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WO1998001133A1 - Inhibiteurs de la resorption osseuse - Google Patents

Inhibiteurs de la resorption osseuse Download PDF

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Publication number
WO1998001133A1
WO1998001133A1 PCT/JP1997/002357 JP9702357W WO9801133A1 WO 1998001133 A1 WO1998001133 A1 WO 1998001133A1 JP 9702357 W JP9702357 W JP 9702357W WO 9801133 A1 WO9801133 A1 WO 9801133A1
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WIPO (PCT)
Prior art keywords
group
substituted
nitrogen
substituent
pharmaceutically acceptable
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PCT/JP1997/002357
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English (en)
Japanese (ja)
Inventor
Kazuhiko Aibe
Yukihiro Takebayashi
Yasutaka Ishii
Osamu Noshiro
Ichio Noda
Susumu Igarashi
Original Assignee
Yamanouchi Pharmaceutical Co., Ltd.
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Application filed by Yamanouchi Pharmaceutical Co., Ltd. filed Critical Yamanouchi Pharmaceutical Co., Ltd.
Priority to AU33596/97A priority Critical patent/AU3359697A/en
Publication of WO1998001133A1 publication Critical patent/WO1998001133A1/fr

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    • 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
    • C07K5/06165—Dipeptides with the first amino acid being heterocyclic and Pro-amino acid; Derivatives thereof
    • 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
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a drug, particularly a bone resorption inhibitor containing a compound having a selective cathepsin K inhibitory action, particularly a bone resorption inhibitor containing a proline derivative or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a novel proline derivative or a pharmaceutically acceptable salt thereof, which has a selective cathepsin KP adverse effect and is useful as a bone resorption inhibitor.
  • bone diseases associated with osteogenesis imperfecta and accelerated osteolysis include an increase in the elderly population, an increase in the age of menopause, an increase in renal dialysis patients, and an increase in diseases such as malignant ulcer hypercalcemia. In the background, it is steadily increasing. Above all, osteoporosis tends to cause fractures and may cause bedridden elderly people. Therefore, establishment of effective prevention and treatment is desired.
  • Bone resorption involves the simultaneous excretion of both calcium salt, the quality of bone support, and type I collagen, an organic component.Osteoclasts play an important role in this bone resorption. Is a multinucleated giant cell. That is, when osteoclasts come into contact with bone, a ⁇ 4 microenvironment is created between osteoclasts and the bone surface [J. Cell. Biol. 101, 2210-2222 (1985), and Anat. Rec. 224, 317]. -324 (1989)], and the boneless part of the bone occurs. Type I collagen is thought to have been digested by proteases.
  • Bone breakdown is caused by an imbalance between bone formation and bone resorption, and a relative increase in bone resorption.
  • the molecular factors of osteolysis are related to the failure of calcium absorption and deposition, and to the collagen fiber, an organic component that is the bone supporting tissue. It has become clear that there are two types related to the enhancement of ⁇ .
  • a drug that suppresses the increase of bone collagen fibers is expected to be a drug for preventing or treating bone diseases associated with bone erosion such as osteopathy by inhibiting bone resorption.
  • type I collagen an organic component of bone supporting tissue
  • cysteine proteinase particularly cathepsin L
  • Cysteine protease especially cathepsin L, plays an important role in ⁇ t ⁇ , and it has been thought that a cathepsin L inhibitor would be useful as a drug to suppress that ⁇
  • cathepsin L is converted into various cells other than osteoclasts in vivo, it is feared that its inhibitory activity may affect cells other than osteoclasts.
  • Patent Publication WO95 / 24182 discloses inventions such as polynucleotides encoding cathepsin O.
  • the gazette discloses the possibility of treating osteoporosis and bone metastasis tumor by inhibiting cathepsin O together with the specific invention, but there is nothing other than the fact that cathepsin O is specific to osteoclasts. The rationale was not disclosed. It has been reported that the compound E-64 having a cathepsin L inhibitory action represented by the following formula also has a cathepsin K inhibitory action (FEBS Lett. 357, 129-134 (1995), J. Biol Chem. 271). , 2126-2132 (1996), and J. Biol. Chem.
  • E-64 has a bone resorption inhibitory activity, it is a non-selective, broad-spectrum cysteine protease inhibitor, and its action is based on cathepsin K inhibitory action or cathepsin L-based action. It was unknown.
  • Hei 5-3 4 5 7 5 4, Hei 7-89 986, and Hei 5-1 7 8 7 5 8 include eu-Leu, Leu-Met, Leu-Leu -Derivatives of dipeptides or peptides such as Leu are described, and it is described that these are useful for prevention or treatment of bone diseases. No description of cathepsin K inhibitory effect of these compounds
  • Japanese Patent Application Laid-Open No. 63-253601 discloses a cathepsin BP represented by the following formula, which includes a part of the compounds of the present invention, and an amino acid derivative having a harmful action, Although it is stated that it is used for the treatment or prevention of bone resorption, only the results of the force tepsin B assay test are shown, and No specific effect is disclosed. Subsequent studies of cathepsin B inhibitors have reported that some compounds that selectively inhibit cathepsin B do not inhibit bone resorption (FEBS Lett. 321, 247-250 (1993)).
  • n 0 or 1
  • m 0, 1 or 2
  • X is H or N-protecting group
  • Y is each independently an ⁇ -amino acid residue which may be protected.
  • R is a force that is ⁇ or CH 3 or a methylene, methine or phenyl group, which is attached to the ⁇ -carbon atom to which it is attached, optionally protected ⁇ — R ′ is an optionally substituted aryl which is an amino acid side chain.
  • cathepsin ⁇ ⁇ which is specifically expressed in osteoclasts, has been expected to be involved in bone resorption.However, even if it is blocked like cathepsin ⁇ , which has homology to cathepsin ⁇ ⁇ , it inhibits bone resorption. There are some examples that do not show the effect, and elucidation of the effect has been eagerly awaited. Under such a state of the art, the present inventors carried out screening using a commercially available synthetic substrate as a test compound and searched for a cathepsin-selective structure using a screening system using ⁇ sagicathepsin ⁇ and human cathepsin L.
  • the compound of the present invention which has selectivity for cathepsin ⁇ , has no undesired physiological action based on the inhibitory action of other cystine proteases such as cathepsin L, and is destructive. It is useful as a bone resorption inhibitor that acts specifically on bone cells, as a preventive or therapeutic agent for bone diseases associated with bone breakdown.
  • the present invention relates to a selective cathepsin KP compound having a harmful effect, a pharmaceutically acceptable carrier, and a bone resorption inhibitor comprising porcine.
  • the compound having a selective cathepsin K inhibitory action of the present invention refers to a compound having an action of selectively inhibiting only the activity of cathepsin K without inhibiting the activity of other cysteine proteases (particularly cathepsin L). It is.
  • the compound having a selective cathepsin KP harmful effect is a compound having a cathepsin KP harmful effect of 50 times or more, more preferably 10 times or more, of the cathepsin L inhibitory effect in the test method of Experimental Example 1 described in the present specification.
  • Bone resorption is a compound that has a catecholin KP more than 10 times stronger than the inhibitory effect on cathepsin B, papain, trypsin, chymotrypsin and thrombin. It is a yield inhibitor.
  • a compound having a selective cathepsin K inhibitory activity is preferably a proline derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof, and is preferably a bone resorption inhibitor.
  • X a part excluding the c-terminal carbonyl group of the amino acid residue whose side chain may be protected
  • R 1 protecting group for an amino group
  • n 0 or 1
  • R 3 a group that inhibits the activity of the SH group of cysteine protease
  • R 4 a hydrogen atom, a hydroxyl group or a phenyl group.
  • X is a compound of the formula NH—CHR 2 — (wherein R 2 is a hydrogen atom, an alkyl group, a lower alkenyl group, an aryl group, an aralkyl group, an imidazole-41-T-lower alkyl group or an indole-1 3 f is a lower alkyl group; the alkyl group and the lower alkenyl group include a halogen atom, a lower alkoxy group, a hydroxyl group, a mercapto group, an alkylthio group, an aralkyloxy group, an aryloxy group, a nitrite group, a carboxyl group, a carbamoyl group, Mono- or di-lower alkyl group selected from rubamoyl group, lower alkanoylamino group, amino group, mono- or di-lower alkylamino group, guanidino group and ditrognidino group
  • the aryl group and the aralkyl group may be substituted with one or more substituents, and a lower alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group, a mercapto group, an alkylthio group, a nitrogen atom, a carboxyl group , Trifluoromethyl group, sorbamoyl group, mono- or di-lower alkyl rubamoinole group, lower alkanoylamino group, amino group, mono- or di-lower alkylamino group, guanidino group and nitroguanidino group It may be replaced by one or more substituents.
  • R 2 has a functional group containing an oxygen, sulfur or nitrogen atom, these functional groups may be protected.
  • R s represents a hydrogen atom, a hydroxyl group or a phenyl group.
  • the protecting group for the amino group of R 1 is a lower alkanoyl group, a benzoyl group, a benzyl group, a benzyloxycarbonyl group, a t-butoxycarbonyl group, a t-butyl group, a phenylcarbamoyl group, or a phenylsulfonyl group
  • a lower alkanoyl group a benzoyl group, a benzyl group, a benzyloxycarbonyl group, a t-butoxycarbonyl group, a t-butyl group, a phenylcarbamoyl group, or a phenylsulfonyl group
  • the present invention relates to a novel proline derivative represented by the following general formula (III) or a pharmaceutically acceptable salt thereof, which has a bone resorption inhibiting activity based on a selective cathepsin K inhibitory activity.
  • X " a part of the ⁇ -amino acid residue other than the C-terminal carbonyl group which may have a protected side chain
  • R 1 a a protecting group for an amino group
  • n 0 or 1
  • R 4a a hydrogen atom, a hydroxyl group or a phenyl group.
  • R 1 '- ( G) n- is benzyl O alkoxycarbonyl group, and R 4' when the water atom, One X.
  • R 10 - (G ) n- is Benzoiru group, and when R 4 'is a hydrogen atom, one chi beta - R 3a has the formula one Ar g- H, or one Ar g (COOCH 2 P h) One H A compound represented by the formula: )
  • X a has the formula - NH- CHR 2 - (wherein, R 2 is a hydrogen atom, an alkyl group, a lower an alkenyl group, Ariru group, Ararukiru group, imidazo one Lou 4- Iru lower alk Kill group or Indo one A 3-alkyl lower alkynole group, wherein the alkyl group and the lower alkenyl group are a halogen atom, a lower alkoxy group, a hydroxyl group, a mercapto group, an alkylthio group, an aralkyloxy group, an aryloxy group, a nitrite group, a carboxyl group, and a carbamoyl group.
  • an aryl group and an aralkyl group may be a lower alkyl group, a halogen atom, Alkoxy group, hydroxyl group, mercapto group, alkylthio group, nitro group, carboxyl group, trifluoromethyl group, carbamoyl group, mono- or di-lower alkyl canolebamoyl group, lower alkanoylamino group, amino group, mono Or one or more substituents selected from a di-lower alkylamino group, a guanidino group and a nitroguanidino group, and the above-mentioned group of R 2 is a functional group
  • R 5 represents a hydrogen atom, a hydroxyl group or a phenyl group
  • R 5 represents a pharmaceutically acceptable salt thereof.
  • R 3a is (1) an aldehyde group; (2) a cyano group; (4) a lower group / rekoxycarbonyl / letheninole group; (5) a phenoxymethylcarbonyloxymethylcarbonyl group; (6) Phenylthiomethylcanolebonyl group; (7) phenoxycarbinole group which may have a substituent selected from the group consisting of a lower alkoxy group, a dinitro group and a halogen atom; (8) a lower alkoxy group; A aralkyl carbonyloxymethylcarbonyl group having a substituent selected from the group consisting of a hydroxyl group and a hydrogen atom; (9) a substituent selected from the group consisting of a lower alkyl group and a hydroxyl group; A carbonyl group substituted with a nitrogen-containing saturated heterocyclic group; (10) optionally condensed with a benzene ring, (lower alkoxy group, amino group, mono
  • a nitrogen-containing 5-membered heteroaryl group which may have a group; (11) a carbonyl group substituted with a nitrogen-containing 5-membered heteroaryl group which may be condensed with a benzene ring; (13) a proline derivative or a proline derivative thereof, which is a nitrogen-containing 6-membered heteroaryl group optionally substituted with a halogen atom;
  • a pharmaceutically acceptable salt of (f) R is (1) an aldehyde group, a proline derivative or a pharmaceutically acceptable salt thereof,
  • R 3 ′ is substituted with (9) a nitrogen-containing saturated heterocyclic group which may have a substituent.
  • R 3 ′ which is a substituted carbonyl group or a pharmaceutically acceptable salt thereof,
  • R 3 ′ may be condensed with a benzene ring or may have a substituent A 5- or 6-membered heteroaryl group-containing proline derivative or a pharmaceutically acceptable salt thereof,
  • R 3 ′ is a carbonyl group substituted with a 5- or 6-membered nitrogen-containing heteroaryl group which may be condensed with a benzene ring or may have a substituent.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising the proline derivative represented by the above general formula (1 ′) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, particularly a cathepsin K inhibitor. Also concerns.
  • an amino acid is a natural or unnatural amino acid and has the general formula H 2 N— (CH 2 ) mC (R 2 ) (R 2 ) -COOH
  • m 0 or 1
  • R 2 and R 2 ′ represent an amino acid side chain; the same applies hereinafter.
  • Amino acid residues are defined as one hydrogen atom of the amino group at the N-terminal of these amino acids and the hydroxyl group of the carboxylic acid at the C-terminal.
  • Amino acid residues may have stereoisomers (L-form, D-form, or S-configuration, R-configuration) based on the presence of asymmetric carbon.
  • stereoisomers L-form, D-form, or S-configuration, R-configuration
  • Amino acids can be represented by three letter abbreviations, for example, see Ho uben-Weyl, Methoden derorganischen Cheraie (Method of Organic Chemistry) Vol Xol / 1 and 2, Stuttgart (1974) be able to.
  • amino acid residue represented by “X or X ′” “a part of the amino acid residue except for the C-terminal carbonyl group of the amino acid residue which may be S-protected ((1))” Expressed by letter abbreviations for amino acids.
  • Preferred amino acid residues in the “parts except for the C-terminal carboxy group of the ( ⁇ _) amino acid residue whose side chain may be protected” represented by X or X ′ of the present invention include, for example, Arg (Arginine), Tyr (tyrosine), Nle (norleucine), Val (parin), Aib ( ⁇ -methyl-alanine), Phe (phenylalanine), Phg (phenylglycine), Nva (nonolevulin), Leu (Leucine), Abu ( ⁇ -aminobutyric acid), Gly (glycine), Hyp (hydroxyproline), Pro (proline), Lys (lysine), Typ (tryptophan), Cha (cyclohexylalanine) ), Glu (gunoletamic acid), Met (methionine), lie (isoleucine), Thi ( ⁇ — (2-Cheninole) monoalanine), Thr (threonine), Ala (aranan), Ser (serine), Asp
  • amino acid residues may be D-form, L-form or DL-form, but L-form is more preferable.
  • the side chain may be protected means that when a functional group containing an oxygen, sulfur or nitrogen atom is present in the side chain of the amino acid, these functional groups may be protected.
  • these protecting groups are well known to those skilled in the art, for example, * The P mark ti des Volume 3 Protection of Functional Groups in Peptide Synthesis EG Gross, J. Meienhofer Edit., Academic Press, New York (1981), Ohihi's Chemistry of the Amino Acids "Volume 2 (1961), etc.
  • the Peptides s “Volume 3, pages 7 to 46, describes a protecting group for an amino group, an alkynyl group, and trifluoroacetyl.
  • benzoyl group in which benzene ring may be substituted lower alkoxycarbonyl group, benzyloxycarbonyl group in which benzene ring may be substituted, benzyl group in which benzene ring may be substituted, benzene ring May be substituted, including phenyl-sulfonyl group, phenylcarbamoyl group, t-butyl group, etc.
  • protective groups for the guanidino group nitro group, ⁇ -toluenesulfonyl group, ⁇ -methoxyphenylsulfoninole group, benzylinoleoxycarbol group (hereinafter abbreviated as ⁇ )), t-butyloxycarbonyl group (including Boc)
  • the protecting group for the nitrogen atom of the imidazole ring (including benzyl, trityl, 2,4-dinitrophenyl, benzizyl, Z, Boc, etc.)
  • X or X A preferred group of the formula is represented by a specific structural formula: —NH—CHR 2 — (wherein R 2 is a side chain of an amino acid residue, and is preferably a hydrogen atom, an alkyl group, or a lower alkenyl group.
  • an aryl group and an aralkyl group include a lower alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group, a mercapto group, an alkylthio group, a nitro group, a carboxy group, a trifluoromethyl group, a carbamoyl group, and a mono- or di-alkyl group.
  • R may be substituted with one or more substituents selected from an alkylcarbamoyl group, an alkanoylamino group, an amino group, a mono- or di-alkylamino group, a guanidino group and a ditroguanidino group.
  • R 5 represents a hydrogen atom, a hydroxyl group or a phenyl group.
  • lower alkyl groups J include, for example, methyl, ethyl, propyl, Isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butylinole group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-1 methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group Hexyl group, isohexyl group, 1-methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1,3-dimethylbutyl group
  • Alkyl group J is an alkyl group of the C physician 6 lower alkyl group pressurized forte, C 7 -. 1 0 alkyl group, for example, heptyl, Okuchiru group, nonyl group, decyl group, 3-methyl Examples include a heptyl group and a 3,4-dimethyloctyl group.
  • the “lower alkenyl group” is a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, a bier group, an aryl group, a 1-propenyl group, a 1-methylvinyl group, a 1-butene group.
  • aryl group means an aromatic hydrocarbon ring group, preferably an aryl group having 6 to 14 carbon atoms, specifically, a phenyl group, a naphthyl group, an indenyl group, and an aryl group. And a tritol group and a phenanthryl group.
  • phenyl, naphthyl Group Preferably phenyl, naphthyl Group.
  • the “aralkyl group” is a group in which an arbitrary hydrogen atom of the above “lower alkyl group” is substituted with the above “aryl group”, and specifically, a benzyl group, a phenethyl group, a 1-phenylethyl group, Examples include a phenylpropyl group, a 2-phenylpropyl group, a 1-phenylbutyl group, a 5-phenylpentyl group, a 1-naphthylmethyl group, and a 2-naphthylmethyl group. Preferably, it is a benzyl group.
  • the "imidazo-1-yl lower alkyl group” and the “indo-3-yl lower alkyl group” are those in which any hydrogen atom of the lower alkyl group is an imidazo-1-yl group or indole-3-inole. These are a group substituted with a group, preferably an imidazole-4-ylmethyl group (side chain of histidine) and an indole-3-ylmethyl group (side chain of tributophan).
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom, an iodine atom and the like. Preferably, they are a fluorine atom and a chlorine atom.
  • Examples of “ ⁇ & f and alkoxy group” include, for example, methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, tert-butoxy group, pentyloxy (amyloxy) group, isopentyl group
  • Examples include xy group, tert-pentyloxy group, neopentyloxy group, 2-methylbutoxy group, 1,2-dimethylpropoxy group, 11-ethylpropoxy group, hexyloxy group and the like. Methoxy groups and ethoxy groups are particularly preferred.
  • lower alkylthio group examples include groups in which a hydrogen atom of a mercapto group is substituted with the above “lower alkyl group”. Specific examples include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, and a butylthio group. Group, isobutylthio group, pentylthio group, isopentylthio group, hexylthio group and the like.
  • alkylthio groups having 1 to 4 carbon atoms are preferable, and carbon atoms of methylthio group, ethylthio group, propylthio group and isopropylthio group are preferable.
  • Alkylthio groups of 1 to 3 are particularly preferred.
  • the “aralkyloxy group” is a group in which a hydrogen atom of a hydroxyl group is substituted with the above-mentioned aralkyl group, and examples thereof include a benzyloxy group, a phenethyloxy group, and a 1-naphthylmethyloxy group.
  • the “aryloxy group” is a group in which a hydrogen atom of a hydroxyl group is substituted by the above aryl group, and examples thereof include a phenoxy group and an 11-naphthyloxy group.
  • the “mono- or di-lower alkyl group” is a group formed by substituting one or two hydrogen atoms with the above alkyl group.
  • Di-lower alkyl group In the case of a rubamoyl group, the two alkyl groups may be the same or different.
  • Examples of the mono-lower alkyl rubamoyl group include a methylcarbamoyl group, an ethynole rubamoyl group, a propyl canolebamoyl group, an isopropyl canolebamoyl group, a butyl carbamoyl group, an isobutyl carbamoyl group, a sec-butyl carbamoyl group, and a tert-butyl carbonyl group.
  • Examples include a levamoyl group and a pentylcarbamoyl group.
  • di-lower alkyl canolebamoyl group examples include a dimethylcarbamoyl group, a diethylcarbamoyl group, a dipropyl / levamoinole group, a methinoleethylcarbamoyl group, a methylpropyl-lubamoyl group, a methylisopropyl-lubamoyl group, and a methylbutyl-carbamoyl group.
  • f alkanoyl group examples include formyl group, acetyl group, propionyl group, butynole group, isobutyl group, valeryl group, isovaleryl group, bivaloyl group, hexanoyl group and the like.
  • Examples of the lower alkanoylamino group j include a formylamino group, an acetylamino group, a propionylamino group, a butylamino group, an isobutylamino group, a valerylamino group, an isovalerylamino group, a bivaloylamino group, and a hexanoylamino group.
  • the “mono or di-lower alkylamino group” is an amino group in which one or two hydrogen atoms have been substituted with the above-mentioned alkyl group.
  • the two alkyl groups may be the same or different.
  • the mono-lower alkylamino group include a methylamino group, an ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, an isobutylamino group, a sec-butyl / reamino group, a tert-butylamino group, and a pentylamino group.
  • Examples of the lower alkylamino group include a dimethylamino group, a acetylamino group, a dipropylamino group, a methinoethylamino group, a methylpropylamino group, a methylpropylamino group.
  • Examples include a isopropylamino group, a methylbutylamino group, a methylisobutylamino group, an ethylpropylamino group, and an ethylisopropylamino group.
  • Examples of the “protecting group for an amino group” of R 1 or R le in the present invention include those commonly used as a protecting group for an amino group at the N-terminal or side chain of a peptide. Examples of the protecting group for an amino group described on pages 7 to 46 of 3, include protecting groups described in Protective Groups in Organic Synthesis Greene & Wuts, New York (l 981).
  • the carbonyl group and benzene ring may be substituted with p-methoxy, p-nitro or p-chloro, and the benzyl and benzene rings may be substituted with p-methyl S or p-methoxy.
  • a group that inhibits the activity of the SH group of cysteine protease refers to a cysteine that is substituted or added to the C-terminus instead of a chromophore, as is usually performed in the creation of peptide drugs, especially enzyme inhibitors by the synthetic substrate method.
  • a 1,3-dioxolanyl group or a carbonyloxymethylcarbonyl group which may be condensed with a benzene ring or may have a substituent, and is substituted by a 5- or 6-membered nitrogen-containing heteroaryl group. Certain compounds are exemplified.
  • lower alkoxycarbonylethenyl group j is a carbonylethenyl group substituted by the lower alkoxy group, and specifically, methoxycarbenylethenyl group, ethoxycarbonylethyl group, propoxycarborethenyl group. Group.
  • aryloxymethylcarbonyloxymethylcarbonyl group is a methylcarbonyloxymethylcarbonyl group substituted with the above-mentioned aryloxy group, specifically, phenoxymethylcarbonyloxymethylcarbonyl And 11-naphthyloxymethylcarbonyloxymethylcarbonyl group.
  • arylthiomethylcarbonyl group is a methylcarbonyl group substituted with a arylthio group, wherein the arylthio group is a hydrogen atom of a mercapto group. Is a group substituted with Specific examples include a phenylthiomethylcarbonyl group.
  • aryloxycarbonyl group is a carbonyl group substituted by the aryloxy group, and specifically includes a phenoxycarbonyl group, an 11-naphthyloxycarbonyl group, and the like.
  • arylcarbonyloxymethylcarbonyl group and the “aralkylcarbonyloxymethylcarbonyl group” are respectively the carbonyloxymethylcarbonyl group substituted by the above-mentioned aryl group and IS aralkyl group.
  • Examples include a benzoyloxymethylcarbonyl group, a naphthylcarbonyloxymethylcarbonyl group, a benzylcarbonyloxymethylcarbonyl group, and a naphthylmethylcarboxy / reoxymethylcarbonyl group.
  • the “5- or 6-membered nitrogen-containing heteroaryl group that is condensed with a benzene ring” has at least one nitrogen atom and further has one heteroatom selected from a sulfur atom and an oxygen atom.
  • a 5- or 6-membered monocyclic heteroaryl which may be contained or a condensed ring in which the 5- or 6-membered heteroaryl is condensed with a benzene ring; Imidazolyl group, virazolyl group, thiazolyl group, isothiazolyl group, oxazolyl group, isoxazolyl group, triazolyl group, oxaziazolyl group Group, thiaziazolyl group, tetrazolyl group, pyridyl group, pyrimidinyl group, pyridazinyl group, virazinyl group, and condensed with benzene ring, indolyl group, isoindolyl group, ind
  • it may be condensed with a benzene ring! /, A nitrogen-containing 5-membered heteroaryl group, more preferably a thiazolyl group, an oxazolyl group, a benzothiazolyl group, or a benzoxazolyl group.
  • Examples of the “carbonyl group substituted with a 5- or 6-membered nitrogen-containing heteroaryl group which may be condensed with a benzene ring” include the above-mentioned “5- or 6-membered nitrogen-containing heteroaryl group optionally condensed with a benzene ring”.
  • a carbonyl group bonded to a benzene group preferably a carbonyl group condensed with a benzene ring, or a carbonyl group substituted with a nitrogen-containing 5-membered heteroaryl group, more preferably a thiazolyl group or an oxazolyl group , Carbonyl groups substituted with benzothiazolyl group, benzoxazolyl group, etc.
  • the ⁇ carbo / reoxymethylcarbonyl group substituted with a 5- or 6-membered nitrogen-containing heteroaryl group which may be condensed with a benzene ring, And a nitrogen-containing 5- or 6-membered heteroaryl group ", preferably a pyridylcarbonyloxymethyl group, a pyrazinylcarbonyloxymethyl group or the like.
  • aryloxymethylcarbonylmethylcarbonyl group arylthiomethylcarbonyl group
  • aryloxycarbonyl group arylarylcarbonyloxymethylcarbonyl group
  • aralkylcarbonyl Oxymethylcarbonyl group "”
  • Nitrogen-containing 5- to 6-membered heteroaryl group optionally condensed with a benzene ring Benzene ring
  • Nitrogen-containing 5- to 6-membered heteroaryl group optionally condensed with a benzene ring A carbonyl group substituted with a benzene ring and a carbonyloxymethylcarboyl group substituted with a 5- or 6-membered nitrogen-containing heteroaryl group which may be condensed with a benzene ring, respectively.
  • the substituent may be a substituent, and the substituent is not particularly limited as long as it is a substituent commonly used by those skilled in the art.
  • the lower alkyl group is a halogen atom, a lower alkoxy group, a carboxyl group, an amino group, and May be substituted with 1 to 4 substituents selected from the group consisting of di-lower alkylamino groups,), lower alkoxy groups, lower alkoxycarbonyl groups, carboxyl groups, halogen atoms, nitro groups, cyano Group, amino group, mono- or di-lower alkylamino group, hydroxyl group, Ci-3 alkylenedioxy group and the like.
  • the “lower alkoxycarbonyl group” is a carbonyl group substituted by the lower alkoxy group, and includes, for example, a methoxycarbonyl group, an ethoxycarbonyl group, a propoxycarbonyl group and the like.
  • Examples of the "rc ⁇ a alkylenedioxy group” include a methylenedioxy group, an ethylenedioxy group and a propylenedioxy group.
  • the “nitrogen-containing saturated heterocyclic group which may be cross-linked” includes, in addition to the nitrogen-containing saturated heterocyclic group, an azabicyclo-1- [3,3,1] —4-octyl group or the like. Kachibana ring group.
  • the “aralkylamino group” is a group in which a hydrogen atom of an amino group is substituted with a StilE aralkyl group, and examples thereof include a benzylamino group and a phenethylamino group.
  • the “carbonyl group substituted with a nitrogen-containing saturated heterocyclic group” as the “nitrogen-containing saturated heterocyclic group”, specifically, 1-azetiduryl group, 1-pyrrolidinyl group, pyridino group, morpholino group A 4- to 8-membered nitrogen-containing saturated heterocyclic group which can be bonded via a nitrogen atom such as a 1-piperazinyl group, a 1-imidazolidinyl group, a 1-homopiperazinyl group, or a 1-birazolidinyl group;
  • the “carbonyl group substituted with a saturated heterocyclic group” is a group in which the nitrogen-containing saturated heterocyclic group is bonded to a carbonyl group via its nitrogen atom.
  • i-piperazinylcarbonyl group is there.
  • the “carbonyl group substituted with a nitrogen-containing saturated heterocyclic group” may have any one or more substituents, and may be any substituent that is commonly used by those skilled in the art. Although there is no particular limitation, preferably a lower alkyl group (1 to 4 lower alkyl groups selected from the group consisting of halogen atoms, alkoxy groups, carboxyl groups, amino groups and mono- or di-lower alkylamino groups) ), Lower alkoxycarbonyl group and the like. In particular, it is preferable to have these substituents on the ring nitrogen atom of the 1-piperazinyl group, the 1-imidazolidinyl group, the 1-homopiperazinyl group and the 1-birazolidinyl group.
  • the proline residue forming the proline skeleton of the compounds represented by the general formulas (I) and (I ′) of the present invention may be a D-form, an L-form, or a DL-form, but the L-form is more preferable.
  • the compounds of the general formulas (I) and () of the present invention may form a salt depending on the type of the substituent.
  • the present invention includes these pharmaceutically acceptable salts.
  • such salts include ⁇ , hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid, formic acid, acetic acid, propionic acid, butyric acid, isobutyric acid, valeric acid, isovaleric acid, vivano ⁇ , Acid addition salts with organic acids such as oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, citric acid, malic acid, tartaric acid, carbonic acid, methanesulfonic acid, ethanesulfonic acid, glutamic acid, and aspartic acid And the like.
  • the compounds of the general formulas (I) and (1 ′) have at least one asymmetric carbon atom, and include optical antipodes, racemates and diastereomers.
  • the compounds of the general formulas (I) and ( ⁇ ) may have a tautomer based on a guanine I ⁇ 'hydrido group and a guanidino group of arginine.
  • these compounds have cis-trans isomers based on the cyclic structure of proline.
  • the present invention includes isolated isomers of various isomers such as these optical isomers and tautomers, and mixtures thereof.
  • the compounds of the general formulas (I) and (1 ′) of the present invention may further have a crystalline polymorph as a hydrate or as a solvate such as an ethanol solvate depending on the production conditions.
  • the compound of the general formulas (I) and () of the present invention includes a hydrate, a solvate, or a crystal of each of the polymorphs. Substances having a shape are included. (Manufacturing method)
  • the compounds of the general formulas (I) and (II) and the pharmaceutically acceptable salts thereof of the present invention can be produced by applying various synthetic methods utilizing the features of the structure.
  • the compounds of the general formulas (I) and (1 ′) of the present invention have a protecting group for an amino group usually used in the field of peptide drugs at the N-terminus of proline, and further include an amino acid residue. It has a group at the C-terminal that inhibits the activity of the SH group of the cysteine protease in place of the carboxyl group, and may have various substituents. In some cases, it is advantageous in production to protect the group at the stage of a raw material or an intermediate with a protecting group which does not participate in the reaction.
  • Such a protecting group may be removed and converted into the functional group, and then, if necessary, a protecting group usually employed in the field of peptide medicine may be introduced.
  • a protecting group those well known to those skilled in the art can be used.
  • the protective group described in rotective Groups in Organic Synthesis Green & Wuts, New York (1981) and the like can be employed as the i-protection not involved in the reaction.
  • the protection used in peptide synthesis is described in The Peptides Volume 3 "Protection of Functional Groups in Peptide Synthesis” EG Gross, J. Meienhofer Edit., Academic Press, New York (1981), and “Chemistry of the Amino Acids "Volume 2 (1961) and the like.
  • R 12 is an activating group in a hydroxyl group or a hydroxyl group
  • R 13 is a protecting group for a hydrogen atom or an amino group. meaning I do.
  • the compound of the general formula (I) is prepared by amidating a corresponding proline derivative ( ⁇ ) or a reaction activated compound at the carboxyl group thereof with a corresponding aminocarboxylic acid derivative (IV) or a salt thereof by a conventional method. Can be manufactured.
  • compound (IV) may have its amino group protected by a protecting group to form a secondary amine.
  • a protecting group to form a secondary amine.
  • Examples of the activated form of the carboxyl group include acid halides such as acid chloride and acid bromide; acid azides obtained by reacting an ester with hydrazine and alkyl nitrite; and ordinary esters such as methyl ester and ethyl ester.
  • a condensing agent In the condensation reaction, it is preferable to use a condensing agent.
  • the condensing agent used include 11- (3-dimethylaminopropyl) -13-ethylcarbodiimide (EDCI), N, N— Dicyclohexylcarbodiimid (DCC), diphenylphosphorylazide (DPPA), isobutyl chloroformate, carberdiimidazole, benzotriazolyl N-hydroxytrisdimethylaminophosphonidiumhexafluorolin
  • a condensing agent generally used for peptide bond formation such as a compound salt (Bop reagent), may be used.
  • Additives that may be used together with condensing agents such as EDCI and DCC include, in addition to the above-mentioned HO BT and HONSu, 3-hydroxy-14-oxo-1,3,4-dihydro-1,2,3-benzotriazine ( HOOB t).
  • a base such as trimethylamine, diisopropylethylamine, triethylamine (TEA), pyridine, picoline, lutidine, NMM, N, N-dimethylaniline, etc.
  • TAA triethylamine
  • pyridine pyridine
  • picoline lutidine
  • NMM N, N-dimethylaniline
  • the reaction proceeds smoothly In some cases.
  • the reaction is carried out in a solvent under cooling to room temperature.
  • Solvents used are methylene chloride, dichloroethane, black form, carbon tetrachloride, ether, tetrahydrofuran (THF), dioxane, dimethoxetane, ethyl acetate, benzene, toluene, xylene, N, N-dimethylinoformamide.
  • DMSO dimethylsulfoxide
  • the protecting group is introduced by applying any method commonly used in the field of peptide reactions.
  • the protecting group of the amino group is an acyls or urethane-type protecting group
  • the reaction can be carried out in the same manner as in the above-mentioned amide bond formation reaction.
  • the carboxyl group-protecting group is an ester
  • a conventional esteration reaction can be applied.
  • the protecting group for the hydroxyl group is an ether-based protecting group
  • the protecting group can be introduced by reacting the alcohol compound with the corresponding protecting group halido-sulfonate in the presence of a base.
  • a protective group is used and its removal is necessary, remove the protective group.
  • the removal of the protecting group is performed by applying any method commonly used in the field of peptide reaction, for example, when the protecting group of the amino group is a substituted or unsubstituted benzyloxycarbonyl group, Reduction is preferred, and in some cases, acid treatment with hydrobromic acid Z-acetic acid, hydrobromic acid notrifluoroacetic acid (TFA), hydrofluoric acid, or the like is used.
  • urethane-type protecting groups such as t-butoxycarbonyl group
  • acid treatment with hydrobromic acid acetic acid, trifluoroacetic acid Z hydrochloric acid, hydrochloric acid / acetic acid, nodioxane hydrochloride or the like is advantageously applied.
  • the hydroxyl-protecting group can be removed by sodium or liquid ammonium treatment or TFA treatment, and depending on the type of protecting group, it can be easily removed by catalytic reduction or, in the case of an acyl-based protecting group, by hydrolysis in the presence of an acid or alkali. .
  • the protective group for the carbonyl group is a methyl group or an ethyl group, it is converted to a genated group; when it is a substituted or unsubstituted benzyl group, it is converted to a catalytic group or genated. Each can be easily removed.
  • R 1 G, X, R 4 and n have the above-mentioned meanings, R 14 represents an active group in a hydroxyl group or a carboxyl group, and R 15 represents an amine residue.
  • the compound having an amide-type C-terminal group represented by the general formula (Ia) is prepared by reacting the corresponding carboxylic acid or a reaction activated form (V) at the carboxyl group thereof with an amine represented by the general formula (VI) or It can be produced by amidating the salt with a conventional method.
  • the reaction can be carried out in the same manner as in the first production method.c
  • R 1 6 represents a halogen atom, hydroxyl group, mixed acid anhydride residue, or an ester residue.
  • the alcohol compound represented by the general formula ( ⁇ ) in which R 3 is a hydroxymethyl group is obtained by reducing the corresponding carboxylic acid or its derivative ( ⁇ ) such as an acid anhydride, a mixed acid anhydride, or an acid ester as a raw material. Can be manufactured.
  • a chlorine atom, a bromine atom or the like is used as a halogen atom
  • a residue constituting the same anhydride as the mixed acid anhydride is used as a mixed acid anhydride residue
  • a methyl group is used as an ester residue
  • Ester residues commonly used when synthesizing alcohols from carboxylic esters such as ethyl groups by reduction are exemplified.
  • the reduction is preferably carried out by adding a reducing agent to an organic solvent such as DMF, THF or the like which does not take part in a solvent such as NMF or diisopropylethylamine if necessary, and adding a reducing agent.
  • a reducing agent include sodium borohydride, sodium trimethoxyborohydride, lithium aluminum hydride, lithium trimethoxyaluminum hydride, alane, diisobutylaluminum hydride, diborane, and the like. Is appropriately selected in consideration of
  • the compound of the general formula (lb) in which R 3 is anoside is produced, for example, by oxidizing the alcohol compound ( ⁇ ) obtained by the method (a) as a raw material. can do.
  • Acid ⁇ typically, benzene, preparative ⁇ Reen, xylene, black hole benzene, Mechirenkurori de in a solvent which does not participate in the reaction such as ether, chromium trioxide (C r0 3) - pyridine (P yr), Cr0 3 ⁇ -Power to add an oxidizing agent such as Pyr or DMS ⁇
  • a base such as triethylamine
  • sulfur trioxide (SO a ) Add an oxidizing agent such as Pyr or oxalyl chloride It is advantageous to carry out.
  • the compound in which R 3 is a chloromethyl group may be a halogenating agent such as hydrohalic acid when the j
  • a halogenating agent such as hydrohalic acid when the j
  • the compound in which R 3 is an acetal derivative such as a 1,3-dioxolanyl group can be obtained by converting the corresponding ano, human, or conductor into a solvent such as benzene or toluene in the presence of a medium such as p-toluenesulfonic acid. It is produced by reacting a diol. The reaction is carried out by removing water generated under heating and refluxing with a dehydrating agent of ⁇ & or etinoorthoformate! ⁇ .
  • a compound in which R 3 is a lower alkoxycarbonylethenyl group is produced by reacting a corresponding anohyperconductor with phosphoylide.
  • Reaction? IL3 ⁇ 4 depends on the type of raw material used and is not particularly limited.
  • the solvent dimethoxetane, dimethyl sulfoxide, tetrahydrofuran or the like is usually used.
  • the compound in which R 3 is an aryloxycarbonyl group can be produced in the same manner as in the first production method, except that substituted phenols are used instead of amine.
  • a compound in which R 3 is a piperazine derivative is produced by reacting the corresponding N-Boc form with an acid such as hydrogen chloride or trifluoroacetic acid, followed by deprotection.
  • the reaction varies depending on the type of raw materials used and the reaction conditions, and is not particularly limited.
  • the solvent an alcohol solvent, dichloromethane or the like is usually used.
  • the compound in which R 3 is a heteroaryl-substituted carbonyl group is produced by reacting the corresponding tertiary amino acid or ester derivative with a lithium salt of heteroaryl.
  • the reaction is usually carried out at a temperature in the range of 178 ° C to room temperature, and tetrahydrofuran, getyl ether or the like is used as a solvent.
  • the compound in which R 3 is a benzoxazole or benzothiazole derivative is obtained by amidating the corresponding carboxylic acid and an aminophenol derivative or a 2-aminothiophenol derivative according to the first production method. It is produced by heating under reflux or heating under reflux in the presence of an acid catalyst such as p-toluenesulfonic acid.
  • an acid catalyst such as p-toluenesulfonic acid.
  • benzene, toluene or the like is used as the solvent.
  • a compound in which R 3 is an oxazole or thiazole derivative is produced by heating and refluxing in a solvent such as ethanol from the corresponding bromomethyl ketone derivative and an amido or thioamido conductor as raw materials. .
  • a compound in which R 3 is a cyano group is prepared by converting the corresponding amide derivative to a thiol-n-cylide derivative in the presence of a base such as phosphorus oxychloride or morpholine. It is manufactured by 3 ⁇ 4k.
  • the reaction medium varies depending on the type of raw materials used and the reaction conditions, and is not particularly limited.
  • the compound wherein R 3 is a substituted carbonyloxymethylcarbonyl group is prepared by converting the corresponding bromomethyl ketone derivative and carboxylic acid derivative in a solvent such as N, N-dimethylformamide with a fluorocarbon such as potassium fluoride.
  • a solvent such as N, N-dimethylformamide
  • a fluorocarbon such as potassium fluoride
  • the starting bromomethylketone derivative can be obtained by a method well known to those skilled in the art, for example, amino acid It is produced by a method of converting a boxyl group into a mixed acid anhydride, treating it with diazomethane, and further treating it with hydrogen bromide to convert it to bromomethyl ketone.
  • the compound of the present invention can also be produced by a solid phase method using a resin such as 2-mouth trityl resin.
  • a resin such as 2-mouth trityl resin.
  • an amine such as piperazine
  • add an amino acid with the N-terminal amino group protected amidate in the same manner as in the first production method, and then remove the N-terminal amino group protecting group.
  • a proline derivative having a protected amino group is added, amidation is performed in the same manner, and finally, the product is eliminated from the resin using an acid such as trifluoroacetic acid to obtain the desired piperazine derivative of the present invention.
  • the proline derivative of the present invention can be synthesized using a method well known in the field of peptide synthesis (for example, Izumiya et al., “Basic and Experimental Peptide Synthesis”, 1998 (Maruzen)).
  • the addition and deprotection of protecting groups for N-terminal amino acids, amino acid side chains and C-terminal carboxyl groups are described in “The Peptides” Volume 3 “Protection of Functional Groups in Peptide Synthesis” EG Gross, J. Meienhofer Edit., Academic Press, The methods described in New York (1981) and iTC Chemistry of the Amino Acids "Volume 2 (1961) can be used.
  • the starting compounds used in the method for producing the active ingredient compound of the present invention may be commercially available or may be produced by a known method (for example, “Basic and Experimental Peptide Synthesis” by Izumiya of FilE, 1985, (circle), and RM Williams Synthesis of Optically Active ⁇ -Aminoacids Pergamon Press, Oxford (1989)) or a method according to a known production method.
  • the reaction product obtained by each of the above production methods is isolated and purified as various solvates such as a free compound, a salt thereof or a hydrate. Salt can be produced by subjecting it to a conventional process.
  • Isolation and purification are carried out by applying ordinary chemical operations such as extraction, m, distillation, crystallization, filtration, recrystallization, and various types of chromatography.
  • optical isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers.
  • the optical isomers can be separated by a general racemic resolution method, for example, fractional crystallization or chromatography.
  • the optical isomer can also be synthesized from an appropriate optically active starting compound. Available ⁇ ii available
  • the bone resorption inhibitor of the present invention which has a specific cathepsin ⁇ inhibitor, acts specifically on osteoclasts and has little effect on the activity of other cysteine proteases. It has no side effects, and can prevent or cure bone associated with accelerated bone breakdown.
  • bone diseases associated with such bone breakdown iSii include osseous fibrosis, renal penetrating bone a disease, evil ulcer high calcium ⁇ , bone paget disease and the like.
  • the proline derivative represented by the general formula ( ⁇ ) or ( ⁇ ) of the present invention has a selective inhibitory activity on cathepsin K, and a compound having a selective cathepsin K inhibitor of the present invention. It has been reported that 3 ⁇ 4 has significant bone resorption inhibition by the following ⁇ Silil ⁇ .
  • Cathepsin L and K enzyme activities were measured using the following commercially available synthetic substrates (manufactured by Peptide Laboratories).
  • cathepsin L derived from human kidney
  • the method of Methods in Enzymology Vol. 80, 540-541 * 3 ⁇ 4 was modified ⁇ and the cathepsin L enzyme activity was measured for each species.
  • reaction was stopped by adding 50 / z 1 of a reaction stop solution (PH 4.3) containing sodium acetate (10 OmM), sodium acetate (3 OmM) and acid (7 OmM) to the reaction mixture.
  • a reaction stop solution PH 4.3
  • the fluorescence of the reaction solution containing 7-amino-4-methinorecmarin (AMC) fiber-synthesized from the synthetic substrate was measured at an excitation wavelength of 355 nm and an observation wavelength of 460 rim.
  • the amount of AMC (nmo 1 / min) from firefly ⁇ S was determined.
  • Cathepsin K ⁇ 3 ⁇ 43 ⁇ 4 activity for each substrate was measured using the genetically modified cathepsin K.
  • ML S (2-Morpholinoethanesulfonic acid, monohydrate) (50 mM)
  • the above cathepsin K was added to a buffer solution (pH 5.5) containing, disodium EDTA (2 mM) and dithiothreitol (4 mM) to prepare ⁇ .
  • dithiothreitol was added to Kamimitsumi buffer to a concentration of 8 mM ⁇ g, and then each of the above-mentioned synthetic substrates (1) (Peptide Lab.) was added to a concentration of 20 M.
  • a substrate solution was prepared. Enzyme solution 100 ⁇ 1 and buffer solution 100; z1 were mixed and incubated at 37 for 60 minutes.
  • the reaction was stopped by adding 50 ⁇ 1 of a reaction stop solution (pH 4.3) containing sodium acetate (100 mM), sodium nitrate (30 mM) and acetic acid (70 mM) to the S solution.
  • a reaction stop solution pH 4.3
  • the fluorescence of the reaction mixture containing 7-amino-4-methylcoumarin (AMC) was measured at an excitation wavelength of 355 nm and an observation wavelength of 460 nm, and the AM was determined from each substrate by the enzyme as described above.
  • the amount of C was determined.
  • the cathepsin L inhibitory activity of the compound of the present invention was measured in the same manner as in the method for measuring the cathepsin L ⁇ ⁇ activity of each substrate using human ⁇ ⁇ ⁇ -derived cathepsin L. That is, ⁇ was prepared in the same manner using the same buffer as that used in the jf self cathepsin L ⁇ 3 ⁇ 43 ⁇ 4 measurement, while adding the same buffer to which dithiothreitol was added to a concentration of 8 mM.
  • the substrate solution 100 1 and the DMSO solution 2 ⁇ 1 containing the measurement sample were mixed, and incubated at 37 ° C for 30 minutes.
  • the reaction was stopped by adding the same reaction stop solution ( ⁇ 4.3) 5 ⁇ 1 to the reaction solution, and then the reaction solution containing 7-amino-4 monomethylcoumarin (AMC) fiber-fibred from fiber :)
  • the feg was measured in the same manner, and the degree of inhibition of the enzymatic activity of cathepsin L on the substance of the specimen (inhibition rate) was determined by the following equation.
  • Inhibition rate () [1- (sample value-blank value) / (control value-blank value)] x 100
  • the cathepsin ⁇ inhibitory activity of the ff of the present invention was measured in the same manner as in the above-described cathepsin K 3 ⁇ 4 assay using recombinant cathepsin K.
  • a substrate solution was prepared by adding Boc-AGPR-MCA as a synthetic substrate at a ratio of 40.
  • the ⁇ solution 100 1, m 100 ⁇ ⁇ and the DMS 0 solution 21 containing the measurement sample were mixed, and the mixture was incubated at 37 for 60 minutes. After stopping S by adding 5Qn ⁇ to iffiS reaction stop solution (pH 4.3), the fluorescence of the reaction solution containing AMC ⁇ from the substrate was measured in the same manner, and cathepsin K to the synthetic substrate of the sample was measured. The degree of inhibition of the enzyme activity (inhibition rate) was determined in the same manner as the above-mentioned cathepsin L inhibition rate.
  • MES (10 OmM), disodium EDTA (1 OmM), dithiole A liver solution of cathepsin B (manufactured by CALB IOCHEM) was added to a buffer solution (pH 6.0) containing glucose (16 mM) to prepare a ⁇ solution.
  • Z-RR-MCA was added to the supernatant to a concentration of 20 M to prepare a substrate solution.
  • DMS0 solution I containing 1001, 100 ⁇ 1 and the measurement sample was mixed and incubated at 37 for 30 minutes.
  • reaction stop solution PH4.3
  • the degree of inhibition of the activity was determined in the same manner as for cathepsin L.
  • a buffer pH 6.8 containing HE PE S (10 OmM), disodium EDTA (1 OmM), and dithiothreitol (16 mM), add 0 g pine (SI GMAt ⁇ 3 ⁇ 4) (33 g). / m 1).
  • a substrate solution was prepared by adding Bz—R—MCA (Bz represents a benzoyl group) to the above buffer to a concentration of 20 M ⁇ .
  • the DMS 0 solution 2 ⁇ 1 containing mioo ⁇ , substrate solution ⁇ ⁇ ⁇ , and the sample to be measured were mixed, and incubated at 37 ° C for 30 minutes.
  • Trypsin SIGMA ⁇ was added to a buffer (pH 7.5) containing Tris-HC1 (10 OmM) (10 ⁇ g / 1) to prepare a ⁇ solution.
  • Bz—R—MCA Bz represents a benzoyl group
  • Chymothribine (manufactured by SIGMA) was added (0.1 gZml) to a buffer solution (pH 7.5) containing Tris-HC1 (10 OmM) to prepare a night. Meanwhile, Su on words ⁇ c-LLVY- MCA (Sue is succinyl group, L is a lysine residue, Y is a respectively tyrosine residue) was added so as to ⁇ 3 ⁇ 4 degree of 20 W M, a substrate solution prepared did. 00 1 solution 100 1 and DMS 0 solution 21 containing a measurement sample were mixed, and incubated at 37 for 30 minutes.
  • the reaction was stopped by adding TiSSJ ⁇ stopping solution (pH 4.3) 50 to the reaction solution, and the fluorescence of ⁇ solution containing AMC ⁇ t from the substrate was measured in the same manner.
  • the inhibition of the ⁇ activity of chymotrypsin by 5 T on the synthetic substrate was determined in the same manner as for cathepsin L above.
  • a difficult solution was prepared by adding the solution to the key of 0 M. i001, 100 ⁇ l of the base solution, and 2 ⁇ / 1 of the DMSO solution containing the test sample were mixed, and incubated at 37 for 30 minutes. After stopping the reaction by adding jfSS stop solution (PH 4.3) 501 to the reaction solution, the fluorescence of the solution containing AMC, which was removed from the solution, was measured in the same manner. The degree of inhibition of production (inhibition rate) was determined in the same manner as for cathepsin L described above.
  • the selectivity of cathepsin K to cathepsin L was low for known E-64 and dipeptide or triptide derivatives of leucine.
  • the compounds of Examples of the present invention have high potency and potential for cathepsin L. It also had selectivity for cathepsin B by about two orders of magnitude. It also has high selectivity for other cysteine proteases, indicating that the example compounds of the present application have selective cathepsin ⁇ -blocking activity.
  • a suspension of osteoclasts was prepared using Pergum (JW strain, male, 5 days old). Then ivory pieces (6 mm diameter, 0. 5 m thick) was placed in a 9 6 well plastic flop rate Bok each Uweru was added 1 0 0 1 cell suspension containing 1 0 5 cells, 2 After time, 100 ⁇ 1 N-1 MEM containing the sample was added. This was cultured under 5% CO 2 rice cake for 24 hours. After culture, ivory pieces are lightly polished, hematoxylin is applied, and the number and area of pits (absorption pits) are analyzed using an image processing device (Luzex III, Image Analyzer NIREC0) to inhibit bone resorption. Activity was measured.
  • an image processing device Luzex III, Image Analyzer NIREC0
  • Wistar rats (5 weeks old, male, 6 rats per group) were administered the compound of the present invention in the following manner. Each dose was administered subcutaneously on the back. 75 minutes later, PTH 1-34) was intravenously administered at 33 / gZkg. Blood was collected 45 minutes after the administration of PTH (1-34), and the concentration of ionized calcium in the blood was measured using an electrolyte analyzer SERA-252 (manufactured by HORIBA, Ltd.). Table 4 shows the results.
  • the one or more active substances comprise at least one inert diluent, such as lactose, mannitol, glucose, hydroxypropylcellulose, marine cellulose, starch. , Polyvinylpyrrolidone, and magnesium aluminate metasilicate.
  • the composition may be formulated according to the usual practice with additives other than inert diluents, such as lubricants such as magnesium stearate, disintegrants such as calcium cellulose glycolate, stabilizers such as lactose, A solubilizing agent such as glutamic acid or aspartic acid may be contained.
  • Tablets or pills may be coated with sugar-coated sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate and the like, or with films of gastric or enteric substances.
  • Liquid preparations for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, and commonly used inert diluents, such as Contains purified water and ethanol.
  • the composition may contain, in addition to the inert diluent, adjuvants such as wetting agents and suspending agents, sweetening agents, flavoring agents, flavoring agents and preservatives.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • examples of the 7 sex solutions and suspensions include distilled water for use in (1) and physiological saline.
  • non-aqueous solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 ( Product name).
  • Such compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (eg, lactose), solubilizing agents (eg, glutamic acid, aspartic acid). May be included.
  • These are sterilized by, for example, passing through a bacteria retention filter, blending a bactericide or irradiation. They can also be produced as sterile solid products and dissolved in sterile water or sterile application solvent before use.
  • the medicament of the present invention When the medicament of the present invention is used as a bone resorption inhibitor for the purpose of preventing or treating a patient, it is usually administered orally or parenterally.
  • the dose is determined as appropriate for each individual case, taking into account the patient's symptoms, age, sex, body weight, treatment, administration route, and treatment time.
  • the daily dose is 1 to 200 mg orally.
  • An appropriate time is selected for continuous intravenous administration. Since the dose varies depending on the purpose of prevention and various other conditions, a smaller or larger dose than the above dose range may be sufficient.
  • FIG. 1 is a graph showing the measurement results of the enzymatic activities of cathepsins K and L for each synthetic substrate.
  • FIG. 2 is a 1 H-NMR spectrum diagram of N-acetylprolylnorleucinal (Ac-Pro-N1e-H) obtained in Example 4.
  • FIG. 3 is an H-NMR spectrum diagram of N-acetylprolyltyrosinyl (Ac-Pr0-Tyr-H) obtained in Example 5. Best Mode for MS
  • Ac represents an acetyl group
  • IPE represents isopropyl ether.
  • Other abbreviations are as described above.
  • Table 5 shows the chemical shifts and assignments of H-NMR.
  • the present compound exists as a tautomer mixture of a carpinolamine derivative in which a guanidino group and an aldehyde group form a cyclic structure in a solution state under NMR measurement conditions, This is considered to be a phenomenon peculiar to the alginal-containing peptide, as has been observed for leupeptin.
  • FIG. 1 shows the H-NMR data of this product.
  • FIG. 3 shows the H-NMR data of this product.
  • the extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure.
  • Example 17 1-benzyloxycarbinol L-prolinole L-phenylalaninal (440mg, 1.15mmol), ethyl ethyl orthoformate (340mg, 2.31mol) and ethylene glycol (140mg, 2.31mmo toluene (5ml) solution Then, molecular sieves 4A (100 mg) and p-toluenesulfonic acid monohydrate (60 mg, 0.3 nunol) were added to the mixture, and the mixture was stirred with heating under reflux for 30 minutes. The extract was washed with 1N aqueous sodium hydroxide solution, water and saturated saline in that order, dried over anhydrous sodium sulfate, and concentrated under reduced pressure.
  • Trifluoroacetic acid (5 ml) was added to a solution of 1- (1-benzoylyl L-prolyl-L-leucyl) -1- (tert-butoxycarbonyl) piperazine (970 mg, 1.94 mmol) in dichloroethane (10 ml). Stirred for hours. After concentrating the reaction solution, the obtained residue was neutralized with a saturated aqueous solution of potassium carbonate and extracted with chloroform.
  • the extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and dried with 1- (1-benzoyl-L-prolyl-L 1-port isyl) pidazine (790 mg, 1.94 mmol, quant ).
  • Benzyloxycarbonyl L-proline 250 mg, 1.0 mmol is dissolved in 1.25 mL of dimethylformamide, and the solution is equally distributed to 5 places (1 row) of a 96-well deep well.
  • reaction solution was poured into five test tubes containing ether and 1 N hydrochloric acid, respectively, extracted and separated, and the ether layer was concentrated under reduced pressure and dried under reduced pressure. Each residue was dissolved in 1 mL of anhydrous methylene chloride, 86 mg of Molecular Sieves 4A powder was added, and pyridinium chlorochromate (86 mg, 0.4 mmol) was added to each, followed by shaking at room temperature for 1 hour. The reaction solution was eluted using a silica gel column with ether as the solvent. The ether solvent was passed through florisil, and the solvent was distilled off under reduced pressure.
  • A 1-benzyloxycarbonyl-l-prolyl-DL-n-xylina 1 (0.6m), (b) 1 benzyloxycarbonyl L-prolyl _ ⁇ -methyl-1-DL-alaninyl (0.2mg), (c) 1 benzyloxycarbonyl L —Prolyl —DL—Fenylalaninal (0.2 mg), (d) 1-Benzyloxycarbinyl L—Prolyl-DL—Phenyldaricinyl (O.lmg;), and (e) 1-Benzyloxycarbo Nilou L-prolilue DL-norvalinal (0.1 mg) was obtained.
  • 2-Clot mouth Trityl resin (lmmol / g, 60g, 60mmol / g) was swollen with anhydrous methylene chloride (600mL) under a stream of argon, and anhydrous piperazine (25.8g, 0.30mol) in anhydrous methylene chloride (100mL) was added. The mixture was added at a stretch, and diisopropylpropylethylamine (60 mL, 0.34 mol) was further added, followed by shaking at room temperature day and night.
  • the resin was filtered and methylene chloride (5O OmL), dimethylformamide (500mL), diisopropyl alcohol (50OmL), dimethylformamide (50OmL), methanol (50OmL), ether (5O OmL), And sequentially washed. It was dried under reduced pressure for one day and used for the next reaction.
  • the obtained resin is divided into 12 equal parts and added to a 6 mL filter tube to make a total of 96 filter tubes.Next, remove the total of 8 tubes from each of the 8 types of 12 filter tubes, and perform the following reactions. went. 0.5 mL of dimethylformamide was added to the filter tube to swell the resin, and 0.2 mL of benzylcarbonyloxy-l-hydroxyproline in dimethylformamide solution adjusted to 1 mol / L and benzotriazole-1 were added.
  • Boc tert-butoxycarbonyl group
  • HPLC Liquid chromatograph (Equipment: Hitachi L-7100 type pump, Les 7200 type autosampler, L-7400UV detector, D-7500 type chromatograph data processing)
  • HPLCMS Liquid chromatographic spectrum (Equipment: Thermo Quest TSQ7000)
  • Effluent condition a (Column: Merckne: LiChrospher 100 RP-18 (4.0 ⁇ , 25 t, 5 ⁇ ))
  • Solvent Fischer Ichi HPLC grade MeOH (A452J-4) and distilled water (W5J-4) Trifluoroacetic acid manufactured by Kanto Chemical Co., Ltd. (Cat. No. 40578-00))
  • Outflow conditions: MeOH solution of 5nunol trifluoroacetic acid: 5 distilled water solution of trifluorotrifluoroacetic acid 5:95 to 100: 0 with a gradient applied ImL / rain 5min, 100: 0 for 3min, detection: 254nio)
  • #b outflow condition b (Column:.
  • Effluent condition d (Column: A-302 S-5 ODS column (4.6 nm x 150 mm, 5 ⁇ ), manufactured by Yemushi Ichisha)
  • Solvent: HPLC grade MeOH (A452J-4) manufactured by Fischer and distilled water (W5J- Using 4), MeOH solution of 5 mmol trifluoroacetic acid: 5 mL distilled aqueous solution of trifluoroacetic acid 1 0: 90 to 60: 40 mL with a gradient of 40 mL, flow out for 20 minutes, detection: 220 ⁇ )
  • L-Trp-N-Boc (N-tert-butoxycarbonyl) one L-tryptophanyl group
  • L-Glu (O-Bu-t) (O-tert-butyl) one L-glutaryl group

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Abstract

La présente invention concerne des médicaments, en particulier des inhibiteurs de la résorption osseuse dont le principe actif doté d'effets inhibiteurs sélectifs de la cathepsine K est constitué notamment de dérivés représentés par la formule générale (I) ou l'un de ses sels admis en pharmacie. Dans cette formule générale (I), X est un groupe fonctionnel (sauf dans le cas du groupe carbonyl à terminaison C) d'un radical d'acide aminé sont la chaîne latérale est facultativement protégée, R1 est un groupe protégeant le radical amino, G est un radical glycine, n est un entier valant 0 ou 1, R3 est un groupe inhibant l'activité du groupe SH de la cystéine protéase, et R4 est hydrogène, hydroxy ou phényl.
PCT/JP1997/002357 1996-07-08 1997-07-08 Inhibiteurs de la resorption osseuse WO1998001133A1 (fr)

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AU33596/97A AU3359697A (en) 1996-07-08 1997-07-08 Bone resorption inhibitors

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WO2000055126A2 (fr) * 1999-03-15 2000-09-21 Axys Pharmaceuticals, Inc. Nouveaux composes et compositions utiles comme inhibiteurs de protease
WO2001047886A1 (fr) * 1999-12-24 2001-07-05 F. Hoffmann-La Roche Ag Derives du nitrile en tant qu'inhibiteurs de la cathepsine k
US6353017B1 (en) 1997-11-05 2002-03-05 Novartis Ag Dipeptide nitriles
US6469047B1 (en) * 1999-09-24 2002-10-22 Genentech, Inc. Tyrosine derivatives
US6531474B1 (en) 1998-03-19 2003-03-11 Vertex Pharmaceuticals Incorporated Inhibitors of caspases
US6642239B2 (en) 2000-02-10 2003-11-04 Novartis Ag Dipeptide nitrile cathepsin K inhibitors
US6902721B1 (en) * 1998-07-10 2005-06-07 Osteoscreen, Inc. Inhibitors of proteasomal activity for stimulating bone growth
US6951861B1 (en) 1999-10-07 2005-10-04 Smithkline Beechan Corporation Chemical compounds
US6977256B2 (en) 2001-11-14 2005-12-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin S inhibitors
EP1616859A1 (fr) 1998-11-12 2006-01-18 Seikagaku Corporation Composés d'acide cyclohexyl carboxylique substitués
US7030116B2 (en) 2000-12-22 2006-04-18 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7060702B2 (en) 2000-10-17 2006-06-13 Smithkline Beecham Corporation Chemical compounds
US7064123B1 (en) 2000-12-22 2006-06-20 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
US7189713B2 (en) 2002-02-08 2007-03-13 Glaxo Group Limited Piperidine derivatives
US7196099B2 (en) 2001-09-14 2007-03-27 Aventis Pharmaceuticals Inc. Compounds and compositions as cathepsin inhibitors
WO2007080885A1 (fr) 2006-01-11 2007-07-19 Seikagaku Corporation Derive de cycloalcanecarboxamide et son procede de production
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US7553861B2 (en) 2005-04-22 2009-06-30 Alantos Pharmaceuticals Holding, Inc. Dipeptidyl peptidase-IV inhibitors
WO2010121918A1 (fr) * 2009-04-20 2010-10-28 F. Hoffmann-La Roche Ag Dérivés de proline comme inhibiteurs de la cathepsine
EP2270005A1 (fr) 2000-05-19 2011-01-05 Vertex Pharmceuticals Incorporated Promédicament inhibiteur d'ECI
US8481725B2 (en) 2006-01-11 2013-07-09 Seikagaku Corporation Cycloalkylcarbonylamino acid derivative and process for producing the same
WO2014199645A1 (fr) 2013-06-14 2014-12-18 生化学工業株式会社 CORPS α-OXOACYL AMINO-CAPROLACTAM
WO2014199644A1 (fr) 2013-06-14 2014-12-18 生化学工業株式会社 DÉRIVÉ α-OXOACYL AMINO-CAPROLACTAM
US9116157B2 (en) 2010-11-05 2015-08-25 Brandeis University Ice-cleaved alpha-synuclein as a biomarker
JP2015227349A (ja) * 2005-03-02 2015-12-17 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． カテプシンｋ阻害組成物
US11851422B2 (en) 2021-07-09 2023-12-26 Aligos Therapeutics, Inc. Anti-viral compounds
US12065428B2 (en) 2021-09-17 2024-08-20 Aligos Therapeutics, Inc. Anti-viral compounds

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