(12) United States Patent
`Quallich et al.
`
`I 1111111111111111 11111 lllll 111111111111111 111111111111111 IIIIII IIII IIII IIII
`US006794388B2
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,794,388 B2
`Sep.21,2004
`
`(54) SUCCINIC ACID SALTS OF
`5,7,14-TRIAZATETRACYCLO
`9
`[10.3.1.02
`11 .04
`] -HEXADECA-1(11),3,5,
`•
`•
`7,9-PENTAENE AND PHARMACEUTICAL
`COMPOSITIONS THEREOF
`
`(75)
`
`Inventors: George J. Quallich, North Stonington,
`CT (US); Lewin T. Wint, Wilmette, IL
`(US)
`
`(73) Assignee: Pfizer Inc., New York, NY (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by O days.
`
`(21) Appl. No.: 10/305,845
`
`(22)
`
`Filed:
`
`Nov. 27, 2002
`
`(65)
`
`Prior Publication Data
`
`US 2003/0149044 Al Aug. 7, 2003
`
`(58) Field of Search ............................ 514/250, 214.03;
`544/343; 540/578
`
`(56)
`
`WO
`WO
`
`References Cited
`
`FOREIGN PATENT DOCUMENTS
`
`WO9935131
`1157726
`
`7/1999
`11/2001
`
`Primary Examiner-Bruck Kifle
`(74) Attorney, Agent, or Firm-P. C. Richardson; P. H.
`Ginsburg; A D. Joran
`
`(57)
`
`ABSTRACT
`
`The present invention is directed to the succinate salts of
`10
`5, 7, 13-triazatetracyclo[ 9 .3 .1. 02
`. 04
`8 ]-pentadeca -2( 10),3,
`•
`•
`5,8-tetraene
`
`(XX}}
`
`(60)
`
`Related U.S. Application Data
`Provisional application No. 60/334,245, filed on Nov. 29,
`2001.
`Int. Cl.7 ................... C07D 471/08; A61K 31/4995
`(51)
`(52) U.S. Cl. ........................................ 514/250; 544/343
`
`and pharmaceutical compositions thereof. The invention is
`also directed to a process for preparation of the succinate
`salts.
`
`18 Claims, 4 Drawing Sheets
`
`Apotex Exhibit 1021.001
`
`

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`ApoteX Exhibit 1021.002
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`Apotex Exhibit 1021.002
`
`

`

`U.S. Patent
`US. Patent
`
`Sep.21,2004
`Sep. 21, 2004
`
`Sheet 2 of 4
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`US 6,794,388 B2
`US 6,794,388 B2
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`Sep.21,2004
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`

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`
`Sep.21,2004
`Sep. 21, 2004
`
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`US 6,794,388 B2
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`Apotex Exhibit 1021.005
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`

`

`US 6,794,388 B2
`
`1
`SUCCINIC ACID SALTS OF
`5,7,14-TRIAZATETRACYCLO
`9
`11 .04
`[10.3.1.02
`] -HEXADECA-1(11),3,5,
`•
`•
`7,9-PENTAENE AND PHARMACEUTICAL
`COMPOSITIONS THEREOF
`
`This application claims benefit of Application No.
`60/334,245 filed Nov. 29, 2001.
`The present invention is directed to the succinate salts of
`5,8,14-triazatetracyclo[l0.3. l .02
`11 .04
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene
`
`(XX}}
`
`5
`
`2
`1999 and 09/514,002, filed Feb. 25, 2000). The foregoing
`applications, owned in common with the present application
`and incorporated herein by reference in their entirety, generi(cid:173)
`cally recite pharmaceutically acceptable acid addition salts
`for the compounds referred to therein.
`The succinate salts of the present invention exhibits
`properties, including those of solid-state stability and com(cid:173)
`patibility with certain drug product formulation excipients,
`that render it preferable among known salts of 5,8,14-
`11 .04
`10 triazatetracyclo[lO .3.1.02
`9 ]-hexadeca-2(11 ),3,5, 7 ,9-
`•
`•
`pentaene. Further, the succinate salt formation is an
`extremely efficient means of purifying 5,8,14-
`11
`triazatetracyclo[ 10 .3 .1.02
`.04
`9 ]-hexadeca -2( 11 ),3,5, 7 ,9-
`•
`•
`pentaene.
`
`15
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is the observed powder X-ray diffraction pattern of
`the anhydrous succinate salt of 5,8,14-triazatetracyclo
`11 .04
`9 ]-hexadeca-2(11),3,5,7,9-pentaene (y axis
`[10.3.1.02
`•
`•
`20 is linear counts per second; X in degrees 2 theta).
`FIG. 2 is the differential scanning calorimetric trace of the
`anhydrous succinate salt of 5,8,14-triazatetracyclo
`11 .04
`[ 10 .3 .1.02
`9 ]-hexadeca-2( 11 ),3,5, 7 ,9-pentaene.
`•
`•
`FIG. 3 is the observed powder X-ray diffraction pattern of
`the succinate salt hydrate of 5,8,14-triazatetracyclo
`11 .04
`[10.3.l.02
`9 ]-hexadeca-2(11),3,5,7,9-pentaene (y axis
`•
`•
`is linear counts per second; X in degrees 2 theta).
`FIG. 4 is the differential scanning calorimetric trace of the
`succinate salt hydrate of 5,8,14-triazatetracyclo[lO.
`11 .04
`3.1.02
`9 ]-hexadeca-2(11 ),3,5, 7,9-pentaene.
`•
`•
`
`and pharmaceutical compos1t10ns thereof. The succinate
`salts can take an anhydrous form or a hydrated form.
`11 .04
`The compound, 5,8,14-triazatetracyclo[l0.3.1.02
`9
`](cid:173)
`•
`•
`hexadeca-2(11),3,5,7,9-pentaene, binds to neuronal nico(cid:173)
`tinic acetylcholine specific receptor sites and is useful in
`modulating cholinergic function. This compound is useful in
`the treatment of inflammatory bowel disease (including but
`not limited to ulcerative colitis, pyoderma gangrenosum and 25
`Crohn's disease), irritable bowel syndrome, spastic
`dystonia, chronic pain, acute pain, celiac sprue, pouchitis,
`vasoconstriction, anxiety, panic disorder, depression, bipolar
`disorder, autism, sleep disorders, jet lag, amyotrophic lateral
`sclerosis (ALS), cognitive dysfunction, hypertension, 30
`bulimia, anorexia, obesity, cardiac arrythmias, gastric acid
`hypersecretion, ulcers, pheochromocytoma, progressive
`supramuscular, palsy, chemical dependencies and addictions
`(e.g., dependencies on, or addictions to nicotine (and/or
`tobacco products), alcohol, benzodiazepines, barbiturates, 35
`opioids or cocaine), headache, migraine, stroke, traumatic
`brain injury (TEI), obsessive-compulsive disorder (OCD),
`psychosis, Huntington's chorea, tardive dyskinesia,
`hyperkinesia, dyslexia, schizophrenia, multi-infarct
`dementia, age-related cognitive decline, epilepsy, including 40
`petit mal absence epilepsy, senile dementia of the Alzhe(cid:173)
`imer's type (AD), Parkinson's disease (PD), attention deficit
`hyperactivity disorder (ADHD) and Tourette's Syndrome.
`The succinate salts of this invention may also be used in
`a pharmaceutical composition in combination with an anti- 45
`depressant such as, for example, a tricyclic antidepressant or
`a serotonin reuptake inhibiting antidepressant (SRI), in order
`to treat both the cognitive decline and depression associated
`with AD, PD, stroke, Huntington's chorea or traumatic brain
`injury (TEI); in combination with muscarinic agonists in 50
`order to stimulate both central muscarinic and nicotinic
`receptors for the treatment, for example, of ALS, cognitive
`dysfunction, age-related cognitive decline, AD, PD, stroke,
`Huntington's chorea and TEI; in combination with neu(cid:173)
`rotrophic factors such as NGF in order to maximize cholin(cid:173)
`ergic enhancement for the treatment, for example, of ALS,
`cognitive dysfunction, age-related cognitive decline, AD,
`PD stroke, Huntington's chorea and TEI; or in combination
`with agents that slow or arrest AD such as cognition
`enhancers, amyloid aggregation inhibitors, secretase
`inhibitors, tau kinase inhibitors, neuronal anti-inflammatory
`agents and estrogen-like therapy.
`Compounds that bind to neuronal nicotinic receptor sites,
`9
`11 .0 4
`including 5 ,8,14-triazatetracyclo[ 10.3 .1.0 2
`•
`](cid:173)
`•
`hexadeca-2(11),3,5,7,9-pentaene, and its hydrochloride salt,
`are referred to in WO 99/35131, published Jul. 15, 1999
`(corresponding to U.S. Ser. Nos. 09/402,010, filed Sep. 28,
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to the succinate salt of
`11.04
`5,8,14-triazatetracyclo[l0.3.l .02
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene. In particular, the present invention relates to
`the anhydrous and hydrate forms of this succinate salt.
`Particularly preferred is the anhydrous succinate salt.
`Another embodiment of the invention relates to a phar(cid:173)
`maceutical composition comprising the succinate salt of
`11.04
`5,8,14-triazatetracyclo[l0.3.l .02
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene and a pharmaceutically acceptable carrier or
`excipient, particularly, one for use in the treatment of
`inflammatory bowel disease (including but not limited to
`ulcerative colitis, pyoderma gangrenosum and Crohn's
`disease), irritable bowel syndrome, spastic dystonia, chronic
`pain, acute pain, celiac sprue, pouchitis, vasoconstriction,
`anxiety, panic disorder, depression, bipolar disorder, autism,
`sleep disorders, jet lag, amyotrophic lateral sclerosis (ALS),
`cognitive dysfunction, hypertension, bulimia, anorexia,
`obesity, cardiac arrythmias, gastric acid hypersecretion,
`ulcers, pheochromocytoma, progressive supramuscular
`palsy, chemical dependencies and addictions (eq., depen(cid:173)
`dencies on, or addictions to nicotine (and/or tobacco
`55 products), alcohol, benzodiazepines, barbiturates, opioids or
`cocaine), headache, migraine, stroke, traumatic brain injury
`(TEI), obsessive-compulsive disorder (OCD), psychosis,
`Huntington's chorea, tardive dyskinesia, hyperkinesia,
`dyslexia, schizophrenia, multi-infarct dementia, age-related
`60 cognitive decline, epilepsy, including petit mal absence
`epilepsy, senile dementia of the Alzheimer's type (AD),
`Parkinson's disease (PD), attention deficit hyperactivity
`disorder (ADHD) and Tourette's Syndrome. Another more
`preferred embodiment of the invention is wherein the phar-
`65 maceutical composition above is useful in the treatment of
`nicotine dependency, addiction and withdrawal, most
`preferably, for use in smoking cessation therapy.
`
`Apotex Exhibit 1021.006
`
`

`

`US 6,794,388 B2
`
`5
`
`3
`The present invention further relates to a the method of
`treating inflammatory bowel disease (including but not
`limited to ulcerative colitis, pyoderma gangrenosum and
`Crohn's disease), irritable bowel syndrome, spastic
`dystonia, chronic pain, acute pain, celiac sprue, pouchitis,
`vasoconstriction, anxiety, panic disorder, depression, bipolar
`disorder, autism, sleep disorders, jet lag, amyotrophic lateral
`sclerosis (ALS), cognitive dysfunction, hypertension,
`bulimia, anorexia, obesity, cardiac arrythmias, gastric acid
`hypersecretion, ulcers, pheochromocytoma, progressive
`supramuscular palsy, chemical dependencies and addictions
`(e.q., dependencies on, or addictions to nicotine (and/or
`tobacco products), alcohol, benzodiazepines, barbiturates,
`opioids or cocaine), headache, migraine, stroke, traumatic
`brain injury (TEI), obsessive-compulsive disorder (OCD),
`psychosis, Huntington's chorea, tardive dyskinesia,
`hyperkinesia, dyslexia, schizophrenia, multi-infarct
`dementia, age-related cognitive decline, epilepsy, including
`petit mal absence epilepsy, senile dementia of the Alzhe(cid:173)
`imer's type (AD), Parkinson's disease (PD), attention deficit
`hyperactivity disorder (ADHD) and Tourette's Syndrome
`comprises administering to a subject in need of treatment a
`therapeutically effective amount of the succinate salt of
`11 .04
`5,8,14-triazatetracyclo[l0.3. l .02
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene thereof. Another more preferred embodiment
`of the invention relates to a method of treatment for nicotine
`dependency, addiction and withdrawal, in particular for use
`in smoking cessation therapy activity, comprising the
`administration of the succinate salt of 5,8,14-triazatetracyclo
`11 .04
`[10.3.1.02
`9 ]-hexadeca-2(11),3,5,7,9-pentaene to a sub- 30
`•
`•
`ject in need thereof.
`The invention also relates to a process for the preparation
`of the anhydrous succinate salt of 5,8,14-triazatetracyclo
`11 .04
`[10.3.1.02
`9 ]-hexadeca-2(11),3,5,7,9-pentaene com(cid:173)
`•
`•
`prising the steps of
`11.04
`9
`(i) contacting 5,8,14-triazatetracyclo[l0.3.1.02
`](cid:173)
`•
`•
`hexadeca-2(11 ),3,5, 7,9-pentaene in a suitable solvent
`with succinic acid; and
`(ii) collecting the crystals formed.
`A preferred embodiment is wherein the suitable solvent is
`selected from the group consisting of a (CcC 6)alkyl
`alcohol, a (CcC6)alkyl ketone or a (CcC6)alkyl ether in the
`presence of water. More preferably, the suitable solvent is
`acetone or 2-propanol. Most preferably, the suitable solvent 45
`is 2-propanol. Preferably, the process of the invention is
`wherein the contacting of step (i) is carried out by contacting
`11 .04
`5,8,14-triazatetracyclo[l0.3. l .02
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene in solution phase with a solution of succinic
`acid. Preferably, the contacting step is carried out over a 50
`period of between 1 and 24 hours, more preferably between
`5 and 15 hours, and comprising stirring or mixing the
`resulting mixture. A preferred embodiment of the process is
`wherein step (i) is run between ambient temperature and the
`refluxing temperature of the solvent; more preferably, 55
`between ambient temperature and the refluxing temperature
`of 2-propanol, i.e., about 80° C.; most preferably, the
`process in run between 30 and 60° C.
`
`4
`pentaene are only slightly hygroscopic and have high aque(cid:173)
`ous solubility. These characteristics make the succinate salt
`highly suitable for pharmaceutical formulation use.
`Although in general the acid addition salts of 5,8,14-
`triazatetracyclo[l0.3.l .02
`11 .04
`9 ]-hexadeca-2(11 ),3,5,7,9-
`•
`•
`pentaene are all crystalline, the majority of those salts are so
`hygroscopic as to render them poor candidates for pharma(cid:173)
`ceutical formulation use. The anhydrous succinate salt of the
`present invention exhibits a hygroscopicity of approxi-
`10 mately 1.97% wt/wt on exposure to 90% relative humidity
`in a moisture chamber. The aqueous solubility of the anhy(cid:173)
`drous succinate salt is 442 mg/ml. Further, the anhydrous
`11 .04
`9
`succinate salt of 5,8,14-triazatetracyclo[l0.3.1.02
`](cid:173)
`•
`•
`hexadeca-2(11),3,5,7,9-pentaene exhibits excellent solid
`15 state stability both in light and elevated temperatures as well
`as high humidity challenges.
`The aqueous solubility of the anhydrous succinate salt has
`been measured under various conditions: > 10 mg/mL in pH
`4 buffer; >10 mg/mL in pH 10 buffer; >10 mg/mL in 0.1 N
`20 HCl; and >10 mg/mL in 0.1 N NaOH. The solubility of the
`anhydrous succinate salt has also been measured in various
`solvents: > 10 mg/mL in methanol; 0.1 mg/mL in acetonitrile
`and <0.01 mg/mL in hexane. The hygroscopicity of the
`anhydrous succinate salt has also been measured under
`25 various conditions: 0.0% moisture gain at 20% Relative
`Humidity; 0.3% moisture gain at 40% Relative Humidity;
`0.6% moisture gain at 60% Relative Humidity; 0.9% mois(cid:173)
`ture gain at 80% Relative Humidity and 1.3% moisture gain
`at 95% Relative Humidity.
`The anhydrous succinate salt has been prepared under
`different conditions via dissolving 5,8,14-triazatetracyclo
`11 .0 4
`[10.3.1.0 2
`9 ]-hexadeca-2(11 ),3,5, 7,9-pentaene in
`•
`•
`acetone or 2-propanol and then added to a succinic acid
`solution also in acetone. A slurry is formed and allowed to
`35 stir at 20 to 25° C. for approximately 24 hours. The product
`crystallizes on agitation to give the desired anhydrous salt
`usually in high yield. The product crystals are small and
`generally agglomerated or aggregated together. The hydrate
`salt can be formed via the use of a water containing solvents,
`40 i.e., 50:50 mixtures of acetone or 2-propanol.
`Differential Scanning Calorimetry
`The solid state thermal behavior of the succinate salt of
`the invention was investigated by differential scanning calo(cid:173)
`rimetry (DSC). The trace for the anhydrous succinate salt is
`shown in FIG. 2; the hydrate succinate salt in FIG. 4. The
`DSC thermogram was obtained on a Mettler Toledo DSC
`821 e (STARe System). Generally, samples between 1 and 10
`mg were prepared in crimped aluminum pans with a small
`pinhole. The measurements were run at a heating rate of 5°
`C. per minute in the range of 30 to 300° C.
`As seen in FIG. 2, the anhydrous succinate salt exhibits
`onset of melt transition at about 198° C. (more precisely
`measured at 197.8° C.). As seen in FIG. 4, the succinate salt
`hydrate exhibits tow solid-solid transitions with onsets at
`about 70° C. and about 144 ° C., and an onset of melt
`transition at about 191 ° C. (more precisely measured at
`190.9° C.). One of skill in the art will however note that in
`DSC measurement there is a certain degree of variability in
`actual measured onset and peak temperatures which occur
`60 depending on rate of heating, crystal shape and purity, and
`other measurement parameters. Further, the anhydrous suc(cid:173)
`cinate salt is characterized in that it forms prism-shaped
`crystals and has an onset of melting transition point at about
`198° C. as measured by differential scanning calorimetry
`65 (DSC). Further, the anhydrous succinate salt of the invention
`is also characterized in having an aqueous solubility of 442
`mg/ml and a native pH of 4.7 in aqueous solution. In
`
`DETAILED DESCRIPTION OF THE
`INVENTION
`
`11 .04
`9
`The compound, 5,8,14-triazatetracyclo[l0.3.1.02
`](cid:173)
`•
`•
`hexadeca-2(11),3,5,7,9-pentaene is a nicotinic partial ago(cid:173)
`nist for the treatment of a number of CNS diseases, disorders
`and conditions including, in particular, nicotine dependency,
`addiction and withdrawal. The succinate salts of 5,8,14-
`11 .04
`9 ]-hexadeca-2(11 ),3,5, 7,9-
`triazatetracyclo[l 0.3.1.02
`•
`•
`
`Apotex Exhibit 1021.007
`
`

`

`US 6,794,388 B2
`
`6
`
`TABLE III-continued
`
`Powder X-ray Diffraction Pattern for with Intensities and Peak Locations
`of Diffraction Lines for the Succinate Salt Hydrate.
`
`Angle
`20
`
`16.5
`19.4
`24.2
`28.3
`
`d-value
`(A)
`
`5.4
`4.6
`3.7
`3.2
`
`I
`(rel.)
`
`74
`100
`32
`45
`
`5
`addition, the anhydrous succinate salt has a hygroscopicity
`of approximately 1.97% at 90% relative humidity.
`Powder X-ray Diffraction Patterns
`The power x-ray diffraction patterns for the succinate salt
`of the invention was collected using a Bruker D5000 dif-
`fractometer (Bruker AXS, Madison, Wis.) equipped with
`copper radiation CuK"" fixed slits (1.0, 1.0, 0.6 mm), and a
`Kevex solid state detector. Data was collected from 3.0 to
`40.0 degrees in two theta (28) using a step size of 0.04
`degrees and a step time of 1.0 seconds.
`The x-ray powder diffraction pattern of the succinate salts
`were conducted with a copper anode with wavelength 1 at
`1.54056 and wavelength 2 at 1.54439 (relative intensity:
`0.500). The range for 28 was between 3.0 to 40.0 degrees
`with a step size of 0.04 degrees, a step time of 1.00 second,
`a smoothing width of 0.300 and a threshold of 1.0.
`The diffraction peaks at diffraction angles (28) in the
`measured powder X-ray diffraction analysis for the anhy(cid:173)
`drous succinate salt are shown in Table I. The relative
`intensities, however, may change depending on the crystal 20
`size and morphology. The actual measured powder diffrac(cid:173)
`togram is displayed in FIG. 1.
`
`5
`
`10
`
`Table IV sets forth the 28 and the d-spacings for the
`highest relative intensities for the powder x-ray diffraction
`15 pattern of the hydrate succinate salt.
`
`TABLE IV
`
`Powder X-ray Diffraction Intensities and Peak Locations for the Succinate
`Salt H drate.
`
`Angle
`20
`
`13.0
`16.5
`19.4
`
`d-value
`(A)
`
`6.8
`5.4
`4.6
`
`I
`(rel.)
`
`73
`74
`100
`
`25
`
`TABLE I
`
`Powder X-ray Diffraction Pattern for with Intensities and Peak
`Locations of Diffraction Lines.
`
`Angle
`20
`
`6.5
`13.1
`16.5
`17.0
`19.8
`22.2
`23.8
`
`d-value
`(A)
`
`13.5
`6.7
`5.4
`5.2
`4.5
`4.0
`3.7
`
`I
`(rel.)
`
`38%
`100
`49
`78
`63
`79
`77
`
`Table II sets forth the 28 and the d-spacings for the highest
`relative intensities for the powder x-ray diffraction pattern.
`
`TABLE II
`
`Powder X-ray Diffraction Intensities and Peak Locations for Anhydrous
`Succinate Salt.
`
`Angle
`20
`
`13.1
`17.0
`22.2
`23.8
`
`d-value
`(A)
`
`6.7
`5.2
`4.0
`3.7
`
`I
`(rel.)
`
`100
`78
`79
`77
`
`The diffraction peaks at diffraction angles (28) in the
`measured powder X-ray diffraction analysis for the succi(cid:173)
`nate salt hydrate are shown in Table III. The relative
`intensities, however, may change depending on the crystal
`size and morphology. The actual measured powder diffrac(cid:173)
`togram is displayed in FIG. 3.
`
`TABLE III
`
`Powder X-ray Diffraction Pattern for with Intensities and Peak Locations
`of Diffraction Lines for the Succinate Salt Hydrate.
`
`Angle
`20
`
`6.5
`13.0
`
`d-value
`(A)
`
`13.6
`6.8
`
`I
`(rel.)
`
`30%
`73
`
`The succinate salts of the invention (hereafter "the active
`salts") can be administered via either the oral, transdermal
`( e.g., through the use of a patch), intranasal, sub lingual,
`30 rectal, parenteral or topical routes. Transdermal and oral
`administration are preferred. An active salt can, most
`desirably, administered in dosages ranging from about 0.01
`mg up to about 1500 mg per day, preferably from about 0.1
`to about 300 mg per day in single or divided doses, although
`35 variations will necessarily occur depending upon the weight
`and condition of the subject being treated and the particular
`route of administration chosen. However, a dosage level that
`is in the range of about 0.001 mg to about 10 mg per kg of
`body weight per day is most desirably employed. Variations
`40 may nevertheless occur depending upon the weight and
`condition of the persons being treated and their individual
`responses to said medicament, as well as on the type of
`pharmaceutical formulation chosen and the time period and
`interval during which such administration is carried out. In
`some instances, dosage levels below the lower limit of the
`aforesaid range may be more than adequate, while in other
`cases still larger doses may be employed without causing
`any harmful side effects, provided that such larger doses are
`first divided into several small doses for administration
`throughout the day.
`An active salt can be administered alone or in combina(cid:173)
`tion with pharmaceutically acceptable carriers or diluents by
`any of the several routes previously indicated. More
`particularly, an active salt can be administered in a wide
`variety of different dosage forms, e.g., they may be com-
`55 bined with various pharmaceutically acceptable inert carri(cid:173)
`ers in the form of tablets, capsules, transdermal patches,
`lozenges, troches, hard candies, powders, sprays, creams,
`salves, suppositories, jellies, gels, pastes, lotions, ointments,
`aqueous suspensions, injectable solutions, elixirs, syrups,
`60 and the like. Such carriers include solid diluents or fillers,
`sterile aqueous media and various non-toxic organic sol(cid:173)
`vents. In addition, oral pharmaceutical compositions can be
`suitably sweetened and/or flavored. In general, an active salt
`is present in such dosage forms at concentration levels
`ranging from about 5.0% to about 70% by weight.
`For oral administration, tablets containing various excipi(cid:173)
`ents such as microcrystalline cellulose, sodium succinate,
`
`45
`
`50
`
`65
`
`Apotex Exhibit 1021.008
`
`

`

`US 6,794,388 B2
`
`7
`calcium carbonate, dicalcium phosphate and glycine may be
`employed along with various disintegrants such as starch
`(preferably corn, potato or tapioca starch), alginic acid and
`certain complex silicates, together with granulation binders
`like polyvinylpyrrolidone, sucrose, gelatin and acacia. 5
`Additionally, lubricating agents such as magnesium stearate,
`sodium lauryl sulfate and talc can be used for tabletting
`purposes. Solid compositions of a similar type may also be
`employed as fillers in gelatin capsules; preferred materials in
`this connection also include lactose or milk sugar, as well as 10
`high molecular weight polyethylene glycols. When aqueous
`suspensions and/or elixirs are desired for oral administration
`the active ingredient may be combined with various sweet(cid:173)
`ening or flavoring agents, coloring matter and, if so desired,
`emulsifying and/or suspending agents, together with such 15
`diluents as water, ethanol, propylene glycol, glycerin and
`various combinations thereof.
`For parenteral administration, a solution of an active salt
`in either sesame or peanut oil or in aqueous propylene glycol
`can be employed. The aqueous solutions should be suitably
`buffered (preferably pH greater than 8), if necessary, and the
`liquid diluent first rendered isotonic. These aqueous solu(cid:173)
`tions are suitable for intravenous injection purposes. The
`oily solutions are suitable for intraarticular, intramuscular
`and subcutaneous injection purposes. The preparation of all
`these solutions under sterile conditions is readily accom(cid:173)
`plished by standard pharmaceutical techniques well known
`to those skilled in the art.
`It is also possible to administer an active salt topically and
`this can be done by way of creams, a patch, jellies, gels,
`pastes, ointments and the like, in accordance with standard
`pharmaceutical practice.
`The following example illustrates the methods and com(cid:173)
`pounds of the present invention. It will be understood,
`however, that the invention is not limited to the specific
`Examples.
`
`8
`filtration, washed with 2-propanol (18 ml) and dried at 20 to
`30° C. under vacuum for about 24 hours.
`
`EXAMPLE 2
`
`Succinate Salt Hydrate of 5,8,14-Triazatetracyclo
`11 .04
`9 ]-hexadeca-2( 11 ),3,5, 7 ,9-pentaene
`[ 10 .3 .1.02
`•
`•
`A reactor was charged with the anhydrous succinate salt
`prepared in Example 1 and water (500 mL). The suspension
`was stirred at about 40 C for about 12 hours. The crystalline
`product was filtered and dried in vacuum to afford the
`succinate hydrate salt.
`What is claimed is:
`1. A succinate salt of 5,8,14-triazatetracyclo[lO.
`3.1.02
`11 .04
`9 ]-hexadeca-2(11 ),3,5, 7,9-pentaene.
`•
`•
`2. The compound according to claim 1 wherein the salt is
`anhydrous.
`3. A compound according to claim 2 having an x-ray
`diffraction pattern characterized substantially by an x-ray
`diffraction pattern peaks as measured with copper radiation
`20 of a 28 of about 13.3 and 17.2.
`4. A compound according to claim 2 having an x-ray
`diffraction pattern characterized substantially by the follow(cid:173)
`ing principal x-ray diffraction pattern peaks expressed in
`terms of 28 and d-spacings as measured with copper radia-
`25 tion:
`
`Angle
`20
`
`13.1
`17.0
`22.2
`23.8
`
`d-value
`(A)
`
`6.7
`5.2
`4.0
`3.7
`
`30
`
`35
`
`EXAMPLE 1
`
`Anhydrous Succinate Salt of 5,8,14-
`Triazatetracyclo[ 10 .3 .1.02
`11 .04
`9 ]-hexadeca -2( 11 ),3,
`•
`•
`5,7,9-pentaene
`
`Succinic Acid
`2-propanol
`
`5. A compound according to claim 2 characterized by an
`onset of melting/decomposition transition at about 198° C.
`6. A pharmaceutical composition comprising a compound
`according to claim 2 and a pharmaceutically acceptable
`40 earner.
`7. A compound according to claim 1 wherein the salt is a
`hydrate.
`8. A compound according to claim 7 having an x-ray
`diffraction pattern characterized substantially by the follow-
`45 ing principal x-ray diffraction pattern peaks expressed in
`terms of 28 and d-spacings as measured with copper radia(cid:173)
`tion:
`
`50
`
`55
`
`Angle
`20
`
`13.0
`16.5
`19.4
`
`d-value
`(A)
`
`6.8
`5.4
`4.6
`
`A 200 ml reactor was charged with the free base 5,8,14-
`triazatetracyclo[l 0.3.1.02
`11 .04
`9 ]-hexadeca-2(11 ),3,5, 7,9-
`•
`•
`pentaene (9 g; 0.047 mol) and 2-propanol (90 ml, 10 ml/g).
`The mixture was warmed to 50 to 55° C. to give a solution.
`The mixture was filtered to remove any specks and fibers 60
`present. The clarified solution ( at 50 to 55° C.) was treated
`with a clarified solution of succinic acid (7.1 g., 0.0598 mol,
`1.4 equiv.) dissolved in 2-propanol (36 ml) over about 5 to
`15 minutes. The mixture was stirred at 50 to 55° C. for about
`1 hour allowing crystallization to occur. The crystal slurry
`was cooled to Oto 5° C. over about 1 hour and the final slurry
`was stirred for about 1 hour. The product was isolated by
`
`9. A compound according to claim 7 characterized by an
`onset of melting/decomposition transition at about 198° C.
`10. A pharmaceutical composition comprising a com(cid:173)
`pound according to claim 7 and a pharmaceutically accept(cid:173)
`able carrier.
`11. A method of treatment for nicotine dependency, addic(cid:173)
`tion or withdrawal in a mammal comprising the adminis(cid:173)
`tration of a compound according to any of claim 1 to a
`65 subject in need thereof.
`12. A process for the preparation of the anhydrous suc(cid:173)
`cinate salt of 5,8,12-triazatetracyclo[l0.3.1.02
`9
`11 .04
`•
`]-
`•
`
`Apotex Exhibit 1021.009
`
`

`

`US 6,794,388 B2
`
`9
`hexadeca-2(11),3,5,7,9-pentaene according to claim 2 com(cid:173)
`prising the steps of
`9
`11.04
`(i) contacting 5,8,14-triazatetracyclo[l0.3.1.02
`•
`•
`](cid:173)
`hexadeca-2(11 ),3,5, 7,9-pentaene in a suitable solvent
`with succinic acid; and
`(ii) collecting the crystals formed.
`13. A process according to claim 12 wherein the suitable
`solvent is selected from the group consisting of a (CcC 6)
`alkyl alcohol, (CcC6)alkyl ketone and (CcC6)alkyl ether.
`14. A process according to claim 12 wherein the suitable 10
`solvent is acetone or 2-propanol.
`15. A process according to claim 12 wherein the contact(cid:173)
`ing of step (i) is carried out by contacting 5,8,14-
`11 .04
`9 ]-hexadeca-2(11 ),3,5, 7,9-
`triazatetracyclo[l 0.3.1.02
`•
`•
`pentaene in solution phase with a solution of succinic acid.
`
`10
`16. A process according to claim 12 wherein the contact(cid:173)
`ing step is carried out over a period of between 1 and 24
`hours.
`17. A process for the preparation of the succinate salt
`11 .0 4
`9
`s hydrate of 5,8,14-triazatetracyclo[l0.3.1.0 2
`](cid:173)
`•
`•
`hexadeca-2(11),3,5,7,9-pentaene according to claim 7 com(cid:173)
`prising the steps of
`11 .04
`9
`(i) contacting 5,8,14-triazatetracyclo[l0.3.1.02
`](cid:173)
`•
`•
`hexadeca-2(11),3,5,7,9-pentaene in a suitable solvent
`with succinic acid; and
`(ii) collecting the crystals formed.
`18. A process according to claim 17 wherein the suitable
`solvent is a mixture of 2-propanol or acetone and water.
`
`* * * * *
`
`Apotex Exhibit 1021.010
`
`