es IV, the aminoketones V are prepared from substi-tuted phenacyl halides III, in which formulae R1 through R3 are as defined sub formula I, and X is halogen, especially chlorine or bromine.

R3-N-C~12-C~I2-C~ ~R1 j~ ~ce~

(III) (I~) (V) The eompounds IV are obtained by Michael addition of amines (R3-NH2) to equimolar amounts of acrylonitrile in methanol.
The conversion to compounds V is advantageously carried out in an inert solvent sueh as eth~r, ac.~etone or a ehlorinated hyclrocarbon, for example methylene chloride;
the reaetion temperature beiny in a range of from ~30 to C ~
The hydrogen halide formed in the reaction of III
to IV is advanta~eous'.y absorbed by a suitable base.
Especial]y suitable are tertiary amines which are unfit for quaternization with III. Suitable amines are for example 1,4~diaza-bieyelo/ 2,2,2 7Octane, 1,5-diaza-bieyelo/ 4,3,0_7non~5-ene or N,N-di.isopropylet.hy].amine. The most simple method consists howevel^ in usiny a double excess of amine IV. In the ease whe.re R3 is hydroyen, a 3~

- 5 - HOR 82/F 025_ mixture of 3-ami.nopropionic acid nitril.e ~IV, R -- H) and one of the above acid-binding agents, for example in a solvent as indicated above, is advantageously intro-duced first into the reaction vessel and the phenacyl halide, dissolved in the same solvent, is added dropwise at temperatures of below 5-8~C.
The compounds V may alternatively be usec1. in crude form for the subsequent cyclization to the compounds II, so that their purification by crystallization or distillation can be omitted.
Cyclization of V to II is generally carried out in a basic medium by treating a compound V in an appropriate alcohol such as methanol, ethanol, isopropanol or tert.-butyl alcohol with a corresponding alkali metal a]coholate, preferably sodium alcoholate. The reaction temperature is .. from -20C to the reflux temperature of the reaction mixture. The reacti.on being complete, the product can.be isolated by adc1ing water.
Alternatively, cyclization is possihle under acidic conditions; the use of a Lewis acid such as aluminum chloride or boron trifluoride beiny recommended in this case. For exa~.ple, a compound V is introduced with cooling into boron trifluoricle etherate, and depending on the substituents the reaction solution is maintained at a .25. temperature of from -10C to the reflux temperatu~e of the reaction mixture until the reaction is complete. By addition of water, the compounds VI c.ry~tallize in cold state, or they can be separated by extraction us:ing an organic .solvent.

Y~ ~ ? ~ ]:T

V VI `' . .

~ 3~3~)6 - 6 - _OE e2,~ 025 By treatin(, th~ compound VI obtained with aqueous alka~is such as a solution o~ sodium hydroxide, amrnonia or bicarbonate, it is easily split hydrolytica]ly to give a compound II.
This process of acid cyclization is particularly recommended in the case where R1 and R2 are metlloxy -substituents.
For convertin~ the compounds II to I, they are treated suitably with hydrazine hydrate. ~dvantageous are reflux temperatures in hydrazine hydrate or alcoholic solutions. Suitable alcohols are primary alcoho]s such as methanol or ethanol, secondary alco}lols such as isopropanol, or tertiary alcohols such as tert.-butanol. The conversion to compound I may also be performed with hydrazine in glacial acetic acid.
The reaction being complete, the reaction mixture is concentrated and the compound I is isolated in accordance with its basic character by converting it to a water-soluble salt by adding a mineral acid, extractin~ the aqueous salt solution with a water-immiscible solvent in order to remove neutral impurities, and therl liberating the base again by adjusting the pH of the water phase in the alkaline range. Alternatively, the compound I may be precipitated by adding water, or extracted by means of an organic water~immiscible solvent.
The optional sp]itting-off of a benzyl group may be carried out as follows:
Especially advantageous is the hydrogeno1ytic splitting in the presence of Raney nickel in an acidic medium. Other methods may be applied alternatively, for example sp]itting with elementary sodium in ]iquid ammonia, or treatment with tetra]in (or another easily oxidizable hydrocarbon splittLng off hydrogen] in the presence of a noble metal catalyst, -for c-~xample pa]ladium on charcoal, at elevated temperature, especially at 110-1~0C.
The compounds of the :invellt:ion have va]uable pharma--cological properties. In animal tests, they inhikit the ~ ~.9;~,V6 -- 7 ~ ~IOE ~2/F 025 secretion of gastric acid. They are therefore suitable as medicaments Eor the prevention and therapy of gastric ulcers.
The novel compounds can be administered as medicaments either per se or in admixture witth physiologically tolerated auxiliaries or carrier materials. For oral administration the compounds of the formnla I are mixed with the usual substances and transformed according to customary methods into the usual forms of adrninistration, for example tablets, push-fit capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions.
Suitable inert carrier materials are, for example, magnesium carbonate, lactose or corn starch. For tab1ets, the compounds can be formulated as dry or moist granules.
As oily carriers or solvents especially vegetable and mineral oils can be used, for example sunflower oil, olive - oil or paraffin oil.
For intravenous application, the active compounds or the salts thereof with physiologically tolerable organic or inorganic acids are dissolved in substances customary for this purpose. Examples of organic acids are acetic~ propionic, lactic, malonic, succinic, maleic, fumaric, citric, malic, tartaric, benzoic, o}~yethane--sulfonic, aceturic (acetylaminoacetic), ethylenediamine-tetraace-tic, embonic (1,1~-methylene-bis-(2-hydroxy-3-` naphthoic)) acid, and synthetic resins con.aining acidic groups. Examples of inorganic acids are hydroIlalic acids such as hydrochloric or hydrobromic acid, sulflIric, phosphoric and amidosulfonic acid.
Suitable solvents for intravenous administration are, for example, water, physiological sodium chloride solution, which can be provided with furt-her additives such as alcohols, (for ex~ propanediol or glycerol), or sugar solutions, (for ex~ ylucose or mannitol solutions).
The fol]owing Exarnp]es illustrate the invention.

3~

Example I
5-(2-i~.ethylaminoethyl)~ pyrazole a) N-Methyl-N-(2-p~yl-2-_xo-ethyl)-3-am _ propion~e_ acid nitrile 0.1 Mol of phenacylbromide is dissolved in 100 ml of acetone, and 0.2 mol of 3-methylamlnopropionic acid nitrile, dissolved in 50 ml of acetone, is added at 0C.
The batch is stirred for 15 hours at room tempexature, the solution is filtered off from undissolved ammonium salt, and concentrated. The crude product is sufficiently pure for the further reaction.
b) 3-Amino-2-benzo~l-1-methyl-~-~d:~,g,~lL~rrole 0.1 ~ol of N~methyl-N-(2-phenyl-2-oxo-e-thyl~-3-amino--propionic acid nitrile 1s dissolvecl in 200 ml of rrlethano].
After addition of 0.3 mol of sodium methylate, the - mixture is refluxed for 2 hours. Subsequent]y, the reaction mix-ture is poured on-to 800 ml of a mixture of iee and water, extracted with methylene chloride, the organic phase is dried and concentrated. The remaining oil crystallizes slowly (m.p. 115-117C), and it is sufficiently pure for the further reaction.
-c) 5-(2-Methylaminoethyl-3-phenyl-pyrazole 0.03 Mol of 3-amino-2-benzoyl~ methyl-~,5-dihydro-pyrrole in 50 ml of ethanol are refluxed for 4 hours a~ter having added 8 ml of hydrazine hydrate. Subsequently, the reaction mixture is pouxed onto 200 ml of water, and extrac-~ed with ethyl acetate. After drying and concen-tration of the orgaIlic phase, an oily crude product is obtained which is convertect to the salt with oxalic acid.
M.p. 137C (oxala-te).
Example 2 - 5-(2-Benzylamino~thyl)-3-~heny~ ~razole _ _ . . .
-a)-N-Benzyl-N-(2-~ _ny__2-oxo--e-thyl)-3-aminopropio~ ac:~d nitrile Aceording to Example 1a irom phenacylbromide and 3-benzylaminopropionic acid nitrile. Crude product reactecl further.

~9~3~6 b) 3-Amino-2-benz.oyl~ benz~4,5-~di~o-pyr.role According to ~xamplc lb from N--benzyl-N-(2-phenyl-2-oxc>-e-thyl)-3--aminopropionic acid nitrile.
m.p.: 149-150C (diethyl ether) 5 c) 5-(2-Be zylaminoethyl)-3=phelly -~yrazcle According to Example 1c from 3-amino-2-benzoyl-1-benzyl-4,5-dihydro-pyr.role and hydrazine in methano]
m.p.: 109C (free base) 213-215C (hydrochlori.de) Example 3 5-(2-Benzylaminoethy )-3-(3,4-dimetho~yphenyl)-~y_a%ole a)- N-Benzyl-N-/ 2-(3!4--dimethoxyphenyl)-2-oxo-ethyl_7-3-_ aminopropionic ac d nltrile_ Corresponding to Example 1a from 3,4-dimethoxy-phenacylbromide and 3-benzylaminopropionic acid nitrile.
- 15 m.p.: 79-82C (diethyl ether) ' b)''1-Benzyl--7-(3,4-dimethoxyphe_~1)-5,5-difluor.o-2,3-_ dihydro-6-oxa-4-azonia-5-borato-indole 0.1 Mol c~f N-benzyl--N-/ 2-(3,4-dirnethoxypheny].)-2-oxo-ethyl_7-3-amino-propionic acid nitrile in 100 ml of boron .20 trifluoride etherate is maintained for 16 hours at 90-9SC. The reaction mixture is then poured onto ice, adjusted to neutral wit:h aqueous an~monia solution, and extracted with ethyl ace-tate. After drying and concen-tration of the organ.ic phase an oil is obtained which is 25 crystallized from isopropanol.
M.p. 175-176C.
-c) 3-Ami.no-1-benæyl~2-(3,4--dime-lhoxyben7oyl)-4,5--dil-1~^o pyrro]e 0.05 Mol of the compound prepared according to 30 Example 3b is suspended in 100 Ml of concentrated aqueous sodium hydroxide solution, and stirred for 24 hours at room temperature. The precipitate is suction-:E'iltered, . . washed to neutral and the filter cake is dried.
M.p. 134-136C.

~ 33~06 - 10 -- HO _82/F 025 d) 5-(2-senzy]aminoeth~-3-(3~4-dimetho~x~hen~)-p~ra%ole __ _ ___ ___ From 3-amino~ benzyl-2-(3,4-dimethoxybenzoyl)-4,5~
dihydropyrrole by treatment with hydrazine in t.-hutanol accordinc~ to Example 1c.
Example 4 ' 5-/ 2-(2-Chlorobel~y~amino)-ethyl_7-3-phenyl-pyrazole a) N-(2-Chlorobenzyl)-N-(2~phenyl-2-oxo-ethyl)-3-amino-propionic acid nitrile.
From 1 mol of phenacylbxomide and 1 mol o~ 3-(2 chloroberlzy:Lamino)-propionic acid nitrile accordin~ to Example 1a with 1 mol of N,N-diisopropyl-e-thylamine a~
acid acceptor. The crude product was reacted further.
b) 3-Amino~-2~benzoyl-1-(2-chlorobenzyl-4,5-dihy~lro-pyrrole.
From N-(2-chlorobenzyl)-N-(2-phenyl-2-oxo-ethyl)-3-amino-propionic acid nitrile by treatment with methylate according to Examp],e 1b.
m.p.: 151C.
c) 5-/ 2-(2~-Chlorobelizylamino)-ethyl_7-3--phenyl -pyrazole.
From 3-amino-2-benzoyl-1-(2-chlorobenzyl)-4,5-dihydro-pyrrole by treatment with hydrazine in methancl accordins to Example 1c.
m.p.: 206-207~C (HCl) ~ le 5 S-/ 2-(4-Meth~ _zy~_mino)-ethyl 7-3-phe~ yrazole a) N-(4-Methylbenzyl)-N-(2~phellyl-2-oxo~ethyl)-3-amino-propionic aci~ nitrile From phenacylbromidc and 3-(4-methylbenzylamino)-propionic acid nitrile according to Example 1a.
b) 3-~Amino--2-benzoyl-1-(4-methylbenzyl)-4,5-dihydro-pyrrole.
From N-(4-rnetllylbenzyl)-N-(2-pllerlyl-2-oxo--ethyl)-3-amino-prcpionic acid nitrile by treatment with methylate according to Example 1b.

~'33~
~ E1OE 82/F_025 c) 5-/ 2-(4-Methylbenzylamino)-ethyl_ 7 - 3-phenyl~
pyrazole.
From 3-amino-2-benzoyl-1-~4-methylbenzy])-4,S-dihydro-pyrrole by t~eatment ~7ith hydrazine in isopropanol according to Example 1c.
Example 6 5-[2~ Methoxybenzylami.no)-ethyl]-3--phenyl~p~_ zole a) N-(3-Methoxybenzy])-N-(2-phenyl-2-oxo--ethyl)-3--amino-propionic acid nitrile.
From 1 mol of phenacylbromide and 1 mol of 3-~3-methoxybenzyl-amino)-propionic acid nitri]e according l.o Example 1a, wi.th 1 mol of N,N-diisopropylethylamine as acid acceptor.
b) 3-Amino-2-benzoyl-1-(3-methoxybenzyl)-4,5-dihydro-pyrazole.
From N-(3-methoxybenzyl)-N-(2-phenyl-2-oxo-ethyl)-3 aminopropionic acid nitrile by treatment with methylate accQr~in~ to Example 1b.
c) 5-[2-(3-Methoxybenzylamino)-ethyl]-3-phenyl-pyrazole From 3-amino-2-bellzoyl-1-(3-methoxyhenzyl)-4,5-dihydro-pyrrole by treatment with hydrazine in methanol according to Example 1c.
m.p.: 195C (oxalate) E mple 7_ _ 5-[2-(3,4-Dim~thox~b_nzy mi.no)-e'chyl]--3--phen~
pyrazole a) N-(3,4--Dimethoxybenzyl)-N-(2-phenyl-2-oxo-ethyl)-3-amino-propionic acid nitril.e.
From phenacylbrolni.de and 3-(3,4--dimetho.Yyber)Y.yl~mino)-propi.onic acid nitrile accord.irlg to Example 1a.
b) 3-Amino-2-benzoyl-1-(3,4-dimethoxyben7.yl)-4,5-di.hyclro--pyrrole.
From N-(3,4-dilrlethoxyphenyl)-N-~2-phenyl-2-oxc)-ethyl)-3~amino--propion-c acid nitrile by 'creatment with methylate according to Exalnple 1b~

3~;~)6 ,i - 12 - HOE _ /F ~5 .~
c) 5-[2-(3,~-Dimethoxybenzylamino)-ethyl]-3-pheny]-pyrazole From 3-amino-2-benzoyl-1-(3,4--dimethoxybenzyl~-~,5-dihydro-pyrrole by treatrnellt with hydrazine in ethanol according to ~xample 1c.
Example 3 _ _ - 5-[2-(2-Phe_ylethLl m no)-etl~ 3-phenyl-pyrazole a) N-(2-Phenylethyl)-N-(2-phenyl-2--oxo-ethy])~3-amino-propionic acid nitrile.
From phenacylbromide and 3--(2-phenylethylamino)-propionic acid nitrile according to Example 1a.
b) 3-tlmino-2-benzoyl-1-(2-phenylethyl)-4,5-dihydro-pyrrole From N-(2-phenylethyl)-N-(2-phenyl-2-oxo-etllyl)-3-amino-propionic acid nitrile by treatment with methylate accordir.g to Example 1b.
c) 5-[2-(2-Pheny]ethylamino)-ethyl]-3-phenyl-pyrazole From 3-amino-2-benzoyl-1-(2-phenylethyl)-~,5-dihydro-pyrrole by treatment with hydrazine in ethanol corres-ponding to Example 1c.
Example 9 5-[2-(3-Phenylpropylami_o)-ethyl] _-~henyl-pyrazole a) N-(3-Phenylpropyl)-N-(2-phenyl-2-oxo-ethyl)-3-, amino-propionic acid nitrile.
From 1 mol of phenacy]bromide and 1 mol of 3-(3-phenyl-propylamino)-propionic acid nitrile accordillc~ to Example 1a, with 1 mol of N,N-diisopropyl-ethylalnine as acid acceptor.
b) 3-Amino-2-benzoyl-1-(3-phenylpropyl)-4,5-dihydro-pyrrole From N-(3--phenylpropyl)-N-(2-phenyl-2 oxo-ethyl)-3-amino-propionic acld nitrile by treatment Witll methylate according to Exarlple 1b.
c) 5-[2-(3-Phenylpropylamino)-et'ny:L]-3-phenyl~
pyrazole .

~L~
- 13 E~OE 82/F _025 From 3-t;m:ino-2-belzoyl-1-(3-pheny]propyl)--4,5-dihydro-pyrro].e by tr~atment with hydra.~ine in i.sopropanol aeeordin~ to Examp]e 1e.
Example 1 0 5-[2-Benzy].amino_ethyll-3--~4-ehlorophenyl~~eyrazol_ a) N-Benzyl-N-(2-(4-chloropllenyl)-2-oxo-ethyl)-3-arnino-propionie aeid nitrile From 4-ehlorophenacylbromide and 3-(benzylamino)--propionie acid ni-trile according -to Exampl.e 1a.
b) 3-Amino-2-(4-chlorohenzoyl)-1~benzyl-4,5-dlhydro-pyrrole From N-(senzyl)-N~(2-(4-chlorophenyl)-2-os~o-~thyl)-3-amino-propionic aeid nitrile by treatment with methylate . aeeording to Example 1b.
e) 5-[2-Benzylamino-ethyl]-3-(4-ehlorophenyl)-pyrazole From 3-amino-2-(4-chlorobenzoyl)-1-benzyl 4,5-dihydro-pyrrole by treatment with hydrazine in ethanol aceording to Example 1c.
m.p.: 182-184C (HCl) Example 11_ 5-[2-(Chlorobenzylamino)-ethyl-3- 4-chlorophenyl) _ pyrazole a) N-(2-Chlorobenzyl)-N-[2-(4-ehlorophenyl)-2-oxo' ethyl]-3-amino-propionie acid ni-trile From 4-chlorophenacylbromide and 3-(2-chlorobenzylamino~-propionie acid nitri.le aceording to Example 1a.
b) 3--Amino 2-l4-ehlorohenzoyl)-1-(2-chloroberlzyl)-

4,5-dihydro-pyrl.ole.
From N-(2-chlorobenzyl)-N-[2-(4-ehlorophenyl)-2-oxo-ethyl]-3-amino-propionie acid ni.trile by trea.tment with methylate aceording to Example 1b.
e) 5-[2-(2-Chlorobenzylamino)-ethyl]-3-(4-ehloro~-phenyl)-pyrazole.
From 3-amino-2-(4-chlorohenzoyl)--1-(2--chlcjrobc-~nzyl) 4,5-dihydro-pyrrole by treatment with hydrazine i.n alcoho].
aecording to Exarr.ple 1c.
m.p.: 241 C (2 HCl) .

~36~
- 14 - ~IOE S2/F 02 E ~mple 12 S-[2-Me 1 ]am~no-e-tllyl]-3-(4 chl_rophen~lL-J~yxazo~e a) N-Methyl-N-[2-(4-chlorophenyl)-2-oxo-ethyl]-3-amino-propionic acid nitrile Erom 4-chlorophenacylbromide and 3--methylamino-propionic acid nitrile according to Example 1a.
b) 3-Amino-2-(4-chlor~be~oyl)-1-methy]--4,5-dihydro-pyrrole.
From N--methyl-N-[2-(~-chlorophenyl)-2-oxo-etilyl]-3-amino-propionic acid nitrile by treatment with methylate according to Example 1b.
m.p.: 143C.
c~ 5-[2-Methy]amino-etllyl]-3-(4-chloropllerlyl)-pyrazole From 3-amino-2-(4-chlorobenzoyl)-1-methyl-4,5-dihydr-o--pyrrole by treatment with hydrazine in alcohol according to Example 1c.
m.p. 118C.
Example 13

- 5-[2-(4-Chlorobenzylamino)-e-thyl]-3-phen~ y~_ole a) N-(~-Chlorobenzyl)-N-[2-phenyl 2-oxo ethyl]-3-amino-propionic acid nitrile.
From phenacylbromide and 3-(4-cllloroberlzylamino)-propionic acid nitrile accordincJ to Example 1a~
b) 3-Amino-2-benzoyl-1--(4-ch]orobenzyl)--4,5-dihydro--pyrrole.
From N-(~--chlorobenzy])-N--[2-phenyl-2-oxo-ethyl]-3-amino-propionic acid nitrile by treatment with methylate - according to Example 1b.
m.p.: 175C
c) 5-[2-(4-Chlorobenzylamino)-etllyl]--3-phenyl-pyLazole From 3-amino-2-benzoyl-1-~(4~ch]orobenzyl)-~,S-dihydro-pyrrole by treatmellt with hydrazine ln alcohol according -to Example 1c.
m.p.: 156C (2 ~Cl~

3&it)~ ~

Example 19 _ _ 5-[2-(2-Ch_orobenz~amino)-eth~ phenyl-~yrazole _ a) N-(2-Cnlorobenæyl-N-[2-phenyl-2-oxo-ethyl]~3-amino-propionic acid nitrile.
From phenacylbromide and 3-(2-chlorobenzylamino)-propionic acicl nitrile according to Example1a.
b) 3-~nino--2-benzoyl-1 (2-chlorobenzyl)~4,5-dihyc1ro-pyrro]e.
From N-~2-chlorobenzyl)-N-[2-phenyl-2-oxo-ethyl]-3-amino-propionic acid nitrile by treatment w:ith methylate according to ~xample 1b.
m.p.: 151C
c) 5-[2-(2--Chlorobenzylamino)-ethy]]-3-phenyl-pyrazole From 3-amino-2-benzoyl-1-(2-chlorobenzy])-4,5-dihydro-pyrrole by treatment with hydrazine in alcohol according to Example 1c.
Example 15 5-(2-AminQethyl)-3-p}1eny]-pyrazole From 5-(2-benzylaminoethyl)--3-phenylpyrazole by catalytic hydrogenation with Raney nickel as catalyst in methanol at 50C and 50 atmospheres gage within 50 hours of reaction time. After separation of the catalyst, an oil is obtained which can be crystallized from ethyl acetate.
M.p. 118-120C

Claims

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:

1. A process for the preparation of a substituted phenyl-pyrazole derivative of the formula I

I

and the salts thereof with physiologically acceptable acids, wherein R1 and R2, which may be identical or different, are hydrogen, halogen, alkyl or alkoxy having from 1 to 4 carbon atoms, nitro or amino, R3 is hydrogen, a saturated or unsaturated, linear or branched alkyl radical having from 1 to 8 carbon atoms, or a cycloalkyl radical having from 5 to 8 carbon atoms; the alkyl or cyclo-alkyl radical in turn may be substituted by a phenyl radical or a phenyl radical which may be mono- or disubstituted by halogen, nitro, amino or alkyl or alkoxy having from 1 to 4 carbon atoms, in which an aminopyrroline of the formula II

II

wherein R1 to R3 are as defined above, is reacted with hydrazine or its hydrate to yield a compound of the formula I, a compound of the formula I wherein R3 is benzyl may be converted to a compound of the formula I in which R3 is hydrogen by splitting off the benzyl group, and a physiologically acceptable salt may be prepared by reaction with a physiologically acceptable acid.

2. A substituted phenylpyrazole derivative of the formula I as defined in claim 1, and the salts thereof with physiologically acceptable acids, whenever obtained according to a process as claimed in claim 1 or by an obvious chemical equivalent thereof.