WO2022175514A1 - N-(pyridin-2-yl)-acétamides utilisés comme inhibiteurs de p2x3 - Google Patents

N-(pyridin-2-yl)-acétamides utilisés comme inhibiteurs de p2x3 Download PDF

Info

Publication number
WO2022175514A1
WO2022175514A1 PCT/EP2022/054203 EP2022054203W WO2022175514A1 WO 2022175514 A1 WO2022175514 A1 WO 2022175514A1 EP 2022054203 W EP2022054203 W EP 2022054203W WO 2022175514 A1 WO2022175514 A1 WO 2022175514A1
Authority
WO
WIPO (PCT)
Prior art keywords
general formula
compound
tert
compounds
butyl
Prior art date
Application number
PCT/EP2022/054203
Other languages
English (en)
Inventor
Marcus Koppitz
Holger Siebeneicher
Elisabeth Pook
Antje Rottmann
Jens Nagel
Oliver Martin FISCHER
Original Assignee
Bayer Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Bayer Aktiengesellschaft filed Critical Bayer Aktiengesellschaft
Publication of WO2022175514A1 publication Critical patent/WO2022175514A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/14—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • P2X purinoreceptors are a family of ligand-gated ion channels that are activated by ATP. To date, seven members of this family have been cloned, comprising P2X1-7 [Burnstock 2013, front Cell Neurosci 7:227]. These channels can exist as homomers and heteromers [Saul 2013, front Cell Neurosci 7:250].
  • Purines such as ATP have been recognized as important neurotransmitters and by acting via their respective receptors they have been implicated in various physiological and pathophysiological roles [Burnstock 1993, Drug Dev Res 28:196-206; Burnstock 2011, Prog Neurobiol 95:229-274; Jiang 2012, Cell Health Cytoskeleton 4:83-101].
  • the P2X family members in particular the P2X3 receptor has been recognized as an important mediator of nociception [Burnstock 2013, Eur J Pharmacol 716:24-40; North 2003, J Phyiol 554:301-308; Chizh 2000, Pharmacol Rev 53:553-568]. It is mainly expressed in dorsal root ganglia in a subset of nociceptive sensory neurons.
  • P2X3 receptor During inflammation the expression of the P2X3 receptor is increased, and activation of P2X3 receptor has been described to sensitize peripheral nerves [Fabretti 2013, front Cell Neurosci 7:236].
  • the prominent role of the P2X3 receptor in nociception has been described in various animal models, including mouse and rat models for acute, chronic and inflammatory pain.
  • P2X3 receptor knock-out mice show a reduced pain response [Cockayne 2000, Nature 407:1011-1015; Souslova 2000, Nature 407:1015-1017].
  • P2X3 receptor antagonists have been shown to act anti-nociceptive in different models of pain and inflammatory pain [Ford 2012, Purin Signal 8 (Suppl 1):S3-S26].
  • the P2X3 receptor has also been shown to integrate different nociceptive stimuli. Hyperalgesia induced by PGE2, ET-1 and dopamine have all been shown to be mediated via release of ATP and activation of the P2X3 receptor [Prado 2013, Neuropharm 67:252-258; Joseph 2013, Neurosci 232C: 83-89]. Besides its prominent role in nociception and in pain-related diseases involving both chronic and acute pain, the P2X3 receptor has been shown to be involved in genitourinary, gastrointestinal and respiratory conditions and disorders, including overactive bladder and chronic cough [Ford 2013, front Cell Neurosci 7:267; Burnstock 2014, Purin Signal 10(1):3-50].
  • ATP-release occurs in these 2 examples from epithelial cells, which in turn activates the P2X3 receptor and induces contraction of bladder and lung muscles respectively leading to premature voiding or cough.
  • P2X3 subunits do not only form homotrimers but also heterotrimers with P2X2 subunits.
  • P2X3 subunits and P2X2 subunits are also expressed on nerve fibres innervating the tongue, therein taste buds [Kinnamon 2013, front Cell Neurosci 7:264].
  • receptors containing P2X3 and/ or P2X2 subunits are involved in the transmission of taste from the tongue (bitter, sweet, salty, umami and sour).
  • P2X3 and P2X2/3 nonselective receptor antagonists Compounds blocking both the exclusively P2X3 subunit containing ion channel (P2X3 homomer) as well as the ion channel composed of P2X2 and P2X3 subunit (P2X2/3 heterotrimer) are called P2X3 and P2X2/3 nonselective receptor antagonists [Ford, Pain Manag 2012].
  • Clinical PhII trials demonstrated that AF-219, a P2X3 antagonist, leads to taste disturbances in treated subjects by affecting taste sensation via the tongue [e.g. Abdulqawi et al, Lancet 2015; Strand et al, 2015 ACR/ARMP Annual Meeting, Abstract 2240]. This side effect has been attributed to the blockade of P2X2/3 channels, i.e.
  • P2X2 and P2X3 subunits are expressed on sensory nerve fibers innervating the tongue. Knock-out animals deficient for P2X2 and P2X3 subunits show reduced taste sensation and even taste loss [Finger et al, Science 2005], whereas P2X3 subunit single knock-outs exhibit a mild or no change in phenotype with respect to taste. Moreover, 2 distinct populations of neurons have been described in the geniculate ganglion expressing either P2X2 and P2X3 subunits or P2X3 subunit alone.
  • P2X3-homomeric receptor-selective antagonists are deemed to be superior towards non-selective receptor antagonists and are considered to represent a solution towards the problem of insufficient patient compliance during chronic treatment as indicated by increased drop-out rates during PhII trials [Strand et al, 2015 ACR/ARMP Annual Meeting, Abstract 2240 and A. Ford, London 2015 Pain Therapeutics Conference, congress report].
  • WO 2011/017142 substituted bicyclic urea compounds of formula (I) and their use in the treatment of hyperproliferative diseases, such as cancer, in mammals. have been described.
  • WO 2020011921 relates to fused heterocyclic derivatives of formula (I) and their use as antagonists of P2X3 and P2X2/3 receptor activity, pharmaceutical compositions comprising such compounds, and methods of treatment and/or prevention of pain and chronic pain and tolerance to analgesic, respiratory disorders and dysfunctions, and treatment of overactive bladder, bladder pain syndrome, dysuria and in general in genitourinary diseases, cardiovascular disorders and more in general for the potential treatment of visceral organ diseases and disorders characterized by the involvement of P2X3 and P2X2/3 receptors.
  • the state of the art described does not describe the specific N-(pyridin-2-yl)-acetamide compounds of general formula (I) of the present invention as defined herein or an isomer, enantiomer, diastereomer, racemate, hydrate, solvate, or a salt thereof, or a mixture of same, as described and defined herein, and as hereinafter referred to as “compounds of the present invention”, or their pharmacological activity. Therefore, the problem of the present invention lies in the provision of novel N-(pyridin-2-yl)- acetamide compounds which are useful for the treatment or prophylaxis of diseases associated with the P2X3 receptor, in particular of neurogenic disorders.
  • substituted means that one or more hydrogen atoms on the designated atom or group are replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded. Combinations of substituents and/or variables are permissible.
  • optionally substituted means that the number of substituents can be equal to or different from zero. Unless otherwise indicated, it is possible that optionally substituted groups are substituted with as many optional substituents as can be accommodated by replacing a hydrogen atom with a non-hydrogen substituent on any available carbon or nitrogen or oxygen atom. Commonly, it is possible for the number of optional substituents, when present, to be 1, 2, 3, 4 or 5, in particular 1 or 2.
  • the term “one or more”, e.g. in the definition of the substituents of the compounds of general formula (I) of the present invention, means 1, 2, 3, 4 or 5, particularly 1, 2, 3 or 4, more particularly 1, 2 or 3, even more particularly 1 or 2.
  • a composite substituent be composed of more than one parts, e.g. (C 1 -C 4 -alkoxy)-(C 1 -C 4 -alkyl)-, it is possible for the position of a given part to be at any suitable position of said composite substituent, i.e.
  • the C 1 -C 4 -alkoxy part can be attached to any carbon atom of the C 1 -C 4 -alkyl part of said (C 1 -C 4 -alkoxy)-(C 1 -C 4 -alkyl)- group.
  • a hyphen at the beginning or at the end of such a composite substituent indicates the point of attachment of said composite substituent to the rest of the molecule.
  • a ring comprising carbon atoms and optionally one or more heteroatoms, such as nitrogen, oxygen or sulfur atoms for example, be substituted with a substituent, it is possible for said substituent to be bound at any suitable position of said ring, be it bound to a suitable carbon atom and/or to a suitable heteroatom.
  • C 1 -C 4 -alkyl means a linear or branched, saturated, monovalent hydrocarbon group having 1, 2, 3, or 4 carbon atoms, e.g. a methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, or tert-butyl group, or an isomer thereof. Particularly, said group has 1, 2 or 3 carbon atoms (“C 1 -C 3 -alkyl”), e.g.
  • five-membered heterocyclic ring containing 2 to 3 nitrogen atoms means a monocyclic, saturated, partially unsaturated, or aromatic heterocycle with 5 ring atoms in total, which contains two or three ring nitrogen atoms. Said five-membered heterocyclic ring, without being limited thereto, can be imidazolidin, pyrazolidin, dihydroimidazol, imidazol, pyrazol, or triazol, for example.
  • C 1 -C 6 as used in the present text, e.g.
  • C 1 -C 6 -alkyl means an alkyl group having a finite number of carbon atoms of 1 to 6, i.e. 1, 2, 3, 4, 5 or 6 carbon atoms.
  • C 3 - C 7 as used in the present text, e.g. in the context of the definition of “C 3 -C 7 -cycloalkyl”, means a cycloalkyl group having a finite number of carbon atoms of 3 to 7, i.e.3, 4, 5, 6 or 7 carbon atoms.
  • C 1 -C 6 encompasses C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 1 -C 6 , C 1 -C 5 , C 1 -C 4 , C 1 -C 3 , C 1 -C 2 , C 2 -C 6 , C 2 -C 5 , C 2 - C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C 5 , and C 5 -C 6 ;
  • C 2 -C 6 encompasses C 2 , C 3 , C 4 , C 5 , C 6 , C 2 -C 6 , C 2 -C 5 , C 2 -C 4 , C 2 -C 3 , C 3 -C 6 , C 3 -C 5 , C 3 -C 4 , C 4 -C 6 , C 4 -C
  • the term “leaving group” means an atom or a group of atoms that is displaced in a chemical reaction as stable species taking with it the bonding electrons.
  • a leaving group is selected from the group comprising: halide, in particular fluoride, chloride, bromide or iodide, (methylsulfonyl)oxy, [(trifluoromethyl)sulfonyl]oxy, [(nonafluorobutyl)- sulfonyl]oxy, (phenylsulfonyl)oxy, [(4-methylphenyl)sulfonyl]oxy, [(4-bromophenyl)sulfonyl]oxy, [(4-nitrophenyl)sulfonyl]oxy, [(2-nitrophenyl)sulfonyl]oxy, [(4-isopropylphenyl)sulfonyl]oxy, [(2,4,6-triisopropy
  • the invention therefore includes one or more isotopic variant(s) of the compounds of general formula (I), particularly deuterium-containing compounds of general formula (I).
  • the term “Isotopic variant” of a compound or a reagent is defined as a compound exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • the term “Isotopic variant of the compound of general formula (I)” is defined as a compound of general formula (I) exhibiting an unnatural proportion of one or more of the isotopes that constitute such a compound.
  • the expression “unnatural proportion” means a proportion of such isotope which is higher than its natural abundance.
  • isotopes to be applied in this context are described in “Isotopic Compositions of the Elements 1997”, Pure Appl. Chem., 70(1), 217-235, 1998.
  • isotopes include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine and iodine, such as 2 H (deuterium), 3 H (tritium), 11 C, 13 C, 14 C, 15 N, 17 O, 18 O, 32 P, 33 P, 33 S, 34 S, 35 S, 36 S, 18 F, 36 Cl, 82 Br, 123 I, 124 I, 125 I, 129 I and 131 I, respectively.
  • the isotopic variant(s) of the compounds of general formula (I) preferably contain deuterium (“deuterium- containing compounds of general formula (I)”).
  • Isotopic variants of the compounds of general formula (I) in which one or more radioactive isotopes, such as 3 H or 14 C, are incorporated are useful e.g. in drug and/or substrate tissue distribution studies. These isotopes are particularly preferred for the ease of their incorporation and detectability.
  • Positron emitting isotopes such as 18 F or 11 C may be incorporated into a compound of general formula (I). These isotopic variants of the compounds of general formula (I) are useful for in vivo imaging applications.
  • Deuterium- containing and 13 C-containing compounds of general formula (I) can be used in mass spectrometry analyses in the context of preclinical or clinical studies.
  • Isotopic variants of the compounds of general formula (I) can generally be prepared by methods known to a person skilled in the art, such as those described in the schemes and/or examples herein, by substituting a reagent for an isotopic variant of said reagent, preferably for a deuterium-containing reagent.
  • a reagent for an isotopic variant of said reagent preferably for a deuterium-containing reagent.
  • deuterium from D 2 O can be incorporated either directly into the compounds or into reagents that are useful for synthesizing such compounds.
  • Deuterium gas is also a useful reagent for incorporating deuterium into molecules.
  • Catalytic deuteration of olefinic bonds and acetylenic bonds is a rapid route for incorporation of deuterium.
  • Metal catalysts i.e. Pd, Pt, and Rh
  • Pd, Pt, and Rh metal catalysts in the presence of deuterium gas can be used to directly exchange deuterium for hydrogen in functional groups containing hydrocarbons.
  • a variety of deuterated reagents and synthetic building blocks are commercially available from companies such as for example C/D/N Isotopes, Quebec, Canada; Cambridge Isotope Laboratories Inc., Andover, MA, USA; and CombiPhos Catalysts, Inc., Princeton, NJ, USA.
  • deuterium-containing compound of general formula (I) is defined as a compound of general formula (I), in which one or more hydrogen atom(s) is/are replaced by one or more deuterium atom(s) and in which the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than the natural abundance of deuterium, which is about 0.015%. Particularly, in a deuterium-containing compound of general formula (I) the abundance of deuterium at each deuterated position of the compound of general formula (I) is higher than 10%, 20%, 30%, 40%, 50%, 60%, 70% or 80%, preferably higher than 90%, 95%, 96% or 97%, even more preferably higher than 98% or 99% at said position(s).
  • the abundance of deuterium at each deuterated position is independent of the abundance of deuterium at other deuterated position(s).
  • the selective incorporation of one or more deuterium atom(s) into a compound of general formula (I) may alter the physicochemical properties (such as for example acidity [C. L. Perrin, et al., J. Am. Chem. Soc., 2007, 129, 4490], basicity [C. L. Perrin et al., J. Am. Chem. Soc., 2005, 127, 9641], lipophilicity [B. Testa et al., Int. J.
  • deuterium substitution reduces or eliminates the formation of an undesired or toxic metabolite and enhances the formation of a desired metabolite (e.g. Nevirapine: A. M. Sharma et al., Chem. Res. Toxicol., 2013, 26, 410; Efavirenz: A. E. Mutlib et al., Toxicol. Appl. Pharmacol., 2000, 169, 102).
  • the major effect of deuteration is to reduce the rate of systemic clearance. As a result, the biological half-life of the compound is increased.
  • the potential clinical benefits would include the ability to maintain similar systemic exposure with decreased peak levels and increased trough levels.
  • Deuterated drugs showing this effect may have reduced dosing requirements (e.g. lower number of doses or lower dosage to achieve the desired effect) and/or may produce lower metabolite loads.
  • a compound of general formula (I) may have multiple potential sites of attack for metabolism. To optimize the above-described effects on physicochemical properties and metabolic profile, deuterium-containing compounds of general formula (I) having a certain pattern of one or more deuterium-hydrogen exchange(s) can be selected.
  • the deuterium atom(s) of deuterium-containing compound(s) of general formula (I) is/are attached to a carbon atom and/or is/are located at those positions of the compound of general formula (I), which are sites of attack for metabolizing enzymes such as e.g. cytochrome P 450 .
  • cytochrome P 450 sites of attack for metabolizing enzymes such as e.g. cytochrome P 450 .
  • stable compound' or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • the compounds of the present invention optionally contain one or more asymmetric centres, depending upon the location and nature of the various substituents desired. It is possible that one or more asymmetric carbon atoms are present in the (R) or (S) configuration, which can result in racemic mixtures in the case of a single asymmetric centre, and in diastereomeric mixtures in the case of multiple asymmetric centres. In certain instances, it is possible that asymmetry also be present due to restricted rotation about a given bond, for example, the central bond adjoining two substituted aromatic rings of the specified compounds.
  • Preferred compounds are those which produce the more desirable biological activity.
  • Separated, pure or partially purified isomers and stereoisomers or racemic or diastereomeric mixtures of the compounds of the present invention are also included within the scope of the present invention.
  • the purification and the separation of such materials can be accomplished by standard techniques known in the art.
  • the optical isomers can be obtained by resolution of the racemic mixtures according to conventional processes, for example, by the formation of diastereoisomeric salts using an optically active acid or base or formation of covalent diastereomers.
  • Examples of appropriate acids are tartaric, diacetyltartaric, ditoluoyltartaric and camphorsulfonic acid.
  • Mixtures of diastereoisomers can be separated into their individual diastereomers on the basis of their physical and/or chemical differences by methods known in the art, for example, by chromatography or fractional crystallisation.
  • the optically active bases or acids are then liberated from the separated diastereomeric salts.
  • a different process for separation of optical isomers involves the use of chiral chromatography (e.g., HPLC columns using a chiral phase), with or without conventional derivatisation, optimally chosen to maximise the separation of the enantiomers.
  • Suitable HPLC columns using a chiral phase are commercially available, such as those manufactured by Daicel, e.g., Chiracel OD and Chiracel OJ, for example, among many others, which are all routinely selectable. Enzymatic separations, with or without derivatisation, are also useful.
  • the optically active compounds of the present invention can likewise be obtained by chiral syntheses utilizing optically active starting materials. In order to distinguish different types of isomers from each other reference is made to IUPAC Rules Section E (Pure Appl Chem 45, 11-30, 1976).
  • the present invention includes all possible stereoisomers of the compounds of the present invention as single stereoisomers, or as any mixture of said stereoisomers, e.g.
  • (R)- or (S)- isomers in any ratio.
  • Isolation of a single stereoisomer, e.g. a single enantiomer or a single diastereomer, of a compound of the present invention is achieved by any suitable state of the art method, such as chromatography, especially chiral chromatography, for example.
  • the compounds of the present invention can exist as N-oxides, which are defined in that at least one nitrogen of the compounds of the present invention is oxidised. The present invention includes all such possible N-oxides.
  • the present invention also covers useful forms of the compounds of the present invention, such as metabolites, hydrates, solvates, prodrugs, salts, in particular pharmaceutically acceptable salts, and/or co-precipitates.
  • the compounds of the present invention can exist as a hydrate, or as a solvate, wherein the compounds of the present invention contain polar solvents, in particular water, methanol or ethanol for example, as structural element of the crystal lattice of the compounds. It is possible for the amount of polar solvents, in particular water, to exist in a stoichiometric or non- stoichiometric ratio. In the case of stoichiometric solvates, e.g.
  • a hydrate, hemi-, (semi-), mono- , sesqui-, di-, tri-, tetra-, penta- etc. solvates or hydrates, respectively, are possible.
  • the present invention includes all such hydrates or solvates.
  • the compounds of the present invention to exist in free form, e.g. as a free base, or as a free acid, or as a zwitterion, or to exist in the form of a salt.
  • Said salt may be any salt, either an organic or inorganic addition salt, particularly any pharmaceutically acceptable organic or inorganic addition salt, which is customarily used in pharmacy, or which is used, for example, for isolating or purifying the compounds of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • pharmaceutically acceptable salt refers to an inorganic or organic acid addition salt of a compound of the present invention.
  • S. M. Berge, et al. “Pharmaceutical Salts,” J. Pharm. Sci.1977, 66, 1-19.
  • a suitable pharmaceutically acceptable salt of the compounds of the present invention may be, for example, an acid-addition salt of a compound of the present invention bearing a nitrogen atom, in a chain or in a ring, for example, which is sufficiently basic, such as an acid-addition salt with an inorganic acid, or “mineral acid”, such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, bisulfuric, phosphoric, or nitric acid, for example, or with an organic acid, such as formic, acetic, acetoacetic, pyruvic, trifluoroacetic, propionic, butyric, hexanoic, heptanoic, undecanoic, lauric, benzoic, salicylic, 2-(4-hydroxybenzoyl)-benzoic, camphoric, cinnamic, cyclopentanepropionic, digluconic, 3-hydroxy-2-naphthoic, nico
  • an alkali metal salt for example a sodium or potassium salt
  • an alkaline earth metal salt for example a calcium, magnesium or strontium salt, or an aluminium or a zinc salt
  • acid addition salts of the claimed compounds to be prepared by reaction of the compounds with the appropriate inorganic or organic acid via any of a number of known methods.
  • alkali and alkaline earth metal salts of acidic compounds of the present invention are prepared by reacting the compounds of the present invention with the appropriate base via a variety of known methods.
  • the present invention includes all possible salts of the compounds of the present invention as single salts, or as any mixture of said salts, in any ratio.
  • the present invention includes all possible crystalline forms, or polymorphs, of the compounds of the present invention, either as single polymorph, or as a mixture of more than one polymorph, in any ratio.
  • the present invention also includes prodrugs of the compounds according to the invention.
  • prodrugs here designates compounds which themselves can be biologically active or inactive, but are converted (for example metabolically or hydrolytically) into compounds according to the invention during their residence time in the body. DETAILED DESCRIPTION OF THE INVENTION
  • the present invention relates to compounds of general formula (II) wherein: the unit L 1 - L 2 represents a group selected from:
  • R 5 represents hydrogen, C 1 -C 4 -alkyl, or cyclopropyl; and stereoisomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention relates to compounds of general formula (III) wherein: R 5 represents hydrogen, C 1 -C 4 -alkyl, or cyclopropyl; and stereoisomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention relates to compounds of general formula (IV) wherein: R 5 represents hydrogen or C 1 -C 4 -alkyl; and stereoisomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention relates to compounds of general formula (V) wherein: R 5 represents hydrogen or C 1 -C 4 -alkyl; and stereoisomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention relates to compounds of general formula (VI) wherein: R 5 represents hydrogen or C 1 -C 4 -alkyl; and stereoisomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention relates to compounds of general formula (VII) wherein: R 5 represents hydrogen or C 1 -C 4 -alkyl; and stereoisomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • the present invention relates to compounds of general formula (VIII) wherein: R 5 represents hydrogen or C 1 -C 4 -alkyl; and stereoisomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same.
  • R 5 represents hydrogen or C 1 -C 4 -alkyl
  • stereoisomers, N-oxides, hydrates, solvates, and salts thereof, and mixtures of same covers any sub-combination within any embodiment or aspect of the present invention of compounds of general formula (I), supra.
  • the present invention covers methods of preparing compounds of the present invention of general formula (I), said methods comprising the steps as described in the Experimental Section herein.
  • the compounds according to the invention of general formula (I) are prepared according to the following schemes 1 to 6.
  • Nitrile hydrolysis to obtain the corresponding amide of formula 3 can be achieved by oxidative alkaline hydrolysis using hydrogen peroxide and an appropriate aqueous base, like for example aqueous Na 2 CO 3 solution in an appropriate solvent like acetone at temperatures between -30°C and +80°C.
  • Cyclization to dioxopyridopyrimidine of formula 4 may be accomplished by reaction of intermediate 3 with an appropriate activated carbonyl reagent, like for example carbonyl diimidazole in an appropriate solvent, like DMA at temperatures ranging from r. t. to 150°C.
  • Dioxo compound 5 can be converted to chloro oxo compound 6 using an appropriate chlorinating reagent, like for example phosphoroxichloride under basic conditions using for example DIPEA in an appropriate solvent like acetonitrile at temperatures ranging from r. t. to reflux.
  • Hydrazide compound 7 may be obtained by reaction of chloro precursor 6 with the appropriate hydrazide in an appropriate solvent like for example dioxane at elevated temperatures ranging from 40 °C to 80°C.
  • 5-bromopyridine-2,3-dicarboxylic acid can be converted to the corresponding anhydride of formula 2 using an appropriate activating agent, like for example HATU, EDC or thionyl chloride, optionally in presence of a base like DIPEA in an appropriate solvent like DMF at temperatures ranging from -30°C to 60°C.
  • Anhydride 2 may be converted to mono methyl ester 3 using methanol in an appropriate solvent, for example dioxane at temperatures ranging from r. t. to 60°C.
  • tert butyl ester side chain may be possible by Friedel Crafts acylation of intermediate 3 with 3-tert-butoxy-3-oxo-propanoic acid in presence of Lewis acid, like for example MgCl2 and an activating agent, like for example CDI to afford intermediate of general formula 4.
  • Lewis acid like for example MgCl2
  • an activating agent like for example CDI
  • Reaction with hydrazine leads to cyclized oxo pyridazine of formula 5.
  • Oxo pyridazine 5 can be converted to chloro compound 6 using an appropriate chlorinating reagent, like for example phosphoroxichloride under basic conditions using for example DIPEA in an appropriate solvent like acetonitrile at temperatures ranging from r. t. to reflux.
  • Tricyclic compound of general formula 7 may be obtained by reaction of chloro precursor 6 with the appropriate hydrazide in an appropriate solvent like for example dioxane at elevated temperatures ranging from 40°C to 80°C.
  • Introduction of an amine, like for example morpholine, is possible by nucleophilic substitution of bromo precursor of general formula 7 with the respective amine in an appropriate solvent like for example DMSO under elevated temperatures ranging from 80°C to 150°C.
  • Deprotection of the tert butyl ester in compounds of general formula 8 may be possible by treatment with acid, for example HCl in dioxane or with TFA oprionally in an appropriate solvent like dichloromethane at temperatures ranging from - 30°C to 60°C.
  • Target compounds of general formula (IV) are accessible using acid precursor 9, 5-fluoropyridin-2-amine as amine component and an appropriate acid activating agent like HATU in the presence of base, like for example N-methyl morpholine in an appropriate solvent like DMF at temperatures between -30°C and + 60°C.
  • an amine like for example morpholine
  • nucleophilic substitution of bromo precursor of formula 5 with the respective amine in an appropriate solvent like for example DMSO under elevated temperatures ranging from 80°C to 150°C.
  • Ester deprotection to acid intermediate of general formula 6 is possible by treatment with an appropriate acid, for example HCl in an appropriate solvent like dioxane at temperatures ranging from r. t. to reflux.
  • Target compounds of general formula (V) are accessible using acid precursor 6, 5-fluoropyridin-2-amine as amine component and an appropriate acid activating agent like HATU in the presence of base, like for example N-methyl morpholine in an appropriate solvent like DMF at temperatures between -30°C and + 60°C.
  • Target compounds of general formula (VI) are accessible using acid precursor 7, 5-fluoropyridin-2- amine as amine component and an appropriate acid activating agent like HATU in the presence of base, like for example N-methyl morpholine in an appropriate solvent like DMF at temperatures between -30°C and + 60°C.
  • Scheme 4 Compounds of general formula (VII) can be synthesised according to the route depicted in Scheme 5.
  • Commercially available 5-bromo-3-fluoropicolinonitrile 1 can be converted in a SNAr reaction using an appropriate glycine ester, for example glycine tert-butyl ester in presence of an appropiate base, such as DIPEA in an appropriate solvent like DMA at temperatures between 70°C and 140°C.
  • the pyridyl glycine esters of formula 3 can be obtained in a transition metal catalysed coupling reaction with nucleophiles like amines, preferably morpholine, or alkohols by using for example a Pd- or Cu catalyst in presence of an appropriate ligand like a mono- or bidentate phosphine ligang and an appropriate base like potassium tert-butylate in an aprotic solvent such as DMF at temperatures ranging from 80°C to 150°C..
  • Cyclization to aminopyrimidinone intermediates of formula 4 may be performed by reaction with trichloroacctyl isocyanate that can subsequently be condensed with 2-halogen substituted carboxylic acids of formula 5 to receive pyrazolones of formula 6.
  • carboxylic acids of formula 5 have to be activated using for example a chlorinating reagent such as oxalyl chloride in presence of a catalytic amount of DM and a base such as DIPEA in an appropriate aprotic solvent such as DMA.
  • Deprotection of the tert butyl ester in compounds of general formula 6 may be possible by treatment with acid, for example HCl in dioxane or with TFA oprionally in an appropriate solvent like dichloromethane at temperatures ranging from -30°C to 60°C.
  • Target compounds of general formula (VII) are accessible using acid precursor 7, 5-fluoropyridin-2- amine as amine component and an appropriate acid activating agent like HATU in the presence of base, like for example N-methyl morpholine in an appropriate solvent like DMF at temperatures between -30°C and +60°C.
  • the nitriles of formula 3 may be converted with optionally substituted 1,2-diamino ethanes of formula 4 in the presence of a base like triethylamine and an aprotic solvent such as DMA at temperatures ranging from 80°C to 180°C.
  • a base like triethylamine and an aprotic solvent such as DMA at temperatures ranging from 80°C to 180°C.
  • the resulting imidazoline intermediates of formula 5 can be cyclized to the pyrimidinones of formula 6 with an appropriate activated carbonyl reagent, like for example carbonyl diimidazole in an appropriate solvent, like DMA at temperatures ranging from r. t. to 150°C.
  • Deprotection of the tert butyl ester in compounds of general formula 6 may be possible by treatment with acid, for example HCl in dioxane or with TFA oprionally in an appropriate solvent like dichloromethane at temperatures ranging from -30°C to 60°C.
  • Target compounds of general formula (VIII) are accessible using acid precursor 7, 5-fluoropyridin-2-amine as amine component and an appropriate acid activating agent like HATU in the presence of base, like for example N-methyl morpholine in an appropriate solvent like DMF at temperatures between -30°C and +60°C.
  • Scheme 6 formula (I) of the present invention demonstrate a valuable pharmacological spectrum of action and pharmacokinetic profile if supported by data, both of which could not have been predicted.
  • the present invention also relates to a method for using a compound of formula (I) and compositions thereof, to treat mammalian neurogenic diseases and disorders.
  • This method comprises administering to a mammal in need thereof, including a human, an amount of a compound of formula (I) or composition thereof, which is effective to treat the disease or disorder.
  • Neurogenic diseases and disorders include but are not limited to genitourinary, gastrointestinal, respiratory diseases, cardiovascular disease associated with autonomic imbalance caused by increased chemoreceptor sensitivity, and pain as such as well as pain-related diseases, conditions and disorders, gynecological diseases, urinary tract disease states, pain-related diseases and disorders, pain-associated diseases and disorders, neurological diseases and disorders, neurodegenerative diseases and disorders and dermatological diseases and disorders.
  • Gynecological diseases include but are not limited to dysmenorrhea (primary and secondary dysmenorrhea), dyspareunia, endometriosis, and adenomyosis; endometriosis-associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular dysmenorrhea, dyspareunia, dysuria, or dyschezia; endometriosis-associated proliferation; pelvic hyper- sensitivity. Preference is given to endometriosis and to moderate to severe pain associated with endometriosis in women of reproductive age.
  • Urinary tract disease states include, but are not limited to those associated with the bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive urinary bladder and symptoms related to overactive urinary bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular Interstitial cystitis; idiopathic bladder hypersensitivity and bladder pain syndrome,.
  • urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity
  • benign prostatic hypertrophy prostatic hyperplasia
  • prostatitis detrusor hyperreflexia
  • overactive bladder Preference is given to overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, urinary frequency and nocturia. Furthermore, preference is given to interstitial cystitis and bladder pain syndrome as well.
  • Neurological diseases and disorders include, but are not limited to epilepsy, partial and generalized seizures.
  • Respiratory diseases and disorders include, but are not limited to asthma, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis, acute cough, chronic cough including chronic idiopathic and refractory and/ or unexplained chronic cough, bronchospasm and interstitial lung disease (including idiopathic pulmonary fibrosis). Preference is given to refractory and/ or unexplained chronic cough.
  • COPD chronic obstructive pulmonary disease
  • COPD chronic obstructive pulmonary disease
  • pulmonary fibrosis acute cough
  • chronic cough including chronic idiopathic and refractory and/ or unexplained chronic cough
  • Cardiovascular diseases and disorders include, but are not limited to those associated with nerve fiber sensitization, and/or other pathological conditions associated with autonomic imbalance caused by increased chemoreceptor sensitivity, in particular for the treatment of breathing disorders, Cheyne Stokes respiration, central and obstructive sleep apnea, cardiovascular disease, hypertension, resistant hypertension, and heart failure, which are related to increased activity of P2X3 receptors.
  • Gastrointestinal dieases and disorders include, but are not limited to irritable bowel syndrome (IBS), epigastric pain syndrome (functional dyspepsia syndrome), functional abdominal bloating with distension, inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS; gastroesophageal reflux, gastrointestinal distension, ulcerative colitis (Crohn’s disease).
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • IBS D irritable bowel syndrome with diarrhea
  • Neurodegenerative diseases and disorders include, but are not limited to Alzheimer's disease, Multiple Sclerosis, Parkinson’s disease, Brain ischemia and traumatic brain injury.
  • Dermatological diseases and disorders include, but are not limited to Prurigo nodularis, chronic pruritus of unknown origin, pruritus due to kidney or liver disease, Brachioradial pruritus, Rosacea, Chronic hand eczema, Dyshidrotic eczema, Atopic dermatitis and Psoriasis. Pain-related diseases and disorders include, but are not limited to acute, chronic, inflammatory and neuropathic pain syndromes.
  • Pain-related diseases and disorders include, but are not limited to pain syndromes selected from the group consisting of acute, chronic, inflammatory and neuropathic pain, preferably inflammatory pain, low back pain, surgical pain, postsurgical neuropathic pain, posttraumatic neuropathic pain, visceral pain, dental pain, periodontitis, premenstrual pain, endometriosis- associated pain, pain associated with fibrotic diseases, central pain, pain due to burning mouth syndrome, pain due to burns, pain due to migraine, cluster headaches, pain due to nerve injury, pain due to neuritis, neuralgias, pain due to poisoning, pain due to ischemic injury, pain due to interstitial cystitis, cancer-related neuropathic pain, chemotherapy-related neuropathic pain, pain due to viral, parasitic or bacterial infections, pain due to traumatic nerve-injury, pain due to post- traumatic injuries (including fractures and sport injuries), pain due to trigeminal neuralgia, pain associated with small fiber neuropathy, pain associated with diabetic neuropathy
  • Pain-associated diseases and disorders include, but are not limited to hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome), gout, arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headaches, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgias, poisoning, ischemic injury, interstitial cystitis, cancer, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment-induced neuropathy, pruritus; impaired wound healing and disease of the skeleton like degeneration of the joints.
  • NP-DPN diabetic peripheral neuropathy
  • cancer and/ or chemotherapy related neuropathic pain to postherpetic neuralgia and to postsurgical and/ or posttraumatic neuropathic pain.
  • the present invention relates to a method for using the compounds of the present and compositions thereof to treat inflammation, in particular neurogenic inflammation.
  • inflammation is also understood to include any inflammatory disease, disorder or condition per se, any condition that has an inflammatory component associated with it, and/or any condition characterized by inflammation as a symptom, including, inter alia, acute, chronic, ulcerative, specific, allergic, infection by pathogens, immune reactions due to hypersensitivity, entering foreign bodies, physical injury, and necrotic inflammation, and other forms of inflammation known to those skilled in the art.
  • the term thus also includes, for the purposes of this invention, inflammatory pain, pain generally and/or fever.
  • the present invention relates to a method for using the compounds of the present invention and compositions thereof to treat fibromyalgia, myofascial disorders, viral infections (e.g.
  • influenza common cold, herpes zoster, hepatitis C and AIDS
  • bacterial infections fungal infections, surgical or dental procedures
  • arthritis osteoarthritis, juvenile arthritis, rheumatoid arthritis, juvenile onset rheumatoid arthritis, rheumatic fever, ankylosing spondylitis
  • Hodgkin's disease systemic lupus erythematosus, vasculitis, pancreatitis, nephritis, bursitis, conjunctivitis, ulceris, scleritis, uveitis, wound healing, dermatitis, eczema, stroke, autoimmune diseases, allergic disorders, rhinitis, ulcers, mild to moderately active ulcerative colitis, familial adenomatous polyposis, coronary heart disease, sarcoidosis and any other disease with an inflammatory component.
  • the present invention relates to a method for using the compounds of the present invention and compositions thereof to treat mammalian, including human disorders and diseases which are not linked to inflammatory mechanisms, such as in the reduction of bone loss in a subject.
  • Diseases that may be mentioned in this regard include osteoporosis, osteoarthritis, Paget's disease and/or periodontal diseases.
  • the inventive compounds can therefore be used in medicaments for treatment and/or prophylaxis of the above-mentioned diseases. These diseases and/ or disorders have been well characterized in humans, but also exist with a similar etiology in other mammals and can be treated by administering pharmaceutical compositions of the present invention.
  • treating or “treatment” as used in the present text is used conventionally, e.g., the management or care of a subject for the purpose of combating, alleviating, reducing, relieving, improving the condition of a disease or disorder, such as neurogenic disorders or diseases.
  • the compounds of the present invention can be used in therapy and prevention, i.e. prophylaxis, of neurogenic diseases, conditions and disorders.
  • the present invention covers pharmaceutical compositions, in particular a medicament, comprising a compound of general formula (I), as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • a compound of general formula (I) as described supra, or a stereoisomer, a tautomer, an N-oxide, a hydrate, a solvate, a salt thereof, particularly a pharmaceutically acceptable salt, or a mixture of same, and one or more excipients), in particular one or more pharmaceutically acceptable excipient(s).
  • excipients in particular one or more pharmaceutically acceptable excipient(s).
  • Conventional procedures for preparing such pharmaceutical compositions in appropriate dosage forms can be utilized.
  • the present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at
  • the compounds according to the invention can have systemic and/or local activity.
  • they can be administered in a suitable manner, such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • a suitable manner such as, for example, via the oral, parenteral, pulmonary, nasal, sublingual, lingual, buccal, rectal, vaginal, dermal, transdermal, conjunctival, otic route or as an implant or stent.
  • the compounds according to the invention can be administered in suitable administration forms.
  • the compounds according to the invention for oral administration, it is possible to formulate the compounds according to the invention to dosage forms known in the art that deliver the compounds of the invention rapidly and/or in a modified manner, such as, for example, tablets (uncoated or coated tablets, for example with enteric or controlled release coatings that dissolve with a delay or are insoluble), orally- disintegrating tablets, films/wafers, films/lyophylisates, capsules (for example hard or soft gelatine capsules), sugar-coated tablets, granules, pellets, powders, emulsions, suspensions, aerosols or solutions. It is possible to incorporate the compounds according to the invention in crystalline and/or amorphised and/or dissolved form into said dosage forms.
  • Parenteral administration can be effected with avoidance of an absorption step (for example intravenous, intraarterial, intracardial, intraspinal or intralumbal) or with inclusion of absorption (for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal).
  • absorption step for example intravenous, intraarterial, intracardial, intraspinal or intralumbal
  • absorption for example intramuscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal.
  • Administration forms which are suitable for parenteral administration are, inter alia, preparations for injection and infusion in the form of solutions, suspensions, emulsions, lyophylisates or sterile powders.
  • Examples which are suitable for other administration routes are pharmaceutical forms for inhalation [inter alia powder inhalers, nebulizers], nasal drops, nasal solutions, nasal sprays; tablets/films/wafers/capsules for lingual, sublingual or buccal administration; suppositories; eye drops, eye ointments, eye baths, ocular inserts, ear drops, ear sprays, ear powders, ear-rinses, ear tampons; vaginal capsules, aqueous suspensions (lotions, mixturae agitandae), lipophilic suspensions, emulsions, ointments, creams, transdermal therapeutic systems (such as, for example, patches), milk, pastes, foams, dusting powders, implants or stents.
  • inhalation inter alia powder inhalers, nebulizers
  • nasal drops nasal solutions, nasal sprays
  • tablets/films/wafers/capsules for lingual, sublingual or buccal
  • compositions according to the invention can be incorporated into the stated administration forms. This can be effected in a manner known per se by mixing with pharmaceutically suitable excipients.
  • Pharmaceutically suitable excipients include, inter alia, • fillers and carriers (for example cellulose, microcrystalline cellulose (such as, for example, Avicel ® ), lactose, mannitol, starch, calcium phosphate (such as, for example, Di-Cafos ® )), • ointment bases (for example petroleum jelly, paraffins, triglycerides, waxes, wool wax, wool wax alcohols, lanolin, hydrophilic ointment, polyethylene glycols), • bases for suppositories (for example polyethylene glycols, cacao butter, hard fat), • solvents (for example water, ethanol, isopropanol, glycerol, propylene glycol, medium chain-length triglycerides fatty oils, liquid polyethylene glycols, paraffins),
  • the present invention furthermore relates to a pharmaceutical composition which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipient(s), and to their use according to the present invention.
  • the present invention covers pharmaceutical combinations, in particular medicaments, comprising at least one compound of general formula (I) of the present invention and at least one or more further active ingredients, in particular for the treatment and/or prophylaxis of neurogenic disorders, in particular of genitourinary, gastrointestinal, respiratory, cardiovascular disease associated with autonomic imbalance caused by increased chemoreceptor sensitivity, and pain-related diseases, conditions and disorders.
  • the present invention covers a pharmaceutical combination, which comprises: • one or more first active ingredients, in particular compounds of general formula (I) as defined supra, and • one or more further active ingredients, suitable for the treatment of neurogenic disorders, genitourinary, gastrointestinal, respiratory, cardiovascular disease associated with autonomic imbalance caused by increased chemoreceptor sensitivity, and pain-related diseases, conditions and disorders.
  • first active ingredients in particular compounds of general formula (I) as defined supra
  • further active ingredients suitable for the treatment of neurogenic disorders, genitourinary, gastrointestinal, respiratory, cardiovascular disease associated with autonomic imbalance caused by increased chemoreceptor sensitivity, and pain-related diseases, conditions and disorders.
  • the term “combination” in the present invention is used as known to persons skilled in the art, it being possible for said combination to be a fixed combination, a non-fixed combination or a kit-of-parts.
  • a “fixed combination” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein, for example, a first active ingredient, such as one or more compounds of general formula (I) of the present invention, and a further active ingredient are present together in one unit dosage or in one single entity.
  • a “fixed combination” is a pharmaceutical composition wherein a first active ingredient and a further active ingredient are present in admixture for simultaneous administration, such as in a formulation.
  • Another example of a “fixed combination” is a pharmaceutical combination wherein a first active ingredient and a further active ingredient are present in one unit without being in admixture.
  • a non-fixed combination or “kit-of-parts” in the present invention is used as known to persons skilled in the art and is defined as a combination wherein a first active ingredient and a further active ingredient are present in more than one unit.
  • a non-fixed combination or kit-of-parts is a combination wherein the first active ingredient and the further active ingredient are present separately. It is possible for the components of the non-fixed combination or kit-of- parts to be administered separately, sequentially, simultaneously, concurrently or chronologically staggered.
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the present invention also covers such pharmaceutical combinations.
  • the compounds of the present invention can be combined with known hormonal therapeutic agents.
  • the compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and/ or prophylaxis of diseases, which are related to or mediated by P2X3 receptor.
  • therapeutic agents or active ingredients are for example, but not limited, to 5-(2,4-Diamino-pyrimidin-5- yloxy)-4-isopropyl-2-methoxy-benzenesulfonamide (Gefapixant/ MK-7264/AF-219), (5-(5-iodo- 2-isopropyl-4-methoxy-phenoxy)-pyrimidine-2,4-diamine (AF-353), 5-[2-isopropyl-4-methoxy-5- (methylsulfonyl)phenoxy]pyrimidine-2,4-diamine (AF-130), 2-[[4-amino-5-(5-iodo-4-methoxy-2- propan-2-ylphenoxy)-pyrimidin-2-yl]amin
  • the compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and/ or prophylaxis of diseases, which are related to other targets like NK1 inhibitors, for example 2- (R)-(4-Fluoro-2-methyl-phenyl)-4-(S)-((8aS)-6-oxohexahydro-pyrrolo[1,2-a]-pyrazin-2-yl)- piperidine-1-carboxylic acid [1-(R)-(3,5-bis-trifluoromethyl-phenyl)-ethyl]-methylamide (Orvepitant), 3-[(3aR,4R,5S,7aS)-5- ⁇ (1R)-1-[3,5-bis(trifluoromethyl)phenyl]ethoxy ⁇ -4-(4- fluorophenyl)octahydro-2H-isoindol-2-yl]cyclopent-2-en-1-one (S
  • the compounds of the present invention can be administered as the sole pharmaceutical agent or in combination with one or more other pharmaceutically active ingredients where the combination causes no unacceptable adverse effects.
  • the present invention also covers such pharmaceutical combinations.
  • the compounds of the present invention can be combined with known indication agents.
  • the compounds of the present invention can be combined with known hormonal therapeutic agents.
  • the compounds of the present invention can be administered in combination or as comedication with Selective Progesterone Receptor Modulators (SPRMs) or hormonal contraceptives.
  • SPRMs Selective Progesterone Receptor Modulators
  • SPRMs and hormonal contraceptives can be administered via oral, subcutan, transdermal, intrauterine or intravaginal route, for example as Combined Oral Contraceptives (COCs), or Progestin-Only-Pills (POPs) or hormone-containing devices like implants, patches or intravaginal rings.
  • COCs include but are not limited to birth control pills or a birth control method that includes a combination of an estrogen (estradiol) and a progestogen (progestin). The estrogenic part is in most of the COCs ethinyl estradiol. Some COCs contain estradiol or estradiol valerate.
  • Said COCs contain the progestins norethynodrel, norethindrone, norethindrone acetate, ethynodiol acetate, norgestrel, levonorgestrel, norgestimate, desogestrel, gestodene, drospirenone, dienogest, or nomegestrol acetate.
  • Birth control pills include for example but are not limited to Yasmin, Yaz, both containing ethinyl estradiol and drospirenone; Microgynon or Miranova containing levonorgestrel and ethinyl estradiol; Marvelon containing ethinyl estradiol and desogestrel; Valette containing ethinyl estradiol and dienogest; Belara and Enriqa containing ethinyl estradiol and chlormadinonacetate; Qlaira containing estradiol valerate and dienogest as active ingredients; and Zoely containing estradiol and normegestrol.
  • POPs are contraceptive pills that contain only synthetic progestogens (progestins) and do not contain estrogen. They are colloquially known as mini pills. POPs include but are not limited to Cerazette containing desogestrel; Microlut containing levonorgestrel and Micronor containing norethindrone. Other Progeston-Only forms are intrauterine devices (IUDs), for example Mirena containing levonorgestrel or injectables, for example Depo-Provera containing medroxyprogesterone acetate, or implants, for example Implanon containing etonogestrel.
  • IUDs intrauterine devices
  • Mirena containing levonorgestrel or injectables for example Depo-Provera containing medroxyprogesterone acetate
  • implants for example Implanon containing etonogestrel.
  • hormone-containing devices with contraceptive effect which are suitable for a combination with the compounds of the present invention are vaginal rings like Nuvaring containing ethinyl estradiol and etonogestrel or transdermal systems like a contraceptive patch, for example Ortho- Evra or Apleek (Lisvy) containing ethinyl estradiol and gestodene.
  • a preferred embodiment of the present invention is the administration of a compound of general formula (I) in combination with a COC or a POP or other Progestin-Only forms as well as vaginal rings or contraceptive patches as mentioned above.
  • the compounds of the present invention can be combined with therapeutic agents or active ingredients, that are already approved or that are still under development for the treatment and/ or prophylaxis of diseases which are related to or mediated by P2X3 receptor.
  • the compounds of the present invention can be administered in combination or as comedication with any substance that can be applied as therapeutic agent in the following indications: Urinary tract disease states associated with the bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyperreactivity; benign prostatic hypertrophy; prostatic hyperplasia; prostatitis; detrusor hyperreflexia; overactive bladder and symptoms related to overactive bladder wherein said symptoms are in particular increased urinary frequency, nocturia, urinary urgency or urge incontinence; pelvic hypersensitivity; urethritis; prostatitis; prostatodynia; cystitis, in particular interstitial cystitis;
  • the compounds of the present invention can be administered in combination or as comedication, independently or in addition to behavioral therapy like diet, lifestyle or bladder training, with anticholinergics like oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium, fesoterdine; ß-3 agonists like mirabegron; neurotoxins like onabutolinumtoxin A; or antidepressants like imipramine, duloxetine.
  • anticholinergics like oxybutynin, tolterodine, propiverine, solifenacin, darifenacin, trospium, fesoterdine
  • ß-3 agonists like mirabegron
  • neurotoxins like onabutolinumtoxin A
  • antidepressants like imipramine, duloxetine.
  • the compounds of the present invention can be administered in combination or as comedication, independently or in addition to behavioral therapy like diet, lifestyle or bladder training, with pentosans like elmiron; NSAIDS (Non-Steroidal Antiinflammatory Drugs), either unselective NSAIDS like ibuprofen, diclofenac, aspirin, naproxen, ketoprofen, indomethacin; as well as Cox-2 selective NSAIDS like Parecoxib, Etoricoxib, Celecoxib; antidepressants like amitriptyline, imipramine; or antihistamines like loratadine.
  • NSAIDS Non-Steroidal Antiinflammatory Drugs
  • the compounds of the present invention can be administered in combination or as comedication with any substance that can be applied as therapeutic agent in the following indications: dysmenorrhea, including primary and secondary dysmenorrhea; dyspareunia; endometriosis; endometriosis-associated pain; endometriosis-associated symptoms, wherein said symptoms are in particular dysmenorrhea, dyspareunia, dysuria, or dyschezia.
  • the compounds of the present invention can be administered in combination or as comedication with pain medicaments, in particular NSAIDS like ibuprofen, diclofenac, aspirin, naproxen, ketoprofen, indomethacin; as well as Cox-2 selective NSAIDS like Parecoxib, Etoricoxib, Celecoxib; or in combination with ovulation inhibiting treatment, in particular COCs as mentioned above or contraceptive patches like Ortho-Evra or Apleek (Lisvy); or with progestogenes like dienogest (Visanne); or with GnRH analogous, in particular GnRH agonists and antagonists, for example leuprorelin, nafarelin, goserelin, cetrorelix, abarelix,
  • the compounds of the present invention can be administered in combination or as comedication with GnRH antagonists like Elagolix, Linzagolix, or Relugolix.
  • GnRH antagonists like Elagolix, Linzagolix, or Relugolix.
  • the compounds of the present invention can be administered in combination or as comedication with Selective Progesterone Receptor Modulators (SPRMs) or Progesterone antagonists like Vilaprisan, Ulipristal acetate, Telapristone, or Mifepristone.
  • SPRMs Selective Progesterone Receptor Modulators
  • Progesterone antagonists like Vilaprisan, Ulipristal acetate, Telapristone, or Mifepristone.
  • the compounds of the present invention can be administered in combination or as comedication with any substance that can be applied as therapeutic agent in the following indications: pain-associated diseases or disorders like hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis), burning mouth syndrome, burns, migraine or cluster headache, nerve injury, traumatic nerve injury, post-traumatic injuries (including fractures and sport injuries), neuritis, neuralgia, poisoning, ischemic injury, interstitial cystitis, trigeminal neuralgia, small fiber neuropathy, diabetic neuropathy, chronic arthritis and related neuralgias, HIV and HIV treatment- induced neuropathy.
  • pain-associated diseases or disorders like hyperalgesia, allodynia, functional bowel disorders (such as irritable bowel syndrome) and arthritis (such as osteoarthritis, rheumatoid arthritis and ankylosing spondylitis),
  • the compounds of the present invention can be combined with other pharmacological agents and compounds that are intended to treat inflammatory diseases, inflammatory pain or general pain conditions.
  • the compounds of the present invention can be administered in combination with inhibitors of PTGES (prostaglandin E synthase), with inhibitors of IRAK4 (interleukin-1 receptor-associated kinase 4) and with antagonists of the prostanoid EP4 receptor (prostaglandin E2 receptor 4).
  • the compounds of the present invention can be administered in combination with pharmacological endometriosis agents, intended to treat inflammatory diseases, inflammatory pain or general pain conditions and/or interfering with endometriotic proliferation and endometriosis associated symptoms, namely with inhibitors of Aldo-keto-reductase1C3 (AKR1C3) and with functional blocking antibodies of the prolactin receptor.
  • pharmacological endometriosis agents intended to treat inflammatory diseases, inflammatory pain or general pain conditions and/or interfering with endometriotic proliferation and endometriosis associated symptoms, namely with inhibitors of Aldo-keto-reductase1C3 (AKR1C3) and with functional blocking antibodies of the prolactin receptor.
  • the compounds of the present invention can be administered in combination or as comedication with cough suppressants like dextromethorphan, benzonatate, codeine or hydrocodone; with inhalative agents to treat eosinophilic bronchitis, COPD or asthma like budesonide, beclomethasone, fluticasone, theophylline, ipatropiumbromid, montelukast or salbutamol; with drugs like proton pump inhibitors which are used to treat acid reflux, for example omeprazole, esomeprazole, lansoprazole, ranitidine, famotidine, cimetidine; and promotility agents such as metoclopramide; with nasal or topical glucocorticoids like fluticasone or mometasone or triamcinolone; or with oral antihistamines like loratadine, fexofenadine or
  • the compounds of the present invention can be combined with other pharmacological agents and compounds that are intended for the treatment, prevention or management of cancer.
  • the compounds of the present invention can be administered in combination with 131I-chTNT, abarelix, abiraterone, aclarubicin, ado-trastuzumab emtansine, afatinib, aflibercept, aldesleukin, alemtuzumab, Alendronic acid, alitretinoin, altretamine, amifostine, aminoglutethimide, Hexyl aminolevulinate,amrubicin, amsacrine, anastrozole, ancestim, anethole dithiolethione, angiotensin II, antithrombin III, aprepitant, arcitumomab, arglabin, arsenic trioxide, asparaginase, axitinib, azacitidine, basiliximab,
  • the compounds of the present invention can be combined with active ingredients, which are well known for the treatment of cancer-related pain and chronic pain.
  • active ingredients include, but are not limited to NSAIDS (either unselective NSAIDS like ibuprofen, diclofenac, aspirin, naproxen, ketoprofen and indomethacin; and Cox-2 selective NSAIDS like Parecoxib, Etoricoxib and Celecoxib), step II opiods like codeine phosphate, dextropropoxyphene, dihydro ⁇ codeine,Tramadol), step III opiods like morphine, fentanyl, buprenorphine, oxymorphone, oxycodone and hydromorphone; and other medications used for the treatment of cancer pain like steroids as Dexamethasone and methylprednisolone; bisphosphonates like Etidronate, Clodronate, Alendronate, Risedronate, and Zoledronate; tricyclic antidepressants like Am
  • the effective dosage of the compounds of the present invention can readily be determined for treatment of each desired indication.
  • the amount of the active ingredient to be administered in the treatment of one of these conditions can vary widely according to such considerations as the particular compound and dosage unit employed, the mode of administration, the period of treatment, the age and sex of the patient treated, and the nature and extent of the condition treated.
  • the total amount of the active ingredient to be administered will generally range from about 0.001 mg/kg to about 200 mg/kg body weight per day, and preferably from about 0.01 mg/kg to about 50 mg/kg body weight per day.
  • Clinically useful dosing schedules will range from one to three times a day dosing to once every four weeks dosing.
  • drug holidays in which a patient is not dosed with a drug for a certain period of time, to be beneficial to the overall balance between pharmacological effect and tolerability. It is possible for a unit dosage to contain from about 0.5 mg to about 400 mg of active ingredient and can be administered one or more times per day or less than once a day.
  • the average daily dosage for administration by injection will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily rectal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily vaginal dosage regimen will preferably be from 0.01 to 200 mg/kg of total body weight.
  • the average daily topical dosage regimen will preferably be from 0.1 to 200 mg administered between one to four times daily.
  • the transdermal concentration will preferably be that required to maintain a daily dose of from 0.01 to 200 mg/kg.
  • the average daily inhalation dosage regimen will preferably be from 0.01 to 100 mg/kg of total body weight.
  • the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g. Biotage SNAP cartidges KP-Sil ® or KP- NH ® in combination with a Biotage autopurifier system (SP4 ® or Isolera Four ® ) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol.
  • chromatography particularly flash column chromatography
  • prepacked silica gel cartridges e.g. Biotage SNAP cartidges KP-Sil ® or KP- NH ® in combination with a Biotage autopurifier system (SP4 ® or Isolera Four ® ) and eluents such as gradients of hexane/ethyl acetate or DCM/methanol.
  • the compounds may be purified by preparative HPLC using for example a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • a Waters autopurifier equipped with a diode array detector and/or on-line electrospray ionization mass spectrometer in combination with a suitable prepacked reverse phase column and eluents such as gradients of water and acetonitrile which may contain additives such as trifluoroacetic acid, formic acid or aqueous ammonia.
  • purification methods as described above can provide those compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt for example, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt for example.
  • a salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to the person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form (e.g.
  • a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.
  • the intermediates and examples according to the invention may be present as rotational isomers, in particular in NMR studies. In cases where the presence of rotamers are clearly visible by NMR, it is stated in the experimental section. Purity figures are generally based on corresponding peak integrations in the LC/MS chromatogram, but may additionally also have been determined with the aid of the 1 H NMR spectrum. In solvent-containing or contaminated batches, the formal yield may be ">100%"; in these cases the yield is not corrected for solvent or purity.
  • ⁇ [ppm] value in ppm and then the signal intensity in round brackets are listed.
  • the ⁇ [ppm] value/signal intensity number pairs for different signal peaks are listed with separation from one another by commas.
  • the intensity of sharp signals correlates with the height of the signals in a printed example of an NMR spectrum in cm and shows the true ratios of the signal intensities in comparison with other signals.
  • peaks or the middle of the signal and the relative intensity thereof may be shown in comparison to the most intense signal in the spectrum.
  • the lists of the 1 H NMR peaks are similar to the conventional 1 H NMR printouts and thus usually contain all peaks listed in a conventional NMR interpretation.
  • they may show solvent signals, signals of stereoisomers of the target compounds which are likewise provided by the invention, and/or peaks of impurities.
  • the peaks of stereoisomers of the target compounds and/or peaks of impurities usually have a lower intensity on average than the peaks of the target compounds (for example with a purity of > 90%).
  • Such stereoisomers and/or impurities may be typical of the particular preparation process.
  • the parameter "MinimumHeight" can be set between 1% and 4%. Depending on the type of chemical structure and/or depending on the concentration of the compound to be analysed, it may be advisable to set the parameters "MinimumHeight" to values of ⁇ 1%.
  • the reaction mixture was stirred for 20 h at 80°C.
  • the reaction was allowed to cool to room temperature and then the solution was partitioned between ethyl acetate and water.
  • the organic layer was washed twice with brine, dried with a water repellant filter and concentrated.
  • the organic layer was washed twice with brine, dried with a water repellant filter and concentrated.
  • the residue was triturated with 10 ml MtBE and the suspension was added to 150 ml hexane were added.
  • the precipitate thus obtained was collected by filtration, washed with hexane and dried to afford 3.28 g (71% yield, 98% purity) of the title compound as a white solid.
  • the reaction mixture was heated at 80°C for 1 h.
  • the reaction mixture was allowed to cool to room temperature and the solution was added to a saturated sodium bicarbonate solution (10 mL).
  • the aqueous phase was extracted with ethyl acetate.
  • the combined organic phases were washed with brine, dried with a water repellant filter and evaporated to dryness.
  • reaction mass (RM#1) was allowed to cool to room temperature.
  • the reaction mass (RM#2) was stirred for 3 h at room temperature, then cooled to 0°C and RM#1 was added portionwise over 5-15 min. The reaction mixture was stirred for 16 h at room temperature. The solvent was removed in vacuo.
  • the reaction mixture was heated to 50°C for 3 hours. After that period, the reaction mixture was evaporated in vacuo. The residue was diluted with dichloromethane (300 mL) and poured into aqueous saturated sodium bicarbonate solution (600 mL). After pH has been confirmed to be ⁇ 7, the layers were separated. The aqueous layer was extracted with dichloromethane (300 mL). The combined organic layer was washed with sodium chloride (5% aq. sol., 2 ⁇ 600 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford 5.63 g (95% yield) of the title compound, that was used in the next step without further purification.
  • the reaction mixture was heated to 100 °C (an oil bath) for 16 hours. The solvent was removed in vacuo. The residue was dissolved in dichloromethane (250 mL), washed with ammonium chloride (aq. sat., 250 mL). Then aqueous layer was extracted with dichloromethane (250 mL). The combined organic layer was washed with ammonium chloride (aq. sat., 500 mL), aqueous sodium chloride solution (5% aq. sol., 2 ⁇ 500 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure.
  • reaction mixture was stirred at 80°C for 16 h. After this time the mixture was allowed to cool to ambient temperature, water (100 ml) was added and the aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine (twice with 30 ml), dried with a water-repellant filter and concentrated to afford 4.21 g (66% yield, 98% purity) of the title compound.
  • reaction mixture was stirred for 16 h at room temperature.
  • To the mixture were added further 0,5 eq.2- bromo-3,3-dimethylbutanoic acid (99 mg, 0.50 mmol; CAS-RN:[50364-40-4]) and 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (648 mg, 3.38 mmol; CAS-RN:[25952- 53-8]) and the reaction was stirred for further 24 h at room temperature. Then the mixture was poured into 20 ml aqueous hydrochloric acid (2M) and extracted with ethyl acetate. The combined organic layers were washed with brine, dried with a water repellent filter and concentrated.
  • 2M ml aqueous hydrochloric acid
  • the reaction mixture was set under nitrogen atmosphere and heated at 120°C for 2 hours.
  • the reaction was cooled to room temperature, water was added and the aqueous phase was extracted with ethyl acetate.
  • the combined organic phases were washed with brine, dried with a water repellant filter and concentrated under reduced pressure.
  • the residue was taken up in 2 ml acetonitrile/water (7:3), filtered via syringe filter and purified by HPLC (Method 1, gradient D). The solvent of the product fractions was evaporated under reduced pressure.
  • the precipitate thus obtained was collected by vacuum filtration, washed with hexane and dried to afford 148 mg (86% yield, 99% purity) of the title compound as a white solid.
  • the reaction mixture was heated at 80°C for 30 minutes. The reaction mixture was allowed to cool to room temperature and the solution was added to 10 ml saturated sodium bicarbonate solution. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with brine, dried with a water repellant filter and evaporated to dryness. The crude product was used with further purification in the next reaction.
  • reaction mixture was stirred for 1 h at room temperature.
  • the reaction mixture was diluted with acetonitrile/water (7:3)(2 mL), filtered via syringe filter and purified by HPLC (Method A, gradient C) to afford 7.10 mg (28% yield, 99% purity) of the title compound as a white powder.
  • reaction mixture was stirred for 1 hours at room temperature.
  • the reaction was quenched with 20 ml hydrochloric acid (1M) and extracted with ethyl acetate. The combined organic phases were washed with brine and concentrated. The obtained solid was suspended in methyl tert-butyl ether (15 ml), stirred vigorously for 10 minutes.
  • EXPERIMENTAL SECTION – BIOLOGICAL ASSAYS Examples were tested in selected biological assays one or more times. When tested more than once, data are reported as either average values or as median values, wherein • the average value, also referred to as the arithmetic mean value, represents the sum of the values obtained divided by the number of times tested, and • the median value represents the middle number of the group of values when ranked in ascending or descending order. If the number of values in the data set is odd, the median is the middle value. If the number of values in the data set is even, the median is the arithmetic mean of the two middle values. Examples were synthesized one or more times.
  • the cell line is stably transfected with the human P2X3 receptor and a calcium-sensitive photoprotein, mitochondrial photina, which, after reconstitution with the cofactor coelenterazine, emits light in dependence of calcium binding [Bovolenta S, Foti M, Lohmer S, Corazza S., J Biomol Screen. 2007 Aug;12(5):694-704].
  • the strength of the photina luminescence signal corresponds to the level of receptor activation upon agonist binding. An inhibitor would decrease the signal depending on its potency and concentration. Bioluminescence was detected using a suitable luminometer [Milligan G, Marshall F, Rees S, Trends in Pharmacological Sciences 17, 235-237 (1996)].
  • Test procedure On the day before the assay, the cells are plated out in culture medium (DMEM/F12 (PAN, P04- 41451), 10% FCS) in 384-well microtiter plates and kept in a cell incubator (96% humidity, 5% v/v CO 2 , 30°C). On the day of the assay medium is replaced by 2 mM Ca-tyrode buffer containing 5 ⁇ g/ml coelenterazine. Plates are incubated for 3 hours at 37°C (96% humidity, 5% v/v CO 2 ). After incubation the test substances in various concentrations are placed for 10 minutes in the wells of the microtiter plate before the agonist ⁇ , ⁇ -methylene-ATP at EC 50 concentration is added.
  • the resulting light signal is measured immediately in the luminometer. 2) and 3) Intracellular calcium measurement to compare antagonist activity at human P2X3 receptors (hP2X31321N1) and at human P2X2/3 receptors (hP2X231321N1)
  • the comparison of antagonistic activity at the P2X3 versus the P2X23 receptor of the compounds of the invention were performed by use of recombinant cell lines. These cell lines derived originally from the human astrocytoma cell line 1312N1 (Macintyre EH, Pontén J, Vatter AE. Acta Pathol Microbiol Scand A. 1972;80(2):267-83).
  • the cell lines are stably transfected with the human P2X3 receptor forming homotrimeric P2X3 receptors or are co-transfected with P2X2 and P2X3 forming heterotrimeric P2X23 receptors. Stimulation of the receptors with the agonist ATP leads to a conformational change of the receptors and influx of extracellular calcium ions through the open ion channel. The cytoplasmatic calcium transient is detected via the calcium sensitive dye Fluo8. The strength of Fluo8 fluorescence signal corresponds to the level of receptor activation. An inhibitor would decrease the signal depending on its potency and concentration. Fluorescence was measured by use of a suitable fluorescence reader.
  • Test procedure On the day before the assay, the cells were plated in culture medium (DMEM high glucose, 10% FCS, 1% MEM non-essential amino acids , 4mM Glutamax) in 384-well poly-D-lysine coated microtiter plates and kept in a cell incubator (96% humidity, 5% v/v CO 2 , 37°C). On the day of the assay medium was exchanged by Fluo8 containing buffer and incubated for 60 minutes. Test compounds were added at various concentrations and plates were incubated for 10 minutes. In the fluorescence reader a 3 seconds baseline measurement was performed and the agonist ATP was applied at EC 50 concentration of the respective receptor during constant fluorescence measurement for 120 seconds. Results:

Landscapes

  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Pulmonology (AREA)
  • Endocrinology (AREA)

Abstract

La présente invention concerne des composés N-(pyridin-2-yl)-acétamides substitués de formule générale (I), dans laquelle X, Y, R1, R2, R3, R4 et R5 sont tels que définis dans la description, des procédés de préparation desdits composés, des compositions pharmaceutiques et des combinaisons comprenant lesdits composés et l'utilisation desdits composés pour la fabrication de compositions pharmaceutiques pour le traitement ou la prophylaxie de maladies, en particulier de maladies neurogènes, en tant qu'agent unique ou en combinaison avec d'autres principes actifs.
PCT/EP2022/054203 2021-02-22 2022-02-21 N-(pyridin-2-yl)-acétamides utilisés comme inhibiteurs de p2x3 WO2022175514A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP21158431 2021-02-22
EP21158431.3 2021-02-22
EP21191055.9 2021-08-12
EP21191055 2021-08-12

Publications (1)

Publication Number Publication Date
WO2022175514A1 true WO2022175514A1 (fr) 2022-08-25

Family

ID=80595415

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2022/054203 WO2022175514A1 (fr) 2021-02-22 2022-02-21 N-(pyridin-2-yl)-acétamides utilisés comme inhibiteurs de p2x3

Country Status (1)

Country Link
WO (1) WO2022175514A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112778311A (zh) * 2019-11-01 2021-05-11 上海翰森生物医药科技有限公司 含氮并环类衍生物抑制剂、其制备方法和应用
CN112778311B (zh) * 2019-11-01 2024-06-04 上海翰森生物医药科技有限公司 含氮并环类衍生物抑制剂、其制备方法和应用

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017142A1 (fr) 2009-08-06 2011-02-10 Merck Patent Gmbh Nouveaux composés d'urée bicyclique
WO2012112363A1 (fr) 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Inhibiteurs de cystéine protéases, les cathepsines
WO2019081343A1 (fr) * 2017-10-27 2019-05-02 Bayer Aktiengesellschaft Nouveaux dérivés de pyrazolo-pyrrolo-pyrimidine-dione utilisés en tant qu'inhibiteurs de p2x3
WO2020011921A1 (fr) 2018-07-12 2020-01-16 Recordati Industria Chimica E Farmaceutica Spa Antagonistes du récepteur p2x3

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011017142A1 (fr) 2009-08-06 2011-02-10 Merck Patent Gmbh Nouveaux composés d'urée bicyclique
WO2012112363A1 (fr) 2011-02-14 2012-08-23 Merck Sharp & Dohme Corp. Inhibiteurs de cystéine protéases, les cathepsines
WO2019081343A1 (fr) * 2017-10-27 2019-05-02 Bayer Aktiengesellschaft Nouveaux dérivés de pyrazolo-pyrrolo-pyrimidine-dione utilisés en tant qu'inhibiteurs de p2x3
WO2020011921A1 (fr) 2018-07-12 2020-01-16 Recordati Industria Chimica E Farmaceutica Spa Antagonistes du récepteur p2x3

Non-Patent Citations (32)

* Cited by examiner, † Cited by third party
Title
"Isotopic Compositions of the Elements 1997", PURE APPL. CHEM., vol. 70, no. 1, 1998, pages 217 - 235
A. E. MUTLIB ET AL., TOXICOL. APPL. PHARMACOL., vol. 169, 2000, pages 102
A. M. SHARMA ET AL., CHEM. RES. TOXICOL., vol. 26, 2013, pages 410
B. TESTA ET AL., INT. J. PHARM., vol. 19, no. 3, 1984, pages 271
BOVOLENTA SFOTI MLOHMER SCORAZZA S., J BIOMOL SCREEN, vol. 12, no. 5, August 2007 (2007-08-01), pages 694 - 704
BURNSTOCK, CELL NEUROSCI, vol. 7, 2013, pages 227
BURNSTOCK, DRUG DEV RES, vol. 28, 1993, pages 196 - 206
BURNSTOCK, EUR J PHARMACOL, vol. 716, 2013, pages 24 - 40
BURNSTOCK, PROG NEUROBIOL, vol. 95, 2011, pages 229 - 274
BURNSTOCK, PURIN SIGNAL, vol. 10, no. 1, 2014, pages 3 - 50
C. J. WENTHUR ET AL., J. MED. CHEM., vol. 56, 2013, pages 5208
C. L. PERRIN ET AL., J. AM. CHEM. SOC., vol. 127, 2005, pages 9641
C. L. PERRIN ET AL., J. AM. CHEM. SOC., vol. 129, 2007, pages 4490
CAS, no. 157750-90-8
CHIZH, PHARMACOL REV, vol. 53, 2000, pages 553 - 568
F. MALTAIS ET AL., J. MED. CHEM., vol. 52, 2009, pages 7993
F. SCHNEIDER ET AL., ARZNEIM. FORSCH. / DRUG. RES., vol. 56, 2006, pages 295
FABRETTI, FRONT CELL NEUROSCI, vol. 7, 2013, pages 267
FINGER ET AL., SCIENCE, 2005
GARCIA-GUZMAN MSTUHMER WSOTO F: "Molecular characterization and pharmacological properties of the human P2X3 purinoceptor", BRAIN RES MOL BRAIN RES, vol. 47, no. 1-2, September 1997 (1997-09-01), pages 59 - 66, XP002105595, DOI: 10.1016/S0169-328X(97)00036-3
JIANG, CELL HEALTH CYTOSKELETON, vol. 4, 2012, pages 83 - 101
JOSEPH, NEUROSCI, vol. 232C, 2013, pages 83 - 89
MACINTYRE EHPONTEN JVATTER AE, ACTA PATHOL MICROBIOL SCAND A, vol. 80, no. 2, 1972, pages 267 - 83
MILLIGAN GMARSHALL FREES S, TRENDS IN PHARMACOLOGICAL SCIENCES, vol. 17, 1996, pages 235 - 237
NORTH, J PHYIOL, vol. 554, 2003, pages 301 - 308
PRADO, NEUROPHARM, vol. 67, 2013, pages 252 - 258
PURE APPL CHEM, vol. 45, 1976, pages 11 - 30
S. M. BERGE ET AL.: "Pharmaceutical Salts", J. PHARM. SCI., vol. 66, 1977, pages 1 - 19, XP002675560, DOI: 10.1002/jps.2600660104
SOUSLOVA, NATURE, vol. 407, 2000, pages 1015 - 1017
STRAND ET AL., ACR/ARMP ANNUAL MEETING, 2015
TJIO J. H.PUCK T. T., J. EXP. MED., vol. 108, 1958, pages 259 - 271
VANDENBEUCH ET AL., J PHYSIOL, 2015

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112778311A (zh) * 2019-11-01 2021-05-11 上海翰森生物医药科技有限公司 含氮并环类衍生物抑制剂、其制备方法和应用
CN112778311B (zh) * 2019-11-01 2024-06-04 上海翰森生物医药科技有限公司 含氮并环类衍生物抑制剂、其制备方法和应用

Similar Documents

Publication Publication Date Title
WO2018024602A1 (fr) 2,7-diazaspiro [4,4] nonanes
TW201629037A (zh) 新穎經取代吲唑、其製法、包含其之醫藥製劑及其製備藥劑之用途
EP3638670B1 (fr) Dérivés de pyrrolopyridine substitués utilisés en tant que modulateurs de map4k1 pour le traitement de maladies cancéreuses
AU2017269871B2 (en) (8-(phenylsulfonyl)-3,8-diazabicyclo(3.2.1)oct-3-yl) (1H-1,2,3-triazol-4-yl)methanones
WO2020260463A1 (fr) Analogues de3-(5-méthyl-1,3-thiazol-2-yl)-n-{(1r)-1-[2-(trifluoro-méthyl)pyrimidin-5-yl]éthyl}benzamide
US20200246347A1 (en) Substituted Pyrrolopyridine-Derivatives
US11319324B2 (en) Pyrazolo-pyrrolo-pyrimidine-dione derivatives as P2X3 inhibitors
US20190307728A1 (en) Methods of treatment with a 2,4,5-trisubstituted 1,2,4-triazolone
WO2022175514A1 (fr) N-(pyridin-2-yl)-acétamides utilisés comme inhibiteurs de p2x3
WO2022029063A1 (fr) Pyrido[1,2,4]triazolo[1,5-c]pyrimidin-5-amines
WO2023118092A1 (fr) Pyrazolo [1,5-a] pyrido [3,2-e] pyrimidines et pyrazolo [1,5-a] [1,3] thiazolo [5,4-e] pyrimidines en tant qu'inhibiteurs de p2x3 pour le traitement de troubles neurogènes
WO2018114670A1 (fr) [4-(phénylsulfonyl)pipérazin-1-yl](1h-1,2,3-triazol-4-yl)méthanones
WO2022253943A1 (fr) Formes cristallines de 3-(5-méthyl-1,3-thiazol-2-yl)-5-[(3r)-tétrahydrofuran-3-yloxy]-n-{(1r)-1-[2-(trifluoro-méthyl)pyrimidin-5-yl]éthyl}-benzamide
EP3555101A2 (fr) [(phénylsulfonyl)octahydro-épiminoisoindol-yl](1h-1,2,3-triazol-5-yl)méthanones
WO2018114672A1 (fr) [4-(phénylsulfonyl)pipérazin-1-yl](1h-1,2,3-triazol-4-yl)méthanones

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22706834

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22706834

Country of ref document: EP

Kind code of ref document: A1