US3867389A - Alpha-(n-benzoyloxy and phenylamino alkyl-piperazino)-beta-benzoyl-propionic acid derivatives - Google Patents

Alpha-(n-benzoyloxy and phenylamino alkyl-piperazino)-beta-benzoyl-propionic acid derivatives Download PDF

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US3867389A
US3867389A US359440A US35944073A US3867389A US 3867389 A US3867389 A US 3867389A US 359440 A US359440 A US 359440A US 35944073 A US35944073 A US 35944073A US 3867389 A US3867389 A US 3867389A
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Thomas Raabe
Adolf Stachel
Josef Scholtholt
Rolf-Eberhard Nitz
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Cassella Farbwerke Mainkur AG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/145—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/63—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups

Definitions

  • the present invention relates to new pharmacologically valuable ketone derivatives exhibiting a distinct dilatory action on the cerebral vessels and which have the general formula and their pharmaceutically acceptable acid addition salts, wherein R stands for a member selected from the group consisting of CN, CONH COOH, COONa and COOK,
  • R stands for a member selected from the group consisting of and groups and to processes for producing said ketone derivatives.
  • the present invention relates to new, pharmacologically valuable ketone derivatives of the general forwherein R, stands for CN, CONH COOH, COONa or COOK, R stands for X stands for alkylene having 1 to 4 carbon atoms,
  • Y stands for -O-CO or -CONH- R and R each stand for hydrogen or alkyl having up to 6 carbon atoms
  • R stands for hydrogen or OH
  • nucleus I may have I to 3 alkoxy, halogen, alkyl or nitro substituents,
  • nucleus Il may have i to 3 alkoxy, halogen or alkyl substituents, and
  • nucleus III may be substituted by l to 3 methoxy groups
  • the compounds of general formula l contain at least one basic nitrogen atom and may consequently form or be formed as salts, in particular hydrohalides, and the invention extends to such acid addition salts, Where pharmaceutically acceptable.
  • Preferred halogen substituents for the nucleus I and /or the nucleus II are fluorine, chlorine and bromine.
  • Preferred alkyl substituents of the nuecleus I and of the nucleus [1 contain 1 to 8 carbon atoms.
  • Preferred alkoxy substuents are methoxy groups.
  • the compounds of formula I may be prepared, for example, by the addition of amines of the general formula to compounds of the general formula Those compounds of formula I in which R stands for and Y represents the -OCO group, so that they have the general formula may also be synthesized by the addition of amines hav- I ing the general formula to compounds of the general formula III followed by esterifiction of the adduets with bcnzoic acid derivatives of the general formula wherein Z stands for a halogen atom or the radical Those compounds of formula I in which R stands for a nitrile group may also be prepared by addition of HCN to vinylogous amines of the general formula COOII VII VIII
  • the chlorides Xl necessary for this purpose may be prepared, as far as they are not yet described in literature, according to known per se methods.
  • the simplest method for the prepartion of the chlorides Xl consists in the addition, in the presence of Friedel-Crafts-type catalysts, of suitable acid chlorides XV on acetylene according to the following reaction equation:
  • Initial compounds of formula III wherein R represents the COOH group may be prepared either by diazotation of the corresponding carbonamides XX according to the following reaction scheme or directly by saponification ofthe nitriles XIX according to the following scheme or by reaction of maleic acid anhydride with the corresponding benzene derivatives under the conditions of the Freidel-Crafts reaction l O o
  • the compounds of general formula l of the present invention are valuable pharamaceuticals. They exert, especially where R, means CN, for instance, a distinct dilatory action on the cerebral vessels and are, in this respect, far superior to other known substances of this kind.
  • the compounds of the present invention and their pharmaceutically acceptable salts may be employed together with pharmaceutically acceptable diluents or carriers for the preparation of pharmaceutical formulations such as tablets, dragees, suppositories, capsules, solutions, suspensions or emulsions.
  • These pharmaceutical preparations may also contain other therapeutically active substances.
  • propionitrile-hydrochloride (a-methyl-B-hydroxy-pheni.v.
  • hydrochloride (a-methyl-B-hydroxy- 2.0 +90 14 1 1 phenethylamlno)-propioi, l0 HS/+50 17 nitrile hydrochloride trimethoxyphenethyl- +22/+2 8 amino)-propionitrilehydrochloride tn'methoxyanilino)-carbonylmethyl-piperazinyl- 1.0 10.0 30 +8 (1 ')]-propionitn'lep.o. i.d.
  • the water-insoluble part is separated, dried, recrystallized once from benzene/petroleum ether and converted with ethanolic hydrochloric acid and with the 5 concurrent use of anhydrous ether to the hydrochloride.
  • the hydrochloride is reconverted in the usual manner to the base. After recrystallization from benzene/petroleum ether one obtains the 3-(pchlorobenzoyl)-2-(a-methyl-B-hydroxy-phenethylamino)-propionitrile having a melting point of l 12-1 14.
  • the same product is' obtained by treating N-[Z- (2',3,4-trimethoxybenzoyl)-l-cyanoethyl]-N'-(acet- 3,4',5-trimethoxy-anilido)piperazine-hydrochloride (prepared by addition of Z-[piperazinyl (l)]-acetic acid-3',4',5-trimethoxyanilide on 2',3,4-trimethoxybenzoylacrylonitrile analogously to the prescription of Example 5, melting point: 181) with concentrated sulfuric acid.
  • the acid may be converted with an equimolar amount of sodium ethylate to its sodium salt.
  • the 2,3,4'-trimethoxybenzoylacrylic acid required as starting material may be prepared as follows:
  • a solution consisting of 27 g. piperazine in 100 c.c. isopropanol is admixed, while stirring at room tempera,- ture, with a solution consisting of 14 g. N-chloroacetyl- 3',4,5-trimethoxyani1ine in 60 c.c. dioxane.
  • the reaction solution is then heated for 7 hours under reflux, evaporated and the residue is dissolved in 2N sodium hydroxide solution and chloroform.
  • the chloroform phase is separated.
  • the aqueous phase is again extracted with CHCl both chloroform extracts are combined, washed and concentrated in vacuo.
  • the remaining oil solidifies by the addition of diisopropylether. Obtained are after suction-filtration 15 g. 2- [piperazinyl (l)]-acetic acid-3,4,5'-trimethoxyanilide having a melting point of 125.
  • EXAMPLE 3 2 g. 3'-methoxybenzoylacrylonitrile are dissolved in 30 c.c. dioxane, 1.39 g. N-hydroxyethylpiperazine are added and the solution is first allowed to stand for one hour at room temperature and then concentrated in vacuo. The residue is recrystallized from benzene/petroleum ether. Obtained are 3.2 g. N-[2-(mmethoxybenzoyl)-l cyano-ethyll-N'-[hydroxyethy1]- piperazine having a melting point of 126l28.
  • a solution consisting of 17.8 g. ethyl formiate and 30 g. 3-methoxyacetophenone is added dropwise, while stirring at 8-10, to a suspension of 13 g. sodium methylate in 100 c.c. anhydrous benzene. Stirring is continued for another 16 hours at room temeprature, then the reaction mixture is sucked off, washed with anhydrous alcohol and the residue is dried in vacuo. Obtained are 38.9 g. of the sodium salt of the 3'-methoxybenzoylvinyl alcohol.
  • l A compound of the formula wherein Z stands for a member selected from the group consisting of OH. NH; and ONa, X stands for alkylene with l 4 carbon atoms, Y stands for a member selected from the group consisting of OCO and CO-NH. the nucleus 1 being selected from the group consisting of phenyl and mono-, diand trimethoxyphenyl. and nucleus ll being selected from the group consisting of phenyl and mono-, diand trimethoxyphenyl, and the pharmaceutically acceptable acid addition salts of said compounds.
  • nucleus I is monomethoxyphenyl
  • Z is OH
  • X is C H
  • Y is OCO-
  • nucleus ll is trimethoxyphenyl
  • Y is -OCO
  • nucleus ll is trimethoxyphenyl
  • pharmaceutically acceptable addition salts of said compound
  • nucleus 1 is trimethoxyphenyl
  • Z is -OH
  • X is --CH Y is CONH
  • nucleus [1 is trimethoxyphenyl

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  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to new pharmacologically valuable ketone derivatives exhibiting a distinct dilatory action on the cerebral vessels and which have the general formula

AND THEIR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS, WHEREIN R1 stands for a member selected from the group consisting of CN, -CONH2, -COOH, -COONa and -COOK, R2 stands for a member selected from the group consisting of

X stands for alkylene having 1 to 4 carbon atoms, Y stands for a member selected from the group consisting of -OCO- and -CO-NH-, R3 and R4 each stand for a member selected from the group consisting of hydrogen and alkyl having 1 to 6 carbon atoms, R5 stands for a member selected from the group consisting of hydrogen and -OH, the nucleus I may have 1 to 3 alkoxy, halogen, alkyl or nitro substituents, THE NUCLEUS II may have 1 to 3 alkoxy, halogen or alkyl substituents THE NUCLEUS III may be substituted by 1 to 3 methoxy groups and to processes for producing said ketone derivatives.

Description

United States Patent [191 Raabe et al.
[451 Feb. 18,1975
[ ALPHA-(N-BENZOYLOXY AND Pl-IENYLAMINO ALKYL-PIPERAZINO)-BETA-BENZOYL- PROPIONIC ACID DERIVATIVES [75] lnventors: Thomas Raabe, Heusenstamm uber Offenbach, Germany; Aldolf Stachel, deceased, late of Offenbach, Germany by Ingeburg Lydia Katharina Stachel, heiress; Josef Scholtholt, Frankfurt am (Main)-Fechenheim; Rolf-Eberhard Nitz, Bergen-Enkheim, both of Germany [73] Assignee: Cassela Farbwerke Mainkur Aktiengesellschaft, Frankfurt (Main), Germany [22] Filed: May 11, 1973 [21] Appl. No.: 359,440
Related US. Application Data [62] Division of Ser. No. 239,359, March 29, 1972.
[52] US. Cl. 260/268 R, 260/268 CN, 260/465 K, 260/465 E, 260/518 R, 260/518 A, 260/558 [51] Int. Cl C07d 51/70 [58] Field of Search 260/268 R, 268 CN [56] References Cited UNITED STATES PATENTS 3,594,384 7/1971 Stachel et al 260/268 CN Primary Examiner-Donald G. Daus Assistant Examiner-Jose Tovar Attorney, Agent, or Firm-Francis M. Crawford [57] ABSTRACT The present invention relates to new pharmacologically valuable ketone derivatives exhibiting a distinct dilatory action on the cerebral vessels and which have the general formula and their pharmaceutically acceptable acid addition salts, wherein R stands for a member selected from the group consisting of CN, CONH COOH, COONa and COOK,
R stands for a member selected from the group consisting of and groups and to processes for producing said ketone derivatives.
5 Claims, No Drawings 1 ALPHA-(N-BENZOYLOXY AND PHENYLAMINO ALKYL-PIPERAZINO)-BETA-BENZOYL- PROPIONIC ACID DERIVATIVES This application is a division of application Ser. No, 239,359, filed Mar. 29, I972.
The present invention relates to new, pharmacologically valuable ketone derivatives of the general forwherein R, stands for CN, CONH COOH, COONa or COOK, R stands for X stands for alkylene having 1 to 4 carbon atoms,
Y stands for -O-CO or -CONH- R and R each stand for hydrogen or alkyl having up to 6 carbon atoms, and
R stands for hydrogen or OH,
the nucleus I may have I to 3 alkoxy, halogen, alkyl or nitro substituents,
the nucleus Il may have i to 3 alkoxy, halogen or alkyl substituents, and
the nucleus III may be substituted by l to 3 methoxy groups,
The symbols R,, R R R R X and Y used in the above formula have the same meanings throughout the specification, and nuclei indexed I, II or III may be substituted as defined above.
The compounds of general formula l contain at least one basic nitrogen atom and may consequently form or be formed as salts, in particular hydrohalides, and the invention extends to such acid addition salts, Where pharmaceutically acceptable.
Preferred halogen substituents for the nucleus I and /or the nucleus II are fluorine, chlorine and bromine. Preferred alkyl substituents of the nuecleus I and of the nucleus [1 contain 1 to 8 carbon atoms. Preferred alkoxy substuents are methoxy groups.
The compounds of formula I may be prepared, for example, by the addition of amines of the general formula to compounds of the general formula Those compounds of formula I in which R stands for and Y represents the -OCO group, so that they have the general formula may also be synthesized by the addition of amines hav- I ing the general formula to compounds of the general formula III followed by esterifiction of the adduets with bcnzoic acid derivatives of the general formula wherein Z stands for a halogen atom or the radical Those compounds of formula I in which R stands for a nitrile group may also be prepared by addition of HCN to vinylogous amines of the general formula COOII VII VIII
or, in some cases, by diazotation of the corresponding carbonamides X according to the following reaction equation:
OOH
XI v
with trimethylamine and subsequent reaction with KCN:
V..- XIX...
The chlorides Xl necessary for this purpose may be prepared, as far as they are not yet described in literature, according to known per se methods. The simplest method for the prepartion of the chlorides Xl consists in the addition, in the presence of Friedel-Crafts-type catalysts, of suitable acid chlorides XV on acetylene according to the following reaction equation:
In the case of certain acid chlorides this reaction is difficult to carry out, for instance if the nucleus 1 bears one or more alkoxy groups. In this case the corresponding acetophenones XVl are subjected to an alkaline ester condensation with formiates. From the sodium or potassium salts XVII of the benzoylvinylalcohols thus obtained it is possible to prepare by way of hydrolysis the benzoylvinylalcohols XVIII which on their part may be converted with suitable chlorinating agents, such as thionylchloride or phosphortrichloride, to the benzoylvinylehlorides X1:
HCOOCzHs I C CH3 NaO CH3 XVI XVII
XVIII Initial compounds of formula lll wherein R represents the CONH group may be prepared by partial saponification of the corresponding nitriles, for in- 4 stance with concentrated sulfuric acid according to the following reaction scheme:
Initial compounds of formula III wherein R represents the COOH group may be prepared either by diazotation of the corresponding carbonamides XX according to the following reaction scheme or directly by saponification ofthe nitriles XIX according to the following scheme or by reaction of maleic acid anhydride with the corresponding benzene derivatives under the conditions of the Freidel-Crafts reaction l O o The compounds of general formula l of the present invention are valuable pharamaceuticals. They exert, especially where R, means CN, for instance, a distinct dilatory action on the cerebral vessels and are, in this respect, far superior to other known substances of this kind. The compounds of the present invention and their pharmaceutically acceptable salts may be employed together with pharmaceutically acceptable diluents or carriers for the preparation of pharmaceutical formulations such as tablets, dragees, suppositories, capsules, solutions, suspensions or emulsions.
These pharmaceutical preparations may also contain other therapeutically active substances.
Pharmacological investigations of the dilatory action of compounds according to the invention on the cerebral vessels were carried out in anaesthetized dogs by observing the changes in blood flow and oxygen tension of the brain-surface. The dogs were anaesthetized with Urethane-Chloralose-Dial-Nembutal (250-1 5- 1 0-4 mg./kg. i.v.). Over the left-hand hemisphere of the brain the skull and the dura mater were opened by circular incision with a diameter of 2 to 3 cms. A heatconductive probe (Standard model P l of Messrs. Hartmann and Braun A.G., Frankfurt/Main) was applied to the brain under a slight pressure for local blood flow determinations in the cerebral cortex (Literature consuited: K. GOLENHOFFEN, H. HENSEL, G. HlLDE- BRANDT: Durchblutungsmessung mit Warmeleitelementen in Forschung und Klinik, Georg Thieme Verlag Stuttgart, I963). Besides the heat-conductive probe, a teflon-coated multiwire-platinum electrode The following table gives the results of the above pharmacological investigations.
6 7 EXAMPLE 1 2.87 g. p-chlorobenzoylacrylonitrile (formula:
dioxane, 2.27 g. norephedrin are added, the reaction mixture is completely dissolved with gentle heating and then allowed to stand for 48 hours at room temperature. Subsequently, it is concentrated in vacuo. The residue obtained is a dark colored oil which solidifies by the addition of petroleum ether. It is then sucked off, dried and triturated several times with warm water.
Maximal change Maximal change in Maximal change of Preparation LD 50 Dosage of the cerebral oxygen tension of the blood pressure gjkg. mg./kg. blood flow the brain'surface (systolic/diastolic) mouse in in min. in in minutes in 70 in minutes 3-( 3'-methoxybenzoyl)-2- 1.0 5.0 +153 +32/+5l l5 (a-methyl-B-hydroxy-phenp.o. i.v.
ethylamino)-propionitrile +142 180 0/0 3-(2,3,4' trimethoxy- 5.0 +228 30 +47 3 +24l+25 l3 hydroxy-phenethylamino)- pro. 10.0 +173 +200 50 +38l+26 18 propionitrile i.d.
benzoyD-Z-(a-methyl-B- i.v.
hydroxy-phenethylamino)- 1 v 10.0 +44 25 +75 16 3/14 7 propionitrile-hydrochloride benzoyD-Lta-methyl-B- 5.0 +121 38 +34 14 +18l+40 30 hydroxy-phenethylamino)- i.v.
propionitrile-hydrochloride (a-methyl-B-hydroxy-pheni.v.
ethylaminol-propionitrile 7.0 +133 18 0/0 hydrochloride i.d.
(u-methyl-:b-hydroxy-phen- 2.0 +205 19 +106 42 +l27/+|52 elhylaminol-propionitrile- H i.v.
hydrochloride (a-methyl-B-hydroxy- 2.0 +90 14 1 1 phenethylamlno)-propioi, l0 HS/+50 17 nitrile hydrochloride trimethoxyphenethyl- +22/+2 8 amino)-propionitrilehydrochloride tn'methoxyanilino)-carbonylmethyl-piperazinyl- 1.0 10.0 30 +8 (1 ')]-propionitn'lep.o. i.d. 20 +2 n+5 20 dihydrochloride razinyl(1')]-propionitriledihydrochloride comparative substance: 10.0 0 0 0 0 0 I 0 cinnarizine i.d.
The following examples are given for the purpose of a better understanding of the nature and the objects of this invention. The temperatures are given in degrees Centigrade.
The water-insoluble part is separated, dried, recrystallized once from benzene/petroleum ether and converted with ethanolic hydrochloric acid and with the 5 concurrent use of anhydrous ether to the hydrochloride. The hydrochloride is reconverted in the usual manner to the base. After recrystallization from benzene/petroleum ether one obtains the 3-(pchlorobenzoyl)-2-(a-methyl-B-hydroxy-phenethylamino)-propionitrile having a melting point of l 12-1 14.
calculated: C (16.6 H 56 found; 66.3 5 5 8 Yield: 2.) g. 56.571 of the theoretical tone. The dry product is then suspended in 90 c.c. benzene, a solution consisting of 3.8 g. trimethylam monium chloride in 4 c.c. water is added and a further solution consisting of7 g. KCH in 36 c.c. water is added dropwise while cooling with ice and stirring. The reaction mixture is then heated to room temperature, stirred for another hours, the benzene phase is separated and the aqueous phase is extracted twice with benzene. The combined benzene phases are washed once with water, dried with Na SO and concentrated inv vacuo. By recrystallization of the muddy residue from ligroin one obtains the pchlorobenzoylacr ylonitrile having a melting point of l44l46.
Analysis: (C H Cl N,O
calculated: C 62.6 H 3.1 N 7 found: 63.0 3.5 7. Yield: 7.9 g. 59.4% of the theoretical Analogously to the description given hereinbefore it is possible to prepare, for instance, the following benzoylacrylonitriles:
Melting I point Boiling (degrees) point Gal [5 83-85 3-Cll3OCull4 J2 I o OCII=ClI-Cl Melting I point (degrees) Boiling point 0on5 94l2 mm. Z-Br-Calh 119123/2 mm. 3-NO2C6ll-I 74 4-(ll:|(Julli. 107111/2mm. 4 (zlln-Culh 112118/1 mm. l-(/(tll17-'(/I'll4-- 178-l85/1.5 mm.
2,4,5-Cl3"-Callz EXAMPLE 2 3.09 g. 2-[piperazinyl(1)]-acetic acid-33435 trimethoxyanilide are dissolved in 50 c.c. dioxane, 2.66 g. 2,3,4-trimethoxybenzoylacrylic acid are added and the mixture is stirred for 30 hours at The separated precipitate is sucked off, washed first with dioxane, then thoroughly with water, dried and finally boiled with c.c. alcohol. The residue thus obtained is the 3-[2',3,4-trimethoxybenzoyl]-2- [4-(3,4,5-trimethoxyanilino)-oxoethyl-piperazinyl (l)]-propionic acid.
The same product is' obtained by treating N-[Z- (2',3,4-trimethoxybenzoyl)-l-cyanoethyl]-N'-(acet- 3,4',5-trimethoxy-anilido)piperazine-hydrochloride (prepared by addition of Z-[piperazinyl (l)]-acetic acid-3',4',5-trimethoxyanilide on 2',3,4-trimethoxybenzoylacrylonitrile analogously to the prescription of Example 5, melting point: 181) with concentrated sulfuric acid. The acid may be converted with an equimolar amount of sodium ethylate to its sodium salt.
Melting point: 250 dec.
The 2,3,4'-trimethoxybenzoylacrylic acid required as starting material may be prepared as follows:
4.5 g. 2,3,4-trimethoxybenzoyl-acrylic acid amide are dissolved with stirring in 34 c.c. concentrated sulfuric acid. The mixture is cooled down to an internal temperature of45, 3.55 g. NaNO are added and then 10 c.c. water are slowly added dropwise with stirring, whereby the temperature rises to -l0. Subsequently, a further 51 c.c. water are added dropwise in such a manner that finally the temperature reaches +3 and stirring in continued for another minutes at room temperature. The reaction mixture is then sucked off, the residue is washed with water, dissolved in soda solution of 10%, filtered off from a slightly turbid mass and the filtrate is acidified with hydrochloride acid of 10%. Obtained is an oily precipitate which solidifies after a short while. The reaction product is sucked off, washed with water and dried, then dissolved with gentle heating in toluene and filtered off from a minor residue. The filtrate is admixed with petroleum ether and the separated precipitate is sucked off. Obtained is the 2',3',4'- trimethoxybenzoylacrylic acid.
Melting point: 89-90 Analysis: (C H Cl N Ofl Analysis: (CUHHOB) calculated: C 55.5 H 6.0 N 7.2 calculated: c 58.6 H 5.3 o 36.1 found: found: 5 3 5 Yield: 2.9 g. 53% of the theoretical Yield: 3.3 g. 73% of the theoretical The 3'-methoxybenzoylacrylonitrile required as The 2-[piperazinyl (l)]-acetic aeid-3,4,5- starting material may be prepared analogously to the trimethoxy-anilide which is also required as starting material may be prepared as follows:
18.3 g of 3,4,5-trimethoxyaniline and 10.1 g. triethylamine are dissolved in 300 c.c. anhydrous dioxane, 1 1.3 g. chloroacetylchloride are added at -20 with stirring and the reaction mixture is stirred for 16 hours at room temperature. It is then sucked off from the separated triethylammonium chloride, the filtrate is evaporated in vacuo, the residue is treated with ether and sucked off.
Obtained are 23 g. N-ch1oroacetyl-3',4,5'- trimethoxy-aniline having a melting point of 103.
A solution consisting of 27 g. piperazine in 100 c.c. isopropanol is admixed, while stirring at room tempera,- ture, with a solution consisting of 14 g. N-chloroacetyl- 3',4,5-trimethoxyani1ine in 60 c.c. dioxane. The reaction solution is then heated for 7 hours under reflux, evaporated and the residue is dissolved in 2N sodium hydroxide solution and chloroform. The chloroform phase is separated. the aqueous phase is again extracted with CHCl both chloroform extracts are combined, washed and concentrated in vacuo. The remaining oil solidifies by the addition of diisopropylether. Obtained are after suction-filtration 15 g. 2- [piperazinyl (l)]-acetic acid-3,4,5'-trimethoxyanilide having a melting point of 125.
EXAMPLE 3 2 g. 3'-methoxybenzoylacrylonitrile are dissolved in 30 c.c. dioxane, 1.39 g. N-hydroxyethylpiperazine are added and the solution is first allowed to stand for one hour at room temperature and then concentrated in vacuo. The residue is recrystallized from benzene/petroleum ether. Obtained are 3.2 g. N-[2-(mmethoxybenzoyl)-l cyano-ethyll-N'-[hydroxyethy1]- piperazine having a melting point of 126l28.
3.2 g. of the hydroxyethylpiperazine are dissolved in 40 c.c. dioxane, 1.03 g. triethylamine are added and, at room temperature. a solution consisting of 2.33 g. 3,4,- S-trimethoxybenzoylehloride in 15 c.c. dioxane is added dropwise while stirring. Subsequently, the reaction mixture is stirred for another 16 hours at room temperature. A further 0.54 g. triethylamine as well a solution consisting of 1.14 g. 3.4,5-trimethoxybenzoylchloride in dioxane are added and this mixture is again stirred for 16 hours at room temperature. After sucking off, the filtrate is concentrated in vacuo, the residue is dissolved in ethanolic hydrochloric acid and admixed with ether. The precipitate obtained is a slightly muddy hydrochloride. After conversion to the base and subsequent reconversion to the hydrochloride one obtains the N-[2-(m-methoxybenzoyl-l-cyanoethyl]-N-[ 3 ,4,5-trimethoxybenzoyloxyethyl]- piperazine-dihydrochloride in the form of crystals melting at 146.
description given in Example 1 from 3'-methoxybenzoylvinylchloride. The 3-methoxybenzoylvinylchloride required for this purpose may be prepared as follows:
A solution consisting of 17.8 g. ethyl formiate and 30 g. 3-methoxyacetophenone is added dropwise, while stirring at 8-10, to a suspension of 13 g. sodium methylate in 100 c.c. anhydrous benzene. Stirring is continued for another 16 hours at room temeprature, then the reaction mixture is sucked off, washed with anhydrous alcohol and the residue is dried in vacuo. Obtained are 38.9 g. of the sodium salt of the 3'-methoxybenzoylvinyl alcohol.
24.2 g. of the sodium salt are suspended in c.c. benzene. Subsequently, c.c. water and 60 c.c. sulfuric acid of 10% are added and the mixture is vigorously stirred. When it is completely dissolved, the benzene layer is separated and the aqueous phase is extracted twice with benzene.
The combined benzene extracts are then gently heated under reflux with 15.4 g. thionylehloride, the excess thionyl chloride and the benzene are then distilled off in vacuo and the residue is fractionated in vacuo.
Obtained is the 3'-methoxy-benzoylvinylehloride.
Boiling point: l50/3-4 mm. Analysis: (C H CIO calculated: C 61.0 H 4.5 found: 60.7 4.5 Yield: 16.2 g. 38% of the theoretical Analogously, the following methoxylated benzoylvinylchlorides may be prepared from the corresponding acetophenones via the sodium salts of the benzoylvinylalcohols:
added and the mixture is stirred for 20 hours at room temperature, then heated during one hour at 80 and the solution is concentrated in vacuo. The remaining oil solidifies when it is treated with ether. The residue is sucked off. washed with ether. then dissolved in warmed ethyl acetate and the filtrate is admixed with 1 1 petroleum ether whereby a precipitate is formed which crystallizes after a short while. It is sucked off and the residue is washed with petroleum ether.
EXAMPLE 8.8 g. 3,4',5-trimethoxybenzoylacrylonitrile and I l g. 2-[piperazinyl (l) -acetic acid-3 ,4',5
I I I O O n T Obtamed ,3 trimethoxyanilide are stirred for 7 hours at 70 in 120 mmethoxlfbenzoyn'l'carbonamldo'ethyll 5 c.c. dioxane. The solution is then cooled down to room norephcdrmtemperature, filtered off from residual parts, if any, and the filtrate is evaporated in vacuo. The oily residue is dissolved in little anhydrous dioxane, admixed with Melting point: i05 etheric hydrochloric acid, and the precipitate is sucked Arwlysisl (C'ZZHZKNZOH) off and washed several times with ether. Subsequently, culculmed: C 635 H 67 N 647 O 23.] it is treated with water, whereby first muddy mass is found: 63.4 7.1 6.4 23.5 formed which solidifies while further standing. The 67% hememal solid product is sucked off, suspended in dilute soda so lution and immediately extracted three times with chloreform. The chloroform solution is washed with water, The 4I trimethoxybenzoylacrylic acid amide dried and concentrated in vacuo. The resinous residue 9 i Q quired as Starting material may be prepared as follows. is dissolvedin anhydrous dioxane, admixed withether c 8 g 2,,3i,4i trimethoxybenzoylacrylonitrne are hydrochloric acid and the separated precipitate is solved in 40 c.c. concentrated sulfuric acid and heated sulcked Off and Washefj ether The resldue in a water bath to an internal temperature of 75. At surred for one hollr m about 30 CC waterfiwhereby this temperature, the mixture is allowed to stand for 3 first a mud'dy mass is agaln formed wh'ch sohqlfies after minutes then Cooled and poured Onto about 120 g ice a short while. After sucking off and recrystallizing from Q I I I I The precipitated residue is sucked off and washed l ki b 1 T' h l N 'm-$3 twice with little iced water. By recrystallization of the trlmethoxy 3 'f l y f 9 residue from water and with the concurrent use oflittle mmet oxyamh 0)-plperazme'hydrochlonde' methanol one obtains the 2',3,4-trimethoxybenzoylacrylic acid amide.
Melting point: 178 Analysis: (CMHMCMNJOX) calculated: C 56.7 H 6.2 CI 6.0 N 9.4 found: 56.8 6.4 5.8 9.6 Melting point: ll52 Analysis: (C1;,H,,,NO5)
niculineti: 5x1: H 5.7 N 5.3 35 Analogously to the description given in Examples l gl l f s g 7M Tihcmctiil 5 the following compounds of the present invention may be obtained:
I -C()Cll2(]jll-lt:
I I Melting R: {)Oil'li, (degrees) 2,3,4-(CIIiOhCaH: CN 30m -N No2H40-oo--oc11i 2,3,4-(CH30)3C6H2 o ONHQ (ion: 18?
Q -N N"C21I40' C 0 00113 CH-B 2,3,4-(CH30)3C6H2 CN 107 NCH2CH 4-cinocnn COOII ooiii 221 N N mil-in u (to mini 1 Hull 3-(,Jllu()-(.-nll5 (.N n2
- I()ll (!l'lcm on i Y 3 )-3 flI 2 CN 108 2 Hydrochloride. D291. ,s What we claim is: l. A compound of the formula wherein Z stands for a member selected from the group consisting of OH. NH; and ONa, X stands for alkylene with l 4 carbon atoms, Y stands for a member selected from the group consisting of OCO and CO-NH. the nucleus 1 being selected from the group consisting of phenyl and mono-, diand trimethoxyphenyl. and nucleus ll being selected from the group consisting of phenyl and mono-, diand trimethoxyphenyl, and the pharmaceutically acceptable acid addition salts of said compounds.
2. Compound according to claim 1, wherein nucleus I is monomethoxyphenyl, Z is OH, X is C H Y is OCO- and nucleus ll is trimethoxyphenyl, and
Y is -OCO, nucleus ll is trimethoxyphenyl, and the pharmaceutically acceptable addition salts of said compound.
5. Compound according to claim 1, wherein nucleus 1 is trimethoxyphenyl, Z is -OH, X is --CH Y is CONH, nucleus [1 is trimethoxyphenyl, and the pharmaceutically acceptable addition salts of said compound.

Claims (5)

1. A COMPOUND OF THE FORMULA
2. Compound according to claim 1, wherein nucleus I is monomethoxyphenyl, Z is -OH, X is -C3H6-, Y is -O-CO- and nucleus II is trimethoxyphenyl, and the pharmaceutically acceptable addition salts of said compound.
3. Compound according to claim 1, wherein nucleus I is trimethoxyphenyl, Z is -NH2, X is -C2H4-, Y is -O-CO-, nucleus II is trimethoxyphenyl, and the pharmaceutically acceptable addition salts of said compound.
4. Compound according to claim 1, wherein in nucleus I is trimethoxyphenyl, Z is -ONa, X is -C3H6-, Y is -O-CO-, nucleus II is trimethoxyphenyl, and the pharmaceutically acceptable addition salts of said compound.
5. Compound according to claim 1, wherein nucleus I is trimethoxyphenyl, Z is -OH, X is -CH2-, Y is -CO-NH-, nucleus II is trimethoxyphenyl, and the pharmaceutically acceptable addition salts of said compound.
US359440A 1972-03-29 1973-05-11 Alpha-(n-benzoyloxy and phenylamino alkyl-piperazino)-beta-benzoyl-propionic acid derivatives Expired - Lifetime US3867389A (en)

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3962247A (en) * 1974-07-16 1976-06-08 Fuji Chemical Industry Co., Ltd. Alpha-cyanoamine compounds and a process for producing the same

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3594384A (en) * 1967-10-12 1971-07-20 Cassella Farbwerke Mainkur Ag Pharmacologically-active trimethoxybenzoxyalkyl-piperazino(1')compounds

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3594384A (en) * 1967-10-12 1971-07-20 Cassella Farbwerke Mainkur Ag Pharmacologically-active trimethoxybenzoxyalkyl-piperazino(1')compounds

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3962247A (en) * 1974-07-16 1976-06-08 Fuji Chemical Industry Co., Ltd. Alpha-cyanoamine compounds and a process for producing the same

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