# Patent

## Title
Cyclic pyrimidin-4-carboxamides as CCR2 receptor antagonists for treatment of inflammation, asthma and COPD

## Abstract

The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases, especially pulmonary diseases like asthma and COPD.

## Background
This application is a continuation of U.S. Ser. No. 13/140,591, filed Aug. 10, 2011.


FIELD OF INVENTION
The present invention relates to novel antagonists for CCR2 (CC chemokine receptor 2) and their use for providing medicaments for treating conditions and diseases where activation of CCR2 plays a causative role, especially pulmonary diseases like asthma and COPD, neurologic disease, especially of pain diseases, immune related diseases, especially diabetes mellitus including diabetes nephropathy, and cardiovascular diseases, especially atherosclerotic disease.
BACKGROUND OF THE INVENTION
The chemokines are a family of small, proinflammatory cytokines, with potent chemotatctic activities. Chemokines are chemotactic cytokines that are released by a wide variety of cells to attract various cells, such as monocytes, macrophages, T cells, eosinophils, basophils and neutrophils to sites of inflammation.
Chemokine receptors, such as CCR2 or CCR5 have been implicated as being important mediators of inflammatory and immunoregulatory disorders and diseases as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. Accordingly, agents which modulate chemokine receptors such as the CCR2 and CCR5 receptor would be useful in such disorders and diseases.
In particular it is widely accepted that numerous conditions and diseases involve inflammatory processes. Such inflammations are critically triggered and/or promoted by the activity of macrophages, which are formed by differentiation out of monocytes. It has further been found that monocytes are characterized by, e.g., a high expression of membrane-resident CCR2, whereas the CCR2 expression in macrophages is lower. CCR2 is a critical regulator of monocytes trafficking, which can be described as the movement of the monocytes towards an inflammation along a gradient of monocyte chemoattractant proteins (MCP-1, MCP-2, MCP-3, MCP-4).
Therefore, in order to reduce macrophage-induced inflammation, it would be desirable to block the monocyte CCR2 by an antagonist, so that the monocytes can be less triggered to move towards an inflammation area for conversion into macrophages.
Based on the aforesaid there is a need for providing effective antagonists for CCR2, which are pharmacologically acceptable.


DESCRIPTION OF THE INVENTION
It has now been found that such effective CCR2 inhibitors can be provided by compounds according to general formula (I),




wherein R1 is -L1-R7,

wherein L1 is a linker selected from a bond or a group selected from —C1-C2-alkylene, and —C1-C2-alkenylene which optionally comprises one or more groups selected from —O—, —C(O)—, and —NH— in the chain and which is optionally substituted by a group selected from among —OH, —NH2, —C1-C3-alkyl, O—C1-C6-alkyl, and —CN,

wherein R7 is a ring selected from among —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, and —C5-C10-heteroaryl,

wherein the ring R7 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, and -halogen,

or wherein the ring R7 is optionally substituted with one or more groups selected from among —C1-C6-alkyl, —O—C1-C6-alkyl, —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C1-C6-alkenyl, and —C1-C6-alkynyl, optionally being further substituted by one or more groups selected from —OH, —NH2, —C1-C3-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and ═O,

or wherein the ring R7 is optionally further bi-valently substituted on two neighbouring ring atoms, such that an annellated ring is formed by one or more groups selected from among —C1-C6-alkylene, —C2-C6-alkenylene and —C4-C6-alkynylene, in which one or two carbon centers may optionally by replaced by 1 or 2 hetero atoms selected from N, O and S, the bivalent group being optionally substituted by one or more groups selected from —OH, —NH2, —C1-C3-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and ═O;

R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, —CF3, —OCF3, —OCF2H, and —OCFH2;

R3 is selected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, —OCH3, and —CN;

R4 and R5 are independently selected from among an electron pair, —H, —C1-C6-alkyl, —NH2, —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, —C5-C10-heteroaryl, and —C(O)—N(R8,R8′), with R8 and R8′ independently being selected from among —H and —C1-C6-alkyl,

wherein R4 and R5 if different from an electron pair or —H are optionally independently substituted with one or more groups selected from among -halogen, —OH, —CF3, —CN, —C1-C6-alkyl, —O—C1-C6-alkyl, —O—C3-C8-cycloalkyl, —O—C3-C8-heterocyclyl, —O—C5-C10-aryl, —O—C5-C10-heteroaryl, —C0-C6-alkylene-CN, —C0-C4-alkylene-O—C1-C4-alkyl, —C0-C4-alkylene-O—C3-C8-cycloalkyl, —C0-C4-alkylene-O—C3-C8-heterocyclyl, —C0-C4-alkylene-O—C5-C10-aryl, —C0-C4-alkylene-O—C5-C10-heteroaryl, —C0-C4-alkylene-Q-C0-C4-alkyl-N(R9,R9′), —C0-C4-alkylene-N(R10)-Q-C1-C4-alkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-N(R10)-Q-C5-C10-aryl, —C0-C4-alkylene-N(R10)-Q-C5-C10-heteroaryl, —C0-C4-alkylene-Q-N(R11,R11′), —C0-C4-alkylen-N(R12)-Q-N(R13,R13′), —C0-C4-alkylen-R14, —C0-C4-alkylene-Q-C1-C6-alkyl, —C0-C4-alkylene-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-Q-C5-C10-aryl, —C0-C4-alkylene-Q-C5-C10-heteroaryl, —C0-C4-alkylene-O-Q-N(R15,R10, and —C0-C4-alkylene-N(R16)-Q-O—(R17)

wherein Q is selected from among —C(O)— and —SO2—

wherein R12, R16, are independently selected from among —H, —C1-C6-alkyl, and —C3-C6-cycloalkyl,

wherein R9, R9′, R10, R11, R11′, R13, R13′, R15, R15′ are independently selected from among —H and —C1-C6-alkyl, and —C3-C6-cycloalkyl,

or wherein R9 and R9′, R11 and R11′, R13 and R13′, R15 and R15′, together form a —C2-C6-alkylene group, preferably a —C5-C6-alkylene group,

wherein R14 and R17 are independently selected from among —H, —C1-C6-alkyl, —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, and —C3-C8-heterocyclyl, wherein said —C3-C8-heterocyclyl optionally comprises nitrogen and/or —SO2— in the ring, and wherein R14 and R17 are optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —SO2—C1-C4-alkyl,

or wherein R4 and/or R5 are independently a group of the structure -L2-R18,

wherein L2 is selected from among —NH—, and —N(C1-C4-alkyl)-,

wherein R18 is selected from among —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, and —C3-C8-heterocyclyl,

wherein R18 is optionally substituted by one or more groups selected from among halogen, —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, —NH—C(O)—C1-C6-alkyl, —N(C1-C4-alkyl)-C(O)—C1-C6-alkyl, —C(O)—C1-C6-alkyl, —S(O)2—C1-C6-alkyl, —NH—S(O)2—C1-C6-alkyl, —N(C1-C4-alkyl)-S(O)2—C1-C6-alkyl, and —C(O)—O—C1-C6-alkyl,

and wherein R4, R5 and R18 are optionally further substituted by spiro-C3-C8-cycloalkyl or spiro-C3-C8-heterocyclyl such that together with R4, R5 and/or R18 a spirocycle is formed,

wherein said spiro-C3-C8-heterocyclyl optionally comprises one or more groups selected from among nitrogen, —C(O)—, —SO2—, and —N(SO2—C1-C4-alkyl)- in the ring,

or wherein R4, R5 and R18 are optionally further bi-valently substituted by one or more spirocyclic or annellated ring forming groups selected from among —C1-C6-alkylene, —C2-C6-alkenylene, and —C4-C6-alkynylene, in which one ore two carbon centers may optionally be replaced by one or two hetero atoms selected from among N, O and S and which may optionally be substituted by one or more groups on one ring atom or on two neighbouring ring atoms selected from among —OH, —NH2, —C1-C3-alkyl, O—C1-C6-alkyl, —CN, —CF3, —OCF3, and halogen;

R6 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;

A is selected from among a single bond, ═CH—, —CH2—, —O—, —S—, and —NH—;

n is 1, 2 or 3;

Z is C or N,

as well as in form of their acid addition salts with pharmacologically acceptable acids, as well as in form of their solvates and/or hydrates.

Preferred compounds of formula (I) according to the invention are compounds with R2, R3, R4, R5, R6, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L2, Z, Q, and n as herein before or below defined, wherein R1 is -L1-R7,
with L1 being a linker selected from a bond or a group selected from among —C1-C2-alkylene, and —C1-C2-alkenylene optionally comprising one or more groups selected from among —O—, —C(O)—, and, —NH— in the chain and optionally being substituted by a group selected from among —OH, —NH2, —C1-C3-alkyl, O—C1-C6-alkyl, and —CN,

wherein R7 is a ring selected from among —C3-C8-cycloalkyl, —C5-C10-aryl, —C3-C8-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O, and —C5-C10-heteroaryl comprising 1 or 2 hetero atoms selected from among N, and O,

wherein the ring R7 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, and -halogen,

or wherein the ring R7 is optionally substituted with one or more groups selected from among —C1-C6-alkyl, —O—C1-C6-alkyl, —C5-C10-aryl, —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C1-C6-alkenyl, and —C1-C6-alkynyl, optionally being substituted by one or more groups selected from —OH, —NH2, —C1-C3-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and ═O,

or wherein the ring R7 is optionally further bi-valently substituted by one or more annellated ring forming groups selected from among —C1-C6-alkylene, —C2-C6-alkenylene and —C4-C6-alkynylene, in which one or two carbon centers may optionally by replaced by 1 or 2 hetero atoms selected from N, and O, wherein the bivalent group is optionally substituted by one or more groups selected from —OH, —NH2, —C1-C3-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and ═O;

Preferred compounds of formula (I) according to the invention are compounds with R2, R3, R4, R5, R6, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L2, Z, Q, and n as herein before or below defined, wherein R1 is -L1-R7,
wherein L1 is a linker selected from among a bond, methylene, ethylene, methenylene, and ethenylene,
wherein L1, if different from a bond, is optionally substituted with one or more groups selected from among methyl, and ethyl,
wherein R7 is a ring selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, tetrahydrofuranyl, tetrahydropyranyl, oxepanyl, phenyl, pyridyl, and furanyl,
wherein the ring R7 is optionally substituted with one or more groups selected from among —F, —Cl, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, -t-butyl, —CF3, —O—CF3, —CN, —O-methyl, -furanyl and -phenyl, wherein said furanyl and said phenyl are optionally independently substituted by one or more groups selected from among —C1-C6-alkyl, or halogen, —OCH3, —CF3, and —OCF3.

or wherein R7 is bi-valently substituted by one or more groups selected from among





on two neighbouring ring atoms, such that an annellated ring is formed.

Preferred compounds of formula (I) according to the invention are compounds with R2, R3, R4, R5, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L2, Z, Q, and n as herein before or below defined, wherein R1 is -L1-R7,
and wherein L1 is a linker selected from among a bond, methylene, ethylene, methenylene, and ethenylene and wherein L1 is optionally substituted with one or more of methyl or ethyl and wherein L1 optionally comprises one or more —O— atoms.
Preferred compounds of formula (I) according to the invention are compounds with R2, R3, R4, R5, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L2, Z, Q, and n as herein before or below defined, wherein R1 is selected from among




























Preferred compounds of formula (I) according to the invention are compounds with R1, R3, R4, R5, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′′, R14, R15, R15′′, R16, R17, R18, A, L1, L2, Z, Q, and n as herein before or below defined, wherein R2 is selected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, -butyl, -i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH2, —C≡CH, and —OCH3, more preferred from among H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, and —OCH3.
Preferred compounds of formula (I) according to the invention are compounds with R1, R3, R4, R5, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Z, Q, and n as herein before or below defined, wherein R2 is selected from among —H, -Methyl, -Ethyl, —Br, and —OCH3.
Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R4, R5, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Z, Q, and n as herein before or below defined, wherein R3 is selected from among —H, and -methyl.
Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R3, R6, R7, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Z, Q, and n as herein before or below defined, wherein R4 and R5 are independently selected from among an electron pair, —H, -i-propyl, -amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and —C(O)—N(R8,R8′), with R8 and R8′ independently being selected from among —H and —C1-C6-alkyl,
wherein R4 and R5 are optionally independently substituted with one or more groups selected from among -fluoro, -methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl, -t-butyl, -hydroxy, —CF3, —OCF3, —CN, —O—CH3, —O—C2H5, —O—C3H7, —CH2—CN, —CH2—O—CH3, —(CH2)2—O—CH3, —C(O)—CH3, —C(O)—C2H5, —C(O)—C3H7, —COOH, —C(O)—NH2, —C(O)—NH—CH3, —C(O)—N(CH3)2, —NH—C(O)—CH3, —N(CH3)C(O)—CH3, —NH—C(O)—C2H5, —N(CH3)—C(O)—C2H5, —NH—C(O)—C3H7, —N(CH3)—C(O)—C3H7, —NH—SO2—CH3, —N(CH3)—SO2—CH3, —N(C2H5)—SO2—CH3, —N(C3H7)—SO2—CH3, —NH—SO2—C2H5, —N(CH3)—SO2—C2H5, —N(C2H5)—SO2—C2H5, —N(C3H7)—SO2—C2H5, —NH—SO2—C3H7, —N(CH3)—SO2—C3H7, —N(C2H5)—SO2—C3H7, —N(C3H7)—SO2—C3H7, —NH—SO2—C3H5, —N(CH3)—SO2—C3H5, —N(C2H5)—SO2—C3H5, —N(C3H7)—SO2—C2H5, —CH2—NH—SO2—CH3, —CH2—N(CH3)—SO2—CH3, —CH2—NH—SO2—C2H5, —CH2—N(CH3)—SO2—C2H5, —CH2—NH—SO2—C3H7, —CH2—N(CH3)—SO2—C3H7, —CH2—NH—SO2—C3H5, —CH2—N(CH3)—SO2—C3H5, —NH—C(O)—NH2, —N(CH3)—C(O)—NH2, —NH—C(O)—NH—CH3, —N(CH3)—C(O)—NH—CH3, —NH—C(O)—N(CH3)2, —N(CH3)—C(O)—N(CH3)2, —SO2—NH2, —SO2—NH(CH3), —SO2—N(CH3)2, —C(O)—NH—C2H5, —C(O)—N(CH3)—C2H5, —C(O)—N(CH3)—C3H7, —C(O)—N(CH3)—C4H9, —C(O)—NH—CH(CH3)—C2H5, —C(O)—N(CH3)—CH(CH3)—C2H5, —CH2—C(O)—NH2, —CH2—C(O)—NH—CH3, —CH2—C(O)—N(CH3)2, —N(CH3)—SO2—N(CH3)2, -phenyl, -pyridin-4-yl, —CH2-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl, -3-methyl-[1,2,4]oxadiazol-5-yl,




Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R3, R6, R7, R8, R8′, R9, R9′′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Z, Q, and n as herein before or below defined, wherein R4 and R5 are independently selected from among an electron pair, —H, -amino, -piperidinyl, -tetrahydropyranyl, and -pyrrolidinyl,
wherein R4 and R5 are optionally independently substituted with one or more groups selected from among -fluoro, —CF3, -hydroxy, —O—CH3, —OCF3, —CN, —NH—SO2—CH3, —N(CH3)—SO2—CH3, —N(C2H5)—SO2—CH3, —N(C3H7)—SO2—CH3, —NH—SO2—C2H5, —N(CH3)—SO2—C2H5, —N(C2H5)—SO2—C2H5, —N(C3H7)—SO2—C2H5, —NH—SO2—C3H7, —N(CH3)—SO2—C3H7, —N(C2H5)—SO2—C3H7, —N(C3H7)—SO2—C3H7, —NH—SO2—C3H5, —N(CH3)—SO2—C3H5, —N(C2H5)—SO2—C3H5, —N(C3H7)—SO2—C2H5, —CH2—NH—SO2—CH3, —CH2—N(CH3)—SO2—CH3, —CH2—NH—SO2—C2H5, —CH2—N(CH3)—SO2—C2H5, —CH2—NH—SO2—C3H7, —CH2—N(CH3)—SO2—C3H7, —CH2—NH—SO2—C3H5, —CH2—N(CH3)—SO2—C3H5, —NH—C(O)—NH2, —N(CH3)—C(O)—NH2, —NH—C(O)—NH—CH3, —N(CH3)—C(O)—NH—CH3, —NH—C(O)—N(CH3)2, —N(CH3)—C(O)—N(CH3)2, —SO2—NH2, —SO2—NH(CH3), —SO2—N(CH3)2, —C(O)—NH—C2H5, —C(O)—N(CH3)—C2H5, —C(O)—N(CH3)—C3H7, —C(O)—N(CH3)—C4H9, —C(O)—NH—CH(CH3)—C2H5, —C(O)—N(CH3)—CH(CH3)—C2H5, —CH2—C(O)—NH2, —CH2—C(O)—NH—CH3, —CH2—C(O)—N(CH3)2, —N(CH3)—SO2—N(CH3)2, -pyridin-4-yl, —CH2-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl, -3-methyl-[1,2,4]oxadiazol-5-yl,




Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R3, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, A, L1, Z, Q, and n as herein before or below defined, wherein R4 and R5 are independently a group of the structure -L2-R18, wherein L2 is selected from among —NH—, —N(CH3)— and —N(C2H5)—, wherein R18 is selected from among -tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, -morpholinyl, -chromanyl, -octahydro-pyrano-pyrrolyl, -octahydro-pyrano-pyridinyl, -octahydro-pyrano-oxazinyl, -oxaspirodecanyl, and -tetrahydro-naphthyridinyl, wherein R18 is optionally substituted by one or more groups selected from among —F, —CF3, —OCF3, —CN, —OH, —O—CH3, —CH3, —NH—C(O)—CH3, —N(CH3)—C(O)—CH3, —C(O)—CH3, —S(O)2—CH3, —NH—S(O)2—CH3, —N(CH3)—S(O)2—CH3, and —C(O)—O—C2H5.
Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R3, R4, R5, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Z, Q, and n as herein before or below defined, wherein R4, R5 and R18 are optionally further bi-valently substituted by one or more groups selected from among




on one ring atom or on two neighboring ring atoms, such that spirocyclic or annellated rings are formed.

Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R3, R5, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Z, Q, and n as herein before or below defined, wherein R4 is selected from among































Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R3, R4, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Z, Q, and n as herein before or below defined, wherein R5 is selected from among an electron pair, —H, and —C(O)—NH2.
Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R3, R4, R5, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Z, Q, and n as herein before or below defined, wherein R6 is selected from among —H, —CH3, —C2H5, —O—CH3, —O—C2H5, —F, —CF3, and —OCF3, and more preferred wherein R6 is selected from among H, and —O—CH3, and most preferred wherein R6 is —H.
Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R3, R4, R5, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, L1, L2, Z, Q, and n as herein before or below defined, wherein A is selected from among a single bond, ═CH—, —CH2, —O—, and —NH—, and more preferred wherein A is selected from among —O— and —NH—, and most preferred wherein A is —NH—.
Preferred compounds of formula (I) according to the invention are compounds with R1, R2, R3, R4, R5, R6, R7, R8, R8′, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Q, and n as herein before or below defined, wherein Z is selected from among C, and N, and more preferred wherein Z is C.
All of the above embodiments under formula (I) have to be understood to optionally be present in form of their individual optical isomers, mixtures of their individual optical isomers, or racemates, as well as in form of their acid addition salts with pharmacologically acceptable acids, as well as in form of their solvates and/or hydrates.
DEFINITIONS
Unless otherwise stated, all the substituents are independent of one another. If for example there might be a plurality of C1-C6-alkyl groups as substituents in one group, in the case of three substituents C1-C6-alkyl, one may represent methyl, one n-propyl and one tert-butyl.
Within the scope of this application, in the definition of possible substituents, these may also be represented in the form of a structural formula. An asterisk (*) in the structural formula of the substituent is to be understood as being the linking point to the rest of the molecule. Moreover, the atom of the substituent which follows the linking point is referred to as the atom in position number 1. Thus, for example, the groups N-piperidinyl (Piperidin-A), 4-piperidinyl (Piperidin-B), 2-tolyl (Tolyl-C), 3-tolyl (Tolyl-D), and 4-tolyl (Tolyl-E) are shown as follows:




If there is no asterisk (*) in the structural formula of the substituent, each hydrogen atom may be removed from the substituent and the valency thus freed may act as a binding site to the rest of a molecule. Thus, for example, (Tolyl-F) may represent 2-tolyl, 3-tolyl, 4-tolyl, and benzyl




By the term “branched or unbranched, saturated or unsaturated C1-C6-carbon chain” it is meant a chain of carbon atoms, which is constituted by six carbon atoms arranged in a row and which can optionally further comprise branches or one or more hetero atoms selected from N, O or S. Said carbon chain can be saturated or unsaturated by comprising double or triple bonds.
By the term “C1-C6-alkyl” (including those which are part of other groups) are meant branched and unbranched alkyl groups with 1 to 6 carbon atoms and by the term “C1-C4-alkyl” are meant branched and unbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to 4 carbon atoms are preferred. Examples for alkyl groups with 1-6 carbon atoms include: methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, neo-pentyl or hexyl. Optionally the abbreviations Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, t-Bu, etc. may also be used for the above-mentioned groups. Unless stated otherwise, the definitions propyl, butyl, pentyl and hexyl include all the possible isomeric forms of the groups in question. Thus, for example, propyl includes n-propyl and iso-propyl, butyl includes iso-butyl, sec-butyl and tert-butyl etc.
By the term “C1-C8-alkylene” (including those which are part of other groups) are meant branched and unbranched alkylene groups with 1 to 8 carbon atoms. By the term “C2-C8-alkylene” are meant branched and unbranched alkylene groups with 2 to 8 carbon atoms. By the term “C2-C6-alkylene” are meant branched and unbranched alkylene groups with 2 to 6 carbon atoms. By the term “C1-C4-alkylene” are meant branched and unbranched alkylene groups with 1 to 4 carbon atoms. By the term “C1-C2-alkylene” are meant branched and unbranched alkylene groups with 1 to 2 carbon atoms. By the term “C0-C4-alkylene” are meant branched and unbranched alkylene groups with 0 to 4 carbon atoms, thus also a single bond is encompassed. By the term “C1-C3-alkylene” are meant branched and unbranched alkylene groups with 1 to 3 carbon atoms. Examples for C1-C8-alkylene include: methylene, ethylene, propylene, 1-methylethylene, butylene, 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene, pentylene, 1,1-dimethylpropylene, 2,2-dimethylpropylene, 1,2-dimethylpropylene, 1,3-dimethylpropylene, hexylene, heptylene or octylene. Unless stated otherwise, the definitions propylene, butylene, pentylene, hexylene, heptylene and octylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propyl also includes 1-methylethylene and butylene includes 1-methylpropylene, 1,1-dimethylethylene, 1,2-dimethylethylene.
If the carbon chain is to be substituted by a group which together with one or two carbon atoms of the alkylene chain forms a carbocyclic ring with 3, 5 or 6 carbon atoms, this includes the following examples of the rings:




By the term “C2-C6-alkenyl” (including those which are part of other groups) are meant branched and unbranched alkenyl groups with 2 to 6 carbon atoms and by the term “C2-C4-alkenyl” are meant branched and unbranched alkenyl groups with 2 to 4 carbon atoms, provided that they have at least one double bond. Alkenyl groups with 2 to 4 carbon atoms are preferred. Examples for C2-C6-alkenyls include: ethenyl or vinyl, propenyl, butenyl, pentenyl, or hexenyl. Unless stated otherwise, the definitions propenyl, butenyl, pentenyl and hexenyl include all the possible isomeric forms of the groups in question. Thus, for example, propenyl includes 1-propenyl and 2-propenyl, butenyl includes 1-, 2- and 3-butenyl, 1-methyl-1-propenyl, 1-methyl-2-propenyl etc.
By the term “methenylene” is meant a group with 1 carbon atom, provided that it is linked by a single bond as well as on the other side by a double bond:




By the term “C2-C8-alkenylene” (including those which are part of other groups) are meant branched and unbranched alkenylene groups with 2 to 8 carbon atoms and by the term “C2-C6-alkenylene” are meant branched and unbranched alkylene groups with 2 to 6 carbon atoms. By the term “C1-C2-alkenylene” are meant alkenylene groups with 1 to 2 carbon atoms, provided that they have at least one double bond, whereas by the term “C1-alkenylene” is meant “methenylene”. Examples for C2-C8-alkenylenes include: ethenylene, propenylene, 1-methylethenylene, butenylene, 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene, pentenylene, 1,1-dimethylpropenylene, 2,2-dimethylpropenylene, 1,2-dimethylpropenylene, 1,3-dimethylpropenylene, hexenylene, heptenylene or octenylene. Unless stated otherwise, the definitions propenylene, butenylene, pentenylene and hexenylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus, for example, propenyl also includes 1-methylethenylene and butenylene includes 1-methylpropenylene, 1,1-dimethylethenylene, 1,2-dimethylethenylene.
By the term “C2-C6-alkynyl” (including those which are part of other groups) are meant branched and unbranched alkynyl groups with 2 to 6 carbon atoms and by the term “C2-C4-alkynyl” are meant branched and unbranched alkynyl groups with 2 to 4 carbon atoms, provided that they have at least one triple bond. Examples for C2-C6-alkynyls include: ethynyl, propynyl, butynyl, pentynyl or hexynyl. Unless stated otherwise, the definitions propynyl, butynyl, pentynyl and hexynyl include all the possible isomeric forms of the groups in question. Thus for example propynyl includes 1-propynyl and 2-propynyl, butynyl includes 1-, 2-, and 3-butynyl, 1-methyl-1-propynyl, 1-methyl-2-propynyl etc.
By the term “C2-C8-alkynylene” (including those which are part of other groups) are meant branched and unbranched alkynylene groups with 2 to 8 carbon atoms and by the term “C2-C6-alkynylene” are meant branched and unbranched alkylene groups with 2 to 6 carbon atoms. Examples of C2-C8-alkynylenes include: ethynylene, propynylene, 1-methylethynylene, butynylene, 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene, pentynylene, 1,1-dimethylpropynylene, 2,2-dimethylpropynylene, 1,2-dimethylpropynylene, 1,3-dimethylpropynylene, hexynylene, heptynylene or octynylene. Unless stated otherwise, the definitions propynylene, butynylene, pentynylene and hexynylene include all the possible isomeric forms of the groups in question with the same number of carbons. Thus for example propynyl also includes 1-methylethynylene and butynylene includes 1-methylpropynylene, 1,1-dimethylethynylene, 1,2-dimethylethynylene.
By the term “ring” are meant carbocycles, which can be saturated, unsaturated or aromatic and which optionally can comprise one or more hetero atoms selected from N, O or S.
By the term “—C3-C8-heterocyclyl” are meant three-, four-, five-, six-, or seven-membered, saturated or unsaturated heterocyclic rings which may contain one, two, or three heteroatoms, selected from among oxygen, sulfur, and nitrogen, while the ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one. By the term “—C5-C8-heterocyclyl” are meant five-, six-, or seven-membered, saturated or unsaturated heterocyclic rings which may contain one, two, or three heteroatoms, selected from among oxygen, sulfur, and nitrogen, while the ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one. Examples include:




Unless otherwise mentioned, a heterocyclic ring (or “heterocycle”) may be provided with a keto group. Examples include:




By the term “C3-C8-cycloalkyl” (including those which are part of other groups) are meant cyclic alkyl groups with 3 to 8 carbon atoms. Likewise, by the term “C3-C6-cycloalkyl” are meant cyclic alkyl groups with 3 to 6 carbon atoms. Examples of C3-C8-cycloalkyls include: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl. Unless otherwise stated, the cyclic alkyl groups may be substituted by one or more groups selected from among methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.
By the term “aryl” (including those which are part of other groups) are meant aromatic ring systems. By the term “C5-C10-aryl” (including those which are part of other groups) are meant aromatic ring systems with 5 to 10 carbon atoms. Preferred are “C6-C10-aryl” groups whereas aromatic rings are meant with 6 to 10 carbon atoms. Examples include: phenyl or naphthyl. Also preferred are “C5-C6-aryl” groups whereas aromatic rings are meant with 5 to 6 carbon atoms Unless otherwise stated, the aromatic ring systems may be substituted by one or more groups selected from among methyl, ethyl, iso-propyl, tert-butyl, hydroxy, fluorine, chlorine, bromine and iodine.
By the term “C5-C10-heteroaryl” (including those which are part of other groups) are meant five- or six-membered heterocyclic aromatic groups or 5-10-membered, bicyclic heteroaryl rings which may contain one, two, or three heteroatoms selected from among oxygen, sulfur, and nitrogen, and contain so many conjugated double bonds that an aromatic system is formed. The following are examples of five- or six- or nine-membered heterocyclic aromatic groups:




Preferred are “C5-C6-heteroaryl” groups whereas aromatic rings are meant five- or six-membered heterocyclic aromatic groups. Unless otherwise stated, these heteroaryls may be substituted by one or more groups selected from among methyl, ethyl, isopropyl, tert-butyl, hydroxy, fluorine, chlorine, bromine, and iodine.
When a generic combined groups are used, for example —X—C1-C4-alkyl- with X being a functional group such as —CO—, —NH—, —C(OH)— and the like, the functional group X can be located at either of the ends of the —C1-C4-alkyl chain.
By the term “spiro-C3-C8-cycloalkyl” (spiro) are meant 3-8 membered, spirocyclic rings while the ring is linked to the molecule through a carbon atom. By the term “spiro-C3-C8-heterocyclyl” (spiro) are meant 3-8 membered, spirocyclic rings which may contain one, two, or three heteroatoms selected from among oxygen, sulfur, and nitrogen, while the ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one.
Unless otherwise mentioned, a spirocyclic ring may be provided with an oxo, methyl, or ethyl group. Examples include:




“Halogen” within the scope of the present invention denotes fluorine, chlorine, bromine or iodine. Unless stated to the contrary, fluorine, chlorine and bromine are regarded as preferred halogens.
“Linker” within the scope of the present invention denominates a bivalent group or a bond.
The above listed groups and residues can be combined to form more complex structures composed from carbon chains and rings or the like.
Compounds of general formula (I) may have acid groups, chiefly carboxyl groups, and/or basic groups such as e.g. amino functions. Compounds of general formula (I) may therefore occur as internal salts, as salts with pharmaceutically useable inorganic acids such as hydrochloric acid, sulphuric acid, phosphoric acid, sulphonic acid or organic acids (such as for example maleic acid, fumaric acid, citric acid, tartaric acid or acetic acid) or as salts with pharmaceutically useable bases such as alkali or alklaline earth metal hydroxides or carbonates, zinc or ammonium hydroxides or organic amines such as e.g. diethylamine, triethylamine, triethanolamine inter alia.
As mentioned hereinbefore, the compounds of formula (I) may be converted into the salts thereof, particularly for pharmaceutical use, into the physiologically and pharmacologically acceptable salts thereof. These salts may on the one hand be in the form of the physiologically and pharmacologically acceptable acid addition salts of the compounds of formula (I) with inorganic or organic acids. On the other hand, if R is hydrogen, the compound of formula (I) may also be converted by reaction with inorganic bases into physiologically and pharmacologically acceptable salts with alkali or alkaline earth metal cations as counter ion. The acid addition salts may be prepared for example using hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. It is also possible to use mixtures of the above-mentioned acids. The alkali and alkaline earth metal salts of the compound of formula (I) are preferably prepared using the alkali and alkaline earth metal hydroxides and hydrides thereof, of which the hydroxides and hydrides of the alkaline earth metals, particularly of sodium and potassium, are preferred and sodium and potassium hydroxide are particularly preferred.
If desired, the compounds of general formula (I) may be converted into the salts thereof, particularly, for pharmaceutical use, into the pharmacologically acceptable acid addition salts with an inorganic or organic acid. Suitable acids include for example succinic acid, hydrobromic acid, acetic acid, fumaric acid, maleic acid, methanesulphonic acid, lactic acid, phosphoric acid, hydrochloric acid, sulphuric acid, tartaric acid or citric acid. It is also possible to use mixtures of the above-mentioned acids.
The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids—such as for example acid addition salts with hydrohalic acids—for example hydrochloric or hydrobromic acid or organic acids—such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.
The compounds according to the invention may optionally occur as racemates, but they may also be obtained as pure enantiomers/diastereomers.
The invention relates to the compounds in question, optionally in the form of the individual optical isomers, mixtures of the individual enantiomers or racemates, in the form of the tautomers as well as in the form of the free bases or the corresponding acid addition salts with pharmacologically acceptable acids—such as for example acid addition salts with hydrohalic acids—for example hydrochloric or hydrobromic acid or organic acids—such as for example oxalic, fumaric, diglycolic or methanesulphonic acid.
The compounds according to formula (I) according to the invention have the meanings hereinbefore whereas in particular the preferred embodiments defined by R1, R2, R3, R4, R5, R6, R7, R8, R9, R9′, R10, R11, R11′, R12, R13, R13′, R14, R15, R15′, R16, R17, R18, A, L1, L2, Z, Q, and n in each case are independently selected of one another.
Therapeutic Applications
The above exemplary substances have been tested for binding to CCR2 using a binding assay as outlined herein below:
Cell Culture:
THP-1 cells (human acute monocytic leukaemia cells) were cultured under standardized conditions at 37° C. and 5% CO2 in a humidified incubator. THP-1 cells were cultivated in RPMI 1640 medium (Gibco 21875) containing 1% MEM-NEAA (Gibso 11140) 2 mM L-glutamine, 1.5 g/L sodium bicarbonate, 4.5 g/L glucose, 10 mM HEPES and 1.0 mM sodium pyruvate, 90%; 10% fetal calf serum (FCS Gibco 10500-064).
Membranes were prepared from THP-1 cells. THP-1 cells were centrifuged at 300×g at 4° C. for 10 min. The cell pellet was resuspendet in Phosphate Buffer Saline (PBS, including 10 μM Pefabloc and a protease inhibitor mix ‘complete’, Boehringer Mannheim (1 tablet/50 ml)), to a concentration of 80 cells/ml. The membrane preparation was performed by disrupting the cells by nitrogen decomposition (at 50 bar, for 1 h) in a “Nitrogen Bombe” (Parr Instrument). Cell debris was removed by centrifugation (800×g at 4° C., 1 min). The supernatant was centrifuged at 80000×g, 4° C. for 30 min to sediment the cell membranes. Usually 50 mg of protein (Bradford assay) were yielded from 1×10E9 cells. The membranes were resuspendet in 25 mM HEPES, 25 mM MgCl2, 1 mM CaCl2, 10% Glycerine for storage in aliquots at −80° C. in 25 mM HEPES, 25 mM MgCl2, 1 mM CaCl2, 10% Glycerine and stored at −80° C.
Receptor Membrane Binding Assay:
Perkin Elmer NEX 332 Jod 125 MCP-1, Stock: 2200 Ci/mmol solved in 2000 μl assay buffer, stored at −20° C. THP-1 membrane were adjusted with 25 mM HEPES, pH 7.2; 5 mM MgCl2; 0.5 mM CaCl2; 0.2% BSA assay buffer to a concentration of 2.5 g/15 μl. Amersham Biosciences PVT-WGA Beads (RPNQ0001) were adjusted with assay buffer to a concentration of 0.24 mg/30 μl. For preparation of the membrane-bead-suspension membranes and beads were incubated for 30 min at RT under rotation (60 rpm) with a ratio of 1:2. Test compounds dissolved in 100% DMSO to a concentration of 10 mM and are further diluted with 100% DMSO to 1 mM. All additional compound dilutions were obtained with assay buffer, final 1% DMSO. Compounds, membrane-bead-suspension and [125I]MCP-1 (ca. 25000 cpm/10 μl) were incubated. Bound radioactivity was determined by scintillation counter after 8 h. Determination of affinity of test compounds (dissociation constant hKi) is calculated by iterative fitting of experimental data using the “easy sys” program, which is based on law of mass action (Schittkowski K. (1994), Numerische Mathematik, Vol. 68, 129-142).
All of the above-referenced examples have been found to have an activity in this assay of 10 μM or less.



















CCR2 % ctrl 



Example
hKi 
@ 10 μM







 1
32
1



 2
222
13



 3
204
14



 4
1593
43



 5
616
26



 6
1928
41



 7
306
16



 8
1023
36



 9
974
32



 10
650
27



 11
1710
38



 12
664
29



 13
1332
42



 14
387
22



 15
200
14



 16
1904
40



 17
302
18



 18
3505
52



 19
269
40



 20
303
24



 21
2660
51



 22
466
24



 23
169
7



 24
4029
58



 25
2406
47



 26
914
30



 27
620
25



 28
4176
58



 29
2097
40



 30
446
18



 31
790
28



 32
37
2



 33
22
0



 34
62
4



 35
24
5



 36
10
1



 37
11
4



 38
69
13



 39
36
2



 40
174
9



 41
11
6



 42
433
16



 43
566
17



 44
1639
27



 45
501
17



 46
225
12



 47
222
14



 48
1778
26



 49
97
7



 50
928
22



 51
290
13



 52
175
12



 53
18
4



 54
356
13



 55
200
17



 56
127
8



 57
93
10



 58
336
12



 59
55
5



 60
44
5



 61
46
2



 62
38
3



 63
54
7



 64
65
8



 65
176
8



 66
138
8



 67
1423
27



 68
98
7



 69
63
7



 70
80
6



 71
117
12



 72
81
7



 73
38
2



 74
71
2



 75
67
7



 76
132
12



 77
650
27



 78
740
28



 79
89
10



 80
53
7



 81
52
8



 82
43
4



 83
43
3



 84
69
4



 85
55
13



 86
39
3



 87
78
9



 88
58
6



 89
770
29



 90
127
10



 91
236
23



 92
175
14



 93
123
6



 94
211
8



 95
170
2



 96
939
21



 97
665
17



 98
214
2



 99
1826
32



100
395
18



101
986
35



102
224
15



103
1605
30



104
617
31



105
687
31



106
405
13



107
232
12



108
627
20



109
213
11



110
527
28



111
464
27



112
378
21



113
3306
46



114
62
8



115
847
33



116
198
16



117
285
19



118
2162
41



119
1033
37



120
499
30



121
147
15



122
415
23



123
542
26



124
361
20



125
446
25



126
399
23



127
665
35



128
445
26



129
336
21



130
4266
50



131
55
6



132
672
31



133
205
15



134
399
23



135
888
19



136
773
14



137
634
14



138
145
6



139
443
9



140
692
16



141
422
7



142
529
8



143
422
8



144
91
7



145
181
17



146
3
7



147
40
8



148
119
4



149
41
10



150
12
3



151
14
7



152
44
7



153
27
1



154
123
15



155
76
8



156
18
8



157
1147
23



158
6
0



159
25
4



160
43
3



161
1996
30



162
3798
43



163
1560
32



164
353
15



165
222
15



166
227
16



167
246
16



168
51
9



169
2287
54



170
705
31



171
356
16



172
736
28



173
89
6



174
2718
53



175
434
14



176
648
31



177
1252
43



178
27
0



179
1637
42



189
4812
60



181
3607
58



182
2991
53



183
426
45



184
908
30



185
4209
53



186
78
8



187
256
15



188
3934
53



189
170
13



190
783
27



191
519
20



192
1446
37



193
1536
35



194
491
25



195
141
14



196
666
19



197
33
4



198
58
1



199
534
9



200
108
5



201
101
6



202
292
7



203
641
11



204
123
6



205
135
11



206
44
3



207
1180
35



208
99
7



209
177
7



210
83
0



211
140
5



212
731
24



213
430
14



214
711
20



215
2146
42



216
4283
59



217
4326
54



218
281
8



219
476
22



220
979
27



221
172
12



222
1306
31



223
244
14



224
1230
35



225
21
0



226
1170
36



227
333
22



228
331
16



229
1133
39



230
1845
45



231
215
15



232
924
34



233
194
8



234
401
19



235
460
26



236
175
14



237
133
9



238
239
14



239
2319
33



240
104
7



241
522
21



242
516
21



243
1615
40



244
366
24



245
555
15



246
306
2



247
149
6



248
576
17



249
3249
36



250
1263
32



251
439
75



252
38
6



253
350
17



254
101
11



255
33
5



256
438
25



257
186
14



258
64
4



259
277
16



260
493
20



261
120
8



262
224
13



263
1968
27



264
41
3



265
462
23



266
149




267
487
20



268
119
5



228a
1564
9



228b
2
4



228c
29
0



228d
91
1



228e
3720
40



228f
15
1



228g
169
6



228h
5
0



269
2340
36



270
179
9



271
1608
15



272
155
8



273
1435
27



274
4421
48



275
593
19



276
1842
23



277
1376
34



278
1078
32



279
192
9



280
1435
32



281
1012
24



282
1527
39



283
4421
48



284
1514
42



285
1306
35



286
965
19



287
2547
33



288
738
13



289
1667
34



290
1601
28



291
3123
32



292
136
15



293
717
27



294
230
16



295
140
0



296
69
3



297
164
10



298
599
17



299
70
6



300
136
8



275a
29
0



275b
26
3



275c
2932
38



275d
318
10














Example
hKi







228go
54



228gp
1354



228ga
23



228gb
3828



228gc 
561



228gd 
1094



228ge 
37



228gf 
145



228gg 
1026



228gh 
4066



228gi 
1101



228gj
55



228gk 
44



228gl
537



228gm
28



228gn 
333



275da
4



275db
33



275dc 
11



275dd 
40



275de 
16



275df 
15



275dg 
12



275dh
3



275di
1



275dj
4



159a
10



159b
7



159c
13



159d
15



159e
28



159f
14



159g
15



159h
39



159i
24



159k
22



159l
22



159m
9



159n
233



159o
12



159p
7



159q
10



159r
2578



159s
1314



159t
1202



159u
29



159w
9



159y
169



159x
147



159z
11



159aa
18



159ba
11



159ca
3



159da
5



159ea
7



159fa
35



159ga
28



159ha
27



159ia
17



159ja
18



159ka
19



159la
19



159ma
20



159na
21



159oa
29



159pa
32



159qa
19



159ra
22



159sa
22



159ta
27



159ua
23



159wa
33



159ya
18



159xa
21



159za
6



159ab
27



159bb
48



159cb
39



159db
16



159eb
72



159fb
199



159gb
39



159hb
20



159ib
15



159jb
39



159kb
24



159lb
12



159mb
14



159nb
88



159ob
118



159pb
10



159qb
69



159rb
54



159sb
21



159tb
13



159ub
18



159wb
16



159yb
15



159xb
6



159zb
15



159ac
5936



159bc
3492



159cc
10



159dc
38



159ec
961



159fc
13



159gc
26



228ha
32



301
22



302
32



275dk
17



275dl
372










Based on the ability of the substances described by formula (I) to effectively bind to CCR2 a range of therapeutic applications can be envisaged. The present invention provides a method for modulating or treating at least one MCP-1 related disease, in a cell, tissue, organ, animal, or patient, as known in the art or as described herein, using at least one CCR2 antagonist of the present invention. The present invention also provides a method for modulating or treating at least one MCP-1 related disease, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of malignant disease, metabolic disease, an immune or inflammatory related disease, a cardiovascular disease, an infectious disease, or a neurologic disease. Such conditions are selected from, but not limited to, diseases or conditions mediated by cell adhesion and/or angiogenesis. Such diseases or conditions include an immune disorder or disease, a cardiovascular disorder or disease, an infectious, malignant, and/or neurologic disorder or disease, or other known or specified MCP-1 related conditions. In particular, the CCR2 antagonists are useful for the treatment of diseases that involve inflammation such as COPD, angiogenesis such as disease of the eye and neoplastic disease, tissue remodeling such as restenosis, and proliferation of certain cells types particularly epithelial and squamous cell carcinomas. Particular indications include use in the treatment of atherosclerosis, restenosis, cancer metastasis, rheumatoid arthritis, diabetic retinopathy and macular degeneration. The antagonists may also be useful in the treatment of various fibrotic diseases such as idiopathic pulmonary fibrosis, diabetic nephropathy, hepatitis, and cirrhosis. Thus, the present invention provides a method for modulating or treating at least one CCR2 related disease, in a cell, tissue, organ, animal, or patient, as known in the art or as described herein, using at least one CCR2 antagonist of the present invention. Particular indications are discussed below:
Pulmonary Diseases
The present invention also provides a method for modulating or treating at least one malignant disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: pneumonia; lung abscess; occupational lung diseases caused be agents in the form or dusts, gases, or mists; asthma, bronchiolitis fibrosa obliterans, respiratory failure, hypersensitivity diseases of the lungs iricludeing hypersensitivity pneumonitis (extrinsic allergic alveolitis), allergic bronchopulmonary aspergillosis, and drug reactions; adult respiratory distress syndrome (ARDS), Goodpasture's Syndrome, chronic obstructive airway disorders (COPD), idiopathic interstitial lung diseases such as idiopathic pulmonary fibrosis and sarcoidosis, desquamative interstitial pneumonia, acute interstitial pneumonia, respiratory bronchiolitis-associated interstitial lung disease, idiopathic bronchiolitis obliterans with organizing pneumonia, lymphocytic interstitial pneumonitis, Langerhans' cell granulomatosis, idiopathic pulmonary hemosiderosis; acute bronchitis, pulmonary alveolar, proteinosis, bronchiectasis, pleural disorders, atelectasis, cystic fibrosis, and tumors of the lung, and pulmonary embolism.
Malignant Diseases
The present invention also provides a method for modulating or treating at least one malignant disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: leukemia, acute leukemia, acute lymphoblastic leukemia (ALL), B-cell, T-cell or FAB ALL, acute myeloid leukemia (AML), chromic myelocytic leukemia (CML), chronic lymphocytic leukemia (CLL), hairy cell leukemia, myelodyplastic syndrome (MDS), a lymphoma, Hodgkin's disease, a malignant lymphoma, non-hodgkin's lymphoma, Burkitt's lymphoma, multiple myeloma, Kaposi's sarcoma, colorectal carcinoma, pancreatic carcinoma, renal cell carcinoma, breast cancer, nasopharyngeal carcinoma, malignant histiocytosis, paraneoplastic syndrome/hypercalcemia of malignancy, solid tumors, adenocarcinomas, squamous cell carcinomas, sarcomas, malignant melanoma, particularly metastatic melanoma, hemangioma, metastatic disease, cancer related bone resorption, cancer related bone pain, and the like.
Immune Related Diseases
The present invention also provides a method for modulating or treating at least one immune related disease, in a cell, tissue, organ, animal, or patient including, but not limited to, at least one of rheumatoid arthritis, juvenile rheumatoid arthritis, systemic onset juvenile rheumatoid arthritis, psoriatic arthritis, ankylosing spondilitis, gastric ulcer, seronegative arthropathies, osteoarthritis, inflammatory bowel disease, ulcerative colitis, systemic lupus erythematosis, antiphospholipid syndrome, iridocyclitisluveitisloptic neuritis, idiopathic pulmonary fibrosis, systemic vasculitis/wegener's granulomatosis, sarcoidosis, orchitislvasectomy reversal procedures, allergiclatopic diseases, asthma, allergic rhinitis, eczema, allergic contact dermatitis, allergic conjunctivitis, hypersensitivity pneumonitis, transplants, organ transplant rejection, graft-versus-host disease, systemic inflammatory response syndrome, sepsis syndrome, gram positive sepsis, gram negative sepsis, culture negative sepsis, fungal sepsis, neutropenic fever, urosepsis, meningococcemia, traumalhemo ̃ ̃hage, burns, ionizing radiation exposure, acute pancreatitis, adult respiratory distress syndrome, rheumatoid arthritis, alcohol-induced hepatitis, chronic inflammatory pathologies, sarcoidosis, Crohn's pathology, sickle cell anemia, diabetes, nephrosis, atopic diseases, hypersensitity reactions, allergic rhinitis, hay fever, perennial rhinitis, conjunctivitis, endometriosis, asthma, urticaria, systemic anaphalaxis, dermatitis, pernicious anemia, hemolytic diseases, thrombocytopenia, graft rejection of any organ or tissue, kidney transplant rejection, heart transplant rejection, liver transplant rejection, pancreas transplant rejection, lung transplant rejection, bone marrow transplant (BMT) rejection, skin allograft rejection, cartilage transplant rejection, bone graft rejection, small bowel transplant rejection, fetal thymus implant rejection, parathyroid transplant rejection, xenograft rejection of any organ or tissue, allograft rejection, anti-receptor hypersensitivity reactions, Graves disease, Raynoud's disease, type B insulin-resistant diabetes, asthma, myasthenia gravis, antibody-meditated cytotoxicity, type IU hypersensitivity reactions, systemic lupus erythematosus, POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes syndrome), polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes syndrome, antiphospholipid syndrome, pemphigus, scleroderma, mixed connective tissue disease, idiopathic Addison's disease, diabetes mellitus, chronic active hepatitis, primary billiary cirrhosis, vitiligo, vasculitis, post-MI cardiotomy syndrome, type IV hypersensitivity, contact dermatitis, hypersensitivity pneumonitis, allograft rejection, granulomas due to intracellular organisms, drug sensitivity, metabolic/idiopathic, Wilson's disease, hemachromatosis, alpha-1-antitrypsin deficiency, diabetic retinopathy, hashimoto's thyroiditis, osteoporosis, hypothalamic-pituitary-adrenal axis evaluation, primary biliary cirrhosis, thyroiditis, encephalomyelitis, cachexia, cystic fibrosis, neonatal chronic lung disease, chronic obstructive pulmonary disease (COPD), familial hematophagocytic lymphohistiocytosis, dermatologic conditions, psoriasis, alopecia, nephrotic syndrome, nephritis, glomerular nephritis, acute renal failure, hemodialysis, uremia, toxicity, preeclampsia, OKT3 therapy, anti-CD3 therapy, cytokine therapy, chemotherapy, radiation therapy (e.g., including but not limited toasthenia, anemia, cachexia, and the like), chronic salicylate intoxication, and the like.
Cardiovascular Diseases
The present invention also provides a method for modulating or treating at least one cardiovascular disease in a cell, tissue, organ, animal, or patient, including, but not limited to, at least one of cardiac 25 stun syndrome, myocardial infarction, congestive heart failure, stroke, ischemic stroke, hemorrhage, arteriosclerosis, atherosclerosis, restenosis, diabetic ateriosclerotic disease, hypertension, arterial hypertension, renovascular hypertension, syncope, shock, syphilis of the cardiovascular system, heart failure, cor pulmonale, primary pulmonary hypertension, cardiac arrhythmias, atrial ectopic beats, atrial flutter, atrial fibrillation (sustained or paroxysmal), post perfusion syndrome, cardiopulmonary bypass inflammation response, chaotic or multifocal atrial tachycardia, regular narrow QRS tachycardia, specific arrythrnias, ventricular fibrillation, His bundle arrythmias, atrioventricular block, bundle branch block, myocardial ischemic disorders, coronary artery disease, angina pectoris, myocardial infarction, cardiomyopathy, dilated congestive cardiomyopathy, restrictive cardiomyopathy, valvular heart diseases, endocarditis, pericardial disease, cardiac tumors, aordic and peripheral aneuryisms, aortic dissection, inflammation of the aorta, occulsion of the abdominal aorta and its branches, peripheral vascular disorders, occulsive arterial disorders, peripheral atherlosclerotic disease, thromboangitis obliterans, functional peripheral arterial disorders, Raynaud's phenomenon and disease, acrocyanosis, erythromelalgia, venous diseases, venous thrombosis, varicose veins, arteriovenous fistula, lymphederma, lipedema, unstable angina, reperfusion injury, post pump syndrome, ischemia-reperfusion injury, and the like. Such a method can optionally comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one CCR2 antagonist to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.
Neurologic Diseases
The present invention also provides a method for modulating or treating at least one neurologic disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: Neuropathic pain such as low back pain, hip pain, leg pain, non-herpetic neuralgia, post herpetic neuralgia, diabetic neuropathy, nerve injury-induced pain, acquired immune deficiency syndrome (AIDS) related neuropathic pain, head trauma, toxin and chemotherapy caused nerve injuries, phantom limb pain, multiple sclerosis, root avulsions, painful traumatic mononeuropathy, painful polyneuropathy, thalamic pain syndrome, post-stroke pain, central nervous system injury, post surgical pain, carpal tunnel syndrome, trigeminal neuralgia, post mastectomy syndrome, postthoracotomy syndrome, stump pain, repetitive motion pain, neuropathic pain associated hyperalgesia and allodynia, alcoholism and other drug-induced pain; neurodegenerative diseases, multiple sclerosis, migraine headache, AIDS dementia complex, demyelinating diseases, such as multiple sclerosis and acute transverse myelitis; extrapyramidal and cerebellar disorders' such as lesions of the corticospinal system; disorders of the basal ganglia or cerebellar disorders; hyperkinetic movement disorders such as Huntington's Chorea and senile chorea; drug-induced movement disorders, such as those induced by drugs which block CNS dopamine receptors; hypokinetic movement disorders, such as Parkinson's disease; Progressive supra-nucleo Palsy; structural lesions of the cerebellum; spinocerebellar degenerations, such as spinal ataxia, Friedreich's ataxia, cerebellar cortical degenerations, multiple systems degenerations (Mencel, Dejerine-Thomas, Shi-Drager, and Machado-Joseph); systemic disorders (Refsum's disease, abetalipoprotemia, ataxia, telangiectasia, and mitochondrial multi.system disorder); demyelinating core disorders, such as multiple sclerosis, acute transverse myelitis; and disorders of the motor unit’ such as neurogenic muscular atrophies (anterior horn cell degeneration, such as amyotrophic lateral sclerosis, infantile spinal muscular atrophy and juvenile spinal muscular atrophy); Alzheimer's disease; Down's Syndrome in middle age; Diffuse Lewy body disease; Senile Dementia of Lewy body type; Wernicke-Korsakoff syndrome; chronic alcoholism; Creutzfeldt-Jakob disease; Subacute sclerosing panencephalitis, Hallerrorden-Spatz disease; and Dementia pugilistica, and the like.
Fibrotic Conditions
In addition to the above described conditions and diseases, the present invention also provides a method for modulating or treating fibrotic conditions of various etiologies such as liver fibrosis (including but not limited to alcohol-induced cirrhosis, viral-induced cirrhosis, autoimmune-induced hepatitis); lung fibrosis (including but not limited to scleroderma, idiopathic pulmonary fibrosis); kidney fibrosis (including but not limited to scleroderma, diabetic nephritis, glomerular pehpritis, lupus nephritis); dermal fibrosis (including but not limited to scleroderma, hypertrophic and keloid scarring, burns); myelofibrosis; Neurofibromatosis; fibroma; intestinal fibrosis; and fibrotic adhesions resulting from surgical procedures.
The present invention also provides a method for modulating or treating at least one wound, trauma or tissue injury or chronic condition resulting from or related thereto, in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: bodily injury or a trauma associated with surgery including thoracic, abdominal, cranial, or oral surgery; or wherein the wound is selected from the group consisting of aseptic wounds, contused wounds, incised wounds, lacerated wounds, non-penetrating wounds, open wounds, penetrating wounds, perforating wounds, puncture wounds, septic wounds, infarctions and subcutaneous wounds; or wherein the wound is selected from the group consisting of ischemic ulcers, pressure sores, fistulae, severe bites, thermal burns and donor site wounds; or wherein the wound is anaphthous wound, a traumatic wound or a herpes associated wound. Donor site wounds are wounds which e.g. occur in connection with removal of hard tissue from one part of the body to another part of the body e.g. in connection with transplantation. The wounds resulting from such operations are very painful and an improved healing is therefore most valuable. Wound fibrosis is also amenable to CCR2 antagonist therapy as the first cells to invade the wound area are neutrophils followed by monocytes which are activated by macrophages. Macrophages are believed to be essential for efficient wound healing in that they also are responsible for phagocytosis of pathogenic organisms and a clearing up of tissue debris. Furthermore, they release numerous factors involved in subsequent events of the healing process. The macrophages attract fibroblasts which start the production of collagen. Almost all tissue repair processes include the early connective tissue formation, a stimulation of this and the subsequent processes improve tissue healing, however, overproduction of connective tissue and collegen can lead to a fibrotic tissue characterized as inelastic and hypoxic. The CCR2 antagonist of the invention can be used in methods for modulating, treating or preventing such sequelae of wound healing.
Other Therapeutic Uses of CCR2 Antagonists
The present invention also provides a method for modulating or treating at least one infectious disease in a cell, tissue, organ, animal or patient, including, but not limited to, at least one of: acute or chronic bacterial infection, acute and chronic parasitic or infectious processes, including bacterial, viral and fungal infections, HIV infection, HIV neuropathy, meningitis, hepatitis (A, B or C, or the like), septic arthritis, peritonitis, pneumonia, epiglottitis, E. coli 0157:h7, hemolytic uremic syndrome/thrombolytic thrombocytopenic purpura, malaria, dengue hemorrhagic fever, leishmaniasis, leprosy, toxic shock syndrome, streptococcal myositis, gas gangrene, Mycobacterium tuberculosis, Mycobacterium avium intracellulare, Pneumocystis carinii pneumonia, pelvic inflammatory disease, orchitislepidydimitis, legionella, lyme disease, influenza a, epstein-barr virus, vital-associated hemaphagocytic syndrome, vital encephalitisiaseptic meningitis, and the like.
Any method of the present invention can comprise administering an effective amount of a composition or pharmaceutical composition comprising at least one CCR2 antagonist to a cell, tissue, organ, animal or patient in need of such modulation, treatment or therapy.
Besides being useful for human treatment, these compounds are also useful for veterinary treatment of companion animals, exotic animals and farm animals, including mammals, rodents, and the like.
Combinations
The compounds of formula I may be used on their own or in conjunction with other active substances of formula I according to the invention. If desired the compounds of formula I may also be used in combination with other pharmacologically active substances. It is preferable to use for this purpose active substances selected for example from among betamimetics, anticholinergics, corticosteroids, other PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, MRP4-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists and PI3-kinase inhibitors or double or triple combinations thereof, such as for example combinations of compounds of formula I with one or two compounds selected from among

    
    
        betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,
        anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors, EGFR-inhibitors and LTD4-antagonists,
        PDE4-inhibitors, corticosteroids, EGFR-inhibitors and LTD4-antagonists
        EGFR-inhibitors, PDE4-inhibitors and LTD4-antagonists
        EGFR-inhibitors and LTD4-antagonists
        CCR3-inhibitors, iNOS-inhibitors (inducible nitric oxide synthase-inhibitors), (6R)-L-erythro-5,6,7,8-tetrahydrobiopterin (hereinafter referred to as “BH4”) and the derivatives thereof as mentioned in WO 2006/120176 and SYK-inhibitors (spleen tyrosine kinase-inhibitors)
        anticholinergics, betamimetics, corticosteroids, PDE4-inhibitors and MRP4-inhibitors.
    
    


The invention also encompasses combinations of three active substances, each selected from one of the above-mentioned categories of compounds.
The betamimetics used are preferably compounds selected from among albuterol, bambuterol, bitolterol, broxaterol, carbuterol, clenbuterol, fenoterol, formoterol, arformoterol, zinterol, hexoprenaline, ibuterol, isoetharine, isoprenaline, levosalbutamol, mabuterol, meluadrine, metaproterenol, orciprenaline, pirbuterol, procaterol, reproterol, rimiterol, ritodrine, salmeterol, salmefamol, soterenol, sulphonterol, tiaramide, terbutaline, tolubuterol, CHF-1035, HOKU-81, KUL-1248, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzyl-sulphonamide, 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol, 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetate ethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid, 8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and 1-(4-ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
Preferably the beta mimetics are selected from among bambuterol, bitolterol, carbuterol, clenbuterol, fenoterol, formoterol, hexoprenaline, ibuterol, pirbuterol, procaterol, reproterol, salmeterol, sulphonterol, terbutaline, tolubuterol, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide, 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 4-hydroxy-7-[2-{[2-{[3-(2-phenylethoxy)propyl]sulphonyl}ethyl]-amino}ethyl]-2(3H)-benzothiazolone, 1-(2-fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, 5-hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one, 1-(4-amino-3-chloro-5-trifluoromethylphenyl)-2-tert.-butylamino)ethanol, 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetate ethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1 dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid, 8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and 1-(4-ethoxycarbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanol, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
Particularly preferred betamimetics are selected from among fenoterol, formoterol, salmeterol, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide, 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, 1-[3-(4-methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2-butylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimethylaminophenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2-propylamino]ethanol, 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2-propylamino]ethanol, 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetate ethyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1 dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid, 8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-{4-[3-(4-methoxyphenyl)-1,2,4-triazol-3-yl]-2-methyl-2-butylamino}ethanol, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
Of these betamimetics those which are particularly preferred according to the invention are formoterol, salmeterol, 3-(4-{6-[2-hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-benzenesulphonamide, 6-hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(ethyl 4-phenoxy-acetate)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-phenoxy-acetic acid)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[1,1-dimethyl-2-(2,4,6-trimethylphenyl)-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl)-1,1-dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 6-hydroxy-8-{1-hydroxy-2-[2-(4-isopropyl-phenyl)-1.1 dimethyl-ethylamino]-ethyl}-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethyl-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 8-{2-[2-(4-ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one, 4-(4-{2-[2-hydroxy-2-(6-hydroxy-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-ethylamino]-2-methyl-propyl}-phenoxy)-butyric acid, 8-{2-[2-(3,4-difluoro-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4H-benzo[1,4]oxazin-3-one and 5-[2-(5,6-diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinolin-2-one, optionally in the form of the racemates, enantiomers, diastereomers thereof and optionally in the form of the pharmacologically acceptable acid addition salts, solvates or hydrates thereof.
According to the invention the acid addition salts of the betamimetics are preferably selected from among hydrochloride, hydrobromide, hydriodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonat, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate. Of the above-mentioned acid addition salts the salts of hydrochloric acid, methanesulphonic acid, benzoic acid and acetic acid are particularly preferred according to the invention.
The anticholinergics used are preferably compounds selected from among the tiotropium salts, oxitropium salts, flutropium salts, ipratropium salts, glycopyrronium salts, trospium salts, tropenol 2,2-diphenylpropionate methobromide, scopine 2,2-diphenylpropionate methobromide, scopine 2-fluoro-2,2-diphenylacetate methobromide, tropenol 2-fluoro-2,2-diphenylacetate methobromide, tropenol 3,3′,4,4′-tetrafluorobenzilate methobromide, scopine 3,3′,4,4′-tetrafluorobenzilate methobromide, tropenol 4,4′-difluorobenzilate methobromide, scopine 4,4′-difluorobenzilate methobromide, tropenol 3,3′-difluorobenzilate methobromide, -scopine 3,3′-difluorobenzilate methobromide, tropenol 9-hydroxy-fluorene-9-carboxylate-methobromide, tropenol 9-fluoro-fluorene-9-carboxylate-methobromide, scopine 9-hydroxy-fluoren-9-carboxylate methobromide, scopine 9-fluoro-fluorene-9-carboxylate methobromide, tropenol 9-methyl-fluorene-9-carboxylate methobromide, scopine 9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine benzilate methobromide, cyclopropyltropine 2,2-diphenylpropionate methobromide, cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate methobromide, cyclopropyltropine 9-methyl-fluorene-9-carboxylate methobromide, cyclopropyltropine 9-methyl-xanthene-9-carboxylate methobromide, cyclopropyltropine 9-hydroxy-fluorene-9-carboxylate methobromide, methyl-cyclopropyltropine 4,4′-difluorobenzilate methobromide, tropenol 9-hydroxy-xanthene-9-carboxylate-methobromide, scopine 9-hydroxy-xanthene-9-carboxylate methobromide, tropenol 9-methyl-xanthene-9-carboxylate methobromide, scopine 9-methyl-xanthene-9-carboxylate methobromide, tropenol 9-ethyl-xanthene-9-carboxylate methobromide, tropenol 9-difluoromethyl-xanthene-9-carboxylate methobromide, scopine 9-hydroxymethyl-xanthene-9-carboxylate methobromide, optionally in the form of the solvates or hydrates thereof.
In the above-mentioned salts the cations tiotropium, oxitropium, flutropium, ipratropium, glycopyrronium and trospium are the pharmacologically active ingredients. As anions, the above-mentioned salts may preferably contain chloride, bromide, iodide, sulphate, phosphate, methanesulphonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulphonate, while chloride, bromide, iodide, sulphate, methanesulphonate or p-toluenesulphonate are preferred as counter-ions. Of all the salts, the chlorides, bromides, iodides and methanesulphonate are particularly preferred.
Of particular importance is tiotropium bromide. In the case of tiotropium bromide the pharmaceutical combinations according to the invention preferably contain it in the form of the crystalline tiotropium bromide monohydrate, which is known from WO 02/30928. If the tiotropium bromide is used in anhydrous form in the pharmaceutical combinations according to the invention, it is preferable to use anhydrous crystalline tiotropium bromide, which is known from WO 03/000265.
Corticosteroids used here are preferably compounds selected from among prednisolone, prednisone, butixocortpropionate, flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, betamethasone, deflazacort, RPR-106541, NS-126, (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate and (S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.
Particularly preferred is the steroid selected from among flunisolide, beclomethasone, triamcinolone, budesonide, fluticasone, mometasone, ciclesonide, rofleponide, dexamethasone, NS-126, (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate and (S)-(2-oxo-tetrahydro-furan-3S-yl) 6,9-difluoro-11-hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-diene-17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.
Particularly preferred is the steroid selected from among budesonide, fluticasone, mometasone, ciclesonide and (S)-fluoromethyl 6,9-difluoro-17-[(2-furanylcarbonyl)oxy]-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene-17-carbothionate, optionally in the form of the racemates, enantiomers or diastereomers thereof and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.
Any reference to steroids includes a reference to any salts or derivatives, hydrates or solvates thereof which may exist. Examples of possible salts and derivatives of the steroids may be: alkali metal salts, such as for example sodium or potassium salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates thereof.
Other PDE4 inhibitors which may be used are preferably compounds selected from among enprofyllin, theophyllin, roflumilast, ariflo (cilomilast), tofimilast, pumafentrin, lirimilast, arofyllin, atizoram, D-4396 (Sch-351591), AWD-12-281 (GW-842470), NCS-613, CDP-840, D-4418, PD-168787, T-440, T-2585, V-11294A, CI-1018, CDC-801, CDC-3052, D-22888, YM-58997, Z-15370, N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, (−)p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamide, (R)-(+)-1-(4-bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolidone, 3-(cyclopentyloxy-4-methoxyphenyl)-1-(4-N′-[N-2-cyano-S-methyl-isothioureido]benzyl)-2-pyrrolidone, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexane-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], (R)-(+)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, (S)-(−)-ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidin-2-ylidene]acetate, 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, enantiomers or diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.
Particularly preferably the PDE4-inhibitor is selected from among enprofyllin, roflumilast, ariflo (cilomilast), arofyllin, atizoram, AWD-12-281 (GW-842470), T-440, T-2585, PD-168787, V-11294A, CI-1018, CDC-801, D-22888, YM-58997, Z-15370, N-(3,5-dichloro-1-oxo-pyridin-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide, cis[4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexane-1-carboxylic acid], 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-one, cis[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol], 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine and 9-cyclopentyl-5,6-dihydro-7-ethyl-3-(tert-butyl)-9H-pyrazolo[3,4-c]-1,2,4-triazolo[4,3-a]pyridine, optionally in the form of the racemates, enantiomers or diastereomers and optionally in the form of the pharmacologically acceptable acid addition salts, solvates and/or hydrates thereof.
By acid addition salts with pharmacologically acceptable acids which the above-mentioned PDE4-inhibitors might be in a position to form are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.
LTD4-antagonists which may be used are preferably compounds selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707, L-733321, 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl)phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcyclopropane-acetic acid, 1-(((1(R)-3(3-(2-(2,3-dichlorothieno[3,2-b]pyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane-acetic acid and [2-[[2-(4-tert-butyl-2-thiazolyl)-5-benzofuranyl]oxymethyl]phenyl]acetic acid, optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.
Preferably the LTD4-antagonist is selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001, MEN-91507 (LM-1507), VUF-5078, VUF-K-8707 and L-733321, optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.
Particularly preferably the LTD4-antagonist is selected from among montelukast, pranlukast, zafirlukast, MCC-847 (ZD-3523), MN-001 and MEN-91507 (LM-1507), optionally in the form of the racemates, enantiomers or diastereomers, optionally in the form of the pharmacologically acceptable acid addition salts and optionally in the form of the salts and derivatives, solvates and/or hydrates thereof.
By acid addition salts with pharmacologically acceptable acids which the LTD4-antagonists may be capable of forming are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate. By salts or derivatives which the LTD4-antagonists may be capable of forming are meant, for example: alkali metal salts, such as, for example, sodium or potassium salts, alkaline earth metal salts, sulphobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogen phosphates, palmitates, pivalates or furoates.
The EGFR-inhibitors used are preferably compounds selected from among 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidin, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, Cetuximab, Trastuzumab, ABX-EGF and Mab ICR-62, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.
Preferred EGFR inhibitors are selected from among 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-diethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(N,N-bis-(2-methoxy-ethyl)-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-ethyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((R)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-((S)-tetrahydrofuran-3-yloxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-7-[3-(morpholin-4-yl)-propyloxy]-6-[(vinylcarbonyl)amino]-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, 4-{[3-chloro-4-(3-fluoro-benzyloxy)-phenyl]amino}-6-(5-{[(2-methanesulphonyl-ethyl)amino]methyl}-furan-2-yl)quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amino]-1-oxo-2-buten-1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-7-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-6-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(dimethylamino)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)sulphonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methanesulphonylamino-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-aminocarbonylmethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)sulphonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-acetylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(4-methyl-piperazin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-isopropyloxycarbonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[N-(2-methoxy-acetyl)-N-methyl-amino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(cis-2,6-dimethyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methyl-morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2,2,1]hept-5-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(3-methoxypropyl-amino)-carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, and Cetuximab, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.
It is particularly preferable within the scope of the present invention to use those EGFR-inhibitors which are selected from among 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-({4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopentyloxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-[(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyrrolo[2,3-d]pyrimidine, 3-cyano-4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-buten-1-yl]amino}-7-ethoxy-quinoline, 4-[(R)-(1-phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{2-[4-(2-oxo-morpholin-4-yl)-piperidin-1-yl]-ethoxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-amino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(piperidin-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidin-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-ethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{trans-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(piperidin-1-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-ethanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidin-4-yloxy]-7-(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(cis-4-{N-[(piperidin-1-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{cis-4-[(morpholin-4-yl)carbonylamino]-cyclohexan-1-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7(2-methoxy-ethoxy)-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(N-methyl-N-2-methoxyethyl-amino)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-ethyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline, and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.
Particularly preferred EGFR-inhibitors according to the invention are the compounds selected from among 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-cyclopropylmethoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(S)-(tetrahydrofuran-3-yl)oxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholin-4-yl)-ethoxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2-buten-1-yl}amino)-7-cyclopropylmethoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6,7-bis-(2-methoxy-ethoxy)-quinazoline, 4-[(3-chloro-4-fluorophenyl)amino]-6-{[4-(morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholin-4-yl)-1-oxo-2-buten-1-yl]amino}-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methanesulphonylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[2-(2-oxopyrrolidin-1-yl)ethyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-acetyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline, 4-[(3-ethynyl-phenyl)amino]-6-{1-[(morpholin-4-yl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-{1-[(2-methoxyethyl)carbonyl]-piperidin-4-yloxy}-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[cis-4-(N-acetyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-methylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[trans-4-(N-methanesulphonyl-N-methyl-amino)-cyclohexan-1-yloxy]-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(trans-4-{N-[(morpholin-4-yl)carbonyl]-N-methyl-amino}-cyclohexan-1-yloxy)-7-methoxy-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholin-4-yl)-ethoxy]-7-[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline, 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-methanesulphonyl-piperidin-4-yloxy)-7-methoxy-quinazoline and 4-[(3-chloro-4-fluoro-phenyl)amino]-6-(1-cyano-piperidin-4-yloxy)-7-methoxy-quinazoline optionally in the form of the racemates, enantiomers or diastereomers thereof, optionally in the form of the pharmacologically acceptable acid addition salts, the solvates and/or hydrates thereof.
By acid addition salts with pharmacologically acceptable acids which the EGFR-inhibitors may be capable of forming are meant, for example, salts selected from among the hydrochloride, hydrobromide, hydroiodide, hydrosulphate, hydrophosphate, hydromethanesulphonate, hydronitrate, hydromaleate, hydroacetate, hydrobenzoate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulphonate, preferably hydrochloride, hydrobromide, hydrosulphate, hydrophosphate, hydrofumarate and hydromethanesulphonate.
Examples of dopamine agonists which may be used preferably include compounds selected from among bromocriptine, cabergoline, alpha-dihydroergocryptine, lisuride, pergolide, pramipexol, roxindol, ropinirol, talipexol, terguride and viozan. Any reference to the above-mentioned dopamine agonists within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts and optionally hydrates thereof which may exist. By the physiologically acceptable acid addition salts which may be formed by the above-mentioned dopamine agonists are meant, for example, pharmaceutically acceptable salts which are selected from the salts of hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, methanesulphonic acid, acetic acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid and maleic acid.
Examples of H1-antihistamines preferably include compounds selected from among epinastine, cetirizine, azelastine, fexofenadine, levocabastine, loratadine, mizolastine, ketotifen, emedastine, dimetinden, clemastine, bamipin, cexchlorpheniramine, pheniramine, doxylamine, chlorophenoxamine, dimenhydrinate, diphenhydramine, promethazine, ebastine, desloratidine and meclozine. Any reference to the above-mentioned H1-antihistamines within the scope of the present invention includes a reference to any pharmacologically acceptable acid addition salts which may exist.
Examples of PAF-antagonists preferably include compounds selected from among 4-(2-chlorophenyl)-9-methyl-2-[3 (4-morpholinyl)-3-propanon-1-yl]-6H-thieno-[3,2-f]-[1,2,4]triazolo[4,3-a][1,4]diazepines, 6-(2-chlorophenyl)-8,9-dihydro-1-methyl-8-[(4-morpholinyl)carbonyl]-4H,7H-cyclo-penta-[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepines.
MRP4-inhibitors used are preferably compounds selected from among N-acetyl-dinitrophenyl-cysteine, cGMP, cholate, diclofenac, dehydroepiandrosterone 3-glucuronide, dehydroepiandrosterone 3-sulphate, dilazep, dinitrophenyl-s-glutathione, estradiol 17-β-glucuronide, estradiol 3,17-disulphate, estradiol 3-glucuronide, estradiol 3-sulphate, estrone 3-sulphate, flurbiprofen, folate, N5-formyl-tetrahydrofolate, glycocholate, clycolithocholic acid sulphate, ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholic acid sulphate, methotrexate, MK571 ((E)-3-[[[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3-oxopropyl]thio]methyl]thio]-propanoic acid), α-naphthyl-β-D-glucuronide, nitrobenzyl mercaptopurine riboside, probenecid, PSC833, sildenafil, sulfinpyrazone, taurochenodeoxycholate, taurocholate, taurodeoxycholate, taurolithocholate, taurolithocholic acid sulphate, topotecan,
trequinsin and zaprinast, dipyridamole, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof.
Preferably the invention relates to the use of MRP4-inhibitors for preparing a pharmaceutical composition for the treatment of respiratory complaints, containing the PDE4B-inhibitors and MRP4-inhibitors, the MRP4-inhibitors preferably being selected from among N-acetyl-dinitrophenyl-cysteine, dehydroepiandrosterone 3-sulphate, dilazep, dinitrophenyl-S-glutathione, estradiol 3,17-disulphate, flurbiprofen, glycocholate, glycolithocholic acid sulphate, ibuprofen, indomethacin, indoprofen, lithocholic acid sulphate, MK571, PSC833, sildenafil, taurochenodeoxycholate, taurocholate, taurolithocholate, taurolithocholic acid sulphate, trequinsin and zaprinast, dipyridamole, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof.
The invention relates more preferably to the use of MRP4-inhibitors for preparing a pharmaceutical composition for treating respiratory complaints, containing the PDE4B-inhibitors and MRP4-inhibitors according to the invention, the MRP4-inhibitors preferably being selected from among dehydroepiandrosterone 3-sulphate, estradiol 3,17-disulphate, flurbiprofen, indomethacin, indoprofen, MK571, taurocholate, optionally in the form of the racemates, enantiomers, diastereomers and the pharmacologically acceptable acid addition salts and hydrates thereof. The separation of enantiomers from the racemates can be carried out using methods known from the art (e.g. chromatography on chiral phases, etc.).
By acid addition salts with pharmacologically acceptable acids are meant, for example, salts selected from among the hydrochlorides, hydrobromides, hydroiodides, hydrosulphates, hydrophosphates, hydromethanesulphonates, hydronitrates, hydromaleates, hydroacetates, hydrobenzoates, hydrocitrates, hydrofumarates, hydrotartrates, hydrooxalates, hydrosuccinates, hydrobenzoates and hydro-p-toluenesulphonates, preferably the hydrochlorides, hydrobromides, hydrosulphates, hydrophosphates, hydrofumarates and hydromethanesulphonates.
The invention further relates to pharmaceutical preparations which contain a triple combination of the PDE4B-inhibitors, MRP4-inhibitors and another active substance according to the invention, such as, for example, an anticholinergic, a steroid, an LTD4-antagonist or a betamimetic, and the preparation thereof and the use thereof for treating respiratory complaints.
The iNOS-inhibitors used are preferably compounds selected from among: S-(2-aminoethyl)isothiourea, aminoguanidine, 2-aminomethylpyridine, AMT, L-canavanine, 2-iminopiperidine, S-isopropylisothiourea, S-methylisothiourea, S-ethylisothiourea, S-methyltiocitrulline, S-ethylthiocitrulline, L-NA (Nω-nitro-L-arginine), L-NAME (Nω-nitro-L-arginine methylester), L-NMMA (NG-monomethyl-L-arginine), L-NIO (Nω-iminoethyl-L-ornithine), L-NIL (Nω-iminoethyl-lysine), (S)-6-acetimidoylamino-2-amino-hexanoic acid (1H-tetrazol-5-yl)-amide (SC-51) (J. Med. Chem. 2002, 45, 1686-1689), 1400 W, (S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-butyric acid (GW274150) (Bioorg. Med. Chem. Lett. 2000, 10, 597-600), 2-[2-(4-methoxy-pyridin-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine (BYK191023) (Mol. Pharmacol. 2006, 69, 328-337), 2-((R)-3-amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile (WO 01/62704), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-6-trifluoromethyl-nicotinonitrile (WO 2004/041794), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-benzonitrile (WO 2004/041794), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-benzonitrile (WO 2004/041794), (2S,4R)-2-amino-4-(2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5-yl-butan-1-ol (WO 2004/041794), 2-((1R.3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-5-chloro-nicotinonitrile (WO 2004/041794), 4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy-nicotinonitrile (WO 02/090332), substituted 3-phenyl-3,4-dihydro-1-isoquinolinamines such as e.g. AR-C102222 (J. Med. Chem. 2003, 46, 913-916), (1S.5S.6R)-7-chloro-5-methyl-2-aza-bicyclo[4.1.0]hept-2-en-3-ylamine (ONO-1714) (Biochem. Biophys. Res. Commun. 2000, 270, 663-667), (4R.5R)-5-ethyl-4-methyl-thiazolidin-2-ylideneamine (Bioorg. Med. Chem. 2004, 12, 4101), (4R.5R)-5-ethyl-4-methyl-selenazolidin-2-ylideneamine (Bioorg. Med. Chem. Lett. 2005, 15, 1361), 4-aminotetrahydrobiopterine (Curr. Drug Metabol. 2002, 3, 119-121), (E)-3-(4-chloro-phenyl)-N-(1-{2-oxo-2-[4-(6-trifluoromethyl-pyrimidin-4-yloxy)-piperidin-1-yl]-ethylcarbamoyl}-2-pyridin-2-yl-ethyl)-acrylamide (FR260330) (Eur. J. Pharmacol. 2005, 509, 71-76), 3-(2,4-difluoro-phenyl)-6-[2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy]-2-phenyl-pyridine (PPA250) (J. Pharmacol. Exp. Ther. 2002, 303, 52-57), methyl 3-{[(benzo[1.3]dioxol-5-ylmethyl)-carbamoyl]-methyl}-4-(2-imidazol-1-yl-pyrimidin-4-yl)-piperazin-1-carboxylate (BBS-1) (Drugs Future 2004, 29, 45-52), (R)-1-(2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidine-2-carboxylic acid (2-benzo[1.3]dioxol-5-yl-ethyl)-amide (BBS-2) (Drugs Future 2004, 29, 45-52) and the pharmaceutical salts, prodrugs or solvates thereof.
Other iNOS-inhibitors which may be used within the scope of the present invention are antisense oligonucleotides, particularly antisense oligonucleotides that bind iNOS-coding nucleic acids. For example, WO 01/52902 describes antisense oligonucleotides, particularly antisense-oligonucleotides, which bind iNOS-coding nucleic acids, for modulating the expression of iNOS. Those iNOS-antisense-oligonucleotides as described particularly in WO 01/52902 may therefore also be combined with the PDE4-inhibitors of the present invention on the basis of their similar activity to the iNOS inhibitors.
Compounds which may be used as SYK-inhibitors are preferably compounds selected from among: R343 or R788.
Pharmaceutical Formulations
Suitable forms for administration are for example tablets, capsules, solutions, syrups, emulsions or inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.1 to 90 wt. %, preferably 0.5 to 50 wt. % of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specified hereinafter.
The preparations may be administered orally in the form of a tablet, as a powder, as a powder in a capsule (e.g. a hard gelatine capsule), as a solution or suspension. When administered by inhalation the active substance combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.
Preferably, therefore, pharmaceutical formulations are characterised in that they contain one or more compounds of formula I according to the preferred embodiments above.
It is particularly preferable if the compounds of formula I are administered orally, and it is also particularly preferable if they are administered once or twice a day. Suitable tablets may be obtained, for example, by mixing the active substance(s) with known excipients, for example inert diluents such as calcium carbonate, calcium phosphate or lactose, disintegrants such as corn starch or alginic acid, binders such as starch or gelatine, lubricants such as magnesium stearate or talc and/or agents for delaying release, such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise several layers.
Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with substances normally used for tablet coatings, for example collidone or shellac, gum arabic, talc, titanium dioxide or sugar. To achieve delayed release or prevent incompatibilities the core may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed release, possibly using the excipients mentioned above for the tablets.
Syrups containing the active substances or combinations thereof according to the invention may additionally contain a sweetener such as saccharine, cyclamate, glycerol or sugar and a flavour enhancer, e.g. a flavouring such as vanillin or orange extract. They may also contain suspension adjuvants or thickeners such as sodium carboxymethyl cellulose, wetting agents such as, for example, condensation products of fatty alcohols with ethylene oxide, or preservatives such as p-hydroxybenzoates.
Capsules containing one or more active substances or combinations of active substances may for example be prepared by mixing the active substances with inert carriers such as lactose or sorbitol and packing them into gelatine capsules.
Suitable suppositories may be made for example by mixing with carriers provided for this purpose, such as neutral fats or polyethyleneglycol or the derivatives thereof.
Excipients which may be used include, for example, water, pharmaceutically acceptable organic solvents such as paraffins (e.g. petroleum fractions), vegetable oils (e.g. groundnut or sesame oil), mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carriers such as e.g. natural mineral powders (e.g. kaolins, clays, talc, chalk), synthetic mineral powders (e.g. highly dispersed silicic acid and silicates), sugars (e.g. cane sugar, lactose and glucose), emulsifiers (e.g. lignin, spent sulphite liquors, methylcellulose, starch and polyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc, stearic acid and sodium lauryl sulphate).
For oral administration the tablets may, of course, contain, apart from the abovementioned carriers, additives such as sodium citrate, calcium carbonate and dicalcium phosphate together with various additives such as starch, preferably potato starch, gelatine and the like. Moreover, lubricants such as magnesium stearate, sodium lauryl sulphate and talc may be used at the same time for the tabletting process. In the case of aqueous suspensions the active substances may be combined with various flavour enhancers or colorings in addition to the excipients mentioned above.
It is also preferred if the compounds of formula I are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of formula I have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional physiologically acceptable excipients.
Within the scope of the present invention, the term propellant-free inhalable solutions also includes concentrates or sterile ready-to-use inhalable solutions. The preparations which may be used according to the invention are described in more detail in the next part of the specification.
Inhalable Powders
If the active substances of formula I are present in admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to prepare the inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), polyalcohols (e.g. sorbitol, mannitol, xylitol), salts (e.g. sodium chloride, calcium carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or glucose is preferred, particularly, but not exclusively, in the form of their hydrates. For the purposes of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred. Methods of preparing the inhalable powders according to the invention by grinding and micronising and by finally mixing the components together are known from the prior art.
Propellant-Containing Inhalable Aerosols
The propellant-containing inhalable aerosols which may be used according to the invention may contain 1 dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane) and mixtures thereof. The propellant-driven inhalation aerosols used within the scope of the use according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lubricants and pH adjusters. All these ingredients are known in the art.
Propellant-Free Inhalable Solutions
The compounds of formula I according to the invention are preferably used to prepare propellant-free inhalable solutions and inhalable suspensions. Solvents used for this purpose include aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water on its own or a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of 2 to 7, preferably 2 to 5, using suitable acids. The pH may be adjusted using acids selected from inorganic or organic acids. Examples of particularly suitable inorganic acids include hydrochloric acid, hydrobromic acid, nitric acid, sulphuric acid and/or phosphoric acid. Examples of particularly suitable organic acids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also be used, particularly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as flavourings, antioxidants or complexing agents, such as citric acid or ascorbic acid, for example. According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH. Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions used for the purpose according to the invention. Preferred co-solvents are those which contain hydroxyl groups or other polar groups, e.g. alcohols—particularly isopropyl alcohol, glycols—particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is not an active substance but which can be formulated with the active substance or substances in the pharmacologically suitable solvent in order to improve the qualitative properties of the active substance formulation. Preferably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents. The preferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, vitamin A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body. Preservatives may be used to protect the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art. For the treatment forms described above, ready-to-use packs of a medicament for the treatment of respiratory complaints are provided, containing an enclosed description including for example the words respiratory disease, COPD or asthma, a pteridine and one or more combination partners selected from those described above.
EXPERIMENTAL PROCEDURES AND SYNTHETIC EXAMPLES










LIST of ABBREVIATIONS
















ACN
acetonitrile


APCI
atmospheric pressure chemical ionization (in MS)


Ctrl
control


DAD
diode array detector


DMA
N,N-dimethylacetamide′


DMF
N,N-dimethylformamide


DMSO
dimethyl sulfoxide


EI
electron impact (in MS)


ESI
electrospray ionization (in MS)


ex
example


GC/MS
gas chromatography with mass spectrometric detection


h
hour(s)


HATU
O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium 



hexafluorophosphate


HPLC
high performance liquid chromatography


HPLC/
coupled high performance liquid chromatography-mass 


MS
spectrometry


min
minutes


MS
mass spectrometry


NMR
nuclear magnetic resonance


Rt
retention time (in HPLC)


sec
secondary


TBTU
O-(1H-benzo-1,2,3-triazol-1-yl)-N,N,N′,N′- tetramethyluronium



tetrafluoroborate


tert
tertiary


TFA
trifluoroacetic acid


TLC
thin-layer chromatography


UV
ultraviolet absorption









Analytical Methods

HPLC Methods

Methods:

    
    
        1A
        Column: Sunfire MS-C8, 5 μm, 4.6×100 mm
        Mobile phase: A=(10 nM aqueous solution of NH4COOH)+10% ACN;
        
            B=ACN+10% (10 nM aqueous solution of NH4COOH).
        
        
        Flow rate: 1500 μL/min
        Gradient: A/B (95/5%) for 1 min then to A/B (5/95%) in 10 min for 2 min.
        1E
        Column: Symmetry C8, 5 μm, 3×150 mm
        Mobile phase: A=(10 nM aqueous solution of NH4COOH)+10% ACN;
        
            B=ACN+10% (10 nM aqueous solution of NH4COOH).
        
        
        Flow rate: 1200 μL/min
        Gradient: A (100%) for 1.5 min then to B (100%) in 10 min for 3 min
        1E (Fusion)
        Column: Synergy Fusion RP80A, 4 μm, 4.6×100 mm
        Mobile phase: A=(10 nM aqueous solution of NH4COOH)+10% ACN;
        
            B=ACN+10% (10 nM aqueous solution of NH4COOH).
        
        
        Flow rate: 1200 μL/min
        Gradient: A (100%) for 1.5 min then to B (100%) in 10 min for 3 min
        1E (Hydro)
        Column: Synergy Hydro RP80A, 4 μm, 4.6×100 mm
        Mobile phase: A=(10 nM aqueous solution of NH4COOH)+10% ACN;
        
            B=ACN+10% (10 nM aqueous solution of NH4COOH).
        
        
        Flow rate: 1200 μL/min
        Gradient: A (100%) for 1.5 min then to B (100%) in 10 min for 3 min
        Equipment:
        Instrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD,
        Detection: UV @ 254 nm
        Detection: Finnigan MSQ, quadrupole
        Ion source: APCI

Method:

        1F
        Column: Xterra MS-C8, 3.5 μm, 4.6×50 mm
        Mobile phase: A=(H2O+0.1% TFA)+10% ACN; B=ACN
        Flow rate: 1300 μL/min
        Gradient: A (100%) then to A/B (10/90%) in 3.25 min for 0.75 min
        1Fa
        Column: Xterra MS-C18, 5 μm, 4.6×50 mm
        Mobile phase: A=(H2O+0.1% NH4COOH)+10% ACN; B=ACN
        Flow rate: 1300 μL/min
        Gradient: A (100%) then to A/B (10/90%) in 3.25 min for 0.75 min
        Equipment:
        Instrument: HPLC/MS Waters. Hp1c Alliance 2695 DAD, ZQ Quadrupole
        Detection: UV @ 254 nm
        Detection: Waters ZQ, Quadrupole;
        Ion source: ESI

Methods:

        2A
        Column: X-Terra MS C18 4.6×50 mm, 3.5 μm;
        
            Column Temperature: 40.0° C.
        
        
        Mobile phase: A=H2O+0.1% TFA; B=ACN+0.1% TFA
        Flow rate: 1500 L/min
        Gradient:
    
    














Time
A %
B %

















0.00
95.00
5.00


2.00
0.00
100.00


2.49
0.00
100.00


2.50
95.00
5.00









    
    
        2B
        Column: X-Terra MS C18 4.6×50 mm, 3.5 μm;
        
            Column Temperature: 40.0° C.
        
        
        Mobile phase: A=H2O+0.1% TFA; B=ACN+0.1% TFA
        Flow rate: 1000 μL/min
        Gradient:
    
    














Time
A %
B %

















0.00
95.00
5.00


0.40
95.00
5.00


4.00
2.00
98.00


4.35
2.00
98.00


4.50
95.00
5.00









    
    
        2C
        Column: Sunfire C18 4.6×50 mm, 3.5 μm;
        
            Column Temperature: 40.0° C.
        
        
        Mobile phase: A=H2O+0.1% TFA; B=ACN+0.1% TFA
        Flow rate: 1500 μL/min
        Gradient:
    
    














Time:
A %
B %

















0.00
95.00
5.00


2.00
0.00
100.00


2.49
0.00
100.00


2.50
95.00
5.00









    
    
        Equipment
        Instrument: Waters ZQ2000 mass spectrometer
        Detection: HP1100 HPLC+DAD (Wavelength range: 210 to 500 nM)
        
            +Gilson 215 Autosampler
        
        
        Ion source: ESI+

Method:

        2Ca
        Column: MERCK; Chromolith Flash; RP18e; 25×4.6 mm
        Mobile phase: A=water+0.1% HCOOH; B=ACN+0.1% HCOOH
        Flow rate: 1.6 ml/min
        Gradient:
    
    














A %
B %
Time [min]







90
10
0.00


10
90
2.70


10
90
3.00


90
10
3.30









    
    
        2Cb
        Column: MERCK; Chromolith Flash; RP18e; 25×4.6 mm
        Mobile: A=water+0.1% HCOOH; B=MeOH
        Flow rate: 1.6 ml/min
        Gradient:
    
    














A %
B %
Time [min]

















90
10
0.00


0
100
2.50


0
100
3.50









    
    
        Equipment
        Instrument: Agilent Technology; HP 1200 Series, DAD SL
        Detection: UV 240-254 nm
        Detection: Waters ZQ Single Quad
        Ion source: ESI+

Method:

        2F
        Column: Symmetry Shield RP8, 5 μm, 4.6×150 mm
        Mobile phase: A=(H2O+HCOOH 0.1%)+10% ACN
        
            B=ACN+10% (H2O+0.1% HCOOH)
        
        
        Flow rate: 1000 μL/min
        Gradient: A/B (95/5%) for 1.5 min then to A/B (5/95%) in 10 min for 1.5 min
        2M
        Column: Symmetry Shield RP8, 5 μm, 4.6×150 mm
        Mobile phase: A=(H2O+HCOOH 0.1%)+10% ACN
        
            B=ACN+10% (H2O+0.1% HCOOH)
        
        
        Flow rate: 1200 μL/min
        Gradient: A/B (90/10%) for 1.5 min then to A/B (5/95%) in 10 min for 2 min
        Equipment:
        Instrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD, LCQDuo Ion Trap
        Detection: UV λ 254 nm
        Detection: Finnigan LCQDuo Ion Trap
        Ion source: ESI

Method:

        2G
        Eluent: A=H2O+0.05% TFA; B=ACN
        Column: Waters SunFire C18 30×100 mm 5 μm
        
            Gradient: slope 5%/min
        
        
    
    




















Initial: 
Flow = 40 mL/min
% A = 80
% B = 20



  8 min
Flow = 40 mL/min
% A = 40
% B = 60



  9 min
Flow = 40 mL/min
% A = 40
% B = 60



  10 min
Flow = 40 mL/min
% A = 5 
% B = 95



  11 min
Flow = 40 mL/min
% A = 5 
% B = 95



11.5 min
Flow = 40 mL/min
% A = 80
% B = 20










    
    
        
        
            Stop run after 12 min Pre-run method: Initial condition for 3 min
        
        
        Equipment:
    
    















Detector MS Waters ZQ:
Detector DAD Waters 996:













File:
APrep_ESI.ipr
Start Wavelength: 
210 nm


Polarity:
ESI+
End Wavelength:
600 nm


Mass range:
130 to 900 amu
Resolution:
 1.2 nm




Sampling rate:
1 spectra/sec











Sample Manager mod Waters 2767:
Make up pump mod Waters 515:













Injection type:
partial loop
Flow =
1000 μL/min


Injection Volume:
set to Open
Solvent =
ACN/Water/Formic 


Access Login 
5000 uL
(90/10/0.1)
acid 


mask Syringe size:

Splitter:
1:1000


Trigger:
mixed Total 





scan




UV plus MS A
5000 uL




Loop Volume:









Method:

    
    
        2G a
        Column: BEH C18, 1.8 um, 2.1×100 mm
        Mobile phase: A=(H2O+NH4COOH 0.1%)
        
            B=ACN+10% H2O
        
        
        Flow rate: 450 μL/min
        Gradient: 100% A for 1.5 min then to 100% B in 2.2 min
        2 Gb
        Column: BEH C18, 1.7 um, 2.1×50 mm
        Mobile phase: A=H2O 90%+0.1% TFA+10% ACN
        
            B=ACN+10% H2O
        
        
        Flow rate: 480 μL/min
        Gradient: A/B (90:10), then to A/B (10:90) in 1.2 minutes for 0.46 minute
        Equipment:
        Instrument: UPLC/MS AcquityWaters
        Detection: UV λ 254 nm
        Detection: Waters SQD, Quadrupole
        Ion source: ESI

Method:

        2H (isocratic)
        Column: DAICEL (IC) 5 μm, 4.6×250 mm
        Mobile phase: A=(hexane+0.2% diethylamine); B=(MeOH/EtOH 50/50%).
        
            A/B=50/50%
        
        
        Flow rate: 1 ml/min
        2I (isocratic)
        Column: DAICEL AS-H 5 μm, 4.6×250 mm
        Mobile phase: A=Hexane; B=EtOH (con AS-H), IPA (con AD-H)
        
            A/B=98/2%
        
        
        Flow rate: 1 ml/min
        Equipment
        Instrument: LC Agilent Technologies. HPLC 1100 Serie, DAD Version A.
        Detection: UV 220-300 nm

GC-MS Methods:

Method:

        3A
        Column: Agilent DB-5MS, 25m×0.25 mm×0.25 μm
        Carrier gas: Helium, 1 ml/min costant flow
        Oven Program: 50° C. (hold 1 min.), to 100° C. in 10° C./min, to 200° C. in 20° C./min, to 300° C. in 30° C./min
        Equipment
        Instrument: GC/MS Finnigan TRACE GC, TRACE MS quadrupole
        Detection: TRACE MS quadrupole
        Ion source: EI

Microwave Heating:

        Discover® CEM instruments, equipped with 10 and 35 mL vessels.
    
    


Synthesis of Intermediates
Intermediate 1a




Potassium hydroxide (37.9 g, 0.67 mol) was suspended in 200 ml of dry ethanol, formamidine acetate (28.1 g, 0.27 mol) and diethyl oxalpropionate (50 ml, 0.27 mol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was cooled to room temperature and the precipitate formed was filtered, washed with ethanol and diethyl ether, dissolved in 200 ml of water and the solution obtained acidified by a 37% aqueous solution of hydrochloric acid until pH=2. The acidic aqueous solution was concentrated under vacuum and the residue obtained was suspended and stirred in 100 ml of methanol. The insoluble inorganic salts were filtered off. The solution was concentrated. 15 g (97.4 mmol) of the desired compound were obtained.
Intermediate 1b




was synthesized in analogy to Intermediate 1a, starting from acetamidine hydrochloride.

Intermediate 1c





Potassium-tert-butylate (185.4 g, 1.65 mol) was dissolved in 650 ml of dry ethanol and added slowly at −10° C. to a suspension of 2-ethyl-3-oxo-succinic-acid diethyl ester (274.3 g, 1.27 mol) and formamidine acetate (171.4 g, 1.65 mol). The reaction mixture was stirred at room temperature overnight, concentrated in vacuum and ice water was added. The mixture was acidified by a 37% aqueous solution of hydrochloric acid until pH=5 and extracted with chloroform. After drying the organic layer, evaporation of the solvent in vacuum and crystallization from ethyl acetate/hexane (2:3) gave 38 g (0.19 mol) of the desired compound.
Intermediate 1d




A suspension of sodium tert-butoxide (3.9 g, 40.5 mmol) in 25 ml dry ethanol was added to a solution of diethyl oxalpropionate (3.0 ml, 16.2 mmol) and O-methylisourea hydrochloride (2.15 g, 19.5 mmol) in 25 ml dry ethanol and the reaction mixture was refluxed for 18 h. The reaction mixture was allowed to cool to room temperature and the precipitate removed by filtration. The filtrate was concentrated in vacuum, and the residue was purified by reversed phase HPLC to give the desired product (752 mg, 3.5 mmol).
Intermediate 1e




Intermediate 1d (550 mg, 2.6 mmol) was dissolved in a 4 M aqueous solution of sodium hydroxide (3.0 ml, 12.0 mmol) and stirred for 3 h at room temperature. The reaction mixture was acidified with concentrated hydrochloric acid to yield the desired product as precipitate (443 mg, 2.4 mmol).
Intermediate 2a




Intermediate 1a (7.0 g, 45.4 mmol) was suspended in 35 ml of thionyl chloride (0.45 mol), 0.10 ml of DMF was added and the reaction mixture was refluxed for 1 h. The reaction mixture was concentrated in vacuum. 8.6 g (45 mmol) of the desired product were obtained and used in the next steps without further purification.
Intermediate 2b




was synthesized in analogy to Intermediate 2a, starting from Intermediate 1b.

Intermediate 2c





was synthesized in analogy to Intermediate 2a, starting from Intermediate 1e.
Intermediate 3a




Potassium carbonate (43.34 g, 0.31 mol) was suspended in 350 ml of dry ethanol. A solution of Intermediate 2a (20 g, 0.10 mol) in 10 ml of dichloromethane was added slowly at 0° C. The reaction mixture was allowed to reach room temperature and stirred for 1 h. Potassium carbonate was filtered off and the solvent was removed under vacuum. The crude product was purified by flash chromathography (BIOTAGE SP1; silica gel cartridge: 65 i; eluent: dichloromethane/ethyl acetate=95/5%). 5.3 g (26 mmol) of the desired compound were obtained.
Intermediate 3b




was synthesized in analogy to Intermediate 3a, starting from Intermediate 2b.
Intermediate 3c




Intermediate 1c (38 g, 0.19 mol) was added to a mixture of phosphorpentachloride (40.3 g, 0.19 mol) in 240 ml of phosphoroxychloride. The reaction mixture was refluxed until a clear solution was observed. The reaction mixture was concentrated in vacuum. The crude product obtained was purified by destillation in vacuum. 12 g (94.5 mmol) of the desired compound were obtained and used in the next steps without further purification.
Intermediate 3d




5-Bromo-6-hydroxy-pyrimidine-4-carboxylic acid ethyl ester (63 g, 0.26 mol) was suspended in 140 ml of phosphoroxychloride. Phosphorpentachloride (54 g, 0.26 mmol) was added and the reaction mixture was refluxed 72 h. The reaction mixture was concentrated in vacuum and the crude product was suspended and stirred in warmed-up hexane (50° C.); a precipitate was formed and filtered off. The filtrate was concentrated under vacuum to obtain 64 g (243 mmol) of the desired product which was used in the next steps without further purification.
Intermediate 4a




3-Phenylcyclohexanone (500 mg, 2.87 mmol) and 1-isocyanomethanesulfonyl-4-methyl-benzene (750 mg, 3.84 mmol) in 10 ml of 1,2-dimethoxyethane were stirred at 0° C. A solution of potassium tert-butoxide (650 mg, 5.79 mmol) in 10 ml of 1,2-dimethoxyethane and 20 ml of tert-butanol was added dropwise and the reaction mixture was allowed to reach room temperature and stirred overnight. The reaction mixture was diluted with diethyl ether and washed with ice water. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. 439 mg (2.3 mmol) of the desired product were obtained.
Intermediate 4b




was synthesized in analogy to Intermediate 4a, starting from (R)-3-Phenylcyclohexanone.

    
    
        GC/MS (method 3A) Rt=11.52 min and 11.68 min (diastereoisomeric mixture) [M]+=185

Intermediate 4c

    
    






was synthesized in analogy to Intermediate 4a, starting from (S)-3-Phenylcyclohexanone.

    
    
        GC/MS (method 3A) Rt=11.50 min and 11.65 min (diastereoisomeric mixture) [M]+=185
    
    


The following intermediates were synthesized in analogy to Intermediates 4a.












Starting 




ketone
Intermediate
STRUCTURE







3-(4-Chloro-phenyl)- cyclohexanone
4d






 


3-(4-Fluoro-phenyl)- cyclohexanone
4e






 


3-(4-Methoxy-phenyl)- cyclohexanone
4f






 


3-(4-Methyl-phenyl)- cyclohexanone
4g






 


3-(3-Fluoro-phenyl)- cyclohexanone
4h






 


3-isopropyl- cyclohexanone
4i






 


3-(5-Methyl-furan- 2-yl)-cyclohexanone
4j






 


3- Phenylcyclopentanone
4k






 


3-(4-Chloro-phenyl)- cyclopentanone
4l






 


3-(4-Fluoro-phenyl)- cyclopentanone
4m













Intermediate 4n





Intermediate 4j (400 mg, 2.11 mmol) was purified by flash chromatography (Biotage SP1 cartridge 25 g; eluent: cyclohexane/ethyl acetate=99/1%). 60 mg (0.22 mmol) of diastereoisomerically pure cis-intermediate was eluted as second fraction (relative stereochemistry assigned by NMR).

    
    
        GC/MS (method 3A) Rt=9.62 min
        [M]+=189

Intermediate 4o

    
    






Intermediate 4n (120 mg, 4.22 mmol) was separated by chiral semipreparative HPLC. 20 mg of enantiomerically pure intermediate 4o were obtained (absolute stereochemistry unknown). Chiral HPLC (method 2I (isocratic)) Rt=6.94 min
Intermediate 4p




Further elution of the column gave 20 mg of enantiomerically pure intermediate 4p (absolute stereochemistry unknown).
Chiral HPLC (method 21 (isocratic)) Rt=7.27
Intermediate 5




Intermediate 4b (2.1 g, 11.28 mmol) was stirred under reflux in 20 ml of 96% sulfuric acid and 20 ml of water overnight. The reaction mixture was cooled, treated with a 30% aqueous solution of sodium hydroxide and ice and washed with dichloromethane. The basic water phase was treated with 37% aqueous solution of hydrochloric acid. The acidic aqueous solution was extracted with dichloromethane. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. 1.85 g (9.1 mmol) of the desired compound were obtained as a diastereoisomeric mixture and used in the next steps without further purification.
Intermediate 6a




Intermediate 5 (1.85 g, 9.06 mmol, mixture of 2 diastereomers) and triethylamine (2.02 ml, 14 mmol) were stirred at 0° C. in 10 ml of tetrahydrofuran. A solution of ethylchloroformate (1.29 ml, 13.58 mmol) in 5 ml of tetrahydrofuran was added dropwise and the reaction mixture was stirred at 0° C. for 1 h. Then, 10 ml of a 30% aqueous solution of ammonium hydroxide were added dropwise and the reaction mixture was allowed to reach room temperature and stirred overnight. The reaction mixture was concentrated under vacuum, dissolved with dichloromethane, washed with a 1M aqueous solution of sodium hydroxide, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica cartridge 70 g; eluent: dichloromethane/methanol=99/1%). 145 mg (0.71 mmol) of diastereoisomerically pure (1R,3R)-3-phenyl-cyclohexanecarboxylic acid amide (relative stereochemistry assigned by NMR) were obtained.

    
    
        GC/MS (method 3A) Rt=12.88 min
        [M]+=203

Intermediate 6b

    
    






Further elution of the column gave 230 mg (1.13 mmol) of the diastereoisomerically pure (1S,3R)-3-phenyl-cyclohexanecarboxylic acid amide (relative stereochemistry assigned by NMR).

    
    
        GC/MS (method 3A) Rt=13.03 min
        [M]+=203

Intermediate 6c

    
    






Intermediate 4c (300 mg, 1.61 mmol) was stirred under reflux in 2 ml of 96% sulfuric acid and 2 ml of water for 3 h. The reaction mixture was cooled, treated with a 30% aqueous solution of sodium hydroxide and ice and washed with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica cartridge 20 g; eluent: dichloromethane/methanol=99/1%). 37 mg (0.18 mmol) of the diastereomerically pure (1S,3S)-3-phenyl-cyclohexanecarboxylic acid amide were obtained (relative stereochemistry assigned by NMR).

    
    
        GC/MS (method 3A) Rt=12.88 min
        [M]+=203

Intermediate 6d

    
    






Further elution of the column gave 40 mg of the diastereomerically pure (1R,3S)-3-phenyl-cyclohexanecarboxylic acid amide (0.2 mmol) (relative stereochemistry assigned by NMR).

    
    
        GC/MS (method 3A) Rt=13.03 min
        [M]+=203

Intermediate 6e

    
    






5-Bromo-3-furan carboxylic acid (1.0 g, 5.23 mmol), phenylboronic acid (0.77 g, 6.28 mmol), tetrakis(triphenylphosphine)palladium(0) (1.21 g, 1.04 mmol) and a 2M solution of sodium carbonate (6.28 ml, 12.57 mmol) were dissolved in 12 ml of 1,2-dimethoxy-ethane and the reaction mixture was stirred under nitrogen atmosphere at 80° C. for 18 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane and treated with a 1M aqueous solution of hydrochloric acid until pH 1. The organic phase was separated, dried over sodium sulphate and concentrated under vacuum. The carboxylic acid was obtained and used without further purification for the synthesis of intermediate 6e in analogy to intermediate 6a.
Intermediate 6f




Intermediate 6f was synthesized in analogy to intermediate 6a, starting from trans 3-(4-chlorophenyl)-cyclobutan carboxylic acid (prepared as described in literature for the preparation of trans 3-phenyl-cyclobutan-carboxylic acid: Wiberg, K. B.; Dailey, W. P.; Walker, F. H.; Waddell, S. T.; Crocker, L. S.; Newton, M. Journal of the American Chemical Society; 1985, 107, 7247-7257).
Intermediate 6g




Intermediate 6g was synthesized in analogy to Intermediate 6a, starting from cis 3-(4-chlorophenyl)-cyclobutan carboxylic acid (prepared as described in literature for the preparation of cis 3-phenyl-cyclobutan-carboxylic acid: Wiberg, K. B.; Dailey, W. P.; Walker, F. H.; Waddell, S. T.; Crocker, L. S.; Newton, M. Journal of the American Chemical Society; 1985, 107, 7247-7257).
Intermediate 7a




Intermediate 4a (390 mg, 2.10 mmol) and Raney-Nickel (10 mg) in 10 ml of 1M solution of ammonia in ethanol was stirred under a hydrogen atmosphere (4 bar) overnight. The reaction mixture was filtered on a celite pad and concentrated under vacuum. The crude product was purified by flash chromatography (dichloromethane/methanol/NH3(30% aqueous solution)=95/5/0.1%) to obtain 217 mg (1.15 mmol) of the desired product.
Intermediate 7b




2.85 ml of a 1M solution of lithium aluminium hydride (2.85 mmol) in tetrahydrofuran was dissolved in 10 ml of tetrahydrofuran and stirred at 0° C. under nitrogen atmosphere. Intermediate 6a (145 mg, 0.71 mmol) in 10 ml of tetrahydrofuran was added dropwise. The reaction mixture was stirred at 0° C. for 2 h and then quenched with water and ice. The reaction mixture was extracted with dichlorometane. The organic phase was washed with a 1M aqueous solution of sodium hydroxide, brine, dried over sodium sulfate and concentrated under vacuum. 100 mg (0.55 mmol) of the desired product were obtained.

    
    
        GC/MS (method 3A) Rt=11.53 min
        [M]+=189

Intermediate 7c

    
    






was synthesized in analogy to Intermediate 7b, starting from Intermediate 6b.

    
    
        GC/MS (method 3A) Rt=11.47 min
        [M]+=189

Intermediate 7d

    
    






was synthesized in analogy to Intermediate 7b, starting from Intermediate 6c.

    
    
        GC/MS (method 3A) Rt=11.53 min
        [M]+=189

Intermediate 7e

    
    






was synthesized in analogy to Intermediate 7b, starting from Intermediate 6d.

    
    
        GC/MS (method 3A) Rt=13.03 min
        [M]+=189
    
    


The following intermediates were synthesised in atalogy to Intermediate 7a.












Starting 




Intermediate
Intermediate
STRUCTURE







4d
7f






 


4e
7g






 


4f
7h






 


4g
7i






 


4h
7j






 


4i
7k






 


4k
7l






 


4l
7m






 


4m
7n






 


4n
7o






 


4o
7p






 


4p
7q













Intermediate 7r





was synthesized in analogy to intermediate 7b, starting from intermediate 6e.

Intermediate 7s





was synthesized in analogy to intermediate 7b, starting from intermediate 6f.

Intermediate 7t





was obtained and isolated as side product in the preparation of Intermediate 7s

Intermediate 7u





was synthesized in analogy to Intermediate 7b, starting from Intermediate 6g.

Intermediate 7v





was obtained and isolated as side product in the preparation of Intermediate 7u.

Intermediate 8a





Tris(dibenzylideneacetone)dipalladium (1.71 g, 1.87 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (2.32 g, 3.72 mmol) were stirred in 30 ml of toluene for 10 min under argon athmosphere.
Piperidine-3-yl-methyl-carbamic acid tert-butyl ester (2 g, 9.33 mmol), bromobenzene (1.27 ml, 0.01 mol) and sodium tert-butoxide (1.43 g, 14.93 mmol) were added and the reaction mixture was stirred under reflux overnight. The reaction mixture was concentrated under vacuum, the crude product was dissolved in dichlorometane and the organic phase was filtered on a celite pad. The organic phase was washed with an aqueous saturated sodium carbonate solution, with brine, dried over sodium sulfate, concentrated under vacuum. The crude product obtained was dissolved in methanol and loaded onto a SCX cartridge (25 g). After washing with methanol the product was eluted with a 2M solution of ammonia in methanol. 1.17 g (4.03 mmol) of the desired product were obtained and used in next steps without any other purification.
Intermediate 9a




To a solution of Intermediate 8a (1.1 g, 3.79 mmol) in 10 ml of 1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane (15 ml, 60 mmol) was added dropwise; the reaction mixture was stirred at room temperature overnight before being concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartride: 50 g; eluent: dichloromethane/methanol=95/5%). 250 mg (1.31 mmol) of the desired compound were obtained.
The following intermediates were synthesized in analogy to Intermediates 8a and 9a.















Starting 
Starting 
Inter-

Inter-



amine
bromide
mediate
STRUCTURE
mediate
STRUCTURE







(S)-1- Pyrrolidin-3- ylmethyl- carbamic acid tert- butyl ester
bromo- benzene
8b




9b






 


(R)-1- Pyrrolidin-3- ylmethyl- carbamic acid tert- butyl ester
bromo- benzene
8c




9c






 


Piperidine-3- yl-methyl- carbamic acid tert- butyl ester
1-bromo- 4- trifluoro methyl- benzene
8d




9d













Intermediate 10





Piperidine-3-yl-methyl-carbamic acid tert-butyl ester (100 mg, 0.47 mmol), 2-chloro-4-fluoro-benzonitrile (72.5 mg, 0.47 mmol) and N,N-diisopropylethylamine (0.160 ml, 1.23 mmol) were dissolved in 10 ml of DMF and the reaction mixture was stirred at 125° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was purified by flash chromatography (Isolute silica gel cartride: 5 g; eluent: ethyl acetate). 125 mg (0.36 mmol) of the desired compound were obtained.
Intermediate 11




To a solution of Intermediate 10 (125 mg, 0.36 mmol) in 5 ml of 1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane (0.12 ml, 480 mmol) was added dropwise; the reaction mixture was stirred at room temperature overnight before being concentrated under vacuum. 102 mg (0.36 mmol) of the desired compound were obtained.
Intermediate 12




A solution of 4-methanesulfonylamino-piperidine-1-carboxylic acid tert-butyl ester (500 mg; 1.79 mmol) in 5 ml of acetonitrile was cooled to −5° C., iodoethane (308 mg, 1.79 mmol) and sodium hydride (96 mg, 3.59 mmol) were added; the reaction mixture was allowed to warm to room temperature and stirred for 72 h.
The reaction mixture was concentrated under vacuum; the residue was dissolved in ethyl acetate and washed with an aqueous saturated sodium bicarbonate solution and then with water.
The organic phase was dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartridge: 10 g, eluent: dichloromethane) to obtain 332 mg (1.1 mmol) of the desired compound.
Intermediate 13




To a solution of intermediate 12 (330 mg, 1.1 mmol) in 20 ml of 1,4-dioxane, a 4M solution of hydrochloric acid in 1,4-dioxane (4.06 ml, 16 mmol) was added dropwise; the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum to obtain 262 mg (1.1 mmol) of the desired compound.
Intermediate 14




trans-4-Azido-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester (1.6 g, 6.24 mmol), Pd/C 10% (200 mg) and acetic acid (1.6 ml) were dissolved in 25 ml of methanol and the reaction mixture was stirred under hydrogen atmosphere (4 bar) for 3 h. The reaction mixture was filtered on a celite pad and concentrated under vacuum. The crude product was purified by flash chromatography (Biotage SP1 cartridge 65 i, eluent: dichloromethane/methanol=95/5%). 900 mg (3.91 mol) of the desired compound were obtained.

Intermediate 15a





Intermediate 14 (900 mg, 3.91 mmol) and N,N-diisopropylethylamine (0.86 ml, 5 mmol) were dissolved in 25 ml of dichloromethane. The reaction mixture was cooled to 0° C. and methanesulfonylchloride (0.33 ml, 4.30 mmol) was added. The reaction mixture was stirred at 0° C. for 20 min, then, water was added. The organic phase was separated, washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica cartridge: 10 g, eluent: hexane/ethyl acetate=50/50%). 170 mg (0.55 mol) of the desired compound were obtained.
Intermediate 15b




Intermediate 15a (350 mg, 1.13 mmol) and potassium carbonate (157 mg, 1.13 mmol) were dissolved and stirred in 15 ml of acetonitrile. A solution of iodomethane (0.071 ml, 1.13 mmol) in 5 ml of acetonitrile was added dropwise and the reaction mixture was warmed to 60° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in ethyl acetate. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, separated, dried over sodium sulfate and concentrated under vacuum. 300 mg (0.93 mmol) of the desired compound were obtained and used in the next steps without further purification.
Intermediate 16a




Intermediate 15a (170 mg, 0.55 mmol) in 2 ml of 1,4-dioxane was stirred at 10° C. A 4M solution of hydrochloric acid in 1,4-dioxane (8 ml, 32 mmol) was added dropwise and the reaction mixture was stirred at room temperature for 5 h. The reaction mixture was concentrated under vacuum to obtain 115 mg (0.55 mmol) of the desired compound.
Intermediate 16b




was synthesized in analogy to Intermediate 16a, starting from Intermediate 15b.

Intermediate 17





was synthesized in analogy to Intermediate 15a, starting from (3S,4R)-4-amino-3-methoxy-piperidine-1-carboxylic acid tert-butyl ester.

Intermediate 18





Intermediate 17 (660 mg, 2.14 mmol) in 10 ml of 1,4-dioxane was stirred at 10° C. Trifluoroacetic acid (2 ml, 26 mmol) was added dropwise and the reaction mixture was stirred at room temperature 18 h. The reaction mixture was concentrated under vacuum to obtain 600 mg (1.86 mmol) of the desired compound, used in the next step without further purification.
Intermediate 19a




N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (11 g, 47.91 mmol) was suspended in 200 ml of 1,2-dichloroethane, N,N-diisopropylethylamine (17.12 ml, 96.17 mmol) and 1-(tert-butoxycarbonyl)-piperidin-4-one (9.58 g, 48.08 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (12.23 g, 57.50 mmol) was added and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution.
The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Biotage SP1; silica gel cartridge: 65 i; eluent: ethyl acetate/methanol=50/50%) to obtain 7.2 g (19.2 mmol) of the desired compound.
Intermediate 20a




Intermediate 19a (7.2 g, 19.2 mmol) was suspended in 20 ml of 1,4-dioxane, a 4M solution of hydrochloric acid (48 ml, 192 mmol) in 1,4-dioxane was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum. 6.3 g (18 mmol) of the desired compound were obtained.

The following intermediates were synthesized in analogy to Intermediates 19a and 20a.















Starting 
Starting 
Carbamate 

Diamino 



ketone
amine
Intermediate
STRUCTURE
Intermediate
STRUCTURE







1-(tert- butoxy- carbonyl)- 4-oxo- piperidine
Ethane- sulfonic acid methyl- piperi- din-4-yl- amide
19b




20b






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
(R)-N- Pyrrolidin- 3-yl- methane sulfonamide
19c




20c






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
(S)-N- Pyrrolidin- 3-yl- methane sulfonamide
19d




20d






 


1-(tert- butoxy- carbonyl)- 4-oxo- piperidine
Ethane- sulfonic acid piperi- din-4-yl- amide
19e




20e






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
Piperidine- 4- carboxylic acid methyl amide
19f




20f






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
Piperidine- 4- sulfo-nic acid methyl amide
19g




20g






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
(R)- Pyrrolidine- 3- carboxilic acid methyl- amide
19h




20h






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperi- dine
(S)- Pyrrolidine- 3- carboxilic acid methyl- amide
19i




20i






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
(S)- Pyrrolidine- 3- carboxilic acid amide
19j




20j






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
16a
19k




20k






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
(R)- Pyrrolidine- 3- carboxilic acid amide
19l




20l






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
47b
19lf




20lf






 


1-(tert- butoxy- carbonyl)- 4- oxo- piperidine
47c
19lg




20lg













Intermediate 19Ia





4-Methylamino-piperidine-1-carboxylic acid tert-butyl ester (500 mg, 1.87 mmol) was suspended in 10 ml of 1,2-dichloroethane. Tetrahydro-pyran-4-one (0.17 ml, 1.87 mmol) was added and the reaction mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (593 mg, 2.80 mol) was added and the reaction mixture was stirred for 18 h. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution.
The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartridge 10 g; eluent: dichloromethane/methanol=94/6%). 240 mg (0.80 mmol) of the desired compound were obtained.
Intermediate 20Ia




Intermediate 19Ia (240 mg, 0.80 mmol) was suspended in 10 ml of 1,4-dioxane, a 4M solution of hydrochloric acid (2.0 ml, 8.0 mmol) in 1,4-dioxane was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum. 200 mg (0.74 mmol) of the desired compound were obtained.
The following intermediates were synthesized in analogy to Intermediates 19Ia and 20Ia















Starting 
Starting 
Carbamate 

Amino 



amine
ketone
Intermediate
STRUCTURE
Intermediate
STRUCTURE







4- Methyl- amino- piperidine- 1-car- boxylic acid tert- butyl ester
3- Methoxy- tetra- hydro- pyran-4- one
19lb




20lb






 


4- Methyl- amino- piperidine- 1-car- boxylic acid tert- butyl ester
2,6- dimethyl- tetra- hydro- pyran-4- one
19lc




20lc






 


4- Methyl- amino- piperidine- 1-car- boxylic acid tert- butyl ester
4,4- difluoro- cyclo- hexa- none
19ld




20ld






 


4-amino- piperidine- 1-car- boxylic acid tert- butyl ester
3- Methoxy- tetra- hydro- pyran-4- one
19le




20le













Intermediate 19m





N-methyl-N-piperidin-4-yl-methanesulfonamide hydrochloride (1.13 g, 4.95 mmol) was suspended in 10 ml of 1,2-dichloroethane, N,N-diisopropylethylamine (2.6 ml, 14.9 mmol) and N-carbethoxy-3-methoxy-piperidin-4-one (1 g, 4.95 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.16 g, 14.85 mol) was added and the reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution.
The organic phase was dried over sodium sulfate and concentrated under vacuum. 1.5 g (3.97 mmol) of the desired compound were obtained and used without further purification.
Intermediate 20m




Intermediate 19m (1.5 g, 3.97 mmol) and potassion hydroxide (4.46 g, 7.94 mmol) were suspended in 25 ml of ethanol and the reaction mixture was stirred under reflux overnight. The reaction mixture was concentrated under vacuum and the crude product was loaded on a SCX cartridge (25 g) and eluted with a 2M solution of ammonia in methanol. 1.2 g (3.97 mmol) of the desired compound were obtained.
Intermediate 21




Piperidin-4-yl-carbamic acid tert-butyl ester (6 g, 30 mmol) and 1-(benzyloxycarbonyl)-4-oxopiperidine (9.6 g, 48 mmol) were dissolved in 50 ml of dichloromethane and the reaction mixture was stirred at room temperature for 30 min; sodium triacetoxyborohydride (12.23 g, 57.5 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was treated with acetone/isopropyl ether and the precipitate obtained was filtered off. 8.4 g (20 mmol) of the desired product were obtained.
Intermediate 22




To a solution of intermediate 21 (8.4 g, 20 mmol) in 150 ml of 1,4-dioxane previously cooled to 0° C., 12.6 ml (50 mmol) of a 4M solution of hydrochloric acid in 1,4-dioxane were added dropwise; the reaction mixture was allowed to warm to room temperature and was stirred at that temperature overnight. The solid precipitated from the reaction mixture was filtered off and dried at 50° C. under vacuum to obtain 6 g (15 mmol) of the desired compound.
Intermediate 23




Intermediate 22 (6.0 g, 15 mmol) was suspended in 55 ml of dichloromethane; triethylamine (6.43 ml, 46 mmol) was added and the reaction mixture was cooled to 0° C. and stirred at that temperature for 30 min. Methanesulfonyl chloride (1.43 ml, 18 mmol) in 5 ml of dichloromethane was added dropwise. The reaction mixture was stirred at 0° C. for 1 h; then water was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, with brine, dried over sodium sulfate and concentrated under vacuum. The crude product was treated with diisopropyl ether, the precipitate was filtered off and dried. 5 g (13 mmol) of the desired product were obtained.
Intermediate 24




Intermediate 23 (5 g, 13 mmol) was dissolved in 50 ml of methanol; acetic acid (1.5 ml, 25.3 mmol) and Pd/C 10% (500 mg) were added in sequence and the reaction mixture was stirred under a hydrogen atmosphere (3 bar) at room temperature for 5 days. The reaction mixture was filtered on a celite pad and the organic phase was loaded on a SCX cartridge (10 g). After washing with methanol, the desired compound was eluted with a 2M solution of ammonia in methanol. 3.7 g (4.6 mmol) of the title compound were obtained.
Intermediate 25a




Intermediate 24 (1.1 g, 4.21 mmol) was suspended in 20 ml of dry dichloromethane, N,N-diisopropylethylamine (1.47 ml, 8.42 mmol) and DMF (137 μl, 1.67 mmol) were added and the reaction mixture was stirred under nitrogen atmosphere and cooled to 0° C. Intermediate 2a (812 mg, 4.21 mmol) in 5 ml of dichloromethane was added dropwise and the reaction mixture was allowed to warm up to room temperature and stirred for 1.5 h; the reaction mixture was diluted with dichloromethane and washed with an aqueous saturated sodium bicarbonate solution. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (isolate silica gel cartridge: 10 g; eluent: dichloromethane/methanol=95/5%). 1.0 g (2.41 mmol) of the title compound were obtained.
The following intermediates were synthesized in analogy to Intermediate 25a.














Piperidine
Chloro- 



Core 
Inter-
pyrimidine 



Intermediate
mediate
Intermediate
STRUCTURE







2a
20a
25b






 


2a
20b
25c






 


2a
20f
25d






 


2a
20h
25e






 


2a
[1,4′]-Bi- piperidinyl- 4-ol
25f






 


2a
4-Methoxy- [1,4′]bi- piperidinyl
25g






 


2a
4-Piperidin- 4-yl-morpho- line
25h






 


2a
[1,4′]Bi- piperidinyl
25i






 


2a
[1,4′]-Bi- piperidinyl- 3-ol
25j






 


2b
24
25k






 


2b
20a
25l






 


2b
[1,4′]-Bi- piperidinyl- 4-ol
25m






 


2c
20a
25n






 


2a
20le
25o













Intermediate 26a





Intermediate 3a (10 g, 49.35 mmol) and N,N-diisopropylethylamine (17 ml, 99 mmol) were dissolved in 20 ml of dry DMF; 2-(3,4-dichloro-phenyl)-ethylamine (9.57 g, 49.35 mmol) in 10 ml of dry DMF was added and the reaction mixture was stirred at 90° C. for 2 h. The reaction mixture was cooled to room temperature, water was added and the reaction mixture was extracted with dichloromethane; the organic phase was concentrated under vacuum, the crude product was suspended and stirred in diethyl ether and the precipitate was filtered off and dried. 10.2 g (28.8 mmol) of the desired compound were obtained.
Intermediate 27a




Intermediate 26a (10.0 g, 28.25 mmol) was dissolved in 70 ml of ethanol and a solution of LiOH (3.52 g, 83.88 mmol) in 70 ml of water was added. The reaction mixture was stirred at 70° C. for 1 hour, concentrated under vacuum and the remaining aqueous solution was acidified by 20 ml of 4M solution of hydrochloric acid in 1,4-dioxane; the precipitate formed was filtered off and dried. 8.6 g (26.37 mmol) of the desired product were obtained.
The following intermediates were synthesized in analogy to Intermediates 26a and 27a.















Core 







Inter-

Ester 

Acid 



mediate
Amine
Intermediate
STRUCTURE
Intermediate
STRUCTURE







3a
3,4- Dichloro- benzyl- amine
26b




27b






 


3a
4-tert-butyl- benzyl- amine
26c




27c






 


3a
biphenyl-3- ylmethan- amine
26d




27d






 


3b
4-tert-butyl- benzyl- amine
26e




27e






 


3c
2-(3,4- dichloro- phenyl)- ethylamine
26f




27f






 


3c
biphenyl-3- yl-methan- amine
26g




27g






 


3d
biphenyl-3- yl-methan- amine
26h




27h






 


3a
Inter- mediate 7c
26ha




27ha






 


3d
Inter- mediate 7c
26hb




27hb






 


3a
Inter- mediate 7p
26hc




27hc






 


3a
Inter- mediate 7q
26hd




27hd






 


3a
Inter- mediate 7t
26he




27he






 


3a
Inter- mediate 7v
26hf




27hf






 


3b
Inter- mediate 7t
26hr




27hr






 


3b
Inter- mediate 7v
26hs




27hs













Intermediate 26i





Intermediate 3d (2 g, 7.53 mmol) and N,N-diisopropylethylamine (1.97 ml, 11.3 mmol) were dissolved in 15 ml of dry DMF; 4-tertbutyl-benzylamine (1.6 ml, 9.04 mmol) was added and the reaction mixture was stirred at 60° C. for 18 h. The reaction mixture was cooled to room temperature, water was added and the reaction mixture was extracted with dichloromethane; the organic phase was concentrated under vacuum and the crude product was purified by flash chromatography (BIOTAGE SP1; silica gel cartridge: 65 i; eluent: hexane/ethyl acetate=70/30%). 1.5 g (3.82 mmol) of the desired compound were obtained.
Intermediate 26ib




Intermediate 26hb (75 mg, 179 mol), tributyl(vinyl)tin (200 μl, 685 mol) and bis(triphenylphosphine)palladium chloride (13 mg, 18 mol) were added to 3 ml 1,2-dichloroethane. The reaction mixture was heated in the microwave for 4 h at 120° C. Then, the solvent was removed in vacuum and the residue was purified by reversed phase HPLC to give the desired product (56 mg, 117 mmol).
Intermediate 26ic




was synthesized in analogy to intermediate 26ib, starting from intermediate 26hb and tributyl(ethynyl)tin.

Intermediate 27i





Intermediate 26i (500 mg, 1.27 mmol) and CuCN (114 mg, 1.27 mmol) were dissolved in 5 ml of DMA and the reaction mixture was stirred at 100° C. overnight. The reaction mixture was cooled, diluted with dichloromethane and the organic phase was washed with water, dried over sodium sulfate and concentrated under vacuum. 30 mg (0.1 mmol) of the crude product were obtained and used in the next step without purification.
Intermediate 27ib




was synthesized in analogy to 27a starting from intermediate 26ib.

Intermediate 27ic





was synthesized in analogy to 27a starting from intermediate 26ic.

Intermediate 28a





Intermediate 27a (4 g, 12.14 mmol), TBTU (3.9 g, 12.14 mmol) and N,N-diisopropylethylamine (5.34 ml, 30.35 mmol) were dissolved in 25 ml of DMF. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 30 min; then piperidin-4-one hydrochloride (1.66 g, 12.14 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with a saturated aqueous solution of sodium bicarbonate, with a 1M aqueous solution of sodium hydroxide, with brine, then dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (BIOTAGE SP1; silica gel cartridge: 65 i; eluent: dichloromethane/methanol=95/5%). 2.2 g (5.4 mmol) of the desired compound were obtained.
The following intermediates were synthesized in analogy to intermediate 28a.













Acid 





Intermediate
Amine
Intermediate
STRUCTURE







27b
Piperidin-4-one
28b






 


27c
Piperidin-4-one
28c






 


27d
Piperidin-4-one
28d






 


27g
Piperidin-4-one
28e






 


27c
Azepan-4-one
28f






 


27e
Piperidin-4-one
28g













Intermediate 29





Intermediate 28a (500 mg, 1.22 mmol), piperazine-1-carboxylic acid tert-butyl ester (228 mg, 1.23 mmol) and 2-picoline borane complex (131.3 mg, 1.22 mmol) in 15 ml of methanol were stirred at room temperature for 72 h; the reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with water, dried over sodium sulfate, filtered and concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartridge: 20 g; eluent: dichloromethane/methanol=98/2%). 280 mg (0.48 mmol) of the desired compound were obtained.
Intermediate 30




Intermediate 29 (280 mg, 0.48 mmol) was dissolved in 6 ml of 1,4-dioxane; 4 ml (16 mmol) of a 4M solution of hydrochloric acid in 1,4-dioxane were added dropwise and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under vacuum. 240 mg (0.46 mmol) of the desired compound were obtained.
Intermediate 31




Intermediate 27c (500 mg, 1.67 mmol), TBTU (643 mg, 2 mmol) and N,N-diisopropylethylamine (0.29 ml, 1.67 mmol) were dissolved in 5 ml of DMF. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 10 min; then[1,4]diazepan-1-carboxylic acid tert-butyl ester (334 mg, 1.67 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated solution of sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was suspended in diisopropyl ether and stirred, the solid obtained was filtered and dried. 700 mg (1.45 mmol) of the desired compound were obtained.
Intermediate 32




Intermediate 31 (600 mg; 1.24 mmol) was suspended in 5 ml of diethyl ether, 5 ml of a 1M solution of hydrochloric acid in diethyl ether was added dropwise and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under vacuum and the crude product was loaded on a SCX cartridge (10 g) and eluted with a 2M solution of ammonia in methanol. 470 mg (1.23 mmol) of the title compound were obtained.
Intermediate 33




Intermediate 3a (1.5 g, 7.47 mmol) and tetrakis(triphenylphosphine)palladium (143.9 mg, 0.12 mmol) were suspended in 40 ml of toluene under nitrogen atmosphere; 4-tert-butyl-benzylzinc bromide (29.9 ml, 15 mmol) was added dropwise and then the reaction mixture was stirred at 20° C. for 8 h. 5 ml of methanol, 40 ml of water and 100 ml of dichloromethane were added. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by flash chromatography (Biotage column 40M+; eluent: dichloromethane/ethyl acetate=95/5%). 230 mg (0.74 mmol) of the desired compound were obtained.
Intermediate 34




To a solution of 4-tert-butylphenylacetylene (5 ml, 28 mmol) in 20 ml of dry tetrahydrofuran under nitrogen atmosphere, a solution of catecholborane (3.41 ml, 31 mmol) in 20 ml of dry tetrahydrofuran was added dropwise. The reaction mixture was refluxed for 2 h and then concentrated under vacuum; the crude product obtained was dissolved in ethyl acetate and the organic phase was washed with a 2 M aqueous solution of hydrochloric acid. The organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by flash chromatography (Biotage column 40M+; eluent: dichloromethane/ethyl acetate=95/5%). 230 mg (0.82 mmol) of the desired compound were obtained.
Intermediate 35




Intermediate 3a (600 mg, 3 mmol), intermediate 34 and tetrakis(triphenylphosphine)palladium (347 mg, 0.3 mmol) were dissolved in 3.6 ml of a 2 M aqueous solution of sodium carbonate and 40 ml of 1,2 dimethoxyethane. The reaction mixture was stirred at 80° C. overnight. Water was added and the reaction mixture was extracted with dichloromethane. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product obtained was purified by flash chromatography (Biotage column 40M+; eluent: dichloromethane/ethyl acetate=95/5%). 550 mg (1.60 mmol) of the desired compound were obtained.
Intermediate 36




Intermediate 35 (250 mg, 0.77 mmol) was dissolved in 5 ml of ethanol and 5 ml of tetrahydrofuran. Pd/C (35 mg) was added and the reaction mixture was stirred under hydrogen atmosphere (1 atm) at room temperature overnight. The reaction mixture was filtered on a celite pad and concentrated under vacuum. 170 mg (0.52 mmol) of the desired compound were obtained.
Intermediate 37




Palladium acetate (170 mg, 0.75 mmol) and 2,2′-bis(diphenylphosphino)-1,1′-binaphtyl (936 mg, 1.5 mmol) were dissolved in 25 ml of 1,4-dioxane and stirred at 40° C. for 30 minutes. 2-chloro-3-methylpyridine-4-carboxylic acid ethyl ester (500 mg, 2.5 mmol), 3,4-dichlorobenzylamine (680 mg, 5 mmol) and cesium carbonate (715.5 mg, 3.76 mmol) were added and the reaction mixture was refluxed for 48 h. The solvent was concentrated under vacuum and the crude product was loaded on a SCX cartridge (100 g) and eluted with a 2M solution of ammonia in methanol. The solvent was concentrated under vacuum and the crude product obtained was purified by flash chromatography (Biotage column 25M+; eluent: ethyl acetate). 250 mg (0.73 mmol) of the desired compound were obtained.
Intermediate 38




3-(Bromomethyl)biphenyl (150 mg, 0.58 mmol), sodium carbonate (188 mg, 1.75 mmol) and 3-amino-2-methyl-benzoic acid ethyl ester (0.1 ml, 0.58 mmol) were mixed in 2 ml of DMF and stirred at 100° C. for 2 hours. The solvent was then concentrated under vacuum and the crude product was purified by reverse phase preparative HPLC. 131 mg (0.37 mmol) of the desired compound were obtained.
Intermediate 39a




Intermediate 35 (300 mg, 0.92 mmol) was dissolved in 4 ml of ethanol and 4 ml of water. Lithium hydroxide (194 mg, 4.7 mmol) was added and the reaction mixture was stirred at 70° C. for 2 h, concentrated under vacuum and the remaining aqueous solution was acidified by 10 ml of a 4M solution of hydrochloric acid in 1,4-dioxane and extracted with dichloromethane; the organic phase was separated, washed with brine, dried over sodium sulfate and concentrated under vacuum. 250 mg (0.84 mmol) of the desired product were obtained.

The following intermediates were synthesized in analogy to intermediate 39a












Ester 
Acid 



Intermediate
Intermediate
STRUCTURE







33
39b






 


36
39c






 


37
39d






 


38
39e













Intermediate 40a





Intermediate 27c (660 mg, 2.20 mmol), TBTU (849 mg, 2.65 mmol) and N,N-diisopropylethylamine (0.57 ml, 3.31 mmol) were dissolved in 25 ml DMF. The reaction mixture was stirred under nitrogen atmosphere at room temperature for 10 min; then piperidin 4-yl carbamic acid tert-butyl ester (441 mg, 2.20 mmol) was added and the reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with dichloromethane and washed with an aqueous saturated solution of sodium bicarbonate. The organic phase was separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Biotage SNAP column 50 g; eluent: dichloromethane/methanol=90/10%). 990 mg (2.05 mmol) of the desired compound were obtained.
Intermediate 41a




Intermediate 40a (990 mg, 2.05 mmol) was suspended in 50 ml of 1,4-dioxane, a 4M solution of hydrochloric acid (8.5 ml, 34 mmol) in 1,4-dioxane was added dropwise. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum. 780 mg (18 mmol) of the desired compound were obtained.
The following intermediates were synthesized in analogy to Intermediates 40a and 41a.















Starting 
Starting 
Carbamate 

Amine



acid
amine
Intermediate
STRUCTURE
intermediate
STRUCTURE







Inter- mediate  27ha
piperidin 4-yl  carbamic acid  tert-butyl  ester
40b




41b













Intermediate 42





4,4-Difluorocyclohexanone (500 mg, 3.73 mmol) and potassium hydroxide (502 mg, 8.95 mmol) were dissolved in 10 ml of methanol. The reaction mixture was cooled to 0° C. and a solution of iodine (1.04 g, 4.10 mmol) in 20 ml of methanol was added dropwise within 1 h. The reaction mixture was stirred at room temperature for 18 h, and then concentrated under vacuum. The crude product was stirred in 10 ml of dichlorometane and the precipitate was filtered off. The filtrate was concentrated under vacuum and 480 mg of the desired product (2.45 mmol) were obtained as an oil.
Intermediate 43




Sodium hydride (196 mg, 4.89 mmol) was suspended in 10 ml of tetrahydrofurane. The reaction mixture was cooled to 0° C. and a solution of Intermediate 42 (480 mg, 4.45 mmol) in 5 ml of tetrahydrofurane was added dropwise. The reaction mixture was stirred at 0° C. for 1 h, then iodomethane (0.305 ml, 4.89 mmol) was added. The reaction mixture was stirred at room temperature for 4 h. 0.1 ml of a 37% aqueous solution of hydrochloric acid and 0.1 ml of water were added, then additional 0.3 ml of a 37% aqueous solution of hydrochloric acid were added. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under vacuum and 400 mg (2.44 mmol) of the desired product were obtained as an oil.
Intermediate 44




Iodomethane (3.48 ml, 55.88 mmol) was dissolved in 250 ml of tetrahydrofurane, the reaction mixture was stirred at 0° C. under nitrogen atmosphere and sodium hydride (60% on mineral oil, 2.23 mg, 5.88 mmol) was added. After 15 minutes, trans 4-azido-tetrahydropyran-3-ol (4.0 g, 27.94 mmol) was added and the reaction mixture was allowed to reach room temperature and stirred for 18 h. 50 ml of water were added, the organic phase was separated, dried over sodium sulphate and concentrated under vacuum. The crude oil obtained was purified by flash chromatography (Biotage SNAP column 100 g; eluent: dichloromethane/ethyl acetate=80/20%). 200 mg (1.27 mmol) of the desired regioisomer were obtained as trans racemate (relative configuration assigned by NMR).
Intermediate 45




Intermediate 44 (200 mg, 1.27 mmol) was dissolved in 250 ml of methanol, Pd/C (50 mg) was added and the reaction mixture was stirred under hydrogen atmosphere (4 bar) for 18 h. The reaction mixture was filtered on a celite pad and the organic phase was concentrated under vacuum. 110 mg (0.84 mmol) of the desired product were obtained as trans racemate.
Intermediate 46a




3-Methoxy-tetrahydro-pyran-4-one (500 mg, 3.84 mmol), benzylamine (0.42 ml, 3.84 mmol) and Raney-Nickel (100 mg) were suspended in 20 ml of dry ethanol and the reaction mixture was stirred under hydrogen atmosphere (4.5 bar) for 3 days. The reaction mixture was filtered on a celite pad and the organic phase was concentrated under vacuum. The crude product obtained was dissolved in 10 ml of methanol, loaded on a SCX cartridge (10 g) and eluted with a 2M solution of ammonia in methanol. The solvent was concentrated under vacuum and the crude product obtained was purified by flash chromatography (Isolute cartridge 10 g; eluent: dichloromethane/methanol=96/4%). 163 mg (0.73 mmol) of the desired product were obtained as cis racemate (relative configuration assigned by NMR).
Intermediate 46b




3-Methoxy-tetrahydro-pyran-4-one (1 g, 7.68 mmol), (R)-(+)-1-phenylethylamine (0.99 ml, 7.68 mmol) and Raney-Nickel (200 mg) in 10 ml dry ethanol were stirred under a hydrogen atmosphere (5 bar) for 15 days. The reaction mixture was diluted with 20 ml of methanol and 20 ml of tetrahydrofurane, stirred for 15 minutes, filtered on a celite pad and concentrated under vacuum. The crude product was loaded on a SCX cartridge (50 g). The cartridge was washed with methanol and the desired product was eluted with a 7 M solution of ammonia in methanol. The basic organic phase was concentrated under vacuum and the crude product obtained was purified by flash chromatography (dichloromethane/methanol=98/2%) to obtain 710 mg (3.02 mmol) of the desired product as single stereoisomer (diastereoisomeric purity confirmed and relative cis stereochemistry assigned by NMR).
Intermediate 46c




was synthesised in analogy to Intermediate 46b, starting from 3-Methoxy-tetrahydro-pyran-4-one and (S)-(−)-1-phenylethylamine (diastereoisomeric purity confirmed and relative cis stereochemistry assigned by NMR).

Intermediate 47a





Intermediate 46a (163 mg, 0.73 mmol) was dissolved in 10 ml of methanol, Pd/C (50 mg) was added and the reaction mixture was stirred under hydrogen atmosphere (4.5 bar) for 18 h. The reaction mixture was filtered on a celite pad and the organic phase was concentrated under vacuum. 80 mg (0.61 mmol) of the desired product were obtained as cis racemate.
Intermediate 47b




Intermediate 46b (1.18 g, 5.01 mmol), Pd/C 10% (200 mg) and acetic acid (0.3 ml, 5.01 mmol) in 20 ml of methanol were stirred under a hydrogen atmosphere (5 bar) for 18 h. The reaction mixture was diluted with 20 ml of methanol, stirred for 15 minutes, filtered on a celite pad and concentrated under vacuum. The crude product was loaded on a SCX cartridge (50 g). The cartridge was washed with methanol and the desired product was eluted with a 7M solution of ammonia in methanol. The basic organic phase was concentrated under vacuum and 513 mg (3.91 mmol) of the desired product were obtained as single stereoisomer.
Intermediate 47c




was synthesised in analogy to Intermediate 47b, starting from Intermediate 46c

Intermediate 48b





Intermediate 47b was stirred in diethyl ether and a 2M solution of hydrochloric acid in diethyl ether was added drop-wise until a white solid was formed. The reaction mixture was concentrated under vacuum, the crude product was suspended in methanol and the reaction mixture was concentrated under vacuum to give the desired hydrochloride.
Intermediate 48c




was synthesised in analogy to Intermediate 48b, starting from Intermediate 47c.

Intermediate 49a





3-(trifluoromethyl)benzaldheyde (6.46 ml, 48.24 mmol) was dissolved in 80 ml of dry tetrahydrofurane, the reaction mixture was cooled to −78° C. and a 0.5M solution of 3-butenylmagnesiumbromide in tetrahydrofurane (106.13 ml, 53.06 mmol) was added dropwise over 30 minutes. The reaction mixture was stirred at −78° C. for 30 minutes. Then, the reaction mixture was allowed to reach room temperature and stirred 18 h. Then, 100 ml of a saturated aqueous solution of ammonium chloride and 200 ml of ethyl acetate were added. the organic layer was separated, dried over sodium sulfate and concentrated under vacuum. 7.75 g (33.69 mmol) of the desired product were obtained.
Intermediate 50a




Intermediate 49a was dissolved in 70 ml of dry dichloromethane, the reaction mixture was stirred under nitrogen atmosphere at 0° C. and N-bromosuccinimmide was added. The reaction mixture was allowed to reach room temperature and stirred for 48 h. The reaction mixture was concentrated under vacuum. The crude product was purified by flash chromatography (Isolera cartridge eluent: hexane/ethyl acetate=90/10%) to obtain the desired product as diastereoisomeric mixture.
Intermediate 51a




Intermediate 50a was purified by flash chromatography (Isolera cartridge; eluent: hexane/ethyl acetate=98/2%). 2.3 g (7.44 mmol) of the trans diastereoisomer were obtained as racemic mixture (relative stereochemistry assigned by NMR).
Intermediate 52a




Further elution of the column gave 1.05 g (3.39 mmol) of the cis diastereoisomer as racemic mixture (relative stereochemistry assigned by NMR).
The following intermediates were synthesized in analogy to Intermediates 49a, 50a, 51a and 52a












Starting 




aldehyde
Intermediate
STRUCTURE







3-Methyl- benzaldheyde
49b






 



50b






 



51b






 



52b






 


4-Methyl- benzaldheyde
49c






 



50c






 



51c






 



52c






 


4-Fluoro-3- methyl- benzaldheyde
49d






 



50d






 



51d






 



52d






 


3-Fluoro- 4-methyl- benzaldheyde
49e






 



50e






 



51e






 



52e






 


4-Chloro- benzaldheyde
49f






 



50f






 



51f






 



52f






 


4- Trifluoro- methyl- benzaldheyde
49g






 



50g






 



51g






 



52g













Intermediate 53a





Intermediate 50a (1.7 g, 5.49 mmol) was dissolved in 5 ml of DMSO and the reaction mixture was stirred under nitrogen atmosphere at room temperature. Phtalimide potassium salt (2.54 g, 13.75 mmol) and sodium iodide (240 mg, 1.60 mmol) were added and the reaction mixture was stirred at 70° C. for 18 h. The reaction mixture was cooled to room temperature and diluted with 40 ml of a saturated aqueous sodium bicarbonate solution and with 100 ml of ethyl acetate. The organic layer was separated, dried on sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Isolera cartridge; eluent: hexane/ethyl acetate=85/15%) to yield 1.2 g (3.2 mmol) of the phtalimido intermediate. The phtalimido intermediate (1.2 g, 3.2 mmol) was dissolved in 15 ml of methanol. Hydrazine hydrate (1.24 ml, 25.60 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was concentrated under vacuum. The crude product was dissolved in 10 ml of dichlorometane, the organic layer was washed with water, separated, dried on sodium sulfate and concentrate under vacuum. 474 mg (1.93 mmol) of the desired product were obtained.
Intermediate 54a




was synthesized in analogy to Intermediate 53a starting from intermediate 51a

Intermediate 55a





was synthesized in analogy to Intermediates 53a starting from intermediate 52a.

The following intermediates were synthesized in analogy to Intermediates 53a, 54a and 55a.












Starting 




Intermediate
Intermediate
STRUCTURE







50b
53b






 


50c
53c






 


50d
53d






 


50e
53e






 


50f
53f






 


50g
53g






 


2-bromo- methyl- 4-phenyl- tetrahydro- furan
53h






 


51b
54b






 


51c
54c






 


51d
54d






 


51e
54e






 


51f
54f






 


51g
54g






 


52e
55e






 


52b
55b






 


52c
55c






 


52d
55d






 


52f
55f






 


52g
55g













Intermediate 56





2,3-Dihydro-pyrano[3,2-b]pyridine-4one (250 mg, 1.7 mmol) and Raney-Nickel (25 mg) were added to a solution of ammonia in ethanol (10 ml) and the reaction mixture was stirred under hydrogen atmosphere (3 bar) for 18 h at room temperature. Then, the catalyst was removed by filtration on a celite pad and the mixture was concentrated under vacuum. The residue was purified by reversed phase HPLC to give the desired product (129 mg, 600 μmol).
Synthesis of Examples
E and G within the scope of this invention denotes C or N, preferred nitrogen.
The examples of this invention are synthesized according to the following general synthetic procedures:
Synthetic Procedure A:




Examples: 1-159gc; 289-302
Synthetic Procedure B:




Examples: 160-247; 228a; 228ga-228gn; 229-247




Examples: 286-288




Examples: 228b-228g; 228go; 228gp
Synthetic Procedure C:




Examples: 248-283; 275a-275dj
Example 1




Intermediate 25b (70 mg, 0.16 mmol), 4-tert-butyl-benzylamine (32 mg, 0.19 mmol) and N,N-diisopropyl-ethyl amine (0.042 ml, 0.24 mmol) in 2 ml of dry 1,4-dioxane were stirred at 70° C. overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Silica Isolute cartridge 5 g; eluent: ethyl acetate/methanol=90/10%). 16 mg (0.027 mmol) of the desired product were obtained.
HPLC (Method 2F): Rt. (min)=7.59
[M+H]+=557
The following examples were synthesized in analogy to the preparation of Example 1.





















HPLC 



Ex 




Rt. 



#
STRUCTURE
Intermediate
Amine
[M + H]+
(min)
Method







2




25i
2-(3,4- dichloro- phenyl)- ethyl- amine
476
7.98
1E


 


3




25f
2-(3,4- dichloro- phenyl)- ethyl- amine
492
2.91
B


 


4




25f
3- trifluoro methyl- benzyl- amine
478
6.77
1E


 


5




25f
4- trifluoro- methoxy- benzyl- amine
494
6.78
1E


 


6




25f
3-fluoro- 5- trifluoro methyl- benzyl- amine
496
6.73
1E


 


7




25f
4-tert- butyl- benzyl- amine
466
7.45
1E


 


8




25f
3- trifluoro methoxy- benzyl- amine
494
7.08
1E


 


9




25f
4- trifluoro methyl- benzyl- amine
478
6.63
1E


 


10




25f
3-fluoro- 4- trifluoro methyl- benzyl- amine
496
6.85
1E


 


11




25f
2-(3- trifluoro methyl- phenyl)- ethyl- amine
492
7.23
1E


 


12




25f
2-(4- trifluoro methyl- phenyl)- ethyl- amine
492
7.37
1E


 


13




25f
(4- (trifluoro- methyl)- cyclo- hexyl)- methan- amine
484
6.82
1E


 


14




25f
2-(4- trifluoro- methoxy- phenyl)- ethyl- amine
508
7.37
1E (Fusion)


 


15




25f
4-phenyl- butyl- amine
452
7.15
1E


 


16




25f
2- phenoxy- ethyl- amine
440
7.10
1E (Fusion)


 


17




25f
3-phenyl- propyl- amine
438
7.83
1E (Fusion)


 


18




25f
2-benzyl- oxy- ethyl- amine
454
5.83
1E (Hydro)


 


19




25f
chroman- 3-yl- methan- amine
466
7.85
1E (Fusion)


 


20




25f
(1- phenyl- pyrrolidin- 3-yl)- methan- amine
479
7.05
1E (Hydro)


 


21




25f
2-fluoro- 4- trifluoro methyl- benzyl- amine
496
8.38
1E (Fusion)


 


22




25f
4-phenyl- cyclo- hexyl- amine
478
9.38
1E (Fusion)


 


23




25f
indan-2- yl- methan- amine
450
6.55
1E (Hydro)


 


24




25f
chroman- 3- ylamine
452
6.18
1E (Hydro)


 


25




25f
(R)- (1,2,3,4- tetra- hydro- naphtalen- 2- yl)amine
450
7.08
1E (Hydro)


 


26




25f
(1,2- dihydro- cyclo- butabenz en-1-yl)- methan- amine
436
6.93
1E (Hydro)


 


27




25f
(2,3- dihydro- benzo- furan- 2-yl)- methan- amine
452
6.47
1E (Hydro)


 


28




25f
Cyclo- hexyl- amine
402
4.90
1E


 


29




25f
benzo- furan-5- ylmethan amine
450
6.73
1E (Hydro)


 


30




25f
3-chloro- 4- methyl- benzyl- amine
458
7.75
1E (Hydro)


 


31




25f
3,4- dimethyl- benzyl- amine
438
7.37
1E (Hydro)


 


32




25c
3-chloro- 4- methyl- benzyl- amine
563
6.98
2F


 


33




25c
3-chloro- 4- trifluoro methyl- benzyl- amine
617
9.47
1E (Hydro)


 


34




25c
4- isopropyl- benzyl- amine
557
7.03
2F


 


35




25c
3,4- dichloro- benzyl- amine
583
8.65
1E (Hydro)


 


36




25c
2-(3,4- dichloro- phenyl)- ethyl- amine
597
9.72
1E (Hydro)


 


37




25c
4-tert- butyl- benzyl- amine
571
9.28
1E (Hydro)


 


38




25c
9a
598
1.45
2F


 


39




25c
4-chloro- 3-fluoro- benzyl- amine
567
8.82
1E (Hydro)


 


40




25c
(1- phenyl- piperidin- 4yl)- methan- amine
598
8.98
1E (Hydro)


 


41




25c
9b
584
8.92
1E (Hydro)


 


42




25h
9a
479
8.67
1E (Hydro)


 


43




25h
3-chloro- 4- methyl- benzyl- amine
444
8.63
1E (Hydro)


 


44




25h
3-fluoro- 4- methyl- benzyl- amine
428
7.58
1E (Hydro)


 


45




25h
4-chloro- 3-fluoro- bemzyl- amine
448
7.88
1E (Hydro)


 


46




25h
indan- 2yl- methan- amine
436
8.27
1E (Hydro)


 


47




25h
3-chloro- 4- trifluoro methyl- benzyl- amine
498
7.30
2F


 


48




25h
3,4- difluoro- benzyl- amine
432
4.20
2G


 


49




25b
4-chloro- benzyl- amine
535
7.38
2F


 


50




25h
chroman- 3- ylmethan amine
452
7.85
1E (Hydro)


 


51




25h
(1- phenyl- pyrrolidin- 3-yl)- methan- amine
465
8.93
1E (Hydro)


 


52




25h
4-tert- butyl- benzyl- amine
452
7.18
2F


 


53




25b
2-(3,4- dichloro- phenyl)- ethyl- amine
583
7.97
1E (Hydro)


 


54




25b
(6-tert- butyl- pyridin- 3-yl)- methan- amine
558
7.73
1E (Hydro)


 


55




25b
4-fluoro- 3- methyl- benzyl- amine
533
8.05
1E (Hydro)


 


56




25b
4-ethyl- benzyl- amine
529
8.35
1E (Hydro)


 


57




25b
chroman- 3- ylmethan amine
557
7.62
1E (Hydro)


 


58




25b
(1- phenyl- piperidin- 4yl)- methan- amine
584
8.05
1E (Hydro)


 


59




25b
3-chloro- 4-methyl- benzyl- amine
549
8.22
1E (Hydro)


 


60




25b
(1- phenyl- pyrrolidin- 3-yl)- methan- amine
570
8.07-8.47
1E (Hydro)


 


61




25b
indan- 2yl- methan- amine
541
8.03
1E (Hydro)


 


62




25b
3-chloro- 4- trifluoro methyl- benzyl- amine
603
8.68
1E (Hydro)


 


63




25b
4-chloro- 3-fluoro- benzyl- amine
553
7.55
1E (Hydro)


 


64




25b
4- isopropyl- benzyl- amine
543
6.82
2F


 


65




25b
3-fluoro- 4- methyl- benzyl- amine
533
8.57
1E (Hydro)


 


66




25b
3-chloro- benzyl- amine
535
6.72
2F


 


67




25b
4- methoxy- benzyl- amine
531
2.39
2F


 


68




25b
3-chloro- 4-fluoro- benzyl- amine
553
7.57
2F


 


69




25a
4-tert- butyl- benzyl- amine
543
7.97
1E (Hydro)


 


70




25a
4- trifluoro methoxy- benzyl- amine
585
7.63
1E (Hydro)


 


71




25a
chroman- 3- ylmethan amine
543
6.75
1E (Hydro)


 


72




25a
3,4- dichloro- benzyl- amine
555
7.30
1E (Hydro)


 


73




25a
indan- 2yl- methan- amine
527
7.35
1E (Hydro)


 


74




25a
(1- phenyl- pyrrolidin- 3-yl)- methan- amine
555
7.43-7.80
1E (Hydro)


 


75




25a
3-chloro- 4- trifluoro methyl- benzyl- amine
589
7.48
2F


 


76




25a
4-chloro- 3-fluoro- benzyl- amine
539
2.07
1F


 


77




25e
3-chloro- 4- trifluoro methyl- benzyl- amine
539
8.23
1E (Hydro)


 


78




25e
4-chloro- 3-fluoro- benzyl- amine
489
7.33
1E (Hydro)


 


79




25l
chroman- 3- ylmethan amine
571
8.13
1E (Hydro)


 


80




25l
4-chloro- 3-fluoro- benzyl- amine
567
8.36
1E (Hydro)


 


81




25l
3-chloro- 4- trifluoro methyl- benzyl- amine
617
9.12
1E (Hydro)


 


82




25l
3,4- dichloro- benzyl- amine
583
8.83
1E (Hydro)


 


83




25l
4-tert- butyl- benzyl- amine
571
9.73
1E (Hydro)


 


84




25l
(1- phenyl- pyrrolidin- 3-yl)- methan- amine
584
8.70-9.02
1E (Hydro)


 


85




25l
9c
584
9.1
1E (Hydro)


 


86




25l
indan- 2yl- methan- amine
555
8.80
1E (Hydro)


 


87




25l
9a
598
8.97
1E (Hydro)


 


88




25k
3,4- dichloro- benzyl- amine
569
7.78
1E (Hydro)


 


89




25k
3-phenyl- cyclo- hexyl- amine
569
8.45
1E (Hydro)


 


90




25k
chroman- 3- ylmethan amine
557
7.20
1E (Hydro)


 


91




25m
2-(3,4- dichloro- phenyl)- ethyl- amine
506
7.87
1E


 


92




25m
3,4- dichloro- benzyl- amine
492
7.62
1E


 


93




25d
(1- phenyl- pyrrolidin- 3-yl)- methan- amine
520
7.70
1E (Hydro)


 


94




25g
4- isopropyl- benzyl- amine
466
6.71
2F


 


95




25g
4-chloro- 3-fluoro- benzyl- amine
476
9.18
1E (Hydro)


 


96




25g
(1- phenyl- piperidin- 4-yl)- methan- amine
507
9.55
1E (Hydro)


 


97




25g
9a
507
1.22
2F


 


98




25g
3-chloro- 4- methyl- benzyl- amine
472
9.62
1E (Hydro)









Example 99




Intermediate 2a (200 mg, 1.047 mmol) was dissolved in 30 ml of dichlorometane. [1,4′]Bipiperidinyl-4-ol (192 mg, 1.047 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under vacuum and the crude product was dissolved in 1 ml of DMSO. Phenethylamine (0.6 ml, 4.73 mmol) and N,N-diisopropyl-ethyl amine (0.013 ml, 0.075 mmol) were added and the reaction mixture was stirred at 80° C. overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 331 mg (0.616 mmol) of the desired product were obtained.
HPLC (Method C): Rt. (min)=1.34
[M+H]+=424
The following examples were synthesized in analogy to the preparation of Example 99.























HPLC



Ex

Inter-


[M + 
Rt•
Meth-


#
STRUCTURE
mediate
Intermediate
Amine
H]+
(min)
od







100




2a
[1,4′]- Bipiperidin- yl-3-ol
Biphenyl- 3-yl- methan- amine
486
1.53
2C


 


101




2a
[1,4′] Bipiperidin- yl-4-ol
Biphenyl- 4-yl- methan- amine
486
1.51
2C


 


102




2a
[1,4′] Bipiperidin- yl-4-ol
Biphenyl- 3-yl- methan- amine
486
1.52
2C


 


103




6-chloro- pyrimidine- 4-carbonyl  chloride
[1,4′]- Bipiperidin- yl-3-ol
Biphenyl- 4-yl- methan- amine
472
1.59
2C









Example 104




Intermediate 25i (17 mg, 0.05 mmol), 3-fluoro-4-methyl-benzylamine (10 mg, 0.075 mmol) and diisopropyl-ethyl amine (0.013 ml, 0.075 mmol) in 1 ml of dry DMSO were stirred at 80° C. overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 20 mg (0.047 mmol) of the desired product were obtained.
HPLC (Method C): Rt. (min)=1.45
[M+H]+=426
The following examples were synthesized in analogy to the preparation of Example 104.


















Inter-


HPLC



Ex

me-


Rt•
Meth-


#
STRUCTURE
diate
Amine
[M + H]+
(min)
od







105




25f
2-(3-chloro-4- methoxy- phenyl)-ethyl- amine
488
 1.43
2C


 


106




25f
2-(4- isopropyl- phenyl)- ethylamine
466
 2.88
2B


 


107




25h
3,4-dichloro- benzyl-amine
464
5.6
1A


 


108




25f
Cyclohexyl- methan-amine
416
 2.67
2B


 


109




25f
3,4-dichloro- benzyl-amine
478
 2.81
2B


 


110




25f
4-chloro- benzyl-amine
444
1.6
2A


 


111




25f
3-chloro-4- fluoro-benzyl- amine
462
 1.63
2A


 


112




25f
2-(4-tert-butyl- phenyl)- ethylamine
480
1.8
2A


 


113




25f
(1-phenyl- piperidin-4- yl)methan- amine
493
 1.32
2A


 


114




25f
7a
492
 7.42
2F


 


115




25f
2-(3,4- difluoro- phenyl)- ethylamine
460
 1.61
2A


 


116




25f
3-chloro-4- trifluoro- methyl- benzyl-amine
512
 1.74
2A


 


117




25f
4-chloro-3- fluoro-benzyl- amine
462
 1.64
2A


 


118




25f
4-fluoro-3- methyl- benzyl-amine
442
 1.61
2A


 


119




25f
2-(3-chloro-4- methoxy- phenyl)-ethyl- amine
488
 1.63
2A


 


120




25f
3-fluoro-4- methyl- benzyl-amine
442
 1.61
2A


 


121




25f
(4- phenylcyclo- hexyl)- methan-amine
492
 1.78
2A


 


122




25f
2-(3-chloro- phenyl)- ethylamine
458
 1.63
2A


 


123




25f
3-chloro- benzyl-amine
444
1.6
2A


 


124




25f
2-(4-chloro- phenyl)- ethylamine
458
 1.65
2A


 


125




25f
4-chloro-3- trifluoro- methyl- benzyl-amine
512
 1.74
2A


 


126




25f
2-(3,4- dimethyl- phenyl)- ethylamine
452
 1.68
2A


 


127




25i
4-chloro- benzyl-amine
428
 1.65
2A


 


128




25i
3-chloro-4- fluoro-benzyl- amine
446
 1.67
2A


 


129




25i
2-(4-tert-butyl- phenyl)- ethylamine
464
 1.84
2A


 


130




25i
(1-phenyl- piperidin-4- yl)-methan- amine
477
 1.37
2A


 


131




25i
7a
476
 1.84
2A


 


132




25i
2-(3,4- difluoro- phenyl)- ethylamine
444
 1.66
2A


 


133




25i
3-chloro-4- trifluoro- methyl- benzyl-amine
496
 1.79
2A


 


134




25i
4-chloro-3- fluoro-benzyl- amine
446
 1.67
2A


 


135




25i
4-fluoro-3- methyl- benzyl-amine
426
 1.65
2A


 


136




25i
2-(3-chloro-4- methoxy- phenyl)- ethylamine
472
 1.66
2A


 


137




25i
3-fluoro-4- methyl- benzyl-amine
426
 1.65
2A


 


138




25i
(4- phenylcyclo- hexyl)- methan-amine
476
 1.84
2A


 


139




25i
2-(3-chloro- phenyl)- ethylamine
442
 1.68
2A


 


140




25i
3-chloro- benzyl-amine
428
 1.64
2A


 


141




25i
2-(4-chloro- phenyl)- ethylamine
442
 1.69
2A


 


142




25i
4-chloro-3- trifluoro- methyl- benzyl-amine
496
 1.79
2A


 


143




25i
2-(3,4- dimethyl- phenyl)- ethylamine
436
 1.72
2A


 


144




25f
7a
492
7.7
2H (iso- cratic)


 


145




25f
7a
492
10.2 
2H (iso- cratic)









Example 146




Intermediate 25b (80 mg, 0.18 mmol), Intermediate 7c (40 mg, 0.21 mmol) and N,N-diisopropyl-ethyl amine (0.046 ml, 0.26 mmol) in 0.2 ml of dry 1,4-dioxane were mixed in a microwave vial and reacted in the following conditions: Power 100, Ramp 5 min, Hold 2 h, Temperature 150° C., Pression 150° C., Stirring. The reaction mixture was concentrated under vacuum and diluted with dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 36 mg (0.06 mmol) of the desired product were obtained.
HPLC (Method 1E Hydro): Rt. (min)=9.52
[M+H]+=583
The following examples were synthesized in analogy to the preparation of Example 146


















Inter-


HPLC



Ex

me-


Rt•



#
STRUCTURE
diate
Amine
[M + H]+
(min)
Method







147




25c
(trans-2- phenyl- cyclo- propyl) methan- amine
555
 8.48
1E (Hydro)


 


148




25b
(1,2,3,4- tetrahydro- naphthalen- 1-yl)- methan- amine
555
 8.62
1E (Hydro)


 


149




25b
9c
570
8.7
1E (Hydro)


 


150




25b
7d
583
 9.12
1E (Hydro)


 


151




25b
7e
583
 9.22
1E (Hydro)


 


152




25b
(trans-2- phenyl- cyclo- propyl)- methan- amine
541
 8.03
1E (Hydro)


 


153




25b
2-(4-tert- butyl- phenyl)- ethyl-amine
571
 9.42
1E (Hydro)


 


154




25b
11
643
 8.65
1E (Hydro)


 


155




25b
9a
584
 8.52
1E (Hydro)


 


156




25b
9b
570
 8.48
1E (Hydro)


 


157




25b
Quinolin-3- ylmethan- amine
552
 1.28
2F


 


158




25b
7b
583
 9.48
1E (Hydro)


 


159




25l
9b
584
 8.85
1E (Hydro)


 


159a




25n
7a
613
 2.21
2Ca


 


159b




52n
4-tert-butyl- benzyl- amine
587
 1.89
2Ca


 


159c




25b
7m
603
 9.88
1E (Hydro)


 


159d




25b
7l
569
 9.62
1E (Hydro)


 


159e




25b
C- Cyclohexyl- methyl- amine
507
 8.37
1E (Hydro)


 


159f




25b
C-(4- isopropyl- cyclo- hexyl)- methyl- amine
549
10.12
1E (Hydro)


 


159g




25b
C-(3- methyl- cyclo- hexyl)- methyl- amine
521
 9.25
1E (Hydro)


 


159h




25b
C-(3,3- dimethyl- cyclo- hexyl)- methyl- amine
535
 9.68
1E (Hydro)


 


159i




25d
7a
533
 9.53
1E (Hydro)


 


159k




25b
C-(4-ethyl- cyclo- hexyl)- methyl- amine
535
 9.98
1E (Hydro)


 


159l




25b
C-(4- methyl- cyclo- hexyl)- methyl- amine
521
 9.28
1E (Hydro)


 


159m




25a
7a
569
 9.33
1E (Hydro)


 


159n




25b
C-(3- pyridin-2yl- cyclo- hexyl)- methyl- amine
584
 7.90  8.05
1E (Hydro)


 


159o




25b
C-(4-tert- butyl-cyclo- hexyl)- methyl- amine
563
10.87
1E (Hydro)


 


159p




25d
7c
533
 9.53
1E (Hydro)


 


159q




25b
7b
587
 9.37
1E (Hydro)


 


158r




25b
C-[4-(1H- Benzo- imidazol-2- yl)-cyclo- hexyl]- methyl- amine
623
 7.17
1E (Hydro)


 


159s




25b
C-[(4- phenyl- morpholin- 2-yl)- methyl- amine
586
 7.73
1E (Hydro)


 


159t




25b
C-(1-pheny- cyclo- hexyl)- methyl- amine
583
9.5
1E (Hydro)


 


159u




25b
C-(5-pheny- furan-2yl)- methyl- amine
567
 8.93
1E (Hydro)


 


159w




25b
9d
652
 9.57
1E (Hydro)


 


159y




25b
2-(1-methyl- 1H-indol- 3yl)-ethyl- amine
568
8.2
1E (Hydro)


 


159x




25b
C-Indan-1- yl-methyl- amine
541
 8.27
1E (Hydro)


 


159z




25b
7g
601
9.8
1E (Hydro)


 


159aa




25d
7g
551
 9.47
1E (Hydro)


 


159ba




25a
7g
587
 9.32 
1E (Hydro)


 


159ca




25a
7f
603
 9.95
1E (Hydro)


 


159da




25b
7f
617
10.5 
1E (Hydro)


 


159ea




25d
7f
567
7.4
2F


 


159fa




25b
C-cyclo- heptyl- methyl- amine
521
 8.88
1E (Hydro)


 


159ga




25l
54a
653
 5.38
2M


 


159ha




25b
54a
639
 5.94
2M


 


159ia




25b
54b
585
 5.42
2M


 


159ja




25l
54b
599
 4.76
2M


 


159ka




25l
55g
653
 9.37
1E (Hydro)


 


159la




25b
55g
639
 9.02
1E (Hydro)


 


159ma




25b
54g
639
 9.07
1E (Hydro)


 


159na




25b
53e
603
8.6
1E (Hydro)


 


159oa




25l
53c
599
 9.01
1E (Hydro)


 


159pa




25b
53a
639
 8.38
1E (Hydro)


 


159qa




25l
53a
653
 8.85
1E (Hydro)


 


159ra




25b
53b
585
 7.86
1E (Hydro)


 


159sa




25l
53b
599
 8.36
1E (Hydro)


 


159ta




25l
53e
617
 9.03
1E (Hydro)


 


159ua




25l
54f
619
 8.63
1E (Hydro)


 


159wa




25b
54f
605
 8.10
1E (Hydro)


 


159ya




25l
54d
617
 5.08
2M


 


159xa




25b
7h
613
 9.95
1E (Hydro)


 


159za




25b
7i
597
10.52
1E (Hydro)


 


159ab




25b
53f
605
9.0
1E (Hydro)


 


159bb




25b
C-(3- methyl- cyclo- pentyl)- methyl- amine
507
 8.53
1E (Hydro)


 


159cb




25b
53c
585
 8.77
1E (Hydro)


 


159db




25b
7j
601
10  
1E (Hydro)


 


159eb




25b
53h
571
 7.93
1E (Hydro)


 


159fb




25b
C-(5- phenyl- tetrahydro- furan-3yl)- methyl- amine
571
 7.83
1E (Hydro)


 


159gb




25b
54c
585
 8.36
1E (Hydro)


 


159hb




25b
53g
639
 8.94
1E (Hydro)


 


159ib




25l
53g
653
 9.27
1E (Hydro)


 


159jb




25b
55c
585
 8.38
1E (Hydro)


 


159kb




25g
7g
524
 2.87
1Fa


 


159lb




25g
7f
540
 3.02
1Fa


 


159mb




25b
7r
567
 8.85
1E (Hydro)


 


159nb




25b
C- Bicyclo [4.2.0]octa- 1(6),2,4- trien-7-yl- methyl- amine
527
 7.53
1E (Hydro)


 


159ob




25b
C-Chroman- 2yl-methyl- amine
557
7.9
1E (Hydro)


 


159pb




25b
C-(1,2,3,4- Tetra-hydro- naphthalen- 2-yl-)- methyl- amine
555
 8.47
1E (Hydro)


 


159qb




25b
C-(2,3- Dihydro- benzo-furan- 2yl)-methyl- amine
543
7.4
1E (Hydro)


 


159rb




25b
C-(5- Chloro-2,3- Dihydro- benzo-furan- 2yl)-methyl- amine
557
6.5
2F


 


159sb




25b
C-(6- Chloro- croman-3- yl)-methyl- amine
591
 8.09
1E (Hydro)


 


159tb




25b
7s
589
9.8
1E (Hydro)


 


159ub




25b
7t
555
 9.07
1E (Hydro)


 


159wb




25b
7u
589
9.7
1E (Hydro)


 


159yb




25b
7v
555
 9.02
1E (Hydro)


 


159xb




25b
7o
587
 9.55
1E (Hydro)


 


159zb




25b
7k
549
10.37
1E (Hydro)


 


159ac




25b
C-(tetra- hydro- pyran-4-yl)- methyl- amine
509
 5.92
1E (Hydro)


 


159bc




25b
C-(tetra- hydro- pyran-3-yl)- methyl- amine
509
 6.15
1E (Hydro)


 


159cc




25l
7o
601
 5.40
2M


 


159dc




25o
C- cyclohexyl- methyl- amine
446
 1.23
2Gb


 


159ec




25o
Indan-2-yl- amine
466
 1.24
2Gb


 


159fc




25o
C-Indan-2- yl-methyl- amine
480
 2.97
2Ga


 


159gc




25b
C-(1,2,3,4- Tetra-hydro- quinolin-2- yl)-methyl- amine
556
 1.35
2Ca









Example 160




Intermediate 28b (80 mg, 0.20 mmol), Intermediate 13 (74 mg, 0.30 mmol) and N,N-diisopropyl-ethylamine (0.087 ml, 0.51 mmol) in 2 ml of dichloromethane were stirred at room temperature for 10 min. Sodium triacetoxyborohydride (129 mg, 0.61 mmol) was added and the reaction mixture was stirred at room temperature overnight. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 39 mg (0.06 mmol) of the desired product were obtained.
HPLC (Method 2F): Rt. (min)=7.25
[M+H]+=583
The following examples were synthesized in analogy to the preparation of Example 160.


















Inter-


HPLC



Ex

me-
Amine or
[M + 
Rt•



#
STRUCTURE
diate
Ketone
H]+
(min)
Method







161




28f
N-Methyl- N- piperidin- 4-yl- methane- sulfon- amide
571
 7.17
2F


 


162




28f
Morpho- line
466
   9.97- 10.27
1E


 


163




28f
Pyrrolidine
450
 7.06
2F


 


164




28a
4,4- difluoro- piperidine
512
 8.17
1E


 


165




28a
(R)- pyrrolidin- 3-ol
478
 7.62
1E


 


166




28a
(S)- pyrrolidin- 3-ol
478
 7.57
1E


 


167




28a
4-fluoro- piperidine
494
 7.37
2F


 


168




28a
N- piperidin- 4yl- methan- sulfon- amide
569
 7.28
1E (Fusion)


 


169




28a
(S)-N- piperidin- 3yl- methan- sulfon- amide
569
 8.50
1E


 


170




28a
N- piperidin- 4yl- isobutyr- amide
561
 7.58
1E


 


171




28a
N- piperidin- 4yl- acetamide
533
 7.07
2F


 


172




28a
Piperidin- 4- carboxylic  acid amide
519
 7.07
1E (Fusion)


 


173




28a
Piperidin- 4- carboxylic  acid  methyl- amide
533
 7.73
1E (Fusion)


 


174




28a
(R)-N- piperidin- 3yl- methan- sulfon- amide
569
 8.48
1E (Fusion)


 


175




28a
(S)- piperidine- 3- carboxylic  acid amide
519
 8.70
1E (Fusion)


 


176




28a
(S)- piperidine- 3- carboxylic  acid  methyl  amide
533
 7.03
2F


 


177




28a
(S)- piperidine- 3- carboxylic  acid  dimethyl  amide
547
 7.15
2F


 


178




28a
N-Ehtyl- N- piperidin- 4-yl- methane- sulfon- amide
597
 9.62
1E (Hydro)


 


179




28a
(S)- piperidine- 3-carbxylic  acid
520
 6.60
1E (Fusion)


 


180




28b
Methyl-(3- methyl- oxetan- 3yl- methyl)- amine
492
 8.05
1E (Hydro)


 


181




28b
2- (methoxy- ethyl)- methyl- amine
466
 7.72
1E (Hydro)


 


182




28b
Methyl- amino- aceto- nitrile
447
 8.00
1E (Hydro)


 


183




28b
2,3- dihydro- 1H- isoindole
496
 9.52
1E (Hydro)


 


184




28b
4-trifluoro- methyl- piperidine
530
 9.60
1E (Hydro)


 


185




28b
18
585
 7.33
1E (Hydro)


 


186




28b
Piperidin- 4- carboxylic  acid  methyl- amide
519
 7.42
1E (Hydro)


 


187




28b
Piperidin- 4yl-urea
520
 7.05
2F


 


188




28b
2- methan- sulfonyl- 2,8-diaza- spiro[4.5]- decane
595
 8.32
1E (Hydro)


 


189




28b
4-(1,1- dioxo-iso- thia- zolidin-2- yl)- piperidine
581
 8.23
1E (Hydro)


 


190




28b
2,8- diazaspiro [4.5] decan-1- one
531
 7.58
1E (Hydro)


 


191




28b
16a
585
 7.65
1E (Hydro)


 


192




28b
1- piperidin- 4-yl- pyrrolidin- 2-one
545
 8.08
1E (Hydro)


 


193




28b
Azetidin- 3-carbxylic  acid  methyl- amide
491
 7.55
1E (Hydro)


 


194




28b
N-methyl- N- piperidin- 4yl- acetamide
533
 7.87
1E (Hydro)


 


195




28b
Ethan- sulfonic- acid- piperidin- 4-yl-amide
569
 8.15
1E (Hydro)


 


196




28c
Piperidine- 4-sulfonic  acid  dimethyl- amide
557
 9.11
1E (Hydro)


 


197




28b
Propan-2- sulfonic  acid- piperidin- 4-yl-amide
583
 8.37
1E (Hydro)


 


198




28c
4-ethoxy- piperidine
494
10.75
1E (Hydro)


 


199




28c
N- piperidin- 4-methyl- methan- sulfon- amide
557
 9.45
1E (Hydro)


 


200




28c
4-tert- butyl- piperidine
506
 7.86
2F


 


201




28c
4- (piperidin- 4-yl)- pyridine
527
10.88
1E (Hydro)


 


202




28c
Piperidine- 4-carbo- nitrile
475
 9.77
1E (Hydro)


 


203




28c
4-(3,4- difluoro- phenoxy)- piperidine
578
11.05
1E (Hydro)


 


204




28c
2- (piperidin- 4-yloxy)- pyridine
543
10.38
1E (Hydro)


 


205




28c
Propan-2- sulfonic- acid- piperidin- 4-yl-amide
571
 9.12
1E (Hydro)


 


206




28c
N-Ethyl- N- piperidin- 4-yl- methane- sulfon- amide
571
10.18
1E (Hydro)


 


207




28g
Piperidine- 4-sulfonic  acid  dimethyl- amide
571
 9.67
1E (Hydro)


 


208




28c
4- methoxy- piperidine
480
 2.21
2G


 


209




28c
2-methyl- morpho- line
466
 3.46
2F


 


210




28c
3-Phenyl- pyrroli- dine
512
 9.68
2F


 


211




28c
Piperidin- 4- carboxylic  acid sec- butyl  amide
549
 9.53
1E (Hydro)


 


212




28c
4-(3,5- dimethyl- [1,2,4]- triazol-4- yl)- piperidine
545
 8.93
1E (Hydro)


 


213




28c
4-(3- methyl- [1,2,4]- oxadiazol- 5-yl)- piperidine
532
 8.21
2F


 


214




28c
N-methyl- 2-(R)-(pyr- rolidin-2- yl)  acetamide
507
 9.35
1E (Hydro)


 


215




28c
N-methyl- 2-(S)-(pyr- rolidin-2- yl)  acetamide
507
 9.24
1E (Hydro)


 


216




28c
N,N- dimethyl- 2-(R)-(pyr- rolidin-2- yl)  acetamide
521
 9.71
1E (Hydro)


 


217




28c
N,N- dimethyl- 2-(S)-(pyr- rolidin-2- yl)  acetamide
521
 9.72
1E (Hydro)


 


218




28c
2,6- dimethyl- morpho- line
480
 8.92
2F


 


219




28c
(R)-3- methoxy- pyrroli- dine
466
 7.23
2F


 


220




28c
(S)-3- methoxy- pyrroli- dine
466
 7.23
2F


 


221




28c
Piperidine- 4-sulfonic  acid  methyl- amide
543
 8.50
1E (Hydro)


 


222




28c
N-azetidin- 3-yl-N- methyl- methane- sulfon- amide
529
 8.65
1E (Hydro)


 


223




28c
N-azetidin- 3-yl- methane- sulfon- amide
515
 8.02
1E (Hydro)


 


224




28c
4-methyl- piperidine- 4- carboxylic  acid  methyl- amide
521
 9.00
1E (Hydro)


 


225




28c
4-phenyl- piperidine
526
10.83
1E (Hydro)


 


226




28b
N-methyl- N-(S)- (pyrroli- din-3yl)- methane- sulfon- amide
555
 8.04
1E (Hydro)


 


227




28b
16b
599
 8.13
1E (Hydro)


 


228




28b
Piperidine- 4-sulfonic  acid amide
541
 7.12
1E (Hydro)


 


228a




28c
Methyl- (tetra- hydro- pyran-3- yl)-amine
480
10.05
1E (Hydro)


 


228b




41b
3- methoxy- tetrahydro- pyran-4- one
522
 9.25
1E (Hydro)


 


228c




41a
3- methoxy- tetrahydro- pyran-4- one
496
 8.87
1E (Hydro)


 


228d




41a
3-fluoro- tetrahydro- pyran-4- one
484

1E (Hydro)


 


228e




41a
N-carb- ethoxy-3- methoxy- 4- piperidone
567
 7.42
2F


 


228f




41a
4- chroman- one
514
10.31
1E (Hydro)


 


228g




41a
43
530
 9.76
1E (Hydro)


 


228ga




28c
47a
496
 5.77
2M


 


228gb




28c
1-(2- Methoxy- ethyl)- 3a,4,5,6,7, 7a- hexahydro- 1H- pyrazolo- [3,4- c]pyridine
546
 9.55
1E (Hydro)


 


228gc




28c
1-((R)-3- Amino- piperidin- 1-yl)- ethanone
507
 8.85
1E (Hydro)


 


228gd




28c
(R)-1- Methane- sulfonyl- piperidin- 3-yllamine
543
 9.11
1E (Hydro)


 


228ge




28c
3- Phenoxy- methyl- pyrrolidine
542
10.92
1E (Hydro)


 


228gf




28c
3- Pyrrolidin- 3-yl- pyridine
527
10.00
1E (Hydro)


 


228gg




28c
3- Trifluoro- methyl- 5,6,7,8- tetrahydro- [1,6] naphthyri- dine
567
 7.69
2F


 


228gh




28c
C- (Tetra- hydro- pyran-2- yl)methyl- amine
480
 2.09
2Cb


 


228gi




28c
56
515
 2.18
2Cb


 


228gj




28c
1-Oxa-3,8- diaza- spiro[4,5] decan-2- one
521
 8.30
1E (Hydro)


 


228gk




28c
4- Piperidin- 4-yl- benzo- nitrile
551
10.35
1E (Hydro)


 


228gl




28c
4-(3,4- Difluoro- benzyl)- piperidine
576
11.42
1E (Hydro)


 


228gm




28c
8-Aza- bicyclo [3.2.1] octan-3-ol
492
 9.30
1E (Hydro)


 


228gn




28c
45
496
 5.96
2M


 


228go




41a
3- Methoxy- tetrahydro- pyran-4- one
508
 5.77
2M


 


228gp




41a
3-Tetrazol- 2-yl- tetrahydro- pyran-4- one
534
 7.09
2F









Example 228h




Example 228b (22 mg, 0.032 mmol), formaldehyde (0.003 ml, 0.096 mmol), N,N-diisopropyl-ethylamine (0.008 ml, 0.048 mmol) and trifluoroacetic acid (0.005 ml) in 1.5 ml of methanol were stirred at room temperature for 5 min. Sodium cyanoborohydride (10 mg, 0.160 mmol) was added and the reaction mixture was stirred at room temperature overnight. The organic phase was concentrated under vacuum. The crude product was purified by flash chromatography (Isolute silica gel cartridge 5 g, eluent: ethyl acetate/methanol=7:3%). 8.4 mg (0.016 mmol) of the desired product were obtained.
The following examples were synthesized in analogy to the preparation of Example 228h.



















HPLC



Ex

Starting

Rt-



#
STRUCTURE
example
[M + H]+
(min)
Method




















228ha




228ga
510
5.72
2M









Example 229




Intermediate 28a (100 mg, 0.25 mmol), (S)-3-hydroxypiperidine (67 mg, 0.49 mmol) and trimethylorthoformate (1.07 ml, 9.82 mmol) in 5 ml of methanol were stirred at 60° C. for 1 h. 2-picoline borane complex (26 mg, 0.25 mmol) was added and the reaction mixture was stirred at 60° C. overnight. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 64 mg (0.13 mmol) of the desired product were obtained.
HPLC (Method 1E): Rt. (min)=7.18
[M+H]+=492
The following examples were synthesized in analogy to the preparation of Example 229.





















HPLC



Ex

Inter-


Rt-



#
STRUCTURE
mediate
Amine
[M + H]+
(min)
Method







230




28a
1- piperazin- 1-yl- ethanone
519
7.13
2F


 


231




28a
(R)- piperidin- 3-ol
492
7.35
1E (Fusion)


 


232




28a
(R)- pyrrolidin- 3- carboxylic acid amide
505
7.83
1E (Fusion)


 


233




28b
3-fluoro- piperidine
480
8.32
1E (Hydro)









Example 234




Intermediate 28d (20 mg, 0.05 mmol), 2-methyl-morpholine (0.012 ml, 0.10 mmol), sodium triacetoxyborohydride (43 mg, 0.20 mmol), acetic acid (0.05 ml) and trimethylorthoformate (0.05 ml) in 0.9 ml of DMA were stirred at room temperature for 3 h. The reaction mixture was concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 3 mg (0.006 mmol) of the desired product were obtained. HPLC (Method A): Rt. (min)=1.74
[M+H]+=486
The following examples were synthesized in analogy to the preparation of Example 234.





















HPLC



Ex

Inter-

[M +
Rt-
Meth-


#
STRUCTURE
mediate
Amine
H]+
(min)
od







235




28b
Azepane
476
1.72
2A


 


236




28d
Dimethyl- piperidin- 4yl-amine
513
1.64
2A


 


237




28a
2-methyl- morpholine
492
1.72
2A


 


238




28b
Pyrrolidin- 3-ol
464
1.65
2A


 


239




28d
Pyrrolidin- 3-ol
472
1.71
2A


 


240




28a
2-phenyl- morpholine
554
1.84
2A


 


241




28a
Pyrrolidin- 3-ol
478
1.68
2A


 


242




28b
[1,4]-oxa- zepane
478
1.66
2A


 


243




28d
[1,4]-oxa- zepane
486
1.72
2A


 


244




28b
4,4- difluoro- piperidine
498
1.72
2A


 


245




28b
Azepan- 4-ol
492
1.65
2A


 


246




28a
(3S,4R)- piperidine- 3,4-diol
508
1.66
2A


 


247




28a
Azepan- 4-ol
506
1.68
2A









Example 248




Intermediate 27e (105 mg, 0.33 mmol), TBTU (215 mg, 0.67 mmol) and N,N-diisopropyl-ethylamine (0.12 ml, 0.67 mmol) in 2 ml DMF were stirred at room temperature for 5 min. Intermediate 20f (100 mg, 0.33 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Si Isolute cartridge (5 g); eluent: ethyl acetate/methanol=90/10%). 30 mg (0.057 mmol) of the desired product were obtained.
HPLC (Method 1E Hydro): Rt. (min)=9.2
[M+H]+=521
The following examples were synthesized in analogy to the preparation of Example 248.


















Inter-


HPLC



Ex

med-

[M +
Rt-



#
STRUCTURE
iate
Amine
H]+
(min)
Method







249




27i
20a
568
10.07
1E (Hydro)


 


250




27c
1- pyrrolidin- 3-yl- piperidine
436
1.5
1E (Hydro)


 


251




27c
[1,3′]- Bipyrrolidinyl
422
10.35
1E (Hydro)


 


252




27a
[1,4′]- Bipiperidinyl- 4′ carboxylic acid amide
519
 8.60
1E (Fusion)


 


253




27a
4- pyrrolidin- 1yl- piperidine
462
 7.07
2F


 


254




27b
20g
555
 7.50
1E (Hydro)


 


255




27b
20a
569
 8.15
1E (Hydro)


 


256




27b
20j
491
 7.03
1E (Hydro)


 


257




27b
20i
505
 7.43
1E (Hydro)


 


258




27b
20d
541
 7.50
1E (Hydro)


 


259




27b
20c
541
 7.48
1E (Hydro)


 


260




27b
20h
505
 7.85
1E (Hydro)


 


261




27c
20f
507
 8.70
1E (Hydro)


 


262




27e
20g
557
 9.11
1E (Hydro)


 


263




27c
20m
587
 8.79
2F


 


264




27c
20e
557
 8.85
1E (Hydro)


 


265




27c
201
479
 8.37
1E (Hydro)


 


266




27e
20f
521
9.2
1E (Hydro)


 


267




27e
201
493
 8.93
1E (Hydro)


 


268




39b
20a
542
 3.54
2F


 


269




39b
4- piperidin- 4-yl- morpholine
436
 7.46
2F


 


270




39a
20a
553
 8.28
2F


 


271




39a
4- piperidin- 4-yl- morpholine
449
 7.60
2F


 


272




39c
20a
556
 7.98
2F


 


273




39c
4- piperidin- 4-yl- morpholine
450
 7.29
2F


 


274




39d
24
554
 8.28
1E (Hydro)


 


275




39d
[1,4′]- bipiperidinyl- 4-ol
477
 7.77
1E (Hydro)


 


275a




27c
201a
480
10.03
1E (Hydro)


 


275b




27c
201b
510
 9.48
1E (Hydro)


 


275c




27c
201c
508
10.27
1E (Hydro)


 


275d




27c
201d
514
10.13
1E (Hydro)


 


275da




27hc
201g
526
 9.16
1E (Hydro)


 


275db




27hd
201g
526
 9.18
1E (Hydro)


 


275dc




27hs
201g
508
 7.25
1F


 


275dd




27hf
201f
494
 6.53
2F


 


275de




27hr
201g
508
 8.55
1E (Hydro)


 


275df




27he
201g
494
 8.07
1E (Hydro)


 


275dg




27hf
201g
494
 8.10
1E (Hydro)


 


275dh




27ha
201f
522
 9.03
1E (Hydro)


 


275di




27ha
201g
522
 9.00
1E (Hydro)


 


275dj




27ha
201a
536
 9.76
1E (Hydro)


 


275dk




27ib
20a
595
 2.16
2Cb


 


275dl




27ic
20a
593
 2.20
2Cb









Example 276




Intermediate 27g (50 mg, 0.14 mmol), HATU (55 mg, 0.14 mmol) and N,N-diisopropyl-ethylamine (0.05 ml, 0.28 mmol) in 2 ml DMF were stirred at room temperature for 5 min. 4-piperidin-4-yl-morpholine (24 mg, 0.14 mmol) was added and the reaction mixture was stirred at room temperature 3 h. The reaction mixture was concentrated under vacuum and the crude product was dissolved in dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 80 mg (0.13 mmol) of the desired product were obtained.
HPLC (Method C): Rt. (min)=1.57
[M+H]+=486
The following examples were synthesized in analogy to the preparation of Example 276.





















HPLC



Ex

Inter-

[M +
Rt-



#
STRUCTURE
mediate
Amine
H]+
(min)
Method







277




27h
4-piperidin- 4-yl- morpholine
536
1.69
2C


 


278




27h
[1,4′]- Bipiperidinyl- 4-ol
550
1.65
2C


 


279




27a
4-piperidin- 4-yl- morpholine
478
1.52
2C


 


280




27f
[1,4′]- Bipiperidinyl- 4-ol
506
1.52
2C


 


281




27f
4-piperidin- 4-yl- morpholine
492
1.53
2C


 


282




27g
[1,4′]- Bipiperidinyl- 4-ol
500
1.55
2C


 


283




39e
[1,4′]- Bipiperidinyl- 4-ol
484
1.66
2C









Example 284




Intermediate 30 (45 mg, 0.088 mmol) and N,N-diisopropylethylamine (0.05 ml, 0.27 mmol) were dissolved in 5 ml of dichloromethane. The reaction mixture was stirred at 0° C. and isobutyrylchloride (0.01 ml, 0.09 mmol) was added. The reaction mixture was stirred at 0° C. for 20 min, then it was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was suspended and stirred in diisopropyl ether, the solid filtered off to obtain 30 mg (0.05 mmol) of the desired compound.
HPLC (Method 1E): Rt. (min)=7.02
[M+H]+=547
The following examples were synthesized in analogy to the preparation of Example 284.





















HPLC



Ex




Rt-



#
STRUCTURE
Intermediate
Chloride
[M + H]+
(min)
Method







285




30
Methane- sulfonyl chloride
555
6.91
2F









Example 286




Intermediate 32 (100 mg, 0.26 mmol) and cyclopentanone (0.02 ml, 0.26 mmol) in 2 ml of dichloromethane were stirred at room temperature for 10 min. Sodium triacetoxyborohydride (132 mg, 0.62 mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC. 31 mg (0.07 mmol) of the desired product were obtained.
HPLC (Method 2F): Rt. (min)=7.52
[M+H]+=450
The following examples were synthesized in analogy to the preparation of Example 286.





















HPLC



Ex




Rt-



#
STRUCTURE
Intermediate
Ketone
[M + H]+
(min)
Method







287




32
Acetone
424
7.24
2F


 


288




32
Tetrahydro- pyran-4-one
466
7.18
2F









Example 289




Intermediate 25b (200 mg, 0.46 mmol) 4-tert-butylphenylboronic acid (99 mg, 0.56 mmol), tetrakis(triphenylphosphine)palladium (53 mg, 0.05 mmol) and 0.56 ml of a 2M aqueous solution of sodium carbonate in 2 ml of 1,2-dimethoxyethane were stirred at 80° C. overnight. After cooling to room temperature, water was added and the reaction mixture was extracted with dichloromethane. The organic phase was washed with an aqueous saturated sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Si Isolute cartridge (5 g); eluent: ethyl acetate/methanol=95/5%). 41 mg (0.08 mmol) of the desired product were obtained.
HPLC (Method 1E Hydro): Rt. (min)=9.93
[M+H]+=528
Example 290




Intermediate 25b (60 mg, 0.14 mmol) and 4-chlorophenol (0.014 ml, 0.14 mmol) were dissolved in 2 ml of DMF. Cesium carbonate (45 mg, 0.14 mmol) was added and the reaction mixture was stirred at room temperature overnight. The solvent was concentrated under vacuum, the crude product was dissolved in dichloromethane and the organic phase was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Si Isolute cartridge (5 g); eluent: dichlorometane/ethyl acetate=90/1%). 50 mg (0.09 mmol) of the desired product were obtained.
HPLC (Method 1E Hydro): Rt. (min)=8.9
[M+H]+=522
The following example was synthesized in analogy to the preparation of Example 290.





















HPLC



Ex




Rt-



#
STRUCTURE
Intermediate
Phenol
[M + H]+
(min)
Method







291




25b
4- tertbutyl- phenol
544
7.64
2F









Example 292




Sodium hydride (19 mg, 0.46 mmol) and 4-chloro-3-methylbenzylalcohol (44 mg, 0.28 mmol) were suspended in 5 ml of dry tetrahydrofuran. The reaction mixture was stirred at room temperature for 10 min, then Intermediate 25b (100 mg, 0.23 mmol) was added. The reaction mixture was stirred at 50° C. overnight. The solvent was concentrated under vacuum, the crude product was dissolved in dichloromethane and the organic phase was washed with water, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (Si Isolute cartridge (5 g); eluent: dichlorometane/methanol=95/5%). 40 mg (0.07 mmol) of the desired product were obtained.
HPLC (Method 1E Hydro): Rt. (min)=9.95
[M+H]+=550
The following examples were synthesized in analogy to the preparation of Example 292.


















Inter-


HPLC



Ex

medi-


Rt-



#
STRUCTURE
ate
Phenol
[M + H]+
(min)
Method







293




25b
4-hydroxy- methyl- benzonitrile
527
 8.17
1E (Hydro)


 


294




25b
(3-fluoro-4- methyl- phenyl)- methanol
534
 9.12
1E (Hydro)


 


295




25b
(1-phenyl- pyrrolydin- 3-yl)- methanol
571
10.2 
1E (Hydro)


 


296




25b
(4-tert- butyl- phenyl)- methanol
558
 2.71
1F


 


297




25f
(4-tert- butyl- phenyl)- methanol
466
 9.50
1E (Hydro)


 


298




25h
(4-tert- butyl- phenyl)- methanol
453
 8.01
2F


 


299




25a
(4-tert- butyl- phenyl)- methanol
544
 9.68
1E (Hydro)


 


300




25d
(4-tert- butyl- phenyl)- methanol
508
10.25
1E (Hydro)


 


301




25n
(4-tert- butyl- phenyl)- methanol
588
 2.20
2Ca


 


302




25n
(3-Phenyl- cyclo- hexyl)- methanol
614
 2.18
2Ca

## Claims

1. A compound according to formula (I),



wherein
R1 is -L1-R7,
wherein L1 is a linker selected from a group selected from among —C1-C2-alkylene, and —C1-C2-alkenylene which optionally comprises one or more groups selected from —O—, —C(O)—, and —NH— in the chain and which is optionally substituted by a group selected from among —OH, —NH2, —C1-C3-alkyl, O—C1-C6-alkyl, and —CN,
wherein R7 is a ring selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, pyrrolidinyl, piperidinyl, azepanyl, phenyl, pyridyl, and furanyl,
wherein the ring R7 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, and -halogen,
or wherein the ring R7 is optionally substituted with one or more groups selected from among —C1-C6-alkyl, —O—C1-C6-alkyl, —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C1-C6-alkenyl, and —C1-C6-alkynyl, optionally being substituted by one or more groups selected from among —OH, —NH2, —C1-C3-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and ═O,
or wherein the ring R7 is optionally further bi-valently substituted on two neighbouring ring atoms, such that an annellated ring is formed by one or more groups selected from among —C1-C6-alkylene, —C2-C6-alkenylene and —C4-C6-alkynylene, in which one or two carbon centers may optionally by replaced by 1 or 2 hetero atoms selected from N, O and S, the bivalent group being optionally substituted by one or more groups selected from —OH, —NH2, —C1-C3-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and ═O;
wherein R2 is selected from among —H, -halogen, —CN, —C1-C4-alkyl, —CH═CH2, —C≡CH, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R3 is selected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, —OCH3, and —CN;
wherein R4 and R5 are independently selected from among an electron pair, —H, and a group selected from among —C1-C6-alkyl, —NH2, —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, —C5-C10-heteroaryl, and —C(O)—N(R8,R8′), with R8 and R8′, independently being selected from among —H, and —C1-C6-alkyl,
and wherein R4 and R5 if different from an electron pair or —H are optionally independently substituted with one or more groups selected from among -halogen, —OH, —CF3, —CN, —C1-C6-alkyl, —O—C1-C6-alkyl, —O—C3-C8-cycloalkyl, —O—C3-C8-heterocyclyl, —O—C5-C10-aryl, —O—C5-C10-heteroaryl, —C0-C6-alkylene-CN, —C0-C4-alkylene-O—C1-C4-alkyl, —C0-C4-alkylene-O—C3-C8-cycloalkyl, —C0-C4-alkylene-O—C3-C8-heterocyclyl, —C0-C4-alkylene-O—C5-C10-aryl, —C0-C4-alkylene-O—C5-C10-heteroaryl, —C0-C4-alkylene-Q-C0-C4-alkyl-N(R9,R9′), —C0-C4-alkylene-N(R10)-Q-C1-C4-alkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-N(R10)-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-N(R10)-Q-C5-C10-aryl, —C0-C4-alkylene-N(R10)-Q-C5-C10-heteroaryl, —C0-C4-alkylene-Q-N(R11,R11′), —C0-C4-alkylen-N(R12)-Q-N(R13,R13′), —C0-C4-alkylen-R14, —C0-C4-alkylene-Q-C1-C6-alkyl, —C0-C4-alkylene-Q-C3-C8-cycloalkyl, —C0-C4-alkylene-Q-C3-C8-heterocyclyl, —C0-C4-alkylene-Q-C5-C10-aryl, —C0-C4-alkylene-Q-C5-C10-heteroaryl, —C0-C4-alkylene-O-Q-N(R15,R15′), and —C0-C4-alkylene-N(R16)-Q-O—(R17),
wherein Q is selected from among —C(O)—, and —SO2—,
wherein R12, R16, are independently selected from among —H, —C1-C6-alkyl, and —C3-C6-cycloalkyl,
wherein R9, R9′, R10, R11, R11′, R13, R13′, R15, R15′, are independently selected from among —H, —C1-C6-alkyl, and —C3-C6-cycloalkyl,
or wherein R9 and R9′, R11 and R11′, R13 and R13′, R15 and R15′ together form a —C2-C6-alkylene group,
wherein R14 and R17 are independently selected from among —H, —C1-C6-alkyl, —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, and —C3-C8-heterocyclyl, wherein said —C3-C8-heterocyclyl optionally comprises nitrogen and/or —SO2— in the ring, and wherein R14 and R17 are optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —SO2—C1-C4-alkyl,
or wherein R4 and/or R5 are independently a group of the structure -L2-R18,
wherein L2 is selected from among —NH— and —N(C1-C4-alkyl)-,
wherein R18 is selected from among —C5-C10-aryl, —C5-C10-heteroaryl, —C3-C8-cycloalkyl, and —C3-C8-heterocyclyl,
wherein R18 is optionally substituted by one or more groups selected from among halogen, —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, —NH—C(O)—C1-C6-alkyl, —N(C1-C4-alkyl)-C(O)—C1-C6-alkyl, —C(O)—C1-C6-alkyl, —S(O)2—C1-C6-alkyl, —NH—S(O)2—C1-C6-alkyl, —N(C1-C4-alkyl)-S(O)2—C1-C6-alkyl, and —C(O)—O—C1-C6-alkyl,
wherein R6 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein A is —NH—;
wherein n is 1, 2 or 3;
wherein Z is C or N,
as well as in form of their acid addition salts with pharmacologically acceptable acids.

2. The compound of claim 1,
wherein
R1 is -L1-R7,
and wherein L1 is a group selected from among methylene, ethylene, methenylene, and ethenylene,
wherein L1 is optionally substituted with one or more groups selected from among methyl, and ethyl,
wherein L1 optionally comprises one or more —O— atoms,
wherein the ring R7 is optionally substituted with one or more groups selected from among —F, —Cl, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, -t-butyl, —CF3, —O—CF3, —CN, —O-methyl, furanyl and phenyl, wherein said furanyl and said phenyl are optionally independently substituted by one or more groups selected from among —C1-C3-alkyl, halogen, —OCH3, —CF3, and —OCF3,
or wherein the ring R7 is bi-valently substituted by one or more groups selected from among





on two neighbouring ring atoms, such that an annellated ring is formed.

3. The compound of claim 1, wherein R1 is selected from among

4. The compound of claim 1, wherein R2 is selected from among —H, -methyl, -ethyl, -propyl, -i-propyl, -cyclopropyl, -butyl, -i-butyl, -t-butyl, —F, —Cl, —Br, —I, —CN, —CH═CH2, and —C≡CH.

5. The compound of claim 1, wherein R2 is selected from among —H, -methyl, -ethyl, and —Br.

6. The compound of claim 1, wherein R3 is selected from among —H, and -methyl.

7. The compound of claim 1, wherein R4 and R5 are independently selected from among an electron pair, —H, and a group selected from among-i-propyl, -amino, -pyrrolidinyl, -piperidinyl, -morpholinyl, -azepanyl, -oxazepanyl, -piperazinyl, -azetidinyl, -tetrahydropyranyl, -cyclopentyl, -cyclohexyl, and —C(O)—N(R8,R8′), with R8 and R8′ independently being selected from among —H and —C1-C6-alkyl,
wherein R4 and R5 if different from an electron pair, and —H are optionally independently substituted with one or more groups selected from among -fluoro, -methyl, -ethyl, propyl, -i-propyl, -butyl, -i-butyl, -t-butyl, -hydroxy, —CF3, —OCF3, —CN, —O—CH3, —O—C2H5, —O—C3H7, —CH2—CN, —CH2—O—CH3, —(CH2)2—O—CH3, —C(O)—CH3, —C(O)—C2H5, —C(O)—C3H7, —COOH, —C(O)—NH2, —C(O)—NH—CH3, —C(O)—N(CH3)2, —NH—C(O)—CH3, —N(CH3)C(O)—CH3, —NH—C(O)—C2H5, —N(CH3)—C(O)—C2H5, —NH—C(O)—C3H7, —N(CH3)—C(O)—C3H7, —NH—SO2—CH3, —N(CH3)—SO2—CH3, —N(C2H5)—SO2—CH3, —N(C3H7)—SO2—CH3, —NH—SO2—C2H5, —N(CH3)—SO2—C2H5, —N(C2H5)—SO2—C2H5, —N(C3H7)—SO2—C2H5, —NH—SO2—C3H7, —N(CH3)—SO2—C3H7, —N(C2H5)—SO2—C3H7, —N(C3H7)—SO2—C3H7, —NH—SO2—C3H5, —N(CH3) SO2—C3H5, —N(C2H5)—SO2—C3H5, —N(C3H7)—SO2—C2H5, —CH2—NH—SO2—CH3, —CH2—N(CH3) SO2—CH3, —CH2—NH—SO2—C2H5, —CH2—N(CH3)—SO2—C2H5, —CH2—NH—SO2—C3H7, —CH2—N(CH3)—SO2—C3H7, —CH2—NH—SO2—C3H5, —CH2—N(CH3)—SO2—C3H5, —NH—C(O)—NH2, N(CH3)—C(O)—NH2, —NH—C(O)—NH—CH3, —N(CH3)—C(O)—NH—CH3, —NH—C(O)—N(CH3)2, —N(CH3)—C(O)—N(CH3)2, —SO2—NH2, —SO2—NH(CH3), —SO2—N(CH3)2, —C(O)—NH—C2H5, —C(O)—N(CH3)—C2H5, —C(O)—N(CH3)—C3H7, —C(O)—N(CH3)—C4H9, —C(O)—NH—CH(CH3)—C2H5, —C(O)—N(CH3)—CH(CH3)—C2H5, —CH2—C(O)—NH2, —CH2—C(O)—NH—CH3, —CH2—C(O)—N(CH3)2, —N(CH3)—SO2—N(CH3)2, -phenyl, -pyridin-4-yl, —CH2-3-methyl-oxetan-3-yl, —O-1,2-difluoro-phen-5-yl, —O-pyridin-2-yl, -pyrrolidine-2-one-1-yl, -3,5-dimethyl-[1,2,4]triazol-4-yl, 3-methyl-[1,2,4]oxadiazol-5-yl,




or wherein R4 and R5 are independently a group of the structure -L2-R18,
wherein L2 is selected from among —NH—, —N(CH3)—, and —N(C2H5)—,
and wherein R18 is selected from among -tetrahydropyranyl, -cyclopropyl, -cyclobutyl, -cyclopentyl, -cyclohexyl, -cycloheptyl, -cyclooctyl, -pyrrolidinyl, -piperidinyl, -piperazinyl, and -morpholinyl,
wherein R18 is optionally substituted by one or more groups selected from among —F, —CF3, —OCF3, —CN, —OH, —O—CH3, —CH3, —NH—C(O)—CH3, —N(CH3)—C(O)—CH3, —C(O)—CH3, —S(O)2—CH3, —NH—S(O)2—CH3, —N(CH3)—S(O)2—CH3, and —C(O)—O—C2H5.

8. The compound of claim 1, wherein R4 is selected from among

9. The compound of claim 1, wherein R5 is selected from among an electron pair, —H, and —C(O)—NH2.

10. The compound of claim 1, wherein R6 is selected from among —H, —CH3, —C2H5, —O—CH3, —O—C2H5, —F, —CF3, and —OCF3.

11. The compound of claim 1, wherein R6 is H or —O—CH3.

12. The compound of claim 1, wherein Z is C.

13. A method for the treatment of chronic obstructive pulmonary disease comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmacologically acceptable salt thereof.

14. A method for the treatment of neuropathic pain comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 or a pharmacologically acceptable salt thereof.

15. A compound according to claim 1 selected from the group consisting of







































































































































































































and the pharmaceutically acceptable acid addition salts thereof.