WO 98/07697
`
`PCT/[397/00924
`
`-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,
`
`comprising administering to said mammal an effective amount of a compound of 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
`
`1O
`
`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
`
`

`

`
`Interi. mal Application No
`
`
`
`PCT/IB 97/00924
`
`. CLASSlFICATlON 0F SUBJECT MATTER
`
`PC 6
`C07D211/62
`C07D211/46
`C07D211/58
`C07D295/18
`C07D211/34
`
`
`A61K3l/495
`C07C311/29
`A61K31/445
`A61K31/18
`
`
`
`
`
`According to International Patent Classification (IPC) or to both national classification and lPC
`
`
`B. FIELDS SEARCHED
`
`
`Minimum documentation searched (classification system followed by classrlioation symbols)
`IPC 6
`C070 C07C A61K
`
`
`
`
`
`
`
`INTERNAJHONAL SEARCH REPORT
`
`A I
`
`
`
`Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched
`
`
`
`Electronic data base consulted during the International search (name at data base and, where practical, search terms used)
`
`
`
`C. DOCUMENTS CONSIDERED TO BE RELEVANT
`
`Citation of document. with indication, where appropriate. of the relevant passages
`
`Y
`
`Y
`
`Y
`
`P,X
`
`
`
`
`
`
`
`
`
`EP 0 606 046 A (CIBA-GEIGY AG) 13 July
`1994
`see claims
`
`NO 95 35275 A (BRITISH BIOTECH
`PHARMACEUTICALS LIMITED) 28 December 1995
`see claims
`
`wo 96 00214 A (CIBA—GEIGY AG) 4 January
`1996
`see claims
`
`
`
`
`
`
`wo 96 27583 A (PFIZER INC.) 12 September
`1996
`see the whole document
`
`
`
`
` D Further documents are listed in the continuation of box 0. " S eciai cote cries of cited documents :
`
`g
`p
`'A' document defining the general state at the art which is not
`considered to be ol particular relevance
`
`Patent tamily members are listed in annex.
`
`'1" later document published after the international filing date
`or priority date and not in conflict with the application but
`cited to understand the principle or theory underlying the
`invention
`
`'X' document of particular relevance' the claimed invention
`'E' earlier document but published on or after the international
`cannot be considered novel or cannot be considered to
`”Mg date
`involve an inventive step when the document is taken alone
`'L' document which may thin: doubts on priority claim“) or
`particular relevance. the claimed invention
`A
`.
`v
`-
`v
`'V' document of
`-
`.
`a
`-
`-
`in ii:
`is cited to establio the publication date of another
`cannot be considered to involve an inventive step when the
`”who” or other special reason (a. specified)
`document is combined with one or more other such docu-
`'0' document referring to an oral disclosure, use, exhibition or
`ments. such combination being obvious to a person skilled
`other means
`in th' art.
`'P' document published prior to the international filing date but
`'8.‘ document member of the same patent family
`later than the priority date claimed
`
`Date of the actual completion at the international search
`Date of mailing of the international search report
`
`
`14 October 1997
`
`
`Authorized officer
`Name and mailing address of the ISA
`
`
`European Patent Office. PB. 5818 Patentlaan 2
`
`NL - 2280 HV Rijswiik
`
`
`
`Tel. (+31-70) 340-2040. Tx. 31 651 epo nl,
`
`
`Fax: (+3140) 340-3016
`
` Chouly, J
`
`Form PCT/l3A/210 (second sheet) (July 1992)
`
`23, ll]. 97'
`
`AQUESTIVE EXHIBIT 1007
`
`page 1602
`
`AQUESTIVE EXHIBIT 1007 page 1602
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`In
`
`.iational application No.
`PCT/18 97/00924
`
`Box l Observations where certain claims were found unsearchable (Continuation of item 1 of first sheet)
`
`
`
`
`This International Search Report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:
`
`1,
`
`2.
`
`
`
`
`
`
`Claims Nos‘:
`
`because they relate to subject matter not required to be searched by this Authority, namely.
`
`see FURTHER INFORMATION sheet PCT/ISA/ZlO
`
`
`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, specilically:
`
`3‘ D Claims Nos:
`
`because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
`
`
`
`Box ll Observations where unity of invention is lacking (Continuation of item 2 at first sheet)
`
`This lntemational Searching Authority found multiple inventions in this international application. as follows:
`
`
`
` As all required additional search lees were timely paid by the applicant, this international Search Report covers all
`searchable claims
`
`
` As all searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment
`cl any additional fee.
`
`
`
`As only some of the required additional search fees were timely paid by the applicant, this International Search Report
`covers only those claims for which fees were paid, specifically claims Nos.‘
`
`3‘
`
` No requrred additional search lees 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:
`
`
`
`I: The additional search fees were accompanied by the applicant's protest.
`E] No protest accompanied the payment of additional search fees.
`
`AQUESTIVE EXHIBIT 1007 page 1603
`
`Remark on Protest
`
`Form PGT/lSA/21O (continuation 0! first sheet (1 )) (July 1992)
`
`QUESTIVE EXHIBIT 1007
`
`page 1603
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`lntemationalAppiication No. PCTIB 97 00924
`
`FURTHER INFORMATION CONTINUED FROM PCT/ISM 210
`
`This international search report has not been established in respect of
`certain claims under Article 17(2)(a) for the follow1ng reasons:
`
`Claims Nos.:
`
`claims 1-10 have been searched incompletely (see attached
`
`Authority, namely:
`
`
`
`
`
`
`
`
`sheet)
` because they relate to subject matter not required to be searched by this
`
`
`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 B, Chapter III,3.7).Thus the search was
`
`
`directed powards (but not
`limited to) compounds having variables as
`represented in the examples.
`
`
`
`
`
`
`
`
`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
`alleged effects of the compound/composition.
`
`
`
`
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1604
`
`page 1604
`
`

`

`INTERNATIONAL SEARCH REPORT
`
`Information on patent lamily members
`
`Intern
`
`.xal Application No
`
`PCT/IE 97/00924
`
`, Patgnt document
`Cited In search report
`
`Publication
`date
`
`Patent family
`member(s)
`
`Publication
`date
`
`NO 9600214
`
`A
`
`04—01-96
`
`EP 606046
`
`A
`
`13-07—94
`
`NO 9535275
`
`A
`
`28—12-95
`
`>>>>>>>>>>
`>>>>>>>>>>>>>> W N.
`
`5506242
`2536995
`2192092
`0766672
`965156
`965568
`5552419
`5646167
`5672615
`9505206
`
`5455258
`5265593
`2112779
`940012
`70536
`6256293
`9400276
`940038
`250517
`5506242
`5552419
`5646167
`5672615
`9400048
`
`2746595
`2746695
`2193691
`2193692
`0766664
`0766665
`965153
`9535276
`2303850
`2303629
`965515
`
`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
`
`03-10-95
`04-05-95
`07-07-94
`07-07-94
`30—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
`
`15-01—96
`15-01-96
`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
`
`
`
`Pom PCTItSA/210 (pawn! lamily annex) (July 1992)
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1605
`
`page 1605
`
`

`

`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, 82, 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).
`
`Published
`With international search report.
`
`(21) International Application Number:
`
`(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) Inve11tors/Applicants(for US only): BURGESS, Laurence, Ed-
`ward [US/US]; 5617 Slick Rock Court, Boulder, CO 80301
`(US). RIZZI, James, Patrick [US/US]; 7180 Longview
`Drive, Niwot, CO 80503 (US).
`
`(74) Agents: SPIEGEL, Allen, J. et al.; Pfizer Inc., 235 East 42nd
`Street, New York, NY 10017 (US).
`
`
`
`
`
`PCT
`
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`
`
`
`_ INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`
`(51) International Patent Classification 6 :
`WO 98/30566
`
`16 July 1998 (16.07.98)
`
`
`(11) International Publication Number:
`
`C07D 493/08, A61K 31/34
` (43) International Publication Date:
`
`
`
` (54) Title: CYCLIC SULFONE DERIVATIVES
`
`(57) Abstract
`
`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) and analgesics, and in combination with cytotoxic drugs such as adriamycin, daunomycin, Cis—platinum,
`etoposidc, taxol, taxotere and other alkaloids, such as vincristine, in the treatment of cancer.
`
`0
`
`X
`2'
`3
`Y
`
`(I)
`
`,s<o>
`Fir
`
`H
`
`“0/
`
`
`
`4
`AQUESTIVE EXHIBIT 1007 page 1606
`
`AQUESTIVE EXHIBIT 1007
`
`page 1606
`
`
`
`

`

`[—
`
`FOR THE PURPOSES OF INFORMATION ONLY
`
`
`
`
`
`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
`
`Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`Albania
`ES
`LS
`Lesotho
`SI
`Slovenia
`Armenia
`FI
`LT
`Lithuania
`SK
`Slovakia
`Austria
`FR
`LU
`SN
`Luxembourg
`Senegal
`Australia
`GA
`LV
`Latvia
`SZ
`Swaziland
`GB
`MC
`Monaco
`TD
`Azerbaijan
`Chad
`GE
`MD
`TG
`Bosnia and Herzegovina
`Republic of Moldova
`Togo
`Barbados
`GH
`MG
`TJ
`Madagascar
`Tajikistan
`GN
`MK
`Belgium
`TM
`Turkmenistan
`The former Yugoslav
`Burkina Faso
`GR
`TR
`Republic of Macedonia
`Turkey
`HU
`Mali
`TT
`Bulgaria
`Trinidad and Tobago
`Benin
`[E
`UA
`Ukraine
`Mongolia
`[L
`Brazil
`Mauritania
`UG
`Uganda
`IS
`Belarus
`Malawi
`US
`United States of America
`Canada
`IT
`Mexico
`UZ
`Uzbekistan
`JP
`VN
`Viet Nam
`Central African Republic
`Niger
`KE
`Netherlands
`Congo
`YU
`Yugoslavia
`Switzerland
`KG
`ZW
`Zimbabwe
`Norway
`COte d’Ivoire
`KP
`New Zealand
`Cameroon
`Poland
`China
`Portugal
`Cuba
`Romania
`Czech Republic
`Russian Federation
`Sudan
`Gemiany
`Denmark
`Sweden
`Estonia
`Singapore
`
`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
`Kazakstan
`Saint Lucia
`Liechtenstein
`Sri Lanka
`Liberia
`
`KR
`KZ
`LC
`LI
`LK
`LR
`
`ML
`MN
`MR
`MW
`MX
`NE
`NL
`N0
`NZ
`PL
`PT
`R0
`RU
`SD
`SE
`SG
`
`
`
`AQUESTIVE
`
`EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1607
`
`page 1607
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`-1-
`
`CYCLIC SULFONE DERIVATIVES
`
`Background of the Invention
`
`10
`
`15
`
`20
`
`25
`
`30
`
`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 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
`(hereinafter NSAlD’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 as arthritis (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 well as HIV-infection (J. Leuk. Biol., 5_2 (2): 244—248, 1992).
`
`Tumor necrosis factor is recognized to be involved in many infectious and auto—
`
`immune diseases (W. Fiers, FEBS Letters, 1991, _2_8_5, 199). Furthermore, it has been
`
`shown that TNF is the prime mediator of the inflammatory response seen in sepsis and
`
`septic shock (C.E. Spooner et al., Clinical immunology an_d lmmunogathology, 1992,
`
`gag s11).
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1608
`
`page 1608
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`-2-
`
`The present invention relates to a compound of the formula
`
`Summafl of the Invention
`
`5
`
`,S(O)
`
`Flr‘
`
`H
`N
`
`H0/
`
`0
`
`0
`
`X
`
`Y
`
`or a pharmaceutically acceptable salt thereof, wherein the broken line represents an
`
`10
`
`optional double bond;
`
`n is O, 1 or 2;
`
`X and Y are each independently CF!1 wherein R‘
`
`is hydrogen,
`
`(CI-C6)alkyl
`
`optionally
`
`substituted
`
`by
`
`(C1-Ce)alkylamino,
`
`(C1-Cs)alkylthio,
`
`(C1-C6)alkoxy,
`
`trifluoromethyl, (Cs-C,o)aryl, (Cs-Cg)heteroaryl, (C6—C1o)arylamino, (C6-C,o)aiylthio, (C6-
`
`15
`
`C1o)aryloxy, (C5-C9)heteroarylamino, (CS-Cg)heteroarylthio, (C5-C9)heteroaryloxy, (Cs-
`
`C,o)aryl(C6-C1o)aryl,
`
`(Ca-Ce)cycloalkyl,
`
`hydroxy(C,-C6)alkyl,
`
`(C1-
`
`Cs)alkyl(hydroxymethylene),piperazinyl,(C6-C1o)aryl(C,-Ca)alkoxy,(CS-Cs)heteroaryl(C1-
`
`Cs)alkoxy, (C1-Cs)acylamino, (C1-C6)acylthio, (C1-Cs)acyloxy, (C1-Cs)alkylsulfinyl, (Ce-
`
`C,O)arylsulfinyl, (C1-C6)alkylsulfonyl, (Cs—C,o)arylsulfonyl, amino, (C,-Cs)alkylamino or
`
`20
`
`((C1-C6)alkyl)2amino;
`
`trifluoromethyl,
`
`(C1—C6)alky|
`
`(difluoromethylene),
`
`(C1C3)alkyl(difluoromethylene)(C1-Ca)alkyl,
`
`(C6-Cm)aryl,
`
`(CS—Cg)heteroaryl,
`
`(C3-
`
`C5)cycloalkyl,
`
`(C,-CG)alkyl-(hydroxymethylene), R3(C,-Cs)alkyl wherein R3
`
`is
`
`(C1—
`
`C6)acylpiperazino,
`
`(Ce-C1o)arylpiperazino,
`
`(C5-C9)heteroarylpiperazino,
`
`(C,-
`
`Cs)alkylpiperazino,
`
`(C6—C,°)aryl(C1-C6)alky|piperazino,
`
`(Cs-C9)heteroaryl(C,-
`
`25
`
`Cs)alkylpiperazino, morpholino, thiomorpholino, piperidino, pyrrolidino, piperidyl, (C1-
`
`06)alky|piperidyl,
`
`(C6-C1o)arylpiperidyl,
`
`(C5-C9)heteroarylpiperidyl,
`
`Cfi)a|kylpiperidyl(C1-C6)alkyl,
`
`(C6-C1o)ary|piperidyl(C1-Cs)alkyl,
`
`(C1-
`
`(Cs-
`
`C9)heteroarylpiperidyl(C1-C6)alkyl or (C1—Ce)acylpiperidyl;
`
`or a group of the formula
`
`30
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1609
`
`page 1609
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`wherein r is O to 6;
`
`10
`
`15
`
`2O
`
`25
`
`30
`
`D is hydroxy, (C1-Ca)alkoxy, piperidyl, (C1-C6)alkylpiperidyl, (CS-C1 o)arylpiperidyl,
`
`(Cs-Cg)heteroarylpiperidyl, (C1-C6)acylpiperidyl or NFt‘R5 wherein F!4 and R5 are each
`
`independently selected from the group consisting of hydrogen, (C1-CG)aIkyI optionally
`
`substituted by (C1-C6)alkylpiperidyl, (Cs—C,o)arylpiperidyl, (Cs-Cs)heteroarylpiperidyl, (CG-
`
`C1o)aryl, (C5-CQ)heteroaryl, (C6-C,o)aryl(C6-C1o)aryl or(C3—C6)cycloalky|; (CG—C,o)aryl, (CS-
`
`Cs)heteroaryl,
`
`(C6-C,°)aryl(C6-C,o)aryl,
`
`(C3-06)cycloalkyl,
`
`R6(C2—Ca)alkyl,
`
`(C1—
`
`C5)alkyl(CHR5)(C,-C5)alkyl wherein R6
`
`is hydroxy,
`
`(C1-Ce)acyloxy,
`
`(C1-Ca)alkoxy,
`
`piperazino, (C1—Cs)acylamino, (C1-Cs)alkylthio, (Cs-C1o)arylthio, (C1-Ce)alkylsulfinyl, (C6-
`
`C,o)arylsulfinyl, (C1-Ce)alkylsulfoxyl, (C6-Cm)arylsulfoxyl, amino, (C1-C6)alkylamino, ((C1-
`
`C6)alkyl)2amino,
`
`(C1-Cs)acylpiperazino,
`
`(C1-Ce)alkylpiperazino,
`
`(C6-C,°)aryl(C,-
`
`Cs)a|kylpiperazino,(C5~Cs)heteroaryl(C,-C6)alkylpiperazino,morpholino,thiomorpholino,
`
`piperidino or pyrrolidino; R7(C,-C6)alkyl, (C1-C5)alkyl(CHR7)(C1-Cs)alkyl wherein R7 is
`
`piperidyl or (C1-C6)alkylpiperidyl; and CH(R")COR9 wherein R6 is hydrogen, (C1-C6)alkyl,
`
`(Cs-C,o)aryl(C,—C5)alkyl, (C5-C9)heteroaryl(C,~Ce)alkyl, (C1-C8)alkylthio(C,—C6)alkyl, (C6-
`
`C1o)arylthio(C,-Cs)alkyl, (C1-C6)a|kylsulfinyl(C,—C6)alkyl, (CG-C1°)arylsulfinyl(C,-C6)alkyl,
`
`(C,~C5)alkylsulfonyl(C,-C6)alkyl,
`
`(Ce-C,o)arylsulfonyl(C,-Ce)alkyl, hydroxy(C,-Ce)alkyl,
`
`amino(C,-Cs)alkyl,
`
`(C1-Ce)alkylamino(C,-Cs)alkyl,
`
`((C,-C6)alkylamino)2(C,-C6)a|kyl,
`
`R‘OR”NCO(C,-Ce)alkyl or R‘OOCO(C,-C5)a|kyl wherein R‘° and R“
`
`are each
`
`independently selected from the group consisting of hydrogen,
`
`(C1-C6)a|kyl,
`
`(CG-
`
`C,o)aryl(C,-Cs)alkyl and (CS-Cg)heteroaryl(C,-Ce)alkyl; and R9 is R120 or R‘ 2Fl‘3N wherein
`
`R” and Ft‘3 are each independently selected from the group consisting of hydrogen,
`
`(C1-Cs)alkyl, (C6-C,o)aryl(C,-C3)alkyl and (Cs-Cg)heteroaryl(C,-C6)a|kyl; and
`
`Ar
`
`is
`
`(C1-C5)alkyl,
`
`(C5-C,o)aryl,
`
`(Ce-C,0)aryloxy(C6-C,o)aryl,
`
`(C6-C,o)aryl(Cs—
`
`C,o)aryl,
`
`(C6-C1o)aryl(C5-C,o)aryl(C,-C5)alkyl,
`
`(CB-C,o)aryloxy(CS-Cg)heteroaryl,
`
`(C5—
`
`Cs)heteroaryl,
`
`(C1-Cs)alkyl(CG-Cm)aryl,
`
`(C1-C6)alkoxy(C6-C,o)aryl,
`
`(C6-C,0)aryl(C,-
`
`Cs)alkoxy(C6-C,o)aryl,
`
`(Ce-C,o)aryI(C,-Ce)alkoxy(C,-C6)alkyl,
`
`(CS-Cs)heteroaryloxy(06-
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1610
`
`page 1610
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`.4-
`
`C,o)aryl, (C,-Ce)alkyl(Cs-Cs)heteroaryl, (C,-Cs)alkoxy(C5-Cg)heteroaryl, (Cs-C,o)aryl(C,-
`C5)alkoxy(Cs-Cg)heteroaryl, (Cs-Cg)heteroaryloxy(C5-Cs)heteroaryl, (CG-0,0)aryloxy(C,-
`Ce)alkyl, (Ca-Cg)heteroaryloxy(C,~C6)alkyl, (C,-Cs)alkyl(CG-C,o)aryloxy(CG-C1o)aryl, (C,-
`Ce)alkyl(CS-Cg)heteroaryloxy(CS-C1o)aryl,
`(C1-Cs)alkyl(C6-C,o)aryloxy(Cs-Cs)heteroaryl,
`
`5
`
`(C,-Cs)alkoxy(Cs-C,o)aryloxy(C6-C,o)aryl,(C,-C6)alkoxy(Cs—C9)heteroaryloxy(Cs—C,o)aryl
`
`or (C,-C6)alkoxy(C6-C1o)aryloxy(Cs-Cs)heteroaryl wherein each aryl group is optionally
`
`substituted byfluoro, chloro, bromo, (C1-C6)alkyl, (C1-Ca)alkoxyorperfluoro(C1-C3)alkyl.
`
`The term “alkyl", as used herein, unless otherwise indicated, includes saturated
`
`monovalent hydrocarbon radicals having straight, branched or cyclic moieties or
`combinations thereof.
`
`10
`
`The term "alkoxy", as used herein, includes alkyl-O groups wherein "alkyl" is
`defined above.
`
`The term "aryl", as used herein, unless othenivise indicated, includes an organic
`
`radical derived from an aromatic hydrocarbon by removal of one hydrogen, such as
`
`15
`
`phenyl or naphthyl, optionally substituted by 1 to 3 substituents independently selected
`
`from the group consisting of fluoro, chloro, cyano, nitro, trifluoromethyl, (C1-C6)alkoxy,
`
`(Ce-C,o)aryloxy, trifluoromethoxy, difluoromethoxy and (C1-C6)alkyl.
`
`The term "heteroaryl", as used herein, unless otherwise indicated, includes an
`
`organic radical derived from an aromatic heterocyclic compound by removal of one
`
`20
`
`hydrogen, such as pyridyl, furyl, pyrroyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl,
`
`tetrazolyl,
`
`pyrazinyl,
`
`pyrimidyl,
`
`quinolyl,
`
`isoquinolyl, benzofuryl,
`
`isobenzofuryl,
`
`benzothienyl, pyrazolyl,
`
`indolyl,
`
`isoindolyl, purinyl, carbazolyl,
`
`isoxazolyl,
`
`thiazolyi,
`
`oxazolyi, benzthiazoiyl or benzoxazoiyl, optionally substituted by 1 to 2 substituents
`
`independently selected from the group consisting of fluoro, chloro, trifluoromethyl, (C,-
`
`25
`
`C6)alkoxy, (CB-C,o)aryloxy, trifluoromethoxy, difluoromethoxy and (C1—C6)alkyl.
`
`The term "acyl", as used herein, unless otherwise indicated, includes a radical
`
`of the general formula RCO wherein R is 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 compounds of formula I include those wherein n is 2.
`
`Other preferred compounds of formula I 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-
`
`Other preferred compounds of formula I
`
`include those wherein Ar is (C,-
`
`Ca)alkoxy(Cs-C,0)aryl(Cs-C,o)aryl(C,-Cs)alkoxy(C6-C,O)aryl,4—fluorophenoxy(CG-C,o)aryl,
`
`4-fluorobenzyloxy(Ce-C,o)ary| or (C,-C6)alkyl(C6-C,o)aryloxy(Cs-C,o)aryl.
`
`More preferred compounds of formula I include those wherein n is 2, X and Y
`
`are both CFl1 wherein R‘
`
`is hydrogen and Ar
`
`is
`
`(C1-C8)alkoxy(C6-C,o)aryl,
`
`(C6—
`
`C,o)aryl(C,—Cs)alkoxy(C6-C,o)ary|, 4-fluorophenoxy(Ce-C,o)aryl, 4-fluorobenzyloxy(Cs-
`
`C,O)aryl or (C,-Cs)alkyl(C6—C,o)aryloxy(Ce-C,o)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, epiderrnolysis 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 tumor necrosis factor (TNF) in a mammal, including a human, comprising
`
`an amount of a compound of formula I 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 mammal an effective amount of
`
`a compound of formula I or a pharmaceutically acceptable salt thereof.
`
`The present invention also relates to 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 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 mammai,
`
`including a
`
`human, comprising administering to said mammal an amount of a compound of
`
`formula I 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/IB97/01582
`
`-5-
`
`Detailed Description of the Invention
`
`The following reaction Schemes illustrate the preparation of the compounds of
`
`the present invention. Unless othenNise 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/IB97/01582
`
`-7-
`
`SCHEME 1
`
`Cl
`1
`I
`2?20 —-.
`W
`
`Na
`I
`O: I8:0
`Dr
`
`VI I
`
`VI
`
`I
`
`COEH
`
`a
`-—’
`
`0
`/“ ‘
`CIr‘
`0
`
`V 1
`
`3
`
`4
`
`COeH
`
`I
`
`S
`
`/
`fir
`
`IV
`
`0
`
`14
`
`R
`
`H
`
`—.
`
`Y
`
`0
`
`0
`
`OH
`
`H
`
`0:820
`IIJP
`
`I
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1614
`
`page 1614
`
`028:0
`
`ID
`
`r
`
`III
`
`O:|S:O
`9r
`
`II
`
`0
`
`5
`
`O
`
`I
`Y
`
`[I
`Y
`
`5
`
`1O
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`-8-
`
`In reaction 1 of Scheme 1, the aryl sulfonyl chioride compound of formula VII
`
`is converted to the corresponding sodium aryl sulfonate compound of formula VI by
`reacting VII with sodium iodine in the presence of a polar aprotic solvent, such as
`
`acetone, under inert atmosphere. The reaction mixture is stirred, at room temperature,
`
`5
`
`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 presence of a polar aprotic solvent, such
`
`as methylene chloride. The reaction mixture is stirred under inert atmosphere, at room
`
`10
`
`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 IV by treating
`V with a base, such as triethylamine, in a polar aprotic solvent, such as methylene
`
`15
`
`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 compound of formula III by heating IV with an excess
`
`amount of a compound of the formula
`
`20
`
`~
`
`0
`
`/
`\
`X—Y
`
`25
`
`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 III
`
`is converted to the
`
`corresponding N-(R‘4)-carboxamide compound of formula II, wherein Fl14
`
`is O-
`
`substituted oxy, such as O-benzylhydroxy or trimethylsilyl ethylhydroxy by reacting III
`
`30 with an activating agent, such as dimethylaminopyridine/dicyclohexylcarbodiimide, and
`
`an O-substituted hydroxyiamine, such as benzylhydroxylamine hydrochloride or O—
`
`trimethyl-silylethylhydroxylamine,
`
`in the presence of a polar aprotic solvent, such as
`
`methylene chloride, under inert atmosphere. The reaction mixture is stirred, at room
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1615
`
`page 1615
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`.9.
`
`temperature, for a time period between about 15 hours to about 25 hours, preferably
`about 20 hours.
`
`In reaction 6 of Scheme 1, the compound of formula II
`
`is converted to the
`
`corresponding hydroxamic acid compound of formula I 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 It with trifluoroacetic acid or boron
`
`trifluoride diethyl etherate in a polar aprotic solvent, such as methylene chloride, or (3)
`
`treating II with tetrabutyl ammonium fluoride in a polar aprotic solution, such as
`
`tetrahydrofuran. The reaction mixture is stirred for a time period between about 2 hours
`
`to about 4 hours, preferably about 3 hours.
`
`Pharmaceutically acceptable salts of the acidic compounds of the invention are
`
`salts 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,
`
`such as ammonium,
`
`trimethyl-ammonium, diethylammonium,
`
`and tris-
`
`(hydroxymethyl)-methylammonium slats.
`
`Similarly acid addition salts, such as of mineral acids, organic carboxylic and
`
`organic sulfonic acids eg. hydrochloric acid, methanesulfonic acid, maleic acid, are
`
`also possible provided a basic group, such as pyridyl, constitutes part of the structure.
`
`The ability of the compounds of formula I or their pharmaceutically acceptable
`
`salts (hereinafter also referred to as the compounds of the present invention) to inhibit
`
`matrix metalloproteinases 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 ifl vitro assay tests.
`
`Biological Assay
`
`Inhibition of Human Collagenase (MMP-1)
`
`Human recombinant collagenase is activated with trypsin using the following
`
`ratio:
`
`10 ,ug trypsin per 100 ,ug of collagenase. The trypsin and collagenase are
`
`incubated at room temperature for 10 minutes then a five fold excess (50 ,ug/io ,ug
`
`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 ---->120pM --—~> 12 pM -—->1.2pM ---> 0.12pM
`
`10
`
`15
`
`20
`
`25
`
`30
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1616
`
`page 1616
`
`

`

`WO 98/30566
`
`PCT/lB97/01582
`
`-1 o-
`
`Twenty-five microiiters of each concentration is then added in triplicate to
`
`appropriate wells of a 96 well microfiuor plate. The final concentration of inhibitor will
`
`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, no inhibitors) are set in
`wells D7-D12.
`
`Collagenase is diluted to 400 ng/ml and 25 pl is then added to appropriate wells
`
`of the microfiuor plate. Final concentration of collagenase in the assay is 100 ng/ml.
`
`Substrate (DNP-Pro-Cha—Giy-Cys(Me)—His-Ala—Lys(NMA)—NH2) is made as a 5 mM
`
`stock in dimethyi suifoxide and then diluted to 20 uM in assay buffer. The assay is
`
`initiated by the addition of 50 pi substrate per well of the microfiuor plate to give a final
`
`concentration of 10 pM.
`
`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 lCso values. The zero time is used as a
`
`blank for each compound at each concentration and these values are subtracted from
`
`the 120 minute data. Data is plotted as inhibitor concentration vs % control (inhibitor
`
`fluorescence divided by fluorescence of collagenase alone x 100).
`
`iCso's are
`
`determined from the concentration of inhibitor that gives a signal that is 50% of the
`control.
`
`if
`
`iCSO's are reported to be <0.03 ”M then the inhibitors are assayed at
`
`concentrations of 0.3 ,uM, 0.03 pM, 0.03 pM and 0.003 ,uM.
`
`inhibition of Gelatinase (MMP-Z)
`
`Inhibition of gelatinase activity is assayed using the an-Pro-Cha—Giy-Cys(Me)-
`
`His-Aia—Lys(NMA)-NH2 substrate (10 ,uM) under the same conditions as inhibition of
`
`human collagenase (MMP—1).
`
`72kD gelatinase 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/mi.
`
`inhibitors are diluted as for inhibition of human collagenase (MMP-1) to give
`
`10
`
`15
`
`20
`
`25
`
`30
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 1617
`
`page 1617
`
`

`

`WO 98/30566
`
`PCT/IB97/01582
`
`-11-
`
`final concentrations in the assay of 30 pM, 3 ,uM, 0.3 pM and 0.03 ,uM.
`
`Each
`
`concentration is done in triplicate.
`
`Fluorescence readings (360 nm excitation, 460 emission) are taken at time zero
`
`and then at 20 minutes intervals for 4 hours.
`
`lCSO's are determined as per inhibition of human collagenase (MMP-1).
`
`lf leo's
`
`are reported to be less than 0.03 ,uM,
`
`then the inhibitors are assayed at final
`
`concentrations of 0.3 ,uM, 0.03 pM, 0.003