JPH08104685A - Lactol derivative, its production and use - Google Patents

Abstract

PURPOSE: To obtain the new compound having a cathepsin L-inhibiting action and a bone absorption-inhibiting action and useful as an agent for preventing and treating osteoporosis because of directly acting on the bone to improve its metabolism. CONSTITUTION: This compound formula I (Q is one or two amino acid residues; R<3> is carboxyl or acyl; A is alkylene; B is H, alkyl, acyl) or its salt, e.g. (3 S)-3-[[N-tert-butoxycarbonyl-(L)-phenylalanyl]amino]-2-hydroxytetrahyd rofurane. The compound of formula I wherein B is H is obtained by subjecting a compound of formula II to a reduction reaction preferably by a method using diisobutyl aluminum hydride as a reducing agent at -80 to 100 deg.C. The compound of formula I wherein B is alkyl or acyl is also obtained by alkylating or acylating the compound of formula I wherein B is H.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a preventive treatment for osteoporosis containing as an active ingredient a lactol derivative having a cathepsin L inhibitory action and a bone resorption inhibiting action or a salt thereof, and the derivative or a pharmaceutically acceptable salt thereof. Regarding agents.

[0002]

2. Description of the Related Art Osteoporosis is a pathological condition or disease in which the quantity of bone is reduced to a certain extent or more, which causes some symptoms or danger. Its main symptoms are kyphosis of the spine, lumbar spine and vertebral bodies, femoral neck, lower radius, ribs, upper humerus and other fractures. In bone tissue, bone formation and bone destruction due to bone resorption are constantly repeated in a balanced manner, and osteoblasts play a central role in bone formation and osteoclasts play a central role in bone resorption. The balance between bone formation and bone destruction due to bone resorption is disturbed, and when bone resorption occurs more strongly than bone formation, it is accompanied by a quantitative decrease in bone. Therefore, agents that suppress bone resorption are considered to be useful for the prevention and treatment of osteoporosis, and bone resorption inhibiting substances such as estrogen agents and calcitonin have been administered as therapeutic agents for osteoporosis. However, when these therapeutic agents are administered, the subject to be administered may be limited or the effect may be uncertain, and a sufficient effect has not been obtained. Therefore, the development of new preventive and therapeutic methods for increased bone resorption is desired. In recent years, it has been revealed that cathepsin L, which is a protease secreted by osteoclasts in the process of bone resorption, is greatly involved in the degradation of collagen, which is a bone supporting protein. Therefore,
By inhibiting the activity of cathepsin L, it is possible to prevent the degradation of bone collagen due to bone resorption, which is considered to be useful for the preventive treatment of osteoporosis. Conventionally, leupeptin (leu
Peptin), antipain, etc.
-304074, 2-304075, 2-3040
The epoxysuccinic acid derivative disclosed in Japanese Patent Publication No. 85 etc. is known to have a cathepsin L inhibitory action as one of its inhibitory actions.

Examples of the lactol derivative having a 3-amino-2-hydroxyfuran and 3-amino-2-hydroxypyran skeleton include, for example, Tetrahedron Letters, Vol. 30, page 5421 (19).
1989), Canadian Journal of Chemistry, 60, 55
8 pages (1982), Canadian Journal of Chemistry, 5
6, 119 (1978), European Journal of Medicinal Chemistry.
nal of Medicinal Chemistry), vol. 12, p. 317 (1
977), Chemical and Pharmaceutical Bulleti (Chemical and Pharmaceutical Bulleti
n), Vol. 16, p. 1881 (1968) are known. However, none of these compounds describe cathepsin L inhibitory action, and 3-
Amino-2-hydroxyfuran and 3-amino-2-
A compound in which the 3-position amino group of the hydroxypyran skeleton is bound to an amino acid derivative is not known.

[0004]

However, the above-mentioned epoxysuccinic acid derivative has an inhibitory effect on proteases other than cathepsin L as disclosed in the patent publication,
It has not been put to practical use as a preventive and therapeutic drug for osteoporosis. The present invention is intended to provide a lactol derivative which is a compound structurally completely different from a conventional substance having a cathepsin L inhibitory action.

[0005]

Means for Solving the Problems The present inventors have earnestly studied for the purpose of developing a more general drug having a selective inhibitory action on cathepsin L and directly acting on bone to suppress bone resorption. I went. As a result, the following general formula (Ia) or (I
The lactol derivative represented by b) is a strong cathepsin L.
It was found that it has an inhibitory action and exerts an excellent bone resorption inhibiting action by directly acting on the bone, and further research was conducted to complete the present invention.

That is, the present invention provides (1) general formula (Ia)

[Chemical 9] [Wherein, Q is an optionally substituted 1 or 2 amino acid residue, R ³ is an optionally esterified carboxyl group or acyl group, A is an alkylene group, B is hydrogen, An alkyl group or an acyl group which may be substituted is shown. ] The compound or its salt represented by these, (2) General formula (I)

[Chemical 10] (In the formula, R ¹ and R ² are the same or different, and are hydrogen or an optionally substituted hydrocarbon group, and R ³ is an optionally esterified carboxyl group or an acyl group,
A represents an alkylene group, B represents hydrogen, an optionally substituted alkyl group or an acyl group, and m and n each represent 0 or 1. However, when m and n are both 0, R ³
Represents an optionally esterified carboxyl group or acyl group having 7 or more carbon atoms. ] Or a salt thereof, (3) the compound or salt thereof according to the above (1) or (2), wherein A is a lower alkylene group having 2 to 4 carbon atoms, (4) substituted with B The alkyl group which may be substituted is a lower alkyl group having 1 to 6 carbon atoms which may be substituted, or a salt thereof, or (5) the acyl group of B is a carboxylic acid. A compound or a salt thereof according to the above (1) or (2), which is an acyl group derived from (6) an aryl group which may be substituted with an optionally substituted hydrocarbon group of R ¹ or R ² ; The compound or salt thereof according to (2) above, which is an optionally substituted aliphatic hydrocarbon group, (7) wherein the optionally substituted aryl group of R ¹ or R ² is monocyclic or fused polycyclic. An aromatic hydrocarbon ring group having 6 to 14 carbon atoms in the formula or 5 Is membered aromatic heterocyclic group (6) The compound according or a salt thereof, is (8) R ¹ or optionally substituted aliphatic hydrocarbon group R ^2, (i) 1 to 8 carbon atoms Saturated aliphatic hydrocarbon group,
(ii) C2-C8 unsaturated aliphatic hydrocarbon group, (iii) C3-C7 saturated alicyclic hydrocarbon group, (iv) C5-C7
The unsaturated alicyclic hydrocarbon group, or (v) a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms, which is substituted with an alicyclic hydrocarbon group, or a salt thereof, (9) The above (2), wherein R ¹ or R ² is a lower alkyl group.
The compound or salt thereof described in (10) The compound or salt thereof described in (2) above, wherein R ¹ or R ² is an arylalkyl group, and (11) the acyl group of R ³ which may be substituted. The compound or a salt thereof according to the above (1) or (2), which is an acyl group derived from an acid, a sulfonic acid, a sulfinic acid, a carbamic acid or a thiocarbamic acid; (12) The above (1) wherein m is 1 and n is 1 ( 2) The compound or salt thereof, (13) The compound or salt thereof described in (2) above, wherein m is 1 and n is 0, (14) The compound (2) above, wherein m is 0 and n is 0. A compound or salt thereof, (15) general formula (IIa)

[Chemical 11] [In the formula, Q represents an optionally substituted 1 or 2 amino acid residue, R ³ represents an optionally esterified carboxyl group or acyl group, and A represents an alkylene group. ] The method for producing the compound or salt thereof according to the above (1), which comprises subjecting the compound represented by the formula to a reduction reaction; (17) The general formula (II)

[Chemical 12] (In the formula, R ¹ and R ² are the same or different, and are hydrogen or an optionally substituted hydrocarbon group, and R ³ is an optionally esterified carboxyl group or an acyl group,
A is an alkylene group, and m and n are 0 or 1 respectively.
Indicates. However, when both m and n are 0, R ³ represents an optionally esterified carboxyl group or acyl group having 7 or more carbon atoms. ] The method for producing the compound or the salt thereof according to (2) above, which comprises subjecting the compound represented by the formula to a reduction reaction, and (18) after the reduction reaction, further subjecting to an alkylation or acylation reaction. (19) A cathepsin L inhibitor comprising the compound represented by the general formula (Ia) or a pharmaceutically acceptable salt thereof, (20) the general formula (Ib),

[Chemical 13] (In the formula, R ¹ and R ² are the same or different, and are hydrogen or an optionally substituted hydrocarbon group, and R ³ is an optionally esterified carboxyl group or an acyl group,
A represents an alkylene group, B represents hydrogen, an optionally substituted alkyl group or an acyl group, and m and n each represent 0 or 1. ] A cathepsin L inhibitor comprising a compound represented by: or a pharmaceutically acceptable salt thereof, (21) comprising a compound represented by the general formula (Ia) or a pharmaceutically acceptable salt thereof A bone resorption inhibitor, (22) a bone resorption inhibitor comprising a compound represented by the general formula (Ib) or a pharmaceutically acceptable salt thereof, and (23) for the prevention and treatment of osteoporosis (2
A bone resorption inhibitor as described in 1) or (22) is provided. The lactol derivative according to the present invention is a compound structurally completely different from a conventional substance having a cathepsin L inhibitory action. Further, no known lactol derivative having 3-amino-2-hydroxyfuran and 3-amino-2-hydroxypyran skeleton has a cathepsin L inhibitory action. In addition, the general formula (I
The compounds a) and (I) have a novel structure in that the amino group at the 3-position is bound to an amino acid derivative.

In the description herein, suitable examples and explanations included within the scope of the present invention will be described in detail below. Unless otherwise specified, the constituent amino acids in the present specification mean L-form, and their abbreviations are IUPAC (International Union of Pure and Applied) such as Gly: glycine, Leu: leucine, and Ile: isoleucine.
Chemistry) -IUB (International Union of Biochem
It is described according to the naming convention of istry). As the amino protecting group, an amino protecting group known in the art can be used. For example, acetyl, benzyloxycarbonyl, 4
-Methoxybenzyloxycarbonyl, t-butoxycarbonyl, phthalyl, formyl and the like are preferably used, and benzyloxycarbonyl is particularly preferable. In the above formula, the optionally substituted amino acid residue represented by Q is a natural or unnatural L-type or D-type α-
Any amino acid may be used. For example, glycine, an α-L-amino acid or an α-D-amino acid which is a natural protein-constituting amino acid (eg, α-L-type or α-D-type, alanine, valine, leucine, isoleucine, serine, threonine, Asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, cysteine, methionine, phenylalanine, tyrosine, tryptophan, histidine, proline, etc.), and preferably glycine, α-L-form, alanine, valine, leucine, Examples thereof include isoleucine, phenylalanine, tyrosine, methionine and aspartic acid.
In the above formula, the optionally substituted amino acid residue represented by Q may have 1 to 3 substituents at the synthesizable substitution position. Such substituents will be described later.
The same as the substituents in the optionally substituted aromatic hydrocarbon group, aromatic heterocyclic group and aliphatic hydrocarbon group represented by R ¹ and R ² can be mentioned.

Examples of the optionally substituted hydrocarbon group represented by R ¹ and R ² in the above formula include an aryl group and an aliphatic hydrocarbon group. Examples of the aryl group in the optionally substituted hydrocarbon group represented by R ¹ and R ² include a monocyclic or condensed polycyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms, and 1 A 5- to 6-membered aromatic heterocyclic group containing 2 to 1 nitrogen atom and 1 sulfur atom or oxygen atom, and these aromatic heterocyclic groups are 6-membered ring containing 2 or less nitrogen atoms. , Benzene ring or 1
It may be condensed with a 5-membered ring containing one sulfur atom.
Examples of the aromatic hydrocarbon ring group include phenyl, naphthyl, anthryl, phenanthryl, acenaphthylenyl and the like. Examples of the aromatic heterocyclic group include 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 6-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl, 2-pyrazinyl ,
2-pyrrolyl, 3-pyrrolyl, 2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 3-pyrazolyl, 4-pyrazolyl,
Isothiazolyl, isoxazolyl, 2-thiazolyl, 4-
Thiazolyl, 5-thiazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl, 1,2,4-triazol-3-yl, 1,2,3-triazol-4-yl, tetrazol-5-yl, benzimidazole -2-yl, indol-3-yl,
1H-indazolyl, benzo [b] furanyl, isobenzofuranyl, benz [b] thienyl, 1H-pyrrolo [2,3-b] pyrazin-2-yl, 1H-pyrrolo [2,3-b] pyridine-6 -Ill,
1H-imidazo [4,5-b] pyridin-2-yl, 1H-imidazo [4,5-c] pyridin-2-yl, 1H-imidazo [4,5-b] pyrazin-2-yl and the like can be mentioned. To be

The aliphatic hydrocarbon group in the optionally substituted hydrocarbon group represented by R ¹ and R ² is, for example, each of the following groups i) to v), that is, i) having 1 to 1 carbon atoms. 8 saturated aliphatic hydrocarbon groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, t.-butyl, pentyl, isopentyl, neopentyl, t.-pentyl, hexyl, isohexyl, C _1-8 alkyl groups such as heptyl and octyl), ii) unsaturated aliphatic hydrocarbon groups having 2 to 8 carbon atoms (eg,
Ethenyl, 1-propenyl, 2-propenyl, 1-butenyl,
2-butenyl, 3-butenyl, 2-methyl-1-propenyl, 1-
C ₂ such as pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 3-methyl-2-butenyl, 1-hexenyl, 3-hexenyl, 2,4-hexadienyl, 5-hexenyl, 1-heptenyl, 1-octenyl _-8 alkenyl groups and the like, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-
Pentynyl, 4-pentynyl, 1-hexynyl, 3-hexynyl, 2,4-hexadiynyl, 5-hexynyl, 1-heptynyl, etc. C _2-8 alkynyl group such as 1-octynyl), iii) of 3 to 7 carbon atoms Saturated alicyclic hydrocarbon group (eg,
C _3-7 cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl), iv) unsaturated alicyclic hydrocarbon groups having 5 to 7 carbon atoms (eg, 1-cyclopentenyl, 2- C _5-7 cyclo such as cyclopentenyl, 3-cyclopentenyl, 1-cyclohexenyl, 2-cyclohexenyl, 3-cyclohexenyl, 1-cycloheptenyl, 2-cycloheptenyl, 3-cycloheptenyl and 2,4-cycloheptadienyl Alkenyl group), v) saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms substituted with the saturated or unsaturated alicyclic hydrocarbon group described above (eg,
C _3-7 cycloalkyl-C _1-8 alkyl or the like or C _5-7
Cycloalkenyl-C _1-8 alkyl and the like, specifically, for example, cyclopropylmethyl, cyclopropylethyl,
Cyclobutylmethyl, cyclopentylmethyl, 2-cyclopentenylmethyl, 3-cyclopentenylmethyl, cyclohexylmethyl, 2-cyclohexenylmethyl, 3-cyclohexenylmethyl, cyclohexylethyl, cyclohexylpropyl, cycloheptylmethyl, cycloheptylethyl, etc.) Can be mentioned.

In the above formula, the optionally substituted aromatic hydrocarbon group, aromatic heterocyclic group and aliphatic hydrocarbon group represented by R ¹ and R ² are substituted at the synthesizable substitution position. It may have 1 to 3 groups. As such a substituent, an aryl group, an aliphatic hydrocarbon group, a non-aromatic heterocyclic group, an acyl group, an optionally esterified carboxyl group, an optionally substituted amino group, or an optionally substituted Examples thereof include a hydroxyl group, an optionally substituted thiol group, a halogen atom, a nitro group and an optionally substituted phosphono group. Examples of the aryl group and the aliphatic hydrocarbon group are the same as those listed as the aryl group and the aliphatic hydrocarbon group represented by R ¹ and R ² . As the non-aromatic heterocyclic group, a 5- to 7-membered heterocyclic group containing one sulfur atom, a nitrogen atom or an oxygen atom, or 2 to
5- to 6-membered heterocyclic group containing 4 nitrogen atoms, such as oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thioranyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl, piperazinyl, homopiperidyl, pyrrolinyl or imidazolidinyl. And non-aromatic heterocyclic groups. These non-aromatic heterocyclic groups may be condensed with a benzene ring, a 6-membered ring containing 2 or less nitrogen atoms, or a 5-membered ring containing 1 sulfur atom. Specific examples of the fused non-aromatic heterocyclic group include chromanyl, isochromanyl, indolinyl, isoindolinyl, thiochromanyl, isothiochromanyl and the like.

As the acyl group, an acyl group derived from an optionally substituted carboxylic acid, sulfonic acid, sulfinic acid, carbamic acid, thiocarbamic acid or the like, for example, a general formula, --COR ⁴ , --SO ₂ R ⁶ , -SOR ¹⁰ , -CONHR ⁷ or -CSNHR ⁸ [R ⁴ , R ⁶ , R ¹⁰ , R ⁷ and R ⁸ each independently represent a hydrocarbon group which may be substituted. ] And the like. R ⁴ , R ⁶ ,
Examples of the optionally substituted hydrocarbon group represented by R ¹⁰ , R ⁷ or R ⁸ are the same as those exemplified as the optionally substituted hydrocarbon group represented by R ¹ or R ^2. Is mentioned. The acyl group preferably has the general formula -CO
R ⁹ [R ⁹ is hydrogen, C _1-10 alkyl, C _2-10 alkenyl,
Alternatively, it represents an aromatic group. ] A group represented by, specifically, for example, formyl, acetyl, propionyl, butyryl,
Isobutyryl, valeryl, isovaleryl, pivaloyl,
Hexanoyl, heptanoyl, octanoyl, cyclobutanecarbonyl, cyclopentanecarbonyl, cyclohexanecarbonyl, cycloheptanecarbonyl, crotonyl, 2-cyclohexenecarbonyl or benzoyl,
Nicotinol and the like can be mentioned. As the carboxyl group which may be esterified, for example, a compound represented by the general formula —COOR ⁵
[R ⁵ is C _1-6 alkyl, C _2-6 alkenyl or C _6-10
Indicates aralkyl, etc. ] A group represented by, specifically, for example, a bond of a carboxyl group and an alkyl group having 1 to 6 carbon atoms, that is, C _1-6 alkoxycarbonyl and the like (eg, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, Isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl, tert.-butoxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, etc.), a combination of a carboxyl group and an alkenyl group having 2 to 6 carbon atoms, that is, C _2-6 alkenyloxycarbonyl etc. (eg allyloxycarbonyl, crotyloxycarbonyl, 2-pentenyloxycarbonyl, 3-hexenyloxycarbonyl etc.), bond between carboxyl group and aralkyl group having 6 to 10 carbon atoms What I did, namely C
_6-10 aralkyloxycarbonyl and the like (eg, benzyloxycarbonyl, phenethyloxycarbonyl, etc.) can be mentioned. The amino group which may be substituted,
Amino or alkyl having 1 to 10 carbons, 2 to 2 carbons
10 alkenyl, aromatic group or acyl group substituted with 1 or 2 amino groups (-NH ₂ group) (eg, methylamino, dimethylamino, ethylamino, diethylamino, dibutylamino, diallylamino, cyclohexylamino, Phenylamino, N-methyl-N-phenylamino, acetylamino, benzoylamino and the like).

The hydroxyl group which may be substituted is a hydroxyl group or an appropriate substituent for this hydroxyl group, particularly, those having a hydroxyl group-protecting group, such as alkoxy, alkenyloxy, aralkyloxy and acyloxy. In addition, aryloxy may be mentioned. Examples of the alkoxy include alkoxy having 1 to 10 carbon atoms (eg, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert.-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyl. Oxy, heptyloxy, nonyloxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like) are preferred. Examples of the alkenyloxy include alkenyloxy having 2 to 10 carbon atoms (eg, allyloxy, crotyloxy, 2-pentenyloxy, 3-hexenyloxy, 2-cyclopentenylmethoxy, 2-cyclohexenylmethoxy, etc.). preferable. Examples of the aralkyloxy include phenyl
C _1-4 alkyloxy (eg, benzyloxy, phenethyloxy, etc.) can be mentioned. As the acyloxy,
Preferred are alkanoyloxy having 2 to 4 carbon atoms (eg, acetyloxy, propionyloxy, n-butyryloxy, isobutyryloxy, etc.). Examples of the aryloxy include phenoxy and 4-chlorophenoxy.

Examples of the thiol group which may be substituted include a thiol group and an appropriate substituent for the thiol group, particularly one having a thiol group-protecting group such as alkylthio, aralkylthio and acylthio. Can be mentioned. Examples of the alkylthio include alkylthio having 1 to 10 carbon atoms (eg, methylthio, ethylthio, propylthio, isopropylthio, butylthio,
Isobutylthio, sec-butylthio, tert.-butylthio,
Pentylthio, isopentylthio, neopentylthio,
Hexylthio, heptylthio, nonylthio, cyclobutylthio, cyclopentylthio, cyclohexylthio, etc.) are preferred. As the aralkylthio, for example, phenyl-C _1-4 alkylthio and the like (eg, benzylthio, phenethylthio and the like) are preferable. The acylthio is preferably an alkanoylthio having 2 to 4 carbon atoms (eg, acetylthio, propionylthio, n-butyrylthio, isobutyrylthio, etc.). Examples of halogen include fluorine, chlorine, bromine and iodine, with fluorine and chlorine being particularly preferred. Examples of the phosphono group which may be substituted include dimethoxyphosphoryl, diethoxyphosphoryl, dipropoxyphosphoryl, diisopropoxyphosphoryl, ethylenedioxyphosphoryl, trimethylenedioxyphosphoryl or tetramethylenedioxyphosphoryl. Each of R ¹ and R ² is preferably hydrogen, a lower alkyl group or an aryl lower alkyl group, and particularly preferably a linear or branched C _1-5 alkyl group or a phenyl C _1-5 lower alkyl group. , These may be substituted with the above-mentioned hydroxyl group or thiol group, for example, CH ₃ -S-CH ₂ -CH _2- , HO-
C ₆ H ₄ -CH ₂ - and the like.

In the above formula, R ³ represents an optionally esterified carboxyl group or acyl group. However, in the above general formula (I) or (II), m and n
When both are 0, R ³ is an optionally esterified carboxyl group or acyl group having 7 or more carbon atoms, preferably an optionally esterified carboxyl group or acyl group having 7 to 50 carbon atoms. Etc. As the optionally esterified carboxyl group represented by R ³ ,
The above-mentioned optionally substituted aromatic hydrocarbon group represented by R ¹ and R ² , an optionally esterified carboxyl group exemplified as the substituent in the aromatic heterocyclic group and the aliphatic hydrocarbon group. And an alkoxycarbonyl group (eg, methoxycarbonyl, ethoxycarbonyl, tert.-butoxycarbonyl, phenoxycarbonyl, benzyloxycarbonyl, etc.) are preferable, and benzyloxycarbonyl is particularly preferable. The acyl group represented by R ³ , as the substituent in the above-mentioned optionally substituted aromatic hydrocarbon group represented by R ¹ and R ² , an aromatic heterocyclic group and an aliphatic hydrocarbon group. The same as the exemplified acyl group can be mentioned. The optionally substituted alkoxycarbonyl group or acyl group represented by R ³ has a substituent (an acyl group similar to the above, an optionally esterified carboxyl group, a substituted 1 to 3 optionally substituted amino group, optionally substituted hydroxyl group, optionally substituted thiol group, halogen atom, nitro group or optionally substituted phosphono group) Good.

In the above formula, examples of the alkylene group represented by A include those having a carbon chain of 2 to 4, and an ethylene group or a propylene group is particularly preferable. In the above formula, B is preferably hydrogen. The optionally substituted alkyl group represented by B has 1 to optionally substituted carbon atoms.
6 lower alkyl groups (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,
tert-butyl, pentyl, isopentyl, hexyl and the like). Examples of the acyl group represented by B are the substituents in the above-mentioned optionally substituted aromatic hydrocarbon group represented by R ¹ and R ² , an aromatic heterocyclic group and an aliphatic hydrocarbon group. The same acyl groups as those mentioned above can be mentioned, and an acyl group derived from a carboxylic acid is particularly preferable. The optionally substituted alkyl group or acyl group represented by B has a substituent (acyl group similar to the above, optionally esterified carboxyl group, substituted or not) at the synthesizable substitution position. 1 to 3 optionally substituted amino groups, optionally substituted hydroxyl groups, optionally substituted thiol groups, halogen atoms, nitro groups or optionally substituted phosphono groups).

In the present invention, the general formulas (Ia) and (I
The salt of the compound of b) is preferably a pharmaceutically acceptable salt, for example, a salt with an inorganic base, a salt with an organic base, a salt with an inorganic acid, a salt with an organic acid, a salt with a basic or acidic amino acid. Etc., and they can be prepared according to known methods. Preferable examples of salts with inorganic bases include alkali metal salts such as sodium salt and potassium salt; alkaline earth metal salts such as calcium salt and magnesium salt;
And aluminum salts, ammonium salts and the like. Preferable examples of the salt with an organic base include, for example, trimethylamine, triethylamine, pyridine, picoline, ethanolamine, diethanolamine, triethanolamine, dicyclohexylamine or N, N'-.
Examples thereof include salts with dibenzylethylenediamine and the like.
Preferable examples of salts with inorganic acids include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like. Suitable examples of salts with organic acids include formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, benzenesulfonic acid or p. -Salts such as toluene sulfonic acid are included. Suitable examples of salts with basic amino acids include salts with arginine, lysine, ornithine, and the like, and preferable examples of salts with acidic amino acids include salts with aspartic acid, glutamic acid, etc. To be The production method of the compound of the present invention is described in detail below.

Method A

Embedded image Wherein each symbol has the same meaning as described above. In this law,
Compound (II) is subjected to a reduction reaction to produce compound (I-1). This reduction reaction can be carried out by a method known per se. For example, reduction with a metal hydride, reduction with a metal-hydrogen complex compound, reduction with diborane and substituted borane, catalytic hydrogenation and the like are used. That is, this reaction is carried out by treating the compound (II) with a reducing agent. As the reducing agent, an alkali metal borohydride (eg,
Sodium borohydride, lithium borohydride, etc.),
A metal-hydrogen complex compound such as lithium aluminum hydride,
Catalytic reduction using hydrogen with metal hydrides such as sodium hydride, organotin compounds (triphenyltin hydride etc.), nickel compounds, zinc compounds and other metals and metal salts, palladium, platinum, rhodium and other transition metal catalysts. Examples of the agent include diborane and the like, and among them, diisobutylaluminum hydride is advantageously used.

This reaction is carried out in an organic solvent that does not affect the reaction. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloromethane, 1,2-dichloroethane and 1,1,2,2-tetrachloroethane. , Diethyl ether, tetrahydrofuran,
Dioxane, etc. ethers, methanol, ethanol, propanol, isopropanol, alcohols such as 2-methoxyethanol, amides such as N, N-dimethylformamide, or a mixed solvent thereof are appropriately selected depending on the type of reducing agent. Used. The reaction temperature is-
100 ° C. to 150 ° C., particularly −80 ° C. to 100 ° C. are preferable, and the reaction time is about 1 to 24 hours. The lactol derivative (I-1) thus obtained can be isolated and purified by known separation and purification means such as concentration, concentration under reduced pressure, solvent extraction, crystallization, recrystallization, phase transfer, chromatography and the like.

The starting compound (II) of the present invention can be produced, for example, by the following method. Method B

[Chemical 15] Wherein each symbol has the same meaning as described above. In this law,
(II) is produced by reacting the compound (III) or the reactive derivative at the carboxyl group or a salt thereof with the compound (IV) or a reactive derivative at the amino group or a salt thereof. Suitable reactive derivatives at the amino group of compound (IV) include Schiff base type imino or its enamine type tautomer formed by the reaction of compound (IV) with a carbonyl compound such as aldehyde or ketone; (IV) and bis (trimethylsilyl)
A silyl derivative formed by reaction with a silyl compound such as acetamide, mono (trimethylsilyl) acetamide, bis (trimethylsilyl) urea;
Examples thereof include derivatives produced by the reaction of (IV) with phosphorus trichloride or phosgene. For suitable salts of the compound (IV) and its reactive derivative, the acid addition salts exemplified for the compound (I) may be referred to.

Suitable reactive derivatives at the carboxyl group of the compound (III) include acid halides, acid anhydrides, activated amides, activated esters and the like. Suitable examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid and the like. , Sulfite, thiosulfate, sulfuric acid, sulfonic acids such as methanesulfonic acid,
Mixed acid anhydrides with aliphatic carboxylic acids such as acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, trichloroacetic acid or acids such as aromatic carboxylic acids such as benzoic acid; symmetry Acid anhydrides; activated amides with imidazole, 4-substituted imidazole, dimethylpyrazole, triazole or tetrazole; or for example cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, Trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester , Pyranyl ester, pyridyl ester, piperidyl ester, an activated ester, such as 8-quinolinyl ester with or e.g. N, N- dimethylhydroxylamine, 1-hydroxy -2- (1H) - pyridone, N-
Examples thereof include esters with N-hydroxy compounds such as hydroxysuccinimide, N-hydroxyphthalimide, and 1-hydroxy-1H-benzotriazole.

These reactive derivatives are the compounds used
It can be arbitrarily selected depending on the type of (III). Suitable salts of the reactive derivative of the compound (III) include, for example, alkali metal salts such as sodium salt and potassium salt, alkaline earth metal salts such as calcium salt and magnesium salt, ammonium salt such as trimethylamine salt and triethylamine salt. Base salts such as organic base salts such as pyridine salt, picoline salt, dicyclohexylamine salt and N, N-dibenzylethylenediamine salt. The reaction is usually carried out in a conventional solvent such as water, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, pyridine. The reaction can be carried out in any other organic solvent as long as it is a solvent that does not adversely influence the reaction. These conventional solvents may be used as a mixture with water.

In this reaction, when the compound (III) is used in the form of a free acid or a salt thereof, N, N'-dicyclohexylcarbodiimide;N-cyclohexyl-N'-
Morpholinoethylcarbodiimide; N-cyclohexyl-
N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylaminopropyl) carbodiimide; N, N'-carbonylbis (2-methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate;
Isopropyl polyphosphate; Phosphorus oxychloride; Diphenylphosphoryl azide; Thionyl chloride; Oxalyl chloride; For example, ethyl chloroformate; Lower alkyl haloformates such as isopropyl chloroformate; Triphenylphosphine; 2-Ethyl-7-hydroxybenzisoxazolium salt , 2-Ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazole; 1-
(p-chlorobenzenesulfonyloxy) -6-chloro-1H-benzotriazole; so-called Vilsmeier reagent prepared by reaction of N, N'-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. It is desirable to carry out the reaction in the presence of a conventional condensing agent such as The reaction is also carried out in the presence of an inorganic or organic base such as alkali metal hydrogen carbonate, tri (lower) alkylamine, pyridine, N- (lower) -alkylmorpholine, N, N-di (lower) alkylbenzylamine, etc. You may go to The reaction temperature is not particularly limited, but the reaction is usually performed under cooling or heating.

The starting compound (III) of Method B is produced by the following Method C to Method J. C method

Embedded image [In the formula, L represents a carboxy-protecting group, and other symbols have the same meanings as described above. The carboxy protecting group represented by L 1 includes a protecting group usually used in the field of peptide synthesis, such as an ester derivative.

In this method, the compound (V) or a reactive derivative at the carboxyl group or a salt thereof is treated with the compound (V
After producing (VII) by reacting with I) or its reactive derivative at the amino group or a salt thereof, the compound (III-1) is produced by subjecting it to elimination reaction of carboxy protecting group. The reaction of the compound (V) or its reactive derivative at the carboxyl group or its salt with the compound (VI) or its reactive derivative at its amino group or its salt is carried out in the same manner as in Method B. For the carboxy-protecting group elimination reaction of compound (VII), all the conventional methods used for the carboxy-protecting group elimination reaction, such as hydrolysis, reduction, elimination using Lewis acid and the like, can be applied. When the carboxy protecting group is an ester, it can be eliminated by hydrolysis or elimination with a Lewis acid. The hydrolysis is preferably carried out in the presence of a base or an acid.

Suitable bases are, for example, alkali metal hydroxides (eg sodium hydroxide, potassium hydroxide etc.), alkaline earth metal hydroxides (eg magnesium hydroxide, calcium hydroxide etc.), alkali metal carbonates. (Eg sodium carbonate, potassium carbonate etc.), alkaline earth metal carbonates (eg magnesium carbonate, calcium carbonate etc.), alkali metal bicarbonates (sodium bicarbonate, potassium bicarbonate etc.), alkali metal acetates (eg sodium acetate) , Potassium acetate etc.), alkaline earth metal phosphates (eg magnesium phosphate, calcium phosphate etc.), alkali metal hydrogen phosphates (eg disodium hydrogen phosphate, dipotassium hydrogen phosphate etc.), inorganic bases, tris Alkylamines (eg trimethylamido) , Triethylamine, etc.), picoline, N- methylpyrrolidine, N- methylmorpholine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,4
Examples thereof include organic bases such as diazabicyclo [2,2,2] non-5-ene and 1,8-diazabicyclo [5,4,0] -7-undecene.

Hydrolysis with a base is often carried out in water or a hydrophilic organic solvent or a mixed solvent.
Suitable acids include organic acids (eg formic acid etc.) and inorganic acids (eg hydrochloric acid, hydrobromic acid, sulfuric acid etc.). This hydrolysis is usually carried out in an organic solvent, water or a mixed solvent composed of these. The reaction temperature is not particularly limited and is appropriately selected depending on the type of the carboxy protecting group and the method of elimination. For elimination using a Lewis acid, a compound (VII) or a salt thereof is treated with a Lewis acid such as boron trihalide (eg, boron trichloride, boron trifluoride), titanium halide (eg, titanium tetrachloride, tetrabromide). Titanium etc.), aluminum halide (eg aluminum chloride, aluminum bromide etc.), trihaloacetic acid (eg trichloroacetic acid, trifluoroacetic acid etc.) and the like. This elimination reaction is preferably carried out in the presence of a cation scavenger (eg anisole, phenol etc.), and usually, a nitroalkane (eg nitromethane, nitroethane etc.), an alkylene halide (eg methylene chloride, ethylene chloride etc.), It is carried out in a solvent such as diethyl ether, carbon disulfide, or another solvent that does not adversely influence the reaction. These solvents may be used as a mixture thereof. The elimination by reduction is preferably applied to elimination of a protecting group such as haloalkyl (eg, 2-iodoethyl, 2,2,2-trichloroethyl) ester, aralkyl (eg, benzyl) ester, and the like. The reduction method used in this elimination reaction includes, for example, a metal (eg, zinc, zinc amalgam, etc.) or a salt of a chromium compound (eg, chromium chloride, chromium acetate) and an organic or inorganic acid (eg, acetic acid, propionic acid). , Hydrochloric acid, etc.); conventional catalytic reduction in the presence of a conventional metal catalyst (eg palladium carbon, Raney nickel, etc.). The reaction temperature is not particularly limited, and the reaction is usually performed under cooling, at room temperature or under heating.

Method D

[Chemical 17] [Each symbol in the formula has the same meaning as described above. In this law,
After producing (X) by reacting compound (IX) or a reactive derivative at a carboxyl group or a salt thereof with compound (VIII) or a reactive derivative at an amino group or a salt thereof, elimination of a carboxy protecting group is performed. The reaction is carried out to produce the compound (III-2). This method is performed in the same manner as the C method.

Method E

Embedded image [Each symbol in the formula has the same meaning as described above. In this law,
Compound (XI) or a salt thereof is reacted with compound (VIII) or a salt thereof to produce (XII), which is then subjected to a carboxy-protecting group elimination reaction to produce compound (III-3). The reaction of (VIII) and (XI) is carried out in a suitable solvent. Examples of the solvent include benzene, toluene,
Aromatic hydrocarbons such as xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, alcohols such as methanol, ethanol and propanol, ethyl acetate, acetonitrile, pyridine, N, N-
Dimethylformamide, dimethylsulfoxide, chloroform, dichloromethane, 1,2-dichloroethane,
1,1,2,2-tetrachloroethane, acetone, 2-
Butanone and a mixed solvent thereof may be mentioned. (VIII)
The reaction of (XI) with sodium hydroxide, potassium hydroxide,
Alkali metal salts such as potassium carbonate, sodium carbonate, sodium hydrogen carbonate, pyridine, triethylamine,
It is carried out in the presence of an amine such as N, N-dimethylaniline or the like, and an appropriate base such as sodium hydride or potassium hydride, and the amount of these bases to be used is preferably about 1 to 5 mol relative to the compound (IX). This reaction is generally -20 ° C to 150 ° C,
It is preferably carried out at about -10 ° C to 100 ° C. The compound (XII) thus obtained is subjected to a deprotecting group reaction to produce a compound (III-3). This deprotection group reaction is
It is performed in the same manner as the deprotecting group reaction in Method C.

Method F

[Chemical 19] [Each symbol in the formula has the same meaning as described above. In this law,
Compound (III-3) is produced by reacting compound (XIII) or a salt thereof with compound (XI) or a salt thereof. This sulfonylation reaction is usually carried out using an amino acid derivative (XI
II) as a sodium salt aqueous solution, and after reacting with the compound (XI), it is acidified, so-called Schotten-Baumann (S
chotten Baumann). G method

Embedded image [Each symbol in the formula has the same meaning as described above. In this law,
Compound (III-2) is produced by reacting compound (XIII) or a salt thereof with compound (XIV) or a salt thereof. This acylation reaction is performed in the same manner as in Method F.

Method H

[Chemical 21] [Each symbol in the formula has the same meaning as described above. In this law,
Compound (III-4) is produced by reacting compound (XIII) or a salt thereof with compound (XV) or a salt thereof. This method is performed in the same manner as the G method.

Method I

[Chemical formula 22] [Each symbol in the formula has the same meaning as described above. In this law,
Compound (VIII) or a salt thereof is reacted with compound (XVI) to give (XVII), which is then subjected to a carboxy-protecting group elimination reaction to give compound (III-5).
The reaction between compound (VIII) or a salt thereof and compound (XVI) is carried out in a suitable solvent. Examples of the solvent include aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and dimethoxyethane, ethyl acetate, acetonitrile, pyridine, N, N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, 1 Examples thereof include 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, acetone, 2-butanone and a mixed solvent thereof. Compound (XVI)
The amount of the compound used is preferably about 1 to 5 mol based on the compound (VIII). This reaction is generally carried out at -20 ° C to 150 ° C, preferably about -10 ° C to 100 ° C. The compound (XVII) thus obtained was converted to a compound (XVII) by subjecting it to a deprotecting group reaction.
(III-5) is produced. This deprotection group reaction is performed in the same manner as the deprotection group reaction in Method C.

J method

[Chemical formula 23] [Each symbol in the formula has the same meaning as described above. In this law,
Compound (VIII) or a salt thereof is reacted with compound (XVIII) to give (XIX), which is then subjected to elimination reaction of a carboxy protecting group to give compound (III-6). This reaction is performed in the same manner as Method I.

The starting compound (II) for Method A can also be produced by the following method. K method

[Chemical formula 24] [In the formula, M represents an amino group-protecting group, and other symbols have the same meanings as described above. Examples of the amino protecting group represented by M include a protecting group usually used in the field of peptide synthesis, such as an oxycarbonyl derivative, and preferably benzyloxycarbonyl is used. In this method, a compound (XX) or a reactive derivative at a carboxyl group or a salt thereof is reacted with a reactive derivative at a compound (IV) or an amino group or a salt thereof.
After producing (XXI), it was subjected to the elimination reaction of the amino protecting group,
Compound (XXII) is produced. Compound (XX) or a reactive derivative at a carboxyl group or a salt thereof, and a compound
The reaction with (IV) or its reactive derivative at the amino group or its salt is carried out in the same manner as in Method B. Compound
The amino protecting group elimination reaction of (XXI) can be eliminated by all the conventional methods used for the amino protecting group elimination reaction. For example, elimination of the benzyloxycarbonyl group is carried out by catalytic reduction in the presence of a conventional metal catalyst (eg palladium carbon, Raney-nickel, etc.). The reaction temperature is not particularly limited as long as it does not cause an undesirable side reaction, and the reaction is usually performed under cooling, at room temperature or under heating. Then compound (XXII)
In the same manner as in the reaction of compound (VIII) with compound (IX) in Method D or the reaction of compound (XIII) with compound (XIV) in Method G.
Sulfonylation in the same manner as the reaction of I) with compound (XI), oxycarbonylation in the same manner as the reaction of compound (VIII) with compound (XV) in Method H, and compound (VIII) in the method I Carbamoylation is carried out in the same manner as in the reaction of (XVI) with compound (VIII) and compound (XVI
Thiocarbamoylation is carried out in the same manner as in the reaction of II) to produce the compound (II). Among the compounds represented by the general formula (I), the compound in which B is an acyl group can be produced according to the L method.

L method

[Chemical 25] [In the formula, B ¹ represents an acyl group, and other symbols have the same meanings as described above. Examples of the acyl group represented by B ¹ include those similar to the acyl group represented by B. In this method, compound (I-2) is produced by subjecting lactol derivative (I-1) to an acylation reaction.

In this method, (I-2) is produced by reacting compound (XXII) or a reactive derivative at the carboxyl group with compound (I-1). Suitable reactive derivative at the carboxyl group of the compound (XXII) includes acid halide, acid anhydride, activated amide, activated ester and the like. Suitable examples of the reactive derivative include acid chloride; acid azide; substituted phosphoric acid such as dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acid, dialkyl phosphorous acid and the like. , Sulfurous acid, thiosulfuric acid, sulfuric acid, sulfonic acids such as methanesulfonic acid, eg, acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, trichloroacetic acid, etc. or benzoic acid, etc. Mixed acid anhydrides with acids such as aromatic carboxylic acids; symmetrical acid anhydrides; imidazoles,
Activated amides with 4-substituted imidazoles, dimethylpyrazoles, triazoles or tetrazoles; or for example cyanomethyl esters, methoxymethyl esters, dimethyliminomethyl esters, vinyl esters, propargyl esters, p-nitrophenyl esters, trichlorophenyl esters, pentachlorophenyl ester,
Activated ester such as mesylphenyl ester, phenylazophenyl ester, phenylthioester, p-nitrophenylthioester, p-cresylthioester, carboxymethylthioester, pyranyl ester, pyridyl ester, piperidyl ester, 8-quinolylthioester, or for example. N, N-dimethylhydroxyamine, 1-hydroxy-2- (1H) -pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, 1-hydroxy
Examples thereof include esters with N-hydroxy compounds such as -1H-benzotriazole. These reactive derivatives can be arbitrarily selected. The reaction is usually water, alcohols such as methanol and ethanol, acetone, dioxane, acetonitrile, chloroform, methylene chloride, ethylene chloride, tetrahydrofuran, ethyl acetate,
The reaction is carried out in a conventional solvent such as N, N-dimethylformamide or pyridine, but the reaction can be carried out in any other organic solvent as long as it does not adversely affect the reaction. These conventional solvents may be used as a mixture with water. In this reaction, when compound (XXII) is used in the form of a free acid or a salt thereof, N, N'-
Dicyclohexylcarbodiimide; N-cyclohexyl-
N'-morpholinoethylcarbodiimide; N-cyclohexyl-N '-(4-diethylaminocyclohexyl) carbodiimide; N, N'-diethylcarbodiimide, N, N'-diisopropylcarbodiimide, N-ethyl-N'-(3-dimethylamino Propyl) carbodiimide; N, N'-carbonylbis (2-
Methylimidazole); pentamethylene ketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene; 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride Diphenylphosphoryl azide; thionyl chloride; oxalyl chloride; eg ethyl chloroformate; lower alkyl haloformates such as isopropyl chloroformate; triphenylphosphine;
2-Ethyl-7-hydroxybenzisoxazolium salt, 2
-Ethyl-5- (m-sulfophenyl) isoxazolium hydroxide inner salt; N-hydroxybenzotriazole; 1- (p-chlorobenzenesulfonyloxy) -6-chloro
-1H-benzotriazole; in the presence of a conventional condensing agent such as a so-called Vilsmeier reagent prepared by the reaction of N, N'-dimethylformamide with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, etc. It is desirable to carry out the reaction. The reaction also includes alkali metal hydrogen carbonate, tri (lower) alkylamine, pyridine, N-
It may be carried out in the presence of an inorganic or organic base such as (lower) -alkylmorpholine, N, N-di (lower) alkylbenzylamine and the like. The reaction temperature is not particularly limited,
Usually, the reaction is performed under cooling or heating. Among the compounds represented by the general formula (I), the compound in which B is an alkyl group can be produced according to the M method.

M method

[Chemical formula 26] [In the formula, B ² represents an alkyl group, and other symbols have the same meanings as described above. ] As an alkyl group represented by B ² ,
The same as the alkyl group represented by B can be mentioned. In this method, compound (I-1) or (I-2) is reacted with compound (XXIII) in the presence of an acid (I
-3) is manufactured. This reaction involves a large excess of (XXII
I) as a solvent, an inorganic acid such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, p-toluenesulfonic acid, or the like is used as a compound (I-
It is carried out by adding 0.001 to 1.0 molar equivalent to 1) or (I-2). The reaction temperature is not particularly limited, but is preferably 0 to 50 ° C., and is carried out for 0.5 to 100 hours, especially 0.5 to 10 hours. General formula (I
The compound represented by the formula (-1) is a compound (I-
It can also be prepared from compound (I-2) according to Method O or 3).

N method

[Chemical 27] In this method, compound (I-3) is carried out in a water-containing solvent in the presence of an acid. Examples of the water-containing solvent include alcohols such as methanol, ethanol and propanol, ethers such as ethyl ether, tetrahydrofuran and dioxane,
A mixed solvent of acetonitrile, acetone, 2-butanone, N, N-dimethylformamide, dimethyl sulfoxide and the like and water can be mentioned. Examples of the acid include hydrochloric acid, sulfuric acid,
Examples thereof include nitric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid and the like. The amount of the acid used is 0.001 to 1.0 molar equivalent with respect to compound (I-3), and the reaction temperature is not particularly limited, but 0 to 50 ° C. is preferable, and the reaction is performed for 0.5 to 100 hours.

Method O

[Chemical 28] This hydrolysis reaction is carried out according to a known method in a water-containing solvent in the presence of an acid or a base. As the water-containing solvent, alcohols such as methanol, ethanol and propanol,
Ethers such as ethyl ether, tetrahydrofuran, dioxane, acetonitrile, acetone, 2-butanone, N, N-dimethylformamide, dimethyl sulfoxide and the like and a mixed solvent of water can be mentioned. Examples of the acid include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid and the like. The amount of the acid used is the compound (I-
0.001 to 1.0 molar equivalent to 2), the reaction temperature is not particularly limited, but is preferably 0 to 100 ° C., 0.5
~ 100 hours, especially 0.5-10 hours.
Examples of the base include potassium hydroxide, sodium hydroxide,
Examples thereof include lithium hydroxide, potassium carbonate, sodium carbonate and the like. The amount of the base used is 1 to 5 molar equivalents relative to compound (I-2), and the reaction temperature is not particularly limited, but 0 to
100 degreeC is preferable and it is carried out for 0.5 to 100 hours, especially 0.5 to 10 hours. The compound represented by general formula (I-5) can also be produced from compound (I-4) according to Method P.

P method

[Chemical 29] [In the formula, B ³ represents an acyl group or an alkyl group, and other symbols have the same meanings as described above. Examples of the acyl group or alkyl group represented by B ³ include those similar to the acyl group or alkyl group represented by B. In this method,
Compound (I-4) is subjected to a deprotecting group reaction in the same manner as in the reaction of compound (XXI) to compound (XXII) in Method K to give compound (XXIV). Then, the compound (XXIV) is treated with the compound (I- in the same manner as in the reaction from the compound (XXII) to the compound (II) in Method K.
5) is manufactured. Starting compound of Method P, general formula (I-4)
The compound represented by can also be produced according to the Q method.

Q method

Embedded image Wherein each symbol has the same meaning as described above. ] This method is
It is done in the same way as the law. The compound represented by the general formula (II) can also be produced according to the R method.

R method

[Chemical 31] [In the formula, W represents a lower alkyl group, and other symbols have the same meanings as described above. The deprotection group reaction of compound (XXVI) can be carried out by converting compound (XXI) to compound (XXI in Method K.
It is carried out in the same manner as the reaction to I). Compound (XXVI
The reaction of I) with compound (III) is carried out in the same manner as Method B. The lactonization of compound (XXVIII) is carried out by heating compound (XXVIII) in a solvent in the presence of an acid according to a conventional method. Examples of the solvent include alcohols such as methanol, ethanol and propanol, aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as ethyl ether, tetrahydrofuran and dioxane, acetonitrile, acetone and 2-butanone.
Examples thereof include N, N-dimethylformamide, dimethylsulfoxide, and the like, with preference given to benzene, toluene,
Aromatic hydrocarbons such as xylene. As the acid,
Examples thereof include hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, acetic acid, p-toluenesulfonic acid and the like. The amount of the acid used is the compound (XX
VIII) 0.001 to 1.0 molar equivalents, the reaction temperature is not particularly limited, but is preferably 0 to 150 ° C,
It is carried out for 0.5 to 100 hours, especially 0.5 to 10 hours. The compound represented by the general formula (IV) can be produced according to the S method.

S method

Embedded image Wherein each symbol has the same meaning as described above. ] Compound (X
The lactonization reaction of XVI) is carried out by the compound (X
It is carried out in the same manner as the reaction of XVIII) to compound (II). The deprotection group reaction of compound (XXIX) is carried out in the same manner as the reaction of compound (XXI) to compound (XXII) in Method K. The compound represented by the general formula (XXV) can be produced according to Method T.

T method

[Chemical 33] Wherein each symbol has the same meaning as described above. ] Compound (X
The reaction from XIX) to compound (XXX) is carried out by Method A followed by Method M or Method A followed by Method L. The deprotection group reaction of compound (XXX) is carried out in the same manner as the reaction of compound (XXI) to compound (XXII) in Method K. The compound represented by the above general formula (Ia) is
General formula (I-1) (when B is hydrogen in (Ia)), (I-2) (when B is an acyl group in (Ia))
Alternatively, the compound represented by (I-3) (in the case where B is an alkyl group in (Ia)) can be produced according to the method for producing a compound in which at least one of m and n is 1. In addition, the compound represented by the above general formula (IIa) is produced according to the method for producing a compound represented by the above general formula (II) in which at least one of m and n is 1. You can

Object compound of the present invention (Ia) or (Ib)
Is a solid formulation such as tablets, capsules, granules, powders, etc .;
It can be administered orally or parenterally as a liquid preparation such as an injection. As a pharmaceutically acceptable carrier,
Various conventional organic or inorganic carrier substances are used as formulation materials, and excipients, lubricants, binders in solid formulations,
It is used as a disintegrant, a solvent in a liquid preparation, a solubilizing agent, a suspending agent, an isotonicity agent, a buffering agent, a soothing agent and the like. If necessary, formulation additives such as preservatives, antioxidants, coloring agents and sweeteners can also be used. Preferable examples of excipients include lactose, sucrose, D-mannitol, starch, crystalline cellulose, light anhydrous silicic acid and the like. Preferable examples of the lubricant include magnesium stearate, calcium stearate, talc, colloidal silica and the like. Preferable examples of the binder include crystalline cellulose, sucrose, D-mannitol, dextrin, hydroxypropyl cellulose, hydroxypropylmethyl cellulose, polyvinylpyrrolidone and the like. Preferable examples of the disintegrant include starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium and the like. Preferable examples of the solvent include water for injection, alcohol, propylene glycol, macrogol, sesame oil, corn oil and the like. Preferable examples of the solubilizing agent include polyethylene glycol, propylene glycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate,
Examples include sodium citrate. Suitable examples of the suspending agent include surfactants such as stearyl triethanolamine, sodium lauryl sulfate, lauryl aminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate, and the like, for example, polyvinyl alcohol. , Polyvinylpyrrolidone, sodium carboxymethyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and other hydrophilic polymers.

Preferable examples of the tonicity agent include sodium chloride, glycerin, D-mannitol and the like. Preferred examples of the buffer include phosphate,
Buffers such as acetate, carbonate, citrate and the like can be mentioned. Preferred examples of the soothing agent include benzyl alcohol and the like. Suitable examples of preservatives include, for example, paraoxybenzoic acid esters, chlorobutanol, benzyl alcohol, phenethyl alcohol,
Examples include dehydroacetic acid and sorbic acid. Preferable examples of the antioxidant include sulfite, ascorbic acid and the like. The compound (Ia) or (Ib) of the present invention has a strong cathepsin L inhibitory action, an excellent bone resorption inhibitory action, and low toxicity. For example, the compounds prepared in Example 60 and Example 94 were orally administered to mice at a rate of 500 mg / kg, respectively,
No deaths were observed. Therefore, the compound (Ia) or (Ib) of the present invention can be used for the prevention or treatment of osteoporosis in mammals (eg, mouse, rat, rabbit, dog, cat, cow, pig, human etc.). This compound (Ia)
Alternatively, when (Ib) or a pharmaceutically acceptable salt thereof is used as a prophylactic / therapeutic agent for osteoporosis, the daily dose for an adult is 1 to 1000 mg, preferably 10 to 600 mg for oral administration. The drug of the present invention has a strong cathepsin L inhibitory action and a bone resorption inhibitory action, and acts directly on bone to improve bone metabolism. In addition, compound (Ia) or (Ib) and salts thereof have low toxicity, and are therefore extremely useful as prophylactic / therapeutic agents for osteoporosis. In addition, the compound (Ia) or (Ib) in the present invention has a calcification-promoting effect on osteoblasts, that is, since it has a bone formation-promoting activity, it is a mammal (eg, mouse, rat, rabbit, dog, cat, cow). ,Pig,
It is used as a medicine for various bone diseases and tooth diseases of humans and the like, and can be used, for example, as an osteogenesis promoter in bone repair and bone transplantation. It can also be used for treatment of non-bonded fractures, artificial fixation, and reconstruction of alveolar bone. For example, the compound (Ia) or (Ib) is a metal,
It can be used by being attached to or contained in artificial bone or the like made of ceramics or polymers. Artificial bones
It is preferable to make the surface porous so that the compound (Ia) or (Ib) can be released in the living tissue when it is transplanted to the bone defect site.

Compound (Ia) or (Ib) of the present invention
Is dispersed in a suitable dispersant, binder, diluent, etc. (eg, collagen, physiological saline, citric acid solution, acetic acid solution, hydroxyapatite, fibrin, or a mixture thereof) and applied to artificial bone. Alternatively, it can be attached or contained by impregnation and drying. Such artificial bone is transplanted to the bone defect portion and firmly fixed to the defect portion. The artificial bone immobilizing agent is a physiologically acceptable dispersion medium, a binder, a diluent, or another component effective for bone regeneration (for example, calcium) in which the compound (Ia) or (Ib) of the present invention is an active ingredient. ) Etc. can be mixed and adjusted. The artificial bone fixative can also be used so as to fill the gap between the artificial bone to be transplanted in the bone defect portion of the host and the bone defect portion without adhering or containing the artificial bone fixative. The compound (Ia) or (Ib) of the present invention has low toxicity and can be safely used. For example, the compound (Ia) or (Ib) is locally administered to a bone defect site or a bone loss site in an amount of about 0.1 to 100 mg (preferably 0.1 to 100 mg). 10 mg) can be administered.

Action Next, the pharmacological action of the compound (Ia) or (Ib) will be shown with reference to experimental examples. Experimental Example 1 (Human Cathepsin L Inhibitory Activity) EPC Application No. 93109879.2 (Publication No. 05)
No. 76953A2) recombinant human cathepsin L obtained by the method described in Example 8 of the specification was diluted with Diluent [0.1% Brij35 (Si
gma))] to adjust the concentration to 1 μg / ml. Diluent 46 μL, 0.1M DTT 2 μ in 1 μL of this enzyme dilution
L and 25 μL activator / buffer (340 mM sodium acetate, 60 mM acetic acid, 4 mM EDTA disodium salt, pH
5.5) was added and mixed. Add 1 μL of sample diluted to 10 ^-2 M with dimethylsulfoxide (DMSO) to 20 μM ZP
After adding 25 μL of he-Arg-NMec (enzyme substrate solution) and incubating at 30 ° C for 10 minutes, 100 μL of reaction stop solution (100 mM sodium monochloroacetate, 30 mM sodium acetate, pH 4.3)
Was added. The above reaction was carried out on a 96-well fluoro plate (Labo System). After stopping the reaction, the fluorescence of free aminomethylcoumarin (aminomethylcoumarin) was measured at a wavelength of 365 using a fluorometer FCA (manufactured by Baxter).
The fluorescence at a wavelength of 450 nm obtained by excitation of nm was measured.
In addition, 1 μL of DMSO containing no sample was used as a control for the experiment, and the fluorescence measurement value obtained in this reaction was 100%.
It was made active. For residual activity of 10% or less,
Using the diluted sample solution, the residual activity was measured according to the above procedure, the IC ₅₀ value was calculated, and the results are shown in [Table 1].

[Table 1]

Experimental Example 2 (Bone resorption inhibiting action) The bone resorption action was measured by the method of Royce [Journal of
Clinical Investigation (J.Clin.Inves
t.), No. 44, 103-116 (1965)]. That is, ⁴⁵ Sprague-Dawley rats on the 18th day of pregnancy
Ca (isotope of calcium, CaCl ₂ solution) was subcutaneously injected at 50 μCi, the abdomen was opened the next day, and the fetal rat was taken out aseptically, and the left and right forearm bones (radius,
The ulna) was separated from the trunk, and connective tissue and cartilage were removed as much as possible to obtain a bone culture sample. BGJb Medium (Fitton-Jackson modification; GIBCO Laboratorie
Bone serum albumin (final concentration: 2 mg / mL) was added to 0.6 mL of a medium, and the bone was added to each piece at 37 ° C. for 24 hours. The bone was tested for the test compound (final concentration 10 μM
Alternatively, the cells were cultured for 2 days in the above medium supplemented with 30 μM). The ratio of ⁴⁵ Ca which was released from the bone into the Medeiumu (%) is, ⁴⁵ Ca ⁴⁵ radioactivity and in bone Ca in medium
Was measured according to the following formula.

[Equation 1] Bone from a litter of fetuses was similarly tested without compound 2
The one cultured for a day was used as a control group. The average value ± standard deviation of the values obtained from 5 bones in each group was calculated, and the ratio (%) of this value to the value of the control group was calculated and shown in [Table 2].

[Table 2] The present invention will be described in detail with reference to the following Reference Examples and Examples. In addition,
In the Reference Examples and Examples, the optical rotation is room temperature (22 to 25 ° C).
It was measured at.

Reference Example 1 N-benzyloxycarbonyl- (L) -homoserine (9.0
g), 1-hydroxybenzotriazole (HOBt) (5.4g) and N, N-dimethylformamide (DMF) (50mL) under ice-cooling 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (7.5g) was added, and the mixture was stirred at room temperature for 14
After stirring for time, the reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer is a 10% aqueous citric acid solution,
Wash with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in that order, dry (MgSO ₄ ) and evaporate the solvent to give (S) -3- (N-benzyloxycarbonylamino) tetrahydrofuran-2-one.
(7.0 g, 84.3%) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless needles. Melting point 129-130
° C. Optical rotation [α] _D −0.5 ° (c 0.52, CHCl ₃ ).

Reference Example 2 (S) -3- (N-benzyloxycarbonylamino) tetrahydrofuran-2-one (1.56 g) was dissolved in ethanol (100 mL), and palladium-carbon (5%, 0.5 g) was added at room temperature. The catalytic reduction reaction was carried out at atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue is N, N-dimethylformamide (DMF) (20 mL)
, N- (tert.butoxycarbonyl)-(L) -phenylalanine (Boc-Phe-OH) (1.94 g), 1-hydroxybenzotriazole (HOBt) (1.1 g) was added, and then ice-cooled 1- Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (1.5 g) was added, the mixture was stirred at room temperature for 14 hr, the reaction mixture was poured into ice-water, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried (MgSO ₄ ) and evaporated to remove (S) -3-[[N-tert. Butoxycarbonyl- (L) -phenylalanyl] amino] tetrahydrofuran-2-one (the structural formula shown below) (1.8 g, 78.3%) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless crystals. Melting point 132-133 ° C. Optical rotation [α] _D -9.1 ° (c 0.51, CHCl ₃ ).

Embedded image

Reference Examples 3 to 7 In the same manner as in Reference Example 2, compounds shown in Table 3 were obtained.

[Table 3] Ph: phenyl, Cbz: benzyloxycarbonyl, 1-Np:
1-naphthyl, Ile: isoleucine, Val: valine, Ph
e: Phenylalanine

Reference Example 8 (S) -3-[[N-benzyloxycarbonyl- (L) -phenylalanyl] amino] tetrahydrofuran-2-one (1.5 g)
Dissolved in tetrahydrofuran (35 mL), palladium-carbon
(5%, 0.8g) was added and the catalytic reduction reaction was carried out at room temperature and atmospheric pressure.
The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residue is N, N-
Dissolve in dimethylformamide (DMF) (35 mL), add valproic acid [(C ₃ H ₇ ) ₂ CHCOOH] (0.622 g) and 1-hydroxybenzotriazole (HOBt) (0.66 g), and then under ice cooling.
1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD.HCl) (0.902g) was added, and after stirring at room temperature for 14 hours, the reaction mixture was poured into ice-water and extracted with ethyl acetate. . The ethyl acetate layer is a 10% aqueous citric acid solution,
Water, a saturated aqueous solution of sodium hydrogencarbonate, and a saturated aqueous solution of sodium chloride were washed in this order, dried (MgSO ₄ ), and the solvent was distilled off to give (S) -3-[[N-valproyl- (L) -phenylalanyl] amino] tetrahydrofuran. 2-one (the following structural formula) was obtained (0.55 g, 38%). Recrystallized from dichloromethane-ether. Colorless prism crystals. Melting point 203-205 ° C. Optical rotation [α] _D -39.3 ° (c 0.52, CHCl ₃ ).

Embedded image

Reference Example 9 (S) -3-[[N-benzyloxycarbonyl-
Tetrahydrofuran (35 mL) with (L) -phenylalanyl] amino] tetrahydrofuran-2-one (1.3 g)
-Dissolved in ethanol (10 mL), palladium-carbon (5
%, 0.847 g) was added and the catalytic reduction reaction was carried out at room temperature and atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residual oil was treated with N, N-dimethylformamide (DMF) (35
(mL) and 1-naphthalenesulfonyl chloride (0.847 g) was added. The mixture was cooled to 0 ° C. and 4-dimethylaminopyridine (DMAP) (0.4
78 g) was added and the mixture was stirred at 0 ° C. for 1.5 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and saturated brine in this order, dried (MgSO ₄ ), and evaporated. The residue was subjected to silica gel column chromatography, chloroform-ethyl acetate (1: 1,
(S) -3-[[N- (1
-Naphthalenesulfonyl)-(L) -phenylalanyl] amino] tetrahydrofuran-2-one (the following structural formula) (0.6 g, 40%) was obtained. Recrystallized from ethyl acetate-isopropyl ether. Colorless prism crystals. Melting point 93-94 [deg.] C. Optical rotation [α] _D -117.3 ° (c 0.52, CHC
l ₃ ).

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Reference Example 10 (S) -3-[[N-benzyloxycarbonyl-
(L) -Leucyl] amino] tetrahydrofuran-2-one (1.5 g) was dissolved in tetrahydrofuran (150 mL), palladium-carbon (5%, 0.2 g) was added, and the catalytic reduction reaction was performed at room temperature and atmospheric pressure. went. The catalyst was filtered off and the filtrate was α-
Naphthyl isocyanate (0.76 g) was added. The mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and (S) -3-[[N- (1-naphthylcarbamoyl)-(L) -leucyl] amino] tetrahydrofuran-2-one (the structural formula shown below) (1.05 g, 63
%) Was obtained. Recrystallized from chloroform-methanol-isopropyl ether. Colorless crystals. Melting point 213-2
14 ° C. Optical rotation [α] _D −25.6 ° (c 0.19, CH ₃ O
H).

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Reference Example 11 (S) -2- (N-benzyloxycarbonylamino)
-5-Hydroxyvaleric acid tert. Butyl ester [The Journal of Organic Chemistry, 55, 17
Obtained according to the method described on page 11 (1990). ]
(5.1 g) was dissolved in benzene (100 mL), p-toluenesulfonic acid (0.05 g) was added, and the mixture was stirred under reflux for 1 hr. Ethyl acetate (100 mL) was added to the reaction mixture, and the mixture was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in that order, dried (MgSO ₄ ) and the solvent was evaporated. The residue is
Subject to silica gel column chromatography and elute with ethyl acetate-hexane (1: 2, v / v) to obtain (S) -3- (N-benzyloxycarbonylamino).
-2-oxotetrahydropyran (2.0 g, 51%)
Was obtained as an oil. NMR (δ ppm in CD
Cl ₃ ): 1.54-1.74 (1H, m), 1.96-2.10 (2H, m), 2.55
-2.72 (1H, m), 4.36 (2H, t, J = 6.2Hz), 4.37-4.50 (1H,
m), 5.13 (2H, s), 5.62 (1H, broad), 7.34-7.40 (5H,
m). Optical rotation [α] _D + 51.5 ° (c 0.98, CHC
l ₃ ).

Reference Example 12 (S) -2- (N-benzyloxycarbonylamino)
Methyl-5-hydroxyvalerate (5.0 g) was dissolved in tetrahydrofuran (150 mL), palladium-carbon (5
%, 1.0 g) and the catalytic reduction reaction was carried out at room temperature and atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residual oil was treated with N, N-dimethylformamide (DMF) (20 mL).
And N-benzyloxycarbonyl- (L) -phenylalanine (Cbz-Phe-OH) (5.9 g) and 1-hydroxybenzotriazole (HOBt) (3.0 g) were added. The mixture was cooled to 0 ° C. and 1-ethyl-3- (3-
Dimethylaminopropyl) carbodiimide hydrochloride (WSCD
HCl) (4.1 g) was added, and the mixture was added at 0 ° C for 1 hour and then at room temperature for 1 hour.
Stir for 5 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer is a 10% aqueous citric acid solution,
The organic layer was washed with water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in that order, dried (MgSO ₄ ) and the solvent was distilled off. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (1: 1, v / v) to obtain (S) -2-[[N-benzyloxycarbonyl-
Methyl (L) -phenylalanyl] amino] -5-hydroxyvalerate (the following structural formula) (3.0 g, 40%) was obtained. Recrystallized from dichloromethane-hexane. Colorless needles. Melting point 155-157 [deg.] C. Optical rotation [α] _D + 5.4 ° (c 0.50, CHC
l ₃ ).

[Chemical 38]

Reference Example 13 (S) -2-[[N-benzyloxycarbonyl-
Methyl (L) -phenylalanyl] amino] -5-hydroxyvalerate (2.85 g) was dissolved in benzene (100 mL), p-toluenesulfonic acid (0.09 g) was added, and the mixture was stirred under reflux for 1 hr. The reaction mixture was concentrated under reduced pressure, and (S) -3-[[N-benzyloxycarbonyl-
(L) -Phenylalanyl] amino] -2-oxotetrahydropyran (the following structural formula) (2.0 g, 77%) was obtained. Melting point 167-169 [deg.] C. Optical rotation [α] _D + 43.6 ° (c 0.50, CHC
l ₃ ).

[Chemical Formula 39]

Reference Example 14 In the same manner as in Reference Example 12, (S) -2-[[N-benzyloxycarbonyl- (L) -leucyl] amino] -5.
-Methyl hydroxyvalerate (structure below) was obtained as an oil. NMR (δ ppm in CDCl ₃ ): 0.
93 (3H, d, J = 6Hz), 0.94 (3H, d, J = 6Hz), 1.45-2.00 (7H,
m), 2.50 (1H, broad), 3.61 (2H, t, J = 6Hz), 3.74 (3H,
s), 4.14-4.30 (1H, m), 4.53-4.64 (1H, m), 5.10 (2H, m)
s), 5.35 (1H, d, J = 8.6Hz), 7.03 (1H, d, J = 8Hz), 7.34
(5H, s). Optical rotation [α] _D- 12.1 ° (c 0.58, CHC
l ₃ ).

[Chemical 40]

Reference Example 15 In the same manner as in Reference Example 13, (S) -3-[[N-benzyloxycarbonyl- (L) -leucyl] amino] -2.
-Oxotetrahydropyran (the following structural formula) was obtained. Recrystallized from dichloromethane-isopropyl ether.
Colorless crystals. Melting point 126-127 [deg.] C. Optical rotation [α] _D + 25.4 ° (c 0.50, CHC
l ₃ ).

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Reference Examples 16 to 17 In the same manner as in Reference Example 9, compounds shown in [Table 4] were obtained.

[Table 4]

Reference Examples 18 to 21 In the same manner as in Reference Example 2, compounds shown in Table 5 were obtained.

[Table 5]

Reference Examples 22 to 26 In the same manner as in Reference Example 8, compounds shown in [Table 6] were obtained.

[Table 6]

Reference Example 27 In the same manner as in Reference Example 10, (S) -3-[[N- (1-
Naphthylthiocarbamoyl)-(L) -leucyl] amino] tetrahydrofuran-2-one (the following structural formula) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless powder. Melting point 102-105 [deg.] C. Optical rotation [α] _D −26.1 ° (c 0.47, CHC
l ₃ ).

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Example 1 A solution of (S) -3-[[N-tert.butoxycarbonyl- (L) -phenylalanyl] amino] tetrahydrofuran-2-one (0.8 g) in tetrahydrofuran (THF) (30 mL) was added. Then, a toluene solution of diisobutylaluminum hydride (DIBAL-H) (1.5 M, 5.4 mL) was added dropwise at -72 to -69 ° C under an argon atmosphere. After stirring at the same temperature for 30 minutes, water-tetrahydrofuran
(THF) (1: 2, 3 mL) was added dropwise. The reaction mixture was diluted with ethyl acetate (300 mL), stirred at room temperature for 1 hour, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography, and from the portion eluted with ethyl acetate-hexane (1: 1, v / v), (3S) -3-[[N-te
rt. Butoxycarbonyl- (L) -phenylalanyl] amino] -2-hydroxytetrahydrofuran (Structural formula below)
(0.3 g, 37.5%) was obtained as an amorphous solid. Melting point 80-90 ° C. NMR (δ ppm in CDCl ₃ ): 1.41 (9H, s), 1.
60-1.84 (1H, m), 1.93 (1H, d, J = 5.6Hz), 2.19-2.45 (1H,
m), 2.94-3.15 (1H, m), 3.56-4.40 (5H, m), 5.00-5.23 (2
H, m), 6.16-6.36 (1H, m), 7.18-7.39 (5H, m). Optical rotation [α] _D -10.1 ° (c 0.57, CHCl ₃ ).

[Chemical 43]

Examples 2 to 7 In the same manner as in Example 1, compounds shown in Table 7 were obtained.

[Table 7] Ph: phenyl, Cbz: benzyloxycarbonyl, 1-Np:
1-naphthyl, Ile: isoleucine, Val: valine, Ph
e: Phenylalanine 1) Amorphous solid 2) 1/4 hydrate 3) 1/4 hydrate. NMR (δ ppm in CDCl ₃ ): 0.67-0.79 (6H, m), 0.90-1.10 (1
H, m), 1.23-1.50 (2H, m), 1.60-1.85 (1H, m), 1.89-2.30 (1
H, m), 2.78 (0.5H, d, J = 2Hz), 2.99 (0.5H, d, J = 3Hz), 3.39
-3.51 (1H, m), 3.69-4.14 (3H, m), 4.96 (0.5H, d, J = 3Hz),
5.10 (0.5H, t, J = 4Hz), 5.43-5.51 (1H, m), 5.82 (0.5H, bro
ad), 6.20 (0.5H, broad), 7.49-7.76 (3H, m), 7.92-7.97
(1H, m), 8.06-8.10 (1H, m), 8.63-8.68 (1H, m).

Example 8 (3S) -3-[[N-tert.butoxycarbonyl- (L) -phenylalanyl] amino] -2-hydroxytetrahydrofuran
(0.1 g) was dissolved in acetic anhydride (3 mL), 4-dimethylaminopyridine (DMAP) (0.012 g) was added, and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated saline solution in that order and dried.
After (MgSO ₄ ), the solvent was distilled off, and (3S) -2-acetoxy-3-[[Nt
ert. Butoxycarbonyl- (L) -phenylalanyl] amino] tetrahydrofuran (the structural formula below) (0.035 g, 29
%) Was obtained. Recrystallized from ethyl acetate-hexane. Colorless crystals. Melting point 156-157 ° C. Optical rotation [α] _D -49.9 ° (c 0.15, CHCl ₃ ).

[Chemical 44]

Examples 9 to 24 In the same manner as in Example 1, compounds shown in [Table 8] and [Table 9] were obtained.

[Table 8]

[0068]

[Table 9]

Example 25 (3S) -2-acetoxy-3 was prepared in the same manner as in Example 8.
-[[N-benzyloxycarbonyl- (L) -valyl] amino] tetrahydrofuran (the following structural formula) was obtained. Recrystallized from dichloromethane-isopropyl ether-hexane. Colorless crystals. Melting point 173-174 [deg.] C. Optical rotation [α] _D -59.0 ° (c 0.50, CHC
l ₃ ).

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Example 26 (S) -3-[[N-benzyloxycarbonyl-
(L) -Leucyl] amino] tetrahydrofuran-2-
On (6.0 g) of tetrahydrofuran (250 mL)
To the solution, under an argon atmosphere, a toluene solution of diisobutylaluminum hydride (1.5M, 51.6 mL) was added to -7.
It was added dropwise at 0 to -65 ° C. The reaction mixture was warmed to room temperature and diluted with ethyl acetate (400 mL). Then acetic anhydride (20 mL) and 4-dimethylaminopyridine (DM
AP) (0.3 g) was added, and the mixture was stirred at room temperature for 3 hours.
The reaction mixture was washed with 1N-HCl, water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in this order, dried (MgSO ₄ ) and the solvent was distilled off. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (1: 1, v /
(2S, 3S) -2-acetoxy-3-[[N-benzyloxycarbonyl- (L)-
Leucyl] amino] tetrahydrofuran (following structural formula)
(3.3 g, 49%) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless needles. Melting point 1
61-162 ° C. Optical rotation [α] _D -86.6 ° (c
0.53, CHCl _3).

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Example 27 In the same manner as in Example 26, (3S) -2-acetoxy-
3-[[N-benzyloxycarbonyl- (L) -leucyl] amino] tetrahydropyran (the following structural formula) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless crystals. Melting point 142-143 [deg.] C. Optical rotation
[Α] _D- 62.5 ° (c 0.50, CHCl ₃ ).

[Chemical 47]

Example 28 In the same manner as in Example 26, (2S, 3S) -2-acetoxy-3-[[N-benzyloxycarbonyl- (L)
-Phenylalanyl] amino] tetrahydrofuran (the following structural formula) was obtained. Recrystallized from ethyl acetate. Colorless needles. Melting point 175-176 [deg.] C. Optical rotation [α] _D -6
1.4 ° (c 0.61, CHCl ₃ ).

Embedded image

Example 29 (2S, 3S) -2-acetoxy-3-[[N-benzyloxycarbonyl- (L) -leucyl] amino] tetrahydrofuran (3.2 g) was added to ethanol (150 mL).
, Palladium-carbon (5%, 1.5 g) was added,
The catalytic reduction reaction was performed at room temperature and atmospheric pressure. The catalyst was filtered off, and α-naphthyl isocyanate (1.5 g) was added to the filtrate.
The mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and (2S, 3S) -2-acetoxy-3-
[[N- (1-naphthylcarbamoyl)-(L) -leucyl] amino] tetrahydrofuran (the structural formula shown below)
(2.95 g, 89%) was obtained. Recrystallized from dichloromethane-methanol-isopropyl ether. Colorless crystals. Melting point 196-198 [deg.] C. Optical rotation [α] _D −51.
8 ° (c 0.32, CHCl ₃ ).

[Chemical 49]

Examples 30 to 31 In the same manner as in Example 29, the compounds shown in Table 10 were obtained.

[Table 10]

Example 32 (2S, 3S) -2-acetoxy-3-[[N- (1-
Naphthylcarbamoyl)-(L) -leucyl] amino]
Tetrahydrofuran (2.9 g) was added to methanol (50 m
It was suspended in L), a solution of potassium carbonate (0.94 g) in water (5 mL) was added under ice cooling, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ) and the solvent was distilled off to give 2-hydroxy-3-[[N- (1-naphthylcarbamoyl)-
(L) -Leucyl] amino] tetrahydrofuran (the structural formula shown below) (1.95 g, 72%) was obtained. Recrystallized from dichloromethane-methanol-isopropyl ether. Colorless crystals. Melting point 177-178 [deg.] C. Optical rotation
[Α] _D + 29.5 ° (c 0.25, dimethyl sulfoxide). Elemental analysis calculated as C ₂₁ H ₂₇ N ₃ O ₄ 1 / 2H ₂ O: C 63.94; H 7.15; N 10.65 Analytical value: C 64.62; H 7.09; N 10. 78

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Example 33 (3S) -2-acetoxy-3-[[N-benzyloxycarbonyl- (L) -leucyl] amino] tetrahydropyran (1.0 g) was dissolved in ethanol (100 mL), palladium-carbon. (5%, 0.3 g) was added and the catalytic reduction reaction was carried out at room temperature and atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in N, N-dimethylformamide (DMF) (25 mL) and 1-naphthalenesulfonyl chloride (0.59 g) was added. The mixture was cooled to 0 ° C. and 4-dimethylaminopyridine (DMA
P) (0.32 g) was added, and the mixture was stirred at 0 ° C. for 2 hours.
The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried (MgSO ₄ ) and evaporated to remove (3S) -2-acetoxy-3-[[ N
-(1-naphthalenesulfonyl)-(L) -leucyl]
Amino] tetrahydropyran (the following structural formula) (0.83
g, 69%). Recrystallized from dichloromethane-methanol-isopropyl ether. Colorless prism crystals.
Melting point 180-182 [deg.] C. Optical rotation [α] _D -154.5
° (c 0.51, CHCl ₃ ). Elemental analysis _{C 23 H 30 N 2 O 6} S · 1 / 2H 2 O Calculated: C 58.58; H 6.63; N 5.94 Analytical values: C 58.69; H 6.33; N 5 .92

[Chemical 51]

Example 34 In the same manner as in Example 33, (2S, 3S) -2-acetoxy-3-[[N- (4-nitrobenzenesulfonyl)
-(L) -Leucyl] amino] tetrahydrofuran (the structural formula below) was obtained. Recrystallized from ethyl acetate-methanol. Colorless needles. Melting point 197-199 [deg.] C. Optical rotation
[Α] _D- 81.4 ° (c 0.45, CHCl ₃ ).

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Example 35 (3S) -2-acetoxy-3-[[N- (1-naphthalenesulfonyl)-(L) -leucyl] amino] tetrahydropyran (0.5 g) was added to tetrahydrofuran (20 m).
L), 1N-HCl (5 mL) was added, and the mixture was stirred at room temperature for 65
Stir the time. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ) and then the solvent was distilled off. The residue was subjected to silica gel column chromatography, ethyl acetate-hexane (1: 1, v / v).
(3S) -2-hydroxy-3-from the part eluted at
[[N- (1-naphthalenesulfonyl)-(L) -leucyl] amino] tetrahydropyran (Structural formula below)
(0.31 g, 69%) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless crystals. Melting point 1
59-161 ° C. Optical rotation [α] _D -81.5 ° (c
0.27, CHCl _3).

Embedded image Examples 36 to 53 [Table 11] and [Table 12] in the same manner as in Example 35.
Was obtained.

[0079]

[Table 11]

[0080]

[Table 12]

Example 54 (2S, 3S) -2-acetoxy-3-[[N-benzyloxycarbonyl- (L) -leucyl] amino] tetrahydrofuran (1.5 g) was added to ethanol (100 mL).
, Palladium-carbon (5%, 0.5 g) was added,
The catalytic reduction reaction was performed at room temperature and atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in N, N-dimethylformamide (DMF) (20 mL), and N-benzyloxycarbonyl- (L) -leucine (Cbz-Leu-OH).
(1.1 g) and 1-hydroxybenzotriazole
(HOBt) (0.64 g) was added. The mixture is cooled to 0 ° C. and 1-ethyl-3- (3-dimethylaminopropyl)
Carbodiimide hydrochloride (WSCD.HCl) (0.88 g) was added, and the mixture was stirred at 0 ° C for 1 hr and then at room temperature for 15 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine in that order, dried (MgSO ₄ ) and evaporated to remove (2S, 3S) -2-acetoxy-3-.
[[N-benzyloxycarbonyl- (L) -leucyl- (L) -leucyl] amino] tetrahydrofuran (the following structural formula) (1.6 g, 84%) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless crystals.
Melting point 175-176 [deg.] C. Optical rotation [α] _D -104.3
° (c 0.52, CHCl ₃ ).

[Chemical 54]

Examples 55 to 69 In the same manner as in Example 54, [Table 13] and [Table 14]
Was obtained.

[Table 13]

[0083]

[Table 14]

Example 70 (2S, 3S) -2-acetoxy-3-[[N-benzyloxycarbonyl- (L) -leucyl- (L) -leucyl] amino] tetrahydrofuran (0.7 g) was added to ethanol (100 mL). ), Palladium-carbon (5%,
0.25 g) was added and the catalytic reduction reaction was carried out at room temperature and atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in dichloromethane (20 mL) and acetic anhydride (0.1 mL) was added.
3 g) and 4-dimethylaminopyridine (DMAP) (0.
061 g) was added, and the mixture was stirred at room temperature for 15 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed successively with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried (MgSO ₄ ) and evaporated to remove (2S, 3S) -2-acetoxy-3-.
[[N-acetyl- (L) -leucyl- (L) -leucyl] amino] tetrahydrofuran (the following structural formula) (0.
43 g, 74%) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless crystals. Melting point 210-
211 ° C. Optical rotation [α] _D- 147.8 ° (c 0.2
7, CHCl ₃ ).

[Chemical 55]

Example 71 In the same manner as in Example 70, (3S) -2-acetoxy-
3-[[N-acetyl- (L) -leucyl- (L) -leucyl] amino] tetrahydropyran (the structural formula shown below) was obtained. Recrystallized from dichloromethane-methanol. Colorless crystals. Melting point 238-240 [deg.] C. Optical rotation [α] _D −
112.1 ° (c 0.27, CHCl ₃ ).

[Chemical 56]

Example 72 (S) -3- (N-benzyloxycarbonylamino)
A solution of tetrahydrofuran-2-one (4.9 g) in tetrahydrofuran (150 mL) was added to a solution of diisobutylaluminum hydride in toluene (1.5) under an argon atmosphere.
M, 28.0 mL) was added dropwise at -70 to -65 ° C. Water (5 mL) was added dropwise at the same temperature, and then acetic anhydride (20 m
L) and 4-dimethylaminopyridine (DMAP)
(0.3 g) was added and the temperature was raised to room temperature. Ethyl acetate (40
It was diluted with 0 mL) and stirred at room temperature for 3 hours. The reaction mixture was washed with 1N-HCl, water, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine in this order, dried (MgSO ₄ ) and the solvent was distilled off. The residue was subjected to silica gel column chromatography, and eluted with ethyl acetate-hexane (1: 1, v / v) from (3S) -2-acetoxy-3- (N.
-Benzyloxycarbonylamino) tetrahydrofuran was obtained as an oil. This oil was converted to methanol (50
mL), concentrated hydrochloric acid (5 drops) was added, and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, (3S) -3
-(N-benzyloxycarbonylamino) -2-methoxytetrahydrofuran oil (2.3 g, 44%)
I got NMR (δ ppm in CDCl ₃ ): 1.
64-1.80 (1H, m), 2.28-2.48 (1H, m), 3.32 (3H, s), 3.84-
4.08 (2H, m), 4.10-4.20 (1H, m), 4.80 (1H, s), 4.80 (1H, b
road), 5.10 (2H, s), 7.35 (5H, s).

Example 73 (2S, 3S) -2-acetoxy-3-[[N-valproyl- (L) -valyl] amino] tetrahydrofuran (0.55 g) was suspended in methanol (50 mL) and concentrated hydrochloric acid ( (5 drops), and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure and (2S, 3S) -2-methoxy-
3-[[N-valproyl- (L) -valyl] amino]
Tetrahydrofuran (the following structural formula) (0.38 g, 72
%) Was obtained. Recrystallized from ethyl acetate. Colorless crystals. Melting point 150-156 [deg.] C. Optical rotation [α] _D + 18.5 ° (c 0.50, CHCl ₃ ). Elemental analysis Calculated as C ₁₈ H ₃₄ N ₂ O ₄ ¼H ₂ O: C 62.31; H 10.02; N 8.07 Analytical value: C 62.33; H 9.69; N 8. 10

[Chemical 57]

Example 74 (3S) -3- (N-benzyloxycarbonylamino) -2-methoxytetrahydrofuran (2.3 g) was added to tetrahydrofuran (100 mL) -methanol (40 m).
L) was dissolved, palladium-carbon (5%, 0.5 g) was added, and a catalytic reduction reaction was carried out at room temperature and normal pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in N, N-dimethylformamide (DMF) (20 mL), and N-benzyloxycarbonyl- (L) -aspartic acid β-
Methyl ester [Cbz-Asp (OCH ₃₎ -OH] (2.8 g) and 1-hydroxybenzotriazole - Le (HOBt) (1.5
g) was added. This mixture was cooled to 0 ° C., 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (WSCD · HCl) (2.1 g) was added, and the mixture was stirred at 0 ° C. for 1 hr and then at room temperature for 15 hr. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and saturated brine in that order, dried (MgSO ₄ ) and evaporated to remove the solvent (3
S) -3-[[N-benzyloxycarbonyl- (L)
-(3-Methoxycarbonyl) alanyl] amino] -2
-Methoxytetrahydrofuran (the following structural formula) (0.9
5, 48%). Recrystallized from ethyl acetate-hexane. Colorless crystals. Melting point 175-176 [deg.] C. Optical rotation
[Α] _D + 43.7 ° (c 0.50, CHCl ₃ ).

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Examples 75 to 79 In the same manner as in Example 74, the compounds shown in Table 15 were obtained.

[Table 15]

Example 80 (3S) -3-[[N-benzyloxycarbonyl-
(L)-(3-Methoxycarbonyl) alanyl] amino] -2-methoxytetrahydrofuran (0.6 g) was suspended in tetrahydrofuran (20 mL), and 1N-HCl was added.
(5 mL) was added, and the mixture was stirred at room temperature for 72 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried (MgSO ₄ ) and then the solvent was distilled off. The residue was subjected to silica gel column chromatography, and ethyl acetate-hexane (2: 1, v /
(3S) -3-[[N-benzyloxycarbonyl- (L)-(3-methoxycarbonyl) alanyl] amino] -2-hydroxytetrahydrofuran (the structural formula shown below) (0.06 g, 10%) was obtained.
Recrystallized from ethyl acetate. Colorless prism crystals. Melting point 1
43-145 ° C. Optical rotation [α] _D + 14.6 ° (c
0.27, CHCl _3).

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Examples 81 to 84 In the same manner as in Example 80, compounds shown in Table 16 were obtained.

[Table 16]

Example 85 (2S, 3S) -2-acetoxy-3-[[N-benzyloxycarbonyl- (L) -leucyl] amino] tetrahydrofuran (0.8 g) was added to tetrahydrofuran (1
0 mL) and suspended in p-toluenesulfonic acid (0.02).
g) and ethyl glycolate (5 mL) were added, and the mixture was stirred at room temperature for 5 hr. The reaction mixture was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography,
From the portion eluted with ethyl acetate-hexane (1: 1, v / v), ethyl [(3S) -3-[[N-benzyloxycarbonyl- (L) -leucyl] amino] tetrahydrofuran-2-yl] oxyacetate (0.6 g) was obtained as an oil. Dissolve this oil in methanol (5 mL),
A solution of potassium carbonate (0.1 g) in water (5 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction mixture was neutralized with 1N HCl and extracted with ethyl acetate. The ethyl acetate layer is washed with water,
Drying was distilled off (MgSO ₄₎ and the solvent. The residue was dissolved in ethanol (20 mL), 1N-NaOH (0.6 mL) was added, and the mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under reduced pressure to give [(3S) -3-[[N-benzyloxycarbonyl- (L) -leucyl] amino] tetrahydrofuran-
2-yl] oxyacetic acid sodium salt (following structural formula)
(0.35 g, 41%) was obtained. Recrystallized from methanol-ether. Colorless powder. Melting point 125-127 [deg.] C.
Optical rotation [α] _D + 50.7 ° (c 0.33, dimethyl sulfoxide). Elemental analysis _{C 20 H 27 N 2 O 7} Na · 1 / 2H 2 O Calculated: C 54.66; H 6.42; N 6.37 Analytical values: C 54.30; H 6.52; N 6 .27

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Example 86 (2S, 3S) -2-acetoxy-3-[[N- [4-
(N-benzyloxycarbonylamino) benzoyl]
-(L) -Leucyl] amino] tetrahydrofuran (1.0 g) was dissolved in ethanol (100 mL), palladium-carbon (5%, 0.7 g) was added, and the catalytic reduction reaction was performed at room temperature and atmospheric pressure. The catalyst was filtered off, the filtrate was concentrated under reduced pressure, and (2S, 3S) -2-acetoxy-3-[[N-
(4-Aminobenzoyl)-(L) -leucyl] amino] tetrahydrofuran (the structural formula below) (0.61 g,
81%). Recrystallized from dichloromethane-isopropyl ether. Colorless crystals. Melting point 148-150
° C. Optical rotation [α] _D -61.3 ° (c 0.29, CH
Cl _3).

[Chemical formula 61]

Example 87 (2S, 3S) -2-acetoxy-3-[[N- (4-
Nitrobenzenesulfonyl)-(L) -leucyl] amino] tetrahydrofuran (1.0 g) was added to ethanol (1
Dissolved in 00 mL), palladium-carbon (5%, 0.5 g)
Was added and the catalytic reduction reaction was carried out at room temperature and atmospheric pressure. The catalyst was filtered off and the filtrate was concentrated under reduced pressure to give (2S, 3S) -2-acetoxy-3-[[N- (4-aminobenzenesulfonyl)-(L) -leucyl] amino] tetrahydrofuran (structural formula The following) (0.7 g, 74%) was obtained. Recrystallized from ethyl acetate-methanol-ether. Colorless needles. Melting point 189-190 [deg.] C. Optical rotation [α] _D- 59.2
° (c 0.27, dimethyl sulfoxide).

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Example 88 (3S) -3-[[N-benzyloxycarbonyl-
(L) -Isoleucyl] amino] -2-methoxytetrahydrofuran (8.5 g) was dissolved in methanol (250 mL), palladium-carbon (5%, 2.3 g) was added, and the catalytic reduction reaction was carried out at room temperature and atmospheric pressure. . The catalyst was filtered off, and the filtrate was concentrated under reduced pressure. The residual oil was dissolved in N, N-dimethylformamide (DMF) (50 mL) and 1-naphthalenesulfonyl chloride (5.6 g) and 4-dimethylaminopyridine (DMAP) (3.0 g) were added. The mixture was stirred at 0 ° C. for 4 hours. The reaction mixture was poured into ice water and extracted with ethyl acetate. The ethyl acetate layer was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogencarbonate solution and saturated brine in that order, dried (MgSO ₄ ) and evaporated to remove the solvent (3S).
2-Methoxy-3-[[N- (1-naphthalenesulfonyl)-(L) -isoleucyl] amino] tetrahydrofuran (following structural formula) (7.0, 71%) was obtained. Recrystallized from ethyl acetate-hexane. Colorless crystals. Melting point 1
25-127 ° C. Optical rotation [α] _D + 12.8 ° (c
0.56, CHCl _3).

[Chemical formula 63]

Example 89 (2S, 3S) -2-acetoxy-3-[[N- (1-
Naphthylcarbamoyl)-(L) -leucyl] amino]
Tetrahydrofuran (0.1 g) was added to methanol (20 m
L), suspended in concentrated hydrochloric acid (5 drops), and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to (3S) -2.
-Methoxy-3-[[N- (1-naphthylcarbamoyl)-(L) -leucyl] amino] tetrahydrofuran (the structural formula shown below) (0.08 g, 87%) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless crystals. Melting point 184-185 [deg.] C. Optical rotation [α] _D +1
3.0 ° (c 0.27, CHCl ₃ ). Elemental analysis Calculated as C ₂₂ H ₂₉ N ₃ O ₄ .1 / 4H ₂ O: C 65.41; H 7.36; N 10.40 Analytical value: C 65.42; H 7.52; N 10. 39

[Chemical 64]

Example 90 In the same manner as in Example 26, (3S) -2-acetoxy-
3-[[N-benzyloxycarbonyl- (L) -isoleucyl] amino] tetrahydrofuran (following structural formula)
I got Recrystallized from ethyl acetate-hexane. Colorless needles. Melting point 185-187 [deg.] C. Optical rotation [α] _D -6
8.1 ° (c 0.53, CHCl ₃ ).

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Example 91 In the same manner as in Example 33, (2S, 3S) -2-acetoxy-3-[[N- (1-naphthalenesulfonyl)-
(L) -isoleucyl] amino] tetrahydrofuran (the structural formula shown below) was obtained. Recrystallized from dichloromethane-isopropyl ether. Colorless needles. Melting point 158-
160 ° C. Optical rotation [α] _D -153.0 ° (c 0.5
0, CHCl _3).

[Chemical formula 66]

Example 92 In the same manner as in Example 26, (2S, 3S) -2-acetoxy-3-[[N-benzyloxycarbonyl- (L)
-Valyl] amino] tetrahydrofuran (following structural formula)
I got Recrystallized from ethyl acetate. Colorless crystals. Melting point
161-162 ° C. Optical rotation [α] _D −66.6 ° (c
0.53, CHCl _3). Elemental analysis calculated as C ₁₉ H ₂₆ N ₂ O ₆ ¼H ₂ O: C 59.60; H 6.98; N 7.32 Analytical value: C 59.82; H 6.77; N 7. 19

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Examples 93 to 98 In the same manner as in Example 35, the compounds shown in Table 17 were obtained.

[Table 17]

Examples 99 to 106 In the same manner as in Example 54, compounds shown in Table 18 were obtained.

[Table 18]

Example 107 (2S, 3S) -3-[[N-
(1-Naphthalenesulfonyl)-(L) -isoleucyl] amino] -2-propionyloxytetrahydrofuran (the following structural formula) was obtained. Recrystallized from chloroform-isopropyl ether. Colorless crystals. Melting point 157-
159 ° C. Optical rotation [α] _D −142.8 ° (c 0.
65, CHCl _3).

[Chemical 68]

Example 108 In the same manner as in Example 73, (3S) -3-[[N-benzyloxycarbonyl- (L) -phenylalanyl] amino] -2-methoxytetrahydrofuran (the following structural formula) was obtained. It was Recrystallized from ethyl acetate-hexane. Colorless crystals. Melting point 140-142 [deg.] C. Optical rotation [α] _D +
17.1 ° (c 0.51, CHCl ₃ ).

[Chemical 69]

Example 109 In the same manner as in Example 73, [(3S) -3-[[N-benzyloxycarbonyl- (L) -phenylalanyl]] was used.
Amino] tetrahydrofuran-2-yl] ethyl oxyacetate (the following structural formula) was obtained. Recrystallized from ether-isopropyl ether. Colorless crystals. Melting point 103-10
6 ° C. Optical rotation [α] _D + 14.9 ° (c 0.49,
CHCl ₃ ).

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[0105]

INDUSTRIAL APPLICABILITY The compound (Ia) or (Ib) of the present invention has a strong cathepsin L inhibitory action and a bone resorption inhibitory action, and acts directly on bone to improve bone metabolism, and is therefore useful as a pharmaceutical.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 38/00 ADF C07D 309/14 313/02 405/12 213 215 249 413/12 307 C07K 5 / 062 8318-4H // (C07D 405/12 213: 81 307: 22) (C07D 405/12 215: 48 307: 22) (C07D 405/12 249: 10 307: 22) (72) Inventor Junji Mizoguchi 5-18 Tsuzudai, Suita City, Osaka Prefecture D75-206

Claims (23)

[Claims] 1. A general formula: [Wherein, Q is an optionally substituted 1 or 2 amino acid residue, R ³ is an optionally esterified carboxyl group or acyl group, A is an alkylene group, B is hydrogen, An alkyl group or an acyl group which may be substituted is shown. ] The compound or its salt represented by these. 2. A general formula: (In the formula, R ¹ and R ² are the same or different, and are hydrogen or an optionally substituted hydrocarbon group, and R ³ is an optionally esterified carboxyl group or an acyl group,
A represents an alkylene group, B represents hydrogen, an optionally substituted alkyl group or an acyl group, and m and n each represent 0 or 1. However, when m and n are both 0, R ³
Represents an optionally esterified carboxyl group or acyl group having 7 or more carbon atoms. ] The compound or its salt represented by these. 3. The compound according to claim 1, wherein A is a lower alkylene group having 2 to 4 carbon atoms, or a salt thereof. 4. An optionally substituted alkyl group of B is
The compound or a salt thereof according to claim 1 or 2, which is an optionally substituted lower alkyl group having 1 to 6 carbon atoms. 5. The compound or a salt thereof according to claim 1, wherein the acyl group of B is an acyl group derived from a carboxylic acid. 6. The compound according to claim 2, wherein the optionally substituted hydrocarbon group for R ¹ or R ² is an optionally substituted aryl group or an optionally substituted aliphatic hydrocarbon group. Or its salt. 7. The optionally substituted aryl group of R ¹ or R ² is a monocyclic or condensed polycyclic aromatic hydrocarbon ring group having 6 to 14 carbon atoms or a 5 to 6 membered aromatic heterocyclic group. The compound according to claim 6, which is a ring group, or a salt thereof. 8. An optionally substituted aliphatic hydrocarbon group for R ¹ or R ² is (i) a saturated aliphatic hydrocarbon group having 1 to 8 carbon atoms, (ii) an aliphatic hydrocarbon group having 2 to 8 carbon atoms. Saturated aliphatic hydrocarbon group, (i
ii) carbon substituted with a saturated alicyclic hydrocarbon group having 3 to 7 carbon atoms, (iv) unsaturated alicyclic hydrocarbon group having 5 to 7 carbon atoms, or (v) an alicyclic hydrocarbon group The compound or a salt thereof according to claim 6, which is a saturated aliphatic hydrocarbon group of the number 1 to 8. 9. The compound or a salt thereof according to claim ^{2, wherein} R ¹ or R ² is a lower alkyl group. 10. The compound or a salt thereof according to claim ^{2, wherein} R ¹ or R ² is an arylalkyl group. 11. The compound according to claim 1 or 2, wherein the acyl group of R ^{3 is} an acyl group derived from an optionally substituted carboxylic acid, sulfonic acid, sulfinic acid, carbamic acid or thiocarbamic acid. Its salt. 12. The compound or a salt thereof according to claim 2, wherein m 1 is 1 and n is 1. 13. The compound according to claim 2, wherein m is 1 and n is 0, or a salt thereof. 14. The compound or a salt thereof according to claim 2, wherein m is 0 and n is 0. 15. A general formula: [In the formula, Q represents an optionally substituted 1 or 2 amino acid residue, R ³ represents an optionally esterified carboxyl group or acyl group, and A represents an alkylene group. ] The compound represented by these is subjected to a reduction reaction, The manufacturing method of the compound or its salt of Claim 1 characterized by the above-mentioned. 16. The production method according to claim 15, which further comprises an alkylation or acylation reaction after the reduction reaction. 17. A general formula: (In the formula, R ¹ and R ² are the same or different, and are hydrogen or an optionally substituted hydrocarbon group, and R ³ is an optionally esterified carboxyl group or an acyl group,
A is an alkylene group, and m and n are 0 or 1 respectively.
Indicates. However, when both m and n are 0, R ³ represents an optionally esterified carboxyl group or acyl group having 7 or more carbon atoms. ] The compound represented by these is subjected to a reduction reaction, The manufacturing method of the compound or its salt of Claim 2 characterized by the above-mentioned. 18. The production method according to claim 17, which is further subjected to an alkylation or acylation reaction after the reduction reaction. 19. A general formula: [Wherein, Q is an optionally substituted 1 or 2 amino acid residue, R ³ is an optionally esterified carboxyl group or acyl group, A is an alkylene group, B is hydrogen, An alkyl group or an acyl group which may be substituted is shown. ] A cathepsin L inhibitor comprising a compound represented by: or a pharmaceutically acceptable salt thereof. 20. A general formula: (In the formula, R ¹ and R ² are the same or different, and are hydrogen or an optionally substituted hydrocarbon group, and R ³ is an optionally esterified carboxyl group or an acyl group,
A represents an alkylene group, B represents hydrogen, an optionally substituted alkyl group or an acyl group, and m and n each represent 0 or 1. ] A cathepsin L inhibitor comprising a compound represented by: or a pharmaceutically acceptable salt thereof. 21. A compound of the general formula [Wherein, Q is an optionally substituted 1 or 2 amino acid residue, R ³ is an optionally esterified carboxyl group or acyl group, A is an alkylene group, B is hydrogen, An alkyl group or an acyl group which may be substituted is shown. ] A bone resorption inhibitor comprising a compound represented by: or a pharmaceutically acceptable salt thereof. 22. A general formula: (In the formula, R ¹ and R ² are the same or different, and are hydrogen or an optionally substituted hydrocarbon group, and R ³ is an optionally esterified carboxyl group or an acyl group,
A represents an alkylene group, B represents hydrogen, an optionally substituted alkyl group or an acyl group, and m and n each represent 0 or 1. ] A bone resorption inhibitor comprising a compound represented by: or a pharmaceutically acceptable salt thereof. 23. The bone resorption inhibitor according to claim 21 or 22, which is used for prevention and treatment of osteoporosis.