US20200078358A1 - Compounds and Methods for Treatment of Visceral Pain - Google Patents

Compounds and Methods for Treatment of Visceral Pain Download PDF

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US20200078358A1
US20200078358A1 US16/611,174 US201816611174A US2020078358A1 US 20200078358 A1 US20200078358 A1 US 20200078358A1 US 201816611174 A US201816611174 A US 201816611174A US 2020078358 A1 US2020078358 A1 US 2020078358A1
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tetrahydro
cyclopropa
diaza
pentalene
carboxylic acid
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Cheryl Geraldine Lassen
Marcelo Fabian Piccirillo
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Arena Pharmaceuticals Inc
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    • 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
    • C07D403/04—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 directly linked by a ring-member-to-ring-member bond
    • 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
    • A61K31/415—1,2-Diazoles
    • A61K31/416—1,2-Diazoles condensed with carbocyclic ring systems, e.g. indazole
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to certain compounds of Formula Ia and pharmaceutical compositions thereof and their use in methods for the alleviation and/or treatment of visceral pain, for example abdominal pain; pelvic pain; pain from an internal organ; or pain arising from or related to pancreatitis (e.g., chronic pancreatitis), inflammatory bowel disease, endometriosis, interstitial cystitis, prostatitis (e.g., chronic prostatitis), or post-surgical abdominal lesions.
  • the visceral pain arises from or is related to inflammatory bowel disease, for example Crohn's disease.
  • Visceral pain is generally the result of damage or injury to internal organs, and is one of the most common forms of pain. Visceral pain is caused by the activation of pain receptors in the chest, abdomen, or pelvic areas, and can be caused by injury or disease states involving the internal organs, such as the stomach, kidney, gallbladder, urinary bladder, and intestines. Visceral pain can also be caused by problems with abdominal muscles and the abdominal wall, such as spasm. Visceral pain is distinct from somatic pain, which is caused by the activation of pain receptors in either the body surface or musculoskeletal tissues (for example, postsurgical pain from a surgical incision), and from neuropathic pain, which is caused by injury or malfunction to the spinal cord and peripheral nerves.
  • somatic pain which is caused by the activation of pain receptors in either the body surface or musculoskeletal tissues (for example, postsurgical pain from a surgical incision), and from neuropathic pain, which is caused by injury or malfunction to the spinal cord and peripheral nerves.
  • visceral pain examples include abdominal pain; pelvic pain; pain from an internal organ; and pain arising from or related to pancreatitis (e.g., chronic pancreatitis), inflammatory bowel disease, endometriosis, interstitial cystitis, prostatitis (e.g., chronic prostatitis), or post-surgical abdominal lesions.
  • pancreatitis e.g., chronic pancreatitis
  • inflammatory bowel disease e.g., endometriosis, interstitial cystitis
  • prostatitis e.g., chronic prostatitis
  • post-surgical abdominal lesions examples include abdominal pain; pelvic pain; pain from an internal organ; and pain arising from or related to pancreatitis (e.g., chronic pancreatitis), inflammatory bowel disease, endometriosis, interstitial cystitis, prostatitis (e.g., chronic prostatitis), or post-surgical abdominal lesions.
  • IBD inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • opioids that have the potential for developing tolerance/tachyphylaxis, addiction and abuse, and potentially fatal respiratory depression
  • gabapentinoids that are safer than opioids but also produce adverse cognitive effects
  • tricyclic antidepressants that show some efficacy but can also produce somnolence, hypotension, and arrhythmias
  • non-steroidal anti-inflammatories NSAIDs; drugs such as ibuprofen and naproxen which when administered long term may be associated with an increased risk of gastrointestinal injury/bleeding, cardiac events, hypertension, kidney injury, and death.
  • Cannabinoids are a group of extracellular signaling molecules. Signals from these molecules are mediated in animals by two G-protein coupled receptors, Cannabinoid Receptor 1 (CB 1 ) and Cannabinoid Receptor 2 (CB 2 ). CB 1 is expressed most abundantly in the neurons of the CNS but is also present at lower concentrations in a variety of peripheral tissues and cells (Matsuda, L. A. et al. (1990) Nature 346:561-564). In contrast, CB 2 is expressed predominantly, although not exclusively, in non-neural tissues, e.g.
  • CB 1 is believed to be primarily responsible for mediating the psychotropic effects of cannabinoids on the body, whereas CB 2 is believed to be primarily responsible for most of their non-neural effects.
  • Compounds of Formula Ia are particularly useful for the treatment of visceral pain, for example abdominal pain; pelvic pain; male pelvic pain; pain from an internal organ; bladder pain; painful bladder syndrome; post-surgical abdominal pain (e.g., GI resection, hysterectomy, oophorectomy, C-section); or pain associated with: pancreatitis (e.g., chronic pancreatitis), prostatitis (e.g., chronic prostatitis), inflammatory bowel disease (e.g., Crohn's disease), endometriosis, interstitial cystitis, prostatitis (e.g., chronic prostatitis), epididymitis (e.g., chronic epididymitis), or post-surgical abdominal lesions.
  • pancreatitis e.g., chronic pancreatitis
  • prostatitis e.g., chronic prostatitis
  • inflammatory bowel disease e.g., Crohn's disease
  • endometriosis inter
  • the visceral pain arises from or is related to inflammatory bowel disease, for example Crohn's disease.
  • the interstitial cystitis is interstitial cystitis induced by chemotherapy, ulcerative interstitial cystitis, nonulcerative interstitial cystitis, or autoimmune interstitial cystitis.
  • the present disclosure provides methods for treating or alleviating visceral pain in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof:
  • the compound of Formula Ia is (1aS,5aS)-2-(4-oxy-pyrazin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid ((S)-1-hydroxymethyl-2,2-dimethyl-propyl)-amide, (Compound A, also referred to herein as Compound 699) having the structure:
  • the visceral pain is abdominal pain; pain arising from or related to an internal organ; or pain associated with pancreatitis (e.g., chronic pancreatitis), inflammatory bowel disease, endometriosis, interstitial cystitis, prostatitis (e.g., chronic prostatitis), or a post-surgical abdominal lesion.
  • pancreatitis e.g., chronic pancreatitis
  • inflammatory bowel disease e.g., endometriosis, interstitial cystitis
  • prostatitis e.g., chronic prostatitis
  • a post-surgical abdominal lesion e.g., the visceral pain is pain arising from or related to inflammatory bowel disease, for example pain arising from or related to Crohn's disease.
  • the patient is in remission for Crohn's disease, for example where the patient is in remission for Crohn's disease and has chronic visceral pain.
  • the patient has previously been treated with an opioid analgesic for pain arising from or related to inflammatory bowel disease, for example Crohn's disease.
  • the patient is administered a daily dose of Compound A from 10 mg to 400 mg, from one to three times per day.
  • the visceral pain does not arise from or relate to inflammatory bowel disease. In some embodiments, the visceral pain does not arise from or relate to Crohn's disease.
  • the present disclosure provides methods for selectively activating a CB 2 receptor in a patient experiencing visceral pain, comprising administering to the patient a therapeutically effective amount of a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof, for example Compound A, as described above.
  • the present disclosure provides pharmaceutical compositions for alleviation of visceral pain, the compositions comprising a therapeutically effective amount of a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof as described above, for example Compound A.
  • the present disclosure provides the use of compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof as described above, for example Compound A, in the manufacture of a medicament for the treatment or alleviation of visceral pain.
  • FIG. 1 shows the effect of Compound 493 in the FCA-induced hyperalgesia model of inflammatory pain in rats at 1-hour post dosing. See Example 7.
  • FIG. 2 shows the effect of Compound 493 in the monosodium iodoacetate (MIA) model of osteoarthritis in rats at 1-hour post dosing. See Example 5.
  • FIG. 3 shows the effect of 10 mg/kg of Compound 493 on paclitaxel-induced allodynia in rats. See Example 8.
  • FIG. 4 shows the effect of Compound 493 on the skin incision model of post-operative pain in rats. See Example 6.
  • FIG. 5 shows the effect of Compound 455 on body temperature and locomotor activity in rats. See Example 9.
  • FIG. 6 shows the effect of Compound 660 on body temperature and locomotor activity in rats. See Example 9.
  • FIG. 7 shows the effect of Compound 700 on body temperature and locomotor activity in rats. See Example 9.
  • FIG. 8 shows the effect of Compound 667 on body temperature and locomotor activity in rats. See Example 9.
  • FIG. 9 shows the effect of Compound 699/Compound A (10 mpk) compared to vehicle (methyl cellulose) in the STZ-induced PDPN Model. See Example 12.
  • FIG. 10 shows the effect of Compound 919 (10 mpk) compared to vehicle (methyl cellulose) in the STZ-induced PDPN Model. See Example 12.
  • FIG. 11 shows the effect of Compound 699 in an acetic acid-induced writhing model of visceral pain. See Example 13.
  • FIG. 12 shows the effect of Compound 699 in an acetic acid-induced writhing model of visceral pain. See Example 13.
  • VMR visceromotor response
  • CCD colorectal distension
  • treatment and “treating” are to be understood accordingly as embracing treatment or amelioration of symptoms of disease as well as treatment of the cause of the disease.
  • patient may include a human or non-human patient.
  • Method 1 for treating or alleviating visceral pain in a patient in need of such treatment, comprising administering to the patient a therapeutically effective amount of a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof:
  • the disclosure further provides, in one embodiment, a method (Method 2) for selectively activating a CB2 receptor in a patient experiencing visceral pain, comprising administering to the patient a therapeutically effective amount of a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof:
  • the disclosure further provides, in a further embodiment, the use (Use 1) of compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof as described above, for example any of Compounds 1-931 disclosed below, and pharmaceutically acceptable salts, and N-oxides thereof, including for example any the compounds listed in Method 2.7, and pharmaceutically acceptable salts, and N-oxides thereof, for example Compound A, or a pharmaceutically acceptable salt or crystal form thereof, in the manufacture of a medicament for the treatment or alleviation of visceral pain (e.g., in a patient), for example:
  • composition 1 a pharmaceutical composition for alleviation of visceral pain
  • composition 1 comprising a therapeutically effective amount of a compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof as described above, for example Compound A, or a pharmaceutically acceptable salt or crystal form thereof, for example:
  • the present disclosure further provides a method (Method 3) of producing a pharmaceutical composition for alleviation of visceral pain in accordance with any Composition 1 or 1.1-1.28, comprising admixing at least one compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof as described above, for example any of Compounds 1-931 disclosed below, and pharmaceutically acceptable salts, and N-oxides thereof, including for example, any of the compounds listed in Method 2.7, and pharmaceutically acceptable salts, and N-oxides thereof, for example Compound A, or a pharmaceutically acceptable salt or crystal form thereof, and a pharmaceutically acceptable carrier.
  • Method 3 of producing a pharmaceutical composition for alleviation of visceral pain in accordance with any Composition 1 or 1.1-1.28, comprising admixing at least one compound selected from compounds of Formula Ia and pharmaceutically acceptable salts and N-oxides thereof as described above, for example any of Compounds 1-931 disclosed below, and pharmaceutically acceptable salts, and N-oxid
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the pain is mild to moderate pain.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the pain is mild pain.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the pain is moderate pain.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the pain is severe pain.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the pain is moderate to moderately severe pain.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the pain is moderate to severe pain.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the patient has a visual analogue scale pain score of ⁇ 40 mm.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the patient has a Likert numerical rating scale pain score of ⁇ 4.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the pain is moderate to severe pain requiring continuous, around-the-clock opioid therapy for an extended period of time.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the pain is acute pain.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the method is for short-term use (five days or less).
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the pain is chronic visceral pain.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the compound of Formula Ia is provided in an enterically coated dosage form; a delay release dosage form, or a pulsatile release dosage form.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the compound is Compound 699, and the pain is abdominal pain, pelvic pain, pain arising from or related to an internal organ, painful bladder syndrone, pancreatitis, chronic pancreatitis, inflammatory bowel disease, endometriosis, interstitial cystitis, interstitial cystitis induced by chemotherapy, ulcerative interstitial cystitis, nonulcerative interstitial cystitis, autoimmune interstitial cystitis, prostatitis, chronic prostatitis, or post-surgical abdominal lesion.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the compound is Compound 699, and the pain is pain arising from or related to inflammatory bowel disease.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the compound is Compound 699, and the pain is pain arising from or related to Crohn's disease.
  • the present disclosure further provides any Method 1 or 1.1-34; Method 2 or 2.1-2.34; Use 1 or 1.1-15; Composition 1 or 1.1-1.28; or Method 3, wherein the compound is administered at one or more initial doses having an initial dosage amount of the compound, and then is subsequently administered at one or more successive doses having a lower dosage amount of the compound.
  • the initial dose is 100 mg TID and the reduced dose is 50 mg TID; or the initial dose is 25 mg TID and the reduced dose is 25 mg BID.
  • the present disclosure further provides any foregoing Method, Use or Composition, wherein the visceral pain does not arise from or relate to inflammatory bowel disease.
  • the present disclosure further provides any foregoing Method, Use or Composition, wherein the visceral pain does not arise from or relate to Crohn's disease.
  • Some embodiments of the present disclosure include methods, compositions and uses for every combination of one or more compounds selected from the following group, wherein the Compound Number in bold directly preceding the chemical name is used elsewhere in this disclosure:
  • chemical genera of the present disclosure and individual compounds encompass all pharmaceutically acceptable salts, solvates, and particularly hydrates, thereof.
  • the compounds of the Formula Ia of the present disclosure may be prepared according to relevant published literature procedures that are used by one skilled in the art. Exemplary reagents and procedures for these reactions, and specific procedures from the preparation of numerous compounds can be found in International Publication No. WO2011/025541. Protection and deprotection may be carried out by procedures generally known in the art (see, for example, Greene, T. W. and Wuts, P. G. M., Protecting Groups in Organic Synthesis, 3 rd Edition, 1999 [Wiley]).
  • the present invention embraces each diastereoisomer, each enantiomer and mixtures thereof of each compound and generic formulae disclosed herein just as if they were each individually disclosed with the specific stereochemical designation for each chiral carbon. Separation of the individual isomers (such as, by chiral HPLC, recrystallization of diastereoisomeric mixtures and the like) or selective synthesis (such as, by enantiomeric selective syntheses and the like) of the individual isomers is accomplished by application of various methods which are well known to practitioners in the art.
  • the analgesic properties of cannabinoids have been recognized for many years.
  • animal studies have demonstrated that the CB 1 /CB 2 agonists anandamide, THC, CP55,940 and WIN 55212-2 are effective against acute and chronic pain from chemical, mechanical, and thermal pain stimuli (reviewed in Walker and Huang (2002) Pharmacol. Ther. 95:127-135; reviewed in Pacher, P et al. (2006) Pharmacol. Rev. 58(3): 389-462).
  • topical administration of the CB 1 /CB 2 agonist HU-210 attenuates capsaicin-induced hyperalgesia and allodynia (Rukwied, R. et al.
  • CB 1 The role of CB 1 in mediating these analgesic effects is well-documented (reviewed in Manzanares, J. et al. (2006) Current Neuropharmacology 4:239-57; reviewed in Pacher, P. et al. (2006) Pharmacol. Rev. 58(3): 389-462).
  • blockade of peripheral or central CB 1 leads to hyperalgesia (Richardson, J. D. et al. (1997) Eur. J. Pharmacol. 345:145-153; Calignano, A. et al.
  • CB 2 also plays a role in mediating analgesic effects of cannabinoids (reviewed in Guindon and Hohmann (2008) Br. J. Pharmacol. 153:319-334).
  • systemic delivery of the CB 2 -selective agonist AM1241 suppresses hyperalgesia induced in the carrageenan, capsaicin, and formalin models of inflammatory pain in rodents (reviewed in Guindon and Hohmann (2008) Br. J. Pharmacol. 153:319-334).
  • Local (subcutaneous) or systemic administration of AM1241 also reverses tactile and thermal hypersensitivity in rats following ligation of spinal nerves in the chronic constriction injury model of neuropathic pain (Malan, T.
  • CB 2 -specific agonists and/or CB 1 /CB 2 agonists find use in the treatment and/or prophylaxis of acute nociception and inflammatory hyperalgesia, as well as the allodynia and hyperalgesia produced by neuropathic pain.
  • these agonists are useful as an analgesic to treat pain arising from autoimmune conditions; allergic reactions; bone and joint pain; muscle pain; dental pain; nephritic syndrome; scleroderma; thyroiditis; migraine and other headache pain; pain associated with diabetic neuropathy; fibromyalgia, HIV-related neuropathy, sciatica, and neuralgias; pain arising from cancer; and pain that occurs as an adverse effect of therapeutics for the treatment of disease.
  • the Cannabinoid system in inflammatory bowel disease is dysregulated, and the enzymes that breakdown endocannabinoids (e.g. fatty acid amide hydrolase—FAAH) are increased in active inflammatory Crohn's disease.
  • the enzymes that synthesize endocannabinoids e.g. N-acyl-phosphatidylethanolamine-specific phospholipase—NAPE-PLD) are decreased in active inflammatory Crohn's disease and some endocannabinoids are decreased in active inflammatory bowel disease.
  • the CB 2 receptors are located in the target tissue gastrointestinal (GI) cells and local immune cells in both humans and in rodents, and are found in epithelial cells, immune cells, and in enteric neurons where CB 2 mediated sensitivity is observed at visceral afferent nerve endings.
  • GI target tissue gastrointestinal
  • the CB 2 receptor is increased in the ulcerative margin in Crohn's disease, and cannabinoids have been shown to be effective in clinical trials for Crohn's pain.
  • cannabis has been demonstrated to induce a clinical response in patients with Crohn's disease in a prospective placebo-controlled study, and treatment of Crohn's disease with cannabis in an observational study showed improvements in the pain score.
  • CB 2 activation can alleviate abdominal pain without the unwanted cognitive effects of CB 1 receptor activation.
  • a CB 2 agonist has been shown to block mesenteric nerve firing and this effect is blocked in CB 2 knockouts.
  • LCFM probiotic Lactobacillus acidophophilis
  • a reduction of intestinal pain by probiotic Lactobacillus acidophophilis (LCFM) administration in a butyrate-induced model of colonic hypersensitivity is blocked by a CB 2 receptor antagonist.
  • LCFM probiotic Lactobacillus acidophophilis
  • Compound A for recombinant CB 2 receptors were determined using radioligand binding assays and GPCR signaling assays.
  • Compound A was shown to be a full agonist of the CB 2 receptor with a Ki of 6 nM for human CB 2 and EC50 values between 6 nM and 8 nM for the human, rat, and dog receptors.
  • Ki 6 nM for human CB 2
  • EC50 values between 6 nM and 8 nM for the human, rat, and dog receptors.
  • Compound A did not interact with recombinant human, rat, or dog CB 1 receptors, indicating a >1000-fold selectivity across these species.
  • the Compounds of the Formula Ia are particularly useful for the treatment of visceral pain, for example abdominal pain; pelvic pain; pain from an internal organ; or pain arising from or related to pancreatitis (e.g., chronic pancreatitis), inflammatory bowel disease, endometriosis, interstitial cystitis, prostatitis (e.g., chronic prostatitis), or post-surgical abdominal lesions.
  • visceral pain arises from or is related to inflammatory bowel disease, for example Crohn's disease.
  • the Compounds of the Formula Ia are also particularly useful for the treatment of visceral pain in an organ or tissue expressing the CB2 receptor.
  • CB2 receptor expression has been reported, for example, in the spleen, vermiform appendix, lung, terminal ileum of the small intestine, small intestine Peyer's patch, lymph nodes, urinary bladder, stomach, thymus, and sigmoid colon (EMBL-EBI Expression Atlas, accessed Feb. 22, 2017).
  • the severity of the pain can be assessed with self-reported measures as is known in the art. Generally, pain is assessed at rest, with appropriate activity (e.g., ambulation, cough), at baseline (prior to administration of the compound of Formula Ia or a pharmaceutically acceptable salt, solvate, hydrate, and/or N-oxide thereof and at regular intervals thereafter).
  • Some of the most commonly used pain assessment instruments include the visual analog scale (VAS), numeric rating scale (NRS), and categorical Likert scale.
  • VAS is a written assessment that typically utilizes an unmarked 100-mm line with the left end marked as “no pain” and the right end marked as “worst pain imaginable.” Subjects put a mark on the line corresponding to their level of pain.
  • the NRS can be applied in either written or verbal form and typically utilizes a rating from 0 (corresponding to “no pain”) to 10 (corresponding to “worst pain imaginable”).
  • Likert scales are typically four- or five-item instruments (e.g., ratings of “none”, “mild”, “moderate”, “severe”) that attempt to quantify pain.
  • a further aspect of the present invention pertains to pharmaceutical compositions comprising one or more compounds as described herein and one or more pharmaceutically acceptable carriers. Some embodiments pertain to pharmaceutical compositions comprising a compound of the present invention and a pharmaceutically acceptable carrier.
  • Some embodiments of the present invention include a method of producing a pharmaceutical composition for alleviation of visceral pain comprising admixing at least one compound according to Formula Ia and a pharmaceutically acceptable carrier.
  • Formulations may be prepared by any suitable method, typically by uniformly mixing the active compound(s) with liquids or finely divided solid carriers, or both, in the required proportions and then, if necessary, forming the resulting mixture into a desired shape.
  • Liquid preparations for oral administration may be in the form of solutions, emulsions, aqueous or oily suspensions and syrups.
  • the oral preparations may be in the form of dry powder that can be reconstituted with water or another suitable liquid vehicle before use. Additional additives such as suspending or emulsifying agents, non-aqueous vehicles (including edible oils), preservatives and flavorings and colorants may be added to the liquid preparations.
  • Parenteral dosage forms may be prepared by dissolving the compound of the invention in a suitable liquid vehicle and filter sterilizing the solution before filling and sealing an appropriate vial or ampule. These are just a few examples of the many appropriate methods well known in the art for preparing dosage forms.
  • a compound of the present invention can be formulated into pharmaceutical compositions using techniques well known to those in the art. Suitable pharmaceutically-acceptable carriers, outside those mentioned herein, are known in the art; for example, see Remington, The Science and Practice of Pharmacy, 20 th Edition, 2000, Lippincott Williams & Wilkins, (Editors: Gennaro et al.).
  • a compound of the invention may, in an alternative use, be administered as a raw or pure chemical, it is preferable however to present the compound or active ingredient as a pharmaceutical formulation or composition further comprising a pharmaceutically acceptable carrier.
  • Transdermal patches dispense a drug at a controlled rate by presenting the drug for absorption in an efficient manner with minimal degradation of the drug.
  • transdermal patches comprise an impermeable backing layer, a single pressure sensitive adhesive and a removable protective layer with a release liner.
  • the compounds of the invention may thus be placed into the form of pharmaceutical formulations and unit dosages thereof and in such form may be employed as solids, such as tablets or filled capsules, or liquids such as solutions, suspensions, emulsions, elixirs, gels or capsules filled with the same, all for oral use, in the form of suppositories for rectal administration; or in the form of sterile injectable solutions for parenteral (including subcutaneous) use.
  • Such pharmaceutical compositions and unit dosage forms thereof may comprise conventional ingredients in conventional proportions, with or without additional active compounds or principles and such unit dosage forms may contain any suitable effective amount of the active ingredient commensurate with the intended daily dosage range to be employed.
  • the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid.
  • the pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient.
  • dosage units are capsules, tablets, powders, granules or a suspension, with conventional additives such as lactose, mannitol, corn starch or potato starch; with binders such as crystalline cellulose, cellulose derivatives, acacia, corn starch or gelatins; with disintegrators such as corn starch, potato starch or sodium carboxymethyl-cellulose; and with lubricants such as talc or magnesium stearate.
  • the active ingredient may also be administered by injection as a composition wherein, for example, saline, dextrose or water may be used as a suitable pharmaceutically acceptable carrier.
  • active ingredient is defined in the context of a “pharmaceutical composition” and is intended to mean a component of a pharmaceutical composition that provides the primary pharmacological effect, as opposed to an “inactive ingredient” which would generally be recognized as providing no pharmaceutical benefit.
  • the dose when using the compounds of the present invention can vary within wide limits and as is customary and is known to the physician, it is to be tailored to the individual conditions in each individual case. It depends, for example, on the nature and severity of the illness to be treated, on the condition of the patient, on the compound employed or on whether an acute or chronic disease state is treated or prophylaxis conducted or on whether further active compounds are administered in addition to the compounds of the present invention.
  • Some non-limiting preferred dosages for inclusion in the compositions and methods of the present disclosure include: 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85, mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 175 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 225 mg, 230 mg, 240 mg, 250 mg, 260 mg, 275 mg, 280 mg, 290 mg, 300 mg, 325 mg, 350 mg, 375 mg, and 400 mg.
  • Multiple doses may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3, or 4 doses.
  • doses described herein may be administered during the day, especially when relatively large amounts are deemed to be needed, for example 2, 3, or 4 doses.
  • the amount of active ingredient, or an active salt or derivative thereof, required for use in treatment will vary not only with the particular salt selected but also with the route of administration, the nature of the condition being treated and the age and condition of the patient and will ultimately be at the discretion of the attendant physician or clinician.
  • a model system typically an animal model
  • these extrapolations may merely be based on the weight of the animal model in comparison to another, such as a mammal, preferably a human, however, more often, these extrapolations are not simply based on weights, but rather incorporate a variety of factors.
  • compositions of this invention are selected in accordance with a variety factors as cited above.
  • the actual dosage regimen employed may vary widely and therefore may deviate from a preferred dosage regimen and one skilled in the art will recognize that dosage and dosage regimen outside these typical ranges can be tested and, where appropriate, may be used in the methods of this invention.
  • the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more sub-doses per day.
  • the sub-dose itself may be further divided, e.g., into a number of discrete loosely spaced administrations.
  • the daily dose can be divided, especially when relatively large amounts are administered as deemed appropriate, into several, for example 2, 3, or 4-part administrations. If appropriate, depending on individual behavior, it may be necessary to deviate upward or downward from the daily dose indicated.
  • the compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be obvious to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt, solvate or hydrate of a compound of the invention.
  • a suitable pharmaceutically acceptable carrier can be either solid, liquid or a mixture of both.
  • Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted to the desire shape and size.
  • the powders and tablets may contain varying percentage amounts of the active compound.
  • a representative amount in a powder or tablet may contain from 0.5 to about 90 percent of the active compound; however, an artisan would know when amounts outside of this range are necessary.
  • Suitable carriers for powders and tablets are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter and the like.
  • the term “preparation” is intended to include the formulation of the active compound with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is thus in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets and lozenges can be used as solid forms suitable for oral administration.
  • a low melting wax such as an admixture of fatty acid glycerides or cocoa butter
  • the active component is dispersed homogeneously therein, as by stirring.
  • the molten homogenous mixture is then poured into convenient sized molds, allowed to cool and thereby to solidify.
  • Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or sprays containing in addition to the active ingredient such carriers as are known in the art to be appropriate.
  • Liquid form preparations include solutions, suspensions and emulsions, for example, water or water-propylene glycol solutions.
  • parenteral injection liquid preparations can be formulated as solutions in aqueous polyethylene glycol solution.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectable.
  • the compounds according to the present invention may thus be formulated for parenteral administration (e.g. by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the pharmaceutical compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilization from solution, for constitution with a suitable vehicle, e.g. sterile, pyrogen-free water, before use.
  • Aqueous formulations suitable for oral use can be prepared by dissolving or suspending the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents, as desired.
  • Aqueous suspensions suitable for oral use can be made by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • viscous material such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, or other well-known suspending agents.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents and the like.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • Tablets or capsules for oral administration are preferred compositions.
  • the compounds according to the invention may optionally exist as pharmaceutically acceptable salts including pharmaceutically acceptable acid addition salts prepared from pharmaceutically acceptable non-toxic acids including inorganic and organic acids.
  • Representative acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethenesulfonic, dichloroacetic, formic, fumaric, gluconic, glutamic, hippuric, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, oxalic, pamoic, pantothenic, phosphoric, succinic, sulfiric, tartaric, oxalic, p-toluenesulfonic and the like.
  • Certain compounds of the present invention which contain a carboxylic acid functional group may optionally exist as pharmaceutically acceptable salts containing non-toxic, pharmaceutically acceptable metal cations and cations derived from organic bases.
  • Representative metals include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc and the like.
  • the pharmaceutically acceptable metal is sodium.
  • Organic bases include, but are not limited to, benzathine (N 1 ,N 2 -dibenzylethane-1,2-diamine), chloroprocaine (2-(diethylamino)ethyl 4-(chloroamino)benzoate), choline, diethanolamine, ethylenediamine, meglumine ((2R,3R,4R,5S)-6-(methylamino)hexane-1,2,3,4,5-pentaol), procaine (2-(diethylamino)ethyl 4-aminobenzoate), and the like.
  • Certain pharmaceutically acceptable salts are listed in Berge, et al., Journal of Pharmaceutical Sciences, 66:1-19 (1977).
  • the acid addition salts may be obtained as the direct products of compound synthesis.
  • the free base may be dissolved in a suitable solvent containing the appropriate acid and the salt isolated by evaporating the solvent or otherwise separating the salt and solvent.
  • the compounds of this invention may form solvates with standard low molecular weight solvents using methods known to the skilled artisan.
  • Pro-drugs refers to compounds that have been modified with specific chemical groups known in the art and when administered into an individual these groups undergo biotransformation to give the parent compound. Pro-drugs can thus be viewed as compounds of the invention containing one or more specialized non-toxic protective groups used in a transient manner to alter or to eliminate a property of the compound. In one general aspect, the “pro-drug” approach is utilized to facilitate oral absorption.
  • T. Higuchi and V. Stella Pro-drugs as Novel Delivery Systems Vol. 14 of the A.C.S. Symposium Series; and in Bioreversible Carriers in Drug Design , ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, both of which are hereby incorporated by reference in their entirety.
  • Some embodiments of the present invention include a method of producing a pharmaceutical composition for “combination-therapy” comprising admixing at least one compound according to any of the compound embodiments disclosed herein, together with at least one known pharmaceutical agent as described herein and a pharmaceutically acceptable carrier.
  • the compounds of the present invention can be administrated in a wide variety of oral and parenteral dosage forms. It will be apparent to those skilled in the art that the following dosage forms may comprise, as the active component, either a compound of the invention or a pharmaceutically acceptable salt or as a solvate or hydrate thereof. Moreover, various hydrates and solvates of the compounds of the invention and their salts will find use as intermediates in the manufacture of pharmaceutical compositions. Typical procedures for making and identifying suitable hydrates and solvates, outside those mentioned herein, are well known to those in the art; see for example, pages 202-209 of K. J.
  • one aspect of the present invention pertains to hydrates and solvates of compounds of Formula Ia and/or their pharmaceutical acceptable salts, as described herein, that can be isolated and characterized by methods known in the art, such as, thermogravimetric analysis (TGA), TGA-mass spectroscopy, TGA-Infrared spectroscopy, powder X-ray diffraction (XRPD), Karl Fisher titration, high resolution X-ray diffraction, and the like.
  • TGA thermogravimetric analysis
  • TGA-mass spectroscopy TGA-Infrared spectroscopy
  • powder X-ray diffraction (XRPD) powder X-ray diffraction
  • Karl Fisher titration high resolution X-ray diffraction
  • Polymorphism is the ability of a substance to exist as two or more crystalline phases that have different arrangements and/or conformations of the molecules in the crystal lattice. Polymorphs show the same properties in the liquid or gaseous state but they behave differently in the solid state.
  • drugs can also exist as salts and other multicomponent crystalline phases.
  • solvates and hydrates may contain an API host and either solvent or water molecules, respectively, as guests.
  • the guest compound is a solid at room temperature, the resulting form is often called a cocrystal.
  • Salts, solvates, hydrates, and cocrystals may show polymorphism as well. Crystalline phases that share the same API host, but differ with respect to their guests, may be referred to as pseudopolymorphs of one another.
  • Solvates contain molecules of the solvent of crystallization in a definite crystal lattice. Solvates, in which the solvent of crystallization is water, are termed hydrates. Because water is a constituent of the atmosphere, hydrates of drugs may be formed rather easily.
  • CB 2 receptor e.g., human CB 2 receptor
  • HTRF® assay for direct cAMP measurement Gabriel et al., ASSAY and Drug Development Technologies, 1:291-303, 2003
  • CHO-K1 cells were obtained from ATCC® (Manassas, Va.; Catalog # CCL-61).
  • An agonist of the CB 2 receptor was detected in the HTRF® assay for direct cAMP measurement as a compound which decreased cAMP concentration.
  • HTRF® assay An inverse agonist of the CB 2 receptor was detected in the HTRF® assay for direct cAMP measurement as a compound which increased cAMP concentration.
  • the HTRF® assay also was used to determine EC 50 values for CB 2 receptor agonists and inverse agonists.
  • Compounds were also screened for agonists and inverse agonists of the CB 1 receptor (e.g., human CB 1 receptor) using HTRF® assay for direct cAMP measurement (Gabriel et al., ASSAY and Drug Development Technologies, 1:291-303, 2003) in recombinant CHO-K1 cells stably transfected with the CB 1 receptor.
  • CHO-K1 cells were obtained from ATCC® (Manassas, Va.; Catalog # CCL-61).
  • An agonist of the CB 1 receptor was detected in the HTRF® assay for direct cAMP measurement as a compound which decreased cAMP concentration.
  • HTRF® assay An inverse agonist of the CB 1 receptor was detected in the HTRF® assay for direct cAMP measurement as a compound which increased cAMP concentration.
  • the HTRF® assay also was used to determine EC 50 values for CB 1 receptor agonists and inverse agonists.
  • the HTRF® assay kit was purchased from Cisbio-US, Inc. (Bedford, Mass.; Catalog #62AM4PEC).
  • the HTRF® assay supported by the kit is a competitive immunoassay between endogenous cAMP produced by the CHO-K1 cells and tracer cAMP labeled with the dye d2.
  • the tracer binding is visualized by a monoclonal anti-cAMP antibody labeled with Cryptate.
  • the specific signal i.e., fluorescence resonance energy transfer, FRET
  • FRET fluorescence resonance energy transfer
  • the fluorescence ratio (665 nm/620 nm) of the standards (0.17 to 712 nM cAMP) included in the assay was calculated and used to generate a cAMP standard curve according to the kit manufacturer's instructions.
  • the fluorescence ratio of the samples (test compound or compound buffer) was calculated and used to deduce respective cAMP concentrations by reference to the cAMP standard curve.
  • HTRF® assay was carried out using a two-step protocol essentially according to the kit manufacturer's instructions, in 20 ⁇ L total volume per well in 384-well plate format (ProxiPlates; PerkinElmer, Fremont, Calif.; catalog #6008280).
  • To each of the experimental wells was transferred 1500 recombinant CHO-K1 cells in 5 ⁇ L phosphate buffered saline containing calcium chloride and magnesium chloride (PBS+; Invitrogen, Carlsbad, Calif.; catalog #14040) followed by test compound in 5 ⁇ L assay buffer (PBS+supplemented with 0.2% BSA, 4 ⁇ M forskolin and 1 mM IBMX (Sigma-Aldrich, St.
  • the plate was then incubated at room temperature for 1 hour. To each well was then added 5 ⁇ L cAMP-d2 conjugate in lysis buffer and 5 ⁇ L Cryptate conjugate in lysis buffer according to the kit manufacturer's instructions. The plate was then further incubated at room temperature for 1 hour, after which the assay plate was read.
  • the HTRF® readout was accomplished using a PHERAstar (BMG Labtech Inc., Durham, N.C.) or an EnVisionTM (Perkin Elmer, Fremont Calif.) microplate reader.
  • Certain other compounds of the invention had hCB 1 EC 50 values ranging from about 279 pM to about 76.47 ⁇ M in this assay and hCB 2 EC 50 values ranging from about 170 pM to about 44.72 ⁇ M in this assay. Certain other compounds of the invention had hCB 2 EC 50 values ranging from about 94 pM to about 2.7 nM in this assay.
  • CB 2 was cloned into the pCMV-PK vector (DiscoveRx, Fremont, Calif.; catalog #93-0167) and transfected into the CHO-K1 EA-Arrestin parental cell line (DiscoveRx, Fremont, Calif.; catalog #93-0164).
  • CHO-K1 positive clones stably expressing the CB 2 —ProLink fusion protein were identified by their responses to the CB 2 agonist CP55,940.
  • Clone #61 was chosen for its big agonist window and homogenous expression as detected by anti-HA flow cytometry.
  • the PathHunter-arrestin assay measures the interaction of ⁇ -arrestin with activated GPCRs using Enzyme Fragment Complementation (Yan et al., J. Biomol. Screen. 7: 451-459, 2002).
  • a small, 42 amino acid ⁇ -galactosidase fragment, Prolink is fused to the c-terminus of a GPCR, and ⁇ -arrestin is fused to the larger ⁇ -galactosidase fragment, EA (Enzyme Acceptor).
  • Binding of ⁇ -arrestin to the activated GPCR causes the complementation of the two enzyme fragments, forming an active b-galactosidase enzyme which can be measured using the chemiluminiescent PathHunter Flash Detection Kit (DiscoveRx, Fremont, Calif.: catalog #93-0001).
  • the assay The stable CHO-K1 cells expressing CB 2 -Prolink fusion protein were plated overnight in 384-well plates (Optiplate 384-Plus, PerkinElmer, Fremont Calif.; catalog #6007299) at 5000 cells/5 ⁇ L/well in the Opti-MEM medium (Invitrogen, Carlsbad, Calif.; catalog #31985088) with 1% FBS. 5 ⁇ L of test compound diluted in Opti-MEM supplemented with 1% BSA was transferred to each well of the Optiplate. The plates were then incubated at 37° C./5% CO 2 for two hours.
  • ⁇ -Arrestin assay readout was accomplished using a PHERAstar (BMG Labtech Inc., Durham, N.C.) or an EnVisionTM (PerkinElmer, Fremont Calif.) microplate reader.
  • CB 1 was cloned into the pCMV-PK vector (DiscoveRx, Fremont, Calif.; catalog #93-0167) and transfected into the CHO-K1 EA-Arrestin parental cell line (DiscoveRx, Fremont, Calif.; catalog #93-0164).
  • CHO-K1 positive clones stably expressing the CB 1 -ProLink fusion protein were identified by their responses to the CB 1 agonist CP55,940.
  • Clone #3 was chosen for its big agonist window and homogenous expression as detected by anti-HA flow cytometry
  • the PathHunter ⁇ -arrestin assay measures the interaction of ⁇ -arrestin with activated GPCRs using Enzyme Fragment Complementation (Yan et al., J. Biomol. Screen. 7: 451-459, 2002).
  • a small, 42 amino acid ⁇ -galactosidase fragment, Prolink is fused to the c-terminus of a GPCR, and ⁇ -arrestin is fused to the larger b-galactosidase fragment, EA (Enzyme Acceptor).
  • Binding of ⁇ -arrestin to the activated GPCR causes the complementation of the two enzyme fragments, forming an active b-galactosidase enzyme which can be measured using the chemiluminiescent PathHunter Flash Detection Kit (DiscoveRx, Fremont, Calif.: catalog #93-0001).
  • the stable CHO-K1 cells expressing CB 1 -Prolink fusion protein were plated overnight in 384-well plates (Optiplate 384-Plus, PerkinElmer, Fremont Calif.; catalog #6007299) at 5000 cells/5 ⁇ L/well in the Opti-MEM medium (Invitrogen, Carlsbad, Calif.; catalog #31985088) with 1% FBS. 5 ⁇ L of test compound diluted in Opti-MEM supplemented with 1% BSA was transferred to each well of the Optiplate. The plates were then incubated at 37° C./5% CO 2 for two h.
  • Certain other compounds of the invention had hCB 1 EC 50 values ranging from about 2.6 nM to about 89.06 ⁇ M in this assay and hCB 2 EC 50 values ranging from about 643 pM to about 7 ⁇ M in this assay. Certain other compounds of the invention had hCB 1 EC 50 values ranging from about 10.9 nM to about 100 ⁇ M in this assay and hCB 2 EC 50 values ranging from about 384 pM to about 100 ⁇ M in this assay.
  • Radioligand binding assays for human CB 2 receptors were performed using two different agonist radioligands, [ 3 H]CP55,940 and [ 3 H]WIN55,212-2 and similar assay conditions. For both assays, nonspecific binding was determined in the presence of 10 mM unlabeled compound.
  • Competition experiments consisted of addition of 20 mL of assay buffer (50 mM Tris, pH 7.4, 2.5 mM EDTA, 5 mM MgCl 2 , and 0.5 mg/mL of fatty acid free BSA) containing test compound (concentrations ranging from 1 pM to 100 ⁇ M), 25 ⁇ L of radioligand (1 nM final assay concentration for [ 3 H]CP55,904 and [ 3 H]WIN55,212-2), and 50 mL of membranes (20 mg/mL final protein for both assays). Incubations were conducted for 1 hour at room temperature, assay plates were filtered under reduced pressure over GF/B filters, washed with assay buffer and dried overnight in a 50° C. oven. Then, 25 ⁇ L of BetaScint scintillation cocktail was added to each well, and plates were read in a Packard TopCount scintillation counter.
  • assay buffer 50 mM Tris, pH 7.4, 2.5 mM EDTA, 5 m
  • Certain other compounds of the invention had hCB 1 K i values ranging from about 124 nM to about 19.36 ⁇ M in this assay and hCB 2 K i values ranging from about 3.22 nM to about 4.69 ⁇ M in this assay.
  • MIA monosodium iodoacetate
  • the osteoarthritis was induced in 200 g male Sprague Dawley rats. After brief anesthesia by isoflurane rats received a single intra-articular injection of MIA (2 mg) (Sigma Aldrich, Saint Louis, Mo., USA; Cat #19148) dissolved in 0.9% sterile saline in a 50 ⁇ L volume administered through the patella ligament into the joint space of the left knee with a 30 G needle. Following the injection, animals were allowed to recover from anesthesia before being returned to the main housing vivarium.
  • MIA Sigma Aldrich, Saint Louis, Mo., USA; Cat #19148
  • Hind paw weight distribution was determined by placing rats in a chamber so that each hind paw rests on a separate force plate of the incapacitence tester. The force exerted by each hind limb (measured in grams) is averaged over a 3 second period. Three measurements were taken for each rat, and the change in hind paw weight distribution calculated. Peak hind limb grip force was conducted by recoding the maximum compressive force exerted on the hind limb mesh gauge set on the grip strength meter. During the testing, each rat was restrained, and the paw of the injected knee was allowed to grip the mesh. The animal was then pulled in an upward motion until their grip was broken. Each rat is tested 3 times, with the contralateral paw used as a control.
  • mice were base-lined prior to treatment of the test compound.
  • the MIA treated groups of rats (6 per group) were then dosed with either vehicle (PEG400, orally), Compound 493 (at 3 mg/kg, 10 mg/kg, and 30 mg/kg, orally) or with morphine (3 mg/kg, subcutaneously).
  • Dosing volume was 500 ⁇ L.
  • von Frey assay, hind limb weight distribution and/or hind limb grip analysis was performed to measure the efficacy of the test compound.
  • Increase in paw withdrawal threshold (PWT) by Compound 493 in comparison with vehicle shown in FIG. 2 was indicative of the test compound exhibiting therapeutic efficacy in the MIA model of osteoarthritis.
  • Postoperative pain was produced by a 1 cm incision of the skin and muscle of the plantar surface of the rat hind paw as described (Brennan et al., 1996), with minor modifications.
  • rats weighing 200 to 300 g were anesthetized with 2% isoflurane.
  • the plantar surface of the right hind paw was prepared in a sterile manner with a 10% povidone-iodine solution.
  • a 1 cm longitudinal incision was made with a number 11 blade, through skin and fascia of the plantar aspect of the foot, starting in the middle of the paw and extending toward the heel.
  • the plantaris muscle was elevated and incised longitudinally. After hemostasis with gentle pressure, the skin was apposed with 2 mattress sutures of 5-0 nylon. The animals were allowed to recover individually in their cages with clean bedding.
  • the 50% withdrawal threshold was then determined using the up/down method (Chaplan et al., 1994). Each trial started with a von Frey force of 2 g, if there was no withdrawal response, the next higher force was delivered. If there was a response, the next lower force was delivered. This procedure was performed until no response was made at the highest force (15 g or 26 g depending on animal size) or until four stimuli were delivered following the initial response.
  • the 50% paw withdrawal threshold (PWT) was then calculated as described in Chaplan et al., 1994 (Chaplan S. R., Bach F. W., Pogrel J. W., Chung J. M., Yaksh T.
  • FCA Freund's complete adjuvant
  • FCA-induced hyperalgesia was tested with an Analgesy-Meter. Briefly, the Analgesy Meter applied an increasing pressure to the right hind paw. The paw withdrawal threshold was the pressure leading to withdrawal.
  • the mitotic inhibitor, paclitaxel (Taxol®) is one of the most effective and frequently used chemotherapeutic agents for the treatment of solid tumors as well as ovarian and breast cancers. Therapy however is often associated with the unwanted side effects of painful peripheral neuropathy.
  • Rats Male Sprague Dawley rats [200-250 g] (Harlan Laboratories Inc., Livermore, Calif.) were housed three per cage and maintained in a humidity-controlled (40-60%) and temperature-controlled (68-72° F.) facility on a 12 h: 12 h light/dark cycle (lights on at 6:30 am) with free access to food (Harlan Teklad, Orange, Calif., Rodent Diet 8604) and water. Rats were allowed one week of habituation to the animal facility before starting treatment.
  • Rats were treated intraperitoneally, with 2 mg/kg of paclitaxel (Sigma Aldrich, Saint Louis, Mo.) in 10% Cremophor vehicle (500 ⁇ L) on days 0, 2, 4, and 6.
  • paclitaxel Sigma Aldrich, Saint Louis, Mo.
  • Cremophor vehicle 500 ⁇ L
  • Tactile allodynia was tested using von Frey filaments. Briefly, the von Frey assay was performed using the standardized up down method with von Frey filaments, that determine the tactile sensitivity of the paw. By applying the increasingly or decreasingly thicker filaments to the paw in a logarithmic scale of actual force, a linear scale of perceived intensity is determined.
  • paclitaxel assay Eight days after the start of paclitaxel dosing, a baseline measurement (von Frey assay) was performed prior to dosing of compounds.
  • the paclitaxel treated groups of rats (6 per group) were dosed orally, with vehicle (PEG400) or 10 mg/kg Compound 493.
  • vehicle PEG400
  • Compound 493 As a positive control, rats were dosed intraperitoneally with 100 mg/kg gabapentin in water.
  • the dosing volume for oral and peritoneal treatment was 500 ⁇ L.
  • the von Frey assay was performed to measure the efficacy of the test compound 30, 60 and 180 minutes after dosing.
  • mice Male Sprague-Dawley rats (300-400 g) were housed three per cage and maintained in a humidity-controlled (30-70%) and temperature-controlled (20-22° C.) facility on a 12 h: 12 h light/dark cycle (lights on at 7:00 am) with free access to food (Harlan-Teklad, Orange, Calif., Rodent Diet 8604) and water. Rats were allowed one week of habituation to the animal facility before testing.
  • Body temperature was measured using a stainless-steel rat temperature probe connected to a temperature display device (Physitemp TH-5). The probe was inserted rectally to a depth of 1 inch and the reading was recorded approximately 10 s after insertion, when the reading had stabilized.
  • Body temperature was measured immediately before (time 0) and 60 min post-administration of compounds.
  • Locomotor activity was measured using the Hamilton-Kinder Motor Monitor system, which detected blockage of photocell beams in a standard rat cage and transfers this data to a computer. Motor activity was measured for 30 min starting immediately after the second body temperature measurement, from 60 to 90 min post-administration. Compounds were dosed orally in a volume of 2 to 6 mL/kg, suspended or dissolved in 100% PEG 400.
  • FIGS. 5 to 8 showed the effects of 4 different compounds on body temperature and locomotor activity in rats.
  • the compounds depicted in FIG. 6 and FIG. 7 were inactive in these tests at doses ranging from 1 to 100 mg/kg PO.
  • the compound decreased body temperature at the highest dose tested (100 mg/kg), but this effect was not statistically significant; the compound did, however, significantly reduce motor activity.
  • the compound significantly decreased both body temperature and locomotor activity at the highest dose tested (100 mg/kg).
  • Rats receive nerve injury by tight ligation of L5 and L6 spinal nerves close to the spine, before they join (along with L4) to form the sciatic nerve.
  • animals are placed under general anesthesia using continuous inhalation of isoflurane.
  • Surgery is performed in a dedicated surgery room, using sterile instruments, surgical gloves, and aseptic procedures to prevent clinical infections.
  • the surgical site is shaved and disinfected with iodine solution and alcohol. Animals are observed continuously for their level of anesthesia, testing for the animal's reflex response to tail or paw pinch.
  • a heating pad is used to maintain body temperature both during the procedure and while the animals are recovering from anesthesia.
  • Nerve injury is induced by loose ligature of the sciatic nerve.
  • animals are placed under general anesthesia using continuous inhalation of isoflurane.
  • Surgery is performed in a dedicated surgery room, using sterile instruments, surgical gloves, and aseptic procedures to prevent clinical infections.
  • the surgical site is shaved and disinfected with iodine solution and alcohol.
  • Animals are observed continuously for their level of anesthesia, testing for the animal's reflex response to tail or paw pinch and closely monitoring the animal's breathing.
  • a heating pad is used to maintain body temperature while the animals are recovering from anesthesia.
  • a skin incision is made over the femur and the muscle is bluntly dissected to expose the sciatic nerve.
  • ligatures Chromic gut absorbable suture
  • Animals are administered a post-surgery injection of lactated Ringer's solution and returned to their home cages. They are carefully monitored until complete recovery from anesthesia (defined as the ability to move without significant ataxia), typically less than 10 min.
  • Neuropathic animals are first tested 7-15 days post-surgery for tactile allodynia. During this time period, analgesic compounds are tested for their ability to reduce or eliminate these chronic pain symptoms.
  • Tactile allodynia was evaluated at 1, 4 and 6 hours post-dosing. As shown in FIG. 9 and FIG. 10 , both CB2 agonists Compound 699 and Compound 919 showed robust and sustained analgesic efficacy over 6 hours in this model.
  • Writhing is induced in male Sprague Dawley rats by administering glacial acetic acid (1.5%) intraperitoneally (IP).
  • Rats are administered vehicle (PO or IP), Compound 699 (3, 10, or 30 mg/kg) (0.5% MC) (PO), rimonabant (10 mg/kg) (PO) (a CB1 receptor antagonist), AM630 (10 mg/kg) (PO), or morphine (1 mg/kg) (IP) for four days.
  • rats are placed in observation cages and administered compound according to the schedules in Tables D, F, H, and J. Treatment groups are as provided in Tables E, G, I, and K.
  • Writhing behavior is scored when a rat exhibits back arching, abdominal abduction, body stretches and/or forelimb extension. Writhing behavior is scored for 30 minutes in five-minute time bins.
  • Sprague Dawley rats 350-430 g were placed into individual observation cages at Time 0 and injected with vehicle, morphine (positive control), or Compound 699 one hour later. Rats then received saline or acetic acid (IP) 20 minutes after the vehicle, morphine, or Compound 699 dosing (Tables J and K). Writhing behavior was evaluated 20 minutes later and recorded for 30 minutes (in five-minute bins). Results are shown in FIGS. 11 and 12 .
  • Rats with active colitis display allodynia and hyperalgesia to colorectal distension following the administration of trinitrobenzene sulfonic acid (TNBS).
  • Rats with active colitis (4 days after TNBS) induced by intracolonic TNBS are administered Compound 699 to determine whether Compound 699 reduces visceral pain response.
  • Abdominal electromyographic (EMG) electrode implantation is followed by measurement of visceromotor response (VMR) at 0, 20, 40, 60, and 80 mmHg of colorectal distention on day 4. The effect of each treatment on colonic compliance is also determined.
  • Abdominal EMG electrode implantation is followed by measurement of VMR at 0, 20, 40, 60, and 80 mmHg of colorectal distention on day 4. The effect of each treatment on colonic compliance is also determined. Results are shown in FIG. 13 .
  • a randomized, open-label, parallel Phase 2a study is conducted to determine the tolerability, pharmacokinetics, and efficacy of Compound 699 in subjects with Crohn's disease (CD) experiencing abdominal pain.
  • the study population consists of adult male and female subjects aged 18 to 80 years who are diagnosed with abdominal pain due to quiescent to mildly active inflammatory Crohn's disease, as defined by a weekly average abdominal pain score (AAPS) ⁇ 4, with minimal intestinal inflammation, confirmed with a simple endoscopic score (-CD) score ⁇ 10 or fecal calprotectin ⁇ 500 mcg/g. Endoscopy results obtained up to one month prior to screening may be utilized.
  • Eligible subjects enter a screening period of up to four weeks and are randomized in a 1:1 ratio into the study, receiving Compound 699 in oral doses of 25 mg three times daily (TID) or 100 mg capsules TID for 8 weeks. If subjects experience hypotensive symptoms and/or heart rate changes during the trial, they may be administered 50 mg TID (rather than 100 mg TID) or 25 mg BID (rather than 25 mg TID).
  • the analgesic effect of Compound 699 on abdominal pain is scored by subjects in a diary twice daily during screening and three times daily during treatment using an 11-point numeric rating scale from 0 (no abdominal pain) to 10 (worst possible abdominal pain). Additional efficacy assessments include achievement of clinical improvement (defined as a two-component PRO score (stool frequency and abdominal pain) of ⁇ 11), clinical response from baseline to week 8, and change from baseline in C-reactive protein and fecal calprotectin at weeks 4 and 8.
  • a key objective of the study is to assess the tolerability and safety of Compound 699 in subjects with Crohn's disease experiencing abdominal pain. Additional objectives include:

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