(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY(PCT)
`
`(19) World Intellectual Property Organization
`International Bureau
`
`(43) International Publication Date
`18 October 2001 (18.10.2001)
`
`
`
`PCT
`
`(10) International Publication Number
`WO 01/77073 Al
`
`(51)
`
`CO07D 207/08,
`International Patent Classification’:
`207/09, 207/12, 207/14, 209/62, 407/04, A61K 31/40,
`31/435
`
`(21)
`
`International Application Number:
`
`PCT/US01/11001
`
`16711 Trans-Canada Highway, Kirkland, Québec H9H
`3L1 (CA). RYDZEWSKI,Robert [US/US]; 180 Kimball
`Way, South San Francisco, CA 94080 (US). OKAMOTO,
`Osamu [JP/JP]; 2-3, Nihombashi Honcho 2-chome,
`Chuo-ku, Tokyo 103-8416 (JP).
`
`(22)
`
`International Filing Date:
`
`4 April 2001 (04.04.2001)
`
`(74)
`
`Agent: WALLINGER,Nicole, M.; Merck & Co., Inc.,
`126 East Lincoln Avenue, Rahway, NJ 07065-0907 (US).
`
`(25)
`
`Filing Language:
`
`(26)
`
`Publication Language:
`
`English
`
`English
`
`(31)
`
`(30)
`
`Priority Data:
`60/195,557
`
`6 April 2000 (06.04.2000)
`
`US
`
`(71)
`
`except US):
`(for all designated States
`Applicants
`MERCK FROSST CANADA & CO. [CA/CA]; 16711
`Trans-Canada Highway, Kirkland, Québec H9H 3L1
`(CA). AXYS PHARMACEUTICALS, INC. [US/US];
`180 Kimball Way, South San Francisco, CA 94080 (US).
`BANYU PHARMACEUTICALCoO., LTD. [JP/JP]; 2-3,
`Nihombashi Honcho 2-chome, Chuo-ku, Tokyo 103-8416
`(JP).
`
`(72)
`(75)
`
`Inventors; and
`Inventors/Applicants (for US only): PRASIT, Petpi-
`boon [CA/CA]; 16711 Trans-Canada Highway, Kirkland,
`Québec H9H 3L1 (CA). FALGUEYRET, Jean-Pierre
`[CA/CA];
`16711 Trans-Canada Highway, Kirkland,
`Québec H9H 3L1 (CA). OBALLA, Renata [CA/CA];
`
`Designated States (national): AE, AG, AL, AM, AT, AU,
`AZ, BA, BB, BG, BR, BY, BZ, CA, CH, CN, CO, CR, CU,
`CZ, DE, DK, DM, DZ, EE, ES, FI, GB, GD, GE, GH, GM,
`HR, HU,ID,IL, IN, IS, JP, KE, KG, KR, KZ, LC, LK, LR,
`LS, LT, LU, LV, MA, MD, MG, MK, MN, MW, MX, MZ,
`NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM,
`TR, TT, TZ, UA, UG, US, UZ, VN, YU, ZA, ZW.
`
`(84)
`
`Designated States (regional): ARIPO patent (GH, GM,
`KE, LS, MW, MZ, SD, SL, SZ, TZ, UG, ZW), Eurasian
`patent (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), European
`patent (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR,IE,
`TT, LU, MC, NL, PT, SE, TR), OAPI patent (BF, BJ, CF,
`CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG).
`
`Published:
`
`with international search report
`
`For two-letter codes and other abbreviations, refer to the "Guid-
`ance Notes on Codes andAbbreviations" appearing at the begin-
`ning ofeach regular issue ofthe PCT Gazette.
`
`WO01/77073A1
`
`(54) Title: CATHEPSIN CYSTEINE PROTEASE INHIBITORS
`
`(57) Abstract: This invention relates to a novel class of compounds which are cysteine protease inhibitors, including but not limited
`to, inhibitors of Cathepsins K and L. These compoundsare useful for treating diseases in which inhibition of bone resorption is
`indicated, such as osteoporosis.
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`TITLE OF THE INVENTION
`CATHEPSIN CYSTEINE PROTEASE INHIBITORS
`
`10
`
`BACKGROUND OF THE INVENTION
`A variety of disorders in humans and other mammals involve or are
`associated with abnormal bone resorption. Such disorders include, but are not limited
`to, osteoporosis, glucocorticoid induced osteoporosis, Paget's disease, abnormally
`increased bone turnover, periodontal disease, tooth loss, bone fractures, rheumatoid
`arthritis, osteoarthritis, periprosthetic osteolysis, osteogenesis imperfecta, metastatic
`bone disease, hypercalcemia of malignancy, and multiple myeloma. One of the most
`common ofthese disorders is osteoporosis, which in its most frequent manifestation
`occurs in postmenopausal women. Osteoporosis is a systemic skeletal disease
`characterized by a low bone mass and microarchitectural deterioration of bone tissue,
`with a consequent increasein bone fragility and susceptibility to fracture.
`Osteoporotic fractures are a major cause of morbidity and mortality in the elderly
`15
`population. As many as 50% of womenandathird of men will experience an
`osteoporotic fracture. A large segmentof the older population already has low bone
`density and a high risk of fractures. There is a significant need to both prevent and
`treat osteoporosis and other conditions associated with bone resorption. Because
`osteoporosis, as well as other disorders associated with bone loss, are generally
`chronic conditions, it is believed that appropriate therapy will typically require
`
`20
`
`chronic treatment.
`Osteoporosis is characterized by progressive loss of bone architecture
`and mineralization leading to the loss in bone strength and an increasedfracture rate.
`The skeleton is constantly being remodeled by a balance between osteoblasts that lay
`down new boneand osteoclasts that breakdown, or resorb, bone. In some disease
`conditions and advancing age the balance between bone formation and resorption is
`disrupted; bone is removedat a faster rate. Such a prolonged imbalance of resorption
`over formation leads to weaker bone structure and a higher riskof fractures.
`Boneresorption is primarily performed by osteoclasts, which are
`multinuclear giant cells. Osteoclasts resorb bone by forming an initial cellular
`attachmentto bonetissue, followed by the formation of an extracellular compartment
`or lacunae. The lacunae are maintained at a low pH by a proton-ATP pump. The
`acidified environmentin the lacunae allowsfor initial demineralization of bone
`followed by the degradation of boneproteins or collagen by proteases such as cysteine
`
`25
`
`30
`
`35
`
`-l-
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`proteases. See Delaisse, J. M. et al., 1980, Biochem J 192:365-368; Delaisse, J. et al.,
`1984, Biochem Biophys Res Commun :441-447; Delaisse, J. M. et al.,1987, Bone
`8:305-313, which are hereby incorporated by reference in their entirety. Collagen
`constitutes 95 % of the organic matrix of bone. Therefore, proteases involved in
`collagen degradation are an essential component of bone turnover, and as a
`consequence, the development and progression of osteoporosis.
`Cathepsins belong to the papain superfamily of cysteine proteases.
`These proteases function in the normal physiological as well as pathological
`degradation of connective tissue. Cathepsins play a major role in intracellular protein
`degradation and turnover and remodeling. To date, a number of cathepsin have been
`identified and sequenced from a number of sources. These cathepsins are naturally
`found in a wide variety of tissues. For example, cathepsin B, F, H, L, K, S, W, and Z
`have been cloned. Cathepsin K (which is also known bythe abbreviation cat Ks)
`is
`also knownas cathepsin O and cathepsin O2. See PCT Application WO 96/13523,
`Khepri Pharmaceuticals, Inc., published May 9, 1996, whichis hereby incorporated by
`reference in its entirety. Cathepsin L is implicated in normal lysosomalproteolysisas
`well as several disease states, including, but not limited to, metastasis of melanomas.
`Cathepsin S is implicated in Alzheimer’s disease and certain autoimmune disorders,
`including, but not limited to juvenile onset diabetes, multiple sclerosis, pemphigus
`vulgaris, Graves’ disease, myasthenia gravis, systemic lupus erythemotasus,
`rheumatoid arthritis and Hashimoto’s thyroiditis; allergic disorders, including, but not
`limited to asthma; and allogenic immunberesponses,including, but not limited to,
`rejection of organ transplants ortissue grafts.
`Cysteine protease inhibitors such as E-64 (trans-epoxysuccinyl-L-
`leucylamide-(4-guanidino) butane) are known to beeffective in inhibiting bone
`resorption. See Delaisse, J. M. et al., 1987, Bone 8:305-313, which is hereby
`incorporated by reference in its entirety. Recently, cathepsin K was cloned and found
`specifically expressedin osteoclasts See Tezuka, K.etal., 1994, J Biol Chem
`269:1106-1109; Shi, G. P. et al.,1995, FEBS Lett 357:129-134; Bromme, D. and
`Okamoto, K., 1995, Biol Chem Hoppe Seyler 376:379-384;, Bromme, D.et al., 1996,
`J Biol Chem 271:2126-2132; Drake, F. H. et al., 1996, J Biol Chem 271:12511-
`12516, which are hereby incorporated byreference in their entirety. Concurrentto the
`cloning,the autosomalrecessive disorder, pycnodysostosis, characterized by an
`osteopetrotic phenotype with a decrease in bone resorption, was mapped to mutations
`presentin the cathepsin K gene. Todate, all mutations identified in the cathepsin K
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-2 -
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`gene are knownto result in inactive protein. See Gelb, B. D. et al., 1996, Science
`273:1236-1238; Johnson, M.R.et al., 1996, Genome Res 6:1050-1055, which are
`hereby incorporated by reference in their entirety. Therefore, it appears that cathepsin
`K is involved in osteoclast mediated bone resorption.
`Cathepsin K is synthesized as a 37 kDa pre-pro enzyme, which is
`localized to the lysosomal compartment and whereit is presumably autoactivated to
`the mature 27 kDa enzymeat low pH. See McQueney, M.S. e¢ al., 1997, J Biol
`Chem 272:13955-13960; Littlewood-Evans,A. et al., 1997, Bone 20:81-86, which are
`hereby incorporatedby reference in their entirety. Cathepsin K is most closely related
`to cathepsin S having 56 % sequence identity at the amino acid level. The S2P2
`substrate specificity of cathepsin K is similar to that of cathepsin S with a preference
`in the P1 and P2 positions for a positively charged residue such as arginine, and a
`hydrophobic residue such as phenylalanine or leucine, respectively. See Bromme, D.
`et al., 1996, J Biol Chem 271: 2126-2132; Bossard, M.J. et al.,1996, J Biol Chem
`271:12517-12524, which are hereby incorporated by reference in their entirety.
`Cathepsin K is active at a broad pH range with significant activity between pH 4-8,
`thus allowing for goodcatalytic activity in the resorption lacunae of osteoclasts where
`the pH is about 4-5.
`Humantype I collagen, the major collagen in bone is a good substrate
`for cathepsin K. See Kafienah, W., ef al., 1998, Biochem J 331:727-732, which is
`hereby incorporated by referencein its entirety. In vitro experiments using antisense
`-oligonucleotides to cathepsin K, have shown diminished boneresorption ivitro,
`which is probably due to a reduction in translation of cathepsin K mRNA.See Inui,
`T., et al., 1997, J Biol Chem 272:8109-8112, which is hereby incorporated by
`reference in its entirety. The crystal structure of cathepsin K has been resolved. See
`McGrath, M.E., et al., 1997, Nat Struct Biol 4:105-109; Zhao,B., et al., 1997, Nat
`Struct Biol 4: 109-11, which are hereby incorporated by referencein their entirety.
`Also,selective peptide based inhibitors of cathepsin K have been developed See
`Bromime, D., et al., 1996, Biochem J 315:85-89; Thompson,S. K., et al.,1997, Proc
`Natl Acad Sci U S A 94:14249-14254, which are hereby incorporated by reference in
`their entirety. Accordingly, inhibitors of Cathepsin K can reduce bone resorption.
`Such inhibitors would be useful in treating disorders involving boneresorption, such
`
`as osteoporosis.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`Compounds of the instant invention are useful as inhibitors of
`cathepsins. More particularly, the compoundsofthe instant invention are useful as
`inhibitors of Cathepsins K and L.
`It is therefore an object of the invention to provide compounds which
`inhibit cathepsin activity in a mammalin needthereof.
`It is another object of the invention to provide compounds whichare
`useful for treating and/or preventing boneloss in a mammal in needthereof.
`It is another object of the invention to provide compounds which are
`useful to reduce bone loss in a mammalin need thereof.
`It is another object of the invention to provide compounds whichare
`useful for treating and/or preventing bone fractures in a mammal in need thereof.
`It is another object of the invention to provide compounds which are
`useful for treating and/or preventing osteoporosis in a mammal in need thereof.
`It is another object of the invention to provide compounds which are
`useful for treating and/or preventing cathepsin dependent conditions or diseasestates
`in a mammalin need thereof.
`
`5
`
`10
`
`15
`
`SUMMARYOF THE INVENTION
`The present invention relates to compoundsof the following chemical
`
`20
`
`formula:
`
`wWfwa-Zz©wya”.
`
`Z=
`
`25
`
`30
`
`wherein R1 and R2are each independently selected from the group consisting of
`hydrogen,alkyl, oxo, -(CH2)p-NH-S(O)2-R3, -(CH2)p-NH-CO-R4,
`-C(O)2R6, -(CH2)pORS, -OR6, -(CH2)pNR7R8, -CN, -
`NH(CH2)pR3, -(CH2)pR3, -R3 , -C(O)NHR® and -C(O)NR§;
`or R1 and R2 can be joined together to form a system selected from the
`group consisting of aryl, cycloalkyl! and heterocycloalkyl;
`
`A
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`R3is selected from the group consisting ofaryl, arylalkyl, cycloalkyl, and
`heterocycloalkyl, wherein said aryl, arylalkyl and cycloalkyl] groups
`are either unsubstituted or substituted with 1, 2 or 3 halogen atoms;
`R4is selected from the group consisting ofaryl, cycloalkyl, heterocycloalkyl, biaryl,
`CH(R10)-NHC(O)2R3, ORS, (CH2)pR9, (CH2)p(R%q, wherein said
`aryl, cycloalkyl, heterocycloalkyl and biaryl, groups are either
`unsubstituted or substituted with 1, 2 or 3 halogen atoms;
`R5is selected from the group consisting of alkyl, alkenyl, alkynyl, and (CH2)pR9;
`R6is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, and
`CH(R10)-NHC(0O)2R3;
`R7 and R8 are each independently selected from the group consisting of hydrogen,
`alkyl, alkenyl, alkynyl, and —(CH2)pR3;
`or R7 and R8 are joined together to form a system selected from the
`group consisting of aryl and heterocycloalkyl;
`R9is selected from the group consisting of aryl, cycloalkyl and heterocycloalky];
`R10 is selected from the group consisting of the side chains of the naturally occurring
`amino acids or unnaturally occurring amino acids;
`each n is independently an integer from zero to four;
`each p is independently an integer from zero to six;
`each q is independently an integer from zero to four;
`and the pharmaceutically acceptable salts thereof.
`The present invention also relate to pharmaceutical compositions
`comprising the compounds of the present invention and a pharmaceutically acceptable
`carrier.
`
`The present invention also relates to methods for making the
`pharmaceutical compositions of the present invention.
`The present invention also relates to methods of inhibiting cathepsin
`activity and/or treating cathepsin dependent conditions in a mammal in need thereof
`comprising administering to the mammal the compounds and pharmaceutical
`compositions of the present invention.
`The present invention also relates to methodsoftreating, preventing
`and/or reducing bone loss in a mammal in need thereof comprising administering to
`the mammal the compounds and pharmaceutical compositions of the present
`invention.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`5.
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`The present invention also relates to methods of inhibiting treating
`and/or preventing osteoporosis in a mammal in need thereof comprising administering
`to the mammal the compounds and pharmaceutical compositions of the present
`invention.
`
`5
`
`The present invention also relates to methods of reducing boneloss in
`a mammal in need thereof comprising administering to the mammal the compounds
`and pharmaceutical compositions of the present invention.
`The present invention also relates to methodsoftreating and/or
`preventing bone fractures in a mammal in need thereof comprising administering to
`10=the mammal the compounds and pharmaceutical compositions of the present
`invention.
`
`15
`
`The present invention relates to the use of the compounds and
`pharmaceutical compositions of the present invention for the preparation of a
`medicament for treating or preventing boneloss in a mammalin need thereof.
`The present invention relates to pharmaceutical compositions useful
`for treating or preventing bone loss in a mammal comprising a pharmaceutically
`effective amount of compounds of the present invention in association with
`pharmaceutically acceptable carriers.
`
`20
`
`DETAILED DESCRIPTION OF THE INVENTION
`
`The present invention relates to compoundsof the following chemical
`
`formula:
`
`J.
`
`DVL2NJ
`Z2=0-Z
`
`25_wherein R! and R2 are each independently selected from the group consisting of
`hydrogen, alkyl, oxo, -(CH2)p-NH-S(O)2-R3, -(CH2)p-NH-CO-R4,
`-C(O)2R46, -(CH2)pORS, -ORS, -(CH2)pNR7R8, -CN, -
`NH(CH2)pR3, -(CH2)pR3, -R3, -C(O)NHR® and -C(O)NR4;
`or R1 and R2 can be joined together to form a system selected from the
`group consisting of aryl, cycloalkyl and heterocycloalkyl;
`
`30
`
`6 -
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`R3 is selected from the group consisting ofaryl, arylalkyl, cycloalkyl, and
`heterocycloalkyl, wherein said aryl, arylalkyl and cycloalky] groups
`are either unsubstituted or substituted with 1, 2 or 3 halogen atoms;
`R4is selected from the group consisting of aryl, cycloalkyl, heterocycloalkyl, biaryl,
`CH(R10)-NHC(O)2R3, OR5, (CH2)pR9, (CH2)p(R)q, wherein said
`aryl, cycloalkyl, heterocycloalkyl and biaryl, groups are either
`unsubstituted or substituted with 1, 2 or 3 halogen atoms;
`R5is selected from the group consisting of alkyl, alkenyl, alkynyl, and (CH2)pR9;
`RO is selected from the group consisting of hydrogen,alkyl, alkenyl, alkynyl, and
`CH(R10)-NHC(O)oR3;
`R7 and R8 are each independently selected from the group consisting of hydrogen,
`alkyl, alkenyl, alkynyl, and —CH2)pR3;
`or R7 and R8are joined together to form a system selected from the
`group consisting of aryl and heterocycloalky]l;
`RY is selected from the group consisting of aryl, cycloalkyl and heterocycloalkyl;
`R10 is selected from the group consisting of the side chains of the naturally occurring
`amino acids or unnaturally occurring aminoacids;
`each n is independently an integer from zero to four;
`each p is independently an integer from zero to six;
`each q is independently an integer from zero to four;
`and the pharmaceutically acceptable salts thereof.
`In the compoundsofthe present invention, R1 and R2 are each
`-
`independently and preferably selected from the group consisting of: hydrogen,
`(CH2)p-NH-S(0)2-R3, -(CH2)p-NH-CO-R4, -C(O)2R®, -(CH2)pOR5,
`-OR®6,-CN,
`-N(CH2)pR3, -(CH2)pR3, and -C(O)NR®;or R1 and R2 can be joined together to
`form a system selected from the group consisting of aryl, cycloalkyl and
`heterocycloalkyl.
`In the compoundsof the present invention, each n is independently and
`preferably an integer from zero to two.
`In the compoundsof the present invention, R!0 is preferably selected
`from the group consisting of the side chains of leucine and isoleucine.
`In the compoundsof the present invention, each p is independently and
`preferably an integer from zero to four.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`-7 -
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`An embodimentof the invention is a methodof inhibiting cathepsin
`activity in a mammalin need thereof, comprising administering to the mammal a
`therapeutically effective amount of any of the compounds or any of the above
`pharmaceutical compositions described above.
`A class of the embodiment is the method wherein the cathepsin activity
`
`is cathepsin K activity.
`A secondclass of the embodiment is the method wherein the cathepsin
`
`activity is cathepsin L activity.
`Another embodiment of the invention is a method oftreating or
`preventing cathepsin dependentconditions in a mammal in need thereof, comprising
`administering to the mammala therapeutically effective amount of any of the
`compoundsor any of the above pharmaceutical compositions described above.
`A class of the embodimentis the method wherein the cathepsin activity
`
`is cathepsin K activity.
`A secondclass of the embodiment is the method wherein the cathepsin
`
`activity is cathepsin L activity.
`Another embodimentof the invention is a method oftreating or
`preventing boneloss in a mammalin needthereof, comprising administering to the
`mammala therapeutically effective amount of any of the compoundsor any of the
`above pharmaceutical compositions described above.
`Another embodimentof the invention is a method of reducing bone
`loss in a mammalin need thereof, comprising administering to the mammal a
`therapeutically effective amount of any ofthe compoundsor any of the above
`pharmaceutical compositions described above.
`Another embodiment of the invention is a method oftreating or
`preventing bonefractures in a mammal in need thereof, comprising administering to
`the mammal a therapeutically effective amount of any of the compoundsor any of the
`above pharmaceutical compositions described above.
`Another embodiment of the invention is a methodoftreating or
`preventing osteoporosis in a mammalin needthereof, comprising administering to the
`mammala therapeutically effective amount of any of the compoundsor any ofthe
`above pharmaceutical compositions described above.
`Exemplifying the invention is a pharmaceutical composition
`comprising any of the compounds described above and a pharmaceutically acceptable
`carrier. Also exemplifying the invention is a pharmaceutical composition made by
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-8 -
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`combining any of the compounds described above and a pharmaceutically acceptable
`carrier. An illustration of the invention is a process for making a pharmaceutical
`composition comprising combining any of the compounds described above and a
`pharmaceutically acceptable carrier.
`Further exemplifying the invention is the use of any of the compounds
`described abovein the preparation of a medicamentfor the treatment and/or
`prevention of osteoporosis in a mammal in need thereof. Still further exemplifying
`the invention is the use of any of the compounds described abovein the preparation of
`a medicamentfor the treatment and/or prevention of: bone loss, bone resorption, bone
`fractures, and/or disorders related to cathepsin functioning.
`The present invention is also directed to combinations of any of the
`compoundsor any of the pharmaceutical compositions described above with one or
`more agents useful in the prevention or treatment of osteoporosis. For example, the
`compoundsofthe instant invention may be effectively administered in combination
`with effective amounts of other agents such as an organic bisphosphonate or an
`estrogen receptor modulator. Nonlimiting examples of said organic bisphosphonates
`include alendronate, clodronate, etidronate, ibandronate, incadronate, minodronate,
`neridronate, risedronate, piridronate, pamidronate, tiludronate, zoledronate,
`pharmaceutically acceptable salts or esters thereof, and mixtures thereof. Preferred
`organic bisphosphonates include alendronate and pharmaceutically acceptable salts
`and mixtures thereof. Most preferred is alendronate monosodium trihydrate.
`The precise dosage of the bisphosphonate will vary with the dosing
`schedule, the oral potency of the particular bisphosphonate chosen,the age, size, sex
`and condition of the mammal or human, the nature and severity of the disorder to be
`treated, and other relevant medical and physical factors. Thus, a precise
`pharmaceutically effective amount cannot be specified in advance and can be readily
`determined bythe caregiver or clinician. Appropriate amounts can be determined by
`routine experimentation from animal models and humanclinical studies. Generally,
`an appropriate amount of bisphosphonate is chosen to obtain a bone resorption
`inhibiting effect, i.e. a bone resorption inhibiting amountof the bisphosphonateis
`administered. For humans, an effective oral dose of bisphosphonateis typically from
`about 1.5 to about 6000 ug/kg body weight and preferably about 10 to about 2000
`pg/kg of body weight.
`For human oral compositions comprising alendronate,
`pharmaceutically acceptable salts thereof, or pharmaceutically acceptable derivatives
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-9 -
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`thereof, a unit dosage typically comprises from about 8.75 mg to about 140 mg of the
`alendronate compound, on an alendronic acid active weightbasis, i.e. on the basis of
`the corresponding acid.
`For use in medicine, the salts of the compoundsof this invention refer
`to non-toxic "pharmaceutically acceptable salts." Other salts may, however, be useful
`in the preparation of the compounds according to the invention or of their
`pharmaceutically acceptable salts. When the compoundsof the present invention
`contain a basic group, salts encompassed within the term "pharmaceutically
`acceptable salts" refer to non-toxic salts which are generally prepared by reacting the
`free base with a suitable organic or inorganic acid. Representative salts include the
`following: acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate,
`borate, bromide, calcium, camsylate, carbonate, chloride, clavulanate,citrate,
`dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, gluceptate, gluconate,
`glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide,
`hydrochloride, hydroxynaphthoate,iodide, isothionate, lactate, lactobionate, laurate,
`malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate,
`mucate, napsylate, nitrate, N-methylglucamine ammoniumsalt, oleate, oxalate,
`pamoate (embonate), palmitate, pantothenate, phosphate/diphosphate,
`polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate, tannate, tartrate,
`teoclate, tosylate, triethiodide and valerate. Furthermore, where the compoundsof the
`invention carry an acidic moiety, suitable pharmaceutically acceptable salts thereof
`may include alkali metal salts, e.g., sodium or potassium salts; alkaline earth metal
`salts, e.g., calcium or magnesium salts; and salts formed with suitable organic ligands,
`€.g., quaternary ammonium salts.
`The compoundsof the present invention can have chiral centers and
`occur as racemates, racemic mixtures, diastereomeric mixtures, and as individual
`
`diastereomers, or enantiomers with all isomeric forms being includedin the present
`invention. Therefore, where a compoundis chiral, the separate enantiomers,.
`substantially free of the other, are included within the scope of the invention; further
`includedare all mixtures of the two enantiomers. Also included within the scope of
`the invention are polymorphs, hydrates and solvates of the compoundsof the instant
`invention.
`
`The present invention includes within its scope prodrugsof the
`compoundsofthis invention. In general, such prodrugs will be functional derivatives
`of the compoundsofthis invention which are readily convertible in vivo into the
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`-10 -
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`required compound. Thus, in the methods of treatment of the present invention, the
`term "administering" shall encompassthe treatment of the various conditions
`described with the compound specifically disclosed or with a compound which may
`not be specifically disclosed, but which converts to the specified compound in vivo
`after administration to the patient. Conventional procedures for the selection and
`preparation of suitable prodrug derivatives are described, for example, in "Design of
`Prodrugs," ed. H. Bundgaard, Elsevier, 1985, which is incorporated by reference
`herein in its entirety. Metabolites of these compounds include active species
`produced upon introduction of compoundsof this invention into the biological milieu.
`The term "therapeutically effective amount" shall mean that amountof
`a drug or pharmaceutical agent that will elicit the biological or medical response of a
`tissue, system, animal or human that is being sought by a researcheror clinician.
`The term "bone resorption," as used herein, refers to the process by
`which osteoclasts degrade bone.
`The term "alkyl" shall mean straight or branched chain alkanes of one
`to ten total carbon atoms, or any number within this range G.e., methyl, ethyl, 1-
`propyl, 2-propyl, n-butyl, s-butyl, t-butyl, etc.).
`The term "alkenyl" shall mean straight or branched chain alkenes of
`two to ten total carbon atoms, or any numberwithin this range containing at least one
`double bond(i.e., -CH=CHp, -CH»CH=CHb», -CH=CHCHs3, -CH»,CH=C(CHs3)y, etc.).
`
`The term "alkynyl" shall meanstraight or branched chain alkynes of
`two to ten total carbon atoms, or any numberwithin this range containing at least one
`triple bond(i.e., -C=CH, -CHy)C=H, -C=CCH3, -CH»)C=CCH>(CH3)p»,etc.).
`
`The term "cycloalkyl" shall mean cyclic rings of alkanes of three to
`eight total carbon atoms, or any number within this range (i.e., cyclopropyl,
`cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl).
`The term “cycloalkenyl” shall mean a substituting univalent group
`derived by conceptual removal of one hydrogen atom from an unsaturated monocyclic
`hydrocarbon containing a double bond(i.e., cyclopentenyl or cyclohexenyl).
`The term "cycloheteroalkyl," as used herein, shall mean a 3- to 8-
`membered fully saturated heterocyclic ring containing one or two heteroatoms chosen
`from N, O or S. Examples of cycloheteroalkyl groups include, but are not limited to,
`oxiranyl, piperidinyl, pyrrolidinyl, azetidinyl, morpholinyl, piperazinyl.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`-l1-
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`The term "aryl," as used herein, refers to a monocyclic or polycyclic
`system comprising at least one aromatic ring, wherein the monocylic or polycyclic
`system contains 0, 1, 2, 3, or 4 heteroatoms chosen from N, O, or S, and wherein the
`monocylic or polycylic system is either unsubstituted or substituted with one or more
`groups independently selected from hydrogen, halogen, C1-10 alkyl, C3-8 cycloalkyl,
`aryl, aryl Cj-g alkyl, amino, amino C1-8 alkyl, Cj-3 acylamino, C1-3 acylamino C1-8
`alkyl, C1-6 alkylamino, C1-6 alkylamino C1-8 alkyl, C1-6 dialkylamino, C1-6
`dialkylamino-C1-g alkyl, C1-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbony],
`hydroxycarbonyl C1-6 alkyl, C1-5 alkoxycarbonyl, C1-3 alkoxycarbonyl C1-6 allxyl,
`hydroxycarbonyl C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano,trifluoromethyl,
`oxo or C1-5 alkylcarbonyloxy. Examples of aryl include, but are not limited to,
`
`phenyl, naphthyl, pyridyl, pyrazinyl, pyrimidinyl, imidazolyl, benzimidazolyl, indolyl,
`thienyl, furyl, dihydrobenzofuryl, benzo(1,3) dioxolane, oxazolyl, isoxazolyl and
`thiazolyl, which are either unsubstituted or substituted with one or more groups
`independently selected from hydrogen, halogen, C1-10 alkyl, C3-g cycloalkyl, aryl,
`aryl C1-8 alky!, amino, amino C1-8 alkyl, C1-3 acylamino, C1{-3 acylamino C1-g
`alkyl, C1-6 alkylamino, C1-6 alkylamino-C 1-8 alkyl, C1-6 dialkylamino, C16
`dialkylamino C1-8 alkyl, Cj-4 alkoxy, C1-4 alkoxy C1-6 alkyl, hydroxycarbony]l,
`hydroxycarbonyl C1-6 alkyl, C4-5 alkoxycarbonyl, C4-3 alkoxycarbonyl Cj-6 alkyl,
`hydroxycarbony] C1-6 alkyloxy, hydroxy, hydroxy C1-6 alkyl, cyano,trifluoromethyl,
`oxo or C1-5 alkylcarbonyloxy. Preferably, the aryl group is unsubstituted, mono-, di-,
`
`tri- or tetra-substituted with one to four of the above-named substituents; more
`preferably, the aryl group is unsubstituted, mono-, di- or tri-substituted with one to
`three of the above-namedsubstituents; most preferably, the ary! groupis
`unsubstituted, mono- or di-substituted with one to two of the above-named
`
`substituents.
`
`10
`
`15
`
`20
`
`25
`
`Wheneverthe term "alkyl" or "aryl" or either of their prefix roots
`appear in a name ofa substituent (e.g., aryl Co-g alkyl) it shall be interpreted as
`
`including those limitations given above for "alkyl" and "aryl." Designated numbers of
`carbon atoms(e.g., C1-10) shall refer independently to the numberof carbon atomsin
`
`30
`
`an alkyl or cyclic alkyl moiety or to the alkyl portion of a larger substituent in which
`alkyl appears as its prefix root.
`The terms "arylalkyl" and "alkylaryl" include an alkyl portion where
`alkyl is as defined above and to include an ary] portion where aryl is as defined above.
`Examples of arylalkyl include, but are not limited to, benzyl, fluorobenzyl,
`
`35
`
`-12-
`
`

`

`WO 01/77073
`
`PCT/US01/11001
`
`chlorobenzyl, phenylethyl, phenylpropyl, fluorophenylethyl, chlorophenylethyl,
`thienylmethyl, thienylethyl, and thienylpropyl. Examples of alkylaryl include, but are
`not limited to, toluyl, ethylphenyl, and propylpheny]l.
`The term "halogen"shall include iodine, bromine, chlorine and
`
`fluorine.
`
`The term "oxy" means an oxygen (O) atom. The term "thio" means a
`sulfur (S) atom. The term "oxo" means =O. The term “oximino” means the
`=C(H)NOHgroup.
`The term “side chain” refers to the portion of an amino acid that is
`bondedto the tetrahedral alpha carbon that is not the amino or carboxyl group.
`Nonlimiting examples of side chains include -CH2CH2CH2CH2NH3 (lysine) and —
`CHz3(alanine).
`
`The term “naturally occurring amino acids” refers to the aminoacids
`that include alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic
`acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline,
`serine, threonine, tryptophan, tyrosine and valine.
`The term “unnaturally occurring amino acids” refers to amino acids
`that have alpha side chains other than those found in the natural amino