PCT
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`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
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`=
`
`Z
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`3
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification © ;
`
`(11) International Publication Number:
`
`WO 98/54166
`
`CO7D 311/58, A61K 31/35
`
`(43) Internationa] Publication Date:
`3 December 1998 (03.12.98)
`
`
`(21) International Application Number:
`
`PCT/SE98/00907
`
`(22) International Filing Date:
`
`15 May 1998 (15.05.98)
`
`(30) Priority Data:
`9702066-3
`
`30 May 1997 (30.05.97)
`
`SE
`
`(for all designated States except US): ASTRA
`(71) Applicant
`AKTIEBOLAG[SE/SE]; S—151 85 Sédertalje (SE).
`
`(72) Inventors; and
`NYQVIST, Hakan
`(75) Inventors/Applicants (for US only):
`[SE/SE]; Astra Arcus AB, S-I51 85 Sédertilje (SE).
`SOHN, Daniel, D. [US/SE]; Astra Arcus AB, S-151 85
`Sédertalje (SE).
`
`(74) Agent: ASTRA AKTIEBOLAG, Patent Dept., S—I51 85
`Sédertalje (SE).
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE,
`GH, GM, GW, HU,ID, IL, IS, JP, KE, KG, KP, KR, KZ,
`LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, MW,
`MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL,
`TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZW, ARIPO
`patent (GH, GM, KE, LS, MW,SD, SZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,
`IE, IT, LU, MC, NL, PT, SE), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, ML, MR, NE, SN, TD, TG).
`
`Published
`With international search report.
`With amended claims.
`
`(54) Title’ A NEW SALT
`
`(57) Abstract
`
`A new salt (R)-3-N,N-dicyclobutylamino—8—fluoro-3,4-dihydro-2H—1—benzopyran—5—carboxamide hydrogen tartrate, particularly
`the (2R,3R)-tartrate thereof, most particularly the (R)-3-N,N—dicyclobutylamino-8—fluoro—3, 4-dihydro~2H—|—benzopyran—5~carboxamide
`hydrogen (2R,3R)-tartrate monohydrate, processes for the manufacture of said tartrate salt, the use of the salt in medicine, the use of the
`tartrate salt in the manufacture of pharmaceutical formulations, and a method for the treatment of CNS disorders by administration of the
`tartrate salt to a host in need of such treatment.
`
`
`
`Apotex Exhibit 1016.001
`
`Apotex Exhibit 1016.001
`
`

`

`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Céate d'Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`BE
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`cG
`CH
`cI
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`TE
`IL
`Is
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Treland
`Israel
`Iceland
`Ttaly
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`sD
`SE
`SG
`
`Lesotho
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`The former Yugoslav
`Republic of Macedonia
`Mali
`Mongolia
`Mauritania
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`T™
`TR
`TT
`VA
`UG
`US
`UZ
`VN
`YU
`ZW
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`Apotex Exhibit 1016.002
`
`Apotex Exhibit 1016.002
`
`

`

`“WO 98/54166
`
`PCT/SE98/00907
`
`A newsalt
`
`Field of the Invention
`
`The present inventionrelates to a new salt, namely (R)-3-N,N-dicyclobutylamino-8-fluoro-
`
`3,4-dihydro-2H7-1-benzopyran-5-carboxamide hydrogentartrate, particularly the (2R,3R)
`
`form of the tartrate and most particularly the monohydrate thereof. The invention also
`
`relates to processes for the manufacturing ofthesalt, the use ofthe salt in the manufacture
`
`of pharmaceutical formulations, to the use of the salt in medicine and methods of
`
`treatment employingthesalt particularly, in its monohydrate form.
`
`Backgroundofthe Invention
`
`The compound (R)-5-carbamoyl-3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-27- l-
`
`benzopyran, which also may be named(R)-3-N, N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-
`
`2H-1-benzopyran-5-carboxamide and pharmaceutically acceptable salts thereof are
`
`described in WO 95/11891.
`
`The disclosed hydrochloride salt of (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-
`
`2H-1-benzopyran-5-carboxamideis hygroscopic and thus physically instable during
`
`manufacturing as well as during storage.
`
`Disclosure of the Invention
`
`It has now surprisingly been foundthat the salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-
`
`dihydro-2.-1-benzopyran-5-carboxamide hydrogentartrate, particularly the (2R,3R) form
`
`of the tartrate,
`
`in the anhydrous form or as the hemihydrate or monohydrate is physically
`
`more stable during storage than the hydrochloridesalt of said compound,sincethetartrate
`forms of the compoundare not disposed to absorb water to the same degree as the
`
`20
`
`25
`
`30
`
`Apotex Exhibit 1016.003
`
`Apotex Exhibit 1016.003
`
`

`

`~ WO 98/54166
`
`PCT/SE98/00907
`
`hydrochloride salt of the same compound.This property of absorbing wateris also a
`
`problem during storage and during manufactureof, e.g., solid pharmaceutical dosage
`
`formssuchastablets and hard gelatine capsules.
`
`The good solubility and dissolution properties of the anhydroustartrate salt are even more
`
`pronounced for the monohydrateofthe tartrate salt, particularly the (2R,3R)-tartrate
`
`monhydrate. The water is firmly boundin thecrystal lattice and is not released even upon
`
`heating up to 70 °C. This is well above the commonly used process temperatures, e.g.,
`
`during the granulation process,in the production oftablets and hard gelatine capsules.
`
`The good solubility and dissolution properties ofthe tartrate salt from, e.g., the oral drug
`
`delivery point of view, together with the low degree of hygroscopicity under normal
`
`humidity conditions makes the monohydrate form the most suitable form ofthe tartrate
`
`salt, and particularly the (2R,3R)-tartrate monohydrate from a quality assurance standpoint.
`
`Thus, the monohydrate of (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-
`
`benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate, has surprisingly been shown to be
`
`physically stable under normal humidity conditions. To be suitable for long term storage
`
`and is easier to work with in the production of different solid pharmaceutical dosage forms.
`
`20
`
`25
`
`Accordingly, the present invention relates to the salt (R)-3-N,N-dicyclobutylamino-8-
`
`fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogentartrate, particularly to the
`
`salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide
`
`hydrogen (2R,3R)-tartrate and more particularly to the salt (R)-3-N,N-dicyclobutylamino-
`
`8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate
`
`monohydrate.
`
`The present invention includes (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-
`
`benzopyran-5-carboxamide hydrogentartrate, in the form of (2R,3R)-tartrate, (2S,3,5)-
`
`30
`
`tartrate and (2R,3S)-tartrate.
`
`Apotex Exhibit 1016.004
`
`Apotex Exhibit 1016.004
`
`

`

`~ WO 98/54166
`
`PCT/SE98/00907
`
`The salts of the invention may be used as selective 5-HT,, receptor antagonists in the
`
`treatment of CNSdisorders and related medical disturbances. Examples of such disorders
`
`are depression, anxiety, obsessive-compulsive disorder (OCD), anorexia, bulimia, senile
`
`dementia, migraine, stroke, Alzheimer’s disease, cognitive disorders, schizophrenia,
`
`especially cognative dysfunction in schizophrenia, sleep disorders, urinary incontinence,
`
`premenstrual syndrome, hypertension and pain. Examples of such medical disturbancesare
`
`thermoregulatory disturbances, sexual disturbances, disturbances in the cardiovascular
`
`system and disturbancesin the gastrointestinal system.
`
`The novel salt (R)-3-N, N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H-1-benzopyran-5-
`
`carboxamide hydrogentartrate, particularly the (2R,3R) form of the tartrate and most
`
`particularly the monohydrate of said tartrate salt exists preferably in substantially
`
`crystalline form may be formulated into various dosage formsfororal, parenteral, rectal
`
`and other modes of administrations.
`
`Examples of formulationsare tablets, pellets, granules, capsules (e.g. hard gelatine
`
`capsules), aqueous solutions and suspensions.
`
`Usually the active ingredient will constitute from 0.0001 to 99% by weightof the
`
`formulation, more preferably from 0.001 to 30% by weight of the formulation.
`
`20
`
`To produce pharmaceutical formulations containing the active ingredient of the invention
`
`in the form of dosage units for oral applications, one may mixthe active ingredient with a
`
`solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch,
`
`corn starch or amylopectin, a cellulose derivative, a binder such as gelatine or poly-
`
`25
`
`vinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, sodium
`
`stearylfumarate, polyethylene glycol, waxes, paraffin, and the like, and then compressed
`
`into tablets. The active ingredient may be granulated together with excipients using an
`
`aqueousororganic solution of binders, and then dried and screened priorto tablet
`
`compression.
`
`Apotex Exhibit 1016.005
`
`Apotex Exhibit 1016.005
`
`

`

`WO 98/54166
`
`PCT/SE98/00907
`
`If coated tablets are required, the cores, prepared as described above, may be coated with a
`
`concentrated sugar solution which maycontain, e.g., gum arabic, gelatine, talcum,titanium
`
`dioxide, and the like. Alternatively, the tablet can be coated with a polymer known to a
`
`person skilled in theart, that is dissolved in a readily volatile organic solvent or mixture of
`
`organic solvents. Dyestuffs may be addedto these coatings in orderto readily distinguish
`
`between tablets containing different amounts ofactive ingredient.
`
`For the preparation of hard gelatine capsules, the active ingredient may be processedin the
`
`form of granules, and may be admixed with the excipients mentioned abovefortablets.
`
`Forthe preparation of soft gelatine capsules, the active ingredient may be admixed with
`
`e.g. a vegetable oil or polyethylene glycol.
`
`Suppositories for rectal administration may be prepared by dissolving or suspending the
`active ingredient ina molten suppository base such as Witepsol® followed by casting and
`
`cooling.
`
`Gelatine rectal capsules may comprise the active ingredient in admixture with vegetable oi]
`
`or paraffin oil and may contain someofthe polymers and/or dyestuff mentioned above.
`
`20
`
`Aqueoussolutionsfor parenteral or oral administration are produced by dissolving the
`
`active compoundof the invention in water, adjusting the pH and ionic strength with
`
`commonbuffering agents suchas citric acid, phosphoric acid or other similar acids or their
`
`commonlyused salts; sodium carbonate, hydrogen carbonate or other similar salts; or
`
`25
`
`hydrochloric acid or sodium hydroxide. In the case of parenteral solutionsthesterility is
`
`ensured byfinal heatsterilization or, e.g., sterile filtration. Lyophilization, resulting in a
`
`reconstitutable solid product, may also be used.
`
`Suitable daily doses ofthe salt of the invention in therapeutical treatment of humansare
`
`30
`
`about 0.001-100 mg/kg body weight.
`
`Apotex Exhibit 1016.006
`
`Apotex Exhibit 1016.006
`
`

`

`WO 98/54166
`
`PCT/SE98/00907
`
`The specific processes for manufacturing (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-
`
`dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate, (2.5,3.S)-tartrate or
`
`(2R,35)-tartrate, respectively, more specifically the monohydrate thereof, are a further
`
`aspect of the invention.
`
`The process for manufacturing the new salt form (R)-3-N,N-dicyclobutylamino-8-fluoro-
`
`3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate, more specifically
`
`the monohydrate thereof, comprises the following consecutive steps:
`
`1)
`
`‘dissolving (R)-3-N,N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H-1-benzopyran-5-
`
`carboxamidein an appropriate organic solvent, optionally by heating,
`
`ii)
`
`adding (2R,3R)-tartaric acid dissolved in an appropriate aqueous organicor non-
`
`aqueousorganic solvent,
`
`ili) allowing the obtained solution to stand cold in orderto crystallize,
`
`iv) optionally, recrystallizing from an aqueous organic solvent, if a non-aqueous organic
`
`solvent is used instep i1), to obtain the tartrate monohydratesalt.
`
`20
`
`The corresponding (25,3)-tartrate and (2R,3)-tartrate compound are manufactured by
`
`using (25,35)-tartaric acid and (2R,3S)-tartaric acid, respectively in step ii) above.
`
`A moredetailed description of the process of manufacturing is presented in Examples 1
`
`25
`
`and 2.
`
`Starting from the anhydrous form or a mixture of the anhydrous form and the hemihydrate
`
`of (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide
`
`hydrogen (2R,3R), (2S,3S) or (2R,3S)-tartrate, obtained by any suitable process,
`
`Apotex Exhibit 1016.007
`
`Apotex Exhibit 1016.007
`
`

`

`“WO 98/54166
`
`PCT/SE98/00907
`
`recrystallization of the said tartrate from an appropriate aqueous organic solvent will give
`
`the monohydrate of the invention.
`
`Appropriate solvents for dissolving (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-
`
`2H-1-benzopyran-5-carboxamide maybe organic solvents such as tetrahydrofuran,diethyl
`
`ether, acetone, ethanol, methanol and otheralcohols.
`
`Appropriate aqueousorganic solvents usedin the crystallization or recrystallization may be
`
`alcohols, nitriles, esters, or ketones e. g. methanol, ethanol, isopropanol, acetonitrile, or
`
`acetone, preferably acetone.
`
`Example 1
`
`(R)-3-N,N-Dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide
`
`Hydrogen (2R,3R)-Tartrate
`
`(R)-3-N,N-Dicyclobutylamino-8-fluoro-3,4-dihydro-2H- 1-benzopyran-5-carboxamide (100
`
`mg, 0.31 mmol) wasdissolved in tetrahydrofuran (1 mL) by heating and the solution was
`
`20
`
`diluted with diethyl! ether (25 mL). To this solution was added a solution of (2R,3R)-
`
`tartaric acid made by dissolving 55 mg (0.35 mmol) of (2R,3R )-tartaric acid in
`
`tetrahydrofuran (1 mL) and diluting with diethyl ether (25 mL). The milkysolution
`
`obtained wasfiltered and allowed to stand in the refrigerator overnight. The solid was
`
`filtered and dried in a vacuum ovento give the title compound in 142 mg white crystals
`
`25
`
`(98% yield). Mp 174-180°C (DSC). Anal. Calcd. for C22H23FN2Os: C, 56.4; H,6.2; N,
`
`6.0. Found: C, 56.2; H, 5.9; N, 5.6.
`
`30
`
`Apotex Exhibit 1016.008
`
`Apotex Exhibit 1016.008
`
`

`

`WO 98/54166
`
`PCT/SE98/00907
`
`Example 2
`
`(R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide
`
`Hydrogen (2R,3R)-Tartrate Monohydrate
`
`(R)-3-N,N-Dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide(2.0
`
`g, 6.3 mmol) was dissolved in tetrahydrofuran (5 mL) by heating andthe solution was
`
`diluted with diethyl ether (400 mL). To this solution was addeda solution of (2R, 3R)-
`
`tartaric acid madeby dissolving 1.1 g (6.9 mmol) of (2R, 3R)-tartaric acid in
`
`tetrahydrofuran (15 mL) and diluting with diethyl ether (300 mL). The clear solution
`
`obtained wasallowedto stand in the refrigerator over the weekend. The crystalline solid
`
`obtained was filtered andrecrystallized from 1.5% aqueous acetone (400 mL)to give ofthe
`
`title compound 2.6 g sparkly crystals (85% yield). Mp. 174-180°C (DSC). Anal. Calcd. for
`
`C22H25FN20¢9: C, 54.3; H, 6.4; N, 5.8. Found: C, 54.4; H, 6.3; N, 5.6.
`
`20
`
`25
`
`Analytical test method used on the products obtained in Examples 1 and 2
`
`The melting point (Mp) was measured by using differential scanning calorimetry (DSC).
`
`Establisment of water content
`
`a) Thermogravimetric assay
`
`Thermogravimetric measurements performed showedthat the anhydrous form of(R)-3-
`
`N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen
`
`(2R,3R)-tartrate obtained in Example 1 had an initial weight loss of 0.997% w/w. The
`
`initial weight loss of 4.104% w/w for the monohydrate of (R)-3-N,N-dicyclobutylamino-
`
`8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,34)-tartrate
`
`obtained in Example 2 compared favourably with the theoretical water content of a
`
`monohydrate.
`
`Apotex Exhibit 1016.009
`
`Apotex Exhibit 1016.009
`
`

`

`“WO 98/54166
`
`PCT/SE98/00907
`
`b) X-Ray Diffraction
`
`X-ray intensity data were collected on a single-crystal MACH3/CAD4 diffractometer
`
`(Enraf-Nonius, 1994) equipped with graphite monochromatic CuK(a) radiation and a
`
`proportional scintillation counter. The structure was solved by direct methods, S/R92
`(Altomare, Cascarano, Giacovazzo & Guagliardi, 1992) and refined with full-matrix least
`square methods, LSFM (Hansen & Coppens, 1974), within the MolEN software package
`
`(Straver & Schierbeck, 1994). All non-hydrogen atoms were refined anisotropically,
`
`whereas hydrogen atoms not involved in short intermolecular contacts were fixed from a
`late difference Fourier and supplied with isotropic displacement parameters, U,,, = 0.06 A’.
`
`Hydrogen atom positions involved in H-bonding were refined freely and assisted with a
`
`180
`fixed isotropic temperaturefactor, U,,, = 0.06 A’, except for the crystal water hydrogensfor
`which the factor used was U;,, = 0.07 A’.
`
`Figure 1 shows the three-dimensional structure and absolute configuration of (R)-3-N,N-
`
`dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide in relationship
`
`to the (2R,3R)-tartrate portion and the water molecule.
`
`Determination of stability
`
`20
`
`25
`
`Moisture sorption of the monohydrate of (R)-3-N, N-dicyclobutylamino-8-fluoro-3,4-
`
`dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate compared to that of
`
`the anhydrous form of (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-
`
`benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate, as well as to that of the HCl-salt
`
`has been set as a measure of the relative physical stabilities of the respective products.
`
`The moisture sorption analysis, absorption and desorption, respective was performed using
`
`a VTI microbalance, Model MB300W (VTI Corporation, USA)linked to an IBM PC, The
`
`relative humidity (RH) within the balance was monitored using a dew pointanalyser.
`
`30
`
`Approximately 10 mg of substance was dried to constant weight at 60°C and then exposed
`
`Apotex Exhibit 1016.010
`
`Apotex Exhibit 1016.010
`
`

`

`“WO 98/54166
`
`PCT/SE98/00907
`
`stepwise to RHs of from 5 to 90% at 25°C, the step interval being 5%. The desorption
`
`profile was also obtained.
`
`Figure 2 shows the moisture sorption curve of the HCI salt of (R)-3-N,N-
`
`dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide. As seen from
`
`the figure, the HCI salt takes up a considerable amount of moistureat high relative
`
`humidities. At 85% relative humidity the HCI salt has taken up approximately 20% w/w
`
`and exhibits deliquescence.
`
`Figure 2 also showsthe moisture sorption curve of the anhydrous form (anhydrate) of(R)-
`
`3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen
`
`(2R,3R)-tartrate. As seen from the figure, the anhydrous form (anhydrate) absorbs moisture
`
`readily. Ata RH of 90%, about 4.2 % (w/w) moisture was absorbed. The desorption
`profile (the upperpart ofthe curve) indicates that the moisture taken up is firmly bound
`and that the sample has formed a monohydrate.
`
`Figure 2 showsthe moisture sorption curve of the monohydrate of (R)-3-N,N-
`dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H- 1-benzopyran-5-carboxamide hydrogen
`(2R,3R)-tartrate. As seen from the figure the monohydrate absorbs only 2.5% (w/w) at
`
`20
`
`90% RH.Significant uptake of moisture was only recorded at RH of approximately 60% or
`
`above. The desorptionprofile shows that the moisture uptake is reversible.
`
`25
`
`Apotex Exhibit 1016.01 1
`
`Apotex Exhibit 1016.011
`
`

`

`WO 98/54166
`
`PCT/SE98/00907
`
`10
`
`CLAIMS
`
`L. A salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-
`
`carboxamide hydrogentartrate.
`
`A salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-
`
`carboxamide hydrogen (2R,3R)-tartrate.
`
`Thesalt (R)-3-N,N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H-1-benzopyran-5-
`
`carboxamide hydrogen (2R,3R)-tartrate monohydrate.
`
`The salt according to any one of claims 1 to 3 in substantially crystalline form.
`
`A pharmaceutical formulation containing, as active ingredient, the salt according to
`
`any one of claims 1 to 4 in association with a suitable diluent, excipient or an inert
`
`carrier.
`
`A pharmaceutical formulation according to claim 5 for oral administration.
`
`20
`
`The salt according to any one of claims 1 to 4 for use in therapy.
`
`The use of the salt according to any one of claims 1 to 4 in the manufacture ofa
`
`medicament in the prevention or in the treatment of CNSdisorders andrelated
`
`medical disturbances.
`
`The use according to claim 8 in the manufacture of a medicament in preventionorin
`
`the treatment of 5-HT,, receptor antagonist activity related CNS disorders and
`
`medical disturbances.
`
`Apotex Exhibit 1016.012
`
`Apotex Exhibit 1016.012
`
`

`

`WO 98/54166
`
`PCT/SE98/00907
`
`11
`
`10.
`
`The use according to claim 9 in the manufacture of a medicamentin the prevention or
`
`in the treatment of depression.
`
`11.
`
`The use according to claim 9 in the manufacture of a medicament in the prevention or
`
`in the treatment of anxiety.
`
`726
`
`A method for the prevention or the treatment of CNS disorders and related medical
`
`disturbances comprising administration, to a host in need of such treatment, an
`
`effective amountof the salt according to any one of claims1 to 4.
`
`13.
`
`A method according to claim 12 for preventionor the treatment of 5-HT,, receptor
`
`antagonist activity related CNS disorders and medical disturbances.
`
`14.
`
`A methodaccording to claim 13 for the prevention or the treatment of depression.
`
`13.
`
`A method according to claim 13 for the preventionor the treatment ofanxiety.
`
`16..
`
`A process for the manufacture of the salt as defined in any one of claims 1 to 4
`
`characterized by the following consecutive steps:
`
`20
`
`25
`
`i)
`
`dissolving (R)-3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H- 1 -benzopyran-
`
`5-carboxamidein an appropriate solvent, optionally by heating,
`
`ii)
`
`adding (2R, 3R)- ,(2S,3S)- or (2R,3S)-tartaric acid, respectively, dissolved in an
`
`appropriate aqueous organic solvent or non-aqueous organic solvent,
`
`iii) allowing the solution obtained to stand cold to crystallize,
`
`Apotex Exhibit 1016.013
`
`Apotex Exhibit 1016.013
`
`

`

`~ WO 98/54166
`
`PCT/SE98/00907
`
`12
`
`iv) optionally recrystallizing in an appropriate aqueous organic solvent, if a non-
`
`aqueous organic solventis usedin step ii), to obtain the salt defined in any one of
`
`claims3 or 4.
`
`17. A process for the manufacture of the salt as defined in claims 3 to 4 characterized by-
`
`recrystallizing (R)-3-N, N-dicyclobutylamino-8-fluoro-3, 4-dihydro-2H-benzopyran-5-
`
`carboxamide hydrogen (2R,3R)-, (25,35)- or (2R,3S)-tartrate in an appropriate
`
`aqueous organic solvent.
`
`18. A process according to any oneofthe claims 16 or 17, wherein the aqueous organic
`
`solvent is aqueousacetone.
`
`20
`
`25
`
`30
`
`Apotex Exhibit 1016.014
`
`Apotex Exhibit 1016.014
`
`

`

`WO 98/54166
`
`13
`
`PCT/SE98/00907
`
`—
`
`AMENDED CLAIMS
`[received by the International Bureau on 17 September 1998 (17.09.98);
`original claims 1-18 replaced by amended claims 1-17 (2 pages)]
`
`A Salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H- 1 -benzopyran-5-
`
`carboxamide hydrogen (2R,3R)-tartrate.
`
`Thesalt (R)-3-N,N-dicyclobutylamino-8-fluoro-3 ,4-dihydro-2H7-1-benzopyran-5-
`
`carboxamide hydrogen (2R,3R)-tartrate monohydrate.
`
`Thesalt according to any one of claims1 to 2 in substantially crystalline form.
`
`A pharmaceutical formulation containing, as active ingredient, the salt according to
`
`any one of claims 1 to 3 in association with a suitable diluent, excipient or an inert
`
`carrier.
`
`A pharmaceutical formulation according to claim 4 for oral administration.
`
`Thesalt according to any one of claims 1 to 3 for use in therapy.
`
`The useof the salt according to any one of claims 1 to 3 in the manufacture of a
`
`medicamentin the prevention or in the treatment of CNS disorders andrelated
`
`medical disturbances.
`
`15
`
`20
`
`The use according to claim 7 in the manufacture of a medicamentin prevention or
`
`25
`
`in the treatment of S-HT,, receptor antagonistactivity related CNS disorders and
`
`medical disturbances.
`
`The use according to claim 8 in the manufacture of a medicamentin the prevention
`
`or in the treatment of depression.
`
`30
`
`10.
`
`The use accordingto claim 8 in the manufacture of a medicamentin the prevention
`
`or in the treatmentof anxiety.
`
`11.
`
`A methodfor the prevention orthe treatment of CNS disorders and related medical
`
`35
`
`disturbances comprising administration,to a host in need of such treatment, an
`
`effective amountofthe salt according to any one of claims|to 3.
`
`AMENDED SHEET (ARTICLE 19)
`
`Apotex Exhibit 1016.015
`
`Apotex Exhibit 1016.015
`
`

`

`~ WO 98/54166
`
`PCT/SE98/00907
`
`14
`
`12:
`
`A method according to claim 11 for preventionor the treatment of 5-HT,, receptor
`
`antagonistactivity related CNS disorders and medical disturbances.
`
`13.
`
`14.
`
`15;
`
`A method according to claim 12 for the prevention or the treatmentof depression.
`
`A method according to claim 12 for the preventionorthe treatment of anxiety.
`
`A process for the manufacture ofthe salt as defined in any one of claims1 to 3
`
`characterized by the following consecutivesteps:
`
`i)
`
`dissolving (R)-3-N, N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-
`
`benzopyran-5-carboxamide in an appropriate solvent, optionally by heating,
`
`15
`
`20
`
`ii)
`
`adding (2R, 3R)-tartaric acid, respectively, dissolved in an appropriate
`
`aqueous organic solvent or non-aqueous organic solvent,
`
`iii)
`
`iv)
`
`allowing the solution obtained to stand cold to crystallize,
`
`optionally recrystallizing in an appropriate aqueous organic solvent, if a
`
`non-aqueous organic solvent is used in step 1i), to obtain the salt defined in
`
`any one of claims 2 or3.
`
`16.
`
`A process for the manufacture ofthe salt as defined in claims 2 to 3 characterized
`
`by recrystallizing (R)-3-N, N-dicyclobutylamino-8-fluoro-3, 4-dihydro-2H-
`
`25
`
`benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate in an appropriate aqueous
`
`organic solvent.
`
`17.
`
`A process according to any one ofthe claims 15 or 16, wherein the aqueous organic
`
`solvent is aqueous acetone.
`
`30
`
`AMENDED SHEET (ARTICLE 19)
`
`Apotex Exhibit 1016.016
`
`Apotex Exhibit 1016.016
`
`

`

`WO 98/54166
`
`PCT/SE98/00907
`
`CSater
`
`A”
`wl €14-(R)-3-N, N-Dicyclobutylamino-8
`WD15 fluoro-3,4-dihydro-2H-I-
`Ae
`benzopyran-5-carboxamide
`
`
`
`Apotex Exhibit 1016.017
`
`Apotex Exhibit 1016.017
`
`

`

`WO 98/541 66
`
`PCT/SE98/00907
`
`2/2
`
`0000!
`
`0006
`
`szOLY
`
`a00z000i
`
`
`
`
`
`
`
`IOH—FsyeipAyouoweyese}—w-—ayesipAyueayeue]—e—10)SayijoiduONdiosaunjsioyy
`0008=00040009=0005000700°0E
`
`
`
`sejijoiduoljdiosapay}MoUssjoquiAsUadO
`
`
`
`
`
`(%)Apipiunyaatjojay
`
`0052
`
`000¢
`
`00St
`
`;000L
`
`-00S
`
`(%} abuny? jybiam
`
`000
`
`000
`
`Apotex Exhibit 1016.018
`
`Apotex Exhibit 1016.018
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`1
`
`International application No.
`
`PCT/SE 98/00907
`
`A. CLASSIFICATION OF SUBJECT MATTER
`
`TPC6: CO7D 311/58, AGiK 31/35
`According to International Patent Classification (IPC) or to both national classification and IPC
`B. FIELDS SEARCHED
`
`Minimum documentation searched(classification system followed by classification symbols)
`
`IPcé: C07D
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`SE,DK,FI,NO classes as above
`
`Electronic data base consulted during the international search (name of data base and, where practicable, search terms used)
`
`CAS-ONLINE
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Category*| Citation of document, with indication, where appropriate, of the relevant passages
`
`Relevant to claim No.
`
`WO 9511891 Al
`(04.05.95)
`
`(ASTRA AKTIEBOLAG), 4 May
`
`1995
`
`1-11,16-18
`
`+46 8 782 25 00
`
`Further documentsarc listed in the continuation of Box C.
`Special categories of cited documents:
`document defining the general state ofthe art which is not considered
`to be ofparticular relevance
`erlier document but published on orafter the international filing date
`document which may throw doubts on priority claim(s) or whichis
`cited to establish the publication date of another citation or other
`special reason (as specified)
`document referring to an oral disclosure, use, exhibition or other
`means
`document published prior to the internationalfiling date but later than
`the priority date claimed
`
`[x Sce patent family annex.
`later document published aflcr the internationalfiling date or priority
`date and not in conflict with the application but cited to understand
`the principle or theory underlying the invention
`documentofparticular relevance: the claimed invention cannot be
`considered novel or cannot be considered to involve an inventive
`step when the documentis taken alone
`documentofparticular relevance: the claimed invention cannot be
`considered to involve an inventive step when the documentis
`combined with one or more other such documents, such combination
`being obvious to a person skilled in the art
`document memberofthe samepatent family
`
`i
`
`“x”
`
`wye
`
`“&”
`
`Date of mailing of the international search report
`07 -03-
`4998
`Authorized officer
`
`Goran Karlsson
`Telephone No.
`
`Apotex Exhibit 1016.019
`
`Date ofthe actual completion ofthe international search
`
`25 August 1998
`Name and mailing address of the ISA/
`Swedish Patent Office
`Box 5055, S-102 42 STOCKHOLM
`Facsimile No. +46 8 666 02 86
`
`Form PCT/ISA/210 (second sheet) (July 1992)
`
`Apotex Exhibit 1016.019
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`International application No. —
`
`BoxI
`
`Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
`
`PCT/SE 98/00907
`
`This international search report has not been established in respect ofcertain claims underArticle 17(2)(a) for the following reasons: 1.
`
`12-15
`Claims Nos...
`because they relate to subject matter not required to be searched bythis Authority, namely:
`
`A method for treatment of the human or animal body by therapy,
`see Rule 39.1.
`
`2. [J Claims Nos.:
`because they relate to parts of the international application that do not comply with the prescribed requirements to such
`an extent that no meaningful international search can be carried out, specifically:
`
`3.
`
`Claims Nos.:
`because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
`
`Box I] Observations where unity of Invention fs lacking (Continuation of item 2 of first sheet)
`
`This International Searching Authority found multiple inventions in this international application, as follows:
`
`j
`4|
`
`!|,!
`
`1 [| As all required additional search fees were timely paid by the applicant, this intemational search report covers all
`searchable claims.
`
`2:
`
`Asallsearchable claims could be searched without effort justifying an additional fee, this Authority did notinvite payment
`of any additional fee.
`3 : [| As only someofthe required additional search fees were timely paid by the applicant, this international search report
`covers only those claims for which fees were paid, specifically claims Nos.:
`
`-
`
`4. [| No required additional search fees were timely paid by the applicant. Consequently, th's international search report is
`restricted to the invention first mentioned in the claims; itis covered by claims Nos.:
`
`Remark on Protest
`
`[] The additional search fees were accompanied by the applicant’s protest.
`[ Noprotest accompanied the payment of additional search fees.
`Form PCT/ISA/210 (continuation offirst sheet (1)) (July 1992)
`
`Apotex Exhibit 1016.020
`
`Apotex Exhibit 1016.020
`
`

`

`INTERNATIONAL SEARCH REPORT
`Information on patent family members
`
`27/07/98
`
`International application No.
`PCT/SE 98/00907
`
`7
`
`Patent document
`cited in search report
`
`Publication
`Publication
`Patent family
`date
`member(s)
`date
`
`22/05/95
`26/11/96
`04/05/95
`27/11/96
`11/09/96
`14/08/96
`20/05/96
`31/12/96
`28/03/97
`00/00/00
`00/00/00
`28/04/97
`03/06/96
`19/08/96
`01/10/96
`30/05/95
`19/03/96
`01/04/97
`17/06/97
`17/06/97
`24/06/97
`08/07/97
`22/07/97
`12/08/97
`12/08/97
`02/05/95
`
`9408353>PPpPrrrrrrrrrrrITOrrrrrr>r>r>r>d 19/02/98
`
`WO
`
`9511891 Al
`
`04/05/95
`
`AU
`AU
`BR
`CA
`CN
`CZ
`EP
`FI
`HR
`HU
`HU
`IL
`JP
`NO
`PL
`SK
`US
`US
`US
`US
`US
`US
`US
`US
`US
`US
`
`687115
`8069794
`9407910
`2173257
`1136811
`9601114
`0725779
`961809
`940890
`75060
`9601103
`111365
`9504287
`961687
`314086
`43696
`5420151
`5500425
`5616610
`5639772
`5639784
`5641807
`5646309
`5650524
`5656657
`5656658
`
`Form PCT/ISA/210 (patent family annex) (July 1992)
`
`Apotex Exhibit 1016.021
`
`Apotex Exhibit 1016.021
`
`