Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
  • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
  • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
  • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
  • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/06—Antimigraine agents
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
  • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
  • C07D491/04—Ortho-condensed systems

Definitions

• the present invention relates to chroman compounds and related derivatives that have TRPM8 antagonist properties and are useful in preparing medicaments and compositions and in treating diseases and conditions such as those mediated by TRPM8.
• the compounds and compositions may be used to treat various diseases or conditions modulated by TRPM8 such as, but not limited to, migraines and neuropathic pain.
• Cold sensation is derived from activation of the somatosensory system by a cold stimulus.
• Calcium imaging and patch clamp experiments in dissociated trigeminal and dorsal root ganglia neurons have revealed cold stimuli induced calcium influx, suggesting the direct opening of a calcium-permeable ion channels by cold (Thut et al, 2003; Reid, 2005).
• TRPM8 transient receptor potential melastatin 8
• trp-p8 trp-p8
• TRPM8 is highly expressed in sensory neurons of the trigeminal and dorsal root ganglia (McKemy et al, 2002; Peier et al, 2002; Thut et al, 2003). TRPM8 is also expressed in nerve fibers innervating urinary bladder in guinea pigs (Tsukimi et al., 2005) and humans (Mukerji et al., 2006) and believed to contribute to the bladder hypersensitivity. Activation mechanism of TRPM8 by menthol and icilin appears to differ. Icilin requires calcium for robust activation of TRPM8, whereas menthol and cold do not (Chuang et al., 2004).
• TRPM8 is shown to mediate the analgesia by agonists such as menthol and icilin (by desensitization of the receptor) during experimental neuropathic pain in rodents (Proudfoot et al., 2006). Further, attenuation of cold sensation and cold allodynia after chronic constriction injury model of neuropathic pain in TRPM8 knockout mice (Colburn et al., 2007; Dhaka et al, 2007) suggests that antagonists of TRPM8 may be considered as pain therapeutics for chemotherapy-induced pain, neuropathic pain and bladder disorders.
• Mint oil that contains menthol an agonist of TRPM8 has been reported to alleviate pain in post-herpetic neuralgia (Davies et al., 2002), a neuropathic pain condition. Furthermore, oral or intracerebro ventricular injection of menthol decreased nociceptive responses to hot-plate test and acetic acid-induced writhing in mice (Galeotti et al., 2002). These responses are believed to be mediated by the activation and desensitization of the TRPM8. These observations and the knockout mice studies indicate that TRPM8 modulation by antagonists might be beneficial for patients experiencing neuropathic pain.
• TRPM8 antagonist compounds that can be used to treat diseases and conditions mediated by TRPM8 such as, but not limited to, migraines and neuropathic pain and those other conditions described herein.
• the present invention comprises a new class of compounds useful in the treatment of diseases, such as TRPM8-mediated diseases and other maladies, such as inflammatory or neuropathic pain and diseases involving sensory nerve function such as asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis.
• the compounds of the invention are useful for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non- vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, anxiety, depression, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions
• the invention also comprises pharmaceutical compositions comprising the compounds, methods for the treatment of TRPM8-receptor- mediated diseases, such as inflammatory or neuropathic pain, asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis diseases, using the compounds and compositions of the invention, and intermediates and processes useful for the preparation of the compounds of the invention.
• TRPM8-receptor- mediated diseases such as inflammatory or neuropathic pain, asthma, rheumatoid arthritis, osteoarthritis, inflammatory bowel disorders, urinary incontinence, migraine and psoriasis diseases
• the invention provides compounds of Formula I or a pharmaceutically-acceptable salt thereof, a tautomer thereof, a pharmaceutically-acceptable salt of the tautomer, a stereoisomer thereof, or a mixture thereof.
• Compounds of Formula I have the following structure
• W is absent or is selected from -NH-, -NR la -, or O;
• X 1 is selected from -CR 5 - or -N-;
• X 2 is selected from -CR 5 - or -N-;
• X 3 is selected from -CR 5 - or -N-;
• X 4 is selected from -CR 5 - or -N-;
• Z 1 is selected from -CR 6 - or -N-;
• Z 2 is selected from -CR 6 - or -N-;
• Z 3 is selected from -CR 6 - or -N-;
• n 0, 1, or 2;
• R 6 is, at each instance, independently selected from H, halo, OR a , Ci_ 6 alk, or CF 3 ;
• R 7 and R 8 are independently selected from H or Ci_ 6 alk, or R 7 and R 8 , together with the carbon atom to which they are attached, join to form a 3 to 7 membered cycloalkyl ring or a 3-7 membered heterocyclyl ring that includes 1 or 2 heteroatoms selected from O, N, or S;
• R 9 and R 10 are, at each instance, independently selected from H or Ci_ 6 alk;
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk, -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk.
• the compound is not one of the following compounds and is not a salt of one of the following compounds:
• the invention provides compounds of Formula I or a pharmaceutically-acceptable salt thereof, a tautomer thereof, a
• W is absent or is selected from -NH-, -NR la -, or O;
• X 1 is selected from -CR 5 - or -N-;
• X 2 is selected from -CR 5 - or -N-;
• X 3 is selected from -CR 5 - or -N-;
• X 4 is selected from -CR 5 - or -N-;
• Z 1 is selected from -CR 6 - or -N-;
• Z 2 is selected from -CR 6 - or -N-;
• Z 3 is selected from -CR 6 - or -N-;
• R 5 is, at each instance, independently selected from H, Ci.galk, Ci.galkOH,
• R 6 is, at each instance, independently selected from H, halo, OR a , Ci_ 6 alk, or CF 3 ;
• R 7 and R 8 are independently selected from H or Ci_ 6 alk, or R 7 and R 8 , together with the carbon atom to which they are attached, join to form a 3 to 7 membered cycloalkyl ring or a 3-7 membered heterocyclyl ring that includes 1 or 2 heteroatoms selected from O, N, or S;
• R 9 and R 10 are, at each instance, independently selected from H or Ci_ 6 alk;
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, and when R 3 is R b , R b may additionally be an unsaturated 5 or 6-membered monocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, the phenyl, benzyl Ci_ 6 alk, and unsaturated 5 or 6-membered monocyclic ring being substituted by 0, 1, 2 or 3 substituents selected from halo, cyano, oxo, Ci_ 4 alk, Ci_ 4 alkOH,
• the compound is not one of the following compounds and is not a salt of one of the following compounds:
• Y is selected from -0-, -CH 2 -, -NH-, or -NR lb -. In still further such embodiments, Y is selected from -O- or -CH 2 -.
• the compound of Formula I has the Formula II:
• Y is selected from -O- or -CH
• the compound of Formula II has the Formula IIA:
• the compound of Formula I has the Formula III
• the compound of Formula III has the Formula IIIA, IIIB, IIIC, or HID
• the compound of Formula IV has the Formula IV A, IVB, IVC, or IV
• the invention provides pharmaceutical compositions that include the compound of any of the embodiments or the
• the invention provides methods of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, depression, anxiety, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions induced by nec
• Such methods typically include administering the compound according to any of the embodiments or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof to the subject.
• the subject is suffering from neuropathic pain whereas in other embodiments the subject is suffering from migraines or migraine pain.
• the compounds of the invention may also be used to prepare
• the invention provides the use of the compound according to any of the embodiments or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof in the preparation of a medicament.
• the invention provides the use of the compound according to any of the embodiments or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, or the mixture thereof for treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, depression, anxiety, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds,
• the compounds of this invention may have in general several asymmetric centers and are typically depicted in the form of racemic mixtures. This invention is intended to encompass racemic mixtures, partially racemic mixtures and separate enantiomers and diastereomers.
• Ci_ 6 alkyl means an alkyl group comprising a minimum of a and a maximum of ⁇ carbon atoms in a branched, cyclical or linear relationship or any combination of the three, wherein a and ⁇ represent integers.
• the alkyl groups described in this section may also contain one or two double or triple bonds.
• a designation of Coalk indicates a direct bond. Examples of Ci_ 6 alkyl include, but are not limited to the following:
• C a ⁇ alkyl and “C a ⁇ cycloalkyl” relate to acyclic saturated alkyls and cyclic saturated alkyls, respectively.
• cyano refers to a nitrile group which may be written as -C ⁇ N.
• Halo or "halogen” means a halogen atoms selected from F, CI, Br and I.
• Cv-whaloalk means an alk group, as described above, wherein any number, but at least one, of the hydrogen atoms attached to the alk chain are replaced by F, CI, Br or I.
• the group N(R a )R a and the like include substituents where the two R a groups together form a ring, optionally including a N, O or S atom, and include roups such as:
• N(C a -palk)C a -palk wherein a and ⁇ are as defined above, include substituents where the two C a ⁇ alk groups together form a ring, optionally including a N, O or S atom, and include groups such as:
• Heterocycle means a ring comprising at least one carbon atom and at least one other atom selected from N, O and S. Examples of heterocycles that may be found in the claims include, but are not limited to, the following:
• “Pharmaceutically-acceptable salt” means a salt prepared by conventional means, and are well known by those skilled in the art.
• the “pharmacologically acceptable salts” include basic salts of inorganic and organic acids, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaric acid, citric acid, lactic acid, fumaric acid, succinic acid, maleic acid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid and the like.
• suitable pharmaceutically acceptable cation pairs for the carboxy group are well known to those skilled in the art and include alkaline, alkaline earth, ammonium, quaternary ammonium cations and the like.
• pharmaceutically acceptable salts see infra and Berge et al., J. Pharm. Sci. 66: 1 (1977).
• saturated, partially-saturated or unsaturated includes substituents saturated with hydrogens, substituents completely unsaturated with hydrogens and substituents partially saturated with hydrogens.
• saturated 6-member ring systems include, but are not limited to, cyclohexane, morpholine, piperidine, piperazine, and the like; partially-saturated 6-member ring systems include, but are not limited to, cyclohexene, cyclohexa-l,3-diene, 1,2,3,6-tetrahydropyridine, 1,2,3,6- tetrahydropyrazine, 3,6-dihydro-2H-pyran, and the like; and unsaturated 6- member ring systems include, but are not limited to, benzene, pyridine, and the like.
• Saturated, partially-saturated or unsaturated ring systems may be of various types.
• such ring systems may include various numbers of ring members and may be monocyclic or bicyclic.
• such ring systems may be 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 7-, 8-, 9-, 10- or 11-membered bicyclic rings.
• such ring systems may include various numbers of ring members and may be monocyclic or bicyclic.
• such ring systems may be 3-, 4-, 5-, 6- or 7-membered monocyclic rings or 7-, 8-, 9-, 10- or 11-membered bicyclic rings.
• monocyclic and bicyclic rings may containing 0, 1, 2, 3 or 4 heteroatoms selected from N, O and S. In some further such embodiments such rings may contain no more than one O or S atom.
• leaving group generally refers to groups readily displaceable by a nucleophile, such as an amine, a thiol or an alcohol nucleophile. Such leaving groups are well known in the art. Examples of such leaving groups include, but are not limited to, N-hydroxysuccinimide, N-hydroxybenzotriazole, halides, triflates, tosylates and the like. Preferred leaving groups are indicated herein where appropriate.
• Protecting group generally refers to groups well known in the art which are used to prevent selected reactive groups, such as carboxy, amino, hydroxy, mercapto and the like, from undergoing undesired reactions, such as nucleophihc, electrophilic, oxidation, reduction and the like. Preferred protecting groups are indicated herein where appropriate. Examples of amino protecting groups include, but are not limited to, aralkyl, substituted aralkyl, cycloalkenylalkyl and substituted cycloalkenyl alkyl, allyl, substituted allyl, acyl, alkoxycarbonyl, aralkoxycarbonyl, silyl and the like.
• aralkyl examples include, but are not limited to, benzyl, ortho- methylbenzyl, trityl and benzhydryl, which can be optionally substituted with halogen, alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts, such as phosphonium and ammonium salts.
• aryl groups include phenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl), phenanthrenyl, durenyl and the like.
• cycloalkenylalkyl or substituted cycloalkylenylalkyl radicals preferably have 6-10 carbon atoms, include, but are not limited to, cyclohexenyl methyl and the like.
• Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups include benzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl, substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl, phthaloyl and the like.
• a mixture of protecting groups can be used to protect the same amino group, such as a primary amino group can be protected by both an aralkyl group and an aralkoxycarbonyl group.
• Amino protecting groups can also form a heterocyclic ring with the nitrogen to which they are attached, for example,
• heterocyclic groups can further include adjoining aryl and cycloalkyl rings.
• heterocyclic groups can be mono-, di- or tri-substituted, such as nitrophthalimidyl.
• Amino groups may also be protected against undesired reactions, such as oxidation, through the formation of an addition salt, such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
• an addition salt such as hydrochloride, toluenesulfonic acid, trifluoroacetic acid and the like.
• Many of the amino protecting groups are also suitable for protecting carboxy, hydroxy and mercapto groups.
• Alkyl groups are also suitable groups for protecting hydroxy and mercapto groups, such as tert-butyl.
• Silyl protecting groups are silicon atoms optionally substituted by one or more alkyl, aryl and aralkyl groups. Suitable silyl protecting groups include, but are not limited to, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert- butyldimethylsilyl, dimethylphenylsilyl, 1 ,2-bis(dimethylsilyl)benzene,
• silylation of an amino groups provide mono- or di-silylamino groups.
• Silylation of aminoalcohol compounds can lead to a ⁇ , ⁇ , ⁇ -trisilyl derivative.
• Removal of the silyl function from a silyl ether function is readily accomplished by treatment with, for example, a metal hydroxide or ammonium fluoride reagent, either as a discrete reaction step or in situ during a reaction with the alcohol group.
• Suitable silylating agents are, for example, trimethylsilyl chloride, tert-butyl-dimethylsilyl chloride,
• phenyldimethylsilyl chloride diphenylmethyl silyl chloride or their combination products with imidazole or DMF.
• Methods for silylation of amines and removal of silyl protecting groups are well known to those skilled in the art.
• Methods of preparation of these amine derivatives from corresponding amino acids, amino acid amides or amino acid esters are also well known to those skilled in the art of organic chemistry including amino acid/amino acid ester or aminoalcohol chemistry.
• Protecting groups are removed under conditions which will not affect the remaining portion of the molecule. These methods are well known in the art and include acid hydrolysis, hydrogenolysis and the like.
• a preferred method involves removal of a protecting group, such as removal of a benzyloxycarbonyl group by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof.
• a t- butoxycarbonyl protecting group can be removed utilizing an inorganic or organic acid, such as HC1 or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride.
• the resulting amino salt can readily be neutralized to yield the free amine.
• Carboxy protecting group such as methyl, ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can be removed under hydrolysis and hydrogenolysis conditions well known to those skilled in the art.
• Various compounds of the invention contain one or more chiral centers, and can exist as racemic mixtures of enantiomers, mixtures of diastereomers or enantiomerically or optically pure compounds.
• This invention encompasses the use of stereomerically pure forms of such compounds, as well as the use of mixtures of those forms.
• mixtures comprising equal or unequal amounts of the enantiomers of a particular compound of the invention may be used in methods and compositions of the invention.
• These isomers may be asymmetrically synthesized or resolved using standard techniques such as chiral columns or chiral resolving agents.
• Prodrugs of the compounds of this invention are also contemplated by this invention.
• a prodrug is an active or inactive compound that is modified chemically through in vivo physiological action, such as hydrolysis, metabolism and the like, into a compound of this invention following administration of the prodrug to a patient.
• the suitability and techniques involved in making and using prodrugs are well known by those skilled in the art.
• For a general discussion of prodrugs involving esters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) and Bundgaard Design of Prodrugs, Elsevier (1985).
• Examples of a masked carboxylate anion include a variety of esters, such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
• esters such as alkyl (for example, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl (for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (for example, pivaloyloxymethyl).
• Amines have been masked as arylcarbonyloxymethyl substituted derivatives which are cleaved by esterases in vivo releasing the free drug and formaldehyde (Bungaard J. Med. Chem. 2503 (1989
• drugs containing an acidic NH group such as imidazole, imide, indole and the like, have been masked with N- acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).
• the compounds of the invention may also contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute such compounds.
• the compounds may be radiolabeled with radioactive isotopes, such as for example tritium ( 3 H), iodine-125 ( 125 I) or carbon-14 ( 14 C).
• Radiolabeled compounds are useful as therapeutic or prophylactic agents, research reagents, e.g., GPR40 assay reagents, and diagnostic agents, e.g., in vivo imaging agents. All isotopic variations of the compounds of the invention, whether radioactive or not, are intended to be encompassed within the scope of the invention. For example, if a variable is said to be H, this means that variable may also be deuterium (D) or tritium (T).
• treat are meant to include alleviating or abrogating a condition or disease and/or its attendant symptoms. In some instances treating may also involve prevention of symptoms.
• prevent refers to a method of delaying or precluding the onset of a condition or disease and/or its attendant symptoms, barring a subject from acquiring a condition or disease, or reducing a subject's risk of acquiring a condition or disease.
• terapéuticaally effective amount refers to that amount of the compound that will elicit the biological or medical response of a tissue, system, or subject that is being sought.
• therapeutically effective amount includes that amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the condition or disorder being treated in a subject.
• the therapeutically effective amount in a subject will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject to be treated.
• a therapeutically effective amount of a compound or a salt thereof is administered to subjects in various method regimens.
• a therapeutically effective amount of a compound is administered to a subject prior to the onset of a migraine or at the first indication that a migraine may be about to occur or occurring.
• subject is defined herein to include animals such as mammals, including, but not limited to, primates (e.g., humans), cows, sheep, goats, horses, dogs, cats, rabbits, rats, mice and the like. In preferred embodiments, the subject is a human.
• “Pharmaceutically-acceptable salt” refers to a salt of a compound that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound.
• Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, salicylic acid, benzoic acid, 3-(4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic
• compositions are said to comprise A, B, and C, then A, B, and C are in the composition, but D, E, and/or F may be in the composition as well.
• Another aspect of the invention relates to a method of treating acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, depression, anxiety, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders, gastric ulceration, duodenal ulcers, diarrhea, gastric lesions
• Another aspect of the invention relates to the use of a compound according to any of the above embodiments as a medicament.
• Another aspect of the invention relates to the use of a compound according to any of the above embodiments in the manufacture of a medicament for the treatment of acute, inflammatory and neuropathic pain, dental pain, general headache, migraine, cluster headache, mixed-vascular and non-vascular syndromes, tension headache, general inflammation, arthritis, rheumatic diseases, osteoarthritis, inflammatory bowel disorders, anxiety, depression, inflammatory eye disorders, inflammatory or unstable bladder disorders, psoriasis, skin complaints with inflammatory components, chronic inflammatory conditions, inflammatory pain and associated hyperalgesia and allodynia, neuropathic pain and associated hyperalgesia and allodynia, diabetic neuropathy pain, causalgia, sympathetically maintained pain, deafferentation syndromes, asthma, epithelial tissue damage or dysfunction, herpes simplex, disturbances of visceral motility at respiratory, genitourinary, gastrointestinal or vascular regions, wounds, burns, allergic skin reactions, pruritus, vitiligo, general gastrointestinal disorders
• the invention provides a compound of Formula I having the following structure:
• W is absent or is selected from -NH-, -NR la -, or O;
• X 1 is selected from -CR 5 - or -N-;
• X 2 is selected from -CR 5 - or -N-;
• X 3 is selected from -CR 5 - or -N-;
• X 4 is selected from -CR 5 - or -N-;
• Z 1 is selected from -CR 6 - or -N-;
• Z 2 is selected from -CR 6 - or -N-;
• Z 3 is selected from -CR 6 - or -N-;
• n 0, 1, or 2;
• R 6 is, at each instance, independently selected from H, halo, OR a , Ci_ 6 alk, or CF 3 ;
• R 7 and R 8 are independently selected from H or Ci_ 6 alk, or R 7 and R 8 , together with the carbon atom to which they are attached, join to form a 3 to 7 membered cycloalkyl ring or a 3-7 membered heterocyclyl ring that includes 1 or 2 heteroatoms selected from O, N, or S;
• R 9 and R 10 are, at each instance, independently selected from H or Ci_ 6 alk;
• R a is independently, at each instance, H or R b ;
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, the phenyl, benzyl and Ci_ 6 alk being substituted by 0, 1, 2 or 3 substituents selected from halo, oxo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk, -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk;
• the compound is not one of the following compounds, is not a salt thereof, is not a tautomer thereof, is not a salt of a tautomer, is not a stereoisomer thereof, and is not a salt of a stereoisomer:
• Y is selected from -0-, -CH 2 -, -NH-, or -NR -. In still further such embodiments, Y is selected from -O- or -CH 2 -.
• R 5 is H; 0 of Z 1 , Z 2 , and Z 3 are N; W is absent; and R 4 is -F.
• R 3 is -CF 3 whereas in other such embodiments, R 3 is -OCF 3 .
• R 6 is H.
• Y is selected from -O- or -CH 2 -. 16.
• the compounds has the Formula ⁇
• the compound of Formula IV has the Formula IV
• R 3 is selected from H, Ci_ 8 alk, Ci_ 8 alkOH, Ci_ 4 haloalk, halo, or -OR a .
• R 3 is selected from -H, -CH 3 , -F, -CI, -CF 3 , or -OCF 3 .
• R 3 is R b and R b is a phenyl substituted by 0, 1, 2 or 3 substituents selected from halo, Ci_ 4 alk, Ci_ 3 haloalk, -OCi_ 4 alk, -OH, -NH 2 , -OCi_ 4 alk, -OCi_ 4 haloalk, -NHCi_ 4 alk, and -N(Ci_ 4 alk)Ci_ 4 alk.
• R 4 is selected from F, CI, Ci_ 6 alk, -OCi- 6 alk,
• R 5 is selected from Ci_8alk, halo, or -OR a .
• R 5 is selected from -CH 3 , -CI, -F, or -OMe.
• R 1 is the saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring and the monocyclic or bicyclic ring is substituted by 0, 1 , 2, or 3 substituents, wherein the substituents are selected from F, CI, Br, I, oxo, cyano, -CH 3 ,
• R 1 is a phenyl, pyridyl, pyridinonyl, piperidinonyl, pyridazinonyl, pyrazinonyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetradyrofuranyl, tetrahydropyranyl, thiazolyl, isothiazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, triazolyl, oxazolyl, imidazolyl, pyrrolidinonyl, piperidinyl, cyclohexyl, cyclohexanonyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, benzo
• dihydropyrazolooxazinyl indolinonyl, isoindolinonyl, benzooxazolonyl, oxazolopyridinonyl, benzoimidazolonyl, isoindolindionyl, tetrahydroquinolinyl, dihydroquinolinonyl, benzooxazinonyl, dihydrobenzooxazinonyl,
• R 1 is a phenyl, pyridyl, pyridinonyl, pyrazinonyl, pyridazinyl, pyrimidinyl, tetrahydropyranyl, thiazolyl, isothiazolyl, imidazolyl, piperidinyl, quinolinyl, isoquinolinyl, indazolyl, indolinonyl, isoindolinonyl, benzooxazolonyl, dihydroquinolinonyl, imidazopyridinyl, quinolinonyl, indolyl substituted by 0, 1, 2, or 3 substituents.
• the pharmaceutically-acceptable salt thereof the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, the stereoisomer thereof, or the mixture thereof.
• the pharmaceutically-acceptable salt thereof the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, the stereoisomer thereof, or the mixture thereof.
• a pharmaceutical composition comprising the compound according to any one of embodiments 1-97 or the pharmaceutically-acceptable salt thereof, the tautomer thereof, the pharmaceutically-acceptable salt of the tautomer, the stereoisomer thereof, or the mixture thereof, and a pharmaceutically-acceptable diluent or carrier.
• the invention provides a compound of Formula I having the following structure:
• W is absent or is selected from -NH-, -NR la -, or O;
• X 1 is selected from -CR 5 - or -N-;
• X 2 is selected from -CR 5 - or -N-;
• X 3 is selected from -CR 5 - or -N-;
• X 4 is selected from -CR 5 - or -N-;
• Z 1 is selected from -CR 6 - or -N-;
• Z 2 is selected from -CR 6 - or -N-;
• Z 3 is selected from -CR 6 - or -N-;
• n 0, 1, or 2;
• R 6 is, at each instance, independently selected from H, halo, OR a , Ci_ 6 alk, or CF 3 ;
• R 7 and R 8 are independently selected from H or Ci_ 6 alk, or R 7 and R 8 , together with the carbon atom to which they are attached, join to form a 3 to 7 membered cycloalkyl ring or a 3-7 membered heterocyclyl ring that includes 1 or 2 heteroatoms selected from O, N, or S;
• R 9 and R 10 are, at each instance, independently selected from H or Ci_ 6 alk; R a is independently, at each instance, H or R b ; and
• R b is independently, at each instance, phenyl, benzyl or Ci_ 6 alk, and when
• R 3 is R b
• R b may additionally be an unsaturated 5 or 6-membered monocyclic ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, the phenyl, benzyl Ci_ 6 alk, and unsaturated 5 or 6-membered monocyclic ring being substituted by 0, 1, 2 or 3 substituents selected from halo, cyano, oxo, Ci_ 4 alk, Ci_ 4 alkOH,
• the compound is not one of the following compounds, is not a salt thereof, is not a tautomer thereof, is not a salt of a tautomer, is not a stereoisomer thereof, and is not a salt of a stereoisomer:
• Y is selected from -0-, -CH 2 -, -NH-, or -NR -. In still further such embodiments, Y is selected from -O- or -CH 2 -.
• R 5 is H; 0 of Z 1 , Z 2 , and Z 3 are N; W is absent; and R 4 is -F.
• R 3 is -CF 3 whereas in other such embodiments, R 3 is -OCF 3 .
• R 6 is H.
• Y is selected from -O- or -CH 2 -.
• the compound has the Formula ⁇
• the compound has the Formula IIIA'. 153.
• the compound has the Formula IIIB'.
• the compound has the Formula IIIC ' .
• the compound has the Formula HID'.
• the compound has the Formula IV.
• the compound has the Formula IVA'.
• the compound has the Formula IVB'.
• the compound has the Formula IVC
• the compound has the Formula IVD'.
• R 3 is selected from H, Ci_ 8 alk, Ci_ 8 alkOH, Ci_ 4 haloalk, halo, or -OR a .
• R 3 is selected from -H, -CH 3 , -F, -CI, -CF 3 , or -OCF 3 .
• R 3 is selected from -CH 3 , -F, -CI, -CF 3 , or -OCF 3 .
• R 3 is selected from -CF 3 or -OCF 3 .
• R 3 is R b and R b is a pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl, or furanyl substituted by 0.
• R 4 is selected from F, CI, Ci_ 6 alk, -OCi- 6 alk,
• R 4 is selected from -F, -CI, or -OCF3.
• R 5 is selected from Ci_ 8 alk, halo, or -OR a .
• R 1 is the saturated, partially-saturated or unsaturated 3-, 4-, 5-, 6- or 7-membered monocyclic or 7-, 8-, 9-, 10- or 11-membered bicyclic ring and the monocyclic or bicyclic ring is substituted by 0, 1, 2, or 3 substituents, wherein the substituents are selected from F, CI, Br, I, oxo, cyano, -CH 3 ,
• R 1 is a phenyl, pyridyl, pyridinonyl, piperidinonyl, pyridazinonyl, pyrazinonyl, pyridazinyl, pyrimidinyl, pyrazinyl, tetradyrofuranyl, tetrahydropyranyl, thiazolyl, isothiazolyl, furanyl, thiophenyl, pyrazolyl, isoxazolyl, triazolyl, oxazolyl, imidazolyl, pyrrolidinonyl, piperidinyl, cyclohexyl, cyclohexanonyl, quinolinyl, isoquinolinyl, naphthyridinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, benzo
• dihydropyrazolooxazinyl indolinonyl, isoindolinonyl, benzooxazolonyl, oxazolopyridinonyl, benzoimidazolonyl, isoindolindionyl, tetrahydroquinolinyl, dihydroquinolinonyl, benzooxazinonyl, dihydrobenzooxazinonyl,
• R 1 is a phenyl, pyridyl, pyridinonyl, pyrazinonyl, pyridazinyl, pyrimidinyl, tetrahydropyranyl, thiazolyl, isothiazolyl, imidazolyl, piperidinyl, quinolinyl, isoquinolinyl, indazolyl, indolinonyl, isoindolinonyl, benzooxazolonyl, dihydroquinolinonyl, imidazopyridinyl, quinolinonyl, indolyl substituted by 0, 1, 2, or 3 substituents.

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