NZ337889A - Cysteine Protease inhibitors of the Papain superfamily comprising cathepsin K protease inhibitors - Google Patents

Cysteine Protease inhibitors of the Papain superfamily comprising cathepsin K protease inhibitors

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Publication number
NZ337889A
NZ337889A NZ337889A NZ33788998A NZ337889A NZ 337889 A NZ337889 A NZ 337889A NZ 337889 A NZ337889 A NZ 337889A NZ 33788998 A NZ33788998 A NZ 33788998A NZ 337889 A NZ337889 A NZ 337889A
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New Zealand
Prior art keywords
amino
leucine
tetrahydrofuran
galkyl
het
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NZ337889A
Inventor
Andrew D Gribble
Jason Witherington
Robert W Marquis
Daniel Frank Veber
Ashley Edward Fenwick
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Smithkline Beecham Plc
Smithkline Beecham Corp
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Application filed by Smithkline Beecham Plc, Smithkline Beecham Corp filed Critical Smithkline Beecham Plc
Publication of NZ337889A publication Critical patent/NZ337889A/en

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Abstract

A compound according to formula (I) wherein: R1 is R", R"C(O), R"C(S), R"SO2, R"OC(O), R"R'NC(O), or R"OC(O)NR'CH(R6)C(O); R is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl; R is H, C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl; R4 is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl; each R5 independently is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl; R6 is H, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl; R' is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl; R" is C1-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, Ar-C2-6alkenyl; or Het-C2-6alkenyl; X is O or S; n is 1,2,or 3; or a pharmaceutically acceptable salt thereof. Also disclosed is the process for the preparation of the above compound and it's use in the treatment of disease in which inhibition of cysteine protease is a factor, inhibition of bone loss, osteoporosis, gingival or periodontal disease, osteoarthritis or rheumatoid arthritis.

Description

<div class="application article clearfix" id="description"> <p class="printTableText" lang="en">WO 98/50533 PCT/US98/03200 <br><br> PROTEASE INHIBITORS Field of the Invention <br><br> This invention relates to novel protease inhibitors, particularly inhibitors of 5 cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases The compounds of this invention even more particularly relate to those compounds which inhibit cysteine proteases of the papain superfamily, and particularly cysteine proteases of the cathepsin family In the most preferred embodiment, this invention relates to compounds which inhibit cathepsin K Such compounds are 10 particularly useful for treating diseases in which cysteine proteases are implicated, <br><br> especially diseases of excessive bone or cartilage loss, e g , osteoporosis, periodontitis, and arthritis <br><br> Background of the Invention <br><br> 15 Cathepsin K is a member of the family of enzymes which are part of the papain superfamily of cysteine proteases Cathepsins B, H, L, N and S have been described in the literature Recently, cathepsin K polypeptide and the cDNA encoding such polypeptide were disclosed in U.S Patent No. 5,501,969 (called cathepsin O therein) Cathepsin K has been recently expressed, purified, and characterized Bossard, M J , et 20 al, (1996) J. Biol Chem. 271, 12517-12524, Drake, F H , et al, (1996) J Biol Chem 271, 12511-12516, Bromme, D , et al, (1996) J. Biol. Chem. 271, 2126-2132 <br><br> Cathepsin K has been variously denoted as cathepsin O, cathepsin X or cathepsin 02 in the literature The designation cathepsin K. is considered to be the more appropriate one (name assigned by Nomenclature Committee of the International Union 25 of Biochemistry and Molecular Biology) <br><br> Cathepsins of the papain superfamily of cysteine proteases function in the normal physiological process of protein degradation in animals, including humans, e g , in the degradation of connective tissue. However, elevated levels of these enzymes in the body can result in pathological conditions leading to disease Thus, cathepsins have 30 been implicated in various disease states, including but not limited to, infections by Pneumocystis cannn, trypsanoma cruzi, trypsanoma brucei brucei, and Cnthidia fusiculata, as well as in schistosomiasis malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like See International Publication Number WO 94/04172, published on March 3, 1994, and references cited 35 therein See also European Patent Application EP 0 603 873 Al, and references cited therein. Two bacterial cysteine proteases from P gingivallis. called gingipains, have <br><br> - 1 - <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> been implicated in the pathogenesis of gingivitis Potempa, J , et al (1994) Perspectives in Drug Discovery and Design, 2, 445-458 <br><br> Cathepsin K is believed to play a" causative role in diseases of excessive bone or cartilage loss Bone is composed of a protein matrix in which spindle- or plate-shaped 5 crystals of hydroxyapatite are incorporated Type I Collagen represents the major structural protein of bone comprising approximately 90% of the structural protein The remaining 10% of matrix is composed of a number of non-collagenous proteins, <br><br> including osteocalcin, proteoglycans, osteopontm, osteonectin, thrombospondm, <br><br> fibronectin, and bone sialoprotein. Skeletal bone undergoes remodeling at discrete foci 10 throughout life These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement <br><br> Bone resorption is carried out by osteoclasts, which are multinuclear cells of hematopoietic lineage. The osteoclasts adhere to the bone surface and form a tight sealing zone, followed by extensive membrane ruffling on their apical (l e , resorbing) 15 surface This creates an enclosed extracellular compartment on the bone surface that is acidified by proton pumps in the ruffled membrane, and into which the osteoclast secretes proteolytic enzymes The low pH of the compartment dissolves hydroxyapatite crystals at the bone surface, while the proteolytic enzymes digest the protein matrix In this way, a resorption lacuna, or pit, is formed. At the end of this phase of the cycle, 20 osteoblasts lay down a new protein matrix that is subsequently mineralized In several disease states, such as osteoporosis and Paget's disease, the normal balance between bone resorption and formation is disrupted, and there is a net loss of bone at each cycle Ultimately, this leads to weakening of the bone and may result in increased fracture risk with minimal trauma <br><br> 25 The abundant selective expression of cathepsin K in osteoclasts strongly suggests that this enzyme is essential for bone resorption Thus, selective inhibition of cathepsin K may provide an effective treatment for diseases of excessive bone loss, including, but not limited to, osteoporosis, gingival diseases such as gingivitis and periodontitis, Paget's disease, hypercalcemia of malignancy, and metabolic bone 30 disease Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium. Thus, selective inhibition of cathepsin K may also be useful for treating diseases of excessive cartilage or matrix degradation, including, but not limited to, osteoarthritis and rheumatoid arthritis Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding 35 matrix Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases. <br><br> -2- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> It now has been discovered that a novel class of compounds are protease inhibitors, most particularly inhibitors of cathepsin K, and these compounds are useful for treating diseases in which inhibition of bone resorption is indicated, such as osteoporosis and periodontal disease <br><br> 5 <br><br> Summary of the Invention <br><br> An object of the present invention is to provide protease inhibitors, such as inhibitors of cysteine and serine proteases In particular, the present invention relates to 10 compounds which inhibit cysteine proteases, and particularly cysteine proteases of the papain superfamily Preferably, this invention relates to compounds which inhibit cysteine proteases of the cathepsin family and particularly, compounds which inhibit cathepsin K The compounds of the present invention are useful for treating diseases, <br><br> which may be therapeutically modified by altering the activity of such proteases 15 Accordingly, in the first aspect, this invention provides a compound according to formula (I) <br><br> (I) <br><br> 20 In another aspect, this invention provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier <br><br> In yet another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, 25 such as cysteine and serine proteases. In particular, the method includes treating diseases by inhibiting cysteine proteases, and particularly cysteine proteases of the papain superfamily More particularly, the inhibition of cysteine proteases of the cathepsin family, such as cathepsin K is described <br><br> In another aspect, the compounds of this invention are especially useful for 30 treating diseases characterized by bone loss, such as osteoporosis and gingival diseases, such as gingivitis and periodontitis, or by excessive cartilage or matrix degradation, such as osteoarthritis and rheumatoid arthritis <br><br> -3- <br><br> Printed from Mimosa <br><br> \J %0 <br><br> Detailed Descnption of the invention The present invention provides compounds of formula (I): <br><br> (I) <br><br> wherein <br><br> R1 is R", R"C(0), R"C(S), R"S02, R"0C(0), R"RNC(0), or R"0C(0)NRCH(R6)C(0), <br><br> R2 is H, Cj.galkyl, C2-6alkenyl, Ar-C()-6alkyl, or Het-CQ.^alkyl; 10 R3 is H, Cj.galkyl, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl-Co_6alkyl, <br><br> Ar-Co-6alkyl, or Het-Co_6alkyl, <br><br> R4 is H, Cj.galkyl, C2-6alkenyl, Ar-Co-6alkyl, or Het-CQ-galkyl, <br><br> each R^ independently is H, Cj.galkyl, C2-6alkenyl, Ar-C()-6alkyl, or Het-CQ-6alkyl; <br><br> 15 R6 is H, Cj.^alkyl, C2-6alkenyl, C3_6cycloalkyl-Co-6-alkyl, Ar-Co^alkyl, <br><br> Het-Co-ealkyl; <br><br> R is H, Cj.galkyl, C2_6alkenyl, Ar-Co-6alkyl, or Het-Co.galkyl; <br><br> R is C]_galkyl, Ar-C()-6alkyl, Het-CQ-^alkyl, Ar-C2_6alkenyl or Het-C2-6alkenyl; <br><br> 20 X is O or S; <br><br> nisi, 2 or 3; and <br><br> Ar and Het are as hereinbefore defined; <br><br> or a pharmaceutically acceptable salt thereof. <br><br> The present invention includes all hydrates, solvates, complexes and prodrugs of 25 the compounds of this invention. Prodrugs are any covalently bonded compounds which release the active parent drug according to formula (I) in vivo. If a chiral center or another form of an isomeric center is present in a compound of the present invention, all forms of such isomer or isomers, including enantiorners and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a 30 racemic mixture, an enantiomerically enriched mixture, or the racemic mixture may be separated using well-known techniques and an individual enantiomer may be used alone. According to the instant invention, the S-form at the furan nng junction of formula (I) compounds is preferred. <br><br> -4- <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (Z) and trans (E) isomers are within the scope of this invention In cases wherein compounds may exist m tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether 5 existing in equilibrium or predominantly in one form <br><br> The meaning of any substituent at any one occurrence in formula (I) or any subformula thereof is independent of its meaning, or any other substituent's meaning, at any other occurrence, unless specified otherwise With respect to formula (I) <br><br> 10 <br><br> Suitably, and R^ are H and R^ is Cj.galkyl or C2-6alkenyl. Preferably, R^ is i-butyl <br><br> Suitably, each R^ is H <br><br> Suitably, R^ is R OC(O), R SO2 or R C(O), in which R is Ar-Co-6alkyl or 15 Het-cq.galkyl, and, most preferably, R is in which B2 is OH, CN, OCF3, OCj.galkyl, OAr, S02C^_galkyl, Cj.galkyl or halo <br><br> 20 Suitably, n is 1 or 2. Preferably, n is 1 Suitably, X is O <br><br> C <br><br> -5- <br><br> Pnnted from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> In one particular embodiment, this invention is a compound of formula (II) <br><br> til <br><br> (II). <br><br> 5 Preferably, the formula (I) compound of this invention is a compound of formula (Ila) <br><br> 10 <br><br> -.3 H <br><br> N <br><br> i s xs <br><br> (Ila). <br><br> Alternately, the formula (I) compound of this invention is a compound of formula (lib) <br><br> H <br><br> H <br><br> (lib). <br><br> In another embodiment, this invention is a compound of formula (lie) ■-,3 H <br><br> (lie). <br><br> 15 <br><br> 20 <br><br> Specific representative compounds of this invention are <br><br> 4-(/?,5)-Amino-N-[(3,4-methylenedioxybenzoyl)-5-leucine]-tetrahydrofuran-3-one, <br><br> 4-(7?,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-tetrahydrofuran-3-one, <br><br> 4-(7?,S)-Amino-N-[(3,4-dichlorobenzoyl)-,S-leucine]-tetrahydrofuran-3-one, <br><br> 4-(i?,5)-Amino-N-[(2-quinohnecarbonyl)-5-leucine]-tetrahydrofuran-3-one, <br><br> 4-(R, 5J-Amino-N-[(8-quinolinecarbonyl)-S-leucine]-tetrahydrofuran-3-one, <br><br> 4-(7?,iS)-Ammo-N-[(benzyloxycarbonyl)-,S-leucine]-2,2-dibenzyl-tetrahydrofuran-3-oni <br><br> -6 <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> 4-(7?,Sj-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S'-leucine]-tetrahydrofuran- <br><br> 3-one, <br><br> 4-(7?,S)-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-(7?,S)-Amino-N-[(indole-6-ylcarbonyl)-S-leucme]-tetrahydrofuran-3-one, 5 4-(7?,.S)-Amino-N-[(benzofuran-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one, <br><br> 4-f/?,5'/l-Amino-N-[(5-aminobenzo[b]thiophen-2-ylcarbonyl)-5-leucine]-tetrahydrofuran-3-one, <br><br> 4-(,/?,5j-Amino-N-[(5-chlorobenzofuran-2-ylcarbonyl)-5-leucine]-tetrahydrofuran-3-one, 10 4-f/?,5j-Amino-N-[(5-methoxybenzofuran-2-ylcarbonyl)-5-leucine]- <br><br> tetrahydrofuran-3-one, <br><br> 4-(7?„SJ-Amino-N-[(3-bromobenzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-f'/?,5J-Amino-N-[(4-bromobenzoyl)-5-leucine]-tetrahydrofuran-3-one, 4-(7?,S)-Amino-N-[(5-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-15 tetrahydrofuran-3-one, <br><br> 4-f/?,5J-Amino-N-[(4-fluorobenzo[b]thiophen-2-ylcarbonyl)-S-lcucine]-tetrahydrofuran-3-one, <br><br> 4-f/?,Sj-Amino-N-[(4-phenoxybenzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-(7?,S)-Amino-N-[(4-phenylbenzoyl)-S-leucine]-tetrahydrofuran-3-one, 20 4-(7?,S)-Amino-N-[(6-tnfluoromethylbenzo[b]thiophen-2-ylcarbonyl)-,S- <br><br> leucine]-tetrahydrofuran-3-one, <br><br> 4-f/?,5J-Ammo-N-[(4-ethyllbenzoyl)-5-leucine]-tetrahydrofuran-3-one; 4-f/?,5J-Amino-N-[(4-(tert-butyl)benzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-(7?,SJ-Amino-N-[(5-methoxybenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-25 tetrahydrofuran-3-one, <br><br> 4-(7?,5J-Amino-N-[(4-nitrobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahy drofuran-3-one, <br><br> 4-(7?,Sj-Amino-N-[(6-bromobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one, 30 4-(7?,S)-Amino-N-[(5-bromobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]- <br><br> tetrahydrofuran-3-one, <br><br> 4-(R, 5J-Amino-N-[(6-methoxybenzo[b]thiophen-2-ylcarbonyl)-S-leucme]-tetrahydrofuran-3-one, <br><br> 4-S-Amino-N-[(benzo(b)thiophen-2-ylcarbonyl)-5-leucine]-tetrahydrofuran-3- <br><br> 35 one, <br><br> 4-/?-Amino-N-[(benzo(b)thiophen-2-ylcarbonyl)-5-leucine]-tetrahydrofuran-3- <br><br> one; <br><br> -7- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> 4-S-Amino-N-[(2-napthoyl)-S-leucine]-tetrahydrofuran-3-one, 4-7?-Amino-N-[(2-napthoyl)-S-leucine]-tetrahydrofuran-3-one, 4-S-Ammo-N-[(quinoline-2-carbonyl)-S-leucine]-tetrahydrofuran-3-one, 4-/?-Amino-N-[(quinohne-2-carbonyl)-S-leucine]-tetrahydrofuran-3-onc, 5 4-S-Amino-N-[(5-methoxybenzofuran-2-ylcarbonyl)-S-leucine]- <br><br> tetrahydrofuran-3-one, <br><br> 4-S-Amino-N-[((4-pyrid-3-yl)benzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-5-Amino-N-[((4-pyrid-2-yl)benzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-5-Amino-N-[(benzy]oxycarbonyl)-S-leucme]-tetrahydrofuran-3-one, 10 4-5-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-tetrahydrofuran-3-one, <br><br> 4-S-Amino-N-[(benzofuran-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one, 4-S-Amino-N-[(4-[6-mcthylpyrid-3-yl]benzoyl)-S'-leucine]-tetrahydrofuran-3- <br><br> one, <br><br> 4-5-Amino-N-[(5-chlorobenzo[bJthiophen-2-ylcarbonyl)-S-leucine]-15 tetrahydrofuran-3-one, <br><br> 4-5-Amino-N-[((4-pynd-4-yl)benzoyl)-5-leucine]-tetrahydrofuran-3-one, 4-S-Amino-N-[(2-chIorobenzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-S-Amino-N-[(4-bromobenzoyl)-S-Ieucine]-tetrahydrofuran-3-one, 4-iS-Amino-N-[(4-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-20 tetrahydrofuran-3-one, <br><br> 4-S-Amino-N- [(4-benzylpiperidm-1 -ylcarbony l)-S-leucme]-tetrahy drofuran-3- <br><br> one, <br><br> 4-S-Amino-N-[(3,4-dichlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-S-Amino-N-[(3-chlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one, 25 4-(/?,S)-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-tetrahydropyran-3-one, <br><br> 4-(/?,S)-Amino-N-[(4-phenoxybenzoyl)-S-leucine]-tetrahydropyran-3-one, 4-(/?,5)-Amino-N-[(quinolin-2-ylcarbonyl)-S-leucme]-tetrahydropyran-3-one, 4-(/?,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-tetrahydropyran-3-one, 4-(J?,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucme]-30 tetrahydropyran-3-one; and <br><br> 4-(7?,SJ-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrothiophen-3-one, <br><br> or a pharmaceutically acceptable salt thereof <br><br> In yet another aspect, this invention provides novel intermediates useful in the 35 preparation of formula (I) compounds represented by formulae (III), (IV) and (V) <br><br> -8- <br><br> Printed from Mimosa <br><br> r1\ <br><br> Ft <br><br> N <br><br> .5 <br><br> (m) <br><br> wherein. <br><br> Rl is R", R"C(0), R"C(S), R"S02, R"0C(0), R"RNC(0), or R"0C(0)NRCH(R6)C(0); <br><br> R2 is H, Cj.galkyl, C2_6alkenyl, Ar-Co-6aIkyl, or Het-CQ.galkyl; <br><br> R3 is H, Cj^alkyl, C2-6alkenyl, C2-6alkynyI, C3_6cycloalkyl-Co-6alkyl, Ar-C0_6alkyl, or Het-Co_6alkyl; <br><br> R4 is H, Cj.galkyl, C2_6alkenyl, Ar-Co-^alkyl, or Het-CQ.galkyl; <br><br> each R^ independently is H, Cj.galkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-Co-^alkyl; <br><br> R^ is H, Cj.^alkyl, C2_5alkenyl, C3_6cycloalkyl-Co-6-alkyl, Ar-CQ-galkyl, Het-Co_6alkyl; <br><br> r' is H, Cj.galkyl, C2-6alkenyl, Ar-C()-6alkyl, or Het-Co-6alkyl; r" is Cj.^alkyl, Ar-Co-6alkyl, Het-CQ-galkyl, Ar-c2-6alkenyl; or Het-C2-6alkenyi; <br><br> n is 1, 2 or 3; and <br><br> Ar and Het are as hereinbefore defined ; <br><br> or a pharmaceutically acceptable salt thereof, or <br><br> R1 is R", R"C(0), R"C(S), RmS02, R"0C(0), R"RNC(0), or R"0C(O)NR'CH(R6)C(O); <br><br> R- is H, Cj.galkyl, C2-6alkenyl, Ar-Co-6alkyl, or Het-CQ-galkyl; <br><br> R3 is H, Cj.^alkyl, C2-6aIkenyl, c2-6a'kynyl, C3_6cycloalkyl-C()_6alkyl, Ar-C0_6alkyl, or Het-Cg^alkyl; <br><br> R4 is H, Cj.galkyl, C2_5alkenyl, Ar-C()-6alkyl, or Het-CQ.galkyl; <br><br> each R^ independently is H, Cj.^alkyL C2_6alkenyl, Ar-CQ.^alkyl, or Het-Co-galkyl, <br><br> R6 is H, Cj.galkyl, C2_6alkenyl, C3_6cycioalkyl-CQ-6-alkyl, Ar-CQ.galkyl, Het-Co_^alkyl; <br><br> R R' <br><br> (IV) <br><br> wherein: <br><br> R is H, C]_galkyl, C2-6aikenyl, Ar-C()-6aIkyI, or Het-Co^galkyl; R" is Cj_5alkyl, Ar-Co-6alkyl, Het-Co-6a^yl, Ar-C2_6alkenyl; or Het-C2_6alkenyl; <br><br> n is 1, 2 or 3; and <br><br> Ar and Het are as hereinbefore defined; <br><br> or a pharmaceutically acceptable salt thereof, or <br><br> R1 is r", R"C(0), R"C(s), R"s02, R"0C(0), r"r'nC(0), or R"OC( 0)NRCH(R6)C(0); <br><br> RJ is H, Cj.galkyl, C2-6aIkenyl, C2-6alkynyl, C3_6cycloalkyl-Co-6alkyl, Ar-Co.^alkyl, or Het-C^alkyl; <br><br> R4 is H, Cj.galkyl, C2_6alkenyl, Ar-C0-6alkyl, or Het-Co_6alkyl; <br><br> each R5 independently is H, Cj.galkyl, C2-6alkenyl, Ar-Co-6alkyl, or Het-Co-galkyl; <br><br> R6 is H, Cj.galkyl, C2-6alkenyl, C3_6cycIoalkyl-C()_6-alkyl, Ar-CQ^alkyl, Het-Co-galkyl, <br><br> R is H, Chalky!, C2.$alkenyl, Ar-Co_6aIkyl, or Het-CQ-galkyl; R is C!.6alkyl, Ar-Co-6alkyl, Het-Co_galkyl, Ar-C2_galkenyl; or Het-C2-6alkenyl; <br><br> X is O or S; <br><br> n is 1, 2 or 3, <br><br> Ar and Het are as hereinbefore defined; and Resin is Ellmans resin; <br><br> or a pharmaceutically acceptable salt thereof. <br><br> Representative intermediates of this invention are: <br><br> trans-4~( R, S) - Amino-N- [(benzy loxycarbony 1)-S- leucme]-3-hydroxytetrahydrofuran; <br><br> mmy-4-(/?,S)-Amino-N-[(rerr-butoxycarbonyl)-S-!eucine]-3-hydroxytetrahydrofuran; <br><br> rra/i5-4-f^,5j-Amino-N-(5-leucine)-3-hydroxytetrahydrofuran; rranj-4-f/?,Sj-Amino-N-[(3,4-methylenedioxybenzoyl)-5-leucine]-3-hydroxytetrahydrofuran; <br><br> rraHJ-4-f/?&gt;5/)-Ammo-N-[(3,4-dichlorobenzoyl)-5-leucine]-3-hydroxytetrahydrofuran; <br><br> (V) <br><br> wherein: <br><br> - 10- <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> rraras-4-(7?,S/)-Amtno-N-[(2-quinolinecarbonyl)-S-leuctne}&lt;-3-hydroxy tetrahy drofuran, <br><br> rran5-4-(/?,S)-Amino-N-[(benzyioxycarbonyl)-S-leucineJ-3-hydroxy tetrahydropyran, 5 frarts-4-(7?,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3- <br><br> hydroxy tetrahy dropy ran, <br><br> rrans-4-(7?,S]-Anuno-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-hydroxytetrahydrofuran, <br><br> franj-4-(7?,SJ-Amino-N-[(indole-6-yIcarbonyl)-S-]eucine]-3-10 hydroxytetrahydrofuran, <br><br> frawj-4-f'/?&gt;5j-Amino-N-[(5-aminobenzo[b]thiophen-2-y]carbonyl)-5-leucine]-3-hydroxytetrahydrofuran rra/i5-4-Amino-3-hydroxytetrahydrofuran; fra«5-3-Hydroxy-4-benzyloxycarbonylamino-tetrahydrofuran, 15 4-Benzy loxycarbony lamino-tetrahydrofuran-3-one, <br><br> 3,3-Dimethoxy-4-benzyloxycarbonylamino-tetrahydrofuran, 3,3-Dimethoxy-4-amino-tetrahydrofuran rrani-4-S-Amino-3-/?-hydroxytetrahydrofuran, tran5-4-5-Amino-N-[(benzyloxycarbonyl)-S-leucine]-3-/f-20 hydroxytetrahydrofuran, <br><br> frart5-4-S-Anuno-N-(S-leucine)-3-/?-hydroxytetrahydrofuran, <br><br> fran5-4-S-Amino-N-[(3,4-dichlorobenzoyl)-5-leucine]-3-/?-hydroxy tetrahy drofuran, <br><br> rra«5-4-5-Amino-N-[(2-quinolinecarbonyl)-5-leucine]-3-/J-25 hydroxytetrahydrofuran, <br><br> frartj-4-S-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-/?-hydroxytetrahydrofuran, <br><br> rra«5-4-S-Amino-N-[(benzofuran-2-ylcarbonyl)-S-leucine]-3-tf-hydroxytetrahydrofuran, 30 rranj-4-5-Amino-N-[(2-naphthoyl)-5-leucine]-3-i?-hydroxytetrahydrofuran, <br><br> frans-4-S-Amino-N-[(5-methoxybenzofuran-2-ylcarbonyl)-S-leucine]-3-/?-hydroxy tetrahy drofuran, <br><br> j-4-5-Amino-N-[(5-chlorobenzo[b] thiophen-2-y lcarbony l)-5-leucine]-3-/^-hy droxy tetrahydrofuran, 35 frani-4-5-Amino-N-[(4-chlorobenzo[b]thiophen-2-ylcarbonyl)-5-leucine]-3-/?- <br><br> hy droxy tetrahy drofuran, <br><br> fran^-4-S-Amino-N-[(4-bromobenzoyl)-5-leucine]-3-/f-hydroxytetrahydrofuran, <br><br> - 11 - <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> fra/w-4-S-Amino-N-[(4-(pynd-2-yl)benzoyl)-S-leucine]-3-/?-hy droxy tetrahy drofuran, <br><br> rran.y-4-S-Amino-N-[(4-(pyrid-3-yl)benzoy!)-£-leucine]-3-/?-hydroxytetrahydrofuran, 5 lran.s-4-S-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-3-/?- <br><br> hydroxytetrahydrofuran, <br><br> fra«i-4-Amino-3-hydroxytetrahydropyran, rrans-4-(7?,S)-Amino-N-[(benzyioxycarbonyl)-S'-leucine]-3-hy droxytetrahydropyran; <br><br> 10 rranj-4-(7?,S)-Amino-N-(S-leucine)-3-hydroxytetrahydropyran, <br><br> fraas-4-(7?,,S)-Amino-N-[(benzo[b]thiophen-2-y]carbonyl)-S'-leucine]-3-hy droxy tetrahydropy ran, <br><br> /V-benzo[b]thiophene-2-ylcarbonyl-L-leucine methyl ester, /V-benzo[b]thiophene-2-ylcarbonyl-L-Ieucine, <br><br> 15 /V-benzo[b]thiophene-2-ylcarbonyl-L-leucine-S-(methoxycarbonylmethyl)-L,D- <br><br> cysteine ethyl ester, and <br><br> 2-Methoxycarbonyl-4-(/?,S,)-Ammo-N-[(benzo[b]thiophene-2-ylcarbonyl)-S-leucine]-tetrahydrothiophene-3-one, <br><br> or salts thereof <br><br> 20 These intermediates are prepared using methods analogous to that described in <br><br> Schemes 1-4 and the Examples described hereinafter <br><br> Prodrugs of compounds of the present invention may be a prodrug of the ketone functionality of formula (I) compounds, specifically ketals or hemiketals, of the formula (VI) <br><br> 25 <br><br> (VI) <br><br> wherein: <br><br> r1 is r", r"c(0), r"c(S), r"S02, r"0c(0), r"rnc(0), or 30 r"0c(0)nr'ch(r6)c(0), <br><br> r^ is H, Cj.galkyl, C2.galkenyl, Ar-Q)-6alkyl, orHet-C()-6alkyl, r3 is H, Cj.galkyl, C2-6a'kenyl, C2-6a'kynyl, C3_5cycloalkyl-CQ_^alkyl, Ar-C0.6alkyl, or Het-Cg.galkyl, <br><br> - 12- <br><br> Prmted from Mimosa <br><br> R4 is H, Cj.galkyl, C2-6alkenyl, Ar-Co-6a'kyl, or Het-CQ-^alkyl; <br><br> each independently is H, C].galkyl, C2-6alkenyl, Ar-Co-6alkyl, or Het-Co-6a^yl; <br><br> R6 is H, Chalky 1, C2-6alkenyl, C3_6cycloalkyI-Co-6-alkyl, Ar-Co-6alkyl, 5 Het-Co-6 alkyl, <br><br> R' is H, Cj.galkyl, C2-6alkenyl, Ar-Co-6alkyl, or Het-CQ.galkyl; <br><br> R is Chalky!, Ar-Co-6aIkyl, Het-CQ.6alkyl, Ar-C2_6alkenyl; or Het-c2_6alkenyl; <br><br> X is O or S; <br><br> 10 n is 1, 2 or 3, <br><br> Ra and Ra independently are H or Cj^alkyl, with the proviso that when one of Ra or Ra is H, the other is Ci_2alkyl; or together are (CH2)2_3 forming a 5- or 6-membered ring; and <br><br> Ar and Het are as hereinbefore defined; <br><br> 15 or a pharmaceutically acceptable salt thereof. <br><br> Abbreviations and symbols commonly used in the peptide and chemical arts are used herein to describe the compounds of the present invention. In general, the amino acid abbreviations follow the IUPAC-IUB Joint Commission on Biochemical Nomenclature as described m Eur J. Biochem., 158, 9 (1984). The term "ammo acid" 20 as used herein refers to the D- or L- isomers of alanine, argimne, asparagine, aspartic acid, cysteine, glutamme, glutamic acid, glycine, histidine. isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. <br><br> "C}-6 alkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, 25 isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any Cj-galkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R')2&gt; C(O)N(R02, carbamyl or C]-4alkyl, where R'is H or C]_6alkyl. Qjalkyl means that no alkyl group is present in the moiety. Thus, Ar-C^alkyl is equivalent to Ar. <br><br> "C3-6 cycloalkyl" as applied herein is meant to include substituted (i.e., alkyl, 30 OR, SR or halogen) and unsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane. <br><br> "C2-6 alkenyl" as applied herein means an alkyl group of 2 to 6 carbons, wherein a carbon-carbon single bond is replaced by a carbon-carbon double bond. C2-6alkenyl includes ethylene, 1-propene, 2-propene, 1-butene, 2-butene, isobutene and 35 the several isomeric pentenes and hexenes. Both cis and trans isomers are included. <br><br> "c2-6 alkynyl" means an alkyl group of 2 to 6 carbons, wherein one carbon-carbon single bond is replaced by a carbon-carbon triple bond. c2-6 alkynyl includes <br><br> - 13 - <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne, and the simple isomers of pentyne and hexyne <br><br> "Halogen1' or "halo" means F, CI,"Br, and I <br><br> "Ar" or "aryl" means unsubstituted phenyl or naphthyl, or phenyl or naphthyl 5 substituted by one or more of Ph-cq.galkyl, Het-Cg-galkyl, cj.galkoxy, <br><br> Ph-Co-6aikoxy, Het-CQ.galkoxy, OH, (CH2)i-6NRR', 0(CH2)]_6NRR\ wherein each R' independently is H, Cj.galkyl, Ar-Co.^alkyl, or Het-Cg-galkyl, or phenyl or naphthyl substituted by one to three moieties selected from C]-4alkyl, OR', N(R')2, SR', CF3, N02, CN, C02R\ CON(R')2, F, CI, Br and I, or substituted by a 10 methylenedioxy group <br><br> As used herein "Het" or "heterocyclic" represents a stable 5- to 7-membered monocyclic or a stable 7- to 10-membered bicyclic heterocyclic ring, which is either saturated or unsaturated, and which consists of carbon atoms and from one to four heteroatoms selected from the group consisting of N, O and S, and wherein the nitrogen 15 and sulfur heteroatoms may optionally be oxidized, and the nitrogen heteroatom may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring The heterocyclic ring may be attached at any heteroatom or carbon atom which results in the creation of a stable structure, and may optionally be substituted with one or two moieties selected from 20 Ci-4alkyl, OR', N(R')2, SR', CF3, N02, CN, C02R', CON(R')2, F, CI, Br and I, where R' is as defined herein before. Example? of such heterocycles include piperidmyl, piperazmyl, 2-oxopiperazmyl, 2-oxopipendinyl, 2-oxopyrrolodmyl, 2-oxoazepinyl, azepinyl, thienyl, pyrrolyl, 4-piperidonyl, pyrrclidmyl, pyrazolyl, pyrazolidinyl, lmidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, 25 morpholinyl, thiazolidinyl, thiazohnyl, isothiazolyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinohnyl, benzimidazolyl, benzothienyl, benzopyranyl, benzoxazolyl, benzofuranyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorphohnyl sulfoxide, thiamorphohnyl sulfone, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, cinnohnyl, quinazohnyl, quinoxalinyl, 30 1,5-napthyndinyl, 1,6-napthyridinyl, 1,7-napthyndinyl, 1,8-napthyndinyl, tetrazolyl, 1,2,3-triazolyl, and 1,2,4-tnazolyl <br><br> Certain radical groups are abbreviated herein t-Bu refers to the tertiary butyl radical, Boc or BOC refers to the t-butyloxycarbonyl radical, Fmoc refers to the fluorenylmethoxycarbonyl radical, Ph refers to the phenyl radical, and Cbz or CBZ 35 refers to the benzyloxycarbonyl radical <br><br> Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbodnmide, EDC or EDCI refers to N-ethyl-N'(dimethylaminopropyl)- <br><br> - 14- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> carbodnmide HOBT or HOBt refers to 1-hydroxybenzotriazole, JDMF refers to dimethyl formamide, DIEA refers to di-isopropylethylamine, Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide, TFA refers to tnfluoroacetic acid, and THF refers to tetrahydrofuran <br><br> Compounds of the formula (I) are generally prepared by (1) reacting a compound of the formula (III) <br><br> .3 R4 <br><br> R1\ ,N OH <br><br> 10 <br><br> 15 <br><br> R2 <br><br> n; n w <br><br> IX <br><br> (in) <br><br> wherein R', R^, R3, r4; r5 ancj n are as defined in formula (I), with any reactive functional groups protected, with an oxidizing agent, or <br><br> (n) decarboxylating a compound of the formula (IV) <br><br> R3 R4 <br><br> I <br><br> r2 ° (Vg/~ <br><br> COX^alkyl <br><br> (IV) <br><br> wherein R', R^, r3( r4^ r5 ancj n are as defined in formula (I), with any reactive 20 functional groups protected, or <br><br> (in) reacting a compound of the formula (V) <br><br> ——OC1.4alkyl <br><br> * * «03 <br><br> 25 (V) <br><br> - 15- <br><br> Printed from Mimosa <br><br> wherein R*, R3, R4, R^ and n are as defined in formula (I) and Resin is Ellmans resin, with any reactive functional groups protected, with an acid; <br><br> and thereafter removing any protecting groups and optionally forming a 5 pharmaceutically acceptable salt. <br><br> Compounds of the formula (I) are prepared by methods analogous to those described in the solution synthesis method of Scheme 1, or the solid support method of Scheme 2, or the solution synthesis method of Scheme 3. <br><br> - 16- <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> Scheme 1 <br><br> n* \\ <br><br> a) NaN3, ammonium chloride, methanol water, b) 10% Pd/C, EtOH, H2, ethanolic HC1, c) 5 tnmethylacetyl chloride, N-BOC-leucine, DIEA, CH2CI2, d) TFA, CH2CI2, e) RCOC1, sodium hydrogen carbonate, 1,4-dioxane, f) Dess-Martin periodmane, CH2C12 <br><br> Compounds of the general formula (I), wherein n is 1 and is R C(O) are prepared by methods shown in Scheme 1. Treatment of the known epoxide 1-Scheme-1 10 with sodium azide and ammonium chloride in aqueous methanol at elevated temperatures provides the azide 2-Scheme-l Reduction of the azide 2-Scheme-1 utilizing methods that are known in the art, such as reduction with palladium on carbon in ethanol under an atmosphere of hydrogen, provides the amine salt 3-Scheme-l after treatment with ethanolic hydrogen chloride The amine salt 3-Scheme-l may be 15 coupled with a carboxylic acid by methods that are known in the art, such as acylation with an acid chlonde or coupling with an acid in the presence of EDC and HOBT, to provide the amide 4-Scheme-l The fert-butoxycarbonyl group may be removed by treatment with a strong acid, such as TFA, in an aprotic solvent, such as <br><br> -17- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> dichloromethane, to provide 5-Scheme-1 The salt 5-Scheme-1 may be acylated with an acid chloride in 1,4-dioxane in the presence of an aqueous base, such as saturated sodium hydrogen carbonate, to yield 6-Scheme-l" The alcohol 6-Scheme-1 may be oxidized by methods known in the art, such as by treatment with Dess-Martm periodinane, in an aprotic solvent, such as dichloromethane <br><br> Scheme 2 <br><br> POL- <br><br> OMe <br><br> CHO H2N COOMe <br><br> OMe <br><br> NaBH(OAc), <br><br> OMe Ok OMe <br><br> POL- <br><br> R" COOH <br><br> EDC, HOAt <br><br> OMe O <br><br> POL <br><br> ,OMe <br><br> (i) KOTMS, THF <br><br> OMe <br><br> (H) <br><br> H2N <br><br> OMe <br><br> -18- <br><br> SUBSTITUTE SHEET (RULE 26) <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> Scheme 2 (cont) <br><br> PCT/US98/03200 <br><br> Compounds of the general formula (I), wherein R1 is C(0)R', R2 is H, R4 is H, R5 is H, X is 0, and nisi, are prepared by the solid support synthesis (SPS) method shown in Scheme 2 In particular, in the first step, sodium triacetoxyborohydnde is added to a stirred solution of Ellmans resin in DMF containing 1 %HOAc, and then the a-amino acid, methyl ester is added to give rise to 2-Scheme-2 The amine group is coupled with a carboxylic acid by using known methods, such as by the addition of the carboxylic acid with EDC, to give rise to the amide, 3-Scheme-2 Thereafter, the ester group is hydrolysed, for example, with potassium tnmethylsilanoate in THF, and the liberated acid group is coupled with 3,3-dimethoxy-4-amino-tetrahydofuran using, for example, EDC in NMP, to give rise to 4^ Scheme-2 The blocking group is then removed by known cleaving methods, such as by the addition of 7 2 1 TFA/CH2CI2/H2O, to give rise to the desired compound, 5-Scheme-2 <br><br> Compounds of the general formula (I), wherein R1 is C(0)R', R2 is H, R4 is H, Rs is H, X is O, and n is 2, are prepared by the solid support synthesis (SPS) method shown in Scheme 2, except 3,3-dimethoxy-4-arrunotetrahydropyran is substituted for 3,3-dimethoxy-4-amino-tetrahydofuran <br><br> -19- <br><br> SUBSTITUTE SHEET (RULE 26) <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> (a) L-Leu methyl ester, 'Pr2NEt, CH2C12, (b) LiOH, THF/H20, (c) (i)ClC02'Pr, Et3N, CH2C12 (11) L-Cys ethyl ester (111) BrCH2C02Me, (d) (i)NaOMe, MeOH, (11) AcOH/HCl, <br><br> h2o <br><br> Scheme 4, hereinafter, shows the preparation of certain formula (I) compounds which are S-diastereomers at the furan ring junction <br><br> -20- <br><br> SUBSTITUTE SHEET (RULE 261 <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Scheme 4 <br><br> as in Scheme 1 <br><br> The R-diastereomer is prepared in an identical way from the opposite 3-azido-4-hydroxytetrahydrofuran enantiomer n, <br><br> OH <br><br> The intermediates of the present invention, such as 3,3-dimethoxy-4-aminotetrahydofuran, can be prepared according to the method of Scheme 5 <br><br> -21- <br><br> SUBSTITUTE SHEET (RULE 26) <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Scheme 5 <br><br> CbzHN OH <br><br> / <br><br> CBzCI ) ( bleach ca 70% y TEMPO <br><br> ° ca 90 % <br><br> CbzHN <br><br> (MeO)3CH <br><br> pTSA ca 70% <br><br> CbzHN <br><br> OMe <br><br> OMe <br><br> H2N <br><br> H.,,Pd/C <br><br> ca 95% <br><br> OMe <br><br> OMe <br><br> The steps in Scheme 5 are presented as follows First, a nitrogen-protecting group is added by reacting 3-hydroxy-4-aminotetrahydofuran with benzylchloroformate in dioxane containing aqueous sodium carbonate Thereafter, the alcohol group is oxidized by known methods, such as by the addition of bleach containing sodium bicarbonate in the presence of sodium bromide and TEMPO in EtOAc, toluene, and water, to give rise to the ketone The ketone is converted to the dimethylketal by the addition of trimethyl-orthoformate in the presence of paratoluenesulphonic acid in methanol Finally, the protecting group is removed by hydrogenation using, for example, palladium on charcoal in the presence of ethanol under an atmosphere of hydrogen <br><br> -22- <br><br> SUBST1TUTE SHEET (RULE 26) <br><br> Printed from Mimosa <br><br> / <br><br> # <br><br> The starting materials used herein are commercially available or are prepared by routine methods well known to those of ordinary skill in the art and can be found in standard reference books, such as the COMPENDIUM OF ORGANIC SYNTHETIC METHODS, Vol l-VI (published by Wiley-lnterscience). <br><br> Coupling methods to form amide bonds herein are generally well-known to the art The methods of peptide synthesis generally set forth by Bodansky et al, THE PRACTICE OF PEPTIDE SYNTHESIS, Springer-Verlag, Berlin, 1984, E Gross and J Meienhofer, THE PEPTIDES, Vol 1, 1-284 (1979), and J M. Stewart and J.D Young, SOLID PHASE PEPTIDE SYNTHESIS, 2d Ed, Pierce Chemical Co , Rockford, 111., 1984, are generally illustrative of the technique and are incorporated herein by reference <br><br> Synthetic methods to prepare the compounds of this invention frequently employ protective groups to mask a reactive functionality or minimize unwanted side reactions Such protective groups are described generally in Green, T W, PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, John Wiley &amp; Sons, New York (1981) The term "ammo protecting groups" generally refers to the Boc, acetyl, benzoyl, Fmoc and Cbz groups and derivatives thereof as known to the art Methods for protection and deprotection, and replacement of an ammo protecting group with another moiety are well known <br><br> Acid addition saits of the compounds of formula (I) are prepared in a standard manner in a suitable solvent from the parent compound and an excess of an acid, such as hydrochloric, hydrobromic, hydrofluoric, sulfuric, phosphoric, acetic, <br><br> tnfluoro acetic, maleic, succinic or methanesulfonic acid Certain of the compounds form inner salts or zwittenons which may be acceptable Catiomc salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as a hydroxide, carbonate, or alkoxide, containing the appropriate cation, or with an appropriate orgamc amine Cations such as Li+, Na+, K+, Ca++, Mg++ and NH4+ are specific examples of cations present m pharmaceutically acceptable salts Hahdes, sulfate, phosphate, alkanoates (such as acetate and tnfluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present m pharmaceutically acceptable salts <br><br> This invention also provides a pharmaceutical composition which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier Accordingly, the compounds of formula (I) may be used m the manufacture of a medicament Pharmaceutical compositions of the compounds of formula (I) prepared as hereinbefore described may be formulated as solutions or lyophihzed powders for parenteral administration Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable earner prior to use. The liquid formulation may be a buffered, isotonic, aqueous solution Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water, or buffered sodium or ammonium acetate solution Such formulation is especially suitable for parenteral administration, but may also be used for oral administration or contamed m a metered dose inhaler or nebulizer <br><br> - 22a - <br><br> /•&lt;-&gt; - &gt; <br><br> 2 7 oe <br><br> RFPtii'.—, <br><br> for insufflation It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, manmtol, sodium chloride, or sodium citrate <br><br> Alternately, these compounds may be encapsulated, tableted, or prepared in an emulsion or syrup for oral administration Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition Solid earners include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin Liquid earners include syrup, peanut oil, olive oil, saline and water The carrier may also include a sustained release matenal such as glyceryl monostearate or glyceryl distearate, alone or with a wax The amount of solid earner vanes but, preferably, will be between about 20 mg to about 1 g per dosage unit The pharmaceutical preparations are made following the conventional techniques of pharmacy involving milling, mixing, granulating, and compress mg, when necessary, for tablet forms, or milling, mixing and filling for hard gelatin capsule forms. When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension Such a liquid formulation may be administered directly or filled into a soft gelatin capsule <br><br> For rectal administration, the compounds of this invention may also be combined with excipients such as cocoa butter, glycerin, gelatin or polyethylene glycols and molded into a suppository <br><br> The compounds of formula (I) are useful as protease inhibitors, particularly as inhibitors of cysteine and serine proteases, more particularly as inhibitors of cysteine proteases, even more particularly as inhibitors of cysteine proteases of the papain superfamily, yet more particularly as inhibitors of cysteine proteases of the cathepsin family, most particularly as inhibitors of cathepsin K. The present invention also provides useful compositions and formulations of said compounds, including pharmaceutical compositions and formulations of said compounds <br><br> The present compounds are useful for treating diseases m which cysteine proteases are implicated, including infections by Pneumocystis carinu, trypsanoma cruzi, trypsanoma brucei, and Cnthidia fusiculata, as well as in schistosomiasis, malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases m which cathepsin K is implicated, most particularly diseases of <br><br> IMlQifcCi'U/U P,"V. °tn"! ' 0' U2. <br><br> - 22b - <br><br> 2 7 OCT I3SK <br><br> WO 98/50533 PCT/US98/03200 <br><br> excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease Metastatic neoplastic cells also typically express high levels of proteolytic 5 enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention <br><br> The present invention also provides methods of treatment of diseases caused by pathological levels of proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly as inhibitors of cysteine proteases 10 of the papain superfamily, yet more particularly cysteine proteases of the cathepsm family, which methods comprise administering to an animal, particularly a mammal, <br><br> most particularly a human in need thereof a compound of the present invention The present invention especially provides methods of treatment of diseases caused by pathological levels of cathepsin K, which methods comprise administering to an animal, 15 particularly a mammal, most particularly a human in need thereof, an inhibitor of cathepsin K, including a compound of the present invention The present invention particularly provides methods for treating diseases in which cysteine proteases are implicated, including infections by Pneumocystis carina, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata, as well as in schistosomiasis, malaria, tumor metastasis, 20 metachromatic leukodystrophy, muscular dystrophy, amytrophy, and especially diseases in which cathepsin K is implicated, most particularly diseases of excessive bone or cartilage loss, including osteoporosis, gingival disease including gingivitis and periodontitis, arthritis, more specifically, osteoarthritis and rheumatoid arthritis, Paget's disease, hypercalcemia of malignancy, and metabolic bone disease 25 This invention further provides a method for treating osteoporosis or inhibiting bone loss which comprises internal administration to a patient of an effective amount of a compound of formula (I), alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (l e , alendronate), hormone replacement therapy, anti-estrogens, or calcitonin In addition, treatment with a compound of this invention 30 and an anabolic agent, such as bone morphogenic protein, lproflavone, may be used to prevent bone loss or to increase bone mass <br><br> In accordance with this invention, an effective amount of the compounds of formula (I) is administered to inhibit the protease implicated with a particular condition or disease Of course, this dosage amount will further be modified according to the type 35 of administration of the compound For example, "effective amount" for acute therapy, parenteral administration of a compound of formula (I) is preferred An intravenous infusion of the compound in 5% dextrose in water or normal saline, or a similar <br><br> -23- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> formulation with suitable excipients, is most effective, although an intramuscular bolus injection is also useful Typically, the parenteral dose will be about 0 01 to about 100 mg/kg, preferably between 0 1 and 20 mg/kg, in a manner to maintain the concentration of drug in the plasma at a concentration effective to inhibit cathepsin K The 5 compounds are administered one to four times daily at a level to achieve a total daily dose of about 0 4 to about 400 mg/kg/day The precise amount of an inventive -compound which is therapeutically effective, and the route by winch such compound is best administered, is readily determined by one of ordinary skill in the art by comparing the blood level of the agent to the concentration required to have a therapeutic effect 10 Prodrugs of compounds of the present invention may be prepared by any suitable method For those compounds in which the prodrug moiety is a ketone functionality, specifically ketals and/or hemiacetals, the conversion may be effected in accordance with conventional methods <br><br> The compounds of this invention may also be administered orally to the patient, 15 in a manner such that the concentration of drug is sufficient to inhibit bone resorption or to achieve any other therapeutic indication as disclosed herein Typically, a pharmaceutical composition containing the compound is administered at an oral dose of between about 0 1 to about 50 mg/kg m a manner consistent with the condition of the patient Preferably the oral dose would be about 0 5 to about 20 mg/kg 20 No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention <br><br> The compounds of this invention may be tested in one of several biological assays to determine the concentration of a compound which is required to have a given pharmacological effect <br><br> 25 <br><br> -24- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> Determination of cathepsin K proteolytic catalytic activity <br><br> All assays for cathepsin K were carried out with human recombinant enzyme Standard assay conditions for the determination of kinetic constants used a fluorogenic peptide substrate, typically Cbz-Phe-Arg-AMC, and were determined in 100 mM Na 5 acetate at pH 5 5 containing 20 mM cysteine and 5 mM EDTA Stock substrate solutions were prepared at concentrations of 10 or 20 mM in DMSO with 20 (J.M final substrate concentration in the assays. All assays contained 10% DMSO Independent experiments found that this level of DMSO had no effect on enzyme activity or kinetic constants All assays were conducted at ambient temperature Product fluorescence 10 (excitation at 360 nM, emission at 460 nM) was monitored with a Perceptive Biosystems Cytofluor II fluorescent plate reader Product progress curves were generated over 20 to 30 minutes following formation of AMC product. <br><br> Inhibition studies <br><br> 15 Potential inhibitors were evaluated using the progress curve method Assays were carried out in the presence of variable concentrations of test compound Reactions were initiated by addition of enzyme to buffered solutions of inhibitor and substrate Data analysis was conducted according to one of two procedures depending on the appearance of the progress curves in the presence of inhibitors For those compounds 20 whose progress curves were linear, apparent inhibition constants (Ki,app) were calculated according to equation 1 (Brandt et al., Biochemitsry, 1989, 28, 140) <br><br> " = VmA/[Kali + VKU app) +A] (1) <br><br> 25 where v is the velocity of the reaction with maximal velocity Vm , A is the concentration of substrate with Michaelis constant of Ka, and I is the concentration of inhibitor For those compounds whose progress curves showed downward curvature characteristic of time-dependent inhibition, the data from individual sets was analyzed to give k0bs according to equation 2 <br><br> 30 <br><br> [AMC] = vss t + (vq - vss) [] - exp (-kobsO] /kobs (2) <br><br> where [AMC] is the concentration of product formed over time t, vq is the initial reaction velocity, and vss is the final steady state rate Values for k0bs were then 35 analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (k0bs / inhibitor concentration or kGbs / [I]) describing the timers - <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> dependent inhibition. A complete discussion of this kinetic treatment has been fully described (Morrison et al, Adv Enzymol Relat. Areas Mol Biol, 1988, 61, 201) <br><br> One skilled in the art would consider any compound with a K, of less than 50 micromolar to be a potential lead compound Preferably, the compounds used in the 5 method of the present invention have a K, value of less than 1 micromolar Most preferably, said compounds have a K, value of less than 100 nanomolar 4-(R,S)~ Amino-N-[(8-quinolinesulfonyl)-S-leucine]-3-tetrahydrofuran-3-one, a compound of formula (I), has a Kj value that is greater than 10 micromolar. <br><br> 10 Human Osteoclast Resorption Assay <br><br> Aliquots of osteoclastoma-derived cell suspensions were removed from liquid nitrogen storage, warmed rapidly at 37°C and washed xl in RPMI-1640 medium by centnfugation (1000 rpm, 5 min at 4°C) The medium was aspirated and replaced with murine anti-HLA-DR antibody, diluted 1.3 in RPMI-1640 medium, and incubated for 30 15 minutes on ice The cell suspension was mixed frequently <br><br> The cells were washed x2 with cold RPMI-1640 by centnfugation (1000 rpm, 5 mm at 4°C) and then transferred to a sterile 15 mL centrifuge tube The number of mononuclear cells were enumerated in an improved Neubauer counting chamber <br><br> Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse 20 IgG, were removed from their stock bottle and placed into 5 mL of fresh medium (this washes away the toxic azide preservative). The medium was removed by immobilizing the beads on a magnet and is replaced with fresh medium <br><br> The beads were mixed with the cells and the suspension was incubated for 30 minutes on ice The suspension was mixed frequently The bead-coated cells were 25 immobilized on a magnet and the remaining cells (osteoclast-rich fraction) were decanted into a sterile 50 mL centrifuge tube Fresh medium was added to the bead-coated cells to dislodge any trapped osteoclasts This wash process was repeated xlO The bead-coated cells were discarded <br><br> The osteoclasts were enumerated in a counting chamber, using a large-bore 30 disposable plastic pasteur pipette to charge the chamber with the sample The cells were pelleted by centnfugation and the density of osteoclasts adjusted to 1 5xl0^/mL in EMEM medium, supplemented with 10% fetal calf serum and 1 7g/litre of sodium bicarbonate 3 mL aliquots of the cell suspension (per treatment) were decanted into 15 mL centrifuge tubes These cells were pelleted by centnfugation To each tube 3 mL 35 of the appropnate treatment was added (diluted to 50 |iM in the EMEM medium) Also included were appropnate vehicle controls, a positive control (87MEM1 diluted to 100 <br><br> -26- <br><br> Pnnted from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL) The tubes were incubated at 37°C for 30 minutes <br><br> 0 5 mL aliquots of the cells were seeded onto sterile dentine slices in a 48-well plate and incubated at 37°C for 2 hours Each treatment was screened in quadruplicate 5 The slices were washed in six changes of warm PBS (10 mL / well in a 6-well plate) and then placed into fresh treatment or control and incubated at 37°C for 48 hours The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0 2M sodium cacodylate) for 5 minutes, following which they were washed in water and incubated in buffer for 5 minutes at 37°C The slices were then washed in cold water 10 and incubated in cold acetate buffer / fast red garnet for 5 minutes at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water <br><br> The TRAP positive osteoclasts were enumerated by bright-field microscopy and were then removed from the surface of the dentine by sonication Pit volumes were determined using the Nikon/Lasertec ILM21W confocal microscope <br><br> 15 <br><br> Examples <br><br> In the following synthetic examples, unless otherwise indicated, all of the starting materials were obtained from commercial sources Without further elaboration, <br><br> it is believed that one skilled in the art can, using the preceeding description, utilize the 20 present invention to its fullest extent These Examples are given to illustrate the invention, not to limit its scope Reference is made to the claims for what is reserved to the inventors hereunder. <br><br> Example 1 <br><br> 25 <br><br> Preparation of 4-(R.S)-Amino-N-f(3.4-methvlenedioxvbenzovl)-S-leucine1-tetrahvdrofuran-3-one a) rrans-4-Azido-3-hydroxytetrahydrofuran <br><br> 30 <br><br> 3,4-Epoxy tetrahy drofuran (9 g, 105 mmol) was added to a stirred solution of sodium azide (27 g, 415 mmol) and ammonium chloride (9 g, 159 mmol) in aqueous methanol (95%, 200 ml). The reaction was heated to 75°C and stirred for 20 hours The reaction was cooled, filtered and evaporated under reduced pressure The residue was diluted with water and 35 extracted with ethyl acetate, dried and evaporated under reduced pressure to afford the title compound as a colourless oil, 10 g, 74% yield <br><br> -27- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> 'H NMR 5 (CDCI3) 4 32 (m, 1H), 4.09 (dd, 1H, J = 4 8, 9 9 Hz), 3 99 (dd, 1H, J = 4 3, 10 1 Hz), 3 94 (m, 1H), 3 81 (dd, 1H, J = 2 1, 9 9 Hz), 3 73 (dd, 1H, J = 1 8, 10 1 Hz), 2 72 (d, 1H, J = 4 6 Hz) <br><br> 5 b) rrans-4-Amino-3-hydroxytetrahydrofuran hydrochloride <br><br> A mixture of rra«j-4-azido-3-hydroxytetrahydrofuran (10 g, 77 mmol) and 10% palladium on charcoal (1 g) in ethanol (150 ml) was stirred under an atmosphere of hydrogen (35 psi) for 12 hours. The mixture was filtered and treated with 100 ml of ethanolic HCl to 10 afford, after evaporation under reduced pressure, the title compound as a brown solid, 10 5 g, 97% yield, mp 132 °C <br><br> 'H NMR 5 (d6 DMSO) 8.37 (s, 3H), 4 13 (m, 1H), 3 84 (dd, 1H, J = 4.9 and 14 3), 3 76 (dd, 1H, J = 5 5, 10 0 Hz), 3 58 (dd, 1H, J = 2 7, 10 0 Hz), 3.34 (m, 3 H) <br><br> 15 c) rrartj-4-(/?,SJ-Amino-N-[(rm-butoxycarbonyl)-S-leucine}-3-hydroxytetrahydrofuran <br><br> Tnmethylacetyl chloride (3 5 ml, 29 mmol) was added to a stirred solution of N-Boc-L-leucine (7 3 g, 31 mmol) and dnsopropylethylamine (9 ml, 52 mmol) in dichloromethane (200 ml) After 1 h, fra/w-4-amino-3-hydroxytetrahydrofuran HCl (4 g, 28 mmol) was added and the 20 mixture was allowed to stir overnight The reaction mixture was poured into water and extracted with dichloromethane. The combined organic layers were washed with 0.5N HCl, saturated sodium hydrogen carbonate, brine and dned Evaporation under reduced pressure afforded the title compound as a yellow foam, 5 g, 44% yield. <br><br> 'H NMR 5 (CDC13) 8 08 (d, 0 5H, J = 4 8 Hz), 7 89 (d, 0.5H, J = 7 4 Hz), 6 20 (d, 0.5H, J = 8 3 25 Hz), 6 09 (8, 0 5H, J = 8 7 Hz), 4 81 (d, 1H, J = 16 0Hz), 4 40 (m, 2H), 4 20 (m, 2H), 3 77 (m, 2H), 1 60 (m, 3H), 1 50 (s, 9H), 0 92 (m, 6H). <br><br> d) rra/w-4-(7?,S)-Amino-N-(S-leucine)-3-hydroxytetrahydrofuran TFA salt <br><br> 30 ;ra/i.v-4-Amino-N-[(rm-butoxycarbony])-S-leucine]-3-hydroxy tetrahy drofuran (2 5 g, <br><br> 8 0 mmol) was added to a stirred solution of 20% trifluoroacetic acid in dichloromethane (100 ml) After 2 hours, the reaction mixture was evaporated under reduced pressure to afford the title compound as a white gum, 2 6 g, 100% yield <br><br> 'H NMR 8 (MeOD) 4 18 (m, 2H), 4 08 (m, 2H), 3 97 (m, 2H), 3 86 (apparent t, 2H, J = 7 1 Hz), 35 3 69 (dd, 2H, J = 1 6, 7 4 Hz), 1 68 (m, 3H), 0 99 (d, 6H, J = 2 1 Hz). <br><br> -28- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> e) fran.,,-4-('/?,iS'J-Amino-N-[(3,4-methylenedioxybenzoyl)-5'-leucine]-3-hydroxytetrahydrofuran <br><br> Piperonyloyl chloride (400 mg, 2 2 mmol) was added to a stirred solution of trans-A-5 amino-N-(S-leucine)-3-hydroxytetrahydrofuran TFA salt (380 mg, 1 1 mmol) in saturated sodium hydrogen carbonate (10 ml) and 1,4 dioxane (10 ml) The reaction was allowed to stir for 1 hour then diluted with ether The organic layer was washed with IN hydrochloric acid, sodium hydrogen carbonate, brine and dried Evaporation of the solvent gave the title compound as a white foam, 250 mg, 60% yield 10 'H NMR 8 (CDClj) 8 23 (d, 0 5H, J = 4 8 Hz), 8 15 (d, 0.5H, J = 7 4 Hz), 7 85 (d, 0 5H, J = 7 6 Hz), 7 3 (m, 2 H), 6 66 (dd, 1H, J = 8 1,11 5 Hz), 5.92 (d, 2H, J = 6 2 Hz), 4.78 (m, 1H), 4 50 (s, 1H), 4 2 (s, 1H), 4 08-3 75 (m, 4H), 3 74-3 48 (m, 3H), 1 82-1.48 (m, 3H), 0 90 (m, 6H) <br><br> MS calcd for (ClgH2JN,0, + H)\ 365 Found 365 <br><br> 15 f) 4-(/?,S)-Amino-N-[(3,4-methylenedioxybenzoyl)-S-leucine]-tetrahydrofuran-3-one <br><br> Dess-Martin penodinane (500 mg, 1 2 mmol) was added to a stirred solution of trans-4-(R,S)-amino-N-[(3,4-methylenedioxybenzoyl)-S-leucme]-3-hydroxytetrahydrofuran (220 mg, 0 60 mmol) in dichloromethane (10 ml). After 1 hour, ether was added followed by sodium 20 thiosulfate (570 mg, 3 6 mmol). After an additional 15 minutes, the reaction was washed with saturated sodium hydrogen carbonate, brine and dried. Evaporation of the solvent gave the title compound as a white foam, 200 mg, 100% yield <br><br> 'H NMR 8 (CDC13) 8.14 (d, 0.5H, J = 6 2 Hz), 7 90 (d, 0.5H, J = 5 9 Hz), 7 54 (d, 0.5H, J = 7.3 Hz), 7 46 (d, 0 5H, J = 5 1 Hz), 7 23 (d, 1H, J = 6 6 Hz), 7.14 (s, 1H), 6 67 (m, 1H), 5 93 (s, 2H), 25 4 73 (m, 1H), 4 37-3 71 (m, 5H), 1 68 (m, 3H), 0 85 (m, 6H) <br><br> MS calcd for (Cl8H22N206+Hf 363, Found 363 <br><br> Example 2 <br><br> 30 Preparation of 4-//?.5)-Amino-N-r(3.4-dichlorobenzovlVS-leucinel-tetrahvdrofuran-3-one <br><br> Following the procedure of Example l(e-f) except substituting 3,4-dichlorobenzoyl chloride for piperonyloyl chloride the title compound was prepared 'H NMR 8 (MeOD) 8 01 (d, 1H, J = 2 0 Hz), 7 75 (dd, 1H, J = 2 0, 8 3 Hz), 7 61 (d, 1H, J = 8 3 Hz), 4 60 (m, 1H), 4.50-35 3 84 (m, 5H), 1 66 (m, 3H), 1 00 (m, 6H) <br><br> MS calcd for (C,7Cl2H20N2O4+ H)\ 387 &amp; 389, Found. 387 &amp; 389 <br><br> -29- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 3 <br><br> Preparation of 4-//?.S)-Amino-N-r(2-quiholinecarbonvl)-S-1eucine1-tetrahvdrofuran-3-one <br><br> 5 Following the procedure of Example l(e-f) except substituting 2-quinolinecarbonyl chloride for piperonyloyl chloride, the title compound was prepared as a white foam 'H NMR 8 (CDC1,) 8 57 (dd, IH, J = 1 5, 5.1 Hz), 8 20 (m, 3H), 7 77 (m, 2H), 7 62 (m, IH), 7 40 (d, IH, J = 62 Hz), 4 80 (m, IH), 4 57 (m, IH), 4 30 (m, IH), 4.26-3.87 (m, 3H), 1 96-1 71 (m, 3H), 1.00 (m, 6H) <br><br> 10 MS calcd for (C20H,}N3O4+ H)* 370 Found 370 <br><br> Example 4 <br><br> Preparation of 4-//?.S)-Amino-N-r(benzvloxvcarbonvl)-S-leucinel-tetrahvdrofuran-3-one <br><br> 15 <br><br> Following the procedure of Example 1 except substituting N-CBZ-leucine for N-BOC-leucine the title compound was prepared as a white foam 'H NMR 8 (CDC13) 7 31 (m, 5H), 5 71 (app dd, IH, J = 8 4, 14 8 Hz), 5 06 (m, 2H), 4 50 (dd, IH, J = 8 9, <br><br> 18 0 Hz), 4 30-3 88 (m, 4H), 3 80 (app t, IH, J = 9 6Hz), 1 64 (m, 3H), 0 91 (m, 6H) 20 MS calcd for (C,gH2JN205+ H)\ 349 Found 349 <br><br> Example 5 <br><br> Preparation of 4-(/?.,S)-Amino-N-r(3.4-methvlenedioxvbenzovl)-.S-leucinel-25 tetrahvdrofuran-3-one <br><br> Following the procedure of Example 1 except substituting 3,4-methylenedioxybenzoyl chloride for piperonyloyl chloride, the title compound was prepared <br><br> 30 <br><br> -30- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> Example 6 <br><br> Preparation of 4-(/?.S)-Amino-N-r(8-quinolinecarbonvl)-S-leucinel-tetrahvdrofuran-3-one <br><br> 5 <br><br> Following the procedure of Example l(e-f) except substituting 8-qumohnecarbonyl chlonde for piperonyloyl chlonde,the title compound was prepared as a white foam, m p. 123 °C (HCl salt) <br><br> 'H NMR 8 (CDCl,) 11 54 (m, IH), 8 84 (d, IH, J = 1 5 Hz), 8.65 (d, IH, J = 7.2 Hz), 10 8 17 (d, IH, J = 8 0 Hz), 7 86 (d, IH, J = 8 0 Hz), 7.7 (s, IH), 7 54 (t, IH, J = 7.7 Hz), 7 40 (dd, IH, J = 3 8, 7 7 Hz), 4 78 (dd, IH, J = 7.5,13.6 Hz), 4 47 (dd, IH, J = 8.6,13.6 Hz), 4 18 (m, IH), 4.16-3.79 (m, 3H), 1 88 (m, 3H), 0.88 (m, 6H) <br><br> MS calcd for H)': 370 Found 370 <br><br> 15 Example 7 <br><br> Preparation of 4-&lt;7?,S)-Amino-N-r(8-quinolinesulfonvl)-S-leucine1-tetrahvdrofuran-3-one <br><br> 20 Following the procedure of Example l(e-f) except substituting 8- <br><br> quinohnesulfonyl chloride for piperonyloyl chloride,the title compound was prepared as a brown solid m p 98 °C (HCl salt) <br><br> 'H NMR 8 (CDC13) 9 07 (dd, IH, J = 1 7 and 4 3 Hz), 8 40 (m, IH), 8 30 (m, IH), 8 00 (m, IH), 7 66 (m, 2H), 7 11 (d, 0 5H, J = 5.9 Hz), 6.96 (d, 0 5H, J = 5 7 Hz), 4 51 (t, 25 0 5H, d = 8 8 Hz), 4 39 (t, 0 5H, J = 8 7), 4.12-3 71 (m, 4 5H), 3.53 (dd, 0 5H, J = 1 0, <br><br> 5 9 Hz), 1 43 (m, 2H), 0 64 (m, 3H), 0 33 (m, 3H) <br><br> MS calcd for (C„H2,N305S + Hf 406. Found- 406 <br><br> Example 8 <br><br> 30 <br><br> Preparation of 4-(R.S)-Amino-N-1 ((4-methyl-3-pvridinvl)carbonvl)-5-leucinel-tetrahvdrofuran-3-one <br><br> Following the procedure of Example l(e-f) except substituting (4-methyl-3-35 pyridinyl)carbonyl chlonde for piperonyloyl chloride, the title compound was prepared <br><br> -31 - <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> Example 9 <br><br> Preparation of 4-(,/?.S)-Amino-N-['(ben?.vloxvcarbonvlKS'-leucine]-2.2-dibenzvl-tetrahvdrofuran-3-one <br><br> 5 <br><br> Sodium methoxide (140 mg, 2 6 mmol) was added to a stirred solution of 4-(/f,S)-amino-N-[(benzyloxycarbonyl)-5-leucine]-tetrahydrofuran-3-one (300 mg, 0 9 mmol) and benzyl bromide (0 4 ml, 3 4 mmol) in methanol (5 ml) After 12 hours, the reaction was poured into ether (100 ml) and washed with water, brine and dried 10 Evaporation under reduced pressure and purification by flash column chromatography (30% ethyl acetate-hexane) afforded the title compound as a colorless gum, 250 mg, <br><br> 55% yield <br><br> 'H NMR 8 (CDC13) 7 34-7 25 (m, 10 H), 7 24-7 0 (brs, 5 H), 6 56 (s, 0 5 H), 6 37 (s, 0 5 H), 5 18 (d), 1 H, J = 11 5 Hz), 5 07 (m, 2 H), 4 48-4 42 (m, 1 H), 4.20-3 98 (m, 4 H), 15 3 12 (dd, 1 H, J = 12 5 and 12 5 Hz), 2 88 (dd, 1 H, J = 12 5 and 12 5 Hz), 1 72-1 32 (m, 3 H), 0 92-0 76 (m, 6 H) <br><br> MS calcd for (C32H3(N205 = C,H/ 439 Found 439 <br><br> Example 10 <br><br> 20 <br><br> Preparation of 4-C^?.5)-Amino-N-f(benzofb1thiophen-2-vlcarbonvl)-5-leucine1-tetrahvdrofuran-3-one <br><br> Following the procedure of Example l(e-f) except substituting 25 benzo[b]thiophen-2-ylcarbonyl chloride for piperonyloyl chloride, the title compound was prepared <br><br> 'H NMR 8 (CDCy 8.33 (d, 0 5H, J = 6 6Hz), 8 00 (m, IH), 7 78 (m, 4H), 7 38 (m, 2 5H), 4 87 (m, IH), 4 63-3 88 (m, 5H), 1 88 (m, 3H), 1 00 (m, 6H) <br><br> MS calcd for (C„H22N204S - H)\ 373, Found. 373. <br><br> 30 <br><br> Example 11 <br><br> Preparation of 4-(7?.S)-Amino-N-f(3.4-dimethoxvbenzovl)-»S'-leucinel-tetrahvdrofuran-3-one <br><br> 35 <br><br> Following the procedure of Example l(e-f) except substituting 3,4-dimethoxybenzoyl chlonde for piperonyloyl chlonde, the title compound was prepared <br><br> -32- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> 'H NMR 8 (CDC1,) 7 58 (d, 0 5H, J = 6 7Hz), 7 47 (d, 0 5H, J = 6 2Hz), 7 33 (m, 2H), 7 04 (d, 0 5H, J = 8 0Hz), 6 92 (d, 0 5H, J = 8 0Hz), 6 83 (d, 0 5H, J = 8 4Hz), 4 77 (m, IH), 4 53-3 67 (m, 5H), 1 68 (m, 3H), 0.85 (m, 6H). <br><br> MS calcd for (C,9H26N2Os- H)\ 377, Found 377 <br><br> 5 <br><br> Example 12 <br><br> Preparation of 4-f7?.S)-Amino-N-[Yindole-6-vlcarbonvl")-S-leucine]-tetrahvdrofuran-3-one <br><br> 10 <br><br> Following the procedure of Example l(e-f) except substituting indole-6-ylcarbonyl chlonde for piperonyloyl chlonde, the title compound was prepared 'H NMR 8 (d6 DMSO) 8 57-7 48 (m, 7H), 6 43 (s, IH), 4 48-3.55 (m, 6H), 1 80-1 48 (m, 3H), 0 98-0 82 (m, 6H) <br><br> 15 MS calcd for (C^H^Np,- H)*: 356, Found 356 <br><br> Example 13 <br><br> Preparation of 4-f/?.5)-Amino-N-[(benzofuran-2-vlcarbonvl)-5-leucinel-20 tetrahvdrofuran-3-one <br><br> Following the procedure of Example l(e-f) except substituting benzofuran-2-yl-carbonyl chloride for piperonyloyl chloride, the title compound was prepared 'H NMR 8 (CDC13) 8 00-7 25 (m, 7H), 4.90-4 78 (m, IH), 4 53-4.48 (m, IH), 4 38-4 21 (m, IH), 25 4 25-3 92 (m, 3H), 1.88 (m, 3H), 1 68 (m, 3H), 0 97 (m, 6H) <br><br> MS calcd for (C„H22N205- H)* 357, Found. 357 <br><br> Example 14 <br><br> 30 Preparation of 4-f/?.5)-Amino-N-r(5-aminobenzorb1thiophen-2-vlcarbonvl)-S-leucinel-tetrahvdrofuran-3-one <br><br> Following the procedure of Example 1 (e-f) except substituting 5-aminobenzo[b]thiophen-2-ylcarbony] chlonde for piperonyloyl chloride, the title 35 compound was prepared <br><br> -33- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> 'H NMR 8 (CDC13) 8 00-7 71 (m, IH), 7 60 (d, IH, J = 3 3Hz), 7 53 (dd, IH, J = 8 5 and 4 0 Hz), 7 47-6 74 (m, 3H), 4 77 (m, IH), 4 43 (m, IH), 4 38-3 50 (m, 4H) 1 77 (m, 3H), 0 85 (m, 6H) <br><br> MS calcd for (C^N^S + H)* 390, Found 390 <br><br> 5 <br><br> Example 15 <br><br> Preparation of Cyclic Alkoxvketones by Solid Supported Synthesis <br><br> 10 a) 3-/ran.y-Hydroxy-4-benzyloxycarbonylamino-tetrahydrofuran <br><br> Benzylchloroformate (20ml) was added dropwise to a stirred solution of trans-4-ammo-3-hydroxytetrahydrofuran (5g, 20 6mmol) in dioxane (100ml) containing 10% <br><br> aqueous sodium carbonate (200ml) After 3 hours, the mixture was concentrated to 15 remove the dioxane and then extracted with EtOAc. The combined organic layers were washed with saturated sodium bicarbonate, brine and dried (MgSO,t) Evaporation under reduced pressure and purification of the residue by column chromatography afforded the title compound as white crystals, 8.00g, 70% <br><br> 'H NMR 5 (CDC1,) 7 35 (s, 5H), 5.30 (s, 2H), 4 91 (br s, IH), 4 32 (br s, IH), 4 12-4 00 (m, 3H), 20 3 71 -3 62 (m, 2H), 2 72 (s, 1H) <br><br> b) 4-Benzyloxycarbonylammo-tetrahydrofuran-3-one <br><br> A solution of bleach (100ml), containing sodium bicarbonate (7 34g), was added 25 dropwise to a rapidly stirred mixture of 3-hydroxy-4-benzyloxycarbonylamino- <br><br> tetrahydrofuran (21g, 88 mmol), sodium bromide (9.4g), TEMPO (50mg) in EtOAc (140ml), toluene (140ml) and water (40ml) After a persistant orange colour developed the mixture was extracted with EtOAc and the combined organic layers were washed with saturated sodium bicarbonate, brine and dried (MgS04) Evaporation under 30 reduced pressure and purification of the residue by column chromatography afforded the title compound as white crystals, 18g, 87%. <br><br> 'H NMR 8 (CDC1,) 7 35 (s, 5H), 5 30 (s, IH), 5.11 (s, 2H), 4 70 (app t, IH, J = 8 9Hz), 4 36-4.17 (m, 2H), 3 96-3.76 (2H) <br><br> 35 c) 3,3-Dimethoxy-4-benzyloxycarbonylamino-tetrahydrofuran <br><br> Trimethylorthoformate (29ml) was added dropwise to a refluxing solution of 4-benzyloxycarbonylamino-tetrahydrofuran-3-one (18g, 78mmol) and PTSA(500mg) in MeOH (100ml). After 3 hours, the reaction mixture was filtered and concentrated to 40 afford, after column chromatography, the title compound as a yellow oil, 16 2g, 76% <br><br> -34- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> 'H NMR 5 (CDC1,) 7 35 (s, 5H), 5 30 (s, IH), 5 11 (s, 2H), 4 70 (app t, IH, J = 8 9Hz), 4.36-4 17 (m, 2H), 3 96-3 76 (2H) <br><br> d) 3,3-Dimethoxy-4-amino-tetrahydrofuran <br><br> 5 <br><br> A mixture of 3,3-Dimethoxy-4-benzyloxycarbonylamino-tetrahydrofuran (16g, <br><br> 57mmol) and 10% palladium on charcoal (2g) in ethanol (200ml) was stirred under an atmosphere of hydrogen (50psi) for 12 h The mixture was filtered and concentrated to afford the title compound as a yellow oil, 8g, 100% <br><br> 10 'H NMR 5 (CDC1,) 7 04 (s, 5H), 4.22-4 04 (m, 5H), 3 83-3 69 (m, 2H), 3 36 (s, 3H), 3 33 (s, 3H) <br><br> e) SPS using Ellman Linker 15 Step A <br><br> Sodium triacetoxyborohydnde (10 equiv) was added to a stirred solution of Ellmans resm (ref- C.G Boojamra, K M Burow.LA Thompson and J A. Ellman, J Org Chem, 1997, 62, 1240) in DMF containing 1 % HOAc After 5 minutes, the a-amino acid, methyl ester (10 equiv) was added and the mixture was shaken for 1 hour. 20 The resin was then washed with DMF (x7), CH2C12 (x7), ether (x2) and dried to a constant weight <br><br> Step B <br><br> NMP was added to a mixture of the above resm, carboxylic acid (10 equiv) and 25 EDC (10 equiv). The mixture was then shaken for 3 hours then washed with DMF (x3), <br><br> CH2C12 (x3), MeOH (x2) and ether (x2) The resm was then resubjected to the above reaction conditions and again washed after 3 hours <br><br> Step C- <br><br> 30 Potassium tnmethylsilanoate (10 equiv) was added to a shaken mixture of the above resm in THF After 18 hours, the resin was washed with 5% citric acid in THF (x2), THF (x2), THF-H20 (x2), H20 (x2), THF-H20 (x2) and finally THF (x2) <br><br> Step D <br><br> 35 3,3-Dimethoxy-4-amino-tetrahydrofuran (3 equiv) was added to a mixture of the above resin and EDC (3 equiv) in NMP After 3 hours, the resm was washed with DMF (x7), CH2C12 (x7) and ether (x2) The resin was then resubjected to the reaction conditions for a further 3 h, then again washed as above <br><br> 40 <br><br> -35- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> Step E Cleavage <br><br> A mixture of 7 2 1 TFA/CH,CiyH20 was added to the above resin After 2 hours, the mixture was filtered and the resin was further washed with CH2C12 Removal of the solvent afforded the desired tetrahydrofuran-3-one <br><br> 5 <br><br> Example 16 <br><br> Preparation of 4-(R. S)-Amino-N-r('5-chlorobenzofuran-2-vlcarbonvl')-S-leucine1-tetrahvdrofuran-3-one <br><br> 10 <br><br> Following the general details of Example 15, using the appropnate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared <br><br> 'H NMR 5 (CDC1,) 7 62-7 05 (m, 6H), 4 81-4 64 (m, IH), 4 62-4 54 (m, IH), 4 43-3 81 (m, 4H), 15 1 90-1 60 (m, 3H), 1 08-0.81 (m, 6H) <br><br> MS calcd for (C,,H21N205C1 + H)* 393, Found 393. <br><br> Example 17 <br><br> 20 Preparation of 4-(R. S)-Amino-N-IY5-methoxvbenzofuran-2-vlcarbonviyS-leucinel-tetrahvdrofuran-3-one <br><br> Following the general details of Example 15, using the appropriate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title 25 compound was prepared <br><br> 'H NMR 5 (CDC13) 7 65-6 84 (m, 6H), 4.83-4 54 (m, IH), 4 53-4 48 (m, IH), 4 46-3 68 (m, 4H), <br><br> 1 90-1 62 (m, 3H), 1 08-0 81 (m, 6H) <br><br> MS calcd for (C20H24N2O6 + H)* 389, Found. 389. <br><br> 30 Example 18 <br><br> Preparation of 4-&lt;7?.S)-Amino-N-r(4-bromobenzovl')-S-Ieucine1-tetrahvdrofuran-3-one <br><br> Following the general details of Example 15, using the appropnate amino acid 35 methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared <br><br> -36- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> 'H NMR 5 (CDC13) 7 64 (App d, 2H, J = 8 5Hz), 7 60 (App d, 2H, J = 8 5Hz), 4 81-4 67 (m, 1H), 4 62-4 48 (m, 1H), 3 36-4 19 (m, 1H), 4 18-3 78 (m, 3H), 1 81 -1 59 (m, 3H), 1 05-0 80 (m, 6H) <br><br> MS calcd for (C17H2IN204Br)+ 397, Found. 397 <br><br> 5 <br><br> Example 19 <br><br> Preparation of 4-f/?.S)-Amino-N-lY4-bromobenzovl)-S-leucinel-tetrahvdrofuran-3-one <br><br> 10 Following the general details of Example 15, using the appropnate ammo acid methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared <br><br> 'H NMR 8 (CDC13) 7 91 (m, IH), 7 76-7 59 (m, 2H), 7.39-7 18 (m, IH), 7 04-6 89 (m, IH), 7 84-6 68 (m, IH), 4,89-4 4.68 (m, IH), 4 66-4 56 (m, IH), 4 27-3 76 (m, 4H), 1 88-1 68 (m, 15 3H), 1 03-0 78 (m, 6H) <br><br> MS calcd for (Cl7H21N204Br)\ 397, Found" 397 <br><br> Example 20 <br><br> 20 Preparation of 4-f/?.£)-Amino-N-r(5-chlorobenzorbHhioohen-2-ylcarbonvD-S-leucinel-tetrahvdrofuran-3-one <br><br> Following the general details of Example 15, using the appropnate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title 25 compound was prepared <br><br> 'H NMR 8 (CDC13) 7 88-7 67 (m, 5H), 7 48-7 38 (m, IH), 4 81 (br d, IH, J = 6 7Hz), 4 60 (app t, IH, J = 8.8Hz), 4.43-4 30 (m, 1), 4 28-3 84 (m, 3H), 1 86-1.62 (m, 3H), 1 05-0 82 (m, 6H) MS calcd for (C19H2,N204SC1 - H)* 408, Found 408 <br><br> 30 Example 21 <br><br> Preparation of 4-ffl.£)-Amino-N-lY4-fluorobenzofb1thiophen-2-vlcarbonvl)-iS-leucinel-tetrahvdrofuran-3-one <br><br> 35 Following the general details of Example 15, using the appropnate amino acid methyl ester and carboxylic acid reagents consistent with the final product, the title compound was prepared. <br><br> -37- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> 'H NMR 8 (CDCI3) 7 96 (s, IH), 7 68-7.58 (m, 2H), 7 48-7.32 (m, IH), 7.06 (dd, IH, J = 9 0Hz and 9 0 Hz), 4 89-4 72 (m, IH), 4 65-4 55 (app t, IH, J = 8 8Hz), 4 35 (app q, IH, J = 8 2Hz), 4 28-3 82 (m, 3H) 1 88-1.62 (m, 3H), 1 05-0.82 (m, 6H) <br><br> MS calcd for (C„H2lN204SF + H)* 393, Found 393 <br><br> 5 <br><br> Examples 22-66 <br><br> Preparation of Cyclic Alkoxvketones <br><br> 10 By analogous procedures to those described in either Example 1 or Example 15, <br><br> using the appropriate amino acid and acid or acid chloride reagents consistent with the final products, the compounds of Table 1 were prepared 'h NMR spectra and/or mass spectra were consistent with the structures in Table 1 <br><br> 15 Table 1 <br><br> Example r3 <br><br> r" <br><br> synthesis method <br><br> 22 <br><br> -s <br><br> 3,4-difluorophenyl soln <br><br> 23 <br><br> 4-benzvlpiperidin-1 -yl soln <br><br> 24 <br><br> 4-benzylpiperazin-1 -yl soln <br><br> 25 <br><br> 4-(3,4-methylenedioxybenzyl) piperazin-1-yl soln <br><br> 26 <br><br> 4-(tertbutoxycarbonyl)piperazin-1-yl soln <br><br> 27 <br><br> piperazin-1-yl soln <br><br> 28 <br><br> benzimidazol-5-yl soln <br><br> 29 <br><br> 6-quinolyl soln <br><br> 30 <br><br> 5-indolyl soln <br><br> 31 <br><br> 2-naphthyl soln <br><br> 32 <br><br> 2-pyridyl soln <br><br> 33 <br><br> 4-benzyloxyphenyl soln <br><br> 34 <br><br> » <br><br> 3-benzyloxyphenyl soln <br><br> 35 <br><br> » <br><br> 4-hydroxyphenyl soln <br><br> 36 <br><br> " <br><br> 5-nitrobenzo[blthiophen-2-yl soln <br><br> 37 <br><br> " <br><br> 2-(thien-2-yl)ethen-1 -yl soln <br><br> 38 <br><br> " <br><br> 4-methoxyphenyl <br><br> SPS <br><br> -38- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> 39 <br><br> 3-methoxvphenvl <br><br> SPS <br><br> 40 <br><br> » <br><br> 7-ethoxybenzof uran-1 -yl sps <br><br> 41 <br><br> ■ <br><br> 5-nitrobenzofuran-1 -yl sps <br><br> 42 <br><br> " <br><br> 4-(2-methoxyphenyl)phenyl sps <br><br> 43 <br><br> 3-(2-methoxyphenyl)phenyl sps <br><br> 44 <br><br> » <br><br> 4-cyanophenyl sps <br><br> 45 <br><br> ■ <br><br> 3-nilrophenyl sps <br><br> 46 <br><br> « <br><br> 3-(dimethylammoethyl)-4-methoxyphenyl sps <br><br> 47 <br><br> » <br><br> 2-(2-c(ilorophenyl)ethen-1 -yl sps <br><br> 48 <br><br> ■ <br><br> 4-tnfluoromethoxyphenyl sps <br><br> 49 <br><br> • <br><br> 4-methanesulphonylphenyl sps <br><br> 50 <br><br> • <br><br> 4-iodophenyl sps <br><br> 51 <br><br> » <br><br> 4-chlorobenzorblthiophen-2-vl sps <br><br> 52 <br><br> » <br><br> 5,6-dimethoxvbenzofblthiophen-2-yl sps <br><br> 53 <br><br> » <br><br> 5,6-methylenedioxvbenzo[blthiophen-2-vl <br><br> SPS <br><br> 54 <br><br> » <br><br> 7-chlorobenzofblthiophen-2-yl sps <br><br> 55 <br><br> benzo[b]thiophen-2-yl sps <br><br> 56 <br><br> ■■ <br><br> 2-thienyl sps <br><br> 57 <br><br> 3,4-dimethoxyphenvl sps <br><br> 58 <br><br> » <br><br> 4-bromophenyl sps <br><br> 59 <br><br> » <br><br> quinolin-2-yl sps <br><br> 60 <br><br> -s <br><br> 2-thienyl sps <br><br> 61 <br><br> " <br><br> ch3 <br><br> sps <br><br> 62 <br><br> benzo[b]thiophen-2-yl sps <br><br> 63 <br><br> » <br><br> 2-thienyl sps <br><br> 64 <br><br> " <br><br> 3,4-dimethoxyphenyl sps <br><br> 65 <br><br> » <br><br> 4-bromophenyl sps <br><br> 66 <br><br> ■ <br><br> quinolin-2-yl sps <br><br> -39- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 67 <br><br> Preparation of 4-(,/?.S)-Amino-N-r(benzvloxycarbonvl')-,S-leucinel-tetrahvdropvran-3-one <br><br> 5 <br><br> a) fran.s-4-amino-3-hydroxytetrahydropyran hydrochloride <br><br> Following the procedures of Examples 1(a) and 1(b), substituting 3,4-epoxytetrahydropyran for 3,4-epoxytetrahydrofuran, the title compound was prepared <br><br> 10 <br><br> b) rranj-4-(R,S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-3-hydroxytetrahydropyran <br><br> Pivaloyl chloride (5 28 ml, 43 mmol) was added to a solution of N-carbobenzyloxy-L-leucme (12 48 g, 47 mmol) in dichloromethane (300 ml) After 1 hour, a mixture of trans-4-15 amino-3-hydroxytetrahydropyran hydrochloride (6g, 39mmol) and tnethylamine (10 8 ml, 79 mmol) in dichloromethane (100 ml) was added and the mixture allowed to stir overnight The reaction mixture as washed with IN HCl, saturated sodium hydrogen carbonate and dried Evaporation under reduced pressure afforded a pale oil. Punfication by chromatography (ethyl acetate/hexane eluant) gave the rra/w-4-(R,S)-amino-N-[(benzyloxycarbonyl)-S-leucine]-3-20 hydroxytetrahydropyran as a white paste, 5 5 g, 39% yield <br><br> 'H NMR 6 (CDClj) 7.35 (s, 5H), 5 0 (m, 3H), 4 16-3 89 (m, 4H), 3 44-3 36 (m, 2H), 3.13 (t, IH), 1 84-1 53 (m, 2H), 1 28-1 22 (m, 3H), 0 93 (m, 6H). <br><br> c) 4-(R,S)-amino-N-[(benzyloxycarbonyl)-S-leucine]tetrahydropyran-3-one <br><br> 25 <br><br> Following the procedure of Example 1(f), except substituting 4-(R,S)-amino-N-[( <br><br> benzy loxycarbony l)-S-leucine]-3-hydroxytetrahydropyran for4-(R,S)-amino-N-[(3,4-methylenedioxybenzoyl)-S-leucine]-3-hydroxytetrahydrofuran, the title compound was prepared <br><br> 30 'H NMR 8 (d6 DMSO) 8 15 (d, IH), 7.39-7.29 (m, 5H), 5 02 (d, 2H), 4 63 (m, IH), 4.14-4.10 (m, 2H), 3 97-3 83 (m, 3H), 2.10 (m, IH), 1.92 (m, IH), 1.61 (m, IH), 1.45 (m, IH), 0.95 (m, 6H). <br><br> MS calcd for (C,9H26N20,+H)+ 363 Found 363 <br><br> -40- <br><br> Pnnted from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 68 <br><br> Preparation of 4-(7?.S)-Amino-N-r(benzorb1thiophen-2-vlcarbonvl)-S-leucinel-tetrahvdropyran-3-one <br><br> 5 <br><br> a) fran5-4-(R,S)-Amino-N-(S-leucine)-3-hydroxytetrahydropyran hydrochloride <br><br> A mixture of 4-(R,S)-amino-N-[( benzyloxycarbonyl-5-leucine]-3-hydroxytetrahydropyran (2 8 g, 7 75 mmol) and 10% palladium on charcoal (300 mg) in ethanol 10 (100 ml) was stirred under an atmosphere of hydrogen (50 psi) for 12 hours. The mixture was filtered and treated with ethereal HCl to afford, after evaporation under reduced pressure, the title compound as a brown solid, 1 40 g, 68% yield <br><br> 'H NMR 8 (CDC13) 8.30 (m, 2H), 8 02 (m, IH), 4 06-3.92 (m, 4H), 3 50-3.35 (m, 2H), 3 12 (t, IH), 1 89-1 54 (m, 2H), 1 23 (m, 3H), 0.93 (m, 6H) <br><br> 15 <br><br> b) fra«^-4-(R,S)-amino-N-[(benzothiophene-2-carbonyl)-S-leucine]-3-hydroxytetrahydropyran <br><br> Benzothiophene-2-carbonyl chloride (442 mg, 2 25 mmol) was added to a solution of franj-4-(R,S)-amino-N-(S-leucine)-3-hydroxytetrahydropyran (133 mg, 0 5 mmol) in dioxan 20 (7ml) and saturated sodium hydrogen carbonate (7 ml) After 30 min, the reaction mixture was diluted with ethyl acetate, the organic layer washed with saturated sodium hydrogen carbonate, dried and evaporated under reduced pressure to give a white solid Purification by chromatography (ethyl acetate/hexane eluant) gave the fra«.s-4-(R,S)-amino-N-[(benzothiophene-2-carbonyl)-S-leucine]-3-hydroxytetrahydropyran as a white solid, 160 mg, 25 84% <br><br> c) 4-(R,S)-Amino-N-[(benzothiophene-2-carbonyl)-S-leucine]-tetrahydropyran-3-one <br><br> Following the procedure of Example 1(f) except substituting trans-4-(R,S)-amino-N-30 [(benzothiophene-2-carbonyl)-5-Ieucme]-3-hydroxytetrahydropyran for 4-(R,S)-amino-N-[(3,4-methylenedioxybenzoyl)-S-leucme]-3-hydroxytetrahydrofuran, the title compound was prepared. <br><br> 'H NMR 8 (CDC1,) 7 84-7 76 (m, 2H), 7 41 (m, 2H), 7 05 (m, IH), 4 83-4 61 (m, 2H), 4 18-3 77 (m, 4H), 2 73-2 53 (m, IH), 1 98-1 75 (m, 2H), 1 26 (m, 3H), 0 92 (m, 6H) <br><br> 35 MS calcd for (C20HMN,O4S+H)+ 389 Found 389 <br><br> -41 - <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 69 <br><br> Preparation of 4-i7?..S)-Amino-N-f(4-phenoxvbenzovl)-S-leucinel-tetrahvdrofuran-3-one <br><br> 5 By analogous methods to those detailed in Example 15, the title compound was prepared <br><br> 'H NMR 5 (CDC1,, 250 MHz) 7 74 (d, 2 H, J = 10 9 Hz), 7 37 (dd, 2 H, J = 7 7 and 7 7 Hz), 7 20 (dd, 1 H, J = 7.5 and 7 5 Hz), 7 03 (d, 2 H, J = 7 7 Hz), 7 0 (d, 2 H, J = 7 7 Hz), 6 98-6 82 (m, 2 H), 4 83-4 68 (m, 1 H), 4 66-4 45 (m, 1 H), 4 34-3 70 (m, 4 H), 10 1 98-1 54(m,3H), 1 08-0 78 (m, 6 H) <br><br> MS calcd for (C23H2tN205- H)* 409. Found. 409 <br><br> Example 70 <br><br> 15 Preparation of 4-(/?.5)-Amino-N-f(4-phenvlbenzovl)-5-leucinel-tetrahvdrofuran-3-one <br><br> By analogous methods to those detailed in Example 15, the title compound was prepared <br><br> "H NMR S (CDC1,, 250 MHz) 7.83 (d, 2 H, J = 8 2 Hz), 7 70-50 (m, 4 H), 7 48-32 (m, 4 20 H), 7 30-7 12 (m, 1 H), 6 88-6 72 (m, 1 H), 4 88-4 70 (m, 1 H), 4.65-52 (m, 1 H), 4.38-3 78 (m, 4 H), 1 92-1.60 (m, 3 H), 1.08-0 78 (m, 6 H) <br><br> MS calcd for (C23H26N204 - H)*- 393 Found* 393 <br><br> 25 <br><br> Example 71 <br><br> Preparation of 4-(7?.S)-Amino-N-f(6-tnfluoromethvlbenzorblthiophen-2-vlcarbonvl)-S-leucinel-tetrahvdrofuran-3-one <br><br> By analogous methods to those detailed in Example 15, the title compound was 30 prepared <br><br> 'H NMR 5 (DMSO,d6, 250 MHz) 8.82 (d, 1 H, J = 6.0 Hz), 8.43 (s, 1 H), 8.48-8 44 (m, 0 5 H), 8 34 (d, 0 5 H, J = 7 8 Hz), 8 23 (s, 1 H), 8 04 (d, 1 H, J = 8 4 Hz), 7 60 (dd, 1 H, J = 1 5 and 8 5 Hz), 4 49-4.38 (m, 1 H), 4.26-3 68 (m, 5 H), 1 70-1 36 (m, 3 H), 0 80 (d, 3 H, J = 6 Hz), 0 76 (d, 3 H, J = 6 0 Hz) <br><br> 35 MS calcd for (C20H21F3N2O4S - H)*- 443 Found 443 <br><br> -42- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 72 <br><br> Preparation of 4-//?.5)-Amino-N-r(4-ethvllbenzovn-5'-leiiciriel-tetrahvdrofuran-3-one <br><br> 5 By analogous methods to those detailed in Example 15, the title compound was prepared <br><br> 'H NMR 8 (CDC13, 250 MHz) 7 76 (d, 2 H, J = 8 0 Hz), 7 62-7 42 (m, 1 H), 7 22 (d, 2 H, J = 7 8 Hz), 7 04-6 80 (m, 1 H), 4 91-4 73 (m, 1 H), 4 61-4 45 (m, 1 H), 4 36-3 72 (m, 4 H), 2 68 (q, 2 H, J = 7 6 Hz), 1 88-1 58 (m, 3 H), 1 23 (t, 3 H, J = 7 6 Hz), 0 98-0 88 (m, 10 6 H) <br><br> MS calcd for (C19H26N204- H)\ 345 Found. 345 <br><br> Example 73 <br><br> 15 Preparation of 4-C/?.5)-Amino-N-f(4-(tert-butvl)benzovl')-5-leucinel-tetrahvdrofuran-3-one <br><br> By analogous methods to those detailed in Example 15, the title compound was prepared <br><br> 20 'H NMR 8 CDCI3,250 MHz) 7 76 (brd, 2 H, J = 7 5 Hz), 7.46 (brd, 2 H, J = 7 5 Hz), <br><br> 6 92-6 76 (m, 2H), 4 88-4 68 (m, 1 H), 4.58-4 43 (m, 1 H), 4.37-3 71 (m, 4 H), 1 82-1 57 (m, 3 H), 1 32 (s, 9 H), 1.00-0.82 (m, 6 H) <br><br> MS calcd for (C2lH30N2O4+ H)+: 375 Found" 375. <br><br> 25 Example 74 <br><br> Preparation of 4-//?.5)-Amino-N-r(5-methoxvbenzofb1thiophen-2-vlcarbonvlV5-leucinel-tetrahvdrofuran-3-one <br><br> 30 By analogous methods to those detailed in Example 15, the title compound was prepared <br><br> 'H NMR 8 (CDCl,, 250 MHz) 7 84-7 54 (m, 2 H), 7.20 (d, 1 H, J = 2 0 Hz), 7 10 (d, 1 H, J = 2 3 Hz), 7 06 (d, 1 H, J = 2 3 Hz), 6 78 (d, 1 H, J = 8 1 Hz), 4 82-4.68 (m, 1 H), 4 59 (appt, 1 H, J = 8 8 Hz), 4 49-3 61 (m, 4 H), 3 84 (s, 3 H), 1 82-1 58 (m, 3 H), 1 08-0.72 35 (m, 6 H) <br><br> MS calcd for (C20H24N2O,S - H)* 403 Found 403 <br><br> -43- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 75 <br><br> Preparation of 4-(R.S)-Amino-N-f(4-nitrobenzorhlthiophen-2-vlcarboiivl)-5'-leucinel- <br><br> tetrahvdrofuran-3-one <br><br> By analogous methods to those detailed in Example 15, the title compound was prepared <br><br> 'H NMR 8 (CDC1,, 250 MHz) 8 31 (s, 1 H), 7.96 (d, 1 H, J = 7 2 Hz), 7 62-7 18 (m, 4 H), 4.84 (appd, 1 H, J = 7 5 Hz), 4 70-3 72 (m, 5 H), 1.94-1 60 (m, 3 H), 1 11-0 80 (m, 6 10 H). <br><br> MS calcd for (Cl9H2lN3OfiS-NO/. 373 Found 373 <br><br> Example 76 <br><br> 15 Preparation of 4-(r/?.5)-Amino-N-r(6-bromobenzo[blthiophen-2-vlcarbonvl)-5'-leucinel-tetrahvdrofuran-3-one <br><br> By analogous methods to those detailed in Example 15, the title compound was prepared <br><br> 20 'H NMR 8 (CDClj, 250 MHz) 8 03 (s, 1 H), 7 81-7 58 (m, 2 H), 7.54-7 40 (m, 1 H), 7.22-6 98 (m, 2 H), 4.74 (appd, 1 H, J = 7 5 Hz), 4 59 (appq, 1 H, J = 7 5 and 14 0 Hz), 4.48-3 74 (m, 4 H), 1 85-1.58 (m, 3 H), 1 10-0.78 (m, 6 H). <br><br> MS calcd for (C19H2,BrN204S-H)* 452 Found'452 <br><br> 25 Example 77 <br><br> Preparation of 4-C/?.5)-Amino-N-f(5-bromobenzorblthiophen-2-vlcarbonvl)-5-leucinel-tetrahvdrofuran-3-one <br><br> 30 By analogous methods to those detailed in Example 15, the title compound was prepared <br><br> 'H NMR 8 (CDC13,250 MHz) 8.04-7 90 (m, 1 H), 7.88-7 18 (m, 5 H), 4.88-4 68 (m, 1 H), 4 68-4 52 (m, 1 H), 4 46-3 88 (m, 4 H), 1 92-1.52 (m, 3 H), 1 08-0 80 (m, 6 H) MS calcd for (C19H2,BrN204S - H)" 452 Found 452 <br><br> -44- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 78 <br><br> Preparation of 4-//?.5)-Amino-N-[(6-methoxvbenzofblthiophen-2-vlcarbonvl')-5- <br><br> leucinel-tetrahvdrofuran-3-one <br><br> By analogous methods to those detailed in Example 15, the title compound was prepared <br><br> 'H NMR 5 (CDC1,, 250 MHz) 7 79-7 61 (m, 2 H), 7 32-7 14 (m, 2 H), 7 00 (dd, 1 H, J = 1 5 and 8 8 Hz), 6 89-6 67 (m, 1 H), 4 75 (appq, 1 H, J = 8 2 and 16 2 Hz), 4 57 (appt, 1 10 H, J = 8 6 and 17 4 Hz), 4 49-3 71 (m, 4 H), 3 85 (s, 3 H), 1 92-1 52 (m, 3 H), 1 08-0 78 (m, 6 H) <br><br> MS calcd for (C20H,4N,O,S - H)* 403 Found 403 <br><br> Examples 79-93 <br><br> 15 <br><br> By analogous procedures to those described in Example 15, using the appropriate amino acid and acid or acid chlonde reagents consistent with the final products, the compounds of Table 2 were also prepared, 'h NMR spectra and/or mass spectra were consistent with the structures in Table 2 <br><br> 20 <br><br> -45- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> Table 2 <br><br> PCT/US98/03200 <br><br> Example <br><br> R3 <br><br> R" <br><br> synthesis method <br><br> 79 <br><br> -s phenyl <br><br> SPS <br><br> 80 <br><br> 3-chlorophenyl <br><br> SPS <br><br> 81 <br><br> 2-phenylethen-1-yl <br><br> SPS <br><br> 82 <br><br> 3-fluorophenyl <br><br> SPS <br><br> 83 <br><br> 3-hydroxyphenyl <br><br> SPS <br><br> 84 <br><br> 4-methylphenyl <br><br> SPS <br><br> 85 <br><br> 4-isopropvlphenyl <br><br> SPS <br><br> 86 <br><br> 4-trifluoromethylphenyl <br><br> SPS <br><br> 87 <br><br> • <br><br> 4-methylthiophenyl <br><br> SPS <br><br> 88 <br><br> " <br><br> 4-(benzylsulphonylamino)phenyl <br><br> SPS <br><br> 89 <br><br> " <br><br> 4-(diethylaminosulphonyl)phenyl <br><br> SPS <br><br> 90 <br><br> •• <br><br> 4-(acetylamino)phenyl <br><br> SPS <br><br> 91 <br><br> - <br><br> 4-benzoylphenyl <br><br> SPS <br><br> 92 <br><br> » <br><br> 4-acetylphenyl <br><br> SPS <br><br> 93 <br><br> It <br><br> 4-(4-oxopent-1 -yl)phenyl <br><br> SPS <br><br> 5 <br><br> Example 94 <br><br> Preparation of 4-S,-Amino-N-f(ben2orb1thiophen-2-vlcarbonvl)-S-leucine1-tetrahvdrofuran-3-one <br><br> 10 <br><br> (a) fra«i-4-S-Amino-5-R-hydroxytetrahydrofuran hydrochloride <br><br> A mixture of fra«J-4-5-azido-3-/?-hydroxytetrahydrofuran (reft E Martinez, J.L Leighton, D.E Carsten and EN Jacobsen, J. Amer Chem Soc. 1995, 117. 5897} 15 (10 g, 77 mmol) and 10% palladium on charcoal (1 g) in ethanol (150 ml) was stirred under an atmosphere of hydrogen (50 psi) for 12 h The mixture was filtered and treated with 100 ml of ethanolic HCl to afford, after evaporation under reduced pressure, the title compound as a brown solid, 10.5 g, 97% yield m p 132 °C 'H NMR 8 (D30) 4 54-4.52 (m, 1 H), 4 24-4.13 (m, 2 H), 3 98-3 61 (m, 3 H) <br><br> -46- <br><br> Pnnted from Mimosa <br><br> WO 98/50533 <br><br> PCT/U S98/03200 <br><br> (b) r/ww-4-S-Amino-N-[(benzyloxycarbonyl)-.S-leucine]-3-7?-hydroxytetrahydrofuran <br><br> Trimethylacetyl chlonde (5 4 ml, 44 mmol) was added to a stirred solution of N-Cbz-L-leucine (12 7 g, 48 mmol) and tnethylamine (14 ml, 52 mmol) in THF (200 5 ml) After 1 h, trans-4-5-ammo-3-^?-hydroxytetrahydrofuran HCl (5 58 g, 40 mmol) was added and the mixture was allowed to stir at reflux for 16 h The reaction mixture was filtered and evaporated under reduced pressure Flash column chromatography (80% ethyl acetate-hexane) afforded the title compound as a white foam, 10 6 g, 76% yield <br><br> 10 'H NMR 8 (CDC13) 7 76 (d, 1 H, J = 5 3 Hz), 7.33-7 20 (m, 5 H), 6 43 (d, 1 H, J = 8 9 Hz), 5 01 (appd, 2 H, J = 3 0 Hz), 4 60-3.65 (m, 6 H), 1 61-1 42 (m, 3 H), 0 93- 0 88 (m, 6 H) <br><br> (c) fra«.s-4-S-Amino-N-(S-leucine)-3-/?-hydroxytetrahydrofuran hydrochloride <br><br> 15 <br><br> A mixture of rra/ii-4-5-Amino-N-[(carbobenzyloxy)-5-leucine]-3-/?-hydroxytetrahydrofuran (2 0 g, 5 7 mmol and 10% palladium on charcoal (500 mg) in ethanol (100 ml) was stirred under an atmosphere of hydrogen (50 psi) for 12 hours The reaction mixture was then filtered diluted with ethereal HCl (100 ml, 1 molar) and 20 evaporated under reduced pressure to afford the title compound as a white foam, 1.5 g, 100% yield <br><br> 'H NMR 8 (D20) 4 20-4.05 (m, 2 H), 4 06-4 00 (m, 1 H), 3 90-3 83 (m, 2 H), 3 68-3 52 (m, 2 H), 1 65-1 47 (m, 3 H), 0.86-0.78 (m, 6 H) <br><br> 25 (d) f/ww-4-S-Amino-N-[(2-benzo(b)thiophenecarbonyl)-S-leucine-3-tf-hydroxytetrahydrofuran <br><br> N,N-Dnsopropylethylamine (0 4 ml, 2 0 mmol) was added to a stirred solution of fran^-4-5-amino-N-(5-leucine)-3-/?-hydroxytetrahydrofuran HCl salt (380 mg, 1 1 30 mmol) in dichloromethane (10 ml) After 5 minutes benzo[b]thiophene-2-carbonyl chloride (196 mg, 1 0 mmol) was added and the mixture was allowed to stir for 1 h then evaporated under reduced pressure. Flash column chromatography (40% acetone-hexane) afforded the title compound as a white foam, 271 mg, 75% yield 'H NMR 8 (dfi DMSO, 400 MHz) 8.72 (d, 1 H, J = 8 5 Hz), 8 25 (s, 1 H), 8 04 (d, 1 H, J 35 =85 Hz), 7 95 (d, 1 H, J = 8 5 Hz), 7 46-7 43 (m ,2 H), 5 23 (d, 1 H, J = 3 94 Hz), 4 54-4 47 (m, 1 H), 4 03-4 00 (m, 2 H), 3 90 (dd, 1 H, J = 5 4 and 8 9 Hz), 3 82 (dd, 1 H, J = <br><br> -47- <br><br> Pnnted from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> 4 4 and 9 3 Hz) 3 53- 3 48 (m, 2 H), 1 72-1 66 (m, 2 H), 1.52-1 48 (m, 1 H), 0 91 (d, 3 H, J = 6 4 Hz), 0 88 (d, 3 H, J = 6 4 Hz) <br><br> MS calcd for (C~H2JN20,+ H)* 365 Found 365 <br><br> 5 (e) 4-S-Amino-N-[(2-benzo(b)thiophenecarbonyl)-S-leucine]-tetrahydrofuran-3-one <br><br> Dess-Martin periodinane (200 mg, 0 5 mmol) was added to a stirred solution of frans-4-S-Amino-N-[(2-benzo(b)thiophenecarbonyl)-S-leucine-3-/?-hydroxytetrahydrofuran (150 mg, 0 40 mmol) in dichloromethane (10 ml) After 1 h, 10 ether (20 ml) was added followed by sodium thiosulfate (1 g). After an additional 15 mins the reaction was washed with saturated sodium hydrogen carbonate, brine and dried Evaporation of the solvent gave the title compound as a white foam, 147 mg, 100% yield <br><br> 'H NMR 8 (ds DMSO, 400 MHz) 8 82 (d, 1 H, J = 4.0 Hz), 8 46 (d, 1 H, J = 4 0 Hz), 15 8 28 (s, IH), 8 05 (d, 1 H, J = 4 0 Hz), 7 98 (d, 1 H, J = 4 0 Hz), 7 47-7 44 (m, 2 H), 4 54-4 51 (m, 1 H), 4 33-4 18 (m, 3 H), 4.08-3.80 (m, 3 H), 1 74-1.67 (m, 2 H), 1.58-1.56 (m, 1 H), 0 92 (d, 3 H, J = 64 Hz), 0 88 (d, 3 H, J = 64 Hz) <br><br> MS calcd for (C„H22N204- H)*- 373 Found' 373 <br><br> 20 Example 95 <br><br> Preparation of 4-/?-Amino-N-r(2-benzo(b)thiophenecarbonvl)-S-leucine1-tetrahvdrofuran-3-one <br><br> 25 Following the procedures of Example 94(a-e), but starting instead with trans-4- <br><br> 7?-azido-3-S-hydroxytetrahydrofuran (refL E Martinez, J L. Leighton, D E Carsten and E N Jacobsen, J Amer Chem Soc. 1995, 117, 5897) in the method of Example 94(a), the title compound was prepared. <br><br> 'H NMR 8 (d, DMSO, 400 MHz) 8 82 (d, 1 H, J = 4 0 Hz), 8.52 (d, 1 H, J = 4 0 Hz), 30 8 28 (s, IH), 8 01 (d, 1 H, J = 4 0 Hz), 7 95 (d, 1 H, J = 4 0 Hz), 7 47-7 44 (m, 2 H), 4 54-4 51 (m, 1 H), 4.33-4 18 (m, 3 H), 4 33 (appt, 1 H, J = 8.5 Hz), 4.22 (dd, 1 H, J = 8.7 and 16.0 Hz), 4 07 (appd, 1 H, J = 16 6 Hz), 3 90 (appd, 1 H, J = 16 6 Hz), 3 81 (appt, 1 H, J = 8 5 Hz), 1 74-1 67 (m, 2 H), 1.58-1 56 (m, 1 H), 0 92 (d, 3 H, J = 6 4 Hz), 0 88 (d, 3 H, J = 6.4 Hz) <br><br> 35 MS calcd for (C19H22N204- Hf 373 Found' 373 <br><br> -48- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 96 <br><br> Preparation of 4:S-Amino-N-r(2-napthovl')-S-leucinel-tetrahvdrofuran-3-one <br><br> 5 Following the procedures of Example 94, using the appropriate carboxylic acid chloride and the 4-azido-3-hydroxytetrahydrofuran of the required stereochemistry to be consistent with the final product, the following compound was prepared 'H NMR 5 (d6 DMSO, 400 MHz) 8 64 (d, 1 H, J = 3 8 Hz), 8 54 (s, 1 H), 8 42 (d, 1 H, J = 38 Hz), 8 03 (d, 1 H, J = 3 8 Hz), 8 02-7.95 (m, 3 H), 7 62-7 58 (m, 2 H), 4.63-4 60 10 (m, 1 H), 4 35-4 27 (m, 2 H), 4 08 (appd, 1 H, J = 16.8 Hz), 3 86 (appd, 1 H, J = 16 8 Hz), 3 82 (appt, 1 H, J = 8.0 Hz), 1 75-1 64 (m, 2 H), 1 62-1 55 (m, 1 H), 0 92 (d, 3 H, J = 60 Hz), 0 88 (d, 3 H, J = 6 0 Hz) <br><br> MS calcd for (C,,H24N204- H)+ 367 Found 367 <br><br> 15 Example 97 <br><br> Preparation of 4-/?-N-r(2-napthovl)-5-leucine1-tetrahvdrofuran-3-one <br><br> Following the procedures of Example 94, using the appropriate carboxylic acid 20 chlonde and the 4-azido-3-hydroxytetrahydrofuran of the required stereochemistry to be consistent with the final product, the following compound was prepared. <br><br> 'H NMR 8 (ds DMSO, 400 MHz) 8.62 (d, 1 H, J = 3 8 Hz), 8.52 (s, 1 H), 8.50 (d, 1 H, J = 38 Hz), 8.04 (d, 1 H, J = 3 8 Hz), 8 02-7 95 (m, 3 H), 7.62-7.58 (m, 2 H), 4 63-4.60 (m, 1 H), 4 32 (appt, 1 H, J = 8 8 Hz), 4 23 (ddd, 1 H, J = 8 8 and 16 0 Hz), 4 04 (appd, 1 25 H, J = 16 4 Hz), 3 86 (appd, 1 H, J = 16 4 Hz), 3 81 (appt, 1 H, J = 8 0 Hz), 1 75-1.64 (m, 2 H), 1 62-1 55 (m, 1 H), 0 92 (d, 3 H, J = 6 0 Hz), 0 88 (d, 3 H, J = 6 0 Hz) MS calcd for (C2lH24N204- H)\ 367. Found 367 <br><br> Example 98 <br><br> 30 <br><br> Preparation of 4-5-Amino-N-r(quinoline-2-carbonvl)-5-leucinel-tetrahvdrofuran-3-one <br><br> Following the procedures of Example 94, using the appropriate carboxylic acid chlonde and the 4-azido-3-hydroxytetrahydrofuran of the required stereochemistry to be 35 consistent with the final product, the following compound was prepared <br><br> 'H NMR 8 (d6 DMSO, 400 MHz) 8 80 (d, 1 H, J = 9 0 Hz), 8 70 (d, 1 H, J = 6 9 Hz), 8 63 (d, 1 H, J = 8 5 Hz), 8 39 (d, 1 H, J = 2.5 Hz), 8 27 (d, 1 H, J = 2 5 Hz), 8.21 (d, 1 <br><br> -49- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> H, J = 7 9 Hz), 7 95 (appt, 1 H, J = 8 2 Hz), 7 77 (appt, 1 H, J = 7 \ Hz), 4 75-4 66 (m, 1 H), 4 41-4 26 (m, 2 H), 4 16-3 79 (m, 3 H), 1 82-1 63 (m, 3 H), 0 97-0 88 (m, 6 H) MS calcd for (C~H23N304+ H)* 370 Found 370 <br><br> 5 Example 99 <br><br> Preparation of 4-fl-Amino-N-f(qu]noline-2-carbonv0-S-leucine1-teirahvdrofuran-3-one <br><br> Following the procedures of Example 94, using the appropnate carboxylic acid 10 chloride and the 4-azido-3-hydroxytetrahydrofuran of the required stereochemistry to be consistent with the final product, the following compound was prepared 'H NMR 5 (d6 DMSO, 400 MHz) 8 88 (d, 1 H, J = 9 0 Hz), 8 82 (d, 1 H, J = 6 7 Hz), 8 70 (d, 1 H, J = 8 5 Hz), 8 30 (d, 1 H, J = 2 5 Hz), 8 27 (d, 1 H, J = 2 5 Hz), 8 21 (d, 1 H, J = 7 9 Hz), 8.02 (appt, 1 H, J = 7 0 Hz), 7 87 (appt, 1 H, J = 7 0 Hz), 4 82-4 73 (m, 1 15 H), 4 48-3 88 (m, 5 H), 1 88-1 70 (m, 3 H), 1 05-1 02 (m, 6 H) <br><br> MS calcd for (C2„H23N304 + H)+ 370 Found* 370 <br><br> Example 100 <br><br> 20 Preparation of 4-S-Amino-N-r(5-methoxvbenzofuran-2-vlcarbonvl)-S-leucinel-tetrahvdrofuran-3-one <br><br> Following the procedures of Example 94, using the appropnate carboxylic acid chlonde and the 4-azido-3-hydroxytetrahydrofuran of the required stereochemistry to be 25 consistent with the final product, the following compound was prepared <br><br> 'H NMR 5 (d6 DMSO, 400 MHz) 8 73 (d, 1 H, J = 8 4 Hz), 8 52 (d, 1 H, J = 7 0 Hz), 7 65-7.62 (m, 2 H), 7 33 (d, 1 H, J = 2 6 Hz), 7 12 (dd, 1 H, J = 2 6 and 9 2 Hz), 4.64-4 55 (m, 1 H), 4.42-4 30 (m, 2 H), 4 18-3 87 (m, 3 H), 3 86 (s, 3 H), 1 84-1 57 (m, 3 H), 0.98-0 87 (m, 6 H). <br><br> 30 MS calcd for (CMHMN206 + H)* 389 Found 389 <br><br> Examples 101-108 <br><br> By analogous procedures to those described in Example 15, using the 35 appropnate ammo acid and acid or acid chlonde reagents consistent with the final products, the compounds of Table 3 were also prepared. NMR spectra and/or mass spectra were consistent with the structures in Table 3. <br><br> -50- <br><br> Printed from Mimosa <br><br> Example r3 <br><br> r" <br><br> synthesis method <br><br> 101 <br><br> A <br><br> 6-hydroxybenzo[b]thiophen-2-yl <br><br> SPS <br><br> 102 <br><br> •• <br><br> 5-hydroxybenzo[blthiophen-2-yl <br><br> SPS <br><br> 103 <br><br> ■ <br><br> 4-(3-(hydroxymethyl)phenyl)phenyl <br><br> SPS <br><br> 104 <br><br> » <br><br> 3-phenylphenyl <br><br> SPS <br><br> 105 <br><br> • <br><br> 4-(3-oxophenyl)phenyl <br><br> SPS <br><br> 106 <br><br> » <br><br> 4-(3-(aminosulphonyl)phenyl)phenyl <br><br> SPS <br><br> 107 <br><br> Y <br><br> benzo[b]thiophen-2-yl <br><br> SPS <br><br> 108 <br><br> s benzo[b]thiophen-2-yl <br><br> SPS <br><br> Examples 109-126 <br><br> Following the procedures of Example 94, using the appropnate carboxylic acid 10 chloride and the 4-azido-3-hydroxytetrahydrofuran of the required stereochemistry to be consistent with the final products, examples 109-126 were prepared *H NMR spectra and/or mass spectra were consistent with the structures in Table 4 <br><br> Table 4 <br><br> 15 <br><br> O R3 H <br><br> AiVtf <br><br> Example r3 <br><br> r" <br><br> stereochem at 4-position <br><br> 109 <br><br> A <br><br> (pynd-3-yl) phenyl <br><br> S <br><br> 110 <br><br> » <br><br> 4-(pyrid-2-yl)phenyl <br><br> S <br><br> -51 - <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> 111 <br><br> 4-acetylphenyl <br><br> S <br><br> 112 <br><br> benzyloxy <br><br> S <br><br> 113 <br><br> 3,4-dimethoxyphenyl <br><br> S <br><br> 114 <br><br> benzofuran-2-yl <br><br> S <br><br> 115 <br><br> 4-(6-methylpyrid-3-yl)phenyl <br><br> S <br><br> 116 <br><br> 5-chlorobenzo[blthiophen-2-yl <br><br> S <br><br> 117 <br><br> 4-(pyrid-4-yl)phenyl <br><br> S <br><br> 118 <br><br> 2-chlorophenyl <br><br> S <br><br> 119 <br><br> 4-bromophenyl <br><br> S <br><br> 120 <br><br> ■ <br><br> 4-chlorobenzorb1thiophen-2-vl <br><br> S <br><br> 121 <br><br> » <br><br> 4-benzylpiperidin-1 -yl <br><br> S <br><br> 122 <br><br> 3,4-dichlorophenyl <br><br> S <br><br> 123 <br><br> 3,4-dimethoxyphenyl <br><br> R <br><br> 124 <br><br> benzofuran-2-yl <br><br> R <br><br> 125 <br><br> 3-chlorophenyl <br><br> S <br><br> 126 <br><br> 5-chlorobenzofblthiophen-2-yl <br><br> R <br><br> Examples 127-129 <br><br> Using the SPS procedure of Example 15 but substituting 3,3-dimethoxy-4-5 aminotetrahydropyran for 3,3-dimethoxy-4-aminotetrahydrofuran, and using appropnate amino acid and carboxylic acid reagents consistent with the final products, examples 127-129 were prepared ' H NMR spectra and/or mass spectra were consistent with the structures in Table 5 <br><br> 10 Tables <br><br> Example r3 <br><br> r" <br><br> synthesis method <br><br> 127 <br><br> 4-phenoxyphenyl <br><br> SPS <br><br> 128 <br><br> " <br><br> quinolin-2-yl <br><br> SPS <br><br> 129 <br><br> 3,4-dimethoxyphenyl <br><br> SPS <br><br> -52- <br><br> Pnnted from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 130 <br><br> Preparation of 4-(7?.S)-Amino-N-IYbenzofb1thiophen-2-vlcarbonvO-S-leuc)nel-tetrahvdrothiophen-3-one <br><br> 5 <br><br> (a) /V-benzo[b]thiophene-2-ylcarbonyl-L-leucine methyl ester <br><br> Benzo[b]thiophene-2-carbonyl chlonde (4 9 g, 25 mmol) was added to a stirred solution of L-leucine methyl ester (4 5 g, 25 mmol) and dnsopropylethylamine (9 ml, 51 10 mmol) in DCM (200 ml) After stimng for 2 hours at room temperature, the mixture was poured into water and washed with bnne and dried (MgS04) Evaporation under reduced pressure afforded the title compound as a white solid, 7 6 g, 100% yield 'H NMR 8 (CDC13, 250 MHz) 7 88-7.78 (m, 3 H), 7 44-7 38 (m, 2 H), 6 53 (d, 1 H, J = 7 6 Hz), 4 91-4 82 (m, 1 H), 3 78 (s, 3 H), 1 82-1 60 (m, 3 H), 1 00 (app t, 6 H, J = 5 9 15 Hz) <br><br> (b) N-benzo[b]thiophene-2-ylcarbonyl-L-leucme <br><br> Lithium hydroxide (1 41 g, 59 mmol) was added in one portion to a stirred 20 solution of A'-benzo[b]thiophene-2-ylcarbonyl-L-leucine methyl ester (8 99 g, 29 4 <br><br> mmol) in THF/H,0 (1/1, 300 ml) After stirring for 12 hours at room temperature, the mixture was poured into water and acidifed to pH 1 with cHCl and extracted with Et,0 (x2) Evaporation under reduced pressure afforded the title compound as a yellow solid, 6 1 g, 71% yield <br><br> 25 'H NMR 8 (d6 DMSO, 250 MHz) 8 78 (d, 1 H, J = 9 1 Hz), 8.12 (s, IH), 7 92-7 83 (m 2 H), 7 36-7 30 (m, 2 H), 4 37-4 28 (m, 1 H), 1 88-1 47 (m, 3 H), 0.82 (d, 3 H, J = 6 0 Hz), 0 78 (d, 3 H, J = 6 0 Hz) <br><br> (c) /V-benzo[b]thiophene-2-ylcarbonyl-L-leucine-S-(methoxycarbonylmethyl)-L,D-30 cysteine ethyl ester <br><br> Iso-Propyl chloroformate (5 9ml, 1 0M in toluene) was added to a stirred solution of /V-benzo[b]thiophene-2-ylcarbonyl-L-leucine (1 65g, 5 7 mmol) and tnethylamine (1 6 ml, 11.8 mmol) in DCM (20 ml) After 1 hour at room temperature 35 L-cysteine ethyl ester was added followed by tnethylamine (1 6 ml, 11 8 mmol) and the mixture was allowed to stir for a further 6 hours Methyl bromoacetate (0 6 ml, 6 3 mmol) was added and the mixture was left for a further 0 5 hours before being poured <br><br> -53- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> into water and extracted with EtOAc(x3) The combined organic layers were washed with brine, dried (MgS04) and evaporated under reduced pressure Flash column chromatography (40% hexane-Et,0) afforded the title compound as a white solid, 1 6g, <br><br> 70% <br><br> 5 'H NMR 8 (CDClj, 250 MHz) 7 84-7 77 (m, 3 H), 7 66 (d, 0 5 H, J = 8 4 Hz), 7 52 (d, <br><br> 0 5 H, J = 8 4 Hz), 7 40-7 35 (m, 2 H), 7 24 (d, 0 5 H, J = 8 4 Hz), 7 16 (d, 0 5 H, J-= 8 4 Hz), 4 88-4.82 (m, 2 H), 4 23-4 15 (m, 2 H), 3 70 (s, 1 5 H), 3 69 (s, 1 H), 3 36-3 22 (m, 2 H), 3 15-3 08 (m, 2 H), 1 82-1 75 (m, 3 H), 1 28 (t, 1 5 H, J = 4.5 Hz), 1 23 (t, 1 5 H, J = 45 Hz), 0 98-0.95 (m, 6 H). <br><br> 10 <br><br> (d) 4-(/?,SJ-Amino-N-[(benzo[b]thiophene-2-ylcarbonyl)-S-leucine]-tetrahydrothiophene-3-one <br><br> A solution of freshly prepared sodium methoxide (from 75mg of sodium and 2 15 ml of methanol) was added to /V-benzo[b]thiophene-2-ylcarbonyl-L-leucine-S- <br><br> (carbomethoxymethyl)-L,D-cysteine ethyl ester (1 5 g, 3 2 mmol) m methanol (2 ml) at room temperature After 1 hour Et,0 (80 ml) was added, the solution was cooled to 0 °C and the resulting white solid was filtered off The solid was dissolved in 15ml of glacial acetic acid, 10ml of cHCl and 15 ml of H,0 This mixture was stirred at reflux for 0 5 20 hours then cooled to room temperature and extracted with CHCl, (x5) The combined organic layers were washed with NaHC03, brine, dried (MgS04) and evaporated under reduced pressure Flash column chromatography (40% hexane-Et20) afforded the title compound as a white solid, 120 mg, 10% <br><br> 'H NMR 8 (CDC13,400 MHz) 7 88-7 78 (m, 3 H), 7 58 (d, 0 5 H, J = 6.4 Hz), 7 54 (d, 25 0 5 H, J = 6 4 Hz), 7 42-7.35 (m, 3 H), 4 85-4 80 (m, 1 H), 4 43-4 34 (m, 1 H), 3 34-3 23 (m, 3 H), 3 02-2 91 (m, 1 H), 1 76-1 74 (m, 3 H), 0 98-0 85 (m, 6 H) <br><br> MS calcd for (C19H22N203S + H)* 391. Found* 391 <br><br> Example 131 <br><br> 30 <br><br> Preparation of 4-Ammo-N-r( benzorblthiophen-2-vlcarbonvl)-iS-leucinel-3.3-dimethoxvtetrahvdrofuran. diastereomer 1 <br><br> a) 4-(/?,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-3,3-dimethoxytetrahydrofuran <br><br> 35 <br><br> 4-(/?,5,)-Amino-3,3-dimethoxytetrahydrofuran (2 2g, 15mnfol), N-benzyloxycarbonyl-L-leucine (3 98g, 15mmol), EDC (3.17g, 16 5mmol) and hydroxyaminobenztnazole (0 45g, 3 3mmol) <br><br> -54- <br><br> Printed from Mimosa <br><br> WO 98/50533 <br><br> PCT/US98/03200 <br><br> were stirred togeather in a mixture of dichloromethane and tetrahydrofuran (1 1,100ml) at ambient temperature for 12hr The mixture was added to ethyl acetate (300ml), washed with water (2x100ml), dried ( MgS04) and evaporated to dryness Chromatography of the resulting oil on silica gel (ethyl acetate / hexane 1 3 to 1 1 gradient) gave the title compound as an oil 5 (5.27g, 89%) <br><br> 'H NMR 6 (CDC1,) 7 34 (s, 5H), 6 55 (d, IH), 5.11 (m, 3H), 4 34 (q, IH, J = 6 7Hz), 4 20 (m, 2H), 3 77 (s, 2H), 3 51(m, IH), 3 26 (d, 3H, J = 2 3Hz), 3 20(d, 3H, J = 4 7Hz), 1 54 (m, 3H), 0 95 (s, 3H), 0 93 (s, 3H) <br><br> 10 b) Separate diastereomers of 4-Amino-N-(S-leucine)-3,3-dimethoxytetrahydrofuran <br><br> 4-(/?,Sj-Amino-N-[(benzyloxycarbonyl)-S-leucine]-3,3-dimethoxytetrahydrofuran (5.27g, 13 4mmol) was subjected to hydrogenation at 50psi in methanol containing 10% palladium on carbon. After 3 5 hr, the mixture was filtered through celite and the solvent was removed under 15 reduced pressure. Chromatography of the resulting oil (3 5g) on silica gel (CH2C12 containing MeOH, 0-4% gradient) separated the title compound into the two pure single diasteromers diasteromer 1 (faster running) (0 63g) 'H NMR 8 (CDC1,) 7 76 (d, IH, J = 7 3Hz), 4 36 (dd, IH, J = 6 3, 7.2Hz), 4 21 (dd, IH, J = 6.4 ,9 0Hz), 3 80 (s, 2H), 3 57 (dd, IH, J = 5 3, 9 1Hz), 3 41 (dd, IH, J = 3 8, 10 1Hz), 3.30 (s, 3H), 3 24 (s, 3H), 1 73 (m, 2H), 1 35 (m, IH), 0 96 20 (d,3H, J = 6 7Hz), 0 94 (d, 3H, J = 6 6Hz) <br><br> diastereomer 2 (slower running) (0 91g) 'H NMR 8 (CDC1,) 7 77 (d, IH, J = 7 1Hz), 4 36 (dd, IH, J = 6 4, 12 9Hz), 4.21 (dd, IH, J = 6.5, 9 1Hz), 3 80 (s, 2H), 3 55 (dd, IH, J = 5.3, 9 0), 3 38 (dd, IH, j = 4 0, 10.0), 3.30 (s, 3H), 3 25 (s, 3H), 1.72 (m, 2H), 1.38 (m, 1H),0 96 (d, 3H, J = <br><br> 6 7Hz), 0 94 (d, 3H, J = 6.8Hz). <br><br> 25 <br><br> c) 4-Amino-N-[(_benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3,3-dimethoxytetrahydrofuran, diastereomer 1 <br><br> Saturated sodium bicarbonate solution (5ml) was added to a solution of 4-amino-N-(S-leucine)-30 3,3-dimethoxytetrahydrofuran, diastereomer 1 (0 13g, 0 5mmol) in 1 4-dioxane (5ml) followed by benzo[b]thiophen-2-ylcarbonyl chloride (0.39g, 2mmol) After 45 minutes, the mixture was added to ethyl acetate, washed with water, sodium bicarbonate solution and water The organic solution was then dried ( MgSOJ and evaporated to give a white solid (0 47g). Chromatography on silica gel (CH2C12 containing MeOH 0-5% gradient) gave the title compound (0 18g, 89%) as 35 a white solid 'H NMR 8 (CDC1,) 7 88 (s, 1H), 7 74 (m, 3H), 7 34 (m, 2H), 7.18 (d, 1H, J = <br><br> 7 1Hz), 4 82 (m, IH), 4 38 (dd, IH, J = 6.4, 12 3Hz), 4 21 (dd, IH, J = 6 5, 9 2Hz), 3 78 (ABq, 2H, J = 3 8, 9 8Hz), 3 62 (dd, IH, J = 5.2, 9 1Hz), 1 78 (m, 3H), 0.99 (s, 3H), 0 96 (s, 3H) <br><br> -55- <br><br> Printed from Mimosa <br><br> 10 <br><br> WO 98/50533 PCT/US98/03200 <br><br> Examples 132-142 <br><br> By analogous procedures to those described in example 131, using the appropnate diastereomer of 4-amino-N-(S-leucine)-3,3-dimethoxytetrahydrofuran and the carboxylic acid halide reagents consistent with the final products, the compounds of Table 6 were also prepared 'H NMR and mass spectra were consistent with the structures in Table 6 <br><br> Table 6 <br><br> r3 " or" <br><br> ri i\'"&gt;V0r' <br><br> H O L ) <br><br> Example <br><br> R3 <br><br> R" <br><br> Ra <br><br> Ra' <br><br> diastereomer <br><br> 132 <br><br> A <br><br> benzo[b]thiophen-2-yl <br><br> Me <br><br> Me <br><br> 2 <br><br> 133 <br><br> ■ <br><br> indol-5-vl <br><br> » <br><br> 1 <br><br> 134 <br><br> » <br><br> ii <br><br> » <br><br> 2 <br><br> 135 <br><br> quinolin-2-vl <br><br> II <br><br> • <br><br> 1 <br><br> 136 <br><br> " <br><br> i&gt; <br><br> •• <br><br> 2 <br><br> 137 <br><br> n <br><br> 3-bromophenvl <br><br> « <br><br> 1 <br><br> 138 <br><br> II <br><br> » <br><br> i. <br><br> 2 <br><br> 139 <br><br> 4-phenoxyphenyl <br><br> » <br><br> 1 <br><br> 140 <br><br> « <br><br> - <br><br> 2 <br><br> 141 <br><br> indole-6-vl <br><br> ■ <br><br> 2 <br><br> 142 <br><br> benzimidazol-5-yl <br><br> 1 <br><br> -56- <br><br> Printed from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 143 <br><br> Preparation of 4-Amino-N-IY benz6rb1thiophen-2-vlcarbonv1)-S-leucinel-3.3-dimethoxvtetrahvdropvran diastereomer 1 <br><br> 5 <br><br> a) 4-(/?,S/l-Amino-N-[(benzyloxycarbonyl)-5-leucine]-3,3-dimethoxytetrahydropyran <br><br> 4-(R,S)-amino-N-[(benzyloxycarbonyl)-5-leucme]tetrahydropyran-3-one (example 67c, 3 lg, 8 6mmol) was heated at reflux for 12hr with trimethylorthoformate ( 2 8ml) and p-10 toluenesulphomc acid (0 080g) in methanol (50ml) After removing the solvent under reduced pressure, the resulting oil was chromatographed on silica gel (ethyl acetate / hexane gradient) to give the title compound as a white solid ( 2 89g, 80%) <br><br> 'H NMR 5 (CDC1,) 7.29 (s, 5H), 6 99 (m, IH), 6.15 (m, IH), 5 07 (s, 2H), 4 28 (m, IH), 4 18(m, IH), 3 52 (m 4H), 3 19 (s, 3H), 3 14 (s, 3H), 1.85 (m, IH), 1 63 (m, 4H), 0.93 (s, 6H) <br><br> 15 <br><br> b) Separate diastereomers of 4-Amino-N-(5-lcucme)-3,3-dtmethoxytetrahydropyran <br><br> 4-(/?,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-3,3-dimethoxytetrahydropyran was hydrogenated as in example 131b to give, after chromatography, the pure single 20 diastereomers of the title compound diastereomer 1 'H NMR 8 (CDC1,) 7 75 (d, IH, J = 8.1Hz), 4 17 (m, IH), 3 58 (m, 3H), 3 41 (dd, IH, J = 3 5, 9 7Hz), 3 28 (s, 3H), 3 24 (s, 3H), 1 92 (m, IH), 1 71 (m, 4H), 1 30 (m, IH) 0 97 (d, 3H, J = 6 4Hz), 0.94 (d, 3H, J = 6 3Hz) <br><br> diastereomer 2 'H NMR 8 (CDC13) 7 8 (s, IH), 4 16 (m, IH), 3 59 (m, 3H), 3 49 (m, 25 IH), 3 28 (s, 3H), 3 24 (s, 3H), 1 92 (m, IH), 1.72 (m, 4H), 1 41 (m, IH), 0 97 (d, 3H, J = 6 1Hz), 0 95 (d, 3H ,J = 6 0Hz). <br><br> c) 4-Amino-N-[(_benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3,3-dimethoxytetrahydropyran, diastereomer 1 <br><br> 30 <br><br> 4-Amino-N-(S'-leucine)-3,3-dimethoxytetrahydropyran diastereomer 1 was reacted with benzo[b]thiophen-2-ylcarbonyl chloride, as in example 131c, to give the title compound 'H NMR 8 (CDCl,) 7 98 (d, IH, J = 8.3Hz), 7 93 (s, IH), 7 78 (d, 1H,J = 7 7Hz), 7 71 (d, IH, J = 8 3Hz), 7 33 (m, 3H), 4 83 (m, IH), 4 19 (m, IH), 3 69 (m, IH), 3 57 (m, 2H), 35 3 40 (d, IH, J = 13Hz), 3.23 (s, 3H), 3 13 (s, 3H), 1 85 (m, 5H), 0 98 (d, 3H, J = 4 8Hz), 0 96 (d, 3H, J = 5 2Hz) <br><br> -57- <br><br> Pnnted from Mimosa <br><br> WO 98/50533 PCT/US98/03200 <br><br> Example 144 <br><br> Preparation of 4-Amino-N-r( benzoTblthiophen-2-vlcarbonvlV5-leucine1-3.3-dimethoxvtetrahvdropvran diastereomer 2 <br><br> 5 <br><br> Using diastereomer 2 of 4-amino-N-(S-leucine)-3,3-dimethoxytetrahydropyran m the procedure of example 143c, the title compound was prepared <br><br> The above specification and Examples fully disclose how to make and use the 10 compounds of the present invention However, the present invention is not limited to the particular embodiments described hereinabove, but includes all modifications thereof within the scope of the following claims The various references to journals, <br><br> patents and other publications which are cited herein comprise the state of the art and are incorporated herein by reference as though fully set forth <br><br> 15 <br><br> -58- <br><br> Printed from Mimosa <br><br></p> </div>

Claims (1)

  1. <div class="application article clearfix printTableText" id="claims"> <p lang="en"> What is claimed is:<br><br> 1. A compound according to formula (I):<br><br> wherein-<br><br> r1 is r", r"c(0), r"c(s), r"s02, r"0c(0), r"r'NC(0), or r"0c(0)nr'ch(r6)c(0);<br><br> R- is H, Cj.galkyl, C2_6aHcenyl, Ar-Co-6alkyl, or Het-Co-^alkyl;<br><br> R^ is H, Cj.galkyl, C2-6alkenyl, C2-6a^ynyl, C3_6cycloalkyl-C()-6alkyi, Ar-Co-6alkyl, or Het-Co-6alkyl;<br><br> R^ is H, C j.galkyl, C2_6alkenyl, Ar-Co-6alkyl, or Het-CQ-^alkyl,<br><br> each r5 independently is H, Cj^alkyl, C2_6alkenyl, Ar-Co-6alkyl, or Het-Co_6a^yl;<br><br> R^ is H, Cj.galkyl, C2_6alkenyl, C3_6cy.cloalkyl-Co_6alkyl, Ar-Co_6alkyl, Het-Co_6alkyl;<br><br> R' is H, Cj.galkyl, C2_6alkenyl, Ar-Co-6alkyl, or Het-Cg-galkyl,<br><br> R" is Cj.galkyl, Ar-Co-6alkyl, Het-Co_6alkyl, Ar-C2-6alkenyl; or Het-C2.(jalkenyl;<br><br> X is O or S,<br><br> n is 1, 2, or 3; and<br><br> Ar and Het are as hereinbefore defined;<br><br> or a pharmaceutically acceptable salt thereof.<br><br> 2. A compound according to claim 1 wherein R^ and R^ are each H.<br><br> 3. A compound according to claim 1 or 2 wherein R3 is C,^ alkyl C2-6alkenyl.<br><br> 4. A compound according to claim 3 wherein R^ is i-butyl.<br><br> 5. A compound according to any one of claims 1 to 4 wherein R^<br><br> R OC(O), R SO9 or R C(O), m which R is Ar-Co_6alkyl or Het-Co_($alkyl.<br><br> -59-<br><br> o<br><br> 6. A compound according to claim 5 wherein the R group is<br><br> ^&lt;yCH2~<br><br> O-<br><br> CI<br><br> B;<br><br> 9<br><br> 10<br><br> 15<br><br> CI o m which B2 is OH, CN, OCF3, OCj.galkyl, OAr, S02Cj.galkyl, C^alkyl or halo.<br><br> 7 A compound according to any one of claims 1 to 6 wherein n is 1 or 2.<br><br> 8. A compound according to claim 7 wherein n is 1.<br><br> 9. A compound according to any one of claims 1 to 8 wherein X is O.<br><br> 10. A compound according to any one of claims 1 to 9 wherein each R5 is<br><br> 11. A compound according to claim 1 of the formula (Ila):<br><br> r,3 H<br><br> N<br><br> N<br><br> H<br><br> (Ha).<br><br> 12. A compound according to claim 1 of the formula (lib):<br><br> -60-<br><br> WO 98/50533<br><br> PCT/US98/03200<br><br> R1-v<br><br> O<br><br> (lib).<br><br> 13<br><br> 10<br><br> A compound according to claim i of the formula (lie) n3 h<br><br> n ,y<br><br> ' TH<br><br> h<br><br> (lie)<br><br> 14 A compound according to claim 1 which is<br><br> 4-(7?,S)-Amino-N-[(3,4-methylenedioxybenzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-(ft,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-tetrahydrofuran-3-one, 4-(/?,£)-Amino-N-[(3,4-dichlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-(/?,S)-Amino-N-[(2-quinohnecarbonyl)-S-leucine]-tetrahydrofuran-3-one, 4-(/J,5)-Amino-N-[(8-quinolinecarbonyl)-5-leucine]-tetrahydrofuran-3-one, 4-(7?,S')-Amino-N-[(benzyloxycarbonyl)-S-leucine]-2,2-dibenzyl-tetrahydrofuran-3-one 4-(/?,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-<br><br> 15 3-one,<br><br> A-(R, 5&gt;Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-tetrahydrofuran-3-one, 4-(7?,S)-Amino-N-[(indole-6-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one, 4-(7?,SJ-Amino-N-[(benzofuran-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one, 4-(/?,5'J-Amino-N-[(5-aminobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-20 tetrahydrofuran-3-one,<br><br> 4-(/?,S)-Amino-N-[(5-chlorobenzofuran-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one,<br><br> 4-(/?,S)-Amino-N-[(5-methoxybenzofuran-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one; 25 4-(/?,S)-Amino-N-[(3-bromobenzoyl)-S-leucine]-tetrahydrofuran-3-one,<br><br> 4-(/?,5)-Amino-N-[(4-bromobenzoyl)-5-leucine]-tetrahydrofuran-3-one, 4-(/?,5)-Amino-N-[(5-chlorobenzo[b]thiophen-2-ylcarbonyl)-5-leucine]-tetrahy drofuran-3-one,<br><br> 4-(i?,5J-Amino-N-[(4-fluorobenzo[b]thiophen-2-ylcarbonyl)-5-leucine]-30 tetrahy drofuran-3-one,<br><br> -61 -<br><br> Printed from Mimosa<br><br> WO 98/50533<br><br> PCT/US98/03200<br><br> 4-|7?,5)-Amino-N-[(4-phenoxybenzoyl)-5-leucine]-tetrahydrofuran-3-one, 4-(7?,5)-Amino-N-[(4-phenylbenzoyl)-5-leucine]-tetrahydrofuran-3-one, 4-(7?,5/)-Amino-N-[(6-trifluorom~ethylbenzo[b]thiophen-2-ylcarbonyl)-5-leucine] -tetrahy drofuran-3-one, 5 4-(7?, SJ-Amino-N-[(4-ethyllbenzoyl)-S-leucine]-tetrahydrofuran-3-one,<br><br> 4-(/?,5/)-Amino-N-[(4-(tert-butyl)benzoyl)-5-leucine]-tetrahydrofuran-3-one, 4-(7?,S)-Amino-N-[(5-methoxybenzo[b]thiophen-2-ylcarbonyl)-5-leucine]-tetrahydrofuran-3-one,<br><br> 4-(7?,5J-Amino-N-[(4-nitrobenzo[b]thiophen-2-ylcarbonyl)-5-leucine]-10 tetrahydrofuran-3-one,<br><br> 4-(7?,S)-Amino-N-[(6-bromobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one,<br><br> 4-(7?,5)-Amino-N-[(5-bromobenzo[b]thiophen-2-ylcarbonyl)-5-]eucine]-tetrahydrofuran-3-one, 15 4-(7?,5)-Amino-N-[(6-methoxybenzo[b]thiophen-2-ylcarbonyl)-5-leucine]-<br><br> tetrahy drofuran-3-one,<br><br> 4-5-Amino-N-[(benzo(b)thiophen-2-ylcarbonyl)-5-leucine]-tetrahydrofuran-3-<br><br> one,<br><br> 4-^?-Amino-N-[(benzo(b)thiophen-2-ylcarbonyl)-5-leucine]-tetrahydrofuran-3-<br><br> 20 one,<br><br> 4-5-Amino-N-[(2-napthoyl)-5-leucine]-tetrahydrofuran-3-one, 4-/?-Ammo-N-[(2-napthoyl)-5-leucine]-tetrahydrofuran-3-one, 4-5-Amino-N-[(quinoline-2-carbonyl)-5-leucine]-tetrahydrofuran-3-one, 4-/?-Amino-N-[(quinoline-2-carbonyl)-5-leucine]-tetrahydrofuran-3-one, 25 4-5- Amino-N- [(5-methoxybenzofuran-2-y lcarbonyl)-5-leucine]-<br><br> tetrahydrofuran-3-one,<br><br> 4-5-Amino-N-[((4-pyrid-3-yl)benzoyl)-5-leucine]-tetrahydrofuran-3-one, 4-5-Amino-N-[((4-pyrid-2-yl)benzoyI)-5-leucine]-tetrahydrofuran-3-one, 4-5-Amino-N-[(benzy loxycarbony l)-S-leucine]-tetrahydrofuran-3-one, 30 4-5-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-tetrahydrofuran-3-one,<br><br> 4-5-Amino-N-[(benzofuran-2-ylcarbonyl)-S-leucme]-tetrahydrofuran-3-one, 4-5-Amino-N-[(4-[6-methylpynd-3-yl]benzoyl)-5-leucine]-tetrahydrofuran-3-<br><br> one,<br><br> 4-5-Amino-N-[(5-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-35 tetrahydrofuran-3-one,<br><br> 4-5-Amino-N-[((4-pynd-4-yl)benzoyl)-5-leucine]-tetrahydrofuran-3-one, 4-5-Amino-N-[(2-chlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one,<br><br> -62-<br><br> Prmted from Mimosa<br><br> 4-S-Amino-N-[(4-bromobenzoyl)-S-leucine]-tetrahydrofuran-3-one;<br><br> 4-S-Amino-N-[(4-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-one;<br><br> 4-S-Amino-N-[(4-benzylpiperidin-l-ylcarbonyl)-S-leucine]-tetrahydrofuran-3-<br><br> one;<br><br> 4-S-Amino-N-[(3,4-dichlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one;<br><br> 4-5-Amino-N-[(3-chlorobenzoyl)-S-leucine]-tetrahydrofuran-3-one;<br><br> 4-(/?,S)-Ammo-N-[(3,4-dimethoxybenzoyl)-S-leucine]-tetrahydropyran-3-one;<br><br> 4-(7?„S&gt;Amino-N-[(4-phenoxybenzoyl)-S-leucine]-tetrahydropyran-3-one;<br><br> 4-(/?,5)-Amino-N-[(quinoIin-2-ylcarbonyl)-S-leucine]-tetrahydropyran-3-one,<br><br> 4-(/?,5)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-tetrahydropyran-3-one;<br><br> 4-(7?,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydropyran-3-one; or<br><br> 4-(7?,SJ)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-tetrahydrothiophen-3-one,<br><br> or a pharmaceutically acceptable salt thereof.<br><br> 15 A pharmaceutical composition comprising a compound according to any one of claims 1-14 and a pharmaceutically acceptable carrier.<br><br> 16. A compound according to any one of claims 1 to 14 for use as a medicament.<br><br> 17. The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the treatment of diseases in which inhibition of a cysteine protease is a factor.<br><br> 18. The use of a compound according to claim 17 wherein the cysteine protease is cathepsin K.<br><br> 19. The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the inhibition of bone loss.<br><br> 20 The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the treatment of osteoporosis.<br><br> -63-<br><br> 21. The use of a compound of the formula (I) as defined in claim 1 in the manufacture of a medicament for the treatment of gingival or peridontal disease.<br><br> 22. The use of a compound of the formula (I) as defined in claim 1<br><br> in the manufacture of a medicament for the treatment of diseases characterized by excessive cartilage or matrix degradation.<br><br> 23. The use of a compound according to claim 22 wherein the disease characterized by excessive cartilage or matrix degradation is osteoarthritis or rheumatoid arthritis.<br><br> 24. A process for preparing a compound of the formula (I) as defined in claim 1, which process comprises:<br><br> (i) reacting a compound of the formula (III):<br><br> wherein R1, R2, R3, R4, R5 and n are as defined in claim 1, with any reactive functional groups protected, with an oxidizing agent; or<br><br> -64-<br><br> (ii) decarboxylating a compound of the formula (IV):<br><br> (W)<br><br> wherein R1, R2, R3, R4, R5 and n are as defined in claim 1, with any reactive functional groups protected; or<br><br> (iii) reacting a compound of the formula (V):<br><br> wherein R1, R3, R4, R5 and n are as defined in claim 1 and Resin is Ellmans resm, with any reactive functional groups protected, with an acid;<br><br> and thereafter removing any protecting groups and optionally forming a pharmaceutically acceptable salt.<br><br> -65 -<br><br> 25. A compound according to formula (III):<br><br> R3 R4<br><br> 5 wherein:<br><br> r1 is r", r"c(0), r"c(s), r"S02, r"0c(0), r"r'nc(0), or r"0c(0)nrch(r6)c(0);<br><br> R- is H, Cj.galkyl, C2_(5alkenyl, Ar-Q)-6alkyl, or Het-CQ-galkyl;<br><br> R^ is H, Cj.galkyl, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl-Co_6alkyl, 10 Ar-Co_6alkyl, or Het-CQ^alkyl;<br><br> R4 is H, Cj.galkyl, C2_6alkenyl, Ar-Co-6alkyl, or Het-Cg.^alkyl;<br><br> each R^ independently is H, Cj.galkyl, C2_6alkenyl, Ar-Co-6alkyl, or Het-Co-6a'kyl,<br><br> R*&gt; is H, C].galkyl, C2-6alkenyl, C3_6cycloalkyl-C()-6-alkyl, Ar-C^alkyl, 15 Het-Co_galkyl;;r' is H, Cj.galkyl, C^-galkenyl, Ar-C()-6alkyl, or Het-C()-6alkyl, r is C]_6alkyl, Ar-C()-6alkyl, Het-Co-6alkyl, Ar-C2-6alkenyl; or Het-C2_6alkenyl;;n is 1, 2 or 3, and 20 Ar and Het are as hereinbefore defined;;or a pharmaceutically acceptable salt thereof.;26 A compound according to formula (TV):;25;30;R3 R4;N;O;CCLC^alkyl;(iv);wherein:;R1 is R", r"C(0), R"C(S), R"S02, R"0C(0), R"r'NC(0), or R"0C(0)NRCH(R6)C(0);;R- is H, Cj.^alkyl, C2-6alkenyl, Ar-Co^^kyl, or Het-Co_galkyl;;R3 is H, Cj.galkyl, C2-6alkenyl, C2-6a^ynyl, C3_6cycloalkyl-Co_6alkyl. Ar-CQ.galkyl, or Het-CQ.^alkyl;;-66-;R4 is H, C j.galkyl, C2.galkenyl, Ar-C()-6aIkyl, or Het-C'o_6aIkyl;;each R5 independently is H, Cj.galkyl, C2-6alkenyl, Ar-Co-6alkyl, or Het-Co_galkyl;;R6 is H, Cj_&lt;5alkyl, C2_6alkenyl, C3_6cycloalkyl-Co_6-alkyl, Ar-CQ-galkyl, Het-Co_6alkyl,;R is H, Cj.galkyl, C2_6alkenyl, Ar-Co-6alkyl, or Het-CQ.galkyl; R is Cj.galkyl, Ar-C()-6alkyl, Het-C^galkyl, Ar-C2-6alkenyl; or Het-C2-6alkenyl;;n is 1, 2 or 3; and;Ar and Het are as hereinbefore defined;;or a pharmaceutically acceptable salt thereof.;27. A compound according to formula (V):;R1 is r", R"C(0), R"C(S), R"S02, R"0C(0), R"r'NC(0), or R"OC(0)NR'CH(R6)C(0),;r3 is H, Cj.galkyl, C2-6aikenyl, C2-6alkynyI, C3_6cycloalkyl-Co-6a^yl, Ar-Co_&lt;$alkyl, or Het-Chalky 1;;r4 is H, Cj.galkyl, C2.galkenyl, Ar-C(&gt;6a^yl, or Het-CQ.galkyl;;each R^ independently is H, Cj.galkyl, C2-6alkenyl, Ar-Co-6alkyl, or Het-Co^alkyl;;R6 is H, Ci.galkyl, C2_6alkenyl, C3_gcycloalkyl-Co-6-alkyl, Ar-Co^^kyl, Het-Co.galkyl;;R is H, Cj.galkyl, C2_6alkenyl, Ar-C()-6a^yl, or Het-CQ-galkyl; R" is Ci_6alkyl, Ar-Co-galkyl, Het-Co_galkyl, Ar-C2-6alkenyl; or Het-C2_(5alkenyl;;X is O or S;;n is 1, 2 or 3;;Ar and Het are as hereinbefore defined; and Resin is Ellmans resin;;or a pharmaceutically acceptable salt thereof;(V);wherein;67;T fl 8 i?*&amp;<br><br> 23 A compound selected from the group consisting of: rrans-4-(7?,S)-Amino-N-[(benzyloxycarbonyl)-S-leucme]-3-hydroxytetrahydrofuran;<br><br> fran5-4-(/?,^J-Amino-N-[(rerr-butoxycarboriyl)-5-leucine]-3-5 hydroxytetrahydrofuran;<br><br> fran5-4-fi?,5J-Amino-N-(S-leucine)-3-hydroxytetrahydrofuran; rra/25-4-{7?,S)-Amino-N-[(3,4-methylenedioxybenzoyl)-5-leucine]-3-hy droxytetrahydrofuran;<br><br> mzrts-4-(7?,S)-Amino-N-[(3,4-dichlorobenzoyl)-S-leucine]-3-10 hydroxytetrahydrofuran;<br><br> trans-4-(R, Sj-Amino-N-[(2-qumolinecarbonyl)-5-leucine]-3-hy droxy tetrahy drofuran;<br><br> rranj-4-(/?,S)-Amino-N-[(benzyloxycarbonyl)-S-leucine]-3-hydroxytetrahydropyran; 15 rra/25-4-(i?,S)-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-<br><br> hydroxy tetrahy dropy ran,<br><br> rra«5-4-(7?,SJ-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-hydroxytetrahydrofuran;<br><br> /ra«^-4-('/?,5J-Amino-N-[(indole-6-ylcarbonyl)-5-leucine]-3-20 hydroxytetrahydrofuran;<br><br> rranj-4-C/?,5j-Amino-N-[(5-aminobenzo[b]thiophen-2-ylcarbonyl)-5-leucine]-3-hydroxytetrahydrofuran rran5-4-Amino-3-hy droxytetrahydrofuran; rra«5-3-Hydroxy-4-benzyloxycarbonylammo-tetrahydrofuran; 25 4-Benzyloxycarbonylammo-tetrahydrofuran-3-one,<br><br> 3,3-Dimethoxy-4-benzyloxycarbonylamino-tetrahydrofuran; 3,3-Dimethoxy-4-amino-tetrahydrofuran rm«j-4-5-Amino-3-/?-hydroxytetrahydrofuran; rrans-4-S-Amino-N-[(benzyloxycarbonyl)-,S-leucine]-3-/?-30 hydroxytetrahydrofuran;<br><br> rra«5-4-5-Amino-N-(5-ieucine)-3-/?-hydroxytetrahydrofuran; rran5-4-S-Amino-N-[(3,4-dichlorobenzoyI)-S-leucine]-3-i?-hydroxytetrahy drofuran;<br><br> rrans-4-S-Amino-N-[(2-quinolinecarbonyl)-.S-leucine]-3-fl-35 hydroxytetrahydrofuran;<br><br> rrans-4-5'-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-/?-hy droxy tetrahy drofuran;<br><br> -68-<br><br> WO 98/50533<br><br> PCT/US98/03200<br><br> /ra/j5-4-S-Amino-N-[(benzofuran-2-ylcarbony!)-S-leucme]-3-/?-hydroxytetrahydrofuran;<br><br> fran.s-4-S-Amino-N-[(2-naphthoyl)-S-leucine]-3-/?-hydroxytetrahydrofuran, rra«j-4-S-Amino-N-[(5-methoxybenzofuran-2-ylcarbonyl)-S-leucine]-3-/?-5 hydroxytetrahydrofuran,<br><br> fran.r-4-S-Amino-N-[(5-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-/?-hydroxy tetrahydrofuran;<br><br> lran.y-4-S-Amino-N-[(4-chlorobenzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-fl-hydroxytetrahydrofuran, 10 frans-4-S-Amino-N-[(4-bromobenzoyl)-S'-leucine]-3-/?-hydroxytetrahydrofuran,<br><br> rra/jj-4-5-Amino-N-[(4-(pyrid-2-yl)benzoyl)-5-leucine]-3-/f-hydroxytetrahydrofuran,<br><br> franj--4-S-Amino-N-[(4-(pynd-3-yl)benzoyl)-S-leucine]-3-/?-hydroxy tetrahydrofuran, 15 ?ra/?j-4-5-Amino-N-[(3,4-dimethoxybenzoyl)-S-leucine]-3-^?-<br><br> hy droxy tetrahydrofuran,<br><br> ?raHs-4-Amino-3-hydroxytetrahydropyran,<br><br> S&gt;Amino-N-[(benzy loxycarbony l)-S-leucine]-3-hydroxytetrahydropyran,<br><br> 20 trans-4-f R, S)- Amino-N-(5-leucine)-3-hydroxy tetrahydropyran,<br><br> frans-4-Ci?,Sj-Amino-N-[(benzo[b]thiophen-2-ylcarbonyl)-S-leucine]-3-hydroxytetrahydropyran,<br><br> iV-benzo[b]thiophene-2-ylcarbony!-L-leucine methyl ester, iV-benzo[b]thiophene-2-ylcarbonyl-L-leucme, 25 /V-benzo[b]thiophene-2-ylcarbonyl-L-leucme-S-(methoxycarbonylmethyl)-L,D-<br><br> cysteine ethyl ester; or<br><br> 2-Methoxycarbonyl-4-f/?,5j-Amino-N-[(benzo[b]thiophene-2-ylcarbonyl)-5-leucine]-tetrahydrothiophene-3-one,<br><br> or salts thereof<br><br> -69-<br><br> Prxnted from Mimosa<br><br> 29<br><br> wherein-<br><br> R1 is R , R C(0), R C(S), R S02, R 0C(0), R R NC(O), or R"0C(0)NRCH(R6)C(0);<br><br> r2 is H, Cj.galkyl, C2_6alkenyl, Ar-C()-6alkyl, or Het-C^galkyl;<br><br> R3 is H, Cj.galkyl, C2-6alkenyl, C2-6alkynyl, C3_6cycloalkyl-Co_6alkyl, Ar-C0_6alkyl, or Het-CQ-galkyl;<br><br> R4 is H, Cj.galkyl, C2-6alkenyl, Ar-C()-6alkyl, or Het-Co_6alkyl;<br><br> each R5 independently is H, Cj.galkyl, C2.6alkenyl, Ar-Co-6alkyl, or Het-Chalky 1;<br><br> R6 is H, Ci_galkyl, C2_6alkenyl, c3_6cycloalkyl-C()-6-alkyl, At-Cq.<br><br> galkyl, Het-Co-6 alkyl;<br><br> R is H, Cj^alkyl, C2-6alkenyl, Ar-Cogalkyl, or Het-CQ_galkyl;<br><br> R is Cj.galkyl, Ar-Co-6alkyl, Het-CQ-^alkyl, Ar-C2_6alkenyl; or Het-C2-6alkenyl,<br><br> X is O or S,<br><br> n is 1, 2 or 3;<br><br> Ra and Ra independently are H or C]_2alkyl, with the proviso that when one of Ra or Ra is H, the other is Cj.2alkyl; or together are (CH2&gt;2-3 forming a 5- or 6-membered ring; and<br><br> Ar and Het are as hereinbefore defined;<br><br> or a pharmaceutically acceptable salt thereof.<br><br> 30. A compound of the formula (I) as defined in claim 1, substantially as hereinbefore described in any of the foregoing Examples 1 to 130.<br><br> 31. A process for preparing a compound of the formula (I) as defined in claim 1, substantially as hereinbefore described with particular reference to any one of the foregoing Examples 1 to 130<br><br> A compound according to formula (VI):<br><br> R R<br><br> ii °r3<br><br> \ \ ^ORa o<br><br> (VI)<br><br> -70-<br><br> END<br><br> </p> </div>
NZ337889A 1997-05-06 1998-05-06 Cysteine Protease inhibitors of the Papain superfamily comprising cathepsin K protease inhibitors NZ337889A (en)

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