WO2009128521A1 - Inhibiteur de cystéine protéase - Google Patents

Inhibiteur de cystéine protéase Download PDF

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WO2009128521A1
WO2009128521A1 PCT/JP2009/057710 JP2009057710W WO2009128521A1 WO 2009128521 A1 WO2009128521 A1 WO 2009128521A1 JP 2009057710 W JP2009057710 W JP 2009057710W WO 2009128521 A1 WO2009128521 A1 WO 2009128521A1
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substituted
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鵜木元
速水隆志
江口広志
室賀由美子
金子俊幸
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帝人ファーマ株式会社
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/26—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C317/32—Sulfones; Sulfoxides having sulfone or sulfoxide groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton with sulfone or sulfoxide groups bound to carbon atoms of six-membered aromatic rings of the carbon skeleton
    • 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
    • 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]
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/12—Drugs for disorders of the metabolism for electrolyte homeostasis
    • A61P3/14—Drugs for disorders of the metabolism for electrolyte homeostasis for calcium homeostasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/04—Antineoplastic agents specific for metastasis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/04—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C237/10—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by nitrogen atoms not being part of nitro or nitroso groups
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/24—Benzimidazoles; Hydrogenated benzimidazoles 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 in position 2
    • C07D235/30—Nitrogen atoms not forming part of a nitro radical
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/14—Radicals substituted by singly bound hetero atoms other than halogen
    • C07D333/20—Radicals substituted by singly bound hetero atoms other than halogen by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic System
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the present invention relates to a novel compound having a cysteine protease inhibitory activity (particularly cathebsin K inhibitory activity), a method for producing the same, and a cysteine protease inhibitor (particularly a cathebsin ⁇ inhibitor) containing the compound as an active ingredient.
  • the present invention relates to compounds useful for the treatment or prevention of osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone, hypercalcemia, bone metastasis of cancer, or bone pain.
  • the pathology of osteoporosis is characterized by a decrease in bone strength and an increased risk of fractures due to a decrease in bone mass and changes in the fine structure of bone tissue.
  • bone tissue is constantly remodeled by the interaction between bone formation by mesenchymal osteoblasts and bone resorption by hematopoietic osteoclasts, and this balance maintains bone mass. Has been. However, this balance is broken for some reason, and osteoporosis is thought to be caused by the long-lasting state in which bone resorption exceeds bone formation. Since increased bone resorption is closely related to the onset and progression of pathological conditions, it is common to use bone resorption inhibitors in drug therapy for osteoporosis.
  • Osteoclasts which are multinucleated giant cells derived from hematopoietic stem cells, play a role in bone resorption. Osteoclasts differentiate from monocyte / macrophage lineage cells into osteoclast progenitors by the action of various cytokines. The progenitor cells then become mononuclear pre-osteoclasts that are attracted to the bone surface and become colonized, multinucleated and become osteoclasts. When activated, osteoclasts surround the bone surface with a wavy rim composed of complex cytoplasmic processes, dissolve hydroxyapatite by releasing acid, and secrete various proteases to form type I collagen. Decompose the protein matrix such as.
  • proteases involved in its degradation are considered essential components of bone turnover and the development and progression of osteoporosis.
  • the major protease involved in osteoclast matrix degradation is the cysteine protease, and among them, the involvement of the cathepsin family belonging to the Papain 1 family is widely known.
  • cathebucin K is attracting attention because it has been reported to be associated with various pathological conditions.
  • Cathebsin K is one of the enzymes of the cystine cathebsin family that is part of the papain par family of systemin proteases.
  • the members of the cathebsin family that are classified as cysteine proteases include: cathebsin B, cathebsin (:, cathebsin F, cathebsin H, cathebsin L, cathebsin 0, cathebsin S, cathebsin V (also called L 2) ), Cathebsin W and cathepsin Z (also called cathepsin X) are known elsewhere, and cathebsin K has a high level of expression in normal osteoclasts and is the main cysteine protease in these cells.
  • Non-Patent Documents 1 to 3 Cathebsin K is also involved in the function of osteoclasts due to mutations in the cathepsin K gene in dwarfism patients who are thought to be caused by abnormal bone resorption.
  • Non-patent Document 4 Therefore, by selectively inhibiting cathebsin K, osteoporosis, etc. It is expected to be effective treatment for diseases caused by excessive bone resorption In fact, some clinical trials have been conducted on drugs that selectively inhibit cathebucin K, and therapeutic effects can be obtained. (Non-Patent Documents 5 and 6).
  • cathebsin K may be useful in treating other diseases.
  • diseases include autoimmune diseases (eg, rheumatoid arthritis), osteoarthritis, Paget's disease of bone, hypercalcemia, bone metastasis of cancer, or bone pain.
  • cathebsin K is expressed in the synovial membrane and synovial bone destruction sites of patients with rheumatoid arthritis (Non-Patent Documents 7 to 9) and is blocked in disease model animals. Hazardous substances show medicinal properties (Non-patent Documents 10 and 11).
  • the expression level of cathebsin K is elevated in the synovium and cartilage surface layer of osteoarthritis (Non-patent Documents 12 to 14).
  • Cathebsin K expression has been observed in various cancer cells (Non-patent Documents 15 to 19), and its relationship with bone metastasis has been shown (Non-patent Documents 20 and 21).
  • Selective inhibition of cathebsin K may also be useful in treating diseases that develop due to increased osteoclastic bone resorption activity, such as Paget's disease of bone, hypercalcemia, or bone pain.
  • Cathebsin K has attracted attention as a target molecule for the treatment and prevention of diseases, and research and development of cathebsin K inhibitors has been actively conducted.
  • catebucin K inhibitors for example, chain ketone type inhibitors (Non-patent document 22), cyclic ketone type inhibitors (Non-patent documents 23 to 26), aldehyde-type inhibitors (Non-patent document 27) ), ⁇ -ketoamide type inhibitors (Non-patent document 28), ⁇ -arylethylenediamine type inhibitors (Patent documents 1 to 3, Non-patent documents 29, 30, and 34), cyanomethylene type inhibitors ( Patent Literature 4, Non-Patent Literature 3 1 to 33) have been reported.
  • Patent Document 1 describes a compound represented by the following general formula ( ⁇ ) as a low molecular weight compound that inhibits cathebsin ⁇ .
  • Patent Document 1 describes only a compound represented by the following formula (B) as a specific compound.
  • Patent Document 1 Pamphlet of International Publication No. WO02 / 070517
  • Patent Document 2 Japanese Patent Laid-Open No. 2004-256525
  • Patent Document 3 International Publication No. WO00 / 048993
  • Pamphlet Patent Document 4 International Publication No. WO03 / 075836
  • Patent Document 5 International Publication No. WO04 112709 Pamphlet
  • Non-Patent Document 1 J. Biol. Chem., 269, 1106 (1994)
  • Non-patent document 2 Biochem. Biophys. Res. Co. un., 206, p. 89 (1995)
  • Non-patent document 3 FEBS Lett., P. 357, p. 129 U995)
  • Non-Patent Document 4 Science, 273 (1997), p. 1236
  • Non-Patent Document 5 28 th ASBMR, Abstl085
  • Non-Patent Document 6 29 tb ASBMR, Abstll28
  • Non-Patent Document 7 J. Rheumatol., 25, 1887 (1998)
  • Non-Patent Document 8 Am J Pathol., 159, 2167 (2001)
  • Non-Patent Document 9 Arthritis Res Ther., 7, R65-70 (2005)-Non-Patent Document 10: J. Bone Miner. Res., 12, 1396 (1997)
  • Non-Patent Document 11 Science., 319, 624 (2008)
  • Non-Patent Document 12 Arthritis Rheum., 42, 1588 (1999)
  • Non-Patent Document 13 Arthritis Rheum., 46, 663 pages
  • Non-Patent Document 14 Arthritis Rheum., 46, 953 (2002)
  • Non-Patent Document 15 Cancer Res., 57, 5386 (1997)
  • Non-Patent Document 16 Maix Biol., 19, 717 (2001)
  • Non-Patent Document 17 Pancreas., 25, 317 (2002)
  • Non-Patent Document 18 I Bone Miner Res., 18, 222 (2003)
  • Non-Patent Document 19 Am J Clin Pathol., 125, p. 847 (2006)
  • Non-Patent Document 20 Clin Cancer Res., 9, 295 (2003)
  • Non-Patent Document 21 Mol Carcinog., 47, 66 (2008)
  • Non-Patent Document 22 J. Am. Chem. Soc., 1998, 120, 9114-9115
  • Non-Patent Document 23 J. Med. Chem., 1998, 41, 3563-3567
  • Non-Patent Document 24 J. Med. Chem., 2001, 44, 1380-1395
  • Non-Patent Document 25 Bioorg. Med. Chem., 2004, 12, 5689-5710
  • Non-Patent Document 26 J. Med. Chem., 2006, 49, 1597-1612.
  • Non-Patent Document 27 Bioorg. Med. Chem. Let ters., 2004, 14, 275-278
  • Non-Patent Document 2 8 Bioorg. Med. Chem. Letters., 2005, 15, 3540-3546
  • Non-Patent Document 29 J. Med. Chem., 2002, 45, 2352-2354
  • Non-Patent Document 30 Bioorg. Med. -6806
  • Non-patent document 31 J. Med. Chem., 2003, 46, 3709-3727
  • Non-Patent Document 3 2 Bioorg. Med. Chem. Let t., 2004, 14, 4291-4295
  • Non Patent Literature 3 3 J. Med. Chem., 2006, 49, 1066-1079
  • Non-Patent Document 3 4 Bioorg. Med. Chem. Let t., 2004, 14, 87-90 Disclosure of Invention
  • the problem to be solved by the present invention is to provide a compound having an excellent cysteine protease inhibitory action.
  • Another object of the present invention is to treat or prevent a disease selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, bone paedet disease, hypercalcemia, bone metastasis of cancer, and bone pain.
  • a disease selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, bone paedet disease, hypercalcemia, bone metastasis of cancer, and bone pain.
  • the compound having a structure in which a methylene group substituted with a trifluoromethyl group is introduced as a chemical structural feature and a salt thereof have a particularly excellent cysteine protease inhibitory action. Based on these findings, the present invention was completed.
  • the present invention relates to the following.
  • Ar 1 represents 0 6 to ⁇ 0 aryl group or an aromatic heterocyclic group
  • R 1 represents a group selected from Substituent Group 1;
  • m represents an integer of 0 to 3; the scale 3 and! ⁇ 4 are the same or different and are substituted with 1 to 6 identical or different groups selected from a hydrogen atom or substituent group 3; ⁇ Ct Ce alkyl group, 3 to 7 cycloalkyl group, C 4 to C 9 (cycloalkyl) alkyl group, phenyl group, aromatic heterocyclic group, C 7 to C 9 phenyl alkyl group, aromatic heterocyclic ring represents Ci ⁇ C 3 alkyl group) that is substituted with a group;
  • R 3 and R 4 are C! Ce alkyl groups optionally substituted with 1 to 6 identical or different groups selected from Substituent Group 3, a single bond, -0-, -NR 9 -,-S (O) q -can be bonded to each other to form a ring structure with 3 to 7 members including the carbon atom to which R 3 and R 4 are bonded;
  • R 3 and R 4 are not bonded to each other to form a ring structure, one of R 3 and R 4 represents a group that is not a hydrogen atom;
  • L represents a single bond or-(CR'QR 1 1 ) s- ;
  • s represents an integer from 1 to 4.
  • Ar 2 represents a Ce d 0 aryl group or an aromatic heterocyclic group
  • r represents 0 or 1
  • Ar 3 represents a C 6 -C 1 () aryl group, or an aromatic heterocyclic group; n represents 0 or 1
  • R 5 represents a group selected from Substituent Group 1;
  • p is an integer of 0 to 5; the substituent group 1, a hydrogen atom, a halogen atom, Shiano group, a nitro group, - R 6 a, - OR 6a, - O (CO) R ", - COOR 6a, -CON (R 6a ) (R 6b ),-N (R 6a ) (R 6 ,-NR 6a (CO) R 6 b ,-NR 6a (CO) N (R 6b ) (R 6 ,-S (O ) 2 N (R 6a ) (R 6b ), -NR 6a S (O) 2 R 6b , -S (0) q R 6a , and -S i (R 8 ) 3 ; Represents a group consisting of: C, C 6 (alkoxy group, alkylthio group, alkylsulfinyl group, and alkylsulfonyl group) optionally substituted with a halogen atom,
  • R 6a, R 6b and R 6c are the same or different, a hydrogen atom, optionally substituted with R 7 C! Cs alkyl group, optionally substituted with R 7 C 2 ⁇ C 6 alkenyl group, optionally substituted with R 7 C 2 ⁇ C 6 alkynyl group may ⁇ 3 be substituted by R 7 ⁇ (: 7 cycloalkyl, heterocyclyl groups may be substituted with R 7, R A phenyl group that may be substituted with 7 , an aromatic heterocyclic group that may be substituted with R 7 , a Cy C, a 3 aralkyl group that may be substituted with R 7 , or a substituent that is substituted with R 7 alkyl group Ci ⁇ C 3 substituted by heterocyclyl groups may, or substituted in an aromatic heterocyclic group optionally substituted by R 7 C, represents -C 3 alkyl group;
  • R ea and R 6b , R 6 a and R 6c , or R 6b and R 6c, which are present in one group, may be substituted with R 7 ,
  • R 7 To a C 6 alkyl group, a single bond, —0—, —NR 9 —, or S ( ⁇ ). Can be bonded to each other via-to form a ring structure having 3 to 7 members; q represents an integer of 0 to 2;
  • R 7 is a halogen atom, a hydroxyl group, a carboxyl group, a C, -C 4 alkyl group, a di-,-di-alkoxy group, a C, -C 4 alkoxycarbonyl group, a C, -C 4 alkylsulfonyl group, C, -C 4 Alkyl sulf An ynyl group or a cyano group,
  • R 8 represents a Ci Ce alkyl group that may be substituted with R 7 ;
  • R 9 R 10.
  • R 11 are the same or different and each represents a hydrogen atom or a C, -C 6 alkyl group optionally substituted by R 7 . ]
  • A represents a C 6 C 10 aryl group or an aromatic heterocyclic group
  • R 1 represents a group selected from Substituent Group 1;
  • R 3 and R 4 are both case 1 six identical or different optionally Ci Ce alkyl group optionally substituted by a group selected from Substituent Group 3 is a single bond, - 0 - - NR 9 - - Bonded to each other via S (0) q -and can form a ring structure of 3 7 including the carbon atom to which R 3 and R 4 are bonded;
  • R 3 and R 4 are not bonded to each other to form a ring structure, one of R 3 and R 4 represents a group that is not a hydrogen atom;
  • Ar 2 represents a C 6 C 10 aryl group or an aromatic heterocyclic group
  • Ar 3 represents a Ce d 0 aryl group or an aromatic heterocyclic group
  • n represents 0 or 1
  • R 5 represents a group selected from Substituent Group 1;
  • p is an integer of 0 to 5; the substituent group 1, a halogen atom, Shiano group, a nitro group, - R 6a, - OR 6a , - O (CO) R 6 a, - COOR 6a, - CON ( R 6a ) (R 6b ),-N (R 6a ) (R 6 ,-NR 6a (CO) R 6b ,-N
  • R 6 a (CO) N (R 6b ) (R 6c ),-S (O) 2 N (R 6 a ) (R 6b ),-NR 6a S (O) 2 R 6b ,-S (O) q
  • the substituent group 3 may be substituted with a halogen atom, a hydroxyl group, and a halogen atom (an alkoxy group, an alkylthio group, An alkylsulfinyl group, and an alkylsulfonyl group);
  • R 6 a, R 6b and R 6 c are the same or different, a hydrogen atom, optionally substituted with R 7 C, -C 6 alkyl group, optionally substituted with R 7 C 2 -C 6 alkenyl group, optionally substituted with R 7 C 2 -C 6 alkynyl group, may also be 3 to be substituted with R 7 (: 7 cycloalkyl group, the optionally substituted with R 7 heterocyclyl group, a phenyl group which may be substituted with R 7, optionally substituted aromatic optionally heterocyclic group R 7, optionally substituted with R 7 ( ⁇ ⁇ (:, 3 Ararukiru group, R 7 represents in the optionally substituted substituted by heterocyclyl group the Ci ⁇ Cs alkyl group, or C substituted with also an aromatic heterocyclic group optionally substituted by R 7, a -C 3 alkyl group ;
  • R 6a and R 6b , R 6a and R 6c , or R 6b and R 6C present in one group may be substituted with R 7 Ci Ce If an alkyl group, a single bond, - ⁇ -, - NR 9 -, or S (O) q - ring structure membered 3-7 linked to one another via can be formed; q is 0 Represents an integer of 2;
  • R 7 represents a halogen atom, a hydroxyl group, a carboxyl group, C, -C 4 alkyl group, C, -C 4 alkoxy, C, ⁇ C 4 alkoxycarbonyl group, C, -C 4 alkylsulfonyl group, or a C, ⁇ C 4 alkyls Represents the Rufiel group,
  • R 8 and R 9 are the same or different and represent a Ci Ce alkyl group which may be substituted with R 7 . ]
  • R 3 may be substituted with 1 to 6 fluorine atoms (C, C 6 alkyl group, C 3 C 7 cycloalkyl group, C 4 C 9 (cycloalkyl) alkyl group ⁇ Represents;
  • R 3 represents an isobutyl group optionally substituted by 1 to 6 fluorine atoms
  • R la represents - ⁇ R 6a , or -N (R 6a ) (R 6b );
  • R lb represents a halogen atom, -R 6a , -OR 6a , or -N (R 6a ) (R 6b ), or a compound or a medically acceptable salt thereof according to (1) to (3).
  • R 1 Represents- N (R 6a ) (R 6b ),
  • R ld represents a group selected from Substituent Group 1.
  • a pharmaceutical composition comprising the compound according to any one of (1) to (14), or a medically acceptable salt thereof, and a pharmaceutically acceptable carrier.
  • a cathebsin K inhibitor comprising the compound according to any one of (1) to (14) or a medically acceptable salt thereof as an active ingredient.
  • the present invention provides a novel compound having an excellent cysteine protease inhibitory action (particularly cathebsin K inhibitory action).
  • the present invention provides a treatment or prevention for a disease selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone, hypercalcemia, bone metastasis of cancer, and bone pain.
  • a disease selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone, hypercalcemia, bone metastasis of cancer, and bone pain.
  • a disease selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone, hypercalcemia, bone metastasis of cancer, and bone pain.
  • each substituent is common to each site.
  • any variable eg R 6a , R 6b , R 6c , R 7 , R 8, etc.
  • the definition is defined in each component being independent.
  • combinations of substituents and variables are only allowed if such a combination results in a chemically stable compound. If the substituent itself is substituted with more than one group, these multiple groups can be on the same or different carbons as long as a stable structure results.
  • Ce C, 0 aryl group means a group formed by leaving one hydrogen atom bonded to a ring of an aromatic hydrocarbon having 6 to 10 carbon atoms.
  • Non-limiting examples include phenyl group, naphthyl group, indenyl group, tetrahydronaphthyl group, indanyl group, and azulenyl group.
  • the “C 7 -C, 3 aralkyl group” means a group formed by substituting an alkyl group having 1 to 3 carbon atoms with one of the above-mentioned 0 6 to 0 aryl groups at an arbitrary position.
  • Non-limiting examples include benzyl group, phenethyl group, naphthylmethyl group, and naphthylethyl group.
  • the “aromatic heterocyclic group” is a 3 to 10-membered monocyclic or bicyclic ring containing 1 to 5 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom.
  • a compound having a certain aromaticity Means a ring system.
  • “3- to 10-membered monocyclic or bicyclic aromatic ring system” has 1 to 5 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom.
  • a bicyclic aromatic heterocyclic group if one ring is an aromatic ring or an aromatic heterocyclic ring, the other ring may be a non-aromatic ring structure.
  • the number of heteroatoms in the aromatic heterocyclic group and the combination thereof are not particularly limited as long as they can constitute a predetermined number of rings and can exist chemically and stably.
  • aromatic heterocyclic groups include, but are not limited to, pyridyl group, virazyl group, pyrimidyl group, pyridazinyl group, furyl group, chenyl group, pyrazolyl group, 1,3-dioxanthdanyl.
  • heterocyclyl group means 1 to 4 heteroatoms selected from the group consisting of an oxygen atom, a sulfur atom, and a nitrogen atom as a heteroatom, and is saturated even if partially unsaturated. Or a monovalent group obtained by removing a hydrogen atom from a 3- to 10-membered monocyclic or bicyclic aliphatic heterocyclic ring.
  • the number of heteroatoms in the heterocyclyl group and the combination thereof are not particularly limited as long as they can form a predetermined number of rings and can exist chemically stably.
  • heterocyclyl groups include, but are not limited to, for example, piperidyl groups, piperidino groups, pyrrolidinyl groups, pyrrolinyl groups, tetrahydrofuryl groups, dihydrovinylyl groups, hexahydroazepinyl groups, piperazinyl groups, quinuclidinyl groups.
  • the “octalogen atom” means a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
  • ⁇ ⁇ alkyl group means a saturated linear or branched aliphatic hydrocarbon group having 1 to 6 carbon atoms.
  • Non-limiting examples include, for example, methyl group, ethyl group, n-propyl group, n-butyl group, n-pentyl group, n-hexyl group, isopropyl group, isobutyl group, s-butyl group, t-butyl group Group, isopentyl group, 2-methylbutyl group, neopentyl group, 1-ethylpropyl group, 4-methylpentyl group, 3-methylpentyl group, 2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group, 2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 2,3-di
  • C 3 -C 7 cycloalkyl group means a cycloalkyl group having 3 to 7 carbon atoms.
  • Non-limiting examples include cyclic alkyl groups such as cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, and cycloheptyl group.
  • c 4 to c 9 (cycloalkyl) alkyl group means that the “c, to c 3 alkyl group” is substituted with one “c 3 to c 7 cycloalkyl group” at any position. Means a group.
  • Non-limiting examples include, for example, cyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl group, cyclopropylethyl group, cyclobutylethyl group, cyclopentyl group An ethyl group, a cyclohexylethyl group, a cycloheptylethyl group, and the like.
  • the “c 7 to c 9 phenylalkyl group” means a group in which the “.! ⁇ Ji; ⁇ alkyl group” is substituted with one phenyl group at any position, and is not limited thereto. Examples thereof include benzyl group, phenethyl group, and phenylpropyl group.
  • c, ⁇ c 6 alkoxy group means a group consisting of the above “c, ⁇ c 6 alkyl group” and an oxy group.
  • Non-limiting examples include, for example, a methoxy group, an ethoxy group, an n-propoxy group, an isopropoxy group, an n-butoxy group, an S-butoxy group, a 2-methylpropoxy group, an n-pentyloxy group, an iso Pentyloxy group, 2-methylbutoxy group, 1-ethylpropoxy group, 2,2-dimethylpropoxy group, n-hexyloxy group, 4-methylpentoxy group, 3 -Methylpentoxy group, 2-methylpentoxy group, 3,3-dimethylbutoxy group, 2,2-dimethylbutoxy group, 1,1-dimethylbutoxy group, t-butoxy group and the like.
  • FCi Ce alkylthio group means a group consisting of the aforementioned rCi Cfi alkyl group ”and a thio group.
  • Non-limiting examples include methylthio group, ethylthio group, and isopropylthio group.
  • a ". ( ⁇ - (alkylsulfinyl group” means the “C, -C 6 alkyl group” and consists of a scan Rufieru group group as but are not limited to, for example, Mechirusuru Finiru Group, ethylsulfinyl group, isopropylsulfinyl group, etc.
  • “rCt Ce alkylsulfonyl group” means a group consisting of the above-mentioned rC! Ce alkyl group ”and a sulfonyl group. Examples that are not included include a methylsulfonyl group, an ethylsulfonyl group, and an isopropylsulfonyl group.
  • C, ⁇ (: 6 alkoxycarbonyl group means a group consisting of the above “(:!- ⁇ Ce alkoxy group” and a carbonyl group.
  • methoxycarbonyl is not limited thereto.
  • the “C 2 -C 6 alkenyl group” means a straight or branched chain having 2 to 6 carbon atoms having a double bond.
  • Means an aliphatic hydrocarbon group including, but not limited to, vinyl, aryl, 1-propenyl, 2-butenyl, 3-butenyl, 2-methyl-1-prop Nyl group, 2-methyl-2-propenyl group, 4-pentenyl group, 5-hexenyl group, 4-methyl-3-pentenyl group and the like.
  • the “C 2 -C 6 alkynyl group” means a straight chain or branched aliphatic hydrocarbon group having 2 to 6 carbon atoms having a double bond, and is not limited thereto. Examples include ethynyl group, propargyl group, 3-methylpropargyl group, petitil group, 2-butyne-1-yl group, pentyl group, and hexynyl group.
  • the alkyl group of C, C 6 which may be substituted with 1 to 6 identical or different groups selected from substituent group 3 means that the rCt Ce alkyl group is any In the position, it may be substituted with “1 to 6 identical or different groups selected from substituent group 3”, and 2 to 6 groups selected from substituent group 3 When replaced, the same, ⁇ . ; Alkyl groups may be substituted with the same group or may be substituted with different groups.
  • R 7 such as “Ci to C 6 alkyl group optionally substituted with R 7 ” and “C 3 to C 7 cycloalkyl group optionally substituted with R 7 ” in the present invention.
  • the upper limit of the number of substitution of R 7 to be substituted is 10 when R 7 is a halogen atom, 5 when R 7 is a substituent other than a halogen atom, and 0 to 3 R 7 Is preferably substituted with.
  • “C” such as “C,” represents a carbon atom, and the number after that represents the number of carbon atoms.
  • “ji-ji” represents a range of 1 to 6 carbon atoms.
  • rCi C alkyl group means that the alkyl group defined by “(:, to (: 6 alkyl group”) has 1 to 4 carbon atoms.
  • the present invention relates to a compound represented by the above formula (1) or a medically acceptable salt thereof, in particular, a compound represented by the above formula (1A), or a medically acceptable salt thereof.
  • constants common to the compound represented by the formula (1) and the compound represented by the formula (1A) will be described together:
  • Ar ' represents a C 6 -C 10 Ariru group, or an aromatic heterocyclic group.
  • the “substituent group 1” is a hydrogen atom, a halogen atom, a cyan group, a nitro group, -R 6a , -OR 6a , -O (CO) R 6a ,-COOR 6 a ,-CON (R 6a ) (R 6b ),-N (R 6a ) (R 6b ),-NR 6a (CO) R 6b ,-NR 6a (CO) N (R 6b ) ( 6 R,-S (O) 2 N (R 6a ) (R 6 ,-NR 6a S (O) 2 R 6b ,-S (O) q R 6a , and-S i ( R 8 ) represents a group consisting of 3.
  • q represents an integer of 0-2.
  • R 6a, R 6b and R 6c are the same or different, a hydrogen atom, optionally substituted with R 7 C i Ce alkyl group, optionally substituted with R 7 C 2 ⁇ C 6 alkenyl group, optionally substituted with R 7 C 2 ⁇ C 6 alkynyl group, Ji may be substituted with R 7 3 ⁇ .
  • R 7 is a halogen atom, a hydroxyl group, a carboxyl group, a C, to C 4 alkyl group, a C! C alkoxy group,, to. It represents an alkoxycarbonyl group, a CLCA alkylsulfonyl group, ( ⁇ -alkyl sulfinyl group, or cyan group).
  • each substituent in Substituent Group 1 is substituted with R 6 a and R 6b , R 6 a and R 6 c , or R 6 b and R 6 c force R 7 present in one group.
  • R 6 a and R 6b , R 6 a and R 6 c , or R 6 b and R 6 c force R 7 present in one group.
  • R 6 a and R 6b , R 6 a and R 6 c , or R 6 b and R 6 c force R 7 present in one group.
  • the “ring structure having 3 to 7 members” as R 1 may contain 2 or less heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as atoms forming such a ring structure. Good.
  • R 1 that forms such a “ring structure having 3 to 7 members” include, but are not limited to, for example, 1-piperidyl group, 1-pyrrolidinyl group, morpholino group, thiomorpholino group, 1, 1-dioxochi morpholine-4-yl group, 1-piperazinyl group, and the like.
  • R 1 represents a group selected from the substituent group 1.
  • substituted group 1 is halo gen atom, Shiano group, a nitro group, - R 6a, - OR 6a , - O (CO) R 6 a, - CO_ ⁇ _R 6a, - C ON (R 6a ) (R 6b ),-N (R 6a ) (R 6b ),-NR 6a (CO) R 6b ,-NR 6a (CO) N (R 6b ) (R 6c ),-S (O) 2 N (R 6a ) (R 6b ), -NR 6a S (O) 2 R 6b , -S (O) q R 6a , and -S i (R 8 ) 3 .
  • R 6 a, R 6b and R 6c are the same or different, a hydrogen atom, optionally substituted with R 7 C, ⁇ C 6 alkyl group, optionally substituted with R 7 C 2 ⁇ C 6 alkenyl group, optionally substituted C 2 even though -C 6 alkynyl group in R 7, optionally substituted ⁇ 3-7 cycloalkyl group R 7, the optionally substituted with R 7 heterocyclyl group, a phenyl group which may be substituted with R 7, an aromatic substituted with R 7 heterocyclic group, an optionally substituted C 7 to d 3 Ararukiru group R 7, with R 7 Represents a C t to C 3 alkyl group substituted with an optionally substituted heterocyclyl group, or a C, to C 3 alkyl group substituted with an aromatic heterocyclic group optionally substituted with R 7 .
  • R 8 represents a C 1, to C 6 alkyl group which may be substituted with R 7
  • R 7 represents a halogen atom, a hydroxyl group, a carboxyl group, a Ci C alkyl group, a dialkoxy group, a Ci C alkoxycarbonyl group, a ⁇ CA alkylsulfonyl group, or a Ci C alkylsulfinyl group.
  • R 6 a and R 6 present in the one group, R 6 a and 1 6 (; substituted or scale 615 and at 1 month 13 ⁇ 4 7?? tea even Yoi (: 1 ⁇ (: 6 Arukiru Aru case in groups, a single bond, - 0 -, - NR 9 -, or - S (O) q - Number 3 attached to one another via It can form a ring structure of 7.
  • q represents an integer of 0 to 2
  • R 9 represents a Ct Ce alkyl group which may be substituted with R 7 .
  • the “ring structure having 3 to 7 members” as R 1 may contain 2 or less heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as atoms forming such a ring structure. Good.
  • R 1 that forms such a “ring structure having 3 to 7 members” include, but are not limited to, for example, 1-piperidyl group, 1-pyrrolidinyl group, morpholino group, thiomorpholino group, 1, 1-dioxochi morpholine-4-yl group, 1-piperazinyl group, and the like.
  • R 1 includes a halogen atom, —R 6 a , —OR 6 a , and —N (R 6 a ) (R 6b ).
  • m represents the integer of 0-3, Preferably the integer of 1-3 is represented.
  • a preferable example of a combination of “Eight!” 1 , “R ′”, and “m” (one A r 1 — (R 1 ) m ) can be represented by the following structural formula. -61-
  • R la represents —OR 6a , or —N (R 6a ) (R 6b );
  • R lb represents a halogen atom, -R 6a , -OR 6a , or -N (R 6a ) (R 6b ).
  • R 6 a and R 6b in R la and R ′ b are the same as the definitions of R 6a and R 6b in the R 1 group.
  • Particularly preferred R la in the formula (2) includes -N (R 6a ) (R 6b ).
  • R ld represents a group selected from the substituent group 1.
  • R 6 a and R 6b in R lc are the same as those defined R 6a and R 6b of R 1 groups of the formula (1A).
  • the definition of the group selected from Substituent Group 1 in R ld is the same as the definition of the group selected from Substituent Group 1 in Formula (1A).
  • R 6a and R 6b are each represented by R 7
  • R 6a and R 6b may represent the above-mentioned “ring structure of 3 to 7 members” when the alkyl group of C! Ce optionally substituted with is represented.
  • R 3 and R 4 may be the same or different and may be substituted with 1 to 6 identical or different groups selected from a hydrogen atom or substituent group 3.
  • Substituent group 3 represents a group consisting of a halogen atom, a hydroxyl group, and d to C 6 (alkoxy group, alkylthio group, alkylsulfinyl group, and alkylsulfonyl group) which may be substituted with a halogen atom.
  • R 3 and R 4 are C, C 6 alkyl groups optionally substituted with 1 to 6 identical or different groups selected from Substituent Group 3, a single bond,-0 -,-NR 9
  • a ring structure having 3 to 7 members including the carbon atom to which R 3 and R 4 are bonded can be formed.
  • q represents an integer of 0-2.
  • R 9 represents a case, hydrogen or R 7 in the optionally substituted Ci Cg alkyl group of the formula (1), the case of formula (1A), optionally substituted with R 7 C i to C 6 represents an alkyl group.
  • the “ring structure having 3 to 7 members” formed by R 3 and R 4 is a hetero atom of 2 or less selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as the atoms forming such a ring structure. May be included.
  • Examples of such a “ring structure having 3 to 7 members” include, but are not limited to, cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, tetrahydrofuran, tetrahydropyran, pyrrolidine, pipette, and the like.
  • Examples include ring structures such as lysine, thiolane, and thiane.
  • R 3 and R 4 When R 3 and R 4 are not bonded to each other to form a ring structure, one of R 3 and R 4 represents a group that is not a hydrogen atom. Preferred examples of the combination of R 3 and R 4 include groups represented by the following chemical formulas.
  • R 3 may be substituted with 1 to 6 fluorine atoms (C, C 6 alkyl group, C 3 C 7 cyclo An alkyl group, a C 4 to C 9 (cyclic alkyl) alkyl group ⁇ , and a combination in which R 4 represents a hydrogen atom.
  • R 3 represents is 1-6 substituents which may be an isobutyl group by a fluorine atom
  • combination R 4 represents a hydrogen atom.
  • L represents a single bond or-(CR'OR 1 1 ) s- . Where s! Represents any integer of ⁇ 4.
  • R 1 D and R 11 are the same or different and each represents a hydrogen atom or a C 1, to C 6 alkyl group which may be substituted with R 7 .
  • L is preferably a single bond.
  • Ar 2 represents a C 6 -C 1 () aryl group or an aromatic heterocyclic group. Specific examples of the “aryl group” and the “aromatic heterocyclic group” are as defined above.
  • the preferred “aryl group” or “aromatic heterocyclic group” of Ar 2 includes a phenyl group, A naphthyl group, a enyl group, a pyrazolyl group, a benzofuryl group, a benzocheryl group, an indolyl group, a benzothiazolyl group, a benzoimidazolyl group, a benzoxazolyl group, an imidazolyl group, and a thiazolyl group.
  • a C 6 to C 1 D aryl group (particularly a phenyl group) or a pyridyl group is preferable.
  • Ar 2 is
  • the aromatic heterocyclic ring is particularly excellent when it represents a pyridine ring substituted with a hydroxyl group, that is, a pyridone ring.
  • r represents 0 or 1, preferably 1.
  • n described later represents 0.
  • Ar 3 represents a C 6 to C 1 Q aryl group or an aromatic heterocyclic group.
  • aryl group and the “aromatic heterocyclic group” are as defined above, but the preferred “aryl group” or “aromatic heterocyclic group” of Ar 3 includes a phenyl group, Examples include pyridyl group, birazinyl group, pyrimidinyl group, pyridazinyl group, furyl group, chenyl group, pyrazolyl group, isoxazolyl group, isothiazolyl group, imidazolyl group, and thiazolyl group.
  • n represents 0 or 1.
  • R 5 represents a group selected from the substituent group 1.
  • the definitions of “substituent group 1”, “R 6a ”, “R 6b ”, “R 6c ”, “R 7 ”, and “qj” in “R 5 ” in the formula (1) and the formula (1A) are as follows: respectively the formulas (1) and (1A) of the "scale 1", “substituent group 1" in the "R 6 a,” “R 6b”, “R 6c”, “R 7", and “q”
  • specific examples of preferred R 5 include a halogen atom, a cyano group, -R 6a , -OR 6a , -COOR 6a , and -N (R 6a ) (R 6b ).
  • the “ring structure having 3 to 7 members” as R 5 may contain 2 or less heteroatoms selected from the group consisting of an oxygen atom, a nitrogen atom and a sulfur atom as atoms forming such a ring structure. Good.
  • R 5 forming such a “ring structure having 3 to 7 members” include, but are not limited to, for example, 1 -piperidyl group, 1 -pyrrolidinyl group, morpholino group, thiomorpholino group, 1, 1- Examples include dioxochiomorpholin-4-yl group and 1-piperazinyl group.
  • p represents an integer of 0 to 5, preferably an integer of 0 to 3.
  • At least one of the groups substituting R 1 and R 1 , R 5 and R 5 represents -COOH, a compound or Its medically acceptable salt is Excellent stability and preferable.
  • a compound in which at least one of the group substituting RR 1 , R 5 , and R 5 represents a cyano group or a medically acceptable salt thereof is also excellent in metabolic stability. Is preferable.
  • preferred combinations of “L”, “Ar 2 ”, “Ar 3 ”, “R 5 ”, “r”, “n”, “p” ((R 5 ) p- (Ar 3 ) n ⁇ (Ar 2 ) As an example of r -L-), it can be represented by the following structural formula.
  • the compounds represented by the formula (1 A) are preferable.
  • a r A r 2 , A r 3 , RR 3 , R 4, R 5, R 6 a , R 6b, R 6c, R 7, R 8, n, m, and as a combination of p was preferably a combination of preferred groups together as described above for each, and particularly preferably A combination of groups is more preferred.
  • Table 1 lists preferred compounds and their medically acceptable salts (hereinafter referred to as “preferred compounds”) among the compounds represented by the formula (1).
  • HATU O-(7-azabenzo-azol-1 -yl)-N, N, N ', N' -tetramethyl uronium hexafluorophosphate
  • PyBOP Benzotriazol-1-yloxytris (pyrrolidino) phosphonium hexafluorophosphate
  • X-Phos 2-(Di-tert-Ptylphosphino)-2 ', 4', 6,-Triisopropyl
  • the compound of the formula (7) can be synthesized using, for example, the method described in US Patent No. US 2006030731.
  • an imine intermediate of the formula (6) is synthesized by reacting the amino derivative of the formula (4) with the ketone derivative of the formula (5).
  • the compound of formula (7) can be synthesized by reacting this imine intermediate of formula (6) with an appropriate reducing agent.
  • ketone derivatives of formula (5) for example, Te tr ah edr on, 2006, 62, 5092-5098. and Angew. Ch em. Int. Ed., 1998, 37, 6, 820-821. It can be synthesized with reference to.
  • the compound of the formula (7) is disclosed in WO 2003075836 pamphlet, J. Org. Ch em., 2006, 71, 4320-4323., Bioor g. Med. Ch em. t., 2008, 18, 923-928. etc. That is, first, the amine derivative of the formula (8) in which the hydroxyl group is protected with an appropriate protecting group is converted to trifluoro. React with acetaldehyde to synthesize imine intermediate of formula (9). On the other hand, according to a general method, an organolithium reagent of formula (10) or an organometallic reagent such as a Grignard reagent is prepared.
  • the intermediate of formula (11) can be synthesized.
  • the compound of formula (7) can be synthesized by removing the hydroxyl-protecting group P and oxidizing it.
  • a compound of formula (7) can be prepared in the presence of a suitable activator of a carboxyl group (eg HATU, PyBOP), in the presence of a suitable base (eg triethylamine, N-ethyl-N, N-diisopropylamine).
  • a suitable activator of a carboxyl group eg HATU, PyBOP
  • a suitable base eg triethylamine, N-ethyl-N, N-diisopropylamine.
  • the compound of formula (1) can be reacted with an amine derivative of formula (12) in a suitable organic solvent (eg DMF, THF) at a temperature range from 0 to the temperature at which the solvent is heated to reflux.
  • a suitable organic solvent eg DMF, THF
  • a compound of formula (7) can be prepared in the presence of a suitable activator of a carboxyl group (eg HATU, PyBOP), in the presence of a suitable base (eg triethylamine, N-ethyl-N, N-diisopropylamine) or In the absence, in an appropriate organic solvent (for example, DMF, THF), the reaction is performed with an appropriately protected amine derivative represented by formula (13) at a temperature range from 0 to the temperature at which the solvent is heated to reflux.
  • a suitable activator of a carboxyl group eg HATU, PyBOP
  • a suitable base eg triethylamine, N-ethyl-N, N-diisopropylamine
  • an appropriate organic solvent for example, DMF, THF
  • the compound of formula (14) can be synthesized by deprotection under suitable deprotection conditions.
  • the compound of formula (14) can be used in the presence or absence of a suitable additive (eg, myristic acid) in the presence or absence of a suitable Cu reagent (eg, copper (II) acetate).
  • a suitable additive eg, myristic acid
  • a suitable Cu reagent eg, copper (II) acetate
  • a base eg 2,6-lutidine, triethylamine, N-ethyl-N, N-diisopropylamine
  • a suitable organic solvent eg toluene, acetonitrile, DMF, 2-propanol
  • the compound represented by the formula (1) can be synthesized by reacting with a reagent having a leaving group represented by the formula (15) in a solvent within a temperature range from 0 to the temperature at which the solvent is heated to reflux. it can.
  • a compound of formula (1) or a compound of formula (11) is converted into an appropriate Pd catalyst (eg, Pd 2 (dba) 3) and an appropriate ligand (eg, X-Phos;), or
  • a suitable Pd catalyst and ligand complex eg PdC 1 2 (dppf) ⁇ CH 2 C 1 2
  • a suitable base eg cesium carbonate, tert-butoxypotassium
  • WB (OR) 2 W is an aryl group or aromatic heterocyclic group
  • a solvent for example, DMF, 2-propanol, water
  • R 5 is a bromine atom or an iodine atom
  • the formula obtained by converting the structure of R 5 to Shiano group (I d) and formula (lid ) can be synthesized.
  • R 5 When n or r is 1, the structure of R 5 can be converted to a cyan group by performing a Negishi cross-coupling reaction. That is, a compound of the formula (1) or a compound of the formula (1 1) is converted into an appropriate Pd catalyst (for example, Pd 2 (dba) 3 ) and an appropriate ligand (for example, X-Phos;), or an appropriate Pd catalyst and ligand complex (eg P d C 1 2 (dp pf) ⁇ CH 2 C 1 2 ) in the presence of a suitable solvent (eg DMF, THF)
  • a compound of formula (1d) or formula (lid) can be synthesized by reacting with an appropriate metal cyanide reagent (for example, Zn (CN) 2 ) at the refluxing temperature.
  • an appropriate metal cyanide reagent for example, Zn (CN) 2
  • the compound of formula (1) or the compound of formula (1 1) is heated in a suitable solvent (eg DMF, THF) from room temperature.
  • a suitable solvent eg DMF, THF
  • a compound of formula (Id) or (lid) can be synthesized by reacting with an appropriate metal cyanide reagent (eg, KCN) at the refluxing temperature.
  • R 5 When n or r is 1, the structure of R 5 can be converted to -N (R 6a ) (R 6b ) by performing a Buchwald-Hartwig cross-coupling reaction. That is, a compound of formula (1) or a compound of formula (11) is converted into an appropriate Pd catalyst (eg, Pd 2 (dba) 3 ) and an appropriate ligand (eg, X-Phos), or Pd catalyst and ligand complex (eg PdC l 2 (dppf) ⁇ CH 2 C 1 2 ) in the presence of a suitable base (eg cesium carbonate, tert-butoxypotassium) in a suitable solvent (For example, toluene, DMF) or in a mixed solvent thereof at room temperature to the temperature at which the solvent is heated to reflux, by reacting with the amine represented by (R 6a ) (R 6b ) NH, the formula (le) Alternatively, a compound of formula (1 le) can be synthesized.
  • the compound of formula (1) or the compound of formula (1 1) is replaced with a suitable base (eg N-ethyl-N, N diisopropylamine).
  • a suitable base eg N-ethyl-N, N diisopropylamine.
  • a suitable solvent eg DMF, THF
  • the compound of formula (1) or the compound of formula (1 1) is converted into an appropriate Pd catalyst (eg, Pd 2 (dba) 3) and an appropriate ligand (eg, X-Phos), or In the presence of P (eg, P d C 1 2 (dppf) ⁇ CH 2 C 1 2 ) and in the presence of a suitable Cu catalyst (eg, copper iodide (I), copper bromide (I))
  • a base eg, triethylamine, jetylamine, piperidine
  • a suitable solvent eg, DMF, THF, triethylamine
  • the compound of the formula (1) or the compound of the formula (1 1) when R 5 is a bromine atom or an iodine atom, the compound of the formula (lg) and the formula (1 lg) is obtained by performing hydrogen reduction.
  • a suitable solvent for example, methanol, ethanol, tetrahydrofuran
  • a suitable Pd catalyst for example, Pd / C
  • the compound of formula (lg) or the compound of formula (1 lg) can be synthesized by reacting with an appropriate hydrogen source (for example, hydrogen gas, ammonium formate, cyclohexene).
  • a conversion reaction known to those skilled in the art can be performed on the compound of the formula (1) of the present invention.
  • the compound of the formula (1) of the present invention has an easily convertible substituent such as - ⁇ (CO) R 6a , -COOR 6a , a nitro group, etc.
  • Each can be converted by performing a known reaction. That is, for example, - the 0 (CO) R 6a represents a hydroxyl group, - COOR 6a is carboxyl group, or a hydroxymethyl group, a nitro group to amino group can be converted, respectively.
  • the compound of the formula (1) of the present invention has a hydroxy group
  • the compound of the present invention having a substituent such as -OR 6a and -O (CO) R 6a is obtained by a reaction well known to those skilled in the art. It can be converted to the compound of formula (1).
  • the present invention also relates to a medically acceptable salt of the compound represented by the formula (1).
  • salts include salts with inorganic acids such as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid, phosphoric acid, and carbonic acid; maleic acid, fumaric acid, citrate, malic acid, tartaric acid, lactic acid, succinic acid, Benzoic acid, oxalic acid, methanesulfonic acid, benzenesulfonic acid, P-toluenesulfonic acid, salts with organic acids such as acetic acid, trifluoroacetic acid, formic acid; glycine, lysine, arginine, histidine, ornithine, glutamic acid, asparagine Salts with amino acids such as acids; Salts with alkali metals such as sodium, potassium and lithium; Salts with alkaline earth metals such as Lucium and Magnesium; Salts with metals such as aluminum
  • the compounds of the present invention also include stereoisomers, racemates, and all possible optically active compounds of the compound represented by formula (1).
  • the compounds of the invention may give rise to tautomers depending on the combination of each substituent, and such tautomers are also included in the compounds of the present invention. Examples of combinations of substituents that give rise to such tautomers include, but are not limited to, the following structures.
  • the compound represented by the formula (1) of the present invention and a medically acceptable salt thereof are excellent cysteine prosthesis. It has a thease inhibitory effect and a particularly superior cathebsin K inhibitory effect. Due to its excellent cysteine protease inhibitory action, the compound represented by the formula (1) of the present invention and a medically acceptable salt thereof are useful as cysteine protease inhibitors (especially cathebsin K inhibitors). .
  • the compound represented by the formula (1) of the present invention and a medically acceptable salt thereof are osteoporosis, osteoarthritis, rheumatoid arthritis, bone paget, which can be applied clinically as a cathebsin K inhibitor. It can be used as a medicament for the treatment or prevention of diseases selected from the group consisting of diseases, hypertensive rumumemia, bone metastasis of cancer, and bone pain.
  • the compound represented by the formula (1) and a medically acceptable salt thereof can be made into a pharmaceutical composition together with a pharmaceutically acceptable carrier and / or diluent.
  • This pharmaceutical composition can be formed into various dosage forms and administered orally or parenterally.
  • Parenteral administration includes, for example, intravenous, subcutaneous, intramuscular, transdermal, or rectal administration.
  • the preparation containing one or more of the compounds represented by the formula (1) of the present invention or a medically acceptable salt thereof as an active ingredient is a carrier or excipient usually used for formulation, It is prepared using the additive.
  • the carrier for the preparation may be either solid or liquid, such as lactose, magnesium stearate, starch, talc, gelatin, agar, pectin, gum arabic, olive oil, sesame oil, cocoa butter, Examples include ethylene glycol and other commonly used ones.
  • Administration may be in any form of oral administration such as tablets, pills, capsules, granules, powders, solutions, etc., or injections such as intravenous injections, intramuscular injections, suppositories, parenteral administration such as transdermal. Good.
  • the compound represented by the formula (1) of the present invention and a medically acceptable salt thereof are used as pharmaceuticals in terms of safety, stability, efficacy, sustained action, physical properties, pharmacokinetics, preservability, manufacturability, etc. It has good properties.
  • the compound represented by the formula (1) of the present invention or a medically acceptable salt thereof varies depending on the type of disease, administration route, patient symptom, age, sex, body weight, etc.
  • the dose can be administered in the range of 0.1 to 100 mg, preferably in the range of 1 to 10 O mg, in one or several divided doses. However, since the dose varies depending on various conditions, a dose smaller than the above dose may be sufficient, or a dose exceeding the above range may be required.
  • symptom can be divided into 0.1 to 10 O mg, preferably 0.1 to 1 O mg once or several times per day for adults. It is desirable to administer accordingly.
  • Example The present invention will be described below based on specific examples. However, the present invention is not limited to these examples.
  • the compound numbers given to the respective compounds in the following examples correspond to the compound numbers given to the compounds listed as preferred specific examples in Table 1 above.
  • the structure of the isolated new compound can be analyzed by mass spectrometry using a single quadrupole instrument equipped with 1 H NMR and Z or an electron spray source, and other suitable analyzes. Confirmed by law.
  • reaction solution was diluted with ethyl oxalate and washed with a mixed solution of saturated saline and saturated aqueous sodium bicarbonate (9: 1).
  • the organic layer was dried over anhydrous sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by silica gel column chromatography to obtain the title compound (50: 1 lm g, free form).
  • the reaction solution was allowed to return to room temperature, filtered through Celite, and the celite was washed with ethyl acetate.
  • the filtrate was diluted with water, the organic layer was separated, and the aqueous layer was extracted with ethyl acetate.
  • the organic layers were combined, dried over sodium sulfate and filtered, and the filtrate was concentrated under reduced pressure.
  • the residue was purified by high performance liquid chromatography.
  • the obtained title compound (27, trifluoroacetate) was diluted with ethyl acetate and washed with an aqueous sodium hydrogen carbonate solution.
  • the organic layer was dried over sodium sulfate and then filtered, and the filtrate was concentrated under reduced pressure to obtain the title compound (27: 7 mg, free form).
  • reaction solution was returned to room temperature, filtered through celite, and ethyl acetate.
  • the filtrate was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography to give the title compound (33: 1 Omg, trifluoroacetate).
  • Acetic acid (0.2 mL) was added to a DMF solution (2 mL) of tert-butyl N- (2-oxoethyl) strong rubamate (90 mg) and 2-aminopyridine (56 mg), and the mixture was stirred at room temperature for 1 hour.
  • Sodium borohydride (94 mg) was added to the reaction solution, and the mixture was further stirred at room temperature for 1 hour.
  • Ethyl acetate and water were added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and filtered.
  • HPLC high-performance liquid chromatography
  • TOF-MS time-of-flight mass spectrometer
  • Table 4 below shows the retention time (unit: minute) of the compound in the HPLC analysis under the following analysis conditions as the HPLC retention time.
  • Solvent B 10% ⁇ 70% Solvent A: 90% ⁇ 30% 1 3 to 14 minutes, Solvent B: 70% —100% Solvent A: 30% ⁇ 0%
  • Cathebsin K inhibitory activity was measured for compounds synthesized according to the methods of the above Examples or in the same manner.
  • the compound numbers shown in Table 3 below correspond to the compound numbers given to the compounds listed as preferred specific examples in Tables 1A to 1M above.
  • Cathebsin K used for the evaluation of inhibitory activity was expressed transiently in animal cells HEK293 T cells (manufactured by Gennhunter), and the cell fraction was collected with a surfactant to obtain an active enzyme.
  • Enzyme solution A was prepared at 2.1 times the final concentration with Atsey buffer (5 OmM sodium acetate, 50 mM sodium chloride, 2 mM DTT, ⁇ 2.5. ⁇ ).
  • Test compound solution ⁇ was prepared with dimethyl sulfoxide (DMSO) to a final concentration of 50 times.
  • Substrate solution C is a fluorescent buffer benzyloxycarbonyl-L-leucyl-L-arginyl-4-methyl-coumaryl-7-amide (Z-Leu-Arg-MCA (Peptide Institute)) Prepared to 10 with liquid.
  • Test compound solution B (1.6 L) was added to enzyme solution A (38.4 L), mixed, and incubated for 15 minutes at room temperature.
  • Substrate solution C (40 L) was added to this incubation solution and reacted at room temperature for 30 minutes.
  • This enzyme reaction solution was measured at an excitation wavelength of 355 nm and a measurement wavelength of 460 nm, and the enzyme activity was calculated from the fluorescence intensity of the released 7-amino-4-methylcoumarin.
  • the inhibition rate of the test compound was calculated based on the enzyme activity when DMSO was added instead of the test compound solution B as 100%, and the 50% inhibitory concentration against cathepsin K was calculated by fitting the dose response curve.
  • Example 40 A metabolic stability test using human liver microsomes was performed on the compounds synthesized according to the methods of the above Examples and the compound of the formula (B) (compound disclosed in International Publication No. WO 0 2 Z0705 17 pamphlet) The residual rate of each compound was calculated.
  • test compound solution (10 /, I O O M acetonitrile solution) was added to human liver microsome solution (950 / xL) on an ice bath, and this solution was divided into two equal parts. One was solution A and the other was solution B.
  • the composition of the human liver microsome solution is as follows.
  • Purified water Acetonitrile (50 0 j L) was added to 5 30 L solution A (4 80 ML) on an ice bath, followed by 25 mM N ADPH solution (20 / zL). After stirring with vortex, the mixture was centrifuged at 4 for 10 minutes (3 000 rpm), and the supernatant was used as a sample with a reaction time of 0 minutes.
  • the compound represented by the above formula (1) of the present invention and a medically acceptable salt thereof have a cysteine protease inhibitory action (particularly cathebsin ⁇ inhibitory action) and can be applied clinically as a cysteine protease inhibitor. It is used as a medicine for treating or preventing a disease selected from the group consisting of osteoporosis, osteoarthritis, rheumatoid arthritis, Paget's disease of bone, hypercalcemia, cancer bone metastasis, and bone pain. be able to.

Abstract

La présente invention concerne un composé possédant une excellente activité inhibitrice sur une cystéine protéase ; et un agent pharmaceutique pour le traitement ou la prévention d’une maladie choisie dans le groupe constitué de l’ostéoporose, l’ostéo-arthrose déformante, la polyarthrite rhumatoïde, la maladie de Paget des os, l’hypercalcémie, les métastases osseuses du cancer et les douleurs osseuses. L’invention concerne spécifiquement : un composé représenté par la formule (1) ou l’un de ses sels pharmaceutiquement acceptables ; et un agent pharmaceutique ou une composition pharmaceutique renfermant le composé ou le sel pharmaceutiquement acceptable en tant que principe actif.
PCT/JP2009/057710 2008-04-15 2009-04-10 Inhibiteur de cystéine protéase WO2009128521A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014523888A (ja) * 2011-06-27 2014-09-18 ニユーロン・フアーマシユーテイカルズ・エツセ・ピー・アー フッ素化アリールアルキルアミノカルボキサミド誘導体
KR20210126157A (ko) * 2013-11-08 2021-10-19 인사이트 홀딩스 코포레이션 인돌아민 2,3-디옥시게나제 억제제의 합성 방법

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002515411A (ja) * 1998-05-21 2002-05-28 スミスクライン・ビーチャム・コーポレイション プロテアーゼ阻害剤
WO2002070517A2 (fr) * 2001-03-02 2002-09-12 Merck Frosst Canada & Co. Inhibiteurs de cysteine protease de type cathepsine
JP2005537216A (ja) * 2001-10-09 2005-12-08 スミスクライン ビーチャム コーポレーション セリンおよびシステインプロテアーゼの阻害剤としてのプロピルカーバメート誘導体

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2002515411A (ja) * 1998-05-21 2002-05-28 スミスクライン・ビーチャム・コーポレイション プロテアーゼ阻害剤
WO2002070517A2 (fr) * 2001-03-02 2002-09-12 Merck Frosst Canada & Co. Inhibiteurs de cysteine protease de type cathepsine
JP2005537216A (ja) * 2001-10-09 2005-12-08 スミスクライン ビーチャム コーポレーション セリンおよびシステインプロテアーゼの阻害剤としてのプロピルカーバメート誘導体

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2014523888A (ja) * 2011-06-27 2014-09-18 ニユーロン・フアーマシユーテイカルズ・エツセ・ピー・アー フッ素化アリールアルキルアミノカルボキサミド誘導体
KR20210126157A (ko) * 2013-11-08 2021-10-19 인사이트 홀딩스 코포레이션 인돌아민 2,3-디옥시게나제 억제제의 합성 방법
KR102617531B1 (ko) * 2013-11-08 2023-12-27 인사이트 홀딩스 코포레이션 인돌아민 2,3-디옥시게나제 억제제의 합성 방법

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