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  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings
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  • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
  • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
  • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• compositions containing the same and their use as inhibitors of neutrophil elastase activity, pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and/or prevention of pulmonary, gastrointestinal and genitourinary diseases, inflammatory diseases of the skin and the eye and other autoimmune and allergic disorders, allograft rejection, and oncological diseases.
• WO12002502 WO2014029831, WO2014029832 and WO2014029830.
• Neutrophil elastase is a 29 kDa serine protease. It is expressed in bone marrow precursor cells, stored in the granula of peripheral blood granulocytes at high
• neutrophil elastase activity leads to ECM degradation, increases migration and chemotaxis of monocytes and vascular smooth muscle cells and directly affects components of the coagulation and fibrinolytic pathways (PAI-1 and TFPI). Increased activity of neutrophil elastase is associated with chronic inflammatory and fibrotic diseases of several organs.
• the potential of neutrophil elastase inhibitors as
• Inhibitors of neutrophil elastase will therefore have an important role for the treatment of different diseases like COPD, idiopathic pulmonary fibrosis and other fibrotic diseases, cancer, acute lung injury, acute respiratory distress syndrome, bronchiectasis, cystic fibrosis, alpha1-antitrypsin deficiency and others.
• the problem of the present invention is to prepare new compounds which on the basis of their pharmaceutical effectiveness as inhibitors of neutrophil elastase activity, may be used therapeutically, that is for the treatment of pathophysiological processes caused by increased activity of neutrophil elastase.
• the compounds of the present invention have the following properties which are advantageous in view of the indications of the current invention.
• the compounds according to the present invention including the physiologically acceptable salts, are effective as inhibitors of neutrophil elastase and exhibit favourable inhibitory potency, as determined by the half maximal inhibitory concentration (IC 50 ), in an enzymatic inhibition assay.
• Some compounds according to the present invention, including the physiologically acceptable salts are additionally effective as inhibitors of neutrophil serin protease proteinase 3 and exhibit favourable inhibitory potency, as determined by the half maximal inhibitory concentration (IC 50 ), in an enzymatic inhibition assay.
• This inhibitory activity on a second neutrophil serin protease may be benificial for pharmacological efficacy.
• Some compounds according to the present invention exhibit favourable in vivo potency, as determined, for example, by the half maximal effective dose (ED 50 ), in models of human neutrophil elastase-induced lung injury in mouse or rat, for instance as described in Tremblay et al. (Chest 2002, 121, 582-588) or T. Stevens et al. (J. Pharm. Exp. Ther. 2011, 339, 313-320).
• Some compounds according to the present invention, including the physiologically acceptable salts exhibit favourable metabolic stability in an in vitro microsomal assay for metabolic stability as described in E. Kerns & L.
• Di Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1 st ed, 2008), chapter 29 and references therein.
• An improved metabolic stability in an in vitro test system is expected to translate into a re- cuted in vivo clearance (CL), because the metabolic conversion in the liver is reduced.
• permeability in the efflux direction permeability in the efflux direction divided by the permeability in the influx direction
• in vitro Caco-2 or MDCK cell layer method as described in E. Kerns & L. Di (Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1 st ed, 2008), chapter 26 and 27 and references therein.
• an improved, that is reduced efflux ratio is expected to translate into a higher fraction of the drug absorbed in the intestinal tract, thus, resulting in higher dose-normalized systemic exposure (AUC).
• Some compounds according to the present invention including the physiologically acceptable salts, exhibit favourable aqueous solubility in a kinetic or thermodynamic solubility method as described in E. Kerns & L. Di (Drug-like properties: concepts, 15 structure design and methods: from ADME to toxicity optimization, Elsevier, 1 st ed, 2008), chapter 25 and references therein.
• improved aqueous solubility is expected to translate into a higher fraction of the drug absorbed in the intestinal tract resulting in higher dose-normalized systemic exposure (AUC) and/or oral bioavailability (F oral ) and/or peak plasma concentration after administration (C max ). Furthermore, improved aqueous solubility is expected to reduce development challenges, such as expensive formulations, increased development time, high drug load. Comparatively higher dose-normalized systemic exposure (AUC) can be advantageous in several ways: (1) If a certain systemic exposure (AUC) needs to be achieved for efficacy, the drug can be dosed in a lower amount.
• AUC systemic exposure
• Lower dosages have the advantages of lower drug load (parent drug and metabolites thereof) for the patient causing potentially less side effects, and lower production costs for the drug product.
• Comparatively higher dose- normalized systemic exposure (AUC) can lead to increased efficacy or prolonged duration of action of the drug when the same dose is applied.
• Some compounds according to the present invention, including the physiologically acceptable salts exhibit favourable metabolic stability, favourable permeability and favourable aqueous solubility. Accordingly, some compounds of the present invention are expected to exhibit favourable pharmacokinetic (PK) properties after oral dosing, in particular favourable systemic exposure (area under the curve, AUC), thus, leading to favourable efficacy in vivo.
• PK pharmacokinetic
• PK properties can be determined in pre-clinical animal species, for example mouse, rat, hamster, dog, guinea pig, mini pig, cynomolgus monkey, rhesus monkey.
• the PK properties of a compound can be described, for example, by the following parameters: Mean residence time (MRT), elimination half-live (t 1/2 ), volume-of-distribution (V D ), area under the curve (AUC), clearance (CL) and bioavailability after oral administration (F oral ), peak plasma concentration after administration (C max ), time to reach Cmax (T max ).
• Some compounds according to the present invention and metabolites thereof are devoid of the hydrazine sub-structure that causes structural alerts for mutagenicity and
• CYP cytochrome P450
• E. Kerns & L. Di Drug-like properties: concepts, structure design and methods: from ADME to toxicity optimization, Elsevier, 1 st ed, 2008), chapter 32 and references therein.
• Cytochrome P450 (CYP) induction can affect the pharmacokinetics of a drug molecule upon multiple dosing, which can result in pharmacokinetic drug-drug interactions with co-administered drugs. CYP induction can lead to decreased exposure of the inducing compound (e.g.
• CYP induction can also lead to an increase in the metabolism of a drug causing changes in pharmacological (active metabolite) and toxicological (toxic metabolite) outcomes.
• R 1 is selected from the group consisting of
• R 1.1 is selected from the group consisting of
• R 1.2 is selected from the group consisting of
• R 1.3 denotes a 4- to 10-membered heterocyclic or heteroaryl ring, containing one, two, three or four elements independently selected from among N and O, each of the rings optionally substituted with one or two substituents independently selected from among morpholinyl, -NHCOCH 3 , -N(CH 3 )COCH 3, –COCH 3 , -OH, -NH 2 ,-N(CH 3 ) 2 and C 1-3 alkyl, R 1.4 , R 1.5 are independently selected from the group consisting of morpholinyl, -NH 2 , -OH, F, -N(CH 3 ) 2, -O-CH 3 and -SO 2 -CH 3, R 1.6 , R 1.9 , R 1.10 are independently selected from the group consisting of -CO-
• R 1.8 is -O-CH 3
• R 1.12 is selected from the group consisting of, -NH-R 1.13 , -N(CH 3 )-R 1.13 , and
• R 1.13 denotes a group selected from among C 3-6 -cycloalkyl, C 1-4 - alkyl, each optionally substituted by a group selected from among halogen and OH, and
• a 6-membered heterocyclic ring containing one to four heteroatoms independently selected from among N, O and S, optionally
• R 2 is phenyl or pyridinyl, each substituted with CF 3, -CHF 2 , C 1-4 alkyl and halogen
• R 3 is selected from the group consisting of R 3.1 , R 3.1 -CO-, R 3.1 -O-CO- , R 3.1 SO 2 -, R 3.1 R 3.2 N-CO-, R 3.1 R 3.2 N-CO-CH 2 -;
• R 3.1 is selected from the group consisting of H, -C 1-4 alkyl, -C 3-6 cycloalkyl, -C 1-4 - haloalkyl and -C 3-6 -halocycloalkyl,
• R 3.2 is selected from the group consisting of H and C 1-4 -alkyl; or,
• R 3 is selected from the group consisting of R 3.1 R 3.2 N-CO- and R 3.1 R 3.2 N-CO- CH 2 -,
• R 3.2 and R 3.1 may form, together with the nitrogen atom to which they are bound, a ring independently selected from the group consisting of azetidine, pyrrolidine, piperidine, piperazine and N-C 1-4 -alkyl-piperazine; or optical and geometrical isomers, solvates, hydrates or salts, preferably pharmaceutically acceptable salts, thereof.
• C 1-6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
• C 1-6 -alkyl means an alkyl group or radical having 1 to 6 carbon atoms.
• the skilled artisan can see the radical attachment point(s) to the molecule from the free valences of the group itself.
• aryl-C 1-3 -alkyl- means an aryl group which is bound to a C 1-3 -alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
• aryl-C 1-3 -alkyl- means an aryl group which is bound to a C 1-3 -alkyl-group, the latter of which is bound to the core or to the group to which the substituent is attached.
• An asterisk or a broken line may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined.
• the term "3-carboxypropyl-group” represents the following substituent:
• the terms "1-methylpropyl-", “2,2-dimethylpropyl-” or “cyclopropylmethyl-” group represent the following groups:
• the asterisk may be used in sub-formulas to indicate the bond which is connected to the core molecule as defined. Many of the followings terms may be used repeatedly in the definition of a formula or group and in each case have one of the meanings given above, independently of one another.
• substituted as used herein, means that any one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded, and that the substitution results in a stable compound.
• prevention should be understood synonymous and in the sense that the risk to develop a condition mentioned hereinbefore is reduced, especially in a patient having elevated risk for said conditions or a corresponding anamnesis, e.g. elevated risk of developing metabolic disorder such as diabetes or obesity or another disorder mentioned herein.
• prevention of a disease means the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease.
• the purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders.
• treatment means therapeutic treatment of patients having already developed one or more of said conditions in manifest, acute or chronic form, including symptomatic treatment in order to relieve symptoms of the specific indication or causal treatment in order to reverse or partially reverse the condition or to delay the progression of the indication as far as this may be possible, depending on the condition and the severity thereof.
• treatment of a disease means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder.
• Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.
• a given chemical formula or name shall encompass tautomers and all stereo, optical and
• geometrical isomers e.g. enantiomers, diastereomers, E/Z isomers etc. and racemates thereof as well as mixtures in different proportions of the separate enantiomers, mixtures of diastereomers, or mixtures of any of the foregoing forms where such isomers and enantiomers exist, as well as salts, including pharmaceutically acceptable salts thereof and solvates thereof such as for instance hydrates including solvates of the free compounds or solvates of a salt of the compound. All isomeric forms (especially all stereoisomeric forms, e.g.
• some of the compounds of the present invention contain more than one stereogenic center, that is more than one asymmetrically substituted carbon or sulfur atom, and may therefore be isolated as pure diastereomers or as diastereomeric mixtures, both in optically active or racemic forms.
• the invention contemplates all conceivable stereoisomers, particularly the diastereomers and enantiomers mentioned herein, e.g. in substantially pure form, in enriched form (e.g. substantially free of any or all other undesired enantiomers and/or diastereomers and/or in any mixing ratio, including the racemic forms, as well as the salts thereof.
• substantially pure stereoisomers can be obtained according to synthetic principles known to a person skilled in the field, e.g. by separation of corresponding mixtures, by using stereochemically pure starting materials and/or by stereoselective synthesis. It is known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, e.g. starting from optically active starting materials and/or by using chiral reagents. Enantiomerically pure compounds of this invention or intermediates may be prepared via asymmetric synthesis, for example by preparation and subsequent separation of appropriate diastereomeric compounds or intermediates which can be separated by known methods (e.g.
• enantioselective crystallization from a conglomerate of enantiomorphous crystals under suitable conditions; or by (fractional) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary.
• halogen generally denotes fluorine, chlorine, bromine and iodine.
• prodrug refers to (i) an inactive form of a drug that exerts its effects after metabolic processes within the body converting it to a usable or active form, or (ii) a substance that gives rise to a pharmacologically active metabolite, although not itself active (that is an inactive precursor).
• prodrug or “prodrug derivative” mean a covalently-bonded derivative, carrier or precursor of the parent compound or active drug substance which undergoes at least some biotransformation prior to exhibiting its pharmacological effect(s).
• prodrugs either have metabolically cleavable or otherwise convertible groups and are rapidly transformed in vivo to yield the parent compound, for example, by hydrolysis in blood or by activation via oxidation as in case of thioether groups.
• Most common prodrugs include esters and amide analogs of the parent compounds.
• prodrug is formulated with the objectives of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (e.g., increased hydrosolubility), and/or decreased side effects (e.g., toxicity).
• prodrugs themselves have weak or no biological activity and are stable under ordinary conditions.
• Prodrugs can be readily prepared from the parent compounds using methods known in the art, such as those described in A Textbook of Drug Design and Development, Krogsgaard-Larsen and H. Bundgaard (eds.), Gordon & Breach, 1991, particularly Chapter 5: "Design and Applications of Prodrugs”; Design of Prodrugs, H.
• prodrug as used herein means a prodrug of a compound of the invention which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and effective for their intended use, as well as the zwitterionic forms, where possible.
• pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, and commensurate with a reasonable benefit/risk ratio.
• pharmaceutically acceptable salts refer to derivatives of the disclosed compounds wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
• such salts include salts from ammonia, L-arginine, betaine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine (2,2’-iminobis(ethanol)), diethylamine, 2-(diethylamino)-ethanol,
• DL-mandelic acid methanesulfonic acid, galactaric acid, naphthalene-1,5-disulfonic acid, naphthalene-2-sulfonic acid, 1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, octanoic acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid (embonic acid), phosphoric acid, propionic acid, (-)-L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid.
• compositions can be formed with cations from metals like aluminium, calcium, lithium, magnesium, potassium, sodium, zinc and the like.
• the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound which contains a basic or acidic moiety by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a sufficient amount of the appropriate base or acid in water or in an organic diluent like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof.
• Salts of other acids than those mentioned above which for example are useful for purifying or isolating the compounds of the present invention also comprise a part of the invention.
• C 1-n -alkyl wherein n is an integer from 2 to n, either alone or in combination with another radical denotes an acyclic, saturated, branched or linear hydrocarbon radical with 1 to n C atoms.
• C 1-5 -alkyl embraces the radicals H 3 C-,
• C 1-n -alkylene wherein n is an integer 2 to n, either alone or in combination with another radical, denotes an acyclic, straight or branched chain divalent alkyl radical containing from 1 to n carbon atoms.
• C 1-4 -alkylene includes -CH 2 -, -CH 2 -CH 2 -, -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -, -C(CH 3 ) 2 -, -CH(CH 2 CH 3 )-, -CH( CH 3 )-CH 2 -, -CH( CH 3 )-CH 2 -, -CH 2 -CH(CH 3 )-, -CH 2 -CH 2 -CH 2 -CH(CH 3 )-, -CH(CH 3 )-CH 2 - CH 2 -, -CH 2 -CH(CH 3 )-CH 2 -, -CH 2 -C(CH 3 ) 2 -, -C(CH 3 ) 2 -CH 2 -, -CH(CH 3 )-CH(CH 3 )-, -CH 2 - CH(CH 2 CH 3 )-, -CH(CH 2 CH 3 )-,
• C 3-n -cycloalkyl wherein n is an integer from 4 to n, either alone or in combination with another radical denotes a cyclic, saturated, unbranched hydrocarbon radical with 3 to n C atoms.
• C 3-7 -cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl.
• halo added to a “alkyl”, “alkylene” or “cycloalkyl” group (saturated or unsaturated) is such a alkyl or cycloalkyl group wherein one or more hydrogen atoms are replaced by a halogen atom selected from among fluorine, chlorine or bromine, preferably fluorine and chlorine, particularly preferred is fluorine. Examples include: H 2 FC-, HF 2 C-, F 3 C-.
• aryl as used herein, either alone or in combination with another radical, denotes a carbocyclic aromatic monocyclic group containing 6 carbon atoms which may be further fused to a second five- or six-membered, carbocyclic group which may be aromatic, saturated or unsaturated.
• Aryl includes, but is not limited to, phenyl, indanyl, indenyl, naphthyl, anthracenyl, phenanthrenyl, tetrahydronaphthyl and dihydronaphthyl.
• heterocyclyl means a saturated or unsaturated mono- or polycyclic-ring system including aromatic ring system containing one or more elements selected from N, O, S, S(O) or S(O) 2 , consisting of 3 to 14 ring atoms wherein none of the heteroatoms is part of the aromatic ring.
• heterocyclyl is intended to include all the possible isomeric forms; thus, the term “heterocyclyl” includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• heteroaryl means a mono- or polycyclic-ring systems containing one or more elements selected from N, O, S, S(O) or S(O) 2 , consisting of 5 to 14 ring atoms wherein at least one of the heteroatoms is part of aromatic ring.
• heteroaryl is intended to include all the possible isomeric forms;
• heteroaryl includes the following exemplary structures which are not depicted as radicals as each form may be attached through a covalent bond to any atom so long as appropriate valences are maintained:
• R 1 is is selected from the group consisting of–CO-R 1.1 , R 1.11 and -CH 12
• R 1.1 is selected from the group consisting of -NH 2 , -NH-C 1-4 -alkyl, -NH-CH 2 -R 1.6 , -NH-CH(CH 3 )-R 1.9 ,
• -NH-CH 2 -CH 2 -R 1.4 , -NH-CH 2 -CH 2 -CH 2 -R 1.7 , -NH-CH 2 -CH 2 -CH 2 -R 1.8 , -N(C 1-3 -alkyl) 2, -N(CH 3 )-CH 2 -CH 2 -R 1.5 , -N(CH 3 )-CH 2 -R 1.10 , -NH-R 1.2 , R 1.3 , -OH, -OCH 3 and -NH-CH 2 -C ⁇ CH, R 1.2 is selected from the group consisting of
• R 1.3 denotes a 4-to 6-membered heterocyclic or heteroaryl ring, containing one, two or three elements independently selected from among N and O, each of the rings optionally substituted with one or two substituents independently selected from among morpholinyl, -NHCOCH 3 ,
• R 1.4 is selected from the group consisting of
• R 1.5 is selected from the group consisting of
• R 1.6 , R 1.9 , R 1.10 are independently selected from the group consisting of -CO-morpholinyl, -CN, -CF 3 , CHF 2 , -C(CH 3 ) 2 OH and -C(CH 3 ) 2 NH 2 or are independently selected from the group consisting of
• phenyl and a 4-to 6-membered heterocyclic or heteroaryl ring containing one, to four elements independently selected from among N and O, each of the rings optionally substituted with C 1-3 alkyl or CN, R 1.7 is -OH, -O-CH 3
• R 1.8 is -O-CH 3
• R 1.11 denotes a 5-to 6-membered heterocyclic or 5-to 6-membered
• R 1.12 is selected from the group consisting of -NH-C 1-4 -alkyl, -NH-R 1.13 and
• R 1.13 denotes a 6-membered heterocyclic ring, containing one to four heteroatoms independently selected from among N, O and S, n is 1 or 2
• R 2 is phenyl or pyridinyl, each substituted with CF 3 or CHF 2
• R 3 is H or methyl
• R 1 is selected from the group consisting of
• R 1.1 is selected from the group consisting of
• R 1.2 is selected from the group consisting of
• R 1.4 is selected from the group consisting of morpholinyl
• R 1.5 is selected from the group consisting of morpholinyl
• R 1.6 is selected from the group consisting of–CO-morpholinyl, -CN, -CF 3 , CHF 2 , -C(CH 3 ) 2 OH, -C(CH 3 ) 2 CN and -C(CH 3 ) 2 NH 2 or is selected from the group consisting of
• R 1.7 is -OH, -O-CH 3,
• R 1.8 is -O-CH 3
• R 1.9 is formula c.1,
• R 1.10 is selected from the group consisting of formulas c.3, c4, c.5, c.7, c8, and c.9,
• n 1 or 2
• R 2 is phenyl or pyridinyl, each substituted with CF 3
• R 3 is H or methyl or a pharmaceutically acceptable salt thereof.
• R 1.1 is selected from the group consisting of
• R 1.3 is a residue of formula b.10, n is 1
• R 2 is phenyl substituted with CF 3, or a pharmaceutically acceptable salt thereof. Embodied are the above compounds of formula 1, wherein R 2 is a residue of formula d.1 or d.2
• Another embodiment of the current invention are the above compounds of formula 1 for use as a medicament.
• Another embodiment of the current invention are the above compounds of formula 1 for use as a medicament for the treatment of asthma and allergic diseases, gastrointestinal inflammatory diseases, glomerulonephritis, eosinophilic diseases, chronic obstructive pulmonary disease, infection by pathogenic microbes and rheumatoid arthritis.
• Another embodiment of the current invention are the above compounds formula 1 for use as a medicament for the treatment of neutrophilic diseases, cystic fibrosis (CF), non-cystic fibrosis, idiopathic pulmonary fibrosis, bronchiectasis, ANCA-associated vasculitis, lung cancer, bronchiectasis, emphysema, chronic bronchitis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary hypertension, pulmonary arterial hypertension (PAH) and Alpha-1-antitrypsin deficiency (AATD).
• neutrophilic diseases cystic fibrosis (CF), non-cystic fibrosis, idiopathic pulmonary fibrosis, bronchiectasis, ANCA-associated vasculitis, lung cancer, bronchiectasis, emphysema, chronic bronchitis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary hypertension
• Another embodiment of the current invention are the above compounds formula 1 for use as a medicament for the treatment of obesity and related inflammation, insulin resistence, diabetes, fatty liver and liver steatosis.
• a further embodiment of the present invention is a compound of formula 1, for use as a medicament for the treatment of traumatic brain injury, abdominal aortic aneurism and Graft vs. Host Disease (GvHD).
• Another embodiment of the current invention is a method of treatment or prevention of diseases in which neutrophil elastase inhibitors have a therapeutic benefit, which method comprises administration of a therapeutically or preventively effective amount of a compounds of formula 1 to a patient in need thereof.
• Another embodiment of the current invention is a pharmaceutical composition containing one or more compounds of formula 1 or a pharmaceutically active salt thereof.
• a pharmaceutical composition comprising additionally to a compound of formula 1, a pharmaceutically active compound selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, Cathepsin C inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor antagonists and SYK-inhibitors, but also combinations of two or three active substances.
• a pharmaceutically active compound selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4-inhibitors, LTD4-antagonists, EGFR-inhibitors, Cathepsin C inhibitors, CRTH2 inhibitors, 5-LO-inhibitors, Histamine receptor antagonists and SYK-inhibitors, but also combinations of two or three active substances.
• a pharmaceutically active compound selected from the group consisting of betamimetics, anticholinergics, corticosteroids, PDE4-in
• R 1 is R 1.a and R 1.a is phenyl
• Embodied is a compound of formula 1, wherein
• R 1 is phenyl
• Embodied is a compound of formula 1, wherein
• R 1 is phenyl
• Embodied is a compound of formula 1, wherein
• R 1.1 is selected from the group consisting of -NH 2 , -NH-C 1-4 -alkyl, -NH-R 1.6 , -NH-CH 2 -R 1.6 , -NH-CH(CH 3 )-R 1.9 -NH-CH 2 -CH 2 -R 1.4 , -NH-CH 2 -CH 2 -CH 2 -R 1.7 , -NH-CH 2 -CH 2 -CH 2 -R 1.8 , -N(CH 3 )-CH 2 -CH 2 -R 1.8 , -N(CH 3 ) 2 -N(CH 3 )-CH 2 -CH 2 -R 1.5 , -N(CH 3 )-CH 2 -R 1.10 , -NH-R 1.2 , R 1.3 , -OH, -OCH 3 and -NH-CH 2 -C ⁇ CH. Embodied is a compound of formula 1, wherein
• R 1.1 is selected from the group consisting of
• Embodied is a compound of formula 1, wherein
• R 1.2 is selected from the group consisting of
• Embodied is a compound of formula 1, wherein
• R 1.3 is selected from the group consisting of formulas b.1 to b.37
• Embodied is a compound of formula 1, wherein
• R 1.3 is a group of formula b.10.
• Embodied is a compound of formula 1, wherein
• R 1.4 is selected from the group consisting of morpholinyl
• R 1.5 is selected from the group consisting of morpholinyl
• Embodied is a compound of formula 1, wherein
• R 1.6 is selected from the group consisting of–CO-morpholinyl
• Embodied is a compound of formula 1, wherein
• R 1.6 is selected from the group consisting of–CO-morpholinyl
• R 1.6 is selected from the group consisting of formulas c.1 to c.12.
• Embodied is a compound of formula 1, wherein
• R 1.7 is–OH or -O-CH 3.
• Embodied is a compound of formula 1, wherein
• R 1.8 is -O-CH 3.
• Embodied is a compound of formula 1, wherein
• R 1.9 is selected from the group consisting of formulas c.1.
• Embodied is a compound of formula 1, wherein
• R 1.10 is selected from the group consisting of formulas c.3, c4,c.5, c.7, c8,
• Embodied is a compound of formula 1, wherein
• R 1.11 is selected from the group consisting of formulas f.2, f.6, f.7, f.9 and f.10
• Embodied is a compound of formula 1, wherein
• R 1.11 is selected from the group consisting of formulas e.1 to e.9
• Embodied is a compound of formula 1, wherein
• R 1.11 is selected from the group consisting of formulas e.2, e.6, e.7 and e.9,
• Embodied is a compound of formula 1, wherein
• R 1.12 is selected from the group consisting of -NH-C 1-4 -alkyl, -NH-R 1.13 and
• N-containing heterocyclic ring bound via N-atom to the core structure, optionally containing additional to the N-atom one to 3
• heteroatoms independently selected from among N, O and S.
• Embodied is a compound of formula 1, wherein
• R 1.12 is selected from the group consisting of -NH-C 1-4 -alkyl, morpholinyl and tetrahydropyranyl.
• Embodied is a compound of formula 1, wherein
• R 1.13 denotes a 6-membered heterocyclic ring, containing one to four heteroatoms independently selected from among N, O and S.
• Embodied is a compound of formula 1, wherein
• R 2 is phenyl or pyridinyl, each substituted with CF 3 or CHF 2
• Embodied is a compound of formula 1, wherein
• R 2 is phenyl or pyridinyl, each substituted with CF 3
• Embodied is a compound of formula 1, wherein
• R 2 is phenyl substituted with CF 3.
• Embodied is a compound of formula 1, wherein
• R 2 is a residue of formula d.1
• Embodied is a compound of formula 1, wherein
• R 2 is a residue of formula d.2
• Embodied is a compound of formula 1, wherein
• R 3 is H or methyl.
• Embodied is a compound of formula 1, wherein
• R 3 is methyl .
• Embodied is a compound of formula 1, wherein
• R 3 is hydrogen. Embodied is a compound of formula 1, wherein n is 1.
• Embodied is a compound of formula 1, wherein n is 2.
• Embodied are the compounds of formula 1, wherein the compounds are selected from the group consisting of examples 2, 2.1, 11.2, 13.1, 15.8, 20.b, 21, 22, 23, 24 and 25.
• Embodied are the compounds of formula 1, wherein the compounds are selected from the group consisting of examples 2, 2.1, 11.2, 13.1, 20.b, 21, 22, 23, 24 and 25.
• Embodied are the compounds of formula 1, wherein the compounds are selected from the group consisting of examples 2, 20.b, 21, 22, 23, 24 and 25.
• Embodied are the compounds of formula 1, wherein the compounds are selected from the group consisting of examples 2, 20.b, 21, 22, 23 and 24.
• Any and each other of the definitions of R 1 , R 2 , R 3 , n, R 1.1 to R 1.13 , R 3.1 and R 3.2 may be combined with each other.
• the compounds according to the present invention and their intermediates may be obtained using methods of synthesis which are known to the one skilled in the art and described in the literature of organic synthesis.
• the compounds are obtained in analogous fashion to the methods of preparation explained more fully hereinafter, in particular as described in the experimental section.
• the order in carrying out the reaction steps may be varied. Variants of the reaction methods that are known to the one skilled in the art but not described in detail here may also be used.
• the general processes for preparing the compounds according to the invention will become apparent to the one skilled in the art studying the following schemes. Starting materials are commercially available or may be prepared by methods that are described in the literature or herein, or may be prepared in an analogous or similar manner.
• Step A intermediate I ⁇ intermediate II
• a strong Br ⁇ nsted or a Lewis acid for example sulfuric acid, hydrogen chloride, p-toluenesulfonic acid, Amberlyst 15, tetrafluoroboric acid, trifluoroacetic acid or boron trifluoride, either without solvent as a melt or in a suitable solvent, such as benzene, toluene, acetonitrile, diethyl ether, chloroform, acetic anhydride or mixtures thereof.
• reaction takes place within 1 to 24 hours.
• Preferred reaction temperatures are between room temperature and 160 °C, or the boiling point of the solvent, respectively.
• the reaction is done with molten ethyl carbamate as reactant and a catalytic amount of concentrated sulfuric acid at temperatures of 140-160 °C without any additional solvent.
• the chlorination (Step B, intermediate II ⁇ intermediate III) can be done as described in Vovk et al. (Synlett 2006, 3, 375-378) and Sinitsa et al. (J. Org. Chem.
• intermediate II by heating intermediate II together with a chlorinating agent, for example phosphorous pentachloride, phosphoryl chloride or sulfuryl chloride in an organic solvent, for example benzene or toluene.
• a chlorinating agent for example phosphorous pentachloride, phosphoryl chloride or sulfuryl chloride in an organic solvent, for example benzene or toluene.
• the reaction takes place within 1 to 24 hours. Preferred reaction temperatures are between 50 °C and 150 °C.
• intermediate III can be prepared as described in Jochims et al. (Chem. Ber. 1982, 115, 860-870) by ⁇ -halogenation of aliphatic isocyanates, for example benzyl iso- cyanate, using for example a bromination agent, for example N-bromosuccinimide.
• Isocya- nates can be synthesized as described in US6207665 and in Charalambides et al. (Synth. Commun. 2007, 37, 1037-1044) , by reacting an amine precursor with phosgene.
• Intermediates V (Step C, intermediate IV ⁇ intermediates V) can be prepared as described in Chen et al. (Synth. Commun. 2010, 40, 2506-2510) and Tietcheu et al. (J. Heterocyclic Chem.
• intermediates V can be prepared as described in Scott et al. (J. Med. Chem. 1993, 36, 1947-1955) by direct condensation of the 1,3-dicarbonyl compound with an amine under reflux in a suitable solvent, for example benzene or toluene with azeotropic re- moval of water.
• intermediates V can be prepared as described in Mariano et al. (J. Org. Chem. 1984, 49, 220-228) by reacting an amine with 3-chloro-2-cyclopenten-1- one, which can be prepared from cyclopentane-1,3-dione.
• Intermediates VI (Step D, intermediate III intermediates VI) can be prepared as described in Vovk et al.
• Step E intermediate I ⁇ intermediate VII
• a suitable sulfinate for example sodium benzenesulfinic acid
• a suitable carbamate for example methyl carbamate or tert-butyl carbamate
• a suitable acid for example formic acid
• a suitable solvent for example tetrahydrofurane, ethanol, methanol or a mixture of solvents, for example tetrahydrofurane and water.
• a suitable lewis acid for example trimethylsilyl chloride, can be used as acid and acetonitrile or toluene can be used as solvent.
• the reaction takes place within 1-6 days. Preferred reaction temperatures are between 0 °C and 50 °C, most preferred room temperature.
• Step F intermediate VII ⁇ intermediates VIII
• a suitable base for example sodium hydride or sodium tert-butoxide
• a suitable organic solvent for example tetrahydrofurane or 2-methyltetrahydrofuran.
• Preferred reaction temperatures are between 0 °C and 50 °C, most preferred room temperature.
• Step G intermediates VIII ⁇ intermediates IX
• a suitable acid for example hydrogen chloride
• a suitable solvent for example 1,4-dioxane.
• the reaction takes place between 1-72 hours.
• Preferred reaction temperatures are between 0 °C and room temperature, most preferred room temperature.
• Intermediates VI (Step H, intermediates IX ⁇ intermediates VI) can be prepared as described in Csütörtöki et al. (Tetrahedron Lett.
• Intermediates VII can be prepared as described in WO04024700 by reacting intermediates VI with an alkylating agent, for example a dialkyl sulfate, for example dimethyl sulfate, an alkyl halide, for example methyl iodide or an alkyl sulfonylate, for example benzyl tosylate, in the presence of a suitable base, for example sodium hydride, sodium hydroxide, cesium carbonate, lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, an organolithium reagent, for example tert-butyllithium or a Grignard reagent, for example isopropylmagnesiumchloride, in an organic solvent, for example tetrahydrofurane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane,
• an alkylating agent for example a
• reaction takes place within 1-72 hours. Preferred reaction temperatures are between 0 °C and 100 °C.
• Compounds according to the present invention IX, X and XII and intermediates XI and VIII are accessible via the synthetic routes depicted in scheme 4; R II , R 1.1 , R 1.11 , R 2 and R 3.1 have the meanings as defined hereinbefore and hereinafter.
• n has the meaning 1 or 2.
• Step L intermediates VII ⁇ compounds of the invention X
• a boronic acid derivative (acid or ester, e.g. pinacol ester)
• a suitable catalyst such as 1,1’-Bis(di-tert- butylphosphino)ferrocene palladium dichloride or [1,1’-bis(diphenylphosphino)-ferrocene]- dichloropalladium(II) as a 1:1 complex with dichloromethane
• a base for example alkali carbonates, hydrogencarbonates, phosphates, hydrogenphosphates or acetates, especially cesium carbonate, in an organic solvent, for example tetra- hydrofurane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane or dichloromethane.
• a base for example alkali carbonates, hydrogencarbonates, phosphates, hydrogenphosphates or acetates, especially sodium acetate, in an alcohol,
• Step K intermediates VIII ⁇ compounds of the invention IX
• Step K can be prepared by basic hydrolysis of intermediates VIII using e.g. alkali hydroxides like lithium hydroxide in a mixture of water and a polar organic solvent like THF, dioxane, DMF, DMSO or acetonitrile, preferably dioxane.
• the reaction takes place within 10 min to 24 h.
• reaction temperatures are between 0 ° C and 100 °C, for example r.t..
• the reaction has to be monitored by TLC or HPLC to minimize decomposition of the molecule.
• Intermediates XI (Step M, compounds of the invention IX ⁇ intermediates XI) can be prepared by reaction of compounds of the invention IX with 1,1’-carbonyldiimidazole followed by reaction with reducing agents like complex borohydrides (stable enough in water), preferably sodium borohydride in a mixture of water and a polar organic solvent like THF or dioxane. The reaction takes place within 10 min to 24 h.
• Preferred reaction temperatures are between -20 ° C and 25 °C, for example 5-10 O C.
• Compounds of the invention XII (Step N, compounds of the invention IX ⁇ compounds of the invention XII) can be prepared by reaction of compounds of the invention IX with an appropriate amine or ammonium salt in the presence of a sufficient amount of a base like N-N-diisopropylethyl amine (DIPEA) in a polar solvent like DMF, THF or dioxane using standard literature procedures.
• DIPEA N-N-diisopropylethyl amine
• the carboxylic acids IX has to be activated in advance by reaction with an activating agent such as O-(7-Azabenzotriazol-1-yl)-N,N,N’,N’- tetramethyluronium hexafluorophosphate (HATU) or O-(Benzotriazol-1-yl)- N,N,N’,N’- tetramethyluroniumtetrafluoroborate (TBTU) and N,N-diisopropylethyl amine (DIPEA).
• the reaction takes place within 10 min to 24 h.
• Preferred reaction temperatures are between -20 ° C and 80 °C, preferably at r.t.
• Compounds according to the present invention XIII are accessible via the synthetic routes depicted in scheme 5; R 1.11 and R 2 have the meanings as defined hereinbefore and hereinafter. n has the meaning 1 or 2.
• Step O intermediates VI ⁇ compounds of the invention XIII; or Step Ob, intermediates VII ⁇ compounds of the invention XIIIb
• a boronic acid derivative (acid or ester, e.g.
• compounds of the invention XIIIb (Step Ib, intermediates XIII ⁇ compounds of the invention XIIIb) can be prepared as described in WO04024700 by reacting intermediates XIII with an alkylating agent, for example a dialkyl sulfate, for example dimethyl sulfate, an alkyl halide, for example methyl iodide or an alkyl sulfonylate, for example benzyl tosylate, in the presence of a suitable base, for example sodium hydride, sodium hydroxide, cesium carbonate, lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexamethyldisilazide, an organolithium reagent, for example tert-butyllithium or a Grignard reagent, for example isopropylmagnesiumchloride, in an organic solvent, for example tetrahydrofurane, N,N-dimethylform
• Step P compounds of the invention XIII ⁇ compounds of the invention XIV
• a sulfonylating agent for example methanesulfonyl chloride or para-toluenesulfonyl chloride
• a base for example sodium hydride, lithium diisopropylamide, potassium hexamethyldisilazide, lithium hexa- methyldisilazide
• an organolithium reagent for example tert-butyllithium or a Grignard re- agent, for example iso-propylmagnesiumchloride, in an organic solvent, for example tetra- hydrofurane, N,N-dimethylformamide, acetonitrile, 1,4-dioxane or dichloromethane.
• Step Q compounds of the invention XIII ⁇ intermediates XV
• a base for example triethylamine
• N,N-diisopropylethylamine or N-methylmorpholine optionally in the presence of a catalyst, for example 4-dimethylaminopyridine, in an organic solvent, for example dichloromethane, tetrahydrofurane, acetonitrile or N,N-dimethylformamide.
• a catalyst for example 4-dimethylaminopyridine
• organic solvent for example dichloromethane, tetrahydrofurane, acetonitrile or N,N-dimethylformamide.
• Preferred reaction temperatures are between 0 °C and 50 °C, most preferred room temperature.
• Step R intermediates XV ⁇ compounds of the invention XVI
• an organic solvent for example dichloromethane, acetonitrile, tetrahydrofurane, 1,4-dioxane, toluene or N,N-dimethylformamide.
• the reaction takes place within 1-72 hours.
• Preferred reaction temperatures are between 0 °C and 50 °C, most preferred room temperature.
• Step S compounds of the invention XI ⁇ intermediates XVII
• an organic solvent for example dichloromethane, acetonitrile, tetrahydrofurane or 1,4- dioxane. The reaction takes place within 1-24 hours. Preferred reaction temperatures are between 0 °C and 50 °C, most preferred room temperature.
• Step T intermediates XVII ⁇ compounds of the invention XVIII
• a reducing reagent like sodium triacetoxyborohydride or sodium cyanoborohydride in an organic solvent, for example N,N-dimethylformamide or 1,2- dichloroethane.
• Preferred reaction temperatures are between 0 °C and 50 °C, most preferred room temperature.
• Step U compounds of the invention XI ⁇ intermediates XIX
• a halogenating reagent for instance phosphorus tribromide in an organic solvent, for example dichloromethane
• the reaction takes place within 1-24 hours.
• Preferred reaction temperatures are between 0 °C and 50 °C.
• Compounds of the invention XVIII (Step V, intermediates XIX ⁇ compounds of the invention XVIII) can be prepared by reacting intermediates XIX with an amine R1.12 in the presence of a base like potassium carbonate in an organic solvent, for example N,N- dimethylformamide or 1,2-dichloroethane.
• reaction temperatures are between 0 °C and 100 °C.
• room temperature denotes a temperature of about 20 °C.
• 1 H NMR spectra and/or mass spectra have been obtained of the compounds prepared. Compounds given with a specific configuration at a stereocenter are isolated as pure isomers. The retention times given are measured under the following conditions (TFA:
• Formic acid (3.9 mL, 104 mmol) is added to a solution of tert-butyl carbamate (1.90 g, 16.2 mmol), 2-bromo-4-cyanobenzaldehyde (3.41 g, 16.2 mmol) and sodium benzenes- ulfinate (2.67 g, 16.2 mmol) in a mixture of tetrahydrofurane (7.0 mL) and water (60 mL). The mixture is stirred at room temperature for 6 days. Water (180 mL) is added and the precipitate is filtered and washed with water. The precipitate is treated with tert-butyl methyl ether (30 mL), and the mixture is stirred for 30 min.
• Sodium hydride (60% in mineral oil, 360 mg, 9.00 mmol) is added in portions to a mixture of 3-(3-(trifluoromethyl)phenylamino)cyclopent-2-enone (2.16 g, 8.96 mmol) and 2- methyltetrahydrofuran (30 mL). After 30 min tert-butyl (2-bromo-4-cyanophenyl)-(phenyl- sulfonyl)methylcarbamate (Step 1, 3.35 g, 7.43 mmol) is added and the mixture is stirred at room temperature for 2 h. Water is added and the phases are separated.
• Methyliodide (3.61 mL, 58.0 mmol) is added to a solution of 3-bromo-4-(2,5-dioxo-1-(3- (trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4- yl)benzonitrile (intermediate 3, 23.0 g, 48.3 mmol) and cesium carbonate (20.5 g, 62.8 mmol) in N,N-dimethylformamide (230 mL). The mixture is stirred at room temperature overnight. Water and ethyl acetate are added and the phases are separated.
• intermediate 8 is assigned based on the X-ray structure of derivatives (e.g. example 2) in complex with neutrophil elastase.
• Methyliodide (3.55 mL, 57.1 mmol) is added to a solution of 3-Bromo-4-[2,5-dioxo-1-(3- trifluoromethyl-phenyl)-1,2,3,4,5,6,7,8-octahydro-quinazolin-4-yl]-benzonitrile
• Oxazole (10 g, 144.797 mmol) is dissolved in 400 mL abs. diethylether under argon. The solution is cooled to -78 O C and n-butyllithium (1.6 M solution in hexane, 100 mL, 160 mmol) is added slowly at that temperature. After stirring for 1 h triisopropylsilyl trifluoromethanesulfonate (40.265 mL, 144.797 mmol) in 100 mL abs. diethylether is added slowly. The mixture is warmed to r.t. within 12 h, and the solvent is evaporated in vacuo.
• 2-Triisopropylsilanyl-oxazole (intermediate 16, 10 g, 44.365 mmol) is dissolved in 40 mL abs. diethylether under argon. The solution is cooled to -78 O C and n-butyllithium (1.6 M solution in hexane, 100 mL, 160 mmol) is added slowly at that temperature. After stirring for 1 h boronic acid triispropylester (12 mL, 52.193 mmol) 20 mL abs. THF is added slowly. The mixture is stirred for 2 h, and is warmed to r.t.. The mixture is quenched with methanol.
• Table 1 The following examples of Table 1 are prepared in analogy of 5-cyano-2-[3-methyl-2,5- dioxo-1-(3-trifluoromethyl-phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopentapyrimidin-4-yl]- benzamide (example 1), using the appropriate amine as starting material.
• Examples 1.2 and 1.4– 1.35 are prepared using triethylamine as base.
• Examples 1.76-1.85 are prepared using O-(7-zabenzotriazole-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate as coupling reagent and triethylamine as base.
• example 2 The configuration of example 2 is assigned based on the X-ray structure of example 2 in complex with neutrophil elastase.
• Table 2 The following examples of Table 2 are prepared in analogy of 5-cyano-2-[(R)-3-methyl- 2,5-dioxo-1-(3-trifluoromethyl-phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopentapyrimid in-4-yl]-benzamide (example 2), using the appropriate amine as starting material.
• Table 2
• Table 3 The following examples of Table 3 are prepared in analogy of 5-cyano-N-(3-hydroxy- cyclopentyl)-2-[3-methyl-2,5-dioxo-1-(3-trifluoromethyl-phenyl)-2,3,4,5,6,7-hexahydro- 1H-cyclopentapyrimidin-4-yl]-benzamide (example 3), using the appropriate amine as starting material.
• Table 4 The following examples of Table 4 are prepared in analogy of 5-cyano-2-[3-methyl-2,5- dioxo-1-(3-trifluoromethyl-phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopentapyrimidin-4-yl]- N-piperidin-4-yl-benzamide (example 4), using the appropriate amine as starting material.
• Table 4
• Examples 11.4, 11.5, 11.6, 11.9, 11.12-11.18 are synthesized using acetonitrile as solvent and potassium carbonate as base. Table 8
• Example 15.6 is synthesized using acetonitrile as solvent and potassium carbonate as base. Table 9
• Table 11 The following examples of Table 11 are prepared in analogy of 3-Furan-3-yl-4-[3-methyl- 2,5-dioxo-1-(3-trifluoromethyl-phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopentapyrimidin-4- yl]-benzonitrile (example 11), using the appropriate boronic acids or boronic acid esters as starting material.
• Example 19.6 is synthesized using cesium carbonate as base, dioxane as solvent and 5- (4,4,5,5-Tetramethyl-[1 ,3,2]dioxaborolan-2-yl)-2-triisopropylsilanyl-oxazole (intermediate 33) as reagent.
• the silylgroup is deprotected with trifluoroacetic acid/water 1:1.
• Tetrakis(triphenylphospine)palladium (0) (10.6 mg, 0.009 mmol) is added and the mixture is stirred at 80 °C over night.
• the reaction mixture is filtrated over a layer of silica gel and basic aluminum oxide 1:1 and purified by reversed phase HPLC. Crystallisation from isopropanol yielded 28 mg product.
• ESI mass spectrum [M+H] + 490; Retention time HPLC: 0.93 min (method Z011_S03).
• the enantiomer separation is performed by preparative supercritical fluid chromatography on a chiral phase (Daicel Chiralpak IA, 10 x 250 mm, 5 ⁇ m, 10% isopropanol and 20 mM NH 3 in supercritical CO 2 , 40 °C, flow 10 ml/min, 120 bar back pressure).Yield 43 mg; retention time: 1.31 min (early eluting enantiomer) (method: I_IA_20_IPA_NH3).
• the correct stereochemistry is assigned by X-Ray crystallography. EXAMPLE 25
• HUMAN NEUTROPHIL ELASTASE ASSAY Materials Human neutrophil elastase was purchased from Calbiochem (Cat.No.: 324681 ) and the elastase substrate MeOSuc-Ala-Ala-Pro-Val-AMC from Bachem (Cat.No.: I-1270). All other materials were of the highest grade commercially available. The following buffers were used: Compound buffer: 100mM Tris, 500mM NaCl, adjusted to pH 7.5; Assay buffer: 100mM Tris, 500mM NaCl, adjusted to pH 7.5, containing 0.01%BSA.
• Test compounds were prediluted in DMSO and subsequently in compound buffer (5% DMSO final). 5 ⁇ L of these compound dilutions were mixed with 10 ⁇ l Neutrophil elastase (9 ng/ml in assay buffer) in a black 384 well OptiPlate (Perkin Elmer, Cat No.: 6007270) and incubated for 15 min at room temperature. Subsequently 10 ⁇ L substrate solution in assay buffer were added (250 ⁇ M final concentration) and the plates were incubated for 60 min at room temperature. After inactivation of the enzyme, fluorescence intensities were measured at 380 nm excitation and 460 nm emission wavelengths.
• Each plate contains wells with a high value control (DMSO+enzyme+substrate) and wells with a low value control (DMSO+inactivated enzyme+substrate).
• IC 50 values were estimated using a sigmoidal concentration response curve with variable slope. Means of low values were taken as 0%, means of high values as 100%.
• the IC 50 values of selected compounds in the Neutrophil Elastase assay are listed in Table 12.
• Zymosan (100 mg) is mixed with saline (0.9%, 10 mL) and stored at 4 °C for up to one week (note: zymosan does not dissolve in the saline and is used as a suspension).
• a single 45 ml blood sample is taken into a 50 ml tube containing citrate (3.13%, 5 mL) and the tube is gently inverted 4 times.
• zymosan working solution (5 mL) is added. • After the addition of zymosan working solution, the tubes are capped, mixed gently and incubated at 22 °C for 15 min on a shaker at 20 rpm.
• the enzyme activity is measured using the fluorogenic substrate MeOSuc- Ala-Ala-Pro-Val-AMC (Bachem Cat. No. I-1270, substrate concentration: 250 ⁇ M, pH 7.5, 25 mM TRIS buffer, 250 mM NaCl) in analogous fashion as described for the human neutrophil assay.
• a dose response curve is generated to calculate the EC 50 of the inhibitor.
• the analysis of the data is performed by the calculation of the percentage of fluorescence in the presence of the test compound compared to the fluorescence of the vehicle control after subtracting the background fluorescence:
• An inhibitor of the neutrophil elastase enzyme will give values between 100 %control (no inhibition) and 0 %control (complete inhibition).
• the metabolic degradation of the test compound is assayed at 37 °C with pooled human liver microsomes.
• the final incubation volume of 100 ⁇ l per time point contains TRIS buffer pH 7.6 (0.1 M), magnesium chloride (5 mM), microsomal protein (1 mg/ml) and the test compound at a final concentration of 1 ⁇ M.
• the reactions are initiated by addition of beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM) and terminated by transfering an aliquot into acetonitrile after different time points.
• NADPH-independent degradation is monitored in incubations without NADPH, terminated at the last time point.
• the [%] remaining test compound after NADPH independent incubation is reflected by the parameter c(control) (metabolic stability).
• the quenched incubations are pelleted by centrifugation (10’000 g, 5 min). An aliquot of the supernatant is assayed by LC-MS/MS for the amount of parent compound.
• the half-life (t 1/2 INVITRO) is determined by the slope of the semilogarithmic plot of the concentration-time profile.
• the half-life (t 1/2 INVITRO) values of selected compounds in the metabolic stability assay human liver microsomes described above are listed in Table 14. Table 14
• ASSAY FOR THE DETERMINATION OF METABOLIC STABILITY WITH HUMAN HEPATOCYTES The metabolic degradation of the test compound is assayed in a human hepatocyte suspension.
• Human hepatocytes (typically cryopreserved) are incubated in an appropriate buffer system (e.g. Dulbecco ⁇ s modified eagle medium plus 3.5 ⁇ g glucagon / 500 mL, 2.5 mg insulin / 500 mL and 3.75 mg / 500 mL hydrocortison) containing 5% species serum.
• an appropriate buffer system e.g. Dulbecco ⁇ s modified eagle medium plus 3.5 ⁇ g glucagon / 500 mL, 2.5 mg insulin / 500 mL and 3.75 mg / 500 mL hydrocortison
• test compound solution 80 ⁇ M; from 2 mM stock solution in DMSO diluted 1:25 with medium
• 395 ⁇ l hepatocyte suspension cell density in the range 0.25-5*10 6 cells/mL, typically 1*10 6 cells/mL; final concentration of test compound 1 ⁇ M, final DMSO concentration 0.05%).
• the cells are incubated for six hours (incubator, orbital shaker) and samples (25 ⁇ l) are taken at 0, 0.5, 1, 2, 4 and 6 hours. Samples are transferred into acetonitrile and pelleted by centrifugation (5 min). The supernatant is transferred to a new 96-deepwell plate, evaporated under nitrogen and resuspended. The decline of parent compound is analyzed by LC-MS/MS.
• the assay provides information on the potential of a compound to pass the cell membrane, on the extent of oral absorption as well as on whether the compound is actively transported by uptake and/or efflux transporters.
• confluent human cancer colon carcinoma cells 2 (Caco-2) cell monolayers grown on permeable filter supports are used as the in vitro absorption model.
• Apparent permeability coefficients (PE) of the compounds across the Caco-2 monolayers are measured (pH 7.2, 37 °C) in apical-to-basal (AB) (absorptive) and basal-to-apical (BA) (secretory) transport direction.
• AB permeability (PEAB) represents drug absorption from the intestine into the blood
• BA permeability (PEBA) drug secretion from the blood back into the intestine via both passive permeability as well as active transport mechanisms mediated by efflux and uptake transporters that are expressed on the Caco-2 cells.
• the compounds are assigned to permeability/absorption classes by comparison of the AB permeabilities with the AB permeabilities of reference compounds with known in vitro permeability and oral absorption in the human. Identical or similar permeabilities in both transport directions indicate passive permeation, vectorial permeability points to additional active transport mechanisms.
• Higher PEBA than PEAB suggests the involvement of an apical efflux transporter (like P-gp) and/or basolateral uptake transporter; higher PEAB than PEBA permeability suggests involvement of an apical uptake transporter (like PepT1) and/or basolateral efflux transporter (like MRP3).
• Active transport is concentration- dependently saturable.
• Caco-2 cells (1-2 * 10 5 cells/cm 2 area) are seeded on filter inserts (Costar transwell polycarbonate or PET filters, 0.4 ⁇ m pore size) and cultured (DMEM) for 10 to 25 days. Compounds are dissolved in appropriate solvent (like DMSO, 1-20 mM stock solutions).
• the transport solution (TL) is applied to the apical or basolateral donor side for measuring A-B or B-A permeability (3 filter replicates), respectively.
• the receiver side contains HTP-4 buffer supplemented with 2% BSA. Samples are collected at the start and end of experiment from the donor and at various time intervals for up to 2 hours also from the receiver side for concentration measurement by LC-MS/MS or scintillation counting. Sampled receiver volumes are replaced with fresh receiver solution.
• the apparent permeability coefficients (PEAB and PEBA) of selected compounds in the Caco-2 drug transport assay described above are listed in Table 16. TABLE 16
• the aqueous solubility of a compound is determined by comparing the amount dissolved in aqueous buffer (containing 2.5% DMSO) to the amount dissolved in an acetonitrile/water (1/1) solution. Starting from a 10 mM DMSO stock solution, aliquots are diluted with acetonitrile/water (1/1) and McIlvaine buffer pH 6.8, respectively. After 24 h of shaking, the solutions or suspensions are filtered and analyzed by LC-UV. The amount dissolved in buffer is compared to the amount dissolved in the acetonitrile/water (1/1) solution.
• Solubility is measured from 0.001 to 0.125 mg/ml at a DMSO concentration of 2.5%. If more than 90 % of the compound is dissolved in buffer, the value is marked with ">".
• the aqueous solubility of selected compounds in the solubility assay described above is listed in Table 17. TABLE 17
• ASSAY FOR DETERMINATION OF AQUEOUS SOLUBILITY (“Shaked flask method”) Saturated solutions are prepared in well plates by adding an appropriate volume of selected aqueous media (typically in the range of 0.25 - 1.5 ml) into each well which contains a known quantity of solid drug substance (typically in the range 0.5 - 5.0 mg). The wells are shaken or stirred for a predefined time period (typically in a range of 2 - 24 h) and then filtered using approriate filter membranes (typically PTFE-filters with 0.45 ⁇ m pore size). Filter absorption is avoided by discarding the first few drops of filtrate.
• approriate filter membranes typically PTFE-filters with 0.45 ⁇ m pore size
• the amount of dissolved drug substance is determined by UV spectroscopy or by HPLC with UV- detection.
• the pH of the aqueous saturated solution is measured using a glass- electrode pH meter.
• Example 2 example 20.b, example 22, example 21, example 23, example 24 and example 25 exhibit a solubility of >0.01 mg/mL at pH 6.8 in this solubility assay.
• ASSAY FOR DETERMINATION OF CYTOCHROME P450 2C9 INHIBITION The inhibition of cytochrome P450 2C9-isoenzyme catalysed hydroxylation of Diclofenac by the test compound is assayed at 37°C with human liver microsomes. All assays are carried out on a robotic system in 96 well plates.
• the final incubation volume contains TRIS buffer (0.1 M), MgCl 2 (5 mM), human liver microsomes (0.1 mg/ml), Diclofenac (10 ⁇ M) and the test compound at five different concentrations or no compound (high control) in duplicate (e.g. highest concentration 10-50 ⁇ M with subsequent serial 1:4 dilutions).
• reactions are started with the cofactor (NADPH, 1 mM) and stopped by cooling the incubation down to 8 °C and subsequently by addition of one volume of acetonitrile.
• An internal standard solution - usually the stable isotope of the formed metabolite - is added after quenching of incubations.
• the IC 50 of a positive control inhibitor sulfaphenazole
• Example 2 If the inhibition of the reaction is still ⁇ 50% at the highest concentration of the test compound, the IC 50 is assigned "> highest concentration tested" (usually >50 ⁇ M).
• Example 2, example 23, and example 24 exhibit an IC 50 value > 50 ⁇ M in this assay.
• ASSAY FOR DETERMINATION OF CYTOCHROME P450 2C19 INHIBITION The inhibition of cytochrome P450 2C19-isoenzyme catalysed hydroxylation of
• Mephenytoin by the test compound is assayed at 37 °C with human liver microsomes. All assays are carried out on a robotic system in 96 well plates. The final incubation volume contains TRIS buffer (0.1 M), MgCl 2 (5 mM), human liver microsomes (0.5 mg/ml), (S)-Mephenytoin (70 ⁇ M) and the test compound at five different concentrations or no compound (high control) in duplicate (e.g. highest concentration 10-50 ⁇ M with subsequent serial 1:4 dilutions).
• reactions are started with the cofactor (NADPH, 1 mM) and stopped by cooling the incubation down to 8 °C and subsequently by addition of one volume of acetonitrile.
• the IC 50 of a positive control inhibitor is determined.
• ASSAY FOR DETERMINATION OF CYTOCHROME P450 2C8 INHIBITION The inhibition of cytochrome P450 2C8-isoenzyme catalysed deethylation of Amodiaquine by the test compound is assayed at 37°C with human liver microsomes. All assays are carried out on a robotic system in 96 well plates. The final incubation volume contains TRIS buffer (0.1 M), MgCl 2 (5 mM), human liver microsomes (0.05 mg/ml), Amodiaquine (1 ⁇ M) and the test compound at five different concentrations or no compound (high control) in duplicate (e.g. highest concentration 10-50 ⁇ M with subsequent serial 1:4 dilutions).
• CYTOCHROME P450 INDUCTION To assess induction of metabolizing enzyme CYP3A4, cryopreserved HepaRG® cells are seeded at a density of 1.0 x 105 per 96 well. Cells are allowed to equilibrate for 72 hours prior to exposure of 10 ⁇ M test article for 48 hours with renewal of test article every 24 hours. Known prototypical CYP3A4 inducers Rifampicin is used as a positive control at a concentration of 25 ⁇ M. After 48 hours of exposure, medium containing the test article is removed and cells were washed with phosphate buffered saline (PBS) prior to mRNA isolation.
• PBS phosphate buffered saline
• the compounds of general formula 1 may be used on their own or combined with other active substances of formula 1 according to the invention.
• the compounds of general formula 1 may optionally also be combined with other pharmacologically active substances. These include, ß2-adrenoceptor-agonists (short and long-acting), anti- cholinergics (short and long-acting), anti-inflammatory steroids (oral and topical corticosteroids), cromoglycate, methylxanthine, dissociated-glucocorticoidmimetics, PDE3 inhibitors, PDE4- inhibitors, PDE7- inhibitors, LTD4 antagonists, EGFR- inhibitors, Dopamine agonists, PAF antagonists, Lipoxin A4 derivatives, FPRL1 modulators, LTB4- receptor (BLT1, BLT2) antagonists, Histamine H1 receptor antagonists, Histamine H4 receptor antagonists, dual Histamine H1/H3-receptor antagonists, PI3-kinase inhibitors, inhibitor
• Prostasin-inhibitors Melanocortin receptor (MC1R, MC2R, MC3R, MC4R, MC5R) modulators, CGRP antagonists, Endothelin antagonists, TNF ⁇ antagonists, anti-TNF antibodies, anti-GM-CSF antibodies, anti-CD46 antibodies, anti-IL-1 antibodies, anti-IL-2 antibodies, anti-IL-4 antibodies, anti-IL-5 antibodies, anti-IL-13 antibodies, anti-IL-4/IL-13 antibodies, anti-TSLP antibodies, anti-OX40 antibodies, mucoregulators, immuno- therapeutic agents, compounds against swelling of the airways, compounds against cough, VEGF inhibitors, but also combinations of two or three active substances.
• PHARMACEUTICAL COMPOSITIONS Suitable preparations for administering the compounds of formula will be apparent to those with ordinary skill in the art and include for example tablets, pills, capsules, suppositories, lozenges, troches, solutions, syrups, elixirs, sachets, injectables, inhalatives and powders etc.
• Suitable tablets may be obtained, for example, by mixing one or more compounds according to formula I with known excipients, for example inert diluents, carriers, disintegrants, adjuvants, surfactants, binders and/or lubricants .
• the tablets may also consist of several layers.
• INDICATIONS The compounds of the invention and their pharmaceutically acceptable salts have activity as pharmaceuticals, in particular as inhibitors of neutrophil elastase, and thus may be used in the treatment of: 1.
• obstructive diseases of the airways including: asthma, including bronchial, allergic, intrinsic, extrinsic, exercise-induced, drug-induced (including aspirin and NSAID-induced) and dust-induced asthma, both intermittent and persistent and of all severities, and other causes of airway hyper-responsiveness; chronic obstructive pulmonary disease (COPD); bronchitis, including infectious and eosinophilic bronchitis; emphysema; alpha1-antitrypsin deficiency; bronchiectasis; cystic fibrosis; sarcoidosis; farmer's lung and related diseases; hypersensitivity pneumonitis; lung fibrosis, including cryptogenic fibrosing alveolitis, idiopathic interstitial pneumonias, fibrosis complicating anti-neoplastic therapy and chronic infection, including tuberculosis and aspergillosis and other fungal infections; complications of lung transplantation; vasculitic and COPD
• psoriasis psoriasis, atopic dermatitis, contact dermatitis or other eczematous dermatoses, and delayed-type hypersensitivity reactions; phyto- and photodermatitis; seborrhoeic dermatitis, dermatitis herpetiformis, lichen planus, lichen sclerosus et atrophica, pyoderma
• panniculitis panniculitis;cutaneous lymphomas, non-melanoma skin cancer and other dysplastic lesions; drug-induced disorders including fixed drug eruptions; 3. eyes: blepharitis; conjunctivitis, including perennial and vernal allergic conjunctivitis; ulceris; anterior and posterior uveitis; choroiditis; autoimmune, degenerative or inflammatory disorders affecting the retina; ophthalmitis including sympathetic ophthalmitis; sarcoidosis; infections including viral , fungal, and bacterial; 4.
• nephritis including interstitial and glomerulonephritis; nephrotic syndrome; cystitis including acute and chronic (interstitial) cystitis and Hunner's ulcer; acute and chronic urethritis, prostatitis, epididymitis, oophoritis and salpingitis; vulvo- vaginitis; Peyronie's disease; erectile dysfunction (both male and female); 5. allograft rejection: acute and chronic following, for example, transplantation of kidney, heart, liver, lung, bone marrow, skin or cornea or following blood transfusion; or chronic graft versus host disease; 6.
• oncology treatment of common cancers including prostate, breast, lung, ovarian, pancre- atic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 8.
• common cancers including prostate, breast, lung, ovarian, pancre- atic, bowel and colon, stomach, skin and brain tumors and malignancies affecting the bone marrow (including the leukaemias) and lymphoproliferative systems, such as Hodgkin's and non-Hodgkin's lymphoma; including the prevention and treatment of metastatic disease and tumour recurrences, and paraneoplastic syndromes; and, 8.
• virus diseases such as genital warts, common warts, plantar warts, hepatitis B, hepatitis C, herpes simplex virus, molluscum contagiosum, variola, human immunodeficiency virus (HIV), human papilloma virus (HPV), cytomegalovirus (CMV), varicella zoster virus (VZV), rhinovirus, adenovirus, coronavirus, influenza, para-influenza; bacterial diseases such as tuberculosis and mycobacterium avium, leprosy; other infectious diseases, such as fungal diseases, chlamydia, Candida, aspergillus, cryptococcal meningitis, Pneumocystis carnii, cryptosporidiosis, histoplasmosis, toxoplasmosis, trypanosome infection and leishmaniasis and 9.
• virus diseases such as genital warts, common warts, plantar wart
• the present invention is directed to compounds of general formula 1 which are useful in the prevention and/or treatment of a disease and/or condition wherein the activity of inhibitors of neutrophil elastase is of therapeutic benefit, including but not limited to the treatment and/or prevention of asthma and allergic diseases, gastrointestinal inflammatory diseases, glomerulonephritis, eosinophilic diseases, chronic obstructive pulmonary disease, infection by pathogenic microbes, rheumatoid arthritis,
• neutrophilic diseases cystic fibrosis (CF), non-cystic fibrosis, idiopathic pulmonary fibrosis, bronchiectasis, ANCA-associated vasculitis, lung cancer, bronchiectasis, emphysema, chronic bronchitis, acute lung injury (ALI), acute respiratory distress syndrome (ARDS), pulmonary hypertension, pulmonary arterial hypertension (PAH), Alpha-1-antitrypsin deficiency (AATD.),
• obesity and related inflammation e.g. chronic adipose tissue inflammation, adipose inflammation, high-fat diet induced inflammation, insulin resistence, diabetes, fatty liver and liver steatosis.
• the present invention relates to a compound of general formula 1 as a medicament.
• the present invention relates to methods for the treatment or prevention of above mentioned diseases and conditions, which method comprises the administration of an effective amount of a compound of general formula 1 to a human being.
• a therapeutically effective dose will generally be in the range from about 0.01 mg to about 100 mg/kg of body weight per dosage of a compound of the invention; preferably, from about 0.1 mg to about 20mg/kg of body weight per dosage.
• the dosage range would be from about 0.7 mg to about 7000 mg per dosage of a compound of the invention, preferably from about 7.0 mg to about 1400 mg per dosage. Some degree of routine dose optimization may be required to determine an optimal dosing level and pattern.
• the active ingredient may be administered from 1 to 6 times a day. The actual pharmaceutically effective amount or therapeutic dosage will of course depend on factors known by those skilled in the art such as age and weight of the patient, route of administration and severity of disease. In any case the active ingredient will be

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