PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`1,
`
`1
`
`.
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 6 :
`
`(11) International Publication Number:
`
`WO 98/54166
`
`A1
`C07D 311/58, A61K 31/35
`(43) International Publication Date:
`3 December 1998 (03.12.98)
`
`(21) International Application Number:
`
`PCT/SE98/OO907
`
`(22) International Filing Date:
`
`15 May 1998 (15.05.98)
`
`(30) Priority Data:
`970206673
`
`30 May 1997 (30.05.97)
`
`SE
`
`(for all designated States except US): ASTRA
`(71) Applicant
`AKTIEBOLAG [SE/SE]; $7151 85 deertalje (SE).
`
`(72) Inventors; and
`NYQVIST, Hakan
`(75) Inventors/Applicants (for US only):
`[SE/SE]; Astra Arcus AB, S—151 85 Sedertalje (SE).
`SOHN, Daniel, D. [US/SE]; Astra Arcus AB, 5—151 85
`Sodeitalje (SE).
`
`(74) Agent: ASTRA AKTIEBOLAG; Patent Dept.,
`deertéilje (SE).
`
`8—151 85
`
`(81) Designated States: AL, AM, AT, AU, AZ, BA, BB, BG, BR,
`BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GE, 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, T1“, 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—l-benzopyran—S—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.
`
`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
`
`Albania
`Armenia
`Austria
`Australia
`Azerbaijan
`Bosnia and Herzegovina
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d’Ivoire
`Cameroon
`China
`Cuba
`Czech Republic
`Germany
`Denmark
`Estonia
`
`ES
`FI
`FR
`GA
`GB
`GE
`GH
`GN
`GR
`HU
`IE
`[L
`IS
`IT
`JP
`KE
`KG
`KP
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Guinea
`Greece
`Hungary
`Ireland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakslan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`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
`TM
`TR
`TT
`UA
`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
`
`LS
`LT
`LU
`LV
`MC
`MD
`MG
`MK
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`SG
`
`
`
`ApoteX Exhibit 1016.002
`
`Apotex Exhibit 1016.002
`
`

`

`7W0 98/54166
`
`.
`
`PCT/SE98/00907
`
`A new salt
`
`Field of the Invention
`
`The present invention relates to a new salt, namely (R)-3-N,N—dicyclobuty1amino—8—fluoro—
`
`3,4-dihydro-2H-1-benzopyran—5-carboxamide hydrogen tartrate, particularly the (2R,3R)
`
`form of the tartrate and most particularly the monohydrate thereof. The invention also
`
`relates to processes for the manufacturing of the salt, the use of the salt in the manufacture
`
`of pharmaceutical formulations, to the use of the salt in medicine and methods of
`
`treatment employing the salt particularly, in its monohydrate form.
`
`Backgound of the Invention
`
`The compound (R)—5-carbamoyl-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-
`
`benzopyran, which also may be named (R)—3-N,N-dicyclobutylamino-S-fluoro-3,4-dihydro-
`
`2H-1-benzopyran—5-carboxamide and pharmaceutically acceptable salts thereof are
`
`described in W0 95/ 1 1891.
`
`The disclosed hydrochloride salt of (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-
`
`2H-1-benzopyran-5-carboxamide is hygroscopic and thus physically instable during
`
`manufacturing as well as during storage.
`
`Disclosure of the Invention
`
`It has now surprisingly been found that the salt (R)-3—N,N—dicyclobutylamino—8-fluoro-3,4—
`
`dihydro-ZH—l~benzopyran-5-carboxamide hydrogen tartrate, 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 hydrochloride salt of said compound, since the tartrate
`
`forms of the compound are not disposed to absorb water to the same degree as the
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`Apotex Exhibit 1016.003
`
`Apotex Exhibit 1016.003
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`

`

`T WO 98/54166
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`PCT/SE98/00907
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`hydrochloride salt of the same compound. This property of absorbing water is also a
`
`problem during storage and during manufacture of, e.g., solid pharmaceutical dosage
`
`forms such as tablets and hard gelatine capsules.
`
`The good solubility and dissolution properties of the anhydrous tartrate salt are even more
`
`pronounced for the monohydrate of the tartrate salt, particularly the (2R,3R)—tartrate
`
`monhydrate. The water is firmly bound in the crystal 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 of tablets and hard gelatine capsules.
`
`The good solubility and dissolution properties of the 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 of the tartrate
`
`salt, and particularly the (2R,3R)-tartrate monohydrate fiom a quality assurance standpoint.
`
`Thus, the monohydrate of (R)-3-N,N—dicyclobutylamino-8—fluor0-3,4-dihydro-2H—l-
`
`benzopyran—S—carboxamide hydrogen (2R,3R) —taitrate, 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.
`
`Accordingly, the present invention relates to the salt (R)—3—N,N—dicyclobutylamino~8-
`
`fluoro—3,4—dihydro-2H—l-benzopyran-5-carboxamide hydrogen tartrate, particularly to the
`
`salt (R)-3—N,N—dicyclobutylamino—8-fluoro—3,4-dihydro-2H—l -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—l-
`
`benzopyran-S-carboxamide hydrogen tartrate, in the form of (2R,3R)-tartrate, (23,35)-
`
`tartrate and (2R,3S)—tartrate.
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`ApoteX Exhibit 1016.004
`
`Apotex Exhibit 1016.004
`
`

`

`7 WO 98/54166
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`PCT/SE98/00907
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`The salts of the invention may be used as selective 5-HT1A receptor antagonists in the
`
`treatment of CNS disorders 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 co gnative dysfunction in schizophrenia, sleep disorders, urinary incontinence,
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`premenstrual syndrome, hypertension and pain. Examples of such medical disturbances are
`
`therrnoregulatory disturbances, sexual disturbances, disturbances in the cardiovascular
`
`system and disturbances in the gastrointestinal system.
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`The novel salt (R)-3-N,N-dicyclobutylamino-8-fluor0-3,4-dihydro—2H—1—benzopyran-5-
`
`carboxamide hydrogen tartrate, 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 forms for oral, parenteral, rectal
`
`and other modes of administrations.
`
`Examples of formulations are 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 weight of the
`
`formulation, more preferably from 0.001 to 30% by weight of the formulation.
`
`To produce pharmaceutical formulations containing the active ingredient of the invention
`
`in the form of dosage units for oral applications, one may mix the 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-
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`vinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, sodium
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`stearylfumarate, polyethylene glycol, waxes, paraffin, and the like, and then compressed
`
`into tablets. The active ingredient may be granulated together with excipients using an
`
`aqueous or organic solution of binders, and then dried and screened prior to tablet
`
`compression.
`
`Apotex Exhibit 1016.005
`
`Apotex Exhibit 1016.005
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`

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`7WO 98/54166
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`PCT/SE98/00907
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`If coated tablets are required, the cores, prepared as described above, may be coated with a
`
`concentrated sugar solution which may contain, 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 the art, that is dissolved in a readily volatile organic solvent or mixture of
`
`organic solvents. Dyestuffs may be added to these coatings in order to readily distinguish
`
`between tablets containing different amounts of active ingredient.
`
`For the preparation of hard gelatine capsules, the active ingredient may be processed in the
`
`form of granules, and may be admixed with the excipients mentioned above for tablets.
`
`For the 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 in a molten suppository base such as Witepsol® followed by casting and
`
`cooling.
`
`Gelatine rectal capsules may comprise the active ingredient in admixture with vegetable oil
`
`or paraffin oil and may contain some of the polymers and/or dyestuff mentioned above.
`
`Aqueous solutions for parenteral or oral administration are produced by dissolving the
`
`active compound of the invention in water, adjusting the pH and ionic strength with
`
`common buffering agents such as citric acid, phosphoric acid or other similar acids or their
`
`commonly used salts; sodium carbonate, hydrogen carbonate or other similar salts; or
`
`hydrochloric acid or sodium hydroxide. In the case of parenteral solutions the sterility is
`
`ensured by final heat sterilization or, e. g., sterile filtration. Lyophilization, resulting in a
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`reconstitutable solid product, may also be used.
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`Suitable daily doses of the salt of the invention in therapeutical treatment of humans are
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`30
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`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—ZH—l-benzopyran—S—carboxamide hydrogen (2R,3R)—tartrate, (ZS,3S)-tartrate or
`
`(2R,3S)—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—l—benzopyran—S-carboxamide hydrogen (2R,3R)-tartrate, more specifically
`
`the monohydrate thereof, comprises the following consecutive steps:
`
`l0
`
`l5
`
`20
`
`i)
`
`dissolving (R)-3-N,N-dicyclobutylamino-S-fluoro-3,4-dihydro—2H—l-benzopyran-5-
`
`carboxamide in an appropriate organic solvent, optionally by heating,
`
`ii)
`
`adding (2R,3R)-tartaric acid dissolved in an appropriate aqueous organic or non-
`
`aqueous organic solvent,
`
`iii) allowing the obtained solution to stand cold in order to crystallize,
`
`iv) optionally, recrystallizing from an aqueous organic solvent, if a non—aqueous organic
`
`solvent is used in step ii), to obtain the tartrate monohydrate salt.
`
`The corresponding (2S,3S)-tartrate and (2R,3S)—tartrate compound are manufactured by
`
`using (25,3S)—tartaric acid and (2R,3S)-tartaric acid, respectively in step ii) above.
`
`A more detailed description of the process of manufacturing is presented in Examples 1
`
`25
`
`and 2.
`
`Starting fiom 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—l -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
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`

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`7WO 98/54166
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`PCT/SE98/00907
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`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—S—fluoro—3,4—dihydro-
`
`2H—l—benzopyran-5-carboxamide may be organic solvents such as tetrahydrofuran, diethyl
`
`ether, acetone, ethanol, methanol and other alcohols.
`
`Appropriate aqueous organic solvents used in 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—B-fluoro—3,4-dihydro—2H—1—benzopyran-S—carboxamide
`
`Hydrogen (2R,3R)-Tartrate
`
`(R)-3-N,N—Dicyclobutylamino-8-fluoro-3 ,4—dihydro—2H— l -benzopyran—5 -carboxamide (100
`
`mg, 0.31 mmol) was dissolved in tetrahydrofuran (1 mL) by heating and the solution was
`
`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 milky solution
`
`obtained was filtered and allowed to stand in the refrigerator overnight. The solid was
`
`filtered and dried in a vacuum oven to give the title compound in 142 mg white crystals
`
`(98% yield). Mp 174-180°C (DSC). Anal. Calcd. for C22H23FN2031 C, 56.4; H, 6.2; N,
`
`6.0. Found: C, 56.2; H, 5.9; N, 5.6.
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`Apotex Exhibit 1016.008
`
`Apotex Exhibit 1016.008
`
`

`

`TWO 98/54166
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`PCT/SE98/00907
`
`Example 2
`
`(R)-3—N,N-dicyclobutylamino—8—fluoro—3,4—dihydro-ZH-l-benzopyran-S-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 and the solution was
`
`diluted with diethyl ether (400 mL). To this solution was added a solution of (2R, 3R)-
`
`tartaric acid made by dissolving 1.1 g (6.9 mmol) of (2R, 3R)-tartan’c acid in
`
`tetrahydrofuran (15 mL) and diluting with diethyl ether (300 mL). The clear solution
`
`obtained was allowed to stand in the refrigerator over the weekend. The crystalline solid
`
`obtained was filtered and recrystallized from 1.5% aqueous acetone (400 mL) to give of the
`
`title compound 2.6 g sparkly crystals (85% yield). Mp. 174-180°C (DSC). Anal. Calcd. for
`
`C22H25FN209: C, 54.3; H, 6.4; N, 5.8. Found: C, 54.4; H, 6.3; N, 5.6.
`
`Analvtical 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) Thermogravirnetric assay
`
`Thennogravimetn'c measurements performed showed that 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,3R)-tartrate
`
`obtained in Example 2 compared favourably with the theoretical water content of a
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`monohydrate.
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`Apotex Exhibit 1016.009
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`Apotex Exhibit 1016.009
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`

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`CW0 98/54166
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`PCT/SE98/00907
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`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(0t) radiation and a
`
`proportional scintillation counter. The structure was solved by direct methods, SIR92
`(Altomare, Cascarano, Giacovazzo & Guagliardi, 1992) and refined with full-matrix least-
`
`square methods, LSFM (Hansen & Coppens, 1974), within the MolEN sofiware 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, Uiso = 0.06 A2.
`
`Hydrogen atom positions involved in H-bonding were refined freely and assisted with a
`
`150
`fixed isotropic temperature factor, U. = 0.06 A2, except for the crystal water hydrogens for
`
`which the factor used was Uiso = 0.07 A2.
`
`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
`
`Moisture sorption of the monohydrate of (R)-3-N, N-dicyclobutylamin0-8-fluoro-3,4-
`
`dihydro-ZH—l-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—l-
`
`benzopyran-S—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 point analyser.
`
`Approximately 10 mg of substance was dried to constant weight at 60°C and then exposed
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`ApoteX Exhibit 1016.010
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`Apotex Exhibit 1016.010
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`TWO 98/54166
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`PCT/SE98/00907
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`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 HCl salt of (R)—3—N,N-
`
`dicyclobutylamino—8-fluoro-3,4-dihydro-2H—l-benzopyran—S-carboxamide. As seen from
`
`the figure, the HCl salt takes up a considerable amount of moisture at high relative
`
`humidities. At 85% relative humidity the HCl salt has taken up approximately 20% w/w
`
`and exhibits deliquescence.
`
`Figure 2 also shows the moisture sorption curve of the anhydrous fonn (anhydrate) of (R)-
`
`3—N,N—dicyclobutylamino—8—fluoro—3,4—dihydro—2H—l -benzopyran—5~carboxamide hydrogen
`
`(2R,3R)~tartrate. As seen from the figure, the anhydrous form (anhydrate) absorbs moisture
`
`readily. At a RH of 90%, about 4.2 % (w/w) moisture was absorbed. The desorption
`
`profile (the upper part of the curve) indicates that the moisture taken up is firmly bound
`
`and that the sample has formed a monohydrate.
`
`Figure 2 shows the 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
`
`90% RH. Significant uptake of moisture was only recorded at RH of approximately 60% or
`
`above. The desorption profile shows that the moisture uptake is reversible.
`
`10
`
`15
`
`20
`
`25
`
`ApoteX Exhibit 1016.011
`
`Apotex Exhibit 1016.011
`
`

`

`TWO 98/54166
`
`PCT/SE98/00907
`
`10
`
`CLAIMS
`
`1. A salt (R)-3~N,N-dicyclobuty1amin0—8-fluoro-3,4-dihydro-2H—l—benzopyran-S-
`
`carboxamide hydrogen tartrate.
`
`2. Asalt (R)-3-N,N-dicyclobutylamino—8—fluoro-3,4—dihydro-2H—l-benzopyran-5-
`
`carboxamide hydrogen (2R,3R)—tartrate.
`
`3. The salt (R)-3-N,N-dicyclobuty1amino-8-fluoro-3,4-dihydro-2H—1-benzopyran-5-
`
`carboxamide hydrogen (2R,3R)—tartrate monohydrate.
`
`4. The salt according to any one of claims 1 to 3 in substantially crystalline form.
`
`5. 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.
`
`6. A pharmaceutical formulation according to claim 5 for oral administration.
`
`7. The salt according to any one of claims 1 to 4 for use in therapy.
`
`8. The use of the salt according to any one of claims 1 to 4 in the manufacture of a
`
`medicament in the prevention or in the treatment of CNS disorders and related
`
`medical disturbances.
`
`IO
`
`15
`
`20
`
`9. The use according to claim 8 in the manufacture of a medicament in prevention or in
`
`the treatment of 5-HT1A 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 medicament in the prevention or
`
`in the treatment of depression.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`16..
`
`10
`
`15
`
`20
`
`25
`
`The use according to claim 9 in the manufacture of a medicament in the prevention or
`
`in the treatment of anxiety.
`
`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 amount of the salt according to any one of claims 1 to 4.
`
`A method according to claim 12 for prevention or the treatment of 5-HT1A receptor
`
`antagonist activity related CNS disorders and medical disturbances.
`
`A method according to claim 13 for the prevention or the treatment of depression.
`
`A method according to claim 13 for the prevention or the treatment of anxiety.
`
`'A process for the manufacture of the salt as defined in any one of claims 1 to 4
`
`characterized by the following consecutive steps:
`
`i)
`
`dissolving (R)-3-N,N—dicyclobuty1amino-8—fluoro—3,4—dihydro—2H—l—benzopyran-
`
`5-carboxamide in an appropriate solvent, optionally by heating,
`
`ii)
`
`adding (2R, 3R)— ,(2S,3S)— or (2R,3S)-tartan'c 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
`
`

`

`1WO 98/54166
`
`PCT/SE98/00907
`
`12
`
`iv) optionally recrystallizing in an appropriate aqueous organic solvent, if a non—
`
`aqueous organic solvent is used in step ii), to obtain the salt defined in any one of
`
`claims 3 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)-, (2S,3S)— or (2R,3S)—tartrate in an appropriate
`
`aqueous organic solvent.
`
`10
`
`18.
`
`A process according to any one of the claims 16 or 17, wherein the aqueous organic
`
`solvent is aqueous acetone.
`
`15
`
`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-S-fluoro-3,4-dihydro-2H-1-benzopyran-5-
`
`carboxamide hydrogen (2R,3R)-tartrate.
`
`The salt (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H—l-benzopyran—5-
`
`carboxamide hydrogen (2R,3R)-tartrate monohydrate.
`
`The salt according to any one of claims 1 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.
`
`The salt according to any one of claims 1 to 3 for use in therapy.
`
`The use of the salt according to any one of claims 1 to 3 in the manufacture of a
`
`medicament in the prevention or in the treatment of CNS disorders and related
`
`medical disturbances.
`
`The use according to claim 7 in the manufacture of a medicament in prevention or
`
`in the treatment of 5-HTIA receptor antagonist activity related CNS disorders and
`
`medical disturbances.
`
`The use according to claim 8 in the manufacture of a medicament in the prevention
`
`or in the treatment of depression.
`
`The use according to claim 8 in the manufacture of a medicament in the prevention
`
`or in the treatment of anxiety.
`
`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 amount of the salt according to any one of claims 1 to 3.
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10.
`
`11.
`
`5
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`AMENDED SHEET (ARTICLE 19)
`
`ApoteX Exhibit 1016.015
`
`Apotex Exhibit 1016.015
`
`

`

`g WO 98/54166
`
`14
`
`PCT/SE98/00907
`
`12.
`
`A method according to claim 1 1 for prevention or the treatment of 5-HTl A receptor
`
`antagonist activity related CNS disorders and medical disturbances.
`
`13.
`
`A method according to claim 12 for the prevention or the treatment of depression.
`
`14.
`
`A method according to claim 12 for the prevention or the treatment of anxiety.
`
`15.
`
`A process for the manufacture of the salt as defined in any one of claims 1 to 3
`
`characterized by the following consecutive steps:
`
`i)
`
`dissolving (R)-3-N, N—dicyclobutylarnino-8-fluoro-3 ,4-dihydro-2H— l -
`
`benzopyran—S-carboxarnide in an appropriate solvent, optionally by heating,
`
`ii)
`
`adding (2R, 3R)—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,
`
`iv)
`
`optionally recrystallizing in an appropriate aqueous organic solvent, if a
`
`non-aqueous organic solvent is used in step ii), to obtain the salt defined in
`
`any one of claims 2 or 3.
`
`10
`
`15
`
`20
`
`16.
`
`A process for the manufacture of the salt as defined in claims 2 to 3 characterized
`
`by recrystallizing (R)—3-N,N-dicyclobutylamino-8-fluoro-3, 4-dihydro-2H—
`
`25
`
`benzopyran-S-carboxamide hydrogen (2R,3R)-tartrate in an appropriate aqueous
`
`organic solvent.
`
`17.
`
`A process according to any one of the 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
`
`7/2
`
`E?afer
`
` (-015 fluoro—B, 4-dihydro—2H—l-
`
`\C benzopyran-E-carboxamic/e
`
`ApoteX Exhibit 1016.017
`
`Apotex Exhibit 1016.017
`
`

`

`WO 9854166
`
`PCT/SE98/00907
`
`2/2
`
`8.3“
`
`3.9“
`
`W
`
`.mmm
`
`8%8%8%8.8
`8.33cm86m8%
`
`
`
`
`
`$505535309:255m203E?chO
`
`
`
`£253229mm
`
` fix;
`
`
`
`
`
`GILT9mi>cocoEmumeHIII2935.5BmEmFIT5“.92:058:9892222
`
`
`
`
`
`8mm
`
`gcm.
`
`3mu
`
`.8S
`
`.8m
`
`(%/ afium/D Mme/I4
`
`so6
`
`g.Q
`
`ApoteX Exhibit 1016.018
`
`Apotex Exhibit 1016.018
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`1
`
`A. CLASSIFICATION OF SUBJECT MATTER
`
`International application No.
`
`PCT/SE 98/00907
`
`IPC6: C07D 311/58, A61K 31/35
`According to International Patent Classification (IPC) or to both national classification and WC
`B. FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`
`IPC6: C07D
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`SE,DK,FI,N0 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
`
`A
`
`NO 9511891 A1 (ASTRA AKTIEBOLAG), 4 May
`(04.05.95)
`
`1995
`
`Relevant to claim No.
`
`1-11,16-18
`
`Further documents are listed in the continuation of Box C.
`
`Special categories of eited documents:
`document defining the general state ol'the art which is not considered
`to be of particular relevance
`erher document but published on or alter the international filing date
`document which may throw doubts on priority claim(s) or which is
`cited to establish the publication date of another Citation or other
`special reason (as spectfted)
`document referring to an oral disclosure, use, exhibition or other
`means
`document published prior to the international filing date but later than
`the priority date claimed
`
`”T”
`
`”X”
`
`”Y”
`
`“8L”
`
`a See patent family annex.
`later document published after the intemalional filing date or priority
`date and not in conflict with the application but. cited to understand
`the principle or theory underlying the invention
`document of particular relevance: the claimed invention cannot be
`eonstdered novel or cannot be considered to involve an inventive
`step when the document is taken alone
`document of particular relevance: the claimed invention cannot be
`considered to involve an inventive step when the document is
`combined with one or more other such documents, such combination
`being ohvious to a person skilled in the art
`document member ot'the same patent family
`
`Date of the actual completion of the international search
`
`Date of mailing of the international search report
`
`25 Au-ust 1998
`Name and mailing address of the ISA/
`Swedish Patent Office
`
`07ee ea
`Authorized oliicer
`
`Box 5055, 3-102 42 STOCKHOLM
`Facsimile No. +46 8 666 02 86
`Form PCT/[SA/210 (second sheet) (July 1992)
`
`Goran Karlsson
`Tole-hone N0.
`+ 46 8 782 25 00
`
`ApoteX Exhibit 1016.019
`
`Apotex Exhibit 1016.019
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`International application No.
`
`4“
`
`Box]
`
`Observations where certain claims were found unsearchable (Continuation ol'ltern 1 of first sheet)
`
`PCT/SE 98/00907
`
`
`
`
`This international search report has not been established in respect ofcertain claimsunder Article 17(2)(a) for the following reasons:
`
`
`
`
`1.
`
`12-15
`Claims Nos:
`because they relate to subject matter not required to be searched by this Authority, namely:
`
`A method for treatment of the human or animal body by therapy,
`see Rule 39.1.
`
`
`
`
`
`
`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:
`
`
`
`
`
`
`
`I
`Il
`
`llul
`
`Claims Nos.:
`
`because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a)i
`
`
`Box 11 Observations where unity oflnventlon is lacking (Continuation ofltem 2 of first sheet)
`
`This International Searching Authority found multiple inventions in this international application, as follows:
`
`1. D As all required additional search fees were timely paid by the applicant, this international search report covers all
`searchable claims.
`
`2. D Asallsearchableclaimscouldbesearchedwithouteffortjustifyinganadditionalfee,thisAuthoritydidnotinvitepayment
`ofany additional fee.
`
`3. D As only some of the required additional search fees were timely paid by the applicant, this international search report
`Y
`P
`P
`Y
`covers on]
`those claims for which fees were aid, 5 ecificall
`claims Nos:
`
`-
`
`4. D No required additional search fees were timely paid by the applicant. Consequently, this international search report is
`restricted to the invention first mentioned in the claims;
`it is covered by claims N03,:
`
`Remark on Protat
`
`E] The additional search fees were accompanied by the applicant’s protest.
`D No protest accompanied the payment ofadditional search fees.
`
`Form PCT/lSA/ZIO (continuation of first sheet (1)) (July 1992)
`
`ApoteX Exhibit 1016.020
`
`Apotex Exhibit 1016.020
`
`

`

`INTERNATIONAL SEARCH REPORT
`Information on patent family members
`
`International application No.
`
`7’
`
`27/07/98
`
`PCT/SE 98/00907
`
`cited in Search report
`
`Publication
`date
`
`Patent family
`member(s)
`
`Publication
`date
`
`NO
`
`9511891
`
`A1
`
`04/05/95
`
`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
`
`>>>>>>>>>>>>>>fiDU>>>>>>>>>m
`
`19/02/98
`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