Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
  • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
  • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
• • 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
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
• • 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
  • A61P3/08—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
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
  • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
  • C07D403/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

• Marijuana (Cannabis sativa L.) and its derivatives have been used for centuries for medicinal and recreational purposes.
• a major active ingredient in marijuana and hashish has been determined to be ⁇ 9-tetrahydrocannabinol ( ⁇ 9-THC).
• ⁇ 9-THC ⁇ 9-tetrahydrocannabinol
• CBl and CB2 G-protein coupled receptors
• the CBl receptor is primarily found in the central and peripheral nervous systems and to a lesser extent in several peripheral organs.
• the CB2 receptor is found primarily in lymphoid tissues and cells.
• ligands for the cannabinoid receptors derived from arachidonic acid have been identified (anandamide, 2-arachidonoyl glycerol, and 2-arachidonyl glycerol ether). Each is an agonist with activities similar to ⁇ -THC, including sedation, hypothermia, intestinal immobility, antinociception, analgesia, catalepsy, anti-emesis, and appetite stimulation.
• CBl modulators characterized as an inverse agonista or an antagonists, N-
• the invention is concerned with the use of these novel compounds to selectively antagonize the Cannabinoid-1 (CBl) receptor.
• compounds of the present invention are useful as centrally acting drugs in the treatment of psychosis, memory deficits, cognitive disorders, Alzheimer's disease, migraine, neuropathy, neuro-inflairunatory disorders including multiple sclerosis and Guillain-Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma, anxiety disorders, stress, epilepsy, Parkinson's disease, movement disorders, and schizophrenia.
• the compounds are also useful for the treatment of substance abuse disorders, particularly abuse and/or addiction to opiates, alcohol, marijuana, and nicotine, including smoking cessation.
• the compounds are also useful for the treatment of obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy.
• the compounds are also useful for the treatment of constipation and chronic intestinal pseudo-obstruction.
• the compounds are also useful for the treatment of cirrhosis of the liver.
• the compounds are also useful for the treatment of asthma.
• the present invention is also concerned with treatment of these conditions, and the use of compounds of the present invention for manufacture of a medicament useful in treating these conditions.
• the present invention is also concerned with treatment of these conditions through a combination of compounds of formula I and other currently available pharmaceuticals.
• the invention is also concerned with pharmaceutical formulations comprising one of the compounds as an active ingredient, as well as processes for preparing the compounds of this invention.
• X is selected from:
• Li yet another subclass of this class X is methyl.
• R.2 and R? are each independently selected from: (1) hydrogen,
• R2 Li a subclass of this class, R2 is selected from:
• R3 is selected from:
• R.2 is selected from: (1) hydrogen,
• R3 is selected from methyl, and hydroxyl. Li another subclass of the present invention, R2 and R ⁇ are each fluoro.
• R2 is fluoro and R3 is methyl.
• R ⁇ is selected from:
• Li one subclass, R ⁇ is selected from:
• Li another subclass, R8 is selected from: (1) R15,
• R 8 is selected from:
• R8 is Rl5.
• R 8 is selected from:
• R8 is selected from:
• R9 is selected from:
• R 9 is selected from:
• R ⁇ is Rl 5.
• R9 is selected from:
• R ⁇ is:
• R9 is selected from:
• RlO i s selected from: (1) Rl5,
• RlO is selected from:
• RlO is selected from:
• RlO is Rl5.
• RlO is:
• RlO is selected from:
• RlO is chloro
• each Rl 5 is a 5-membered unsaturated heterocyclic ring selected from:
• Rh and Ri are each independently selected from: -H, -OH, -SH, -NH2,Ci_3 alkyl, -CF3 ; and each Rk is selected from: -H, and C 1.3 alkyl.
• each Rl5 ⁇ s independently selected from:
• Rh and Ri are each independently selected from: — H, -OH, -SH, -NH2, methyl, and -CF3 ; and each Rk is selected from: -H, and methyl.
• each Rl 5 is independently selected from:
• Rh is selected from: -H, -OH, and -NH2
• each Rk is selected from: -H, and methyl.
• each Rl 5 is independently selected from:
• Rl 5 j s selected from:
• each R n is independently selected from: (1) -H,
• each R" is independently selected from:
• each Ri is independently selected from
• each Ri is independently selected from:
• each Ri is independently selected from: (1) -H,
• each Ri is hydrogen
• each R ⁇ is independently selected from: (1) -H, and
• each R ⁇ is independently selected from:
• R ⁇ , R.9, and RlO is Rl5.
• R ⁇ is RlS.
• R ⁇ is Rl 5.
• RlO is Rl 5.
• Alkyl as well as other groups having the prefix “alk”, such as alkoxy, alkanoyl, means carbon chains which may be linear or branched or combinations thereof.
• alkyl groups include methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, sec- and tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl.
• Aryl means mono- or bicyclic aromatic rings containing only carbon atoms. Examples of aryl include phenyl, naphthyl, and the like.
• Halogen includes fluorine, chlorine, bromine and iodine.
• Compounds of Formula I may contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereorneric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
• Tautomers are defined as compounds that undergo rapid proton shifts from one atom of the compound to another atom of the compound. Some of the compounds described herein may exist as tautomers with different points of attachment of hydrogen. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
• Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or ethyl acetate or a mixture thereof.
• the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
• any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
• crystalline forms for compounds of the present invention may exist as polymorphs and as such are intended to be included in the present invention.
• some of the compounds of the instant invention may form solvates with water or common organic solvents. Such solvates are encompassed within the scope of this invention.
• Racemic mixtures can be separated into their individual enantiomers by any of a number of conventional methods. These include chiral chromatography, derivatization with a chiral auxiliary followed by separation by chromatography or crystallization, and fractional crystallization of diastereomeric salts.
• salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
• Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
• Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
• basic ion exchange resins such
• pharmaceutically acceptable salt further includes all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate/diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollyl
• Compounds of the present invention are modulators of the CBl receptor.
• the compounds of structural formula I are antagonists or inverse agonists of the CBl receptor.
• Compounds of this invention are modulators of the CBl receptor and as such are useful as centrally acting drugs in the treatment of psychosis; memory deficits; cognitive disorders; Alzheimer's disease; migraine; neuropathy; neuro-inflammatory disorders including multiple sclerosis and Guillain- Barre syndrome and the inflammatory sequelae of viral encephalitis, cerebral vascular accidents, and head trauma; anxiety disorders; stress; epilepsy; Parkinson's disease; movement disorders; schizophrenia; substance abuse disorders, particularly to opiates, alcohol, marijuana, and nicotine; obesity or eating disorders associated with excessive food intake and complications associated therewith, including left ventricular hypertrophy, as well as treating or preventing obesity in other mammalian species, including canines and felines; cirrhosis of the liver; non-alcoholic fatty liver disease (NAFLD); non-alcoholic steatohepatitis (NASH); asthma;
• the compounds of the present invention possess a 5-membered, carbon-linked, partly or fully unsaturated, heterocylic moiety and are metabolized by both oxidative and nonoxidative mechanisms.
• This heterocyclic moiety is amenable to secondary metabolic processing and/or oxidative cleavage, which provides a favorable metabolic profile.
• the compounds of the present invention exhibit mixed mechanisms of metabolism or clearance. It is highly desirable that the clearance and/or excretion of drugs from targeted patients be mediated by more than one mechanism rather than be dependent .upon a single mechanism to clear the drug from the patient. This is a desirable feature to avoid potential drug- drug interactions or genetic polymorphisms in a single clearance mechanism that might contribute to broad patient to patient variability.
• mixed mechanisms of clearance may avoid undesirable rises in drug exposure in patients with compromised organ function; for example, liver function impairment or kidney disease.
• compounds of the present invention may have more limited patient to patient variability in exposure and a greater safety profile.
• prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 50 mg per kg, and most preferably 0.1 to 10 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outside these limits in some cases.
• compositions which comprises a compound of Formula I and a pharmaceutically acceptable carrier.
• composition is intended to encompass a product comprising the active ingredient(s), and the inert ingredient(s) (pharmaceutically acceptable excipients) that make up the carrier, as well as any product which results, directly or indirectly, from combination, complexation or aggregation of any two or more of the ingredients, or from dissociation of one or more of the ingredients, or from other types of reactions or interactions of one or more of the ingredients.
• the pharmaceutical compositions of the present invention encompass any composition made by admixing a compound of Formula I, additional active ingredient(s), and pharmaceutically acceptable excipients.
• Any suitable route of administration may be employed for providing a mammal, particularly a human or companion animal such as a dog or cat, with an effective dosage of a compound of the present invention.
• oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed.
• Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
• the pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients.
• Suitable topical formulations of a compound of formula I include transdermal devices, aerosols, creams, solutions, ointments, gels, lotions, dusting powders, and the like.
• the topical pharmaceutical compositions containing the compounds of the present invention ordinarily include about 0.005% to 5% by weight of the active compound in admixture with a pharmaceutically acceptable vehicle.
• Transdermal skin patches useful for administering the compounds of the present invention include those well known to those of ordinary skill in that art.
• the compounds of Formula I can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
• compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules (including timed release and sustained release formulations), pills, cachets, powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion, including elixirs, tinctures, solutions, suspensions, syrups and emulsions.
• capsules including timed release and sustained release formulations
• pills including timed release and sustained release formulations
• cachets powders, granules or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-
• each tablet, cachet, or capsule contains from about 0.01 to 1,000 rag, particularly 0.01, 0.05, 0.1, 0.5, 1.0, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 15, 25, 30, 40, 50, 75, 100, 125, 150, 175, 180, 200, 225, 250, 500, 750 and 1,000 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
• Additional suitable means of administration of the compounds of the present invention include injection, intravenous bolus or infusion, intraperitoneal, subcutaneous, intramuscular and topical, with or without occlusion.
• Exemplifying the invention is a pharmaceutical composition comprising any of the compounds described above and a pharmaceutically acceptable carrier. Also exemplifying the invention is a pharmaceutical composition made by combining any of the compounds described above and a pharmaceutically acceptable carrier.
• An illustration of the invention is a process for making a pharmaceutical composition comprising combining any of the compounds described above and a pharmaceutically acceptable carrier.
• the dose may be administered in a single daily dose or the total daily dosage may be administered in divided doses of two, three or four times daily. Furthermore, based on the properties of the individual compound selected for administration, the dose may be administered less frequently, e.g., weekly, twice weekly, monthly, etc. The unit dosage will, of course, be correspondingly larger for the less frequent administration.
• the dosage administration When administered via intranasal routes, transdermal routes, by rectal or vaginal suppositories, or through a continual intravenous solution, the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
• Compounds of Formula I may be used in combination with other drugs that are used in the treatment/prevention/suppression or amelioration of the diseases or conditions for which compounds of Formula I are useful. Such other drugs may be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of Formula I.
• a pharmaceutical composition containing such other drugs in addition to the compound of Formula I is preferred.
• the pharmaceutical compositions of the present invention include those that also contain one or more other active ingredients, in addition to a compound of Formula I.
• Examples of other active ingredients that may be combined with a compound of Formula I include, but are not limited to: antipsychotic agents, cognition enhancing agents, anti-migraine agents, anti-asthmatic agents, antiinflammatory agents, anxiolytics, anti-Parkinson's agents, anti-epileptics, anorectic agents, serotonin reuptake inhibitors, other anti-obesity agents, as well as antidiabetic agents, lipid lowering agents, and antihypertensive agents which may be administered separately or in the same pharmaceutical compositions.
• Specific DP-IV inhibitors of use in combination with a compound of the present invention are selected from T-CCS ⁇ -B-amino ⁇ jS-trifluoropheny ⁇ butanoylJ-S-CtrifluoromethyO-Sj ⁇ JjS-tetrahydro- 1 ,2,4-triazolo[4,3-a]pyrazine.
• the compound of formula I is favorably combined with 7- [(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-(trifluoromethyl)-5,6,7,8-tetrahydro-l,2,4- triazolo[4,3-a]pyrazine, and pharmaceutically acceptable salts thereof.
• the obesity-related disorders herein are associated with, caused by, or result from obesity.
• obesity-related disorders include overeating and bulimia, hypertension, diabetes, elevated plasma insulin concentrations and insulin resistance, dyslipidemias, hyperlipidemia, endometrial, breast, prostate and colon cancer, osteoarthritis, obstructive sleep apnea, cholelithiasis, gallstones, heart disease, abnormal heart rhythms and arrythmias, myocardial infarction, congestive heart failure, coronary heart disease, sudden death, stroke, polycystic ovarian disease, craniopharyngioma, the Prader-Willi Syndrome, Frohlich's syndrome, GH-deficient subjects, normal variant short stature, Turner's syndrome, and other pathological conditions showing reduced metabolic activity or a decrease in resting energy expenditure as a percentage of total fat-free mass, e.g, children with acute lymphoblastic leukemia.
• obesity-related disorders are metabolic syndrome, also known as syndrome X, insulin resistance syndrome, sexual and reproductive dysfunction, such as infertility, hypogonadism in males and hirsutism in females, gastrointestinal motility disorders, such as obesity-related gastro- esophageal reflux, respiratory disorders, such as obesity-hypoventilation syndrome (Pickwickian syndrome), cardiovascular disorders, inflammation, such as systemic inflammation of the vasculature, arteriosclerosis, hypercholesterolemia, hyperuricaemia, lower back pain, gallbladder disease, gout, and kidney cancer.
• the compounds of the present invention are also useful for reducing the risk of secondary outcomes of obesity, such as reducing the risk of left ventricular hypertrophy.
• the compounds of formula I are also useful for treating or preventing obesity and obesity-related disorders in cats and dogs.
• the term "mammal" includes companion animals such as cats and dogs.
• substance abuse disorders includes substance dependence or abuse with or without physiological dependence.
• the substances associated with these disorders are: alcohol, amphetamines (or amphetamine-like substances), caffeine, cannabis, cocaine, hallucinogens, inhalants, marijuana, nicotine, opioids, phencyclidine (or phencyclidine-like compounds), sedative-hypnotics or benzodiazepines, and other (or unknown) substances and combinations of all of the above.
• compounds of structural formula I are useful for aiding in stopping consumption of tobacco and are useful in treating nicotine dependence and nicotine withdrawal.
• the compound of form I may be used in combination with a nicotine agonist or a partial nicotine agonist, including varenicline and selective alpha-4 beta 2 nicotinic partial agonists such as SSR 591813, or a monoamine oxidase inhibitor (MAOI), or another active ingredient demonstrating efficacy in aiding cessation of tobacco consumption; for example, an antidepressant such as bupropion, doxepine, ornortriptyline; or an anxiolytic such as buspirone or clonidine.
• a nicotine agonist or a partial nicotine agonist including varenicline and selective alpha-4 beta 2 nicotinic partial agonists such as SSR 591813, or a monoamine oxidase inhibitor (MAOI), or another active ingredient demonstrating efficacy in aiding cessation of tobacco consumption
• an antidepressant such as bupro
• the method of treatment of this invention comprises a method of modulating the CBl receptor and treating CBl receptor mediated diseases by administering to a patient in need of such treatment a non-toxic therapeutically effective amount of a compound of this invention that selectively antagonizes the CBl receptor in preference to the other CB or G-protein coupled receptors.
• Step 2 N ⁇ r(»y)-f4-chlorophenyl')f3-cvanophenyl')methyn-2-methylpropane-2-fR ' )- sulfanamide
• Step 3 3-f(-?)-amino(4-chloropheny ⁇ methvnbenzonitrile hydrochloride
• a solution of 850 mg (2.45 mmole) of N-[(S)-(4-chlorophenyl)(3-cyanophenyl)methyl]-2- methylpropane-2-(i?)-sulfinamide in 20 mL of CH3OH was added 2.5 mL of 4M HCL in dioxane. The solution was stirred at room temperature for 45 min, then was diluted with 40 mL ether. The solids were collected by filtration to afford the title compound as a white solid; 1 H-NMR(CDCIs) ⁇ 1.6 (s, 2H, br), 5.24 (s, IH), 7.24-7.78 (m, 8H).
• the supernatant was decanted and the solids were triturated with two 20 mL portions of CH2CI2 an ⁇ two 20 mL portions of ether.
• the combined organic extracts were washed with saturated aqueous NH4CI solution and brine, dried over Na2SO4 and concentrated to afford the title compound as a mixture of 4 diastereomers.
• the mixture was purified by flash chromatography on silica gel using a step gradient of 3 column volumnes each of 1%, then 2%, then 4%, then 6% ethyl acetate-hexane to afford two diastereomers of the title compound.
• This compound was prepared according to the procedures in WO 05/000809, Example 49.
• This compound was prepared according to the procedures in WO 05/000809, Example 74.
• Step 1 Ethyl f2J?V(3-bromo-5-fluorophenyl > )ri-fdiphenylmethylV3-hvdroxyazetidin-3-vnacetate
• the title compound was prepared from ethyl 3-bromo-5-fluorophenylacetate and l-[bis- phenylmethyl]azetidin-3-one (Preparation 2) by the procedure described in Step 2 of Preparation 3 except that lithium hexamethyldisilamide was used instead of butyllithium to form the ketene acetal;
• Mass Spectrum: m/e 498 (M+l, 79fir), 500 (M+l, Sl ⁇ r)
• Step 2 Ethyl ( " 3-bromo-5-fluorophenyl)ri-fdiphenylmethyl)azetidin-3-ylidene1acetate
• Step 3 Ethyl fB-bromo-S-fluorophenvDri-rdiphenylmethvDazetidin-S-yliacetate
• Step 4 l-( " 3-Bromo-5-fluorophenv ⁇ -l-ri-(diphenylmethyl)azetidin-3-yll-2-methylpropan-2-ol
• Step 5 (I-SVl -(3-bromo-5-fluorophenyr)- 1 -[ " 1 -( " diphenylmethyl)azetidin-3-yll-2-methylpropan-2- ol
• Step 6 3-[(l ⁇ S)-l-(3-bromo-5-fluorophenvlV2-fluoro-2-methvlpropvl]-l-fdiphenylmethyl ' ) azetidine
• the title compound was prepared from (l-S)-l-(3-bromo-5-fluorophenyl)-l-[l-(diphenylmethyl) azetidin-
• Step 7 3-[fl ) ->)-l-f3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl1azetidine
• Step 8 3-[(5)- ⁇ 3-[(15)-l-(3-Bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-l-yl ⁇ (4- chlorophenvDmethyllbenzonitrile
• Step 9 3-((liS)-l- ⁇ l-[(S)-(4-chlorophenyl)(3-cyanophenyl)methyl]azetidin-3-yl ⁇ -2-fluoro-2- methylpropylV5-fluorobenzonitrile
• Step 2 3 - f 1 -f 1 -(diphenylmethyl)azetidin-3-yl " )-2-fluoro-2-methylpropyl ⁇ -5-fluorobenzoic acid
• the reaction of mixture of 7.15g (17.18 mmol) of 3- ⁇ l-[l(diphenylmethyl)azetidin-3-yl]-2-fluoro-2- methylpropyl ⁇ -5-fiuorobenzonitrile (Step 1), 125 mL of EtOH, and 70 mL of 5N NaOH was refluxed for 3.5h. Then it was adjusted to pH 4-5 with 12N HCl and concentrated to remove solvents.
• Step 3 Ethyl 3 - ( 1 -f 1 -f diphenylmethvDazetidin-3 -yl1-2-fluoro-2-rnethylpropyl ⁇ -5-fluorobenzoate
• Step 4 Ethyl 3-(l-azetidin-3-yl-2-fluoro-2-methylpropyl)-5-fluorobenzoate
• Ethyl 3- ⁇ l-[l-(diphenylmethyl)azetidin-3-yl]-2-fluoro-2-methylpropyl ⁇ -5-fluorobenzoate (7.6g, 16.40 mmol) was hydrogenated in 150 mL of EtOH in the presence 3.4g of Pd(OH)2 under 50 Psi pressure hydrogen for 24 h. Then it was filtered to remove the solid and washed with CH2CI2. The combined organic layer was concentrated and washed with hexanes/ether to afford the title compound as an white solid.
• Step 1 Methyl 4-r ⁇ '3-cvano ⁇ henyl)(hvdroxy ' )methyl '
• benzoate A solution of 3.0 g (15 mmole) of methyl 4-(chlorocarbonyl)benzoate and 183 mg (0.2 mmole) of tris(dibenzylideneacetone)dipalladium(0) was cooled to 0 0 C under N2. After 5 min, 32 mL of a 0.5 M solution of (3-cyanophenyl)(iodo)zinc in THF was added dropwise and the solution was stirred at rt. After 4 h, the reaction was quenched by addition of saturated NH4CI solution and 30 mL ether.
• Step 3 Methyl 4-ff5)-r3-cvanophenvnf3-r(l-?)-l-r3.5-difluorophenyl')-2-fluoro-2-methylpropyn azetidin- 1 -yl ⁇ methvDbenzoate
• PREPARATION 28 Isopropyl 4-(Cy>-(3-cyanophenyl ' K3-[(15)-l-( ' 3,5-difluorophenyl)-2-fluoro-2-methylpropynazetidin-l- vUmethyl ⁇ benzoate
• Step 1 3-[(5)- ⁇ 3-[(15)-l-(3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropyl]azetidin-l-yl ⁇ (4- chlorophenvDmethv ⁇ -N'-hydroxybenzenecarboximidamide
• Step 2 3-(3-rr ⁇ )-
• Step 1 5-r3-fl-azetidin-3-yl-2-fluoro-2-methylpropylV5-fluorophenyl1-2-methyl-2H-tetrazole
• Step 2 3-[(4-chlorophenyl)('3-(2-fluoro-l-r3-fluoro-5-(2-methyl-2H-tetrazol-5-yl)phenyl1-2- methyl ⁇ ropyl)azetidin-l-vD ⁇ nethv ⁇ benzonitrile
• Step 5 3-
• a solution of 21.1 mL (0.24 mol) of oxalyl chloride in 500 mL CH2CI2 a solution of 34.2 mL (0.48 mol) of DMSO in 50 mL CH2CI2 was added slowly at -78 0 C. After the reaction mixture was stirred for
• Step 6 Methyl (3-bromo-5-fluorophenyl)(l-r(.y)-(4-chlorophenv ⁇ (3-cvanophenyl)methyll azetidin-3-ylidene>acetate
• a solution of 14.55g (58.87 mmol) of methyl (3-bromo-5-fluorophenyl)acetate in 200 mL of THF at - 78 0 C 5 was added a solution of 56.80 mL (56.80 mmol) (IM in THF) of LHMDS.
• Step 7 methyl (2.S)-(3-bromo-5-fluorophenyl)(l-r( ⁇ -(4-chlorophenyl)(3-cvanophenv ⁇ methyl '
• azetidin-3-yl ⁇ acetate To a solution of 27.15g (51.64 mmol) of methyl (3-bromo-5-fluorophenyl) ⁇ l-[(5)-(4-chlorophenyl)(3- cyanophenyl)methyl]azetidin-3-ylidene ⁇ acetate in 120 mL of THF and 220 mL of MeOH, were added small portions of sodium borohydride (total: 740 mg, 31.05 mmol) at -5-0 0 C.
• Step 8 3-rfS)- ⁇ 3-
• a portion of 7.84 g (31.80 mmol) of cerium (JH) chloride (anhydrous) was stirred for 30 min under N2 at rt.
• 120 mL of THF (anhydrous) was added, and the slurry was stirred for another 30 min at rt.
• Step 9 3-f(.?)-r3-[(liy)-l-f3-bromo-5-fluorophenyl)-2-fluoro-2-methylpropynazetidin-l-vH(4- chlorophenvDmethvllbenzonitrile
• HF 70% hydrogen fluoride pyridine
• reaction mixture was poured slowly to a mixture of 250 mL of water, 74 g of NaOH, 300 mL of aq NaHCO3, 30Og of ice and 50OmL of CH2CI2 with rapid stirring.
• the pH of the mixture was adjusted to 7-8, and the mixture was filtered to remove solids.
• the aqueous layer was extracted with three 300 mL portions of CH2CI2- The combined organic layer was dried over Na2S04 and concentrated.
• Step 10 3-
• Step 11 Ethyl 3-r(S>-(3-[(l.y)-l-(3-bromo-5-fluoro ⁇ henylV2-fluoro-2-methylpropynazetidm-l- vU(4-chlorophenyl)methvnbenzoate
• 3-[(5)- ⁇ 3-[(15)-l-(3-bromo-5-fluorophenyl)-2-fluoro-2- methylpropyl]azetidin-l-yl ⁇ (4-chlorophenyl)methyl]benzoic acid in 230 mL of EtOH was added a solution of 25 mL of 4N HCl in dioxane.
• Step 12 Ethyl 3-(fS>-f4-chlorophenynf3-r(l-S r )-l-(3-cvano-5-fluorophenylV2-iluoro-2-methyl- propyliazetidin- 1 -yl>methvl " )benzoate
• Step 13 S- ⁇ S'j- ⁇ -chlorophenvnfS-rd-S ⁇ -l-fS-cvano-S-fluorophenvD ⁇ -fluoro ⁇ -methylpropy ⁇ azetidin-1 -yl ) methvDbenzohvdrazide
• Step 14 S-ffl ⁇ -l-fl-lf ⁇ -chlorophenylXS ⁇ -oxo ⁇ .S-dihvdro-l ⁇ -oxadiazol ⁇ -vDphenvn methvUazetidin-3-ylV2-fluoro-2-methylpropyl "
• 3-((5)-(4-chlorophenyl) ⁇ 3-[(15)-l-(3-cyano-5-fluorophenyl)-2- fluoro-2-methylpro ⁇ yl]azetidin-l-yl ⁇ methyl)benzohydrazide was added 3.73 mL
• Example 27 4-(( ⁇ )-(3-rfl-?)-l-f3.5-difluorophenyl)-2-fluoro-2-methylpropyl]azetidin-l-yl>f3-f5-oxo- 4,5-dihydro- L3 ,4-oxadiazol-2-yI)phenyl '
• methyl ⁇ -benzonitrile Mass Spectrum: m/e 519 (M+l).
• the binding assay for CB2 receptor is done similarly with recombinant human CB2 receptor expressed in CHO cells.
• Compounds of Examples 1-27 have IC50S of less than 1 micromolar in the CBl binding assay.
• the compounds of Examples 1-27 are selective CBl antagonist/inverse agonist compounds having IC50s 100-fold greater in the CB2 binding assay than in the CBl assay, and generally have IC50s of greater than one micromolar in the CB2 binding assay.
• Cannabinoid Receptor-1 (CBl) Functional Activity Assay This assay is described in Biological Example 2 of WO 05/00809.
• CBl antagonist/inverse agonist compounds of the present invention generally have EC50s of less than 1 micromolar in the CBl functional assay and selective CBl antagonist/inverse agonists have generally have EC5OS of greater than 1 micromolar in the CB2 functional assay.
• BIOLOGICAL EXAMPLE 4 Chronic weight reduction studies in rats or mice: General Procedure This assay is described in Biological Example 1 of WO 05/00809.

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