WO2021233752A1 - Antagonistes de trpa1 pour le traitement de maladies associées à la douleur et à l'inflammation - Google Patents

Antagonistes de trpa1 pour le traitement de maladies associées à la douleur et à l'inflammation Download PDF

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Publication number
WO2021233752A1
WO2021233752A1 PCT/EP2021/062583 EP2021062583W WO2021233752A1 WO 2021233752 A1 WO2021233752 A1 WO 2021233752A1 EP 2021062583 W EP2021062583 W EP 2021062583W WO 2021233752 A1 WO2021233752 A1 WO 2021233752A1
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WIPO (PCT)
Prior art keywords
trifluoromethyl
cyclohexanol
fluoroanilino
pain
disorders
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PCT/EP2021/062583
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English (en)
Inventor
ONDOZABAL Hideki MIYATAKE
Alexis LAUX-BIEHLMANN
Bernd Elger
Stefanie MESCH
Andrea Rotgeri
Antje Rottmann
Daniel BASTING
Ulrich Bothe
Stefan BÄURLE
Daryl Simon Walter
Stuart Robert FLANAGAN
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Bayer Aktiengesellschaft
Bayer Pharma Aktiengesellschaft
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Publication of WO2021233752A1 publication Critical patent/WO2021233752A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/42—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having amino groups or hydroxy groups bound to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention is directed to the use of such compounds for manufacturing a pharmaceutical composition for the treatment or prophylaxis of a disease, in particular in mammals, such as but not limited to diseases associated with pain and inflammation, or for the treatment or prophylaxis of pain-related/associated diseases, conditions and disorders and pain syndromes, gynecological diseases, urinary tract disorders and diseases, cancer and cancer-related pain, neurological disorders, respiratory disorders, gastrointestinal disorders, metabolic disorders, neurodegenerative disorders, skin disorders, cardiovascular disorders and inflammatory diseases.
  • a pharmaceutical composition for the treatment or prophylaxis of a disease in particular in mammals, such as but not limited to diseases associated with pain and inflammation, or for the treatment or prophylaxis of pain-related/associated diseases, conditions and disorders and pain syndromes, gynecological diseases, urinary tract disorders and diseases, cancer and cancer-related pain, neurological disorders, respiratory disorders, gastrointestinal disorders, metabolic disorders, neurodegenerative disorders, skin disorders, cardiovascular disorders and inflammatory diseases.
  • WO2018/029288A1 is reporting 1-sulfonyl-2-carboxamide-pyridyl analogs identified as Transient Receptor Potential Ankyrin 1 (TRPA1) antagonists useful for treating diseases and conditions including but not limited to pain, inflammation and endometriosis.
  • W02018/180460A1 is reporting norbornane analogs identified as Transient Receptor Potential Ankyrin 1 (TRPA1) antagonist and
  • WO2019/152465A1 is reporting 3,7-dihydropurine-2,6-dione analogs identified as Transient Receptor Potential Ankyrin 1 (TRPA1) antagonist useful for treating diseases and conditions including but not limited to pain and inflammation.
  • JP2018/127440 is reporting isopropylcyclohexane analogs identified as Transient Receptor Potential Ankyrin 1 (TRPA1) antagonist or/and as Transient Receptor Potential Vanilloid 4 (TRPV4) antagonists useful for treating diseases and conditions including but not limited to pain and inflammation.
  • TRPA1 Transient Receptor Potential Ankyrin 1
  • TRPV4 Transient Receptor Potential Vanilloid 4
  • W02 018/0230149A1 is reporting 3,7-dihydropurine-2,6-dione analogs, different from WO20 19/152465A1 , identified as Transient Receptor Potential Ankyrin 1 (TRPA1) antagonist useful for treating diseases and conditions including but not limited to pain and inflammation.
  • TRPA1 in gynecological conditions and only published information is referring to descriptive TRPA1 expression in rat and human tissues. Indeed, an estrogen-dependent up-regulation of TRPA1 has been described in the rat endometrium, TRPA1 mRNA was found to be significantly higher in the peritoneum from women with endometriosis and TRPA1 immunopositive cells were found in rectosigmoid deep infiltrating endometriosis lesions [Greaves 2014, J Clin Endocrinol Metab 99(9):E1738-43; Pohoczky 2016, J Mol Endocrinol 56(2): 135-49; Bohonyi 2017, Mol Pain 13:1744806917705564.
  • inhibitors of TRPA1 of the current invention represent valuable compounds that should complement therapeutic options either as single agents or in combination with other drugs.
  • Endometriosis affects 5-10% of women of reproductive age and is defined as the growth of endometrial tissue in ectopic locations, found primarily within the pelvic cavity. This extra-uterine growth is accompanied by infiltration of pro-inflammatory macrophages as cardinal sign of disease leading to a chronically inflamed microenvironment and contributing to chronic pain symptoms.
  • R 3 represents hydrogen or fluoro
  • the present invention covers compounds of general formulae (la) and (lb): in which:
  • R 1 represents hydrogen, fluoro, or chloro
  • R 4 represents hydrogen or fluoro; and hydrates, solvates, and salts thereof, and mixtures of same.
  • the invention is directed to a method for the treatment and/or prophylaxis of a disease comprising the step of administrating to a patient in need a compound of general formula (la), (lb), (Ic), or (Id) as disclosed above, or the invention is directed to the use of a compound of general formula (la), (lb), (Ic), or (Id) as disclosed above for treatment or prophylaxis of a disease or the invention is directed to the use of compound of general formula (la), (lb), (Ic), or (Id) as disclosed above for manufacturing pharmaceutical compositions for the treatment or prophylaxis of diseases.
  • the disease is preferably selected from the list of;
  • Pain-associated diseases or 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.
  • Gynecological diseases include but are not limited to primary and secondary dysmenorrhea, dyspareunia, vulvudynia, endometriosis, adenomyosis, endometriosis-associated pain, endometriosis-associated symptoms, wherein said symptoms are in particular abdominal pain, dysmenorrhea, dyspareunia, dysuria, dyschezia or pelvic hypersensitivity, uterine fibroids, or uterine fibroids associated pain symptoms.
  • Urinary tract diseases or disorders include but are not limited to disorders and diseases associated with bladder outlet obstruction; urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyper reactivity; 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; kidney disease as hyperprostaglandin E syndrome, and classic Bartter syndrome.
  • urinary incontinence conditions such as reduced bladder capacity, increased frequency of micturition, urge incontinence, stress incontinence, or bladder hyper reactivity
  • benign prostatic hypertrophy prostatic hyperplasia
  • Cancer and cancer-related pain include but are not limited to, for example: solid tumours, such as cancers of the breast, respiratory tract, brain, reproductive organs, digestive tract, urinary tract, eye, liver, skin, head and neck, thyroid, parathyroid and their distant metastases. Those disorders also include lymphomas, sarcomas, and leukaemias.
  • breast cancers include, but are not limited to, invasive ductal carcinoma, invasive lobular carcinoma, and ductal carcinoma in situ, and lobular carcinoma in situ.
  • cancers of the respiratory tract include, but are not limited to, small-cell and non-small-cell lung carcinoma, as well as bronchial adenoma and pleuropulmonary blastoma.
  • Lymphomas include, but are not limited to, AIDS-related lymphoma, non-Hodgkin's lymphoma, cutaneous T-cell lymphoma, Burkitt lymphoma, Hodgkin's disease, and lymphoma of the central nervous system.
  • Sarcomas include, but are not limited to, sarcoma of the soft tissue, osteosarcoma, malignant fibrous histiocytoma, lymphosarcoma, and rhabdomyosarcoma.
  • Leukemias include, but are not limited to, acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, and hairy cell leukemia.
  • Neurological disorders include but are not limited to epilepsy, partial and generalized seizures, addiction, encephalitis, fibromyalgia, Amyotrophic lateral sclerosis, anxiety disorders including generalized anxiety disorder and depression disorders,
  • Respiratory disorders include but are not limited to asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, interstitial pulmonary fibrosis, bronchospasm, chronic chough, persistent chronic chough, refractory chronic cough and idiopathic chronic cough.
  • Gastrointestinal disorders include but are not limited to irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), biliary colic and other biliary disorders, renal colic, diarrhea-dominant IBS; gastroesophageal reflux, gastrointestinal distension, Crohn's disease and the like.
  • IBS irritable bowel syndrome
  • IBD inflammatory bowel disease
  • biliary colic and other biliary disorders
  • renal colic diarrhea-dominant IBS
  • gastroesophageal reflux gastroesophageal reflux
  • gastrointestinal distension Crohn's disease and the like.
  • Metabolic disorders include but are not limited to fatty liver disorders, NASH (Non- Alcoholic Steato-Hepatitis); fibrotic diseases including lung fibrosis, heart fibrosis, kidney fibrosis and fibrosis of other organs; metabolic syndrome including, for example, insulin resistance, hypertension, refractory hypertension, dyslipoproteinaemia and obesity, diabetes mellitus, in particular Diabetes type II, myocardial infarction; atherosclerosis; lipid disorders and polycystic ovary syndrome.
  • NASH Non- Alcoholic Steato-Hepatitis
  • fibrotic diseases including lung fibrosis, heart fibrosis, kidney fibrosis and fibrosis of other organs
  • metabolic syndrome including, for example, insulin resistance, hypertension, refractory hypertension, dyslipoproteinaemia and obesity, diabetes mellitus, in particular Diabetes type II, myocardial infarction
  • atherosclerosis lipid disorders and polycystic ovary syndrome.
  • Neurodegenerative disorders include but are not limited to Alzheimer's disease, Multiple Sclerosis, Parkinson's disease, brain ischemia, traumatic brain injury and spinal cord injury.
  • Cardiovascular disorders include but are not limited to ischemia reperfusion injury, cardiac ischemia, myocardial infarction, stroke, heart failure, hypertensive diseases, thromboembolic disease and thrombosis.
  • the present invention covers pharmaceutical compositions comprising compound(s) of formulae (la), (lb), (lc), and (Id) as disclosed above and one or more pharmaceutically acceptable excipients.
  • Pharmaceutically acceptable excipient is defined as a filler (such as sugars, such as lactose, sucrose, dextrose and dextrates; sugar alcohols, such as mannitol, sorbitol and xylitol); carbonates and phosphates of alkaline earth metals, such as calcium carbonate and calcium phosphate; celluloses, such as powdered cellulose and microcrystalline cellulose; colloidal silica; titanium dioxide; kaolin; talc), lubricants (such as magnesium stearate), carrier substances (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g.
  • liquid polyethylene glycols such as polyethylene glycols
  • emulsifiers and dispersants or wetting agents for example sodium dodecylsulphate, polyoxysorbitan oleate
  • binders for example polyvinylpyrrolidone
  • synthetic and natural polymers for example albumin
  • stabilizers e.g. antioxidants, for example ascorbic acid
  • colouring matter e.g. inorganic pigments, for example iron oxides
  • the pharmaceutically acceptable excipient is a filler or a binder.
  • the present invention furthermore covers pharmaceutical compositions, in particular medicaments, which comprise at least one compound according to the invention, conventionally together with one or more pharmaceutically suitable excipients, and to their use for the above mentioned purposes.
  • the present invention covers the intermediate compounds which are disclosed in the Example Section of this text, infra.
  • the present invention covers an antagonist or inhibitor of Transient Receptor Potential Ankyrin 1 (TRPA1) for use in the treatment and/or prevention of patient in need
  • TRPA1 is expressed in inflammatory cell types and in diseased tissue of endometriosis patients, and also showed that TRPA1 inhibition shall present an alleviating effect on these conditions, such dysmenorrhea, dyspareunia, dysuria, dyschezia, endometriosis, endometriosis » associated pain or endometriosis-associated symptoms like inflammatory pain.
  • the antagonist or inhibitor is for treating endometriosis, endometriosis-associated pain or endometrioses-associated symptoms like inflammatory pain.
  • 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.
  • 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”.
  • halogen or “halogen atom” means a fluorine, chlorine, bromine or iodine atom, particularly fluorine, chlorine or bromine atom.
  • 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.
  • Preferred isomers are those which produce the more desirable biological activity.
  • These separated, pure or partially purified isomers or racemic mixtures of the compounds of this 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.
  • appropriate acids are tartaric, diacetyl tartaric, 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.
  • 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.
  • 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 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.
  • polar solvents in particular water
  • 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 may 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
  • 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.
  • 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 a carcinoma,
  • the starting materials are either commercially available or can be prepared according to procedures available from the public domain, as understandable to the person skilled in the art. Specific examples are described in the Experimental Section.
  • Scheme 1 describes the preparation of trans-isomers of general formulae (la) and (lb) with the meaning of R 1 and R 2 as defined in general formula (I) supra.
  • Epoxidation reaction (step c) of alkene (IV) to epoxide rac-(V) can be achieved by the usage of oxidizing agents, such as meta-chloroperbenzoic acid (mCPBA) or hydrogenperoxide in dichloromethane at RT.
  • oxidizing agents such as meta-chloroperbenzoic acid (mCPBA) or hydrogenperoxide in dichloromethane at RT.
  • Epoxide opening reaction (step d) of epoxide rac-(V) can be achieved using scandium-(lll)-trifluoromethanesulfonate as a Lewis acid in toluene, in presence of the desired nucleophilic aniline at 60 °C to give access to compounds of general formulae (la) and (lb).
  • the enantiomers can be separated by methods known to the person skilled in the art. Other alternative methods/routes known to the person skilled in the art can also be utilized to access compounds of general formulae (la) and (lb) and it is not limited to the conditions listed above.
  • step a The introduction of trifluoromethyl group (step a) can be achieved by reacting compounds of general formula (VI) with Me 3 Si-CF 3 or Et 3 Si-CF 3 and tetra-n-butylammonium fluoride in tetrahydrofuran at between 0 °C to RT to give racemic alcohols of general formula rac- (VII),
  • step b) The following dehydration reaction (step b) can be performed, for example, using thionyl chloride in presence of dimethylamino pyridine and pyridine between RT to 45 °C to access alkenes of general formula (VIII).
  • Epoxide opening reaction (step d) of epoxides of general formula rac-(IX) can be achieved using scandium-(III)-trifIuoromethanesulfonate as a Lewis acid in toluene, in presence of the desired nucleophilic anilines at 60 °C to give access to compounds of general formula (Ic) and (Id), after separation of enantiomers by methods known to the person skilled in the art.
  • Other alternative methods/routes known to the person skilled in the art can also be utilized to access compounds of general formulae (Ic) and (Id) and it is not limited to conditions listed above.
  • the compounds according to the invention 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.
  • 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
  • the compounds 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
  • 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
  • surfactants for example sodium dodecyl sulfate
  • lecithin for example sodium dodecyl sulfate
  • lecithin for example sodium dodecyl sulfate
  • lecithin for example sodium dodecyl sulfate
  • phospholipids for example sodium dodecyl sulfate
  • phospholipids for example, fatty alcohols (such as, for example, Lanette ® ), sorbitan fatty acid esters (such as, for example, Span ® ), polyoxyethylene sorbitan fatty acid esters (such as, for example, Tween ® ), polyoxyethylene fatty acid glycerides (such as, for example, Cremophor ® ), polyoxethylene fatty acid est
  • buffers for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • acids and bases for example phosphates, carbonates, citric acid, acetic acid, hydrochloric acid, sodium hydroxide solution, ammonium carbonate, trometamol, triethanolamine
  • isotonicity agents for example glucose, sodium chloride
  • adsorbents for example highly-disperse silicas
  • viscosity-increasing agents for example polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, carboxymethylcellulose-sodium, starch, carbomers, polyacrylic acids (such as, for example, Carbopol ® ); alginates, gelatine),
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab ® ), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol ® )
  • disintegrants for example modified starch, carboxymethylcellulose-sodium, sodium starch glycolate (such as, for example, Explotab ® ), cross- linked polyvinylpyrrolidone, croscarmellose-sodium (such as, for example, AcDiSol ® )
  • lubricants for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil ® )
  • mould release agents for example magnesium stearate, stearic acid, talc, highly-disperse silicas (such as, for example, Aerosil ® )
  • coating materials for example sugar, shellac
  • film formers for films or diffusion membranes which dissolve rapidly or in a modified manner for example polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohol, hydroxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, cellulose acetate, cellulose acetate phthalate, polyacrylates, polymethacrylates such as, for example, Eudragit ® )),
  • capsule materials for example gelatine, hydroxypropylmethylcellulose
  • polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ® ), polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • synthetic polymers for example polylactides, polyglycolides, polyacrylates, polymethacrylates (such as, for example, Eudragit ® ), polyvinylpyrrolidones (such as, for example, Kollidon ® ), polyvinyl alcohols, polyvinyl acetates, polyethylene oxides, polyethylene glycols and their copolymers and blockcopolymers),
  • stabilisers for example antioxidants such as, for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gal late
  • antioxidants for example, ascorbic acid, ascorbyl palmitate, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gal late
  • preservatives for example parabens, sorbic acid, thiomersal, benzalkonium chloride, chlorhexidine acetate, sodium benzoate
  • colourants for example inorganic pigments such as, for example, iron oxides, titanium dioxide
  • flavourings • flavourings, sweeteners, flavour- and/or odour-masking agents.
  • the compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to the person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent. In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using for example prepacked silica gel cartridges, e.g.
  • 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. salt, free base etc.) of 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.
  • Absolute configuration of example 16 was determined to be (1R, 2R) by comparison of experimentally measured vibrational circular dichroism (VCD) spectra with the calculated (ab initio) VCD spectrum for (1R, 2R)-2-(4-fluoroanilino)-1-(trifluoromethyl)cyclohexan-1- ol.
  • VCD vibrational circular dichroism
  • Method A Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2.1 mm; eluent A: water + 0.1 vol % formic acid (99%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
  • Method B Instrument: Waters Acquity UPLCMS SingleQuad; Column: Acquity UPLC BEH C18 1.7 pm, 50x2.1mm; eluent A: water + 0.2 vol % aqueous ammonia (32%), eluent B: acetonitrile; gradient: 0-1.6 min 1-99% B, 1.6-2.0 min 99% B; flow 0.8 ml/min; temperature: 60 °C; DAD scan: 210-400 nm.
  • Method C Instrument: Agilent 1290 UPLCMS 6230 TOF; column: BEH C 18 1.7 pm, 50x2.1mm; Eluent A: water + 0.05 % formic acid (99%); Eluent B: acetonitrile + 0.05 % formic acid (99%); gradient: 0-1.72-90% B, 1.7-2.090% B; flow 1.2 ml/min; temperature: 60°C; DAD scan: 190-400 nm.
  • Reaction times are either specified explicitly in the protocols of the experimental section, or reactions were run until completion. Chemical reactions were monitored and their completion was judged using methods well known to the person skilled in the art, such as thin layer chromatography, e.g. on plates coated with silica gel, or by LCMS methods.
  • the mixture was extracted 3 times with dichloromethane. To the combined organic layers was added under stirring sat. NaHCO 3 solution until the pH of the aqueous layer was >7. The phases were separated and the organic layer was washed with water and dried with sodium sulfate. The crude product solution was directly taken to the next step.
  • Step 2 Synthesis of 4,4-difluoro-1-(trifluoromethyl)cyclohexene 4,4-difluoro-1-(trifluoromethyl)cyclohexanol (42 g, crude) was dissolved at rt in dichloromethane (115 ml) and thionyl chloride (32.4 ml, 444 mmol) was added drop-wise. Then 4-dimethylaminopyridine (724 mg, 5.93 mmol) was added and pyridine (36 ml, 444 mmol) was added drop-wise. After 10 min stirring at rt, the mixture was stirred overnight at 45°C.
  • Step 3 Synthesis of 4,4-difIuoro-1-(trifIuoromethyI)-7-oxabicydo[4.1.0]heptane
  • a solution of 4,4-difluoro-1-(trifluoromethyl)cyclohexene (ca. 1.34 mmol in 8.5 mL dichloromethane) was added at rt 2M aqueous sodium hydroxide solution (0.40 mL) and hydrogenperoxide (0.13 mL, 35% solution) The mixture was stirred at rt for 3 days. Then a sat. aqueous sodium bicarbonate solution was slowly added drop-wise and the mixture stirred for further 10 min.
  • 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
  • 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. When synthesized more than once, data from biological assays represent average values or median values calculated utilizing data sets obtained from testing of one or more synthetic batch.
  • Cells expressing TRPA1 were cultured in DMEM medium (Gibco #41965-039), 10% FCS, 14.5 mM HEPES, 1 mM sodium pyruvate, 1x non-essential amino acids (Gibco #11140-035) without selection antibiotics and frozen in 90% culture medium/ 10% DMSO.
  • frozen cells were thawed, resuspended in fresh culture medium supplemented with 2 ⁇ g/ml poly-D-lysine (Sigma P6407) and seeded into black 384- well microtiter plates with clear bottom (Greiner #781092) at a density of 6000-8000 cells/well in 30 ⁇ I/well.
  • the seeded plates were incubated overnight at 37°C, 5% CO2. Prior to the measurement, culture medium was removed and cells were incubated for 30 min at 37°C in 30 ⁇ I/well tyrode buffer (2mM CaCI2, 130 mM NaCI, 5 mM KCI, 20 mM HEPES, 1 mM MgCI2, 5 mM NaHCO3, pH 7.4, 0.01% BSA and 200 ⁇ g/ml brilliant black) supplemented with Fluo-8 AM calcium dye for cells without GCaMP6.
  • 30 ⁇ I/well tyrode buffer 2mM CaCI2, 130 mM NaCI, 5 mM KCI, 20 mM HEPES, 1 mM MgCI2, 5 mM NaHCO3, pH 7.4, 0.01% BSA and 200 ⁇ g/ml brilliant black
  • Half-log serial dilutions of the test compounds were prepared in DMSO starting at a concentration of 10 mM. Before the measurement, the compounds were further diluted 100-fold in tyrode buffer and added to the cells (10 ⁇ l/well) resulting in final concentrations between 25 ⁇ M and 0.8 nM. The plates were incubated with compounds for 10 min at room temperature.
  • DRG were isolated from ⁇ 6 week old female Sprague Dawiey rats and treated with 400 ⁇ I of 10 mM HEPES containing dipase 0.5 mg/ml, collagenase 2.5 mg/ml, and 6 mg/ml BSA.
  • the ganglion were triturated, passed through a 50 pm filter and plated at a density of 5000 cells/well in a 96 well plates.
  • DRG cells were cultured for 72 h prior to running the assay.
  • DRG neurons were pretreated with the compound for 20 min prior to the addition of supercinnamaldehyde (SCMA, TRPA1-receptor agonist).
  • SCMA supercinnamaldehyde
  • CGRP ELISA kit Berlin bioreagents #A05482
  • the ELISA plates were prepared according to the manufacturer's instructions, 100 ⁇ I of the collected supernatant added and the plates incubated at 4 °C overnight. The plates were then washed, 200 mI of Ellman's reagent added and the absorbance measured at 414 nm using a Safire plate reader (Tecan), CGRP content was converted to pg/ml using a standard curve
  • TRPA1 has been shown to be co-localized with CGRP in a subset of sensory neurons, and its activation leads to CGRP release from central and peripheral nerve endings.
  • SCMA (3 ⁇ M) stimulated CGRP release from rat DRG neurons, and the effect was inhibited by preincubation with the compound (Table 3).
  • Example 16 was tested in the model of intraplantar cinnamaldehyde (CA)-induced nocifensive pain behaviors in male Sprague Dawley rats. Briefly, 50 ⁇ I of CA at 5 mM was injected at the plantar surface of one hind paw. Immediately after injection, the number and the duration of nocifensive behaviors (including licking or flinching) were quantitated by a blinded experimenter during 5 minutes.
  • Example 16 or vehicle (10% DMSO, 40% Solutol, 50% water for injection, vol/vol) were dosed via oral route (p.o.) 1 hour before CA injection.
  • Data were expressed as the mean number of flinches, the mean duration of licking behaviors and the mean duration of nocifensive behaviors for each treatment group. Data were analysed by performing a one way ANOVA. Planned comparison of means (each versus vehicle) was performed by using a Dunnett's post hoc test, provided that a main effect was detected. For p values less than 0.05, the results were deemed to be statistically significant.
  • Table 5 Average plasma levels of example 16 as test compound 75 minutes after treatment
  • Intraplantar CFA in the rat induced acute inflammatory pain characterized by a robust reduction of PWT 24 hours after injection.
  • Oral administration of example 16 24 hours after intraplantar CFA, prevented the development of inflammatory pain after the injection of CFA.
  • significant reduction of inflammatory pain was observed 2 hours post-dose after 10 and 30 mg/kg, and 4 hours post-dose after 30 mg/kg (see Table 6).
  • Table 6 Rat CFA in vivo model data for example 16 as test compound

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Abstract

La présente invention concerne des composés de formule générale (I) tels que décrits et définis dans la description, des procédés de préparation desdits composés, des composés intermédiaires utiles pour la préparation desdits composés, des compositions pharmaceutiques comprenant lesdits composés, et l'utilisation desdits composés pour la fabrication de compositions pharmaceutiques destinées au traitement ou à la prophylaxie de maladies. Les composés de formule générale (I), tels que décrits et définis dans la description, trouvent leur utilisation dans l'inhibition du récepteur de l'ankyrine 1 à potentiel de récepteur transitoire (TRPA1). En particulier, l'invention concerne l'utilisation de tels composés pour la fabrication d'une composition pharmaceutique destinée au traitement ou à la prophylaxie d'une maladie, en particulier chez les mammifères, tels que, mais sans s'y limiter, des maladies associées à la douleur et à l'inflammation, ou pour le traitement ou la prophylaxie de maladies, affections et troubles liés/associés à la douleur et des syndromes de la douleur, les maladies gynécologiques, les troubles et les maladies du tractus urinaire, le cancer et la douleur liée au cancer, les troubles neurologiques, les troubles respiratoires, les troubles gastro-intestinaux, les troubles métaboliques, les troubles neurodégénératifs, les troubles cutanés, les troubles cardiovasculaires et les maladies inflammatoires.
PCT/EP2021/062583 2020-05-19 2021-05-12 Antagonistes de trpa1 pour le traitement de maladies associées à la douleur et à l'inflammation WO2021233752A1 (fr)

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