OA16887A

OA16887A - Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof.

Info

Publication number: OA16887A
Application number: OA1201400163
Authority: OA
Inventors: Armin Heckel; Sara Frattini; Dieter Hamprecht; Joerg Kley
Original assignee: Boehringer Ingelheim International Gmbh
Priority date: 2011-11-02
Filing date: 2012-10-29
Publication date: 2016-01-18

Abstract

The present invention relates to compounds of general formula (I)

Description

1. Field ofthe Invention

The présent Invention relates to compounds of general formula (I) n kim

(0.

and the tautomers and the salts thereof, particularly the pharmaceutically acceptable salts thereof with Inorganlc or organic acids and bases, which hâve valuable pharmacological properties, particularly an inhibitory effect on épithélial sodium channels, the use thereof for the treatment of diseases, particularly diseases ofthe lungs and airways.

2. Background to the invention

Amiloride type compounds are known from the prior art as active substances for example for the treatment of diseases ofthe lungs and airways (J.Med.Chem. 49 (2006) 4098-4115). WO 08135557 discloses compounds of similar structure showing ENaC (Epithelial Sodium Channel) inhibitor activity.

The problem ofthe présent invention is to préparé new compounds which may be used therapeutically for the treatment of pathophysiological processes treatable by the blockade of an épithélial sodium channel, particularly for the treatment of the lungs and airways.

3. Detailed Description of the invention

It has surprisingly been found that the problem mentioned above is solved by compounds of formula (I) and (IC) of the présent invention.

The présent invention therefore relates to a compound of formula (i)

-116887

wherein s A dénotés a bond or is selected from the group consisting of O, -CHr, -CH₂CH₂-, -CH₂CH₂CH2-, -CHrO-, -CHrNR^A1- and -NR^A1-, preferably bond, -CH_r and -CH₂CH₂-, wherein

R*¹ dénotés hydrogen or Ci_e-alkyl, preferably hydrogen or C^ralkyl,

B dénotés

-CHr or -CH₂CHr, preferably -CHr, or provided that A is not O or -NR^A1, B dénotés a bond

D, E dénoté Independently from each other a bond or -CHr, preferably -CHr,

F dénotés optionally substituted aryl, preferably phenyl, preferably substituted by R², is R³, R⁴, R®, R⁷, R²¹, R³*, R⁴·, R®* or R⁷*, or optionally substituted heteroaryl, preferably thiophenyl, pyridyl, pyrlmidinyl or pyridonyl, preferably substituted by R², R³, R⁴, R®, R⁷, R²¹, R³·, R⁴¹, R®* or R⁷¹.

F most preferably dénotés phenyl, 4-halo-phenyl, particularly preferred phenyl, so G dénotés a group of formula (g.1), (g.2) or (g.3)

(0-2)

-216887

R¹ is selected from the group consisting of hydrogen,C^-alkyl, optionally substituted 5- to 7-membered heterocyclyl-CO-, op5 tionally substituted 5- to 7-membered heterocyclyl-NH-CO-, R^t1-SOr, R¹ ’-CwalkylNH-CO-, H3C-NH-CO-, R^-O-CO-CHrNH-CO-, R^1J2-C2^-alkyl-N(CM-alkyl)-CO-l H3C -N(CM-alkyl)-CO-, R^1J2'⁴-O-CO-CH2-N(CM-alkyl)-CO-, R’-’-C^-alkyl-CO-, R¹⁴-C₂. β-alkyl-, optionally substituted phenyl-CHr. R^’-O-CO- CHr, HO-CO-CH_r and HOSO2-CH2-,

R¹⁵-Ci_6-alkyl-CO- and wherein

R¹·¹ is selected from the group consisting of Ci .«-alkyl-,

H₂NC(NH)NH -C^-alkyl-, R¹²¹ R¹²²N-CM-alkyl-,

R¹·²¹ R¹²² R¹²³N*-C_M-alkyl, HOCO-C_M-alkyl- and

Ci.3-aikyl-OCO-Ci-4-alkyl-,

R^1-2 is selected from the group consisting of hydrogen, H₂NC(NH)NH -,

R^1J1 _R122_N. rI.2.1 _ri.m r’^n*-, R^’.HN-CfNR^{12 3})-NH-,

R^u<O-CO-, R¹'^2S-O-CO-NH-and HO-CO-, HOSOr, preferably R¹¹¹ R^1Z2N-, R^12-1 R^1-2-2 R¹ⁱ³N*- and R¹ ^-HN-CiNR¹²>NH20 wherein

R¹·²·¹ dénotés hydrogen or C_1j6-alkyl, preferably hydrogen or Cm-alkyl, most preferably Cm-alkyl,

R¹·²·² dénotés hydrogen or Ci-e-alkyl, preferably hydrogen or Cm-alkyl, most preferably C_M-alkyl, or

R¹·²·¹ and R^1,2·² together form a 4- to 7- membered hetercyclic ring containing one N-atom, preferably a 6- or 5-membered heterocyclic ring

R^1,2·³ dénotés Ci^-alkyl, preferably CM-alkyl,

R^1-2·⁴ dénotés hydrogen or C^-alkyl. preferably hydrogen or CM-alkyl,

R¹·² ’ dénotés hydrogen or Ci^-alkyl, preferably hydrogen or CM-alkyl,

-316887

R¹³	is selected from the group consisting of hydrogen, CM-alkyl, C^-alkyl-O-, op-
		tionally substituted phenyl, R^13,1 R^{1,3 a}N-, R^1-2·¹ R^1,2·² R^1-2,3N*-, R¹'^2J-HN-C(NR¹²³)-NH-, H₂NC(NH)NH-, R^1A4-O-CO, HO-CO- and HOSOr, wherein
5		R¹·³·¹ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, R¹·³·² dénotés hydrogen or CM-alkyl, or R¹·³·¹ and R^1,3·² together form a 4- to 7- membered hetercyclic ring containing one N-atom, preferably a 6-membered heterocyclic ring containing one N-
10		atom, preferably hydrogen or CM-alkyl,
	RU	is selected from the group consisting of hydrogen, R¹·⁴·¹ R^1A2N-, R¹⁴¹ R¹·⁴² R^1A’N*·, H₂N-C(NH)-NH-, R^1-4-3-HN-C(NR^1-44)-NH, optionally sub-
15		stituted phenyl, R^-O-CO-, R¹-⁴-⁴-O-CO-NH-, HO-CO- and HOSOr, wherein R¹·⁴⁴ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, R¹·⁴·² dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, R¹·⁴·³ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, most
20		preferably CM-alkyl, R¹·⁴·⁴ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, most preferably CM-alkyl,
	R¹·⁵	is selected from the group consisting of hydrogen, C^-alkyl-O-, R^tM R¹¹²N-,
25		ri.s.i ri.m r1-s-3n*.₍ ^N-CfNHJ-NH-, optionally substituted phenyl, R^1S-3-OCO-, R^tM-O-CO-NH-, HO-CO-, HOSOr, wherein R^1S·¹ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, R^1,5·² dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, most
30		preferably CM-alkyl, R^13-3 dénotés hydrogen or 0,^-alkyl preferably hydrogen or CM-alkyl, most preferably CM-alkyl, R¹⁵⁴ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl,
35	Rie	dénotés R^tM R^1B'²N-, wherein R¹*·¹ dénotés hydrogen or CM-alkyl; preferably hydrogen or methyl,

-416887

R¹’·² dénotés hydrogen or C^-alkyl; preferably hydrogen or methyl,

R^1b is selected from the group consisting of C^-alkyl,

R¹⁴-C2-e-alkyl-, optionally substituted phenyl-CH2-, R^{14 3}-O-CO- CH2- and HO-COCH2-, preferably CM-alkyl, particularly preferred methyl, wherein

R¹⁴ is selected from the group consisting of hydrogen, R¹·⁴·¹ R¹·^{4 2}N-,

R¹⁴¹ R¹⁴² R¹⁴³ N*-, H2N-C(NH)-NH·, R¹⁴³-HN-C(NR^{1 4 4})-NH, optionally substituted phenyl, R^{14 3}-O-CO-, R¹⁴⁴-0-C0-NH-, HO-CO- and HOSO2-, wherein

R¹⁴·¹ dénotés hydrogen or C^-alkyl, preferably hydrogen or C^-alkyl,

R¹⁴·² dénotés hydrogen or C^-alkyl, preferably hydrogen or C^-alkyl,

R¹⁴·³ dénotés hydrogen or C^-alkyl, preferably hydrogen or C_M-alkyl, most preferably C_M-alkyl,

R¹⁴⁴ dénotés hydrogen or C^-alkyl, preferably hydrogen or C_M-alkyl, most preferably C^-alkyl,

R¹· dénotés C^-alkyl, preferably methyl,

X* dénotés any anion forming a pharmaceutically acceptable sait, preferably selected from among CF₃-COO*·, Cl·, I', Br', HCOO* and CH₃-COO',most preferably Cl* and

CF₃-COO*,

L dénotés a bridging group -CO-NH-^-alkyl-NH-CO-, -COC^-alkyl-CO-, or -C₂^alkyl-, forming a compound of formula (IC), whereby the molecular entities of formula (IC) connected by L may be identical or different

-516887

R⁵ dénotés Cl or Br, preferably Cl, optionally In the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, optionally in form of the hydrates, solvatés or prodrugs thereof and optionally the pharmacologically acceptable acid addition salts thereof.

Preferred compounds of formula (IA), (IB) or (IC.1) are those wherein io is

(IA)

(IB) dénotés a bond, -CHr. -CHîCHj- or CH2-O-, preferably -CH₂CH2-.

is selected from the group consisting of hydrogen, Cuj-alkyl, optionally substituted piperazinyl-CO-, optionally substituted piperidinyl-NH-CO-, R¹'¹-SOr, R¹'²-C2^-alkyi-NH-CO-, H3C-NH-CO-.

R^t24-O-CO-CH2-NH-CO-, R^1!-C2-4-alkyl-N(Ci-4-alkyl)-CO-, H3C -N(C_M-alkyl)-CO-₍R^1J4-O-CO-CH2-N(CiM-alkyl)-CO-. R¹³- C^-alkyl-CO-, R¹⁴-C2^-alkyl-, optionally substituted phenyl-CHr. R¹⁴³-O-CO-CH₂-, HO-CO-CH_r and HOSO_rCH_r, R^1s-Ci_e-alkyl-CO- and R¹’-C(NH)-, wherein

R^1,1 dénotés Cm-alkyl-;

-616887

R¹·² Is selected from the group consisting of hydrogen, R^1-2,1 R^1Z2N-, R¹²¹ R¹'²² R^t2-³N*-, R¹²⁴-O-CO-, HO-CO- and r^us-O-CO-NH-, wherein

R¹·²·¹ dénotés hydrogen or CM-alkyl; preferably hydrogen or CM-alkyl, R¹·²·² dénotés hydrogen or CM-alkyl; preferably hydrogen or CM-alkyl, R¹²³ dénotés hydrogen or CM-alkyl; preferably hydrogen or CM-alkyl, R¹·²·⁴ dénotés CM-alkyl; preferably C_M-alkyl,

R¹·²’ dénotés CM-alkyl; preferably CM-alkyl,

R¹·³ is selected from the group consisting of hydrogen, CM-alkyl, CM-alkyl-O-, and optionally substituted phenyl

R¹·⁴ Is selected from the group consisting of hydrogen, R^14,1 R¹⁴'²N-,

R’⁴1 R¹⁴² R¹⁴³N\ HjN-CîNHJ-NH-, R¹'^4î-HN-C(NR¹'⁴⁴)-NH-, optionally substituted phenyl, R¹⁴³-O-CO-, R¹⁴⁴-0-C0-NH-, HO-CO- and HOSOr, wherein

R¹·⁴·¹ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl,

R^1-4·² dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl,

R¹⁴·³ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, most preferably CM-alkyl,

R^1-4·⁴ dénotés hydrogen or C_M-alkyl, preferably hydrogen or CM-alkyl, most preferably CM-alkyl,

R^1,5 Is selected from the group consisting of hydrogen, CM-alkyl-O-,

R¹⁸⁴ R^{1 W}N-, R¹·²’¹ R¹²·² R¹¹³N*-, H₂N-C(NH)-NH-, R^1S3-O-CO-,

R^{1,s 4}-O-CO-NH-, optionally substituted phenyl, wherein

R¹·⁸·¹ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl,

R^18,2 dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, most preferably CM-aikyl,

R¹·⁸·³ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl, most preferably CM-alkyt,

R¹·⁸·⁴ dénotés hydrogen or CM-alkyl, preferably hydrogen or CM-alkyl,

R¹⁸ dénotés R¹*·¹ R¹⁸²N-, wherein

R¹·⁸·¹ dénotés hydrogen or CM-alkyl; preferably hydrogen or methyl,

-716887

R¹’ ² dénotés hydrogen or Ci^-alkyl; preferably hydrogen or methyl,

R^1b dénotés C_M-alkyl, preferably methyl,

R¹’ dénotés C^-alkyl, preferably methyl,

X dénotés any anion forming a pharmaceutically acceptable sait, preferably selected from among CF₃-COO‘·, Cl·, I*, Br, HCOO' and CH₃-COO‘,most preferably CI and CFj-COO*

L dénotés a bridging group -CO-NH-^-alkyl-NH-CO-, -COC^-alkyl-CO- or -Cî^-alkyl-, forming a compound of formula (IC.1), whereby the molecular entities of formula (IC.1 ) connected by L may be identical or different

R‘

i

(ic.1),

R², R³, R⁴, R®, R⁷ R²¹, R³·, R⁴*, R⁸·, R⁷¹ independently from each other are selected from the group consisting of hydrogen, halogen, CN, Ci^-alkyl, Ci.₃-alkyl-O-, Ci_₃-alkylOCO-, -COOR^4-1, -CONR⁴²R⁴³ and -OR⁴·¹, preferably hydrogen, wherein

R^4,1 dénotés hydrogen or CM-alkyl, preferably hydrogen or C^ralkyl, particularly preferred hydrogen or methyl

R⁴·² dénotés hydrogen or CM-alkyl, preferably hydrogen or Of-2-alkyl, particularly preferred hydrogen or methyl

R⁴·³ dénotés hydrogen or CM-alkyl, preferably hydrogen or C^ralkyl, particularly preferred hydrogen or methyl or

-816887

R³ and R⁴ or R³¹ and R⁴¹ together dénoté -O-C^-alkyl-O-; preferably -O-C^-alkyl-O-, optionally In the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, optionally in form of the hydrates, solvatés or prodrugs thereof and optionally the pharmacologically acceptable acid addition salts thereof.

Particularly preferred are compounds of formula (IA), wherein

A dénotés a bond, -CH₂- or -CH₂CH₂-,

R¹ is selected from the group consisting of hydrogen, optionally substituted piperazinyl-CO*, optionally substituted piperidinylNH-CO-, C^-alkyl, C_M-alkyl-SO₂-, C_M-alkyl-NH-CO-, H₂N-CO-, H₂N-C_M-alkyl-, H₂NCM-alkyl-CO-, H₂N-C^-alkyl-NH-CO-, Phenyl-CO-, Phenyl-CHrCO-,

Phenyl-CHr, C_M-alkyl-CO-, C_M-alkyl -O- C^-alkyl-CO-, (CH₃)2N-C_M-alky!-, (CH^N-C^-alkyl-NH-CO-, (CH₃)₃N*-C^-alky1-NH-CO-, (CH₃)₃N*-C_M-alkyl-CO-, (CH₃)₃N*-C₂^-alkyl-, (CH₃)N*-C_M-alkyi-N(C_M-alky1)-CO-, H₂N-C(NH)-NH-Cm-NH-CO-, C^-alkyl-O-CO-, C^-alkyl-O-CO-CM-alkyl-, C^-alkyl-O-CO-C_r4-alky1-CO-, C_M-aiky1-O-CO-C_M-alkyl-NH-CO-, C^-alkyl-O-CO-NH-C^-alkyl-, C^-alkyl-O-CO-NH-C_M-alkyl-CO-, C^-alky1-O-CO-NH-C_M-alkyl-NH-CO-, HOCO-C_M-alkyl-, HOCO-C_M-alky!-CO-, HOCO-C_M-alkyl-NH-CO-, H₂N-CNH- and H₂NC(NH)NH-C,^-alkyl-CO-,

R³ independently from each other are selected from the group consisting of hydrogen, halogen, CN, C^-alkyl and C_ralkyl-O-,

R^e independently from each other are selected from the group consisting of hydrogen, halogen, CN, C^-alky! and Ci-alkyl-OR³ are selected from the group consisting of hydrogen, halogen, CN and C^-alkyl,

R⁴ independently from each other are selected from the group consisting of hydrogen, halogen, CN, C_w-alkyl, C_M-alkyl-OCO-, -COOR⁴¹ and -CONR⁴²R⁴³, wherein

R^4,1 dénotés hydrogen or CM-alkyl, preferably hydrogen or methyi;

R⁴² dénotés hydrogen or CM-alkyt, preferably hydrogen or methyi;

R^4,3 dénotés hydrogen or CM-alkyl, preferably hydrogen or methyi;

or

R³ and R⁴ together dénoté -O-Ci.₃-alkyl-O-; preferably -O-Ci_₂-alky1-O-;

-916887 optionally ln the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts thereof.

s Also partîcularly preferred are compounds of formula (IC.1) wherein

A dénotés a bond, -CH2- or -CHjCHr,

L dénotés a bridglng group -CO-NH-^-alkyl-NH-CO-, forming a compound of formula IC or IC.1,

R², R²* Independently from each other are selected from the group consisting of hydrogen, halogen, CN, C_M-alkyl and C_ralkyl-O-,

R®, R® Independently from each other are selected from the group consisting of hydrogen, halogen, CN, Cm-alkyl and Ci-alkyl-OR³, R³¹ are selected from the group consisting of hydrogen halogen, CN and C^-alkyl,

R⁴, R⁴¹ Independently from each other are selected from the group consisting of hydrogen halogen, CN, C_w-alkyl, C_M-alkyl-OCO-, -COOR⁴¹ and -CONR⁴²R⁴³, wherein

R^4-1 dénotés hydrogen or Cu-alkyl, preferably hydrogen or methyl;

R^4,2 dénotés hydrogen or C_M-alkyl, preferably hydrogen or methyl;

R⁴³ dénotés hydrogen or C_M-alkyl, preferably hydrogen or methyl;

or

R³ and R⁴ or R³* and R⁴· together dénoté -O-Ci.₃-alkyl-O-; preferably 0-0,.2-alkyl-O-;

optionally ln the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts 25 thereof.

Also partîcularly preferred are compounds of formula (IB) wherein

R^1b dénotés Ci^-alkyl, preferrably methyl, and

R¹* dénotés C^-alkyl, preferably methyl, optionally ln the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, optionally in form of the hydrates, solvatés or prodrugs thereof and optionally the pharmacologically acceptable acid addition salts thereof.

Also partîcularly preferred are compounds of formula (IC) wherein

L dénotés a bridglng group -CO-NH-Cî-e-alkyl-NH-CO-,

-1016887 forming a compound of formula (IC) or (IC.1), optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, optionally in form of the hydrates, solvatés or prodrugs thereof and optionally the pharmacologically acceptable acid addition salts thereof.

s

Especially preferred are compounds of formula (IA), (IB) or (IC.1), wherein

R², R³, R⁴, R’ and R^T dénoté hydrogen.

Also especially preferred are compounds of formula (IA), (IB) or (IC.1), wherein

I0 R², R³, R⁴, R®, R^T, R*, R^3-, R⁴·, R®· and R^T* dénoté hydrogen.

Also especially preferred are compounds of formula (IA), (IB) or (IC), wherein

A dénotés -CH2CH2-, and

E, D dénoté -CH₂ts

A further embodiment of the current invention are compounds of formula (I), (IA), (IB) or (IC) or a pharmaceutically acceptable sait thereof as a médicament, preferably compounds of formula (IA), (IB) or (IC)

A further embodiment of the current invention are compounds of formula (I), (IA), (IB) or (IC), preferably compounds of formula (IA), (IB) or (IC), or a pharmaceutically acceptable sait thereof for the treatment of respiratory diseases or complainte, and allergie diseases of the airways.

Preferred are compounds of formula (I) or (IC), preferably compounds of formula (IA), (IB) or 25 (IC), or a pharmaceutically acceptable sait thereof for the treatment of a disease selected from among chronic bronchitis, acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergie bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinslc or allergie), pédiatrie asthma, bronchiectasis, allergie alveolitis, allergie or non-allergie rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alpha-130 antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema, pneumonitis of different origins, e.g. radiation-induced or caused by aspiration or infectious pneumonitis, preferably chronic bronchitis, acute bronchitis, bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergie), cystic fibrosis and pédiatrie asthma, preferably chronic bronchitis, COPD and 35 cystic fibrosis.

-1116887

A pharmaceutical composition comprising at least one compound according to to the invention or a pharmaceutically acceptable sait thereof and a pharmaceutically acceptable carrier.

A further embodiment of the current invention is médicament combinations which contain, besides one or more compounds according to the invention, as further active substances, one or more compounds selected from among the categories of further ENaC inhibitors, betamimetics, anticholînergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFRInhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, MAP-kinase Inhibitors, MPR4-lnhibitors, iNOS-Inhibitors, SYK-Inhibitors, and cystic fibrosis transmembrane régulait) tor (CFTR) and CFTR potentiators, preferably VX-770 and VX-809, or double or triple combinations thereof.

4. Used Terms and Définitions is 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 spécification, however, unless specified to the contrary, the following terms hâve 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, C^-alkyl means an alkyl group or radical having 1 to 6 carbon atoms.

In general In single groups like HO, H₂N, OS, O₂S, NC (cyano), HOOC. F₃C or the like, the skilled artisan can see the radical attachment point(s) to the molécule from the free valences 25 of the group Itself. For combined groups comprising two or more subgroups, the last or first named subgroup hyphenated at the end Is the radical attachment point, for example, the substituent aryl-Ci-s-alkyl- means an aryl group which is bound to a C^-alkyl-group, the latter of which Is bound to the core or to the group to which the substituent is attached.

When a compound of the présent invention is depicted in the form of a chemical name and as a formula, in case of any discrepancy the formula shall prevail. An asterisk may be used in sub-formulas to indicate the bond which is connected to the core molécule as defined.

For example, the term 3-carboxypropyl-group represents the following substituent:

O

-I216887 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 molécule as defined.

Many of the following terms may be used repeatedly in the définition of a formula or group and in each case hâve one of the meanings given above, Independently of one another.

Unless specifically indicated, according to the invention a given chemical formula or name shall encompass tautomers and all stéréo, optical and geometrical isomers (e.g. enantiois mers, diastereomers, E/Z isomers etc.) and racemates thereof as well as mixtures in different proportions of the separate enanttomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enanttomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvatés thereof such as for instance hydrates inciuding solvatés of the free compounds or solvatés of a sait of the compound.

The term substituted as used herein, means that any one or more hydrogens on the designated atom is replaced with a sélection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.

By the term optionally substituted is meant within the scope of the invention the abovementioned group, optionally substituted by a lower-molecular group. Examples of lowermolecular groups regarded as chemically meaningful are groups consisting of 1-200 atoms. Preferably such groups hâve no négative effect on the pharmacoiogical efficacy of the com30 pounds. 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 tum be substituted by functional groups.

-1316887 • A number of aromatîc or non-aromatic ring Systems consisting of carbon atoms and optionally heteroatoms which may be linked by one or more carbon chatns, optionaily interrupted by heteroatoms, optionaily substituted by heteroatoms or other common functional groups.

s

The expression treatment or therapy means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, Including symptomatic treatment in order to relieve symptoms of the spécifie indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of 10 the indication as far as this may be possibie, depending on the condition and the severity thereof. Thus the expression treatment of a disease as used herein means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment inciudes the administration of the active compounds to eliminate or control the disease, condition or disorder as is weil as to alleviate the symptoms or complications associated with the disease, condition or disorder.

The phrase pharmaceutically acceptable is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animais without 20 excessive toxicity, irritation, allergie response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.

As used herein, pharmaceutically acceptable salts refer to dérivatives 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, minerai 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, eth30 ylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnésium hydroxide,

4-(2-hydroxyethyl)-morpholine_I piperazine, potassium hydroxide, 1-(2-hydroxyethyl)pyrrolidine, sodium hydroxide, triethanolamine (2,2’,2-nitrilotris(ethanol))₁ tromethamine, zinc hydroxide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, Laspartic 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

-1416887 acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, Dglucuronlc acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexanolc acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lactobionic acid, lauric acid, lysine, maleic acid, (-)-L-malic acid, mas Ionic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1,5disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphtholc acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxaiic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-J-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, io thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, calcium, lithium, magnésium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66,1-19). Where not a basic residue such as an amine is présent but a quatemary ammonium compound the anions corresponding for example to the acids u listed above may provide pharmaceutically acceptable counter ions. Further examples are hydrogen carbonate, carbonate and carbonate x0.5. As the skilled person will appreciate, salts including potentially plurivalent ions may exist in different stoichiometric ratios, depending on whether the plurivalent ion is présent In a single or multiple charged form. For example, the charge state of a polyvalent acid will dépend on the degree of its deprotonation.

The pharmaceutically acceptable salts of the présent 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 suffîcient amount of the appropriate base or acid in water or in an organic dilu25 ent like ether, ethyl acetate, éthanol, isopropanol, or acetonitrile, or a mixture thereof.

Salts of other acids than those mentioned above which for example are useful for purifying or Isolating the compounds of the présent invention (e.g. trifluoro acetate salts,) also comprise a part of the invention.

As used herein the term “prodrug refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active métabolite, although not itself active (i.e. an inactive precursor).

The terms “prodrug or prodrug dérivative mean a covalently-bonded dérivative, carrier or precursor of the parent compound or active drug substance which undergoes at ieast some

-1516887 biotransformation prior to exhibiting its pharmacological effect(s). Such prodrugs either hâve metabolically cleavable or otherwise convertible groups and are rapidly transformed In vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as In case of thioether groups. Most common prodrugs Include esters and amide analogs of 5 the parent compounds. The prodrug Is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosotubility), and/or decreased side effects (e.g., toxicity). In general, prodrugs themselves hâve weak or no biological activity and are stable under ordinary conditions. Prodrugs can 10 be readily prepared from the parent compounds using methods known In the art, such as those described in ATextbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: Design and Applications of Prodrugs; Design of Prodrugs, H. Bundgaard (ed.), Elsevier, 1985; Prodrugs: Topical and Ocular Drug Delivery, K.B. Sloan (ed.), Marcel Dekker, 1998; Methods in Enzymology, K.

is Widder et al. (eds.), Vol. 42, Academie Press, 1985, particularly pp. 309-396; Burger’s Médicinal Chemistry and Drug Discovery, 5th Ed., M. Wolff (ed.), John Wiley & Sons, 1995, particularly Vol. 1 and pp. 172-178 and pp. 949-982; Pro-Drugs as Novel Delivery Systems, T. Higuchl and V. Stella (eds.), Am. Chem. Soc., 1975; Bioreversible Carriers in Drug Design, E.B. Roche (ed.), Elsevier, 1987, each of which is incorporated herein by reference in their 20 entireties.

The term pharmaceutically acceptable prodrug’ as used herein means a prodrug of a compound of the Invention which is, within the scope of Sound medical judgment, sultable for use in contact with the tissues of humans and lower animais without undue toxicity, Irritation, al2s lergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterlonic forms, where possible.

The term aryl’ as used herein, either alone or in combination with another radical, dénotés a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further 30 fused to a second 5- or 6-membered carbocyclic group which may be aromatic, saturated or unsaturated. Aryl includes, but is not limited to, phenyl, Indanyl, Indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.

The term heterocyclyl or heterocyclic ring* means a saturated or unsaturated mono- or polycyclic-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. The term heterocycle Is intended to Include ail the possible isomeric forms.

-I616887

Thus, the term heterocyclyl or heterocyclic ring” 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:

-1716887

-1816887

The term heteroaryl means a mono- or polycyclic-ring System 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 inio tended to include ali 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:

-1916887

ίο The term monocyclîc Cs-rheterocyclyl means a saturated or unsaturated non-aromatic monocyclic-ring system containing one or more heteroatoms selected from N, O or S(O)_r.wherein r = 0,1 or 2, consisting of 5 to 7 ring atoms. The term * monocyclîc Cs-rheterocyclyl is intended to inciude ail the possible isomeric forms.

is Thus, the term monocyclîc Cs-rheterocyclyl 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:

-2016887 •u· p—

S' ΰ

N<_N

The term monocyclic C^-heteroaryl means a monocyclic-ring system containing one or more heteroatoms selected from N, O or S(O)_f, wherein r - 0,1 or 2, consisting of 5 or 6 ring atoms wherein at least one of the heteroatoms is part of aromatic ring. The term monocyclic Cs4r heteroaryl* is intended to include ail the possible isomeric forms.

Thus, the term monocyclic C^-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:

O

The term bicyclic Ce-w-heterocyclyl means a saturated or unsaturated bicyclic-ring system including aromatic ring Systems containing one or more heteroatoms selected from N, O or

-2216887

S(0)_r .wherein r = 0.1 or 2, consisting of 8 to 10 ring atoms wherein the heteroatoms is optionally part of the aromatic ring. The term bicyclic Ce-w-heterocyclyl’ is intended to include ail the possible isomeric forms.

s Thus, the term bicyclic Ce-io-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:

-2316887

The term annelated species of aryl or heterocyclyl as used herein, either alone or in combination with another substituent wherein the annelated species présents as an aryl-het (a), a het-aryl (b) or a het-het (c) annélation means a monovalent substituent derived by removal of 5 one hydrogen from an aromatic monocyclic system or aromatic multicyclic Systems containing carbon atoms, which is annelated to a five-, six- or seven-membered saturated or unsaturated (including aromatic) heteracycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur or io a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, which is annelated to an aromatic monocyclic system or aromatic multicyclic Systems containing carbon atoms or a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle is containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur, which is annelated to a five-, six-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, oxygen and sulfur.

Suitable examples of an annelated species of aryl or het Include: quinolinyl, 1-lndoyl, 320 indoyl, 5-indoyl, 6-indoyl, indolizinyl, benzimidazyl or purinyl.

The term halogen as used herein means a halogen substituent selected from fluoro, chloro, bromo or iodo.

The term C^-alkyl, wherein n is an integer from 2 to n, either alone or In combination with another radical dénotés an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term C^-alkyl embraces the radicals HaC-, H3C-CH2-, H₃C-CH_rCH₂-, HaC-CH(CHa)-, HjC-CHrCHrCHr, HaC-CHrCHiCHa)-, H3C-CH(CH₃)-CH₂-, HaC-CiCHa)^, HaC-CHrCHrCHrCHr, H₃C-CH_rCH_rCH(CH₃)-, HaC-CH_rCH(CHa)-CHr.

H₃C-CH(CH₃)-CHrCH_r, H₃C-CH_rC(CH₃)r, H₃C-C(CH₃)_rCHr, H₃C-CH(CH₃)-CH(CH₃)- and H₃C-CH₂-CH(CH₂CH₃)-.

The term C^-cycloalkyl, wherein n is an integer from 4 to n, either alone or In combination with another radical dénotés a cyclic, saturated, unbranched hydrocarbon radical with 3 to n 35 C atoms. For example the term C^rcycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.

-2516887 ln ail cases of contradictions between structure and their naming structure shall prevail.

5. Preferred Embodiments

The symbol A dénotés a bond or Is selected from the group consisting of O, -CH₂-, -CH₂CHr. -CH₂CH₂CHr, -CH_rO-, -CH₂-NR^A1- and -NR^A1-, preferably bond. -CH_r and -CH₂CH_r, wherein

R^a1 dénotés hydrogen or C^-aikyl, preferably hydrogen or C^alkyl.

The symbol B dénotés -CH₂- or-CH₂CH₂-, preferably -CH₂-, or provided that A Is not O or -NR^A1, a bond.

The symbol D dénotés a bond or -CHr. preferably -CHr.

The symbol E dénotés a bond or -CH₂-, preferably -CHr.

The symbol F dénotés optionally substituted aryl, preferably phenyl, preferably substituted by R² R³ R⁴ R® R⁷ R^2a R³* R⁴* R^* or R^^a or optionally substituted heteroaryl, preferably thiophenyl, pyridyl, pyrimidinyl or pyridonyl, most preferably phenyl, 4-halo-phenyl or pyridyl, particularly preferred phenyl.

The symbol G dénotés a group of formula (g.1), (g.2) or (g.3)

-2616887

The substituent R¹ Is selected from the group consisting of hydrogen, C^-alkyl, optionaliy substituted 5- to 7-membered heterocyclyl-CO-, wherein preferably the heterocyclyl ring contains one or two N-atoms, optionaliy substituted 5- to 7-membered heterocyclyl-NH-CO-, wherein preferably the heterocyclyl ring contains one or two N-atoms, R^1,1-SOr, R^-C^-alkyl-NH-CO-, HjC-NH-CO-, R^1J4-O-CO-CH2-NH-CO-, R^1J-C_2Jralkyl-N(C^-alkyl)-CO-, H₃C -NÎCM-alkylJ-CO-, io R’^-O-CO-CHî-NtCm-alkylï-CO-, R¹³-Ci_6-alkyl-CO-, R¹⁴-C2^-alkyl-, optionaliy substituted phenyl-CHz-, R^UJ-O-CO- CHr, HO-CO-CHr and HOSO2-CH₂-, R^1s-C,^-alkyl-CO- and R^te-C(NH)-, wherein

R¹·¹ Is selected from the group consisting of Ci-4-alkyl-, H2NC(NH)NH -C^-alkyl-, R¹²¹ R^t22N-CM-alkyl-, is R¹²¹ R^1-22 R^1A3N*-C_M-alkyl₁ HOCO-C_M-alkyl- and

Cvs-alkyl-OCO-Cm-alkyl-,

R¹·² Is selected from the group consisting of hydrogen, H₂NC(NH)NH-,

R¹²¹ R1.2.2N_ R1i,1 R1.2J R1-2JN*.( R^12î-HN-C(NR^{12 3})-NH-, R¹²⁴-O-CO-, R¹²⁵-0-C0-NH- and HO-CO-, HOSOr, preferably R¹²¹ R¹²²N-,

R¹·²·¹ R¹²² R¹²³ N*-, R’^-HN-CÎNR^J-NH-, wherein

R¹·²¹ dénotés hydrogen or Ci^-alkyl, preferably hydrogen or Ci^-alkyl, more preferably Cm-alkyl, most preferably methyl

R¹·²² dénotés hydrogen or C^-alkyi, preferably hydrogen or Ci-4-alkyl,

More preferably C^-alkyl, most preferably methyl or

R¹·²¹ and R¹·²·² together build a 4- to 7- membered hetercyclic ring containg one N-atom, preferably a 5- or 6-membered heterocyclic ring

3o | R^12-3 dénotés C^alkyl, preferably Ci^-alkyl, most preferably methyl

R¹·²⁴ dénotés hydrogen or C^-alkyl, preferably hydrogen or Cm-alkyl, R¹·²’ dénotés hydrogen or CM-alkyl, preferably hydrogen or C^-alkyl,

R¹·³ is selected from the group consisting of hydrogen, Ci^-alkyl, Ci-e-alkyl-O-, op35 tionally substituted phenyl, R¹³¹ R^1X2N-, R^1,21 R¹·²² R¹'²³N*-,

R¹²³«HN-C(NR¹²³)-NH, H₂NC(NH)NH-, R¹²⁴-0-C0, HO-CO-and HOSOr, wherein

-2716887

R⁰·¹ dénotés hydrogen or C^-alkyl, preferably hydrogen or C_M*alkyl,

R¹·^3,2 dénotés hydrogen or Ci-e-alkyl, or

R¹·³·¹ and R¹³² together build a 4- to 7- membered hetercyclic ring containing one N-atom, preferably a 5- or 6-membered heterocyclic ring containing one N-atom, preferably hydrogen or Cw-alkyl,

R^1-4 Is selected from the group consisting of hydrogen, R¹·⁴·¹ R^1-4-2N-,

R¹⁴¹ R¹'⁴·² R^m-’N⁺-, H2N-C(NH)-NH-, R¹⁴³-HN-C(NR¹⁴⁴)-NH-, optionally substituted phenyl, R¹⁴³-O-CO-, R¹⁴⁴-O-CO-NH-, HO-CO- and HOSOr, wherein

R¹’⁴¹ dénotés hydrogen or C^-alkyl, preferably hydrogen or ÜM-alkyl, R¹·⁴·² dénotés hydrogen or C^-alkyl, preferably hydrogen or C^-alkyl,

R¹·⁴·³ dénotés hydrogen or C^-alkyl, preferably hydrogen or ÜM-alkyl, most preferably ÜM-alkyl,

R¹·⁴·⁴ dénotés hydrogen or C^-alkyl, preferably hydrogen or Cm-alkyl, most preferably Cn-alkyl,

R¹·⁵ Is selected from the group consisting of hydrogen, C^-alkyl-O-, R¹’·¹ R^1S2N-, R¹’·¹ R¹'⁵² R^{i s}-³N*·, H₂N-C(NH)-NH-, optionally substituted phenyl, R^{13 3}-OCO-, R^1M-O-CO-NH-, HO-CO-, HOSOr.

wherein

R^ts·¹ dénotés hydrogen or Ci-e-alkyl, preferably hydrogen or CM-alkyl,

R¹’·² dénotés hydrogen or Ci-e-alkyl, preferably hydrogen or Cu-alkyl, most preferably CM-alkyl,

R^tsJ dénotés hydrogen or C^-alkyl preferably hydrogen or C^-alkyl, most preferably C^-alkyl,

R¹·®·⁴ dénotés hydrogen or C^-alkyl, preferably hydrogen or Cm-alkyl,

R^te dénotés R¹®·¹ R¹ · ²N-, wherein

R^1,8·¹ dénotés hydrogen or C^-alkyl, preferably hydrogen or methyl,

R¹⁸·² dénotés hydrogen or C^-alkyl, preferably hydrogen or methyl.

Preferably R¹ is selected from the group consisting of

-2816887 hydrogen, C^-alkyl, C_M-alkyl-SO₂-, CM-alky!-NH-CO- ,H₂N-CO-,

H₂N-C^-alky1-, H₂N-C_M-atkyl-CO-, H₂N-C_M-alkyl-NH-CO-, Phenyl-CO-,

Phenyl-CHrCO-, Phenyl-CHr, C^-alkyl-CO-, C^-alky! -O- C_M-alkyl-CO-, (CH₃)₂NC_M-alkyl-, (CHafeN-CM-alkyl-NH-CO-, (CH₃)₃N⁺-C_M-alkyl-NH-CO-, (CH₃)N*-C_Ms alkyl-N(C_M-alkyl)-CO-, (CHaïX-C^-alkyl-, (CH^NT-C^-alkyl-CO-,

H₂N-C(NH)-NH-C^-NH-CO-, C^-alkyl-O-CO-, C^-alkyl-O-CO-Cm-alkyl-,

C^j-alkyl-O-CO-Crx-alkyl-CO-, C^-alkybO-CO-C^-alkyl-NH-CO-, C^-alkyl-O-CO-NH-CM-alkyl-, C^-alkyl-O-CO-NH-C_M-alky!-CO-, C^-alkyl-O-CO-NH-CM-alkyl-NH-CO-, HOCO-C_M-alky1-, HOCO-C_M-alkyl-CO-, io HOCO-C_M-alky!-NH-CO-, H₂N-CNH- and H₂NC(NH)NH-C₁₄-alkyl-CO-.

or

Also preferred R¹ Is selected from among a group of below listed formulas (c1) to (C5):

*

Particularly preferred R¹ dénotés hydrogen or Is selected from the group consisting of 20 C^-alkyl, C_M-alkyl-SOr , C_M-alkyl-NH-CO-, H₂N-CO-, H₂N-C_M-aikyl-,

H₂N-C_M-alkyl-CO-_t H₂N-C_M-alky!-NH-CO-, Pheny!-CO-, Phenyl-CH₂-CO-, Phenyl-CHr, C^-alkyl-CO-, C^-alkyl -O- C_M-alkyl-CO-, (CH₃)₂N-C_M-alkyl-, (CH₃)₂N-C_M-alky!-NH-CO-, (CH₃)₃N⁺-CM-alkyl-NH-CO-, (CH3)3N*-C2^-alky!-, (CH3)3N⁺-CM-atkyl-CO-,H₂N-C(NH)-NH-Ci4_S-NH-CO-, C^-alkyl-O-CO-, C^-alkyl-O25 CO-C_M-alkyl-, C^-alkyl-O-CO-Cr^alkyl-CO-, C_M-alky!-O-CO-CM-alkyl-NH-CO-, C,.

e-alky!-O-CO-NH-C_M-alkyl-, C^-alkyl-O-CO-NH-CM-alkyl-CO-,

C_M-alkyl-O-CO-NH-C_M-alkyl-NH-CO-, HOCO-C_M-alky1-, HOCO-C_M-alkyl-CO-,

HOCO-C_M-alky!-NH-CO- and H₂N-CNH-,

-2916887

The substituent R*· dénotés C^-alkyl, preferably methyl.

s X* dénotés any anion forming a pharmaceutically acceptable sait, preferably selected from among CF₃-COO‘, CI', I', Br’, HCOO'and CH₃-COO'',most preferably Cl' and CF₃COO'.

The substituent R^1b is selected from the group consisting of C_M-alkyl,

R^1<-C2-e-alkyl-, optionally substituted phenyl-CH2-, R¹⁴'³-O-CO- CHrand HO-CO-CH₂, preferably Cn-alkyl, particularly preferred methyl, wherein

R¹·⁴ is selected from the group consisting of hydrogen, R¹'⁴'¹ R¹·⁴^-,

R¹·⁴·¹ R^1,4-2 R^1XSN\ H2N-C(NH)-NH-, R¹⁴³-HN-C(NR¹⁴⁴)-NH, optionally subis stituted phenyl, R¹'⁴³-O-CO-, R^t4-⁴-O-CO-NH-, HO-CO- and HOSO2-, wherein

R¹·^4,1 dénotés hydrogen or C^-alkyl, preferably hydrogen or CM-alkyl, R¹·⁴·² dénotés hydrogen or Ci_e-alkyl, preferably hydrogen or CM-alkyl, R^1-4·³ dénotés hydrogen or C^-alkyl, preferably hydrogen or C^-alkyl, most 20 preferably CMalkyl,

R¹·⁴·⁴ dénotés hydrogen or C^-alkyl, preferably hydrogen or C_M-alkyl, most preferably C_M-alkyl.

The symbol L dénotés a bridging group -CO-NH-C^-alkyl-NH-CO-, -COC^-alkyl-CO- or

-C^-alkyl-, forming a compound of formula (IC), whereby the molecular entities of formula (IC) connected by L may be identical or different ,

-3016887 preferably forming a compound of formula (IC.1 ), whereby the molecular entities of formula (IC.1) connected by L may be identical or different,

i

(IC.1),

The substituents R² and R²· independently from each other are selected from the group consisting of hydrogen, halogen, CN, Ci-e-alkyl, C_M-alkyt-O-, C,.₃-alkyl-OCO-, -COOR^4t, io -CONR⁴²R⁴³ and -OR^4t, preferably hydrogen, wherein

R⁴·¹ dénotés hydrogen or CM-alkyl, preferably hydrogen or Ci^-alkyl, particularly preferred hydrogen or methyl,

R^4-2 dénotés hydrogen or CM-alkyl, preferably hydrogen or C^alkyl, particularly prêts ferred hydrogen or methyl,

R^4-3 dénotés hydrogen or CM-alkyl, preferably hydrogen or C_V2-alkyl. particularly preferred hydrogen or methyl.

The substituents R³ and R³· independently from each other are selected from the group con20 sisting of hydrogen, halogen, CN, CM-alkyl, Cu-alkyl-O-, Ci.₃-alkyl-OCO-, -COOR⁴’¹,

-CONR⁴²R⁴³ and -OR^4-1, preferably hydrogen, wherein

R⁴·¹ dénotés hydrogen or CM-alkyl, preferably hydrogen or Ci._ralkyl, particularly preferred hydrogen or methyl,

2s R^4,2 dénotés hydrogen or CM-alkyl, preferably hydrogen or Ci^-alkyl, particularly preferred hydrogen or methyl,

-3116887

R⁴·³ dénotés hydrogen or Cm-alkyl, preferably hydrogen or Cvralkyl. particularly preferred hydrogen or methyl.

The substituents R⁴ and R⁴ Independently from each other are selected from the group con5 sisting of hydrogen, halogen , CN, C^-alkyl-O-Ci.₃-alkyl-OCO-, -COOR⁴·¹,

-CONR^4JR⁴·³ and -OR⁴·¹, preferably hydrogen, wherein

R⁴·¹ dénotés hydrogen or Cm-alkyl, preferably hydrogen or Ci.₂-alkyl, particularly preferred hydrogen or methyl,

R⁴'² dénotés hydrogen or Cm-alkyl, preferably hydrogen or Cvralkyl, particularly preferred hydrogen or methyl,

R⁴·³ dénotés hydrogen or Cm-alkyl, preferably hydrogen or Cvralkyl, particularly preferred hydrogen or methyl, or u R³ and R⁴ or R³* and R⁴· together dénoté -O-C^-alkyl-O-; preferably -O-Ci.2-alkyl-O-.

The substituent R^s dénotés Cl or Br, preferably Cl.

The substituent R® and R®¹ independently from each other are selected from the group consisting of hydrogen, halogen, CN, CM-alkyl, Ci.₃-alkyl-O-, Cvs-alkyl-OCO-, -COOR⁴·¹, 20 -CO N R⁴² R⁴³ and -OR⁴·¹, preferably hydrogen, wherein

R⁴·² dénotés hydrogen or Ci-4-alkyl, preferably hydrogen or Ci.₂-alkyl, particularly pre25 ferred hydrogen or methyl,

R⁴·³ dénotés hydrogen or Cm-alkyl, preferably hydrogen or Ci^-alkyl, particularly preferred hydrogen or methyl.

The substituent R⁷ and R⁷¹ Independently from each other are selected from the group consisting of hydrogen, halogen, C^-alkyl, CN, Cvu-alkyl-O-, C^-alkyl-OCO-, -COOR⁴·¹, 30 -CONR⁴²R⁴³ and -OR⁴·¹, preferably hydrogen, wherein

R^4-1 dénotés hydrogen or Cu-alkyl, preferably hydrogen or Cvralkyl, particularly preferred hydrogen or methyl,

R⁴² dénotés hydrogen or Cm-alkyl, preferably hydrogen or Ci.ralkyl, particularly pre35 ferred hydrogen or methyl,

R^4,3 dénotés hydrogen or C^-alkyl, preferably hydrogen or Ci^-alkyl. particularly preferred hydrogen or methyl.

-3216887

Any of the définitions of R¹ to R⁷ described above may be combined with each other to form an embodiment of the invention.

6. Préparation

The following methods are suitable for preparing compounds of general formula (IA), (IB) or (IC).

The compounds according to the invention may be obtained using methods of synthesis io which are known to one skilled In the art and described In the literature of organic synthesis. General methods for functional groups protection and deprotection steps are described e.g. in: Greene, T.W. and Wuts, P.G.M. (eds.): Protective Groups in Organic Synthesis, third édition 1999; John Wiley and Sons, inc. Preferably the compounds are obtained analogously to the methods of préparation explalned more fully hereinafter, In particular as described in the is experimental section.

Compounds of general formula (I) can be prepared by reacting S-methylisothioureas of formula (II) with primary amines of formula (III) in a solvent like THF, acetonitrile or DMF or in a solvent mixture, preferably In the presence of a base, especially when the primary amine (III) is applied as an acid addition sait, preferably at between 18 C to 90 C.

2o Compounds of general formula (I) can be converted Into compounds of general formula (la) by reaction with BOC2O In the presence of a base, preferably triethylamine, in a solvent like e.g. THF.

Compounds of general formulas (I) and (la) can be modified using methods of synthesis which are known to the one skilled in the art and described In the literature of organic syn2$ thesis, preferably by functional group protection or deprotection steps, or hydrogénations.

Furthermore, the group R¹ in compounds of general formula (la) can be modified under conditions not compatible with the acylguanidine group présent In compounds of general formula I, preferably by alkylation of tertiary amino groups to yield quatemary ammonium compounds.

Compounds of general formula (la) can be converted into compounds of general formula (I) by removal of the BOC moiety under standard acidic deprotection conditions.

-3316887

Scheme 1:

-3416887

A preferred realization of Scheme 1 is Scheme 1.1.

Scheme 1.1:	Q NH,
	A	AA
h₂n	U	^xnh₂
		(IM)

(m.1)

Compounds of general formula (II) can be prepared by reacting S-methylisothiourea (which may be generated in situ from its sait by addition of base) with a 1 -(tertbutylcarbamoyl)prop1-en-2-yl carboxylate of general formula (IV) in a solvent like DCM, THF or a mixture of these solvents, preferably at between -10 ‘C to 25 C.

io Compounds of general formula (IV) can be prepared from the respective carboxylîc acid of general formula (V) and a 2-tert-butyl-5-methyl-isoxazolium sait of general formula (VI), which can be applied as an isolated sait (e.g. the hexafluorophosphate sait; X = PF_e) or generated In situ from tert-butanol, 5-methylisoxazole and trifluoromethanesulphonic acid. The latter reaction is preferably performed In a solvent like DMF or in a solvent mixture with the addition of triethylamine or another base, preferably while cooling to 0-10 ’C.

-3516887

Compounds of general formula (III) can be obtained from compounds of general formula (XV) by réduction of the nitrile group, preferably by hydrogénation with raney-nickel as catalyst under hydrogen pressure in the presence of excess ammonia in a solvent like e.g. methanol. The group R^e ln compounds of general formula (XV) can be modified using methods of synthesis which are known to the one skllled ln the art and described in the literature of organic synthesis, preferably by functional group protection or deprotection steps, estérifications, amidations, or hydrogénations. Depending on the nature of R^e, this moiety can be removed using methods of synthesis which are known to the one skllled in the art and described in the literature of organic synthesis, especially of protective group removal to yield compounds of general formula (XVI). Compounds of general formula (XVI) can be converted Into compounds of general formula (XV) using methods of synthesis which are known to the one skilled ln the art and described ln the literature of organic synthesis, especially by acylation, alkylation, or reductlve amination.

Compounds of general formula (XV), wherein D represents -CHr or-CHrCHr can be prepared by reaction of alkylatlng agents of general formula (VI) with 4-cyanoplperidines of general formula (VII) in a solvent like THF, wherein the compound of general formula (VII) Is deprotonated by a base, preferably LDA, n-BuLi or NaH, preferably at a température between -80 ^eC and 0 °C and wherein LG represents a leaving group, preferably Cl, Br, I, mesylate or tosylate and wherein G represents an acyl moiety, preferably the BOC group. Compounds of general formula (XV), wherein A represents a bond can be prepared by double alkylation of phenylacetonitriles of general formula (IX) with bis-chloroethylamines of

-3616887 general formula (VIII) with the addition of a base, preferably NaH in a solvent, preferably

DMF, wherein R' represents an acyl molety, preferably the BOC group.

Scheme 3:

N

A = bond

R' +

(XV)

H (xvi)

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s Compounds of general formula (X), wherein L represents chain with at least 2 carbon atoms, can be prepared by reaction of (XI) with an acid preferably TFA or HCl In a solvent like THF, dioxane, dichloromethane, DMF or water, preferably at a température between 10 ’C and 50 •C.

(XIII) is Compounds of general formula (XII), wherein L represents chain with at least 2 carbon atoms can be prepared by a reaction sequence starting with (XIII) protecting it with BOC anhydride, quatemization with alkylhalogenide preferably alkytiodide in a solvent like acetone,

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THF, dioxane or dichloromethane, preferably at a température between 10 °C and 50 ’C foilowed by deprotection with acids.

R'

hn nh₂ (XIV)

Compounds of general formula (XIV), wherein L represents chain with at least 2 carbon atoms can be prepared by reaction compounds of general formule (X) with 1H-1.2.4-triazoleio 1-carboxamidlne or S-methylisothioureas in DMF preferably at a température between 50 ’C and 90 ^eC.

7. Examples is 7.1 Synthesis of Intermediates

Intermediate A. 61

3,5-diamino-6-chloropyrazine-2-carboxylic acid

Cl

OH

Η₂Ν N NH₂ h₂n -N nh_{2 Æ61}

A mixture of methyl 3,5-cliamino-6-ch!oropyrazine-2-carboxylate (100 g; 494 mmol), methanol (11) and NaOH (6 mol/l in water; 240 mL; 1.44 mol) is refluxed for 3 h. The mixture is allowed to cool to r.t. and then neutralized by addition of hydrochloric acid (6 mol/l in water; approx. 240 mL). Water (200 mL) is added. The precipitate formed is filtered off with suction, washed with water and dried at 60*C.

Yield: 99.6 g (107% of theory)

C₅H₅CIN₄O2 ESI Mass spectrum: m/z = 189 [M+H]+; m/z = 187 [M-H]’

Intermediate A.62

3,5-diamino-6-bromopyrazine-2-carboxylic acid is prepared from methyl 3,5-diamîno-6- bromopyrazine-2-carboxylate (which is prepared from methyl 3,5-diamino-6-chloropyrazine-3916887

2-carboxylate as described in J.Med.Chem. 10 (1967) 66-75) analogously to the procedure described for the synthesis of intermediate A.61

Intermediate B.61

-(tert-butylcarbamoyl)prop-l -en-2-yl 3,5-diamino-6-chloropyrazine-2-carboxylate

Stage 1 :

A mixture of fert-butanoi (21.0 mL; 226 mmol) and 5-methylisoxazole (18.0 mL; 221 mmol) is io cooled with an ice-bath. Trifluoromethanesulphonic acid (20.0 mL; 221 mmol) is added dropwise with continued cooling. The resulting mixture is stirred for 1 h without further cooling.

Stage 2:

To a solution or suspension of 3,5-diamino-6-chloropyrazine-2-carboxylic acid (Intermediate u A.61 ; 14.0 g; 74.2 mmol) and triethylamine (31.0 mL; 222 mmol) in DMF (100 mL) is added the mixture prepared In stage 1. The resulting mixture is stirred for 4 h at r.L Ice-water is added with stirring. The precipitate formed is filtered off with suction, washed with water and dried at 65^eC to yield the title compound.

Yield: 18.2 g (75% of theory)

2o CuHiaCINjOj ESI Mass spectrum: m/z » 328 [M+H]+; m/z = 326 [M-H]'

TLC (Silica; DCM/MeOH 9:1): R_f = 0.4

Intermediate B.62

-(2-methyl-2-butyl-carbamoyl)prop-1 -en-2-yl 3,5-diamino-6-bromopyrazine-2-carboxylate

Stage 1:

A mixture of 2-methyl-2-butanol (5.75 mL; 51 mmol) and 5-methylisoxazole (4.42 mL; 51 mmol) is cooled with an ice-bath. Trifluoromethanesulphonic acid (4.84 mL; 54 mmol) is add30 ed dropwise with continued cooling. The resulting mixture is stirred over night without further cooling. Stage 2:

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To a solution or suspension of 3,5-diamino-6-bromopyrazine-2-carboxylic acid (Intermediate A.62; 5.00 g; 21.5 mmol) and triethylamine (7.48 mL; 54 mmol) in DMF (50 mL) cooled with an ice-bath is added dropwise the mixture prepared ln stage 1. The resulting mixture is stirred for 4 h at r.t, then poured on Ice-water. The precipitate formed is filtered off with suc5 tion, washed with water and dried at 50’C to yield the title compound.

Yield: 7.53 g (91% of theory)

CuHîoBrNsOa ESI Mass spectrum: m/z - 386 [M+H]+; m/z = 384 [M-H]*

Intermediate C.61 io 3,5-diamino-6-chloro-N-[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide

To NaOH (1 mol/l ln water; 9.2 mL; 9.2 mmol) is added S-methylisothiourea sulphate (1.78 g;

6.1 mmol. The mixture is stirred until complété solution Is achieved. TBME/THF (1:1; 30 mL) and then 1-(tert-butylcarbamoyl)prop-1-en-2-y13,5-diamino-6-chloropyrazine-2-carboxy!ate is (Intermediate B.61; 2.00 g; 6.10 mmol) are added and the mixture is stirred at r.t. over night, then water (6 mL) is added. The precipitate formed is filtered off with suction, washed successively with water, methanol and then with diethyl ether and then dried at 50 ’C to yield the title compound.

Yield: 1.33 g (84% of theory)

C₇H₉CIN_eOS ESI Mass spectrum: m/z = 261 [M+HJ+; m/z = 259 [M-H]*

Intermediate C.62

3,5-diamino-6-bromo-/V-[(methylsulfany1)methanimidoyl]pyrazine-2-carboxamide

2

To NaOH (1 mol/l in water; 30 mL; 30 mmol) Is added S-methylisothiourea sulphate (5.42 g;

19.5 mmol. The mixture is stirred until complété solution is achieved. TBME/THF (1:1; 100 mL) and then 1-(2-methyl-2-butyl-carbamoyl)prop-1-en-2-yl 3,5-diamino-6-bromopyrazine-2carboxylate (Intermediate B.62; 7.52 g; 19.5 mmol) are added and the mixture Is stirred at r.t.

over night, then water (100 mL) Is added. The precipitate formed is filtered off with suction, washed with THF/water (1:2) and then dried at 50 ’C to yield the title compound.

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Yield: 5.44 g (92% of theory)

CrHgBrNeOS ESI Mass spectrum: m/z = 305 [M+H]+

D.2

To a solution of 21.10 g di-isopropylamine in 300 mL anhydrous THF is added 83.7 mL 2.5 M solution of n-butyl lithium In THF dropwise at -78^eC. The resuitant solution is stirred at this température for 30 min. Then a solution of 40.00 g 1-N-BOC-4-cyanoplperidine in 300 mL THF is added dropwise. After 1 h stirring 51.99 ml (2-bromo-ethyl)-benzene Is added dropio wise. After the addition the réaction mixture is allowed to warm up to room température and stirred overnight. 100 mL water is added to quench the réaction. THF is removed to leave a slurry which is partitioned between ethyl acetate and water. After a séparation the organic layer is washed with sat. aq. NH₄CI and brine, dried with Na₂SO4 and concentrated under reduced pressure. Purification by column chromatography results In 57.23 g of Intermediate is D.2. TLC (EA/PE 1/8) R_f: 0.4.

D.8 ^N D.8

Intermediate D.8 Is obtained using a similar procedure as described for intermediate D.2 uti20 lizlng benzyl bromide as alkylating agent. TLC (ethylacetate (EA)/petroleum ether (PE)) 1/9) Rr: 0.3.

C.17

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Intermediate C.17 Is obtained using a similar procedure as described for intermediate D.2 using 4-(2-bromoethyl)benzoic acid as alkylating agent. TLC (MeOH/dichloromethane (DCM) 5/95) R_f: 0.4.

C.18

Intermediate C.18 is obtained treating C.17 with ammonia and TBTU in dichloromethane.

ίο B.17

2.40 ml methyl iodide dropwise. The reaction mixture is stirred at room température for 12 h. Then water Is added and the mixture Is extracted with diethyl ether. The organic phases are is pooled, dried over Na₂SO₄ and evaporated. The resulting crude product is purified by FC resuiting in 3.40 g of Intermediate B.17. TLC (EA/PE 2/3) R_f: 0.6.

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D.45

To a solution of 2.00 g N-BOC-N,N-bis(2-chloroethyl)amine and 1.10 g (2-methoxyphenyl)acetonitrile In 15 ml THF and 5 ml DMF Is added 0.78 g of NaH in portions at r.t. and the mixs ture is stirred at 55*C for 16 h. The reaction is quenched by addition of cold water and extracted with ethyl acetate. The organic layer is washed with brine and water, dried over Na₂SO₄ filtered and evaporated under reduced pressure. The crude solid is triturated with a mixture of CHCI₃ and ether filtered and dried resulting in 1.0g of intermediate D.45. TLC (EA:PE 3/7) R,: 0.6.

D.43 and D.44

D.43 and D.44 are obtained using a similar procedure as described for intermediate D.45 uti lizing the corresponding benzyl cyanides.

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A mixture of 2.50 g of piperidine D.2 and 40 ml 25% TFA in dichloromethane are stirred for

1.5 h at room température. The solvent is evaporated, methanolic hydrochloric acid is added and the solvent evaporated again giving rise to 2.53 g of intermediate C.2.

ESI-MS m/z: 215, The corresponding TFA sait of C.2 is obtained by purification of the crude 5 product by préparative reversed-phase HPLC with TFA as modifier.

C.8. C.43, C.44 and C.45

The following intermediates are obtained using a similar procedure as described for intermediate C.2 with a modified workup: neutralization of the reaction mixture with saturated Na10

HCO₃ solution followed by an aqueous workup.

ΐΐ B.2

ethylamine and 50 ml THF are stirred at 50^eC for 2 h. The reaction mixture is concentrated under reduced pressure and water is added and finally extracted with dichloromethane. The 2o combined organic phases are dried over MgSO₄ and evaporated yielding 1.65 g of intermediate B.2.

ESI-MS m/z: 300, 344

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B.4. B.8. B.12. B.18. B.19. B.43. B.44. B.45. B.48 and Β.49

The following Intermedlates are obtained using a similar procedure as described for intermediate B.2 utilizing the corresponding isocyanates. DCM can be used as an alternative solvent.

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0.22 ml Triethylamine is added slowly to a mixture of 0.34 g piperidine trifluoroacetate C.2,

0.32 g triphosgene and 5 ml dichloromethane. The mixture is strirred at room température for h and 0.17 ml Ν,Ν-dimethyl-ethylendiamine are added and the reaction mixture is stirred at room température ovemight. The reaction mixture is concentrated under redueed pressure, a mixture of DMF, methanol and TFA is added, and the resulting mixture is filtered and purified ίο by préparative reversed-phase HPLC. The product-containing fractions are pooled and evaporated. The resulting residue is taken up with dichloromethane and a 4N NaOH solution is added. The organic phase is separated by a phase separator cartridge. Evaporation gives lise to 0.22 g of intermediate B.10. ESI-MS m/z: 329.

is B.33 B.34 B.39 B.35 B.36 B.38 B.40, B.51, B.52, B.53, B.54, B.55 and B.56

The following intermediates are obtained using a similar procedure as described for intermediate B.10 using the corresponding amines.

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-st-

B.53

To a suspension of 0.75 g of I.T-carbonyldip^Atriazole) in 5 ml of THF, a solution of 0.5 ml of 1-methylpiperazine dissolved in 5 ml of THF is added dropwise. The reaction mixture is stirred at room température for 40 minutes, then a solution of 0.5 g of intermediate C.2 (as free base) in 5 ml of THF is added dropwise and the réaction mixture is stirred at 60‘C overnight. The solvent Is evaporated, the crude product obtained is partitioned between dichloromethane and water and the organic phase is separated, dried over sodium sulfate and concentrated under vacuum. The crude product is purified by flash chromatography (eluent: AcOEt/MeOH=80/20) and re-purified by préparative LC-MS (reverse phase; NH4COOH) 150 mg of intermediate B.53 are obtained.

B.54 and B.55

The following intermediates are obtained using a similar procedure as described for intermediate B.53 using the corresponding amines

B.56

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B.56 is prepared following a similar procedure as in the préparation of B.53 starting from commercially available 4-cyano-4-phenylpiperidine and N,N-dimethylethylenediamine.

B.3

lntermediate B.3 Is prepared by reductive amination of lntermediate C.2 with formaldéhyde io and NaCNBHj in THF.

B.7 and B.21

The following Intermediates are obtained using a similar procedure as described for intermediate B.3 utilizing the corresponding carbonyl compounds.

B.5

-5016887

Intermediate B.5 is prepared by acylation of intermediate C.2 with benzoyl chloride and triethylamine in dichloromethane.

s B.1, B.11, B.13, B, 14, B.9 B.20 and B.47

The following intermediates are obtained using a similar procedure as described for intermediate B.5 using the corresponding acid chlorides.

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B.22

To a mixture of 1.07 g intermediate C.2,1.42 g N-BOC-beta alanine, 2.5 g EDCI in 50 ml anhydrous THF is added 4.90 ml triethylamine and 0.1 g DMAP. The reaction mixture is stirred s at r.t. ovemight. Water is added and the mixture concentrated and extracted with ethyl acetate. The combined organic phases are washed with sat. aq. NH₄CI and brine, dried over Na₂SO₄ and concentrated. The residual crude product is purified by FC giving rise to intermediate B.22 ίο B.23, B.25, B.24, B.26. B.27. B.46 and B.42

The foilowing intermediates are obtained using a similar procedure as described for interme diate B.22 using the corresponding acids.

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B.46 (Starting material: 3-Carboxy-propyl-trimethyl-ammonium chloride)

B.6

CS2CO3 in acetonitrile.

B.15

The intermediate B.15 was obtained using the following procedure.

methyi iodide at room température. The resulting reaction mixture was stirred for 16 hours.

Then the reaction mixture was diluted with ethyl acetate, washed with water followed by brine. The organic layer was dried over Na₂SO₄and concentrated under reduced pressure.

The crude product was purified by chromatography eluting with 18% ethyl acetate/petroleum ether on a silica gel column

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B.50

The following intermediate is obtained using a similar procedure as described for intermediate B. 15 using methyl iodlde.

B.16, B.28, B.29, B.30, B.31, B.32 and B.37

The following intermediates are obtained using a similar procedure as described for intermediate B.6 using the corresponding amines and the corresponding alkyl halides as alkylating 10 agents, K₂CO₃ and acetone.

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A.2

A suspension of 1.83 g of nitrile B.2, 0.40 g Raney-Nickel and 40 ml of a methanolic solution of ammonia are hydrogenated at room température and 3 bar H₂ for 23 h. In case of incomplète conversion additional catalyst and solvent are added and hydrogénation is continued for 5 h at 50’C. The catalyst is removed by nitration and the filtrate evaporated giving rise to io 1.95 g of intermediate A.2. ESI-MS m/z: 304

A.1. A.3, A.4, A.5, A.6, A.7, A.10, A.11, A.12, A.13, A.14, A.15, A.16, A.17, A.18, A.19, A.22, A.23, A.25, A.28, A.29, A.32, A.33, A.34, A.39, A.48, A.51, A.52, A.53, A.54, A.55, A.56 and A.57 u The following intermediates are obtained from the corresponding nitrites using a similar procedure as described for intermediate A.2.

-5516887

p •ss·

A.53 (Starting material: B.46)

A.54 (starting material: B.51)

N5

A. 59

io To a solution of 50 mg of intermediate B.55 in 3 ml of THF, 0.1 ml of borane tetrahydrofuran complex is added dropwise. The reaction mixture is stirred at room température for 30 min, then at 40^eC for 3h. 0.1 ml of borane tetrahydrofuran complex is added again and the reacton mixture is stirred at 50°C ovemight. The reaction mixture is partitioned between dichloromethane and water, the organic phase is washed with a saturated NaHCO3 water sois lution, dried over phase separator and concentrated under vacuum to give 42 mg of intermediate A.59.

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A.60

To a solution of 1 g of intermediate B.56 in 20 ml of THF stirred at -78’C, 1.2 ml of a 2M solution of lithium aluminium hydride in THF is added dropwise. The mixture is allowed to reach room température and stirred ovemight. The solvent is concentrated, the reaction mixture is partitioned between dichloromethane and water and organic phase is dried over phase separator and concentrated under vacuum to give 500 mg of crude product. 200 mg of this crude product are purifîed by préparative LC-MS (reverse phase; NH₄COOH). 60 mg of pure intermediate A.60 are obtained.

7.2 Synthesis of examples

Example 1

4-[N'-(3,5-Diamino-6-chloro-pyrazÎne-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1 carboxylic acid tert-butyl ester

A mixture of 80 mg (0,3 mmol) 4-aminomethyl-4-phenethyl-piperidine-1-carbocylic acid tertbutyl ester (A.55) and 104 mg (0,3 mmol) 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2methyl-isothiourea (intermediate C.61) in 2 ml acetonitrile is stirred at 70°C for 48 hours. Then the reaction mixture is concentrated under reduced pressure and the residue is purified by préparative reverse phase HPLC (gradient of acetonitrile and water + 0.2% trifluoroacetic acid, 25*C ). Fractions containing the title compound were concentrated under reduced pressure. Yield: 116 mg.

*6216887

The following compounds are prepared accordingly from starting materials as indicated:

s

Table 1:

ES) mass spectrum: Rétention time HPLC:

[M+H]* = 531

2,51 min (method M1 ).

Example	A	R¹	R’	R^s	R*	Starting material	Fn â O	S m i « o + +	Ret, [min]	HPLC Method
1.1	-CHrCHr	O II —ω— Il * O 1—	H	H	H	A.1	0,034	509	1,21	M2
1.2	-CH₂-CH₂-	« A HN ^O	H	H	H	A.2	0,008	516	1,28	M2
1.3	-CHrCHr	s	H	H	H	A.3	0,033	445	1,67	M1
1.4	-CH_rCH_r	À H₂N ^0	H	H	H	A.4	0,027	474	1,21	M2
1.5	-ch₂-ch₂-	cA	H	H	H	A.5	0,034	535	2,23	M1

-6316887

Example	A	R¹	R^a	R³	R⁴	Starting material	es	S m £ <2 s + +	Ret. [min]	HPLC Method
1.6	-CHrCHî-	y	H	H	H	A.6	0,040	521	1,90	M2
1.7	-CH₂-CH_r	*	H	H	H	A.7	0,063	473	0,95	M2
1.8	CH2	À HN O	H	H	H	A.8	0,017	502	1.25	M2
1.9	-CHz-CH^·	Â	H	H	H	A.9	0,011	503	1,41	M2
1.10	-CHrCHr	À ^Hhl 0	H	H	H	A.10	0,036	545	1.42	M4
1.11	-CHrCHr	y	H	H	H	A.11	0,017	515	1,49	M2
1.12	-CH_rCHr	e J4N^0	H	H	H	A.12	0,012	502	1,30	M2
1.13	ΌΗςΌΗ?·	y	H	H	H	A.13	0,013	501	1,36	M2

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Example	A	R’	R²	R³	R⁴	Starting material	IC 50 [μΜ]	ESI* (M+HJ+	Ret. [min]	HPLC Method
1.14	-CHrCHr	”/· /O	H	H	H	A.14	0,020	545	1,23	M2
1.15	-CHrCHr	* /\ CF3-COO-	H	H	H	A.15	0,091	459 (M+ )	1,05	M2
1.16	-CHrCHr	* Y /0	H	H	H	A.16	0,002	503	1,07	M2
1.17	CHrCHr		H	H	COOMe	A.17	0,056	589
1.18	-CHrCHr	t HN'^O V /0	H	H	H	A.18	0,028	546	1,30	M2
1.19	-CHrCHr	« HN'^O	H	H	H	A.19	0,024	560	1,33	M2
1.20	-CHr	Y /0	H	H	H	A.20	0,075	531	1,04	M6

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Example	A	R¹	R^a	R^s	R⁴	Starting material	rô SS	ESI+ (M+H)+	Ret. [min]	HPLC Method
1.21	-CH_r	* 1	H	H	H	A.21	0,089	431
1.22	-CHrCHr	Y	H	H	H	A. 22	0,037	602	1,26	M7
1.23	-CHrCHr	O O	H	H	H	A.23	0,026	502	1,19	M6
1.24	-CH_r	Λ O^NH Y	H	H	H	A.24	0,027	574	1.19	M8
1.25	-CHrCHr	<γ Y	H	H	H	A.25	0,018	588	1.27	M7
1.26	-CHr	O O	H	H	H	A.26	0,019	616	1.27	M7

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Example	A	R’	R³	R³	R*	Starting material	En 3 m •=3 o	ESI+ (M+H)+	Ret. [min]	HPLC Method
1.27	-CH_r		H	H	H	A.27	0,033	588	1.24	M7
1.28	-CH_rCH_r	• y	H	H	H	A.28	0,036	588	1.08	M7
1.29	-CHrCHî-	y I	H	H	H	A.29	0,086	516	0.90	M7
1.30	-ch₂-	V	H	H	H	A.30	0,070	489	1.13	M8
1.31	-CHr	y I	H	H	H	A.31	0,287	502	0.87	M7
1.32	-CHrCHr	*	H	H	H	A.32	0,046	502	0.90	M7

-6716887

Example	A	R’	R^J	R³	R⁴	Starting material	eô SS	? ^mχ£2 s + +	Ret. [min]	HPLC Method
1.33	-CHrCHr	• O^NH °Y	H	H	H	A.33	0,007	617	1.14	M6
1.34	-CH2-CH2-	0^··	H	H	H	A.34	0,010	631	1.18	M6
1.35	-CH_r	HN^O ΟγΝΗ V	H	H	H	A.35	0,011	603	1.65	M5
1.36	-CH_r	• hijAo HIT	H	H	H	A.36	0,018	617	1.68	M5
1.37	-CH_r	J	H	H	H	A.37	0,064	574	1.42	M5

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Example	A	R¹	R¹	R³	R*	Starting material	PÔ 23	S m + ω 3 + +	Ret. [min]	HPLC Method
1.38	-CH_r	• HN^O y	H	H	H	A.38	0,042	545	1.38	M4
1.39	-CH2CH2	/ —Z \ ^T	H	H	H	A.39	0,023	559	1.44	M4
1.40	-CH2·	« A,	H	H	H	A.40	0,029	531	1.35	M5
1.41	-CH2-	*	H	H	H	A.41	0,091	488	1.20	M5
1.42	bond		H	H	H	A.42	0,025	503	2,28	M1
1.43	bond	* hnX	H	H	H	A.43	0,041	488	1.52	M3

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Example	A	R¹	r^!	R^J	R⁴	Starting material	eô 23	ESI+ (M+HJ+	Ret. [min]	HPLC Method
1.44	bond	• HN^O A	H	-O-CH2-O-	A.44	0,046	532	1,56	M3
1.45	bond	A	0Me	H	H	A.45	0,066	533	1,78	M3
1.46	-CH_r		H	H	H	A.46	0,061	517	1,83	M3
1.47	bond	°\	H	H	H	A.47	0,029	517	1,000	M6
1.48	-CHz-CHr	Λ /Νχ.	H	H	H	A.51	0,13	516	1.0	M7
1.49	-CHrCHr	* /K . \ Cl	H	H	H	A.52	0,022	530	1,01	M7
1.50	-CH2-CH2-	Λ A	H	H	H	A.53	0,015	558	1,50	M5

-7016887

Example	A	R’	R®	R⁵	R⁴	Starting material	IC50 [μΜ]	Sm + en +	Ret. [min]	HPLC Method
1.51	-CHz-CHz-	\ O	H	H	COOMe	A.54
1.52	-CHz-CHr	* HN'^'O	H	H	CONH2	A.56

Example 1.53

To a solution of 140 mg (0.36 mmol) of intermediate A.57 in 2.5 ml of DMF, 0.13 ml of N,N s -diisopropylethilamine is added. The reaction mixture is stirred at room température for 10 minutes then 85 mg (0.33 mmol) of 1-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-2-methyl· isothiourea is added. The reaction mixture is heated at 70°C for 3 hours.

The solvent Is removed and the crude product obtained is purified by flash chromatography (first eluent: AcOEt/MeOH=90/10 in order to remove impurities; second eluent dichloroio methane/MeOH/NH3 from 90/10/0.1 to 50/50/0.1 to give the desired product).

Yield: 55 mg.

IC50[pM] = 0.014

ESI mass spectrum: [M+HJ* = 557

Rétention time HPLC: 5.60 min (method M9).

Table 1.1:

-7116887

Example	A	R¹	R¹	R³	R⁴	Starting material	e ô 2g	? ^ms? +	Ret [min]	HPLC Method
1.54	-CHrCHr	• cAn	H	H	H	A.58	0.046	571	5.38	M10
1.55	-CHrCH_r	•	H	H	H	A.59	n.a.	629	3.52	M11
1.56	bond	• O^N^\|	H	H	H	A.60	n.a.	517	3.08	M11

s Example 2

N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N’-(4-phenethyl-piperidin-4-ylmethyl-guanidine

A mixture of 50 mg (0,3 mmol) 4-[N’-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)to guanidinomethyl]-4-phenethyl-piperidine-1-carboxylic acid tert-butyl ester (Example 1) in 1 ml dichloromethane is stirred with 250 pl trifluoroacetic acid at room température for 2 h.

Then the reaction mixture is concentrated under reduced pressure.

Yield: 40 mg.

ESI mass spectrum: [M+H]* = 431

-7216887

Rétention time HPLC: 1,78 min (method M1 ).

Table 2:

Example	A	R¹	R²	R³	R⁴	Starting material	o en o F 2	3 m + ω 3 + +	Ret [min]	Méthode HPLC
2.1	-CHrCHr	• H	H	H	COOMe	1.17	0,394	489
2.2	•CHrCHr	A	H	H	H	1.22	0,01S	502
2.3	-CHrCHr	h₂n	H	H	H	1.23	0,023	530	1.03	M7
2.4	-CH_r	A nh₂	H	H	H	1.24	0,059	508 (M+ CL)-	0.90	M6
2.5	•CHrCHr	*	H	H	H	1.28	0,065	488	0.89	M6

-7316887

Example	A	R¹	R²	R³	R⁴	Starting material	ô U1 0 Ç	ESI+ (M+H)+	Ret. [min]	Méthode HPLC
2.6	-CHrCHj-	* HN^O H₂hF	H	H	H	1.34	0,02ε	531	1.57	M4
2.7	-CH2-CH2-	• HN^O nh₂	H	H	H	1.33	0,016	517	1.56	M4
2.8	-CH2-	Z	H	H	H	1.26	0,061	516	0.97	M7
2.9	-ch₂-	Λ h₂n	H	H	H	1.27	0,093	488	0.96	M7
2.10	bond	H	0Μθ	H	H	1.45	0,20C	433	1,26	M3
2.11	-CH₂-	H	H	H	H	1.46	0,055	417	1,31	M3
2.12	-ch₂-	« ^HTsl^O nh₂	H	H	H	1.35	0,017	503	0,93	M6
2.13	-CH₂-	« HN^O HjhF	H	H	H	1.36	0,025	517	0,93	M6

-7416887

Example	A	R¹	R²	R³	R⁴	Starting material	IC50 [μΜ]	ESI+ (M+H)+	Ret. [min]	Méthode HPLC
2.14	-CH_r		J	H	H	H	1.37	0,12	474	0,85	M6

Example 3 (^(N’-CS.S-Diamino-G-chloro-pyrazine^-carbonylJ-guanidinomethyll^phenethyl-pÎperidin-ls yl) acetlc acid

mmol) {4-[N'-(3,5-diamÎno-6-chloiO-pyrazÎne-2-carbonyl)-guanidinomethyi]-4-phenethyl15 piperidin-1-yl}-acetic acid methyl ester (Example 1.16 ) in 5 ml methanol and 235 μΙ 4 N

NaOH is stirred at 50°C for 1 hour. Then the solution is acidified with 470 μΙ 4 N HCl and concentrated under redueed pressure. The residue is purified by préparative reverse phase HPLC (gradient of acetonitrile and water + 0.2% trifluoroacetic acid, 25°C ). Fractions containing the title compound were concentrated under redueed pressure.

Yield: 35 mg.

ESI mass spectrum: [M+H]* = 489

Rétention time HPLC: 1,33 min (method M2)

Table 3:

-7516887

Example	A	R1	R2	R3	R4	Starting material	^8	? ^m± + +	Ret. [min]	Méthode HPLC
3.1	-ch₂-ch₂-	0 0	H	H	H	1.14	0,040	531	1,21	M2
3.2	-CHrCHr	Â HN O ctOh	H	H	H	1.19	0,149	546	1,43	M2
3.3	-CHrCHj-	• HN^^O V OH	H	H	H	1.18	0,010 1	532	1.27	M2

Example 4

4-[N^,-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-pÎperidine-1carboxamidine

A mixture of 70 mg (0,15 mmol) N-^.S-diamino-e-chloro-pyrazine-Z-carbonylï-N'-tAphenethyl-piperidin-4-ylmethyl-guanidine (Example 2 ), 124 pl triethylamine and 28 mg (0,19 mmol) 1H-1.2.4-triazole-1-carboxamidine monohydrochloride in 5 ml DMF is stirred at 70 ’C ίο for 2 hours. Then 1 ml methanol is added and the mixture is purified by préparative reverse phase HPLC (gradient of acetonitrile and water + 0.2% trifluoroacetic acid, 25’C ). Fractions containing the title compound were concentrated under reduced pressure.

Yield: 15 mg.

ESI mass spectrum: [M+H]* = 473 is Rétention time HPLC: 0,93 min (method M7)

Table 4:

-7616887

Example	A	R¹	r^!	R¹	R⁴	Starting material	•ε o S ⁰¹w 0	S m â? +	Ret. [min]	Méthode HPLC
4.1	-CH2-CH2-	Λ HN HN^NHj	H	H	H	2.2	0,012	544	1.01	M7
4.2	-CH2-CH2-	/' HN HN^NH₂	H	H	H	2.3	0,018	570 (M-H)-	1.51	M4

Example 5 s (2-((4-[N'-(3₁5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethylpiperidine-1 -carbonyl)-amino)-ethyl]-trimethyl-ammonium chloride

1.55 g 4-[N’-(3₁5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethylpiperidine-1-carboxylic acid (2-dimethylamino-ethyl)-amide (example 1.40), 0.9 ml triethylaio mine and 1.1g BOC anhydride were dissolved in 50 ml THF and stirred over night. The organic layer is separated and concentrated under reduced pressure.

Yield: 1.3 g

-7716887

A mixture of 1.3 g Ex. 5A and 200 μΙ methyl iodide in 10 ml acetone is stirred overnight at room température. Then the reaction mixture is concentrated under reduced pressure and 5 s ml of a 50% solution of trifluoroacetic acid in dichloromethane is added and stirred for 2 h at room température. Then the mixture is co-evaporated with methanolic hydrochloric acid. The residue is purified via préparative reverse phase HPLC (gradient of acetonitrile and water + 0.2% trifluoroacetic acid, 25°C ). Fractions containing the title compound were concentrated under reduced pressure and finally co-evaporated with methanolic hydrochloric acid.

io Yield: 820 mg.

ESI mass spectrum: [M]* = 559

Rétention time HPLC: 0,97 min (method M7)

The following compounds are prepared accordingly from starting materials as indicated: Table 5:

Example	A	R¹	R²	R^J	R⁴	Starting material	’π o 38	ESI+ (M+H1+	Ret. [min]	Méthode HPLC
5.1	-CHrCHr	• ηνΆ> ïfa-	H	H	H	1.39	0,027	573 (M+ )	1,013	M7

-7816887

5.2	-CHrCHr	• hAo I ♦ Cl'	H	H	COOMe	1.51	0,074	617	1,01	M7
5.3	-CH_rCH₂-	« HN^O _ I ♦ CI'	H	H	CONH2	1.52	0.12	301 (M+ +)	0,80	M7
5.4	-CH_rCH₂-	• a	H	H	H	1.53	0.051	571	2.80	M9
5.5	-CHrCHr	rr^N	H	H	H	1.54	0.052	585	3.47	M1 1
5.6		t rA —K I HCOO	H	H	H	1.56	n.a.	531	4.88	M1 1

Example 6

A mixture of 115 mg A.48 and 104 mg (0.3 mmol) 1-(3,5-Diamino-6-chloro-pyrazine-2carbonyl)-2-methyl-iSothiourea in 25 ml THF are stirred at 70^eC for 80 hours. Then the reaction mixture is concentrated under reduced pressure and the residue is purified via chroma-7916887 tography (Silica, dichloromethane/rnethanol plus 10% ammonia 9:1 to 6/4). Fractions containing the title compound were concentrated under reduced pressure.

Yield: 27 mg.

ESI mass spectrum: [M+H]* = 1001 s Rétention time HPLC: 1,41 min (method M2 ).

Table 6

Example	Structure	Startimg material	IC 50 [μΜ]	ESI+ (M+H)+	Ret. [min]	Méthode HPLC
6.1	-Q		A.49	0,097	(M+H)/2 + 515	1,52	M2
	^ηΎγ c HN >	Y
		O l \
	y
	O_/~ y
	nh₂
	M
	HjN	Cl

-8016887

Example 7

N-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-N'-(4-phenethyl-1-phenylacetyl-piperidin-4ylmethylj-guanidine

To a mixture of 70 mg (0.14 mmol) N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-N^,-(4phenethyl-piperidin-4-ylmethyl)-guanidine (example 2) and 118 pl Hunig's base in 5 ml dichloromethane 27 μΜ (0,21 mmol) phenacetylchloride is dropwise added and stirred at room io température overnight. Then the mixture concentrated under reduced pressure. The residue

Is purified via préparative reverse phase HPLC (gradient of acetonitrile and water + 0.2% trifluoroacetic acid, 25°C ). Fractions containing the title compound were concentrated under reduced pressure.

Yield: 9 mg.

u ESI mass spectrum: [M+H]* = 549

Rétention time HPLC: 1,42 min (method M2)

Example 8

4-[N‘-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanÎdinomethyl]-4-phenethyl-piperidine-120 carboxylic acid propylamide

H.

To a mixture of 100 mg (0.198 mmol) N-(3,5-diamino-6-chloro-pyrazine-2-carbonyl)-N'-(425 phenethyl-piperidin-4-ylmethyl)-guanidine (example 2) and 29 μΙ DBU in 5 ml THF 12 μΜ (0.2 mmol) N-propylisocyanat is dropwise added and stirred at room température for 2 h. Then the mixture is concentrated under reduced pressure. The residue is purified via préparative

-8116887 reverse phase HPLC (gradient of acetonitrile and water + 0.2% trifluoroacetic acid, 25^eC ).

Fractions containing the title compound were concentrated under reduced pressure.

Yield: 10mg.

ESI mass spectrum: [M+H]* - 516 s Rétention time HPLC: 2,2 min (method M1 )

Example 9

N-[1-(2-Amino-acetyl)-4-phenethyl-piperidin-4-ylmethyl-N’-(3,5-diamino-6-chloro-pyrazine-2carbonylj-guanidine

A mixture of 130 mg (0,35 mmol) [2-(4-aminomethyl-4-phenethyl-piperidin-1-yl)-2-oxo-ethyl]carbamic acid tert-butyl ester (A.50) and 80 mg (0,3 mmol) 1-(3,5-diamino-6-chloro-pyrazineis 2-carbonyl)-2-methyl-isothiourea in 5 ml tetrahydrofuran is stirred at 70’C ovemight. Then the reaction mixture is concentrated under reduced pressure and the residue is purifîed via préparative reverse phase HPLC (gradient of acetonitrile and water + 0.2% trifluoroacetic acid, 25’C). Fractions containing the title compound were concentrated under reduced pressure. Then the residue is co-evaporated with methanolic hydrochloric acid in order to remove 2o the protecting group.

Yield: 37 mg.

ESI mass spectrum: [M+H]* = 488

Rétention time HPLC: 1,08 min (method M7).

Example 10

4-{4-[N^,-(3,5-Diamino-6-bromo-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidin

1-yl)-4-oxo-butyric acid methyl ester

-8216887

[(methylsulfanyl)methanimidoyl]pyrazine-2-carboxamide (lntermediate C.62) instead of intermediate C.61.

ESI mass spectrum: [M+H]* » 589

Rétention time HPLC: 0.72 min (method M12)

IC50[pM] = 0.032

Example 11

4-{4-[N’-(3,5-Diamino-6-bromo-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidin-

ample 3, applying example 10 as starting material.

ESI mass spectrum: [M+H]* = 575

Rétention time HPLC: 0.49 min (method M13)

IC50[pM] = 0.502

8. Analytical methods

HPLC/MS Methods

Method: M1

Waters ZQ2000; Waters 1515 pump, Waters PDA 996 Detector, Waters 2747 Injector

Mobile Phase: A: Water + 0.1% formic acid

-8316887

B: Acetonitrile + 0.1% formic add

Gradient:

time In min	%A	%B	flow rate in ml/min
0.00	95.0	5.0	1.00
0.10	95.0	5.0	1.00
3.10	2.00	98.00	1.00
4.50	2.00	98.00	1.00
5.00	95.0	5.0	1.00

Stationary Phase: X-terra™ MS C18 2,5 pm 4.6 mm x 30 mm

Column température about. 25°C

Diode array détection wave length range 210 - 420 nm mass range m/z 80 to 800

Ionization: ESI positive

Method: M2

Waters ZQ2000; Waters 1515 Pump, Waters PDA 996 Detector, Waters 2747 Injector

Mobile Phase: A: water + 0.1 % formic acid

B: Acetonitrile + 0.1% formic acid

Gradient:

time in min	%A	%B	flow rate in ml/min
0.00	95.0	5.0	1.5
2.00	0.0	100	1.5
2.50	0.0	100	1.5
2.60	95.0	5.0	1.5

Stationary Phase: X-terra™ MS C18 2,5 pm 4,6 mm x 30 mm Column température about. 25’C

Diode array détection range 210 - 420 nm

Mass range m/z 80 to 800

Ionization : ESI positive/negative

Method: M3 Analytical column: XBridge C18 (Waters technologies)

XBridge C18,4.6 x 30 mm, 2,5 pm column température 60’C

Mobile phase A: H2O: trifluoroacetic add 99.9:0.1

Mobile phase B: Methanol: trifluoroacetic add 99.9:0.1

-84·

Gradient:

time in min	%A	%B	flow rate in ml/min
0.0	95	5	4
0.05	95	5	3
2.05	0	100	3
2.10	0	100	4
2.35	0	100	4

Method: M4 s Analytical column: XBridge C18 (Waters technologies) XBridge C18,4.6 x 30 mm, 2.5 pm column température 60°C Mobile phase A: H2O: trifluoroacetic acid 99.9:0.1

Mobile phase B: Methanol: 100 io Gradient:

time in min	%A	%B	flow rate in ml/min
0.0	95	5	4
0.05	95	5	3
2.05	0	100	3
2.10	0	100	4.5
2.40	0	100	4.5

Method: M5

Analytical column: Sunfire C18 (Waters technologies)

Sunflre C18, 4.6 x 30 mm, 2.5 pm column température 60*C is Mobile phase A: H2O: trifluoroacetic acid 99.9:0.1

Mobile phase B: Methanol: 100

Gradient:

Method: M6

-8516887

Analytical column: XBridge C18 (Waters technologies) XBridge C18,3.0x 30 mm, 2.5 pm column température 60°C Mobile phase A: H2O: trifluoroacetic acid 99.9:0.1

Mobile phase B: Methanol: 100

Gradient:

time In min	%A	%B	flow rate in ml/min
0.0	95	5	2.2
0.30	95	5	2.2
1.50	0	100	2.2
1.55	0	100	2.9
1.65	0	100	2.9

Method: M7

Analytical column: Sunfire C18 (Waters technologies) îo Sunfire C18,3.0 x 30 mm, 2.5 pm column température 60’C

Mobile phase A: H2O: trifluoroacetic acid 99.9:0.1

Mobile phase B: Methanol: 100

Gradient:

time in min	%A	%B	flow rate in ml/min
0.0	95	5	1.8
0.25	95	5	1.8
1.70	0	100	1.8
1.75	0	100	2.5
1.90	0	100	2.5

Method: M8

Analytical column: XBridge C18 (Waters technologies)

XBridge C18,3.0x 30 mm, 2.5 pm column température 60°C 20 Mobile phase A: H2O: Ammonia 99.9:0.1

Mobile phase B: Methanol: 100

Gradient:

time in min	%A	%B	flow rate in ml/min
0.0	95	5	2.2
0.30	95	5	2.2

-8616887

1.50	100	2.2
1.55	100	2.9
1.70	100	2.9

Method: M9

Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, MSQ single quadrupole Column: Synergi Hydro RP100A, 2,5 pm, 3 x 50 mm s Mobile phase: A = H2O 90% + 10% CH3CN + NH4COOH 5 mM

B = CH3CN 90% + H2O 10%

Gradient:

time in min	%A	%B	flow rate in ml/min
0.0	100	0	1.2
4.00	0	100	1.2
5.30	0	100	1.2
5.50	100	0	1.2
6.00	100	0	1.2

Détection: UV 254 nm ίο Détection: Finnigan MSQ, single quadrupole

Ion source: APCI+/APCIScan range: 100-900 amu

Method: M10 is Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, MSQ single quadrupole

Column: Synergi Hydro RP100A, 2,5 pm, 3 x 50 mm

Mobile phase: A = H2O 90% + 10% CH3CN + NH4COOH 5 mM

B = CH3CN 90% + H2O 10%

Gradient:

time in min	%A	%B	flow rate in ml/min
0.0	100	0	1.2
1.5	100	0	1.2
9.00	0	100	1.2
10.50	0	100	1.2
11.00	100	0	1.2
12.00	100	0	1.2

Détection: UV 254 nm

-8716887

Détection: Finnigan MSQ, single quadrupole

Ion source: APCI+/APCIScan range: 100-900 amu $ Method: M11

Instrument: LC/MS Waters Alliance 2695 HPLC System DAD, Quattro Micro Triple quadrupole

Column: Atlantis dC18 50m 4,6x50 mm, Temp 35*C

Mobile phase: A = H₂O 90% + 10% CH₃CN + CF₃COOH 0,05% ίο B = CH₃CN 90% + 10% H₂O

Gradient:

time in min	%A	%B	flow rate in ml/min
0.0	100	0	1.3
0.70	100	0	1.3
4.5	0	100	1.3
5.8	0	100	1.3
6.00	100	0	1.3

Détection:	UV 254 nm
Détection:	Quattro Micro, triple quadrupole
is Ion source:	ES+
Scan range:	90-1000 amu

Method: M12

Column:	Sunfire, 3 x 30 mm, 2.5 pm (Waters)
Gradient time [min]	% Sol [H2Q,0.1%TFA]	% Sol [Acetonitrile]	Flow [ml/min]	Temp [’C]
0.00	97	3	2.2	60
0.20	97	3	2.2	60
1.20	0	100	2.2	60
1.25	0	100	3	60
1.40	0	100	3	60

Method: M13

Column:	Sunfire C18, 2.1 x 30 mm, 2.5 pm (Waters)
Gradient time [min]	% Sol [H2Q,0.1%TFA]	% Sol [Acetonitrile]	Flow [ml/min]	Temp [*C]

-8816887

0.0	99	1	1.5	60
0.02	99	1	1.5	60
1.00	0	100	1.5	60
1.10	0	100	1.5	60

9. PHARMACOLOGICAL TEST METHOD

Ussing Chamber: Mouse kidney M-1 cells were cultivated in DMEM containing 5% FCS s and 5μΜ dexamethasone for 10 to 12 days on polyester transweli filters. Filters were inserted into a teflon-coated well-plate which fit into the in-house ussing chamber system. Prior to measurement the medium of M-1 cells was replaced with Caco-2 transport buffer (Invitrogen, Germany). During measurements, the Ussing chamber température was kept at 37^eC. Short circuit currents (l_sc) were measured in the voltage-clamp mode using an in-house built amlo plifier (Boehringer Ingelheim, Biberach) with the software package Lab View for data acquisition and analysis. The transepithelial electrical résistance (TEER) was determined by the application of voltage steps of ±5mV every 5 sec. Compounds were administered at a final concentration of 3μΜ or at increasing concentrations (1-3-10μΜ) to the apical solution. At the end of each experiment the amiloride sensitive l_SC was measured by adding 3μΜ amiloride i5 to the apical compartment. Results are expressed as inhibition in percent of the amiloride effect or as IC50. Results are listed in tables 1 to 5 and further examples listed above.

10. Indications

As has been found, the compounds of formula (I) are characterised by their wide range of applications in the therapeutic field. Particular mention should be made of those applications for which the compounds according to the invention of formula (I) are preferably suited on account of their pharmaceutical efficacy as ENaC inhibitors. Examples include respiratory 25 diseases or complaints, or allergie diseases of the airways,

Particular mention should be made of the prévention and treatment of diseases of the airways and of the lung which are accompanied by increased mucus production, inflammations and/or obstructive diseases of the airways. Examples include acute, allergie or chronic bron30 chitis, chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema, allergie or non-aliergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, Farmer's disease, hyperreactive airways, infectious bronchitis or pneumonitis, pédiatrie asthma, bronchiectases, pulmonary fibrosis, ARDS (acute adult respiratory distress syndrome), bronchial oe

-8916887 dema, pulmonary oadama, bronchitis, pneumonia or interstitial pneumonia triggered by various causes, such as aspiration, Inhalation of toxic gases, or bronchitis, pneumonia or Interstitial pneumonia as a resuit of heart failure, irradiation, chemotherapy, cystic fibrosis or mucoviscidosis, or alpha 1-antitrypsin deficiency.

Particularly preferably the présent invention relates to the use of compounds of formula (I) for preparing a pharmaceutical composition for the treatment of Inflammatory or obstructive diseases of the upper and lower respiratory tract including the lungs, such as for example allergie rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, COPD, chronic bronchitis, 10 chronic sinusitis, asthma, particularly COPD, chronic bronchitis, cystic fibrosis and asthma.

It is most préférable to use the compounds of formula (I) for the treatment of inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, cystic fibrosis, particularly COPD, chronic bronchitis and cystic fibrosis.

is

The actual pharmaceutically effective amount or therapeutic dosage will of course dépend on factors known by those skilled in the art such as âge and weight of the patient, route of administration and severity of disease. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered 2o based upon patient's unique condition.

11. Combinations

The compounds of formula (I) may be used on their own or in conjunction with other active 25 substances of (I) according to the invention. If desired the compounds of formula (I) may also be used in combination with other pharmacologically active substances.

Therefore the invention further relates to médicament combinations which preferably contain, besides one or more compounds of formula (I), as further active substances, one or more compounds selected from among the categories of further ENaC Inhibitors, betamimetics, 30 anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, MAP-kinase Inhibitors, MPR4-lnhibitors, iNOS-Inhibitors, SYK-Inhibitors, corrections of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators, or double or triple combinations thereof.

Examples of preferred betamimetics which may be mentioned include Albuterole, Arfor35 moterole, Bambuterole, Bitolterole, Broxaterole, Carbuterole, Clenbuterole, Fenoterole, Formoterole, Hexoprenaline, Ibuterole, Isoetharine, Isoprénaline, Levosalbutamole, Mabuterole, Meluadrine, Metaproterenole, Milveterol, Orciprenaline, Pirbuterole, Procaterole, Reproter-9016887 oie, Rimiterole, Ritodrine, Salmefamole, Salmeterole, Soterenole, Sulphonterole, Terbutaline,

Tiaramide, Tolubuterole, Zînterole, Nolomirole, and • 1-(2-chloro-4-hydroxyphenyl)-t-butylaminoethanole, • (-)-2-[7(S)-[2(R)-Hydroxyⁱ2-(4-hydroxyphenyl)-ethylaminol-5₁6,7,8-tetrahydro-2- naphthyloxy]-N,N-dimethylacetamide hydrochloride monohydrate, • 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)benzyl-sulfonamide • 5-[2-i5,6-Diethyl-indan-2-ylamino)-1-hydroxy-ethyl]-8-hydroxy-1H-quinoline-2-one • 4-Hydroxy-7-[2-{[2-([3-(2-phenylethoxy)propyl]sulphonyl}ethyll-amino}ethyl]-2(3H)- io benzothiazolone • 1-(2-Fluoro-4-hydroxyphenyl)-2-[4-(1-benzimidazolyl)-2-methyl-2-butylaminolethanole • 1-[3-(4-Methoxybenzyl-amino)-4-hydroxyphenyl]-2-[4-(1-benzimidazolyl)-2-methyl-2butylaminojethanole • 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-N,N-dimeth>daminophenyl)-2is methyl-2-propylaminolethanole • 1-[2H-5-hydroxy-3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-methoxyphenyl)-2-methyl-2propy!amino]ethanola • 1 -[2H-5-hydroxy^3-oxo-4H-1,4-benzoxazin-8-yl]-2-[3-(4-n-butyloxyphenyl)-2-methyl-2propylamino]ethanole · 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}ethanole • 5-Hydroxy-8-(1-hydroxy-2-isopropylaminobutyl)-2H-1,4-benzoxazin-3-(4H)-one • 1-(4-Amino-3-chloro-5-trifluormethylphenyl)-2-tert.-butylamino)ethanole • 6-Hydroxy-8-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1_t1’dimethyl-ethylamino]-ethyl}-4H’ benzo[1,4]oxazin-3-one • 6-Hydroxy-8-(1-hydroxy-2-[2-(4-phenoxy-acetic acid ethylester)-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>4Hbenzo[1,4]oxazin-3-one

3o · 8-{2-[1, 1-Dimethyl-2-(2,4_l6-trimethylphenyl>ethylamino]-1-hydroxy-ethyl>6-hydroxy-4Hbenzo[1,4]oxazin-3-one • 6-Hydroxy-8-{1-hydroxy-2-[2-(4-hydroxy-phenyl>1_l1-dimethyl-ethylamino]-ethyl}-4Hbenzo[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-4Hbenzo[1,4]oxazin-3-one

-9116887 • 8-{2-[2-{4-Ethoxy-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4Hbenzo[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)-bulyric acid · 8-{2-[2-{3,4-Difluor-phenyl)-1,1-dimethyl-ethylamino]-1-hydroxy-ethyl}-6-hydroxy-4Hbenzo[1,4]oxazin-3-one • 1-(4-Ethoxy-carbonylamino-3-cyano-5-fluorophenyl)-2-(tert.-butylamino)ethanole • N-[2-Hydroxy-5-( 1 -hydroxy-2-{2-[4-(2-hydroxy-2-phenyl-ethylamino)-phenyl]-ethylamino}io ethylj-phenylj-formamide • 8-Hydroxy-5-(1-hydroxy-2-{2-[4-(6-methoxy-biphenyl-3-ylamino)-phenyl]-ethylamino}ethyl )-1 H-quinolin-2-one • 8-Hydroxy-5-[1-hydroxy-2-{6-phenethylamino-hexylamino)-ethyl]-1H-quinolin-2-one • 5-[2-{2-{4-[4-(2-Amino-2-methyl-propoxy)-phenylamino]-phenyl}-ethylamino)-1 -hydroxyis ethyl]-8-hydroxy-1 H-quinolin-2-one • [3-{4-{6-[2-Hydroxy-2-(4-liydroxy-3-hydroxyniethyl-phenyl)-ethylamino]-hexyloxy}-butyl)-

5-methyl-phenyl]-urea • 4-(2-{6-[2-(2_l6-Dîchloro-benzyloxy)-ethoxy]-hexylamino}-1-hydroxy-ethyl)-2- hydroxymethyl-phenole • 3-(4-{6-[2-Hydroxy-2-(4-hydroxy-3-hydroxymethyl-phenyl)-ethylamino]-hexyloxy}-butyl)benzenesulfonamide • 3-(3-{7-[2-Hydroxy-2-(4-hydroxy-3-hydroxynielhyl-phenyl)-ethylamino]-heptyloxy}-propyl)benzenesulfonamide

2s · 4-(2-{6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino)-1 -hydroxy-ethyl)-2hydroxymethyl-phenole • N-Adamantan-2-yl-2-(3-(2-[2-hydroxy-2-(4-hydroxy-3-hydroxyniethyl-phenyl)-ethylamino]propyl)-phenyl)-acetamide · (R,S)-4-(2-{[6-{2,2-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2(hydroxymethyl)phenole • (R,S)-4-(2-{[6-(2_l2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2- (hydroxymethyl)phenole • (R,S)-4-(2-{[4_l4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2-

3î (hydroxymethyl)phenole • (R,S)-4-(2-{[6-{4,4-Difluoro-4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2(hydroxymethyl)phenole

-9216887 • (R,S)-5-(2-([6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-8hydroxyquinolin-2(1 H)-one • (R,S)-[2-((6-[2,2-Difluoro-2-(3-methylphenyl)ethoxy]hexyl}amino)-1 - hydroxyethyl]-2(hydroxymethyl)phenole · 4-(1 R)-2-([6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxyethyl)-2(hydroxymethyl)phenol • (R,S)-2-(Hydroxymethyl)-4-(1-hydroxy-2-([4,4_l5l5-tetrafluoro-6-(3-phenylpropoxy)hexyl]amino}ethyl)phenole • (R,S)-[5-(2-([6-(2,2-Difluoro-2-phenylethoxy)hexyl]amino}-1-hydroxy-ethyl)-2- hydroxyphenyl]formamide • (R,S)-4-[2-((6-[2-(3-Bromophenyl)-2,2-difluoroethoxy]hexyl)amino)-1-hydroxyethyl]-2(hydroxymethyl)phenole • (R, S)-N-[3-(1,1 -Difluoro-2-([6-((2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl)phenyl]ethyl)amino)hexyl]oxy}ethyl)phenyl]urea u · 3-(3-(1,1-difluoro-2-([6-({2-hydroxy-2-[4-hydroxy-3-(hydroxymethyl) phenyljethyl}amino)hexyl]oxy}ethyl)phenyl]imidazolidine-2,4-dione • (R,S)-4-[2-({6-[2,2-difluoro-2-(3-methoxyphenyl)ethoxy]hexyl)amino)-1-hydroxyethyl]-2(hydroxymethyl)phenole • 5-((1 R)-2-([6-(2,2-difluoro-2-phenylethoxy)hexyl]amino}-1 -hydroxyethyl)-8- hydroxyquinolin-2(1 H)-one • 4-((1R)-2-([4,4-Difluoro-6-(4-phenylbutoxy)hexyl]amino}-1-hydroxy-ethyl)-2(hydroxymethyl)phenole • (R,S)-4-(2-([6-(3,3-Difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy-ethyl)-2(hydroxymethyl)phenole · (R,S)-(2-([6-(2,2-Dîfluoro-2-phenylethoxy)-4_l4-difluorohexyl]amino}-1 -hydroxyethy l)-2(hydroxymethyl)phenole • (R,S)-4-(2-([6-(2,2-difluoro-3-phenylpropoxy)hexyl]amino}-1-hydroxy ethyl)-2(hydroxymethyl)phenole • 3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-(2-[2-(4-hydroxy-2-oxo-2,3- dihydro-benzothiazol-7-yl)-ethylamino]-ethyl}-propionamide • N-(2-Diethylamino-ethyl)-N-(2-[2-{4-hydroxy-2-oxo-2,3-dihydro-benzothiazol-7-yl)ethylamino]-ethyl}-3-(2-naphthalen-1-yl-ethoxy)-propionamide • 7-[2-(2-(3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl}-ethylamino)-1-hydroxy-ethyl]-

4-hydroxy-3H-benzothlazol-2-one and 7-[( 1 R)-2-(2-{3-[2-(2-Chloro-phenyl)-ethylamino]- propylsulfanyl)-ethylamino)-1-hydroxy-ethyl]-4-hydroxy-3H-benzothiazol-2-one optionally in racemic form, as enantiomers, diastereomers or as pharmacologically acceptable salts, solvatés or hydrates. Preferred are salts selected from the group consisting of hy

-9316887 drochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred anticholinergics which may be mentioned include Tiotropium salts, preferred the bromide sait, Oxitropium salts, preferred the bromide sait, Flutropium salts, preferred the bromide sait, Ipratropium salts, preferred the bromide sait, Aclidinium salts, preferred the bromide sait, Glycopyrronium salts, preferred the bromide sait, Trospium salts, preferred the chloride sait, Tolterodin. From the above mentioned salts the pharmacologically 10 active part is the cation, possible anions are chloride, bromide, iodide, sulfate, phosphate, methansulfonate, nitrate, maleate, acetate, citrate, fumarate, tartrate, oxalate, succinate, benzoate or p-toluenesulfonate. Further examples of preferred anticholinergics are selected from among • 2,2-Diphenylpropionic acid tropenole ester-methobromide is · 2,2-Diphenylpropionic acid scopine ester-methobromide • 2-Fluor-2,2-Diphenylacetic acid scopine ester-methobromide • 2-Fluor-2,2-Diphenylacetic acid tropenole ester-methobromide • S.S'A^-Tetrafluorbenzil acid tropenole ester-methobromide • S.S'A^-Tetrafluorbenzil acid scopine ester-methobromide · 4,4'-Difluorbenzil acid tropenole ester-methobromide • 4,4'-Difluorbenzil acid scopine ester-methobromide • 3,3'-Difluorbenzil acid tropenole ester-methobromide • 3,3’-Difluorbenzil acid scopine ester-methobromide • 9-Hydroxy-fluorene-9-carbon acid tropenole ester -methobromide · 9-Fluor-fluorene-9-carbon acid tropenole ester -methobromide • 9-Hydroxy-fluorene-9-carbon acid scopine ester -methobromide • 9-Fluor-fluorene-9-carbon acid scopine ester methobromide • 9-Methyl-fluorene-9-carbon acid tropenole estermethobromide • 9-Methyl-fluorene-9-carbon acid scopine estermethobromide

3o · Benzil acid cyclopropyl tropine ester-methobromide • 2,2-Diphenylpropionic acid cyclopropyl tropine ester-methobromide • 9-Hydroxy-xanthene-9-carbon acid cyclopropyl tropine ester-methobromide • 9-Methyl-fluorene-9-carbon acid cyclopropyl tropine ester-methobromide • 9-Methyl-xanthene-9-carbon acid cyclopropyl tropine ester-methobromide · 9-Hydroxy-fluorene-9-carbon acid cyclopropyl tropine ester -methobromide • 4,4-Difluorbenzil acid methylestercyclopropyl tropine ester-methobromide • 9-Hydroxy-xanthene-9-carbon acid tropenole ester -methobromide

-9416887 • 9-Hydroxy-xanthene-9-carbon acid scopine ester methobromide • 9-Methyl-xanthene-9-carbon acid tropenole ester -methobromide • 9-Methyl-xanthene-9-carbon acid scopine estermethobromide • 9-Ethyl-xanthene-9-carbon acid tropenole ester methobromide • 9-Difluormethyl-xanthene-9-carbon acid tropenole ester -methobromide • 9-Hydroxymethyl-xanthene-9-carbon acid scopine ester -methobromide.

Examples of preferred corticosteroids which may be mentioned include Beclomethasone, Betamethasone, Budesonide, Butixocorte, Ciclesonide, Deflazacorte, Déxaméthasone, Etiprednole, Flunisolide, Fluticasone, Loteprednole, Mometasone, Prednisolone, Prednisone, Rofleponide, Triamcinolone, Tipredane, and • {20R-16alpha,17alpha-[butylidenebis(oxy)]-6alpha,9alpha-difluoro-11beta-hydroxy-

17beta-(methylthio)androsta-4-en-3-one}, • 9-fluoro-11beta,17,21-trihydroxy-16alpha-methylpregna-1,4-diene-3,20-dione 21cyclohexanecarboxylate 17-cyclopropanecarboxylate, • 16,17-butylidene dioxy-6,9-difluoro-11 -hydroxy- 17-(methylthio)androst-4-en-3-one • Flunisolide-21-[4'-(nitrooxymethyl) benzoate] • 6,9-Difluoro-17-[(2-furanylcarbonyl)oxy]-11 -hydroxy-16-methyl-3-oxo-androsta-1,4-dien17-carbothion acid (S)-fluoromethylester, • 6,9-Difluoro-11 -hydroxy-16-methyl-3-oxo-17-propionyloxy-androsta-1,4-dien-17carbothion acid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester, and • 6alpha,9alpha-difluoro-11beta-hydroxy-16alpha-methyl-3-oxo-17alpha-(2,2,3,3tertamethylcyclopropylcarbonyl)oxy-androsta-1,4-diene-17beta-carboxylic acid cyanome thyl ester optionally in racemic form, as enantiomers, diastereomers or as pharmacologically acceptable salts, solvatés or hydrates. Examples for preferred salts and dérivatives are alkali salts,

i.e. sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acétates, dichloroacetates, propionates, dihydrogenphosphates, palmitates, pivalates orfuroates.

Examples of preferred PDE4-inhibtors which may be mentioned include Enprofylline, Theophylline, Roflumilaste, Ariflo (Cilomilaste), Tofimilaste , Pumafentrine , Lirimilaste , Apremilaste, Arofylline, Atizorame, Oglemilastum, Tetomilaste and • 5-[(N-(2,5-dichloro-3-pyridinyl)-carboxamide]-8-methoxy-quinoline • 5-[N-{3,5-dichloro-1-oxido-4-pyridinyl)-carboxamide]-8-methoxy-2-(trifluoromethyl)quinoline

-9516887 • N-(3,5-dichloropyrid-4-yl}-[1-{4-fluorobenzyl}-5-hydroxy-indole-3-yl]glyoxy1 acid amide ), 9- [(2-fluorophenyl)methyl]-N-methyl-2-(trifluoromethyl)-9H-purine-6-amine 4-[(2R)-2-[3(cyclopentyloxy)-4-methoxyphenyl]-2-phenylethyl]-pyridÎne, • N-KSR^SAe.Z-tetrahydiO-g-methyi^xo-l-phenylpyrrolop.ZJ-jknMjbenzodiazepin-ayl]-4-Pyridinecarboxamide, • 4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-1-(2-methoxyethyl)-2(1H}pyridinone, • 2-[4-[6,7-diethoxy-2,3-bis(hydroxymethyl)-1-naphthalenyl]-2-pyridÎnyl]-4-(3-pyridinyi}1(2H)-Phthalazinone, • (3-(3-cyclopenyloxy-4-methoxybenzyl)-6-ethylamino-8-isopropyl-3H-purine, • beta-[3-(cyclopentyloxy)-4-methoxyphenyl]-1,3-dihydro-1,3-dioxo-2H-isoindole-2propanamide, • 9-ethyl-2-methoxy-7-methyl-5-propyl- imidazo[1,5-a]pyrido[3,2-e]pyrazin-6(5H)-one • 5-[3-(cyclopentyloxy)-4-methoxyphenyl]-3-[(3-methylphenyl)methyl] (3S,5S}-2piperidinone, • 4-[1-[3,4-bis(difluoromethoxy)phenyl]-2-(3-methyl-1-oxido-4-pyridinyi)ethyl]-alpha_lalphabis(trifluoromethyl)-Benzenemethanol • N-(3,5-Dichloro-1-oxo-pyridine-4-yl)-4-difluoromethoxy-3-cyclopropylmethoxybenzamide • (-)p-[(4aR*,10bS*)-9-Ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2methylbenzo[s][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamid e • (R)-(⁺)-H4-Bromobenzyl)-4-[(3-cyclopentyloxy)-4-methoxyphenyl]-2-pyrrolÎdone • 3-(Cyclopentyloxy-4-methoxyphenyl)-1-(4-N^,-[N-2-cyano-S-methyl-isothÎoureido]benz^)-

2-pyrrolidone • cis[4-Cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1 -carbon acid] • 2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan1-one • cis[4-Cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol] • (R)-(⁺}-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-yliden]acetate • (S)-(-)-Ethyl[4-(3-cyclopentyloxy-4-methoxyphenyl)pyrrolidine-2-yliden]acetate • 9-Cyclopentyl-5,6-dihydro-7-ethyl-3-(2-thienyl)-9H-pyrazolo[3_l4-c]-1,2,4-triazolo[4,3ajpyridine • g-Cyclopentyl-S.G-dihydro-Z-ethyl-S-ttert-butyl^H-pyrazoloIS^cJ-I.Z^triazolo^.Sajpyridine optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvatés or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydro-9616887 methansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrata rtra te, hydrooxalate, hydrosuccinate, hydrobenzoate und hydra-p-toluenesulfonate.

• Examples of preferred LTD4-antagonists which may be mentioned Include Montelukast, Pranlukast, Zafirlukast, Masikulast, L-733321 (see compound 2ab of D. Guay et al, Bioorg. Med. Chem. Lett. 8 (1998) 453-458) and(E)-8-[2-[4-[4-(4Fluorophenyl)butoxy]phenyl]ethenyl]-2-{1H-tetrazole-5-yl)-4H-1-benzopyran-4-one (MEN91507) • 4-[6-Acetyl-3-[3-(4-acetyl-3-hydroxy-2-propylphenylthio)propoxy]-2-propylphenoxy]-butyric acid (MN-001) • 1-{((R)-(3-(2-{6,7-Difluoro-2-quinolinyl)ethenyl)phenyl)-3-{2-{2- hydroxy-2propyl)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-{1hydroxy-1 -methylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid • p-fP-^tert-Butyl^-thiazolylJ-S-benzofuranylJoxymethylJphenyllaceticacid optionally in racemic form, as enantiomers, diastereomers or as pharmacologically acceptable salts, solvatés or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydraiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydratartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate. Further examples for optionally preferred salts and dérivatives are alkali salts, I.e. sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acétates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates.

Examples of prefened EGFR-inhibitors which may be mentioned Include Cetuximab, Trastuzumab, Panitumumab Gefitinib, Canertinib, Erlotinib, Mab ICR-62 and • 4-[(3-Ch lo r-4-fl uorph en yl )amino]-6-{[4-(m orpholine-4-yl )-1 -oxo-2- buten e-1 -yl]ami no}-7cyclopropylmethoxy-quinazoline • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-diethylamÎno)-1-oxo-2-butene-1-yl]amino)-7cyclopropylmethoxy-quinazoline • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N_lN-dimelhylamino)-1-oxo-2-butene-1-yl]amino)-

7-cyclopropylmethoxy-quinazoline • 4-[(R)-{1-Phenyl-ethyl)amino]-6-{[4-(morpholine-4-yl)-1-oxo-2-butene-1-yl]amino}-7cyclopentyloxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2butene-1-yl]amino}-7-cyclopropylmethoxy-qulnazoline

-9716887 • 4-[(3-ChIor-4-fluor-phenyI)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2butena-1-yl]amino}-7-[(SXtatrahydrofuran-3-yl)oxy]-quinazolina • 4-[(3-ChIor-4-fluor-phenyl)amino]-6-{[4-((R)-2-methoxymethyl-6-oxo-morpholine-4-yl)-1 oxo-2-butene-1-yl]amino}-7-cyclopropylmethoxy-quinazoline s · 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-((S)-6-methyl-2-oxo-morpholine-4-yl)-ethoxy]-7methoxy-quinazoline • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{{4-[N-{2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2butene-1-yl}amino)-7-cyclopropylmethoxy-quinazoline • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}io 7-cyclopentyloxy-quinazoline • 4-[(RX1-Phenyl-ethyl)amino]-6-([4-(N,N-bis-(2-methoxy-ethyl)-amino}-1-oxc>-2-butene-1yl]amino}-7-cyclopropylmethoxy-quinazolÎne • 4-[(RX1-Phenyl*ethyl)amino]-64{4-[N42-methoxy^thyl)-N-ethyl-amino]-1-oxo-2-butene1-yl}amino)-7-cyclopropylmethoxy-quinazoIine is · 4-[(RX1-Phenyl-ethyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amino]-1-oxo-2butene-1-yl}amino)-7-cyclopropylmathoxy-quÎnazoline • 4-[(RX1-Phenyl-ethyl)amino]-6-{{4-[N-(tetrahydropyran-4-yl)-N-methyl-amino]-1-oxo-2butene-1-yl}amino)-7-cycIopropylmethoxy-quinazolÎne • 4-[(3-Chlor-4-fluorphanyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butena-1-yl]amino}20 7-{(R)-tetrahydrofuran-3-yloxy}-quinazoIine • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amîno}7-((S)-tetrahydrofuran-3-yloxy)-quinazoline • 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N-(2-methoxy-ethyl)-N-methyl-amîno]-1-oxo-2butene-1-yl}amino)-7-cyclopentyloxy-quinazoline · 4-[(3-Chlor-4-fluorphanyl)amino]-6-{[4-(N-cyclopropyl-N-methyl-amino)-1-oxo-2-butene-1yl]amino}-7-cyclopentyloxy-quinazoline • 4-[(3-ChIor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1-oxo-2-butene-1-yl]amino}7-[(RXtatrahydrofuran-2-yl)methoxy]-quinazoline • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(N,N-dimethylamino)-1 -oxo-2-butene-1 -yljamino}-

7-[(SXtetrahydrofuran-2-yl)methoxy]-quinazoline • 4-[(3-Ethinyl-phenyl)amino]-6,7-bis-(2-mathoxy-ethoxy)-quinazolÎne • 4-[(3-Chlor-4-fluorphenyl)amino]-7-[3-(morpholine-4-yl)-propyloxy]-6[(vinylcarbonyl)aminoj-quinazoline • 4-[(R)-(1-Phenyl-ethyl)amino]-6-(4-hydroxy-phenyl)-7H-pyiTolo[2_I3-d]pyrimidine · 3-Cyano-4-[(3-chlor-4-fluorphenyl)amino]-6-([4-(N,N-dimethylamino)-1 -oxo-2-butene-1yl]amino)-7-ethoxy-quinoline

-9816887 • 4-{[3-Chlor-4-(3-fluor-benzyloxy)-phenyl]amino}-6-(5-{[(2-methansulfonylethyl)amino]methyl)-furan-2-yl)quinazoline • 4-[(R)-(1-Phenyl-ethyl)amino]-6-{[4-((R)-6-methyl-2-oxo-morpholine-4-yl)-1-oxo-2-butene1-yl]amino}-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluorphenyl)amino]-6-{[4-(morpholine-4-yl)-1 -oxo-2-butene-1 -yl]amino}-7· [(tetrahydrofuran-2-yl)melhoxy]-quinazoline • 4-[(3-Chlor-4-fluorphenyl)amino]-6-({4-[N,N-bis-(2-methoxy-ethyl)-amlno]-1-oxo-2-butene1-yl}amino)-7-[(tetrahydrofuran-2-yl)methoxy]-quinazoline • 4-[(3-Ethinyl-phenyl)amino]-6-{[4-(5,5-dimethyl-2-oxo-morpholine-4-yl)-1 -oxo-2-butene-1 yl]amino)-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyi)amino]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-elhoxy]-7· [(R)-(tetrahydrofuran-2-yl)methoxy]-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-7-[2-(2,2-dÎmethyl-6-oxo-morpholine-4-yl)-ethoxy]-6[(S)-(tetrahydrofuran-2-yl)methoxy]-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{2-[4-(2-oxo-morpholine-4-yl)-piperidÎn-1-yl]-ethoxy}7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(tert.-butyloxycarbonyl)-piperidine-4-yloxy]-7methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-amino-cyclohexane-1-yloxy)-7-methoxyquinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methansulfonylamino-cyclohexane-1-yloxy)7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-3-yloxy)-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidine-4-yloxy)-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(morpholine-4-yl)carbonyl]-piperidine-4-yloxy}-7· methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(methoxymethyl)carbonyl]-piperidine-4-yloxy}-7methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(piparidine-3-yloxy)-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-acetylamino-ethyl)-piperidine-4-yloxy]-7methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(letrahydropyran-4-yloxy)-7-ethoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-((S)-tetrahydrofuran-3-yloxy)-7-hydroxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-methoxy-ethoxy)quinazoline

-9916887 • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(dimethylamino)sulfonylamino]-cyclohexane-

-yloxy}-7-methoxy-quinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)carbonylamino]cyclohexane-1-yloxy}-7-methoxy-quinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-{trans-4-[(morpholine-4-yl)sulfonylamino]cyclohexane-1-yloxy}-7-methoxy-quinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-(tetrahydropyran-4-yloxy)-7-(2-acetylamino-ethoxy)quinazoline

4-[(3-Chlor-4-fluor-phenyl)aminoI-6-(tetrahydropyran-4-yloxy)-7-{2-methansulfonylaminoethoxyj-quinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(piperidine-1-yl)carbonylI-plperidine-4-yioxy}-7methoxy-quinazoline

4-[(3-Chlor-4-fluor-phenyi)amino]-6-(1-aminocarbonylmethyl-piperidine-4-yloxy)-7methoxy-quinazoline

4-[(3-Chlor-4-fluor-phenyi)amino]-6-(cis-4-{N-[(tetrahydropyran-4-yi)carbonyl]-N-methylamino}-cyclohexane-1-yloxy)-7-methoxy quinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(morpholine-4-yl)carbonyl]-N-methylamino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cîs-4-{N-[(morpholÎne-4-yl)sulfonyl]-N-methyl-amino}cyclohexane-1-yloxy)-7-methoxy-quinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-ethansulfonylamino-cyclohexane-1-yloxy)-7methoxy-quinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-pÎperidine-4-yloxy)-7-ethoxyquinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methansulfonyl-piperidine-4-yloxy)-7-{2-methoxyethoxy)-quinazoline

4-[(3-Chlor-4-fluor-phenyl)amino]-6-[1-(2-methoxy-acetyl)-pÎperidine-4-yloxyI-7-(2methoxy-ethoxy)-quinazoline

4-[(3-Chlor-4-fluor-phenyi)amino]-6-(cis-4-acetylamino-cyclohexane-1-yloxy)-7-methoxyquinazoline

4-[(3-Ethinyl-phenyl)amino]-6-[1-{tert-butyloxycarbonyl)-piperidine-4-yloxy]-7-methoxyquinazoline

4-[(3-Ethinyl-phenyl)amino]-6-(tetrahydropyran-4-yloxy]-7-methoxy-quinazoline

4-[(3-Chlor-4-fluor-phenyl)aminoI-6-(cis-4-{N-[(piperidine-1-yl)carbonyl]-N-methyl-amÎno}cyclohexane-1-yloxy)-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(cis-4-{N-[(4-methyl-pÎperazine-1-yl)carbonyl]-N- methyl-amino}-cyclohexane-1-yloxy)-7-methoxy-quinazoline

-10016887 • 4-[(3-Chlor-4-fluor-phanyl)amino]-6-{cis-4-[(morpholina-4-yl)carbonylamino]-cyclohaxana1 -yloxy)-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[2-(2-oxopynOlidina-1-yl)ethyl]-piperidine-4-yloxy}7-methoxy-quinazoline · 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1 -[(morpholina-4-yl)carbonyl]-piperidina-4-yloxy}-7(2-methoxy-ethoxy)-quinazolina • 4-[(3-Ethinyl-phanyl)amino]-6-(1-acetyl-piperidina-4-yloxy)’7-methoxy-quinazoline • 4-t(3-Ethinyl-phenyl)amino]-6-(1-methyl-piperidina-4-yloxy)-7-melhoxy-quinazolina • 4-[(3-Ethinyl-phenyl)amino]-6-(1-methansulfonyl-piparidina-4-yloxy)-7-mathoxy- io quinazolina • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-methyl-piperidina-4-yloxy)-7(2-methoxy-ethoxy)quinazolina • 4-[(3-Chlor-4-nuor-phenyl)amino]-6-(1-isopropyloxycarbonyl-piparidina-4-yloxy)-7mathoxy-quinazollne is · 4-[(3-Chlor-4-nuor-phanyl)amino]-6-(cis-4-methylamino-cyclohaxana-1-yloxy)-7-melhoxychinazoline • 4-[(3-Chlor-4-nuor-phenyi)amino]-6-{cis-4-[N-(2-malhoxy-acetyl)-N-methyl-amino]cyclohaxana-1-yloxy)-7-methoxy-quinazoline • 4-[(3-Ethinyl-phanyl)amino]-6-(piparidine-4-yloxy)-7-methoxy-quinazolina · 4-[(3-Ethinyl-phenyl)amino]-6-[1-(2-methoxy-acetyl)-piperidina-4-yloxy]-7-methoxyquinazolina • 4-[(3-Ethinyl-phanyl)amino]-6-{1-[(morpholina-4-yl)carbonylJ-piperidina-4-yloxy}-7melhoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)aminoJ-6-{1-t(cis-2_>6-dimathyl-morpholina-4-yl)carbon^]- piparidina-4-yloxy}-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(2-methyl-morpholina-4-yl)carbonyl]-piparidÎne-4yloxy}-7-methoxy-quinazoline • 4-[(3-Chlor-4-nuor-phanyl)amino]-6-{1-[(S,S)-(2-oxa-5-aza-bicyclo[2.2.1]hept-5yl)carbonyl]-piparidine-4-yloxy}-7-methoxy-quinazolina · 4-[(3-Chlor-4-fluor-phenyl)amino]-6-{1-[(N-melhyl-N-2-methoxyethyl-amino)carbonylJplparidina-4-yloxy}-7-methoxy-quinazoline • 4-[(3-Chlor-4-nuor-phenyl)amino]-6-(1-elhyl-pîperidina-4-yloxy)-7-methoxy-quinazolina • 4-[(3-Chlor-4-fluor-phanyl)amino]-6-{1-[(2-mathoxyethyl)carbonyl]-piperidina-4-yloxy}-7methoxy-quinazolina · 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-[(3-methoxypropyl-amino)-carbonyl]-piparidine-4yloxy}-7-melhoxy-quinazolina

-10116887 • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-methansulfonyl-N-methyl-amino)cyclohexane-1-yloxy]-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[cis-4-(N-acety1-N-methyl-amino)-cyclohexane-1yloxy]-7-methoxy-quinazoline · 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-methylamino-cyclohexane-1-yloxy)-7methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-[trans-4-(N-methansulfonyl-N-methyl-amino)cyclohexane-l-yloxy]-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-dimethylamino-cyclohexane-1-yloxy}-7- methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(trans-4-(N-[(morpholine-4-yl)carbonyl]-N-methylamino)-cyclohexane-1-yloxy)-7-methoxy-quinazoline • 4-[(3-Chlor-4-fluor-phenyl)amlno]-6-[2-(2,2-dimethyl-6-oxo-morpholine-4-yl)-ethoxy]-7[(SHtefr3hydrofuran-2-yl)methoxy]-quinazoline is · 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1 -methansulfonyl-piperidine-4-yloxy)-7-methoxyquinazoline • 4-[(3-Chlor-4-fluor-phenyl)amino]-6-(1-cyano-piperidine-4-yloxy)-7-methoxy-quinazoline optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically ac20 ceptable salts, solvatés or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred dopamine antagonists which may be mentioned include Bromocriptine, Cabergoline, Alpha-Dihydroergocryptine, Lisuride, Pergolide, Pramipexole, Roxindole, Ropinirole, Talipexole, Terguride and Viozane, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvatés or hydrates.

jo Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate and hydro-p-toluenesulfonate.

Examples of preferred antiallergic agents which may be mentioned include Epinastine, Cetirizine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Mizolastine, Ketotifene, Emedastine, Dimetindene, Clemastine, Bamipine, Cexchlorpheniramine, Pheniramîne, Doxyla-10216887 mine, Chlorphenoxamine, Dimenhydrinate, Diphenhydramine, Promethazine, Ebastine, Olopatadine, Desloratidine and Meclozine, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvatés or hydrates.

Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred PAF antagoniste which may be mentioned include Lexipafante and • 4-(2-Chlorphenyl)-9-meth^-2-[3(4-morpholÎnyl)-3-propanone-1-^]-6H-thieno-[3_l2-f]- [1,2,4]triazolo[4,3-a][1,4]diazepine • 6-(2-Chlorphenyl)-8_l9-dihydro-1-meth^-8-[(4-morpholinyl)carbonyl]-4H_I7H-cyclo-penta[4,5]thieno-[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine optionally in racemic form, as enantiomers, diastereomers or as pharmacologically acceptable salts, solvatés or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydrolodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronltrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred MAP kinase Inhibitors which may be mentioned include • Bentamapimod (AS-602801) • Doramapimod (BIRB-796), • 5-Carbamoylindole (SD-169), • 6-[(aminocarbonyl)(2,6-difluorophenyl)amino]-2-(2,4-difluorophenyl)-3-pyridine carboxamide (VX-702), • alpha-[2-[[2-(3-pyridinyl)ethyl]aminol-4-pyrimidinyl]-2-benzothiazole acetonitrile (AS601245), • 9,12-Epoxy-1H-diindolo[1,2,3-fg:3’,2’,r-kl]pyrrolo[3,4-i][1,6]benzodiazodne-10-Carboxylic acid (CEP-1347), • 4-[3-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)-1 H-pyrazole-4-yl]-pyrimidine (SC-409), optionally in racemic form, as enantiomers, diastereomers or as pharmacologically acceptable salts, solvatés or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydrotodide, hydrosulfate, hydrophosphate, hydro-10316887 methansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosucdnate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred MRP4 inhibitors which may be mentioned include N-Acetyldinitrophenyl-Cysteine, cGMP, Cholate, Diclofenac, Déhydroépiandrostérone 3-glucuronide, Déhydroépiandrostérone 3-suiphate, Dilazep, Dinitrophenyl-S-glutathione, Estradiol 17-betaglucuronide, Estradiol 3,17-disulphate, Estradiol 3-glucuronide, Estradiol 3-sulphate, Estrone

3-sulphate, Flurbiprofen, Folate, N5-formyl-tetrahydrofolate, Glycocholate, Glycolithocholic acid sulphate, Ibuprofen, Indomethadn, Indoprofen, Ketoprofen, Lithocholic acid sulphate, Methotrexate, (E)-3-[[[3-[2-(7-Chloro-2-quinolinyl)ethenyl]phenyl]-[[3-dimethylamino)-3oxopropyl]thio]methyl]thio]-propanoic acid alpha-Naphthyl-beta-D-glucuronide, Nitrobenzyl mercaptopurine riboside, Probenecid, Valspodar, Sildenafil, Sulfinpyrazone, Taurochenodeoxycholate, Taurocholate, Taurodeoxycholate, Taurolithochoîate, Taurolithocholic acid sulphate, Topotecan, Trequinsin, Zaprinast and Dipyridamol, optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically acceptable salts, solvatés or hydrates.

Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosucdnate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred iNOS-Inhibitors which may be mentioned include S-(2Aminoethyl)isothio-urea, Aminoguanldine, 2-Aminomethylpyridlne, 5,6-dihydro-6-methyl-4H1,3-thiazine-2-amine (AMT), L-Canavanin, 2-lminopiperidine, S-lsopropylisothiourea, SMethylisothiourea, S-Ethylisothiourea, S-Methylthiocitrulline, S-Ethylthiocitrulline, L-NA (N^wNitro-L-arginin), L-NAME (N“-Nitro-L-argininrnethylester), L-NMMA (N^w-Monomethyl-Larginin), L-NIO (N“-lminoethyl-L-omithin), L-NIL (N^w-iminoethyl-lysin), (S)-6Acetimidoylamino-2-amino-hexanoic acid (1H-tetrazole-5-yl)-amide N-[[3(aminomethyl)phenyl]methyl]-ethanimidamide, (S)-4-(2-acetimidoylamino-ethylsulfanyl)-2amino-buturic acid ,2-[2-(4-Methoxy-pyridine-2-yl)-ethyl]-3H-imidazo[4,5-b]pyridine, 2-((R)-3amino-1-phenyl-propoxy)-4-chîor-5-fluorbenzonitrile, 2-((1 R,3S)-3-amÎno-4-hydroxy-1thiazole-S-yl-butylsulfanylJ-e-trifluoromethyl-nicotinonitrile, 2-((1 R,3S)-3-amino-4-hydroxy-1thiazole-S-yl-butylsulfanylH-chlor-benzonitrile, 2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-ylbutylsulfanylJ-S-chlor-benzonitrile, (2S,4R)-2-amino-4-(2-chlor-5-trifluoromethyl· phenylsulfanylH-thiazole-S-yl-butane-l-ol, 2-((1R,3S)-3-amino-4-hydroxy-1-thiazole-5-ylbutylsulfanyl)-5-chlor-nicotinonitrile, 4-((S)-3-amino-4-hydroxy-1-phenyl-butylsulfanyl)-6methoxy-nicotinonitrile and substituted 3-phenyl-3,4-dihydro-1-isoquinolinamine as for in-I0416887 stance 1 S,5S,6R)-7-Chlor-5-methyl-2-aza-bicyclo[4.1.0]hept-2-ene-3-ylamin (4R,5R)-5-Ethyl-

4-methyl-thiazolidine-2-ylideneamine,(1S,5S,6R)-7-Chlor-5-methyl-2-aza-bicyclo[4.1.0]hept2-ene-3-ylamin, (4R,5R)-5-Ethyî-4-methyl-thiazolidine-2-ylideneamine, (4R,5R)-5-Ethyî-4methyl-selenazolidine-2-ylideneamine, 4-Aminotetrahydrobiopterine, (E)-3-(4-Chlor-phenyl)N-( 1-{2-oxo-2-[4-(6-trifluormethyl-pyrimidine-4-yloxy)-piperidine-1 -yl]-ethylcarbamoyl}-2pyridine-2-yl-ethyî)-acrylamide, S-^ADifluor-phenylJ-e-^-^imidazole-l-ylmethyl-phenoxy)ethoxy]-2-phenyl-pyridine, 3-{[(Benzo[1,3]dioxol-5-ylmethyî)-carbamoyl]-methyl}-4-{2imidazole-1-yl-pyrimidine-4-yî)-piperazine-1-carbon acid methyîester, (R)-1-(2-imidazole-1yî-6-methyl-pyrimidine-4-yl)-pyrrolidine-2-carbon acid (2-benzo[1,3]dioxol-5-yl-ethyî)-amide, optionally in racemic form, as enantiomers, diastereomers or as pharmacologically acceptable salts, solvatés or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.

Further examples of preferred iNOS-Inhibitors which may be mentioned include antisense-Oligonucleotide, especially those antisense-Oligonucleotide bindung iNOS-coding nucleintc acids, examples therefore are disclosed in WO 01/52902.

Examples of preferred SYK-inhibitors which may be mentioned include

2-[(2-aminoethyl)amino]-4-[(3-bromophenyl)amino]-5-pyrimidinecarboxamide; 2-[[7-(3,4-dimethoxyphenyl)imidazo[1,2-c]pyrimidine-5-yl]amino]-3-pyridinecarboxamide;

6- [[5-fluoro-2-[3,4,5-trimethoxyphenyl)amino]-4-pyrimidinyl]amino]-2,2-dimethyl-2Hpyrido[3,2-b]-1,4-oxazin-3(4H)-one;

N-[3-bromo-7-(4-methoxyphenyî)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

7- (4-methoxyphenyl)-N-methyl-1,6-naphthyridine-5-amine;

N-[7-{4-methoxyphenyî)-1,6-naphthyridine-5-yl]-1,3-propanediamine; N-[7-(2-thienyl)-1,6-naphthyridine-5-yl-1,3-propanediamine;

N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-ethanediamine; N-[7-(4-methoxyphenyl)-2-(trifluoromethyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

N-[7-(4-methoxyphenyl)-3-phenyl-1,6-naphthyridine-5-yl]-1,3-propanediamine; N-(7-phenyl-1,6-naph thyridine-5-yl )-1,3-propanediamine;

N-[7-(3-fluorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine; N-[7-(3-chlorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine; N-[7-[3-(trifluoromethoxy)phenyl]-1,6-naphthyridine-5yl]-1,3-propanediamine; N-[7-{4-fluorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

-10516887 • N-[7-(4-fluorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-(4-chlorophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-(4’-methyl[1,1 ’-biphe nyl]-4-yl )-1,6-naphthyridine-1,3-propanediamine;

• N-[7-[4-(dimethylamino)phenyl]-1,6-naph thyrid ine-5-yl]-1,3-propanediamine;

• N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-[4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamlne;

• N-[7-[4-[[2-(dimethylamino)ethyl]methylaminoJphenyl]-1,6-naph thyridine-5-yl]-1,3propanediamine;

• N-[7-(4-bromophenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-(4-methylphenyl)-1,6-naphlhyridine-5-yl]-1,3-propanediamine;

• N-[7-[4-(melhyllhio)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-[4-(1 -methylethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• 7-[4-(dimethylamino)phenyl]-N-methyl-1,6-naphthyridine-5-amine;

• 7-[4-(dimethylamino)phen^]-N,N-dimethyl-1,6-naphthyridine-5-amine;

• N-[7-[4-(dimelhylamino)phenyl]-1,6-naphthyridine-5-yl]-1,4-butanediamine;

• N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,5-pentanediamine;

• 3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]oxy]-1-propanole;

• 4-[5-(4-aminobutoxy)-1,6-naphthyridine-7-ylJ-N,N-dimethyl-benzenamine;

• 4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-1 -butanole;

• N-[7-[4-(dimelhylamino)phenyl]-1,6-naphthyridine-5-yl]-N-methyl-1,3-propanediamine;

• N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-N'-methyl-1,3-propanediamine;

• N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-N,N’-dimethyl-1,3propanediamine;

• 1 -amlno-3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-2-propanole;

• N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-2,2-dimethyl-1,3-propanediamine;

• 7-[4-(dimethylamino)phenyl]-N-(3-pyridinylmethyl)-1_I6-naphthyridine-5-amine;

• N-[(2-aminophenyl)methyl]-7-[4-(dimethylamino)phenyl]-1,6-naphlhyridine-5-amine;

• N-[7-[6-(dimethylamino)[1 ,T-biphenyl]-3-yl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-[3-chloro-4-(diethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-[4-(dielhylamino)phenyl]-3-melhyl-1,6-naphlhyridine-5-yl]-1,3-propanediamine;

• N-[7-(3’-flu o ro[1,1 '-biphenyl]-3-yl )-1,6-naphthyridine-5-yl]-1,2-elhanediamin, • N-[7-(4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,6-naphthyridine-1,3-propanediamine;

• N,N'-bis(3-aminopropyl)-7-(4-methoxyphenyl)-2,5-diamine;

• N-[7-(4-methoxyphenyl)-2-(phenylmethoxy)-1,6-naphthyridine-5-yl]-1,6-naphthyridine-1,3propanediamine;

-10616887 • N5-(3-aminopropyl)-7-(4-methoxyphenyi)-N2-(phenylmethyl)-2,5-diamine;

• N-[7-(2-naphthalenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-(2'-fluoro[1,r-biphenyl]-4-yl)-1_l6-naphthyridine-5-yl]-1,3-propanedÎamine;

• N-[7-(3,4,5-trimelhoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

s · N-[7-(3,4-dimethylphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• 1-amino-3-[[7-(2-naphthalenyl)-1,6-naphthyridine-5-yl]amino]-2-propanole;

• 1-amino-3-[[7-i2'-fluoro[1 ,T-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]amino]-2-propanole;

• 1 -amino-3-[[7-(4^,-methoxy[1,1 '-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]amino]-2-propanoie;

• 1 -amino-3-[[7-(3,4,5-trimethoxyphenyl)-1,6-naphthyridine-5-yl]amino]-2-propanoie;

io · 1-amino-3-[[7-(4-bromophenyl)-1,6-naphthyridine-5-yl]amino]-2-propanole;

• N-[7-{4'-methoxy[1,1 '-biphe nyl]-4-yl)-1,6-naphthyridine-5-yl]-2,2-dimethyl-1,3propanediamine;

• 1-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]-2-propanole;

• 2-[[2-[[7-[4-(dimethylamino)phenyl]-1_l6-naphthyridine-5-yl]amino]ethyl]thio]-ethanole; u · 7-[4-(dÎmethylamino)phenyl]-N-(3-methyl-5-isoxazolyl)-1,6-naphthyridine-5-amine;

• 7-[4-(dimethylamÎno)phenyl]-N-4-pyrimidinyl-1,6-naphthyridine-5-amine;

• N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-cyclohexane diamine;

• N.N-dimethyl-A-lS-ÎI-piperazinylJ-l.â-naphthyridine-Z-yll-benzenamine;

• 4-[5-(2-methoxyethoxy)-1,6-naphthyridine-7-yl]-N,N-dimethyl-benzenamine;

· 1-[7-Î4-(dimethylamÎno)phenyl]-1,6-naphthyridine-5-yl]-4-piperidinole;

• 1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-3-pyrrolidinole;

• 7-[4-(dimethylamÎno)phenyl]-N-(2-furanylmethyl)-1_l6-naphthyridine-5-amine;

• 7-[4-(dimethylamino)phenyl]-N-[3-(1H-imidazole-1-yl)propyl]-1,6-naphthyridine-5-amine;

• 1-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-4-piperidine carboxamide;

· 1 -[3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]amino]propyl]-2-pyrrolidinone;

• N-[3'-Î5-[(3-aminopropyl)amino]-1,6-naphthyridine-7-yl][1 ,r-biphenyl]-3-yl]-acetamide;

• N-[7-Î4’-fluoro[ 1,1 '-biphenyl]-4-yl)-1,6-na ph thyrid ine-5-yl]-1,3-propanediamine;

• N-[4'-[5-[(3-aminopropyl)amino]-1,6-naphthyridine-7-yl][1,1'-biphenyl]-3-yl]-acetamide;

• N-[7-[4-(1,3-benzodioxol-5-yl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

· N-[7-[4-(2-thÎenyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-[4-fluoro-3-(trifluoromethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-[4-(3-pyridinyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-(1,3-benzodioxol-5-yl)-1,6-na phth yridin e-5-yl]-1,3-propanediamine,‘ • N-[7-(6-methoxy-2-naphthalenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

· 7-f4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1,6-naphthyridine-5-amine;

• 3-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]methylamino]-propanenitrile;

-10716887 • 7-[4-(di methylamin o)phenyl]-N-[ 1 -(phenylmethyl)-4-piperidinyl]-1,6-naphthyridine-5amine;

• N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-cyclohexanediamin, s ♦ N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-Cyclohexanediamine, (1R.2S)rel-.

• N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,2-benzene dimethanamine;

• N-[7-[4-(diethylamino)phenyl]-1,6-naphthyridÎne-5-yl]-1,4-butanediamine;

• N-[7-[3',5'-bis(trifluoromethyl)[1,1 *-biphenyl]-4-yl]-1,6-naphthyridine-5-yl]-,3- io propanediamine;

• N-EÎ-tS’-methoxytl, 1 ’-biphe ny t]-4-yl}-1,6-na phthyr id in e-5-yl]-1,3-propanediamine;

• N-[743'-fluoro[1,r-biphenyl]-4-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• 4-[[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]oxy]-1-butanole;

• N-[7-[4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;

is · 7-[4-(dimethylamino)phenyl]-N-(2,2,6,6-tetramethyl-4-piperidinyl)-1,6-naphthyridine-5amine;

• N-[7-[3-bromo-4-(dimethylamino)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-( 1 -methyl-1 H-indo te-5-yl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-[3-(trifluo romethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

· N-[7-[4-(trifluoromethyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-(3-bromo-4-methoxyphenyl)-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N-[7-[4-[[3-(dimethylamino)propyi]methyiamino]phenyl]-1,6-naphthyridine-5-yl]-1,4cyclohexanediamine;

• N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyrid ine-5-yl]-1,4- cyclohexanediamine;

• N-[7-[4-(dimethylamino)-3-methoxyphenyl]-1,6-naphthyridine-5-yl]-1,4cyclohexanediamine;

• N-[7-[4-(4-morpholinyl)phenyi]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;

• N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,4-cyclohexanediamine;

3o · 4-[[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]oxy]cyciohexanole;

• N-[7-[3-bromo-4-(4-morpholinyl)phenyl]-1,6-naphthyridine-5-yl]-1,3-propanediamine;

• N,N-dimethyl-4-[5-(4-methyl-1-piperazinyi)-1,6-naphthyridine-7-yl]-benzenamine;

• 4-[[7-[4-[[3-(dimethylamÎno)propyi]methylamino]phenyl]-1,6-naphthyridine-5-yl]oxy]- cyclohexanole;

• N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1,6-naphthyridine-5-yl]-1,4-10816887 butanediamin;

• [3-[[5-[(3-aminopropyl)aminoI-7-(4-methoxyphenyl)-1,6-naphthyridine-2-yl]amino]propyl]carbamic acid-1,1-dimethylethyl ester, s optionally in racemic form, as enantiomers, diastereomers or as pharmacologically acceptable salts, solvatés or hydrates. Preferred are salts selected from the group consisting of hydrochloride, hydrobromide, hydroiodlde, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacelate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.

Examples of preferred cystic fibrosis transmembrane regulators (CFTR) and CFTR potentiators which may be mentioned Include, preferably VX-770 and VX-809 is 12. Formulations

Suitable forms for administration are for example Inhalable powders or aérosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.2 to 50 wt%, preferably 5 to 25 wt.% of the total composition, Le. in amounts which are sufficient to achieve the dosage range specified hereinafter.

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 (I) according to the preferred embodiments 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) hâve to be made available in forms suitable for inhalation. Inhalable préparations include inhalable powders, propellant-containing metered-dose aérosols or propellant-free inhalable solutions, which are optionally présent in admlxture with conventions! physiological· ly acceptable excipients.

Within the scope of the présent invention, the term propellant-free inhalable solutions also include concentrâtes or stérile ready-to-use inhalable solutions. The préparations which may be used according to the invention are described in more detail in the next part of the specifi35 cation.

Inhalable powders

-[0916887

If the active substances of formula (I) are présent In admixture with physiologically acceptable excipients, the following physiologically acceptable excipients may be used to préparé the inhalable powders according to the invention: monosaccharides (e.g. glucose or arabinose), disaccharides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g.

s 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 io 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-contalnlng inhalable aérosols

The propellant-containing inhalable aérosols which may be used according to the invention is may contain a compound of formula (I) dissolved in the propellant gas or in dispersed form.

The propeliant gases which may be used to préparé the inhalation aérosols 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 dérivatives of methane, ethane, propane, butane, cyclopropane orcy20 clobutane. The propellant gases mentioned above may be used on their own or in mixtures thereof. Particularly preferred propellant gases are fluorinated alkane dérivatives selected from TG134a (1,1,1,2-tetrafluoroethane), TG227 (1,1,1,2,3,3,3-heptafluoropropane)and mixtures thereof. The propellant-driven inhalation aérosols used within the scope of the use according to the invention may also contain other ingrédients such as co-solvents, stabilisera, 25 surfactants, antioxidants, lubricants and pH adjustera. Ail these ingrédients are known In the art.

Propellant-free Inhalable solutions

The compounds of formula (I) according to the Invention are preferably used to préparé pro30 pellant-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 éthanol. 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 hy35 drochioric 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, maleîc acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid

-11016887 etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which hâve already formed an acid addition sait 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 hâve other properties in addition to their acidifying qualifies, 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 isopropyi alcohol, glycols - particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context dénoté 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 hâve no pharmacological effect or, in connection with the desired therapy, no appréciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya iecithin, 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 isotonie 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 médicament for the treatment of respiratory complainte are provided, containing an enclosed description including for example the words respiratory disease, COPD orasthma, a compound according to the invention and one or more combination partners selected from those described above.

The following example illustrâtes the présent invention without restricting its scope:

-11116887

Capsule for powder inhalation capsule contains: active substance 0.5 mg s lactose for inhalation 5.0 ma

5.5 mg

Préparation:

The active substance is mixed with lactose for inhalation. The mixture is packed into cap suies in a capsule-making machine (weight of the empty capsule approx. 50 mg).

ίο weight of capsule: 55.5 mg size of capsule = 3

Claims

Patent Claims

1. A compound of formula (I) (I) wherein

A dénotés a bond or is selected from the group consisting of O, -CHr, -CH₂CHr, -CH₂CH₂CH2-, -CHz-O-, -CHî-NR*¹- and -NR*¹-,

10 wherein

R*¹ dénotés hydrogen or C^-alkyl,

B dénotés

-CH₂- or -ϋΗ₂ΟΗ2-, or provided that A is not O or -NR^A1, B dénotés a bond is D, E dénoté independently from each other a bond or -CH₂-,

F dénotés optionally substituted aryl, or optionally substituted heteroaryl,

G dénotés a group of formula (g.1), (g.2) or (g.3)

-113F wherein

R¹ is selected from the group consisting of hydrogen, Ci^-alkyl, optionally substituted 5- to 7-membered heterocyclyl-CO-, op5 tionally substituted 5- to 7-membered heterocyclyl-NH-CO-, R’-’-SOr, R’^-Cî^-alkylNH-CO-, H₃C-NH-CO-, R’^-O-CO-CHrNH-CO-, R^u-CM-alkyl-N(Ci^-alkyî)-CO-, H3C -N(CM-alkyl)-CO-, R’^-O-CO-CHrNiCM-alkylJ-CO-, R’-’-C^-alkyl-CO-, R¹⁴-^. e-alkyl-, optionally substituted phenyl-CHr, R^,-4,-O-CO- CHr, HO-CO-CHr and HOSO_rCHr, ίο R’-’-c^-alkyl-CO- and R’^e-C(NH)-, wherein

R¹·¹ is selected from the group consisting of CM-alkyl-, H2NC(NH)NH-C^-alkyl-, R^1A1 R’^N-Cm-alkyl-, R¹·²·’ R¹²² R’^V-Cm-alkyl, HOCO-CM-alkyl- and is Ci-3-alkyl-OCO-Cm-alkyl-,

R¹·² is selected from the group consisting of hydrogen, HîNCÎNHJNH -,

R^1JJ R^1,2JN-, R^1-2,1 R¹’²·² R¹’²‘^î-HN-C(NR¹²³)-NH-, R’ ^-O-CO-, r’^-O-CO-NH- and HO-CO-, HOSO_r, wherein

20 R^1-2·¹ dénotés hydrogen or Ci-e-alkyl,

R¹·²·² dénotés hydrogen or C^-alkyl, or

R¹·²·¹ and R¹¹² together form a 4- to 7- membered hetercyclic ring containg one N-atom,

25 R¹·²·³ dénotés hydrogen or Ci-e-alkyî,

R¹·²·⁴ dénotés hydrogen or Ci-e-alkyl,

R¹·²·’ dénotés hydrogen or C^-alkyl,

R¹·³ is selected from the group consisting of hydrogen, Ci^-alkyl, C^-alkyl-O-, opjo tionally substituted phenyl, R¹¹·¹ R^11ÏN-, R^1-2·¹ R^1,2·² R¹’²‘³N*-₁

R’^-’-HN-CiNR¹²³)-NH-, H₂NC(NH)NH-, R’^-O-CO-, HO-CO- and HOSO₂-, wherein

R¹¹·¹ dénotés hydrogen or C₁_₆-alkyl,

R^1,3·² dénotés hydrogen or Ci^-alkyl,

35 or

R^1-3-1 and R¹¹² together form a 4- to 7- membered hetercyclic ring containing one N-atom,

-114F

R¹⁴ is selected from the group consisting of hydrogen, R^1,4·¹ R^1,4,2N-,

R¹⁴¹ rkj ri-4.3N*_( h2N-C(NH)-NH-, R¹‘⁴‘³-HN-C(NR¹⁴⁴)-NH-, optionally substituted phenyl, R¹'⁴'³-O-CO-, R¹⁴⁴-O-CO-NH-, HO-CO- and HOSO2-, wherein

R¹·⁴·¹ dénotés hydrogen or Ci-e-alkyl,.

R¹·⁴·² dénotés hydrogen or C^-alkyl,

R¹·⁴·³ dénotés hydrogen or Ci-e-alkyl,.

R^1,4·⁴ dénotés hydrogen or C^-alkyl.

R¹·⁵ is selected from the group consisting of hydrogen, C^-alkyl-O-,

R¹⁵¹ Ri-5.2N_f Ri.s.i ri.m R1.S.ÎN*., h2N-C(NH)-NH-, optionally substituted phenyl, R^1s-³-O-CO-, R^1m-O-CO-NH-, HO-CO- and HOSO2-, wherein

R¹·®·¹ dénotés hydrogen or C^-alkyl,.

R¹·⁵·² dénotés hydrogen or C^-akyl,

R¹·⁵·³ dénotés hydrogen or C^-alkyl,

R¹’·⁴ dénotés hydrogen or C^-alkyl,.

R¹ ® dénotés R¹®^-1 R¹®'²N-, wherein

R¹®·¹ dénotés hydrogen or C^-alkyl;

R¹®·² dénotés hydrogen or Ci-e-alkyl;

R^1b i$ selected from the group consisting of C^-alkyl, R¹’⁴-C₂_e-alkyl-, optionally substituted phenyl-CH₂-, R’ ^’-O-CO- CH₂- and HO-COCH₂R¹* dénotés C^-alkyl,

X* dénotés any anion forming a pharmaceutically acceptable sait,

L dénotés a bridging group -CO-NH-C^-alkyl-NH-CO-, -COCi_e-alkyl-CO-,

-C₂^-alkyl-, forming a compound of formula (IC), whereby the molecular entities of formula (IC) connected by L may be Identical or different

-115F

R^s dénotés Cl or Br,

5 and the pharmacologically acceptable acid addition salts thereof.
2. The compound of formula (IA), (IB) or (IC.1) according to claim 1, characterized in that

R² (IB)

A dénotés a bond, -CHr or -CH₂CH₂-, -CH₂-O-,

R¹ is selected from the group consisting of hydrogen, C^-alkyl, optionally substituted piperidinyl-CO-, optionally substituted pi20 perazinyl-CO-, optionally substituted piperidinyl-NH-CO-, R¹¹-SO2-, R¹²-C2^-alkyl-NH-116F

CO-, H3C-NH-CO-,

R^1J<O-CO-CHrNH-CO-, R¹²-C2^alkyl-N(CM-alkyl)-CO-, H₃C -N(C_M-alkyl)-CO-, R¹-²⁴-O-CO-CH2-N(CM-alkyl)-CO-, R’-’-C^-alkyl-CO-, R¹'⁴-C2^alkyl-, optionally substituted phenyl-CHï-, R¹'⁴³-O-CO-CH₂-, HO-CO-CH2- and HOSO2-CH2-, R¹'⁵-C,^-alkyl-CO- and R^ie-C(NH)-, wherein

R¹·¹ dénotés C_M-alkyl-;

R¹·² is selected from the group consisting of hydrogen, R’·²·’ R¹²²N-, R¹·²·¹ R¹·²·² R¹ NS R¹ⁱ⁴-O-CO-, HO-CO- and R¹ⁱ⁵O-CO-NH-,

wherein R¹-²·¹ dénotés hydrogen or C_M-alkyl, _R1X2 dénotés hydrogen or C^-alkyl, r1X3 dénotés hydrogen or C^-alkyl, R¹²⁴ dénotés C^-alkyl, rI.2.5 dénotés C^-alkyl,

R¹·³ is selected from the group consisting of hydrogen, C^-alkyl, C^-alkyl-O-, and optionally substituted phenyl

R¹·⁴ is selected from the group consisting of hydrogen, R¹·^4-1 R¹⁴²N-,

R¹·⁴·’ R¹⁴² R¹⁴³ N*-, H2N-C(NH)-NH-, R¹'⁴³-HN-C(NR¹'⁴⁴)-NH-, optionally substituted phenyl, R¹⁴³-O-CO-, R^1A4-O-CO-NH-, HO-CO- and HOSOr, wherein

R¹·⁴·¹ dénotés hydrogen or C^-alkyl, r’·⁴·² dénotés hydrogen or C^-alkyl,

R¹·⁴·³ dénotés hydrogen or C^-alkyl,

R¹·⁴·⁴ dénotés hydrogen or C^-alkyl,

R^1,5 is selected from the group consisting of hydrogen, C^-alkyl-O-, R¹·*·¹ _Ri.5J_N._{f r}iai _Ri.ia _R<-2în*-, H₂N-C(NH)-NH·, R¹ⁱ³-O-CO-, r¹⁵-⁴-O-CO-NH-, optionally substituted phenyl, wherein

R¹·¹¹ dénotés hydrogen or C^-alkyl,

R^1,5·² dénotés hydrogen or C^-alkyl,

R^1SÎ dénotés hydrogen or C^-alkyl,

R¹·⁵·⁴ dénotés hydrogen or C^-alkyl,

-117J s

R^1b

R¹· χL is

S

R^1b

R¹* xL is

R¹·* dénotés of R¹*¹ Κ^1Λ2Ν·, wherein

R¹·*·¹ dénotés hydrogen or CM-alkyl;

R¹’·² dénotés hydrogen or CM-alkyl, is selected from the group consisting of CM-alkyl, dénotés CM-alkyl, dénotés any anion forming a pharmaceutically acceptable sait, dénotés a bridging group -CO-NH-C₂^-alkyl-NH-CO-, -COCi-e-alkyl-CO- or

-C2^-alkyl-, forming a compound of formula (1C.1), whereby the molecular entities of formula (IC.1) connected by L may be Identical or different (IC.1),

R*, R^e, R⁷ R²¹, R³¹, R⁴, R⁶¹, R⁷· independently from each other are selected from the group consisting of hydrogen, halogen, CN, CM-alkyl, CM-alkyl-O-, CM-alkylOCO-. -COOR⁴·¹, -CONR^R⁴·³ and -OR⁴’¹, wherein

R^4,1 dénotés hydrogen or CM-alkyl,

R⁴·² dénotés hydrogen or CM-alkyl,

-118-

R⁴·³ dénotés hydrogen or ÛM-alkyl, or

R³ and R⁴ or R³⁴ and R⁴¹ together dénoté -O-Ci.₃-alkyl-O-;

5 and the pharmacologically acceptable acid addition salts thereof.
3. The compound of formula (IA) according to claim 2, characterized in that io A dénotés a bond, -CH₂- or -CH₂CH2-,

R¹ is selected from the group consisting of hydrogen, optionally substituted piperazinyl-CO-, optionally substituted pîperidinylNH-CO-, C^-alkyl, C_M-alkyl-SO₂-, C^-alkyl-NH-CO-, H₂N-CO-, H₂N-C_M-alkyl-, H₂NCm-alkyl-CO-, H₂N-C_M-alkyl-NH-CO-, Phenyl-CO-, Phenyl-CH_rCO-, is Phenyl-CHr, C^-alkyl-CO-, C^-alkyl -O- C_M-alkyl-CO-, (CHa^N-CM-alkyl-, (CH₃)₂N-C_M-alkyl-NH-CO-, (CH₃)₃N*-C_M-alkyl-NH-CO-, (CH₃)₃N*-CM-alkyl-CO-, (CH₃)₃N*-C₂^-alkyl-, (CH₃)N*-C_M-alkyl-N(C_M-alkyl)-CO-,

H₂N-C(NH)-NH-C_14S-NH-CO·, C^-alkyl-O-CO-, C_14S-alkyl-O-CO-C_M-alkyl-, C^-alkyl-O-CO-Crvalkyl-CO-, C_M-alkyl-O-CO-C_M-alkyl-NH-CO-,

20 Ci^-alkyl-O-CO-NH-Cm-alkyl-, Ci^-alkyl-O-CO-NH-Ci_4-alkyl-CO-,

C_14i-alkyl-O-CO-NH-C_M-alkyl-NH-CO-, HOCO-Cm-alkyl-, HOCO-C_M-alkyl-CO-, HOCO-C_M-alkyl-NH-CO-and H₂N-CNH-, H₂NC(NH)NH-C^-alkyl-CO-,

R² independently from each other are selected from the group consisting of hydrogen, 2s halogen, CN, C^-alkyl and Cpalkyl-O-,

R^e independently from each other are selected from the group consisting of hydrogen, halogen, CN, Cm-alkyl and Ci-alkyl-OR³ are selected from the group consisting of hydrogen halogen, CN and CM-alkyl, R⁴ independently from each other are selected from the group consisting of hydrogen 3o halogen, CN, Cm-alkyl, Cm-alkyl-OCO-, -COOR⁴¹ and -CONR⁴²R⁴³, wherein

R⁴·¹ dénotés hydrogen or C^-alkyl,

R⁴·² dénotés hydrogen or Ci-4-alkyl,

R⁴·³ dénotés hydrogen or Ci-4-alkyl,

35 or

R³ and R⁴ together dénoté -O-Ci.₃-alkyl-O-;

-11916887 and the pharmacologically acceptable acid addition salts thereof. ,
4. The compound of formula (IC.1 ) according to anyone of daims 1 or 2, s characterized in that

A dénotés a bond, -CH₂- or -CH₂CH_r.

L dénotés a bridging group -CO-NH-C₂^-alkyl-NH-CO-, forming a compound of formula IC or IC.1, ίο R¹, R²* independently from each other are selected from the group consisting of hydrogen, halogen, CN, CM-alkyl and C_ralkyl-O-,

R®, R®¹ independently from each other are selected from the group consisting of hydrogen, halogen, CN, CM-alkyl and Cralkyl-OR^J, R³* are selected from the group consisting of hydrogen halogen, CN and CM-alkyl, is R⁴, R⁴*independently from each other are selected from the group consisting of hydrogen halogen, CN, CM-alkyl, C_M-alkyl-OCO-, -COOR⁴¹ and -CONR⁴²R⁴³, wherein

R^4,1 dénotés hydrogen or CM-alkyl,

R⁴² dénotés hydrogen or CM-alkyl,

20 R^4,3 dénotés hydrogen or CM-alkyl, or

R³ and R⁴ or R³¹ and R⁴* together dénoté -O-Ci_₃-alkyl-O-;

and the pharmacologically acceptable acid addition salts thereof.
5. The compound of formula (IB) according to anyone of daims 1 or 2, characterized in that

R^1b dénotés CM-alkyl, and

3o R¹* dénotés CM-alkyl, and the pharmacologically acceptable acid addition salts thereof.
6. The compound of formula (IC) according to anyone of daims 1, 2 or 4,

35 charaderized in that

L dénotés a bridging group -CO-NH-C₂^-alkyl-NH-CO-,

-12016887 forming a compound of formula (IC) or (IC.1), and the pharmacologically acceptable acid addition salts thereof.
7. The compound according to anyone of ciaims 2 to 6, characterized in that R², R³, R⁴, R®, R^T dénoté hydrogen.
8. The compound according to anyone of ciaims 1 to 7, characterized in that

A dénotés -CH₂CHr>

and

E, D dénoté -CHr.
9. The compound according to anyone of ciaims 1 to 7, characterized In that the compound is selected from the group consisting of compounds (1) to (12):

-12116887

-12216887

-12316887
10. A compound according to anyone of daims 1 to 9 or a pharmaceutically acceptable sait thereof as a médicament.
11. A compound according to anyone of daims 1 to 9 or a pharmaceutically acceptable sait î thereof for the treatment of a disease selected from among respiratory diseases or complainte and allergie diseases of the airways.
12. A compound according to anyone of daims 1 to 9 or a pharmaceutically acceptable sait thereof for the treatment of a disease selected from among chronic bronchitis, acute bronchi- io tis, bronchitis caused by bacterial or viral infedion or fungi or helminthe, allergie bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergie), paediatric asthma, bronchiectasis, allergie alveolitis, allergie or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alpha-1-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary is oedema, pneumonitis of different origins.
13. A pharmaceutical composition comprising at least one compound according to anyone of daims 1 to 9 or a pharmaceutically acceptable sait thereof and a pharmaceutically acceptable carrier.
14. Médicament combinations which contain, besides one or more compounds of a compound according to anyone of daims 1 to 9, as further active substances, one or more compounds selected from among the categories of further ENaC inhibitors, betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine

25 agonists, H1-antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-lnhibitors, iNOS-Inhibitors, SYK-Inhibitors, corrections ofthe cysticfibrosis transmembrane regulator (CFTR) and CFTR potentiators or double or triple combinations thereof.