US 2011 0046148A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0046148 A1 Himmelsbach et al. (43) Pub. Date: Feb. 24, 2011
(54) SPIROCYCLIC HETEROCYCLES Publication Classification MEDCAMENTS CONTAINING SAD (51) Int. Cl. COMPOUNDS, USE THEREOF AND METHOD A 6LX 3L/2199 (2006.01) FOR THEIR PRODUCTION C07D 403/2 (2006.01) A 6LX 3/57 (2006.01) (75) Inventors: Frank Himmelsbach, A6IP37/08 (2006.01) Mittelbiberach (DE); Birgit Jung, A6IP 29/00 (2006.01) Laupheim (DE); Ralf Lotz, (52) U.S. Cl...... 514/252.15:544/231:544/230; Schemmerhofen (DE) 51.4/266.23 Correspondence Address: (57) ABSTRACT MICHAEL P. MORRIS The present invention relates to spirocyclic heterocycles of BOEHRINGERINGELHEMI USA CORPORA general formula (I) TION 900 RIDGEBURY ROAD, P. O. BOX 368 RIDGEFIELD, CT 06877-0368 (US) (I) R NN1 H (73) Assignee: BOEHRINGERINGELHEM INTERNATIONAL GMBH, O Ingelheim am Rhein (DE) N1 N O l 2 Rb, (21) Appl. No.: 12/865,431 N Rd -NNyN1 (22) PCT Filed: Feb. 5, 2009 (86). PCT No.: PCT/EP2009/000805 the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts S371 (c)(1), thereof with inorganic or organic acids, which have valuable (2), (4) Date: Nov. 4, 2010 pharmacological properties, particularly an inhibitory effect on signal transduction mediated by tyrosine kinases, the use (30) Foreign Application Priority Data thereof for the treatment of diseases, particularly tumoral diseases as well as benign prostatic hyperplasia (BPH), dis Feb. 7, 2008 (EP) ...... O81O13534 eases of the lungs and airways, and the preparation thereof. US 2011/0046148 A1 Feb. 24, 2011
SPROCYCLIC HETEROCYCLES eroaryl-C-alkyl and heteroaryl-C-alkyl-O. MEDCAMENTS CONTAINING SAD while the above-mentioned phenyl groups are mono COMPOUNDS, USE THEREOF AND METHOD or disubstituted by groups R. FOR THEIR PRODUCTION 0011 and I0012 R denotes hydrogen, 0013 or 0001. The present invention relates to spirocyclic hetero 0014 a group selected from among cycles of general formula (0.015 F, Cl, Brand CH 10016) R' denotes hydrogen, or a group, optionally substi (I) tuted, selected from among R NN1 H 0017 C-alkyl, C-cycloalkyl- and C-cycloalkyl C-3-alkyl, O 0018. R. denotes hydrogen, or an optionally substituted N1 N O group selected from among C-alkyl, C-cycloalkyl, l 2 Rb, Co-cycloalkyl-C-alkyl, C-alkyl-CO, C-cy N Rd X cloalkyl-CO, C-cycloalkyl-C-alkyl-CO, C-alkyl N SO, C-cycloalkyl-SO, C-cycloalkyl-C-alkyl 1NA SO, phenyl-CO— and phenyl-SO, 0019 R denotes hydrogen or the tautomers, the stereoisomers, the mixtures thereof and the 0020 a group selected from among salts thereof, particularly the physiologically acceptable salts 0021 F, Cl, Br, I, OH, C-alkyl, C-alkyl-O, C thereof with inorganic or organic acids, which have valuable alkyl-O substituted by 1 to 3 fluorine atoms, C-7-cy pharmacological properties, particularly an inhibitory effect cloalkyl-O, C-7-cycloalkyl-C-alkyl-O, tetrahydrofu on signal transduction mediated by tyrosine kinases, the use ran-3-yl-O, tetrahydropyran-3-yl-O, tetrahydro-pyran thereof for the treatment of diseases, particularly tumoral 4-yl-O. tetrahydrofuranyl-C-alkyl-O- and diseases as well as benign prostatic hyperplasia (BPH), dis tetrahydropyranyl-Ca-alkyl-O, eases of the lungs and airways and the preparation thereof. O 0002 The problem of the present invention is to prepare I0022) R' C-alkyl, while the linking of the groups new compounds which on the basis of their pharmaceutical R* may take place via each C atom of the alkyl group, effectiveness as tyrosine-kinase inhibitors, may be used O therapeutically, i.e. for the treatment of pathophysiological 0023 R C-alkyl-O, wherein the group R is sepa processes caused by hyperfunction of tyrosine kinases. rated from the oxygen atom by at least 2 C atoms, O DETAILED DESCRIPTION OF THE INVENTION 0024 a group selected from among pyrrolidin-2-yl-C- 0003. It has surprisingly been found that the problem men 4-alkyl-O, pyrrolidin-3-yl-C-alkyl-O, piperidin-2-yl tioned above is solved by compounds of formula (I), wherein C-alkyl-O, piperidin-3-yl-C-alkyl-O, piperidin-4- the groups R* to R and A have the meanings given hereinaf yl-Ca-alkyl-O. azepan-2-yl-C-alkyl-O. azepan-3- ter. yl-Ca-alkyl-O. azepan-4-yl-Ca-alkyl-O, morpholin 0004. The present invention therefore relates to com 2-yl-C-alkyl-O, morpholin-3-yl-C-alkyl-O. 1-(C- pounds of general formula (I), 3-alkyl)-pyrrolidin-2-yl-Ca-alkyl-O. 1-(C-alkyl)- pyrrolidin-3-yl-C-alkyl-O. 1-(C-alkyl)-piperidin (I) 2-yl-C-alkyl-O. 1-(C-alkyl)-piperidin-3-yl-Ca R NN1 H alkyl-O. 1-(C-alkyl)-piperidin-4-yl-Ca-alkyl-O, 1-(C-alkyl)-azepan-2-yl-C-alkyl-O. 1-(Cis O alkyl)-azepan-3-yl-C-alkyl-O, 1-(C-alkyl)- N1 N O azepan-4-yl-C-alkyl-O, 4-(C-alkyl)-morpholin-2- l 2 -R yl-Ca-alkyl-O- and 4-(C-alkyl)-morpholin-3-yl N Rd N C-alkyl-O. RC -NNy 0025 wherein I0026) R' denotes a group, which may be identical or different, selected from among OH, C-alkyl-O, C wherein cycloalkyl-O, NH, C-alkyl-NH. (C-alkyl).N. 0005 R* denotes a phenyl or 1-phenylethyl group, (2-methoxyethyl)-N, pyrrolidin-1-yl, piperidin-1-yl. wherein the phenyl nucleus is substituted in each case by aZepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl, 2-oxa the groups R' to R, wherein 5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3. 0006) R' and R which may be identical or different, 2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piper denote hydrogen or a group selected from among azin-1-yl 4-(C-alkyl)-piperazin-1-yl, 1,4-diazepan 0007 F, Cl, Br, I, OCHF, OCHF OCF, CHF, 1-yl 4-(C-alkyl)-1,4-diazepan-1-yl, HCO. NH, CHF, CF, CN, NO, NH, and OH, C-alkyl-CO—NH, C-alkyl-O-C-alkyl-CO— 0008 or NH, C-alkyl-O CO. NH, HNCONH, C-alkyl 0009 a group selected from among NH CO. NH, (C-alkyl)-N CONN, pyrrolidin-1- 0010 C-alkyl, C-alkyl-O, C-alkenyl, C yl-CO. NH, piperidin-1-yl-CO. NH, piperazin-1-yl alkynyl, phenyl, phenyl-O, phenyl-C-alkyl- and CO. NH, 4-(C-alkyl)-piperazin-1-yl-CO. NH, phenyl-C-alkyl-O, heteroaryl, heteroaryl-O, het morpholin-4-yl-CO. NH and C-alkyl-SO. NH, US 2011/0046148 A1 Feb. 24, 2011
while the pyrrolidinyl, piperidinyl, azepan-1-yl, piperazinyl, Sclerodermy, sarcoidosis and Boeck's disease, and for treat 1,4-diazepan-1-yl, morpholinyl- and 1,4-oxazepan-4-yl ing complications in asthma and COPD triggered by viral, groups mentioned above in the definition of the group R may bacterial or other causes, for treating viral or bacterial infec each additionally be substituted by one or two C-alkyl tions of the airways or lungs. groups, 0044. It is also particularly preferred to use the compounds and of formula (I) in cases of inflammatory orallergic complaints wherein the above-mentioned phenyl groups are mono- or in which autoimmune reactions are involved. It is also par disubstituted by groups R, wherein ticularly preferred to use the compounds of formula (I) in (0027 R denotes hydrogen, or cases of a disease in the form of benign or malignant tumours. 0028 a group, which may be identical or different, 0045. The invention further relates to a pharmaceutical selected from among formulation containing a compound of formula (I). (0029 F, Cl, Br, I, OH, CN, C-alkyl, C-alkyl-O, 0046 Preferably an orally administered pharmaceutical CHF, CF - O CHF, formulation containing a compound of formula (I) is used. 0030 and 0047. The invention further relates to medicament combi 0031 - O CF, nations which contain, besides one or more compounds of and formula (I), as further active Substances, one or more com unless stated otherwise, the above-mentioned alkyl groups pounds selected from among the categories of betamimetics, may be straight-chain or branched, anticholinergics, corticosteroids, further PDE4-inhibitors, 0032. A denotes —CO or C-C-alkylene, LTD4-antagonists, EGFR-inhibitors, dopamine agonists, 0033 while the C-C-alkylene group may be 1-, H1-antihistamines, PAF-antagonists and PI3-kinase inhibi 2-, 3- or 4-substituted by a group R. tors or double or triple combinations thereof. and I0034) R' which may be identical or different, denotes Terms and Definitions Used hydrogen, or a group selected from among OH, C-C- 0048. By the term “optionally substituted” is meant within alkyl and —O-C-C-alkyl the scope of the invention the above-mentioned group, optionally in the form of the tautomers, the racemates, the optionally substituted by a lower-molecular group. Examples enantiomers, the diastereomers and the mixtures thereof, and of lower-molecular groups regarded as chemically meaning optionally the pharmacologically acceptable acid addition ful are groups consisting of 1-25 atoms. Preferably such salts, solvates and hydrates thereof. groups have no negative to effect on the pharmacological 0035. Preferred compounds of formula (I) are those efficacy of the compounds. wherein For example the groups may comprise: 0036 R. denotes a group selected from among 3-chloro 0049 Straight-chain or branched carbon chains, option 2-fluoro-phenyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2- ally interrupted by heteroatoms, optionally substituted fluoro-phenyl, 2-fluoro-3-methyl-phenyl, 2-fluoro-5-me by rings, heteroatoms or other common functional thyl-phenyl, 4-fluoro-3-methyl-phenyl- and 3-chloro-2- groups. methyl-phenyl, 0050 Aromatic or non-aromatic ring systems consist 0037 RandR which may be identical or different, ing of carbon atoms and optionally heteroatoms, which 0038 denote hydrogen or C-alkyl, may in turn be substituted by functional groups. 0039) R' denotes C-alkyl-O, 0051. A number of aromatic or non-aromatic ring sys unless stated otherwise, the above-mentioned alkyl groups tems consisting of carbon atoms and optionally heteroa may be straight-chain or branched, toms which may be linked by one or more carbon chains, 0040. A denotes —CHCH, while the —CH2CH2— optionally interrupted by heteroatoms, optionally Sub group may be substituted by 1 or 2 methyl groups, stituted by heteroatoms or other common functional optionally in the form of the tautomers, the racemates, the groups. enantiomers, the diastereomers and the mixtures thereof, and 0.052 Also included in the subject-matter of this invention optionally the pharmacologically acceptable acid addition are the compounds according to the invention, including the salts, Solvates and hydrates thereof. salts thereof, wherein one or more hydrogen atoms, for 0041. The invention further relates to compounds of for example one, two, three, four or five hydrogen atoms, are mula (I) for use as medicaments. replaced by deuterium. 0042 Preferably the compounds of formula (I) are used in 0053 Where a hyphen open on one side"- is used in the cases of inflammatory or allergic diseases of the airways. structural formula of a substituent, this hyphen is to be under 0043. The compounds of formula (I) are particularly pref stood as the linkage point to the remainder of the molecule. erably used in cases of a disease selected from among chronic The substituent replaces the corresponding groups R. R. bronchitis, acute bronchitis, bronchitis caused by bacterial or etc. If no hyphen open on one side is used in the structural viral infection or fungi or helminths, allergic bronchitis, toxic formula of a Substituent, the linkage point to the remainder of bronchitis, chronic obstructive bronchitis (COPD), asthma the molecule is clear from the structural formula itself. (intrinsic orallergic), paediatric asthma, bronchiectasis, aller 0054 Compounds of general formula (I) may contain acid gic alveolitis, allergic or non-allergic rhinitis, chronic sinusi groups, primarily carboxyl groups, and/or basic groups such tis, cystic fibrosis or mucoviscidosis, alpha-1-antitrypsin as e.g. amino functions. Compounds of general formula (I) deficiency, cough, pulmonary emphysema, interstitial lung may therefore be present as internal salts, as Salts with phar diseases, alveolitis, hyperreactive airways, nasal polyps, pull maceutically useable inorganic acids such as hydrochloric monary oedema, pneumonitis of different origins, e.g. radia acid, Sulphuric acid, phosphoric acid, Sulphonic acid or tion-induced or caused by aspiration or infectious pneumoni organic acids (such as for example maleic acid, fumaric acid, tis, collagenoses such as lupus erythematodes, systemic citric acid, tartaric acid or acetic acid) or as salts with phar US 2011/0046148 A1 Feb. 24, 2011
maceutically useable bases such as alkali metal or alkaline 0060 glycols, preferably ethyleneglycol, diethyleneg earth metal hydroxides or carbonates, Zinc or ammonium lycol; hydroxides or organic amines such as e.g. diethylamine, tri 0061 ethers/glycolethers, preferably diethyl ether, tert ethylamine, triethanolamine, inter alia. For preparing the butyl-methylether, dibutylether, anisol, 1,4-dioxane, tet alkali metal and alkaline earth metal salts of the compound of rahydrofuran, mono-, di-, tri-, polyethyleneglycol formula (I), it is preferable to use the alkali metal and alkaline ethers; earth metal hydroxides and hydrides, while the hydroxides 0062 ketones, preferably acetone, butanone, cyclohex and hydrides of the alkali metals, particularly sodium and anone, potassium are preferred, and Sodium and potassium hydrox 0.063 esters, preferably acetic acid esters, glycolesters: ide are particularly preferred. (See also Pharmaceutical Salts, 0.064 amides and other nitrogen compounds, prefer S. M. Birge et al., J. Pharm. Sci. (1977), 66, 1-19) ably N,N-dimethylformamide, pyridine, N-methylpyr 0055 As already mentioned, the compounds of general rolidone, acetonitrile; formula (I) may be converted into the salts thereof, particu 0065 sulphur compounds, preferably carbon disul larly for pharmaceutical use, into the pharmacologically phide, dimethylsulphoxide, Sulpholane; acceptable acid addition salts thereof with an inorganic or 0.066 nitro compounds, preferably nitrobenzene: organic acid. Suitable acids for this purpose include for 0067 halogenated hydrocarbons, preferably dichlo example Succinic acid, hydrobromic acid, acetic acid, romethane, chloroform, tetrachlormethane, tri- and tet fumaric acid, maleic acid, methanesulphonic acid, lactic acid, rachloroethene, 1,2-dichloroethane, chlorofluorocar phosphoric acid, hydrochloric acid, Sulphuric acid, tartaric bons; acid or citric acid. In addition, mixtures of the above-men 0068 aliphatic or alicyclic hydrocarbons, preferably tioned acids may be used. benzines, petroleum ether, cyclohexane, methylcyclo 0056. The present invention relates to the respective com hexane, decaline, terpene-L.; or pounds, optionally in the form of the individual diastere 0069 aromatic hydrocarbons, preferably benzene, tolu omers, mixtures of the individual diastereomers and/or indi ene, o-Xylene, m-Xylene, p-Xylene; vidual enantiomers, mixtures of the individual enantiomers or or corresponding mixtures thereof. racemates thereof, in the form of the tautomers as well as in 0070 The term diastereomerically pure describes within the form of the free bases or the corresponding acid addition the scope of the present invention compounds of formula (I), salts with pharmacologically acceptable acids—such as for which are present in a diastereomeric purity of at least 85% example acid addition salts with hydrohalic acids—for de, preferably at least 90% de, particularly preferably >95% example hydrochloric or hydrobromic acid or organic de. The term de (diastereomeric excess) is known in the art acids—such as for example tartaric acid, fumaric acid, citric and describes the optical purity of diastereomeric com acid or methanesulphonic acid. pounds. 0057. “Protective groups” for the purposes of the present 0071. The term enantiomerically pure describes within the invention is a collective term for organic groups with which Scope of the present invention compounds of formula (I), certain functional groups of a molecule containing a number which are present in an enantiomerical purity of at least 85% of active centres can temporarily be protected from attack by ee, preferably at least 90% ee, particularly preferably >95% reagents so that reactions take place only at the desired (un ee. The termee (enantiomeric excess) is known in the art and protected) sites. The protective groups should be introduced describes the optical purity of chiral compounds. selectively under mild conditions. They must be stable for the 0072 By the term “C-alkyl (including those which are duration of the protection under all the conditions of the part of other groups) are meant branched and unbranched reactions and purifying procedures which are to be carried alkyl groups with 1 to 6 carbon atoms and by the term "Ca out; racemisations and epimerisations must be suppressed. alkyl are meant branched and unbranched alkyl groups with Protective groups should be capable of being cleaved again 1 to 4 carbon atoms. Preferred are alkyl groups with 1 to 4 under mild conditions selectively and ideally in high yields. carbonatoms, particularly preferably alkyl groups with 1 to 2 The choice of a Suitable protective group, the reaction condi carbon atoms. Examples include: methyl, ethyl, n-propyl. tions (solvent, temperature, duration, etc.), and also the iso-propyl. n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, options for removing a protective group are known in the art iso-pentyl, neo-pentyl or hexyl. The abbreviations Me, Et, (e.g. Philip Kocienski, Protecting Groups, 3rd ed. 2004, THI n-Pr. i-Pr, n-Bu, i-Bu, t-Bu, etc. may optionally also be used EME, Stuttgart, ISBN: 3131370033). for the above-mentioned groups. Unless stated otherwise, the 0058. By an “organic solvent' is meant, within the scope definitions propyl, butyl, penty1 and hexyl include all the of the invention, an organic, low-molecular Substance which possible isomeric forms of the groups in question. Thus, for can dissolve other organic Substances by a physical method. example, propyl includes n-propyl and iso-propyl, butyl To be suitable the prerequisite for the solvent is that neither includes iso-butyl, sec-butyl and tert-butyl etc. the dissolving Substance nor the dissolved Substance should 0073. By the term “C-alkylene' (including those which be chemically altered during the dissolving process, i.e. the are part of other groups) are meant branched and unbranched components of the solution should be recoverable in their alkylene groups with 1 to 3 carbon atoms. Preferred are alky original form by physical separation processes Such as distil lene groups with 1 to 2 carbon atoms. Examples include: lation, crystallisation, Sublimation, evaporation or adsorp methylene, ethylene, propylene, 1-methylethylene, butylene, tion. For various reasons, not only the pure solvents but also 1-methylpropylene, 1,1-dimethylethylene and 1,2-dimethyl mixtures that combine the dissolving properties may be used. ethylene. Unless stated otherwise, the definition alkylene Examples include: includes all the possible isomeric forms of the groups in 0059 alcohols, preferably methanol, ethanol, propanol, question with the same number of carbons. Thus, for butanol, octanol, cyclohexanol: example, propylene also includes 1-methylethylene. US 2011/0046148 A1 Feb. 24, 2011
0074 By the term “C-7-cycloalkyl (including those I0086) “Halogen' within the scope of the present invention which are part of other groups) are meant cyclic alkyl groups denotes fluorine, chlorine, bromine or iodine. Unless stated to with 3 or 7 carbon atoms. Examples include: cyclopropyl. the contrary, fluorine, chlorine and bromine are regarded as cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Unless preferred halogens. otherwise Stated, the cyclic alkyl groups may be substituted I0087. The substituent R may represent a phenyl or 1-phe by one or more groups selected from among methyl, ethyl, nylethyl group, preferably a phenyl group, wherein the phe iso-propyl, tert-butyl, hydroxy and fluorine. nyl nucleus is substituted in each case by the groups R' to R. 0075. By the term “aryl' (including those which are part of I0088 Particularly preferably the substituent R" denotes a other groups) are meant aromatic ring systems with 6, 10 or group, selected from among 3-chloro-2-fluoro-phenyl, 14 carbon atoms. Examples include: phenyl, naphthyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, anthracenyl or phenanthrenyl, the preferred aryl group being 2-fluoro-3-methyl-phenyl, 2-fluoro-5-methyl-phenyl, phenyl. Unless otherwise stated, the aromatic groups may be 4-fluoro-3-methyl-phenyl- and 3-chloro-2-methyl-phenyl. substituted by one or more groups R. Most particularly preferably the substituent R* denotes a 0076 Particularly preferably the term “aryl” in each case 3-chloro-2-fluoro-phenyl group. denotes a phenyl group which is mono- or disubstituted by I0089. The substituent R may represent hydrogen, or an R, wherein the substituents R may be identical or different optionally Substituted group selected from among C-alkyl, and C-cycloalkyl- and C-cycloalkyl-C-alkyl, preferably 0077 R denotes hydrogen, or hydrogen and C-alkyl, particularly preferably hydrogen 0078 a group selected from among and methyl. (0079 F, Cl, Br, I, OH, CN, C-alkyl, C-alkyl-O, 0090 The substituent R may represent hydrogen, or an CHF, CF - O CHF, optionally Substituted group selected from among C-alkyl, 0080 and Co-cycloalkyl, C-cycloalkyl-C-alkyl, C-alkyl-CO, I0081 - O CF. Co-cycloalkyl-CO, C-cycloalkyl-C-alkyl-CO, C I0082. By the term “heteroaryl” are meant 5-10-membered alkyl-SO, C-cycloalkyl-SO. , Cle-cycloalkyl-C- mono- or bicyclic heteroaryl rings, wherein up to three C alkyl-SO, phenyl-CO— and phenyl-SO, preferably hydro atoms may be replaced by one or more heteroatoms selected gen and C-alkyl, particularly preferably hydrogen and from among oxygen, nitrogen and Sulphur, these rings con methyl. taining sufficient conjugated double bonds to form an aro I0091. The substituent R may denote hydrogen or matic system. Each of the above-mentioned heterocycles may 0092 a group selected from among optionally also be fused to a benzene ring. The heteroaryl 0.093 F. Cl, Br, I, OH, C-alkyl, C-alkyl-O, C rings may, unless otherwise described, carry one or more alkyl-O substituted by 1 to 3 fluorine atoms, C-cy Substituents, for example. cloalkyl-O, C-7-cycloalkyl-C-alkyl-O, tetrahydrofu 0083. The ring may be linked to the molecule via a carbon ran-3-yl-O, tetrahydropyran-3-yl-O, tetrahydro-pyran atom or, if available, via a to nitrogenatom. The following are 4-yl-O. tetrahydrofuranyl-C-alkyl-O- and examples of five- or six-membered heterocyclic aromatic tetrahydropyranyl-C-alkyl-O. groups: O 0094) R' C-alkyl, wherein the linking of the groups R* may take place via each C atom of the alkyl group, O I0095) R' C-alkyl-O, wherein the group R is sepa rated from the oxygen atom by at least 2 C atoms, O NR 0096 a group selected from among pyrrolidin-2-yl-C- N O 4-alkyl-O, pyrrolidin-3-yl-C-alkyl-O, piperidin-2-yl C-alkyl-O, piperidin-3-yl-C-alkyl-O, piperidin-4- yl-Ca-alkyl-O. azepan-2-yl-C-alkyl-O. azepan-3- ()o- is (OOOON- . 4. N4. N-N- yl-C-alkyl-O. azepan-4-yl-C-alkyl-O, morpholin s 2-yl-C-alkyl-O, morpholin-3-yl-C-alkyl-O. 1-(C. 3-alkyl)-pyrrolidin-2-yl-Ca-alkyl-O. 1-(C-alkyl)- pyrrolidin-3-yl-C-alkyl-O. 1-(C-alkyl)-piperidin ON 2-yl-C-alkyl-O. 1-(C-alkyl)-piperidin-3-yl-Ca 0084 Examples of 5-10-membered bicyclic heteroaryl alkyl-O. 1-(C-alkyl)-piperidin-4-yl-C-alkyl-O. rings include pyrrolizine, indole, indolizine, isoindole, inda 1-(C-alkyl)-azepan-2-yl-C-alkyl-O. 1-(Cis Zole, purine, quinoline, isoquinoline, quinoxaline, benzimi alkyl)-azepan-3-yl-C-alkyl-O, 1-(C-alkyl)- dazole, benzofuran, benzothiophene, benzothiazole, ben aZepan-4-yl-C-alkyl-O, 4-(C-alkyl)-morpholin-2- Zoisothiazole, pyridopyrimidine, pteridine, yl-Ca-alkyl-O and 4-(C-alkyl)-morpholin-3-yl-C- pyrimidopyrimidine. 4-alkyl-O , I0085 Particularly preferably, the term “heteroaryl preferably C-alkyl-O particularly preferably CH denotes a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl O—, group, which is mono- or disubstituted in each case by the wherein the pyrrolidinyl, piperidinyl, azepan-1-yl, piperazi group R, wherein the substituents R may be identical or nyl, 1,4-diazepan-1-yl, morpholinyl and 1,4-oxazepan-4-yl different and R is as hereinbefore defined. groups mentioned above in the definition of the group R may US 2011/0046148 A1 Feb. 24, 2011 each additionally be substituted by one or two C-alkyl Methods of Preparation groups, and 0117 The following methods are suitable, for example, wherein the above-mentioned phenyl groups are mono- or for preparing compounds of general formula (I): disubstituted by groups R. a) reacting a compound of general formula 0097. The substituent R' may denote hydrogen or (II) 0.098 a group selected from among RS N Y H (0099 F, Cl, Br, I, OCHF, OCHF, OCF, CHF, CHF, CF, CN, NO, NH, and OH, 01.00 or N O- H, 0101 a group selected from among 0102 C-alkyl, C-alkyl-O, C-alkenyl, C-alky nyl, phenyl, phenyl-O, phenyl-C-alkyl, phenyl-C- l 4. Rd alkyl-O, heteroaryl, heteroaryl-O, heteroaryl-C-alkyl and heteroaryl-C-alkyl-O. wherein 0103 wherein the above-mentioned phenyl groups are R" and Rare as hereinbefore defined, with a compound of mono- or disubstituted by groups R. general formula preferably hydrogen, fluorine, chlorine, bromine or methyl, particularly preferably hydrogen, fluorine, chlorine or (III) methyl. Z! I0104. The substituent R may represent hydrogen or 0105 a group selected from among 01.06 F, Cl, Br, I, OCHF, OCHF, OCF, CHF, CHF, CF, CN, NO, NH, and OH, 01.07 or 0.108 a group selected from among 0109 C-alkyl, C-alkyl-O, C-alkenyl, C-alky wherein nyl, phenyl, phenyl-O, phenyl-C-alkyl, phenyl-C- R. R. and A are as hereinbefore defined and Z' denotes a alkyl-O, heteroaryl, heteroaryl-O, heteroaryl-C-alkyl leaving group such as a halogen atom, e.g. a chlorine, bro and heteroaryl-C-alkyl-O, wherein the above-men mine or iodine atom, a Sulphonyloxy group Such as a meth tioned phenyl groups are mono- or disubstituted by anesulphonyloxy or p-toluenesulphonyloxy group or a groups R. hydroxy group. preferably hydrogen, fluorine, chlorine or methyl, particu With a compound of general formula (III), wherein Z' larly preferably hydrogen, fluorine or chlorine. denotes a halogenatom or a Sulphonyloxy group, the reaction 0110. The substituent R may represent hydrogen, or is expediently carried out in a solvent such as ethanol, iso 0111 a group selected from among F, Cl, Brand CH propanol, acetonitrile, toluene, tetrahydrofuran, 1.4-dioxane, preferably hydrogen. N,N-dimethylformamide, dimethylsulphoxide or N-meth I0112. The substituent R may represent a group, which ylpyrrolidinone, preferably in the presence of a base Such as may be identical or different, selected from among potassium carbonate, caesium carbonate, potassium hydrox OH, C-alkyl-O, C-cycloalkyl-O, NH, C-alkyl-NH. ide, potassium-tert-butoxide, sodium hydride or N-ethyl-di (C-alkyl)-N. (2-methoxyethyl)-N, pyrrolidin-1-yl, piperi isopropylamine, at temperatures in the range from 20° C. to din-1-yl, azepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl, 160° C., for example attemperatures in the range from 60°C. 2-oxa-5-aza-bicyclo[2.2.1]hept-5-yl, 3-oxa-8-aza-bicyclo[3. to 140° C. 2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl, piperazin I0118 With a compound of general formula III wherein Z' 1-yl 4-(C-alkyl)-piperazin-1-yl, 1.4-diazepan-1-yl 4-(C- denotes a hydroxy group, the reaction is carried out in the 3-alkyl)-1,4-diazepan-1-yl, HCO. NH, C-alkyl-CO— presence of a dehydrating agent, preferably in the presence of NH, C-alkyl-O C-alkyl-CO. NH, C-alkyl-O- a phosphine and an aZodicarboxylic acid derivative such as CO. NH, HNCONH, C-alkyl-NH CO. NH, (C- e.g. triphenylphosphine/diethyl azodicarboxylate, conve alkyl)-N CONN, pyrrolidin-1-yl-CO. NH, piperidin-1- niently in a solvent such as methylene chloride, acetonitrile, yl-CO. NH, piperazin-1-yl-CO. NH, 4-(C-alkyl)- tetrahydrofuran, 1.4-dioxane, toluene or ethyleneglycol piperazin-1-yl-CO. NH, morpholin-4-yl-CO. NH and diethylether at temperatures between -50 and 150° C., but C -alkyl-SO. NH-. preferably attemperatures between -20 and 80° C. 0113. The substituent R may represent hydrogen, or b) In order to prepare compounds of general formula I 0114 a group, which may be identical or different, wherein RandR each denote a hydrogen atom and A rep Selected from among resents a —CO— group, reacting a compound of general 0115 F, Cl, Br, I, OH, CN, C-alkyl, C-alkyl-O, formula CHF, CF, —O CHF and —O—CF. A may denote —CO or -C-C-alkylene, preferably (IV) —CHCH R NN1 H I0116 wherein the C-C-alkylene group may be 1-, 2-, 3- or 4-, preferably 1- or 2-substituted by a group R, O The substituent R, which may be identical or different, may N1 N represent hydrogen, or O, a group selected from among OH, C-C-alkyland—O—C- se Rd 2 C-alkyl, preferably methyl. A particularly preferred definition of A is —CH2CH2—. US 2011/0046148 A1 Feb. 24, 2011
wherein sium carbonate, triethylamine or N-ethyl-diisopropylamine, R" and Rare as hereinbefore defined, with an alkali metal attemperatures in the range from 20°C. and 160° C., prefer cyanide and ammonium carbonate. ably from 60° C. to 120° C. However, the reaction is prefer 0119 The reaction is carried out for example in a solvent ably carried out in isopropanol at the boiling temperature of or mixture of Solvents such as methanol, ethanol, ethanol/ the reaction mixture. water or isopropanol at temperatures between ambient tem 0.122 The reaction of a compound of general formula (V) perature and 120° C. Further references to the synthesis of to obtain a compound of general formula (I) may also be hydantoins can be found for example in the following publi carried out as a one-pot reaction, for example inacetonitrile in cation: Meusel, M. Guetschow, M., Organic Preparations the presence of triethylamine. and Procedures International (2004), 36(5), 391-443. d) In order to prepare compounds of general formula I c) reacting a compound of general formula (V) wherein R* denotes one of the optionally substituted alkyloxy groups mentioned hereinbefore: reacting a compound of general formula (V) O
O (VIII) HN O RS-H lsN Ra N1 Rb, N1N O O -N-A se OH -R. wherein R. R. R. and Aare as hereinbefore defined, with a halogenating agent, for example an acid halide such as thio -N-A nyl chloride, thionyl bromide, phosphorus trichloride, phos phorus pentachloride orphosphorus oxychloride, to obtain an wherein R. R. R. and A are as hereinbefore defined, with a intermediate compound of general formula (VI), compound of general formula Zi-Ra, (DX) (VI) Z2 wherein R. denotes a group selected from among Cla-alkyl, C-alkyl substituted by 1 to 3 fluorine atoms, C-7-cy O cloalkyl, C-7-cycloalkyl-C-alkyl, tetrahydrofuran-3-yl, tetrahydropyran-3-yl, tetrahydro-pyran-4-yl, tetrahydrofura nyl-C-alkyl and tetrahydropyranyl-C-alkyl, lsN C Ra O N1 Rb, O (0123 R C-alkyl, wherein the group R is sepa N-A RC rated from Z by at least 2 C atoms, O 0.124 a group selected from among wherein R, R, R and Aare as hereinbefore defined and Z 0.125 pyrrolidin-2-yl-C-alkyl, pyrrolidin-3-yl-C- denotes a halogen atom Such as a chlorine or bromine atom, alkyl, piperidin-2-yl-C-alkyl, piperidin-3-yl-Ca and Subsequent reaction with a compound of general formula alkyl, piperidin-4-yl-C-alkyl, azepan-2-yl-Ca (VII), alkyl, azepan-3-yl-C-alkyl, azepan-4-yl-C-alkyl, morpholin-2-yl-Ca-alkyl, morpholin-3-yl-Ca-alkyl, R NH, (VII), 1-(C-alkyl)-pyrrolidin-2-yl-Ca-alkyl, 1-(C- wherein R is as hereinbefore defined, or the salts thereof. alkyl)-pyrrolidin-3-yl-Ca-alkyl, 1-(C-alkyl)-piperi 0120. The reaction with the halogenating agent is option din-2-yl-Ca-alkyl, 1-(C-alkyl)-piperidin-3-yl-Ca ally carried out in a solvent such as methylene chloride, alkyl, 1-(C-alkyl)-piperidin-4-yl-C-alkyl, 1-(C- chloroform, acetonitrile or toluene and optionally in the pres alkyl)-azepan-2-yl-C-alkyl, 1-(C-alkyl)-azepan-3- ence of a base such as N,N-diethylaniline, pyridine, triethy yl-C-alkyl, 1-(C-alkyl)-azepan-4-yl-C-alkyl, lamine or N-ethyl-diisopropylamine at temperatures in the 4-(C-alkyl)-morpholin-2-yl-C-alkyl, 4-(Cis range from 20° C. to 160° C., preferably from 40° C. to 120° alkyl)-morpholin-3-yl-C-alkyl, and C. Preferably, however, the reaction is carried out with thionyl I0126 Zi denotes a leaving group such as a halogen atom, chloride and catalytic amounts of N,N-dimethylformamide at an alkylsulphonyloxy, arylsulphonyloxy or a hydroxy group. the boiling temperature of the reaction mixture or, however, 0127. If the leaving group is a halogen atom Such as a with phosphorus oxychloride inacetonitrile in the presence of chlorine, bromine or iodine atom or an alkylsulphonyloxy or triethylamine at the boiling temperature of the reaction mix arylsulphonyloxy group Such as the methanesulphonyloxy or ture. p-toluenesulphonyloxy group, the reaction is preferably car 0121 The reaction of the compound of general formula ried out in the presence of an organic or inorganic base Such (VI) with the compound of general formula (VII) or the salts as potassium carbonate, caesium carbonate, potassium thereof is conveniently carried out in a solvent such as etha hydroxide, sodium hydride or N-ethyl-diisopropylamine. If nol, isopropanol, acetonitrile, 1,4-dioxane or N,N-dimethyl the leaving group is a hydroxy group, the reaction is carried to formamide, optionally in the presence of a base Such as potas out in the presence of a dehydrating agent, preferably in the US 2011/0046148 A1 Feb. 24, 2011 presence of a phosphine and an aZodicarboxylic acid deriva preferably from 3 to 5 bar. A 2,4-dimethoxybenzyl group is tive such as e.g. triphenylphosphine? diethyl azodicarboxy preferably cleaved in trifluoroacetic acid in the presence of late. anisol, thioanisol, pentamethylbenzene or triethylsilane. e) In order to prepare compounds of general formula I I0129. An optionally substituted benzyl group or a tert.- wherein R* denotes a R' C-alkyl-O group, wherein butyl group may for example also be cleaved by treating with the group R' is separated from the oxygenatom by at least 2 an acid such as trifluoroacetic acid, hydrochloric acid or Catoms, and R' denotes a group selected from among NH2, hydrobromic acid, optionally using a solvent Such as 1,4- C-alkyl-NH. (C-alkyl).N. (2-methoxyethyl)-N, pyrroli dioxane, isopropanol, methylene chloride or toluene, option din-1-yl, piperidin-1-yl, azepan-1-yl, morpholin-4-yl, 1,4- ally in the presence of anisole, thioanisole, pentamethylben oxazepan-4-yl, 2-oxa-5-aza-bicyclo2.2.1]hept-5-yl, 3-oxa Zene or triethylsilane. 8-aza-bicyclo[3.2.1]oct-8-yl, 8-oxa-3-aza-bicyclo[3.2.1]oct 0.130 A 2-(trimethylsilyl)ethyl group is cleaved for 3-yl, piperazin-1-yl 4-(C-alkyl)piperazin-1-yl, 1,4- example by treatment with fluorides to such as tetrabutylam diazepan-1-yl 4-(C-alkyl)-1,4-diazepan-1-yl: reacting a monium fluoride, optionally using a solvent Such as tetrahy compound of general formula drofuran or 1,4-dioxane. I0131 Other suitable protective groups and possible ways of introducing and cleaving them are described for example in O (X) “Protective Groups in Organic Synthesis” by Theodora W. RS -H /*Rb Greene and Peter G. M. Wuts, Wiley-VCH, or Philip Kocien N ski, Protecting Groups, 3rd ed. 2004, THIEME. O g) In order to prepare compounds of general formula I N1 N wherein R denotes a hydrogen atom: cleaving a protective group from a compound of general l 4. O RC -A formula C-4-Alkyl-Z' (XIII) wherein R", R, R and Aare as hereinbefore defined and Z' denotes a leaving group Such as a halogen atom, e.g. a chlo RS-H rine, bromine or iodine atom or a Sulphonyloxy group such as a methanesulphonyloxy or p-toluenesulphonyloxy group, N1N O O with H. R.' (XI) se Rd N1 Rb, wherein R' is as hereinbefore defined. f) In order to prepare compounds of general formula I wherein -N-A R" denotes a hydrogen atom: cleaving a protective group from a compound of general wherein R, R, R and Aare as hereinbefore defined and R formula denotes a protective group, for example an optionally Substi tuted benzyl group or a formyl, acetyl, trifluoroacetyl, meth oxycarbonyl, ethoxycarbonyl, tert.-butoxycarbonyl or benzy (XII) loxycarbonyl group. R H 0.132. The protective group is cleaved, for example, hydro NN1 lytically in an aqueous solvent, e.g. In water, isopropanol/ O water, acetic acid/water, tetrahydrofuran/water or 1,4-diox ane?water, in the presence of an acid such as trifluoroacetic s O acid, hydrochloric acid or Sulphuric acid or in the presence of l N2 Rd N1 Rb, an alkali metal base such as Sodium hydroxide or potassium hydroxide or aprotically, e.g. in the presence of iodotrimeth N-A ylsilane, attemperatures between 0 and 120°C., preferably at temperatures between 10 and 100° C. 0.133 An optionally substituted benzyl group, or a benzy wherein R, R, R and A are as hereinbefore defined and R' loxycarbonylbenzyl group is cleaved, for example, hydro denotes a protective group, for example an optionally Substi genolytically, e.g. with hydrogen in the presence of a catalyst tuted benzyl group, a tert.-butyl group or a 2-(trimethylsilyl) Such as palladium/charcoal in a suitable solvent Such as ethyl group. methanol, ethanol, ethyl acetate or glacial acetic acid, option 0128. An optionally substituted benzyl group is for ally with the addition of an acid such as hydrochloric acid at example cleaved hydrogenolytically, e.g. with hydrogen in temperatures between 0 and 100° C., but preferably is at the presence of a catalyst Such as palladium/charcoal in a temperatures between 20 and 60° C., and under a hydrogen Suitable solvent such as methanol, ethanol, ethyl acetate or pressure of 1 to 7 bar, but preferably from 3 to 5 bar. glacial acetic acid, optionally with the addition of an acid I0134. A tert-butyloxycarbonyl group is preferably such as hydrochloric acid, at ambient temperatures between 0 cleaved by treatment with an acid such as trifluoroacetic acid and 100° C., but preferably at ambient temperatures between or hydrochloric acid, optionally using a solvent Such as meth 20 and 60°C., and under a hydrogen pressure of 1 to 7 bar, but ylene chloride, 1,4-dioxane, methanol or diethyl ether. US 2011/0046148 A1 Feb. 24, 2011
0135 A trifluoroacetyl group is preferably cleaved by drides and carboxylic acids with activating agents such as treatment with an acid Such as hydrochloric acid, optionally N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide in the presence of a solvent such as acetic acid attemperatures or O-(benzotriazol-1-yl)-N.N.N'N'-tetramethyluronium-tet between 50 and 120° C. or by treatment with sodium hydrox rafluoroborate and Sulphonyl halides as Sulphonylating ide Solution, optionally in the presence of a solvent Such as agents, and/or if a compound of general formula I is obtained tetrahydrofuran attemperatures between 0 and 50° C. which contains an amino, alkylamino or imino group, it may 0136. Other suitable protective groups and possible ways be converted by alkylation or reductive alkylation into a cor of introducing and cleaving them are described for example in responding alkyl compound of general formula I and/or “Protective Groups in Organic Synthesis” by Theodora W. ifa compound of general formula I is obtained which contains Greene and Peter G. M. Wuts, Wiley-VCH, or Philip Kocien an alkoxycarbonyl group, it may be converted by ester cleav ski, Protecting Groups, 3rd ed. 2004, THIEME. ing into a carboxylic acid, and/or if a compound of general h) In order to prepare compounds of general formula I formula I is obtained which contains an alkoxycarbonyl wherein A denotes a —C-C-alkylene group: group, it may be converted by reaction with an amine into a cyclising a compound of general formula carboxylic acid amide derivative and/or ifa compound of general formula I is obtained which contains a carboxy group, it may be converted by reaction with an R H (XIV) amine into a carboxylic acid amide derivative. NN1 0.141. In the reactions described hereinbefore any reactive groups present Such as hydroxy, amino, alkylamino or imino O groups may be protected during the reaction by conventional protective groups which are cleaved again after the reaction. s O 0.142 For example a protecting group for a hydroxy group N - Rd Z5 might be the trimethylsilyl, acetyl, trity1, benzyl or tetrahy dropyranyl group. 0.143 Protecting groups for an amino, alkylamino or imino group might be, for example, the formyl, acetyl, trif luoroacetyl, ethoxycarbonyl, tert.-butoxycarbonyl, benzy wherein R", R, R and Rare as hereinbefore defined, A loxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxyben denotes a -C-C-alkylene group and Zdenotes a leaving Zyl group. group Such as a halogen atom, a hydroxy or alkyloxy group. 0144. Any protective group used is optionally Subse 0.137 If the leaving group is a hydroxy group, the reaction quently cleaved for example by hydrolysis in an aqueous is carried out in the presence of a dehydrating agent Such as Solvent, e.g. in water, isopropanol/water, acetic acid/water, N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarbodiimide, tetrahydrofuran/water or 1,4-dioxane?water, in the presence O-(benzotriazol-1-yl)-N.N.N'N'-tetramethyluronium-tet of an acid such as trifluoroacetic acid, hydrochloric acid or rafluoroborate (TBTU) or O-(7-azabenzotriazol-1-yl)-N.N. Sulphuric acid or in the presence of an alkali metal base Such N',N'-tetramethyluronium-hexafluorophosphate (HATU), as sodium hydroxide or potassium hydroxide or aprotically, conveniently in a solvent such as methylene chloride, N.N- e.g. in the presence of iodotrimethylsilane, at temperatures dimethylformamide, acetonitrile, tetrahydrofuran, 1.4-diox between 0 and 120° C., preferably at temperatures between ane or ethyleneglycol diethyl ether at temperatures between 10 and 100° C. -50° C. and 100°C., but preferably at temperatures between 0145 A benzyl, methoxybenzyl or benzyloxycarbonyl -20° C. and 60° C. group, however, is cleaved by hydrogenolysis, for example, 0138 If the leaving group is a halogen atom, the reaction e.g. with hydrogen in the presence of a catalyst Such as pal is preferably carried out in the presence of a base Such as ladium/charcoal in a Suitable solvent Such as methanol, etha triethylamine, pyridine or N-ethyl-diisopropylamine, conve nol, ethyl acetate or glacial acetic acid, optionally with the niently in a solvent such as methylene chloride, N,N-dimeth addition of an acid such as hydrochloric acid attemperatures ylformamide, acetonitrile, tetrahydrofuran, 1.4-dioxane or between 0 and 100° C., but preferably at temperatures ethyleneglycol diethyl ether attemperatures between -50° C. between 20 and 60°C., and under a hydrogen pressure of 1 to and 100° C., but preferably attemperatures between -20°C. 7 bar, but preferably from 3 to 5 bar. A 2,4-dimethoxybenzyl and 60° C. group, however, is preferably cleaved intrifluoroacetic acid in 0.139. If the leaving group is an alkyloxy group, the reac the presence of anisole, thioanisole, pentamethylbenzene or tion is optionally carried out in the presence of a base Such as triethylsilane. potassium carbonate, Sodium hydroxide, triethylamine or 0146 A tert-butyl or tert-butyloxycarbonyl group is pref N-ethyl-diisopropylamine, conveniently in a solvent such as erably cleaved by treatment with an acid such as trifluoroace methanol, ethanol, isopropanol, methylene chloride, N.N- tic acid or hydrochloric acid or by treating with iodotrimeth dimethylformamide, acetonitrile, tetrahydrofuran, 1.4-diox ylsilane, optionally using a solvent such as methylene ane or ethyleneglycol diethyl ether at temperatures between chloride, 1,4-dioxane, methanol, isopropanol or diethyl ether. -50° C. and 120°C., but preferably at temperatures between 0147 A trifluoroacetyl group is preferably cleaved by O° C. and 80° C. treatment with an acid Such as hydrochloric acid, optionally 0140. If according to the invention a compound of general in the presence of a solvent Such as acetic acid attemperatures formula I is obtained which contains an amino, alkylamino or between 50 and 120° C. or by treatment with sodium hydrox imino group, this may be converted by acylation or Sulpho ide Solution, optionally in the presence of a solvent such as nylation into a corresponding acyl or Sulphonyl compound of tetrahydrofuran attemperatures between 0 and 50° C. general formula I, wherein the acylating agents used may be 0.148. Other suitable protective groups and possible ways for example carboxylic acid halides, carboxylic acid anhy of introducing and cleaving them are described for example in US 2011/0046148 A1 Feb. 24, 2011
“Protective Groups in Organic Synthesis” by Theodora W. 0155 For example, the compounds of general formula (V) Greene and Peter G. M. Wuts, Wiley-VCH, or Philip Kocien and (VI) may be obtained as follows: ski, Protecting Groups, 3rd ed. 2004, THIEME. 0149 Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or dias Scheme 1 tereomers, as mentioned hereinbefore. Thus, for example, Z cis/trans mixtures may be resolved into their cis and trans O isomers, and is compounds with at least one optically active carbon atom may be separated into their enantiomers. N -R', 0150. Thus, for example, the cis/trans mixtures obtained \-X may be resolved by chromatography into the cis and trans O A isomers thereof, the compounds of general formula I obtained PG OH RC which occur as racemates may be separated by methods NN (III) known perse (cf. Allinger N. L. and Eliel E. L. in “Topics in Stereochemistry”, Vol. 6, Wiley Interscience, 1971) into their lss Rd optical antipodes and compounds of general formula I with at (XV) least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differ O ences using methods known per se, e.g. by chromatography PG O and/or fractional crystallisation, and, if these compounds are NN O obtained in racemic form, they may Subsequently be resolved ls Rb into the enantiomers as mentioned above. N Ra 0151. The enantiomers are preferably separated by col N-A umn separation on chiral phases or by recrystallisation from M an optically active solvent or by reacting with an optically RC active Substance which forms salts or derivatives such as e.g. (XVI) esters or amides with the racemic compound, particularly O acids and the activated derivatives or alcohols thereof, and O separating the diastereomeric mixture of salts or derivatives HN O thus obtained, e.g. on the basis of their differences in solubil ity, whilst the free antipodes may be released from the pure lsN Rd N1 Rb diastereomeric salts or derivatives by the action of suitable A. agents. Optically active acids in common use are e.g. the D N-A and L-forms of tartaric acid or dibenzoyltartaric acid, di-o- M tolyltartaric acid, malic acid, mandelic acid, camphorsul RC phonic acid, glutamic acid, aspartic acid or quinic acid. An (V) optically active alcohol may be for example (+) or (-)-men Z2 thol and an optically active acyl group in amides, for example, may be a (+)- or (-)-menthyloxycarbonyl. O Na O 0152. Furthermore, the compounds of formula I obtained may be converted into the salts thereof, particularly for phar ls Rb maceutical use into the physiologically acceptable salts with N Rd N1 / inorganic or organic acids or bases. Acids which may be used N-A for this purpose include for example hydrochloric acid, A hydrobromic acid, Sulphuric acid, methaneSulphonic acid, RC ethaneSulphonic acid, benzenesulphonic acid, p-toluenesul (VI) phonic acid, phosphoric acid, fumaric acid, Succinic acid, benzoic acid, Salicylic acid, mandelic acid, lactic acid, mal onic acid, citric acid, L-malic acid, L-tartaric acid or maleic 0156 Starting from a compound of general formula (XV), acid. Suitable bases for this purpose include for example wherein PG denotes a protective group Such as for example Sodium hydroxide solution, potassium hydroxide solution, benzyl, 4-methoxybenzyl or 2,4-dimethoxybenzyl, the reac calcium hydroxide, diethanolamine or N-methyl-D-glucam tion is carried out with a compound of general formula (III) 1. analogously to the previously described processa) to obtain a 0153. The compounds of general formulae II to XIV used compound of general formula (XVI). The compounds of gen as starting materials are known from the literature to some eral formula (XV) are known from the literature (cf. e.g. WO extent or may be obtained by methods known from the litera ture (cf. Examples Ito XII), optionally with the additional 2004/108664 or WO 2007/003486) or may be obtained by introduction of protecting groups. methods known from the literature. 0154 Standard processes for preparing the starting mate 0157. The cleaving of the protective group from a com rials are described for example in “March's Advanced pound of general formula (XVI) to obtain a compound of Organic Chemistry’ by Michael B. Smith and Jerry March, general formula (V) is carried out, if PG denotes benzyl, with Wiley-VCH or in “Science of Synthesis/Houben-Weyl pub hydrogen, for example, in the presence of a catalyst Such as lished by Thieme. palladium/charcoal (e.g. analogously to Example XI). The US 2011/0046148 A1 Feb. 24, 2011 cleaving of the protective group if PG denotes 4-methoxy 0.165. The following compounds are obtained analogously benzyl or 2,4-dimethoxybenzyl may also be carried out oxi to Example I: datively (e.g. with cerium(IV)-ammonium nitrate or with 2,3- (1) methyl trans-1-amino-4-4-(3-chloro-2-fluoro-pheny dichloro-5,6-dicyano-1,4-benzoquinone) or with acids (e.g. lamino)-7-methoxy-quinazolin-6-yloxy-cyclohexanecar with trifluoroacetic acid in the presence of anisole, thioani sole, pentamethylbenzene or triethylsilane). boxylate 0158. A compound of general formula (V) may then be converted into a compound of general formula (VI), as described in the previous process c). The meanings for R. R. R.A, Z and Z in the compounds of Scheme 1 are defined as mentioned hereinbefore. C NH
0159. As already mentioned hereinbefore, the compounds of general formula (I) according to the invention and the F N21 physiologically acceptable salts thereof have valuable phar macological properties, particularly an inhibiting effect on signal transduction mediated by the Epidermal Growth Factor lsN receptor (EGF-R), whilst this may be achieved for example by inhibiting ligand bonding, receptor dimerisation or tyrosine kinase itself. It is also possible to block the transmis sion to of signals to components located further downstream. 0160 The following Examples are intended to illustrate (0166 Mass spectrum (ESI): m/z 475, 477 M+H" the present invention without restricting it: (2) methyl trans-4-4-(3-chloro-2-fluoro-phenylamino)-7- methoxy-quinazolin-6-yloxy)-1-(2-methylamino-ethy Preparation of the Starting Compounds lamino)-cyclohexanecarboxylate Example I Methyl trans-1-(2-amino-ethylamino)-4-4-(3- chloro-2-fluoro-phenylamino)-7-methoxy-Quinazo lin-6-yloxy-cyclohexanecarboxylate C NH
(0161 F Na
lsN
C NH
F NN N21 H
lsN (0167 Mass spectrum (ESI): m/z 532,534 M+H" (3) methyl cis-1-(2-amino-ethylamino)-4-4-(3-chloro-2- fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy-cy HN clohexanecarboxylate
0162 3.30 ml trifluoroacetic acid are added to 1.60 g methyl trans-1-(2-tert.-butoxycarbonylamino-ethylamino)- 4-4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazo lin-6-yloxy-cyclohexanecarboxylate in 13 ml to methylene C NH chloride. The reaction mixture is stirred for three hours at ambient temperature, then another 1 ml trifluoroacetic acid is added. After a further hour the reaction is finished and the reaction mixture is evaporated down, taken up in methylene chloride and some methanol and made alkaline with 10% potassium carbonate solution. The organic is phase is sepa rated off and the aqueous phase is extracted with methylene chloride. The combined organic phases are dried on magne sium Sulphate and evaporated down. HN (0163 Yield: 1.30 g (97% of theory) (0164. Mass spectrum (ESI"): m/z =518, 520 M+H" US 2011/0046148 A1 Feb. 24, 2011 11
Example II 0172. The following compounds are obtained analogously to Example II: (1) methyl trans-1-2-(N-tert-butoxycarbonyl-N-methyl amino)-ethylamino-4-4-(3-chloro-2-fluoro-phenylamino)- Methyl trans-1-(2-tert-butoxycarbonylamino-ethy 7-methoxy-quinazolin-6-yloxy-cyclohexanecarboxylate lamino)-4-4-(3-chloro-2-fluoro-phenylamino)-7- methoxy-quinazolin-6-yloxy-cyclohexanecarboxy late
C NH (0168 F Na
lsN
C NH
F N21 (0173 Mass spectrum (ESI"): m/z =632, 634 M+H" (2) methyl cis-1-(2-tert.-butoxycarbonylamino-ethylamino)- 4-4-(3-chloro-2-fluoro-phenylamino)-7-methoxy-quinazo lsN lin-6-yloxy-cyclohexanecarboxylate
HN C NH
F O O so N21 O
lsN O - O NH
HN 0169 0.44 g N-tert-butoxycarbonyl-2-aminoacetalde hyde are added to 1.20 g methyl trans-1-amino-4-4-(3- so chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6- O yloxy-cyclohexanecarboxylate in 40 ml of tetrahydrofuran (0174) Mass spectrum (ESI"): m/z =618, 620 M+H" under an argon atmosphere. Then 0.18 ml glacial acetic acid Example III and 0.80 g sodium triacetoxyborohydride are added and the Methyl trans-1-tert-butoxycarbonylamino-4-4-(3- chloro-2-fluoro-phenylamino)-7-methoxy-quinaZo reaction mixture is stirred overnight at ambient temperature. lin-6-yloxy-cyclohexanecarboxylate As the reaction has not yet finished, 90 mg N-tert.-butoxycar bonyl-2-aminoacetaldehyde and 200 mg Sodium triacetoxy 0175 borohydride are both added twice more. After a further night at ambient temperature the reaction is complete. The reaction mixture is diluted with ethyl acetate and combined with C NH
Sodium hydroxide solution. The organic phase is separated off and the aqueous phase is extracted with ethyl acetate. The F Na combined organic phases are washed with Saturated sodium chloride solution, dried on magnesium Sulphate and evapo lsN rated down. The crude product is further reacted without any further purification. (0170 R-value: 0.35 (silica gel, methylene chloride/metha no1/conc. ammonia=90:10:1) (0171 Mass spectrum (ESI"): m/z =618, 620 M+H" US 2011/0046148 A1 Feb. 24, 2011
0176 A mixture of 3.30 g 4-(3-chloro-2-fluoro-pheny Example V lamino)-7-methoxy-quinazolin-6-ol in 23 ml N,N-dimethyl formamide is heated to 50°C. Then 2.30g potassium carbon Methyl cis-1-tert-butoxycarbonylamino-4-hydroxy ate and 4.40 g methyl cis-1-tert.-butoxycarbonylamino-4- cyclohexanecarboxylate methaneSulphonyloxy-cyclohexanecarboxylate are added. The reaction mixture is heated to 80° C. and stirred overnight 0184 at this temperature. Then a further 1.00 g methyl cis-1-tert.- butoxycarbonylamino-4-methaneSulphonyloxy-cyclohexan HO ecarboxylate and 0.90g potassium carbonate are added. After another four hours at 80°C. the reaction mixture is cooled to ambient temperature, diluted with ethyl acetate and washed several times with water. The organic phase is washed with saturated Sodium chloride Solution, dried on magnesium Sul phate and evaporated down. The flask residue is purified by chromatography through a silica gel column with methylene chloride/methanol/conc. ammonia (98/2/0.1 to 8/2/0.1). 0177. Yield: 5.50 g (93% of theory) 0178 Mass spectrum (ESI); m/z =575, 577 M+H" 0185. 4.50 g methyl 1-tert-butoxycarbonylamino-4-oxo cyclohexanecarboxylate in 45 ml of tetrahydrofuran are com bined with 6 ml of water and 630 mg sodiumborohydride Example IV under anargon atmosphere. The reaction mixture is stirred for two hours at ambient temperature, diluted with diethyl ether, Methyl cis-1-tert-butoxycarbonylamino-4-methane combined with 1N hydrochloric acid and stirred thoroughly. Sulphonyloxy-cyclohexanecarboxylate The organic phase is separated off, washed with 10% potas sium carbonate solution and Saturated Sodium chloride solu 0179 tion, dried on magnesium Sulphate and evaporated down. A colourless oil is left, which slowly crystallises overnight. 0186 Yield: 4.39 g (97% of theory) 0187 Mass spectrum (ESI): m/z 274 M+H" Example VI Methyl 1-tert.-butoxycarbonylamino-4-oxo-cyclo hexanecarboxylate 0188
0180 1.40 ml methanesulphonic acid chloride are slowly added dropwise to 4.39 g methyl cis-1-tert-butoxycarbony lamino-4-hydroxy-cyclohexanecarboxylate and 2.80 ml tri ethylamine in 45 ml methylene chloride while cooling with an ice bath, keeping the temperature below 10° C. Then the reaction mixture is allowed to come up to ambient tempera ture and stirred overnight. 20 ml of saturated sodium hydro 0189 3.90 g potassium carbonate and 1.30 ml methyl gen carbonate Solution are then added, the phases are sepa iodide are added to 4.65 g 1-tert-butoxycarbonylamino-4- rated and the aqueous phase is extracted with methylene oxo-cyclohexanecarboxylic acid in 45 ml N,N-dimethylfor chloride. The combined organic phases are washed with Satu mamide and the reaction mixture is stirred for three hours at rated Sodium chloride Solution, dried on magnesium Sulphate ambient temperature. Then the solvent is distilled off using and evaporated down, leaving a viscous oil. The crude prod the rotary evaporator and the residue is divided between 10% potassium carbonate solution and diethyl ether. The aqueous uct is further reacted without any further purification. phase is separated off and extracted with diethyl ether and the 0181. Yield: 5.44 g (96% of theory) combined organic phases are washed with Saturated sodium 01821 R-value: 0.50 (silica gel, methylene chloride/metha chloride solution, dried on magnesium Sulphate and evapo nol=95:5) rated down. A colourless oil is left, which slowly crystallises. 0183 Mass spectrum (ESI"): m/z. 352 M+H" (0190. Mass spectrum (ESI"): m/z 272 M+H" US 2011/0046148 A1 Feb. 24, 2011 13
Example VII -continued Methyl cis-1-amino-4-4-(3-chloro-2-fluoro-pheny lamino)-7-methoxy-quinazolin-6-yloxy-cyclohexan ecarboxylate C NH (0191) F O O N1 N OH 2 '', N NH2
C NH 0196. A mixture of 3.00 g syn/anti-8-4-(3-chloro-2- F N1 N fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy)-1,3- diaza-spiro4.5 decan-2,4-dione and 30 ml of 2 N sodium le hydroxide solution is heated to 135° C. with stirring for N approx. 25 h. After cooling to ambient temperature the reac tion mixture is neutralised with hydrochloric acid. Then the water is distilled off in vacuo using the rotary evaporator, 0.192 1.95 g cis/trans-1-amino-4-4-(3-chloro-2-fluoro during which time a precipitate is formed, which is suction phenylamino)-7-methoxy-quinazolin-6-yloxy-cyclohexan filtered and dried. The crude product thus obtained is further ecarboxylic acid are dissolved in a little methanol and while reacted without any further purification. cooling with an ice bath this mixture is added dropwise to a (0197) Yield: 1.95 g (69% of theory) solution of 700 ul thionyl chloride in 20 ml of methanol. The (0198 Mass spectrum (ESI): m/z 461, 463 M+H" reaction mixture is heated to ambient temperature overnight with stirring and then refluxed for a further 2 h. As there is still Example IX no reaction to be seen, the reaction mixture is cooled, com syn/anti-8-4-(3-chloro-2-fluoro-phenylamino)-7- bined with another 700 ulthionyl chloride while cooling with methoxy-quinazolin-6-yloxy)-1,3-diaza-spiro4.5 an ice bath and refluxed for another 8 h. As the reaction is still decan-2,4-dione not complete after cooling to ambient temperature, another 700 ul thionyl chloride are added while cooling with an ice 0199. bath. After a further 4 h of refluxing the reaction is complete and the solvent is distilled offusing the rotary evaporator. The flask residue is divided between methylene chloride and 10% potassium carbonate Solution. The aqueous phase is separated off and extracted with methylene chloride. The combined organic phases are dried on magnesium Sulphate and evapo C NH rated down. The flask residue is chromatographed through a F O O reversed phase column with an acetonitrile/water/ammonia N1 N mixture as eluant, in the course of which the cis and trans compounds can be separated. l 2 'YN N O (0193 Yield: 330 mg (16% of theory) N H (0194 Mass spectrum (ESI): m/z 475, 477 M+H" O Example VIII 0.195 cis/trans-1-amino-4-4-(3-chloro-2-fluoro-pheny C NH
lamino)-7-methoxy-quinazolin-6-yloxy-cyclohexanecar F boxylic acid N1 N
N -
C NH 0200. A suspension of 3.00 g 4-4-(3-chloro-2-fluoro F N1 N phenylamino)-7-methoxy-quinazolin-6-yloxy-cyclohex anone in 30 ml 60% aqueous ethanol is combined with 2.10 g le ammonium carbonate and 470 mg potassium cyanide and the N reaction mixture is refluxed for 2 h. After cooling to ambient temperature another 0.50 gammonium carbonate and 100 mg potassium cyanide are added and the reaction mixture is US 2011/0046148 A1 Feb. 24, 2011
refluxed for a further 2 h. Then the mixture is left overnight to (2) 4-(2,4-difluoro-3-methyl-phenyl)amino-6-(4-oxo-cy cool to ambient temperature, during which time a light-co clohexyloxy)-7-methoxy-quinazoline loured precipitate is formed. This is suction filtered, washed with water and dried. F 0201 Yield: 3.05 g (87% of theory) (0202 Mass spectrum (ESI"): m/z 486, 488 M+H" NH Example X F N1 N O 4-4-(3-chloro-2-fluoro-phenylamino)-7-methoxy quinazolin-6-yloxy-cyclohexanone leN O 0203
(0209 Mass spectrum (ESI"): m/z 414 M+H" (3) 4-(2-fluoro-3-methyl-phenyl)amino-6-(4-oxo-cyclo C NH hexyloxy)-7-methoxy-quinazoline F N1 N O
leN O NH
0204 3.25 ml phosphorus oxychloride are added drop wise to 6.50 g. 6-(1,4-dioxa-spiro4.5 dec-8-yloxy)-7-meth l 2 oxy-3H-quinazolin-4-one in 65 ml acetonitrile under an F CN O argon atmosphere. Then the reaction mixture is heated to 40° C., combined dropwise with 5.00 ml triethylamine and refluxed for 2 h. After cooling to ambient temperature 1.40 ml triethylamine and 2.60 ml 3-chloro-2-fluoro-aniline, dis 0210 Mass spectrum (ESI"): m/z 396 M+H" solved in 5 ml acetonitrile, are added and the reaction mixture is stirred overnight at 40° C. Then a further 0.70 ml of (4) 4(3-chloro-2-methyl-phenyl)amino-6-(4-oxo-cyclo 3-chloro-2-fluoro-aniline dissolved in 2 ml acetonitrile are hexyloxy)-7-methoxy-quinazoline added dropwise and the reaction mixture is stirred for a fur ther 10h. After cooling to ambient temperature the precipitate formed is suction filtered, taken up in 1 N hydrochloric acid, combined with 6 N isopropanolic hydrochloric acid and C NH stirred at ambient temperature until the ketal cleaving is com plete. The precipitate formed is suction filtered and combined with methylene chloride and 1 N sodium hydroxide solution. The aqueous phase is separated off and extracted with meth l 2 ylene chloride, the combined extracts are evaporated down CN N O and the flask residue is brought to crystallisation with diiso propylether. 0205 Yield: 5.90 g (73% of theory) 0206 Mass spectrum (ESI"): m/z 416, 418 M+H" 0211 Mass spectrum (ESI"): m/z 412, 414 M+H" 0207. The following compounds are obtained analogously (5) 4-(5-chloro-2-fluoro-phenyl)amino-6-(4-oxo-cyclo to Example X: hexyloxy)-7-methoxy-quinazoline 1) 4-(2-fluoro-5-methyl-phenyl)amino-6-(4-oxo-cyclo hexyloxy)-7-methoxy-quinazoline
F
C NH NH
O N1 N l 2 CN N O N - O O
0208 Mass spectrum (ESI"): m/z 396 M+H" 0212 Mass spectrum (ESI"): m/z 416, 418 M+H" US 2011/0046148 A1 Feb. 24, 2011
(6) 4-(4-fluoro-3-methyl-phenyl)amino-6-(4-oxo-cyclo activated charcoal (10%) and hydrogenated at 60°C. until the hexyloxy)-7-methoxy-quinazoline uptake of hydrogen has ended. Then the glacial acetic acid is distilled off using the rotary evaporator and evaporated off F with toluene. The flask residue is mixed with water and made alkaline with Saturated Sodium hydrogen carbonate solution. The precipitate formed is suction filtered and dried. NH 0218 Yield: 20.30 g (95% of theory) 0219 Mass spectrum (ESI"): m/z 333 M+H" N1 N O Example XII
N - O 3-benzyl-6-(1,4-dioxa-spiro4.5dec-8-yloxy)-7- methoxy-3H-quinazolin-4-one 0213 Mass spectrum (ESI"): m/z 396 M+H" 0220 (7) 4-(3-fluoro-5-methyl-phenyhamino-6-(4-oxo-cyclo O hexyloxy)-7-methoxy-quinazoline O F N lsN O N O 7 NH 0221, 20.00 g 3-benzyl-6-hydroxy-7-methoxy-3H quinazolin-4-one in 150 ml N,N-dimethylformamide are heated to 50°C., then 16.00g potassium carbonate and 20.00 l 2 g 1,4-dioxa-spiro4.5 dec-8-yl methaneSulphonate are added CN S.O and the reaction mixture is stirred overnight at 80°C. Then another 6.00 g potassium carbonate and 8.00 g 1,4-dioxa spiro4.5 dec-8-yl methanesulphonate are added and the 0214) Mass spectrum (ESI): m/z 396 M+H" mixture is stirred for a further 4 hat 80° C. Within the next 24 (8) (R)-4-(1-phenylethyl)amino-6-(4-oxo-cyclohexyloxy)- h a total of a further 6.00 g potassium carbonate and 10.00 g 7-methoxy-quinazoline 1,4-dioxa-spiro4.5 dec-8-yl methaneSulphonate are added batchwise until the reaction is complete. After cooling to ambient temperature a total of 450 ml of water are very slowly added dropwise with stirring, whereupon a precipitate is formed which is suction filtered, washed with water and dried. 0222 Yield: 27.20 g (91% of theory) 0223 Mass spectrum (ESI): m/z 423 M+H" Preparation of the End Compounds Example 1 anti-9-4-(3-chloro-2-fluoro-phenylamino)-7-meth oxy-quinazolin-6-yloxy)-1,4-diaza-spiro5.5unde can-5-one 0215 Mass spectrum (ESI"): m/z 392 M+H" 0224 Example XI 6-(1,4-Dioxa-spiro4.5 dec-8-yloxy)-7-methoxy-3H quinazolin-4-one 0216 C NH F O N21 O HN lsN lsN O N O 0225 1.30 ml 4N sodium hydroxide solution are added to 7 1.30 g methyl trans-1-(2-amino-ethylamino)-4-4-(3-chloro 0217 27.20 g of 3-benzyl-6-(1,4-dioxa-spiro4.5 dec-8- 2-fluoro-phenylamino)-7-methoxy-quinazolin-6-yloxy-cy yloxy)-7-methoxy-3H-quinazolin-4-one are dissolved in 270 clohexanecarboxylate in 14 ml of methanol and the reaction ml glacial acetic acid, combined with 2.70 g palladium on mixture is stirred for three hours at ambient temperature. US 2011/0046148 A1 Feb. 24, 2011
Then the solvent is distilled off in vacuo using the rotary triacetoxyborohydride are added to 400 mg anti-9-4-(3- evaporator. The flask residue is purified by chromatography chloro-2-fluoro-phenylamino)-7-methoxy-quinazolin-6- through a silica gel column with methylene chloride/metha yloxy)-1,4-diaza-spiro5.5undecan-5-one in 12 ml of tet no1/conc. ammonia (98/2/0.1 to 8/2/0.1) as eluant. The prod rahydrofuran. The reaction mixture is stirred overnight at uct fractions are evaporated down and stirred with diisopro ambient temperature, diluted with ethyl acetate, combined pylether. The solid residue is suction filtered and dried. with 1N sodium hydroxide solution and stirred. The organic 0226. Yield: 700 mg (57% of theory) phase is separated off, washed with water and Saturated 10227 R-value: 0.30 (silica gel, methylene chloride/metha Sodium chloride Solution, dried on magnesium Sulphate and no1/conc. ammonia=90:10:1) evaporated down. The flask residue is purified by chromatog 0228 Mass spectrum (ESI"): m/z 486, 488 M+H" raphy through a silica gel column with methylene chloride/ 0229. The following compounds are obtained analogously methanol/conc. ammonia (99/1/0.2 to 8/2/0.1) as eluant. The to Example 1: crude product is stirred with methanol, suction filtered and (1) anti-9-4-(3-chloro-2-fluoro-phenylamino)-7-methoxy dried. quinazolin-6-yloxy-4-methyl-1,4-diaza-spiro5.5undecan 0234 Yield: 230 mg (56% of theory) 5-one 0235 Mass spectrum (ESI"): m/z 500, 502 M+H" 0236. The following compound is obtained analogously to Example 2: (1) anti-9-4-(3-chloro-2-fluoro-phenylamino)-7-methoxy quinazolin-6-yloxy)-1,4-dimethyl-1,4-diaza-spiro5.5un C NH decan-5-one F N21 ls N C NH
F N21 0230 Mass spectrum (ESI): m/z 500, 502 M+H" (2) syn-9-4-(3-chloro-2-fluoro-phenylamino)-7-methoxy ls quinazolin-6-yloxy)-1,4-diaza-spiro5.5undecan-5-one N
0237 Mass spectrum (ESI): m/z 514, 516 M+H" C NH Example 3 F O O syn/anti-8,4-(3-chloro-2-fluoro-phenylamino)-7- N21 l methoxy-quinazolin-6-yloxy)-1,3-diaza-spiro4.5 ls .NN decan-2,4-dione N O HN 0238
0231 Mass spectrum (ESI): m/z 486, 488 M+H" Example 2 C NH anti-9-4-(3-chloro-2-fluoro-phenylamino)-7-meth F O O oxy-quinazolin-6-yloxy-1-methyl-1,4-diaza-spiro5. N1 N 5undecan-5-one l 2 'YN 0232 N O H- O
C NH
C NH F Na F N1 N lsN N -
0233 125ul of 37% aqueous formaldehyde solution, fol lowed by 50 ul of glacial acetic acid and 280 mg sodium US 2011/0046148 A1 Feb. 24, 2011
0239 A suspension of 3.00 g 4-4-(3-chloro-2-fluoro 0249. The compounds of general formula (I) according to phenylamino)-7-methoxy-quinazolin-6-yloxy-cyclohex the invention thus inhibit signal transduction by tyrosine anone in 30 ml of 60% aqueous ethanol is combined with 2.10 kinases, as demonstrated by the example of the human EGF gammonium carbonate and 470 mg potassium cyanide and receptor, and are therefore useful for treating pathophysi the reaction mixture is refluxed for 2 h. After cooling to ological is processes caused by hyperfunction of tyrosine ambient temperature a further 0.50 g ammonium carbonate kinases. These are e.g. benign or malignant tumours, particu and 100 mg potassium cyanide are added and the reaction larly tumours of epithelial and neuroepithelial origin, mixture is refluxed for a further 2 h. Then it is left overnight metastasisation and the abnormal proliferation of vascular to cool to ambient temperature, during which time a light endothelial cells (neoangiogenesis). Moreover, EGFR inhibi coloured precipitate is formed. This is suction filtered, tors are useful for the treatment of viral infections in which washed with water and dried. the virus uses the signal transduction pathway of the EGFR 0240 Yield: 3.05 g (87% of theory) for entering or attacking the cell or for replication or for the 0241 Mass spectrum (ESI"): m/z 486, 488 M+H" reaction of the host to the virus. 0250. The compounds according to the invention are also Biological Test useful for preventing and treating diseases of the airways and lungs which are accompanied by increased or altered produc 0242. The biological properties of the new compounds are tion of mucus caused by stimulation of tyrosine kinases, e.g. investigated as follows, for example: in inflammatory diseases of the airways Such as chronic bron 0243 The inhibition of the EGF-R-mediated signal trans chitis, chronic obstructive bronchitis, asthma, bronchiectasis, mission can be demonstrated e.g. with cells which express allergic or non-allergic rhinitis or sinusitis, cystic fibrosis, human EGF-R and whose survival and proliferation depend C.1-antitrypsin deficiency, or coughs, pulmonary emphy on stimulation by EGF or TGF-alpha. A murine haematopoi sema, pulmonary fibrosis and hyperreactive airways. The etic cell line is genetically modified so as to express func compounds are also useful for treating viral or bacterial com tional human EGF-R. The proliferation of this cell line can plications and for treating viral or bacterial infections of the therefore be stimulated by EGF. airways or lungs when tyrosine kinase is activated during the 0244. The test is carried out as follows: entry, replication or tissue reaction of the host. 0245. The cells are cultivated in RPMI/1640 medium. The 0251. The compounds are also suitable for treating dis proliferation is stimulated with 20 ng/ml of human EGF eases of the gastrointestinal tract and bile duct and gallblad (Promega). To investigate the inhibitory activity of the com der which are associated with disrupted activity of the pounds according to the invention these compounds are dis tyrosine kinases, such as may be found e.g. in chronic inflam solved in 100% dimethylsulphoxide (DMSO) and added to matory changes such as cholecystitis, Crohn's disease, ulcer the cultures in various dilutions, the maximum DMSO con ative colitis, and ulcers in the gastrointestinal tract or Such as centration being 1%. The cultures are incubated for 48 hours may occur in diseases of the gastrointestinal tract which are at 37° C. associated with increased secretions, such as Menetrier's dis 0246. In order to determine the inhibitory activity of the ease, secreting adenomas and protein loss syndrome. compounds according to the invention the relative cell num 0252. In addition, the compounds of general formula I and ber is measured in O.D. Units using the Cell Titer 96TM the physiologically acceptable salts thereof may be used to AQueous Non-Radioactive Cell Proliferation Assay treat other diseases caused by abnormal function of tyrosine (Promega). The relative cell number is calculated as a per kinases. Such as e.g. epidermal hyperproliferation (psoriasis), centage of the control and the concentration of active Sub benign prostatic hyperplasia (BPH), inflammatory processes, stance which inhibits the proliferation of the cells by 50% diseases of the immune system, hyperproliferation of hae (IC50) is derived therefrom. matopoietic cells, the treatment of nasal polyps, etc. 0247 The compounds of general formula (I) according to 0253) The compounds of formula (I) may be used on their the invention exhibit ICso values of <10 micromolar, prefer own or in combination with other active substances of for ably <1 micromolar, for example. mula (I). Optionally the compounds of formula (I) may also be used in combination with W, wherein W denotes a phar macologically active Substance and is selected (for example) Inhibition of EGFR-dependent proliferation from among the betamimetics, anticholinergics, corticoster Compound (Example No.) ICsonM oids, PDE4-inhibitors, LTD4-receptor (cysLT1, cysLT2, cysLT3) antagonists, EGFR-inhibitors, dopamine-agonists, 1 4 1 (1) 2 H1-antihistamines, PAF-antagonists, SYK-inhibitors, PDE3 1 (2) 2 inhibitors, lipoxin A4 derivatives, FPRL1 modulators, LTB4 2 1 receptor (BLT1, BLT2) antagonists, histamine H1 receptor 2 (1) 2 antagonists, histamine H4 receptor antagonists, PI3 kinase inhibitors, inhibitors of non-receptor tyrosine kinases such as for example LYN, LCK, SYK, ZAP-70, FYN, BTK or ITK, Indications inhibitors of MAP kinases such as for example p38, ERK1, ERK2, JNK1, JNK2, JNK3 or SAP, inhibitors of the NF 0248. As has been found, the compounds of formula (I) are kappaB signal pathway Such as for example IKK kinase characterised by their versatility in the therapeutic field. Par inhibitors, iNOS inhibitors, MRP4 inhibitors, leukotriene ticular mention should be made of the possible applications biosynthesis inhibitors such as for example 5-lipoxygenase for which the compounds of formula (I) according to the (5-LO) inhibitors, cELA2 inhibitors, leukotriene A4 hydro invention are preferably used on the basis of their pharma lase inhibitors or FLAP inhibitors, non-steroidal anti-inflam ceutical efficacy as tyrosine inhibitors. matory agents (NSAIDs), CRTH2 antagonists, DP1-receptor
US 2011/0046148 A1 Feb. 24, 2011 hydroxyethyl-2-(hydroxymethyl)phenol, (R.S) N-3-(1,1- cyclopropyltropine 9-hydroxy-xanthene-9-carboxylate difluoro-2-6-(2-hydroxy-2-4-hydroxy-3- methobromide, cyclopropyltropine 9-methyl-fluorene-9-car (hydroxymethyl)phenylethylamino)hexyloxyethyl) boxylate methobromide, cyclopropyltropine 9-methyl-xan phenylurea, 3-3-(1,1-difluoro-2-6-(2-hydroxy-2-4- thene-9-carboxylate methobromide, cyclopropyltropine hydroxy-3-(hydroxymethyl)phenylethyl-amino)hexyl 9-hydroxy-fluorene-9-carboxylate methobromide, cyclopro oxyethyl)phenyl)imidazolidine-2,4-dione, (R.S)-4-2-(6- pyltropine methyl 4,4'-difluorobenzilate methobromide, tro 2,2-difluoro-2-(3-methoxyphenyl)ethoxylhexylamino)-1- penol 9-hydroxy-xanthene-9-carboxylate methobromide, hydroxyethyl-2-(hydroxymethyl)phenol, 5-((1R)-2-6-(2, scopine 9-hydroxy-xanthene-9-carboxylate methobromide, 2-difluoro-2-phenylethoxy)hexylamino-1-hydroxyethyl)- tropenol 9-methyl-xanthene-9-carboxylate-methobromide, 8-hydroxyquinolin-2(1H)-one, 4-((1R)-2-4.4-difluoro-6- scopine 9-methyl-xanthene-9-carboxylate-methobromide, (4-phenylbutoxy)hexylamino-1-hydroxy-ethyl)-2- tropenol 9-ethyl-xanthene-9-carboxylate methobromide, tro (hydroxymethyl)phenol, (R.S)-4-(2-6-(3.3-difluoro-3- penol 9-difluoromethyl-xanthene-9-carboxylate methobro phenylpropoxy)hexylamino-1-hydroxy ethyl)-2- mide, scopine 9-hydroxymethyl-xanthene-9-carboxylate (hydroxymethyl)phenol, (R.S)-(2-6-(2,2-difluoro-2- methobromide. phenylethoxy)-4.4-difluorohexylamino-1-hydroxyethyl)- 0263. The above-mentioned compounds may also be used 2-(hydroxymethyl)phenol and (R.S)-4-(2-6-(2,2-difluoro as salts within the scope of the present invention, while 3-phenylpropoxy)hexylamino-1-hydroxy-ethyl)-2- instead of the methobromide, the metho-X salts may be used (hydroxymethyl)phenol, wherein X may have the meanings given hereinbefore for X. optionally in the form of other racemates, enantiomers, dias 0264 Compounds which may be used as corticosteroids tereomers and optionally in the form of the pharmacologi are preferably those selected from among beclomethasone, cally acceptable acid addition salts, Solvates or hydrates betamethasone, budesonide, butiXocort, ciclesonide, deflaza thereof. Preferably, according to the invention, the acid addi cort, dexamethasone, etiprednol, flunisolide, fluticaSone, tion salts of the betamimetics are selected from among the loteprednol, mometaSone, prednisolone, prednisone, rofile hydrochloride, hydrobromide, hydroiodide, hydrosulphate, ponide, triamcinolone, tipredane and pregna-1,4-diene-3.20 hydrophosphate, hydromethanesulphonate, hydronitrate, dione, 6-fluoro-1 1-hydroxy-16,17-(1-methylethylidene)bis hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, (oxy)-21-4-(nitrooxy)methylbenzoyloxy), (66., 11B, 16 hydrotartrate, hydroxalate, hydroSuccinate, hydrobenzoate 6)–(9CI) (NCX-1024), 16,17-butylidenedioxy-6,9-difluoro and hydro-p-toluenesulphonate. 11-hydroxy-17-(methylthio)androst-4-en-3-one (RPR 0261 Examples of anticholinergics which may be used 106541), (S)-fluoromethyl 6,9-difluoro-17-(2-furanylcarbo here preferably include compounds which are selected from nyl)oxy-11-hydroxy-16-methyl-3-oxo-androsta-1,4-diene among: tiotropium salts, preferably the bromide salt, 17-carbothionate, (S)-(2-oxo-tetrahydro-furan-3S-yl) 6.9- oxitropium salts, preferably the bromide salt, flutropium difluoro-1 1-hydroxy-16-methyl-3-oxo-17-propionyloxy salts, preferably the bromide salt, ipratropium salts, prefer androsta-1,4-dien-17-carbothionate, cyanomethyl 6alpha, ably the bromide salt, aclidinium salts, preferably the bro 9alpha-difluoro-11beta-hydroxy-16alpha-methyl-3-oxo mide salt, glycopyrronium salts, preferably the bromide salt, 17alpha-(2,2,3,3-tetramethylcyclopropylcarbonyl)oxy trospium salts, preferably the chloride salt, tolterodine, (3R)- androsta-1,4-diene-17beta-carboxylate, optionally in the 1-phenethyl-3-(9H-xanthen-9-carbonyloxy)-1-azoniabicy form of the racemates, enantiomers or diastereomers thereof clo2.2.2]octane-salts. In the above-mentioned salts the cat and optionally in the form of the salts and derivatives thereof, ions are the pharmacologically active constituents. AS X the solvates and/or hydrates thereof. Any reference to steroids anions the above-mentioned salts may preferably contain includes a reference to any salts or derivatives, hydrates or chloride, bromide, iodide, Sulphate, phosphate, methane solvates thereof which may exist. Examples of possible salts Sulphonate, nitrate, maleate, acetate, citrate, fumarate, tar and derivatives of the steroids may be: alkali metal salts, such trate, oxalate. Succinate, benzoate or p-toluenesulphonate, as for example Sodium or potassium salts, Sulphobenzoates, while chloride, bromide, iodide, sulphate, methanesulpho phosphates, isonicotinates, acetates, dichloroacetates, propi nate or p-toluenesulphonate are preferred as counter-ions. Of onates, dihydrogen phosphates, palmitates, pivalates or all the salts the chlorides, bromides, iodides and methane furoates. Sulphonates are particularly preferred. 0265 PDE4-inhibitors which may be used are preferably 0262. Other specified compounds are: tropenol 2,2-diphe compounds selected from among enprofyllin, theophyllin, nylpropionate methobromide, scopine 2,2-diphenylpropi roflumilast, arifilo (cilomilast), tofimilast, pumafentrin, lir onate methobromide, scopine 2-fluoro-2,2-diphenylacetate imilast, apremilast, arofyllin, atizoram, oglemilastum, methobromide, tropenol 2-fluoro-2,2-diphenylacetate tetomilast, and 5-(N-(2,5-dichloro-3-pyridinyl)-carboxa methobromide, tropenol 3.3',4,4-tetrafluorobenzilate metho mid-8-methoxy-quinoline (D-4418), 5-N-(3.5-dichloro-1- bromide, scopine 3,3',4,4-tetrafluorobenzilate methobro oxido-4-pyridinyl)-carboxamid-8-methoxy-2-(trifluorom mide, tropenol 4,4'-difluorobenzilate methobromide, scopine ethyl)-quinoline (D-4396 (Sch-351591)), N-(3,5- 4,4'-difluorobenzilate methobromide, tropenol 3,3'-difluo dichloropyrid-4-yl)-1-(4-fluorobenzyl)-5-hydroxy-indol-3- robenzilate methobromide, scopine 3,3'-difluorobenzilate ylglyoxylic acid amide (AWD-12-281 (GW-842470)), methobromide; tropenol 9-hydroxy-fluorene-9-carboxylate 9-(2-fluorophenyl)methyl-N-methyl-2-(trifluoromethyl)- methobromide, tropenol 9-fluoro-fluorene-9-carboxylate 9H-purin-6-amine (NCS-613), 4-(2R)-2-3-(cyclopenty methobromide, scopine 9-hydroxy-fluorene-9-carboxylate loxy)-4-methoxyphenyl-2-phenylethyl-pyridine (CDP methobromide, scopine 9-fluoro-fluorene-9-carboxylate 840), N-(3R)-3,4,6,7-tetrahydro-9-methyl-4-oxo-1- methobromide; tropenol 9-methyl-fluorene-9-carboxylate phenylpyrrolo3.2.1-jk 1.4benzodiazepin-3-yl)-4- methobromide, scopine 9-methyl-fluorene-9-carboxylate pyridinecarboxamide (PD-168787), 4-6,7-dethoxy-2,3-bis methobromide, cyclopropyltropine benzilate methobromide, (hydroxymethyl)-1-naphthalenyl-1-(2-methoxyethyl)-2 cyclopropyltropine 2,2-diphenylpropionate methobromide, (1H)-pyridinone (T-440), 2-4-6,7-diethoxy-2,3-bis
US 2011/0046148 A1 Feb. 24, 2011 22
{N-2-(ethoxycarbonyl)-ethyl-N-(ethoxycarbonyl) (MN-001), 1-(((R)-(3-(2-(6,7-difluoro-2-quinolinyl)ethenyl) methylamino-1-oxo-2-buten-1-yl)aminol-7-cyclopropyl phenyl)-3-(2-(2-hydroxy-2-propyl)phenyl)thio)methylcy methoxy-quinazoline, clopropaneacetic acid, 1-(((1(R)-3(3-(2-(2,3-dichlorothieno optionally in the form of the racemates, enantiomers, diaste 3.2-bipyridin-5-yl)-(E)-ethenyl)phenyl)-3-(2-(1-hydroxy reomers thereof and optionally in the form of the pharmaco 1-methylethyl)phenyl)propyl)thio)methyl) logically acceptable acid addition salts, Solvates or hydrates cyclopropaneacetic acid, 2-2-(4-tert-butyl-2-thiazolyl)-5- thereof. According to the invention the preferred acid addition benzofuranyloxymethylphenyl)acetic acid optionally in the salts are selected from among hydrochloride, hydrobromide, form of the racemates, enantiomers, diastereomers thereof hydriodide, hydroSulphate, hydrophosphate, hydromethane and optionally in the form of the pharmacologically accept Sulphonate, hydronitrate, hydromaleate, hydroacetate, able acid addition salts, solvates or hydrates thereof. Accord hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, ing to the invention the preferred acid addition salts are hydroSuccinate, hydrobenzoate and hydro-p-toluenesulpho selected from among hydrochloride, hydrobromide, hydrio nate. dide, hydroSulphate, hydrophosphate, hydromethaneSulpho 0267 Dopamine receptor agonists used here are prefer nate, hydronitrate, hydromaleate, hydroacetate, hydrocitrate, ably compounds selected from among bromocriptin, caber hydrofumarate, hydrotartrate, hydroxalate, hydroSuccinate, golin, alpha-dihydroergocryptin, lisuride, pergolide, prami hydrobenzoate and hydro-p-toluenesulphonate. pexol, roXindol, topinirol, talipexol, tergurid and vioZan, 0271. By salts or derivatives which the LTD4-receptor optionally in the form of the racemates, enantiomers, diaste antagonists are optionally capable of forming are meant, for reomers thereof and optionally in the form of the pharmaco example: alkali metal salts, such as for example Sodium or logically acceptable acid addition salts, Solvates or hydrates potassium salts, alkaline earth metal salts, Sulphobenzoates, thereof. According to the invention the preferred acid addition phosphates, isonicotinates, acetates, propionates, dihydrogen salts are selected from among hydrochloride, hydrobromide, phosphates, palmitates, pivalates or furoates. hydriodide, hydroSulphate, hydrophosphate, hydromethane 0272. Histamine H1 receptor antagonists that may be used Sulphonate, hydronitrate, hydromaleate, hydroacetate, are preferably compounds selected from among epinastine, hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, cetirizine, azelastine, fexofenadine, levocabastine, lorata hydroSuccinate, hydrobenzoate and hydro-p-toluenesulpho dine, mizolastine, ketotifen, emedastine, dimetinden, clem nate. astine, bamipine, ceXchlorpheniramine, pheniramine, doxy 0268 PAF-antagonists used here are preferably com lamine, chlorophenoxamine, dimenhydrinate, pounds selected from among lexipafant and 4-(2-chlorophe diphenhydramine, promethazine, ebastine, olopatadine, nyl)-9-methyl-2-3 (4-morpholinyl)-3-propanon-1-yl)-6H desloratidine and meclozine, optionally in the form of the thieno-3.2-f-1.2.4 triazolo 4.3-a 1.4diazepines, 6-(2- racemates, enantiomers, diastereomers thereof and option chlorophenyl)-8.9-dihydro-1-methyl-8-(4-morpholinyl) ally in the form of the pharmacologically acceptable acid carbonyl-4H.7H-cyclo-penta-4.5thieno-3.2-f 1.2.4 addition salts, Solvates or hydrates thereof. According to the triazolo 4.3-a 1.4diazepines, invention the preferred acid addition salts are selected from optionally in the form of the racemates, enantiomers, diaste among hydrochloride, hydrobromide, hydriodide, hydrosul reomers thereof and optionally in the form of the pharmaco phate, hydrophosphate, hydromethaneSulphonate, hydroni logically acceptable acid addition salts, Solvates or hydrates trate, hydromaleate, hydroacetate, hydrocitrate, hydrofuma thereof. According to the invention the preferred acid addition rate, hydrotartrate, hydroxalate, hydroSuccinate, salts are selected from among hydrochloride, hydrobromide, hydrobenzoate and hydro-p-toluenesulphonate. hydriodide, hydroSulphate, hydrophosphate, hydromethane 0273. Histamine H4 receptor antagonists that may be used Sulphonate, hydronitrate, hydromaleate, hydroacetate, are preferably compounds Such as e.g. (5-chloro-1H-indol-2- hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, yl)(4-methyl-1-piperazinyl)-methanone (JNJ-7777120), hydroSuccinate, hydrobenzoate and hydro-p-toluenesulpho optionally in the form of the racemates, enantiomers, diaste nate. reomers thereof and optionally in the form of the pharmaco 0269 LTB4-receptor antagonists used here are preferably logically acceptable acid addition salts, Solvates or hydrates compounds selected from among for example amebulant thereof. According to the invention the preferred acid addition (ethyl 4-3-4-1-(4-hydroxyphenyl)-1-methylethyl salts are selected from among hydrochloride, hydrobromide, phenoxymethylphenylmethoxyphenyliminomethyl hydriodide, hydroSulphate, hydrophosphate, hydromethane carbamate), optionally in the form of the racemates, enanti Sulphonate, hydronitrate, hydromaleate, hydroacetate, omers, diastereomers thereofandoptionally in the form of the hydrocitrate, hydrofumarate, hydrotartrate, hydroxalate, pharmacologically acceptable acid addition salts, Solvates or hydroSuccinate, hydrobenzoate and hydro-p-toluenesulpho hydrates thereof. According to the invention the preferred nate. acid addition salts are selected from among hydrochloride, 0274 Inhibitors of non-receptor tyrosine kinases that may hydrobromide, hydriodide, hydrosulphate, hydrophosphate, be used such as for example LYN, LCK, SYK, ZAP-70, FYN, hydromethanesulphonate, hydronitrate, hydromaleate, BTK or ITK are preferably compounds selected from among hydroacetate, hydrocitrate, hydrofumarate, hydrotartrate, 2-(2-aminoethyl)amino-4-(3-bromophenyl)amino-5-py hydroxalate, hydroSuccinate, hydrobenzoate and hydro-p- rimidinecarboxamide: 2-7-(3,4-dimethoxyphenyl)imidazo toluenesulphonate. 1.2-cpyrimidin-5-ylamino-3-pyridinecarboxamide; 0270) LTD4-receptor antagonists used here are preferably 6-5-fluoro-2-3.4,5-trimethoxyphenyl)amino-4-pyrimidi compounds selected from among montelukast, pranlukast, nyl)amino-2,2-dimethyl-2H-pyrido 3.2-b-1,4-oxazin-3 Zafirlukast, and (E)-8-2-4-4-(4-fluorophenyl)butoxylphe (4H)-one; N-3-bromo-7-(4-methoxyphenyl)-1,6-naphthyri nyl]ethenyl-2-(1H-tetrazol-5-yl)-4H-1-benzopyran-4-one din-5-yl-1,3-propanediamine, 7-(4-methoxyphenyl)-N- (MEN-91507), 446-acetyl-3-3-(4-acetyl-3-hydroxy-2-pro methyl-1,6-naphthyridin-5-amine; N-7-(4- pylphenylthio)propoxy-2-propylphenoxybutyric acid methoxyphenyl)-1,6-naphthyridin-5-yl-1,3-
US 2011/0046148 A1 Feb. 24, 2011 24 eridinyl)-1,6-naphthyridin-5-amine; N-7-3-bromo-4-(dim (S)-4-(2-acetimidoylamino-ethylsulphanyl)-2-amino-bu ethylamino)phenyl-1,6-naphthyridin-5-yl-1,3-propanedi tyric acid (GW274150), 2-2-(4-methoxy-pyridin-2-yl)- amine; N-7-(1-methyl-1H-indol-5-yl)-1,6-naphthyridin-5- ethyl-3H-imidazo[4,5-b]pyridine (BYK191023), 2-((R)-3- yl-1,3-propanediamine; N-7-3-(trifluoromethyl)phenyl amino-1-phenyl-propoxy)-4-chloro-5-fluorobenzonitrile, 1.6-naphthyridin-5-yl-1,3-propanediamine; N-7-4- 2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl-butylsulpha (trifluoromethyl)phenyl-1,6-naphthyridin-5-yl-1,3- nyl)-6-trifluoromethyl-nicotinonitrile, 2-((1R,3S)-3-amino propanediamine; N-7-(3-bromo-4-methoxyphenyl)-1,6- 4-hydroxy-1-thiazol-5-yl-butylsulphanyl)-4-chloro-ben naphthyridin-5-yl-1,3-propanediamine; N-7-4-3- (dimethylamino)propylmethylaminophenyl-1,6- Zonitrile, 2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5-yl naphthyridin-5-yl-1,4-cyclohexanediamine; N-7-4-2- butylsulphanyl)-5-chloro-benzonitrile, (2S,4R)-2-amino-4- (dimethylamino)ethylmethylaminophenyl-1,6- (2-chloro-5-trifluoromethyl-phenylsulphanyl)-4-thiazol-5- naphthyridin-5-yl-1,4-cyclohexanediamine; N-7-4- yl-butan-1-ol. 2-((1R,3S)-3-amino-4-hydroxy-1-thiazol-5- (dimethylamino)-3-methoxyphenyl-1,6-naphthyridin-5- yl-butylsulphanyl)-5-chloro-nicotinonitrile, 4-((S)-3-amino yl-1,4-cyclohexanediamine; N-7-4-(4-morpholinyl) 4-hydroxy-1-phenyl-butylsulphanyl)-6-methoxy phenyl-1,6-naphthyridin-5-yl-1,4-cyclohexanediamine; nicotinonitrile, Substituted 3-phenyl-3,4-dihydro-1- N-7-3-bromo-4-(4-morpholinyl)phenyl-1,6-naphthyridin isoquinolinamine such as e.g. (1S,5S,6R)-7-chloro-5- 5-yl-1,4-cyclohexanediamine; 4-7-4-2-(dimethy methyl-2-aza-bicyclo4.1.0 hept-2-en-3-ylamine (ONO lamino)ethylmethylaminophenyl-1,6-naphthyridin-5-yl) 1714), (4R,5R)-5-ethyl-4-methyl-thiazolidin-2- oxy-cyclohexanol: N-7-3-bromo-4-(4-morpholinyl) ylideneamine, (4R,5R)-5-ethyl-4-methyl-selenazolidin-2- phenyl-1,6-naphthyridin-5-yl-1,3-propanediamine; N.N- ylideneamine, 4-aminotetrahydrobiopterine, (E)-3-(4- dimethyl-4-5-(4-methyl-1-piperazinyl)-1,6-naphthyridin-7- chloro-phenyl)-N-(1-2-oxo-2-4-(6-trifluoromethyl yl-benzenamine; 4-7-4-3-(dimethylamino)propyl pyrimidin-4-yloxy)-piperidin-1-yl-ethylcarbamoyl-2- methylaminophenyl-1,6-naphthyridin-5-yloxy pyridin-2-yl-ethyl)-acrylamide (FR260330), 3-(2,4-difluoro cyclohexanol: N-7-4-2-(dimethylamino)ethyl phenyl)-6-2-(4-imidazol-1-ylmethyl-phenoxy)-ethoxy-2- methylaminophenyl-1,6-naphthyridin-5-yl-1,4- phenyl-pyridine (PPA250), methyl 3-Rbenzo. 1.3dioxol-5- butanediamine; 1,1-dimethylethyl 3-5-(3-aminopropyl) ylmethyl)-carbamoyl-methyl)-4-(2-imidazol-1-yl amino-7-(4-methoxyphenyl)-1,6-naphthyridin-2-ylamino pyrimidin-4-yl)-piperazine-1-carboxylate (BBS-1), (R)-1- propyl-carbamate, optionally in the form of the racemates, (2-imidazol-1-yl-6-methyl-pyrimidin-4-yl)-pyrrolidin-2- enantiomers, diastereomers thereof and optionally in the carboxylate (2-benzo. 1.3dioxol-5-yl-ethyl)-amide (BBS-2) form of the pharmacologically acceptable acid addition salts, and the pharmaceutical salts, prodrugs or Solvates thereof. solvates or hydrates thereof. According to the invention the (0278. As iNOS-inhibitors within the scope of the present preferred acid addition salts are selected from among hydro invention it is also possible to use antisense oligonucleotides, chloride, hydrobromide, hydriodide, hydrosulphate, hydro particularly those antisense oligonucleotides that bind iNOS phosphate, hydromethaneSulphonate, hydronitrate, hydro coding nucleic acids. For example, WO 01/52902 describes maleate, hydroacetate, hydrocitrate, hydrofumarate, antisense oligonucleotides, particularly antisense oligonucle hydrotartrate, hydroxalate, hydroSuccinate, hydrobenzoate otides that bind iNOS coding nucleic acids, for modulating and hydro-p-toluenesulphonate. the expression of iNOS. (0275 MAP Kinase inhibitors used are preferably com (0279 MRP4-inhibitors used are preferably compounds pounds selected from among: selected from among N-acetyl-dinitrophenyl-cysteine, 0276 bentamapimod (AS-602801), doramapimod cGMP cholates, diclofenac, dehydroepiandrosterone 3-glu (BIRB-796), 5-carbamoylindole (SD-169), 6-Raminocarbo curonide, dehydroepiandrosterone 3-sulphate, dilaZep, dini nyl)(2,6-difluorophenyl)amino-2-(2,4-difluorophenyl)-3- trophenyl-S-glutathione, estradiol 17-glucuronide, estradiol pyridinecarboxamide (VX-702), alpha-2-2-(3-pyridinyl) 3,17-disulphate, estradiol 3-glucuronide, estradiol 3-sul ethylamino-4-pyrimidinyl-2-benzothiazoleacetonitrile phate, estrone 3-sulphate, flurbiprofen, folate, n5-formyl-tet (AS-601 245), 9,12-epoxy-1H-diindolo.1.2.3-fg:3'2", 1'-kl rahydrofolate, glycocholate, glycolithocholic acid Sulphate, pyrrolo3.4-i 1.6 benzodiazocine-10-carboxylic acid (CEP ibuprofen, indomethacin, indoprofen, ketoprofen, lithocholic 1347) and 443-(4-chlorophenyl)-5-(1-methyl-4-piperidinyl)- acid sulphate sulphate, methotrexate, ((E)-3-342-(7- 1H-pyrazole-4-yl-pyrimidine (SC-409), chloro-2-quinolinypethenylphenyl-3-dimethylamino)-3- optionally in the form of the racemates, enantiomers, diaste Oxopropylthiomethylthio-propanoic acid), alpha-naph reomers thereof and optionally in the form of the pharmaco thyl-beta-D-glucuronide, nitrobenzyl mercaptopurine logically acceptable acid addition salts, Solvates or hydrates riboside, probenecid, sildenafil. Sulphinepyrazone, tauro thereof. chenodeoxycholate, taurocholate, taurodeoxycholate, tau 0277 iNOS-inhibitors used are preferably compounds rolithocholate, topotecan, trequinsin, Zaprinast and dipy selected from among: S-(2-aminoethyl)isothiourea, ami ridamole, optionally in the form of the racemates, noguanidine, 2-aminomethylpyridine, 5,6-dihydro-6-me enantiomers and diastereomers thereof and the pharmaco thyl-4H-1,3-thiazin-2-amine (AMT), L-canavanine, 2-imi logically acceptable acid addition salts and hydrates thereof. nopiperidine, S-isopropylisothiourea, S-methylisothiourea, 0280. The leukotriene biosynthesis inhibitors used such as S-ethylisothiourea, S-methyltiocitrulline, S-ethylthiocitrul for example those selected from among the 5-lipoxygenase line, L-NA (N'-nitro-L-arginine), L-NAME (N'-nitro-L- (5-LO) inhibitors, cELA2 inhibitors, leukotriene A4 hydro argininemethylester), L-NMMA (N'-monomethyl-L-argin lase inhibitors or FLAP inhibitors, are preferably compounds ine), L-NIO (N'-iminoethyl-L-ornithine), L-NIL (N'- selected is from among Zileuton, tipelukast, licofelone, dara iminoethyl-lysine), (S)-6-acetimidoylamino-2-amino pladib, optionally in the form of the racemates, enantiomers hexanoic acid (1H-tetrazol-5-yl)-amide (SC-51), N-3- and diastereomers thereof and the pharmacologically accept (aminomethyl)phenylmethyl-ethanimidamide (1400W), able acid addition salts and hydrates thereof. US 2011/0046148 A1 Feb. 24, 2011
0281. Non-steroidal anti-inflammatories (NSAIDs) that Zumab, optionally in the form of the racemates, enantiomers may be used are preferably compounds selected from among and diastereomers thereof and optionally in the form of the piroXicam, diclofenac, naproxen, flurbiprofen, fenoprofen, pharmacologically acceptable acid addition salts, prodrugs, ketoprofen, ibuprofen, nimeSulide, indomethacin, Sulindac, solvates or hydrates thereof. aZapropaZone, phenylbutaZone, aspirin; meloxicam, cele 0288. Mucoregulators that may be used are preferably coxib, rofecoxib, Valdecoxib, lumarocoxib, parecoxib, compounds selected from among: tenoxicam and etoricoxib, optionally in the form of the race 3-2-oxo-2-2-3-(trifluoromethyl)phenylamino-3-pyridi mates, enantiomers and diastereomers thereof and optionally nylethyl-1 (3H)-isobenzofuranone (MSI-2216), erdosteine, in the form of the pharmacologically acceptable acid addition fluorovent, talniflumate, fudosteine, optionally in the form of salts, prodrugs, Solvates or hydrates thereof. the racemates, enantiomers and diastereomers thereof and 0282 CRTH2 antagonists used are preferably compounds optionally in the form of the pharmacologically acceptable selected from among ramatroban and laropiprant, optionally acid addition salts, prodrugs, Solvates or hydrates thereof. in the form of the racemates, enantiomers and diastereomers 0289 PPARgamma agonists that may be used are prefer thereof and optionally in the form of the pharmacologically ably compounds selected from among: rosiglitaZone, ciglita acceptable acid addition salts, prodrugs, Solvates or hydrates Zone, pioglitaZone and N-2-2-(3-fluorophenyl)imino-4- thereof. 4-(4-morpholinyl)phenyl-3(2H)-thiazolyl)ethyl-N'- 0283 DP1-receptor modulators used are preferably com methyl-urea (SMP-028), optionally in the form of the pounds selected from among 7-(1R,2R,3S,5S)-2-(5-hy racemates, enantiomers and diastereomers thereof and droxybenzobthien-3-yl)carbonyl)amino-6,6-dimethylbi optionally in the form of the pharmacologically acceptable cyclo[3.1.1 hept-3-yl), (5Z)-5-heptenoic acid (S-5751), acid addition salts, prodrugs, Solvates or hydrates thereof. laropiprant, and 2-4-(1R,2S,3R,5R)-5-chloro-2-(3S)-3- cyclohexyl-3-hydroxy-1-propyn-1-yl)-3-hydroxycyclopen 0290 Rho kinase inhibitors that may be used are prefer tylbutylthioacetic acid (TS-002), optionally in the form of ably compounds such as e.g. Fasudil, optionally in the form of the racemates, enantiomers and diastereomers thereof and the racemates, enantiomers and diastereomers thereof and optionally in the form of the pharmacologically acceptable optionally in the form of the pharmacologically acceptable acid addition salts, prodrugs, Solvates or hydrates thereof. acid addition salts, prodrugs, Solvates or hydrates thereof. 0284. Thromboxane receptor antagonists used here are 0291 Adenosine receptor modulators that may be used are preferably compounds selected from among seratrodast, preferably compounds selected from among 4-(3,4-dichlo N-(1,1-dimethylethyl)aminocarbonyl-2-(4-methylphe rophenyl)-5-(4-pyridinyl)-2-thiazolamine (CGH-2466), nyl)amino)-5-nitro-benzenesulphonamide (BM-573), (+/-)- 3-ethyl-3,9-dihydro-1-propyl-8-1-3-(trifluoromethyl)phe Sodium 2-(4-chlorophenylsulphonylaminomethyl)-indan-5- nyl)methyl)-1H-pyrazol-4-yl)-1H-purine-2,6-dione (CVT yl)acetate monohydrate (Z-335) and 2-4-(4- 6883), N-(4-cyanophenyl)-2-[4-(2.3.6.9-tetrahydro-2,6-di chlorophenyl)sulphonyl)aminobutyl 3-4-(1- OXO-1,3-dipropyl-1H-purin-8-yl)phenoxy-acetamide methylethyl)-2-thiazolylmethoxyphenylmethylamino (MRS-1754), optionally in the form of the racemates, enan sulphonyl-benzoic acid (KP-496), is optionally in the form tiomers and diastereomers thereof and optionally in the form of the racemates, enantiomers and diastereomers thereof and of the pharmacologically acceptable acid addition salts, pro optionally in the form of the pharmacologically acceptable drugs, Solvates or hydrates thereof. acid addition salts, prodrugs, Solvates or hydrates thereof. 0292 Bradykinin (BK2 or BK1) antagonists that may be 0285 Chemokine receptor antagonists that may be used used are preferably compounds selected from among icati are preferably compounds selected from among N-5-chloro bant and 1-piperazinepentanaminium, delta-amino-4-4- 2-2-(2R)-4-(4-fluorophenyl)methyl-2-methyl-1-piper 2,4-dichloro-3-(2,4-dimethyl-8-quinolinyl)oxymethyl azinyl)-2-oxoethoxyphenyl-urea hydrochloride (1:1) (BX phenylsulphonylaminoltetrahydro-2H-pyran-4-yl 471), 2. N-(1S,2S,4R)-4-(aminocarbonyl)-1-(3- carbonyl-N,N,N-trimethyl-c-oxo, chloride, hydrochloride fluorophenyl)methyl-2,7-dihydroxy-7-methyloctyl (1:1:1), (deltaS)—(MEN-16132), is optionally in the form of quinoxalinecarboxamide (CP-481715), (4,6-dimethyl-5- the racemates, enantiomers and diastereomers thereof and pyrimidinyl)-4-(3S)-4-(1R)-2-methoxy-1-4- optionally in the form of the pharmacologically acceptable (trifluoromethyl)phenylethyl-3-methyl-1-piperazinyl-4- acid addition salts, prodrugs, Solvates or hydrates thereof. methyl-1-piperidiny-methanone (Sch-417690), 2-hydroxy 0293 Endothelin antagonists that may be used are prefer N,N-dimethyl-3-2-(1R)-1-(5-methyl-2-furanyl)propyl ably compounds selected from among actelion-1, ambrisen amino-3,4-dioxo-1-cyclobuten-1-yl)amino-benzamide tan, Sitaxsentan, N-(2-acetyl-4,6-dimethylphenyl)-3-(4- (SCH-527123) and 14.8, 11-tetraazacyclotetradecane, 1.11, chloro-3-methyl-5-isoxazolyl)aminosulphonyl-2- 4-phenylenebis(methylene)bis, hydrochloride (1:8) (AMD thiophenecarboxamide (TBC-3214) and bosentan, optionally 3100), optionally in the form of the racemates, enantiomers in the form of the racemates, enantiomers and diastereomers and diastereomers thereof and optionally in the form of the thereof and optionally in the form of the pharmacologically pharmacologically acceptable acid addition salts, prodrugs, acceptable acid addition salts, prodrugs, Solvates or hydrates solvates or hydrates thereof. thereof. 0286 Neurokinin (NK1 or NK2) antagonists that may be 0294 Interleukin 1-beta converting enzyme (ICE) inhibi used are preferably compounds selected from among: Saredu tors that may be used are preferably compounds selected from tant, nepadutant and figopitant, optionally in the form of the among pralnacasanand N-(4-amino-3-chlorobenzoyl)-3-me racemates, enantiomers and diastereomers thereof and thyl-L-valyl-N-(2R,3S)-2-ethoxytetrahydro-5-oxo-3-fura optionally in the form of the pharmacologically acceptable nyl-L-prolinamide (VX-765), optionally in the form of the acid addition salts, prodrugs, Solvates or hydrates thereof. racemates, enantiomers and diastereomers thereof and 0287 Sphingosine1-phosphate receptor modulators that optionally in the form of the pharmacologically acceptable may be used are preferably compounds such as e.g. Sonepci acid addition salts, prodrugs, Solvates or hydrates thereof. US 2011/0046148 A1 Feb. 24, 2011 26
0295 Toll-like receptor (TLR) modulators that may be 0304 Preferred PI3 kinase antagonists which may be used used are preferably compounds selected from among residui here are preferably compounds selected from among 5-(qui mod, heplisav, resatorvid (TAK-242), optionally in the form noxalin-6-ylmethylene)thiazolidine-2,4-dione (AS-605240), of the racemates, enantiomers and diastereomers thereof and 2-(6-amino-9H-purin-9-yl)methyl-5-methyl-3-(2-meth optionally in the form of the pharmacologically acceptable ylphenyl)-4(3H)-quinazolinone (C-87114), and 2-methyl-2- acid addition salts, prodrugs, Solvates or hydrates thereof. 4-3-methyl-2-oxo-8-(quinoline-3-yl)-2,3-dihydroimidazo 0296 HMG-CoA Reductase inhibitors that may be used 4.5-cquinolin-1-yl)phenylpropionitrile (BEZ-235), are preferably compounds selected from among lovastatin, optionally in the form of the racemates, enantiomers and simvastatin, pravastatin, fluvastatin and avorvastatin, option diastereomers thereof and optionally in the form of the phar ally in the form of the racemates, enantiomers and diastere macologically acceptable acid addition salts, prodrugs, Sol omers thereof and optionally in the form of the pharmaco vates or hydrates thereof. logically acceptable acid addition salts, prodrugs, Solvates or (0305 Preferred CCR5 antagonists which may be used hydrates thereof. here are preferably compounds selected from among maravi 0297 VLA-4 antagonists that may be used are preferably roc (4,4-difluoro-N-(1S)-3-(3-exo)-3-3-methyl-5-(1-me compounds selected from among natalizumab, Valategrast, thylethyl)-4H-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]oct-8- optionally in the form of the racemates, enantiomers and yl)-1-phenylpropyl-cyclohexanecarboxamide), CCR5 diastereomers thereof and optionally in the form of the phar mAb004, Vicriviroc ((4.6-dimethyl-5-pyrimidinyl)-4-(3S)- macologically acceptable acid addition salts, prodrugs, Sol 4-(1R)-2-methoxy-1-4-(trifluoromethyl)phenylethyl-3- vates or hydrates thereof. methyl-1-piperazinyl-4-methyl-1-piperidinyl-methanone) 0298 SHIP agonists that may be used are preferably com and nifeviroc (N-1-((3S,4R)-1-(cyclopentylcarbonyl)-4- pounds selected from among 2.3.4.4a.5.6,6a, 11.11a, 11b hydroxy-4-phenyl-3-pyrrolidinyl)methyl-4-piperidinyl-N- decahydro-44.6a, 7.11b-pentamethyl, (4aS,6aR.11aR, 2-propen-1-yl-(4-nitrophenyl)methyl ester-carbaminic acid), 11bS)-1H-benzo C. fluoren-9-ol (AQX-MN100) and optionally in the form of the racemates, enantiomers and MN-106, optionally in the form of the racemates, enanti diastereomers thereof and optionally in the form of the phar omers and diastereomers thereof and optionally in the form of macologically acceptable acid addition salts, prodrugs, Sol the pharmacologically acceptable acid addition salts, pro vates or hydrates thereof. drugs, Solvates or hydrates thereof. (0306 Preferred CXCR1 or CXCR2 antagonists which 0299 Anti-TNF-antibodies which may be used here are may be used here are preferably compounds such as e.g. preferably compounds selected from among infliximab, 3-3-(dimethylamino)carbonyl-2-hydroxyphenyl)amino adalimumab, golimumab, cytoFab and etanercept. 4-(R)-1-(5-methylfuran-2-yl)propylaminocyclobut-3- 0300 Substances to counter swelling of the airways that ene-1,2-dione (SCH-527123), may be used are preferably compounds selected from among optionally in the form of the racemates, enantiomers and phenylephrine, phenylpropanolamine, pseudophedrine, diastereomers thereof and optionally in the form of the phar oxymetazoline, epinephrine, naphazoline, Xylometazoline, macologically acceptable acid addition salts, prodrugs, Sol propylhexedrine and (levo-desoxyephedrine, optionally in vates or hydrates thereof. the form of the racemates, enantiomers and diastereomers 0307 Preferred substances, according to the invention, are thereof and optionally in the form of the pharmacologically the acid addition salts of the above mentioned MAP kinase acceptable acid addition salts, prodrugs, Solvates or hydrates inhibitors, iNOS inhibitors, MRP4 inhibitors, leukotriene thereof. biosynthese inhibitors, non-steroidal anti-inflammatory 0301 Antitussive substances that may be used are prefer agents (NSAIDs), CRTH2 antagonists, DP1-receptor modu ably compounds selected from among hydrocodone, carami lators, thromboxane receptor antagonists, chemokine recep phen, carbetapentane and dextramethorphan, optionally in tor antagonists, neurokinin (NK1 or NK2) antagonists, sph the form of the racemates, enantiomers and diastereomers ingosine-1-phosphate receptor modulators, mucoregulators, thereof and optionally in the form of the pharmacologically PPAR gamma agonists, Rho kinase inhibitors, adenosine acceptable acid addition salts, prodrugs, Solvates or hydrates receptor modulators, bradykinin receptor antagonists, endot thereof. helin antagonists, interleukin 1-beta converting enzyme 0302 Preferred lipoxin A4 derivatives which may be used (ICE) inhibitors, toll-like receptor (TLR) modulators, HMG here are preferably compounds selected from among 7,9,11, CoA reductase inhibitors, VLA-4 antagonists, SHIP agonists, 13-eicosatetraenoic acid, 5,6,15-trihydroxy, (5S,6R,7E9E, anti-TNF-antibodies, substances to combat swelling of the 11Z,13E,15R)-(15-epi-lipoxin a4), 7,9,11,13-eicosatet airways, antitussive substances, lipoxin A4 derivatives, PI3 raenoic acid, 16-(4-fluorophenoxy)-5,6,15-trihydroxy, (5S, kinase antagonists, FPRL1-modulators, CCR5 antagonists, 6R,7E9E, 11Z,13E15S)-(ATL-1), aspirin-triggered lipoxin CXCR1 or CXCR2-antagonists also selected from among the A(4) and analogues, protectin D1 (4,7,11,13,15,19-docosa hydrochloride, hydrobromide, hydriodide, hydrosulphate, hexaenoic acid, 10,17-dihydroxy, (4Z,7Z,10R,11E,13E,15Z, hydrophosphate, hydromethanesulphonate, hydronitrate, 17S,197)-, resolvin E1 (6,8,10,14, 16-eicosapentaenoic acid, hydromaleate, hydroacetate, hydrocitrate, hydrofumarate, 5,12,18-trihydroxy, (5S,6Z.8E,10E, 12R,14Z,16E, 18R)-) hydrotartrate, hydroxalate, hydroSuccinate, hydrobenzoate and benzo-lipoxin A4 analogues, and hydro-p-toluenesulphonate. optionally in the form of the racemates, enantiomers and diastereomers thereof and optionally in the form of the phar Formulations macologically acceptable acid addition salts, prodrugs, Sol 0308 The compounds according to the invention may be vates or hydrates thereof. administered by oral, transdermal, inhalative, parenteral or 0303 Preferred FPRL1-modulators which may be used Sublingual route. The compounds according to the invention here are preferably compounds such as e.g. methyl 5(S),6(R), are present as active ingredients in conventional preparations, 7-trihydroxyheptanoate, optionally in the form of the race for example in compositions consisting essentially of an inert mates, enantiomers and diastereomers thereof and optionally pharmaceutical carrier and an effective dose of the active in the form of the pharmacologically acceptable acid addition Substance, such as for example tablets, coated tablets, cap salts, prodrugs, Solvates or hydrates thereof. Sules, lozenges, powders, Solutions, Suspensions, emulsions, US 2011/0046148 A1 Feb. 24, 2011 27 syrups, Suppositories, transdermal systems etc. An effective nylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, dose of the compounds according to the invention is between water/glycerol, water/sorbitol, water/polyethylene glycol, 0.1 and 5000, preferably between 1 and 500, more preferably propylene glycol, Stearyl alcohol, carb-oxymethylcellulose between 5-300 mg/dose for oral administration, and between or fatty Substances such as hard fat or Suitable mixtures 0.001 and 50, preferably between 0.1 and 10 mg/dose for thereof to produce conventional galenic preparations such as intravenous, Subcutaneous or intramuscular administration. plain or coated tablets, capsules, powders, Suspensions, solu For inhalation, according to the invention, Solutions contain tions, sprays or Suppositories. ing 0.01 to 1.0, preferably 0.1 to 0.5% active substance are suitable. For administration by inhalation the use of powders, 0315. The Examples which follow illustrate the present ethanolic or aqueous solutions is preferred. It is also possible invention without restricting its scope: to use the compounds according to the invention as a Solution for infusion, preferably in a physiological Saline or nutrient Examples of Pharmaceutical Formulations saline Solution. A) Coated Tablets Containing 75 mg of Active Substance 0309 The compounds according to the invention may be Composition: used on their own or in conjunction with other active Sub stances according to the invention, optionally also in conjunc 0316 tion with other pharmacologically active Substances. Suitable formulations include, for example, tablets, capsules, Supposi tories, Solutions, syrups, emulsions or dispersible powders. Corresponding tablets may be obtained for example by mix 1 tablet core contains: ing the active Substance(s) with known excipients, for active substance 75.0 mg calcium phosphate 93.0 mg example inert diluents, such as calcium carbonate, calcium corn starch 35.5 mg phosphate or lactose, disintegrants such as maize starch or polyvinylpyrrollidone 10.0 mg alginic acid, binders such as starch or gelatine, lubricants hydroxypropylmethylcellulose 15.0 mg Such as magnesium Stearate or talc and/or agents for delaying magnesium Stearate 1.5 mg release, Such as carboxymethyl cellulose, cellulose acetate phthalate, or polyvinyl acetate. The tablets may also comprise 230.0 mg several layers. Coated tablets may be prepared accordingly by coating cores produced analogously to the tablets with Sub stances normally used for tablet coatings, for example colli Preparation: done or shellac, gumarabic, talc, titanium dioxide or Sugar. To 0317. The active substance is mixed with calcium phos achieve delayed release or prevent incompatibilities the core phate, corn starch, polyvinyl-pyrrolidone, hydroxypropylm may also consist of a number of layers. Similarly the tablet coating may consist of a number of layers to achieve delayed ethylcellulose and half the specified amount of magnesium release, possibly using the excipients mentioned above for the stearate. Blanks 13 mm in diameter are produced in a tablet tablets. making machine and these are then rubbed through a screen 0310 Syrups containing the active substances or combi with a mesh size of 1.5 mm using a suitable machine and nations thereof according to the invention may additionally mixed with the rest of the magnesium Stearate. This granulate contain a Sweetener Such as saccharine, cyclamate, glycerol is compressed in a tablet-making machine to form tablets of or Sugar and a flavour enhancer, e.g. a flavouring Such as the desired shape. Vanillin or orange extract. They may also contain Suspension 0318 Weight of core: 230 mg adjuvants or thickeners such as Sodium carboxymethyl cellu 0319 die: 9 mm, convex lose, wetting agents such as, for example, condensation prod The tablet cores thus produced are coated with a film consist ucts of fatty alcohols with ethylene oxide, or preservatives ing essentially of hydroxypropylmethylcellulose. The fin Such as p-hydroxybenzoates. ished film-coated tablets are polished with to beeswax. 0311 Solutions for injection are prepared in the usual way, 0320 Weight of coated tablet: 245 mg. e.g. with the addition of preservatives such as p-hydroxyben Zoates, or stabilisers such as alkali metal salts of ethylenedi B) Tablets Containing 100 mg of Active Substance amine tetraacetic acid, and transferred into injection vials or Composition: ampoules. 0312 Capsules containing one or more active Substances 0321 or combinations of active Substances may for example be prepared by mixing the active Substances with inert carriers Such as lactose or Sorbitol and packing them into gelatine capsules. 1 tablet contains: active substance 100.0 mg 0313 Suitable suppositories may be made for example by lactose 80.0 mg mixing with carriers provided for this purpose, such as neutral corn starch 34.0 mg fats or polyethyleneglycol or the derivatives thereof. polyvinylpyrrollidone 4.0 mg 0314 Forpharmaceutical use the compounds according to magnesium Stearate 2.0 mg the invention are generally used for warm-blooded verte brates, particularly humans, in doses of 0.01-100 mg/kg of 220.0 mg body weight, preferably 0.1-15 mg/kg. For administration they are formulated with one or more conventional inert car 0322 Method of Preparation: riers and/or diluents, e.g. with corn starch, lactose, glucose, 0323. The active substance, lactose and starch are mixed microcrystalline cellulose, magnesium Stearate, polyvi together and uniformly moistened with an aqueous Solution US 2011/0046148 A1 Feb. 24, 2011 28 of the polyvinylpyrrolidone. After the moist composition has E) Suppositories Containing 150 mg of Active Substance been screened (2.0 mm mesh size) and dried in a rack-type Composition: drier at 50° C. it is screened again (1.5 mm mesh size) and the lubricant is added. The finished mixture is compressed to 0334 form tablets. 0324 Weight of tablet: 220 mg 0325 Diameter: 10 mm, biplanar, facetted on both sides 1 Suppository contains: and notched on one side. active substance 150.0 mg polyethyleneglycol 1500 550.0 mg C) Tablets Containing 150 mg of Active Substance polyethyleneglycol 6000 460.0 mg polyoxyethylene sorbitan monostearate 840.0 mg Composition: 2,000.0 mg 0326 Preparation: 1 tablet contains: 0335. After the suppository mass has been melted the active substance 150.0 mg active Substance is homogeneously distributed therein and the powdered lactose 89.0 mg melt is poured into chilled moulds. corn starch 40.0 mg colloidal silica 10.0 mg polyvinylpyrrollidone 10.0 mg F) Suspension Containing 50 mg of Active Substance magnesium Stearate 1.0 mg Composition: 300.0 mg 0336
Preparation: 100 ml of Suspension contain: 0327. The active substance mixed with lactose, corn starch active substance 1.00 g and silica is moistened with a 20% aqueous polyvinylpyrroli carboxymethylcellulose-Na-salt 0.10 g methyl p-hydroxybenzoate 0.05 g done solution and passed through a screen with a mesh size of propyl p-hydroxybenzoate 0.01 g 1.5 mm. The granules, dried at 45° C., are passed through the glucose 10.00 g same screen again and mixed with the specified amount of glycerol 5.00 g magnesium Stearate. Tablets are pressed from the mixture. 70% sorbitol solution 20.00 g flavouring 0.30 g 0328 Weight of tablet: 300 mg dist. water ad 100 ml 0329 die: 10 mm, flat D) Hard Gelatine Capsules Containing 150 mg of Active Preparation: Substance 0337 The distilled water is heated to 70° C. The methyl Composition: and propyl p-hydroxybenzoates together with the glycerol and sodium salt of carboxymethylcellulose are dissolved 0330 therein with stirring. The solution is cooled to ambient tem perature and the active Substance is added and homoge neously dispersed therein with stirring. After the Sugar, the 1 capsule contains: sorbitol solution and the flavouring have been added and dissolved, the Suspension is evacuated with stirring to elimi active substance 150.0 mg nate air. corn starch (dried) approx. 180.0 mg lactose (powdered) approx. 87.0 mg 0338 5 ml of Suspension contain 50 mg of active Sub magnesium Stearate 3.0 mg Stance. approx. 420.0 mg G) Ampoules Containing 10 mg Active Substance Composition: Preparation: 0339 0331. The active substance is mixed with the excipients, passed through a screen with a mesh size of 0.75 mm and homogeneously mixed using a suitable apparatus. The fin active substance 10.0 mg ished mixture is packed into size 1 hard gelatine capsules. 0.01 N hydrochloric acid C.S. double-distilled water ad 2.0 ml 0332 Capsule filling: approx. 320 mg 0333 Capsule shell: size 1 hard gelatine capsule. US 2011/0046148 A1 Feb. 24, 2011 29
Preparation: 1. A compound of the formula (I) 0340. The active substance is dissolved in the necessary (I) R H amount of 0.01 NHCl, made isotonic with common salt, n N Y filtered sterile and transferred into 2 ml ampoules. O O H) Ampoules Containing 50 mg of Active Substance N1 N Composition: l 2 N -R N Rd / N-A 0341 M RC wherein, active Substance 50.0 mg R" denotes a phenyl or 1-phenylethyl group, wherein the 0.01 N hydrochloric acid C.S. phenyl nucleus is Substituted in each case by the groups double-distilled water ad 10.0 ml R" to R, wherein R" and R which may be identical or different, denote hydrogen or a group selected from among Preparation: F, Cl, Br, I, OCHF, OCHF, OCF, CHF, CHF, CF, CN, NO, NH, and OH, 0342. The active substance is dissolved in the necessary O amount of 0.01 NHCl, made isotonic with common salt, a group selected from among filtered sterile and transferred into 10 ml ampoules. Ca-alkyl, C-alkyl-O, C2-s-alkenyl, C2-s-alkynyl, phe nyl, phenyl-O, phenyl-C-alkyl, phenyl-C-alkyl-O, I) Capsules for Powder Inhalation Containing 5 mg of Active heteroaryl, heteroaryl-O, heteroaryl-C-alkyl, het eroaryl-C-alkyl-O, while the above-mentioned phe Substance nyl groups are mono- or disubstituted by groups R. 0343) 1 capsule contains: and R denotes hydrogen, O a group selected from among active substance 5.0 mg F, Cl, Brand CH lactose for inhalation 15.0 mg R" denotes hydrogen, or a group, optionally substituted, Selected from among C-alkyl, C-cycloalkyl- and 20.0 mg C-6-cycloalkyl-C-s-alkyl, R denotes hydrogen, or an optionally Substituted group Selected from among C6-alkyl, Cs-e-cycloalkyl, C.- Preparation: cycloalkyl-C-alkyl, C-alkyl-CO, C-cycloalkyl CO, C-cycloalkyl-C-alkyl-CO, C-alkyl-SO, 0344. The active substance is mixed with lactose for inha Co-cycloalkyl-SO, C-cycloalkyl-C-alkyl-SO, lation. The mixture is packed into capsules in a capsule phenyl-CO— and phenyl-SO, making machine (weight of the empty capsule approx. 50 R" denotes hydrogen or mg). a group selected from among (0345 weight of capsule: 70.0 mg F, Cl, Br, I, OH, C-alkyl, C-alkyl-O, C-alkyl-O 0346) size of capsule-3 substituted by 1 to 3 fluorine atoms, C-cycloalkyl O, C-7-cycloalkyl-Ca-alkyl-O, tetrahydrofuran-3- yl-O, tetrahydropyran-3-yl-O, tetrahydro-pyran-4-yl J) Solution for Inhalation for Hand-Held Nebulisers Contain O, tetrahydrofuranyl-Ca-alkyl-O- and ing 2.5 mg Active Substance tetrahydropyranyl-C-alkyl-O. 0347 1 spray contains: O R C-alkyl, while the linking of the groups R* may take place via each C atom of the alkyl group, O active Substance 2.500 mg benzalkonium chloride 0.001 mg R C-alkyl-O, wherein the group R is separated 1N hydrochloric acid C.S. from the oxygen atom by at least 2 C atoms, ethanol/water (50/50) ad 15.000 mg O a group selected from among pyrrolidin-2-yl-Ca alkyl-O, pyrrolidin-3-yl-C-alkyl-O, piperidin-2- yl-Ca-alkyl-O, piperidin-3-yl-C-alkyl-O, piperi Preparation: din-4-yl-Ca-alkyl-O. azepan-2-yl-C-alkyl-O. aZepan-3-yl-C-alkyl-O. azepan-4-yl-C-alkyl-O. 0348. The active substance and benzalkonium chloride are morpholin-2-yl-C-alkyl-O, morpholin-3-yl-Ca dissolved in ethanol/water (50/50). The pH of the solution is alkyl-O. 1-(C-alkyl)-pyrrolidin-2-yl-C-alkyl-O. adjusted with 1N hydrochloric acid. The resulting solution is 1-(C-alkyl)-pyrrolidin-3-yl-Ca-alkyl-O. 1-(C- filtered and transferred into suitable containers for use in alkyl)-piperidin-2-yl-Ca-alkyl-O. 1-(C-alkyl)-pi hand-held nebulisers (cartridges). peridin-3-yl-C-alkyl-O. 1-(C-alkyl)-piperidin Contents of the Container: 4.5 g. 4-yl-C-alkyl-O. 1-(C-alkyl)-azepan-2-yl-C- US 2011/0046148 A1 Feb. 24, 2011 30
alkyl-O. 1-(C-alkyl)-azepan-3-yl-C-alkyl-O. 2. A compound Compounds according to claim 1, wherein, 1-(C-alkyl)-azepan-4-yl-C-alkyl-O, 4-(C- R" denotes a group selected from among 3-chloro-2-fluoro alkyl)-morpholin-2-yl-Ca-alkyl-O- and 4-(C- phenyl, 3-chloro-4-fluoro-phenyl, 5-chloro-2-fluoro-phenyl, alkyl)-morpholin-3-yl-Ca-alkyl-O. 2-fluoro-3-methyl-phenyl, 2-fluoro-5-methyl-phenyl, while 4-fluoro-3-methyl-phenyl- and 3-chloro-2-methyl-phenyl R" denotes a group, which may be identical or different, selected from among OH, C-alkyl-O, C-cy grOup, cloalkyl-O, NH, C-alkyl-NH. (C-alkyl)-N, RandR which may be identical or different, (2-methoxyethyl)-N, pyrrolidin-1-yl, piperidin-1-yl, denote hydrogen or C-alkyl, aZepan-1-yl, morpholin-4-yl, 1,4-oxazepan-4-yl, R" denotes Cis-alkyl-O, 2-oxa-5-aza-bicyclo 2.2.1]hept-5-yl, 3-oxa-8-aza unless Stated otherwise, the above-mentioned alkyl groups bicyclo 3.2.1]oct-8-yl, 8-oxa-3-aza-bicyclo 3.2.1 may be straight-chain or branched, oct-3-yl, piperazin-1-yl 4-(C-alkyl)-piperazin-1- A denotes —CH2CH2, while the —CHCH group may yl, 1,4-diazepan-1-yl 4-(C-alkyl)-1,4-diazepan-1- be substituted by 1 or 2 methyl groups, y1, HCO. NH, C-alkyl-CO. NH, C-alkyl-O- or a tautomer or pharmacologically acceptable salt thereof. C-alkyl-CO. NH, C -alkyl-O CO. NH, 3. (canceled) HNCONH, C-alkyl-NH CO. NH, (C-alkyl) N CONH. pyrrolidin-1-yl-CO. NH, piperidin-1- 4. A method for treating inflammatory or allergic diseases yl-CO. NH, piperazin-1-yl-CO. NH, 4-(C- of the airways which method comprises administering to a alkyl)-piperazin-1-yl-CO. NH, morpholin-4-yl host Suffering from an inflammatory or allergic disease of the CO. NH and C-alkyl-SO. NH, airways a therapeutically effective amount of a compound while the pyrrolidinyl, piperidinyl, azepan-1-yl, piperazinyl, according to claim 1 or 2. 1,4-diazepan-1-yl, morpholinyl- and 1,4-oxazepan-4-yl 5. The method of claim 4 wherein the disease to be treated groups mentioned above in the definition of the group R may is selected from the group consisting of chronic bronchitis, each additionally be substituted by one or two C-alkyl acute bronchitis, bronchitis caused by bacterial or viral infec groups, and tion or fungi or helminths, allergic bronchitis, toxic bronchi wherein the above-mentioned phenyl groups are mono- or tis, chronic obstructive bronchitis (COPD), asthma (intrinsic disubstituted by groups R, wherein orallergic), paediatric asthma, bronchiectasis, allergicalveo R denotes hydrogen, or litis, allergic or non-allergic rhinitis, chronic sinusitis, cystic a group, which may be identical or different, selected fibrosis or mucoViscidosis, alpha-1-antitrypsin deficiency, from among cough, pulmonary emphysema, interstitial lung diseases, F, Cl, Br, I, OH, CN, C-alkyl, C-alkyl-O, CHF, alveolitis, hyperreactive airways, nasal polyps, pulmonary CF, —O CHF, and —O CF, oedema, pneumonitis of different origins, e.g. radiation-in and duced or caused by aspiration or infectious pneumonitis, unless stated otherwise, the above-mentioned alkyl groups collagenoses such as lupus erythematodes, systemic sclero may be straight-chain or branched, dermy, sarcoidosis and Boeck's disease. A denotes —CO or —C-C-alkylene, 6. The method of claim 4 wherein the disease to be treated while the -C-C-alkylene group may be 1-, 2-, 3- or is chronic obstructive bronchitis (COPD) or asthma. 4-substituted by a group R, 7. (canceled) and 8. A pharmaceutical composition comprising a compound R” which may be identical or different, denotes hydrogen, according to claim 1 or 2 and a pharmaceutically acceptable O carrier or diluent. a group selected from among OH, C-C-alkyl and 9-10. (canceled) —O-C-C-alkyl or a tautomer or pharmacologically acceptable salt thereof.