EP0000174A1 - Derivatives of aminobenzoic acids, process for their preparation and pharmaceutical compositions containing them. - Google Patents

Derivatives of aminobenzoic acids, process for their preparation and pharmaceutical compositions containing them. Download PDF

Info

Publication number
EP0000174A1
EP0000174A1 EP78100206A EP78100206A EP0000174A1 EP 0000174 A1 EP0000174 A1 EP 0000174A1 EP 78100206 A EP78100206 A EP 78100206A EP 78100206 A EP78100206 A EP 78100206A EP 0000174 A1 EP0000174 A1 EP 0000174A1
Authority
EP
European Patent Office
Prior art keywords
general formula
hydrogen
aminobenzoic acid
group
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP78100206A
Other languages
German (de)
French (fr)
Other versions
EP0000174B1 (en
Inventor
Gunter Dr. Metz
Manfred Dr. Specker
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
LUDWIG MERCKLE KG CHEM PHARM FABRIK
Ludwig Merckle GmbH and Co KG Chem Pharm Fabrik
Original Assignee
LUDWIG MERCKLE KG CHEM PHARM FABRIK
Ludwig Merckle GmbH and Co KG Chem Pharm Fabrik
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by LUDWIG MERCKLE KG CHEM PHARM FABRIK, Ludwig Merckle GmbH and Co KG Chem Pharm Fabrik filed Critical LUDWIG MERCKLE KG CHEM PHARM FABRIK
Publication of EP0000174A1 publication Critical patent/EP0000174A1/en
Application granted granted Critical
Publication of EP0000174B1 publication Critical patent/EP0000174B1/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/08—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by hetero atoms, attached to ring carbon atoms
    • C07D207/09—Radicals substituted by nitrogen atoms, not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/70—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings condensed with carbocyclic rings or ring systems
    • C07D239/72—Quinazolines; Hydrogenated quinazolines
    • C07D239/86—Quinazolines; Hydrogenated quinazolines with hetero atoms directly attached in position 4
    • C07D239/88—Oxygen atoms
    • C07D239/90—Oxygen atoms with acyclic radicals attached in position 2 or 3
    • 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
    • C07D295/12—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 singly or doubly bound nitrogen atoms
    • C07D295/125—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/13—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 singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • 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
    • C07D295/16—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 acylated on ring nitrogen atoms
    • C07D295/18—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 acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids

Definitions

  • the invention further relates to the aminobenzoic acid derivatives of the general formula (III) formed by ring closure with an -NHY group of the general formula (I) in the o-position wherein R 1 R 2 , R 3 , R 4 , Z, X, R 6 , R 7 , R 8 and n have the meaning given above, with the proviso that at least one of the radicals R 3 or R 4 represents a hydrogen atom.
  • Halogen atoms in the Z radical are fluorine, chlorine, bromine and iodine atoms, preferably chlorine and fluorine atoms.
  • the p and o positions, especially the p position, are preferred.
  • the trifluoromethyl group is preferably in the m position.
  • alkyl radicals examples include the methyl, ethyl, propyl, isopropyl, n-butyl and tert. Butyl group. If R 8 is a haloalkyl radical, the methoiodide, ethoiodide radical, the butyl bromide and the phenylpropenyl bromide radical are preferred.
  • the invention further relates to a process for the preparation of the aminobenzoic acid derivatives of the general formula (I), characterized in that a carboxylic acid of the general formula wherein Y / has the meaning given above or a reactive derivative of this carboxylic acid with a
  • Another method is that the aminobenzoic acid of the general formula (V) or its reactive derivative, advantageously with the introduction of a formyl or acetyl radical as a protective group for the NH 2 radical, is first reacted with the diamine of the general formula (VII.) and after the protective group has been removed is reacted with the carboxylic acid of the general formula (IV) or its reactive derivative.
  • the process is expediently modified such that isatoic anhydride is a reactive derivative of / aminobenzoic acid of the general formula (V), optionally substituted by R, and R 2 , is reacted with the diamine of the general formula (VII) in a suitable solvent and the aminobenzoic acid derivative of the general formula thus obtained is reacted with the carboxylic acid of the general formula (IV) or its reactive derivative.
  • Suitable acid derivatives are e.g. B. acid chlorides, acid anhydrides, esters and the accessible by reaction of the carboxyl group with halogen formic acid esters, respectively. Alkyl carbonic anhydrides.
  • the direct reaction of the carboxylic acid (IV) with the aminobenzoic acid (V) or the direct reaction of the aminobenzoic acid (VI) with the diamine (VII) is preferably carried out in aromatic hydrocarbons or halogenated hydrocarbons while heating to reflux temperature with simultaneous use of water-releasing components, such as, for. B. phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, dicyclohexylcarbodiimide.
  • reaction of the acid derivatives with the diamine (VII) is preferably carried out in halogenated hydrocarbons or ethers at room temperature or with heating to boiling temperature.
  • the alkyl carbonic anhydride derivative formed is expediently not isolated, but instead reacted directly with the diamine (VII) in a one-step process.
  • the basic aminobenzoic acid derivatives of the general formula (I) obtained can be reacted with pharmaceutically customary acids, such as. B. hydrohalic acids, citric acid, fumaric acid, salicylic acid, nicotinic acid, and with the acids of the general formula (IV) u. (V are converted into the corresponding salts or quaternized by reaction with haloalkanes.
  • the cyclized aminobenzoic acid derivatives of the general formula (III) which are formally formed by water elimination can be prepared by heating the corresponding aminobenzoic acids in suitable solvents or solvent-free, or directly obtainable from the reaction of the aminobenzoic acid of the general formula (VI) or its reactive derivative with the diamine of the general formula (VII).
  • the steric hindrance in the cyclized compounds of the general formula (III) means that at least one of the two radicals R 3 and R 4 in group Y must represent a hydrogen atom.
  • the compounds according to the invention in particular have excellent antilipemic activity with good tolerability.
  • the therapeutic activity of the compounds according to the invention according to Examples 2, 43, 75, 83 and 86 was demonstrated in animal experiments on female rats against the known antilipaemica 2- (p-chlorophenoxy) -2-methyl-propionic acid (clofibric acid), its ethyl ester (clofibrate); and tested against one of the starting compounds of the general formula (VI), namely 2- [2- (p-chlorophenoxy) -2-methylpropionamido] benzoic acid (Ref. 1).
  • the compounds or the vehicle 1% tragacanth solution
  • the effectiveness was investigated in normolipaemic rats (10 animals / group) with a body weight of 50 to 60 g, who received a standardized, pelleted laboratory diet (normal diet) over the entire test period.
  • the diet consisted essentially of raw proteins and carbohydrates with a raw fat content of max. 3.9%, enriched with vitamins, minerals and amino acids.
  • a pharmacological screening of selected compounds of the general formulas (II) and (III) showed that, in addition to antilipemic activity, they also have valuable therapeutic properties.
  • the compounds according to Examples 14 and 57 inhibit platelet aggregation with an activity which is superior to that of adenosine and acetylsalicylic acid.
  • the compounds according to Examples 89, 93 and 94 show in particular antiarrhythmic and cardiotropic properties, as well as a pronounced ⁇ -adrenergic inhibition which has the same effect or is superior to the known reference compounds, such as Practalol or Prinodolol.
  • the medicaments according to the invention contain one or more aminobenzoic acid derivatives of the general formula (I) as active substance.
  • the application is preferably oral, e.g. B. in the form of tablets or capsules, the usual pharmaceutical carriers and auxiliaries, such. B. lactose, starch, talc and magnesium stearate. Their pharmaceutically acceptable salts are particularly suitable for use in injection solutions.
  • the compounds according to the invention are administered in oral or rectal daily doses of 250 to 1500 mg, preferably 500 to 750 mg, in the customary pharmaceutical forms or as a solution for injection in daily doses of 50 to 250 mg, preferably 100 to 200 mg .
  • the benzamide accessible by treatment with dilute sodium hydroxide solution from hydrochloride has an F p of 87 ° C.

Landscapes

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

Abstract

Aminobenzoesäurederivate der allgemeinen Formal <IMAGE> in der R1 Wasserstoff, Chlor, Hydroxy, Acetoxy oder C1 -C3-Alkoxy, R2 Wasserstoff, Chlor oder Sulfamoyl, R5 Wasserstoff oder kombiniert mit R6 ein C2-C3Alkylen, Y die Gruppe <IMAGE> oder in ortho-Stellung zusammen mit dem Wasserstoffatom am Stickstoff und mit R5 die Gruppe <IMAGE> darstellt, wobei R3 Wasserstoff oder Methyl R4 Wasserstoff, C1-C3-Alkyl oder mit Z substituiertes Phenoxy und Z Wasserstoff, Halogen oder Trifluormethyl bedeuten, X C1-C3-Alkylen, das gegebenenfalls unter Substitution mit R6 ein 5- oder 6-gliedriges aliphatisches oder aromatishces Ringsystem bildet, R6 C1-C4-Alkyl, oder in Kombination mit X ein C3-C4-Cycloalkylen oder -arylen, R7 Wasserstoff, C1-C3-Alkyl, Formyl, die Gruppe Y oder zusammen mit R6 ein C4-C5-Cycloalkylen oder zusammen mit X und R6 Pyridylmethyl, R8 Wasserstoff oder gegebenenfalls Halogen- oder Phenyl-substituiertes C1-C4-Alkyl oder C1-C4- Alkenyl, n den Wert 0 oder 1, darstellen, und im Falle n=1 deren Salze mit pharmazeutisch veträglichen Säureresten, sind hergestellt. Diest Verbindugen besitzen antilipämische Aktivität. Man erhält diese Verbindungen durch Reaktion von Aminobenzoesäure oder gegebenenfalls deren reaktionfähige oder geschützte Derivate mit einer Säure der Formel YOH und einer Diamine, eine andere Reaktionsfolge ist auch möglich. Ein Verfahren zur Herstellung Arzneimittel, die diese Verbindugen enthalten ist auch beschrieben.Aminobenzoic acid derivatives of the general form <IMAGE> in which R1 is hydrogen, chlorine, hydroxy, acetoxy or C1-C3-alkoxy, R2 is hydrogen, chlorine or sulfamoyl, R5 is hydrogen or in combination with R6 a C2-C3alkylene, Y is the group <IMAGE> or in ortho position together with the hydrogen atom on nitrogen and with R5 represents the group <IMAGE>, where R3 is hydrogen or methyl R4 is hydrogen, C1-C3-alkyl or Z substituted phenoxy and Z is hydrogen, halogen or trifluoromethyl, X C1-C3 -Alkylene, which optionally forms a 5- or 6-membered aliphatic or aromatic ring system with substitution with R6, R6 C1-C4-alkyl, or in combination with X a C3-C4-cycloalkylene or -arylene, R7 hydrogen, C1-C3 -Alkyl, formyl, the group Y or together with R6 a C4-C5-cycloalkylene or together with X and R6 pyridylmethyl, R8 hydrogen or optionally halogen- or phenyl-substituted C1-C4-alkyl or C1-C4-alkenyl, n den Represent value 0 or 1, and in Fa ll n = 1 whose salts with pharmaceutically acceptable acid residues are produced. These compounds have anti-lipemic activity. These compounds are obtained by reacting aminobenzoic acid or, if appropriate, its reactive or protected derivatives with an acid of the formula YOH and a diamine, another reaction sequence is also possible. A method of making drugs containing these compounds is also described.

Description

Gegenstand der Erfindung sind neue Aminobenzoesäurederivate der allgemeinen Formel

Figure imgb0001
in der

  • R1 Wasserstoff, Chlor, Hydroxy, Acetoxy oder C1-C3-Alkoxy,
  • R2 Wasserstoff, Chlor oder Sulfamoyl,
  • R5 Wasserstoff oder kombiniert mit R6 ein C2-C3-Alkylen,
  • Y die Gruppe
    Figure imgb0002
    oder in ortho-Stellung zusammen mit dem Wasserstoffatom am Stickstoff und mit R5 die Gruppe
    Figure imgb0003
    darstellt, wobei
  • R3' Wasserstoff oder Methyl
  • R4 Wasserstoff, C1-C3-Alkyl oder mit Z substituiertes Phenoxy und
  • Z Wasserstoff, Halogen oder Trifluormethyl bedeuten,
  • X C1-C3-Alkylen, das gegebenenfalls unter Substitution mit R6 ein 5- oder 6-gliedriges aliphatisches oder aromatisches Ringsystem bildet,
  • R6 C1-C4-Alkyl, oder in Kombination mit X ein C3-C4-Cycloalkylen oder -arylen,
  • R7 Wasserstoff, C1-C3-Alkyl, Formyl, die Gruppe Y oder zusammen mit R6 ein C4-C5-Cycloalkylen oder zusammen mit X und R6 Pyridylmethyl,
  • R8 Wasserstoff oder gegebenenfalls Halogen- oder Phenyl-substituiertes C1-C4-Alkyl oder C1-C4-Alkenyl,
  • n den Wert 0 oder 1,

darstellen, und im Falle n = 1 deren Salze mit pharmazeutisch verträglichen Säureresten.The invention relates to new aminobenzoic acid derivatives of the general formula
Figure imgb0001
 in the
  • R 1 is hydrogen, chlorine, hydroxy, acetoxy or C 1 -C 3 alkoxy,
  • R 2 is hydrogen, chlorine or sulfamoyl,
  • R 5 is hydrogen or combined with R 6 is a C 2 -C 3 alkylene,
  • Y the group
    Figure imgb0002
     or in the ortho position together with the hydrogen atom on nitrogen and with R 5 the group
    Figure imgb0003
     represents, where
  • R3 'is hydrogen or methyl
  • R 4 is hydrogen, C 1 -C 3 alkyl or phenoxy substituted with Z and
  • Z is hydrogen, halogen or trifluoromethyl,
  • XC 1 -C 3 alkylene, which optionally forms a 5- or 6-membered aliphatic or aromatic ring system with substitution with R 6 ,
  • R 6 is C 1 -C 4 alkyl, or in combination with X is a C 3 -C 4 cycloalkylene or arylene,
  • R 7 is hydrogen, C 1 -C 3 -alkyl, formyl, the group Y or together with R 6 a C 4 -C 5 -cycloalkylene or together with X and R 6 pyridylmethyl,
  • R 8 is hydrogen or optionally halogen- or phenyl-substituted C 1 -C 4 alkyl or C 1 -C 4 alkenyl,
  • n is 0 or 1,

represent, and in the case of n = 1 their salts with pharmaceutically acceptable acid residues.

Hierunter fallen die Aminobenzoesäurederivate der allgemeinen Formel II

Figure imgb0004
in der R1, R2, R 3, R4, R5, Z, X, R6, R7, R8 und n die vorstehende Bedeutung besitzen.This includes the aminobenzoic acid derivatives of the general formula II
Figure imgb0004
 in which R 1 , R 2 , R 3 , R 4 , R 5 , Z, X, R 6 , R 7 , R 8 and n have the meaning given above.

Gegenstand der Erfindung sind ferner die durch Ringschluß mit einer in o-Stellungbefindlichen -NHY-Gruppe der allgemeinen Formel (I) gebildeten Aminobenzoesäurederivate der allgemeinen Formel,(III)

Figure imgb0005
worin R1 R2, R3, R4, Z, X, R6, R7, R8 und n die obige Bedeutung besitzen, mit der Maßgabe, daß mindestens einer der Reste R3 oder R4 ein Wasserstoffatom darstellt.The invention further relates to the aminobenzoic acid derivatives of the general formula (III) formed by ring closure with an -NHY group of the general formula (I) in the o-position
Figure imgb0005
 wherein R 1 R 2 , R 3 , R 4 , Z, X, R 6 , R 7 , R 8 and n have the meaning given above, with the proviso that at least one of the radicals R 3 or R 4 represents a hydrogen atom.

Als Halogenatome im Rest Z kommen Fluor, Chlor, Brom und Jodatome, vorzugsweise Chlor- und Fluoratome in Frage. Die p- und o-Stellung, insbesondere die p-Stellung, wird bevorzugt. Die Trifluormethylgruppe steht bevorzugt in m-Stellung.Halogen atoms in the Z radical are fluorine, chlorine, bromine and iodine atoms, preferably chlorine and fluorine atoms. The p and o positions, especially the p position, are preferred. The trifluoromethyl group is preferably in the m position.

Beispiele für geeignete Alkylreste sind die Methyl-, Äthyl-, Propyl-, Isopropyl-, n-Butyl- und tert. Butylgruppe. Bedeutet R8 einen Halogenalkylrest, so sind der Methojodid,- Äthojodidrest, der Butylbromid- und der Phenylpropenylbromidrest bevorzugt.Examples of suitable alkyl radicals are the methyl, ethyl, propyl, isopropyl, n-butyl and tert. Butyl group. If R 8 is a haloalkyl radical, the methoiodide, ethoiodide radical, the butyl bromide and the phenylpropenyl bromide radical are preferred.

Die Erfindung betrifft ferner ein Verfahren zur Herstellung der Aminobenzoesäurederivate der allgemeinen Formel (I), dadurch gekennzeichnet, daß man eine Carbonsäure der allgemeinen Formel

Figure imgb0006
worin Y/die oben angegebene Bedeutung besitzt oder ein reaktionsfähiges Derivat dieser Carbonsäure mit einerThe invention further relates to a process for the preparation of the aminobenzoic acid derivatives of the general formula (I), characterized in that a carboxylic acid of the general formula
Figure imgb0006
 wherein Y / has the meaning given above or a reactive derivative of this carboxylic acid with a

Aminobenzoesäure der allgemeinen Formel

Figure imgb0007
in der R1 und R2 die oben angegebene Bedeutung besitzen oder deren reaktionsfähigem Derivat zur Reaktion bringt und die erhaltene Aminobenzoesäure der allgemeinen Formel
Figure imgb0008
oder deren reaktionsfähiges Derivat mit einem Diamin der allgemeinen Formel
Figure imgb0009
worin R5, R6, R7 und X die oben angegebene Bedeutung haben, umsetzt und sodann gegebenenfalls zur Herstellung einer quartären Ammoniumverbindung die Gruppe R8 mit der oben angegebenen Bedeutung in an sich bekannter Weise einführt.Aminobenzoic acid of the general formula
Figure imgb0007
 in which R 1 and R 2 have the meaning given above or their reactive derivative brings to reaction and the aminobenzoic acid of the general formula obtained
Figure imgb0008
 or their reactive derivative with a diamine of the general formula
Figure imgb0009
 wherein R 5 , R 6 , R 7 and X have the meaning given above, and then optionally introduces the group R 8 with the meaning given above in a manner known per se to prepare a quaternary ammonium compound.

Ein weiteres Verfahren besteht darin, daß die Aminobensoesäure der allgemeinen Formel (V) oder deren reaktionsfähiges Derivat, zweckmäßig unter Einführung eines Formyl- oder Acetylrestes als Schutzgruppe für den NH2-Rest, zunächst mit dem Diamin der allgemeinen Formel (VII.) umgesetzt wird und nach Entfernen der Schutzgruppe mit der Carbonsäure der allgemeinen Formel (IV) oder deren reaktionsfähigem Derivat zur Reaktion gebracht wird.Another method is that the aminobenzoic acid of the general formula (V) or its reactive derivative, advantageously with the introduction of a formyl or acetyl radical as a protective group for the NH 2 radical, is first reacted with the diamine of the general formula (VII.) and after the protective group has been removed is reacted with the carboxylic acid of the general formula (IV) or its reactive derivative.

Sofern in der allgemeinen Formel (I) die Gruppe - NH-Y in o-Stellung steht, wird das Verfahren zweckmäßig derart abgeändert, daß Isatosäureanhydrid als reaktionsfähiges Derivat der/Aminobenzoesäure der allgemeinen Formel (V), gegebenenfalls substituiert mit R, und R2, mit dem Diamin der allgemeinen Formel (VII) in einem geeigneten Lösungsmittel umgesetzt wird und das hierbei erhaltene Aminobenzoesäurederivat der allgemeinen Formel

Figure imgb0010
mit der Carbonsäure der allgemeinen Formel (IV) oder deren reaktionsfähigem Derivat zur Reaktion gebracht wird.If the group - NH-Y is in the o-position in the general formula (I), the process is expediently modified such that isatoic anhydride is a reactive derivative of / aminobenzoic acid of the general formula (V), optionally substituted by R, and R 2 , is reacted with the diamine of the general formula (VII) in a suitable solvent and the aminobenzoic acid derivative of the general formula thus obtained
Figure imgb0010
 is reacted with the carboxylic acid of the general formula (IV) or its reactive derivative.

Geeignete Säurederivate sind z. B. Säurechloride, Säureanhydride, Ester sowie die durch Umsetzung der Carboxylgruppe mit Halogenameisensäureestern zugänglichen Alkylkohlensäureester resp. Alkylkohlensäureanhydride.Suitable acid derivatives are e.g. B. acid chlorides, acid anhydrides, esters and the accessible by reaction of the carboxyl group with halogen formic acid esters, respectively. Alkyl carbonic anhydrides.

Die direkte Umsetzung der Carbonsäure (IV) mit der Aminobenzoesäure (V) oder die direkte Umsetzung der Aminobenzoesäure (VI) mit dem Diamin (VII)erfolgt bevorzugt in aromatischen Kohlenwasserstoffen oder Halogenkohlenwasserstoffen unter Erwärmung auf Rückflußtemperatur bei gleichzeitigem Einsatz von wasserabspaltenden Komponenten, wie z. B. Phosphoroxychlorid, Phosphortrichlorid, Phosphorpentachlorid, Dicyclohexylcarbodiimid.The direct reaction of the carboxylic acid (IV) with the aminobenzoic acid (V) or the direct reaction of the aminobenzoic acid (VI) with the diamine (VII) is preferably carried out in aromatic hydrocarbons or halogenated hydrocarbons while heating to reflux temperature with simultaneous use of water-releasing components, such as, for. B. phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, dicyclohexylcarbodiimide.

Die Umsetzung der Säurederivate mit dem Diamin (VII) erfolgt bevorzugt in Halogenkohlenwasserstoffen oder Äthern bei Raumtemperatur oder unter Erwärmen bis auf Siedetemperatur.The reaction of the acid derivatives with the diamine (VII) is preferably carried out in halogenated hydrocarbons or ethers at room temperature or with heating to boiling temperature.

Bei der Umsetzung der Carbonsäure mit einem Chlorameisensäureester wird zweckmäßig das gebildete Alkylkohlensäureanhydridderivat nicht isoliert, sondern in einem Einstufenverfahren direkt mit dem Diamin (VII) zur Reaktion gebracht.When the carboxylic acid is reacted with a chloroformate, the alkyl carbonic anhydride derivative formed is expediently not isolated, but instead reacted directly with the diamine (VII) in a one-step process.

Die erhaltenen basischen Aminobenzoesäurederivate der allgemeinen Formel (I) können durch Umsetzung mit pharmazeutisch gebräuchlichen Säuren, wie z. B. Halogenwasserstoffsäuren, Citronensäure, Fumarsäure, Salizylsäure, Nicotinsäure, sowie mit den Säuren der allgemeinen Formel (IV)u. (V in die entsprechenden Salze überführt werden oder durch Umsetzung mit Halogenalkanen quaternisiert werden.The basic aminobenzoic acid derivatives of the general formula (I) obtained can be reacted with pharmaceutically customary acids, such as. B. hydrohalic acids, citric acid, fumaric acid, salicylic acid, nicotinic acid, and with the acids of the general formula (IV) u. (V are converted into the corresponding salts or quaternized by reaction with haloalkanes.

Im Falle der o-Substitution mit der Gruppe - NH-Y sind die formal durch Wasserabspaltung entstandenen cyclisierten Aminobenzoesäurederivate der allgemeinen Formel (III) darstellbar durch Erhitzen der entsprechenden Aminobenzoesäuren in geeigneten Lösungsmitteln oder lösungsmittelfrei, oder direkt erhältlich bei der Umsetzung der Aminobenzoesäure der allgemeinen Formel (VI) oder deren reaktionsfähigem Derivat mit dem Diamin der all- gemeinen Formel (VII). Bei beiden Herstellungsverfahren ist einzuschränkend anzuführen, daß infolge sterischer Hinderung bei den cyclisierten Verbindungen der allgemeinen Formel (III) wenigstens einer der beiden Reste R3 und R4 in der Gruppe Y ein Wasserstoffatom darstellen muß.In the case of o-substitution with the group - NH-Y, the cyclized aminobenzoic acid derivatives of the general formula (III) which are formally formed by water elimination can be prepared by heating the corresponding aminobenzoic acids in suitable solvents or solvent-free, or directly obtainable from the reaction of the aminobenzoic acid of the general formula (VI) or its reactive derivative with the diamine of the general formula (VII). In both production processes, it should be mentioned that the steric hindrance in the cyclized compounds of the general formula (III) means that at least one of the two radicals R 3 and R 4 in group Y must represent a hydrogen atom.

Die erfindungsgemäßen Verbindungen besitzen insbesondere eine ausgezeichnete antilipämische Aktivität bei guter Verträglichkeit.The compounds according to the invention in particular have excellent antilipemic activity with good tolerability.

Die therapeutische Wirksamkeit der erfindungsgemäßen Verbindungen nach Beispiel 2, 43, 75, 83 und 86 wurde im Tierversuch an weiblichen Ratten gegen die bekannten Antilipaemica 2-(p-Chlorphenoxy)-2-methyl-propionsäure (Clofibrinsäure), deren Äthylester (Clofibrat); sowie gegen eine der Ausgangsverbindungen der allgemeinen Formel (VI), nämlich 2-[2-(p-Chlorphenoxy)-2-methyl- propionamido]-benzoesäure (Ref. 1) getestet. Hierbei wurden die Verbindungen bzw. das Vehikel (1 %-ige Traganthlösung) über einen Versuchszeitraum von 14 Tagen mittels Schlundsonde verabfolgt, 24 Stunden nach der letzten Gabe wurden die Blutproben zur Bestimmung der Serumcholesterin-und Serumtriglyzeridspiegel entnommen.The therapeutic activity of the compounds according to the invention according to Examples 2, 43, 75, 83 and 86 was demonstrated in animal experiments on female rats against the known antilipaemica 2- (p-chlorophenoxy) -2-methyl-propionic acid (clofibric acid), its ethyl ester (clofibrate); and tested against one of the starting compounds of the general formula (VI), namely 2- [2- (p-chlorophenoxy) -2-methylpropionamido] benzoic acid (Ref. 1). Here, the compounds or the vehicle (1% tragacanth solution) were administered by gavage over a test period of 14 days, 24 hours after the last dose, the blood samples were taken to determine the serum cholesterol and serum triglyceride levels.

In einer ersten Serie wurde die Wirksamkeit an normolipaemischen Ratten (10 Tiere/Gruppe) mit einem Körpergewicht von 50 bis 60 g untersucht, die über den gesamten Versuchszeitraum eine standardisierte, pellet ierte Labordiät (Normaldiät) erhielten. Die Diät bestand im-wesentlichen aus Rohproteinen und Kohlehydraten bei einem Rohfettgehalt von max. 3,9 %, angereichert mit Vitaminen, Mineralstoffen und Aminosäuren.In a first series, the effectiveness was investigated in normolipaemic rats (10 animals / group) with a body weight of 50 to 60 g, who received a standardized, pelleted laboratory diet (normal diet) over the entire test period. The diet consisted essentially of raw proteins and carbohydrates with a raw fat content of max. 3.9%, enriched with vitamins, minerals and amino acids.

Die Ergebnisse dieser Serie sind in der Tabelle 1 zusammengefaßt. Die angegebenen Werte der prozentualen Veränderung (+ %) beziehen sich auf den jeweiligen Gruppen- . mittelwert (mg %) der Kontrollgruppe, der an 20 Tieren bestimmt wurde. Die Signifikanz p ist ebenfalls auf die Kontrollwerte bezogen.

Figure imgb0011
The results of this series are summarized in Table 1. The stated values of the percentage change (+%) relate to the respective group. mean (mg%) of the control group, which was determined in 20 animals. The significance p is also related to the control values.
Figure imgb0011

In einer zweiten Studie wurde die Wirksamkeit an hypercholesterinämischen Ratten gemäß den Angaben von Berger et. al., Proc. Soc. Exp. Biol. 132, 253 (1969) untersucht. Die anfangs normolipämischen Tieren erhielten zur Erzielung einer artefiziellen Hyperlipidämie die oben beschriebene Normaldiät in pulverisierter Form, die'mit 2 % Cholesterin, sowie 1 % Cholsäure versetzt wurde. Die Ergebnisse dieser Studie sind in Tabelle 2 zusammengefaßt, wobei sich die angegebenen Veränderungen ebenfalls auf den Gruppenmittelwert der Kontrollgruppe beziehen.

Figure imgb0012
In a second study, the efficacy in hypercholesterolemic rats was determined according to Berger et. al., Proc. Soc. Exp. Biol. 132, 253 (1969). The initially normolipemic animals were given the normal diet described above in pulverized form, to which they had been given hyperlipidemia, to which 2% cholesterol and 1% cholic acid had been added. The results of this study are summarized in Table 2, the changes indicated also relating to the group mean of the control group.
Figure imgb0012

Berücksichtigt man, daß in den getesteten erfindungsgemäßen Verbindungen bezüglich der Lipidsenkung der Clofibrinsäurerest das aktive Prinzip darstellt und daß unter den besonders erschwerten Bedingungen des Hypercholesterintests die dosierte Menge der Verbindungen nach Beispiel 2, 43 und 86 einer Verabreichung von 128 mg/kg Clofibrinsäure, die der Verbindung nach Beispiel 75 sogar nur 64 mg/kg Clofibrinsäure entspricht, so ergibt sich hieraus im Vergleich zu Clofibrinsäure und Clofibrat ein wesentlich höherer therapeutischer Index. Überraschend hingegen ist völlige Inaktivität der getesteten Referenzverbindung der allgemeinen Formel (VI) (Ref. 1). übereinstimmend mit den Ergebnissen der Tabelle 2 dürfte als gesichert gelten, daß die graduelle Aktivität der Verbindungen hauptsächlich vom basischen Rest gemäß allgemeiner Formel (VII) bestimmt wird.It is taken into account that in the compounds according to the invention tested the clofibrinic acid residue is the active principle with regard to the lipid lowering and that under the particularly difficult conditions of the hypercholesterol test the metered amount of the compounds according to Examples 2, 43 and 86 an administration of 128 mg / kg of clofibrinic acid, which the Compound according to Example 75 even corresponds to only 64 mg / kg of clofibric acid, this results in a significantly higher therapeutic index compared to clofibric acid and clofibrate. However, it is surprising that the tested reference compound of the general formula (VI) (ref. 1) is completely inactive. Consistent with the results in Table 2, it can be assumed that the gradual activity of the compounds is mainly determined by the basic radical according to general formula (VII).

Wie ein pharmakologisches Screening an ausgewählten Verbindungen der allgemeinen Formel (II) und (III)zeigte, besitzen diese neben antilipämischer Aktivität noch wertvolle therapeutische Eigenschaften. So hemmen die Verbindungen nach Beispiel 14 und 57 die Blutblättchenaggregation mit einer Aktivität, die der von Adenosin und Acetylsalicylsäure überlegen ist. Die Verbindungen nach Beispiel 89, 93 und 94 zeigen insbesondere antiarrhytmische und cardiotrope Eigenschaften, sowie eine ausgeprägte ß-adrenergische Hemmung, die den bekannten Referenzverbindungen, wie Practalol oder Prinodolol, wirkungsgleich oder überlegen ist.A pharmacological screening of selected compounds of the general formulas (II) and (III) showed that, in addition to antilipemic activity, they also have valuable therapeutic properties. The compounds according to Examples 14 and 57 inhibit platelet aggregation with an activity which is superior to that of adenosine and acetylsalicylic acid. The compounds according to Examples 89, 93 and 94 show in particular antiarrhythmic and cardiotropic properties, as well as a pronounced β-adrenergic inhibition which has the same effect or is superior to the known reference compounds, such as Practalol or Prinodolol.

Die erfindungsgemäßen Arzneimittel enthalten eine oder mehrere Aminobenzoesäurederivate der allgemeinen Formel (I) als Wirkstoff. Die Anwendung erfolgt vorzugsweise oral, z. B. in Form von Tabletten oder Kapseln, die gegebenenfalls übliche pharmazeutischen Trägerstoffe und Hilfsmittel, z. B. Laktose, Stärke, Talk und Magnesiumstearat enthalten. Zur Anwendung in Injektionslösungen sind insbesondere deren pharmazeutische verträglichen Salze geeignet.The medicaments according to the invention contain one or more aminobenzoic acid derivatives of the general formula (I) as active substance. The application is preferably oral, e.g. B. in the form of tablets or capsules, the usual pharmaceutical carriers and auxiliaries, such. B. lactose, starch, talc and magnesium stearate. Their pharmaceutically acceptable salts are particularly suitable for use in injection solutions.

Die Verabreichung der erfindungsgemäßen Verbindungen erfolgt, je nach dem Fall, in oralen oder rektalen Tagesdosen von 250 bis 1500 mg, vorzugsweise 500 bis 750 mg, in den üblichen pharmazeutischen Formen oder als Injektionslösung in Tagesdosen von 50 bis 250 mg, vorzugsweise 100 bis 200 mg.Depending on the case, the compounds according to the invention are administered in oral or rectal daily doses of 250 to 1500 mg, preferably 500 to 750 mg, in the customary pharmaceutical forms or as a solution for injection in daily doses of 50 to 250 mg, preferably 100 to 200 mg .

Die Herstellung der erfindungsgemäßen Verbindungen wird anhand folgender Beispiele beschrieben:The preparation of the compounds according to the invention is described using the following examples:

Beispiel 1example 1

13,7 g (0,1 Mol) 3-Aminobenzoesäure werden unter Zusatz von 10 g (0,1 Mol) Triäthylamin in 150 ml Chloroform suspendie mit 20,5 g 1 0,1 Mol) p-Chlorphenoxyacetylchlorid versetzt und 5 Stunden unter Rückfluß erwärmt. Nach dem Erkalten wird das gebildete Kristallisat abgesaugt. Es werden 23,3 g (76,5 %) 3-(p-Chlorphenoxyacetamido)-benzoesäure.vom Fp 208° C erhalten.13.7 g (0.1 mol) of 3-aminobenzoic acid are added with the addition of 10 g (0.1 mol) of triethylamine in 150 ml of chloroform with 20.5 g of 1 0.1 mol) of p-chlorophenoxyacetyl chloride and under 5 hours Reflux heated. After cooling, the crystals formed are suctioned off. 23.3 g (76.5%) of 3- (p-chlorophenoxyacetamido) benzoic acid are obtained, mp 208 ° C.

15,24 g (0,05 Mol) dieser Amidobenzoesäure werden in 100 ml Toluol unter Zusatz von 6,4 g (0,055 Mol) Diäthylaminoäthylami suspendiert und mit 7,7 g (0,05 Mol) Phosphoroxychlorid ver setzt. Der Ansatz wird anschließend 6 Stunden unter Rückfluß erwärmt. Nach dem Erkalten wird die Lösung mit Wasser geschüttelt und mit verdünnter Natronlauge alkalisiert. Nach dem Abtrennen der alkalischen Phase wird die Lösung nochmals mit Wasser gewaschen. Der nach dem Abdestillieren des Lösungsmittels verbleibende Rückstand wird aus wenig Diisopropyläther kristallisiert, wobei 16,8 g (83,2 %) 3-(p-Chlor- phenoxyacetamido)-N-(2-diäthylaminoäthyl)-benzamid vom Fp 100 erhalten werden.15.24 g (0.05 mol) of this amidobenzoic acid are suspended in 100 ml of toluene with the addition of 6.4 g (0.055 mol) of diethylaminoethylamide and mixed with 7.7 g (0.05 mol) of phosphorus oxychloride. The mixture is then heated under reflux for 6 hours. After cooling, the solution is shaken with water and made alkaline with dilute sodium hydroxide solution. After the alkaline phase has been separated off, the solution is washed again with water. The residue remaining after distilling off the solvent is crystallized from a little diisopropyl ether, 16.8 g (83.2%) of 3- (p-chlorophenoxyacetamido) -N- (2-diethylaminoethyl) benzamide of mp 100 being obtained.

Elementaranalyse:

Figure imgb0013
Hydrochlorid Fp 92° C.Elemental analysis:
Figure imgb0013
 Hydrochloride mp 92 ° C.

Beispiel 2Example 2

64 g (0,2 Mol) 4-[2-(p-Chlorphenoxy)-2-methyl-propionamido]-benzoesäure vom Fp 1910 C werden mit 24 g Thionylchlorid in 200 ml Toluol umgesetzt und 6 Stunden auf 100° C erwärmt. Das nach dem Erkalten gebildete Kristallisat wird abgesaugt, wobei 45 g (66,3 %) des entsprechenden Säurechlorids vom Fp 148° erhalten werden. 17,8 g (0,052 Mol) dieses Säurechlorids werden in 150 ml Chloroform gelöst und mit 6 g 1- (2-Aminoäthyl) -pyrrolidin unter Erwärmen umgesetzt. Die mit verdünnter Natronlauge und Wasser gewaschene Chloroformlösung wird eingedampft und der Rückstand aus Aceton kristallisiert. Es werden 14,5 g (64,3 %) 4-[2-(p-Chlorphenoxy)-2-methyl-propionamido]-N-(1-äthyl- pyrrolidinyl-2-methyl)-benzamid vom Fp 180 ° erhalten.64 g (0.2 mol) of 4- [2- (p-chlorophenoxy) -2-methyl-propionamido] benzoic acid, mp 191 0 C are reacted with 24 g of thionyl chloride in 200 ml of toluene and heated for 6 hours at 100 ° C . The crystals formed after cooling are suctioned off, 45 g (66.3%) of the corresponding acid chloride having a melting point of 148 ° being obtained. 17.8 g (0.052 mol) of this acid chloride are dissolved in 150 ml of chloroform and reacted with 6 g of 1- (2-aminoethyl) pyrrolidine with heating. The chloroform solution washed with dilute sodium hydroxide solution and water is evaporated and the residue is crystallized from acetone. 14.5 g (64.3%) of 4- [2- (p-chlorophenoxy) -2-methyl-propionamido] -N- (1-ethyl-pyrrolidinyl-2-methyl) -benzamide of mp 180 ° are obtained .

Elementaranalyse:'

Figure imgb0014
Hydrochlorid Fp 191° C.Elemental analysis: '
Figure imgb0014
 Hydrochloride mp 191 ° C.

Beispiel 3Example 3

16,7 (0,05 Mol) 2-[2-(p-Chlorphenoxy)-2-methyl-propionamido]-benzoesäure vom Fp 1990 C werden in 60 ml Toluol suspendiert und nacheinander mit 2,05 g Phosphortrichlorid und 5,9 g 2-Diäthylaminoäthylamin versetzt. Der Ansatz wird noch 5 Stunden unter Rückfluß erwärmt und nach dem.Erkalten mit verdünnter Natronlauge und Wasser gewaschen.16.7 (0.05 mole) of 2- [2- (p-chlorophenoxy) -2-methyl-propionamido] benzoic acid, mp 199 0 C are suspended in 60 ml of toluene and treated successively with 2.05 g of phosphorus trichloride and 5, 9 g of 2-diethylaminoethylamine were added. The mixture is heated under reflux for a further 5 hours and, after cooling, washed with dilute sodium hydroxide solution and water.

Nach dem Abdestillieren des Lösungsmittels werden 10 g (42 %) 2-[2-(p-Chlorphenoxy)-2-methyl-propionamido)-N-(2-diäthylaminoäthyl)-benzamid als öl erhalten. Der ölige Rückstand wird in Diisopropyläther gelöst und mit isopropanolischer Salzsäure bis pH 3 versetzt. Das hierbei gebildete Hydrochlorid wird abgesaugt und zeigt nach dem Trocknen einen Fp von 149 ° C. Die Titration mit 0,1 N HClO4 in Eisessig unter Zusatz von Quecksilberacetat ergibt einen Gehalt von 102,8 %.After the solvent has been distilled off, 10 g (42%) of 2- [2- (p-chlorophenoxy) -2-methyl-propionamido) -N- (2-diethylaminoethyl) benzamide are obtained as an oil. The oily residue is dissolved in diisopropyl ether and mixed with isopropanolic hydrochloric acid to pH 3. The hydrochloride formed in this way is suctioned off and, after drying, has an mp of 149 ° C. The titration with 0.1 N HClO 4 in glacial acetic acid with the addition of mercury acetate gives a content of 102.8%.

Beispiel 4Example 4

16,3 (0,1 Mol) Isatosäureanhydrid werden in 100 ml Toluol suspendiert und mit 11,6 g (0,1 Mol) 2-Diäthylaminoäthylamin versetzt. Die erhaltene Suspension wird 4 Stunden gerührt, wobei unter milder exothermer Reaktion und Abspaltung von CO2 allmählich Lösung eintritt. Nach dem Stehen über Nacht wird die filtrierte Lösung mit verdünnter Salzsäure ausgeschüttelt. Die salzsaure wäßrige Phase wird mit NaOH alkalisiert und mit Chloroform extrahiert. Nach dem Abdampfen des Lösungsmittels werden 20,8 g (88,4 %) N-(2-Diäthylaminoäthylt-2-amino-benzamid als öl erhalten.
10 g (0,042 Mol) .dieses Amids werden in Chloroform mit 8,6 g (0,042 Mol) p-Chlorphenoxyessigsäurechlorid umgesetzt. Die mit verdünnter Natronlauge, sowie Wasser gewaschene Chloroformlösung wird eingedampft, wobei 12,8 g (75,7 %) 2-(p-Chlorphenoxyacetamido)-N-(2-di- äthylaminoäthyl)-benzamid vom Fp 109 ° C erhalten werden. Citrat Fp 111 ° C / Maleinat Fp 134 ° C.16.3 (0.1 mol) of isatoic anhydride are suspended in 100 ml of toluene, and 11.6 g (0.1 mol) of 2-diethylaminoethylamine are added. The suspension obtained is stirred for 4 hours, solution gradually taking place with a mild exothermic reaction and elimination of CO 2 . After standing overnight, the filtered solution is shaken out with dilute hydrochloric acid. The hydrochloric acid aqueous phase is made alkaline with NaOH and extracted with chloroform. After evaporation of the solvent, 20.8 g (88.4%) of N- (2-diethylaminoethyl-2-amino-benzamide) are obtained as an oil.
10 g (0.042 mol) of this amide are reacted in chloroform with 8.6 g (0.042 mol) of p-chlorophenoxyacetic acid chloride. The chloroform solution washed with dilute sodium hydroxide solution and water is evaporated to give 12.8 g (75.7%) of 2- (p-chlorophenoxyacetamido) -N- (2-di-ethylaminoethyl) benzamide, mp 109 ° C. Citrate mp 111 ° C / maleinate mp 134 ° C.

Beispiel 5Example 5

30,6 g (0,2 Mol) 5-Amino-2-hydroxy-benzoesäure werden gemäß Verfahren nach Beispiel 1 mit 41 g (0,2 Mol) p-Chlorphenoxyacetylchlorid umgesetzt. Es werden 62,7 g (97,5 %) 5-(p-Chlorphenoxyacetamido)-2-hydroxybenzoesäure vom Fp 227 ° C erhalten.30.6 g (0.2 mol) of 5-amino-2-hydroxy-benzoic acid are reacted with 41 g (0.2 mol) of p-chlorophenoxyacetyl chloride according to the method of Example 1. 62.7 g (97.5%) of 5- (p-chlorophenoxyacetamido) -2-hydroxybenzoic acid, mp 227 ° C., are obtained.

Die Umsetzung mit Acetahhydrid ergibt 5-(p-Chlorphenoxy- acetamido)-2-acetylbenzoesäure vom Fp 198 0 C in einer Ausbeute von 58,5 %.The reaction with Acetahhydrid gives 5- (p-chlorophenoxy acetamido) -2-acetylbenzoic acid, mp 198 0 C in a yield of 58.5%.

36,4 g (0,1 Mol) dieser Acetylbenzoesäure werden in 200 ml Tetrahydrofuran unter Zusatz von 12,0 g (0,12 Mol) Triäthylamin suspendiert. Bei einer Temperatur von 5° bis 10° C werden 13,0 g (0,12 Mol) Chlorameisensäureäthylester zugesetzt und der Ansatz noch 3 Stunden gerührt, wobei nach 2 Stunden die Kühlung entfernt wird. 12,8 g (0,1 Mol) 1-Aethyl-2-(aminomethyl)-pyrrolidin werden unter Rühren zugesetzt. Nach dem Stehen über Nacht wird das Lösungsmittel weitgehend im Vakuum eingedampft und der Rückstand mit Wasser zerlegt.36.4 g (0.1 mol) of this acetylbenzoic acid are suspended in 200 ml of tetrahydrofuran with the addition of 12.0 g (0.12 mol) of triethylamine. 13.0 g (0.12 mol) of ethyl chloroformate are added at a temperature of 5 ° to 10 ° C. and the batch is stirred for a further 3 hours, cooling being removed after 2 hours. 12.8 g (0.1 mol) of 1-ethyl-2- (aminomethyl) pyrrolidine are added with stirring. After standing overnight, the solvent is largely evaporated in vacuo and the residue is broken down with water.

Das hierbei abgeschiedene zähe öl wird mit Chloroform aufgenommen und mit verdünnter Natronlauge und Wasser gewaschen. Der nach dem Eindampfen verbleibende ölige Rückstand kristallisiert aus wenig Diisopropyläther, wobei 24,7 g (52,2 %) 5-(p-Chlorphenoxyacetamido)-2-acetyl-N-(1-äthylpyrrolidinyl-2-methyl)-benzamid vom Fp 139 0 C erhalten werden. Die Gehaltsbestimmung durch Titration mit 0,1 N HClO4 in Eisessig zeigt einen Gehalt von 103,4 %.The viscous oil thus separated is taken up in chloroform and washed with dilute sodium hydroxide solution and water. The oily residue remaining after evaporation crystallized from a little diisopropyl ether, 24.7 g (52.2%) of 5- (p-chlorophenoxyacetamido) -2-acetyl-N- (1-ethylpyrrolidinyl-2-methyl) -benzamide of mp 139 0 C can be obtained. The content determination by titration with 0.1 N HClO 4 in glacial acetic acid shows a content of 103, 4%.

Beispiel 6Example 6

1 g (21 mMol) des nach Beispiel 5 hergestellten Benzamid wird in wäßriger Natronlauge unter Zusatz von wenig Äthanol 15 Minuten auf ca. 80 ° C erwärmt und anschließend mit verdünnter Salzsäure angesäuert. Nach Extraktion mit Chloroform werden nach dem Abdampfen der Lösungsmittel 0,8 g (88,2 %) 5-(p-Chlorphenoxyacetamido)-2-hydroxy-N-(1-äthylpyrrolidinyl-2-methyl)-benzamid Hydrochlorid vom Fp 112 ° C erhalten.1 g (21 mmol) of the benzamide prepared according to Example 5 is heated in aqueous sodium hydroxide solution with a little ethanol for 15 minutes at about 80 ° C and then acidified with dilute hydrochloric acid. After extraction with chloroform, after evaporation of the solvents, 0.8 g (88.2%) of 5- (p-chlorophenoxyacetamido) -2-hydroxy-N- (1-ethylpyrrolidinyl-2-methyl) -benzamide hydrochloride, mp 112 ° C received.

Das durch Behandeln mit verdünnter Natronlauge aus Hydrochlorid zugängliche Benzamid zeigt einen Fp von 87 0 C.The benzamide accessible by treatment with dilute sodium hydroxide solution from hydrochloride has an F p of 87 ° C.

Beispiel 7Example 7

4,16 , (0,01 Mol) der Verbindung nach Beispiel 89 werden in 30 ml Äthanol gelöst und mit 1,42 g (0,01 Mol) Methyljodid versetzt. Die Lösung wird 2 Stunden unter Rückfluß erwärmt und anschließend unter Vakuum eingedampft. Der Rückstand wird aus Äthanol unter Zusatz von Aceton kristallisiert. Es werden 5,5 g (98,5 %) des entsprechenden Methojodids vom Fp 114 ° C erhalten.4.16 (0.01 mol) of the compound according to Example 89 are dissolved in 30 ml of ethanol and 1.42 g (0.01 mol) of methyl iodide are added. The solution is heated under reflux for 2 hours and then evaporated under vacuum. The residue is crystallized from ethanol with the addition of acetone. 5.5 g (98.5%) of the corresponding methoiodide, mp 114 ° C., are obtained.

Beispiel 8Example 8

2,75 g (0,005 Mol) des Methojodids nach Beispiel 7 werden in 20 ml einer Mischung aus Aceton und Methanol gelöst und mit 0,7 g Ag Cl versetzt. Die Suspension wird kurz erwärmt und noch warm vom ausgefallenen Ag J abfiltriert. Beim Abkühlen kristallisiert das entsprechende Methochlorid, das aus wenig Äthanol unter Zusatz von Aceton umkristallisiert wird. Ausbeute 1,86 g (80 %) vom Fp 139 0 C.2.75 g (0.005 mol) of the methoiodide according to Example 7 are dissolved in 20 ml of a mixture of acetone and methanol, and 0.7 g of Ag Cl are added. The suspension is heated briefly and filtered while still warm from the precipitated A g J. On cooling, the corresponding methochloride crystallizes, which is recrystallized from a little ethanol with the addition of acetone. Yield 1.86 g (80%) of mp 139 0 C.

Entsprechend den Verfahren nach Beispiel 1 bis 6, sowie den Beispielen,7 und 8 im Falle der quartären Amide wurden weitere Verbindungen hergestellt, die zusammen mit den Verbindungen der vorgehenden Beispiele 1 bis 8 in den nachstehenden Tabellen tabellarisch erfaßt sind.

Figure imgb0015
Figure imgb0016
Figure imgb0017
Figure imgb0018
Figure imgb0019
Figure imgb0020
Figure imgb0021
Figure imgb0022
Figure imgb0023
Figure imgb0024
Figure imgb0025
Figure imgb0026
Figure imgb0027
Figure imgb0028
Figure imgb0029
Figure imgb0030
Figure imgb0031
 In accordance with the processes according to Examples 1 to 6 and Examples 7 and 8 in the case of the quaternary amides, further compounds were prepared which are tabulated together with the compounds of the preceding Examples 1 to 8 in the tables below.
Figure imgb0015
Figure imgb0016
Figure imgb0017
Figure imgb0018
Figure imgb0019
Figure imgb0020
Figure imgb0021
Figure imgb0022
Figure imgb0023
Figure imgb0024
Figure imgb0025
Figure imgb0026
Figure imgb0027
Figure imgb0028
Figure imgb0029
Figure imgb0030
Figure imgb0031

Die Herstellung der ringgeschlossenen Verbindungen gemäß allgemeiner Formel (III) wird in den folgenden Beispielen beschrieben. Entsprechend den beschriebenen Verfahren hergestellte weitere Verbindungen sind in der anschließenden Tabelle insgesamt tabellarisch erfaßt.The preparation of the ring-closed compounds according to general formula (III) is described in the following examples. Further compounds produced in accordance with the described processes are tabulated in the table below.

Beispiel 93Example 93

5,0 g (0,014 Mol) 2-(p-Chlorphenoxyacetamido)-4-chlor-benzoylchlorid werden in 100 ml Chloroform mit 1,7 g (0,014 Mol) 2-Diäthylaminoäthylamin versetzt und der Ansatz 8 Stunden unter Rückfluß erwärmt. Nach dem Abkühlen wird mit verdünnter Natronlauge sowie Wasser gewaschen und das Lösungsmittel im Vakuum abdestilliert. Der verbleibende Rückstand wird aus Diisopropyläther kristallisiert, wobei 3,3 g (53,7 %) 2-(p-Chlorphenoxymethyl)-3-(2-diäthylaminoäthyl)-7-chlor-4(3H)-chinazolinon vom Fp 104 ° C erhalten werden.5.0 g (0.014 mol) of 2- (p-chlorophenoxyacetamido) -4-chloro-benzoyl chloride are mixed in 100 ml of chloroform with 1.7 g (0.014 mol) of 2-diethylaminoethylamine and the mixture is heated under reflux for 8 hours. After cooling, it is washed with dilute sodium hydroxide solution and water and the solvent is distilled off in vacuo. The remaining residue is crystallized from diisopropyl ether, 3.3 g (53.7%) of 2- (p-chlorophenoxymethyl) -3- (2-diethylaminoethyl) -7-chloro-4 (3H) -quinazolinone, mp 104 ° C. be preserved.

Elementaranalyse:

Figure imgb0032
Hydrochlorid Fp 188 0 C.Elemental analysis:
Figure imgb0032
 Hydrochloride mp 188 0 C.

Beispiel 94Example 94

8,1 g (0,02 Mol) der Base nach Beispiel 4 vom Fp 109 0 C werden in einem Reaktionsgefäß 15 Minuten trocken auf 180 - 200 ° C erwärmt, wobei gebildetes Wasser durch angelegtes schwaches Vakuum gegen Ende der Reaktionszeit abgesaugt wird. Nach dem Abkühlen wird die Schmelze aus Diisopropyläther kristallisiert, wobei 7,05 g (91,4 %) 2-(p-Chlor- phenoxymethyl)-3-(2-diäthylaminoäthyl)4-(3H)-chinazolinon vom Fp 85 ° C erhalten werden.8.1 g (0.02 mole) of the base according to Example 4, mp 109 0 C in a reaction vessel 15 minutes dry to 180-200 ° C heated while water formed is filtered off by applied weak vacuum towards the end of the reaction time. After cooling, the melt is crystallized from diisopropyl ether, 7.05 g (91.4%) of 2- (p-chlorophenoxymethyl) -3- (2-diethylaminoethyl) 4- (3H) -quinazolinone, mp 85 ° C. be preserved.

Elementaranalyse:

Figure imgb0033
Hydrochlorid Fp 194° C - 36-
Figure imgb0034
Figure imgb0035
 Elemental analysis:
Figure imgb0033
 Hydrochloride mp 194 ° C - 36-
Figure imgb0034
Figure imgb0035

Claims (6)

1. Aminobenzoesäurederivate der allgemeinen Formel
Figure imgb0036
in der R1 Wasserstoff, Chlor, Hydroxy, Acetoxy oder C1-C3- Alkoxy, R2 Wasserstoff, Chlor oder Sulfamoyl, R5 Wasserstoff oder kombiniert mit R6 ein C2-C3-Alkylen; Y die Gruppe
Figure imgb0037
oder in ortho-Stellung zusammen mit dem Wasserstoffatom am Stickstoff und mit R5 die Gruppe
Figure imgb0038
darstellt, wobei Wasserstoff oder Methyl R4 wasserstsoff, C1-C3-Alkyl oder mit Z substituiertes Phenoxy und Z Wasserstoff, Halogen oder Trifluormethyl bedeuten, X C1-C3-Alkylen, das gegebenenfalls unter Substitution mit R6 ein 5- oder 6-gliedriges aliphatisches oder aromatisches Ringsystem bildet, R6 C1-C4-Alkyl, oder in Kombination mit X ein C3-C4-Cycloalkylen oder -arylen, R7 Wasserstoff, C1-C3-Alkyl, Formyl, die Gruppe Y oder zusammen mit R6 ein C4-C5-Cycloalkylen oder zusammen mit X und R6 Pyridylmethyl, R8 Wasserstoff oder gegebenenfalls Halogen- oder Phenyl-substituiertes C1-C4-Alkyl oder C1-C4-Alkenyl, n den Wert 0 oder 1,
darstellen, und im Falle n = 1 deren Salze mit pharmazeutisch verträglichen Säureresten.1. Aminobenzoic acid derivatives of the general formula
Figure imgb0036
 in the R 1 is hydrogen, chlorine, hydroxy, acetoxy or C 1 -C 3 alkoxy, R 2 is hydrogen, chlorine or sulfamoyl, R 5 is hydrogen or combined with R 6 is a C 2 -C 3 alkylene; Y the group
Figure imgb0037
 or in the ortho position together with the hydrogen atom on nitrogen and with R 5 the group
Figure imgb0038
 represents, where Hydrogen or methyl R 4 hydrogen, C 1 -C 3 alkyl or Z substituted phenoxy and Z is hydrogen, halogen or trifluoromethyl, X C1 - C3 alkylene, which optionally forms a 5- or 6-membered aliphatic or aromatic ring system with substitution with R 6 , R 6 is C 1 -C 4 alkyl, or in combination with X is a C 3 -C 4 cycloalkylene or arylene, R 7 is hydrogen, C 1 -C 3 alkyl, formyl, the group Y or together with R 6 a C 4 -C 5 cycloalkylene or together with X and R 6 pyridylmethyl, R 8 is hydrogen or optionally halogen- or phenyl-substituted C 1 -C 4 alkyl or C 1 -C 4 alkenyl, n is 0 or 1,
represent, and in the case of n = 1 their salts with pharmaceutically acceptable acid residues. 2. Aminobenzoesäurederivate nach Anspruch 1 der Formel
Figure imgb0039
in der R1, R2, R3, R4, R5, Z, X, R6, R7, R8 und n die Bedeutung gemäß Anspruch 1 besitzen.2. Aminobenzoic acid derivatives according to claim 1 of the formula
Figure imgb0039
 in which R 1 , R 2 , R 3 , R 4 , R 5 , Z, X, R 6 , R 7 , R 8 and n have the meaning according to Claim 1. 3. Aminobenzoesäurederivate nach Anspruch 1 der Formel II
Figure imgb0040
in der R1, R2, R3, R41 Z, X, R6, R7, R8 und n die Bedeutung gemäß Anspruch 1 besitzen, mit der Maßgabe, daß mindestens einer der Reste R3 oder R4 ein Wasserstoffatom darstellt.3. aminobenzoic acid derivatives according to claim 1 of formula II
Figure imgb0040
 in which R 1 , R 2 , R 3 , R 41 Z, X, R 6 , R 7 , R 8 and n have the meaning according to claim 1, with the proviso that at least one of the radicals R 3 or R 4 is a hydrogen atom represents. 4. Verfahren zur Herstellung der Verbindungen nach Anspruch 1, dadurch gekennzeichnet, daß man in an sich bekannter Weise entweder a) eine Carbonsäure der allgemeinen Formel
Figure imgb0041
worin Y die in Anspruch 1 genannte Bedeutung besitzt, oder deren reaktionsfähiges Derivat mit einer Aminobenzoesäure der allgemeinen Formel
Figure imgb0042
 in der R1 und R2 die in Anspruch 1 angegebene Bedeutung besitzen, zur Reaktion bringt und die erhaltene Aminobenzoesäure der allgemeinen Formel
Figure imgb0043
oder deren reaktionsfähiges Derivat mit einem Diamin der allgemeinen Formel
Figure imgb0044
, worin R5, R6, R7 und X die in Anspruch 1 angegebene Be-deutung besitzen, zur Reaktion bringt und sodann gegebenenfalls die Gruppe R8 mit der in Anspruch 1 angegebenen Bedeutung in an sich bekannter Weise einführt, oder b) eine Aminobenzoesäure der allgemeinen Formel (V) gegebenenfalls unter Einführung eines Formyl- oder Acetylrestes als Schutzgruppe für den NH2-Rest oder deren reaktionsfähiges Derivat mit dem Diamin der allgemeinen Formel (VII) umsetzt und nach Entfernen der Schutzaruppe mit einer Carbonsäure der allgemeinen Formel (IV) oder deren reak-' tionsfähigem Derivat zur Reaktion bringt und sodann gegebenenfalls die Gruppe R8 in an sich bekannter Weise einführ oder c) eine Aminobenzoesäure der allgemeinen Formel (V) mit einem Halogenameisensäureester umsetzt und ohne Isolierung das Reaktionsprodukt weiter in einem Einstufenverfahren mit einem Diamin der allgemeinen Formel (VII) zur Reaktion bringt oder in entsprechender Weise eine Aminobenzoesäure der allgemeinen Formel (V), gegebenenfalls unter Einführung eines Formyl- oder Acetylrestes als Schutzgruppe, mit einem Diamin der allgemeinen Formel (VII) zur Reaktion bringt, und nachträglich, gegebenenfalls nach Entfernen der Schutzgruppe, mit einer Carbonsäure der allgemeinen Formel (IV) oder deren reaktionsfähigem Derivat zur Reaktion bringt. 4. A process for the preparation of the compounds according to claim 1, characterized in that either in a manner known per se a) a carboxylic acid of the general formula
Figure imgb0041
 wherein Y has the meaning given in claim 1, or its reactive derivative with an aminobenzoic acid of the general formula
Figure imgb0042
 in which R 1 and R 2 have the meaning given in claim 1, brings to reaction and the aminobenzoic acid of the general formula obtained
Figure imgb0043
 or their reactive derivative with a diamine of the general formula
Figure imgb0044
 Wherein R 5, R 6, R 7 and X e-significance as defined in Claim 1 B, is reacted, and then, if appropriate, the radical R 8 with the specified in claim 1 in a known manner, inserts, or b) an aminobenzoic acid of the general formula (V) optionally with the introduction of a formyl or acetyl radical as a protective group for the NH 2 radical or its reactive derivative with the diamine of the general formula (VII) and after removal of the protective group with a carboxylic acid of the general Bringing formula (IV) or its reactive derivative to the reaction and then optionally introducing the group R 8 in a manner known per se or c) reacting an aminobenzoic acid of the general formula (V) with a halogen formic acid ester and, without isolation, reacting the reaction product further in a one-step process with a diamine of the general formula (VII) or in a corresponding manner an aminobenzoic acid of the general formula (V), optionally under Introduction of a formyl or acetyl radical as a protective group, with a diamine of the general formula (VII), and subsequently, optionally after removal of the protective group, with a carboxylic acid of the general formula (IV) or its reactive derivative. 5. Verfahren zur Herstellung der Verbindungen nach Anspruch 1, mit o-ständiger NH-Y-Gruppe, dadurch gekennzeichnet, daß Isatosäureanhydrid als reaktionsfähiges Derivat der Aminobenzoesäure der allgemeinen Formel (V), gegebenenfalls substituiert mit R1 und R2' mit einem Diamin der allgemeinen Formel (VII) umgesetzt wird und das erhaltene Aminobenzoesäurederivat der allgemeinen Formel
Figure imgb0045
worin R1, R2, R5, R6, R7 und X die in Anspruch 1 angegebene Bedeutung besitzen, mit der Carbonsäure der allgemeinen Formel (IV) oder deren reaktionsfähigem Derivat zur Reaktion gebracht wird.5. A process for the preparation of the compounds according to claim 1, with o-NH-Y group, characterized in that isatoic anhydride as a reactive derivative of aminobenzoic acid of the general formula (V), optionally substituted with R 1 and R 2 ' with a diamine of the general formula (VII) is reacted and the aminobenzoic acid derivative of the general formula obtained
Figure imgb0045
 wherein R 1 , R 2 , R 5 , R6, R 7 and X have the meaning given in claim 1, is reacted with the carboxylic acid of the general formula (IV) or its reactive derivative. 6. Arzneimittel, gekennzeichnet durch einen Gehalt an einer oder mehreren Verbindungen gemäß einem der Ansprüche 1 bis 3, gegebenenfalls zusammen mit üblichen pharmazeutischen Trägerstoffen und Hilfsstoffen.6. Medicament, characterized by a content of one or more compounds according to one of claims 1 to 3, optionally together with conventional pharmaceutical carriers and auxiliaries.
EP78100206A 1977-07-04 1978-06-21 Derivatives of aminobenzoic acids, process for their preparation and pharmaceutical compositions containing them. Expired EP0000174B1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2730174A DE2730174C2 (en) 1977-07-04 1977-07-04 Aminobenzoic acid derivatives and medicaments containing such aminobenzoic acid derivatives
DE2730174 1977-07-04

Publications (2)

Publication Number Publication Date
EP0000174A1 true EP0000174A1 (en) 1979-01-10
EP0000174B1 EP0000174B1 (en) 1981-12-30

Family

ID=6013128

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100206A Expired EP0000174B1 (en) 1977-07-04 1978-06-21 Derivatives of aminobenzoic acids, process for their preparation and pharmaceutical compositions containing them.

Country Status (6)

Country Link
US (1) US4294851A (en)
EP (1) EP0000174B1 (en)
AT (1) AT360972B (en)
CA (1) CA1108139A (en)
DE (2) DE2730174C2 (en)
IT (1) IT1098345B (en)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0294330A2 (en) * 1987-06-03 1988-12-07 Ciba-Geigy Ag Cationic disazo dyes
EP0620218A1 (en) * 1993-04-16 1994-10-19 ALFA WASSERMANN S.p.A. Heterocyclic compounds active in gastro-intestinal pathologies
US20170152769A1 (en) * 2015-11-26 2017-06-01 Man Truck & Bus Ag Variable valve drive having a rocker lever

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4761416A (en) * 1986-07-25 1988-08-02 Syntex (U.S.A.) Inc. N-N-disubstituted-ω-[2-amino-3-(carbonylmethyl)-3, 4-dihydroquinazolinyl]oxyalkylamides and related compounds
GB9214120D0 (en) * 1991-07-25 1992-08-12 Ici Plc Therapeutic amides
US6207665B1 (en) 1997-06-12 2001-03-27 Schering Aktiengesellschaft Piperazine derivatives and their use as anti-inflammatory agents
US6337332B1 (en) * 1998-09-17 2002-01-08 Pfizer Inc. Neuropeptide Y receptor antagonists
SE9901875D0 (en) * 1999-05-25 1999-05-25 Astra Pharma Prod Novel compounds
US7351719B2 (en) * 2002-10-31 2008-04-01 Boehringer Ingelheim Pharma Gmbh & Co. Kg Amide compounds having MCH-antagonistic activity and medicaments comprising these compounds
CA2534428A1 (en) * 2003-08-13 2005-03-03 Paul A. Tempest Melanin concentrating hormone receptor antagonists
RU2006131787A (en) * 2004-02-06 2008-03-20 Шеринг Акциенгезельшафт (De) PIPERASIN DERIVATIVES INHIBITING CHEMOKIN AND THEIR APPLICATION FOR TREATMENT OF MULTIPLE MYELOMA

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3192214A (en) * 1962-10-12 1965-06-29 Olin Mathieson Basic anilide derivatives
DE1595915A1 (en) * 1964-01-13 1970-02-12 Ile De France Process for the preparation of heterocyclic benzamides
DE1957319A1 (en) * 1968-11-28 1970-06-11 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of 2,3-substituted quinazolinone derivatives
DE2612321A1 (en) * 1975-03-24 1976-10-07 Claude Dufour NEW SALICYLIC ACID DERIVATIVES AND PHARMACEUTICAL PRODUCTS CONTAINING THEM
DE2623228A1 (en) * 1976-05-24 1977-12-01 Merckle Kg Chem Pharm L N-ACYL SUBSTITUTED BENZAMIDES, METHOD FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING SUCH BENZAMIDES

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4021481A (en) * 1969-06-27 1977-05-03 Nyegaard & Co. A/S Amido derivatives of 2,4,6-triiodobenzoic acids containing at least one N-hydroxyalkyl and at least two hydroxyl groups
US3719687A (en) * 1970-07-22 1973-03-06 Riker Laboratories Inc N-(2-dialkylaminoalkylene)amides of 1,1-dihydroperfluoroalkoxy-substituted aryl acids and salts thereof
US3840598A (en) * 1970-08-07 1974-10-08 Sterling Drug Inc 4,4'-disubstituted-bis(benzamides)
GB1374366A (en) * 1972-07-21 1974-11-20 Science Union & Cie Propanol derivatives and a process for their preparation
US4070485A (en) * 1974-03-18 1978-01-24 Science Union Et Cie Alkoxy anilides process for preparing the same and pharmaceutical compositions

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3192214A (en) * 1962-10-12 1965-06-29 Olin Mathieson Basic anilide derivatives
DE1595915A1 (en) * 1964-01-13 1970-02-12 Ile De France Process for the preparation of heterocyclic benzamides
DE1957319A1 (en) * 1968-11-28 1970-06-11 Egyt Gyogyszervegyeszeti Gyar Process for the preparation of 2,3-substituted quinazolinone derivatives
DE2612321A1 (en) * 1975-03-24 1976-10-07 Claude Dufour NEW SALICYLIC ACID DERIVATIVES AND PHARMACEUTICAL PRODUCTS CONTAINING THEM
DE2623228A1 (en) * 1976-05-24 1977-12-01 Merckle Kg Chem Pharm L N-ACYL SUBSTITUTED BENZAMIDES, METHOD FOR THEIR MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING SUCH BENZAMIDES

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0294330A2 (en) * 1987-06-03 1988-12-07 Ciba-Geigy Ag Cationic disazo dyes
EP0294330A3 (en) * 1987-06-03 1990-08-08 Ciba-Geigy Ag Cationic disazo dyes
EP0620218A1 (en) * 1993-04-16 1994-10-19 ALFA WASSERMANN S.p.A. Heterocyclic compounds active in gastro-intestinal pathologies
US20170152769A1 (en) * 2015-11-26 2017-06-01 Man Truck & Bus Ag Variable valve drive having a rocker lever

Also Published As

Publication number Publication date
US4294851A (en) 1981-10-13
IT7825221A0 (en) 1978-06-30
DE2861461D1 (en) 1982-02-18
ATA477678A (en) 1980-07-15
EP0000174B1 (en) 1981-12-30
DE2730174A1 (en) 1979-02-22
CA1108139A (en) 1981-09-01
AT360972B (en) 1981-02-10
IT1098345B (en) 1985-09-07
DE2730174C2 (en) 1981-12-10

Similar Documents

Publication Publication Date Title
EP0242851B1 (en) N-(2&#39;-aminophenyl)-benzamide derivatives, process for their manufacture and their application in the treatment of neoplastic illness
DE2706977A1 (en) BENZOESAEURS AND THEIR DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF
DE2536206C2 (en) 3-Quinolinecarboxylic acid derivatives, processes for their preparation and pharmaceutical compositions
DE3249054T1 (en) (1- (2-BENZOXAZOLYL) -HYDRAZINO) -ALKYLNITRILE DERIVATIVES
DE2311570C2 (en) 4-aminoquinolines, processes for their preparation and pharmaceutical preparations containing them
DE2856753A1 (en) N-SUBSTITUTED OMEGA -AMINOALKANOYL- OMEGA -AMINOALKANIC ACIDS, THEIR USE AND METHOD FOR THE PRODUCTION THEREOF, AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
EP0028765B1 (en) Alkyl-urea derivatives for the treatment of lipometabolic diseases; process for their preparation, their use in medicaments for the treatment of lipometabolic disorders, medicaments containing them, process for the preparation of the medicaments, and some alkyl-urea derivatives
EP0000174B1 (en) Derivatives of aminobenzoic acids, process for their preparation and pharmaceutical compositions containing them.
DE2012138C3 (en) N {4- (β-pyrazine-2-carboxyamido-ethyl) benzenesulphonyl] -N &#39;- cycloalkylureas and pharmaceutical preparations containing them
DE3211934A1 (en) SALICYL ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS AND THEIR USE
DE2941288C2 (en)
DE1770414B2 (en) Quinuclidine-2 and quinuclidine-3-carboxylic acid anilides, processes for their preparation and pharmaceutical compositions containing them
DE2446100B2 (en) Phenoxyalkanecarboxamides of thiazolidinecarboxylic acids, process for their preparation and pharmaceuticals
DE3642497A1 (en) SUBSTITUTED AMINOPROPIONIC ACID AMIDES, METHOD FOR THE PRODUCTION THEREOF, THEIR SUBSTANCES AND THEIR USE AND THE NEW INTERMEDIATES PRODUCED IN THE PRODUCTION
DE2513136B2 (en) N- (I -benzylpiperid-4-yl) -benzamides, process for their preparation and pharmaceutical preparations containing them
DE1518125A1 (en) Aminosaeuramides and process for their preparation
DE2711149B2 (en)
EP0049494B1 (en) Esters of 7-hydroxyalkyl-1,3-dimethyl xanthines, process for their preparation and their application as lipid diminishers
DE2310827C3 (en) Phenylalanine derivatives heterocyclically substituted in the phenyl nucleus
DE1493513C3 (en) Sulphamylanthranilic acids, their therapeutically useful salts, processes for their production and pharmaceutical preparations containing them
DE2012667C3 (en) 3- (4-substituted-1-piperazinyl) -carbonylmethyl-2-benzothiazolinones and their acid addition salts, processes for their preparation and pharmaceutical preparations containing these compounds
DE2609574B2 (en) 1- (4-FLUORO-3-TRIFLUOROMETHYLTHIO-PHENYL) -PIPERAZINE, ITS SALT, PROCESS FOR THE PREPARATION THEREOF AND MEDICINAL PRODUCTS
DE2639935A1 (en) BENZOESAEURS AND METHOD FOR THEIR PRODUCTION
DE2029991C3 (en) 2-Hydroxy-5-aminobenzamides, processes for their preparation and pharmaceuticals containing these compounds
DE3620215A1 (en) BENZAMIDES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THEM

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): BE CH DE FR GB LU NL SE

17P Request for examination filed
GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Kind code of ref document: B1

Designated state(s): BE CH DE FR GB LU NL SE

REF Corresponds to:

Ref document number: 2861461

Country of ref document: DE

Date of ref document: 19820218

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19910521

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: LU

Payment date: 19910529

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: BE

Payment date: 19910605

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19910611

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: CH

Payment date: 19910627

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19910628

Year of fee payment: 14

Ref country code: DE

Payment date: 19910628

Year of fee payment: 14

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19910630

Year of fee payment: 14

EPTA Lu: last paid annual fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: LU

Free format text: LAPSE BECAUSE OF NON-PAYMENT OF DUE FEES

Effective date: 19920621

Ref country code: GB

Effective date: 19920621

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19920622

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: CH

Effective date: 19920630

Ref country code: BE

Effective date: 19920630

BERE Be: lapsed

Owner name: LUDWIG MERCKLE K.G. CHEM. PHARM. FABRIK.

Effective date: 19920630

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19930101

NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
GBPC Gb: european patent ceased through non-payment of renewal fee

Effective date: 19920621

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: FR

Effective date: 19930226

REG Reference to a national code

Ref country code: CH

Ref legal event code: PL

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19930302

REG Reference to a national code

Ref country code: FR

Ref legal event code: ST

EUG Se: european patent has lapsed

Ref document number: 78100206.8

Effective date: 19930109

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT