CA2129374A1 - Carbonamides, pharmaceutical compositions containing these compounds and processes for their preparation - Google Patents

Carbonamides, pharmaceutical compositions containing these compounds and processes for their preparation

Info

Publication number
CA2129374A1
CA2129374A1 CA002129374A CA2129374A CA2129374A1 CA 2129374 A1 CA2129374 A1 CA 2129374A1 CA 002129374 A CA002129374 A CA 002129374A CA 2129374 A CA2129374 A CA 2129374A CA 2129374 A1 CA2129374 A1 CA 2129374A1
Authority
CA
Canada
Prior art keywords
group
carbon atoms
general formula
piperidinyl
alkyl
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.)
Abandoned
Application number
CA002129374A
Other languages
French (fr)
Inventor
Frank Himmelsbach
Gunter Linz
Helmut Pieper
Volkhard Austel
Thomas Muller
Johannes Weisenberger
Brian Guth
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
Publication of CA2129374A1 publication Critical patent/CA2129374A1/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/52—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups or amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/20—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/10—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C07C229/16—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of hydrocarbon radicals substituted by amino or carboxyl groups, e.g. ethylenediamine-tetra-acetic acid, iminodiacetic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/46—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C229/48—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino or carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups and carboxyl groups bound to carbon atoms of the same non-condensed ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/52—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/81—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/54—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/24—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/38—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a ring other than a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/40—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
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    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/48—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring being part of a condensed ring system of the same carbon skeleton
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/41—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by carboxyl groups, other than cyano groups
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    • C07C255/00—Carboxylic acid nitriles
    • C07C255/45—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C255/47—Carboxylic acid nitriles having cyano groups bound to carbon atoms of rings other than six-membered aromatic rings to carbon atoms of rings being part of condensed ring systems
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    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/57—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and carboxyl groups, other than cyano groups, bound to the carbon skeleton
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/16—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by singly-bound oxygen atoms
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    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/24—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atom of at least one of the carbamate groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
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    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/30—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom
    • C07D211/32—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by doubly bound oxygen or sulfur atoms or by two oxygen or sulfur atoms singly bound to the same carbon atom by oxygen atoms
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/34—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D211/62—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals attached in position 4
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    • 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
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    • 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
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Abstract

Abstract The invention relates to carbonamides of general formula A - B - C - D - E - F - G (I) wherein A to G are defined as in claim 1, the tautomers thereof, the stereoisomers thereof including the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts with inorganic or organic acid or bases, which have valuable pharmacological properties, preferably inhibitory effects on aggregation, and to pharmaceutical compositions containing the compounds, the use thereof and processes for their preparation.

Description

2~2~37~

S01~6g2.578 DR. KARL THOMAE GMBH Case 5/1138-FL
D-88397 Biberach/Ri~ Foreign filing text Carbonamides, pharmaceutical compositions containing these compounds and processes for their preparation The invention relates to carbonamides of general formula A - B - C - D - E - F - G (I) the tautomers thereof, the stereoisomers including mixtures thereof and the salts thereof, in particular the physiologically acceptable salts with inorganic or organic acids or bases which have valuable pharmacological properties, preferably aggregation-inhibiting properties, pharmaceutical compositions containing these compounds, the use thereof and processes for their preparation.

In general formula I above:

A represents an azacycloalkyl or azacycloalkenyl group each having 5 to 7 ring members or an azabicycloalkyl group having 6 to 9 ring members, in which the nitrogen atom, provided it is not in a bridging position, carries in each case the group Rl wherein Rl represents a hydrogen atom, an alkyl group optionally substituted by an aryl group, an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, in which a methoxy or ethoxy moiety may additionally be substituted by a phenyl group, or Rl represents a R2-co-o-(HcR3)-o-co- group, in . ~ ~-: - : : : . - .

~:

- 2 - ~12~37~
which R2 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group, or a cycloalkyl or cycloalkoxy group each having 3 to 7 carbon atoms and ~
R3 represents a hydrogen atom or an alkyl group, or A represents an alkyl or cycloalkyl group substituted by a Rl-NH group in which the alkyl ~oiety may contain 1 to 4 carbon atoms, the cycloalkyl moiety may contain 3 to 7 carbon atoms and Rl is as hereinbefore defined, or A represents a diazacycloalkyl group having 5 to 7 ring members in which one of the nitrogen atoms carries a group Rl wherein Rl is as hereinbefore defined, or A represents a 4-pyridyl group;

B represents an alkylene group having 1 to 4 carbon atoms, an alkenylene group having 2 to 4 carbon atoms, an oxygen or sulphur atom, a carbonyl or -NR4- group in which , R4 represents a hydrogen atom, an alkyl, alkylcarbonyl, alkyloxycarbonyl or alkylsulphonyl group optionally substituted in the alkyl moiety by an aryl group, or R4 represents an arylcarbonyl or arylsulphonyl group, or B represents a -W-alkylene- or -alkylene-W- group with the proviso that, if A denotes an HNRl-alkyl group, B cannot represent an -alkylene-W- group, wherein W

2~2937~
represents an oxygen or sulphur atom, a carbonyl, sulphinyl, sulphonyl or -NR4- group and R~ i8 as hereinbefore defined, or B represents an alkylene-CO-NRs- group which is bound to the group C via the nitrogen atom and in which Rs is a hydrogen atom or an alkyl group optionally substituted by an aryl group, or B represents a -CONRs- or -NRsCO- group wherein Rs is as hereinbefore defined, or, if A represents an alkyl or cycloalkyl group substituted by an RlNH-alkyl group, B may also denote a bond, and generally A and B together may not represent a RlNH-alkyl-CO or R1NH-alkyl-CO-NRs group, C represents a 1,3- or 1,4-phenylene group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms, by alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, hydroxy, nitro or (RsNR6)- groups, wherein the substituents may be identical or different with the proviso that at the same time A may not represent a pyridyl group and B a -CO-, -CH2-, -CH=CH- or -CONH- group and Rs is as hereinbefore defined and R6 represents a hydrogen atom, an alkyl group optionally substituted by an aryl group, an alkylsulphonyl group having 1 to 5 carbon atoms in the alkyl moiety, an alkylcarbonyl, arylalkylcarbonyl, arylcarbonyl, aralkylsulphonyl or arylsulphonyl group, ;` ` :

_ 4 _ 2~29~7;~
or C represents a cycloalkylene group having 5 to 7 carbon ato~s in which one or two ~CH- units may each be replaced by a nitrogen atom, whilst A and C may not simultaneously represent piperidine rings if B is a - (CH2) 3- group, or or C represents a cycloalkylene group having 5 to 7 carbon atoms in which two adjacent methylene groups are replaced by an o-phenylene sroup, whilst the saturated part is bound to group B or, if B represents a bond, to group A, and the unsaturated part is bound to group D;

D represents an alkylene, alkylene-carbonyl, carbonyl-alkylene, alkylene-CO-NR5, -CO-NRs-alkylene or -NRs-CO-alkylene group wherein Rs i9 as hereinbefore defined, or D represents a carbonyl group, or D represents an -~RsCONRs- or -NRsCO- group or, if B
and C together do not represent a -CH2CH2-CONH-l,3-phenylene group, D may also represent a -CONRs- group wherein Rs is as hereinbefore defined;

E represents an alkylene group having 1 to 5 carbon atoms whilst A, B, C, D and E together cannot simultaneously represent a 2-[[4-(Rl-piperidin-4-yl-aminocarbonyl)-phenyl]-aminocarbonyl]-ethyl or 2-[4-[2-(R~-piperazin-4-yl)-ethyl]-phenyl]-ethyl group, or E represents an alkenylene group having 3 to 5 carbon atoms or a vinylene group, i~ A is not an aminocyclohexyl group, .
or E represents a 1,3- or 1,4-phenylene group optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by an alkyl or alkoxy group, wherein the substituents may be identical or different, with the - 2~,~9'~,7~ `

proviso that E cannot be an optionally substituted phenylene group, if C and D together represent a phenylenemethyl-, phenylenecarbonyl, cyclohexylenemethyl or cyclohexylenecarbonyl group and A simultaneously represents a RlNH-alkyl group, or A, B, C and D together represent an aminomethyl-cyclohexylcarbonylamino group, an aminomethyl-phenylaminocarbonyl or aminomethyl-phenylcarbonylethyl group, or E represents a cycloalkylene group having 5 to 7 carbon atoms optionally substituted by an alkylsulphonyl group with 1 to 5 carbon atoms in the alkyl moiety, by an alkyl, hydroxy, alkoxy, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, aralkylsulphonyl, arylsulphonyl or (R5NR6)- group, wherein one or two ~CH-units may be substituted by a nitrogen atom or one or two ~CH2 groups may be substituted by a >NH- group, wherein Rs and R6 are as hereinbefore defined, or, if F does not represent a bond, E may also denote an alkylene-NR7 group wherein the bond to the group F is via the nitrogen atom and wherein .

R7 represents a hydrogen atom, an alkyl, arylalkyl, alkylcarbonyl, arylalkylcarbonyl, arylcarhonyl, arylalkylsulphonyl or arylsulphonyl group, an alkylsulphonyl group having 1 to 5 carbon atoms, an R50-alkylene-C0 group or an alkyl group substituted by an R8-C0- group wherein Rs is as hereinbefore defined and --` 212~3~

R8 represents an hydroxy, amino, alkylamino, dialkylamino, alkoxy or arylalkoxy group;
F represents a bond, an alkylene group having 1 to 4 carbon atoms wherein, if at the same time A is an RlNH-alkyl group, D, E and F
together cannot represent an alkylene group having more than 3 carbon atoms, or F represents a -W'-alkylene group wherein W~
represents an oxygen or sulphur atom, a sulphinyl, sulphonyi or an -NR~- group and the bond to group E is effected via group w~ and R4 is as hereinbefore defined;
and G represents a carbonyl group which is substituted by a hydroxy group, by an alkoxy group having 1 to 6 carbon atoms, by a cycloalkyloxy or cycloalkylalkoxy group each having 3 to 7 carbon atoms in the cycloalkyl moiety, by an aryloxy group, by a phenoxy group substituted in the 2,3- or 3,4-position by an alkylene bridge having 3 to 5 carbon atoms, or by an R2-CO-o-(HCR3)-o- group, wherein R2 and R3 are as hereinbefore defined, or G represents a phosphono, O-alkyl-phosphono, o,o~-dialkyl-phosphono, sulpho or tetrazol-5-yl group, ::
wherein at least ll bonds must be positioned between group G and the NRl group of group A or, if group A is a pyridyl group, the pyridyl nitrogen; and "an aryl group" as hereinbefore defined may represen~ a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms, or by alkyl or alkoxy groups, wherein the substituents may be identical or different, 0.~ . . . . -2~2~7l~

and unless specified otherwise the above alkyl, alkylene or alkoxy moieties each contain 1 to 3 carbon atoms.

Preferred compounds oE the above general formula I are those wherein:

A represents an aminoalkyl group having 1 to 4 carbon atoms in the alkyl moiety, an aminocycloalkyl group having 4 to 6 carbon atoms in the cycloalkyl moiety, a piperidyl, tetrahydropyridyl or piperazinyl group wherein in each of the above-mentioned groups a nitrogen atom carries a group R1 and Rl represents a hydrogen atom, an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, a benzyl, benzyloxycarbonyl or CH3-CO-O-CH2-O-CO-group, or A represents a quinuclidinyl or 4-pyridyl group;

B represents an alkylene group having 1 to 4 carbon atoms, a vinylene group, an oxygen atom, a carbonyl group or a -CH2-CONH- group wherein the nitrogen atom is bound to group C, a -W-C~2- or -CH2-W- group with the proviso that if A
represents a HNRl-alkyl group, B cannot represent a -CH2-W- group, wherein W is an oxygen or sulphur atom, a sulphinyl, sulphonyl or -NR4- group or, if the bond to group C is via group W, also a carbonyl group wherein R4 represents a hydrogen atom or a benzyloxycarbonyl group, ~:,..",~

- 212~7~

or B represents a -CO-NH- or -NH-CO- group, or, if A represents an aminoalkyl or aminocycloalkyl group substituted at the nitrogen by group Rl, B may also represent a bond, and in general A and B together may not represent an Rl-NH-alkyl-CO- or Rl-NH-alkyl-CONH- group;

C represents a 1,3- or 1,4-phenylene group which may be substituted by a fluorine, chlorine or bromine atom, by an alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl or alkylsulphonyl group each having 1 or 2 carbon atoms, with the proviso that at the same time A may not represent a pyridyl group and B a -CO-, -CH2-, -CH=CH- or -CONH- group, or C represents a cyclohexylene, piperidinylene or piperazinylene group whilst A and C cannot simultaneously represent piperidine rings if B is a - (CH2~ 3- group, :~

or C represents a 1,2,3,4-tetrahydro-naphthylene group in which the saturated part is bound to group A and the unsaturated part is bound to group D;

D represents a -CO-, -CO-NR5-, -NR5-Co- or -NR5-Co-NR5 group, wherein R5 represents a hydrogen atom or a methyl or ethyl group, or D represents a -CH2-CO- or -CH2-CO-NH- group wherein the ~ethylene group is bound in each case to group C, or a -CO-NH-CH2- group wherein the carbonyl group is bound to group C;

~i :~ - . . . .

212~37~
g E represents an alkylene group having 2 to 5 carbon atoms, whilst A, B, C, D and E together may not represent a 2-[[4-(Rl-piperidin-4-yl-aminocarbonyl)-phenyl]-aminocarbonyl]-ethyl group, or E represents a cyclohexylene group optionally substituted by an alkylsulphonylamino group having 1 to 5 carbon atoms in the alkyl moiety, or by an amino, ~ormylamino, acetylamino or propionylamino group, or E represents a piperidinylene group optionally substituted at the nitrogen atom by an alkylsulphonyl group having 1 to 5 carbon atoms, or E represents a piperazinylene group, or if A
represents an Rl-NH-alkyl group and C and D do not together represent a phenylenecarbonyl or cyclohexylenecarbonyl group or if A, B, C, D together do not represent an aminomethyl-cyclohexylcarbonylamino or aminomethyl-phenylaminocarbonyl group, E may also represent a 1,3- or 1,4-phenylene group, or if F does not represent a bond, E may also represent ::
an alkylene-NR7 group wherein the bond to group F is effected via the nitrogen atom and wherein the alkylene moiety may contain 1 to 3 carbon atoms and R7 represents a hydrogen atom, an alkylsulphonyl group having 1 to 5 carbon atoms, an alkoxycarbonylmethyl group ha~ing 1 or 2 carbon atoms in the alkoxy moiety, a benzyl, carboxymethyl, aminocarbonylmethyl, hydroxymethylcarbonyl or benzyloxymethylcarbonyl group;
F represents a bond, ~ ., ~ . , . . - , - lo 2~2937~
an alkylene group having 1 to 3 carbon atoms, an -O-alkylene group having 1 to 2 carbon atoms wherein the bond to group E is effected via the oxygen atom; and G represents a carbonyl group which is substituted by a hydroxy group, by an alkoxy group having 1 to 5 carbon atoms, by a cyclohexyloxy, indanyloxy or R2-Co-o-(HCR3)-o- group, wherein R2 represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a cyclohexyloxy group and R3 represents a hydrogen atom or a methyl group;

wherein at least ll bonds must be positioned between group G and the NRl group of group A or, if A represents a pyridyl group, the pyridyl nitrogen, in particular those compounds of general formula I
wherein:

A represents an aminomethyl, aminoethyl, piperidyl, tetrahydropyridyl, piperazinyl, aminocyclopentyl or aminocyclohexyl group wherein in each of the above groups a nitrogen atom carries a group Rl and Rl represents a hydrogen atom, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a benzyl group, or A represents a quinuclidinyl or 4-pyridyl group;
B represents an ethylene or vinylene group, an oxygen atom, a carbonyl, -NH-CO- or -CO-NH- group, 212937 ~

a -CH2-CONH- group wherein the nitrogen atom is bound to group C, an -O-CH2- group wherein the methylene group is bound to group C, a -CH2-W- group with the proviso that, if A represents an Rl-NH-methyl or Rl-NH-ethyl group, B does not represent a -CH2W- group wherein W is bound to group C and represents an oxygen atom, a -CO- or -NR4- group wh~rein R4 denotes a hydrogen atom or a benzyloxycarbonyl group, or, if A represents an Rl-NH-methyl, Rl-NH-ethyl, Rl-NH-cyclopentyl or Rl-NH-cyclohexyl group, B may also represent a bond and in general A and B together cannot represent an Rl-NH-alkyl-CO- or Rl-NH- alkyl-CONH- group;

C represents a cyclohexylene or piperidinylene group or a 1l2/3/4-tetrahydro-naphthylene group wherein the --saturated part is bound to group A and the unsaturated part to group D, or with the proviso that, at the same -time, A may not represent a pyridyl group and B a -CO-, -CH=CH- or -CONH- group, C may also represent a 1,3- or 1,4-phenylene group;
D represents a -CO- group, an -NH-CO-, -CO-NH- or -HNCONH- group, a -CH2CO- or -CH2-CO-NH- group wherein the methylene group is bound in each case to group C, or a -CONH-CH2-group wherein the CO group is bound to group C, ~12~37 ~

E represents an alkylene group having 2 to 4 carbon atoms, a cyclohexylene group optionally substituted by an alkylsulphonylamino group having 1 to 4 carbon atoms in the alkyl moiety, or by an amino or acetylamino group, a piperidinylene group optionally substituted at the nitrogen atom by an alkylsulphonyl group having l to 4 carbon atoms, or if C and D together do not represent a phenylenecarbonyl or cyclohexylene-carbonyl group when A
is simultaneously an Rl-NH-methyl- or Rl-NH-ethyl- group, or if A, B, C and D together do not represent an aminomethyl-cyclohexyl-carbonylamino group, E may also represent a 1,3--or 1,4-phenylene group, or if F does not represent a bond, E may also represent a -CH2CH2-NR7- group wherein the bond to group F is via the nitrogen atom and R7 represents a hydrogen atom, an alkylsulphonyl group having 1 to 4 carbon atoms, an alkoxycarbonylmethyl group having 1 or 2 carbon atoms in the alkoxy moiety, a benzyl, carboxymethyl, aminocarbonylmethyl, hydroxymethylcarbonyl or benzyloxymethylcarbonyl group;
F represents a bond, an alkylene group having 1 or 2 carbon atoms, an -O-CH2 group wherein the oxygen atom is bound to group E, and 2~2937~

G represents a carbonyl group which is substituted by a hydroxy group or by an alkoxy group having 1 to 3 carbon atoms, wherein at least 11 bonds must be positioned between group G and the NRlgroup of group A or, if group A
represents a pyridyl group, the pyridyl nitrogen;

the tautomers, the stereoisomers thereof including the mixtures thereof, and salts thereof.

Particularly preferred compounds of the above general formula I are those in which:

A represents a 4-pyridyl group, a quinuclidinyl group or an aminomethyl, aminoethyl or piperidyl group optionally substituted on the nitrogen atom by a benzyl group, wherein the piperidyl group is not bound to groups B or C via the ring ni~rogen atom;

B represents an oxygen atom, a -CH2CH2-, -O-CH2-, -CO-NH-or -NH-CO- group or a -CH20- group with the proviso that if A represents an aminomethyl or aminoethyl group, B
cannot represent a -CH2-O- group, or, if A represents an aminomethyl or aminoethyl group optionally substituted on the nitrogen atom by a benzyl group, B may also denote a bond, and in general A and B together cannot represent an H2N-alkyl-CONH group optionally benzylated on the amine nitrogen;

C represents a cyclohexylene or piperidinylene group or a 1,2,3,4-tetrahydro-naphthylene group wherein the saturated part is bound to group A and the unsaturated part is bound to group D, 'h. ~ - . - : . ; - : -21~937 ~.c or C represents a 1,3- or 1,4-phenylene group with the proviso that at the same time A may not represent a pyridyl group and B a -CH=CH- or -CONH- group;

D represents a -CO- group or a -CO-NH- group wherein the carbonyl group is bound to group C, or D represents an -NHCONH- group;

E represents a cyclohexylene group optionally substituted by an alkylsulphonylamino group having 1 to 4 carbon atoms in the alkyl moiety or by an amino group, or E represents a piperidinylene group or, if C and D
together do not represent a phenylenecarbonyl or cyclohexylenecarbonyl group when at the same time A is an aminomethyl or aminoethyl group optionally substituted on the nitrogen atom by a benzyl group, or if A, ~, C and D together do not represent an aminomethyl-cyclohexylcarbonylamino group, F. may also represent a 1,3- or 1,4-phenylene group, or if F does not represent a bond, E may also represent a -CH2CH2-NH- group substituted on the nitrogen atom by an alkylsulphonyl group having 1 to 4 carbon atoms in the alkyl moiety, wherein the bond to group F is via the nitrogen atom;
F represents a bond, an alkylene group having 1 or 2 carbon atoms, an -O-CH2- group in which the oxygen atom is bound to group E; and G represents a carbonyl group which is substituted by a hydroxy group or by an alkoxy group having 1 to 3 carbon atoms, X129~7~

wherein at least 11 bonds must be positioned between the nitrogen atom of the relevant group A and group G, the tautomers thereof, the stereoisomers thereof including the mixtures thereof and salts thereof.

More particularly those compounds of the above general formula I wherein:
-A represents a 2-aminoethyl, piperidin-4-yl or quinuclidin-4-yl group;

B represents an oxygen atom, a -CH2CH2- or -O-CH2- group or a -CH20- group with the proviso that, if A represents a 2-amino-ethyl group, B cannot represent a -CH2-O-group, or, if A is a 2-aminoethyl group, B may also denote a bond;

C represents a 1,3- or 1,4-phenylene group or a 1,4-piperidinylene group;

D represents a -CO- group or a -CO-NH- group in which the carbonyl group is linked to group C;

E represents a cyclohexylene group optionally substituted ~y an amino group, or a 1,4-piperidinylene group, or, if C and D together do not represent a phenylenecarbonyl group when A simultaneou~ly represents an-aminoethyl group, E may also represent a 1,4-phenylene group;

F represents a bond, a -CH2-, -CH2CH2- or -O-CH2- wherein the oxygen atom is bound to group E; and - 2~3~

G represents a carbonyl group which is substituted by a hydroxy group or by an alkoxy group having 1 to 3 carbon atoms, wherein at least 11 bonds must be positioned between the nitrogen atom of the relevant group A and group G, ` the tautomers thereof, the stereoisomers including the mixtures thereof and salts thereof.

The following compounds are especially particularly preferred:

(a) 4-carboxymethyl-1-[4-[2-(4-quinuclidinyl)-ethyl]-benzoyl]-piperidine, (b) 1-carboxy-cis-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexylamine, (c) trans-4-[4-[(4-quinuclidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid, (d) trans-4-[[4-[4(-piperidinyl)-oxymethyl]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid, (e) trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid, (f) trans-4-[4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid, (g) trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid methylester and :

(h) 3-[trans-4-[4-[(2-amino-ethyloxy)-benzoylamino]- ~.
cyclohexyl]-propionic acid, ~ ;

- 17 - 2~2~37~
the tautomers thereof and salts thereof.

The new compounds may be prepared using for example the following methods:

a) in order to prepare compounds of general formula I, wherein A is as hereinbefore defined and G is a carboxyl group or G is as hereinbefore defined and A has the meanings for A specified above with the proviso that A
contains an H-N~ or Rl-NH- group wherein Rl represents a hydrogen atom or an alkyl group optionally substituted by an aryl group:
reaction of a compound of general formula Aa _ B - C - D - E - F - Ga (II) .
(wherein B to F are as hereinbefore defined, Aa has the meaning of A and Ga has the meaning of G as hereinbefore defined, with the proviso that Aa contains a group which may be converted into an imino or Rl'-NX-group by means of hydrolysis, treatment with an acid, thermolysis or hydrogenolysis, or Ga represents a group which may be converted into a carboxyl group by means of hydrolysis, treatment with an acid, thermolysis or hydrogenolysis, or Aa contains a group which may be converted into an imino or Rl'-NH- group by means of hydrolysis, treatment with an acid, thermolysis or hydrogenolysis and Ga represents a group which may be converted into a carboxyl group by means of hydrolysis, treatment with an acid, thermolysis or hydrogenolysis, :
wherein Rl' represents a hydrogen atom or an alkyl group optionally substituted by an aryl group), ., ::`:- ' ' ' ~ ,~ : .

- 18 - ~12937~
using hydrolysis, treatment with an acid, thermolysis or hydrogenolysis to form a compound of general formula I
wherein A is as hereinbefore defined and G represents a carboxyl group or G is as hereinbefore defined and A has the meanings of A as hereinbefore defined with the proviso that A contains an H-N~ or R1'-NH- group wherein R1' is as hereinbefore defined.

- For example, functional derivatives of the carboxyl group such as the unsubstituted or substituted amides, esters, thioesters, trimethylsilylesters, orthoesters, iminoesters, amidines or anhydrides thereof, or the nitrile group may be converted into a carboxyl group, using hydrolysis, esters with tertiary alcohols e.g. tert.-butylester may be converted into a carboxyl group, by means of treatment with an acid or using thermolysis, and esters with aralkanols, e.g. benzylester may be converted into a carboxyl group, using hydrogenolysis, and imino groups which are substituted by a protective group such as a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.-butyloxycarbonyl or benzyloxycarbonyl group, may be converted, by means of hydrolysis, or imino groups which are substituted by a protective group such as a benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group, using hydrogenolysis, to form a free imino group.

The hydrolysis is appropriately carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, 212~37 ~

trichloroacetic acid or trifluoroacetic acid or mixtures thereof, or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between -10 and 120DC, e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.

If Ga in a compound of formula II represents a cyano- or aminocarbonyl group, then these groups may also be converted into the carboxyl group at temperatures between 0 and 50C by means of a nitrite, e.g. sodium nitrite, in the presence of an acid such as sulphuric acid, whereby these groups are appropria~ely used at the same time as a solvent.

If, for example, in a compound of formula II Aa contains or Ga represents a tert.butyloxycarbonyl group, the tert.butyl group may also be cleaved by treating with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, `' chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane, preferably at temperatures of between -10 and 120C, for example at temperatures of between 0 and 60C, or else by treating thermally, -optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, for example at temperatures of between 40 and 120~C, whereby an N-carboxy-imino compound optionally :
2~2~3~

contained in the reaction mixture is at the same time decarboxylated.

If, for example, in a compound of formula II Aa contains or Gn represents a benzyloxycarbonyl group, the benzyl group may also be hydrogenolytically cleaved in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50C, e.g. at ambient temperature, and a hydrogen pressure of 1 to 5 bar, whereby an N-carboxy-imino compound optionally contained in the reaction mixture may at the same time be decarboxylated.

b) In order to prepare compounds of general formula I, wherein B, C or D contain or represent a carbonyl group bound to a nitrogen atom:
reaction of a carboxylic acid of general formula .

A - Ba _ COOH (III) with a compound of general formula H-Ca - D - E - F - G (IV) or of a carboxylic acid of general formula HOOC-Ca - D - E - F - G (V) with a compound of general formula A - Bb _ H (VI ) or of a carboxylic acid of general formula 2~2~37~1 ~ 21 -A - B - Ca - COOH (VI I ) with a compound of general formula H - Db _ E - F - G (VIII) or of a carboxylic acid of general formula HOOC - Da _ E - F - G (IX) with a compound of general formula A ~ B - Cb - H tX) or of a carboxylic acid of general formula A - B - C - Da _ COOH (XI ) with a compound of general formula .~
H-Eb - F - G (XII) ~ -~ ~ .
or of a carboxylic acid of general formula HOOC - Ea _ F - G (XI I I ) :~ -, with a compound of general formula A - B ~ C - Db _ H (XIV) :;

wherein A-to G are as hereinbefore defined, Ba,- ca, Da and Ea each have the meanings given above ~or B~ C, D and E respectively, with the proviso that B, C, D or E additionally contains the carboxyl group which takes part in the reaction or one of the reactive derivatives thereof or, instead of a carbonyl group by .. ~ . .

212~37~

means of which they are bound to a nitrogen atom of an adjacent group, a carboxyl group or one of the reactive derivatives thereof, Bb, Cb, Db and Eb each have the meanings ~iven above for B, C, D and E respectively, with the proviso that B, C, D or E additionally contains the H2N or HNRs group which takes part in the reaction or, instead of a nitrogen atom via which they are bound to a carbonyl group of an adjacent group, the reactive amino or imino group.

During the reaction it is also possible to use a reactive derivative of the corresponding carboxylic acid of general formula III, V, VII, IX, XI or XIII, for example the halide such as the chloride or bromide, the symmetrical or mixed anhydride, together with a carbonic acid monoalkylester or an aliphatic carboxylic acid such as pivalic acid or the activated esters thereof such as 4-nitrophenylester, the thioesters thereof or the imidazolide thereof.

The reaction is optionally carried out in a solvent o_ solvent mixture such as methylene chloride, ~ -dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or to particular advantage in a corresponding amine of general formula IV, VI, VIII, X, XII or XIV, in the presence of a dehydrating agent, for example in the presence of isobutylchloroformate, thionylchloride, trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,N'-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4-dimethylamino-pyridine N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, suitably at temperatures between 0 and 150C, preferably at temperatures between 0 and 80C.

~2937 ~

c) In order to prepare compounds of general formula I
wherein R4 represents an alkyl, alkylcarbonyl or alkyloxycarbonyl group optionally substituted in the alkyl moiety by an aryl group, or R4 represents an arylcarbonyl, alkylsulphonyl or arylsulphonyl group and/or R6 or R8 represent an alkyl, arylalkyl, alkylcarbonyl, arylalkylcarbonyl, arylcarbonyl, arylalkylsulphonyl or arylsulphonyl group, an alkylsulphonyl group having 1 to 5 carbon atoms, an alkyl group substituted by an R3-Co- group or an alkylcarbonyl group substituted by an RsO- group:

Reaction of a compound of general formula A - B - C - D - E - F - G (XV) (wherein A to G are as hereinbefore defined with the proviso that at least one of groups B or E contains an -NH- group not bound to a carbonyl group) with a compound of general formula Zl _ Ra (XVI) wherein Ra with the exception of the hydrogen atoms has the.
meanings given above for R4, R6 or R9 and Zl represents a leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a sulphonic acid ester group e.g. a methanesulphonyloxy or p-toluenesulphonyloxy group, or in the case of an acylation also an alkylcarbonyloxy or alkoxycarbonyloxy group~or Zl together with an adjacent hydrogen atom of group Ra denote an oxygen atom.

The alkylation with a compound of formula XVI, in which ~: ' ' ` ,, ' ~ ` ' .; ` ` `

.

Z1 represents a nucleophilic leaving group, is appropriately carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide or dimethylformamide, optionally in the presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine which may simultaneously serve as solvent, at temperatures between -30 and 100C, but preferably at temperatures between -10 and 80C.

The acylation or sulphonylation with a compound of general formula XVI is appropriately carried out in a solvent such as tetrahydrofuran, methylene chloride, chloroform, dimethylformamide, water or mixtures of these solvents optionally in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as triethylamine, N-ethyldiisopropylamine, N-methyl-morpholine or pyridine which may simultaneously serve as solvent, at temperatures between -30 and 100C, but preferably at temperatures between -10 and 60C.

The reductive alkylation with a carbonyl compound of general formula XVI is carried out in the presence of a complex metallic hydride such as sodium borohydride, lithium borohydride or sodium cyanoborohydride, suitably at a pH value of 6-7 and at ambient temperature, or in the presence of an hydrogenation catalyst, for example with hydrogen in the presence of palladium/charcoal or Raney nickel, at a hydrogen pressure of 1 to 5 bar.
However the methylation is preferably carr ed out in the presence of formic acid as a reducing agent at elevated temperature, for example at temperatures bétween 60 and 120C.

- 25 - 2 1 2 937 ll d) In order to prepare compounds of general formula I
wherein B represents an oxyalkylene or alkyleneoxy group each having 1 to 3 carbon atoms:

Reaction of a compound of general formula A Z2 (XVII) with a compound of general formula Z3 - C - D - E - F - G (XVIII) wherein A and C to G are as hereinbefore defined, one of groups Z2 or Z3 represents a hydroxy group or an alkyl group having 1 to 3 carbon atoms and substituted by a hydroxy group and the other group of groups Z2 or Z3 represents a leaving group or an alkyl group having 1 to 3 carbon atoms and substituted by a leaving group, wherein the leaving group represents, for example, a chlorine, bromine or iodine atom or a sulphonic acid ester group such as methanesulphonyloxy or p-toluenesulphonyloxy group.

The reaction is appropriately carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide or dimethylformamide optionally in ~he presence of a base such as sodium carbonate, potassium carbonate, cesium carbonate, sodium hydride, potas~ium tert.butylate or sodium hydroxide solution or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine which may simultaneously serve as solvent, at temperatures between -30 and lOO~C, but preferably at temperatures between -10 and 80C.
e) In order to prepare a compound of general formula I, 212~37~

wherein A represents an alkyl group having 1 to 4 carbon atoms and suhstituted by an amino group:

Xeduction of a compound of general formula NC- (CH2)n - B - C - D - E - F - G (XIX) wherein B to G are as hereinbefore defined and n represents the number 0, 1, 2 or 3.
`~
The reduction is preferably carried out in a suitable -solvent such methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition orC an acid such as hydrochloric acid, in the presence of catalytically activated hydrogen, for example hydrogen in the presence of Raney nickel, platinum or palladium/charcoal, or in the presence of a metallic hydride such as sodium borohydride, lithium borohydride or lithium aluminium hydride, at temperatures between 0 and lOO~C, preferably at temperatures between 20 and 80C.

f) In order to prepare compounds of general formula I
wherein B represents an alkylene group having 2 or 3 carbon atoms and/or A represents a piperidinyl group:
Reduction of a compound of general formula Ac _ Bc _ C - D - E - F - G tXX) whereln C to G are as hereinbefore defined, and Ac has the meanings given above for A and c represents an alkenylene group having 2 or 3 carbon ato~s or .2~37~

Bc has the meanings given above for B and Ac represents a pyridyl group.

The reduction is preferably carried out with hydrogen in the presence of a catalyst such as palladium/charcoal, platinum, platinum dioxide or Raney nickel in a solvent such as methanol, ethanol, ethyl acetate or glacial acetic acid, optionally while adding an acid such as hydrochloric acid, at temperatures between 0 and 50C, but preferably at ambient temperature, and at a hydrogen.
pressure of 1 to 7 bar, but preferably of 3 to 5 bar.

g) In order to prepare compounds of general formula I
wherein Rl represents an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, in which the methoxy or ethoxy moiety may additionally be substituted by a phenyl group, or Rl represents an R2-Co-o-(HcR3) group: .
Reaction of a compound of general formula Ad _ B - C - D - E - F - G (XXI) (wherein B to G are as hereinbefore defined and Ad has the meanings given above for A with the proviso that A contains an H-N< group or represents an alkyl or cycloalkyl group substituted by an amino group, wherein the alkyl moiety may contain 1 to 4 carbon atoms and the cycloalkyl moiety may contain 3 to 7 carbon atoms) with a compound of general formula Z~ - Rl" (XXII) wherein Rl" represents an alkoxycarbonyl group having a total of 2 to 6 carbon atoms wherein a methoxy or ethoxy moiety . . .. ...

- 2~ - 212~37~
may additionally be substituted by a phenyl group, or R' repre~ents an R2-Co-o-(HCR3)-o-Co- group wherein R2 and R3 are as hereinbefore defined, and Z4 represents a leaving group such as a halogen atom, an aryloxy, arylthio, alkoxycarbonyloxy, aralkoxycarbonyloxy or N-imidazolyl group, for example a chlorine or bromine atom or a 4-nitro-phenoxy group.

The acylation is appropriately carried out in a solvent such as tetrahydrofuran, methylene chloride, chloroform, dimethylformamide, water or mixtures of these solvents, optionally in the presence of a base such as sodium carbonate, potassium carbonate or sodium hydroxide solution or in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine which may simultaneously serve as ~olvent, at temperatures between -30 and 100C, but preferably at temperatures between -10 and 60C.

h) In order to prepare compounds of general formula I
wherein G repre~ents a carbonyl group which may be substituted by an alkoxy group having l to 6 carbon atoms, by a cycloalkoxy group having 3 to 7 carbon atoms or by a phenoxy group which may be substituted in the 2,3- or 3,4-position by an alkylene bridge having 3 to 5 carbon atoms:

Reaction of a carboxylic acid of general formula A - B - C - D - E - F - COOH (XXIII) wherein A to F are as hereinbefore defined, or the reactive derivatives optionally prepared in the reaction mixture, with an alcohol of general formula HO - Rb (XXIV) : - : . .:

- 29 - 2i2937~
wherein Rb represents an alkyl group having l to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or a phenyl group which may be substituted in the 2,3- or 3,4-position by an alkylene bridge having 3 to 5 carbon atoms.

Reactive derivatives of a compound of general formula XXIII include, for example, the acid chlorides, acid azides, mixed anhydrides with aliphatic or aromatic carboxylic acids or carbonic acid monoesters thereof, the imidazolides thereof and esters thereof such as alkyl, aryl and aralkyl esters, e.g. methyl, ethyl, isopropyl, pentyl, phenyl, nitrophenyl or benzyl esters.

The reaction of a carboxy compound is optionally carried out in a solvent or solvent mixture such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane or to particular advantage in a corresponding alcohol of general formula XXIV, optionally in the presence of an acid such as hydrochloric acid or in the presence of a dehydrating agent, for example in the presence of isobutylchloroformate, thionylchloride, trimethylchlorosilane, sulphuric acid, methanesulphonic acid, p-toluenesulphonic acid, phosphorus trichloride, phosphorus pentoxide, N,N'-dicyclohexylcarbodiimide, N,NI-dicyclohexylcarbodiimide/N-hydroxysuccinimide or 1-hydroxy-benzotriazole and optionally additionally in the presence of 4-dimethylaminopyridine, N,N'-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, suitably at temperatures between 0 and 150C, preferably at temperatures between 0 and 80DC.

The reaction of a corresponding alkoxycarbonyl compound with an alcohol of general formula XXIII is preferably carried out in a corresponding alcohol as a solvent, - 30 - 212937~
optionally in the presence of a further solvent such as methylene chloride or ether, preferably in the presence of an acid such as hydrochloric acid, at temperatures between 0 and 150C, preferably at temperatures between 50 and 100C.

i) In order to prepare compounds of general formula I
wherein G represents a carbonyl group which is substituted by an alkoxy group having 1 to 6 carbon atoms, by a cycloalkoxy group having 3 to 7 carbon atoms or by a R2-Co-o-(HCR3)-o- group:
Reaction of a compound of general formula A - B - C - D - E - F - COOH ( XX I I I ) wherein A to F ~re as hereinbefore defined, with a compound of general formula Zs _ RC (XXV) wherein Rc represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or an R2-Co-o-(HCR3)- group wherein R2 and R3 are as hereinbefore defined, and Zs represents a leaving group such as a halogen atom or a sulphonic acid ester group, for example a chlorine or bromine atom, or a methanesulphonyloxy or p-toluenesulphonyloxy group.

The reaction is preferably carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide or dimethylformamide optionally in the presence of a reaction catalyst such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate, potassium carbonate or . _ . ,, .. , . , . .. , .. . . ~ ... . . .. . . . . . . ... . ... . . .

~l;

2~2937~

sodium hydroxide solution or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methyl-morpholine which may simultaneously serve as a solvent, or optionally in the presence of silver carbonate or silver oxide, at temperatures between -30 and 100C, but preferably at temperatures between -10 and 80C.

j) In order to prepare compounds of general formula I
wherein at least one of the groups C or E represent a cyclohexylene group:
Hydrogenation of a compound of general formula A - B - Cd - D _ Ed - F - G (XXVI) wherein A, B, D, F and G are as hereinbefore defined, Cd and Ed have the meanings given above for C and E with the proviso that at least one of groups Cd or Ed represents a phenylene group.

The hydrogenation is carried out in the presence of a catalyst such as platinum, platinum dioxide or rhodium/platinum, in a solvent such as methanol, ethanol, glacial ac~tic acid or water, optionally in the presence of an acid such as hydrochloric acid, with hydrogen at a hydrogen pressure of 3 to 5 bar, at temperatures between 0 and 50~C, preferably at ambient temperature.

k) In order to prepare compounds of general formula I
wherein D represents an -NRsCONRs- group:
Reacting a compound of general formula A - B - C - Ul (XXVII) 212937l~

with a compound of general Eormula U2 - E - F - G (XXVIII) wherein ~, B, E, F and G are as hereinbefore defined, one of groups Ul or U2represents an HNRs- group and the other group of groups Ul or u2 represents a Z5-Co-NR5-group wherein Rs is as hereinbefore defined and Z6 represents a nucleophilic leaving group such as a halogen atom, an alkoxy group having 1 to 3 carbon atoms or an imidaæol-1-yl group or Z6 and Rs together represent a further carbon-nitrogen bond.

The reaction is suitably carried out in a solvent such as tetrahydrofuran, methylene chloride, chloroform, dimethylformamide or mixtures of these solvents optionally in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine, N-methyl-morpholine or pyridine which may simultaneously serve as a solvent, at temperatures between -30 and lOO~C, but preferably at temperatures between -10 and 60~C, whereby leaving compounds of the above general formulae XXVII and XXVIII are prepared to particular advantage in the reaction mixture.

1) In order to prepare compounds of general formula I
wherein A represents an azacyclohexenyl group substituted at the nitrogen atom by an optionally aryl substituted Cl3-alkyl group:

Reduction of a compound~ optionally formed in the reaction mixture, of general formula .i,". :. . :-;...:,:- -2~2937~

Ae _ B - C - D - E - F - G (XXIX) wherein B to G are as hereinbefore defined and A~ represents a 4-pyridyl group substituted at the nitrogen atom by an optionally aryl substituted Cl3-alkyl group) with a complex metal hydride.

The reduction is preferably carried out in a suitable solvent such as methanol, methanol/water, methanol/water/ammonia, ethanol, ether, tetrahydrofuran, dioxane or dimethylformamide, optionally with the addition of an acid such as hydrochloric acid in the presence of a metal hydride such as sodium borohydride, lithium borohydride or lithium aluminium hydride, at temperatures between 0 and 100C, preferably at temperatures between 20 and 80C.

If, according to the invention, a compound of general formula I which contains a sulphenyl group is obtained, then this compound can be converted into a corresponding sulphinyl or sulphonyl compound of general formula I, by oxidation, or if, according to the invention, a compound of formula I-wnich contains a sulphinyl group is obtained, then this compound can be converted into a corresponding sulphonyl compound of general formula I, by oxidation.

The subsequent oxidation is preferably carried out in a solvent or solvent mixture, for example in water, water/pyridine, acetone, methylene chloride, glacial acetic acid, glacial acetic acid/acetic anhydride, dilute sulphuric acid or trifluoroacetic acid, depending on the oxidising agent used, preferably at temperatures between -80 and 100C.

~.: . .

~` :

2l~9~7~l In order to prepare a corresponding sulphinyl compound of general formula I, the oxidation ls appropriately carried out usin~ one equivalent o~ the oxidation agent used, for example with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or Eormic acid at 0 to 20C or in acetone at 0 to 60C, using a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50DC or using m-chloroperbenzoic acid in methylene chloride or chloroform at -20 to 60C, using sodium metaperiodate in aqueous methanol or ethanol at -15 to 25C, using bromine in glacial acetic acid or aqueous acetic acid optionally in the presence of a weak base such as sodium acetate, using N-bromosuccinimide in ethanol, using tert.butylhypochlorite in methanol at -80 to -30C, using iodine benzodichloride in aqueous pyridine at 0 to 50C, using nitric acid in glacial acetic acid at 0 to 20~C, using chromic acid in glacial acetic acid or in acetone at 0 to 20C and using sulphuryl chloride in methylene chloride at -70C, and the resultant thioether-chlorine complex is appropriately hydrolysed with aqueous ethanol.

In order to prepare a sulphonyl compound of general formula I, the oxidation, if based on a corresponding sulphinyl compound, is suitably carried out with one or mor~ equivalents of the oxidising agent used or, if based on a corresponding sulphenyl compound, is suitably carrie~ out with two or more equivalents of the oxidising agent used, for example with hydrogen peroxide in acetic acid/acetic anhydride, trifluoroacetic acid or in formic acid at 20 to 100C, or in acetone at 0 to 60C, with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform, at temperatures between 0 and 60C, with nitric acid in glacial acetic acid at 0 to 20C, with chromic acid or potassium permanganate in glacial acetic acid, ''f.' ` ' `: ` ` ' ' , .. .
.,.
,, ~ . .

`

- 35 - ~ 37~
water/sulphuric acid or in acetone at 0 to 20C.

In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, phosphono, O-alkyl-phosphono, amino, alkylamino, imino or amidino groups may be protected during the reaction by means of conventional protecting groups which are removed again after the reaction.

For example the protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, tert.butyl, trityl, benzyl or tetrahydropyranyl group, the protecting group for a carboxy group may be a trimethylsilyl, methyl, ethyl, tert.butyl, allyl, benzyl or tetrahydropyranyl group, the protecting group for a phosphono group may be an alkyl group such as a methyl, ethyl, isopropyl or n-butyl group, or a phenyl or benzyl group, the protecting group for an amidino group optionally substituted by an alkyl group may be a benzyloxycarbonyl group, the protecting group for an amino, alkylamino or imino group may be a formyl, acetyl, trifluoroacetyl, ethoxycarbonyl, tert.butoxycarbonyl, allyloxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and for an amino group a phthalyl group may also be considered and the protecting group for the nitrogen atom of a l-aza-bicycloalkyl group such as a quinuclidinyl group may be a benzyl group or borane.
The optional subsequent cleaving of a protecting group ~... - . , ....... ~ .
;:.. : . . . ':
.:: ~ , . .

212~37~

used may, for example, be carried out hydrolytically in an a~ueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as sodium hydroxide or potassi.um hydroxide, or by ether cleaving, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 120~C, preferably at temperatures between 10 and 100C.

However, a benzyl, methoxybenzyl or benzyloxycarbonyl group may, for example, be cleaved hydrogenolytically, e.g. using hydrogen in the presence of a catalyst such as palladium/charcoal, in a solvent such as methanol, ethanol, ethyl acetate or acetic acid, optionally with the addition of an acid such as hydrochloric acid, at temperatures between 0 and 100C, but preferably at temperatures between 20 and 60~C, and under a hydrogen pressure of 1 to 7 bar, but preferably up to 5 bar. A
2,4-dimethoxybenzyl group, however, is preferably cleaved in trifluoroacetic acid in the presence of anisole.

A tert.butyl or tert.butyloxycarbonyl group is preferably cleaved by treating with an acid such as tri~luoroacetic acid or hydrochloric acid, or by treating with iodotrimethylsilane optionally while using a solvent such as methylene chloride, dioxane, methanol or ether.

A trifluoroacetyl group is preferably cleaved by treating with an acid such as hydrochloric acid optionally in the presence of a solvent such as acetic acid, at temperatures between 50 and 120~C, or by treating with sodium hydroxide solution optionally in the presence of a solvent such as tetrahydrofuran, at ".. : .
,.,,; ~..
. :,. . ~ :
., . .

2~ 2937 ~

temperatures between 0 and 50C.

An allyloxycarbonyl group is ~leaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of an allyl group acceptor such as morpholine or 1,3-dimedone, at temperatures between 0 and 100C, preferably at ambient temperature and under inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as l,4-diazabicyclo[2.2.2~octane at temperatures between 20 and 70C.

A phthalyl group is preferably cleaved in the presence of hydrazine or a primary amine such as methylamine, ethylamine or n-butylamine, in a solvent such as methanol, ethanol, isopropanol, toluene/water or dioxane at temperatures between 20 and 50C.

The complex of a 1-aza-bicycloalkyl group such as the quinuclidinyl group with borane is preferably cleaved by treating with an acid such as hydrochlori_ acid and preferably in the presence of an alcohol such as methanol, ethanol or butanol, at temperatures between 0C and the boiling temperature of the reaction mixture.

The cleavage of only one alkyl group from an O,O'-dialkylphosphono group is preferably carried out using sodium iodide in a solvent such as acetone, ethylmethylketone, acetonitrile or dimethylformamide, at temperatures between 40 and 150C, but preferably at temperatures between ~0 and 100C.

The cleavage of both alkyl groups from an O,O~-dialkylphosphono group may for example be carried out . ~ . . ~ - - -'~;: ', .
,`,: ' ', ~ : . .
. ~: .: -212937~

using iodotrimethylsilane, bromotrimethylsilane or chlorotrimethylsilane/sodium iodide in a solvent such as methylene chloride, chloroform or acetonitrile, at temperatures between oC and the boiling temperature of the reaction mixture, but preferably at temperatures between 2~ and 60C.

Furthermore the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers as mentioned before. Thus, for example, cis/trans mixtures may be resolved into cis and trans isomers, and compounds with at least one optically active carbon atom may be resolved into their enantiomers.

Thus, for example, the cis/trans mixtures obtained may be resolved by chromatography into the cis and trans isomers thereof, the compounds of general formula I
obtained which occur in racemate form may be separated into their optical antipodes using methods known (Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) and compounds of general formula I having at least 2 asymmetrical carbon atoms may be separated on the basis of their physical-chemical differences using known methods, e.g. by chromatography and/or fractional crystallisation, into the diastereomers thereof, which, if they occur in racemic form, may subsequently be separated into the enantiomers as mentioned above.

The separation of enantiomers is preferably effected by column separation on chiral phases or by reçrystallisation from an optically active solvent or by reacting with an optically active substance, especially an acid or an activated derivative thereof or an alcohol, which forms salts or derivatives such as esters or amides with the racemic compound and separation of i,.. -:: : - : :- .... : . - . -.

212~37'~

the diastereomeric salt mixture or derivatives thus obtained, e.g. on the basis of their different solubilities, whilst the free antipodes may be released from the pure diastereomeric salts by the action of suitable agents. Particularly common, optically active acids include, for example, the D- and L-forms of tartaric acid or dibenzoyl tartaric acid, di-o-tolyl tartaric acid, malic acid, mandelic acid, camphor sulphonic acid, glutamic acid, aspartic acid and quinic acid. Examples of optically active alcohols include, for example (-~)- or (-)-menthol and examples of optically active acyl groups in amides include, for example, (+)- or (-)-menthyloxycarbonyl.

Moreover, the compounds of formula I obtained may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts thereof with inorganic or organic acids. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.

In addition, the new compounds of formula I thus obtained, if they contain a carboxyl group, may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, more particularly, for pharmaceutical use, into the physiologically acceptable acid salts thereof. Examples of suitable bases include sodium hydroxide or potassium hydroxide, arginine, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.

The compounds used as starting materials are known from the literature in some cases or may be obtained by methods known from the literature (see the Examples).

:, ~ ~ :- .. -` 2~2937~ - 40 -As already mentioned, the new carbonamides oE general formula I and the salts thereof, more particularly the physiologically acceptable salts thereof with inorganic or organic acid or bases, have valuable properties.
Thus, the new compounds of general formula I wherein A
contains a basic group or a group which may optionally be converted 1~ vivo into a basic group and G denotes a carboxyl, phosphono, O-alkyl-phosphono or 5-tetrazolyl group or a group which may optionally be converted in ~iYQ into a carboxyl, phosphono, 0-alkyl-phosphono or 5-tetrazolyl group, e.g. a carbonyl group substituted by an alkoxy or cycloalkoxy group, have valuable pharmacological properties, and in addition to having an inhibitory effect on inflammation and bone degradation, they have in particular antithrombotic, antiaggregatory and tumour- or metastasis-inhibiting effects.

The O,O'-dialkyl-phosphono compounds of general formula I are valuable intermediate products for preparing ~-alkyl-phosphono and phosphono compounds of general formula I.

By way of example, th~ compounds of general formula I
were investigated for their biological effects as follows:

1. Inhlbition of binding of 3H-BIBU 52 to human thrombocytes:

A suspension of human thrombocytes in plasma is incubated with 3H-BIBU 52 [= (3S, 5S) -5- [ (4 ' -amidino-4-biphenylyl)oxymethyl]-3-[(carboxyl)methyl] -2-pyrrolidinone[3-3H-4-biphenylyl]], which replaces the l2sI
fibrinogen ligand known from the literature (see German Patent Application P 42 14 245.8 of the same applicant, dated 30.04.1992, internal reference: Case 5/1093-FL) and various concentrations of the substance to be 212937~

tested. The free and bound ligand are separated by centrifuging and quantitatively determined by scintillation counting. The inhibition of 3H-BIsu 52 binding by the test substance is determined from-the measurements obtained.

In order to do this, donor blood is taken from an anticubital vein and anticoagulated with trisodium citrate (final concentration 13 mM). The blood is centrifuged for 10 minutes at 170 x g and the supernatant platelet-rich plasma (PRP) is removed. The remaining blood is v.igorously centrifuged once more in order to obtain plasma. Th~ PRP is diluted 1:10 with autologous plasma. 750 ml are incubated with 50 ml of physiological saline solution, 100 ml of test substance solution, 50 ml of 14C-sucrose (3700 Bq) and 50 ml of 3H-BIBU 52 (final concentration: 5 nM) at ambient temperature for 20 minutes. In order to measure the non-specific binding, 5 ml of BIBU 52 (final concentration: 30 mM) are used instead of the test substance. The samples are centrifuged for 20 seconds at 10,000 x g and the supernatant is poured off. 100 ml thereof are measured in order to determine the free ligand. The pellet is dissolved in 500 ml of 0.2N NaOH, 450 ml are mixed with 2 ml of scintillator and 25 ml of 5N HCl and measured. The residual plasma remaining in the pellet is determined from the 14C-content and the bound ligand is determined from the 3H-measurement.
After the non-specific binding has been deducted, the pellet activity is plotted against the concentration of the test substance and the concentration for a 50 inhibition of binding is determined.

2. Antithrombotic activity MethQd . .

2~2937~

Thrombocyte aggregation is measured using the Born and Cross method (J. Physiol. 170: 397 (1964)) in platelet-rich plasma taken from healthy volunteers. To inhibit coagulation the blood is mixed with 3.14~ sodium-citrate in a volume ratio of 1:10.

Collagen-induc~_aggre~lation The pattern of the decrease in optical density of the platelet suspension is photometrically measured and recorded after the addition of the aggregation-triggering substance. The rate of aggregation is determined from the angle of inclination of the density curve. The point on the curve where there is maximum light transmittance is used to calculate the optical density.

The quantity of collagen used is as small as possible but sufficient to produce an irreversible reaction curve. Standard commercial collagen produced by Hormonchemie of Munich is used.

Before the addition of the collagen the plasma is incubated for 10 minutes with the substance at 37C.

From the measurements obtained an ECso is determined graphically, which denotes the concentration giving a 50% change in the optical density in terms of the inhibition of aggregation.

The following Table shows the results found:

212937 ~

Substance Fibrlnogen binding Inhibition of (Example No.) test platelet ICso [nM] aggregation ECso [nM]

1(1) 360 610 - 1(7) 1500 3100 1(9) 130 1300 1(14) 6900 23000 3 `85 360 3(4) 2100 2060 3(7) 49000 45000 3(8) 6400 5800 3(9) 2300 3200 3(15) 630 1200 3(16) 160 270 3(17) 91 300 3(23) 190 270 3(24) 15Q0 4410 3(30) 120Q 1070 3(32) - 1200 4(23) 180 370 4(32) 130 970 4(34) 840 3370 22(5) 430 2800 The compounds according to the invention are well tolerated because after intravenous administration of 30 mg/kg of the compounds of Example 1(2), 3, 3(17) and 4(23) to 3 mice in each case, no animals died.

In the light of their inhibitory effect on cell-cell or cell-matrix interactions~ the new carbonamides of general formula I and the physiologically acceptable addition salts thereof are suitable for .

` 2~2~7'~

- 4~ -combating or preventing diseases in which smaller or greater cell aggregates occur or in which cell-matrix interactions play a part, e.g. i.n treating or preventing venous and arterial thrombosis, cerebrovascular ~
diseases, lung embolism, cardiac infarction, arteriosclerosis, osteoporosis and the metastasis of tumours and the treatment of genetically caused or acquired disorders of cell interactions with one another or with solid structures. They are also suitable for parallel therapy in thrombolysis with fibrinolytics or vascular interventions such as transluminal angioplasty or in the treatment of shock, psoriasis, diabetes and inflammation.

For treating or preventing the diseases mentioned above the dosage is between 0.1 mg and 30 mg/kg of body weight, preferably 1 mg to 15 mg/kg of body weight, given in up to 4 doses per day. For this purpose the compounds of formula I produced according to the invention, optionally in conjunction with other active substances such as thromboxane receptor antagonists and thromboxane synthesis inhibitors or combinations thereof, serotonin antagonists, ~-receptor antagonists, alkylnitrates such as glycerol trinitrate, phospho-diesterase inhibitors, prostacyclin and the analogues thereof, ~ibrinolytics such as tPA, prourokinase, urokinase, streptokinase, or anticoagulants such as heparin, dermatan sulphate, activated protein C, vitamin K antagonists, hirudine, inhibitors of thrombin or other activated clotting factors, may be incorporated together with one or more inert conventional carriers and/or diluents, e.g. corn starch, lactose, sucrose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, stearylalcohol, carboxymethylcellulose or fatty . .
',.,`' ~ : :
.",, ' ' ' ' ' ~ "

21293~ l~

substances such as hard fat or suitable mixtures thereof, into conventional ~alenic preparations such as plain or coated tablets, capsules, powders, suspensions, solutions, sprays or suppositories.

The Examples which follow are intended to illustrate the invention:
-2~29~
- ~6 -~m~

3-[2-(4-Quinuclidinyl)-ethyl]-benzoic acid-hydrochloride 0.~1 g of methyl 3-[2-(4-quinuclidinyl)-ethyl]-benzoate are refluxed in a mixture of 5 ml of ethanol and 1.5 ml of 2N sodium hydroxide solution for 30 minutes. The mixture is then concentrated by evaporation, the resultant residue is stirred with a mixture of tert.butylmethylether and acetone and the solid product obtained is filtered off. After adding 3N of hydrochloric acid until a neutral reaction takes place, the mixture is concentrated to dryness and is again concentrated down.
Yield: 0.35 g (79% of theory), R~ value: 0.47 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) The following compounds are obtained analogously:

(1) 4-[2-(4-quinuclidinyl)-ethyl]-benzoic acid-hydrochloride Rf value: 0.44 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) (2) 1-~[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-carbonyl]-4-carboxymethyl-piperidine Lithium hydroxide is used in a tetrahydrofuran/water mixture at ambient temperature.
Rf value: 0.42 (silica gel; methylene chloride/methanol =
9 : 1 ) (3) trans-4-[~(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]carbonylamino]-cyclohexane-carboxylic acid The method used is as under (2).
Melting point: 207-2G9C (decomp.) (4) 4-[(l-benzyl-4-piperidinyl)-aminocarbonyl]-benzoic .... .

- 47 - ~ 9~ 7 acid-hydrochloride Tetrahydrofuran is used as a solvent.
Rf value: 0.17 (silica gel; methylene chloride/methanol =
9 : 1 ) -(5) trans-4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-cyclohexane-carboxylic acid The sarne method is used as under (2).
Rf value: 0.70 (silica gel; methylene chloride/methanol 4:1) (6) ~-[N-benzyloxycarbonyl-N-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoic acid The same method i~ used as under (2).
Melting point: 150-152C, Rf value: 0.55 (silica gel; methylene chloride/methanol =
9 : 1 ) (7) 4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-benzoic acid The same method is used as under (2).
Melting point: above 300C, Rf value: 0.27 (silica gel; methylene chloride/methanol =
9 : 1 ) (8) 3-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-benzoic acid The same method is used as under (2).
Rf value: 0.29 (silica gel; methylene chloride/methanol =
15:1) (9) 4-[2-(tert.butyloxycarbonyl-amino)-ethyloxy]-benzoic acid Methanol is used and heated to 50C.
Melting point: 179-181C, Rf value: 0.38 (silica gel; cyclohexane/ethyl acetate =
1 : 1 ) ~ : . .-: .

- 48 - ~ 7~
(10) 3-[N-benzyloxycarbonyl-N-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoic acid Rf value: 0.48 (silica gel; methylene chloride/methanol =
9:1) ~
-(11) 4-[trans-2-(4-pyridyl)-ethenyl]-benzoic acid The same method is used as under (2).
Melting point: above 330C, Rf value: 0.50 (Reversed Phase Ylate RP18; methanol/5 sodium chloride solution = 6:4) (12) 1-[2-(1-tert.butyloxycarbonyl-4-piperidinyl)-ethyl]-piperidine-4-carboxylic acid The same method is used as under (2).
Rf value: 0.14 (silica gel; methylene chloride/methanol =
9 : 1 ) (13) 4-[(4-benzyl-piperazino)-carbonylamino]-benzoic acid Lithium hydroxide in tetrahydrofuran is used.
Rf value: 0.25 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.2~) (14) trans-4-ethoxycarbonyl-cyclohexane carboxylic acid Potassium hydroxide is used at ambient temperature.
Melting point: 82-84r~Ct Rf value: 0.57 (silica gel; methylene chloride/methanol =
9 : 1 ) ~15) 1-[2-(1-tert.butyloxycarbonyl-4-piperidinyl)-ethyl]-piperidine-4-carboxylic acid The same method is used under (2).
Rf value: 0.06 (silica gel; methylene chloride/methanol =
9 : 1 ) (16) 4-(3-tert.butyloxycarbonylamino-propyl)-benzoic , " ~
~,~., , - . .
'y~
r~
, ,, ~ . . .

2~29~7l~

acid 2N oE sodium hydroxide solution in dioxane is used.
Melting point: l50~C ~sintering from 146C) Rf value: 0.58 (silica gel; cyclohexane/ethyl acetate =
1 : 1 ) ' ExamR~

Methyl 3-[2-(4-quinuclidinyl)-ethyl]-benzoate 0.4 g of methyl 3-[2-(4-quinuclidinyl)-ethenyl]-benzoate are treated in 10 ml of ethyl acetate at ambient temperature for 5.5 hours with hydrogen at 5 bar, in the presence of 10% palladium charcoal. The mixture is filtered off from the catalyst and evaporated down.
Yield: 0.41 g (100~ of theory), Rf value: 0.24 (silica gel; methylene chloride/methanol/conc. ammonia = 8:2:0.2) The following compound is obtained analogously:

(1) methyl 4-[2-(4-quinuclidinyl)-ethyl]-benzoate Rf value: 0.31 (silica gel; methylene chloride/methanol/conc. ammonia = 8:2:0.2) Exam~le III

Methyl 3-[2-(4-Quinuclidinyl)-ethenyl]-benzoate 1.23 g of methyl 3-(triphenylphosphonio-methyl)-benzoate-bromide is suspended in 15 ml of tetrahydrofuran and, after cooling in an ice bath, 0.28 g of potassium tert.butylate is added under nitrogen. The mixture is stirred for 15 minutes and 0.3 g of quinuclidine-4-aldehyde is added. It is stirred for 3.5 hours at ambient temperature and mixed with saturated sodium chloride solution and a little water. The organic phase is separated off and the r. '- - ~ t ~12~

aqueous phase is extracted with tetrahydrofuran and tert.butylmethylether. The organic phases are concentrated by evaporation and the residue is purified on aluminium oxide by chromatography (eluant: fi~stly ethyl acetate, then ethyl acetate/methanol 9:1).
Yield: 0.4 g (68% of theory), Rf value: 0.37/0.44 (cis/trans-isomers; silica gel;
methylene chloride/methanol/conc.
ammonia = 8:2:0.3) The following compound is obtained analogously:

(1) methyl 4-[2-(4-quinuclidinyl)-ethenyl]-benzoate Rf value: 0.36/0.45 (cis/trans-isomers, silica gel;
methylene chloride/methanol/conc.
ammonia = 8:2:0.3) Example ~V

4-[(4-Quinuclidinyl)-methyloxy]-benzoic acid A mixture of 4.3 g of 4-[(4-quinuclidinyl)-methyloxy]-benzonitrile, 70 ml of glacial acetic acid and 35 ml of conc. hydrochloric acid are refluxed for 20 hours. The solution is cooled with ice water and the precipitate is filtered off.
Yield: 3.5 g (66~ of theory), Melting point: above 250C
Rf value: 0.56 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Example V

4-[(4-Quinuclidinyl)-methyloxy]-benzonitrile 0.96 g of a 55~ suspension of sodium hydride in oil is suspended in 5 ml of dimethylformamide, cooled in ice water and mixed with a solution of 5.1 g of 4-~$ ~
'.',"` ~ ` - .
.'.,- ~ : : - , " ,.

~12~3~

hydroxymethyl-quinuclidine in 40 ml of dimethylformamide. The mixture is stirred for 10 minutes at ambient temperature, a solution of 4.8 g of 4-fluorobenzonitrile in 15 ml of dimethylformamide is added and stirred for 3 hours at ambient temperature.
It is mixed with ice water whereupon the desired product precipitates.
Yield: 4.3 g (49~ of theory), Melting point: 176-178C
Rf value: 0.61 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Exam~lç VI

l-[[(1-tert.Butyloxycarbonyl-4-piperidinyl)-methyl]-carbonyl]-4-(methoxycarbonyl-methyl)-piperidine Prepared from 1-tert.butyloxycarbonyl-piperidine-4-acetic acid and 4-(methoxycarbonyl-methyl)-piperidine analogously to Example 5.
Melting point: 70-72~C

The following compounds are obtained analogously:

(1) methyl trans-4-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-carbonylamino]-cyclohexane carboxylate Melting point: 140-141C

~2) methyl 4-[(1-benzyl-4-piperidinyl)-aminocarbonyl]-benzoate Melting point: 197-199C
Rf value: 0.65 (silica gel; methylene chloride/methanol = 9:1) (3) methyl trans-4-~(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-cyclohexane carboxylate .~,r~

- 52 - 2~ 7;~
Melting point: 198-200C (Decomp.) value: 0.67 (silica gel; methylene chloride/methanol = 9:1) (4) 1-[4-[N-benzyloxycarbonyl-N-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoyl3-4-(2-methoxycarbonyl-ethyl)-piperidine Rf value: 0.67 (silica gel; methylene chloride/methanol = 9:1) (5) 1-~4-[N-benzyloxycarbonyl-N-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoyl]-4-(methoxycarbonyl-methyl)-piperidine Rf value: 0.71 (silica gel; methylene chloride/methanol = 9:1~ ' (6) ethyl 4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-benzoate Melting point: 174-176C, Rf value: 0.62 (silica gel; methylene chloride/mPthanol = 9:1~

(7) ethyl 3-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-benzoate Rf value: 0.76 (silica gel; methylene chloride/methanol = 9:1) (8) methyl trans-4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-cyclohexane carboxylate Melting point: 170-172C
R~ value: 0.52 (silica gel; methylene chloride/methanol = 19:1) j"; ~

'r,.~'.. - . ~ :

~2~r~

Examp~e VII

Ethyl 4-[N-benzyloxycarbonyl-N-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]benzoate A mixture of 5.5 g of ethyl 4-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]benzoate, 2.4 ml of benzyloxycarbonylchloride, 16.7 ml of lN sodium hydroxide solution and 150 ml of methylene chloride are stirred for 7 days at ambient temperature. The methylene chloride phase is concentrated and the residue is used directly in Example I(6).
Rf value: 0.90 (silica gel; methylene chloride/methanol -9 : 1 ) The following compound is obtained analogously:

(1) ethyl 3-[N-benzyloxycarbonyl-N-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoate Rf value: 0.89 (silica gel; methylene chloride/ethyl acetate = 4:1) Example VIII

Ethyl 4-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]benzoate A mixture of 0.8 g of acetic acid and 20 ml of dioxane is added dropwise to a mixture, cooled with ice water, of l g of ethyl 4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-benzoate, 0.51 g of sodium borohydride and 40 ml of dioxane. The mixture is heated for 4 hours under refluxing, stirred for 16 hours at ambient temperature, mixed, whilst cooling, with water ",, . ~ . . ~ . . .

.?

23L2~37~

and the major part of dioxane is removed ln vacuo. The remaining liquid phase is extracted with methylene chloride. l'he methylene chloride phase is concentrated by evaporation and the residue is triturated with ether until it is crystalline.
Yield: 0.73 g (75~ of theory), Melting point: 152-154C
- Rf value: 0.89 (silica gel; methylene chloride/ethyl acetate = 9:1) The following compounds are obtained analogously:

(1) 1-tert.Butyloxycarbonyl-4-hydroxymethyl-piperidine After refluxing ~or three hours in tetrahydrofuran using ethyl 1-tert.butyloxycarbonyl-piperidine-4-carboxylate and lithium borohydride Rf value: 0.40 (silica gel; cyclohexane/ethyl acetate =
1 : 1 ) ~2) ethyl 3-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoate Rf value: 0.95 (silica gel; methylene chloride/methanol =
9 : 1 ) (3) 1-tert.butyloxycarbonyl-4-(2-hydroxy-ethyl)-piperidine The method is analogous to (1) and a 25:1 mixture of tetrahydrofuran and methanol is used Rf value: 0.30 (silica gel; cyclohexane/ethyl acetate =
1 : 1 ) Example IX

N-(cis-4-Amino-1-methoxycarbonyl-cyclohexyl)-n-butanesulphonamide-hydrochloride 4.1 g of N-(cis-4-N,N-dibenzylamino-1-methoxycarbonyl-r~

~3r, ,.

3 7 ~

cyclohexyl)-n-butanesulphonamide is dissolved in loo ml of methanol, a total of 4 g of 10~ palladium/charcoal is added and the mixture is treated with hydrogen at 5 bar for an hour at 50C. It is suction filtered from the catalyst, evaporated down again, mixed with methanolic hydrochloric acid, evaporated down again and the residue is triturated with ether.
Yield: 1.1 g (38~ of theory), Rf value: 0.65 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.25) The following compounds are obtained analogously:

(1) 4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-piperidine Palladium hydroxide on charcoal is used.
Rf value: 0.18 (silica gel; methylene chloride/methanol~conc. ammonia = 9:1:0.1) (2) N-(cis-4-amino-1-methoxycarbonyl-cyclohexyl)-acetamide-hydrochloride Rf value: 0.38 (silica gel; methylene chloride/methanol/conc.
ammonia = 4:1:0.25) (3) tert.butyl N-(cis-4-amino-1-methoxycarbonyl-cyclohexyl)-carbamate A 1:1 mixture of methanol and ethyl acetate is used.
Rf value: 0.06 (silica gel; methylene chloride/methanol = 15:1~

(4) methyl trans-4-(4-hydroxy-benzoylamino)-cyclohexane carboxylate It is hydrogenated for 2 hours at 40C.
Melting point: 177-180C, Rf value: 0.53 (silica gel; methylene ~12937~

chloride/methanol = 9:1) (5) tert.butyl trans-4-amino-cyclohexyloxy acetate Rf value: 0.57 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Exam~le X

N-(cis-4-N,N-Dibenzylamino-1-methoxycarbonyl-cyclohexyl)-n-butanesulphonamide 6.27 g of cis-4-N,N-dibenzylamino-l-methoxycarbonyl-cyclohexylamine are dissolved in 100 ml of methylene chloride, mixed with ~.6 ml of n-butanesulphonylchloride and 10.7 ml of pyridine and stirred for 16 hours at ambient temperature. The mixture is concentrated by evaporation, the residue is triturated with water, suction filtered, and the filtrate is extracted with ethyl acetate and the organic phase is evaporated down.
The residue is combined with the solid product obtained above and purified over a silica gel column (eluant:
methylene chloride/ethyl acetate = 20:1).
Yield: 14.0 g (48 ~ of theory), Rf value: 0.65 (silica gel; cyclohexane/ethyl acetate = 1:1) The following compounds are obtained:

(1) N-tcis-4-N,N-dibenzylamino-1-methoxycarbonyl-cyclohexyl)-acetamide Acetyl chloride and triethylamine in tetrahydrofuran are used.
Rf value: 0.58 (silica gel; methylene chloride/methanol/conc. ammonia = 9:1:0.1) (2) tert.butyl N-(cis-4-N,N-dibenzylamino-1-methoxycarbonyl-cyclohexyl)-carbamate r , . ~

2~ ~937~

Pyrocarbonic acid di-tert.butylester in tetrahydrofuran is used and reEluxed or 16 hours.
Rf value: 0.84 (silica gel; methylene chloride/methanol = 15:1) (3) 1-n-bukanesulphonyl-5-(tert.butyloxycarbonyl-amino)-cis-2-methoxycarbonyl-piperidine Triethylamine is used as base. -Rf value: 0.40 (silica gel; cyclohexane/ethyl acetate = 2:1) (4) 4-(methoxycarbonyl-methyl)-1-t4-nitro-benzoyl)-piperidine The method is analogous to (1) and a 1:1 mixture of tetrahydrofuran and dimethyl~ormamide is used.
Rf value: 0.46 (silica gel; methylene chloride/methanol = 15:1) (5) 1-tert.butyloxycarbonyl-4-(methanesulphonyloxy-methyl)-piperidine The method used is as under ~3).
Rf value: 0.57 (silica gel; methylene chloride/methanol = 15:1) (6) ethyl 4-[2-(tert.butyloxycarbonyl-amino)-ethoxy]-benzoate The method is analogous to (2) using dioxane/water (1:1) as solvent while adding 4N sodium hydroxide solution (2.2 equivalents) Melting point: 59-62OC, R~ value: 0.60 (silica gel; cyclohexane/ethyl acetate = 3:3) (7) methyl 3-[4-(4-chloromethyl-benzoylamino)-phenyl]-propionate The method is analogous to (1) and carried out in methylene chloride with N,N-diisopropylethylamine .^ :

-` 2~2~37~

as base.
Melting point: 127-131C
Rf value: 0.82 (silica gel; methylene chloride/ethyl acetate = 9:1) Exam~le ~I `

cis-4-N,N-Dibenzylamino-l-methoxycarbonyl-cyclohexylamine 35 g of 1-carboxy-cis-4-N,N-dibenzylamino-cyclohexylamine-dihydrochloride is suspended in 500 ml of methanol. It is saturated with hydrogen chloride, stirred for 16 hours at ambient temperature and heated for 5 hours under reflux. It is evaporated down, the residue is dissolved in water, washed with ethyl acetate, set to pH 8.5 using sodium hydroxide solution and extracted with ethyl acetate after suction filtering the precipitate. The ethyl acetate phase is concentrated by evaporation and the residue is purified on silica gel by chromatography (eluant:
cyclohexane/ethyl acetate = 1:1).
Yield: 18.2 g (61~ of theory), Rf value: 0.51 (silica gel; methylene chloride/methanol =
15:1) The following compound is obtained analogously:

(1) methyl trans-4-amino-cyclohexyloxy-acetate The starting product is the associated tert.butylester and the process is carried out at ambient temperature.
Melting point: 157-160C, Rf value: 0.80 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) .~ .. ~: : - .

~`:

-" 212 9 3 7 ~

Example XI~

l-Carboxy-cis-4-N,N-dibenzylamino-cyclohexylamine-dihydrochloride 30.4 g of 8-dibenzylamino-1,3-diaza-spiro~4,5~decan-2,4-dione is dissolved in a mixture of 150 ml of glacial acetic acid and 150 ml of concentrated hydrochloric acid and heated in a pressure vessel to 130C for 78 hours.
It is evaporated down, the residue is triturated with acetone, the solid product is taken up in methanol, treated with activated chaxcoal and concentrated by evaporation.
Yield: 35.0 g (100% of theory), Rf value: 0.40 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.2S) Example XIII

8-Dibenzylamino-1,3-diaza-spiro[4,5]decan-2,4-dione 31.8 g of 4-dibenzylamino-cyclohexanone is dissolved in 400 ml of ethanol, mixed with a solution of 27 g of ammonium carbonate in 200 ml of water and 8.8 g of potassium cyanide. The mixture is stirred for 5 hours at 50~C and then for 16 hours at ambient temperature.
It is cooled down to 4C and the precipitate formed is suction filtered.
Yield: 30.4 g (77.2% of theory), Rf value: 0.30 (silica gel; methylene chloride/methanol =
15 : 1 ) 212937~

Example XIV

4-Dibenzylamino-cyclohexanone _ 36 g of 4-dibenzylamino-cyclohexanone-ethyleneketal is dissolved in 300 ml of lN hydrochloric acid and stirred for 16 hours at ambient temperature. It is made alkaline with lON sodium hydroxide solution, extracted with ether and the organic phase is concentrated by evaporation.
Yield: 31.8 g ~100~ of theory), Rf value: 0.39 (silica gel; cyclohexane/ethyl acetate =
5:1) Example XV

4-Dibenzylamino-cyclohexanone-ethylene ketal 35 g of 4-benzylamino-cyclohexanone-ethylene ketal and 27.9 ml of N,N-diisopropyl-ethylamine are dissolved in 100 ml of methanol and mixed with 16.6 ml of benzylbromide. The mixture is stirred for 5 hours at ambient temperature, concentrated by evaporation, mixed with water and extracted with ethyl acetate. The ethyl acetate phase is concentrated by evaporation and triturated with a 5:1 mixture of cyclohexane and ethyl acetate. The precipitated product is filtered off, the mother liquor is concentrated and subjected to a column separation (silica gel; cyciohexane/ethyl acetate = 9:1) whereupon a further fraction of the product is obtained.
Yield: 36.1 g (75~ of theory), Rf value: 0.49 (silica gel; cyclohexane/ethyl acetate =
5:1) The following compounds are obtained analogously:

(1) N-benzyl-N-(2-tert.butyloxycarbonylamino-ethyl)-.", ~,.. , ~ .

2 1 2 9 ~ 7 ~:JL

glycine-ethylester The process is carried ou~ in ethanol with ethyl bromoacetate.
Rf value: 0.24 (silica gel; cyclohexane/ethyl acetate =
5: 1) (2) trans-4-N,N-dibenzylamino-cyclohexanol The process is carried out in a 1:1 mixture of water and ethanol with potassium carbonate as a base.
Melting point: 97-99C, Rf value: 0.58 (silica gel; methylene chloride/methanol =
1 9 : 1 ) (3) methyl 1-[2-(1-tert.butyloxycarbonyl-4-piperidinyl)-ethyl]-piperidine-4-carboxylate Rf value: 0.42 (silica gel; methylene chloride/methanol =
9 : 1 ) (4) methyl 1-[2-(1-tert.butyloxycarbonyl-4-piperidinyl)-ethyl]-piperidine-4-carboxylate Rf value: 0.35 (silica gel; methylene chloride/methanol =
9 : 1 ) F.xam~le XVI

4-Benzylamino-cyclohexanone-ethylene ketal A solution of 3.1 g of 1,4-cyclohexane-dione-monoethylene ketal and 22 ml of benzylamine in 500 ml of methanol is treated in the presence of 5 g of Raney nickel at 50C with hydrogen at 5 bar. It is suction filtered from the catalyst, concentrated by evaporation and purified over silica gel (eluant: ethyl acetate/methanol = 20:1 to 10:1) Yield: 35.2 g (72% of theory), Rf value: 0.50 ~silica gel; methylene chloride/methanol =
9 : 1 ) .~,-:. .

~ ' ~ ~2~3~

Exam~le XVII

1-Benzyl-4-[(l-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-piperidine 12.2 g of a 55~ suspension of sodium hydride in oil is added to a solution of 50.3 g of 1-benzyl-4-hydroxy-piperidine in 350 ml of dimethylformamide, the mixture is stirred for 2 hours at ambient temperature, 76.9 g of 1-text.butyloxycarbonyl-4-mesyloxymethyl-piperidine is added and the mixture stirred for 16 hours at ambient temperature. Water is added, the mixture is extracted with ethyl acetate, the ethyl acetate phase is evaporated down and the residue is purified over silica gel (eluant: methylene chloride/methanol = 30:1 to 20:1) Yield: 39.2 g (38% of theory), Rf value: 0.14 (silica gel; methylene chloride/methanol =
15 : 1 ) The ~ollowing compounds are obtained analogously:

(1) methyl 3-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]benzoate Potassium tert.butylate is used.
Rf value: 0.78 (silica gel; methylene chloride/methanol =
15 : 1 ) (2) tert.butyl trans-4-N,N-dibenzylamino-cyclohexyloxy-acetate Tert.butyl bromoacetate in toluene and 50~ sodium hydroxide solution are used while adding tetra-n-butylammonium hydrogen sulphate.
Rf value: 0.48 (silica gel; cyclohexane/ethyl acetate =
4 : 1 ) ~`".

2~9~7~

Example XVI~I

N-(2-Amino-ethyl)-N-benzyl-glycine-ethylester-dihydrochloride 20.1 g of ethyl N-benzyl-N-(2-tert.butyloxycarbonylamino-ethyl)-glycinate is dissolved in 50 ml of ethanol, mixed with 200 ml of ethereal hydrochloric acid and stirred for 16 hours at ambient temperature. The mixture is concentrated by evaporation and the residue is used without further purification.
Yield: 18.3 g (99~ of theory), Rf value: 0.39 (silica gel; methylene chloride/methanol/conc. ammonia = 9:1:0.1) The following compounds are obtained analogously:

(1) 5-amino-1-n-butanesulphonyl-cis-2-methoxycarbonyl-piperidine-hydrochloride Methanol/ethereal hydrochloric acid is used and stirred for 3 hours at ambient temperature.
Rf value: 0.30 (silica gel; methylene chloride/methanol/conc. ammonia = 9:1:0.1) (2) 4-[(1-benzyl-4-piperidinyl)-oxymethyl]-piperidine-dihydrochloride A 2:1:1 mixture of dioxane, methanol and ethereal hydrochloric acid is used.
Rf value: 0.09 (silica gel; methylene chloride/methanol/conc. ammonia = 9:1:0.1) (3) methyl trans-4-[~4-piperidinyl)-carbonylamino]-cyclohexanecarboxylate-trifluoroacetate The process is carried out with trifluoroacetic acid in methylene chloride.
Melting point- 180-181DC (decomp.) Rf value: 0.57 (Reversed Phase Plate RP18; methanol/5%

~ 6~ 9~7~!~
sodium chloride solution a 6: 4 ) (4) methyl trans-4-(piperazinocarbonylamino)-cyclohexanecarboxylate The method is carried out analogously to (3) and the product is used in the next stage without further purification.

E~cam~L~Ix 5-(tert.Butyloxycarbonylamino)-2-methoxycarbonyl-piperidine 8.0 g of 5-(tert.butyloxycarbonylamino)-2-methoxycarbonyl-pyridine is dissolved in 105 ml of glacial acetic acid and treated with hydrogen at 5 bar in the presence of 1.05 g of palladium/rhodium catalyst for 3.5 hours at ambient temperature. It is suction filtered from the catalyst, concentrated by evaporation and the residue is distributed between saturated potassium carbonate solution and ethyl acetate. After treating with activated charcoal, the ethyl acetate phase is concentrated by evaporation.
Yield: 7.74 g (95% of theory), Rf value: 0.18 (silica gel; methylene chloride/methanol -15 : 1 ) The following compound is obtained analogously:

(l) 3-[trans-[4-(acetylaminomethyl)-cyclohexyl]-propionic acid The process is carried out with a platinum/rhodium catalyst in methanol and the remaining product is immediately re-used after being concentrated by evaporation.
Melting point: 91-94C
R~ value: 0.44 (Reversed Phase Plate RP8; methanol/5 .. . .

~%~

sodium chloride solution = 6:4) Example ~

1-(4-Amino-benzoyl)-4-(methoxycarbonylmethyl)-piperidine 12.7 g of 4-(methoxycarbonyl-methyl)-1-(4-nitro-benzoyl)-piperidine is dissolved in 200 ml of methanol and treated with hydrogen at 3 bar in the presence of 1.5 y of Raney nickel at 50C for 4 hours. It is suction filtered from the catalyst and evaporated down.
Yield: 11.7 g (100% of theory), Rf value: 0.34 (silica gel; methylene chloride/methanol =
15:1 Example X~I

Methyl trans-4-(4-benzyloxybenzoyl-amino)-cyclohexane carboxylate Prepared from 4-benzyloxy-benzoic acid and methyl trans-4-amino-cyclohexanecarboxylate analogously to Example 7(2).
Melting point: 194-196C, Rf value: 0.55 (silica gel; methylene chloride/methanol =
15:1) Exam~e XXII

Ethyl 4-(2-amino-ethyloxy)-benzoate-hydrochloride 26.8 g of methyl 4-(cyanomethyloxy)-benzoate is dissolved in 250 ml of ethanol, mixed with 30 ml of ethereal hydrochloric acid and treated with hydrogen at 4 bar in the presence of 2.5 g of 10% palladium/charcoal at ambient temperature. The mixture is heated to 70C, , "., ~

., .~: ~ .
,.,.;t ` `

2129~7~

suction filtered from the catalyst, cooled with ice water and the crystals filtered off. A further fraction is obtained by evaporating the filtrate down and treating the residue with ethanol/ether.
Yield: 26.2 g (81% of theory), Melting point: 205-208C
Rf value: 0.61 (silica gel;
- toluene/dioxane/methanol/conc. ammonia =
2:5:2:1) The following compound is obtained analogously:

(1) methyl 4-(3-aminopropyl)-benzoate-hydrochloride The process is carried out in methanolic hydrochloric acid.
Melting point: above 210C
Rf value: 0.60 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4 Example XXIII

Ethyl 4-~trans-2-(4-pyridyl)-ethenyl]-benzoate A mixture of 3 g of ethyl 4-iodobenzoate, 1.87 g of 4-vinyl-pyridine, 3.34 g of triethylamine, 0.04 g of palladium acetate and 0.21 g of tri-o-tolyl-phosphine are stirred under nitrogen for 4 hours at 100C. The mixture is taken up in methylene chloride, washed with water and the organic phase is concentrated by evaporation. The residue is purified over silica gel (eluant: methylene chloride/methanol = 50:1).
Yield: 1.45 g (52% of theory), Melting point: 74-76~C (~ther/petroleum ether) Rf value: 0.74 (silica gel; methylene chloride/methanol =
g : 1 ) ~1~937~

Example ~IV
l-tert.Butyloxycarbonyl-4-(2-iodo-ethyl)-piperidine -12.2 g of iodine is added to a solution of 10 g of 1-tert.butyloxycarbonyl-4-(2-hydroxy-ethyl)-piperidine, 12.5 g of triphenylphosphine and 4.5 g of imidazole and stirred for an hour at ambient temperature. The precipitate is suction filtered and washed with toluene.
The combined filtrates are concentrated by evaporation and boiled up with 250 ml of petroleum ether. After cooling, the precipitated triphenylphosphineoxide is suction filtered and the filtrate is evaporated to dryness.
Yield: 13 g (88% of theory), Rf value: 0.79 (silica gel; cyclohexane/ethyl acetate =
1 : 1 ) Exam~le X~V

Ethyl 4-[(4-benzyl-piperazino)-carbonylamino]-benzoate 10.6 g of 4-ethoxycarbonyl-phenylisocyanate is dissolved in 150 ml of dioxane and mixed dropwise with a solution of 10.1 ml of benzylpiperazine in 50 ml of dioxane at 10C. The mixture is stirred for 30 minutes at ambient temperature, concentrated by evaporation and the residue is triturated with ether.
Yield: 19.0 g (93% of theory), Rf value: 0.41 (silica gel; methylene chloride/methancl/conc. amm~nia = 9:1:0.1) i . , . . .. i . .... .

1r.. :. ' - - . .

212937~

E~am~le XXVI

Methyl 3-[4-(4-cyanomethyl-benzoylamino)-phenyl]-propionate 21.6 g of methyl 3-[4-(4-chloromethyl-benzoylamino)-phenyl]-propionate are added in batches to a mixture, stirred at 60C, of 3.5 g of sodium cyanide and 65.5 ml of dimethylsulphoxide. The mixture is stirred for 4 hours at 60C, it is left to stand overnight at ambient temperature, mixed with water, extracted with ethyl acetate and methylene chloride, the combined organic phases are washed with saturated sodium chloride solution and concentrated by e~aporation. The residue is recrystallised from isopropanol.
Yield: 21.5 g (83% of theory), Melting point: 144-146C
Rf value: 0.44 (silica gel; methylene chloride/ethyl acetate = 9:1) Exam~le ~XVII

l-[(l-Benzyl-4-piperidinyl)-aminocarbonyl]-piperidine-4-carboxylic acid-hydrochloride Prepared from ethyl l-[(l-benzyl-4-piperidinyl)-aminocarbonyl]-piperidine-4-carboxylate analogously to Example 3(1).
Rf value: 0.44 (silica gel; methylene chloride/methanol =
4 : 1 ) Example_X~VIII

Ethyl 1-[(1-benzyl-4-piperidinyl)-aminocarbonyl]-piperidine-4-carboxylate Prepared analogously to Example 8 from 4-amino-1-benzyl-:.,,., ~
. . .

- 69 2 ~
piperidine and ethyl piperidine-4-carboxylate.
Rf value: 0.33 (silica gel; methylene chloride/methanol =
9 : 1 ) -Exam~le XxIX

Methyl trans-4-[(1-tert.butyloxycarbonyl-4-piperazinyl)-carbonylamino]-cyclohexane-carboxylate Prepared analogously to Example 24 from N-tert.butyloxycarbonyl-piperazine and methyl trans-4-amino-cycloh~xane-carboxylate-hydrochloride with triethylamine as a base.
Melting point: 203-205C (decomp.) Rf value: 0.41 (silica gel; methylene chloride/methanol =
19 : 1 ) Exam~ xX~

Methyl 3-[trans-4-(aminomethyl)-cyclohexyl]-propionate-hydrochloride ._ A solution of 3.6 g of 3-[trans-4-(aminomethyl)-cyclohexyl]-propionic acid-hydrochloride in 20 ml of methanol is mixed dropwise with 1.3 ml of thionylchloride and stirred for 3 hours while slightly heating. The mixture is concentrated by evaporation and stirred with a~etone.
Yield: 3.1 g (82% of theory), Melting point: 196-200C
Rf value: 0.67 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) ;~.*.~

21~37~

Exam~le XXXI

3-[trans-4-(Aminomethyl)-cyclohexyl]-propionic acid-hydrochloride .
19.4 g of 3-[trans-[4-(acetylaminomethyl)-cyclohexyl]-propionic acid is heated with 300 ml of half-concentrated hydrochloric acid for 16 hours under reflux. The mixture is concentrated by evaporation, concentrated again twice from toluene and the resultant residue is recrystallised from toluene.
Yield: 3.7 g (20~ of theory), Rf value: 0.78 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) E~ample XXXII

Methyl 4-(3-tert.Butyloxycarbonylamino-propyl)-benzoate . _ _ . . .
A solution of 2.31 g of pyrocarbonic acid di-tert.butylester in 20 ml of tetrahydrofuran and 5 ml of 2N sodium hydroxide solution are added dropwise to a suspension of 2.21 g of methyl 4-(3-aminopropyl)-benzoate-hydrochloride in 20 ml of tetrahydrofuran. The mixture is stirred for 16 hours at ambient temperature, washed with sodium chloride solution and the organic phase is evaporated down.
Yield: 2.83 g (100~ of theory), Melting point: 50-54C
Rf value: 0.75 (silica gel; cyclohexane/ethyl acetate =
1 : 1 ) -, ", ~ - ~ . - -."

- 71 - 212~7~
E~

trans-4-[3-[2-(4-Quinuclidinyl)-ethyl]-ben~oylamino]-cyclohexane-carboxylic acid . . ~
0.2 g of methyl trans-4-[3-[2-(4-quinuclidinyl)-ethyl]-benzoylamino]-cyclohexanoate is dissolved in 5 ml of tetrahydrofuran and 1 ml of water, mixed with 1 ml of 2N
sodium hydroxide solution and stirred for 3 hours at ambient temperature. 0.12 g of ammonium chloride, dissolved in 1 ml of water, is added and the mixture is concentrated until crystallisation starts. It is cooled in an ice bath, the precipitate formed is filtered off and washed with a little water and acetone.
Yield: 1.63 g (92 % of theory), Melting point: above 250C
Rf value: 0.44 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Calc. x 0.25 HCl: C 70.18 H 8.26 N 7.12 Cl 2.25 Found : 69.89 8.44 6.97 2.24 The following compounds are obtained analogously:

(1) 4-carboxymethyl-1-[4-[2-(4-quinuclidinyl)-ethyl]-ben~oyl]-piperidine Melting point: above 250C
Rf value: 0.50 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Calc. x 0.5 H2O: C 70.20 H 8.45 N 7.12 Found : 69.98 8.32 7.10 (2) trans-4-[4-[2-(4-quinuclidinyl)-ethyl]-benzoylamino]-cyclohexane carboxylic acid Melting point: above 250C
Rf value: 0.51 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Calc. x 0.7 H2O: C 69.56 H 8.48 N 7.05 ,............ - ~ :
t,, ~

- 72 - ~ ~2~7~
Found : 69.37 8.60 7.09 (3) 4-carboxymethyl-l-[4-[(4-quinuclidinyl)-methyloxy]-benzoyl]-piperidine The sodium hydroxide basified solution is set to pH 7 using hydrochloric acid and evaporated down. The residue is mixed with methanol, the methanolic solution is evaporated down and the remaining residue is treated in the same way. The residue remaining is stirred for minutes with isopropanol at 50C whereupon the crystalline product remains.
Melting point: 293-300C
Rf value: 0.63 (Reversed Phase Plate RP8;
methanol/5~ sodium chloride solution = 6:4) (4) trans-4-[4-[N-benzyloxycarbonyl-N-[(4-piperidinyl)-methyl]-amino]-benzoylamino]-cyclohexane-carboxylic acid Lithium hydroxide in a tetrahydrofuran/water mixture is used.
Melting point: 202-205C (decomp.) Rf value- 0.18 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 9:1) (5) 1-[[1-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-carbonyl]-4-piperidinyl]-carbonyl]-4-carboxymethyl-piperidine The method used is analogous to (4).
Melting point: 174C, sintering from 154c R~ value: 0.35 (silica gel; methylene chloride/ethanol = 9:1) (6) l-[[[1-[(l-tert.bu~yloxycarbonyl-4-piperidinyl~-carbonyl]-4-piperidinyl]-methyl]-carbonyl]-4-carboxymethyl-piperidine The method used is analogous to (4).
The compound is used without isolation in Example 4(9).

... .. .. .. ..

,, . . ~ .

:

2~2937l~

(7~ N-[1-carboxy-cis-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexyl]-n-butanesulphonamide lN sodium hydroxide solution is used.
Melting point: 228C (decomp.) R~ value: 0.40 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (8) N-[l-carboxy-cis-4-[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-cyclohexyl]-acetamide The method used is as under (7).
Melting point: 264C (decomp.) Rf value: 0.10 (silica gel; methylene chloride/methanol/conc. ammonia =
2:1:0.25) (9) 1-carboxy-cis-4-[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-cyclohexylamine The method used is as under (7).
Melting point: 90C (decomp.) Rf value: 0.08 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (10) N-hydroxyacetyl-N-[2-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycine The method used is as under (7).
Melting point: 148C (decomp.) Rf value: 0.22 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (11) N-benzyloxyacetyl-N-[2-[[4-[(4-piperidinyl~-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycine The method used is as under (7).
Rf value: 0.40 (silica gel; methylene .

2~93~a~

chloride/methanol/conc. ammonia = 2:1:0.25) (12) N-(aminocarbonyl-methyl)-N-[2-[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-ethyl]-glycine The method used is as under (7).
Rf value: 0.18 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (13) N-[2-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycine The method used is as under (7).
Melting point: 168C (decomp.) Rf value: 0.15 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (14) N-carboxymethyl-N-[2-[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-ethyl]-glycine The method used is as under (7).
Melting point: 202OC (decomp.) Rf value: 0.06 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (15) 4-carboxymethyl-1-[[4-[(4-piperidinyl)-carbonylamino]-benzoyl]-piperidine The method used is as under (7).
Melting point: 291C (decomp.) Rf value: 0.16 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (16) N-n-butanesulphonyl-N-[2-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycine j A 1:1 mixture of tetrahydrofuran and lN sodium hydroxide 2~2~37~

solution is used.
Melting point: 193C (decomp.) Rf value: 0.45 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (17) trans-4-[3-[[(4-piperidinyl)-methyl]-amino]-benzoylamino]-cyclohexane carboxylic acid-hydrochloride The method used is analogous to (4).
Rf value: 0.49 (Reversed Phase Plate RP18; methanol/5 sodium chloride solution = 6:4) ..
~18) trans-4-[4-[(1-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(19) trans-4-[[4-[(1-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(20) trans-4-[~4-[(l-methoxycarbonyl-4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(21) trans-4-[4-[(4-quinuclidinyl)-methylsulphenyl]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(22) trans-4-[4-[(4-piperidinyl)-sulphenylmethyl]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(23) trans-4-[4-[(4-piperidinyl)-sulphinylmethyl]-benzoylamino~-cyclohexane carboxylic acid The method used is analogous to (4).

~ ~ , -. ,. ~ . .

`` 21~937~

(24) trans-4-[4-[(4-piperidinyl)-sulphonylmethyl]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (~).

(25) trans-4-[4-[(4-quinuclidinyl)-methyloxy]-3-chlorobenzoylamino~-cyclohexane carboxylic acid The method used is analogous to (4).

(26) trans-4-[[4-~2-(4-piperidinyl)-ethyl]-phenyl]-aminocarbonyl]-cyclohexane carboxylic acid The method used is analogous to (4).
Melting point: 306-308C (decomp.) Rf value: 0.18 (Reversed Phase Plate RP18; methanol/5 sodium chloride solution = 6:4) (27) trans-4-[[1-[2-(4-piperidinyl)-ethyl]-4-piperidinyl~-aminocarbonyl]-cyclohexane carboxylic acid The method used is analogous to (4).

(28) trans-4-~[4-[2-(4-quinuclidinyl)-ethyl]-phenyl]-aminocarbonyl]-cyclohexane carboxylic acid The method used is analogous to (4).

(29) trans-4-[4-[2-(4-piperidinyl)-ethenyl]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(30) trans-4-~[4-(1-piperazino-2-propyl)-phenyl]-aminocarbonyl]-cyclohexane carboxylic acid The method used is analogous to (4).

(31) trans-4-[4-(2-piperazino-ethyl)-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(32) trans-4-[[l-[2-(4-piperidinyl)-ethyl]-4-piperazinyl]-carbonylamino]-cyclohexane carboxylic acid ~129~7 ll The method used is analogous to (4).

(33) 1-carboxymethyl-4-[4-[2~(4-quinuclidinyl)-ethyl]-benzoyl]-piperazine The method.used is analogous to (4).

(34) trans-4-~4-[(4-quinuclidinyl)-methyloxy]-3-fluorobenzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(35) trans-4-[3-bromo-4-[(4-quinuclidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(36) trans-4-[4-[(4-quinuclidinyl)-methyloxy]-3-methyl-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(37) trans-4-[4-[(4-~uinuclidinyl)-methyloxy]-3-methoxybenzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(38) trans-4-[4-[(4-quinuclidinyl)-methyloxy]-3-methylsulphenyl-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(39) trans-4-[3-methylsulphinyl-4-[(4-piperidinyl)-methyloxy]benzoylamino~-cyclohexane carboxylic acid The method used is analogous to (4).

(40) trans-4-[3-chloro-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(41) trans-4-~3-fluoro-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid , ;, .

212937f~

The method used is analogous to (4).

(42) trans-4-[3-bromo-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(43) trans-4-[3-methyl-4-[(4-piperidinyl)-methyloxyJ-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(44) trans-4-[3-methoxy-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(45~ trans-4-[3-methylsulphenyl-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(46) trans-4-[3-methylsulphonyl-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(47) trans-4-[[4-[(4-piperidinyl)-methyloxy]-phenyl]-aminocarbonyl]-cyclohexane carboxylic acid The method used is analogous to (4).

(48~ trans-4-[4-[(4-piperidinyl)-methylsulphenyl]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(49) trans-4-[4-[(4-piperidinyl)-methylsulphinyl]-benzoylamino]-cyclohexane carboxylic acid The method used is analogous to (4).

(50) trans-4-[4-[(4-piperidinyl)-methylsulphonyl~-benæoylamino]-cyclohexane carboxylic acid The method used is analogous to ~4).

2~2~7~

(51) 4-carboxymethyl-1-[4-(piperazino-carbonylamino)-benzoyl]-piperidine Rf value: 0.09 (silica gel; methylene chloride/methanol/conc. ammonia -= 2:1:0.25) (52) 1-[4-l(4-benzyl-piperidino)-carbonylamino]-benzoyl]-4-carboxymethyl-piperidine Rf value: 0.24 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.25) (53) 3-[3-[~-(2-amino-ethyl)-benzoylamino]-phenyl]-propionic acid Melting point: above 250C
Rf value: 0.57 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) Calc.: C 69.21 H 6.45 N 8.97 Found: 68.95 6.76 8.66 (54) 3-[4-[3-(2-amino-ethyl)-benzoylamino]-phenyl]-propionic acid Melting point: from 250C (decomp.) Rf value: 0.60 (Reversed Phase Plate RP8; methanol/5%
` sodium chloride solution = 6:4) Calc. x 1 H2O : C 65.44 H 6.71 N 8.88 Found : 64.91 6.60 8.42 (55) 3-[4-(4-aminomethyl-benzoylamino)-phenyl]-propionic acid Melting point: above 250C
Calc.: C 68.44 H 6.08 N 9.39 Found: 69.10 6.19 9.56 i56) trans-1-L~-L(cis-2-amino-cyclopentyl)-oxy7-benzoyl-amino7-4-(2-carboxy-ethyl)-cyclohexane-hydrochloride The ester is saponified with 3N hydrochloric acid Me1ting point: 224-226C

- 80 - 212937~

(57) trans-1-L4 -~ trans-2-amino-cyclop~ntyl)-oxY7-benzoyl-amino~7-4-(2-carboxy-ethyl)-cyclohexane-hydrochloride The ester is saponified with 3N hydrochlorid acid.
Melting point: 219-221C
(58) 3-[4-(4-cyanomethyl-benæoylamino) phenyl]-propionic acid The process is carried out with sodium hydroxide solution in dioxane.
Melting point: 220-223C
Rf value: 0.31 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) (S9) 5-[[4-[2-(4-piperidinyl)-ethyl]-phenyl]-aminocarbonyl]-valeric acid-hydrochloride The method used is analogous to (4).
Melting point: 232-235C
Rf value: 0.21 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (60) 3-[[[4-[2-(4-piperidinyl)-ethyl]-phenyl]-aminocarbonyl]amino]-propionic acid-hydrochloride The method used is analogous to (4).
Melting point: 182-184C (decomp.) Rf value: 0.49 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) ;
: : :
Methyl trans-4-[3-[2-(4-quinuclidinyl)-ethyl]-benzoylamino]-cyclohexane carboxylate-hydrochloride 0.35 g of 3-[2-(4-quinuclidinyl)-ethyl]-ben20ic acid-hydrochloride is heated to 80C for 6 hours in 5 ml of thionylchloride. The mixture is left to stand for 16 hours at ambient temperature, excess thionylchloride is removed in vacuo, toluene is added and the mixture is again concentrated by evaporation. The concentrated `
21293~1 ~

residue is suspended, together with 0.35 g of methyl trans-4-amino-cyclohexanecarboxylate, in 5 ml o~
acetonitrile. 1 g o~ triethylamine, dissolved in 1 ml of acetonitrile, is added dropwise whilst stirring at ambient temperature and the mixture is stirred for another 3 hours. It is concentrated by evaporation, the residue is taken up with ice water and extracted at first twice with ethyl acetate and then several times with chloroform. The combined organic phases are concentrated by evaporation and the residue is stirred with acetone and the resultant solid product is filtered off.
Yield: 0.22 g (36% of theory), Melting point: 240-244C
Rf value: 0.39 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) The following compounds are obtained analogously:

(1) 1-[4-[2-(4-quinuclidinyl)-ethyl]-benzoyl]-4-(methoxycarbonyl-methyl)-piperidine-hydrochloride Melting point: 220-222C
Rf value: 0.39 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Calc.: C 66.27 H 8.11 N 6.44 Cl 8.15 -Found: 66.00 8.08 6.50 8.33 (2) methyl trans-4-[4-[2-(4-quinuclidinyl)-ethyl]-benzoylamino]-cyclohexane carboxylic acid-hydrochloride Melting point: above 250C
Rf value: 0.37 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Calc. x 0.5 H2O: C 64.92 H 8.17 N 6.31 Cl 7.98 Found : 64.51 8.13 6.44 7.66 (3) methyl trans-4-[4-[(4-quinuclidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylate-hydrochloride %~29~

The process is carried out in pyridine.
Melting point: 175-180C
Rf value: 0.37 ~Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:~) ~

~ [4-~(4-quinuclidinyl)-methyloxy]-benzoyl]-4-(methoxycarbonyl-methyl)-piperidine-hydrochloride The process is carried out in pyridine.
The product is further processed without purification.
Rf value: 0.40 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) (5) ethyl N-benzyloxyacetyl-N-[2-[[4-[(1-tert~butyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycinate The process is carried out in methylene chloride with N,N-diisopropyl-ethylamine.
Rf YalUe: 0.71 (silica gel; m thylene chloride/methanol/conc. ammonia = 9:1:0.1) (6) 4-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonyl]-butyric acid The acylation is carried out with glutaric acid anhydride.
Rf value: 0.2~ (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.25) (7) ethyl N-n-butanesulphonyl-N-[2-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycinate The sulphonylation is carried out with n-butanesulphonylchloride in methylene chloride with N,N-diisopropyl-ethylamine as base.
Rf value: 0.74 (silica gel; methylene chloride/methanol/conc. ammonia ~12~3~

= 9:1:0.1) (8) methyl trans-4-[4-[(4-quinuclidinyl)-methylsulphenyl]-benzoylamino]-cyclohexane carboxylate (9) methyl trans-4-[4-[(4-quinuclidinyl)-methyloxy]-3-chloro-benzoylamino]-cyclohexane carboxylate (10) methyl trans-4-[4-[(4-quinuclidinyl)-methyloxy]-3-methylsulphenyl-benzoylamino]-cyclohexane carboxylate (11) methyl trans-4-[4-[~4-quinuclidinyl~-methyloxy]-3-fluoro-benzoylamino]-cyclohexane carboxylate (12) methyl trans-4-[3-bromo-4-[(4-quinuclidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylate (13) methyl trans-4-[4-[(4-quinuclidinyl)-methyloxy]-3-methyl-benzoylamino]-cyclohexane carboxylate (14) methyl trans-4-[4-[(4-quinuclidinyl)-methyloxy3-3-methoxy-benzoylamino]-cyclohexane carboxylate (15) methyl trans-4-[[4-[2-(4-quinuclidinyl)-ethyl]-phenyl]-aminocarbonyl]-cyclohexane carboxylate (16) 1-[4-[2-(4-quinuclidinyl)-ethyl]-benzoyl]-4--(methoxycarbonyl-methyl)-piperazine (17) methyl 3-[4-(4-cyano-benzoylamino)-phenyl]-propionate The process is carried out in tetrahydrofuran.
Melting point: 142-144C
Rf value: 0.60 (silica gel; cyclohexane/ethyl acetate = 1:1) (18) ethyl trans-4-[[4-[2-(4-pyridyl)-ethyl]-phenyl]-%i29~7~

aminocarbonyl]cyclohexane carboxylate The process i9 carried out analogously to (5) in tetrahydrofuran.
Melting point: 164-165C
Rf value: 0.65 (silica gel; methylene chloride/methanol = 9:1) (19) methyl 5-[[4-[2-(4-pyridyl)-ethyl]-phenyl]-aminocarbonyl]-valeriate The method used is analogous to (18).
Melting point: 110-112C
Rf value: 0.64 (silica gel; methylene chloride/methanol = 9:1) E~m~le 3 trans-4-[4-[(Quinuclidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylic acid-hydrochloride 0.5 g of methyl trans-4-[4-[(4-quinuclidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate is dissolved in 5 ml of glacial acetic acid and mixed with 5 ml of water and 5 ml of concentrated hydrochloric acid whilst cooling. The mixture is stirred for 16 hours at ambient temperature and concentrated by evaporation ln vacuo.
Yield: 0.52 g (99~ of theory), Melting point: above 200C
R~ value: 0.52 ~Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) The following compounds are obtained analogously:

(1) 4-carboxymethyl-1-[trans-4-[[(4-piperidinyl~-methyl]-carbonylamino]-cyclohexylcarbonyl]-piperidine-hydrochloride Saponification is effected ~ith 6N of hydrochloric acid .:` :.: ' : :`: . . :' : . ` ` ` ,, 12937~

at ambient temperature.
Rf value: 0.44 (Reversed Phase Plate RP18; methanol/5 sodium chloride solution = 6:4) (2) trans-4-~[[1-[[~4-piperidinyl)-methyl]-carbonyl]-4-piperidinyl]-methyl]-carbonylamino]-cyclohexane carboxylic acid-hydrochloride The method used is analogous to (1).
Rf value: 0.47 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (3) 4-(2-carboxy-ethyl)-1-[trans-4-[(4-piperidinyl)-carbonylamino]-cyclohexylcarbonyl]-piperidine-hydrochloride From l-[trans-4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-cyclohexylcarbonyl]-4-(2-methoxycarbonyl-ethyl)-piperidine.
The method used is analogous to (1).
Melting point: 254-256C (decomp.) Rf value: 0.~4 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (4) trans-4-[4-[(4-piperidinyl)-aminocarbonyl]-benzoylamino]-cyclohexane carboxylic acid-hydrochloride Melting point: above 300C
Rf-value: 0.49 (Reversed Phase Plate RP18; Methanol/5%
sodium chloride solution = 6:4) ~5) trans-4-[4-[(1-benzyl-4-piperidinyl)-aminocarbonyl]-benzoylamino]-cyclohexane carboxylic acid-hydrochloride Melting point: 287-289C
RE value: 0.30 (Reversed Phase Plate RP18;
methanol/5~ sodium chloride solution = 6:4) (6) 4-carboxymethyl-1-[trans-4-[(4-piperidinyl)-carbonylamino]-cyclohexylcarbonyl]-piperidine-212937 !~

hydrochloride The preparation is carried out according to the method described under (3).
Melting point: 139-142C (decomp.) R~ value: 0.52 (Reversed Phase Plate RP18;
methanol/5~ sodium chloride solution = 6:4) (7) 4-(2-carboxy-ethyl)-1-[4-f[(4-piperidinyl)-methyl]-amino]-benzoyl]-piperidine-hydrochloride The method is analogous to (1).
Melting point: 178-181C (decomp.) Rf value: 0.39 (Reversed Phase Plate RPl8;
methanol/5% sodium chloride solution = 6:4) (8) 4-carboxymethyl-1-[4-[[(4-piperidinyl)-methyl]-amino]-benzoyl]-piperidine-hydrochloride The method used is analogous to (1).
Melting point: 152-156C
Rf value: 0.47 (Reversed Phase ~late RP18;
methanol/5~ sodium chloride solution = 6:4) (9) trans-4-[4-[(4-piperidinyl)-carbonylamino]-benzoylamino]-cyclohexane carboxylic acid-hydrochloride The method used is analogous to (1).
Melting point: above 300C
Rf value: 0.55 (Reversed Phase Plate RP18;
methanol/5~ sodium chloride solution = 6:4) (10) N-benzyl-N-[2-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycine-dihydrochloride The method used is analogous to (1).
Melting point: 158C (decomp.) 212~7~

f value: 0.48 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (11) 1-n-butanesulphonyl-2-carboxy-cis-5-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino~-piperidine-hydrochloride The method used is analogous to (1) at 50C.
Rf value: 0.45 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (12) 4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-butyric acid The method used is analogous to (1).
Melting point: 190-193C
Rf value: 0.67 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.2~) (13) 5-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonyl~-valeric acid-hydrochloride The method used is analogous to (1).
Melting point: 143-145C
Rf value: 0.22 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.25) (14) 3-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-propionic acid-hydrochloride Melting point: 199C (decomp.) Rf value: 0.25 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (15) trans-4-[3-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid-hydrochloride - 88 - 2~2937~
The method used is analogous to (1).
Melting point: 282C (decomp.) Rf value: 0.16 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.25) (16) trans-4-[[4-[(4-piperidinyl)-oxymethyl]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid-hydrochloride The method used is analogous to (1).
Melting point: 227C (decomp.) ¦ Rf value: 0.09 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.25) (17) trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid The method used is analogous to (1).
Melting point: 260C (decomp.) Rf value: 0.23 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (18) trans-4-[[4-[(1-benzyl-4-piperidinyl)-oxymethyl]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid-hydrochloride The method used is analogous to (1).
Rf value: 0.33 (silica gel; methylene chloride/methanol/
`~3 conc. ammonia = 4:1:0.25) ~' (19) 3-[3-[(trans-4-amino-cyclohexyl)-carbonylamino~-benzoylamino]-propionic acid-hydrochloride The method used is analogou~ to (1).
Melting point: 203C (decomp.) Rf value: ~.27 -(silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) , .. ~

212937~
(20) 4-[3-[(trans-4-amino-cyclohexyl)-carbonylamino]-benzoylamino]-butyric acid-hydrochloride The method used is analogous to (1).
Melting point: 201C (decomp.) Rf value: 0.27 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (21) 3-[4-[(trans-4-amino-cyclohexyl)-carbonylamino]-benzoylamino]-propionic acid-hydrochloride It is stirred for 4 hours at 50C.
Melting point: above 315C
R~ value: 0.22 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (22) 4-[4-[(trans-4-amino-cyclohexyl)-carbonylamino]-benzoylamino]-butyric acid-hydrochloride The method used is analogous to (1).
Melting point: 259C (decomp.) Rf value: 0.19 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (23) trans-4-[4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid-hydrochloride The preparation is carried out according to the method described under (3).
Melting point: 295-300C
Rf value: 0.18 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.25) (24) 3-[trans-4-[(2-aminomethyl-1,2,3,4-tetrahydro-6-naphthyl)-carbonylamino]-cyclohexyl]-propionic acid-hydrochloride Melting point: above 250C

2 ~ 2 ~7 f value: 0.38 (Reversed Phase Plate RP8;
methanol/5% sodium chloride solution = 6:4) (25) [trans-4-[(2-aminomethyl-1,2,3,4-tetrahydro-6-naphthyl)-carbonylamino]-cyclohexyloxy]-acetic acid-hydrochloride Melting point: 220-225C (sintering starts from 203C) R~ value: 0.59 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) (26) 4-carboxymethyl-1-[3-[[t4-piperidinyl)-methyl]-amino]-benzoyl]-piperidine-hydrochloride Rf value: 0.50 (Reversed Phase Plate RP18;
methanol/5% sodium chloride solution = 6:4) (27) 4-carboxymethyl-1-[4-[2-(4-piperidinyl)-ethyl]-benzoyl]-piperidine-hydrochloride The method used is analogous to (1).
Melting point: 158-160C (decomp.) Rf value: 0.45 (Reversed Phase Plate RP18;
methanol/5~ sodium chloride solution = 6:4) (28) trans-4-[2-(4-piperidinyl)-ethyl]-benzoylamino]-cyclohexane carboxylic acid-hydrochloride The method used is analogous to (1).
Melting point: 291-293C (decomp.) Rf value: 0.54 (Reversed Phase Plate RP18;
methanol/5% sodium chloride solution = 6:4) (29) 4-carboxymethyl-1-[4-[2-(4-pyridyl)-ethyl]-benzoyl]-piperidine-hydrochloride The method used is analogous to (1).
Melting point: 209-211C (decomp.) - 91 - 2i2937'~
f value: 0.54 (Reversed Phase Plate RP18;
methanol/5% sodium chloride solution = 6:4) (30) trans-4-[4-[2-(4-pyridyl)-ethyll-benzoylamino]-cyclohexane-carboxylic acid-hydrochloride The method used is analogous to (1).
Melting point: 306-308C (decomp.) Rf value: 0.47 (Reversed Phase Plate RP18;
methanol/5% sodium chloride solution = 6:4) (31) 4-carboxymethyl-1-[[1-[2-~4-piperidinyl)-ethyl]-4-piperidinyl]-carbonyl]-piperidine-dihydrochloride The method used is analogous to (1).
Melting point: 229-231C (decomp.) Rf value: 0.28 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (32) trans-1-[4-(2-amino-ethyl)-benzoylamino]-4-(2-carboxyethyl)-cyclohexane-hydrochloride It is heated on a steam bath with 2N hydrochloric acid.
Melting point: above 250C
Rf value: 0.63 (Reversed Phase Plate RP8;
methanol/5% sodium chloride solution = 6:4) Calc. x 0.7 H2O: C 58.83 H 7.79 N 7.62 Cl 9.74 Found : 59.00 7.75 7.57 9.27 (33) trans-4-[[1-[(4-piperidinyl)-carbonyl]-4-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid-hydrochloride The method used is analogous to (1).
Melting point: 299-301C (decomp.) Rf value: 0.70 (Reversed Phase Plate RP18;
methanol/5% sodium chloride solution = 6:4) ~2~7~

(34~ trans-4-[[1-[(4-piperidinyl)-aminocarbonyl]-4-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid-hydrochloride The method used is analogous to (1).
Melting point: 190-193C

(35) trans-4-[[1-[2-(4-piperidinyl~-ethyl]-4-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid The method used is analogous to (1).
Melting point: above 300C
Rf value: 0.09 (silica gel; methylene chloride/methanol/conc.
ammonia = 4:1:0.2) (36) trans-4-~[4-[2-(4-piperidinyl)-ethyl]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid (37) trans-4-[[1-[2-(4-piperidinyl)-ethyl]-4-piperazinyl]carbonylamino]-cyclohexane carboxylic acid dihydrochloride The method used is analogous to (1).
Melting point: above 300C
Rf value: 0.78 (Reversed Phase Plate RP18; methanol/5%
- sodium chloride solution = 6:4) (38) 3-[trans-4-[[4-(2-aminoethyl)-benzoylamino]-methyl]-cyclohexyl]-propionic acid-hydrochloride Melting point: 238-240C
Rf value: 0.49 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) (39) 3-[trans-4-[4-(3-aminopropyl)-benzoylamino]-cyclohexyl]-propionic acid The method used is analogous to (3) using a 1:1 mixture of 3N hydrochloric acid and glacial acetic acid.
Melting point: above 250C
Rf value: 0.57 (Reversed Phase Plate RP8; methanol/5%

';'' ~

:,., ,., ~,,, : ' :

" ~2937~

sodium chloride solution = 6:4) Exam~le 4 Methyl trans-4-[~[1-[[(4-piperidinyl)-methyl]-carbonyl]-4-piperidinyl]-methyl]-carbonylamino]-cyclohexane-carboxylic acid-hydrochloride 1.2 g of methyl trans-4-[[[1-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-carbonyl]-4-piperidinyl]-methyl]-carbonylamino]-cyclohexane-carboxylate is stirred in a mixture of 30 ml of methylene chloride and 15 ml of trifluoroacetic acid for 2 hours at ambient temperature.
The mixture is evaporated down, dissolved in methanol, mixed with ethereal hydrochloric acid and evaporated down whereupon the product is obtained as a foam.
Yield: 1.14 g (100% of theory), Rf value: 0.32 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) The following compounds are obtained analogously:

~1) 4-(methoxycarbonyl-methyl)-1-[trans-4-[[(4-piperidinyl)-methyl]-carbonylamino]-cyclohexylcarbonyl]-piperidine-hydrochloride Rf value: 0.28 (Revers~d Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (2) 4-(2-methoxycarbonyl-ethyl)-1-[trans-4-[(4-piperidinyl)-carbonylamino]-cyclohexylcarbonyl]-piperidine-trifluoroacetate Melting point: 188-190C (decomp.) Rf value: 0.50 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (3) 4-(methoxycarbonyl-methyl)-1-[trans-4-[(4-piperidinyl)-carbonylamino]-cyclohexylcarbonyl]-212937ll piperidine-trifluoroacetate Melting point: 194-197C (decomp.) Rf value: 0.55 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (4) 4-(2-methoxycarbonyl-ethyl)-1-[4-[[(4-piperidinyl)-methyl]-amino]-benzoyl]-piperidine-hydrochloride Melting point: 194-197C (decomp.) Rf value: 0.21 (silica gel; methylene chloride/methanol = 9:1) (5) 4-(methoxycarbonyl-methyl)-1-[4-[[(4-piperidinyl)-methyl]-amino]-benzoyl]-piperidine-hydrochloride Melting point: 165-175C (decomp.) Rf ~alue: 0.15 (silica gel; methylene chloride/methanol = 9:1) (6) methyl trans-4-[4-[N-benzyloxycarbonyl-N-[(4-piperidinyl)-methyl]-amino]-benzoylamino3-cyclohexane-carboxylate-hydrochloride Melting point: 188-190C (decomp.) Rf value: 0.38 (silica gel; methylene chloride/methanol = 9:1) (7) methyl trans-4-[4-[(4-piperidinyl)-carbonylamino]-benæoylamino]-cyclohexane-carboxylate-trifluoroacetate Melting point: 240-241C (decomp.) Rf value: 0.40 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (8) 4-carboxymethyl-1-[[1-[[(4-piperidinyl)-methyl]-carbonyl]-4-piperidinyl]-carbonyl]-piperidine-hydrochloride A mixture of dioxane and ethereal hydrochloric acid ~3:1) is used.
Mel~ing point: 174C (decomp., sintering starts at 154C) . : : :

~12~37~

R~ value: 0.10 (silica geli methylene chloride/methanol = 4:1) (9) 4-carboxymethyl-1-[[[1-[(4-piperidinyl)-carbonyl]-4-piperidinyl]-methyl]-carbonyl]-piperidine-hydrochloride The method used is as under (8).
Melting point: 180-184C (sintering starts at 160C) R value: 0.10 (silica gel; methylene chloride/ethanol = 9:1) (lo) N-~1-methoxycarbonyl-cis-4-[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-cyclohexyl]-n-butanesulphonamide-hydrochloride A mixture of methanol and ethereal hydrochloric acid (1:1) is used.
Rf value: 0.80 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.25) (11) N-[1-methoxycarbonyl-cis-~-[[4-[(4-piperidinyl)-methyloxy3-1-piperidinyl]-carhonylamino]-cyclohexyl]-acetamide-hydrochloride The method used is as under (10).
Rf value: 0.29 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.25) (12) 1-methoxycarbonyl-cis-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexylamine-dihydrochloride The method used is as under (lO).
Rf value: 0.25 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.25) (13) ethyl N-benzyloxyacetyl-N-[2-~[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycine-'.' "' . " ' ' ' ".; ' . . ~ ' " . ': ~' ` ` . , .

212937~

hydrochloride The method used is analogous to (lo) using ethanol.
Rf value: 0.47 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.25) (14) ethyl N-(aminocarbonyl-methyl)-N-[2-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycinate dihydrochloride The method used is analogous to (13).
Rf value: 0.31 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.25) (15) ethyl N-[2-[[4-[~4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycinate dihydrochloride The method used is as under (13).
Rf value: 0.36 (silica gel; methylene chloride/methanol/conc. ammonia = 4:1:0.~5) (16) N-(ethoxycarbonyl-methyl)-N-[2-[[4-[(4-piperidinyl)-methyloxy~-l-piperidinyl]-carbonylamino]-ethyl]-glycine-dihydrochloride Ethereal hydrochloric acid in methylene chloride is used.
Rf value: 0.36 (silica gel; methylene chloride/methanol/conc. ammonia = 2:1:0.2S) (17) ethyl N-benzyl-N-[2-[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-ethyl]-glycinate-dihydrochloride A mixture of methanolic and ethereal hydrochloric acid is used.
Rf value: 0.15 (silica gel; methylene 212937~

chloride/methanol/conc. ammonia =
9:1:O.1) (18) 1-n-butanesulphonyl-2-methoxycarbonyl-cis-5~[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-piperidine-hydrochloride The method used is as under (10).
Rf value: 0.45 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.25) (l9) methyl 4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-butyrate-hydrochloride The method used is as under (10).
Rf value: 0.13 (silica gel; methylene chloride/methanol/conc. ammonia =
9:1:0.1) (20) methyl 5-[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonyl]-valeriate Ethereal hydrochloric acid is used.
Rf value: 0.14 (silica gel; methylene chloride/methanol/conc. ammonia =
9:1:0.1) (21) methyl trans-4-[3-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexanecarboxylate-hydrochloride Melting point: 216-218C.
Rf value: 0.20 (silica gel; methylene chloride/methanol = 15:1) (22) 4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonyl]-butyric acid-hydrochloride The metho~ used is as under (8).
Melting point: 149C (decomp.) Rf value: 0.09 (silica gel; me~hylene chloride/methanol/conc. ammonia =

... . .,, . ... . .. . . .. , , . , ~

212~37'~

4:1:0.25) (23) methyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylate hydrochloride The method used is as under (10).
Melting point: 173C (decomp.) Rf value: 0.15 (silica gel; methylene chloride/methanol = 9:1:0.1) ~24) methyl 3-[3-[(trans-4-amino-cyclohexyl)-carbonylamino]-benzoylamino]-propionate-hydrochloride A 1:1:1 mixture of dioxane, methanol and ethereal hydrochloric acid is used.
Rf value: 0.38 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.25) (25) methyl 4-[[3-[(trans-4-amino-cyclohexyl)-carbonylamino]-benzoylamino]-butyrate-hydrochloride The method used is as under (24).
Melting point: 197C (decomp.) R~ value: 0.67 (silica gelj methylene chloride/methanol/conc. ammonia =
2:1:0.25) (26) ~-(methoxycarbonyl-methyl)-1-[4-[(4-piperidinyl)-carbonylamino]-henzoyl]-piperidine Dioxane/ethereal hydrochloric acid (3:2.5) is used.
Melting point: 68-71C
Rf value: 0.23 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.25) (27) ethyl N-n-butanesulphonyl-N-[2-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycinate-hydrochloride ~``"` 212937~

The method used is as under (13).
Rf value: 0.52 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.25) (28) methyl 3-[4-[(trans-4-amino-cyclohexyl)-carbonylamino]-benzoylamino]-propionate-hydrochloride The method used is às under (8).
Melting point: 306C (decomp.) R~ value: 0.23 (silica gel; methylene chloride/methanol/conc. ammonia =
4:~:0.25) (29) methyl 4-[4-[(trans-4-amino-cyclohexyl)-carbonylamino]-benzoylamino]-butyrate The method used is as under (8).
Rf value: 0.30 (silica geli methylene chloride/methanol/conc. ammonia =
4:1:0.25) (30) methyl trans-4-[4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride The method used is as under (8).
Melting point: 250-~55C
Rf value: 0.49 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.25) (31) trans-4-[4-(2-amino-ethyloxy)-benzoylamino]-cycloh~xyl-acetic acid-hydrochloride 3N hydrochloric acid is used and heated to 85C for 6 hours.
Melting point: above 250C
R~ value: 0.62 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) Calc.: C 57.22 H 7.06 N 7.85 Cl~ 9.93 Found: 56.81 6.95 7.84 10.30 .

9 3 ~ ~

(32) 3-[trans-4-[~-[(2-amino-ethyloxy)-benzoylamino]-cyclohexyl]-propionic acid-hydrochloride The method used is as under (31).
Melting point: above 250C
Rf value: 0.52 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) Calc.: C 58.29 H 7.34 N 7.55 Cl 9.56 Found: 58.11 7.38 7.42 9.73 (33) trans-4-[~-(2-amino-ethyloxy)-benzoylamino]-cyclohexane-carboxylic acid-hydrochloride The method used is as under (31).
Melting point: above 250C
Rf value: 0.65 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Calc.: C 56.06 H 6.76 N 8.17 Cl 10.34 Found: 55.77 6.77 8.09 10.44 (34) trans-4-[4-(2-amino-ethyloxy)-benzoylamino]-cyclohexyloxy-acetic acid-hydrochloride The method used is as under (31).
Melting point: above 250C
Rf value: 0.74 (Reversed Phase Plate RP8;
methanol/5% sodium chloride solution =
6:4) Calc.: C 54.76 H 6.76 N 7.51 Cl 9.51 Found: 54.99 6.84 7.52 9.60 (35) 3-[4-[4-(2-amino-ethyloxy)-benzoylamino]-phenyl]-propionic acid_hydrochloride The method used is as under (31).
Melting point: above 250C
R~ value: 0.57 (Reversed Phase Plate ~P8; methanol/5%
sodium chloride solution = 6:4) Calc.: C 59.26 H 5.80 N 7.68 Cl 9.72 Found: 59.17 5.80 7.76 9.60 2~2~37'~
(36) methyl trans-4-[3-[N-benzyloxycarbonyl-N-[(4-piperidinyl)-methyl]-amino]-benzoylamino]-cyclohexane-carboxylate-hydrochloride Melting point: 266-268C (decomp.) Rf value: Q.33 (silica gel; methylene chloride/methanol = g:l) (37) 1-~3-lN-benzyloxycarbonyl-N-[(4-piperidinyl)-methyl]-amino]-benzoyl]-4-(methoxycarbonyl-methyl)-piperidine-hydrochloride Rf value: 0.37 (silica gel; methylene chloride/methanol = 9:1) (38) 4-[4-(2-amino-ethyloxy)-benzoylamino]-phenylacetic acid-hydrochloride 3N hydrochloric acid is used and heated to 90C for 15 hours.
Melting point: above 250C
R~ value: 0.62 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) Calc.: C 58.21 H 5.46 N 7.99 Cl 10.11 Found: 58.22 5.42 8.14 9.87 (39) 4-(methoxycarbonyl-methyl)-1-~[1-[2-(4-piperidinyl)-ethyl]-4-piperidinyl]-carbonyl]-piperidine-dihydrochlorideA mixture of methanol and ethereal hydrochloric acid (1:4) is used.
Melting point: 286-288OC (decomp.) Rf value: 0.13 (silica gel; methylene chloride/methanol = 4:1) (40) methyl trans-4-[4-[(4-piperidinyl)-sulphenylmethyl]-benzoylamino]-cyclohexane carboxylate-hydrochloride (41) methyl trans-4-[4-[(4-piperidinyl)-" 212~37~

sulphonylmethyl.]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (42) methyl trans-4-[3-chloro-4-[(4-piperidinyl)~
methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (43) methyl trans-4-[3-fluoro-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (44) methyl trans-4-[3-bromo-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (45) methyl trans-4-[3-methyl-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride ~46) methyl trans-4-[3-methoxy-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (47) methyl trans-4-[3-methylsulphenyl-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (48) methyl trans-4-[3-methylsulphonyl-4-[(4-piperidinyl)-methyloxy]-benzoylamino~-cyclohexane-carboxylate-hydrochloride (49) methyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-phenyl]-aminocarbonyl]-cyclohexane-carboxylate-hydrochloride (50) methyl trans-4-[[4-[2-(4-piperidinyl)-ethyl]-phenyl]-aminocarbonyl]-cyclohexane-carboxylate-hydrochloride Melting point: 260-263 C (decomp.) - 103 ~ ~2~37~

(51) methyl trans-4-[[1-[2-(4-piperidinyl~-ethyl]-4-piperidinyl]-aminocarbonyl]-cyclohexane-carboxylate-hydrochloride (52~ methyl trans-4-[4-[2-(4-piperidinyl)-ethenyl]-benæoylamino]-cyclohexane-carboxylate-hydrochloride (53) methyl trans-4-[[4-(1-piperazino-2-propyl)-phenyl]-aminocarbonyl]-cyclohexane-carboxylate-hydrochloride (54) methyl trans-4-[4-(2-piperazino-ethyl)-benzoylamino~-cyclohexane-carboxylate-hydrochloride (55) methyl trans-4-[[1-[2-(4-piperidinyl)-ethyl]-4-piperazinyl]-carbonylamino]-cyclohexane-carboxylate-bis-trifluoroacetate Melting point: 193-195C (decomp.) Rf value: 0.60 (Reversed Phase Plate RP18; methanol/5 sodium chloride solution = 6:4) (56) methyl trans-4-[4-[(4-piperidinyl)-methylsulpbenyl]-benzoylamino]-cyclohexane-carboxylate hydrochloride (57) methyl trans-4-[4-[(4-piperidinyl)-methylsulphonyl]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (58) trans-1-[4-[(cis-2-amino-cyclopentyl)-oxy]-benzoylamino]-4-(2-methoxycarbonyl-ethyl)-cyclohexane (59) trans-1-[4-[(trans-2-amino-cyclopentyl)-oxy]-benzoylamino~-4-(2-methoxycarbonyl-ethyl)-cyclohexane (60) methyl trans-4-[[1-[(4-piperidinyl)-carbonyl]-4-7 ~

piper.idinyl]-carbonylamino]-cyclohexane-carboxylate-hydrochloride Melting point: 283-285C
Rf value: 0.43 (Reversed Phase Plate RP18; methanol/5 sodium chloride solution = 6:4) (61) methyl trans-4-[[1-[2-(4-piperidinyl)-ethyl]-4-piperidinyl]-carbonylamino]-cyclohexane-carboxylate The method used is as under (10) Melting point: abo~e 300C
Rf value: 0.20 (silica gel; methylene chloride~methanol/conc. ammonia =
~ 0.2) (62) methyl trans-4-[[4-[2-(4-piperidinyl)-ethyl]-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate Example 5 Methyl trans-4-[[[1-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-carbonyl]-4-piperidinyl]-methyl]-carbonylamino]-cyclohexane-carboxylate 1.4 g of 1-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-carbonyl]-4-carboxymethyl-piperidine i9 dissolved in 100 ml of tetrahydrofuran, mixed with 0.83 ml of chlorodiphenyl-phosphine and cooled to -10C.
0.57 ml of ~riethylamine is added, stirred for 30 minutes and finally mixed with 0.81 g of methyl trans-4-amino-cyclohexane-carboxylate-hydrochloride and 0.57 ml of triethylamine. After stirring for an hour at -10C, the mixture is allowed to reach ambient temperature and finally refluxed for 2 hours. It is poured on water, extracted with ethyl acetate and the organic phases are concentrated by-evaporation. The residue is purified by chromatography over silica gel (eluant: methylene chloride/methanol = 30:i) - 105 - 2~937~
Yield: 1.27 g (66~ of theory), Melting point: 122-124C
Rf value: 0.52 (silica gel; methylene chloride/methanol = 9:1) The following compounds are obtained analogously:

(1) 1-[trans-4-[[(1-tert.butyloxycarbonyl-4-piperidinyl) -methyl]-carbonylamino]-cyclohexylcarbonyl]-4-(methoxycarbonyl-methyl)-piperidine Melting point: 162-164C (decomp.) (2) 1-[trans-4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-cyclohexylcarbonyl]-4-(2-methoxycarbonyl-ethyl)-piperidine Melting point: 177-179C (decomp.) Rf-ValUe: O . 38 (silica gel; methylene chloride/methanol = 4:1) (3) methyl trans-4-[4-[(1-benzyl-4-piperidinyl)-aminocarbonyl]-benzoylamino]-cyclohexane carboxylate methylester hydrochloride Melting point: 272-276C (decomp.) Rf value: 0.29 (silica gel; methylene " chloride/methanol = 9:1) (4) 1-[trans-4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-cyclohexylcarbonyl]-4-(methoxycarbonyl-methyl)-piperidine Rf value: 0.41 (silica gel; methylene chloride/methanol = 9:1) (5) methyl trans-4-[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonylamino]-benzoylamino]-cyclohexane carboxylate Melting point: 264-268OC (decomp.) Rf value: 0.65 (silica gel, methylene chloride/methanol - 106 - 212937~
= 9:1) (6) methyl trans-4-[3-[N-benzyloxycarbonyl-N-[(l-tert.butyloxycarbonyl-4-piperldinyl)-methyl]-amino]-benzoylamino]-cyclohexane carboxylate Rf value: 0.67 (silica gel; methylene chloride/methanol = 9:1) (7) l-[3-[N-benzyloxycarbonyl-N-[(l-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoyl]-4-(methoxycarbonylmethyl)-piperidine Rf value: 0.65 (silica gel; methylene chloride/methanol = 9:1) (8) methyl trans-4-[4-[N-benzyloxycarbonyl-N-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoylamino]-cyclohexane-carboxylate Rf value: 0.61 (silica gel; methylene chloride/methanol = 9:1) (9) 4-(methoxycarbonyl-methyl)-1-[4-[trans-2-(4-pyridyl)-ethenyl]-benzoyl]-piperidine A 3:2 mixture of dimethylformamide and tetrahydrofuran is used.
Melting point: 133-135C
Rf value: 0.62 (silica gel; methylene chloride/methanol = 9:1) (10) methyl trans-4-[4-[trans-2-(4-pyridyl)-ethenyl]-benzoylamino~-cyclohexane-carboxylate Melting point: 239-241C (decomp.) Rf value: 0.60 (silica gel; methylene chloride/methanol = 9:1) (11) 1-[[1-[2-(1-tert.butyloxycarbonyl-4-piperidinyl)-ethyl]-4-piperidinyl]-carbonyl]-4-(methoxycarbonyl-methyl)-piperidine 2~2~7 f~

Rf value: 0.43 (silica gel; methylene chloride/methanol = 9:1) (12) methyl trans-4-[[1-[(1-tert.butyloxycarbonyl-4-piperidinyl~-carbonyl]-4-piperidinyl]-carbonylamino]-cyclohexane-carboxylate Melting point: 230-232C (decomp.) Rf value: 0.28 (silica gel; methylene chloride/methanol = 19:1) (13) methyl trans-4-[[1-[2-(1-tert.butyloxycarbonyl-4-piperidinyl)ethyl]-4-piperidinyl]-carbonylamino]-cyclohexane-carboxyla~e Melting point: 202-204C
Rf value: 0.56 ~silica gel; methylene chloride/methanol = 4:1) E~m~le 6 Methyl trans-4-[4-[(4-piperidinyl)-aminocarbonyl]-benzoylamino]-cyclohexane-carboxylate-hydrochloride 1.3 g of methyl trans-4-[4-L(1-benzyl-4-piperidinyl)-aminocarbonyl]-benzoylamino]-cyclohexane-carboxylate-hydrochloride is treated with hydrogen at 5 bar, at ambient temperature for 6 hours, in a mixture of 80 ml of methanol, 10 ml of water and 2 ml of lN hydrochloric acid, in the presence of 0.5 g of 10~ palladium/
charcoal. It is suction filtered from the catalyst, concentrated, again concentrated by evaporation after adding acetone and the residue is triturated with acetone.
Yield: 0.98 g (93~ of theory), Melting point: 284-285C
R~ value: 0.26 (silica gel; methylene chloride/methanol = 4:1) 212937l~

The following compounds are obtained analogously:

(l) 1-[4-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoyl]-4-(2-methoxycarbonyl-ethyl)-pipexldlne .From 1-[4-[N-benzyloxycarbonyl-N-[(l-tert.butyloxycarbonyl-4-piperidinyl)-methyl]-amino]-benzoyl]-4-t2-methoxycarbonylethyl)-piperidine. The reaction is carried out in methanol without the addition of acid.
Rf value: 0.66 (silica gel; methylene chloride/methanol = 9:1) (2) 1-[4-[[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyl3-amino]-benzoyl]-4-(methoxycarbonyl-methyl)-piperidine The method used is analogous to (1).
Rf value: 0.53 (silica gel; methylene chloride/methanol = 9:1) (3) ethyl N-hydroxyacetyl-N-[2-[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino3-ethyl]-glycinate-hydrochloride From-ethyl N-benzyloxyacetyl-N-[2-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycinate The reaction is carried out in pure ethanol.
The compound is produced in a mixture with the corresponding lactone. This mixture is used directly in `~
the next stage.
Rf value: 0.40 ~silica gel; methylene - chloride/methanol/conc. ammonia =
2:1:0.25) (4) ethyl N-[2-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-ethyl]-glycinate .. . ~

- log 212937~
The reaction is carried out in ethanol with palladium hydroxide on charcoal.
R~ value: 0.56 (silica gel; methylene chloride/methanol/conc. ammonia =-9:1:O.1) (5) methyl trans-4-[[4-[(4-piperidinyl)-oxymethyl]-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate The reaction is carried out in a 10:1 mixture of methanol and methanolic hydrochloric acid.
R~ value: 0.11 (silica gel; methylene chloride/methanol/conc. ammonia =
~ : 1 : O . 1 ) (6) methyl trans-4-[3-[[(4-piperidinyl)-methyl]-amino]-benzoylamino]-cyclohexane-carboxylate-hydrochloride The method used is analogous to (1).
Melting point: 183-186 C (decomp.) Rf value: 0.17 (Reversed Phase Plate RP18; methanol/S~
sodium chloride solution = 6:4) (7) 4-(methoxycarbonyl-methyl)-1-[3-[[(4-piperidinyl)-methyl]-amino]-benzoyl]-piperidine-hydrochloride The method used is analogous to (1).
Rf value: 0.16 ~Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (8) trans-4-[4-[[(4-piperidinyl)-methyl]-amino]-benzoylamino]-cyclohexane carboxylic acid-hydrochloride The method used is analogous to (1), using ethanol as solvent.
Melting point: 294-296C (decomp.) Rf value: ~.47 (Reversed Phase Plate RP18; methanol/5%
sodium chloride solution = 6:4) (9) methyl trans-4-[4-[[(4-piperidinyl)-methyl]-amino]-benzoylamino]-cyclohexane carboxylate-hydrochloride The method used is analogous to (1).

,":~", , " . ~ ,~ . ",".

2~937~

(10) 4-(methoxycarbonyl-methyl)-1-~4-(piperazino-carbonylamino)-benzoyl]-piperidine Palladium hydroxide on charcoal and methanol as solvent are used.
Rf value: 0.54 (silica gel; methylene chloride/methanol/conc. ammonia =
2:1:0.25) Calc. x 0.5 H2O: C 60.4~ H 7.35 N 1~.10 Found : 60.60 7.41 14.25 (11) methyl trans-4-[[1-[(4-piperidinyl)-aminocarbonyl~-4-piperidinyl]-carbonylamino]-cyclohexane-carboxylate The method used is analogous to (1).
Melting point: 148-151C
Rf value: 0.16 (silica gel; methylene chloride/methanol/conc. ammonia =
4:1:0.2) (12) ethyl trans-4-[[4-[2-(4-piperidinyl)-ethyl]-phenyl]-aminocarbonyl]-cyclohexane-carboxylate-hydrochloride The starting compound is ethyl trans-4-[[4-[2-(1-benzyl-1,2,3,6-tetrahydro-4-pyridyl)-ethyl]-phenyl]-aminocarbonyl]-cyclohexane carboxylate and the process is carried out with palladium hydroxide on charcoal in a 96:4 mixture of methanol and lN hydrochloric acid.
Melting point: 260-263C (decomp.) Rf value: 0.08 (silica gel; methylene chloride/methanol = 9:1) (13) ethyl 5-[[4-[2-(4-piperidinyl)-ethyl]-phenyl]-aminocarbonyl]-valeriate-hydrochloride The method used is analogous to (12).
Melting point: 158-160C
R~ value: 0.07 (silica gelj methylene chloride/methanol = 9:1) ~x~

212937~1 (14) methyl 3-[[[4-[2-(4-piperidinyl)-ethyl]-phenyl]-aminocarbonyl~-amino]-propionate-hydrochloride The method used is analogous to (12).
Melting point: 198~200C (decomp.) Rs value: ~.04 ~silica gel; methylene chloride/methanol = 9:1) 1-[[1-[[(1-tert.Butyloxycarbonyl-4-piperidinyl)-methyl]-carbonyl]-4-piperidinyl]-carbonyl]-4-(methoxycarbonyl-methyl)-piperidine .
1.3 g of tert.butyloxycarbonyl-4-carboxymethyl-piperidine is dissolved in 80 ml of tetrahydrofuran.
0.96 g of carbonyldiimidazole is added, the mixture is stirred for an hour at ambient temperature, 0.82 ml of triethylamine and 1.8 g of 4-(methoxycarbonyl-methyl)-1-(4-piperidinyl-carbonyl)-piperidine-hydrochloride are added and the mixture is stirred for a further 16 hours at ambient temperature. It is poured into a diluted potassium hydrogen sulphate solution, extracted with ethyl acetate and the organic phases are concentrated by evaporation.
Yi.eld: 1.05 g (40% of theory), Rf value: 0.72 (silica gel; methylene chlorideJmethanol = 9:1) The following compounds are obtained analogously:

(1) 1-[[[1-[(1-tert.butyloxycarbonyl-4-piperidinyl)-carbonyl]-4-piperidinyl]-methyl]-carbonyl]-4-(methoxycarbonylmethyl)-piperidine R~ value: 0.55 (silica gel; methylene chloride/ethanol = 9:1) (2) methyl trans-4-[3-[(1-tert.butyloxycarbonyl-4-" ., . . . .. , .. . . ....... , .. . .... . . , .. . , ~ , , . , . . - , , - , . .. . .

212937 ~

piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate The process is carried out with O-(lH-1-benzotriazolyl)-N,N,N',N'-tetramethyluronium-tetrafluoroborate in dimethylformamide.
Rf value: 0.63 (silica gel; methylene chloride/methanol = 15:1) (3) 1-[4-[(1 tert.butyloxycarbonyl-4-p.iperidinyl)-carbonylamino]-benzoyl]-4-(methoxycarbonyl-methyl)-piperidine From 1-(4-amino-benzoyl)-4-(methoxycarbonyl-methyl)-piperidine and 1-tert.butyloxycarbonyl-piperidine-4-carboxylic acid.
4-dimethylamino-pyridine is used.
Rf value: 0.37 (silica gel; ethyl acetate) (4) methyl trans-4-~4-[2-(tert.butyloxycarbonyl-amino)-ethyloxy]-benzoylamino]-cyclohexyl-acetate The method used is analogous to (2).
Melting point: 160-162C
Rf value: 0.24 (silica gel; cyclohexane/ethyl acetate = 1:1) Calc.: C 63.57 H 7.89 N 6.45 Found: 63.33 7.91 5.57 (5) methyl 3-[trans-4-[4-[2-(tert.butyloxycarbonyl-amino)-ethyloxy]-benzoylamino]-cyclohexyl]-propionate The method used is analogous to (2).
Melting point: 188-190C
value: 0.43 (silica gel; cyclohexane/ethyl acetate = 2:3) Calc.: C 6a.26 H 8.09 N 6.25 Found: 64.11 8.22 6.25 .

(6) methyl trans-4-[4-[2-(tert.butyloxycarbonyl-amino)-ethyloxy]-benzoylamino]-cyclohexane-carboxylate 212937~1i The method used is analogous to (2).
Melting point: 191-193C
Rf value: 0.35 (silica gel; cyclohexane/ethyl acetate = 2:3) Calc.: ~ C 62.84 H 7.67 N 6.66 Found: 62.52 7.65 6.66 (7) methyl trans-4-[4-[2-(tert.butyloxycarbonyl-amino)-ethyloxy]-benzoylamino]-cyclohexyloxy-acetate The method used is analogous to (2).
Melting point: 162-164C
Rf value: 0.36 (silica gel; cyclohexane/ethyl acetate = 3:7) Calc.: C 61.32 H 7.60 N 6.22 Found: 61.00 7.63 6.21 (8) methyl 3-[4-[4-[2-(tert.butyloxycarbonyl-amino)-ethyloxy]-benzoylamino]-phenyl]-propionate The method used is analogous to (2).
Melting point: 154-156C
Rf value: 0.31 (silica gel; cyclohexane/ethyl acetate = 3:2) Calc.: C 65.14 H 6.83 N 6.33 Found: 64.69 6.82 6.35 (9) methyl 3-[trans-4-[(2-cyano-1,2,3,4-tetrahydro-6-naphthyl)-carbonylamino]-cyclohexyl]-propionate The method used is analogous to (2).
Rf value: 0.15 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution a 6:4) (10) methyl ~rans-4-[(2-cyano-1,2,3,4-tetrahydro-6-naphthyl)-carbonylamino]-cyclohexyloxy-acetate The method used is analogous to (2).
Rf value: 0.33 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) 212937f.1 (11) methyl 4-[4-[2-(tert.butyloxycarbonyl-amino)-ethyloxy]-benæoylamino]-phenyl-acetate The method used is analogous to (2).
Melting point: 179-181C
Rf value: 0.50 (silica gel; cyclohexane/ethyl acetate = 1:1) Calc.: C 64.47 H 6.59 N 6.54 Found: 64.92 6.64 6.73 (12) 1-[4-[(4-benzyl-piperazino)-carbonylamino]-benzoyl]-4-(methoxycarbonyl-methyl)-piperidine N,N'-dicyclohexyl-carbodiimide is used with the addition of l-hydroxy-benzotriazole in dimethylformamide. -~
Rf value: 0.52 (silica gel; methylene chloride/methanol/conc. ammonia =
9:1:0.1) (13) trans-1-(4-cyanomethyl-benzoylamino)-4-(2-methoxycarbonyl-ethyl)-cyclohexane The method used is analogous to (2).
Melting point: 186-189C
Rf value: 0.51 (silica gel; methylene chloride/methanol = 9:1) (14) ethyl 3-[4-(3-cyanomethyl-benzoylamino)-phenyl]-propionate N,N'-dicyclohexyl-carbodiimide is used in the presence o~ triethylamine and 1-hydroxy-benzotriazole in tetrahydrofuran.
Melting point: 96-98C
Rf value: 0.46 (silica gel; cyclohexane/ethyl acetate ~

(15) methyl trans-4-[[1-[(1-benzyl-4-piperidinyl)-aminocarbonyl]--4-piperidinyl]-carbonylamino]-cyclohexane-carboxylate The method used is analogous to (2) in tetrahydrofuran - 115 - 21~293~;
and with the addition of 1-hydroxy-lH-benzotriazole and N-methyl-morpholine.
Melting point: 223-225C
Rf value: 0.78 (silica gel; methylene chloride/methanol (16) methyl 3-[trans-4-[(4-cyanomethyl-benzoylamino)-methyl]-cyclohexyl]-propionate-hydrochloride The method used is analogous to (2).
Melting point: 138-140C
Rf value: 0.1~ (Reversed Phase Plate RP8; methanol~5 sodium chloride solution = 6:4) (17) methyl 3-[trans-4-[4-(3-tert.butyloxycarbonylamino-propyl)-benzoylamino]-cyclohexyl]-propionate The method used is analogous to (2).
Melting point: 160C
Rf value: 0.49 (silica gel; methylene chloride/methanol = 19:1) ~amR~

N-[cis-4-[[4-[(1-tert.Butyloxycarbonyl-4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-1-methoxycarbonyl-cyclohexyl~-n-butanesulphonamide 1 g of N-(cis-4-amino-1-methoxycarbonyl-cyclohexyl)-n-butanesulphonamide-hydrochloride is added to a solution of 0.6 g of 4-nitro-phenyl-chloroformate in 20 ml of tetrahydrofuran and cooled to -15C. A solution of 1.3 ml of triethylamine in 20 ml of tetrahydrofuran is added and the mixture is stirred for 4 hours at ambient temperature. 0.9 g of 4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-piperidine is added and the mixture is stirred for another 16 hours at ambient temperature. It is suction filtered from the precipitate, the filtrate is mixed with ethyl acetate, ~1 - 116 - ~ l~ ~ ~ I ~
the organic phase is successively washed with 0.5 molar potassium hydrogen sulphate solution, lN sodium hydroxide solution and saline solution and concentrated by evaporation. The residue is purified over a silica gel column (eluant: methylene chloride/methanol = 30:1).
Yield: 1.14 g (61% of theory), Rf value: 0.45 (silica gel; methylene - chloride/methanol/conc. ammonia =
9:1:0.1) The following compounds are obtained analogously:

(1) N-[cis-4-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-1-methoxycarbonyl-cyclohexyl]-acetamide Rf value: 0.48 (silica gel; methylene chloride/methanol/conc. ammonia =
9:1:0.1) (2) tert.~utyl N-[cis-4-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-1-- methoxycarbonyl-cyclohexyl]-carbamate Rf value: 0.49 (silica gel; methylene - chloride/methanol/conc. ammonia =
9:1:0.1) (3) ethyl N-benzyl-N-[2-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl~-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycinate Rf value: 0.45 (silica gel; methylene chloride/methanol 15:1) (4) 1-n-butanesulphonyl-5-[[4-[~1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cis-2-methoxycarbonyl-piperidine R~ value: 0.56 (silica gel; ethyl acetate) 2~2937~

(5) methyl 3-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-propionate Rf value: 0.35 (silica gel; methylene chloride/methanol = 15:1) (6) methyl trans-4-[~4-[(1-benzyl-4-piperidinyl)-oxymethyl]-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate Rf value: 0.55 (silica gel; methylene chloride/methanol/conc. ammonia =
9:1:0.1) (7) methyl trans-4-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate Rf value: 0.75 (silica gel; methylene chloride/methanol/conc. ammonia =
9:1:0.1) Example 9 .

Ethyl N-(aminocarbonyl-methyl)-N-[2-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-l-piperidinyli-carbonylamino]-ethyl]-glycinate .
To a solution of 1.5 g of ethyl N-[2-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-ethyl]-glycinate and 0.7 ml of N,N-diisopropyl-ethylamine in lO ml of methylene chloride, 0.45 g of 2-bromo-acetamide is added and the mixture is stirred for 16 hours at ambient temperature.
It is concentrated by evaporation and the residue is purified by chromatography on silica gel (eluant: ethyl acetate/ethanol = 10:1) Yield: 1.4 g (83% of theory), Rf value: 0.18 (silica gel; ethyl acetate/methanol =

:,.:: : ` . , .

- 118 - 212937~
g 1, The following compounds are obtained analogously:

(1) tert.butyl N-[2-[[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-ethyl]-N-(ethoxycarbonylmethyl)-glycinate Rf value: 0.42 (silica gel; methylene chloride/methanol = 15:1) (2) methyl trans-4-[[1-[2-(1-tert.butyloxycarbonyl-4-piperidinyl)-ethyl]-4-piperazinyl]-carbonylamino]-cyclohexanecarboxylate The process is carried out in chloroform using triethylamine.
Melting point: 155-157C (decomp.) Rf value: 0.54 (silica gel; methylene chloride/methanol = 9:1) ,Example 10 Methyl trans-4-[4-[(1-tert.butyloxycarbonyl-4-piperidinyl)-methyloxy]-~enzoylamino]-cyclohexane-carboxylate 0.56 g of methyl trans-4-(4-hydroxy-benzoylamino)-cyclohexane carboxylate is dissolved in 11 ml of dimethylformamide, mixed with 0.98 g of cesium carbonate and stirred for 2 hours at ambient temperature. 0.61 g of 1-tert.butyloxycarbonyl-4-(methanesulphonyloxy-methyl)-piperidine is added and the mixture is stirred for 4 hours at 60C. It is poured on S00 ml of water, extracted with ethyl acetate, the organic phases are concentrated by evaporation and the residue is purified over silica gel (eluant:
methylene chloride/methanol = 20:1).
Yield: 0.81 g (85 % of theory), A~ ` ' ` ~ ~ : .

212937~

Melting point: 192-195C
R value: 0.54 (silica gel; methylene chloride/methanol = 9:1) Methyl 3-[trans-4-[(2-aminomethyl-1,2,3,4-tetrahydro-6-naphthyl)-carhonylamino]-cyclohexyl]-propionate-hydrochloride 0.6 g of methyl 3-[trans-4-[(2-cyano-1,2,3,4-tetrahydro-6-naphthyl)-carbonylamino]-cyclohexyl]-propionate-hydrochloride is dissolved in a mixture of 20 ml of methanol and 1.5 ml of methanolic hydrochloric acid and treated with hydrogen at 4 bar for 5 hours at ambient temperature in the presence of 0.3 g of 10% palladium/
charcoal. The catalyst is filtered off and the filtrate is evaporated down.
Yield: 0.5 g (75 ~ of theory), Melting point: above 250C
Rf value: 0.32 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) The following compounds are obtained analogously:

(1) methyl [trans-4-[~2-aminomethyl-1,2,3,4-tetrahydro-6-naphthyl)-carbonylamino]-cyclohexyloxy]-acetate-hydrochloride Rf value: 0.50 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) (2) methyl 3-[trans-4-[[4-(2-aminoethyl)-benzoylamino]-methyl]-cyclohexyl~-propionate-hydrochloride Melting point: 266-268C
Rf value: 0.35 (Reversed Phase Plate RP8; methanol/5%
sodium chloride solution = 6:4) ~ 2937~

~m~

4-(Methoxycarbonyl-methyl)-1-[4-[2-(4-piperid.inyl)-ethyl]-benzoyl]-piperidine-hydrochloride .
1 g of 4-(methoxycarbonyl-methyl)-1-[4-[trans-2-(4-pyridyl)-ethenyl]-benzoyl]-piperidine is dissolved in 80 ml of glacial acetic acid and treated with hydrogen at 2 bar for 1.5 hours at ambient temperature, after adding 0.1 g of platinum dioxide. The mixture is concentrated by evaporation and the residue is purified by chromatography on silica gel (eluant: methylene chloride/methanol/conc. ammonia = 15:1:0.1). The relevant fractions of the eluate are evaporated down, taken up in acetone and mixed with ethereal hydrochloric acid.
Yield: 0.62 g (56 % of theory~, Melting point: 184-186C (decomp.) Re value: 0.24 (Reversed Phase Plate RP18; methanol/5 sodium chloride solution = 6:4) The following compounds are obtained analogously:

(1) methyl trans-4-[4-[2-(4-piperidinyl)-ethyl]-benzoylamino]-cyclohexane carboxylate-hydrochloride Melting point: 220-222OC (decomp.) R~ value: 0.34 (Reversed Phase Plate RP18; methanol/5 sodium chloride solution = 6:4) - 121 - 2~29~7~
E~ample l~

4-(Methoxycarbonyl-methyl)-l-[4-[2-t4-pyridyl)-ethyl]-benzoyl]-plperidine 1 g of 4-(methoxycarbonyl-methyl)-1-[4-[trans-2-(4-pyridyl)-ethenyl]-benzoyl]-piperidine is dissolved in 100 ml of methanol and treated with hydrogen at 5 bar for 1 hour at ambient temperature, in the presence of 0.4 g of 10% palladium/charcoal. It is suction filtered from the catalyst, evaporated down and crystallised from ether/petroleum ether.
Yield: 0.85 g (85 % of theory), Melting point: 88-9oC
Rf value: 0.39 (silica gel; methylene chloride/methanol = 19:1) The following compound is obtained analogously:

(1) methyl trans-4-[4-[2-(4-pyridyl)-ethyl]-benzoylamino]-cyclohexane carboxylate Melting point: 178-180C (decomp.) Rf value: 0.39 (silica gel; methylene chloride/methanol = 19:1) Example 14 Methyl trans-4-[[4-[(1-acetoxymethyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylate Prepared from methyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylate and carbonic acid acetoxymethyl-(4-nitro-phenyl)-ester in methylene chloride in the presence of N,N-diisopropyl-ethylamine at ambient temperature.
I

212937~

The following compounds are obtained analogously:

(1) methyl trans-4-[4-[(1-acetoxymethyloxycarbonyl-4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexanè-carboxylate (2) methyl trans-4-[[4-[~1-acetoxymethyloxycarbonyl-4-piperidinyl)-oxymethyl]-1-piperidinyl)]-carbonylamino]-cyclohexane-carboxylate ~am~le 1~

1-(Cyclohexyloxycarbonyloxy)-ethyl trans-4~[4-[[1-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate Prepared from trans-4-[4-[tl-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylic acid and carbonic acid (l-chloroethyl)-cyclohexylester in dimethylformamide, in the presence of potassium carbonate and sodium iodide.

The following compounds are obtained analogously:

(1) 1-(cyclohexyloxycarbonyloxy)-ethyl trans-4-[[4-[(1-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate (2) (pivaloyloxy)-methyl trans-4-[[4-[(1-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylate (3) l-(ethoxycarbonyloxy)-ethyl ~rans-4-[4-[(1-benzyloxycarbonyl-4-pip~ridinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate (4) 1-(ethoxycarbonyloxy)-ethyl trans-4-[[4-[(1-21293~

benzyloxycarbonyl-4-piperidinyl)-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate Methyl trans-4-[[4-[(1-methoxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate Prepared from methyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-l-piperidinyl]-carbonylamino]-cyclohexane-carboxylate and methylchloroformate in tetrahydrofuran, in the presence of triethylamine.

The following compounds are obtained analogously:

(1) methyl trans-4-[4-~(1-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate (2) methyl trans-4-[[4-[(1-b~nzyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino~-cyclohexane-carboxylate Example 17 5-Indanyl trans-4-[4-(1-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate Prepared from trans-4-[4-[(1-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylic acid by treating with thionylchloride at ambient temperature with the addition of a little dimethylformamide, concentrating by evaporation and reacting the acid chloride thereby formed with S-indanol in the presence of triethylamine and a li~tle 4-~!.';:

- 124 - 212937/~
dimethylamino-pyridine in methylene chloride at ambient temperature .

The following compound is obtained analogously:

~1) 5-indanyl trans-4-[[4-[(1-benzyloxycarbonyl-4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate Example 18 5-indanyl trans-4-[4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride Prepared from 5-indanyl trans-4-[4-[(1 benzyloxycarbonyl-4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate by treating with hydrogen at 5 bar in a 10:1:0.8 mixture of tetrahydrofuran, water and lN hydrochloric acid, in the presence of palladium/charcoal at ambient temperature.

The following compounds are obtained analogously:

(1) 5-indanyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate-hydrochloride (2) 1-(cyclohexyloxycarbonyloxy)-ethyl trans-4-[4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (3) l-(cyclohexyloxycarhonyloxy)-ethyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane-carboxylate-hydrochloride (4) pivaloyloxymethyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane-~.. ~ . . ..... .. -212937~

carboxylate (5) 1-(ethoxycarbonyloxy)-ethyl trans-4-~4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (6) 1-(ethoxycarbonyloxy)-ethyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]carbonylamino]-cyclohexane-carboxylate ~xam~le 19 isobutyl trans-4-[4-[(4-quinuclidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride Prepared from trans-4-[4-[(4-quinuclidinyl)-methyloxy~-benzoylamino]-cyclohexane-carboxylic acid and isobutanol in the presence of thionylchloride by heating to 70C.

The following compounds are obtained analogously:

(1) cyclohexyl trans-4-[4-[2-(4-quinuclidinyl)-ethyl]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (2) isopropyl trans-4-[4-[2-(4-piperidinyl)-methyloxy]-benzoylamino~-cyclohQxane-carboxylate-hydrochloride (3) cyclohexyl trans-4-[4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (4) ethyl trans-4-~4-[2-(4-quinuclidinyl)-ethyl]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (5) ethyl trans-4-[4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-carboxylate-hydrochloride (6) ethyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-~ ! ` ` ' . ., , .` . ` : . .:.: :

,1.~.. : :' ' : :.. '-: :.` ~ : ' ': , .: ' : . ~ , , - . . . ..

- 126 - 212937~
piperidinyl]-carbonylamino]-eyelohexane-carboxylate-hydrochloride ~Q

Methyl trans-4-[4-[(4-piperidinyl)-sulphinylmethyl]-benzoylamino]-cyclohexane-carboxylate .
Prepared from methyl trans-4-[4-[(4-piperidinyl)-sulphenylmethyl]-benzoylamino]-cyclohexane-earboxylate with 30% hydrogen peroxide in glacial acetie aeid whilst eooling with ice.

The following compounds are obtained analogously:

(1) methyl trans-4-[3-methylsulphinyl-4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane-earboxylate .
(2) methyl trans-4-[4-[(4-piperidinyl)-methylsulphinyl]-benzoylamino]-eyelohexane-earboxylate Exam~le 21 .
trans-1-[[4-[(2-Amino-ethyloxy)-eyclohexyl]-earbonylamino]-4-(2-earboxy-ethyl)-eyclohexane-hydrochloride 0.25 g of 1-[4-(2-amino-ethyloxy)-benzoylamino]-4-(2-earboxyethyl)-cyclohexane-hydroehloride is hydrogenated in 20 ml of water, in the presenee of 100 mg of a rhodium/platinum eatalyst (Nishimura eatalyst), using hydrogen at 4 bar at ambient temperature. The reaetion mixture is heated on a steam bath, the catalyst is suction filtered off and the filtrate is evaporated down n vaeuo. It is evaporated twiee again with toluene and the residue is digested with acetone. It is filtered - 127 21~93~
and the filtrate is washed with acetone and ether.
Yield: 0.14 g (55 ~ of theory), Melting point: above 250C
R~ value: 0.54 (Reversed Phase Plate RP8; methanol/S~
sodium chloride solution = 6:4) Calc. x 1.1 HCl x 1.2 H2O:
C 54.03 H 8.44 N 7.00 Cl 9.75 Found: 53.49 8.50 7.05 9.95 The following compound is obtained analogously:

(1) trans-1-[[4-(2-amino-ethyl)-cyclohexyl]-carbonylamino]-4-(2-carboxy~ethyl)-cyclohexane-hydrochloride Exam~le 22 trans-1-[4-(2-Amino-ethyl)-ben~oylamino]-4-(2-methoxycarhonyl-ethyl)-cyclohexane-hydrochloride A mixture of 1.6 g of trans-1-(4-cyanomethyl-benzoyl-amino)-4-(2-methoxycarbonyl-ethyl)-cyclohexane, 400 ml of methanol, 4.7 ml of methanolic hydrochloric acid and 0.5 g of 10% palladium/charcoal is treated for 3 hours at ambient temperature using hydrogen at 4 bar. The mixture is suction filtered from the catalyst, concentrated by evaporation and triturated, while heating, in a 1:1 mixture of tert.butylmethylether and ethyl acetate. It is filtered and the residue is stirxed with acetone at boiling temperature. After cooling the solid product is suction filtered off.
Yield: 1.2 g (67 ~ of theory), Melting point: above 250C
Rf value: 0.46 (silica gel; methylene chloride/methanol = 4:1) he following compounds are obtained analogously:

(1) methyl 3-[3-[4-(2-amino-ethyl)-benzoy phenyl]-propionate-hydrochloride Melting point: above 250C
Rf value: 0.50 (silica gel;
- dioxane/toluene/methanol/conc. ammonia = 10:4:4:1) Calc.: C 62.89 H 6.39 M 7.72 Cl 9.77 Found: 62.62 6.55 7.83 9.69 (2) ethyl 3-[4-[3-(2-amino-ethyl)-benzoylamino]-phenyl]-propionate-hydrochloride Melting point: above 250C
R~ value~: 0. 34 (silica gel; methylene chloride/methanol = 8:2) Calc.: C 63.74 H 6.69 N 7.43 Found: 63.82 6.75 7.57 (3) methyl 3-[4-(4-aminomethyl-benzoylamino)-phenyl]-propionate-hydrochloride Melting point: above 250C
Rf value: 0.48 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) Calc.: C 61.98 H 6.07 N 8.03 Cl 10.16 Found: 61.78 6.08 7.90 10.30 (4) 3-[4-[4-(2-amino-ethyl)-benzoylamino]-phenyl]-propionic acid Raney nickel in methanolic ammonia is used at 50C and allowed to react for 8.5 hours.
Melting point: above 330C
Rf value: 0.53 (Reversed Phase Plate RP8; methanol/5 sodium chloride solution = 6:4) Calc. x 0.5 H2O: C 67.27 H 6.59 N 8.72 Found : 67.02 6.46 8.72 - 129 - 212937'1 Ethyl trans-4-[[4-[2-(1-benzyl-1,2,3,6-tetrahydro-4-pyridyl)-ethyl]-phenyl]-aminocarbonyl]-cyclohexane-carboxylate l.9 g of ethyl trans-4-[[4-[2-(4-pyridyl)-ethyl]-phenyl3-aminocarbonyl]-cyclohexane-carboxylate and 1.2 ml of benzylbromide are refluxed in 25 ml of acetonitrile for one hour. The mixture is concentrated and the residue triturated with ether. The precipitate formed is suction filtered off, dissolved in 100 ml of ethanol, mixed in batches with 0.4 g of sodium borohydride ~nd stirred for 16 hours at ambient temperature. 400 ml of water is added, the precipitate is suction filtered off and dissolved in ethyl acetate.
The dried ethyl acetate solution i~ concentrated, the residue is triturated with ether and the solid product obtained is suction filtered.
Yield: 2.22 g (94~ of theory), Melting point: 130-132aC
Rf value: 0.37 (silica gel; methylene chloride/methanol = 9:1) The following compounds are obtained analogously:

(1~ ethyl 5-E[4-[2-(1-benzyl-1,2,3,6-tetrahydro-4-pyrid~ ethyl~-phenyl]-aminocarbonyl]-valeriate Melting point: 54-55C
Rf value: 0.49 (silica gel; methylene chloride/methanol = 9:1) (2) methyl 3-[[[4-[2-(1-benzyl-1,2,3,6-tetrahydro-4-pyridyl)-ethyl]-phenyl]-aminocarbonyl]-amino]-propionate Melting point: 94-95C
Rf value: 0.68 (silica gel; methylene chloride/methanol = 9:1) .
21293~

Example 24 Methyl 3-~[[4-[2-(4-pyridyl)-ethyl]-phenyl-aminocarbonyl]-amino]-propionate 2.1 g of imidazole is added to a solution of 3.4 g of carbonyldiimidazole in 50 ml of tetrahydrofuran. The mixture is cooled in an ice bath, mixed with a solution of 4 g of 4-[2-(4-amino-phenyl)-ethyl]-pyridine, stirred for one hour and a mixture of 2.82 g of ~-alanine-methylester-hydrochloride and 50 ml of tetrahydrofuran and 3.5 ml of N,N-diisopropyl-ethylamine is added. It is stirred for 48 hours at ambient temperature and refluxed for one hour. The mixture is concentrated, the residue is distributed between ethyl acetate and water.
The ethyl acetate phases are evaporated down and the residue is purified by chromatography on silica gel (eluant: ethyl acetate).
Yield: 4.05 g (61~ of theory), Melting point: 119-121C
Rf value: 0.63 (silica gel; methylene chloride/methanol = 9:1) ~,. :: ~ . . ,:
i' ,"

- 131 - 21293~
Ex~mple 25 Dry ampoule containing 2.5 mg of active substance per 1 ml Composition:

Active substance 2.5 mg Mannitol 50.0 mg Water for injections ~ 1.0 ml Preparation:

The active substance and mannitol are dissolved in water. After transferring the solution to the ampoule, it is freeze-dried.

At the point of use, the solution is made up with water for injections.

Example 26 Dry ampoule containing 35 mg of active substance per 2 ml Composition:

Active substance 35.0 mg Mannitol 100.0 mg Water for injections ~ 2.0 ml Preparation:

The active substance and mannitol are dissolved in water. After transf2rring the solution to the ampoule, -- 132 - ~129~7~
it is freeze-dried.

At the point of use, the solution is made up with water for injections.

Exam~le 27 Tablet containing 50 mg of active substance Composition:

(1) Active substance 50.0 mg (2) Lactose 98.0 mg (3) Corn starch 50.0 mg (4) Polyvinylpyrrolidone 15.0 mg (5) Magnesium stearate 2.0 mg 215.0 mg Preparation:

(1), (2) and (3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granules. From this mixture, compressed tablets are produced, biplanar, facetted on both sides and notched on one side. Diameter of tablets: 9 mm.

Exam~L~_Z8 Tablet containing 350 mg of active substance Composition:

(1) Activ~ substance 350.0 mg (2) Lactose 136.0 mg (3) Corn starch 80.0 mg - 133 - 212~37~
(4) Polyvinylpyrrolidone 30.0 mg (5) Magnesium stearate 4.0 mg 600.0 mg Preparation:

(1), (2) and ~3) are mixed together and granulated with an aqueous solution of (4). (5) is added to the dried granules. From this mixture, compressed tablets are produced, biplanar, facetted on both sides and notched on one side. Diameter of tablets: 12 mm.

E~am~le 29 Capsules containing 50 mg of active substance Composition:

(1) Active substance 50.0 mg (2) Dried corn starch 58.0 mg (3) Powdered lactose 50.0 mg (4) Magnesium stearate 2.0 mq 160.0 mg Preparation:

(1) is triturated with (3). This triturate is added to the mixture of (2) and (4), with thorough mixing.

This powdered mixture is packed into size 3 hard gelatin oblong capsules in a capsule filling machine.

~12~3~

Example 30 Capsules containing 350 mg of active substance -Composition:

(1) Active substance 350.0 mg (2) Dried corn starch 46.0 mg (3) Powdered lactose 30.0 mg (4) Magnesium stearate 4.0 mg 430.0 mg Preparation:

(1) is triturated with (3). This triturate is added to the mixture of (2) and (4), with thorough mixing.

This powdered mixture is packed into size O hard gelatin oblong capsules in a capsule filling nachine.

.

Claims (12)

1. Carbonamides of general formula A - B - C - D - E - F - G (I) wherein A represents an azacycloalkyl or azacycloalkenyl group each having 5 to 7 ring members or an azabicycloalkyl group having 6 to 9 ring members, in which the nitrogen atom, provided it is not in a bridging position, carries in each case a group R1 wherein R1 represents a hydrogen atom, an alkyl group optionally substituted by an aryl group, an alkoxycarbonyl group having a total of 2 to 6 carbon atoms in which a methoxy or ethoxy moiety may additionally be substituted by a phenyl group, or R1 denotes a R2-CO-O-(HCR3)-O-CO- group, in which R2 represents an alkyl group having 1 to 5 carbon atoms, an alkoxy group, or a cycloalkyl or cycloalkyloxy group each having 3 to 7 carbon atoms and R3 represents a hydrogen atom or an alkyl group, or A represents an alkyl or cycloalkyl group substituted by a R1-NH group in which the alkyl moiety may contain 1 to 4 carbon atoms, the cycloalkyl moiety may contain 3 to 7 carbon atoms and R1 is as hereinbefore defined, or A represents a diazacycloalkyl group having 5 to 7 ring members in which one of the nitrogen atoms carries a group R1 wherein R1 is as hereinbefore defined, or A represents a 4-pyridyl group:

B represents an alkylene group having 1 to 4 carbon atoms, an alkenylene group having 2 to 4 carbon atoms, an oxygen or sulphur atom, or a carbonyl or -NR4- group in which R4 represents a hydrogen atom, or an alkyl, alkylcarbonyl, alkyloxycarbonyl or alkylsulphonyl group optionally substituted in the alkyl moiety by an aryl group, or R4 represents an arylcarbonyl or arylsulphonyl group, or B represents a -W-alkylene- or -alkylene-W- group (with the proviso that if A denotes an HNR1-alkyl group B
cannot represent an -alkylene-W- group) wherein W
represents an oxygen or sulphur atom, or a carbonyl, sulphinyl, sulphonyl or -NR4- group and R4 is as hereinbefore defined, or B represents an alkylene-CO-NR5- group which is bound to the group C via the nitrogen atom and in which R5 is a hydrogen atom or an alkyl group optionally substituted by an aryl group, or B represents a -CONR5- or -NR5CO- group wherein R5 is as hereinbefore defined, or, if A represents an alkyl or cycloalkyl group substituted by an R1NH-alkyl group, B may also denote a bond, and generally A and B together may not represent a R1NH-alkyl-CO or R1NH-alkyl-CO-NR5 group;
C represents a 1,3- or 1,4-phenylene group which may be mono- or disubstituted by fluorine, chlorine or bromine atoms, or by alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl, alkylsulphonyl, hydroxy, nitro or (R5NR6)- groups, wherein the substituents may be identical or different, with the proviso that at the same time A may not represent a pyridyl group and B a -CO-, -CH2-, -CH=CH- or -CONH- group and R5 is as hereinbefore defined and R6 represents a hydrogen atom, an alkyl group optionally substituted by an aryl group, an alkylsulphonyl group having 1 to 5 carbon atoms in the alkyl moiety, an alkylcarbonyl, arylalkylcarbonyl, arylcarbonyl, aralkylsulphonyl or arylsulphonyl group, or C represents a cycloalkylene group having 5 to 7 carbon atoms in which one or two >CH- units may each be replaced by a nitrogen atom, although A and C may not simultaneously represent piperidine rings if B is a -(CH2)3- group, or C represents a cycloalkylene group having 5 to 7 carbon atoms in which two adjacent methylene groups are replaced by an o-phenylene group, and in which the saturated part is bound to group B or, if B represents a bond, to group A, and the unsaturated part is bound to group D;

D represents an alkylene, alkylene-carbonyl, carbonyl-alkylene, alkylene-CO-NR5, -CO-NR5-alkylene or -NR5-CO-alkylene group wherein R5 is as hereinbefore defined, or D represents a carbonyl group, or D represents an -NR5CONR5- or -NR5CC- group or, if B
and C together do not represent a -CH2CH2-CONH-1,3-phenylene group, D may also represent a -CONR5- group, wherein R5 is as hereinbefore defined;
E represents an alkylene group having 1 to 5 carbon atoms although A, B, C, D and E cannot together represent a 2-[[4-(R1-piperidin-4-yl-aminocarbonyl)-phenyl]-aminocarbonyl]-ethyl or 2-[4-[2-(R1-piperazin-4-yl)-ethyl]-phenyl]-ethyl group, or E represents an alkenylene group having 3 to 5 carbon atoms or a vinylene group, if A is not an aminocyclohexyl group, or E represents a 1,3- or 1,4-phenylene group optionally mono- or disubstituted by a fluorine, chlorine or bromine atom or by an alkyl or alkoxy group, wherein the substituents may be identical or different, with the proviso that E cannot be an optionally substituted phenylene group if C and D together represent a phenylenemethyl, phenylenecarbonyl, cyclohexylenemethyl or cyclohexylenecarbonyl group and A simultaneously represents a R1NH-alkyl group, or A, B, C and D together represent an aminomethyl-cyclohexylcarbonylamino group, an aminomethyl-phenylaminocarbonyl or aminomethyl-phenylcarbonylethyl group, or E represents a cycloalkylene group having 5 to 7 carbon atoms in which one or two >CH- units may be substituted by a nitrogen atom or one or two >CH2- groups may be substituted by a >NH- group, and which is optionally substituted by an alkylsulphonyl group having 1 to 5 carbon atoms in the alkyl moiety, or by an alkyl, hydroxy, alkoxy, alkylcarbonyl, aralkylcarbonyl, arylcarbonyl, aralkylsulphonyl, arylsulphonyl or (R5NR6)-group, wherein R5 and R6 are as hereinbefore defined, or if F does not represent a bond, E may also denote an alkylene-NR7- group wherein the bond to group F is via the nitrogen atom and wherein R7 represents a hydrogen atom, an alkyl, arylalkyl, alkylcarbonyl, arylalkylcarbonyl, arylcarbonyl, arylalkylsulphonyl or arylsulphonyl group, an alkylsulphonyl group having 1 to 5 carbon atoms, an R5O-alkylene-CO- group or an alkyl group substituted by an R8-CO- group wherein R5 is as hereinbefore defined and R8 represents an hydroxy, amino, alkylamino, dialkylamino, alkoxy or arylalkoxy group;
F represents a bond, or F represents an alkylene group having 1 to 4 carbon atoms, although if A is an R1NH-alkyl group, D, E and F
cannot together represent an alkylene group having more than 3 carbon atoms, or F represents a -W'-alkylene group, wherein W' represents an oxygen or sulphur atom, or a sulphinyl, sulphonyl or an -NR4- group and the bond to group E is effected via group W' and R4 is as hereinbefore defined;
and G represents a carbonyl group which is substituted by a hydroxy group, by an alkoxy group having 1 to 6 carbon atoms, by a cycloalkyloxy or cycloalkylalkoxy group each having 3 to 7 carbon atoms in the cycloalkyl moiety, by an aryloxy group, by a phenoxy group substituted in the
2,3- or 3,4-position by an alkylene bridge having 3 to 5 carbon atoms, or by an R2-CO-O-(HCR3)-O- group, wherein R2 and R3 are as hereinbefore defined, or G represents a phosphono, O-alkyl-phosphono, O,O'-dialkyl-phosphono, sulpho or tetrazol-5-yl group, wherein at least 11 bonds must be positioned between group G and the NR1 group of group A or, if group A is a pyridyl group, the pyridyl nitrogen; and "an aryl group" as hereinbefore defined may represent a phenyl group optionally mono- or disubstituted by fluorine, chlorine or bromine atoms, or by alkyl or alkoxy groups, wherein the substituents may be identical or different and, unless specified otherwise, the above alkyl, alkylene or alkoxy moieties each contain 1 to 3 carbon atoms, the tautomers thereof, the stereoisomers thereof including the mixtures and salts thereof.

2. Carbonamides of general formula I according to claim 1, wherein A represents an aminoalkyl group having 1 to 4 carbon atoms in the alkyl moiety, an aminocycloalkyl group having 4 to 6 carbon atoms in the cycloalkyl moiety, or a piperidyl, tetrahydropyridyl or piperazinyl group wherein in each of the above-mentioned groups a nitrogen atom carries a group R1 and R1 represents a hydrogen atom, an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, or a benzyl, benzyloxycarbonyl or CH3-CO-O-CH2-O-CO-group, or A represents a quinuclidinyl or 4-pyridyl group;
B represents an alkylene group having 1 to 4 carbon atoms, a vinylene group, an oxygen atom, a carbonyl group or a -CH2-CONH- group wherein the nitrogen atom is bound to group C, a -W-CH2- or -CH2-W- group (with the proviso that if A
represents a HNR1-alkyl group B cannot represent a -CH2-W- group) wherein W is an oxygen or sulphur atom or a sulphinyl, sulphonyl or -NR4- group or, if the bond to group C is via group W, W may also represent a carbonyl group, wherein R4 represents a hydrogen atom or a benzyloxycarbonyl group, or B represents a -CO-NH- or -NH-CO- group, or, if A represents an aminoalkyl or aminocycloalkyl group substituted at the nitrogen by group R1, B may also represent a bond, and in general A and B together may not represent an R1-NH-alkyl-CO- or R1-NH-alkyl-CONH- group;
C represents a 1,3- or 1,4-phenylene group which may be substituted by a fluorine, chlorine or bromine atom, or by an alkyl, alkoxy, alkylsulphenyl, alkylsulphinyl or alkylsulphonyl group each having 1 or 2 carbon atoms, with the proviso that at the same time A may not be a pyridyl group and B a -CO-, -CH2-, -CH=CH- or -CONH-group, or C represents a cyclohexylene, piperidinylene or piperazinylene group although A and C cannot simultaneously represent piperidine rings if B is a -(CH2)3- group, or C represents a 1,2,3,4-tetrahydro-naphthylene group in which a saturated part is bound to group A and the unsaturated part is bound to group D;

D represents a -CO-, -CO-NR5-, -NR5-CO- or -NR5-CO-NR5-group, wherein R5 represents a hydrogen atom, or a methyl or ethyl group, or D represents a -CH2-CO- or -CH2-CO-NH- group wherein the methylene group is bound in each case to group C, or a -CO-NH-CH2- group wherein the carbonyl group is bound to group C;

E represents an alkylene group having 2 to 5 carbon atoms although A, B, C, D and E together may not represent a 2-[[4-(R1-piperidin-4-yl-aminocarbonyl)-phenyl]-aminocarbonyl]-ethyl group, or E represents a cyclohexylene group optionally substituted by an alkylsulphonylamino group having 1 to 5 carbon atoms in the alkyl moiety, or by an amino, formylamino, acetylamino or propionylamino group, or E represents a piperidinylene group optionally substituted on the nitrogen atom by an alkylsulphonyl group having 1 to 5 carbon atoms, or E represents a piperazinylene group, or if A
represents an R1-NH-alkyl groupand C and D do not together represent a phenylenecarbonyl or cyclohexylenecarbonyl group or if A, B, C, D together do not represent an aminomethyl-cyclohexylcarbonylamino or aminomethyl-phenylaminocarbonyl group, E may also represent a 1,3- or 1,4-phenylene group, or, if F does not represent a bond, E may also represent an alkylene-NR7 group wherein the bond to group F is via the nitrogen atom and wherein the alkylene moiety may contain 1 to 3 carbon atoms and R7 represents a hydrogen atom, an alkylsulphonyl group having 1 to 5 carbon atoms, an alkoxycarbonylmethyl group having 1 or 2 carbon atoms in the alkoxy moiety, or a benzyl, carboxymethyl, aminocarbonylmethyl, hydroxymethylcarbonyl or benzyloxymethylcarbonyl group;
F represents a bond, an alkylene group having 1 to 3 carbon atoms, or an -O-alkylene group having 1 to 2 carbon atoms wherein the bond to group E is via the oxygen atom; and G represents a carbonyl group which is substituted by a hydroxy group, by an alkoxy group having 1 to 5 carbon atoms, or by a cyclohexyloxy, indanyloxy or R2-CO-O-(HCR3)-O- group, wherein R2 represents an alkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 3 carbon atoms or a cyclohexyloxy group and R3 represents a hydrogen atom or a methyl group, wherein at least 11 bonds must be positioned between group G and the NR1 group of group A or, if group A
represents a pyridyl group, the pyridyl nitrogen, the tautomers thereof, the stereoisomers thereof including the mixtures and salts thereof.
3. Carbonamides of general formula I according to claim 1 wherein A represents an aminomethyl, aminoethyl, piperidyl, tetrahydropyridyl, piperazinyl, aminocyclopentyl or aminocyclohexyl group wherein in each of the above groups a nitrogen atom carries a group R1 and R1 represents a hydrogen atom, an alkoxycarbonyl group having a total of 2 to 5 carbon atoms or a benzyl group, or A represents a quinuclidinyl or 4-pyridyl group;
B represents an ethylene or vinylene group, an oxygen atom, a carbonyl, -NH-CO- or -CO-NH- group, a -CH2-CONH- group wherein the nitrogen atom is bound to group C, an -O-CH2- group wherein the methylene group is bound to group C, a -CH2-W- group (with the proviso that, if A represents an R1-NH-methyl or R1-NH-ethyl group, B may not represent a -CH2W- group) wherein W is bound to group C and represents an oxygen atom, or a -CO- or -NR4- group wherein R4 denotes a hydrogen atom or a benzyloxycarbonyl group, or, if A represents an R1-NH-methyl, R1-NH-ethyl, R1-NH-cyclopentyl or R1-NH-cyclohexyl group, B may also represent a bond and in general A and B together cannot represent an R1-NH-alkyl-CO- or R1-NH-alkyl-CONH- group;
C represents a cyclohexylene or piperidinylene group or a 1,2,3,4-tetrahydro-naphthylene group wherein the saturated part is bound to group A and the unsaturated part to group D, or with the proviso that at the same time A does not represent a pyridyl group and B a -CO-, -CH=CH- or -CONH- group, C may also represent a 1,3- or 1,4-phenylene group;
D represents a -CO- group, an -NH-CO-, -CO-NH- or -HNCONH- group, or a -CH2CO- or -CH2-CO-NH- group wherein the methylene group is bound in each case to group C, or a -CONH-CH2-group wherein the CO group is bound to group C;
E represents an alkylene group having 2 to 4 carbon atoms, a cyclohexylene group optionally substituted by an alkylsulphonylamino group having 1 to 4 carbon atoms in the alkyl moiety, or by an amino or acetylamino group, a piperidinylene group optionally substituted at the nitrogen atom by an alkylsulphonyl group having 1 to 4 carbon atoms, or if C and D together do not represent a phenylenecarbonyl or cyclohexylene-carbonyl group when A
is simultaneously an R1-NH-methyl- or R1-NH-ethyl- group, or if A, B, C and D together do not represent an aminomethyl-cyclohexyl-carbonylamino group, E may also represent a 1,3- or 1,4-phenylene group, or, if F does not represent a bond, E may also represent a -CH2CH2-NR7- group wherein the bond to group F is via the nitrogen atom and R7 represents a hydrogen atom, an alkylsulphonyl group having 1 to 4 carbon atoms, an alkoxycarbonylmethyl group having 1 or 2 carbon atoms in the alkoxy moiety, a benzyl, carboxymethyl, aminocarbonylmethyl, hydroxymethylcarbonyl or benzyloxymethylcarbonyl group;
F represents a bond, an alkylene group having 1 or 2 carbon atoms, an -O-CH2 group wherein the oxygen atom is bound to group E; and G represents a carbonyl group which is substituted by a hydroxy group or by an alkoxy group having 1 to 3 carbon atoms, wherein at least 11 bonds must be positioned between group G and the NR1 group of group A or, if group A
represents a pyridyl group, the pyridyl nitrogen; and the tautomers, the stereoisomers thereof including the mixtures thereof and salts thereof.
4. Carbonamides of general formula I according to claim 1, wherein A represents a 4-pyridyl group, a quinuclidinyl group or an aminomethyl, aminoethyl or piperidyl group optionally substituted on the nitrogen atom by a benzyl group, wherein the piperidyl group is not bound to groups B or C via the ring nitrogen atom;
R represents an oxygen atom, a -CH2CH2-, -O-CH2-, -CO-NH-or -NH-CO- group or a -CH2O- group with the proviso that if A represents an aminomethyl or aminoethyl group, B
cannot represent a -CH2-O- group, or, if A represents an aminomethyl or aminoethyl group optionally substituted at the nitrogen atom by a benzyl group, B may also represent a bond, and in general A and B together cannot represent an H2N-alkyl-CONH group optionally benzylated on the amine nitrogen;
C represents a cyclohexylene or piperidinylene group or a 1,2,3,4-tetrahydro-naphthylene group wherein the saturated part is bound to group A and the unsaturated part is bound to group D, or C represents a 1,3- or 1,4-phenylene group with the proviso that at the same time A may not represent a pyridyl group and B a -CH=CH- or -CONH- group;
D represents a -CO- group or a -CO-NH- group wherein the carbonyl group is bound to group C, or D represents an -NHCONH- group;
E represents a cyclohexylene group optionally substituted by an alkylsulphonylamino group having 1 to 4 carbon atoms in the alkyl moiety or by an amino group, or E represents a piperidinylene group, or, if C and D do not together represent a phenylenecarbonyl or cyclohexylenecarbonyl group when at the same time A is an aminomethyl or aminoethyl group optionally substituted at the nitrogen atom by a benzyl group, or if A, B, C and D together do not represent an aminomethyl-cyclohexylcarbonylamino group, E may also represent a 1,3- or 1,4-phenylene group, or, if F does not represent a bond, E may also represent a -CH2CH2-NH- group substituted on the nitrogen atom by an alkylsulphonyl group having 1 to 4 carbon atoms in the alkyl moiety, wherein the bond to group F is via the nitrogen atom;
F represents a bond, an alkylene group having 1 or 2 carbon atoms, an -O-CH2- group in which the oxygen atom is bound to group E; and G represents a carbonyl group which is substituted by a hydroxy group or by an alkoxy group having 1 to 3 carbon atoms, wherein at least 11 bonds must be positioned between the nitrogen atom of the relevant group A and group G;
the tautomers thereof, the stereoisomers including the mixtures thereof and the salts thereof.
5. Carbonamides of general formula I according to claim 1, wherein A represents a 2-aminoethyl, piperidin-4-yl or quinuclidin-4-yl group;
B represents an oxygen atom, a -CH2CH2- or -O-CH2- group or a -CH2O- group with the proviso that, if A represents a 2-amino-ethyl group, B cannot represent a -CH2-O- group or, if A is a 2-aminoethyl group, B may also represent a bond;
C represents a 1,3- or 1,4-phenylene group or a 1,4-piperidinylene group;
D represents a -CO- group or a -CO-NH- group in which the carbonyl group is linked to group C;
E represents a cyclohexylene group optionally substituted by an amino group, or a 1,4-piperidinylene group, or, if C and D together do not represent a phenylenecarbonyl group when A simultaneously represents an aminoethyl group, E may also represent a 1,4-phenylene group;
F represents a bond, a -CH2-, -CH2CH2- or -O-CH2- group wherein the oxygen atom is bound to group E; and G represents a carbonyl group which is substituted by a hydroxy group or by an alkoxy group having 1 to 3 carbon atoms, wherein at least 11 bonds must be positioned between the nitrogen atom of the relevant group A and group G; and the tautomers thereof, the stereoisomers including the mixtures thereof and the salts thereof.
6. The following compounds of general formula I
according to claim 1:
(a) 4-carboxymethyl-1-[4-[2-(4-quinuclidinyl)-ethyl]-benzoyl]-piperidine, (b) 1-carboxy-cis-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexylamine, (c) trans-4-[4-[(4-quinuclidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid, (d) trans-4-[[4-[4(-piperidinyl)-oxymethyl]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid, (e) trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylic acid, (f) trans-4-[4-[(4-piperidinyl)-methyloxy]-benzoylamino]-cyclohexane carboxylic acid, (g) methyl trans-4-[[4-[(4-piperidinyl)-methyloxy]-1-piperidinyl]-carbonylamino]-cyclohexane carboxylate and (h) 3-[trans-4-[4-[(2-amino-ethyloxy)-benzoylamino]-cyclohexyl]-propionic acid, the tautomers thereof and salts thereof.
7. Physiologically acceptable salts of the compounds according to at least one of claims 1 to 6, with inorganic or organic acids or bases.
8. Pharmaceutical composistions containing a compound according to at least one of claims 1 to 6 or a physiologically acceptable salt according to claim 7 optionally in addition to one or more inert carrier substances and/or diluents.
9. Use of a compound according to at least one of claims 1 to 7 for preparing a pharmaceutical composition suitable for combating or preventing illness in which smaller or larger cell aggregates occur or cell matrix interactions are involved.
10. A process for preparing a pharmaceutical composition according to claim 8, characterised in that a compound according to at least one of claims 1 to 7 is incorporated into one or more inert carrier substances and/or diluents, using a non-chemical method.
11. A process for preparing carbonamides according to claims 1 to 7, characterised in that a) in order to prepare compounds of general formula I, wherein A is as defined in claims 1 to 6, and G
represents a carboxyl group or G is as defined in claims 1 to 6 and A has the meanings given for A in claims 1 to 6 with the proviso that A contains an H-N< or R1-NH group wherein R1 denotes a hydrogen atom or an alkyl group optionally substituted by an aryl group: a compound of general formula Aa - B - C - D - E - F - Ga (II) (wherein B to F are defined as in claims 1 to 6, Aa has the meaning of A and Ga has the meaning of G as given in claims 1 to 6, with the proviso that Aa contains a group which may be converted into an imino or R1'-NH-group by means of hydrolysis, treatment with an acid, thermolysis or hydrogenolysis, or Ga represents a group which may be converted into a carboxyl group by means of hydrolysis, treatment with an acid, thermolysis or hydrogenolysis, or Aa contains a group which may be converted into an imino or R1'NH- group by means of hydrolysis, treatment with an acid, thermolysis or hydrogenolysis and Ga represents a group which may be converted into a carboxyl group by means of hydrolysis, treatment with an acid, thermolysis or hydrogenolysis, wherein R1' represents a hydrogen atom or an alkyl group optionally substituted by an aryl group), using hydrolysis, treatment with an acid, thermolysis or hydrogenolysis, is converted into a compound of general formula I wherein A is as defined in the above claims 1 to 6 and G is a carboxyl group or G is defined as in the above claims 1 to 6 and A has the meanings given for A
in claims 1 to 6, with the proviso that A contains an H-N< or R1'-NH- group, wherein R1' is as hereinbefore defined, or b) in order to prepare compounds of general formula I, wherein B, C or D contain or represent a carbonyl group bound to a nitrogen atom: a carboxylic acid of general formula A - Ba - COOH (III) is reacted with a compound of general formula H-Ca - D - E - F - G (IV) or a carboxylic acid of general formula HOOC-Ca - D - E - F - G (V) is reacted with a compound of general formula A - Bb - H (VI) or a carboxylic acid of general formula A - B - Ca - COOH (VII) is reacted with a compound of general formula H - Db - E - F - G (VIII) or a carboxylic acid of general formula HOOC - Da - E - F - G (IX) is reacted with a compound of general formula A - B - Cb - H (X) or a carboxylic acid of general formula A - B - C - Da - COOH (XI) is reacted with a compound of general formula H-Eb - F - G (XII) or a carboxylic acid of general formula HOOC - Ea - F - G (XIII) is reacted with a compound of general formula A - B - C - Db - H (XIV) wherein A to G are as defined in claims 1 to 6, Ba, ca, Da and Ea each have the meanings given in claims 1 to 6 for B, C, D and E respectively with the proviso that B, C, D or E additionally contains the carboxyl group which takes part in the reaction or one of the reactive derivatives thereof or, instead of a carbonyl group by means of which they are bound to a nitrogen atom of an adjacent group, a carboxyl group or one of the reactive derivatives thereof, Bb, Cb, Db and Eb each have the meanings given in claims 1 to 6 for B, C, D or E respectively with the proviso that B, C, D or E additionally contains the H2N or HNR5 group which takes part in the reaction or, instead of a nitrogen atom via which they are bound to a carbonyl group of an adjacent group, the reactive amino or imino group, or c) In order to prepare compounds of general formula I
wherein R4 represents an alkyl, alkylcarbonyl or alkyloxycarbonyl group optionally substituted in the alkyl moiety by an aryl group, or R4 represents an arylcarbonyl, alkylsulphonyl or arylsulphonyl group and/or R6 or R8 represent an alkyl, arylalkyl, alkylcarbonyl, arylalkylcarbonyl, arylcarbonyl, arylalkylsulphonyl or arylsulphonyl group, an alkylsulphonyl group having 1 to 5 carbon atoms, an alkyl group substituted by an R8-CO- group or an alkylcarbonyl group substituted by an R5O- group:
a compound of general formula A - B - C - D - E - F - G (XV) (wherein A to G are as defined in claims 1-6, with the proviso that at least one of groups B or E contain an -NH- group not bound to a carbonyl group) is reacted with a compound of general formula Z1 _ Ra (XVI) wherein Ra, with the exception of the hydrogen atoms, has the meanings given in claims 1 to 6 for R4, R6 or R8 and Z1 represents a leaving group, or in the case of an acylation also an alkylcarbonyloxy or alkoxycarbonyloxy group or Z1 together with an adjacent hydrogen atom of group Ra denotes an oxygen atom, or d) In order to prepare compounds of general formula I

wherein B represents an oxyalkylene or alkyleneoxy group each having 1 to 3 carbon atoms:
a compound of general formula A - Z2 (XVII) is reacted with a compound of general formula Z3 - C - D - E - F - G (XVIII) wherein A and C to G are as defined in claims 1 to 6, one of groups Z2 or Z3 represents a hydroxy group or a hydroxy substituted alkyl group having 1 to 3 carbon atoms and the other group of groups Z2 or Z3 represents a leaving group or an alkyl group having 1 to 3 carbon atoms and substituted by a leaving group, or e) In order to prepare a compound of general formula I, wherein A represents an amino-substituted alkyl group having 1 to 4 carbon atoms:
a compound of general formula NC- (CH2)n - B - C - D - E - F - G (XIX) (wherein B to G are as defined in claims 1 to 6 and n represents the number 0, 1, 2 or 3) is reduced, or f) In order to prepare compounds of general formula I
wherein B represents an alkylene group having 2 or 3 carbon atoms and/or A represents a piperidinyl group:
a compound of general formula AC Bc - C - D - E - F - G (XX) (wherein C to G are as defined in claims 1 to 6, Ac has the meanings given for A in claims 1 to 6 and Bc represents an alkenylene group having 2 or 3 carbon atoms or Bc has the meanings given for B in claims 1 to 6 and Ac represents a pyridyl group) is reduced, or g) In order to prepare compounds of general formula I
wherein R1 represents an alkoxycarbonyl group having a total of 2 to 6 carbon atoms, in which a methoxy or ethoxy moiety may additionally be substituted by a phenyl group, or R1 represents an R2-CO-O-(HCR3)-O-CO
group:
a compound of general formula Ad - B - C - D - E - F - G (XXI) (wherein B to G are as defined in claims 1 to 6 and Ad has the meanings given for A in claims 1 to 6, with the proviso that A contains an H-N< group or represents an alkyl or cycloalkyl group substituted by an amino group, wherein the alkyl moiety may contain 1 to 4 carbon atoms and the cycloalkyl moiety may contain 3 to 7 carbon atoms) is reacted with a compound of general formula Z4 - R10 ( XX II) wherein R1" represents an alkoxycarbonyl group having a total of 2 to 6 carbon atoms wherein a methoxy or ethoxy moiety may additionally be substituted by a phenyl group, or R1 represents an R2-CO-O-(HCR3)-O-CO- group wherein R2 and R3 are as defined in claims 1 to 6, and Z4 represents a leaving group, or h) In order to prepare compounds of general formula I
wherein G represents a carbonyl group which may be substituted by an alkoxy group having 1 to 6 carbon atoms, by a cycloalkyloxy group having 3 to 7 carbon atoms or by a phenoxy group which may be substituted in the 2,3- or 3,4-position by an alkylene bridge having 3 to 5 carbon atoms:
a carboxylic acid of general formula A - B - C - D - E - F - COOH (XXIII) (wherein A to F are as defined in claims 1 to 6) or the reactive derivatives optionally prepared in the reaction mixture, is reacted with an alcohol of general formula HO - Rb (XXIV) wherein Rb represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or a phenyl group which may be substituted in the 2,3- or 3,4-position by an alkylene bridge having 3 to 5 carbon atoms, or i) In order to prepare compounds of general formula I
wherein G represents a carbonyl group which is substituted by an alkoxy group having 1 to 6 carbon atoms, by a cycloalkyloxy group having 3 to 7 carbon atoms or by a R2-CO-O-(HCR3)-O- group:
a compound of general formula A - B - C - D - E - F - COOH (XXIII) (wherein to F are as defined in claims 1 to 6) is reacted with a compound of general formula Z5 - Rc (XXV) wherein Rc represents an alkyl group having 1 to 6 carbon atoms, a cycloalkyl group having 3 to 7 carbon atoms or a R2-CO-O-(HCR3)- group wherein R2 and R3 are as defined in claims 1 to 6, and Z5 represents a leaving group, or j) In order to prepare compounds of general formula I
wherein at least one of the groups C or E represent a cyclohexylene group:
a compound of general formula A - B - Cd - D - Ed - F - G (XXVI) (wherein A, B, D, F and G are as defined in claims 1 to 6, Cd and Ed have the meanings given for C and E in claims 1 to 6, with the proviso that at least one of groups Cd or Ed represent a phenylene group) is hydrogenated, or k) In order to prepare compounds of general formula I
wherein D represents a -NR5CONR5- group:
a compound of general formula A - B - C - U1 (XXVII) is reacted with a compound of general formula U2 - E - F - G (XXVIII) A, B, E, F and G are as defined in claims 1 to 6, one of groups U1 or U2 represents an HNRs- group and the other group of groups U1 or u2 represents a Z6-CO-NR5-group wherein R5 is defined as in claims 1 to 6 and Z6 represents a nucleophilic leaving group or Z6 and Rs together represent a further carbon-nitrogen bond, or 1) In order to prepare compounds of general formula I
wherein A represents an azacyclohexenyl group substituted at the nitrogen atom by an alkyl group having 1 to 3 carbon atoms and optionally substituted by an aryl group:

a compound, optionally formed in the reaction mixture, of general formula Ae - B - C - D - E - F - G (XXIX) (wherein B to G are as defined in claims 1 to 6 and Ae represents a 4-pyridyl group substituted at the nitrogen atom by an alkyl group having 1 to 3 carbon atoms and optionally substituted by an aryl group) is reduced with a complex metal hydride, and if desired, a compound of general formula I thus obtained which contains a sulphenyl group is converted into a corresponding sulphinyl or sulphonyl compound of general formula I, by means of oxidation, or a compound of general formula I thus obtained which contains a sulphinyl group is converted into a corresponding sulphonyl compound, by means of oxidation, or a compound of general formula I thus obtained is resolved into the stereoisomers thereof and/or if necessary a protecting group used during the reactions to protect any reactive groups is removed by cleaving and/or a compound of general formula I thus obtained is converted into the salts thereof, more particularly for pharmaceutical use into the physiologically acceptable salts thereof with an inorganic or organic acid or base.
12. A commercial package containing, as active pharmaceutical ingredient, a carbonamide of the general formula (I) according to any one of claims 1 to 6, or a physiologically acceptable salt thereof, together with instructions for its use for combating or preventing illnesses in which smaller or larger cell aggregates occur or cell matrix interactions are involved.
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US7504511B2 (en) 2003-04-25 2009-03-17 Sanofi-Aventis 2-acylamino-4-phenylthiazole derivatives, preparation thereof and therapeutic application thereof
US7777041B2 (en) 2003-04-25 2010-08-17 Sanofi-Aventis 2-acylamino-4-phenylthiazole derivatives, preparation thereof and therapeutic application thereof
US8163926B2 (en) 2005-09-30 2012-04-24 Astrazeneca Ab Process for the synthesis of piperidinyl sulphonate esters
US8865899B2 (en) 2005-09-30 2014-10-21 Astrazeneca Ab Chemical process for the synthesis of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
US9815816B2 (en) 2005-09-30 2017-11-14 Genzyme Corporation Chemical process for the synthesis of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
US10344015B2 (en) 2005-09-30 2019-07-09 Genzyme Corporation Chemical process for the synthesis of 4-(4-bromo-2-fluoroanilino)-6-methoxy-7-(1-methylpiperidin-4-ylmethoxy)quinazoline
US8044052B2 (en) 2006-10-18 2011-10-25 Pfizer Inc. Biaryl ether urea compounds
US10023528B2 (en) 2011-04-13 2018-07-17 Bayer Pharma Aktiengesellschaft Branched 3-phenylpropionic acid derivatives and their use
US10259776B2 (en) 2011-04-13 2019-04-16 Bayer Intellectual Property Gmbh Branched 3-phenylpropionic acid derivatives and their use
US11377417B2 (en) 2011-04-13 2022-07-05 Bayer Intellectual Property Gmbh Branched 3-phenylpropionic acid derivatives and their use
US11344519B2 (en) 2018-07-24 2022-05-31 Bayer Pharma Aktiengesellschaft Orally administrable modified-release pharmaceutical dosage form

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