WO1998001133A1 - Bone resorption inhibitors - Google Patents

Abstract

Drugs, in particular, bone resorption inhibitors containing as the active ingredient compounds having selective cathepsin K inhibitory effects, among all, proline derivatives represented by general formula (I) or pharmaceutically acceptable salts thereof, wherein each symbol has the meaning as specified below: X: a moiety (except for the C-terminal carbonyl group) of an amino acid residue with its side chain optionally protected; R1: an amino-protective group; G: a glycine residue; n: 0 or 1; R3: a group inhibiting the activity of the SH group of cysteine protease; and R4: hydrogen, hydroxy or phenyl.

Description

 Bone resorption inhibitor Technical field

 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. Background art

 In recent years, 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.

 Normal bone metabolism rests on a balance between bone formation and bone resorption.

 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. According to previous studies, 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 ^^.

Therefore, 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. In the process of bone resorption by osteoclasts, it was revealed that type I collagen, an organic component of bone supporting tissue, is extremely well-reduced by cysteine proteinase, particularly cathepsin L, in lysosomes. 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 ^^ [FEBS Lett. 280, 311-315 (1991), Delaisse, JM & Vaes, G. (1992) in: Biology and Physiology of the Osteoclast (Rifkin, BR & Gay, CV, eds) pp. 290-314, CRC Pre ss, Boca Raton , J. Histochem. Cytochem. 41, 1075-1083 (1993), BlOmedica 7 (6), 629 (1992), FEBS Lett. 342, 308-312 (1994), FEBS Lett. 336. 289-292 (199) 4) and J. Biol. Chem. 269, 1106-1109 (1994)] ₀

 However, since 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.

On the other hand, a novel cathepsin gene (cathepsin II), which is specifically expressed in osteoclasts, was isolated from egrets. It has been reported that this cathepsin II shows a high degree of homology with cathepsins S and L [J. Biol. Chem. 269, 1106-1109 (1994)]. In addition, there has been a report on the molecular closing of human cathepsin K. This human cathepsin (also known as cathepsin 0, O2 or X) has 94% identity with ゥ sagi cathepsin K. Biophys. Res. Commun. 206, 89-96 (1995), and J. Biol. Chem. 271, 21, 12511-516 (1996). )] ₀

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. 271, 12517-12524 (1996)). Although 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.

 Japanese Unexamined Patent Publication Nos. 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

 In J. Biol. Chem. 271, 21, 12517-524, as a result of examining the substrate specificity of cathepsin K, the best substrate, Cbz-Leu-Arg-AMC (Cbz: benzyloxycarbonyl) It has been disclosed that multiple substrates are affected by cathepsin K, including the / group and AMC (fluorophore). As one of the substrates used, Cbz-Gly-Pro-Arg-AMC is also disclosed. No selectivity with other cathepsins is disclosed. No specific cathepsin K inhibitor is described.

 To date, no compound that selectively inhibits cathepsin K has been reported, and no bone resorption inhibiting activity apparently based on the selective inhibitory activity of cathepsin K has been reported.

On the other hand, 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)).

R

X "(Y) m ~ NH ~ CH" COCH ₀ -CHCO) n ~ R '

Wherein n is 0 or 1, m is 0, 1 or 2, X is H or N-protecting group, and Y is each independently an α-amino acid residue which may be protected. And R is a force that is Η or CH ₃ or a methylene, methine or phenyl group, which is attached to the α-carbon atom to which it is attached, optionally protected _α — R ′ is an optionally substituted aryl which is an amino acid side chain.)

 As described above, cathepsin 発 現, which is specifically expressed in osteoclasts, has been expected to be involved in bone resorption.However, even if it is blocked like cathepsin 相同, which has homology to cathepsin 阻 害, 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. As a result, they found that a synthetic substrate having a partial structure of proline-anoreginine (Pro-Arg) was selectively hydrolyzed only by cathepsin K. Therefore, amino acid conversion is carried out based on this Pro-Arg structure, and a group that inhibits the activity of the SH group of cysteine protease at the C-terminus is introduced into N * ig. As a result of repeated investigations, a group of compounds having excellent selectivity and having harmful effects on cathepsin KP of the present invention was found. The present invention has been made based on the fact that these selective cathepsin KP compounds having an harmful action have an excellent bone resorption inhibiting action, and the present invention has been made.

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.

 That is, 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. Preferably, 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.

 In particular, 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.

 (The symbols in the formula have the following meanings.

 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,

 G: glycine residue,

 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. ) W In the compound represented by the above general formula (I), more preferably,

 (a) a compound wherein X is a moiety excluding the C-terminal carboxy group of an α-amino acid residue which may have a protected side chain,

(b) 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. When the above group of R ² has a functional group containing an oxygen, sulfur or nitrogen atom, these functional groups may be protected. )

, Or expression

(Wherein, R ^s represents a hydrogen atom, a hydroxyl group or a phenyl group).

(c) a group that inhibits the activity of SH groups R ³ cis Ting protease, aldehyde group; Shiano group; Formula one C (= 0) CF _3, one _{C (= 0) CF 2 CF} 3, one P ( = O) (OH) ₂ , one C (= θ) CH ₂ OCH ₂ CF ₃ , one CH ₂ C 1, one S0 ₂ F, or one BY ¹ Y ² (where Y ¹ and Y ² are the same or A hydroxy group, a fluoro group, a lower alkoxy group, or an amino group which may be mono- or di-monosubstituted with a lower alkyl group. Ethenyl group; aryloxymethylcarbonyloxymethylcarbonyl group which may have a substituent; arylthiomethylcarbonyl group which may have a substituent; Aryloxycarbonyl group optionally having substituents; aryloxycarbonylmethylcarbonyl group optionally having substituents; aralkylcarbonyloxymethylcarbonyl group optionally having substituents; A carbonyl group substituted with a nitrogen-containing saturated heterocyclic group; a nitrogen-containing 5- or 6-membered heteroaryl group which may be condensed with a benzene ring or may have a substituent; a benzene ring A nitrogen-containing 5- or 6-membered carbonyl group substituted with a 5- or 6-membered heteroaryl group which may be condensed with a 1,3-dioxolanyl group; May Yo Le have a substituent, a Karuboniruo carboxymethyl carbonyl group substituted with a heteroaryl group nitrogen-containing 5 or 6-membered compound,

(d) 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 compound that is Or

 (e) A compound in which n = 0. Furthermore, 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.

 0

(The symbols in the formula have the following meanings.

X ": a part of the α-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,

G: glycine residue,

n: 0 or 1,

R ³ ": (1) aldehyde group; (2) cyano group; (3) Formula (1) C (= 0) CF ₃ , — C (= θ) CF ₂ CF ₃ , — P (= θ) (OH) ₂ , — C (= 0) CH ₂ CH ₂ CF ₃ , — CH ₂ C 1, one S0 ₂ F, or one BY ¹ Y ² (where Y ¹ and Υ ² are the same or different and are hydroxyl, fluoro, A lower alkoxy group or an amino group which may be mono- or di-substituted by a lower alkyl group.); (4) a lower alkoxycarbonyl ethenyl group; (5) a substituent Aryloxymethylcarbonyloxymethylcarbonyl group; (6) arylthiomethylcarbonyl group which may have a substituent; (7) aryloxymethylcarbonyloxycarbonyl group which may have a substituent; (8) optionally substituted aralkylcarbonyloxymethylcarbonyl group; (9) optionally substituted nitrogen-containing group (10) a nitrogen-containing 5- to 6-membered heteroaryl group which may be condensed with a benzene ring or may have a substituent; (11) a benzene ring substituted with a benzene ring; A nitrogen-containing 5- or 6-membered carbonyl group which may be condensed or may have a substituent, and which is substituted by a teroaryl group; (12) a 1,3-dioxolanyl group; or (13) a benzene ring A nitrogen-containing 5- or 6-membered heteroaryl group-substituted carbonyloxymethinolecarbonyl group which may be condensed or may have a substituent;

R ^4a : a hydrogen atom, a hydroxyl group or a phenyl group.

However, the following compounds are excluded.

^{(1) R 1 '- (} G) n- is benzyl O alkoxycarbonyl group, and R ^4' when the water atom, One X. One R ^3e force formula

 A compound which is a group represented by one of V a 1—H, -Me t—H, —L ys—H, —A rg—H, or —Phe—H;

(2) When R ^l fl-(G) n— is a benzyloxycarbonyl group and R ⁴ ′ is a hydroxyl group, one X ^a — R ^3a is

formula

A compound which is a group represented by, and

^{(3) 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: )

 In the compound represented by the above general formula (1 ′), more preferably,

^(a) 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. Group, mono- or di-lower alkyl group, substituted with one or more substituents selected from a rubamoyl group, a lower alkanoylamino group, an amino group, a mono- or di-lower alkylamino group, a guanidino group and a ditrognidino group And 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 containing an oxygen, sulfur or nitrogen atom. When these have, these functional groups may be protected.)

, Or expression

(Wherein, R ⁵ represents a hydrogen atom, a hydroxyl group or a phenyl group) or a pharmaceutically acceptable salt thereof.

(b) Χ 'is Ar g, N le, Tyr, Ph e, Le u, Pro, Hyp, G 1 y, Va l, A ib, Ph g, Nv a, Ab u, p—C l —A side chain may be protected, selected from the group consisting of Phe, I 1 e, Th r, Th i, Tr p, Lys, Ch a, G 1u and O «Met— C-terminal force of amino acid residue Proline derivative which is the part excluding reportyl group or its pharmaceutically acceptable (c) the protecting group for the amino group of R ^la is lower alkanoinole, benzoyl, benzyl, benzyloxycarbonyl, t-butoxycarbonyl, t-butyl, phenylcanolebamoyl, or phenylsulfonyl; A proline derivative or a pharmaceutically acceptable salt thereof,

 (d) a proline derivative wherein n = 0 or a pharmaceutically acceptable salt thereof,

(e) 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- or di-lower group) A phenyl group which may be substituted with a (alkylamino group or a nitrogen-containing saturated ring group), or a 5- or 6-membered nitrogen-containing heteroaryl group which may be substituted with a (cycloalkyl group or a lower alkyl group). Selected from the group consisting of a lower alkyl group, a nitrogen-containing saturated heterocyclic group which may be substituted or may be bridged by an aralkyl group, and an aralkylamino group which may be substituted by a cycloalkyl group. 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,

(g) R ³ ′ is substituted with (9) a nitrogen-containing saturated heterocyclic group which may have a substituent. (H) R ³ ′ which is a substituted carbonyl group or a pharmaceutically acceptable salt thereof, (h) 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,

(i) 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. Oral phosphorus derivatives or pharmaceutically acceptable salts thereof,

(j) A proline derivative or a pharmaceutical derivative thereof, wherein R ^3e is (13) a carbonyloxymethylcarbonyl group substituted by a 6-membered nitrogen-containing nitrooxy group which may be substituted by a halogen atom. A salt acceptable to or

(k) A proline derivative or a pharmaceutically acceptable salt thereof, wherein R ⁴ ′ is a hydrogen atom.

Further, the present invention relates to 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.

Hereinafter, the present invention will be described in detail.

In the present specification, 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

(In the formula, m represents 0 or 1, R ² and R ² ′ represent an amino acid side chain; the same applies hereinafter.) Means an α-amino acid (m = 0) or) 3-amino acid (m = l) I do. 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.

—General formula -HN- (CH ₂ ) mC (R ² ) (R ² ,) one CO—

Is a group represented by Therefore, in the specification of the present application, Γthe portion excluding the C-terminal carbonyl group of the (α-) amino acid residue whose side chain may be protected represented by X or X * ”

It is a group represented by the general formula — (— (CH ₂ ) mC (R ² ) (R ² ')-.

 Amino acid residues may have stereoisomers (L-form, D-form, or S-configuration, R-configuration) based on the presence of asymmetric carbon. In addition, cis-trans isomers based on the ring structure of proline and the N-terminal protecting group, and tautomers such as arginine may exist depending on the type of side chain. It includes all of these isomers.

 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.

In the specification of the present application, the 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 (α_) 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 (α-methyl-alanine), Phe (phenylalanine), Phg (phenylglycine), Nva (nonolevulin), Leu (Leucine), Abu (α-aminobutyric acid), Gly (glycine), Hyp (hydroxyproline), Pro (proline), Lys (lysine), Typ (tryptophan), Cha (cyclohexylalanine) ), Glu (gunoletamic acid), Met (methionine), lie (isoleucine), Thi (β— (2-Cheninole) monoalanine), Thr (threonine), Ala (aranan), Ser (serine), Asp (Aspartic acid), Hyl (hydroxy pyridine), Cys (cysteine), His (histidine), Hse (homoserine), Hcy (homocysteine), Orn (orditin), Gin (glutamine), Asn (asparagine), / 3 A 1 a alanine). More preferably, it is an α-amino acid residue. Particularly preferred are Nle, Leu, Val, Nva, Ile, Abu, Phe, and Phg. Most preferred are Nle, Leu, Val, Nva, Ile, Abu. In addition, these amino acid residues may be D-form, L-form or DL-form, but L-form is more preferable.

 Further, "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. To indicate that 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. For example," The Peptides s "Volume 3, pages 7 to 46, describes a protecting group for an amino group, an alkynyl group, and trifluoroacetyl. Group, 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.)

On pages 60 to 70, protective groups for the guanidino group (nitro group, ρ-toluenesulfonyl group, Ρ-methoxyphenylsulfoninole group, benzylinoleoxycarbol group (hereinafter abbreviated as Ζ)), t-butyloxycarbonyl group (including Boc)

On pages 70-80, the protecting group for the nitrogen atom of the imidazole ring (including benzyl, trityl, 2,4-dinitrophenyl, benzizyl, Z, Boc, etc.)

On page 82 there is a protecting group for the nitrogen atom of the bilazolyl ring, on pages 82 to 84 there is a protecting group for the nitrogen atom of the indole ring (including formyl group, Z, etc.). Is Carboki Protecting groups for xyl groups (including methyl, ethyl, t-butyl, benzyl, etc.) are described in pp. 137-169, and thiol protecting groups (methyl, t-butyl, Benzinole, p-methoxyphenylmethyl, ethylaminocarbonyl, and Z) are listed on pages 170-201, and hydroxyl protecting groups (benzyl, t-butyl, methyl,

Z, tosyl group, etc.) are disclosed. In the present invention, these protecting groups can be used as appropriate.

Also 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, an aralkyl group, an imidazo-1-yl lower alkyl group or an indole-3-yl lower alkyl group, wherein the alkyl group and the lower alkenyl group are a halogen atom, a lower alkoxy group, a hydroxyl group, Mercapto group, alkylthio group, aralkyloxy group, aryloxy group, nitro group, carboxyl group, carbamoyl group, mono- or di-lower alkyl / rebamoinole group, lower alkanoylamino group, amino group, mono or It may be substituted with one or more substituents selected from di-lower alkylamino, guanidino, and ditroguanidino groups. And 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. ^When the above group ² has a functional group containing an oxygen, sulfur or nitrogen atom, these functional groups are protected as described above.

You may. ), Or formula

(In the formula, R ⁵ represents a hydrogen atom, a hydroxyl group or a phenyl group.)

The term “lower” in the definition of the group represented by the general formula (I) or (Γ) in the present specification means a straight or branched carbon chain having 1 to 6 carbon atoms, unless otherwise specified. Thus, "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, 2,3-dimethylbutyl group, 3,3-dimethylbutyl group, 1-ethylbutyl group, 2-ethylbutyl group, 1,1,2-trimethylpropyl group, 1, 2, 2 —Trimethylpropyl group, 1-ethyl-1-methylpropyl group, 1-ethyl-12-methylpropyl group. Among them, those having 1 to 4 carbon atoms are preferable, and a methyl group, an ethyl group, a propyl group, and an isopropyl group are particularly preferable.

"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. 2-norethyl group, 2-butenyl group, 3-butenyl group, 2-methynolyl 1-propenyl group, 2-methylaryl group, 1-methyl-1-propenyl group, 1-methylaryl group, 1-pentenyl group, 2- Pentynole, 3-pentenyl, 4-pentenyl, 3-methyl-11-buteninole, 3-methyl-2-butenyl, 3-methyl-3-butenyl, 2-methyl-1-butenyl, 1 , 1-dimethylaryl group, 1,2-dimethylinole 1-propeninole group, 1-ethinolene 2-propeninole group, 1-hexeninole group, 2 1-hexenyl group, 3-hexenyl group, 1, 1 —Dimethyl-3-buteninole group, 3, 3-one Examples thereof include a dimethyl-1-butenyl group, a 1-methyl-1-pentyl group, a 4-methyl-11-pentenyl group, a 4-methyl-3-pentenyl group, and among them, an alkenyl group having 3 to 4 carbon atoms is preferable.

The term "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. 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).

 Examples of the “halogen atom” 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.

 Examples of the “lower alkylthio group” 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. Among them, 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. Examples of the di-lower alkyl canolebamoyl group 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. , Methylisobutylcarbamoyl, ethylpropylcarbamoyl, ethylisopropylcanolebamoyl and the like.

 Examples of the "f alkanoyl group" 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. In the case of a di-lower alkylamino group, the two alkyl groups may be the same or different. Examples of 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). For example, a lower alkanol group; a trifluoroacetyl group; a benzene ring which may be substituted with a p-methoxycarbonyl group, a p-phenylsulfonamide carbonyl group, a p-methoxy 、 or p-nitro group; Benzyl group; lower alkoxycarbonyl group; benzene ring in which the benzene ring may be substituted with (p-methoxy, p-nitro, p-chloro or o- (N, N-dimethylcarboxamide) 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. And a phenylsulfonyl group, a phenylcarbamoyl group, a t-butyl group, and the like.

 "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. Groups that inhibit the activity of the SH group of protease (for example, The Journal of Biological Chemistry Vol. 270 No. 33 1925-1 9231 (1995), TiPS-October 1993 Vol. 14366-376, J. Med. Chem. 1994, 37, 4538-4 554), a group which directly inhibits the activity of SH group, such as anohydric group [-C (= 0) H], and a trifluoro group. There are groups (transition state analogs) that do not directly bond to the SH group but maintain the transition state and inhibit its activity like the roacetyl group. In the present invention, in addition to the group that inhibits the activity of the SH group of cysteine proteinase well known to those skilled in the art, the form of the inhibition is unknown, but it actually inhibits the activity of cathepsin K. It is also included in the “group that inhibits the activity of the SH group of cysteine protease”.

Such groups, § zone hydrin group; Shiano group; Formula one _{C (= θ) CF 3,} - C (= 0) CF 2 CF 3, one P (= 0) (OH) 2, - C ( = 0) CH ₂ OCH ₂ CF ₃ , One CH ₂ C or — S〇 ₂ F, or — BY ¹ Y ² (wherein 丫¹ and 丫² are the same or different and are a hydroxyl group, a fluoro group, a lower alkoxy group, an amino group or a mono- or di- A lower alkylamino group;) an alkoxycarbenyl group; an optionally substituted aryloxymethylcarboxyloxymethylcarbonyl group; A good arylthiomethylcarbonyl group; an optionally substituted aryloxycarbonyl group; an optionally substituted arylcarbonylcarbonylmethylcarbonyl group; An aralkyl carbonyloxymethylcarbonyl group which may be substituted; a carbonyl group substituted with a nitrogen-containing saturated group which may have a substituent; a substituent which may be condensed with a benzene ring; I A 5- or 6-membered nitrogen-containing heteroaryl group which may be condensed with a benzene ring or may have a substituent; and a carbonyl substituted with a 5- or 6-membered nitrogen-containing heteroaryl group. 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.

Further, as R ^3a in the general formula (Γ), among the above groups, (1) aldehyde group; (2) cyano group; (3) Formula 1 C (= 0) CF ₃ , 1 C (= 0 ) CF ₂ CF ₃ , one P (= 0) (OH) ₂ , -C (= 0) CH ₂ OCH ₂ CF ₃ , one CH ₂ C 1, —SO ₂ F, or one BY ¹ Y ² (where And Y ¹ and Y ² are the same or different and represent an amino group which may be mono- or di-substituted by a hydroxyl group, a fluoro group, a lower alkoxy group or a lower alkyl group.) (4) lower (5) aryloxymethylcarboxy-carbonylmethylcarbonyl group which may have a substituent; (6) arylthiomethylcarboxy group which may have a substituent. (7) an aryloxycarbonyl group optionally having a substituent; (8) an aralkylcarbonyloxymethylcarbonyl group optionally having a substituent; (9) a carbonyl group substituted with a nitrogen-containing saturated heterocyclic group which may have a substituent; and (10) a carbonyl group which may be condensed with a benzene ring or may have a substituent. 5- to 6-membered nitrogen heteroaryl group; (11) It may be condensed with a benzene ring or may have a substituted group! / And is substituted with a 5- or 6-membered nitrogen-containing heteroaryl group. (12) 1,3-dioxolanyl group; or (13) condensed with benzene ring A carbonyloxymethylcarbonyl group which may be substituted or substituted with a nitrogen-containing 5- or 6-membered heteroaryl group which may be substituted.

 Here, "lower alkoxycarbonylethenyl group j" is a carbonylethenyl group substituted by the lower alkoxy group, and specifically, methoxycarbenylethenyl group, ethoxycarbonylethyl group, propoxycarborethenyl group. Group.

 The “aryloxymethylcarbonyloxymethylcarbonyl group” is a methylcarbonyloxymethylcarbonyl group substituted with the above-mentioned aryloxy group, specifically, phenoxymethylcarbonyloxymethylcarbonyl And 11-naphthyloxymethylcarbonyloxymethylcarbonyl group.

 The “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.

 The "aryloxycarbonyl group" is a carbonyl group substituted by the aryloxy group, and specifically includes a phenoxycarbonyl group, an 11-naphthyloxycarbonyl group, and the like.

 The “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, indazolyl group, quinolyl group, isoquinolyl group, quinazolinyl group, quinoxalinyl Group, cinnolinyl group, benzimidazolyl group, 1,2-benzoisoxazolyl group, benzoxazolyl group, benzothiazolyl group and the like. Preferably, 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 Γcarbo / 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.

The above-mentioned “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 "," 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.

 Here, 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. ,

 Further, when is a "5- or 6-membered nitrogen-containing heterocyclic group optionally condensed with a benzene ring", in addition to the above-mentioned substituents, a lower alkoxy group, an amino group, a mono- or di- or A »phenyl group which may have a substituent such as an alkylamino group or a nitrogen-containing saturated ring group; a nitrogen-containing saturated heterocyclic group which may have a substituent such as a cycloalkyl group or a lower alkyl group; A lower alkyl group substituted with an alkyl group; a nitrogen-containing saturated heterocyclic group which may have a substituent such as an aralkyl group and may be crosslinked; and has a substituent such as a cycloalkyl group. Alternatively, it may be substituted with a realalkylamino group or the like.

 Here, 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. Further, 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.

In 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. Preferably, i-piperazinylcarbonyl group is there. Bins 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. Examples of such salts include 麵, 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.

 Further, the compounds of the general formulas (I) and (1 ′) have at least one asymmetric carbon atom, and include optical antipodes, racemates and diastereomers. Further, the compounds of the general formulas (I) and (Γ) may have a tautomer based on a guanine I ^ 'hydrido group and a guanidino group of arginine. In addition, 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.

Further, 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. In some cases, 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. As such 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. These protecting groups may be appropriately selected depending on the reaction conditions. The method for producing the compounds represented by the following general formulas (I) and (1 ') of the present invention is shown below. In the following description, the method for producing the compound (I) will be described in detail, including the method for producing the compound (1 ').

First manufacturing method

(Wherein RG, X, R ³ , R ⁴ and n have the above-mentioned meanings, R ¹² is an activating group in a hydroxyl group or a hydroxyl group, and 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 (Π) 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.

Here, compound (IV) may have its amino group protected by a protecting group to form a secondary amine. When the amino chain of X or R ³ is a group participating in the reaction, an appropriate protecting group is introduced, and if necessary, the protecting group is removed after the reaction.

 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. An active ester obtained by reacting with a phenolic compound such as p-nitrophenol or an N-hydroxylamine compound such as N-hydroxysuccinimide (HON Su) or 1-hydroxybenzotriazole (HOBT); A symmetrical acid anhydride; an organic acid-based mixed acid anhydride obtained by reacting with a monoalkyl carbonate or an organic acid, or a phosphoric acid obtained by reacting with diphenylphosphoryl chloride or N-methylmorpholine (NMM) Mixed acid anhydrides such as mixed acid anhydrides; and the like.

 In the condensation reaction, it is preferable to use a condensing agent. Examples of 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).

Also, depending on the method applied, it is possible to react to the presence of a base such as trimethylamine, diisopropylethylamine, triethylamine (TEA), pyridine, picoline, lutidine, NMM, N, N-dimethylaniline, etc. 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. C (DM

F), dimethylsulfoxide (DMSO) and the like, which are used in warworms or as an arbitrary mixed solvent.

The protecting group is introduced by applying any method commonly used in the field of peptide reactions.For example, when 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. When the carboxyl group-protecting group is an ester, a conventional esteration reaction can be applied. When 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.

If 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. For other 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. . When 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.

 When the substituent of compound (I) is the same as the above-mentioned protecting group, the corresponding unsubstituted compound can be obtained in the same manner as the removal of the above-mentioned protecting group. Second manufacturing method

(Wherein, 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

Third manufacturing method

(Wherein, R \ G, X, R 4 and n have the meanings given above, 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 (Π) in which R ³ is a hydroxymethyl group is obtained by reducing the corresponding carboxylic acid or its derivative (ΥΠ) such as an acid anhydride, a mixed acid anhydride, or an acid ester as a raw material. Can be manufactured.

 Here, 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. Examples of the 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

(Wherein, RG, X, R ⁴ and n have the meaning described above.)

The compound of the general formula (lb) in which R ³ is anoside is produced, for example, by oxidizing the alcohol compound (Π) 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 ·驗-Power to add an oxidizing agent such as Pyr or DMS Ο In the presence of 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.

 Other manufacturing methods

 (1) Halogenoalkyli dani

In the compound of the general formula (I) of the present invention, the compound in which R ³ is a chloromethyl group may be a halogenating agent such as hydrohalic acid when the j | alcohol derivative (Π) is used as a raw material. Can be produced by a conventional method.

 (2) Acetalization

In the compound of the present invention, 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! ^.

 (3) Substitute Orefin leader

Among the compounds of the present invention, a compound in which R ³ is a lower alkoxycarbonylethenyl group is produced by reacting a corresponding anohyperconductor with phosphoylide. Reaction? IL¾ depends on the type of raw material used and is not particularly limited. As the solvent, dimethoxetane, dimethyl sulfoxide, tetrahydrofuran or the like is usually used.

 (4) Esterification

In the compound of the present invention, 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.

 (5) Boc removal

Among the compounds of the present invention, 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. As the solvent, an alcohol solvent, dichloromethane or the like is usually used.

 (6) Heteroaryl Carboni Rui

In the compound of the present invention, 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.

 (7) Cyclization reaction 1

In the compound of the present invention, 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. As the solvent, benzene, toluene or the like is used.

 (8) Cyclization reaction 2

Among the compounds of the present invention, 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. .

 (9) Nitrilization

In the compound of the present invention, 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 ¾k. The reaction medium varies depending on the type of raw materials used and the reaction conditions, and is not particularly limited.

 (10) Substituted carbonyloxymethylcarbonylation

In the compound of the present invention, 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. This is a method for obtaining a substituted carbonyldioxymethyl ketone derivative by reacting the presence of a chloride salt. The reaction and the solvent are not particularly limited, depending on the type of raw materials used and the reaction conditions. 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.

 (11) Synthesis by solid phase method

 The compound of the present invention can also be produced by a solid phase method using a resin such as 2-mouth trityl resin. For example, after adding an amine such as piperazine to the resin, 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. Thus, 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.

 In addition, 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 α-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.

Various isomers can be isolated by a conventional method utilizing the physicochemical difference between the isomers. For example, 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 κ 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. Examples of bone diseases associated with such bone breakdown iSii include osseous fibrosis, renal penetrating bone a disease, evil ulcer high calcium α, bone paget disease and the like.

 In addition, it was reported that cathepsin Κ is also expressed in osteoarthritis (Biochem. Biophys. Res. Co., Ltd. 206 (1), 89-96 (1995)). Compounds having an inhibitory effect may also be useful for preventing or treating osteoarthritis.

 The proline derivative represented by the general formula (一般) or (Ϊ) 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 ¾ has significant bone resorption inhibition by the following ^ Silil ^^. Experimental example 1

Exploratory test for structures exhibiting cathepsin K properties using commercially available synthetic substrates

 (1) Test substance

Cathepsin L and K enzyme activities were measured using the following commercially available synthetic substrates (manufactured by Peptide Laboratories).

 Z-FR-MCA

 PFR-MCA

 (D) -FFR-MCA

 Z-GPR-MCA

 Bo c-AGPR-MCA

 B o c -VRP-MC A

(Note that the amino acid residues in the above formula Where F is phenylalanine residue, R is arginine residue, P is proline residue, G is glycine residue, A is alanine residue, V is valine residue, and other symbols are Z Is a benzyloxycarbonyl group, MCA is a 4-methinorecmarin-17-inoleamino group (fluorophore), and Boc is a t-butoxycarbonyl group. )

 (2) Weaving method

 A. Method for measuring catabsin L ^ g property in each ¾K

 Using cathepsin L derived from human kidney, the method of Methods in Enzymology Vol. 80, 540-541 * ¾ was modified ^^ and the cathepsin L enzyme activity was measured for each species.

 To a buffer solution (pH 5.5) containing sodium acetate (340 mM), acetic acid (60 mM), and disodium EDTA (4 mM), cathepsin L (protogen) derived from human 肾 was added, and the amount of 20 ng / m1 was returned. A liquid was prepared. On the other hand, dithiothreitol was added to the above buffer so as to have a concentration of 8 mM, and then the above-mentioned (1) substrate (manufactured by Peptide Laboratories) was added to a concentration of 20 to prepare a ¾W solution. . Enzyme solution 100 ^ 1 and solution 1001 were mixed and incubated at 37 for 30 minutes. The 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. 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.

Β · Method for measuring cathepsin K m¾ property for each substrate

 Expression in transfected cells using Husa and osteoclasts (J. Biol. Chem. Vol. 269 (2), 1106-1109 (1994)) and bacteria. Cathepsin K ^ ¾¾ 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 ^^. On the other hand, 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. 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.

 (3) Experimental results

 Figure 1 shows the experimental results.

 As is evident from the results, the synthetic substrate having Pr0-Arglfi on the hybrid side is produced at a rate of ^^ with cathepsin K, whereas no enzymatic reaction with cathepsin L was observed. It was suggested that the P r 0-A rg structure on the C ^ side has no affinity for the ^ site of cathepsin K and the ^ site of cathepsin L. Experimental example 2

Selective cathepsin K inhibitory activity of the compound of the present invention

 (1) Fiber method

 A. Method for measuring cathepsin L inhibitory activity

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 ^ 各 activity of each substrate using human 用 い る -derived cathepsin L. That is, ^^ was prepared in the same manner using the same buffer as that used in the jf self cathepsin L ^ ¾¾ measurement, while adding the same buffer to which dithiothreitol was added to a concentration of 8 mM. L ヽ, Z— FR— as synthetic substrate 801

MCA was added to a concentration of 10 M to prepare a substrate solution. this

 100 I, the substrate solution 100 1 and the DMSO solution 2β1 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 (ρΗ4.3) 5 Οίί 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. Perform the same treatment using a DMSO solution containing no sample, measure the fluorescence, and use it as a control value.Add 100 ^ 1 of the substrate solution and 100 μl of i-distilled water to the DMS 0 solution 21 of the sample to be measured. After incubation, the fluorescence J¾ of the solution to which stop solution 501 was added was measured and set as a blank value.

Inhibition rate () = [1- (sample value-blank value) / (control value-blank value)] x 100

 B. Method for measuring cathepsin K inhibitory activity

 The cathepsin Κ inhibitory activity of the ff of the present invention was measured in the same manner as in the above-described cathepsin K ¾ assay using recombinant cathepsin K. In other words, use the same buffer as the buffer used for jf-cathepsin Kg ^ fg property measurement, and prepare the same ^^ solution in the same manner as above, while dithiothreitol has a concentration of 8 mM. Using the same buffer added as above, 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 μ \ 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.

 C. Method for measuring cathepsin B inhibitory activity

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. On the other hand, 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. After terminating the reaction by adding 50β1 of a reaction stop solution (PH4.3) to the reaction solution, the fluorescence of the reaction solution containing AMC obtained from the substrate was measured in the same manner, and the cathepsin B against the synthetic substrate of the sample was measured. The degree of inhibition of the activity (inhibition ratio) was determined in the same manner as for cathepsin L.

 D. Papain inhibitory activity assay

To 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 ± ¾) (33 g). / m 1). On the other hand, 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 2β1 containing mioo ι, substrate solution ιοο ^^ ι, and the sample to be measured were mixed, and incubated at 37 ° C for 30 minutes. After stopping the reaction by adding IiiaaS stop solution (pH 4.3) 50 \ to the reaction solution, the fluorescence of the solution containing AMC ^^ from the substrate was measured in the same manner, and the total Inhibition of papain's ^ ¾ property (inhibition rate) was determined in the same manner as that for cathepsin L.

 E. Trypsin inhibitory assay

 Trypsin (SIGMA ^^) was added to a buffer (pH 7.5) containing Tris-HC1 (10 OmM) (10 μg / 1) to prepare a ^^ solution. On the other hand, Bz—R—MCA (Bz represents a benzoyl group) was added to the buffer.

M was added to obtain a difficult solution. Return fluid 1 00 1,

100 1 and DMS 0 solution 2β1 containing the test sample were mixed, and incubated at 37 for 30 minutes. After stopping the reaction by adding 50 1 stop solution (pH 4.3) to the reaction solution, the fluorescence of the solution containing AMC from the substrate is removed. Is similarly measured to inhibit the ^ S property of trypsin to the synthetic substrate of the sample

(Inhibition rate) was determined in the same manner as in the above cathepsin L.

 F. Method for measuring chymotribine inhibitory activity

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衝液c-LLVY- MCA (Sue is succinyl group, L is a lysine residue, Y is a respectively tyrosine residue) was added so as to ί¾ 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 (inhibition rate) was determined in the same manner as for cathepsin L above.

 G. Method for measuring thrombin inhibitory activity

T ris -HC 1 (5 OmM) , C a C 1 2 (1 mM), the Na C 1 (15 OmM) buffer containing (pH 7. 9), Suronpin the (SI GMA¾J¾) was added, prepare an enzyme solution did. On the other hand, Bo c—VPR—MCA

A difficult solution was prepared by adding the solution to the key of 0 M. i001, 100 µl of the base solution, and 2ί / 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.

 (2) Experimental results

 The experimental results are shown in Tables 1 and 2.

Inhibitory activity against various cysteine proteases (IC _{5o J} uM) Comp. UB fl ap lryp then nymo 丄 ΠΓΟΙΠΟ

Ε-64 0.0018 U- UU5 U.U o> 1U> 1U〉 1ϋ

Z-LL-H 0.0018 0.0064 NT NT Ni NI Nl

Z-LLL-H 0.0027 0.0016 NT NT NT NT NT

Ex. 2 0.016〉 10 2.7 0.33〉 10〉 10〉 10

Ex. 3 0.010〉 10 1.1 0.33 0.10〉 10〉 10 8 r

 Ex. 4 0.024> 10 2.0 0.47〉 10> 10〉 10

Ex. 5 0.2〉 10> 1U 0.0> 1U> 1U

 Ex. 14 0.29〉 10> 10 4.4〉 10> 10〉 10

Ex. 15 0.028> 10 6.5 1.5〉 10〉 10> 10

Ex. 16 0.027> 10〉 10 0.70〉 10〉 10> 10 The symbols in the table have the following meanings

Co. Immediate:: Test ^ !, Cath-K: Cathepsin K, Cath-L: Cathepsin, Cath-B: Cathepsin B, Pap: Papain, Tryp: Trypsin, Chymo: Chymotrypsin, Throrab: Thrombin, Ex .: Difficult example, NT: Not difficult, Z-LL-H: ZL eu—L eu—H, Z-LLL-H: Z—L e uL e uL e uH

Table 2 Cathepsin K and L inhibitors of the present invention ^; (IC ₅₀ ^ M)

As a result, the selectivity of cathepsin K to cathepsin L was low for known E-64 and dipeptide or triptide derivatives of leucine. On the other hand, 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 κ-blocking activity. Experiment 3

Bone resorption inhibitory activity

 (1) Bone resorption inhibitory assay

 Resin Coimun. 192 (2), 495-502 (1993) and Bone Miner. 17, 347-359 (1992).

That is, 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.

 (2) Experimental results

As a result, the compound of the present invention exhibited an excellent bone resorption inhibitory activity. Table 3 shows the results.

Table 3 Bone resorption inhibitory results

 : P <0.01 Dunnett test (vs control)

 *: P <0. 05 Dunnett test (vs controller nore)

In the table, "PTH. VD process" ^{P TH (1-34) 10- 8 (} M), vitamin D (1, 25) 10- ⁹ that was added to the system (M), "Pit" is P It area average value Shows the soil standard error.

 Experiment 4

 Effect on high calcium Jfa— of rats induced by PTH (1-34) (subcutaneous administration)

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.

 Table 4 Effect of ^ T on high calcium Jte (subcutaneous administration)

 **: Ρ <0.01 Dunett test (vs. controller 1)

 *: P <0.05 Dunnett test (vs. controller 1)

 In the table, "Ca" indicates the mean standard error of the blood calcium (n = 6). The pharmaceutical composition of the present invention comprising the compound having R-type cathepsin KP and a pharmaceutically acceptable carrier comprises one or more of compounds having selective cathepsin K inhibitory activity, It can be prepared by a commonly used method using pharmaceutical carriers, excipients, and other additives that are usually used for formulation. Administration can be in the form of tablets, pills, capsules, granules, powders, liquids, etc., or parenteral administration by intravenous, intramuscular, etc. at, suppositories, etc. Is also good.

As the solid substance for oral administration according to the present invention, tablets, powders, granules and the like are used. In such a solid composition, 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. Examples of 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.

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. Usually, the daily dose is 1 to 200 mg orally. mgZk g, 0.1 to parenteral administration; I 0 O mgZk g ， 'is preferable, it is administered once or in 2 to 4 times, or 30 minutes to 24 hours a day 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. BRIEF DESCRIPTION OF THE FIGURES

 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

 Hereinafter, the present invention will be described in more detail with reference to examples. The compounds of the present invention are not limited to the following examples. In addition, the manufacturing method of the raw material ^ J used in the examples will be described as an example.

In the following examples, Ac represents an acetyl group, and IPE represents isopropyl ether. Other abbreviations are as described above.

Example 1

Synthesis of Ac-Pro-A rg (NO ₂ )-o 1 (alcohol)

(1) Synthesis of Boc—Ar g (NO ₂ ) -o 1 (alcohol) from B oc -A rg (NO ₂ ) OH

Boc—A rg (NO ₂ ) —〇H (9.57 g, 30 mm o I) was suspended in a mixed solvent of DMF (5 m I) and THF (15 Om 1), and NMM (3.36, 3 Omm o 1) was added and dissolved. Under cooling, ethyl carbonate (2.86 ml, 3 Ommo 1) was added under cooling, and the mixture was stirred for 5 minutes. Then, sodium borohydride (3.4 g, 9 Ommo 1) was added under cooling to −60 ° C. After dropwise addition of methanol (250 ml), the mixture was stirred at 110 to 0 for 10 minutes, and the pH was adjusted to 4 to 5 by adding 1N hydrochloric acid (66 ml), and methanol was distilled off. The ethyl acetate (150 ml) was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off. Ether and IPE were added to the residue to give an oily substance. The supernatant was removed, and the residue was crystallized from chloroform and ethyl acetate / ether to give 6.2 g of the desired product (yield 67%).

(2) B oc -A rg ( NO) - o 1 ( alcohol) from Ac- P ro - A rg (N0 2) - o Synthesis of 1 (alcohol)

_{B oc - A rg (NO 2} ) - o 1 (. 1. 53 g 5mmo l) in TFA to (20 m i) was added and distilled off T FA after stirring under cooling for 10 minutes excess. To the residue was added 4.1N hydrochloric acid / dioxane (1.46 m then 6 mmo 1), followed by ether. The precipitate was collected by filtration and washed with ether. It was dissolved in DMF (80 ml) and the pH was adjusted to 5 with triethylamine under cooling. Dissolve A c—Pro—OH (809 mg, 5.15 mmo 1) and HO OB t (864 mg.5.3 mmo 1), cool to −10 and cool with EDC I (970 to 5.3 mmo 1). The solution was dropped and reacted for 3 hours. After distilling off DMF, the residue was dissolved in water (50 ml) and washed with a black hole form. Water was distilled off, and the precipitated insolubles were filtered off and adsorbed on a 005-column (丫 ^., 30 x 250 mm). After washing with 0.1% TFA, elution was carried out with 0.1% TSA (0.1% TFA (linear concentration gradient for 60 minutes)). The fractions (150) were collected and lyophilized, and 1.5 g (yield: 87%) of the desired product was obtained as a precipitate from black form Z ether.

Example 2

Synthesis of Ac—Pro—Arg (NO ₂ ) -H (aldehyde) from A c -P ro -A rg (NO ₀ ) -o 1 (anolecol)

Ac-P r oA rg (N0 ) ~ ol (344mg, 1 mm o 1) was dissolved in anhydrous DM SO (2m l), was added TEA (417m l, 3 mmo 1 ) at room temperature, then S0 ₃ ' A solution of Pyr (477 mg, '3 mmol) in anhydrous DMSO (1.5 ml) was added and stirred for 40 minutes. Under cooling, water (12 ml) was added, and 50% TFA (100-2001) was added to adjust the pH to 1. It was injected onto an ODS-column (ΥMC, 30 × 250 mm) and eluted with 0-20% acetonitrile Ζ0.1% TFA (linear gradient over 80 minutes). Collect fraction I (fractions 39-57) and fraction II (fractions 60-69) and freeze-dry 139 mg (Yield, 40.6%) from Fraction I and 10 Omg (Yield, 29.2%) from Fraction II.

Example 3

Synthesized from Ac-P ro -Ar g (NO n) one H (aldehyde) of the A c- P ro- A rg one H (aldehyde)

 NH

NH,

A c - P ro - A rg (NO 2) -. H ( Fraction II, l O Omg, 0. 29mm o I) was dissolved in methanol (30 m I), formic acid (0. 55ml 14. 5mmo 1 ) Was added. After suspending and adding 20% palladium hydroxide carbon catalyst (3 Omg) in methanol (20 ml) and water (0.5 ml), hydrogen gas was passed through a 30 ° C water bath for 2.5 hours. After removing the catalyst, water (100 ml) was added and methanol was distilled off. Again, water (100 ml) was added, followed by washing with ether and freeze-drying. The obtained crude peptide was injected onto an ODS-column (YMC. 30 × 250 mm) and eluted with 0-20% acetonitrile Z0.196TFA (linear concentration gradient for 80 minutes). A Fractions (45-47) that showed a strong positive reaction with the aldehyde reagent were collected and freeze-dried to obtain 1 lmg (yield, 13%) of the desired product.

 Mass spectrum (FAB): m / z 2 98.4 [M + H] +

 H-NMR (27 OMH z, in DMSO, TMS internal standard)

 Table 5 shows the chemical shifts and assignments of H-NMR.

 Table 5

 δ ffil

1. 4-2. 3 A c + P rp, A rg— H 3 —, 7-CH ₀ (1 1 H) 3.0-3.6 Pro, A rg-H 5 — CH. (*)

 3.6-3.9 A r g-H α-C H (1 H)

 4.3-4.5 Pro a— CH (1 H)

 5.2-5.3 A r g-H H of carbinolamine (about 1 H)

 6.4-6.7 A r g-H 0 H (about 1 H) of carbinolamine

7.4-7.5 A r g-H NH of the guanidino group (3 H)

 7.6-8.0 A r g-H of α-NH (1 H)

 9.3-9.5 CHO of A r g—H (slight)

 * The number of protons overlapping with the water signal is not determined.

 Based on the above physicochemical properties, 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.

Example 4

Synthesis of A c -P roN Le -H (aldehyde)

(1) Synthesis of Ac-Pro-Nle-ol (alcohol) from Ne-ol-HCl (alcohol)

 Ac-Pro (620 mg, 4 mmoI), N1e--o1.HC1 (657 mg, 4.2 mmo1) and HOOB t (71 mg, 4.4 mmol) DMF

(40 ml), and dissolved in 10. Under cooling to C, EDC I (865 ^ 1, 4: 4 mmo 1) was added dropwise and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, and after washing with ethyl acetate, water and DMF were distilled off. The residue was dissolved in black hole form and washed with saturated saline. After drying over anhydrous magnesium sulfate, the chloroform was distilled off, and IPE was added for crystallization. After dissolving in water (60 m I) and filtering off insolubles, Dowex 1 X 2 (acetic acid type, 20m

It passed through the column of 1). After water was distilled off, the residue was dissolved in ethyl acetate, and crystallization was performed by adding diethyl ether and IPE. The crystals were collected by filtration and dried to give 85 Omg of the desired product (yield 82.5%).

 (2) Synthesis of Ac-Pro-Me-H from Ac-Pro-Nle-o1 (alcohol)

 Ac-Pro-N1e-o1 (256 mg, 1 mmo1) was dissolved in anhydrous DMS0 (4 ml) and TEA (5601, 4ramo1) was added at room temperature. did. Then, an anhydrous DMSO solution (4 ml) of SO · Pyr (637 mg, 4 mmo 1) was added, and the mixture was stirred for 10 minutes. Under cooling, add 0.01% TFA water (120 ml), inject into ODS—force ram (YMC, 30 × 250 mm), and 5% —50% acetonitrile Z0.1% Elution was performed with TFA (60-minute linear gradient). The fractions (31-43) were collected, lyophilized, and purified by ODS-force chromatography under the same conditions as above. The fractions (30-32) were collected and freeze-dried to obtain the desired product (yield 35.4%).

Figure 2 shows the H-NMR data of this product. Example 5

 Synthesis of A c -Pro-Tyr-H (aldehyde)

(1) D 1 "ー 01 ^ 6 * 1 {〇 From 1 to 8. 1" 0—D r 1 OMe Synthesis A c -P ro (97 Omg, 6.2 mmo I) T yr -OMe- HC 1 (1

39 g, 6 mmo 1) and HOOB t (1.02 g, 6.3 mmol) were dissolved in DMF (30 ml), and cooled to 10 ° C. 5 ml, 6.3 mmo 1) was added dropwise, and the mixture was stirred at room temperature for 2 hours. After distilling off DMF, the residue was dissolved in ethyl acetate and washed with saturated saline. After drying over anhydrous magnesium sulfate, ethyl acetate was distilled off, dissolved in IPE, and solidified by adding hexane. It was dissolved in methanol (20 ml), water (80 ml) was added, and the precipitated insoluble material was removed by filtration. The solution was passed through a column of Dowex 1 X2 (acetic acid type .10m 1). After methanol and water were distilled off, the residue was dissolved in IPE and hexane was added for crystallization. The crystals were collected by filtration and dried to give 1.8 g (yield 90%) of the desired product.

(2) Eight. -? 1 "0—cho 7 1" —01 ^ 6 to 80—? 1 "0—cho 7 1"-0 1 (synthesis of alcohol

Ac-Pro-Tyr-OMe (1.2 g, 3.6 mmoI) was dissolved in a mixed solvent (70 ml) of ethanol and THF, and lithium chloride (229 mg, 9 mm o 1) and sodium borohydride (34 1 mg, 9 mmo 1). Two hours later, lithium chloride (229 mg, 5.4 mmol) and sodium borohydride (204 mg, 5.4 mmol) were added, and the mixture was further reacted for 1.5 hours. After adding 1N hydrochloric acid (10 ml) to the reaction solution, the solvent was distilled off. The residue was dissolved in saturated saline, and the desired product was extracted with chloroform. After the extract was dried over anhydrous magnesium sulfate, the porphyrin form was distilled off, and IPE was added to solidify. After dissolving in methanol, remove methanol The residue was crystallized by adding IPE to the residue. The crystals were collected by filtration and dried to give 46 Omg of the desired product (yield: 41.8%).

 (3) Synthesis of Ac—Pro—Tyr—H from Ac-Pro-Tyr-ol (alcohol)

 A c -ProT yr -ol (2 14 mg, 0.7 mm o 1) was added to TEA (444 8 β I 3.211111 0 1) and 300 '? 1 "(446 mg, 2.8 mm o l). In the same manner as in Example 4 (2), the desired product (100 mg, yield 46.9%) was obtained.

Figure 3 shows the H-NMR data of this product.

Reference example 1

 To a solution of L-phenylalaninol (4.54 g, 30.0 mmol) and benzyloxycarboryl L-proline (8.23 g, 33.0 mmol) in Ν, Ν-dimethylformamide (100 ml) was added 1- Hydroxybenzotriazole (6.08 g, 45.0 mmol) and 1- (3-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride (6.90 g, 36.0 mmol) were added, and the mixture was stirred at room temperature for 5 hours. Was. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained crystalline residue was recrystallized from ethanol to give 1-benzyloxycarbonyl-2-L-prolyl-L-phenylalaninol (7.92 g, 20.7 mmol, 69%).

Similarly, the following compounds of Reference Examples 2 to 6 were obtained.

Reference example 2

 1 Benzyloxycanoleone L-Prolinole N-Methoxy-N-Methylenol L One bit isinamide

Reference example 3

 1 Benzyloxycarbonyl _ L-Prolinole L-mouth isinol

Reference example 4

 1 N-dioxycarbonyl 2 L-prolyl 1 L isocyanamide Reference Example 5

 1- (1-benzyloxycarbonyl-1 L-prolyl-1 L-leucyl) 1-4-1 (tert-butoxyca ^^ pol) Piperazine

Reference example 6

 1 Benzoinore 1 L-Prolyl 1 L Isinol

Reference Example 7

1 A solution of 1- (tert-butoxycarbonyl) -14- (L-prolyl-1-L-leucyl) piperazine (790 mg, 2.0 mmol) and 4-dimethylaminopyridine (20 mg) in pyridine (15 ml) was added at room temperature. Benzoyl chloride (340 mg, 2.4 mmol) was added dropwise and stirred for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract is washed sequentially with water, 10% citrate and saturated saline, dried over anhydrous sodium sulfate, crimped under reduced pressure, and dried under reduced pressure. (Tert-butoxycarbonyl) Piperazine (1.02 g, 2.0 mmol, quant) was obtained.

Reference Example 8

 To a solution of 1-benzy / reoxycarbonyl L-prolyl L-leucinol (6.14 mg, 17.62 mmol) in ethanol (100 ml) was added 10% palladium-carbon (610 mg), and 5.5 at room temperature under a hydrogen atmosphere. Stirred for hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to obtain L-prolyl L-leucinol (4.14 g, 17.62 mmol, quant).

Similarly, the following compound of Reference Example 9 was obtained.

Reference Example 9

 1- (tert-butoxycarbonyl) -4- (L-prolyl-L-leucyl) pi-azine

Reference example 10

 To a solution of 1- (tert-butoxycarbonyl) -14- (L-prolyl-l-leucyl) pirazine (790mg, 2.0mmol) in pyridine (15ml) was added benzenesulfoyl chloride (420mg, 2.4mmol) at room temperature. ) Was added dropwise and stirred for 5 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed successively with water, 10% citric acid and saturated saline, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 1- (tert-butoxycarbonyl) -14- (1-phenylsulfonyl- L-Prolyl-L-leucyl) pidazine (1.10 g, 2.0 mmol, quant) was obtained.

Reference example 1 1

 To a solution of phenylisocyanate (260 mg, 2.2 mmol) in tetrahydrofuran (15 ml) at room temperature was added 1- (tert-butoxycarbonyl) 1 4- (L-prolyl-L-leucyl) pidazine (790 mg, 2.0 mmol) ) Was added and stirred for 1.5 hours. The reaction solution is concentrated, and the obtained crystalline residue is washed with getyl ether to give 1- (tert-butoxycanoleponyl) 1- (1-phenylene / rebamoinole 1 L-prolyl 1 L-port) (Isyl) piperazine (920 mg, 1.78 mmol, 81 "¼) was obtained.

Reference example 1 2

(3 S) 1-3-(N-benzyloxycarboninoleamino) 1-1-1-4-phenyl-2-butanone (1.0 g, 3.01 mmol) of N, N-dimethylformamide (30 ml) ) Solution, thiophenol (0.46 ml, 4.52 mmol) and sodium carbonate (640 mg, 6.02 mmol) were added. The mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and reduced under reduced pressure. Acetonitrile (30 ml) was added to the obtained residue, and trimethylsilane iodide (0.54 ml, 3.79 mmol) was added dropwise with and stirred for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. To the obtained residue was added 4 N hydrogen chloride monoethyl acetate, and the mixture was concentrated again. The obtained crystalline residue is washed with geethylether to give (3S) -3- (N-benzyloxynoreponyoleamino) -14-phenylenolate 1-pheninolethiol-2-butanone hydrochloride The salt (370 mg, 1.37 mmol, 45%) was obtained. Example 6

 To a solution of 1-benzyloxycarbonyl L-prolyl-L-phenylalanine (700 mg, 1.77 mmol), Ν, ア ミ -dimethylformamide (20 ml), pyrrolidine (0.30 ml, 3.54 bandol), 1-Hydroxybenzotriazole (360 mg, 2.65 mmol) and 1- (3-dimethylaminopropyl) -1-3-ethylcarbodiimide hydrochloride (440 mg, 2.30 mmol) were added, and the mixture was stirred at room temperature for 1 hour. did. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 7: 3), and purified by elution with 1- (1-benzyloxycarbonyl-L-prolyl-L-phenylalanyl) pyrrolidine (520 mg). , 1.16 mmol, 65%).

Similarly, in the following example? ~ 13 compounds were obtained.

Example 7

 1— (1 benzyloxycarbonyl _ L-prolyl— L-phenylalanyl) piperidine

Example 8

 1- (1-Penzinoleoxycanolebonyl-L-Prolyl-L-Fenrylara2nole)-4-Methylbiperazine

Example 9

4-(1 benzyloxycarbonyl- 1 L-prolyl- 1-L-phenylalanyl) Morpholine

Example 10

 1— (1 Benzyloxycarbone L—Prolyl L—Fenylaralanyl) azetidine

Example 1 1

 1-(1-benzyloxycarbonyl L-prolyl-L-phenylalanil)-4-hydroxypropyl

Example 1 2

 1 1 (1 Benzoru L 1 Prolyl 1 L 1 mouth Isil) 1-4 Hydroxypiridine

Example 13

 (3 S) —3— [(1-benzyloxycarbonyl-L-prolyl) amino] — 4-—two-one-one two-one-butane

Example 14

 1 L-Proxy-l-canolebonyl-L-prolyl-L-phenylalaninol (1.91 g, 5.0 marl), triethylamine (2.02 g, 20.0 mmol) and dichloromethane (15 ml) in a stream of argon A solution of pyridine sulfur trioxide (2.39 g, 15.0 nunol) in dimethyl sulfoxide (8.0 ml) was added dropwise at 5 ° C, and the mixture was stirred for 1.5 hours. Water was added to the reaction solution, and extracted with ethyl acetate. The extract was washed successively with 1 N hydrochloric acid, water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; liquid form: methanol = 98: 2) to give 1-benzyloxycarbonyl-L-prolyl-L-phenylal-nal. (1640 mg, 4.31 mmol, 86%).

 Similarly, the following compounds of Examples 15 to 16 were obtained.

Example 15

 1 Benzinoleoxy canoleboninole L 1 prolyl 1 L 1 bite

Example 16

 1—Benzy 7 Le L-Prolyl-L L-Portable Ishinal

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. Purified with 1 (eluent; hexane: ethyl ethyl ester = 1: 1), 1-benzyloxynorreboninole L-prolinolein L-fueninoleanlanina monoethylene ethylene acetate (300 mg, 0.71 mmol, 61%) I got

Example 18

To a suspension of 60% sodium hydride (50 mg. 1.24 mmol) in 1,2-dimethoxetane (10 ml) was added dropwise ethyl ethylethyl phosphonoacetate (280 mg, 1.24 mmol) at 5 ° C under an argon stream, and the solution was added at room temperature. Stirred for 0 minutes. After cooling to 5 ° C again, a solution of 1-benzyloxycarbonyl-1L-prolyl-1L-phenylalaninal (430mg, 1.13mmol) in 1,2-dimethoxetane (7ml) was added dropwise. The mixture was stirred at room temperature for 6 hours, and further stirred at 50 ° C for 45 minutes. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed successively with water and saturated saline, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 2), and ethyl (4S) — [(1-benzyloxycarbonyl-L-prolyl) a Mino] one 5- phenyl one 2- pentenoate ^{(120mg, 0.27mmol, 24 0/} 0) was obtained.

Example 19

1 To a solution of 1-pentinoleoxy / Lepino-leno-L-proli / le-L-phenyl / lealanine (700 mg, 1.77 mmol) and N, N-dimethylformamide (20 ml) was added 4-methoxyphenol (286 mg, 2.30 mmol), 1-hydroxybenzotriazole (360 mg, 2.65 mmol), and 1- (3-dimethylaminopropyl) -13-ethylcarposimid hydrochloride (440 mg, 2.30 mg). The mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed successively with saturated aqueous sodium hydrogen carbonate and saturated brine, dried over anhydrous magnesium sulfate and reduced under reduced pressure. The obtained residue is subjected to silica gel column chromatography. (Eluent; chloroform: methanol = 98: 2) Further purification by thin-layer chromatography (developing solvent; chromatography: methanol = 95: 5) yielded 4-methoxyphenyl 1-pentinoleoxycano. Levonir-L-Prolyl-L-Fueni / Learina

-183 g (183 mg, O.36 mmol, 21%) was obtained.

Similarly, the following compounds of Examples 20 to 21 were obtained.

Example 20

 Phenyl 1-benzyloxycarbonyl-1 L-prolyl-1 L-phenylalina

Example 2 1

 4 One-way mouth fu-nore 1 One-benzyloxycarbonyl one L-prolyl L One-way isinate

Example 22

 1 Benzyloxycarbonyl L-prolyl-L-phenylalanine (700 mg, 1.77 mmol), toluene (20 ml), pentafluorophenol (390 mg, 2.12 mmol), 4-dimethylaminopyridine ( 20mg) and 1,3-dihexylhexylcarbodiimide (547mg, 2.65mg) were added and stirred at room temperature for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; form: black mouth) to give pentafluorophenic acid / l-pentinoleoxycarbonyl-L-prolyl-L-phenylalaninate (374 mg, 0.67 mmol) , 38%).

Similarly, the following compounds of Examples 23 to 24 were obtained.

Example 23

 4 12 Torofuenoren 1-Penzinoleoxycanoleboninore _ L-Prolinole L-Phenylalanine

Example 2 4

 3 1-Fluoro 4-1-2-Meth Phenyl 1-Benzinoleoxycarboninole L-L-Mouth L-Leucine

Example 2 5

1 1 (1-Penzinoleoxycanolebonyl-L-prolyl-L L-mouth isinore) 1-41 To a solution of (tert-butoxycarbonyl) piperazine (1.02 g, 1.93 mmol) in methanol (20 ml) was added a 4 N solution of hydrogen chloride in ethyl acetate (20 ml), and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated, diluted with ethyl acetate, and neutralized with saturated aqueous sodium hydrogen carbonate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and concentrated to 1- (1-benzyloxy-L-prolyl-L-l-isyl) piperazine (700 mg, 1.62 mmol, 84%).

Example 26

 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 ).

 Similarly, the following compounds of Examples 27 to 28 were obtained.

Example 2 7

 1- (1-phenylcarbamoyl-l-prolyl-l-leucyl) pidazine Example 28

 1— (1-phenylsulfonyl-1-L-proli / le-L-leucyl) pidazine Example 2 9

1-benzyloxycarbonyl L-prolyl L-mouth isocyanamide (1.55 g, 4.29 mmol), N-methylmorpholine (1.42 ml, 12.9 mmol) in Ν, Ν-dimethylformamide (20 ml) solution Thionyl chloride (0.47 ml, 6.44 mmol) was added dropwise at 0 ° C, and the mixture was stirred for 2 hours. Saturated aqueous sodium hydrogen carbonate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed successively with 1 N hydrochloric acid and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; chloroform: methanol = 99: 1) to obtain 1-benzyloxycarbonyl-N-[(S) 11-cyano. [1-Methylbutyl] 1 L-proline amide (825 mg, 2.41 mmol, 56%) was obtained. Example 30

 To a solution of thiazol (360 mg, 4.23 mol) and tetrahydrofuran (20 ml) was added butyllithium (1.6 M hexane solution, 2.64 ml, 4.22 mraol) under a stream of argon under -76. Stirred for 20 minutes. To the reaction solution was added a solution of 1-benzyloxycarbonyl-L-prolyl-N-methoxy-N-methyl-L-one-port isocyanamide (860 mg, 2.12 fraction ol) and tetrahydrofuran (10 ml), and Stir for 5 hours. To the reaction solution was added a saturated aqueous solution of ammonium chloride, and the mixture was extracted with ethyl acetate. The extract was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 3: 1) to give 2- (1-benzyloxycarbonyl-L-brolyl-L-one-isyl) thiazole ( 200 mg, 0.47 ol, 22%).

Similarly, the following compound of Example 31 was obtained.

Example 3 1

 2-(1-Penzinoleoxy power / Repo-Linol L-Prolinole 1 L-Mouth Ichinore) 1 2-Benzothiazonole

Example 3 2

To a solution of 1-benzyloxy L-prolyl-L-leucine (360 mg, 0.99 mraol) and N, N-dimethylformamide (10 ml) was added 2-aminophenol (120 rag, 1.01 mmol), Droxybenzotriazole (150 mg, 1.1 mmol) and 11- (3-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride (210 mg, 1.10 mmol) were added, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, which was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was dissolved in toluene (50 ml), p-toluenesulfonic acid monohydrate (20 mg, 0.1 mmolol) was added, and the mixture was heated under reflux for 4 hours. After the reaction solution was cooled to room temperature, it was washed successively with a saturated aqueous solution of sodium hydrogencarbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; toluene: ethyl acetate = 3: 1), and 1_benzyloxycarbonyl-2- (N-[(S) -13-methyl-11- (2-benzo) Oxazolyl) butyl] -L-proline amide (310 mg, 0.71 mmol, 72%). Example 3 3

 1 Benzinoleoxycanoleboninole L-proline l-L-leucine (360 mg, 0.99 mmol) and tetrahydrofuran (10 ml) in a solution of tetrahydrofuran (10 ml) under argon flow at 10 t. Ethyl carbonate (0.11 ml, 1.15 promoting ol) and N-methylmorpholine (0.13 ml, 1.18 mmol) were added, and the mixture was stirred for 30 minutes. 2-Aminothiophenol (0.12 ml, 1.12 mmol) was added to the reaction solution, and the mixture was stirred at room temperature for 3 hours, and further heated under reflux for 3 hours. After the reaction solution was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate. The extract was washed successively with a saturated aqueous solution of sodium hydrogen carbonate and saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent; hexane: ethyl acetate = 1: 1) to give 1-benzyloxycarboninole N — [(S) —3-methyl-1- (2-) Benzothiazolyl) butyl] -shi-proline amide (330 mg, 0.73, 1,74%) was obtained.

 In the same manner as in Example 14, the following compound of Example 34 was obtained.

Example 3 4

 1—Acetinolay 31

Example 3 5

 (a) Dissolve oxalyl chloride (0.42 mL, 4.48 mmol) in 50 mL of methylene chloride under a stream of argon and slowly add 0.96 mL of dimethyl sulfoxide at -78 ° C, then add 1-benzinoleoxycarbonylglycyl. 5 mL of a methylene chloride solution of -L-prolyl L-norleucinole (1.5 g, 3.7 mmol) was added, and the mixture was stirred for 2 hours. After adding 3.0 mL of triethylamine and further stirring at −10 ° C. for another 3 hours, the reaction solution was poured into a mixture of methylene chloride and an aqueous solution of hydrogen sulfate and extracted, and the organic layer was deionized water and The extract was washed with saturated saline, dried over anhydrous magnesium, and evaporated under reduced pressure. The obtained residue is purified by silica gel column chromatography and eluted with methylene chloride or a mixed solvent of methylene chloride and methanol to give the corresponding 1-benzyloxycarbonylglycyl-s-prolyl-L-norleleucinal (1.30 g, 3.22 mmol, 87%) (colorless and transparent oil).

The following compounds were obtained in the same manner.

(b) 1-benzyloxycarbonyl-L-prolyl-L-noryl isocyanate Example 3 6

 (a) 2,6-bistrifur in a 0.5 mL solution of 1- (1-benzyloxycarbonylglycyl-L-prolyl) -L-norleucyl bromomethyl ketone (0.10g, 0.20mmol) in dimethylformamide Oromethylbenzoic acid (67 mg, 0.26 mmol) and fluorinated lithium (30 mg, 0.51 mmol) were added, and the mixture was stirred day and night. The reaction solution was poured into a mixed solvent of ether and sodium bicarbonate water, extracted, and the organic layer was washed with saturated saline, dried over anhydrous magnesium, and evaporated under reduced pressure. The residue was purified by silica gel thin layer chromatography using a mixture of hexane and ethyl acetate (1: 2). Methyl 2,6-bistrif-noleolomethyl benzoate (79.5 mg, 0.12 mmol, 58.6%, clear, colorless, oily) was obtained.

The following compounds were obtained in the same manner.

 (b) 1- (1-benzyloxycarbonyldaricyl-L-prolyl) 1-L-nore-mouth isino-methinole 2,6-dichlorobenzoate

 (c) 1- (1-benzyloxycarbonyldaricyl-L-prolyl) — L-norleucylmethyl (R) — (1-)-1-methoxyphenyl acetate

 (d) 1— (1 Benzyloxycarbonyldaricyl-L-prolyl) 1-L-Norelet Icinoremethinole 13-Feninolepropionate

 (e) 1-(1 benzoyl carboxy-L-prolyl) 1 L-nor-opening isolenomethinole 2,6-dicyclo-opening benzoate

 (f) 1- (1-benzyloxycarbonyl-L-prolyl) 1-L-nor-mouth / lemeth / le 2,4,6-triclo-mouth benzoate Example 3 7

1 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. Each solution of 1-hydroxybenzotriazole (47 mg, 0.30 mmol) in 0.3 mL of dimethylformamide and 11- (3-dimethylaminopropyl) -13-ethylethyl carbodiimid hydrochloride (46 mg, 0.30 mmol). (24 mmol) in 0.3 mL of dimethylformamide. DL-2-amino-3-methyl-1-butanol, DL-2-amino-2-methyl-1-butanol, DL-2-amino-3-phenyl-11-propanol, 2-amino-2-phenyl A 0.25 ml solution of dimethylethanol and DL-2-amino-11-pentanol in dimethylformamide was added to separate wells in a volume of 0.25 ml each, and 0.045 ml of diisopropyl pyrethylamine was added to each well, followed by ultrasonic stirring for 20 minutes. Thereafter, vortex stirring was performed for 3 hours. Each 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 _ α-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.

Example 38

 The following compound was obtained by treating in the same manner as in Example 37.

 (a) l-tert-butoxycarbonyl-L-prolyl-DL-homoalaninal

(b) l-tert-butoxycarbonyl-L-prolyl-DL-valinal

 (c) l-tert-butoxycarbone L-prolyl-α-methyl-DL-alaninyl

 (d) l-tert-butoxycarbonyl L-prolyl-DL-phenylalanine (e) 1-tert-butoxycarbonyl L-prolyl-DL-phenyldaricinyl (f) l-tert-butoxycarbonyl _L —Prolyl—DL—Mouth Isinal

 (g) 1-tert-butoxycarbonyl L-prolyl-DL-cloth

(h) 1-tert-butoxycarbonyl L-prolyl-DL-) 3-ketophenyla Lanina

 (i) 1-tert-butoxycarbonyl L-prolyl-DL-norevalinal Example 39

 (1 Benzyloxycarboxy-L-prolyl) 1-L-norleucylbromomethyl ketone (0.30 g, 0.68 mmol) in 3.0 mL of dimethylformamide is aliquoted into six 10 mL vials. Note that 2,6-bistrifluoromethylbenzoic acid (31 mg, 0.12 bandol), 3,5-dinitrobenzoic acid (25 mg, 0.12 mmol), and 4-methoxycarbonylcarbonylbenzoic acid (22 mg, 0.12 mmol) were added. , 4-chlorobenzoic acid (19mg, 0.12mmol), 3,5-dichlorobenzoic acid (23mg, 0.12mmol), 4-fluorobenzoic acid (17mg, 0.12mmol) (25 mg, 0.43 mmol) was added to each, and the mixture was stirred at room temperature for 8 hours. 4 mL of ether was added to each, and 1 mL of saturated aqueous sodium bicarbonate was slowly added and stirred well to extract an ether layer. It is concentrated under reduced pressure and (a) (1-benzyloxycarbonyl-L-prolyl) -l-norleucylmethyl 2,6-bistrifluoromethylbenzoate, (b) (1-benzyloxy) Carbonyl L-prolyl) 1-L-norleucylmethyl 3,5-dinitrobenzoate, (c) (1-benzinoleoxycarbonyl-L-prolysle) 1-L-nor-isocyanolemethyl 4- Methoxycanolebonyl benzoate, (d) (1-benzyloxycarbol-L-prolyl) 1-L-norleucylmethyl 4-cyclobenzoate, (e) (1-benzyloxycarbonyl) (L-prolyl) 1-L-norleucylmethyl 3,5-dicyclobenzoate, and (f) (1-benzyloxycarbone L-lupole) 1-L-norleucylmethyl 4 _fluorobenzoate I got one.

Example 40

 The following compound was obtained by treating in the same manner as in Example 39.

 (a) (1-Benzyloxycarbonyl-L-prolyl) 1-L-nor-isocyanolemethyl pyrazine carboxylate

 (b) (1-benzyloxycarbonyl-1-L-brrolyl) -1-L-norleucylmethyl phenoxyacetate

(c) (1-benzyloxycarbonyl-L-prolyl) 1-L-norleucylmethyl 2-chloro-3-pyridinecarboxylate (d) (1-Benzyloxycanolebonyl-l-prolyl) 1-L-noroleucylmethyl 2,4,6-trimethylbenzoate

 (e) (1-benzyloxycarbonyl L-prolyl) 1-L-norleucylmethyl 3,1-funoleolol 4'-hydroxypheninolecetate Example 4 1

Synthesis of Example Compounds by Solid Phase Method:

 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.

1.2 g (ab.l.2 mmol) of the above resin was added to eight 12 mL filter tubes, and then Ν-α-9-fluorenylmethoxycarbonylglycine (594 mg, 2 mmol) and -α-19-fluorenylmethoxycarbonylcarbonyl were added. Droxyproline (706 mg, 2 mmol), N-α-9-fluorenyl methoxycarbonyl-L-leucine (706 mg, 2 mmol), Ν-α-9-Funoleolenyl methoxycarboninole D-leucine (706 mg, 2 mmol), N- α-9-Fluorenylmethoxycarbonyl-1-L-phenylalanazine (774 mg, 2 marl ol), Ν-α-9-Fluorenylmethoxycarbone D-phenylalanine (774 mg, 2 mmol), N-α-9-fluorenylmethoxycarbo Add 2 L-proline (674 mg, 2 mmol) and Ν--9-fluorenyl methoxycarbonyl-D-proline (674 mg, 2nunol) to separate filter tubes, and add Add 8 mL of dimethyltriamide of zotriazo-l-l-loxy-l-tris-pyrrolidinophosphoniumhexafluorophosphate (1.04 g, 2 mmol) and 0.88 mL of disopropylethylamine, and filter the tube. Then, a plunger and a cap were put on the plate, and the plate was attached to a rotating plate. After that, the rotating plate was rotated and stirred at room temperature for 1.5 hours. The reaction solution is filtered by suction. The gin was washed with 6 mL X 3 of dimethylformamide. Further, 6 mL of a 20% piperidine in dimethylformamide solution was added to each filter tube, and the mixture was rotated and stirred using a rotary plate for 2 hours. The reaction solution was subjected to suction filtration, and the resin was washed with 6 mL of dimethylformamide × 3. 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. (1) Add 0.2 mL of a solution of roux-tris-pyrrolidinophosphonium hexafluorophosphate in dimethylformamide, add 0.08 mL of diisopropylethylamine, attach a plunger and a cap to the filter tube, and attach it to the rotating plate. After mounting, the rotating plate was rotated and stirred at room temperature for 2 hours. The reaction solution was suction-filtered, and each resin was washed with dimethylformamide (3 mL × 3), methylene chloride (2 mL × 3), methanol (3 mL × 3), ether (3 mL × 3), and dried under reduced pressure for one day. To each resin, 2 mL of a 10% trifluoroacetic acid solution in methylene chloride was added, and reacted at room temperature for 1.5 hours. The reaction solution was collected in a test tube by suction filtration and distilled off under reduced pressure. (A) 1- (1 benzyloxycarbonyl 1 L-hydroxyprolylglycylbiperazine, (b) 1- (1 —Benzyloxy deer ^^ bonoxy 1 L-hydroxyprolinole L-hydroxyprolinole) piperazine, (c) 1- (1-benzyloxycarbonyl L-hydroxy droxyprolyl 1 L — Mouth isil) piperazine, (d) 1- (1-benzyloxycarbonyl-l-hydroxyprolyl-D-mouth isyl) piperazine, (e) 1- (1-benzyloxycarbonyl-L-h Droxyprolyl-L-phenylalanil) pidazine, (f) 111- (1-benzyloxycarbonyl-L-hydroxydroxyprolyl-D-phenylalanil) pidazine, ( _g ) 1- (1-be Nyloxycarbon L-Hydro Shipuroriru one L- prolyl) piperidines Rajin, and (h) 1 - (1-Benjiruoki Shikarubo -. Le obtain an L over human Dorokishipuroriru one D- prolyl) piperidines Rajin Example 4 2

The following compound was obtained by treating in the same manner as in Example 41. (01) 1- (1-benzyloxycarbonyl-L-prolinoleregylsylpiperazine

(02) 1-one (1-benzyloxycarbonyl L-prolyl-l-hydroxyprolyl) piperazine

 (03) 1- (1-benzyloxycarbonyl-l-prolyl-l-l-isyl)

 (04) 1— (1-benzyloxycarbonyl-L-prolyl—D-leucyl) piperazine

 (05) 1-1 (1-Benzyloxycanoleboninole L-Prolyl-L-Fernara 2 /) Piperazine

 (06) 1— (1—benzinoleoxycarbonyl L-prolyl-D-phenyallara) V) pidazine

 (07) 1- (1-benzinoleoxycanolebonyl-l-prolyl-l-prolinole) p-azine

 (08) 1— (1-benzyloxycarbonyl-L-prolyl-D-prolinole) piperazine

 (09) 1- (1-benzyloxycarbonylglycyl-L-prolylglycylpiperazine

 (10) 1- (1-benzyloxycarbonyldaricyl-L-prolyl-L-hydroxyloxyl) piperazine

 (11) 1- (1-benzyloxycarbonyldaricyl-L-prolyl-L-mouth) piperazine

 (12) 1- (1-benzyloxycarbonylglycyl-L-prolyl-D-mouth isole) piperazine

 (13) 1- (1-benzyloxycarbonylglycyl-L-prolyl-L-phen-2-norellaninole) piperazine

 (14) 1- (1-benzyloxycarbonylglycyl-L-prolyl-D-phenylaranyl) pidazine

(15) 1- (1-benzyloxycarbonyldaricyl-L-prolyl-L-prolyl) piperazine (16) 1- (1-benzyloxycarbonylglycyl-1-L-prolyl-D-prolinole) piperazine

 (17) 1- (1-benzyloxycarbonyl L-hydroxyprolyl-1-L-isoleucyl) piperazine

 (18) 1- [1-benzyloxycarbonyl-l-hydroxyprolyl- (Ν-ε-acet / re) -l-lysine / re] pidazine

 (19) 1- [1-benzyloxycarbonyl L-hydroxyprolyl- (Ν-ε-benzyloxycarbonyl) -l-lidinyl] pidazine

 (20) 1- [1-benzyloxycanolebonyl-L-hydroxyprolyl- (O-tert-butynole) -L-threonyl] pidazine

 (21) 1- [1-Benzyloxycarbonyl L-Hydroxyprolyl-3- (2-Chenyl) 1-Aranyl] pidazine

 (22) 1- (1-benzyloxycarbonyl-l-hydroxyprolyl-N-in-t-butoxycarbonyl-l-tryptophanyl) piperazine

 (23) 1- (1-benzyloxycarbonyl-l-prolyl-l-isoleucyl) piperazine

 (24) 1- [1-benzyloxycanoleboninole-l-prolyl- (N-ε-acetyl) -l-lidinyl] pidazine

 (25) 1- [1-benzyloxycarbonyl-l-prolyl- (Ν-ε-benzyloxycarbyl) -l-lysini / le] piperazine

 (26) 1- [1-benzyloxycanolebonyl-L-prolyl- (Ο-tert-butynole) -l-L-threonyl] pidazine

 (27) 1- [1-benzyloxycarbonyl-L-prolyl-β- (2-phenyl) -1-L-aranyl] pidazine

 (28) 1- (1-benzyloxycarbonyl-1 L-prolyl N-in-t-butoxycarboryl L-tryptophanyl) piperazine

 (29) 1- (1-benzyloxycarbonyl L-prolyl-L-cyclohexyl alanyl) piperazine

(30) 1- [1 benzyloxycarbonyl L-prolyl (O-tert-butyl Nore) One L-Gnoretharyl] pidazine

 (31) 1- (1-benzyloxycarbonyl-L-prolyl-L-methyol) piperazine

 (32) 1- (1-benzyloxycarbonyl-L-prolyl-L-phenyldaricyl) piperazine

Example 43

 (1-Benzyloxycarbonylglycyl-L-prolyl) -L-noryl isyl bromomethyl ketone (0.33 g, 0.66 mmol) in 3.3 mL of ethanol was dispensed in equal volumes into 11 test tubes. 4-Methoxybenzothioamide (10.0 mg, 0.06 mmol), 4-imidazoyl acetothioamide hydrochloride (10.3 mg, 0.06 mmol), 1'-cyclopropyl-1-imidazoyl acetothioamide (10.6 mg, 0.06 mmol), 1

[3,3,1] —4-octylthioamide (11,81 ^, 0.06 fraction 01), 4-dimethylaminobenzothioamide hydrochloride (13.0111 0.06 fraction 01), 4benzyl 1-pyrazulthioamide (14.1 mg) , 0,06mmol), 4-Pyrrolidinylbenzothioamide hydrochloride (14.6mg, 0.06mmol), 4-Dethylaminobenzthioamide hydrochloride (14.7mg, 0.06mmol), _α- Cyclopropinolevenzylthiodirea (14.9 mg, 0.06 mmol), 1-benzyl-3-pyrrolidinylthioamide hydrochloride (15.6 mg, 0.06 mmol), 4-dipropylaminobenzothioamide hydrochloride (16.6 mg, 0.06 mmol) separately And refluxed at 80 ° C. The solvent was distilled off under reduced pressure, and (a) N- {1- [2- (4-methoxyphenyl) thiazo-41-yl])-1-pentyl 1-benzyloxycarbonylglycyl-L-prolineamide,

(b) Ν- {1- [2- (4-Imidazolyl) methylthiazo-41-yl]}-1-1-pentyl 1-benzyloxycarbonylglycyl-L-proline amide, (c) -1 -1- {2-[(1-cyclohexyl) -1-imidazolyl] methylthiazo-41-yl]} ― 1-pentynole 1-benzyloxycanoleboninoleglycyl-L-prolinamide,

(d) Ν- {1— [2— (1-azabicyclo- [3,3,1] -14-octyl) thiazo-4-yl]}-1—pentyl 1-benzyloxycarbonylglycyl-L- Prolinamide, (e) N -1— (2-[(4-dimethyaminophenyl) thiazo-41-yl]}-111-pentyl 1-benzyloxycarbonylglycyl-L-prolinamide,

(f) N-1- {2- [1- (4-benzylpiperazinyl) thiazo-4-yl]}-1 —Pentyl 1-benzyloxycarbonylglycyl-L-proline amide, (g) N-1- {2-[(4-pyrrolidylphenyl) thiazo-41-yl]} — 1-pentynole Xycarbonyldaricyl-L-proline amide, (h) N -1- {2-[(4-Jetylaminophenyl) thiazo-4-yl]} —1pentyl 1-benzyloxycarbonyldaricyl -S-proline amide, (i) N-1— {2-[(cyclopropylpheninolemethyl) aminothiazolyl-4-yl]} — 1-pentyl 1-benzyloxycarbonylglycyl-L-proline amide, (J) N-1— {2-[(1 benzylpyrrolidine-13-yl) thiazo-4-yl]} — 1pentyl 1-benzyloxycarbonyldaricyl-L-proline amide, and ( k) N-1- {2-[(4-dipropylaminophenyl) thiazo-4-yl]} -one pen Le 1 one base Nji Ruo alkoxycarbonyl Dali sill - give the L- Purorin'ami de. Tables 6 and 7 show the structural formulas and physicochemical properties of the reference example compounds, and Tables 8 and 11 show the structural formulas and physicochemical properties of the example compounds.

 The symbols in the table have the following meaning. The three-letter abbreviation of the amino acid residue is as described above.

 Ref Reference example number

 Ex. Example number

mp. melting point

 H then stock: Nuclear magnetic resonance spectrum

 T S: TMS internal standard

 Anal .: Elemental analysis value

calcd .: Calculated value

found: experimental value

m / Z: Mass spectrometry value (m / Z)

m / e: mass spectrometry value (m / e)

 FAB: FAB method

 APCI: APC I method

Str .: Structural formula Ph: phenyl group

 Bn: benzyl group

i-Bu: Isobutyl group

 1 -pipe: piperazinyl group

 Boc: tert-butoxycarbonyl group

 Z: benzyloxycarbonyl group

 Py-3-yl: 3-pyridyl group

 Mes: Mesityl group (2,4,6-trimethylphenyl group)

 Ac: acetyl group

 Bu: butyl group

 Me: methyl group

 Et: ethyl group

 Pyra-2-yl: Pyrazini / le group

_{2, 6-CF 3 -C 6} H 3: 2, 6- Visto Riffle O b methyl-phenylalanine group

_{2, 6- CI- C 6 H 3} : 2, 6- Axis every mouth phenyl group

_{2, 4, 6- CI- H 2} : 2, 4, 6- trichloro port phenyl group

3, 5-N0 ₂ -C ₆ fl ₃ : 3,5-Dinito pheninole group

_{3, 5-C1- C 6 H} 3: 3, 5- Axis every mouth phenyl group

3-F-4-0H-C ₆ Ho: 3-fluoro-4-hydroxypheninole 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)

#a: Effluent condition _a (Column: Merckne: LiChrospher 100 RP-18 (4.0 廳, 25 t, 5 μΐη)) 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:. Waiemushi one company Ltd. A-302 S-5 ODS column (4 6顏x 0.99 negation, 5 _{M m),} solvent: Fuishiya manufactured HPLC grade MeOH (A452J- 4) and distilled water (W5J-4), 0.5¾ trifluorofluoroacetic acid in MeOH: 0.5% trifluoroacetic acid in distilled water = 20: 8 to 100: 0 with a gradient of 0.8 to 0.8 mL / min) l For 5 minutes, flow out 100: 0 for 15 minutes, detection: 254-10)

 #c: Outflow condition c (Column: A-302 S-5 ODS col 圆 n (4.6 times x 0mm, 5 μπ), Solvent: HPLC grade MeOH (A452J-4) manufactured by Fisher and distilled water ( Using W5J-4), 5 mmol of trifluoroacetic acid in MeOH: distilled water of 5 trifluorotrifluoroacetic acid = linL / niiri for 20 minutes with a gradient of 5:95 to 100: 0, detection: 220 nm.)

#d: Effluent condition d (Column: A-302 S-5 ODS column (4.6 nm x 150 mm, 5 μπι), 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 ^)

#e: Effluent condition e (Column: エ ± ム ± A-302 S-5 ODS column (4.6 mm x 150 mm, 5 / um), Solvent: HPLC grade MeOH (A452J-4) manufactured by Fisher and distilled water (W5J-4), 5nunol trifluoroacetic acid in MeOH solution: 5 mmol trifluoroacetic acid in distilled water = 5:95 to 100: 0 with a gradient of 1 mL / min for 5 minutes, detection: 220ΠΙΙ1Ο)

 #f: Outflow condition f (Column: ヮ Jamushi I ίϋ¾ A-302 S-5 ODS column (4.6 thigh x 0 dragon,

 5 丽), Solvent: Using HPLC grade MeOH (A452J-4) manufactured by Fisher and distilled water (W5J-4), use 5-phase trifluoroacetic acid! leOH solution: 5 fractions ol Trifluoroacetic acid in distilled water = 50: 50-80: 20 gradient, lmL / niiri 2 5 min, detection: 220mno) ret. time: retention time

 P-Cl-DL-Phe: D L— p—Chloro-phenylenyl

 / 3-(= 0) -DL-Phe: D L— 3—Ketophenylalaer group

 L-Lys-N-ε-Ac: (Ν-ε-acetyl) One L-lysinyl group

 L-Lys-Ν-ε-Ζ: (Ν-ε-benzyloxycarbonyl) one L-lysinyl group

 L-Thr (O-Bu-t): (O-tert-butyl) — L-threonyl group

L-Trp-N-Boc: (N-tert-butoxycarbonyl) one L-tryptophanyl group L-Glu (O-Bu-t): (O-tert-butyl) one L-glutaryl group

Table 6

 8

/.SeZ0/L6df/lDd

sdT / 613d80 / 6 OAV:

00

08

6 ¾

tsezo / z.6df / iDd 〇

00

Jp, c no ZH L-Nle 3.5-C1-C6H3-C m / e 549 (C1 = 35, C1 = 35), 551 (C1 = 35

OOCH _2- , C1 = 37) (FAB)

 HPLC #a ret.time: 13.04min

39 (f) z H L-Nle 4-F-C6H4-CO m / e 499,521 (M + Na) (FAB)

OCH ₂ -HPLC ret.time: 11.54min

40 (a) z H L-Nle Pyra-2-yI-COO m / e 483 (APCI)

CH ₂ -HPLCMS #b ret.time: 13.20min

40 (b) z H L-Nle PhOCH ₂ COO m / e 511 (APCI)

CH ₂ -HPLCMS #b ret.time: 15.25min

^ K ^c ) z H L-Nle 2-Cl-Py-3-yl-tn / e 516 (APCI)

COOCH ₂ -HPLCMS #b ret.time: 14.20min z H L-Nle Mes-COO- m / e 523 (APCI)

CH ₂ -HPLCMS #b ret.time: 17.00min

40 (e) z H L-Nle 3-F-4-OH-C6 m / e 529 (APCI)

H3-COOCH ₂ -HPLCMS #b ret.time: 14.40min

41 (a) z OH Gly 1-Pipe m / Z 391 (APCI)

 HPLCMS #c ret.time: 7.20min

41 (b) z OH L-Hyp 1-Pipe m / Z 447 (APCI)

 HPLCMS #c ret.time: 8.25min

41 (c) z OH Le Leu 1-Pipe m Z 447 (APCI)

 HPLCMS #e ret.time: 10.00min

41 (d) z OH D-Leu 1-Pipe m / Z 447 (APCI)

 HPLCMS #c ret.time: 9.30min

41 (e) z OH L-Phe 1-Pipe m / Z 481 (APCI)

 HPLCMS #e ret.time: 9.40min

41 (z OH D-Phe 1-Pipe m / Z 481 (APCI)

HPLCMS #c ret.time: 9.45min

(13) Z-Gly H L-Phe 1-Pipe m / Z 522 (APCI)

 HPLCMS #c ret.time: 9.85min (14) Z-Gly H D-Phe Pipe m / Z 522 (APCI)

 HPLCMS #c ret.time: 9.85min (15) Z-Gly H L-Pro 1-Pipe m / Z 472 (APCI)

 HPLCMS #c ret.time: 9.35min (16) Z-Gly H D-Pro 1-Pipe m / Z 472 (APCI)

 HPLCMS #d ret.time: 1 1.00min (17) Z OH De De 1-Pipe m / Z 447

 HPLCMS #d ret.time: 1 1.70min (18) Z OH L-Lys-N-E-Ac 1-Pipe m / Z 504

 HPLCMS #d ret.time: 9.20min (19) Z OH L-Lys-Ν-ε-Ζ 1-Pipe m / Z 596

 HPLCMS #d ret.time: 13.10min (20) Z OH Thr Thr (0-Bu-t) 1-Pipe m / Z 491

 HPLCMS #c ret.time: 9.85min (21) Z OH L-Thi 1-Pipe m / Z 487

 HPLCMS #d ret.time: 1 1.50min (22) Z OH L-Trp-N-Boc 1-Pipe m / Z 620

 HPLCMS #f ret.time: 20.50min (23) Z H L-De 1-Pipe m / Z 431 (APCI)

 HPLCMS #d ret.time: 12.75min (24) Z H L-Lys-N-E-Ac 1-Pipe m / Z 488 (APCI)

 HPLCMS #d ret.time: 13.85min (25) Z H L-Lys-N-E-Z 1-Pipe m / Z 580 (APCI)

 HPLCMS #d ret.time: 13.80min (26) Z H Re Thr (O-Bu-t) 1-Pipe m / Z 475 (APCI)

HPLCMS #c ret.time: 10.40min

1

Claims

Scope of the claim A bone resorption inhibitor comprising a compound having a selective cathepsin K inhibitory action and a pharmaceutically acceptable carrier.

 2. The bone resorption inhibitor according to claim 1, wherein the compound having a selective cathepsin II inhibitory activity is a proline derivative represented by the following general formula (I) or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings.

X: a portion excluding the C-terminal carboxy group of an amino acid residue whose side chain may be protected,

R ¹ : protecting group for an amino group,

G: glycine residue,

n: 0 or 1,

R ³ : a group that inhibits the activity of the SH group of cysteine protease,

 4: hydrogen atom, hydroxyl group or fuunyl group. )

3. The bone resorption inhibitor according to claim 2, wherein X is a portion other than the C-terminal carboxy group of the α-amino acid residue whose side chain may be protected.

X is a compound of the formula 一 CH— CHR ² — (wherein R ² is a hydrogen atom, an alkyl group, a lower alkenyl group, an aryl group, an aralkyl group, an imidazo-41-yl-lower alkyl group or Indole-1-3-^-lower alkyl group, wherein the alkyl group and 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 nitro group, and a carboxyl group. , Carbamoyl group, mono or di-lower alkyl force It may be substituted with one or more substituents selected from a rubamoyl group, a lower alkanoylamino group, an amino group, a mono- or di-lower alkylamino group, a guanidino group and a ditroguanidino group. The aralkyl group includes a lower alkyl group, a halogen atom, a lower alkoxy group, a hydroxyl group, a mercapto group, an alkynolethio group, a nitro group, a carboxyl group, a trifluoromethyl group, a fulbamoyl group, a mono- or di-lower alkyl group. Or a lower alkanoylamino group, an amino group, a mono- or di-lower alkylamino group, a guanidino group and a nitroguanidino group. When the above group of R ² has a functional group containing an oxygen, sulfur or nitrogen atom, these functional groups may be protected. ) Or formula (wherein, R ³ represents a hydrogen atom, a hydroxyl group or a phenyl group.)

 4. The bone resorption inhibitor according to claim 3, which is a group represented by the formula:

5. The group which inhibits the activity of the SH group of the cysteine protease of R ³ is an aldehyde group; a cyano group; a formula C (= θ) CF ₃ , a C (= 0) CF ₂ CF ₃ , a P (= O) (OH) ₂ , -C (= θ) CH ₂ OCH ₂ CF ₃ , — CH ₂ C 1, -S 0 ₂ F, or one BY ¹ Y ² (where Y ¹ and Y ² are The same or different, and represents an amino group which may be mono- or di-substituted by a hydroxyl group, a fluoro group, a lower alkoxy group or a lower alkyl group.): A lower alkoxycarbenylethenyl group; Optionally substituted aryloxymethylcarbonyloxymethylcarbonyl group; optionally substituted arylthiomethylcarbinyl group; optionally substituted aryloxycarbonyl group; An arylcarbonyloxymethylcarbonyl group which may have a substituent; A good aralkylcarbonyloxymethylcarbonyl group; a carbonyl group substituted by a nitrogen-containing saturated heterocyclic group which may have a substituent; 5- or 6-membered nitrogen-containing heteroaryl group which may be condensed with a benzene ring and optionally substituted with a 5- or 6-membered nitrogen-containing heteroaryl group which may have an S substituent A 1,3-dioxolanyl group; or a carbonyloxymethylcarbonyl group substituted with a 5- or 6-membered nitrogen-containing heteroaryl group which may be condensed with a benzene ring and may have a substituent. 3. The bone resorption inhibitor according to claim 2.

6. The protecting group for the amino group of R ¹ is a lower alkanoyl group, a benzoyl group, a benzyl group, a benzyl / reoxycanolevo / re, a t-butoxycarbonyl group, a t-butyl group, a phenylcarbamoyl group, or a phenylsulfonyl. 3. The bone resorption inhibitor according to claim 2, which is a group.

 7. The bone resorption inhibitor according to claim 2, wherein n = 0.

 8. A proline derivative represented by the following general formula () or a pharmaceutically acceptable salt thereof.

(The symbols in the formula have the following meanings.

X ^a : ^a portion of the α-amino acid residue, which may have a protected side chain, excluding the C-terminal luponyl group,

R ^{1 a} : a protecting group for an amino group,

 G: glycine residue,

 n: 0 or 1,

R ^{3 a} : (1) aldehyde group; (2) cyano group; (3) Formula C (= 0) CF ₃ , — C (= 0) CF ₂ CF ₃ , -P (= θ) (OH) ₂ , — C (= θ) CH ₂ OCH ₂ CF ₃ , one CH ₂ C 1, one S0 ₂ F, or one BY ¹ Y ² (where Y ¹ and Y ² are the same or different and are a hydroxyl group, a fluoro group A lower alkoxy group or an amino group which may be mono- or di-substituted with a lower alkyl group.); (4) a lower alkoxycarbonyl ethenyl group; (5) a group having a substituent Good aryloxymethylcarbonyloxymethi (6) an arylthiomethylcarbonyl group optionally having a substituent; (7) an aryloxycarbonyl group optionally having a substituent; (8) an aryloxymethyl group which may have a substituent. An aralkylcarbonyloxymethyl carbonyl group which may be substituted; (9) a carbonyl group substituted by a nitrogen-containing saturated heterocyclic group which may have a substituent; and (10) a benzene ring condensed with a benzene ring. (11) a nitrogen-containing 5 to 6-membered heteroaryl group which may be condensed with a benzene ring or may have a substituent; A carbonyl group substituted with a membered heteroaryl group; ( ₁₂ ) a 1,3-dioxolanyl group; or (13) a benzene ring which may be condensed or have a substituent, Carbonyl methoxymethylinoreca substituted with 5- or 6-membered heteroaryl group Reboniru group,

^Ra : a hydrogen atom, a hydroxyl group or a fuunyl group.

However, the following compounds are excluded.

(1) When R ^la — (G) n— is a benzyloxycarbonyl group and R ^{4 a} is a hydrogen atom, one X ^a — R ^{3 a} is

formula

 -V a 1 _H, one Met—H, —Lys _H, one Arg—H, or a compound represented by -Phe—H,

(2) When R ^la _ (G) n— is a benzyloxycarbonyl group and R ⁴ is a hydroxyl group, one X ^a — R ^3a is

A compound represented by OH, and

(3) When R ^la — (G) n— is a benzoyl group, and R ^{4 a} is a hydrogen atom, — X ^a — R ^{3 a} has the formula —Ar g—H or —Ar g (COOCH ₂ P h) A compound that is a group represented by 1 H. )

9. X ^a is 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-lower alkyl A alkyl group or an indole-3-yl lower alkyl 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 nitro group, and a carboxyl group. One or more substituents selected from the group consisting of a carbamoyl group, a mono- or di-lower alkyl group, a rubamoyl group, a lower alkanoylamino group, an amino group, a mono- or di-lower alkylamino group, a guanidino group and a nitroguanidino group. The aryl group and the aralkyl group may be substituted with a lower alkyl group, a halogen atom, Alkoxy group, hydroxyl group, mercapto group, alkylthio group, nitro group, carboxyl group, trinoleolomethyl group, rubamoyl group, mono- or di-lower alkyl rubamoyl group, lower alkanoylamino group, amino group, mono- or mono- It may be substituted with one or more substituents selected from a di-lower alkylamino group, a guanidino group and a nitrogua-dino group, and the above-mentioned group of R ² is a functional group containing an oxygen, sulfur or nitrogen atom. When these have, these functional groups are protected

It may be. ), Or formula

(Wherein R ³ represents a hydrogen atom, a hydroxyl group or a phenyl group). The proline derivative or a pharmaceutically acceptable salt thereof according to claim 8, which is a group represented by the formula:

0. X ^a force ;, A rg, N le, Ty r, Ph e, Le eu, Pro, Hy p, G ly, Va l, A ib, Ph g, Nva, Ab u, p_Cl—P C of the α-amino acid residue whose side chain may be protected, which is selected from the group consisting of he, I 1 e, Thr, Thi, Trp, Lys, Cha, Glu and Met. 10. The proline derivative or the pharmaceutically acceptable salt thereof according to claim 9, which is a portion excluding a terminal carbonyl group.

1. Protecting group of the amino group of R ^{1 a} is lower Arukanoiru group, Benzoiru group, benzyl group, benzyl O butoxycarbonyl group, t one-butoxycarbonyl group, t chromatography Bed butyl group, phenylene carbamoyl group, or a phenyl 9. The proline derivative according to claim 8, which is a sulfonyl group, or a pharmaceutically acceptable salt thereof.

 2. The proline derivative or the pharmaceutically acceptable salt thereof according to claim 8, wherein n = 0.

. 3 R ^{3 a} is (1) an aldehyde group, (2) Shiano group; (4) lower alkoxy carbonylation Rueteniru group; (5) phenoxyethanol methylcarbonyl O carboxymethyl Ca carbonyl group; (6) phenylene (7) a phenoxycarbonyl group optionally having 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 hydroxyl group and An aralkylcarbonylcarbonylmethylcarbonyl group which may have a substituent selected from the group consisting of halogen atoms; (9) a alkarylcarbonyloxymethylcarbonyl group which may have a substituent selected from the group consisting of lower alkyl groups and hydroxyl groups; A carbonyl group substituted with a good nitrogen-containing saturated heterocyclic group; (10) which may be condensed with a benzene ring, (lower alkoxy group, amino group, mono- or di-lower alkyl group) A phenyl group which may be substituted with a phenyl group, a cycloalkyl group or a lower alkyl group, or a 5- or 6-membered nitrogen-containing heteroaryl group. Selected from the group consisting of a substituted lower alkyl group, a nitrogen-containing saturated heterocyclic group which may be substituted or bridged with an aralkyl group, and an aralkylamino group which may be substituted with a cycloalkyl group. (11) a nitrogen-containing 5-membered heteroaryl group which may have a substituent; (11) a carbonyl group which is substituted with a nitrogen-containing 5-membered heteroaryl group which may be condensed with a benzene ring; (12) 1 9. The process according to claim 8, which is a 1,3-dioxolar group; or (13) a carbonyldimethoxymethylcarbonyl group substituted by a 6-membered nitrogen-containing heteroaryl group which may be substituted by a halogen atom. Loline derivative or a pharmaceutically acceptable salt thereof.

14. R ^{3 a} is (1) a proline derivative or a pharmaceutically acceptable salt thereof pharmaceutical of according to claim 8, wherein an aldehyde group.

15. The proline derivative according to claim 8, wherein R ^3a is (9) a carbon group substituted with a nitrogen-containing saturated heterocyclic group which may have a substituent, or a pharmaceutically acceptable salt thereof. Acceptable salts.

1 6. R ^{3 a} is (1 0) have a benzene ring condensed with even well substituent Moyore, claims 8, wherein the a Teroari Ichiru group nitrogen-containing 5 or 6-membered Or a pharmaceutically acceptable salt thereof.

1 7. R ^{3 a} is (1 1) a benzene ring fused with optionally carbonyl groups substituted with Teroari Ichiru group to be well substituent or nitrogen-containing 5 have a 6-membered claims 9. The proline derivative or the pharmaceutically acceptable salt thereof according to item 8.

1 8. R ^{3 a} is (1 3) proline derivative according to claim 8, wherein substituted with a halogen atom is a carbonyl O carboxymethyl group substituted with Te Roariru group to nitrogen-containing 6-membered or Its pharmaceutically acceptable salts.

1 9. The proline derivative or the pharmaceutically acceptable salt thereof according to claim 8, wherein R ^4a is a hydrogen atom.

 20. A pharmaceutical composition comprising the proline derivative or the pharmaceutically acceptable salt thereof according to claim 8, and a pharmaceutically acceptable carrier.

21. The pharmaceutical composition according to claim 20, which is a selective cathepsin K inhibitor.