3H,4H,5H,6H,7H-pyrimido[4,5-b][1,4]oxazin-4,6-dione derivatives as TRPA1 inhibitors

Abstract

The present disclosure provides certain 3H,4H,5H,6H,7H-pyrimido[4,5-b][1,4]oxazin-4,6-dione derivatives that are inhibitors of transient receptor potential ankyrin 1 (TRPA1) and are therefore useful in the treatment of diseases that can be treated by inhibition of TRPA1. The present disclosure also provides pharmaceutical compositions containing them and processes for preparing the compounds.

Description

Technical Field

[0001] This disclosure provides certain 3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione derivatives, which are transient receptor potential ankylosing protein 1 (TRPA1) inhibitors and are therefore suitable for treating diseases that can be treated by inhibiting TRPA1. This disclosure also provides pharmaceutical compositions containing these compounds and methods for preparing said compounds. Background Technology

[0002] Transient receptor potential (TRP) channels are a group of voltage-gated ion channels primarily located on the plasma membrane of many mammalian cell types. Approximately 30 structurally related TRP channels exist, grouped into the following groups: TRPA, TRPC, TRPM, TRPML, TRPN, TRPP, and TRPV. Member A of the transient receptor potential cation channel subfamily, 1 (TRPA1) (also known as transient receptor potential ankyrin 1), is the sole member of the TRPA gene subfamily. Structurally, TRPA channels are characterized by multiple N-terminal ankyrin repeats (approximately 14 in the N-terminus of human TRPA1), which give rise to the "A" in the ankyrin name (Montell, 2005).

[0003] TRPA1 is highly expressed in the plasma membranes of sensory neurons in the dorsal root and tuberous ganglia serving both the skin and lungs, as well as in the small intestine, colon, pancreas, skeletal muscle, heart, brain, bladder, and lymphocytes (https: / / www.proteinatlas.org / ), and in human pulmonary fibroblasts.

[0004] TRPA1 is the most well-known sensor of environmental stimuli, evoking somatosensory patterns such as pain, cold, and itching. TRPA1 is activated by a variety of reactive, electrophilic stimuli (e.g., allyl isothiocyanate, reactive oxygen species) and non-reactive compounds (e.g., icilin), and is involved in coughs associated with asthma, chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), or postviral cough, as well as chronic idiopathic coughs and coughs in sensitive patients (Song and Chang, 2015; Grace and Belvisi, 2011). TRPA1 inhibitors are used to treat IPF, with studies showing that cough causes elevated TGF-β levels, and cough is very common in IPF due to the link between cough and lung injury (Xie et al., 2009; Froese et al., 2016; Tschumperlin et al., 2003; Yamamoto et al., 2002; Ahamed et al., 2008). Acute lung injury caused by SARS-CoV-2 infection is mediated at least in part by reactive oxygen species (ROS). ROS are direct activators of TRPA1. Furthermore, desensitization of TRPA1 via spicy food consumption is thought to modulate the Nrf2 pathway and reduce oxidative stress (Bousquet et al., 2020; Bousquet et al., 2021). Therefore, TRPA1 inhibitors show promise in treating lung injury caused by SARS-CoV-2. TRPA1 antagonists inhibit calcium signaling triggered by cough-induced factors such as oxidative stress from cigarette smoke extract (CSE), release of inflammatory mediators, and downregulation of antioxidant gene expression (Lin et al., 2015; Wang et al., 2019). TRPA1 antagonists have been effective in studies of atopic dermatitis (Oh et al., 2013; Wilson et al., 2013), contact dermatitis (Liu et al., 2013), psoriasis-associated pruritus (Wilson et al., 2013), and IL-31-dependent pruritus (Cevikbas et al., 2014). TRPA1 function gain in humans is associated with familial paroxysmal pain syndrome (Kremeyer et al., 2010). TRPA1 antagonists are effective in a behavioral model of migraine-associated touch pain (Edelmayer et al., 2012). TRPA1 expression is selectively increased in the trigeminal ganglion innervating damaged teeth compared to its expression in the trigeminal ganglion innervating healthy teeth (Haas et al., 2011). Several anesthetics are known to be TRPA1 agonists, including isoflurane (Matta et al., 2008), providing a theoretical basis for TRPA1 inhibitors to alleviate postoperative pain.TRPA1 knockout mice and wild-type mice treated with TRPA1 antagonists exhibited anxiolytic and antidepressant-like phenotypes (de Moura et al., 2014). Based on studies showing a mechanistic link between AMPK and TRPA1 inverse regulation, TRPA1 inhibitors are expected to have benefits in the treatment of diabetic neuropathy (Hiyama et al., 2018; Koivisto and Pertovaara, 2013; Wang et al., 2018). TRPA1 knockout mice exhibited smaller myocardial infarction size compared to wild-type mice (Conklin et al., 2019). TRPA1 knockout and pharmacological interventions inhibited TNBS-induced colitis in mice (Engel et al., 2011). In a mouse model of cerebral ischemia, TRPA1 knockout and TRPA1 antagonists reduced myelin sheath damage (Hamilton et al., 2016). In a mouse model of gout with monosodium urate, urate crystals and joint inflammation were reduced in TRPA1 knockout mice (Moilanen et al., 2015). TRPA1 deficiency in rats improves joint inflammation and hyperalgesia in a rat model of acute gout attack (Trevisan et al., 2014). TRPA1 activation triggers an inflammatory response in osteoarthritis chondrocytes (Nummenmaa et al., 2016). TRPA1 inhibition and gene deletion reduce inflammatory mediators in chondrocytes of osteoarthritis-affected mice and in mouse cartilage (Nummenmaa et al., 2016). Finally, TRPA1 knockout mice show improved weight-bearing in osteoarthritis-affected limbs in a MIA-induced knee swelling model (Horvath et al., 2016). TRPA1 is differentially expressed in the bladder epithelium of rats with bladder outlet obstruction (Du et al., 2007) and in the bladder epithelium of patients (Du et al., 2008). TRPA1 receptor modulation attenuates bladder overactivity in a rat model of spinal cord injury (Andrade et al., 2011), and intrathecal administration of TRPA1 antagonists attenuates cyclophosphamide-induced cystitis in rats with reflex hypervoyage (Chen et al., 2016).

[0005] Therefore, there is a desire to provide potent TRPA1 inhibitors.

[0006] A review of various structural types of TRPA1 inhibitors was published in S. Skerratt, Progress in Medicinal Chemistry, 2017, Vol. 56, 81-115; D. Preti, G. Saponaro, A. Szallasi, Pharm. Pat. Anal. (2015) 4(2), 75-94; and H. Chen, Transient receptor potential ankyrin 1 (TRPA1) antagonists: a patent review (2015-2019), Expert Opin Ther Pat., 2020.

[0007] WO2017 / 060488 discloses a compound as a TRPA1 antagonist, which has the following general structural formula.

[0008]

[0009] Among them, the TRPA1 activity disclosed in Examples 53, 72, 73, 86 and 90 in calcium flux analysis has an IC50 of less than 100 nM. 50 .

[0010] L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809, disclose quinazolinone-based TRPA1 antagonists, which include compounds with the following general structural formula.

[0011]

[0012] Compound 31 (where R is OH) was disclosed in FLIPR analysis to have IC 50 It exhibits 58 nM of TRPA1 antagonistic activity and has an intrinsic clearance rate of <14 μL / min / kg in human liver microsomes. Detailed Implementation

[0013] This invention discloses a novel 3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione derivative, which is an inhibitor of transient receptor potential ankylosing protein 1 (TRPA1) and has appropriate pharmacological and pharmacokinetic properties, enabling it to be used as a pharmaceutical agent to treat conditions and / or diseases that can be treated by inhibiting TRPA1.

[0014] The compounds of the present invention can provide several advantages, such as enhanced efficacy, high metabolic and / or chemical stability, high selectivity, safety and tolerability, enhanced solubility, enhanced permeability, desired plasma protein binding, enhanced bioavailability, suitable pharmacokinetic profiles, and the possibility of forming stable salts.

[0015] The compounds of the present invention

[0016] This invention provides a 3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione derivative, which is a surprisingly potent inhibitor of TRPA1 (Analysis A), further characterized by...

[0017] - Modified stability in human liver microsomes (Analysis B)

[0018] - Modified stability in human hepatocytes (Analysis C).

[0019] The compounds of this invention differ structurally from Examples 53, 72, 73, 86, and 90 of WO2017 / 060488 and Example 31 of L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809, because they contain a substituted 3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione core and a substituent adjacent to a second aliphatic alcohol. This structural difference unexpectedly leads to the following advantageous combination: (i) inhibition of TRPA1, (ii) stability in human liver microsomes, and (iii) stability in human hepatocytes.

[0020] Stability in human liver microsomes refers to the sensitivity of a compound to biotransformation in a scenario where drugs with favorable pharmacokinetic properties are selected and / or designed as a first screening step. The liver is the primary site of metabolism for many drugs. Human liver microsomes contain cytochrome P450 (CYP) and therefore represent a model system for studying phase I drug metabolism in vitro. Enhanced stability in human liver microsomes is associated with several advantages, including increased bioavailability and a sufficient half-life, which allows for reduced and less frequent dosing in patients. Therefore, enhanced stability in human liver microsomes is an advantageous feature of compounds intended for use as pharmaceuticals. Thus, in addition to the ability to inhibit TRPA1, the compounds of the present invention are expected to have favorable in vivo clearance and therefore a desired duration of action in humans.

[0021] Stability in human hepatocytes refers to a compound's sensitivity to biotransformation in a context of selecting and / or designing drugs with favorable pharmacokinetic properties. The liver is the primary site of metabolism for many drugs. Human hepatocytes contain cytochrome P450 (CYP) and other drug-metabolizing enzymes, and therefore represent a model system for studying in vitro drug metabolism. (Importantly, compared to liver microsomal analysis, hepatocyte analysis also encompasses phase II biotransformation and liver-specific transport protein-mediated processes, and therefore represents a more complete system for drug metabolism studies). Enhanced stability in human hepatocytes is associated with several advantages, including increased bioavailability and sufficient half-life, which allows for reduced and less frequent dosing in patients. Therefore, enhanced stability in human hepatocytes is a favorable feature for compounds intended for drug use.

[0022] This invention provides novel compounds of formula (I).

[0023]

[0024] in

[0025] A is selected from the group consisting of: phenyl, thienyl, benzofuranyl, and benzothienyl, wherein A is unsubstituted or via halogen and C. 1-4 -alkyl group R 1 One or two members are replaced.

[0026] Another embodiment of the invention relates to a compound of formula (I), wherein A is selected from the group consisting of phenyl, thiophene, benzofuran, and benzothiophene, and wherein A is unsubstituted or via a group R consisting of F, Cl, I, and CH3. 1 One or two members are replaced.

[0027] Another embodiment of the invention relates to a compound of formula (I), wherein A is selected from the group consisting of phenyl, benzofuranyl, and benzothiophene, and wherein A is unsubstituted or via a group R consisting of F, Cl, I, and CH3. 1 One or two members are replaced.

[0028] Another embodiment of the present invention relates to a compound of formula (I), wherein A is selected from the group consisting of:

[0029]

[0030] And A is unsubstituted or has not been converted by the group R. 1 One or two members are replaced.

[0031] And R 1 As defined in any of the foregoing implementation schemes.

[0032] The preferred choice is the compound of formula (I) selected from the group consisting of the following groups.

[0033]

[0034] Terms and definitions used

[0035] Terms not explicitly defined herein shall be given the meanings that would be given to those skilled in the art based on the disclosure and context. However, unless the opposite meaning is specified, the following terms as used in the specification shall have the indicated meanings and follow the conventions described below.

[0036] In the groups, radicals, or portions defined below, the number of carbon atoms is usually indicated before the group, e.g., C 1-6 Alkyl refers to an alkyl group having 1 to 6 carbon atoms. Typically, in groups such as HO, H₂N, (O)S, (O)₂S, NC (cyano), HOOC, F₃C, or similar groups, the group attachment point of the molecule can be determined by the free valence of the group itself. For composite groups containing two or more daughter groups, the last named daughter group is the group attachment point, for example, the substituent "aryl-C". 1-3 -alkyl- indicates bonding to C 1-3 aryl group of alkyl group, C 1-3 -alkyl- groups are bonded to the core or to groups to which the substituent is attached.

[0037] In cases where the compounds of this invention are described by chemical name or as a chemical formula, the chemical formula shall prevail in the event of any inconsistency. An asterisk may be used in the subsidiary formula to indicate bonds attached to the core molecule as defined.

[0038] The atomic numbering of a substituent begins with the atom closest to the core or the group to which the substituent is attached.

[0039] For example, the term "3-carboxypropyl-group" represents the following substituents:

[0040]

[0041] The carboxyl group is attached to the third carbon atom of the propyl group. The terms "1-methylpropyl-", "2,2-dimethylpropyl-", or "cyclopropylmethyl-" represent the following groups:

[0042]

[0043] An asterisk can be used in a subform to indicate a bond that is attached to the core molecule as defined.

[0044] The term "C" alone or in combination with another group 1-n-alkyl (where n is an integer selected from 2, 3, 4 or 5) represents an acyclic, saturated, branched or straight-chain hydrocarbon group having 1 to n carbon atoms. For example, the term C 1-5 -Alkyl groups include H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C-CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0045] The term "fluorine" added to "alkyl," "alkylene," or "cycloalkyl" (saturated or unsaturated) refers to an alkyl or cycloalkyl in which one or more hydrogen atoms are substituted by fluorine atoms. Examples include (but are not limited to): H2FC-, HF2C-, and F3C-.

[0046] The term phenyl refers to a group of the following ring.

[0047]

[0048] The term thiophene group refers to a group with the following ring.

[0049]

[0050] The term benzofuranyl refers to a group with the following ring.

[0051]

[0052] The term benzothiophene group refers to a group with the following ring.

[0053]

[0054] The term 3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione refers to the following core group.

[0055]

[0056] As used herein, the term “substituted” means that one or more hydrogen atoms on a specified atom are selectively replaced by the indicated group, provided that the substitution does not exceed the normal valence of the indicated atom and that the substitution produces a stable compound.

[0057] Unless expressly indicated, throughout the specification and appended claims, the given chemical formula or name shall cover tautomers and all stereo, optical and geometric isomers (e.g., mirror-image isomers, non-mirror-image isomers, E / Z isomers, etc.) and their racemates, as well as mixtures of individual mirror-image isomers in different proportions, mixtures of non-mirror-image isomers, or mixtures of any of the foregoing forms (if the isomers and mirror-image isomers are present), and their salts (including pharmaceutically acceptable salts) and their solvates, such as hydrates, including solvates of the free compound or solvates of salts of the compound.

[0058] Generally, substantially pure stereoisomers can be obtained according to synthetic principles known to those skilled in the art, such as by separating the corresponding mixtures, by using stereochemically pure starting materials, and / or by stereoselective synthesis. Optically active forms are known in the art, for example by resolving racemic forms or by synthesizing, for example, starting from optically active starting materials and / or by using chiral reagents.

[0059] The mirror-image isomeric pure compounds or intermediates of the present invention can be prepared via asymmetric synthesis, for example by preparation and subsequent separation of suitable non-mirror-image isomeric compounds or intermediates that can be separated by known methods (e.g., by chromatographic separation or crystallization) and / or by chiral reagents, such as chiral starting materials, chiral catalysts or chiral auxiliaries.

[0060] Furthermore, those skilled in the art know how to prepare mirror-image isomer pure compounds from corresponding racemic mixtures, for example by chromatographic separation of the corresponding racemic mixture on a chiral stationary phase; or by resolution of the racemic mixture using a suitable resolving agent, for example by forming a non-mirror-image isomer salt of the racemic compound with an optically active acid or base, subsequent resolution of the salt, and release of the desired compound from the salt; or by deriving the corresponding racemic compound using an optically active chiral auxiliary reagent, followed by separation of the non-mirror-image isomer and removal of the chiral auxiliary group; or by kinetic resolution of the racemic mixture (e.g., by enzymatic resolution); by mirror-image selective crystallization from aggregates of mirror-image isomer crystals under suitable conditions; or by (partial) crystallization from a suitable solvent in the presence of an optically active chiral auxiliary agent.

[0061] This article uses the phrase “pharmaceutically acceptable” to refer to compounds, materials, compositions, and / or dosage forms that are suitable for use within the limits of reasonable medical judgment without excessive toxicity, irritation, allergic reactions, or other problems or complications, and that are commensurate with a reasonable benefit / risk ratio.

[0062] As used herein, “pharmaceutically acceptable salt” refers to a derivative of the disclosed compound in which the parent compound forms a salt or complex with an acid or base.

[0063] Examples of acids that form pharmaceutically acceptable salts with a parent compound containing a basic moiety include inorganic or organic acids such as benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentian acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0064] Examples of cations and bases that form pharmaceutically acceptable salts with parent compounds containing acidic moieties include Na. + K + Ca 2+ Mg 2+ NH4 + L-arginine, 2,2'-iminodiethanol, L-lysine, N-methyl-D-glucosamine, or tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing a basic or acidic moiety using conventional chemical methods. Typically, the salts are prepared by reacting the free acidic or basic form of the compound with a sufficient amount of a suitable base or acid in water or an organic diluent (e.g., diethyl ether, ethyl acetate, ethanol, isopropanol, or acetonitrile (or mixtures thereof)).

[0065] Salts of other acids (e.g., trifluoroacetates) that can be used, for example, to purify or separate the compounds of the present invention are also part of the present invention.

[0066] Biological analysis

[0067] Assessment of TRPA1 activity

[0068] Analysis A: TRPA1 analysis

[0069] The activity of the compounds of this invention can be confirmed using the following in vitro TRPA1 cell analysis:

[0070] method:

[0071] The human HEK293 cell line (Perkin Elmer, product number AX-004-PCL) overexpressing the human TRPA1 ion channel was used as the assay system for compound efficacy and activity. Compound activity was determined by measuring the effect of the compound on intracellular calcium concentration induced by the agonistic effect of AITC (allyl isothiocyanate) in a FLIPRtetra system (Molecular Devices).

[0072] Cell culture:

[0073] Cell lines were obtained as frozen cells in cryovials and stored at -150°C until use.

[0074] Cells were grown in MEM / EBSS medium (10% FCS and 0.4 mg / mL Genticin). It was important that the cell density not exceed 90% confluence. For subculturing, cells were isolated from flasks using Versene. The day before analysis, cells were isolated, washed twice with medium (MEM / EBSS medium with 10% FCS), and 20,000 cells were seeded at 20 μL / well in 384-well poly-D-lysine-coated plates (black, clear bottom, Cat. 356697) from Corning. The plates were incubated at 37°C / 5% CO2 for 24 hours prior to analysis.

[0075] Compound preparation

[0076] The test compound was dissolved in 100% DMSO at a concentration of 10 mM, and diluted to a concentration of 5 mM in DMSO in the first step, followed by successive dilution steps in 100% DMSO. The dilution factor and the number of dilution steps can be varied as needed. Typically, eight different concentrations are prepared at a 1:5 dilution, and other intermediate dilutions (1:20) of the substance are performed using HBSS / HEPES buffer (1xHEPES, Cat. 14065 from Gibco, 20 mM HEPES, Cat. 83264 from SIGMA, and 0.1% BSAC, Cat. 11926 from Invitrogen, pH 7.4).

[0077] FLIPR analysis:

[0078] On the analysis day, cells were washed three times with analysis buffer, leaving 20 μL of buffer in each well. 10 μL of Ca6 kit (Cat. R8191 Molecular Devices) loading buffer in HBSS / HEPES was added to the cells, and the plate was incubated at 37°C / 5% CO2 for 120 min. 10 μL of the compound or control from an intermediate dilution plate in HBSS / HEPES buffer / 5% DMSO was carefully added to each well. The luminescence (indicating calcium influx or release) was read on a FLIPRtetra device for 10 min to monitor the compound-induced effect (e.g., agonist effect). Finally, 10 μL of the agonist AITC 50 μM (final concentration 10 μM) dissolved in HBSS / HEPES buffer / 0.05% DMSO was added to each well, followed by an additional 10 min reading on a FLIPRtetra device. The area under the signal (AUC) after AITC addition was used for IC50 / % inhibition calculation.

[0079] Data evaluation and calculation:

[0080] Each analytical microtiter plate contains wells with a mediator (1% DMSO) control substitute compound as a control for AITC-induced luminescence (100% CTL; high control) and wells with a mediator control but without AITC as a control for nonspecific luminescence changes (0% CTL; low control).

[0081] Data analysis was performed by calculating the area under the signal curve for each individual well. Based on this value, the percentage value (AUC(sample) - AUC(low))*100 / (AUC(high) - AUC(low)) was calculated for each substance concentration measurement using MegaLab software (internally developed). The IC50 value was calculated from the percentage control value using MegaLab software. Calculation: [y=(ad) / (1+(x / c)^b)+d], a=low value, d=high value; x=concentration M; c=IC50 M; b=hill slope; y=%ctrl

[0082] Table 1: Biodata of the compounds of the present invention obtained from analysis A

[0083] Example <![CDATA[hTRPA1 IC 50 [nM]]]> 1 57 2 12 3 27 4 39 5 39 6 51 7 120

[0084] Table 2: Biodata of the background art compounds obtained in analysis A (Examples 53, 72, 73, 86, and 90 in WO2017 / 060488).

[0085] Examples in WO2017 / 060488 <![CDATA[hTRPA1 IC 50 [nM]]]> 53 36 72 14 73 28 86 67 90 41

[0086] Table 3: Biodata of the background technology compound obtained in analysis A (Example 31 in L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809).

[0087]

[0088] Assess microsomal clearance rate

[0089] Analysis B: Microsomal clearance rate:

[0090] The metabolic degradation of the test compound was analyzed using collected liver microsomes at 37°C. Each 100 μl final culture volume at each time point contained 0.1 M TRIS buffer (pH 7.6 at RT), 5 mM magnesium chloride, 1 mg / ml microsomal protein, and a final concentration of 1 μM of the test compound.

[0091] After a short pre-incubation period at 37°C, the reaction was initiated by adding the reduced form of β-nicotinamide adenine dinucleotide phosphate (NADPH, 1 mM) and terminated at different time points (0, 5, 15, 30, 60 min) by transferring aliquots of the sample to the solvent. Additionally, NADPH-independent degradation was monitored in the NADPH-free culture, which was terminated at the last time point. The percentage of remaining test compounds after NADPH-independent culture is reflected by parameter c (control) (metabolic stability). The quenched culture was pelleted by centrifugation (10000 g, 5 min).

[0092] The amount of parent compound in aliquots of the supernatant was analyzed by LC-MS / MS. The half-life (t1 / 2INVITRO) was determined by the slope of the semi-logarithmic plot of the concentration-time curve.

[0093] The intrinsic clearance rate (CL_INTRINSIC) is calculated by taking into account the amount of protein in culture:

[0094] CL_INTRINSIC[μl / min / mg protein]=(Ln 2 / (half-life[min]*protein content[mg / ml]))*1000

[0095] CL_INTRINSIC_INVIVO[ml / min / kg]=(CL_INTRINSIC[μL / min / mg protein]x MPPGL[mg protein / g liver]x liver factor[g / kg body weight]) / 1000

[0096] Qh[%]=(CL[ml / min / kg] / liver blood flow[ml / min / kg])

[0097] Hepatocellular, human: 120 x 10^6 cells / g liver

[0098] Liver factor, human: 25.7 g / kg body weight

[0099] Blood flow, human: 21 ml / (min x kg)

[0100] Table 4: Biodata of the compounds of the present invention obtained from analysis B

[0101] Example Human LM[%Qh] 1 <23 2 <23 3 <23 4 <23 5 29 6 56 7 <23

[0102] Table 5: Biodata of the background art compounds obtained in analysis B (Examples 53, 72, 73, 86, and 90 in WO2017 / 060488).

[0103] Examples in WO2017 / 060488 Human LM[%Qh] 53 <23 72 30 73 38 86 <23 90 39

[0104] Table 6: Biodata of the background technology compound obtained in analysis B (Example 31 in L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809).

[0105]

[0106] Assess hepatocyte clearance rate

[0107] Analysis C: Hepatocyte clearance rate

[0108] The metabolic degradation of the test compounds was analyzed in hepatocyte suspension. Hepatocytes (cryopreserved) were placed in Dulbecco's modified eagle medium containing 5% species serum (supplemented with 3.5 μg glucagon / 500 mL, 2.5 mg insulin / 500 mL and 3.75 mg hydrocortisone / 500 mL).

[0109] After pre-incubation in an incubator (37°C, 10% CO2) for 30 min, 5 μl of the test compound solution (80 μM; diluted 1:25 from 2 mM in DMSO using culture medium) was added to 395 μl of hepatocyte suspension (depending on species, cell density ranged from 0.25 to 5 million cells / mL, typically 1 million cells / mL; final concentration of test compound was 1 μM, final concentration of DMSO was 0.05%).

[0110] Cells were cultured for six hours (in a culture vessel and on a fixed-track oscillator) and samples (25 μl) were collected at 0, 0.5, 1, 2, 4, and 6 hours. The samples were transferred to acetonitrile and pelleted by centrifugation (5 min). The supernatant was transferred to a new 96-well plate, evaporated under nitrogen, and resuspended.

[0111] The reduction of the parent compound was analyzed by HPLC-MS / MS.

[0112] CLint is calculated as follows: CL_INTRINSIC = dose / AUC = (C0 / CD) / (AUD + clast / k) × 1000 / 60. C0: initial concentration during culture [μM], CD: cell density of viable cells [10e6 cells / mL], AUD: area under the data [μM xh], clast: concentration of the last data point [μM], k: slope of the regression line due to maternal reduction [h-1].

[0113] The calculated in vitro intrinsic liver clearance can be scaled up to intrinsic in vivo liver clearance and used to predict in vivo hepatic blood clearance (CL) using a liver model (fully stirred model).

[0114] CL_INTRINSIC_INVIVO[ml / min / kg] = (CL_INTRINSIC[μL / min / 10e6 cells] x hepatocellular [10e6 cells / g liver] x liver factor [g / kg body weight]) / 1000

[0115] CL[ml / min / kg] = CL_INTRINSIC_INVIVO[ml / min / kg] x Liver blood flow[ml / min / kg] / (CL_INTRINSIC_INVIVO[ml / min / kg] + Liver blood flow[ml / min / kg])

[0116] Qh[%]=(CL[ml / min / kg] / liver blood flow[ml / min / kg])

[0117] Hepatocellular, human: 120 x 10^6 cells / g liver

[0118] Liver factor, human: 25.7 g / kg body weight

[0119] Blood flow, human: 21 ml / (min x kg)

[0120] Table 7: Biodata of the compounds of the present invention obtained from analysis C

[0121] Example Human hepatocytes [%Qh] 1 9 2 34 3 31 4 22 5 22 6 37 7 9

[0122] Table 8: Biodata of the background art compounds obtained in analysis C (Examples 53, 72, 73, 86, and 90 in WO2017 / 060488).

[0123] Examples in WO2017 / 060488 Human hepatocytes [%Qh] 53 25 72 50 73 36 86 12 90 61

[0124] Table 9: Biodata of the background technology compound obtained in analysis C (Example 31 in L. Schenkel et al., J. Med. Chem. 2016, 59, 2794-2809).

[0125]

[0126]

[0127] Assessing penetration

[0128] Caco-2 cells (1-2×10) 5 Cells / 1cm 2 (Area) Inoculated into filter inserts (Costartranswell polycarbonate or PET filter, 0.4 μm pore size) and cultured (DMEM) for 10 to 25 days.

[0129] The compound was dissolved in a suitable solvent (e.g., DMSO, 1-20 mM stock solution). The stock solution was diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4 x7H2O, 0.41 mM NaH2PO4 xH2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.2) to prepare delivery solutions (0.1-300 μM compound, final DMSO <= 0.5%). Delivery solutions (TL) were applied to the top or bottom supply side for measuring AB or BA permeability (3 filters repeated). Samples were collected from the supply side at different time intervals for up to 2 hours at the beginning and end of the experiment for concentration measurement by HPLC-MS / MS or scintillation counting. The sampled receiving volume was replaced by fresh receiving solution.

[0130] Assess plasma protein binding

[0131] This balanced dialysis (ED) technique was used to determine approximate fractional binding of test compounds to plasma proteins in vitro. Dialysis cells (micro 0.2) were used with Diagnorm Teflon. Each unit consisted of donor and recipient chambers separated by an ultrathin semi-permeable membrane with a molecular weight cutoff of 5 kDa. The stock solution of each test compound was prepared at 1 mM in DMSO and diluted to a final concentration of 1.0 μM. Subsequent dialysis solutions were prepared in pooled human or rat plasma (containing NaEDTA) from male and female donors. Aliquots of 200 μL of dialysis buffer (100 mM potassium phosphate, pH 7.4) were aliquoted into the buffer chamber. Aliquots of 200 μL of the test compound dialysis solution were aliquoted into the plasma chamber. Incubation was performed at 37°C for 2 hours under rotation.

[0132] At the end of the dialysis period, the dialysate was transferred to a reaction tube. The buffer fraction contained 0.2 mL ACN / water (80 / 20). A 25 μL aliquot of the plasma dialysate was transferred to a deep-well plate and mixed with 25 μL ACN / water (80 / 20), 25 μL buffer, 25 μL calibration solution, and 25 μL internal standard solution. Protein precipitation was performed by adding 200 μL ACN. A 50 μL aliquot of the buffer dialysate was transferred to a deep-well plate and mixed with 25 μL blank plasma, 25 μL internal standard solution, and 200 μL ACN. The samples were measured on an HPLC-MS / MS system and evaluated using Analyst software. The binding percentage was calculated using the following equation: Binding % = (Plasma concentration - Buffer concentration / Plasma concentration) × 100.

[0133] Assess solubility

[0134] The saturated solution was prepared in a well plate (format depending on the robot) by adding an appropriate volume of the selected aqueous medium (typically in the range of 0.25–1.5 ml) to each well, each well containing a known amount of solid active pharmaceutical ingredient (typically in the range of 0.5–5.0 mg). The wells were shaken or stirred for a predetermined period of time (typically in the range of 2–24 h) and then filtered using an appropriate filter membrane (typically a PTFE filter with a pore size of 0.45 μm). Filter absorption was avoided by discarding the first few drops of filtrate. The amount of dissolved active pharmaceutical ingredient was determined by UV spectroscopy. Furthermore, the pH of the saturated aqueous solution was measured using a glass electrode pH meter.

[0135] Assess pharmacokinetic characteristics

[0136] The test compound was administered intravenously or orally to the individual test species. Blood samples were collected at several time points after administration of the test compound, anticoagulated, and centrifuged.

[0137] The concentration of the analyte (i.e., the administered compound and / or metabolite) in the plasma sample was quantified. PK parameters were calculated using a non-compartmental method. AUC and Cmax were normalized to a dose of 1 μmol / kg.

[0138] In vitro assessment of metabolism in human hepatocytes

[0139] The metabolic pathways of compounds were investigated using primary human hepatocytes in suspension. After revival from cryopreservation, human hepatocytes were cultured in Dalberg modified Eagle medium containing 5% human serum supplemented with 3.5 μg glucagon / 500 ml, 2.5 mg insulin / 500 ml, and 3.75 mg hydrocortisone / 500 ml.

[0140] After pre-culturing in a cell culture incubator (37℃, 10% CO2) for 30 min, the test compound solution was added to the hepatocyte suspension to obtain 1.0*102 6 Up to 4.0*10 6 The final cell density was determined by the number of cells per ml (depending on the metabolic conversion rate of the compound observed using primary human hepatocytes), the final concentration of the test compound was 10 μM, and the final concentration of DMSO was 0.05%.

[0141] Cells were incubated in a cell culture incubator on a horizontal shaker for six hours, and samples were collected after incubation at 0, 0.5, 1, 2, 4, or 6 hours, depending on the metabolic conversion rate. Samples were quenched in acetonitrile and pelleted by centrifugation. The supernatant was transferred to a 96-well plate, evaporated under nitrogen, and resuspended, followed by bioanalysis by liquid chromatography-high resolution mass spectrometry to identify putative metabolites.

[0142] The structure is based on Fourier-Transform-MS n Data is provisional. Metabolites are reported as a percentage of the parent cell in human hepatocyte cultures, with a critical limit of ≥4%.

[0143] Treatment

[0144] This invention relates to compounds of general formula 1, which can be used for the prevention and / or treatment of diseases and / or conditions related to or regulated by TRPA1 activity, including (but not limited to) the treatment and / or prevention of fibrotic diseases, inflammatory and immunomodulatory conditions, respiratory or gastrointestinal diseases or discomforts, ophthalmic diseases, inflammatory diseases of the joints and inflammatory diseases of the nasopharynx, eyes and skin, and pain and neurological conditions. The conditions, diseases and discomforts include cough, idiopathic pulmonary fibrosis, other interstitial lung diseases and other fibrotic diseases, asthma or allergic diseases, eosinophilic disease, chronic obstructive pulmonary disease, and inflammatory and immunomodulatory conditions (e.g., rheumatoid arthritis and atherosclerosis), as well as pain and neurological conditions (e.g., acute pain, surgical pain, chronic pain and depression) and bladder conditions.

[0145] Compounds of general formula 1 can be used for the prevention and / or treatment of the following:

[0146] (1) Cough, such as chronic idiopathic cough or chronic refractory cough, cough associated with asthma, COPD, lung cancer, post-viral infection and idiopathic pulmonary fibrosis and other interstitial lung diseases.

[0147] (2) Pulmonary fibrotic diseases, such as pneumonia or interstitial pneumonia associated with collagen degeneration, such as lupus erythematosus, generalized scleroderma, rheumatoid arthritis, polymyositis and dermatomyositis; idiopathic interstitial pneumonia, such as idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, pulmonary alveolar proteinosis, Langerhans cell histiocytosis. Histiocytosis, pleural parenchymal elastic fiber hyperplasia, interstitial lung diseases of known etiology, such as interstitial pneumonia due to occupational exposure (e.g., asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), pigeon fancier's lung (birds), or other occupational airborne triggers (e.g., metal dust or mycobacteria), or interstitial pneumonia caused by treatment (e.g., radiation, methotrexate, amiodarone, nitrofurantoin, or chemotherapy agents), or granulomatous diseases such as granulomatous polyangiitis, Churg-Strauss syndrome. Syndrome), sarcoidosis, allergic pneumonia, or interstitial pneumonia caused by various etiologies (e.g., aspiration, inhalation of toxic gases or vapors, bronchitis or pneumonia, or caused by heart failure, X-rays, radiation, chemotherapy, M. Boeck syndrome or sarcoidosis, granulomatosis, cystic fibrosis or myxopathy, interstitial pneumonia caused by α-1-antitrypsin deficiency), acute lung injury caused by SARS-CoV-2 infection or pulmonary fibrosis secondary to SARS-CoV-2 infection.

[0148] (3) Other fibrotic diseases, such as liver bridging fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endocardial fibrosis, old myocardial infarction, glial scars, arterial stiffness, joint fibrosis, Dupuytren's contracture, scar tumors, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, and adhesive synovitis.

[0149] (4) Inflammatory, autoimmune, or allergic diseases and conditions, such as allergic or non-allergic rhinitis or sinusitis, chronic sinusitis or rhinitis, nasal polyps, chronic sinusitis, acute sinusitis, asthma, childhood asthma, allergic bronchitis, alveolitis, airway hyperresponsiveness, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bronchitis or pneumonia, eosinophilic cellulitis (e.g., Welles syndrome), eosinophilic pneumonia (e.g., Loeffler's syndrome). Eosinophilic syndrome, chronic eosinophilic pneumonia, eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-type hypersensitivity, non-allergic asthma; exercise-induced bronchoconstriction; chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, cough, emphysema; systemic allergic reactions or anaphylactic reactions, drug allergies (e.g., to penicillin, cephalosporins), eosinophilic polymyalgia syndrome due to intake of contaminated tryptophan, insect sting allergy; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Sjogren's syndrome. Psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, immune thrombocytopenic purpura (ITP in adults, neonatal ITP, and childhood ITP), immunological hemolytic anemia (autoimmune and drug-induced), Evans syndrome (immune thrombocytopenic purpura), neonatal Rh disease, Goodpasture's syndrome (anti-GBM disease), celiac disease, autoimmune cardiomyopathy, juvenile diabetes mellitus; glomerulonephritis, autoimmune thyroiditis, Behcet's disease; graft rejection (e.g., in transplantation), including allogeneic graft rejection or graft-versus-host disease; inflammatory bowel disease, such as Crohn's disease. Diseases and ulcerative colitis; spinal joint diseases; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory skin diseases such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous and allergic vasculitis); erythema nodosum; eosinophilic bulbomyositis, eosinophilic bulb fasciitis, cancer with leukocyte infiltration of the skin or organs;Ophthalmic diseases, such as age-related macular degeneration, diabetic retinopathy and diabetic macular edema, keratitis, eosinophilic keratitis, keratoconjunctivitis, vernal keratoconjunctivitis, scarring, anterior segment scarring, blepharitis, palpebral conjunctivitis, bullous diseases, cicatricial pemphigoid, conjunctival melanoma, papillary conjunctivitis, dry eye syndrome, episcleritis, glaucoma, glioma, granuloma annulare, Graves' ophthalmopathy, intraocular melanoma, pinguecula, proliferative vitreoretinopathy, pterygium, scleritis, uveitis, acute gout attacks, gout, or osteoarthritis.

[0150] (5) Pain, such as chronic idiopathic pain syndrome, neuropathic pain, hypoesthesia, tenderness to touch, migraine, toothache and postoperative pain.

[0151] (6) Depression, anxiety, diabetic neuropathy and bladder disorders, such as bladder outlet obstruction, overactive bladder, cystitis; myocardial reperfusion injury or cerebral ischemia injury.

[0152] Therefore, the present invention relates to compounds of general formula 1 as pharmaceutical agents.

[0153] Furthermore, the present invention relates to the use of compounds of general formula 1 for the treatment and / or prevention of diseases and / or conditions related to or regulated by TRPA1 activity.

[0154] Furthermore, this invention relates to the use of compounds of formula 1 for the treatment and / or prevention of fibrotic diseases, inflammatory and immunomodulatory conditions, respiratory or gastrointestinal diseases or discomforts, ophthalmic diseases, inflammatory diseases of the joints and nasopharynx, eyes and skin, pain and neurological disorders. The conditions, diseases and ailments include cough, idiopathic pulmonary fibrosis, other interstitial lung diseases and other fibrotic diseases, asthma or allergic diseases, eosinophilic disease, chronic obstructive pulmonary disease, and inflammatory and immunomodulatory conditions (e.g., rheumatoid arthritis and atherosclerosis), as well as pain and neurological disorders (e.g., acute pain, surgical pain, chronic pain and depression) and bladder disorders.

[0155] Furthermore, the present invention relates to the use of compounds of general formula 1 for the treatment and / or prevention of the following:

[0156] (1) Cough, such as chronic idiopathic cough or chronic refractory cough, cough associated with asthma, COPD, lung cancer, post-viral infection and idiopathic pulmonary fibrosis and other interstitial lung diseases.

[0157] (2) Pulmonary fibrotic diseases, such as pneumonia or interstitial pneumonia associated with collagen degeneration, such as lupus erythematosus, generalized scleroderma, rheumatoid arthritis, polymyositis and dermatomyositis; idiopathic interstitial pneumonia, such as idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia, respiratory bronchiolitis with interstitial lung disease, desquamative interstitial pneumonia, cryptogenic organizing pneumonia, acute interstitial pneumonia and lymphocytic interstitial pneumonia, lymphangioleiomyomatosis, alveolar proteinosis, Langerhans cell histiocytosis, pleural parenchymal elastic fiber hyperplasia; interstitial lung diseases of known etiology, such as interstitial pneumonia due to occupational exposure, such as asbestosis, silicosis, miner's lung (coal dust), farmer's lung (hay and mold), pigeon fancier's lung (birds), or other occupational airborne diseases. Interstitial pneumonia caused by airborne triggers (such as metal dust or mycobacteria), or by treatments (such as radiation, methotrexate, amiodarone, nitrofurantoin, or chemotherapy agents), or granulomatous diseases such as granulomatous polyangiitis, Chauvin-Schwarz syndrome, sarcoidosis, hypersensitivity pneumonitis, or interstitial pneumonia caused by various etiologies (such as aspiration, inhalation of toxic gases or vapors, bronchitis or pneumonia, or interstitial pneumonia caused by heart failure, X-rays, radiation, chemotherapy, M. Boeck's disease or sarcoidosis, granulomatous disease, cystic fibrosis or myxopathy, α-1-antitrypsin deficiency), acute lung injury caused by SARS-CoV-2 infection, or pulmonary fibrosis secondary to SARS-CoV-2 infection.

[0158] (3) Other fibrotic diseases, such as liver bridging fibrosis, cirrhosis, non-alcoholic steatohepatitis (NASH), atrial fibrosis, endocardial fibrosis, old myocardial infarction, glial scars, arterial stiffness, joint fibrosis, Dupuytren's contracture, scar tumors, scleroderma / systemic sclerosis, mediastinal fibrosis, myelofibrosis, Peyronie's disease, nephrogenic systemic fibrosis, retroperitoneal fibrosis, and adhesive synovitis.

[0159] (4) Inflammatory, autoimmune, or allergic diseases and conditions, such as allergic or non-allergic rhinitis or sinusitis, chronic sinusitis or rhinitis, nasal polyps, chronic sinusitis, acute sinusitis, asthma, childhood asthma, allergic bronchitis, alveolitis, airway hyperresponsiveness, allergic conjunctivitis, bronchiectasis, adult respiratory distress syndrome, bronchial and pulmonary edema, bronchitis or pneumonia, eosinophilic cellulitis (e.g., Wells syndrome), eosinophilic pneumonia (e.g., Löffler's syndrome, chronic eosinophilic pneumonia), eosinophilic fasciitis (e.g., Shulman's syndrome), delayed-type hypersensitivity, non-allergic asthma; exercise-induced bronchitis. Constriction; Chronic obstructive pulmonary disease (COPD), acute bronchitis, chronic bronchitis, cough, emphysema; systemic allergic reactions or anaphylactic reactions, drug allergies (e.g., to penicillin, cephalosporins), eosinophilic globulin-myalgia syndrome due to intake of contaminated tryptophan, insect sting allergy; autoimmune diseases, such as rheumatoid arthritis, Graves' disease, Scheringer's syndrome, psoriatic arthritis, multiple sclerosis, systemic lupus erythematosus, myasthenia gravis, immune thrombocytopenic purpura (ITP in adults, neonatal thrombocytopenic purpura, ITP in children), immunological hemolytic anemia (autoimmune and drug-induced), Evans syndrome (thrombocytopenic purpura). Platelet-Rich leukopenia, neonatal Rh disease, Gupassard syndrome (anti-GBM disease), celiac disease, autoimmune cardiomyopathy, juvenile diabetes mellitus; glomerulonephritis, autoimmune thyroiditis, Becette's disease; graft rejection (e.g. in transplantation), including allogeneic graft rejection or graft-versus-host disease; inflammatory bowel diseases, such as Crohn's disease and ulcerative colitis; spinal joint diseases; scleroderma; psoriasis (including T-cell mediated psoriasis) and inflammatory skin diseases, such as dermatitis, eczema, atopic dermatitis, allergic contact dermatitis, urticaria; vasculitis (e.g., necrotizing, cutaneous, and allergic vasculitis); erythroderma nodosum Spots; eosinophilic bulbomyositis, eosinophilic bulbofascitis, cancer with leukocytic infiltration of the skin or organs; ophthalmic diseases such as age-related macular degeneration, diabetic retinopathy and diabetic macular edema, keratitis, eosinophilic bulbokeratitis, keratoconjunctivitis, vernal keratoconjunctivitis, scarring, anterior segment scarring, blepharitis, palpebral conjunctivitis, bullous diseases, cicatricial pemphigoid, conjunctival melanoma, papillary conjunctivitis, dry eye, episcleritis, glaucoma, glioma, granuloma annulare, Graves' ophthalmopathy, intraocular melanoma, pinguecula, proliferative vitreoretinopathy, pterygium, scleritis, uveitis, acute gout attack, gout or osteoarthritis.

[0160] (5) Pain, such as chronic idiopathic pain syndrome, neuropathic pain, hypoesthesia, tenderness to touch, migraine, toothache and postoperative pain.

[0161] (6) Depression, anxiety, diabetic neuropathy and bladder disorders, such as bladder outlet obstruction, overactive bladder, cystitis; myocardial reperfusion injury or cerebral ischemia injury.

[0162] In other respects, the present invention relates to compounds of general formula 1, which are used for the treatment and / or prevention of the diseases and conditions mentioned above.

[0163] In other respects, the present invention relates to the use of compounds of general formula 1 in the preparation of pharmaceutical agents for the treatment and / or prevention of the diseases and conditions mentioned above.

[0164] In other aspects of the invention, the invention relates to a method for treating or preventing the diseases and conditions mentioned above, the method comprising administering an effective amount of a compound of formula 1 to a human.

[0165] Combination therapy

[0166] The compounds of the present invention may be further combined with one or more, preferably one, other therapeutic agents. According to one embodiment, the additional therapeutic agent is selected from the group consisting of: therapeutic agents that can be used to treat the diseases or conditions described above, specifically those associated with fibrotic diseases, inflammatory and immunomodulatory conditions, respiratory or gastrointestinal diseases or discomforts, inflammatory diseases of the joints or nasopharynx, eyes and skin (e.g., cough, idiopathic pulmonary fibrosis, other interstitial lung diseases, asthma or allergic diseases, eosinophilic disease, chronic obstructive pulmonary disease, atopic dermatitis), and autoimmune disorders (e.g., rheumatoid arthritis and atherosclerosis), or therapeutic agents that can be used to treat ophthalmic diseases, pain, and depression.

[0167] Other therapeutic agents suitable for the combination specifically include those that, for example, enhance the therapeutic effect of one or more active substances with respect to one of the mentioned indications and / or allow for a reduction in the dosage of one or more active substances.

[0168] Therefore, the compounds of the present invention can be combined with one or more other therapeutic agents selected from the group consisting of: antifibrotic agents, antitussives, anti-inflammatory agents, anti-atopic dermatitis agents, analgesics, anticonvulsants, anxiolytics, sedatives, skeletal muscle relaxants, or antidepressants.

[0169] Antifibrotic agents include nintedanib, pirfenidone, phosphodiesterase-IV (PDE4) inhibitors (e.g., roflumilast), autotaxin inhibitors (e.g., GLPG-1690 or BBT-877); connective tissue growth factor (CTGF) blocking antibodies, such as pamrevlumab; B cell activating factor receptor (BAFF-R) blocking antibodies, such as lanalumab; α-V / β-6 blocking inhibitors, such as BG-00011 / STX-100; recombinant pentraxin-2 (PTX-2), such as PRM-151; c-Jun N-terminal kinase (JNK) inhibitors, such as CC-90001; galactoglobulin-3 inhibitors, such as TD-139; G protein-coupled receptor 84 (GPR84) inhibitors, such as GLPG-1205; dual inhibitors of G protein-coupled receptor 84 / G protein-coupled receptor 40, such as PBI-4050; Rho-associated coiled-coil protein kinase 2 (ROCK2) inhibitors, such as KD-025; heat shock protein 47 (HSP47) small interfering RNA, such as BMS-986263 / ND-L02-s0201; Wnt pathway inhibitors, such as SM-04646; LD4 / PDE3 / 4 inhibitors, such as Tipelukast; recombinant immunomodulatory domains of histyl-tRNA synthetase (HARS), such as ATYR-1923; prostaglandin synthase inhibitors, such as ZL-2102 / SAR-191801. 15-Hydroxy-eicosapentaenoic acid (15-HEPE, e.g., DS-102); lysyl oxidase, such as LOXL2 inhibitors, e.g., PAT-1251, PXS-5382 / PXS-5338; phosphatidylinositol 3-kinase (PI3K) / mammalian target of rapamycin (mTOR) dual inhibitors, e.g., HEC-68498; calpain inhibitors, e.g., BLD-2660; mitogen-activated protein kinase kinase kinase kinase kinase 19 (MAP3K19) inhibitors, e.g., MG-S-2525; chitinase inhibitors, e.g., OATD-01; mitogen-activated protein kinase kinase kinase 2 (MAPKAPK2) inhibitors, e.g., MMI-0100; transforming growth factor β1 (TGF-beta1) small interfering RNA, e.g., TRK250 / BNC-1021; or lysophosphatidylcholine receptor antagonists, e.g., BMS-986278.

[0170] Cough suppressants include, for example, purine receptor 3 (P2X3) receptor antagonists, such as gefapixant, S-600918, BAY-1817080, or BLU-5937; neurokinin 1 (NK-1) receptor antagonists, such as olpipitan or aprepitan; nicotinic acetylcholine receptor α7 subunit stimulators, such as ATA-101 / bradanicline; codeine, gabapentin, pregablin, or azithromycin.

[0171] Anti-inflammatory agents include corticosteroids such as prednisolone or dexamethasone; cyclooxygenase-2 (COX2) inhibitors such as celecoxib, rofecoxib, parecoxib, valdecoxib, deracoxib, etoricoxib, or lumiracoxib; prostaglandin E2 antagonists; leukotriene B4 antagonists; leukotriene D4 antagonists such as montelukast; 5-lipoxygenase inhibitors; or other nonsteroidal anti-inflammatory drugs (NSAIDs) such as aspirin, diclofenac, diflunisal, etodolac, ibuprofen, or indomethacin.

[0172] Anti-atopic dermatitis agents include cyclosporin, methotrexate, mycophenolate mofetil, azathioprine, phosphodiesterase inhibitors (e.g., apremilast, crisaborole), Janus-associated kinase (JAK) inhibitors (e.g., tofacitinib), neutralizing antibodies against IL-4 / IL-13 (e.g., dupilumab), IL-13 (e.g., lebrikizumab, tralokinumab), and IL-31 (nemolizumab).

[0173] Analgesics can be opioid-like, such as morphine, oxymorphine, levorphanol, oxycodone, propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone, meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine, butorphanol, nalbuphine, and pentazocine; or non-opioid-like, such as acetaminophen.

[0174] Antidepressants include tricyclic antidepressants such as amitriptyline, clomipramine, desipramine, doxepin, imipramine, and nortriptyline; selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine, paroxetine, sertraline, citalopram, and escitalopram; and norepinephrine reuptake inhibitors (SNRIs) such as maprotiline, lofepramine, mirtazapine, oxaprotiline, fezolamine, and tomoxetine. Antidepressants such as duloxetine, mianserin, buproprion, hydroxybuproprion, nomifensine, and viloxazine; dual serotonin-norepinephrine reuptake inhibitors (SNRIs), such as duloxetine, venlafaxine, desvenlafaxine, and levomilnacipran; atypical antidepressants such as trazodone, mirtazapine, vortioxetine, vilazodone, and bupropion; or monoamine oxidase inhibitors (MAOIs), such as tranylcypromine, phenelzine, or isocarboxazid.

[0175] Anxiolytics include benzodiazepines such as alprazolam, bromazepam, chlordiazepoxide, clonazepam, clorazepate, diazepam, flurazepam, lorazepam, oxazepam, temazepam, triazolam, or tofisopam; or non-benzodiazepines. Diazazepine hypnotics, such as eszopiclone, zaleplon, zolpidem, or zopiclone; or carbamates, such as meprobamate, carisoprodol, tybamate, or lorbamate; or antihistamines, such as hydroxyzine, chlorpheniramine, or diphenhydramine.

[0176] Sedatives include, for example, barbiturate sedatives such as amobarbital, aprobarbital, butabarbital, butabital, mephobarbital, methabarbital, methohexital, pentobarbital, secobarbital, talbutal, thiamylal, or thiopental; or non-barbiturate sedatives such as glutethimide, meprobamate, methaqualone, or dichloral phenazone.

[0177] Skeletal muscle relaxants include baclofen, meprobamate, cyclobenzaprine, metaxalone, mesocarbamol, tizanidine, chlorzoxazone, or orphenadrine.

[0178] Other suitable combination pairings include acetylcholinesterase inhibitors, such as donepezil; 5-HT-3 antagonists, such as ondansetron; metabotropic glutamate receptor antagonists; antiarrhythmic agents, such as mexiletine or phenytoin; or NMDA receptor antagonists.

[0179] Further suitable combination partners are incontinence drugs, such as anticholinergics, such as oxybutynin, tolterodine, darifenacin, fesoterodine, solifenacin, or trospium; or bladder muscle relaxants, such as mirabegron; or alpha blockers, such as tamsulosin, alfuzosin, silodosin, doxazosin, or terazosin.

[0180] The dosage of the combination drugs mentioned above is usually 1 / 5 to 1 / 1 of the lowest recommended normal dose.

[0181] Therefore, in another aspect, the present invention relates to the use of the compounds of the invention in combination with one or more other therapeutic agents described above and below for the treatment of diseases or conditions that may be affected by or mediated by TRPA1, particularly as described above and below.

[0182] In other aspects, the present invention relates to a method for treating a patient with a disease or condition that may be affected by TRPA1 inhibition, comprising the step of administering to a patient requiring the treatment a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more other therapeutic agents.

[0183] In other respects, the present invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof in combination with one or more other therapeutic agents for the treatment of a disease or condition in patients in need that may be affected by TRPA1 inhibition.

[0184] In another aspect, the present invention relates to a method for treating a patient with a disease or condition mediated by TRPA1 activity, comprising the step of administering to a patient, preferably a human, a therapeutically effective amount of the compound of the present invention and a therapeutically effective amount of one or more other therapeutic agents described above and below.

[0185] The compounds of this invention can be used in combination with other therapeutic agents simultaneously or at staggered times.

[0186] The compounds of the present invention and one or more other therapeutic agents may be present together in a formulation (e.g., tablets or capsules) or separately in two identical or different formulations (e.g., so-called kit-of-parts).

[0187] Therefore, in another aspect, the present invention relates to pharmaceutical compositions comprising the compounds of the present invention and one or more other therapeutic agents described above and below, as well as optionally one or more inert carriers and / or diluents.

[0188] In another aspect, the present invention relates to the use of the compounds of the present invention in a cough measuring device.

[0189] Other features and advantages of the invention can be understood from the following more detailed examples, which illustrate the principles of the invention by way of example.

[0190] preparation

[0191] The compounds and intermediates of the present invention can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature. Preferably, the compounds are obtained using preparation methods similar to those explained more fully below, specifically as described in the experimental section. In some cases, the order of the reaction steps may be changed. Variations of reaction methods known to those skilled in the art but not described in detail herein may also be used.

[0192] Those skilled in the art will understand the general process for preparing the compounds of the present invention after studying the following scheme. Any functional groups in the starting materials or intermediates may be protected using conventional protecting groups. These protecting groups may be cleaved again at appropriate stages within the reaction sequence using methods well known to those skilled in the art.

[0193] The compounds of this invention are prepared by the synthetic methods described below, wherein the substituents of the general formula have the meanings given above. The methods described are intended to be illustrative of the invention and not to limit the scope of the target compounds and the compounds claimed in the examples. Where the preparation of the starting compound is not described, it is commercially available or can be prepared in a manner similar to that of the known compounds or methods described herein. Substances described in the literature are prepared according to the disclosed synthetic methods. Abbreviations are defined in the Examples section.

[0194] Option 1:

[0195]

[0196] In Scheme 1, the compound of Formula I can be synthesized by N-alkylation of intermediate (A) with chloromethylene-oxadiazole (B) in the presence of a base (e.g., potassium carbonate).

[0197] Option 2:

[0198]

[0199] In Scheme 2, 5-aminopyrimidine-4,6-diol is amidated with activated acetic acid (e.g., chloro-acetyl chloride) carrying a leaving group at the α-position, followed by cyclization in the presence of a base (e.g., DIPEA) to obtain (C). N-alkylation of the pyrimidinone (C) with a protecting group (e.g., p-methoxybenzyl) can be achieved by treating (C) with a suitable reagent carrying a leaving group (e.g., p-methoxybenzyl chloride, PMB-Cl) in the presence of a base (e.g., K₂CO₃). This allows for subsequent N-methylation (e.g., using MeI) of (D) in the presence of a base (e.g., K₂CO₃) to obtain (E). Finally, the protecting group of (E) is cleaved under suitable conditions (e.g., for PMB: trifluoroacetic acid, 100 °C) to obtain intermediate (A).

[0200] Option 3:

[0201]

[0202] In Scheme 3, α-cyanoketone (E) synthesized from carboxylic acid ester (D) is reduced enantioselectively to provide alcohol (F) using a suitable catalytic system employing a combination of a transition metal complex (e.g., Ru or Ir) with a chiral ligand (e.g., [(1S,2S)-(-)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amide) and a hydrogen source (e.g., a triethylamine formate complex). A hydroxylamine is added to the alcohol (F) to provide dihydroxypropanediamine (G). The dead cycle of chloromethylene-oxadiazole (B) can be achieved by stirring the reaction mixture with chloroacetyl chloride in the presence of a base (e.g., DIPEA).

[0203] Example

[0204] preparation

[0205] The compounds and intermediates of the present invention can be obtained using synthetic methods known to those skilled in the art and described in the organic synthesis literature (e.g., using the methods described in "Comprehensive Organic Transformations", 2nd edition, Richard C. Larock, John Wiley & Sons, 2010 and "March's Advanced Organic Chemistry", 7th edition, Michael B. Smith, John Wiley & Sons, 2013). Preferably, the compounds are obtained using preparation methods similar to those explained more fully below, particularly as described in the experimental section. In some cases, the order in which the reaction scheme is carried out can be changed. Variations of the reactions known to those skilled in the art but not described in detail herein can also be used. Those skilled in the art will understand the general methods for preparing the compounds of the present invention after studying the schemes described below. The starting compounds can be commercially available or prepared by methods described in the literature or herein, or in a similar or analogous manner. Before carrying out the reaction, any corresponding functional groups in the starting compounds can be protected with conventional protecting groups. The protecting group may be further cleaved at a suitable stage within the reaction sequence using methods well known to those skilled in the art and described in the literature (e.g., "Protecting Groups", 3rd edition, Philip J. Kocienski, Thieme, 2005 and "Protective Groups in Organic Synthesis", 4th edition, Peter GMWuts, Theodora W. Greene, John Wiley & Sons, 2006). The terms "ambient temperature" and "room temperature" are used interchangeably and specify a temperature of approximately 20°C, for example, between 19°C and 24°C.

[0206] abbreviation:

[0207]

[0208]

[0209] Preparation of intermediates

[0210] Intermediate I

[0211] Intermediate I.1 (General Pathway)

[0212] (3S)-3-(4-chlorophenyl)-3-hydroxypropionitrile

[0213]

[0214] 10.0 g (55.7 mmol) of 4-chlorobenzoylacetonitrile was added to 100 mL of ACN under an inert atmosphere. 142 mg (0.23 mmol) of chloro([(1S,2S)-2-amino-1,2-diphenylethyl](4-toluenesulfonyl)amido(trimethylmethyl)ruthenium(II) (CAS174813-81-1) was added dropwise, followed by 8.30 mL (19.8 mmol) of triethylamine formate complex (5:2). After stirring at RT for 3 h, the solvent was removed under vacuum. Water was added to the remaining crude mixture, and this mixture was extracted twice using EtOAc. The organic layers were combined, dried over MgSO4, filtered, and the solvent was removed under vacuum to provide intermediate I.1.

[0215] C9H8ClNO (M=181.6g / mol)

[0216] ESI-MS: 226 [M+HCOO] -

[0217] R t (HPLC): 0.81 min (Method B)

[0218] The following compounds were prepared using suitable starting materials with a procedure similar to that described for intermediates I.1. As those skilled in the art will understand, these similar examples may involve variations in general reaction conditions.

[0219]

[0220] Intermediate II

[0221] Intermediate II.1 (General Pathway)

[0222] (3S)-3-(4-chlorophenyl)-N,3-dihydroxypropanediamine

[0223]

[0224] 9.82 g (54.1 mmol) of (3S)-3-(4-chlorophenyl)-3-hydroxypropionitrile (intermediate I.1) was added to 100 mL of MeOH, and the mixture was stirred at 75 °C for 1.5 h. After cooling to RT, all volatiles were removed under vacuum to obtain a crude product, which was used without further purification.

[0225] C9H 11 ClN2O2 (M=214.6g / mol)

[0226] ESI-MS: 215 [M+H] +

[0227] R t (HPLC): 0.60 min (Method B)

[0228] The following compounds were prepared using suitable starting materials with a procedure similar to that described for intermediates II.1. As those skilled in the art will understand, these similar examples may involve variations in general reaction conditions.

[0229]

[0230]

[0231] Intermediate III

[0232] Intermediate III.1 (General Pathway)

[0233] (1S)-2-[5-(chloromethyl)-1,2,4-oxadiazol-3-yl]-1-(4-chlorophenyl)ethyl-1-ol

[0234]

[0235] Add 10.0 mL (57.8 mmol) of DIPEA to 11.2 g (52.4 mmol) of intermediate II.1 in 55 mL of NMP. Cool the mixture to 0 °C, then slowly add 4.60 mL (57.7 mmol) of chloroacetyl chloride dissolved in 5 mL of NMP and stir the mixture at 0 °C for 45 min. Then heat the mixture to up to 95 °C and continue stirring for 4 h. After cooling to RT, add 200 mL of water and extract the resulting mixture three times with EtOAc. Combine the organic layers, dry over MgSO4, filter, and remove the solvent under vacuum. Purify the residue by column chromatography (silica gel; PE / EtOAc, 7 / 3).

[0236] C 11 H 10 Cl2N2O2 (M=273.1g / mol)

[0237] ESI-MS: 271 [MH] -

[0238] R t (HPLC): 0.93 min (Method B)

[0239] The following compounds were prepared using suitable starting materials with a procedure similar to that described for intermediates III.1. As those skilled in the art will understand, these similar examples may involve variations in general reaction conditions.

[0240]

[0241]

[0242] Intermediate IV

[0243] Intermediate IV.1 (General Pathway)

[0244] 3-(6-fluoro-1-benzothiophene-2-yl)-3-oxopropionitrile

[0245]

[0246] 0.36 g (9.00 mmol) of NaH (60% in oil) was added to 0.63 g (3.00 mmol) of methyl 6-fluoro-1-benzothiophene-2-carboxylate in 9.0 mL of anhydrous toluene and 0.78 mL of anhydrous ACN at RT under an inert atmosphere. The mixture was heated to reflux and stirred for 16 h, cooled to room temperature, poured onto ice / water (30 mL), and treated with 2 M HCl to pH 1. EtOAc (20 mL) was added and the phases were separated. The aqueous phase was extracted again with EtOAc (20 mL), and the combined organic phases were washed with brine (20 mL) and the solvent was removed under reduced pressure. The crude product was purified by silica gel column chromatography using a gradient (30% to 40%) of EtOAc / hexane.

[0247] C 11 H6FNOS (M=219.23g / mol)

[0248] ESI-MS: 218 [MH] -

[0249] R t (HPLC): 3.31 min (E)

[0250] The following compounds were prepared using suitable starting materials with a procedure similar to that described for intermediates IV.1. As those skilled in the art will understand, these similar examples may involve variations in general reaction conditions.

[0251]

[0252]

[0253] intermediate V

[0254] 3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione

[0255]

[0256] 7.5 mL (94.41 mmol) of chloroacetyl chloride was slowly added to 10.0 g (127.10 mmol) of 5-aminopyrimidine-4,6-diol in 300 mL of DMF at 65 °C with stirring. After stirring at 65 °C for 1.5 h, 36.1 mL (129.94 mmol) of DIPEA was slowly added to the reaction mixture, and stirring was continued at 65 °C for 45 min. The reaction mixture was concentrated under reduced pressure, treated with water, and the precipitate was filtered, washed with a small amount of EtOH, and dried.

[0257] C6H5N3O3 (M=167.1g / mol)

[0258] ESI-MS: 168 [M+H] +

[0259] R t (HPLC): 0.20 min (Method G)

[0260] Intermediate VI

[0261] 3-[(4-methoxyphenyl)methyl]-5-methyl-3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione

[0262]

[0263] 680 mg (4.07 mmol) of 3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione (intermediate V) in 15 mL of DMF was treated with 843 mg (6.10 mmol) of potassium carbonate and stirred at RT for 15 min. 0.58 mL (4.27 mmol) of 1-(methyl)-4-methoxybenzene was added and the reaction mixture was stirred for 20 h. 843 mg (6.10 mmol) of potassium carbonate and 0.30 mL (4.88 mmol) of iodomethane were added and the reaction mixture was stirred at RT for 20 h. 0.26 mL (4.07 mmol) of iodomethane was added and the reaction mixture was stirred at RT for 20 h. The mixture was filtered, concentrated under reduced pressure, and purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA).

[0264] C 15 H 15 N3O4 (M=301.3g / mol)

[0265] ESI-MS: 302 [M+H] +

[0266] R t(HPLC): 0.95 min (Method B)

[0267] Intermediate VII

[0268] 5-Methyl-3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione

[0269]

[0270] 5.30 g (14.07 mmol) of 3-[(4-methoxyphenyl)methyl]-5-methyl-3H,4H,5H,6H,7H-pyrimido[4,5-b][1,4]oxazine-4,6-dione (intermediate VI) was treated with 16 mL of TFA and stirred at 100 °C for 1.5 h. Subsequently, the reaction mixture was stirred in a microwave at 120 °C for 15 min, poured onto ice water, and filtered. The filtrate was lyophilized and used directly without further purification.

[0271] C7H7N3O3 (M=181.2g / mol)

[0272] ESI-MS: 182 [M+H] +

[0273] R t (HPLC): 0.37 min (Method B)

[0274] Preparation of the final compound

[0275] Example 1 (General Procedure)

[0276] 3-({3-[(2S)-2-(4-chlorophenyl)-2-hydroxyethyl]-1,2,4-oxadiazol-5-yl}methyl)-5-methyl-3H,4H,5H,6H,7H-pyrimidino[4,5-b][1,4]oxazine-4,6-dione

[0277]

[0278] A mixture of 30 mg (0.11 mmol) intermediate VII, 20 mg (0.11 mmol) intermediate III.1, and 30 mg (0.22 mmol) K2CO3 in 1.0 mL DMF was stirred at RT for 1 h. The reaction mixture was filtered, and the filtrate was purified by reversed-phase HPLC (ACN / H2O gradient, 0.1% TFA) to obtain the desired product.

[0279] C 18 H 16 ClN5O4 (M=417.80g / mol)

[0280] ESI-MS: 418 [M+H] +

[0281] R t (HPLC): 0.44 min (Method A)

[0282] 1 H NMR (400MHz, DMSO-d6) δppm:2.90-3.10(m,2H),3.33(s,3H),4.82(s,2H),4.96(dd,J=7.9,5.7Hz,1H),5.48(s,2H),7.32-7.39(m,4H),8.44(s,1H)

[0283] The following compounds were prepared using suitable starting materials with a procedure similar to that described in the general procedure for Example 1. As those skilled in the art will understand, these similar examples may involve variations in the general reaction conditions.

[0284]

[0285]

[0286] Analytical data for the compounds listed in the table above:

[0287]

[0288]

[0289] Analytical HPLC methods

[0290] Method A

[0291]

[0292] Analytical column: XBridge BEH C18 2.1x30mm, 1.7μm; Column temperature: 60℃

[0293] Method B

[0294]

[0295] Analytical column: Stable Bond (Agilent) 1.8 μm; 3.0 x 30 mm; column temperature: 60℃

[0296] Method C

[0297]

[0298]

[0299] Analytical column: Sunfire (Waters) 2.5 μm; 3.0 x 30 mm; column temperature: 60℃

[0300] Method D

[0301]

[0302] Preparative column: Sunfire (Waters) C18 3.0 x 30 mm 2.5 μm; Column temperature: 60℃

[0303] Method E

[0304]

[0305] Analytical column: AQUITY UPLC C18_2.1x50mm_1.8μm. Column temperature: 25℃

[0306] Method F

[0307]

[0308]

[0309] Analytical column: AQUITY UPLC C18_2.1x50mm_1.8μm. Column temperature: 25℃

[0310] Method G

[0311]

[0312] Analytical column: Zorbax StableBond (Agilent) C18 3.0 x 30 mm 1.8 μm; Column temperature: 60 °C

[0313] Method H

[0314]

[0315] Analytical column: XBridge Phenyl_2.1x30mm, 1.7μm; Column temperature: 60℃

Claims

1. A compound of formula (I), (I) in A is selected from the group consisting of: phenyl, thienyl, benzofuranyl, and benzothienyl, wherein A is unsubstituted or via halogen and C. 1-4 -alkyl group R 1 One or two members are replaced.

2. The compound of formula (I) according to claim 1, wherein R 1 Selected from F, Cl, I and CH3.

3. The compound of formula (I) according to any one of claims 1 or 2, wherein A is selected from the group consisting of: and And A is unsubstituted or has not been converted by the group R 1 One or two members are replaced.

4. The compound of formula (I) according to claim 1, wherein the compound is selected from the group consisting of: and 。 5. A salt of a compound according to any one of claims 1 to 4.

6. A pharmaceutically acceptable salt of a compound according to any one of claims 1 to 4.

7. A pharmaceutical composition comprising at least one compound of formula I according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

8. Use of a compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment or prevention of inflammatory airway diseases or fibrotic diseases or cough.

9. Use of a compound of formula (I) according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the preparation of a medicament for the treatment or prevention of idiopathic lung disease or cough.

10. The use according to claim 9, wherein the idiopathic lung disease is idiopathic pulmonary fibrosis.

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