NZ194317A - Benzoic acid derivatives and pharmaceutical compositions containing them - Google Patents

Benzoic acid derivatives and pharmaceutical compositions containing them

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Publication number
NZ194317A
NZ194317A NZ194317A NZ19431780A NZ194317A NZ 194317 A NZ194317 A NZ 194317A NZ 194317 A NZ194317 A NZ 194317A NZ 19431780 A NZ19431780 A NZ 19431780A NZ 194317 A NZ194317 A NZ 194317A
Authority
NZ
New Zealand
Prior art keywords
group
ethyl
benzoic acid
formula
acid
Prior art date
Application number
NZ194317A
Inventor
G Griss
R Sauter
W Grell
R Hurnaus
E Rupprecht
N Kaubisch
J Kahling
B Eisele
H Pieper
K Noll
Original Assignee
Thomae Gmbh Dr K
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
Priority claimed from DE19792928352 external-priority patent/DE2928352A1/en
Priority claimed from DE19792949259 external-priority patent/DE2949259A1/en
Priority claimed from DE19803016650 external-priority patent/DE3016650A1/en
Priority claimed from DE19803016651 external-priority patent/DE3016651A1/en
Application filed by Thomae Gmbh Dr K filed Critical Thomae Gmbh Dr K
Priority to NZ20247880A priority Critical patent/NZ202478A/en
Publication of NZ194317A publication Critical patent/NZ194317A/en

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    • 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
    • C07D207/30—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 two double bonds between ring members or between ring members and non-ring members
    • C07D207/32—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D207/325—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 two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • C07D207/327—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/38—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
    • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 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
    • C07D211/40—Oxygen atoms
    • C07D211/42—Oxygen atoms attached in position 3 or 5
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 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
    • C07D211/40—Oxygen atoms
    • C07D211/44—Oxygen atoms attached in position 4
    • C07D211/46—Oxygen atoms attached in position 4 having a hydrogen atom as the second substituent in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings 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 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
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/70—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/68—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D211/72—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D211/74—Oxygen atoms
    • C07D211/76—Oxygen atoms attached in position 2 or 6
    • 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
    • C07D213/72—Nitrogen atoms
    • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
    • 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
    • C07D213/81—Amides; Imides
    • C07D213/82—Amides; Imides in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/14—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D295/155—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals with the ring nitrogen atoms and the carbon atoms with three bonds to hetero atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
    • 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
    • C07D295/20—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 carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Description

New Zealand Paient Spedficaiion for Paient Number 1 94317 1 943 1 / Patents Form No. 5 NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION CHEMICAL COMPOUNDS I/WE DR KARL THOMAE GESELLSCHAFT MIT BESCHRANKTER HAFTUNG, a Body Corporate organised under the laws of the Federal Republic of Germany, of Biberach an der Riss, Federal Republic of Germany hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement:- 194317 This invention relates to new carboxylic acid derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use as pharmaceuticals.
According to one feature of the present invention we provide compounds of general formula I, Ri 4 CO-NH-Y-CH-f' \-Z \=/ <*> wherein R represents a hydrogen, chlorine or bromine 1q atom or a cyclic alkyleneimino group; represents a hydrogen, fluorine, chlorine or bromine atom; a C^_galkyl or C^_galkoxy group; a phenyl-(Ci_3alk°xy) group; a hydroxy, nitro, amino, cyano or carboxy group; or a Cj^alkanoylamino, (C-^^alkoxy)-15 carbonyl or di (C. -alkyl)aminosulfonyl group; X J (0" ^ t • R2 and R^/ which may be the same or different/ ftlthe# each reprepents^a^Cj^alkyl, C-^^alkenyl, cycloalkyl, phenyl ' (^^—aikenyl^ , phenyl or adamantyl group, or together with the nitrogen atom to which they are attached, they represent C^_galkylenimino group optionally substituted by 1 or 2 C^_^alkyl groups or by a Cj^alkoxy, hydroxy, phenyl, carboxy or ^2-4 alkoxycarbonyl group and/or in which a methylene group of the imino ring may optionally be replaced by a further _25 imino group (which may itself optionally be substituted PATENrre; , 1 1 NOV 1982 194317 by a C^jalkyl, C2_4alkoxycarbonyl, phenyl, halophenyl, benzyl, pyridyl or furoyl group), by an oxygen or v sulfur atom or by a carbonyl, sulfoxide or sulfony^/group ; a saturated or partly unsaturated C^_^0aza-bicycloalkyl 5 group; a piperidino group substituted in the 3- and 5- positiorisby a total of either 3 or 4 Cj^alkyl groups; a Cggl,4-dioxa-8-aza-spiroalkyl group; or a trimethylenimino, 1 ^"jjpyrffolyl, tetrahydropyridino, heptamethylenimino, octa-methylenimino, nonamethylenimino, decamethylenimino, 10 undecamethylenimino or dodecamethylenimino group; represents a hydrogen atom or a C^_.jalkyl •group; X represents a nitrogen atom or a group =CH-; Y represents an oxygen atom; an imino group; 15 or a methylene group optionally substituted by 1 or 2 C^_3alkyl groups; &nd Z represents a hydrogen or halogen atom ; a nitro, amino, cyano, formyl, hydroxymethyl or carboxy-ethylene group; an optionally esterified carboxy group; 20 a methyl group (optionally substituted by 2 or 3 alkoxy groups or by a carboxy, (C^^alkoxy) carbonyl or ethylenedioxy group); an acetyl group (optionally substituted by a carboxy group or a C^_4alkoxycarbonyl group. ); an ethyl or ethylene group substituted by 1 or 25 2 C2_4 alkoxycarbonyl groups or by two carboxy groups); an aminocarbonyl group (substituted by one or two substituents selected from C^_^alkyl groups, C^ycycloalkyl groups and C.j_7alkenyl groups); a piperidinocarbonyl, morpholinocarbonyl, thiomorpholino-carbonyl or N-(C1_3alkyl)-piperazinocarbonyl group; or an ethyl group (substituted by a carboxy group); and, where R^ and R^ together with the nitrogen atom to which they are attached, represent a cyclic imino group as defined above, and/or where Z represents or —-—--•35.. contains a carboxy group, the salts thereof- The above compounds according to the invention ' 1 ^0VS982 exhibit interesting pharmacological properties and in """ ■ particular an effect on intermediary metabolism. Thus these compounds possess a blood-sugar lowering and/or lipid lowering activity.
It will be appreciated that, for pharmaceutical use, the salts referred to above will be physiologically compatible. Other salts may find use, however, for example in the preparation of the compounds of general formula I and their physiologically compatible salts.
In the above compounds according to the invention R may, for example, represent a hydrogen, chlorine or bromine atom or a pyrrolidino, piperidino or hexamethylenimino group.
R^ may, for example, represent a hydrogen, fluorine, chlorine or bromine atom or a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, isopentyl, hexyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, |tert. butQxy, pentyl-oxy, isopentyloxy, neopentyloxy, tert.pentoxy, hexyloxy, benzyloxy, 1-phenylethoxy, 2-phenylethoxy, 1-phenylpropoxy, 2-phenylpropoxy, 3--phenylpropoxy, nitro, cyano, amino, formylamino, acetamido, propionylamino, carboxy, methoxy-carbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxy-carbonyl, dimethylaminosulfonyl, diethylaminosulfonyl, dipropylaminosulfony1, ethyl-methylaminosulfonyl, methyl-propylaminosulfonyl or ethyl-propylaminosulfonyl group.
R2 and R^ together with the nitrogen atom to which they are attached, may, for example, represent a dimethylamino, diethylamino, dipro-pylamino, diisopropylamino, dibutylamino, diisobutyl- amino, dlpentylamlno, dihexylamlno, diheptylamino, N-methyl-ethylamino, N-methyl-propylamino t N-isopropyl-propylamino, N-isobutyl-propylamino, N-methyl-isopropylamino, N-methyl-butylamino, N-ethyl-butylamlno, N-ethyl-isopropylamino, N-ethyl-pentylamino, N-propyl-butylamino, N-propyl-heptyl- 194317 amino, dicyclohexylamino, N-methyl-cyclohexylamino, N-ethyl-cyclohexylamino, N-propyl-cyclohexylamino, N-isobutyl-cyclohexylamlno, dibenzylamlno, N-methyl-benzylamino, N-ethyl-benzylamino, N-propyl-benzylamino, N-isopropyl-5 benzylamino, N-butyl-benzylamino, N-heptyl-benzyl- amino, N-methyl-phenylethylamino, N-methyl-phenylpropyl-amino, N-ethyl-phenylethylamino, N-propyl-phenylethyl-amino, N-butyl-phenylpropylamino, diallylamino, dibutenyl-amlno, dipentenylamino, diheptenylamino, N-methyl-adaman-10 tylamino, N-ethyl-adamantylamino, N-propyl-adamantylamino, trimethylenimi.no, pyrrolidino, piperidino, hexamethylenimino, heptamethylenimino, octamethylenimino, nonamethylenimino, decamethylenimino, undecamethylenimino, dodecamethylenimino, methyl-pyrrolidino, dimethyl-pyrrolidino, 1,2,3,6-tetra-15 hydro-pyridino, methyl-piperidino, dimethyl-piperidino, trimethyl-piperidino, tetramethyl-piperidino, ethyl-piperidino, diethyl-piperidino, methyl-ethyl-piperidino, propyl-piperidino, dipropyl-piperidino, methyl-propyl-piperidino, isopropyl-piperidino, ethyl-propyl-piperi-20 dino, butyl-piperidino, isobutyl-piperidino, tert.butyl- piperidino, cis-3»5-dimethyl-piperidino, trans-3,5-dimethyl-piperidino, cis-3>5-diethyl-piperidino, trans-3,5-dipropyl-piperidino, hydroxy-pyrrolidino, hydroxy-piperidino, methoxy-pyrrolidino, methoxy-piperidino, ethoxy-piperidino, propoxy-25 piperidino, isopropoxy-piperidino, phenyl-piperidino, carbo xy-pyrrolidino, carboXy - piperidino, methoxycar- bonyl-piperidino, ethoxycarbonyl-piperidino, propoxycarbonyl-piperidino, isopropoxycarbonyl-piperidino, 3,3,5,5-tetramethyl-piperidino, 3,3,5,5-tetraethyl-piperidino, 3,3,5,5-tetra- FLjrre4.-ci CM pujcr propyl-piperidino, fryrrolldea^-1-yl, fliperldona-1-yl, #-><? yCXJMclsvazepLSi c.n ^exahydroaz^pinone/-1 - yl f morpholino, methyl-morpholino, dimethyl-morpholino, propyl-morpholino, thiomorpholino, methyl-thiomorpholino, dimethyl-thiomorpholino, ft~ox±do* — i-0XA.de tjuoiftcrphc/U^no - I-cacccle thiomorpholino/, dimethyl-fl-oxidothlomorphejrlad, H->1 dloxldo4 " dunc^cle o ~ tfccclc thiomorpholino/, dlmethyl-p-, 1 -dioxldothiomorphollnu1, plpera- 11 NQV 12 194317 zlno, N-methyl-piperazino, N-ethyl-piperazino, N-propyl-piperazlno, N-lsopropyl-piperazlno, N-phenyl-piperazino, N-chlorophenyl-piperazino> N-bromophenyl-piperazino, N-pyridyl-piperazlno, N-methoxycarbonyl-piperazino, N-ethoxy-5 carbonyl-piperazino, N-propoxycarbonyl-plperazlno, N-furoyl- . isoQUiS\ crUs) plperazino, tetrahydro-frsoqulnollny-2-yl, octahydro-iso-£tt4aoHntf-2-yl , decataydro-^o$&oltn4-2-yl , tetrahydro-3-enzaze^in^- 3 - y 1, decahydro-3-jbaz effin^-3-y 1» JsoLncCcri ftoncis} octahydro-foolndolg-2-»yl, 3-aza-blcyclo-ponan^-3-yl, 1° 1 ^-dioxa-S-aza-spiro/^^/deean^-S-yl or 1,4-dloxa-8-aza-spiro/E 9 6/l^a<Weaai(-8-yl -group, R4 may represent a hydrogen atom or a methyl, ethyl, propyl or Isopropyl group.
Y may for example represent an oxygen atom or an 15 imino, methylene, methylmethylene, ethyl-methylene, propyl-methylene, dimethyl-methylene, diethyl-methylene or methyl-propyl-methylene group.
Z may for example, represent a hydrogen, chlorine or bromine atom or a nitro, amino, cyano, formyl, 20 hydroxymethyl, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, heptoxycarbonyl, allyloxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, phenylethoxycarbonyl, 25 cyclopropoxy-carbonyl, cyclopentoxycarbonyl, cyclohexyloxy-carbonyl, cycloheptoxycarbonyl, methyl, dimethoxymethy1, diethoxymethyl, triethoxymethyl, dipropoxymethyl, tri-propoxymethyl, carboxymethyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, propoxycarbonylmethyl, 1,3-dioxolan-30 2-yl, acetyl, carboxyacetyl, methoxycarbonylacetyl, ethoxycarbonylacetyl, isopropoxycarbonylacetyl, 2-carboxy-ethylene, 2-methoxycarbonylethylene, 2-ethoxycarbonyl-ethylene, 2-carboxyethyl, 2-methoxycarbonylethyl, 2-ethoxycarbonyl-ethyl, 2-isopropoxycarbonyl-ethyl, r ^' ^-^is-carboxy-ethyl, 2,2-b is-ethoxycarbonyl-ethy 1, J t NOV $32 194317 amlnocarbonyl, methylamlnocarbonyl, ©thylaminocarbonyl, isopropylaminocarbonyl, butylamlnocarbonyl, pentylamino-carbonyl, hexylamlnocarbonyl, heptylaminocarbonyl, allyl-aminocarbonyl, dlallylaminocarbonyl, dimethylaminocarbonyl, 5 diethylaminocarbonyl, dlpropylaminocarbonyl, dihexylamino-carbonyl, N-methylethylaminocarbonyl, cyclopropylamino-carbonyl, cyclopentylaminocarbonyl, cyclohexylaminocarbonyl, cycloheptylaminocarbonyl, dicyclohexylaminocarbonyl, N-methyl-cyclohexylaminocarbonyl, N-ethyl-cyclohexylamlnocarbonyl, 10 N-propyl-cyclohexylaminocarbonyl, N-pentyl-cyclohexylamino-carbonyl, piperidinocarbonyl, morpholinocarbonyl, thiomor-pholinocarbonyl, N-methyl-plperazlnocarbonyl, N-ethyl-piper-azlnocarbonyl or N-propyl-plperazlnocarbonyl group .
Of the above compounds of the invention, preferred compounds are those wherein R represents a hydrogen atom; represents a hydrogen, fluorine, chlorine or bromine at®m; a C^_6alkoxy, C^_4alkyl or C2_4alkoxycarbonyl group; or a hydroxy, cyano, carboxy, nitro, amino, acetamido, 20 dimethylaminosulfonyl or benzyloxy group; either R2 represents a C^_g alkyl group or a cyclohexyl, phenyl, benzyl, adamantyl or allyl group and a ( R3 represents a C^_g alkyl group or an Jal±y group; or R2 and R^ together with the nitrogen atom to which they are 25 attached, represent a C4_^2alkylenimino group; a piperidino group (substituted by a alkyl, phenyl, hydroxy, methoxy, carboxy or C2_4alkoxycarbonyl group); a piperidino group (substituted both in the 3- and in the 5-positions by a C-^alkyl group) ; a piperidino group (substituted both in the 3- and in the 5-positionsby 2 C1 -alkyl groups); 1— J -/-o a morpholino, thiomorpholino, ,jt oxido/thiomorpholino/ or - \,l-oUUK/c4<i A grrl-dioxlde-/thiomorpholino^ group (each said group being optionally substituted by 1 or 2 methyl groups); a piperazino group (optionally substituted in the 4-position 35 by a methyl, benzyl, phenyl, chlorophenyl, pyridyl, furoyl 194317 t> V l~p^<robj{ Pf>C' f id OJl — or C2_4alkoxycarbonyl group); or a fcyrro4y-|., {?iperldonfr7 (2)-yl-(l) , 1,2,3,6-tetrahydro-pyridino, l,4-diazo-8-aza-spiro- (4,5j<ftecan^-8-yl, 1,4-dioxa-8-aza-spiro (4,61 " uncieu*~n tsoL^iclof jmdecana-8-yl, octahydro-j.-soindol^-2-yl, 1,2, 3,4-tetrahydro- /■$ Of ULtsXo ics\ lisCJ^U-lvlO U-Sl ~ JbfloquinolTnc/-2-yl, 1,2,3,4,5,6,7, 8-octahydro-^styjtt±TtolineV ISOCf U-CST. cf tc-si 2-yl, decahydro-^equinoi±irei-2-Yl, l,2,4/5-tetrahydro-3- bcn-za. ~z<zpLsi V/iz«.ze^t/i pen»a»ep4B«-3-yl, decahydro-3-benzazepin0-3-yl or nonasi 3-aza-bicyclo-£enan^-3-yl group; R^ represents a hydrogen atom or a methyl group; 10 Y represents a methylene, methyl-methylene or dimethyl-methylene group, an imino group or an oxygen atom; and Z represents a carboxy, cyano, formyl or hydroxymethyl group; a C2_yalkoxycarbony1 group; a cyclohexyloxy-15 carbonyl, benzyloxycarbonyl, diethoxymethyl, carboxy- methyl, bis-2,2-ethoxycarbonyl-ethyl, 2-carboxy-ethylene or 2-ethoxycarbonyl-ethyl group; an acetyl group optionally substituted by a carboxy or ethoxycarbonyl group; or a 2-carboxy-ethyl group.
Of these preferred compounds especially preferred are those wherein is present in the 5-positlon of the phenyl or pyridyl nucleus and more especially (1) those wherein j^Luor <,r\ CL R^ represents a hydrogen, (frlu-roin^, chlorine or 25 bromine atom or a C^^alkyl, C^^alkoxy, carboxy, cyano or nitro group; 1*2 and R^ together with the nitrogen atom to which they are attached, represent a N,N-di (C^^alkyl) amino or N-(C^^alkyl)-cyclohexylamino group; a pyrrolidino, piperidino, hexamethylenimino, heptamethylenimino, octamethylenimino or nonamethylenimino group; a piperidino group (substituted by a C^_4alkyl, methoxy or phenyl group); a piperidino group (substituted both in the 3- and in the 5-positions by 1 or 2 methyl or ethyl groups); a morpholino 35 or thiomorpholino group (each said group being optionally 194317 substituted in the 2- and 6-positions by a methyl group); or _ c(& to/l a 1,4-dioxa-8-aza-spiro[4,5jflGoand-8-yl, l,4-dioxa-8-aza-spiroA,6_Jftndcoang^yX, octahydro-J-3oindo±^-2-yl, be '1 Zci'zePLs'i 1,2,4,5-tetrahydro-3H-3-^enzazeplnW-3-yl, decahydro-3H-3-benz- 3-aza-bicyclo^»2,27l^a^-3-yl or N-methyl-adamantyl-(1)-amino group, X represents the group =CH-; and Z represents a C^_^alkoxycarbonyl group or a carboxy, formyl or hydroxymethyl"group: and (2) those wherein R^ represents a chlorine or bromine atom or a methyl, ethyl or methoxy group; r R2 and R^ /bo^eh.Lei with the nitrogen atom to which they are attached, represent a pyrrolidino, piperidino, methyl-piperidino, 4-methoxy-piperidino, 4-phenyl-piperidino, hexa-methylenlmino, heptamethylenimino, octamethylenimino, nona-methylenimino, 3,5-dimethyl-piperidino, morpholino, 2,6-di-methyl-morpholino, thiomorpholino, 2,6-dimethyl-thiomorpho- rr ~r lino, 1,4-dioxa-8-aza-spiro/4,£/£ec«n^-8-yl, , 1,2,3,4-tetra- ISO-JiMS1cr£Ls~T IS cri-L-r\ hydro-.Esuqulnoling-2-yl, decahydro-j.soquinoline-2-yl, ben zar^e/-><->v . 1,2,4,5ytetrahydro-3H-3-pcnzazoplflg-3-yl, decahydro- ^ b('n~Za.~Z£p<-+i jsc>u\eJa/ . 3H-3-perizazepins-3-yl, octahydro-J.-soindol^-2-yl or N-methyl- adamantyl-(1)-amino group; or a piperidino group substituted in the 4-position by a C2_4alkyl group.
Particularly preferred of the above compounds according to the invention are the following: a) 4-^2-(5-chloro-2-piperidino-benzoylamino)-ethyl]benzoic acid, b) 4- £2- (5-ethyl-2-piperidino-benzoylamino) -ethylj benzoic acid, . r cie c<x-o — c) 4-[2- (5-chloro-2- (1,4-dioxa- 8-aza-spiro £4, 5^]flccan£ » 8-yl)benzoylamino)-ethyl^benzoic acid, d) 4-[2-(5-chloro-2-octamethylenimino-benzoylamino)-ethylj benzoic acid, e) 4-£2-(5-chloro-2-(2,6-dimethylmorpholino)-benzoylamino)- 1 C A "Z ff 2 ethyl]-benzoic acid, f) 4-£2-(5-chloro-2-(cis-3,5-dimethylpiperidino)-benzoylamino)-ethyjbenzoic acid, and their C^^alkyl esters and acid addition salts thereof.
The compounds of general formula I may for example, be prepared by the following processes, which processes constitute further features of the present invention: A Reaction of an acid of formula IV, R COOH ^ (IV) "R3 (wherein R, R^, R2, R3 and X are as hereinbefore defined), or a reactive derivative thereof which may optionally be prepared in situ in the reaction mixture, with an amine of formula V, H2N — Y — CH 2 (V) (wherein R4, Y and Z are as hereinbefore defined) or, where Z does not contain a carboxy or amino group and an acid of formula IV is used, an N-activated derivative thereof.
Thus, the process concerns the acylation of an amine of formula V with either an acid of formula IV, preferably in the presence of a dehydrating agent or an acid activating agent or with a functional derivative of the acid of formula IV, or the reaction of an acid of 2 5 formula IV with an N-activated derivative of an amine of formula V wherein Z does not j-e- 1 9 C 3 - n - present or contain a carboxy or amino group, which N-activated derivatives may optionally be prepared In situ from the amine of formula V by means of an agent serving to activate the amino group.
Functional derivatives of the acid of formula IV which may be used and which may also optionally be prepared In Situ in the reaction mixture, include for example alkyl, aryl and aralkyl esters and thioesters such as e.g. the methyl, ethyl, phenyl or benzyl esters; imidazolides; acid halides such as e.g. the acid chloride or bromide; acid anhydrides; mixed anhydrides with aliphatic or aromatic carboxylic acids, sulfenic acids, sulfinic acids or sulfonic acids or carbonic acid ! ' esters, e.g. with acetic acid, propionic acid, £-tolu- enesulfonic acid or O-ethyl carbonic acid; O-triphenyl phosphonium complexes; N-acyloxy imides; azides ; and nitriles ; as well as the corresponding amino-thiobenzoic acid derivatives. The N-activated derivative of the amine of formula V where Z ddes not represent or contain a carboxy or amino group, may for example be a phosphazo derivative.
Acid activating and/or dehydrating agents which may be used include for example esters of chloroformic acid such as e.g. ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'- carbonyldiimidazole, N,N'-thionyldiimidazole, boron trifluoride etherate and triphenyl phosphine/carbon tetrachloride.
The reaction is conveniently carried out in the presence of a solvent such as e.g. methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene or dimethylfon^amide and optionally in the presence of an inorganic base such as e.g. sodium carbonate or a tertiary organic base such as e.g. triethylamine or pyridine. If desired the base may <r K , rVyf % simultaneously serve as solvent. The reaction may optionally be effected in the presence of an acid activating agent. Convenient temperatures for the reaction are from -25 to 250°C, preferably, however, from -10°C to the boiling point of the reaction mixture. If a derivative of the compound of formula IV or V is formed in situ in the reaction mixture it need not be isolated. The reaction can also if desired be carried out without a solvent and water formed during the reaction may, if desired by removed by azeotropic distillation, e.g. by heating with toluene in a water separator funnel, or by addition of a drying agent such as e.g. magnesium sulfate or a molecular sieve.
B for the preparation of compounds of general formula I wherein R^ represents a hydrogen, fluorine, chlorine or bromine atom; a C^_galkyl or C^_galkoxy group; a nitro, cyano or carboxy group; or a C^^alkanoylamino, (C^^alkoxy) carbonyl or di (C^^alkyl) aminosulfonyl gropp; X represents a group =CH-^; and Y represents a methylene group (optionally substituted by 1 or 2 C^^alkyl groups): Reaction of a compound of formula VI, [wherein R, R4 and Z are as hereinbefore defined; Ra1 represents a hydrogen, fluorine, chlorine or bromine atom; a C^_galkyl or C^_galkoxy group; a nitro, cyano or carboxy group; or a C^^alkanoylamino, (C^_3alkoxy)-carbonyl or di(C^_3alkyl)aminosulfonyl group; Y1 represents a methylene group (optionally substituted by 1 or 2 alkyl groups); and E represents a halogen atom] with an amine of formula VII, 1 9 4.3 i 7 -ii- H - N (VII) (wherein R2 and are as hereinbefore defined).
The halogen atom, mentioned in the definition of the exchangeable radical E, is especially a chlorine or 5 bromine atom, or, where R^ represents a nitro group, alternatively a fluorine atom.
The reaction is conveniently carried out in the presence of a solvent such as e.g. water, water/methanol, water/ethanol, water/isopropanol, dimethylformamide or in 10 an excess of the amine of formula VII. Optionally the reaction is effected in the presence of an inorganic or tertiary organic base. A reaction accelerator such as e.g. copper may also optionally be used is desired. If desired, the reaction may be carried out in a closed vessel, 15 and e.g. at temperatures of from 20 to 150°C, preferably, however, at the boiling point of the reaction mixture, e.g. at 100°C. The reaction can, if desired, be carried out without a solvent.
C for the preparation of compounds of general formula 20 i wherein Z represents a carboxy group and Y represents an oxygen atom or a methylene group (optionally substituted by 1 or 2 C^_3 alkyl groups): Oxidation of a compound of formula VIII, - CH A (VIII) 1 9 4o 1 [wherein R, R^, R2, R^, and X are as hereinbefore defined; Y2 represents an oxygen atom or a methylene group (optionally substituted by 1 or 2 alkyl groups); and A represents a group transformable into a carboxy 5 group by oxidation] whereby the desired compound of formula I is obtained.
A in the compound of formula VIII may, for example,by a formyl group or an acetal thereof; a hydroxymethyl group or an ether derivative thereof; or an unsubstituted or 10 substituted acyl group such as e.g. an acetyl, chloroacetyl, propionyl. malonic acid-(l)-yl or malonic ester-(l)-yl group.
The reaction is carried out with an oxidising agent conveniently in the presence of a solvent such as water, 15 glacial acetic acid, pyridine or carbon tetrachloride. Preferred temperatures are from O to 100°C, more preferably from 20 to 50 °C. Oxidation may, for example, be effected with silver oxide/sodium hydroxide solution; manganese dioxide/acetone or methylene chloride; hydrogen 20 peroxide/sodium hydroxide solution; bromine or chlorine/ sodium hydroxide solution or potassium hydroxide solution; or chromium trioxide/pyridine.
D for the preparation of compounds of general formula I wherein Z represents a carboxy group: Hydrolysis of a compound of formula IX, R CO - NH "-fx ■ X N 3 194317 (wherein R, R^, R2, R^, R^/ X and Y are as hereinbefore defined and B represents a group transformable into a carboxy group by hydrolysis).
B in the compound of formula IX may, for example, 5 be a cyano group or a functional derivative of the carboxy group such as an unsubstituted or substituted amide, ester, thioester, orthoester, iminoether, amidine or anhydride group, a malonic ester-(l)-yl group, a tetrazolyl oxaZo/ group or an optionally substituted 1,3-pxazolg-(2)-yl or oxclzcL dihydro-l,3-<^xaaol£-(2)-yl group.
The hydrolysis is conveniently carried out in the presence of either an acid such as hydrochloric acid, sulfuric acid, phosphoric acid or trichloroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide. Suitable solvents for the hydrolysis include e.g. ethanol, water/ethanol, water/ isopropanol or water/dioxan and preferred temperatures o tzynpescctuses are from"-10 to 120 C, e.g. at pernperautes of from ambient temperature to the boiling point of the reaction mixture.
If in the compound of formula IX, B represents a cyano group, the reaction may conveniently be carried out, if desired, in the presence of ethanol/hydrogen chloride, whereby the corresponding imino or ortho ester 25 is formed in the reaction mixture which by addition of water may be converted to the corresponding ester which in turn may be hydrolysed.
E for the preparation of compounds of general formula I wherein either R2 represents a alkyl, cycloalkyl, phenyl(C1_3alkyl) or C3_7alkenyl group and R3 represents a C1_?alkyl, C3_?cycloalkyl, C^alkenyl, phenyl-(C-^alkyl) or adamantyl group or R2 and R3, together with the nitrogen atom to which they are attached, represent a alkylenimino ring, a aLkyl-substituted 194317 piperidino group or a piperidino group (substituted both in the 3- and in the 5-positiors br a alkyl group); and Y represents a methylene group (optionally substituted by 1 or 2 alkyl groups): Reaction of a compound, optionally formed in situ in the reaction mixture, of formula X, (X) R ^ \ >V00 - m - Y1 - CH -/ V ' ~c,x,. - w x N [(wherein R, R^ R4, X, Z and are as hereinbefore defined and R^' represents a hydrogen atom, a alkyl, C3_7 cycl-oalkyl, alkenyl, phenyl(C^_3 alkyl) or adamantyl group or, together with R2* in formula XI, a straight chain alkylene group, a alkyl- substituted n-pentylene group or a n-pentylene group (substituted both in the 2-position and in the 4-position 15 by a alkyl group)] with a compound of formula XI, r2' - G (XI) [wherein R2' represents a alkyl, cycloalkyl, phenyl(C^_2 alkyl) or C^_7 alkenyl group or, together with ' in formula Xi, a straight chain alkylene group, a C^_4 alkyl-substituted n-pentylene group or a n-pentylene group (substituted both in the 2- and in the 4-positions by a alkyl group) and G represents a nucleophilically exchangeable group such as for example a halogen atom or a sulfonyloxy group, e.g. a chlorine, N.Z. PATENT OFFICE 11 NOV 1982 received 194317 bromine or iodine atom or a methanesulfonyloxy or p-toluene-sulfonyloxy group].
The alkylating agent of formula XI may for example be a halide or sulfate such as e.g. methyl iodide, ethyl iodide, propyl bromide, benzyl chloride, benzyl bromide, dimethyl sulfate or diethyl sulfate.
The reaction is conveniently carried out in the a. soLS£SI~£? presence of^such as acetone, tetrahydrofuran, dimethyl-formamide, dimethyl sulfoxide or hexamethyl phosphoric 10 acid triamide and optionally in the presence of an inorganic base such as e.g. sodium carbonate, potassium carbonate or potassium tert.butylate or a tertiary organic base such as e.g. pyridine. Preferred temperatures are from 0 to 150°C most preferably from 20 to 75°C. 15 If a carboxylic acid of formula X is used, this acid may, depending on the reaction conditions employed, e.g. at temperatures above ambient temperature and in the presence of an alcoholate as a base, be converted simultaneously into the corresponding ester.
Where R2' in formula XI represents a methyl group, methylation can also be carried out using formaldehyde as the compound of formula XI in the presence of a reducing agent, e.g. formic acid or hydrogen in the presence of a hydrogenation catalyst, e.g. palladium or platinum, 25 optionally in the presence of a solvent such as e.g. formic acid or glacial acetic acid and conveniently at temperatures up to the boiling point of the reaction mixture.
The compound of formula X may, if desired, be 30 prepared in situ by reaction of a corresponding sub- —~" oun h*j cts !Cl & stituted isatoic acid ftnhydridc with an appropriate amine of formula V.
F for the preparation of compound cf general formula I 194317 lb wherein Y represent an oxygen atom or an imino group: Reaction of a compound of formula XII, (wherein R, R^, R2, R-j and X are as hereinbefore defined and Y, represents an oxygen atom or an imino group), or an J VIII alkali metal salt thereof, with a compound of formula JXZT, (wherein R. and Z are as hereinbefore defined and L 4 represents a nucleophilically exchangeable group such as, for example, a halogen atom or a sulfonyloxy group, e.g. a chlorine, bromine or iodine atom or a methylsulfonyloxy, £-toluenesulfonyloxy or methoxysulfonyloxy group).
The reaction is conveniently carried out in the presence of a solvent such as water/ethanol, water/ isopropanol, tetrahydrofuran, dioxan, acetone, dimethyl-formamide., dimethyl sulfoxide or hexamethyl phosphoric acid triamide, preferably in the presence of a base such as e.g. sodium carbonate, sodium hydroxide, potassium hydroxide or potassium tert.butylate. Preferred temperatures are from 0 to 150°C preferably the boiling point of the reaction mixture, e.g. at temperatures of R *4 194317 from 50 to 100°C. If an ester is used, this ester may, depending on the reaction conditions employed, e.g. at elevated temperatures and in the presence of an excess of base, be simultaneously converted into the corresponding carboxylie acid.
E for the preparation of compounds of general formula I wherein represents a hydrogen, fluorine, chlorine, or bromine atom, a C^_g alkyl or alkoxy group, a phenyl(C^_3 alkojty) group, a nitro or cyano group or a alkoxy)carbonyl or di(C^_3 alkyl)aminosulfonyl group; X represents a group =CH-; and Y represents a methylene group (optionally.substituted by 1 or 2 alkyl groups): Reaction of an amide of formula XIV, (XIV) ^R, (wherein R, R2 and R^ are as hereinbefore defined and represents a hydrogen, fluorine, chlorine or bromine atom, a alkyl or alkoxy group, a phenyl(C^_3 alkoxy) group, a nitro or cyano group or a (C^_3 alkoxy)~ carbonyl or di(C^_3 alkyl)aminosulfonyl group), or an alkali metal salt thereof with a compound of formula XV, M - Y1 - CH —^ ^-Z (XV) (wherein and Z are as hereinbefore defined, and M represents a nucleophilically exchangeable group such 194317 as e.g. a halogen atom or a sulfonyloxy group).
The reaction is conveniently carried out in the presence of a solvent such as tetrahydrofuran, dioxan, toluene, dimethylformamide, dimethylsulfoxide or hexamethyl phosphoric acid triamide optionally in the presence of a base such as e.g. sodium hydride or potassium te^hmtyiate. Preferred temperatures are from 20 to 180°C, most preferably from 50 to 150°C.
H for the preparation of compounds of general formula I wherein represents a hydrogen, fluorine, chlorine or bromine atom, a alkyl or Cj_g alkoxy group, a phenyl- (C^_2 alkoxy) group or a hydroxy, nitro, carboxy or alkanoylamino group; X represents a group =€H-; Y represents a methylene group (optionally substituted by 1 or 2 alkyl groups) and Z represents a carboxy group: CcU" booc.-uUcti^n of a compound of formula XVI, CO - NH- -»o (XVI) (wherein R, R^, R^, and are as hereinbefore defined and R° represents a hydrogen, fluorine, chlorine or bromine atom, C^_g alkyl or g alkoxy group, a phenyl— (C^^^ alkoxy) group or a hydroxy, nitro, carboxy or alkanoylamino grouji with an oxalyl halide or phosgene in the presence of a Lewis acid.
This Friedel-Crafts focylatiort is conveniently carried out in the presence of a solvent such as nitrobenzene or carbon disulfide. The Lewis acid is 1 k • T 4 preferably aluminium chloride and preferred temperatures are from 0 to 80°C most preferably from 20 to 60°C. I for the preparation of compounds of general formula I wherein represents a hydrogen, fluorine, chlorine 5 or bromine atom, a alkyl or alkoxy group, a phenyl(C^_2 alkoxy) group or a nitro, carboxy, alkanoylamino or (C1_3 alkoxy) carbonyl group; X represents a group =CH-; Y represents a methylene group (optionally substituted by 1 or 2 alkyl groups); and Z represents a carboxy group: Reaction of a compound of formula XVII, CO - HH - Tj- CH f\ COCH. (*VII) / "2 II R W 3 N R3 (wherein R, R2, R^, R4 and Y^ are as hereinbefore defined and R^ represents a hydrogen, fluorine, chlorine or bromine atom, a C-^-6 alkyl or alkoxy group, a phenyl- (Ci_3 alkoxy) group or a nitro, carboxy, alkanoy1- amino or alkoxy) carbonyl group) with a hypohalite which hypohalite may optionally be prepared in situ in the reaction mixture.
The reaction is conveniently carried out in the presence of a solvent such as water/tetrahydrofuran or water/dioxan and at temperatures of from 0 to 80°C, most preferably from 25 to 50°C. i c ^ ^ ^ J for the preparation of compounds of general formula I wherein Z represents an esterified carboxy group: Esterification of a compound of formula I (wherein Z represents a carboxy group).
K for the preparation of compounds of general formula I wherein Z represents an aminocarbonyl group (substituted by one or two substitutents selected from alkyl groups, groups and alkenyl groups) or a pipericfaocarbonyl , morpholinocarbonyl, thiomorpholinocarbonyl or N-(C^_2 alkyl)-piperazinocarbpnyl group: Amidation of a compound of formula 1 (wherein Z represents a carboxy group).
The esterification or amidation in processes J and K above is conveniently carried out in the presence of a solvent, such as the corresponding alcohol or amine, pyridine, toluene or dioxan and conveniently in the presence of an acid activating and/or dehydrating agent such as e.g. thionyl chloride, ethyl chloroformate, N,N'-dicyclohexylcarbodiimide or carbonyldiimidazole or by transesterification, e.g. with a corresponding carbonate. Preferred temperatures are from 0 to 50°C, most preferably ambient temperature.
L for the preparation of compounds of general formula I wherein and/or Z represents an amino group: Reduction of a compound of formula I (wherein R^ and/or Z represents a nitro group).
The reduction of the nitro compound is preferably carried out in the presence of a solvent such as water, water/ethanol, methanol, glacial acetic acid,, ethyl acetate or dimethylformamide. Conveniently reduction may be effected with hydrogen in the presence of a hydrogenation catalyst such as e.g. Raney nickel, platinum I 104317 as or palladium/charcoal; with metals such as iron, tin or zinc in the presence of an acid; with salts such as iron Jtea?ri(II) sulfate, tin(II) chloride or sodium dithionite; or with hydrazine in the presence of Raney nickel.
Preferred temperatures are from 0 to 50°C, most preferably, ambient temperature.
M for the preparation of compounds of general formula I wherein R^ represents a hydroxy or cyano group or a fluorine, chlorine or bromine atom and/or Z represents a 10 chlorine or bromine atom cr a cyano group: Conversion of a compound of formula I (wherein R^ and/or Z represents a amino group) via the corresponding diazonium salt into the desired compound of formula I.
The diazonium salt is conveniently prepared in the presence of a suitable solvent, e.g. in water/ hydrochloric acid, methanol/hydrochloric acid or dioxan/ hydrochloric acid, by diazotisation of the amino compound with a nitrite, e.g. sodium nitrite or an ester 20 of nitrous acid, preferably at low temperature, e.g. at temperatures of from -10 to 5°C.
The subsequent reaction of the diazonium salt, e.g. the fluoroboriate, the hydrosulfate in sulfuric acid or the hydrochloride is carried out in the presence of 25 copper or a corresponding copper(I) salt such as e.g. copper(I) chloride/hydrochloric acid, copper(I) bromide/ hydrobromic acid or trisodium-copper(I) tetracyanide at pH 7, preferably at slightly elevated temperature, e.g. at temperatures of from 15 to 100°C.
- N for the preparat ion of compounds of general formula I wherein R^ represents a alkoxy or phenyl(C^_3 alkoxy) group: Alkylation of a compound of formula I (wherein R^ represents a hydroxy group). - * 19^1 ■ & a - i\ - The O-alkylation is conveniently carried out with a corresponding halide or sulfonic acid ester, e.g. with methyl iodide, dimethyl sulfate, ethyl bromide, benzyl £-toluenesulfonate or isopropyl methanesulfonate, 5 optionally in the presence of a base such as e.g. sodium hydride, potassium hydroxide or potassium tetft-butylate / and preferably in the presence of s solvent such as e.g. diethyl ether, tetrahydrofuran, dioxan., ethanol, pyridine or dimethylformamide. Preferred temperatures are from 10 0 to 75°C, most preferably, ambient temperature . O for the preparation of compounds of general formula I wherein represents a alkanoylamirP group: Acylation of a compound of formula I (wherein 15 R^ represents an amino group).
The acylation is conveniently carried out in the presence of a solvent such as methylene chloride, ether, tetrahydrofuran or an excess of the acylating agent, e.g. formic acid, acetic acid or propionic acid or their 20 acid anhydrides, acid chlorides or esters. Optionally the acylation may be effected in the presence of an inorganic base or a tertiary organic base, which simultaneously may also serve as a solvent. Also optionally present is an acid activating or dehydrating 25 agent. Preferred temperatures are from -25 to 150°C, most preferably from -10 to the boiling point °f the reaction mixture.
P for the preparation of compounds of general formula I wherein R^ represents a carboxy group and/or R2 30 and R^, together with the nitrogen atom to which they are attached, represent a alkylenimino group substituted by a carboxy group: Hydrolysis of a compound of formula I ^herein R^ represents a (C1_^ alkoxy)carbonyl group and/or 35 R2 and R^, together with the nitrogen atom to which they are attached, represent a alkylenimino group 194317 - J15 - substituted by a ^2-4 alkoxycarbonyl group).
The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, phcophort c sulfuric acid, fahosphroic acid or trifluoroacetic acid 5 or in the presence of a base such as sodium hydroxide or potassium hydroxide, in the presence of a solvent such as e.g. ethanol, water/ethanol, water/isopropanol or water/dioxan and preferably at elevated temperatures, e.g. at the boiling point of the reaction mixture. 10 Q for the preparation of compounds of general formula I wherein R2 and R^, together with the nitrogen atom to which they are attached, represent a piperazino group: Debenzylation of a compound of formula I (wherein R2 and R^, together with the nitrogen atom to which they 15 are attached, represents an N-benzylpiperazino group). R for the preparation of compounds of general formula.I wherein represents a hydrogen atom: Dehalogenation of a compound of formula I (wherein R^ represents a chlorine or bromine atom). 20 The debenzylation and the dehalogenation in processes Q and R above are conveniently carried out in the presence of a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid by means of catalytically activated hydrogen, e.g. with hydrogen, preferably at a 25 pressure of 1 to 5 bar, in the presence of platinum or palladium/charcoal. Preferred temperatures are from 0 to 75°C, most preferably ambient temperature.
S for the preparation of compounds of general formula I wherein Z represents a hydroxymethyl group: 30 Reduction of a compound of formula I (wherein Z represents an optionally esterified carboxy group) by means of a complex metal hydride.
The reduction with the metallic hydride is conveniently carried out with for example lithium aluminium hydride, 194317 preferably in the presence of a solvent such as e.g. diethyl ether, tetrahydrofuran or dioxan. Preferred temperatures are from 0 to 100°C, most preferably the boiling point of the reaction mixture.
T for the preparation of compounds of general formula I wherein Z represents a formal group: Oxidation of a compound of formula I (wherein Z represents a hydroxymethyl group).
The oxidation of the hydroxymethyl groipis conve-10 niently carried out with a metallic oxide such as e.g. manganese dioxide preferably in the presence of a solvent such as e.g. acetone or dichloromethane. Preferred temperatures are from 0 to 50°C, most preferably, ambient temperature. " u for the preparation of compounds of general formula I wherein Z represents an ethyl group substituted by 2 C2_4 alkoxycarbonyl groups.
Subjection of a compound of formula I (wherein Z represents a hydroxymethyl group) to halogenation and clt c C| - ? cxJlUi (J subsequent reaction with a| malonic acid ester.
The conversion of a hydroxymethyl group into a halomethyl group is carried out with a halogenating agent such as e.g. thionyl chloride, phosphorus- trichloride, phosphorus tribromide or phosphorus pentachloride, 25 preferably in the presence of a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene. Subsequent reaction is preferably with an alkali metal salt of the malonic acid ester, e.g. diethyl malonate. Preferred temperatures are from 0 to 100°C, most 30 preferably from 20 to 50°C.
V for the preparation of compounds of general formula I wherein Z represents a di(C^_3 alkoxy)methyl group: Acetalisation of a compound of formula I (wherein Z 3'- represents a formyl group). 27 - 194317 The acetal formation is conveniently carried out in the presence of a corresponding alcohol as solvent, e.g. in methanol or ethanol and in the presence of an acid such as e.g. hydrochloric acid or sulfuric acid or 5 by reacetalisation with a corresponding orthoester, e.g. triethyl orthoformate. Preferred temperatures are from 0 to 100°C, most preferably from 30 to 60°C.
W for the preparation of compounds of general formula I-wherein Z represents an ethylene group substituted by a carboxy or C2-4 alkoxycarbonyl group: Condensation of a compound of formula I (wherein Z v\fltKmalonic acid, a malonic acid ester or a trialkylphosphbne acetate represents a formyl group)/followed, if required by hydrolysis of the product thus obtained whereby the desired compound of formula:I is obtained. 15 The condensation of the formyl compound is con veniently carried out in the presence of a solvent such as pyridine or tetrahydrofuran, with malonlo acid> with ^"ma-lonlo aold cotcr or a trialkylphosphone acetatq/ optionally in the presence of a base as condensating 20 agent, e.g. in the presence of potassium tertbutylate, sodium hydride or piperidine. Preferred temperatures are from 0 to 100°C. The acid,where required, is obtained by subsequent acidification, e.g. with hydrochloric acid or sulfuric acid.
X for the preparation of compounds of general formula 1 wherein Z represents an acetyl group optionally substituted by a C2_4 alkoxycarbonyl group: Subjection of a compound of formula I (wherein Z represents a hydrogen atom) to Friedel-Crafts 30 acylation.
The Friedel-Crafts acylation is conveniently carried out with a corresponding acid halide or acid anhydride in a solvent such as e.g. carbon disulfate, methylene 1943 of a Friedel-Crafts catalyst such as e.g. aluminium chloride. Preferred temperatures are from 0 to 50°Cf most preferably ambient temperature.
Y for the preparation of compounds of general formula I wherein Z represents a tri(C^_3 alkoxy)methyl group: Subjection of a compound of formula I (wherein Z represents a cyano group) to alcoholysis via the corresponding imino ester.
The alcoholysis is preferably carried out in the presence of a corresponding anhydrous alcohol as solvent, e.g. in anhydrous methanol, ethanol or propanol, and in the presence of an acid such as e.g. hydrochloric or sulfuric acid, preferably at elevated temperatures, most preferably at the boiling point of the reaction mixture.
Z for the preparation of compounds of general formula I wherein Z represents a C2_4 alkoxycarbonyl group: Hydrolysis of a compound of formula I (wherein Z represents a tri(C^_3 alkoxy)methyl group).
The hydrolysis of the orthoester is conveniently carried out in the presence of a solvent such as water/ methanol, water/dioxan, water/ethanol or water/propanol and in the presence of an acid such as e.g. hydrochloric acid, preferably at low temperatures, e.g. ambient temperature.
AA for the preparation of compounds of general formula I wherein Z represents a carboxymethyl group: Heating of a compound of formula I (wherein Z represents an acetyl group) with an amine and sulfur and subsequent heating of the thioamide thus obtained with an inorganic base, i.e. according to the Willgerodt reaction.
The Willgerodt reaction is conveniently carried out in the presence of an alcoholic solvent such as a-9 methanol, ethanol or isopropanol, by heating the acetyl compound with an amine, e.g. with morpholine, in the presence of sulfur. The thus obtained thioamine is subsequently converted to the corresponding acetic acid derivative by heating in the presence of an inorganic base such as e.g. sodium hydroxide. According to a particularly advantageous embodiment the reaction is carried out at the boiling point of the reaction mixture. AB for the preparation of compounds of general formula I wherein Z represents a formyl group: Conversion of a compound of formula I (wherein Z represents a carboxy group) into a corresponding sulfonic acid hydrazide and subsequent subjection of the said sulfonic acid hydrazide to disproportionation.
The disproportionation of the sulfonic acid hydrazide, preferably obtained by reaction of a hydrazine with an appropriate reactive carboxylic acid derivative, is conveniently carried out in the presence of a base such as e.g. sodium carbonate and in a solvent such as e.g. ethylene glycol preferably at temperatures of from 100 to 200°C, most preferably at from 160 to 170°C.
AC for the preparation of compounds of general formula I wherein R1 represents a hydrogen, fluorine, chlorine or bromine atom or a alkyl, alkoxy or phenyl(C^_3 alkoxy) group; X represents a group =CH-; Y represents a methylene group (optionally substituted by 1 or 2 C^_3 alkyl groups); and Z represents a carboxy group: Conversion of a compound of formula I [wherein represents a hydrogen, fluorine, chlorine or bromine atom or a C^_g alkyl, alkoxy or phenyl(C^_^ alkoxy) group; X represents a group =CH-; Y represents a methylene group (optionally substituted by 1 or 2 alkyl groups); and Z represents a chlorine or bromine atom] into a corresponding organometallic derivative and reaction of the 194317 said orcanometallic derivative with carbon dioxide.
The conversion of an acid of formula I into a corresponding organometallic compound is conveniently carried out in the presence of an inert solvent such as 5 e.g. diethyl ether, tetrahydrofuran, dioxan or tetrahydrofuran/n-hexane optionally under an inert gasr e.g. nitrogen, preferably with an appropriate lithium compound, e.g. butyl lithium in n-hexane. Preferred temperatures are from -60 to +50°C. The thus obtained 10 solution of the organometallic derivative may then be added to solid carbon dioxide under an inert gas.
Compounds of general formula I wherein and R^, together with the nitrogen atom to which they are attached represent a cyclic imino group as hereinbefore 15 defined may, if desired, be converted into their acid addition salts, e.g. their physiologically compatible acid addition salts, by reaction with an acid. Suitable acids include, for example hydrochloric, hydrobromic, sulfuric, phosphoric, lactic, citric, tartaric, succinic, 20 maleic and fumaric acids. Compounds of general formula I wherein Z represents or contains a carboxy group may also be converted into their salts with bases, e.g. their physiologically compatible salts, by reaction with a base. Suitable bases include, for example, sodium 25 hydroxide, potassium hydroxide and cyclohexylamine.
The compounds of general formulae IV to XVII are in general known from the literature or may be obtained according to processes known from the literature.
A number of the compounds useful in the above described 30 processes and in particular a number of those of formula IV and XIV are novel compounds which are not only useful as intermediates in the preparation of compounds of general formula I but also themselves exhibit interesting pharmacological properties and in particular 35 a lipid lowering activity. These uAncM cxjt> descnJoecl Thus according—Lu a lurLher feature of tho procont 1 194317 and claimed in our co-pending Application No. 202478 of even date herewith are those of general formula la, '-Tr w 4 V><,> wherein R,. represents a fluorine, chlorine or bromine atom or an amino, cyano, hydroxy, alkoxy or phenyl(C^_^ alkoxy) group; Rg and R^, together with the nitrogen atom to which they are attached, represent an alkyl)-cyclohexylamino group; an N~(c±_3 alkyl)-phenylamino or N~(c^_3 alkyl)-benzylamino group; a alkylenimino group; a piperidino group (substituted by alkyl, alkoxy, C2_4 alkoxycarbonyl or phenyl group); a piperidino group (substituted by 2, 3 or 4 alkylgroups); a morpholino or thiomorpholino group (each optionally substituted by 1 or 2 .alkyl groups); a piperazino group (substituted in the 4-position by a alkyl, C2_4 alkoxycarbonyl, phenyl, halophenyl, pyridyl, benzyl or furoyl group); a saturated or partly 20 unsaturated C, ,n aza-bicycloalkyl group; or a C, Q 1,4-dioxa-8-aza-spiro-alkyl, pyrrolidonqr or tetrahydro-pyridino group; and W represents a carboxy, aminocarbonyl, cyano or C2_^ alkoxycarbonyl group; and their acid addition salts and, where W represents a carboxy group., their salts with bases.
As with the compounds of general formula I it will be appreciated that^.—£er-"T3Harmaceutical use, the salts of thTT"l5ompounda of general formula la will be V * . y W NOV J 982 */ - 2rA - 194317 isoindole■2- yl group;—emd W represents a carboxy, aminocarbonyl, methKjtfy-carbonyl or cyano group.
Of these preferred compounds especially' preferred are those wherein is present in the 5-^osition of the benzene ring and more especially those/wherein R^ represents a alkoxy cjitoup or a chlorine or bromine atom; Rg and R^, together with the nitrogen atom to which they are attached, repre^nt a Cg_g alkylenimino group or a 1, 4-dioxa-8-aza-spij?t> [4 , 5] decane-8-yl, l,4-dioxa-8-aza-spiro [4 , 6] unde^rane-8-yl, decahydro-3-benzazepino or 4-methoxy-piperiraino group; and W reprjersents a carboxy group.
A particularly preferred compound is 5-chloro-2- (1, 4//clioxa-8-aza-spiro [4 , 5] decane-8-yl) -benzoic acid and its acid addiLiun salts.
The compounds of general formula la may, for example, be obtained according to the following processes/-which processes aro ctill further feature^ jbf the present invontio^: a) for the preparation of compounds of general formula la wherein R,. represents an amino gjcoup: Reduction of a compound of formula II, \ R. (wherein R,, R_ and W are as hereinbefore defined).
D / The reduction is conveniently carried out in the y« 194317 presence of a solvent such as methanol, ethanol, water, water/ethanol, dioxan, methanol/dioxan, ethyl acetate, dimethylformamide or dioxan/dimethylformamide.
Preferably reduction is effected with catalytically 5 activated hydrogen, e.g. with hydrogen in the presence of a hydrogenation catalyst such as e.g. palladium/charcoal, platinum or Raney nickel, for example at a hydrogen pressure of 1 to 10 bar; with hydrazine^ in the presence of Raney nickel; with nascent hydrogen, e.g. with 10 zinc/acetic acid, tin/hydrochloric acid or iron/ hydrochloric acid; or with k metal salt, e.g. tin(II) chloride/hydrochloric acid or iron (I I) sulfate/sulfuric acid. Preferred temperatures are from 0 to 50°C, most preferably ambient temperature. b) for the preparation of compounds of general formula la wherein R<- represents a hydroxy or cyano group or a fluorine, chlorine or bromine atom: Reaction of a compound of formula la as hereinbefore defined (wherein R,- represents an amino group) with a 20 nitrite and subsequent heating of the diazonium salt thus obtained, if required in the presence of copper or of a corresponding copper(I) salt. axmed The reaction is conveniently out in the presence of a solvent such as e.g. water/hydrochloric acid, methanol/hydrochloric acid or dioxan/hydrochloric acid. As the nitrite for example sodium nitrite or an ester of nitrous acid m.iy be used, preferably at low -i o n temperatures, e.g. at temperatures of from i-JO to 5 C.
The corresponding diazonium salt thus obtained, e.g. a fluoroborate, a hydrosulfate in sulfuric acid or a hydrochloride is converted optionally in the presence of copper or of a corresponding copper(I) salt such as e.g. copper(I) chloride/hydrochloric acid, copper(l) 194317 bromide/hydrobromic acid or trisodium-copper(I) tetracyanide at pH 7, into the desired compound of formula la by heating for example to temperatures of from 15 to 90°C. c) for the preparation of compounds of general formula la wherein R5 represents a C1-6 alkoxy or phenyl(C1-3 alkoxy) group: Alkylation of a compound of formula la as hereinbefore defined (wherein R- represents a hydroxy group) Jiflk with a compound of formula irTjy D - R5' (in) (wherein Rj.' represents a Cj_6 alkyl or phenyl (C^^ alkyl) group and D represents a nucleophilically exchangeable group or, together with a hydrogen atom on the a carbon of R,-1, a diazo group) followed where required by hydrolysis of the product thus obtained whereby the desired compound of formula la is obtained.
D in the compound of formula III may, for example, be a chlorine, bromine or iodine atom or a sulfonyloxy group such as e.g. a methanesulfonyloxy, p-toluenesulfonyloxy or methoxysulfonyloxy group.
The reaction is conveniently carried out in the presence of a solvent such as ether, tetrahydrofuran , ethanol, acetone, dimethylformamide or dimethyl sulfoxide and optionally in the presence of a base such as,e.g. sodium carbonate, potassium carbonate, barium hydroxide, sodium ethylate or potassium tert. butylate. The alkylating agent of formula III may, for example, be diazomethane, diazoethane, methyl iodide, ethyl iodide, isopropyl bromide, butyl bromide, dimethyl sulfate, diethyl sulfate or methyl p-toluene-sulfonate. Preferred temperatures are from 0 to 100°C>, - a - 194317 most preferably from 15 to 70°C.
If W in the compound of formula la represents a carboxy group, this group may simultaneously be esterified when alkylating with a diazoalkane or when 5 alkylating in the presence of a strong base. The ester thus obtained may subsequently, if desired, be converted back into the corresponding carboxylic acid by means of hydrolysis in the presence of an acid or a base, d) for the preparation of compounds of general 10 formula la wherein W represents a carboxy group: Hydrolysis of a compound of formula la (wherein W represents a cyano, aminocarbonyl or C2_^ alkoxycarbonyl presence of a solvent miscible with water such as e.g. methanol, ethanol, dioxan, water/ethanol or water/ tetrahydrofuran and in the presence of an acid such as hydrochloric acid or sulfuric acid or of a base such as sodium or potassium hydroxide, preferably at elevated 20 temperatures, e.g. at the boiling point of the reaction mixture. converted, if desired, into their acid addition salts by reaction with an acid. Compounds of general formula la where W represents a carboxy group may be converted into salts with bases by reaction with a base. Suitable acids and bases for the formation of such salts include those exemplified above in relation to the compounds of general formula I.
As with the compounds of general formulae IV to XVII the compounds of formula II and III are generally known from the Jbitorautc* or may be prepared by processes known from the literature. Thus, for example, compounds of general formula II and IV can be obtained by reaction of 35 a 2-chloro- or 2-bromo-nitro-carboxylic acid or a The hydrolysis is preferably carried out in the The compounds of general formula la may be i i ' CLMVU'C- 1>b - ^r- 1943 1 7 derivative thereof with a corresponding amine; subsequent reduction of the nitro group in the thus obtained 2-amino compound by means of catalytically activated hydrogen, nascent hydrogen or a metal or metal salt; and by conversion of the thus obtained amino compound via a corresponding diazonium salt into the desired compound of formula II or IV. For the preparation of a starting compound of general formula II or IV, wherein represents an alkoxy or phenylalkoxy group, 10 preferably a hydroxy carboxylic acid is first obtained and subsequently alkylated followed, if necessary, by hydrolysis.
A compound of formula V wherein Y does not represent an imino group or an oxygen atom may be obtained for 15 example by reaction of a corresponding 4-(a-bromoalkyl)-benzene derivative with sodium cyanide and subsequent catalytic hydrogenation of the thus obtained cyano compound.
A compound of formula V wherein Y represents an 20 imino group or a oxygen atom may be obtained for example by reaction of a corresponding 4-(a-bromoalkyl)-benzene derivative with a hydroxamic acid or an ester thereof or with an acyl-hydrazine followed, if necessary, by hydrolysis.
A compound of formula V wherein Y represents an imino may also be obtained by reaction of a 4-formyl- or 4-acyl-benzene derivative with an N-acyl hydrazine, with subsequent reduction of the obtained hydrazone, e.g. by means of catalytic hydrogenation, and followed by 30 hydrolytic removal of the acyl radical. The thus obtained ester of formula V can be converted, if desired, by means of hydrolysis into the corresponding carboxylic acid.
Compounds of general formulae VI, VIII, IX, X, XIV, 35 XVI and XVII useful as starting materials, may be obtained 31 194317 by reaction of a corresponding carboxylic acid with ammonia or a corresponding amine in the presence of an acid activating or dehydrating agent.
Compounds of general formula XII may be obtained by reaction of a corresponding carboxylic acid ester with hydrazine or hydroxylamine.
Compounds of general formulae XIII and XV may be obtained by halogenation of a corresponding alcohol or by reaction of a sulfonic acid halide with a corresponding alcohol in the presence of a base.
The compounds of general formula la and the compounds of general formula I wherein Z represents a hydrogen or halogen atom or a nitro, amino or cyano groupyas may be seen;are useful intermediates in the preparation of new compounds of general formula I.
As mentioned above, the new compounds of general jpiiyvuA <x. i ^ormuladi I |smel—fa show interesting pharmacological properties and especially an effect on intermediary metabolism. Thus, the compounds of general formula I possess particularly a blood-sugar lowering and/or lipid lowering activity ^nd the compounds of general formula la pooooas a lipid lowering activity/.
For examples the compounds A = 4-/2-(5-Chloro-2-dimethylamino-benzoylamino)-ethyl7- benzoic acid, B = 4-/5-(5-Bromo-2-dimethylamino-benzoylamino)-ethyl/benzole acid, C = 4-/2-(5-Chloro-2-piperidino-benzoyiamino)-ethyl7benzoic acid methyl ester, *b% - Mr - 1 c J X 4-/5- (5-Chloro-2-piperidino-benzoylamino)-ethyl/benzoic acid, 4-/5-(5-Chloro-2-(2-methyl-piperidino)-benzoylamino)-ethyl/benzoic acid, 4-/5-(5-Chloro-2-(3-methyl-piperidino)-benzoylamino)-ethyl/benzoic acid, 4-/5-(5-Chloro-2-(4-methyl-piperidino)-benzoylamino)-ethyl/benzoic acid, 4-/5-(5-Chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl/benzoic acid methyl ester, 4-/5-(5-Chloro-2-(3»5-dimethyl-piperidino)-benzoylamino)-ethyl/benzoic acid, 4-/2-(5-Chloro-2-(4-methoxy-piperidino)-benzoylamino)-ethyl/benzoic acid, 4-/5-(5-Methoxy-2-piperidino-benzoylamino)-ethyl/benzoic acid hydrochloride, 4-/5-(5-Chloro-2-heptamethylenimino-benzoylamino)-ethyl/-benzoic acid, 4-/5-(5-Chloro-2-(1,4-dioxa-8-aza-spiro/£,£/decane-8-yl-benzoylamino)-ethyl/benzoic acid, 4-/5-(5-Chloro-2-hexamethylenimino-benzoylamino)-ethyl/-benzoic acid, 4-/5-(5-Chloro-2-thiomorpholino-benzoylamino)-ethyl7-benzoic acid, 1 3R - yt- Q « 4-/5-(5-Bromo-2-piperidino-benzoylamino)-ethyl/benzoic acid, H « 4-/5-(5-Chloro-2-piperidino-benzoylamlno)-1-methyl-ethyl/benzoic acid, S = 4-/5-(5-Bromo-2-(2-methyl-piperidino)-benzoylamino)-ethyl/benzoic acid, T s 4-/5-(5-Chloro-2-(2,6-dimethyl-morpholino)-benzoyl-amino) -ethyl/benzoic acid, U =» 4-/5-(5-Chloro-2-(2,6-dimethyl-thiomorpholino)-benzoyl-10 amino)-ethyl/benzoic acid, V = 4-/5-(5-Bromo-2-heptamethylenimino-benzoylamino)-ethyl/- benzoic acid ethyl ester, ¥ = 4-/5-(5-Bromo-2-heptamethylenimino-benzoylamino)-ethyl/-benzoic acid, X = 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/-benzolc acid, Y = 4-/5-(5-Chloro-2-(decahydro-isoquinoline-2-yl)-benzoyl- amino) -ethyl/benzoic acid hydrochloride, Z = 4-/5-(5-Bromo-2-octamethylenimino-benzoylamino)-ethyl/-20 benzoic acid hydrochloride, AA = 4-/5-(5-Ethyl-2-piperidino-benzoylamino)-ethyl/benzoic acid, BB » 4-/5-(5-Methyl-2-piperidino-benzoylamino)-ethyl/benzoic acid, CC « 4-/5-(2-(N-Adamantyl-(1)-N-methylamino)-5-chloro-benzoyl-amino)-ethyl/benzoic acid, 194317 h.0 - >2 - DD a 4-/2-(2-Piperidino-nicotinoylamino)-ethyl/benzoic acid, EE = 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyi7-benzoic acid ethyl ester, FF = 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7-benzyl alcohol, GG « N1-(1-(4-Carboxyphenyl)-ethyl)-N^-(5-chloro-2-piperi-- dino-benzoyl)-hydrazine, and HH ■ 4-/T-(5-Chloro-2-octamethylenimino-benzoylaminoxy)-ethyl/benzoic acid were tested in comparison to II = 4-/?-(2-Ethylamino-5-chloro-benzoylamino)-ethyl7benzoic 8 r i h S h. acid (see Example 5 of /Belgiari Patent Specification '/53S'•/ if- S 3, No. &37/311) and—the compounds KK = 5-Chloro-2-(1,4-dioxa-8-aza-spiro/5^9/decane-8-yl)-benzoic acid, LL = 2-(Decahydro-3-benzazepijKSy)-5-chloro-benzoic acid, MM = 2-(Decahydro-3-bej*£azepino)-5-bromo-benzoic acid, NN » 5-Chloro-^A4-methoxy-piperidino)-benzoic acid and 00 - 5^M8thoxy-2-octamethylonlmlno benzoic acid were tested on their lipid lowering properties - .j^ - 1. Blood-sugar lowering activity: The blood-sugar lowering activity of the test compounds was determined in home-bred female rats with a weight of 180 - 220 g. 24 hours before starting 5 the test the animals were starved. Before the test the compounds were suspended in 1.5% methyl cellulose and administered to the animals by means of an oesophageal tube.
Blood was taken before administering the test compounds as well at 1, 2, 3 and 4 hours after administration each from the retroorbital plexus vein. 50 Xjg of each sample were deproteinized with 0.5 ml of ' ■) 0.33 N perchloric acid and centrifuged. The glucose content was determined in the supernatant according to the Hexokinase method by means of an analysis photometer.
The statistical evaluation was performed with the t-test according to Student with p = 0.05.
The following table contains the obtained values in percent compared with the controls: Table 1 Test mg/kg mg/kg mg/kg compound 1 2 3 4 1 2 3 4 1 2 3 4 hours hours hours A -31 -21 -10 -10 -32 -18 n.s. n.s. -12 n.s. n.s. n. s.
B -33 -23 n. s. n.s. -14 - 9 n. s. n.s. n.s. n.s. n.s. n.s.
C -44 -37 -23 -24 -41 -26 -23 -14 -31 -21 -18 -15 D -44 -43 -41 -38 -33 -37 -36 -26 -37 -34 -28 -30 E -42 -43 -38 -31 -34 -24 -14 n. s. -31 -18 n.s. n.s.
F -51 -48 -41 -40 -41 -40 -44 -39 -44 -42 -38 -35 G -30 -24 -27 -25 -24 -26 n.s. n.s. -24 -20 -21 -13 H -35 -41 -44 -38 -39 -46 -33 -20 -42 -47 -42 -43 I -41 -37 -38 -40 -39 -38 -30 -40 -47 -46 -49 -50 1943 1 7 V2- -pf- Continuation of table 1: Test 25 ,^/kg 10 «g/kg 5 mg/kg com— pound 123 4 1234 1234 hours hours hours K -43 , -44 -39 -34 -40 -34 -16 n.s. -40 -32 -20 n.s.
L -47 -39 -29 -27 -34 n.s. -15 -16 -37 -29 n.s. -40 n.s.
M -38 -40 -38 -36 -38 -37 -38 -36 -42 -41 -34 N -43 -41 -36 -25 -35 -34 -24 -19 -36 -17 -10 n.s. 0 -41 -37 -33 -24 -42 -39 -25 -22 -33 -26 -28 -15 P -37 -41 -32 -30 -37 -30 -26 -21 -29 -19 n.s. n.s.
Q -38 -39 -34 -37 -40 -42 -43 -44 -32 -40 -32 -23 R -52 -37 -37 -30 -25 -28 -21 -21 -27 -25 n.s. n.s.
S -42 -44 -38 -32 -39 -34 -24 -12 T -48 -29 -25 -33 U -41 -43 -41 -40 V -34 -43 -39 -40 -19 -19 -24 -26 W -44 -49 -41 -46 -34 -36 -38 -38 X -51 -44 -39 -41 -45 -43 -45 -46 -37 -43 -37 -49 Y -40 -45 -45 -49 -46 -79 -38 -46 Z -45 -43 -42 -35 AA -40 -44 -29 -39 -41 -40 -32 -32 £B -40 -31 -14 n.s. cc -39 -42 -41 -38 DD -39 -26 -22 -25 -37 -18 n.s. n.s. -28 -17 n.s. n. s.
EE -42 -41 -43 -41 -42 -41 -40 -43 -42 -41 -40 -43 FF -35 -36 -28 -23 GG n.s, . -31 -33 -22 -15 -25 -13 n. s.
HH -41 -21 n.s. n.s.
II n.s. n.s. n.s. n. s. n.s. = statistically not significant <r3 - - 194317 H—Decrease of serum 5 hours afterjjig-t compound administration, all other^v^JUies^Tere found 24 hours after lasL lOiupuuiid administration. 1. Acute Toxicity: The acute toxicity was determined in home-bred female and male mice with a body weight of 20 - 26 g after oral administration (suspension in 1% methyl cellulose) of a single dose. Observation time: at least 7 days.
The following table contains the values obtained: Test peroral toxicity compound A >2000 mg/kg (0 out of 6 animals died) B >1000 mg/kg (0 out of 5 animals died) D . >2000 mg/kg (0 out of 6 animals died) H >1000 mg/kg (0 out of 6 animals died) 0 >1000 mg/kg (0 out of 10 animals died) T >1000 mg/kg (0 out of 10 animals died) V >1000 mg/kg (0 out of 10 animals died) W >1000 mg/kg (9 out of 6 animals died) X >1000 mg/kg ( ) out of 6 animals died) ft#-—* >2000 mg/kg—(J out of 10 animalb dieiiy Based on their pharmacological properties the compounds of general formula I according to the invention and their physiologically compatible salts are suitable for the treatment of diabetes mellitus 15 Lllts compounds of qcncral formula la aro Guitabl^ ^or tho treatment—of artboroaolcrooi a and of hyper—/ ^ipidemic conditions,—particularly of—typo—IIA,—IIB anj IV-. kV - 4S7 - 194317 ,'S- ■ ■ According to a further feature of the present invention there are provided pharmaceutical compositions comprising, as active ingredient , at least one compound of formula I as hereinbefore defined-or, where 1*2 arid toaether with the nitrogen atom to which they are attached, represent a cyclic imino group as herein defined and/or where Z represents or contains a carboxy group, a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient, as wel1 as a method of treating patients suffering from or susceptible to diabetes mellitus which comprises administering an effective amount of at least one Compound of formula I as hereinbefore defined or, where R2 and R^ together with the nitrogen atom to which they are attached, represent a cyclic imino group as herein defined and/or where. Z represents or contains a carboxy group, a physiologically compatible salt thereof.
According—Lu a yeL fuiLlier—fedLuie u£—Llie uibb^iiL invention there are provided pharmaceutical cptfipositions comprising as active ingredient, at leas£/one compound of formula Ta as hereinbefore defined oj?-,''a physiologically compatible acid addition salt tj^erfeof in association with a pharmaceutical carrier or^xcipient as well as a method of treating patient suf^ring from or susceptible to artherosclerosis afrtT/or hyperlipidemic conditions which comprises administering to the said patient an effective amount of^t least one compound of formula la as herein-bcfor^aofined or a phyoiologically compatible r-alt thereof.
F6r pharmaceutical administration the compounds of -j Q uA ^ i general fcrmulaal I Jand Iq and their physiologically compatible salts may be incorporated into the conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. |rhe"c;ompositions containing compounds of genera-3r~formula I-i fttay,—for examplef—bo proceflted in a form suitable—for/ ' 11 19431 - $- c^ral,—rgctal or parenteral adminiatration. ^^PrcXe^rcd-forms include, for example, plajLru-4ratrlets7 coated tablets, capsules, suppogjLfcertgs^suspensions and solutions e.g. for injection^ Compositions containing compounds of general formula I are preferably in a form suitable for galenic administration. Preferred forms include, for example, plain tablets, coated tablets, capsules, powders and suspensions.
The active ingredient may be incoporated in excipients customarily employed in pharmaceutical compositions such as, for example, talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents and/or preservatives.
Advantageously the compositions may be formulated as dosage Units, each unit being adapted to supply a fixed dose of active ingredient. Suitable dosage units for adults contain from 1 to 50 mg, preferably from 2.5 to 20 mg of active ingredient of formula I or a salt thereof which may, for example be administered 1 or 2 times daily from 5 to 200 mg,—preferably from 5— fiO mg of active ingredient of formula la or a salt/ jLhereo^. The oral daily dosage of the compound off£irm&±a la or salt thereof, which may be varied—aectfrding to the compound used, the suhjc^t~-krc^a€ed and the complaint concerned^^jaay-r-'foreyample, be from 10 to 500 mg, prcrforably from 15 to 15 0 mg per day in—adults.
The following non-limiting examples serve to illustrate the present invention. i+l> ~ AS 194317 Preparation of the starting products: Preparation 1 2-(Decahydro-^soqulnolln^-2-vl)-5-nltro-benzolc acid 19 g (0.136 mol) of decahydro-isoquinoline, 27.3 g (0.136 mol) of 2-chloro-5-nitro-benzoic acid and 38.6 g of potassium carbonate were refluxed in 500 nl of ethanol for 18 hours whilst stirring. After distilling off the ethanol, the residue was dissolved in 800 ml of water and was adjusted to pH 4 by addition of 2N hydrochloric acid, whereby the reaction product was obtained in crystalline form.
Yield: 38 g (92 % of theory), M.p.: 132 - 134°C (isopropanol) Calc.: C 63.14 H 6.62 N 9.20 Pound: 63.02 6.48 9.38 Preparation 2 Je c<M- 2-(l .4-Dioxa-8-aza-splro/5,57Aecana-8-yl)-5-nitro-benzolc acid A mixture of 20.1 g (0.1 mol) of 2-chloro-5-nitro-benzoic acid and of 42.9 g (0.3 mol) of 1,4-dioxa-8-aza-spiro/Zf,£7decane was heated for 8 hours in 200 ml of ethanol up to the reflux temperature. After distilling off the solvent, the evaporation residue was taken up in water and adjusted to pH 5.2 by addition of 2N hydrochloric acid/whereby the product was precipitated. Subsequently, the reaction product was extracted with chloroform and dried over sodium sulfate and after distilling off the solvent, the compound was crystallized.
Yield: 12 g (39 % of theory), M.p.: 155°C (ethanol).
Calc.: C 54.54 H 5.24 N 9.09 Found: 54.20 5.13 8.97 V7 - & - 1943 Analogously to the Preparations 1 and 2 the following oompcuncfe were prepared: 2-(2-Methyl-piperidino)-5-nitro-benzoic acid Yield: 99 % of theory, m.p.: 164°C. 2-(3-M®thyl-piperidino)-5-nitro-benzoic acid Yield: 85 % of theory, m.p.: 161°C. 2-(4-Methyl-piperidino)-5-nitro-benzoic acid Yield: 85 % of theory, m.p.: 155°C. 2-(3-Ethyl-6-methyl-piperidino)-5-nitro-benzoic acid Yield: 76 % of theory, m.p.:<20°C. 2-(3»5-Dimethyl-piperidino)-5-nitro-benzoic acid Yield: 65 # of theory, m.p.: 172°C. 2-(4-Methoxy-piperidino)-5-nitro-benzoic acid Yield: 68 % of theory, m.p.: 140°C.
-Nitro-2-(4-phenyl-piperidino)-benzoic acid Yield: 88 % of theory, m.p.: 196°C. 2-(4-Ethoxycarbonyl-piperidino)-5-nitro-benzoic acid Yield: 82 % of theory, m.p.: 160°C.
-Nitro-2-thiomorpholino-benzoic acid Yield: 80 % of theory, m.p.: 235°C.
-Nitro-2-(1,2,4,5-tetrahydro-3 benzazeplno)-benzoic acid Yield: 68 % of theory, m.p.: 222°C.
-Nitro-2-(1,2,3»4-tetrahydro-isoquinolino)-benzoic acid Yield: 70 % of theory, m.p.: 195°C. 4-6 1 px - -Nitro-2-(A-phenyl-piperazino)-benzoic acid Yield: 88 % of theory, m.p.: 196°C.
-Nitro-2-(4-pyridyl-(2)-piperazino)-benzoic acid Tield: 66 % of theory, m.p.: 192°C. 2-(trans-3»5-Dimethylpiperidino)-5-nitro-benzoic acid Tield: 63 % of theory, m.p.: 132°C. 2-(3,3»5,5-Tetramethyl-piperidino)-5-nitro-benzoic acid Yield: 98 % of theory, m.p.: 138°C. 2-(3 *5-Dimethyl-morpholino)-5-nitro-benzoic acid Yield: 75 % of theory, m.p.: 164°C. 2-(3»5-Dimethyl-thiomorpholino)-5-nitro-benzoic acid Yield: 70 % of theory, m.p.: 118°C. 2-(3-Aza-bicyclo/J,2,27nonane-3-yl)-5-nitro-benzoic acid Yield: 72 % of theory, m.p.: 221°C.
-Nitro-2-nonamethylenlmino-benzoic acid Yield: 80 % of theory, m.p.: 127°C. i -Nitro-2-decamethylenimino-benzoic acid Yield: 92 % of theory, m.p.: 128°C.
-Nitro-2-undecamethylenimino-benzoic acid Yield: 91 % of theory, m.p.: 120°C.
-Nitro-2-dodecamethylenimino-benzoic acid Yield: 95 % of theory, m.p.: 115°C. 2-(N-Methyl-N-phenylamino)-5-nitro-benzoic acid Yield: 10 % of theory, m.p.: 115°C. - &-2" - 19431? 2-(N-Ethyl-N-cyclohexylamino)-5-nitrO-benzoic acid Yields 78 % of theory, m.p.: 74°C. 2-(N-Butyl-N-cyclohexylamino)-5-nitro-benzoic acid Yield: 84 % of theory, a.p.: 56°C. 2-(N-Cyclohexyl-N-isobutylamino)-5-nitro-benzoic acid Yield: 63 # of theory, m.p.: < 20°C. i>e7vzaz&Pkn 2-(Decahydro-5-ftgttgazepind-3-yl)-5-nitro-benzoic acid Yield: 98 % of theory, m.p.: < 20°C.
* I SOLrtdol 2- ( Octahydro-J-aolndpilfe-2-yl) -5-nitro-benzoic acid Yield: 80 % of theory, m.p.: 128°C. 2-(4-Isopropyl-piperidino)-5-nitro-benzoic acid Yield: 79 # of theory, m.p.: 142°C. 2-(4-tert.Butyl-piperidino)-5-nitro-benzoic acid Yield: 57 % of theory, m.p.: 136°C. uri c/eca/i 2-(1,4-Dioxa-8-aza-Spiro/^,67itndecuxii-8-yl)-5-nitro-benzoic acid Yield: 75 # of theory, m.p.: 135°C. 2,4-Dipiperidino-5-nitro-benzoic acid Yield: 31 # of theory, m.p.: 152°C. 4-Chloro-2-piperidino-5-nitro-benzoic acid Yield: 18 # of theory, m.p.: 133°C.
-Nitro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid Yield: 58 % of theory, m.p.: 215°C. 2-(N-Methyl-N-benzylamino)-5-nitro-benzoic acid Yield: 93 % of theory, m.p.: 123 - 126°C. - 194317 2-/£-(4-Chlorophenyl)-piperazino7-5-nitro-benzoic acid^ hydrochloride Yield: 71.5 % of theory, m.p.: 225 - 227°C (decomp.). 2-(4-Carbethoxy-piperazino)-3-nitro-benzoic acid Yield: 23.1 % of theory, m.p.: 155 - 156°C. 2-/5-(2-Furoyl)-piperazino7-5-nitro-benzoic acid Yield: 64.8 % of theory, m.p.: 200 - 205°C. 2-(4-Benzyl-piperazino)-5-nitro-benzoic acid hydrochloride Yield: 86.6 % of theory, m.p.: 142 - 145°C.
Preparation 3 2-Hexamethylenlmino-5-nltro-benzoic acid nitrlle A mixture of 18.4 g (0.11 mol) of 2-chloro-5-ttitro-benzoic acid nitrile and of 22.4 g (0.21 mol) of hexamethylenimine was refluxed for 4 hours in 250 ml of ethanol. After cooling the product was oily precipitated by addition of 500 ml of water. The precipitate was taken up in chloroform and after drying with sodium sulfate and distilling off the chloroform, the evaporation residue was recrystallized from ethanol. Yield: 19.7 g (73 % of theory), M.p.: 70°C.
Calc.: C 63.65 H 6.16 H 17.13 Found: 63.80 6.07 17.05 ~ 194317 Preparation of the ^en^/products of general formula la: Example a -Amlno-2- (decahydro-^rgoquinolln£-2-yl)-benzoic acid i ISLs\ 36 g (0.118 mol) of 2-(decahydro-^rSoqu±noi±n^-2-yl)-5-nitro-benzoic acid were dissolved in 250 ml of dimethyl formamide and the solution was hydrogenated at room temperature with a hydrogen pressure of 5 bar by addition of 10 % palladium , . charcoal as catalyst. After /finished hydrogen absorptior^, the catalyst was filtered off, the solvent was distilled off in vacuo and the residue was recrystallized from ethanol.
Yield: 31.2 g (96 % of theory), M.p.: 252°C.
Calc.: C 70.04 H 8.08 N 10.20 Found: 70.09 7.85 10.12 Example B clec<*s\ -Amlno-2-(l.4-dloxa-8-aza-spiro/?.57d^&afl4-8-vl)-benzolc acid cle-Cc-n. 12 g (0.039 mol) of 2-(1,4-dioxa-8-aza-spiro/2+#£7jiite««iW-8-yl)-5-nitro-benzoic acid were hydrogenated at room temperature in 100 ml of dimethyl formamide at a hydrogen pressure of 5 bar by addition of 10 % palladium charcoal as catalyst. After finished hydrogen absorption the catalyst was filtered off, the solvent was distilled off and recrystallized from ethanol.
Yield: 9 g (83 % of theory), M.p.: 209°C.
Calc.: C 60.42 H 6.56 N 10.07 Found: 60.18 6.58 10.12 "2 - >5 - 194317 Analogously to the Example A and B the following compounds were prepared: -Amino-2-pyrrolidino-benzoic acid Yield: 79 % of theory, m.p.: 208°C.
-Amino-2-(2-methyl-piperidino)-benzoic acid Yield: 84 % of theory, m.p.: 240°C. methiL -Amino-2-(3-peth* -piperidino)-benzoic acid Yield: 75 % of theory, m.p.: 192°C.
-Amino-2-(4-methyl-piperidino)-benzoic acid Yield: 88 # of theory, m.p. : 215°C. j -Amino-2-(3-ethyl-6-methyl-piperidino)-benzoic acid Yield: 59 % of theory, m.p.: 219°C.
-Amino-2-(cis-3,5-dimethyl-piperldino)-benzoic acid Yield: 87 96 of theory, m.p.: 234°C.
-Amino-2-(4-methoxy-piperidino)-benzoic acid Yield: 80 % of theory, m.p.: 228°C.
-Amino-2-heptamethylenimino-benzoic acid Yield: 64 96 of theory, m.p. : 214°C.
-Amino«-2- (4-phenyl-piperidino)-benzoic acid Yield: 76 % of theory, m.p.: 275°C.
-Amino-2-(4-ethoxycarbonyl-piperidino)-benzoic acid Yield: 85 % of theory, m.p.: 203°C.
-Amino-2-thiomorpholino-benzoic acid Yield: 76 % of theory, m.p.: 193°C. „!/_ 194317 -Amino-2-(1,2,4,5-tetrahydro-3 benzazeplno)-benzoic acid Yield: 86 % of theory, m.p.: 258°C.
-Amino-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid Yield: 66 % of theory, m.p.: 220°C.
-Amino-2-(4-phenyl-piperazino)-benzoic acid Yield: 83 96 of theory, m.p.: 255°C.
-Amino-2-(4-pyridyl-(2)-piperazino)-benzoic acid Yield: 80 % of theory, m.p.: 248°C.
-Amino-2-(trans-3 , 5-dimethyl-piperidino)-benzoic acid Yield: 89 96 of theory, m.p.: 156°C.
-Amino-2-(3,3,5,5-tetramethyl-piperidino)-benzoic acid Yield: 98 % of theory, m.p.: <20°C.
-Amino-2-(3,5-dimethyl-morpholino)-benzoic acid Yield: 83 96 of theory, m.p.: 255°C.
-Amino-2-(3,5-dimethyl-thiomorpholino)-benzoic acid Yield: 50 96 of theory, m.p.: 233°C. nana-n -Amino-2- (3-aza-bicyclo/5,2 f2/fionan<j-3-yl)-benzoic acid Yield: 86 96 of theory, m.p.: 288°C.
-Amino-2-octamethylenimino-benzoic acid Yield: 88 96 of theory, m.p.: 191°C.
-Amino-2-nonamethylenimino-benzoic acid Yield: 80 96 of theory, m.p. : 212°C.
-Amino-2-decamethylenimino-benzoic acid Yield: 52 96 of theory, m.p.: 202°c. 194317 -Amino-2-undecamethylenimino-benzoic acid Yield: 93 96 of theory, m.p.: 242°C.
-Amlno-2-dodecamethylenimino-benzoic acid Yield: 59 96 of theory, m.p.: 224°C.
-Amino-5-(N-methyl-N-phenylamino)-benzoic acid Yield: 47 96 of theory, m.p.: 184°C.
-Amino-2-f (N-ethyl-N-cyclohexylamino)-benzoic acid Yield: 66 % of theory, m.p.: 160°C.
-Amino-2-(N-butyl-N-cyclohexylamino)-benzoic acid Yield: 48 96 of theory, m.p.: 140°C.
-Amino-2-(N-cyclohexyl-N-isobutylamino)-benzoic acid Yield: 62 96 of theory, m.p.: < 20°C. — b<zn zciz.epen -Amino-2-(decahydro-3 fbenzazepln^-3-yl)-benzolc acid Yield: 54 96 of theory, n.p. : 204°C. isouicto ( -Amino-2-(octahydro-J.«ei»d6X^-2-yl)-benzoic acid Yield: 43 96 of theory, m.p. : 228°C.
-Amino-2-(4-isopropyl-piperidino)-benzoic acid Yield: 50 96 of theory, m.p.: 231°C.
-Amino-2-(4-tert.butyl-piperidino)-benzoic acid Yield: 81 96 of theory, m.p.: 276°C.
OL/y deceit -Amino-2-(1,4-dioxa-8-aza-spiro/5,67]fff*deea«^-8-yl)-benzoic acid Yield: 49 96 of theory, m.p. : 235°C.
-Amino-2-(l,2,3,6-tetrahydro-pyridino)-benzoic acid Yield: 51 96 of theory, m.p.: 232°C. 194317 -Amino-2-(4-methyl-piperazino)-benzoic acid hydrochloride Yield: 90 % of theory, m.p.: <20°C.
-Amino-2-(N-methy1-N-benzylamino)-benzoic acid Yield: 95 % of theory, m.p.: <20°C -Amino-2-/?-(4-chloro-phenyl)-piperazino7benzoic acid hydrochloride Yield: 80.5 # of theory, m.p.: 305°C (decomp.).
-Amino-2-(4-carbethoxy-piperazino)-benzoic acid Yield: 87.5 % of theory, m.p.: 195 - 197°C.
-Amino-2-/5-(2-furoyl)-piperazino7benzoic acid Yield: 97 % of theory, m.p.: £20°C.
-Amino-2~(4-benzyl-piperazino)-benzoic acid hydrochloride Yield: 80 % of theory, m.p.: 200 - 210°C.
Example c l$oa ujsicytcsx -Chloro-2-(decahydro-^6oqulnol4W-2-yl)-benzoic acid iS oy ulcs}<jLCS\ g (0.0365 mol) of 5-amino-2-(decahydro-fooqulnolln^-2-yl)-benzoic acid were dissolved in 55 ml of semi-conc. hydrochloric acid and the solution was diazotized at 0°C by dropwlse addition of a solution of 2.7 g (0.039 mol) of sodium nitrate in 10 ml of water. After the addition was finished the reaction mixture was stirred for 15 minutes and subsequently, the diazonium salt solution was dropped into a suspension of 4 g of copper powder in 40 ml of conc. hydrochloric acid. After stirring over night a deep green homogeneous solution was obtained, which was diluted with 100 ml of water and subsequently was completely extracted with chloroform. After drying over sodium sulfate the chloroform evaporation residue was purified by chromato- f>ihca <&l lJ|j*«^,graphy over a ftiliotfgel column with an eluant of ethyl acetate/ methanol = 9.5 : 0.5. * f 194317 - S-A- Yield: 4.8 g (45 % of theory), M.p.: 138°C.
Calc.: C 65.41 H 6.85 N 4.76 CI 12.06 Found: 65.51 7.07 4.89 12.32 Example p cteccxs\ -Chloro-2-(1.4-dioxa-8-aza-splro/5.57decage-8-yl)-benzoic acid 8.5 g (0.031 mol) of 5-amino-2-(l ,4-dioxa-8-aza-spiro/£,57- . clc'Ce*-*1, . <feeah^-8-yl)-benzoic acid were dissolved in 28 ml of semi-conc. hydrochloric acid and diazotized at 0°C with a solution of 2.4 g (0.034 mol) of sodium nitrite in 10 ml of water. adcloci. cOvj>u.n<D € The diazonium salt solution was propped whilst stirring to a suspension of 3 g of copper powder in 3 ml of.conc. hydrochloric j m nec* acid. After ^inishea nitrogen formation|the reaction mixture was stirred for 2 hours, diluted with water and extracted with chloroform. After drying over sodium sulfate the solvent was distilled cfAtx-r off and ymen digesting the evaporation residue with petroleum ether, 6.1 g (66 % of theory) of the compound were obtained. M.p.: 180°C.
Calc.: C 56.47 H 5.42 N 4.71 Found: 56.11 5.37 4.83 Analogously to the Examples C and D the following compounds were prepared: -Chloro-2-pyrrolidino-benzoic acid Yield: 30 % of theory, m.p.: 164°C.
-Chloro-2-(2-methyl-piperidino)-benzoic acid Yield: 74 % of theory, m.p. : 124°C.
-Chloro-2-(3-methyl-piperidino)-benzoic acid Yield: 47 96 of theory, m.p.: 165°C. 51 ~ ~ 4 Mi- I % 4 ^ <5 -Chloro-2-(4-methyl-piperidino)-benzoic acid Tield: 52 % of theory, m.p.: 107°C. 2-(3-Ethyl-6-methyl-piperidino)-5-chloro-benzoic acid Tield: 73 % of theory, m.p.: <20°C.
-Chloro-2-(cis-3,5-dimethyl-piperidino)-benzoic acid Tield: 46 % of theory, m.p.: 167°C.
-Chloro-2-(trans-3»5-dimethyl-piperidino)-benzoic acid Tield: 63 % of theory, m.p.: 132°C.
-Chloro-2-(4-methoxy-piperidino)-benzoic acid Tield: 63 % of theory, m.p.: 136°C.
-Chloro-2-heptamethylenimino-benzoic acid Tield: 58 # of theory, m.p.: C 20°C.
-Chloro-2-(4-phenyl-piperidino)-benzoic acid Tield: 51 % of theory, m.p.: 217°C.
-Chloro-2-(4-ethoxycarbonyl-piperidino)-benzoic acid Tield: 97 # of theory, m.p. : <20°C.
-Chloro-2-hexamethylenimino-benzoic acid Tield: 34 % of theory, m.p.: 113°C.
-Chloro-2-thiomorpholino-benzoic acid Tield: 16 % of theory, m.p.: 160°C.
-Chloro-2-(1,2,4,5-tetrahydro-3 benzazeplno)-benzoic acid Tield: 59 % of theory, m.p.: 174°C.
-Chloro-2-(1,2,3,4-tetrahydro-isoquinolino)-benzoic acid Tield: 50 % of theory, m.p.: 182°C.
" H ~ 194317 -Chloro-2-(4-phenyl-piperazino)-benzoic acid Yield: 42 56 of theory, m.p.: 154°C.
-Chloro-2-(4-pyridyl-(2)-piperazino)-benzoic acid Yield: 45 56 of theory, m.p.: 168°C.
-Bromo-2-(2-methyl-piperidino)-benzoic acid Yield: 31 56 of theory, m.p.: 168°C.
-Chloro-2-(3,3,5,5-tetramethyl-piperidino)-benzoic acid Yield: 62 56 of theory, m.p.: <20°C.
-Bromo-2-(4-methoxy-piperidino)-benzoic acid Yield: 48 56 of theory, m.p.: 138°C.
-Chloro-2-(3,5-dimethylmorpholino)-benzoic acid Yield: 50 56 of theory, m.p.: 174°C.
-Chloro-2-(3,5-dimethyl-thiomorpholino)-benzoic acid Yield: 18 56 of theory, m.p.: 134°C.
-Bromo-2-heptamethylenimino-benzoic acid Yield: 15 56 of theory, m.p.: 104°C. __ _ ncmasi -Chloro-2-(3-aza-bicyclo/3,2,2/iteRarte/-3-yl)-benzoic acid Yield: 16 56 of theory, m.p.: 199°C.
-Chloro-2-octamethylenimino-benzoic acid Yield: 70 56 of theory, m.p. : 84°C.
-Chloro-2-nonamethylenimino-benzoic acid Yield: 30 56 of theory, m.p.: 78°C.
-Chloro-2-decamethylenimino-benzoic acid Yield: 65 56 of theory, m.p.: 70°C. :# ~ ^2 ~ 194317 -Chloro-2-undecamethylenimino-benzoic acid Yield; 41 % of theory, m.p.: 41°C.
-Chloro-2-dodecaaethyleni«inoi-benzoic acid Yield: 36 J6 of theory, m.p.: 40°C.
-Chloro-2-(N-phenyl-N-methylamino)-benzoic acid Yield: 27 % of theory, m.p.: 164°C. 2-(N-Ethyl-N-cyclohexylamino)-5-chloro-benzoic acid Yield: 24 # of theory, m.p.: 152°C. 2-(N-Butyl-N-cyclohexylamino)-5-chloro-benzoic acid Yield: 16 % of theory, m.p.: 145°C.
-Chloro-2-(N-cyclohexyl-N-isobutylamino)-benzoic acid Yield: 22 % of theory, m.p.: 131°C. - ben-Lcxrz ep cs\ -Chloro-2-(decahydro-3 ^e»z«xep±ntf-3-yl)-benzoic acid Yield: 70 % of theory, m.p.: 153°C. ~ benzajz-eptsi.
-Bromo-2-(decahydro-3 fbenzazcpinj(-3-yl)-benzoic acid Yield: 54 % of theory, m.p.: 154°C.
/ SO tn ci c->/_ -Chloro-2- (octahydro-jhso±ndtrl^-2-yl)-benzoic acid Yield: 33 % of theory, m.p.: 164°C.
-Bromo-2-octamethylenimino-benzoic acid Yield: 48 % of theory, m.p.: 94°C.
-Chloro-2-(4-isopropyl-pipe ridino)-benzoic acid Yield: 43 % of theory, m.p.: 172°C.
-Chloro-2-(4-tert.butyl-pif^ridino)-benzoic acid Yield: 35 % of theory, m.p.: 161°C. 1 Kwt- 6 0 " *3 ~ 194317 u/l Ctc<~r\ -Chloro-2-(l ,4-dioxa-8-aza-splro/5,67frndecanqf-8-yl)-benzoic acid Yield: 42 % of theory, m.p.: 163°C.
-Chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoic acid Yields 73 % of theory, m.p.: 173°C.
-Chloro-2-(4-methyl-piperazino)-benzoic acid hydrochloride Yields 75 % of theory, m.p.: 132°C (decomp.).
-Chloro-2-(N-methyl-N-benzylamino)-benzoic acid Yields 18.2 % of theory, m.p.s 156 - 157°C.
-Chloro-2-/?-(4-chloro-phenyl)-piperazino7benzoic acid Yield: 30.5 % of theory, m.p.s 228 - 230°C.
-Chloro-2-/5-(2-furoyl)-piperazino7benzoic acid Yields 33.1 % of theory, m.p.s 200 - 202°C. 2-(4-Benzyl-piperazino)-5-chloro-benzoic acid hydrochloride Yield: 42.8 % of theory, m.p.s 230 - 232°C (decomp.).
Example B -Amino-hexamethylenlmlno-benzolc acid nitrile 21.4 g (0.087 mol) of 2-hexamethylenimino-5-nitro-benzoic acid nitrile were dissolved in 200 ml of dioxane and 500 ml of methanol and the solution was hydrogenated at room temperature with a hydrogen pressure of 5 bar in the presence of 10 % palladium charcoal as catalyst. After filtering off the catalyst and distilling off the solvent, 20 g (100 % of theory) of the compound were obtained.
M.p.: <. 20°C. 61 " M' " 194317 Example F -Chlorb-2-hexamethylenlmlno-benzolc acid nitrile g (0.092 mol) of 5-amino-2-hexamethylenimino-benzoic acid nitrile were dissolved in 90 ml of semi-conc. hydrochloric acid and at 0°C the solution was diazotized by dropwisely adding a solution of 6.5 g (0.094 mol) of sodium nitrite in t4)Cy j UJTX-7 ml of water. After /finished addition^the reaction mixture was stirred for 15 minutes. The diazonium salt solution was actled d->tfunoZ- Jireppe^ whilst stirring to a solution of copper-(I)/chloride in conc. hydrochloric acid, which was warmed up to 70°C.
After the nitrogen formation was finished, the reaction solution was extracted with chloroform. After drying over sodium sulfate and distilling off the chloroform, the evaporation si//ca residue was purified by chromatography over a/-sirlloage^ column (eluant: toluene).
Yield: 5 g (23 % of theory), M.p.: <20°C.
Example G -Chloro-2-hexamethvlenlmlno-benzoic acid g (0.021 mol) of 5~chloro-2-hexamethylenimino-benzoic acid nitrile were heated in 32 g of potassium hydroxide solution and 20 ml of water for 8 hours up to 170°C. The cold melt was dissolved in water and the amide was precipitated quantitatively by acidifying to a pH value of 5. By hydrolysis with semi-conc. hydrochloric acid 3.6 g (67.4 % of theory) of the compound were obtained.
M.p.: 113°C.
Analogously to the Example F.to G the following compounds were prepared; p&f&fr ..^Morphollno-5-nltro-benzoic acid nitrile LtH0VW^-d: 78 % of theory, m.p.: 138°C.
~ Kf ~ 114317 -Amino-2-morpholino-benzoic acid nitrile Yield: 68 % of theory, m.p.: 142°C.
-Chloro-2-morpholino-benzoic acid nitrile YieLd: 20 % of theory, m.p.: 57°C.
-Chloro-2-morpholino-benzamide Yield: 98 % of theory, m.p.: 280°C.
*. -Chloro-2-morpholino-benzoic acid Yield: 60 % of theory, m.p.: 157°C.
Example H -Cyano-2-octamethvlenlmlno-benzolc acid 26.2 g (0.1 mol) of 5-amino-2-octamethylenimino-benzoic acid were dissolved in 38 ml of cone, hydrochloric acid, 280 ml of water were added and the solution was diazotized at 0°C by dropwise addition of a solution of 7.6 g (0.11 mol) of sodium nitrite in 30 ml of water. After stirring for 30 minutes the solution was adjusted to pH 7 by means of sodium carbonate. Subsequently, a solution of trisodium-tetracyano-copper-(I)y/ complex was dropwisely added at 0°C to the diazonium salt solution.
This copper-(I)^complex solution was obtained in the following way: 32 g (0.128 mol) of copper sulfate x 5 H20 and 8.7 g of sodium chloride in 100 ml of water were reduced to the copper-(I)^chloride by means of a sodium hydrogene sulfite solution, consisting of 6.6 g (0.0635 mol) of sodium[4ay4ro^enq( sulfite/ 4.4 g of sodium hydroxide in 50 ml of water. The precipitated copper-(I)^chloride was suction filtered, suspended in 50 ml of water and dissolved in a solution of 17 g (0.346 mol) of sodium cyanide in 30 ml of water.
After the nitrogen formation was finished, the reaction mixture was heated for 1 hour up to 70°C. After cooling the reaction mixture was adjusted to pH 5.5 by means of 2N hydrochloric acid and extracted with chloroform. The chloroform phases were dried over sodium sulfate and after distilling off the chloro 194317 form, the obtained crude product was purified over a silica^ gel column with ethyl acetate as eluant.
Yield: 9 g (30 % of theory), M.p.: 20°C.
Calc.: C 70.56 H 7.AO N 10.28 Found: 70.38 7.20 10.10 Example J 2-Heptamethylenlmlno-5-hydroxv-benzolc acid 26.7 g (0.107 mol) of 5-amino-2-heptamethylenimino-benzoic acid were dissolved in 190 ml of 3N sulfuric acid and the solution was diazotized at 0°C with a solution of 8.3 g (0.12 mol) of sodium nitrite in 30 ml of water, which was added dropwisely. After stirring for 30 minutes, 2 g of finely pulverized.urea were added. The diazonium salt tLClclceI C'-'Upu^K) (L solution was propped whilst stirring to 320 ml of 50 % sulfuric acid, vhich juap warmed up to 90°C. After j£±n±shed nitrogen formatior^, the reaction mixture was adjusted at room temperature to pH A by means of ammonia and extracted with chloroform. After drying over sodium sulfate and distilling off the chloroform, the obtained dry residue was purified over Silica gel 3 * a |&±iicagej. column by means of chloroform as eluant.
After recrystallization from isopropanol, 8 g (30 % of theory) of the compound were obtained.
M.p.: 199°C Calc.: C 67.A5 H 7.68 N 5.61 Found: 66.87 7.71 5.65 Analogously to the Example J the following compounds were prepared: 2-Hexamethylenimino-5-hydroxy-benzoic acid Yield: 2A % of theory, m.p.: 21A°C. c -Hydroxy-2-o^tamethylenimino-benzoic acid Yield: 27 % of theory, m.p.: 208°C. - jjf- 104317 -Hydroxy-2-(4-tert.butyl-piperidino)-benzoic acid Yield: 33 % of theory, m.p.: 240°C -Hydroxy-2-(cis-3,5-dimethyl-piperidino)-benzoic acid Yield: 67.4 % of theory, m.p.: 248 - 250°C.
Example K -Methoxy-2-ootamethy1enimlno-benzoic acid 0.6 g (25 mmol) of sodium hydroxide were mixed with 3.2 g (12.2 mmol) of 5-hydroxy-2-octamethyleniaino-benzoic acid in 20 ml of absolute dimethyl formamide and the reaction mixture was warmed up to 50°C, whereby the the sodium salt partly precipitated. After addition of 5.2 g (36.6 mmol) of methyl iodide in 3 ml of absolute dimethyl formamide the mixture was stirred for 5 hours at room temperature. After distilling off the dimethyl formamide the crude 5-methoxy-2-octamethylenimino-benzoic acid-methyl ester Sf lie/X was purified over a ^iifcagel column by means of chloroform as eluant.
Yield: 90 % of theory, m.p.: 20°C.
This ester was hydrolyzed at 80°C by means of sodium hydroxide solution. After acidifying to a pH value of 5.2, the ester was extracted with chloroform, dried over sodium sulfate and the evaporation residue was digested with petroleum ether.
Yield: 85 % of theory, M.p.: 84°C.
Calc.: C 69.28 H 8.35 N 5.04 Found: 69.12 8.29 4.95 Analogously to Example K the following compounds were prepared: 2-Hexamethylenimino-5-methoxy-benzoic acid ■■ Yield: 88 % of theory, m.p.: 141°C. 11 ■ If ' t1943 " 2-Heptamethylenimino-5-methylenimino-5-methoxy-benzoic acid Yield: 30 96 of theory, m.p.: 120°C. 2-Heptamethylenimino-5-isopropyloxy-benzoic acid Yield: 78 56 of theory, m-p.: 120°C.
-Ethoxy-2-octamethylenimino-bexizoic acid Yield: 87 56 of theory, m.p.: *20°C.
-Isopropyloxy-2-octamethylenimino-benzoic acid Yield: 60 56 of theory, m.p.: 78°C.
-Butyl-(2)-oxy-2-octamethylenimino-benzoic acid Yield: 48 56 of theory, m.p.: <20°C.
-Methoxy-2-(4-tert.butyl-piperidino)-benzoic acid Yield: 22 56 of theory, m.p.: 156°C.
-Methoxy-2-(3»5-cis-dimethyl-piperidino)-benzoic acid Yield: 90 56 of theory, m.p.: 124°C.
-Hexyloxy-2-piperidino-benzoic acid Yield: 73 56 of theory, m.p. : 72°C.
-Benzyloxy-2-piperidino-benzoic acid Yield: 41 56 of theory, m.p. : 188°C. i 1} 194317 Preparation of the end products of general formula I: Example 1 4-/2-(5-Chloro-2-dimethylamino-benzoylamino)-ethyl7-benzoic acid Jnet-hyleatep1 1.03 g (6.3 m mole) of N,N'-carbonyl-diimidazole were added to a solution of 1.06 g (5.3 m mole) of 5-chloro-2-dimethyl- Lc trZi f-Uj aLfi^uu cc^j aminobenzoic acid in 5 ml of absolute /tetrahydrofuran^ at room temperature. After 1-2 hours a solution of 1.13 g (6.3 m mole) of .4-(2-amino-ethyl)-benzoic acid methyl ester (X' LroJ'^j cX^OjA.'~fasi in 2 ml of /tetrahydrofuran© was added to the formed imidazo-lide..After standing for 16 hours at room temperature the (<• tYT^^CtfC>-]A,LS<XS\ was distilled off in a rotation evaporator. The. crude ester was purified by chromatography over si-hca. a fB±i±cngei column with toluene/ethyl acetate (9:1). The dry residue of the combined fractions, which contain the purified ester, jJerei treated with petroleum ether.
Yield: 0.9 g (47.5 % of theory), M.p.: 94°C Calc.: C 62.7 H 5.88 N 7.57 found: 63.3 5.86 7.75 Example 2 4-/2-(5-Chloro-2-dlmethvlamlno-benzoylaniino)-ethyl7-benzolc acid 0.55 g (1.56 m mole) of 4-/5-(5-9hloro-2-dimethylamino-benzoyl- /?)tI ester amino)-ethyl/-benzoic acid foethyle&tey* were dissolved in 40 ml of a mixture consisting of methanol/dioxane (2:1). After addition of 0.29 g (4.8 m mole) of potassium hydroxide, dissolved .
Ctdcicd dKfUJVOtc in 3 nl of water, at room^ temperature 30 ml of water were propped to the solution slowly^that no precipitation of the ester took place. After some hours the organic solvent was distilled off in a rotation evaporator, the aqueous phase was extracted with chloroform and adjusted to a pH value of 5.5 by means of 2N hydrochloric acid, whereby the acid precipitated. 194317 tc -p- Yield: 0.38 g (70 % of theory), M.p.: 165°C Calc.: C 62.45 H 5.52 N 8.06 Found: 62.30 5.62 7.87 Example 3 4-/2-(5-Chloro-2-dimethvlamino-benzovlamlno)-ethyl7-benzoic acid 0.32 g (1 m mole) of 4-/?-(2-amino-5-chloro-benzoylamino)-ethyl7-benzoic acid (m.p.: 196°C, prepared from 2-amino-5-chloro-benzoic acid and 4-(2-amino-ethyl-benzoic acid/methylester' analogously to Example 1 and subsequent alkaline saponification analogously to Example 2) were treated in 10 ml of formalin and 30 ml of glacial acetic acid after addition of 500 mg of 10 % palladium charcoal at room temperature in an autoclave at a pressure of 5 bar with hydrogen. After filtration and distilling off the solvents, the acid was dissolved in sodium hydroxide solution and precipitated with 2N hydrochloric acid.
Yield: 0.11 g (30 96 of theory) M.p.: 165°C Calc.: C 62.45 H 5.52 N 8.06 Found: 62.38 5.68 7.90 Example 4 4-/2-(5-Chloro-2-dlmethylamlno-benzovlamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-methylamino-benzoylamino)-ethyl7-benzoic acid (m.p.: 205°C) analogously to Example 3.
Yield: 30 % of theory, M.p.: 165°C 6< ' n' 194317 Example 5 4-/?-(5-Chloro-2-dimethylamino-benzoylamino)-ethyl7-benzoic mo. est*? f acid teethrlester 1.06 g (5.3 n mole) of 5-chloro-2-dimethylamino-benzoic acid were converted to the acid chloride by means of 7 ml of thionyl chloride at 40 - 50°C. After distilling off the thionyl chloride the crude acid chloride was reacted in 10 ml of absolute pyridine with 0.95 g (5.3 m mole) of 4-(2-aminoethyl)-benzoic acid rwurkyt ester Jaethyleste*'. After stirring for 2 hours at room temperature, the reaction mixture was heated to 50 - 70°C for approx. 20 minutes and subsequently the pyridine was distilled off in a rotation evaporator. The dry residue was dissolved in ice water, made alkaline with sodium hydroxide solution and this solution was extracted with chloroform. The dry residue of the chloroform extracts, dried over sodium sulfate, was purified by chro- Sclica ^c-( clucLsrt matography over a £±l±cagei column (J&lvtenp: toluene/ethyl acetate =9:1).
Yield: 1.4 g (73 % of theory), M.p.: 94°C Calc.: C 62.7 H 5.88 N 7.57 Found: 62.9 5.73 7.63 Example 6 4-/5-(5-Bromo-2-dimethylamino-benzoylamino)-ethyl7-benzoic nietfitjl ez>tes> acid tnethylre&tey Prepared from 5-bromo-2-dimethylamino-benzoic acid and 4-(2-ami-no-ethyl)-benzoic acid es5ter analogously to Example 1.
Yield: 93.5 % of theory, M.p.: 99°C Calc.: C 56.35 H 5.21 N 6.90 Found: 56.10 5.32 7.01 6' 1 ■vi- 194317 Example 7 4-/2-(5-bromo-2-dlmethylamlno-benzovlamino)-ethyl7-benzolc acid Prepared from 4-/2-(5-bromo-2-dimethvlamino-benzoylamino)- Example 8 4-/2- C5-Jj'luoro-2-dimethylamino-benzoylamino)-ethyl7-benzoic acid Methylester Prepared from 5-fluoro-2-dimethylamino-benzoic acid and / \ watjufi *2star- 4-(2-amino-ethyl;-benzoic acid ftet-hyles-ter analogously to Example 1.
Yield: 44 # of theory, M.p.: 56°C Calc.: C 66.30 H 6.14 N 8.13 Found: 66.28 6.22 8.13 Example 9 4-/*?-(5-Fluoro-2-dlmethylamino-benzoylamino )-ethyl7-benzoic acid Prepared from 4-V5-(5-fluoro-2-dimethylamino-benzoylamino)-ethyl7-benzoic acid feothylcotef by alkaline hydrolysis analogously to Example 2.
Yield: 73 % of theory, M.p.: 108°C Calc.: C 65.55 H 5.80 N 8.47 Found: 64.98 5-68 8.38 hydrolysis ana- Yield: 77 % of theory, M.p.: 187°C Calc.: C 55.4 H 4.89 N 7.16 Found: 55.2 4.97 7.01 7f 194317 Example 10 4-/5-(2-Dimethylamino-benzoylamino)-ethyl7-benzoic acid Ineffiiffilesll# r Prepared from 2-dimethylamino-benzoic acid and 4-(2-amino- metAijl ester ethyl)-benzoic acid faethylestef analogously- to Example 1. The reaction was carried out at 60 - 70°C.
Yield: 98 % of theory, M.p.: 74°C Calc;: C 70.0 H 6.78 N 8.56 Found: 69.8 6.92 8.54 Example 11 4-/?-(2-Dimethvlamino-rbenzovlamino)-ethyl7-benzolc acid Prepared from 4-/£-(2-dimethylamino-benzoylamino)-ethyl7- ryjit&ist ester benzoic acid foothy 1 cartel/ by alkaline hydrolysis analogously to Example 2.
Yield: 84 % of theory, M.p.: 107°C Calc.: C 69.25 H 6.45 N 8.96 Found: 69.50 6.62 9.00 Example 12 4-/5-(5-Chloro-2-diethylamino-benzoylamino)-ethyl7-benzoic acid-^^fehvies^er Prepared from 5-chloro-2-diethylamino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid /ife^h^L colter analogously to Example 1.
Yield: 51 % of theory, M.p.: 93°C Calc.: C 64.86 H 6.48 N 9.12 Found: 65 01 6.54 9.38 1/ " 194317 Example 15 4-/?-(5-Chloro-2-diethvlamino-benzoylamino)-ethyl7-benzolc acid Prepared from 4-/2-(5-chloro-2-diethylamino-benzoylamino)- _ esfcr ethyl/-benzoic acid teethy1ester by alkaline hydrolysis analogously to Example 2.
Yield: 80 % of theory, M.p.: 95°C Calc.: C 64.10 H 6.17 N 7.46 Found: 64.20 6.09 7.32 Example 14 4-/2-(5-Chloro-2-diisobutylamino-benzoylaraino)-ethyl7-benzoic acld frthylesteif Prepared from 5-chloro-2-diisobutylamino-benzoic acid and ester 4-(2-amino-ethyl)-benzoic acid /gthyleotcy analogously to Example 1.
Yield: 20 % of theory, M.p.: <20°C Calc.: C 68.03 H7.69 N 6.10 CI 7.72 Found: 68.59 7.68 5.93 7.51 Example 15 4-/2-(5-Chloro-2-diisobutylamino-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-diisobutylamino-benzoylamino)- _ <ZS tzr ethyl/-benzoic acid felhyleste*1 by alkaline hydrolysis analogously to Example 2. ~1? - H ~ 194317 Yield: 90 % of theory, M.p.: 113°C Calc.: C 66.88 H 7.24 N 6.49 CI 8.22 Found: 66.50 7.28 6.32 8.40 Example 16 4-/2-(5-Pjjlor<>^2-dipentylamino-benzoylamino)-ethyl7-benzoic acid Prepared from 5-chloro-2-dipentylami^no-benzoic acid and 4-(2-amino-ethyl)-benzoic acid fcthyieate^ analogously to Example 1.
Yield: 83 % of theory, M.p.: 118 - 120°C Calc.: C 69.05 H 8.07 N 5.75 CI 7.28 Found: 68.84 7.99 6.05 7.54 Example 17 4-/2-(5-Chloro-2-dlpentylamino-benzoylamlno)-ethyl7-benzolc acid Prepared from 4-/3-(5-chloro-2-dipentylamino-benzoylamino- _ <ester ethyl/-benzoic acid pthyleste? by alkaline hydrolysis analogously to Example 2.
Yield: 36.5 % of theory, M.p.: < 20°C.
Calc.: C 68.03 H 7.68 N 6.10 CI 7.72 Found: 67.93 7.64 6.02 7.86 Wm:,'; 71 ti ' 194317 Example 18 4- /2-(5-Chloro^2-(1-pyrrolyl)-benzoylamino)-ethy!7-benzoic acid ifr^hylesier Prepared from 5-chloro-2-(1-pyrrolyl)-benzoic acid and . x ni&ttLiii ester 4-(2-amino-ethyl)-benzoic acid frethylcgtefr analogously to Example 1.
Yield: 64 % of theory, M.p.: 120 - 121°C Calc.: C 65.88 H 5.00 N7.32 CI 9.26 Found: 65.86 4.85 7.47 9.38 Example 19 4-/2-(5-Chloro-2-(1-pyrrolyl)-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-(1-pyrrolyl)-benzoylamino)-ethyl7-benzoic acid ^ncthy 1 eo^ceij by alkaline hydrolysis analogously to Example 2.
Yield: 26 96 of theory, M.p.: 250 - 255°C Calc.: C 65.13 H 4.65 N 7.59 CI 9.61 Found: 65.07 4.74 7.34 9.07 Example 20 4-/2- ( 5-Chloro-2- (N-c^cl^ohexyl-methylamino) -benzoylamino )-ethyl7-benzoic acid pthVlcaxcti Prepared from 2-(N-cyclohexyl-methylamino)-5-chloro-benzoic acid and 4-(2-amino-ethyl-benzoic acid ^tltylesle/' analogously to Example 1.
Yield: 45 % of theory, *:M.p.: 98°C Calc.: C 67.78 H 7.05 N 6.33 ^fcdund: 67.60 6.81 6.28 i V' " 7t " 194317 Example 21 4-(5-Chloro-2-/N-cyclohexyl-methylamino7-benzoylamino)-ethyl7-benzolc acid Prepared from 4-/?-(5-chloro-2-/N-cyclohexylmethylamino7- _ (dhul CstC benzoylamino)-ethyl/-benzoic acid ^tnyleotea/ by alkaline hydrolysis analogously to Example 2.
Yield: 58 % of theory, M.p.: 166°C Calc.: C 66.58 H 6.56 N 6.75 Found: 66.63 6.79 6.66 Example 22 4-(5-Bromo-2-piperidino-benzoylamino)-ethylj-benzoic acid 'Sterr ' - Prepared from 5-bromo-2-Diperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ft\hfflos%ei/ analogously to Example 1.
Yield: 87 % of theory, M.p.: 76°C Calc.: C 60.13 H 5.92 N 6.09 Found: 60.35 5.97 6.19 Example 23 4-/2-(5-Bromo-2-piperldlno-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-bromo-2-piperidino-benzoylamino)-ethyl7-benzoic acid ^fctey-lester by alkaline hydrolysis analogously to Example 2.
Yield: 99 % of theory, M.p.: 201°C Calc.: C 58.47 H5.37 N 6.49 ..Found: 58.56 5.40 6.55 11 H- 194317 Example 24 4-/£-(5-Chloro-2-pyrrolidino-benzoylamino)-ethyl7-benzoic acid f" C' £ Prepared from 5-chloro-2-pyrrolidino-benzoic acid and 4-(2-ami- nxatt^l ester no-ethyl;-benzoic acid ftothylco£er analogously to Example 1. Yield: 43 % of theory, M.p.: 164°C Calc.: C 65.19 H 5.99 N 7.24 Found: 65.35 6.00 7.23 Example 25 4-/2-(5-Chloro-2-pyrrolidino-benzoylamino)-ethyl7-benzolc acid Prepared from 4-/2-(5-chloro-2-pyrrolidino-benzoylamino)-ethyl7- />LeJPMjl QStZf benzoic acid feethyles^eg1 by alkaline hydrolysis analogously to Example 2.
Yield: 68 % of theory, M.p.: 184°C Calc.: C 64.42 H 5.68 N 7.52 CI 9.51 Found: 64.46 5.96 7.47 9.38 ■•APAYDv' Si 11 KCVDy Example 26 4-/2-(5-Chloro-2-piperidino-benzoylamino)-ethyl7-benzoic acid frethyle &t et ___ f Prepared from 5-chloro-2-piperidino-benzoic acid and 4-(2-amino- . <25 t&f ethyl)-benzoic acid foethyleaterf analogously to Example 1.
Yield: 72 96 of theory, M.p. : 98°C Calc.: C 66.00 H 6.29 N 7.00 Found: 66.00 6.37 6.81 "Jfe -** - 194317 Example 27 4-/?-(5-Chloro-2-piperldino-benzovlamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-piperidino-benzoylamino)-ethyl7- osbeS benzoic acid /nethytL enter by alkaline hydrolysis analogously to Example 2. \ Yield: 82 % of theory, M.p.: 200°C Calc.: C 65.20 H 5.98 N 7.24 Found: 65.10 6.00 7.30 Example 28 4-/?-(5-Chloro-2-(2-methyl-piperidino)-benzoylamino)-ethyl7- , . 4 . ZStzr benzoic acid Prepared from 5-chloro-2-(2-methyl-piperidino)-benzoic acid and 4-(2-aminoethyl)-benzoic acid faothylootog' analogously to Example 1.
Yield: 23 96 of theory, M.p. : 82°C Calc.: C 66.57 H 6.56 N 6.75 Found: 66.82 6.42 6.78 Example 29 4-/2- (5-Chloro-2- (2-methyl-piperidino) -benzoylamino) -erthyl7-benzoic acid Prepared from 4-/5-(5-chloro-2-^2-mert;hyl-piperidino)-benzoyl-amino)-ethyl7-benzoic acid ^ot^ylasted by alkaline saponification analogously to Example 2.
Yield: 57 % of theory, ■tr ,_J*_ r : 178°C BKjSviaic.: C 65.91 H 6.29 N 6.99 1 i Found: 65.73 6.28 7.13 17 ?o ' 194317 Example 30 4-/?- (5-Chloro-2-(3-methyl-piperidino)-benzoylamino)-ethyl7- nvui^il ~ benzoic acid Prepared from 5-chloro-2-(3-methyl-piperidino)-benzoic acid and 4-(2-amino-ethyl;-benzoic acid /nethyleatey analogously to Example 1.
Yield: 51 % of theory, M.p.: 93°C Calc.: C 66.57 H 6.56 N 6.75 Found: 66.52 6.38 6.81 Example 31 4-/?-(5-Chloro-2-(3-methyl-piperidino)-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2,-(3-methyl-piperidino)-benzoyl- watfa-fC esttLr amino)-ethyl/-benzoic acid petftyleste? by alkaline hydrolysis analogously to Example 2.
Yield: 83 % of theory, M.p.: 194°C Calc.: C 65.91 H 6.29 N 6.99 Found: 66.20 6.25 6.95 Example 32 4-/5- (5-Chloro-2-(4-methyl-p iperidino)-benzoylamino)-ethyl7- *" es tc' ~~ benzoic acid fnethylester Prepared from 5-chloro-2-(4-methyl-piperidino)-benzoic acid , , , /nethLft ester and 4-(2-amino-ethyl)-benzoic acid jmothyleptcf analogously to Example 1.
Yield: 48 % of theory, 7*^4 55°C - Calc.: C 66.57 H 6.56 N 6.75 J t f\?0v'Foundj 66.38 6.35 6.82 p.- - Sd - 194317 Example 35 4-/2-(5-Chloro-2-(4-methyl-p iperidino)-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-(4-methyl-piperidino)-benzoyl- _ <?5ter amino)-ethyl/-benzoic acid fcetnylesteiT by alkaline hydrolysis analogously to Example 2.
Yield: 83 % of theory, M.p.: 211°C Calc.: C 65.91 H 6.29 N 6.99 Found: 66.07 6.25 7.02 Example 54 4-/2-(5-Chloro-2-(5-ethyl-2-methyl-piperidino)-benzoylamino)- rnitKsjl as tn.tr ethylz-benzolc acid toetftyle3ter Prepared from 5-chloro-2-(5-ethyl-2-methyl-piperidino)-benzoic-acid and 4-(2-amino-ethyl)-benzoic acid /actttylocto^ analogously to Example 1.
Yield: 10 % of theory, M.p.: Z.20°C Calc.: C 67.78 H 7.05 N 6.33 Found; 68.00 7.10 6.50 Example 35 4-/2-(5-Chloro-2-(5-ethyl-2-methyl-piperidino)-benzoylamino) ethyl7-benzoic acid Prepared from 4-/5-(5-chloro-2-(5-ethyl-2-methyl-piperidino)-benzoylamino)-ethyl/-benzoic acid /notnylootoff by alkaline hydrolysis analogously to Example 2.
Yield: 60 % of theory, M.p.: 40°C 1<\ - ^2 ~ 194317 Calc.: C 67.19 H 6./31 N 6.53 Found: 67.30 6.98 6.42 Example 36 4-/£-(5-Chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl7- mothM I c-sfor benzoic acid frethylester Prepared from 5-chloro-2-(3,5-dimethyl-piperidino)-benzoic acid , , . methyl ectv and 4-*(2-amino-ethyl)-benzoic acid faethylesteg analogously to Example 1.
Yield:.85 % of theory, M.p.: 95°C Calc.: C 67.20 H 6.81 N 6.53 Found: 67.14 6.62 6.68 Example 37 4-/5-(5-Chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl7- ester — benzoic acid Imethylestey 2.7 g (0.01 mole) of 5-chloro-2-(3,5-dimethyl-piperidino)-benzoic acid were refluxed for 4.5 hours with 3.57 g (0.03 mole) of thionyl chloride in 20 ml of chloroform. Subsequently the reaction mixture was evaporated in vacuo. The residue ,>fa§ dissolved in aclciecf djvpuno e ml of chloroform and at room temperature /droppod whilst stirring to a solution consisting of 2.16 g (0.01 mole) of methyl esteJ 4-(2-amino-ethyl)-benzoic acid Jnethylesterr hydrochloride and 3.03 g (0.03 mole) of triethylamine, dissolved in 15 ml of chloroform. The addition was finished after 15 minutes. Subsequently the reaction mixture was refluxed for 30 minutes.
After cooling the reaction mixture was washed two times with water and one time with jtiiiu4ed acetic acid. The chloroform phase was dried over sodium sulfate and evaporated. The ob-^-il.ttained residue was further purified over a jsirlioagejL column ff/^(chloroform/acetone = 9:1). After evaporating the solvent, the pure fractions were recrystallized from methylene^- 194317 chloride/petroleum ether (20/1).
Yield: 3.3 g (77 % of theory), M.p.: 94 - 95°C Calc.: C 67.20 H 6.81 N 6.53 CI 8.27 Found: 67.11 6.78 6.70 8.39 Example 38 4-{2-(5-Chloro-2-(3,5-dimethyl-piperidino)-benzoylamino)-ethyl7-benzolc acid 2.15 g (0.005 mole) of 4-/2-(5-chloro-2-(3^-d:toethyl-piperi-dino)-benzoylamino)-ethyl7-benzoic acid faetffiyleaten1' were refluxed for 30 minutes in 50 ml of ethanol and 10 ml of 1N sodium Ol ccjcr- hydroxide solution. After cooling the /greatest part of the alcohol was removed in vacuo and the residue was mixed with 60 ml of water. After weakly acidifying with acetic acid to approx. pH 6, a precipitate was obtained, which after some standing was suction filtered and recrystallized from isopro-panol .
Yield: 1.82 g (87.5 % of theory), M.p.: 204 - 206°C Calc.: C 66.58 H 6.56 N 6.75 CI 8.55 Found: 66.59 6.48 6.71 8.45 Example 39 4-/2-(5-Chloro-2-(4-raethoxy-piperidino)-benzoylamino)-ethvl7- ester benzoic acid fct&ylesteff Prepared from 5-chloro-2-(4- nethoxy-piperidino)-benzoic a id and 4-(2-aminoethyl)-benzoic acid ^^yloh^crt analogously ' o Example 1.
Yield: 60 % of theory, M.p". : < 20°C.
Calc.: C 64.78 H 6.57 N 6.30 Found: 64.95 6.62 6.15 - 194317 Example 40 4-/5-(5-Chloro-2-(4-methoxy-piperidino)-benzoylamino)-ethyl7-benzolc acid Prepared from 4-/2-(5-chloro-2-(4-methoxy-piperidino)-benzoyl- x -y UtAcjl Csdf amino)-ethyl/-benzoic acid /rteftylestei* by alkaline hydrolysis analogously to Example 2.
Yield: 85 % of theory, M.p.: 188°C Calc.j C 63.38 H 6.04 N 6.72 Found: 63.46 5.95 6.72 Example 41 4-/2-(5-Methoxy-2-piperidino-benzoylamino)-ethyl7-benzoic acid c t-ul* I <?<{-? r Prepared from 5-methoxy-2-piperidino-benzoic acid and 4-(2-ami-noethyl)-benzoic acid analogously to Example 1.
Yield: 66 96 of theory, M.p.: 118°C Calc.: C 70.22 H 7.36 N 6.82 Found: 70.76 7.42 7.36 Example 42 4-/5-(5-Methoxy-2-piperidino-benzoylamino)-ethyl7-benzoic acid hydrochloride Prepared from 4-^5-(5-methoxy-2-piperidino-benzoylamino)-ethyl7-benzoic acid feth^lel^er by alkaline hydrolysis analogously to Example 2. The obtained compound was converted to the hydrochloride in acetone with isopropanolic hydrochloric acid.
Yield: 91 % of theory, M.p.: 158°C. $1. " " 194317 Calc.: C 63.07 H 6.49 N 6.68 Found: 63.00 6.31 6.61 Example 43 4-/5-(5-Chloro-2-heptamethyleneimino-benzoylamino)-ethyl7- est&S ~ benzoic acid frthylesteff Prepared from 5-chloro-2-heptamethyleneimino-benzoic acid and . .ethyl 4- (2-aminoethyl) -benzoic acid jcthylestey analogously to Example 1.
Yield: 24 % of theory, M.p.: < 20°C Calc.: C 67.78 H 7.05 N 6.33 Found: 67.95 7.16 6.33 Example 44 4-Jj>- (5-Chloro-2-heptame thyl eneimino-benzoylamino) -e thyl7-benzoic acid Prepared from 4-/5-(5-^h^oro-2-heptamethyleneimino-benzoylamino) • ethyl7-benzoic acid pth^leatcv by alkaline hydrolysis analogously to Example 2.
Yield: 47 % of theory, M.p.: 186°C Calc.: C 66.57 H 6.56 N 6.75 Found: 66.45 6.43 6.70 If4317 Example 45 4-/2-(5-Nitro-2-piperidino-benzoylamino)-ethyl7-benzoic acid ettiii cstjrr tyfehvlofitey Prepared from 5-nitro-2-piperidino-benzoic acid and estC Vfel&J 4- (2-aminoethyl)-benzoic acid ^tnyle&teg analogously to Example 1.
Yield: 70 % of theory, M.p.: 104°C Calc..: C 64.92 H 6.40 N 9.87 Found: 65.17 6.38 9.67 Example 46 4-/?-(5-Nitro-2-piperldino-benzoylamino)-ethvl7-benzolc acid Prepared from 4-^/2-(5-nitro-2-piperidino-benzoylamino)-ethyl7- . <z.th£\ aster benzoic acid pthyloctey by alkaline hydrolysis analogously to Example 2.
Yield: 69 % of theory, M.p.: 194 - 195°C Calc.: C 63.46 H 5.83 N 10.57 Found: 63.20 5.79 10.38 Example 47 4-/2-(5-Chloro-2-(4-phenyl-piperidino)-benzoylamino)-ethyl7- />1 e^W/ es tzr ~ benzoic acid fre^hyl^stejf- Prepared from 5-chlcro-2-(4-phenyl-^ig,e^idino^-benzoic acid and 4-(2-amino-ethy3 )-benzoic acid frgth^rlestei1 analogously to Example 1.
Yield: 62 % of theory, M.p.: 124°C Calc.: C 70.50 H 6.13 N 5.87 Found: 70.60 6.26 5.84 «<f 194317 Example 48 4-/5- (5-Chloro-2-(4-phenyl-piperidino)-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/5-(5-chloro-2-(4-phenyl-piperidino)-benzoyl- _ mitfufC ester amino)-ethyl/-benzoic acid Jiethyiester by alkaline hydrolysis analogously to Example 2.
Yield: 92 % of theory, M.p.: 188°C Calc.: C 70.04 H 5.88 N 6.05 Found: 70.12 6.08 6.05 Example 49 analogously to Example 1.
Yield: 45 % of theory, M.p.: 167°C Calc.: C 62.81 H 5.93 N 6.11 Found: 62.80 5.89 5.93 benzoylamino)-ethyl7-benzoic acid Prepared from 4-/5-(5-chloro~2-(1,4-dioxa-8-aza-S{ (8))-benzoylamino )-ethyl7-benzoic acid jl gr by alkaline hydrolysis analogously to Example 2. - - 194317 Yield: 82 % of theory, M.p.: 190°C Calc.: C 61.95 H 5.88 N 6.28 Found: 61.74 6.03 6.52 Example 51 4-/?-(5-Chloro-2-(4-ethoxycarbonyl-piperidino)-benzoylamino)-ethyl7-benzoic acid ffieth^lesfer Prepared from 5-chloro-2-(4-ethoxycarbonyl-piperidino)-benzoic rr>jLtk*i( esfe/-' acid and 4-(2-aminoethyl)-benzoic acid ftethyleste# analogously to Example 1.
Yield: 17 % of theory, M.p.: 70°C Calc.: C 63.48 H 6.18 N 5.92 Found: 63.30 6.08 5.91 Example 52 4-/2-(5-Chloro-2-(4-hydroxycarbonyl-piperidino)-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-chloro-2-(4-ethoxycarbonyl-piperidlno)- _ <55 hzs benzoylamino)-ethyl/-benzoic acid /methyl ootoif by alkaline hydrolysis analogously to Example 2.
Yield: 71 % of theory, M.p.: 238°C Calc.: C 61.32 H 5.38 N 6.50 Found: 61.32 5.33 6.71 i - - 1T4317 Example 53 4-/2-(5-Chloro-2-hexamethyleneimino-benzoylamino)-ethyl7-ben- osix£r zoic acid irethylester Example 54 4-/2-(5-Chloro-2-hexamethyleneimino-benzoylamino)-ethyl7-benzoic acid Prepared from 4-/2-(5-qhloro-2-hexamethyleneimino-benzoylamino)- pnetfyl es'tey ethyl7-benzoic acid /netnyleat-eg by alkaline hydrolysis analogously to Example 2.
Yield: 89 % of theory, M.p.: 182°C Calc.s C 66.00 H 6.29 N 6.99 Found: 66.20 6.40 7.15 Example 55 4-/2-(5-Chloro-2-morpholino-benzoylamino)-ethyl7-benzoic acid Prepared from 5-chloro-2-morpholino-benzoic acid and YHitAul Q'six.v 4-(2-aminoethyl)-benzoic acid ftethyleste? analogously to Example 1.
Yield: 80 % of theory, M.p.: 111°C Example 1.
Yield: 72 % of theory, M.p. : 81 °C Calo.: C 66.60 H 6.56 N 6.75 Found: 66.28 6.30 6.67 Found: Calc. : C 62.55 H 5.75 N 6.95 62.48 5.74 6.94 *j4r 1T4317 Example 56 4-/2-(5-Chloro-2-morpholino-benzoylamlno)-ethyl7-benzolc acid Prepared from 4-/2-(5-chloro-2-morpholino-benzoylamino)-ethyl7-benzoic acid Jnetteylee:te-f by alkaline hydrolysis analogously to Example 2.
Yield: 78 % of theory, M.p.: 186°C Calc.: C 61.75 H 5.44 N 7.20 Found: 61.60 5.41 7.10 Example 57 4-/2-(5-Chloro-2-thiomorpholino-benzoylamino)-ethyl7-benzoic rnefW es &y acid grethyl e start ■ Prepared from 5-chloro-2-thiomorpholino-benzoic acid and /MJL&'f I C'$,k>r 4-(2-amino-ethyl)-benzoic acid Methylester analogously to Example 1.
Yield: 45 % of theory, M.p.: 160°C Calc.: C 60.20 H 5.53 N 6.69 Found: 60.62 5.76 6.96 Example 58 4-fl-(5-Chloro-2-thiomorpholino-benzoylamino)-ethyl7-benzolc acid Prepared from 4-/?-(5^chloro-2^thiomorpholino-benzoylamino)-ethyl7-benzoic acid inetnyletter by alkaline hydrolysis analogously to Example 2.
Yield: 57 % of theory, M.p.: 210°C Calc.: C 59.32 H 5.23 N 6.92 Found: 59.25 5.19 6.80 9/1 194317 Example 59 4-/?- (5^hloro-2-thiomorpholino-benzoylamino ) -ethyl7-benzoic acid methylester^S-oxide Prepared from 5-chloro-2-thiomorpholino-benzoic acid-S-oxide and 4-(2-amino-ethyl;-benzoic acid pethylester analogously to Example 1.
Yield: 63 % of theory, M.p.: 152°C Calc.: C 57.99 H 5.33 N 6.44 Found: 58.30 5.22 6.52 Example 60 4-/2-(5-Chloro-2-thiomorpholino-benzoylamino)-ethyl7-benzoic acid-S-oxide ; .
I Prepared from 4-/2-(5-^lyLorg-2-thiomorpholino-benzoylamino)-ethyl7-benzoic acid ftet&ylester^S-oxide by alkaline hydrolysis analogously to Example 2.
Yield: 82 % of theory, M.p.: 202°C Calc.: C 57.07 H 5.03 N 6.66 Found: 57.46 5.07 6.30 Example 61 be'lZa.~£-C'pLsuj [ 4-/2- ( 5-Chlor 0-2-/T, 2,4,5-tetrahydro-3H-3-benzazep±ne-y^- (317- v -r nia&y-fl esfer- benzoylamino)-ethylz-benzoic acid ' hen PLyn - Prepared from 5-chloro-2*/T,2,4,5-tetrahydro-3H-3-tycnzazeplnfcT yl-(327-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyls-ester analogously to Example 1.
Yield: 69 % of theory, M.p.: 126°C !0Vi,r/ Calc.: C 70.04 H 5.88 N 6.05 Found: 70.20 5.81 5.94 - ^ - 194317 Example 62 A-/?- (5-Chloro-2-/T, 2, A, 5-tetrahydro-3H-3-|ienzazepxne-yi-(3.27-benzoYlamlno)-ethyl7-benzoic acid Prepared from A-/5-(5-chloro-2-/T,2,A,5-tetrahydro-3H-3-benz-azf-puu^j es iz-'' frzeplne^yl- (3j./~benzoylamlno )-ethyl/-benzolc acid /methyleate^ by alkaline hydrolysis analogously to Example 2.
Yield: 89 96 of theory, M.p.: 1A8°C Calc.: C 69.55 H 5.61 N 6.2A Found: 69.87 5.90 6.10 Example 63 A-/5- (5-Chloro-2-/T,2,3, A-tetrahydro-t^oquinoiineK-yj- (2)7-benzoylamino)-ethyl/-benzoic acid tncthylester Prepared from 5-chloro-2-/Tf2,3,A-tetrahydro-i«oquinolyl-(2j[7- benzoic acid and A-(2-amino-ethyl)-benzoic acid analogously to Example 1 .
Yield: A3 96 of theory, M.p.: 9A°C Calc.: C 69.55 H 5.61 N 6,2A Found: 69.65 5.65 6.1A Example 6A l$0CjU4si0 I A-/2-(5-Chloro-2-/T,2,3,A-tetrahydro-fooquineliny-y^-(227-benzoYlamino)-ethYl7-benzoic acid )$OQ Ltc/lc?(Us~) Prepared from A-/?-(5-chloro-2-/T,2,3,A-tetrahydro-isoquinoline^ yl-(2jT7-benzoylamino)-ethyl7-benzoic acid by alka- ,2,3, A-tetrahydro-tsoqt oic acid pf^rfr^r bj lo - ej line hydrolysis analogously to Example 2.
Tield: 86 % of theory, M.p.: 173°C Calc.: C 69.04 H 5.33 N 6.44 CI 8.15 Found: 68.45 5.56 6.21 8.57 Example 65 4-(5-Chloro-^-f4-phenyl-piperazino) -benzoylamino) -ethyl7-benzoic acid JnetfaYjteater Prepared from 5-chloro-2-(4-phenyl-piperazino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ftetnylenter analogously to Example 1.
Yield: 40 % of theory, M.p.: 132°C Calc.: C 67.84 H 5.90 N 8.79 Found: 67.72 5.92 8.66 Example 66 4-/5-(5-Chloro-2-(4-phenyl-piperazino)-benzoylamino)-ethyl7-benzoic acid 194337 Prepared from 4-/?- (5-chloro-2>-^4-ph^yl-piperazino)-benzoyl-amino)-ethyi7-benzoic acid /pettfylesLe^ by alkaline hydrolysis analogously to Example 2.
Yield: 82 % of theory, M.p.: 166°C Calc.: C 67.07 H 5.65 N 9.06 Found: 67.30 5.96 8.99 -"V >'< 104317 Exaaple 67 4-/2-(5-Chloro-2-(4-pyridyl-(2)-piperazino)-benzoylamino)- — £>n:r ethvl7-benzoic acid Imethvlesteir Prepared from 5-chloro-2-/^-(2-pyrldyl)-piperazino/-benzoic acid and 4-(2-amino-ethyl)-benzoip ^e^flea^r hydro chloride in the presence of /fehioj^ylchlorld^ and trlethylaolne analogously to Example 37* Yield: 44.6 96 of theory, M.p. of the hydrochloride: 153 - 154°C Calc.: C 60.58 H 5.48 N 10.87 CI 13.76 Found: 60.31 5.52 10.68 13.93 Example 68 4-/2-(5-Chloro-2-(4-pyridyl-(2)-piperazino)-benzoylamino-ethyl/-benzoic acid Prepared from 4-/2-(5-chloro-2-(4-pyridyl-(2)-piperazino)- _ ■.n&Jtkfjl dStrkr benzoylamino-ethyl/-benzoic acid /metfayleatei? by alkaline hydrolysis analogously to Example 2.
Yield: 27 % of theory, M.p.: 120°C (decomp.).
Calc.: C 64.58 H 5.42 N 12.05 CI 7.63 Found: 64.36 5.49 11.87 7.48 - % ft- 194317 Example 69 4-/5-(5-Chloro-2-piperidino-benzoylaaino)-1-methyl-ethyl7-benzoic acid Methylester Prepared from 5-chloro-2-piperidino-benzoic^acid ^and 4- (2-amino-1 -methyl-ethyl)-benzoic acid jaeth^FleirfeOT analogously to Example 1.
Yield: 42.7 % of theory, M.p.: 93 - 94°C Calc.: C 66.57 H 6.56 CI 8.54 N 6.75 Found: 66.82 6.57 8.47 6.58 Example 70 4-/5- (5-Chloro-2-piperidino-benzoylamino)-1-methyl-ethyl/-benzolc acid Prepared from 4-/5-(5-chloro-2-piperidino-benzoylamino)-1-methyl ethylz-benzoic acid ^etnyiFSte^ by alkaline hydrolysis analogously to Example 2.
Yield: 76 % of theory, M-p. : 192 - 194°C Calc.: C 65.91 H 6.28 CI 8,84 N 6.99 Found: 66.00 6.30 8.77 6.87 Example 71 4-/2r-(5-Chloro-2-dimethylamino-benzoylamino)-1-methyl-ethyl7- benzolc acid Prepared from 4-/5-(5-chloro-2-dimeth^lamino-benzoylamino)-1-methyl-ethyl7-benzoic acid /netffyleater by alkaline hydroly sis analogously to Example 2. i i *py- 194317 Yield: 86 % of theory, M.p.: 159 - 161°C Calc.: C 63.23 H 5.87 CI 9.83 N 7.76 Found: 63.42 6.07 9.56 7.67 Example 72 4-/?- (5-Chloro-2j-<^imeth^lamino-benzoylamlno)-1 -methyl-ethyl/-benzoic acid dtethVtesterl Prepared from 5-chloro-2-dimethylamino-benzoic acid and 4-(2-amino-1-methyl-ethyl)-benzoic acid analogous ly to Example 1.
Yield: 61.5 % of theory, M.p.: 79 - 80°C Calc.: C 64.07 H 6.18 CI 9.46 N 7.47 Found: 64.40 6.52 9.14 7.20 Example 73 4-/5-(5-Amino-2-piperidino-benzoylamino)-ethyl7-benzoic acid eb^il es ter g (70.5 m mole) of 4-/2-(5-nitro-2-piperidino-benzoylamino)- _ etfcfr- ester ethyl/-benzoic acid Jktnylesltff were hydrogenated at room temperature in 500 ml of methanol: ethanol (1:1) and palladium charcoal as catalyst at a hydrogen pressure of 5 bar. After separating the catalyst and distilling off the solvent the compound was purified by filtration over ft ill teasel with ethyl acetate 1 L as jaluens.
Yield: 93 % of theory, M.p. : 4 20°C Calc.: C 69.84 H 7.39 N 10.62 Found: 70.10 7.20 10.43 WLWTSKro&EGg j i favssi, 194317 Example 74 4-/5-(5-Amino-2-piperidino-ben2oylamino)-ethyl7-benzoic acid dihydrochlorlde ■ Prepared from 4-/?-(5-amino-2-piperidino-benzoylamino)-ethvl7- Example 2. Subsequently the product was converted in acetone to the dihydrochlorlde by means of isopropanolic hydrochloric acid.
Yield: 87 % of theory, M.p.: 70°C Calc.: C 57.26 H 6.18 N 9.54 Found: 57.40 6.30 9.52 Example 75 ' • * to-2-piperidino-benzoyla«ino)-ethy3jr-benzoic Prepared from 2.5 g (6.3 m mole) of^4-^/5-(^-amino-2-piperidino-benzoylamino)-ethyl7-benzoic acid [ethjrlesWr and 25 ml of aceti acid anhydride at room temperature. The precipitated reaction product was washed with ether.
Yield: 1.9 g (69 % of theory), M.p.: 165°C Calc.: C 68.62 H 7.14 N 9.60 Found: 68.92 7.09 9.50 IV4317 £ ^ u.fY\ pic 7/ 4-/5-(5-Acetamino-2-piperidino-benzoylamino)-ethyl7-benzoic acid ; a c e o Prepared from 4-/?- (5-Jloetaain4>-2-plperldino-benzoylamlno ) -ethyl7-benzoic acid /bth^loo'fep by alkaline hydrolysis analogously to Example 2.
Yield: 98 # of theory, M.p.: 212°C Calc.: C 67.46 H 6.64 V 10.26 Found: 67.00 6.67 10.04 Example 77 4-/2-(5-Dimethylaminosulfonyl-2-piperidino-benzoylamino)-ethvl7-benzoic acid Methyl ester Prepared from 5-dimethylaminosulfonyl-2-piperidino-benzoic acid and 4- ( 2-e thy lamino) -benzoic acid jmetSyles^eii analogously to Example 1.
Yield: 77 % of theory, M.p.: 138 - 140°C Calc.: C 60.87 H 6.60 N 8.87 S 6.77 Found: 61.08 6.67 8.86 6,80 Example 78 4-/2-(5-Dimethylaminosulfonyl-2-piperidino-benzoylamino)-ethyl7-benzolc acid Prepared from 4-/?-(5-dimethylaminosul^cnyl-2-piperidino-benzoylamino)-ethyi7-benzoic acid /nett^yles^e* by alkaline saponification analogously to Example 2. 194317 Yield: 91 96 of theory, M.p.: 220°C Calc.: C 60.11 H 6.36 N 9.14 S 6.98 Found: 60.30 6.42 8.96 6.98 Example 79 4-/2- (5-Cyano-2-piperidino-benzoylamino)-ethyl7-benzoic acid ~ Prepared from 5-cyano-2-piperidiny-benzoic acid and 4-(2-aminoethyl)-benzoic acid /etKylee^eiy analogously to Example 1.
Yield: 76 96 of theory, M.p.: 97°C Calc.: C 71.08 H 6.71 N 10.36 Found: 71.37 6.74 10.33 Example 80 4-/2-(5-Cyano-2-plperldino-benzovlamlno)-ethvl7-benzoic acid Prepared from 4-/?-(5-Cyano-2-piperidino-benzoylamino)-ethyl7-benzoic acid |ot^rlcB^ex) by alkaline hydrolysis analogously to Example 2.
Yield: 40 96 of theory, M.p.: 190°C Calc.: C 70.00 H 6.14 N 11.13 Found: 69.81 6.03 10.98 17 - y>o ~ 194317 Example 81 4-/?- ( 5-Ethoxjrcarbon^l-2-piperldino-benzoylamiiao ) -ethyl7-benzoic acid letnvlester hydrochloride 2.5 g (6.2 m mole) of ^-^!5-(!|-cyano-2-piperidino-benzoylamino)-ethyl7-benzolc acid ^h^e^ev were dissolved in 80 nl of ethanol and saturated with hydrogen chloride. After standing for 6 days at room temperature the solvent was evaporated, the residue was dissolved In ice-water, adjusted to a pH value of 9 by means of sodium hydroxide solution and extracted with chloroform. After drying over sodium sulfate and distilling off the solvent, the evaporation residue was converted in ether to the hydrochloride by means of jetheritt hydrochloric acid.
Yield: 2.5 g (89.1 % of theory), M.p.: 86 - 88°C Calc.: C 63.85 H 6.80 N 5.72 CI 7.24 Found: 63.71 6.69 5.74 7.11 Example 82 4-/?-(5-Hydroxycarbonyl-2-piperidino-benzoylamino)-ethyl7-benzoic acid Prepared by alkaline hydrolysis from 4-/?-(5-ethoxycarbonyl-2-piperidino-benzoylamlno)-ethyl7-benzoic acid ^t^lestes* hydrochloride analogously to Example 2.
Yield: 92 % of theory, M.p.: 242°C Calc.: C 66.65 H 6.10 N 7.06 Found: 65.96 6.18 7.23 194317 Example 85 "-Z2- (2-(4-Hydroxy-piperidino)-5-nitro-benzoylamino)-ethyl7-benzolc acid ^S^h^iel^t a) 4-/5-(2-chloro-5-nitro-benzoylamino)-ethyl7-benzoic acid meP^j I Q f>bzS imothvleator ; 8 g (40 a mole) of 2-chloro-5^it^o-berizoic acid were converted in 40 ml of absolute jbetrah^te^irflm^ to the imida-zolide by means of 6.8 g (44 m mole) of N^'-carbonyl-di-imidazole. After a reaction time of 2 hourSj 7.9 g^(44 m mole) of 4-(2-amino-ethyl)-benzoic acid ffieth^ies^ef were added at room temperature and the mixture was stirred for approx. 16 hours. After distilling off the solvent, the crude product was purified by chromatography over a sili-jeag^i column (£±uen4: toluene/ethyl acetate 1:1).
Yield: 12 g (83 % of theory), M.p.: 163°C Calc.: C 56.28 H 4.17 N 7.72 Found: 56.58 4.41 7.82 b) 4-/5-(2-(4-hydroxy-piperidino)-5-nitro-benzoylamino)-ethylJ - nvatn^i I <2sbf benzoic acid inethvlestei? A solution of 5 g (14 m mole) of 4-/5-(2-chloro-5-nitro-benzoylamino)-ethyl7-benzoic acid in 100 ml of ethanol was refluxed with 2.83 g (28 m mole) of 4-hy-droxy-piperidine for 14 hours. After distilling off the solvent in a rotation evaporator, the dry residue was dis- clcLut_ P solved in ice water, adjusted with /diluted^ hydrochloric acid to pH 5 and extracted with chloroform. After drying over sodium sulfate, distilling off the chloroform, the residue was crystallized from isopropanol.
Yield: 5.5 g (92 % of theory), M.p.: 147°C q"l " 1-02 ~ 194317 Example 84 4- /2-(5-Amino-2-(4-hydroxy-piperidino)-benzoylamino )-ethyl7-benzoic acid _ .3 g (12.4 m mole) of 4-/2-(2-(4-hy<froxy-j>iperidino)-5-nitro-benzoylamino )-ethyl7-benzoic acid jinet-h^l-e ater were hydrogenated in 100 ml of methanol with 10 % palladium charcoal at room temperature and at a hydrogen pressure of 1 bar.
Yield: 91 56 of theory, M.p.: 78°C.
Example 85 4-/2- (5-Chloro-2-(4-hydroxy-piperidino)-benzoylamino)-ethyl7- mct&y 7 esfev benzoic acid getnylestei? ■ .5 g (52 m mole) of 4-/2-(5-amino-2-(4-hydroxy-piperidino)- _ QsbZr benzoylamino)-ethyl/-benzoic acid ^aetnyleste? were dissolved in 80 ml of semi-concentrated ice-cold hydrochloric acid and diazotized with a solution of 4 g of sodium nitrite in 25 ml a. dcU-cJ^ cLrtypufio & of ice-cold watefr. This solution was propped to a suspension of 6 g of copper powder and 10 ml of Ijydrochloric acid. After finished/ development of nitroge^/a viscous oil was precipitated. This oil was extracted with chloroform and after drying over sodium sulfate purified over a /silicagel column with 6:Ulaun-t ethyl acetate: methanol (9:1) as frlueny.
Yield: 30 56 of theory, M.p. : 4. 20°C Calc.: C 63.38 H 6.04 N 6.72 Found: 63.62 6.21 6.55 I oo - " 194317 Example 86 4-/?- (5-Chloro-2-(4-hydroxy-piperidino)-benzoylamino)-ethyl7-benzolc acid 4.5 g (11.3 m mole) of 4-/?-(5-amino-2-(4-hydroxy-piperidino)-benzoylamino)-ethyl7-benzoic acid were dissolved in 20 ml of semi-concentrated hydrochloric acid and the solution was diazotized with 0.87 g (12.4 m mole) of sodium nitrite, dissolved in 6 ml of water, at 0°C. This solution was added dropwisely to a suspension of 1.2 g of copper powder in-3 ml of concentrated hydrochloric acid. After stirring for 2 hours the reaction mixture was heated to 75°C for approx. 20 minutes. The cooled solution was extracted with chloroform, the chloroform solutioh was dried with sodium sulfate and the evaporation Silica C/zi residue was purified over a /slllcagel column with chloroform: , . .eUcuitr ' methanol (9:1) as fsiueriy* Yield: 2.4 g (52 % of theory), M.p.: 190°C Calc.: C 62.6 H 5.75 N 6.93 Found: 62.14 5.84 6.83 Example 87 4- /?- (5-Chloro-2-(3-hydroxy-piperidino)-benzoylamino)-ethyl7- I <tsizr benzoic acid Prepared from 4-/2-(5-amino-2-(3-hydroxy-piperidino)-benzoyl-amino)-ethyl/-benzoic acid yethyleste^ analogously to Example 85.
Yield: 30 % of theory, M.p.: 20°C Calc.: C 63.38 H 6.04 N 6.72 Found: 63.48 6.21 6.65 K < 194317 Example 88 4-/?-(5-Chloro-2-(3-hydroxy-piperidino)-benzoylamino)-ethyl7-benzolc acid hydrate Prepared from 4-/2-(5-amino-2-(3-hydroxy-piperidino)-benzoyl-amino)-ethyl7-benzolc acid^laetttylesterr analogously to Examp-le 86.
Tield: 40 % of theory, M.p.: 100 - 110°C Calc.: C 59.93 H 5.98 N 6.65 Found: 60.19 6.08 6.62 Example 89 4-/2- (2-(3-Hydroxy-piperidino)-5-nitro-benzoylamino)-ethyl/- //UtS-ujl esbzf benzoic acid imetnylBBteir Prepared from 4-/?-(2-chloro-5-nltro-benzoylamino)-ethyl7-benzoic acid pothylcstey and 3-hydroxy-piperidine analogously to Example 83.
Yield: 43.5 % of theory, M.p.: 78 - 80°C Example 90 4-/?-(5-Amino-2-(3-hydroxy-piperidino)-benzoylamino)-ethyl7- rtuiifcu/ £s tes benzoic acid laethvle&ter Prepared from 4-/?-(3-hy(droxy-piperidino)-5-nitro-benzoylamino)-ethyl7-benzolc acid jmct&yles^er by jcatalytloal hydrogenation analogously to Example 84.
Yield: 90 % of theory, M.p.: 82°C w - 194317 Example 91 Ethyl 4- [2-(2-piperidino-5-propyloxy-benzoylamino)-ethyl7- benzoate 1.3 g (8mmol) of N,N'-carbonyl-diimidazole were added to a solution of 2 g (7.6 mmol) of 2-piperidino-5-propyloxy-benzoic acid In 60 ml of absolute /tetrahydrofuranf. Subsequently the solution was heated to reflux temperature for 10 - 14 hours excluding moisture. After the imidazolide was formed approx. quantitatively, the solution was mixed with 1.5 g (8mmol) of ethyl 4-(2-amino-ethyl)-benzoate and <x was heated to boiling for/further 4-6 hours. After distilling i i<Z .... off the tetrahydrefuranej in a rotation evaporator, the crude ' 8*1. ester was purified chromatographically over a yBilioogel column with toluene/ethyl acetate (9:1) as solvent. The fractions containing the purified ester, were combined and the solvent was distilled off.
Yield: 2.4 g (72 % of theory), M.p.: 4 20°C Calc.: C 71.20 H 7.81 N 6.38 Found: 71.30 8.02 6.54 Example 92 4-/5-(2-Piperidino-5-propyloxy-benzoylamino)-ethyl/benzoic acid hydrochloride 1.8 g (4.1 mmol) of ethyl 4-/5-(2-piperidino-5-propyloxy-benzoyl-amino)-ethyl7benzoate were dissolved in a mixture of 15 ml of methanol and 15 ml of dioxane. At room temperature 1 ml of 30 % sodium hydroxide solution, diluted with 30 ml of water, was added SIA.CS) }&el slowly to the ester solution^that no permanent precipitation of the ester was formed. The addition was finished after approx. 2 hours. After stirring for a few hours the organic solvents were distilled off in a rotation evaporator, the aqueous phase was extracted with chloroform and was adjusted to pH 4 L with 2 N hydrochloric acid. After extraction with chloroform, . &K 194317 drying the chloroform phase and distilling off the chloroform, the hydrochloride was precipitated froa a solution in aceton* }IMCL/~O chfoY I < with isopropanolic fiyarochlorld acid.
Yields 1.65 g (90 % of theory), M.p.: 236°C Calc.: C 64.48 H 7.00 N 6.26 CI 7.93 Found: 64.24 7.06 6.17 8.13 Example 93 Ethyl (5-isopropyloxy-2-piperidino-benzoylamino)-ethyl7-benzoate Prepared analogously to Example 91 from 5-isopropyloxy-2-piperidino-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 58 % of theory, M.p.: 70 - 72°C Calc.: C 71.20 H 7.81 N 6.38 Found: 71.10 7.74 6.40 Example 94 4- fjt- (5-1 sopropyloxy- 2-piperidino-benzoylamino) - ethy!7benzoic acid hydrochloride Prepared analogously to Example 92 from ethyl 4-/?-(5-iso-propyloxy-2-piperidino-benzoylamino)-ethyl7benzoate by alkaline hydrolysis.
Yield: 82 % of theory, M.p.: 225 - 226°C Calc.: C 64.48 H 6.98 N 6.26 CI 7.93 Found: 64.77 7.30 6.40 7.79 1 94 3 1 7 Example 95 Ethyl 4-/2-(5-hexyloxy-2-plperidino-benzoyl8unino)-ethyl7-benzoate Prepared analogously to Example 92 from 5-hexyloxy-2-plperldino benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yields 61 % of theory, M.p.s 66°C Calc.: C 72.47 H 8.38 N 5.82 Founds 72.68 8.29 5.87 Example 96 / 4- /2- (5-Hexyloxy-2-piperidino-benzoylamino) -ethyl/benzoic acid hydrochloride Prepared analogously to Example 92 from ethyl 4-/2-(5-hexyloxy-2-piperidino-benzoylamino)-ethyl7benzoate by alkaline hydrolysis. Yield: 87 % of theory, M.p.: 152 - 154°C Calc.: C 66.30 H 7.62 N 5.72 CI 7.24 Found: 66.43 7.98 5.77 7.26 Example 97 Ethyl 4-/?-(5-benzyloxy-2-piperidino-benzoylamino)-ethyl/-benzoate ' Prepared analogously to Example 91 from 5-benzyloxy-2-plperidino benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 55 % of theory, M.p.: 120°C Calc.: C 74.04 H 7.04 N 5.75 Found: 73-90 7.14 6.03 |o4 - - 1943 17 Example 98 4-/2- (5-Berizyloxy-2-piperidino-benzoylamino )-ethyl/benzoic acid ; _ Prepared analogously to Example 92 from ethyl 4-/2-(5-benzyl-oxy-2-piperidino-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 86 % of theory, M.p.: 176°C Calc.: C 73.34 H 6.59 N 6.10 Found: 73.34 6.76 6.13 Example 99 Methyl 4-/2-(5-chloro-2-piperidino-benzoylamino)-2-methyl-ethYl7benzoate ■ Prepared analogously to Example 91 from 5-chloro-2-piperidino-benzoic acid and methyl 4-(2-amino-propyl)-benzoate.
Yield: 54 % of theory, M.p.: < 20°C.
Example 100 4-/2-(5-Chloro-2-piperidino-benzoylamino)-2-methyl-ethyl/-benzolc acid Prepared analogously to Example 92 from methyl 4-/2-(5-chloro-2-pi)oeridino-benzoylamino)-2-methyl-ethyl/benzoate by alkaline hydrolysis.
Yield: 49 % of theory, M.p.: 142 - 145°C lot? ~ JjW - 1943 1 7 Calo.: C 65.90 H 6.28 CI 8.84 N 6.98 Pound: 65.85 6.45 8.83 6.99 Example 101 Methyl 4-£1-(3-chloro-2-piperidino-benzoylamino)-ethyl7■ benzoate ' " Prepared analogously to Example 91 from 3-chloro-2-piperidino-benzoic acid and methyl 4-(2-amino-ethyl)-benzoate.
Yield: 63 % of theory, M.p.: 92 - 94°C Calc.: C 65.91 H 6.28 CI 8.85 N 6.99 Found: 65.71 6.19 9.07 6.93 Example 102 4-/5-(3-Chloro-2-piperidino-benzovlamino)-ethyl7benzolc acid Prepared analogously to Example 92 from methyl 4-/?-(3-chloro-2-piperidino-benzoylamino)-ethyl7-benzoate by alkaline hydrolysis.
Yield: 57 % of theory, M.p.: 155 - 158°C Calc.: C 65.19 H 5.99 CI 9.17 N 7.24 Found: 64.96 5.99 9.38 7.50 l«1 - — 1943 1 7 Example 103 Ethyl 4-/2- (4-chloro-2-piperidino-benzoylamino )-ethyl7-benzoate " Prepared analogously to Example 91 from 4-chloro-2-piperidino-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yields 71 % of theory, M.p. s < 20°C Calc.s C 66.58 H 6.56 N 8.54 CI 6.75 Found: 66.58 6.57 8.42 6.99 Example 104 4-/?-(4-Chloro-2-piperidino-benzovlamlno)-ethyl7benzolc acid Prepared analogously to Example 92 from ethyl 4-/2-(4-chloro-2-piperidino-benzoylamino)-ethyl7benzoate by alkaline saponification.
Yields 66.7 % of theory, M.p.: 164 - 166°C Calc.s C 65.20 H 5.99 N 9.16 CI 7.24 Founds 65.31 5.96 9.25 7.48 Example 105 Ethyl 4-/2-(5-bromo-2-(2-methyl-piperidino)-benzoylamino)-ethvlTbenzoate .
Prepared analogously to Example 91 from 5-bromo-2-(2-methyl-piperidino)-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 74 % of theory, M.p. s 98°C ^ 1943 1 7 Calc.: C 60.89 H 6.18 N 5.92 Found: 60.99 6.43 5.78 Example 106 4-/5-(5-Bromo-2-(2-methyl-piperidino)-benzoylamino)-ethyl7~ benzoic acid Prepared analogously to Example 92 from ethyl 4-/5-(5-bromo-2-(2-methyl-piperidino)-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 73 % of theory, M.p.: 183°C Calc.: C 65.91 H 6.29 N 6.99 Found: 65.70 6.35 6.80 Example 107 Methyl 4-/5-(5-chloro-2-(3»5-trans-dimethyl-piperidino)-benzoyl-amino)-ethyl7benzoate Prepared analogously to Example 91 from 5-chloro-2-(3,5-trans- dimethyl-piperidino) -benzoic acid and ethyl 4-(2-amino-ethyl)- benzoic acid.
Yield: 75 % of theory, M.p.: 105 - 107°C Calc.: C 67.20 H 6.81 N 6.53 CI 8.27 Found: 67.40 6.92 6.47 8.26 \0°[ 194317 Example 108 4-/?-(5-Chloro-2-(3»5-trans-dimethyl-piperidino)-benzoylamino)-ethylTbenzolc acid ■ Prepared analogously to Example 92 from methyl 4-/?-(5-chloro-2- ( 315-trans-dimethyl-piperidino ) -benzoylamino ) -ethyljbenzoate by alkaline hydrolysis.
Yield: 86 % of theory, M.p.: 164 - 167°C Calc.: C 66.58 H 6.56 N 6.75 CI 8.55 Found: 66.80 6.71 6.65 8.63 Example 109 Methyl 4-/5-(5-bromo-2-(3,5-cis-dimethyl-piperidino)-benzoyl-amino)-ethvl7benzoate .
Prepared analogously to Example 91 from 5-bro*o-2-(3,5-cis-dimethyl-piperidino) -benzoic acid and methyl 4-(2-amino-ethyl)-benzoate.
Yield: 82 % of theory, M.p.: 142 - 144°C Calc.: C 60.89 H 6.17 N 5.92 CI 16.88 Found: 60.81 6.08 5.85 16.72 \\o "iiV - 1943 1 7 Example 110 4-/5-(5-Bromo-2- ( 3,5-c is-dimethyl-piperidino ) -benzoylamino ) -ethvlTbenzoic acid Prepared analogously to Example 92 from methyl 4-/?-(5-bromo-2-(3,5-cis-dimethyl-piperidino)-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 88 % of theory, M.p.: 184 - 185°C Calc.: C 60.13 H 5.92 N 6.10 CI 17.40 Found: 59.98 5.87 6.02 17.30 Example 111 Ethyl 4-/?- (5-methoxy-2- (3,5-cis-dimethyl-piperidlno )-benzoyl-amlno)-ethvl7benzoate Prepared analogously to Example 91 from 5-methoxy-2-(3,5-cis-dimethyl-piperidino) -benzoic acid and ethyl 2-(amino-ethyl)-benzo-Yield: 14 % of theory, ate M.p.: 97 - 99°C Calc.: C 71.21 H 7.81 N 6.39 Found: 71.29 7.78 6.16 Example 112 4-/2-(5-Methoxy-2-(3,5-cis-dimethyl-piperidino)-benzoylamino)-ethvl7benzoic acid Prepared analogously to Example 92 from ethyl 4-/2- (5-methoxy-2-(3,5-c is-dimethyl-piperidino)-benzoylamino)-ethyl7benzoate by alkaline hydrolysis.
Yield: 53 % of theory, M.p.: 200 - 203°C Ul 1943 1Z Calc.; C 70.22 H 7.37 N 6.82 Found; 70.22 7.38 6.82^ Example 113 Ethyl 4-/?-(5-chloro-2-(3,3,5,5-tetramethyl-piperidino)-benzoyl-amino)-ethvl7benzoate Prepared analogously to Example 91 from 5-chloro-2-(3»3»5»5-tetramethyl-piperidino ) -benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 34 % of theory, M.p.: 108°C Calc.: C 68.85 H 7.49 N 5.94 CI 7.52 Found: 68.75 7.37 5.79 7.69 Example 114 4-/5-(5-Chloro-2-(3,3,5,5-tetramethyl-piperidino)-benzoylamino)-ethyl7benzoic acid ; " Prepared analogously to Example 92 from ethyl 4-/5-(5-chloro-2-(3»3,5,5-tetramethyl-piperidino)-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 99 % of theory, M.p.: 170 - 172°C Calc.: C 67.78 H 7.05 N 6.32 CI 8.00 Found: 67.60 7.09 6.13 7.95 -£}11 194317 Example 115 fx-ptr icJ-cnn Ethyl 4-/?- (5-chloro-2- (friporidone- (2)-yl- (1) ) -b en zoyl amino) -ethyl7benzoate . pLpert dcrn ~ Prepared analogously to Example 91 from 5-chloro-2-(foperidon^1 (2)-yl-(1))-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 42 % of theory, M.p.: 118°C Calc.: C 64.40 H 5.88 N 6.53 Found: 64.32 5.87 6.58 Example 116 \ pLpeftCiloyi 4-/2- (5-Chloro-2- (^Iperidon^- ( 2 ) -yl- (1))-benzoylamino)-ethyl/-benzoic acid hydrate Prepared .^nalogously to Example 92 from ethyl 4-/5-(5-chloro-2-(frlj/crldond-(2)-yl-(1))-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 64 % of theory, M.p.: 190 - 193°C Calc.: C 60.48 H 5-56 N 6.72 Found: 60.74 5.47 6.96 Example 117 Ethyl 4-/£-(5-bromo-2-(4-methoxy-piperidino)-benzoylamino)-ethyl/benzoate Prepared analogously to Example 91 from 5-bromo-2-(4-methoxy-piperidino) -benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Tield: 82 % of theory, : C 20° C \«V -1^- 1943 1 7 Calc.: C 58.90 H 5.97 N 5.72 Pound: 59.25 6.08 5.27 Example 118 4-( 5-Bromo-2- (4-methoxy-piperidino)-benzoylamino)-ethyl7- benzolc acid Prepared analogously to Example 92 from ethyl 4-(5-bromo-2-(4-methoxy-piperidino)-benzoylamino J-ethyl/benzoate by alka line hydrolysis.
Yield: 65 % of theory, M.p.: 186°C Calc.: C 57.28 H 5.46 N 6.07 Found: 56.40 5.46 5.85 Example 119 Ethyl 4-/?- ( 5-chloro-2- ( 2,6-dimethyl-morpholino ) -benzoylamino ) -ethylTbenzoate Prepared analogously to Example 91 from 5-chloro-2-(2,6-dimethyl-morpholino) -benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 52 % of theory, M.p.: 111 - 112°C Calc.: C 64.78 H 6.57 N 6.30 Found: 64.72 6.64 6.24 wyr 1943 •i 7 Example 120 4- /2- ( 5-Chloro-2- ( 2,6-dimethyl-morpholino ) -benzoylamino ) -ethyl7~ benzoic acid .
Prepared analogously to Example 92 from ethyl 4-/2-(5-chloro-2-(2,6-dimethyl-morpholino ) -benzoylamino ) -ethylTbenzoate by alkaline hydrolysis.
Yield: 86 % of theory, M.p.: 232°C Calc,: C 63.38 H 6.04 N 6.72 Found: 63.38 6.28 6.69 Example 121 Ethyl 4-/2-(5-chloro-2-(2,6-dimethyl-thiomorpholino)-benzoyl-amino)-ethvl7benzoate Prepared analogously to Example 91 from 5-chloro-2-(2,6-dimethyl-thiomorpholino)-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 71 % of theory, M.p.: <. 20°C Calc.: C 62.53 H 6.34 N 6.08 Found: 62.60 6.52 6.08 Example 122 4-/2-(5-Chloro-2-(2,6-dimethyl-thiomorpholino)-benzoylamino)-ethvlTbenzolc acid Prepared analogously to Example 92 from ethyl 4-/2-(5-chloro-2-(2,6-dimethyl-thiomorpholino)-benzoylamino)-ethyljbenzoate by alkaline hydrolysis. "^rf ~* 1C 4317 Yield: 51 % of theory, M.p.: 183 - 185°C Calc.: C 61.03 H 5.82 N 6.47 Found: 60.62 6.01 6.30 Example 123 Ethyl 4-/5-(5-chloro-2-(thiomorpholino~1,1-^4o*yd^)-benzoyl-amino)-ethyl7benzoate Prepared analogously to Example 91 from 5-chloro-2-(thiomor- .eLto^udf . pholino-1,1-p±exyde)-benzoic acid and ethyl 4-(2-amino-ethyl) benzoate.
Yield: 40 % of theory, M.p.: 158°C Calc.: C 56.83 H 5.42 N 6.02 Found: 56.78 5.78 6.15 Example 124 Ethyl 4-/5-(2-hexamethyleneimino-5-methoxy-benzoylamino)-ethvlTbenzoate Prepared analogously to Example 91 from 2-hexamethyleneimino-5-methoxy-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 46 % of theory, M.p.: 92°C Calc.; C 70.73 H 7.60 N 6.60 Found: 70.46 7.53 6.72 jilp ~^L9 1943 1 7 Example 125 4-/?- ( 2-Hexamethyleneimlno-5-methoxy-benzoylamino) -ethyl/-benzoic acid hydrochloride Prepared analogously to Example 92 from ethyl 4-/5-(2-hexa-methyleneimino-5-methoxy-benzoyl-amino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 92 % of theory, M.p.: 126°C Calc.: C 63.30 H 6.75 N 6.46 CI 8.18 Found: 63.80 7.24 6.57 7.62 Example 126 Ethyl 4-/5-(2-heptamethyleneimino-5-methoxy-benzoylamino)-ethyl7benzoate . .
Prepared analogously to Example 91 from 2-heptamethyleneimino- -methoxy-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 30 % of theory, M.p.: C 20°C.
Example 127 4-/5- ( 2-Heptamethyleneimino-5-methoxy-benzoylamlno ) -ethyl7 -benzoic acid hydrochloride Prepared analogously to Example 92 from ethyl 4-/2-(2-hepta-methyleneimino-5-methoxy-benzoylamino)-ethyl7benzoate by alkaline saponification.
Yield: 97 % of theory, M.p.: 110 - 112°C Calc.: C 59.68 H 6.88 N 5.80 Found: 60.80 6.87 5.63 ir7 i>d " 194317 # Example 128 Ethyl 4-/5-(2-heptamethyleneimino-5-isopropyloxy-benzoylamino)-ethvl7benzoate Prepared analogously to Example 92 from 2-heptamethyleneimino-5-isopropyloxy-benzoic acid and ethyl 4-(2-amino-ethyl)-benzo-ate.
Yield: 62 % of theory, M.p.: C 20°C Calc.:, C 72.07 H 8.20 N 6.00 Found: 72.20 8.16 5.90 Example 129 4-/5- (2-Heptamethyleneimino-5-isopropyloxy-benzoylamino)-ethyl7benzoic acid hydrochloride Prepared analogously to Example 92 from ethyl 4-/5-(2-hepta- methyleneimino-5-isopropyloxy-benzoylamino)-ethyl7benzoate by alkaline hydrolysis.
Yield: 91 96 of theory, M.p.: 202°C Calc.: C 65.73 H 7.42 N 5.90 CI 7.46 Found: 65.85 7.58 5.82 7.23 Example 130 Ethyl 4-/5-(5-bromo-2-heptamethyleneimino-benzoylamino)-ethyl7-benzoate . prepared euialogously to Example 91 from 5-bromo-2-heptamethylene-imino-benzoic acid and ethyl 4-(2-amino-ethy^-benzoate.
Yield: 42.5 96 of theory, A C 61.80 H 6.50 N 5.78 Br 16.40 61.60 6.40 5.74 16.40 1i£ - - 194317 Example 151 4-/5- (5-Bromo-2-heptamethyleneimino-benzoylamino J-ethyl/-benzoic acid Prepared analogously to Example 92 from ethyl 4-/5-(5-bromo 2-heptamethyleneimino-benzoylamino)-ethyl7benzoate by alkaline hydrolysis.
Yield: 94 # of theory, M.p.: 189°C Calc.: C 60.13 H 5.92 N 6.10 Br 17.39 Found: 59.97 6.01 6.05 17.51 Example 132 [)crt7 cu\ Ethyl 4-/5-(2-(3-aza-bicyclo/5,2,27^enan^-3-yl)-5-chloro-benzoyl-amino) -ethyl7benzoate - Prepared analogously to Example 91 from 2-(3-aza-bicyclo/5,2 ,27- t\crr>oy\ . . . ^enan^-5-yl)-5-chloro-benzoic acid and ethyl 4-(2-amino-ethyl;-benzoate.
Yield: 82 % of theory, M.p.: 114°C Calc.: C 68.63 H 6.87 N 6.16 Found: 68.78 7.08 6.16 Example 135 f)cmcu\ 4-/5-(2-(5-aza-bicyclo/5,2,2/i£e»«R^-5-yl)-5-chloro-benzoyl -amlno)-ethyl7benzoic acid hydrochloride prepared analogously to Example 92 from ethyl 4-/2-(2-(3-aza-bicyclo/5,2,27^S®l-5-yl )-5-chloro-benzoylamino) -ethyl/benzo-ate by alkaline hydrolysis.
-S>- 194317 Yield: 98 % of theory* M.p.: 158°C Calc.: C 62.20 H 6.03 N 6.05 CI 15.30 Found: 62.76 6.37 6.07 15.25 Example 134 Ethyl 4-/2-(5-chloro-2-octamethyleneimino-benzoylamino)-ethylTbenzoate ' Prepared analogously to Example 91 froa 5-chloro-2-octamethylene-inino-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 41 % of theory, M.p.: 4 20°C Calc.: C 68.33 H 7.28 N 6.13 Found: 68.15 7.10 6.09 Example 135 4-(5-Chloro-2-octamethyleneimino-benzoylamino)-ethyl/benzoic acid Prepared analogously to Example 92 from ethyl 4-/5-(5-chloro-2-octamethyleneimino-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 94 % of theory, M.p.: 172°C Calc.: C 67.20 H 6.81 N 6.53 Found: 66.90 6.76 6.39 a 1 943 1 7 Example 156 Ethyl 4-/2- (5-chloro-2-nonamethyleneimino-benzoylamino)-ethvlTbenzoate Prepared analogously to Example 91 from 5-chloro-2-nonamethylene-imlno-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 24 % of theory, M.p.: < 20°C C 69.14 H 7.09 N 5.97 CI 7.56 69.38 7.28 6.13 7.88 Example 157 4-/2- ( 5-Chloro-2-nonamethyleneimino-benzoylamino ) -ethyl/-benzoic acid Prepared analogously to Example 92 from ethyl 4-/2-(5-chloro-2-nonamethyleneimino-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 82 % of theory, M.p.: 175 - 174°C Calc.: C 68.00 H 6.63 N 6.35 CI 8.04 Found: 67.62 6.78 6.23 7.SO Example 158 Ethyl 4-/2-(5-chloro-2-decamethyleneimino-benzoylamino)-ethyl/-benzoate Prepared analogously to Example 91 from 5-chloro-2-decamethylene-imino-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 65 # of theory, M.p.: < 20°C Calc.: C 69.33 H 7.69 N 5.78 Found: 69.29 7.64 5.92 )c^_ ~ 123 ~ Calc.: Found: . J 943 1 Example 159 4-/5- ( 5-Chloro-2-decamethyleneimino-benzoylamino) -ethyl/-benzoic acid Prepared analogously to Example 92 from ethyl 4- (5-chloro-2-decamethyleneimino-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 58 # of theory, M.p.: 177°C Calc.: C 68.33 H 7.28 N 6.13 Found: 68.43 7.28 6.41 Example 140 Ethyl 4-/5-(5-chloro-2-undecamethyleneimino-benzoylamino)-ethvl/benzoate Prepared analogously to Example 91 from 5-chloro-2-undecamethyle-neimino-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 71 % of theory, M.p.: 80°C Calc.i C 69.79 H 7.88 N 5.61 Found: 69.35 7.66 5.84 Example 141 4-/2-(5-Chloro-2-undecamethyleneimino-benzoylamino)-ethyl/-benzolc acid Prepared analogously to Example 92 from ethyl 4-/?-(5-chloro-2-undecamethyleneimino-benzoylamino)-ethyl/benzoate by alkali ne hydrolysis. 1943 17 Yield: 77 % of theory, M.p.: 218 - 220°C Calc.: C 68.04 H 7.49 N 5.95 Found: 68.34 7.21 6.19 Example 142 Ethyl 4-(5-chloro-2-dodecamethyleneimino-benzoylamino)-ethyl7benzoate Prepared analogously to Example 92 from 5-chloro-2-dodecamethylene-imino-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 53 % of theory, M.p.: < 20°C Calc.: C 70.22 H 8.05 N 5.46 Found: 70.56 7.77 5.71 Example 143 4-/?-(5-Chloro-2-dodecamethyleneimino-benzoylamino)-ethyl7-benzoic acid ■ Prepared analogously to Example 92 from ethyl 4-/?-(5-chloro-2-dodecamethyleneimino-benzoylamino)-ethyl7benzoate by alkaline saponification.
Yield: 33 % of theory, M.p.: 185 - 187°C Calc.: C 69.33 H 7.69 N 5.78 Found: 69.17 7.54 5.95 1943 1 7 Example 144 Ethyl 4-/2-(5-chloro-2-(N-methyl-anilino)-benzoylamino)-ethvlTbenzoate Prepared analogously to Example 91 from 5-chloro-2-(N-methyl-anilino) -benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 70 % of theory, M.p.: *20°C.
Example 145 4-/2- ( 5-Chl oro-2- (N-methyl-anilino ) -benzoylamino ) -ethyl/-benzoic acid ^ .
Prepared analogously to Example 92 from ethyl 4-/2-(5-chloro-2- (N-methyl-anilino) -benzoylamino) -ethyl/benzoate by alkaline hydrolysis.
Yield: 65 % of theory, M.p.: 186 - 188°C Calc.: C 67.56 H 5.80 N 6.85 Found: 67.81 5.66 6.87 Example 146 Ethyl 4-/2-(2-(N-ethyl-cyclohexylamino)-5-chloro-benzoylamino)-ethyl/benzoate Prepared analogously to Example 91 from 2-(N-ethyl-cyclohexyl-amino)-5-chloro-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate.
Yield: 41 % of theory, M.p.: 94°C.
Calc.: C 68.33 H 7.28 N 6.13 Found: 68.00 7.10 6.03 uu- - \pr 1 943 1 Example 147 4-/?-(2-(N-Ethyl-cyclohexylamino)-5-chloro-benzoylamino)-ethylTbenzolc acid .
Prepared analogously to Example 92 from ethyl 4-/2-(2-(N-ethyl-cyclohexylamino)-5-chloro-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 63 96 of theory, M.p.: 163°C Calc.: C 67.20 H 6.81 N 6.53 Found: 67.25 6.67 6.45 Example 148 Ethyl 4-/2- (2- (N-butyl-cyclohexylamino)-5-chloro-benzoylamino)-ethyl/benzoate Prepared analogously to Example 91 from 2-(N-butyl-cyclohexyl-amino)-5-chloro-benzoic acid and ethyl 4-(2-amino-ethyl)-benzo- ate.
Yield: 46 % of theory, M.p.: 77°C Calc.: C 69.33 H 7.60 N 5.78 Found: 69.12 7.69 5.78 Example 149 4-/2-(2-(N-Butyl-cyclohexylamino)-5-chloro-benzoylamino)-ethyl/-benzoic acid , Prepared analogously to Example 92 from ethyl 4-/2-(2-(N-butyl-cyclohexylamino) -5-chloro-benzoylamino)-ethyl/benzoate by alkaline hydrolysis. 1 V O 6' Yield: 79 % of theory, M.p.: 85°C Calc.: C 68.33 H 7.28 N 6.13 Found: 68.44 7.18 6.40 Example 150 Ethyl 4-/2-(5-chloro-2-(N-isobutyl-cyclohexylamino)-benzoyl-amino) -ethvlTbenzoate Prepared analogouiBly to Example 91 from 5-chloro-2-(N-isobutyl-cyclohexylamino)-benzoic acid and ethyl 4-(2-amino-ethyl)-benzo-ate.
Yield: 46 % of theory, M.p.: 83°C Calc.: C 69.33 H 7.69 N 5.78 Found: 69.17 7.54 5.66 Example 151 4-/2-(5-Chloro-2-(N-isobutyl-cyclohexyla mLno)-benzoylamino)-ethvlTbenzoic acid Prepared analogusly to Example 92 from ethyl 4-/5-(5-chloro-2-(N-isobutyl-cyclohexylamino)-benzoylamino)-ethyl/benzoate by alkaline saponification.
Yield: 62 % of theory, M.p.: 129°C Calc.: C 68.33 H 7.28 N 6.13 Found: 68.30 7.18 6.17 t lio Example 152 Methyl 4-/5-(5-chloro-2-dimethylamino-benzoylamino)-2-methyl-ethvlTbenzoate ' Prepared analogously to Example 91 from 5-chloro-2-diaethyl-amlno-benzoic acid and methyl 4-(2-amino-propyl)-benzoate. Yield: 34 % of theory, M.p.: 20°C.
Example 153 4- /?- ( 5-Chloro-2-dimethylamino-benzoylamino )-2-methyl-ethyl7-benzoic acid Prepared analogously to Example 92 from methyl 4-/?-(5-chloro-2-dimethylamino-benzoylamino)-2-methyl-ethyl7benzoate by alkaline hydrolysis.
Yield: 49 % of theory, M.p.: 142 - 145°C.
Calc.t C 63.22 H 5.86 N 7.76 Found: 62.90 5.98 7.54 Example 154 Methyl 4-/5-(3-chloro-2-dimethylamino-benzoylamino)-ethyl7-benzoate _______ Prepared analogously to Example 91 from 3-chloro-2-dimethyl-amino-benzoic acid and methyl 4-(2-amino-ethyl)-benzoate. Yield: 76 % of theory, M.p. : C 20°C. 1^43 i 7 Example 155 4-/?-(3-Chloro-2-dimethylamlno-benzoylamlno)-ethyl7benzolc acid Prepared analogously to Example 92 from methyl 4-/2-(3-chloro-2-dimethylamino-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 76 % of theory, M.p.: 175 - 178°C Calc.: C 62.33 H 5-52 N 8.08 CI 10.22 Found: 62.60 5.56 8.26 10.27 Example 156 Methyl 4-/?- (2-dimethylamino-5-methoxy-benzoylamino )-ethyl/■ benzoate - Prepared analogously to Example 91 from 2-dimethylamino-5-methoxy-benzoic acid and methyl 4-(2-amino-ethyl)-benzoate.
Yield: 81 % of theory, M.p.: C 20°C.
Example 157 4-/2-(2-Dimethvlamino-5-methoxy-benzoylamino)-ethvl/benzoic acid Prepared analogously to Example 92 from methyl 4-/I-(2-dimethyl-amino-5-methoxy-benzoylamino)-ethyl/benzoate by alkaline hydrolysis.
Yield: 71 % of theory, M.p.: 147 - 150°C Calc.: C 66.65 H 6.48 N 8.18 Found: 66.85 6.35 8.12 > 1,'t - 194317 Example 158 Ethyl 4-/5- (4-chloro-2-dimethylamino-benzoylamino)-ethyl/-benzoate 3.55 g (10 mmol) of ethyl 4-/5-(4-amino-2-dimethylamino-benzoyl-amino)-ethyl/benzoate (m.p.: 135 - 136°C, prepared by hydrogenation of ethyl 4-/5-(2-dimethylamino-4-nitro-benzoylamino)-ethyl/-benzoate with palladium/charcoal) were diazotized in 4 ml of conc. hydrochloric acid and approx. 5 g of ice by propwiseiy j^ing-Ja^aolution of 820 mg (11.6 mmol) of sodium nitrite in 5 ml of,water. After 30 minutes the diazonium salt solution cLcldfi-x. dUvfoU^iC- was £reppe^ to a suspension of 1i2 g of copper bronze in 1 ml of conc. hydrochloric acid at room temperature. After standing over night, the reaction mixture was diluted with water and extracted with chloroform. The evaporated chloroform extracts Stltca Mfcf cUccisit were purified column-chromatographically on pllioagel (plueng: toluene/ethyl acetate = 1:1; « 0.75).
Yield: 27 % of theory, M.p.: 97 - 99°C.
Calc.: C 64.08 H 6.18 N 9.46 CI 7.47 Found: 64.37 6.42 9.32 7.44 Example 159 4-/5-(4-Chloro-2-dimethylamino-benzovlamino)-ethyl/benzoic acid Prepared analogously to Example 92 from ethyl 4-/5-(4-chloro-2-dimethylamino-benzoylamino)-ethyl/benzoate by alkaline saponification.
Yield: 95 % of theory, M.p.: 163 - 165°C Calc.: C 62.34 H 5.52 N 10.22 CI 8.08 Found: 61.92 5.55 10.60 8.15 tr - n <-? % 3 Example 160 Ethyl 4-/5- ( 2-dimethylamino-4-nitro-benzoylamino)-ethyl7-benzoate Prepared analogously to Example 91 from 2-dimethylamino-4-nitro-benzoic acid and ethyl 4-(2-amino-ethyl)-benzoate. Yield: 95 % of theory, M.p.: 145°C Calc.: C 62.33 H 6.01 N 10.90 Pound: 62.73 6.00 11.09 Example 161 Methyl 4-/?- (6-chloro-2-dimethylamino-benzoylamlno)-ethyl7■ benzoate Prepared analogously to Example 91 from 6-ohloro-2<-dimethyl-amino-benzoic aoid and methyl 4-(2-amino-ethyl)-benzoate. Yield: 25 % of theory, M.p.: 115 - 117°C Calc.t C 63.24 H 5.87 N 7.76 CI 9.83 Found: 63.33 5.73 7.90 9.92 Example 162 4-/?-(6-Chloro-2-dimethvlamlno-benzovlamino)-ethvl7benzoic acid Prepared analogously to Example 92 from methyl 4-/5-(6-chloro-2-dimethylamino-benzoylamino)-ethyl7benzoate by alkaline hydrolysis.
Yield: 35 # of theory, M.p.: 155 -< 158°C Calc.: C 62.34 H 5.52 N 8.08 CI 10.22 Found: j 62.98 5.73 7.92 10.11 - - 194317 .i Example 11>3 Ethyl 4-/5-/2-(4-benzyl-piperazino)-5-chloro-benzoylamino7- ethvlTbenzoate Prepared analogously to Example 91 from 2-(4-benzyl-piperazi-no)-5-chloro-benzoic acid.
Yield: 39 % of theory, M.p.: <20°C Calc.: C 68.83 H 6.37 N 7.00 CI 8.30 Found: 68.97 6.52 6.93 8-21 Example 164 Ethyl 4-/2-/2-piperazino-benzoylamlno7ethyl7benzoate Prepared from ethyl 4-/2-/2-(4-benzyl-piperazino)-5-chloro- benzoylamino/ethyljbenzoate by jbatalffiblcal hydrogenation with palladium/charcoal at room temperature and at a hydrogen pressu re of 1 bar.
Yield: 60 % of theory, M.p.: <20°C Calc.: C 69.27 H 7.13 N 11.01 Found: 69.22 7.11 10.90 'V - 194317 Example 165 u^no Us7 4-/2- (5-Chloro-2-(decahydro-1 floqulnul-Lu^-2-yl)-benzoylamino )-ethvl7benzolc acid ethyl ester " A mixture of 2.5 g (8.5 mmol) of 5-chloro-2-(decahydro- tS <OCfU**1tTt4S~l jbgequinoline'-2-yl)-benzoic acid and 1.4 g (8.6 mmol) of carbonyl diimidazole was heated to boiling in 30 ml of absolute tetrahydrofuran for 8 hours. 1.64 g (8.6 mmol) of 4-(2-aminoethyl)-benzoic acid ethyl ester were added to the formed imidazolide and the reaction mixture was refluxed for further 12 hours. After distilling off the st./ic a gW solvent, the ester was purified oyer a frilicagel column by means of toluene/ethyl acetate (9:1) as eluant.
Yield: 2.7 g (68 % of theory), M.p.: <20°C.
Calc.: C 69.14 H 7.09 N 5.97 CI 7.55 Found: 69.43 6.98 6.10 7.76 Example 166 tSC><2 U-cSloLtSI 4-/2-(5-Chloro-2-(decahydro-|soquinolinq/-2-yl)-benzoylamlno)-ethyl7benzoic acid hydrochloride ISajLCMs-t a t-^s\ 1.9 g (4.1 mmol) of 4-/2-(5-chloro-2-(decahydro-4oo(julnolinp-2-yl)-benzoylamino)-ethyl7benzoic acid ethyl ester were dissolved in a mixttire of 20 ml of dioxane and 20 ml of methanol. After addition of 5 ml of 30 % sodium hydroxide solution, dilu- hycL/vUjsgei ted with 20 ml of wat^r, the ester was hydpollzeti at room temperature. After some hours the organic solvents were distilled off. After extraction with chloroform the aqueous phase was adjusted to pH 4 - 5 by means of 2N hydrochloric acid and the acid, which precipitated at this pH value, was extracted with chloroform. After drying ari distilitng off the chloroform, the hydrochloride was precipitated in acetone by means of isopropanolic hydrochloric acid. ■■ ' " 0«>. ! 5^ - 1-3^ - Yield: 1.5 g (77 # of theory), M.p.; 226°C.
Calc.: C 62.88 H 6.33 N 5.86 Found: 62.60 6.36 5.93 Example 167 htn*aZt'f>LS\ h-f/L-(5-Chloro-2-(decahydro-3-peBzazcpln4-3-yl)-benzoylamino)-ethvl7benzolc acid ethyl ester Prepared analogously to Example 165 from 5-chloro-2-(decahydro- 3-^^gQzopin^-3-yl)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 97 # of theory, M.p.: 4.20°C.
Calc.: C 69.62 H 7.30 N 5.80 CI 7.33 Found: 69.88 7.22 5.63 7.46 Example 168 be'TZjZ~Z.CrpLS\ 4-/2- (5-Chloro-2- (decahydro-3-J>eneetaepla^-3-yl) -benzoylamino )-ethvlTbenzoic acid hydrochloride hzn?cL~i<? f>ts\ Prepared from 4-/2-(5-chloro-2-(decahydro-3~^onzaaopinp-3-y1)-benzoylamino)-ethyl7benzoic acid ethyl ester by alkaline hydrolysis analogously to Example 166.
Yield: 84 % of theory, M.p.: 216°C.
Calc.: C 63.53 H 6.56 N 5.69 CI 14.42 Found: 63.51 6.59 5.76 14.35 194317 Cl 14.85 14.76 , ' 194317 Example 169 4-/?- (5-Bro«o-2- (decahydro-3-^eazarep±ni-3-yl) -benzoylamino ) -ethvl7benzolc acid ethyl eater Prejjared^ analogous ly to Example 165 from 5-bromo-2- (decahydro- 3-^enzaze^tt^-3-yl)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 98 % of theory, M.p.: < 20°C.
Calc.: C 63.75 H 6.68 N 5.31 Br 15.14 Found: 64.06 6.56 5.16 15.00 Example 170 b&nza. z_eyj w\ 4- /2- (5-Bromo-2- (decahydro- 3-p«uzazepln|(-3-yl) -benzoylamino) -ethyl7benzolc acid hydrochloride Prepared analogously to Example 166 from 4-/?-(5-bromo-2-(deca-hydro-3-ftengazoj$in$-3-yl)-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 84 % of theory, M.p.: 216°C.
Calc.: C 58.26 H 6.01 N 5.22 CI 6.61 Br 14.91 Found: 58.22 5.85 5.34 6.65 15.00 Example 171 _ ISO csxclol 4-/2-(5-Chloro-2-(octahydro-fcr tindolg-2-yl)-benzoylamlno)-ethyl7benzoic acid ethyl ester analogously to Example 165 from 5-chloro-2-(octahydro--2-yl)-benzoic acid end 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 72 % of theory, ^Mrp.. : 20°C.
Calc.: C 68.63 H 6.86 N 6.15 CI 7.79 Found: 68.72 6.92 6.20 7.94 Prepare^ JSC? tjiclo i • -JA- 1S4317 ' i l Example 172 isotsxcLol 4-/2- ( 5-Chloro-2- ( octahydro-^soindolql- 2-yl) -benzoylamino ) -ethvl7benzolc acid hydrochloride Prepared analogously to Example 166 from 4-/?-(5-chloro-2- (octahydro-^ oolmrel-<t-2-yl)-benzoylamino )-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield; 83 % of theory, M.p.j 214°C.
Calc.: C 62.20 H 6.09 N 6.04 CI 15.32 Found: 62.45 6.23 6.13 15.70 Example 173 4-/2-(5-Bromo-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester Prepared analogously to Example 165 from 5-bromo-2-octamethylen-imino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 84 % of theory, M.p.: C20°C.
Calc.: C 62.27 H 6.63 N 5.58 Br 15.93 Found: 62.40 6.66 5.53 15.96 Example 174 4-/2-(5-Bromo-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid hydrochloride ; Prepared analogously to Example 166 from 4-/£-(5-bromo-2-octa-methylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 90 % of theory, M.p.: 164°C.
Calc.: C 56.53 H 5.92 N 5.49 Br 15.67 CI 6.95 Found: 56.82 5-96 5.47 14.85 6.59 1 > <4 ^ 1 7 Example 175 4-/5- (5-Cyano-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester • Prepared analogously to Example 165 from 5-cyano-2-octamethylen-imino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 30 56 of theory, M.p.: 94°C.
Calc.: C 72.45 H 7.43 N 9.38 Found: 72.50 7.50 9.41 Example 176 4-/2-(5-Cyano-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ' ' Prepared analogously to Example 166 from 4-/?-(5-cyano-2-octa-methylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 87 % of theory, M.p.: 186°C.
Calc.: C 71.57 H 6.96 N 10.01 Found: 71.50 7.14 9.66 Example 177 4-/2- (2-0ctamethylenimino-5-n i tro-benzoylamino)-ethyl/benzoic acid ethvl ester Prepared analogously to Example 165 from 2-octamethylenimino- -nitro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 50 % of theory, M.p.: 116°C.
Calc.: C 66.79 H 7.11 N 8.98 Found: 67.00 7.17 9.04 Vbh t >43 Example 178 4-/?- (2-0ctamethylenimino-5-nitro-benzoylamino ) -ethyl/-benzoic acid hydrochloride ; ■ Prepared analogously to Example 166 from 4-/5- (2-octamethy-1 enimino-5-nitro-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 93 % of theory, M.p.: 148°C.
Calc.: C 62.06 H 6.74 N 9.24 CI 4.53 Found: 62.46 6.46 9.10 4.76 Example 179 4-/5- (5-Amino-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester dihydrochlorlde Prepared from 4-/2-(2-octamethylenimino-5-nitro-benzoylamino)-ethyl/benzoic acid ethyl ester by catalytic hydrogenation in methanolic solution at a hydrogen pressure of 5 bar at room temperature by means of 10 % palladium charcoal as catalyst. Yield: 79 % of theory, M.p.: 162°C.
Calc.: C 61.16 H 7.30 N 0.22 CI 13.90 Found: 61.50 7.84 8.54 13.50 Example 180 4-Z5- (5-Amino-2-octamethyleniBi ino-benzoylamino )-ethyl/benzoic acid hydrochloride Prepared analogously to Example 166 from 4-/?-(5-amino-2-octamethyl enim.ino-benzoylamino)-ethyl/benzoic acid ethyl ester hydrochloride by alkaline hydrolysis. " \jxr~ 1 ^ 8 Yield: 50 # of theory, M.p.: 130°C.
Calc.: C 64.62 H 7.23 N 9.42 CI 7.94 Found: 63.90 7.10 9.20 7.74 Example 181 4- /2- ( 2-0ctamethylenimino- 5-methoxy-benzoylamino ) - ethyl/-benzoic acid ethyl eater • • Prepared analogously to Example 165 from 2-octamethylenimino- -methoxy-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 80 % of theory, M.p.: < 20°C.
Calc.: C 71.65 H 8.01 N 6.18 Found: 71.65 8.15 6.25 Example 182 4-/2- (2-0ctamethylenimino-5-methoxy-benzoylamino ) -ethyl/benzoic acid hydrochloride , " Prepared analogously to Example 166 from 4-/2-(2-octamethylenimino- 5-me thoxy-benzoylamino) -ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 83 % of theory, M.p.: 216°C.
Calc.: C 65.13 H 7.21 N 6.07 CI 7.68 Found: 64.53 7.39 5.96 7.70 Example 183 4-/2-(5-Ethoxy-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester prepared analogously to Example 165 from 5-ethoxy-2-octamethylen 1 S -v S i imino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 66 % of theory, M.p.: C 20°C.
Calc.: C 72.07 H 8.20 N 6.00 Found: 72.25 8.21 6.06 Example 184 4-/2- (5-Ethoxy-2-oc tame thylenimino-benzoylamlno)-ethyl/benzoic acid hydrochloride ' .
Prepared analogously to Example 166 from 4-/?-(5-ethoxy-2-octa-methylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 98 % of theory, m.p.: 172°C.
Calc.: C 65.73 H 7.42 N 5.89 CI 7.46 Found: 65.50 7.20 5.79 7.19 Example 185 4-/2- (5-Isopropyloxy-2-octamethylenimino-benzoylamino ) -ethyl/-benzoic acid ethyl ester Prepared analogously to Example 165 from 5-isopropyloxy-2-octa- methylenimino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 87 % of theory, M.p.: <20°C.
Calc.: C 72.47 H 8.38 N 5.82 Found: 73.04 8.44 5.76 w\ ~ 1^2- ~ '(& ^v. ^45 'I Example 186 4-/2- ( 5-Isopropyloxy-2-octamethylenimino-benzoylamino)-ethyl/-benzoic acid hydrochloride .
Prepared analogously to Example 166 from 4-/2-(5-isopropyloxy-2-octamethylenlmlno-benzoylamlno)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 93 % of theory, M.p.: 152°C.
Calc.: C 66.30 H 7.62 N 5.72 CI 7.24 Found: 66.40 7.50 5.54 7.11 Example 187 4-/2- (5-Butyl- (2)-oxy- 2-oc tamethylenlmlno-benzoylamlno )-ethyl/-benzolc acid ethyl ester ! ' Prepared analogously to Example 165 from 5-butyl-(2)-oxy-2-octa- methylenlmlno-benzolc acid and 4-(2-amlno-ethyl)-benzoic acid ethyl ester.
Yield: 64 % of theory, M.p. : C20°C.
Calc.: C 72.84 H 8.56 N 5.66 Founds 72.58 8.48 5.27 Example 188 4-/2- (5-Butyl- (2 )-oxy-2-octamethylenimino-benzoylamino )-ethyl/-benzoic acid hydrochloride Prepared analogously to Example 166 from 4-/2-(5-butyl-(2)-oxy-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 88 % of theory, M.p.: 142°C.
Calc.: C 66.84 H 7.81 N 5.56 CI 7.04 Found: 66.40 7.84 5.20 6.71 1 > *2 1 7 4-/?-(5-Chloro-2-(4-isopropyl-piperidino)-benzoylamino)-ethyl7-benzolc acid ethyl eater ' Prepared analogously to Example 165 from 5-chloro-2-(4-isopropyl piperidino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 72 % of theory, M.p.: C 20°C.
Calc.: C 68.03 H 7.69 N 6.10 CI 7.73 Found: 68.20 7.62 6.20 7.41 Example 190 4-/2- (5-Chloro-2- (4-isopropyl-piperidino )-benzoylamino )-ethyl7-benzoic acid Prepared analogously to Example 166 from 4-/2-(5-chloro-2-(4-isopropyl-piperidino)-benzoylamino)-ethyl7benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 75 % of theory, M.p.: 164°C.
Calc.: C 67.20 H 6.81 N 6.53 CI 8.27 Found: 67.40 6.94 6.74 8.41 Example 191 4-/2-(5-Chloro-2-(4-tert.butyl-piperidino)-benzoylamino)-ethylJ-benzolc acid ethyl ester prepared analogously to Example 165 from 5-chloro-2-(4-tert.butyl- piperidino) -benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 63 % of theory, M.p.: 103°C.
Calc.: C 68.84 H 7.49 , N 5.95 CI 7.53 Found: 69.10 7.60 6.20 7.90 194317 Example 192 4-/2-(5-Chloro-2-(4-tert.butyl-piperidino)-benzoylamino)-ethyl/-benzoic acid Prepared analogously to Example 166 from 4-/?-(5-chloro-2- (4-tert.butyl-piperidino)-benzoylaminoJ-ethyl/henzoic acid ethyl ester.
Yield: 87 % of theory, M.p.: 160°C.
Calc.; C 67.78 H 7.05 N 6.33 CI 8.00 Found: 67.93 7.21 6.50 8.20 Example 193 4-/2- (5-Chloro-2- (1t4-dioxa-8-aza-Bplro/5,67imdeean^-8-yl)-ben-zoYlamlno)-ethYl7benzolc acid ethyl ester .
Prepared analogously to Example 165 from 5-chloro-2-(1,4-dioxa-8-aza-spiro/7,67vfct3eoane-8-yl)-benzoic acid and 4-(2-amino-ethyl ) -benzoic acid ethyl ester.
Yield: 43 # of theory, M.p.: <20°C.
Calc.: C 64.12 H 6.42 N 5.75 CI 7.28 Found: 64.40 6.31 6.01 7.62 Example 194 __ _ 4-/2-(5-Chloro-2-(1,4-dioxa-8-aza-spiro/4,67iftndecan6-8-yl)-benzoylamino)-ethyl7benzoic acid Prepared analogously to Example 166 from 4-/2-(5-chloro-2-(1,4-dioxa-8-aza-spiro/5,67/andooan^-8-yl)-benzoylamino)-ethyl7benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 71 % of theory, M.p.: 185°C.
Calc.: C 62.81 H 5.93 N 6.10 CI 7.72 Founds 63.02 6.05 6.11 7.98 1^ - J-45 - 1943 17 Example 195 4-/2- (2-Diallylamino-5-chloro-benzoylamino )-ethyl/benzoic acid ethvl eater Prepared analogously to Example 165 from 2-diallylamino- -chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 48 % of theory, M.p.: < 20°C.
Calc.: C 67.52 H 6.29 N 6.55 Found: 67.64 6.38 6.56 Example 196 4-/2- (2-Dlallylamino-5-chloro-benzoylamino)-ethylTbenzoic acid Prepared analogously to Example 166 from 4-/2-(2-diallylamino- -chloro-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 75 # of theory, M.p.: 130°C.
Calc.: C 66.24 H 5.81 N 7.02 Found: 66.50 5.83 6.92 Example 197 4-/2-(5-Nitro-2,4-dipiperidino-benzoylamino)-ethyl/benzoic acid ethyl ester Prepared analogously to Example 165 from 5-nitro-2,4-dipiperi-dino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester. Yield: 40 # of theory, M.p.: C20°C.
Calc.: C 66.12 H 7.13 N 11.01 Found: 66.13 7.09 11.05 '¥*" 1 > 4- 3 ' Example 198 4- fl- ( 5-Nitro-2.4-dlplperldlno-benzoylamlno ) -ethyl/benzoic acid Prepared analogously to Example 166 from 4-/5-(5-nitro-2,4-di-piperidino-benzoylamlno)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 95 56 of theory, M.p.: 208°C, Calc.: C 64.98 H 6.71 N 11.65 Found: 64.40 6.72 11.03 Example 199 4-/5- (5-Amino-2,4-dipiper idino-benzoylamino)-ethyl/benzoic acid ethyl ester 1.4 g (2.8 mmol) of 4-/5-(5-nitro-2,4-dipiperidino-benzoyl-amino)-ethyl/benzoic acid ethyl ester were dissolved in 100 ml of ethanol and the solution was hydrogenated at room temperature at a hydrogen pressure of 5 bar by means of 10 56 palladium charcoal as catalyst. After filtering off the catalyst and distilling off the methanol 0.8 g (60 56 of theory) of the compound were obtained by crystallization from acetone.
M.p.: 172°C Calc.: C 70.26 H 8.00 N 11.70 Found: 70.39 8.19 11.72 Example 200 4-/5-(5-Amino-2,4-dipiperidino-benzoylamino)-ethyl/benzoic acid hydrochloride Prepared analogously to Example 166 from 4-/5-(5-amino-2,4-dipiper idino-benzoylamino) -ethyl/benzoic acid ethyl ester by alkaline hydrolysis. jj ^ ^ Yield: 95 % of theory, ■.p.: 271°C.
Calc.: C 64.11 H 7.24 N 11.50 CI 7.27 Found: 64.40 7.27 11.33 7.50 Example 201 4-/?-(2-(N-Adamantyl-(1)-N-methyl-amlno)-5-chloro-benzoylamino) • ethvl7benzoic acid ethvl ester Prepared analogously to Example 165 from 2-(N-adamantyl-(1)-N-methyl-amino)-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 0.85 g (34 % of theory), M.p.: « 20°C.
Calc.: C 70.36 H 7.13 N 5.66 CI 7.16 Found: 70.05 7.08 5.46 7.07 Example 202 4-/2- ( 2- (N-Adamantyl- (1) -N-methyl-amino) -5-chloro-benzoylamino) ■ ethvlTbenzoic acid Prepared analogously to Example 166 from 4-/?-(2-(N-adamantyl-(1)-N-methyl-amino)-5-chloro-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 0.33 g (64 % of theory), M.p.: 207°C.
Calc.: C 69.44 H 6.69 N 6.00 CI 7.59 Found: 69.13 6.44 6.02 7.93 1943 Example 203 4- /5- (5-Chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoylamino)-ethvl7benzoic acid ethyl ester Prepared analogously to Example 165 from 5-chloro-2-(1,2,3»6-tetrahydro-pyridino)-benzoic acid and 4-(2-amino-ethyl) -benzoic acid ethyl ester.
Yield: 4.7 g (88 # of theory), M.p.: < 20°C.
Calc.; C 66.90 H 6.10 N 6.78 CI 8.59 Found: 67.60 6.21 7.02 8.54 Example 204 4-/5-(5-Chloro-2-(1,2,3,6-tetrahydro-pyridino)-benzoylamino)-ethvlTbenzoic acid Prepared analogously to Example 166 from 4-/5-(5-chloro-2-(1,2,3»6-tetrahydro-pyridino)-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield; 2.27 g (73.7 % of theory), M.p.: 181 - 182°C.
Calc.: C 65.54 H 5.50 N 7.28 CI 9.21 Found: 65.50 5.49 7.32 9.12 Example 205 4-/5-(5-Chloro-2-(N-isobutyl-N-propyl-amino)-benzoylamino)-ethylTbenzoic acid ethvl ester Prepared analogously to Example 165 from 5-chloro-2-(N-isobutyl N-propyl-amino)-ben2oic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 5.8 g (86.8 % of theory), M.p.: 4. 20°C.
Calc.: C 67.48 H 7.47 N 6.30 CI 7.97 Found: 67.70 7.63 6.26 7.96 - - yri - kl 943 1 7 Example 206 4-/5- ( 5-Chloro-2- (N-isobutyl-N-propyl-amino) -benzoylamino) -ethvlTbenzolc acid Prepared analogously to Example 166 from 4-/5-(5-chloro-2-(N-isobutyl-N-propyl-amino)-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline hydrolysis.
Yield: 2.7 g (79 # of theory), M.p.: 128°C.
Calc.: C 66.25 H 7.01 N 6.72 CI 8.50 Pound: 66.60 7.08 6.66 8.64 Example 207 4-/5- (2-N, N-Diethylamino-3-nethyl-benzoylamino ) - ethyl/-benzoic acid methyl ester Prepared analogously to Example 165 from 2-N,N-diethylamino - 3-methyl-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester.
Yield: 57 % of theory, M.p.: C20°C.
Calc.: C 71.71 H 7.66 N 7.61 Found: 71.71 7.83 7.55 Example 208 4-/5-(2-N,N-Diethylamino-3-nethyl-benzoylamino)-ethyl/-benzoic acid Prepared analogously to Example 166 from 4-/5-(2-N,N-diethyl-amino-3-methyl-benzoylamino)-ethyl/benzoic acid methyl ester by alkaline saponification.
Yield: 63.1 % of theory, M.p.: 150 - 152°C Calc.: C 71.15 H 7.39 N 7.-91 Found: 71.01 7.38 8.13 >47 . - 'H un Example 209 4-/2-(5-Chloro-2-(4-(2-furoyl)-piperazino)-benzoylamino)-ethvlTbenzoic acid methyl ester Prepared analogously to Example 165 from 5-chloro-2-(4-(2-furoyl)-piperazino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester.
Yield: 80.4 % of theory, M.p.: 93 - 95°C.
Calc.: C 62.97 H 5.28 M 8.47 CI 7.15 Found: 62.88 5.30 8.36 7.32 Example 210 4-/2-(5-Chloro-2-(4-(2-furoyl)-piperazino)-benzoylamino)-ethylTbenzoic acid ' Prepared analogously to Example 166 from 4-/5-(5-chloro-2-(4-(2-furoyl)-piperazino)-benzoylamino)-ethyl/benzoic acid methyl ester by alkaline saponification.
Yield: 26.4 % of theory, M.p.: 187 - 188°C.
Calc.: C 62.31 H 5.02 N 8.72 CI 7.36 Found: 62.08 4.95 8.56 7.61 Example 211 4-/5-(5-Chloro-2-(N-methyl-N-benzylamino)-ethyl/benzoic acid ethyl ester Prepared analogously to Example 165 from 5-chloro-2-(N-methyl- N-benzylamino) -benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 47 % of theory, M.p.: 93 - 95°C.
Calc.: C 69.25 H 6.03 N 6.21 CI 7.86 Found: 69.50 6.35 6.31 7.90 f 94 3 Example 212 4-/5- ( 5-Chloro-2- (N-methyl-N-benzylaaino ) -benzoylamino ) -ethvlTbenzoic acid • Prepared analogously to Example 166 from 4-/5-(5-chloro-2- (N-methyl-N-benzylamino ) -benzoylamino )-ethyl/benzoic acid ethyl ester by alkaline saponification* Yields 64.2 % of theory, M.p.: 127 - 128°C.
Calc.: C 68.16 H 5.48 N 6.62 CI 8.38 Found: 68.01 5.59 6.81 8*54 Example 213 4-/2- (2- ( 4-Ethoxycarbonyl-piperazino )-5-chloro-benzoyl-amino )-ethyl7benzolc acid ethyl ester Prepared analogously to Example 165 from 2-(4-ethoxycarbonyl-piperazino)-5-chloro-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 71.2 % of theory, M.p.: < 20°C.
Calc.: C 61.53 H 6.20 N 8.61 CI 7.26 Found: 61.78 6.30 8.23 7.21 Example 214 4-/5- (2- (4-Ethoxycarbonyl-piperazino )-5-chloro-benzoylamino)-ethylTbenzoic acid Prepared analogously to Example 166 from 4-/5- (2-(4-ethoxy-carbonyl-piperazino)-5-chloro-benzoylamino )-ethyl/benzoic acid ethyl ester by alkaline saponification. llfcCf - ipr - 1943 Yield: 93 % of theory, M.p.: 168 - 170°C.
Calc.: C 60.06 H 5.70 N 9.14 CI 7.71 Pound: 59.93 5.91 9.20 7.97 Example 215 4-/5- ( 5-Ethyl-2-piperidino-benzoylamino ) -ethyl/benzoic acid ethyl eater Prepared analogously to Example 217 from 6-ethyl-1-(5-bromo-pentyl)-4H-3,1-benzoxazine-2,4-(lH)-dione and 4-(2-amino-ethyl) -benzoic acid ethyl ester.
Yield: 55.6 % of theory, M.p.: £20°C.
Calc.: C 73.50 H 7.90 H 6.86 Pound: 73.26 7.88 6.97 Example 216 4-/5-(5-Ethvl-2-plperldlno-benzovlamlno)-ethvl7benzolc acid Prepared analogously to Example 166 from 4-/5-(5-ethyl-2-piperidino-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline saponification.
Yield: 84.5 % of theory, M.p.: 177°C.
Calc.: C 72.60 H 7.42 N 7.36 Found: 72.59 7.28 7.16 Example 217 K-&- (5-Methyl-2-piperidino-benzoylamino)-ethyl/benzoic acid ethvl ester .6 g (32.5 mmol) of 1-(5-bromo-pentyl)-6-methyl-4H-3»1-benz-oxazine-2,4-(1H)-dione /"prepared from 1,5-dibromopentane and 194317 I 6-methyl-4H-3f1-benzoxazine-2,4-(1H)-diong7 were stirred at room temperature In 100 ml of absolute dioxane with 19.3 g (0.1 mol) of 4-(2-amino-ethyl)-benzoic acid ethyl ester and 13 g of N-ethyl-diisopropylamine for 4 days. The reaction mixture was evaporated, mixed with water and extracted with chloroform. The dried chloroform extracts were evaporated and chromatographed on ^iiioa^el with toluene/ethyl acetate (10:1) as eluant.
Yield: 6.85 g (53.5 % of theory), M.p.: <20°C.
Calc.: C 73.07 H 7.66 N 7.10 Found: 72.62 7.15 7.12 Example 218 4-/2-(5-Methyl-2-plperldino-benzoylamino)-ethyl7benzolc acid Prepared analogously to Example 166 from 4-/2-(5-methyl-2-piperidino-benzoylamino)-ethyl7benzoic acid ethyl ester by alkaline saponification.
Yield: 80 % of theory, M.p.: 199 - 200°C.
Calc.: C 72.11 H 7.15 N 7.64 Found: 72.10 6.95 7.70 Example 219 4-/2-(5-Chloro-2-(4-p-chlorophenyl-piperazino)-benzoylamino)-ethvlTbenzolc acid ethvl ester Prepared analogously to Example 165 from 5-chloro-2-(4-p-chloro-phenyl-piperazino)-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 64.1 % of theory, M.p.: 153 - 155°C.
Calc.: C 63.88 H 5.55 N 7.98 CI 13.47 Found: 63.77 5.47 7.93 13.40 1943 17 Example 2,18 4-/5-(2-Piperidino-nicotlnoylaaino)-ethyl/benzoic acid ethvl ester Prepared analogously to Example 165 from 2-piperidino-nicotlnic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 70.3 % of theory, M.p.: 56 - 58°C.
Calc.: C 69.27 H 7.13 N 11.02 Found: 69.23 7.14 11.55 Example.221 4-/5- (2-Plperidino-nicotinovlaaino )-ethvlTbenzoic acid Prepared analogously to Example 166 from 4-/5-(2-piperidino- nicotinoylamino)-ethyl/benzoic acid ethyl ester by alkaline saponification.
Yield: 54.2 96 of theory, M.p.: 153 - 155°C.
Calc.: C 67.97 H 6.56 N 11.89 Found: 68.23 6.39 11.60 Example 222 4-/5-(2- Octamethylenimino-nicotinoylamino)-ethyl/benzoic acid methyl ester Prepared analogously to Example 165 from 2-octamethylenimino-nicotinic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester. Yield: 41 % of theory, M.p.: C20°C.
Calc.: C 69.84 H 7.39 N 10.63 Found: 70.02 7.51 10.42 I*?! Example 223 4-/?- (2-Octamethvlenlmlno-nlcotlnoylamino )-ethyl7benzoic acid Prepared analogously to Example 166 from 4-/2-(2-octamethylen-imino-nlcotinoylamino)-ethyl/benzoic acid methyl ester by alkaline saponification.
Yield: 63 96 of theory, M.p.: 179 - 181°C.
Calc.: C 69.84 H 7.39 N 10.63 Found: 70.02 7.51 10.42 Example 224 4-/2-(5-Chloro-2-(4-methyl-piperazino)-benzoylamino)-ethyl7-benzoic acid methyl ester Prepared analogously to Example 165 from 5-chloro-2-(4-methyl-piperazino )-benzoic acid hydrochloride and 4-(2-amino-ethyl)-benzoic acid methyl ester.
Yield: 52 % of theory, M.p.: *20°C.
Calc.: C 63.53 H 6.30 N 10.11 CI 8.52 Found: 63.62 6.05 10.23 8.28 Example 225 4-/2-(5-Chloro-2-piperidino-benzoylamino)-2-methyl-propyl7-benzoic acid ethyl efiter .
Prepared analogously to Example 165 from 5-chloro-2-piperidino-benzoic acid and 4-(2-amino-2-methyl-propyl)-benzoic acid ethyl ester hydrochloride (m.p.: 199°C).
Yield: 51 % of theory, M.p.: A 20°C.
Calc.: C 67.78 H 7.05 N 6.32 CI 8.00 Found: 67.75 6.91 6.05 7.87 ** 1rv3i7 Example 226 4-/5- ( 5-Chloro-2-piperidino-benzoylamino ) -2-methyl-propyl7-benzoic acid ' Prepared analogously to Example 166 from 4-/5-(5-chloro-2-piperidino-benzoylamino)-2-methylpropyl7benzoic acid ethyl ester by alkaline saponification.
Yield: 62 % of theory, M.p.: 208°C.
Calc.: C 66.58 H 6.56 N 6.75 C1 8.55 Found: 66.90 6.71 6.50 8.52 Example 227 4-/5-(5-Chloro-2-(1,2,3*4,5*6,7* 8-octahydro-isoqulnoline-2-yl)-benzoylamino)-ethvl7benzoic acid ethvl ester Prepared analogously to Example 165 from 5-chloro-2-(1,2,3*4-5,6,7,8-octahydro-isoquinoline-2-yl)-benzoic acid and 4-(2-amino-ethyl )-benzoic acid ethyl ester.
Yield: 58 % of theory, M.p.: c 20°C.
Calc.: C 69.44 H 6.68 N 5.99 CI 7.59 Found: 69.62 6.72 6.10 7.72 Example 228 4-/2-(5-Chloro-2-(1,2,3*4,5,6,7,8-octahydro-isoquinoline-2-yl)-benzoylamino)-ethvl7benzolc acid hydrochloride Prepared analogously to Example 166 from 4-/2-(5-chloro-2-(1,2,3,4,5.6,7,8-octahydro-isoquinoline-2-yl)-benzoylamino-ethyljbenzoic acid ethyl ester by alkaline hydrolysis.
Yield: 82 % of theory, M.p.: 220°C.
Calc.: C 63.15 H 5.93 N 5.89 CI 14.93 Found: 63.45 6.09 6.02 15.90 \Sp. - - 194317 Example 229 4-/5- ( 5-Chloro-2-octamethylenimino-benzoylamlno ) -ethyl7-benzoic acid methyl eater Prepared analogously to Example 165 from 5-chloro-2-octa-methylenlmino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid methyl ester.
Yield: 83 % of theory, M.p.: <20°C.
Calc. : C 67.78 H 7.05 N 6.32 CI 8.00 Found: 67.96 7.21 6.54 8.20 Example 230 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7- benzoic acid ethyl ester Prepared from 4-/5-(5-Chloro-2-octamethylenimino-benzoyl-amino)-ethyl/benzoic acid and absolute ethanol with stoichiometric amounts of thionyl chloride.
Yield: 86 % of theory, M.p.: < 20°C.
Calc.: C 68.33 H 7.27 N 6.13 CI 7.75 Found: 68.21 7.40 6.20 7.62 Example 231 4-/5- (5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/-benzoic acid cyclohexyl ester 3 g (7 mmol) of 4-/2-(5-chloro-2-octamethylenimino-benzoyl-amino)-ethyl7benzoic acid in 30 ml of absolute pyridine were converted at room temperature into the imidazolide by means of 1.2 g (7.4 mmol) of carbonyl diimidazole. After addition of 1.48 g (14.8 mmol) of cyclohexanol the reaction mixture was heated to JXttf boiling ftemperuluri/ for 2 to 3 hours. After distilling off the solvent the crude product was purified by NOV.., n 184317 Si hea chromatography over a ^ilicagel column by means of toluene/ ethyl acetate as eluant.
Yields 2.7 g (75 % of theory), M.p.: 88°C.
Calc.: C 70.50 H 7.70 N 5.48 CI 6.93 Found: 70.60 8.23 5.26 6.69 Example 232 4-/2- (5-Chloro-2-octamethylenimino-benzoylanino)-ethyl/benzoic acid tert.butyl ester 4.3 g (0.01 mol) of 4-/5-(5-chloro-2-octamethylenimino-benzoyl-amino)-ethyl/benzoic acid were suspended in 150 ml of Acetic/ peid^tert.butyl /eet^. After addition of 1.43 g (0.011 mol) of 70 # perchloric acid the reaction mixture was stirred for 24 hours at room temperature. The reaction mixture was taken up in 500 ml of chloroform and the chloroform solution was carefully extracted with water. The crude product obtained from the chloroform phase after drying over sodium sulfate siUcc*. oe ( was purified by chromatography over a jslllctrgoj. column by means of toluene/ethyl acetate as eluant.
Yield: 3 g (62 % of theory), M.p.: <20°C.
Calc.: C 69.33 H 7.68 N 5.77 CI 7.30 Found: 69.64 7.78 5.78 7.40 Analogously to jthej Examples 229 to 231 the following compounds were prepared: v J 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7- benzoic acid propyl ester Yield: 70 % of theory, m.p. : <, 20°C. 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/-benzoic acid isopropyl ester ^^T^rt;Yield: 84 % of theory, m.p.: 4. 20°C. ^ f ^0v'4_/J_(5-chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic 194317 acid butyl ester Yields 90 % of theory, m.p.s <20°C. 4-/5-(5-Chloro-2-octamethyleni«ino-benzoylaaino)-ethyl7- benzoic acid isobutyl ester Yields 74 % of theory, m.p. £20°C. 4-/5- ( 5-Chloro-2-octamethylenimino-benzoylamino ) -e thyl7~ benzoic acid hexyl ester Yield: 63 # of theory, m.p. s £20°C. 4- /?- (5-Chloro-2-oc tame thylenimino-benzoylamino ) -ethyl7- benzoic acid benzyl ester Yield: 83 % of theory, m.p.: ^20°C. i Example 233 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-«thyl7~ benzyl alcohol 4.57 g (0.01 mol) of 4-/5-(5-chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester were dissolved in 100 ml of absolute ether. This solution was added to a suspension of 0.72 g (0.011 mol) of lithium aluminium hydride in 30 ml of absolute ether and the reaction mixture was heated to^tfe^ boiling jtemperatur/ for 1 hour. After cooling 15 ml of water were added cautiously and the reaction mixture was filtered. The ether phase was dried over sodium sulfate and the crude s^//ccc Qe.( product was purified by chromatography over a allicagel column by means of toluene/ethyl acetate (1:1) as eluant.
Yield: 3.5 g (84 % of theory), M.p.: <20°C.
Calc.: C 69.46 H 7.52 N 6.75 CI 8.54 Found: 69.32 7.58 6.75 8.80 151 ") ■ ' " 194317 Example 234 4-/2- (5-Chloro-2-octamethylenimino-benzoylamino )-ethyl7-benzvl malonic acid diethyl ester A solution of 2.58 g (5.5 mmol) of 4-/J-(5-chloro-2-octa-methylenimino-benzoylamino)-ethyl7benzyl chloride hydrochloride (prepared from 2.3 g (5.5 mmol) of 4-/J-(5-chloro-2-octamethylen-imino-benzoylamino)-ethyl7benzyl alcohol and thionyl chloride in chloroform) in 25 ml of absolute ethanol was added drop-wisely to a solution of 3.2 g (20 mmol) of malonic acid diethyl ester and 20 mmol of sodium ethylate in absolute ethanol. Subsequently, the reaction mixture was refluxed for 4 hours, evaporated, acidified with diluted hydrochloric acid and extracted with chloroform. After evaporation of the extracts, the reaction product was purified by chromatography over a silica^ gel column with toluene/ethyl acetate (10:1).
Yield: 1.7 g (60.7 96 of theory), M.p.: 80 - 82°C.
Calc.: C 66.83 H 7.42 N 6.36 CI 5.03 Found: 66.83 7.51 6.62 5.07 Example 235 /2-(5-Chloro-2-octamethylenlmlno-benzoYlamino)-ethyl7benzene Prepared analogously to Example 165 from 5-chloro-2-octamethy-lenimino-benzoic acid and 2-phenyl-ethylamine.
Yield: 69 % of theory, M.p.: 66°C.
Calc.: C 71.76 H 7.59 N 7.17 CI 9.39 Found: 72.00 7.65 7.27 9.21 Example 236 4-/2-(5-»Chloro-2-piperidlno-benzoylamino)-ethyl7acetophenone cticJifcroetAasie ^ g (15 mmol) of aluminium chloride in 10 ml of jkichloro cthan^ \<A 194317 Were reacted with 0.6 g (7.6 mmol) of acetyl chloride whilst cooling. After addition of 1 .g (2.92 mmol) of /5-(5-chloro-2-piperidino-benzoylamlno)-ethyl7benzene the reaction mixture was stirred for 3 hours at 40 - 45^^ After evaporation the residue was mixed with ice-cold ftilutefl hydrochloric acid, extracted with chloroform and the extracts were dried over sodium sulfate and evaporated. The reaction product was purified SIIHM. fjeij by chromatography over £±ilcagel by means of chloroform/ethyl acetate (10:1) as eluant.
Yield: 0.42 g (37.4 % of theory), M.p.s - 61 - 63°C.
Calc.: C 60.65 H 6.55 N 7.28 CI 9.01 Found: 68.73 6.76 7.33 9.16 Example 237 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino )-ethyl7~ acetophenone hydrochloride ' Prepared analogously to Example 236 by reaction of /?-(5-chloro-2-octamethylenimino-benzoylamino)-ethyl/benzene with acetyl chloride in the presence of aluminium chloride.
Yield: 41 % of theory, M.p.: 160°C.
Calc.: C 64.79 H 6.96 N 6.04 CI 15.30 Found: 64.91 7.05 5.98 15.11 Example 238 4-/2-(5-Chloro-2-piperidino-benzoylamino)-ethyl/phenyl acetic acid 4.86 g (10 mmol) of 4-/?-(5-chloro-2-piperidino-benzoylamino)-ethyl/phenyl-thioacetic acid morpholide (m.p.: X.20°C, prepared from 4-/2-(5-chloro-2-piperidino-benzoylamino)-ethyl7acetophenone with sulfur and morpholine according to the method of Willgerodt) (C/L ->*- 194317 were boiled for 2 days in 50 ml of ethanol with 2 g (50 mmol) of sodium hydroxide. Subsequently, the reaction mixture was evaporated, mixed with water and extracted with ether. The aqueous phase was acidified, the formed precipitate was suction filtered and recrystallized from acetonitrile.
Yield: 0.96 g (24 % of theory), M.p.: 151°C.
Calc.: C 65.91 H 6.28 N 6.99 CI 8.84 Found: 65.61 6.34 7.18 8.77 Example 239 4- /5- (5-Chloro-2-octamethylenimino-benzoylamino ) -ethyl7-benzaldehyde ' A 0.3$ g (0.59 mmol) of N -&-(2-(5-chloro-2-octamethylenimino)- p benzoylamino)-ethyl)-benzoyl)-N -tosyl-hydrazine ( m.p.: 153 -158°C, prepared from 4-/5-(5-chloro-2-octamethylenimino-benzoylamino )-ethyl7benzoic acid and tosyl hydrazine with carbonyl diimidazole in tetrahydrofuran)were added to a suspension of 0.35 g of finely pulverized anhydrous sodium carbonate in 3.5 ml of ethylene glycol, heated in an oil bath up to 160 - 170°C. After 1.5 minutes (formation of gas was finished) the oil bath was removed. Some minutes later the reaction mixture was mixed with a lot of ice, extracted twice with ether and dried. The combined extracts were UJnC K'"-Pc+\ pcU.& filtered and evaporated in vacuo, jwhereby a flight yellow resinous oil was obtained. This oil was purified by chromatography over a cafe^L column by means of chloroform/ acetone (20:1) as eluant.
Yield: 66 % of theory, M.p.: £. 20°C.
Calc.: mol peak m/e » 412/414 (1 CI) Found: mol peak m/e = 412/414 (1 Cl) M.p. of the hydrochloride x 0.5 H20: 156°C.
Calc.: C 62.88 H 6.82 N 6.11 Cl 15.46 Found: 62.85 7.11 6.05 15.43 (t>° 194317 Example 240 4-/5- ( 5-Chloro-2-octame thylenimino-benzoylamino ) -ethyl7-benzaldehvde A solution of 0.50 g (1.2 mmol) of 4-/5-(5-chloro-2-octa-methylenimino-benzoylamino)-ethyl/benzyl alcohol in 75 ml of absolute acetone was shaked for 2 hours with 7.5 g of active manganese dioxide at room temperature. The reaction mixture was filtered over celite on a G4-frit and the filtrate .was evaporated in vacuo. The obtained brownish viscous oil was purified by chromatography over a column with chloroform/acetone (20x1) as eluant.
Yield: 5 % of theory, Mp.: £20°C.
Calc.: mol peak m/e « 412/414 (1 Cl) Found: mol peak m/e « 412/414 (1 Cl).
Example 241 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethy]J7benz-aldehyde diethyl acetal A mixture of 0.23 g (0.56 mmol) of 4-/5-(5-chloro-2-octamethy-lenimino-benzoylamino)-ethyl7benzaldehyde, 0.20 ml (1.2 mmol) of orthoformic acid/-triethyl ester, 0.02 g of ammonium chloride and 0.2 ml of anhydrous ethanol was heated for 30 minutes at 90°C. After cooling the mixture was poured into 2N-amBonia and extracted with ether. The extract was dried over sodium sulfate and evaporated in vacuo. The evaporation tUira gaj residue was purified by chromatography over a /allicaget column with toluene/acetone (10:1) as eluant.
Yield: 23 % of theory, M.p.: <20°C.
—Calc.: mol peak m/e « 486/488 r: ' Found: mol peak m/e - 486/488. 194317 f.r-- 4-/2- (5-Chloro-2-octamethylenimino-benzoylamino ) -ethyl7-cinnamic acid - A mixture of 1 g (2.4 mmol) of 4-/5-(5-chloro-2-octamethylen-imino-benzoylamlno)-ethyl7benzaldehyde and 1 g (10 mmol) of malonic acid was heated in 10 ml of absolute pyridine for 1 hour up to 100°C after adding 0.5 ml of piperidine. Ice-cold ftilut&d hydrochloric acid was added and the formed precipitate was suction filtered. The praoipitata was purified by chromatography over silica gel with toluene/ethyl acetate (1:1) as eluant.
Yield: 21 % of theory, M.p.: 9CPC.
Calc.: C 68.63 H 6.87 N 6.16 Cl 7.79 Found: 68.69 6.82 6.10 7.83 Example 243 4-/2-(5-Chloro-2-piperidino-benzoylamino)-ethyl7benzoylacetic acid ethvl ester Prepared analogously to Example 236 by acylation of /?-(5-chloro-2-piperidino-benzoylamino)-ethyl/benzene with malonic acid ethyl ester according to the method of Friedel-Crafts.
Yield: 21 % of theory, M.p.: <20°C.
Calc.: m/e 456/458 (1 Cl) Found: m/e 456/458 (1 Cl).
Example 244 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7nitro benzene Prepared analogously to Example 165 from 5-chloro-2-octamethy-lenimino-benzoic acid and 4-(2-amino-ethyl)-nitro^benzene.
Yield: 85 % of theory, |6x ~ l-ef " 194317 M.p.! 102°C.
Calc.: C 64.25 H 6.56 N 9.77 Cl 8.24 Found: 64.45 6.57 9.73 8.24 Example 245 4- /2- (5-Chlor o-2-octamethvleninino-benzovlamino)-ethvl7anlline Prepared from 4-/2- (5-chloro-2-octamethylenimino-benzoylamino) ethyl7nltro/benzene by reduction with tin-(lI)^chloride In hydrochloric acid.
Yield: 74 % of theory, M.p.: 87°C.
Calc.: C 69.07 H 7.56 N 10.50 Cl 8.86 Found: 69.10 7.77 10.61 9.10 Example 246 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7toluene hydrochloride Prepared analogously to Example 165 from 5-chloro-2-octamethy-lenimino-benzoic acid and 4-(2-amino-ethyl)-toluene.
Yield: 69 # of theory, M.p.: 167 - 171°C.
Calc.: C 66.20 H 7.41 N 6.44 Cl 16.29 Found: 66.78 7.39 6.87 15.90 Example 247 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7chloro- benzene ■ Prepared analogously to Example 165 from 5-chloro-2-octamethy-lenimino-benzoic acid and 4-(2-amino-ethyl)-chlorobenzene. Yield: 66 96 of theory, M.p.: 58°C.
Calc.: C 65.87 H 6.73 N 6.68 Found: 65.99 6.55 6.51 - Ikp— 194317 Example 248 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7-benzoic acid nitrile ' 4.36 g (0.01 mol) of 4-/5-(5-chloro-2-octamethylenimino-benzoylamino)-ethyl/aniline were dissolved in 3*8 nl of conc. hydrochloric acid. The solution was diluted with 28 ml of water and diazotized at 0° by dropwise addition of a solution of 0.76 g (0.011 mol) of sodium nitrite in 3 ml of water. After stirring for 30 minutes the reaction mixture was adjusted to pH 6 by means of sodium carbonate.
The, diazonium salt solution was added dropwise at 0°C to ' -M a £ewly prepared solution of trisodium-tetracyano-copper-(I)fcomplex.
/This complex solution was prepared from 3*2 g (0.0128 mol) of copper sulfate x 5 1^0 and 0.87 g of sodium chloride, dissolved in 10 ml of water. After reduction to the copper-(I)^chloride with a solution of 0.66 g of sodium sulfite and 0:44 g of sodium hydroxide in 5 ml of water, the washed copper-(I)^chloride was added to a solution of 1.7 g of sodium cyanide in 30 ml of water7. h-HS-necs After finished! nitrogen formation/jthe reaction mixture was warmed for 1 hour up to 70°C. After cooling the reaction mixture was extracted with chloroform at a pH value of 8. The crude product obtained from the chlorofdrm extracts was purified over a silica gal column (eluant: toluene/ethyl acetate « 8:2) Yield: 38 % of theory, M.p.: 102°C.
Calc.: C 70.31 H 6.88 N 10.25 Cl 8.64 Found: 70.50 6.59 10.45 8.92 Example 249 4-/2-(5-Chloro-2-oct;imethylenimino-benzoylamino)-ethyl7ortho-benzolc acid ethyl eater " •jEquimolar amounts of 4-/5-(5-chloro-2-octamethylenimino-benzoyl aminoj-ethyl/benzoic acid nitrile and absolute ethanol were /saturated with hydrogen chloride in ether. The reaction mixture was allowed to rest for 4 days at 4°C, whereby the imino ether precipitated as hydrochloride, partly in oily and partly in crystalline form. After decanting the solvent and washing with ether an excess of absolute ethanol was added at 4°C and the reaction mixture was left standing for 2 days at this temperature. After distilling off the solvent, the crude product was purified by chromatography over a silica gel column with toluene as eluant.
Yield: 30 % of theory, M.p.: 4L20oC.
Calc.: C 67.84 H 8.16 N 5.27 Cl 6.67 Found: 67.60 8.05 5.14 6.43 Example 250 4-/5- ( 5-Chloro-2-octamethylenimino-benzoylamino )-ethyl/-benzolc acid morphollde 2 g (4.7 mmol) of 4-/5-(5-chloro-2-octamethylenimino-benzoyl-amino)-ethyl/benzoic acid were dissolved in 20 ml of absolute pyridine and converted quantitatively into the imidazolide by addition of 0.83 g (5.1 mmol) of carbonyl diimidazole at room temperature. After addition of 0.41 g of morpholine the reaction mixture was refluxed for 6 hours. Subsequently, the pyridine was distilled off and the evaporation residue was purified by chromatography over a silica gel column with toluene/ethyl acetate (6:4) as eluant.
Yield: 1.8 g (76.5 % of theory), M.p.: <■ 20°C.
Calc.: C 67.52 H 7.29 N 8.44 Found: 67.01 7.35 8.17 Example 251 4-/5- (5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/-benzoic acid piperidlde 2 g (4.7 mmol) of 4-/5-(5-chloro-2-octamethylenimino-benzoyl- 194317 amino)-ethyl/benzoic acid were suspended In 30 ml of absolute toluene and converted by means of 0.65 ml of triethylamine Into the salt. After cooling to -10°C, 0.5 g (4.7 mmol) of ethyl chloroformate were added and the mixture was stirred for 30 minutes. Subsequently, 0.4 g (4.7 mmol) of plperldlne were added to the farmed anhydride. After 2 hours the solvents were distilled off and the crude product was purified by chromatography over a silica gel column with ethyl acetate as eluant.
Yield: 2 g (86 % of theory), M.p.: < 20°C.
Calc.: C 70.21 H 7.72 N 8.47 Found: 70.42 7.83 8.51 Analogously to^tKe^Examples 250 and 251 the following compounds were prepared: 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid amide Yield: 75 # of theory, m.p.: 122°C.
Calc.: C 67.35 H 7.07 N 9.82 Found: 67.95 7.48 9.78 4-/?-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid dipropylamide Yield: 75 % of theory, m.p.: <, 20°C.
Calc.: C 70.35 H 8.27 N 8.21 Found: 69.95 8.04 7.94 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid diallylamide Yield: 70 56 of theory, m.p.: <20°C.
Calc.: C 70.90 H 7.54 N 8.27 Found: 70.23 7.30 7.98 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid thiomorpholide ;Yield: 70 % of theory, m.p.: <20°C.
" Calc.: C 65.41 H 7.06 N 8.17 ^^Found: 65 • 54 7-14 7.93 \\ob - y&s - i 943 1 7 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid-N-methyl-piperazide Yield: 75 % of theory, m.p.: 4,20°C.
Calc.: C 68.15 H 7.69 N 10.96 Found: 68.23 7.73 11.08 4-/2- (5-Chloro-2-octamethylenimino-benzoylamino ) -ethyl/benzoic acid-N-ethyl-N-cyclohexylamide Yield: 58 % of theory, a.p.: < 20°C.
Calc.: C 71.42 H 8.24 N 7.81 Found: 71.60 8.30 7.57 4-/2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid isopropylamide Yield: 54 % of theory, m.p.: 171°C Calc.: C 68.99 H 7.72 N 8.94 Found: 69.34 7.52 8.74 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid butylamide Yield: 53 % of theory, m.p.: 163°C.
Calc.: C 69.47 H 7.91 N 8.68 Found: 69.53 7.95 8.72 Example 252 1 ? N -(1-(4-Ethoxycarbonyl-phenyl)-ethyl)-N -(5-chloro-2-piperi- dino-benzovl)-hydrazine A mixture of 2.4 g (10 mmol) of 5-chloro-2-piperidino-benzoic acid and 15 ml of anhydrous tetrahydrofuran was reacted with 1.62 g (10 mmol) of N,N-carbonyl diimidazole. The reaction mixture was stirred for 5 minutes at 20°C and then was refluxed for 45 minutes. The solution was cooled and at 20°C a solution of 2.08 g (10 mmol) of 4-(l-hydrazine-ethyl)-benzoic acid ethyl ester (freshly prepared from the corresponding quantity of 4-(1-hydrazino-ethyl)-benzoic acid ethyl ester hydrochloride of 1943 1 7 m.p.: 98 - 100°C by reaction with the stoichiometric amount of aqueous sodium hydroxide solution with ice cooling, extraction with chloroform and evaporation of the dried chloroform extract at 30°C in vacuo7 in 9 ml of anhydrous tetrahydrofuran was added. After stirring over night at room temperature the reaction mixture was evaporated in vacuo and the residue was distributed between water and chloroform. The combined chloroform extracts were dried and filtered and the filtrate was evaporated in vacuo. The red-brown oily evaporation residue was purified by chromatography over a silica gel column with toluene/acetone (8:1) as eluant.
Yield: 41.9 % of theory, M.p.: 20°C (slight yellow oil).
Calc.: mol peak m/e ■ 429/431 (1 Cl) Found: mol peak m/e » 429/431 (1 Cl).
Example 253 N1' -(1-(4-Ethoxycarbonyl-phenyl)-ethyl)-N^-(5-chloro-2-dimethyl-amino-benzovl)-hydrazine Prepared analogously to Example 252 from 5-chloro-2-dimethyl-amino-benzoic acid, carbonyl diimidazole and 4-(1-hydrazino-ethyl)-benzoic acid ethyl ester in ianhydrous tetrahydrofuran.
Yield: 18 % of theory, M.p.: < 20°C.
Calc.: mol peak m/e « 389/391 (1 Cl) Found: mol peak m/e ■ 389/391 (1 Cl).
Example 254 -(1-(4-Carboxyphenyl)-ethyl)-N^-(5-chloro-2-piperidino-benzoyl)-hydrazine A mixture of 1.8 g (4.2 mmol) of N1-(1-(4-ethoxycarbonyl-phenyl)- p ethyl)-N-(5-chloro-2-piperidino-benzoyl)-hydrazine and 0.20 g l&L 1^43 1 of (5 mmol) of sodium hydroxide was stirred for 5 hours at 60°C in 8 ml of ethanol and 8 ml of water. After removing the ethanol in vacuo the reaction mixture was adjusted to pH 6 by means of 2N hydrochloric acid and extracted several times with ethyl acetate. The combined extracts were washed with water, dried over sodium sulfate, filtered and evaporated in vacuo. The solid evaporation residue was recrystallized from methanol.
Yield: 45.8 % of theory, M.p.: 212 - 215°C.
Calc.: C 62.76 H 6.02 N 10.45 Pound: 62.90 6.07 10.44 Example 255 N^-(1-(4-Carboxyphenyl)-ethyl)-N^-(5-chloro-2-dimethylamino-benzovl)-hydrazine Prepared analogously to Example 254 from N -(1-(4-ethoxycarbo-nyl-phenyl)-ethyl)-N -(5-chloro-2-dimethylamino-benzoyl)-hydrazine by saponification with sodium hydroxide.
Yield: 34.4 # of theory, M.p.t 210 - 212°C Calc.: C 59.75 H 5.57 H 11.61 Found: 59.32 5.60 11.41 Example 256 4-/T-(5 -Chloro-2-octamethylenimino-benzoylaminoxy)-ethyl/benzoic acid methyl ester A mixture of 2 g (7.1 mmol) of 5-chloro-2-octamethylenimino-benzoic acid and 1.2 g (7.4 mmol) of carbonyl diimidazole was stirred for 40 minutes at 20°c in 10 ml of anhydrous pyridine. 1.4 g (7.2 mmol) of 4-(1-aminoxy-ethyl)-benzoic acid methyl ester /&esWy prepared analogously to Example 252 from 4-(l-ami-noxy-ethyl)-benzoic acid methyl ester hydrochloride of m.p. 158 - 160°C7 were added and the mixture was stirred over night ~J^2 " 1 at 100°C. After evaporation In vacuo to dryness the residue was purified by chromatography over a silica gel column with toluene/ethyl acetate (9:1) as eluant.
Yield: 41 96 of theory, M.p.: < 20°C.
Example 257 4- ( 5-Chloro-2-octamethylenimino-benzoylaminoxy-methyl) -benzoic acid methyl ester Prepared analogously to Example 256 from 5-chloro-2-octamethy-lenimino-benzoic acid, carbonyl-dl imidazole and 4-(aminoxy-methyl) -benzoic acid methyl ester freshly prepared from the hydrochloride of m.p. 252 - 255°C/ ^ anhydrous pyridine. Yield: 38 % of theory, M.p.: <.20°C.
Calc.: mol peak m/e * 444/446 (1 Cl) Found: mol peak m/e ■ 444/446 (1 Cl).
Example 258 4-/T- (5-Chloro-2-dimethylamino-benzoylaminoxy) -ethyl/benzoic acid methyl ester Prepared analogously to Example 256 from 5-chloro-2-dimethyl-amino-benzoic acid, carbonyl diimidazole and 4-(1-aminoxy-ethyl)-benzoic acid methyl ester, but in anhydrous tetrahydrofuran at 20°C and a reaction time of 16 hours.
Yield: 59 % of theory, M.p.; <20°C. no 1^431 Example 259 ' 4-/T-(5-Chloro-2-(cis-3,5-dinethyl-piperidino)-benzoylaminoxy)-ethvi7benzoic acid methyl eater Prepared analogously to Example 256 from 5-chloro-2-(cie-3,5-dimethyl-piperidino)-benzoic acid, carbonyl diimidazole and 4-(1-aminoxy-ethyl)-benzoic acid methyl ester.
Yield: 85 % of theory, M.p.: <20°C.
Example 260 4-/T- ( 5-Chloro-2-piperidino-benzoylaminoxy)-ethyl/benzoic acid methyl ester A mixture of 7.55 g (25.8 mmol) of 5-chloro-2-piperidino-benzhydroxamic acid potassium salt (m.p. 153°C, (decomp.)) and 6.30 g of 4-(1-bromo-ethyl)-benzoic acid methyl ester was stirred for 18 hours at 20°C in 20 ml of dimethyl formamide. Subsequently, the reaction mixture was mixed with the 3-fold quantity of water and extracted with ether. The ether extract was dried and filtered and the filtrate was evaporated in vacuo. The evaporation residue was purified by chromatography over a silica gel column with cyclohexane/ ethyl acetate (1:1) as eluant.
Yield: 69.2 % of theory, M.p.: < 20°C.
Calc.: C 63.37 H 6.04 Cl 8.50 N 6.72 Found: 63.54 6.17 8.49 6.63 Example 261 4-(5-Chloro-2-dimethylamino-benzoylaminoxy-methyl)-benzoic acid 4.2 g (19 mmol) of 4-bromo-methyl-benzoic acid were added to a mixture of 4.8 g (19 mmol) of 5-chloro-2-dimethylamino-benz-hydroxamic acid potassium salt (m.p. 140°C, (decomp.)) and 1.06 g (19 mmol) of potassium hydroxide in 50 ml of ethanol/ 194317 water (1:1) and the mixture was refluxed for 6 hours. After evaporating in vacuo the evaporation residue was dissolved In water by addition of potassium hydroxide solution. After extraction with ethyl acetate the aqueous phase was adjusted to pH 7 and again extracted with ethyl acetate. This ethyl acetate extract was dried and filtered and evaporated in vacuo. The evaporation residue was purified twice by chromatography over a silica gel column with chloroform/methanol (9:1 and 4:1) as eluant. The uniform fractions were combined and evaporated and the evaporation residue was partitioned between water and ethyl acetate. The ethyl acetate extract was evaporated in vacuo and a colorless oil was obtained, which crystallized when flrlLuraling with ether.
Yield: 1.5 % of theory, M.p.: 160 - 161°C.
Calc.: C 58.53 H 4.91 N 8.03 Found: 58.49 5.10 7.88 Example 262 4-/T-(5-Chloro-2-piperldlno-benzovlamlnoxv)-ethvl7benzolc acid A solution of 6.0 g (14.4 mmol) of 4-/T-(5-chloro-2-piperidino-benzoylaminoxy)-ethyl7benzoic acid methyl ester and 1.15 g (28.8 mmol) of sodium hydroxide was heated in 100 ml of ethanol for 6 hours at 50 - 60°C. After evaporating in vacuo the residue was distributed between /diitrfced hydrochloric acid and chloroform. The chloroform extract was dried and filtered and the filtrate was evaporated in vacuo. The evaporation residue was re-crystallized from a chloroform/methanol mixture by addition of petroleum ether.
Yield: 44.8 % of theory, M.p.: 201 - 203°C.
Calc.: C 62.61 H 5.76 Cl 8.80 N 6.96 Found: 62.68 5.67 8.76 6.96 t] vf f fee; 1943 Example 263 4-/T-(5-Chloro-2-dime thylaailno-benzoylaminoxy)-ethyl/benzoic acid • Prepared analogously to Example 252 from 4-/T-(5-chloro-2-di-methylamino-benzoylaminoxy)-ethyl/benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/water. The reaction mixture Was, however, extracted with ethyl acetate and recrystallized from ethanol.
Yield: 65.7 % of theory, M.p.: 202 - 205°C.
Calc.: C 59.58 H 5.28 Cl 9.77 N 7.72 Pound: 59.70 5.34 10.00 7.90 Example 264 4-/T- (5-Chloro-2-(ci s-3,5-dimethyl-piperidino)-benzoylaminoxy)-ethvlTbenzoic acid Prepared analogously to Example 252 from 4-/T-(5-chloro-2-(cis-3,5-dimethyl-piperidino)-benzoylaminoxy)-ethyl/benfeoic acid methyl ester by saponification with sodium hydroxide in ethanol/water.
Yield: 63.8 % of theory, M.p.: 205 - 208°C.
Calc.: C 64.10 H 6.32 Cl 8.23 N 6.50 Found: 64.40 6.66 8.44 6.50 Example 265 4-(5-Chloro-2-octame thylenimino-benzoylaminoxy-methyl)-benzoic acid Prepared analogously to Example 252 from 4-(5-chloro-2-octa-methylenimino-benzoylaminoxy-methyl)-benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/water. ^6 1943 1 Yield: 43.1 % of theory, M.p.: 135 - 138°C (from ether).
Calc.: C 64.10 H 6.32 Cl 8.23 N 6.50 Found: 64.29 6.29 8.33 6.73 Example 266 4-/T- (5-Chloro-2-oc tamethylenimino-benzoylaminoxy) -ethyl/-benzoic acid Prepared analogously to Example 252 from 4-/T-(5-chloro- 2-octamethylenimino-benzoylaminoxy)-ethyl7benzoic acid methyl ester by saponification with sodium hydroxide in ethanol/ water.
Yield: 69 % of theory, M.p.: 187 - 190°C.
Calc.: C 64.78 H 6.57 Cl 7.97 N 6.30 Found: 64.60 6.58 7.88 6.16 Example 267 3-/5-/5- (5-Chloro-2-piperidino-benzoylamino )-ethyl/phenyl/-propionlc acid ethvl ester 0.5 ml (5 mmol) of carbon tetrachloride and subsequently 2.45 ml (17.5 mmol) of triethylamine were added to a mixture of 1.2 g (5 mmol) of 5-chloro-2-piperidino-benzoic acid, 1.5 g (5.8 mmol) of 3-/5- (2-amino-ethyl )-phenyl7propionic acid ethyl ester hydrochloride and 1.84 g (7 mmol) of triphenylphosphine in 30 ml of absolute acetonitrile. The reaction was stirred for 20 hours at room temperature, the precipitate was filtered off and the filtrate was evaporated. The evaporation residue was purified by chromatography over a silica gel column with toluene/ethyl acetate (5:1) as eluant.
Yield: 1.2 g (54.5 % of theory), M.p.: C20°C.
Calc.: C 67.78 H 7.05 N 6.32 Cl 8.00 Found: 67.33 6.91 6.16 8.09 i-T-K -yt - 1943 1 7 Example 268 3- /5- /5- ( 5-Chloro-2-piperidino-benzoylamino ) - e thy 17phenyl/-propionic acid Prepared analogously to Example 166 by saponification of 3-/5-/5- (5-chloro-2-piperidino-benzoylamino )-ethyl7phenyl7-proplonlc acid ethyl ester.
Yields 80 % of theory, M.p.s 139°C.
Calc.s C 66.57 H 6.56 N 6.75 Cl 8.54 Founds 66.51 6.62 6.60 8.40 Example 269 3-/5- /5- (5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7~ phenvl7proplonlc acid ethyl ester ' Prepared analogously to Example 267 from 5-chloro-2-octamethylen-imino-benzoic acid and 3-/5-(2-amino-ethyl)-phenyl/propionic acid ethyl ester hydrochloride.
Yields 76 96 of theory, M.p. s < 20°C.
Calc.s C 69.33 H 7.69 N 5.78 Cl 7.31 Founds 69.22 7.59 5.66 7.26 Example 270 3-/5-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethy17-phenvl7proplonlc acid Prepared analogously to Example 166 from 3-/5-/5- (5-chloro-2-octamethylenimino-benzoylamino)-ethyl7phenyl7propionic acid ethyl ester by alkaline saponification.
Yield: 79 % of theory, - I 9 4 "6 1 7 M.p.i 92 - 94°C.
Calc.s C 68.33 H 7.28 N 6.13 Cl 7.76 Found: 68.54 7.38 6.28 7.81 Example 271 4-/5-(2-Piperidino-5-propyl-benzoylamino)-ethyl/benzoic acid ethvl ester | Prepared analogously to Example 217 from 1-(5-bromo-pentyl)-6-propyl-4H-3,1-benzoxazine-2,4-(lH)-dione and 4-(2-amino-ethyl )-benzoic acid ethyl ester.
Yield: 41 % of theory, M.p. : < 20°C.
Calc.: C 73.90 H 8.11 N 6.63 Found: 73.45 7.92 6.42 Example 272 4-/5-(5-Butyl-2-piperidino-benzoylamino)-ethyl/benzoic acid ethvl ester " Prepared analogously to Example 217 from 6-butyl-1-(5-bromo-pentyl )-4H-3,1-benzoxazine-2,4-(1H)-dione and 4-(2~amino-ethyl)-benzoic acid ethyl ester.
Yield: 59 % of theory, M.p.: 4.20°C.
Calc.: C 74.28 H8.31 N 6.42 Found: 73.90 8.05 6.13 1 r> /i i I if x" Example 273 4-/5- (4-Chloro-5-nitro-2-piperidino-benzoylamino) -ethyl/~ benzoic acid ethyl ester Prepared analogously to Example 165 froa 4-chloro-5-nitro- 2-piperidino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yield: 20 % of theory, M.p.: <20°C.
Calc.: C 60.06 H 5.70 N 9.13 Cl 7.70 Found: 60.20 5.78 9.25 7.85 Example 27*4 4-/5- (5-Chloro-2-octamethylenimino-benzoylamino )-ethyl/benzoic acid A mixture of 0.45 g (1 mmol) of 4-/5-(5-chloro-2-octamethylen-imino-benzoylamino)-ethyl/benzaldehyde hydrochloride, 5.al of 0.5 N-sodium hydroxide solution and 0.30 g (1.3 mmol) of silver oxide was heated on a steam bath whilst heavy stirring for 45 minutes. After cooling the reaction mixture was acidified with 2N-sulfuric acid and extracted with ether. The organic phase was dried, filtered and evaporated in vacuo. The evaporation residue was purified by chromatography over a silica gel column with chloroform/methanol (10:1).
Yield: 34 96 of theory, M.p.: 172°C.
Example 275 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/-benzoic acid sodium salt g (11.7 mmol) of 4-/5-(5-chloro-2-octamethylenimino-benzoyl-amino)-ethyl/benzoic acid were dissolved in 20 ml of absolute tetrahydrofuran. The solution was mixed with a sodium ethylate solution, which was prepared from 0.27 g (11.7 mmol) of sodium 4 . fH_ 194317 i i uJ\<ere<4f<yr\ and 10 ml of ethanol, jWhereby the sodium salt was precipitated.
After addition of 80 ml of ether the reaction mixture was stirred for 1 hour, suction filtered and dried at 80°C in a circulation air drier.
Yields 4.5 g (85 % of theory), M.p.s 290°C.
Calc.s C 63.92 H 6.26 N 6.21 Founds 63.90 6.35 6.18 Example 276 4-/?-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7-benzoic acid hydrochloride g (11.7 mmol) of 4-/?-(5-chloro-2-octamethylenimino-benzoyl-amino)-ethyl/benzoic acid were hot dissolved in 150 ml of acetone. The solution was filtered and the hydrochloride was precipitated by means of isopropanolic hydrochloric acid.
Yields 5 g (92 % of theory), M.p.s 205°C.
Calc.s C 61.93 H 6.50 N 6.01 Cl 15.23 Founds 62.10 6.86 6.24 14.85 Example 277 4-/2-(5-Ethyl-2-octamethylenimino-benzoylamin©)-®thyl7benzoic acid ethvl ester Prepared analogously to Example 165 from 5-ethyl-2-octamethylen-imino-benzoic acid and 4-(2-amino-ethyl)-benzoic acid ethyl ester.
Yields 78 % of theory, A M.p.: 4. 20°C.
~ Calc.: C 74.63 H 8.50 N 6.22 Founds 74.41 8.10 6.01 ) "7 $ - Jn - 194317 Example 278 4-/2- (5-Ethyl-2-octamethylenlaino-benzoylaaino)-ethyl/benzoic acid Prepared analogously to Example 166 froa 4-/2-(5-ethyl-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester by alkaline saponification.
Yield: 85 % of theory, M.p.: 145°C.
Calc.: C 73.90 H 8.11 N 6.63 Found: 74.15 8.15 6.42 Example 279 4-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl/benzoic acid ethyl ester , .6 g (0.02 mol) of 5-chloro-2-octamethylenimino-benzoic acid in 50 al of absolute toluene were reacted with 2 g (0.02 mol) of triethylamine and subsequently converted at -5°C to the mixed anhydride by means of 2,2 g (0.02 mol) of ethyl chloro-formate. After stirring for 30 minutes a solution of 4-(2-ami no-ethyl)-benzoic acid ethyl ester in 30 ml of chloroform was added. The solution was prepared from 4.59 (0.02 mol) of 4-(2-amino-ethyl)-benzoic acid ethyl ester hydrochloride and |fehe equimolar quantity of 2 g (0.02 mol) of triethylamine. After stirring for 3 hours at room temperature, hydrochloric acid was added, the organic phases were separated and dried over sodium sulfate. After distilling off the solvent the 4-(2-ethoxycarbonylamino-ethyl)-benzoic acid ethyl ester formed CL pro cCu c-i- as ftide1 'product was separated on a silica gel column with toluene/ethyl acetate (9:1) as eluant.
Yield: 1.6 g (18 % of theory), M.p. : < 20°C.
Calc.: C 68.33 H 7.28 N 6.13 Found: 68.62 7.25 5.90 pc' ~ l-#2 ~ 104317 Example 280 4-/5- (5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7-benzolc acid .6 g (0.02 mol) of 5-chloro-2-octamethylenimino-benzoic acid In 50 ml of absolute toluene were reacted with 2 g (0.02 mol) of triethylamine and subsequently converted at -5°C to the mixed anhydride by means of 2.2 g (0.02 mol) of ethyl chloroformate. After stirring for 30 minutes a solution of 3.3 g (0.02 mol) of 4-(2-amino-ethyl) -benzoic acid in 20 ml of 1N sodium hydroxide solution was added and the reaction mixture was stirred for 4 hours at room temperature. Subsequently, 30 ml of water were added, the organic phase was separated and again extracted with chloroform. From the aqueous phase the acid was precipitated by acidifying with 1N hydrochloric acid to pH 5.5. The obtained acid was recrystallized from ethyl acetate and a yield of 1.2 g (14 % of theory) was obtained.
M.p.: 172°C.
Calc.: C 67.20 H 6.81 N 6.53 Found: 66.92 6.77 6.43 Example 281 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7-benzolc acid 8.87 g (12.6 mmol) of copper-(II)^di-/^-chloro-2-octamethylen-imino-benzoate7dihydrochloride (prepared from 5-amino-2-octamethylen-benzoic acid via the diazonium salt with copper-(i)^-chloride, m.p. 177 - 178°C) were dissolved in 25 ml of absolute pyridine. Whilst ice-cooling 3 g (25.3 mmol) of thio-nyl chloride were added dropwise, -eo that the temperature remains at 20 - 30°C. After stirring for 30 minutes 4.9 g (25.3 mmol) of 4-(2-amino-ethyl)-benzoic acid ethyl ester, dissolved in 5 ml of absolute pyridine, were added and the ^reaction mixture was warmed for 3 hours up to 70°C. After 1Q4317 distilling off the pyridine, the residue was dissolved in a mixture of 50 ml of methanol and 50 ml of dioxane and the solution was stirred for 16 hours at room temperature after addition of 4.6 g of potassium hydroxide, dissolved in 90 ml of water. Subsequently, the solvents were distilled off, the evaporation residue was dissolved in 140 ml of water and after adjusting to a pH of 5*5, the product was precipitated and recrystallized from ethyl acetate.
Yield: 4.1 g (38 % of theory), M.p.: 172°C.
Calc.:, C 67.20 H 6.81 N 6.52 Cl 8.26 Found: 61.10 6.72 6.45 8.20 Example 282 4-/2-(5-Chloro-2-octamethylenimino-benzoylaminoJ-ethyl/-benzoic acid ethvl ester .5 g (15 mmol) of copper-(II)^di-/5-chloro-2-octamethylen-imino-benzoate7dihydrochloride-complex (prepared from 5-amino-2-octamethylenimino-benzoic acid via the diazonium salt and copper-(I)^chloride, m.p. 177 - 178°C) in 25 ml of absolute pyridine were reacted with 5.4 g (33 mmol) of carbonyl diialda zole, wher€bycarbon dioxide was formed. After stirring for 30 minutes at room temperature 6.8 g (35 mmol) of 4-(2-amino-ethyl) -benzoic acid ethyl ester, dissolved in 5 ml of absolute pyridine, were added and the reaction mixture was heated for 3 hours up to 70°C. After distilling off the pyridine, the residue was dissolved in water and extracted at pH 4 by means of chloroform. The chloroform extracts were dried over sodium sulfate and evaporated. . The residue was purified by chromatography over a silica gel column with toluene/ethyl acetate as eluant.
Yield: 10 g (66 J6 of theory), M.p.: < 20°C.
Calc.: C 68.33 H 7.28 N 6.13 Cl 7.75 Found: 68.30 7.22 5.91 7.66 «l - 194317 Example 283 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7- benzolc acid 8.4 g (0.02 mol) of 4-/5-(5-chloro-2-octamethylenimino-benzoylamino )-ethyl7chloro benzene (m.p.: 58°C) were dissolved in 80 ml of tetrahydrofuran. The solution was cooled to -60°C and 18 ml (0.04 mol) of a pre-cooled molar solution of n-butyl-lithium in hexane were added under nitrogen frtmospher^f. After 15 minutes this reaction mixture was added to approx. 10 g of finely pulverized carbon dioxide under nitrogen ^teeaosphep^. After warming to room temperature the reaction mixture was evaporated and the evaporation residue was dissolved in water. The product was adjusted to pH 5.5 and precipitated in water. After recrystallization from ethyl acetate the product was purified chromatographically.
Yield: 1 g (12 % of theory), M.p.» 172°C.
Calc.: C 67.20 H 6.81 N 6.52 Cl 8.26 Found: 67.00 6.72 6.46 8.19 Example 284 4-/5-(5-Chloro-2-octamethylenamino-benzoylamino)-ethyl/-benzolc acid 7.6 g (0.06 mol) of oxalyl chloride were added dropwisely at 0 to 5°C to a solution of 11.5 g (0.03 mol) of 2-(5-chloro-2-octamethylenimino-benzoylamino)-ethylbenzene in 50 ml of carbon disulfide. Subsequently, 8 g (0.06 mol) of aluminium chloride were added and after stirring for 1 hour again the same quantities of oxalyl chloride and aluminium chloride were added. The reaction mixture was heated for 2 to 3 hours up to 50°C. Then the cooled solution was mixed with ice water ^ _ hydrochloric acid and extracted with chloroform.
?,A'C>v £3t>^ * * <.
|£Z- hop 194317 The dried evaporation residue was recrystallized twice from ethyl acetate by adding charcoal.
Yields 2.4 g (19 % of theory), M.p.s 172°C.
Calc.s C 67.20 H 6.81 N 6.52 Cl 8.26 Found: 67.11 6.45 6.45 8.19 Example 285 4-/?-(5-Chloro-2-plperldlno-benzoylamino)-ethyl7benzolc acid A solution of 0.60 g (1.56 mmol) of 4-/5-(5-chloro-2-piperidino-benzoylamino)-ethyl7acetophenone in 6 ml of dioxane was added dropwisely within 15 minutes at 35 - 40°C to a stirred sodium hypobromite solution (prepared from 0.92 g (23 mmol) of sodium hydroxide, dissolved in 4.5 ml of water, and from 0.36 ml (7 mmol) of bromine whilst ice cooling). After 40 minutes at 35 - 40°C an aqueous sodium Jhy&rejenjb sulfite/solution and water was added and the mixture was evaporated in vacuo. The residue was dissolved in water, the solution was acidified with 2N hydrochloric acid whilst cooling and the obtained precipitate was taken up in a mixture of ether/ethyl acetate. The organic phase was dried over sodium sulfate, filtered and evaporated in vacuo. The nearly colorless solid residue was recrystallized from acetone, filtered and dried at 110°C/ 30 torr.
Yield: 0.06 g (10 % of theory), M.p.: 201 - 203°C.
Calc.: C 65.19 H 5.99 Cl 9.16 N 7.24 Found: 65.53 5.91 9.32 7.10 Example 286 4-/5-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl7benzoic acid ; Prepared analogously to Example 285 from 4-/?-(5-chloro-2-octa-oethylenimino-benzoylamino)-ethyl7acetophenone with sodium hypobromite solution. 194317 Yields 11 56 of theory, M.p.: 171 - 172°C.
Calc.s C 67.19 H 6.81 Cl 8.26 N 6.53 Founds 67.50 6.75 6.53 6.24 Example 287 4-/2-(5-Chloro-2-piperidino-benzoylamino)-ethyl7benzoic acid ethvl ester 0.82 g (0.002 mol) of 4-/2-(2-bromo-5-chloro-benzoylamino)-ethyl/benzoic acid ethyl ester (m.p.s 116 - 118°C, prepared by reaction of 2-bromo-5-chloro-benzoic acid with 4-(2-amino-ethyl )-benzoic acid ethyl ester analogously to proces a)) were heated \ ' itirring with 0.85 g (0.01 mol) of piperidine and with a amount of copper powder for 1 hour up to 100°C. After cooling the reaction mixture was acidified with acetic acid and extracted thrice with chloroform. The combined chloroform phases were dried over sodium sulfate. After distilling off the solvent, the remaining residue was purified over a silica gel column with chloroform/ethyl acetate (19s1) as eluant.
Yield: 0.49 g (48 % of theory), Calc.: mol peak m/e: 414/416 (1 Cl) Found: mol peak m/e: 414/416 (1 Cl).
Example 288 4-/5- (5-Chloro-2-piperidino-benzoylamino)-ethyl/benzoic acid ethvl ester 0.48 g (0.002 mol) of 5-chloro-2-piperidino-benzoic acid amide (m.p.: 140 - 142°C, prepared from 5-chloro-2-piperidino-benzoic acid by reaction with carbonyl diimidazole and ammonia) were heated whilst stirring in 5 ml of absolute toluene with 0.09 g (0.002 mol) of 55 % sodium hydride for 10 minutes up to approx. Trt~ J<si>z,h<?cJ — 60°C. After £±»4she4 hydrogen formation^the reaction mixture was cooled to room temperature and solution of 0.51 g (0.002 mol) of 4-(2-bromo-ethyl)-benzoic acid ethyl ester (M+ «■ 256/258 m/e 1 Br, prepared from 4-(2-hydroxyethyl- - <KT7 - 1943 1 7 benzoic acid ethyl ester with thionyl bromide) in 2 ml of absolute toluene was added dropwisely. Subsequently, the reaction mixture was refluxed for 6 hours. After cooling aqueous ethanol was added thereto and the reaction mixture was extracted several times. The combined chloroform extracts were dried over sodium sulfate and the solvent was distilled off. The residue was purified over a silica gel column with chloroform/ethyl acetate (19:1) as eluant. Yield: 0.2 g (25 % of theory), Calc.: mol peak m/e » 414/416 (1 Cl) Found: mol peak m/e ■ 414/416 (1 Cl).
Example 289 / 4-/2- (5-Chloro-2-octamethylenimino-benzoylamino )-ethyl7-benzoic acid ethvl ester 8.2 g (0.02 mol) of A-/5-(5-chloro-2-octamethylenimino-benzoyl-amino)-ethyl/benzoic acid nitrile (m.p.: 102°C) were dissolved in 80 ml of ethanol and saturated with hydrogen chloride. After 24 hours the reaction mixture was warmed for 1 hour up to 50°C and the solvents were distilled off. The evaporation residue was dissolved in ice water, adjusted to pH 9 and extracted with chloroform. After evaporating the organic phase the residue was purified by chromatography over a silica gel column.
Yield: 6.4 g (70 96 of theory), M.p.: < 20°C.
Calc.: C 68.33 H 7.27 N 6.12 Cl 7.75 Found: 68.32 7.29 6.12 7.90.
I Example ;j Tablets containing 5 mg of 4-/?- (5-chloro-2- ( 3,5-dimethyl-piperidino)-benzoylamino)-ethvl7-benzolc acid Composition: 1 tablet contains: Active ingredient (1) 5.0 mg Corn starch (2) 62.0 mg Lactose (3) 48.0 mg Polyvinyl pyrrolidone (4) 4.0 mg Magnesium stearate (5) 1.0 mg 120.0 mg Method of preparation: 1, 2,3 and 4 were mixed and moistened with water. The moist mixture was granulated through a screen of mesh size 1.5 mm and dried at approx. 45°C. The dry granulate was granulated through a screen of 1.0 mm mesh size and mixed with 5* The finished mixture wa3 pressed to tablets on a tablets press with punches of 7 mn diameter and an unilateral notch.
Weight of tablets: 120 mg Example XX Coated tablets contlining 2.5 mg of 4-/?-(5-chloro-2-octa-methylenimino-benzo ylamino)-ethyl7benzoic- acid 1 coated tablet core contains: Active ingredient (1) 2.5 mg Potato starch (2) 44.0 mg Lactose (3) .0 mg Polyvinyl pyrrolidone (4) 3.0 mg Magnesium stearate (5) 0.5 mg 80.0 mg 1 y 4= 3 Method of preparation: 1, 2, 3 and 4 were mixed well and moistened with water. The moist mass was granulated through a screen of mesh size 1 mm, dried at approx. 45°C and the granulate was again granulated through the same screen. After adding of 5, curvatured coated tablet cores of a diameter of 6 mm were pressed on a tablets pressing machine. The coated tablet cores thus prepared, were covered in conventional manner with a coating, which essentially consists of sugar and talcum The finished coated tablets were polished with wax.
Weigh of coated tablets: 120 mg Example III Tablets containing 10 mg of 4-(5-chloro-2-hexamethylene-lmlno-benzovlamino)-ethvl7-benzoic acid Composition: 1 tablet contains: Active ingredient 10.0 mg Lactose pulverized 70.0 mg Corn starch 31.0 mg Polyvinyl pyrrolidine 8.0 mg Magnesium stearate 1.0 mg 120.0 mg ljp - 1943 1 Method of preparation: The mixture of active ingredient, lactose and corn starch was moistened with a 20 # solution of polyvinyl pyrrolidone in water. The moist mass was granulated through a screen with a mesh size of 1.5 mm and dried at 45°C. The dried granulate was granulated through a screen of 1 mm mesh size and homogeneously mixed with magnesium stearate.
Weight of tablets: 120 mg Punch: 7 mm 0 with a notch.
Example IV Coated tablets containing 5 mg of 4-/?-(5-chloro-2-hexamethylene imino-benzovlamino)-ethvl7benzoic acid 1 coated tablet core contains: Active ingredient 5.0 mg Calcium phosphate secondary 70.0 mg Corn starch 50.0 mg Polyvinyl pyrrolidone 4.0 mg Magnesium stearate 1.0 nig 130.0 mg Method of preparation: The mixture, consisting of the active ingredient, the calcium phosphate and the corn starch, was moistened with a 15 % solution of polyvinylpyrrolidone in water. The moist mass was granulated through a screen of 1 mm mesh size, dried at 45°C and again passed through the same screen. The granulate was mixed with the above mentioned amount of magnesium stearate and the mixture thus obtained was pressed into coated tablet cores. 1943 r Weight of core: 130 mg Punch: 7 mm The thus prepared coated tablet cores were covered according to conventional manner with a layer consisting of sugar and talcum. The finished coated tablets were polished with wax. Weight of coated tablet: 180 mg Example v Tablets containing 10 mg of 4-/2-(5-chloro-2-piperidino-benzoyl-amlno)-ethvl7-benzolc acid Composition: 1 Tablet contains: Active ingredient Lactose pulverized Corn starch Polyvinyl pyrrolidone Magnesium stearate Method of preparation: The tablets were prepared analogously to Example C. .0 mg 70.0 mg 31.0 mg 8.0 mg 1.0 mg 120.0 mg Example VI Coated tablets containing 5 mg of 4-/?-(5-chloro-2-piperidino-benzoylamino)-ethyl7-benzoic acid ■ 1 Coated tablet core contains: m Active ingredient 5.0 mg Calcium phosphate secondary 70.0 ng Corn starch 50.0 mg Polyvinyl pyrrolidone 4.0 mg Magnesium stearate 1.0 mg 130.0 mg 184317 Method of preparation: The coated tablets were prepared analogously to Example D.
■Example VI^- Suppositories containing 30 mg of 5-chloro-2-(1,4-diox$ 8-aza-splro/5.)-benzoic acid Composition: . 1 suppository contains: Active ingredient Suppository mass (e.g. Witepsol W 45 Witepsol E 75) Method of prepara 0.030 g 1.700 g The pulveri^d active ingredient was added, with stirring, to the mp^ten mixture of the Witepsol masses tempered to 40°C. The m^ft was then poured into cooled moulds. After complete scarification the suppositories were removed from the moulds id paekcd in a suitable manneri -5DEC1983 RECEIVED no 194317 Example VIII Gelatine capsules containing 5 mg of 5-chloro-2-(1,4-dioxa-8-aza-splro/5.s7ftecan^-8-yl)-benzoic acid 1 capsule contains: Active ingredient Corn starch, dried Corn starch, pulverized Magnesium stearate Method of preparation: 200.0 mg The active ingredient and the auxiliary products were mixed. The mixture was passed through a screen of 0.75 mm mesh size and homogeneously dispersed in a Suitable mixer. The powder obtained was filled into gelatine capsules of size 3 (Parke Davis) by a capsule filling ana closing machine.
Example IX Tablets containing 25 jd,g of 5-chloro-2-(1,4-dioxa-8-aza-splro/7t5 7&ecane-8-y]/j-benzoic acid 1 tablet contains? Active ingrediepix Lactose Corn starch Polyvinyl pyrrolidone Magnesium/stearate Methgd of preparation .0 mg 35.0 mg 15.0 mg 4.5 mg 0.5 mg 80.0 mg e active ingredient was mixed with the lactose and starch and he mixture obtained was then homogeneously moistened w.1th the ±^4iOJL I -aqueous solution of the polyvinyl pyrrolidone.
Moist screening: 1.5 mm mesh size Drying: in a circulating air drier at Dry screening: 1.0 mm mesh size The dry granulate was pressed into tablets ai r addition of the magnesium stearate.
Tablets: 6 mm 0, faceted on both sit^s, dividing slot on one side, biplanar Example X Coated tablets containip^ 25 mg of 5-chloro-2-(1,4-dioxa-e-aza-splro/5. c;7dooang-8-vl)-benzoic acid The tablet cores/were prepared analogously to Example H. Pressing was to biconvex coated tablet cores of 80.0 mg veight, 6 jam 0 and radius of curvature 5 mm.
The cpfes were coated with a conventional sugar suspension tOya weight of 110 mg in a coating pan and subsequently polished With a polish suspension. — V \ ' . - - *94 - 194317

Claims (5)

  1. WHAT WE CLAIM IS t 1. Compounds of general formula I, R *1 V CO - NH - Y - CH 1 ✓R2 N 3 R„ (I) wherein R represents a hydrogen, chlorine or bromine atom or a cyclic alkylenimino group; represents a hydrogen, fluorine, chlorine or bromine atom; a C-^_g alkyl or alkoxy group^a phenyl- (Ci_3 alkoxy) group; a hydroxy, nitro, amino, cyano or carboxy group; ot a C1-3 alkanoylamino, alkoxy)- carbonyl or di (C, ^alkyl)aminosulfonyl group; R. and R-, f-fc/hicft may be the same or different/ , <xstd J mpiytszn-h ,, , ,, ' Either each frepreaenta a alkyl, alkenyl, C-^-j cycloalkyl, phenyKC-^-alkyi), phenyl or adamantyl group ' or together with the nitrogen atom to which they are attached, they represent a C^_g alkylenimino group [optionally substituted by 1 or 2.C1_4 alkyl'groups or by a alkoxy, hydroxy, phenyl, carboxy or C^ alkoxycarbonyl group and/or in which a methylene group of the imino ring may optionally be replaced by a further imino group (which may itself optionally be substituted by a al^y^^C2-4 ^^oxycarbonyl, phenyl, halophenyl, benzyl, pyridyl or furoyl group)y by an oxygen or sulfur atom or by a carbonyl, sulfoxide or sulfonyl group]; a saturated or partly unsaturated c-y_^o aza~kicycloalkyl group; a piperidino group substituted in the 3- and 5-positions by a total of either 3 or 4 C^_-,alkvl rrroups; a Cg_g 1,4-dioxa-8-aza-(sp(iro-alkyl group; or a trimethylenimino, pyVrQ$yi tetrahydropyridino, hepta methylenimino, octamethylenimino, nonamethylenimino, J f decamethylenimino, undecamethylenimino or dodecamethylen- & yx> - 194317 imino group; R^ represents a hydrogen atom or a alkyl group; X represents a nitrogen atom or a group =CH-; Y represents an oxygen atom; an imino group; or a methylene group optionally substituted by 1 or 2 alkyl groups; and Z represents a hydrogen or halogen atom; a nitro, amino, cyano, formyl, hydroxymethyl or carboxyethylene group; an optionally esterified carboxy group; a methyl group (optionally substituted by 2 or 3 alkoxy groups or by a carboxy, (C^-3 alkoxy)carbonyl or ethylenedioxy group); an acetyl group (optionally substituted by a carboxy group or a C2_4 alkoxycarbonyl group); an ethyl or ethylene group (substituted by 1 or 2 ^2-4 alkoxycarbonyl groups or by two carboxy groups); an amino-carbonyl group (substituted by one or two substituents selected from alkyl groups, cycloalkyl and C2-7 alkenyl groups); a piperidinocarbonyl morpholino-carbonyl, thiomorpholinocarbonyl or N- (C^^alkyl) -piper-azinocarbony1 group; or an ethyl group (substituted by a carboxy1 group): and, where and together with the nitrogen atom to which they are attached, represent a cyclic imino group as defined above, and/or where Z represents or contains a carboxy group, the salts thereof.
  2. 2. Compounds as claimed in claim 1 wherein R .represents a hydrogeh atom; rePresents a hydrogen, fluorine, chlorine or bromine atom; a C1_g alkoxy, C^ alkyl or C2_4 alkoxycarbonyl group; or a hydroxy, cyano, carboxy, nitro, amino, acetamido, dimethylaminosulfonyl or benzyloxy group; either R2 represents a Cx_6 alkyl group or a cyclohexy1, phenyl, benzyl, adamantyl or allyl group and represents a C^_6 alkyl group or an allyl group; or i n(f- - >r? - 194317 'Hoy®# benzyl, phenyl, chlorophenyl, pyridyl, furoyl or C' i - PJTo Ut I pif>e r t'cl o n ^ ^ alkoxycarbonyl group); or a jpyrroiyl., kiporidong- and R^ together with the nitrogen atom to. which they are attached, represents C. , P alkylenimino group; . ,. suksiitu,tz.cT~ a piperidino group (£ub3ituted by a C1_4 alkyl, phenyl, hydroxy, methoxy, carboxy or C_ . alkoxycarbonyl group); SULkstUM.ttz.cl a piperidino group (frubcitutod both in the 3- and in the 5-positions by a alkyl group); a piperidino group (substituted both in the 3- and in the 5-positions by 2 C _ alkyl groups); a morpholino, tii/amer phoits>o-\-ozc-Lci e ^ ' - hI - dtcocicXe ' ^ ^ dioxido -thiomorpholino^ group (each said group being optionally substituted by 1 or 2 methyl groups); a piperazino group (optionally substituted in the 4-position by a methyl, C, I ftafc>oridbn$- (2) -yl- (1) , 1,2,3,6-tetrahydropyridino, 1,4-dioxa-8~aza-spiro (2,5] decan-8.-yl, 1, 4-dioxa-8-aza-spiro [4,6] undecan-8-^1, iSocncJoC isooouio octahydro-iooindojre-2-yl, 1,2,3, 4-tetrahydro-i-se^u ' /SO<? uuslO Lis* 2-yl, 1,2,3,4,5,6,7, 8-octahydro-<booquinoli ne-2-yl, iLcnoUsi decahydro-£soqui-nolin&-2-yl, 1,2,4, 5-tetrahydro-3-he.ri7.oci.Q.pO\ be.nzjccz.ep lSi penzaadpine-3-y1, decahydro-3-fconzagcpina-3-yl or 3- £ b'ic<ucLpnoncJur[ K aza-picycXononarrat-3-yl group; R^ represents a hydrogen atom or a methyl group; Y represents a methylene, methyl-methylene or dimethylmethylene group, an imino group or an oxygen atom; and Z represents a carboxy, cyano, formyl or hydroxymethyl group; a C2_y alkoxycarbonyl group; a cyclohexy-loxycarbony1, benzyloxcarbonyl, diethoxymethyl, carboxy-methyl, bis-2,2-ethoxycarbonyl - ethyl, 2-carboxy-ethylene or 2-ethoxycarbonyl-ethyl group; an acetyl group optionally substituted by a carboxy or ethoxycarbonyl group; or a 2-carboxyethyl group.
  3. 3. Compounds as claimed in claim 2 wherein R^ is present in the 5-position of the phenyl or pyridyl nucleus.
  4. 4. Compounds as claimed in claim 3 wherein R^ represents a hydrogen, fluorine, chlorine or Sru-i^-r'-y 184317 bromine atom or a alkyl, alkoxy, carboxy, cyano or nitro group; 1*2 and together with the nitrogen atom to which they are attached, represent a N,N-di (Cj^alkyl) ~ amino or N- (C^^alkyl) cyclohexylamino group; a pyrrolidino, piperidino, hexamethylenimino, heptamethy-lenimino, octamethylenimino or nonamethylenimino group; a piperidino group ( substituted by a C^._^ alkyl, methoxy or phenyl group); a piperidino group (substituted both "in the 3- and in the 5-positions by 1 or 2 methyl or ethyl groups); a morpholino or thiomorpholino group (each said group being optionally substituted in the 2- and 6-positions by a methyl group); or a 1,4-dioxa-8-aza- aeccUl undCLCCLSX spiro [4,5] -flecan<a-8-yl, 1, 4-dioxa-8-aza-spiro [4,6] ftndeoan^- iso tndol yl, octahydro-ftaoindolia-2-yl, 1, 2 , 3, 4-tetr.nhydro-ir.o- auxvi o feuinolina-2-yl, 1,2,3,4,5,6,7,8-octahydro- isocjm^\oU/i (sop u.L^7oUs\ fr3oquinolirref-2-yl, decahydro-jhsoeftainolin^- , ~ • r- , , bevi-zecZ-GLpon 2-yl, 1 ,2 , 4 ,5-tetrahydro-3H-3-focngazGpine-3-yl, decahydro-3H-3-|bongagcping-3-yl, 3-aza-bicyclo [3 , 2,2]- ncmasi ftenanfc-3-yl or N-methyl-adamantyl-(1)-amino group; X represents the group =CH-; and Z represents a C2_4 alkoxycarbonyl group or a carboxy, formyl or hydroxymethyl group.
  5. 5. Compounds as claimed in claim 3, wherein R^ represents a chlorine or bromine atom 'or a methyl, ethyl or methoxy group; R2 and R^ together with the nitrogen atom to which they are attached, represent a pyrrolidino, piperidino, methyl-piperidino, 4-methoxy-piperidino, 4-phenyl-piperidino, hexamethylenimino, heptamethylenimino, octamethylenimino, nonamethylenimino, 3,5-dimethyl-piperidino, morpholino, 2,6-dimethyl-morpholino, thiomorpholino, 2,6-dimethyl-thiomorpholino, 1,4-dioxa- - - 194317 daoccn 8-aza-spiro[4,5]flccan<fe-8-yl, 1,2,3,4-tetrahydro-isoquino-^in<fe-2-yl, decahydro-i-so^ui^e^ft«-2-yl, 1,2,4,5-tetrahydro-3H-3-)bonaaBo|<ing-3ryl, decahydro-3H-3- tcviZCL"Z_e/?'-/i iSOLsicla^i fcenzazeparre-3-yl, octahydro-^-soindolg-2-yl or N-methyl-adamantyl-(1)-amino group; or a piperidino group substituted in the 4-position by a C2_4 alkyl group. 6. 4-[2- (5-Chloro-2-piperidino-benzoylamino)-ethyl]-benzoic acid and its alkyl esters and acid addition salts thereof. ' 1. 4- [2- (5-Ethyl-2-piperidino-benzoylamino) -ethyl]-* benzoic acid and its alkyl esters and acid addition salts thereof. c/ec*xyl 8 . 4- [2- (5-Chloro-2- (1,4—dioxa-8-aza-spiro [4,5] (jtccan^-8-yl)-benzoylamino)-ethyl]benzoic acid and its alkyl esters and acid addition salts thereof. 9. 4-[2-(5-Chloro-2-octamethylenimino-benzoylamino)-ethyl]benzoic acid and its alkyl esters and acid addition salts thereof. 10. 4-[2-(5-Chloro-2-(2,6,-dimethylmorpholino)-benzoylamino)-ethyl]-benzoic acid and its alkyl esters and acid addition salts thereof. 11. 4-[2- (5-Chloro-2- [cis-3,5-dimethylpiperidino)-benzoylamino)-ethyl]benzoic acid and its alkyl esters and acid addition salts thereof. 12. Physiologically compatible acid addition salts of compounds of general formula I as defined in claim 1 wherein R2 and , together with the nitrogen atom to which they are attached, represent a cyclic imino group as defined in claim 1. 13. Physiologically compatible salts of compounds of general formula I as defined in claim 1, wherein Z represents or contains a carboxy group, with bases. W7 - 20t> - 194317 14. Compounds of general formula I as defined in claim 1 wherein R represents a hydrogen atom; R^ is in the 5-position and represents a hydrogen, fluorine, chlorine or bromine atom; a alkoxy group; a nitro, amino, cyano or carboxy group; or a alkanoylamino, alkoxycarbonyl or di (C^^alkyl) amino sulfonyl group; . . R~ and R^ / -whicU may be the same or different/ npiZ'se'iJt /eilhef each jrcprcGont^ a alkyl or C^-7 cycloalkyl group or, together with the nitrogen atom to which they attached, they represent a C4_g alkylenimino group [optionally substituted by 1 or 2 alkyl groups or by a C^_.j alkoxy, hydroxy, phenyl, carboxy or C2-4 alkoxycarbonyl group and/or in which a methylene group of the imino ring may optionally be replaced by a further imino group (which may itself optionally be substituted by a phenyl or pyridyl group), by an oxygen or sulfur atom or by a sulfoxide group]; or a pyrrolyl, tetrahydro-isoquinolyl, tetrahydro-benzazepinyl or 1,4-dioxa-8-aza-spiro[4,5]decanyl group; X represents a group =CH~; Y represents a methylene group; and Z represents a carboxy or (C^_4alkoxy)carbonyl group; and, where R2 and R^ together with the nitrogen atom to which they are attached, represent a cyclic imino group as defined above and/or where Z represents a carboxy group, the physiologically compatible salts thereof. 15- Compounds of general formula I as claimed in claim 1 wherein R represents a hydrogen atom; R^ represents a hydrogen, chlorine or bromine atom; a alkoxy group; a benzyloxy group; or a nitro or amino group; - 2&1 - 194317 ddtfxc r R_ and R-. /■ whicH may be the same or different./ usid G&ch ^ mains'/\£r Jfetteil /represents a alkyl, C3_7 cycloalkyl or phenyl group or, together with the nitrogen atom to which they are attached, they represent a alkylenimino group; a piperidino group (in which a methylene group is replaced by a methylmethylene, methoxymethylene, imino or benzylimino group); a piperidino group (substituted in the 3- and 5-positions" by a total of either 3 or 4 alkyl groups); a piperidino group (substituted in both the 3- and 5-positions by a C^_3 alkyl group and in which the methylene group in the 4-positions of the piperidino ring is optionally replaced by an oxygen or sulfur atom or by a sulfoxide or sulfonyl group); rthioMprphoLno ~l~divxieie or a ft-TirndibxidoLhiomorphoj^bnx^ or aza-bicycloalkyl group; R^ represents a hydrogen atom; X represents a group =CH-; Y represents a methylene group optionally substituted by a alkyl group; and Z represents a carboxy or alkoxy)carbonyl group; and, where R2 and R^ together with the nitrogen atom to which they are attached, represent a cyclic imino group as defined above and/or where Z represents a carboxy group, the physiologically compatible salts thereof. 16. Compounds of general formula I as claimed in claim 1 wherein R represents a hydrogen or chlorine atom or a piperidino group; R^ represents a hydrogen, fluorine, chlorine or bromine atom; a C1-6 alkyl or C-^g alkoxy group; or a hydroxy, amino, nitro or cyano group; either R2 represents a C1_3 alkyl, phenyl(C-^alkyl), or C3_7 alkenyl group and R3 represents a C^_7 alkyl, C3_7alkenyl or adamantyl group, or R2 and R3, together with the nitrogen atom to which they are attached, \C\<\ - ^0-2 - represent a alkylenimino group; a piperidino group (substituted by a alkyl group); a piperidino group (substituted both in the 3- and in the 5-position:S by a alkyl group); a piperazino group (substituted in the 4-position by a alkyl, ^2-4 alkoxycarbonyl, halo- phenyl or furoyl group); or a tetrahydropyridino, octahydro-isoquinolinyl, decahydro-isoguinolinyl, is olncJoUfl decahydro-benzazepino or octahydro-|>-soindol'a group?--and Z represents a hydrogen or halogen atom; a nitro, amino, cyano, formyl or hydroxymethyl group; an optionally esterified carboxy group; a methyl group (optionally substituted by 2 or 3 alkoxy groups or by a (C-^-3 alkoxy)carbonyl or ethylendioxy group); an acetyl group (optionally substituted by a carboxy or a C2_^ alkoxycarbonyl group); an ethyl or ethylene group (substituted by 1 or 2 C2_4 alkoxycarbonyl groups or by two carboxy groups); an aminocarbonyl group (substituted by one or two substituents selected from alkyl groups, C cycloalkyl groups and alkenyl groups); a piperidino- carbonyl, morpholinocarbonyl, thiomorpholinocarbonyl or N- ( alkyl)-piperazinocarbonyl group; or an ethyl group (substituted by a carboxy group); and, where R2 and R^ together with the nitrogen atom to which they are attached represent a cyclic imino group as defined above and/or where Z represents or contains a carboxy group, the salts thereof. 17. Compounds as claimed in claim 1, other than those claimed in any one of claims 6 to 11, as herein specifically disclosed in any one of Examples 1 to 289. 18. Compounds as claimed in claim 14, other than those claimed in any one of claims 6 to 11, as herein specifically disclosed in any one of Examples 1 to 90. 19. Compounds as claimed in claim 15, other than those claimed in any one of claims 6 to 11, as herein specifically disclosed in any one of Examples 91 to 164. - -Turo W 4 3 1 7 20. Compounds as claimed in claim 16, other than those claimed in any one of claims 6 to 11, as herein specifically disclosed in any one of Examples 165 to 278. 21. A process for the preparation of compounds of general formula I as defined in claim 1 which comprises reacting an acid of formula IV, (IV) ( wherein R , Ri' R2' R3 an(^ X are as claim 1) or a reactive derivative thereof, with an amine of formula V, . H2N - Y - CH -ft 2 (V) ( wherein , Y and Z are as defined in claim 1)- or, where Z does not represent or contain a carboxy or amino group and an acid of formula IV is used, an N-activated derivative thereof. 22. A process as claimed in claim 21 wherein an acid of formula IV or a functional derivative thereof is reacted with an amine of formula V. A 23. A process as claimed in claim 22 wherein a functional derivative of the acid of formula IV, formed in situ, is reacted with the amine' of formula V. 24. A process as claimed in claim 22 or claim 23 wherein 1 94 s. » f i - 2x>C an ester, thioester, imidazolide, acid halide, acid anhydride, mixed anhydride O-triphenyl phosphonium complex, N-acyloxy imide, azide or nitrile or a corresponding amino-thiobenzoic ester derivative is reacted with the amine of formula V. 25. A process as claimed in claim 2 2 wherein an acid of formula IV is reacted with an amine of formula V in the presence of a dehydrating or acid activating agent. 26. A process as claimed in claim 21 wherein an acid of formula IV is reacted with an N-activated derivative of an amine of formula V in which Z does not represent or contain a carboxy or amino group. 27. A process as claimed in claim 26 wherein the N-activated derivative is formed in situ. 28. A process as claimed in claim 26 or claim 27 wherein the N-activated derivative is a phosphazo derivative. 29. A process as claimed in any one of claims 21 to 28 wherein the reaction is effected in the presence of a solvent. 30. A process as claimed in any one of claims 21 to 29 wherein the reaction is effected in the presence of a base. 31. A process as claimed in any one of claims 21 to 30 wherein water formed during the reaction is removed by azeotropic distillation or by addition of a drying agent. 32. A process as claimed in any one of claims 21 to 31 wherein the reaction is effected at temperatures of from -10°C to the boiling point of the reaction mixture. 33. A process for the preparation of compounds of general formula I as defined in claim 1 wherein represents a hydrogen, fluorine, chlorine or bromine atom; Cl_6 alkyl or a alkoxy group; a nitro, cyano or carboxy 1943 1 7 Tjo-T- group; or a alkanoy lamino, (C^_3alkoxy) carbonyl or di- (C^_3alkyl) aminosulfonyl group ; X represents a group =CH- ; and Y represents a methylene group (optionally substituted by 1 or 2 C1 3 alkyl groups), which comprises reacting a compound of formula VI, Rh co-™-\-ch/~\z (vi) Cwherein R, R^ and Z are as defined in claim 1; Ra represents a hydrogen, fluorine, chlorine or bromine atom; a C1_6 alkyl or C1_6 alkoxy group; a nitro, cyano or carboxy group; or a C^_3alkanoylamino, (C1_3alkoxy) carbonyl or di (C^alkyl) aminosulfonyl group; Y^ represents a methylene group (optionally substituted by 1 or 2 C1-3 alkyl groups; and E represents a halogen atom J with an amine of formula VII, ^ R, ^ 2 H ~ (VII) R3 (wherein R2 and R3 are as defined in claim 1) . 34. A process as claimed in claim 33 wherein the reaction is effected in the presence of water, aqueous methanol, aqueous ethanol, aqueous isopropanol, dimethylformamide or an excess of the amine of formula VII as solvent. 35. A process as claimed in claim 33 or claim 34 wherein the reaction is effected in the presence of a base and/or of a reaction accelerator. 36. A process as claimed in any one of claims 33 to 35 1 943 1 7 Z&3 wherein the reaction is effected .at the boiling point of the reaction mixture. 37. A process as claimed in claim 33 for the preparation of compounds of general formula I wherein is in the 3-position and represents a nitro group. 38. A process as claimed in claim 33 for the preparation of compounds of general formula I wherein R^ is in the 5-position and represents a nitro group. 39. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents a carboxy group and Y represents an oxygen atom or a methylene group (optionally substituted by 1 or 2 alkyl groups) which comprises oxidising a compound of formula VIII, (VIII) X 2 "•s fwherein R/ R^ / ^' R3' R4 and X are as defined in claim 1; Y0 represents an oxygen atom or a methylene group (optionally substituted by 1 or 2 alkyl groups); and A represents a group transformable into a carboxy group by oxidation] whereby the desired compound of formula I is obtained. 40. A process as claimed in claim 39 wherein, in the compound of formula VIII, A represents a formyl group or an acetal thereof; a hydroxymethyl group or an ether derivative thereof; or an unsubstituted or substituted 1P^ - 2&1 - 194317 acyl group. 41. A process as claimed in claim 39 or claim 40 wherein the oxidation is effected at temperatures of from 20 to 50°C. 42. A process as claimed in any one of claims 39 to 41 wherein oxidation is effected by means of silver oxide/ sodium hydroxide solution; manganese dioxide/acetone or methylene chloride; hydrogen peroxide/sodium hydroxide ..solution; bromine or chlorine/sodium hydroxide solution or potassium hydroxide solution; or chromium trioxide/ pyridine. 43. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents a carboxy group which comprises hydrolysing a compound of formula IX, (IX) £ wherein R, R^, R2, R^, R^ , X and Y are as defined in claim 1 and B represents a group transformable into a carboxy group by hydrolysis). 44. A process as claimed in claim 43 wherein, in the compound of formula IX, B represents a cyano, unsubstituted or substituted amide, ester, thioester, orthoester, iminoether, amidine or anhydride group; a malonic ester— (l)-vl group; a tetrazolyl group; or an optionally O/XtZol oX«. "Z-o/ substituted 1,3-ftxazol<fc- (2)-yl or dihydro -1,3-<£xa&edJ£-(2)-yl group. 45. A process as claimed in claim 43 or claim 44 wherein hydrolysis is carried out in the presence of an acid. 2,<^r - 1943i7 46. A process as claimed in claim 43 or claim 44 wherein hydrolysis is carried out in the presence of a base. 47. A process as claimed in any one of claims 43 to 46 wherein the hydrolysis is effected at temperatures of from ambient temperature to the boiling point of the reaction mixture. 48. A process for the preparation of corrpounds of general formula I as defined in claim 1 wherein either represents a C.^ alley 1, 7 cycloalkyl, phenyl (C^^alkyl) or C^_-j alkenyl group and represents a Calkyl, C^_^ cycloalkyl, alkenyl, phenyl (C^^alkyl) or adamantyl group or R2 and , together with the nitrogen atom to which they are attached, represent a C^_g alkylenimino ring, a alkyl-substituted piperidino group or a piperidino group (substituted both in the 3-position and in the 5-positions by a alkyl.group); and Y represents a methylene group (optionally substituted by 1 or 2 Cj_3 alkyl groups), which comprises reacting a compound. of formula X, m ^wherein co - nh - yl- ch h V (X) R, R 1' R> X and Z are as defined in claim 1, Y^ is as defined in claim 33 and R^ represents a hydrogen atom, a alkyl, C3_7 cycloalkyl, alkenyl, phenyl (C1_3alkyl) or adamantyl group, or together with R2 in formula XI, a straight chain C^_g alkylene group, a alkyl-substituted n-pentylene group or a n- N.Z. PATENT Of F ICC 13 JAN 1984 received 209 - Zob 1943 1 7 pentylene group (substituted both in the 2-position and in the 4-position by a a^kyl group)with a compound of formula XI, V " G (XI) [wherein represents a ^ alkyl, -j cycloalkyl, phenyl(C^ ^ alkyl) or -j alkenyl group or, together with in formula X, a straight chain ^ alkylene group, a ^ alkyl-substituted n-pentylene group or a n-pentylene group (substituted both in the 2-position and in the 4-position by a alkyl group) and G represents a nucleophilically exchangeable group]. 49. A process as claimed in claim 48 wherein, in the compound of formula XI, G represents a halogen atom or a sulfonyloxy group. 50. A process as claimed in claim 48 or claim 49 wherein the reaction is carried out in the presence of a base. 51. A process as claimed in any one of claims 48 to 50 wherein the reaction is carried out at temperatures of from 20 to 75°C. 52. A process as claimed in claim 48, for the preparation of compounds of general formula I in which R2 represents a methyl group, wherein the compound of formula X is reacted with formaldehyde in the presence of a reducing agent. 53. A process as claimed in any one of claims 48 to 52 wherein the compound of formula X is prepared in situ. 54. A process for the preparation of compounds of - yCsf-TjoI '*¥43 1 7 general formula I as defined in claim 1 wherein Y represents an oxygen atom or an imino group which comprises reacting a compound of formula XII, (XII) (wherein R, R^, R£, R^ and X are as defined in claim 1 and represents an oxygen atom or an imino group), or an alkali metal salt thereof, with a compound of formula XIII, • *4 L - CH o- (XIII) (wherein R. and Z are as defined in claim 1 and L 4 represents a nucleophilically exchangeable group). 55. A process as claimed in claim 54 wherein, in the compound of formula XIII, L represents a chlorine, bromine or iodine atom or a methylsulfonyloxy, £-toluenesulfonyloxy or methoxysulfonyloxy group. 56. A process as claimed in claim 54 or claim 55 wherein the reaction is effected in the presence of a base. 57. A process as claimed in any one of claims 54 to 56 wherein the reaction is effected at temperatures of from 50 to 100°C. I - &{ - * S* 4 3 I 7 asos1 58. A process for the preparation of compounds of general formula I as defined in claim 1 wherein represents a hydrogen, fluorine, chlorine or bromine atom, a ^ alkyl or ^ alkoxy group, a phenyl(C^ ^alkoxy) grouP> a nitro or cyano group or a (C^ ^alkoxycarbonyl or di(C^ Iky1)aminosulfonyl group; X represents a group =CH-; and Y represents a methylene group (optionally substituted by 1 or 2 ^ alkyl groups), which comprises reacting an amide of formula XIV, r ^R (XIV) 3 (wherein R, R£ and are as defined in claim 1 and R^ represents a hydrogen, fluorine, chlorine or bromine atom, a ^ alkyl or ^ alkoxy group, a phenyl(C^_2 alkoxy) group, a nitro or cyano group or a (C^ ^alkoxy)carbonyl or di(C^ ^alkyl)aminosulfonyl group) or an alkali metal salt thereof with a compound of formula XV, (XV) 1 - - tD°i 194317 (wherein and Z are as defined in claim 1, is as defined in claim 33 and M represents a nucleophilically exchangeable group). 59. A process as claimed in claim 58 wherein, in the compound of formula XV, M represents a halogen atom or a sulfonyloxy group. 60. A process as claimed in claim 58 or claim 59 wherein the reaction is effected in the presence of a base. 61. A process as claimed in any one of claims 58 to 60 wherein the reaction is effected at temperatures of from 50 to 150°C. 62. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R-^ represents a hydrogen, fluorine, chlorine or bromine' atom, a 'C^ ^ alkyl or alkoxy group, a phenyl(C^ ^ alkoxy) group o.r a hydroxy, nitro, carboxy, or ^ alkanoylamino group; X represents a group =CH-; Y represents a methylene group (optionally substituted by 1 or 2 C, - alkyl groups); and Z Oxj^c<xujlaJh-*~ici represents a carboxy group, which comprises ftcylatlng J a compound of formula XVI c R. (XVI) a 10 - >ii - 194317 i-r h ! SK-- .. t ■ te '> - V - ^ H * ff;- (wherein R, R£, R^ and R^ are as defined in claim 1, is as defined in claim 33 and R^ represents a hydrogen, fluorine, chlorine or bromine atom, a ^ alkyl or alkoxy group, a phenyl(C^ ^ alkoxy) group or a hydroxy, nitro, carboxy or ^ alkanoyl-amino group) with an oxalyl halide or phosgene in the presence of a Lewis acid. 63. A process as claimed in claim 62 wherein the Lewis acid is aluminium chloride. 64. A process as claimed in claim 62 or claim 63 wherein the ftcylacioa is effected at temperatures of from 20 to 60°C. 65. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R^ represents a hydrogen, fluorine, chlorine or bromine atom, a alkyl or £-^-6 alkoxy group, a phenyl(C^_^ alkoxy) group or a nitro, carboxy, ^ alkanoylamino or (C^ ^ alkoxy)carbonvl group; X represents a group =CH-; Y represents a methylene group (optionally substituted by 1 or 2 alkyl groups); and Z represents a carboxy group, which comprises reacting a compound of formula XVII, H co - nh - - ch c0ch? (xvii) II ^ r2 ~~ (wherein R, R£, R3 and R^ are as defined in claim 1, 5» 3 - I V # ^ is as defined in claim 33 and represents a hydrogen, fluorine, chlorine or bromine atom, a ^ alkyl or alkoxy group, a phenyl(C^_^ alkoxy) group or a nitro, carboxy, ^ alkanoylamino or (C^ ^ alkoxy)carbonyl group) with a hypohalite. 66. A process as claimed in claim 65 wherein the hypohalite is prepared in situ. 67. A process as claimed in claim 65 or claim 66 wherein the reaction is effected at temperatures of from 25 to 50°C. 68. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents an esterified carboxy group which comprises esterifying a compound of formula I as defined in claim 1 (wherein Z represents a carboxy group). 69. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents an aminocarbonyl group (substituted by one or two substituents selected from ^ alkyl groups, -j cycloalkyl groups and -j alkenyl groups) or a piperidinocarbonyl, morpholinocarbonyl, thio-morpholinocarbonyl or N-(C^ ^ alkyl)-piperazinocarbonyl group which comprises amidating a compound of formula I as defined in claim 1 (wherein Z represents a carboxy group). 70. A process as claimed in claim 68 or claim 69 wherein the esterification or amidation is effected in the presence-of an acid activating and/or dehydrating agent. I rs ~ 'I v 43 17 71. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R^ and/or Z represents an amino group which comprises reducing a compound of formula I as defined in claim 1 (wherein R^ and/or Z represents a nitro group). 72. A process as claimed in claim 71 wherein reduction is effected by means of hydrogen in the presence of a hydrogenation catalyst; iron, tin or zinc in the presence of an acid; iron(II) sulfate, tin(Il) chloride or sodium dithionite; or hydrazine in the presence of Raney nickel. 73. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R^ represents a hydroxy or cyano group or a fluorine, chlorine or bromine atom and/or Z represents a chlorine or bromine atom or a cyano group which comprises converting a compound of formula I as defined in claim 1 (wherein R^ and/or Z represents an amino group) via the corresponding diazonium salt into the desired compound of formula I. 74. A process as claimed in claim 73 wherein the diazonium salt is the fluoroborate, hydrosulfate or hydrochloride. 75. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R^ represents a alkoxy or phenyl(C^_^ alkoxy) group which comprises alkylating a compound of formula I as defined in claim 1 (wherein R^ represents a hydroxy group). 76. A process as claimed in claim 75 wherein alkylation is effected by means of an appropriate halide or sulfonic ~ul~ 194317 acid ester. 77. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R^ represents a ^ alkanoylamino group which comprises acylating a compound of formula I as defined in claim 1 (wherein R^ represents an amino group). 78. A process as claimed in claim 77 wherein the acylation is effected in the presence of a base and/or an acid activating and/or dehydrating agent. 79. A process as claimed in claim 77 or claim 78 wherein acylation is effected by means of an acid, acid anhydride, acid chloride or an ester. 80. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R^ represents a carboxy group and/or R2 and R^» together with the nitrogen atom to which they are attached, represent a ^ alkylenimino group substituted by a carboxy group, which comprises hydrolysing a compound of formula I as defined in claim 1 (wherein R^ represents a (£-^3 alkoxy)carbonyl group and/or R£ and R^, together with the nitrogen atom to which they are attached, represent a alkylenimino group substituted by a C0 . alkoxycarbonyl group). 2-4 80 81. A process as claimed in claim 2*5 wherein hydrolysis is effected in the presence of hydrochloric, sulfuric, phosphoric or trifluoroacetic acid or sodium or potassium hydroxide. 82. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R2 and R^, together with the nitrogen atom to which they are attached, represent a piperazino group - ji7 - *14- 194317 i 4 which comprises debenzylating a compound of formula I as defined in claim 1 (wherein and R^, together with the nitrogen atom to which they are attached, represent an N-benzylpiperazino group). 83. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R^ represents a hydrogen atom which comprises dehalogenating a compound of formula I as defined in claim 1 (wherein R^ represents a chlorine or bromine atom). 83 S3 84. A process as claimed in claim .8-i or claim wherein debenzylation or dehalogenation is effected by means of catalytically activated hydrogen. 85. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents a hydroxymethyl group which comprises reducing a compound of formula I as defined in claim 1 (wherein Z represents an optionally esterified carboxy group) by means of a complex metal hydride. 86. A process as claimed in claim 85 wherein the complex metal hydride is lithium aluminium hydride. 87. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents a formyl group which comprises oxidising a compound of formula I as defined in claim 1 (wherein Z represents a hydroxymethyl group). 88. A process as claimed in claim 87 wherein oxidation is effected by means of a metallic oxide. 89. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents an ethyl group substituted by 2 I * - - 194317 ^ alkoxycarbonyl groups which comprises subjecting a compound of formula I as defined in claim 1 (wherein Z represents a hydroxymethyl group) to halogenation di ( and subsequent reaction with a^ malonic acid ester. 90. A process as claimed in claim 89 wherein halogenation is effected with thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride. ,91. A process as claimed in claim 89 or claim 90 wherein the halomethyl derivative formed on halogenation is reacted with an alkali metal salt of the malonic acid ester. 92. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents a di(C^ ^ alkoxy)methyl group which comprises acetalising a compound of formula I as defined in claim 1 (wherein Z represents a formyl group). 93. A process as claimed in claim 92 wherein acetalisation is effected by means of the appropriate alcohol in the presence of an acid or by means of an appropriate orthoester. 94. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents an ethylene group substituted by a carboxy or ^ alkoxycarbonyl group which comprises condensing a compound of formula I as defined in claim matont c exccd-/ en. matonic accd estf oc tria(lcy(p)tcophon& ace-tciMt. 1 (wherein Z represents a formyl group)/followed, if required, by hydrolysis of the product thus obtained whereby the desired compound of formula I is obtained. 95. A process as claimed in claim 94 wherein the con cle n S ajb. 'S cctSftC'd eyijJr formyl'derivative of formula I is condensed-with - 194317 n y malonic acid,—a malonic acid ester or a trialkylphoaphonc aootabo optionally in the presence of a base. 96. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents an acetyl group optionally substituted by a ^ alkoxycarbonyl group which comprises subjecting a compound of formula I as defined in claim 1 (wherein Z represents a hydrogen atom) to Friedel-Crafts acylation. 97. A process as claimed in claim 96 wherein acylation is effected by means of an acid halide or acid anhydride in the presence of aluminium chloride. 98. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents a tri(C^ ^ alkoxy)methyl group which comprises subjecting a compound of formula I as defined in claim 1 (wherein Z represents a cyano group) to alcoholysis via the corresponding imino ester. 99. A process as claimed in claim 98 wherein alcoholysis is effected by means of an appropriate alcohol in the presence of an acid. 100. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents a C2-4 alkoxycarbonyl group which comprises hydrolysing a compound of formula I as defined in claim 1 (wherein Z represents a tri(C^ ^ alkoxy)methyl group). 101. A process as claimed in claim 100 wherein the hydrolysis is effected in the presence of an acid. 102. A process for the preparation of compounds of general formula I as defined in claim 1 wherein - | V <—tf ^ Qxl Z represents a carboxymethyl group which comprises heating a compound of formula I as defined in claim 1 (wherein Z represents an acetyl group) with an amine and sulfur and subsequently heating the thioamide thus obtained with an inorganic base. 103. A process as claimed in claim 102 wherein the acetyl derivative of formula I is heated with morpholine and sulfur and the thioamide thus obtained is heated with sodium hydroxide. 104. A process for the preparation of compounds of general formula I as defined in claim 1 wherein Z represents a formyl group which comprises converting a compound of formula I as defined in claim 1 (wherein Z represents a carboxy group) into a corresponding sulfonic acid hydrazide and subsequently subjecting the said sulfonic acid hydrazide to disproportionation. 105o A process as claimed in claim 104 wherein the formyl derivative of formula I is reacted with an appropriate hydrazine and the disproportionation of the sulfonic acid hydrazide obtained is carried out in the presence of a base. 106. A process for the preparation of compounds of general formula I as defined in claim 1 wherein R-^ represents a hydrogen, fluorine, chlorine or bromine atom or a ^ alkyl, ^ alkoxy or phenyl-(Ci_3 alkoxy) group; X represents a group =CH-; Y represents a methylene group (optionally substituted by 1 or 2 alkyl groups); and Z represents a carboxy group which comprises - >ri - Q '1 ■?, •; 7 y 'I1 o/ . / converting a compound of formula I as defined in claim 1 [wherein R^ represents a hydrogen, fluorine, chlorine or bromine atom or a alkyl, ^ alkoxy or phenyl- (Ci_3 alkoxy) group; X represents a group =CH-; Y represents a methylene group (optionally substituted by 1 or 2 alkyl groups); and Z represents a chlorine or bromine atom], into a corresponding organometallic derivative and reacting the said organometallic derivative with carbon dioxide. 107. A process as claimed in claim 106 wherein the chloro or bromo derivative of formula I is converted into a corresponding organolithium compound. 108. A process for the preparation of acid addition salts of compounds of general formula I as defined in claim 1 wherein R£ and R^ together with the nitrogen atom Which they are attached represent a cyclic imino group as defined in claim 1 which comprises reacting a compound of formula I as defined in claim 1 (wherein R^ and R^ together with the nitrogen atom to which they are attached represent a cyclic imino group as defined in claim 1) with an acid. 109o A process for the preparation of salts of compounds of general formula I wherein Z represents or contains a carboxy group with bases which comprises reacting a compound of formula I as defined in claim 1 (wherein Z represents or contains a carboxy group) with a base. 110. A process as claimed in claim 108 or claim 109 for the preparation of physiologically compatible salts. *o\ 19 ^OV S982 • „ -J 1943 17 111. A process as claimed in any one of claims 21, 38, 39, 43,-48, 68, 71, 73, 77, 80 and 110 for the preparation of compounds as claimed in claim 14. 112. A process as claimed in any one of claims 21, 37, 38, 39, 43, 48, 68, 71, 73, 75, 82, 83 and 110 for the preparation of compounds as claimed in claim 15. 113. A process as claimed in any one of claims 21, 39, 43, 48, 54, 68, 69, 71, 73, 75, 85, 87, 89, 92, 94, 96, 98, 100, 102, 104 and 110 for the preparation of compounds as claimed in claim 16. 114. A process for the preparation of compounds as claimed in claim 1 substantially as herein described. 115. A process for the preparation of compounds as claimed in claim 1 substantially as herein described in any one of Examples 1 to 289. 116. A process for the preparation of compounds as claimed in claim 14 substantially as herein described in any one of Examples 1 to 90. 117. A process for the preparation of compounds as claimed in claim 15 substantially as herein described in any one of Examples 91 to 164. 118. A process for the preparation of compounds as claimed in claim 16 substantially as herein described in any one of Examples 165 to 278. 119. Compounds as claimed in claim 1 whenever prepared by a process as claimed in any one of claims 21 to 110, 114 and 115. 120. Compounds as claimed in claim 14 whenever prepared by a process as claimed in claim 111 or claim 116. 121. Compounds as claimed in claim 15 whenever prepared 1943 17 O-'Zo by a process as claimed in claim 112 or claim 117. 122. Compounds as claimed in claim 16 whenever prepared by a process as claimed in claim 113 or claim 118. 123. Pharmaceutical compositions comprising, as active ingredient, at least one compound of formula I as defined in claim 1 or, where and together with the nitrogen atom to which they are attached, represent a cyclic imino group as defined in claim 1 and/or where Z represents or contains a carboxy group, a physiologically compatible salt thereof in association with a pharmaceutical carrier or excipient. 124. Compositions as claimed in claim 123 in a form suitable for galenic administration. 125. Compositions as claimed in claim 123 or claim 124 in the form of plain tablets, coated tablets, capsules, powders and suspensions. 126. Compositions as claimed in any one of claims 123 to 125 in the form of dosage units. 127. Compositions as claimed in claim 126 wherein each dosage unit contains from 1 to 50 mg of active ingredient. 128. Compositions as claimed in claim 127 wherein each dosage unit contains from 2.5 to 20 mg of active ingredient. 129. Compositions as claimed in any one of claims 123 to 128 wherein the active ingredient comprises a compound of formula I as defined in any one of claims 6 to 11 or a physiologically compatible salt thereof. 130. Compositions as claimed in claim 123 wherein the active ingredient comprises a compound as claimed in claim 14. 19431'V L * Vl - >^4 - dO-\ 131. Compositions as claimed in claim 123 wherein the active ingredient comprises a compound as claimed in claim 15. 132. Compositions as claimed in claim 123 wherein the active ingredient comprises a compound as claimed in claim 16. 133. Pharmaceutical compositions as claimed in claim 123 substantially as herein described. 134. Pharmaceutical compositions substantially as herein described in any one of Examples I, III, IV, V and VI. 135. Pharmaceutical compositions substantially as herein described in Example II. CAREY attorneys FOR THE applicants
NZ194317A 1979-07-13 1980-07-11 Benzoic acid derivatives and pharmaceutical compositions containing them NZ194317A (en)

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NZ20247880A NZ202478A (en) 1979-07-13 1980-07-11 Substituted amino-substituted benzene derivatives and pharmaceutical compositions

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DE19792928352 DE2928352A1 (en) 1979-07-13 1979-07-13 Hypoglycaemic 2-amino-benzamido-ethyl-benzoic acid derivs. - prepd. e.g. by reaction of 2-amino-benzoic acid derivs. with 4-aminoethyl-benzoic acid derivs.
DE19792949259 DE2949259A1 (en) 1979-07-13 1979-12-07 Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity
DE19803016650 DE3016650A1 (en) 1979-07-13 1980-04-30 Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity
DE19803016651 DE3016651A1 (en) 1980-04-30 1980-04-30 Amino-pyridine or benzene carboxylic acid derivs. - with metabolic, esp. hypoglycaemic and hypolipaemic, activity

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DE3211934A1 (en) * 1982-03-31 1983-10-13 Hoechst Ag, 6230 Frankfurt SALICYL ACID DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF, PHARMACEUTICAL PREPARATIONS BASED ON THESE COMPOUNDS AND THEIR USE
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