NZ738967B2 - Novel annelated phenoxyacetamides - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein R1, R2, R3, and Z-have one of the meanings as indicated in the specification or a pharmaceutically acceptable salt thereof, to the use of compounds of formula (I) as a medicament, to pharmaceutical composition comprising at least one compound of formula (I), as well as to medicament combinations containing one or more compounds of formula (I). The claimed compounds are epithelial sodium channel (ENaC) inhibitors and so have potential therapeutic use in the treatment of respiratory and allergic diseases. compound of formula (I), as well as to medicament combinations containing one or more compounds of formula (I). The claimed compounds are epithelial sodium channel (ENaC) inhibitors and so have potential therapeutic use in the treatment of respiratory and allergic diseases.

Description

NOVEL ANNELATED PHENOXYACETAMIDES FIELD OF THE ION The present invention relates to compounds of formula (I) O R2 I 3 CI N\ N R (I) l H A} /—< Z O 0 N NH2 RV wherein R1, R2, R3, and Z" have one of the meanings as indicated in the specification or a pharmaceutically acceptable salt thereof, to the use of compounds of formula (I) as a medicament, to pharmaceutical composition comprising at least one compound of formula (I), as well as to medicament combinations containing one or more compounds of formula (I).

BACKGROUND TO THE INVENTION WO2011079087, WO2015007516, WO2015007519, and 007517 disclose amides of 3 ,5-diaminohalo-pyrazinecarboxylic acid of related structure showing ENaC (Epithelial Sodium Channel) inhibitor activity.

Venanzi teaches that the amino group in position 5 of the pyrazine moiety of amiloride and its analogs is essential for the stability of the blocking complex with ENaC (Venanzi et al., Journal ofMedicinal Chemistry, 1992, Vol. 35 (9), 1643-1649).

The problem ofthe present invention is to e further nds for therapeutic use for the treatment of pathophysio logical processes treatable by the blockade of an epithelial sodium channel, ularly for the treatment of the lungs and airways.

Such compounds should be potent inhibitors of ENaC. Suitable IC50 values determined in the Ussing r assay are typically below 30 nM.

Aditionally, such compounds should exhibit a low permeability which is cial for topical lung treatment. Suitable permeability values determined in the CALU-3 cells assay are typically below 6 X 10'7 cm/s.

Aditionally, such compounds should have high solubility in aqueous media which is cial for administration by inhalation of an aqueous solution. Suitable solubility values in s buffer with a physiologically acceptable pH value are 2% or higher.

Aditionally, such compounds should have high hydrolytic stability in s media which is beneficial for stration by inhalation of an aqueous on.

Aditionally, such compounds should inhibit in vivo water resorption in the lung upon topical administration. Topical lung administration of pharmaco logically active doses of the compounds ofthe present invention should not or only to a low extent increase plasma aldosterone levels.

Surprisingly, it has been found that the claimed 3-aminochloro-pyrazine-2—carboxylic acid tives which do not possess an amino group in position 5 of the pyrazine moiety are potent ENaC tors and fiarther possess the additional characteristics outlined above.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula (I), O R2 I 3 CI N\ N R (I) i H z / N\. fl< O 0 N NH2 RV wherein R1 and R2 are independently selected from ethyl, 2-hydroxyethyl, ahydrofuranylmethyl and 4-tetrahydropyranylmethyl; R3 is selected from a moiety NRaRb, wherein R81 and Rb are independently selected from hydrogen, C1-C4-alkyl and l-(2-ethoxyethyl)piperidinyl, wherein said C1-C4-alkyl may carry 1 or 2 substituents selected from hydroxyl, amino, C1-C4-alkylamino, di-C1-C4- alkylamino, (dimethylphosphinoyl)methoxy, 4-(dimethylphosphinoyl)phenyl, 6-methyl- 3-hydroxy—pyridinyl and the oxyanion of 6-methylhydroxy-pyridinyl, ed that at least one of R81 and Rb is different from hydrogen, or wherein R81 and Rb together with the nitrogen they are attached to form a heterocyclic moiety selected from piperidine and l-oxothiomorpholinyl, wherein the heterocyclic moiety may carry 1 or 2 substituents selected from NHZ; and Z" is selected from chloride, bromide, iodide, hydroxide, ensulfate, sulfate, nitrate, phosphate, formate, acetate, trifluoroacetate, filmarate, citrate, tartrate, oxalate, succinate, mandelate, esulfonate and p-toluenesulfonate, or Z" may be absent if R81 or Rb is C1-C4-alkyl and carries the oxyanion of 6-methylhydroxy— pyridinyl; or a pharmaceutically acceptable salt f.

The compounds of a (I) or the pharmaceutically acceptable salts thereof as defined herein are ularly suitable for the treatment of pathophysio logical processes ble by the block- ade of an epithelial sodium channel, ularly for the treatment of the lungs and airways.

Accordingly the present invention further relates to compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use as a medicament.

The present invention further relates to compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof for use in the ent of a disease selected from among respiratory diseases or complaints and allergic diseases of the airways.

The t ion further relates to compounds of formula (I) as d herein or pharmaceutically acceptable salts thereof for use in 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), pediatric asthma, bronchiectasis, allergic alveolitis, ic or non- allergic rhinitis, chronic sinusitis, cystic fibrosis or scidosis, alpha-l-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung diseases, alveolitis, hyperreactive s, nasal polyps, pulmonary oedema, pneumonitis of different origins, and dry eyes.

The present invention further relates to a pharmaceutical composition comprising at least one compound of a (I) as defined herein or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.

The present invention further relates to medicament ations containing besides one or more compounds of formula (I) as defined herein or pharmaceutically acceptable salts thereof, as further active substance one or more compounds selected from among the categories of further ENaC inhibitors, betamimetics, olinergics, osteroids, PDE4-inhibitors, LTD4- antagonists, EGFR-inhibitors, dopamine agonists, Hl antihistamines, PAF-antagonists, MAP- kinase inhibitors, MPR4-Inhibitors, iNOS-Inhibitors, SYK—Inhibitors, corrections of the cystic s transmembrane regulator (CFTR) and CFTR potentiators or double or triple combinations thereof.

TERMS AND DEFINITIONS Terms not specifically defined herein should be given the meanings that would be given to them by one of skill in the art in light of the disclosure and the t. As used in the specification, however, unless specified to the contrary, the following terms have the meaning indicated and the following conventions are adhered to.

In the groups, radicals, or moieties defined below, the number of carbon atoms is often ed preceding the group, for e, C1_6-alkyl means an alkyl group or radical having 1 to 6 car- bon atoms.

In general in single groups like HO, HZN, OS, 02S, NC (cyano), HOOC, F3C or the like, the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself. For combined groups sing two or more subgroups, the terminal term in- dicates the radical attachment point, for example, the substituent "aryl-C1_3-alkyl" means an aryl group which is bound to a lkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.

If a compound of the present invention is depicted in form of a chemical name and as a formula, in case of any discrepancy the formula shall prevail.

Many ofthe following terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.

Unless specifically indicated, according to the invention a given chemical formula or name shall encompass tautomers and all stereo, optical and geometrical isomers (e.g. enantiomers, diastere- omers, E/Z isomers etc.) and racemates thereof as well as mixtures in ent proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically accepta- ble salts thereof and so lvates thereof such as for instance hydrates including so lvates of the free compounds or solvates of a salt of the compound.

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

The expressions "prevention", ylaxis", "prophylactic treatment" or ntive treatment" used herein should be understood synonymous and in the sense that the risk to develop a condi- tion mentioned hereinbefore is reduced, ally in a patient haVing elevated risk for said con- ditions or a corresponding anamnesis, e.g. elevated risk of developing metabolic disorder such as diabetes or obesity or another disorder mentioned herein. Thus the sion "prevention of a disease" as used herein means the ment and care of an individual at risk of developing the disease prior to the clinical onset of the e. The purpose of prevention is to combat the pment of the disease, condition or er, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or cations and to prevent or delay the development of related diseases, conditions or disorders. Success of said preventive treatment is reflected statistically by reduced incidence of said condition within a patient popula- tion at risk for this condition in comparison to an equivalent patient population without preven- tive treatment.

The sion ment" or "therapy" means therapeutic treatment of patients haVing already developed one or more of said conditions in manifest, acute or chronic form, including sympto- matic treatment in order to relieve symptoms of the c indication or causal ent in or- der to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity f Thus the expression "treatment of a disease" as used herein means the management and care of a patient haVing de- veloped the disease, condition or disorder. The purpose of ent is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to elimi- nate or control the disease, condition or disorder as well as to alleviate the ms or compli- cations associated with the disease, condition or disorder.

The term "pharmaceutically acceptable" is employed herein to refer to those compounds, materi- als, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals t excessive toxici- ty, irritation, allergic response, or other problem or complication, and commensurate with a rea- sonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to derivatives of the disclosed com- pounds wherein the parent compound is modified by making acid or base salts thereof. Examples ofpharmacologically acceptable salts include, but are not limited to, mineral or organic acid salts ofbasic residues such as amines; alkali or organic salts of acidic residues such as carboxylic ac- ids; and the like. For example, such salts include salts from a, L-arginine, betaine, benethamine, hine, m hydroxide, choline, deanol, diethanolamine (2,2’- iminobis(ethanol)), lamine, 2-(diethylamino)-ethanol, 2-aminoethanol, ethylenediamine, N—ethyl-glucamine, hydrabamine, lH-imidazole, lysine, magnesium hydroxide, 4-(2- hydroxyethyl)-morpholine, piperazine, potassium hydroxide, l-(2-hydroxyethyl)-pyrrolidine, sodium hydroxide, triethanolamine (2,2’,2"-nitrilotris(ethanol)), tromethamine, zinc ide, acetic acid, 2.2-dichloro-acetic acid, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, ben- zenesulfonic acid, benzoic acid, 2,5-dihydroxybenzoic acid, 4-acetamido-benzoic acid, (+)- camphoric acid, (+)-camphor-lO-sulfonic acid, carbonic acid, cinnamic acid, citric acid, cyclamic acid, decanoic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, sulfonic acid, 2-hydroxy-ethanesulfonic acid, nediaminetetraacetic acid, formic acid, filmaric acid, galactaric acid, gentisic acid, oheptonic acid, D-gluconic acid, D-glucuronic acid, - ic acid, glutaric acid, 2-oxo-glutaric acid, glycerophosphoric acid, glycine, glycolic acid, hexano- ic acid, hippuric acid, hydrobromic acid, hydrochloric acid, isobutyric acid, DL-lactic acid, lac- ic acid, lauric acid, lysine, maleic acid, (-)—L-malic acid, malonic acid, delic acid, methanesulfonic acid, galactaric acid, naphthalene-l,5-disulfonic acid, naphthalenesulfonic acid, l-hydroxynaphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L- utamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, c acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and un- decylenic acid. Further pharmaceutically acceptable salts can be formed with cations from metals like aluminium, m, m, magnesium, potassium, sodium, zinc and the like. (also see Pharmaceutical salts, Berge, S.M. et al., J. Pharm. Sci., (1977), 66, 1-19).

The pharmaceutically able salts of the present invention can be synthesized from the par- ent compound which contains a cationic group and optionally an onal basic or acidic moie- ty by conventional chemical methods. Generally, such salts can be prepared by reacting other salt forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mix- ture thereof. Moreover, rions can lly be exchanged by ion exchange chromatog- raphy.

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

The term "C1_n-alkyl", wherein n is an integer from 2 to 11, either alone or in combination with another radical denotes an acyclic, saturated, ed or linear hydrocarbon radical with l to n C atoms. For example the term C1_4-alkyl, as used herein and in ther terms C1_4-alkylamino and di-C1_4-alkylamino, embraces the radicals H3C-, H3C-CH2-, H3C-CH2-CH2-, (CH3)—, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, and H3C-C(CH3)2-.

In all cases of contradictions between structure and their naming, structure shall prevail.

PREFERRED MENTS One particular embodiment of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salt thereof, wherein at least one of R1 and R2 is ethyl. Preferred are compounds of formula (I) or pharmaceutically acceptable salt thereof, wherein both of R1 and R2 are ethyl.

Another particular embodiment of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salt thereof, wherein R1 or R2 is selected from 2-hydroxyethyl, (S)- ahydrofilranylmethyl, and 4-tetrahydropyranylmethyl.

Another particular embodiment of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salts thereof, wherein Z" is selected from chloride, formate, and trifluoroacetate.

Another ular embodiment of the present ion relates to compounds of formula (I) or pharmaceutically acceptable salt thereof, wherein in R81 or Rb in the definition of R3 is C1-C4- alkyl which carries 1 substituent selected from dimethylphosphinoylmethoxy and 4- (dimethylphosphinoyl)phenyl. r particular embodiment of the present invention relates to compounds of formula (I) or pharmaceutically acceptable salt thereof, ng at least one primary or secondary amino group, i.e compounds of formula (I) or pharmaceutically acceptable salt thereof, wherein at least one of R81 or Rb in the definition of R3 is C1-C4-alkyl, wherein C1-C4-alkyl carries at least one substituent selected from amino and C1-C4-alkylamino, or compounds of formula (I) or pharma- ceutically acceptable salt thereof, n R81 and Rb in the definition of R3 together with the ni- trogen they are attached to are piperidine carrying l or 2 substituents selected from NHZ.

Another particular embodiment of the present ion relates to compounds of formula (I) or pharmaceutically able salt thereof, wherein R81 or Rb in the definition of R3 is C1-C4-alkyl ng ylhydroxy-pyridinyl or theoxyanion of 6-methylhydroxy-pyridinyl.

Preferred are compounds of formula (I) or the pharmaceutically acceptable salts thereof, wherein R3 is selected from o NH2 0 4 4 4 \z \( ~Z 9 9 9 9 9 9 O \P/\ (N 2 OH (NH, (NH gm?—\Z ’ | Another particular embodiment of the present invention relates to nds of formula (I) or pharmaceutically acceptable salts thereof, selected from 0 8 01 N\ N 2 { U< F F /P:O /—ll— CI N N// NfH / N/Y \< N NH2 l O O F /< F 0’ WO 28927 Another particular embodiment of the t invention relates to compounds of formula (1) characterized by a topological polar surface area value (TPSA) of at least 150. The term "topo- logical polar surface area" as used herein refers to a value calculated as disclosed for the frag- ment based PSA in Ertl P. et al., J. Med. Chem, 43 (2000), 3714-3717. Such nds of for- mula (I) will usually have a TPSA value in the range of from 150 to 250. Such compounds are in particular compounds selected from WO 28927 0 8 Cl N\ N 2 V W Any of the substituents defined above may be combined with each other to form onal com- pounds not specifically exemplified above. Particularly red are compounds of formula (I) or the pharmaceutically acceptable salts thereof wherein at least 2, 3, or 4 ofthe substituents de- fined herein have one of the particular or preferred meaning as defined herein.

PREPARATION The following methods are suitable for preparing compounds of general formula (I).

The compounds according to the invention may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of c synthesis. Gen- eral methods for onal groups protection and deprotection steps are bed e.g. in: Greene, T.W. and Wuts, P.G.M. : Protective Groups in Organic Synthesis, third edition 1999; John Wiley and Sons, Inc. Preferably the compounds are obtained analogously to the methods of preparation explained more fillly hereinafter, in particular as described in the exper- imental section. 2015/069152 {firmII:{ 0 N R1/2-X I32 z N NW" O—R N —> fi< O N.

O O/Y \R 0/ 0 O (V) 0 (IV) 0 R2 ,RZ Z.

CI N [l Z — N O—R \ N m< ~ H2N | H L NL N/ MN 0 O O O 2 R R" (III) (II) O 2 O R2 ,R R3H I Z z 3 CI N OH 0' N R \ N A a N | /\(N\ H .. I. H .+ m< N/ 0 0 O 0 NH2 R" N NH2 R" (Na) (0 Compounds of general formula (I) can be prepared by standard amidation procedures from acids of general formula (Ila) and primary or secondary amines of general formula R3H applying e.g. the coupling reagent HATU. Obvious to the one skilled in the art, the counterion Z" of a perma- nently charged product, e.g. (I), may generally be different from the counterion Z" of the ently charged starting material, e. g. (Ila), depending on the conditions of synthesis and purifica- tion. Amines R3H can be prepared using methods of sis which are known to one skilled in the art and described in the literature of organic synthesis. The scope of the substituents of amines R3H may exceed what is claimed for compounds of general formula (I) hereinafter. The substituents in compounds R3H may e.g. carry protecting groups necessary or ageous in the amidation step. R3 can be modified in subsequent tic steps through e.g. deprotection and/or amidation reactions.

Compounds of l formula (Ila) can be prepared by standard ester cleavage procedures from esters of l formula (II). The residue R in compounds of general formulas (11) through (XI) may be selected from e.g. methyl, ethyl, or tert—butyl. Furthermore, within the reaction sequence, the residue R may be d by applying e.g. ester cleavage followed by esterif1cation proce- dures.

Compounds of general formula (II) can be prepared by standard amidation procedures from amines of general a (III) and 3-aminochloro-pyrazine-2—carboxylic acid applying e.g. the coupling reagent HATU.

Amines of general formula (111) can be prepared from compounds of general formula (IV) by removing the phthalimide protecting group ng standard deprotection procedures, e.g. heating with hydrazine hydrate in ethanol.

Benzimidazolium compounds of general formula (IV) can be prepared by tion of - idazoles of general formula (V) by e.g. heating with an appropriate alkylating agent RIX or RZX (e.g. an optionally substituted alkyl bromide) in a suitable t like e.g. THF. 0 IIRl/Z O R3H 521/2 * film} a {QM} 0 OH R3 (V3 ) 0% (VIII ) Ofiof 1 R1/2_X O R O R I Z' ' 3 I R H z R3 OH (IV) —> "WN /—< —> "N /_< 0/ 0 O R1/ 0/ R1/N O O (IVa) (VII) (I) (VI) Alternatively, compounds of general formula (I) can be ed by standard amidation proce- dures from 3-aminochloro-pyrazine-2—carboxylic acid and primary amines of general formula (VI) applying e. g. the coupling reagent HATU.

Amines of general formula (VI) can be prepared from compounds of l formula (VII) by removing the phthalimide protecting group ng standard deprotection procedures, e.g. heating with hydrazine hydrate in ethanol.

Compounds of general formula (VII) can be prepared by standard amidation procedures from acids of general formula (IVa) and primary or secondary amines of general formula R3H apply- ing e.g. the coupling reagent HATU. Compounds of general formula (IVa) can be prepared by standard ester cleavage procedures from esters of general formula (IV). Alternatively, com- pounds of general formula (VII) can be prepared by alkylation ofbenzimidazoles of general formula (VIII) by e.g. g with an appropriate alkylating agent RlX or RZX (e.g. an al- ly substituted alkyl halide) in a suitable solvent like e.g. THF.

Compounds of general formula (VIII) can be prepared by standard amidation procedures from acids of general formula (Va) and primary or secondary amines of general formula R3H applying e. g. the ng reagent HATU. Compounds of general a (Va) can be prepared by stand- ard ester cleavage ures from esters of general formula (V).

X X 0’ Of H2N-R1/2 HN + I + O ,N N —> I 1' 0WO\ \N+ 0 0" o R ,, 0 0%O\R (XII) (XI) 0 R1/2 IR l NWN HN N@ ‘— o o 0 \R H2N@ 0% 0%‘R (V) 0 (IX) 0 Benzimidazoles of general formula (V) can be prepared from phenylenediamines (IX) in a two step prodecure comprising (i) amidation with aloylglycine using e.g. the coupling reagent TBTU and (ii) ring closure under acid catalysis, e.g. in glacial acetic acid at elevated tempera- ture. Phenylenediamines of general formula (IX) can be prepared from the respective nitroan- ilines (X) by standard nitro reduction ions (e.g. catalytic hydrogenation using raney-nickel as a catalyst).

Nitroaninlines of general a (X) can be prepared from aryl halides of l formula (XI) by philic substitution with a primary amine HzN-R1 or HzN-RZ. The leaving group X in compounds (XI) may be F or C1. The substituents R1 or R2 present in the amine applied may ex- ceed the claims for R1 and R2 in compounds of general a (I). R1 and R2 may e. g. contain protective groups that can be removed at later stages by standard deprotection procedures.

Aryl halides of general formula (XI) can be prepared by alkylation of appropriate nitro-halo- phenols (XII) with bromo- or chloroacetic acid esters at ed temperature in the presence of a base like e.g. potassium carbonate in a solvent like e. g. ACN.

WO 28927 Compounds of formula (I), as defined hereinbefore, are salts containing an anion Z". These ani- ons Z" may be derived from synthesis or purification or changed from one c species to an- other suitable anionic species by methods known to those d in the art. Examples of such s are ion exchange using for example ion exchange resins or displacement of an acid rion from its salt using another, usually stronger, acid. For example, treatment of a com- pound of formula (I), as defined hereinbefore, where Z" is CFgCOO', with HCl in a suitable sol- vent, such as water, methanol or diethyl ether, may produce a compound of formula 1, as defined hereinbefore, where Z" is Cl".

Certain compounds of formula (I), as defined hereinbefore, may n groups that may be filr- ther ted into the salts thereof, for pharmaceutical use ularly into pharmaceutically acceptable salts with inorganic or organic acids and bases. Acids which may be used for this purpose include for example hydrochloric acid, romic acid, ric acid, methanesul- phonic acid, phosphoric acid, filmaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid. Corresponding processes are known to the d person.

Moreover, where one or more stereoisomers may exist, the compounds of general formula (I) or intermediates in the synthesis of compounds of general formula (I) may be obtained as mixtures and then resolved into their stereoisomers, e.g. enantiomers and/or diastereomers. Thus, for ex- ample, cis/trans mixtures may be resolved into their cis and trans isomers, and racemic com- pounds may be separated into their enantiomers.

Thus, for example, the cis/trans mixtures may be resolved by chromatography into the cis and trans isomers thereof. The compounds of general formula (I) or intermediates in the sis of compounds of general formula (I), which occur as racemates may be separated by s known per se (cf. Allinger N. L. and Eliel E. L. in "Topics in Stereochemistry", Vol. 6, Wiley Interscience, 1971) into their optical antipodes and compounds of general formula (I) or inter- mediates in the synthesis of compounds of general formula (I) with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differ- ences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.

The racemates are preferably resolved by column chromatography on chiral phases or by crystal- lization from an optically active solvent or by reacting with an optically active nce which forms salts or tives such as esters or amides with the racemic compound. Salts may be formed with enantiomerically pure acids for basic compounds and with enantiomerically pure bases for acidic compounds. Diastereomeric derivatives are formed with enantiomerically pure auxiliary compounds, e.g. acids, their activated derivatives, or alcohols. Separation of the dia- stereomeric mixture of salts or derivatives thus obtained may be achieved by taking advantage of their different physico-chemical properties, e.g. differences in solubility; the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Op- tically active acids in common use for such a purpose are e. g. the D- and L-forms of tartaric acid, dibenzoyltartaric acid, yltartaric acid, malic acid, mandelic acid, camphorsulfonic acid, glutamic acid, aspartic acid, or quinic acid. Optically active alcohols applicable as auxiliary resi- dues may be, for example, (+) or nthol and optically active acyl groups in amides may be, for example, (+)- or (-)-menthyloxycarbonyl.

The substances ing to the invention are isolated and purified in a manner known per se, for example by distilling off the solvent under reduced pressure and recrystallizing the residue ob- tained from a suitable solvent or subjecting it to one of the customary purification methods, such as, for example, column chromatography on a suitable support al.

The compounds according to the invention are advantageously able using the methods de- scribed in the examples that , which may also be combined for this purpose with methods known to the skilled person from his/her expert knowledge. Likewise, fiarther nds ac- cording to this invention, whose ation are not explicitly bed in the following exam- ples, can be ed analogously or similarly to the examples.

EXAMPLES Other features and advantages of the present invention will become apparent from the following more detailed examples which illustrate, by way of example, the principles of the ion.

Where no salt forms of compounds are specified, the compound may exist as a free base or a salt or a zwitterion, depending on the chemical structure, the synthesis conditions and the processes ofworkup and purification applied. The skilled person will appreciate that the compound is not limited to a certain salt form. Where salt forms of compounds are specified, the stoichiometry of the counterion is y omitted. In case of multiply charged counterions the d person will appreciate that the resulting salt form is uncharged, leading to the ponding iometry.

The skilled person will appreciate that the compound is not limited to the mono salt form and that it may exist as a , trisalt or other compound : counterion stoichiometries. Furthermore, the skilled person will appreciate that such compound may unexpectedly exist as a salt with a different counterion, depending on the synthesis conditions and the processes ofworkup and pu- ion d. Solely for the purpose of yield determination, an estimate of the nature of the counterion and of compound : counterion stoichiometry is made (as indicated by the formula given).

SYNTHESIS OF INTERMEDIATES The following intermediates can be prepared as described in the literature given in the table: Intermediate Structure Literature and ts 1.1 F US2015/18315 ("compound VII.2") 7 0M30 < o Lg 1.2 F US2009/163552 q0 f [/N o o o L< 1.3 Intermediate 1.3 can be prepared starting from 4- F ;:> o 0 7 + \—< 7< 3-nitrophenol analogously to the procedure O—N o "0 described for the synthesis of intermediate 12 (US2009/163552).

I.4 H2N\/\O/\P/,O Zeitschrift fuer Naturforschung, B: Chemical Sci- ences 50,7 (1995) 1086-90 1.5 WAN N\ Intermediate 1.5 can be prepared analogously to the H | OH / HO procedure described for the synthesis of 6-Methyl- 2-(methylaminomethyl)-pyridinol in J.Am.Chem.Soc. 71 (1949) 2968-71.

Intermediate 11.1 0 1.1 A mixture of the aryl halide ediate 1.3 (17.2 g; 63.6 mmol), (tetrahydropyranyl)- methylamine (11.5 g; 99.6 mmol) and potassium carbonate (13.2 g; 95.3 mmol) in ACN (100 ml) is stirred at 60°C for 2 h. The mixture is ated and the residue is taken up in EE and washed with brine. The organic layer is separated, dried (MgSO4) and evaporated.

C18H26N206 ESI Mass spectrum: m/z = 367 [M+H]+ The following intermediates are prepared accordingly from the respective aryl halide and the re- sprective amine as indicated. Depending on conditions applied, the syntheses may yield a free base, a TFA salt or other salt forms which can be applied equally to the syntheses of example compounds described below. g Aryl halide amine ap- g g Structure _ _ Synthes1s comment. applied p11ed H 0&0 ' OH 2 Ho/VN eq am1ne,no a' dd '- . 1 11.2 1.1 tional base; solvent: \N+ J (5| ""2 -THF e .am1ne; no a 1- 11.3 1.2 O;N+ X tional base, solvent. (ljl NH2 THF; reaction at r.t.

H 2 ' ‘ dd '- \/N 0&0 . 1 11.4 eq amine, no a 7 1.1 K tional base; solvent: O\N+ NHZ (Ijl THF; reaction at r.t. 1ntermediate 111.1 OOJNHAQOLQJV111.1 ediate 11.1 (23.1 g; 63.1 mmol) in THF (200 ml) is hydrogenated in a Parr apparatus (50 CC; 3 bar hydrogen; st: 2.00 g Raney-Nickel. The catalyst is filtered off and the solvent is evaporated.

C18H28N204 HPLC analytics: RT = 0.45 min (HPLC method A) The following ediates are prepared ingly from the respective starting material as indicated. Depending on conditions applied, the syntheses may yield a free base, a TFA salt or other salt forms which can be applied equally to the syntheses of example compounds described below.

. Starting ma- 0.) 0' g % Structure terial ap- Synthesis comment 4.. "ES LB plied N O 111 2 HO/\/ $0 - 11 2 J - N Reaction at r.t.; 111.3 0 U o 11.3 X cata yst:1 Pd/C 50/0 HZN 9 Reaction in methanolic ammonia 111.4 P— V111 I at r.t.

VUN OJ1 1115 j 11.4 catalyst: Pd/C 5% 1ntermediate 1V.1 0 N ;N/\f<©/O\/f Ar0 O 0 1v.1 Step 1: A mixture of the diamino intermediate 111.1 (21.2 g; 63.1 mmol), THF (250 ml), N—phthaloyl glycine (13.0 g; 63.1 mmol), TBTU (20.3 g; 63.14 mmol) and ylamine (9.63 ml; 69.4 mmol) is stirred at RT for 4h. The mixture is poured on ice-water (800 ml) and stirred until the ice is melted. The itate is filtered off with n, washed with water and dried at 65 °C.

Step 2: The so formed intermediate is taken up in acetic acid (30 ml) and dioxane (120 ml) and stirred at 95 CC over night. The mixture is evaporated, taken up in EE and extracted successively with Na2C03 solution and water. The organic layer is separated and evaporated. The residue is tritu- rated with TBDME, filtered off with suction and dried at 50 °C.

C28H31N306 ES1 Mass um: m/z = 506 [M+H]+ The following intermediates are prepared accordingly from the respective diamino compound as indicated. In cases where itation does not occur, the intermediates are extracted. Depend- ing on conditions applied, the syntheses may yield a free base, a TFA salt or other salt forms which can be applied equally to the syntheses of example compounds described below. . diamino a) 0 g % Structure compound Synthesis comment a ‘55 '6 applied 1V.2 / 6 111.2 Crystallization from EE O Step 2: on in AcOH at 100 0 KO c’C; crude product stirred in HCl IV.3 NWN {,0 111.3 (4 M in dioxane) at 100 0c for 4h, N 0 0H 0 evaporated, triturated with diethyl ether o r % 40 IV.4 N!WQ/CK/g 111.5 Crystallized from ACN o O Intermediate V.l O V.l A e of the acid intermediate 1V.3 (2.00 g; 4.24 mmol), the amine thiomorpholine-l-oxide (505 mg; 4.24 mmol), TBTU (1.36 g; 4.24 mmol), triethylamine (1.19 ml; 8.48 mmol) and DMF (20 ml) is stirred at r.t. for 2h. The mixture is poured on ice-water, then ted with EB. The organic layer is separated, dried (MgSO4), filtered and evaporated. The residue is purified by sil- ica gel chromatography (DCM/MeOH 0->10%).

C27H28N4O6S ESI Mass spectrum: m/z = 537 [M+H]+ The following nds are prepared accordingly applying the respective acid and amine as indicated. Depending on conditions applied, the procedures may yield a de salt, a TFA salt or bis-TFA salt, a zwitterion or other salt forms. ,3 B E’ o m 4.. a jg '71 a a 5 E g g % 3 E E E 25 E 5 (2‘ 8 E < E O // 0 N FYL 7 O CI Purificationb. RP- F O CI y | N/\WN F N\ OH v.2 / N+ 0/ <0 I x1.1 / HPLC(C18;water- N NH 2 V / N NH 2 ACN—TFA) 1ntermediate V1.1 V1.1 Step 1: A mixture of the benzimidazole intermediate IV.2 (5.00 g; 11.8 mmol), iodoethane (4.77 ml; 59.0 mmol) and ACN 50 ml) is heated to 120 oC wave irradiation; closed ) for Step 2: The mixture is evaporated and the residue is stirred at 65 CC for 1h in aq. HCl (4 mol/l; 50 ml; 200 mmol). The mixture is freeze-dried.

Workup: The residue is purified by RP-HPLC (C18; water/ACN/TFA).

N306 ESI Mass spectrum: m/z = 424 [M+H]+ HPLC analytics: RT = 0.37 min (HPLC method A) The following intermediates are prepared accordingly from the respective benzimidazole as indi- cated. Depending on ions applied, the syntheses may yield a free base, a TFA salt or other salt forms which can be applied equally to the syntheses of example compounds described be- low.

Benz- a.) o' g E Structure imidazole Synthesis comment E g applied 0 NWNK NL©70AC" Step 2. reactlon at 80.. oC, product.

V1.2 IV.1 filtered off upon cooling to r.t.; no Cli freeze-drying nor chromatography F 0’ V1.3 6 N/WN V.1 Step 2 omitted 0 {Ni} °( L< O // I, N O V1.4 dilm /—< IV.4 Step 2 omitted O O O < < ediate V11.1 VII.1 A mixture of benzonitri1e (2.29 g; 10.0 mmol), dimethy1phosphinoxide (800 mg; 10.3 mmol), triethy1amine (6.97 ml; 50 mmol) and ACN (50 m1) is degassed and kept under Argon atmosphere. Xantphos (400 mg; 0.691 mmo 1), tris(dibenzy1ideneacetone)dipa11adium (300 mg; 0.328 mmol) and cesium carbonate (4.0 g; 12.3 mmol) are added and the mixture is stirred under Argon at 80 CC for 2h. Water is added and the e is extracted with EB. The organic layer is separated, dried (MgSO4) and evaporated. The residue is purified by silica gel chromatpgraphy (DCM / MeOH ).

C9H10NOP HPLC analytics: RT = 0.59 min (HPLC method B) Intermediate V111.1 VIII.1 Step 1: The acid intermediate V1.1 (1.06 g; 1.97 mmol) is taken up in THF (10 m1).

Step 2: TBDMS chloride (594 mg; 3.94 mmol) and imidazole (268 mg; 3.94 mmol) are added and the mixture is stirred at r.t. for 3 days.

Step 3: CD1 (479 mg; 2.96 mmol) is added, and after 30 min stirring, the amine intermediate 111.4 (360 mg; 1.97 mmol) is added and the mixture is further stirred over night.

Step 4: TFA (3 m1) is added and the mixture is stirred at r.t for 1h.

Workup: The mixture is ated and the e is purified by RP-HPLC (C18; wa- ter/ACN/TFA).

C31H34N4O6P ESI Mass spectrum: m/z = 589 [M+H]+ HPLC analytics: RT = 0.39 min (HPLC method A) The ing compounds are prepared accordingly applying the respective acid and amine as indicated. Depending on conditions applied, the procedures may yield a chloride salt, a TFA salt or bis-TFA salt, a zwitterion or other salt forms. ed1ate Structure app11ed applied Ac1d Amine Synthesis comment N HO N O WFC m< — N o o N v111.2 o \ / v1.2 15 Steps 2 and 4 omitted Intermediate IX.1 /\\ , HO O O AUN 0%!" HO 0 "moo F F F H2N N p F F F K / \ IX.1 A mixture of intermediate VIII.1 (210 mg; 0.254 mmol), hydrazine hydrate (57.8 ul; 0.762 mmol) and ethanol (5 ml) is stirred at 70 CC (bath temperature) for 2h. bles are filtered off by suction, the filtrate is evaporated and purified by RP-HPLC (C18, water / ACN / TFA).

C23H32N4O4P X CzOng X C2H02F3 ESI Mass spectrum: m/z = 459 [M+H]+ HPLC analytics: RT = 0.26 min (HPLC method A) The following ediates are prepared accordingly from the respective protected amines as indicated. Depending on conditions d, the syntheses may yield a TFA salt or other salt forms which can be applied equally to fiarther synthesis steps.

Pro- B tected $43 Structure amine Synthesis comment E ap— plied F 0 :/_—\ >~—F _07HO F IX.2 o F V1112 >——F HO F o F o’ IX.3 AUN 0 K/SQO V1.3 F OH K r Reaction in N O 1X4 H N /< ACN/EtOH 1'1' 5- 2 W V14 eq. hydrazine hy- \/ u—NHZ drate Intermediate X.l \/N\©OH< Cr OH CIH A mixture of intermediate IX.4 (13.5 g; 32.2 mmol) and aq. HCl (4 mol/l; 100 ml; 400 mmol) is stirred at 80 0C for 2h, then cooled to r.t.. Insolubles are filtered off and discarded. The filtrate is freeze-dried after addition ofACN.

C14H20N303 x HCl x Cl ESI Mass spectrum: m/z = 278 [M]+ Intermediate XI.l H2N/\W+N o VN\@O/_< CI 0— CIH XI.1 A mixture of intermediate X.l (14.3 g; 40.8 mmol) and methanolic HCl (50 ml) is refluxed for min, then filtered hot and evaporated to dryness.

C15H22N303 x HCl x Cl ESI Mass spectrum: m/z = 292 [M]+ ediate XII.1 CI N\ N// O \E "N /—< CIT N/ N O OH NH2 ( XII.1 A mixture of intermediate V.2 (2.00 g; 3.57 mmol) and aq. HCl (1 mol/l; 7.13 ml; 7.13 mmol) is stirred at 50 °C over night. The e is cooled to 1 CC, the precipitate formed is filtered off with suction and dried at 50 oC.

C19H22C1N6O4 x Cl ESI Mass spectrum: m/z = 433 [M]+ Intermediate XIII.1 N NH2 CIH XIII.1 Step 1: To a mixture of -amino)-piperidine (1.00 g; 4.99 mmol), DIPEA (1.72 ml; 9.99 mmol) and DMF (3.0 ml) is added dropwise at r.t. 2-bromoethyl-ethylether (840 mg; 5.49 mmol). The mixture is stirred for further 2 h, then water is added and the mixture is extracted with diethyl ether. The organic layer is separated, dried and evaporated to dryness.

Step 2: The BOC-protected intermediate obtained from step 1 is suspended in aq. HCl (6.10 ml; 24.4 mmol). The mixture is stirred at r.t. for l h, then evaporated to dryness.

X HCl SYNTHESIS OF EXAMPLES Example 1.01 A mixture of 3-aminochloro-pyrazinecarboxylic acid (26.0 mg; 0.150 mmol), the amine ediate 1X3 (100 mg; 0.151 mmol), TBTU (53.0 mg; 0.165 mmol), triethylamine (63.2 ul; 0.450 mmol) and DMF (5.0 ml) is stirred at r.t. over night. Volatiles are evaporated and the resi- due is purified by RP-HPLC (C18; water-ACN—TFA).

C26H33C1N7OSS x CzOng ESI Mass spectrum: m/z = 590 [M+H]+ HPLC analytics: RT = 0.42 min (HPLC method D) The following example compounds are ed accordingly from the respective amine as indi- cated. Depending on conditions applied, the syntheses may ctedly yield other counterion stoichiometries or other salt forms.

Example No. Structure Amme applied M+ (m1n) RT HPLC method OH F 0’ \ \P:o CI N F O rfiw/’ N \ 1X1 614 39 A N o H N NH2 V a< O N// HO>—\N ’ CI N O __ 1-03 0 N NH2 ON\ / 5 E 2 < F O F 0 g F4’—< F4’—< F OH O F OH Example 2.01 2.01 Step 1: To a mixture of intermediate XII.1 (120 mg; 0.243 mmol), TBTU (156 mg; 0.486 mmol), triethylamine (101 ul; 0.729 mmol) and DMF (3.0 ml) is added the amine tert—butyl N—(3- aminopropyl)carbamate (42.3 mg; 0.243 mmol). The mixture is d at r.t. for 3 h, then evapo- rated.

Step 2: The BOC-protected intermediate is purified by C (C18; water-ACN—TFA), taken up in aq. HC1 (37%; 1.0 ml) and evaporated to dryness.

Step 3: The crude product is purified by RP-HPLC (C18; water-ACN—TFA).

C22H30C1N803 x CzOng x CzHOng ESI Mass um: m/z = 489 [M+H]+ HPLC analytics: RT = 3.02 min (HPLC method C) The following example compounds are prepared accordingly from the respective amine as indi- cated. Depending on conditions applied, the syntheses may unexpectedly yield other counterion stoichiometries or other salt forms.

Q. q_9 ‘D "‘ a.) D O E 0 Structure a3 63 E :32 E g E 53 <94"5 a8 F LU (08 mg F OH H FF 0 Hf" N o N+ /_< \ 0% a l\ 2.02 NH2 <\Oo o o N~\< $ 2 o 2.03 HNZg: omltted :23 15 05 C O 3 5 3 Step WO 28927 2 9‘5 "E Q. a?) 80 8 0 + a3? Structure 8 a 63 E 2 v 53 :32 m <94 a8 F mg HJ N on 8 Ed 2.04 ‘1' o m N :2 E M e 2.05 l" o M m N \o 0 NH2 v 206 / <3 m o 8 . —N g m m 3H MNOW" 3 2.07 ( )—\ E E 7 a? g o—\ o O ) H2N Jo >< "g 0— LL (a) Step 2 omitted; purification by RP-HPLC (C18; water-ACN-formic acid) ANALYTICAL METHODS AND PREPARATIVE CHROMATOGRAPHY As a rule, 1H-NMR and mass spectra have been obtained for the compounds prepared. Mass peaks given (e.g. (M)+, (M+H)+, O)-) refer to monoisotopic molecular weight.

Preparative HPLC: Stationary phase (unless stated otherwise): XBridge C18; 10 um or SunFire C18; 10 um (both from waters, WWW.Waters.com) Analytical HPLC/MS Methods The HPLC retention times given are measured under the following parameters.

HPLC method A : SunFire C18, 2.1 x 30 mm, 2.5 um (Waters) Gradient % Sol % Sol [ACN] Flow [ml/min] Temp [0C] time [min] [H20,0.1%TFA] 0.00 99 1 1.5 60 0.02 99 1 1.5 60 1.00 0 100 1.5 60 1.10 0 100 1.5 60 HPLC method B Column: SunFire, 3 x 30 mm, 2.5 um (Waters) Gradient % Sol % Sol [ACN] Flow [ml/min] Temp [0C] time [min] .1%TFA] 0.00 97 3 2.2 60 0.20 97 3 2.2 60 1.20 0 100 2.2 60 1.25 0 100 3 60 1.40 0 100 3 60 HPLC method C Column: Atlantis dC18 5um 4,6 X 50 mm, Temp 35°C Mobile phase: A = H20 90% + 10% CH3CN + CF3COOH 0,05% B = CH3CN 90% + 10% H2O Time in min %A %B flow rate in ml/min 0.00 100 0 1.3 0.70 100 0 1.3 4.5 0 100 1.3 .80 0 100 1.3 6.00 100 0 1.3 HPLC method D Column: XBridge BEH C18, 2.1 x 30 mm, 1.7 um (Waters) Gradient % Sol % Sol [ACN] Flow [ml/min] Temp [0C] time [min] [H20,0. 1%TFA] 0.00 99 l 1.6 60 0.02 99 l 1.6 60 1.00 0 100 1.6 60 1.10 0 100 1.6 60 The ing abbreviations are used above and hereinafter: ACN Acetonitrile Aq. Aqueous BOC tert-Butoxycarbonyl Cbz enzyloxy CH Cyclohexane DCM Dichloromethane DIPEA Diisopropyl-ethylamine DMAP 4-Dimethylaminopyridine DMF N,N—Dimethylformamide DPPF 1,l'-Bis(diphenylphosphino)ferrocene EDC l(3-dimethylaminopropyl)carbodiimide hydrochloride EE Ethyl acetate Eq. Molar equivalent ESI Electrospray ionization h Hour HATU O-(7-Azabenzotriazo l- l -yl)-N,N,N ’ ,N ’ -tetramethyluronium hexafluorophosphate HCl Hydrochloric acid KOH Potassium hydroxide 1 Litre LiHMDS Lithium bis(trimethylsilyl)amide M mol/1 Min Minutes Mp melting point NaOH Sodium ide n.d. not determined NMP N—Methylpyrrolidone Pd/C palladium on charcoal r.t. ambient temperature (about 20°C) RT retention time TBME Methyl tert-butyl ether TBDMS Tert-butyl-dimethylsilyl- TBTU 2-( l H-Benzotriazol— l -yl)- l , l ,3 ,3 -tetramethyluronium-tetrafluoroborate TEA Triethylamine TFA Trifluoroacetic acid THF Tetrahydrofilrane TLC Thin Layer Chromatography TMS Trimethylsilyl Xantphos 4 5 -Bis(diphenylphosphino)-9 , , 9-dimethylxanthene PHARMACOLOGICAL TEST METHOD The IC50 values of the e compounds given above were determined in the Ussing Chamber assay.

Ussing Chamber: Mouse kidney M-l cells were cultivated in DMEM containing 5% FCS and SuM dexamethasone for 10 to 12 days on polyester ell filters. Filters were inserted into a coated well-plate which fit into the ussing chamber system. Prior to measurement the me- dium ofM-l cells was replaced with Caco-2 transport buffer (Invitrogen, Germany). During measurements, the Ussing chamber temperature was kept at 37°C. Short circuit currents (I_sc) were measured in the voltage-clamp mode with the software package Lab View for data acquisi- tion and analysis. The transepithelial electrical resistance (TEER) was determined by the a- tion ofvoltage steps of ::5mV every 5 sec. Compounds were stered at a final concentra- tion of 3uM or at increasing concentrations (110uM) to the apical on. At the end of each experiment the amiloride sensitive I_SC was measured by adding 3uM amiloride to the apical compartment. Results are expressed as tion in percent of the amiloride effect or as IC50.

With the example compounds given above, the ing IC50 values were determined in the Ussing Chamber assay: Example 1.01 1.02 1.03 2.01 2.02 2.03 2.04 2.05 2.06 2.07 ICso [nM] 10 10 8 1 2 1 3 3 1 3 Permeability in CALU-3 cells: Permeability measurements across zed, confluent CALU-3 cell monolayers grown on per- meable filter ts are used to provide information on the potential of a compound to pass the lung epithelium. Apparent permeability coefficients (Papp) of the compounds across the CALU- 3 cell monolayers are measured (pH 7.4, 37°C) in apical-to-basal (AB) and to-apical (BA) transport direction. AB permeability (Papp, AB) represents drug absorption from the lung lumen into the blood and BA permeability (Papp, BA) drug transport from the blood into the lung lu- men mainly via passive permeability since Calu-3 cells as well as lung epithelial cells do not ex- press efflux orters like P-gp, while uptake transporters may be expressed.

CALU-3 cells (1-2 X 105 cells/l cm2 area) are seeded on filter s (Costar transwell polycar- bonate filters, 0.4 um pore size) and cultured (for 10 — 12 days DMEM) until tight monolayers are formed. Compounds of interest are ved in appropriate solvent (DMSO, 10 mM stock solution). Stock solutions are diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4 x 7H20, 0.41 mM NaH2PO4xH20, 15 mM HEPES, 20 mM glucose, 0.25 % BSA, pH 7.4) to prepare the transport solutions (10 uM compound, f1nalDMSO <= 0.5 %). The ort solution (TL) is applied to the apical or basolateral donor side for measuring A-B or B-A permeability (3 filter replicates), respectively. The receiver side contains the same buffer as the donor side. After 30 min of ac- commodation, samples are collected at the start t0 = 0 min and at the end of the ment tn = 90 min from the donor and at 0, 30, 60, and 90 min also from the receiver chamber. Volume re- moved is replenished by HTP-4 buffer. The compound concentration in the samples is measured by HPLC-MS/MS or scintillation counting. The permeability coefficient (Papp) and efflux ratio are calculated according to: Papp [cm/s] = (concentration receiver [nM] * volume receiver [mL]/time interval [sec])*(l/filter area)*(l/donor concentration [nM]).

With example compounds given above, the following permeability values were ined in the CALU-3 cells assay: Example 1.01 1.02 1.03 2.01 2.04 2.05 2.06 PapépaAB 0.8 0.6 0.4 0.2 <07 0.4 <1 [10' cm/s] PapépaBA 0.3 0.3 0.1 0.5 0.4 0.1 0.2 [10' cm/s] INDICATIONS As has been found, the compounds of formula (I) are characterized by their wide range of appli- cations in the therapeutic field. Particular n should be made of those applications for which the compounds according to the invention of formula (I) are ably suited on account oftheir pharmaceutical efficacy as ENaC inhibitors. Examples include respiratory diseases or ints, allergic diseases of the airways, or dry eyes.

Particular mention should be made of the prevention and treatment of diseases of the airways and ofthe lung which are accompanied by increased mucus production, inflammation and/or obstruc- tive diseases of the airways. Examples include acute, allergic or c bronchitis, chronic ob- structive bronchitis (COPD), coughing, pulmonary emphysema, allergic or non-allergic is or sinusitis, chronic is or sinusitis, asthma, alveolitis, Farmer's disease, hyperreactive air- ways, infectious bronchitis or pneumonitis, paediatric asthma, bronchiectases, pulmonary flbro- sis, ARDS (acute adult respiratory distress syndrome), bronchial oedema, ary oedema, bronchitis, pneumonia or titial nia triggered by various causes, such as aspiration, inhalation of toxic gases, or bronchitis, pneumonia or interstitial pneumonia as a result of heart failure, irradiation, chemotherapy, cystic fibrosis or mucoviscidosis, or alphal-antitrypsin defi- ciency.

Particularly preferably the present ion relates to the use of nds of formula (I) for preparing a pharmaceutical composition for the treatment of inflammatory or obstructive diseas- es of the upper and lower respiratory tract including the lungs, such as for example allergic rhini- tis, chronic rhinitis, bronchiectasis, cystic fibrosis, COPD, chronic bronchitis, chronic sinusitis and asthma.

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

The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of admin- ion and severity of e. In any case the combination will be administered at dosages and in a manner which allows a pharmaceutically effective amount to be delivered based upon pa- tient’s unique condition.

COMBINATIONS The compounds of formula (I) may be used on their own or in conjunction with other active sub- stances of formula (1) according to the invention. If desired the nds of a (I) may also be used in combination with other pharmaco logically active nces.

Therefore the invention fiarther relates to medicament combinations which preferably n, besides one or more compounds of a (I) or a salt thereof, as fithher active substances, one or more compounds selected from among the categories of further ENaC inhibitors, betamimet- ics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, do- pamine agonists, Hl-antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4-Inhibitors, nhibitors, SYK—Inhibitors, corrections of the cystic fibrosis transmembrane regulator (CFTR) and CFTR potentiators, or double or triple combinations thereof.

FORMULATIONS Suitable forms for administration are for example inhalable powders or aerosols. The content of the pharmaceutically effective compound(s) in each case should be in the range from 0.2 to 50 wt%, preferably 0.5 to 25 wt% of the total composition, i.e. in amounts which are sufficient to achieve the dosage range specif1ed after.

Administered by inhalation the active nce combination may be given as a powder, as an aqueous or aqueous-ethanolic solution or using a propellant gas formulation.

Preferably, therefore, pharmaceutical formulations are characterised in that they contain one or more compounds of formula (1) according to the preferred embodiments above.

It is also preferred if the compounds of formula (I) are administered by inhalation, particularly preferably if they are administered once or twice a day. For this purpose, the compounds of for- mula (I) have to be made available in forms suitable for inhalation. Inhalable preparations in- clude ble powders, propellant-containing metered-dose aerosols or propellant-free inhala- ble solutions, which are optionally present in admixture with conventional physiologically ac- ceptable excipients.

Within the scope of the present invention, the term propellant-free inhalable solutions also in- clude concentrates or sterile ready-to-use inhalable solutions. The preparations which may be used according to the invention are described in more detail in the next part of the specification.

Inhalable powders If the active substances of formula (I) are present in admixture with physiologically acceptable ents, the following physiologically acceptable excipients may be used to prepare the inhal- able powders according to the invention: monosaccharides (e. g. e or arabinose), disaccha- rides (e.g. lactose, saccharose, maltose), oligo- and polysaccharides (e.g. dextran), cohols (e.g. ol, mannitol, xylitol), salts (e.g. sodium chloride, calcium ate) or es of these excipients with one another. Preferably, mono- or disaccharides are used, while the use of lactose or e is preferred, particularly, but not exclusively, in the form of their hydrates.

For the es of the invention, lactose is the particularly preferred excipient, while lactose monohydrate is most particularly preferred. Methods of preparing the inhalable powders accord- ing to the invention by grinding and micronising and by finally mixing the components together are known from the prior art.

Propellant-containing inhalable aerosols The lant-containing inhalable aerosols which may be used according to the invention may n a compound of formula (1) dissolved in the propellant gas or in dispersed form. The propellant gases which may be used to prepare the inhalation aerosols according to the invention are known from the prior art. Suitable lant gases are selected from among hydrocarbons such as n-propane, n-butane or isobutane and halohydrocarbons such as preferably fluorinated derivatives of methane, ethane, propane, butane, cyclopropane or cyclobutane. The propellant gases mentioned above may be used on their own or in mixtures f Particularly preferred propellant gases are fluorinated alkane derivatives ed from TGl34a ,2-tetrafluoroethane), TG227 (l,l,l,2,3,3,3-heptafluoropropane) and mixtures thereof The propellant-driven inhalation aerosols used within the scope of the use according to the invention may also contain other ingredients such as co-solvents, stabilisers, surfactants, antioxidants, lub- ricants and pH adjusters. All these ingredients are known in the art.

Propellant-free inhalable solutions The compounds of formula (1) according to the invention are preferably used to prepare propel- lant-free inhalable solutions and inhalable suspensions. Solvents used for this purpose e aqueous or alcoholic, preferably ethanolic solutions. The solvent may be water on its own or a mixture of water and ethanol. The solutions or suspensions are adjusted to a pH of 3 to 7 using suitable acids. The pH may be adjusted using acids selected from inorganic or c acids.

Examples of particularly suitable nic acids include hydrochloric acid, romic acid, nitric acid, sulphuric acid and/or phosphoric acid. es of particularly suitable organic ac- ids include ascorbic acid, citric acid, malic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, acetic acid, formic acid and/or propionic acid etc. Preferred inorganic acids are hydrochlo- ric and sulphuric acids. It is also possible to use the acids which have already formed an acid addition salt with one of the active substances. Of the organic acids, ascorbic acid, fumaric acid and citric acid are preferred. If desired, mixtures of the above acids may also be used, particular- ly in the case of acids which have other properties in addition to their acidifying qualities, e.g. as ings, antioxidants or complexing , such as citric acid or ascorbic acid, for example.

According to the invention, it is particularly preferred to use hydrochloric acid to adjust the pH.

Co-solvents and/or other excipients may be added to the propellant-free inhalable solutions used for the purpose according to the invention. Preferred co-solvents are those which contain hy- droxyl groups or other polar , e.g. ls - ularly isopropyl l, glycols - par- ticularly propyleneglycol, polyethyleneglycol, polypropyleneglycol, ether, glycerol, polyoxyethylene alcohols and polyoxyethylene fatty acid esters. The terms excipients and additives in this context denote any pharmaco logically acceptable substance which is not an active sub- stance but which can be formulated with the active substance or substances in the pharmaco logi- cally suitable solvent in order to improve the ative properties of the active substance for- mulation. ably, these substances have no pharmacological effect or, in connection with the desired therapy, no appreciable or at least no undesirable pharmacological effect. The excipients and additives include, for example, surfactants such as soya in, oleic acid, sorbitan esters, such as polysorbates, polyvinylpyrrolidone, other stabilisers, complexing agents, antioxidants and/or preservatives which guarantee or prolong the shelf life of the finished pharmaceutical formulation, flavourings, vitamins and/or other ves known in the art. The additives also include pharmacologically acceptable salts such as sodium chloride as isotonic agents. The pre- ferred excipients include antioxidants such as ascorbic acid, for example, provided that it has not already been used to adjust the pH, n A, vitamin E, tocopherols and similar vitamins or provitamins occurring in the human body. Preservatives may be used to t the formulation from contamination with pathogens. Suitable preservatives are those which are known in the art, particularly cetyl pyridinium chloride, benzalkonium chloride or benzoic acid or benzoates such as sodium benzoate in the concentration known from the prior art.

For the treatment forms described above, ready-to-use packs of a medicament for the treatment ofrespiratory complaints are provided, containing an ed description ing for example the words respiratory disease, COPD or , a compound according to the invention and one or more combination partners selected from those described above.

WHAT

Claims (1)

WE CLAIM l. A compound of formula (I), O R2 I 3 CI N\ N R (I) N _ l H A} /—< Z O 0 N NH2 RV wherein R1 and R2 are independently selected from ethyl, 2-hydroxyethyl, 2-tetrahydrofi1ranylmethyl and 4-tetrahydropyranylmethyl; R3 is selected from a moiety NRaRb, wherein R81 and Rb are ndently selected from hydrogen, C1-C4-alkyl and l-(2-ethoxyethyl)piperidinyl, wherein C1-C4- alkyl may carry 1 or 2 substituents selected from hydroxyl, amino, C1-C4- alkylamino, di-C1-C4-alkylamino, (dimethylphosphinoyl)methoxy, 4- 15 (dimethylphosphinoyl)phenyl, 6-methylhydroxy-pyridinyl and the oxyanion of 6-methylhydroxy-pyridin-2—yl, provided that at least one of R81 and Rb is different from en, or wherein R81 and Rb together with the nitrogen they are attached to form a heterocyclic 20 moiety selected from piperidine and hiomorpholinyl, wherein the heterocyclic moiety may carry 1 or 2 substituents selected from NHZ; and Z" is selected from chloride, bromide, iodide, hydroxide, hydrogensulfate, sulfate, nitrate, phosphate, e, acetate, trifluoroacetate, fumarate, e, tartrate, 25 oxalate, succinate, mandelate, methanesulfonate and p-toluenesulfonate, or Z" may be absent if R81 or Rb is C1-C4-alkyl and carries the oxyanion of 6-methyl hydroxy-pyridinyl; 30 or a pharmaceutically acceptable salt thereof. 2. A compound according to claim 1 or a pharmaceutically acceptable salt f, wherein at least one of R1 and R2 is ethyl. 3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein both of R1 and R2 are ethyl. 4. A compound according to any one of claims 1 to 3 or a pharmaceutically 5 acceptable salt thereof, wherein Z is selected from de, formate, and trifluoroacetate. 5. A compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein R3 is selected from 6. A compound ing to claim 1, selected from the group consisting of Cl N N N NH 2 O O –O O F F P O NH 2 Cl HN N N O + N O (2.03), O O H O Cl N N N H + N F N NH O O O 2 F F O (2.04), N NH NH 2 N F F HO F (2.05), (14176724_1):KZA Cl HN N N O + N O NH 2 (2.06), Cl N N N O– N NH 2 O O N O (1.03), Cl N N O –O O N+ F F N NH 2 O N O (1.1), NH 2 Cl HN N N O + N O NH 2 O F F , (14176724_1):KZA Cl HN N N O + N O NH 2 , and Cl HN N N O + N O NH 2 O F F F (2.02), or a pharmaceutical acceptable salt thereof. 7. A compound according to any one of claims 1 to 6, which is Cl N N N NH 2 O O –O O F F P O 5 (1.02), NH 2 Cl HN N N O + N O (2.03), O O H O Cl N N N H + N F N NH O O O 2 F F O (2.04), N NH NH 2 N F F HO F Cl HN N N O + N O NH 2 (2.06), (14176724_1):KZA Cl N N N O– N NH 2 O O N O , Cl N N O –O O N+ F F N NH 2 O N O (1.1), NH 2 Cl HN N N O + N O NH 2 O F F (2.01), Cl HN N N O + N O (2.07), and (14176724_1):KZA Cl HN N N O + N O NH 2 O F F F (2.02). 8. A method of synthesising a pharmaceutically acceptable salt of the compounds according to claim 7 wherein the parent compound, which contains a cationic group, is reacted by conventional chemical methods. 5 9. A method of synthesising a pharmaceutically able salt of the nds according to claim 8 wherein the parent compound, which ns a cationic group, is reacted with a ient amount of the appropriate base or acid in water or an organic diluent. 10. A pharmaceutically acceptable salt of the parent compound of compound (1.02) 10 according to claim 7. 11. A pharmaceutically acceptable salt of the parent compound of compound (2.03) according to claim 7. 12. A pharmaceutically acceptable salt of the parent compound of compound (2.04) according to claim 7. 15 13. A pharmaceutically acceptable salt of the parent compound of compound (2.05) according to claim 7. 14. A pharmaceutically acceptable salt of the parent compound of compound (2.06) according to claim 7. 15. A ceutically acceptable salt of the parent compound of compound (1.03) 20 according to claim 7. (14176724_1):KZA 16. A pharmaceutically acceptable salt of the parent nd of compound (1.1) according to claim 7. 17. A pharmaceutically acceptable salt of the parent compound of compound (2.01) according to claim 7. 5 18. A pharmaceutically acceptable salt of the parent compound of compound (2.07) according to claim 7. 19. A pharmaceutically acceptable salt of the parent compound of compound (2.02) according to claim 7. 20. Use of a compound according to any one of claims 1 to 19 or a pharmaceutically 10 acceptable salt thereof for the manufacture of a medicament. 21. Use of a nd according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof for in the manufacture of a medicament for the treatment of a disease selected from among respiratory diseases or complaints and allergic diseases of the airways. 15 22. Use of a nd 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 among chronic bronchitis, acute bronchitis, bronchitis caused by bacterial or viral infection or fungi or helminths, allergic itis, toxic itis, chronic obstructive bronchitis (COPD), asthma, paediatric 20 , bronchiectasis, allergic alveolitis, ic or non-allergic rhinitis, chronic sinusitis, idiopathic pulmonary fibrosis, cystic fibrosis or mucoviscidosis, alpha-

1.-antitrypsin deficiency, cough, pulmonary emphysema, interstitial lung es, alveolitis, hyperreactive airways, nasal polyps, pulmonary oedema, pneumonitis of different s, and dry eyes. 25 23. A pharmaceutical composition comprising at least one nd according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. 24. ment combination which contains, besides one or more compounds according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof, as further active substances, one or more compounds selected from among the categories of further ENaC inhibitors, betamimetics, anticholinergics, 5 corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, H1-antihistamines, PAF-antagonists, MAP-kinase inhibitors, MPR4- Inhibitors, iNOS-Inhibitors, SYK-Inhibitors, correctors of the cystic is transmembrane regulator (CFTR) and CFTR potentiators or double or triple combinations f. 10 Boehringer Ingelheim International GmbH By the eys for the Applicant SPRUSON & FERGUSON Per: