CA1176246A - Carboxylic acid amides, their preparation and their use as pharmaceutical compositions - Google Patents

Carboxylic acid amides, their preparation and their use as pharmaceutical compositions

Info

Publication number
CA1176246A
CA1176246A CA000393789A CA393789A CA1176246A CA 1176246 A CA1176246 A CA 1176246A CA 000393789 A CA000393789 A CA 000393789A CA 393789 A CA393789 A CA 393789A CA 1176246 A CA1176246 A CA 1176246A
Authority
CA
Canada
Prior art keywords
group
compound
carbon atoms
acid
ethyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
CA000393789A
Other languages
French (fr)
Inventor
Wolfgang Grell
Gerhart Griss
Robert Sauter
Rudolf Hurnaus
Eckhard Rupprecht
Nikolaus Kaubisch
Joachim Kahling
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Boehringer Ingelheim Pharma GmbH and Co KG
Original Assignee
Dr Karl Thomae GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Dr Karl Thomae GmbH filed Critical Dr Karl Thomae GmbH
Application granted granted Critical
Publication of CA1176246A publication Critical patent/CA1176246A/en
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • 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
    • C07D207/18—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 one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—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 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, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/263—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms
    • C07D207/27—2-Pyrrolidones with only hydrogen atoms or radicals containing only hydrogen and carbon atoms directly attached to other ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • C07D211/36—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
    • C07D211/68—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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/79—Acids; Esters
    • C07D213/80—Acids; Esters in position 3
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • 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
    • C07D295/06—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 halogen atoms or nitro radicals
    • C07D295/073—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 halogen atoms or nitro radicals with the ring nitrogen atoms and the substituents 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
    • C07D295/04—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
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/096—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur 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
    • C07D295/04—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
    • C07D295/10—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 doubly bound oxygen or sulphur atoms
    • C07D295/112—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 doubly bound oxygen or sulphur atoms with the ring nitrogen atoms and the doubly bound oxygen or sulfur 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
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms 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
    • C07D295/04—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
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/22—Radicals substituted by singly bound oxygen or sulfur atoms etherified
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
    • C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
    • C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
    • 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

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Endocrinology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Emergency Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Hydrogenated Pyridines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Indole Compounds (AREA)
  • Other In-Based Heterocyclic Compounds (AREA)
  • Pyrrole Compounds (AREA)
  • Optical Record Carriers And Manufacture Thereof (AREA)
  • Photoreceptors In Electrophotography (AREA)
  • Medicinal Preparation (AREA)
  • Carbon And Carbon Compounds (AREA)

Abstract

ABSTRACT OF THE DISCLOSURE

Compounds of general formula I

,(I) wherein R1 and R2 represent alkyl or cycloalkyl groups or together with the nitrogen atom to which they are attached, represent a cyclic imino group, R2 represents a hydrogen or a halogen atom, an optionally substituted hydroxy, mercapto, amino, carboxy or aminocarbonyl group, or a nitro, alkanoyl, aminosulfonyl, trifluoromethyl or cyano group, R4 represents a hydrogen atom or an alkyl group.
R5 represents a hydrogen or a halogen atom or an alkyl group, A represents a bond or an optionally substituted methylene, ethylene or vinylidene group, B represents a methylene or ethylene group optionally substituted by an alkyl group and W represents a hydrogen or a halogen atom, a cyano, alkanoyl or nitro group, an optionally substituted amino or aminocarbonyl group.
a carboxy group or an ester thereof, a formyl group or an acetal thereof or an optionally substituted alkyl group); and salts thereof formed with acids and bases. Processes for the preparation of the new compounds as well as pharmaceutical compositions containing them are also objects of this invention.
The new compounds show valuable pharmaceutical properties, especially effects on intermediary metabolism and a blood-sugar lowering activity.

Description

- 1 ~1762~6 ClrEMICAL CO.MPOUNDS

This invention relates to new carboxylic acid amides, to processes .for their preparation and to pharmaceutical compositions containing them, and also to their use in the treatment of disorders of irtermediary metabolism.
According to one feature of the present invention there are provided compounds of general formula I
~4 ~ W
3 ~ A - N - C0 - B ~ ,(I) ~ 1 5 N~R2 [wherein Rl and R2, which may be the same or di.tterent, each represents an alkyl aroup containina 1 to 6 carbon atoms or a cycloalkyl aroup containina 5 to 7 carbon atoms, or Rl and X2 together with the nitroaen atom to which they are attached represent an unbranched alkyleneimino group containing 3 to 6 carbon atoms optionally substituted by 1 or 2 alkyl aroups, each containina 1 to 3 carbon atoms, or by a hydroxy aroup and in which a meth~lene ~roup may optionally be replaced by a carbonyl aroup, by an oxyaen or sulfur atom or by an imino group (which may optionallv be substituted by an alkyl group containina 1 to 3 carbon atom, ~n aralkyl aroup containing 7 to 10 carbon atoms or by a phenyl or halophenyl group) or an ethylene group mav optionally be replaced by an O-phenylene croup;
and unbranched alkenyleneimino qroup containinq 4 to 6 carbon atoms; a saturated or partly unsaturated azabicvcloalkyl group containing 6 to 10 carbon atoms an aza-1,4-dioxa-spiro-alkyl aroup containin~ 6 to ~ carbon atoms; or a heptamethyleneimino, octamethyleneimino, nonamethyleneimino or decamethyleneimino qroup; R3 represents a hydroaen or haloaen atom, a trifluorometh~], alkyl, hvdroxy, alkoxy, alkanoyloxy, mercapto, alkylmercanto, nitro, amino, cvano, 1 ~762~

alkanoyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkylamino-carbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylamino, dialkyl-amino, alkanoylamino, alkoxycarbonylamino or alkylsulfonylamino group (wh~rein each alkyl part in the above mentioned groups may contain from 1 to 3 carbon atoms), an aralkoxy group containing 7 to 10 carbon atoms or an arylcarbonylamino group; R4 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms; R5 represents a hydrogen atom, a halogen atom or an alkyl group con-taining 1 to 3 earbon atoms; A represents a bond, a methylene or ethylene group optionally substituted by a methyl, ethyl or isopropyl group, a methylene or ethylene group substituted by two alkyl groups each containing 1 to 3 carbon atoms, a methylene group substituted by a cycloalkyl group containing 3 to 7 carbon atoms or by a hydroxyalkyl, carboxyl, alkoxycarbonyl, or phenyl group, wherein each of the alkyl parts may contain from 1 to 3 carbon atoms, a cycloalkylidene group containing 3 to 7 carbon atoms or a vinylidene group of formula /
C
--C --wherein R6 and R7, whieh may be the same or different, eaeh represents a hydrogen atom or one of the radieals R6 and R7 represents a methyl group or a cycloalkyl group containing 3 to 7 earbon atoms and the other is as defined above or R6 and R7 together with the earbon atom to which they are attaehed, represent a cycloalkylidene radical containing 5 to 7 carbon atoms; B
represents a methylene or ethylene group optionally substituted by an alkyl group containing 1 to 3 carbon atoms and W represents a hydrogen or halogen atom, a nitro group, an amino group ~optionally ..~

- 3 - 1~624~

substituted by an alkanoyl qroup containina 1 to 3 carbon atoms) an alkyl aroup containina 1 to 3 carbon atoms ~optionally substituted by a hydroxy or carboxy ~roup or by one or two alkoxycarbonyl ~roups containina 2 to 4 carbon atoms each), an alkenyl group containinq 2 to 5 carbon atoms substituted by a carboxy or alkoxycarbonyl group containing 2 to 4 carbon atoms, an alkanoyl qroup containinq 1 to 3 carbon atoms, a dialkoxymethyl or trialkoxymethyl group containinq 1 to 3 carbon atoms in each alkyl part, an alkylenedioxymethyl group containinq
2 or 3 carbon atoms in the alkylene part, a 1,3-oxazoline-2-yl or cyano aroup, an aminocarbonyl group (optionally substituted by one or two alkyl qroups containing 1 to 4 carbon atoms in each alkyl part), an unbranched alkyl-eneiminocarbonyl aroup containing 5 to 8 carbon atoms a morpholinocarbonyl aroup, a (dialkyldioxolane-yl)-alkoxycarbonyl group containing 7 to 10 carbon atoms or a carboxy group or esterfied carboxy ~roup wherein if the said ester group consists of an alkyl qroup containina 1 to 6 carbon atoms this may be substituted, in any but the ~-position, by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, 1,3-dimethylxanthin~7-yl, alkanolyoxy, aroyl-oxy, aralkanoyloxy or pyridine-carbonyloxy group or by two hydroxy groups - except in the case of any methyl or methylene aroup in the above cases, which can only be substituted by one hydroxy aroup or bv a aroup of formula B - CO - N - A ~

R5 R1 \ R2 _ 4 _ 1~7624~

wherein A~ B~ Rl, R2, R3~ R4 and R5 are as hereinbefore defined whereby each alkyl part of the above alk~l ester substitutents ~ycontain from 1 to 3 carbon atoms), and salts thereof.
The new compounds posses~ interesting ~harmacoloaical properties, especially in qeneral an e~fect an inter-medlary metab~lism and in particular a blood-su~ar lowerin~
activity.
~ or ~harmaceutical use, the salts referred to above will of course be physiolo~ically compatible salts formed with acids or ~ases, but other salts may find use in the preparation of the compounds of formula I and the~r physiologically compatible salts. The term "sa~ts formed with acids or bases" inclu~es salts formed with inor~anic or or~anic acids or bases.
The invention extends to all ~ossible iso~ers, including optional isomers, of compo~nds of formula I.
Rl and R2 together with the nitroqen atom ma-~ represent for example, dimethylamino, diethylamino,di~ropyl~no, dibutyl~no diisobutylamino, dipentylamino, dihexylamino, N-methyl-N-ethylamino, N-methyl-N-propylamino, N-isopropyl-N-propylamino, N-isobutyl-N-propylamino, N-methyl-N-iso-propyla~ino, N-methyl-N-butylamino, N-ethyl-N-butylamino, N-ethyl-N-isopropylamino, N-ethyl-N-pentylamino, N-propyl-N-butylamino, N-methyl-N-cyclopentylamino, N-ethyl-N-cyclopentylamino, N-methyl-N-cyclohe~ylamino, N-ethyl-N-cyclohexylamino, N-propyl-N-cyclohexylamino, N-isobutyl-N-cyclohexylamino, pyrrolidino, piperidino, he~amethyleneimino, heptamethyleneimino, octamethylen-imino, nonamethyleneimino, decamethyleneimino, dimethyl_ azetidino, methyl-pyrrolidino, dimethyl-pyrrolidino, ethyl-pyrrolldino, methyl-piperidi~o, dimethyl-piperidino J
ethyl-piperidino, di~thyl-piperidino, methyl-ethyl-piperi-dino, propyl-piperidino, methyl-propyl-piperidino, iso-propyl-piperidino, cis-3,5-dimethyl-piperidino, tr~ns-
3,5-dimethyl-piperidino, morpholino, thiomorpholino, piperazino, N-methyl-piperazino, N-ethyl-piperazino, N-propyl-piperazino, N-isopropyl-piperazino, N-benzyl-piperazino, N-(2-phenyl-ethyl)-piperazino, N-(3-phenyl-propyl) piperazino, N-phenyl-piperazino, N-fluorophenyl-piperazino, N-chlorophenyl-piperazino, N-bromophenyl-pipera-zino, hydroxy-pyrrolidino, hydroxy-piperidino, hydroxy-hexamethy~
leneimino, pyrrolidone-1-yl, piperidone-1-yl, hexahydroazepino-ne-1-yl, tetrahydro-isoquinoline-2-yl, octahydro-isoquinoline-2-yl, decahydro-iso~uinoline-2-yl, dihydro-isoindole-2-yl, hexahydro-isoindole-2-yl, octahydro-isoindole-2-yl, tetrahydro-3-benzazepine-3-yl, decahydro-3-benzazepine-3-yl, 3-aza-bicyclo ~ .2._7heptane-3-yl, 3-az~-bicyclo-.2. ~ octane-3-yl, 3-aza-bicyclo ~ .3.3 nonane-3-yl, 1,4-dioxa-7-aza-spîro ~ , g nonane-7-yl, 1,4-dioxa-7-aza-spiro ~ ,~ decane-7-yl, 1,4-dioxa-8-aza-spiro ~ , ~ decane-8-yl, 1,4-dioxa-8-aza-spiro ~ , 0 undecane-8-yl, pyrrolino or tetrahydropyridine group;
R3 may represent, for example, a hydroaen, fluorine, chlorine, bromi.ne or iodine atom, or a methyl, eth~l, pro~yl, iso~ropyl, hydroxy, methoxy, 2~ ethoxy, propoxy, isopropoxy, acetoxy, propionyloxy, mercapto, methylmercapto, ethylmercapto, propylmer-capto, isopropylmercapto, trifluoromethyl, nitro, cyano, formyl, acetyl, propionyl, aminosul~onyl, amino, methylamino, ethylamino, propylamino, di-methylamino, diethylamino, dipropylaminc, diisopropyl-amino, N-methyl-N-ethyl-amino, N-methyl-N-isopropyl-~mino, N-ethyl-N-propylamino, formylamino, acetylamino, propionylami~o, methylsulfonylamino, ethylsulfonyl-amino, propylsulfonylamino, isopropylsulfonylamino, carboxy, methoxycarbonyl, ethoxycarbonyl, propoxycar-bonyl, isopropoxycarbonyl, methoxycarbonylamino, ethoxy_ carbonylamino, propoxycarbonylamino, isopropoxy-carbonylamino, ben~oylamino, benzyloxy, 1-phenyl-ethoxy, 2-phenyl-ethoxy, 3-phenyl-propoxy, aminocar-bonyl, methylaminocarbonyl, ethylaminocarbonyl, iso-propylaminocarbonyl, dimethylaminocarbonyl, diethyl-aminocarbonyl, dipropylaminocarbonyl, methyl-ethyl-~ 176246 aminocarbonyl, or methyl-propylaminocarbonyl group;
R4 may represent a hydrogen atom, or a methyl, ethyl, propyl or an isopropyl group;
R5 may represent a hydrogen, fluorine, chlorine, bromine or an iodine atom, or a methyl, ethyl, propyl or an isopropyl group;
A may represent, for example, a single bond, or a methylene, ethylidene, ethyl-methylene, isopropyl-methylene, dimethyl-methylene, diethyl-methylene, dipropyl-methylene, methyl-ethyl-methylene, methyl-propyl-methylene, ethyl-propyl-methylene, ethyl-isopropyl-methylene, ethylene, methyl-ethylene, ethyl-ethylene, propyl-ethylene, dimethyl-ethylene, cyclopropyl-methvlene, cyclobutyl-methylene, cyclopentyl-methylene, cyclohexyl-methylene, cycloheptyl-methylene, cyclopropylidene, cyclobutylidene, cyclopentylidene, cyclohexylidene, cycloheptylidene, carboxymethy-lene, methoxycarbonyl-methylene, ethoxycarbonyl-methylene, propoxycarbonyl-methylene, hydroxymethyl-methylene, l-hydroxyethyl-methylene, 2-hydroxyethyl-methylene, l-hydroxypropyl-methylene, 3-hydroxypropyl-methylene, phenyl-methylene, vinylidene, methyl-vinylidene, cyclopentyl-vinylidene, cyclohexyl-vinylidene, cyclopropylidene-methylene, cyclopentylidene-methylene, cyclohexylidene-methylene or cycloheptylidene-methylene group;

,~

R may represent, for exam~le, a methylene, ethylene, ethyl-idene, propyl-methylene or isopropyl-methylene aroup; and may represent, for example, a hydroaen, chlorine, bromine or iodine atom, or a methyl, ethvl, ?ropyl, isopro~yl, hydroxy-methyl, l-hydroxyethyl, 2-hydroxyethyl, l-hydroxyPropyl, 3-hydroxypropyl, carboxymethyl, 1-carboxyethyl, 2-carb-oxy~thyl, 3-carboxy-propyl, methoxycarbonyl-methyl, ethoxycarbonyl-methyl, propoxycarbonyl-methyl, 2-meth-oxycarbonyl-ethyl, 2-ethoxycarbonyl-ethyl, 3-ethoxy-carbonylpropyl, bi~-(methoxycarbonyl)-methyl, bis-(ethoxy-carbonyl)-methyl, 2,2-bi 5-( ethoxycarbonyl)-ethyl, carboxy-~inyl, carboxy-propenyl, carboxy-pentenyl, ~etho~ycarbonyl-vinyl, ethoxycarbonyl-~inyl, propoxy-carbonyl-vinyl, formyl, acet~l, propionyl, dimethoxy-methyl, diethoxy-methyl, dipropoxy-methyl, trimethoxy-methyl, triethoxy-methyl, 1,2-ethylenedioxy-methyl, 1,3-prop~lenedioxy-mothyl, cyano, nitro, amino, formyl-amino, aceta~ino, propionylamino~ 1,3-oxazoline-2-yl, aminocarbonyl, methyla~inocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, isopropylaminocarbonyl, butylamino-carbo~yl, dimethylamlnocarbonyl, diethylaminocarbo~yll dipropylaminocarbonyl, dibutylaminocarbonyl, pyrrolidino-carbonyl, piperidinocarbonyl, hexamethyleneiminocarbonyl, hepta~ethyleneiminocarbonyl, morphol~nocarbonyl, carboxy, methoxycarbonyl, ethoxyc~rbonyl, propoxycarbonyl, iso-propoxycarbonyl, butoxycarbonyl, tert.butoxycarbonyl, pentoxycarbonyl, hexoxycarbonyl, heptoxycarbonyl, octoxy-carbonyl, allyloxycarbonyl, butenyloxycarbonyl~ benzyl-oxycarbonyl, 1-phenylethoxycarbonyl, 2-phenylethoxy-carbonyl, 3-phenylpropoxycarbonyl, 2-hydroxyethoxy-carbonyl, 2-hydroxypropoxycarbonyl, 3-hydroxypropoxycar-bonyl, 2-methoxyethoxycarbonyl, 2-ethoxyethoxycarbonyl, (2,2-dimethyl-dioxolane-4-yl)-methoxycarbonyl, 2-(2,2-di-methyl-dioxolane-4-yl)-ethoxycarbonyl, (2,2-diethyl-dioxo-lane-4-yl)-methoxy-carbo~yl, 2-(2,2-diethyl-dioxolan-4-yl)-ethoxycarbonyl, 3-(2,2-dimethyl-dioxolane-4-yl)-propoxy-carbonyl, 2-aminoethoxycarbonyl, 2-dimethylamino-ethoxycarbonyl, 2-diethylamino-ethoxycarbonyl, 2-(1,3-di-methyl-xanthine-7-yl)-ethoxycarbonyl, 2-acetoxy-ethoxy-carbonyl~ 2-benzyloxy-ethoxycarbonyl, 2-phenylacetoxy-ethoxycarbonyl, 2-pyridinecarbonyloxy-ethoxycarbonyl, 2,3-dihydroxy-propoxycarbonyl, 3,4-dihydroxy-butoxycarbonyl, 2-[4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]benzoyloxy]ethoxycarbonyl or 3-[4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoyloxy]propoxy-carbonyl group.
Preferred compounds of the above general formula I are, however, those wherein Rl and R2 together with nitrogen atom to which they are attached represent a dialkylamino or N-alkyl-cyclohexylamino group, wherein each alkyl part may contain from1 to 4 carbon atoms, an unbranched alkyleneimino group containing 3 to 6 carbon atoms (optionally substituted by one or two methyl groups)/ a hydroxypiperidino, piperidone-1-yl, tetrahydro-pyridino, morpholino, thiomorpholino, N-methylpiperazino, N-benzyl-piperazino, N-chlorophenyl-piperazino, heptamethyleneimino or octamethylene-imino group, a saturated or partly unsaturated azabicycloalkyl group containing 7 to 9 carbon atoms, an unbranched alkyleneimino group containing 4 to 6 carbon atoms wherein one ethylene group is replaced by a o-phenylene group, or a 1,4-dioxa-aza-spiro-alkyl group containing 7 or 8 carbon atoms;
R3 represents a hydrogen, fluorine, chlorine, bromine or iodine atom, or a methyl, trifluoromethyl, hydroxy, methoxy, benzyloxy, acetoxy, mercapto, methylmercapto, nitro, amino, dimethylamino, acetylamino, methylsulfonylamino, benzoylamino, ethoxy-carbonylamino, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, acetyl or aminosulfonyl group;
R4 represents a hydrogen atom ox a methyl group;
R5 represents a hydrogen atom, a chlorine atom or a methyl group;

~ -8-.~

1 1~6246 A represents a bond, or a methylene group (optionally substituted by methyl, ethyl, isopropyl, phenyl, cyclohexyl, carboxy, methoxycarbonyl or a hydroxymethyl group), a dimethyl-methylene, cyclopropylidene or ethylene group or a vinylidene group of formula C

--C
wherein R6 and R7, which may be the same or different, each represents a hydrogen atom or one of the radicals R6 and R7 represents a methyl group and the other is as defined above, or R6 and R7 together with the carbon atom to which they are attached represent a cycloalkylidene radical containing 1 to 3 carbon atoms;
B represents a methylene, ethylidene or ethylene group; and W represents a hydrogen atom, or a methyl, ethyl, hydroxymethyl, cyano or carboxyvinylene group, an alkyl group containing 1 to 3 carbon atoms substituted by a carboxy group or by one or two alkoxycarbonyl groups containing 2 to 4 carbon atoms each, a carbonyl group (substituted by a hydrogen atom, a methyl, ethyl, hydroxy alkoxy, (2,2-dimethyl-dioxolane-4-yl)-methoxy, benzyloxy, pyridyl-methoxy, amino, alkylamino, dialkylamino, piperidino or morpholino group), whereby any alkyl part in the aforementioned groups may contain from 1 to 3 carbon atoms, or a group of formula o - C - O - (CH2)n 8 wherein n is 2, 3, or 4; and R8 represents a hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy, pyridinecarbonyloxy group, a dialkylamino group containing 1 to 3 carbon atoms in each alkyl part, a 1,3-dimethyl-_g _ l 17824G
xanthine-7-yl group or a group of formula / Z~ ~B - CO - N - A ~ 3 N

R5 / \

wherein A, s, Rl, R2, R3, R4 and R5 are as hereinbefore defined;
and especially those compounds of general formula I wherein the radical R

\ R

is in the 2-position and the radical W is in the 4'-position.
Especially preferred are compounds of general formula Ia A - N - CO - CH2 ~ - W

3 ~ ~ R ,(I~) wherein Rl and R2 together with the nitrogen atom to which they are attached, represent a dimethylamino, pyrrolidino, methyl-pyrrolidino, piperidino, methylpiperidino, dimethylpiperidino, tetrahydro-pyridino, 2-octahydroisoindolo or hexamethyleneimino group; R3 represents a hydrogen, fluorine or a chlorine atom or a methyl group;
A represents a methylene group (optionally substituted by a cyclohexyl, phenyl, methoxycarbonyl, ethoxycarbonyl, methyl, ethyl or isopropyl group), or a dimethylmethylene group or a ',~ -1 ~-1 17~24~

vinylidene group of formula C

C
wherein R6 and R7 each represents a hydrogen atom or together with the carbon atom to which they are attached represent a cyclohexylidene group; and W represents a methyl, hydroxymethyl or a carboxymethyl group, or -lOa-1 i762~6 a carbonyl group (substituted by a hydro~en atom, a methyl, hydroxy, methoxy, ethoxy, propoxy, isopropoxy~ 2-hydroxyethoxy, 2-methoxyethoxy, (2,2-dimethyl-dioxolane-4-yl)-methoxy, or a 2--diethvlaminoethoxv qroup).
The compounds of formula I may, for examPle, be prepared by the following processes, which ~rocesses constitute further features of the present invention:
a) Acylation of an amine of general formula II

~ A - N ,(II) 3 ~ J
~X, 1 N ~R

wherein A, Rl, R2, R3 and R4 are as hereinbefore defined, (or if A represents one of the above mentioned vinylidene groups one of its tautomers~or its lithium or magnesium halide complex) with a carboxylic acid of general formula III

HOOC- B ~ ,(III) wherein R5 and B are as hereinbefore defined and rA~ represents W as hereinbefore defined or represents a carboxvl ~roup protected by a protective radical, or with reactive derivatives thereof optionally ~repared in the reaction mixture.
Suitable reactive derivatives of a compound of aeneral formula III include, for example, esters (such as the methyl, ethyl or benzyl ester), thioesters (such as the methylthio or ethylthioester), halides (such as the acid chloride~, anhydrides or imidazolides thereof.
The reaction is convenientlv carried out in a solvent, such as for example methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, - 12 ~ 6 2 4 ~

toluene, acetonitrile or dimethylformamide, optionally in the presence of an acid-activatina or a dehvdratina a~ent, (e.a. in the presence of ethyl chloroformate, thionvl chloride, phosphorous trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N-dicyclohexvlcarbodiimide/N-hydroxy-succinimide, N,N'-carbonyldiimidazole, N,N'~
thionyldiimidazole, or triphenyl phosphine/carbon tetrachloride), or of an a~ent activatin~ the amino ~roup (e.g. phosphorous chloride) and optionally in the presence of an inorrsanic base such as, for example, sodium carbonate or a tertiary or~anic base such as triethyl-amine or pyridine, which simultaneously may serve as a solvent, at temperatures between -25 and 250C, preferably, however, at temperatures between -10C and the boilin~ temperature of the used solvent. The reaction mav also be carried out without a solvent. Furthermore, the water which is formed during the reaction may be removed by azeotropic distillation (e.g. bv heatina with toluene in a water separator funnel) or by addition of a dryina a~.~ent such as maanesium sulfate or a molecular sieve.
If necessary, the subse~suent removal of a ~rotective radical is preferably carried out hydrolytically,conveniently in the presence of either an acid (such as, for example, hydrochloric, sulfuric,phosphoric or trichloroacetic acid) or a base such as sodium hydroxide or potassium hydroxide in a solvent such as for examnle water, methanol, ethanol, ethanol/water, water/isopropanol or water/dioxan at temperature between -10 and 120C, e.a. at temperatures between room temperature and the boilina temperature 3~ of the reaction mixture. A tert.hut~l radical used as protective radical may also be removed thermolytically (optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan) and preferably in the presence of a catalytic 3~ amount of an acid such as,for example, p-toluenesulonic, sulfuric, phosphoric or polyphosphoric acid.
Furthermore, a benzyl radical used as protective radical may also be removed ilydro~enolytically (in the presence of a hydroaenation catalyst such as 1 17624~

palladium/charcoal) in a solvent such as, for example, methanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethyl formamide.
b~ For the preparation of compounds o.f general formula I, wherein W represents a carboxy group:
Cleavage of a compound of aeneral formula IV
R

~ A - N - CO - B ~ D

R~ ~ ~ R2 R5 ,(IV) wherein Rl, R2, R3, R4, P~5, A and B are defined as mentioned before and D represents a aroup which nay be converted into a carboxy group by means of hydrolysis, thermolysis or hydrogenolysis.
Suitable hydrolysable aroups include, for example, carboxy derivatives (such as unsubstituted or substituted amides, esters, thioesters, orthoesters, iminoethers, 1~ amidines or anhydrides), a nitrile group, a malonic ester-tl)-yl group, a tetrazolyl group or an optionally substituted 1,3-oxazole-2-yl or 1,3-oxazoline-2-yl group.
Suitable thermolytically cleavable groups include, for example, esters with tertiary alcohols, e.g. the tert.
butyl ester.
Suitable hydrogenolytically cleavable qroups include, for example, aralkyl groups, e.g. the benzvl aroup.
The hydrolysis is conveniently carried out either in the presence o~ an acid (such as for example, hydrochloric,sulfuric, phosphoric or trichloroacetic acid) or a base (such as sodium hydroxide or potassium hydroxide) in a solvent such as, for example, water/methanol, ethanol, water/ethanol, water/isopropanol or water/dioxan at - 14 - 117624~

temperatures between -lO and 120C, e.a. at temperatures between room temperature and the boiling temperature of the reaction mixture.
Thus if, for example, D in a compound of general formula IV represents a nitrile or aminocarbonyl group, these groups may be converted into a carboxy group with a nitrite, e.a. sodium nitrite, in the presence of an acid (such as sulfuric acid~, whereby conveniently this acid is simultaneously used as a solvent, at temperatures between 0 and 50C; if for example , D
represents a tert.butyloxycarbonyl group, the tert.butyl group may be split off thermolytically (optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxan~ and preferably in the presence of a catalytic amount of an acid such as p-toluenesulfonic, sulfuric, phosphoric or polyphosphoric acid preferably at the boilina temperature of the used solvent, e.g. at temperatures between 40 and 100C; or if for example D represents a benzyloxycarbonyl group, the benzyl aroup may be split off hydroaenolytically in the presence of a hydro~enation catalyst such as palladium/charcoal in a solvent such as for example, methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxan or dimethyl formamide preferably at temperatures between 0 and 50C, e.a.
at room temperature, and at a hydroaen pressure of 1 to 5 bar. During the hydrogenolysis other qroups may optionally simultaneously be reduced, e.g. a halogen compound may be dehalogenated, a nitro aroup may be converted into the corresponding amino group, or a vinvli-dene group into the corresponding alkylidene group .
c) Reaction of a compound, optionally formed in the reaction mixture, of general formula V

3 ~ 4 ~ 5 N - R ' - 15 ~ 62~5 wherein R3, R4, R5, A, B, and W are as hereinbefore defined and, R2' represents a hydrogen atom or has the meanings mentioned before for R2, with a compound of general formual VI
Rl' - E (VI) [wherein Rl' has the meanings mentioned before for Rl or together with the radical R2' of formula V represents a straight-chained alkylene group containing 4 to 6 caxbon atoms (optionally substituted by one or two alkyl aroups containing 1 to 3 carbon atoms) or an n--pentylene group in which the third methylene aroup is replaced by an oxygen or sulfur atom, and E represents a nucleophilically exchangeable aroup such as a halogen atom or a sulfonyloxy aroup (e.g. a chloxine, bromine or an iodine atom or a 15 methanesulfonyloxy or p-toluenesulfonyloxy group), or also a hydrogen atom if in Rl' one methylene group is replaced by an aldehyde or ketone carbonyl group], if necessary in the presence of a reducina agent,and optional subsequent hydrolysis.
Suitable alkylating agents of formula VI include, for example, the corresponding halides or sulfates such as methyl iodide, ethyl iodide, propyl bromide, dimethyl sulfate or diethyl sulfate.
The reaction is conveniently carried out in a solvent such as,for example, acetone, tetrahydrofuran, dimethyl formamide, dimethylsulfoxide or hexamethyl phosphoric acid triamide, optionally in the presence of an inoraanic base (such as sodium carbonate, potassium carbonate or potassium tert.butylate) or tertiary oraanic base (such as pyridine) at temperatures between 0 and 150C; preferably, however, at temperatures between 20 and 75C. If a compound of general formula V is used wherein W represents a carboxyl group, this carboxyl group may simultaneously be converted into the correspondina ester depending on the reaction conditions, e.g. at temperatuxes above room temperature and in the presence of a base, for example sodium carbonate.
The methylation may optionally also be carried out 1 1~62~
so that a compound of aeneral formula V is reaeted with formalin in the presenee of a reducina aaent, e.a. formic aeid or hydroqen in the presenee of a hydrogenation eatalyst (e.q. palladium or platinum), optionally in a solvent such as formie acid or alacial acetie aeid at temperatures up to the boiling temperature of the reaction mixture.
Moreover, the alkylation may oPtionally also be carried out with a corresponding carbonyl compound in the presence of a hydride such as sodium cyanoborohydride in a solvent such as for example acetonitrile/glacial acetic aeid or dimethyl formamide/aeetic aeid preferably at pH
7 and at temperatures between 0 and 50C.
The subsequent hydrolysis is preferably earried out in an aqueous solvent sueh as water/methanol, water/ethanol or water/dioxan in the presenee of an aeid (sueh as hydroehlorie or sulfuric acid) or a base (such as sodium or potassium hydroxide) at temperatures between 50 and 1 0 0 C .
d) For the preparation of compounds of general formula I wherein W represents a carboxy aroup, an alkanoyl aroup eontaining 1 to 3 earbon atoms or an alkyl group containing 1 to 3 carbon atoms:
Reaction of a compound of general formula VII

A - N - C0 - ~ ~ ,(VII) N

wherein Rl, R2, R3, R~, R5, A and B are as hereinbefore defined, with phosaene, an oxalyl halide, an alkyl or alkanoyl halide containing 1 to 3 carbon atoms in the alkyl part or with hydrogen cyanide and a hydroaen halide (preferably hydrogen chloride), in the presence of a ~ewis acid.
Suitable halides inelude ehlorides and bromides, and - 17 - 117624~

the L.ewis acid is preferably aluminium chloride.
The reaction is preferably carried out in a solvent such as methylene chloride, nitrobenzene, chlorobenzene, dichlorobenzene, tetrachloroethane or carbon disulfide or in polyphosphoric acid at temperatures between 0 and 120C, preferably, however at temperatures between 20 and 80C.
If in a compound of,general formula VII,R3 represents a hydrogen atom, this may simultaneously be replaced by a corresponding alkyl or acyl radical.
e) For the preparation of compounds of general formula I wherein W represents a carbox~ group;
Reaction of a compound of general formula VIII

R3 ~ A - - CO - B ~ COCH3 N
~ R2 wherein Rl, R2, R3, R4, R5, A and ~ are as hereinbefore defined, with a hypohalite optionally prepared in the reaction mixture. The reaction is conveniently carried out in a solvent ~such as for examnle water/tetrahydrofuran or water/dioxan) and in the presence of a base (such as sodium hydroxide or potassium hydroxide) at temperatures between 0 and 80C; preferably, however, at temperatures between 25 and 50C.
f) For the preparation of compounds of general formula I wherein W represents a carboxy group:
Oxidation of compound of general formula IX

R3 ~ R4 ~ ,(IX) N
~ R2 - 18 - ~ 17~4~

wherein Rl, R2, R3, R4, R5, A and B are as hereinbefore defined and G represents a aroup which may be converted by means of oxidation into a carboxy group.
Such an oxidizable group includes for example a formyl group or one of its acetals, a hydroxymethyl aroup or one of its ethers, or an unsubstituted or substituted acyl group ( such as an acetyl, chloroacetyl, propionyl, malonic acid-(l)-yl qrou~ or a malonic ester-(l)-yl aroup).
The reaction is carried out by means of an oxidizing agent in a solvent ~such as for example water, alacial acetic acid, pyridine or carbon tetrachloride) at temperature between 0 and 100C, conveniently, however, at temperatures between 20 and 50C. The reaction is preferably carried out with silver oxide/sodium hydroxide solution, manganese dioxide/acetone or methylene chloride, hydrogen peroxide/
sodium hydroxide solution, bromine or chlorine/sodium or potassium hydroxide solution or chromium trioxide/pyridine.
g) For the preparation of compounds of aeneral formula I, wherein R3 represents a nitro aroup:
Reaction of a compound of general formula X
R
4 ~ W
3 ~ A - N - CO - B ~ ,(X) (wherein R4, R5, A, B and W are as hereinbefore defined, R3 represents a nitro qroup and Y represents a nucleophilically exchanaeable radical such as a haloaen atom) with an amine of general formula XI

H - ~ ,(XI) - 19 ~ 762~

(wherein Rl and R2 are defined as mentioned before), and optional subse~uent hydrolysis.
The term "a halogen atom" used in the definition of the exchangeable radical Y particularly represents a S fluorine, chlorine or a bromine atom, and preferably in the o- or p-position relative to the nitro group.
The reaction is conveniently carried out in a solvent such as for example, water, water/methanol, water/
ethanol, water/isopropanol, water/dioxan, methanol, ethanol, dimethyl formamide, or in an excess of the amine of general formula XI and/or the N-formyl derivate thereof ~optionally in the presence of an inorganic or tertiary organic base), optionally in the presence of a reaction accelerator such as copper or a copper salt and optionally in a closed vessel at temperatures between 20 and 150C;
preferably, however at the boilin~ temperature of the reaction mixture (e.g. at 100C~. The reaction may, however, be carried out without a solvent.
The optional subsequent hydrolysis is conveniently carried out in an aqueous solvent such as for example methanol/water, ethanol/water or dioxan/water in the presence o an acid (such as hydrochloric or sulfuric acid) or a base such as sodium or potassium hydroxide at temperatures ketween 50 and 100C.
h) For the preparation of compounds of general formula I, wherein A represents a group of formula CE~
I

- CH -wherein R6 and R7 are as hereinbefore defined:
Reduction of an enamide of general formula XII

I 17&245 R R
6~ ~, 7 3~ ~Rl , (XII) R

1' 2' R3, R4, R5, R6 ~ R7, B and W are as hereinbefore defined.
The reduction is preferably carried out with hydrogen in the presence of a hydrogenation catalyst such as palladium/charcoal or platinum in a solvent such as for example methanol, ethanol, isopropanol, ethanol/water glacial acetic acid, ethyl acetate, dioxan, tetrahydrofuran, dimethyl formamide, benzene, or benzene/ethanol at temperatures between 0 and 100C, preferably, however at temperatures between 20 and 50C, and a hydrogen pressure of 1 to 5 bar. When using a chiral hydrogenation catalyst such as a transition metal 1T-complex, e.g. a complex made from rhodium chloride and (+) or (-) 0,0-isopropylidene-2,3-dihydroxy-1,4-bis-(diphenylphosphino)-butane (=DIOP), the hydrogenation is effected enantioselectively. Moreover, other reduceable groups may be reduced during the catalytic hydrogenation, e.g. a nitro group to an amino group or a chlorine or a bromine atom to a hydrogen atom.
i) For the preparation of compounds of general formula I, wherein R4 represents a hydrogen atom and A represents a methylene or ethylene group (optionally substituted by a methyl, ethyl or isopropyl group), a methylene or ethylene group substituted by 1 ~7~245 two alkyl groups containing 1 to 3 carbon atoms each, a methylene group (substituted by a cycloalkyl group containing 3 to 7 carbon atoms, by a carboxyl, alkoxycarbonyl, or phenyl group, whereby each of the aforementioned alkyl parts may contain from 1 to 3 carbon atoms), or a cycloalkylidene group 4 to 7 carbon atoms:
Reaction of a compound of general formula XIII

R3~ A' - OH

N.~Rl , (XIII) \R2 [wherein ~1' R2 and R3 are as hereinbefore defined and A' represents a methylene or ethylene group (optionally substituted by a methyl, ethyl or isopropyl group), a methylene or ethylene group substituted by two alkyl groups containing 1 to 3 carbon atoms each, a methylene group (substituted by a cycloalkyl group containing 3 to 7 carbon atoms, carboxyl, alkoxycarbonyl, or phenyl group, whereby each of the above mentioned alkyl parts may contain from 1 to 3 carbon atoms), or a cycloalkylidene group containing ~ to 7 carbon atoms], with a compound of general formula XIV

N:- C - B ~
R5 , (XIV) wherein R5, s and W are as hereinbefore defined.

The reaction is carried out in the presence of a strong acid, which simultaneously may serve as solvent, preferably in ~ -21-l 17~24¢
concentrated sulfuric acid, at temperatures between 20 and 150C, preferably at temperatures between 80 and 100C.
According to a further feature of the present invention, a compound of general formula I thus obtained wherein W represents the carboxy group, may if desired, subsequently be converted into a corresponding compound of general formula I wherein W represents an ester or amide -21a-1 ~76246 group by esterification or amidation and/cr- a compound of general formula I wherein R3 and/or W represent(s) a nitro group, may subsequently be converted by reduction into a corresponding compound of aeneral formula I wherein R3 and/or W represent(s) an amino group; and/or a compound of general formula I wherein R3 and/or W re-present(s) amino group, may subsequently be converted via a correspondina diazonium salt into a corresponding compound of general formula I wherein R3 represents a hydrogen or a halogen atom, a hydroxy, alkoxy, mercapto, alkylmercapto, chlorosulfonyl, or cyano group and/or W represents a hydrogen or a halogen atom or a cyano aroup. O?tionally a compound of general formula I thus obtained, wherein R3 represents a hydroxy group, may subsequently be converted by alkylation into a corresponding compoun~ o~ ~eneral formula I wherein R3 represents an alkoxy aroup, or a compound of formula I thus obtained, wherein R3 represents a chlorosulfonyl group, may subsequently be converted by ammonia into a corresponding compound of qeneral formula I wherein R3 represents an aminosulfonyl group; and/or a compound of general formula I wherein R3 represents an amino group may subsequently be converted by means of acylation into a correspondina compound of aeneral formula I wherein R3 represents an alkanoylamino, aroylamino, alkoxycarbonylamino or an alkylsulfonylamino group; and/or a compound of general formula I wherein R3 represents an amino aroup may subsequently be converted by means of alkylation into a correspondina compound of general formula I wherein R3 represents an alkylamino or a dialkylamino group; and/or a compound of general formula I wherein R3 represents a chlorine or a bromine atom may subsequently converted by means of dehalogenation into a correspondina compound of general formula I wherein R3 represents a hydrogen atom; and/or a compound of general formula I wherein R3 represents a nitrile group may subsequently be converted by means of hydrolysis or alcoholysis into a correspondinq compound of general formula I, wherein R3 represents an aminocarbonyl, carboxy or an alkoxycarbonyl aroup;
and/or a compound of general formula I wherein R3 1 ~7624~

represents a carboxy or alkoxycarbonyl aroup and/or W
represents an(optionally esterifie~)carboxy aroup may subsequently be converted by means of reduction into a correspondina compound of cteneral formula I wherein R3 S and/or W represents a formyl or hydroxymethyl aroup;
and/or a compound of general formula I wherein W represents an alkoxycarbonyl aroup (wherein the alkoxy aroup may contain from 2 to 6 carbon atoms) substituted in any but the ~-position by a hydroxy aroup may be converted into a compound of general formula I wherein the said hvdroxy group is replaced by an acyloxy group, by acylation;
and/or a compound of general formula I, wherein T^~ represents a hydroxymethyl aroup may subsequently be converted (via a correspondina halomethyl compound) by reaction with a malonic acid diester, into a correspondina compound of general formula I wherein W represents an ethvl group substituted by two alkoxycarbonyl arours; and/or a compound of general formula I wherein W represents a formyl group may subsequently be converted by condensation and optional subsequent hydrolysis and/or decarboxylation into a corresponding compound of general formula I wherein W
represents a vinyl aroup substituted by a hydroxycarbonyl or alkoxycarbonyl group; and/or a compound of general formula I wherein W represents an ethyl group substituted by two alkoxycarbonyl groups may subsequently be converted by hydrolysis and decarboxylation into a correspondin~
compound of aeneral formula I wherein W represents an ethyl group substituted by a carboxy group; and/or a compound of general formula I wherein W represents a carboxy group.
may subsequently be converted via a sulfonic acid hydrazide and subsequent disproportionation into a correspondina compound of general formula I wherein W
represent a formyl aroup; and/or a compound of qeneral formula I wherein Rl and R2 together with the ni.troaen ato~ to which they are attached represent an aza-1,4-dioxa-spiro-alkyl group containina 6 to 8 carbon atoms, may subsequently be converted by means of hydrolysis in the presence of an acid into a corresponding compound of aeneral formula I

l 1~624~

wherein ~l and ~2 toaether with the nitroaen atom to which they are attached represent an unbranched alkyleneimino group containing 4 to 6 carbon atoms wherein a methylene group is replaced by a carbonyl qroup; and/or a compound of aeneral formula I wherein Rl and R2 toaether with the nitrogen atom to which they are attached represent an unbranched alkyleneimino group containing 4 to 6 carbon atoms, wherein a methylene group is replaced by a carbonyl group, may subsequently be converted by means of reduction into a corresponding hydroxy-alkyleneimino compound of aeneral formula I; and /or a compound of general formula I wherein W represents an aminocarbonyl group may subsequently be converted by means of dehydratation into a corresponding compound of general formula I wherein ~T represent a cyano group.
The dehydratation is preferably carried out with a dehydratina aqent such as for example phosphorus pentoxide, sulfuric acid or p-toluene sulfonic acid chloride optionally in a solven~ such as methylene chloride or pyridine at temperatures between 0 and 100C, preferably, at temperaturesbetween 20 and 80C.
The esterification is conveniently carried out in a solvent, such as, for example, the corresponding alcohol, pyridine, toluene, methylene chloride, tetrahydrofuran or dioxan, in the presence of an acid-activatina and/or dehydratina aaent such as thionyl chloride, ethyl chloroformate, carbonyl diimidazole, N,N'-dicyclo-hexylcarbodiimide or the isourea ether thereof, optionally in the presence of a reaction accelerator such as copper chloride or by transesterification, e.g. with a corresponding carbonic acid diester, at temperatures between 0 and 100C, preferably, however, at temperature between 20C and the boilina temperature of the corresponding solven~.
The amidation is conveniently carried out in a solvent such as methylene chloride, chloroform, carbon tetrachloride, ether, tetrahydrofuran, dioxan, benzene, toluene, acetonitrilie or dimethyl formamide, 1 17~24~

optionally in the ~resence of an acid activatin~ agent or a dehydratina agent, e.~. in the presence of ethyl chloroformate, thionyl chloride, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexyl carbodiimide,
5 N,N'-dicyclohexyl carbodiimide/N-hydroxy succin-imide, N,N'-carbonyldiimidazole, N,N'-thionyldiimidazole, or tri phenyl phosphine/ carbon tetrachloride, or of an agent activa-ting the amino group, e.g. phosphorus trichloride, and optio nally in the presence of an i~organic base such as sodium lO carbonate or a tertiary organic base such as triethylamine or pyridine, which simultaneously may serve as solvent, at temperatures between -25 and 250C, preferably, however, at temperatures between -10C and the boiling temperature of the used solvent. The reaction may also be carried out without 15 a solvent. ~oreover the water, which is formed during the reaction, ma~,~ be removed by means of azeotropic distilla-tion, e.g. by heating with toluene in a water separator funnel, or by addition of a drying agent such as magnesium sulfate or a molecular sieve~
( The reduction of the nitro compound is prefer-ably carried out in a solven'c such as water, water/ethanol, methanol, glacial acetic acid, ethyl acetate or dimethyl formamide appropriately wit~ hydrogen in the presence of a hydrogenation catalyst such as Raney-nickel, platinum 25 or palladium/charcoal, with metals such as iron, tin or zinc in the presence of an acid, with metal salts such as iron(II)sulfate, tin(II)ch]oride or sodium dithioniteJ or with hydrazine in the pre~ence of Raney-nickel at tempera-tures between 0 and 50C, preferably, however, at room 30 temperatures The react~on of the diazonium salt, (e.g. the fluoroborate J the hydrosulfate in sulfuric acid, the hydro-chloride or the hydroiodide)is carried out9 if necessaryJ
in the presence of copper or a corresponding copper (I) 3alt 35 such as copper (I) chlor:ide/hydrochloric acidJ copper (I) bromide/hydrobromic acid, trisodium copper(l)tetracyanide at pH 7, or an alkali metal xanthogenate, or copper (II) chloride/sulfur dioxide in alacial acetic acid optionally with the addition of magnesium chloride, at slightly elevated temperatures, e.g. at temperatures between 15 and 100C. The subsequent reaction with hypophosphorous acid is preferably carried out at -5 to 0C. The diazonium salt is conveniently prepared in a solvent such as, for example water/hydrochloric acid, methanol/hydrochloric acid, ethanol/hydrochloric acid or dioxan/hydrochloric acid, by means of diazotization of a correspondin~ amino compound with a nitrite, e.a. sodium nitrite or an ester of nitrous acid, at lower temperatures, e.g. at temperatures between -10 and 5C.
The acylation is conveniently carried out in a solvent such as methylene chloride, ether tetrahydro'uran or in an excess o.f the used acylating agent e.g. formic acid, acetic acid or propionic acid. or their anhydrides, acid chlorides or esters, optionally in the presence of an inorganic or a tertiary organic base, which simultaneously may serve as solvent, and optionally in the presence of an acid-activating agent or of a dehydrating agent at temperatures between -25 and 150C, preferably, however, at temperatures between -10C
and the boiling temperature of the reaction mixture.
The N-alkylation is conveniently carried out with a corresponding halide or sul~onic acid ester, (e.a. methyl iodide, dimethyl sulfate, ethyl bromide or p-toluenesulfonic acid ethyl ester), optionally in the presence of a base such as sodium hydride, potassium hydroxide or potassium tert.butylate and preferably in a solvent such as for example, diethyl ether, tetrahydrofuran, dioxan, ethanol, pyridine or dimethyl formamide, at temperatures between 0 and 75C; preferably, however, at room temperature. The methylation may, also be carried out with formalclehyde/formic acid (appropriately at the boiling temperature of the reaction mixture) and the alkylation may be carried out with a corresponding ~ 27 ~ 624~

carbonyl compound in the presence of a hydride such as sodium cyanoborohydride in a solvent such as acetonitrile acetic acid or dimethyl formamide/acetic acid preferably at pH 7 and at temperatures between 0 and 50C.
The dehaloaenation is conveniently carried out in a solvent such as methanol, ethanol, ethyl acetate, glacial acetic acid or dimethvl formamide by means of catalytically activated hydrogen, e.~. with hydrogen in the presence of platinum or palladium/charcoal, at temperatures between 0 and 75C, preferably, however, at room temperature, and at a hydrogen pressure of l -5 bar.
The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric sulfuric, phosphoric, polyphosphoric or trifluoroacetic acid or in the presence of a base such as sodium hydroxide or potassium hydroxide in a solvent such as for example, water, ethanol, water/ethanol, water/isopropanol or water/
dioxan at elevated temperatures, e.g. at the boiling temperature of the reaction mixture. The hydrolysis can however, be also carried out with a nitrite, e.q.
sodium nitrite, in the presence of an acid such as sulfuric acid, whereby this may conveniently serve simultaneously as solvent, at temperatures between 0 and 50C. The subsequent alcoholysis is conveniently carried out in the presence of a hydrogen halide, e.a. hydrogen chloride, at tmeperatures between 20C and the boilina temperaute of the used alcohol.
The reduction is preferably carried out with a metal hydride, e.a. with a complex metal hydride such as lithium aluminium hydride, in a solvent such as, for example, diethyl ether, tetrahydrofuran or dioxan at temperatures between 0 and 100C, preferably however, at temperature between 20 and 60C.
The 0-alkylation is conveniently carried out with a corresponding halide, sulfonic acid ester or diazoalkane, e.g. with methyl iodide, dimethyl sulfate, ethyl bromide, p-toluene sulfonic acid ethyl ester, methanesulfonic acid isopropyl ester or diazomethane 1 ~6246 optionally in the presence of a base such as sodium hydride, potassium hydroxide or potassium-tert. butylate and preferably in a solvent such as diethyl ether, tetrahydro-furan, dioxan, methanol, ethanol, pyridine or dimethyl formamide at temperatures between 0 and 75C, preferably, however, at room temperature.
The conversion of a hvdroxymethyl group into a halomethyl group is carried out with a haloaenating agent such as for example, thionyl chloride, phosphorus trichloride, phosphorus tribromide or phosphorus pentachloride in a solvent such as methylene chloride, carbon tetrachloride, benzene or nitrobenzene and subsequent reaction with a malonic acid ester, e.g. with an alkali salt cf the malonie acid diethyl ester, at temperatures between 0 and 100C, preferably, however, at temperatures between 20 and 50C.
The condensation of a formyl compound is conveniently earried out in a solvent such as pyridine or tetrahydrofuran with malonic acid, with a malonic aeid ester, with a dialkylphosphonoacetic acid ester or an alkoxycarbonylmethylene-triphenyl-phosphone, optionally in the presence of a base as-a condensation agent, e.g. in the presence of piperidine, potassium-tert.butylate or sodium hydride, at temperatures between 0 and 100C-Py subsequent acidification, (e.a. with hydrochloric orsulfuric acid) or by subsequent alkaline hydrolysis, the desired acid is obtained.
~ he hydrolysis is decarboxylation is conveniently carried out in the presence of an acid such as hydrochloric,sulfuric, phosphoric, polyphosphoric or trifluoroacetic acid in a solvent such as for example, water, ethanol, water/ethanol, water/isopropanol or water/dioxan at elevated temperatures, e.g. at the boiling temperature of the reaction mixture.
The disproportionation of a sulfonic acid hydrazide, which is obtained by reacting the correspond-ing hydrazine with the corresponding reactive carboxylic acid derivative, is carried out in the presence of a base - 29 ~ 4~

such as sodium carbonate in a solvent such as eth~lene glycol at temperatures between 100 and 200C, preferably, however, at 160 - 170C.
The compounds of aeneral formula I obtained by the above processes may if desired be converted into their addition salts, especially into their physiologically compatible salts with inoraanic or organic acids or bases by conventional methods such as by reacting the compounds as bases with a solution of the corresponding acids in a suitable solvent, or by reactina the compounds as acids with a solution of the corresponding bases in a suitable solvent. Suitable acids include, for example, hydrochloric acid, hydrochloric acid, hydrobromic acid sulfuric acid, phosphoric acid, lactic acid, citric acid, tartaric acid, succinic acid, maleic acid and fumaric acid. Suitable bases include, for example, sodium or potassium hydroxide and cyclohexylamine.
The compounds of general formula II to XIV used as starting materials are known from the literature or may be prepared according to known processes.
Thus, for example,a compound of general formula II wherein A represents a bond can be obtained by reduc~ion of the corresponding nitro compound, for example by means of catalytically activated or nascent hydroaen or by means of sodium dithionite or bv reaction of the correspondinq com~ound hv a Hofmann, Curtius, Lossen, or Schmidt reaction.
For example a compound of general formula II, wherein, A represents a vinylidene aroup or the tautomeric ketimine can be obtained by reaction of the corres~ondina nitrile with the corresponding Grignard or lithium compound and subsequent hydrolysis or by reaction of the corresponding ketone with the corresponding amine in the presence of titanium tetrachloride. ~or further reaction with a compound of qeneral formula III or its reactive derivatices, especially acid chlorides, an oraanometallic complex can be used.

1 17~24~

For example a compound of general formula II, wherein A does no-t represent a bond or a vinylidene group, can be obtained by reduction of the corresponding nitrile with lithium aluminium hydride, by reaction o the corresponding nitrile with the corresponding Grignard or Lithium compound and optionally with subsequent lithium aluminium hydride reduction or subsequent hydrolysis to the ketimine, which subsequently is reduced with catalytically activated hydrogen, with a complex metal hydride or with nascent hydrogen, by hydrolysis or bv hydrazinolysis of the corresponding phthalimido compound, by reaction of the corresponding ketone with ammonium formate and subsequent hydrolysis or with a ammonium salt in the presence of sodium cyanoborohydride, by reduction of the correspondina oxime with lithium aluminium hydride, with catalytically activated or nascent hydrogen, by reduction of the correspondina N-benzyl or N-l-phenylethyl Schiff's base, e.g. with a complex metal hydride in ether or tetrahydrofuran at temperatures between -78 and the boiling temperature of the used solvent and subsequent cleavage of the benzyl or l-phenylethyl aroup by means of catalytic hydroaenation by Ritter reaction of a correspondina alcohol and potassium cyanide in sulfuric acid, or by a Hofmann, Curtius, Lossen or Schmidt reaction. An amine o.f general formula II thus obtained with a chiral center can be resolved, e.q. by fractional crystallization of the diastereoisomeric salts usina optionally active acids and subsequent decomposition of the salts or by the formation of diastereoisomeric compounds, their separation and subsequent resolution into enantiomers. Furthermore, an optionally active amine of general formula II can also be prepared by enantioselective reduction of the corresponding ketimine by means of complex boron or aluminium hydrides, in which some of the hydride hydrogen atoms are replaced by optically alctive alcoholate radicals, or by means of hydroaen in the presence of a suitable chiral hydrogenation catalyst, or in an analoaous 1 17624~

manner startina from an M~benzyl or optionally optically active N~l-phenethyl Schiff's base and optionally subsequent cleavaae of the benzyl or l-phenethyl radical.
A compound of general formula II wherein R4 represents a lower alkyl radical may be ohtained by reduction of the correspondinq N-acyl compound, e. a .
by means of lithium aluminium hydride.
The compounds of aeneral formulae IV, V, and VII
to X used as starting materials may each be obtained by reaction of an amine with a carboxylic acid or one of its reactive derivatives and optional subsequent hydrolysis.
A compound of general formula VIII can be obtained by Friedel-Crafts acetylation of the corresponding acetyl-unsubstituted compound.
A compound of general formula XII used as a starting material can be obtained preferably by acylation of the corresponding ketimine or tautomeric forms with the corresponding carboxylic acid or one of its reactive derivatives.
A compound of aeneral formula XIII used as a start-ing material can be obtained by reduction of the correspond-ing carbonyl compound with the corresponding Grignard or lithium reagent.
The compounds of general formula I posess 5 valuable pharmacological properties, and in qeneral show benefical effects on intermediary metabolism, and especially, however, a blood-sugar lowering activity.
For example the following compounds have been tested with regard to their biological properties:

~ ~7624~

A - 4- ~ 2-Pyrrolidino-benzyl)-aminocarbonylmethyl7bcnzoic acid, B = 4- ~1-(2-Pyrrolidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid, C = 4- ~1-(5-Chloro-2-pyrrolidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid, D = 4- ~ 2-Piperidino-benzyl)-aminocarbonylmethyl7benzoic acid, E = 4~ (2-Piperidino-phenyl)-ethenyl)-aminocarbonylmethyl7-benzoic acid, F = 4- ~1-(6-Chloro-2-piperidino-phenyl)-ethenyl)-aminocarbo-nylmethyl7benzoic acid, G = 4- ~1-(6-Methyl-2-piperidino-phenyl)-ethenyl)-aminocarbo-nylmethyl7benzoic acid, - ~i3 ~ 62~

H = 4- ~ 1-(2-Piperidino~phenyl)-ethyl)-aminocarbonylmethy~7-benzoic acid, I = Ethyl 4-~ 1-(2-Piperidino-phenyl)-ethyl)-aminocarbonyl-methyl~benzoate, K = (+)Ethyl 4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonyl-methyl~ benzoate L = 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-- benzoic acid-(2,2-dimethyl-dioxolane-4-yl)-methyl ester, M e 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-toluene, N = 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzyl alcohol, O z 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzaldehyde, P = 4- ~1-(2-Piperidino~phenyl)-ethyl)-aminocarbonylmethyl7-phenyl acetic acid, Q = 4- ~1-(4-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid, R = 4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbo-nyl-methyl7benzoic acid, S = Ethyl 4-/(1-(6-Chloro-2-piperidino-phenyl)-ethyl)-amino-carbonylmethylfbenzoate, T = 4- ~1-(5-Fluoro-2-piperidino-phenyl)-ethyl)-amino-carbonyl-methy ~benzoic acid, U - 4~ (4-Methyl-2 piperidino-phenyl)-ethyl)-amino-carbonyl-methyl7benzoic acid, V = 4- ~1-(5-Methyl-2-piperidino-phenyl)-ethyl)-amino-carbonyl-methyl7benzoic acid, W = 4- ~ 2-(2-Piperidino-phenyl)-Z~propyl)-aminocarbonyl-methyl7benzoic acid, X = 4- ~1-(2-Piperidino-phenyl)-2-methyl-propyl)-amino-carbonyl-methy ~ benzoic acid, Y - 4- ~ 2-Piperidino-benzhydryl)-aminocarbonylmethy ~benzoic acid, Z - 4- ~1-(2-(1,2,~,6-Tetrahydro-pyridino)-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid, AA = 4- ~1-(2-(3-Methyl-piperidino)-phenyl)-ethyl)-amino-carbonylmethyl7benzoic acid, 15 AB = 4- ~1-(2-Hexahydroazepino-phenyl)Oethyl)-aminocarbonyl-methyl7benzoic acid, AC = 4- ~1-(2-Octahydroisoindolo-phenyl)-ethyl)-aminocarbo-nyl-methy ~benzo~c acid, AD = Ethyl 4~ -Methoxycarbonyl-2-piperidino-benzyl)-amino=
carbonylmethy~ benzoate and AE = (+) 4- L( 1 (2-Piperidino-phenyl)-ethyl)-aminocarbonyl-methyllbenzoic acid.
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 the test the animals were starved. Before the test the compounds were ~ ~62~
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 as at 1J 2, 3 and 4 hours after administration from the retroorbital plexus vein. 50 ~g of each sample were deproteinized with 0.5 ml of 0.33 N perchloric acid and centrifuged.
The glucose content in ~he supernatant was determined according to the Hexokinase method by means of an analysis photometer. The statistical evaluation was per-formed with the t-test according to Student with p = 0.05.

The following table contains the obtained values in percent compared with the 1 n controls:

Table 1:

F-- I _ Test 25 mg/kg 10 mg/kg 5 mg/kg Com- _ pound 1 2 3 4 1 2 3 4 1 2 3 4 hours hours hours __ ~ ~
A -36 -23 -14 n.s. -22 n.s. -10 n.s.
B -42 -35 -31 -13 -38 -18 n.s. n.s.
C -40 -30 -26 -22 -26 -17 n.s. n.s.

F -45 -42 -38 -32 -44 -39 -32 -24 -47 -33 -26 n.s.
G -31 -15 n.s. n.s.

I -24 -27 -17 -13 -22 -22 n.s. n.s.

N ! 40 -40 -30 -31 -35 -29 n.s. n.s O 1_46 -47 -37 -36 -46 -41 -39 ~35 1 -43 -35 -26 -23 ~r ~ 17~2~6 Continuation of Table 1:

I Test 25 mg/kg 10 mg/kg 5 mg/kg com- ~ I . _ pound 1 2 3 4 1 2 3 4 1 2 3 4 hours hours hours _ _ _, 1 .
P -41 -26 -19 n.s. -27 -18 n.s. n.s.

R -36 -36 -34 -28 -36 -34 -26 -20 -17 -18 -11 n.s.

U -37 -18 n.s. n.s. -42 -15 n.s. n.s.

W -32 -34 -27 -20 -19 -24 -16 n.s.

Y -44* -44* -41* -42* -44 -38 -41 -37 AB -45 -46 -39 -34 -41 -35 -24 -17 -29 -18 n.s. n.s.

AE** _ _ ~ -41 -34 -20 n.s.

* = dose: 20 mg/kg ** = dose: 1 mg/kg n.s. = statistically not significant 2. 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: 14 days The following table contains the values obtained:

..:

- ~7 - 117624~

Test com- orientating toxicity pound H ~2 00~ mg/kg p.o. (1 out of 10 animals died) R > 2 000 mg/kg p.o. (0 out of 10 a~imals died) Y ~ 2 000 mg/kg p.o. (0 out of 6 animals died) The compounds of general formula I are suitable for the treatment of diabetes mellitus due to their benefical effects on intermediary metabolism and their blood-suaar lowerina activity.
According to a yet further feature of the present invention there are provided pharmaceutical compositions comprising as active ingredient at least one compound of aeneral formula I as hereinbefore defined or a physioloaically compatible salt thereof, in association with one or more ~harmaceutical carriers or excipients.
For pharmaceutical administration, the compounds of general formula I or their physioloqically compatible salts may be incorporated into conventional preparations in either solid or liquid form, optionally in combination with other active ingredients. The compositions may, for example, be presented in a form suitable for oral or parenteral administration. Preferred forms include, for example, tablets, coated tablets, capsules, powders or suspensions.
The active inaredient may be incorporated in excipients customarily employed in pharmaceutical compositions such as 'or example, corn starchl lactose, magnesium stearate, aqueous or non-aaueous vehicles, fatty substances of animal or vecetable oriain, paraffin ~5 derivatives, polyvinyl pyrrolidone, potato starch, various wetting, dispersina or emulsifying agents and/or preservatives.
Advantageously the compositions may be formulated as dosage units, each dosaae unit being adapted to supnly a fixed dose of active inaredient. Suitable sinale dosage units for adults contain from 1 to 50 mq, I 17~246 preferably 2.5 to 20 mq of active inqredient according to the invention. Such dosage units may, for example, be administered 1 or 2 times dailv~ The total daily dosage may, however, be varied according to the compound used, the sub~ect treated and the complaint concerned.
Accordina to a yet further feature of the present invention there is provided a method of treating a patient suffering from, or susceptible to disorders of intermediary metabolism and/or blood suaar w~ich comprises administerina to the said patient an effective amount of a compound of formula I, as hereinbefore defined, or a physioloqically compatible salt thereof.
The following non-limiting examples serve to illustrate the present invention:

- :39 -Example 1 1176246 4- ~1-(5-Chloro-2-dimethylamino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid methyl ester 1.67 g (0~0103 mol) of carbonyl diimidazole were added with stirring at 20C to a solution of 2.00 g (0.0103 mol) of 4-methoxycarbonyl-phenyl acetic acid in 13.5 ml of absolute tetrahydrofuran. Subsequently the mixtur~ was heated to re-flux temperature for 45 minutes excluding moisture. After cooling to room temperature 2.05 g (0.0103 mol) of 1-(5-chloro-2-dimethylamino-phenyl)-ethylamine irL 7 ml of absolute tetra-hydrofuran were added and the reaction mixture was stirred over night at 20C. After evaporating in vacuo the evaporation re-sidue was purified by column chromatography on silica gel (toluene/acetone = 10/1).
15Yield: 2.6 g (66.7 % of theory), M.p.: 153 - 155C (from ether).
Calc.: C 64.08 H 6.18 Cl 9.46 N 7.47 Found: 64.30 6.04 9.70 7.39 Analogously to Example 1 the following compounds were prepared:

4- ~1-(5-Chloro-2-dipropylamino-phenyl)-ethyl)-aminocarbonyl-m thyl7benzoic acid methvl ester Yield: 42 % of theory, M.p.: 135 - 137C (from ether/petroleum ether) Calc.: C 66~83 H 7.25 Cl 8.23 N 6.50 Found: 66.95 7-35 8.35 6.05 4- ~1-(5-Chloro-2-dibutylamino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid methyl ester _ _ Yield: 64.8 % of theory, M.p.: 110 - 112C.
Calc.: C 68.03 H 7.69 Cl 7.72 N 6.10 Found: 67.86 7.61 7.73 6.17 - ~o -1 1~624~
4- ~1~(5-Chloro-2-N-cyclohexyl-N-methylamino-phenyl)-ethyl)-aminocarbon~lmethyl7benzoic acid methyl ester Yield: 63.9 % of theory, M.p.: 152 - 153C (ether).
Calc.: C 67.78 H 7.05 C1 8.00 N 6.32 Found: 67.70 6.92 8.24 6.46 4- ~ 5-Chloro-2-pyrrolidino-benzyl)-aminocarbonylmethyl7-benzoic acid methyl ester Yield: 68.1 % of theory, lO M.p.: 1~9 141C (methanol) Calc.: C 65.19 H 5.99Cl 9.17 N 7.24 Found: 65.46 5.91 9.26 7.41 4- ~1-(5-Chloro-2-pyrrolidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzolc acid methvl ester 15 Yield: 58.3 % of theory, M p.: 133 - 135C (methanol) Calc.: C 65.91 H 6.29 C1 8.84N 6.99 Fo~nd: 66.24 6.19 8.75 7.13 4- ~ 5-Chloro-2-piperidino-benzyl)-aminocarbonylmethy ~-20 benzoic acid meth~1 ester Yield: 75.1 % of theory, M.p.: 123 - 125C (ether) Calc.: C 65.91 H 6.29Cl 8.84N 6.99 Found: 66.05 6.13 8.86 7.21 4- ~1-(5-Chloro-2-piperidino-benzyl)-aminocarbonyl)-ethyl7-benzoic acid methyl ester ___ Yield: 70.4 ~ of theory, M.p.: 142 - 144C (ether).

~ 41 ~ 6 2 4 ~
Calc.: C 66 57 H 6.56 Cl 8.55 N 6.75 Found: 66.50 6.49 8.44 6.86 4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid methyl ester 5 Yield: 69.5 % o~ theory, M.p.: 147 - 149C (ether).
Calc.: C 66.57 H 6.56 Cl 8.55 N 6.75 Found: 66.33 6.54 8.67 6.85 4-1T1-(5~Chloro-2-(3-methyl-piperidino)_phenyl)_ethyl)_ C~ 10 aminocarbonylmethY17benzoic acid methyl ester Yield: 54.~ % of theory, M.p.: 160 - 162C (methanol).
Calc.: C 67.20 N 6.81 Cl 8.27 N 6.53 Found: 67.27 6.81 8.13 6.45 4- ~1-(5-Chloro-2-(3,5-cis-dimethyl-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid methyl ester_ Yield: 44 % of theory, M.p.: 190 - 193C (methanol) Calc.: C 67.78 H 7.05 Cl 8.00 ` N 6.32 ~J 20 Found: 67.50 7.05 8.25 6.48 4-L~1-(5-Chloro-2-piperidino-phenyl)-propyl)-aminocarbonyl-methyl7benzoic acid methyl ester Yield: 65.9 % of theory, M.p.: 142 - 144C (ether).
25 Calc.: C 67.20 H 6.81 Cl 8.26 N 6.53 ~ound: 67.45 6.63 8.38 6.63 - ~i2 ~ 2 4 ~

4- ~1-(5-Chloro-2-piperidino-phenyl)-2-methyl-propyl)-amino-carbonvlmethyl7benzoic acid methyl ester Yield: 61.4 ~ of theory, M~p.: 156 - 158C (ether).
Calc.: C 67.78 H 7.05 Cl 8.00N 6.32 Found: 67.80 7.17 7.89 6.28 4-L~1-(5-Chloro-2-morpholino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid methyl ester Yield: 69.8 % of theory, M.p.: 156 - 158C (ether).
Calc.: C 63.38 H 6.04 Cl 8.50N 6.72 Found: 63.24 6.12 8.70 6.85 4- ~1-(5-Chloro-2-thiomorpholino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid methyl ester 15 Yield: 68.2 % of theory, M.p.: 167 - 169C (ether).
Calc.: C 61.03 H 5.82 Cl 8.19N 6.47 S 7.41 Found: 60.83 5.77 8.33 6.49 7.39 4- ~1-(5-Chloro-2-(hexahydro-1H-azepino)-phenyl)-ethyl)-aminocarbonvlmethYl7benzoic acid methyl ester Yield: 41.7 % of theory, M.p.: 146 - 147C (methylene chloride/petroleum ether).
Calc.: C 67.19 H 6.81 Cl 8.27 N 6.53 Found: 66.90 6.66 8.30 6.39 4- ~1-(5-Chloro-2-octahydroazocino-phenyl)-ethyl)-amino-carbonylmethyl7benzoic acid_methyl ester Yield: 30 % of theory, M.p.: 154 - 156C

_ ~3 1 ~7624~
Calc.: mol peak m/e = 442/444 (1 chlorine) Found: m/e = 442/444 (1 chlorine) 4- ~1-(5-Chloro-2-(octahydro-1H-azonino)-phenyl)-ethyl)-aminocarbon~lmethyl7benzoic acid methyl ester Yield: 38 % of theory~
M.p.: 184 - 185C (chloroform/toluene) Calc.: C 68.32 H 7.28 N 6.13 Found: 68.10 7.30 6.28 4- ~ 2-(5-Chloro-2-piperidino-phenyl)-2-propyl)-aminocarbonyl-methyl7benzoic acid methyl ester Yield: 84.4 % of theory, M.p.: 162 - 164C
Calc.: mol peak m/e = 428/4~0 (1 chlorine) Found: m/e = 428/430 (1 chlorine) 4- ~1-(5-Nitro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid meth~l ester Yield: 68.3 % of theory, M.p.: 178 - 180C (toluene) Calc.: C 64.93 H 6.40 N 9.88 Found 65.05 6.43 9.87 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid methyl ester Yield: 59.1 % of theory, M.p.: 145 - 147C
Calc.: C 72.61 H 7.42 N 7.36 Found: 72.35 7.39 7.40 1 17~24~
4- ~ 5-Methyl-2-piperidino-benzyl)-aminocarbonylmethyl7-benzoic acid methyl ester _ _ Yield: 32.9 ~ o~ theory, M.p.: 124 - 126C (pe-troleum ether/acetone) 5 Calc.: mol peak m/e = 380 Found: m/e = 380 N-(4-Nitro-phenacetyl)-N-/1-(2-piperidino-phenyl)-ethvl7amine Yield: 62.4 % of theory, M.p.: 165 - 167C (ether) Calc.: C 68.64 H 6.86 N 11.44 Found: 68.73 6.88 11.63 N-(4-Acetyl-phenacetyl~-N- ~-(2-piperidino-phenyl)-ethyl7amine Yield: 32.4 % of theory, M.p.: 162 - 164C (ether) Calc.: C 75.79 H 7.74 N 7.69 Found: 75.51 7.86 7.38 N-(4-Acetyl-phenacetyl)-N- ~ -(5-chloro-2-piperidino-phenyl)-ethyl7amine _ _ _ Yield: 50.3 % of theory, M.p.: 162 - 163C (ether) Calc.: C 69.24 H 6.82 N 7.02 Found: 68.88 6.63 6.70 2- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid methYl ester 25 Yield: 82 % of theory, M.p.: 107 - 108C
Calc.: C 72.60 H 7.42N 7.36 Found: 72.79 7.38 7.53 _ 45 - 11762~6 3~ (2-Plperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid ethyl ester Yield: 47 % of theory, M.p.: 155C
5 Calc.: C 73.07 H 7.67N 7.10 Found: 73,30 7.58 7.17 3-Chloro-4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid ethyl ester Yield: 63 % of theory, lO M.p.: 123 - 124C
Calc.: C 67.20 H 6.81Cl 8.27 N 6.53 Found: 67.28 6.84 8.36 6~50 4- ~1-(2-(1,2,3,4-Tetrahydro-isoquinoline-2-yl)-phenyl)-ethyl)-aminocarbon,vlmethyl7benzoic acid ethyl ester 15 Yield: 43 ~ of theory, M.p.: 142 - 144C
Calc.: C 75.99 H 6.83 N 6.33 Found: 75.64 6.75 6.~5 4-~r1-(2-Piperidino-phenyl)-ethvl)-aminocarbonylmethyl7toluene 20 Yield: 59 % of theory, M.p.: 136 - 138C
Calc.: C 78.53 H 8.39 N 8.33 Found: 78.58 8.16 8.26 4- ~ 5-Chloro-2-piperidino-anilino)-carbonylmethyl7benzoic acid 25 ~ethyl ester Yield: 40.3 % of theory, M.p.: 156 - 158C (methanol/toluene) Calc.: C 65.19 H 5.99 Cl 9.16 Found: 65.20 6.15 9.40 - 15 ~ I l~B24~
4- ~ -(2-Piperidino-anilino-carbonyl)-ethy_7benzoic acid-methyl ester _ _ _ _ Yield: 26.9 % of theory, M.p.: 71- 73C (petroleum ether) Calc.: C 72.10 ~ 7.15 N 7.65 Found: 72.00 7.09 7.94 4- ~1-(2-(1,2,3,6-Tetrahydro-pyridino)-phenyl)-ethyl)-amino-carbonylmethyl7benzoic acid ethyl ester Yield: 63.4 % of theory, M.p.: 125 - 127C (ether) Calc.: C 73.44 H 7.19 N 7.14 Found: 73.38 7.13 7.13 4- ~ 2-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester 15 Yield: 68 % o~ theory, M.p.: 95 - 97C (ethanol) Calc.: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 67.75 6.76 8.22 6.24 4~ (5-Fluoro-2-piperidino-phenyl)-ethyl)-ami~ocarbonyl-methvllbenzoic acid ethvl ester Yield: 47.3 % of theory, M.p.: 138 - 140C (ether) Calc.: C 69.88 H 7.99 N 6.79 Found: 70.10 7.10 6.87 _ 47 -- tl762~
4~ (5-Nitro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester Yield: 56.5 % of theory, M.p.: 144 - 147C (ethanol) 5 Calc.: C 65.59 H 6.65 N 9.56 Found: 65.78 6.56 9.73 4- ~ 2-(1-(2-Piperidino-phenyl)-ethyl)-aminocarbonyl)-ethyl7-benzoic_acid methyl ester Yield: 90 % of theory, .~ 10 M.p.: 129 - 131C
Calc .: C 73.06 H 7.67 N 7.10 Found: 72.61 7.77 7.52 4- ~ 2-Hydroxy-1-(2-piperidino-phenyl)-ethyl)-aminocarbonyl-methvl7benzoic acid ethyl ester 15 Yield: 44.4 % of theory, M.p.: 132 - 135C (petroleum ether/acet~ne) Calc.: C 70.22 H 7.37 N 6.82 m/e = 410 Found: 70.02 7.25 6.77 m/e = 410 4- ~1-(5-Hydroxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-20 methyl7benzoic acid ethyl ester Yield: 64.2 % of theory, M~po 150 - 151C (ether) Calc.: C 70.22 H 7.37 N 6.82 m/e = 410 Found: 70.37 7.17 6.81 m/e = 410 25 4- ~ ~ -Methoxycarbonyl-2-piperidino-ben~yl)-aminocarbonyl-methyl7benzoic acid_ethyl ester Yield: 59 % of theory, M.p.: 110 - 112C (petroleum ether/acetone) Calc.: C 68.47 H 6.90 ~ 6.39 m/e = 438 3Q Found: 68.57 6.64 6.46 m/e = 438 - 48 ~ 6 2 ~ `~

4~ (5-Chloro-2-(2-methyl-piperidino)-phenyl)-ethyl)-aminocarbonvlmethyl7benzoic acid ethyl ester Yield: 71.3 % of theory, M.p.: ~ 20C
Calc.: m/e = 442/444 (1 chlorine) Found: m/e = 4421444 (1 chloriné) 4- ~1-(2-Hexahydroazepino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl_ester Yield: 68 % of theory, M.p.: 145 - 148C (toluene) Calo.: C 73.50 H 7.90 N 6.86 Found: 73.35 8.04 6.89 4- ~1-(2- ~ ,4-Dioxa-8-azaspiro ~ , ~ decyl-(8~7phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid ethyl ester Yield: 64.3 % of theory, M.p.: 143 - 145C (petroleum ether/acetone) Calc.: C 69.01 H 7.13 N 6.19 Found: 69.30 7.38 6.21 4- ~1-(2-~2-Methyl-pyrrolidino)-phenyl)-ethyl)-aminocarbonyl-methY17benzoic acid ethyl ester Yield: 72 % of theory, M.p.: 94 - 97C
Calc.~ C 73.07 H 7.66 N 7.10 Found: 72,25 7.67 7.11 4-L~1-(3-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester _ _ I

Yield: 39,5 % of theory, M.p.: 178 - 179C
Calc.: m/e = 408 5 ~ound: m/e = 408 4- ~1-(3-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic ac d ethvl ester Yield: 52,6 /0 of theory, Calc.: m/e = 428/430 (1 chlorine) Found: m/e = 428/430 (1 chlorine) Example 2 (~) 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy17- 1 benzoic acid ethyl ester _ _ 231,4 mg (1,43 m mol) of carbonyl diimidazole were added to a solution of 290,9 mg (1.40 m mol) of 4-ethoxycarbonyl-phenyl acetic acid in 6 ml of tetrahydrofuran, Subsequently the mixture was heated to reflux temperature for 1,5 hours excluding moisture. After cooling to room temperature 0,~85 ml (-2.78 m mol) of triethylamine (dried over potassium hydroxide) and 360 mg (1.30 m mol) of (~ (2-piperidino-phenyl)-ethyl-amine dihydrochloride ~ ,p, 242C (decomp,); L~C720 = + 14.8 (c = 1; methanol )7 together with 2 ml of tetrahydrofuran were added and the mixture was stirred for 4 hours at 50 C in ~n oil bath. After evaporating in vacuo the evaporation residue was distributed between chloroform and water. The chloroform extract was dried over sodium sulfate, filtered through a G3-glas frit and evaporated in vacuo to dryness. The obtained residue was purified by column chromatography on silica gel (chloroform/methanol = 6:1), - 50 - l 17~246 Yield: 229 mg (44.7 % of theory), M.p.: 89 - 90C (ether) ~7D0 = 8.2 ( G = 1; methanol) Calc.: C 73.07 H 7.66 N 7.10 m/e = 394 5 Found: 73.20 7.68 7.14 m/e = 394 Analogously to Example 2 was prepared:

(-) 4- ~1-(2-Piperidino-phenyl)~ethyl)-aminocarbonylmethyl7-benzoic acid ethyl ester from (-) 1~(2-piperidino-phenyl)-ethylamino ~ihydrochloride 10 t~.p.: 239 - 242C (decomp.); /~ 20: -19.6 (c = 1; methanoll7.
Yield: 41.1 % of theory, M.p.: 77 - 79C (ether/cyclohexane) r~ 720 = -6.2 (c _ 1; methanol) Calc.: C 73.07 H 7.66 N 7.10 m/e = 394 15 Fourd: 72.67 7.75 6.82 m/e = 394 Exam~le 3 4- ~1-(4-Chloro-2-piperidino-phenyl)-ethyl)~aminocarbonyl~
meth~l7benzoic acid ethvl ester 2.3 ml (0.023 mol) of carbon tetrachloride were added to a 20 solution of 5.5 g (0.023 mol) of 1-(4-chloro~2-piperidino-phenyl)~ethylamine, 4.8 g (0.023 mol) of 4-ethoxycarbonyl-phenyl acetic acid, 7.3 g (0.028 mol) of triphenyl phosphine and 3.2 ml (0.023 mol) of triethylamine in 50 ml of aceto-nitrile and the mixture was stirred for 24 hours at room 25 temperature After evaporating in vacuo the evaporation re~
sidue was distributed between 100 ml of water and ethyl ace-tate. The combined organic extracts, which were dried over sodium sulfate, were filtered, evaporated in vacuo and the evaporation residue was purified by column chromatography 30 on silica gel (toluene/ ethyl acetate = 4:1).
Yield: 6.1 g (62 % of theory), M.p.: 126 - 128C
Calc.: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 67.43 6.97 8.16 6.40 - 51 - 1~7624~

Analogously to Example 3 the following compounds were prepared:

4~ (4-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester Yield: 48.2 ~ of theory, M.p.: 120 - 122C
Calc.: C 73.50 H 7.89 N 6.86 Found: 73.61 7.95 6.73 4- ~1-(2-(4-Methyl-piperidino)~phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester Yield: 55.8 % of theory, M.p.: 125 - 128C (ether) Calc.: C 73.50 H 7.90 N 6.86 Found: 73.30 7.99 7.20 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -15 benzoic acid ethyl ester _ Yield: 71 % of theory, M.p.: 147 - 148C
Calc.: C 73.06 H 7.67N 7.10 Found: 73.54 8.04 6.95 4- ~1-(2-Piperidîno-phenyl)-ethyl)-aminocarbonylmethyl7-phenyl acetic acid Prepared from 1-(2-piperidino-phenyl)-ethylamine and p-phenylene diacetic acid.
Yield: 27 % of theory, M.p.: 186 - 189C
Calc.: C 72.60 H 7.42N 7.36 ~ound: 72.75 7.65 7.11 624 ~
4- ~ 2-Piperidino-benzhydryl)-aminocarbonylmethyl7benzoic acid ethyl ester Yield: 87.4 % of theory, M.p.: 160 - 162C
5 Calc.: C 76.29 H 7.06N 6.14 Found: 76.44 7.08 6.17 4- ~ 5-Chloro-2-piperidino-benzhydryl)-aminocarborylmethyl7-benzoic acid ethyl ester Yield: 78 % of theory, 10 M.p.: 202 - 204C
Calc.: C 70,93 H 6.36Cl 7.22 N 5.71 Found: 70.85 6.40 7.11 5~45 4- ~1-(4-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid ethyl ester 15 Yield: 39 % of theory, M.p.: 118 - 120C
Calc.: C 73.07 H 7.67N 7.10 Found: 73.20 7.78 7.11 4- ~1-(2-(4-Methyl-piperazino)-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethYl ester Yield: 53 % of theory, M.p.: 130 - 132C
Calc.: C 70.38 H 7.63 N 10.26 Found: 70.41 7.53 10.13 4-LI1-(2~(4-Benzyl-piperazino)-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester __ _ Yield: 75 ~ of theory M.p.: 135 - 136C
Calc.: C 74020 H 7.26 N 8.66 Found: 74.45 7.34 8.54 - 53 - Il7~24~

4- ~1-(2-(4-p-chlorophenyl-piperazino)-phenyl)-ethyl)-amino-carbonylmethyl7benzoic acid eth~l ester _ _ _ __ Yield: 48.5 % of theory, M.p.: 178 - 180C
Calc.: C 68.83 H 6.37 N 8.30Cl 7~01 Found: 68.71 6.22 8.41 6.82 4- ~ ~ -Cyclohexyl-2-piperidino-benzyl)-aminocarbonylmethyl7 benzoic acid ethvl ester ~. .. .. ~
Yield: 75 % of theory, lO M.p.: 135C
Calc.: C 75.29 H 8.28N 6.06 Found: 75.11 8,13 5,99 N-(4-Chloro-phenacetyl)-N~ (2-piperidino-phen~l)-ethyl7amine Yield: 79 % of theory, 15 M.p.: 150 - 152C
Calc.: C 70.67 H 7.06 Cl 9.93 N 7.85 Found: 70.94 7.84 10.09 7.90 4- ~ 2-Pyrrolidino-benzhydryl)-aminocarbonylmethy_7benzoic acid ethvl ester _.

20 Yield: 57 % of theory, M.p.: 163 - 165C
Calc.: C 75.99 H 6.83N 6.33 Found: 75.45 6.52 6.10 -- 54 - I 17524~

4-~2-Hexamethyleneimino-benzhydryl)-aminocarbonylmethyl7-benzoic acid ethyl ester Yield: 68 % of theory, M.p.: 151 - 154C
Calc.: C 76. 56 H 7.28 N 5.95 Found: 76. 43 7.19 6.01 Example 4 4-LT1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid ethyl ester ~

lO 11.2 g (0.0539 mol) of 4-ethoxycarbonyl-phenylacetic acid, 17 g (0.0647 mol) of triphenyl phosphine, 22.6 ml (0.162 mol) of` triethylamine and 5.2 ml (0.0539 mol) of carbon tetrachlo-ride were successively added with stirring to a solution of 10.9 g (0.0539 mol) of freshly prepàred (2-piperidinophenyl)-15 methyl-ketimine in 100 ml of acetonitrile. The solution, which was clear after a short time, was stirred for 20 hours at 20C.
The resultant precipitate (triethylamine hydrochloride) was filtered off and the filtrate was evaporated i~n vacuo. The evaporation residue was purified by column chromatography 20 on silica gel (toluene/acetone = 10:1).
Yield: 15 g (70.1 % of theory), M.p.: 112 - 115C (ether) Calc.: C 73.44 H 7.19 N 7.14 Found: 73.28 7. 32 6.96 25 Analogously to Example 4 the following compounds were prepared:

4-LTbC -Cyclohexylidene-2-piperidino-benzyl)-aminocarbonyl-methyl7benzoic acid et~ ter_ _ -Yield: 24 % of theory, M.p.: 131 - 133C
Calc.: C 75.62 H 7. 8~ N6. o~
Found: 75.59 7-47 6.01 _ 55 - 11~ 6 24 6 4- ~1-(2-Piperidino-phenyl)-propenyl)-aminocarbonylmethyl7-benzoic acid ethYl ester Yield: 65,0 % of theory (E- and Z-isomeric mixture) M.p.: of the polar isomer: 82-84C
Calc.: C 73.86 H 7.44 N 6,89 Found: 73.73 7.57 7.01 Example 5 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid ethyl ester 10 ~ solution of 50.6 g (0.267 mol) of 4-ethoxycarbonyl-phen-acetyl chloride in 120 ml of methylene chloride was dropped with slight ice cooling to a stirred solution of 49.6 g (0.243 mol) of 1-(2-piperidinophenyl)-ethylamine ~ P- o 6:
100 - 107C; m.p. of the dihydrochloride: 23~ - 237C (decomp. ~7 - 15 and 37.3 ml (0.267 mol) of triethylamine in 245 ml of methylene chloride at an internal temperature of 20 - 30C. After stirring for 2 hours at room temperature, the resultant precipitate was filtered off~ washed once with methylene chloride, and the combined methylene chloride phases were extracted successive-ly twice with water, once with 10 % aqueous ammonia, twicewith water, once~; with 100 ml of 3 % hydrochloric acid and twice with water. The methylene chloride phase was dried over sodium sulfate and evaporated in vacuo. The evaporation re-sidue was crystallized from ether.
Yield: 88.8 g (92.7 ~ of theory), M.p.: 148 - 150C

~ ~7624&
- 56 ~

Analogously to Example 5 the following compounds were prepared:

4- ~ 5-Methyl-2-piperidino-benzyl)-aminocarbonylmethyl7benzoic acid ethvl ester Yield: 22.5 % of theory, M.p.: 116.5 - 117C (ethanol/petroleum ether) Calc.: C 73.07 H 7.66 N 7.10 Found: 73.48 7.62 7.15 4- ~1-(5-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester a Yield: 20.2 % of theory, M. p.: 132 - 132.5C (ethanol) Calc.: C 73.50 H 7.90 N 6.86 Found: 73.49 7.74 6.94 4- ~1-(5-Methoxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-15 methyl7benzoic_a i~ er _ _ _ __ Yield: 35.8 % of theory, M.p.: 131 - 132C (ethanol) Calc.: C 70.73 H 7.60 N 6.60 Found: 70.98 7.59 6.38 ~ .
4- ~1-(2-Piperidino-phenyl)-ethyl)-N-methylamino-carbonyl-methyl7benzoic acid ethvl ester Yield: 65.2 % of theory, M.p.: C 20C
Calc.: C 73.50 H 7.90 N 6.86 25 Found: 72.99 7.60 6.87 ~ 176246 4- ~1-(2-Decahydro-isoquinoline-2-yl)-phenyl)-ethyl)-amino-carbonylmethylZbenzoic acid ethyl ester Yield: 44 % of theory, M.p.: 159C
Calc.: C 74.95 H 8.08 N 6.24 Found: 75.09 8.01 6.01 4- ~1-(2-(1,2,3,4,5,6,7,8-Octahydro-isoquinoline-2-yl)-phenyl)-ethyl~-aminocarbonylmethyl7benzoic_ cid ethyl ester Yield: 35 % of theory, W lO M.p.: 115 - 117C
Calc.: C 75.30 H 7.67 N 6.27 Found: 75.18 7.37 5.89 4- ~1-(2-Octahydro-isoindole-2-yl)-phenyl)-ethyl)-aminocarbonyl-methvl7benzoic acid ethyl ester Yield: 36 % of theory, M.p.: 141C
Calc.: C 74.62 H 7.88 N 6.44 Found: 74.70 7.97 6.42 4- ~1-(3-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -v 20 benzoic acid ethyl ester Yîeld: 24 % of theory, M.p.: 164C
Calc.: C 73.07 H 7.66N 7.10 Found: 72.80 7.48 7.13 2s 4-/¦1-(6-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester Yield: 17 % of theory, M.p.: ~ 20C
Calc.: C 67.20 H 6.81 Cl 8.26 N 6.53 m/e = 423/30 30 Found: 67.96 6.56 8.80 6.67 m/e = 423/30 - 58 - ~ 2 ~ ~
4~ (6-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester Yield: 3.5 % of theory, M.p.: C 20C
Calc.: C 73.49 H 7.89 N 6.85m/e = 408 Found: 73.80 7.61 7.01m/e = 408 4-L~1-(2-(3-Aza-bicyclo ~ .2._7nonane-3-yl)-phenyl)-ethyl)-aminocarbonYlmethYl7benzoic acid ethYl ester Yield: 0.5 % of theory, M.p.: ~ 20 C
Calc.: m/e = 434 Found: m/e = 434 N~ (5-Chloro-2-piperidino-phenyl)-ethyl7-N-phenacetYlamine Yield: 53.5 % of theory, lS M.p.: 134 - 136 C (ethanol) Calc.: C 70.67 H 7.06Cl 9.94N 7.85 Found: 70.40 7.32 9.77 7.68 Example 6 4- ~1-(2-Piperidino-phenyl)-ethenyl)-aminocarbonylmethyl7-benzoic acid ethyl ester A solution of 2.49 g (0.011 mol) of 4-ethoxycarbonylphen-acetyl chloride in 10 ml of methylene chloride was adde~
with ice cooling over 15 minutes to a stirred solution of 2.02 g (0.010 mol) of freshly prepared methyl-(2-piperidino-phenyl)-ketimine and 1.53 ml of (0.011 mol) of triethylamine in 10 ml of methylene chloride at an internal temperature o~

~ '9 ~ 1 1~624~
1 to 6C. The reaction mixture was stirred for 20 minutes at 20C and poured into cold sodium hydroa~n car~onate solution.
After extracting several times the organic extract was washed ~nce with water, dried over sodium sulfate, filtered, and 5 evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone = 50:1).
Yield: 1.86 g (47.7 % of theory), M.p.: 113 - 116C (ethanol) Calc.: C 73.44 H 7.19 N 7.14 m/e = 392 lO Found: 72.95 6.98 7.22 m/e = 392 Analogously to Example 6 the following compounds were prepared:

4- ~1-(6-Chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-methyl7benzoic acid ethyl ester Yield: 37 % of theory, 15 M.p.: 102 - 105C
Calc.: C 67.51 H 6.37 Cl 8.30 N 6.56 m/e = 426/28 Found: 67.86 6.39 8.58 6.23 m/e = 426/28 4- ~1-~6-Methyl-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-methyl7benzoic acid ethYl ester 20 Yield: 41 % of theory, M.p.: 116 - 118C
Calc.: C 73.86 H 7.43 N 6.89 Found: 73.75 7.43 6.77 Exam~le 7 4-L~1-(2-Piperidino-phenyl)-ethenyl)-aminocarbonylmethy ~ -benzoic acid ethyl ester A solution of 1.55 g (6.86 m mol) of 4-ethoxycarbonyl-phenacetyl chloride in 5 ml of methylene chloride was ~dded with stirring to a suspension o~ 2.20 g (6.Z4 m mol) of magnesium iodide- ~ ethyl-(2-piperidino-phenyl)-ketimino7-complex in 15 ml of methylene chloride, whereby the internal temperature rose ~rom 20 to 30C. After stirring for 2 hours at room temperature, the reaction mixture was mixed with wa-V ter whilst stirring and extracted several times with methylenechloride. The methylene chloride solution was washed thrice with water, dried over sodium sulfate, filtered and evapora-ted in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone = 50:2).
Yield: 1.1 g (45.8 % of theory), M.p.: 115 - 118C (ethanol) Calc.: C 73.44 H 7.19 N 7.14 Found: 73.30 7~06 7.16 20 Analogously to Example 7 the following compound was prepared:

4- ~1-(5-Chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-~ methyl7benzoic acid ethYl ester Yield: 39.5 % of theory, M.p.: 142 - 145C (ethanol) 25 Calc.: C 67.51 ~ 6.37 C1 8.30 N 6.56 Found: 67.51 6.37 8.36 6.49 - 6l - ~76~45 Example 8 4- ~1-(5-Chloro-2-dimethylamino-phenyl)-ethyl)-aminocarbonyl-methvl7benzoic acid A ~olution of 2.0 g (0.00534 mol) of 4- ~1-(5-chloro-2-di methylamino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid-methyl ester and 0.32 g (0.00801 mol) of sodium hydroxide in 23 ml of ethanol and 7 ml of water was stirred for 2 hours at 50C. After evaporating in v_cuo, water was added and the reaction mixture was ad~usted to pH 6 by means of 2 N-hydro-chloric acid and extracted with ethyl acetate. The organic ,~ phase was extracted with water, dried over sodium sulfate, filtered and e~aporated in vacuo. The evaporation residue was recrystallized from ether.
Yield: 1.7 g (88 % of theory), M.p.: 190 - 192C
Calc.: C 63.24 H 5.87Cl 9.83 N 7.76 Found: 62.90 5.81 10.02 7.90 Analogously to Example 8 the following compounds were prepared:

4-~ 1-(5-Chloro-2-dipropylamino-phenyl)-ethyl)-aminocarbonyl-20 methvl7benzoic acid ~' Yield: 87.6 % of theory, M.p.: 203 - 205C
Calc.: C 66.25 H 7.01Cl 8.50 N 6.72 Found: 65,97 6.96 8.52 6.55 4- ~1-(5-Chloro-2-dibutylamino-phenyl)-ethyl)-aminocarbonyl-methYl7benzoic acid .

Yield: 77.3 % of theory, M.p.: 200 - 2~2C
Calc.: C 67.47 H 7.48Cl 7.97 N 6.30 30 Found: 67.45 7.60 8.28 6.44 - 62 ~ 6~5 4- ~1-(5~Chloro-2-N-cyclohexyl-N-methylamino-phenyl)-ethyl)-Yield: 88.2 % of theory, M.p.: 198 - 200C (ether).
Calc.: C 67.20 H 6.81 Cl 8.27 N 6.53 Found: 67.10 6.73 8.16 6.47 4- ~5 Chloro-2-pyrrolidino-benzyl)-aminocarbonylmethyl7-benzoic acid Yield: 84.2 % of theory, lO M.p.: 208 - 210C (ethyl acetate) Calc.: C 64.42 H 5.68 Cl 9.51N 7.51 Found: 64.70 5.68 9.58 7.60 4- ~1-(5-Chloro-2-pyrrolidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid _ __ _ -Yield: 81.1 % of theory, M.p.: 202 - 204C (ethyl acetate) Calc.: C 65.20 H 5.99 Cl 9.17 N 7.24 Found: 65.02 6,12 9.32 7.10 4- ~ 5-Chloro-2-piperidino-benzyl)-aminocaroonylmethyl7-20 benzoic acid __ Yield: 78 % of theory, M.p.: 164 - 166C
Calc.: C 65.19 H 5.99Cl 9.17N 7.24 Found: 65.50 5.76 9.24 7.36 4- ~1-(5-Chloro-2-piperidino-benzyl)-aminocarbonyl)-ethyl7-benzoic acid _ __ __ _ Yield: 81.1 % of theory, M.p.: 213 - 216C (acetone/ether) - 63 - t ~7624~

Calc.: C 65.90 H 6.29 C1 8.84 N 6.99 Found: 66.30 6.40 9.00 7.04 4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid 5 Yield: 84.9 % of theory, M.p.: 213 - 215C (ether) Calc.: C 65.91 H 6.29Cl 8.85 N 6.99 Found: 66.18 6.19 8.88 7.12 4- ~1-(5-Chloro-2-(3-methyl-piperidino)-phenyl)-ethyl)-amino-carbonylmethyl7benzoic acid _ _ Yield: 69.2 % of theory, M.p.: 208 - 210C (ethyl acetate) Calc.: C 66.57 H 6.56 Cl 8.55N 6.75 Found: 66.36 6.77 8.58 6.80 4- ~1-(5-Chloro-2-(3,5-cis-dimethyl-piperidino)-phenyl)-ethyl)-aminocarbon~lmethyl7benzoic acid _ Yield: 82.2 % of theory, M.p.: 212 - 214C (ether) Calc.: C 67.20 H 6.81 Cl 8.26 N 6.53 ~J 20 Found: 66.95 6.69 8.43 6.68 4- ~1-(5-Chloro-2-piperidino-phenyl)-propyl)-aminocarbonyl-methyl7benzoic acid_ _ _ Yield: 81.5 % of theory, M.p.: 200 - 203C (ether) 25 Calc.: C 66.57 H 6.56Cl 8.55N 6.75 Found: 66.74 6.35 8.59 6.45 - 64 - ~17~2~6 4- ~1-(5-Chloro-2-piperidino-phenyl)-2-methyl-propyl)-aminocarbonylmethyl7benzoic acid Yield: 82.7 % of theory, M.p.: 236 - 240C (ethyl acetate) 5 Calc.: C 67.20 H 6.81 C1 8.27N 6.53 Found: 67.19 6.56 8.14 6.39 4- ~1-(5-Chloro-2-morpholino-phenyl)-ethyl)-aminocarbonyl-methvl7benzoic acid _ _ Yield: 85.6 % of theory, C~ 10 M.p.: 201 - 203C (ether) Calc.: C 62.60 H 5.75Cl 8.80N 6.95 Found: 62.30 5,82 8.83 6.85 4~ (5-Chloro-2-thiomorpholino-phenyl)-ethyl)-aminocar-bonvlmethyl7benzoic acid _ _ 15 Yield: 87.6 % of theory, M.p.: 216 - 217C (ether) Calc.: C 60.20 H 5.53C1 8.4~N 6.69 Found: 59.90 5.51 8.61 6.53 4- ~1-(5-Chloro-2-(hexahydro-1H-azepino)-phenyl)-ethyi)-20 aminocarbonylmethyl7benzoic acid Yield: 81.2 % of theory, M.p.: 202 - 204C (chloroform/toluene) Calc.: C 66.58 H 6.56 Cl 8,55N 6.75 Found: 66.60 6.~7 8.50 6.59 - 6s ~

4~ (5-Chloro-2-octahydroazocino-phenyl)-ethyl)-amino-carbonylmethyl7benzoic acid Yield: 44.4 % of theory, M.p~: 196 - 197C (chloroform/petroleum ether) Calc.: C 67.19 H 6.81 N 6.53 Found: 67.10 6.97 6.37 4- ~1-(5-Chloro-2-(octahydro-1H-azonino)-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid Yield: 74.7 % of theory, M.p.: 204 - 206C (ethyl acetate/petroleum ether) Calc.: C 67.78 H 7.05 N 6.~2 Found: 67.50 7.03 6.04 4- ~ 2-(5-Chloro-2-piperidino-phenyl)-2-propyl)-amino-carbonylmethyl7benzoic acid 15 Yield: 82.9 % of theory, M.p.: 227 - 229C (acetone) Calc.: C 66.57 H 6.56Cl 8.55N 6.75 Found: 66.03 6.66 8.67 6.59 4- ~1-(5-Nitro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-20 methyl7benzoic acid Yield: 95.6 % of theory, M.p.: 252 - 254C (ether) Calc.: C 64.22 H 6.12N 10.21 Found: 64.20 6.17 10.12 -- 66 ~ 624~

4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid Yield: 85 % of theory, M.p.: 170 - 172C
Calc.: C 72.11 H 7.15N 7.64 Found: 71.94 7.03 7.72 4- ~ 2-(2-Piperidino-phenyl)-2-propyl)-aminocarbonylmethyl7-benzoic acid Yield: 72.7 % of theory, M.p.: 213 - 215C
Calc.: C 72.61 H 7.42N 7.36 Found: 72.52 7.31 7.45 4- ~ 5-Methyl-2-piperidino-benzyl)-aminocarbonylmethyl7-benzoic acid 15 Yield: 64.6 % of theory, M.p.: 120 - 122C
Calc.: C 72.11 H 7.15N 7.64 m/e = 366 Found: 72.42 7.38 7.45 m/e = 366 M.p. of the hydrochloride: 266C (decomp.) Calc.: C 65.58 6.76 8.80 N 6.95 Found: 65.00 6.62 9.40 7.00 4- ~2-Piperidino-anilino)-carbonylmethyl7benzoic acid x 0.25 HCl Yield: 72.5 % of theory, M.p.: 216 - 217C
Calc.: (x 0.25 HCl) C 69.11 H 6.45 Cl 2.55 N 8.06 Found: 69.40 6.32 3.08 8.37 4- ~ 5-Chloro~2-piperidino-anilino)-carbonylmethyl7benzoic acid h~drochloride Yield: 51.3 % of theory, M.p.: 232C (decomp.) 5 Calc.: C 58.68 H 5.42Cl 17.32N 6.84 Found: 58.26 5.44 17.97 6.74 4- ~ -(2-Piperidino-anilino-carbonyl)-ethyl7benzoic acid semihydrate Yield: 69.9 ~ of theory, lO M.p.: 151 - 153C (petroleum ether/acetone) Calc.: (x 0.5 H20) C 69.78 H 6.97 N 7.75 Found: 69.30 6.82 7.46 4- ~ -(1-(2-Piperidino-phenyl)-ethyl)-aminocarbonyl)-ethyl7-benzoic acid x 0.2 H20 _ _ 15 Yield: 71.4 % of theory, M.p.: 171 - 172C (acetone/petroleum ether) Calc.: (x 0.2 H20) C 71.91 H 7.45 N 7.29 Found: 71.90 7.30 7.03 Example 9 20 4- ~1-(5-Benzyloxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid 244 mg (0.487 m mol) of 4-L~1-(5-benzyloxy-2-piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ benzoic acid ethyl ester in 2.5 ml of ethanol were heated with stirring with 0.73 ml of 1N sodium 25 hydroxide solution in a bath of 50C, until (after 3 hours) no ester could be detected in the thinlayer chromatogram.
After addition of 0.7~ ml of 1N hydrochloric acid, the reac-tion mixture was evaporated in vacuo and distributed between ethyl acetate and water. The organic extract was dried over sodium sulfate, filtered and evaporated in vacuo.
The evaporation residue was recrystallized from methanol.
Yield: 191 mg (8~ % of theory), M.p.: 220 - 222C
Calc.: C 73.71 H 6.83 N 5.93 Found: 73.21 6.67 5.80 Analogously to Example 9 the following compounds were prepared:

4- ~1-(2-Hexahydroazepino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid _ 10 Yield: 68.5 % of theory, M.p.: 174 - 176C (ethyl acetate) Calc.: C 72.61 H 7.42 N 7.36 Found: 72.36 7.34 7.38 4- ~1-(2-(1,2,3,6-Tetrahydro-pyridino)-phenyl)-ethyl)-amino-15 carbonylmethyl7benzoic acid Yield: 68.2 % of theory, M.p.: 158 - 160C (ethyl acetate) Calc.: C 72.51 H 6.64 N 7.69 Found: 72.20 6.66 7.74 ~J 20 4- ~ 2-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid Yield: 75 % of theory, M.p.: 192 - 195C (ethyl acetate) Calc.: C 65.91 H 6.29 Cl 8.84 N 6.99 25 Found: 66.39 6.17 8.45 6.78 69 t ~6~4~

4~ (5-Fluoro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7ben~oic acid Yield: 52.9 % of theory, M.p.: 174 - 176C (ethyl acetate) Calc.: C 68.73 H 6.55 N 7.29 Found: 68.30 6.48 7.45 4- ~ 5-Methyl-2-piperidino-benzyl)-aminocarbonylmethyl7-benzoic acid Yield: 53.9 % of theory, 10 M.p.: 120 - 122C (ethanol) Calc.: C 72.11 H 7.15N 7.64 m/e - 366 Found: 72.45 7.04 7.64 mf e = 366 4- ~1-(5-Cyano-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid .

15 Yield: 71.6 % of theory, M.p.: 198 - 200C (ether) Calc.: C 70.57 H 6.44N 10.73 Found: 70.17 6.38 11.00 4- ~1-(5-Carboxy-2-piperidino-phenyl)~ethyl)-aminocarbonyl-'J 2 methyl7benzoic acid o Prepared from the corresponding diethyl ester by saponifi-cation with 2.5 equi~alents of sodium hydroxide.
Yield: 73.5 % of theory, M.p.: 260C (decomp.) Calc-: C 67.30 H 6.38 N 6.82 Found: 67.76 6.62 6.85 - 70 ~ 2 4 6 4~ (2- ~ ,4-Dioxa-8-azaspiro ~ . ~ decane-8-yl7phenyl)-ethyl~-aminocarbonylmeth~17benzoic acid semihydrate Yield: 85.7 ~ of theory, M.p.: 130 - 135C (petroleum ether/acetone) Calc.: (x 0.5 H20) C 66.49 H 6.74 N 6.46 Found: 66.56 6.65 6.46 4- ~ -Hydroxy-1-(2-piperidino phenyl)-ethyl)-aminocarbonyl-meth 17benzoic acid Y, Yield: 65 % of theory, lQ M.p.: 155 - 157C tdecomp) (petroleum ether/+ acetone) Calc.: m/e = 382 Found: m/e = 382 4- ~1-(5-Chloro-2-(2-methyl-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl7benzoic_acid 15 Yield: 64.1 % of theory, M.p.: 195 - 198C (ethyl acetate) Calc.: C 66.57 H 6.56 Cl 8.54N 6.75 Found: 66.01 6.25 8.32 6.90 4- ~1-(5-Aminocarbonyl-2-piperidino-phenyl)-ethyl)-amino-carbonylmethyl7benzoic acid Yield: 86 % of theory, M.p.: 231 - 235C (ethyl acetate) Calc.: C 67.46 H 6.65 N 10.26 Found: 67.96 6.68 10.11 - 71 - 1 17624~
4- ~1-(2-(4-Methyl-piperidino)-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid Yield: 67.7 % of theory, M.p. : 173 - 175C (chloroform) Calc.: C 72.61 H 7.42 N 7.36 Found: 72.20 7.36 7.45 4- ~1-(2-Piperidino-phenyl)-ethyl)-N-methylaminocarbonyl-methyl7benzoic acid hvdrochloride Conversion of the viscous betain (72 % crude) into the hydro-chloride by means of hydrochloric acid in isopropanolic solu-tion.
Yield: 32 ~ of theory, M.p.: 222 - 230C (decomp.) (ethanol) Calc.: C 66.25 H 7.01 Cl 8.50 N 6.71 Found: 66.07 6.37 8.37 6.58 2- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -benzoic acid Yield: 7 % of theory, M,p.: 135C (decomp.) Calc.: C 72.10 H 7.15N 7.64 Found: 72.29 7.03 7.37 3- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid _ _ _ _ Yield: 86 ~ of theory, M.p.: 205 - 207C
Calc.: C 72.11 H 7.15N 7.64 Found: 72.30 7.29 7.71 1 17~246 3-Chloro-4- ~1~(2-piperidino-phenyl)-ethyl)-amino-carbonyl-methyl7benzoic acid Yield: 38 % of theory, M.p.: from 175C sintering, from 190C clear melt Calc.: C 65.91 H 6.29 Cl 8.84 N 6.99 Found: 65.42 6.32 9.05 6.77 4- ~1-(2-(1,2,3,4-Tetrahydro-isoquinoline-2-yl)-phenyl)-ethyl~-aminocarbonylmethyl7benzoic acid Yield: 59 % of theory, M.p. 207 - 209C
Calc.: C 75.34 H 6.32 N 6.76 Found: 75.30 6.29 6.67 4~ (3-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid _ _ _ _ 15 Yield: 33 % of theory, M.p.: 206 - 208C
Calc.: C 72.09 H 7.15 N 7.64 Found: 72.04 7.14 7.57 4- ~1-(6-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-20 methYl7benzoic acid Yield: 35 % of theory, M.p.: 148 - 150C
Calc.: C 65.91 H 6.28 Cl 8.84 N 6.98 Found: 65.45 6.36 9.63 6.84 ~ 73 ~ 1 176246 4- ~1-(6-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid Yield: 33 % of theory, M.p.: 170C
5 Calc.: C 72.60 H 7.41N 7.36 Found: 72.45 7.34 7.32 4- ~1-(2-(Octahydro-isoindole-2-yl)-phenyl)-ethyl)-amino-carbonyl7benzoic acid _ _ Yield: 64 % of theory, M.p.: 130C
Calc.: C 73.86 H 7.43N 6.89 Found: 73.60 7.47 6.72 4- ~1-(2-Decahydro-isoquinoline-2-yl)-phenyl)-ethyl)-amino-carbonvlmethvl7benzoic acid Yield: 71 % of theory, M.p.: 220 - 221C
Calc.: C 74.25 H 7.66N 6.66 m/e = 420 Found: 74.45 7.50 6.58 m/e = 420 4- ~1-(2-(1,2,3,4,5,6,7,8-Octahydro-isoquinoline-2-yl)-v 20 phenvl)-ethyl)-aminocarbonylmethyl7benzoic acid Yield: 99 % of theory, M.p.: 70C (decomp.) Calc.: (x 0,5 H20) C 73.05 H 7.30 N 6.54 m/e = 418 Found: 73.00 7.165.98 m/e = 418 _ 7~ - L176~46 4~ (4-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid Yield: 82.1 % of theory, M.p.: 200 - 202C
5 Calc.: C 65.91 H 6.29Cl 8.84N 6.99 Found: 66.06 6.40 9.01 6.93 4- ~1-(4-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid Yield: 66.5 % of theory, 10 M.p.: 110 - 115C
Calc.: C 72.60 H 7.42N 7.36 Found: 72.50 7.52 7.46 2-Piperidino-benzhydrYl~=aminocarbonylmethyl7benzoic acid Yield: 88 % of theory, 15 M.p.: 232 - 234C
Calc.: C 75.68 H 6.59 N 6.54 Found: 75.16 6.52 6.74 4- ~ 5-Chloro-2-piperidino-benzhydryl)-aminocarbonylmethyl7-benzoic acid 20 Yield: 78.5 % of theory, M.p.: 255 - 260C
Calc.: C 70.05 H 5.88Cl 7.66N 6.o5 Found: 70.50 5.76 7.36 6.06 4-/¦1-(4-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid_ Yield: 81 % of theory, M.p.: 208 - 210C
5 Calc.: C 72.11 H 7.15 N 7.64 Found: 72.24 7.26 7.54 4- ~1-(2-(4-Methyl-piperazino)-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid Yield: 65 % of theory, M.p.: 150 - 153C
Calc.: C 69.27 H 7.13 N 11.02 Found: 69.62 7.65 10.64 4- ~1-(2-(4-Benzyl-piperazino)-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid hvdrochlor de 15 Yield: 32 % of theory, M.p.: 180C
Calc.: C 68.07 H 6.53 Cl 7.18N 8.51 Found: 67.85 6.56 7.18 8.51 4- ~1-(2-(4-p-Chlorophenyl-piperazino)-phenyl)-ethyl)-amino-'~ 20 carbon~lmethyl7benzoic acid .
Yield: 75 % of theory, M.p.: 212C (decomp.) Calc.: C 67.84 H 5.90Cl 7.42N 8.79 Found: 67.74 6.22 7 59 8.82 - 76 ~ 4~
4- ~ ~ -Cyclohexyl-2-piperidino-benzyl)-aminocarbonylmethyl7-benzoic acid Yield: 33 ~ of theory, M.p.: 199 - 202C
5 Calc.: C 74.62 H 7.89N 6.45 Found: 74.60 7.54 6.66 ~+~-4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid x 0 3 H 0 ~ 2 -- _ _ Yield: 40 % of theory, lO M.p.: 107C (decomp. (isopropanol/ether) r~72 = + 7.3 (c = 1; methanol) Calc.: (x 0.3 H20) C 71.02 H 7.25 N 7.52 m/e = 366 Found: 70.90 7.22 7.42 m/e = 366 (-)-4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-15 ben~olc acid sodium salt .
Crude yield of betain: 77 % of theory, Calc.: m/e = 366 Found: m/e = 366 Conversion into the sodium salt by means of 1 equivalent of 20 sodium hydroxide solution in ethanol.
M.p. of the sodium salt: 190C (decomp.) 4- ~1-(2-Piperidino-phenyl)-ethenyl)-aminocarbonylmethyl7-benzoic acid . . ~ .

Yield: 53.6 ~ of theory, 25 M.p.: 158 - 160C (ethanol) Calc.: C 72.51 H 6.64N 7.69 Found: 72.40 6.34 7.51 1 1 7624fi 4-[~1-(5-Cllloro-2-piperidino-phenyl)-ethenyl)-am~nocarbonyl-methyl] benzoic acid Yield: 78.7 ~ of theory, M.p.: 198 - 200C (acetone) Calc.: C 66.24 H 5.81 Cl 8.88 N 7.02 Found: 65.74 5.72 9.37 7.10 4-[(~-Cyclohexylidene-2-piperidino-benzyl)-aminocarbonyl-methyll benzoic acid Yield: 21 % of theory, M.p.: 213 - 216C
Calc.: C 74.97 H 7.46 N 6.48 Found: 74.3 7.52 6.48 4-[(1-(6-Chloro-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-methyl] benzoic acidYield: 39 % of theory, M.p.: 162C
Calc.: C 66.24 H 5.81 Cl 8.88 N 7.02 m/e = 398/400 Found: 66.48 5.84 8.88 6.85 m/e = 398/400 4-~(1-(6-Methyl-2-piperidino-phenyl)-ethenyl)-aminocarbonyl-methyl] benzoic acidYield: 49 % of theory, M.p.: 128 - 130C
Calc.: m/e - 378 Found: m/e = 378 4-[(1-(2-Piperidino-phenyl)-propenyl)-aminocarbonyl-methyl] benzoic acid Yield: 65 % of theory, M.p. (Z - form): 185 - 187C (ethyl acetate) Calc.: C 72.99 1-l 6.92 N 7.40 Found (Z - form): 73.10 6~99 7.56 M.p. (E - form): 108 - 110C

- 78 ~ 2 ~ 6 4~ (5-Hydroxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid semihy~ra-te Saponification with 2.5 equivalents of sodium hydroxide.
Yield: 55.9 % of theory, 5 Foam (~rom ether) Calc.: (x 0.5 H20) C 67.50 H 6.95 N 7.16 Found: 67.11 7.15 6.87 4- ~1-(2-(2-Methyl-pyrrolidino)-phenyl)-ethyl)-amino-carbonylmethyl7benzoic acid lO Yield: 62 ~ of theory, M.p.: 169 - 172C
Calc.: C 72.11 H 7.15N 7.64 Found: 71.96 6.82 7.51 4- ~1-(5-Aminosulfonyl-2-piperidino-phenyl)-ethyl)-amino-15 carbonylmethyl7benzoic acid _ _ _ Yield: 19.2 % of theory, M.p.: 210C (decomp.) Calc.: C 59.30 H 6.11N 9.43 m/e = 445 Found: 58.80 5.87 9.06 m/e = 445 20 4- ~1-(2-Piperidino-phenyl)-prop~l)-aminocarbonylmethyl7-benzoic acid Yield: 71.4 ~ of theory, M.p.: 208 - 210C (ethanol) Calc.: C 72.61 H 7.42N 7.36 Found: 72.30 7.44 7.45 25 Example 10 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid_ _ _ _ _ A solution of 13.5 g (0.338 mol) of sodium hydroxide in 50 ml of water was added to 88.8 g (0.225 mol) of 4-L~1-(2-piperi-30 dino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid ethyl ester - 79 - Ll7624~
in 8~0 ml of ethanol and the mixture was stirred at an internal temp~rature of 60C until no starting product could be detected in the thinlayer chromatogram (approx. 45 minutes). After adding 400 ml of water the reaction mi~ture was adjusted at 25C
5 to p~ = 5.8 lusin~ a pE~ meter) by means of semi-concen-trated hydrochloric acid. After a short time crystallization began.
After standing over~night at 20C, the precipitate was fil-tered off and the crystals obtained were washed several times with water. Subsequently, the crystals were dissolved in methylene ch~oride and washed with alittle water. After dry-ing the organic phase over sodium sulfate, the solution was filtered and the solvent was removed in vacuo, whereby a solid evaporation ~esidue of 57.5 g was obtained.
The ethanolic hydrochloric filtrate (pH = 5.8) was adjusted to pH = 5.0 by means of semi-concentrated hydrochloric acid, then the ethanol was distilled of in vacuo and the evaporated so-lution was cooled in ice. The resultant precipitate was fil-tered off, dissolved in methylene chloride, separated from the a~ueous phase, the methylene chloride solution was dried, filtered and evaporated in vacuo. The solid evaporation re-sidue obtained was 13;0 g. Both evaporation residues (together 70.5 g) were recrystallized from the 5- to 6-fold amount of ethanol/water (80/20) under addition of activated charcoal.
Yield: 62 % of theory, M.p.: 16~ - 164C
Calc.: C 72.11 H 7.15 N 7.64 Found: 72.13 7.25 7.75 If on completion of the saponification, af~er the addition of water and coolina to 25C immedia~ely the 30 pH is ad~usted to 5.0, and then continued as ~escribed above, 75.9~ of the dried evaporation residue may be obtained without further processin~ the etharlolic hydrochloric filtrate, which even before tlne final recrystallization ~ave a correct elementar~ analysis.
35 M.p. 172 - 176C
Calc.: C72.ll H 7.15 N 7.6~
Found: 71.90 7.08 7.52 1 1762~

Analogously to Example 10 the following compounds were prepared:

4- ~1-(5-Methyl-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid Yield: 56.6 % of theory, M.p.: 215 - 217C (ethanol) Calc.: C 72.61 H 7.42N 7.36 Found: 72.71 7.49 7.25 4- ~ dc-carboxy-2-piperidino-benzyl)-aminocarbonylmethyl7 benzoic acid x o.66 H20 ~' 10 Prepared by saponification of the 4~ -methoxycarbonyl-2-piperidino-benzyl)-aminocarbonylmethyl7benzoic acid ethyl ester with 2.5 equivalents of sodium hydroxide.
Yield: 72.2 % of theoryJ
M.p.: 235 - 240C (decomp.) (methanol/chlQrQform) Calc.: (x 0.66 H20) C 64.69 H 6.33 N 6.85 Found: 64.64 6.23 6.61 Exam~le 11 4- ~1-(2-Piperidino-phenyl) ethyl)-aminocarbonylmethyl7-benzoic acid sodium salt monoh~drate ~ .
500 mg (1.26 m mo:L) of 4- ~ 2-piperidino-phenyl)-ethyl)-aminocarbonylmethy_7benzoic acid ethyl ester ln 5 ml of - ethanol were stirred together with 1.26 ml of 1N-sodium hydroxide solution for 1 hour at 50C. After cooling to 0C, the precipitated crystals were filtered off and washed 25 with cold ethanol and with ether.
Yield: 238 mg (48.6 % of theory), M.p.: 245 - 250C
Calc.: (x 1 H20) C 65.01 H 6.69 N 6.89 Found: 65.40 6.83 6.72 76~4 ~?s Analogously to Example 11 the following compound was prepared:

4~ (5-Methoxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid sodium salt monoh~drate Yield: 17.5 96 of theory, M.p.: 212 - 215C
Calc.: (x 1 H20) C 63.28 ~I 6.70 N 6.42 Found: 63.20 6.82 6.51 From the sodium salt was obtained analogously to Example 9 the corresponding acid as monohydrate:
~lO M.p.: 187 - 189C (ethanol/water) Calc.: (x 1 H20) C 66.40 H 7.29 N 6.76 Found: 66.87 6.97 6.80 Example 1 2 4-Lr1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-5 benzoic acid sodium salt x 0.6 H20 8.4 g (0.0229 mol) of 4-~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid were dissolved at 60 to 65C
in 80 ml of ethanol. To this solution 22.9 ml of 1N sodium hydroxide solution were added with stirring and stirring was ~ continued for 30 minutes. After cooling to 20C, a precipitate was obtained. After cooling to 0C, the precipitate was filtered and washed with cold ethanol and ether, The precipitate thus obtained,of m.p. 250 - 251C, was recrystalli-zed from ethanol/water (7/3).
,~ Yield: 7.2 g (78.6 % of theory), M.p.: 253 - 255C
Calc.: (x o . 6 H20): C 66.18 H 6.61 N 7.02 Found: 66.10 6.64 7.13 1 ~7~24~
Examl~le 13 4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy~7-benzoic acid -100 mg (0.237 m mol) of 4-L~1-(2-piperidino-phenyl)-ethyl)-5 aminocarbonylmethyl7benzoic acid-tert.butyl ester in 5 ml of benzene were heated together with some crystals of p-toluene sulfonic acid hydrate to reflux temperature for half a day. According to the thinlayer chromatogram then no starting product could be detected, and according 10 to the Rf-value and mass spectrum the desired product was formed.
M.p.: 163 - 165C
Calc.: m/e = 366 F'ound: m/e = 366 15 EYample 14 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarhonylmethyl7-benzoic acid o.46 g (1 m mol) of 4-~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid benzyl ester in 20 ml of 20 ethanol were hydrogenated at 0.25 g of palladium/charcoal at 50C and a hydrogen pressure of 5 bar. After 5 hours the catalyst was filtered off over celite and the filtrate was evaporated in vacuo. The evaporation residue was re-crystallized from ethanol/water (8/2).
25 Yield: O.Z6 g (71 % of theory), M.p.: 163 - 165C
Calc.: C 72.11 H 7.15 N 7.64 Found: 72.30 7.25 7. a1 Example 15 30 4-~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methvl7benzoic acid 2.54 g (0.02 mol) of oxalyl chloride were dropped at 0 to 5C

2 4 fi to a stirred solution of 3.57 g (0.01 mol) of N~ (5-chloro~
2-piperidino-phenyl)-ethyl7-N~/~henacetyl7amine in 16 ml of carbon disulfide and subsequently 2.67 g (0.02 mol) of alumi-nium chloride were added. After one hour again the same amounts 5 of oxalyl chloride and aluminium chloride were added and the mixture was heated subsequently for 3 hours up to 50C. After -cooling, ice water and hydrochloric acid were added and the reaction mixture was extracted with chloroform. The organic extract was dried and filtered and evaporated in vacuo. The 10 evaporation residue was purified by column chromatography on silica gel (chloroform/methanol = 10:1).
Yield: o.60 g (15 % of theory), ~;_ M.p.: 213 - 214C (ether) Calc.: C 65.91 H 6.29 Cl 8.85 N 6.99 Found: 66.13 6.05 8.97 7.25 Example 16 N-~-Acetyl-phenacetyl7-N-L~-(5-chloro-2-piperidino-phenyl)-ethyl7amine A solution of 0.6 ml (8.43 m mol) of acetyl chloride in 20 5 ml of methylene chloride was added at an internal tempera-ture of 0 to 5C to 1.12 g (8.43 m mol) of aluminium chloride ~_,, in 10 ml of methylene chloride. Subsequently, at 0 to 5C, a solution of 1 g (2.81 m mol) of N-~-(5-chloro-2-piperidino-phenyl)-ethy~7-N-/phenacetyl7amine in 5 ml of methylene chlo-25 ride was added with stirring. The reaction mixture was stirred for 1 hour at 3C and for 2 days at 20C. After decomposing under cooling with ice water and hydrochloric acid, the methylene chloride phase was separated and the aqueo-ls phase was extracted with chloroform. The comblned organic phases were 30 drled over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone = 4:1).
~ield: 0.28 g (25 % of theory), M.p.: 160 - 161C
Calc.: C 69.24 H 6. 82 Cl 8.89 N 7.02 m/e = ~98/400 Found: 69.55 6 ~ 99 9.45 6.85 m/e = 398/400 ~4 1 17~246 Example 17 4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid A solution of 1.23 g (0.0031 mol) of N- ~ -acetyl-phen-acety ~ -N- ~ -(5-chloro-2-piperidino-phenyl)-ethyl7amine in 12 ml of dioxan was a~ded over 15 minutes at 35 - 40C to a stirred sodium hypobromite solution /Pre-pared from 1.84 g (0.046 mol) of sodium hydroxide, dis-solved in 9 ml of water, and 0.72 ml (0.014 mol) of bromine under ice coolin~7. After 40 minutes at 35 - 40C aqueous sodium hydrogen sulfite solution and water was added and the mixture was evaporated in ~acuo. The residue was dis-solved with water, acidified under cooling with 2N~hydrochlo-ric acid and extracted with ether/ethyl acetate. The organic phase was dried and filtered, and evaporated in vacuo.
The evaporation residue was recrystallized from ether.
Yield: 0.14 g (11 % of theory), M.p.: 213 - 215C
Calc.: C 65.91 H 6.29 Cl 8.85 N 6.99 2Q Found: 65.78 5.98 8.95 7.17 Analogously to Example 17 the following compound was prepared:

4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid Yield: 15 % of theory, M.p.: 170 - 171C
Calc.: C 72.11 H 7.15N 7.64 Found: 72.45 7.G1 7.48 Example 18 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzaldehyde Prepared from 4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbo-~ ~7624~

nylmethyl7benzyl alcohol by oxidat:ion with active manga-nese dioxide in absolute acetone and subsequent purifi~
cation by column chromatography on silica gel (chloroform/
acetone = 20:1).
5 Yield: 4 ~ of theory, M.p.: 159C
Calc.: C 75.40 H 7.48 N 7.99 Found: 75.05 7.18 7.67 Example 19 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid Prepared from 4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbo-nylmethyl7benzaldehyde by heating with silver oxide in the presence of 1N sodium hydroxide solution for 20 minutes on ~ steam bath 9 subsequent acidification with 2N sulfuric acid at pH = 5, extraction with ethyl acetate and purifi-cation by column chromatog~aphy on silica gel (toluene/
acetone = 1:1).
Yield: 3 ~ of theory 20 M.p.: 168 - 170C
Calc.: m/e = 366 Found: m/e = 366 Example 20 4- ~1-(2-Piperidino-phenyl)_ethyl)-aminocarbonylmethyl7-benzoic acid ethyI ester 5.5 g (0.014 mol) of 4- ~1-(2-piperidino-phenyl)-ethenyl)-aminocarbonylme-thyl7benzoic acid ethyl ester in 110 ml of ethanol were hydrogenated at 1.5 g of palladium/charcoal (10 %) at 20C and a hydrogen pressure of 5 bar. After - 30 30 minutes the catalyst was filtered off over celite and .

-~f l 176246 the filtrate was evaporated in vacuo to a volume of 20 ml.
100 ml of petroleum ether were adde and the mixture was cooled to 0C.
Yield: 4.7 g (85.5 ~0 of theory), 5 M.p.: 152 - 154C
Calc.: C 73.0~ H 7.66 N 7.10 Found: 72.80 7.63 7.08 Analogously to Example 20 the following compound was prepared:

4-~-(2-Piperidino-phenyl)-propyl)-aminocarbonylmethy_7benzoic lO acid ethYl ester V

Yield: 70.8 % of theory, M.p.: 132 - 134C
Calc.: C 73.00 H 7.90 N 6.86 Found: 73.71 7.88 6.77 15 Example 21 4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid 100 mg (0.2744 m mol) of 4-f~1-(2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl7benzoic acid in 5 ml of absolute ethanol 20 were hydrogenated at 50 mg of palladium/charcoal (10 %) at 20C and at a hydrogen pressure of 1 bar under sha~sing.
After 1.5 hours the catalyst was filtered off and the fil-trate was evaporated in vacuo.
._ Yield: 91 % of theory, 25 M.p.: 170 - 171C
Calc.: m/e = 366 Found: m/e = 366 ~7 1 17~24~;

Example 22 4-~1-(2-Piperidino-phenyl)-ethyl)-amlnocarbonylmethyl7-benzoic acid semihydrate 200 mg (0.5014 m mol) of 4-L~1-(5-chloro-2-piperidino-5 phenyl)-ethenyl)-aminocarbonylmethyl7benzoic acid in 10 ml of absolute ethanol were hydrogenated at 100 mg of palladium/charcoal (10 %) at 50C and at hydrogen pressure of 1 ,bar under shaking. After 1.5 hours the catalyst was filtered off, 5 ml of water were added, adjusted to pH = 6 10 by means of 1N-sodium hydroxide solution and the ethanol was evaporated in_. A colourless precipitate was ob-tained, which was filtered after cooling~
Yield: 100 mg (53.1 % of theory), M.p.: 135C
Calc.: (x 0.5 H20) C 70.36 H 7.24 N 7.46 m/e = 366 Found: 70.31 7.44 7.78 m/e = 366 Example 23 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7 benzoic acid ethvl ester ~, 20 1.6 ml of conc. sulfuric acid were added in little drops to ' a' mixture of 2 g (9.74 m mol) of 1-(2-piperidino-phenyl)-ethanol and 4 g (21.1 m mol) of 4-cyanomethyl-benzoic acid ethyl ester whilst stirring and cooling with ice by keeping the internal temperature at 35 to 40C. Subsequently, the 25 mixture was heated for 2.5 hours in a bath of 80C, further 2 g (10.5 m mol) of ~-cyanomethyl benzoic acid ethyl ester and 0.8 ml of conc. sulfuric acid were added and heating was continued for 1 hour at 80C and for 3 hours at 100C.
After that time no starting alcohol could be detected in 30 the thinlayer chromatogram. After cooling to 20C the mix-ture was extracted with ethyl acetate whilst stirring and 8~
24~

cooling ice water was added. After extracting several timeswith ethyl acetate, the organic extract was dried over sodium sulfate, filtered and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone = 10:1). From the pre-fractions 0.5 g of 2-piperidino-styrol were isolated.
Yield: 0.66 g (17.4 % of theory), M.p.: 147 - 150C (ethanoI) Calc.: C 73.07 H 7.66 N 7.10 Found: 73.26 7.55 6.90 Example 24 4- ~'1-(5-Chloro-2-piperidino-phenyl)-ethyl~-aminocarbonyl-methyl7benzoic acid 0.4 ml (5.55 m mol) of thionyl chloride were added to a stirred solution of 1 g (5.55 m mol) of 4-carboxy-phenyl-acetic acid and of 1.32 g (5.55 m mol) of 1-(5-chloro-2-piperidino-phenyl)-ethylamine in 10 ml of absolute py-ridine, whereby the internal temperature rised from 20C
to 35C. The deep-brown reaction mixture was stirred for 3 hours at 20C and evaporated in vacuo. The evaporation residue was distributed between water (at pH = 3 after addition of 2N hydrochloric acid) and chloroform. The or-ganic extract was dried and filtered and evaporated in vacuo.
The evaporation residue was purified by column chromatography 25 on silica gel (chloroform/methanol = 10 Yield: 1.06 g (48 % of theory), M.p.: 212 - 214C (ether) Calc.: C 65.91 H 6.29 Cl 8.85 N 6.99 Found: 65.79 6.01 8.69 6.87 ~9 ~ 176245 Analogously to Example 24 the following compounds were prep~red:

4- ~1-(2~Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid Yield: 52 % of theory, M.p.: 169 - 171C
Calc.: C 72.11 H 7.15N 7.64 Found: 71.84 6.87 7.72 4~ (2-(4-Oxo-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic_acid _ _ _ _ _ _ lQ Yield: 32 % of theory, M.p.: 177 - 130C (decomp.) (acetone/petroleum ether) Calc.: C 69.46 H 6.36 N 7.36 Found: 69.62 6.41 7.50 4- ~1-(2-(4-Hydroxy-piperidino)-phenyl)-ethyl)-aminocarbonyl-methvl7benzoic acid x 0.66 H20 _ _ Yield: 23.5 % of theory, M.p.: 176 - 179C (decomp.) (acetone/petroleum ether) Calc.: (x o.66 H20) C 66.97 H 6.81 N 7.10 Found: 67.12 6.78 7.26 V
4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzonitrile Prepared from 4-cyano-phenyl acetic acid.
Yield: 51 ~ of theory, M.p.: 155 - 157C (ethyl acetate) Calc.: C 76.05 H 7.25 N 12.09 Found: 76.41 7.10 12.20 9') 117624~

ExamPle 25 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzyl alcohol _ _ _ Prepared from 4-L~1-(2-piperidino-phenyl)-ethyl)-aminocarbonyl-5 methyl7benzoic acid ethyl ester by lithium aluminium hydride reduction in tetrahydrofuran.
Yield: 39 ~ of theory, M.p.: 104 - 106C
Calc.: C 74.96 H 8.00N 7.94 Found: 74.80 7.80 7.80 Example_26 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7 benzyl malonic acid diethyl ester_ A solution of 3.7 g (10 m mol) of 4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzyl chloride ~ .p.: 12~ - 125C;
prepared from the alcohol described in Example 25 by means of thionyl chloride in chlorofor_ 7 in 35 ml of absolute ethanol was added to a solution of sodium malonic acid diethyl ester f~repared from 0.7 g (30 m mol) of sodium in 25 ml of absolute ethanol and 4.8 g (30 m mol) of malonic acid diethyl este ~ .
A catalytic amound of potassium iodide was added and the 1 1 ~624fi mixture was refluxed for 16 hours. After evaporating in vacuo, the evaporation residue was adjustedlneutral by means of hydrochloric acid and extracted with methylene chloride. The organic extract was dried over sodium sul-5 fate, filtered and and evaporated in vacuo. The evapora-tion residue was purified by column chromatog-aphy on silica gel (toluene/acetone = 6:1).
Yield: ~.0 g (60 ~0 of theory), M.p.: <20 C
lO Calc.: m/e = 494 Found: m/e = 494 Example 27 3- ~ ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -phenyl7prop onic_acid 15 5 ml of 1N-sodium hydroxide solution were added to a solution of 0.85 g (1.7 m mol) of 4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzyl malonic acid diethyl ester in 18 ml of ethanol. After stirring for 2 hours at 50C, the mixture was evaporated in vacuo, and water and 5 ml of 1N-20 hydrochloric acid were added. The formed precipita-te was filtered off, dried in vacuo and heated for 30 minutes up to 120C, whereby carbon dioxide was liberated . The product was purified by column chromatography on silica gel (chloroform/methanol = 20:1).
25 Yield: 0.15 g (22.4 % of theory), M.p.: 68 - 70C
Calc.: C 73.06 H 7.67 N 7.10 m/e = 394 Found: 72.64 7.42 6.81 m/e = 394 ,3, 1176246 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzaldehyde Prepared by heating crude N1- ~ - ~1-(2-piperidino-5 phenyl)-ethyl)-aminocarbonylmethyl7benzoyl7-N2-tosyl-- hydra~ine in anhydrous sodium carbonate at 160 - 170C
in ethylene glycol ~ repared from 4-/¦1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid and tosyl-hydrazine with carbonyl diimidazole in tetrahydrofuran7.
lO Yield: 10 % of theory, M.p.: 159C
Calc.: C~75.40 H 7.48N 7,99 Found: 74.99 7.24 7.60 Example 29 15 4-/T1-(2-piperidino-phenyl)-ethyl)-aminocaIbonylmethyl7 - benzoic acid 0.50 g (1.247 m mol) of 4- ~1-(5-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid in 20 ml of absolute ethanol were hydrogenated at 0.25 g of palladium/charcoal ; 20 (10 %) at 50C and a hydrogen pressure of 5 bar. After 2 hours the catalyst was filtered off over celite and after evaporatlng i vacuo the residue was distributed at pH = 6 be-tween water and ethyl acetate. The organic extract was washed with water, dried and filtered and evaporated ln vacuo.
25 Yield: 0.31 g (67 % of theory), M.p.: 170 - 172C (ether) Calc.: C 72.11 H 7.15 N 7.64 Found: 71.76 6.98 7.51 ()3 Il76246 Analogously to Example 29 the following compounds were prepared:

4- ~ 2-(2-Piperidino-phenyl)-2-propyl)-aminocarbonylmethy ~ ~
benzoic acid _ _ _ _ _ _ _ _ Yield: 68.5 ~ of theory, 5 M.p.: 213 - 215C
Calc.: C 72.61 H 7.42N 7.36 Found: 72.43 7.25 7.40 4- ~1-(2-Dimethylamino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid -lO Yield: 53.3 ~ of theory, M.p.: 165 - 168C (acetone/petroleum ether) Calc.: C 69.92 H 6.79 N 8.59 Found: 69.88 6.83 8.49 4-/~2-PYrrolidino-benzyl)-aminocarbonYlmethyl7benzoic acid Yield: 55 % of theory, M.p.: 212 - 215C (methanol) Calc.: C 70.99 H 6.55 N 8.28 Found: 70.97 6.91 8.15 4- ~1-(2-Pyrrolidino-phenyl)-ethyl)-aminocarbonylmethyl7-20 benZoic acid .

Yield: 25 % of theory, M.p.: 155 - 157C (acetone/ether) Calc.: C 71.57 H 6.86 N 7.95 Found: 71.22 6.75 8.42 117~2~6 4-/~2-PiPeridino-benzyl~-aminocarbonylmethyl7benzoic acid Yield: 60.4 ~ of theory, M.p.: 175 - 177C (acetone) Calc~: C 71.57 H 6.86 N 7.95 Found: 71.48 7.00 8.09 4-L~2-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -benzoic acid Yield: 60.4 % of theory, M.p.: 164 - 166C (ethyl acetate) Calc.: C 72.11 H 7.15 N 7.64 Found: 72.35 7.18 7.76 4- ~1-(2-(2-Methyl-piperidino)-phenyl)-ethyl)-aminocarbonyl-methvl7benzoic acid Yield: 90.9 % of theory, M.p.: 171 - 173C (petroleum ether/acetone) Calc.: C 72.61 H 7.42 N 7.36 Found: 72.30 7.39 7.43 4- ~1-(2-(3-Methyl-piperidino)-phenyl)-ethyl)-aminocarbonyl-methyl7b nzoic acid Yield: 86.3 % of theory, M.p.: 170 - 173C (petroleum ether/acetone) Calc.: C 72.61 H 7.42 N 7.36 Found: 72.20 7.28 7.12 4- ~1-(2-Dipropylamino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid . . . _ . . . _ . .

Yield: 51.1 % of theory, M.p.: 175 - 178C (ethyl acetate) Calc.: C 72.22 H 7.91 ~ 7.32 Found: 72.10 8.05 7.69 ~)5 tl7~45 4~ (2-Piperidino-phenyl)-2-methyl-propyl)-aminocarbonyl-methvl7benzoic acid _ _ Yield: 86 % of theory, M.p.: 215 - 217C (acetone) 5 Calc.: C 73.06 H 7.67 N 7.10 Found: 73.10 7.55 6.99 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid methyl ester Prepared from 4-/r1-(5-chloro-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid methyl ester.
Yield: 37.2 % of theory, M.p.: 145 - 147C
Calc.: C 72.61 H 7.42 N 7.36 Found: 72.47 7.30 7.56 4- ~ 2-piperidino-anilino)-carbonylmethyl7benzoic acid methyl ester Prepared from 4- ~ 5-chloro-2-piperidino-anilino)-carbonyl-methyl7benzoic acid methyl ester.
Yield: 60 ~0 of theory, M.p.: 85 - 86C (toluene/petroleum ether) ~ Calc.: C 71.57 H 6.86 N 7.96 Found: 71.48 6.92 8.39 '3~ 624~
N-Phenacetyl-N-l1-(2-piperidino-phenyl)-ethyl7amine Prepared from N-L1-(5-chloro-2-piperidino-phenyl)-ethyl7-N-phenacetyl-amine.
Yield: 54.6 % of theory, M.p.: 120 - 121C (petroleum ether/acetone) Calc.: C 78.22 H 8.13 N 8.69 Found~ 77.90 8.24 8.75 Example 30 4-L¦1-(5-Amino-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid methyl ester _ _ 2.0 g (0.0047 mol) of 4- ~1-(5-nitro 2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid methyl ester in 20 ml of dimethyl formamide were hydrogenated at 0.2 g of palladium/charcoal (10 %) in a Parr apparatus at 20C and a hydrogen pressure of 1 bar. When the hydrogen absorption was finished (2 hours), the catalyst was filtered off over celite and evaporated +o dryness in vacuo.
Yield: 1.8 g (95 % of theory), M.p.: 140 - 142C (toluene).

Analogously to Example 30 the following compounds were prepared:

4- ~1-(5-Amino-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester Yield: 97.8 % of theory, M.p.: 148 - 149.5C (cyclohexane) Calc.: C 70.39 H 7.63 N 10.26 Found: 70.20 7.67 9~60 4-L~1~(5-Amino-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid _ Prepared from 4-L~1-(5-nitro-2-piperidino-phenyl)-ethyl3-aminocarbonylmethyl7benzoic acid.

I 1 762~6 Y;eld: 85.7 % of theory, M.~.: 223 - 225C (ether) Calc.: C 69.27 H 7.13 11.02 Found: 69.18 7.04 11.35 N-[4-Amino-phenacetyl]-N-[1-(2-piperidino-phenyl)-ethyl]-amine dihydrochloride _ _ _ semihydrate Prepared from N-[4-nitro-phenacetyl]-N-[(1-(2-piperidino-phenyl)-ethyl]amine.
Conversion of the crude amino compound into the dihydrochloride in ethanol was by means of ethereal hydrochloric acid.
Yield: 17.5 % of theory, M.p.: 238C (decomp.) Calc.: (x 2 HCl x 0.5 H20)C 60.12H 7.21 Cl 16.91 Found: 60.52 7.52 17.05 Example 31 4-[(1-(5-Bromo-2-piperidino-phenyl?-ethyl)-aminocarbonylmethyl]benzoic acid A solution of 0.072 g (1.05 m mol) of sodium nitrite in 0.5 ml of water was added at an internal temperature of 0 to 5C to 0.40 g (1.05 m mol) of 4-[(1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]benzoic acid in 2 ml of semi-conc. aqueous hydrobromic acid. The resultant diazonium salt solution was then added to 0.196 g of copper (I) bromide in 2 ml of 48 %
hydrobromic acid, whereby considerable formation of gas occurred. The reaction mixture was stirred for 1.5 hours at an internal temperature of 45 - 50C, cooled and adjusted to pH 4 by means of 4N sodium hydroxide solution. After extraction with warm e-thyl acetate, the extract was washed with water, dried and filtered. After evaporating in vacuo, the obtained residue was purified by column chromatography on silica gel (chloroform/methanol = 7:1).

I t7~24 6 Yield: 0.08 g (17 % of theory), M.p.: 212 - 213C (ethyl acetate/petroleum ether) Calc.: C 59.32 H 5.66 Br 17.94 N 6.29 Found: 59.30 5.71 17.85 6.48 Analogously to Example 31 the i'ollowing compound was prepared:

4- ~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid Prepared by diazotization of 4- ~1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid in conc.
HCl and Sandmeyer reaction with copper (I) chloride.
Yield: 25.2 % Gf theory, M.p.: 213 - 215C
Calc.: C 65.91 H 6.29 Cl 8.85 N 6.99 Found: 66.20 6.~1 8.87 6.~2 If the reaction is carried out in hydrochloric acid without copper (I) chloride, a yield of 19 % of theory is obtained.
Furthermore, 9 % of the corresponding 5-hydroxy compound is obtained.

Example 32 ~20 4- ~1-(5-Iodo-2-piperidino-phenyl) ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester A solution of 0.17 g (2.44 m mol) of sodium nitrite in 0.52 ml of water was slowly added at 0 to 5C whilst stirring to 1.0 g (2.44 m mol) of 4- ~1-(5-amino-2-piperi-dino-phenyl)-ethyl)-aminocarbonylmethyl7benZoiC acid ethyl ester in 1.9 ml of semi-conc. hydriodic acid and the solu-tion was warmed to 20C over 1 hour. After heating for 2 hours at 100C, the reaction mixture was cooled and ex-tracted with ethyl acetate. The organic phase was washed ~ 1~6246 with dilute sodium bicarbonate solution and with water, dried over sodium sulfate, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone = 5:1).
5 Yield: 0.011 g (0.93 % of theory), M.p.: 145 - 147C (ether) Calc.: C 55.39 H 5.62 N 5.38 m/e = 520 Found: 55.95 5.53 5.05 m/e = 520 Example ~3 lO 4- ~1-(5-Cyano-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl_ester _ _ A solution of 0.34 g (4.88 m mol) of sodium nitrite in 2.3 ml of water was ~d~, with stirring at -5 to 0C, to 2.0 g (4.88 m mol) of 4- ~1-(5-amino-2-piperidino-phenyl)-15 ethyl)-aminocarbonylmethyl7benzoic acid ethyl ester in 4.0 ml of water and 3.5 ml of conc. hydrochloric acid. The mixture - was stirred for 15 minutes and then neutralized with 1.1 g of calcium carbonate. The suspension thus obtained was added by means of 2xlSml portions of water into a 0C solution, which 20 was prepared from 0.568 g (6-.~4 m mol) of copper (I) cyanide, 1.24 g (19 m mol) of potassium cyanide and 5.8 ml of water, whereby immediately a red-coloured precipitate was obtained.
The reaction mixture was heated whilst stirring for 30 minu-tes at an internal temperature of 45C, then for 30 minutes 25 at 70C and for 60 minutes at 95C. The red-coloured spot was now no lo~ger visible in the thinlayer chromatogram, The reaction mixture was cooled to 20C and extracted with ethyl acetate. The organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo. The 30 evaporation residue was purified by two column chromatogra-phies on sllica gel ((a) toluene/acetone = 10:1, (b) methylene chloride/acetonitril~glacial acetic acid =10:1:0.05). Besides the corresponding 5-Cl- and 5~H-compourds, the desired 5-cyano compound was obtained.
35 Yield: 0.1~6 g (9 % of theory), M.p.: 165 - 167C (ether) ~ 1 76246 Calc.: C 71.58 ~ 6.97 N 10.02 m/e = 419 Found: 71.64 6.94 9.72 m/e = 419 Example 34 4-L~1-(5-Aminosulfonyl-2-piperidino-phenyl)-ethyl)-amino-carbonvlmethvl7benzoic acid ethvl ester a) A solution of 0.37 g (5.36 m mol) of sodium nitrite in 0.7 ml of water was added with stirring at 4 to 6C
to a suspension of 2.0 g (4.88 m mol) of 4- ~1-(5-amino-2-piperidino-phenyl)-aminocarbonylmethy ~ benzoic acid ethyl ester in 2.02 ml of semi-conc. hydrochloric acid.
Subsequently, 0.37 g (3.89 m mol) of ma~nesium chloride were added. The mixture thus obtained was dropped sub-sequently at 30C to a solution, which w`as prepared from 4.9 ml of glacial acetic acid (saturated with sulfur di-oxide) and 0.27 g of copper(II)chloride dihydrate. There-b~ the internal temperature rose to 40C and nitrogen was formed. After stirring for 15 minutes in a bath at 50C, 7.5 ml of water were added and the mixture was ex-tracted with chloroform. The organic extract was dried over sodium sulfate, filtered, and evaporated in vacuo.
The viscous, red-brown evaporation residue (2.7 g; still chloroform-containing) contained besides the correspon-ding 5-chloro-compound the desired 4- ~1-(5-chlorosulfonyl-2-piperidino-phenyl)-ethyl)-aminocarbonylmethy_7benzoic acid ethyl ester.

b) A solution of the evaporation residue obtained according to Example a) in 10 ml of chloroform was added at 2C
whilst stirring to 50 ml of conc. ammonia. After 30 minu-tes saturated sodium chloride solution was added to ob-tain separation of the phases. After extractingwith chloroform, the organic extract was dried and fil-tered and e~aporated in vacuo. The evaporation residue was purified by column chromatography on silica gel l o l 1 1~624~
(chloroform/methanol = 10:1). Besides 55 ~ of the corres-ponding 5-chloro-compound the desired 5-aminosulfonyl compound was obtained as foam.
Yield: 32 % of theory, Calc.: m/e = 473 Fourd: m/e = 473 Example 35 4-~¦1-(5-Dimethylamino-2-piperidino-phenyl)-ethyl)-aminocarbonvlmethyl7be~zoic acid , 10 10 g (1.589 m mol) of sodium-cyanoboro - hydride and after 2 minutes 0.056 ml of glacial acetic acid were added at 20C to a stirred solution of 0.20 g (0.5242 m mol) of 4-/¦1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbo-nylmethyl7benzoic acid and 0.45 ml of 40 % formalin in 2 ml of acetonitri~ and 1 ml of absolute dimethyl ~orm-amide, After 1.5 hours the reaction mixture was evapora-ted in vacuo. The evaporation residue was dissolved in , .
water by addition of hydrochloric acid at pH 2 - 3.
After several ~ extrac-tior~ with chloroform the aqueous phase was adjusted to pH 6 to 7 by means of saturated sodium hydrogen carbonate solution an~lextracted several times with chloroform. This organic extract was dried and filtered. After evaporating in vacuo the evapora-tion residue was recrystallized from isopropanol. The colour-less crystals were washed with absolute ether.
Yield: 0.09 g (42.8 % of theory), M.p.: 185C (decomp. from 175C) Calc.: C 70.39 H 7.63 N 10.26 Found: 70.10 7.63 10.47 Example 36 4- ~1-(5-Acetylamino-2-piperidino-phenyl)-ethyl)-amino-carbonylmethYl7benzoic acid 0.10 g (0.262 m mol) of 4- ~1-(5-amino-2-piperidino-phenyl)-ethyl)-aminocarbonylmet~ly ~ benzoic acid in 1 ml of acetic an-11~624~
hydride were stirred for 6 hours at 20C, then evaporatedin vacuo, distilled off several times with toluene, and . . ~
the evaporation residue was recrystallized from ether.
Yield: 0.08 g (72.7 /0 of theory), M.p.: 241 - 243C
Calc.: C 68.07 H 6.90 N 9.92 Found: 67.53 6.8~ 9.72 Example 37 4- ~1-(5-Benzoylamino-2-piperidino-phenyl)-ethyl)-amino-carbon~lmethyl7benzoic acid _ _ 0.30 ml (2.62 m mol) of benzoyl chloride were added to a solution of 1 g (2.62 m mol) of 4- ~1-(5-amino-2-piperi-dino-phenyl)-ethyl)-aminocarbonylmethy ~benzoic acid and 0.37 ml (~ 62 m mol) of triethylamine in 10 ml of anhy-drous dimethyl formamide. After stirring for 2 hours at 20 - 30C, the reaction mixture was evaporated in vacuo and distributed between water and ethyl acetate. The or-ganic phase was dried and filtered and evaporated ~IL~
The evaporation residue (1.12 g) was recrystallized from ethanol by addition of acti~ated charcoal.
Yield: 0.5 g (39.4 % of theory), M.p.: 225 - 227C
Calc.: C 71.73 H 6.43 N 8.65 Found: 7i.70 6.50 8.66 Analogously to Example 37 the following compound was prepared:

4~ (5-Ethoxycarbonylamino-2-piperidino-phenyl)-ethyl)-aminocarbonylmethvl7benzoic acid Yield: 34.2 % o~ theory, M.p.: 220C (decomp.) Calc.: C 66.21 H 6.89 N 9.26 Found: 65.97 6.83 9.57 lO3 ~ 17624t3 Example 38 4~ (5-Methylsulfonylamino-2-piperidino-phenyl)ethyl)-aminocarbo~Ylmethvl7benzoic acid 0.20 ml (0.262 m mol) of mesyl chloride were added to a solution of 0.10 g (0.262 m mol) f 4-L~1-(5-amino-2-pi-peridino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid in 1 ml of anhydrous pyridine. After the exothermic reac-tion was finished the mixture was allowed to stand for 4 hours at 20C. Subsequently the reaction mixture was evaporated in vacuo and the evaporation residue was di-~;~ stributed at pH 2 - 3 between water and chloroform. The acidic aqueous phase was adjusted to pH 6 to 7 by means of sodium hydrogen carbonate solution and extracted with chloroform. This chloroform extract was dried and filtered.
The residue obtained after evaporating in vacuo was puri-fied by column chromatography on silica gel (chloroform/
methanol = 4:1).
Yield: 0.03 g (25 %. of theory), M.p.: 210 - 220C (decomp.) (ether) Calc.: mol peak m/e = 459 Found: m/e = 459 Example 3g V
4-LT1-(5-Acetoxy-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid 0.35 g (0.915 m mol) of 4-~1-(5-hydroxy-2-piperidinophenyl)-ethyl)-aminocarbonylmethyl7benzoic acid were heated together with 0.103 ml (1.098 m mol) of acetic a~hydride on the steam bath and after standing for 4 days at 20C, the reaction mixture was recrystallized from methanol.
Yield: 0.16 g (41.2 % of theory), M. p.: 218 - 221C
Calc.: C 67.91 H 6.65 N 6.60 Found: 67.70 6.~5 6.55 1~4 1 ~76246 Example 40 4~ (5-Methoxy-2-piperidino-phenyl)-ethyl)-amino-carbon~lmethyl7benzoic acid methyl ester A solution of 60 mg (0,157 m mol) of 4- ~1-(5-hydroxy-2-piperidino-phenyl)-ethylj-aminocarbonylmethyl7benzoic acid in 1 ml of methanol (~ 1 drop of water) was add~
dropwise ~ an ethereal diazomethane solution, un-til no formation of gas took place. To destroy excess diazomethane 2N acetic acid was added. After evaporating in vacuo, the evaporation residue was distributed be-tween toluene/ether and dilute sodium hydroxide solution.
After drying, filtering and evaporating the organic phase in vacuo, the evaporation residue was purified by column chromatography on silica gel (chloroform/methanol = 5:1).
Yield: 27 % of theory, M.p~: Foam Calc.: mol Feak m/e = 410 Found: m/e = 410 Example 41 4- ~1-(5-Benzyloxy-2-piperidino-phenyl)-ethyl)-amino-carbonvlmeth~l7benzoic acid ethYl ester ~ solution of 0.50 g (1.218 m mol) of 4- ~1-(5-hydroxy-2-piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ benzoic acid ethyl es-ter in 10 ml of anhydrous dimethyl formamide was quickly ad~ed to a suspension of 1.353 m mol of sodium hydride (32.5 mg of a 50 % suspension in oil) in 2 ml of anhydrous dimethyl formamide. ~fter stirring for 1.5 hours at 20C, 0.16 ml (1.353 m mol) of benzyl bromide, dissolved in 2.3 ml of anhydrous dimethyl formamide, were added and stirring was continued for 16 hours at 20C.
After evaporating in vacuo the residue was distributed between water and ether. The organic extract was dried~

filtered and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone = 10:1).
Yield: 0.34 g (55~7 % of theory), M.p.: 155 - 157G (ether) Calc.: C 74.37 H 7.25 N 5.60 Found: 74.11 7.41 5.39 Example 42 4- ~1-(5-Aminocarbonyl-2-piperidino-phenyl)-ethyl)-amino-carbonylmethyl7benzoic acid ethyl ester 3.8 g (9.06 m mol) of 4- ~1-(5-cyano-2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid ethyl ester and ~8 g of polyphosphoric acid were stirred for 2.5 hours at 80 - 90C. Under ice-cooling,water was added care-fully and the reaction mixture was extra~ted with ethyl aceta-te and adjustedlalkaline by means of conc. ammonia. The or-ganic phase was washed with water, dried and evaporated in vacuo. The evaporation residue was purified by column chro-matography on silica gel (chloroform/methanol = 20/1).
Yield: 1 g (25.2 % of theory), M.p.: 188 - 189C (ethanol) Calc.: C 68.63 H 7.14 N 9.60 ~J Found: 68.42 6.95 9.46 Example 43 4~ (5-Ethoxycarbonyl-2-piperidino-phenyl)-ethyl)-amino-carbonvlmethvl7benzoic acid ethvl ester U~r refluxr dried hydrog~n chloride was introduced into a solution of 1.1 g (2.62 m mol) of 4- ~1-(5-cyano-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid ethyl ester in 22 ml of absolute etha-nol until after 4 hours no nitri~ could be detected. The ~ 176246 reaction mixture was evaporated in vacuo, mixed with water and ether, and adjusted to alkaline by means of sodium hydrogen carbonate solution. The separated ether phase was extracted with water, dried and filtered, and evaporated in vacuo. The evaporation residue was purfied by column chroma-tography on silica gel (methylene chloride/acetonitrile/glacial acetic acid = lO:l:O.n5).
Yield: 0.6 g (49.2 % of theory), M.p.: 136 - 138C (ether) Calc.: C 69.51 H 7.35 N 6.00 Found: 69.28 7.34 5.83 Example 44 4-[(1-(2-(4-Oxo-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl~benzoic acid A solution of 2.9 g (6.86 m mol) of 4-[(1-(2-[1,4-dioxa-8-aza-spiro[4.5]decane-8-yl]phenyl)-ethyl)-aminocarbonylmethyl]benzoic acid semihydrate in 40 ml of acetone was adjusted to pH = 2 by the addition of 2N hydrochloric acid. After stirring for 6 nours at 50C 5 drops of conc. hydrochloric acid were added and the mixture was allowed to stand for 16 hours at 20C. The reaction mixture was evaporated in vacuo, mixed with water and ethyl acetate and adjusted to pH = 6 by means of 2N ammonia. After extracting several times with ethyl acetate, the combined organic extracts were washed with water, dried, filtered, and evaporated in vacuo. The evaporation residue was re-crystallized from acetone/petroleum ether.
Yield: 1.9 g (73.1 ~ of theory), M.p.: 177 - 180C (decomp.) Calc.: C 69.46 H 6.36 ~ 7.36 Found: 69.75 6.33 7.29 , ~

~ 1 76~46 Example 45 4-[~1-(2-(4-Hydroxy-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl]benzoic acid x 0.66 H o 0.224 g (5.92 m mol) of sodium boro-hydride were added in portions with stirringto a solution of 1 g (2.63 m mol) of 4-[(1-(2-(4-oxo-piperidino)-phenyl)-ethyl)-aminocarbonylmethyl]be~zoic acid in 20 ml of absolute ethanol. After stirring for 1.5 hours at room temperature, the reaction mixture was adjusted to acidic by means of 2N hydrochloric acid, evaporated in vacuo, mixed with ;;ater and ethyl acetate, and adjusted to pH ~ 6 by means of 2N sodium hydroxide solution.
After extracting several times with ethyl acetate, the organic phase was dried, filtered, and the extract was evaporated in vacuo. The evaporation residue was recrystallized from petroleum ether.
Yield: 0.78 g (75 % of theory), M.p.: 175 - 180C (decomp.) Calc.: (x 0.66 H20) C 66.97H 6.81 N 7.10 Found: 66.72 6.62 6.98 Example 46 4-~(1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl~-benzoic acid propyl ester O.g4 g (5.80 m mol) of carbonyl diimidazole were added to a solution of 2 g (5.46 m mol) of 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl]benzoic acid in 20 ml of absolute tetrahydrofuran and the mixture was heated to reflux temperature for 30 minutes excluding moisture. Subsequently, 1.64 ml (2.2 m mol) of l-propanol were added, the reaction mixture was stirred for 18 hours at 20oc and heated for 8 hours to reflux temperature. After evaporating in vacuo, the evaporation residue was purified by column chromatography on silica gel (toluene/acetone = 10:1).
Yield: 1.3 g (58.3 % of theory), M.p.: 150 - 151C (ethyl acetate) ,~

l08 1 1~62~6 Calc.: C 73.51 H '7.90 N 6.86 Found: 73,70 7.78 6.92 Analogously to Example 46 the following compounds were propared:

5 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid isopro~yl ester Yield: 45 % of theory, M.p.: 141 - 143C (ether) Calc.: C 73.51 H 7.90 N 6.86 Found: 73.20 7.79 6.70 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid butvl ester Yield: 49 96 of theory, M.p.: 148C (ether/toluene) Calc.: C 73.90 H 8.11 N 6.63 Found: 74.10 7.99 6.70 4-/¦1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methvl7benzoic acid ethyl ester Yield: 41 % o:E theory, 20 M.p.: 130 - 133C (ether) Calc.: C 67.21 H 6.81 Cl 8.26 N 6.53 Found: 66.90 6.65 8.32 6.67 4-L~1-(5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid bUtYl ester 25 Yield: 30.7 % of theory, M.p.: 115 - 118C
Calc.: C 68.33 H 7.27 Cl 7.75 N 6.12 Found: 68.20 7.23 7.68 5.95 4~ (5-Chloro-2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoic acid tert.butyl es~er Yield: 1 % of theory, Calc.: mol peak m/e = 456/8 5 Found: m/e = 456/8 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid-(2-methoxyethyl ester) Yield: 56 % of theory, M.p.: 155 - 157C (ethyl acetate) lO Calc.: C 70.74 H 7.60 N 6.60 Found: 70.55 7.38 6.47 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid7-(2,2-dimethyl-dioxolane-4-yl?-methyl7ester Yield: 30.5 yO of theory, 15 M.p.: 110 - 112C (ether) Calc.: C 69.98 H 7.55 N 5.83 m/e = 480 Found: 69.80 7.50 5.76 m/e = 480 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid benzyl ester _ _ ~0 Yield: 73.7 % of theory, M.p.: 126 - 128C (ethyl acetate) Calc.: C 76.28 H 7.06 N 6.14 Found: 76.33 7.20 6.03 4-l¦1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy ~ -25 benzoic acid-(2-hydroxy-ethyl)-ester After addition of 10 equivalents of ethylene glycol the reaction mixture was heated to reflux temperature for 17 hours.
Yield: 71.4 % of theory, M.p.: 128 - 129 C (ethyl acetate/ether) llo 1 1 7624~

Calc.: C 70.21 H 7.36 N 6.82 m/e = 410 Found: 70.14 7.42 6.70 m/e = 410 1,2-Bis ~ ~ (2-piperidino-phenyl)-ethyl)-aminocarbonyl-methyl7benzoyloxy7ethane After addition of 0.5 equivalents of ethylene glycol the reaction mixture was heated to reflux temperature for 17 hours.
Yield: 43.5 % of theory, M.p.: 188 -191C (toluene) Calc.: C 72.80 H 7.17 N 7.38 m/e = 758 Found: 72.85 7.07 7.37 m/e = 758 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid-(2-diethvlamino-ethyl)-ester Yield: 56.7 % of theory, M.P.: 99 - 101C (petroleum ether) Calc.: C 72.23 H 8.44 N 9.03 Found: 72.40 8.37 8.95 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid-2-(1,3-dimethvl-xanthine~7-vl)-ethyl ester As solvent absolute pyridine was used. After addition of 1 equivalent of 7-(2-hydroxy-ethyl)-theophylline and after addition of a little piece of metallic sodium the reaction mixture was stirred for 4 hours in the bath of 130C.
Yield: 40.9 ~ of theory, M.p.: 121 - 12~C (ether) Calc.: C 65.01 H 6.34N 14.68 m/e = 572 Found: 64.78 6.38 14.90 m/e = 572 Example 47 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethy,~ -benzoic acid methyl ester_ ~ mixture of 2 g (5.46 m mol) of 4- ~ 1-(2-piperidino-phenyl)-Il] 1~ 24~

ethyl)-aminocarbonylmethy ~ benzoic acid, 0.53 g of methanol, 0.38 ml of conc. sulfuric acid, and 1.65 ~l of 1,2-dichloro-ethane was refluxed for 24 hours, then evaporated in vacuo, dissolved in chloroform, and extracted with diluted sodium hydrogen carbonate solution. The organic phase was washed with water, dried, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/acetone = 5:1).
Yield: 0.93 g (44.8 % of theory), M.p.: 146 - 147C
Calc.: C 72.60 H 7.42 N 7.36 Found: 72.19 7.33 7.01 Exam~le 48 4- ~ 2-(2-Piperidino-phenyl)-2-propyl)-aminocarbonylmethy ~ -benzoic acid ethYl ester 0.20 g (0.526 m mol)~of 4- ~ 2-(2-piperidino-phenyl)-2-propyl)-aminocarbonylmethyl7benzoic acid and 2 ml of 4N ethanolic hydrochloric acid were stirred at 20C. After 36 hours, the reaction mixture was evaporated in vacuo, and the evaporation residue was distributed between wa-~er (at pH - 8 by addition of ammonia (10 %~) and ethyl acetate. The organic phase was washed with water, dried, filtered, and evaporated in vacuo.
The evaporation residue was purified by column chromatography on silica gel (toluene/acetone = 10:1).
Yield: 0.079 g (36.7 % of theory), M.p.: 151 - 153C (ether) Calc.: C 73.50 H 7.90 N 6.86 Found: 73.40 7.95 6.96 I:12 1.~ 76246 Example 49 4~ (2-Piperidino-phenyl)-ethylj-aminocarbonylmethy~ 7-benzoic acid tert.butyl ester A mixture of 3.60 g (17.4 m mol) of N,N'-dicyclohexyl-carbodiimide, 1.9 ml (20.4 m mol) of tert.butanol and 0.036 g (o.36 m mol) of copper(I)chloride was stirred for 3 days at room temperature, then 12 ml of methylene chloride were added, and the solution thus obtained was added to a solution of 2 g (5.46 m mol) of 4-L~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethy~7benzoic acid in 80 ml of methylene chloride. After stirring for 16 hours at 20C, the resultant precipitate was filtered off, washed with methylene chloride, and the methylene chlori-de solution was evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (toluene/
acetone = 15:1).
Yield: 0.45 g (19.7 % of theory), M.p.: 125 - 127C (ether) Calc.: C 73.90 H 8.11 N 6.63 Found: 74.20 8.09 6.77 Exam~le 50 - 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid 2-(nicotinoyloxy)-ethyl ester A solution of 0.16 g (1.13 m mol) of nicotinic acid chlo-ride in 5 ml of me-thylene chloride was quickly ~dded to a solution of 0.45 g (1.10 m mol) of 4-L~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethy_7benzoic acid (2-hydroxy-ethyl)-ester and 0.16 ml (1.16 m mol) of triethylamine in 10 ml of methylene chloride. After stirrin~ for 4 hours at 20C, the reaction mixture was extracted with water, dried, and the methylene chloride solution was filtered and evaporated in vacuo. The evaporation residue was purified by column chromato-graphy on silica gel (chloroform/acetone = 3:1).

ll3 1.~ 7624~

Yield: 0.34 g (60 % of theory), M.p.: 103 - 105C (ether) Calc.: C 69.88 ~ 6.45 N 8.15 Found: 70.13 6.55 8.13 5 Example 51 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmet;hyl7-benzamide 2.3 g (0.0142 mol) of carbonyl diimidazole were given to 4.76 g (0.013 mol) of 4-~1-(2-piperidino-phenyl)-ethyl)-lO aminocarbonylmethyl7benzoic acid in 60 ml of absolute pyridine and the mixture was subsequently heated for 45 minutes to 50C. After cooling in a carbon dioxide/methanol bath 7 ml of liquid ammonia were added and heated for 20 hours to 80C in an autoclave. Subsequently the reaction mixture 15 was cooled and evaporated in vacuo. The residue was dissolved in 50 ml of hot methanol, 200 ml of water were added and the mixture was allowed to rest over-night. The crystalline pre-cipitate was suction filtered and recrystallized from metha-nol by addition of activated charcoal.
20 Yield: 3.5g (73.6 yO of theory), M.p.: 197 - 199C
Calc.: C 72.30H 7.45 N 11.50 Found: 72.307.45 11.32 Example 52 25 4-~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-N-meth lbenzamide Y _ _ 2 g (5.46 m mol) of 4-L~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethy~7benzoic acid and 0.94 g (5.80 m mol) of carbonyl diimidazole in 20 ml of absolute pyridine were 30 heated to reflux temperature for 1 hour. Subsequently, 0.41 g (6.07 m mol) of methylamine hydrochloride were added and the mixture was stirred for 1 hour at 20C and refluxed for 2 hours Af-ter evaporating in vacuo, the residue was distri-11'1 1176246 buted between water and methylene chloride; the organic extractwas dried, filtered, and evaporated in vacuo. mhe evapora-tion residue was purified by column chromatography on silica gel (chloroform/methanol/conc. ammonia = 10:1:0.05).
Yield: 1.7 g (82 ~ of theory), M.p.: 218 - 220C (isopropanol) Calc.: C 72.77 H 7.70 N 11.07 Found: 72088 7.67 10.91 Analogously to Example 52 the following compound was prepared:

4- ~1-(2-Piperidino-phenyl) ethyl)-aminocarbonylmethyl7-N,N dimethvl-benzamide _ _ -Yield: 52.5 % of theory, M.p.: 148 - 150C ~ethyl acetate) Calc.: C 73.26 H 7.94 N 10.68 Found: 73.60 7.85 10.73 Example 53 4- ~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-N but l-benzamide -- Y _ _.

0.94 g (5.80 m mol) of carbonyl diimidazole were added to the solution of 2 g (5.46 m mol) of 4-/r1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid in 20 ml of absolute tetrahydrofuran. The mixture was heated to reflux temperature for 30 minutes, 0.44 g (6.1 m mol) of 1-butylamine were added, and the reaction mixture was again refluxed for 2 hours. After evaporating in vacuo, the evaporation residue was purified by column chromatography on silica gel (chloroform/acetone = 6:1).
Yield: 1.65 g (71.7 % of theory), M.p.: 178 - 181C (ethyl acetate) Calc.: C 74.09 H 8.37 N 9.97 Found: 74.34 8.26 9.95 ' I j 1 17624~

Analogously to Example 53 the following compounds were obtained:

4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid piperidide Yield: 73.8 % of theory, M.p.: 131 - 133C (toluene) Calc.: C 74 .79 H 8.14 N 9.69 m/e ~ 433 Found: 75.13 7.99 9.48 m/e = 433 4~ (2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzoic acid morpholide _ _ _ _ _ lO Yield: 50.5 % of theory, M.p.: 148 - 150C (ethyl acetate/ether) Calc.: C 71.69 H 7.64 N 9.65 Found: 71.60 7.80 9.57 Example 54 ]5 4-L~1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl7-benzonitrile 1.14 g (6 m mol) of p-toluene-sulfonic acid chloride were added in two portions whilst stirring at room temperature 'J to a mixture of 2.19 g (6 m mol) of 4-L~1-(2-piperidino-20 phenyl)-ethyl)-aminocarbonylmethyl7benzamide and 1.07 g (13.5 m mol) of absolute pyridine. The reaction mixture was stirred for 15 minutes at 20C and then for 2 hours at 50C. After cooling, water was added, the mixture was adjustedl~alkaline by means of conc. ammonia, and extracted ~'5 thrice with chloroform. The combined chloroform extracts were washed with water, dried over sodium sulfate, filtered, and evaporated in vacuo. The evaporation residue was purified by column chromatography on silica gel (chloroform/ethyl acetate = 4:1).

I 176~4~
Yield: 1.15 g (55.3 % of theory), M p.: 155 - 157C (ethyl acetate) Calc.: C 76.05 H 7.25 N 12.09 Found: 76.30 7.07 11.90 117 ~ 4~

Example A

Tablets containing 5 mg of 4~ (2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl7benzoic acid Composition:
5 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. 45C. The dry granulate was granulated through a screen of 1.0 mm mesh size and mixed with 5. The finished mixture was pressed to tablets on a tablets press with punches of 7 mm diameter and an unilateral notch.
Weight of tablet: 120 mg Example B

Coated tablets containing 2.5 mg of 4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbonYlmethyl7benzoic acid 1 coated tablet core contains:
Active ingredient (1)2.5 mg Potato starch (2) 44.0 mg Lactose (3) 30.0 mg Polyvinyl pyrrolidone (4)3.0 mg Magnesium stearate (5)0.5 mg 80.0 mg I l ~ 1 17 ~246 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. 45C 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 tab-let cores thus prepared, were covered in conventional manner with a coating, which essentially consists of sugar and tal-cum. The finished coated tablets were polished with wax.
Weight of coated tablets: 120 mg.

Example C
.

Tablets containing 10 mg of 4- ~1 (2-piperidino-phenyl)-ethvl)-aminocarbonylmeth~17benzoic acid COmposition:
1 tablet contains:
Active ingredient 10.0 mg Lactose pulverized 70.0 mg Corn starch 31.0 mg Polyvinyl pyrrolidone 8.0 mg Magnesium stearate 1.0 mg 120.0 mg Method of preparation: 1 17 6 2 ~ g 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 45C. The dried granulate was granulated through a screen of 1 mm mesh size and homo-geneously mixed with magnesium stearate.
Weight of tablets: 120 mg Punch: 7 mm ~ with a notch.

lO Example D
Coated tablets containing 5 mg of 4- ~1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethvl7benzoic acid 1 coated tablet core contains:
Active ingredient 5.0 mg 15 Calcium phosphate secondary70.0 mg Corn starch 50.0 mg Polyvinyl pyrrolidone4.0 mg Magnesium stearate 1.0 mg 130.0 mg 20 Method of preparation:

The mixture, consisting of the active ingredient, the cal-cium phosphate and the corn starch, was moistened with a 15 % solution of poly~inyl pyrrolidone in water. The moist mass was granulated through a screen of 1 mm mesh size, 25 dried at 45C 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.

1~0 Weight of core: 130 mg 117624~
Punch: 7 mm 0 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.

Claims (44)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for preparing a compound of general formula I

(I) [wherein R1 and R2, which may be the same or different, each represents an alkyl group containing 1 to 6 carbon atoms or a cycloalkyl group containing 5 to 7 carbon atoms, or R1 and R2 together with the nitrogen atom to which they are attached represent an unbranched alkyleneamino group containing 3 to 6 car-bon atoms optionally substituted by 1 or 2 alkyl groups, each containing 1 to 3 carbon atoms, or by a hydroxy group and in which a methylene group may op-tionally be replaced by a carbonyl group, by an oxygen or sulfur atom or by an imino group (which may optionally be substituted by an alkyl group containing 1 to 3 carbon atoms, an aralkyl group containing 7 to 10 carbon atoms or by a phenyl or halophenyl group) or an ethylene group may optionally be replaced by an O-phenylene group; and unbranched alkenyleneimino group containing 4 to 6 carbon atoms; a saturated or partly unsaturated azabicycloalkyl group contain-ing 6 to 10 carbon atoms; an aza-1,4-dioxaspiro-alkyl group containing 6 to 8 carbon atoms; or a heptamethyleneimino, octamethyleneimino, nonamethyleneimino or decamethyleneimino group, R3 represents a hydrogen or halogen atom, a tri-fluoromethyl, alkyl, hydroxy, alkoxy, alkanoyloxy, mercapto, alkylmercapto, nitro, amino, cyano, alkanoyl, carboxy, alkoxycarbonyl, aminocarbonyl, alkyl-aminocarbonyl, dialkylaminocarbonyl, aminosulfonyl, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino or alkylsulfonylamino group (wherein each alkyl moiety in the above mentioned groups contains from 1 to 3 carbon atoms), an aralkoxy group containing 7 to 10 carbon atoms or an arylcarbonylamino group;
R4 represents a hydrogen atom or an alkyl group containing 1 to 3 carbon atoms; R5 represents a hydrogen atom, a halogen atom or an alkyl group containing 1 to 3 carbon atoms; A represents a bond, a methylene or ethylene group optionally substituted by a methyl, ethyl or isopropyl group, a methylene or ethylene group substituted by two alkyl groups each containing 1 to 3 carbon atoms, a methylene group substituted by a cycloalkyl group containing 3 to 7 carbon atoms or by a hydroxyalkyl, carboxyl, alkoxycarbonyl, or phenyl group, wherein each of the alkyl moieties contains from 1 to 3 carbon atoms, a cycloalkylidene group containing 3 to 7 carbon atoms or a vinylidene group of formula wherein R6 and R7, which may be the same or different, each represents a hydrogen atom or one of the radicals R6 and R7 represents a methyl group or a cycloalkyl group containing 3 to 7 carbon atoms and the other is a hydrogen atom, or R6 and R7 together with the carbon atom to which they are attached represent a cycloalkylidene radical containing 5 to 7 carbon atoms; B represents a methylene or ethylene group optionally substituted by an alkyl group containing 1 to 3 carbon atoms; and W represents a hydrogen or halogen atom, a nitro group, an amino group (optionally substituted by an alkanoyl group containing 1 to 3 carbon atoms), an alkyl group containing 1 to 3 carbon atoms (optionally substituted by a hydroxy or carboxy group or by one or two alkoxycarbonyl groups containing 2 to 4 carbon atoms each), an alkenyl group containing 2 to 5 carbon atoms substituted by a carboxy or alkoxycarbonyl group containing 2 to 4 carbon atoms, an alkanoyl group containing 1 to 3 carbon atoms, a dialkoxymethyl or trialkoxymethyl group containing 1 to 3 carbon atoms in each alkyl part, an alkylenedioxymethyl group containing 2 or 3 carbon atoms in the alkylene part, a 1,3-oxazoline-2-yl or cyano group, an aminocarbonyl group (optionally substituted by one or two alkyl groups containing 1 to 4 carbon atoms in each alkyl moiety), an unbranched alkyleneiminocarbonyl group containing 5 to 8 carbon atoms, a morpholinocarbonyl group, a (dialkyldioxolan-yl)-alkoxycarbonyl group containing 7 to 10 carbon atoms or a carboxy group or esterified carboxy group, wherein if the said ester group consists of an alkyl group containing 1 to 6 carbon atoms this may be substituted, in any but the .alpha. -position, by a hydroxy, alkoxy, amino, alkylamino, dialkylamino, 1,3-dimethylxanthine-7-yl, alkanoyloxy, aroyloxy, aralkanoyloxy or pyridine-carbonyloxy group or by two hydroxy groups - except in the case of any methyl or methylene group in the above cases, which can only be substituted by one hydroxy group or by a group of formula wherein A, B, R1, R2, R3, R4 and R5 are as hereinbefore defined[wherein each alkyl moiety of the above alkyl ester contains from 1 to 3 carbon atoms], or a physiologically compatible salt thereof, which process comprises (a) reacting an amine of general formula II

(II) wherein A, R1, R2, R3 and R4 are as defined above (or if A represents one of the above mentioned vinylidene groups one of its tautomers, or a lithium or magnesium-halide complex thereof) with a carboxylic acid of general formula III

(III) wherein R5 and B are as defined above and W' represents W as defined above or represents a carboxyl group protected by a protective radical, or with a reactive derivative thereof, optionally prepared in the reaction mixture, and if necessary cleaving off a protective radical;
(b) for the preparation of a compound of general formula I wherein W represents a carboxy group, hydrolytically, thermolytically or hydrogeno-lytically reacting a compound of general formula IV

(IV) wherein R1, R2, R3, R4, R5, A and B are as defined above and D represents a group being transformable into a carboxy group by means of hydrolysis, thermo-lysis or hydrogenolysis;

(c) alkylating a compound (optionally formed in the reaction mixture) of general formula (V) wherein R3, R4, R5, A, B and W are as defined above and R2' represents a hydrogen atom or is as defined above for R2, with a compound of general formula VI
R1' - E (VI) wherein R1' represents R1 as defined above or together with the radical R2' in the above compound of formula V represents a straight-chained alkylene group containing 4 to 6 carbon atoms (optionally substituted by one or two alkyl groups containing 1 to 3 carbon atoms) or an n-pentylene group wherein the third methylene group is replaced by an oxygen or sulfur atom, and E represents a nucleophillically exchangeable group or (if in the radical R1' a methylene group is replaced by an aldehyde or ketone carbonyl group) a hydrogen atom, if necessary in the presence of a reducing agent and optionally subsequently hydrolyzing the product obtained;
(d) for the preparation of a compound of general formula I, wherein W represents a carboxy group, an alkanoyl group, an alkanoyl group containing 1 to 3 carbon atoms or an alkyl group containing 1 to 3 carbon atoms, reacting a compound of general formula VII

(VII) wherein R1, R2, R3, R4, R5, A and B are as defined above with phosgene, an oxalyl halide, an alkyl or alkanoyl halide containing 1 to 3 carbon atoms each in the alkyl moiety or with hydrogen cyanide and a hydrogen halide in the presence of a Lewis acid;
(e) for the preparation of a compound of general formula I wherein W represents a carboxy group, reacting a compound of general formula VIII

(VIII) wherein R1, R2, R3, R4, R5, A and B are as defined above with a hypohalite (optionally formed in the reaction mixture) in the presence of an alkali base;
(f) for the preparation of a compound of general formula I, wherein W represents a carboxy group, oxidizing a compound of general formula IX

(IX) wherein K1, K2, K3, K4, K5, A and B are as defined above and G represents a group which may be converted into a carboxy group by means of oxidation;
(g) for the preparation of a compound of general formula I, wherein R3 represents a nitro group, reacting a compound of general formula X

(X) wherein R4, R5, A, B and W are defined above, R3 represents a nitro group and Y represents a nucleophilically exchangeable radical, with an amine of general formula XI

(XI) wherein R1 and R2 are as defined above, and optionally subsequently hydrolyzing the product obtained;
(h) for the preparation of a compound of general formula I, wherein A represents a group of formula wherein R6 and R7 are as defined above, reducing a compound of general formula XII (XII) wherein R1, R2, R3, R4, R5, R6, R7, B and W are as defined above, with hydrogen in the presence of a hydrogenation catalyst;
(i) for the preparation of a compound of general formula I [wherein R4 represents a hydrogen atom and A represents a methylene or ethylene group (optionally substituted by a methyl, ethyl or isopropyl group), a methylene or ethylene group substituted by two alkyl groups containing 1 to 3 carbon atoms each, a methylene group substituted by a cycloalkyl group contain-ing 3 to 7 carbon atoms, by a carboxyl group, by an alkoxycarbonyl group wherein the alkyl moiety contains from 1 to 3 carbon atoms, or by a phenyl group, or a cycloalkylidene group containing 4 to 7 carbon atoms], reacting a compound of general formula XIII

(XIII) wherein R1, R2 and R3 are as defined above, and A' represents a methylene or ethylene group (optionally substituted by a methyl, ethyl or isopropyl group), a methylene or ethylene group substituted by two alkyl groups containing 1 to 3 carbon atoms each, a methylene group (substituted by a cycloalkyl group containing 3 to 7 carbon atoms, or a carboxyl group, or an alkoxycarbonyl group wherein the alkyl moiety contains from 1 to 3 carbon atoms, or a phenyl group), or a cycloalkylidene group containing 4 to 7 carbon atoms, with a compound of general formula XIV

(XIV) wherein R5, B and W are as defined above, in the presence of a strong acid;
(j) converting a compound of formula I wherein W represents a carboxy group, initially obtained, by means of esterification or amidation into an ester or amide derivative thereof;
(k) reducing a compound of formula I, wherein R3 and/or W represent nitro groups, initially obtained, to a compound of formula I wherein R3 and/or W represent amino groups;
(l) convering a compound of formula I initially obtained, wherein R3 and/or W represent an amino group, via a diazonium salt into a compound of formula I wherein R3 represents a hydrogen or a halogen atom, a hydroxy, alkoxy, mercapto, alkylmercapto, chlorosulfonyl or cyano group and/or W represents a hydrogen or a halogen atom or a cyano group;
(m) alkylating a compound of formula I wherein R3 represents a hydroxy group, to yield a compound of formula I wherein R3 represents an alkoxy group;
(n) converting a compound of formula I wherein R3 represents a chlorosulfonyl group by means of ammonia to a compound of formula I wherein R3 represents an aminosulfonyl group;
(o) acylating a compound of formula I initially obtained wherein R3 represents an amino group to yield a compound of formula I wherein R3 re-presents an alkanoylamino, aroylamino, alkoxycarbonylamino or alkylsulfonylamino group;
(p) converting a compound of formula I initially obtained wherein R3 represents an amino group, by alkylation to a compound of formula I wherein R3 represents an alkyl- or dialkylamino group;
(q) converting a compound of formula I initially obtained wherein R3 represents a chlorine or a bromine atom by dehalogenation to a compound of formula I wherein R3 represents a hydrogen atom;
(r) converting a compound of formula I initially obtained wherein R3 represents a nitrile group by hydrolysis or alcoholysis to a compound of formula I wherein R3 represents an aminocarbonyl, carboxycarbonyl or alkoxy-carbonyl group;
(s) reducing a compound of formula I initially obtained wherein R3 represents a carboxycarbonyl or alkoxycarbonyl group and/or W represents a carboxy or esterified carboxy group, to a compound of formula I wherein R3 and/or W represents a formyl or hydroxymethyl group;

(t) acylating a compound of formula I initially obtained, wherein W represents an alkoxycarbonyl group (wherein the alkoxy group may contain from 2 to 6 carbon atoms) substituted in any but the .alpha.-position by a hydroxy group, to a compound of formula I wherein W represents an acyloxy group;
(u) halogenating a compound of formula I initially obtained, where-in W represents a hydroxymethyl group, and then reacting the product with a malonic acid diester to form a compound of formula I wherein W represents an ethyl group substituted by two alkoxycarbonyl groups;
(v) converting a compound of formula I initially obtained, wherein W represents a formyl group, by means of condensation and optional subsequent hydrolysis and/or decarboxylation to a compound of formula I wherein W represents a vinyl group substituted by a hydroxycarbonyl or alkoxycarbonyl group;
(w) converting a compound of formula I initially obtained, wherein W represents an ethyl group substituted by two alkoxycarbonyl groups, by hydrolysis and decarboxylation to a compound of formula I wherein W represents an ethyl group substituted by one carboxy group;
(x) converting a compound of formula I initially obtained, wherein W represents a carboxy group, via a sulfonic acid hydrazide and subsequent dis-proportionation into a compound of formula I wherein W represents a formyl group;
(y) hydrolysing a compound of formula I initially obtained, wherein R1 and R2 together with the nitrogen atom to which they are attached represent an aza-1,4-dioxaspiro-alkyl group containing 6 to 8 carbon atoms, to a compound of formula I wherein R1 and R2 together with the nitrogen atom to which they are attached represent an unbranched alkyleneimino group containing 4 to 6 carbon atoms wherein a methylene group is replaced by a carbonyl group;
(z) reducing a compound of formula I initially obtained, wherein R1 and R2 together with the nitrogen atom to which they are attached represent an unbranched alkyleneimino group containing 4 to 6 carbon atoms wherein a methylene group is replaced by a carbonyl group, to a corresponding hydroxy-alkyleneimino compound of formula I:
(aa) dehydrating a compound of formula I initially obtained, wherein W represents an aminocarbonyl group, to a compound of formula I wherein W represents a cyano group; or (bb) converting a compound of formula I initially obtained into a physiologically compatible salt thereof with an organic or inorganic acid or base, or converting a salt of a compound of formula I initially obtained into a compound of formula I.
2. A process as claimed in claim 1(a), wherein the reaction is carried out in a solvent at a temperature between -25 and 250°C.
3. A process as claimed in claim 1(a) or 2 wherein the reaction is carried out in the presence of an acid-activating or dehydrating agent.
4. A process as claimed in claim 1(a) or 2 wherein the reaction is carried out in the presence of an amine-activating agent.
5. A process as claimed in claim 1(a) or 2 wherein the reaction is carried out in the presence of an inorganic or tertiary organic base.
6. A process as claimed in claim 1(a) or 2 wherein water formed during the reaction is removed by azeotropic distillation or by addition of a drying agent.
7. A process as claimed in claim 1(b) wherein the reaction is carried out in a solvent at a temperature between room temperature and the boiling temperature of the reaction mixture.
8. A process as claimed in claim 1(b) or 7, wherein the hydrolysis or thermolysis is carried out in the presence of an acid or base.
9. A process as claimed in claim 1(b), wherein, if in the compound of formula IV, D represents a nitrile or aminocarbonyl group, the reaction is carried out in the presence of a nitrite and an acid.
10. A process as claimed in claim 9 wherein the nitrite is sodium nitrite and the acid is sulfuric acid.
11. A process as claimed in claim 1(c), wherein the reaction is car-ried out in a solvent at a temperature between 0 and 150°C.
12. A process as claimed in claim 1(c) or 11, wherein the reaction is carried out in the presence of an inorganic or tertiary organic base.
13. A process as claimed in claim 1(c), wherein the alkylation is carried out with a carbonyl compound in the presence of a hydride at pH 7.
14. A process as claimed in claim 13 wherein the hydride is sodium cyanoborohydride.
15. A process as claimed in claim 1(c) or 11, wherein a methylation reaction is carried out using formaldehyde in the presence of formic acid, or hydrogen in the presence of a hydrogenation catalyst.
16. A process as claimed in claim 1(d), wherein the reaction is car-ried out in a solvent at a temperature between 0 and 120°C.
17. A process as claimed in claim 1(d) or 16, wherein the Lewis acid is aluminium chloride.
18. A process as claimed in claim 1(e) wherein the reaction is carried out in a solvent at a temperature between 0 and 80°C.
19. A process as claimed in claim 1(f) wherein the reaction is carried out in a solvent at a temperature between 0 and 100°C.
20. A process as claimed in claim 1(g), wherein the reaction is carried out in a solvent at a temperature between 20 and 150°C.
21. A process as claimed in claim 1(g) or 20, wherein the reaction is carried out at the boiling temperature of the reaction mixture.
22. A process as claimed in claim 1(g) or 20, wherein the reaction is carried out in the presence of an excess of the amine of formula XI and/or the N-formyl derivative thereof.
23. A process as claimed in claim 1(g), wherein the reaction is carried out in the presence of an inorganic or tertiary organic base and/or a reaction accelerator and/or in a pressure vessel.
24. A process as claimed in claim 23 wherein the reaction accelerator comprises copper or a copper salt.
25. A process as claimed in claim 1(h) wherein the reaction is carried out in a solvent.
26. A process as claimed in claim 1(h) or 25, wherein the reaction is carried out at a hydrogen pressure of 1 to 5 bar.
27. A process as claimed in claim 1(h) or 25, wherein the reaction is carried out at a temperature between 0 and 100°C.
28. A process as claimed in claim 1(i), wherein the strong acid is sulfuric acid.
29. A process as claimed in claim 1(i) or 28, wherein the reaction is carried out in a solvent at a temperature between 20 and 150°C.
30. A process as claimed in claim 1, wherein starting compounds are chosen in which R1 and R2 together with the nitrogen atom to which they are attached, represent a dialkylamino or N-alkylcyclohexylamino group (wherein each alkyl moiety may contain from 1 to 4 carbon atoms), an unbranched alkylene-imino group containing 3 to 6 carbon atoms (optionally substituted by one or two methyl groups), a hydroxypiperidino, piperidone-1-yl, tetrahydro-pyridino, morpholino, thiomorpholino, N-methyl-piperazino, N-benzyl-piperazino, N-chloro-phenyl-piperazino, heptamethyleneimino or octamethyleneimino group, a saturated or partyl unsaturated azabicycloalkyl group containing 7 to 9 carbon atoms, an unbranched alkyleneimino group containing 4 to 6 carbon atoms (wherein an ethylene group is replaced by an o-phenylene group), or a 1,4-dioxa-azaspiro-alkyl group containing 7 to 8 carbon atoms; R3 represents a hydrogen, fluorine, chlorine, bromine, or iodine atom or a methyl, trifluoromethyl, hydroxy, methoxy, benzyloxy acetoxy, mercapto, methylmercapto, nitro, amino, dimethylamino, acetylamino, methylsulfonylamino, benzoylamino, ethoxycarbonylamino, cyano, carboxy, methoxycarbonyl, ethoxycarbonyl, aminocarbonyl, acetyl or aminosulfonyl group, R4 represents a hydrogen atom or a methyl group; R5 represents a hydrogen atom, a chlorine atom or a methyl group; A represents a bond, a methylene group (optionally substituted by a methyl, ethyl or isopropyl group, or by a phenyl, cyclohexyl, carboxy, methoxycarbonyl or hydroxymethyl group), a dimethylmethylene, cyclopropylidene or ethylene group, or a vinylidene group of formula wherein R6 and R7 each represents a hydrogen atom or one of the radicals R6 and R7 represents a methyl group and the other of the radicals R6 and R7 represents a hydrogen atom, or R6 and R7 together with the carbon atom to which they are attached represent a cycloalkylidene radical containing 5 or 6 carbon atoms; B
represents a methylene, ethylidene or ethylene group; and W represents a hydrogen atom, a methyl, ethyl, hydroxymethyl, cyano or carboxyvinylene group, an alkyl group containing 1 to 3 carbon atoms substituted by a carboxy group or by one or two alkoxycarbonyl groups containing 2 to 4 carbon atoms each, a carbonyl group (substituted by a hydrogen atom, a methyl, ethyl, hydroxy, alkoxy, (2,2-dimethyldioxolan-4-yl)-methoxy, benzyloxy, pyridylmethoxy, amino, alkylamino, dialkylamino, piperidino or morpholino group, each alkyl moiety in the above groups containing from 1 to 3 carbon atoms) or a group of formula wherein n is 2, 3 or 4, and R8 represents a hydroxy, methoxy, ethoxy, acetoxy, benzoyloxy, or pyridinecarbonyloxy group, a dialkylamino group containing 1 to 3 carbon atoms in each alkyl moiety, a 1,3-dimethylxanthine-7-yl group, or a group of formula wherein A, B and R1, R2, R3, R4 and R5 are as defined above.
31. A process as claimed in claim 30, wherein starting compounds are chosen in which the radical is present in the 2-position and the radical W is present in the 4'-position.
32. A process according to claim 1 for preparing a compound of general formula Ia (Ia) wherein R1 and R2 together with the nitrogen atom to which they are attached, represent a dimethylamino, pyrrolidino, methylpyrrolidino, piperidino, methyl-piperidino, dimethylpiperidino, tetrahydro-pyridino, 2-octahydro-isoindolo, or hexamethyleneimino group, R3 represents a hydrogen, fluorine or chlorine atom or a methyl group, A represents a methylene group (optionally substituted by a cyclohexyl, phenyl, methoxycarbonyl or ethoxycarbonyl group or a methyl, ethyl or isopropyl group), a dimethylmethylene group or a vinylidene group of formula wherein R6 and R7 each represents a hydrogen atom or together with the carbon atom to which they are attached represent a cyclohexylidene group, and W
represents a methyl, hydroxymethyl or carboxymethyl group, a carbonyl group (substituted by a hydrogen atom or by a methyl, hydroxy, methoxy9 ethoxy, propoxy, isopropoxy, 2-hydroxyethoxy, 2-methoxyethoxy, (2,2-dimethyl-dioxolan-4-yl)-methoxy or 2-diethylaminoethoxy group) or a physiologically compatible salt thereof, wherein appropriately substituted starting compounds are chosen.
33. A process as claimed in claim 32 wherein starting compounds are chosen in which R1 and R2 together with the nitrogen atom to which they are attached, represent a pyrrolidino, piperidino, methylpiperidino, hexamethylene-imino, tetrahydro-pyridino or 2-octahydro-isoindolo group, R3 represents a hydrogen, fluorine or chlorine atom or a methyl group, A represents a methylene group (optionally substituted by a methyl, isopropyl, phenyl or methoxycarbonyl groups or a dimethyl-methylene or vinylidene group and W represents a methyl, hydroxymethyl, carboxymethyl, formyl or carboxy group or an alkoxycarbonyl group optionally substituted by a (2,2-dimethyl-dioxolan-4-yl) group and wherein the alkoxy moiety contains from 1 to 3 carbon atoms.
34. A process as claimed in claim 1, wherein starting compounds are chosen in which R1 and R2, which may be the same or different, each represents an alkyl group containing 1 to 6 carbon atoms or a cycloalkyl group containing 5 to 7 carbon atoms, or R1 and R2 together with the nitrogen atom to which they are attached, represent an alkyleneimino group containing 4 to 10 carbon atoms in the alkylene ring (optionally substituted by one or two alkyl groups each containing 1 to 3 carbon atoms) a morpholino or a thiomorpholino group, R3 represents a hydrogen or a halogen atom, a trifluoro-methyl, alkyl, hydroxy, alkoxy, mercapto, alkylmercapto, cyano, nitro, amino, aminocarbonyl, alkylamino, dialkylamino, or alkylsulfonylamino group, wherein each alkyl moiety in the above mentioned groups contains from 1 to 3 carbon atoms, A represents a methylene or ethylene group optionally substituted by one or two alkyl groups each containing 1 to 2 carbon atoms, R4 and R5 each represent a hydrogen atom, B is as defined in claim 1, and W, which is in the para position, represents a carboxy group or an ester thereof.
35. A process for preparing 4-[(1-(2-piperidino-phenyl)-ethyl)-amino-carbonylmethyl]-benzoic acid or the methyl or ethyl ester thereof or a physiolo-gically compatible salt thereof, which comprises (a) reacting 4-methoxycarbcnyl-phenylacetic acid with 1-(2-piperidino-phenyl)-ethylamine; (b) reacting 4-ethoxycarbonylphenylacetic acid with 1-(2-piperidino-phenyl)-ethylamine di-hydrochloride; (c) reacting 4-ethoxycarbonyl-phenylacetic acid with (2-piperidinophenyl)-methyl-ketimine; (d) if desired, hydrolysing a methyl or ethyl ester obtained in step (a), (b) or (c) to the acid; (e) oxidizing 4-[(1-(2-piperidino-phenyl)-ethyl)-aminocarbonylmethyl] benzaldehyde; (f) hydrogenating 4-[(1-(2-piperidino-phenyl)-ethenyl)-aminocarbonylmethyl]-benzoic acid or the ethyl ester thereof; and (g) if desired, converting an ester or the acid to a physiologically compatible salt thereof.
36. A process for preparing 4-[(2-piperidino-benzhydryl)-aminocarbonyl-methyl]-benzoic acid or the methyl or ethyl ester thereof or a physiologically compatible salt thereof, which comprises (a) reacting 1-(2-piperidino-benz-hydryl)-ethylamine with 4-methoxycarbonyl or 4-ethoxycarbonyl-phenylacetic acid;
and (b) if desired, hydrolysing the methyl or ethyl ester to form the acid and (c) if desired converting the acid or ester to a physiologically compatible salt thereof.
37. A compound of general formula (I) defined in claim 1 or a physiologically compatible salt thereof, whenever prepared by the process claimed in claim 1, or by an obvious chemical equivalent thereof.
38. A compound of formula (I) defined in claim 1 wherein R1, R2, R3, R4, R5, A, B and W are as defined in claim 30, or a physiologically compatible salt thereof, whenever prepared by the process claimed in claim 30, or by an obvious chemical equivalent thereof.
39. A compound of formula (I) defined in claim 1 wherein R1, R2, R3, R4, R5, A, B and W are as defined in claim 30, wherein the radical is present in the 2-position and the radical W is present in the 4'-position, or a physiologically compatible salt thereof, whenever prepared by the process claimed in claim 31, or by an obvious chemical equivalent thereof.
40. A compound of formula (Ia) defined in claim 32 or a physiologically compatible salt thereof, whenever prepared by the process claimed in claim 32, or by an obvious chemical equivalent thereof.
41. A compound of formula (I) as defined in claim 1 wherein B, R4 and R5 are as defined in claim 1 and A, R1, R2, R3 and W are as defined in claim 33 or a physiologically compatible salt thereof, whenever prepared by the process claimed in claim 33, or by an obvious chemical equivalent thereof.
42. A compound of formula (I) as defined in claim 1, wherein A, B, R1, R2, R3, R4, R5 and W are as defined in claim 34, or a physiologically compatible salt thereof, whenever prepared by the process claimed in claim 34, or by an obvious chemical equivalent thereof.
43. 4-[(1-(2-Piperidino-phenyl)-ethyl)-aminocarbonylmethyl]-benzoic acid or the methyl or ethyl ester thereof or a physiologically compatible salt thereof, whenever prepared by the process claimed in claim 35, or by an obvious chemical equivalent thereof.
44. 4-[(2-Piperidino-benzhydryl)-aminocarbonylmethyl]-benzoic acid, or the methyl or ethyl ester thereof or a physiologically compatible salt thereof, whenever prepared by the process claimed in claim 36, or by an obvious chemical equivalent thereof.
CA000393789A 1981-01-10 1982-01-08 Carboxylic acid amides, their preparation and their use as pharmaceutical compositions Expired CA1176246A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3100575.6 1981-01-10
DE19813100575 DE3100575A1 (en) 1981-01-10 1981-01-10 "NEW BENZOESAEURS, THEIR PRODUCTION AND THEIR USE AS MEDICINAL PRODUCTS"

Publications (1)

Publication Number Publication Date
CA1176246A true CA1176246A (en) 1984-10-16

Family

ID=6122419

Family Applications (1)

Application Number Title Priority Date Filing Date
CA000393789A Expired CA1176246A (en) 1981-01-10 1982-01-08 Carboxylic acid amides, their preparation and their use as pharmaceutical compositions

Country Status (22)

Country Link
EP (1) EP0058779B1 (en)
JP (1) JPS57145850A (en)
KR (1) KR880001773B1 (en)
AT (1) ATE9464T1 (en)
AU (1) AU557959B2 (en)
CA (1) CA1176246A (en)
CS (1) CS228910B2 (en)
DD (1) DD204478A5 (en)
DE (2) DE3100575A1 (en)
DK (1) DK536581A (en)
ES (2) ES508587A0 (en)
FI (1) FI820061L (en)
GB (1) GB2090834B (en)
HU (1) HU186024B (en)
IE (1) IE52260B1 (en)
IL (1) IL64733A0 (en)
NO (1) NO820047L (en)
NZ (1) NZ199449A (en)
PL (1) PL135033B1 (en)
PT (1) PT74261A (en)
SU (1) SU1253429A3 (en)
ZA (1) ZA82111B (en)

Families Citing this family (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4735959A (en) * 1981-01-10 1988-04-05 Dr. Karl Thomae Gmbh Carboxylic acid amides and pharmaceutical compositions containing them
EP0099017B1 (en) * 1982-07-06 1988-03-02 Dr. Karl Thomae GmbH Phenyl-acetic-acid derivatives, their preparation and pharmaceutical compostions containing them
US5312924A (en) * 1983-12-30 1994-05-17 Dr. Karl Thomae Gmbh Phenylacetic acid benzylamides
DE3523466A1 (en) * 1985-07-01 1987-01-08 Thomae Gmbh Dr K NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
DE3347565A1 (en) * 1983-12-30 1985-07-11 Thomae Gmbh Dr K NEW PHENYL ACETIC DERIVATIVES, MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS AND METHOD FOR THE PRODUCTION THEREOF
GB8903592D0 (en) * 1989-02-16 1989-04-05 Boots Co Plc Therapeutic agents
GB9119920D0 (en) * 1991-09-18 1991-10-30 Glaxo Group Ltd Chemical compounds
ATE204262T1 (en) * 1991-09-18 2001-09-15 Glaxo Group Ltd BENZANILIDE DERIVATIVES AS 5-HT1D ANTAGONISTS
GB9119932D0 (en) * 1991-09-18 1991-10-30 Glaxo Group Ltd Chemical compounds
WO1995006044A1 (en) * 1993-08-20 1995-03-02 Smithkline Beecham Plc Amide and urea derivatives as 5ht1d receptor antagonists
FR2763590B1 (en) * 1997-05-22 2000-03-24 Synthelabo ACID DERIVATIVES [[[(ARYLMETHYL) AMINO] CARBONYL] ALKYL] - AROMATICS, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION
US7582766B2 (en) 2003-06-09 2009-09-01 Boehringer Ingelheim International Gmbh Inhibitors of papilloma virus
CN1305863C (en) * 2004-12-27 2007-03-21 浙江大学 Method for synthesizing (S)-isopropyl-(2-piperidine) phenyl-methylhistamine
WO2006134341A1 (en) * 2005-06-13 2006-12-21 Merck Sharp & Dohme Limited Therapeutic agents
DE102008046995B4 (en) * 2008-09-12 2010-08-26 Stada Arzneimittel Ag 2-ethoxy-benzoic acid
CN110234643A (en) * 2017-01-27 2019-09-13 基恩菲特公司 ROR gamma modulators and application thereof

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
BE764238A (en) * 1971-03-17 1971-09-13 Lilly Industries Ltd PHENYLALKYLAMINE DERIVATIVES
AT332375B (en) * 1973-04-13 1976-09-27 Thomae Gmbh Dr K PROCESS FOR THE PRODUCTION OF NEW AMINOBENZYLAMINES AND THEIR ACID ADDITION SALTS
US4145435A (en) * 1976-11-12 1979-03-20 The Upjohn Company 2-aminocycloaliphatic amide compounds

Also Published As

Publication number Publication date
DE3166213D1 (en) 1984-10-25
ZA82111B (en) 1983-09-28
PL234661A1 (en) 1982-09-13
IE820039L (en) 1982-07-10
GB2090834A (en) 1982-07-21
ES8305749A1 (en) 1983-04-16
EP0058779A3 (en) 1982-11-17
KR880001773B1 (en) 1988-09-13
HU186024B (en) 1985-05-28
AU557959B2 (en) 1987-01-15
FI820061L (en) 1982-07-11
ES513781A0 (en) 1983-04-16
ATE9464T1 (en) 1984-10-15
KR830009071A (en) 1983-12-17
ES8304070A1 (en) 1983-02-16
EP0058779B1 (en) 1984-09-19
IL64733A0 (en) 1982-03-31
DD204478A5 (en) 1983-11-30
DK536581A (en) 1982-07-11
PL135033B1 (en) 1985-09-30
SU1253429A3 (en) 1986-08-23
IE52260B1 (en) 1987-08-19
NO820047L (en) 1982-07-12
AU7928982A (en) 1982-07-22
EP0058779A2 (en) 1982-09-01
NZ199449A (en) 1985-09-13
DE3100575A1 (en) 1982-09-02
PT74261A (en) 1982-02-01
ES508587A0 (en) 1983-02-16
JPS57145850A (en) 1982-09-09
CS228910B2 (en) 1984-05-14
GB2090834B (en) 1984-11-28

Similar Documents

Publication Publication Date Title
CA1176246A (en) Carboxylic acid amides, their preparation and their use as pharmaceutical compositions
DE69103206T2 (en) New derivatives of aminopiperidine, aminopyrrolidine and aminoperhydroazepine, process for their preparation and medicaments containing them.
Iwanami et al. Synthesis and neuroleptic activity of benzamides. Cis-N-(1-benzyl-2-methylpyrrolidin-3-yl)-5-chloro-2-methoxy-4-(methylamino) benzamide and related compounds
IE57700B1 (en) Chemical compounds
US4490369A (en) Benzazepine derivatives, their pharmaceutical compositions and method of use
DD292911A5 (en) PROCESS FOR THE PREPARATION OF PYRROLIDINE DERIVATIVES
US4069223A (en) 4-Aminomethyl-1-(3,3,3-triarylpropyl)-4-arylpiperidine and derivatives thereof
DE69413535T2 (en) 1-PHENYLAL CANNON AS 5-HT4 RECEPTOR LIGANDE
DE69300192T2 (en) Piperazinyl and piperidinylcyclohexenes and cyclohexanes.
US4735959A (en) Carboxylic acid amides and pharmaceutical compositions containing them
DE2711655C2 (en)
DD149071A5 (en) PREPARATION OF 2-SUBSTITUTED TRANS-5-ARYL-2,3,4,4A, 5,9B-HEXAHYDRO-1H-PYRIDO SQUARE BRACKET ON 4,3-B SQUARE BRACKET TO INDOLE
CH637934A5 (en) METHOD FOR PRODUCING NEW DERIVATIVES OF PERHYDRO-AZA-HETEROCYCLEN.
CA1247101A (en) 5-alkyl-1-phenyl-2-piperazinoalkylpyrazolin-3-one compounds, intermediates and methods for their preparation, and pharmaceutical compositions containing them
CA1211445A (en) Isoquinoline derivatives, a process for their preparation, pharmaceutical formulations based on these compounds and the use thereof
CA1138461A (en) Phenyl piperazine derivatives having antiagressive activity
US2555353A (en) 3-tertiaryaminoalkyl-2-pyrrolidones and process for preparing same and related products
CA1108633A (en) 1-aryloxy-2-hydroxy-3-aminopropanes and process for preparing same
CA1214773A (en) Phenylacetic acid derivatives, the preparation thereof and pharmaceutical compositions containing these compounds
CA1105037A (en) N-(4-pyrazolidinyl) benzamides
EP0025501B1 (en) N-aminoalkyl indole derivatives and their salts, processes for their preparation and medicaments containing these compounds
EP0157399A2 (en) 4-(5H-Dibenzo[a,d]cyclohepten-5-yl) piperidine compounds
EP0037990A1 (en) Phenyl quinolizidines, corresponding pharmaceutical preparations, the preparation of the active compounds and corresponding starting compounds
Klioze et al. Synthesis and antihypertensive activity of 2-benzamido-1, 2, 3, 4, 6, 7, 12, 12b-octahydroindolo [2, 3-a] quinolizines
WO1983002610A1 (en) Derivatives of 3,3-dialkyl-indolin and of 3,3-alkylene-indolin, method for producing them and pharmaceutical preparations containing them

Legal Events

Date Code Title Description
MKEC Expiry (correction)
MKEX Expiry