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`
`EXHIBIT 46
`
`EXHIBIT 46
`
`
`
`

`
`Case 1:14-cv-01453-LPS Document 43-15 Filed 10/22/15 Page 2 of 123 PageID #: 1059
`Case 1:14—cv—O1453—LPS Document 43-15 Filed 10/22/15 Page 2 of 123 Page|D #: 1059
`
`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`Intematronal Bureau
`
`
`
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 5 :
`
`(11) International Publication Number:
`
`W0 97/21724
`
`C07,] 7]/00, A61K 31/58
`
`A1
`
`(43) International Publication Date:
`
`19 June 1997 (1906.97)
`
`(21) International Application Number:
`
`PCT/US96/19220
`
`(22) International Filing Date:
`
`6 December 1996 (0612.96)
`
`(74) Agents: BENNETT, Dennis. A. et al.; G.D. Scarle & Co..
`Corporate Patent Dept., PO. Box 51 10, Chicago, IL 60680-
`51 10 (US).
`
`’
`
`(30) Priority Data:
`08/569,269
`
`8 December I995 (08.l2.9S)
`
`US
`
`(60) Parent Application or Grant
`(63) Related by Continuation
`US
`Filed on
`
`08/569,269 (CON)
`8 December 1995 (O8.l2.95)
`
`(71) Applicant (for all designated States except US): G.D. SEARLE
`& CO. [US/US]; Corporate Patent Dept., PO. Box SI 10,
`Chicago, IL 60680-5110 (US).
`
`(72) Inventors; and
`S.
`TIOENG, Foe,
`(75) InventorsIAppIicants (for US only):
`[US/US]; 875 Sugar Hill Drive, Manchester, MO 63021
`(US). CURRIE, Mark, G.
`[US/US]; 404 Mason Ridge
`Drive, St. Charles, MO 63304 (US). ZUPEC, Mark, E.
`[US/US]; 9l4 Glen Hollow Drive, O’Fallon,
`IL 62269
`(US).
`
`(81) Designated States: AL. AM, AT, AU, AZ, BB, BG, BR, BY,
`CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GE, GE, HU,
`IL, IS, JP, KE, KG, KP, KR, KZ, LK, LR, LS, LT. LU, LV.
`MD, MG, MK, MN, MW’, MX, N0, N7., PL, PT, RO, RU,
`SD, SE, SG, SI, SK, TJ, TM, TR, "IT, UA, UG, US, UZ,
`VN, ARIPO patent (KE, LS, MW, SD, SZ, UG), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, 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.
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`amendments.
`
`(54) Title:
`
`STEROID NITRITE ESTER DERIVATIVES USEFUL AS ANTLINFLAMMATORY DRUGS
`
`(57) Abstract
`
`The present invention discloses novel steroid nitrite ester derivatives, and to their use treating inflammatory diseases.
`
`MED_DYM_00004328
`
`

`
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`
`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.
`
`AM
`AT
`AU
`BB
`BE
`BF
`BC
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`Cl
`CM
`CN
`CS
`CZ
`DE
`DK
`BE
`ES
`F1
`FR
`GA
`
`Armenia
`Austria
`Australia
`Barbados
`Belgium
`Burkina Faso
`Bulgaria
`Benin
`Brazil
`Belarus
`Canada
`Central African Republic
`Congo
`Switzerland
`Cote d‘Ivoire
`Cameroon
`China
`Czechoslovakia
`Czech Republic
`Germany
`Denmark
`Estonia
`Spain
`Finland
`France
`Gabon
`
`GB
`GE
`GN
`GR
`HU
`[E
`IT
`JP
`KE
`KG
`Kl’
`
`KR
`K7.
`LI
`LK
`LR
`LT
`LU
`LV
`MC
`MD
`MG
`ML
`MN
`MR
`
`United Kingdom
`Georgia
`Guinea
`Greece
`Hungary
`Ireland
`Italy
`Japan
`Kenya
`Kyrgystan
`Democratic People's Republic
`of Korea
`Republic of Korea
`Kazakhstan
`Liechtenstein
`Sri Lanka
`Liberia
`Lithuania
`Luxembourg
`Latvia
`Monaco
`Republic of Moldova
`Madagascar
`Mali
`Mongolia
`Mauritania
`
`MW
`MX
`NE
`N I.
`N0
`NZ
`PL
`PT
`R0
`RU
`S1)
`SE
`SG
`SI
`SK
`SN
`SZ
`TD
`TG
`TJ
`TT
`UA
`UG
`US
`UZ
`VN
`
`Malawi
`Mexico
`Niger
`Netherlands
`Norway
`New Zealand
`Poland
`Portugal
`Romania
`Russian Federation
`Sudan
`Sweden
`Singapore
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`
`MED_DYM_00004329
`
`

`
`Case 1:14-cv-01453-LPS Document 43-15 Filed 10/22/15 Page 4 of 123 PageID #: 1061
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`
`wo 97/21724
`
`PCT/US96/19220
`
`"TIER ID PIT ITE E‘. TEF. DERI ATI
`
`S
`
`EJSEFEIL A5 flTI—INFLAl\/IIVIALORY DRLJQE
`
`5
`
`B
`
`k r
`
`nd
`
`f
`
`h
`
`n
`
`i n
`
`Fig d of
`
`the Invention
`
`The present
`
`invention relates to novel steroid nitrite
`
`10
`
`ester derivatives, and to their use treating inflammatory
`
`diseases.
`
`nel§_te_cLar‘.t
`
`15
`
`Steroids, specifically of the glucocorticoid class of
`
`molecules, are known to possess anti—inflammatory and
`
`immunomodulatory activities and are commonly utilized for
`
`the treatment of numerous autoimmune and inflammatory
`
`diseases. However,
`
`their beneficial effects are often slow
`
`20
`
`to develop and accompanied by many dose—limiting side-
`
`effects. Nitric oxide donors, such as nitroglycerin, have
`
`also been utilized as pharmaceutical agents with prominent
`
`beneficial effects on the cardiovascular system. Many of
`
`the biological actions of nitric oxide potentially
`
`25
`
`counteract
`
`the side—effects of the glucocorticoids and may
`
`enhance their therapeutic actions.
`
`The present
`
`invention
`
`relates to novel steroid nitrite ester derivatives that
`
`possess the combined biological properties of
`
`glucocorticoids and nitric oxide donors in a single
`
`30 molecule.
`
`These molecules have an advantage over currently
`
`utilized glucocorticoids in that they rapidly elicit
`
`beneficial pharmacological effects,
`
`such as bronchial
`
`relaxation,
`
`through the release of nitric oxide.
`
`It is
`
`intended that these novel molecules be utilized for
`
`35
`
`therapy,
`
`in particular their use as anti—inflammatory and
`
`immunosuppressive drugs for the treatment of rheumatic
`
`diseases,
`
`immunological disorders, skin disorders,
`
`inflammation,
`
`transplant rejection, cancer, osteoporosis,
`
`rhinitis and asthma with lowered side—effects.
`
`40
`
`MED_DYM_00004330
`
`

`
`Case 1:14-cv-01453-LPS Document 43-15 Filed 10/22/15 Page 5 of 123 PageID #: 1062
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`
`WO 97/21724
`
`PCT/US96/19220
`
`2
`
`Glucocorticoids are commonly utilized for the
`
`pharmacologic treatment of inflammation and undesirable
`
`immune system reactions.
`
`These steroids have the capacity
`
`to prevent or suppress the development of inflammation
`
`5
`
`resulting from a number of different injurious agents
`
`including infectious,
`
`immunological, chemical, mechanical,
`
`and radiation. Glucocorticoids are also effective in the
`
`treatment of immune system disorders including autoimmune
`
`diseases such as rheumatoid arthritis and lupus, and
`
`10
`
`transplant rejection. However,
`
`the therapeutic
`
`applications of these steroids are somewhat limited due to
`
`toxicity and side—effects.
`
`The major side effects of
`
`the
`
`glucocorticoids are hypertension, peptic ulcers,
`
`increased
`
`susceptibility to infections, osteoporosis, hyperglycemia,
`and vascular occlusion.
`
`15
`
`It has been known since the early 1980's that the
`
`vascular relaxation brought about by acetylcholine is
`
`dependent on the presence of the endothelium and this
`
`20
`
`activity was ascribed to a labile humoral factor termed
`
`endothelium—derived relaxing factor (EDRF).
`
`The activity
`
`of nitric oxide (NO) as a vasodilator has been known for
`
`well over 100 years and NO is the active component of
`
`amylnitrite ester, glyceryltrinitrate and other
`
`25
`
`nitrovasodilators.
`
`The recent identification of EDRF as NO
`
`has coincided with the discovery of a biochemical pathway
`
`by which NO is synthesized from the amino acid L—arginine
`
`by the enzyme nitric oxide synthase. The NO released by the
`
`constitutive enzyme acts as a transduction mechanism
`
`30
`
`underlying several physiological responses.
`
`The NO
`
`produced by the inducible enzyme is a cytotoxic molecule
`
`for tumor cells and invading microorganisms.
`
`NO is the endogenous stimulator of
`
`the soluble
`
`35
`
`guanylate cyclase and is involved in a number of biological
`
`actions in addition to endothelium—dependent relaxation
`
`including cytotoxicity of phagocytic cells and cell—to~cell
`
`communication in the central nervous
`
`system (see Mongada
`
`et al, Bigghemigal Eharmacolggyy 38, 1709-1715 (1989) and
`
`MED_DYM_00004331
`
`

`
`Case 1:14-cv-01453-LPS Document 43-15 Filed 10/22/15 Page 6 of 123 PageID #: 1063
`Case 1:14—cv—01453—LPS Document 43-15 Filed 10/22/15 Page 6 of 123 Page|D #: 1063
`
`WO 97/21724
`
`PCT/US96/19220
`
`3
`
`Monc
`
`- et
`
`1
`
`Pharm
`
`1o ical
`
`'
`
`4
`
`, 109-142 (1991).
`
`Furthermore, NO has been shown to possess anti—thrombotic
`
`(see Mgngada et a1, Qggrnal gf Qardigvasgular Pharmacglogy
`
`17, S25 (1991), B rne e al. Worl Patent
`
`1i ation
`
`5 WO94Q342l—A2 and Schonafinger et a1., German Patent
`
`application DE4223800—A1 ), bronchorelaxant
`
`(Persson et al.
`
`European ggnrnal of Pharmagglogy, 249, R7—R8
`
`(1993), anti
`
`inflammatory, microbialcidal
`
`(Alspaugh and Granger
`
`Infection and Immunity 59, 2291-2296 (1991) and
`
`10
`
`gastroprotective (see Wallace et a1, Eurgpean Journal of
`
`Ph rm
`
`1
`
`2 7, 249~255 (1994) effects in animal models.
`
`In addition, nitric oxide has been suggested to be
`
`effective against the loss of bone in in Vitro models of
`
`osteoporosis (Maclntyre et al, Proc,Natl,Acad.Sci.USA 88,
`
`15
`
`2936-2940 (1991) and in inhibiting angiogenesis,
`
`tumour
`
`growth and metastasis in in vivo animal models
`
`(Pipili—
`
`Synetgs et al, British Jgurnal of Eharmagglogy, 116,
`
`1829—
`
`1834 (1995).
`
`In United States Patents 3,930,970, 3,298,941
`
`and 3,215,713, a novel photochemical process for the
`
`20
`
`preparation of diol mononitrates from alcohol nitrites
`
`is
`
`disclosed.
`
`In United States Patents 3,639,434, 3,743,741
`
`and 3,839,369,
`
`the preparation of steroid nitrate esters
`
`and their uses as intermediates is disclosed.
`
`In German
`
`Patent 1643034,
`
`a method for the preparation of steroid
`
`25
`
`nitrate esters is disclosed.
`
`In Canadian Patent 975755 and
`
`969927, a process for the preparation and acidolysis of
`
`nitrate esters of 21—a1coho1s of the pregnane series is
`
`disclosed, respectively.
`
`In British Patent 1,082,573 and
`
`1,082,574, a process for the preparation of steroid—11—
`
`30
`
`nitrate esters and their uses as intermediates is disclosed
`
`Thus,
`
`these properties make nitric oxide an ideal
`
`agent to enhance the actions of corticosteroids in the
`
`treatment of various diseases mentioned earlier by both
`
`35
`
`increasing their biological effects as well as by reducing
`
`their side effects.
`
`The present
`
`invention relates to novel
`
`nitrite ester esters of steroids, processes for their
`
`preparation, pharmaceutical compositions containing them,
`and methods for their use.
`
`MED_DYM_00004332
`
`

`
`Case 1:14-cv-01453-LPS Document 43-15 Filed 10/22/15 Page 7 of 123 PageID #: 1064
`Case 1:14—cv—O1453—LPS Document 43-15 Filed 10/22/15 Page 7 of 123 Page|D #: 1064
`
`EXHIBIT 47
`
`EXHIBIT 47
`
`
`
`

`
`Case 1:14-cv-01453-LPS Document 43-15 Filed 10/22/15 Page 8 of 123 PageID #: 1065
`Case 1:14—cv—O1453—LPS Document 43-15 Filed 10/22/15 Page 8 of 123 Page|D #: 1065
`
`INTERNATIONAL SEARCH REPORT
`.<>rmauon on paucnt lamxly members
`
`lntcm' Nnal Appllcauon No
`
`PC]/US 96/19220
`
`Patent document
`cited in search report
`
`DE 2222491
`
`A
`
`
`
`Pubiicauun
`date
`
`16-11-72
`
`
`
`
`Patent family
`mt.-mber(s)
`
`AT
`AT
`AU
`AU
`CA
`FR
`NL
`SE
`
`316767 A,B
`331428 A,B
`469581 B
`4172272 A
`975755 A
`2143664 A
`7206134 A
`385590 B
`7503290 A
`
`
`
`Publication
`date
`
`15-06-74
`25-08-76
`19-02-76
`08-11-73
`07-10-75
`09-02-73
`09-11-72
`12-07-76
`
`
`
`
`Farm PCT/lSA,I2lll (paunv. 1'ami|y u-max) (July 1992)
`
`MED_DYM_00004369
`
`

`
`Case 1:14-cv-01453-LPS Document 43-15 Filed 10/22/15 Page 9 of 123 PageID #: 1066
`Case 1:14—cv—O1453—LPS Document 43-15 Filed 10/22/15 Page 9 of 123 Page|D #: 1066
`
`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property
`Organization
`International Bureau
`
`(43) International Publication Date
`12 February 2004 (12.02.2004)
`
` (10) International Publication Number
`
`WO 2004/013156 A1
`
`(51) International Patent Classification7:
`A61K 31/58, A6 1P 11/00
`
`C07,] 33/00,
`
`MUTZ, Michael
`Freiburg (DE).
`
`[DE/DE]; Mozaitstrasse 33, 79104
`
`(21) International Application Number:
`PCT/EP2003/0083 14
`
`(74) Agent: GRUBB, Philip; Novartis AG, Corporate Intellec-
`tual Property, CH—4002 Basel (CH).
`
`(22) International Filing Date:
`
`28 July 2003 (28.07.2003)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`(30) Priority Data:
`0217504.0
`
`English
`
`English
`
`29 July 2002 (29.07.2002)
`
`GB
`
`(71) Applicant (for all designated States except A7} US): NO-
`VARTIS AG [CH/CH]; Lichtstrasse 35, CH—4056 Basel
`(CH).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK,
`LT, LU, LV, MA, MD, MK, MN, MX, NI, NO, NZ, OM,
`PG, PH, PL, PT, RO, RU, SC, SE, SG, SK, SY, TJ, TM,
`TN, TR, TT, UA, US, UZ, VC, VN, YU, ZA, ZW.
`
`(84) Designated States (regional): Eurasian patent (AM, AZ,
`BY, KG, KZ, MD, RU, TJ, TM), European patent (AT, BE,
`BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU,
`IE, IT, LU, MC, NL, PT, RO, SE, SI, SK, TR).
`
`(71) Applicant (forAT only): NOVARTIS PHARMA GMBH
`[AT/AT]; Brunner Strasse 59, A—1230 Vienna (AT).
`
`Published:
`
`with international search report
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): JORDINE, Guido
`[DE/DE]; Lehener Strasse 148, 79106 Freiburg (DE).
`
`For two—letter codes and other abbreviations, refer to the ”Guid—
`ance Notes on Codes andAbbreviations” appearing at the begin-
`ning of each regular issue of the PCT Gazette.
`
`(54) Title:
`POLYMORPIHS OF A KNOWN TPHOPHENECARBOXYLIC ACID DODECAHYDROCYCLOPENTA (A)
`PHENANTHRENYL ESTER
`
`(57) Abstract: Polymorphic crystal forms of 3—methylthiophene—2—carhoxylic acid (6S,9R,10S,11S,13S,16R,17R)—9—chloro—6—flu—
`oro—11—hydroxy—l7—methoxycarbonyl—10,13,16—trimethyl—3—oxo—6,7,8,9,10,1 1,12,13,14, 15,16,17—dodecahydro—3H—cy—
`clopenta[a]phenanthren—l7—yl ester. The crystal forms possess anti—inflammatory activity and have very good stability. Methods
`for preparing the crystal forms are also described.
`
`MED_DYM_00004370
`
`
`
`WO2004/013156A1||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||1
`
`

`
`Case 1:14-cv-01453-LPS Document 43-15 Filed 10/22/15 Page 10 of 123 PageID #: 1067
`Case 1:14—cv—O1453—LPS Document 43-15 Filed 10/22/15 Page 10 of 123 Page|D #: 1067
`
`WO 2004/013156
`
`PCT/EP2003/008314
`
`POLYMORPHIS OF A KNOWN THIOPHENECARBOXYLIC ACID DODECAHYDROCYCLOPENTA (A)
`PHENANTHRENYL ESTER
`
`This invention relates to new polymorphic crystal forms of a compound of formula I and
`
`methods for preparing them.
`
`
`
`The compound of formula I, namely 3-methylthiophene-2-carboxylic acid (6S,9R,1OS,11S,
`
`1 3S,1 6R,1 7R)—9-chloro-6-fluoro—1 1 -hydroxy-17-methoxycarbonyl-10, 1 3,1 6-trimethyl—3-oxo-
`
`6,7,8,9,10,1 1,12,13,14,15,16,17—dodecahydro—3H—cyclopenta [a]phenanthren—17—yl ester,
`
`possesses a high anti—inflammatory activity. This activity can be demonstrated by its
`
`inhibition of TNF-alpha synthesis and release in a human macrophage cell line and by its
`
`inhibition of inflammatory conditions, particularly in the airways, e.g. inhibition of eosinophil
`
`activation, in animal models, e.g. mouse or rat models of airways inflammation, for example
`
`as described by Szarka et al, J. Immunol. Methods (1997) 202:49-5 7; Renzi et al, Am. Rev.
`
`Respir. Dis. (1993) 148:932—939; Tsuyuki et al., J. Clin. Invest. (1995) 96:2924-2931; and
`
`Cernadas et al (1999) Am. J. Respir. Cell Mol. Biol. 20:1-8.
`
`_ This compoundhas been investigated for use as a pharmaceutical. The existence of Various
`
`crystallisation polymorphic forms of the compound has been explored in order to determine
`
`the most appropriate form of the compound for the proposed use.
`
`Novel crystal forms of the compound of formula I have now been isolated. Some of these
`
`novel crystal forms have very good stability, facilitating their use in the preparation of
`
`pharmaceutical dosage forms.
`
`MED_DYM_00004371
`
`

`
`Case 1:14-cv-01453-LPS Document 43-15 Filed 10/22/15 Page 11 of 123 PageID #: 1068
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`
`WO 2004/013156
`
`PCT/EP2003/008314
`
`Accordingly, the present invention provides in one aspect a compound of formula I
`
`
`
`in a crystal form A that has a melting point, by Differential Scanning Calorimetry, of about
`
`264°C with simultaneous decomposition, at a heating rate of 20° C/min and the following
`
`characteristic diffraction lines (29 in angular degrees : O.2°) in the X-ray diffraction pattern
`
`thereof: 3.6°, 7.3°, 13.4°, 14.6°, 18.3°, 22.0°, 25.3°, 25.9°, Z9.5°; or
`
`in a crystal form B that has a melting point, by Differential Scanning Calorimetry, of about
`
`270°C withsimultaneous decomposition, at a heating rate of 20° C/min and the following
`
`characteristic diffraction lines (29 in angular degrees : 0.2°) in the X—ray diffraction pattern
`
`thereof: 7.2°, 9.3°, 12.0°, 12.8°,13.1°, 14.5°, 17.4-°, 20.4-°, 23.2° and 25.8°.
`
`Crystal form A may be prepared by crystallising the compound of formula I from a solution
`
`thereof in an organic solvent such as isopropanol, ethyl acetate, n—butanol, hexane, heptane,
`
`tert—butylmethylether, toluene or tetrahydrofuran, for example by equilibrating the compound
`
`in that solvent over 24 hours at 25° C, or analogously such as hereinafter described in
`
`Example 1. The crystallisation may be induced by, for example, cooling a supersaturated
`
`solution of the compound of formula I in the solvent, or by adding to the solution of the
`
`compound of formula I a solvent in which the compound of formula I is less soluble. The
`
`starting solution of the compound of formula I may be at ambient or elevated (up to reflux)
`
`temperature.
`
`Crystal form B may be prepared by crystallising the compound of formula I from a solution
`
`thereof in a polar organic solvent such as ethanol, methanol or methylene chloride, for
`
`example by equilibrating the compound in that solvent over 24 hours at 25° C, or analogously
`
`such as hereinafter described in Example 2. The crystallisation may be induced by, for
`
`example, cooling at supersaturated solution of the compound of formula I in the polar solvent,
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`or by adding to the solution of the compound of formula I a polar solvent in which the
`
`compound of formula I is less soluble. The starting solution of the compound of formula I
`
`may be at ambient or elevated (up to reflux) temperature.
`
`For the preparation of each of the crystal forms, Working up may be carried out generally
`
`using known procedures for the separation of the crystallisate from the mother liquor, for
`
`example by filtration, with or without the assistance of pressure and/or vacuum, or by
`
`centrifugation, and subsequent drying of the crystallisate.
`
`In the presence of ethanol crystal form A converts to crystal form B. In the presence of
`
`isopropanol crystal form B converts to crystal form A.
`
`The crystal forms can be distinguished in particular by their X-ray powder diagrams. X-ray
`diagrams taken With a diffractometer and using Cu-KOL1-radiation are preferably used to
`
`characterise solids of organic compounds. X-ray powder diffraction diagrams are particularly
`
`useful to determine the crystal form or modification of the compound of formula I. The use of
`
`such diagrams is described in the accompanying Examples.
`
`Crystal form A appears to be more thermodynamically stable than crystal form B in the solid
`
`state. However, in suspension with solvents the stability is solvent dependent.
`
`The compound of formula I may be prepared in accordance with the method given in Example
`
`26 of international patent application W0 O2/00679.
`
`Given its anti-inflammatory activity, the compound of formula I in crystal form A or B is
`
`useful in the treatment of inflammatory conditions, particularly inflammatory or obstructive
`
`airways diseases. Treatment in accordance With the invention may be symptomatic or
`
`prophylactic.
`
`Inflammatory or obstructive airways diseases to which the present invention is applicable
`
`include asthma of whatever type or genesis including both intrinsic (non—allergic) asthma and
`
`extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitic asthma,
`
`exercise-induced asthma, occupational asthma and asthma induced following bacterial
`
`infection. Treatment of asthma is also to be understood as embracing treatment of subjects,
`
`e.g. of less than 4 or 5 years of age, exhibiting wheezing symptoms and diagnosed or
`
`diagnosable as “wheezy infants”, an established patient category of major medical concern
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`4
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`and now often identified as incipient or early-phase asthmatics. (For convenience this
`
`particular asthmatic condition is referred to as “wheezy-infant syndrome”.)
`
`Prophylactic efficacy in the treatment of asthma will be evidenced by reduced frequency or
`
`severity of symptomatic attack, e.g. of acute asthmatic or bronchoconstrictor attack,
`
`improvement in lung function or improved airways hyperreactivity. It may further be
`
`evidenced by reduced requirement for other, symptomatic therapy, i.e. therapy for or intended
`
`to restrict or abort symptomatic attack when it occurs, for example anti—inflammatory (e.g.
`
`corticosteroid) or bronchodilatory. Prophylactic benefit in asthma may in particular be
`
`apparent in subjects prone to “morning dipping”. “Morning dipping” is a recognised
`
`asthmatic syndrome, common to a substantial percentage of asthmatics and characterised by
`
`asthma attack, e.g. between the hours of about 4 to 6 am, i.e. at a time normally substantially
`
`distant from any previously administered symptomatic asthma therapy.
`
`Other inflammatory or obstructive airways diseases and conditions to which the present
`
`invention is applicable include acute lung injury (ALI), adult respiratory distress syndrome
`
`(ARDS), chronic obstructive pulmonary, airways or lung disease (COPD, COAD or COLD),
`
`including chronic bronchitis or dyspnea associated therewith, emphysema, as well as
`
`exacerbation of airways hyperreactivity consequent to other drug therapy, in particular other
`
`inhaled drug therapy. The invention is also applicable to the treatment of bronchitis of
`
`whatever type or genesis including, e.g., acute, arachidic, catarrhal, croupus, chronic or
`
`phthinoid bronchitis. Further inflammatory or obstructive airways diseases to which the
`
`present invention is applicable include pneumoconiosis (an inflammatory, commonly
`
`occupational, disease of the lungs, frequently accompanied by airways obstruction, whether
`
`chronic or acute, and occasioned by repeated inhalation of dusts) of whatever type or genesis,
`
`including, for example, aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis,
`
`silicosis, tabacosis and byssinosis.
`
`Having regard to its anti-inflammatory activity, in particular in relation to inhibition of
`eosinophil activation, the compound of formula I in crystal form A or B is also useful in the
`
`treatment of eosinophil related disorders, e.g. eosinophilia, in particular eosinophil related
`
`disorders of the airways (e.g. involving morbid eosinophilic infiltration of pulmonary tissues)
`
`including hypereosinophilia as it effects the airways and/or lungs as well as, for example,
`
`eosinophil-related disorders of the airways consequential or concomitant to L6ffler’s
`
`syndrome, eosinophilic pneumonia, parasitic (in particular metazoan) infestation (including
`
`tropical eosinophilia), bronchopulmonary aspergillosis, polyarteritis nodosa (including Churg-
`
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`Strauss syndrome), eosinophilic granuloma and eosinophil-related disorders affecting the
`
`airways occasioned by drug-reaction.
`
`The compound of formula I in crystal form A or B is also useful in the treatment of
`
`inflammatory conditions of the skin, for example psoriasis, contact dermatitis, atopic
`
`dermatitis, alopecia areata, erythema multiforma, dermatitis herpetiformis, scleroderma,
`
`vitiligo, hypersensitivity angiitis, urticaria, bullous pemphigoid, lupus erythematosus,
`
`pemphisus, epidermolysis bullosa acquisita, and other inflammatory conditions of the skin.
`The compound of formula I in crystal form A or B may also be used for the treatment of other
`
`diseases or conditions, in particular diseases or conditions having an inflammatory
`
`component, for example, treatment of diseases and conditions of the eye such as
`
`conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose
`
`including allergic rhinitis, diseases of the joints such as rheumatoid arthritis and inflammatory
`
`bowel disease such as ulcerative colitis and Crohn’s disease.
`
`The compound of formula I in crystal form A or B is also useful as a co-therapeutic agent for
`
`use in conjunction with other drug substances for treatment of airways diseases, particularly
`
`bronchodilatory or anti-inflammatory drug substances, particularly in the treatment of
`
`obstructive or inflammatory airways diseases such as those mentioned hereinbefore, for
`
`example as potentiators of therapeutic activity of such drugs or as a means of reducing
`
`required dosaging or potential side effects of such drugs. The compound of formula I in
`
`crystal form A or B may be mixed with the other drug in a fixed pharmaceutical composition
`
`or it may be administered separately, before, simultaneously with or after the other drug.
`
`Such anti—inflammatory drugs include steroids, in particular glucocorticosteroicls such as
`
`budesonide, beclamethasone dipropionate, fluticasone propionate, ciclesonide or mometasone
`
`furoate and compounds described in WC 0200679, WO 0288167, WO 0212266 and WO
`
`02100879; LTB4 antagonists such as those described in US 5451700; LTB4 antagonists such
`
`as those described in US 5451700; LTD4 antagonists such as montelukast and zafirlukast;
`
`dopamine receptor agonists such as cabergoline, bromocriptine, ropinirole and 4—hydroxy-7-
`
`[2—[[2—[[3—(2-phenylethoxy)-propyl]sulfonyl]ethyl]amino]ethyl]-2(3H)—benzothiazolone and
`
`pharmaceutically acceptable salts thereof (the hydrochloride being Viozan® ~ Astrazeneca);
`
`PDE4 inhibitors such as Ariflo® (GlaxoSmith Kline), Roflumilast (Byk Gulden),V—11294A
`
`(Napp), BAY19—8004 (Bayer), SCH-351591 (Schering—Plough), Arofylline (Almirall
`
`Prodesfarma), PD189659 (Parke-Davis), AWD-12-281 (Asta Medica), CDC—801 (Celgene)
`
`and KW-4490 (Kyowa Hakko Kogyo); A2a agonists such as those described in EP 1052264,
`
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`6
`
`EP 1241176, WO 0023457, WO0077018, W0 0123399, WO 0160835, WO 0194368, WO
`
`0200676, W0 0222630, W0 0296462, WO 0127130, W0 0127131, W0 9602543, W0
`
`9602553, WO 9828319, WO 9924449, WO 9924450, WO 9924451, WO 9938877, WO
`
`9941267, WO 9967263, WO 9967264, WO 9967265, WO 9967266, WO 9417090, EP
`
`409595A2 and W0 0078774; and A2b antagonists such as those described in W0 O2/42298.
`
`Such bronchodilatory drugs include anticholinergic or antimuscarinic agents, such as those
`
`described in El’ 424021, US 5171744 (Pfizer) and W0 01/04118 (Almirall Prodesfarma) and
`
`but in particular ipratropium bromide, oxitropium bromide and tiotropium bromide, and
`
`beta-2 adrenoceptor agonists such as salbutamol, terbutaline, salmeterol and, especially,
`
`formoterol and pharmaceutically acceptable salts thereof, and compounds (in free or salt or
`
`solvate form) of formula I of PCT International Publication No. W0 O0/75114, which
`document is incorporated herein by reference, preferably compounds of the Examples thereof,
`especially a compound of formula
`
`HO
`
`I
`
`CH,
`
`CH,
`
`in free or pharmaceutically acceptable salt or solvate form.
`
`H
`
`fan
`
`Combinations of the compound of formula I in crystal form A or B and beta—2 agonists, PDE4
`
`inhibitors or LTD4 antagonists may be used, for example, in the treatment of COPD or,
`
`particularly, asthma.
`
`Combinations of the compound of formula I in crystal form A or B and anticholinergic or
`
`antimuscarinic agents, PDE4 inhibitors, LTB4 antagonists may be used, for example, in the
`
`treatment of asthma or, particularly, COPD.
`
`In accordance with the foregoing, the invention also provides a method for the treatment of an
`
`inflammatory condition, particularly an inflammatory or obstructive airways disease, which
`
`comprises administering to a subject, particularly a human subject, in need thereof an effective
`
`amount of the compound of formula I in crystal form A or B as hereinbefore described. In
`
`another aspect the invention provides the use of the compound of formula I in crystal form A
`
`or B for the manufacture of a medicament for the treatment of an inflammatory condition,
`
`particularly an inflammatory or obstructive airways disease.
`
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`EXHIBIT 48
`
`EXHIBIT 48
`
`
`
`

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`(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`
`
`(43) International Publication Date
`20 February 2003 (20.02.2003)
`
`(10) International Publication Number
`
`PCT
`
`W0 03/013427 A2
`
`(51) International Patent Classificationlz
`
`A6lK
`
`(21) International Application Number:
`
`PCT/US02/24586
`
`(22) International Filing Date:
`
`1 August 2002 (01.08.2002)
`
`(25) Filing Language:
`
`(26) Publication Language:
`
`English
`
`English
`
`(30) Priority Data:
`60/367,341
`
`3 August 2001 (03.08.2001)
`
`US
`
`except US:
`(for all designated States
`(71) Applicant
`SMITHKLINE
`BEECHAM
`CORPORATION
`
`[US/US]; One Franklin Plaza, Philadelphia, PA 19101
`(US).
`
`(74) Agents: LEVY, David, J. et al.; GlaxoSmithKline, Corpo-
`rate Intellectual Property Department, Five Moore Drive,
`PO Box 13398, Research Triangle Park, NC 27709 (US).
`
`(81) Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EC, EE, ES, FI, GB, GD, GE, GH,
`GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC,
`LK, LR, LS, LT, LU, LV, MA, MD, MG, MK, MN, MW,
`MX, MZ, NO, NZ, OM, PH, PL, PT, RO, RU, SD, SE, SG,
`SI, SK, SL, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ,
`VN, YU, ZA, ZM, ZW.
`
`(84) Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZM, ZW),
`Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
`European patent (AT, BE, BG, CH, CY, CZ, DE, DK, EE,
`ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE, SK,
`TR), OAPI patent (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
`GW, ML, MR, NE, SN, TD, TG).
`
`(72) Inventors; and
`PARTRIDGE,
`(75) Inventors/Applicants aor US only):
`John, Joseph [US/US]; GlaxoSmithKline, Five Moore
`Drive, PO Box 13398, Research Triangle Park, NC 27709
`(US). WALKER, Dwight, Sherod [US/US]; Glaxo-
`SmithKline, Five Moore Drive, PO Box 13398, Research
`Triangle Park, NC 27709 (US).
`
`Published:
`
`without international search report and to be republished
`upon receipt of that report
`
`For two—letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations " appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`(54) Title: A METHOD FOR PREPARING FLUTICASONE DERIVATIVES
`
`
`
`Thioacid Furoate
`
`6c1,9a-difluoro-17c1-[(2-furanylcarbony|)oxy}- 11[3-hydroxy-
`16oc-methyI-3-oxoandrosta-1,4,—diene-17$-carboth ioic acid
`
`6a,9oL-d ifIuoro-170:-[(2-furanylca rbonyl)oxy]-1113-hyd roxy- 16a-methyl-
`3-oxoa ndrosta-1.4-diene-17[3-carbothioic acid S-fluoromethyl ester
`
`(57) Abstract:
`1706- [(2— furanylcarbonyl)oxy] -1 1B—hydroXy—160c—methyl—3 —0Xoan—
`A method for preparing 60c,90c—difluoro—
`drosta—1,4—diene—17B—carbothioicacid S—fluoromethyl ester from a thiocarboxylic acid by reacting the thiocarboxylic acid with a
`solution containing chlorofluoromethane and a mild base medium at a temperature in the range of —60° C to 90° C.