`Bogle et al.
`
`I 1111111111111111 11111 111111111111111 11111 1111111111 111111111111111 IIII IIII
`US006890927B2
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 6,890,927 B2
`May 10, 2005
`
`(54) TARTRATE SALTS OF 5,8, 14-
`TRIAZATERACYCLO[l0.3.1.02,11 04.9](cid:173)
`HEXADECA-2(11),3,5,7,9-PENTAENE AND
`PHARMACEUTICAL COMPOSITIONS
`THEREOF
`
`(75)
`
`Inventors: David E. Bogle, Jewett City, CT (US);
`Peter R. Rose, Ledyard, CT (US);
`Glenn R. Williams, East Aurora, NY
`(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.: 10/139,730
`
`(22) Filed:
`
`May 6, 2002
`
`( 65)
`
`Prior Publication Data
`
`US 2003/0166701 Al Sep. 4, 2003
`
`Related U.S. Application Data
`(60) Provisional application No. 60/290,861, filed on May 14,
`2001.
`
`(51)
`
`Int. Cl.7 ...................... C07D 241/36; A61K 31/50;
`A61K 31/495
`(52) U.S. Cl. .............................. 514/252.1; 514/255.04;
`544/343
`(58) Field of Search ......................... 514/252.1, 255.04,
`514/214.03; 544/343; 540/578
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`10/1969 Carson .................... 260/294.7
`3,471,503 A
`2002/0016498 Al * 2/2002 Am Ende et al. ........... 562/400
`
`FOREIGN PATENT DOCUMENTS
`
`EP
`EP
`WO
`
`8/2000
`1078637
`2/2001
`1078637
`7/1999
`WO9935131
`OTHER PUBLICATIONS
`Paul H. Mazzochi, et. al., "Synthesis and Pharmacological
`Activity
`of
`2,3,4,5-Tetrahydro-1,
`5-Methano-lH-3-Benzazepines", J. Med. Chem., vol. 22,
`No. 4, 1979, pp 455-457, XP002090422.
`* cited by examiner
`Primary Examiner-Bruck Kifle
`(74) Attorney, Agent, or Firm-Peter
`Lorraine B. Ling; A David Joran
`ABSTRACT
`(57)
`
`C. Richardson;
`
`The present invention is directed to the tartrate salts of
`5,8,14-triazatetracyclo[l0.3.l .02
`11.04
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene:
`
`(X)J>,
`
`and pharmaceutical compos1t10ns thereof. The present
`invention in particular is directed to the L-tartrate salt, and
`further to the various polymorphs of the L-tartrate salt,
`including two distinct anhydrous polymorphs (referred to
`herein as Forms A and B) and a hydrate polymorph (referred
`to herein as Form C). In addition, the present invention is
`also directed to the D-tartrate salt of 5,8,14-triazatetracyclo
`11 .04
`9 ]-hexadeca-2(11),3,5,7,9-pentaene and the
`[10.3.1.02
`•
`•
`various polymorphs thereof; as well as the D,L-tartrate salt
`thereof and its polymorphs, and the meso-tartrate salt thereof
`and its polymorphs.
`
`40 Claims, 20 Drawing Sheets
`
`Apotex Exhibit 1001.001
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 1 of 20
`
`US 6,890,927 B2
`
`C>
`C"')
`
`CD
`C'd
`c..,
`Cf.)
`
`C'd
`+-'
`C> CD
`..c::
`N
`I-
`I
`N
`
`C"')
`
`C>
`0
`0
`C")
`
`C>
`0
`0
`N
`
`C>
`0
`0
`
`~
`
`0
`
`~
`
`(cid:127)
`
`C!J
`LL
`
`0
`C>
`0
`co
`
`0
`0
`0
`r,....
`
`0
`0
`0
`c.o
`
`0
`0
`0
`Lt")
`
`c::::
`:.:J
`
`C>
`0
`0
`-.:::f"
`
`-Cl)
`
`+-'
`C:
`::::J
`0
`c..:>
`._.
`
`Apotex Exhibit 1001.002
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 2 of 20
`
`US 6,890,927 B2
`
`N
`
`.
`C!l
`LL-
`
`a.,
`crj
`(.)
`Cf)
`I
`ro
`+-'
`0
`<D
`C'J ..c::
`I-
`I
`C'J
`
`C')
`
`0
`0
`0
`LO
`
`0
`0
`0
`-.:::t"
`
`0
`0
`0
`C")
`
`0
`0
`0
`C'J
`
`0
`0
`0
`.,-
`
`0
`
`II
`
`0
`0
`0
`.,-
`.,-
`
`0
`0
`0
`0
`.,-
`
`0
`0
`0
`CJ')
`
`0
`0
`0
`00
`
`0
`0
`0
`I"--
`
`I
`0
`0
`0
`(.0
`
`-U)
`(_) -
`
`+-'
`c:: c::
`:::J
`:.....i
`0
`
`Apotex Exhibit 1001.003
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 3 of 20
`
`US 6,890,927 B2
`
`(cid:127)
`
`C!l
`LL
`
`0
`0
`0
`U":)
`
`0
`0
`0
`""-t"
`
`0
`0
`0
`('I')
`
`......
`C: C:
`·- :::::s
`_J 0
`
`-en
`c..J --
`
`I
`
`octS
`N +-'
`<l.'.>
`..c:
`I-
`I
`N
`
`0
`
`Apotex Exhibit 1001.004
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 4 of 20
`
`US 6,890,927 B2
`
`C)
`M
`
`Cl)
`~
`c.:,
`OU)
`N I
`ro
`4--J
`CD
`..c
`I-
`I
`N
`
`0
`.,..-
`
`CV:>
`
`0
`0
`0
`0
`M
`
`0
`0
`0
`0
`N
`
`0
`
`0
`0
`0
`0
`~
`
`0
`0
`0
`0
`
`"""
`
`<(
`~ .
`(!J
`LL
`
`0
`0
`0
`0
`0
`~
`
`0
`0
`0
`C)
`0)
`
`C)
`0
`0
`0
`00
`
`0
`0
`0
`0
`r--
`
`0
`0
`0
`0
`c.o
`
`C
`_j
`
`0
`0
`0
`0
`LO
`
`-en
`(.) ---
`
`+-'
`i::
`:::J
`0
`
`Apotex Exhibit 1001.005
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 5 of 20
`
`US 6,890,927 B2
`
`cc
`~
`(cid:127)
`
`~
`LL
`
`C>
`C>
`0
`C>
`C>
`C>
`0
`C>
`~ 0
`~ ~
`
`0
`0
`0
`0
`0)
`
`0
`0
`C,
`0
`00
`
`0
`C>
`0
`0
`r--..
`
`C>
`0
`0
`0
`CD
`
`+-'
`i=:
`C
`~ :::l
`a
`
`0
`0
`0
`0
`0
`0
`0
`0
`C)
`0
`0
`0
`Ln ~ ("I)
`
`-Cl)
`(_) ---
`
`C>
`N
`
`CL:)
`C'CI
`c..:,
`CJJ
`I
`......
`C'CI
`Cl)
`..c
`I-
`I
`N
`
`er.>
`
`0
`0
`0
`0
`N
`
`0
`
`0
`0
`0
`0
`~
`
`Apotex Exhibit 1001.006
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 6 of 20
`
`US 6,890,927 B2
`
`<(
`LO
`.
`C!J
`LL
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`C) 0
`r-,... c.o LC? ~ Ct) C\J
`,-- ,--
`,--
`-r-
`,--
`-r-
`
`CD
`n1
`(_)
`UJ
`I
`ro
`+-'
`ci,
`..c:::
`I-
`I
`N
`
`0
`N
`
`0
`,--
`
`C")
`
`0
`
`I
`l
`j
`
`I
`0 C)
`0
`0 C) 0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`c:, c:, 0
`0
`0
`0
`0
`0
`0
`en co r-,... c.o LO ~ Ct) N
`-r-
`
`0
`0
`0
`0
`0
`0
`,-- 0
`,--
`
`+-'
`C: C:
`::J :::3
`0
`
`,-- -U)
`0 -
`
`Apotex Exhibit 1001.007
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 7 of 20
`
`US 6,890,927 B2
`
`cc
`LO
`.
`C!J
`LL
`
`0
`0
`0
`en
`
`0
`0
`0
`00
`
`0
`0
`0
`r--
`
`0
`0
`0
`LC")
`
`0
`0
`0
`
`'°
`
`+-'
`C C:
`:::::,
`_J
`
`0
`0
`0
`-.:;:t"
`
`--Cl)
`0 c.., --
`
`Cl)
`rd
`c.,
`0 U)
`N
`I
`rd
`+-'
`<D
`..c
`I-
`I
`N
`
`0
`,--
`
`0
`0
`0
`C")
`
`Apotex Exhibit 1001.008
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 8 of 20
`
`US 6,890,927 B2
`
`c.o
`.
`CJ
`LL.
`
`CD
`~
`c:..,
`Oen
`N I
`c,::J
`+-'
`CD
`.c
`I-
`I
`N
`
`0
`0
`0
`-=::t"
`
`0
`0
`0
`er,
`
`0
`0
`0
`N
`
`0
`0
`0
`T9"
`
`M
`
`0
`
`0
`0
`0
`T9"
`T9"
`
`0
`0
`0
`0
`T9"
`
`0
`0
`0
`O')
`
`0
`0
`0
`00
`
`0
`C)
`0
`r--
`
`0
`0
`0
`c.o
`
`0
`0
`0
`LO
`
`-V'J
`C: =
`::::i
`C) -
`
`+-'
`
`::::I
`0
`
`Apotex Exhibit 1001.009
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 9 of 20
`
`US 6,890,927 B2
`
`<:(
`
`r-..... .
`CJ
`u...
`
`*
`
`*
`
`*
`
`*
`
`,
`
`*
`
`0
`-.::::1"'
`
`0
`(0
`
`0
`CX)
`
`0
`C>
`......
`
`0
`N
`......
`
`0
`......
`-.::::1"'
`
`C>
`......
`tO
`
`C>
`......
`CX)
`
`0
`0
`N
`
`0
`N
`N
`
`0
`-.::::1"'
`N
`
`Apotex Exhibit 1001.010
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 10 of 20
`
`US 6,890,927 B2
`
`co
`f',-
`.
`(!5
`u..
`
`*
`*
`
`* *
`
`*
`
`..
`
`0
`,--
`,--
`
`0
`CV)
`,--
`
`0
`N
`
`0
`-.::I"
`
`C)
`co
`
`0 co
`
`0
`0
`,--
`
`0
`N
`,--
`
`0
`-.::I"
`,--
`
`C> co
`,--
`
`0 co
`,--
`
`0
`0
`N
`
`0
`N
`N
`
`C>
`-.::I"
`C'\J
`
`Apotex Exhibit 1001.011
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 11 of 20
`
`US 6,890,927 B2
`
`(.)
`r--,...
`
`(!J
`u_
`
`*
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`*
`
`E
`c..
`c..
`
`0
`C'J
`
`0
`M
`
`CJ
`""'2'"
`
`0
`Lt)
`
`0
`tO
`
`c:,
`r--
`
`0
`00
`
`c:,
`en
`
`0
`0
`T"'""
`
`c:::,
`T"'""
`,--
`
`0
`C'J
`T"'""
`
`C>
`er::,
`,--
`
`c:::,
`-.;r-
`,--
`
`C>
`i.n
`,--
`0 c.o
`
`T"'""
`c:,
`r--,--
`
`C>
`c:o
`T"'""
`
`0
`O')
`,--
`
`0
`c:,
`C'J
`c:::,
`,--
`C'J
`
`C>
`C'J
`C'J
`c:,
`CV'.)
`C'J
`c:,
`-.:;;r-
`C'J
`c:,
`i.n
`C'J
`
`Apotex Exhibit 1001.012
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 12 of 20
`
`US 6,890,927 B2
`
`FIG. 8A
`
`N4
`
`Apotex Exhibit 1001.013
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 13 of 20
`
`US 6,890,927 B2
`
`FIG. 88
`
`09X
`
`Apotex Exhibit 1001.014
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 14 of 20
`
`US 6,890,927 B2
`
`< C') .
`
`(.!:)
`LL.
`
`C)
`0
`
`C
`E
`
`0
`Ln
`
`0
`C")
`
`0
`N
`
`0
`Ln
`N
`
`0
`0
`N
`
`0
`Ln
`-r-
`
`0
`LO
`
`0
`0
`LO$
`X
`E
`<,__ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ __,
`m
`
`Apotex Exhibit 1001.015
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 15 of 20
`
`US 6,890,927 B2
`
`cc
`O') .
`C!J -u,_
`
`(_)
`0
`
`C:
`E
`
`0
`L.n
`
`0
`t.n
`N
`
`0
`0
`N
`
`0
`Lr:>
`T"""
`
`0
`0
`T"""
`
`0
`LO
`
`0
`("')
`
`0
`N
`
`0
`T"""
`
`0
`0
`i.n:S:
`X
`~ L...._ _ _ _ _ _ _ _ _ _ _,E=--------------
`
`Apotex Exhibit 1001.016
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 16 of 20
`
`US 6,890,927 B2
`
`c..,
`0
`
`c:::
`E
`
`C>
`LO
`
`C>
`LO
`C"J
`
`0
`0
`N
`
`0
`Ln
`
`~
`
`C>
`C>
`~
`
`C>
`C")
`
`0
`N
`
`0
`
`('_)
`O')
`•
`
`(.!J -LL
`
`0
`X
`Cl)
`<
`
`LOS:
`E
`
`Apotex Exhibit 1001.017
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 17 of 20
`
`US 6,890,927 B2
`
`<C
`C)
`,--
`
`(cid:127)
`
`C, -LL
`
`Cl)
`C'd
`0 en
`0
`N '
`C'd +-a.:,
`..c:
`f-
`I
`N
`
`0
`T"""
`
`0
`0
`0
`CV')
`
`0
`0
`0
`N
`
`+-
`c: C:
`· - ::J
`_J 0
`
`-en
`c..J -
`
`0
`0
`0
`T"""
`
`0
`
`Apotex Exhibit 1001.018
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 18 of 20
`
`US 6,890,927 B2
`
`CD
`0
`.
`-r-
`C!J
`u...
`
`CD
`~
`c.:,
`Cf.)
`o '
`NJg
`CD
`..c::
`I-
`I
`N
`
`-1'-I -,---,--~,--,.-.-,---,---.--,.........--,-.-,--,--,,.-,--.-,--.---,--,--r-,.-r,r.---r c-1)
`0
`O
`0
`0
`0
`C>
`C>
`0
`0
`0
`N
`T"""
`c-1)
`
`-CJ)
`·- :::,
`(..') --
`
`+-'
`C
`C
`_J 0
`
`Apotex Exhibit 1001.019
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 19 of 20
`
`US 6,890,927 B2
`
`c_,
`0
`
`0
`l()
`N
`
`0
`C)
`N
`
`0
`l()
`,---
`
`0
`0
`,---
`
`0
`LO
`
`•
`(.!J
`LL.
`
`0
`X
`CD
`<
`
`Apotex Exhibit 1001.020
`
`
`
`U.S. Patent
`
`May 10, 2005
`
`Sheet 20 of 20
`
`US 6,890,927 B2
`
`cc
`,-(cid:173)
`,--.
`C!l
`LL
`
`c..:>
`0
`
`0
`Ln
`C"J
`
`0
`c:,
`N
`
`0
`Ln
`T"""
`
`0
`c:,
`T"""
`
`0
`Lt")
`
`0
`X
`Q.")
`< L . . . - - - - - - - - - - - - - - - - - - - - - - - '
`
`Apotex Exhibit 1001.021
`
`
`
`US 6,890,927 B2
`
`1
`TARTRATE SALTS OF 5,8, 14-
`TRIAZATERACYCLO[l0.3.1.02,11 04.9](cid:173)
`HEXADECA-2(11),3,5, 7,9-PENTAENE AND
`PHARMACEUTICAL COMPOSITIONS
`THEREOF
`
`This application claims the benefit of U.S. Provisional
`Application Ser. No. 60/290,861, filed May 14, 2001.
`The present invention is directed to the tartrate salts of
`5,8,14-triazatetracyclo[l0.3. l .02·11 .04·9]-hexadeca-2(11 ),3,
`5,7,9-pentaene:
`
`(X:Xl>·
`
`N
`
`5
`
`2
`order to stimulate both central muscanmc 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-
`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
`10 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,
`including 5 ,8 ,14-triazatetracyclo[ 10.3 .1.02·11 .04·9]-
`15 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. No. 09/402,010, filed Sep. 28,
`1999 and Ser. No. 09/514,002, filed Feb. 25, 2000). The
`foregoing applications, owned in common with the present
`20 application and incorporated herein by reference in their
`entirety, generically recite pharmaceutically acceptable acid
`addition salts for the compounds referred to therein.
`The L-tartrate salt of the present invention exhibits
`properties, including those of high solid-state stability and
`25 compatibility with certain drug product formulation
`excipients, that render it superior to previously known salts
`of 5,8,14-triazatetracyclo[l0.3. l.02·11.04·9]-hexadeca-2(11 ),
`3,5,7,9-pentaene. Further, the D-tartrate and D,L-tartrate
`salts exhibit properties that also make them appropriate for
`30 drug product formulation use.
`
`and pharmaceutical compos1t10ns thereof. The present
`invention in particular is directed to the L-tartrate salt, and
`further to the various polymorphs of the L-tartrate salt,
`including two distinct anhydrous polymorphs (referred to
`herein as Forms A and B) and a hydrate polymorph (referred
`to herein as Form C). In addition, the present invention is
`also directed to the D-tartrate salt of 5,8,14-triazatetracyclo
`[10.3.1.02·11 .04·9]-hexadeca-2(11),3,5,7,9-pentaene and the
`various polymorphs thereof; as well as the D,L-tartrate salt
`thereof and its polymorphs, and the meso-tartrate salt thereof
`and its polymorphs.
`The compound, 5,8,14-triazatetracyclo[l0.3.1.02·11 .04·9](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
`Crohn's disease), irritable bowel syndrome, spastic 35
`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, drug/toxin-induced
`cognitive impairment (e.g., from alcohol, barbiturates, vita- 40
`min deficiencies, recreational drugs, lead, arsenic, mercury),
`disease-induced cognitive impairment (e.g., arising from
`Alzheimer's disease (senile dementia), vascular dementia,
`Parkinson's disease, multiple sclerosis, AIDS, encephalitis,
`trauma, renal and hepatic encephalopathy, hypothyroidism, 45
`Pick's disease, Korsakoff's syndrome and frontal and sub(cid:173)
`cortical dementia), hypertension, bulimia, anorexia, obesity,
`cardiac arrhythmias, gastric acid hypersecretion, ulcers,
`pheochromocytoma, progressive supramuscular palsy,
`chemical dependencies and addictions (e.g., dependencies 50
`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, Hunting(cid:173)
`ton's chorea, tardive dyskinesia, hyperkinesia, dyslexia, 55
`schizophrenia, multi-infarct dementia, age-related cognitive
`decline, epilepsy, including petit mal absence epilepsy,
`attention deficit hyperactivity disorder (ADHD), Tourette's
`Syndrome, particularly, nicotine dependency, addiction and
`withdrawal; including use in smoking cessation therapy.
`The tartrate salts of this invention may also be used in a
`pharmaceutical composition in combination with an antide(cid:173)
`pressant 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 65
`with AD, PD, stroke, Huntington's chorea or traumatic brain
`injury (TEI); in combination with muscarinic agonists in
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`FIG. 1 is a powder X-ray diffraction of the anhydrous
`L-tartrate salt Form A of 5,8,14-triazatetracyclo
`[10.3.1.02·11 .04·9]-hexadeca-2(11),3,5,7,9-pentaene (y axis
`is linear counts per second; X in degrees 2 theta).
`FIG. 2 is the powder X-ray diffraction of the anhydrous
`L-tartrate salt Form B of 5,8,14-triazatetra-cyclo
`[10.3.l.02·11 .04·9]-hexadeca-2(11),3,5,7,9-pentaene (y axis
`is linear counts per second; X in degrees 2 theta).
`FIG. 3 is the powder X-ray diffraction of the L-tartrate salt
`hydrate Form C of 5,8,14-triazatetra-cyclo
`[10.3.1.02·11 .04·9]-hexadeca-2(11),3,5,7,9-pentaene (y axis
`is linear counts per second; X in degrees 2 theta).
`FIG. 4Ais the calculated powder X-ray diffraction pattern
`of the anhydrous Form B L-tartrate salt of 5,8,14-triazatetra(cid:173)
`cyclo[l0.3.l.02·11.04·9]-hexadeca-2(11),3,5,7,9-pentaene (y
`axis is linear counts per second; X in degrees 2 theta). FIG.
`4B is the calculated powder X-ray diffraction pattern of the
`Form C L-tartrate salt hydrate of 5,8,14-triazatetra-cyclo
`[10.3.1.02·11 .04·9]-hexadeca-2(11),3,5,7,9-pentaene (y axis
`is linear counts per second; X in degrees 2 theta).
`FIG. 5Ais the calculated powder X-ray diffraction pattern
`(lower trace) laid over the observed X-ray diffraction pattern
`(upper trace) for the anhydrous Form B L-tartrate salt of
`5,8,14-triazatetra-cyclo[l0.3. l .02·11.04·9]-hexadeca-2(11 ),3,
`5,7,9-pentaene (y axis is linear counts per second; X in
`degrees 2 theta). FIG. SB is the calculated powder X-ray
`60 diffraction pattern (lower trace) laid over the observed X-ray
`diffraction pattern (upper trace) for the Form C L-tartrate salt
`hydrate of 5,8,14-triazatetra-cyclo[l0.3.1.02·11 .04·9](cid:173)
`hexadeca-2(11),3,5,7,9-pentaene (y axis is linear counts per
`second; X in degrees 2 theta).
`FIG. 6 is the overlay of the powder X-ray diffraction
`patterns of the Form A (lower trace), Form B (middle trace)
`and Form C (upper trace) L-tartrate salts of 5,8,14-
`
`Apotex Exhibit 1001.022
`
`
`
`US 6,890,927 B2
`
`4
`when examined by solid state 13C NMR cross-polarization
`magic angle spinning techniques, it exhibits the following
`principal resonance peaks (±0.1 ppm) downfield from 100
`ppm (adamantane standard 29.5 ppm): 178.4, 149.3, 147.4,
`145.1, and 122.9 ppm.
`In another embodiment of the invention, the L-tartrate of
`11.04
`5,8,14-triazatetracyclo[l0.3.l .02
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene is another anhydrous L-tartrate salt
`polymorph, referred to herein as Form B. The L-tartrate salt
`Form B is characterized by the principal x-ray diffraction
`pattern peaks expressed in terms of 28 and d-spacings as
`measured with copper radiation (within the margins of error
`indicated):
`
`Angle 20 (±0.2)
`
`d-value (A) (±0.2)
`
`5.9
`12.8
`14.4
`15.3
`16.9
`17.2
`21.8
`23.8
`25.1
`
`15.0
`6.9
`6.1
`5.8
`5.2
`5.2
`4.1
`3.7
`3.5
`
`3
`11
`9 ]-hexadeca -2( 11 ),3,5, 7, 9-
`. 04
`triazatetra -cyclo[ 10 .3 .1.02
`•
`•
`pentaene (y axis is linear counts per second; X in degrees 2
`theta).
`FIGS. 7A, 7B and 7C are the solid state 13C NMR spectra
`of the L-tartrate salts of 5,8,14-triazatetra-cyclo 5
`11 .04
`[10.3.1.02
`9 ]-hexadeca-2(11 ),3,5, 7,9-pentaene Forms
`•
`•
`A, B and C, respectively, as measured by cross-polarization
`magic angle spinning (CPMAS) at 295 Kon a Bruker 7 mm
`wide-bore magic angle spinning (WB MAS) probe posi(cid:173)
`tioned in a Bruker Avance DRX 500 MHz NMR Spectrom- 10
`eter. Peaks marked with asterisks(*) are spinning sidebands
`which are displaced at multiples of the spinning frequencies
`along both sides of the real peaks ( centerbands).
`FIG. SA is the X-ray crystal structure (absolute
`configuration) for the anhydrous Form B L-tartrate salt of 15
`11.04
`5,8,14-triazatetra-cyclo[l0.3.l .02
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene. FIG. SB is the X-ray crystal structure
`( absolute configuration) for the Form C L-tartrate salt
`11 .04
`9
`hydrate of 5,8,14-triazatetra-cyclo[l0.3.1.0 2
`]-
`•
`•
`hexadeca-2(11),3,5,7,9-pentaene.
`FIG. 9A, 9B and 9C are the differential scanning calori(cid:173)
`metric traces for the L-tartrate salts Forms A, B and C,
`11 .04
`9
`respectively, of 5,8,14-triazatetra-cyclo[l0.3.1.02
`](cid:173)
`•
`•
`hexadeca-2(11),3,5,7,9-pentaene.
`FIG. lOA and lOB are the powder X-ray diffraction
`patterns of the D,L-tartrate salt Forms X and Y, respectively,
`11.04
`of 5,8,14-triazatetracyclo[l0.3. l.02
`9 ]-hexadeca-2(11 ),
`•
`•
`3,5,7,9-pentaene (y axis is linear counts per second; X in
`degrees 2 theta).
`FIGS. llA and llB are the differential scanning calori(cid:173)
`metric traces for the D,L-tartrate salts Forms X and Y,
`11 .04
`9
`respectively, of 5,8,14-triazatetra-cyclo[l0.3.1.02
`](cid:173)
`•
`•
`hexadeca-2(11),3,5,7,9-pentaene.
`
`20
`
`25
`
`The L-tartrate salt Form B has a single crystal x-ray
`structure (absolute configuration) as set forth in FIG. SA
`Further, the Form B forms orthorhombic crystals belonging
`30 to the P2(1)2(1)2(1) space group. Form B is further char(cid:173)
`acterized in having an onset of melting at about 215° C. as
`measured by differential scanning calorimetry at a heating
`rate of 5 degrees per minute. Further, Form B of the
`invention is also characterized in having an aqueous solu-
`35 bility of about 156 mg/ml and a native pH of about 3.3 in
`aqueous solution. In addition, Form B has a hygroscopicity
`of approximately 0.2% at 90% relative humidity.
`The L-tartrate Form B is also characterized in that when
`examined by solid state 13C NMR cross-polarization magic
`40 angle spinning techniques, it exhibits the following principal
`resonance peaks (±0.1 ppm) downfield from 100 ppm
`(adamantane standard 29.5 ppm): 179.2, 178.0, 147.4,
`145.2, 144.4, 124.8 and 122.5 ppm.
`In another embodiment of the invention, the L-tartrate of
`11.04
`5,8,14-triazatetracyclo[l0.3.l .02
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene is the hydrate L-tartrate salt, referred to
`herein as Form C. The L-tartrate Form C is characterized by
`the principal x-ray diffraction pattern peaks expressed in
`terms of 28 and d-spacings as measured with copper radia(cid:173)
`tion (within the margins of error indicated):
`
`45
`
`50
`
`SUMMARY OF THE INVENTION
`
`The present invention relates to the tartrate salts of
`11 .04
`5,8,14-triazatetracyclo[l0.3. l .02
`9 ]-hexadeca-2(11 ),3,
`•
`•
`5,7,9-pentaene. The tartrate salts of the invention include the
`L-tartrate, D-tartrate, D,L-tartrate and meso-tartrate salts.
`In particular, the present invention relates to the L-tartrate
`11 .04
`salt of 5,8,14-triazatetracyclo[l0.3.l.02
`9 ]-hexadeca-2
`•
`•
`(11),3,5,7,9-pentaene.
`In one embodiment of the invention, the L-tartrate of
`11 .04
`9 ]-hexadeca-2(11 ),3,
`5,8,14-triazatetracyclo[l0.3. l .02
`•
`•
`5,7,9-pentaene is the anhydrous L-tartrate salt, referred to
`herein as Form A The L-tartrate Form A is characterized by
`the principal x-ray diffraction pattern peaks expressed in
`terms of 28 and d-spacings as measured with copper radia(cid:173)
`tion (within the margins of error indicated):
`
`Angle 20 (±0.2)
`
`d-value (A) (±0.2)
`
`6.1
`12.2
`13.0
`14.7
`16.8
`19.4
`21.9
`24.6
`
`14.5
`7.2
`6.8
`6.0
`5.3
`4.6
`4.1
`3.6
`
`Angle 20 (±0.2)
`
`d-value (A) (±0.2)
`
`55
`
`60
`
`5.9
`11.8
`16.5
`21.2
`23.1
`23.8
`26.5
`
`15.1
`7.5
`5.4
`4.2
`3.8
`3.7
`3.4
`
`The L-tartrate crystal Form Ais characterized in that it has
`a onset of melt at about 223° C. as measured by differential
`scanning calorimetry at a heating rate of 5 degrees per
`minute. The L-tartrate Form A is also characterized in that
`
`The hydrate L-tartrate crystal Form Chas a single crystal
`structure as set forth in FIG. SB. Further, the hydrate Form
`65 C forms monoclinic crystals belonging to the P2(1) space
`group. Form C is further characterized in having an onset of
`a solid-solid transition at about 72° C. and an onset of
`
`Apotex Exhibit 1001.023
`
`
`
`US 6,890,927 B2
`
`5
`melting transition at about 220° C. Because Form B converts
`to the hydrate Form C upon contact with 100% relative
`humidity, Form Chas the same aqueous solubility as Form
`B.
`The L-tartrate Form C is also characterized in that when
`examined by solid state 13C NMR cross-polarization magic
`angle spinning techniques, it exhibits the following principal
`resonance peaks (±0.1 ppm) downfield from 100 ppm
`(adamantane standard 29.5 ppm): 179.0, 176.1, 147.5, 144.5
`and 124.6 ppm.
`A further embodiment of the invention is directed to the
`9
`D-tartrate salt of 5,8,14-triazatetracyclo[l0.3.1.02
`11 .04
`](cid:173)
`•
`•
`hexadeca-2(11),3,5,7,9-pentaene. In particular, the present
`invention is directed to the three D-tartrate salt polymorphs
`(referred to here as Forms A', B' and C') which exhibit the
`same x-ray diffraction characteristics, hygroscopicity, water
`content and thermal characteristics as Forms A, B and C of
`the L-tartrate salt.
`In another embodiment, the present invention relates to
`the D,L-tartrate salt of 5,8,14-triazatetracyclo
`[10.3.1.02
`11 .04
`9 ]-hexadeca-2(11),3,5,7,9-pentaene, and in
`•
`•
`particular, two polymorphs, an anhydrous form (herein
`referred to as Form X) and a hydrate form (herein referred
`to as Form Y).
`The D,L-tartrate Form Xis characterized by the principal
`x-ray diffraction pattern peaks expressed in terms of 28 and
`d-spacings as measured with copper radiation (within the
`margins of error indicated):
`
`Angle 20 (±0.2)
`
`d-value (A) (±0.2)
`
`6.0
`11.9
`15.0
`17.1
`22.1
`24.5
`
`14.6
`7.4
`5.9
`5.2
`4.0
`3.6
`
`The D,L-tartrate Form Xis further characterized in having
`an onset of a melting transition at about 212° C.
`The D,L-tartrate Form Y is characterized by the principal
`x-ray diffraction pattern peaks expressed in terms of 28 and
`d-spacings as measured with copper radiation (within the
`margins of error indicated):
`
`Angle 20 (±0.2)
`
`d-value (A) (±0.2)
`
`6.2
`12.0
`15.2
`18.1
`24.0
`25.1
`
`14.2
`7.4
`5.8
`4.9
`3.7
`3.5
`
`The D,L-tartrate Form Y is further characterized in having
`an onset of a solid-solid transition at about 131 ° C. and an
`onset of melting transition at about 217° C.
`Another embodiment of the invention relates to a phar(cid:173)
`maceutical composition comprising at least one of polymor(cid:173)
`phic Forms A, B or C, preferably Form B, of the L-tartrate
`salt of 5,8,14-triazatetracyclo[l0.3.l.02
`11 .04
`9 ]-hexadeca-2
`•
`•
`(11),3,5,7,9-pentaene and a pharmaceutically acceptable
`carrier or excipient, for use in the treatment of inflammatory
`bowel disease (including but not limited to ulcerative colitis,
`pyoderma gangrenosum and Crohn's disease), irritable
`
`30
`
`35
`
`6
`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), cog-
`s nitive dysfunction, drug/toxin-induced cognitive impair(cid:173)
`ment (e.g., from alcohol, barbiturates, vitamin deficiencies,
`recreational drugs, lead, arsenic, mercury), disease-induced
`cognitive impairment ( e.g., arising from Alzheimer's disease
`(senile dementia), vascular dementia, Parkinson's disease,
`10 multiple sclerosis, AIDS, encephalitis, trauma, renal and
`hepatic encephalopathy, hypothyroidism, Pick's disease,
`Korsakoff's syndrome and frontal and subcortical
`dementia), hypertension, bulimia, anorexia, obesity, cardiac
`arrhythmias, gastric acid hypersecretion, ulcers,
`15 pheochromocytoma, progressive supramuscular palsy,
`chemical dependencies and addictions (e.g., dependencies
`on, or addictions to nicotine (and/or tobacco products),
`alcohol, benzodiazepines, barbiturates, opioids or cocaine),
`headache, migraine, stroke, traumatic brain injury (TEI),
`20 obsessive-compulsive disorder (OCD), psychosis, Hunting(cid:173)
`ton's chorea, tardive dyskinesia, hyperkinesia, dyslexia,
`schizophrenia, multi-infarct dementia, age-related cognitive
`decline, epilepsy, including petit mal absence epilepsy,
`attention deficit hyperactivity disorder (ADHD), and
`25 Tourette's Syndrome. Another more preferred embodiment
`of the invention is wherein the pharmaceutical composition
`is useful in the treatment of nicotine dependency, addiction
`and withdrawal; most preferably, for use in smoking cessa(cid:173)
`tion therapy.
`The present invention further relates to pharmaceutical
`compositions for the uses described in the foregoing para(cid:173)
`graph comprising any one of the D-tartrate salt of, the
`D,L-tartrate salt of, or the meso-tartrate salt of 5,8,14-
`11 .04
`9 ]-hexadeca-2(11 ),3,5, 7 ,9-
`triazatetracyclo[lO .3.1.02
`•
`•
`pentaene.
`The present invention further relates to a method of
`treating inflammatory bowel disease (including but not
`limited to ulcerative colitis, pyoderma gangrenosum and
`Crohn's disease), irritable bowel syndrome, spastic
`40 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, drug/toxin-induced
`cognitive impairment (e.g., from alcohol, barbiturates, vita-
`45 min deficiencies, recreational drugs, lead, arsenic, mercury),
`disease-induced cognitive impairment ( e.g., arising from
`Alzheimer's disease (senile dementia), vascular dementia,
`Parkinson's disease, multiple sclerosis, AIDS, encephalitis,
`trauma, renal and hepatic encephalopathy, hypothyroidism,
`Pick's disease, Korsakoff's syndrome and frontal and sub(cid:173)
`cortical dementia), hypertension, bulimia, anorexia, obesity,
`cardiac arrhythmias, 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, opioids or cocaine),
`headache, migraine, stroke, traumatic brain injury (TEI),
`obsessive-compulsive disorder (OCD), psychosis, Hunting(cid:173)
`ton's chorea, tardive dyskinesia, hyperkinesia, dyslexia,
`60 schizophrenia, multi-infarct dementia, age-related cognitive
`decline, epilepsy, including petit mal absence epilepsy,
`attention deficit hyperactivity disorder (ADHD), and
`Tourette's Syndrome comprises administering to a subject in
`need of treatment a therapeutically effective amount of any
`65 of Forms A, B or C of the L-tartrate salt of 5,8,14-
`11 .04
`9 ]-hexadeca-2(11 ),3,5, 7 ,9-
`triazatetracyclo[lO .3.1.02
`•
`•
`pentaene, preferably Form B. Another more preferred
`
`50
`
`55
`
`Apotex Exhibit 1001.024
`
`
`
`US 6,890,927 B2
`
`5
`
`7
`embodiment of the invention relates to a method of treat(cid:173)
`ment for nicotine dependency, addiction and withdrawal, in
`particular for use in smoking cessation therapy activity,
`comprising the administration of any of Forms A, B or C of
`the L-tartrate salt of 5,8,14-triazatetracyclo
`[10.3.1.02
`11 .04
`9 ]-hexadeca-2(11 ),3,5,7,9-pentaene, prefer(cid:173)
`•
`•
`ably Form B, to a subject in need thereof.
`The present invention further relates to methods of treat(cid:173)
`ment described in the foregoing paragraph comprising the
`administration of any of the D-tartrate salt, the D,L-tartrate 10
`salt or the meso-tartrate salt of 5,8,14-triazatetracyclo
`[10.3.1.02
`11 .04
`9 ]-hexadeca-2(11),3,5,7,9-pentaene to a sub(cid:173)
`•
`•
`ject in need thereof.
`The term "treating" as used herein, refers to, and includes,
`reversing, alleviating, inhibiting the progress of, or prevent- 15
`ing a disease, disorder or condition, or one or more symp(cid:173)
`toms thereof; and the term "treatment" refers to the act of
`treating, as defined above.
`The invention also relates to a process for the preparation
`of the Form A of L-tartrate salt of 5,8,14-triazatetracyclo
`[10.3.1.02
`11 .04
`9 ]-hexadeca-2(11),3,5,7,9-pentaene 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 between 1 and 2 equivalents of L-tartaric acid; and
`(ii) collecting the crystals formed.
`A preferred embodiment of this invention relates to the
`above process wherein 1.1 equivalents of L-tartaric acid is
`employed and the tartaric acid is added to a solution con(cid:173)
`taining the free base. A preferred mode of practicing this
`process is wherein the contact step is allowed to proceed for
`less than 2 hours. A more preferred embodiment of this
`invention relates to the above process wherein the contact
`step (i.e., step "(i)" above) is allowed to proceed above 45° 35
`C. Another preferred embodiment of this invention relates to
`the above process wherein the suitable solvent is selected
`from the group consisting of a (CcC 6)alkyl alcohol, a
`(C1-C 6)alkyl ketone or a (CcC6)alkyl ether, acetonitrile
`and (CcC 6)alkyl esters (e.g., ethyl acetate, isopropyl
`acetate, etc.). More preferably, the suitable solvent is ethanol
`or methanol.
`The invention further relates to a process for the prepa(cid:173)
`ration of Form A' of the D-tartrate salt comprising steps (i)
`and (ii) referred to above for making Form A of the L-tartrate
`salt, but using D-tartaric acid in step (i) in place of L-tartaric
`acid.
`The invention also relates to a process for the preparation
`of Form B of L-tartrate salt of 5,8,14-triazatetracyclo
`11 .04
`9 ]-hexadeca-2(11),3,5,7,9-pentaene com(cid:173)
`[10.3.1.02
`•
`•
`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 about 1 to about 2.3 equivalents of L-tartaric acid;
`and
`(ii) collecting the crystals formed.
`A preferred embodiment of this invention relates to the
`above process wherein about 1.1 to about 2.2 equivalents,
`more preferably 1.1 equivalents, of L-tartaric acid is
`employed and the free base in solution is added to a solution 60
`containing L-tartaric acid. A preferred mode of practicing
`this process is wherein the contact step is allowed to proceed
`for a minimum of 1 hours; more preferably, for at least 2
`hours; most preferably, longer than 12 hours. A preferred
`embodiment is wherein the suitable solvent is selected from
`the group consisting of a (CcC6)alkyl alcohol, a (CcC6 )
`alkyl ketone or a (CcC 6)alkyl ether, acetonitrile and
`
`8
`(CcC 6)alkyl esters ( e.g., ethyl acetate, isopropyl acetate,
`etc.). More preferably, the suitable solvent is methanol or
`ethanol, most preferably methanol.
`The invention further relates to a process for the prepa-
`ration of Form B' of the D-tartrate salt comprising steps (i)
`and (ii) referred to above for making Fo