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
  • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• • 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
  • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• • 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
  • A61P25/22—Anxiolytics
• • 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
  • A61P25/24—Antidepressants
• • 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
  • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/04—Anorexiants; Antiobesity agents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/06—Antihyperlipidemics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/26—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/28—Radicals substituted by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
  • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
  • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

• the present disclosure is generally directed to compounds that can inhibit DAGLa and/or ⁇ activity, compositions comprising such compounds, and methods for inhibiting DAGLa and/or ⁇ activity.
• Diacylglycerol Lipase enzymes are esterases that hydrolyze diacylglycerol to form the endogenous cannabinoid 2-arachidonyl glycerol (2 -AG) (J Cell Biol
• DAGLa is predominantly expressed throughout the CNS with limited expression in the periphery, whereas DAGL is predominantly expressed in peripheral tissues (J5 Cell Biol 2003;763:463-8). Immunohistochemical studies have demonstrated
• DAGLa is localized post-synaptically, consistent with its role in generating 2-AG which acts as a retrograde messenger activating presynaptic cannabinoid receptors including CB 1 (JNeurosci 2007;27(14):3663-3676, PLoS August 2007; 8:e709).
• mice that lack DAGLa expression exhibit decreased tissue concentrations of 2-AG.
• the DAGLa knockout animals exhibit multiple phenotypes in animal models relevant to human diseases. For example, in models predictive of activity in affective disorders, DAGLa -/- animals exhibit anxiolytic and antidepressant phenotypes.
• DAGLa -/-5 animals also are resistant to diet-induced obesity, have decreased food intake. These animals also exhibit decreased body weight, body fat, sensitivity to pain, and improved cognitive performance demonstrating broad therapeutic potential for the enzyme.
• DAGLa and/or ⁇ activity are predicted to have therapeutic utility in the treatment of schizophrenia, psychosis, bipolar disorder, depression, anxiety, pain, cognitive impairment, diabetes, obesity, hepatic steatosis, dyslipidemias, and other related disease states.
• Currently, the only reported inhibitors of DAGL are chemically reactive molecules, that as such, can be expected to have limited utility due to lack of selectivity (Bioorganic & Medicinal Chemistry Letters (2008), 18(22), 5838-5841).
• Ar 1 is selected from naphthyl and phenyl, wherein the phenyl is substituted with 0, 1, or 2 substituents independently selected from alkyl, halo, haloalkoxy, alkoxy, and
• Ar 2 is selected from hydrogen, phenyl, naphthyl, pyrimidinyl, thiazolyl, and quinolinyl, wherein the phenyl, naphthyl, pyrimidinyl, thiazolyl, and quinolinyl are each substituted with 0, 1, or 2 substituents independently selected from alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, cyano, and halo;
• R 1 is selected from hydrogen, cyano, halo, alkyl, alkoxy, and haloalkoxy; and R 2 and R 3 are each lower alkyl; or
• R 2 and R 3 together with the carbon atom to which they are attached, form a 3- to 5-membered carbocyclic ring optionally containing an oxygen atom.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- to 5- membered carbocyclic ring optionally containing an oxygen atom.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- to 5- membered carbocyclic ring optionally containing an oxygen atom and Ar 1 is naphthyl.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- to 5- membered carbocyclic ring optionally containing an oxygen atom, Ar 1 is naphthyl, R 1 is halo and Ar 2 is hydrogen.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- to 5- yclic ring optionally containing an oxygen atom and Ar 1 is
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- to 5- yclic ring optionally containing an oxygen atom, Ar 1 is R 1 is halo, and Ar 2 is hydrogen.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- to 5- cyclic ring optionally containing an oxygen atom, Ar 1 is 1 2
• R is hydrogen
• Ar is phenyl optionally substituted with two halo groups.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- to 5- membered carbocyclic ring optionally containing an oxygen atom and Ar 1 is phenyl substituted with 0, 1, or 2 groups selected from alkyl, halo, haloalkoxy, alkoxy, and cyano.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- to 5- membered carbocyclic ring optionally containing an oxygen atom, Ar 1 is phenyl substituted with 0, 1, or 2 groups selected from alkyl, halo, haloalkoxy, alkoxy, and cyano, R 1 is halo, and Ar 2 is hydrogen.
• the present disclosure provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 , together with the carbon atom to which they are attached, form a 3- to 5- membered carbocyclic ring optionally containing an oxygen atom, Ar 1 is phenyl substituted with 0, 1, or 2 groups selected from alkyl, halo, haloalkoxy, alkoxy, and cyano, R 1 is hydrogen and Ar 2 is selected from phenyl, pyrimidinyl, and thiazolyl, wherein the phenyl, pyrimidinyl, and thiazolyl are substituted with 0, 1, or 2 groups independently selected from alkyl, alkoxy, trifluoromethyl, trifluoromethoxy, and halo.
• composition comprising a pharmaceutically acceptable amount of a compound of Formula (I), or a
• the present disclosure provides a method for treating a disorder associated with DAGLa and/or DAGLP activity, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
• the disorder is selected from schizophrenia, psychosis, bipolar disorder, depression, anxiety, pain, cognitive impairment, diabetes, obesity, hepatic steatosis, and dyslipidemia.
• the disorder is selected from schizophrenia, bipolar disorder, depression, anxiety, diabetes, obesity, hepatic steatosis, and dyslipidemia.
• C2-6 alkenyl denotes an alkenyl group containing two to six carbon atoms. Where these designations exist they supercede all other definitions contained herein.
• alkoxy refers to an alkyl group attached to the parent molecular moiety through an oxygen atom.
• alkyl refers to a group derived from a straight or branched chain saturated hydrocarbon containing from one to six carbon atoms.
• cyano refers to -CN.
• halo and halogen, as used herein, refer to F, CI, Br, or I.
• haloalkoxy refers to a haloalkyl group attached to the parent molecular moiety through an oxygen atom.
• haloalkyl refers to an alkyl group substituted with one, two, three, or four halogen atoms.
• Asymmetric centers may exist in the compounds of the present disclosure. These centers are designated by the symbols "R” or “S”, depending on the configuration of substituents around the chiral carbon atom. It should be understood that the disclosure encompasses all stereochemical isomeric forms, or mixtures thereof, which possess the ability to inhibit DAGL. Individual stereoisomers of compounds can be prepared synthetically from commercially available starting materials which contain chiral centers or by preparation of mixtures of enantiomeric products followed by separation such as conversion to a mixture of diastereomers followed by separation or recrystallization, chromatographic techniques, or direct separation of enantiomers on chiral chromatographic columns. Starting compounds of particular stereochemistry are either commercially available or can be made and resolved by techniques known in the art.
• Certain compounds of the present disclosure may also exist in different stable conformational forms which may be separable. Torsional asymmetry due to restricted rotation about an asymmetric single bond, for example because of steric hindrance or ring strain, may permit separation of different conformers.
• the present disclosure includes each conformational isomer of these compounds and mixtures thereof.
• isotopes include those atoms having the same atomic number but different mass numbers.
• isotopes of hydrogen include deuterium and tritium.
• isotopes of carbon include 13 C and 14 C.
• Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically- labeled reagent in place of the non-labeled reagent otherwise employed. Such compounds may have a variety of potential uses, for example as standards and reagents in determining biological activity. In the case of stable isotopes, such compounds may have the potential to favorably modify biological, pharmacological, or pharmacokinetic properties.
• the compounds of the present disclosure can exist as pharmaceutically acceptable salts.
• pharmaceutically acceptable salt represents salts or zwitterionic forms of the compounds of the present disclosure which are water or oil-soluble or dispersible, which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
• the salts can be prepared during the final isolation and purification of the compounds or separately by reacting a suitable nitrogen atom with a suitable acid.
• Representative acid addition salts include acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate; digluconate, dihydrobromide, diydrochloride, dihydroiodide, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2 -hydroxy ethanesulfonate, lactate, maleate, mesitylenesulfonate, methanesulfonate, naphthylenesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 3-phenylproprionate, picrate, pivalate, propionate, succinate, tartrate,
• Basic addition salts can be prepared during the final isolation and purification of the compounds by reacting a carboxy group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation or with ammonia or an organic primary, secondary, or tertiary amine.
• the cations of pharmaceutically acceptable salts include lithium, sodium, potassium, calcium, magnesium, and aluminum, as well as nontoxic quaternary amine cations such as ammonium,
• tetramethylammonium tetraethylammonium
• methylamine dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, ⁇ , ⁇ -dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, ⁇ , ⁇ -dibenzylphenethylamine, and ⁇ , ⁇ '- dibenzylethylenediamine.
• Other representative organic amines useful for the formation of base addition salts include ethylenediamine, ethanolamine,
• compositions which include therapeutically effective amounts of compounds of Formula (I) or pharmaceutically acceptable salts thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.
• therapeutically effective amount refers to the total amount of each active component that is sufficient to show a meaningful patient benefit. When applied to an individual active ingredient, administered alone, the term refers to that ingredient alone.
• the term refers to combined amounts of the active ingredients that result in the therapeutic effect, whether administered in combination, serially, or simultaneously.
• the compounds of Formula (I) and pharmaceutically acceptable salts thereof are as described above.
• the carrier(s), diluent(s), or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
• a process for the preparation of a pharmaceutical formulation including admixing a compound of Formula (I), or a pharmaceutically acceptable salt thereof, with one or more pharmaceutically acceptable carriers, diluents, or excipients.
• pharmaceutically acceptable refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio, and are effective for their intended use.
• compositions may be presented in unit dose forms containing a predetermined amount of active ingredient per unit dose. Dosage levels of between about 0.01 and about 250 milligram per kilogram (“mg/kg”) body weight per day, preferably between about 0.05 and about 100 mg/kg body weight per day of the compounds of the present disclosure are typical in a monotherapy for the prevention and treatment of disease. Typically, the pharmaceutical compositions of this disclosure will be administered from about 1 to about 5 times per day or alternatively, as a continuous infusion. Such administration can be used as a chronic or acute therapy.
• mg/kg milligram per kilogram
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending on the condition being treated, the severity of the condition, the time of administration, the route of administration, the rate of excretion of the compound employed, the duration of treatment, and the age, gender, weight, and condition of the patient.
• Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of an active ingredient. Treatment may be initiated with small dosages substantially less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstances is reached.
• the compound is most desirably administered at a concentration level that will generally afford effective results without causing any harmful or deleterious side effects.
• compositions of this disclosure comprise a combination of a compound of the present disclosure and one or more additional therapeutic or prophylactic agent
• both the compound and the additional agent are usually present at dosage levels of between about 10 to 150%, and more preferably between about 10 and 80% of the dosage normally administered in a monotherapy regimen.
• compositions may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, nasal, topical (including buccal, sublingual, or transdermal), vaginal, or parenteral (including subcutaneous, intracutaneous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intralesional, intravenous, or intradermal injections or infusions) route.
• Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient with the carrier(s) or excipient(s). Oral administration or administration by injection are preferred.
• compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in- water liquid emulsions or water-in-oil emulsions.
• the active drug component can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
• an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
• Powders are prepared by comminuting the compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing, and coloring agent can also be present.
• Capsules are made by preparing a powder mixture, as described above, and filling formed gelatin sheaths.
• Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate, or solid polyethylene glycol can be added to the powder mixture before the filling operation.
• a disintegrating or solubilizing agent such as agar-agar, calcium carbonate, or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.
• suitable binders include starch, gelatin, natural sugars such as glucose or beta- lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, and the like.
• Lubricants used in these dosage forms include sodium oleate, sodium chloride, and the like.
• Disintegrators include, without limitation, starch, methyl cellulose, agar, betonite, xanthan gum, and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant, and pressing into tablets.
• a powder mixture is prepared by mixing the compound, suitable comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelating, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or and absorption agent such as betonite, kaolin, or dicalcium phosphate.
• the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage, or solutions of cellulosic or polymeric materials and forcing through a screen.
• the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules.
• the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc, or mineral oil.
• the lubricated mixture is then compressed into tablets.
• the compounds of the present disclosure can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps.
• a clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material, and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.
• Oral fluids such as solution, syrups, and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
• Syrups can be prepared by dissolving the compound in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic vehicle.
• Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and
• polyoxyethylene sorbitol ethers preservatives, flavor additive such as peppermint oil or natural sweeteners, or saccharin or other artificial sweeteners, and the like can also be added.
• dosage unit formulations for oral administration can be microencapsulated.
• the formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax, or the like.
• the compounds of Formula (I), and pharmaceutically acceptable salts thereof can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
• Liposomes can be formed from a variety of phopholipids, such as cholesterol, stearylamine, or phophatidylcholines.
• the compounds of Formula (I) and pharmaceutically acceptable salts thereof may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled.
• the compounds may also be coupled with soluble polymers as targetable drug carriers.
• Such polymers can include polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamidephenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palitoyl residues.
• the compounds may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
• a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates, and cross-linked or amphipathic block copolymers of hydrogels.
• compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
• the active ingredient may be delivered from the patch by iontophoresis as generally described in Pharmaceutical Research 1986, 3(6), 318.
• compositions adapted for topical administration may be formulated as ointments, creams, suspensions, lotions, powders, solutions, pastes, gels, sprays, aerosols, or oils.
• compositions adapted for rectal administration may be presented as suppositories or as enemas.
• compositions adapted for nasal administration wherein the carrier is a solid include a course powder having a particle size for example in the range 20 to 500 microns which is administered in the manner in which snuff is taken, i.e., by rapid inhalation through the nasal passage from a container of the powder held close up to the nose.
• suitable formulations wherein the carrier is a liquid, for administration as a nasal spray or nasal drops, include aqueous or oil solutions of the active ingredient.
• Fine particle dusts or mists which may be generated by means of various types of metered, dose pressurized aerosols, nebulizers, or insufflators.
• compositions adapted for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulations.
• compositions adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats, and soutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.
• the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use.
• Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules, and tablets.
• formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
• patient includes both human and other mammals.
• treating refers to: (i) preventing a disease, disorder or condition from occurring in a patient that may be predisposed to the disease, disorder, and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder, or condition, i.e., arresting its development; and (iii) relieving the disease, disorder, or condition, i.e., causing regression of the disease, disorder, and/or condition.
• This disclosure is intended to encompass compounds having Formula (I) when prepared by synthetic processes or by metabolic processes including those occurring in the human or animal body (in vivo) or processes occurring in vitro.
• the compounds of the present disclosure may be prepared using the reactions and techniques described in this section as well as other synthetic methods known to those of ordinary skill in the art.
• the reactions are performed in solvents appropriate to the reagents and materials employed and suitable for the transformation being effected.
• all proposed reaction conditions including choice of solvents, reaction temperature, duration of the experiment and workup procedures, are chosen to be the conditions standard for that reaction, which should be readily recognized by one skilled in the art. It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reactions proposed. Such restrictions to the substituents which are compatible with the reaction conditions will be readily apparent to one skilled in the art and alternate methods must then be used.
• Arylcycloalkyl amine intermediates A can be treated with aryl sulfonylchlorides B the presence of base and catalytic DMAP to give sulfonamide intermediates of type C.
• Subsequent alkylation with methyl bromoacetate can give sulfonamides esters of type D.
• Examples E of the invention can be formed by hydrolysis of the intermediate esters D with, for example, sodium hydroxide in methanol.
• Reagents and conditions a), Hunig's base, cat. DMAP, DCM, rt, overnight b) methyl bromoacetate, BEMP-resin, acetonitrile, 80 °C, overnight c) NaOH, MeOH, rt.
• Reagents and conditions a), Hunig's base, cat. DMAP, DCM, rt, overnight b) methyl bromoacetate, BEMP-resin, acetonitrile, 80 °C, overnight.
• Ar boronic acid Pd2(dba)3.
• dicylohexyl(2',3 ',6'-triisopropylbiphenyl-2-yl)phosphine 100°C, 3h.
• Black non-binding surface Corning plates (3655) were spotted with 0.9 ⁇ , of compound in twenty point 1 :3 dilutions. The same volume of dimethyl sulfoxide (DMSO) was added to column 23 of the plate. In column 24, 0.9 ⁇ . of 2-(N-(4- cyclohexylphenyl)-2,2-dimethylchroman-6-sulfonamido)acetic acid was manually added as a blank to normalize the data.
• DMSO dimethyl sulfoxide
• a membrane prep from a stable HEK cell line expressing LG586 was prepared by the Cell Resource Group at BMS in Hopewell, NJ.
• the protein concentration of the membrane prep was 1.28 ⁇ g/ ⁇ L. These stocks were kept at - 80°C in 1 mL aliquots.
• membrane was thawed to room temperature and then added to the assay buffer, lOOmM HEPES in MQ water at pH 7.5.
• concentration of the LG586 enzyme in the assay is 0.005 ⁇ g/mL.
• the substrate used in this assay was purchased from Sigma ( 9876) p- nitrophenyl butyrate (PNP).
• the substrate is received in the liquid form and must be diluted with DMSO. Stocks were kept in -20°C at 1M concentrations. The final concentration of the substrate is 250 ⁇ .
• Enzyme was added to the plates 80 ⁇ 11 using a Multi-drop Combi (Thermo). The plates were incubated with the compound for 10 minutes at room temperature. Then 9 ⁇ of substrate was added to each well and the plates were immediately read on the Viewlux Imager (Perkin Elmer) in absorbance mode with the excitation filter of 405nm and emission filter of 564/250nm. The read was kinetic, plates were read once every 30 seconds for 5 minutes and then slopes were calculated for each well and the data was reduced with in-house software.

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