# Patent

## Title
Selective CCR2 antagonists

## Abstract

The present invention relates to novel and selective 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 as well as pain.

## Background
FIELD OF INVENTION
The present invention relates to novel and selective antagonists for CCR2 (CC chemokine receptor 2), the method for producing the same, 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.
CCR2 antagonists, which modulate chemokine receptors such as the CCR2 and CCR5 receptor are disclosed by WO 2010/070032.
Based on the aforesaid there is a need for providing effective antagonists for CCR2, which are pharmacologically acceptable and which show selective activity for Chemokine receptors CCR2, whereas an activity for Chemokine receptors CCR5 is reduced.


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




wherein R3 is —C5-C6-heterocyclyl, which contains one, or two heteroatoms, selected from among oxygen, and nitrogen, optionally being substituted by one or more groups selected from among —OH, —NH2, —C1-C6-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, —C(O)—CH3, and ═O;
or wherein R3 denotes a group selected from among —CH2F, —CHF2, and —CF3;
wherein A is a group selected from among




wherein R7 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R8 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein Q is selected from among CH2 and O, and wherein R9 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
and wherein R10 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein R11 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R12 is a ring selected from among —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, and —C5-C10-heteroaryl,
wherein the ring R12 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, —C1-C6-alkyl, —S—C1-C3-alkyl, and -halogen,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)-,
and wherein R13 is selected from among —C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O,
and wherein R13 is optionally substituted by one or more groups selected from among among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen,
or wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C2-C6-alkylene group such that a ring is formed,
wherein one carbon atom may be replaced by a group selected from among NH, and O,
and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl
wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein R5 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein G and E are independently selected from among C—H or N;
wherein n is 1, 2 or 3;
as well as in form of their acid addition salts with pharmacologically acceptable acids.
Preferred compounds of the invention are compounds according to formula (I)




wherein R3 is —C5-C6-heterocyclyl, wherein this —C5-C6-heterocyclyl denotes a 5 or 6 membered, saturated or unsaturated heterocyclic ring in that the 5 or 6 atoms of the ring system could be carbon atom or heteroatom, and wherein one, or two of the 5 or 6 atoms are heteroatoms, selected from among oxygen, and nitrogen, optionally being substituted by one or more groups selected from among —OH, —NH2, —C1-C6-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, —C(O)—CH3, and ═O;
or wherein R3 denotes a group selected from among —CH2F, —CHF2, and —CF3;
wherein A is a group selected from among




wherein R7 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R8 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein Q is selected from among CH2 and O, and wherein R9 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
and wherein R10 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein R11 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R12 is a ring selected from among —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, and —C5-C10-heteroaryl,
wherein the ring R12 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, —C1-C6-alkyl, —S—C1-C3-alkyl, and -halogen,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)-,
and wherein R13 is selected from among —C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O,
and wherein R13 is optionally substituted by one or more groups selected from among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen,
or wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C2-C6-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among NH, and O,
and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl
wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein R5 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein G and E are independently selected from among C—H or N;
wherein n is 1, 2 or 3;
as well as in form of their acid addition salts with pharmacologically acceptable acids.
Preferred compounds of the invention are compounds according to formula (I)




wherein R3 denotes a 5 or 6 membered, saturated or unsaturated heterocyclic ring in that the 5 or 6 atoms of the ring system could be carbon atom or heteroatom, and wherein one, or two of the 5 or 6 atoms are heteroatoms, selected from among oxygen, and nitrogen, optionally being substituted by one or more groups selected from among —OH, —NH2, —C1-C6-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, —C(O)—CH3, and ═O;
or wherein R3 denotes a group selected from among —CH2F, —CHF2, and —CF3;
wherein A is a group selected from among




wherein R7 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R8 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein Q is selected from among CH2 and O, and wherein R9 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
and wherein R10 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein R11 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R12 is a ring selected from among —C3-C8-cycloalkyl, a 3 to 8 membered, saturated or unsaturated heterocyclic ring in that the 3 to 8 atoms of the ring system could be carbon atom or heteroatom, and wherein one, or two of the 3 to 8 atoms are heteroatoms, selected from among N, and O, —C5-C10-aryl, and —C5-C10-heteroaryl,
wherein the ring R12 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, —C1-C6-alkyl, —S—C1-C3-alkyl, and -halogen,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)-,
and wherein R13 denotes a 5 or 6 membered, saturated or unsaturated heterocyclic ring in that the 5 or 6 atoms of the ring system could be carbon atom or heteroatom, and wherein one, or two of the atoms are heteroatoms, selected from among N, and O, and wherein R13 is optionally substituted by one or more groups selected from among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen,
or wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C2-C6-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among NH, and O, and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl
wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein R5 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein G and E are independently selected from among C—H or N;
wherein n is 1, 2 or 3;
as well as in form of their acid addition salts with pharmacologically acceptable acids.
Preferred compounds of the invention are compounds according to formula (I)




wherein R3 is —C5-C6-heterocyclyl, which contains one, or two heteroatoms, selected from among oxygen, and nitrogen, optionally being substituted by one or more groups selected from among —OH, —NH2, —C1-C6-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, —C(O)—CH3, and ═O;
wherein A is a group selected from among




wherein R7 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R8 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein Q is selected from among CH2 and O, and wherein R9 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
and wherein R10 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein R11 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R12 is a ring selected from among —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, and —C5-C10-heteroaryl,
wherein the ring R12 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, —C1-C6-alkyl, —S—C1-C3-alkyl, and -halogen,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)-,
and wherein R13 is selected from among —C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O,
and wherein R13 is optionally substituted by one or more groups selected from among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen,
or wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C2-C6-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among NH, and O, and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl
wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein R5 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein G and E are independently selected from among C—H or N;
wherein n is 1, 2 or 3.
Preferred compounds of the invention are compounds according to formula (I)




wherein R3 is —C5-C6-heterocyclyl, which contains one, or two heteroatoms, selected from among oxygen, and nitrogen, optionally being substituted by one or more groups selected from among —OH, —NH2, —C1-C6-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, —C(O)—CH3, and ═O;
wherein A is a group selected from among




wherein R7 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R8 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein Q is selected from among CH2 and O, and wherein R9 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
and wherein R10 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)-,
and wherein R13 is selected from among —C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O,
and wherein R13 is optionally substituted by one or more groups selected from among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen,
or wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C2-C6-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among NH, and O, and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl
wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein R5 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein G and E are independently selected from among C—H or N;
wherein n is 1, 2 or 3.
Preferred compounds of the invention are compounds according to formula (I)




wherein R3 is —C5-C6-heterocyclyl, which contains one, or two heteroatoms, selected from among oxygen, and nitrogen, optionally being substituted by one or more groups selected from among —OH, —NH2, —C1-C6-alkyl, —O—C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, —C(O)—CH3, and ═O;
wherein A is a group selected from among




wherein R11 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R12 is a ring selected from among —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, and —C5-C10-heteroaryl,
wherein the ring R12 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, —C1-C6-alkyl, —S—C1-C3-alkyl, and -halogen,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)-,
and wherein R13 is selected from among —C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O,
and wherein R13 is optionally substituted by one or more groups selected from among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen,
or wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C2-C6-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among NH, and O, and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl
wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein R5 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein G and E are independently selected from among C—H or N;
wherein n is 1, 2 or 3.
Preferred compounds of the invention are compounds according to formula (I)




wherein R3 denotes a group selected from among —CH2F, and —CHF2,
wherein A is a group selected from among




wherein R7 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R8 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein Q is selected from among CH2 and O, and wherein R9 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R10 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein R11 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R12 is a ring selected from among —C3-C8-cycloalkyl, —C3-C8-heterocyclyl, —C5-C10-aryl, and —C5-C10-heteroaryl,
wherein the ring R12 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, —C1-C6-alkyl, —S—C1-C3-alkyl, and -halogen,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)-,
and wherein R13 is selected from among —C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O,
and wherein R13 is optionally substituted by one or more groups selected from among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen,
or wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C2-C6-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among NH, and O, and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl
wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein R5 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein G and E are independently selected from among C—H or N;
wherein n is 1, 2 or 3.
Preferred compounds of the invention are compounds according to formula (I)




wherein R3 denotes a group selected from among —CH2F, —CHF2, and —CF3;
wherein A is a group selected from among




wherein Q is selected from among CH2 and O, and wherein R9 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
and wherein R10 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)-,
and wherein R13 is selected from among —C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O,
and wherein R13 is optionally substituted by one or more groups selected from among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen,
or wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C2-C6-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among NH, and O, and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl;
wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein R5 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein G and E are independently selected from among C—H or N;
wherein n is 1, 2 or 3.
Preferred compounds of the invention are compounds according to formula (I)




wherein R3 denotes —CF3;
wherein A is a group selected from among




wherein Q is selected from among CH2 and O, and wherein R9 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
and wherein R10 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)-, and wherein R13 is selected from among —C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O,
and wherein R13 is optionally substituted by one or more groups selected from among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen, or wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C2-C6-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among NH, and O, and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl;
wherein R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C4-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
wherein R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein R5 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
wherein G and E are independently selected from among C—H or N;
wherein n is 1, 2 or 3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, A, E, G, L1, Q, and n as herein before or below defined,
wherein R3 is a group selected from among




wherein R14 is a group selected from among —H, —C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and —C(O)—CH3;
wherein R15 is a group selected from among —H, —C1-C6-alkyl, —CN, —CF3, and —C(O)—CH3;
wherein R16 is a group selected from among —H, —C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and —C(O)—CH3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, A, E, G, L1, Q, and n as herein before or below defined,
wherein R3 is a group selected from among




wherein R14 denotes —H.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, A, E, G, L1, Q, and n as herein before or below defined,
wherein R3 is a group selected from among




wherein R14 denotes —H;
wherein R15 denotes —C(O)—CH3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, A, E, G, L1, Q, and n as herein before or below defined,
wherein R3 is a group selected from among




wherein R16 denotes —CH3; more preferred wherein R3 denotes




Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R3 is a group selected from among —CH2F, —CHF2, and —CF3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R3 is a group selected from among —CH2F, —CHF2.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R11, R12, R13, R14, R15, R16, E, G, L1, and n as herein before or below defined,
wherein A is a group of the structure




wherein Q denotes CH2, and wherein R9 denotes —H, and wherein R10 is a group selected from among —H, —CH3, and —CF3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R10 denotes —CF3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16, E, G, L1, Q, and n as herein before or below defined,
wherein A is a group of the structure




wherein R12 is a ring selected from among —C6-aryl,
wherein the ring R12 is optionally substituted with one or more groups selected from among —CF3, —O—CF3, —CN, —C1-C6-alkyl, —S—C1-C3-alkyl, and -halogen;
wherein R11 is a group selected from among —H, -halogen, and —C1-C4-alkyl.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16, E, G, L1, Q, and n as herein before or below defined,
wherein A is a group of the structure




wherein R12 is a ring selected from among —C6-aryl,
wherein the ring R12 is optionally substituted with one or more groups selected from among —CF3, —C1-C6-alkyl, —S—C1-C3-alkyl, and -halogen;
wherein R11 is a group selected from among —H, -halogen, and —C1-C4-alkyl.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R11 denotes —H.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R13, R14, R15, R16, E, G, L1, Q, and n as herein before or below defined,
wherein A is a group of the structure




wherein R12 is a ring selected from among —C6-aryl,
wherein the ring R12 is optionally substituted with one or more groups selected from among —CF3, —CH3, and —Cl, more preferred wherein R12 is a group selected from among —CF3, and —Cl; and wherein R11 denotes —H.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, E, G, L1, Q, and n as herein before or below defined,
wherein A is a group of the structure




wherein R7 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
and wherein R8 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R9, R10, R11, R12, R13, R14, R15, R16, E, G, L1, Q, and n as herein before or below defined,
wherein A is a group of the structure




wherein R7 and R8 are selected from among -halogen, more preferred wherein R7 and R8 denote —Cl.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R2 is a group selected from among —H, —CH3, —OCH3, and -cyclopropyl.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R2 denotes —H.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R2 denotes —CH3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R4 is selected from among —H, —CH3, —OCH3, —CF3, and —OH.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R4 denotes —H.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R5 is selected from among —H, —CH3, —C2H5, —O—CH3, —O—C2H5, —F, —CF3, and —OCF3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R5 denotes —H.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R14, R15, R16, A, E, G, Q, and n as herein before or below defined,
wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(CH3)—,
and wherein R13 is —C6-heterocyclyl comprising an O atom,
wherein R13 is optionally substituted by a group selected from among —O—C1-C4-alkyl, and -halogen.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R14, R15, R16, A, E, G, Q, and n as herein before or below defined,
wherein R6 is a group of the structure -L1-R13,
wherein L1 denotes —NH—,
and wherein R13 is —C6-heterocyclyl comprising an O atom,
wherein R13 denotes —OCH3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R14, R15, R16, A, E, G, Q, and n as herein before or below defined,
wherein R6 is a group of the structure -L1-R13,
wherein L1 denotes —NH—,
and wherein R13 is —C6-heterocyclyl comprising an O atom,
wherein R13 denotes —F.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R14, R15, R16, A, E, G, Q, and n as herein before or below defined,
wherein R6 is a group of the structure




Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R14, R15, R16, A, E, G, Q, and n as herein before or below defined,
wherein R6 is a group of the structure




Preferred compounds of formula (I) according to the invention are compounds R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C5-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among O,
and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C1-alkyl)-SO2—C1-C3-alkyl.
Preferred compounds of formula (I) according to the invention are compounds R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C5-alkylene group such that a ring is formed, wherein one carbon atom is replaced by O.
Preferred compounds of formula (I) according to the invention are compounds R2, R3, R4, R5, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n as herein before or below defined,
wherein R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1′, together form a —C5-alkylene group such that a ring is formed, and wherein such ring is optionally substituted with a group selected from among —N(CH3)—SO2—CH3.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, L1, Q, and n as herein before or below defined,
wherein G and E are N.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, L1, Q, and n as herein before or below defined,
wherein G denotes C—H and wherein E denotes N.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, L1, Q, and n as herein before or below defined,
wherein E denotes C—H and wherein G denotes N.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, L1, Q, and n as herein before or below defined,
wherein G and E are C—H.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, and Q as herein before or below defined,
wherein n is 1.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, and Q as herein before or below defined,
wherein n is 2.
Preferred compounds of formula (I) according to the invention are compounds R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, and Q as herein before or below defined,
wherein n is 3.
The present invention also relates to process for preparing a compound of formula (I) as herein before or below defined, wherein R1, R1′, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, R12, R13, R14, R15, R16, A, E, G, L1, Q, and n have the meanings defined hereinbefore.
The present invention also relates to a process for synthesizing the compounds of formula (I) according to preparation method A.
The present invention also relates to the intermediate products for synthesizing the compounds of formula (I).
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.
It has now been found that such compounds as herein before or below defined could be used as a medicament.
It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of inflammatory diseases. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from inflammatory diseases of the respiratory tract. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from chronic obstructive pulmonary disease, asthma, and cystic fibrosis. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of neurologic diseases, preferably for the treatment of pain diseases especially for the treatment of inflammatory and neuropathic pain disease, especially for the treatment of chronic pain. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of immune related diseases, preferably for the treatment of diabetes mellitus. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of cardiovascular diseases, preferably for the treatment of peripheral atherosclerotic disease. It has been found that such compounds as herein before or below defined could be used for making a medicament for the treatment of diabetic nephropathy.
The present invention discloses compounds as herein before or below defined as medicaments. It also discloses compounds as herein before or below defined as medicaments for the treatment of inflammatory diseases. It also discloses compounds as herein before or below defined as medicaments for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from inflammatory diseases of the respiratory tract. It also discloses compounds as herein before or below defined as medicaments for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from chronic obstructive pulmonary disease, asthma, and cystic fibrosis. It also discloses compounds as herein before or below defined as medicaments for the treatment of neurologic diseases, preferably for the treatment of pain diseases especially for the treatment of inflammatory and neuropathic pain disease, especially for the treatment of chronic pain. It also discloses compounds as herein before or below defined as medicaments for the treatment of immune related diseases, preferably for the treatment of diabetes mellitus. It also discloses compounds as herein before or below defined as medicaments for the treatment of cardiovascular diseases, preferably for the treatment of peripheral atherosclerotic disease. It also discloses compounds as herein before or below defined as medicaments for the treatment of diabetic nephropathy.
It has been found that such compounds as herein before or below defined could be used for the treatment of inflammatory diseases. It has been found that such compounds as herein before or below defined could be used for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from inflammatory diseases of the respiratory tract. It has been found that such compounds as herein before or below defined could be used for the treatment of inflammatory diseases, wherein the inflammatory diseases are selected from chronic obstructive pulmonary disease, asthma, and cystic fibrosis. It has been found that such compounds as herein before or below defined could be used for the treatment of neurologic diseases, preferably for the treatment of pain diseases especially for the treatment of inflammatory and neuropathic pain disease, especially for the treatment of chronic pain. It has been found that such compounds as herein before or below defined could be used for the treatment of immune related diseases, preferably for the treatment of diabetes mellitus. It has been found that such compounds as herein before or below defined could be used for the treatment of cardiovascular diseases, preferably for the treatment of peripheral atherosclerotic disease. It has been found that such compounds as herein before or below defined could be used for the treatment of diabetic nephropathy.
Definitions
Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the context. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.
In the groups, radicals, or moieties defined below, the number of carbon atoms is often specified preceding the group, for example, —C1-C6-alkyl means an alkyl group or radical having 1 to 6 carbon atoms. In general, for groups comprising two or more subgroups, the last named subgroup is the radical attachment point, for example, the substituent “aryl-C1-C3-alkyl-” means an aryl group which is bound to a C1-C3-alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
If a compound of the present invention is depicted both in the form of a chemical name and as a formula, in case of any discrepancy the formula shall prevail. An asterisk is may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
For example, the term “3-carboxypropyl-group” represents the following substituent:




wherein the carboxy group is attached to the third carbon atom of the propyl group. The terms “1-methylpropyl-”, “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:




The asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
Many of the following terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
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




The term “substituted” as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
The term “optionally substituted” is meant within the scope of the invention the above-mentioned group, optionally substituted by a lower-molecular group. Examples of lower-molecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Preferably such groups have no negative effect on the pharmacological efficacy of the compounds. For example the groups may comprise:

    
    
        Straight-chain or branched carbon chains, optionally interrupted by heteroatoms, optionally substituted by rings, heteroatoms or other common functional groups.
        Aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms, which may in turn be substituted by functional groups.
        A number of aromatic or non-aromatic ring systems consisting of carbon atoms and optionally heteroatoms which may be linked by one or more carbon chains, optionally interrupted by heteroatoms, optionally substituted by heteroatoms or other common functional groups.
    
    


The term “branched or unbranched, saturated or unsaturated C1-C6-carbon chain” it is meant a chain of carbon atoms, which is constituted by 1 to 6 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.
If the carbon chain is to be substituted by a group which together with one or two carbon atoms of an alkylene chain forms a carbocyclic ring with 3, 5 or 6 carbon atoms, this includes the following examples of the rings:




The term “C1-Cn-alkyl”, wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C1-C5-alkyl embraces the radicals H3C—, H3C—CH2—, H3C—CH2—CH2—, H3C—CH(CH3)—, H3C—CH2—CH2—CH2—, H3C—CH2—CH(CH3)—, H3C—CH(CH3)—CH2—, H3C—C(CH3)2—, H3C—CH2—CH2—CH2—CH2—, H3C—CH2—CH2—CH(CH3)—, H3C—CH2—CH(CH3)—CH2—, H3C—CH(CH3)—CH2—CH2—, H3C—CH2—C(CH3)2—, H3C—C(CH3)2—CH2—, H3C—CH(CH3)—CH(CH3)— and H3C—CH2—CH(CH2CH3)—.
The term “C1-C6-alkyl” (including those which are part of other groups) means branched and unbranched alkyl groups with 1 to 6 carbon atoms and the term “C1-C4-alkyl” means branched and unbranched alkyl groups with 1 to 4 carbon atoms. Alkyl groups with 1 to 4 carbon atoms are preferred. The term “C1-C3-alkyl” means branched and unbranched alkyl groups with 1 to 3 carbon atoms and the term “C2-C4-alkyl” means branched and unbranched alkyl groups with 2 to 4 carbon atoms. 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.
The term “C1-Cn-alkylene” wherein n is an integer 2 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms. For example the term C1-C4-alkylene includes —CH2—, —CH2—CH2—, —CH(CH3)—, —CH2—CH2—CH2—, —C(CH3)2—, —CH(CH2CH3)—, —CH(CH3)—CH2—, —CH2—CH(CH3)—, —CH2—CH2—CH2—CH2—, —CH2—CH2—CH(CH3)—, —CH(CH3)—CH2—CH2—, —CH2—CH(CH3)—CH2—, —CH2—C(CH3)2—, —C(CH3)2—CH2—, —CH(CH3)—CH(CH3)—, —CH2—CH(CH2CH3)—, —CH(CH2CH3)—CH2—, —CH(CH2CH2CH3)—, —CH(CH(CH3))2— and —C(CH3)(CH2CH3)—.
The term “C1-C8-alkylene” (including those which are part of other groups) means branched and unbranched alkylene groups with 1 to 8 carbon atoms. The term “C1-C6-alkylene” means branched and unbranched alkylene groups with 1 to 6 carbon atoms. The term “C2-C8-alkylene” means branched and unbranched alkylene groups with 2 to 8 carbon atoms.
The term “C2-C6-alkylene” means branched and unbranched alkylene groups with 2 to 6 carbon atoms. The term “C4-C5-alkylene” means branched and unbranched alkylene groups with 4 to 5 carbon atoms. The term “C2-C6-alkylene” means branched and unbranched alkylene groups with 2 to 6 carbon atoms. The term “C1-C4-alkylene” means branched and unbranched alkylene groups with 1 to 4 carbon atoms. The term “C1-C2-alkylene” means branched and unbranched alkylene groups with 1 to 2 carbon atoms. The term “C1-alkylene” means an alkylene groups with 1 carbon atom. The term “C5-alkylene” means branched and unbranched alkylene groups with 5 carbon atoms. The term “C0-C4-alkylene” means branched and unbranched alkylene groups with 0 to 4 carbon atoms, thus also a single bond is encompassed. The term “C0-C3-alkylene” means branched and unbranched alkylene groups with 0 to 3 carbon atoms, thus also a single bond is encompassed. The term “C1-C3-alkylene” means 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.
A —C1-alkylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C3-carbocycle. A —C2-alkylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C4-carbocycle. A —C3-alkylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C5-carbocycle. A —C4-alkylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C6-carbocycle. A —C5-alkylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C7-carbocycle. A —C6-alkylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C8-carbocycle.
In the definition of possible substituents, which are linked to such C1-C6-alkylene groups forming a C3-C8-carbocycle, it is to be understood that any of the atoms of the resulting C3-C8-carbocycles could be the linking point for such a substituent.
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:




The term “C2-Cn-alkenyl”, is used for a group as defined in the definition for “C1-Cn-alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
The term “C2-C6-alkenyl” (including those which are part of other groups) means branched and unbranched alkenyl groups with 2 to 6 carbon atoms and the term “C2-C4-alkenyl” means 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.
The term “methenylene” means 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. The asterisks (*) in the structural formula is to be understood as being the linking points to the rest of the molecule, whereas the valency of the rest of the molecule be freed thus a single and a double bond can be formed by replacement of further hydrogens at the binding site if applicable:




The term “C2-Cn-alkenylene” is used for a group as defined in the definition for “C1-Cn-alkylene” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a double bond.
The term “C2-C8-alkenylene” (including those which are part of other groups) means branched and unbranched alkenylene groups with 2 to 8 carbon atoms and the term “C2-C6-alkenylene” means branched and unbranched alkenylene groups with 2 to 6 carbon atoms, provided that they have at least one double bond. The term “C3-C6-alkenylene” means branched and unbranched alkenylene groups with 3 to 6 carbon atoms, provided that they have at least one double bond. The term “C4-alkenylene” means branched and unbranched alkenylene groups with 4 carbon atoms, provided that they have at least one double bond. The term “C1-C2-alkenylene” means alkenylene groups with 1 to 2 carbon atoms, provided that they have at least one double bond, whereas the term “C1-alkenylene” means “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.
A —C3-alkenylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C5-carbocycle. A —C4-alkenylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C6-carbocycle. A —C5-alkenylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C7-carbocycle. A —C6-alkenylene group, which is linked to a structure on two neighbouring ring atoms such that an annellated ring is formed, results to a C8-carbocycle.
In the definition of possible substituents, which are linked to such C3-C6-alkenylene groups forming a C5-C8-carbocycle, it is to be understood that any of the atoms of the resulting C5-C8-carbocycles could be the linking point for such a substituent.
The term “C2-Cn-alkynyl”, is used for a group as defined in the definition for “C1-Cn-alkyl” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond.
The term “C2-C6-alkynyl” (including those which are part of other groups) means branched and unbranched alkynyl groups with 2 to 6 carbon atoms and the term “C2-C4-alkynyl” means 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.
The term “C2-Cn-alkynylene” is used for a group as defined in the definition for “C1-Cn-alkylene” with at least two carbon atoms, if at least two of those carbon atoms of said group are bonded to each other by a triple bond.
The term “C2-C8-alkynylene” (including those which are part of other groups) means branched and unbranched alkynylene groups with 2 to 8 carbon atoms and the term “C2-C6-alkynylene” means branched and unbranched alkynylene groups with 2 to 6 carbon atoms, provided that they have at least one triple bond. 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.
The term “carbocyclyl” as used either alone or in combination with another radical, means a mono- bi- or tricyclic ring structure consisting of 3 to 14 carbon atoms. The term “carbocycle” refers to fully saturated and aromatic ring systems and partially saturated ring systems. The term “carbocycle” encompasses fused, bridged and spirocyclic systems:




The term “ring” means carbocycles, which can be saturated, unsaturated or aromatic and which optionally can comprise one or more hetero atoms selected from N, O or S.
The term “heterocyclyl” means a saturated or unsaturated mono- or polycyclic-ring systems including aromatic ring system containing one or more heteroatoms selected from N, O or S(O)r, wherein r=0, 1 or 2, consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the aromatic ring. The term “heterocycle” is intended to include all the possible isomeric forms.
Thus, the term “heterocyclyl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:













The term “Cm-heterocyclyl” means m-membered, saturated or unsaturated heterocyclic rings, which may contain one, two, or three heteroatoms, selected from among oxygen, sulfur, and nitrogen. Hence such “—Cm-heterocyclyl” results in a ring system, which consists of m atoms within the ring, whereas the atoms of ring system could be carbon atom or heteroatom.
The term “—C3-C8-heterocyclyl” means three-, four-, five-, six-, seven-, or eight-membered, saturated or unsaturated heterocyclic rings which may contain one, two, or three heteroatoms, selected from among oxygen, sulfur, and nitrogen. The ring may be linked to the molecule through a carbon atom or through a nitrogen atom, if there is one. The term “—C5-C8-heterocyclyl” means five-, six-, seven-, or eight-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. The term “—C5-C6-heterocyclyl” means five-, or six-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. The term “—C5-heterocyclyl” means five-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. The term “—C6-heterocyclyl” means six-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 for C5-heterocyclyl include:




Examples for C6-heterocyclyl include:




Examples for C7-heterocyclyl include:




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




The term “C3-Cn-cycloalkyl”, wherein n is an integer from 3 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms. For example the term C3-C7-cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
The term “C3-C8-cycloalkyl” (including those which are part of other groups) means cyclic alkyl groups with 3 to 8 carbon atoms. Likewise, the term “C3-C6-cycloalkyl” means 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.
The term “C3-Cn-cycloalkenyl”, wherein n is an integer from 3 to n, either alone or in combination with another radical, denotes an cyclic, unsaturated but nonaromatic, unbranched hydrocarbon radical with 3 to n C atoms, at least two of which are bonded to each other by a double bond. For example the term C3-C7-cycloalkenyl includes cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl cycloheptadienyl and cycloheptatrienyl.
The term “aryl” (including those which are part of other groups) means aromatic ring systems. The term “C5-C10-aryl” (including those which are part of other groups) means aromatic ring systems with 5 to 10 carbon atoms. Preferred are “C6-C10-aryl” groups, meaning aromatic ring systems 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.
The term “heteroaryl” means a mono- or polycyclic-ring systems containing one or more heteroatoms selected from N, O or S(O)r, wherein r=0, 1 or 2, consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term “heteroaryl” is intended to include all the possible isomeric forms.
Thus, the term “heteroaryl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:







The term “C5-C10-heteroaryl” (including those which are part of other groups) means 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:




Examples for C5-heterocyclic aromatic ring (C5-heteroaryl) include:




Examples for C6-heterocyclic aromatic ring (C6-heteroaryl) include:




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.
The term “spiro-C3-C8-cycloalkyl” (spiro) means 3-8 membered, spirocyclic rings while the ring is linked to the molecule through a carbon atom, and whereas the resulting 3-8 membered carbocycle is formed by alkylene groups with 2 to 7 carbon atoms. The term “spiro-C5-cycloalkyl” (spiro) means 5 membered, spirocyclic rings while the ring is linked to the molecule through a carbon atom, whereas the resulting 5 membered carbocycle is formed by an alkylene group with 4 carbon atoms. The term “spiro-C3-C8-cycloalkenyl” (spiro) means 3-8 membered, spirocyclic rings while the ring is linked to the molecule through a carbon atom, whereas the resulting 3-8 membered carbocycle is formed by alkenylene groups with 2 to 7 carbon atoms. The term “spiro-C5-cycloalkenyl” (spiro) means 5 membered, spirocyclic rings while the ring is linked to the molecule through a carbon atom, whereas the resulting 5 membered carbocycle is formed by alkenylene groups with 4 carbon atoms.
The term “spiro-C3-C8-heterocyclyl” (spiro) means 3-8 membered, saturated or unsaturated, 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. The term “spiro-C5-heterocyclyl” (spiro) means 5 membered, saturated or unsaturated, 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 used herein, “pharmaceutically acceptable salts” refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. For example, such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2′-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassium hydroxide, 1-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2′,2′′-nitrilotris(ethanol)), tromethamine, zinc hydroxide, acetic acid, 2,2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)-camphoric acid, (+)-camphor-10-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, ethylenediaminetetraacetic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, D-glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanoic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (−)-L-malic acid, malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (−)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S. M. et al., J. Pharm. Sci., (1977), 66, 1-19).
The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
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 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.
Unless specifically indicated, throughout the specification and the appended claims, a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastereomers, E/Z isomers etc. . . . ) and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound.
Hence 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, R7, R8, R9, R10, R11, L1, E, G, Z, Q, X, A, m and n in each case are independently selected of one another.
Therapeutic Applications
(i) CCR2 Binding Assay:
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 Jod125 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 μg/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 referenced examples have been found to have an activity in this assay (CCR2) of 10 μM or less:














Example
hKi [nM](CCR2)



















1
3



2
2



3
4



4
2



5
14



6
20



7
8



8
11



9
38



10
15



11
0.8



12
0.6



13
5



14
3



15
3



16
1



17
2



18
5



19
3



20
0.6



21
2



22
0.7



23
1



24
1



25
1



26
5



27
15



28
11



29
2



30
3



31
15



32
5



33
7



34
4



35
2



36
2



37
8



38
37



39
4



40
7



41
2



42
17



43
19



44
4



45
17



46
34










(ii) CCR5 Binding Assay:

The above exemplary substances have been tested for binding to CCR5 using a binding assay as outlined herein below:
Cell Culture:
CHO, (Gα16) human CCR5 cells were cultured under standardized conditions at 37° C. and 5% CO2 in a humidified incubator. CHO (Gα16) human CCR5 cells were cultivated in Ham's F12 (Invitrogen; #31765068) supplemented with 10 μg/ml Puromycin (Invitrogen; #A11139-03), 200 μg/ml Zeocin (Invitrogen; #45-0003) and 10% FCS (Gibco; #10500-064).
Membrane Preparation:
Membranes were prepared from CHO (Gα16) human CCR5 cells. Cells were cultured on 245 cm×245 cm plates (Nunc; #166508) 2-3 days before membrane preparation (usually 80-100 plates to obtain 80 mg protein).
Cells were scraped off the plates with a big scraper and washed with 2×5 ml ice cold Phosphate Buffer Saline (PBS; Invitrogen; #14040-174). Cell suspension was collected in a glass bottle (on ice). Cell suspension was harvested at 1400 rpm and 4° C. for 10 min and washed in PBS. Cell pellet was resuspended in 40 ml PBS with protease inhibitor mix ‘complete’ (Roche; #11873580001; 1 tablet/50 ml).
For gentle cell disruption the membrane preparation was performed by using a homogenizer (potter). Cells were homogenized for 5-10 min.
Membranes were centrifuged at 1000 rpm and 4° C. for 5 min Supernatant (=membrane) was harvested in a new falcon tube and remaining cell pellet homogenized again for 5-10 min with PBS with protease inhibitor mix and centrifuged. Collected supernatant was centrifuged at 40000 rpm and 4° C. for 30 min to sediment the cell membranes.
The membranes were resuspended in 25 mM HEPES, 25 mM MgCl2, 1 mM CaCl2, 10% Glycerine for storage in aliquots at −80° C. Membranes were diluted to a concentration of 5 mg/ml (Bradford Assay).
Receptor Membrane Binding Assay:
[125I]RANTES, Stock: 1825 Ci/mmol, 25 μCi (Bio Trend #A3-AI-676) was solved in 1000 μl assay buffer (100 mM NaCl; 10 mM MgCl2; 50 mM Tris-HCl; 1 mM EDTA; 0.1% BSA, pH 7.6), stored at −20° C.
CHO (Gα16) human CCR5 membrane were solved on ice and adjusted with assay buffer to a concentration of 2.5 μg/15 μl.
Amersham Biosciences PVT-WGA Beads (GE Healthcare; #RPNQ0001) were adjusted with assay buffer to a concentration of 8 mg/ml. For preparation of the membrane-bead-suspension, membranes and beads were incubated for 30 min at RT under rotation 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. 7 μl compound dilution, 45 μl membrane-bead-suspension and 10 μl [125I]RANTES (ca. 20000 cpm/10 μl) were incubated at RT. Bound radioactivity was determined by scintillation counter after 6 h. Determination of affinity of test compounds (dissociation constant Ki) 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).
The activity in this assay (CCR5) are shown in the following tables for all referenced examples:














Example
hKi [nM] (CCR5)



















1
265



2
150



3
700



4
310



5
4580



6
17300



7
380



8
5870



9
3400



10
850



11
430



12
46



13
1300



14
2090



15
270



16
210



17
180



18
460



19
350



20
31



21
75



24
50



26
130



27
750



28
1350



29
53



34
190



35
160



37
1370



40
230



45
3450



46
3680










CCR2/CCR5-Selectivity for Chemokine Receptor Anatgonists:

CCR2/CCR5-selectivity can be shown for Chemokine receptors antagonists by calculating the CCR5/CCR2 activity ratio of these both assays (hKi values). The compounds claimed by the invention feature a CCR5/CCR2 activity ratio of above 10. Preferred compounds show a CCR5/CCR2 activity ratio of above 20. Further preferred compounds show a CCR5/CCR2 activity ratio of above 30. Further preferred compounds show a CCR5/CCR2 activity ratio of above 40. Further preferred compounds show a CCR5/CCR2 activity ratio of above 50. Further preferred compounds show a CCR5/CCR2 activity ratio of above 70. Further preferred compounds show a CCR5/CCR2 activity ratio of above 100. Further preferred compounds show a CCR5/CCR2 activity ratio of above 120. Further preferred compounds show a CCR5/CCR2 activity ratio of above 140. Further preferred compounds show a CCR5/CCR2 activity ratio of above 30. Further preferred compounds show a CCR5/CCR2 activity ratio of above 160. Further preferred compounds show a CCR5/CCR2 activity ratio of above 180. Further preferred compounds show a CCR5/CCR2 activity ratio of above 200. Further preferred compounds show a CCR5/CCR2 activity ratio of above 250. Further preferred compounds show a CCR5/CCR2 activity ratio of above 300. Further preferred compounds show a CCR5/CCR2 activity ratio of above 400.
Another embodiment of the present invention is characterized by an enhanced permeability. Experimental assays can predict the permeability. These assays can be cell based as in Caco-2 cell culture assays. (C. G. Wermuth: The practice of Medicinal Chemistry, Elsevier Academic Press, 2nd edition 2003, p 344).
Therapeutic Uses
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 including 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, H is 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: Inflammatory pain, chronic pain, 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 β2-adrenoceptor-agonists (short and lon-acting betamimetics), anti-cholinergics (short and lon-acting), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4-inhibitors, PDE7-inhibitors, LTD4 antagonists, EGFR— inhibitors, Dopamine agonists, statins, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4-receptor (BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, Histamine H4 receptor antagonists, dual Histamine H1/H3-receptor antagonists, PI3-kinase inhibitors, inhibitors of non-receptor tyrosine kinases as for example LYN, LCK, SYK (spleen tyrosine kinase-inhibitors), ZAP-70, FYN, BTK or ITK, inhibitors of MAP kinases as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, inhibitors of the NF-kappaB signalling pathway as for example IKK2 kinase inhibitors, iNOS inhibitors (inducible nitric oxide synthase-inhibitors), MRP4 inhibitors, leukotriene antagonists, leukotriene biosynthese inhibitors as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4 Hydrolase inhibitors or FLAP inhibitors, non-steroidal antiinfiammatory drugs (NSAIDs) including COX-2 inhibitors, CRTH2 antagonists, DP1-receptor modulators, Thromboxane receptor antagonists, CCR1 antagonists, CCR4 antagonists, CCR5 antagonists, CCR6 antagonists, CCR7 antagonists, CCR8 antagonists, CCR9 antagonists, CCR10 antagonists, CCR11 antagonists, CXCR1 antagonists, CXCR2 antagonists, CXCR3 antagonists, CXCR4 antagonists, CXCR5 antagonists, CXCR6 antagonists, CX3CR1 antagonists, Neurokinin (NK1, NK2) antagonists, Sphingosine 1-Phosphate receptor modulators, Sphingosine 1 phosphate lyase inhibitors, Adenosine receptor modulators as for example A2a-agonists, modulators of purinergic rezeptors as for example P2X7 inhibitors, Histone Deacetylase (HDAC) activators, Bradykinin (BK1, BK2) antagonists, TACE inhibitors, PPAR gamma modulators, Rho-kinase inhibitors, interleukin 1-beta converting enzyme (ICE) inhibitors, Toll-Like receptor (TLR) modulators, HMG-CoA reductase inhibitors, VLA-4 antagonists, ICAM-1 inhibitors, SHIP agonists, GABAa receptor antagonist, ENaC-inhibitors, Melanocortin receptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists, TNFalpha antagonists, anti-TNF antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies, mucoregulators, immunotherapeutic agents, compounds agianst swelling of the airways, compounds against cough, antiviral drugs, opiate receptor agonists, cannabionoid agonists, sodium channel blockers, N-type calcium channel blockers, serotonergic and noradrenergic modulators, proton pump inhibitors, local anesthetics, VR1 agonists and antagonists, Nicotinic acetylcholine receptor agonists, P2X3 receptor antagonists, NGF agonists and antagonists, NMDA antagonist, potassium channel modulators, GABA modulators, serotonergic and noradrenergic modulators, anti-migraine drugs. The invention also encompasses combinations of three active substances, each selected from one of the above-mentioned categories of compounds. Said list is not considered to have a limiting character.
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.
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-5-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.
The PDE4-inhibitor used are preferably compounds 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.
EGFR-inhibitors which may be 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.
Preferable the 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-[(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.
EGFR-inhibitors are preferably 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.
MRP4-inhibitors are preferably selected from among N-acetyl-dinitrophenyl-cysteine, dehydroepiandrosterone 3-sulphate, dilazep, dinitrophenyl-5-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.
Particularly preferred MRP4-inhibitors are 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 CCR2 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), 1400W, (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.
Compounds which may be used as SYK-inhibitors are preferably compounds selected from among: R343 or R788.
Examples of preferred MAP kinase inhibitors, as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, which may be mentioned include SCIO-323, SX-011, SD-282, SD-169, NPC-037282, SX-004, VX-702, GSK-681323, GSK-856553, ARRy-614, ARRY-797, ARRY-438162, ARRY-p38-002, ARRY-371797, AS-602801, AS-601245, AS-602183, CEP-1347, KC706, TA-5493, RO-6226, Ro-1487, SC-409, CBS-3595, VGX-1027, PH-797804, BMS-582949, TA-5493 and BIRB-796 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred inhibitors of the NF-κB signalling pathway including IKK2 kinase inhibitors which may be mentioned include: MD-1041, MLN-041 and AVE-0547 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred Leukotriene biosynthesis inhibitors, as for example 5-Lipoxygenase (5-LO) inhibitors, cPLA2 inhibitors, Leukotriene A4 hydrolase inhibitors oder FLAP inhibitors, which may be mentioned include zileuton, tipelukast, licofelone, darapladib, TA-270, IDEA-033, IDEA-070, NIK-639, ABT-761, fenleuton, tepoxalin, AM-103, AM-803, Abbott-79175, Abbott-85761, PLT-3514, CMI-903, PEP-03, CMI-977, MLN-977, CMI-947, LDP-977, efipladib, PLA-695, veliflapon, MK-591, MK-886 and BAYx1005 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred non-steroidal anti-inflammatory agents (NSAIDs) which may be mentioned include COX-2 inhibitors: propionic acid derivatives (alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenhufen, fenoprofen, flubiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid, and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin, and zomepirac), fenamic acid derivatives (meclofenamic acid, mefenamic acid, and tolfenamic acid), biphenyl-carboxylic acid derivatives, oxicams (isoxicam, meloxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetyl salicylic acid, sulfasalazine) and the pyrazolones (apazone, bezpiperylon, feprazone, mofebutazone, oxyphenbutazone, phenylbutazone), and the coxibs (celecoxib, valecoxib, rofecoxib and etoricoxib) optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred CCR1 antagonists which may be mentioned include AZD-4818, CCX-354, MLN-3701, MLN-3897, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred CCR5 antagonists which may be mentioned include maraviroc, INCB-15050. CCR5 mAb004, GSK-706769, PRO-140, SCH-532706, vicriviroc and nifeviroc optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred CXCR1 or CXCR2 antagonists which may be mentioned include SCH-527123 and SB-656933 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred Neurokinin (NK1 or NK2) antagonists which may be mentioned include Saredutant, Nepadutant, PRX-96026 and Figopitant optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred purinergic receptor modulators, including P2X7 inhibitors, which may be mentioned include AZD-9056 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred PPAR gamma modulators which may be mentioned include Rosiglitazone, Ciglitazone, Pioglitazone and SMP-028 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred Interleukin 1-beta converting enzyme (ICE) inhibitors which may be mentioned include Pralnacasan, VRT-18858, RU-36384, VX-765 and VRT-43198 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred Toll-like receptor (TLR) modulators which may be mentioned include Resiquimod, PF-3512676, AVE-0675, Heplisav, IMO-2055, CpG-28, TAK-242, SAR-21609, RC-52743198 and 852A optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred VLA4 antagonists which may be mentioned include Natalizumab, Valategrast, TBC-4746, CDP-323 and TL-1102 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred ICAM-1 inhibitors which may be mentioned include BIRT-2584 optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred anti-TNF antibodies which may be mentioned include Infliximab, Adalimumab, Golimumab. CytoFab and Etanercept.
Examples of preferred mucoregulators which may be mentioned include MSI-2216, Erdosteine, Fluorovent, Talniflumate, INO-4995, BIO-11006, VR-496 and fudosteine optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Examples of preferred Antiviral drugs which may be mentioned include acyclovir, tenovir, pleconaril, peramivir, pocosanol.
Examples of preferred Antibiotic drugs like gentamicin, streptomycin, geldanamycin, doripenem, cephalexin, cefaclor, ceftazichine, cefepime, erythromycin, vancomycin, aztreonam, amoxicillin, bacitracin, enoxacin, mafenide, doxycycline, chloramphenicol.
Examples of preferred opiate receptor agonists are selected from among morphine, propoxyphene (Darvon), tramadol, buprenorphin.
Examples of preferred anti-TNF antibodies or TNF-receptor antagonists such as but not limited to Etanercept, Infliximab, Adalimumab (D2E7), CDP 571, and Ro 45-2081 (Lenercept), or biologic agents directed against targets such as but not limited to CD-4, CTLA-4, LFA-1, IL-6, ICAM-1, C5 and Natalizumab.
Examples of preferred IL-1 receptor antagonists such as but not limited to Kineret; Sodium channel blockers: carbamazepine, mexiletine, lamotrigine, tectin, lacosamide
Examples of preferred N-type calcium channel blockers are selected from among Ziconotide.
Examples of preferred Serotonergic and noradrenergic modulators such as but not limited to paroxetine, duloxetine, clonidine, amitriptyline, citalopram;
Examples of preferred Histamine H1 receptor antagonists such as but not limited to bromophtniramint, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdiJazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, deslo-ratadine, fexofenadine and levocetirizine.
Examples of preferred Histamine H2 receptor antagonists such as but not limited to cimetidine, famotidine and ranitidine.
Examples of preferred proton pump inhibitors such as but not limited to omeprazole, pantoprazole and esomeprazole.
Examples of preferred Leukotriene antagonists and 5-lipoxygenase inhibitors such as but not limited to zafirlukast, montelukast, pranlukast and zileuton.
Examples of preferred local anesthetics such as but not limited to ambroxol, lidocaine.
Examples of preferred potassium channel modulators such as but not limited to retigabine.
Examples of preferred GABA modulators such as but not limited to lacosamide, pregabalin, gabapentin.
Examples of preferred anti-migraine drugs such as but not limited to sumatriptan, zolmitriptan, naratriptan, eletriptan, telcegepant.
Examples of preferred NGF antibodies such as but not limited to RI-724.
Combination therapy is also possible with new principles for the treatment of pain e.g. P2X3 antagonists, VR1 antagonists, NK1 and NK2 antagonists, NMDA antagonists, mGluR antagonists and the like.
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 above-mentioned 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 colourings 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 the active substances of formula (I) 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/MS coupled high performance liquid chromatography-mass spectrometry
    min minutes
    MS mass spectrometry
    NMP N-Methyl-2-pyrrolidinone
    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
    THF tetrahydrofurane
    TLC thin-layer chromatography
    UV ultraviolet absorption

Analytical Methods

HPLC methods

Method:



Y3-1













Column:
Waters; XBridge C18, 4.6 × 30 mm, 3.5 μm, at 60° C.


Mobile:
A = water + 0.1% NH4OH; B = MeOH














Gradient:
A %
B %
Time [min]
Flow rate [ml/min]






95
5
0.00
4



95
5
0.15
4



0
100
1.70
4



0
100
2.25
4









2Ha













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 μL/min












Gradient:
% B
Minutes






10
0.00



90
2.70



90
3.00



10
3.30









Equipment:

    
    
        Instrument: Agilent Technology; HP 1100 Series, DAD
        Detection: UV 190-400 nm
        Detection: Agilent Technology; HP 1100 MSD
        Ion source: ESI+

Method:

    
    


Z1-2













Column:
Waters; XBridge C18, 3 × 30 mm, 2.5 μm, at 60° C.


Mobile:
A = water + 0.1% TFA; B = MeOH














Gradient:
A %
B %
Time [min]
Flow rate [ml/min]






95
5
0.00
2.2



95
5
0.05
2.2



0
100
1.40
2.2



0 
100
1.80
2.2









Z1-5













Column:
Waters; XBridge C18, 3 × 30 mm, 2.5 μm, at 60° C.


Mobile:
A = water + 0.1% TFA; B = MeOH














Gradient:
A %
B %
Time [min]
Flow rate [ml/min]






95
5
0.00
1.9



95
5
0.20
1.9



0
100
1.55
1.9



0
100
1.60
2.4



0
100
1.80
2.4









Z2-2













Column:
Waters; Sunfire C18, 3 × 30 mm, 2.5 μm, at 60° C.


Mobile:
A = water + 0.1% TFA; B = MeOH














Gradient:
A %
B %
Time [min]
Flow rate [ml/min]






95
5
0.00
2.2



95
5
0.05
2.2



0
100
1.40
2.2



0
100
1.80
2.2









Z3-1













Column:
Waters; XBridge C18, 3 × 30 mm, 2.5 μm, at 60° C.


Mobile:
A = water + 0.1% NH4OH; B = MeOH














Gradient:
A %
B %
Time [min]
Flow rate [ml/min]






95
5
0.00
2.2



95
5
0.05
2.2



0
100
1.40
2.2



0
100
1.80
2.2









Equipment:

    
    
        Instrument: Agilent Technology; 1200 Series, DAD
        Detection: UV 210-400 nm
        Detection: Agilent Technology; 1200 MSD
        Ion source: ESI+

Method:

    
    


1E (Hydro)

    
    
        Column: Synergy Hydro RP80A, 4 μm, 4.6×100 mm
        Mobile phase: A=(10 mM aqueous solution of NH4COOH)+10% ACN;
        
            B=ACN+10% (10 mM 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:

    
    


2FF

    
    
        Column: Symmetry Shield RPB, 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

Equipment:

        Instrument: HPLC/MS ThermoFinnigan HPLC Surveyor DAD, LCQFLEET Ion Trap
        Detection: UV 254 nm
        Detection: Finnigan LCQDuo Ion Trap
        Ion source: ESI

Method:

    
    


2Ja (Isocratic)

    
    
        Column: DAICEL Chiralpack AD-H 5 μm, 4.6×250 mm
        Mobile phase: A=Hexane; B=Isopropanol
        
            A/B=80/20%
        
        
        Flow rate: 1 ml/min

Equipment

        Instrument: LC Agilent Technologies. HPLC 1100 Serie, DAD Version A.
        Detection: UV 220-300 nm
    
    


SYNTHESIS OF INTERMEDIATES
Intermediate 1a




Diethylmethyl malonate (4 g, 27.4 mmol) and 10 ml methanol were added to sodium methoxide (30% in methanol, 26 ml, 140 mmol) and stirred for 15 min at 0° C. A solution of commercially available 2-fluoro-acetamidine (2.1 g, 27.4 mmol) in 10 ml MeOH was added dropwise to the reaction mixture. The reaction mixture was stirred for 1 h at 0° C. Then, the reaction mixture was allowed to warm to room temperature and stirred for 2 h. The mixture was acidified by addition of 4 N HCl and then cooled in an ice bath. The formed precipitate was filtered and dried to give the desired product.
Intermediate 1b




was synthesized in analogy to intermediate 1a starting from commercially available dimethyl malonate.
Intermediate 1c




was synthesized in analogy to intermediate 1a starting from commercially available 2,2-difluoro-acetamidine.
Intermediate 1d




Commercially available tetrahydropyran-4-carboxamidine (3.5 g, 17 mmol), diethyl-oxalpropionate (3.2 ml, 17 mmol) and potassium carbonate (5.88 g, 42.5 mmol) were suspended under nitrogen atmosphere in 60 ml ethanol and stirred under reflux for 4 h. The reaction mixture was cooled to room temperature, filtered and concentrated under vacuum. The crude product was loaded on a SCX cartridge and eluted with a 7M solution of ammonia in methanol. The crude product was purified by flash chromatography (eluent: dichlorometane/methanol=90/10) to give the desired product.
Intermediate 1e




was synthesized in analogy to intermediate 1d starting from commercially available 5-methyl-isoxazole-3-carboxamidine.
Intermediate 1f




was synthesized in analogy to intermediate 1d starting from commercially available piperidine-4-carboxamidine.
Intermediate 1g




Intermediate 1f (1.5 g, 5.65 mmol) was dissolved in 4 ml ethanol, then acetic anhydride (1.15 g, 11.3 mmol) and N,N-diisopropylethylamine (1 ml, 0.01 mol) were added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 30 min, then it was concentrated under vacuum. 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 (eluent: dichloromethane/methanol=90/10) to give the desired product.
Intermediate 2a




Intermediate 1a (3.5 g, 22.1 mmol) was added to phosphoryl chloride (10 ml) and the reaction mixture was stirred overnight at 60° C. The reaction mixture was poured onto ice water. Then, the mixture was extracted with dichloromethane (2×). The combined organic layers were concentrated under vacuum to give the desired product.
Intermediate 2b




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




DMF (100 μl) was added to a mixture of intermediate 1c (0.8 g, 4.5 mmol) and thionylchloride (5 ml, 69 mmol) and the reaction mixture was refluxed over night. The reaction mixture was poured onto ice water. Then, the mixture was extracted with dichloromethane (2×). The combined organic layers were washed with 2 N NaOH and brine, dried and concentrated under vacuum to give the desired product.
Intermediate 2d




Intermediate 1d (1.1 g, 4.13 mmol) and phosphorus oxychloride (6 ml) was refluxed at 130° C. for 2 h. The reaction mixture was concentrated under vacuum, the residue was diluted with toluene and the organic phase was concentrated under vacuum. The crude product was diluted with ethyl acetate and the organic phase was washed with of a cooled saturated aqueous sodium carbonate solution. The organic phase was concentrated under vacuum to yield the desired product.
Intermediate 2e




was synthesized in analogy to intermediate 2d starting from Intermediate 1e.
Intermediate 2f




was synthesized in analogy to intermediate 2d starting from Intermediate 1g.
Intermediate 3a




N,N-diisopropylethylamine (0.7 ml, 3.8 mmol) was added to a mixture of commercially available 7-trifluoromethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (402 mg, 1.7 mmol) and intermediate 2a (300 mg, 1.5 mmol) in 3 ml NMP. The reaction mixture was heated for 1 h at 100° C. Then, ethyl acetate was added and the mixture was washed with water (2×). The organic layer was dried over sodium sulfate and concentrated in vacuum to give the desired product.
The following intermediates were synthesized in analogy to intermediate 3a starting from the corresponding di-chloro-pyrimidine intermediates:















di-






Cl-pyrimidine
Source/
Cl-pyrimidine



Starting amine
intermediate
intermediate
intermediate
STRUCTURE















WO2011073154
3b






 










2c
3c






 










2b
3d






 










2b
3e













Intermediate 3f




Intermediate 2d (350 mg, 1.23 mmol) and N,N-diisopropylethylamine (0.63 ml, 3.7 mmol) were dissolved in 10 ml dry 1,4-dioxane; commercially available 7-trifluoromethyl-1,2,3,4-tetrahydro-isoquinoline hydrochloride (290 mg, 1.2 mmol) was added and the reaction mixture was refluxed for 18 h. The reaction mixture was cooled to room temperature, water was added and the mixture was extracted with dichloromethane. The organic phase was washed with a saturated aqueous sodium bicarbonate solution and concentrated under vacuum to give the desired product.
The following intermediates were synthesized in analogy to intermediate 3f starting from the corresponding chloro-pyrimidine intermediates:
















Source/
Ester





inter-
inter-




Cl-pyrimidine
medi-
medi-



Starting amine
intermediate
ate
ate
STRUCTURE















2d
3fa






 










2d
3g






 










2e
3h






 










2e
3ha






 










2e
3i













Intermediate 3j




Intermediate 2a (500 mg, 2.6 mmol) and commercially available 3,4-dichloro-aniline (415 mg, 2.6 mmol) were heated in 2.5 ml p-toluenesulfonic acid (33%) in acetic acid for 45 min at 130° C. in the microwave. Then, water was added and the mixture was extracted with dichloromethaned (2×). The organic layer was dried over sodium sulfate and concentrated under vacuum to give the desired product.
Intermediate 3k




Intermediate 2f (480 mg, 1.5 mmol) was diluted in 5 ml tetrahydrofurane and 5 ml water, lithium hydroxide (93 mg, 2.2 mmol) was added and the reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum. The residue was dissolved in 10 ml of a 4 M solution of hydrochloric acid in 1,4-dioxane, the solution was stirred at room temperature for 10 minutes and then concentrated under vacuum. The residue was dissolved in dichloromethane, the formed precipitate was filtered off and the filtrate was concentrated under vacuum giving the desired product.
Intermediate 4a




A mixture of intermediate 3a (690 mg, 1.9 mmol), palladium acetate (43 mg, 191 μmol), commercially available 1,1′-bis(diphenylphosphino)-ferrocene (106 mg, 191 μmol), sodium acetate (472 mg, 5.7 mmol) in 10 ml methanol and 10 ml DMF was stirred under a carbon monoxide atmosphere (5 bar) over night at 80° C. The mixture was filtered and concentrated under vacuum. The residue was purified by reverse phase HPLC to give the corresponding ester.
A solution of lithium hydroxide (103 mg, 4.3 mmol) in 10 ml water was added to a solution of the ester (550 mg, 1.4 mmol) in 10 ml THF. The reaction mixture was stirred for 1 h at room temperature. Then, ethyl acetate and water were added and the layers were separated. The aqueous layer was acidified with 1 N hydrochloric acid. The desired product precipitated.
The following intermediates were synthesized in analogy to intermediate 4a starting from the corresponding chloro-pyrimidine:













Cl-





pyrim-





idine

Acid



inter-

inter-



medi-

medi-



ate
STRUCTURE
ate
STRUCTURE







3b




4b






 


3c




4c






 


3d




4d






 


3e




4e






 


3j




4f













Intermediate 4g




Intermediate 3f (640 mg, 1.1 mmol) was dissolved in 15 ml tetrahydrofurane and a solution of LiOH (188 mg, 4.5 mmol) in 15 ml water was added. The reaction mixture was stirred at 50° C. for 2 h and then concentrated under vacuum. Water was added and the mixture was acidified with 5 ml of a 4M solution of hydrochloric acid in water. The aqueous phase was extracted with dichloromethane (2×20 ml). The organic phase was dried over sodium sulfate and concentrated under vacuum to give the desired product.
The following intermediates were synthesized in analogy to intermediate 4g.













Ester

Acid



inter-

inter-



medi-

medi-



ate
STRUCTURE
ate
STRUCTURE







3fa




4ga






 


3g




4h






 


3h




4i






 


3ha




4ia






 


3i




4j













Intermediate 4k




Intermediate 3k (200 mg, 0.67 mmol), a 4M solution of hydrochloric acid in 1,4-dioxane (0.35 ml) and commercially available 3,4-dichloro-aniline (141.4 mg, 0.87 mmol) were mixed in a microwave vial and reacted in the following conditions: Power 150, Ramp 2 min, Hold 30 min, Temperature 110° C., Pressure 250 psi, Stirring. The reaction mixture was diluted with dichloromethane, washed with a saturated aqueous sodium bicarbonate solution, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase preparative HPLC to give the desired compound.
Intermediate 6a




3-Fluoro-tetrahydro-pyran-4-one (4 g, WO2003093231) was suspended in 40 ml of 1,2-dichloroethane, 1-(tert-butoxycarbonyl)-piperidin-4-one (2.8 g, 23.7 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. Sodium triacetoxyborohydride (7.57 g, 35.56 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 sodium bicarbonate solution. The organic phase was dried over sodium sulfate and concentrated under vacuum. The crude product was purified by flash chromatography (eluent: dichloromethane/methanol=95/5) to obtain 4 g (13.2 mmol) of the desired compound.
Intermediate 6b




Preparative Chiral HPLC Separation of Intermediate 6a gave the isomerically pure cis-intermediate (first eluted cis-enantiomer, relative stereochemistry assigned by NMR).
Chiral HPLC (method 2Ja isocratic): Rt=5.197 min
Intermediate 6c




Further elution of the column gave the second eluted cis-enantiomer (relative stereochemistry assigned by NMR).
Chiral HPLC (method 2Ja isocratic): Rt=6.012 min
Intermediate 7a




Intermediate 6a (1.5 g, 5.0 mmol) was suspended in 50 ml of 1,4-dioxane and a 4M solution of hydrochloric acid (6.2 ml, 24.8 mmol) in 1,4-dioxane was added dropwise. The reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under vacuum to give the desired compound.
The following intermediates were synthesized in analogy to intermediate 7a.













Boc-

Amino-



intermediate
STRUCTURE
intermediate
STRUCTURE







6b




7b






 


6c




7c













SYNTHESIS OF EXAMPLES
The examples of this invention are synthesized according to the following general synthetic procedure:
Synthetic Procedure A




Examples: 1-46
Example 1




Intermediate 4b (73 mg, 0.18 mmol), TBTU (43 mg, 0.13 mmol) and N,N-diisopropyl-ethylamine (69.4 mg, 0.22 mmol) in 2 ml DMF were stirred at room temperature for 5 min (3R,4R)-3-methoxy-tetrahydro-pyran-4-yl)-piperidin-4-yl-amine (WO2011073154) (67.7 mg, 0.27 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 separated, dried over sodium sulfate and concentrated under vacuum. The crude product was purified by reverse phase HPLC to give the desired product.
HPLC (2Ha): Rt. (min)=2.098
[M+H]+=602
The following examples were synthesized in analogy to the preparation of Example 1.


















Inter-


HPLC



Ex

medi-


Rt.



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





















 2




4b




602
2.102
2Ha


 


 3




4ga




618
9.82
1E(Hydro)


 


 4




4ga




618
9.8
1E(Hydro)


 


 5




4ga
7b
606
9.68
1E(Hydro)


 


 6




4ia
7c
603
9.77
1E(Hydro)


 


 7




4ia




615
9.85
1E(Hydro)


 


 8




4ga
7c
606
9.7
1E(Hydro)


 


 9




4ia
7b
603
9.73
1E(Hydro)


 


10




4ia




615
9.83
1E(Hydro)


 


11




4g




618
7.38
2FF


 


12




4g




618
9.9
1E(Hydro)


 


13




4g
7b
606
9.53
1E(Hydro)


 


14




4g
7c
606
9.4
1E(Hydro)


 


15




4h
7c
664
7.23
2FF


 


16




4h
7b
664
7.25
2FF


 


17




4a




566
1.444
Y3-1


 


18




4a




566
1.44
Z3-1


 


19




4f
7a
514
1.181
Z3-1


 


20




4f




526
1.21
Z3-1


 


21




4f




526
1.209
Z1-2


 


22




4j




673
8.02
2FF


 


23




4j
7b
661
8
2FF


 


24




4j
7c
661
8.03
2FF


 


25




4j




673
8.02
2FF


 


26




4i




615
7.89
2FF


 


27




4i
7b
603
7.86
2FF


 


28




4i
7c
603
7.85
2FF


 


29




4i




615
7.88
2FF


 


30




4d




556
1.129
Z3-1


 


31




4d
7a
544
1.122
Z3-1


 


32




4d




556
1.126
Z3-1


 


33




4b




572
1.231
Z1-2


 


34




4c




584
1.142
Z1-2


 


35




4c




584
1.14
Z1-2


 


36




4f




587
1.195
Z2-2


 


37




4f
7c
514
1.05
Z1-2


 


38




4f




482
1.191
Z2-2


 


39




4e




588
1.185
Z1-5


 


40




4e
7a
576
1.177
Z1-5


 


41




4e




588
1.185
Z1-5


 


42




4k
7c
607
7.22
2FF


 


43




4k
7b
607
7.99
1E(Hydro)


 


44




4k




619
7.19
2FF


 


45*




4a
7a
554
1.239
Z3-1


 


46*




4a
7a
554
1.282
Z3-1





*Amide coupling of intermediate 4a and intermediate 7a (in analogy to protocol above) was followed by purification by reverse phase HPLC. The first fraction eluted was example 45 (cis-isomer, relative stereochemistry assigned by NMR). Further elution gave example 46 (trans-isomer, relative stereochemistry assigned by NMR).

## Claims

1. A compound according to formula (I),



wherein R3 is a group selected from among




wherein R14 is a group selected from among —H, —C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and —C(O)—CH3;
wherein R15 is a group selected from among —H, —C1-C6-alkyl, —CN, —CF3, and —C(O)—CH3; and
wherein R16 is a group selected from among —H, —C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and —C(O)—CH3;
or wherein R3 denotes a group selected from among —CH2F, —CHF2, and —CF3;
wherein A is a group selected from among




wherein R7 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R8 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3,
wherein Q is selected from among CH2 and O, and wherein R9 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3, and wherein R10 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
R6 is a group of the structure -L1—R13,
wherein L1 is selected from among —NH—, and —N(C1-C4-alkyl)- ,
and wherein R13 is selected from among —C5-C6-heterocyclyl comprising 1 or 2 hetero atoms selected from among N, and O,
and wherein R13 is optionally substituted by one or more groups selected from among among —CF3, —OCF3, —CN, —OH, —O—C1-C4-alkyl, —C1-C6-alkyl, and -halogen;
or R6 is a group of the structure —N(R1,R1′),
wherein R1 and R1,, together form a —C2-C6-alkylene group such that a ring is formed, wherein one carbon atom may be replaced by a group selected from among NH, and O,
and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3, —CF3, —OCF3, —CN, -halogen, —C1-C4-alkyl, ═O, and —N(C0-C3-alkyl)-SO2—C1-C3-alkyl;
R2 is selected from among —H, -halogen, —CN, —O—C1-C4-alkyl, —C1-C1-alkyl, —CH═CH2, —C≡CH, -cyclopropyl, —CF3, —OCF3, —OCF2H, and —OCFH2;
R4 is selected from among —H, —C1-C4-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
R5 is selected from among —H, —C1-C1-alkyl, —OH, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3;
G and E are N; and
n is 1, 2 or 3;
or an acid addition salt with a pharmacologically acceptable acid.

2. The compound of claim 1,
wherein R3 is a group selected from among




wherein R14 is a group selected from among —H, —C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and —C(O)—CH3;
wherein R15 is a group selected from among —H, —C1-C6-alkyl, —CN, —CF3, and —C(O)—CH3; and
wherein R16 is a group selected from among —H, —C1-C6-alkyl, —CN, —CF3, —OCF3, halogen, and —C(O)—CH3.

3. The compound of claim 1,
wherein R3 is a group selected from among —CH2F, —CHF2, and —CF3 .

4. The compound of claim 1,wherein A is a group of the structure



wherein Q denotes CH2, and wherein R9 denotes —H, and wherein R10 is a group selected from among —H, —CH3, and —CF3.

5. The compound of claim 1, wherein A is a group of the structure



wherein R7 is selected from among —H, —C1-C4-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3; and
wherein R8 is selected from among —H, —C1-C1-alkyl, —O—C1-C4-alkyl, -halogen, —CN, —CF3, and —OCF3.

6. The compound of claim 1, wherein R2 is a group selected from among —H, —CH3, —OCH3, and -cyclopropyl.

7. The compound of claim 1, wherein R4 is selected from among —H, —CH3, —OCH3, —CF3, and —OH.

8. The compound of claim 1, wherein R5 is selected from among —H, —CH3, —C2H5, —O—CH3, —O—C2H5, —F, —CF3, and —OCF3.

9. The compound of claim 1, wherein R6 is a group of the structure -L1-R13,
wherein L1 is selected from among —NH—, and —N(CH3)—,
wherein R13 is —C6-heterocyclyl comprising an O atom, and
wherein R13 is optionally substituted by a group selected from among —O—C1-C4-alkyl, and -halogen.

10. The compound of claim 1, wherein R6 is a group of the structure-N (R1,R1′),
wherein R1 and R1′, together form a —C5-alkylene group such that a ring is formed,
wherein one carbon atom may be replaced by a group selected from among O,
and wherein such ring is optionally substituted with one or more groups selected from among —OH, —OCH3—CF3, —OCF3—CN, -halogen, —C1-C1-alkyl, ═O, and —N(C0-C1-alkyl)—SO2—C1-C3-alkyl.

11. The compound of claim 1, wherein n is 2.

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





















or an acid addition salt with a pharmacologically acceptable acid.

13. A compound selected from the group consisting of






or an acid addition salt with a pharmacologically acceptable acid.