WO2011119722A2 - Use of anatabine to treat inflammation and methods of synthesizing anatabine - Google Patents
Use of anatabine to treat inflammation and methods of synthesizing anatabine Download PDFInfo
- Publication number
- WO2011119722A2 WO2011119722A2 PCT/US2011/029613 US2011029613W WO2011119722A2 WO 2011119722 A2 WO2011119722 A2 WO 2011119722A2 US 2011029613 W US2011029613 W US 2011029613W WO 2011119722 A2 WO2011119722 A2 WO 2011119722A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- anatabine
- individual
- dose
- formula
- pharmaceutically acceptable
- Prior art date
Links
- 0 *(c1cccnc1)N=C(c1ccccc1)c1ccccc1 Chemical compound *(c1cccnc1)N=C(c1ccccc1)c1ccccc1 0.000 description 1
- CPEGDIGUUSEGQT-UHFFFAOYSA-N C(c1cccnc1)N=C(c1ccccc1)c1ccccc1 Chemical compound C(c1cccnc1)N=C(c1ccccc1)c1ccccc1 CPEGDIGUUSEGQT-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- 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]
-
- 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
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/36—Radicals substituted by singly-bound nitrogen atoms
- C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D213/44—Radicals substituted by doubly-bound oxygen, sulfur, or nitrogen atoms, or by two such atoms singly-bound to the same carbon atom
- C07D213/53—Nitrogen atoms
Definitions
- Inflammation is a protective response to harmful stimuli, such as oxidative stress, irritants, pathogens, and damaged cells.
- the inflammatory response involves the production and release of inflammatory modulators that heal injured tissue and destroy damaged cells, by directly or indirectly producing and/or signaling the release of agents that produce reactive oxygen species.
- an appropriate inflammatory response involves a balance between the destruction of damaged cells and the healing of injured tissue.
- a pharmaceutical composition comprising a therapeutically effective dose of an isolated form of anatabine or a pharmaceutically acceptable salt thereof can be administered to an individual to reduce a symptom of a disorder comprising an NFKB- mediated inflammatory component or to reduce the risk of developing such a disorder.
- the NFicB-mediated inflammatory component is chronic inflammation which occurs, for example, in thyroiditis, cancer, arthritis, Alzheimer's disease, and multiple sclerosis.
- a therapeutically effective dose of an isolated form of anatabine or a pharmaceutically acceptable salt thereof can be administered to an individual for treating alopecia areata or other disorders associated with hair loss.
- therapeutically effective doses of anatabine are provided in an extended release formulation.
- isolated forms of anatabine or pharmaceutically effective salts thereof can be provided in a bottled water product comprising about 100 ml to about 2,000 ml purified water and from about 0.00001 to about 0.0001 wt% of anatabine or a water-soluble salt of anatabine.
- a method is provided to prepare anatabine synthetically.
- benzylhydrylidene-pyridin-3-ylmethyl-amine (Formula I) is prepared by reacting 3-aminomethylpyridine with benzophenoneimine, or benzophenoneimine substituted in one or both aromatic rings.
- the compound of Formula I may then be reacted with a non-nucleophilic base and a dielectrophile to obtain a compound of Formula II.
- the compound of Formula II is then acidified to provide a compound of Formula III.
- a novel method is provided to recover anatabine from a reaction product by contacting the reaction product with methyl t-butyl ether (MTBE). Subsequence distillation yields anatabine with a purity greater than 99%.
- MTBE methyl t-butyl ether
- acceptable pharmaceutical or food-grade salts of anatabine are prepared.
- a compound of Formula I may be prepared as previously described and reacted with a dielectrophile to yield a compound of Formula Ila:
- the dielectrophile may be selected according to the desired alkaloid.
- the compound of Formula Ila is then acidified to provide a compound of Formula Ilia.
- FIG. 1 Graph showing effects of anatabine (AN) on TNFa-induced NFKB activity in vitro. See Example 1.
- FIG. 2 Graph showing effects of a crude extract of smokeless tobacco on TNFa- induced NFKB activity in vitro. See Example 1.
- FIG. 3 Graph showing effects of nicotine and of an alkaloid extract of smokeless tobacco on TNFa-induced NFKB activity in vitro. See Example 1.
- FIG. 4. Graph showing the results of a cytotoxicity assay measuring release of lactate dehydrogenase (LDH) using supernatant from the cells assayed in FIG. 1. See
- FIG. 5 Graph showing the results of a cytotoxicity assay using supernatant from the cells assayed in FIG. 2. See Example 2.
- FIG. 6. Graph showing the results of a cytotoxicity assay using supernatant from the cells assayed in FIG. 3. See Example 2.
- FIG. 7. Graph showing concentrations in rat plasma as a function of time of anatabine and nicotine after a single intravenous bolus injection.
- FIG. 8 Graph showing concentrations of anatabine and nicotine in rat plasma as a function of time (semi-log).
- FIG. 9. Graph showing versus dose for both anatabine and nicotine in male
- FIG. 10 Graph showing concentrations of anatabine or nicotine in rat brain extracts following a single intravenous bolus dose.
- FIG. 11 Graph showing mean concentration of anatabine and nicotine in rat brain extracts 0.5 hours after a single intravenous bolus dose.
- FIG. 12 Nicotine product ion scan.
- FIG. 13 Nicotine sample chromatogram.
- FIG. 14 Anatabine product ion scan.
- FIG. 15 Anatabine sample chromatogram.
- FIG. 16 Nicotine-d3 product ion scan.
- FIG. 17 Nicotine-d3 sample chromatogram.
- FIG. 18 Anatabine-d4 product ion scan.
- FIG. 19 Anatabine-d4 sample chromatogram.
- FIG. 20 Graph showing mean body weights (+ Std Dev) for each treatment group and gender.
- FIGS. 21A-21B Graphs showing mean ( ⁇ SEM) concentration of anatabine in plasma for male or female rats.
- FIG. 21A 0.6 mg/kg body weight (BW);
- FIG. 21B 6.0 mg/kg BW.
- FIGS. 22A-22B Graphs showing mean ( ⁇ SEM) concentration of anatabine in plasma for male and female rats combined.
- FIG. 22A 0.6 mg/kg BW;
- FIG. 22B 6.0 mg/kg BW.
- FIGS. 23A-23B Graphs showing mean ( ⁇ SEM), maximal (Cp, max), and minimal (Cp, min) concentrations of anatabine in plasma for male or female rats.
- FIG. 23 A 0.6 mg/kg BW;
- FIG. 23B 6.0 mg/kg BW.
- FIG. 24 Graph showing effect of S-(-)-anatabine on TNFa-induced NFKB activity in vitro.
- This disclosure describes methods of using a composition comprising an isolated form of anatabine or a salt thereof to treat disorders comprising an inflammatory component, including chronic, low-level inflammation.
- Anatabine is an alkaloid present in tobacco and, in lower concentrations, in a variety of foods, including green tomatoes, green potatoes, ripe red peppers, tomatillos, and sundried tomatoes. Preparation of isolated forms of anatabine is described below. Use of such isolated forms avoids the toxicity associated with tobacco, tobacco extracts, alkaloid extracts, and nicotine.
- NFKB nuclear factor ⁇
- NFKB-mediated transcription is associated with numerous disorders, including those with an inflammatory component, an aberrant immune response, and/or inappropriate cell proliferation.
- Isolated forms of anatabine or salts of such isolated forms anatabine are particularly useful for treating disorders comprising an "NFKB-mediated inflammatory component," i.e. inflammation characterized by, caused by, resulting from, or affected by NFKB-mediated transcription.
- a therapeutically effective dose of an isolated form of anatabine or a pharmaceutically acceptable salt thereof can be administered to an individual for treating alopecia areata or other disorders associated with hair loss.
- Treatment refers to reducing a symptom of the inflammation or resulting disorder but does not require complete cure, either of the inflammation or the disorder.
- "Reduction of a symptom" of a disorder with an NFicB-mediated inflammatory component includes but is not limited to elimination of the symptom as well as reduction in frequency, severity, or duration of the symptom. Reduction of a symptom can be recognized subjectively by the individual or an observer of the individual or can be confirmed by clinical and/or laboratory findings.
- An isolated form of anatabine or a pharmaceutically acceptable salt of such an isolated form of anatabine is administered to the individual at a dose sufficient to reduce a symptom of a disorder with an NFicB-mediated-transcription component.
- "Individual” as used herein includes warm-blooded animals, typically mammals, including humans and other primates.
- Doses typically range from about 1 ⁇ g/kg to about 7 mg/kg body weight (e.g., about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1, 3.2, 3.3, 3.4, 3.5, 3.6, 3.7, 3.8, 3.9, 4, 4.1 , 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, or 5 ⁇ g/kg or about 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1 , 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1 , 2.2, 2.3, 2.4, 2.5, 2.6, 2.7, 2.8, 2.9, 3, 3.1 , 3.2, 3.3, 3.4, 3.5, 3.6,
- an effective dose sufficient to reduce a symptom of a disorder (i.e., an effective dose), including the severity of the disease or disorder, previous treatments, the general health, age, and/or weight of the individual, the frequency of treatments, the rate of release from the composition, and other diseases present.
- This dose may vary according to factors such as the disease state, age, and weight of the subject. For example, higher doses may be administered for treatments involving conditions which are at an advanced stage and/or life- threatening. Dosage regimens also may be adjusted to provide the optimum therapeutic response.
- tablets comprising about 600 ⁇ g anatabine citrate are administered from once to 25 times daily (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) times daily.
- the dose sufficient to reduce the symptom of the disorder can include a series of treatments.
- an individual can be treated with a dose of an isolated form of anatabine or a salt thereof several times per day (e.g., 2-12 or 4- 10 times per day), once daily, or less frequently such as 1-6 times per week.
- Treatments may span between about 1 to 10 weeks (e.g., between 2 to 8 weeks, between 3 to 7 weeks, for about 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks). It will also be appreciated that a dose regimen used for treatment may increase or decrease over the course of a particular treatment.
- the individual is an animal, such as a companion animal, a service animal, a farm animal, or a zoo animal.
- animals include, but are not limited to, canines (including dogs, wolves), felines (including domestic cats, tigers, lions), ferrets, rabbits, rodents (e.g., rats, mice), guinea pigs, hamsters, gerbils, horses, cows, pigs, sheep, goats, giraffes, and elephants.
- an isolated form of anatabine or a pharmaceutically acceptable salt of an isolated form of anatabine can be administered to reduce the risk of developing a disorder comprising an NFicB-mediated inflammatory component (i.e., prophylactically).
- a disorder comprising an NFicB-mediated inflammatory component i.e., prophylactically.
- NFicB-mediated transcription is implicated in an enormous variety of maladies. Based on S-(-)-anatabine's surprising efficacy in interfering with or interrupting this pivotal inflammatory-related activity, anatabine can be expected to have a wide range of therapeutic utilities.
- the disorder is thyroiditis.
- the disorder is an immune or autoimmune disorder.
- the disorder is arthritis, such as rheumatoid arthritis, primary and secondary osteoarthritis (also known as degenerative joint disease).
- the disorder is a spondyloarthropathy, such as psoriatic arthritis, juvenile chronic arthritis with late pannus onset, and enterogenic spondyloarthropathies such as enterogenic reactive arthritis, urogenital spondyloarthropathy, and undifferentiated spondylarthropathy.
- the disorder is a myopathy, such as "soft tissue rheumatism" (e.g., tennis elbow, frozen shoulder, carpal tunnel syndrome, plantar fasciitis, and Achilles tendonitis).
- the disorder is diabetes, either type I diabetes or type II diabetes.
- the disorder is a gastrointestinal inflammatory disorder, such as an inflammatory bowel disease.
- inflammatory bowel disease include, but are not limited to, Crohn's disease, Barrett's syndrome, ileitis, irritable bowel syndrome, irritable colon syndrome, ulcerative colitis, pseudomembranous colitis, hemorrhagic colitis, hemolytic-uremic syndrome colitis, collagenous colitis, ischemic colitis, radiation colitis, drug and chemically induced colitis, diversion colitis, colitis in conditions such as chronic granulomatous disease, celiac disease, celiac sprue, food allergies, gastritis, infectious gastritis, enterocolitis (e.g., Helicobacter pylori-infected chronic active gastritis), and pouchitis.
- inflammatory bowel disease include, but are not limited to, Crohn's disease, Barrett's syndrome, ileitis, irritable bowel syndrome
- the disorder is graft-versus-host-disease (GVHD), systemic lupus erythematosus (SLE), lupus nephritis, Addison's disease, Myasthenia gravis, vasculitis (e.g., Wegener's granulomatosis), autoimmune hepatitis, osteoporosis, and some types of infertility.
- the disorder is vascular inflammatory disease, associated vascular pathologies, atherosclerosis, angiopathy, inflammation- induced atherosclerotic or thromboembolic macroangiopathy, coronary artery disease, cerebrovascular disease, peripheral vascular disease, cardiovascular circulatory disease such as as ischemia/reperfusion, peripheral vascular disease, restenosis following angioplasty, inflammatory aortic aneurysm, vasculitis, stroke, spinal cord injury, congestive heart failure, hemorrhagic shock, ischemic heart disease/reperfusion injury, vasospasm following subarachnoid hemorrhage, vasospasm following cerebrovascular accident, pleuritis, pericarditis, inflammation- induced myocarditis, or a cardiovascular complication of diabetes.
- vascular inflammatory disease associated vascular pathologies, atherosclerosis, angiopathy, inflammation- induced atherosclerotic or thromboembolic macroangiopathy
- the disorder is brain swelling or a neurodegenerative disease such as multiple sclerosis, Alzheimer's disease, or Parkinson's disease.
- the disorder is inflammation related to a kidney disease, nephritis, glomerulonephritis, dialysis, peritoneal dialysis, pericarditis, chronic prostatitis, vasculitis, gout, or pancreatitis.
- the disorder is an anemia.
- the disorder is an ulcer-related disease, such as peptic ulcer disease, acute pancreatitis, or aphthous ulcer.
- the disorder is related to an age-related disease, such as atherosclerosis, fibrosis, and osteoporosis, or a disorder associated with pre-maturity, such as retinopathy, chronic lung disease, arthritis, and digestive problems.
- the disorder is preeclampsia, inflammation related to chemical or thermal trauma due to burns, acid, and alkali, chemical poisoning (MPTP/concavalin/chemical agent/pesticide poisoning), snake, spider, or other insect bites, adverse effects from drug therapy (including adverse effects from amphotericin B treatment), adverse effects from immunosuppressive therapy (e.g., interleukin-2 treatment), adverse effects from OKT3 treatment, adverse effects from GM-CSF treatment, adverse effects of cyclosporine treatment, and adverse effects of aminoglycoside treatment, stomatitis and mucositis due to immunosuppression, or exposure to ionizing radiation, such as solar ultraviolet exposure, nuclear power plant or bomb exposure, or radiation therapy exposure, such as for therapy for cancer.
- chemical poisoning MPTP/concavalin/chemical agent/pesticide poisoning
- snake, spider or other insect bites
- adverse effects from drug therapy including adverse effects from amphotericin B treatment
- immunosuppressive therapy e.g.,
- the disorder is a cancer, such as acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, AIDS-related lymphoma, anal cancer, appendix cancer, grade I (anaplastic) astrocytoma, grade II astrocytoma, grade III astrocytoma, grade IV astrocytoma, atypical teratoid/rhabdoid tumor of the central nervous system, basal cell carcinoma, bladder cancer, breast cancer, breast sarcoma, bronchial cancer, bronchoalveolar carcinoma, Burkitt lymphoma, cervical cancer, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, cutaneous T-cell lymphoma, endometrial cancer, endometrial uterine cancer, ependymoblastoma, ependymoma, esoph
- disorders associated with inflammation in the stomach and/or esophagus such as acid reflux, may be treated.
- Anatabine may have a positive effect on telomere length.
- anatabine can be administered to reduce and/or reverse cellular senescence ⁇ i.e., aging). Conditions associated with cellular senescence can be treated.
- anatabine can be administered to reduce and/or reverse senescence of: a. cells with replicative capacity in the central nervous system, including astrocytes, endothelial cells, and fibroblasts which play a role in age-related diseases as Alzheimer's disease, Parkinson's disease, Huntington's disease, and stroke; b.
- cells with finite replicative capacity in the integument including fibroblasts, sebaceous gland cells, melanocytes, keratinocytes, Langerhan's cells, and hair follicle cells, which may play a role in age-related diseases of the integument such as dermal atrophy, elastolysis and skin wrinkling, sebaceous gland hyperplasia, senile lentigo, graying of hair and hair loss, chronic skin ulcers, and age-related impairment of wound healing; c. cells ⁇ with finite replicative capacity in the articular cartilage, such as chondrocytes and lacunal and synovial fibroblasts, which play a role in degenerative joint disease; d.
- cells with finite replicative capacity in the bone such as osteoblasts and osteoprogenitor cells, which play a role in osteoporosis
- e. cells with finite replicative capacity in the immune system such as B and T lymphocytes, monocytes, neutrophils, eosinophils, basophils, NK cells and their respective progenitors, which may play a role in age-related immune system impairment
- Isolated forms of anatabine and pharmaceutically acceptable salts of such isolated forms of anatabine can be used in conjunction with (i.e., before, after, or at the same time as) other therapies for any disorder with an NFxB-mediated component.
- these therapies include other products that inhibit production of NFKB- mediated inflammatory species.
- dexamethasone glucocorticoids (e.g., prednisone, methyl prednisolone), cyclosporine, tacrolimus, deoxyspergualin, non-steroidal antiinflammatory drugs (NSAIDs) such as aspirin and other salicylates, tepoxalin, synthetic peptide proteosome inhibitors, antioxidants (e.g., N-acetyl-L-cysteine, vitamin C, vitamin E, dithiocarbamate derivatives, curcumin), IL-10, nitric oxide, cAMP, gold-containing compounds, and gliotoxin.
- glucocorticoids e.g., prednisone, methyl prednisolone
- cyclosporine tacrolimus
- deoxyspergualin deoxyspergualin
- non-steroidal antiinflammatory drugs NSAIDs
- antioxidants e.g., N-acetyl-L-cysteine, vitamin C
- Isolated forms of anatabine and pharmaceutically acceptable salts of such isolated forms of anatabine can also be used to improve erectile dysfunction, either administered alone of in conjunction with other therapies such as tadalafil (e.g. CIALIS®), vardenafil (e.g., LEVITRA®, STAXY ®), and sildenafil (e.g., VIAGRA®).
- tadalafil e.g. CIALIS®
- vardenafil e.g., LEVITRA®, STAXY ®
- sildenafil e.g., VIAGRA®
- Anatabine can be prepared synthetically. Such synthetic preparation techniques produce isolated forms of anatabine, either as a racemic mixture or as isolated enantiomers, S-(-)-anatabine or R-(+)-anatabine.
- the chemical structure of anatabine (l,2,3,6-tetrahydro-[2,3']bipyridinyl) is illustrated below, in which * designates an asymmetric carbon.
- Step 1 3-aminomethyl pyridine is reacted with benzophenoneimine (or benzophenoneimine substituted in either or both rings with nitrogen, a halogen, or an alkyl group) to form benzylhydrylidene-pyridin-3-ylmethyl-amine, also referred to herein as Formula I:
- Step 1 may be performed at any suitable temperature range.
- the reaction is exothermic, normally resulting in a temperature increase from ambient to about 45 °C to 55 °C. If desired, the reaction mixture may be heated or cooled. In general, the rate of reaction increases at higher temperature and decreases at lower temperatures.
- step 1 may be performed at about 30 °C to about 60 °C. Most often, step 1 is performed at a temperature of about 45 °C to about 55 °C.
- Step 1 The amount of time needed to complete Step 1 may vary depending on such factors such as reaction temperature and pressure. Normally, the reaction is completed in about 4 to about 9 hours, more usually from about 5 to about 7 hours.
- Step 1 is particularly advantageous as it can be scaled up to facilitate larger scale production.
- the amount of starting material e.g. combined weight of 3- aminomethylpyridine and benzophenoneimine
- the amount of starting material (e.g. combined weight of 3- aminomethylpyridine and benzophenoneimine) used for a batch may be about 500 mg, about 1 g, about 5 g, about 10 g, about 20 g, about 25 g, about 30 g, about 40 g, about 50 g, about 100 g, about 200 g, about 500 g, about 1 kg, about 5 kg, or about 10 kg.
- a medium scale synthesis starts with 20 g to 30 g of starting material.
- a large scale synthesis may start with 1 kg to 5 kg or more of starting material.
- reaction by-product is ammonia rather than water.
- the ammonia escapes from the reaction mixture.
- the reaction temperature— 50 °C, for example— is much lower than the -85 °C used for the water-removing benzene reflux step in the method of Deo et al., "Regioselective alkylation of N- (diphenylmethylidine)-3-(aminomethyl) pyridine: A simple route to minor tobacco alkaloids and related compounds," Tetrahedron Letters, Vol. 37, Issue 8, 19 Feb. 1996, pp. 1 137-1 140.
- Step 1 may proceed in a solvent-less reaction medium such that the purity of the isolated intermediate is enhanced and avoids the need for a workup reaction.
- Purity of Formula I compound typically is about 93-95% whereas the Deo et al. method yields only about 83-85% purity of the intermediate.
- the purity of Formula I compound may be as high as about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, or about 93%. Often, the Formula I compound is about 93 % to about 95% pure.
- step 2i the compound of Formula I is reacted with a non-nucleophilic base, such as lithium diisopropylamide (LDA), and a dielectrophile, such as cis-l,4-dichloro-2- butene to form a compound of Formula II.
- a non-nucleophilic base such as lithium diisopropylamide (LDA)
- a dielectrophile such as cis-l,4-dichloro-2- butene
- the non-nucleophilic base typically is added in a molar excess, for example, at about 1.2 equivalents (eq), about 1.3 eq, about 1.4 eq, about 1.5 eq, about 1.6 eq, about 1.7 eq, about 1.8 eq, about 1.9 eq, or about 2.0 eq.
- the non-nucleophilic base is added in an amount of about 1.3 eq to about 1.7 eq, more usually from about
- the non-nucleophilic base is typically supplied in a chilled state to provide improved reagent stability.
- LDA may be supplied at a temperature of about -30 °C, about -20 °C, about -10 °C, about -5 °C, about 0 °C, about 5 °C, or about 10 °C.
- Most often the non-nucleophilic base is provided at a temperature of about -30 °C to about 0 °C.
- the Step 2i reaction may be incubated for a time suitable for the reaction to go to completion or substantial completion.
- the reaction time for Step 2i often is about 10 minutes, about 20 minutes, about 30 minutes, about 40 minutes, about 50 minutes, or about 1 hour. Often, the reaction is incubated for about 20 to about 40 minutes.
- K'OBu potassium tert butoxide
- K'OBu potassium tert butoxide
- Other alternatives to LDA include sodium hydride, sodamide, and other alkyllithium reagents.
- each of R ⁇ and R 2 is independently selected from the group consisting of chlorine, (CI); bromine, (Br), and iodine, (I), tosylate, mesylate, and triflate.
- Ri and R 2 may both be CI, such that the dielectrophile is cis-l,4-dichloro-2- butene.
- the dielectrophile may be added neat or in a suitable solvent, such as THF.
- Formula II compound is hydrolyzed with acid.
- Treatment with acid may be for any suitable time.
- HC1 (10%) treatment may be for about 5 minutes, about 10 minutes, about 20 minutes, about 30 minutes, or for about 1 hour.
- acid treatment is for about 10 minutes to about 20 minutes.
- Other suitable acids include dilute sulfuric acid and phosphoric acid.
- Formula III compound is basified, such as by treatment with solid K2CO3, then aqueous KOH solution (e.g., 40%) to achieve N-alkylation to yield anatabine.
- Other bases such as Diaza(l ,3)bicyclo[5.4.0]undecane (DBU), di-isopropyl ethylamine, or triethylamine, may also be used.
- DBU Diaza(l ,3)bicyclo[5.4.0]undecane
- DBU di-isopropyl ethylamine
- triethylamine may also be used.
- a method of recovering and purifying anatabine comprises extracting anatabine from the reaction product of Step 2iii using MTBE in a distillation process.
- the anatabine containing solution is basified to saturation with KOH and K2CO3.
- Addition of MTBE to the solution induces phase separation, with the anatabine separated into the organic phase, which provides an additional increase in anatabine purity.
- Subsequent distillation, followed by acid-base work up typically results in an anatabine purity of 99%.
- a method of recovering and purifying anatabine comprises extracting anatabine from the reaction product of Step 2iii using MTBE in a distillation process.
- the anatabine containing solution is basified to saturation with KOH and K2CO3.
- Addition of MTBE to the solution induces phase separation, with the anatabine separated into the organic phase, which provides an additional increase in anatabine purity.
- Subsequent distillation, followed by acid-base work up typically results in an anatabine purity of 99%.
- this purification approach can be scaled up to industrial-scale manufacture. Purification by chromatography, which does not scale up from small- scale production, is avoided. Moreover, MTBE is more environmentally friendly than halogenated compounds such as chloroform. MTBE also improves extraction efficiency relative to halogenated compounds such as chloroform.
- Anatabine prepared according to the methods disclosed herein displays good stability at a variety of temperatures. See, for example, Tables 54 and 55 in Examples 1 1 and 12, respectively. Purity of the anatabine may be retained for extended periods of time. For example, the anatabine may exhibit the indicated purity at 12 days, at 18 days, at 21 days, at 1 month, at 3 months, at 6 months, at 9 months, at 12 months at 18 months, at 24 months, and at 36 months, or longer. Further, anatabine remains stable when stored at a variety of temperatures.
- the anatabine retains the indicated purity when stored at -20 °C to -10 °C, -20 °C to 0 °C, -10 °C to 0 °C, 0 °.C to 4 °C, 2 °C to 8 °C, 5 °C to 10 °C, 10 °C to 15 °C, 15 °C to 25 °C, or 25 °C to 28 °C.
- Stability is determined by any suitable art-recognized method.
- anatabine stability may be monitored by high performance liquid chromatography (HPLC), liquid chromatography-mass spectroscopy (LC-MS), or nuclear magnetic resonance (NMR).
- the synthesis described herein may yield significantly lower concentrations of byproducts, such as benzophenone, which can lower reaction yields and introduce impurities into the product.
- Concentrations of benzophenone, for example, are typically less than about 3 % as compared to 8-12 % that were found when reproducing the Deo et al. synthesis. Moreover, yield was 25% for the present invention but only 10% for the Deo et al synthesis.
- a compound of Formula I may be prepared as previously described and reacted with a dielectrophile to yield a compound of Formula Ila:
- the dielectrophile may be selected according to the desired alkaloid.
- anabasine may be synthesized using 1,4-diiodo-butane; nornicotine may be synthesized using 1,3-diiodo-propane or methanesulfonic acid 4- ethoxy-butyl ester, and so on.
- the compound of Formula Ila is then acidified as previously described to yield a compound of Formula Ilia.
- the synthetic alkaloids may be provided in a variety of compositions.
- the compositions may be in the form of a beverage, a chew, a tablet, a lozenge, a gum, and the like.
- Additional inactive ingredients may be added to improve taste or stability.
- other components such as sweetening and flavoring agents may be added.
- Other active ingredients may be provided as well.
- an isolated form of anatabine can be provided as one or more pharmaceutically acceptable (or food grade) salts of anatabine.
- Anatabine may be adsorbed on a cation exchange resin such as polymethacrilic acid (Amberlite IRP64 or Purolite CI 15HMR), as described in U.S. Patent 3,901,248, the disclosure of which is hereby incorporated by reference in its entirety.
- cation exchange resins have been used commercially in nicotine replacement therapy, e.g., nicotine polacrilex.
- the term "anatabine” as used herein refers collectively to anatabine and its pharmaceutically acceptable salts.
- salts may provide improved chemical purity, stability, solubility, and/or bioavailability relative to anatabine in its native form.
- anatabine salts are described in P. H. Stahl et al., Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim/Zurich: Wiley- VCH/VHCA, 2002, including salts of l-hydroxy-2-naphthoic acid, 2,2-dichloroacetic acid, 2- hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4- aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (L), aspartic acid (L), benzenesulfonic acid, benzoic acid, camphoric acid (+), camphor- 10-sulfonic acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic
- anatabine can be obtained by extraction from tobacco or other plants, such as members of the Solanaceae family, such as datura, mandrake, belladonna, capsicum, potato, nicotiana, eggplant, and petunia.
- a tobacco extract may be prepared from cured tobacco stems, lamina, or both.
- cured tobacco material is extracted with a solvent, typically water, ethanol, steam, or carbon dioxide.
- the resulting solution contains the soluble components of the tobacco, including anatabine.
- Anatabine may be purified from the other components of the tobacco using suitable techniques such as liquid chromatography.
- tobacco material may be substantially denicotinized to remove a majority of other alkaloids such as nicotine, nornicotine, and anabasine. Denicotinizing is usually carried out prior to extraction of anatabine. Methods that may be used for denicotinizing tobacco materials are described, for example, in U.S. Patent 5, 1 19,835, the disclosure of which is hereby incorporated by reference.
- tobacco alkaloids may be extracted from tobacco material with carbon dioxide under supercritical conditions. The tobacco alkaloids may then be separated from the carbon dioxide by dissolving an organic acid or a salt thereof, such as potassium monocitrate, in the carbon dioxide.
- Flue (bright) varieties of tobacco are often used, i.e., Virginia flue.
- Other tobacco varieties may be used, such as Burley, dark-fired, and/or other commercial tobacco varieties.
- Methods for forming aqueous tobacco extracts also are known in the art as described, for example, in U.S. Patent 5,065,775, the disclosure of which is hereby incorporated by reference in its entirety. Additional details on methodology for extracting anatabine from tobacco are disclosed in co-pending and commonly owned U.S. Published Application No. 2010/0154810 Al , the disclosure of which is hereby incorporated by reference in its entirety.
- a pharmaceutical composition for use in the disclosed methods comprises an isolated form of anatabine and a pharmaceutically acceptable vehicle, diluent, or carrier.
- An "isolated form of anatabine,” as used herein, refers to anatabine that either has been prepared synthetically or has been substantially separated from plant materials in which it occurs naturally.
- the isolated form of anatabine as described herein should have a very high purity (including enantiomeric purity in the case of an isolated enantiomer).
- purity refers to the ratio of the weight of anatabine to the weight of the end reaction product.
- purity refers to the ratio of the weight of anatabine to the total weight of the anatabine-containing extract.
- the level of purity is at least about 95%, more usually at least about 96%, about 97%, about 98%, or higher.
- the level of purity may be about 98.5%>, 99.0%, 99.1%, 99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9%, or higher.
- the composition contains levels of other alkaloids, such as nicotine, nomicotine, and anabasine, which are individually about 1 ⁇ g/g or less, and which may be about 0.5 ⁇ g/g or less, about 0.3 ⁇ g/g or less, about 0.1 ⁇ g/g or less, or lower.
- other alkaloids such as nicotine, nomicotine, and anabasine
- Anatabine exists in tobacco and other plants as a racemic mixture of R-(+)-anatabine and S-(-)-anatabine, whose structures are illustrated below.
- anatabine is used herein to refer to any of (1) a racemic mixture of anatabine (R,S) or a salt thereof, (2) a purified form of S-(-)-anatabine or a salt thereof, or (3) a purified form of R-(+)-anatabine or a salt thereof.
- Isolated forms of anatabine or pharmaceutically acceptable salts of anatabine can be provided together with other ingredients, for example, in the form of an elixir, a beverage, a chew, a tablet, a lozenge, a gum, and the like.
- a beverage may be in the form of a bottled water product containing about 100 ml to about 2,000 ml purified water and from about 0.00001 to about 0.0001 wt% of a water-soluble salt of anatabine. Additional inactive ingredients may be added to improve product characteristics, such as taste, color/clarity, and/or stability.
- the bottled water product may also contain other beneficial components, such as vitamins, proteinaceous ingredients, or the like.
- a composition alternatively may be provided in a solid (e.g., powder) form, such as in a packet, which can be combined with water or other liquid (e.g., by an end user) to prepare a beverage.
- compositions may be formulated together with one or more acceptable pharmaceutical or food grade carriers or excipients.
- acceptable pharmaceutical or food grade carrier or excipient means a nontoxic, inert solid, semisolid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
- sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents,
- the pharmaceutical composition may be prepared by any suitable technique and is not limited by any particular method for its production.
- anatabine can be combined with excipients and a binder, and then granulated.
- the granulation can be dry-blended any remaining ingredients, and compressed into a solid form such as a tablet.
- compositions may be administered by any suitable route.
- the compositions may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, via an implanted reservoir, or ingested as a dietary supplement or food.
- parenteral as used herein includes subcutaneous, intracutaneous, intravenous, intramuscular, and intracranial injection or infusion techniques. Most often, the pharmaceutical compositions are readily administered orally and ingested.
- the pharmaceutical compositions may contain any conventional non-toxic pharmaceutically-acceptable carriers, adjuvants or vehicles.
- the pH of the formulation may be adjusted with acceptable pharmaceutical or food grade acids, bases or buffers to enhance the stability of the formulated composition or its delivery form.
- Liquid dosage forms for oral administration include acceptable pharmaceutical or food grade emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
- the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylsulfoxide (DMSO) dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
- inert diluents commonly used in the art such as, for example, water
- Solid dosage forms for oral administration include capsules, tablets, lozenges, pills, powders, and granules.
- the active compound is mixed with at least one inert, acceptable pharmaceutical or food grade excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agaragar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as cetyl alcohol and glyce
- the solid dosage forms of tablets, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract or, optionally, in a delayed or extended manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Tablet formulations for extended release are also described in U.S. Pat. No. 5,942,244.
- Anatabine can be used to reduce elevated blood levels of inflammatory markers such as CRP.
- levels of inflammatory markers can be used to aid in determining doses of anatabine to be administered as well as to monitor treatment of various inflammatory disorders and to assist physicians in deciding on a course of a treatment for an individual at risk of an inflammatory disorder.
- CRP C-reactive protein
- sICAM-1 soluble intercellular adhesion molecule
- ICAM 3 BL-CAM, LFA-2, VCAM-1, NCAM, PECAM, fibrinogen, serum amyloid A (SAA), TNFa, lipoprotein associated phospholipase A2 (LpPlA2), sCD40 ligand, myeloperoxidase, interleukin-6 (IL-6), and interleukin-8 (IL-8).
- SAA serum amyloid A
- LpPlA2 lipoprotein associated phospholipase A2
- sCD40 ligand myeloperoxidase
- IL-6 interleukin-6
- IL-8 interleukin-8
- the level of one or more inflammatory markers can be determined in a patient already receiving anatabine therapy or in an individual at risk for an inflammatory disorder or suspected of having an inflammatory disorder. The level is compared to a predetermined value, and the difference indicates whether the patient will benefit from anatabine administration or from continued anatabine administration.
- the level of inflammatory marker can be determined by any art recognized method. Typically, the level is determined by measuring the level of the marker in a body fluid, for example, blood, lymph, saliva, or urine. The level can be determined by ELISA, or immunoassays or other conventional techniques for determining the presence of the marker. Conventional methods include sending a sample(s) of a patient's body fluid to a commercial laboratory for measurement.
- the predetermined value can take a variety of forms and will vary according to the inflammatory marker.
- the predetermined value can be single cut-off value, such as a median or a mean, or it can be a range.
- the predetermined value also can depend on the individual or particular inflammatory disorder. Appropriate ranges and categories can be selected by those of ordinary skill in the art using routine methods. See US 2006/01 15903; US 2004/0175754.
- Markers such as CRP, sICAM-1, ICAM 3, BL-CAM, LFA-2, VCAM-1 , NCAM, PECAM, fibrinogen, SAA, TNFa, lipoprotein associated phospholipase A2 (LpPlA2), sCD40 ligand, myeloperoxidase, IL-6, and IL-8 are useful markers for systemic inflammation.
- the inflammatory marker is CRP, which is associated both with cardiovascular disease (see US 2006/01 15903) and cancer, such as colon cancer (Baron et al., N. Engl. J. Med. 348, 891-99, 2003).
- Elevated levels of CRP are also observed in patients with insulin-resistance (Visser et al., JAMA. 1999, 282(22):2131 -5). Diabetic and insulin-resistant patients also have elevated levels of TNFa, IL-6, and IL-8 (Roytblat et al., Obes Res. 2000, 8(9):673-5; Straczkowski et al., J Clin Endocrinol Metab. 2002, 87(10):4602-6; Hotamisligil et al., Science. 1996, 271(5249):665-8; Sartipy P, Loskutoff D J. Proc Natl Acad Sci USA. 2003, 100(12):7265-70; Hotamisligil et al., J Clin Invest. 1995, 95(5):2409-15).
- TNFa induces an increase in NFicB-mediated transcription of luciferase; administration of anatabine can reduce this transcription to control levels without cellular toxicity (FIG. 4).
- both nicotine and an alkaloid extract of smokeless tobacco reduce TNFa-induced NFicB-mediated transcription (FIG. 3); at higher doses, the alkaloid extract demonstrates pronounced cytotoxicity (FIG. 6).
- Rats were housed 3 per cage. Cage size met or exceeded the requirements set forth by the Institute for Animal Laboratory Research Guide for the Care and Use of Laboratory Animals.
- the rats were kept in a room maintained at 64-84 °F (22-24 °C) with humidity set at 40-70 %. The room was illuminated with fluorescent lights timed to give a 12 hour-light, 12 hour-dark cycle. Standard rodent diet (PharmaServ lab diet 5001) and water were available for all rats. The feed was analyzed by the supplier, detailing nutritional information and levels of specified contaminants.
- Nicotine hydrogen tartrate (Sigma Aldrich: N5260 Lot# 098K0676) 35.1% (w/w) nicotine;
- (+/-)-nicotine-3 , -d3 (+/-)-nicotine-3 , -d3 (Toronto Research Chemicals: N412423, Lot# 9-BCC- 1 14-2);
- MICROTAINER ® Brand Tubes (K 2 ) EDTA (lot# 9050883); serum separator blood collection tubes (lot# 9104015); and sodium citrate blood collection tubes (lot# 8310564).
- Ten percent neutral-buffered formalin was from Sigma Aldrich, St. Louis, MO (batch# 019K4386).
- Anatabine was administered as a single intravenous (i.v.) injection at doses of 0.10,
- Nicotine was administered as a single intravenous injection at a dose of 0.4 mg/kg.
- Six rats (3 males and 3 females) were dosed per dose group. Blood was collected for plasma at 15, 30, 60, 90, 120, 240, 360, 480, and 1440 minutes post
- Anatabine and nicotine rapidly appear in brain tissue following i.v. administration, and the concentration of anatabine is dose-dependent. At each dose level the mean concentration of anatabine appeared to be higher in the brains of female animals compared to males; however, the differences were not statistically significant.
- Anatabine tartrate (2:3) or nicotine bitartrate was dissolved to the appropriate concentrations in sterile PBS for the i.v. formulations (Table 2).
- the dosing solutions for each test compound were prepared on the basis of the relative content of the anatabine or nicotine base so that the final concentrations are reflective of the actual base concentration.
- Four aliquots of each dose level formulation were collected and stored at -80 °C.
- the test compound, corresponding dose level, number of animals, and sample collection times for Phase I of the study are shown in Table 3.
- the test compound, corresponding dose level, number of animals, and sample collection times for Phase II of the study are shown in Table 4.
- the physical signs of each animal were monitored following administration of the test compound.
- the signal was optimized for each compound by electrospray ionization (ESI) positive or negative ionization mode.
- ESI electrospray ionization
- SIM single ion mode
- Recovery standards were prepared by spiking blank matrix (plasma or brain homogenate) prior to deproteination or after with 23, 62, or 1667 ng/mL of test compound. Deproteination was done by adding 3 columns of methanol containing internal standard with centrifugation to pellet the precipitated protein. Recovery was calculated by dividing the area ratio (peak area of compound over internal standard of the precipitated sample over the recovery standard multiplied by 100. For example: area ratio of spiked plasma/area ratio of spiked deproteinated plasma x 100.
- Calibration samples were prepared by diluting a 50x stock solution of the test compound in PBS with blank matrix to the appropriate concentration and these samples were prepared as described above in the sample preparation. Stock solutions were prepared by serial dilution as shown in Table 5.
- Table 6 shows the results of the LC/MS/MS method development for the determination of the appropriate ionization conditions and the mass to charge ratios (m/z) of the parent and product ions for anatabine and nicotine, and their deuterated analogues. The indicated product m/z ratios were used for the analysis of the relevant test samples.
- Table 9 summarizes the analyses of the dosing solutions used in this study. The per cent differences between the actual and expected concentrations are shown. Except for the lowest dose of anatabine, which was 70 % of the expected concentration, the actual concentrations of test compounds were within 20 % of the expected levels.
- Table 14 lists the plasma concentrations of anatabine and nicotine for all animals at each time point.
- Table 15 summarizes this data in terms of the mean plasma concentrations of the test compound at each time point for males, females and both genders combined. This data is presented graphically in FIG. 7 and FIG. 8 (semi-log plot). The 24-hr data points from all treatment groups were below the limits of quantitation. Between approximately 6 and 8 hours the plasma concentrations of nicotine and anatabine (0.1 mg/kg) were below the limits of quantitation.
- Table 10 and Table 1 1 provide comparisons for several pharmacokinetic parameters between the different treatment groups and between male and female animals. Both nicotine and anatabine can be measured in rat plasma following a single i.v. bolus, and their concentrations appear to be dose-related.
- the elimination half-life t for each of the anatabine treatment groups was significantly greater than that for the nicotine treatment group (2.1x to 2.5x greater; 0.67 hr for nicotine compared to 1.44 to 1.68 hr for anatabine).
- the elimination half-lives were similar among the anatabine treatment groups.
- the longer half-life for anatabine is reflected in the longer mean residence times (MRT), which are about 2-fold longer for anatabine compared to nicotine.
- MRT mean residence times
- V D apparent volume of distribution
- Table 1 1 shows a comparison of these same parameters between male and female rats within each treatment group. There were no statistically significant differences between males and females except in the highest anatabine treatment group (1.0 mg/kg) where the females exhibited a longer elimination half-life and therefore, longer mean residence time than the males (ti /2 , 1.84 ⁇ 0.16 hr and MRT, 2.80 + 0.24 hr, females compared to t ⁇ a, 1.44 ⁇ 0.08 and MRT, 2.18 + 0.12 hr, males). This difference is apparent for all treatment groups, although it only achieved statistical significance in the highest anatabine group.
- the females in this treatment group also displayed a much greater overall exposure (AUCo- > ⁇ ) to anatabine than the male animals. This difference is depicted in FIG. 9, which shows the dose-exposure relationship for anatabine and nicotine. Overall, there appears to be a linear response between dose and exposure for anatabine; it is not possible to determine if the female animals display a non-linear response at high doses of anatabine.
- FIG. 11 shows the dose-concentration response for the 0.5-hour time point for males and females at each dose level. It appears that the brain levels of anatabine begin to level off between 0.75 mg/kg and 1.0 mg/kg.
- Table 14 lists the concentrations of anatabine and nicotine in the brain extracts for all animals at each time point.
- Table 15 summarizes this data in terms of the mean concentrations of the test compound per gram of brain tissue at each time point for males, females and both genders combined. This data is presented graphically in FIG. 10 and in tabular form in Table 12. After the 6-hour time point most concentrations were below the limits of quantitation; however, the test compound concentration was quantifiable in several samples at 24-hours.
- FIG. 11 shows the dose-concentration response for the 0.5-hour time point for males and females at each dose level. It appears that the brain levels of anatabine begin to level off between 0.75 mg/kg and 1.0 mg/kg.
- Both nicotine and anatabine can be measured in rat plasma following a single, bolus, i.v. dose and their concentrations appear to be dose-related.
- the elimination half-life of anatabine is approximately 2- to 2.5-fold greater than that of nicotine, and this is also reflected in a longer mean residence time, which is approximately twice as long as that for nicotine.
- the 24-hr data points from all treatment groups were below the limits of quantitation and it appears that at the doses selected, the test compounds are cleared from rat plasma between 8 and 24 hours post-administration.
- V D The apparent volume of distribution (V D ) was also significantly lower for the nicotine group compared to the anatabine treatment groups. Amongst the anatabine treatment groups, V D was significantly greater for the 0.1 mg/kg dose group compared to either of the two higher doses; however, it is not known whether this is a real difference or whether it is due to variability and the fewer number of measurable data points at the low dose.
- This example reports the evaluation of the toxicity of anatabine or nicotine for a period of fourteen days following a single intravenous injection in Sprague-Dawley rats.
- the toxicity of anatabine and nicotine was evaluated after a single intravenous (i.v.) injection in the rat.
- Anatabine was administered as a single intravenous injection at doses of 0.10, 0.75, or 1.5 mg/kg.
- Nicotine was administered as a single intravenous injection at a dose of 1.50 mg/kg.
- One control group of animals received a single i.v. dose of the vehicle at 5 mL/kg.
- Ten rats (5 males and 5 females) were dosed per group.
- Anatabine or nicotine was dissolved to the appropriate concentrations in sterile PBS for the i.v. formulations (see Table 16).
- the dosing solutions for each test compound were prepared on the basis of the relative content of the anatabine or nicotine base so that the final concentrations reflect the actual base concentrations.
- Four aliquots of each dose formulation were collected and stored at -80 °C.
- the test compound, corresponding dose level, number of animals, and frequency of observations are shown in Table 17.
- Table 19 summarizes the dosing solutions used during the conduct of this study. The per cent differences between the actual and expected concentrations of the test compounds are shown. The actual concentrations were within 20 per cent of the expected levels.
- Tables 28A-F The daily measured body weights for each animal are tabulated in Tables 28A-F and the average daily food consumption is summarized in Tables 29A, B. These data are summarized in Table 20 for the average weight gain over the 14-day observation period and the average daily food consumption, by treatment group and gender.
- FIG. 20 shows the mean body weights of animals in each treatment group on the day of dosing (Day 0) and for each day, thereafter.
- Plasma samples collected for hematology were analyzed, and individual values for the various parameters for each animal are listed in Table 31 (normal ranges, Table 30) and these are summarized in terms of descriptive statistics in Table 23A, Table 23B, and Table 24. Also shown are statistical comparisons between the vehicle controls and the various treatment groups, subdivided by gender.
- Plasma samples collected for blood chemistries were analyzed, and individual values for the various parameters for each animal are listed in Table 33 (normal ranges, Table 32), and these are summarized in terms of descriptive statistics in Tables 26A, 26B, 27A, and 27B. Also shown are statistical comparisons between the vehicle controls and the various treatment groups, subdivided by gender.
- hematology parameters for all treatment groups and genders were within the normal ranges expected for this species or displayed no significant differences when compared to the vehicle controls.
- Activated partial thromboplastin and prothrombin times were similar for all anatabine treatment groups relative to the controls; however, they were higher than the expected normal range.
- Both males and females in the nicotine group displayed significantly shorter clotting times via the intrinsic or contact activation pathway (aPTT) compared to the relevant control animals; however, the values were within the normal ranges for this species. Clotting times via the extrinsic or tissue factor pathway as determined by prothrombin times (PT) were normal.
- the plasma pharmacokinetic profile of orally administered anatabine was investigated in the rat. This study consisted of two groups of 8 animals each, 4 males and 4 females. One group received a total of 0.6 mg anatabine per kilogram body weight (BW) and the second group received 6.0 mg anatabine per kilogram BW in three, divided, oral, doses of 0.2 mg/kg BW (0.6 mg total) or 2.0 mg/kg BW (6.0 mg total). The test compound was administered as anatabine polacrilex and each dose was administered at 0, 4, and 8 hours and was administered in a volume of 5 mL/kg BW. Blood was collected for plasma at 30, 60, 240, 270, 300, 480, 540, 600, 720 and 1440 minutes post initial dose.
- the mean time to maximal plasma concentration following the first two oral doses ranged from 0.50 to 0.88 ⁇ 0.25 hr. There were no significant differences between gender or dose group. After the third dose of test compound, the mean time to maximal plasma concentration ranged from 1.00 to 2.00 + 1.41 hr. Within each dose group there were no significant differences in C p, max between males and females and nor was there any significant change in this parameter over time. In females of the high dose group C p , max appeared to increase from 259.8 ⁇ 35.4 ng/mL to 374.8 ⁇ 122.9 ng/mL; however, the trend was not statistically significant.
- the overall elimination half-life of anatabine following the first oral dose was 1.93 ⁇ 0.73 hr, the mean transit time was 3.01 ⁇ 1.25 hr and the mean absorption time was 0.56 ⁇ 1.25 hr.
- the mean absorption time of 0.56 compares favorably with the calculated T ma values following the first two doses and indicates that the absorption of anatabine occurs within the first 30 to 60 minutes after oral administration.
- Anatabine was stored at 4 °C, protected from light.
- the vehicle was sterile phosphate buffered saline (PBS) (Amresco).
- the test compound was formulated in sterile phosphate buffered saline (PBS) based on the content of anatabine base in the anatabine polacrilex.
- Two formulations were prepared; one for each of the two treatment groups.
- the test compound was formulated for each treatment group just prior to the first dose administration and constantly stirred until dosing was completed (Table 37).
- Four aliquots of each dose level formulation were collected and stored at - 80 °C.
- the test compound, corresponding dose level, and number of animals are shown in Table 38.
- the sample collection times are shown in Table 39.
- the animals were weighed prior to dosing and received three doses p.o. of test compound at a volume of 5 mL/kg. Blood was collected via the venus plexus (retro- orbital) into tubes containing (K 2 ) EDTA. No more than 0.5 mL was collected per time point. For the 1440-minute time point the animals were euthanized, and bled via cardiac puncture.
- Plasma was separated as per package instructions for MICROTAINER® brand collection tubes (3 minutes, 2000x g). Plasma was decanted into microfuge tubes and stored at -80° C. Remaining test compound was placed at -80 °C .
- Sample preparation Plasma samples were treated with three volumes of methanol containing internal standard at 1 ⁇ (R,S)-Antabine-2,4,5,6-d4), incubated 10 min at 4 °C, and centrifuged. The amount of the test agent in the supernatant was determined by LC/MS/MS.
- Calibration samples Calibration curves were determined in rat plasma. Calibration samples were prepared by diluting a 50x stock solution of the test compound in PBS with blank matrix to the appropriate concentration and these samples were prepared as described above in the sample preparation. Stock solutions were prepared by serial dilution as shown in Table 40.
- MAT MTT - MRT, [196] where MRT represents the mean residence time. This was calculated from the mean residence times.
- Table 41 shows the results of the LC/MS/MS method development for the determination of the appropriate ionization conditions and the mass to charge ratios (m/z) of the parent and product ions for anatabine and its deuterated analogue as determined above. The indicated product m/z ratios were used for the analysis of the relevant test samples.
- Table 43 provides a summary of the analyses of the dosing solutions used during the conduct of this study. The per cent differences between the actual and expected concentrations are shown. The lowest dose of anatabine, which was 63% of the expected concentration and the high dose was 84% of the expected level.
- FIG. 21A and FIG. 21B show the mean plasma anatabine concentration-time curves for male and female rats in each of the two dose groups: 0.6 mg/kg (FIG. 21A) and 6.0 mg/kg BW (FIG. 21B).
- FIG. 22A and FIG. 22B show the same data with the values from both males and females combined. In each instance, three plasma concentration maxima can be observed corresponding to the administration of the three divided doses of anatabine polacrilex at 0, 4 and 8 hours. Similarly, two anatabine plasma concentration minima are found prior to administration of the final dose.
- Table 45 shows a comparison of the plasma concentration maxima and minima over time for male and female rats in both treatment groups. There were no statistically significant changes in any of these parameters except for the plasma concentration minima for female rats in the high dose group; C p, min increased from 51.5 ⁇ 26.0 ng/mL to 180.0 ⁇ 30.7 ng/mL.
- AUC mean exposures
- t1 ⁇ 2 elimination half-lives
- MTT mean transit times
- MAT mean absorption times
- terminal elimination half-life There is also a significant difference in the terminal elimination half-life between the two treatment groups (t1 ⁇ 2, terminal; 1 -79 ⁇ 0.64 hr versus 4.53 ⁇ 1.77 hr), where t1 ⁇ 2, terminal refers to the elimination half-life following the final dose of anatabine polacrilex.
- Table 49 provides animal weights and dosing times.
- Table 50 provides measured concentrations of anatabine in rat plasma samples at each time point.
- Table 5 1 provides mean concentration and description statistics of anatabine in plasma samples at each time point.
- Anatabine concentrations can be measured in rat plasma following single and repeat oral dosing.
- the mean time to maximal plasma concentration following the first two oral doses ranged from 0.50 to 0.88 ⁇ 0.25 hr. There were no significant differences between gender or dose group.
- the mean time to maximal plasma concentration ranged from 1 .00 to 2.00 ⁇ 1 .41 hr; although in this instance the first time point measured was at one hour post-dose and therefore, it is possible that actual maximum occurred prior to this time.
- Within each dose group there were no significant differences in C p, max between males and females, nor was there any significant change in this parameter over time. In females of the high dose group C P, max appeared to increase from 259.8 ⁇ 35.4 ng/mL to 374.8 + 122.9 ng/mL; however, the trend was not statistically significant.
- the elimination half-life, mean transit time and mean absorption time following the first oral dose of the test compound are the most reliable estimates of these parameters since the plasma concentration data are not confounded by carry-over amounts from a previous dose.
- the overall elimination half-life of anatabine following the first oral dose was 1 .93 ⁇ 0.73 hr, the mean transit time was 3.01 ⁇ 1 .25 hr and the mean absorption time was 0.56 ⁇ 1 .25 hr.
- the mean absorption time (also often called mean arrival time) of 0.56 compares favorably with the calculated T max values following the first two doses and indicates that the absorption of anatabine occurs within the first 30 to 60 minutes after oral administration.
- Treatment of thyroiditis This example illustrates administering anatabine for treating thyroiditis.
- the patient's condition had advanced to a state where the treating physician recommended a thyroid lobectomy.
- inflammation of the thyroid was reduced to normal levels, such that the patient was no longer in need of a thyroid lobectomy.
- Steps 2i to 2iii Conversion of Formula I to Anatabine using Potassium Tert Butoxide (K'OBu)
- Step 2i To Formula I of Example 1 was added K'OBu (1.5 eq) in THF at -78 °C to -45 °C and the reaction was incubated for 30 min. Cis-l ,4-dichloro-2- butene in 3 vol of THF at -78°C was added, and the temperature was allowed to warm to -45°C. The reaction was allowed to proceed at -45°C for 1-2 hours, providing Formula II.
- the starting material may be added to the K'OBu.
- Step 2ii 10% aqueous hydrochloric acid was added to the solution containing Formula II for 10-20 minutes to provide Formula III.
- Step 2iii The Formula III solution was basified by adding K2CO3 then treated with a 40% aqueous KOH solution to provide anatabine.
- Formula I was prepared according to Example 1. LDA was added to Formula I at - 10 to 0 °C. Cis- l ,4-dichloro-2-butene was added at -78 °C to -45 °C. Steps 2ii and 2iii were performed according to Example 9.
- Step 2iii was extracted with methyl t-butyl ether (MTBE), followed by distillation of the solvent and product distillation using a glass distillation assembly.
- MTBE methyl t-butyl ether
- wiped film or thin film evaporation may be used. Yield of step 2 was 40%; overall yield was 26%.
- Step 2iii was treated with chloroform extraction as described in Deo et al. Chloroform extraction resulted in an anatabine yield of 10%.
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Claims
Priority Applications (13)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2794097A CA2794097C (en) | 2010-03-23 | 2011-03-23 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
PL11714880T PL2549995T3 (en) | 2010-03-23 | 2011-03-23 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
AU2011232478A AU2011232478A1 (en) | 2010-03-23 | 2011-03-23 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
EP19162458.4A EP3524246A1 (en) | 2010-03-23 | 2011-03-23 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
EP21165632.7A EP3871674A1 (en) | 2010-03-23 | 2011-03-23 | Use of anatabine for reducing blood serum levels of c-reactive protein in an individual |
EP19162452.7A EP3524245A1 (en) | 2010-03-23 | 2011-03-23 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
DK11714880.9T DK2549995T3 (en) | 2010-03-23 | 2011-03-23 | USE OF ANATABINE FOR THE TREATMENT OF INFLAMMATION AND METHODS FOR SYNTHETIZING ANATABINE |
EP11714880.9A EP2549995B1 (en) | 2010-03-23 | 2011-03-23 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
ES11714880T ES2869851T3 (en) | 2010-03-23 | 2011-03-23 | Using anatabine to treat inflammation and methods of anatabine synthesis |
AU2017201593A AU2017201593C1 (en) | 2010-03-23 | 2017-03-08 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
AU2019200102A AU2019200102B2 (en) | 2010-03-23 | 2019-01-08 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
AU2019200103A AU2019200103B2 (en) | 2010-03-23 | 2019-01-08 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
AU2020257090A AU2020257090B2 (en) | 2010-03-23 | 2020-10-21 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
Applications Claiming Priority (10)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US12/729,346 US8207346B2 (en) | 2010-03-23 | 2010-03-23 | Methods of synthesizing anatabine |
US12/729,346 | 2010-03-23 | ||
US38381110P | 2010-09-17 | 2010-09-17 | |
US61/383,811 | 2010-09-17 | ||
US38444710P | 2010-09-20 | 2010-09-20 | |
US61/384,447 | 2010-09-20 | ||
US201161439483P | 2011-02-04 | 2011-02-04 | |
US201161439473P | 2011-02-04 | 2011-02-04 | |
US61/439,473 | 2011-02-04 | ||
US61/439,483 | 2011-02-04 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2011119722A2 true WO2011119722A2 (en) | 2011-09-29 |
WO2011119722A3 WO2011119722A3 (en) | 2011-12-29 |
Family
ID=44201080
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2011/029613 WO2011119722A2 (en) | 2010-03-23 | 2011-03-23 | Use of anatabine to treat inflammation and methods of synthesizing anatabine |
Country Status (8)
Country | Link |
---|---|
EP (4) | EP3524245A1 (en) |
AU (5) | AU2011232478A1 (en) |
CA (1) | CA2794097C (en) |
DK (1) | DK2549995T3 (en) |
ES (1) | ES2869851T3 (en) |
PL (1) | PL2549995T3 (en) |
PT (1) | PT2549995T (en) |
WO (1) | WO2011119722A2 (en) |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130053355A1 (en) * | 2011-08-29 | 2013-02-28 | Rock Creek Pharmaceuticals, Inc. | Products for anti-inflammation support |
EP2793026A1 (en) | 2013-04-18 | 2014-10-22 | Centre National de la Recherche Scientifique (CNRS) | New method for monitoring cancer and/or inflammatory reaction based on relb phosphorylation |
WO2020127225A1 (en) | 2018-12-17 | 2020-06-25 | Philip Morris Products S.A. | 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate or a pharmaceutically acceptable solvate thereof |
WO2021255560A1 (en) | 2020-06-15 | 2021-12-23 | Philip Morris Products S.A. | Anatabine powder compositions |
CN113880802A (en) * | 2021-11-09 | 2022-01-04 | 深圳萨特瓦生物科技有限公司 | Tartaric acid-nicotine salt, preparation method and application thereof, and preparation method of anhydrous tartaric acid crystal |
WO2022049486A1 (en) | 2020-09-03 | 2022-03-10 | Philip Morris Products S.A. | Freeze dried low hygroscopicity active powder compositions |
WO2022049487A1 (en) | 2020-09-03 | 2022-03-10 | Philip Morris Products S.A. | Low hygroscopicity active powder compositions |
WO2022049488A1 (en) | 2020-09-03 | 2022-03-10 | Philip Morris Products S.A. | Spray dried low hygroscopicity active powder compositions |
CN115594662A (en) * | 2022-10-19 | 2023-01-13 | 昆明理工大学(Cn) | Preparation method of (S) -nicotine |
WO2023117661A1 (en) | 2021-12-20 | 2023-06-29 | Philip Morris Products S.A. | Increasing anatabine in tobacco leaf by regulating methyl putrescine oxidase |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3901248A (en) | 1970-07-22 | 1975-08-26 | Leo Ab | Chewable smoking substitute composition |
US5065775A (en) | 1990-02-23 | 1991-11-19 | R. J. Reynolds Tobacco Company | Tobacco processing |
US5119835A (en) | 1990-01-31 | 1992-06-09 | B.A.T. Cigarettenfabriken Gmbh | Method for extracting tobacco alkaloids |
US5942244A (en) | 1997-07-31 | 1999-08-24 | Farmo-Nat Ltd. | Local oral herbal slow release tablets |
US20040175754A1 (en) | 2002-10-09 | 2004-09-09 | David Bar-Or | Diagnosis and monitoring of inflammation, ischemia and appendicitis |
US20060115903A1 (en) | 2004-10-06 | 2006-06-01 | The Brigham And Women's Hospital, Inc. | Relevance of achieved levels of markers of systemic inflammation following treatment |
US20100154810A1 (en) | 2008-12-23 | 2010-06-24 | Williams Jonnie R | Tobacco Curing Method |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5276043A (en) * | 1992-04-10 | 1994-01-04 | R. J. Reynolds Tobacco Company | Method for treatment of neurodegenerative diseases |
AU770309B2 (en) * | 1998-06-05 | 2004-02-19 | Regent Court Technologies | Monoamine oxidase (MAO) inhibitors and uses thereof |
WO2001094951A2 (en) * | 2000-06-08 | 2001-12-13 | Board Of Regents, The University Of Texas System | Inhibitors of c-reactive protein induced inflammation |
CA2341952A1 (en) * | 2001-03-23 | 2002-09-23 | Universite Laval | Nicotinic receptor agonists for the treatment of inflammatory pulmonary diseases |
WO2007139753A2 (en) * | 2006-05-22 | 2007-12-06 | Combinatorx, Incorporated | Methods and compositions for the treatment of diseases or conditions associated with increased c-reactive protein, interleukin-6, or interferon-gamma levels |
US8841329B2 (en) * | 2008-09-11 | 2014-09-23 | Dignity Health | Nicotinic attenuation of CNS inflammation and autoimmunity |
-
2011
- 2011-03-23 CA CA2794097A patent/CA2794097C/en active Active
- 2011-03-23 WO PCT/US2011/029613 patent/WO2011119722A2/en active Application Filing
- 2011-03-23 EP EP19162452.7A patent/EP3524245A1/en not_active Withdrawn
- 2011-03-23 EP EP21165632.7A patent/EP3871674A1/en active Pending
- 2011-03-23 ES ES11714880T patent/ES2869851T3/en active Active
- 2011-03-23 PT PT117148809T patent/PT2549995T/en unknown
- 2011-03-23 DK DK11714880.9T patent/DK2549995T3/en active
- 2011-03-23 EP EP19162458.4A patent/EP3524246A1/en not_active Withdrawn
- 2011-03-23 EP EP11714880.9A patent/EP2549995B1/en active Active
- 2011-03-23 AU AU2011232478A patent/AU2011232478A1/en not_active Abandoned
- 2011-03-23 PL PL11714880T patent/PL2549995T3/en unknown
-
2017
- 2017-03-08 AU AU2017201593A patent/AU2017201593C1/en active Active
-
2019
- 2019-01-08 AU AU2019200102A patent/AU2019200102B2/en active Active
- 2019-01-08 AU AU2019200103A patent/AU2019200103B2/en active Active
-
2020
- 2020-10-21 AU AU2020257090A patent/AU2020257090B2/en active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3901248A (en) | 1970-07-22 | 1975-08-26 | Leo Ab | Chewable smoking substitute composition |
US5119835A (en) | 1990-01-31 | 1992-06-09 | B.A.T. Cigarettenfabriken Gmbh | Method for extracting tobacco alkaloids |
US5065775A (en) | 1990-02-23 | 1991-11-19 | R. J. Reynolds Tobacco Company | Tobacco processing |
US5942244A (en) | 1997-07-31 | 1999-08-24 | Farmo-Nat Ltd. | Local oral herbal slow release tablets |
US20040175754A1 (en) | 2002-10-09 | 2004-09-09 | David Bar-Or | Diagnosis and monitoring of inflammation, ischemia and appendicitis |
US20060115903A1 (en) | 2004-10-06 | 2006-06-01 | The Brigham And Women's Hospital, Inc. | Relevance of achieved levels of markers of systemic inflammation following treatment |
US20100154810A1 (en) | 2008-12-23 | 2010-06-24 | Williams Jonnie R | Tobacco Curing Method |
Non-Patent Citations (10)
Title |
---|
"A General Procedure for the Enantioselective Synthesis of the Minor Tobacco Alkaloids Nornicotine, Anabasine, and Anatabine", THE AAPS JOURNAL 2005, vol. 7, no. 3, 2005 |
BARON ET AL., N. ENGL. J. MED., vol. 348, 2003, pages 891 - 99 |
DEO ET AL.: "Regioselective alkylation of N-(diphenylmethylidine)-3-(aminomethyl) pyridine: A simple route to minor tobacco alkaloids and related compounds", TETRAHEDRON LETTERS, vol. 37, no. 8, 19 February 1996 (1996-02-19), pages 1137 - 1140, XP004030090, DOI: doi:10.1016/0040-4039(96)00002-0 |
HOTAMISLIGIL ET AL., J CLIN INVEST., vol. 95, no. 5, 1995, pages 2409 - 15 |
HOTAMISLIGIL ET AL., SCIENCE, vol. 271, no. 5249, 1996, pages 665 - 8 |
P. H. STAHL: "Handbook of Pharmaceutical Salts: Properties, Selection and Use", 2002, WILEY-VCH/VHCA |
ROYTBLAT ET AL., OBES RES., vol. 8, no. 9, 2000, pages 673 - 5 |
SARTIPY P, LOSKUTOFF D J., PROC NATL ACAD SCI USA., vol. 100, no. 12, 2003, pages 7265 - 70 |
STRACZKOWSKI ET AL., J CLIN ENDOCRINOL METAB., vol. 87, no. 10, 2002, pages 4602 - 6 |
VISSER ET AL., JAMA, vol. 282, no. 22, 1999, pages 2131 - 5 |
Cited By (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20130053355A1 (en) * | 2011-08-29 | 2013-02-28 | Rock Creek Pharmaceuticals, Inc. | Products for anti-inflammation support |
WO2013032558A2 (en) * | 2011-08-29 | 2013-03-07 | Rock Creek Pharmaceuticals, Inc. | Products for anti-inflammation support |
WO2013032558A3 (en) * | 2011-08-29 | 2013-09-26 | Rock Creek Pharmaceuticals, Inc. | Products for anti-inflammation support |
EP2751091A4 (en) * | 2011-08-29 | 2015-03-11 | Rcp Dev Inc | Products for anti-inflammation support |
US9387201B2 (en) | 2011-08-29 | 2016-07-12 | Rcp Development, Inc. | Methods of providing anti-inflammation support |
AU2018202701B2 (en) * | 2011-08-29 | 2019-11-21 | Philip Morris Products S.A. | Products for anti-inflammation support |
EP2793026A1 (en) | 2013-04-18 | 2014-10-22 | Centre National de la Recherche Scientifique (CNRS) | New method for monitoring cancer and/or inflammatory reaction based on relb phosphorylation |
WO2014170487A1 (en) | 2013-04-18 | 2014-10-23 | Centre National De La Recherche Scientifique (Cnrs) | New method for monitoring cancer and/or inflammatory reaction based on relb phosphorylation |
WO2020127225A1 (en) | 2018-12-17 | 2020-06-25 | Philip Morris Products S.A. | 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate or a pharmaceutically acceptable solvate thereof |
CN113039180A (en) * | 2018-12-17 | 2021-06-25 | 菲利普莫里斯生产公司 | 3- (1,2,3, 6-tetrahydropyridin-2-yl) pyridine glutarate or pharmaceutically acceptable solvate thereof |
US20210395218A1 (en) * | 2018-12-17 | 2021-12-23 | Philip Morris Products S.A. | 3-(1,2,3,6-tetrahydropyridin-2-yl) pyridine glutarate or a pharmaceutically acceptable solvate thereof |
WO2021255560A1 (en) | 2020-06-15 | 2021-12-23 | Philip Morris Products S.A. | Anatabine powder compositions |
WO2022049486A1 (en) | 2020-09-03 | 2022-03-10 | Philip Morris Products S.A. | Freeze dried low hygroscopicity active powder compositions |
WO2022049487A1 (en) | 2020-09-03 | 2022-03-10 | Philip Morris Products S.A. | Low hygroscopicity active powder compositions |
WO2022049488A1 (en) | 2020-09-03 | 2022-03-10 | Philip Morris Products S.A. | Spray dried low hygroscopicity active powder compositions |
CN113880802A (en) * | 2021-11-09 | 2022-01-04 | 深圳萨特瓦生物科技有限公司 | Tartaric acid-nicotine salt, preparation method and application thereof, and preparation method of anhydrous tartaric acid crystal |
WO2023117661A1 (en) | 2021-12-20 | 2023-06-29 | Philip Morris Products S.A. | Increasing anatabine in tobacco leaf by regulating methyl putrescine oxidase |
CN115594662A (en) * | 2022-10-19 | 2023-01-13 | 昆明理工大学(Cn) | Preparation method of (S) -nicotine |
Also Published As
Publication number | Publication date |
---|---|
CA2794097C (en) | 2016-08-09 |
DK2549995T3 (en) | 2021-05-25 |
WO2011119722A3 (en) | 2011-12-29 |
AU2020257090A1 (en) | 2020-11-19 |
EP3524245A1 (en) | 2019-08-14 |
AU2017201593B2 (en) | 2019-02-28 |
EP2549995A2 (en) | 2013-01-30 |
EP2549995B1 (en) | 2021-04-21 |
EP3871674A1 (en) | 2021-09-01 |
AU2019200103A1 (en) | 2019-01-31 |
AU2019200103B2 (en) | 2020-07-30 |
ES2869851T3 (en) | 2021-10-26 |
AU2017201593C1 (en) | 2019-06-27 |
AU2020257090B2 (en) | 2021-12-02 |
PL2549995T3 (en) | 2021-09-27 |
AU2019200102A1 (en) | 2019-01-31 |
EP3524246A1 (en) | 2019-08-14 |
PT2549995T (en) | 2021-07-29 |
AU2017201593A1 (en) | 2017-03-30 |
AU2019200102B2 (en) | 2020-07-30 |
AU2011232478A1 (en) | 2015-11-19 |
CA2794097A1 (en) | 2011-09-29 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2017201593A1 (en) | Use of anatabine to treat inflammation and methods of synthesizing anatabine | |
US20160030407A1 (en) | Method of Treating Inflammatory Lung Disease | |
US8241680B2 (en) | Nutraceutical product containing anatabine and yerba maté | |
EP3042659A1 (en) | Polymorphic forms of 3-(4-amino-1-oxo-1,3 dihydroisoindol-2-yl)-piperidine-2,6-dione | |
CN101679329A (en) | compositions of tolperisone | |
EP3898607B1 (en) | 3-(1,2,3,6-tetrahydropyridin-2-yl)pyridine glutarate or a pharmaceutically acceptable solvate thereof | |
US20130303497A1 (en) | Deuterated 5-ht1a receptor agonists | |
AU2013259779B2 (en) | N-ethyl-4-hydroxyl-1-methyl-5- (methyl(2,3,4,5,6-pentahydroxyhexyl) amino) -2-oxo-N-phenyl-1,2-dihydroquinoline-3-carboxamide | |
CA3125554A1 (en) | Cyclodextrin dimers, compositions thereof, and uses thereof | |
TW200412954A (en) | N-aryl piperidine substituted biphenylcarboxamides | |
CN110698445B (en) | 3-amine alkyl phthalide compound, preparation method and application thereof | |
US20120196899A1 (en) | Methods and products for treating inflammation | |
AU2017254855A1 (en) | Methods of administering anatabine to treat autism spectrum disorders and seizure disorders | |
CN108727350B (en) | Piperidine alkyl phthalide compounds, preparation method and application thereof | |
CN110698411A (en) | 4- (aminoalkyl) phthalazine-1-ketone compounds, preparation method and application thereof | |
CN114315689B (en) | Disulfanylphthalimide compound, preparation method and application thereof | |
CN115724786A (en) | Amide alkane dithiophthalimide compound, preparation method and application thereof | |
WO2022148850A1 (en) | Compositions comprising anatabine and uses thereof | |
EP2927215A1 (en) | Copper chelators | |
CN110944631A (en) | STAT3 inhibitor formulations |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 11714880 Country of ref document: EP Kind code of ref document: A2 |
|
ENP | Entry into the national phase |
Ref document number: 2794097 Country of ref document: CA |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 3032/KOLNP/2012 Country of ref document: IN Ref document number: 2011714880 Country of ref document: EP |
|
ENP | Entry into the national phase |
Ref document number: 2011232478 Country of ref document: AU Date of ref document: 20110323 Kind code of ref document: A |