PCT
`PCT
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`WORLD INTELLECTUAL PROPERTY ORGANIZATION
`International Bureau
`International Bureau
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
`(51) International Patent Classification 6
`WO 99/65867
`(51) International Patent Classification 6
`WO 99/65867
`CO7C 259/08, CO7D 211/16, A61K 31/47, Al
`CO7C 259/08, CO7D 211/16, A61K 31/47, Al
`
`CO7D 211/22, 213/30, 215/22, 213/40, CO7D 211/22, 213/30, 215/22, 213/40,
`215/20, 401/12, 211/60, 405/14, 417/14,
`215/20, 401/12, 211/60, 405/14, 417/14,
`401/14, 409/14, A61K 31/445 401/14, 409/14, A61K 31/445
`
`
`(11) International Publication Number: (cid:9)
`(11) International Publication Number:
`
`(43) International Publication Date:
`(43) International Publication Date:
`
`23 December 1999 (23.12.99)
`23 December 1999 (23.12.99)
`
`(81) Designated States: AU, BR, CA, CN, CZ, EE, HU, IL, IN, JP, (81) Designated States: AU, BR, CA, CN, CZ, EE, HU, IL, IN, JP,
`
`KR, LT, LV, MX, NO, NZ, PL, RO, SG, SI, SK, TR, UA, KR, LT, LV, MX, NO, NZ, PL, RO, SG, SI, SK, TR, UA,
`
`VN, ZA, Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU,
`VN, ZA, Eurasian patent (AM, AZ, BY, KG, KZ, MD, RU,
`
`TJ, TM), European patent (AT, BE, CH, CY, DE, DK, ES, TJ, TM), European patent (AT, BE, CH, CY, DE, DK, ES,
`FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).
`FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE).
`
`Published
`Published
`With international search report.
`With international search report.
`Before the expiration of the time limit for amending the
`Before the expiration of the time limit for amending the
`claims and to be republished in the event of the receipt of
`claims and to be republished in the event of the receipt of
`amendments.
`amendments.
`
`(21) International Application Number: (cid:9)
`(21) International Application Number: (cid:9)
`
`
`
`PCT/US99/13723 PCT/US99/13723
`
`(22) International Filing Date: (cid:9)
`(22) International Filing Date: (cid:9)
`
`17 June 1999 (17.06.99)
`17 June 1999 (17.06.99)
`
`(30) Priority Data:
`(30) Priority Data:
`60/089,557
`60/089,557
`60/127,599
`60/127,599
`
`17 June 1998 (17.06.98) (cid:9)
`17 June 1998 (17.06.98) (cid:9)
`2 April 1999 (02.04.99) (cid:9)
`2 April 1999 (02.04.99) (cid:9)
`
`US
`US
`US
`US
`
`
`(71) Applicant: DU PONT PHARMACEUTICALS COMPANY (71) Applicant: DU PONT PHARMACEUTICALS COMPANY
`[US/US]; 974 Centre Road, WR-1ST18, Wilmington, DE
`[US/US]; 974 Centre Road, WR-1ST18, Wilmington, DE
`19807 (US).
`19807 (US).
`
`(72) Inventors: XUE, Chu—Baio; 11 Rivendell Court, Hockessin, (72) Inventors: XUE, Chu—Baio; 11 Rivendell Court, Hockessin,
`
`DE 19702 (US). DECICCO, Carl, P.; 17 Ridgewood Turn,
`DE 19702 (US). DECICCO, Carl, P.; 17 Ridgewood Turn,
`Newark, DE 19711 (US). HE, Xiaohua; 12 Old Flint Circle,
`Newark, DE 19711 (US). HE, Xiaohua; 12 Old Flint Circle,
`Hockessin, DE 19707 (US).
`Hockessin, DE 19707 (US).
`
`(74) Agent: VANCE, David, H.; Du Pont Pharmaceuticals Com-
`(74) Agent: VANCE, David, H.; Du Pont Pharmaceuticals Com-
`pany, Legal Patent Records Center, 1007 Market Street,
`pany, Legal Patent Records Center, 1007 Market Street,
`Wilmington, DE 19898 (US).
`Wilmington, DE 19898 (US).
`
`(54) Title: CYCLIC HYDROXAMIC ACIDS AS METALLOPROTEINASE INHIBITORS
`(54) Title: CYCLIC HYDROXAMIC ACIDS AS METALLOPROTEINASE INHIBITORS
`
`3
`
`2 (cid:9)
`
`R1 (cid:9)
`
`A
`
`(I)
`CO
`
`(57) Abstract
`(57) Abstract
`
`
`The present application describes novel cyclic hydroxamic acids of formula (I): or pharmaceutically acceptable salt forms thereof, The present application describes novel cyclic hydroxamic acids of formula (I): or pharmaceutically acceptable salt forms thereof,
`wherein ring B is a 5-7 membered cyclic system containing from 0-2 heteroatoms selected from 0, N, Nita and S(0)p, and 0-1 carbonyl
`wherein ring B is a 5-7 membered cyclic system containing from 0-2 heteroatoms selected from 0, N, NR' and S(0)p, and 0-1 carbonyl
`groups and the other variables are defined in the present specification, which are useful as metalloprotease inhibitors.
`groups and the other variables are defined in the present specification, which are useful as metalloprotease inhibitors.
`
`Ex. 1011 - Page 1
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`
`
`FOR THE PURPOSES OF INFORMATION ONLY 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. Codes used to identify States party to the PCT on the front pages of pamphlets publishing international applications under the PCT.
`
`
`AL AL
`
`AM AM
`
`AT AT
`
`AU AU
`
`AZ AZ
`
`BA BA
`
`BB BB
`
`BE BE
`
`BF BF
`
`BG BG
`
`BJ BJ
`
`BR BR
`
`BY BY
`
`CA CA
`
`CF CF
`
`CG CG
`
`CH CH
`
`CI CI
`
`CM CM
`
`CN CN
`
`CU CU
`
`CZ CZ
`
`DE DE
`
`DK DK
`
`EE EE
`
`
`Albania Albania
`
`Armenia Armenia
`
`Austria Austria
`
`Australia Australia
`
`Azerbaijan Azerbaijan
`
`Bosnia and Herzegovina Bosnia and Herzegovina
`
`Barbados Barbados
`
`Belgium Belgium
`
`Burkina Faso Burkina Faso
`
`Bulgaria Bulgaria
`
`Benin Benin
`
`Brazil Brazil
`
`Belarus Belarus
`
`Canada Canada
`
`Central African Republic Central African Republic
`
`Congo Congo
`
`Switzerland Switzerland
`
`Cote d'Ivoire Cote d'Ivoire
`
`Cameroon Cameroon
`
`China China
`
`Cuba Cuba
`
`Czech Republic Czech Republic
`
`Germany Germany
`
`Denmark Denmark
`
`Estonia Estonia
`
`
`ES ES
`
`Fl Fl
`
`FR FR
`
`GA GA
`
`GB GB
`
`GE GE
`
`GH GH
`
`GN GN
`
`GR GR
`
`HU HU
`
`IE IE
`
`IL IL
`
`IS IS
`
`IT IT
`
`JP JP
`
`KE KE
`
`KG KG
`
`KP KP
`
`
`KR KR
`
`KZ KZ
`
`LC LC
`
`LI LI
`
`LK LK
`
`LR LR
`
`
`Spain Spain
`
`Finland Finland
`
`France France
`
`Gabon Gabon
`
`United Kingdom United Kingdom
`
`Georgia Georgia
`
`Ghana Ghana
`
`Guinea Guinea
`
`Greece Greece
`
`Hungary Hungary
`
`Ireland Ireland
`
`Israel Israel
`
`Iceland Iceland
`
`Italy Italy
`
`Japan Japan
`
`Kenya Kenya
`
`Kyrgyzstan Kyrgyzstan
`
`Democratic People's Democratic People's
`
`Republic of Korea Republic of Korea
`
`Republic of Korea Republic of Korea
`
`Kazakstan Kazakstan
`
`Saint Lucia Saint Lucia
`
`Liechtenstein Liechtenstein
`
`Sri Lanka Sri Lanka
`
`Liberia Liberia
`
`
`LS LS
`
`LT LT
`
`LU LU
`
`LV LV
`
`MC MC
`
`MD MD
`
`MG MG
`
`MK MK
`
`
`ML ML
`
`MN MN
`
`MR MR
`
`MW MW
`
`MX MX
`
`NE NE
`
`NL NL
`
`NO NO
`
`NZ NZ
`
`PL PL
`
`PT PT
`
`RO RO
`
`RU RU
`
`SD SD
`
`SE SE
`
`SG SG
`
`
`Lesotho Lesotho
`
`Lithuania Lithuania
`
`Luxembourg Luxembourg
`
`Latvia Latvia
`
`Monaco Monaco
`
`Republic of Moldova Republic of Moldova
`
`Madagascar Madagascar
`
`The former Yugoslav The former Yugoslav
`
`Republic of Macedonia Republic of Macedonia
`
`Mali Mali
`
`Mongolia Mongolia
`
`Mauritania Mauritania
`
`Malawi Malawi
`
`Mexico Mexico
`
`Niger Niger
`
`Netherlands Netherlands
`
`Norway Norway
`
`New Zealand New Zealand
`
`Poland Poland
`
`Portugal Portugal
`
`Romania Romania
`
`Russian Federation Russian Federation
`
`Sudan Sudan
`
`Sweden Sweden
`
`Singapore Singapore
`
`
`SI SI
`
`SK SK
`
`SN SN
`
`SZ SZ
`
`TD TD
`
`TG TG
`
`TJ TJ
`
`TM TM
`
`TR TR
`
`TT TT
`
`UA UA
`
`UG UG
`
`US US
`
`UZ UZ
`
`VN VN
`
`YU YU
`
`ZW ZW
`
`
`Slovenia Slovenia
`
`Slovakia Slovakia
`
`Senegal Senegal
`
`Swaziland Swaziland
`
`Chad Chad
`
`Togo Togo
`
`Tajikistan Tajikistan
`
`Turkmenistan Turkmenistan
`
`Turkey Turkey
`
`Trinidad and Tobago Trinidad and Tobago
`
`Ukraine Ukraine
`
`Uganda Uganda
`
`United States of America United States of America
`
`Uzbekistan Uzbekistan
`
`Viet Nam Viet Nam
`
`Yugoslavia Yugoslavia
`
`Zimbabwe Zimbabwe
`
`Ex. 1011 - Page 2
`
`

`

`WO 99/65867 (cid:9)
`WO 99/65867
`
`PCT/US99/13723
`PCT/US99/13723
`
`CYCLIC HYDROXAMIC ACIDS AS METALLOPROTEINASE INHIBITORS
`CYCLIC HYDROXAMIC ACIDS AS METALLOPROTEINASE INHIBITORS
`
`
`
`5 5
`
`FIELD OF THE INVENTION
`FIELD OF THE INVENTION
`
`This invention relates generally to novel cyclic This invention relates generally to novel cyclic
`
`hydroxamic acids as metalloproteinase inhibitors, hydroxamic acids as metalloproteinase inhibitors,
`pharmaceutical compositions containing the same, and methods
`pharmaceutical compositions containing the same, and methods
`10 of using the same.
`10 of using the same.
`
`BACKGROUND OF THE INVENTION
`BACKGROUND OF THE INVENTION
`
`There is now a body of evidence that metalloproteinases There is now a body of evidence that metalloproteinases
`(MP) are important in the uncontrolled breakdown of
`(MP) are important in the uncontrolled breakdown of
`15 connective tissue, including proteoglycan and collagen,
`15 connective tissue, including proteoglycan and collagen,
`leading to resorption of the extracellular matrix. This is
`leading to resorption of the extracellular matrix. This is
`
`a feature of many pathological conditions, such as a feature of many pathological conditions, such as
`
`rheumatoid and osteoarthritis, corneal, epidermal or gastric rheumatoid and osteoarthritis, corneal, epidermal or gastric
`ulceration; tumor metastasis or invasion; periodontal
`ulceration; tumor metastasis or invasion; periodontal
`
`20 disease and bone disease. Normally these catabolic enzymes 20 disease and bone disease. Normally these catabolic enzymes
`
`are tightly regulated at the level of their synthesis as are tightly regulated at the level of their synthesis as
`well as at their level of extracellular activity through the
`well as at their level of extracellular activity through the
`action of specific inhibitors, such as alpha-2-
`action of specific inhibitors, such as alpha-2-
`macroglobulins and TIMP (tissue inhibitor of
`macroglobulins and TIMP (tissue inhibitor of
`
`25 metalloproteinase), which form inactive complexes with the 25 metalloproteinase), which form inactive complexes with the
`
`MP's. MP's.
`
`Osteo- and Rheumatoid Arthritis (OA and RA Osteo- and Rheumatoid Arthritis (OA and RA
`
`respectively) are destructive diseases of articular respectively) are destructive diseases of articular
`
`cartilage characterized by localized erosion of the cartilage characterized by localized erosion of the
`
`30 cartilage surface. Findings have shown that articular 30 cartilage surface. Findings have shown that articular
`cartilage from the femoral heads of patients with OA, for
`cartilage from the femoral heads of patients with OA, for
`example, had a reduced incorporation of radiolabeled sulfate
`example, had a reduced incorporation of radiolabeled sulfate
`
`over controls, suggesting that there must be an enhanced over controls, suggesting that there must be an enhanced
`
`rate of cartilage degradation in OA (Mankin et al. J. Bone rate of cartilage degradation in OA (Mankin et al. J. Bone
`
`35 Joint Surg. 52A, 1970, 424-434). There are four classes of 35 Joint Surg. 52A, 1970, 424-434). There are four classes of
`protein degradative enzymes in mammalian cells: serine,
`protein degradative enzymes in mammalian cells: serine,
`cysteine, aspartic and metalloproteinases. The available
`cysteine, aspartic and metalloproteinases. The available
`
`evidence supports that it is the metalloproteinases which evidence supports that it is the metalloproteinases which
`
`Ex. 1011 - Page 3
`
`(cid:9)
`

`

`WO 99/65867 (cid:9)
`WO 99/65867 (cid:9)
`
`PCT/US99/13723
`PCT/US99/13723
`
`are responsible for the degradation of the extracellular
`are responsible for the degradation of the extracellular
`matrix of articular cartilage in OA and RA. Increased
`matrix of articular cartilage in OA and RA. Increased
`activities of collagenases and stromelysin have been found
`activities of collagenases and stromelysin have been found
`in. OA cartilage and the activity correlates with severity of
`in OA cartilage and the activity correlates with severity of
`5 the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-
`5 the lesion (Mankin et al. Arthritis Rheum. 21, 1978, 761-
`766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and
`766, Woessner et al. Arthritis Rheum. 26, 1983, 63-68 and
`Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly
`Ibid. 27, 1984, 305-312). In addition, aggrecanase (a newly
`identified metalloproteinase enzymatic activity) has been
`identified metalloproteinase enzymatic activity) has been
`identified that provides the specific cleavage product of
`identified that provides the specific cleavage product of
`10 proteoglycan, found in RA and OA patients (Lohmander L.S. et
`10 proteoglycan, found in RA and OA patients (Lohmander L.S. et
`al. Arthritis Rheum. 36, 1993, 1214-22).
`al. Arthritis Rheum. 36, 1993, 1214-22).
`Therefore metalloproteinases (MP) have been implicated
`Therefore metalloproteinases (MP) have been implicated
`as the key enzymes in the destruction of mammalian cartilage
`as the key enzymes in the destruction of mammalian cartilage
`and bone. It can be expected that the pathogenesis of such
`and bone. It can be expected that the pathogenesis of such
`15 diseases can be modified in a beneficial manner by the
`15 diseases can be modified in a beneficial manner by the
`administration of MP inhibitors, and many compounds have
`administration of MP inhibitors, and many compounds have
`been suggested for this purpose (see Wahl et al. Ann. Rep.
`been suggested for this purpose (see Wahl et al. Ann. Rep.
`Med. Chem. 25, 175-184, AP, San Diego, 1990).
`Med. Chem. 25, 175-184, AP, San Diego, 1990).
`Tumor necrosis factor (TNF) is a cell associated
`Tumor necrosis factor (TNF) is a cell associated
`cytokine that is processed from a 26kd precursor form to a
`
`17kd active form. TNF has been shown to be a primary
`17kd active form. TNF has been shown to be a primary
`mediator in humans and in animals, of inflammation, fever,
`mediator in humans and in animals, of inflammation, fever,
`and acute phase responses, similar to those observed during
`and acute phase responses, similar to those observed during
`acute infection and shock. Excess TNF has been shown to be
`acute infection and shock. Excess TNF has been shown to be
`25 lethal. There is now considerable evidence that blocking
`lethal. There is now considerable evidence that blocking
`25 (cid:9)
`the effects of TNF with specific antibodies can be
`the effects of TNF with specific antibodies can be
`beneficial in a variety of circumstances including
`beneficial in a variety of circumstances including
`autoimmune diseases such as rheumatoid arthritis (Feldman et
`autoimmune diseases such as rheumatoid arthritis (Feldman et
`al, Lancet, 1994, 344, 1105) and non-insulin dependent
`al, Lancet, 1994, 344, 1105) and non-insulin dependent
`30 diabetes melitus. (Lohmander L.S. et al. Arthritis Rheum.
`30 diabetes melitus. (Lohmander L.S. et al. Arthritis Rheum.
`36, 1993, 1214-22) and Crohn's disease (MacDonald T. et al.
`36, 1993, 1214-22) and Crohn's disease (MacDonald T. et al.
`Clin. Exp. Immunol. 81, 1990, 301).
`Clin. Exp. Immunol. 81, 1990, 301).
`Compounds which inhibit the production of TNF are
`Compounds which inhibit the production of TNF are
`therefore of therapeutic importance for the treatment of
`therefore of therapeutic importance for the treatment of
`
`35 (cid:9)35 inflammatory disorders. Recently it has been shown that a inflammatory disorders. Recently it has been shown that a
`matrix metalloproteinase or family of metalloproteinases,
`matrix metalloproteinase or family of metalloproteinases,
`hereafter known as TNF-convertases (TNF-C), as well as other
`hereafter known as TNF-convertases (TNF-C), as well as other
`
`MP's are capable of cleaving TNF from its inactive to active MP's are capable of cleaving TNF from its inactive to active
`
`20 cytokine that is processed from a 26kd precursor form to a 20 (cid:9)
`
`
`
`2
`2
`
`Ex. 1011 - Page 4
`
`

`

`WO 99/65867 (cid:9)
`WO 99/65867 (cid:9)
`
`PCT/US99/13723
`PCT/US99/13723
`
`15 (cid:9)
`15 (cid:9)
`
`form (Gearing et al Nature, 1994, 370, 555). This invention
`form (Gearing et al Nature, 1994, 370, 555). This invention
`describes molecules that inhibit this conversion and hence
`describes molecules that inhibit this conversion and hence
`the secretion of active TNF-a from cells. These novel
`the secretion of active TNF-a from cells. These novel
`molecules provide a means of mechanism based therapeutic
`molecules provide a means of mechanism based therapeutic
`5 intervention for diseases including but not restricted to
`5 intervention for diseases including but not restricted to
`septic shock, haemodynamic shock, sepsis syndrom, post
`septic shock, haemodynamic shock, sepsis syndrom, post
`ischaemic reperfusion injury, malaria, Crohn's disease,
`ischaemic reperfusion injury, malaria, Crohn's disease,
`inflammatory bowel diseases, mycobacterial infection,
`inflammatory bowel diseases, mycobacterial infection,
`meningitis, psoriasis, congestive heart failure, fibrotic
`meningitis, psoriasis, congestive heart failure, fibrotic
`10 diseases, cachexia, graft rejection, cancer, diseases
`10 diseases, cachexia, graft rejection, cancer, diseases
`involving angiogenesis, autoimmune diseases, skin
`involving angiogenesis, autoimmune diseases, skin
`inflammatory diseases, OA, RA, multiple sclerosis, radiation
`inflammatory diseases, OA, RA, multiple sclerosis, radiation
`damage, hyperoxic alveolar injury, periodontal disease, HIV
`damage, hyperoxic alveolar injury, periodontal disease, HIV
`and non-insulin dependent diabetes melitus.
`and non-insulin dependent diabetes melitus.
`Since excessive TNF production has been noted in
`Since excessive TNF production has been noted in
`several disease conditions also charactarized by MMP-
`several disease conditions also charactarized by MMP-
`mediated tissue degradation, compounds which inhibit both
`mediated tissue degradation, compounds which inhibit both
`MMPs and TNF production may also have a particular advantage
`MMPs and TNF production may also have a particular advantage
`in diseases where both mechansisms are involved.
`in diseases where both mechansisms are involved.
`EP 0,780,286 describes MMP inhibitors of formula A:
`EP 0,780,286 describes MMP inhibitors of formula A:
`
`
`
`20 (cid:9)20 (cid:9)
`
`R1 R2
`R2
`S02—R5
`j02-R5
`O R3 R4
`n3/\ 4
`II
`0 R R
`A
`A
`wherein Y can be NHOH, R1 and R2 can combine to form a
`wherein Y can be NHOH, R1 and R2 can combine to form a
`25 cycloalkyl or heterocyclo alkyl group, R3 and R4 can be a
`25 cycloalkyl or heterocyclo alkyl group, R3 and R4 can be a
`variety of groups including H, and R5 can be substituted
`variety of groups including H, and R5 can be substituted
`aryl.
`aryl.
`WO 97/20824 depicts MMP inhibitors of formula B:
`WO 97/20824 depicts MMP inhibitors of formula B:
`
`Z—Ar
`Z—Ar
`
`HOHN
`HOHN
`
`30
`30
`
`B
`wherein ring V contains six atoms, Z is 0 or S, and Ar is an
`wherein ring V contains six atoms, Z is 0 or S, and Ar is an
`aryl or heteroaryl group. Ar is preferably a monocyclic
`aryl or heteroaryl group. Ar is preferably a monocyclic
`
`3
`3
`
`Ex. 1011 - Page 5
`
`

`

`WO 99/65867 (cid:9)
`WO 99/65867 (cid:9)
`
`PCT/US99/13723
`PCT/US99/13723
`
`aryl group with an optional para substituent or an
`aryl group with an optional para substituent or an
`unsubstituted monocyclic heteroaryl group.
`unsubstituted monocyclic heteroaryl group.
`EP 0,818,442 illustrates MMP inhibitors of formula C:
`EP 0,818,442 illustrates MMP inhibitors of formula C:
`
`HOHN
`HOHN
`
`Ar
`02S Ar
`02S
`
`0
`0
`
`~ZJ
`q
`q ,;(x)
`X)
`Y
`P
`Y
`P
`
`5
`5
`
`C
`C
`wherein Ar is optionally substituted phenyl or naphthyl, Z
`wherein Ar is optionally substituted phenyl or naphthyl, Z
`can be absent and X and Y can be a variety of substituents.
`can be absent and X and Y can be a variety of substituents.
`Compounds of this sort are not considered to be part of the
`Compounds of this sort are not considered to be part of the
`
`10 present invention. 10 present invention.
`The compounds of the present invention act as
`The compounds of the present invention act as
`inhibitors of MMPs, in particular aggrecanase and TNF.
`inhibitors of MMPs, in particular aggrecanase and TNF.
`These novel molecules are provided as anti-inflammatory
`These novel molecules are provided as anti-inflammatory
`compounds and cartilage protecting therapeutics. The
`compounds and cartilage protecting therapeutics. The
`
`15 inhibiton of aggrecanase, TNF-C, and other 15 inhibiton of aggrecanase, TNF-C, and other
`metalloproteinases by molecules of the present invention
`metalloproteinases by molecules of the present invention
`indicates they are anti-inflammatory and should prevent the
`indicates they are anti-inflammatory and should prevent the
`degradation of cartilage by these enzymes, thereby
`degradation of cartilage by these enzymes, thereby
`alleviating the pathological conditions of OA and RA,.
`alleviating the pathological conditions of OA and RA,.
`
`20
`20
`
`SUMMARY OF THE INVENTION
`SUMMARY OF THE INVENTION
`Accordingly, one object of the present invention is to
`Accordingly, one object of the present invention is to
`provide novel cyclic hydroxamic acids which are useful as
`provide novel cyclic hydroxamic acids which are useful as
`metalloprotease inhibitors or pharmaceutically acceptable
`metalloprotease inhibitors or pharmaceutically acceptable
`25 salts or prodrugs thereof.
`25 salts or prodrugs thereof.
`It is another object of the present invention to
`It is another object of the present invention to
`provide pharmaceutical compositions comprising a
`provide pharmaceutical compositions comprising a
`pharmaceutically acceptable carrier and a therapeutically
`pharmaceutically acceptable carrier and a therapeutically
`effective amount of at least one of the compounds of the
`effective amount of at least one of the compounds of the
`
`30 present invention or a pharmaceutically acceptable salt or 30 present invention or a pharmaceutically acceptable salt or
`prodrug form thereof.
`prodrug form thereof.
`
`It is another object of the present invention to It is another object of the present invention to
`provide a method for treating inflammatory disorders
`provide a method for treating inflammatory disorders
`comprising administering to a host in need of such treatment
`comprising administering to a host in need of such treatment
`
`4
`4
`
`Ex. 1011 - Page 6
`
`

`

`WO 99/65867 (cid:9)
`WO 99/65867 (cid:9)
`
`
`
`PCT/US99/13723 PCT/US99/13723
`
`a therapeutically effective amount of at least one of the
`a therapeutically effective amount of at least one of the
`compounds of the present invention or a pharmaceutically
`compounds of the present invention or a pharmaceutically
`
`acceptable salt or prodrug form thereof. acceptable salt or prodrug form thereof.
`It is another object of the present invention to
`It is another object of the present invention to
`5 provide novel compounds of formula (I) for use in therapy.
`5 provide novel compounds of formula (I) for use in therapy.
`It is another object of the present invention to
`It is another object of the present invention to
`provide the use of novel compounds of formula (I) for the
`provide the use of novel compounds of formula (I) for the
`manufacture of a medicament for the treatment of a condition
`manufacture of a medicament for the treatment of a condition
`or disease mediated by MMPs, TNF, aggrecanase, or a
`or disease mediated by MMPs, TNF, aggrecanase, or a
`10 combination thereof.
`10 combination thereof.
`These and other objects, which will become apparent
`These and other objects, which will become apparent
`during the following detailed description, have been
`during the following detailed description, have been
`achieved by the inventors' discovery that compounds of
`achieved by the inventors' discovery that compounds of
`formula (I):
`formula (I):
`
`15
`15
`
`H
`H
`
`I
`I
`or pharmaceutically acceptable salt or prodrug forms
`or pharmaceutically acceptable salt or prodrug forms
`thereof, wherein A, B, R1, R2, and R3 are defined below, are
`thereof, wherein A, B, R1, R2, and R3 are defined below, are
`20 effective metalloprotease inhibitors.
`20 effective metalloprotease inhibitors.
`
`
`DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
`[1] Thus, in an embodiment, the present invention provides
`[1] Thus, in an embodiment, the present invention provides
`a novel compound of formula I:
`a novel compound of formula I:
`
`
`
`25 25
`
`30
`30
`
`R1
`
`A
`
`H
`H
`
`I
`I
`or a stereoisomer or pharmaceutically acceptable salt form
`or a stereoisomer or pharmaceutically acceptable salt form
`
`thereof, wherein; thereof, wherein;
`
`A is selected from -COR5, -CO2H, CH2CO2H, -CO2R6, -CONHOH,
`A is selected from -COR5, -CO2H, CH2CO2H, -0O2R6, -CONHOH,
`-CONHOR5, -CONHOR6, -NHRa, -N(OH)COR5, -SH, -CH2SH,
`-CONHOR5, -CONHOR6, -NHRa, -N(OH)COR5, -SH, -CH2SH,
`-SONHRa, -SN2H2Ra, -PO(OH)2, and -P0(OH)NHRa;
`-SONHRa, -SN2H2Ra, -P0(OH)2, and -P0(OH)NIIRa;
`
`5
`5
`
`Ex. 1011 - Page 7
`
`

`

`WO 99/65867 (cid:9)
`WO 99/65867 (cid:9)
`
`PCT/US99/13723
`PCT/US99/13723
`
`ring B is a 3-8 membered non-aromatic ring with 0-1 carbonyl
`ring B is a 3-8 membered non-aromatic ring with 0-1 carbonyl
`groups and from 0-2 ring heteroatoms selected from 0,
`groups and from 0-2 ring heteroatoms selected from 0,
`N, NR2, and S(0)p, provided that ring B contains a
`N, NR2, and S(0)p, provided that ring B contains a
`
`total of 0-1 ring S and 0 atoms; total of 0-1 ring S and 0 atoms;
`
`5 (cid:9)
`5 (cid:9)
`
`R1 is -U-X-Y-Z-Ua-Xa-Ya-Za;
`R1 is -U-X-Y-Z-Ua-Xa-Ya-Za;
`
`10 (cid:9)
`10 (cid:9)
`
`U is absent or is selected from: 0, NRa', C(0), C(0)0,
`U is absent or is selected from: 0, NRa', C(0), C(0)0,
`OC(0), C(0)NRa', NRa'C(0), OC(0)0, OC(0)NRat , NRa'C(0)0,
`OC(0), C(0)NRa', NRa"C(0), OC(0)0, OC(0)NRa', NRa'C(0)0,
`NRa"C(0)NRa", S(0) p , S(0) pNRa', NRa'S(0) p , and
`NRa'C(0)NRa t , S(0) p , S(0) pNRa', NRa'S(0) p , and
`NRa'S02NRa";
`NRa"SO2NRa';
`
`X is absent or selected from C1_10 alkylene, C2-10
`X is absent or selected from C1-10 alkylene, C2-10
`alkenylene, and C2_10 alkynylene;
`alkenylene, and C2_10 alkynylene;
`
`
`
`15 (cid:9)15 (cid:9)
`
`
`
`Y is absent or selected from 0, NRa', S(0) p, and C(0); Y is absent or selected from 0, NRa', S(0)p, and C(0);
`
`
`
`20 (cid:9)20 (cid:9)
`
`Z is absent or selected from a C3_13 carbocyclic residue
`Z is absent or selected from a C3_13 carbocyclic residue
`substituted with 0-5 Rb and a 5-14 membered
`substituted with 0-5 Rb and a 5-14 membered
`
`heterocyclic system containing from 1-4 heteroatoms heterocyclic system containing from 1-4 heteroatoms
`selected from the group consisting of N, 0, and S and selected from the group consisting of N, 0, and S and
`
`substituted with 0-5 Rb;
`substituted with 0-5 Rb;
`
`
`25 Ua is absent or is selected from: 0, NRa', C(0), C(0)0, 25 Ua is absent or is selected from: 0, NRa', C(0), C(0)0,
`OC(0), C(0)NRa", NRa'C(0), OC(0)0, OC(0)NRa t , NRa'C(0)0,
`OC(0), C(0)NRa', NRa'C(0), OC(0)0, OC(0)NRa', NRa'C(0)0,
`NRa t C(0)NRa t , S(0)p, S(0) pNRa t , NRa t S(0)p, and NRa'C(0)NRa", S(0) p , S(0) pNRa', NRa'S(0) p , and
`
`NRa'SO2NRa';
`NRa'SO2NRa';
`
`30 Xa is absent or selected from C1_10 alkylene, C2_10
`30 Xa is absent or selected from C1_10 alkylene, C2_10
`alkenylene, and C2_10 alkynylene;
`alkenylene, and C2_10 alkynylene;
`
`Ya is absent or selected from 0, NRa", S(0)p, and C(0);
`Ya is absent or selected from 0, NRa', S(0) p, and C(0);
`
`35 (cid:9)
`35 (cid:9)
`
`Za is selected from H, a C3_13 carbocyclic residue
`Za is selected from H, a C3_13 carbocyclic residue
`substituted with 0-5 Rc and a 5-14 membered
`substituted with 0-5 Rc and a 5-14 membered
`heterocyclic system containing from 1-4 heteroatoms
`heterocyclic system containing from 1-4 heteroatoms
`
`6
`6
`
`Ex. 1011 - Page 8
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 99/65867 (cid:9)
`WO 99/65867 (cid:9)
`
`PCT/US99/13723
`PCT/US99/13723
`
`selected from the group consisting of N, 0, and S and
`selected from the group consisting of N, 0, and S and
`substituted with 0-5 Rc;
`substituted with 0-5 Rc;
`
`5 (cid:9)
`5 (cid:9)
`
`provided that U, Y, Z, Ua, Ya, and Za do not combine to form
`provided that U, Y, Z, Ua, Ya, and Za do not combine to form
`a N-N, N-0, 0-N, 0-0, S(0)p-0, 0-S(0)p or S(0)p-S(0)p
`a N-N, N-0, 0-N, 0-0, S(0)p-0, 0-S(0)p or S(0)p-S(0)p
`group;
`group;
`
`10 (cid:9)
`10 (cid:9)
`
`15 (cid:9)
`15 (cid:9)
`
`20
`20
`
`25
`25
`
`30 (cid:9)
`30 (cid:9)
`
`35 (cid:9)
`35 (cid:9)
`
`R2 is selected from H, C1_6 alkylene-Q, C2_6 alkenylene-Q,
`R2 is selected from H, C1_6 alkylene-Q, C2_6 alkenylene-Q,
`C2_6 alkynylene-Q, (CRaRa ')r , O(CRaRa ') r-Q,
`C2_6 alkynylene-Q, (CRaRa ')r , O(CRaRa ') r-Q,
`(CRaRa') r , NRa(CRaRa i ) r-4, (CRaRa ')rC(0)(CRaRa ') r-Q,
`(CRaRa ) r ,NRa (CRaRa' )r-Q, (CRaRa' ) rC (0) (CRaRa ) r-Q,
`(CRaRai ) rC(0)0(CRaRa') r -Q, (CRaRa ') r , OC(0)(CRaRa') r-Q,
`(CRaRa' ) rC (0) 0 (CRaRa ) r-Q, (CRaRa' ) r , OC (0) (CRaRa ) r-Q,
`(CRaRa ') rC(0)NRa(CRaRa') r-Q, (CRaRa') r , NRaC(0) (CRaRa ')r-Q,
`(CRaRa' ) rC (0) NRa ( CRaRa ) r-Q, (CRaRa ) r •NRaC (0) (CRaRa ' ) r-Q,
`(CRaRa ') r , OC(0)0(CRaRa') r-Q,
`(CRaRa ' ) r , OC (0) 0 (CRaRa ) r -Q,
`(CRaRa') r , °C(0)NRa(CRaRa') r-Q,
`(CRaRa ) r OC (0) NRa (CRaRa ) r-Q,
`(CRaRa ') r , NRaC(0)0(CRaRa') r-Q,
`(CRaRa ) r ,NRaC (0) 0 (CRaRa ' ) r -Q,
`(CRaRa ')r , NRaC(0)NRa (CRaRa ') r-4,
`(CRaRa' ) r • NRaC (0 ) NRa (CRaRa ' ) r-Q
`(CRaRa i ) r , S(0)p(CRaRa") r -Q, (CRaRa ') r , S02NRa (CRaRa') r-Q,
`(CRaRai ) r , S(0)p(CRaRa ') r-Q, (CRaRa ')r'S02NRa (CRaRa ')r-0,
`
`(CRaRa' ) r ,NRaS02 (CRaRa' ) r-Q, and
`(CRaRa ') r , NRaS02(CRaRa') r-Q, and
`(CRaRa s ) r , NRaS02NRa(CRaRa') r-Q;
`(CRaRa s ) r ,NRaSO2NRa(CRaRa') r-Q;
`
`Q is selected from H, a C3_13 carbocyclic residue substituted
`Q is selected from H, a C3_13 carbocyclic residue substituted
`with 0-5 Rd and a 5-14 membered heteroaryl system
`with 0-5 Rd and a 5-14 membered heteroaryl system
`containing from 1-4 heteroatoms selected from the group
`containing from 1-4 heteroatoms selected from the group
`consisting of N, 0, and S and substituted with 0-5 Rd;
`consisting of N, 0, and S and substituted with 0-5 Rd;
`
`R3 is selected from H, C1-6 alkylene-Q', C2-6 alkenylene-Q',
`R3 is selected from H, C1-6 alkylene-Q' , C2-6 alkenylene-Q',
`C2_6 alkynylene-Q' , (CRaHa ' ) r ' 0 (CH2) r -Q
`C2_6 alkynylene-Q', (CRaRa ')r , 0(CH2)r-4 1 ,
`
`(CRaRa ' ) r , NRa (CRaRa ) r -Q (cid:9)(CRaRa ') r , NRa(CRaRa') r-41 , (CRaRa ')r , NRaC(0)(CRaRa') r-4',
`(CRaRa' ) r , NRaC (0) (CRaRa ) r -Q
`(CRaRa ') r , C(0)NRa(CRaRa . ) r-41 , (CRaRa ')rc(0)(CRaRa ') r-Q',
`(CRaRa ) r C (0) NRa (CRaRa ) r-Q (cid:9)
`(CRaRa ' ) rC (0) (CRaRa' ) r -Q
`(CRaRa ') rC(0)0(CRaRa ') r -Q', (CRaRa '2) r , S(0)p(CRaRa') r-Q1 ,
`(CRaRa ') rC(0)0(CRaRa ') r -12 1 , (CRaRa '2) r , S(0)p(CRaRa') r-Q',
`and (CRaRa ")r , S02NRa (CRaRa ') r-Q 1 ;
`and (CRaRa ) r , SO2NRa (CRaRa ) r-Q ;
`
`Q' is selected from H, phenyl substituted with 0-3 Rd,
`Q' is selected from H, phenyl substituted with 0-3 Rd,
`naphthyl substituted with 0-3 Rd and a 5-10 membered
`naphthyl substituted with 0-3 Rd and a 5-10 membered
`heteroaryl system containing from 1-4 heteroatoms
`heteroaryl system containing from 1-4 heteroatoms
`selected from the group consisting of N, 0, and S and
`selected from the group consisting of N, 0, and S and
`substituted with 0-3 Rd ;
`substituted with 0-3 Rd;
`
`7
`7
`
`Ex. 1011 - Page 9
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`

`WO 99/65867 (cid:9)
`WO 99/65867 (cid:9)
`
`
`
`PCT/US99/13723 PCT/US99/13723
`
`alternatively, R2 and R3 combine to form a fused benzo ring
`alternatively, R2 and R3 combine to form a fused benzo ring
`substituted with R3';
`substituted with R3 ";
`
`R3 ' is selected from H, (CRaRa ') r-Q', C2_6 alkenylene-Q', C2-6
`R3 ' is selected from H, (CRaRa ')r-4', C2-6 alkenylene-Q 1 , C2-6
`alkynylene-Q', (CRaRa ') r , O(CH2) r-Q 1 , alkynylene-Q', (CRaRa ')r , O(CH2)r -Q 1 ,
`
`(CRaRa ' ) r , NRaC (0) (CRaRa' ) r _Q
`( CRaRa ' ) r , NRa (CRaRa ) r -Q ' (cid:9)
`(CRaRa ) r NRa ( CRaRa ) r -Q ' (cid:9)
`(CRaRa ' ) r , NRaC (0) ( CRaRa ) r -Q
`( CRaRa ) rC ( 0) (CRaRa ) r-Q (CRaRa ' ) rC (0) (CRaRa ' ) r-Q '
`
`(CRaRa' ) r C ( 0 ) NRa (CRaRa ) r-(2 1 (cid:9)
`(CRaRa ) r C ( 0 ) NRa (CRaRa ) r-4 (cid:9)
`(CRaRai ) rC(0)0(CRaRa ')r-T, (CRaRa ') r , S(0)p(CRaRa ')r-T,
`(CRaRa ) r S ( 0) p (CRaRa ) r-4',
`(CRaRa ) rC ( 0 ) 0 (CRaRa ) r-Q (cid:9)
`
`and (CRaRa s ) r , S02NRa(CRaRa') r-Qt; and (CRaRa s ) r , S02NRa(CRaRa ') r-Q t ;
`
`5 (cid:9)
`5 (cid:9)
`
`10
`10
`
`Ra, at each occurrence, is independently selected from H,
`Ra, at each occurrence, is independently selected from H,
`C1_4 alkyl, phenyl and benzyl;
`C1_4 alkyl, phenyl and benzyl;
`
`Ra', at each occurrence, is independently selected from H
`Ra', at each occurrence, is independently selected from H
`and C1_4 alkyl;
`and C1_4 alkyl;
`
`15 (cid:9)
`15 (cid:9)
`
`alternatively, Ra