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  • A61K31/445—Non condensed piperidines, e.g. piperocaine
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  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
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  • C07D—HETEROCYCLIC COMPOUNDS
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  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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  • C07D—HETEROCYCLIC COMPOUNDS
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  • C07D409/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing three or more hetero rings
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  • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

• Cannabis sativa has been used for the treatment of pain for many years.
• ⁇ 9 - tetrahydrocannabinol is a major active ingredient from Cannabis sativa and an agonist of cannabinoid receptors (Pertwee, Brit J Pharmacol, 2008, 153, 199-215).
• Two cannabinoid G protein-coupled receptors have been cloned, cannabinoid receptor type 1 (CBi Matsuda et al, Nature, 1990, 346, 561-4) and cannabinoid receptor type 2 (CB 2 Munro et al, Nature, 1993, 365, 61-5).
• CBi is expressed centrally in brain areas, such as the hypothalamus and nucleus accumbens as well as peripherally in the liver, gastrointestinal tract, pancreas, adipose tissue, and skeletal muscle (Di Marzo et al, Curr Opin Lipidol, 2007, 18, 129- 140).
• CB 2 is predominantly expressed in immune cells, such as monocytes (Pacher et al., Amer J Physiol, 2008, 294, HI 133-Hl 134), and under certain conditions, also in the brain (Benito et al, Brit J Pharmacol, 2008, 153, 277-285) and in skeletal (Cavuoto et al, Biochem Biophys Res Commun, 2007, 364, 105-1 10) and cardiac (Hajrasouliha et al, Eur J Pharmacol, 2008, 579, 246-252) muscle.
• An abundance of pharmacological, anatomical and electrophysiological data, using synthetic agonists, indicate that increased cannabinoid signaling through
• CB 1 /CB 2 promotes analgesia in tests of acute nociception and suppresses hyperalgesia in models of chronic neuropathic and inflammatory pain (Cravatt et al, J Neurobiol, 2004, 61, 149-60; Guindon et al , Brit J Pharmacol, 2008, 153 , 319-334).
• AEA is hydrolyzed by fatty acid amide hydrolase (FAAH) and 2- AG is hydrolyzed by monoacylglycerol lipase (MGL) (Piomelli, Nat Rev Neurosci, 2003, 4, 873-884).
• FAAH fatty acid amide hydrolase
• MDL monoacylglycerol lipase
• endocannabinoid-mediated antinociceptive tone is demonstrated by the formation of AEA in the periaqueductal grey following noxious stimulation in the periphery (Walker et al, Proc Natl Acad Sci USA, 1999, 96, 12198-203) and, conversely, by the induction of hyperalgesia following antisense RNA-mediated inhibition of CBi in the spinal cord (Dogrul et al., Pain, 2002, 100, 203-9).
• MGL inhibitors are potentially useful for the treatment of pain, inflammation, and CNS disorders (Di Marzo et al, Curr Pharm Des, 2000, 6, 1361-80; Jhaveri et al, Brit J Pharmacol, 2007, 152, 624-632; McCarberg Bill et al, Amer J Ther, 2007, 14, 475- 83), as well as glaucoma and disease states arising from elevated intraocular pressure
• the present invention is directed to a compound of Formula (I)
• Y and Z are independently selected from Group a) or Group b) such that one of Y and Z is Group a) and the other is Group b);
• C6-10 aryl is unsubstituted or substituted with a substituent selected from the group consisting of fluoro, chloro, Ci-4alkyl, Ci-4alkoxy, cyano, and trifluoromethyl; or
• an unsubstituted heteroaryl selected from the group consisting of thiazolyl, isothiazolyl, and lH-pyrrolyl;
• Group b) other than phenylmethyl-phenyl is unsubstituted or substituted with one or two substitutents each of which is independently selected from the group consisting of bromo, chloro, fluoro, iodo, Ci_ 4 alkyl, Ci_ 4alkoxy, and 3 ⁇ 4; provided that no more than one substituent is 3 ⁇ 4; and
• R b is selected from the group consisting of trifluoromethyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, 4,4-difluorocyclohexyl, thienyl, pyridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl of 3 ⁇ 4 are unsubstituted or substituted with one or two substitutents each of which is independently selected from the group consisting of trifluoromethyl, methyl, chloro, cyano, and fluoro; R is hydrogen or hydroxy; and enantiomers, diastereomers, solvates and pharmaceutically acceptable salts thereof.
• the present invention also provides, inter alia, a pharmaceutical composition
• a pharmaceutical composition comprising, consisting of and/or consisting essentially of a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent, and a compound of Formula (I) or a pharmaceutically acceptable salt form thereof.
• a pharmaceutical composition comprising, consisting of, and/or consisting essentially of admixing a compound of Formula (I) or a pharmaceutically acceptable salt form thereof, and a pharmaceutically acceptable carrier, a pharmaceutically acceptable excipient, and/or a pharmaceutically acceptable diluent.
• the present invention further provides, inter alia, methods for treating or ameliorating a MGL-modulated disorder in a subject, including a human or other mammal in which the disease, syndrome, or condition is affected by the modulation of the MGL enzyme, such as pain and the diseases that lead to such pain, inflammation and CNS disorders, using a compound of Formula (I) or a pharmaceutically acceptable salt form thereof.
• a subject including a human or other mammal in which the disease, syndrome, or condition is affected by the modulation of the MGL enzyme, such as pain and the diseases that lead to such pain, inflammation and CNS disorders.
• the present invention also provides, inter alia, methods for producing the instant compounds and pharmaceutical compositions and medicaments thereof.
• alkyl refers to straight and branched carbon chains having 1 to 8 carbon atoms. Therefore, designated numbers of carbon atoms (e.g., C 1-8 ) refer independently to the number of carbon atoms in an alkyl moiety or to the alkyl portion of a larger alkyl-containing substituent.
• substituent groups with multiple alkyl groups such as, (Ci_ 6 alkyl) 2 amino-, the Ci- 6 alkyl groups of the dialkylamino may be the same or different.
• alkoxy refers to an -O-alkyl group, wherein the term “alkyl” is as defined above.
• alkenyl and alkynyl refer to straight and branched carbon chains having 2 to 8 carbon atoms, wherein an alkenyl chain contains at least one double bond and an alkynyl chain contains at least one triple bond.
• cycloalkyl refers to saturated or partially saturated, monocyclic or polycyclic hydrocarbon rings of 3 to 14 carbon atoms. Examples of such rings include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and adamantyl.
• benzo-fused cycloalkyl refers to a 5- to 8- membered monocyclic cycloalkyl ring fused to a benzene ring.
• the carbon atom ring members that form the cycloalkyl ring may be fully saturated or partially saturated.
• heterocyclyl refers to a nonaromatic monocyclic or bicyclic ring system having 3 to 10 ring members that include at least 1 carbon atom and from 1 to 4 heteroatoms independently selected from N, O, and S. Included within the term heterocyclyl is a nonaromatic cyclic ring of 5 to 7 members in which 1 to 2 members are N, or a nonaromatic cyclic ring of 5 to 7 members in which 0, 1 or 2 members are N and up to 2 members are O or S and at least one member must be either N, O, or S; wherein, optionally, the ring contains 0 to 1 unsaturated bonds, and, optionally, when the ring is of 6 or 7 members, it contains up to 2 unsaturated bonds.
• heterocyclyl also includes two 5 membered monocyclic heterocycloalkyl groups bridged to form a bicyclic ring. Such groups are not considered to be fully aromatic and are not referred to as heteroaryl groups.
• heterocycle is bicyclic, both rings of the heterocycle are non-aromatic and at least one of the rings contains a heteroatom ring member.
• heterocycle groups include, and are not limited to, pyrrolinyl (including 2H-pyrrole, 2-pyrrolinyl or 3-pyrrolinyl), pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl. Unless otherwise noted, the heterocycle is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
• benzo-fused heterocyclyl refers to a 5 to 7 membered monocyclic heterocycle ring fused to a benzene ring.
• the heterocycle ring contains carbon atoms and from 1 to 4 heteroatoms independently selected from N, O, and S.
• the carbon atom ring members that form the heterocycle ring may be fully saturated or partially saturated.
• benzo-fused heterocycle ring is attached to its pendant group at a carbon atom of the benzene ring.
• aryl refers to an unsaturated, aromatic monocyclic or bicyclic ring of 6 to 10 carbon members. Examples of aryl rings include phenyl and naphthalenyl.
• heteroaryl refers to an aromatic monocyclic or bicyclic aromatic ring system having 5 to 10 ring members and which contains carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O, and S.
• heteroaryl aromatic rings of 5 or 6 members wherein the ring consists of carbon atoms and has at least one heteroatom member. Suitable heteroatoms include nitrogen, oxygen, and sulfur. In the case of 5 membered rings, the heteroaryl ring preferably contains one member of nitrogen, oxygen or sulfur and, in addition, up to 3 additional nitrogens. In the case of 6 membered rings, the heteroaryl ring preferably contains from 1 to 3 nitrogen atoms. For the case wherein the 6 membered ring has 3 nitrogens, at most 2 nitrogen atoms are adjacent.
• heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl, isoindolyl, benzofuryl, benzothienyl, indazolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, benzis oxazolyl,
• heteroaryl is attached to its pendant group at any heteroatom or carbon atom that results in a stable structure.
• halogen refers to fluorine, chlorine, bromine and iodine atoms.
• alkyl or aryl or either of their prefix roots appear in a name of a substituent (e.g., arylalkyl, alkylamino) the name is to be interpreted as including those limitations given above for "alkyl” and "aryl.”
• Designated numbers of carbon atoms e.g., Ci-Ce
• the designated number of carbon atoms includes all of the independent members included within a given range specified.
• C e alkyl would include methyl, ethyl, propyl, butyl, pentyl and hexyl individually as well as sub-combinations thereof (e.g., C 1-2 , Ci_
• a "Ci-Ce alkylcarbonyl" substituent refers to a group of the formula:
• R at a stereocenter designates that the stereocenter is purely of the R-configuration as defined in the art; likewise, the term “S” means that the stereocenter is purely of the ⁇ -configuration.
• S means that the stereocenter is purely of the ⁇ -configuration.
• the terms “*R” or “*S” at a stereocenter are used to designate that the stereocenter is of pure but unknown configuration.
• RS refers to a stereocenter that exists as a mixture of the R- and ⁇ -configurations.
• *RS or “*SR” refer to a stereocenter that exists as a mixture of the R- and ⁇ -configurations and is of unknown configuration relative to another stereocenter within the molecule.
• Unlabeled stereocenters drawn without stereo bond designations are a mixture of the R- and ⁇ -configurations.
• the absolute stereochemistry is as depicted.
• subject refers to an animal, preferably a mammal, most preferably a human, who has been the object of treatment, observation or experiment.
• terapéuticaally effective amount refers to an amount of an active compound or pharmaceutical agent, including a compound of the present invention, which elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation or partial alleviation of the symptoms of the disease, syndrome, condition, or disorder being treated.
• composition refers to a product that includes the specified ingredients in therapeutically effective amounts, as well as any product that results, directly, or indirectly, from combinations of the specified ingredients in the specified amounts.
• MGL inhibitor is intended to encompass a compound that interacts with MGL to substantially reduce or eliminate its catalytic activity, thereby increasing the concentrations of its substrate(s).
• MGL-modulated is used to refer to the condition of being affected by the modulation of the MGL enzyme including the condition of being affected by the inhibition of the MGL enzyme such as pain, and the diseases that lead to such pain, inflammation and CNS disorders.
• the term "affect" or “affected” when referring to a disease, syndrome, condition or disorder that is affected by inhibition of MGL) includes a reduction in the frequency and / or severity of one or more symptoms or manifestations of said disease, syndrome, condition or disorder; and / or include the prevention of the development of one or more symptoms or manifestations of said disease, syndrome, condition or disorder or the development of the disease, condition, syndrome or disorder.
• the compounds of Formula (I) are useful in methods for treating, ameliorating and / or preventing a disease, a syndrome, a condition or a disorder that is affected by the inhibition of MGL.
• Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment, amelioration and / or prevention, a therapeutically effective amount of a compound of Formula (I), or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.
• the compounds of Formula (I), or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof are useful for treating, ameliorating and / or preventing pain; diseases, syndromes, conditions, or disorders causing such pain; inflammation and / or CNS disorders. More particularly, the compounds of Formula (I), or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof are useful for treating, ameliorating and / or preventing inflammatory pain, inflammatory hypersensitivity conditions and / or neuropathic pain, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or an enantiomer, diastereomer, solvate or
• inflammatory pain examples include pain due to a disease, condition, syndrome, disorder, or a pain state including inflammatory bowel disease, visceral pain, migraine, post operative pain, osteoarthritis, rheumatoid arthritis, back pain, lower back pain, joint pain, abdominal pain, chest pain, labor, musculoskeletal diseases, skin diseases, toothache, pyresis, burn, sunburn, snake bite, venomous snake bite, spider bite, insect sting, neurogenic bladder, interstitial cystitis, urinary tract infection, rhinitis, contact dermatitis/hypersensitivity, itch, eczema, pharyngitis, mucositis, enteritis, irritable bowel syndrome, cholecystitis, pancreatitis, postmastectomy pain syndrome, menstrual pain, endometriosis, pain due to physical trauma, headache, sinus headache, tension headache, or arachnoiditis.
• inflammatory hyperalgesia is inflammatory hyperalges
• inflammatory hyperalgesia examples include a disease, syndrome, condition, disorder, or pain state including inflammation, osteoarthritis, rheumatoid arthritis, back pain, joint pain, abdominal pain, musculoskeletal diseases, skin diseases, post operative pain, headaches, toothache, burn, sunburn, insect sting, neurogenic bladder, urinary incontinence, interstitial cystitis, urinary tract infection, cough, asthma, chronic obstructive pulmonary disease, rhinitis, contact
• dermatitis/hypersensitivity and/or dermal allergy itch, eczema, pharyngitis, enteritis, irritable bowel syndrome, inflammatory bowel diseases including Crohn's Disease, ulcerative colitis, benign prostatic hypertrophy, and nasal hypersensitivity.
• the present invention is directed to a method for treating, ameliorating and / or preventing inflammatory visceral hyperalgesia in which a enhanced visceral irritability exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound, salt or solvate of Formula (I).
• the present invention is directed to a method for treating inflammatory somatic hyperalgesia in which a hypersensitivity to thermal, mechanical and/or chemical stimuli exists, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formula (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.
• a further embodiment of the present invention is directed to a method for treating, ameliorating and / or preventing neuropathic pain. Examples of a
• neuropathic pain include pain due to a disease, syndrome, condition, disorder, or pain state including cancer, neurological disorders, spine and peripheral nerve surgery, brain tumor, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndrome, fibromyalgia, chronic fatigue syndrome, lupus, sarcoidosis, peripheral neuropathy, bilateral peripheral neuropathy, diabetic neuropathy, central pain, neuropathies associated with spinal cord injury, stroke, amyotrophic lateral sclerosis (ALS), Parkinson's disease, multiple sclerosis, sciatic neuritis, mandibular joint neuralgia, peripheral neuritis, polyneuritis, stump pain, phantom limb pain, bony fractures, oral neuropathic pain, Charcot's pain, complex regional pain syndrome I and II (CRPS I/II), radiculopathy, Guillain-Barre syndrome, meralgia paresthetica, burning-mouth syndrome, optic neuritis, postfebrile neuritis, migrating neuritis, segmental neuritis
• neuropathic cold allodynia which can be characterized by the presence of a neuropathy-associated allodynic state in which a hypersensitivity to cooling stimuli exists.
• neuropathic cold allodynia include allodynia due to a disease, condition, syndrome, disorder or pain state including neuropathic pain (neuralgia), pain arising from spine and peripheral nerve surgery or trauma, traumatic brain injury (TBI), trigeminal neuralgia, postherpetic neuralgia, causalgia, peripheral neuropathy, diabetic neuropathy, central pain, stroke, peripheral neuritis, polyneuritis, complex regional pain syndrome I and II (CRPS I/II) and radiculopathy.
• neuropathic pain neuralgia
• TBI traumatic brain injury
• trigeminal neuralgia postherpetic neuralgia
• causalgia peripheral neuropathy
• diabetic neuropathy central pain
• stroke peripheral neuritis
• polyneuritis complex regional pain syndrome I and II
• the present invention is directed to a method for treating, ameliorating and / or preventing neuropathic cold allodynia in which a hypersensitivity to a cooling stimuli exists, comprising, consisting of, and/or consisting essentially of the step of administering to a subject in need of such treatment a therapeutically effective amount of a compound of Formula (I) or an enantiomer, diastereomer, solvate or pharmaceutically acceptable salt thereof.
• the present invention is directed to a method for treating, ameliorating and / or preventing CNS disorders.
• CNS disorders include anxieties such as, social anxiety, post-traumatic stress disorder, phobias, social phobia, special phobias, panic disorder, obsessive-compulsive disorder, acute stress disorder, separation anxiety disorder, and generalized anxiety disorder, as well as depression such as, major depression, bipolar disorder, seasonal affective disorder, post natal depression, manic depression, and bipolar depression.
• Embodiments of the present invention include a compound of Formula (I)
• Y and Z are independently selected from Group a) or Group b) such that one of Y and Z is Group a) and the other is Group b);
• Group a) is unsubstituted phenyl or an unsubstituted heteroaryl selected from the group consisting of thiazolyl, isothiazolyl, and lH-pyrrolyl;
• Group a) is unsubstituted phenyl or an unsubstituted heteroaryl selected from the group consisting of thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazolyl, 1H- pyrrol-2-yl, and lH-pyrrol-3-yl;
• Group b) other than phenylmethyl-phenyl is unsubstituted or substituted with one or two substitutents each of which is independently selected from the group consisting of chloro, fluoro, methyl, and 3 ⁇ 4,; provided that no more than one substituent is 3 ⁇ 4; and
• R b is selected from the group consisting of trifluoromethyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, 4,4-difluorocyclohexyl, thienyl, pyridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl of 3 ⁇ 4 are unsubstituted or substituted with one or two substituents each of which is independently selected from the group consisting of trifluoromethyl, methyl, chloro, and fluoro; Group b) is
• benzimidazolyl benzothienyl, and indolyl; iii) phenylmethyl-phenyl wherein the phenyl group of phenylmethyl is unsubstituted or substituted with trifluoromethyl; or
• Group b) other than phenylmethyl-phenyl is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of chloro, fluoro, methyl, and 3 ⁇ 4; provided that no more than one substituent is 3 ⁇ 4; and
• R b is selected from the group consisting of trifluoromethyl, thienyl, pyridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl of 3 ⁇ 4 are optionally independently substituted with one to two trifluoromethyl, methyl, chloro, or fluoro substituents; e) R is hydrogen; and any combination of embodiments a) through e) above, provided that it is understood that combinations in which different embodiments of the same substituent would be combined are excluded;
• An embodiment of the present invention includes a compound of Formula (I)
• Y and Z are independently selected from Group a) or Group b) such that one of Y and Z is Group a) and the other is Group b);
• Group a) is an unsubstituted phenyl or an unsubstituted heteroaryl selected from the group consisting of thiazolyl, isothiazolyl, and lH-pyrrolyl;
• Group b) is
• phenylmethyl-phenyl wherein the phenyl group of phenylmethyl is unsubstituted or substituted with trifluoromethyl or fluoro; or iv) 1 ,3-dihydro-3H-benzimidazol-2-on-yl;
• Group b) other than phenylmethyl-phenyl is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of chloro, fluoro, methyl, and 3 ⁇ 4; provided that no more than one substituent is 3 ⁇ 4; and
• Rbis selected from the group consisting of trifluoromethyl, 2,2,2- trifluoroethyl, 3,3,3-trifluoropropyl, 4,4-difluorocyclohexyl, thienyl, pyridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl of 3 ⁇ 4 are unsubstituted or substituted with one or two substituents independently selected from the group consisting of trifluoromethyl, methyl, chloro, and fluoro;
• R is hydrogen
• Y and Z are independently selected from Group a) or Group b) such that one of Y and Z is Group a) and the other is Group b);
• Group a) is an unsubstituted phenyl or an unsubstituted heteroaryl selected from the group consisting of thiazolyl, isothiazolyl, and lH-pyrrolyl;
• Group b) is
• Group b) other than phenylmethyl-phenyl is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of chloro, fluoro, methyl, and 3 ⁇ 4; provided that no more than one substituent is and
• R b is selected from the group consisting of trifluoromethyl, thienyl, pyridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl of 3 ⁇ 4 are unsubstituted or substituted with one or two substitutents independently selected from the group consisting of trifluoromethyl, methyl, chloro, and fluoro;
• R is hydrogen or hydroxy
• Y and Z are independently selected from Group a) or Group b) such that one of Y and Z is Group a) and the other is Group b);
• Group a) is unsubstituted phenyl or an unsubstituted heteroaryl selected from the group consisting of thiazol-2-yl, thiazol-4-yl, thiazol-5-yl, isothiazolyl, lH-pyrrol- 2-yl, and lH-pyrrol-3-yl;
• Group b) is
• Group b) other than phenylmethyl-phenyl is unsubstituted or substituted with one or two substitutents independently selected from the group consisting of chloro, fluoro, methyl, and 3 ⁇ 4; provided that no more than one substituent is 3 ⁇ 4; and
• Rbis selected from the group consisting of trifluoromethyl, thienyl, pyridinyl, and phenyl; wherein said thienyl, pyridinyl, and phenyl of R b are unsubstituted or substituted with one or two substituents independently selected from the group consisting of trifluoromethyl, methyl, chloro, and fluoro;
• R is hydrogen or hydroxy
• An embodiment of the present invention includes a compound of Formula (I)
• salts of compounds of Formula (I) refer to non-toxic
• Suitable pharmaceutically acceptable salts of compounds of Formula (I) include acid addition salts that can, for example, be formed by mixing a solution of the compound with a solution of a pharmaceutically acceptable acid such as, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
• a pharmaceutically acceptable acid such as, hydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
• suitable pharmaceutically acceptable salts thereof may include alkali metal salts such as, sodium or potassium salts; alkaline earth metal salts such as, calcium or magnesium salts; and salts formed with suitable organic ligands such as, quaternary ammonium salts.
• pharmaceutically acceptable salts include acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate, glutamate, glycollylarsanilate,
• hexylresorcinate hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, N- methylglucamine ammonium salt, oleate, pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate, polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate, teoclate, tosylate, triethiodide, and valerate.
• methanesulfonic acid naphthalene-2-sulfonic acid, naphthalene- 1,5-disulfonic acid, 1- hydroxy -2 -naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, L-pyroglutamic acid, salicylic acid, 4- amino-salicylic acid, sebaic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid and undecylenic acid; and bases including ammonia, L-arginine, benethamine, benzathine, calcium hydroxide, choline, deanol, diethanolamine, diethylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylened
• Embodiments of the present invention include prodrugs of compounds of Formula (I).
• prodrugs will be functional derivatives of the compounds that are readily convertible in vivo into the required compound.
• administering encompasses the treatment or prevention of the various diseases, conditions, syndromes and disorders described with the compound specifically disclosed or with a compound that may not be specifically disclosed, but which converts to the specified compound in vivo after administration to a patient.
• the compounds according to embodiments of this invention may accordingly exist as enantiomers. Where the compounds possess two or more chiral centers, they may additionally exist as diastereomers. It is to be understood that all such isomers and mixtures thereof are encompassed within the scope of the present invention. Furthermore, some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are also intended to be encompassed within the scope of this invention. The skilled artisan will understand that the term compound as used herein, is meant to include solvated compounds of Formula (I).
• the processes for the preparation of the compounds according to certain embodiments of the invention give rise to mixture of stereoisomers
• these isomers may be separated by conventional techniques such as, preparative chromatography.
• the compounds may be prepared in racemic form, or individual enantiomers may be prepared either by enantiospecific synthesis or by resolution.
• the compounds may, for example, be resolved into their component enantiomers by standard techniques such as, the formation of diastereomeric pairs by salt formation with an optically active acid such as, (-)-di-p-toluoyl-d-tartaric acid and/or (+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallization and regeneration of the free base.
• the compounds may also be resolved by formation of diastereomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column.
• compositions including a pharmaceutical composition, comprising, consisting of, and/or consisting essentially of the (+)-enantiomer of a compound of Formula (I) wherein said composition is substantially free from the (-)-isomer of said compound.
• substantially free means less than about 25 %, preferably less than about 10 %, more preferably less than about 5 %, even more preferably less than about 2 % and even more preferably less than about 1 % of the (-)-isomer calculated as
• compositions including a pharmaceutical composition, comprising, consisting of, and consisting essentially of the (-)-enantiomer of a compound of Formula (I) wherein said composition is substantially free from the (+)-isomer of said compound.
• substantially free from means less than about 25 %, preferably less than about 10 %, more preferably less than about 5 %, even more preferably less than about 2 % and even more preferably less than about 1 % of the (+)-isomer calculated as
• compositions comprising compounds of Formula (I) and at least one pharmaceutically acceptable carrier, pharmaceutically acceptable excipient, and/or pharmaceutically acceptable diluent.
• the compounds of Formula (I) may be admixed with any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilizing agent(s), and combinations thereof.
• Solid oral dosage forms such as, tablets or capsules, containing the compounds of the present invention may be administered in at least one dosage form at a time, as appropriate. It is also possible to administer the compounds in sustained release formulations.
• Additional oral forms in which the present inventive compounds may be administered include elixirs, solutions, syrups, and suspensions; each optionally containing flavoring agents and coloring agents.
• compounds of Formula (I) can be administered by inhalation
• intratracheal or intranasal or in the form of a suppository or pessary, or they may be applied topically in the form of a lotion, solution, cream, ointment or dusting powder.
• a cream comprising, consisting of, and/or consisting essentially of an aqueous emulsion of polyethylene glycols or liquid paraffin.
• An alternative means of administration includes transdermal administration by using a skin or transdermal patch.
• compositions of the present invention can also be injected parenterally, for example, intracavernosally, intravenously, intramuscularly, subcutaneously, intradermally, or intrathecally.
• the compositions will also include at least one of a suitable carrier, a suitable excipient, and a suitable diluent.
• compositions of the present invention are best used in the form of a sterile aqueous solution that may contain other substances, for example, enough salts and monosaccharides to make the solution isotonic with blood.
• compositions of the present invention may be administered in the form of tablets or lozenges, which can be formulated in a conventional manner.
• compositions containing at least one of the compounds of Formula (I) as the active ingredient can be prepared by mixing the compound(s) with a pharmaceutically acceptable carrier, a pharmaceutically acceptable diluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques.
• a pharmaceutically acceptable carrier e.g., benzyl alcohol, benzyl ether, benzyl ether, benzyl ether, benzyl, sulfonyl, sulfonyl, adiluent, and/or a pharmaceutically acceptable excipient according to conventional pharmaceutical compounding techniques.
• the carrier, excipient, and diluent may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral, etc.).
• suitable carriers, excipients and diluents include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
• suitable carriers, excipients and diluents include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
• Solid oral preparations also may be optionally coated with substances such as, sugars, or be enterically coated so as to modulate the major site of absorption and disintegration.
• the carrier, excipient and diluent will usually include sterile water, and other ingredients may be added to increase solubility and preservation of the composition.
• injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives such as, solubilizers and preservatives.
• a therapeutically effective amount of a compound of Formula (I) or a pharmaceutical composition thereof includes a dose range from about 0.1 mg to about 3000 mg, or any particular amount or range therein, in particular from about 1 mg to about 1000 mg, or any particular amount or range therein, or, more particularly, from about 10 mg to about 500 mg, or any particular amount or range therein, of active ingredient in a regimen of about 1 to about 4 times per day for an average (70 kg) human; although, it is apparent to one skilled in the art that the therapeutically effective amount for a compound of Formula (I) will vary as will the diseases, syndromes, conditions, and disorders being treated.
• a pharmaceutical composition is preferably provided in the form of tablets containing about 1.0, about 10, about 50, about 100, about 150, about 200, about 250, and about 500 milligrams of a compound of Formula (I).
• a compound of Formula (I) may be administered in a single daily dose, or the total daily dosage may be administered in divided doses of two, three and four times daily.
• Optimal dosages of a compound of Formula (I) to be administered may be readily determined and will vary with the particular compound used, the mode of administration, the strength of the preparation and the advancement of the disease, syndrome, condition or disorder.
• factors associated with the particular subject being treated including subject gender, age, weight, diet and time of administration, will result in the need to adjust the dose to achieve an appropriate therapeutic level and desired therapeutic effect.
• the above dosages are thus exemplary of the average case. There can be, of course, individual instances wherein higher or lower dosage ranges are merited, and such are within the scope of this invention.
• Compounds of Formula (I) may be administered in any of the foregoing compositions and dosage regimens or by means of those compositions and dosage regimens established in the art whenever use of a compound of Formula (I) is required for a subject in need thereof.
• the compounds of Formula (I) are useful in methods for treating and preventing a disease, a syndrome, a condition or a disorder in a subject, including an animal, a mammal and a human in which the disease, the syndrome, the condition or the disorder is affected by the modulation, including inhibition, of the MGL enzyme.
• Such methods comprise, consist of and/or consist essentially of administering to a subject, including an animal, a mammal, and a human in need of such treatment or prevention a therapeutically effective amount of a compound, salt or solvate of Formula (I).
• Scheme A illustrates a route for the synthesis of intermediates that are useful for the preparation of compounds of Formula (I) wherein R is hydrogen.
• a compound of formula Al (wherein P is a conventional amino protecting group) is either commercially available or may be prepared by known methods described in the scientific literature.
• a compound of formula Al may be treated with zinc metal in the presence of TMS-C1, in an aprotic solvent, followed by addition of a compound of formula A2, in the presence of palladium catalyst to afford a compound of formula A3.
• Treatment with benzyl bromide affords the pyridinium bromide of formula A4.
• a compound of formula A4 may be reduced to a compound of formula A5 in the presence of a hydride source such as, sodium borohydride, in an organic alcoholic solvent such as, ethanol. Removal of the benzyl group and reduction of the double bond may be achieved by palladium catalyzed hydrogenation to afford the desired intermediate of formula A6.
• Scheme B illustrates a route for the preparation of compounds of Formula (I)-B wherein Y and Z are as defined herein and R of Formula (I) is hydrogen.
• the amino protecting group (P) of a compound of formula A3 may be removed by conventional synthetic methods to afford a secondary amine of formula Bl.
• the amino group may be coupled with a carboxylic acid of formula B2 (wherein Q is hydroxy) in the presence of an appropriate coupling agent such as HATU, DCC, EDC, HBTU, PyBrOP, and the like, optionally in the presence of a base such as DIPEA, to afford an amide of formula B3.
• an acid chloride of formula B2 (wherein Q is chloro) may be used to effect the acylation of a compound of formula Bl.
• a non- nucleophilic base such as pyridine may be added to afford an amide of formula B3.
• Reduction of the pyridine ring of a compound of formula B3 may be achieved by palladium catalyzed hydrogenation to afford a compound of formula B4.
• a second acylation with an appropriately Y-substituted carboxylic acid or acid chloride of formula B5 affords a compound of Formula (I)-B wherein R of Formula (I) is hydrogen.
• Scheme C illustrates an alternate route for the preparation of compounds of Formula (I)-B wherein Y and Z are as defined herein and R of Formula (I) is hydrogen.
• the compound of formula A6 may be acylated according to the synthetic methods described under Scheme B to afford the acylated compound of formula CI.
• Scheme D illustrates a route for the preparation of compounds of Formula (I)-D wherein Y and Z are as defined herein and R of Formula (I) is hydroxy.
• a compound of formula Dl may be treated with samarium iodide in the presence of HMPA, in an aprotic solvent, followed by the addition of a ketone of formula D2 to afford the condensed product of formula D3. Removal of the benzhydryl group may be effected by palladium catalyzed hydrogenation to afford the free amine of formula D4.
• the amine of formula D4 may be acylated with a Z -substituted compound of formula B2 by the methods previously described herein to afford a compound of Formula (I)-D.
• Scheme E illustrates an alternate route for the preparation of compounds of Formula (I)-D wherein Y and Z are as defined herein and R of Formula (I) is hydroxy.
• a compound of formula Dl may be condensed with a compound of formula El in the presence of samarium iodide and HMPA to afford a compound of formula E2.
• the above prepared zinc iodide reagent of compound la in DMA was added as a suspension.
• the mixture was degassed with vacuum/N2 twice and then heated to 80 °C. (Note: The reaction was exothermic.)
• the progress of the reaction was monitored by HPLC and LC-MS and was complete after 2 h.
• the reaction mixture was cooled to 40 °C; EtOAc (1.6 L) was added and the mixture was stirred for 10 min.
• the insoluble material (excess Zn and Cu
• the separated aqueous phase was extracted with EtOAc (1 L), and the combined organic phases were treated with saturated aqueous NH 4 C1 (0.8 L x 2) and stirred for 15 min (repeated again), washed with 5% aqueous NaHS0 3 (500 mL) and brine (1 L), and dried over MgS0 4 .
• the catalyst was removed by filtration though a diatomaceous earth pad, which was washed with MeOH (50 mL x 3). Concentration of the filtrate at 50 °C under high- vacuum ( ⁇ 10 mmHg) afforded 13.4 g (103% isolated yield, 97% pure at 210 nm, HPLC area%) of pure compound lg as a slight yellowish, thick oil, which contained a trace amount of EtOH residue by ⁇ - MR analysis.
• Methyl thioglycolate 3b (30.3 mmol, 2.76 mL) was added dropwise to a suspension of NaH (60% oil dispersion, 75.8 mmol, 3.03 g) in 10 mL of THF and 50 mL of DMSO at 20 °C. The mixture was stirred for 15 min and a solution of l-(2-fluoro-4- (trifluoromethyl)phenyl)ethanone 3a (24.3 mmol, 5.0 g) in 10 mL of DMSO was added. The reaction mixture was stirred at 20 °C for 4 h and water was added. The mixture was extracted with EtOAc. The organic layer was dried over MgS0 4 and concentrated to give compound 3c as a white solid.
• Lead (IV) acetate (29.9 mmol, 13.3 g) was added in one portion and the mixture was refluxed for 20 min. After cooling, the precipitate was removed by filtration and washed with acetonitrile.
• A. Methyl l-(4-fluorophenyl)-indole-5-carboxylate, 7c A mixture of methyl indole-5-carboxylate 7a (0.5 g, 2.85 mmol), 1 -bromo-4-fluoro-benzene 7b (2 mL, 18.21 mmol), Cul (0.544 g, 2.85 mmol), and K 2 C0 3 (0.591 g, 4.28 mmol) was heated in a microwave reactor at 220 °C for 2.5 h. The reaction mixture was diluted with CH2CI2 and filtered. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 15% EtO Ac/heptane) to give 0.58 g of compound 7c. MS m/z 270.1 (M+H + ).
• Methyl l-(3,4-difluorophenyl)-indole-5-carboxylate, 8b A mixture of methyl indole-5-carboxylate 7a (2 g, 11.4 mmol), l-iodo-3,4-difluoro-benzene 8a (1.5 mL, 12.5 mmol), Cul (0.22 g, 1.14 mmol), trans-N, N'-dimethylcyclohexane-l,2- diamine (0.54 mL, 3.43 mmol), and K 3 PO 4 (6.06 g, 28.5 mmol) in toluene (12 mL) was heated at 110 °C for 7 h.
• A. Methyl 4-((4-fluorophenyl)amino)-3-nitrobenzoate, 9c A mixture of methyl 4-fluoro-3-nitrobenzoate 9a (1 g, 5.02 mmol), 4-fluoroaniline 9b (4.34 mL, 5.02 mmol), and DIPEA (1.04 mL, 6.03 mmol) in DMF (10 mL) was stirred at room temperature for 2 h. Water was added to the mixture, the resulting solid was collected by filtration, washed with water, and dried. The crude compound 9c was used in the next reaction without further purification.
• a solution of l-benzhydryl-3-iodoazetidine 13a (1.4 mmol, 490 mg) in 5 mL of THF was added to a stirring mixture of Sml 2 (0.1 M THF solution, 3 mmol, 30 mL) and 1.7 mL of HMPA. After 5 min, a solution of 1- benzoylpiperidin-4-one 13b (3.1 mmol, 626 mg) in 5 mL of THF was added. The reaction mixture was stirred for 2 h.
• IC5 0 values for compounds of Formula (I) were determined using Excel from a fit of the equation to the concentration-response plot of the fractional activity as a function of inhibitor concentration.
• percent vehicle (2-AG accumulation in the presence of compound/2-AG accumulation in vehicle) x 100.
• ThermoFluor (TF) assay is a 384-well plate-based binding assay that measures thermal stability of proteins 1 ' 2 .
• the experiments were carried out using instruments available from Johnson & Johnson Pharmaceutical Research &
• TF dye used in all experiments was 1,8-ANS (Invitrogen: A-47).
• Screening compound plates contained 100% DMSO compound solutions at a single concentration.
• compounds were arranged in a pre-dispensed plate (Greiner Bio-one: 781280), wherein compounds were serially diluted in 100% DMSO across 11 columns within a series. Columns 12 and 24 were used as DMSO reference and contained no compound.
• the compound aliquots 46 nL were robotically predispensed directly into 384-well black assay plates (Abgene: TF-0384/k) using the Hummingbird liquid handler.
• protein and dye solutions were added to achieve the final assay volume of 3 ⁇ .
• the assay solutions were overlayed with 1 of silicone oil (Fluka, type DC 200: 8541 1) to prevent evaporation.
• Bar-coded assay plates were robotically loaded onto a thermostatically controlled PCR-type thermal block and then heated from 40 to 90 °C degrees at a ramp- rate of 1 °C/min for all experiments. Fluorescence was measured by continuous illumination with UV light (Hamamatsu LC6), supplied via fiber optics and filtered through a band-pass filter (380-400 nm; > 6 OD cutoff). Fluorescence emission of the entire 384-well plate was detected by measuring light intensity using a CCD camera (Sensys, Roper Scientific) filtered to detect 500 ⁇ 25 nm, resulting in simultaneous and independent readings of all 384 wells. A single image with 20-sec exposure time was collected at each temperature, and the sum of the pixel intensity in a given area of the assay plate was recorded vs temperature and fit to standard equations to yield the T m l .
• the Ka values for compounds of Formula (I) were determined from a fit of the equation to the concentration-response plot of the fractional activity as a function of T m .
• quantitative NMR spectroscopy qNMR was used to measure concentration of the initial 100% DMSO compound solutions and, using the same fitting method, qKa values were determined.
• Each rat was placed in a test chamber on a warm glass surface and allowed to acclimate for approximately 10 min.
• a radiant thermal stimulus (beam of light) was focused through the glass onto the plantar surface of each hind paw in turn.
• the thermal stimulus was automatically shut off by a photoelectric relay when the paw was moved or when the cut-off time was reached (20 sec for radiant heat at ⁇ 5 amps).
• An initial (baseline) response latency to the thermal stimulus was recorded for each animal prior to the injection of complete Freund's adjuvant (CFA). Twenty-four hours following intraplantar CFA injection, the response latency of the animal to the thermal stimulus was re-evaluated and compared to the animal's baseline response time.
• CFA complete Freund's adjuvant
• the percent reversal (%R) of hypersensitivity was calculated in one of two different ways: 1) using group mean values or 2) using individual animal values. More specifically:
• Results are given as a mean of the maximum % reversal values calculated for each individual animal.
• rats Prior to testing, rats may be acclimated to the handling procedure twice a day for a period of two days .
• the test consists of placing the left hindpaw on a
• the response threshold of the animal to the mechanical stimulus may be re-evaluated and compared to the animal's baseline response threshold.
• a response may be defined as a withdrawal of the hindpaw, a struggling to remove the hindpaw, or vocalization. Only rats that exhibit at least a 25% reduction in response threshold (i.e., hyperalgesia) may be included in further analysis.
• rats may be administered the indicated test compound or vehicle.
• Post- treatment withdrawal thresholds may be assessed at 1 h.
• Paw withdrawal thresholds may be converted to percent reversal of hypersensitivity according to the following formula:
• CCI Chronic constriction injury
• Male Sprague-Dawley rats (225-450 g) may be used to evaluate the ability of selected compounds to reverse CCI-induced cold hypersensitivity.
• Four loose ligatures of 4-0 chromic gut may be surgically placed around the left sciatic nerve under inhalation anesthesia as described by Bennett et al. (Bennett GJ, Xie YK. Pain 1988, 33(1): 87-107).
• Fourteen to 35 days following CCI surgery subjects may be placed in elevated observation chambers containing wire mesh floors, and five applications of acetone (0.05 mL/application separated by approximately 5 minutes) may be spritzed onto the plantar surface of the paw using a multidose syringe. An abrupt withdrawal or lifting of the paw may be considered a positive response.
• the number of positive responses may be recorded for each rat over the five trials. Following baseline withdrawal determinations, compounds may be administered in the indicated vehicle, by the indicated route (see Table 6). The number of withdrawals may be re-determined 1 to 4 hr after compound administration. Results may be presented as a percent inhibition of shakes, which may be calculated for each subject as [l-(test compound withdrawals / pre-test withdrawals)] x 100 and then averaged by treatment.
• SNL Spinal nerve ligation
• L 5 spinal nerve ligation
• anesthesia may be induced and maintained on isoflurane inhalation.
• Fur may be clipped over the dorsal pelvic area, and a 2-cm skin incision may be made just left of midline over the dorsal aspect of the L4-S2 spinal segments, followed by separation of the paraspinal muscles from spinous processes.
• the transverse process of L 6 may be carefully removed, and the L5 spinal nerve may be identified.
• the left L5 spinal nerve may be ligated tightly with 6-0 silk thread, the muscle may be sutured with 4-0 vicryl, and the skin may be closed with wound clips.
• s.c. saline (5 mL) may be administered.
• Behavioral testing may be performed four weeks post-ligation. Following baseline von Frey determinations to verify the presence of mechanical allodynia, L 5 SNL rats may be orally administered the indicated vehicle or drug. Tactile allodynia may be quantified at 30 , 60, 100, 180, and 300 min post-dosing by recording the force at which the paw ipsilateral to the nerve ligation is withdrawn from the application of a series of calibrated von Frey filaments (0.4, 0.6, 1.0, 2.0, 4, 6, 8 and 15 g; Stoelting; Wood Dale, IL).
• filaments may be applied to the mid-plantar hind paw for approximately 5 seconds to determine the response threshold, a brisk paw withdrawal leads to the presentation of the next lighter stimulus, whereas a lack of a withdrawal response leads to the presentation of the next stronger stimulus.
• a total of four responses after the first threshold detection may be collected.
• the 50% withdrawal thresholds may be interpolated by the method of Dixon as modified by Chaplan et.al, and when response thresholds fall above or below the range of detection, respective values of 15.0 or 0.25 g may be assigned.
• Threshold data from von Frey filament testing may be reported as withdrawal threshold in grams. Data may be normalized and results may be presented as % MPE (maximum possible effect) of the drug calculated according to the following formula:
• % MPE x g/force - baseline g/force X 100

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