WO 98/07697
`
`PCT/1B97/00924
`
`-45-
`
`comprising an amount of a compound of claim 1 effective in such treatment and a
`
`pharmaceutically acceptable carrier.
`
`9.
`
`A method for the inhibition of (a) matrix metalloproteinases or (b) the
`
`production of tumor necrosis factor (TNF)
`
`in a mammal,
`
`including a human,
`
`5
`
`comprising administering to said mammal an effective amount of a compoundof claim
`
`1.
`
`10.
`
`A method for treating a condition selected from the group consisting of
`
`arthritis, cancer,
`
`tissue ulceration, macular degeneration,
`
`restenosis, periodontal
`
`disease, epidermolysis bullosa, scleritis, compounds of formula I may be used in
`
`10
`
`combination with standard NSAID’S and analgesics and in combination with cytotoxic
`
`anticancer agents, and other diseases characterized by matrix metalloproteinase activity,
`
`AIDS, sepsis, septic shock and other diseases involving the production of tumor
`
`necrosis factor (TNF) in a mammal, including a human, comprising administering to
`
`said mammal an amount of a compound of claim 1, effective in treating such a
`
`15
`
`condition.
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1601
`
`page 1601
`
`

`

`
`INTERNATIONAL SEARCH REPORT
`Inten.
`snal Application No
`
`
`
`PCT/IB 97/00924
`
`
` . CLASSIFICATION OF SUBJECT M
`
`CO7D211/62
` CO7D295/18
` C07D211/34
`PC'6
`CO7D211/58
` CO7D211/46
`
`CO7C311/29
`A61K31/445
`AG1K31/495
`AG1K31/18
`
`
`
`
`
`
` According to International Patent Classification (IPC) or to both national classification and IPC
`
`
`
`A ]
`
`B. FIELDS SEARCHED
`
`Minimum documentation searched (classification system followed by classification symbols)
`IPC 6
`CO7D
`CO7C A61K
`
`
`
`Documentation searched other than minimum documentation to the extent that such documents ara included in the fields searched
`
`
`
`Electronic data base consulted during the intemational search (name of data base and, where practical, search terms used)
`
`
`
`C. DOCUMENTS CONSIDEREDTO BE RELEVANT
`
`Citation of dooument, with indication, where appropriate, of the relevant passages
`
`Y
`
`Y
`
`Y¥
`
`PX
`
`WO 96 00214 A (CIBA-GEIGY AG) 4 January
`1996
`see claims
`
`EP © 606 046 A (CIBA-GEIGY AG) 13 July
`1994
`see claims
`
`WO 96 27583 A (PFIZER INC.) 12 September
`1996
`see the whole document
`
`Patent family members arelisted in annex.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`WO 95 35275 A (BRITISH BIOTECH
`PHARMACEUTICALS LIMITED) 28 December 1995
`see claims
`
`
` ° Spaciai categories ofcited documents :
`
`
`
` [| Further documents are listed in the continuation of box C.
`
`7
`;
`;
`-
`°F" later document published after the internationalfiling date
`or priority date and notin conflict with the application but
`cited to understandthe principle or theory underlying the
`invention
`*X* documentof particutar relevance; the claimed invention
`cannot be considered novel or cannot be considered to
`involve an inventive step when the documentis taken alone
`*V* documentof
`-
`.
`;
`i
`i
`Particular relevance; the claimed invantion
`cannot be considered to involve an inventive step when the
`document is combined with one or more other such docu-
`ments, such combination being obvious to a person skilled
`in the art.
`*&* document memberof the same patent family
`
`Date af mailing of the international search report
`23, 10.97
`
`ope
`oe
`we
`A documentefiningoegeneral stateotihe art whichis not
`"E* earlier document but published on or after the intemational
`filing cate
`*L* document which may throw doubts on priority claim(s) or
`which is cited to eatablish the publication date of another
`itati
`;
`+
`citation or other special reason (as specified)
`“O° doosumentreferring to an oral disclosure, use, exhibition or
`other means
`“P* document published priorto the internationalfiling date but
`later than the priority date claimed
`
`Date of the actual campletion of the international search
`
`
`14 October 1997
`
` Authorized officer
`Name and mailing address of the ISA
`European Patent Office, P.B. 5818 Patentiaan 2
`
`NL - 2280 HV Rijswiik
`
`
`
`Tel. (+31-70) 340-2040, Tx. 31651 epo ni,
`
`
`
`Chouly,
`Jd
`Fax: (+31-70) 340-3016
`
`
`Form PCT/SA/210 (second sheet} (July 1992)
`
`AQUESTIVE EXHIBIT 1007
`
`page 1602
`
`AQUESTIVE EXHIBIT 1007 page 1602
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`In.
`
`.1ational application No.
`PCT/IB 97/00924
`
`Box! Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
`
`1.
`
`
`
`
`
`
`
`This international Search Report has not been established in respect of certain claims underArticle 17(2)(a) for the following reasons:
`
`Claims Nos.:
`
`because they relate to subject matter not required to be searched bythis Authority, namely:
`see FURTHER INFORMATION sheet PCT/ISA/210
`
`2.
`
`Claims Nos.:
`becausetheyrelate 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:
`
`
`
`Box ll Observations where unity of invention is lacking (Continuation of item 2 of first sheet)
`
`3. [] Claims Nos.:
`
`because they are dependent claims and are not drafted in accordance with the second andthird sentences of Rule 6.4(a).
`
`
`
`This international Searching Authority found multiple inventions in this international application, as follows:
`
`
`
` Asall required additional search fees were timely paid by the applicant, this international Search Report covers ail
`
`searchable claims.
`
`
` As all searchable claims could be searched withouteffort justifying an additional fee, this Authority did not invite payment
`
`
` [| As only someof the required additional search fees were timely paid by the applicant, this International Search Report
`
`
`[| The additional search fees were accompanied by the applicant's protest.
`
`[_] No protest accompanied the paymentof additional search fees.
`AQUESTIVE EXHIBIT 1007 page 1603
`
`of any additional fee.
`
`covers only those claims for which fees were paid, specifically claims Nos. :
`
` 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 Nos.:
`
`Remark on Protest
`
`Form PCTASA/210 (continuation offirst sheet (1)) (July 1992)
`
`QUESTIVE EXHIBIT 1007
`
`page 1603
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`Intemational Application No. PCTIB 97 00924
`
`FURTHER INFORMATION CONTINUED FROM PCT/SA/
`
`2710
`
`This international search report has not been established in respect of
`certain claims under Article 17(2)(a) for the following reasons:
`
`Claims Nos.:
`sheet)
`
`claims 1-10 have been searched incompletely (see attached
`
`because they relate to subject matter not required to be searched by this
`Authority, namely:
`
`Remark : Although claims 9,10
`are directed to a method of treatment of
`the human/animal body ,
`the search has been carried out and based on the
`
`The claims encompasse such a large number and variety of compounds that a
`complete search is not possible on economic grounds (Guidelines for
`examination in the EPO, Part 8, Chapter III,3.7).Thus the search was
`directed powards (but not
`limited to) compounds having variables as
`represented in the examples.
`
`alleged effects of the compound/composition.
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1604
`
`page 1604
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`aval Application No
`
`PCT/IB 97/00924
`
`Patent document
`cited in search report
`
`Publication
`date
`
`wO 9600214
`
`A
`
`04-01-96
`
`EP 606046
`
`A
`
`5455258
`5265593
`2112779
`940012
`70536
`6256293
`9400276
`940038
`250517
`5506242
`5552419
`5646167
`5672615
`9400048
`
`Information on patent famity members intern
`
`Patent family
`member(s)
`
`5506242
`2536995
`2192092
`0766672
`965156
`965568
`5552419
`5646167
`5672615
`9505206
`
`2746595
`2746695
`2193691
`2193692
`0766664
`0766665
`965153
`9535276
`2303850
`2303629
`965515
`
`rPrPrrrrrrrr?r
`rPrrprrrrrprrYrrprp>r>r>Y
`
`Oo .
`
`Publication
`date
`
`09-04-96
`19-01-96
`04-01-96
`09-04-97
`20-12-96
`17-02-97
`03-09-96
`08-07-97
`30-09-97
`27-12-95
`
`07-07-94
`36-10-95
`13-09-94
`29-07-94
`07-07-94
`26-10-95
`09-04-96
`03-09-96
`08-07-97
`30-09-97
`11-08-94
`
`28-12-95
`28-12-95
`09-04-97
`09-04-97
`20-12-96
`28-12-95
`05-03-97
`26-02-97
`20-02-97
`
`Form PCTHSA/210 (patent tamily annex) (July 1992)
`
`AQUESTIVE EXHIBIT 1007
`
`page 1605
`
`AQUESTIVE EXHIBIT 1007 page 1605
`
`

`

`
`
`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`16 July 1998 (16.07.98)
`
`. INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification © :
`
`(11) International Publication Number:
`WO 98/30566
`C07D 493/08, A61K 31/34
`
`
` (43) International Publication Date:
` (21) International Application Number:
`
`
`
`PCT/IB97/01582|(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, 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, 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).
`
`(22) International Filing Date:
`
`18 December 1997 (18.12.97)
`
`(30) Priority Data:
`60/034,535
`
`6 January 1997 (06.01.97)
`
`US
`
`(71) Applicant (for all designated States except US): PFIZER INC.
`[US/US]; 235 East 42nd Street, New York, NY 10017 (US).
`
`
`
`
`
`
`
`(72) Inventors; and
`(75) Inventors/Applicants (for US only): BURGESS, Laurence, Ed-|Published
`ward [US/US]; 5617 Slick Rock Court, Boulder, CO 80301
`With international search report.
`(US). RIZZI, James, Patrick [US/US]; 7180 Longview
`Drive, Niwot, CO 80503 (US).
`
`
` (34) Title: CYCLIC SULFONE DERIVATIVES
`_$¢0>
`Ar
`H
`
`(74) Agents: SPIEGEL, Allen, J. et al.; Pfizer Inc., 235 East 42nd
`Street, New York, NY 10017 (US).
`
`(57) Abstract
`
`0
`
`HO
`
`A compound of formula (I), wherein n,
`X, Y and Ar are as defined herein, useful
`in
`the treatment of a condition selected from the
`group consisting of arthritis, cancer, tissue ul-
`ceration, macular degeneration, restenosis, pc-
`riodontal disease, epidermolysis bullosa, scle-
`ritis, and other diseases characterized by ma-
`trix metalloproteinase activity, AIDS, sepsis,
`septic shock and other diseases involving the
`production of TNF. In addition, the compounds of the present invention may be used in combination therapy with standard non-steroidal
`anti—inflammatory drugs (NSAID’S) andanalgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, cis—platinum,
`etoposide, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.
`
`x
`i|
`
`:
`
`Y
`
`(I)
`
`
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1606
`
`page 1606
`
`

`

`———
`
`
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`
`
`AL
`AM
`AT
`AU
`AZ
`BA
`BB
`
`BF
`BG
`BJ
`BR
`BY
`CA
`CF
`CG
`CH
`cl
`CM
`CN
`CU
`CZ
`DE
`DK
`EE
`
`Codes used to identify States party to the PCT on the front pages of pamphlcts publishing international applications under the PCT.
`Albania
`ES
`LS
`Lesotho
`SI
`Armenia
`FI
`LT
`Lithuania
`SK
`Austria
`FR
`LU
`SN
`Luxembourg
`Australia
`GA
`LV
`Latvia
`SZ
`GB
`MC
`Monaco
`TD
`Azerbaijan
`GE
`MD
`TG
`Bosnia and Herzegovina
`Republic of Moldova
`Barbados
`GH
`MG
`TJ
`Madagascar
`GN
`MK
`Belgium
`Ti
`The former Yugoslav
`Burkina Faso
`GR
`TR
`Republic of Macedonia
`HU
`Mali
`TT
`Bulgaria
`Benin
`TE
`UA
`Mongolia
`IL
`Brazil
`Mauritania
`UG
`IS
`Belarus
`Malawi
`US
`Canada
`IT
`Mexico
`UZ
`JP
`VN
`Central African Republic
`Niger
`KE
`Netherlands
`Congo
`YU
`Switzerland
`KG
`ZW
`Norway
`Céte d'Ivoire
`KP
`New Zealand
`Cameroon
`Poland
`China
`Portugal
`Cuba
`Romania
`Czech Republic
`Russian Federation
`Sudan
`Germany
`Denmark
`Sweden
`Estonia
`Singapore
`
`Spain
`Finland
`France
`Gabon
`United Kingdom
`Georgia
`Ghana
`Gninea
`Greece
`Hungary
`Treland
`Israel
`Iceland
`Italy
`Japan
`Kenya
`Kyrgyzstan
`Democratic People’s
`Republic of Korea
`Republic of Korea
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`Slovenia
`Slovakia
`Senegal
`Swaziland
`Chad
`Togo
`Tajikistan
`Turkmenistan
`Turkey
`Trinidad and Tobago
`Ukraine
`Uganda
`United States of America
`Uzbekistan
`Viet Nam
`Yugoslavia
`Zimbabwe
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`NO
`NZ
`PL
`PT
`RO
`RU
`SD
`SE
`8G
`
`
`
`AQUESTIVE
`
`EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1607
`
`page 1607
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`-1-
`
`
`CYCLIC SULFONE DERIVATIVES
`
`10
`
`15
`
`20
`
`25
`
`30
`
`Background of the Invention
`The present invention relates to cyclic sulfone derivatives which are inhibitors
`of matrix metalloproteinases or the production of tumor necrosis factor (TNF) and as
`such are useful in the treatment of a condition selected from the group consisting of
`arthritis, cancer,
`tissue ulceration, restenosis, periodontal disease, epidermolysis
`bullosa,scleritis and other diseases characterized by matrix metalloproteinaseactivity,
`AIDS, sepsis, septic shock and other diseases involving the production of TNF.
`In
`addition, the compoundsof the present invention may be used in combination therapy
`with standard non-steroidal anti-inflammatory drugs
`(hereinafter NSAID'S) and
`analgesics for the treatment of arthritis, and in combination with cytotoxic drugs such
`as adriamycin, daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such
`as vincristine, in the treatment of cancer.
`This invention also relates to a method of using such compounds in the
`treatment of
`the above diseases
`in mammals,
`especially humans, and to
`pharmaceutical compositions useful therefor.
`
`There are a number of enzymes which effect the breakdown of structural
`proteins and which are structurally related metalloproteases. Matrix-degrading
`metalloproteinases, such as gelatinase, stromelysin and collagenase, are involved in
`tissue matrix degradation (e.g. collagen collapse) and have been implicated in many
`pathological conditions involving abnormal connective tissue and basement membrane
`matrix metabolism, such asarthritis (e.g. osteoarthritis and rheumatoid arthritis), tissue
`ulceration (e.g. corneal, epidermal and gastric ulceration), abnormal wound healing,
`periodontal disease, bone disease (e.g. Paget's disease and osteoporosis), tumor
`metastasis or invasion, as weil as HIV-infection (J. Leuk. Biol., 52 (2): 244-248, 1992).
`Tumornecrosis factor is recognized to be involved in manyinfectious and auto-
`immune diseases (W. Fiers, FEBS Letters, 1991, 285, 199). Furthermore, it has been
`shownthat TNF is the prime mediator ofthe inflammatory response seenin sepsis and
`
`septic shock (C.E. Spooneret al., Clinical Immunology and Immunopathology, 1992,
`62 $11).
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1608
`
`page 1608
`
`

`

`WO 98/30566
`
`PCT/1B97/01582
`
`-2-
`
`The present invention relates to a compoundof the formula
`
`Summary of the Invention
`
`-
`
`$60)
`H
`N
`
`Ho
`
`oO:
`
`Y
`
`'
`
`0
`
`or a pharmaceutically acceptable salt thereof, wherein the broken line represents an
`optional double bond;
`
`10
`
`nis 0, 1 or 2;
`
`is hydrogen, (C,-C,)alkyl
`X and Y are each independently CR’ wherein R'
`optionally
`substituted
`by
`(C,-C,)alkylamino,
`(C,-C,)alkylthio,
`(C,-C,)alkoxy,
`trifluoromethyl, (C.-C, aryl, (C,-C,)heteroaryl, (C,-C,,)arylamino, (C,-C,,)arylthio, (C,-
`C,,)aryloxy, (C,;-C,)heteroarylamino, (C,-C,)heteroarylthio, (C,-C,)heteroaryloxy, (C,-
`C,.)aryl(C,-C,,)aryl,
`(C,-C,)cycloalkyl,
`hydroxy(C,-C,)alkyl,
`(C,-
`C,)alkyl(hydroxymethylene), piperazinyl, (C.-C, .)aryl(C,-C,)alkoxy,(C,,-C,)heteroaryl(C,-
`C,)alkoxy, (C,-C,)acylamino, (C,-C,)acylthio, (C,-C,)acyloxy, (C,-C,)alkylsulfinyl, (C,-
`C,)arylsulfinyl, (C,-C,)alkylsulfonyl, (C,-C,,)aryisulfonyil, amino, (C,-C,)alkylamino or
`((C,-C,)alkyl),amino;
`trifluoromethyl,
`(C,-C,)alkyl
`(difluoromethyiene),
`(C,C,)alkyl(difluoromethylene)(C,-C,)alkyl,
`(C,-C,,)aryl,
`(C,-C,)heteroaryl,
` (C,-
`C,)cycloalkyl,
`(C,-C,)alkyl-(hydroxymethylene), R°(C,-C,)alkyl wherein R® is
`(C,-
`C,)acylpiperazino,
`(C,-C,,)arylpiperazino,
`(C,-C,)heteroarylpiperazino,
` (C,-
`C,)alkylpiperazino,
`(C,-C,,)aryl(C,-C,)alkylpiperazino,
`(C,-C,)heteroaryl(C,-
`C,)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C,-
`C,)alkyipiperidyl,
`(C,-C,,)arylpiperidyl,
`(C,-C,)heteroarylpiperidy!,
`(C,-
`C,)alkyipiperidyl(C,-C,)alkyl,
`(C,-C,,)arylpiperidy!(C,-C,)alkyl,
`(C,-
`C,)heteroarylpiperidyl(C,-C,)alkyl or (C,-C,)acylpiperidyl;
`
`or a group of the formula
`
`15
`
`20
`
`25
`
`30
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1609
`
`page 1609
`
`

`

`WO98/30566
`
`PCT/1B97/01582
`
`10
`
`15
`
`20
`
`25
`
`30
`
`wherein r is 0 to 6;
`
`Dis hydroxy, (C,-C,)alkoxy, piperidyl, (C,-C,)alkylpiperidyl, (C,-C, o)arylpiperidyl,
`(C,-C,)heteroaryipiperidyl, (C,-C,)acylpiperidyl or NR*R® wherein R* and R® are each
`independently selected from the group consisting of hydrogen, (C,-C,)alkyl optionally
`substituted by (C,-C,)alkylpiperidyl, (C,-C,.)arylpiperidyl, (C,-C,)heteroarylpiperidyl, (C,-
`C, .)aryl, (C.-C,)heteroaryl, (C,-C,,)aryl(C,-C, .)aryl or (C,-C,)cycloalkyl; (C.-C, aryl, (C.-
`C,)heteroaryl,
`(C,-C,,)aryl(C,-C,,)aryl,
`(C,-C,)cycloalkyl,
`R°(C,-C,)alkyl,
`(C,-
`C,)alkyl(CHR®)(C,-C,)alkyl wherein R® is hydroxy,
`(C,-C,)acyloxy,
`(C,-C,)alkoxy,
`piperazino, (C,-C,)acylamino, (C,-C,)alkylthio, (C,-C,.)arylthio, (C,-C,)alkylsulfinyl, (C,-
`C, )aryisulfinyl, (C,-C,)alkylsulfoxyl, (C.-C, ,)arylsulfoxyl, amino, (C,-C,)alkylamino, ((C,-
`C,)alkyl),amino,
`(C,-C,)acylpiperazino,
`(C,-C,)alkylpiperazino,
`(C,-C,,)aryl(C,-
`C,)alkylpiperazino,(C,-C,)heteroaryl(C, -C,)alkylpiperazino,morpholino,thiomorpholino,
`piperidino or pyrrolidino; R’(C,-C,)alkyl, (C,-C,)alkyl(CHR’)(C,-C,)alkyl wherein R’is
`piperidyl or (C,-C,)alkyipiperidyl; and CH(R®)COR® wherein R® is hydrogen, (C,-C,)alkyl,
`(C.-C, .)aryl(C,-C,)alkyl, (C,-C,)heteroaryi(C,-C,)alkyl, (C,-C,)alkylthio(C,-C,)alkyl, (C,-
`C, ,)arylthio(C,-C,)alkyl, (C,-C,)alkylsulfinyi(C,-C,)alkyl, (C,-C,,)arylsulfinyl(C,-C,)alkyl,
`(C,-C,)aikylsulfonyl(C,-C,)alkyl,
`(C,-C,)arylsulfonyl(C,-C,)alkyl, hydroxy(C,-C,)alkyl,
`amino(C,-C,)alkyl,
`(C,-C,)alkylamino(C,-C,)alkyl,
`((C,-C,)alkylamino),(C,-C,)alkyl,
`R'°R™'NCO(C,-C,)alkyl or R'°OCO(C,-C,)alkyl wherein R'® and R"'
`are each
`independently selected from the group consisting of hydrogen,
`(C,-C,)alkyl,
`(C,-
`C, .)aryl(C,-C,)alkyl and (C,-C,)heteroaryl(C,-C,alkyl; and R° is R'7O or R'7R'2N wherein
`R'? and R'° are each independently selected from the group consisting of hydrogen,
`(C,-C,)alkyl, (C.-C, ,jaryl(C,-C,)alkyl and (C,-C,)heteroaryl(C,-C,)alkyl; and
`Ar
`is
`(C,-C,)alkyl,
`(C,-C,,)aryl,
`(C,-C,,)aryloxy(C,-C,,)aryl,
`(C,-C,,)aryl(C,-
`C,,)aryl,
`(C,-C,,)aryl(C,-C,,)aryl(C,-C,)alkyl,
`(C,-C,,)aryloxy(C,-C,)heteroary!,
`(C,-
`C,)heteroaryl,
`(C,-C,)alkyl(C,-C,,)aryl,
`(C,-C,)alkoxy(C,-C,,)aryl,
`(C,-C,,)aryl(C,-
`C,)alkoxy(C,-C, jaryl,
`(C,-C,,)aryl(C,-C,)alkoxy(C,-C,)alkyl,
`(C,-C,)heteroaryloxy(C,-
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1610
`
`page 1610
`
`

`

`WO98/30566
`
`PCT/IB97/01582
`
`4.
`
`C,,)aryl, (C,-C,)alkyl(C,-C,)heteroaryl, (C,-C,)alkoxy(C,-C,)heteroaryl, (C.-C, aryl(C,-
`C,)alkoxy(C,-C,)heteroaryl, (C,-C,)heteroaryloxy(C,-C,)heteroaryl, (C,-C, ,)aryloxy(C,-
`C,)alkyl, (C,-C,)heteroaryloxy(C,-C,)alkyl, (C,-C,)alkyl(C,-C, .aryloxy(C,-C,,.)aryl, (C,-
`C,)alkyl(C,-C,)heteroaryloxy(C,-C,,)aryl,
`(C,-C,)alkyl(C,-C, ,Jaryloxy(C,-C,)heteroaryi,
`(C,-C,)alkoxy(C,-C, ,)aryloxy(C,-C,,)aryl, (C,-C,)alkoxy(C,-C,)heteroaryloxy(C,-C,,)aryl
`or (C,-C,)alkoxy(C,-C,.)aryloxy(C,-C,)heteroary! wherein each aryl groupis optionally
`substitutedby fluoro, chloro, bromo,(C,-C,)alkyl, (C,-C,)alkoxy or perfiuoro(C,-C.)alkyl.
`The term "alkyl", as used herein, unless otherwise indicated, includes saturated
`monovalent hydrocarbon radicals having straight, branched or cyclic moieties or
`combinations thereof.
`
`The term “alkoxy”, as used herein, includes alkyl-O groups wherein "alkyl" is
`defined above.
`
`10
`
`15
`
`20
`
`25
`
`The term "aryl", as used herein, unless otherwise indicated, includes an organic
`radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as
`phenyl or naphthyl, optionally substituted by 1 to 3 substituents independently selected
`from the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, (C,-C,)alkoxy,
`(C,-C, .)aryloxy, trifluoromethoxy, difluoromethoxy and (C,-C,)alkyl.
`The term "heteroaryl", as used herein, unless otherwise indicated, includes an
`organic radical derived from an aromatic heterocyclic compound by removal of one
`hydrogen, suchas pyridyl, furyl, pyrroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl,
`tetrazolyl,
`pyrazinyl,
`pyrimidyl,
`quinolyl,
`isoquinolyl, benzofuryl,
`isobenzofuryi,
`benzothienyl, pyrazolyl,
`indolyl,
`isoindoly!l, purinyi, carbazolyl,
`isoxazolyl,
`thiazolyi,
`oxazolyl, benzthiazolyl or benzoxazolyl, optionally substituted by 1 to 2 substituents
`independently selected from the group consisting of fluoro, chloro, trifluoromethyl, (C,-
`C,)alkoxy, (C,-C,,)aryloxy,trifluoromethoxy, difluoromethoxy and (C,-C,)alkyl.
`The term "acyl", as used herein, unless otherwise indicated, includes a radical
`of the generai formula RCO whereinRis alkyl, alkoxy, aryl, arylalkyl or arylalkyloxy and
`the terms “alkyl” or "aryl" are as defined above.
`The term "acyloxy", as used herein, includes acyl-O groups wherein "acyl" is
`defined above.
`
`30
`
`Preferred compoundsof formula | include those wherein n is 2.
`
`Other preferred compoundsof formula | include those wherein X and Y are both
`CR' wherein R’ is hydrogen.
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1611
`
`page 1611
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`-5-
`
`include those wherein Ar is (C,-
`Other preferred compounds of formula |
`C,)alkoxy(C,-C,,)aryl(C,-C, ,)aryl(C,-C,)alkoxy(C,-C, ,)aryl4-fluorophenoxy(C,-C,,)aryl,
`4-fluorobenzyloxy(C,-C,,)aryl or (C,-C,)alkyl(C,-C, ,)aryloxy(C,-C, aryl.
`More preferred compoundsof formula | include those wherein n is 2, X and Y
`are both CR! wherein R'
`is hydrogen and Ar
`is
`(C,-C,)alkoxy(C,-C,,)aryl,
`(C,-
`C, )aryl(C,-C.)alkoxy(C,-C,.)aryl, 4-fluorophenoxy(C,-C,,)aryl, 4-fluorobenzyioxy(C,-
`C,,)aryl or (C,-C,)alkyl(C,-C, .)aryloxy(C,-C, ,)aryl.
`The present invention also relates to a pharmaceutical composition for (a) the
`treatment of a condition selected from the group consisting of arthritis, cancer, synergy
`with cytotoxic anticancer agents, tissue ulceration, macular degeneration, restenosis,
`periodontal disease, epidermolysis bullosa, scleritis,
`in combination with standard
`NSAID'S and analgesics and other diseases characterized by matrix metalloproteinase
`activity, AIDS, sepsis, septic shock and other diseases involving the production of
`tumor necrosis factor (TNF) or (b) the inhibition of matrix metalloproteinases or the
`production of tumornecrosis factor (TNF) in a mammal, including a human, comprising
`an amount of a compoundof formuia | or a pharmaceutically acceptable salt thereof
`effective in such treatments and a pharmaceutically acceptable carrier.
`The present invention also relates to a method for the inhibition of (a) matrix
`metalloproteinases or (b) the production of tumor necrosis factor (TNF) in a mammal,
`including a human, comprising administering to said mammai an effective amount of
`a compound of formula I or a pharmaceutically acceptable salt thereof.
`The presentinvention also relates to a methodfor treating a condition selected
`from the group consisting of arthritis, cancer, tissue ulceration, macular degeneration,
`restenosis, periodontal disease, epidermolysis bullosa, scleritis, compoundsof formuia
`| may be used in combination with standard NSAID'S and analgesics and in
`combination with cytotoxic anticancer agents, and other diseases characterized by
`matrix metalloproteinase activity, AIDS, sepsis, septic shock and other diseases
`involving the production of tumor necrosis factor (TNF) in a mammal,
`including a
`human, comprising administering to said mammal an amount of a compound of
`formula | or a pharmaceutically acceptable salt thereof effective in treating such a
`condition.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1612
`
`page 1612
`
`

`

`WO 98/30566
`
`PCT/1IB97/01582
`
`-6-
`
`Detailed Description of the Invention
`
`The following reaction Schemesillustrate the preparation of the compoundsof
`
`the present invention. Unless otherwise indicated X, Y and Ar in the reaction Schemes
`
`and the discussion that follow are defined as above.
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1613
`
`page 1613
`
`

`

`WO 98/30566
`
`PCT/1B97/01582
`
`-7-
`
`SCHEME 14
`
`Cl
`big ,
`=o=
`Ar
`
`0
`
`Na
`{
`=S=
`Ar
`
`0
`
`COoH
`
`[
`
`c
`—» 0.
`/ :
`Ar
`0
`
`VII
`
`VI
`
`V
`
`4
`
`CO>H
`
`|
`
`S
`
`
`foAr 0
`
`0=S=0
`
`!A
`
`r
`
`III
`
`IV
`
`0
`
`0
`
`0
`
`0
`
`5
`
`0
`
`10
`
`20
`
`25
`
`pid
`OH
`I _6.HH
`0=S=0
`0—=S—=0
`Ar
`Ar
`
`
`
`
`
`Y
`
`30
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1614
`
`page 1614
`
`

`

`WO98/30566
`
`PCT/IB97/01582
`
`-8-
`
`In reaction 1 of Scheme 1, the aryl sulfonyl chioride compoundof formula VII
`is converted to the corresponding sodium aryl sulfonate compound of formula VI by
`reacting Vil with sodium iodine in the presence of a polar aprotic soivent, such as
`acetone, underinert atmosphere. The reaction mixtureis stirred, at room temperature,
`for a time period between about 12 hours to about 18 hours, preferably about 15 hours.
`In reaction 2 of Scheme 1, the compound of formula VI
`is converted to the
`corresponding 2-iodo-3-(aryl) sulfonyl propionic acid compound of formula V by
`reacting VI with acrylic acid and iodine in the presenceof a polar aprotic solvent, such
`as methylene chloride. The reaction mixture is stirred under inert atmosphere, at room
`temperature, for a time period between about 12 hours to about 3.5 days, preferably
`about 3 days.
`In reaction 3 of Scheme 1, the compound of formula V is converted to the
`corresponding(E)-3-(aryl)sulfonyl-prop-2-enoic acid compound offormula lV by treating
`V with a base, such astriethylamine, in a polar aprotic solvent, such as methylene
`chloride, under inert atmosphere. The reaction is stirred, at room temperature, for a
`time period between about 10 hours to about 24 hours, preferably about 12 hours.
`In reaction 4 of Scheme 1, the compound of formula IV is converted to the
`corresponding carboxylic acid compoundofformuia Ill by heating IV with an excess
`amount of a compound of the formula
`
`f
`\
`A——Y
`
`to reflux in the presence of a polar aprotic solvent, such as toluene, for a time period
`between about 24 hours to about 56 hours, preferably about 48 hours.
`In reaction 5 of Scheme 1, the compound of formula HII
`is converted to the
`corresponding N-(R"*)-carboxamide compound of formula Hl, wherein R™ is O-
`substituted oxy, such as O-benzylhydroxy ortrimethylsilyl ethylhydroxy by reacting III
`with an activating agent, such as dimethylaminopyridine/dicyclohexylcarbodiimide, and
`an O-substituted hydroxylamine, such as benzylhydroxylamine hydrochloride or O-
`trimethyl-silylethyihydroxylamine,
`in the presence of a polar aprotic solvent, such as
`methylene chloride, under inert atmosphere. The reaction mixture is stirred, at room
`
`10
`
`15
`
`20
`
`25
`
`30
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1615
`
`page 1615
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`-g-
`
`temperature, for a time period between about 15 hours to about 25 hours, preferably
`about 20 hours.
`
`10
`
`is converted to the
`In reaction 6 of Scheme 1, the compound of formula II
`corresponding hydroxamic acid compoundofformula | by (1) treating II with hydrogen
`in the presence of a catalyst, such as 5% palladium on barium sulfate, and a polar
`aprotic solvent, such as methanol,
`(2) treating If with trifluoroacetic acid or boron
`trifluoride diethyl etherate in a polar aprotic solvent, such as methylene chloride, or (3)
`treating Il with tetrabutyl ammonium fluoride in a polar aprotic solution, such as
`tetrahydrofuran. The reaction mixtureis stirred for a time period between about 2 hours
`to about 4 hours, preferably about 3 hours.
`Pharmaceutically acceptable salts of the acidic compoundsofthe invention are
`saits formed with bases, namely cationic salts such as alkali and alkaline earth metal
`salts, such as sodium, lithium, potassium, calcium, magnesium, as well as ammonium
`
`slats, and_tris-such as ammonium, trimethyl-ammonium, diethyiammonium,
`
`
`15
`(hydroxymethyl)-methylammonium slats.
`Similarly acid addition salts, such as of mineral acids, organic carboxylic and
`organic sulfonic acids e.g. hydrochioric acid, methanesulfonic acid, maleic acid, are
`also possible provided a basic group, such as pyridyl, constitutes part of the structure.
`Theability of the compoundsof formula I or their pharmaceutically acceptable
`salts (hereinafter also referred to as the compoundsof the present invention) to inhibit
`matrix metalioproteinases or the production of tumor necrosis factor (TNF) and,
`consequently, demonstrate their effectiveness for treating diseases characterized by
`matrix metalloproteinase or the production of tumor necrosis factor is shown by the
`following in vitro assay tests.
`
`20
`
`25
`
`Biological Assay
`Inhibition of Human Collagenase (MMP-1)
`Human recombinant collagenase is activated with trypsin using the following
`10 wg trypsin per 100 wg of collagenase. The trypsin and collagenase are
`ratio:
`incubated at room temperature for 10 minutes thenafive fold excess (50 pg/10 wg
`30
`trypsin) of soybean trypsin inhibitor is added.
`
`10 mM stock solutions of inhibitors are made up in dimethyl sulfoxide and then
`diluted using the following Scheme:
`
`10 mM ------> 120 wM -——> 12 yM -——> 1.2 uM -----> 0.12 uM
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1616
`
`page 1616
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`-10-
`
`Twenty-five microliters of each concentration is then added in triplicate to
`appropriate wells of a 96 well microfiuor plate. The final concentration of inhibitorwill
`be a 1:4 dilution after addition of enzyme and substrate. Positive controls (enzyme, no
`inhibitor) are set up in wells D1-D6 and blanks (no enzyme, noinhibitors) are set in
`wells D7-D12.
`
`Collagenaseis diluted to 400 ng/ml and 25 yl is then added to appropriate wells
`of the microfluor plate. Final concentration of collagenase in the assay is 100 ng/ml.
`Substrate (DNP-Pro-Cha-Gly-Cys(Me)-His-Ala-Lys(NMA)-NH,) is made as a5mM
`stock in dimethyl sulfoxide and then diluted to 20 wM in assay buffer. The assayis
`initiated by the addition of 50 pl substrate per well of the microfiuor plate to give a final
`concentration of 10 wM.
`
`Fluorescence readings (360 nM excitation, 460 nm emission) were taken at time
`0 and then at 20 minute intervals. The assay is conducted at room temperature with
`a typical assay time of 3 hours.
`
`Fluorescence vs time is then plotted for both the blank and collagenase
`containing samples (data from triplicate determinations is averaged). A time point that
`provides a good signal (the blank) and that is on a linear part of the curve (usually
`around 120 minutes) is chosen to determine IC. values. The zero time is used as a
`blank for each compoundat each concentration and these values are subtracted from
`
`the 120 minute data. Data is plotted as inhibitor concentration vs % contro! (inhibitor
`fluorescence divided by fluorescence of collagenase alone x 100).
`IC.,'s are
`determined from the concentration of inhibitor that gives a signal that is 50% of the
`control.
`
`10
`
`15
`
`20
`
`lf iC,,'s are reported to be <0.03 wM then the inhibitors are assayed at
`concentrations of 0.3 yM, 0.03 wM, 0.03 wM and 0.003 wM.
`
`25
`
`Inhibition of Gelatinase (MMP-2)
`Inhibition of gelatinase activity is assayed using the Dnp-Pro-Cha-Gly-Cys(Me)-
`His-Ala-Lys(NMA)-NH, substrate (10 wM) under the same conditions as inhibition of
`
`human collagenase (MMP-1).
`
`30
`
`72kDgelatinase is activated with 1 mM APMA(p-aminophenyl mercuric acetate)
`for 15 hours at 4°C and is diluted to give a final concentration in the assay of 100
`mg/ml.
`Inhibitors are diluted as for inhibition of human collagenase (MMP-1) to give
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1617
`
`page 1617
`
`

`

`WO 98/30566
`
`PCT/TB97/01582
`
`-t1-
`
`Each
`
`final concentrations in the assay of 30 wM, 3 wM, 0.3 wM and 0.03 UM.
`concentration is donein triplicate.
`Fluorescence readings (3860 nm excitation, 460 emission) are taken at time zero
`and then at 20 minutes intervals for 4 hours.
`If IC,,'s
`IC.o's are determined as perinhibition of human collagenase (MMP-1}.
`are reported to be less than 0.03 wM,
`then the inhibitors are assayed at final
`concentrations of 0.3 uM, 0.03 wM, 0.003 wM and 0.003 yM.
`Inhibition of Stromelysin Activity (MMP-3)
`Inhibition of stromelysin activity is based on a modified spectrophotometric
`assay described by Weingarten and Feder
`(Weingarten, H. and Feder,
`J.,
`Spectrophotometric Assay for Vertebrate Collagenase, Anal. Biochem. 147, 4387-440
`(1985)).
`Hydrolysis
`of
`the
`thio
`peptolide
`substrate
`[Ac-Pro-Leu-Gly-
`SCH[CH,CH(CH,).]CO-Leu-Gly-OC,H,] yields a mercaptan fragment that can be
`monitored in the presence of Ellman's reagent.
`Human recombinant prostromelysin is activated with trypsin using a ratio of 1 yl
`of