JP3143530B2 - Cyclopropenone ketal derivative - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel cyclopropenone ketal derivative, and more particularly to a cyclopropenone derivative having a strong inhibitory activity against thiol proteases such as calpain, papain, cathepsin B, cathepsin H and cathepsin L. A novel cyclopropenone ketal derivative useful as an intermediate for the production of

[0002]

2. Description of the Related Art Calpain, papain, cathepsin B,
As the functions of thiol proteases to which cathepsin H, cathepsin L and the like belong in the living body have been elucidated, it has been found that the abnormal enhancement is a cause of various diseases, and thiol protease inhibitors have been shown to be effective in preventing such diseases. It is being used as a remedy. For example,
Calpain inhibitors are effective against animal models such as muscular dystrophy, cataract, myocardial infarction, delayed neuronal death after cerebral infarction, and cathepsin inhibitors are effective for cancer metastasis, muscular atrophy, It is reported that it is effective for osteoporosis and the like. However, peptidyl aldehyde,
Known thiol protease inhibitors such as epoxy succinic acid derivatives have poor oral absorbability, tissue transportability, and cell membrane permeability, so development of new thiol protease inhibitors that solve these problems is desired. ing.

[0003]

The inventors of the present invention have studied the intermediates for producing thiol protease inhibitors which are excellent in oral absorbability, tissue transportability and cell membrane permeability, and have reached the present invention. did.

[0004]

That is, the gist of the present invention is to provide the following general formula (I)

[0005]

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(In the above general formula, R¹Is a protecting group for the amino group
And R^Two, R^FourAnd R⁶Are each independently hydrogen
Represents an atom or an alkyl group having 1 to 5 carbon atoms, or
Iha R ¹And R^TwoTogether represent a phthalyl group;
^ThreeAnd R^FiveAre each independently a hydrogen atom or 3 carbon atoms
A cycloalkyl group having 10 to 10 carbon atoms or an
An alkyl group having 1 to 15 carbon atoms which may be substituted with a reel group
Represents a kill group, or R^FiveAnd R⁶Together
Represents a cycloalkyl group having 3 to 10 carbon atoms, ⁷as well as
R⁸Are each independently substituted with a phenyl group
Represents a good alkyl group having 1 to 5 carbon atoms;
⁷And R⁸Together form an alkyl group having 1 to 5 carbon atoms
2 to 2 carbon atoms optionally having one or more substituents selected
6 may form an alkylene group;⁹Is hydrogen field
, An alkyl group having 1 to 15 carbon atoms,
Chloroalkyl group, alkenyl group having 2 to 15 carbon atoms, substitution
An aryl group having 6 to 10 carbon atoms which may have a group,
A heterocyclic group which may have a substituent, or

[0007]

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(R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, an alkyl group having 1 to 15 carbon atoms, or a
0 represents an aryl group, or R ¹⁰ and R ¹¹ together represent a cycloalkyl group having 3 to 10 carbon atoms. ), And n represents 0 or 1. ) In the cyclopropenone ketal derivative.

Hereinafter, the present invention will be described in detail. In the general formula (I), the protecting group for the amino group represented by R ¹ is tert-butoxycarbonyl (Bo)
c) group, benzyloxycarbonyl (Z) group, 4-methoxybenzyloxycarbonyl (pMZ) group, 4-chlorobenzyloxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, 3,4,5-trimethoxybenzyl Urethane-type protecting groups such as oxycarbonyl group and 9-fluorenylmethoxycarbonyl (Fmoc) group; formyl group, trifluoroacetyl (Tfa) group, p-toluenesulfonyl (Tos) group, 2,4,6-trimethylbenzene Acyl-type protective groups such as a sulfonyl (Mts) group, a benzoyl group and a chloroacetyl group; and alkyl-type protective groups such as a benzyl group, a diphenylmethyl group and a trityl (Trt) group. As the alkyl group having 1 to 5 carbon atoms represented by R ² , R ⁴ and R ⁶ , each independently represents a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, te
Examples thereof include an rt-butyl group, a pentyl group, an isopentyl group, a neopentyl group, and the like, or R ¹ and R ² may be combined to form a phthalyl (Pht) group. R ³
And the alkyl group having 1 to 15 carbon atoms represented by R ⁵ , in addition to those defined for R ² , R ⁴ and R ⁶ , each independently represents a hexyl group, an isohexyl group, a heptyl group, an octyl group, a nonyl group, Decyl group, undecyl group,
Dodecyl group, tridecyl group, tetradecyl group, pentadecyl group and the like, such an alkyl group is a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group, a carbon number such as a cyclodecyl group. It may be substituted with a cycloalkyl group having 3 to 10 or an aryl group having 6 to 10 carbon atoms such as a phenyl group and a naphthyl group. Examples of the cycloalkyl group having 3 to 10 carbon atoms formed by R ⁵ and R ⁶ together include the same groups as defined above. Examples of the alkyl group having 1 to 5 carbon atoms represented by R ⁷ and R ⁸ include the same groups as defined for R ² , R ⁴ and R ^6. Such alkyl groups are substituted with a phenyl group. Is also good. Examples of the alkylene group having 2 to 6 carbon atoms formed by R ⁷ and R ⁸ together include an ethylene group, a trimethylene group, a tetramethylene group, a pentamethylene group, and a hexamethylene group. It may be substituted with one or more alkyl groups selected from the alkyl groups of Formulas 1 to 5. These alkyl groups include the same groups as defined for R ² , R ⁴ and R ⁶ . Examples of the alkyl group having 1 to 15 carbon atoms and the cycloalkyl group having 3 to 10 carbon atoms represented by R ⁹ include the same groups as defined for R ³ and R ⁵ , and alkenyl having 2 to 15 carbon atoms. Examples of the group include vinyl, 1-propenyl, 1-butenyl, 1-pentenyl, 1-hexenyl, 1-heptenyl, 1-octenyl, 1-nonenyl, 1-decenyl, and 1-undecenyl. Group, 1-dodecenyl group, 1-tridecenyl group,
1-tetradecenyl group, 1-pentadecenyl group, allyl group, 2-butenyl group, 3-butenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 2-hexenyl group, 3-hexenyl group, 4- A hexenyl group, a 5-hexenyl group and the like; an aryl group having 6 to 10 carbon atoms includes a phenyl group and a naphthyl group; such an aryl group is a halogen atom such as a fluorine atom, a chlorine atom and a bromine atom; Group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group,
C1-C5 alkyl groups such as tert-butyl group, pentyl group, isopentyl group, neopentyl group; hydroxyl group; methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-
It may have one or more substituents selected from alkoxy groups having 1 to 5 carbon atoms such as a butoxy group, a tert-butoxy group, a pentyloxy group, an isopentyloxy group, and a neopentyloxy group; Examples of the ring group include a furan ring, a thiophene ring, a pyridine ring, a pyridine oxide ring, a pyrimidine ring, a pyridazine ring, a pyrimidine ring, a benzofuran ring, a benzothiophene ring, a quinoline ring, and a naphthyridine ring. A heterocyclic group having from 1 to 4 selected heteroatoms and a total number of atoms constituting the ring of from 5 to 10; and the heterocyclic group is the same substituent and trimethylsilyl group as defined in the above aryl group. , 1 selected from among Application Benefits ethylsilyl group, a trialkylsilyl group having 3 to 12 carbon atoms such as tert- butyldimethylsilyl group It may have a substituent group above. The alkyl group and aryl group having 6 to 10 carbon atoms having 1 to 15 carbon atoms represented by R ¹⁰ and R ^11, include the same groups as defined under R ³ and R ^5, R ¹⁰ and R
Examples of the cycloalkyl group having 3 to 10 carbon atoms represented by ¹¹ together include the same groups as defined for R ⁵ and R ⁶ .

Preferred compounds of the present invention are as follows. R ¹ is tert- butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group, p- toluenesulfonyl group, 2,4,6-Doo
Represents trimethyl benzene sulfonyl group or trityl group, or represents R ^2, R ⁴ and R ⁶ are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms, or R
¹ and R ² together represent a phthalyl group, and R ³ and R ⁵ are each independently a hydrogen atom or a carbon atom which may be substituted by a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group or a naphthyl group; R ⁵ and R ⁶ together represent a cycloalkyl group having 3 to 6 carbon atoms, and R ⁷ and R ⁸ are each independently substituted with a phenyl group; Represents an alkyl group having 1 to 3 carbon atoms, or R ⁷ and R ⁸ may have one or more substituents selected from alkyl groups having 1 to 3 carbon atoms. Represents an alkylene group of 2 to 4, wherein R ⁹ is a hydrogen atom, an alkyl group having 1 to 6 carbon atoms,
A cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms; having at least one substituent selected from a halogen atom, an alkyl group having 1 to 5 carbon atoms and an alkoxy group having 1 to 5 carbon atoms; A phenyl group or a naphthyl group which may be substituted; at least one substituent selected from a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms and a trialkylsilyl group having 3 to 12 carbon atoms; The compound may have 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom and may have a total number of atoms constituting a ring of 5 to 1
A heterocyclic group of 0; or

[0011]

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(R ¹⁰ and R ¹¹ each independently represent a hydrogen atom, an alkyl group having 1 to 3 carbon atoms and a phenyl group). Further, the asymmetric carbons present in the cyclopropenone derivative represented by the above general formula (I) can each independently be in (R) form, (S) form, or (RS) form. Specific examples of the cyclopropenone derivative represented by the above general formula (I) include compounds shown in Table 1 below when n = 0 and compounds shown in Table 2 below when n = 1. But not limited thereto.

[0013]

[Table 1]

[0014]

[Table 2]

[0015]

[Table 3]

[0016]

[Table 4]

[0017]

[Table 5]

[0018]

[Table 6]

[0019]

[Table 7]

[0020]

[Table 8]

[0021]

[Table 9]

[0022]

[Table 10]

[0023]

[Table 11]

[0024]

[Table 12]

[0025]

[Table 13]

[0026]

[Table 14]

[0027]

[Table 15]

[0028]

[Table 16]

[0029]

[Table 17]

[0030]

[Table 18]

[0031]

[Table 19]

[0032]

[Table 20]

[0033]

[Table 21]

[0034]

[Table 22]

[0035]

[Table 23]

[0036]

[Table 24]

[0037]

[Table 25]

[0038]

[Table 26]

[0039]

[Table 27]

[0040]

[Table 28]

[0041]

[Table 29]

[0042]

[Table 30]

[0043]

[Table 31]

[0044]

[Table 32]

[0045]

[Table 33]

[0046]

[Table 34]

[0047]

[Table 35]

Next, a method for producing the compound of the present invention will be described. The cyclopropenone ketal derivative of the present invention can be produced, for example, by the following method.

[0049]

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(In the above general formula, R¹, R^Two,
R^Three, R^Four, R^Five, R⁶, R⁷, R⁸, R ⁹And n
Is as defined above. ) Known method (Tetrahedron Lette)
rs, 32, 1339, 1991)
Cyclopropyl represented by the above general formula (II)
Lopenone ketal derivative is converted to tetrahydrofuran, diethyl
Dissolved in an ether-based solvent such as
Ethylenediamine, hexamethylphosphoric tria
Auxiliaries such as mido, 1,3-dimethyl-2-imidazolidone
Normal butyl at -40 to -100 ° C in the presence of
Lithium, methyllithium, lithium diisopropyl
Add a strong base such as amide to form a lithio form, and then
By adding an aldehyde derivative represented by the formula (III)
A cyclopropenone ketone represented by the above general formula (I)
Urea derivatives can be obtained. In this reaction
The lithio form of compound (II) produced in
Cerium chloride in tetrahydrofuran, diethyl ether
Suspended in a solvent such as toluene, hexane, etc.
Aldehyde derivative represented by the above general formula (III)
The conductor can also react. In the above general formula (I)
Cyclopropenone ketal derivatives
(Japanese Patent Application No. 4-146024)
Lupine, papain, cathepsin B, cathepsin H, mosquito
Strong inhibition against thiol protease such as tepsin L
Activated cyclopropenone derivatives (Japanese Patent Application No. 4-146)
024).

[0051]

EXAMPLES Hereinafter, the present invention will be described in more detail with reference to Examples, but the present invention is not limited to these Reference Examples and Examples unless it exceeds the gist thereof.

Example 1 2-((2S) -2-tert)
-Butoxycarbonylamino-1-hydroxy-3-methylbutyl) -3-phenylcyclopropenone 2,2
Preparation of -Dimethyl-1,3-propanediyl ketal (Compound No. 65 in Table 1) 2-phenylcyclopropenone 2,2-dimethyl-
Dissolve 3.51 g of 1,3-propanediyl ketal in 30 ml of tetrahydrofuran and add 3.8 g of N, N, N ', N'-tetramethylethylenediamine. The reaction solution is cooled to -78 ° C, 10.5 ml of a 1.55 mol / l n-butyllithium hexane solution is added, and the mixture is stirred for 20 minutes. Next, 8.0 g of cerium chloride heptahydrate was added to 1 mm
Anhydrous cerium chloride prepared by drying at 140 ° C. for 2 hours under reduced pressure of Hg was suspended in 30 ml of tetrahydrofuran, added, stirred for 20 minutes, and then N-te
rt-butoxycarbonyl-L-valinal 1.82 g
Dissolved in 20 ml of tetrahydrofuran and added. -7
After stirring at 8 ° C for 2 hours, 1 ml of water was added to tetrahydrofuran 5
After dissolving in celite, the mixture is added to the reaction solution, the temperature is raised to room temperature, filtered through celite, and the celite is washed well with ethyl acetate. The filtrate was dried over sodium sulfate and filtered.
After concentrating and purifying by silica gel column chromatography (developing solvent: hexane containing 20% ethyl acetate), 2.71 g of the desired product is obtained.

Yield: 72% IR (KBr, cm ^-1 ): 3430, 2960, 185
5,1800, 1710, 1690 NMR (CD ₃ OD, δ): 0.95 to 1.60 (m,
12H), 1.38 (s, 3H), 1.42 (s, 6
H), 1.95-2.15 (m, 1H), 3.60-
3.75 (m, 1H), 3.75 to 3.95 (m, 4
H), 5.0 to 5.10 (m, 1H), 6.03 (d,
J = 10 Hz, 0.33 H), 6.23 (d, J = 10
Hz, 0.67H), 7.40 to 7.65 (m, 3
H), 7.70 to 7.90 (m, 2H) The following compound was produced by the same operation as in Example 1.
The physical properties are described below.

Example 2 Preparation of 2- (2-tert-butoxycarbonylamino-1-hydroxyethyl) cyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 1 in Table 1) NMR ( CDCl ₃ , δ): 0.97 (s, 3H),
1.09 (s, 3H), 1.44 (s, 9H), 3.3
5 to 3.60 (m, 2H), 3.63 (s, 4H),
4.80 to 4.88 (m, 1H), 5.07 to 5.26
(M, 1H), 5.26 to 5.52 (m, 1H), 7.
63 (s, 1H).

Example 3 2-((2S) -2-tert)
-Butoxycarbonylamino-1-hydroxy-3-methylbutyl) cyclopropenone 2,2-dimethyl-
Preparation of 1,3-propanediyl ketal (Compound No. 3 in Table 1) IR (neat, cm ^-1 ): 3380, 1722, 17
08,1690. NMR (CDCl ₃ , δ): 0.87 to 1.10 (m,
12H), 1.43 (s, 7.2H), 1.45 (s,
1.8H), 2.05-2.20 (m, 1H), 3.3
5 to 3.70 (m, 5H), 4.80 to 5.03 (m, 5H)
2H), 7.57 (s, 0.8H), 7.71 (s,
0.2H).

Example 4 2-((2S) -2-tert)
-Butoxycarbonylamino-1-hydroxy-4-methylpentyl) cyclopropenone 2,2-dimethyl-
Production of 1,3-propanediyl ketal (Compound No. 6 in Table 1) IR (neat, cm ^-1 ): 3445, 3360, 17
05. NMR (CDCl ₃ , δ): 0.80 to 0.95 (m,
9H), 1.15 (s, 3H), 1.44 (s, 9
H), 1.55-1.78 (m, 3H), 3.63.
(S, 2H), 3.65 (s, 2H), 3.72-3.
95 (m, 1H), 4.70 to 4.84 (m, 2H),
5.02 to 5.15 (m, 1H), 7.68 (s, 0.
9H), 7.71 (s, 0.1H).

Example 5 2-((2S) -2-tert)
-Butoxycarbonylamino-1-hydroxyhexyl) cyclopropenone Preparation of 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 14 in Table 1) IR (neat, cm ^-1 ): 3460, 3370, 17
00. NMR (CDCl ₃ , δ): 0.85 to 1.0 (m, 3
H), 0.92 (s, 3H), 1.14 (s, 3H),
1.25 to 1.55 (m, 6H), 1.44 (s, 9
H), 3.05-3.15 (m, 0.7H), 3.25.
~ 3.35 (m, 0.3H), 3.61 (s, 2H),
3.63 (s, 2H), 3.65 to 3.85 (m, 0.
7H), 3.85 to 4.05 (m, 0.3H), 4.7.
0 to 4.85 (m, 1H), 4.85 to 4.95 (m,
0.3H), 5.0 to 5.15 (m, 0.7H), 7.
65 (s, 0.7H), 7.72 (s, 0.3H).

Example 6 2-((2S) -2-benzyloxycarbonylamino-1-hydroxyhexyl) cyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 16 in Table 1) Production IR (neat, cm ^-1 ): 3360, 1723. NMR (CDCl ₃ , δ): 0.75 to 0.98 (m,
6H), 1.08 (s, 1.5H), 1.12 (s,
1.5H), 1.18-1.60 (m, 6H), 3.0
4 (s, 0.5H), 3.32 (d, J = 7.8 Hz,
0.5H), 3.55-3.70 (m, 4H), 3.8
0 (m, 0.5H), 4.01 (m, 0.5H), 4.
76 (d, J = 7.8 Hz, 0.5 H), 4.83
(M, 0.5H), 5.11 (s, 2H), 5.13
(M, 0.5H), 5.63 (d, J = 8.1 Hz,
0.5H), 7.65 (s, 0.5H), 7.73
(S, 0.5H).

Example 7 2-((2S) -2-tert)
-Butoxycarbonylamino-1-hydroxyhexyl) -3-methylcyclopropenone Preparation of 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 32 in Table 1) NMR (CDCl ₃ , δ): 0.1. 84 to 0.96 (m,
3H), 0.95 (s, 3H), 1.08 (s, 3
H), 1.28-1.55 (m, 6H), 1.43.
(S, 9H), 2.17 (s, 3H), 3.53-3.
80 (m, 5H), 4.63 to 4.74 (m, 1H),
4.88 to 5.07 (m, 1H).

Example 8 2-((2S) -2-tert)
-Butoxycarbonylamino-1-hydroxy-4-methylpentyl) -3-ethylcyclopropenone 2,2
Preparation of -dimethyl-1,3-propanediyl ketal (Compound No. 34 in Table 1) IR (neat, cm ^-1 ): 3360, 1853, 16
96, 1623. NMR (CDCl ₃ , δ): 0.88 to 1.01 (m,
12H), 1.32 (t, J = 7.7 Hz, 3H),
1.37 to 1.55 (m, 2H), 1.41 (s, 9
H), 1.60-1.78 (m, 1H), 2.69.
(Q, J = 7.7 Hz, 2H), 3.55-3.70
(M, 4H), 3.79-4.02 (m, 1H), 4.
67-4.78 (m, 1H), 4.80-5.03
(M, 1H), 5.16 to 5.22 (m, 1H).

Example 9 2-((2S) -2-tert)
Preparation of -Butoxycarbonylamino-1-hydroxyhexyl) -3-isopentylcyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 41 in Table 1) IR (neat, cm ^-1 ): 3360, 1816, 17
15, 1698. NMR (CDCl ₃ , δ): 0.78 to 0.98 (m,
12H), 1.11 (s, 3H), 1.18 to 1.77.
(M, 9H), 1.43 (s, 9H), 2.53 (d,
J = 7.6 Hz, 2H), 3.56 to 3.80 (m, 5
H), 4.65-4.80 (m, 1H), 4.98-
5.12 (m, 1H).

Embodiment 10 2-((1S, 2S) -2-
Preparation of tert-butoxycarbonylamino-1-hydroxyhexyl) -3-((Z) -1-hexenyl) cyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 53 in Table 1) IR (Neat, cm ^-1 ): 3440, 1785, 17
03. NMR (CDCl ₃ , δ): 0.80 to 0.97 (m,
9H), 1.19 (s, 3H), 1.21-1.80
(M, 10H), 1.43 (s, 9H), 2.35-
2.50 (m, 2H), 2.82 (s, 1H), 3.5
7 to 3.82 (m, 5H), 4.66 to 4.85 (m,
2H), 5.82 to 6.06 (m, 2H).

Example 11 2-[(2S) -2- (N-
Preparation of tert-butoxycarbonyl) methylamino-1-hydroxy-3-methylbutyl] -3-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 74 in Table 1) IR (KBr, cm ^-1 ): 3430, 1798, 168
8,1672. NMR (CD ₃ OD, δ): 0.80 to 1.35 (m,
12H), 1.45 (s, 9H), 2.30 (m, 1
H), 2.69 (s, 1.5H), 2.72 (s, 1.
5H), 3.65 to 3.90 (m, 4H), 4.09
(M, 1H), 5.02 (m, 1H), 7.30-7.
52 (m, 3H), 7.70-7.82 (m, 2H).

Example 12 2-((2S) -2-ter
Preparation of t-butoxycarbonylamino-1-hydroxyhexyl) -3-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 76 in Table 1) IR (KBr, cm ^-1 ): 3310, 1800, 172
0,1792. NMR (CDCl ₃ , δ): 0.80 to 0.98 (m,
3H), 0.99 (s, 3H), 1.21 (s, 3
H), 1.15 to 1.90 (m, 6H), 1.39
(S, 2.7H), 1.43 (s, 6.3H), 3.5
8 (m, 0.7H), 3.68 to 4.95 (m, 4.6
H), 4.95-4.10 (m, 0.7H), 4.88.
-5.07 (m, 1.3H), 5.24 (d, J = 7.
4 Hz, 0.7 H), 7.28 to 7.45 (m, 3
H), 7.69 (d, J = 6.5 Hz, 2H).

Example 13 2- (2-tert-butoxycarbonylamino-1-hydroxy-2-methylpropyl) -3-phenylcyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Table 1) Preparation of Compound No. 82) IR (KBr, cm ^-1 ): 3290, 1800, 167
3. NMR (CDCl ₃ , δ): 0.94 (s, 3H),
1.25 (s, 3H), 1.27 (s, 9H), 1.4
1 (s, 3H), 1.64 (s, 3H), 3.70-
3.90 (m, 4H), 4.77 (d, J = 8.6H)
z, 1H), 4.93 (s, 1H), 5.57 (s, 1
H), 7.28-7.46 (m, 3H), 7.75 (d
d, J = 8.2 Hz, 1.4 Hz, 2H).

Example 14 2-((2S) -2-ter
t-butoxycarbonylamino-1-hydroxy-3-
Preparation of methylbutyl) -3- (4-fluorophenyl) cyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 90 in Table 1) IR (KBr, cm ^-1 ): 3340, 1802 171
0,1695,1602. NMR (CD ₃ OD, δ): 0.90-1.25 (m,
12H), 1.38 (s, 6.3H), 1.42 (s,
2.7H), 2.08 (m, 1H), 3.63 (m, 1
H), 3.70-3.93 (m, 4H), 5.08
(D, J = 4.5 Hz, 0.3 H), 5.02 (d, J
= 4.5 Hz, 0.7H), 6.05 (d, J = 10H)
z, 0.3H), 6.19 (d, J = 10 Hz, 0.7
H), 7.18-7.30 (m, 2H), 7.70-
7.88 (m, 2H).

Example 15 2-((2S) -2-ter
t-butoxycarbonylamino-1-hydroxyhexyl) -3- (2-tolyl) cyclopropenone 2,2-
Preparation of dimethyl-1,3-propanediyl ketal (Compound No. 105 in Table 1) NMR (CDCl ₃ , δ): 0.83 to 1.03 (m,
3H), 0.96 (s, 3H), 1.25 (s, 3
H), 1.25-1.51 (m, 4H), 1.40
(S, 1.8H), 1.43 (s, 7.2H), 1.6
0 to 1.95 (m, 2H), 2.45 (s, 0.6
H), 2.52 (s, 2.4H), 3.65-3.90
(M, 1H), 3.73 (s, 4H), 4.80-5.
20 (m, 2H), 7.05 to 7.30 (m, 3H),
7.55 to 7.65 (m, 1H).

Example 16 2-((2S) -2-ter
Preparation of t-butoxycarbonylamino-1-hydroxyhexyl) -3- (5-trimethylsilyl-2-furyl) cyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 130 in Table 1) NMR (CDCl ₃ , δ): 0.28 (s, 9H),
0.85 to 0.95 (m, 6H), 1.22 (s, 3
H), 1.21-1.85 (m, 15H), 3.65-
4.05 (m, 5H), 4.80 to 5.20 (m, 3
H), 6.70 (d, J = 3.9 Hz, 1H), 6.7.
8 (d, J = 3.9 Hz, 1H).

Example 17 2-((2S) -2-ter
Preparation of t-butoxycarbonylamino-1-hydroxyhexyl) -3- (5-trimethylsilyl-2-thienyl) cyclopropenone 2,2-dimethyl-1,3-propanediyl ketal (Compound No. 139 in Table 1) NMR (CDCl ₃ , δ): 0.34 (s, 9H),
0.84 to 0.97 (m, 6H), 1.24 (s, 3
H), 1.27-1.50 (m, 13H), 1.55-
1.92 (m, 2H), 3.64 to 4.04 (m, 5
H), 4.83-5.30 (m, 2H), 7.21.
(D, J = 3.4 Hz, 1H), 7.38 (d, J =
3.4 Hz, 1H).

Example 18 2-((2S) -2-ter
t-butoxycarbonylamino-1-hydroxy-3-
Methylbutyl) -3- (1-hydroxy-1-methylethyl) cyclopropenone 2,2-dimethyl-1,3-
Preparation of propanediyl ketal (Compound No. 147 in Table 1) NMR (CDCl ₃ , δ): 0.92 to 1.07 (m,
12H), 1.41-1.53 (m, 15H), 1.8.
0 to 2.05 (m, 1H), 3.56 to 3.78 (m,
5H), 4.84 to 4.90 (m, 1H), 5.10
(D, J = 11 Hz, 0.3 H), 5.26 (d, J =
11 Hz, 0.7H), 6.0 (s, 2H).

Example 19 2-((2S) -2-ter
t-butoxycarbonylamino-1-hydroxy-3-
Methylbutyl) -3-[(hydroxy) (phenyl) methyl] cyclopropenone 2,2-dimethyl-1,3-
Preparation of propanediyl ketal (Compound No. 156 in Table 1) NMR (CDCl ₃ , δ): 0.86-1.12 (m,
12H), 1.36 to 1.48 (m, 9H), 1.77.
２．０2.05 (m, 1H), 3.40 to 3.78 (m, 5
H), 4.82 to 4.92 (m, 1H), 5.24 to
5.42 (m, 1H), 5.67 to 5.74 (m, 2
H), 5.98 (s, 1H), 7.25-7.50.
(M, 5H).

Example 20 2-[(2S) -2-((2
S) -2-Benzyloxycarbonylamino-3-methylvalerylamino) -1-hydroxyhexyl] -3-
(4-fluorophenyl) cyclopropenone 2,2-
Preparation of dimethyl-1,3-propanediyl ketal (Compound No. 198 in Table 2) IR (KBr, cm ^-1 ): 3320, 1802,171
0,1660,1602. NMR (CD ₃ OD, δ): 0.70 to 1.18 (m,
15H), 1.18-1.95 (m, 9H), 3.66.
To 3.90 (m, 4H), 4.02 to 4.30 (m, 2
H), 4.95 (m, 1H), 5.02 (s, 2H),
7.10 to 7.40 (m, 7H), 7.40 to 7.60
(M, 1H), 7.70-7.83 (m, 2H).

[0073]

Industrial Applicability The cyclopropenone ketal derivative of the present invention can be used as an intermediate for producing a cyclopropenone derivative having a strong inhibitory activity against thiol proteases such as calpain, papain, cathepsin B, cathepsin H, and cathepsin L. Can be.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ identification code FI C07F 7/10 C07F 7/10 RS (58) Investigated field (Int.Cl. ⁷ , DB name) CA (STN) REGISTRY ( STN)

Claims (2)

(57) [Claims] 1. A compound represented by the following general formula (I)(In the above general formula, R¹Represents an amino-protecting group;
^Two, R^FourAnd R⁶Are each independently a hydrogen atom or charcoal
Represents an alkyl group having a prime number of 1 to 5, or ¹And R
^TwoTogether represent a phthalyl group;^ThreeAnd R^FiveIs
Each independently a hydrogen atom or a C3-10 cycle
Substituted with a cycloalkyl group or an aryl group having 6 to 10 carbon atoms
Represents an optionally substituted alkyl group having 1 to 15 carbon atoms.
Or R^FiveAnd R⁶Together have 3 to 1 carbon atoms
0 represents a cycloalkyl group; ⁷And R⁸Each
And independently has 1 carbon atom which may be substituted with a phenyl group.
Represents an alkyl group of from 5 to 5;⁷And R⁸But one
One or more selected from alkyl groups having 1 to 5 carbon atoms
Alkylene having 2 to 6 carbon atoms which may have the above substituent
May form a R group⁹Is hydrogen atom, carbon number 1
To 15 alkyl groups, cycloalkyl having 3 to 10 carbon atoms
Group, an alkenyl group having 2 to 15 carbon atoms,
Having an aryl group having 6 to 10 carbon atoms and a substituent
An optionally substituted heterocyclic group, or(R^TenAnd R¹¹Are each independently a hydrogen atom and carbon number
An alkyl group having 1 to 15 or an aryl having 6 to 10 carbon atoms
Represents a group or R^TenAnd R¹¹Together have 3 to 1 carbon atoms
Represents a cycloalkyl group of 0. ), And n is 0 or
Or 1 ) Cyclopropenone ketter
Derivatives. 2. R ¹ is a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group, a p-toluenesulfonyl group ,
4,6 tri represents methyl benzenesulfonyl group or trityl group, or represents R ^2, R ⁴ and R ⁶ are each independently a hydrogen atom or an alkyl group having 1 to 3 carbon atoms,
Alternatively, even when R ¹ and R ² together represent a phthalyl group, and R ³ and R ⁵ are each independently substituted with a hydrogen atom or a cycloalkyl group having 3 to 8 carbon atoms, a phenyl group or a naphthyl group. A good alkyl group having 1 to 5 carbon atoms, or R ⁵ and R ^{6 taken} together represent a cycloalkyl group having 3 to 6 carbon atoms, and R ⁷ and R ⁸ are each independently substituted with a phenyl group. Represents an optionally substituted alkyl group having 1 to 3 carbon atoms, or R ⁷ and R
⁸ together represent an alkylene group having 2 to 4 carbon atoms which may have one or more substituents selected from an alkyl group having 1 to 3 carbon atoms, and R ⁹ is a hydrogen atom, An alkyl group having 6 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms; one or more selected from a halogen atom, an alkyl group having 1 to 5 carbon atoms and an alkoxy group having 1 to 5 carbon atoms; A phenyl group or a naphthyl group which may have a substituent; a halogen atom, an alkyl group having 1 to 5 carbon atoms, an alkoxy group having 1 to 5 carbon atoms and 3 to 1 carbon atoms
The total number of atoms constituting a ring having 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, which may have one or more substituents selected from 2 trialkylsilyl groups, 5 to 10 heterocyclic groups; or (R ¹⁰ and R ¹¹ are each independently a hydrogen atom,
Represents an alkyl group and a phenyl group. 2. The cyclopropenone ketal derivative according to claim 1, wherein