WO1998050534A1 - Protease inhibitors - Google Patents

Protease inhibitors Download PDF

Info

Publication number
WO1998050534A1
WO1998050534A1 PCT/US1998/009192 US9809192W WO9850534A1 WO 1998050534 A1 WO1998050534 A1 WO 1998050534A1 US 9809192 W US9809192 W US 9809192W WO 9850534 A1 WO9850534 A1 WO 9850534A1
Authority
WO
WIPO (PCT)
Prior art keywords
amino
pyrrolidine
leucinyl
benzyl
methyl
Prior art date
Application number
PCT/US1998/009192
Other languages
French (fr)
Inventor
Robert W. Marquis
Yu Ru
Daniel F. Veber
Original Assignee
Smithkline Beecham Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Smithkline Beecham Corporation filed Critical Smithkline Beecham Corporation
Priority to CA002289010A priority Critical patent/CA2289010A1/en
Priority to PL98336625A priority patent/PL336625A1/en
Priority to BR9808502-6A priority patent/BR9808502A/en
Priority to AU72885/98A priority patent/AU7288598A/en
Priority to JP54841898A priority patent/JP2001525809A/en
Priority to HU0001285A priority patent/HUP0001285A3/en
Priority to EP98920274A priority patent/EP0991753A4/en
Priority to US09/423,325 priority patent/US6369077B1/en
Priority to IL13166198A priority patent/IL131661A0/en
Publication of WO1998050534A1 publication Critical patent/WO1998050534A1/en
Priority to NO995433A priority patent/NO995433L/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/99—Enzyme inactivation by chemical treatment
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • This invention relates to novel protease inhibitors, particularly inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K.
  • Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
  • 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 al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 1251 1-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132. 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 of Biochemistry and Molecular Biology).
  • 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.
  • elevated levels of these enzymes in the body can result in pathological conditions leading to disease.
  • cathepsins have been implicated in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia fusiculata; as well as in schistosomiasis malaria, tumor metastasis, metachromatic leukodystrophy, muscular dystrophy, amytrophy, and the like. See International
  • Bone is composed of a protein matrix in which spindle- or plate-shaped 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, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein.
  • Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
  • 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 (i.e., resorbing) surface.
  • 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.
  • osteoblasts lay down a new protein matrix that is subsequently mineralized.
  • 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.
  • this leads to weakening of the bone and may result in increased fracture risk with minimal trauma.
  • 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 disease.
  • Cathepsin K levels have also been demonstrated to be elevated in chondroclasts of osteoarthritic synovium.
  • 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 matrix.
  • selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases.
  • 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.
  • An object of the present invention is to provide protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases.
  • this invention provides a compound according to formula (I).
  • this invention provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier.
  • this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K.
  • the compounds of this invention are especially useful for 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.
  • the present invention provides compounds of formula (I): wherein:
  • Y is Ar or NRiR 2 ;
  • R 1 is R", R"C(0), R"C(S), R"S0 2 , R" ⁇ C(0), R"R'NC(0), or R"R'NC(S);
  • R 2 is H, Ci . ⁇ alkyl, C2-6alkenyl, Ar-C()-6alkyl, or Het-Cr j ⁇ alkyl;
  • R 4 is H, C ⁇ _ 6 alkyl, C 2 _6alkenyl, Ar-CQ-6alkyl, or Het-C 0 -6alkyl;
  • R 5 is , Ar-Co-6alkyl, Het-C 0 -6alkyl, adamantyl-C(O)-,
  • R 6 is R", R"C(0), R"C(S), R"S0 2 , R"0C(0), R"R'NC(0), R"R NC(S),or R"OC(0)NR CH(R*)C(0);
  • R is H, Cj.galkyl, C2-6alkenyl, C .gcycloalkyl-Co- ⁇ -alkyl, Ar-Cg-galkyl, Het-CQ-6alkyl; each R independently is H, Cj-galkyl, C2-galkenyl, Ar-C ⁇ -6alkyl, or Het-C 0 -6alkyl; each R independently is Ci .galkyl, C3_6cycloalkyl-Co_6-alkyl, Ar-C ⁇ -6 a lkyl, or Het-C ⁇ - ⁇ alkyl;
  • R'" is H, Cj.galkyl, C ⁇ .gcycloalkyl-C ⁇ - ⁇ alkyl, Ar-Co_6al yl, or Het-Cg- ⁇ alkyl; Z is C(O) or CH 2 ; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
  • the present invention provides compounds of formula (la): wherein:
  • R 1 is R", R"C(0), R"C(S), R"S0 2 , R"0C(0), R"R NC(0), or R"R'NC(S);
  • R 2 is H, Ci . alkyl, C2-6 a lkenyl, Ar-C ⁇ -6alkyl, or Het-Co_6alkyl;
  • R 4 is H, C1.galkyl, C2_6alkenyl, Ar-C ⁇ -6alkyl, or Het-CQ-6alkyl;
  • R 5 is , Ar-Co-6alkyl, Het-C 0 -6alkyl, adamantyl-C(O)-, Ar-C(O)-, or Het-C(O)-;
  • R 6 is R", R"C(0), R"C(S), R"S0 2 , R"0C(0), R"R NC(0), R"R NC(S),or R" ⁇ C(0)NR CH(R*)C(0);
  • R is H, Cj.galkyl, C2-6alkenyl, C3_6cycloalkyl-Cn_6-alkyl, Ar-C Q -6 l yl, Het-Co_6alkyl; each R independently is H, Ci .galkyl, C2-6alkenyl, Ar-C ⁇ -6 a lkyl, or Het-Cn_6alkyl; each R independently is Cj.galkyl, C3_gcycloalkyl-C Q -g-alkyl, Ar-C ⁇ -6alkyl, or Het-Cn.galkyl;
  • R'" is H, Cj.galkyl, C3_6cycloalkyl-Cn-6alkyl, Ar-Co-6alkyl, or Het-Co_6alkyl; Z is C(O) or CH 2 ; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
  • the present invention includes all hydrates, solvates, complexes and prodrugs of 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 enantiomers and diastereomers, are intended to be covered herein.
  • Inventive compounds containing a chiral center may be used as a 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.
  • both the cis (72) and trans (E) isomers are within the scope of this invention.
  • compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
  • R 4 and R'" are each H and R ⁇ is Ci .galkyl or C2-6 a lkenyl.
  • R ⁇ is i-butyl.
  • R-> is benzyl or
  • R' is H
  • R 7 is C ⁇ -galkyl, preferably i-butyl
  • v is R" ⁇ C(0), wherein R" is benzyl
  • Z is CH 2 .
  • Y is NR J R 2 , in which R 2 is H and R 1 is R"C(0) or R"OC(0), and R" in said R! group is Ci .galkyl, Ar-Cn-6alkyl or Het-Cn-6alkyl, and, most preferably, R is tert-butyl,
  • n is 1 or 2.
  • n is 1.
  • the formula (la) compound of this invention is a compound of formula (lb):
  • the formula (la) compound of this invention is a compound of formula (Ic):
  • Specific representative compounds of this invention are: 3-[[N ⁇ -(2-quinolinecarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; l-benzyl-3-[[N ⁇ -(2-quinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine;
  • this invention provides novel intermediates useful in the preparation of formula (I) compounds represented by the formula (II):
  • R 4 is H, Cj.galkyl, C 2 _6alkenyl, Ar-Co-6alkyl, or Het-C 0 _6alkyl;
  • R 5 is R , Ar-Co-6alkyl, Het-C 0 _6alkyl, adamantyl-C(O)-,
  • R 6 is R", R"C(0), R"C(S), R"S0 2 , R"0C(0), R"R'NC(0), R"R NC(S),or R"OC(0)NR CH(R*)C(0);
  • R is H, Cj.galkyl, C2_6alkenyl, C3_6cycloalkyl-Co-6-al yl, Ar-Co-6alkyl, Het-C 0 -6alkyl; each R independently is H, Ci -galkyl, C2-6 a -kenyl, Ar-C ⁇ -6 a lkyl, or Het-Co-6alkyl; each R independently is Cj.galkyl, C3_6cycloalkyl-Co_6-alkyl, Ar-C ⁇ -6alkyl, or Het-Co-6alkyl; R'" is H, Ci .galkyl, C3_6cycloalkyl-Cn-6al yl, Ar-Co-6alkyl, or Het-Co-6alkyl;
  • Z is C(O) or CH 2 ; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
  • amino acid refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine.
  • C ⁇ _6alkyl as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof.
  • Any C]_6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R') , C(0)N(R')2, carbamyl or C ⁇ _- ⁇ alkyl, where R' is H or C ⁇ -6alkyl.
  • C 0 alkyl means that no alkyl group is present in the moiety.
  • Ar-Cnalkyl is equivalent to Ar.
  • C3_6cycloalkyl as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
  • 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 the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
  • C2-6alkynyl 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 acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
  • Halogen or "halo" means F, Cl, Br, and I.
  • Ar or aryl means unsubstituted phenyl or naphthyl; or phenyl or naphthyl substituted by one or more of Ph-Cn-6alkyl, Het-Co- ⁇ alkyl, Cj.galkoxy, Ph-Cn.
  • each R independently is H, C j.galkyl, Ar-Cn-6alkyl, or Het-Co_galkyl; or phenyl or naphthyl substituted by one to three moieties selected from C ⁇ -4alkyl, OR', N(R') 2 , SR', CF 3 , NO 2 , CN, CO 2 R', CON(R'), F, Cl, Br and I, or substituted by a methylenedioxy group.
  • Het or “heterocyclic” or “heteroaryl” 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 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 C ⁇ _4alkyl, OR', N(R 2 , SR', CF 3 , N0 2 , CN, C0 2 R', CON(R , F, Cl, Br and I, where R' is as defined hereinbefore.
  • heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyrany
  • Het also means any heterocyclic moiety encompassed by the above definition of Het which is aromatic in character, e.g., pyridinyl, quinolinyl, isoquinolinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, furyl, thienyl, benzoxazolyl, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-napthyridinyl, 1,6- napthyridinyl, 1,7- napth
  • 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
  • Cbz or CBZ refers to the benzyloxycarbonyl radical.
  • DCC refers to dicyclohexylcarbodiimide
  • DMAP is 2,6-dimethylaminopyridine
  • EDC or EDCI refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide.
  • HOBT or HOBt refers to 1- hydroxybenzotriazole
  • DMF refers to dimethyl formamide
  • BOP refers to benzotriazol- l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate
  • DMAP is dimethylaminopyridine
  • DIEA refers to di-isopropylethylamine
  • Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide
  • NMM is N- methylmorpholine
  • TFA refers to trifluoroacetic acid
  • TFAA refers to trifluoroacetic anhydride
  • KHMDS refers to potassium hexamethyldisilazide
  • THF refers to tetrahydrofuran.
  • Jones reagent is a solution of chromium trioxide
  • R SO2CI in which R is as defined in formula (I) of claim 1, in the presence of base; and thereafter removing any protecting groups and optionally forming a pharmaceutically acceptable salt.
  • 3-Scheme-l may be coupled with an acid using EDC and HOBT in the presence of a base, such as N-methylmorpholine or triethylamine, in an aprotic solvent, such as dichloromethane, to yield 4-Scheme- 1.
  • the protecting group of 4-Scheme-l may be removed with strong acid, such as hydrogen chloride, in ethyl acetate or ether or dioxane and methanol to afford 5-Scheme-l .
  • Coupling of the amine salt 5-Scheme-l may be effected with an acid in the presence of EDC, HOBt and a base, such as N-methylmorpholine, to yield 6-Scheme-l .
  • the 5 ⁇ Scheme- 1 salt may also be converted to the sulphonamide derivative by treatment with a sulphonyl chloride in the presence of a base, such as triethylamine, in an aprotic solvent, such as dichloromethane.
  • the starting materials used herein are commercially available amino acids 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. I- VI (published by Wiley-Interscience). 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-Nerlag, 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.
  • amino 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 amino protecting group with another moiety are well known.
  • Acid addition salts 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, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable.
  • Cationic 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 organic amine.
  • Cations such as Li + , Na + , K + , Ca ++ , Mg ++ and NH4 + are specific examples of cations present in pharmaceutically acceptable salts.
  • Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts.
  • This invention also provides a pharmaceutical composition which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of formula (I) may be used in the manufacture of a medicament.
  • compositions of the compounds of formula (I) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration.
  • Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use.
  • the liquid formulation may be a buffered, isotonic, aqueous solution.
  • 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 contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
  • 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 carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • Liquid carriers include syrup, peanut oil, olive oil, saline and water.
  • the carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax.
  • the amount of solid carrier varies 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 compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier 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 p.o. or filled into a soft gelatin capsule.
  • 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.
  • 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.
  • the present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, 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.
  • Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
  • 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 of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, 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, 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 carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, 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.
  • diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata;
  • 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 (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • a compound of formula (I) alone or in combination with other inhibitors of bone resorption, such as bisphosphonates (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin.
  • treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone may be used to prevent bone loss or to increase bone mass.
  • parenteral administration of a compound of formula (I) is preferred.
  • 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 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 which 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.
  • the compounds of this invention may also be administered orally to the patient, 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.
  • a pharmaceutical composition containing the compound is administered at an oral dose of between about 0.1 to about 50 mg/kg in a manner consistent with the condition of the patient.
  • the oral dose would be about 0.5 to about 20 mg/kg.
  • the compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
  • [AMC] v ss t + (vo - v ss ) [1 - exp (-k 0 b s t)] 2 k 0 bs (2)
  • any compound with a K j of less than 50 micromolar to be a potential lead compound.
  • the compounds used in the method of the present invention have a Kj value of less than 1 micromolar.
  • said compounds have a K j 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.
  • the cells were washed x2 with cold RPMI- 1640 by centrifugation (1000 rpm, 5 min 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.
  • Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse 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.
  • the beads were mixed with the cells and the suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were 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. The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample.
  • the cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xl0 4 /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 centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL).
  • the tubes were incubate at 37°C for 30 min. 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 h. Each treatment was screened in quadruplicate. 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 h. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C. The slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
  • 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 ILM21 W confocal microscope.
  • Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer.
  • CDCI3 is deuteriochloroform
  • DMSO-d ⁇ is hexadeuteriodimethylsulfoxide
  • CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane.
  • Example 8(b) the title compound was produced: 533 MS(ES+) (MH + ).
  • Example 8(c) the title compound was prepared: MS(ES+) 433 (MH + ).
  • Example 14(b) the title compound was produced: MS(ES+) 390.3 (MH + ).
  • N-methoxy-N-methylamine hydrochloride (0.980 g, 10.0 mmol) in DMF (25 mL) was added N-methylmorpholine (1.21 mL, 11.0 mmol), HOBt (1.50 g, 11.1 mmol), 3-(2-pyridyl)-phenylacetic acid (2.36 g, 11.1 mmol), and EDC (2.13 g, 1 1.1 mmol).
  • the reaction was stirred overnight whereupon it was poured into a rapidly-stirred mixture of 150 mL each of EtOAc, 10% NaHCC.3, and brine.
  • Example 22(c) The compound of Example 22(c) (440 mg, 1.2 mmol) was dissolved in 4.0 N HCl in dioxane (20 mL) and stirred at room temperature for 30 min. The solution was concentrated to a white solid and dried under high vacuum for 30 min. To a stirred solution of the residue in DMF (10 mL) was added N-methylmorpholine (400 uL, 3.6 mmol), HOBt (245.6 mg, 1.8 mmol), Boc-Leucine hydrate (449.1 mg, 1.8 mmol), and EDC (352.0 mg, 1.8 mmol). The reaction was stirred overnight whereupon it was partitioned between 50 mL each of EtOAc, 10% Na2C03, and brine.
  • N-methylmorpholine 400 uL, 3.6 mmol
  • HOBt 245.6 mg, 1.8 mmol
  • Boc-Leucine hydrate 449.1 mg, 1.8 mmol
  • EDC 352.0 mg, 1.8
  • Example 28 (a) The compound of Example 28 (a) (4.6 g) was dissolved in 4.0 N HCl in dioxane (100 L) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 2 h to give the title compound: MS (ES+) (MH+) 249.1.
  • Example 50 Following the procedure of Example 45(e), except substituting indole-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 576.4.
  • Example 50 Following the procedure of Example 45(e), except substituting indole-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 576.4.
  • Example 60(a) l-(2,2,2-trichloroethylcarbonyl)-(3S)-[[N ⁇ -(tert-butoxycarbonyl)-L-leucinyl]amino]- pyrrolidine
  • the compound of Example 60(a) (23.9 g) was dissolved in 4.0 N HCl in dioxane (200 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and stored under high vacuum for 30 min.
  • N-methylmorpholine 8.90 mL, 80.9 mmol
  • HOBt 10.88 g, 80.5 mmol
  • Boc-Leucine hydrate 20.09 g, 80.6 mmol
  • EDC 15.44 g, 80.6 mmol
  • Example 60(d) The compound of Example 60(d) (1.57 g, 3.4 mmol) was dissolved in 4.0 N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 30 min to give the title compound: MS (ES+) (MH+) 366.4.
  • Example 67 The compound of Example 67 (1.13 g, 2.8 mmol) was dissolved in 4.0 N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 30 min to give the title compound: MS (ES+) (MH+) 304.3. b) l-(2-phenyl)ethyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
  • Example 74(a) the title compound was prepared: MS (ES+) (MH+) 536.3.
  • Example 79 The compound of Example 79 (508 mg, 1.25 mmol) was dissolved in 4.0 N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 30 min to give the title compound: MS (ES+) (MH+) 308.3. b) l-(4-fluoro)benzyl-(3S)-t[N ⁇ -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
  • Example 82 The compound of Example 82 (512 mg, 1.23 mmol) was dissolved in 4.0 N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 30 min to give the title compound: MS (ES+) (MH+) 315.4.
  • Example 84 Following the procedure of Example 61(b), except substituting the compound of Example 83(a), the title compound was prepared: MS (ES+) (MH+) 469.5.
  • Example 84 Following the procedure of Example 61(b), except substituting the compound of Example 83(a), the title compound was prepared: MS (ES+) (MH+) 469.5.
  • Example 84
  • Example 84 The compound of Example 84 (a) (11.0 g, 39.8 mmol) was dissolved in 4.0 N HCl in dioxane (300 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum. To a stirred solution of the residue in DMF (100 mL) was added N-methylmorpholine (13.1 mL, 119.1 mmol), HOBt (8.07 g, 59.7 mmol), Boc- Leucine hydrate (14.89 g, 59.7 mmol), and EDC (11.44 g, 59.7 mmol).
  • Example 84 The compound of Example 84 (b) (11.6 g, 29.8 mmol) was dissolved in 4.0 N HCl in dioxane (300 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum to give the title compound: MS (ES+) (MH+) 290.4.
  • Example 103 b) l-(2,2,2-trichloroethyl)carbonyl-(3S)-[[N -(tert-butoxycarbonyl)-L-leucinyl]amino]- pyrrolidine
  • the compound of Example 103 (a) (19.9 g) was dissolved in 4.0 N HCl in dioxane (400 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and stored under high vacuum.
  • N- methylmorpholine 8.90 mL, 80.9 mmol
  • HOBt 10.88 g, 80.5 mmol
  • Boc-Leucine hydrate 20.10 g, 80.6 mmol
  • EDC 15.45 g, 80.7 mmol
  • Example 103 (24.5 g) was dissolved in 4.0 N HCl in dioxane (500 L) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum to give the title compound: MS (ES+) (MH+) 375.
  • Example 104 To a stirred solution of the compound of Example 103(e) (106.5 mg, 0.3 mmol) in CH2CI2 (1 mL) was added 4-acetamidobenzaldehyde (59.7 mg, 0.37 mmol). The reaction was stirred 2 h whereupon Na(OAc)3 (140.0 mg, 0.66 mmol) was added. After stirring overnight, the reaction mixture was diluted with CHCI3 (100 mL) and washed with 5% NaHC ⁇ 3 and brine, then dried (MgS ⁇ 4), filtered, and concentrated. Column chromatography (silica gel, 5:95 MeOH : EtOAc) gave 105.1 mg of the title compound: MS (ES+) (MH+) 501.4.
  • Example 104 To a stirred solution of the compound of Example 103(e) (106.5 mg, 0.3 mmol) in CH2CI2 (1 mL) was added 4-acetamidobenzaldehyde (59.7 mg, 0.37 mmol).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Rheumatology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Orthopedic Medicine & Surgery (AREA)
  • Molecular Biology (AREA)
  • Biophysics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Microbiology (AREA)
  • Immunology (AREA)
  • Pain & Pain Management (AREA)
  • General Engineering & Computer Science (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

This invention relates to compounds of formula (I) wherein: Y is Ar or NR1R2; R1 is R'', R''C(O), R''C(S), R''SO¿2?, R''OC(O), R''R'NC(O), or R''R'NC(S); R?2¿ is H, C¿1-6?alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl; R?3¿ is H, C¿2-6?alkenyl, C2-6alkynyl, Het, Ar or C1-6alkyl optionally substituted by OR', SR', NR'2, N(R')C(O)OR'', CO2R', CO2NR'2, N(C=NH)NH2, Het or Ar; R?4¿ is H, C¿1-6?alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl; R?5¿ is (a), Ar-C¿0-6?alkyl, Het-C0-6alkyl, adamantyl-C(O)-, Ar-C(O)-, Het-C(O)-; R?6¿ is R'', R''C(O), R''C(S), R''SO¿2?, R''OC(O), R''R'NC(O), R''R'NC(S), or R''OC(O)NR'CH(R*)C(O); R?7¿ is C¿3-6?cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, Het-C0-6alkyl, Ar-C0-6alkoxy, Het-C0-6alkoxy, or C1-6alkyl optionally substituted by OR', SR', NR'2, N(R')C(O)OR'', CO2R', CO2NR'2, N(C=NH)NH2, Het or Ar; R* is H, C1-6alkyl, C2-6alkenyl, C3-6cycloalkyl-C0-6-alkyl, Ar-C0-6alkyl, Het-C0-6alkyl; each R' independently is H, C1-6alkyl, C2-6alkenyl, Ar-C0-6alkyl, or Het-C0-6alkyl; each R'' independently is C1-6alkyl, C3-6cycloalkyl-C0-6-alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl; R''' is H, C1-6alkyl, C3-6cycloalkyl-C0-6alkyl, Ar-C0-6alkyl, or Het-C0-6alkyl; Z is C(O) or CH2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof, which are inhibitors of cysteine proteases, particularly cathepsin K, and are useful in the treatment of diseases in which inhibition of bone loss is a factor.

Description

PROTEASE INHIBITORS
Field of the Invention
This invention relates to novel protease inhibitors, particularly inhibitors of cysteine and serine proteases, more particularly compounds which inhibit cysteine proteases, even more particularly compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly compounds which inhibit cysteine proteases of the cathepsin family, most particularly compounds which inhibit cathepsin K. Such compounds are particularly useful for treating diseases in which cysteine proteases are implicated, especially diseases of excessive bone or cartilage loss, e.g., osteoporosis, periodontitis, and arthritis.
Background of the Invention
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 al., (1996) J. Biol. Chem. 271, 12517-12524; Drake, F.H., et al., (1996) J. Biol. Chem. 271, 1251 1-12516; Bromme, D., et al., (1996) J. Biol. Chem. 271, 2126-2132. 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 of Biochemistry and Molecular Biology).
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 been implicated in various disease states, including but not limited to, infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei brucei, and Crithidia 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 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 been implicated in the pathogenesis of gingivitis. Potempa, J., et al. (1994) Perspectives in Drug Discovery and Design, 2, 445-458.
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 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, including osteocalcin, proteoglycans, osteopontin, osteonectin, thrombospondin, fibronectin, and bone sialoprotein. Skeletal bone undergoes remodeling at discrete foci throughout life. These foci, or remodeling units, undergo a cycle consisting of a bone resorption phase followed by a phase of bone replacement.
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 (i.e., resorbing) 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, 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.
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 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 matrix. Thus, selective inhibition of cathepsin K may also be useful for treating certain neoplastic diseases. 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.
Summary of the Invention
An object of the present invention is to provide protease inhibitors, particularly such inhibitors of cysteine and serine proteases, more particularly such compounds which inhibit cysteine proteases, even more particularly such compounds which inhibit cysteine proteases of the papain superfamily, yet more particularly such compounds which inhibit cysteine proteases of the cathepsin family, most particularly such compounds which inhibit cathepsin K, and which are useful for treating diseases which may be therapeutically modified by altering the activity of such proteases. Accordingly, in the first aspect, this invention provides a compound according to formula (I).
In another aspect, this invention provides a pharmaceutical composition comprising a compound according to formula (I) and a pharmaceutically acceptable carrier. In yet another aspect, this invention provides a method of treating diseases in which the disease pathology may be therapeutically modified by inhibiting proteases, particularly cysteine and serine proteases, more particularly cysteine proteases, even more particularly cysteine proteases of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, most particularly cathepsin K. In a particular aspect, the compounds of this invention are especially useful for 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.
Detailed Description of the Invention
The present invention provides compounds of formula (I):
Figure imgf000006_0001
wherein:
Y is Ar or NRiR2;
R1 is R", R"C(0), R"C(S), R"S02, R"θC(0), R"R'NC(0), or R"R'NC(S);
R2 is H, Ci .βalkyl, C2-6alkenyl, Ar-C()-6alkyl, or Het-Crj^alkyl;
R3 is H, C2-6alkenyl, C2-6alkynyl, Het, Ar or Ci-galkyl optionally substituted by OR', SR', NR'2, N(R')C(0)OR", C02R', C02NR'2, N(C=NH)NH2, Het or Ar;
R4 is H, Cι _6alkyl, C2_6alkenyl, Ar-CQ-6alkyl, or Het-C0-6alkyl;
R5 is
Figure imgf000006_0002
, Ar-Co-6alkyl, Het-C0-6alkyl, adamantyl-C(O)-,
Ar-C(O)-, or Het-C(O)-;
R6 is R", R"C(0), R"C(S), R"S02, R"0C(0), R"R'NC(0), R"R NC(S),or R"OC(0)NR CH(R*)C(0);
R^ is C3.6cycloalkyl-Co_6alkyl, Ar-Cg-όalkyl, Het-Cn-όalkyl, Ar-Cg-όalkoxy, Het-Co-6alkoxy, or Cι _6alkyl optionally substituted by OR', SR', NR'2, N(R')C(0)OR", C02R', C02NR'2, N(C=NH)NH2, Het or Ar;
R is H, Cj.galkyl, C2-6alkenyl, C .gcycloalkyl-Co-ό-alkyl, Ar-Cg-galkyl, Het-CQ-6alkyl; each R independently is H, Cj-galkyl, C2-galkenyl, Ar-Cθ-6alkyl, or Het-C0-6alkyl; each R independently is Ci .galkyl, C3_6cycloalkyl-Co_6-alkyl, Ar-Cθ-6alkyl, or Het-Cø-βalkyl;
R'" is H, Cj.galkyl, Cβ.gcycloalkyl-Cø-όalkyl, Ar-Co_6al yl, or Het-Cg-όalkyl; Z is C(O) or CH2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
Preferably, the present invention provides compounds of formula (la):
Figure imgf000007_0001
wherein:
R1 is R", R"C(0), R"C(S), R"S02, R"0C(0), R"R NC(0), or R"R'NC(S);
R2 is H, Ci . alkyl, C2-6alkenyl, Ar-Cθ-6alkyl, or Het-Co_6alkyl;
R3 is H, C2-6alkenyl, C2-6alkynyl, Het, Ar or Ci - alkyl optionally substituted by OR', SR', NR'2, N(R')C(0)ORπ, C02R', C02NR'2, N(C=NH)NH2, Het or Ar;
R4 is H, C1.galkyl, C2_6alkenyl, Ar-Cθ-6alkyl, or Het-CQ-6alkyl;
R5 is
Figure imgf000007_0002
, Ar-Co-6alkyl, Het-C0-6alkyl, adamantyl-C(O)-, Ar-C(O)-, or Het-C(O)-;
R6 is R", R"C(0), R"C(S), R"S02, R"0C(0), R"R NC(0), R"R NC(S),or R"θC(0)NR CH(R*)C(0);
R7 is C3_6cycloalkyl-Co-6 lkyl, Ar-Co_6alkyl, Het-Cg-όalkyl, Ar-Cg-όalkoxy, Het-C0_6alkoxy, or Cι-6alkyl optionally substituted by OR', SR', NR'2, N(R')C(0)OR", C02R', C02NR'2, N(C=NH)NH2, Het or Ar;
R is H, Cj.galkyl, C2-6alkenyl, C3_6cycloalkyl-Cn_6-alkyl, Ar-CQ-6 l yl, Het-Co_6alkyl; each R independently is H, Ci .galkyl, C2-6alkenyl, Ar-Cθ-6alkyl, or Het-Cn_6alkyl; each R independently is Cj.galkyl, C3_gcycloalkyl-CQ-g-alkyl, Ar-Cθ-6alkyl, or Het-Cn.galkyl;
R'" is H, Cj.galkyl, C3_6cycloalkyl-Cn-6alkyl, Ar-Co-6alkyl, or Het-Co_6alkyl; Z is C(O) or CH2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
The present invention includes all hydrates, solvates, complexes and prodrugs of 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 enantiomers and diastereomers, are intended to be covered herein. Inventive compounds containing a chiral center may be used as a 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. In cases in which compounds have unsaturated carbon-carbon double bonds, both the cis (72) and trans (E) isomers are within the scope of this invention. In cases wherein compounds may exist in tautomeric forms, such as keto-enol tautomers, each tautomeric form is contemplated as being included within this invention whether existing in equilibrium or predominantly in one form.
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):
Suitably, R4 and R'" are each H and R^ is Ci .galkyl or C2-6alkenyl. Preferably, R^ is i-butyl. Suitably, R-> is benzyl or
Figure imgf000008_0001
, in which R' is H, R7 is Cι -galkyl, preferably i-butyl, v is R"θC(0), wherein R" is benzyl, and Z is CH2.
Suitably, Y is NRJR2, in which R2 is H and R1 is R"C(0) or R"OC(0), and R" in said R! group is Ci .galkyl, Ar-Cn-6alkyl or Het-Cn-6alkyl, and, most preferably, R is tert-butyl,
Figure imgf000008_0002
Suitably, n is 1 or 2. Preferably, n is 1.
In one particular embodiment, the formula (la) compound of this invention is a compound of formula (lb):
Figure imgf000009_0001
In another embodiment, the formula (la) compound of this invention is a compound of formula (Ic):
Figure imgf000009_0002
Specific representative compounds of this invention are: 3-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; l-benzyl-3-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine;
3-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; l-benzyl-3-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[N -(benzyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;
(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; l-benzyl-(3R)-[[Nα-(2-naphthyl)acetyl-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3R)-[[N -(2-naρhthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3R)-[[Nα-(3-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3R)-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3R)-[[Nα-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(2-naphthyl)acetyl-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(3-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[N -(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-4-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-piperidine; l-benzyl-4-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-piperidine; l-benzyl-4-[[Nα-(benzyloxycarbonyl)-L-leucinyl]amino]-piperidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[Nα-(3-isoquinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[Nα-(3-isoquinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N -(2-quinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(l-adamantanecarbonyl)-(3R)-[[Nα-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(l-adamantanecarbonyl)-(3S)-[[Nα-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]- pyrrolidine;
(3R)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(benzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)- [ [Nα-(benzothiazole-6-carbony l)-L-leuciny l]amino]- 1 - [(2S)-4-methy 1-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3R)-[[Nα-(indole-2-carbonyl)-L-leucinyl]amino]- 1 -[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(4-fluorobenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(4-methoxybenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(3,4-dichlorobenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3R)-[[Nα-(thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(4-biphenylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3R)-[[Nα-(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[N -(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl- 2-[t(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]-l- [(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(benzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [f(benzyloxycarbonyl)amino]pentyl]- pyrrolidine;
(3S)-[[Nα-(benzothiazole-6-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(indole-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[Nα-(4-fluorobenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[N -(4-methoxybenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[N -(3,4-dichlorobenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(4-biphenylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [t(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[N -(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[Nα-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[Nα-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-f[Nα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[Nα-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]- pyrrolidine;
1 -(4-pheny l)benzyl-(3S)- [ [Nα-(benzyloxycarbonyl)-L-leuciny l]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]- pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(benzofuran -2-carbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinylJamino]- pyrrolidine; l-(4-phenoxy)benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenoxy)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenoxy)benzyl-(3S)-[[Nα-(2- quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenoxy)benzyl-(3S)-[[Nα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenoxy)benzyl-(3S)-[[Nα-(benzofuran -2-carbonyl)-L-leucinyl]amino]-pyrrolidine l-(4-phenoxy)benzyl-(3S)-[[N -(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]- pyrrolidine; l-(4-fluoro)benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-fluoro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-fluoro)benzyl-(3S)-[[N -(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]- pyrrolidine; l-(4-cyano)benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-cyano)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(3-(2-dimethylaminoethoxy)-4-methoxybenzoyl)-L-leucinyl]amino]- pyrrolidine; l-(4-nitro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-(N,N-dimethylamino)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(4-methoxy)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-pyridyl)methyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-carboxymethyl)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(3,4-methylenedioxy)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(2-naphthyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-indolyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-quinolinyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-quinolinyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(l-naphthyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-quinolinyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-pyrrolyl)methyl-(3S)-f[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-pyridyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-pyridyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-nitro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-acetamido)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-cyano)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-fluoro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-phenoxy)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-chloro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-trifluoromethyl)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(3-trifluoromethyl)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(4-(3-(N,N-dimethylamino)propoxy)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L- leucinyl]amino]-pyrrolidine; l-(4-(isopropyl)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-benzofuranyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-(3-methylbenzo[b]thiophenyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L- leucinyl]amino]-pyrrolidine; l-(2-furanyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-furanyl)methyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-thiophenyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-nitro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; -(3-thiophenyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3,4-dimethoxy)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; and l-(5-nitro-3-furanyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; or a pharmaceutically acceptable salt thereof.
In yet another aspect, this invention provides novel intermediates useful in the preparation of formula (I) compounds represented by the formula (II):
Figure imgf000014_0001
wherein:
R is H, C2-6alkenyl, C2-6alkynyl, Het, Ar or Ci-galkyl optionally substituted by OR', SR', NR'2, N(RT)C(0)OR", C02R', C02NR'2, N(C=NH)NH2, Het or Ar; R4 is H, Cj.galkyl, C2_6alkenyl, Ar-Co-6alkyl, or Het-C0_6alkyl;
6/
R'
R5 is R , Ar-Co-6alkyl, Het-C0_6alkyl, adamantyl-C(O)-,
Ar-C(O)-, or Het-C(O)-;
R6 is R", R"C(0), R"C(S), R"S02, R"0C(0), R"R'NC(0), R"R NC(S),or R"OC(0)NR CH(R*)C(0);
R7 is C3_6cycloalkyl-Co-6alkyl, Ar-Cn-βalkyl, Het-Co-.6alkyl, Ar-Cø.galkoxy, Het-Co-6alkoxy, or Cι-6alkyl optionally substituted by OR', SR', NR o., N(R')C(0)OR", C02R', C02NR'2, N(C=NH)NH2, Het or Ar;
R is H, Cj.galkyl, C2_6alkenyl, C3_6cycloalkyl-Co-6-al yl, Ar-Co-6alkyl, Het-C0-6alkyl; each R independently is H, Ci -galkyl, C2-6a-kenyl, Ar-Cθ-6alkyl, or Het-Co-6alkyl; each R independently is Cj.galkyl, C3_6cycloalkyl-Co_6-alkyl, Ar-Cθ-6alkyl, or Het-Co-6alkyl; R'" is H, Ci .galkyl, C3_6cycloalkyl-Cn-6al yl, Ar-Co-6alkyl, or Het-Co-6alkyl;
Z is C(O) or CH2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
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 in Eur. J. Biochem., 158, 9 (1984). The term "amino acid" as used herein refers to the D- or L- isomers of alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. "Cι _6alkyl" as applied herein is meant to include substituted and unsubstituted methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl, pentyl, n-pentyl, isopentyl, neopentyl and hexyl and the simple aliphatic isomers thereof. Any C]_6alkyl group may be optionally substituted independently by one or two halogens, SR', OR', N(R') , C(0)N(R')2, carbamyl or Cι_-ιalkyl, where R' is H or Cι-6alkyl. C0alkyl means that no alkyl group is present in the moiety. Thus, Ar-Cnalkyl is equivalent to Ar.
"C3_6cycloalkyl" as applied herein is meant to include substituted and unsubstituted cyclopropane, cyclobutane, cyclopentane, and cyclohexane.
"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 the several isomeric pentenes and hexenes. Both cis and trans isomers are included.
"C2-6alkynyl" 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 acetylene, 1-propyne, 2-propyne, 1-butyne, 2-butyne, 3-butyne and the simple isomers of pentyne and hexyne.
"Halogen" or "halo" means F, Cl, Br, and I.
"Ar" or "aryl" means unsubstituted phenyl or naphthyl; or phenyl or naphthyl substituted by one or more of Ph-Cn-6alkyl, Het-Co-βalkyl, Cj.galkoxy, Ph-Cn. 6alkoxy, Het-C0-6alkoxy, OH, (CH2) I_6NR'R', 0(CH ) I_6NR R'; wherein each R independently is H, C j.galkyl, Ar-Cn-6alkyl, or Het-Co_galkyl; or phenyl or naphthyl substituted by one to three moieties selected from Cι-4alkyl, OR', N(R')2, SR', CF3, NO2, CN, CO2R', CON(R'), F, Cl, Br and I, or substituted by a methylenedioxy group.
As used herein "Het" or "heterocyclic" or "heteroaryl" 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 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 Cι_4alkyl, OR', N(R 2, SR', CF3, N02, CN, C02R', CON(R , F, Cl, Br and I, where R' is as defined hereinbefore. Examples of such heterocycles include piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, pyridyl, pyrazinyl, oxazolidinyl, oxazolinyl, oxazolyl, isoxazolyl, morpholinyl, thiazolidinyl, thiazolinyl, thiazolyl, quinuclidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzopyranyl, benzoxazolyl, furyl, pyranyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzoxazolyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-napthyridinyl, 1,6-napthyridinyl, 1,7- napthyridinyl, 1,8-napthyridinyl, tetrazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl. "Het" also means any heterocyclic moiety encompassed by the above definition of Het which is aromatic in character, e.g., pyridinyl, quinolinyl, isoquinolinyl, pyrrolyl, pyrazolyl, imidazolyl, pyridyl, pyrazinyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, furyl, thienyl, benzoxazolyl, oxadiazolyl, benzothiazolyl, benzoisothiazolyl, benzisoxazolyl, pyrimidinyl, cinnolinyl, quinazolinyl, quinoxalinyl, 1,5-napthyridinyl, 1,6- napthyridinyl, 1,7- napthyridinyl, 1,8- napthyridinyl, tetrazolyl, 1,2,3-triazolyl, and 1,2,4-triazolyl. 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, Cbz or CBZ refers to the benzyloxycarbonyl radical.
Certain reagents are abbreviated herein. DCC refers to dicyclohexylcarbodiimide, DMAP is 2,6-dimethylaminopyridine, EDC or EDCI refers to N-ethyl-N'(dimethylaminopropyl)-carbodiimide. HOBT or HOBt refers to 1- hydroxybenzotriazole, DMF refers to dimethyl formamide, BOP refers to benzotriazol- l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, DMAP is dimethylaminopyridine, DIEA refers to di-isopropylethylamine, Lawesson's reagent is 2,4-bis(4-methoxyphenyl)-l,3-dithia-2,4-diphosphetane-2,4-disulfide, NMM is N- methylmorpholine, TFA refers to trifluoroacetic acid, TFAA refers to trifluoroacetic anhydride, KHMDS refers to potassium hexamethyldisilazide, and THF refers to tetrahydrofuran. Jones reagent is a solution of chromium trioxide, water, and sulfuric acid well-known in the art.
Compounds of the formula (I) are generally prepared by reacting a compound of the formula (II):
Figure imgf000017_0001
(II) or a salt thereof, wherein R'", R^, R4, R^ and n are as defined in formula (I), with any reactive functional groups protected, with: (a) R C(0)C1, in which R is as defined in formula (I) of claim 1; or
(b) R C(0)OH, in which R is as defined in formula (I) of claim 1 , in the presence of EDC and HOBT; or
(c) R C(0)H, in which R is as defined in formula (I) of claim 1, followed by reduction; or
(d) R"θC(0)Cl, in which R" is as defined in formula (I) of claim 1, in the presence of base; or
(e) R SO2CI, in which R is as defined in formula (I) of claim 1, in the presence of base; and thereafter removing any protecting groups and optionally forming a pharmaceutically acceptable salt.
Compounds of the formula (I) are prepared by methods analogous to those described in Schemes 1 and 2. Scheme 1
χxx<— OxxAx N ^ NH.+CI-
H cc
3
Figure imgf000018_0001
Figure imgf000018_0002
a) PhCHO, CH2C12, NaBH(OAc)3; b) HCl, EtOAc, CH3OH; c) N-BOC-leucine, EDC, HOBt, NMM, CH2C12; d) HCl, EtOAc, CH3OH; e) quinaldic acid, EDC, HOBt, NMM, CH2C12
Compounds of the general formula (I) wherein n is 1, R^ is an alkyl group and R1 is an R'C(O) can be prepared as outlined in Scheme 1. Reductive alkylation of the commercially available amine 1 -Scheme- 1 (this material available in racemic or enantiomerically pure form) with an aldehyde, such as benzaldehyde or CBZ-leucinal, follwed by treatment with a reducing agent, such as sodium triacetoxyborohydride, affords the tertiary amine 2-Scheme-l. Removal of the protecting group by treating 7_ Scheme- 1 with a strong acid, such as hydrogen chloride, in ethyl acetate or ether or dioxane and methanol affords 3-Scheme-l . 3-Scheme-l may be coupled with an acid using EDC and HOBT in the presence of a base, such as N-methylmorpholine or triethylamine, in an aprotic solvent, such as dichloromethane, to yield 4-Scheme- 1. The protecting group of 4-Scheme-l may be removed with strong acid, such as hydrogen chloride, in ethyl acetate or ether or dioxane and methanol to afford 5-Scheme-l .
Coupling of the amine salt 5-Scheme-l may be effected with an acid in the presence of EDC, HOBt and a base, such as N-methylmorpholine, to yield 6-Scheme-l . The 5^ Scheme- 1 salt may also be converted to the sulphonamide derivative by treatment with a sulphonyl chloride in the presence of a base, such as triethylamine, in an aprotic solvent, such as dichloromethane.
Scheme 2
Figure imgf000019_0001
Figure imgf000019_0002
a) N-BOC-leucine, EDC, HOBT, NMM, CH2C1 ; b) HCl, EtOAc; c) 2-naphthoic acid, EDC, HOBT, CH2C12, NMM
Compounds of the general formula (I) wherein n is 2, R^ is a benzyl group and R' is an R'C(O) can be prepared as outlined in Scheme 1. Acylation of the commercially available 4-amino-l-benzylpiperidine (1 -Scheme- 1) with N-BOC-leucine in the presence of EDC, HOBT and N-methylmorpholine in dichloromethane afforded 2-scheme-2. Removal of the protecting group with anhydrous hydrogen chloride in ethyl acetate or ether or dioxane and methanol gave 3-Scheme-2. Acylation of the amine salt 3-Scheme-2 with a carboxylic acid as described previously afforded Λ_ Scheme-2.
The starting materials used herein are commercially available amino acids 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. I- VI (published by Wiley-Interscience). 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-Nerlag, 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.
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 & Sons, New York (1981). The term "amino 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 amino protecting group with another moiety are well known.
Acid addition salts 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, trifluoroacetic, maleic, succinic or methanesulfonic. Certain of the compounds form inner salts or zwitterions which may be acceptable. Cationic 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 organic amine.
Cations such as Li+, Na+, K+, Ca++, Mg++ and NH4+ are specific examples of cations present in pharmaceutically acceptable salts. Halides, sulfate, phosphate, alkanoates (such as acetate and trifluoroacetate), benzoates, and sulfonates (such as mesylate) are examples of anions present in pharmaceutically acceptable salts. This invention also provides a pharmaceutical composition which comprises a compound according to formula (I) and a pharmaceutically acceptable carrier, diluent or excipient. Accordingly, the compounds of formula (I) may be used in the manufacture of a medicament. Pharmaceutical compositions of the compounds of formula (I) prepared as hereinbefore described may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier 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 contained in a metered dose inhaler or nebulizer for insufflation. It may be desirable to add excipients such as polyvinylpyrrolidone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride or sodium citrate.
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 carriers include starch, lactose, calcium sulfate dihydrate, terra alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin. Liquid carriers include syrup, peanut oil, olive oil, saline and water. The carrier may also include a sustained release material such as glyceryl monostearate or glyceryl distearate, alone or with a wax. The amount of solid carrier varies 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 compressing, 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 p.o. or filled into a soft gelatin capsule.
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.
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.
The present compounds are useful for treating diseases in which cysteine proteases are implicated, including infections by pneumocystis carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, 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. Metastatic neoplastic cells also typically express high levels of proteolytic enzymes that degrade the surrounding matrix, and certain tumors and metastatic neoplasias may be effectively treated with the compounds of this invention.
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 of the papain superfamily, yet more particularly cysteine proteases of the cathepsin family, which methods comprise administering to an animal, particularly a mammal, 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, 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 carinii, trypsanoma cruzi, trypsanoma brucei, and Crithidia fusiculata; as well as in schistosomiasis, malaria, tumor metastasis, 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.
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 (i.e., allendronate), hormone replacement therapy, anti-estrogens, or calcitonin. In addition, treatment with a compound of this invention and an anabolic agent, such as bone morphogenic protein, iproflavone, may be used to prevent bone loss or to increase bone mass.
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 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 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 which 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.
The compounds of this invention may also be administered orally to the patient, 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 in a manner consistent with the condition of the patient. Preferably the oral dose would be about 0.5 to about 20 mg/kg.
No unacceptable toxicological effects are expected when compounds of the present invention are administered in accordance with the present invention.
The compounds of this invention may be tested in one of several biological assays to determine the concentration of compound which is required to have a given pharmacological effect.
Determination of cathepsin K proteolytic catalytic activity
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 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 uM 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 (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.
Inhibition studies
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 whose progress curves were linear, apparent inhibition constants (Ki app) were calculated according to equation 1 (Brandt et al, Biochemitsry, 1989, 28, 140):
v = VmA 2 [Ka(l + 1/Kit app) +A] ( 1 ) where v is the velocity of the reaction with maximal velocity Vm , A is the concentration of substrate with Michaelis constant of Ka, and / 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:
[AMC] = vss t + (vo - vss) [1 - exp (-k0bst)] 2 k0bs (2)
where [AMC] is the concentration of product formed over time t, vo is the initial reaction velocity and vss is the final steady state rate. Values for k0Ds were then analyzed as a linear function of inhibitor concentration to generate an apparent second order rate constant (k0bs / inhibitor concentration or kDbs / [I]) describing the time- 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).
One skilled in the art would consider any compound with a Kj of less than 50 micromolar to be a potential lead compound. Preferably, the compounds used in the method of the present invention have a Kj value of less than 1 micromolar. Most preferably, said compounds have a Kj 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.
Human Osteoclast Resorption Assay
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 centrifugation (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 min on ice The cell suspension was mixed frequently.
The cells were washed x2 with cold RPMI- 1640 by centrifugation (1000 rpm, 5 min 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.
Sufficient magnetic beads (5 / mononuclear cell), coated with goat anti-mouse 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.
The beads were mixed with the cells and the suspension was incubated for 30 min on ice. The suspension was mixed frequently. The bead-coated cells were 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. The osteoclasts were enumerated in a counting chamber, using a large-bore disposable plastic pasteur pipette to charge the chamber with the sample. The cells were pelleted by centrifugation and the density of osteoclasts adjusted to 1.5xl04/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 centrifugation. To each tube 3 mL of the appropriate treatment was added (diluted to 50 uM in the EMEM medium). Also included were appropriate vehicle controls, a positive control (87MEM1 diluted to 100 ug/mL) and an isotype control (IgG2a diluted to 100 ug/mL). The tubes were incubate at 37°C for 30 min. 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 h. Each treatment was screened in quadruplicate. 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 h. The slices were then washed in phosphate buffered saline and fixed in 2% glutaraldehyde (in 0.2M sodium cacodylate) for 5 min., following which they were washed in water and incubated in buffer for 5 min at 37°C. The slices were then washed in cold water and incubated in cold acetate buffer / fast red garnet for 5 min at 4°C. Excess buffer was aspirated, and the slices were air dried following a wash in water.
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 ILM21 W confocal microscope.
Examples Nuclear magnetic resonance spectra were recorded at either 250 or 400 MHz using, respectively, a Bruker AM 250 or Bruker AC 400 spectrometer. CDCI3 is deuteriochloroform, DMSO-dβ is hexadeuteriodimethylsulfoxide, and CD3OD is tetradeuteriomethanol. Chemical shifts are reported in parts per million (d) downfield from the internal standard tetramethylsilane. Abbreviations for NMR data are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of doublets, dt = doublet of triplets, app = apparent, br = broad. J indicates the NMR coupling constant measured in Hertz. Continuous wave infrared (IR) spectra were recorded on a Perkin-Elmer 683 infrared spectrometer, and Fourier transform infrared (FTIR) spectra were recorded on a Nicolet Impact 400 D infrared spectrometer. IR and FTIR spectra were recorded in transmission mode, and band positions are reported in inverse wavenumbers (cm" X Mass spectra were taken on either VG 70 FE, PE Syx API III, or VG ZAB HF instruments, using fast atom bombardment (FAB) or electrospray (ES) ionization techniques. Elemental analyses were obtained using a
Perkin-Elmer 240C elemental analyzer. Melting points were taken on a Thomas-Hoover melting point apparatus and are uncorrected. All temperatures are reported in degrees Centigrade (°C).
Analtech Silica Gel GF and E. Merck Silica Gel 60 F-254 thin layer plates were used for thin layer chromatography. Both flash and gravity chromatography were carried out on E. Merck Kieselgel 60 (230-400 mesh) silica gel.
Where indicated, certain of the materials were purchased from the Aldrich Chemical Co., Milwaukee, Wisconsin, Chemical Dynamics Corp., South Plainfield, New Jersey, and Advanced Chemtech, Louisville, Kentucky. Unless otherwise indicated, all of the starting materials were obtained from commercial sources. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the 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.
Example 1
Preparation of 3-. fN 2-quinolinecarbonyl)-L-leucinyllaminol-l-. (2S)-4-methyl-2- ^, (benzyloxycarbonyl)amino^pentyll-pyrrolidine
a.) 3-[(tert-butoxycarbonyl)amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
To a solution of 3-(tert-butoxycarbonylamino)pyrrolidine (2.0 g, 10.74 mmol) in CH2CI2 was added CBZ-leucinal (3.2 g, 12.88 mmol). The reaction was allowed to stir at room temperature for approximately 1 hour whereupon sodium triacetoxyborohydride (3.4 g, 16.11 mmol) was added in a single portion. The reaction was stirred an additional 2 hours whereupon it was diluted with ethyl acetate and washed with sat'd NaHC03, brine, dried (Na2Sθ4), concentrated and chromatographed (5% CH30H:CH2C12) to give 4.3 g of the title compound: MS(ES+) 420 (MH+). b.) 3-amino-l-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine bis hydrochloride
To a solution of the compound of Example 1(a) (4.3 g) in CH3OH (10 mL) was added 4M HCl in dioxane (10 mL). The reaction was stirred at room temperature for 4 hours whereupon it was concentrated in vacuo to yield 3.97 g of the title compound: MS(ES+) 320 (MH+). c.) 3-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
To a solution of the compound of Example 1(b) (2.0 g, 5.1 mmole) was added EDC (1.27 g, 6.37 mmol) HOBT (724 mg, 5.35 mmol) TEA (1.78 mL, 12.75 mmol) and N-BOC-leucine (1.3 g, 5.35 mmol) The reaction was stirred until complete as indicated by TLC analysis whereupon it was diluted with ethyl acetate and washed with 5% NaHC03, brine, dried (MgS04), filtered, concentrated and chromatographed (5% CH3OH:CH2Cl2) to give 2.7 g of the title compound: MS(ES+) 533 (MH+)
d.) 3-L-leucinyl-l-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine bis hydrochloride
Following the procedure of Example 1(b) except substituting the compound of Example 1(c), the title compound was produced: MS(ES+) 433 (MH+).
e.) 3-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
Following the procedure of Example 1(c) except substituting the compound of Example 1(d) and quinaldic acid for N-BOC-leucine, the title compound was produced: MS(ES+) 588 (MH+).
Example 2
Preparation of l-benzyl-3-r.Nα-(2-quinolinecarbonyl)-L-leucinvHaminol-pyrrolidine
a.) l-benzyl-3-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine
Following the procedure of Example 1(c) except substituting l-benzyl-3- aminopyrrolidine, the title compound was prepared. MS(ES+) 390 (MH+).
b.) l-benzyl-3-L-leucinyl-pyrrolidine bis hydrochloride
Following the procedure of Example 1(b) except substituting the compound of Example 2(a), the title compound was prepared: MS(ES+) 290 (MH+). c.) l-benzyl-3-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine
Following the procedure of Example 1(e) except substituting the compound of Example 2(b), the title compound was prepared: MS(ES+) 445 (MH+).
Example 3
Preparation of 3-. ,Nα-(2-naphthylcarbonyl)-L-leucinvπaminol-l-r(2S)-4-methyl-2- rKbenzyloxycarbonvDaminolpentyll-pyrrolidine
Following the procedure of Example 1 (e) except substituing 2-naphthoic acid for quinaldic acid, the title compound was prepared: MS(ES+) 587 (MH+).
Example 4
Preparation of 1 -benzyl-3-. rNα-(2-naphthylcarbonyl)-L-leucinvπaminol-pyrrolidine
Following the procedure of Example 2(c) except substituting 2-naphthoic acid for quinaldic acid, the title compound was produced: MS(ES+) 444 (MH+).
Example 5
Preparation of l-benzyl-((3S))-. lNα-(benzyloxycarbonyl -L-leucinyHaminol-pyrrolidine a.) 1 -benzy l-((3S))-(tert-butoxycarbony l)amino-pyrrolidine
Following the procedure of Example 1(a) except substituting ((3S))-(-)-3-(tert- butoxycarbonylamino)pyrrolidine for 3-(tert-butoxycarbonylamino)pyrrolidine and benzaldehyde for CBZ-leucinal, the title compound was prepared: MS(ES+) 221.2 (M- C4H8), 277.3 (MH+).
b.) l-benzyl-((3S))-amino-pyrrolidine bis hydrochloride To a solution of the compound of Example 5(a) in methanol was added a 1M
HCl/ether. The reaction was stirred at room temperature until complete as indicated by mass spectral analysis. The reaction was concentrated in vacuo to give a white solid: MS(ES+) 177.0 (MH+). c.) l-benzyl-((3S))-[[Nα-(benzyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine
Following the procedure of Example 1 (c) except substituting the compound of Example 5(b) and CBZ-leucine for BOC-leucine, the title compound was prepared:
MS(ES+) 424.2(MH+).
Example 6
Preparation of 1 -benzyl-((3S))-rrNa-(tgrt-butoxycarbonyl)-L-leucinyllaminol- pyrrolidine Following the procedure of Example 5(c) except substituting BOC-leucine for
CBZ-leucine, the title compound was prepared: MS(ES+) 390.5 (MH+).
Example 7
Preparation of ((3S))-rrNc'-(2-naphthylcarbonyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- IT(benzyloxycarbonyl)amino]pentyll-pyπOlidine
a.) ((3S))-[(t -butoxycarbonyl)amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine Following the procedure of Example 1(a) except substituting ((3S))-(-)-3-(tert- butoxycarbonylamino)pyrrolidine for 3-(tert-butoxycarbonylamino)pyrrolidine the title compound was prepared: MS(ES+) 420 (MH+).
b.) ((3S))- [(tert-butoxycarbony l)amino]- 1 - [(2S)-4-methy 1-2- [f(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
Following the procedure of Example 1(b) except substituting the compound of Example 7(a), the title compound was produced: MS(ES) 320 (MH+)
c.) (3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
Following the procedure of Example 1 (c) except substituting the compound of Example 7(b), the title compound was produced: MS(ES+) 533 (MH+).
d.) (3S)-L-leucinyl-l-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine bis hydrochloride
Following the procedure of Example 1(d) except sustituting the compound of Example 7(c), the title compound was prepared: MS(ES+) 433 (MH+). e.) (3S)-[[Nα-(2-naphythylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
Following the procedure of Example 1(e) except substituting the compound of Example7(d) and substituting 2-naphthoic acid for quinaldic acid, the title compound was produced: MS(ES+) 587 (MH+).
Example 8
Preparation of (3R)-rrNc'-(2-naphthylcarbonyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- . KbenzyloxycarbonvPaminolpentyπ-pyrrolidine
a.) (3R)-[(tert-butoxycarbonyl)amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine Following the procedure of Example 1 (a) except substituting (3R)-(-)-3-(te/ - butoxycarbonylamino)pyrrolidine for 3-(tert-butoxycarbonylamino)pyrrolidine the title compound was prepared: MS(ES+) 420 (MH+).
b.) (3R)-amino-l-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine Following the procedure of Example 1(b) except substituting the compound of
Example 8(a), the title compound was produced: 320 MS(ES) (MH+)
c .) (3R)- [ [Nα-(tert-butoxycarbony l)-L-leuciny ljamino]- 1 - [(2S)-4-methy 1-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine Following the procedure of Example 1 (c) except substituting the compound of
Example 8(b), the title compound was produced: 533 MS(ES+) (MH+).
d.) (3R)-L-leucinyl-l-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine bis hydrochloride Following the procedure of Example 1 (d) except sustituting the compound of
Example 8(c), the title compound was prepared: MS(ES+) 433 (MH+).
e.) (3R)-[[N°-(2-naphthylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine Following the procedure of Example 1 (e) except substituting the compound of
Example 8(d) and substituting 2-naphthoic acid for quinaldic acid, the title compound was produced: MS(ES+) 587 (MH+). Example 9
Preparation of l-benzyl-(3R)-..Nα-(2-quinolineacetonoyl)-L-leucinyHaminol-pyrrolidine
a.) l-benzyl-(3R)-[(tert-butoxycarbonyl)amino]-pyrrolidine
To a solution of ((3R))-(-)-3-(rerf-butoxycarbonylamino)pyrrolidine (2.0 g, 10.73 mmol) in CH2CI2 (20 mL) was added benzaldehyde (1.3 mL, 12.88 mmol). The reaction was stirred at room temperature for 2 hours whereupon sodium triacetoxyborohydride (5.68 g, 26.82 mmol) was added. The reaction was stirred overnight at room temperature whereupon it was diluted with ethyl acetate and washed with sat. K-,C03, water, brine, dried (MgSO.), filtered, concentrated and chromatographed (1 : 1 hex:EtOAc) to give the title compound: MS(ES+) 221.1 (M- C4H8), 277.2 (MH+)
b.) l-benzyl-(3R)-amino-pyrrolidine bis hydrochloride
To a solution of the compound of Example 9(a) in methanol was added 1 N HCl/ether. The suspension was stirred at room temperature until complete as indicated by mass spectral analysis. The reaction was concentrated in vacuo to give the title compound: MS(ES+) 176.9 (MH+).
c). l-benzyl-(3R)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine
Following the procedure of Example 1(c) except substituting the compound of Example 9(b) and N-methylmorpholine for triethylamine, the title compound was produced: MS(ES+) 390.3 (MH+).
d.) l-benzyl-(3R)-[(L-leucinyl)amino]-pyrrolidine bis hydrochloride
To a solution of the compound of Example 9(c) in ethyl acetate and methanol was bubbled HCl gas for ca. 2 mins. The reaction was stirred overnight whereupon it was concentrated in vacuo to afford the title compound: MS(ES+) 290.4 (MH+).
e.) l-benzyl-(3R)-[[Nα-(2-naphthylacetonoyl)-L-leucinyl]amino]-pyrrolidine
To a suspension of the compound of Example 9(d) (75 mg) was added EDC (44.3 mg), HOBT (28.4 mg) NMM (0.14 mL) and 2-naphthylacetic acid. The reaction was stirred overnight at room temperature whereupon it was diluted wiyh ethyl acetae and washed with sat. K2CO3, water , brine, dried (MgS04), filtered, concentrated and chromatographed to give the title compound: MS(ES+) 458.3 (MH+). Example 10
Preparation of l-benzyl-(3R)-r.Nα-(2-naphthylcarbonyl)-L-leucinyllaminol-pyrrolidine
Following the procedure of Example 9(e) except substituting 2-naphthoic acid for 2-naphthylacetic acid, the title compound was prepared: MS(ES+) 444.2 (MH+).
Example 11
Preparation of 1 -benzyl-(3R)-. rN"-(3-quinolinecarbonyl)-L-leucinyllaminol-pyrrolidine
Following the procedure of Example 9(e) except substituting 3- quinolinecarboxylic acid for 2-naphthylacetic acid, the title compound was prepared: MS(ES+) 445.3 (MH+).
Example 12
Preparation of 1 -benzyl-(3R)-r. NM-(2-quinolinecarbonyl)-L-leucinvHaminol-pyrrolidine
Following the procedure of Example 9(e) except substituting quinaldic acid for 2-naphthylacetic acid, the title compound was prepared: MS(ES+) 445.2 (MH+).
Example 13
Preparation of l-benzyl-(3R)-[[Nα-(3-isoquinolinecarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 9(e) except substituting 3- isoquinolinecarboxylic acid for 2-naphthylacetic acid, the title compound was prepared: MS(ES+) 445.3 (MH+). Example 14
Preparation of l-benzyl-(3S)-..Nα-(2-naphthylacetonoyl)-L-leucinyllaminol-pyrrolidine
a.) l-benzyl-(3S)-[(tert-butoxycarbonyl)amino]-pyrrolidine
Following the procedure of Example 9(a) except substituting ((3S))-(-)-3-(tert- butoxycarbonylamino)pyrrolidine for (3R)-(-)-3-(tert-butoxycarbonylamino)pyrrolidine, the title compound was produced: MS(ES+) 277.2 (MH+).
b.) l-benzyl-(3S)-amino-pyrrolidine bis hydrochloride
Following the procedure of Example 9(b) except substituting the compound of example 14(a), the title compound was produced: MS(ES+) 177.0 (MH+).
c.) l-benzyl-(3S)-[[Nα-(terr-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine Following the procedure of Example 9(c) except substituting the compound of
Example 14(b), the title compound was produced: MS(ES+) 390.3 (MH+).
d.) l-benzyl-(3S)-[(L-leucinyl)amino]-pyrrolidine bis hydrochloride
Following the procedure of Example 9(d) except substituting the compound of Example 14(c), the title compound was produced: MS(ES+) 290.3 (MH+).
e.) l-benzyl-(3S)-[[Nα-(2-naphthylacetonoyl)-L-leucinyl]amino]-pyrrolidine
Following the procedure of Example 9(e) except substituting the compound of Example 14(d), the title compound was produced: MS(ES+) 458.4 (MH+).
Example 15
Preparation of l-benzyl-(3S)-frNα-(2-naphthylcarbonyl)-L-leucinyllamino1-pyrrolidine
Following the procedure of Example 14(e) except substituting 2-naphthoic acid for 2-naphthylacetic acid, the title compound was produced: MS(ES+) 444.4 (MH+). Example 16
Preparation of l-benzyl-(3S)-f[Nα-(3-quinolinecarbonyl)-L-leucinyllaminol-pyrrolidine
Following the procedure of Example 14(e) except substituting 3- quinolinecarboxylic acid for 2-naphthylacetic acid, the title compound was produced: MS(ES+) 445.2 (MH+).
Example 17
Preparation of 1 -benzyl-(3S)-.. Nκ-(2-quinolinecarbonyl)-L-leucinyllaminol-pyrrolidine
Following the procedure of Example 14(e) except substituting quinaldic acid for 2-naphthylacetic acid, the title compound was produced: MS(ES+) 445.3 (MH+).
Example 18
Preparation of l-benzyl-(3S)-..N"-(3-isoquinolinecarbonyl)-L-leucinyHaminol- pyrrolidine
Following the procedure of Example 14(e) except substituting 3- isoquinolinecarboxylic acid for 2-naphthylacetic acid, the title compound was produced: MS(ES+) 445.3 (MH+).
Example 19
Preparation of l-benzyl-4-, rNα-(2-naphthylcarbonyl)-L-leucinvHaminol-piperidine
a.) l-benzyl-4-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-piperidine Following the procedure of Example 1(c) except substituting 4-amino-l- benzylpiperidine, the title compound was produced: MS(ES+) 404.1 (MH+).
b.) 1 -benzyl-4-[(L-leucinyl)amino]-piperidine
The compound of Example 19(a) (2.0 g) was dissolved in 4N HCl/dioxane (100 mL). The reaction was stirred at room temperature for 30 minutes whereupon it was concentrated in vacuo to give 1.94 g of the title compound as a white solid: MS(ES+) 304.2 (MH+). c.) l-benzyl-4-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-piperidine
To a solution of the compound of Example 19(b) (240 mg) in DMF (3.0 mL) was added N-methylmorpholine (0.17 mL), HOBT (101.5 mg), 2-naphthoic acid (130.2 mg) and EDC (145.4 mg). The reaction was stirred overnight whereupon it was poured into a rapidly stirred mixture of EtOAc, 10% Na2C >3 and brine (75 mL each). This mixture was stirred for 30 minutes. The organic layer was sepaerated and the aqueous layer was washed with ethyl acetate. The combined organic layers were washed with 10% Na2C03, water, brine, dried (MgS04), filtered, concentrated and chromatographed (ethyl acetate) to give 107 mg of the title compound: MS(ES+) 458.5 (MH+).
Example 20
Preparation of l-benzyl-4-..Nα-(2-quinolinecarbonyl)-L-leucinyl1aminol-piperidine
Following the procedure of Example 19(c) except substituting quinaldic acid for 2-naphthoic acid, the title compound was prepared: MS(ES+) 459.3 (MH+).
Example 21
Preparation of l-benzyl-4-r.Nα-(benzyloxycarbonv])-L-leucinyllaminol-piperidine
To a solution of N-benzyl-4-amino piperidine (0.50 g) in CH2CI2 (10 mL) was added CBZ-leucine (695 mg), EDC (552.5 mg) and HOBT (356.6 mg). The reaction was stirred at room temperature until complete as indicated by TLC analysis. The reaction was dissolved in CHCI3 and washed with 10% Na2C03, brine, dried (MgS04), filtered, concentrated and chromatographed (3:1 EtOAc:hexanes) to give 0.99 g of the title compound: MS(ES-t-) 438 (MH+).
Example 22
Preparation of l-r3-(2-pyridvnphenyll-2-ethyl-(3S)-rrN -(2-naphthylcarbonyl)-L- leucinyllaminol-pyrrolidine
a) N-methyl-N-methoxy-3-(2-pyridyl)-phenylacetamide
To a stirred solution of N-methoxy-N-methylamine hydrochloride (0.980 g, 10.0 mmol) in DMF (25 mL) was added N-methylmorpholine (1.21 mL, 11.0 mmol), HOBt (1.50 g, 11.1 mmol), 3-(2-pyridyl)-phenylacetic acid (2.36 g, 11.1 mmol), and EDC (2.13 g, 1 1.1 mmol). The reaction was stirred overnight whereupon it was poured into a rapidly-stirred mixture of 150 mL each of EtOAc, 10% NaHCC.3, and brine. After stirring for 30 min, the layers were separated and the aqueous layer was washed with fresh EtOAc (1 0 mL). The combined organic layers were washed with 10% Na2Cθ3, and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 3: 1 EtOAc: hexane) gave 2.275 g of the title compound: MS (ES+) (MH+) 257.2.
b) 3-(2-pyridyl)-phenylacetaldehyde To a stirred solution of the compound of Example 22(a) (2.2 g, 8.6 mmol) in anhydrous
THF (20 mL) at -78°C was added a solution of lithium aluminum hydride in THF (22 L, 22.0 mmol). The reaction was stirred for 2 h, then warmed to 0°C and stirred 1 h, whereupon 4.2 g of KHSO4 was added in small portions over 10 min, followed by 100 mL of water in small portions. The reaction mixture was filtered to remove a white precipitate and the filtrate was adjusted to pH 9 by the addition of 1 N NaOH, then extracted with Et2θ (3 x 100 mL). The combined organic layers were washed with brine, then dried (Na2S04), filtered, and concentrated to give 1.878 g of the title compound: MS (ES+) (MH+) 198.1.
c) l-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[Nα-(t -butoxycarbonylamino]-pyrrolidine To a stirred solution of (3S)-(-)-3-(tert-butoxycarbonylamino)pyrrolidine (672.3 mg, 3.6 mmol) in CH2CI2 (15 mL) was added the compound of Example 22(b) (0.94 g, 4.3 mmol). The reaction was stirred 2 h whereupon Na(OAc)3BH (1.68 g, 7.9 mmol) added. After stirring overnight, the reaction mixture was diluted with CHCI3 (150 mL) and washed with H2O, and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 1 :9 MeOH: EtOAc) gave 467 mg of the title compound: MS (ES+) (MH+) 368.
d) l-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[tNα-(tert-butoxycarbonyl)-L-leucinyl]amino]- pyrrolidine
The compound of Example 22(c) (440 mg, 1.2 mmol) was dissolved in 4.0 N HCl in dioxane (20 mL) and stirred at room temperature for 30 min. The solution was concentrated to a white solid and dried under high vacuum for 30 min. To a stirred solution of the residue in DMF (10 mL) was added N-methylmorpholine (400 uL, 3.6 mmol), HOBt (245.6 mg, 1.8 mmol), Boc-Leucine hydrate (449.1 mg, 1.8 mmol), and EDC (352.0 mg, 1.8 mmol). The reaction was stirred overnight whereupon it was partitioned between 50 mL each of EtOAc, 10% Na2C03, and brine. The aqueous layer was washed with fresh EtOAc (50 mL), the combined organic layers were washed with 10% Na2Cθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 5:95 MeOH: EtOAc) gave 204 mg of the title compound: MS (ES+) (MH+) 481.4.
e) l-f3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[Nα-L-leucinyl]amino]-pyrrolidine dihydrochloride The compound of Example 22(d) (200 mg, 0.42 mmol) was dissolved in 4.0 N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 3 h to give the title compound: MS (ES+) (MH+) 381.4.
f) l-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine
To a stirred solution of the compound of Example 22(e) (0.14 mmol) in DMF (2 mL) was added N-methylmorpholine (62 uL, 0.56 mmol), HOBt (31.8 mg, 0.24 mmol), 2-naphthoic acid (37.6 mg, 0.22 mmol), and EDC (41.2 mg, 0.22 mmol). The reaction was stirred overnight whereupon it was partitioned between 50 mL each of EtOAc, 10% Na2Cθ3, and brine. The aqueous layer was washed with fresh EtOAc (50 mL), the combined organic layers were washed with 10% Na2Cθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 5:95 MeOH: EtOAc) gave 40.1 mg of the title compound: MS (ES+) (MH+) 535.4.
Example 23
Preparation of 1 -r3-(2-pyridyl)phenvH-2-ethyl-(3S)-[TNα-(2-quinolinecarbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 22(f), except using 2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+) (MH+) 536.4.
Example 24
Preparation of l-r3-(2-pyridyl)phenyll-2-ethyl-(3S)-[TNα-(3-isoquinolinecarbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 22(f), except using 3-isoquinolinecarboxylic acid, the title compound was prepared: MS (ES+) (MH+) 536.4. Example 25
Preparation of l-.3-(2-pyridyl)phenyll-2-ethyl-(3R)-ITN -(2-naphthylcarbonyl)-L- leucinyllaminol-pyrrolidine
a) l-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[Nα-(tert-butoxycarbonylamino]-pyrrolidine
Following the procedure of Example 22(c), except substituting (3R)-(+)-3-(tert- butoxycarbonylamino)pyrrolidine, the title compound was prepared: MS (ES+) (MH+) 368.4.
b) l-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]- pyrrolidine
Following the procedure of Example 22 (d), except substituting the compound of Example 25 (a), the title compound was prepared: MS (ES+) (MH+) 481.4.
c) l-f3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[Nα-L-leucinyl]amino]-pyrrolidine dihydrochloride Following the procedure of Example 22 (e), except substituting the compound of Example 25 (b), the title compound was prepared: MS (ES+) (MH+) 381.4.
d) l-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine
Following the procedure of Example 22 (f), except substituting the compound of Example 25 (c), the title compound was prepared: MS (ES+) (MH+) 535.3.
Example 26
Preparation of l-r3-(2-pyridyI)phenyll-2-ethyl-(3R)-r.N -(3-isoquinolinecarbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 25(d), except using 3-isoquinolinecarboxylic acid, the title compound was prepared: MS (ES+) (MH+) 536.3.
Example 27
Preparation of l-[3-(2-pyridyl)phenvπ-2-ethyl-(3R)-..Nα-(2-quinolinecarbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 25(d), except using 2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+) (MH+) 536.3.
Example 28
Preparation of l-(l-adamantanecarbonyl)-(3R)-r.Nα-(4-pyridylmethoxycarbonyl)-L- leucinyllaminol-pyrrolidine
a) l-(l-adamantanecarbonyl)-(3R)-[[Nα-(tert-butyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine To a stirred solution of (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (1.87 g, 10.0 mmol) in CH2CI2 (30 mL) at 0°C was added N-methylmorpholine (1.65 mL, 15.0 mmol) and 1- adamantylcarbonyl chloride (2.99 g, 15.0 mmol). The reaction was stirred overnight , gradually warming to room temperature, whereupon it was diluted with 200 mL of CHCI3 , washed with 5% NaHCθ3, H2O, IN HCl, H2O, and brine, then dried (MgS04), filtered, and concentrated to give 4.66 g of the title compound: MS (ES+) (MH+) 349.4.
b) l-(l-adamantanecarbonyl)-(3R)-aminopyrrolidine hydrochloride
The compound of Example 28 (a) (4.6 g) was dissolved in 4.0 N HCl in dioxane (100 L) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 2 h to give the title compound: MS (ES+) (MH+) 249.1.
c) l-(l-adamantanecarbonyl)-(3R)-[[Nα-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]- pyrrolidine
To a stirred solution of the compound of Example 28(b) (143.2 mg, 0.50 mmol) in DMF (2 mL) was added N-methylmorpholine (83 uL, 0.75 mmol), HOBt (101.5 mg, 0.75 mmol), 4- Inoc-Leucine (201.5 mg, 0.76 mmol), and EDC (146.0 mg, 0.76 mmol). The reaction was stirred overnight whereupon it was partitioned between 50 L each of EtOAc, 10% Na2Cθ3, and brine. The aqueous layer was washed with fresh EtOAc (50 mL), the combined organic layers were washed with 10% Na2Cθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 2:98 MeOH: EtOAc) gave 109.0 mg of the title compound: MS (ES+) (MH+) 497.5. Example 29
Preparation of l-(l-adamantanecarbonyl)-(3S)-r.N -(4-pyridylmethoxycarbonyl)-L- leucinvnaminol-pyrrolidine
a) l-(l-adamantanecarbonyl)-(3S)-[[Nα-(tgrt-butyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine
Following the procedure of Example 28(a), except substituting (3S)-(-)-3-(tert- butoxycarbonylamino)pyrrolidine, the title compound was prepared: MS (ES+) (MH+) 349.5.
b) l-(l-adamantanecarbonyl)-(3S)-aminopyrrolidine hydrochloride
Following the procedure of Example 28(b), except substituting the compound of Example 29 (a), the title compound was prepared: MS (ES+) (MH+) 249.1.
c) l-(l-adamantanecarbonyl)-(3S)-[[Nα-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]- pyrrolidine
Following the procedure of Example 28(c), except substituting the compound of Example 29(b), the title compound was prepared: MS (ES+) (MH+) 497.4.
Example 30
Preparation of (3R)-. _Nα-(benzorblthiophene-2-carbonyl)-L-leucinyllamino1-l-r(2S)-4-methyl- 2-[r(benzyloxycarbonyl)aminolpentyll-pyrrolidine
a) (3R)- [ [Nα-(tert-butoxycarbonyl)amino]- 1 - [(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
To a stirred solution of (3R)-(+)-3-(tert-butoxycarbonylamino)pyrrolidine (2 g, 10.7 mmol) in CH2CI2 (200 mL) was added N-CBZ-Leucinal (3.2 g, 12.9 mmol). The reaction was stirred 2 h whereupon Na(OAc)3BH (3.4 g, 16.1 mmol) was added. After stirring overnight, the reaction mixture was diluted with CHCI3 (150 mL) and washed with 5% NaHCθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 3:97 MeOH: CH2C12) gave 3.4 g of the title compound: MS (ES+) (MH+) 420.
b) (3R)-amino-l-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine dihydrochloride The compound of Example 30 (a) (3.4 g) was dissolved in 4.0 N HCl in dioxane (50 mL) and stirred at room temperature for 1 h. The solution was concentrated in vacuo and dried under high vacuum to give 3.37 g of the title compound: MS (ES+) (MH+) 320. c) (3R)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
To a stirred solution of the compound of Example 30(b) (2.36 g, 6.0 mmol) in DMF (25 mL) was added N-methylmorpholine (2.0 mL, 18.2 mmol), HOBt (1.22 g, 9.0 mmol), Boc-
Leucine hydrate (2.25 g, 9.0 mmol), and EDC (1.73 g, 9.0 mmol). The reaction was stirred for 3 h whereupon it was partitioned between 150 mL each of EtOAc, 10% Na2Cθ3, and brine. The aqueous layer was washed with fresh EtOAc (150 mL), the combined organic layers were washed with 10% Na2Cθ3 and brine, then dried (MgS04), filtered, and concentrated. Column chromatography (silica gel, 2: 1 EtOAc: hexane) gave 2.78 g of the title compound: MS (ES+) (MH+) 533.6.
d) (3R)-[[Nα-L-leucinyl]amino]-l-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]- pyrrolidine dihydrochloride The compound of Example 30(c) (2.7 g) was dissolved in 4.0 N HCl in dioxane (100 mL) and stirred at room temperature for 1 h. The solution was concentrated in vacuo and dried azeotropically with toluene to afford a tan solid and stored under high vacuum overnight to give 2.45 g of the title compound: MS (ES+) (MH+) 433.3.
e) (3R)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
To a stirred solution of the compound of Example 30(d) (101.4 mg, 0.2 mmol) in DMF (1 mL) was added N-methylmorpholine (66 uL, 0.6 mmol), HOBt (42.2 mg, 0.3 mmol), benzo[b]thiophene-2-carboxylic acid (53.3 mg, 0.3 mmol), and EDC (57.8 mg, 0.3 mmol). The reaction was stirred overnight whereupon it was partitioned between 50 mL each of EtOAc, 10% Na2Cθ3, and brine. The aqueous layer was washed with fresh EtOAc (50 mL), the combined organic layers were washed with 10% Na2Cθ3 and brine, then dried (MgS04), filtered, and concentrated. Column chromatography (silica gel, 3: 1 EtOAc: hexane) gave 80.4 mg of the title compound: MS (ES+) (MH+) 593.4.
Example 31
Preparation of (3R)-rrNα-(3,4-dimethoxybenzoyl)-L-leucinyllaminol-l-[(2S)-4-methyl-2- r.(benzyloxycarbonyl)aminolpentyH-pyrrolidine
Following the procedure of Example 30(e), except substituting 3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+) 597.4. Example 32
Preparation of (3R)-rrNα-(benzofuran-2-carbonyl)-L-leucinyllamino1-l-l(2S)-4-methyl-2- .. (benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 30(e), except substituting benzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 577.2.
Example 33
Preparation of (3R)-f[Nα-(benzothiazole-6-carbonyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- IT(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 30(e), except substituting benzothiazole-6- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 594.4.
Example 34
Preparation of (3R)-rrNα-(indole-2-carbonyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- r.(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 30(e), except substituting indole-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 576.3.
Example 35
Preparation of (3R)-[rNα-(4-fluorobenzoyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- r(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 30(e), except substituting 4-fluorobenzoic acid, the title compound was prepared: MS (ES+) (MH+) 555.3. Example 36
Preparation of (3R)-riNα-(4-methoxybenzoyl)-L-leucinyllaminol-l-[(2S)-4-methyl-2- IT(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 30(e), except substituting p-4-methoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+) 567.4.
Example 37
Preparation of (3R)-rrNα-(3,4-dichlorobenzoyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- r,(benzyloxycarbonyl)aminolpentyπ-pyrrolidine
Following the procedure of Example 1(e), except substituting 3,4-dichlorobenzoic acid, the title compound was prepared: MS (ES+) (MH+) 605.2.
Example 38
Preparation of (3R)-..Nα-(thiophene-2-carbonyl)-L-leucinyHaminol-l-r(2S)-4-methyl-2- IT(benzyloxycarbonyl)amino.pentyπ-pyrrolidine
Following the procedure of Example 30(e), except substituting thiophene-3-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 543.4.
Example 39
Preparation of (3R)-r.Nα-(4-biphenylcarbonyl)-L-leucinyHaminol-l-. (2S)-4-methyl-2- r[(benzyloxycarbonyl)aminolpentyll-pyrrolidine
To a stirred solution of the compound of Example 30(d) (102.3 mg, 0.2 mmol) in
CH2CI2 (1 mL) at 0°C was added N-methylmorpholine (66 uL, 0.6 mmol) and 4- biphenylcarbonyl chloride (65.2 mg, 0.3 mmol). The reaction was stirred overnight whereupon it was diluted with CHCI3 and washed with 10% Na2C03 and brine, then dried (MgS04), filtered, and concentrated. Column chromatography (silica gel, 3: 1 EtOAc: hexane) gave 55.1 mg of the title compound: MS (ES+) (MH+) 613.5. Example 40
Preparation of (3R)- . , Nα-(5-methox ybenzof uran-2-carbony l)-L-leuciny 11 aminol- 1 - T(2S)-4- methyl-2-IT(benzyloxycarbonyl)arnino1pentvH-pyrrolidine
Following the procedure of Example 30(e), except substituting 5-methoxybenzofuran-2- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 607.4.
Example 41
Preparation of (3R)-[rNα-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl1amino]-l-[(2S)-4- methyI-2-rr(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 30(e), except substituting 5-chlorobenzofuran-2- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 611.4.
Example 42
Preparation of (3R)-rrNα-(7-methoxybenzofuran-2-carbonyl)-L-leucinyllaminol-l-[(2S)-4- methyl-2-r. (benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 30(e), except substituting 7-methoxybenzofuran - 2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 607.4.
Example 43
Preparation of ORHrN -^-chlorobenzolblthiophene^-carbonyπ-L-leucinyllaminol-l-r^S - methyl-Σ-rKbenzyloxycarbonvDaminolpentyll-pyrrolidine
Following the procedure of Example 30(e), except substituting 3- chlorobenzo[b]thiophene-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 627.3. Example 44
Preparation of (3RH . Nα-(3-(2-pyridyl)benzoyl)-L-leucinyπaminol- 1 -. (2S)-4-methyl-2- rKbenzyloxycarbonvDaminolpentyll-pyrrolidine
Following the procedure of Example 30(e), except substituting 3-(2-pyridyl)benzoic acid, the title compound was prepared: MS (ES+) (MH+) 614.4.
Example 45
Preparation of (3S)-rrNα-(benzofblthiophene-2-carbonyl)-L-leucinyllaminol-l -[(2S)-4-methyl- 2-[r(benzyloxycarbonyl)aminolpentyll-pyrrolidine
a) (3S)-[[Nα-(tert-butoxycarbonyl)amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
Following the procedure of Example 30(a), except substituting (3S)-(-)-3-(tert- butoxycarbonylamino)pyrrolidine, the title compound was prepared: MS (ES+) (MH+) 420.
b) (3S)-amino-l-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine dihydrochloride
Following the procedure of Example 30(b), except substituting the compound of Example 45(a), the title compound was prepared: MS (ES+) (MH+) 320.
c) (3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [t(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
Following the procedure of Example 30(c), except substituting the compound of Example 45 (b), the title compound was prepared: MS (ES+) (MH+) 533.5.
d) (3S)-[[Nα-L-leucinyl]amino]-l-[(2S)-4-methyl-2-[[(benzyloxycarbonyl)amino]pentyl]- pyrrolidine dihydrochloride
Following the procedure of Example 30(d), except substituting the compound of Example 45 (c), the title compound was prepared: MS (ES+) (MH+) 433.3.
e) (3S)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine
Following the procedure of Example 30(e), except substituting the compound of Example 45 (d), the title compound was prepared: MS (ES+) (MH+) 593.4. Example 46
Preparation of (3S)-rrNα-(3.4-dimethoxybenzoyl)-L-leucinyllaminol-l-[(2S)-4-methyl-2- [r(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 45(e), except substituting 3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+) 597.5.
Example 47
Preparation of (3S)-rrNα-(benzofuran-2-carbonyl)-L-leucinyllaminol-l-[(2S)-4-methyl-2- rr(benzyloxycarbonyl)aminolpentyn-pyrrolidine
Following the procedure of Example 45(e), except substituting benzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 577.4.
Example 48
Preparation of (3S)-, .Nα-(benzothiazole-6-carbonyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- rr(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 45(e), except substituting benzothiazole-6- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 594.4.
Example 49
Preparation of (3S)-rrN -(indole-2-carbonyl)-L-leucinynaminol-l-r(2S)-4-methyl-2- rKbenzyloxycarbonvDaminolpentyll-pyrrolidine
Following the procedure of Example 45(e), except substituting indole-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 576.4. Example 50
Preparation of (3S)-rrNα-(4-fluorobenzoyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- rr(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 45(e), except substituting 4-fluorobenzoic acid, the title compound was prepared: MS (ES+) (MH+) 555.3.
Example 51
Preparation of (3SH.Nα-(4-methoxybenzoyl)-L-Ieucinyllaminol-l-r(2S)-4-methyl-2- .. benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 45(e), except substituting p-4-methoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+) 567.3.
Example 52
Preparation of (3S)-rrNα-(3.4-dichlorobenzoyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- rr(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 45(e), except substituting 3,4-dichlorobenzoic acid, the title compound was prepared: MS (ES+) (MH+) 605.2.
Example 53
Preparation of (3S)-[rNα-(thiophene-2-carbonyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- .. benzyloxycarbonyl)aminolpentyπ-pyrrolidine
Following the procedure of Example 45(e), except substituting thiophene-3-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 543.2. Example 54
Preparation of (3S)-rrNα-(4-biphenylcarbonyl)-L-leucinyllaminol-l-[(2S)-4-methyl-2- r.(benzyloxycarbonyl)aminolpentyll-pyrrolidine
Following the procedure of Example 39, except substituting the compound of Example 45 (e), the title compound was prepared: MS (ES+) (MH+) 613.4.
Example 55
Preparation of (3SH, Nα-(5-methoxybenzofuran-2-carbonyl)-L-leucinyllaminol- 1 -f (2S)-4- methyl-2-rr(benzyloxycarbonyl)aminolpentvH-pyrrolidine
Following the procedure of Example 45(e), except substituting 5-methoxybenzofuran-2- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 607.4.
Example 56
Preparation of (3S)-rrNα-(5-chlorobenzofuran-2-carbonyl)-L-leucinyllaminol-l-r(2S)-4-methyl- 2-rr(benzyloxycarbonyl)amino1pentyll-pyrrolidine
Following the procedure of Example 45(e), except substituting 5-chlorobenzofuran-2- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 611.4.
Example 57
Preparation of (3S)-rrNα-(7-methoxybenzofuran-2-carbonyl)-L-leucinyllaminol- 1 -. (2SV4- methyl-2-r.(benzyloxycarbonyl)aminolpentyl]-pyrrolidine
Following the procedure of Example 45(e), except substituting 7-methoxybenzofuran -
2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 607.4. Example 58
Preparation of (3S)-[rNα-(3-chlorobenzorblthiophene-2-carbonyl)-L-leucinyllaminol-l-[(2S)-4- methyl-2-.. (benzyloxycarbonyl)aminolpentvH-pyrrolidine
Following the procedure of Example 45(e), except substituting 3- chlorobenzo[b]thiophene-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 627.2.
Example 59
Preparation of (3S)-rrNα-(3-(2-pyridyl)benzoyl)-L-leucinyllaminol-l-r(2S)-4-methyl-2- KbenzyloxycarbonyDaminolpentyn-pyrrolidine
Following the procedure of Example 45(e), except substituting 3-(2-pyridyl)benzoic acid, the title compound was prepared: MS (ES+) (MH+) 614.4.
Example 60
Preparation of 1 -(4-phenyl)benzyI-(3S)-rrNα-(tert-butoxycarbonyl)-L-leucinyl1aminol- pyrrolidine
a) l-(2,2,2-trichloroethylcarbonyl)-(3S)-[[Nα-(tert-butoxycarbonyl)amino]-pyrrolidine
To a stirred solution of (3S)-(-)-3-(tert-butoxycarbonylamino)pyrrolidine (10 g, 53.7 mmol) in CH2CI2 (150 mL) at 0°C was added N-methylmorpholine (6.50 mL, 59.1 mmol), and 2,2,2-trichloroethyl chloroformate (8.20 mL, 59.6 mmol). After stirring overnight, gradually warming to room temperature, the reaction mixture was concentrated to 1/2 original volume, diluted with CHCI3 (250 mL), and washed with 5% NaHC03, H2O, IN HCl, H20, and brine, then dried (MgS04), filtered, and concentrated to give 23.98 g of the title compound: Η-NMR (400 MHz, CDCI3): d (ppm) 4.74 (s, 2H); 4.66 (br m, IH); 4.25 (br m, IH); 3.72 (m, IH); 3.56 (m, 2H); 3.33 (m, IH); 2.19 (m, IH); 1.87 (m, IH); 1.45 (s, 9H).
b) l-(2,2,2-trichloroethylcarbonyl)-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]- pyrrolidine The compound of Example 60(a) (23.9 g) was dissolved in 4.0 N HCl in dioxane (200 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and stored under high vacuum for 30 min. To a stirred solution of the residue in DMF (200 mL) was added N-methylmorpholine (8.90 mL, 80.9 mmol), HOBt (10.88 g, 80.5 mmol), Boc-Leucine hydrate (20.09 g, 80.6 mmol), and EDC (15.44 g, 80.6 mmol). The reaction was stirred overnight whereupon it was partitioned between EtOAc (300 mL), 10% Na2Cθ3 (150 mL), and brine (150 mL). The aqueous layer was washed with fresh EtOAc (100 mL), the combined organic layers were washed with IN HCl, H2O, 10% Na2Cθ3, H2O, and brine, then dried (MgSθ4), filtered, and concentrated to give 27.88 g of the title compound: MS (ES+) (MH+) 474.1.
c) (3S)-[[N -(ϊert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine To a stirred solution of the compound of Example 60(b) (27.7 g) in THF (200 mL) was added a solution of IN NH4OAc (pH 7-7.5, 40 mL), followed by Zn powder (25.06 g). The reaction was stirred for 3 h at room temperature whereupon the slurry was filtered through a pad of Celite, followed by several CHCI3 washes. The combined filtrates were concentrated to remove THF, diluted with additional CHCI3 (300 mL) and washed with 10% Na2C03 and brine, then dried (MgSθ4), filtered, and concentrated to give 16.34 g of the title compound: MS (ES+) (MH+) 300.2.
d) l-(4-phenyl)benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine
To a stirred solution of the compound of Example 60(c) (1.51 g, 5.0 mmol) in CH2CI2 (10 mL) was added 4,4'-biphenylcarboxaldehyde (1.09 g, 6.0 mmol). The reaction was stirred 2 h whereupon Na(OAc)3 (2.34 g, 11.0 mmol) was added. After stirring overnight, the reaction mixture was diluted with CHCI3 (100 mL) and washed with 5% NaHC03 an< brine, then dried (MgS04), filtered, and concentrated. Column chromatography (silica gel, 2: 1 EtOAc: hexane to 3:1 EtOAc: hexane) gave 1.68 g of the title compound: MS (ES+) (MH+) 466.4.
Example 61
Preparation of l-(4-phenyl)benzyl-(3S)-[rNα-(2-naphthylcarbonyl)-L-leucinyllamino1- pyrrolidine
a) 1 -(4-phenyl)benzyl-(3S)-[[N -L-leucinyl]amino]-pyrrolidine dihydrochloride
The compound of Example 60(d) (1.57 g, 3.4 mmol) was dissolved in 4.0 N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 30 min to give the title compound: MS (ES+) (MH+) 366.4.
b) l-(4-phenyl)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine To a stirred solution of the compound of Example 61(a) (132.9 mg, 0.30 mmol) in DMF (1 mL) was added N-methylmorpholine (100 uL, 0.91 mmol), HOBt (62.0 mg, 0.46 mmol), 2- naphthoic acid (78.4 mg, 0.46 mmol), and EDC (87.3 mg, 0.46 mmol). The reaction was stirred overnight whereupon it was partitioned between 50 mL each of EtOAc, 10% Na2C03, and brine. The aqueous layer was washed with fresh EtOAc (50 mL), the combined organic layers were washed with 10% Na2C03 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 2:1 EtOAc: hexane) gave 102.8 mg of the title compound: MS (ES+) (MH+) 520.3.
Example 62
Preparation of l-(4-phenyl)benzyl-(3S)-. rN -(2-quinolinecarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 61 (b), except substituting 2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+) (MH+) 521.3.
Example 63
Preparation of 1 -(4-phenyl)benzyl-(3S)-. lNα-(3,4-dimethoxybenzoyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 61(b), except substituting 3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+) 530.3.
Example 64
Preparation of l-(4-phenyl)benzyl-(3S)-. rNα-(benzofuran-2-carbonyl)-L-leucinyI1aminol- pyrrolidine
Following the procedure of Example 61(b), except substituting benzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 510.3. Example 65
Preparation of l-(4-phenyl)benzyl-(3S)-ITNα-(benzo.blthiophene-2-carbonvI)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 61(b), except substituting benzo[b]thiophene-2- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 526.4.
Example 66
Preparation of l-(4-phenyl)benzyl-(3S)-..Nα-(benzyloxycarbonyl)-L-leucinyπaminol- pyrrolidine
To a stirred suspension of the compound of Example 61(a) (132.9 mg, 0.30 mmol) in CH2CI2 (2 L) at 0°C was added N-methylmorpholine (132 uL, 1.20 mmol), and benzyl chloroformate (53 uL, 0.36 mmol). The reaction was stirred overnight, gradually warming to room temperature, whereupon it was diluted with CHCI3 (100 mL) and washed with 10% Na2C03 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, EtOAc) gave 94.0 mg of the title compound: MS (ES+) (MH+) 500.3.
Example 67
Preparation of l-(2-phenyl)ethyl-(3S)-frNα-(te -butoxycarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 60(d), except substituting phenylacetaldehyde, the title compound was prepared: MS (ES+) (MH+) 404.4.
Example 68
Preparation of l-(2-phenyl)ethyl-(3S)-[rNα-(2-naphthylcarbonyl)-L-leucinvnaminol-pyrrolidine
a) l-(2-phenyl)ethyl-(3S)-[[Nα-L-leucinyl]amino]-pyrrolidine dihydrochloride
The compound of Example 67 (1.13 g, 2.8 mmol) was dissolved in 4.0 N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 30 min to give the title compound: MS (ES+) (MH+) 304.3. b) l-(2-phenyl)ethyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
Following the procedure of Example 61(b), except substituting the compound of Example 68(a), the title compound was prepared: MS (ES+) (MH+) 458.3.
Example 69
Preparation of l-(2-phenyl)ethyl-(3S)-, _N -(2-quinolinecarbonyl)-L-leucinvIlaminol- pyrrolidine
Following the procedure of Example 68(b), except substituting 2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+) (MH+) 459.5.
Example 70
Preparation of 1 -(2-phenyI)ethyl-(3S)-..Nα-(benzorb1thiophene-2-carbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 68(b), except substituting benzo[b]thiophene-2- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 464.3.
Example 71
Preparation of l-(2-phenyl)ethyl-(3S)-rrNα-(benzofuran -2-carbonyl)-L-leucinyllamino1- pyrrolidine
Following the procedure of Example 68(b), except substituting benzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 448.3.
Example 72
Preparation of l-(2-phenyl)ethyl-(3S)-. _N -(3-chlorobenzorblthiophene-2-carbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 68(b), except substituting 3- chlorobenzo[b]thiophene -2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 498.1. Example 73
Preparation of 1 -(4-phenoxy)benzyl-(3S)-[rNα-(?grf-butoxycarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 60(d), except substituting 4-phenoxybenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 482.4.
Example 74
Preparation of l-(4-phenoxy)benzyl-(3S)-. rNα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
a) l-(4-phenoxy)benzyl-(3S)-[[N -L-leucinyl]amino]-pyrrolidine dihydrochloride The compound of Example 73 (1.52 g, 3.2 mmol) was dissolved in 4.0 N HCl in dioxane
(25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 30 min to give the title compound: MS (ES+) (MH+) 382.4.
b) l-(4-phenoxy)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine Following the procedure of Example 61(b), except substituting the compound of
Example 74(a), the title compound was prepared: MS (ES+) (MH+) 536.3.
Example 75
Preparation of l-(4-phenoxy)benzyl-(3S)-ITNα-(2- quinolinecarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 74(b), except substituting 2-quinolinecarboxylic acid, the title compound was prepared: MS (ES+) (MH+) 537.3.
Example 76
Preparation of l-(4-phenoxy)benzyl-(3S)-. ,Nα-(3.4-dimethoxybenzoyl)-L-leucinyHaminol- pyrrolidine
Following the procedure of Example 74(b), except substituting 3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+) 546.3. Example 77
Preparation of l-(4-phenoxy)benzyl-(3S)-, .Nα-(benzofuran -2-carbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 74(b), except substituting benzofuran-2-carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 526.4.
Example 78
Preparation of l-(4-phenoxy)benzyl-(3S)-..Nα-(benzo,blthiophene-2-carbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 74(b), except substituting benzo[b]thiophene-2- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 542.3.
Example 79
Preparation of 1 -(4-fluoro)benzyl-(3S)-rrN -(terr-butoxycarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 60(d), except substituting 4-fluorobenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 408.3.
Example 80
Preparation of l-(4-fluoro)benzyl-(3S)-. rNα-(2-naphthylcarbonyl)-L-leucinyl1aminol- pyrrolidine
a) l-(4-fluoro)benzyl-(3S)-[[Nα-L-leucinyl]amino]-pyrrolidine dihydrochloride
The compound of Example 79 (508 mg, 1.25 mmol) was dissolved in 4.0 N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 30 min to give the title compound: MS (ES+) (MH+) 308.3. b) l-(4-fluoro)benzyl-(3S)-t[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
Following the procedure of Example 61(b), except substituting the compound of Example 80(a), the title compound was prepared: MS (ES+) (MH+) 462.3.
Example 81
Preparation of l-(4-fluoro)benzyl-(3S)-r.Nα-(benzorblthiophene-2-carbonvI)-L- leucinvnaminol-pyrrolidine
Following the procedure of Example 80(b), except substituting benzo[b]thiophene-2- carboxylic acid, the title compound was prepared: MS (ES+) (MH+) 468.3.
Example 82
Preparation of 1 -(4-cyano)benzyl-(3S)-. rNα-(tert-butoxycarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 60(d), except substituting 4-cyanobenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 415.4.
Example 83
Preparation of l-(4-cvano)benzyl-(3S)-r.Nα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
a) l-(4-cyano)benzyl-(3S)-[[Nα-L-leucinyl]amino]-pyrrolidine dihydrochloride
The compound of Example 82 (512 mg, 1.23 mmol) was dissolved in 4.0 N HCl in dioxane (25 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum for 30 min to give the title compound: MS (ES+) (MH+) 315.4.
b) l-(4-cyano)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
Following the procedure of Example 61(b), except substituting the compound of Example 83(a), the title compound was prepared: MS (ES+) (MH+) 469.5. Example 84
Preparation of l-benzyl-(3S)-r.Nα-(benzo.blthiophene-2-carbonyl)-L-leucinyllaminol- pyrrolidine
a) l-benzyl-(3S)-[[Nα-(tgrt-butoxycarbonyl)amino]-pyrrolidine
To a stirred solution of (3S)-(-)-3-(tert-butoxycarbonylamino)pyrrolidine (10 g, 53.7 mmol) in CH2CI2 (125 mL) was added benzaldehyde (6.6 mL, 64.9 mmol). The reaction was stirred 2 h whereupon Na(OAc)3 (25.05 g, 118.2 mmol) was added. After stirring overnight, small aliquots of 5% NaHCθ3 were added until foaming had ceased. The reaction mixture was diluted with CHCI3 (150 mL) and washed with 5% NaHCθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 1 : 1 EtOAc: hexane) gave 11.5 g of the title compound: MS (ES+) (MH+) 277.2.
b) l-benzyl-(3S)-[[Nα-(rert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine
The compound of Example 84 (a) (11.0 g, 39.8 mmol) was dissolved in 4.0 N HCl in dioxane (300 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum. To a stirred solution of the residue in DMF (100 mL) was added N-methylmorpholine (13.1 mL, 119.1 mmol), HOBt (8.07 g, 59.7 mmol), Boc- Leucine hydrate (14.89 g, 59.7 mmol), and EDC (11.44 g, 59.7 mmol). The reaction was stirred overnight whereupon it was diluted with EtOAc (500 mL), and washed with 1 : 1 10% Na2Cθ3 : brine (300 mL). The aqueous layer was washed with fresh EtOAc (150 mL), the combined organic layers were washed with 10% Na2Cθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 1 :2 EtOAc: hexane to 1 : 1 EtOAc: hexane) gave 13.5 g of the title compound: MS (ES+) (MH+) 390.4.
c) l-benzyl-(3S)-[[Nα-L-leucinyl]amino]-pyrrolidine dihydrochloride
The compound of Example 84 (b) (11.6 g, 29.8 mmol) was dissolved in 4.0 N HCl in dioxane (300 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum to give the title compound: MS (ES+) (MH+) 290.4.
d) l-benzyl-(3S)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine
To a stirred solution of the compound of Example 84 (c) (109.2 mg, 0.30 mmol) in DMF (1 mL) was added N-methylmorpholine (100 uL, 0.91 mmol), HOBt (61.6 mg, 0.46 mmol), benzo[b]thiophene-2-carboxylic acid (80.8 mg, 0.45 mmol), and EDC (86.6 mg, 0.45 mmol). The reaction was stirred overnight whereupon it was partitioned between 50 mL each of EtOAc, 10% Na2Cθ3, and brine. The aqueous layer was washed with fresh EtOAc (50 mL), the combined organic layers were washed with 10% Na2Cθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 4: 1 EtOAc: hexane) gave 85.0 mg of the title compound: MS (ES+) (MH+) 450.0.
Example 85
Preparation of l-benzyl-(3S)-irNα-(3,4-dimethoxybenzoyl)-L-leucinyllamino1-pyrrolidine
Following the procedure of Example 84(d), except substituting 3,4-dimethoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+) 454.4.
Example 86
Preparation 1 -benzyl-(3S)- , . Nα-(3-(2-dimethy laminoethoxy )-4-methoxybenzoy D-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 84(d), except substituting 3-(2- dimethylaminoethoxy)-4-methoxybenzoic acid, the title compound was prepared: MS (ES+) (MH+) 511.2.
Example 87
Preparation of l-(4-nitro)benzyl-(3S)-rrN -(2-naphthylcarbonyl)-L-leucinyllaminol-pyrrolidine
a) l-benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
To a stirred solution of the compound of Example 84 (c) (7.25 g, 20.0 mmol) in DMF (50 mL) was added N-methylmorpholine (6.60 mL, 60.0 mmol), HOBt (4.05 g, 30.0 mmol), 2- naphthoic acid (5.17 g, 30.0 mmol), and EDC (5.76 g, 30.1 mmol). The reaction was stirred overnight whereupon it was partitioned between EtOAc (300 mL), 10% Na2C03 (150 mL), and brine (150 mL). The aqueous layer was washed with fresh EtOAc (150 mL), the combined organic layers were washed with 10% Na2Cθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 3: 1 EtOAc: hexane to EtOAc) gave 5.7 g of the title compound: MS (ES+) (MH+) 444.0.
b) (3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
To a stirred suspension of the compound of Example 87(a) (2.22 g, 5.00 mmol) in anhydrous dichloroethane (10 mL) at 0°C, in an oven-dried flask under an Argon atmosphere, was added a solution of 1-chloroethyl chloroformate (600 uL, 5.56 mmol) in dichloroethane, drop- wise over 10 min. After stirring at 0°C for 15 min, the reaction was heated to reflux for 1.5 h, cooled to room temperature, and concentrated. The residue was dissolved in anhydrous MeOH (10 mL) and heated to reflux overnight. The reaction was cooled to room temperature, whereupon it was concentrated, dissolved in H2O, and basified to pH 9-9.5 by the addition of solid Na2C03- The aqueous solution was extracted with CHCI3 (2 x 100 mL), the combined organic layers were washed with brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 10:90 MeOH: CHCI3 to 10:90:0.1 MeOH: CHCI3 : NH4OH) gave 0.82 g of the title compound: MS (ES+) (MH+) 354.3.
c) l-(4-nitro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
To a stirred solution of the compound of Example 87(b) (106.5 mg, 0.30 mmol) in CH2CI2 (1 mL) was added 4-nitrobenzaldehyde (55.5 mg, 0.37 mmol). The reaction was stirred 1.5 h whereupon Na(OAc)3 (141.3 mg, 0.67 mmol) added. After stirring overnight, the reaction mixture was diluted with CHCI3 (100 mL) and washed with 5% NaHC03 and brine, then dried (MgS04), filtered, and concentrated. Column chromatography (silica gel, EtOAc) gave 88.0 mg of the title compound: MS (ES+) (MH+) 489.3.
Example 88
Preparation of l-(4-(N.N-dimethylamino)benzyl-(3S)-..N -(2-naphthylcarbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 87(c), except substituting 4-(N,N- dimethylamino)benzaldehyde, the title compound was prepared: MS (ES+) (MH+) 487.1.
Example 89
Preparation of l-(4-methoxy)benzyl-(3S)-. rNα-(2-naphthylcarbonyl)-L-leucinyl1amino1- pyrrolidine
Following the procedure of Example 87(c), except substituting p-anisaldehyde, the title compound was prepared: MS (ES+) (MH+) 474.4. Example 90
Preparation of 1 -(4-pyridyl)methyl-(3S)-.. Nα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 87(c), except substituting 4- pyridinecarboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 445.4.
Example 91
Preparation of 1 -(4-carboxymethyl)benzyl-(3S)-r. Nα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 87(c), except substituting methyl-4- formylbenzoate, the title compound was prepared: MS (ES+) (MH+) 502.3.
Example 92
Preparation of l-(3,4-methylenedioxy)benzyl-(3SH.N -(2-naphthylcarbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 87(c), except substituting piperonal, the title compound was prepared: MS (ES+) (MH+) 488.2.
Example 93
Preparation of l-(2-naphthyl)methyl-(3S)-r.Nα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 87(c), except substituting 2-naphthaldehyde, the title compound was prepared: MS (ES+) (MH+) 494.2. Example 94
Preparation of 1 -(3-indolyl)methyl-(3S)-, . Nα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 87(c), except substituting indole-3- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 483.4.
Example 95
Preparation of l-(2-quinolinyl)methyl-(3S)-rrNα-(2-naphthylcarbonyl)-L-leucinyllamino1- pyrrolidine
Following the procedure of Example 87c), except substituting quinoline-2- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 495.4.
Example 96
Preparation of l-(3-quinolinyl)methyl-(3S)-rfNα-(2-naphthylcarbonyl)-L-leucinvnaminol- pyrrolidine
Following the procedure of Example 87(c), except substituting quinoline-3- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 495.3.
Example 97
Preparation of l-(l-naphthyl)methyl-(3S)-. _Nα-(2-naphthylcarbonyl)-L-leucinvπamino1- pyrrolidine
Following the procedure of Example 87(c), except substituting 1-naphthaldehyde, the title compound was prepared: MS (ES+) (MH+) 494.3. Example 98
Preparation of 1 -(4-quinolinyl)methyl-(3S)-.. Nα-(2-naphthylcarbonyl)-L-leucinyl1aminol- pyrrolidine
Following the procedure of Example 87(c), except substituting quinoline-4- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 495.3.
Example 99
Preparation l-(3-pyrrolyl)methyl-(3S)-rrNα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 87(c), except substituting pyrrole-2- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 433.3.
Example 100
Preparation of 1 -(3-pyridyl)methyl-(3S)-. lN -(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 87(c), except substituting pyridine-3- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 445.2.
Example 101
Preparation of l-(2-pyridyl)methyl-(3S)-..Nα-(2-naphthylcarbonyl)-L-leucinyl1aminol- pyrrolidine
Following the procedure of Example 87(c), except substituting pyridine-2- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 445.1. Example 102
Preparation of l-(3-nitro)benzyl-(3S)-..N -(2-naphthylcarbonyl)-L-leucinyllaminol-pyrrolidine
Following the procedure of Example 87(c), except substituting 3-nitrobenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 489.3.
Example 103
Preparation of l-(4-acetamido)benzyl-(3S)-..Nα-(2-naphthylcarbonyl)-L-leucinyl]amino1- pyrrolidine
a) l-(2,2,2-trichloroethyl)carbonyl-(3S)-[[Nα-(tgrt-butoxycarbonyl)amino]-pyrrolidine
To a stirred solution of (3S)-(-)-3-(tert-butoxycarbonylamino)pyrrolidine (10 g, 53.7 mmol) in CH2CI2 (150 mL) at 0°C was added N-methylmorpholine (6.50 mL, 59.1 mmol), and 2,2,2-trichloroethyl chloroformate (8.20 mL, 59.6 mmol). After stirring overnight, gradually warming to room temperature, the reaction mixture was diluted with CHCI3 (250 mL) and washed with 5% NaHC03, H 0, IN HCl, H2O, and brine, then dried (MgS04), filtered, and concentrated to give 19.96 g of the title compound: Η-NMR (400 MHz, CDCI3): d (ppm) 4.74 (s, 2H); 4.66 (br m, IH); 4.25 (br m, IH); 3.72 (m, IH); 3.56 (m, 2H); 3.33 (m, IH); 2.19 ( , IH); 1.87 (m, IH); 1.45 (s, 9H).
b) l-(2,2,2-trichloroethyl)carbonyl-(3S)-[[N -(tert-butoxycarbonyl)-L-leucinyl]amino]- pyrrolidine The compound of Example 103 (a) (19.9 g) was dissolved in 4.0 N HCl in dioxane (400 mL) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and stored under high vacuum. To a stirred solution of the residue in DMF (200 mL) was added N- methylmorpholine (8.90 mL, 80.9 mmol), HOBt (10.88 g, 80.5 mmol), Boc-Leucine hydrate (20.10 g, 80.6 mmol), and EDC (15.45 g, 80.7 mmol). The reaction was stirred overnight whereupon it was concentrated to remove most of the DMF, then diluted with EtOAc (300 mL), and washed with brine (150 mL). The aqueous layer was washed with fresh EtOAc (100 mL), the combined organic layers were washed with IN HCl, H2O, 10% Na2Cθ3, H2O, and brine, then dried (MgS04), filtered, and concentrated to give 24.64 g of the title compound: Η-NMR (400 MHz, CDCI3): d (ppm) 6.55 (br m, IH); 4.88 (m, IH); 4.76 (s, 2H); 4.48 (m, IH); 4.03 (m, lH); 3.75 (m, IH); 3.58 (m, 2H); 3.33 (m, IH); 2.19 (m, IH); 1.88 (m, IH); 1.64 (m, 2H); 1.49 (m, IH); 1.44 (s, 9H); 0.93 (m, 6H). c) l-(2,2,2-trichloroethyl)carbonyl-(3S)-[[Nα-L-leucinyl]amino]-pyrrolidine hydrochloride
The compound of Example 103 (b) (24.5 g) was dissolved in 4.0 N HCl in dioxane (500 L) and stirred at room temperature for 1 h. The solution was concentrated to a white solid and dried under high vacuum to give the title compound: MS (ES+) (MH+) 375.
d) l-(2,2,2-trichloroethyl)carbonyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine
To a stirred solution of the compound of Example 103(c) (10.28 g, 25.0 mmol) in DMF (75 mL) was added N-methylmorpholine (4.2 mL, 38.2 mmol), HOBt (5.07 g, 37.5 mmol), 2- naphthoic acid (6.46 g, 37.5 mmol), and EDC (7.18 g, 37.5 mmol). The reaction was stirred overnight whereupon it was concentrated to remove most of the DMF, then partitioned between EtOAc (300 mL), IN HCl (150 mL), and brine (150 mL). The aqueous layer was washed with fresh EtOAc (150 mL), the combined organic layers were washed with IN HCl, H2O, 10% Na2C03, H2O, and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 1 :2 EtOAc : hexane to 1 : 1 EtOAc : hexane) gave 9.74 g of the title compound: MS (ES+) (MH+) 528.1.
e) (3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
To a stirred solution of the compound of Example 103(d) (9.65 g) in THF (75 mL) was added a solution of IN NH4OAc (pH 7-7.5, 15 mL), followed by Zn powder (9.53 g). The reaction was stirred for 5 h at room temperature whereupon fresh Zn (4 g) was added and the reaction was stirred overnight. The slurry was filtered through a pad of Celite, followed by several THF washes. The combined filtrates were concentrated to remove THF, diluted with CHCI3 (300 mL), washed with 10% Na2Cθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 10:90 MeOH : CHCI3 to 10:90:0.25 MeOH : CHCI3 : NH4OH) gave 5.71 g of the title compound: MS (ES+) (MH+) 354.2.
f) l-(4-acetamido)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine
To a stirred solution of the compound of Example 103(e) (106.5 mg, 0.3 mmol) in CH2CI2 (1 mL) was added 4-acetamidobenzaldehyde (59.7 mg, 0.37 mmol). The reaction was stirred 2 h whereupon Na(OAc)3 (140.0 mg, 0.66 mmol) was added. After stirring overnight, the reaction mixture was diluted with CHCI3 (100 mL) and washed with 5% NaHCθ3 and brine, then dried (MgSθ4), filtered, and concentrated. Column chromatography (silica gel, 5:95 MeOH : EtOAc) gave 105.1 mg of the title compound: MS (ES+) (MH+) 501.4. Example 104
Preparation of l-(3-cyano)benzyl-(3S)-frN -(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 103(f), except substituting 3-cyanobenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 469.2.
Example 105
Preparation of l-(3-fluoro)benzy--(3S)-r.Nα-(2-naphthylcarbonyl)-L-leucinyl1aminol- pyrrolidine
Following the procedure of Example 103(f), except substituting 3-fluorobenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 462.3.
Example 106
Preparation of 1 -(3-phenoxy)benzyl-(3S)-, .N -(2-naphthylcarbonyl)-L-leucinyπaminol- pyrrolidine
Following the procedure of Example 103(f), except substituting 3- phenoxybenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 536.3.
Example 107
Preparation of l-(4-chloro)benzyl-(3S)-, ,Nα-(2-naphthylcarbonyl)-L-leucinyllamino1- pyrrolidine
Following the procedure of Example 103(f), except substituting 4-chlorobenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 478.3. Example 108
Preparation of 1 -(4-trifluoromethyl)benzyl-(3S)-.. Nα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 103(f), except substituting 4- (trifluoromethyl)benzaldehyde, the title compound was prepared: MS (ES+) (MH+) 512.3.
Example 109
Preparation of 1 -(3-trifluoromethyl)benzyl-(3S)-r. N -(2-naphthylcarbonyl)-L-leucinyllamino1- pyrrolidine
Following the procedure of Example 103(f), except substituting 3- (trifluoromethyl)benzaldehyde, the title compound was prepared: MS (ES+) (MH+) 512.2.
Example 110
Preparation of l-(4-(3-(N,N-dimethylamino)propoxy)benzyl-(3S)-. rN -(2-naphthylcarbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 103(f), except substituting 4-(3- dimethylaminopropoxy)benzaldehyde, the title compound was prepared: MS (ES+) (MH+) 545.2.
Example 1 11
Preparation of l-(4-(isopropyl)benzyl-(3S)-r.N -(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 103(f), except substituting 4- isopropylbenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 486.4. Example 112
Preparation of l-(2-benzofuranyl)methyl-(3SH.Nα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 103(f), except substituting benzofuran-2- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 484.2.
Example 113
Preparation of 1 -(2-(3-methylbenzo. b1thiophenyl)methyl-(3S)-.. Nα-(2-naphthylcarbonyl)-L- leucinyllaminol-pyrrolidine
Following the procedure of Example 103(f), except substituting 3- methylbenzo[b]thiophene-2-carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 514.2.
Example 114
Preparation of l-(2-furanyl)methyl-(3SHrNα-(2-naphthylcarbonyl)-L-leucinvHaminol- pyrrolidine
Following the procedure of Example 103(f), except substituting furan-2- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 434.1.
Example 115
Preparation of l-(3-furanyl)methyl-(3S)-r.N -(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 103(f), except substituting furan-3- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 434.3. Example 116
Preparation of SB l-(2-thiophenyl)methyl-(3S)-..Nα-(2-naphthylcarbonyl)-L-leucinyHaminol- pyrrolidine
Following the procedure of Example 103(f), except substituting thiophene-3- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 450.3.
Example 1 17
Preparation of l-(2-nitro)benzyl-(3S)-FrNα-(2-naphthylcarbonyl)-L-leucinyllaminol-pyrrolidine
Following the procedure of Example 103(f), except substituting 2-nitrobenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 489.3.
Example 118
Preparation of 1 -(3-thiophenyl)methyl-(3S)-[rNα-(2-naphthylcarbonyl)-L-leucinyllaminol- pyrrolidine
Following the procedure of Example 103(f), except substituting thiophene-2- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 450.2.
Example 119
Preparation of l-(3,4-dimethoxy)benzyl-(3SHrNα-(2-naphthylcarbonyl)-L-leucinyllamino1- pyrrolidine
Following the procedure of Example 103(f), except substituting 3,4- dimethoxybenzaldehyde, the title compound was prepared: MS (ES+) (MH+) 504.2. Example 120
Preparation of 1 -(5-nitro-3-furanyl)methyl-(3S)-[rNα-(2-naphthylcarbonyl)-L-leucinyllamino1 pyrrolidine
Following the procedure of Example 103(f), except substituting 5-nitrofuran-2- carboxaldehyde, the title compound was prepared: MS (ES+) (MH+) 479.1.
The above specification and Examples fully disclose how to make and use the 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, 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.

Claims

What is claimed is:
1. A compound according to formula (I):
Figure imgf000070_0001
wherein:
Y is Ar or NRiR2;
R1 is R", R"C(0), R"C(S), R"S02, R"0C(0), R"R NC(0), or R"R'NC(S); R2 is H, C galkyl, C2_6alkenyl, Ar-Cθ-6alkyl, or Het-C()-6alkyl; R3 is H, C2-6alkenyl, C2-6alkynyl, Het, Ar or Cι_6alkyl optionally substituted by OR', SR', NR'2, N(R")C(0)OR", C02R', C02NR'2, N(C=NH)NH2, Het or Ar; R4 is H, Cj.galkyl, C2-6 lkenyl, Ar-Cθ-6alkyl, or Het-Co_6alkyl;
R' R6/ N^ \
7
R5 is R , Ar-Co-6alkyl, Het-Cø-όalkyl, adamantyl-C(O)-, Ar-C(O)-, or Het-C(O)-;
R6 is R", R"C(0), R"C(S), R"S02, R"0C(0), R"R'NC(0), R"R NC(S),or R"OC(0)NR CH(R*)C(0);
R7 is C3_6cycloalkyl-Co-6alkyl, Ar-Cg-όalkyl, Het-Co-6alkyl, Ar-Co-βalkoxy, Het-Co-6alkoxy, or Chalky 1 optionally substituted by OR', SR', NR'2, N(R C(O)OR", C02R', C0 NR'2, N(C=NH)NH2, Het or Ar;
R* is H, Cμgalkyl, C2_6alkenyl, C3_6cycloalkyl-Co-6-alkyl, Ar-Cn-6alkyl, Het-Co-6alkyl; each R independently is H, C galkyl, C2-6alkenyl, Ar-Cθ-6alkyl, or Het-Co_6alkyl; each R independently is Cj.galkyl, C3_6cycloalkyl-CQ.g-alkyl, Ar-Co-6alkyl, or Het-Co-6alkyl;
R'" is H, Ci -galkyl, C3_6cycloalkyl-Co-6alkyl, Ar-Crj-όalkyl, or Het-Co_6alkyl; Z is C(O) or CH2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
2. A compound according to formula (la):
Figure imgf000071_0001
wherein:
R1 is R", R"C(0), R"C(S), R"S02, R"OC(0), R"R'NC(0), or R"R 'NC(S);
R2 is H, Cj-galkyl, C2-6alkenyl, Ar-Cθ-6alkyl, or Het-Co_6alkyl;
R3 is H, C2-6alkenyl, C2-6alkynyl, Het, Ar or Ci-βalkyl optionally substituted by OR', SR', NR*2, N(R-)C(0)OR", C02R', C02NR'2, N(C=NH)NH2, Het or Ar;
R4 is H, C j-galkyl, C2_6alkenyl, Ar-Cθ-6alkyl, or Het-Cg-όalkyl;
R'
R6/
R5 is R , Ar-Cn-6alkyl, Het-Cø-όalkyl, adamantyl-C(O)-,
Ar-C(O)-, or Het-C(O)-;
R6 is R", R"C(0), R"C(S), R"S02, R"OC(0), R"R 'NC(O), R"R NC(S),or R"OC(0)NR CH(R*)C(0); R7 is C3_6cycloalkyl-Co_6al yl, Ar-Cø-galkyl, Het-Cg-όalkyl, Ar-Co-βalkoxy,
Het-C0_6alkoxy, or Ci-6alky 1 optionally substituted by OR', SR', NR'2, N(R')C(0)OR", C02R', C02NR'2, N(C=NH)NH2, Het or Ar;
R is H, Ci .galkyl, C2_6alkenyl, C3_6cycloalkyl-Co-6-alkyl, Ar-Cg-όalkyl, Het-Co_6alkyl; each R independently is H, Ci .galkyl, C2-6 lkenyl, Ar-Cθ-6alkyl, or
Het-Co_6alkyl; each R independently is Ci .galkyl, C3_6cycloalkyl-Co-6-alkyl, Ar-C()-6alkyl, or Het-Co-6alkyl;
R'" is H, Cj.galkyl, C3_6cycloalkyl-Co-.6al yl, Ar-CQ-6alkyl, or Het-Co-ζalkyl; Z is C(O) or CH2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 wherein R4 and R'" are each H.
4. A compound according to claim 1 wherein R3 is Cj.galkyl.
5. A compound according to claim 4 wherein R3 is i-butyl.
6. A compound according to claim 1 wherein Y is NRJR2, in which R2 is H and R1 is R"C(0) or R"OC(0), and R" in said R1 group is C^galkyl, Ar-Cθ-6alkyl or
Het-Co-6alkyl.
7. A compound according to claim 6 wherein R in said R^ group is tert-butyl,
Figure imgf000072_0001
A compound according to claim 1 wherein n is 1 or 2.
A compound according to claim 8 wherein n is 1.
10. A compound according to claim 1 wherein R^ is benzyl or
Figure imgf000072_0002
, in which R' is H, R7 is Cμgalkyl, R6 is R"θC(0) and Z is CH2.
11. A compound according to claim 10 wherein, in said R-> group, R7 is i- butyl and R" is benzyl.
12. A compound according to claim 2 of the formula (lb):
Figure imgf000073_0001
13. A compound according to claim 2 of the formula (Ic):
Figure imgf000073_0002
14. A compound according to claim 1 which is: 3-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; l-benzyl-3-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine;
3-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; l-benzyl-3-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(benzyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(tgrt-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine;
(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; l-benzyl-(3R)-[[Nα-(2-naphthyl)acetyl-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3R)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3R)-[[N -(3-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3R)-[[N -(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3R)-[[Nα-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(2-naphthyl)acetyl-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(3-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(3-isoquinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-4-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-piperidine; l-benzyl-4-[[N -(2-quinolinecarbonyl)-L-leucinyl]amino]-piperidine; l-benzyl-4-[[Nα-(benzyloxycarbonyl)-L-leucinyl]amino]-piperidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[Nα-(2-quinolinecarbonyl)-L-leucinyllamino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3S)-[[Nα-(3-isoquinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[N -(2-naphthylcarbonyI)-L-leucinyl]amino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[Nα-(3-isoquinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine; l-[3-(2-pyridyl)phenyl]-2-ethyl-(3R)-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(l-adamantanecarbonyl)-(3R)-[[N -(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(l-adamantanecarbonyl)-(3S)-[[Nα-(4-pyridylmethoxycarbonyl)-L-leucinyl]amino]- pyrrolidine;
(3R)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[tNα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(benzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[N -(benzothiazole-6-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3R)-[[Nα-(indole-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(4-fluorobenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[N -(4-methoxybenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(3,4-dichlorobenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3R)-[[N -(thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(4-biphenylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3R)-[[Nα-(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[N -(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[N -(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl- 2-[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3R)-[[Nα-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]- 1 - [(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[N -(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- t[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[tNα-(benzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]- pyrrolidine;
(3S)-t[N -(benzothiazole-6-carbonyl)-L-leucinyl]amino]-l-t(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(indole-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[Nα-(4-fluorobenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(4-methoxybenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[N -(3,4-dichlorobenzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[N -(4-biphenylcarbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[Nα-(5-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[Nα-(5-chlorobenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[Nα-(7-methoxybenzofuran-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; (3S)-[[Nα-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2-
[[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine;
(3S)-[[N«-(3-(2-pyridyl)benzoyl)-L-leucinyl]amino]-l-[(2S)-4-methyl-2- [[(benzyloxycarbonyl)amino]pentyl]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[Nα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[Nα-(benzofuran-2-carbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenyl)benzyl-(3S)-[[N -(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]- pyrrolidine; l-(4-phenyl)benzyl-(3S)-[tNα-(benzyloxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(2-quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]- pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(benzofuran -2-carbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-phenyl)ethyl-(3S)-[[Nα-(3-chlorobenzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]- pyrrolidine; l-(4-phenoxy)benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenoxy)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenoxy)benzyl-(3S)-[[Nα-(2- quinolinecarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenoxy)benzyl-(3S)-[[Nα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine; l-(4-phenoxy)benzyl-(3S)-t[Nα-(benzofuran -2-carbonyl)-L-leucinyl]amino]-pyrrolidine l-(4-phenoxy)benzyl-(3S)-[[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]- pyrrolidine; l-(4-fluoro)benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-fluoro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-fluoro)benzyl-(3S)-t[Nα-(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]- pyrrolidine; l-(4-cyano)benzyl-(3S)-[[Nα-(tert-butoxycarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-cyano)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[N -(benzo[b]thiophene-2-carbonyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(3,4-dimethoxybenzoyl)-L-leucinyl]amino]-pyrrolidine; l-benzyl-(3S)-[[Nα-(3-(2-dimethylaminoethoxy)-4-methoxybenzoyl)-L-leucinyl]amino]- pyrrolidine; l-(4-nitro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-(N,N-dimethylamino)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(4-methoxy)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]aminoJ-pyrrolidine; l-(4-pyridyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-carboxymethyl)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]aminoj- pyrrolidine; l-(3,4-methylenedioxy)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(2-naρhthyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-indolyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-quinolinyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-quinolinyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(l-naphthyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-quinolinyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-pyrrolyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-pyridyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-pyridyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-nitro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-acetamido)benzyl-(3S)-[tNα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-cyano)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-fluoro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-phenoxy)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-chloro)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(4-trifluoromethyl)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; l-(3-trifluoromethyl)benzyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine;
1 -(4-(3-(N,N-dimethy lamino)propoxy)benzy 1-(3S)- [ [N -(2-naphthy lcarbonyl)-L- leucinyl]amino]-pyrrolidine; l-(4-(isopropyl)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-benzofuranyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-(3-methylbenzo[b]thiophenyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L- leucinyl]amino]-pyrrolidine; l-(2-furanyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3-furanyl)methyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-thiophenyl)methyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(2-nitro)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine;
-(3-thiophenyl)methyl-(3S)-[[N -(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; l-(3,4-dimethoxy)benzyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]-pyrrolidine; or l-(5-nitro-3-furanyl)methyl-(3S)-[[Nα-(2-naphthylcarbonyl)-L-leucinyl]amino]- pyrrolidine; a pharmaceutically acceptable salt thereof.
15. A pharmaceutical composition comprising a compound according to any one of claims 1-14 and a pharmaceutically acceptable carrier.
16. A method of inhibiting a cysteine protease which comprises administering a compound according to claim 1.
17. A method according to claim 16 wherein the cysteine protease is cathepsin K.
18. A method of inhibiting bone loss which comprises administering a compound according to claim 1.
19. A method of treating osteoporosis which comprises administering a compound according to claim 1.
20. A method of treating gingival or peridontal disease which comprises administering a compound according to claim 1.
21. A method of treating a disease characterized by excessive cartilage or matrix degradation which comprises administering a compound according to claim 1.
22. A method according to claim 21 wherein said disease is osteoarthritis or rheumatoid arthritis.
23. A compound according to any one of claims 1 to 14 for use as a medicament.
24. 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.
25. The use of a compound according to claim 24 wherein the cysteine protease is cathepsin K.
26. 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.
27. 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.
28. 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.
29. 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 characterized by excessive cartilage or matrix degradation.
30. The use of a compound according to claim 29 wherein the disease characterized by excessive cartilage or matrix degradation is osteoarthritis or rheumatoid arthritis.
31. A process for preparing a compound of the formula (I) as defined in claim 1 , which process comprises:
reacting a compound of the formula (II):
Figure imgf000079_0001
(ID or a salt thereof, wherein R'", R3, R4, R^ and n are as defined in formula (I) of claim l , with any reactive functional groups protected, with: (a) R C(0)C1, in which R is as defined in formula (I) of claim 1 ; or
(b) R C(0)OH, in which R is as defined in formula (I) of claim 1, in the presence of EDC and HOBT; or
(c) R C(0)H, in which R is as defined in formula (I) of claim 1, followed by reduction; or
(d) R"θC(0)Cl, in which R" is as defined in formula (I) of claim 1 , in the presence of base; or
(e) R SO2CI, in which R is as defined in formula (I) of claim 1 , in the presence of base;
and thereafter removing any protecting groups and optionally forming a pharmaceutically acceptable salt.
32. A compound according to formula (II):
Figure imgf000080_0001
wherein:
R3 is H, C2-6alkenyl, C2-6alkynyl, Het, Ar or C]-6alkyl optionally substituted by OR', SR', NR'2, N(R')C(0)OR", C02R', C0 NR'2, N(C=NH)NH2, Het or Ar; R4 is H, Cι_6alkyl, C2_6alkenyl, Ar-Cθ-6alkyl, or Het-C0-6alkyl;
R5 is
Figure imgf000080_0002
, Ar-Cn-6alkyl, Het-Co-6alkyl, adamantyl-C(O)-,
Ar-C(O)-, Het-C(O)- or ;
R6 is R", R"C(0), R"C(S), R"S02, R"0C(0), R"R 'NC(O), R"RNC(S),or R"OC(0)NR CH(R*)C(0); R7 is C3-6cycloalkyl-Cn-6alkyl, Ar-Cn-6alkyl, Het-Crj-όalkyl, Ar-Co-6alkoxy, Het-CQ-6alkoxy, or C]-6alkyl optionally substituted by OR', SR', NR'2, N(R')C(0)OR", C02R', C02NR'2, N(C=NH)NH2, Het or Ar;
R is H, Cj.galkyl, C2-6alkenyl, C3_gcycloalkyl-Co-6-alkyl, Ar-Co-6alkyl, Het-Co-6alkyl; each R independently is H, C^alkyl, C2-6al enyl, Ar-Cθ-6alkyl, or Het-Co_6alkyl; each R independently is C galkyl, C3_6cycloalkyl-Co-6-alkyl, Ar-Cθ-6alkyl, or Het-Co-6alkyl; R" ' is H, C i -6alkyl, C3.6cycloalkyl-C0-6alkyl, Ar-C0.6alkyl, or Het-C0.6alkyl ;
Z is C(O) or CH2; and n is 1, 2 or 3; or a pharmaceutically acceptable salt thereof.
PCT/US1998/009192 1997-05-08 1998-05-06 Protease inhibitors WO1998050534A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
CA002289010A CA2289010A1 (en) 1997-05-08 1998-05-06 Protease inhibitors
PL98336625A PL336625A1 (en) 1997-05-08 1998-05-06 Protease inhibitors
BR9808502-6A BR9808502A (en) 1997-05-08 1998-05-06 Protease inhibitors
AU72885/98A AU7288598A (en) 1997-05-08 1998-05-06 Protease inhibitors
JP54841898A JP2001525809A (en) 1997-05-08 1998-05-06 Protease inhibitor
HU0001285A HUP0001285A3 (en) 1997-05-08 1998-05-06 Pyrrolidine derivatives as protease inhibitors, process for producing them and pharmaceutical compositions containing them
EP98920274A EP0991753A4 (en) 1997-05-08 1998-05-06 Protease inhibitors
US09/423,325 US6369077B1 (en) 1997-05-08 1998-05-06 Protease inhibitors
IL13166198A IL131661A0 (en) 1997-05-08 1998-05-06 Protease inhibitors
NO995433A NO995433L (en) 1997-05-08 1999-11-05 Protease inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US4686597P 1997-05-08 1997-05-08
US60/046,865 1997-05-08

Publications (1)

Publication Number Publication Date
WO1998050534A1 true WO1998050534A1 (en) 1998-11-12

Family

ID=21945814

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1998/009192 WO1998050534A1 (en) 1997-05-08 1998-05-06 Protease inhibitors

Country Status (18)

Country Link
US (1) US6369077B1 (en)
EP (1) EP0991753A4 (en)
JP (1) JP2001525809A (en)
KR (1) KR20010012316A (en)
CN (1) CN1255162A (en)
AU (1) AU7288598A (en)
BR (1) BR9808502A (en)
CA (1) CA2289010A1 (en)
CO (1) CO4950617A1 (en)
HU (1) HUP0001285A3 (en)
IL (1) IL131661A0 (en)
MA (1) MA26494A1 (en)
NO (1) NO995433L (en)
PE (1) PE73799A1 (en)
PL (1) PL336625A1 (en)
TR (1) TR199902752T2 (en)
WO (1) WO1998050534A1 (en)
ZA (1) ZA983843B (en)

Cited By (43)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999025686A1 (en) * 1997-11-18 1999-05-27 Teijin Limited Cyclic amine derivatives and their use as drugs
WO2000029408A1 (en) * 1998-11-13 2000-05-25 Smithkline Beecham P.L.C. Morpholino-ethoxybenzofuran protease inhibitors
WO2000069815A1 (en) * 1999-05-13 2000-11-23 Teijin Limited Ureido-substituted cyclic amine derivatives and their use as drug
WO2000069820A1 (en) * 1999-05-14 2000-11-23 Combichem, Inc. Cyclic amine derivatives and their uses
WO2000069432A1 (en) * 1999-05-18 2000-11-23 Teijin Limited Remedies or preventives for diseases in association with chemokines
WO2001010439A1 (en) * 1999-08-04 2001-02-15 Teijin Limited Cyclic amine ccr3 antagonists
WO2001045700A1 (en) * 1999-12-21 2001-06-28 Smithkline Beecham Corporation Urotensin-ii receptor antagonists
EP1140897A1 (en) * 1998-12-23 2001-10-10 SmithKline Beecham Corporation Protease inhibitors
US6362177B1 (en) 2000-05-16 2002-03-26 Teijin Limited Cyclic amine derivatives and their use as drugs
US6395753B1 (en) * 2001-08-30 2002-05-28 Kowa Co., Ltd. Cyclic amine compounds and pharmaceutical composition containing the same
EP1238970A1 (en) * 1999-12-08 2002-09-11 Teijin Limited Cycloamine ccr5 receptor antagonists
US6756393B2 (en) 2000-03-06 2004-06-29 Acadia Pharmaceuticals, Inc. Azacyclic compounds
US6995268B2 (en) 2000-06-20 2006-02-07 Wayne State University N- and O-substituted 4-[2-(diphenylmethoxy)-ethyl]-1- (phenyl) methyl) piperidine analogs and methods of treating CNS disorders therewith
US7109243B2 (en) 2003-03-24 2006-09-19 Irm Llc Inhibitors of cathepsin S
US7173051B2 (en) 2003-06-13 2007-02-06 Irm, Llc Inhibitors of cathepsin S
US7217719B2 (en) 2001-12-28 2007-05-15 Acadia Pharmaceuticals Inc. Spiroazacyclic compounds as monoamine receptor modulators
EP1796793A2 (en) * 2004-09-07 2007-06-20 Smithkline Beecham Corporation Novel compounds
US7253186B2 (en) 2002-06-24 2007-08-07 Carl-Magnus Andersson N-substituted piperidine derivatives as serotonin receptor agents
US7256207B2 (en) 2003-08-20 2007-08-14 Irm Llc Inhibitors of cathepsin S
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7342027B2 (en) 2002-07-26 2008-03-11 Yuhan Corporation 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof
US7384970B2 (en) 2003-03-24 2008-06-10 Irm Llc Inhibitors of cathepsin S
US7476682B2 (en) 2002-06-24 2009-01-13 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
US7538222B2 (en) 2002-06-24 2009-05-26 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
US7601740B2 (en) 2003-01-16 2009-10-13 Acadia Pharmaceuticals, Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US7732615B2 (en) 2004-09-27 2010-06-08 Acadia Pharmaceuticals Inc. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
US7790899B2 (en) 2004-09-27 2010-09-07 Acadia Pharmaceuticals, Inc. Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
US7820695B2 (en) 2004-05-21 2010-10-26 Acadia Pharmaceuticals, Inc. Selective serotonin receptor inverse agonists as therapeutics for disease
US7863296B2 (en) 2004-05-21 2011-01-04 Acadia Pharmaceuticals, Inc. Selective serotonin receptor inverse agonists as therapeutics for disease
US7915433B2 (en) 2004-04-16 2011-03-29 Wayne State University Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives
US8017791B2 (en) 2003-03-28 2011-09-13 Wayne State University Tri-substituted 2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-ol analogues, and novel, 3,6-disubstituted pyran derivatives
WO2011112685A1 (en) * 2010-03-10 2011-09-15 Janssen Pharmaceutica Nv 4,4-disubstituted piperidine derivatives useful as inhibitors of dipeptidyl peptidase-1 (dpp-1)
US8067457B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
US8067415B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
US8211916B2 (en) 2000-06-20 2012-07-03 Wayne State University N- and O-substituted 4-[2-(diphenylmethoxy)-ethyl]-1-[(phenyl)methyl]piperidine analogs and methods of treating CNS disorders therewith
US8686152B2 (en) 2010-03-10 2014-04-01 Janssen Pharmaceutica Nv 4,4-disubstituted piperidine derivatives useful as inhibitors of dipeptidyl peptidase-1 (DPP-1)
US9050343B2 (en) 2007-03-19 2015-06-09 Acadia Pharmaceuticals Inc. Combination of pimavanserin and risperidone for the treatment of psychosis
US10449185B2 (en) 2017-08-30 2019-10-22 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US10517860B2 (en) 2016-03-25 2019-12-31 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US10953000B2 (en) 2016-03-25 2021-03-23 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US10981870B2 (en) 2015-07-20 2021-04-20 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form
US11135211B2 (en) 2017-04-28 2021-10-05 Acadia Pharmaceuticals Inc. Pimavanserin for treating impulse control disorder
US11464768B2 (en) 2016-12-20 2022-10-11 Acadia Pharmaceuticals Inc. Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis

Families Citing this family (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7071184B2 (en) * 2000-03-21 2006-07-04 Smithkline Beecham Corporation Protease inhibitors
US20040192674A1 (en) * 2003-02-14 2004-09-30 Marquis Robert W. Cathepsin L inhibitors
NZ555320A (en) 2004-12-03 2010-11-26 Schering Corp Substituted piperazines as CB1 antagonists
CA2619706A1 (en) * 2005-08-17 2007-02-22 Schering Corporation Novel high affinity quinoline-based kinase ligands
US20100016289A1 (en) * 2005-11-01 2010-01-21 Kevin Sprott Compounds Useful as Antagonists of CCR2
US20070203183A1 (en) * 2006-01-13 2007-08-30 Schering Corporation Diaryl piperidines as CB1 modulators
WO2007084450A2 (en) * 2006-01-18 2007-07-26 Schering Corporation Cannibinoid receptor modulators
JPWO2008029924A1 (en) 2006-09-08 2010-01-21 大日本住友製薬株式会社 Cyclic aminoalkylcarboxamide derivatives
US20100197564A1 (en) * 2007-04-19 2010-08-05 Schering Corporation Diaryl morpholines as cb1 modulators
WO2009005646A2 (en) * 2007-06-28 2009-01-08 Schering Corporation Substituted piperazines as cb1 antagonists
WO2009005671A2 (en) * 2007-06-28 2009-01-08 Schering Corporation Substituted piperazines as cb1 antagonists
EA201691840A1 (en) 2014-04-04 2017-03-31 Икс-Рикс, Инк. SUBSTITUTED SPYROCYCLIC INHIBITORS AUTOTAXIN

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4301151A (en) * 1979-11-27 1981-11-17 Merck & Co., Inc. Long-lasting agonists of enkephalin
US4680283A (en) * 1984-09-26 1987-07-14 Merck & Co., Inc. Analogs of substance P and eledoisin
US5514694A (en) * 1992-09-21 1996-05-07 Georgia Tech Research Corp Peptidyl ketoamides

Family Cites Families (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2804416A1 (en) 1978-02-02 1979-08-09 Boehringer Mannheim Gmbh NEW PURINE DERIVATIVES, METHOD FOR THE PRODUCTION THEREOF AND MEDICINAL PRODUCTS CONTAINING THESE COMPOUNDS
ES8100016A1 (en) 1978-07-18 1980-04-01 Hoechst Ag 1-(4-Aminopiperidino)-3.4-dihydroisoquinoline derivatives, processes for their preparation, pharmaceutical compositions containing them and their use.
US4443461A (en) 1981-09-10 1984-04-17 John Wyeth & Brother Limited N-[2-[[1-[1H-Indolylalkyl- or oxoalkyl]-4-piperidinyl]-amino]-2-oxoethyl]-arylcarboxamide derivatives
DK386089A (en) 1988-08-12 1990-02-13 Japan Tobacco Inc KATEKOLDERIVATER
IE903196A1 (en) 1989-09-05 1991-03-13 Searle & Co Substituted n-benzylpiperidine amides
WO1991015487A1 (en) * 1990-03-30 1991-10-17 Japan Tobacco Inc. Novel 4h-3,1-benzoxazin-4-one derivative
JPH09501404A (en) 1993-05-26 1997-02-10 スミスクライン・ビーチャム・ラボラトワール・ファルマソーティク New compound
US5827866A (en) * 1995-06-07 1998-10-27 Ortho Pharmaceutical Corporation Peptidyl heterocycles useful in the treatment of thrombin related disorders
DZ2285A1 (en) 1996-08-08 2002-12-25 Smithkline Beecham Corp Cysteine protease inhibitors.

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4301151A (en) * 1979-11-27 1981-11-17 Merck & Co., Inc. Long-lasting agonists of enkephalin
US4680283A (en) * 1984-09-26 1987-07-14 Merck & Co., Inc. Analogs of substance P and eledoisin
US5514694A (en) * 1992-09-21 1996-05-07 Georgia Tech Research Corp Peptidyl ketoamides

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
See also references of EP0991753A4 *
TSUDA M, ET AL.: "POSTSTATIN, A NEW INHIBITOR OF PROLYL ENDOPEPTIDASE VI. ENDOPEPTIDASE INHIBITORY ACTIVITY OF POSTSTATIN ANALOGUES CONTAINING PYRROLIDINE RING", THE JOURNAL OF ANTIBIOTICS, NATURE PUBLISHING GROUP, GB, vol. 49, no. 09, 1 September 1996 (1996-09-01), GB, pages 900 - 908, XP002914236, ISSN: 0021-8820 *
TSUDA M, ET AL.: "POSTSTATIN, A NEW INHIBITOR OF PROLYL ENDOPEPTIDASE VII. N-CYCLOALKYLAMIDE ANALOGUES", THE JOURNAL OF ANTIBIOTICS, NATURE PUBLISHING GROUP, GB, vol. 49, no. 09, 1 September 1996 (1996-09-01), GB, pages 909 - 920, XP002914237, ISSN: 0021-8820 *
YAMASHITA D S, ET AL.: "STRUCTURE AND DESIGN OF POTENT AND SELECTIVE CATHEPSIN K INHIBITORS", JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, AMERICAN CHEMICAL SOCIETY, US, vol. 119, no. 46, 1 November 1997 (1997-11-01), US, pages 11351/11352, XP002914235, ISSN: 0002-7863, DOI: 10.1021/ja972204u *

Cited By (91)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1535909A3 (en) * 1997-11-18 2005-07-13 Teijin Limited Cyclic amine derivatives and their use as drugs
WO1999025686A1 (en) * 1997-11-18 1999-05-27 Teijin Limited Cyclic amine derivatives and their use as drugs
EP1553085A1 (en) * 1997-11-18 2005-07-13 Teijin Limited Cyclic amine derivatives and their use as drugs
EP1535909A2 (en) * 1997-11-18 2005-06-01 Teijin Limited Cyclic amine derivatives and their use as drugs
US6451842B1 (en) 1997-11-18 2002-09-17 Dupont Pharmaceuticals Company Cyclic amine derivatives and their use as drugs
WO2000029408A1 (en) * 1998-11-13 2000-05-25 Smithkline Beecham P.L.C. Morpholino-ethoxybenzofuran protease inhibitors
EP1140897A4 (en) * 1998-12-23 2002-04-03 Smithkline Beecham Corp Protease inhibitors
EP1140897A1 (en) * 1998-12-23 2001-10-10 SmithKline Beecham Corporation Protease inhibitors
WO2000069815A1 (en) * 1999-05-13 2000-11-23 Teijin Limited Ureido-substituted cyclic amine derivatives and their use as drug
US7125895B1 (en) 1999-05-14 2006-10-24 Bristol-Myers Squibb Pharma Research Labs, Inc. Cyclic amine derivatives and their uses
WO2000069820A1 (en) * 1999-05-14 2000-11-23 Combichem, Inc. Cyclic amine derivatives and their uses
KR100673340B1 (en) * 1999-05-18 2007-02-28 데이진 가부시키가이샤 Remedies or preventives for diseases in association with chemokines
WO2000069432A1 (en) * 1999-05-18 2000-11-23 Teijin Limited Remedies or preventives for diseases in association with chemokines
US7390830B1 (en) 1999-05-18 2008-06-24 Teijin Limited Remedies or prophylactics for diseases in association with chemokines
WO2001010439A1 (en) * 1999-08-04 2001-02-15 Teijin Limited Cyclic amine ccr3 antagonists
US7576117B1 (en) 1999-08-04 2009-08-18 Teijin Limited Cyclic amine CCR3 antagonist
EP1201239A1 (en) * 1999-08-04 2002-05-02 Teijin Limited Cyclic amine ccr3 antagonists
EP1201239A4 (en) * 1999-08-04 2004-12-08 Teijin Ltd Cyclic amine ccr3 antagonists
EP1238970A1 (en) * 1999-12-08 2002-09-11 Teijin Limited Cycloamine ccr5 receptor antagonists
EP1238970A4 (en) * 1999-12-08 2003-01-15 Teijin Ltd Cycloamine ccr5 receptor antagonists
WO2001045700A1 (en) * 1999-12-21 2001-06-28 Smithkline Beecham Corporation Urotensin-ii receptor antagonists
US6514970B1 (en) 1999-12-21 2003-02-04 Smithkline Beecham Corporation Urotensin-II receptor antagonists
US6756393B2 (en) 2000-03-06 2004-06-29 Acadia Pharmaceuticals, Inc. Azacyclic compounds
US9296694B2 (en) 2000-03-06 2016-03-29 Acadia Pharmaceuticals Inc. Azacyclic compounds
US6815458B2 (en) 2000-03-06 2004-11-09 Acadia Pharmaceuticals, Inc Azacyclic compounds
US9765053B2 (en) 2000-03-06 2017-09-19 Acadia Pharmaceuticals Inc. Methods of treatment using selective 5-HT2A inverse agonists
US6362177B1 (en) 2000-05-16 2002-03-26 Teijin Limited Cyclic amine derivatives and their use as drugs
US6410566B1 (en) 2000-05-16 2002-06-25 Teijin Limited Cyclic amine derivatives and their use as drugs
US7595331B2 (en) 2000-06-20 2009-09-29 Wayne State University N-and O-substituted 4-[2-(diphenylmethoxy)-ethyl]-1-[(phenyl)methyl]piperidine analogs and methods of treating CNS disorders therewith
US8211916B2 (en) 2000-06-20 2012-07-03 Wayne State University N- and O-substituted 4-[2-(diphenylmethoxy)-ethyl]-1-[(phenyl)methyl]piperidine analogs and methods of treating CNS disorders therewith
US6995268B2 (en) 2000-06-20 2006-02-07 Wayne State University N- and O-substituted 4-[2-(diphenylmethoxy)-ethyl]-1- (phenyl) methyl) piperidine analogs and methods of treating CNS disorders therewith
US6395753B1 (en) * 2001-08-30 2002-05-28 Kowa Co., Ltd. Cyclic amine compounds and pharmaceutical composition containing the same
US7402590B2 (en) 2001-12-28 2008-07-22 Acadia Pharmaceuticals Inc. Spiroazacyclic compounds as monoamine receptor modulators
US7511053B2 (en) 2001-12-28 2009-03-31 Acadia Pharmaceuticals, Inc. Spiroazacyclic compounds as monoamine receptor modulators
US7727999B2 (en) 2001-12-28 2010-06-01 Acadia Pharmaceuticals Inc. Spiroazacyclic compounds as monoamine receptor modulators
US7351707B2 (en) 2001-12-28 2008-04-01 Acadia Pharmaceuticals, Inc. Spiroazacyclic compounds as monoamine receptor modulators
US7217719B2 (en) 2001-12-28 2007-05-15 Acadia Pharmaceuticals Inc. Spiroazacyclic compounds as monoamine receptor modulators
US7282512B2 (en) 2002-01-17 2007-10-16 Smithkline Beecham Corporation Cycloalkyl ketoamides derivatives useful as cathepsin K inhibitors
US7476682B2 (en) 2002-06-24 2009-01-13 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
US7253186B2 (en) 2002-06-24 2007-08-07 Carl-Magnus Andersson N-substituted piperidine derivatives as serotonin receptor agents
US7538222B2 (en) 2002-06-24 2009-05-26 Acadia Pharmaceuticals, Inc. N-substituted piperidine derivatives as serotonin receptor agents
US7342027B2 (en) 2002-07-26 2008-03-11 Yuhan Corporation 1-phenylpiperidin-3-one derivatives and processes for the preparation thereof
US9211289B2 (en) 2003-01-16 2015-12-15 Acadia Pharmaceuticals Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US7994193B2 (en) 2003-01-16 2011-08-09 Acadia Pharmaceuticals Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US8618130B2 (en) 2003-01-16 2013-12-31 Acadia Pharmaceuticals Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US7601740B2 (en) 2003-01-16 2009-10-13 Acadia Pharmaceuticals, Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US7659285B2 (en) 2003-01-16 2010-02-09 Acadia Pharmaceuticals, Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US7713995B2 (en) 2003-01-16 2010-05-11 Acadia Pharmaceuticals, Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US10525046B2 (en) 2003-01-16 2020-01-07 Acadia Pharmaceuticals Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US7732462B2 (en) 2003-01-16 2010-06-08 Acadia Pharmaceuticals Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US10028944B2 (en) 2003-01-16 2018-07-24 Acadia Pharmaceuticals Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US8008323B2 (en) 2003-01-16 2011-08-30 Acadia Pharmaceuticals Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US9566271B2 (en) 2003-01-16 2017-02-14 Acadia Pharmaceuticals Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US8377959B2 (en) 2003-01-16 2013-02-19 Acadia Pharmaceuticals, Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US8921393B2 (en) 2003-01-16 2014-12-30 Acadia Pharmaceuticals Inc. Selective serotonin 2A/2C receptor inverse agonists as therapeutics for neurodegenerative diseases
US7384970B2 (en) 2003-03-24 2008-06-10 Irm Llc Inhibitors of cathepsin S
US7109243B2 (en) 2003-03-24 2006-09-19 Irm Llc Inhibitors of cathepsin S
US8017791B2 (en) 2003-03-28 2011-09-13 Wayne State University Tri-substituted 2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-ol analogues, and novel, 3,6-disubstituted pyran derivatives
US7173051B2 (en) 2003-06-13 2007-02-06 Irm, Llc Inhibitors of cathepsin S
US7256207B2 (en) 2003-08-20 2007-08-14 Irm Llc Inhibitors of cathepsin S
US7507755B2 (en) 2003-08-20 2009-03-24 Irm Llc Inhibitors of cathepsin s
US7915433B2 (en) 2004-04-16 2011-03-29 Wayne State University Tri-substituted 2-benzhydryl 5-benzlamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6 disubstituted pyran derivatives
US8937189B2 (en) 2004-04-16 2015-01-20 Wayne State University Tri-substituted 2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-ol analogues, and novel 3,6-disubstituted pyran derivatives
US8841464B2 (en) 2004-04-16 2014-09-23 Wayne State University Tri-substituted 2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-ol and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-ol analogues, and novel 3,6-disubstituted pyran derivatives
US8519159B2 (en) 2004-04-16 2013-08-27 Wayne State University Tri-substituted 2-benzhydryl-5-benzylamino-tetrahydro-pyran-4-OL and 6-benzhydryl-4-benzylamino-tetrahydro-pyran-3-OL analogues, and novel 3,6-disubstituted pyran derivatives
US7875632B2 (en) 2004-05-21 2011-01-25 Acadia Pharmaceuticals, Inc. Selective serotonin receptor inverse agonists as therapeutics for disease
US7863296B2 (en) 2004-05-21 2011-01-04 Acadia Pharmaceuticals, Inc. Selective serotonin receptor inverse agonists as therapeutics for disease
US7820695B2 (en) 2004-05-21 2010-10-26 Acadia Pharmaceuticals, Inc. Selective serotonin receptor inverse agonists as therapeutics for disease
EP1796793A4 (en) * 2004-09-07 2009-08-05 Smithkline Beecham Corp Novel compounds
EP1796793A2 (en) * 2004-09-07 2007-06-20 Smithkline Beecham Corporation Novel compounds
US7790899B2 (en) 2004-09-27 2010-09-07 Acadia Pharmaceuticals, Inc. Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
US7732615B2 (en) 2004-09-27 2010-06-08 Acadia Pharmaceuticals Inc. N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and crystalline forms
US7923564B2 (en) 2004-09-27 2011-04-12 Acadia Pharmaceuticals, Inc. Synthesis of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy) phenylmethyl)carbamide and its tartrate salt and crystalline forms
US7868176B2 (en) 2004-09-27 2011-01-11 Acadia Pharmaceuticals, Inc. Salts of N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-y1)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and their preparation
US8067457B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
US8067415B2 (en) 2005-11-01 2011-11-29 Millennium Pharmaceuticals, Inc. Compounds useful as antagonists of CCR2
US9050343B2 (en) 2007-03-19 2015-06-09 Acadia Pharmaceuticals Inc. Combination of pimavanserin and risperidone for the treatment of psychosis
WO2011112685A1 (en) * 2010-03-10 2011-09-15 Janssen Pharmaceutica Nv 4,4-disubstituted piperidine derivatives useful as inhibitors of dipeptidyl peptidase-1 (dpp-1)
US8686152B2 (en) 2010-03-10 2014-04-01 Janssen Pharmaceutica Nv 4,4-disubstituted piperidine derivatives useful as inhibitors of dipeptidyl peptidase-1 (DPP-1)
US10981870B2 (en) 2015-07-20 2021-04-20 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form
US10981871B2 (en) 2015-07-20 2021-04-20 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form C
US11840515B2 (en) 2015-07-20 2023-12-12 Acadia Pharmaceuticals Inc. Methods for preparing N-(4-fluorobenzyl)-N-(1-methylpiperidin-4-yl)-N′-(4-(2-methylpropyloxy)phenylmethyl)carbamide and its tartrate salt and polymorphic form c
US10517860B2 (en) 2016-03-25 2019-12-31 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US10953000B2 (en) 2016-03-25 2021-03-23 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US11191757B2 (en) 2016-03-25 2021-12-07 Acadia Pharmaceuticals Inc. Combination of pimavanserin and cytochrome P450 modulators
US11464768B2 (en) 2016-12-20 2022-10-11 Acadia Pharmaceuticals Inc. Pimavanserin alone or in combination for use in the treatment of Alzheimer's disease psychosis
US11135211B2 (en) 2017-04-28 2021-10-05 Acadia Pharmaceuticals Inc. Pimavanserin for treating impulse control disorder
US10646480B2 (en) 2017-08-30 2020-05-12 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US10849891B2 (en) 2017-08-30 2020-12-01 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US10449185B2 (en) 2017-08-30 2019-10-22 Acadia Pharmaceuticals Inc. Formulations of pimavanserin
US11452721B2 (en) 2017-08-30 2022-09-27 Acadia Pharmaceuticals Inc. Formulations of pimavanserin

Also Published As

Publication number Publication date
AU7288598A (en) 1998-11-27
PE73799A1 (en) 1999-10-22
CN1255162A (en) 2000-05-31
CO4950617A1 (en) 2000-09-01
HUP0001285A3 (en) 2000-10-30
KR20010012316A (en) 2001-02-15
EP0991753A4 (en) 2001-07-11
PL336625A1 (en) 2000-07-03
NO995433D0 (en) 1999-11-05
CA2289010A1 (en) 1998-11-12
HUP0001285A2 (en) 2000-09-28
US6369077B1 (en) 2002-04-09
EP0991753A1 (en) 2000-04-12
IL131661A0 (en) 2001-01-28
MA26494A1 (en) 2004-12-20
NO995433L (en) 1999-11-05
BR9808502A (en) 2000-05-23
ZA983843B (en) 1998-11-09
JP2001525809A (en) 2001-12-11
TR199902752T2 (en) 2000-06-21

Similar Documents

Publication Publication Date Title
US6369077B1 (en) Protease inhibitors
EP0936912B1 (en) Inhibitors of cysteine protease
US7071184B2 (en) Protease inhibitors
AU2001243441A1 (en) Protease inhibitors
WO1998008802A1 (en) Inhibitors of cysteine protease
US20040180927A1 (en) Inhibitors of cysteine protease
EP1079821A1 (en) Protease inhibitors
CZ20024086A3 (en) Protease inhibitors
JP2004527575A (en) Protease inhibitor
WO2003053331A2 (en) Protease inhibitors
EP1384713B1 (en) 4-amino-azepan-3-one derivatives as protease inhibitors
CZ395399A3 (en) Protease inhibitors
US20050234038A1 (en) Protease inhibitors
MXPA99010260A (en) Protease inhibitors
US20020082426A1 (en) Protease inhibitors
US20040038965A1 (en) Protease inhibitors
CZ393499A3 (en) Protease inhibitors

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 98804794.2

Country of ref document: CN

Ref document number: 131661

Country of ref document: IL

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AU BA BB BG BR CA CN CZ EE GE HU ID IL IS JP KP KR LC LK LR LT LV MG MK MN MX NO NZ PL RO SG SI SK SL TR TT UA US UZ VN YU

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 72885/98

Country of ref document: AU

Ref document number: 337365

Country of ref document: NZ

WWE Wipo information: entry into national phase

Ref document number: 09423325

Country of ref document: US

ENP Entry into the national phase

Ref document number: 2289010

Country of ref document: CA

Ref document number: 2289010

Country of ref document: CA

Kind code of ref document: A

Ref document number: 1998 548418

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1019997010268

Country of ref document: KR

WWE Wipo information: entry into national phase

Ref document number: PV1999-3953

Country of ref document: CZ

Ref document number: 1999/02752

Country of ref document: TR

Ref document number: PA/a/1999/010260

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 1998920274

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: PV1999-3953

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1998920274

Country of ref document: EP

WWP Wipo information: published in national office

Ref document number: 1019997010268

Country of ref document: KR

WWR Wipo information: refused in national office

Ref document number: PV1999-3953

Country of ref document: CZ

WWW Wipo information: withdrawn in national office

Ref document number: 1019997010268

Country of ref document: KR

WWW Wipo information: withdrawn in national office

Ref document number: 1998920274

Country of ref document: EP