NZ622469B2 - Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof - Google Patents

Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof Download PDF

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NZ622469B2
NZ622469B2 NZ622469A NZ62246912A NZ622469B2 NZ 622469 B2 NZ622469 B2 NZ 622469B2 NZ 622469 A NZ622469 A NZ 622469A NZ 62246912 A NZ62246912 A NZ 62246912A NZ 622469 B2 NZ622469 B2 NZ 622469B2
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alkyl
compound
hydrogen
denotes
phenyl
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NZ622469A
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NZ622469A (en
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Sara Frattini
Dieter Hamprecht
Armin Heckel
Joerg Kley
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Boehringer Ingelheim International Gmbh
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Priority claimed from PCT/EP2012/071352 external-priority patent/WO2013064450A1/en
Publication of NZ622469A publication Critical patent/NZ622469A/en
Publication of NZ622469B2 publication Critical patent/NZ622469B2/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/10—Anthelmintics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings

Abstract

Provided are diaminopyrazine derivative compounds of the general formula (I), wherein the variables are as defined in the specification. Examples of the compounds include 4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1-carboxylic acid tert-butyl ester and 4-[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1-carboxamidine . The compounds are inhibitors of epithelial sodium channels (ENaC). The compounds may be useful in the treatment of respiratory diseases such as cystic fibrosis. -[N'-(3,5-Diamino-6-chloro-pyrazine-2-carbonyl)-guanidinomethyl]-4-phenethyl-piperidine-1-carboxamidine . The compounds are inhibitors of epithelial sodium channels (ENaC). The compounds may be useful in the treatment of respiratory diseases such as cystic fibrosis.

Description

Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof 1. FIELD OF THE INVENTION The present invention relates to compounds of general formula (I) O NH R N B A H N N NH (I), and the tautomers and the salts thereof, particularly the pharmaceutically acceptable salts thereof with inorganic or organic acids and bases, which have valuable pharmacological properties, particularly an inhibitory effect on epithelial sodium channels, the use thereof for the treatment of diseases, particularly diseases of the 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 of the 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 of the present invention is to prepare new compounds which may be used therapeutically for the treatment of pathophysiological processes treatable by the blockade of an epithelial 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 present invention. (11571374_1):KDJ According to a first aspect of the present invention, there is provided a compound of formula (IA), (IB) or (IC.1) O NH Cl N N N R H N N NH (IA) O NH Cl N H N N NH + (IB) O NH Cl N H N N NH N NH N Cl NH O (IC.1) wherein A denotes a bond, -CH - or -CH CH -, -CH -O-, 2 2 2 2 R is selected from the group consisting of hydrogen, C -alkyl, C -alkyl-SO -, C -alkyl-NH-CO- ,H N-CO-, 1-6 1-4 2 1-4 2 H N-C -alkyl-, H N-C -alkyl-CO-, H N-C -alkyl-NH-CO-, Phenyl-CO-, 2 1-4 2 1-4 2 1-4 (11571374_1):KDJ Phenyl-CH -CO-, Phenyl-CH -, C -alkyl-CO-, C -alkyl -O- C -alkyl-CO-, 2 2 1-6 1-6 1-4 (CH ) N-C -alkyl-, (CH ) N-C -alkyl-NH-CO-, (CH ) N -C -alkyl-NH-CO-, 3 2 1-4 3 2 1-4 3 3 1-4 + + + (CH )N -C -alkyl-N(C -alkyl)-CO-, (CH ) N -C -alkyl-, (CH ) N -C -alkyl- 3 1-4 1-4 3 3 2-4 3 3 1-4 CO-, H N-C(NH)-NH-C -NH-CO-, C -alkyl-O-CO-, C -alkyl-O-CO-C -alkyl-, 2 1-6 1-6 1-6 1-4 C -alkyl-O-CO-C - -alkyl-CO-, C -alkyl-O-CO-C -alkyl-NH-CO-, 1-6 1 4 1-6 1-4 C -alkyl-O-CO-NH-C -alkyl-, C -alkyl-O-CO-NH-C -alkyl-CO-, 1-6 1-4 1-6 1-4 C -alkyl-O-CO-NH-C -alkyl-NH-CO-, HOCO-C -alkyl-, HOCO-C -alkyl-CO-, 1-6 1-4 1-4 1-4 HOCO-C -alkyl-NH-CO-, H N-CNH- and H NC(NH)NH-C -alkyl-CO-. 1-4 2 2 1-6 R is selected from among a group of below listed formulas (c1) to (c5): O NH (c1) (c2) (c3) O NH (c4) (c5) R denotes C -alkyl, R denotes C -alkyl, X denotes any anion forming a pharmaceutically acceptable salt, L denotes a bridging group -CO-NH-C -alkyl-NH-CO-, -COC -alkyl-CO- or 2-6 1-6 -C -alkyl-, forming a compound of formula (IC.1), whereby the molecular entities of formula (IC.1) connected by L may be identical or different, 2 3 4 6 7 2a 3a 4a 6a 7a R , R , R , R , R , R , R , R , R , R independently from each other are selected from the group consisting of hydrogen, halogen , CN, C -alkyl, C -alkyl-O-, C -alkyl- 1-4 1-3 1-3 4.1 4.2 4.3 4.1 OCO-, -COOR , -CONR R and -OR , (11571374_1):KDJ wherein R denotes hydrogen or C -alkyl, R denotes hydrogen or C -alkyl, R denotes hydrogen or C -alkyl, 3 4 3a 4a R and R or R and R together denote -O-C -alkyl-O-; or a pharmacologically acceptable acid addition salt thereof.
According to a second aspect of the present invention, there is provided a compound according to the first aspect above or a pharmaceutically acceptable salt thereof for the treatment of a disease selected from among respiratory diseases or complaints and allergic diseases of the airways.
According to a third aspect of the present invention, there is provided a compound according to the first aspect above or a pharmaceutically acceptable salt 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, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), paediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alphaantitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema, and pneumonitis of different origins.
According to a fourth aspect of the present invention, there is provided a pharmaceutical composition comprising at least one compound according to the first aspect above or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
According to a fifth aspect of the present invention, there is provided a medicament combination which contains, besides one or more compounds of a compound according to the first aspect above, 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 agonists, H1-antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-Inhibitors, (11571374_1):KDJ iNOS-Inhibitors, SYK-Inhibitors, corrections of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators or double or triple combinations thereof.
According to a sixth aspect of the present invention, there is provided use of a compound according to the first aspect above for the manufacture of a medicament for the treatment of a disease selected from among respiratory diseases or complaints and allergic diseases of the airways.
According to a seventh aspect of the present invention, there is provided use of a compound according to the first aspect above for the manufacture of a medicament for the treatment of a disease selected from among chronic bronchitis, acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), paediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alphaantitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema, and pneumonitis of different origins.
The present invention therefore relates to a compound of formula (I) (11571374_1):KDJ PC T/EP2012/071352 R'~N N E. D H~N NH~ , wherein s A denotes bond or is selected from the of -CH~-, -CH~CH~-, a group consisting 0, -CH&-NR""- -NR""-, -CH&CH&CH&-, -CH&, and -CH&- and preferably bond, -CHzCHp-, wherein denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& &-alkyl, Io B denotes -CH&- or -CH~CH&-, -CH&-, or preferably or-NR"", provided that A is not 0 B denotes a bond -CH&-, -CH&-, E denote independently from each other a bond or preferably denotes optionally substituted preferably preferably substituted aryl, phenyl, by R' R" R', R', R', R", R", R", R", or or substituted heteroaryl, or pyri- optionally preferably thiophenyl, pyridyl, pyrimidinyl R' R' R', R', R', R', R', R', R', R', preferably substituted or . donyl, by F most preferably denotes 4-halo-phenyl, particularly preferred phenyl, phenyl, G denotes a of formula or group (g.1), (g.2) (g.3) PC T/EP2012/071352 *X x* is selected from the consisting of group substituted to 7-membered heterocyclyl-CO-, op- hydrogen, C& 6-alkyl, optionally - "-S02-, R"'-C24-alkyl- tionally substituted to 7-membered heterocyclyl-NH-CO-, R""-O-CO-CH2-NH-CO-, NH-CO-, H3C-NH-CO-, R"'-C24-alkyl-N(C1 4-alkyl)-CO-, R"'-C& R"'-C2 R""CO-CH2-N(C& -N(C& 4-alkyl)-CO-, 4-alkyl)-CO-, 6-alkyl-CO-, R""CO- 6-alkyl-, substituted phenyl-CH2-, CH2-, HO-CO-CH2- and optionally S02-CH2-, R"'-C& R"'-C(NH)-, 6-alkyl-CO- and wherein is selected from the of 4-alkyl-, group consisting C& R""N-C& H2NC(NH)NH C& 6-alkyl-, 4-alkyl-, R" R" R" N'-C& 4-alkyl- 4-alkyl, HOCO-C& and C1-3 alkyl-OCO-C1 4-alkyl-, is selected from the consisting of hydrogen, H2NC(NH)NH group R" R" R" R" R" N' R" -HN-C(NR" )-NH- R""-O-CO-, R""CO-NH- HO-CO-, and HOS02-, R"'" R"'" R"" R""N'- R""N-, R""-HN-C(NR"")-NH- preferably and wherein R"'" denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& 4-alkyl, most 4-alkyl, preferably C& denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& most 4-alkyl, preferably C& OI R" R" "and 4- 7- together form a to membered hetercyclic ring contain- one N-atom, a or 5-membered heterocyc- ing preferably ring denotes 6-alkyl, preferably 4-alkyl, C& C& denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& PC T/EP2012/071352 is selected from the consisting of 6-alkyl, 6-alkyl-O-, op- group hydrogen, C& C& R"'" R"'" R""R""N'-, R""N-, tionally substituted phenyl, R""-HN-C(NR"")-NH-, R""-O-CO, HO-CO- H2NC(NH)NH-, and HOSO2-, wherein R"'" denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& denotes hydrogen or 6-alkyl, R" R" "and 4- 7- form to membered together a hetercyclic ring containing N-atom, 6-membered one preferably a heterocyclic ring containing one atom, preferably hydrogen or C& 4-alkyl, R"' R"'" R""N-, is selected from the of group consisting hydrogen, R"'" R"" R""N'-, R""-HN-C(NR"")-NH, H N-C(NH)-NH-, subs- optionally R""-O-CO-, R""-O-CO-NH-, tituted HO-CO- and HOSO2-, phenyl, wherein R"'" denotes or or hydrogen C& 6-alkyl, preferably hydrogen C& 4-alkyl, denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& 4-alkyl, denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& 4-alkyl, most preferably 4-alkyl, denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& 4-alkyl, most preferably 4-alkyl, R"' R"'" R""N-, 6-alkyl-O-, is selected from the consisting of hydrogen, C& group R"'" R"" R"" R""N'-, H N-C(NH)-NH-, optionally substituted phenyl, -O-CO-NH-, HO-CO-, CO-, HOSO2-, wherein denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, most C& C& preferably C& 4-alkyl, denotes or 6-alkyl or 4-alkyl, most hydrogen C& preferably hydrogen C& preferably C& 4-alkyl, denotes or 6-alkyl, or 4-alkyl, hydrogen C& preferably hydrogen C& R"'" R""N- denotes wherein R"'" denotes or 6-alkyl; or hydrogen C& preferably hydrogen methyl, PC T/EP2012/071352 denotes hydrogen or 6-alkyl; preferably hydrogen or methyl, is selected from the consisting of 4-alkyl, group C& R""CO- R"'-C26-alkyl-, HO-CO- optionally substituted phenyl-CH2-, CH2- and CH2-, 4-alkyl, particularly preferred preferably C& methyl, wherein R"'" R""N-, is selected from the consisting of group hydrogen, R"'" R""N'-, R""-HN-C(NR"")-NH, H N-C(NH)-NH-, subs- optionally R""-O-CO-, R""-O-CO-NH-, tituted HO-CO- and HOSO2-, phenyl, wherein R"'" denotes or or hydrogen C& 6-alkyl, preferably hydrogen C& 4-alkyl, denotes or or hydrogen C& 6-alkyl, preferably hydrogen C& 4-alkyl, denotes or or most hydrogen C& 6-alkyl, preferably hydrogen C& 4-alkyl, preferably C& 4-alkyl, denotes or or most hydrogen C& 6-alkyl, preferably hydrogen C& 4-alkyl, preferably C& 4-alkyl, denotes C& 6-alkyl, preferably methyl, X denotes any anion forming a pharmaceutically acceptable salt, preferably selected from among CF3-COO, Cl, Br, HCOO and CH3-COO, most preferably Cl and CF3-COO, -CO-NH-C26-alkyl-NH-CO-, -COG& 6-alkyl-CO-, -C26- L denotes a bridging or group alkyl-, forming a compound of formula (IC), dif- whereby the molecular entities of formula connected L be identical or (IC) by may ferent N NH2 D H2N F NH2 PC T/EP2012/071352 denotes Cl or Br, preferably Cl, in the form of the tautomers, the racemates, the enantiomers, the diastereomers optionally s and the mixtures thereof, in form of the solvates or thereof and optionally hydrates, prodrugs the acceptable acid addition salts thereof. optionally pharmacologically Preferred of formula or are those wherein compounds (IA), (IB) (IC.1) Cl N &2 A H2N NH2 (IA) ~J A R Cl N H2N N NH2 N-R"' (IB) -CH2-, A denotes a bond, -CH2CH2- or CH2, preferably -CH2CH2-, is selected from the consisting of group 6-alkyl, substituted piperazinyl-CO-, substituted pi- hydrogen, C1 optionally optionally R"'-C2 "-SO2-, H3C-NH-CO-, peridinyl-NH-CO-, 4-alkyl-NH-CO-, R"'-C2 R""-O-CO-CH2-NH-CO-, 4-alkyl-N(C& 4-alkyl)-CO-, H3C -N(C& 4-alkyl)-CO-, R"'- R"'-C2 R""CO-CH2-N(C& 4-alkyl)-CO-, 6-alkyl-CO-, 6-alkyl-, optionally R""-O-CO-CH2-, HO-CO-CH2- substituted phenyl-CH2-, and HOSO2-CH2-, R"'-C& R"'-C(NH)-, 6-alkyl-CO- and wherein denotes 4-alkyl-; PC T/EP2012/071352 is selected from the consisting of group R"'" R"'" R""R""N'-, R""N-, R""-O-CO-, HO-CO- hydrogen, -O-CO-NH-, wherein R"'" denotes hydrogen or 6-alkyl; preferably hydrogen or 4-alkyl, C& C& denotes hydrogen or 6-alkyl; preferably hydrogen or 4-alkyl, C& C& denotes or 6-alkyl; or 4-alkyl, hydrogen C& preferably hydrogen C& denotes C& 6-alkyl; preferably C& 4-alkyl, denotes C& 6-alkyl; preferably C& 4-alkyl, is selected from the of 6-alkyl-O-, and group consisting hydrogen, C& 6-alkyl, C& optionally substituted phenyl R"' R"'" R""N-, is selected from the of group consisting hydrogen, R"'" R"" R""N'-, R""-HN-C(NR"")-NH-, H N-C(NH)-NH-, subs- optionally R""-O-CO-, R""-O-CO-NH-, tituted HO-CO- and HOSO2-, phenyl, wherein R"'" denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& 4-alkyl, denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& 4-alkyl, denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& 4-alkyl, most preferably 4-alkyl, denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& 4-alkyl, most preferably 4-alkyl, 6-alkyl-O-, is selected from the consisting of hydrogen, C& group R" "R" R" "R" R" N'- R" N- CO- H N-C(NH)-NH- R""-O-CO-NH-, optionally substituted phenyl, wherein R"'" denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& most preferably C& 4-alkyl, denotes or 6-alkyl, or 4-alkyl, most hydrogen C& preferably hydrogen C& preferably C& 4-alkyl, denotes or 6-alkyl, or 4-alkyl, hydrogen C& preferably hydrogen C& R"'" R""N- denotes wherein R"'" denotes or 6-alkyl; or hydrogen C& preferably hydrogen methyl, PC T/EP2012/071352 denotes hydrogen or 6-alkyl; preferably hydrogen or methyl, denotes 4-alkyl, preferably methyl, s denotes C&6-alkyl, preferably methyl, X denotes anion forming a pharmaceutically acceptable salt, preferably selected from CF3-COO, HCOO and CH3-COO, most Cl and among Cl, I, Br, preferably CF3-COO L denotes -CO-NH-C2 6-alkyl-NH-CO-, -COG& 6-alkyl-CO- or a bridging group 6-alkyl-, of formula forming a compound (IC. the molecular entities of formula connected L identical or whereby (IC. may be 1) by different Cl N &A, A H2N NH2 H2N NH2 R4a Cl (IC.
R' R" R', R', R', R', R", R", R", R", independently from each other are selected from the consisting of halogen, CN, 4-alkyl, 3-alkyl-O-, 3-alkyl- group hydrogen, C& C& C& -COOR'", -CONR"R" -OR'", OCO-, and preferably hydrogen, wherein denotes hydrogen or C& 4-alkyl, preferably hydrogen or C& 2-alkyl, particularly pre- ferred hydrogen or methyl denotes hydrogen or 4-alkyl, preferably hydrogen or 2-alkyl, particularly pre- C& C& ferred or methyl hydrogen denotes hydrogen or 4-alkyl, preferably hydrogen or 2-alkyl, particularly pre- C& C& ferred or methyl hydrogen PC T/EP2012/071352 R' R' R" R" -O-C& and or and together denote 3-alkyl; -O-C& 2-alkyl-O-, preferably in the form of the tautomers, the racemates, the enantiomers, the diastereomers optionally s and the mixtures thereof, in form of the solvates or thereof and optionally hydrates, prodrugs the acceptable acid addition salts thereof. optionally pharmacologically are of formula wherein Particularly preferred compounds (IA), denotes -CH2- or -CH2CH2-, a bond, R is selected from the of group consisting hydrogen, optionally substituted piperazinyl-CO-, optionally substituted piperidinyl- NH-CO-, 4-alkyl-NH-CO-, H2N-CO-, H2N- C1 6-alkyl, C1 4-alkyl-S02-, C1 H2N-C1 4-alkyl-, 4-alkyl-CO-, 4-alkyl-NH-CO-, Phenyl-CO-, Phenyl-CH2-CO-, C& H2N-C& 6-alkyl-CO-, 4-alkyl-CO-, Phenyl-CH2-, C& C& 6-alkyl C& (CH3)2N-C& 4-alkyl-, 4-alkyl-NH-CO-, (CH3)3N'-C& 4-alkyl-NH-CO-, (CH3)3N'-C& 4-alkyl-CO-, (CH3)2N-C& (CH3)3N'-C2 4-alkyl-, (CH3)N'-C& 4-alkyl)-CO-, 4-alkyl-N(C& H2N-C(NH)-NH-C& 6-NH-CO-, 6-alkyl-O-CO-, 6-alkyl-O-CO-C& 4-alkyl-, C& C& C& 6-alkyl-O-CO-C&alkyl-CO-, C& 6-alkyl-O-CO-C& 4-alkyl-NH-CO-, 6-alkylCO-NH-C& 6-alkylCO-NH-C& G& 4-alkyl-, C& 4-alkyl-CO-, 6-alkylCO-NH-C& 4-alkyl-NH-CO-, HOCO-C& 4-alkyl-, HOCO-C& 4-alkyl-CO-, H2N-CNH- HOCO-C& 4-alkyl-NH-CO-, and H2NC(NH)NH-C& 6-alkyl-CO-, R independently from each other are selected from the consisting of hydrogen, group halogen, CN, 4-alkyl and C&-alkyl-O-, R independently from each other are selected from the consisting of group hydrogen, 4-alkyl and C&-alkyl halogen, CN, C& are selected from the consisting of halogen, CN and 4-alkyl, group hydrogen, C& independently from each other are selected from the consisting of group hydrogen, -COOR'" -CONR"R", 4-alkyl, 4-alkyl-OCO-, and halogen, CN, C& C& wherein denotes or 4-alkyl, or hydrogen C& preferably hydrogen methyl; denotes or 4-alkyl, or hydrogen C& preferably hydrogen methyl; denotes or 4-alkyl, or hydrogen C& preferably hydrogen methyl; R' R' -O-C& -O-C& 3s and together denote 3-alkyl; 2-alkyl; preferably PC T/EP2012/071352 in the form of the tautomers, the racemates, the enantiomers, the diastereomers optionally and the mixtures thereof, and the acceptable acid addition salts optionally pharmacologically thereof. s Also particularly preferred are compounds of formula (IC. wherein -CH2- A denotes a bond, or -CH2CH2-, L denotes a -CO-NH-C2 6-alkyl-NH-CO-, bridging group of formula IC or IC. forming a compound 1, from each other are selected from the of independently group consisting hydrogen, C&-alkyl-O-, halogen, CN, C& 4-alkyl and from each other are selected from the of independently group consisting hydrogen, C&-alkyl halogen, CN, C& 4-alkyl and are selected from the of CN and group consisting hydrogen halogen, C& 4-alkyl, from each other are selected from the of independently group consisting hydrogen -COOR'" -CONR"R", 4-alkyl-OCO-, halogen, CN, C& 4-alkyl, C& and wherein denotes or or hydrogen C& 4-alkyl, preferably hydrogen methyl; denotes hydrogen or C& 4-alkyl, preferably hydrogen or methyl; denotes hydrogen or C& 4-alkyl, preferably hydrogen or methyl; OI R' R' R" R" -O-C& 3-alkyl; O-C& 2-alkyl; and or and together denote preferably optionally in the form of the tautomers, the racemates, the enantiomers, the diastereomers and the mixtures thereof, and optionally the pharmacologically acceptable acid addition salts 2s thereof.
Also particularly preferred are compounds of formula wherein (IB) denotes 4-alkyl, preferrably methyl, denotes 6-alkyl, C& preferably methyl, in the form of the the the enantiomers, the diastereomers optionally tautomers, racemates, and the mixtures in form of the solvates or thereof and thereof, optionally hydrates, prodrugs the acid addition salts thereof. optionally pharmacologically acceptable Also particularly preferred are compounds of formula wherein (IC) -CO-NH-C2 L denotes a 6-alkyl-NH-CO-, bridging group PC T/EP2012/071352 forming a compound of formula or (IC.
(IC) 1), in the form of the tautomers, the racemates, the enantiomers, the diastereomers optionally and the mixtures thereof, in form of the solvates or thereof and optionally hydrates, prodrugs the acceptable acid addition salts thereof. optionally pharmacologically Especially preferred are compounds of formula or (IC. wherein (IA), (IB) 1), R and denote R, R, R, hydrogen.
Also are of formula or wherein especially preferred compounds (IC.
(IA), (IB) 1), R" R" R', R', R', R', R', R", R", R", Io and denote hydrogen.
Also are of formula or wherein especially preferred compounds (IA), (IB) (IC), A denotes -CH2CH2-, and D denote -CH2- A further embodiment of the current invention are of formula or compounds (I), (IA), (IB) (IC) or a pharmaceutically acceptable salt thereof as a medicament, preferably compounds of formula or (IA), (IB) (IC) 2o A further embodiment of the current invention are compounds of formula or (I), (IA), (IB) (IC), the- preferably compounds of formula or or a pharmaceutically acceptable salt (IA), (IB) (IC), air- reof for the treatment of respiratory diseases or complaints, and allergic diseases of the ways.
Preferred are compounds of formula or preferably compounds of formula or (I) (IC), (IA), (IB) or a pharmaceutically acceptable salt thereof for the treatment of a disease selected (IC), from chronic bronchitis, acute bronchitis, bronchitis caused bacterial or viral infec- among by tion or or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis fungi asthma (intrinsic or pediatric asthma, bronchiectasis, allergic alveolitis, al- (COPD), allergic), or non-allergic rhinitis, chronic sinusitis, fibrosis or mucoviscidosis, alpha lergic cystic ~o interstitial alveolitis, antitrypsin deficiency, cough, pulmonary emphysema, lung diseases, nasal of different hyperreactive airways, pulmonary oedema, pneumonitis origins, polyps, e. radiation-induced or or infectious chronic caused aspiration pneumonitis, preferably g. by bronchitis, acute bronchitis, bronchitis, chronic obstructive bronchitis asthma (intrin- (COPD), sic or fibrosis and chronic bronchitis, COPD and allergic), cystic pediatric asthma, preferably ~s fibrosis. cystic PC T/EP2012/071352 A pharmaceutical composition at least one compound according to to the inven- comprising tion or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
A further embodiment of the current invention is medicament combinations which contain, s besides one or more compounds according to the invention, as further active substances, one or more compounds selected from the categories of further ENaC inhibitors, be- among tamimetics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR- anticholinergics, MAP-kinase inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, inhibitors, MPR4-Inhibitors, iNOS-Inhibitors, SYK-Inhibitors, and cystic fibrosis transmembrane regula- VX-770 VX-809, combi- io tor (CFTR) and CFTR potentiators, preferably and or double or triple nations thereof.
USED TERMS AND DEFINITIONS is Terms not specifically defined herein should be given the meanings that would be given to them one of skill in the art in light of the disclosure and the context. As used in the specifi- indi- cation, however, unless specified to the contrary, the following terms have the meaning cated and the following conventions are adhered to.
In the radicals, or moieties defined below, the number of carbon atoms is often groups, specified preceding the for example, o-alkyl means an alkyl or radical having group, Ci group 1 to 6 carbon atoms.
In general in single like HO, OS, NC HOOC, F&C or the like, the groups H2N, 02S, (cyano), skilled artisan can see the radical attachment to the molecule from the free valences point(s) 2s of the itself. For combined two or more the last or first group groups comprising subgroups, named at the end is the radical attachment for the subgroup hyphenated point, example, &-alkyl-" substituent "aryl-C& means an which is bound to a &-alkyl-group, the aryl group C& latter of which is bound to the core or to the to which the substituent is attached. group so When of the invention is in the form of chemical name and a compound present depicted a in of the formula shall An asterisk as a formula, case any discrepancy prevail. may be used in sub-formulas to indicate the bond which is connected to the core molecule defined.
For the term "3-carboxypropyl-group" the substituent: example, represents following PC T/EP2012/071352 wherein the is attached to the third carbon atom of the The carboxy group propyl group. terms "1-methylpropyl-", 2-dimethylpropyl-" or "cyclopropylmethyl-" represent the group following groups: ~CH~ H3C CH3 The asterisk be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. io Many of the following terms be used repeatedly in the definition of a formula or may group and in each case have one of the meanings given above, independently of one another.
Unless indicated, according to the invention a chemical formula or name specifically given shall tautomers and all and isomers enanti- encompass stereo, optical geometrical (e. is E/Z isomers etc. and racemates thereof well mixtures in differ- omers, diastereomers, as as ent of the enantiomers, mixtures of or mixtures of of proportions separate diastereomers, any the forms where such isomers and enantiomers well foregoing exist, as as salts, including salts thereof and solvates thereof such for instance pharmaceutically acceptable as hydrates solvates of the free or solvates of salt of the including compounds a compound.
The term "substituted" means that one or more on the desig- as used herein, any hydrogens nated atom is with selection from the indicated that the desig- replaced a group, provided atom's nated normal valence is not exceeded, and that the substitution results in a stable compound. substituted" above- the term "optionally is meant within the scope of the invention the lower-molecular lower- mentioned optionally substituted a group. Examples of group, by 1-200 molecular groups regarded as chemically meaningful are groups consisting of atoms. com- Preferably such groups have no negative effect on the pharmacological efficacy of the ~o pounds. For example the groups may comprise: Straight-chain or branched carbon option- chains, optionally interrupted heteroatoms, ally substituted rings, heteroatoms or other common functional groups.
Aromatic or non-aromatic of carbon atoms and het- ring systems consisting optionally which in turn substituted functional eroatoms, may be groups.
PC T/EP2012/071352 A number of aromatic or non-aromatic ring systems consisting of carbon atoms and op- inter- tionally heteroatoms which be linked one or more carbon chains, optionally may by rupted heteroatoms, optionally substituted heteroatoms or other common functional by by oups. "treatment" "therapy" al- The expression or means therapeutic treatment of patients having developed one or more of said conditions in manifest, acute or chronic form, including ready treatment in order to relieve of the specific indication or causal symptomatic symptoms treatment in order to reverse or reverse the condition or to the of partially delay progression io the indication far this on the condition and the as as may be possible, depending severity thereof. Thus the "treatment of disease" herein means the manage- expression a as used ment and care of the condition or disorder. The a patient having developed disease, purpose of treatment is to combat the condition or disorder. Treatment includes the admini- disease, stration of the active to eliminate or control the condition or disorder compounds disease, as is well to alleviate the or associated with the condition or as symptoms complications disease, disorder.
The "pharmaceutically acceptable" is herein to refer to those phrase employed compounds, and/or forms which within the of sound medical materials, compositions, dosage are, scope suitable for in contact with the tissues of human and animals without judgment, use beings com- ~o excessive toxicity, irritation, allergic response, or other problem or complication, and mensurate with a reasonable benefit/risk ratio. salts" As used herein, "pharmaceutically acceptable refer to derivatives of the disclosed compounds wherein the parent compound is modified making acid or base salts thereof.
Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or ganic 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, dietha- nolamine 2'-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ~o ethylenediamine, N-ethyl-glucamine, hydrabamine, 1H-imidazole, lysine, magnesium hydrox- 4-(2-hydroxyethyl)-morpholine, potassium 1-(2-hydroxyethyl)- ide, piperazine, hydroxide, sodium triethanolamine 2"-nitrilotris(ethanol)), tromethamine, zinc pyrrolidine, hydroxide, (2, acetic acid, 2.2-dichloro-acetic acid, acid, alginic acid, ascorbic acid, hydroxide, adipic aspartic acid, benzenesulfonic acid, benzoic acid, 5-dihydroxybenzoic acid, 4-acetamido- ~s benzoic acid, (+)-camphoric acid, (+)-camphorsulfonic 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 PC T/EP2012/071352 acid, fumaric acid, galactaric acid, gentisic acid, D-glucoheptonic acid, D-gluconic acid, glucuronic acid, glutamic acid, glutaric acid, 2-oxo-glutaric acid, acid, glycerophosphoric gly- cine, acid, hexanoic acid, acid, hydrobromic acid, hydrochloric acid, isobu- glycolic hippuric acid, DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, tyric lysine, s malonic acid, DL-mandelic acid, methanesulfonic acid, galactaric acid, naphthalene-1, disulfonic acid, naphthalenesulfonic acid, 1-hydroxynaphthoic acid, nicotinic acid, nitric octanoic oleic orotic oxalic acid acid, acid, acid, acid, acid, palmitic acid, pamoic (embonic 4-amino-salicylic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, (+)-L-tartaric acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, acid, io thiocyanic acid, p-toluenesulfonic acid and undecylenic acid. Further pharmaceutically ceptable salts can be formed with cations from metals like aluminium, calcium, lithium, mag- nesium, 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 present but a quaternary ammonium compound the anions corresponding for example to the acids is 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, depend- exam- ing on whether the plurivalent ion is present in a single or multiple charged form. For the charge state of a polyvalent acid will depend on the degree of its deprotonation. ple, The pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety conventional chemical methods. com- Generally, such salts can be prepared reacting the free acid or base forms of these dilu- pounds with a sufficient amount of the appropriate base or acid in water or in an organic 2s ent like ether, acetate, ethanol, or acetonitrile, or a mixture thereof. ethyl isopropanol, Salts of other acids than those mentioned above which for example are useful for or purifying isolating the compounds of the present invention trifluoro acetate salts, also comprise a (e.g. of the invention. part As herein the term "prodrug" refers to an inactive form of that exerts its effects used a drug after metabolic within the it to usable or active or processes body converting a form, a (ii) substance that rise to active not itself active gives a pharmacologically metabolite, although e. an inactive (i. precursor).
The terms "prodrug" or "prodrug derivative" mean covalently-bonded derivative, carrier or of the or active substance which at least some precursor parent compound drug undergoes PC T/EP2012/071352 biotransformation to exhibiting its pharmacological Such either have prior effect(s). prodrugs metabolically cleavable or otherwise convertible and are transformed in vivo to groups rapidly the parent for in blood or activation via oxidation yield compound, example, by hydrolysis by as in case of thioether Most common include esters and amide analogs of groups. prodrugs s the parent compounds. The is formulated with the objectives of improved chemical prodrug stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of formulation increased hydro- action, improved organ selectivity, improved (e. g. , solubility), and/or decreased side effects (e. toxicity). In general, prodrugs themselves g. , have weak or no biological activity and are stable under ordinary conditions. Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H.
"Design Bundgaard (eds. Gordon 8 Breach, 1991, particularly Chapter 5: and Applications Prodrugs"; of 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.
Widder et a/. Vol. Academic 309-396; Burger's Me- (eds. 42, Press, 1985, particularly ), pp. dicinal Chemistry and Drug Discovery, 5th Ed. M. Wolff (ed. John Wiley 8 Sons, 1995, par- 172-178 ticularly Vol. 1 and and 949-982; Pro-Drugs as Novel Delivery Systems, T. pp. pp.
Higuchi 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 reference in their entireties. com- The term "pharmaceutically acceptable prodrug" as used herein means a of a prodrug pound of the invention which is, within the scope of sound medical suitable for use judgment, in contact with the tissues of humans and lower animals without undue toxicity, irritation, and the like, commensurate with a reasonable benefit/risk ratio, and effec- lergic response, tive for their intended as well as the zwitterionic forms, where possible. use, "aryl" The term as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic containing 6 carbon atoms which be further group may fused to second or 6-membered which saturated or a carbocyclic group may be aromatic, unsaturated. but is not limited anthra- Aryl includes, to, phenyl, indanyl, indenyl, naphthyl, cenyl, phenanthrenyl, tetrahydronaphthyl dihydronaphthyl.
The term "heterocyclyl" or "heterocyclic ring" means saturated or unsaturated mono- or one or more heteroatoms selected from or polycyclic-ring system containing N, 0 S(O), wherein r 1 or of to 14 atoms. The term "heterocycle" is intended to 0, 2, consisting 3 ring include all the isomeric forms. possible PC T/EP2012/071352 ring" Thus, the term "heterocyclyl" or "heterocyclic includes the following struc- exemplary tures which are not depicted as radicals as each form be attached through a covalent bond to atom so as valences are maintained: any long appropriate 0 II 0 S 0 ~S~ &S& 0 0 0 N 0 0 0 0 S 0 0 S N N 0 0 ~? ~? ~? uuuu u u N N N p&'? 6?.6i?. p? p? 0' '0 0 N p PC T/EP2012/071352 p 0 0 0 0 0 0 S 0 S, S, 0 0 S 0 0 The term "heteroaryl" means a mono- or containing one or more het- polycyclic-ring system eroatoms selected from 0 or r 1 or consisting of 5 to 14 atoms N, S(O)„wherein 0, 2, ring wherein at least one of the heteroatoms is of aromatic The term "heteroaryl" is part ring. io tended to include all the isomeric forms. possible the term "heteroaryl" includes the structures which are not de- Thus, following exemplary radicals each form attached covalent bond to atom picted as as may be through a any so valences are maintained: long as appropriate PC T/EP2012/071352 Ci&' Ci) Ci&i /i' ~i' nil nil nil ~El i (1 (1~) N~~N x) x) N N N N N N N 0 S / / ~ / / N N N N X YN N X N ~ ~ ~ / /' N N~ N ~ N~+N N N N N Nd~ N~i N N-N) M N) ~ ~ PC T/EP2012/071352 The term monocyclic C57-heterocyclyl" means a saturated or unsaturated non-aromatic monocyclic-ring containing one or more heteroatoms selected from 0 or system N, S(O), wherein r 1 or consisting of 5 to 7 atoms. The term monocyclic 0, 2, ring C57-heterocyclyl" is intended to include all the possible isomeric forms.
Thus, the term monocyclic C57-heterocyclyl" includes the following structures exemplary which are not radicals each form attached covalent bond to depicted as as may be through a any atom so long as appropriate valences are maintained: S=0 S=0 S=O 0 S 0 0 S 0 0 0 0 N 0 0 0 S 0 0 0, 0, S S S 0 0 0 0 PC T/EP2012/071352 U U D U Q) Q) () U U ~ ~ 0 0 0 0 S 0 0 The term monocyclic ~-heteroaryl means a monocyclic-ring containing one or C5 system more heteroatoms selected from or r 1 or of or N, 0 S(O)„wherein 0, 2, consisting 5 6 ring atoms wherein at least one of the heteroatoms is of aromatic The term "monocyclic part ring. lo C5g- heteroaryl" is intended to include all the isomeric forms. possible the term ~-heteroaryl" includes the structures Thus, monocyclic C5 following exemplary which are not radicals each form attached covalent bond to depicted as as may be through a atom valences are maintained: any so long as appropriate Ci)' C~) Ci)' /i' QN' Uh/ Uk/ ~El PC T/EP2012/071352 (K~) N~~N The term means saturated or unsaturated bicyclic C8 &o-heterocyclyl a bicyclic-ring system s aromatic one or more heteroatoms selected from or including ring systems containing N, 0 wherein r 1 or of to 10 atoms wherein the heteroatoms is op- 0, 2, consisting 8 ring S(o), , of the aromatic The term &o-heterocyclyl" is intended to include tionally part ring. bicyclic C8 all the isomeric forms. possible the term "bicyclic &o-heterocyclyl" includes the structures which Thus, C8 following exemplary 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: S 0 0 0 PC T/EP2012/071352 // ) // Mp 0 Mp 0 0 0 N 0 S 0 0 S 0 0 0 S 0 0 x) x) N N N N N 0 S / / ~ / / N N N N PC T/EP2012/071352 X X ~ N N N ~ ~ ~ N~aN N N N N N-&~ N~~ N~ w s The term "annelated of or heterocyclyl" as used herein, either alone or in combi- species aryl nation with another substituent wherein the annelated presents as an aryl-het a species (a), het-aryl or a het-het annelation means a monovalent substituent derived removal of (b) (c) one from hydrogen an aromatic monocyclic or aromatic multicyclic containing carbon atoms, system systems six- io which is annelated to a five-, or seven-membered saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and two, three or four heteroatoms one, ring selected from and sulfur or nitrogen, oxygen five-, six-, seven-membered a or saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, multi- is oxygen and sulfur, which is annelated to an aromatic monocyclic system or aromatic cyclic systems containing carbon atoms or five-, six-, seven-membered a or saturated or unsaturated (including aromatic) heterocycle containing carbon atoms and one, two, three or four ring heteroatoms selected from nitrogen, five-, six-, seven-membered un- oxygen and sulfur, which is annelated to a or saturated or saturated (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-indoyl, indoyl, 5-indoyl, 6-indoyl, indolizinyl, benzimidazyl or purinyl. "halogen" The term as used herein means a halogen substituent selected from fluoro, chloro, bromo or iodo.
"C& „-alkyl", The term wherein n is an integer from 2 to either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms. For example the term 5-alkyl embraces the radicals H~C-, H~C-CH~-, HgC-CHp-CHp-, HgC-CH(CHg)-, HgC-CHp-CHp-CHp-, HgC-CHp-CH(CHg)-, HgC-CH(CHg)-CHp-, PC T/EP2012/071352 HgC-CHp-CHp-CHp-CHp-, HgC-CHp-CHp-CH(CHg)-, HgC-CHp-CH(CHg)-CHp-, HgC-C(CHg)p-, H~C-CH(CH~)-CH~-CH~-, H~C-CH~-C(CH~)~-, H~C-C(CH~)~-CH~-, H~C-CH(CH~)-CH(CH~)- and HgC-CHp-CH(CHpCHg)-. s The term „-cycloalkyl", wherein n is an integer from 4 to either alone or in combination with another radical denotes a saturated, unbranched hydrocarbon radical with 3 to n cyclic, atoms. For the term includes C example C3-7 cycloalkyl cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. io In all cases of contradictions between structure and their naming structure shall prevail.
PREFERRED EMBODIMENTS The A denotes bond or is selected from the of -CH&-, symbol a group consisting 0, -CH~-NR""- -NR""-, -CH~CH~-, -CH~CH~CH~-, -CH~-O-, and -CH~- and preferably bond, -CHzCHp-, wherein denotes hydrogen or C& 6-alkyl, preferably hydrogen or C& &-alkyl.
-CH&- -CH&-, The symbol B denotes or -CH&CH&-, preferably or -NR"", provided that A is not 0 or a bond.
-CH&-, -CH&-.
The symbol D denotes a bond or preferably -CH&-, -CH&-.
The symbol E denotes a bond or preferably The symbol F denotes optionally substituted aryl, preferably phenyl, preferably substituted R' R' R" R" R', R', R', R", R", R", or or substituted heteroaryl, or pyri- optionally preferably thiophenyl, pyridyl, pyrimidinyl donyl, most 4-halo-phenyl or particularly preferred preferably phenyl, pyridyl, phenyl. ~o The G denotes a of formula or symbol group (g.1), (g.2) (g.3) PC T/EP2012/071352 *N A* (g.3), The substituent is selected from the consisting of group 6-alkyl, substituted to 7-membered heterocyclyl-CO-, hydrogen, C1 optionally wherein the contains one or two N-atoms, subs- preferably heterocyclyl ring optionally tituted to 7-membered heterocyclyl-NH-CO-, wherein the preferably heterocyclyl "-S02-, R"'-C24-alkyl-NH-CO-, contains one or two N-atoms, H3C-NH-CO-, ring R"'-C2 R""-O-CO-CH2-NH-CO-, 4-alkyl-N(C14-alkyl)-CO-, -N(C1 4-alkyl)-CO-, R"'-C2 R""CO-CH2-N(C1 R"'-C16-alkyl-CO-, 4-alkyl)-CO-, 6-alkyl-, optionally R""CO- substituted CH2-, HO-CO-CH2- and HOS02-CH2-, phenyl-CH2-, R"'-C1 R"'-C(NH)-, 6-alkyl-CO- and wherein is selected from the of 4-alkyl-, group consisting C1 R""N-C1 H2NC(NH)NH C1 6-alkyl-, 4-alkyl-, '" ' ' R"' R"' R"' N'-C14-alkyl, HOCO-C14-alkyl- and C1-3 alkyl-OCO-C1 4-alkyl-, is selected from the group consisting of hydrogen, H2NC(NH)NH-, R" R" R" R" R" N' R" R" -HN-C(NR" )-NH- O-CO- R"'" R""CO-NH- R""N-, HO-CO-, and HOS02-, preferably R" R" R" N' R" -HN-C(NR" )-NH- wherein R"'" denotes hydrogen or C1 6-alkyl, preferably hydrogen or C1 4-alkyl, more preferably 4-alkyl, most preferably methyl denotes hydrogen or C1 6-alkyl, preferably hydrogen or C1 4-alkyl, More preferably 4-alkyl, most preferably methyl PC T/EP2012/071352 R" R" "and 4- 7- together build a to membered hetercyclic ring containg one N-atom, a or 6-membered heterocyclic preferably ring denotes C16-alkyl, preferably C14-alkyl, most preferably methyl denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C1 C1 denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C1 C1 is selected from the of 6-alkyl-O-, op- group consisting hydrogen, C1 6-alkyl, C1 R"'" R"'" R""N-, R""N'-, substituted tionally phenyl, R""-HN-C(NR"")-NH, R""-O-CO, HO-CO- and H2NC(NH)NH-, HOSO2-, wherein R"'" denotes or or hydrogen C1 6-alkyl, preferably hydrogen C1 4-alkyl, denotes or hydrogen C16-alkyl, R"'" R"" 4- 7- and build to membered together a hetercyclic ring containing N-atom, 5- 6-membered one preferably a or heterocyclic ring containing one N-atom, preferably hydrogen or C14-alkyl, R1. R"'" R""N-, is selected from the group consisting of hydrogen, R"'" R"" R""N'-, R""-HN-C(NR"")-NH-, N-C(NH)-NH-, subs- H optionally R""-O-CO-, R""-O-CO-NH-, HO-CO- tituted phenyl, and HOSO2-, wherein R"'" denotes hydrogen or C16-alkyl, preferably hydrogen or C14-alkyl, denotes hydrogen or C1 6-alkyl, preferably hydrogen or C1 4-alkyl, denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, most C1 C1 4-alkyl, preferably C1 denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, most C1 C1 4-alkyl, preferably C1 R"'" R""N-, is selected from the consisting of C16-alkyl-O-, group hydrogen, R"'" R"" R"" R""N'-, H N-C(NH)-NH-, substituted optionally phenyl, -O-CO-NH-, CO-, HO-CO-, HOSO2-, wherein R"'" denotes or 6-alkyl, or 4-alkyl, hydrogen C1 preferably hydrogen C1 denotes or 6-alkyl, or 4-alkyl, most hydrogen C1 preferably hydrogen C1 preferably C1 4-alkyl, PC T/EP2012/071352 denotes hydrogen or 6-alkyl preferably hydrogen or 4-alkyl, most C& C& 4-alkyl, preferably C& denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& R"'" R"' R""N- denotes wherein R"'" denotes or 6-alkyl, or hydrogen C& preferably hydrogen methyl, denotes or or hydrogen C& 6-alkyl, preferably hydrogen methyl. is selected from the of Preferably group consisting 4-alkyl-NH-CO-, H2N-CO-, hydrogen, C& 6-alkyl, C& 4-alkyl-S02-, C& 4-alkyl-CO-, 4-alkyl-NH-CO-, Phenyl-CO-, H2N-C& 4-alkyl-, H2N-C& H2N-C& Phenyl-CH2-CO-, 6-alkyl-CO-, 4-alkyl-CO-, Phenyl-CH2-, C& C& 6-alkyl C& (CH3)2N- 4-alkyl-, 4-alkyl-NH-CO-, (CH3)3N'-C& 4-alkyl-NH-CO-, (CH3)N'-C& 4- C& (CH3)2N-C& 4-alkyl)-CO-, (CH3)3N'-C24-alkyl-, (CH3)3N'-C& 4-alkyl-CO-, alkyl-N(C& H2N-C(NH)-NH-C& 6-NH-CO-, 6-alkyl-O-CO-, 6-alkyl-O-CO-C& 4-alkyl-, C& C& C& 6-alkyl-O-CO-C&alkyl-CO-, C& 6-alkyl-O-CO-C& 4-alkyl-NH-CO-, 6-alkylCO-NH-C& 6-alkylCO-NH-C& G& 4-alkyl-, C& 4-alkyl-CO-, 6-alkylCO-NH-C& 4-alkyl-NH-CO-, HOCO-C& 4-alkyl-, HOCO-C& 4-alkyl-CO-, H2N-CNH- HOCO-C& 4-alkyl-NH-CO-, and H2NC(NH)NH-C& 6-alkyl-CO-.
Also preferred is selected from among a of below listed formulas to group (c1) (c5): 0 ~ H (c1) (c3) 0 ~ H (c4) (c5).
PC T/EP2012/071352 Particularly preferred denotes hydrogen or is selected from the consisting of group 6-alkyl, 4-alkyl-S02-, 4-alkyl-NH-CO-, H2N-CO-, H2N-C1 4-alkyl-, C1 C1 C1 H2N-C& 4-alkyl-CO-, H2N-C& 4-alkyl-NH-CO-, Phenyl-CO-, Phenyl-CH2-CO-, Phenyl-CH2-, 6-alkyl-CO-, 6-alkyl 4-alkyl-CO-, 4-alkyl-, C& C& C& (CH3)2N-C& 4-alkyl-NH-CO-, (CH3)3N'-C& 4-alkyl-NH-CO-, (CH3)3N'-C24-alkyl-, (CH3)2N-C& (CH3)3N'-C1 4-alkyl-CO-, H2N-C(NH)-NH-C1 6-NH-CO-, 6-alkyl-O-CO-, 6-alkyl C1 C1 CO-C& 6-alkyl-O-CO-C&alkyl-CO-, 6-alkyl-O-CO-C& 4-alkyl-NH-CO-, 4-alkyl-, C& C& C& 6-alkylCO-NH-C& 6-alkylCO-NH-C& 4-alkyl-CO-, 4-alkyl-, C& 6-alkylCO-NH-C& 4-alkyl-NH-CO-, 4-alkyl-CO-, G& HOCO-C& 4-alkyl-, HOCO-C& 4-alkyl-NH-CO- H2N-CNH-.
HOCO-C& and The substituent denotes C& 6-alkyl, preferably methyl.
X denotes anion selected any forming a pharmaceutically acceptable salt, preferably CF3- from among CF3-COO, Cl, I, Br, HCOO and CH3-COO, most preferably Cl and COO.
The substituent is selected from the consisting of C& 4-alkyl, group R""CO- R"'-C26-alkyl-, CH2-and HO-CO-CH2- optionally substituted phenyl-CH2-, preferably 4-alkyl, particularly preferred methyl, , C& wherein R"' R"'" R""N-, is selected from the consisting of hydrogen, group R"'" R""N'-, R""-HN-C(NR"")-NH, subs- H N-C(NH)-NH-, optionally R""-O-CO-, R""-O-CO-NH-, HO-CO- tituted and HOS02-, phenyl, wherein R"'" denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& denotes hydrogen or 6-alkyl, preferably hydrogen or 4-alkyl, C& C& denotes or 6-alkyl, or 4-alkyl, most hydrogen C& preferably hydrogen C& preferably C& 4-alkyl, denotes or 6-alkyl, or 4-alkyl, most hydrogen C& preferably hydrogen C& 4-alkyl. preferably C& -CO-NH-C2 The L denotes a 6-alkyl-NH-CO-, -COG& 6-alkyl-CO- or symbol bridging group -C2 6-alkyl-, forming a compound of formula (IC), PC T/EP2012/071352 dif- whereby the molecular entities of formula connected L be identical or (IC) by may ferent, .N-F N NH2 D H2N preferably forming a compound of formula (IC. whereby the molecular entities of formula connected L be identical or (IC.1) by may different, ~A. A R Cl N H2N NH2 H2N NH2 N CI (IC.
R' R" con- The substituents and independently from each other are selected from the group -COOR'", sisting of halogen, CN, 6-alkyl, 3-alkyl-O-, 3-alkyl-OCO-, hydrogen, C& C& C& -CONR"R" -OR'", and preferably hydrogen, wherein denotes hydrogen or 4-alkyl, preferably hydrogen or 2-alkyl, particularly pre- C& C& ferred or hydrogen methyl, denotes hydrogen or 4-alkyl, preferably hydrogen or 2-alkyl, particularly pre- C& C& ferred or hydrogen methyl, PC T/EP2012/071352 denotes hydrogen or 4-alkyl, preferably hydrogen or 2-alkyl. particularly pre- C& C& ferred or methyl. hydrogen R' R" con- The substituents and independently from each other are selected from the group -COOR'", sisting of halogen, CN, 4-alkyl, 3-alkyl-O-, 3-alkyl-OCO-, hydrogen, C& C& C& -CONR"R" -OR'", and preferably hydrogen, wherein denotes or or pre- hydrogen C& 4-alkyl, preferably hydrogen C& 2-alkyl, particularly ferred hydrogen or methyl, denotes or or pre- hydrogen C& 4-alkyl, preferably hydrogen C& 2-alkyl, particularly ferred hydrogen or methyl, denotes or or 2-alkyl. pre- hydrogen C& 4-alkyl, preferably hydrogen C& particularly ferred hydrogen or methyl.
R' R" is The substituents and from each other are selected from the con- independently group -COOR'", of 3-alkyl-O-C& 3-alkyl-OCO-, sisting hydrogen, halogen, CN, C& -CONR"R" -OR'", preferably hydrogen, wherein denotes hydrogen or C& 4-alkyl, preferably hydrogen or C& 2-alkyl, particularly pre- ferred hydrogen or methyl, denotes hydrogen or C& 4-alkyl, preferably hydrogen or C& 2-alkyl, particularly pre- ferred hydrogen or methyl, denotes hydrogen or C& 4-alkyl, preferably hydrogen or C& 2-alkyl, particularly pre- ferred hydrogen or methyl, OI R' R' R" R" -O-C& -O-C& 2-alkyl-O-. and or and together denote 3-alkyl; preferably The substituent denotes Cl or Br, preferably Cl.
R' R" The substituent and independently from each other are selected from the con- group -COOR'", sisting of 4-alkyl, 3-alkyl-O-, 3-alkyl-OCO-, hydrogen, halogen, CN, C& C& C& -CONR"R" -OR'", preferably hydrogen, wherein denotes or 4-alkyl, or 2-alkyl, particularly pre- hydrogen C& preferably hydrogen C& ferred or hydrogen methyl, denotes or 4-alkyl, or 2-alkyl, particularly pre- hydrogen C& preferably hydrogen C& ferred or hydrogen methyl, PC T/EP2012/071352 denotes hydrogen or 4-alkyl, preferably hydrogen or 2-alkyl, particularly pre- C& C& ferred or methyl. hydrogen R' R" con- The substituent and independently from each other are selected from the group -COOR'", sisting of halogen, 4-alkyl, CN, 3-alkyl-O-, 3-alkyl-OCO-, hydrogen, C& C& C& -CONR"R" -OR'", and preferably hydrogen, wherein denotes or 4-alkyl, or 2-alkyl, particularly pre- hydrogen C& preferably hydrogen C& ferred hydrogen or methyl, denotes or or pre- hydrogen C& 4-alkyl, preferably hydrogen C& 2-alkyl, particularly ferred hydrogen or methyl, denotes or or 2-alkyl. pre- hydrogen C& 4-alkyl, preferably hydrogen C& particularly ferred hydrogen or methyl.
R" R' of the definitions of to described above combined with each other to form Any may be an embodiment of the invention. 6. PREPARATION The following methods are suitable for preparing compounds of general formula or (IA), (IB) (IC).
The compounds according to the invention be obtained using methods of synthesis which are known to one skilled in the art and described in the literature of organic synthesis.
General methods for functional protection and deprotection steps are described e. groups g. edi- in: Greene, T. W. and Wuts, P.G.M. (eds. Protective Groupsin Organic Synthesis, third tion 7999; John Wiley and Sons, inc. Preferably the compounds are obtained analogously to the methods of explained more hereinafter, in particular as described in the preparation fully experimental section. for- Compounds of general formula can be prepared reacting S-methylisothioureas of (I) by mula with primary amines of formula in a solvent like THF, acetonitrile or DMF or in a (II) (III) ~0 solvent mixture, in the presence of a when the amine preferably base, especially primary (III) is an acid addition at between 18 to applied as salt, preferably 90 Compounds of general formula can be converted into compounds of general formula (la) reaction with in the of in solvent like BOC20 presence a base, preferably triethylamine, a e. THF. ~s Compounds of general formulas and can be modified methods of synthesis (la) using which are known to the one skilled in the art and described in the literature of syn- organic functional or or thesis, preferably group protection deprotection steps, hydrogenations.
PC T/EP2012/071352 con- Furthermore, the in compounds of general formula can be modified under group (la) ditions not compatible with the present in compounds of general formula acylguanidine group alkylation of tertiary amino to ammonium com- I, preferably by groups yield quaternary pounds. s Compounds of general formula can be converted into compounds of general formula (la) (I) removal of the BOC under standard acidic deprotection conditions. by moiety PC T/EP2012/071352 Scheme 1: H, F 0 HN 0 N N F N E D H2N NH2 (la) PC T/EP2012/071352 A preferred realization of Scheme 1 is Scheme 1.1.
Scheme 1.1: R N A (III.
(II. 1) H2N NH2 (I.1) 0 HN 0 H2N NH2 (Ia. s Compounds of general formula can be reacting S-methylisothiourea (which (II) prepared by in situ from its salt addition of with 1-(tert- may be generated base) a butylcarbamoyl)prop1-enyl carboxylate of general formula in a solvent like DCM, THF (IV) or mixture of these at between -10 to 25 a solvents, preferably of formula can from the acid of Compounds general (IV) be prepared respective carboxylic formula and 2-tert-butylmethyl-isoxazolium salt of formula general a general (VI), which can be applied as an isolated salt (e. the hexafluorophosphate salt; X or gen- g. PF6) erated 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 0-10 addition of triethylamine or another base, preferably while cooling to PC T/EP2012/071352 Scheme 2: H gN~ (VI) . R N . N S N N N NH2 NH2 Compounds of general formula can be obtained from compounds of general formula (III) s reduction of the nitrile hydrogenation with raney-nickel as cata- (XV) by group, preferably by lyst under hydrogen pressure in the presence of excess ammonia in a solvent like e. thanol. The in of formula can modified methods group compounds general (XV) be using of synthesis which are known to the one skilled in the art and described in the literature of esterifica- organic synthesis, preferably functional protection or deprotection steps, by group io tions, amidations, or hydrogenations. Depending on the nature of this moiety can be moved using methods of synthesis which are known to the one skilled in the art and scribed in the literature of organic synthesis, especially of protective removal to yield group compounds of general formula (XVI). Compounds of general formula can be converted (XVI) into compounds of general formula using methods of synthesis which are known to the (XV) is one skilled in the art and described in the literature of organic synthesis, especially acyla- tion, alkylation, or reductive amination.
Compounds of general formula wherein D represents CH2- or CH2-CH2- can be pre- (XV), pared reaction of alkylating agents of general formula with 4-cyanopiperidines of gen- by (VI) eral formula in a solvent like THF, wherein the compound of general formula is (VII) (VII) protonated a LDA, n-BuLi or NaH, at a temperature between— by base, preferably preferably 'C 'C 80 and 0 and wherein LG represents a leaving preferably Cl, Br, mesylate or group, I, tosylate and wherein G represents an the BOC acyl moiety, preferably group.
Compounds of general formula wherein A represents a bond can be prepared (XV), by double alkylation of phenylacetonitriles of general formula with bis-chloroethylamines of (IX) PC T/EP2012/071352 general formula with the addition of a base, preferably NaH in a solvent, preferably (Vill) DMF, wherein represents an moiety, preferably the BOC acyl group.
Scheme 3: (IX) (Vll) bond CI CI (Vill) F -CH2- = - - A -CH, or -CH, -CH, (XVII) (XVI) (XV) PC T/EP2012/071352 0, F ~g A E. D H2N NH2 R~N, E. D H2N N (XI) s Compounds of general formula wherein L represents chain with at least 2 carbon atoms, (X), can be reaction of with an acid TFA or HCI in a solvent like THF, prepared by (XI) preferably dichloromethane, DMF or at between 10 and dioxane, water, preferably a temperature 50 (XII) 0 NH H2N NH2 (XIII) is Compounds of general formula wherein L represents chain with at least 2 carbon (XII), atoms can be a reaction sequence starting with it with BOC an- prepared by (XIII) protecting hydride, quaternization with alkylhalogenide preferably alkyliodide in a solvent like acetone, PC T/EP2012/071352 'C 'C fol- THF, dioxane or dichloromethane, at a temperature between 10 and 50 preferably lowed deprotection with acids.
': '~ . .. (XIV) Compounds of general formula wherein L represents chain with at least 2 carbon (XIV), 1H-1. 4- atoms can be prepared reaction compounds of general formule with 2. by (X) io triazolecarboxamidine or S-methylisothioureas in DMF preferably at a temperature 'C 'C. tween 50 and 90 7. EXAMPLES &s 7.1 SYNTHESISOF INTERMEDIATES Intermediate A.61 -diaminochloropyrazinecarboxylic acid A mixture of methyl 5-diaminochloropyrazinecarboxylate 494 mmol), methanol 3, (100 and NaOH mol/I in water; 240 mL; 1.44 mol) is refluxed for 3 h. The mixture is allowed (1 I) (6 to cool to r.t. and then neutralized addition of hydrochloric acid mol/I in water; approx. by (6 240 mL). Water is added. The precipitate formed is filtered off with suction, washed (200 mL) 60'C. with water and dried at 2s Yield: 99.6 (107% of theory) C5H5CIN40~ ESI Mass spectrum: m/z 189 [M+H]+; m/z 187 [M-H] Intermediate A.62 -diamino -diaminobromopyrazinecarboxylic acid is prepared from methyl 3, 3, so bromopyrazinecarboxylate (which is from methyl 5-diaminochloropyrazine- prepared 3, PC T/EP2012/071352 2-carboxylate as described in J.Med. Chem. 10 66-75) to the procedure (1967) analogously described for the synthesis of intermediate A.61 Intermediate B.61 s 1-(tert-butylcarbamoyl)propenyl 5-diaminochloropyrazinecarboxylate CI N Ho . , OH+ s H~N NH~ H~N NH~ B.61 Stage A mixture of tert-butanol 0 226 and 5-methylisoxazole 0 221 is (21. mL; mmol) (18. mL; mmol) io cooled with an ice-bath. Trifluoromethanesulphonic acid 221 is (20.0 mL; mmol) added with continued The mixture is stirred for 1 h without further cool- dropwise cooling. resulting ing.
Stage To solution or of 5-diaminochloropyrazinecarboxylic acid a suspension 3, (Intermediate is A. 14. 74.2 and 222 in DMF is 61; 0 mmol) triethylamine (31.0 mL; mmol) (100 mL) added Ice-water the mixture prepared in stage 1. The resulting mixture is stirred for 4 h at r.t.. is added with stirring. The precipitate formed is filtered off with suction, washed with water and 65'C dried at to yield the title compound.
Yield: 18.2 (75% of theory) ESI Mass spectrum: m/z 328 [M+H]+; m/z 326 [M-H] C$3Hi8CIN503 TLC (Silica; DCM/MeOH 9:1): 0.4 Intermediate B.62 1-(2-methylbutyl-carbamoyl)propenyl 5-diaminobromopyrazinecarboxylate Br N Ho N H~N N NH~ H~N N NH~ B.62 Stage 1: 2-methylbutanol A mixture of (5.75 mL; 51 mmol) and 5-methylisoxazole (4.42 mL; 51 add- mmol) is cooled with an ice-bath. Trifluoromethanesulphonic acid 84 mL; 54 mmol) is ed dropwise with continued cooling. The resulting mixture is stirred over night without further cooling.
Stage 2: PC T/EP2012/071352 To a solution or suspension of 5-diaminobromopyrazinecarboxylic acid (Intermediate A.62; 5.00 21.5 mmol) and triethylamine 48 mL; 54 mmol) in DMF cooled with (7. (50 mL) an ice-bath is added dropwise the mixture in 1. The resulting mixture is prepared stage stirred for 4 h at r.t. then on ice-water. The formed is filtered off with suc- poured precipitate 50'C s tion, washed with water and dried at to the title compound. yield Yield: 7.53 of (91% theory) ESI Mass m/z m/z 384 Ci4H2PBI N503 spectrum: 386 [M+H]+; [M-H] Intermediate C.61 io 5-diaminochloro-N-[(methylsulfanyl)methanimidoyl]pyrazinecarboxamide CI N H2N NH2 HN N C.61 To NaOH mol/I in water; 9.2 mL; 9.2 mmol) is added S-methylisothiourea sulphate (1.78 6.1 mmol. The mixture is stirred until complete solution is achieved. TBME/THF 30 (1:1; mL) and then 1-(tert-butylcarbamoyl)propenyl 5-diaminochloropyrazinecarboxylate is (Intermediate B.61; 2.00 6.10 mmol) are added and the mixture is stirred at r.t. over night, then water is added. The formed is filtered off with suction, washed suc- (6 mL) precipitate cessively with water, methanol and then with diethyl ether and then dried at 50 to the yield title compound.
Yield: 1.33 of (84% theory) ESI Mass spectrum: m/z 261 m/z 259 [M-H] C7HgCIN6OS [M+H]+; Intermediate C.62 -diaminobromo-N-[(methylsulfanyl)methanimidoyl]pyrazinecarboxamide Br N N ~0 0 NH ~ ~ H H2N NH S 0 H2N NH2 H2N NH2 HN NH 2s C62 To NaOH mol/I in water; 30 mL; 30 mmol) is added S-methylisothiourea sulphate (5.42 (1 g; 19.5 mmol. The mixture is stirred until complete solution is achieved. TBME/THF (1:1;100 and then 1-(2-methylbutyl-carbamoyl)propenyl 5-diaminobromopyrazine mL) 3, carboxylate (Intermediate B.62; 7.52 19.5 mmol) are added and the mixture is stirred at r.t. 3o over night, then water is added. The precipitate formed is filtered off with suction, (100 mL) washed with THF/water and then dried at 50 to yield the title compound. (1:2) Yield: 5.44 of (92% theory) PC T/EP2012/071352 ESI Mass spectrum: m/z 305 [M+Hj+ C&H9BrN60S s To a solution of 21.10 di-isopropylamine in 300 mL anhydrous THF is added 83.7 mL 2.5 M -78'C. solution of n-butyl lithium in THF dropwise at The resultant solution is stirred at this temperature for 30 min. Then a solution of 40.00 1-N-BOCcyanopiperidine in 300 mL THF is added dropwise. After 1 h stirring 51.99 ml (2-bromo-ethyl)-benzene is added drop- wise. After the addition the reaction mixture is allowed to warm to room temperature and Io stirred overnight. 100 mL water is added to the reaction. THF is removed to leave a quench which is partitioned between acetate and water. After a separation the organic slurry ethyl is washed with sat. and dried with and concentrated under layer aq. NH4CI brine, Na&SO4 reduced Purification column results in 57.23 of intermediate pressure. by chromatography D.2. TLC (EA/PE 4. 1/8) Rt.
Intermediate D. is obtained similar described for intermediate D.2 uti- 8 using a procedure as lizing benzyl bromide as alkylating agent. TLC (ethylacetate (EA)/petroleum ether 1/9) (PE)) zo Rt. 3.
PC T/EP2012/071352 C.17 Intermediate C.17 is obtained using a similar procedure as described for intermediate D.2 4-(2-bromoethyl)benzoic acid TLC (MeOH/dichloromethane using as alkylating agent. (DCM) /95) Rf.
C.18 Intermediate C.18 is obtained treating C.17 with ammonia and TBTU in dichloromethane.
Io B17 B.17 To a solution of 4.00 intermediate C.17 in 40 ml DMF are added 5.40 and then dry K~CO~ 2.40 ml methyl iodide dropwise. The reaction mixture is stirred at room temperature for 12 h.
Then water is added and the mixture is extracted with diethyl ether. The organic are phases dried over and evaporated. The resulting crude product is purified FC re- pooled, Na~SO4 by suiting in 3.40 of intermediate B.17. TLC (EA/PE 0.6. 2/3) Rf.
PC T/EP2012/071352 D.45 D.45 N-BOC-N, To a solution of 2.00 N-bis(2-chloroethyl)amine and 1.10 (2-methoxyphenyl)- mix- acetonitrile in 15 ml THF and 5 ml DMF is added 0.78 of NaH in portions at r.t. and the 55'C s ture is stirred at for 16 h. The reaction is quenched addition of cold water and tracted with ethyl acetate. The organic layer is washed with brine and water, dried over Na~SO4 filtered and evaporated under reduced pressure. The crude solid is triturated with a mixture of and ether filtered and dried in 1. of intermediate D.45. TLC CHCI3 resulting (EA:PE 3/7) . 0.6.
D.43 and D.44 uti- D.43 and D.44 are obtained using a similar procedure as described for intermediate D.45 lizing the corresponding benzyl cyanides.
D.43 D.44 PC T/EP2012/071352 A mixture of 2.50 of piperidine D.2 and 40 ml 25% TFA in dichloromethane are stirred for 1.5 h at room temperature. The solvent is evaporated, methanolic hydrochloric acid is added and the solvent evaporated again rise to 2.53 of intermediate C.2. giving ESI-MS m/z: 215. The corresponding TFA salt of C.2 is obtained purification of the crude s product reversed-phase HPLC with TFA as modifier. by preparative C.8 C.43 C.44 and C.45 interme- The following intermediates are obtained using a similar procedure as described for diate C.2 with modified neutralization of the reaction mixture with saturated NaH- a workup: CO3 solution followed an aqueous workup.
C.43 C.44 C.45 1s B2 HN~O A mixture of 2.30 hydrochloride C. 1.08 ml 2-isocyanato-propane, 1.99 ml trie- piperidine 2, 50'C and ml THF are stirred at for 2 h. The reaction mixture is concentrated thylamine 50 under reduced and water is and extracted with dichloromethane. The pressure added finally combined are dried over and 1. of interme- organic phases MgSO4 evaporated yielding 65 diate B.2.
ESI-MS m/z: 300, 344 PC T/EP2012/071352 B.4 B.8 B.12 B.18 B.19 B.43 B.44 B.45 B.48 and B.49 The following intermediates are obtained a similar procedure as described for interme- using sol- diate B.2 utilizing the corresponding isocyanates. DCM can be used as an alternative vent.
HN~O B.4 B.8 HN~0 HN~O B.12 B.18 HN~0 HN~0 B.19 B.43 HN~O HN~0 B.45 PC T/EP2012/071352 0 NH HN 0 Q~NH HN~Q N N N N B.48 B.49 B.10 HN~Q B.10 s 0.22 ml Triethylamine is added slowly to a mixture of 0.34 piperidine trifluoroacetate C. 0.32 and 5 ml dichloromethane. The mixture is strirred at room temperature for triphosgene 4 h and 0.17 ml N-dimethyl-ethylendiamine are added and the reaction mixture is stirred at room The reaction mixture is concentrated under reduced temperature overnight. pressure, a mixture of methanol and TFA is and the mixture is filtered and DMF, added, resulting purified io reversed-phase HPLC. The product-containing fractions are and eva- preparative pooled The residue is taken with dichloromethane and 4N NaOH solution is porated. resulting a added. The is organic phase separated a phase separator cartridge. Evaporation gives rise to 0.22 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 intermediates are obtained similar described for interme- following using a procedure as diate B.10 the corresponding amines. using PC T/EP2012/071352 0 NH HN~O HN~O HN~0 B.33 B.34 B.39 0 NH HN HN~0 HN~O HN~0 B.35 e.36 e.38 HN~Q HN~0 HN~O N B.40 B5~ B.52 PC T/EP2012/071352 B.53 +N~O B.53 To a suspension of 0.75 of 1'-carbonyldi(1, 4-triazole) in 5 ml of THF, a solution of 0.5 1, 2, s ml of 1-methylpiperazine dissolved in 5 ml of THF is added dropwise. The reaction mixture is stirred at room temperature for 40 minutes, then a solution of 0.5 of intermediate C.2 60'C free in 5 ml of THF is added dropwise and the reaction mixture is stirred at over- base) night. The solvent is evaporated, the crude product obtained is partitioned between dichlo- romethane and water and the is dried over sodium sulfate and organic phase separated, io concentrated under vacuum. The crude is flash product purified by chromatography (eluent: AcOEt/MeOH=80/20) and re-purified LC-MS preparative (reverse phase; NH4COOH) 150 of intermediate B. are obtained.
B.54 and B.55 is The intermediates are obtained similar described for interme- following using a procedure as diate B.53 the corresponding amines using QNgO B.54 2o B56 PC T/EP2012/071352 B.56 B. is similar in the of B. from 56 prepared following a procedure as preparation 53 starting available 4-cyanophenylpiperidine and N-dimethylethylenediamine. commercially N, Intermediate B. is reductive amination of intermediate C.2 with 3 prepared formaldehyde io and NaCNBH3 in THF.
B.7 and B.21 interme- The following intermediates are obtained using a similar procedure as described for diate B. the 3 utilizing corresponding carbonyl compounds.
B.7 B.21 PC T/EP2012/071352 trie- Intermediate B.5 is prepared acylation of intermediate C.2 with benzoyl chloride and thylamine in dichloromethane. s B.1 B.11 B.13 B.14 B.9 B.20 and B.47 The following intermediates are obtained a similar procedure as described for interme- using diate B.5 using the corresponding acid chlorides.
O=S=O B.1 B.11 B.13 B.14 Io B9 B.20 B.47 PC T/EP2012/071352 B.22 B.22 To mixture of 1.07 intermediate C. 1.42 N-BOC-beta 2. EDCI in ml an- a 2, alanine, 5 50 g g g hydrous THF is added 4.90 ml triethylamine and 0.1 DMAP. The reaction mixture is stirred ace- s at r.t. overnight. Water is added and the mixture concentrated and extracted with ethyl tate. The combined organic phases are washed with sat. NH4CI and brine, dried over and concentrated. The residual crude product is purified FC rise to inter- Na2SO4 by giving mediate B.22 1o B.23 B.25 B.24 B.26 B.27 B.46 and B.42 The following intermediates are obtained a similar procedure as described for interme- using diate B.22 using the corresponding acids. 0 ~ H B.23 B.25 B.24 HN ~0 B.26 B27 B.42 PC T/EP2012/071352 B.46 (Starting material: 3-Carboxy-propyl-trimethyl-ammonium chloride) Intermediate B.6 is prepared alkylation of intermediate C.2 with benzyl bromide and lo in acetonitrile.
CspCOg B.15 The intermediate B.15 was obtained the following procedure. using B.15 0.1 C.2 was dissolved in 5 ml acetone and 1 K&CO& followed drop wise addition of 0, by methyl iodide at room temperature. The resulting reaction mixture was stirred for 16 hours.
Then the reaction mixture was diluted with washed with water followed ethyl acetate, by brine. The was dried over and concentrated under reduced organic layer Na&SO4 pressure. ~o The crude was with 18% product purified chromatography eluting ethyl acetate/petroleum ether on a silica column PC T/EP2012/071352 B.50 The following intermediate is obtained a similar procedure as described for interme- using diate B.15 using methyl iodide.
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 interme- diate B.6 using the corresponding amines and the corresponding alkyl halides as alkylating agents, K&CO& and acetone.
B.16 B.28 B.29 B.32 B.30 B.31 PC T/EP2012/071352 B.37 HN~O A suspension of 1.83 of nitrile B. 0.40 Raney-Nickel and 40 ml of a methanolic solution of ammonia are at room and bar for 23 h. In of incom- hydrogenated temperature 3 H2 case conversion additional and solvent are and is continued plete catalyst added hydrogenation 50'C. for h at The is removed filtration and the filtrate rise to catalyst evaporated giving io 1.95 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 is The following intermediates are obtained from the corresponding nitriles using a similar pro- cedure as described for intermediate A.2.
O=S=O NH2 NH2 A. 1 A.3 A.4 PC T/EP2012/071352 NH2 NH2 A.5 A.6 A.7 HN~O HN~O NH2 NH2 A. 10 A. 11 A. 12 NH NH2 A. 13 A.14 A.15 PC T/EP2012/071352 HN~O A. 16 A.17 A. 18 +N~O HN~O A. 19 A.57 A.
NH2 NH2 A.22 A.23 A.25 NH2 NH2 A.28 A.29 A.32 PC T/EP2012/071352 HN~O HN~O HN~0 NH2 NH2 NH2 A.33 A.34 A.39 0 NH HN 0 0 NH HN 0 NH2 NH2 NH2 NH2 A.48 A.49 HN~O A.8 A.9 A.20 NH2 NH2 A.21 A24 A.26 PC T/EP2012/071352 A.27 A.30 A.31 0 NH HN~O HN~O A.35 A.36 A.37 HN~0 HN~O A. A.40 A.41 PC T/EP2012/071352 HN~O A.46 A.42 A.43 HN~0 HN~0 NH, NH, A.44 A.45 A.47 NH2 NH2 A.55 A.50 A.51 A.52 PC T/EP2012/071352 HN~O A.53 (Starting material: B. A.54 (starting material: B. 46) 51) HN~O s A. material: B. 56 (Starting 52) A.59 +N~O io To solution of of intermediate B. in ml of 0.1 ml of borane a 50 55 3 THF, tetrahydrofuran is The reaction mixture is stirred at room for complex added dropwise. temperature 30 min, 40'C then at for 3h. 0.1 ml of borane is and the reac- tetrahydrofuran complex added again 50'C ton mixture is stirred at overnight. The reaction mixture is partitioned between dichlo- romethane and water, the organic phase is washed with a saturated NaHCO3 water solution, is dried over phase separator and concentrated under vacuum to give 42 of intermediate A.59.
PC T/EP2012/071352 A.60 HN~O A.60 -78'C, To solution of 1 of intermediate B. in 20 ml of THF stirred at 1.2 ml of 2M solu- a 56 a s tion of lithium aluminium in THF is The mixture is allowed to reach hydride added dropwise. room and stirred The solvent is the reaction mixture is temperature overnight. concentrated, between dichloromethane and water and is dried over sepa- partitioned organic phase phase rator and concentrated under vacuum to of crude 200 of this crude give 500 product. mg mg are LC-MS of inter- product purified preparative (reverse phase; NH4COOH). 60 pure by mg io mediate A.60 are obtained. 7.2 SYNTHESIS OF EXAMPLES le 1 ~Exam 4-[N'-(3, is 5-Diaminochloro-pyrazinecarbonyl)-guanidinomethyl]phenethyl-piperidine carboxylic acid tert-butyl ester 0 NH H2N NH2 A mixture of 80 3 mmol) 4-aminomethylphenethyl-piperidinecarbocylic acid tert- mg (0, ester and 1 04 3 1-(3,5-diaminochloro-pyrazinecarbonyl) butyl (A.55) mg (0, mmol) 70'C methyl-isothiourea (intermediate C. in 2 ml acetonitrile is stirred at for 48 hours.
Then the reaction mixture is concentrated under reduced pressure and the residue is purified preparative reverse HPLC of acetonitrile and water 0.2% trifluoroacetic by phase (gradient 'C acid, Fractions containing the title compound were concentrated under reduced 2s pressure.
Yield: 116 PC T/EP2012/071352 ESI mass spectrum: [M+Hj' 531 Retention time HPLC: 51 min (method M1 2, ).
The following compounds are from starting materials as indicated: prepared accordingly Table 1: ~A. A R Cl N H~N NH~ R R Ret.
Q 'g +e [min] -CHp-CHp- H H A. 1 034 509 21 M2 0, 1, 0:S=O -CHp-CHp- M2 1.2 H H A.2 0,008 516 1,28 -CHp-CHp- 1.3 H H A 3 0033 445 67 M1 -CHp-CHp- 1.4 H H A.4 027 474 21 M2 0, 1, -CHp-CHp- H H A.5 034 23 M1 0, 2, -CHp-CHp- M2 1.6 H H A6 0 040 521 1,90 PC T/EP2012/071352 R R Ret.
Q 'g +e [min] 1.7 H2-C H2- H H A.7 063 473 95 M2 0, 0, 1.8 CH2 H H A.8 017 502 25 M2 0, 1, HN 0 -C H2- 1.9 H2-C H H A.9 011 503 41 M2 0, 1, H2-C H2- M4 1.10 H H A. 10 0,036 545 1.42 -C H2- H2-C H H A11 017 515 49 M2 0, 1, -C H2- 1.12 H2-C H H A. 12 012 502 30 M2 0, 1, H ~ 0 1.13 H2-C H2- H H A. 13 013 501 M2 0, 1,36 -C H2- 1.14 H2-C H H A. 14 020 545 23 M2 0, 1, PC T/EP2012/071352 R R R Ret.
Q 'g [min] 1.15 H2-C H2- H H H A. 15 091 459 05 M2 0, 1, CF3-COO- 1.16 H2-C H2- H H H A. 16 002 503 07 M2 0, 1, 1.17 CH2-CH2- H H COO Me A. 17 056 589 H2-C H2- M2 1.18 H H H A. 18 0,028 546 1,30 HN 0 1.19 H2-C H2- H H H A. 19 024 M2 0 560 1,33 I. 0 -CH2- 1.20 H H H A.20 075 531 04 M6 0, 1, 1.21 -CH2- H H H A.21 089 431 PC T/EP2012/071352 R R Ret.
Q 'g [min] 1.22 -CH2-CH2- H H A.22 037 602 26 M7 0, 1, -CH2-CH2- 1.23 H H A.23 026 502 19 M6 0, 1, -CH2- 1.24 H H A.24 027 574 1.19 M8 O~NH 1.25 -CH2-CH2- H H A.25 018 1.27 M7 0, 588 O~NH -CH2- M7 1.26 H A26 0 019 616 1.27 PC T/EP2012/071352 R R Ret.
Q 'g +e [min] -CH2- 1.27 H H A27 033 588 1.24 M7 1.28 H2-C H2- H H A28 036 588 1.08 M7 1.29 H2-C H2- H H A29 086 516 0.90 M7 -CH2- M8 1.30 H H A 30 0,070 489 1.13 -CH2- M7 1.31 H H A 31 0,287 502 0.87 -C H2- 1.32 H2-C H H A32 046 502 0.90 M7 PC T/EP2012/071352 R R Ret.
Q 'g +e [min] 1.33 -CH2-CH2- H H A 33 007 617 1.14 M6 O~NH -CH2-CH2- M6 1.34 H H A34 0,010 631 1.18 -CH2- 1.35 H H A 35 011 603 1.65 M5 O~NH 1. -CH2- H H A 018 617 1. M5 36 36 0, 68 -CH2- M5 1.37 H H A 37 0,064 574 1.42 PC T/EP2012/071352 Ret.
Q 'g +e [min] -CH2- 1.38 A.38 042 1.38 M4 H2-C H2- M4 1.39 A.39 0,023 1.44 HN 0 1.40 -CH2- A.40 029 531 1. M5 0, 35 HN 0 1.41 -CH2- A.41 091 488 1.20 M5 1.42 bond A.42 025 28 M1 0, 503 2, 1.43 bond A.43 041 488 52 M3 0, 1, PC T/EP2012/071352 R R Ret.
Q 'g [min] -O-C H2 1.44 bond A.44 046 532 56 M3 0, 1, HN 0 1.45 bond H A.45 066 533 78 M3 0, 1, -CH2- 1.46 H H H A.46 061 517 83 M3 0, 1, 1.47 bond H H H A.47 029 517 M6 0, 1,000 1.48 H2-C H2- H H H A 51 13 516 M7 0, 1,0 H2-C H2- M7 1.49 H H H A.52 0,022 530 1,01 H2-C H2- M5 1.50 H H H A.53 0,015 558 1,50 PC T/EP2012/071352 R R R Ret.
Q 'g [min] 1.51 H2-C H2- H H COO Me A.54 HN 0 -C H2- 1.52 H2-C H H CONH2 A.56 Example 1.53 H2N NH2 To solution of 140 of intermediate A.57 in 2. ml of 0.13 ml of N a (0.36 mmol) 5 DMF, N, s -diisopropylethilamine is added. The reaction mixture is stirred at room temperature for 10 minutes then 85 (0.33 mmol) of 1-(3,5-diaminochloro-pyrazinecarbonyl)methyl- 70'C isothiourea is added. The reaction mixture is heated at for 3 hours.
The solvent is removed and the crude product obtained is purified flash chromatography (first eluent: AcOEt/MeOH=90/10 in order to remove impurities; second eluent dichlorome- thane/MeOH/NH3 from 90/10/0. 1 to 50/50/0. 1 to give the desired product).
Yield: 55 0.014 IC50[pM] [M+H]' ESI mass spectrum: 557 Retention time HPLC: 5.60 min (method M9).
The following compounds are prepared accordingly from starting materials as indicated: Table 1.1: PC T/EP2012/071352 ~A. A R CI N H~N NH~ R" R4 R R Ret. +e [min] -CHp-CHp- 1.54 A 58 0 046 571 5 38 M10 -CHp-CHp- A59 n a. 629 352 M11 1.56 bond A60 n a. 517 308 M11 s le 2 ~Exam N-(3, 5-Diaminochloro-pyrazinecarbonyl)-N'-(4-phenethyl-piperidinylmethyl-guanidine CI N H~N NH~ A mixture of 50 3 4-[N'-(3, 5-diaminochloro-pyrazinecarbonyl)- mg (0, mmol) Io guanidinomethyl]phenethyl-piperidinecarboxylic acid tert-butyl ester in 1 ml (Example 1) dichloromethane is stirred with 250 trifluoroacetic acid at room temperature for 2 h.
Then the reaction mixture is concentrated under reduced pressure.
Yield: 40 ESI mass spectrum: [M+H]' 431 PC T/EP2012/071352 Retention time HPLC: 78 min (method M1 1, ).
The following compounds are from starting materials as indicated: prepared accordingly Table 2: N ~A. A H2N NH2 17 I Q Km M Ret. n~ R R R [min] 2.1 H2-C H2- H H Me 1.17 394 489 COO 0, H2-C H2- 2.2 H H 1.22 0,019 502 H2-C H2- M7 2.3 H H 1.23 0,023 530 1.03 -CH2- 2.4 H H 1.24 059 508 090 M6 CL)- H2-C H2- H H 1.28 06 488 089 M6 PC T/EP2012/071352 rm Z 17 I Q K rm + M n~ Ret.
R" R~ R4 0 [min] Cl + 2.6 H2-C H2- 1.34 028 531 1.57 M4 HN 0 -C H2- 2.7 H2-C 1.33 0,016 517 1.56 M4 -CH2- 2.8 1.26 061 516 0.97 M7 -CH2- M7 2.9 1.27 0,093 488 0.96 2.10 bond 1.45 200 433 26 M3 0, 1, -CH2- M3 2.11 1.46 0,05 417 1,31 -CH2- 2.12 1.35 017 503 93 M6 0, 0, 2.13 -CH2- 1. 02 517 M6 36 0, 0,93 PC T/EP2012/071352 rm Z 17 I Q K rm + M n~ Ret.
R" R4 0 [min] Cl + -CH2- 2.14 1.37 12 474 85 M6 0, 0, ~Exam 3 (4-(N'-(3, 5-Diaminochloro-pyrazinecarbonyl)-guanidinomethyl]4-phenethyl-piperidin s acetic acid Cl N H3N NH3 A mixture of 145 23 mg (0, (4-[N'-(3, mmol) 5-diaminochloro-pyrazinecarbonyl)-guanidinomethyl]phenethyl- is piperidinyl)-acetic acid methyl ester (Example 1.16 in 5 ml methanol and 235 4 N 50'C NaOH is stirred at for 1 hour. Then the solution is acidified with 470 4 N HCI and concentrated under reduced pressure. The residue is purified preparative reverse phase + 25'C con- HPLC (gradient of acetonitrile and water 0.2% trifluoroacetic acid, Fractions taining the title compound were concentrated under reduced pressure.
Yield: 35 mg.
[M+H]' ESI mass spectrum: 489 Retention time HPLC: 1,33 min (method M2) The following compounds are prepared accordingly from starting materials as indicated: 2s Table 3: Cl N ~A A H2N NH2 R PC T/EP2012/071352 R1 R2 R3 R4 Ret. m [min] H2-C H2- M2 3.1 H H H 1.14 0,040 531 1,21 -C H2-C H2- M2 3.2 H H H 1.19 0, 149 546 1,43 HN 0 0 OH 3. H2-C H2- H H 1.18 010 532 27 M2 3 0, 1, le 4 ~Exam 4-[N'-(3, -Diaminochloro-pyrazinecarbonyl)-guanidinomethyl]phenethyl-pi peridine carboxamidine N N N A mixture of 70 15 mmol) N-(3, 5-diaminochloro-pyrazinecarbonyl)-N'-(4- mg (0, phenethyl-piperidinylmethyl-guanidine (Example 2 124 triethylamine and 28 19 pl mg (0, 1H-1.2.4-triazolecarboxamidine monohydrochloride in 5 ml DMF is stirred at 70 mmol) io for 2 hours. Then 1 ml methanol is and the mixture is reverse added purified preparative + 25'C HPLC of acetonitrile and water 0.2% trifluoroacetic Fractions phase (gradient acid, the title were concentrated under reduced containing compound pressure.
Yield: 15 ESI mass [M+H]' 473 spectrum: is Retention time HPLC: min 0,93 (method M7) The are from materials indicated: following compounds prepared accordingly starting as Table 4: PC T/EP2012/071352 Cl N ~A, A H2N NH2 R R R Ret. rm [min] 4.1 -CHp-CHp- H H H 22 0012 544 1.01 M7 -CHp-CHp- M4 4.2 H H H 2.3 0,018 570 1.51 (M-H)- le 5 ~Exam s (2-((4-[N'-(3, 5-Diaminochloro-pyrazinecarbonyl)-guanidinomethyl]phenethyl- piperidinecarbonyl)-amino)-ethyl]-trimethyl-ammonium chloride Cl N H2N NH2 HN 0 Ex. 5.A 4-[N'-(3, 1.55 5-Diaminochloro-pyrazinecarbonyl)-guanidinomethyl]phenethyl- piperidinecarboxylic acid (2-dimethylamino-ethyl)-amide (example 1. 0.9 ml triethyla- 40), io mine and 1.1 BOC anhydride were dissolved in 50 ml THF and stirred over night. The ganic layer is separated and concentrated under reduced pressure.
Yield: 1.3 PC T/EP2012/071352 Cl N N N N A mixture of 1.3 Ex. 5.A and 200 methyl iodide in 10 ml acetone is stirred overnight at room temperature. 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 Then the mixture is co-evaporated with methanolic acid. The temperature. hydrochloric residue is via reverse HPLC of acetonitrile and water purified preparative phase (gradient 'C 0.2% trifluoroacetic Fractions the title were concentrated acid, containing compound under reduced and co-evaporated with methanolic acid. pressure finally hydrochloric 1o Yield: 820 ESI mass [Mj' spectrum: 559 Retention time HPLC: 97 min (method 0, M7) The are from materials indicated: following compounds prepared accordingly starting as Table 5: CI N ~A.
H2N NH2 R R R Ret. m m Z (n 17 I [min] -C H2-C H2- M7 H H H 1.39 0,027 573 1,013 H ~ 0 PC T/EP2012/071352 -CHp-CHp- H H COOMe 1 51 074 617 01 M7 0, 1, -CHp-CHp- H H CONH2 1 52 0.12 301 80 M7 -CHp-CHp- M9 H H H 1.53 0.051 571 2.80 -CHp-CHp- H H H 1.54 0.052 3.47 M1 H H H 1. n.a. 531 4. M1 56 88 Hcoo ~Exam le 6 N CI Cl N N N N N N N A mixture of 115 A.48 and 104 5-Diaminochloro-pyrazine (0.3 mmol) 1-(3, mg mg 70'C reac- carbonyl)methyl-isothiourea in 25 ml THF are stirred at for 80 hours. Then the chroma- tion mixture is concentrated under reduced pressure and the residue is purified via PC T/EP2012/071352 dichloromethane/methanol 10% ammonia 9:1 to Fractions con- tography (Silica, plus 6/4). taining the title compound were concentrated under reduced pressure.
Yield: 27 ESI mass spectrum: [M+H]' 1001 s Retention time HPLC: 41 min (method M2 1, ).
The following compounds are from starting materials as indicated: prepared accordingly Table 6 Structure IC50 ESI+ Ret. 17 I [IIM] (M+H)+ [min] 6.1 A.49 097 52 M2 0, (M+ H)/2 1, PC T/EP2012/071352 ~Exam le 7 N-(3, 5-Diaminochloro-pyrazinecarbonyl)-N'-(4-phenethylphenylacetyl-piperidin ethyl)-guanidine CI N H2N NH2 -diaminochloro-pyrazinecarbonyl)-N'-(4- To a mixture of 70 14 mmol) N-(3, mg (0.
Hunig's dich- phenethyl-piperidinylmethyl)-guanidine (example and 118 base in 5 ml 2) pl loromethane 27 21 mmol) phenacetylchloride is dropwise added and stirred at room pM (0, io temperature overnight. Then the mixture concentrated under reduced pressure. The residue is purified via preparative reverse phase HPLC (gradient of acetonitrile and water 0.2% 'C trifluoroacetic acid, Fractions containing the title compound were concentrated under reduced pressure.
Yield: 9 mg. is ESI mass [M+H]' 549 spectrum: Retention time HPLC: 42 min (method 1, M2) ~Exam le 8 4-[N'-(3, 5-Diaminochloro-pyrazinecarbonyl)-guanidinomethyl]phenethyl-pi peridine acid carboxylic propylamide 0 NH2 CI N H2N NH2 ~ N 0 To a mixture of 100 198 N-(3, 5-diaminochloro-pyrazinecarbonyl)-N'-(4- mg (0. mmol) phenethyl-piperidinylmethyl)-guanidine and 29 DBU in 5 ml THF 12 2 (example 2) pl pM (0. is dropwise added and stirred at room temperature for 2 h. Then mmol) N-propylisocyanat the mixture is concentrated under reduced The residue is via pressure. purified preparative PC T/EP2012/071352 + 25'C reverse HPLC of acetonitrile and water 0.2% trifluoroacetic acid, phase (gradient ).
Fractions containing the title compound were concentrated under reduced pressure.
Yield: 10 ESI mass spectrum: [M+H]' 516 s Retention time HPLC:2, 2 min (method ~Exam le 9 N-[1-(2-Amino-acetyl)phenethyl-piperidinylmethyl-N'-(3, 5-diaminochloro-pyrazine carbonyl)-guanidine 0 NH2 CI N H2N NH2 A mixture of 130 35 [2-(4-aminomethylphenethyl-piperidinyl)oxo-ethyl]- mg (0, mmol) carbamic acid tert-butyl ester and 80 3 1-(3,5-diaminochloro-pyrazine- (A.50) mg (0, mmol) 70'C is 2-carbonyl)methyl-isothiourea in 5 ml tetrahydrofuran is stirred at overnight. Then the reaction mixture is concentrated under reduced pressure and the residue is purified via reverse HPLC of acetonitrile and water 0.2% trifluoroacetic preparative phase (gradient 'C). acid, Fractions containing the title compound were concentrated under reduced pres- sure. Then the residue is co-evaporated with methanolic hydrochloric acid in order to remove the protecting group.
Yield: 37 mg.
[M+H]' ESI mass spectrum: 488 Retention time HPLC: min 1,08 (method M7). zs le 10 ~Exam 4-(4-[N'-(3, -Diaminobromo-pyrazinecarbonyl)-guanidinomethyl]phenethyl-piperidin- 1-yl)oxo-butyric acid methyl ester PC T/EP2012/071352 Br N H2N NH2 -diaminobromo-N- The compound is prepared as described for example 1.14 3, applying inter- [(methylsulfanyl)methanimidoyl]pyrazinecarboxamide (intermediate C. instead of mediate C.61.
[M+H]' s ESI mass spectrum: 589 Retention time HPLC: 0.72 min (method M12) 0.032 IC50[pM] ~Exam le io 4-(4-[N'-(3, 5-Diaminobromo-pyrazinecarbonyl)-guanidinomethyl]phenethyl-piperidin- 1-yl)oxo-butyric acid Br N H2N NH2 The compound is prepared analogously to the procedure described for the synthesis of ample example 10 as starting material. 3, applying [M+H]' is ESI mass spectrum: 575 Retention time HPLC: 0.49 min (method M13) 0.502 IC50[pM] 8. ANALYTICAL METHODS HPLC/MS Methods Method: M1 2s Waters ZQ2000; Waters 1515 Waters PDA 996 Detector, Waters 2747 Injector pump, Mobile Phase: A: Water 0.1% formic acid PC T/EP2012/071352 B: Acetonitrile 0.1% formic acid Gradient: time in min %A %B flow rate in ml/min 0. 95. 5. 1. 00 0 0 00 0.10 95.0 5.0 1.00 3.10 2. 98. 1. 00 00 00 4.50 2.00 98.00 1.00 . 95. 5. 1. 00 0 0 00 X-terra™ s Stationary Phase: MS C18 5 4.6 mm x 30 mm 2, pm 'C Column temperature about.
Diode array detection wave length range 210 420 nm mass m/z to range 80 800 Ionization: ESI positive Method: M2 Waters Waters 1515 Waters PDA Waters 2747 ZQ2000; Pump, 996 Detector, Injector Mobile Phase: A: water 0.1% formic acid B: Acetonitrile 0.1% formic acid is Gradient: time in min %A %B flow rate in ml/min 0. 95. 5. 00 0 0 2.00 0.0 100 2. 0. 100 50 0 2.60 95.0 5.0 X-terra™ Stationary Phase: MS C18 2,5 4,6 mm x 30 mm 'C Column temperature about.
Diode array detection range 210 420 nm ~0 Mass range m/z 80 to 800 Ionization: ESI positive/negative Method: M3 Analytical column: XBridge C18 (Waters technologies) 60'C XBridge C18, 4.6 x 30 mm, 2.5 column temperature Mobile phase A: H20: trifluoroacetic acid 99.9:0.1 Mobile phase B: Methanol: trifluoroacetic acid 99.9:0.1 PC T/EP2012/071352 Gradient: time in min %A %B flow rate in ml/min 0.0 95 5 0.05 95 5 2.05 100 3 2.10 100 4 2.35 100 4 Method: M4 s column: C18 Analytical XBridge (Waters technologies) 60'C 4. x 2. column XBridge C18, 6 30 mm, 5 ljm temperature Mobile phase A: H20: trifluoroacetic acid 99.9:0.1 Mobile phase B: Methanol: 100 io Gradient: time in min %A %B flow rate in ml/min 0 95 05 95 2.05 100 3 2.10 100 45 2.40 100 45 Method: M5 Analytical column: Sunfire C18 (Waters technologies) 60'C Sunfire C18, 4.6 x 30 mm, 2.5 column temperature is Mobile phase A: H20: 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 0.05 95 5 2. 100 05 3 2.10 100 45 2.40 100 45 2o Method: M6 PC T/EP2012/071352 Analytical column: XBridge C18 (Waters technologies) 60'C XBridge 3.0x 30 2.5 column temperature C18, mm, ljm Mobile A: H20: trifluoroacetic acid 99.9:0.1 phase Mobile B: Methanol: 100 phase Gradient: time in min %A %B flow rate in ml/min 0. 2.2 0 95 5 0.30 95 5 2.2 1.50 100 2.2 1.55 100 29 1.65 100 29 Method: M7 Analytical column: Sunfire C18 (Waters technologies) 60'C io Sunfire C18, 3.0 x 30 mm, 2.5 ljm column temperature Mobile phase A: H20: trifluoroacetic acid 99.9:0.1 Mobile phase B: Methanol: 100 Gradient: time in min %A %B flow rate in ml/min 0. 1. 0 95 8 0.25 95 1.8 1.70 100 1.8 1.75 100 25 1.90 100 25 Method: M8 Analytical column: XBridge C18 (Waters technologies) 60'C XBridge C18, 3.0x 30 mm, 2.5 ljm column temperature Mobile phase A: H20: Ammonia 99.9:0.1 Mobile phase B: Methanol: 100 Gradient: time in min %A %B flow rate in ml/min 0.0 95 2.2 0. 2.2 95 PC T/EP2012/071352 1. 100 2.2 100 2. 1.70 100 2.9 Method: M9 Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, MSQ single quadrupole Column: Synergi Hydro RP100A, 2,5 3 x 50 mm s Mobile phase: A H20 90% 10% CH3CN NH4COOH 5 mM B CH3CN 90% H20 10% Gradient: time in min %A %B flow rate in ml/min 0.0 100 0 1.2 4. 100 1.2 .30 100 1.2 100 0 1.2 6.00 100 0 1.2 Detection: UV 254 nm io Detection: Finnigan MSQ, single quadrupole APCI+/APCI- lon source: 100-900 Scan range: amu Method: M10 is Instrument: LC/MS ThermoFinnigan HPLC Surveyor DAD, MSQ single quadrupole Column: Synergi Hydro RP100A, 2,5 3 x 50 mm Mobile phase: A H20 90% 10% CH3CN NH4COOH 5 mM B CH3CN 90% H20 10% Gradient: time in min %A %B flow rate in ml/min 0.0 100 0 1.2 100 0 1.2 9.00 100 1.2 .50 100 1.2 11.00 100 0 1.2 12.00 100 0 1.2 Detection: UV 254 nm PC T/EP2012/071352 Detection: Finnigan MSQ, single quadrupole lon source: APCI+/APCI- Scan 100-900 amu range: s Method: M11 Instrument: LC/MS Waters Alliance 2695 HPLC DAD, Quattro Micro Triple qua- System drupole 'C Column: Atlantis dC18 5 m 4,6x50mm, Temp Mobile phase: A H20 90% 10% CH3CN CF3COOH 0,05% B CH3CN 90% 10% H20 Gradient: time in min %A %B flow rate in ml/min 0.0 100 1.3 0.70 100 1.3 100 1.3 100 1.3 6.00 100 1.3 Detection: UV 254 nm Detection: Quattro Micro, triple quadrupole is lon source: ES+ Scan 90-1000 amu range: Method: M12 Column: Sunfire, 3 x 30 mm, 2.5 (Waters) '/0 '/0 ['C] Gradient Sol Sol [Acetoni- Flow [ml/min] emp time [min] [H20, 0.1%TFA] trile] 0. 97 2.2 00 60 0.20 97 2.2 60 1.20 100 2.2 1.25 100 60 1.40 100 Method: M13 Column: Sunfire 2.1 x 2.
C18, 30 mm, 5 pm (Waters) Gradient Sol Sol [Acetonitrile] Flow ['C] [ml/min] emp time 0.1 [min] [H20, /oTFA] PC T/EP2012/071352 0.0 99 60 0.02 99 60 1.00 100 60 1.10 100 PHARMACOLOGICAL TEST METHOD Ussing Chamber: Mouse kidney cells were cultivated in DMEM containing 5% FCS s and dexamethasone for 10 to 12 on polyester transwell filters. Filters were inserted 5pM days into a teflon-coated well-plate which fit into the in-house ussing chamber system. Prior to measurement the medium of cells was replaced with Caco-2 transport buffer (Invitrogen, 37'C.
During measurements, the chamber temperature was at Short Germany). Ussing kept circuit currents were measured in the voltage-clamp mode an in-house built (I sc) using io plifier lngelheim, Biberach) with the software Lab View for data acquisi- (Boehringer package tion and analysis. The transepithelial electrical resistance was determined the ap- (TEER) by plication of voltage of +5mV 5 sec. Compounds were administered at a final con- steps every centration of or at concentrations to the solution. At the 3pM increasing (110pM) apical end of each the amiloride sensitive I was measured amiloride experiment SC adding 3pM is to the Results are inhibition in of the amiloride apical compartment. expressed as percent effect or IC50. Results are listed in tables 1 to and further listed above. as 5 examples . INDICATIONS As has been the of formula are characterised their wide of found, compounds range (I) by applications in the therapeutic field. Particular mention should be made of those applications for which the to the invention of formula are suited on compounds according preferably account of their pharmaceutical efficacy as ENaC inhibitors. Examples include respiratory 2s diseases or complaints, or allergic diseases of the airways, air- Particular mention should be made of the prevention and treatment of diseases of the ways and of the lung which are accompanied increased mucus production, inflammations bron- and/or obstructive diseases of the airways. Examples include acute, allergic or chronic co chitis, chronic obstructive bronchitis (COPD), coughing, pulmonary emphysema, allergic or non-allergic rhinitis or sinusitis, chronic rhinitis or sinusitis, asthma, alveolitis, Farmer s dis- hyperreactive infectious bronchitis or pneumonitis, pediatric asthma, bron- ease, airways, chiectases, fibrosis, ARDS adult distress bronchial pulmonary (acute respiratory syndrome), PC T/EP2012/071352 oedema, oedema, bronchitis, pneumonia or interstitial pneumonia pulmonary triggered by various causes, such as aspiration, inhalation of toxic or bronchitis, pneumonia or gases, terstitial pneumonia as a result of heart failure, irradiation, fibrosis or chemotherapy, cystic mucoviscidosis, or alpha1-antitrypsin deficiency.
Particularly preferably the present invention relates to the use of compounds of formula for for the treatment of or obstructive preparing a pharmaceutical composition inflammatory diseases of the upper and lower respiratory tract including the lungs, such as for example allergic rhinitis, chronic rhinitis, bronchiectasis, cystic fibrosis, COPD, chronic bronchitis, io chronic sinusitis, asthma, particularly COPD, chronic bronchitis, cystic fibrosis and asthma.
It is most to the of formula for the treatment of preferable use compounds inflammatory and obstructive diseases such as COPD, chronic bronchitis, chronic sinusitis, asthma, cystic fibrosis, particularly COPD, chronic bronchitis and cystic fibrosis.
The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known those skilled in the art such as and weight of the patient, route of by age ministration 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 patient's based upon unique condition. 1 1. COMBINATIONS The compounds of formula may be used on their own or in conjunction with other active substances of according to the invention. If desired the compounds of formula (I) (I) may also be used in combination with other active substances. pharmacologically Therefore the invention further relates to medicament combinations which contain, preferably besides one or more compounds of formula as further active substances, one or more (I), compounds selected from the categories of further ENaC inhibitors, betamimetics, among ~0 corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopa- anticholinergics, mine H1-antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-Inhibitors, agonists, iNOS-Inhibitors, SYK-Inhibitors, corrections of the fibrosis transmembrane cystic regulator and CFTR or double or combinations thereof.
(CFTR) potentiators, triple of betamimetics which mentioned include Arfor- Examples preferred may be Albuterole, ~s Bitolterole, Broxaterole, For- moterole, Bambuterole, Carbuterole, Clenbuterole, Fenoterole, Isoetharine, Levosalbutamole, moterole, Hexoprenaline, Ibuterole, Isoprenaline, Mabuterole, Milveterol, Pirbuterole, Repro- Meluadrine, Metaproterenole, Orciprenaline, Procaterole, PC T/EP2012/071352 terole, Rimiterole, Ritodrine, Salmefamole, Salmeterole, Soterenole, Sulphonterole, Terbuta- line, Tiaramide, Tolubuterole, Zinterole, Nolomirole, and 1-(2-chlorohydroxyphenyl)-t-butylaminoethanole, 8-tetrahydro (-)[7(S)-[2(R)-Hydroxy(4-hydroxyphenyl)-ethylamino]-5, 6,7, naphthyloxy]-N, N-dimethylacetamide hydrochloride monohydrate, 3-(4-(6-[2-Hydroxy(4-hydroxyhydroxymethyl-phenyl)-ethylamino]-hexyloxy)-butyl)- benzyl-sulfonamide -[2-(5,6-Diethyl-indanylamino)hydroxy-ethyl]hydroxy-1H-quinolineone 4-Hydroxy[2-([2-([3-(2-phenylethoxy)propyl]sul phonyl)ethyl]-amino)ethyl]-2(3H)- benzothiazolone 1-(2-Fluorohydroxyphenyl)[4-(1-benzimidazolyl)methylbutylamino]ethanole 1-[3-(4-Methoxybenzyl-amino)hydroxyphenyl][4-(1-benzimidazolyl)methyl butylamino]ethanole 1-[2Hhydroxyoxo-4H-1, 4-benzoxazinyl][3-(4-N, N-dimethylaminophenyl) methylpropylamino]ethanole 1-[2Hhydroxyoxo-4H-1, 4-benzoxazinyl][3-(4-methoxyphenyl)methyl propylamino]ethanole 1-[2Hhydroxyoxo-4H-1, 4-benzoxazinyl][3-(4-n-butyloxyphenyl)methyl propylamino]ethanole 1-[2Hhydroxyoxo-4H-1, 4-benzoxazinyl](4-[3-(4-methoxyphenyl)-1, 4-triazol- 3-yl]methylbutylamino)ethanole -Hydroxy(1-hydroxyisopropylaminobutyl)-2H-1, 4-benzoxazin(4H)-one 1-(4-Aminochlorotrifluormethylphenyl)tert. -butylamino)ethanole 6-Hydroxy(1-hydroxy[2-(4-methoxy-phenyl)-1, 1-dimethyl-ethylamino]-ethyl)-4H- 4]oxazinone benzo[1, 6-Hydroxy(1-hydroxy[2-(4-phenoxy-acetic acid ethylester)-1, 1-dimethyl-ethylamino]- 4]oxazinone ethyl)-4H-benzo[1, 6-Hydroxy(1-hydroxy[2-(4-phenoxy-acetic acid)-1, 1-dimethyl-ethylamino]-ethyl)-4H- 4]oxazinone benzo[1, 8-(2-[1,1-Dimethyl(2, 6-trimethylphenyl)-ethylamino]hydroxy-ethyl)hydroxy-4H- benzo[1, 4]oxazinone 6-Hydroxy(1-hydroxy[2-(4-hydroxy-phenyl)-1, 1-dimethyl-ethylamino]-ethyl)-4H- benzo[1, 4]oxazinone 6-Hydroxy(1-hydroxy[2-(4-isopropyl-phenyl)-1, 1dimethyl-ethylamino]-ethyl)-4H- 4]oxazinone benzo[1, 8-(2-[2-(4-Ethyl-phenyl)-1, 1-dimethyl-ethylamino]hydroxy-ethyl)hydroxy-4H- 4]oxazinone benzo[1, PC T/EP2012/071352 8-(2-[2-(4-Ethoxy-phenyl)-1, 1-dimethyl-ethylamino]hydroxy-ethyl)hydroxy-4H- benzo[1, 4]oxazinone 4-(4-(2-[2-Hydroxy(6-hydroxyoxo-3, 4-dihydro-2 H-ben zo[1,4]oxazinyl)- ethylamino]methyl-propyl)-phenoxy)-butyric acid 8-(2-[2-(3,4-Difluor-phenyl)-1, 1-dimethyl-ethylamino]hydroxy-ethyl)hydroxy-4H- 4]oxazinone benzo[1, 1-(4-Ethoxy-carbonylaminocyanofluorophenyl)(tert. -butylamino)ethanole N-[2-Hydroxy(1-hydroxy(2-[4-(2-hydroxyphenyl-ethyl amino)-phenyl]-ethyl amino)- ethyl)-phenyl]-formamide 8-Hydroxy(1-hydroxy(2-[4-(6-methoxy-bi phenylyl amino)-phenyl]-ethyl amino)- ethyl)-1H-quinolinone 8-Hydroxy[1-hydroxy(6-phenethylamino-hexylamino)-ethyl]-1H-quinolinone -[2-(2-(4-[4-(2-Aminomethyl-propoxy)-phenylamino]-phenyl)-ethylamino)hydroxy- ethyl]hydroxy-1H-quinolinone [3-(4-(6-[2-Hydroxy(4-hydroxyhydroxymethyl-phenyl)-ethylamino]-hexyloxy)-butyl)- -methyl-phenyl]-urea 4-(2-(6-[2-(2,6-Dichloro-benzyloxy)-ethoxy]-hexylamino)hydroxy-ethyl) hydroxymethyl-phenole 3-(4-(6-[2-Hydroxy(4-hydroxyhydroxymethyl-phenyl)-ethylamino]-hexyloxy)-butyl)- benzenesulfonamide 3-(3-(7-[2-Hydroxy(4-hydroxyhydroxymethyl-phenyl)-ethylamino]-heptyloxy)-propyl)- benzenesulfonamide 4-(2-(6-[4-(3-Cyclopentanesulfonyl-phenyl)-butoxy]-hexylamino)hydroxy-ethyl) hydroxymethyl-phenole N-Adamantanyl(3-(2-[2-hydroxy(4-hydroxyhydroxymethyl-phenyl)-ethylamino]- propyl)-phenyl)-acetamide 2-Difluorop S)(2-([6-(2, nylbutoxy)hexyl]amino)hydroxy-ethyl) (hydroxymethyl)phenole S)(2-([6-(2,2-Difluorophenyl (R, ethoxy)hexyl]amino)hydroxy-ethyl) (hydroxymethyl)phenole S)(2-([4,4-Difluoro(4-p (hydro- (R, nylbutoxy)hexyl]amino)hydroxy-ethyl) xymethyl)phenole ~ 4-Difluorop S)(2-([6-(4, (R, nylbutoxy)hexyl]amino)hydroxy-ethyl) (hydroxymethyl)phenole PC T/EP2012/071352 S)(2-([6-(2,2-Difluorophenyl exyl]amino)hydroxy-ethyl) hydroxyqui- ethoxy)h nolin-2(1H)-one S)-[2-((6-[2,2-Difluoro(3-methylphenyl)ethoxy]hexyl)amino) hydroxyethyl] (hydroxymethyl)phenole 4-(1 R)([6-(2,2-Difluorophenyl exyl]amino)hydroxyethyl) eth oxy)h (hydroxymethyl)phenol 515-tetrafluoro(3-phenylpropoxy)- S)(Hydroxymethyl)(1-hydroxy([4, 4, hexyl]amino)ethyl)phenole S)-[5-(2-([6-(2,2-Difluorophenylethoxy)hexyl]amino)hydroxy-ethyl) hydro- xyphenyl]formamide ~ 2- S)[2-((6-[2-(3-Bromophenyl)-2, 2-difluoroethoxy]hexyl)amino)hydroxyethyl]- (hydroxymethyl)phenole S)-N-[3-(1,1 -Difluoro([6-((2-hydroxy[4-hydroxy(hydroxymethyl)phenyl]- ethyl)amino)hexyl]oxy)ethyl)phenyl]urea 3-[3-(1,1-difluoro([6-((2-hydroxy[4-hydroxy(hydroxymethyl) phenyl]ethyl)- 4-dione amino)hexyl]oxy)ethyl)phenyl]imidazolidine-2, S)[2-((6-[2,2-difluoro(3-methoxyphenyl)ethoxy]hexyl)amino)hydroxyethyl] (hydroxymethyl)phenole R)([6-(2,2-difluorophenyl exyl]amino)hydroxyethyl) hydroxyquino- -((1 oxy)h lin-2(1 H)-one 4-((1 R)([4,4-Difluoro(4-p exyl]amino)hydroxy-ethyl) he nylbutoxy)h (hydroxymethyl)phenole S)(2-([6-(3,3-Difluorophenyl poxy)hexyl]amino)hydroxy-ethyl) (hydroxymethyl)phenole S)-(2-([6-(2,2-Difluorophenyl 4-difluorohexyl]amino)hydroxyethyl) (R, oxy)-4, (hydroxymethyl)phenole S)(2-([6-(2,2-difluorophenylpropoxy)hexyl]amino)hydroxy ethyl) (hydro- xymethyl)phenole ~ 3- 3-[2-(3-Chloro-phenyl)-ethoxy]-N-(2-diethylamino-ethyl)-N-(2-[2-(4-hydroxyoxo-2, dihydro-benzothiazolyl)-ethylamino]-ethyl)-propionamide N-(2-Diethylamino-ethyl)-N-(2-[2-(4-hydroxyoxo-2, 3-dihydro-benzothiazolyl)- ethylamino]-ethyl)(2-naphthalenyl-ethoxy)-propionamide 7-[2-(2-(3-[2-(2-Chloro-phenyl)-ethylamino]-propylsulfanyl)-ethylamino)hydroxy-ethyl]- 4-hydroxy-3H-benzothiazolone and 7-[(1R)(2-(3-[2-(2-Chloro-phenyl)-ethylamino]- propylsulfanyl)-ethylamino)hydroxy-ethyl]hydroxy-3H-benzothiazolone in racemic form, as enantiomers, diastereomers or as accept- optionally pharmacologically able salts, solvates or hydrates. Preferred are salts selected from the consisting of hy- group PC T/EP2012/071352 drochloride, hydrobromide, hydroiodide, hydrosulfate, hydromethansul- hydrophosphate, fonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate. s Examples of preferred anticholinergics which be mentioned include Tiotropium salts, preferred the bromide salt, Oxitropium salts, preferred the bromide salt, Flutropium salts, pre- ferred the bromide the bromide Aclidinium pre- salt, Ipratropium salts, preferred salt, salts, ferred the bromide salt, Glycopyrronium salts, preferred the bromide salt, Trospium salts, preferred the chloride salt, Tolterodin. From the above mentioned salts the pharmacologically io 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 acid ester-methobromide 2,2-Diphenylpropionic tropenole is 2-Diphenylpropionic acid scopine ester-methobromide ~ 2-Fluor-2, 2-Diphenylacetic acid scopine ester-methobromide 2-Fluor-2, ester-methobromide 2-Diphenylacetic acid tropenole ~ 3', 4'-Tetrafluorbenzil ester-methobromide 3, 4, acid tropenole ~ 3', 4'-Tetrafluorbenzil acid ester-methobromide 3, 4, scopine 4'-Difluorbenzil acid tropenole ester-methobromide ~ 4'-Difluorbenzil acid scopine ester-methobromide 3'-Difluorbenzil ester-methobromide 3, acid tropenole 3'-Difluorbenzil acid ester-methobromide 3, scopine 9-Hydroxy-fluorenecarbon acid tropenole ester -methobromide 9-Fluor-fluorenecarbon acid tropenole ester -methobromide 9-Hydroxy-fluorenecarbon acid scopine ester -methobromide 9-Fluor-fluorenecarbon acid scopine ester methobromide 9-Methyl-fluorenecarbon acid estermethobromide tropenole 9-Methyl-fluorenecarbon acid scopine estermethobromide ~0 Benzil acid tropine ester-methobromide cyclopropyl ester-methobromide 2,2-Diphenylpropionic acid cyclopropyl tropine 9-Hydroxy-xanthenecarbon ester-methobromide acid cyclopropyl tropine 9-Methyl-fluorenecarbon acid ester-methobromide cyclopropyl tropine 9-Methyl-xanthenecarbon acid tropine ester-methobromide cyclopropyl ~s 9-Hydroxy-fluorenecarbon acid cyclopropyl tropine ester-methobromide 4'-Difluorbenzil ester-methobromide 4, acid methylester cyclopropyl tropine 9-Hydroxy-xanthenecarbon acid tropenole ester -methobromide PC T/EP2012/071352 9-Hydroxy-xanthenecarbon acid scopine ester methobromide 9-Methyl-xanthenecarbon -methobromide acid tropenole ester 9-Methyl-xanthenecarbon acid estermethobromide scopine 9-Ethyl-xanthenecarbon acid ester methobromide tropenole s 9-Difluormethyl-xanthenecarbon acid tropenole ester -methobromide 9-Hydroxymethyl-xanthenecarbon acid scopine ester methobromide.
Examples of preferred corticosteroids which be mentioned include Beclomethasone, Eti- Betamethasone, Budesonide, Butixocorte, Ciclesonide, Deflazacorte, Dexamethasone, prednole, Flunisolide, Fluticasone, Loteprednole, Mometasone, Prednisolone, Prednisone, Rofleponide, Triamcinolone, Tipredane, and galpha-difluoro-11beta-hydroxy- (20R-16alpha, 17alpha-[butylidenebis(oxy)]-6alpha, ndrostaenone), 17beta-(methylthio)a 9-fluoro-11beta, 4-diene-3, 20-dione 21- 17,21-trihydroxy-16alpha-methylpregna-1, cyclohexanecarboxylate 17-cyclopropanecarboxylate, 17-butylidene 9-difluorohydroxy(methylthio)androstenone 16, dioxy-6, Flunisolide-2'I-[4'-(nitrooxymethyl) benzoate] ~ 4-dien- 9-Difluoro[(2-furanylcarbonyl)oxy]hydroxymethyloxo-androsta-1, 17-carbothion acid (S)-fluoromethylester, ~ 9-Difluoro-1 6-methyloxo-1 4-dien-1 7- 6, 1-hydroxy-1 7-propionyloxy-androsta-1, carbothion acid (S)-(2-oxo-tetrahydro-furan-3S-yl)ester, and ~ 3- 9alpha-difluoro-11beta-hydroxy-16alpha-methyloxo-17alpha-(2, 6alpha, 2,3, tertamethylcyclopropylcarbonyl)oxy-androsta-1, 4-diene-17beta-carboxylic acid cyanomethyl ester optionally in racemic form, as enantiomers, diastereomers or as pharmacologically accept- able salts, solvates or hydrates. Examples for preferred salts and derivatives are alkali salts, i.e. sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, chloroacetates, propionates, dihydrogenphosphates, palmitates, pivalates or furoates.
Theo- Examples of preferred PDE4-inhibtors which be mentioned include Enprofylline, phylline, Roflumilaste, Ariflo (Cilomilaste), Tofimilaste, Pumafentrine, Lirimilaste, Apremi- laste, Arofylline, Atizorame, Oglemilastum, Tetomilaste and -[(N-(2, 5-dichloropyridinyl)-carboxamide]methoxy-quinoline 3s 5-[N-(3,5-dichlorooxidopyridinyl)-carboxamide]methoxy(trifluoromethyl)- quinoline PC T/EP2012/071352 ~ 9- N-(3, 5-dichloropyridyl)-[1-(4-fluorobenzyl)hydroxy-indoleyl]glyoxyl acid amide [(2-fluorophenyl)methyl]-N-methyl(trifluoromethyl)-9H-purineamine 4-[(2R)[3- (cyclopentyloxy)methoxyphenyl]phenylethyl]-pyridine, N-[(3R)-3,4,6,7-tetrahydromethyloxophenylpyrrolo[3, 2, 1-jk][1,4]benzodiazepin yl]Pyridinecarboxamide, 7-diethoxy-2, 4-[6, 3-bis(hydroxymethyl)naphthalenyl](2-methoxyethyl)-2(1H)- pyridinone, 2-[4-[6,7-diethoxy-2, 3-bis(hydroxymethyl)naphthalenyl]pyridinyl](3-pyridinyl)- 1(2H)-Phthalazinone, (3-(3-cyclopenyloxymethoxybenzyl)ethylaminoisopropyl-3H-purine, ~ 3-dioxo-2H-isoindole beta-[3-(cyclopentyloxy)methoxyphenyl]-1, 3-dihydro-1, propanamide, 9-ethylmethoxymethylpropyl- imidazo[1, 5-a]pyrido[3, 2-e]pyrazin-6(5H)-one 5S) -[3-(cyclopentyloxy)methoxyphenyl][(3-methylphenyl)methyl] (3S, piperidinone, 4-[1-[3, alpha- 4-bis(difluoromethoxy)phenyl](3-methyloxidopyridinyl)ethyl]-alpha, bis(trifluoromethyl)-Benzenemethanol N-(3, 5-Dichlorooxo-pyridineyl)difluoromethoxycyclopropylmethoxybenzamide ~ R*,10bS*)Eth oxy (-)p-[(4a oxy-1,2,3,4,4a, hydrometh 10b-hexa methylbenzo[s][1, 6]naphthyridinyl]-N, N-diisopropylbenzamid (R)-(+)(4-Bromobenzyl)[(3-cyclopentyloxy)methoxyphenyl]pyrrolidone 3-(Cyclopentyloxymethoxyphenyl)(4-N'-[Ncyano-S-methyl-isothioureido]benzyl)- 2-pyrrolidone cis[4-Cyano(3-cyclopentyloxymethoxyphenyl)cyclohexancarbon acid] 2-carbomethoxycyano(3-cyclopropylmethoxydifluoromethoxyphenyl)cyclohexan- 1-one cis[4-Cyano(3-cyclopropylmethoxydifluoromethoxyphenyl)cyclohexanol] (R)-(+)-Ethyl[4-(3-cyclopentyloxymethoxyphenyl)pyrrolidineyliden]acetate (S)-(-)-Ethyl[4-(3-cyclopentyloxymethoxyphenyl)pyrrolidineyliden]acetate ~ 3- 9-Cyclopentyl-5, 6-dihydroethyl(2-thienyl)-9H-pyrazolo[3, 4-c]-1, 4-triazolo[4, a]pyridine ~ 3- 9-Cyclopentyl-5, 6-dihydroethyl(tert-butyl)-9H-pyrazolo[3, 4-c]-1, 4-triazolo[4, a]pyridine 3s in racemic enantiomers, diastereomeres or accept- optionally form, as as pharmacologically able solvates or Preferred are salts selected from the of hy- salts, hydrates. group consisting hydromethansul- drochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, PC T/EP2012/071352 fonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.
Examples of preferred LTD4-antagonists which be mentioned include Montelukast, Bio- Pranlukast, Zafirlukast, Masikulast, L-733321 compound 2ab of D. et (see Guay al, Med. Chem. Lett. 8 453-458) and(E)[2-[4-[4-(4- org. (1998) Fluorophenyl)butoxy]phenyl]ethenyl](1H-tetrazoleyl)-4Hbenzopyranone (MEN- 91507) 4-[6-Acetyl[3-(4-acetylhydroxypropylphenylthio)propoxy]propylphenoxy]-butyric acid (MN-001) 1-(((R)-(3-(2-(6,7-Difluoroquinolinyl)ethenyl)phenyl)(2-(2- hydroxy propyl)phenyl)thio)methylcyclopropane-acetic acid, 1-(((1(R)-3(3-(2-(2,3-Dichlorothieno[3, 2-b]pyridinyl)-(E)-ethenyl)phenyl)(2-(1- hydroxymethylethyl)phenyl)propyl)thio)methyl)cyclopropane acetic acid Is acid [2-[[2-(4-tert-Butylthiazolyl)benzofuranyl]oxymethyl]phenyl]acetic optionally in racemic form, as enantiomers, diastereomers or as pharmacologically accept- able salts, solvates or hydrates. Preferred are salts selected from the consisting of hy- group drochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansul- fonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, exam- hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate. Further ples for optionally preferred salts and derivatives are alkali salts, i.e. sodium or potassium salts, sulfobenzoates, phosphates, isonicotinates, acetates, propionates, dihydrogenphos- phates, palmitates, pivalates or furoates.
Examples of preferred EGFR-inhibitors which be mentioned include Cetuximab, Trastu- ICR-62 zumab, Panitumumab Gefitinib, Canertinib, Erlotinib, Mab and eyl)oxobu eyl]amino) 4-[(3-Chl orflu nyl)amino]([4-(morph olin ten orp he cyclopropylmethoxy-quinazoline ~o 4-[(3-Chlorfluorphenyl)amino]([4-(N, N-diethylamino)oxobuteneyl]amino) cyclopropylmethoxy-quinazoline 4-[(3-Chlorfluorphenyl)amino]([4-(N, N-dimethylamino)oxobuteneyl]amino)- 7-cyclopropylmethoxy-quinazoline olin eyl)oxobu ten eyl]amino) 4-[(R)-(1-Phenyl-ethyl)amino]([4-(morph pentyloxy-quinazoline cyclo 4-[(3-Chlorfluor-phenyl)amino]([4-((R)methyloxo-morpholineyl)oxo buteneyl]amino)cyclopropylmethoxy-quinazoline PC T/EP2012/071352 4-[(3-Chlorfluor-phenyl)amino]([4-((R)methyloxo-morpholineyl)oxo buteneyl]amino)[(S)-(tetrahydrofuranyl)oxy]-quinazoline 4-[(3-Chlorfluor-phenyl)amino]([4-((R)methoxymethyloxo-morpholineyl) oxobuteneyl]amino)cyclopropylmethoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino][2-((S)methyloxo-morpholineyl)-ethoxy] methoxy-quinazoline 4-[(3-Chlorfluorphenyl)amino]((4-[N-(2-methoxy-ethyl)-N-methyl-amino]oxo buteneyl)amino)cyclopropylmethoxy-quinazoline 4-[(3-Chl orflu amino)oxobuten eyl]amino)- nyl)amino]([4-(N, N-dim orp he ethyl 7-cyclopentyloxy-quinazoline ~ N-b e is-(2-methoxy-ethyl)-amino)oxobu ten 4-[(R)-(1-Phenyl-ethyl)amino]([4-(N, yl]amino)cyclopropylmethoxy-quinazoline 4-[(R)-(1-Phenyl-ethyl)amino]((4-[N-(2-methoxy-ethyl)-N-ethyl-amino]oxobutene- 1-yl)amino)cyclopropylmethoxy-quinazoline 4-[(R)-(1-Phenyl-ethyl)amino]((4-[N-(2-methoxy-ethyl)-N-methyl-amino]oxo buteneyl)amino)cyclopropylmethoxy-quinazoline 4-[(R)-(1-Phenyl-ethyl)amino]((4-[N-(tetrahydropyranyl)-N-methyl-amino]oxo buteneyl)amino)cyclopropylmethoxy-quinazoline 4-[(3-Chlorfluorphenyl)amino]([4-(N, N-dimethylamino)oxobuteneyl]amino)- 7-((R)-tetrahydrofuranyloxy)-quinazoline 4-[(3-Chlorfluorphenyl)amino]([4-(N, N-dimethylamino)oxobuteneyl]amino)- 7-((S)-tetra hydrofura nyloxy)-quinazolin e 4-[(3-Chlorfluorphenyl)amino]((4-[N-(2-methoxy-ethyl)-N-methyl-amino]oxo buteneyl)amino)cyclopentyloxy-quinazoline ~ e 4-[(3-Chl orflu nyl)amino]([4-(N-cyclopropyl-N-methyl-amino)oxobuten orp he yl]amino)cyclopentyloxy-quinazoline N-dimethylamino)oxobuteneyl]amino)- 4-[(3-Chlorfluorphenyl)amino]([4-(N, 7-[(R)-(tetrahydrofuranyl)methoxy]-quinazoline 4-[(3-Chlorfluorphenyl)amino]([4-(N, N-dimethylamino)oxobuteneyl]amino)- 7-[(S)-(tetrahydrofuranyl)methoxy]-quinazoline 4-[(3-Ethinyl-phenyl)amino]-6, 7-bis-(2-methoxy-ethoxy)-quinazoline 4-[(3-Chlorfluorphenyl)amino][3-(morpholineyl)-propyloxy] [(vinylcarbonyl)amino]-quinazoline 4-[(R)-(1-Phenyl-ethyl)amino](4-hydroxy-phenyl)-7H-pyrrolo[2, 3-d]pyrimidine N-dimethylamino)oxobutene 3-Cyano[(3-chlorfluorphenyl)amino]([4-(N, yl]amino)ethoxy-quinoline PC T/EP2012/071352 4-([3-Chlor(3-fluor-benzyloxy)-phenyl]amino)(5-([(2-methansulfonyl- ethyl)amino]methyl)-furanyl)quinazoline 4-[(R)-(1-Phenyl-ethyl)amino]([4-((R)methyloxo-morpholineyl)oxobutene- 1-yl]amino)methoxy-quinazoline 4-[(3-Chlorfluorphenyl)amino]([4-(morpholineyl)oxobuteneyl]amino) [(tetrahydrofuranyl)methoxy]-quinazoline 4-[(3-Chl N-b is-(2-methoxy-ethyl)-amino]oxobutene- orflu nyl)amino]((4-[N, orp he 1-yl)amino)[(tetrahydrofuranyl)methoxy]-quinazoline 4-[(3-Ethinyl-phenyl)amino]([4-(5, 5-dimethyloxo-morpholineyl)oxobutene yl]amino)-quinazoline 4-[(3-Chlorfluor-phenyl)amino][2-(2, 2-dimethyloxo-morpholineyl)-ethoxy] methoxy-quinazoline 2-dimethyloxo-morpholineyl)-ethoxy] 4-[(3-Chlorfluor-phenyl)amino][2-(2, [(R)-(tetrahydrofuranyl)methoxy]-quinazoline 2-dimethyloxo-morpholineyl)-ethoxy] 4-[(3-Chlorfluor-phenyl)amino][2-(2, [(S)-(tetrahydrofuranyl)methoxy]-quinazoline 4-[(3-Chlorfluor-phenyl)amino](2-[4-(2-oxo-morpholineyl)-piperidinyl]-ethoxy)- 7-methoxy-quinazoline 4-[(3-Chlorflu -butyloxycarbonyl)-pi peridineyloxy] or-phenyl)amino][1-(tert. methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](transamino-cyclohexaneyloxy)methoxy- quinazoline 4-[(3-Chlorfluor-phenyl)amino](transmethansulfonylamino-cyclohexaneyloxy)- 7-methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](tetrahydropyranyloxy)methoxy-quinazoline 4-[(3-Chlorflu or-phenyl)amino](1-methyl-pi peridineyloxy)methoxy-quinazoline 4-[(3-Chlorflu peridineyloxy) or-phenyl)amino](1-[(morph olineyl)carbonyl]-pi methoxy-quinazoline 4-[(3-Chlorflu peridineyloxy) or-phenyl)amino](1-[(meth oxym ethyl)carbonyl]-pi methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](piperidineyloxy)methoxy-quinazoline 4-[(3-Chlorflu or-phenyl)amino][1-(2-acetylamino-ethyl)-pi peridineyloxy] methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](tetrahydropyranyloxy)ethoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino]((S)-tetrahydrofuranyloxy)hydroxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](tetrahydropyranyloxy)(2-methoxy-ethoxy)- quinazoline PC T/EP2012/071352 4-[(3-Chlorfluor-phenyl)amino](trans[(dimethylamino)sulfonylamino]-cyclohexane- 1-yloxy)methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](trans[(morpholineyl)carbonylamino]- cyclohexaneyloxy)methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](trans[(morpholineyl)sulfonylamino]- cyclohexaneyloxy)methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](tetrahydropyranyloxy)(2-acetylamino-ethoxy)- quinazoline 4-[(3-Chlorfluor-phenyl)amino](tetrahydropyranyloxy)(2-methansulfonylamino- ethoxy)-quinazoline 4-[(3-Chlorflu peridineyl)carbonyl]-pi peridineyloxy) or-phenyl)amino](1-[(pi methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](1-aminocarbonylmethyl-piperidineyloxy) methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](cis(N-[(tetrahydropyranyl)carbonyl]-N-methyl- amino)-cyclohexaneyloxy)methoxy quinazoline 4-[(3-Chlorfluor-phenyl)amino](cis(N-[(morpholineyl)carbonyl]-N-methyl- amino)-cyclohexaneyloxy)methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](cis(N-[(morpholineyl)sulfonyl]-N-methyl-amino)- cyclohexaneyloxy)methoxy- quinazoline 4-[(3-Chlorfluor-phenyl)amino](transethansulfonylamino-cyclohexaneyloxy) methoxy-quinazoline 4-[(3-Chlorflu or-phenyl)amino](1-meth ansulfonyl-pi peridineyloxy)ethoxy- quinazoline 4-[(3-Chlorflu or-phenyl)amino](1-meth ansulfonyl-pi peridineyloxy)(2-methoxy- ethoxy)-quinazoline 4-[(3-Chlorflu or-phenyl)amino][1-(2-methoxy-acetyl)-pi peridineyloxy](2- methoxy-ethoxy)-quinazoline 4-[(3-Chlorfluor-phenyl)amino](cisacetylamino-cyclohexaneyloxy)methoxy- quinazoline 4-[(3-Ethinyl-phenyl)amino][1-(tert-butyloxycarbonyl)-pi peridineyloxy]methoxy- quinazoline 4-[(3-Ethinyl-phenyl)amino](tetrahydropyranyloxy]methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](cis(N-[(piperidineyl)carbonyl]-N-methyl-amino)- cyclohexaneyloxy)methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](cis(N-[(4-methyl-piperazineyl)carbonyl]-N- methyl-amino)-cyclohexaneyloxy)methoxy-quinazoline PC T/EP2012/071352 4-[(3-Chlorfluor-phenyl)amino](cis[(morpholineyl)carbonylamino]-cyclohexane- 1-yloxy)methoxy-quinazoline orflu 4-[(3-Chl dineyloxy)- or-phenyl)amino](1-[2-(2-oxopyrroli dineyl)ethyl]-pi peri 7-methoxy-quinazoline 4-[(3-Chlorflu or-phenyl)amino](1-[(morph olineyl)carbonyl]-pi peridineyloxy) (2-methoxy-ethoxy)-quinazoline peridineyloxy)methoxy-quinazoline 4-[(3-Ethinyl-phenyl)amino](1-acetyl-pi 4-[(3-Ethinyl-phenyl)amino](1-methyl-pi peridineyloxy)methoxy-quinazoline 4-[(3-Ethinyl-phenyl)amino](1-meth ansulfonyl-pi peridineyloxy)methoxy- quinazoline 4-[(3-Chlorflu or-phenyl)amino](1-methyl-pi peridineyloxy)-7(2-methoxy-ethoxy)- quinazoline 4-[(3-Chlorflu peridineyloxy) or-phenyl)amino](1-isopropyloxycarbonyl-pi methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](cismethylamino-cyclohexaneyloxy)methoxy- chinazoline 4-[(3-Chlorfluor-phenyl)amino](cis[N-(2-methoxy-acetyl)-N-methyl-amino]- cyclohexaneyloxy)methoxy-quinazoline 4-[(3-Ethinyl-phenyl)amino](piperidineyloxy)methoxy-quinazoline 4-[(3-Ethinyl-phenyl)amino][1-(2-methoxy-acetyl)-piperidineyloxy]methoxy- quinazoline peridineyloxy) 4-[(3-Ethinyl-phenyl)amino](1-[(morph olineyl)carbonyl]-pi methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](1-[(cis-2, 6-dimethyl-morpholineyl)carbonyl]- piperidineyloxy)methoxy-quinazoline 4-[(3-Chlorflu or-phenyl)amino](1-[(2-methyl-morpholineyl)carbonyl]-pi peridine yloxy)methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](1-[(S, S)-(2-oxaaza-bicyclo[2. 2.1]hept peridineyloxy)methoxy-quinazoline yl)carbonyl]-pi 4-[(3-Chlorfluor-phenyl)amino](1-[(N-methyl-Nmethoxyethyl-amino)carbonyl]- piperidineyloxy)methoxy-quinazoline 4-[(3-Chlorflu or-phenyl)amino](1-ethyl-pi peridineyloxy)methoxy-quinazoline 4-[(3-Chlorflu or-phenyl)amino](1-[(2-meth oxyethyl)carbonyl]-pi peridineyloxy) methoxy-quinazoline 4-[(3-Chlorflu peridine or-phenyl)amino](1-[(3-meth oxypropyl-amino)-carbonyl]-pi yloxy)methoxy-quinazoline PC T/EP2012/071352 4-[(3-Chlorfluor-phenyl)amino][cis(N-methansulfonyl-N-methyl-amino)- cyclohexaneyloxy]methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino][cis(N-acetyl-N-methyl-amino)-cyclohexane yloxy]methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](transmethylamino-cyclohexaneyloxy) methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino][trans(N-methansulfonyl-N-methyl-amino)- cyclohexaneyloxy]methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](transdimethylamino-cyclohexaneyloxy) methoxy-quinazoline 4-[(3-Chlorfluor-phenyl)amino](trans(N-[(morpholineyl)carbonyl]-N-methyl- amino)-cyclohexaneyloxy)methoxy-quinazoline 2-dimethyloxo-morpholineyl)-ethoxy] 4-[(3-Chlorfluor-phenyl)amino][2-(2, [(S)-(tetrahydrofuranyl)methoxy]-quinazoline 4-[(3-Chlorflu 1s or-phenyl)amino](1-meth ansulfonyl-pi peridineyloxy)methoxy- quinazoline 4-[(3-Chlorfluor-phenyl)amino](1-cyano-piperidineyloxy)methoxy-quinazoline optionally in racemic form, as enantiomers, diastereomeres or as pharmacologically accept- able salts, solvates or hydrates. Preferred are salts selected from the consisting of hy- group drochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansul- fonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.
Bro- 2s Examples of preferred dopamine antagonists which may be mentioned include Rox- mocriptine, Cabergoline, Alpha-Dihydroergocryptine, Lisuride, Pergolide, Pramipexole, enanti- indole, Ropinirole, Talipexole, Terguride and Viozane, optionally in racemic form, as omers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates. ~0 Preferred are salts selected from the consisting of hydrochloride, hydrobromide, hy- group droiodide, hydrosulfate, hydromethansulfonate, hydronitrate, hydromaleate, hydrophosphate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hy- drobenzoate and hydro-p-toluenesulfonate. ~s Examples of preferred antiallergic which be mentioned include Epinastine, Ceti- agents may rizine, Azelastine, Fexofenadine, Levocabastine, Loratadine, Mizolastine, Ketotifene, Emedastine, Dimetindene, Clemastine, Bamipine, Cexchlorpheniramine, Pheniramine, PC T/EP2012/071352 Doxylamine, Chlorphenoxamine, Dimenhydrinate, Diphenhydramine, Promethazine, Ebas- tine, Olopatadine, Desloratidine and Meclozine, in racemic form, as enantiomers, optionally diastereomeres or as acceptable salts, solvates or hydrates. pharmacologically s Preferred are salts selected from the consisting of hydrochloride, hydrobromide, hy- group droiodide, hydrosulfate, hydromethansulfonate, hydronitrate, hydromaleate, hydrophosphate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, drobenzoate und hydro-p-toluenesulfonate.
Io Examples of preferred PAF antagonists which may be mentioned include Lexipafante and 4-(2-Chlorphenyl)methyl[3(4-morpholinyl)propanoneyl]-6H-thieno-[3, 2-f]- 2,4]triazolo[4, 3-a][1,4]diazepine 6-(2-Chlorphenyl)-8, 9-dihydromethyl[(4-morpholinyl)carbonyl]-4H, 7H-cyclo-penta- ]thieno-[3, 2-f][1, [4, 2,4]triazolo[4, 3-a][1,4]diazepine in racemic form, as enantiomers, diastereomers or as accept- optionally pharmacologically able salts, solvates or hydrates. Preferred are salts selected from the consisting of hy- group drochloride, hydrobromide, hydroiodide, hydrosulfate, hydromethansul- hydrophosphate, fonate, hydronitrate, 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), carbox- 6-[(aminocarbonyl)(2, 6-difluorophenyl)amino](2, 4-difluorophenyl)pyridine amide (VX-702), alpha-[2-[[2-(3-pyridinyl)ethyl]amino]pyrimidinyl]benzothiazole acetonitrile (AS- 601245), ~ 2', ~o 12-Epoxy-1H-diindolo[1, 3-fg:3', 1'-kl]pyrrolo[3, 6]benzodiazocineCarboxylic 9, 2, 4-i][1, acid (CEP-1347), 4-[3-(4-chlorophenyl)(1-methylpiperidinyl)-1H-pyrazoleyl]-pyrimidine (SC-409), in racemic form, as enantiomers, diastereomers or as accept- optionally pharmacologically ~s able salts, solvates or hydrates. Preferred are salts selected from the consisting of hy- group drochloride, hydrobromide, hydroiodide, hydrosulfate, hydromethansul- hydrophosphate, PC T/EP2012/071352 fonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate.
Examples of preferred MRP4 inhibitors which be mentioned include N-Acetyl- s dinitrophenyl-Cysteine, cGMP, Cholate, Diclofenac, Dehydroepiandrosterone 3-glucuronide, 17-beta- Dehydroepiandrosterone 3-sulphate, Dilazep, Dinitrophenyl-S-glutathione, Estradiol Estradiol 17-disulphate, Estradiol 3-glucuronide, Estradiol 3-sulphate, Estrone glucuronide, 3, 3-sulphate, Flurbiprofen, Folate, N5-formyl-tetrahydrofolate, Glycocholate, Glycolithocholic acid sulphate, Ibuprofen, Indomethacin, Indoprofen, Ketoprofen, Lithocholic acid sulphate, Methotrexate, (E)[[[3-[2-(7-Chloroquinolinyl)ethenyl]phenyl]-[[3-dimethylamino) oxopropyl]thio]methyl]thio]-propanoic acid alpha-Naphthyl-beta-D-glucuronide, Nitrobenzyl Taurochenode- mercaptopurine riboside, Probenecid, Valspodar, Sildenafil, Sulfinpyrazone, sul- oxycholate, Taurocholate, Taurodeoxycholate, Taurolithocholate, Taurolithocholic acid phate, Topotecan, Trequinsin, Zaprinast and Dipyridamol, optionally in racemic form, as antiomers, diastereomeres or as pharmacologically acceptable salts, solvates or hydrates.
Preferred are salts selected from the consisting of hydrochloride, hydrobromide, hy- group droiodide, hydrosulfate, hydrophosphate, hydromethansulfonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hy- drobenzoate und hydro-p-toluenesulfonate.
S-(2- Examples of preferred iNOS-Inhibitors which be mentioned include 6-dihydromethyl-4H- Aminoethyl)isothio-urea, Aminoguanidine, 2-Aminomethylpyridine, 3-thiazineamine S- L-Canavanin, 2-lminopiperidine, S-lsopropylisothiourea, 1, (AMT), L-NA Methylisothiourea, S-Ethylisothiourea, S-Methylthiocitrulline, S-Ethylthiocitrulline, (N— Nitro-L-arginin), L-NAME -Nitro-L-argininmethylester), L-NMMA -Monomethyl-L- (N (N L-NIO -Iminoethyl-L-ornithin), L-NIL -iminoethyl-lysin), (S) arginin), (N (N Acetimidoylaminoamino-hexanoic acid (1H-tetrazoleyl)-amide N-[[3- (aminomethyl)phenyl]methyl]-ethanimidamide, (S)(2-acetimidoylamino-ethylsulfanyl) amino-buturic acid, 2-[2-(4-Methoxy-pyridineyl)-ethyl]-3H-imidazo[4, 5-b]pyridine, 2-((R) aminophenyl-propoxy)chlorfluorbenzonitrile, 3S)aminohydroxy 2-((1R, thiazoleyl-butylsulfanyl)trifluoromethyl-nicotinonitrile, 3S)aminohydroxy 2-((1R, thiazoleyl-butylsulfanyl)chlor-benzonitrile, 3S)aminohydroxythiazoleyl- 2-((1R, butylsulfanyl)chlor-benzonitrile, 4R)amino(2-chlortrifluoromethyl- (2S, phenylsulfanyl)thiazoleyl-butaneol, 3S)aminohydroxythiazoleyl- 2-((1R, butylsulfanyl)chlor-nicotinonitrile, 4-((S)aminohydroxyphenyl-butylsulfanyl) methoxy-nicotinonitrile and substituted 3-phenyl-3, 4-dihydroisoquinolinamine for stance 6R)Chlormethylaza-bicyclo[4. 1.0]hepteneylamin 5R)Ethyl- 1S,5S, (4R, PC T/EP2012/071352 4-methyl-thiazolidineylideneamine, 6R)Chlormethylaza-bicyclo[4. 1.0]hept- (1S,5S, 2-eneylamin, 5R)Ethylmethyl-thiazolidineylideneamine, 5R)Ethyl (4R, (4R, methyl-selenazolidineylideneamine, 4-Aminotetrahydrobiopterine, (E)(4-Chlor-phenyl)- N-(1-(2-oxo[4-(6-trifluormethyl-pyrimidineyloxy)-piperidineyl]-ethylcarbamoyl) s pyridineyl-ethyl)-acrylamide, 3-(2,4-Difluor-phenyl)[2-(4-imidazoleylmethyl-phenoxy)- ethoxy]phenyl-pyridine, 3]dioxolylmethyl)-carbamoyl]-methyl)(2- 3-([(Benzo[1, imidazoleyl-pyrimidineyl)-piperazinecarbon acid (R)(2-imidazole methylester, ylmethyl-pyrimidineyl)-pyrrolidinecarbon acid (2-benzo[1, 3]dioxolyl-ethyl)-amide, optionally in racemic form, as enantiomers, diastereomers or as pharmacologically accept- io able salts, solvates or hydrates. Preferred are salts selected from the consisting of hy- group drochloride, hydrobromide, hydroiodide, hydrosulfate, hydrophosphate, hydromethansul- fonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate. iNOS-Inhibitors is Further examples of preferred which may be mentioned include antisense-Oligonucleotide, especially those antisense-Oligonucleotide bindung iNOS-coding nucleinic acids, examples therefore are disclosed in WO 01/52902.
Examples of preferred SYK-inhibitors which may be mentioned include 2-[(2-aminoethyl)amino][(3-bromophenyl)amino]pyrimidinecarboxamide; 2-c]pyrimidineyl]amino]pyridinecarboxamide; 2-[[7-(3,4-dimethoxyphenyl)imidazo[1, 6-[[5-fluoro[3, 2-dimethyl-2H- 4,5-trimethoxyphenyl)amino]pyrimidinyl]amino]-2, 2-b]-1,4-oxazin-3(4H)-one; pyrido[3, N-[3-bromo(4-methoxyphenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; 7-(4-methoxyphenyl)-N-methyl-1, 6-naphthyridineamine; N-[7-(4-methoxyphenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(2-thienyl)-1, 6-naphthyridineyl-1, 3-propanediamine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]-1, 2-ethanediamine; ~o N-[7-(4-methoxyphenyl)(trifluoromethyl)-1, 6-naphthyridineyl]- 3-propanediamine; N-[7-(4-methoxyphenyl)phenyl-1, 6-naphthyridineyl]-1, 3-propanediamine; N-(7-phenyl-1, 6-naphthyridineyl)-1, 3-propanediamine; N-[7-(3-fluorophenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(3-chlorophenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; ~s N-[7-[3-(trifluoromethoxy)phenyl]-1, 6-naphthyridine-5yl]-1, 3-propanediamine; N-[7-(4-fluorophenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(4-fluorophenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; PC T/EP2012/071352 N-[7-(4-chlorophenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(4'-methyl[1, 1'-biphenyl]yl)-1, 6-naphthyridine-1, 3-propanediamine; 6-naphthyridineyl]-1, N-[7-[4-(dimethylamino)phenyl]-1, 3-propanediamine; 6-naphthyridineyl]-1, N-[7-[4-(diethylamino)phenyl]-1, 3-propanediamine; N-[7-[4-(4-morpholinyl)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; ~ 3- N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1, 6-naphthyridineyl]-1, propanedia mine; N-[7-(4-bromophenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; 6-naphthyridineyl]-1, N-[7-(4-methylphenyl)-1, 3-propanediamine; N-[7-[4-(methylthio)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-[4-(1-methylethyl)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; 7-[4-(dimethylamino)phenyl]-N-methyl-1, 6-naphthyridineamine; N-dimethyl-1, 7-[4-(dimethylamino)phenyl]-N, 6-naphthyridineamine; 6-naphthyridineyl]-1, 4-butanediamine; N-[7-[4-(dimethylamino)phenyl]-1, N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]-1, 5-pentanediamine; 3-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]oxy]propanole; 4-[5-(4-aminobutoxy)-1, 6-naphthyridineyl]-N, N-dimethyl-benzenamine; 4-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]amino]butanole; 6-naphthyridineyl]-N-methyl-1, N-[7-[4-(dimethylamino)phenyl]-1, 3-propanediamine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]-N'-methyl-1, 3-propanediamine; ~ N'-dimethyl-1, 3- N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]-N, propanedia mine; 1-amino[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]amino]propanole; 6-naphthyridineyl]-2, 2-dimethyl-1, N-[7-[4-(dimethylamino)phenyl]-1, 3-propanediamine; 7-[4-(dimethylamino)phenyl]-N-(3-pyridinylmethyl)-1, 6-naphthyridineamine; N-[(2-aminophenyl)methyl][4-(dimethylamino)phenyl]-1, 6-naphthyridineamine; ~ 1'-bi N-[7-[6-(dimethylamino) 6-naphthyridineyl]-1, 3-propanediamine; [1, phenyl]yl]-1, N-[7-[3-chloro(diethylamino)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-[4-(dimethylamino)methoxyphenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-[4-(diethylamino)phenyl]methyl-1, 6-naphthyridineyl]-1, 3-propanediamine; ~ N-[7-(3'-fluoro[1, 1'-biphenyl]yl)-1, 6-naphthyridineyl]-1, 2-ethanediamin, N-[7-(4-methoxyphenyl)-1, 6-naphthyridineyl]-1, 6-naphthyridine-1, 3-propanediamine; N'-bis(3-aminopropyl)(4-methoxyphenyl)-2, 5-diamine; ~ 3- N-[7-(4-methoxyphenyl)(phenylmethoxy)-1, 6-naphthyridineyl]-1, 6-naphthyridine-1, mine; propanedia N5-(3-aminopropyl)(4-methoxyphenyl)-N2-(phenylmethyl)-2, 5-diamine; PC T/EP2012/071352 N-[7-(2-naphthalenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(2'-fluoro[1, 1'-biphenyl]yl)-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(3, 6-naphthyridineyl]-1, 4,5-trimethoxyphenyl)-1, 3-propanediamine; N-[7-(3, 6-naphthyridineyl]-1, 4-dimethylphenyl)-1, 3-propanediamine; 1-amino[[7-(2-naphthalenyl)-1, 6-naphthyridineyl]amino]propanole; 1-amino[[7-(2'-fluoro[1, 1'-biphenyl]yl)-1, 6-naphthyridineyl]amino]propanole; 1-amino[[7-(4'-methoxy[1, 1'-biphenyl]yl)-1, 6-naphthyridineyl]amino]propanole; 1-amino[[7-(3, 6-naphthyridineyl]amino]propanole; 4,5-trimethoxyphenyl)-1, 1-amino[[7-(4-bromophenyl)-1, 6-naphthyridineyl]amino]propanole; ~ 3- N-[7-(4'-methoxy[1, 1'-biphenyl]yl)-1, 6-naphthyridineyl]-2, 2-dimethyl-1, mine; propanedia 1-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]amino]propanole; 2-[[2-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]amino]ethyl]thio]-ethanole; 7-[4-(dimethylamino)phenyl]-N-(3-methylisoxazolyl)-1, 6-naphthyridineamine; 7-[4-(dimethylamino)phenyl]-Npyrimidinyl-1, 6-naphthyridineamine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]-1, 3-cyclohexane diamine; N, N-dimethyl[5-(1-piperazinyl)-1, 6-naphthyridineyl]-benzenamine; 4-[5-(2-meth N-dimethyl-benzena oxyethoxy)-1, 6-naphthyridineyl]-N, mine; 6-naphthyridineyl]piperidinole; 1-[7-[4-(dimethylamino)phenyl]-1, 1-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]pyrrolidinole; 7-[4-(dimethylamino)phenyl]-N-(2-furanylmethyl)-1, 6-naphthyridineamine; 6-naphthyridinea 7-[4-(dimethylamino)phenyl]-N-[3-(1H-imidazoleyl) propyl]-1, mine; 1-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]piperidine carboxamide; 1-[3-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]amino]propyl]pyrrolidinone; N-[3'-[5-[(3-aminopropyl)amino]-1, 6-naphthyridineyl][1, 1'-biphenyl]yl]-acetamide; ~ N-[7-(4'-fluoro[1, 1'-biphenyl]yl)-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[4'-[5-[(3-aminopropyl)amino]-1, 1'-biphenyl]yl]-acetamide; 6-naphthyridineyl][1, N-[7-[4-(1,3-benzodioxolyl)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-[4-(2-thienyl)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-[4-fluoro(trifluoromethyl)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; 6-naphthyridineyl]-1, N-[7-[4-(3-pyridinyl)phenyl]-1, 3-propanediamine; N-[7-(1,3-benzodioxolyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(6-methoxynaphthalenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; 7-[4-(dimethylamino)phenyl]-N-(4-pyridinylmethyl)-1, 6-naphthyridineamine; 3-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]methylamino]-propanenitrile; 6-naphthyridine 7-[4-(dimethylamino)phenyl]-N-[1-(phenylmethyl)piperidinyl]-1, PC T/EP2012/071352 amine; N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]-1, 2-cyclohexanediamin, N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]-1, 2-Cyclohexanediamine, 2S)- (1R, rel-. 2-benzene N-[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]-1, dimethanamine; 6-naphthyridineyl]-1, 4-butanediamine; N-[7-[4-(diethylamino)phenyl]-1, ~ 1'-bi 3- N-[7-[3', 5'-bis(trifluorom 6-naphthyridineyl]-, ethyl) [1, phenyl]yl]-1, mine; propanedia N-[7-(3'-methoxy[1, 1'-biphenyl]yl)-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(3'-fluoro[1, 1'-biphenyl]yl)-1, 6-naphthyridineyl]-1, 3-propanediamine; 6-naphthyridineyl]oxy]butanole; 4-[[7-[4-(dimethylamino)phenyl]-1, 6-naphthyridineyl]- 4-cyclohexanediamine; N-[7-[4-(dimethylamino)phenyl]-1, 1, 7-[4-(dimethylamino)phenyl]-N-(2, 6-tetramethylpiperidinyl)-1, 6-naphthyridine 2,6, amine; N-[7-[3-bromo(dimethylamino)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(1-methyl-1H-indoleyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; 6-naphthyridineyl]-1, N-[7-[3-(trifluoromethyl)phenyl]-1, 3-propanediamine; N-[7-[4-(trifluoromethyl)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; N-[7-(3-bromomethoxyphenyl)-1, 6-naphthyridineyl]-1, 3-propanediamine; ~ 4- N-[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1, 6-naphthyridineyl]-1, cyclohexanediamine; ~ 4- N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1, 6-naphthyridineyl]-1, cyclohexanediamine; ~ 4- N-[7-[4-(dimethylamino)methoxyphenyl]-1, 6-naphthyridineyl]-1, cyclohexanedia mine; N-[7-[4-(4-morpholinyl)phenyl]-1, 6-naphthyridineyl]-1, 4-cyclohexanediamine; N-[7-[3-bromo(4-morpholinyl)phenyl]-1, 6-naphthyridineyl]-1, 4-cyclohexanediamine; 4-[[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1, 6-naphthyridineyl]oxy]- cyclohexanole; N-[7-[3-bromo(4-morpholinyl)phenyl]-1, 6-naphthyridineyl]-1, 3-propanediamine; N-dimethyl[5-(4-methylpiperazinyl)-1, 6-naphthyridineyl]-benzenamine; 6-naphthyridineyl]oxy]- 4-[[7-[4-[[3-(dimethylamino)propyl]methylamino]phenyl]-1, cyclohexanole; ~ 4- N-[7-[4-[[2-(dimethylamino)ethyl]methylamino]phenyl]-1, 6-naphthyridineyl]-1, butanedia min; PC T/EP2012/071352 [3-[[5-[(3-aminopropyl)amino](4-methoxyphenyl)-1, 6-naphthyridineyl]amino]propyl]- carbamic acid-1, 1-dimethylethyl ester, optionally in racemic form, as enantiomers, diastereomers or as pharmacologically accept- s able salts, solvates or hydrates. Preferred are salts selected from the consisting of hy- group drochloride, hydrobromide, hydroiodide, hydrosulfate, hydromethansul- hydrophosphate, fonate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, hydrooxalate, hydrosuccinate, hydrobenzoate und hydro-p-toluenesulfonate. io of fibrosis transmembrane and CFTR potentia- Examples preferred cystic regulators (CFTR) tors which mentioned VX-770 and VX-809 may be include, preferably 12. FQRMULATIQNs is Suitable forms for administration are for inhalable or aerosols. The con- example powders tent of the effective in each should in the from pharmaceutically compound(s) case be range 0.2 to wt'/o, to 25 wt. of the total i.e. in amounts which are 50 preferably 5 composition, sufficient to achieve the hereinafter. dosage range specified Administered 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 according to the preferred embodiments above.
It is also preferred if the compounds of formula are administered inhalation, particularly (I) by 2s preferably if they are administered once or twice a For this the compounds of day. purpose, formula have to be made available in forms suitable for inhalation. Inhalable preparations include inhalable powders, propellant-containing metered-dose aerosols or propellant-free inhalable solutions, which are optionally present in admixture with conventional physiologi- cally acceptable excipients.
Within the of the present invention, the term propellant-free inhalable solutions also scope include concentrates or sterile ready-to-use inhalable solutions. The preparations which be used according to the invention are described in more detail in the next of the specifi- part cation.
Inhalable powders PC T/EP2012/071352 If the active substances of formula are present in admixture with physiologically accept- able excipients, the following acceptable excipients be used to physiologically may prepare the inhalable powders according to the invention: monosaccharides or arabi- (e.g. glucose disaccharides lactose, saccharose, oligo- and polysaccharides nose), (e.g. maltose), (e.g. s sorbitol, mannitol, salts sodium chloride, calcium dextran), polyalcohols (e.g. xylitol), (e.g. carbonate) or mixtures of these excipients with one another. Preferably, mono- or disaccha- rides are while the of lactose or is but not exclu- used, use glucose preferred, particularly, sively, in the form of their hydrates. For the purposes of the invention, lactose is the particu- larly preferred excipient, while lactose monohydrate is most particularly preferred. Methods of preparing the inhalable powders according to the invention grinding and micronising and finally mixing the components together are known from the prior art.
Propellant-containing inhalable aerosols The propellant-containing inhalable aerosols which may be used according to the invention contain of formula dissolved in the or in form. may a compound propellant gas dispersed The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable propellant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or mix- cyclobutane. The propellant gases mentioned above be used on their own or in tures thereof. Particularly preferred propellant gases are fluorinated alkane derivatives lected from TG134a 2-tetrafluoroethane), TG227 3-heptafluoropropane) (1,1,1, (1,1,1,2,3,3, and mixtures thereof. The propellant-driven inhalation aerosols used within the scope of the stabi- use according to the invention also contain other ingredients such as co-solvents, lisers, surfactants, antioxidants, lubricants and adjusters. All these ingredients are known in the art.
Propellant-free inhalable solutions The compounds of formula according to the invention are preferably used to pro- (I) prepare pellant-free inhalable solutions and inhalable Solvents for this suspensions. used purpose include or ethanolic solutions. The solvent water on its aqueous alcoholic, preferably may be own or mixture of water and ethanol. The solutions or are to of a suspensions adjusted a pH 2 to 2 to suitable acids. The acids selected 7, preferably 5, using pH may be adjusted using from or acids. of suitable acids include hy- inorganic organic Examples particularly inorganic drochloric nitric acid and/or acid. Exam- acid, hydrobromic acid, acid, sulphuric phosphoric of suitable acids include ascorbic citric malic tartaric ples particularly organic acid, acid, acid, maleic succinic fumaric acetic formic acid and/or acid acid, acid, acid, acid, acid, propionic PC T/EP2012/071352 etc. Preferred inorganic acids are hydrochloric and sulphuric acids. It is also possible to use the acids which have formed an acid addition salt with one of the active substances. already mix- Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, tures of the above acids also be particularly in the case of acids which have other may used, s in addition to their qualities, e. as flavourings, antioxidants or complex- properties acidifying g. such as citric acid or ascorbic acid, for example. According to the invention, it is ing agents, to acid to the particularly preferred use hydrochloric adjust pH.
Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions co-solvents con- io used for the purpose according to the invention. Preferred are those which tain hydroxyl groups or other polar e. alcohols particularly isopropyl alcohol, gly- groups, g. cols particularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, glycolether, glyc- erol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmacologically acceptable substance which is sub- is not an active substance but which can be formulated with the active substance or stances in the pharmacologically suitable solvent in order to improve the qualitative proper- ties of the active substance formulation. Preferably, these substances have no pharmacol- ogical effect or, in connection with the desired therapy, no appreciable or at least no undesir- able pharmacological effect. The excipients and additives include, for example, surfactants such as lecithin, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, soya other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other additives known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents. The preferred excipients include antioxi- dants such as ascorbic acid, for provided that it has not been used to example, already the vitamin vitamin tocopherols and similar vitamins or provitamins occurring in just pH, A, E, the human Preservatives be used to protect the formulation from contamination body. may with Suitable preservatives are those which are known in the art, particularly pathogens. cetyl chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium pyridinium ~0 benzoate in the concentration known from the art. prior For the treatment forms described ready-to-use of medicament for the treat- above, packs a ment of are an enclosed for respiratory complaints provided, containing description including the words COPD or to the example respiratory disease, asthma, a compound according ~s vention and one or more combination selected from those described above. partners The following example illustrates the present invention without restricting its scope: PC T/EP2012/071352 sule for owder inhalation 1 capsule contains: active substance 0.5 s lactose for inhalation ~5.0 m Preparation: The active substance is mixed with lactose for inhalation. The mixture is packed into cap- sules in a capsule-making machine of the capsule approx. 50 (weight empty mg). weight of capsule: 55.5 size of capsule 3 WE

Claims (23)

CLAIM :
1. A compound of formula (IA), (IB) or (IC.1) O NH Cl N A H N N NH (IA) O NH Cl N H N N NH (IB) O NH Cl N A H N N NH H N N NH N Cl (IC.1) wherein A denotes a bond, -CH - or -CH CH -, -CH -O-, 2 2 2 2 R is selected from the group consisting of 11571921 (11571921_1):HJG hydrogen, C -alkyl, C -alkyl-SO -, C -alkyl-NH-CO- ,H N-CO-, 1-6 1-4 2 1-4 2 H N-C -alkyl-, H N-C -alkyl-CO-, H N-C -alkyl-NH-CO-, Phenyl-CO-, 2 1-4 2 1-4 2 1-4 Phenyl-CH -CO-, Phenyl-CH -, C -alkyl-CO-, C -alkyl -O- C -alkyl-CO-, 2 2 1-6 1-6 1-4 (CH ) N-C -alkyl-, (CH ) N-C -alkyl-NH-CO-, (CH ) N -C -alkyl-NH-CO-, 3 2 1-4 3 2 1-4 3 3 1-4 + + + (CH )N -C -alkyl-N(C -alkyl)-CO-, (CH ) N -C -alkyl-, (CH ) N -C -alkyl- 3 1-4 1-4 3 3 2-4 3 3 1-4 CO-, H N-C(NH)-NH-C -NH-CO-, C -alkyl-O-CO-, C -alkyl-O-CO-C -alkyl-, 2 1-6 1-6 1-6 1-4 C -alkyl-O-CO-C - -alkyl-CO-, C -alkyl-O-CO-C -alkyl-NH-CO-, 1-6 1 4 1-6 1-4 C -alkyl-O-CO-NH-C -alkyl-, C -alkyl-O-CO-NH-C -alkyl-CO-, 1-6 1-4 1-6 1-4 C -alkyl-O-CO-NH-C -alkyl-NH-CO-, HOCO-C -alkyl-, HOCO-C -alkyl- 1-6 1-4 1-4 1-4 CO-, HOCO-C -alkyl-NH-CO-, H N-CNH- and H NC(NH)NH-C -alkyl-CO-. 1-4 2 2 1-6 R is selected from among a group of below listed formulas (c1) to (c5): O NH (c1) (c2) (c3) O NH (c4) (c5) R denotes C -alkyl, R denotes C -alkyl, X denotes any anion forming a pharmaceutically acceptable salt, L denotes a bridging group -CO-NH-C -alkyl-NH-CO-, -COC -alkyl-CO- or 2-6 1-6 -C -alkyl-, forming a compound of formula (IC.1), whereby the molecular entities of formula (IC.1) connected by L may be identical or different, 11571921 (11571921_1):HJG 2 3 4 6 7 2a 3a 4a 6a 7a R , R , R , R , R , R , R , R , R , R independently from each other are selected from the group consisting of hydrogen, halogen , CN, C -alkyl, C -alkyl-O-, C 1-4 1-3 1- 4.1 4.2 4.3 4.1 -alkyl-OCO-, -COOR , -CONR R and -OR , wherein R denotes hydrogen or C -alkyl, R denotes hydrogen or C -alkyl, R denotes hydrogen or C -alkyl, 3 4 3a 4a R and R or R and R together denote -O-C -alkyl-O-; or a pharmacologically acceptable acid addition salt thereof.
2. The compound of formula (IA) according to claim 1, characterized in that A denotes a bond, -CH - or -CH CH -, 2 2 2 R is selected from the group consisting of hydrogen, C -alkyl, C -alkyl-SO -, C -alkyl-NH-CO- ,H N-CO-, 1-6 1-4 2 1-4 2 H N-C -alkyl-, H N-C -alkyl-CO-, H N-C -alkyl-NH-CO-, Phenyl-CO-, 2 1-4 2 1-4 2 1-4 Phenyl-CH -CO-, Phenyl-CH -, C -alkyl-CO-, C -alkyl -O- C -alkyl-CO-, 2 2 1-6 1-6 1-4 (CH ) N-C -alkyl-, (CH ) N-C -alkyl-NH-CO-, (CH ) N -C -alkyl-NH-CO-, 3 2 1-4 3 2 1-4 3 3 1-4 + + + (CH )N -C -alkyl-N(C -alkyl)-CO-, (CH ) N -C -alkyl-, (CH ) N -C -alkyl- 3 1-4 1-4 3 3 2-4 3 3 1-4 CO-, H N-C(NH)-NH-C -NH-CO-, C -alkyl-O-CO-, C -alkyl-O-CO-C -alkyl-, 2 1-6 1-6 1-6 1-4 C -alkyl-O-CO-C - -alkyl-CO-, C -alkyl-O-CO-C -alkyl-NH-CO-, 1-6 1 4 1-6 1-4 C -alkyl-O-CO-NH-C -alkyl-, C -alkyl-O-CO-NH-C -alkyl-CO-, 1-6 1-4 1-6 1-4 C -alkyl-O-CO-NH-C -alkyl-NH-CO-, HOCO-C -alkyl-, HOCO-C -alkyl- 1-6 1-4 1-4 1-4 CO-, HOCO-C -alkyl-NH-CO-, H N-CNH- and H NC(NH)NH-C -alkyl-CO-. 1-4 2 2 1-6 R is selected from among a group of below listed formulas (c1) to (c5): O NH (c1) (c2) (c3) 11571921 (11571921_1):HJG O NH (c4) (c5) R independently from each other are selected from the group consisting of hydrogen, halogen, CN, C -alkyl and C -alkyl-O-, 1-4 1 R independently from each other are selected from the group consisting of hydrogen, halogen, CN, C -alkyl and C -alkyl-O- 1-4 1 R are selected from the group consisting of hydrogen halogen, CN and C -alkyl, R independently from each other are selected from the group consisting of hydrogen 4.1 4.2 4.3 halogen, CN, C -alkyl, C -alkyl-OCO-, -COOR and -CONR R , 1-4 1-4 wherein R denotes hydrogen or C -alkyl, R denotes hydrogen or C -alkyl, R denotes hydrogen or C -alkyl, R and R together denote -O-C -alkyl-O-; or a pharmacologically acceptable acid addition salt thereof.
3. The compound of formula (IC.1) according to claim 1, characterized in that A denotes a bond, -CH - or -CH CH -, 2 2 2 L denotes a bridging group -CO-NH-C -alkyl-NH-CO- , 2 2a R , R independently from each other are selected from the group consisting of hydrogen, halogen, CN, C -alkyl and C -alkyl-O-, 1-4 1 6 6a R , R independently from each other are selected from the group consisting of hydrogen, halogen, CN, C -alkyl and C -alkyl-O- 1-4 1 3 3a R , R are selected from the group consisting of hydrogen halogen, CN and C -alkyl, 4 4a R , R independently from each other are selected from the group consisting of hydrogen 4.1 4.2 4.3 halogen, CN, C -alkyl, C -alkyl-OCO-, -COOR and -CONR R , 1-4 1-4 wherein R denotes hydrogen or C -alkyl, 11571921 (11571921_1):HJG R denotes hydrogen or C -alkyl, R denotes hydrogen or C -alkyl, 3 4 3a 4a R and R or R and R together denote -O-C -alkyl-O-; or a pharmacologically acceptable acid addition salt thereof.
4. The compound of formula (IB) according to claim 1, characterized in that R denotes C -alkyl, and R denotes C -alkyl; or a pharmacologically acceptable acid addition salt thereof.
5. The compound of formula (IC.1) according to claim 1 or 3, characterized in that L denotes a bridging group -CO-NH-C -alkyl-NH-CO-; or a pharmacologically acceptable acid addition salt thereof.
6. The compound of formula (IA), (IB), or (IC.1) according to any one of claims 1 to 5, 2 3 4 6 7 characterized in that R , R , R , R , R denote hydrogen; or a pharmacologically acceptable acid addition salt thereof.
7. The compound according to any one of claims 1 to 6, characterized in that A denotes -CH CH -, or a pharmacologically acceptable acid addition salt thereof.
8. The compound according to any one of claims 1 to 3 or claims 5 to 7, characterized in that the compound is selected from the group consisting of compounds (1) to (6) and (8) to (12): 11571921 (11571921_1):HJG Cl N N N N O NH Cl N H N N NH O NH Cl N H N N NH O NH Cl N H N N NH 11571921 (11571921_1):HJG N Cl Cl N N N N N N N O NH H N N NH O NH Cl N H N N NH H N N NH H N N NH (10) 11571921 (11571921_1):HJG Cl N H N N NH (11) O NH Cl N H N N NH (12) or a pharmacologically acceptable acid addition salt thereof.
9. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (1) Cl N N N N or a pharmacologically acceptable acid addition salt thereof.
10. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (2) 11571921 (11571921_1):HJG O NH Cl N H N N NH or a pharmacologically acceptable acid addition salt thereof.
11. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (3) O NH Cl N H N N NH or a pharmacologically acceptable acid addition salt thereof.
12. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (4) O NH H N N NH or a pharmacologically acceptable acid addition salt thereof.
13. The compound according to claim 1 or claim 3 or any one of claims 5 to 8, characterized in that the compound is compound (5) 11571921 (11571921_1):HJG N Cl Cl N N N N N N N or a pharmacologically acceptable acid addition salt thereof.
14. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (6) O NH H N N NH or a pharmacologically acceptable acid addition salt thereof.
15. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (8) O NH Cl N H N N NH or a pharmacologically acceptable acid addition salt thereof.
16. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (9) 11571921 (11571921_1):HJG O NH Cl N H N N NH or a pharmacologically acceptable acid addition salt thereof.
17. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (10) O NH Cl N H N N NH (10) or a pharmacologically acceptable acid addition salt thereof.
18. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (11) O NH Cl N H N N NH (11) or a pharmacologically acceptable acid addition salt thereof.
19. The compound according to claim 1 or claim 2 or any one of claims 6 to 8, characterized in that the compound is compound (12) 11571921 (11571921_1):HJG Cl N H N N NH (12) or a pharmacologically acceptable acid addition salt thereof.
20. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease selected from respiratory diseases, complaints and allergic diseases of the airways.
21. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a disease selected from chronic bronchitis, acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergic bronchitis, toxic bronchitis, chronic obstructive bronchitis (COPD), asthma (intrinsic or allergic), paediatric asthma, bronchiectasis, allergic alveolitis, allergic or non-allergic rhinitis, chronic sinusitis, cystic fibrosis or mucoviscidosis, alphaantitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema, and pneumonitis of different origins.
22. A pharmaceutical composition comprising at least one compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
23. A medicament combination which contains, besides one or more compounds of a compound according to any one of claims 1 to 19, as further active substances, one or more compounds selected from the group consisting of further ENaC inhibitors, betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-Inhibitors, iNOS-Inhibitors, SYK-Inhibitors, corrections of the cystic 11571921 (11571921_1):HJG fibrosis transmembrane regulator (CFTR) and CFTR potentiators or double or triple combinations thereof. Boehringer Ingelheim International GmbH By the Attorneys for the Applicant SPRUSON & FERGUSON Per: 11571921 (11571921_1):HJG
NZ622469A 2011-11-02 2012-10-29 Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof NZ622469B2 (en)

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Application Number Priority Date Filing Date Title
EP11187553 2011-11-02
EP11187553.0 2011-11-02
PCT/EP2012/071352 WO2013064450A1 (en) 2011-11-02 2012-10-29 Heterocyclic compounds, medicaments containing said compounds, use thereof and processes for the preparation thereof

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NZ622469A NZ622469A (en) 2016-08-26
NZ622469B2 true NZ622469B2 (en) 2016-11-29

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