WO 99/52910
`
`PCT/IB99/00503
`
`leukemias and lymphomas), tissue ulceration, restenosis, periodontal disease, epidermolysis
`
`bullosa,
`
`osteoporosis.
`
`loosening of
`
`artificial
`
`joint
`
`implants,
`
`atherosclerosis
`
`(including
`
`atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and brain
`
`aortic aneurysm), congestive heart failure, myocardial infarction. stroke, cerebral ischemia, head
`
`trauma, spinal cord injury, neuro-degenerative disorders (acute and chronic), autoimmune
`
`disorders, Huntington’s disease, Parkinson’s disease, migraine, depression,
`
`periphEral
`
`neuropathy,
`
`pain,
`
`cerebral
`
`amyloid
`
`angiopathy,
`
`nootropic or
`
`cognition
`
`enhancement,
`
`amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, comeai injury, macular
`
`degeneration, abnormai wound healing, burns, diabetes, tumor invasion, tumor growth, tumor
`
`metastasis, comeai
`
`scarring,
`
`scleritis, AIDS,
`
`sepsis,
`
`septic shock and other diseases
`
`characterized by metalloproteinase activity and other diseases characterized by mammalian
`
`reprolysin activity 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 pharmaceutical composition for the inhibition of
`
`(a) matrix metaIIOproteinases or other metalloproteinases involved in matrix degradation, or (b) a
`
`mammalian reprolysin (such as aggrecanase or ADAM's TS-1, 10, 12, 15 and 17, most
`
`preferably ADAM-17) in a mammal,
`
`including a human, comprising an effective amount of a
`
`compound of formula I or a pharmaceutically acceptable sait thereof.
`
`The present invention also relates to a method for treating a condition selected from the
`
`group consisting of arthritis (including osteoarthritis and rheumatoid arthritis), inflammatory bowel
`
`disease, Crohn's disease, emphysema, chronic obstructive pulmonary disease, Alzheimers
`
`disease, organ transplant toxicity, cachexia, allergic reactions, allergic contact hypersensitivity,
`
`cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis,
`
`loosening of artificial joint implants, atherosclerosis (including atherosclerotic plaque rupture),
`
`aortic aneurysm (including abdominal aortic aneurysm and brain aortic aneurysm), congestive
`
`heart failure, myocardial infarction, stroke, cerebral ischemia, head trauma, spinal cord injury,
`
`neuro—degenerative disorders (acute and chronic), autoimmune disorders, Huntington's disease,
`
`Parkinson’s disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid
`angiopathy, nootropic or cognition enhancement, amyotrophic lateral
`sclerosis, multiple
`
`sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing,
`
`burns, diabetes,
`
`tumor invasion,
`
`tumor growth,
`
`tumor metastasis, comeai scarring, scleritis,
`
`AlDS, sepsis, septic shock and other diseases characterized by metalloproteinase activity and
`
`other diseases characterized by mammalian reprolysin activity in a mammal, 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
`
`3O
`
`35
`
`40
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`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2001
`
`page 2001
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`

`

`WO 99/52910
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`PCT/IB99/00503
`
`-10-
`
`The present
`
`invention also relates to a method for
`
`the inhibition of
`
`(a) matrix
`
`metalloproteinases or other metalloproteinases involved in matrix degradation, or
`
`(b) a
`
`mammalian reprolysin (such as aggrecanase or ADAM‘s TS—1, 10, 12, 15 and 17, preferably
`
`ADAM-17) in a mammal,
`
`including a human, comprising administering to said mammal an
`
`effective amount of a compound of formula I or a pharrnaceutically acceptable salt thereof.
`
`This invention also encompasses pharmaceutical compositions containing prodrugs?of
`
`compounds of the formula I. This invention also encompasses methods of treating or preventing
`
`disorders that can be treated or prevented by the inhibition of matrix metalloproteinases or the
`
`inhibition of mammalian reprolysin comprising administering prodrugs of compounds of the
`
`formula I. Compounds of formula I having free amino, amido, hydroxy or carboxylic groups can
`
`be converted into prodrugs. Prodrugs include compounds wherein an amino acid residue, or a
`
`polypeptide chain of two or more (e.g.,
`
`two. three or four) amino acid residues which are
`
`covalently joined through peptide bonds to free amino. hydroxy or carboxylic acid groups of
`
`compounds of formula I. The amino acid residues include the 20 naturally occurring amino acids
`
`commonly designated by three letter symbols and also include, 4-hydroxyproline. hydroxylysine.
`
`demosine,
`
`isodemosine, 3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,
`
`citrulline, homocysteine, homoserine. omithine and methionine sulfone. Prodrugs also include
`
`compounds wherein carbonates, carbamates, amides and alkyl esters which are covalently
`
`bonded to the above substituents of formula l through the carbonyl carbon prodrug sidechain.
`
`One of ordinary skill in the art will appreciate that the compounds of the invention are
`
`useful
`
`in treating a diverse array of diseases. One of ordinary skill
`
`in the art will also
`
`appreciate that when using the compounds of the invention in the treatment of a specific
`
`disease that
`
`the compounds of the invention may be combined with various existing
`
`therapeutic agents used for that disease.
`
`For the treatment of rheumatoid arthritis, the compounds of the invention may be
`
`combined with agents such as TNF-a inhibitors such as anti-TNF monoclonal antibodies and
`
`TNF receptor
`
`immunoglobulin molecules (such as Enbrel®),
`
`low dose methotrexate,
`
`lefunimide, hydroxychloroquine, d-penicilamine, auranofin or parenteral or oral gold.
`
`The compounds of the invention can also be used in combination with existing
`
`therapeutic agents for
`
`the treatment of osteoarthritis.
`
`Suitable agents to be used in
`
`combination include standard non-steroidal anti-inflammatory agents (hereinafter NSAlD's)
`
`such as piroxicam, diclofenac, propionic acids such as naproxen. flubiprofen, fenoprofen,
`
`ketoprofen and ibuprofen, fenamates such as mefenamic acid,
`
`indomethacin, sulindac,
`
`apazone, pyrazolones such as phenylbutazone. salicylates such as aspirin, COX-2 inhibitors
`
`such as
`
`celecoxib and rofecoxib,
`
`analgesics and intraarticular
`
`therapies
`
`such as
`
`corticosteroids and hyaluronic acids such as hyalgan and synvisc.
`
`10
`
`15
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`20
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`25
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`30
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`35
`
`40
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`AQUESTIVE EXHIBIT 1007
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`AQUESTIVE EXHIBIT 1007 page 2002
`
`page 2002
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`

`

`WO 99/52910
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`PCT/IB99/00503
`
`-11-
`
`The compounds of the present invention may also be used in combination with
`
`anticancer agents such as endostatin and angiostatin or cytotoxic drugs such as adriamycin.
`
`daunomycin, cis-platinum, etoposide, taxol, taxotere and alkaloids, such as vincristine, and
`
`antimetabolites such as methotrexate.
`
`The compounds of the present invention may also be used in combination with
`
`cardiovascular agents such as calcium channel blockers.
`
`lipid lowering agents such as
`
`statins, fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptor antagonists and platelet
`
`aggregation inhibitors.
`
`The compounds of the present invention may also be used in combination with CNS
`
`agents such as antidepressants (such as sertraline), anti-Parkinsonian drugs (such as
`
`deprenyl, L-dopa, requlp, miratex, MAOB inhibitors such as selegine and rasagiline. comP
`
`inhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA antagonists.
`
`Nicotine agonists. Dopamine agonists and inhibitors of neuronal nitric oxide synthase), and
`
`anti-Atzheimer’s drugs
`
`such as Aricept,
`
`tacrine, COX-2 inhibitors, propentofylline or
`
`metryfonate.
`
`The compounds of the present invention may also be used in combination
`
`with osteoporosis agents such as droloxifene or fosomax and immunosuppressant agents
`
`such as FK—506 and rapamycin.
`
`Detailed Description of the Invention
`
`The following reaction Schemes illustrate the preparation of the compounds of the
`
`present invention. Unless othenNise indicated n. R1. R2. Q and Z in the reaction Schemes and
`
`the discussion that follow are defined as above.
`
`10
`
`15
`
`20
`
`25
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2003
`
`page 2003
`
`

`

`W0 99/5291 0
`
`PCT/IB99/00503
`
`-1 2-
`
`SCHEME 1
`
`O
`
`LCD/VOL
`
`IX
`
`0
`
`HO
`
`OH
`
`VI
`
`O
`
`0
`
`V
`
`O
`
`O
`
`1
`
`PG 0
`
`1
`
`OPG
`
`VIII
`
`O
`
`PG‘O’UEjOH
`
`VII
`
`O
`
`HO
`
`8—0
`
`IV
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2004
`
`page 2004
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`-13-
`
`SCHEME 1 CONTINUED
`
`o
`
`0N
`H
`
`o
`
`o\
`
`H
`
`II
`
`s Q
`
`‘
`
`9
`$0
`0
`
`0
`
`HO\
`
`IZ
`
`0
`H
`\S—Q
`
`Z
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2005
`
`page 2005
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`SCHEME 2
`
`XIV
`
`PGZO
`
`NH2
`
`XIII
`
`XII
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2006
`
`page 2006
`
`

`

`W0 99/529] 0
`
`PCT/IB99/00503
`
`-15-
`
`SCHEME 2 CONTINUED
`
`1
`
`O
`
`HO
`
`21
`
`XI
`
`H 9
`
`o
`
`QC 0
`
`H
`
`X
`
`l
`
`O
`
`HO
`
`IZ
`
`/:
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2007
`
`page 2007
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`5
`
`-1 6-
`
`SCHEME 3
`
`O
`
`PGZO
`
`“‘3020
`
`X“
`
`o
`
`N—SOZQ
`
`xvn
`
`0
`
`il?‘
`N—son
`
`HO
`
`XVI
`
`o
`
`R1
`
`Ck”
`
`N—SOzQ
`
`xv
`
`o
`
`1
`
`”CK”
`
`Z——-SOZQ
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2008
`
`page 2008
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`-1 7-
`
`SCHEME 4
`
`0
`
`P620
`
`IlI—sozo
`
`XII
`
`I
`
`(:0sz
`
`©/\0
`
`N—SO Q
`
`2
`
`XIX
`
`00sz
`
`0
`
`HO
`
`N—SOZQ
`
`xvm
`
`
`
`o
`
`HOII
`
`Z—SOZQ
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2009
`
`page 2009
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`-18-
`
`Scheme 1 refers to the preparation of compounds of formula I, wherein Z is CH2.
`
`Referring "to Scheme I, a compound of the formula I
`
`is prepared from a compound of the
`
`formula II by hydrogenolysis under an atmosphere of hydrogen in the presence of a catalyst in
`
`a reaction inert solvent. Suitable catalysts include 5% palladium on barium sulfate or 5%
`
`palladium on carbon, preferably 5% palladium on barium sulfate. Suitable solvents include an
`
`10
`
`alcohol such as ethanol, methanol or isopropanol, preferably methanol. The aforesaid
`
`reaction may be performed at a pressure from about 1
`
`to about 5 atmospheres, preferably
`
`about 3 atmospheres. Suitable temperatures for the aforesaid reaction range from about
`
`20°C (room temperature) to about 60°C, preferably the temperature may range from about
`
`20°C to about 25°C (i.e. room temperature). The reaction is complete within about 0.5 hours
`
`15
`
`to about 5 hours, preferably about 3 hours.
`
`20
`
`25
`
`30
`
`Compounds of the formula II can be prepared from compounds of the formula III by
`
`reaction with an oxidant
`
`in a reaction inert solvent.
`
`Suitable oxidants include meta-
`
`chloroperbenzoic
`
`acid,
`
`hydrogen
`
`peroxide
`
`or
`
`sodium perborate,
`
`preferably meta-
`
`chloroperbenzoic acid. Suitable solvents include halogenated solvents such as methylene
`
`chloride or chloroform. preferably methylene chloride. Suitable temperatures for the aforesaid
`
`reaction range from about 0°C to about 60°C. preferably the temperature may range from
`
`about 20°C to about 25°C (i.e. room temperature). The reaction is complete within about 0.5
`
`hours to about 24 hours, preferably about 16 hours.
`
`The compound of formula III is prepared from a compound of formula IV by reaction
`
`with O-benzylhydroxyamine hydrochloride, an activating agent, and a base in a reaction inert
`
`solvent.
`
`Suitable
`
`activating
`
`agents
`
`include
`
`(benzotriazol-1-yloxy)tris(dimethylamino)
`
`phosphonium hexafluorophosphate
`
`or
`
`1-(3~(dimethylaminopropyl)-3-ethylcarbodiimide
`
`hydrochloride,
`
`preferably
`
`(benzotriazol-1-yloxy)tris(dimethylamino)
`
`phosphonium
`
`hexafluorophosphate.
`
`Suitable bases include tertiary amines
`
`such as triethylamine,
`
`diisopropylethylamine or 4-N,N-dimethylaminopyridine, preferably diisopropylethylamine. The
`
`temperature of the aforesaid reaction may range from about 0°C to about 60°C, preferably
`
`about 50°C. Suitable solvents include N,N-dimethylformamide, halogenated solvents such as
`
`methylene chloride or chloroform, or ethers such as THF or diethyl ether; preferably the
`
`solvent is N,N-dimethylformamide. The reaction is complete in about 4 hours to about 48
`
`35
`
`hours. preferably about 16 hours.
`
`Compounds of the formula IV, can be prepared from compounds of the formula V, by
`
`reaction with a compound of the formula QSH. wherein Q is as defined above. in the presence
`
`of a strong base in an aprotic polar solvent. Suitable bases include sodium hydride,
`
`lithium
`
`diisopropylamide, potassium t-butoxide, sodium amide or potassium hydride. preferably
`
`4O
`
`sodium hydride.
`
`Suitable solvents include ethers (such as THF, diethyl ether or 1.2-
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2010
`
`page 2010
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`-19-
`
`dimethoxyethane), or N, N-dimethylformamide, preferably the solvent is THF. The aforesaid
`
`reaction is conducted at about -78°C to about 0°C, preferably at about 22°C (i.e.,
`
`room
`
`temperature) for a period of 30 minutes to about 24 hours, preferably about 2 hours.
`
`Compounds of the formula V are prepared from compounds of the formula VI by
`
`dehydration in the presence of a tertiary amine base, preferably triethylamine, optionally in the
`
`presence of 4-dimethylaminopyridine, and a dehydrating agent in an inert solvent. Sufable
`
`dehydrating agents include trifluoromethanesulfonic anhydride, methanesulfonic anhydride,
`
`methanesulfonyl chloride, p-toluenesulfonyl chloride or benzenesulfonyl chloride, preferably
`
`benzenesulfonyl chloride. Suitable solvents include diethyl ether or dichloromethane. The
`
`reaction is performed at a temperature from about -80°C to about 0°C, preferably about 0°C.
`
`The reaction is carried out for about 10 minutes to 4 hours, preferably about 1 hour.
`
`The compounds of the formula VI are prepared from a compound of formula VII,
`
`wherein PG1 is methyl or ethyl, by saponification with a base, such as lithium hydroxide, in a
`
`solvent mixture. Suitable solvent mixtures include water and methanol or water, methanol
`
`and THF. The reaction is performed at a temperature from about 60°C to about 120°C,
`
`preferably at about the reflux temperature of the solvent mixture used. The reaction is carried
`
`out for about 30 minutes to 24 hours, preferably about 16 hours.
`
`The exo-hydroxymethyl isomer of the compound of the formula Vll
`
`is prepared from a
`
`compound of formula VIII.
`
`In general, a solution of a compound of formula VIII is dissolved in
`
`an inert aromatic solvent, preferably benzene or toluene, and cooled at about -40° C to -20°C,
`
`preferably about -40°C. To the cold solution is added a suitable hindered reducing agent,
`
`preferably disobutylaluminum hydride,
`
`in an inert aromatic
`
`solvent, maintaining the
`
`temperature below -25°C. After the addition is complete, the reaction is maintained below 0°C
`
`for about 3 hours. At about -15°C. a protic solvent, preferably ethanol, is added. After stirring
`
`at about -15°C for about 1 hour, sodium borohydride is added and the reaction is allowed to
`
`warm to about room temperature while stirring for a period of 2 to 24 hours, preferably about
`16 hours.
`
`The endo-hydroxymethyl isomer of the compound of the formula VII can be prepared
`
`from the exo-hydroxymethyl compound of the formula VI by a series of steps which can invert
`
`the sterochemistry about the carbon atom bearing the hydroxymethyl and carboxylic acid
`
`groups.
`
`Specifically.
`
`the exo—hydroxymethyl
`
`isomer of formula VI
`
`is first converted to the
`
`corresponding benzyl ester. Subsequent Jones oxidation of the alcohol to the carboxylic acid
`
`and alkyl ester formation (methyl or ethyl) provides an intermediate mixed benzyl alkyl ester (Le.
`
`the exo ester is methyl or ethyl and the endo ester is benzyl). The benzyl ester is then removed
`
`by hydrogenolysis and the resulting carboxylic acid is reduced to the alcohol by diborane
`
`reduction, providing the endo-hydroxymethyl isomer of the compound of the formula VII.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2011
`
`page 2011
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`-20-
`
`10
`
`15
`
`The compounds formula Vlll, wherein PG1 is ethyl or methyl, are prepared from
`
`compounds of the formula IX. wherein L is methanesulfonyl, benzenesulfonyl or tosyl, by
`
`reaction with dimethyI or diethyl malonate in the presence of a strong base, such as sodium
`
`hydride, in a polar solvent, such as N,N-dlmethylformamide. for a time period between about 4
`
`hours to about 24 hours, preferably about 16 hours. The aforesaid reaction temperature is
`
`between about 70°C to about 150°C, preferably about 140° C.
`
`‘
`
`Compounds of the formula IX are known or can be made by methods well known to
`
`those of ordinary skill in the art.
`
`Compounds of the formula QSH can be prepared by reaction of an alkyl or aryl halide
`
`with sodium sulfhydride as described in Jerry March, Advanced Organic Chemisgy, 360 and 589
`
`(3rd ed, 1985). Alternatively, compounds of the formula QSH can also be prepared by reaction
`
`of an aryl diazonium salt with sodium sulfhydride as described in March id_. at 601. Alternatively,
`
`compounds of the formula QSH can also be prepared by reaction of a Grignard reagent with
`
`suifur as described in March y; at 550. Alternatively, compounds of the formula QSH can also
`
`be prepared by reduction of a sulfonyl chloride, sulfonic acid or disulfide as described in March
`
`20
`
`i_d_. at 1107 and 1110.
`
`Scheme 2 refers to the preparation of compounds of the formula I, wherein Z is >NR',
`
`and R1 is hydrogen. Referring to Scheme 2, compounds of formula I can be prepared from
`
`compounds of the formula X by hydrogenolysis under an atmosphere of hydrogen in the
`
`presence of a catalyst in a reaction inert solvent. Suitable catalysts include 5% palladium on
`
`25
`
`barium sulfate or 5% palladium on carbon, preferably 5% palladium on barium sulfate.
`
`Suitable solvents include an alcohol such as ethanol, methanol or isopropanol, preferably
`
`methanol. The aforesaid reaction may be performed at a pressure from about 1
`
`to about 5
`
`atmospheres, preferably about 3 atmospheres.
`
`Suitable temperatures for the aforesaid
`
`reaction range from about 20°C (room temperature) to about 60°C, preferably the temperature
`
`may range from about 20°C to about 25°C (i.e. room temperature). The reaction is complete
`
`within about 0.5 hours to about 5 hours. preferably about 3 hours.
`
`The compound of formula X is prepared from a compound of the formula XI by
`
`reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base
`
`in
`
`a
`
`reaction
`
`inert
`
`solvent.
`
`Suitable
`
`catalysts
`
`include
`
`(benzotriazoI-1-
`
`yloxy)tris(dimethy|amino)phosphonium hexafluorophosphate or 1-(3-(dimethylaminopropyl)-3-
`
`ethylcarbodiimide
`
`hydrochloride,
`
`preferably
`
`(benzotriazol-1-yloxy)tris(dimethylamino)
`
`phosphonium hexafluorophosphate.
`
`Suitable bases include tertiary amines such as
`
`triethylamine,
`
`diisopropylethylamine
`
`or
`
`4—N,N—dimethylaminopyridine,
`
`preferably
`
`diisopropylethylamine. The aforesaid reaction temperature is from about 0° C to about 60°C,
`
`40
`
`preferably about 50° C. Suitable solvents include N,N-dimethylformamide or halogenated
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2012
`
`page 2012
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`-21-
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`solvents
`
`such as methylene chloride or chloroform; preferably,
`
`the solvent
`
`is N.N-
`
`dimethylformamide. The reaction is conducted over a period of about 4 hours to about 48
`
`hours, preferably about 16 hours.
`
`Compounds of the formula Xl are prepared from compounds of the formula XII,
`
`wherein PG2 is methyl or ethyl, by saponification with a base such as sodium hydroxide in a
`
`solvent mixture such as water and ethanol. The reaction is performed at a temperature‘from
`
`about 60°C to about 100°C, preferably at about the reflux temperature of the solvent mixture
`
`used. The reaction is carried out for about 1 day to 10 days, preferably about 6 days.
`
`The compounds of the formula Xll, wherein P62 is methyl or ethyl, are prepared from
`
`compounds of the formula Xlll, wherein P62 is methyl or ethyl, by reaction with a compound of
`
`the formula QSOZCI in the presence of a base, such as triethylamine, and a polar solvent.
`
`Suitable solvents include N,N-dimethylformamide,
`
`tetrahydrofuran, 1.2-dimethoxyethane,
`
`dioxane. water or acetonitrile, preferably N.N-dimethylformamide. The reaction mixture is
`
`stirred at room temperature for a time period between about
`
`1 hour to about 24 hours.
`
`preferably about 16 hours.
`
`Compounds of the formula Xlll, wherein P62 is methyl or ethyl, are prepared from
`
`compounds of the formula XIV. wherein PG2 is methyl or ethyl, by hydrolysis in the presence of
`
`aqueous mineral acid and a solvent such as diethyl ether.
`
`Suitable mineral acids include
`
`hydrochloric and sulfuric acid, preferably hydrochloric acid. The reaction is carried out at a
`
`temperature ranging from about 0°C to 50°C; preferably the temperatUre may range from about
`
`20°C to about 25°C (i.e. room temperature). The reaction is conducted over a period of about
`
`2 hours to about 48 hours, preferably about 16 hours.
`
`Compounds of the formula XIV, wherein P62 is methyl, ethyl or benzyl, are prepared
`
`from compounds of the fom1ula IX, wherein L is methanesulfonyl, benzenesulfonyl or tosyl, by
`
`reaction with N-diphenylmethylene glycine, methyl, ethyl or benzyl ester, in the presence of a
`
`strong base, such as sodium hydride, in a polar solvent, such as N,N—dimethy|formamide, for a
`
`time period between about 4 hours to about 24 hours, preferably about 16 hours. The aforesaid
`
`reaction temperature is between about 70°C to about 140°C, preferably about 100° C.
`
`Compounds of the formula XIV, wherein P62 is methyl, ethyl or benzyl, are obtained as
`
`mixtures of diastereomers which can be separated by chromatographic means.
`
`Compounds of the formula QSOZCl and formula IX are known or commercially available
`
`or can be made by methods well known to those of ordinary skill in the art.
`
`Scheme 3 refers to the preparation of compounds of the formula I, wherein Z is NR1 and
`
`R1
`
`is (C1—Cs)alkyl,
`
`(C5—C1o)aryl(C1—Cs)alkyl,
`
`(CZ—Cg)heteroaryl(C1-C6)alkyl or a group of the
`
`formula -(CH2),,COZR2, wherein n is 1, 3, 4, 5, or 6 and R2 is (C1-Ce)alkyl.
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2013
`
`page 2013
`
`

`

`WO 99/529] 0
`
`PCT/IB99/00503
`
`-22-
`
`Referring to Scheme 3, compounds of the formula I, wherein Z is NR1 and R1 is (C,—
`
`Cs)a|kyl,
`
`(Cs-Cm)aryl(C1-Ca)alkyl,
`
`(Oz-Cg)heteroaryl(C1-Cs)alkyl or a group of
`
`the formula
`
`-(CH2),,002R2, wherein n is 1, 3, 4. 5, or 6 and R2 is (C1-Cs)alkyl, are prepared from compounds
`
`of the formula XV by hydrogenolysis under an atmosphere of hydrogen in the presence of a
`
`catalyst in a reaction inert solvent. Suitable catalysts include 5% palladium on barium sulfate
`
`10
`
`or 5% palladium on carbon, preferably 5% palladium on barium sulfate. Suitable sohTents
`
`include an alcohol such as ethanol, methanol or isopropanol, preferably methanol. The
`
`15
`
`20
`
`25
`
`aforesaid reaction may be performed at a pressure from about 1
`
`to about 5 atmospheres,
`
`preferably about 3 atmospheres. Suitable temperatures for the aforesaid reaction range from
`
`about 20°C (room temperature) to about 60°C, preferably the temperature may range from
`
`about 20°C to about 25°C (i.e. room temperature). The reaction is complete within about 0.5
`
`hours to about 5 hours, preferably about 3 hours.
`
`The compound of formula XV is prepared from a compound of the formula XVI by
`
`reaction with O-benzylhydroxylamine hydrochloride in the presence of a catalyst and a base
`
`in
`
`a
`
`reaction
`
`inert
`
`solvent.
`
`Suitable
`
`catalysts
`
`include
`
`(benzotriazol-‘I-
`
`y|oxy)tris(dimethylamino)phosphonium hexafluorophosphate or 1-(3-(dimethylaminopropyI)-3-
`
`ethylcarbodiimide
`
`hydrochloride,
`
`preferably
`
`(benzotriazol-1-y|oxy)tris(dimethylamino)
`
`phosphonium hexafluorophosphate.
`
`Suitable bases include tertiary amines such as
`
`triethylamine,
`
`diisopropylethylamine
`
`or
`
`4-N,N-dimethylaminopyridine,
`
`preferably
`
`diisopropylethylamine. The aforesaid reaction temperature is from about 0° C to about 60°C,
`
`preferably about 50° C. Suitable solvents include N,N-dimethylformamide or halogenated
`
`solvents
`
`such as methylene chloride or chloroform, preferably the solvent
`
`is N,N-
`
`dimethylformamide. The reaction is conducted over a period of about 4 hours to about 48
`
`hours, preferably about 16 hours.
`
`The compound of formula XVI
`
`is prepared from a compound of the formula XVII by
`
`30
`
`removal of the benzyl protecting group. Specifically, the benzyl protecting group is removed by
`
`hydrogenolysis using palladium or palladium on carbon in a solvent such as methanol or
`
`ethanol, for a period from about 30 minutes to about 48 hours, preferably 16 hours, at a
`
`temperature of about 20°C to about 25°C (i.e., room temperature).
`
`The compound of formula XVII is prepared from a compound of the formula XII, wherein
`PG2 is benzyl, by reaction with a reactive derivative of an alcohol of the formula R‘OH such as
`
`35
`
`the methanesulfonate, tosylate, chloro, bromo or iodo derivative, preferably the iodo derivative,
`
`in the presence of a base such as potassium carbonate or sodium hydride, preferably sodium
`
`hydride, and a polar solvent, such as N,N-dimethylformamide. The reaction mixture is stirred at
`
`room temperature for a time period between about 60 minutes to about 48 hours, preferably
`about 16 hours.
`
`40
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2014
`
`page 2014
`
`

`

`W0 99/5291 0
`
`PCT/IB99/00503
`
`-23-
`
`The compounds of formula XII, wherein PG2 is benzyl, are prepared according to the
`methods of Scheme 2.
`
`Scheme 4 refers to the preparation of compounds of formula I, wherein Z is >NR‘, R1 is
`
`a group of the formula —(CH2)2002R2 (i.e. n is 2) and R2 is (C1-Cs)alkyl.
`
`Referring to Scheme 4, compounds of said formula I are prepared from compounds of
`
`the formula XVIII, wherein R2 is (C1-Cs)alkyl, by reaction with oxalyl chloride or thionyl chloride,
`
`preferably oxalyl chloride, and a catalyst, preferably about 2% of N,N-dimethy|formamide, in an
`
`inert solvent, such as methylene chloride, to form an in situ acid chloride that is subsequently
`
`reacted with O-trimethylsilylhydroxylamine in the presence of a base, such as pyridine, 4-N,N-
`
`dimethylaminopyridine or triethylamine, preferably pyridine. The reaction is performed at a
`
`temperature of about 22°C (i.e., room temperature) for about 1
`
`to about 12 hours, preferably
`
`about 1 hour.
`
`Compounds of the formula XVIII, wherein R2 is (C1-Ce)alkyl, can be prepared from
`
`compounds of the formula XIX, wherein R2 is (C1-C6)alkyl, by reduction in a polar solvent.
`
`Suitable reducing agents include hydrogen over palladium and hydrogen over palladium on
`
`carbon, preferably hydrogen over palladium on carbon. Suitable solvents include methanol,
`
`ethanol and isopropanol, preferably ethanol.
`
`The aforesaid reaction is performed at a
`
`temperature of about 22°C (i.e., room temperature) for a period of 1 to 7 days, preferably about 2
`
`days.
`
`Compounds of the formula XIX, wherein R2 is (C1-Cs)alkyl, can be prepared from
`
`compounds of the formula XII, wherein PG2 is benzyl, by Michael addition of a propiolate ester
`
`and a base in a polar solvent. Suitable propiolates are of the formula H-CsC-COZRZ, wherein R2
`
`is (C1-C6)alkyl. Suitable bases include tetrabutylammonium fluoride, potassium carbonate, and
`
`cesium carbonate,
`
`preferably tetrabutylammonium fluoride.
`
`Suitable
`
`solvents
`
`include
`
`tetrahydrofuran, acetonitrile, tert-butanol and N,N-dimethylformamide, preferably tetrahydrofuran.
`
`The aforesaid reaction is performed at a temperature of about -10°C to about 60°C, preferably
`
`ranging between 0°C and about 22°C (i.e., room temperature). The compounds of formula XIX
`
`are obtained as mixtures of geometric isomers about the olefinic double bond; separation of the
`
`isomers is not necessary.
`
`10
`
`15
`
`20
`
`25
`
`3O
`
`Compounds of the formula XII, wherein PG2 is benzyl, can be prepared according to the
`methods of Scheme 2.
`
`35
`
`Compounds of said formula I, wherein Z is >NR‘, R1 is a group of the formula
`
`-(CH2),,COZR2 , n is 1
`
`to 6 and R2 is hydrogen are prepared from compounds of formula I,
`
`wherein Z is >NR‘, R1 is a group of the formula -(CH2)n002R2, n is 1 to 6 and R2 is (C1-Cs)alkyl,
`
`by saponification using a base such as sodium hydroxide in a protic solvent such as ethanol,
`
`4O
`
`methanol or water or a mixture such as water and ethanol, water and toluene, or water and THF.
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2015
`
`page 2015
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`-24-
`
`10
`
`15
`
`2O
`
`25
`
`3O
`
`35
`
`The preferred solvent system is water and ethanol. The reaction is conducted for a period of 30
`
`minutes to 24 hours, preferably about 2 hours.
`
`The compounds of the formula 1 which are basic in nature are capable of forming a
`
`wide variety of different salts with various inorganic and organic acids. Although such salts
`
`must be pharrnaceutically acceptable for administration to animals,
`
`it
`
`is often desirable in
`
`practice to initially isolate a compound of the formula I from the reaction mixture as a
`
`pharmaceutically unacceptable salt and then simply convert the latter back to the free base
`
`compound by treatment with an alkaline reagent, and subsequently convert the free base to a
`
`pharrnaceutically acceptable acid addition salt.
`
`The acid addition salts of
`
`the base
`
`compounds of this invention are readily prepared by treating the base compound with a
`
`substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent
`
`medium or
`
`in a suitable organic solvent such as methanol or ethanol. Upon careful
`
`evaporation of the solvent, the desired solid salt is obtained.
`
`The acids which are used to prepare the pharmaceutically acceptable acid addition
`
`salts of the base compounds of this invention are those which form non-toxic acid addition
`
`salts, Le_., salts containing pharmacologically acceptable anions. such as hydrochloride,
`
`hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate,
`
`lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate.
`
`saccharate, benzoate. methanesulfonate and pamoate [L2, 1,1'-methylene-bis-(2-hydroxy-3-
`
`naphthoate)] salts.
`
`Those compounds of the formula I which are also acidic in nature, are capable of
`
`forming base salts with various pharmacologically acceptable cations. Examples of such salts
`
`include the alkali metal or alkalinesearth metal salts and particularly,
`
`the sodium and
`
`potassium salts. These salts are all prepared by conventional techniques. The chemical
`bases which are used as reagents to prepare the pharrnaceutically acceptable base salts of
`
`this invention are those which form non-toxic base salts with the herein described acidic
`
`compounds of formula l. These non—toxic base salts include those derived from such
`
`pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc.
`
`These salts can easiiy be prepared by treating the corresponding acidic compounds with an
`aqueous solution containing the desired pharmacologically acceptable cations, and then
`
`evaporating the resulting solution to dryness, preferably under
`
`reduced pressure.
`
`Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic
`
`compounds and the desired alkali metal alkoxide together, and then evaporating the resulting
`
`solution to dryness in the same manner as before.
`
`In either case, stoichiometn‘c quantities of
`
`reagents are preferably employed in order to ensure completeness of reaction and maximum
`
`40
`
`product yields.
`
`AQUESTIVE EXHIBIT 1007
`
`AQUESTIVE EXHIBIT 1007 page 2016
`
`page 2016
`
`

`

`WO 99/52910
`
`PCT/IB99/00503
`
`-2 5-
`
`The ability of the compounds of formula l or their pharmaceutically acceptable salts
`
`(hereinafter also referred to as the compounds of
`
`the present
`
`invention)
`
`to inhibit
`
`metalloproteinases or mammalian reprolysin and, consequently. demonstrate their effectiveness
`
`for treating diseases characterized by metalloproteinase or the production of tumor necrosis
`
`factor is shown by the following in vitro assay tests.
`
`Biological Assay
`
`inhibition of Human Collagenase (MMP-1)
`
`Human recombinant collagenase is activated with trypsin. The amount of trypsin is
`
`optimized for each lot of collagenase-1 but a typical reaction uses the following ratio: 5 pg trypsin
`
`per 100 pg of collagenase. The trypsin and collagenase are incubated at room temperature for
`
`10 minutes then a five fold excess (50 mg/10 mg trypsin) of soybean