EP0000174A1 - Dérivés d'acides aminobenzoiques, procédé pour leur préparation, compositions pharmaceutiques les contenant. - Google Patents

Dérivés d'acides aminobenzoiques, procédé pour leur préparation, compositions pharmaceutiques les contenant. Download PDF

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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)
English (en)
Other versions
EP0000174B1 (fr
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/fr
Application granted granted Critical
Publication of EP0000174B1 publication Critical patent/EP0000174B1/fr
Expired legal-status Critical Current

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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)
EP78100206A 1977-07-04 1978-06-21 Dérivés d'acides aminobenzoiques, procédé pour leur préparation, compositions pharmaceutiques les contenant. Expired EP0000174B1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE2730174 1977-07-04
DE2730174A DE2730174C2 (de) 1977-07-04 1977-07-04 Aminobenzoesäurederivate und Arzneimittel enthaltend solche Aminobenzoesäurederivate

Publications (2)

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

Family

ID=6013128

Family Applications (1)

Application Number Title Priority Date Filing Date
EP78100206A Expired EP0000174B1 (fr) 1977-07-04 1978-06-21 Dérivés d'acides aminobenzoiques, procédé pour leur préparation, compositions pharmaceutiques les contenant.

Country Status (6)

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

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0294330A2 (fr) * 1987-06-03 1988-12-07 Ciba-Geigy Ag Colorants disazoiques cationiques
EP0620218A1 (fr) * 1993-04-16 1994-10-19 ALFA WASSERMANN S.p.A. Composés hétérocycliques pour les pathologies gastrointestinales
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 (sv) * 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
AU2004266228A1 (en) * 2003-08-13 2005-03-03 Amgen, Inc. Melanin concentrating hormone receptor antagonists
WO2005077372A1 (fr) * 2004-02-06 2005-08-25 Schering Aktiengesellschaft Derives de la piperazine inhibiteurs de la chemokine et leur utilisation pour traiter les myelomes multiples

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 (de) * 1964-01-13 1970-02-12 Ile De France Verfahren zur Herstellung von heterocyclischen Benzamiden
DE1957319A1 (de) * 1968-11-28 1970-06-11 Egyt Gyogyszervegyeszeti Gyar Verfahren zur Herstellung von 2,3-substituierten Chinazolinonderivaten
DE2612321A1 (de) * 1975-03-24 1976-10-07 Claude Dufour Neue salicylsaeurederivate und diese enthaltende pharmazeutische mittel
DE2623228A1 (de) * 1976-05-24 1977-12-01 Merckle Kg Chem Pharm L N-acyl substituierte benzamide, verfahren zu ihrer herstellung und arzneimittel enthaltend solche benzamide

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 (de) * 1964-01-13 1970-02-12 Ile De France Verfahren zur Herstellung von heterocyclischen Benzamiden
DE1957319A1 (de) * 1968-11-28 1970-06-11 Egyt Gyogyszervegyeszeti Gyar Verfahren zur Herstellung von 2,3-substituierten Chinazolinonderivaten
DE2612321A1 (de) * 1975-03-24 1976-10-07 Claude Dufour Neue salicylsaeurederivate und diese enthaltende pharmazeutische mittel
DE2623228A1 (de) * 1976-05-24 1977-12-01 Merckle Kg Chem Pharm L N-acyl substituierte benzamide, verfahren zu ihrer herstellung und arzneimittel enthaltend solche benzamide

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0294330A2 (fr) * 1987-06-03 1988-12-07 Ciba-Geigy Ag Colorants disazoiques cationiques
EP0294330A3 (en) * 1987-06-03 1990-08-08 Ciba-Geigy Ag Cationic disazo dyes
EP0620218A1 (fr) * 1993-04-16 1994-10-19 ALFA WASSERMANN S.p.A. Composés hétérocycliques pour les pathologies gastrointestinales
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
DE2861461D1 (en) 1982-02-18
US4294851A (en) 1981-10-13
DE2730174C2 (de) 1981-12-10
ATA477678A (de) 1980-07-15
AT360972B (de) 1981-02-10
EP0000174B1 (fr) 1981-12-30
IT7825221A0 (it) 1978-06-30
DE2730174A1 (de) 1979-02-22
IT1098345B (it) 1985-09-07
CA1108139A (fr) 1981-09-01

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