WO1998050534A1 - Protease inhibitors - Google Patents
Protease inhibitors Download PDFInfo
- 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
Links
- 0 CC1CC(C)*C1 Chemical compound CC1CC(C)*C1 0.000 description 2
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
Description
Claims
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)
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)
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)
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)
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. |
-
1998
- 1998-05-06 EP EP98920274A patent/EP0991753A4/en not_active Withdrawn
- 1998-05-06 PE PE1998000344A patent/PE73799A1/en not_active Application Discontinuation
- 1998-05-06 US US09/423,325 patent/US6369077B1/en not_active Expired - Fee Related
- 1998-05-06 BR BR9808502-6A patent/BR9808502A/en not_active Application Discontinuation
- 1998-05-06 CA CA002289010A patent/CA2289010A1/en not_active Abandoned
- 1998-05-06 IL IL13166198A patent/IL131661A0/en unknown
- 1998-05-06 JP JP54841898A patent/JP2001525809A/en not_active Ceased
- 1998-05-06 KR KR1019997010268A patent/KR20010012316A/en not_active Application Discontinuation
- 1998-05-06 AU AU72885/98A patent/AU7288598A/en not_active Abandoned
- 1998-05-06 PL PL98336625A patent/PL336625A1/en not_active Application Discontinuation
- 1998-05-06 WO PCT/US1998/009192 patent/WO1998050534A1/en not_active Application Discontinuation
- 1998-05-06 MA MA25064A patent/MA26494A1/en unknown
- 1998-05-06 CN CN98804794A patent/CN1255162A/en active Pending
- 1998-05-06 HU HU0001285A patent/HUP0001285A3/en unknown
- 1998-05-06 TR TR1999/02752T patent/TR199902752T2/en unknown
- 1998-05-07 ZA ZA983843A patent/ZA983843B/en unknown
- 1998-05-08 CO CO98025629A patent/CO4950617A1/en unknown
-
1999
- 1999-11-05 NO NO995433A patent/NO995433L/en not_active Application Discontinuation
Patent Citations (3)
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)
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)
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 |