JPH07109257A - Elastase inhibitor - Google Patents

Abstract

PURPOSE:To provide a novel-diketone derivative having powerful activity to inhibit elastase activity, thus useful as a therapeutic agent for acute arteritis, pulmonary emphysema, arteriosclerosis, arthrorheumatism, metastasis-infiltration, etc. CONSTITUTION:The elastase inhibitor, a diketone derivative of formula I (R is H, lower alkanoylamino, lower alkyloxycarbonylamino or aralkyloxycarbonylamino; R<1> and R<2> are each lower alkyl; R<3> is 3-6C lower alkyl, cycloalkyl-lower alkyl or aryl-lower alkyl), e.g.,(4S)-4-(N-acetyl-L-leucyl-L- prolyl)amino-1-phenyl-2,3-heptanedione. The compound of the formula I can be obtained, for example, by the following processes: a proline derivative of formula II is condensed with a compound of formula III or an acid-added salt thereof using a peptide condensation agent to produce a compound of formula IV, the dithian is then deprotected into a compound of formula V, which is finally oxidized.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a compound represented by the general formula [I]. Since it strongly inhibits elastase of human leukocytes, it causes acute arteritis, emphysema, arteriosclerosis, rheumatoid arthritis, metastasis / invasion of cancer, etc. It is expected to be used as a therapeutic drug.

[0002]

2. Description of the Related Art Many inhibitors of elastase are known, but most of them are irreversible inhibitors that irreversibly bind to the hydroxyl group of serine at the active center to inactivate them and cannot regenerate the enzyme. Therefore, side effects are a concern. On the other hand, reversible inhibitors include substrate-like aldehydes, ketones, boronic acids, or naturally-occurring elastatinal [Journal of Antibiotics].
Volume 28, 337-339 (1975)] Erasnin [Journal of the American Chemical Society (Journal of the American
an Chemical Society) Volume 101,
4386-4388 (1979)] and the like are known.

[0003]

Although the elastase inhibitor is expected to be useful as a therapeutic drug for the above-mentioned diseases, it has not been used as a drug yet because it solves problems such as pharmacokinetics and side effects. This is because the invention has not been carried out, and the invention of a novel elastase inhibitor having a new structure is important.

[0004]

The present inventors have found that a diketone derivative represented by the following general formula [I] strongly inhibits elastase activity and completed the present invention. That is, according to the present invention, the general formula

[0005]

[Chemical 2] [In the formula, R represents a hydrogen atom, a lower alkanoylamino group, a lower alkyloxycarbonylamino group or an aralkyloxycarbonylamino group, R ¹ and R ² represent the same or different lower alkyl groups, and R ³ represents a carbon number. 3 to 6 lower alkyl groups, cycloalkyl lower alkyl groups or aryl lower alkyl groups are shown. ] The compound or its hydrate represented by these is provided.

Next, the meanings of the abbreviations used in the present specification will be described. THF tetrahydrofuran DMF N, N-dimethylformamide DMSO dimethylsulfoxide DCC N, N′-dicyclohexylcarbodiimide EDCI · HCl 1-ethyl-3-
(3-Dimethylaminopropyl) carbodiimide / hydrochloride HOBT / H ₂ O 1-hydroxy-1
H-benzotriazole monohydrate HOSu N-hydroxysuccinimide DPPA diphenylphosphoryl azide PCC pyridinium chlorochromate PDC pyridinium dichromate Next, definitions of various terms referred to in the description of this specification and specific examples thereof. explain.

As used herein, the term "lower" means 6 or less carbon atoms in the group to which this term is attached, unless otherwise specified.

The lower alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group,
Ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group,
Examples thereof include a pentyl group, an isopentyl group, a neopentyl group, a hexyl group and an isohexyl group.

The lower alkanoylamino group has 1 carbon atom.
~ 7 means an amino group substituted with a linear or branched alkanoyl group, for example, an acetylamino group, a propionylamino group, a butyrylamino group, an isobutyrylamino group, a valerylamino group, an isovalerylamino group, Examples thereof include a hexanoylamino group and an isohexanoylamino group.

The lower alkyloxycarbonylamino group means an amino group substituted with an alkyloxycarbonyl group having a lower alkyl group defined above, and examples thereof include a methyloxycarbonylamino group, an ethyloxycarbonylamino group and isopropyloxy. Carbonylamino group, butyloxycarbonylamino group, isobutyloxycarbonylamino group, sec-butyloxycarbonylamino group, pentyloxycarbonylamino group, isopentyloxycarbonylamino group, neopentyloxycarbonylamino group, hexyloxycarbonylamino group, etc. Is mentioned.

The aralkyloxycarbonylamino group means an amino group substituted with an aralkyloxycarbonyl group having an aralkyl group having 6 to 10 carbon atoms,
Examples thereof include p-methoxybenzyloxycarbonylamino group, p-nitrobenzyloxycarbonylamino group and benzyloxycarbonylamino group.

The cycloalkyl lower alkyl group means the above lower alkyl group substituted with a cycloalkyl group having 3 to 6 carbon atoms, for example, cyclopropylmethyl group, 2
-Cyclopropylethyl group, cyclobutylmethyl group, 2
-Cyclobutylethyl group, cyclopentylmethyl group, 2
-Cyclopentylethyl group, cyclohexylmethyl group,
2-cyclohexylethyl group and the like can be mentioned.

The aryl lower alkyl group has 6 to 6 carbon atoms.
It means a lower alkyl group substituted with 10 aryl groups, and examples thereof include a benzyl group, a phenethyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group, a 1-naphthylethyl group and a 2-naphthylethyl group. .

In order to more specifically disclose the compound of the present invention represented by the general formula [I], various symbols in the general formula [I] will be further described with reference to preferable specific examples.

R represents a hydrogen atom, a lower alkanoylamino group, a lower alkyloxycarbonylamino group or an aralkyloxycarbonylamino group. Specifically, the lower alkanoylamino group is an acetylamino group,
Among them, a propionylamino group and a butyrylamino group are preferred, and an acetylamino group is preferable, and the lower alkyloxycarbonylamino group is a methoxycarbonylamino group, an ethoxycarbonylamino group, a propionyloxycarbonylamino group, a butoxycarbonylamino group, an isobutoxycarbonyl group. Amino group, sec-butoxycarbonylamino group, tert-butoxycarbonylamino group, pentyloxycarbonylamino group, isopentyloxycarbonylamino group and the like can be mentioned. Among them, tert-butoxycarbonylamino group is preferable, and the aralkyloxycarbonylamino group. As p-
Examples thereof include a methoxybenzyloxycarbonylamino group, a p-nitrobenzyloxycarbonylamino group, and a benzyloxycarbonylamino group, and among them, a benzyloxycarbonylamino group is preferable.

R ¹ represents a lower alkyl group, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-group.
Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms such as a butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, and an isohexyl group, and among them, a methyl group, a butyl group, an isobutyl group, sec. -Butyl group is preferred.

R ² represents a lower alkyl group, specifically, methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-group.
Examples thereof include a linear or branched alkyl group having 1 to 6 carbon atoms such as a butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, and an isohexyl group, and among them, a methyl group, a propyl group, an isopropyl group, and a butyl group. A group and an isobutyl group are preferred.

R ³ represents a lower alkyl group having 3 to 6 carbon atoms, a cycloalkyl lower alkyl group or an aryl lower alkyl group, and specific examples of the lower alkyl group having 3 to 6 carbon atoms include propyl group and isopropyl group. Group, a butyl group, an isobutyl group, a sec-butyl group, a tert-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, an isohexyl group, and other linear or branched alkyl groups, among which a butyl group is mentioned. , Isobutyl group and sec-butyl group are preferred.

As the cycloalkyl lower alkyl group,
Examples thereof include a cyclopropylmethyl group, a 2-cyclopropylethyl group, a cyclobutylmethyl group, a 2-cyclobutylethyl group, a cyclopentylmethyl group, a 2-cyclopentylethyl group, a cyclohexylmethyl group, and a 2-cyclohexylethyl group, and among them, preferable. Examples thereof include a cyclohexylmethyl group and a 2-cyclohexylethyl group.

Examples of the aryl lower alkyl group include a benzyl group, a phenethyl group, a 1-naphthylmethyl group, a 1-naphthylethyl group, a 2-naphthylmethyl group and a 2-naphthylethyl group. Among them, a benzyl group is preferable. Examples include a phenethyl group.

More specific examples include the following compounds. 1. (4S) -4- (N-acetyl-L-leucyl-L
-Prolyl) amino-1-phenyl-2,3-heptanedione 1. (4S) -4- (N-isohexanoyl-L-prolyl) amino-1-phenyl-2,3-heptanedione 3. (4S) -4- (N-acetyl-L-leucyl-L
-Prolyl) amino-1-phenyl-2,3-pentanedione 4. (4S) -4- (N-benzyloxycarbonyl-
L-leucyl-L-prolyl) amino-1-cyclohexyl-2,3-heptanedione 5. (5S) -5- (N-benzyloxycarbonyl-
L-leucyl-L-prolyl) amino-1-cyclohexyl-3,4-octanedione 6. (4S) -4- (N-benzyloxycarbonyl-
L-leucyl-L-prolyl) amino-1-phenyl-
2,3-heptanedione 7. (4S) -4- (N-acetyl-L-alanyl-L
-Prolyl) amino-1-phenyl-2,3-heptanedione 8. (4S) -4- (N-acetyl-L-alanyl-L
-Prolyl) amino-5-methyl-1-phenyl-2,
3-hexanedione 9. (4S) -4- (N-acetyl-L-alanyl-L
-Prolyl) amino-1-cyclohexyl-5-methyl-2,3-hexanedione 10. (5S) -5- (N-acetyl-L-alanyl-
L-prolyl) amino-1-cyclohexyl-6-methyl-3,4-heptanedione 11. (4S) -4- (N-acetyl-L-leucyl-
L-prolyl) amino-5-methyl-1-phenyl-
2,3-hexanedione 12. (4S) -4- (N-benzyloxycarbonyl-L-alanyl-L-prolyl) amino-5-methyl-
1-phenyl-2,3-hexanedione 13. (3S) -3- (N-benzyloxycarbonyl-L-alanyl-L-prolyl) amino-2-methyl-
4,5-octanedione 14. (3S) -3- (N-benzyloxycarbonyl-L-alanyl-L-prolyl) amino-2-methyl-
4,5-nonanedione 15. (4S) -4- (N-tert-butoxycarbonyl-L-alanyl-L-prolyl) amino-1-cyclohexyl-5-methyl-2,3-hexanedione 16. 17. (3S) -3- (N-tert-butoxycarbonyl-L-leucyl-L-prolyl) amino-2-methyl-4,5-octanedione and 17. (6S) -6- (N-benzyloxycarbonyl-L-leucyl-L-prolyl) amino-2-methyl-
4,5-nonanedione and the like can be mentioned. Of these, compounds 1, 4, 5, 6 and the like are preferable, and 4 and 6 are particularly preferable.

The compound of the general formula [I] of the present invention is produced by the following production method 1 or 2. [Production method 1] General formula

[0023]

[Chemical 3] In the presence of a base, if necessary, a proline derivative represented by

[0024]

[Chemical 4] Or, by condensation with an acid addition salt thereof, a general formula

[0025]

[Chemical 5] To manufacture.

Then, dithiane is deprotected to give a general formula

[0027]

[Chemical 6] It can be produced by converting into

The definitions of R, R ¹ , R ² and R ³ are as described above.

In the condensation of the compound of the general formula [II] and the compound of the general formula [III] in the above production method 1, an inorganic base or an organic base can be used as a base, if necessary, but it is preferable. Organic bases such as triethylamine, piperidine, diisopropylamine, N-methylmorpholine and the like can be mentioned, and DM is used as a solvent.
F, THF, 1,4-dioxane, methylene chloride, chloroform and the like can be mentioned, and as the peptide condensing agent, 1 to 2
Equivalent amounts of DCC, EDCI · HCl, DPPA and the like can be mentioned, and auxiliary agents such as HOBT · H ₂ O and HOSu can be used if necessary. The reaction temperature is -50 ° C.
~ 50 ° C, preferably -15 ° C to 30 ° C, and the reaction time is 30 minutes to 2 days.

As the deprotecting agent for dithiane represented by the general formula [IV], 1 to 5 equivalents of N-bromosuccinimide, cerium ammonium nitrate, thallium ammonium nitrate, mercuric chloride and the like can be mentioned. The reaction solvent is acetone. ,
Acetonitrile, hydrous acetone, hydrous acetonitrile and the like can be mentioned.

Oxidation of compound [V] to compound [I] is 1
-3 equivalents of chromic acid derivatives such as PCC and PDC, pyridine-sulfur trioxide complex-triethylamine, swarm acidation procedure, and comburum oxidation procedure using DMSO. [Production method 2] General formula

[0032]

[Chemical 7] Of the aminoaldehyde derivative [VI] of the general formula

[0033]

[Chemical 8] Of the cyanohydrin derivative of

[0034]

[Chemical 9] To produce a compound of

Then, the compound [VIII] is reacted with a Grignard reagent of the general formula R ³ MgX ¹ [IX] (wherein X ¹ represents a halogen atom) to give a compound of the general formula

[0036]

[Chemical 10] To produce a compound of

P ¹ and P ² are deprotected in the usual way to give the general formula

[0038]

[Chemical 11] To obtain the amino alcohol derivative of.

Compound [XI] was prepared by the same general formula as in Production Example 1 above.

[0040]

[Chemical 12] [I] is produced by condensing and oxidizing the proline derivative of.

Here, P ¹ represents a protecting group for amino group,
P ² represents a hydroxyl-protecting group, X ¹ represents a halogen atom, and R, R ¹ , R ² and R ³ are defined as above.

Next, a method for producing the raw material compounds used in the production method 1 and the production method 2 will be described.

When R is H, the starting compound, proline derivative [II], used in the production method 1 is obtained by acylating proline with a corresponding acylating agent. When R is a lower alkanoylamino group or aralkyloxycarbonylamino group, the usual peptide condensation conditions, that is, active ester method, azide method, mixed acid anhydride method, carbodiimide method, imidazole method, DPPA method,
It can be obtained by condensing the corresponding N-substituted amino acid with proline or proline in which a carboxylic acid is protected by the Woodward method or a condensation method using a redox system, and deprotecting as necessary.

The dithiane derivative [III] has the formula

[0045]

[Chemical 13] Of the compound of the general formula R ³ X ² [XIII] (wherein X ² represents a leaving group), and the compound of the general formula

[0046]

[Chemical 14] Compound of formula [XIV] in the presence of n-butyl lithium

[0047]

[Chemical 15] Of N-protected amino aldehyde of the general formula

[0048]

[Chemical 16] And a protecting group is removed by a general amine deprotection method.

In the raw materials used in Production Method 2, the compound [VI
I] is a known cyanohydrin production method, for example, compound VI
To 1 to 5 equivalents of sodium sulfite and 1 to 5 equivalents of sodium cyanide in a mixed solvent of water and ethyl acetate at 0 to 50 ° C., preferably 15 to 30 ° C. for 30 minutes to 2 days You can get it.

The definitions of R ² , R ³ , P ¹ and P ² are as described above.

The protecting group P ¹ for the amino group is, for example, t
A lower alkoxycarbonyl group such as an ert-butoxycarbonyl group, or an ordinary one such as an arylmethoxycarbonyl group such as a benzyloxycarbonyl group can be used. As the protective group for the hydroxyl group, for example, a lower alkylsilyl group such as a trimethylsilyl group or a tert-butyldimethylsilyl group, or an ordinary one such as an arylmethyl group such as a benzyl group can be used. Also,
As the protecting group for carboxylic acid, for example, a lower alkyl group such as methyl group, ethyl group and the like, an ordinary lower alkyl group such as benzyl group and the like can be used.

As the leaving group, a usual one such as a halogen atom, a methanesulfonyloxy group or a p-toluenesulfonyloxy group can be used.

Elastase Inhibitory Activity The inhibitory activity against human leukocyte elastase is DMSO.
1 μl each of the compound of the present invention dissolved in DMSO and DMSO as a control were added at a concentration of 40 μM N-methoxysuccinyl-L
-Alanyl-L-alanyl-L-prolyl-L-valine 0.2 M Tris buffer (pH 8.5) solution 250 containing 4-methylcoumaryl-7-amide and 1 M sodium chloride solution
After each pre-incubation at 37 ° C. for 3 minutes, 50 μL of 0.2 μg / ml concentration of human leukocyte elastase 0.2 M Tris buffer solution (pH 8.5) was added.
After adding 1 and incubating at 37 ° C for 20 minutes, 2M
The reaction was stopped by adding 1 ml of an aqueous acetic acid solution, and the fluorescence of the supernatant was measured to obtain the value. As a result, Compound 6 was 0.78 μM, Compound 4
Is 6.32 μM, compound 1 is 8.48 μM and compound 5
Showed an IC ₅₀ value of 9.94 μM.

As described above, the compound of the present invention has an excellent inhibitory effect on elastase, is useful in the field of pharmaceuticals, and can be a therapeutic drug for acute arteritis, emphysema, arteriosclerosis, inflammation and the like. When used as a therapeutic agent for such diseases,
The compounds of the present invention can be used alone or in combination with other therapeutic agents.

The compound of the present invention can be mixed with a solid or liquid excipient carrier known in the art and used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration. Examples of the pharmaceutical preparation include liquid preparations such as injections, inhalants, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories. In addition, these preparations may optionally contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants.
Examples of the additive include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate or talc.

The dose of the compound of the present invention as an elastase inhibitor varies depending on the administration method, the age and weight of the patient, the condition of the patient to be treated and the like, but a typical administration method for adults is oral administration. Or parenteral administration, 0.1 to 100 m per day for oral administration to adult patients
g / Kg body weight, and is 0.1 per day for parenteral administration.
01 to 10 mg / Kg body weight.

Next, the present invention will be specifically described with reference to examples. However, the present invention is not limited to the examples.

[0058]

【Example】

Example 1 Production process of (4S) -4- (N-acetyl-L-leucyl-L-prolyl) amino-1-phenyl-2,3-heptanedione (Compound 1) 1. (4S) -4-tert-butoxycarbonyl
Amino-3-hydroxy-1-phenyl-2-heptano
Preparation of trimethylene dithioacetal 2-benzyl-1,3-dithiane 612 mg was added to anhydrous TH
F was dissolved in 3 ml, and 0.7 ml of n-butyllithium (1.6M n-hexane solution) was added at -78 ° C-1.
The mixture was stirred at 5 ° C for 40 minutes. Known Method [Chemical Pharmaceutical Burchin (Chem. Phar
m. Bull. ) 30, p. 1921-1924 (19
82)], a solution of 556.7 mg of N-tert-butoxycarbonylnorvalinal in 3 ml of THF was added, and the mixture was stirred for 15 hours. 20 ml of a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted 3 times with 20 ml of ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure, and the obtained residue was subjected to silica gel column chromatography (Wako-gel ^™ C-200 20 g, chloroform) to concentrate the fraction containing the target substance. , And silica gel column chromatography (Wako-ge)
l ^TM C-200 10 g, hexane-ethyl acetate
8: 1) to give the title compound (102.4 mg).

FABMS [M + H] ⁺ = 412 Step 2. (4S) -4- (N-acetyl-L-leucyl
-L-prolyl) amino-3-hydroxy-1-phenyl
Of ru-2-heptanone trimethylene dithioacetal
191.9 mg of the compound obtained in Production Step 1 was added to 2 m of methylene chloride.
It was dissolved in 1 l, 0.5 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness, 115 mg of N-acetyl-L-leucyl-L-proline was added, and the mixture was dissolved in 4 ml of anhydrous DMF. DPPA 91 μl
And 118 μl of triethylamine were added at −15 ° C. and stirred overnight, 40 ml of ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, and the organic layer was dried and concentrated. The obtained residue is subjected to silica gel column chromatography (Wako-gel ^™
C-200 15 g, chloroform-methanol =
The fraction containing the desired compound was concentrated to dryness by subjecting the mixture to 100: 1 and then 50: 1) to obtain 188.3 mg of the title compound.

FABMS [M + H] ⁺ = 564 step 3.2-[(2S) -2- (N-acetyl-L-ro)
Isyl-L-prolyl) aminovaleryl] -2-benzi
108.5 mg of the compound obtained in the production step 2 of ru-1,3-dithiane was added to anhydrous DMSO.
It was dissolved in 1.2 ml, 0.8 ml of acetic anhydride was added, and the mixture was stirred at room temperature overnight. 40 ml of ethyl acetate was added to the reaction solution,
After washing with saturated aqueous sodium hydrogen carbonate solution and saturated saline,
The organic layer was dried and concentrated. The obtained residue was subjected to silica gel column chromatography (Wako-gel ^™ C-20.
0 10 g, chloroform-methanol = 200: 1
Then, the fraction containing the desired compound was concentrated to dryness by subjecting to 100: 1) to obtain 72.6 mg of the title compound.

FABMS [M + H] ⁺ = 562 step 4. (4S) -4- (N-acetyl-L-leucyl
-L-prolyl) amino-1-phenyl-2,3-pen
62.8 mg of the compound obtained in the production step 3 of tandione was dissolved in 0.5 ml of 97% hydrous acetone to give N-bromosuccinimide 159.
A 1.3 ml solution of 97% water-containing acetone in 1.3 ml was added at 0 ° C., and the mixture was stirred for 30 seconds. A saturated aqueous solution of sodium sulfite was added, and the mixture was partitioned with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate, water, and then saturated saline. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (Wako-gel ^™ C-200 5 g, chloroform-methanol = 200: 1 and then 100:
The fraction containing the desired product in 1) was concentrated to dryness to give the title compound 1
Obtained 2.2 mg.

FABMS [M + H]⁺= 472 Example 2 (4S) -4- (N-benzyloxycarbonyl-L-
Leucyl-L-prolyl) amino-1-cyclohexyl
-Production of 2,3-heptanedione (Compound 4) Step 1. (4S) -4-tert-butoxycarbonyl
Amino-1-cyclohexyl-3-hydroxy-2-he
Synthesis of Ptanone Trimethylenedithioacetal 2-Cyclohexylmethyl-1,3-dithiane 393.
Dissolve 7 mg in anhydrous THF 2 ml and n- at -78 ° C.
Butyllithium (1.59M pentane solution) 1.2ml
Was added and stirred at -15 ° C for 1 hour. N-tert-bu
Toxylcarbonyl norvalinal 201.3 mg TH
The F2 ml solution was added and stirred for 24 hours. Saturated salt in the reaction solution
Add 20 ml of ammonium chloride aqueous solution and add 20 ml of ethyl acetate.
Extract 3 times with ml. The organic layer is washed with saturated saline and dried.
Dried and concentrated under reduced pressure, and the resulting residue is purified by silica gel column chromatography.
Tography (Wako-gel)^TM C-200 20
g, chloroform) and concentrate the fractions containing the desired product.
And then silica gel column chromatography (Wa
ko-gel^TM C-200 10g, hexane-vinegar
82.6 mg of the title compound was obtained by adding ethyl acetate (8: 1).
It was

FABMS [M + H] ⁺ = 418 Step 2. (4S) -4- (N-benzyloxycarbonyl)
L-L-leucyl-L-prolyl) amino-1-cyclo
Hexyl-3-hydroxy-2-heptanone-2,2-
Bis- (1,3- dithiopropyl ) ketal 494 mg of the compound obtained in the above step was added to 3 ml of methylene chloride.
, 1.0 ml of trifluoroacetic acid was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and then anhydrous DMF
It was dissolved in 7 ml and 165 μl of triethylamine was added. This solution was mixed with N-benzyloxycarbonyl-L-leucyl-L-proline 391.7 mg and DPPA 25.
0 μl and 118 μl triethylamine were added to anhydrous DMF.
The solution dissolved in 3 ml was added at −15 ° C. and stirred overnight.
40 ml of ethyl acetate was added to the reaction solution, which was washed with 1N hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution and saturated saline, and then the organic layer was dried and concentrated. The obtained residue was subjected to silica gel column chromatography (Wako-gel ^™ C-20.
0.15 g, chloroform-methanol = 100: 1 and then 50: 1), and the fraction containing the target compound was concentrated to dryness to obtain 289 mg of the title compound.

FABMS [M + H] ⁺ = 662 Step 3. (4S) -4- (N-benzyloxycarbonyl)
L-L-leucyl-L-prolyl) amino-1-cyclo
21.9 mg of the compound obtained in the production step 3 of hexyl-3-hydroxy-2-heptanone was dissolved in 0.5 ml of 97% water-containing acetone to give N-bromosuccinimide 47 m.
g of 97% hydrous acetone 1.0 ml solution was added at 0 ° C.
Stir for 0 minutes. A 10% aqueous sodium sulfite solution was added, the mixture was extracted with ethyl acetate, and the organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water, and then saturated brine. The organic layer was dried and concentrated, and the residue was subjected to silica gel column chromatography (Wako-gel ^™ C-200 5 g, chloroform-methanol = 200: 1 and then 100: 1).
The fraction containing the desired product was concentrated to dryness, and the title compound 12.
2 mg was obtained.

FABMS [M + H]⁺= 572Step 4. (4S) -4- (N-benzyloxycarbonyl)
L-L-leucyl-L-prolyl) amino-1-cyclo
Production of hexyl-2,3-heptanedione  Oxalyl chloride (15 μl) was added to anhydrous methylene chloride 0.3
Dissolve in ml and add 25 μl of DMSO at −78 ° C. 1
Stir for 0 minutes. The compound 45.2 obtained in Step 3 was added to the reaction solution.
A solution of 1.0 mg of anhydrous methylene chloride in 1.0 ml was added, and -78
The mixture was stirred at 40 ° C for 40 minutes and at -20 ° C for 50 minutes. -7
After cooling to 8 ° C. again, 37 μl of triethylamine was added.
After stirring for 25 minutes, the mixture is stirred at -20 ° C for 30 minutes.
I stirred. Add 30 ml of ethyl acetate to the reaction mixture and add 1N hydrochloric acid.
After washing with water, the organic layer is washed with water and saturated aqueous sodium hydrogen carbonate solution.
Then, the extract was washed with saturated brine, dried and concentrated. The obtained residue
Silica gel column chromatography (Wako-g
el^TM C-200 3g, chloroform-methano
-L = 100: 1 and then 50: 1)
The fractions were concentrated to dryness to give 23.2 mg of the title compound.

FABMS [M + H] ⁺ = 570 Example 3 (3S) -3- (N-benzyloxycarbonyl-L-
Alanyl-L-prolyl) amino-2-methyl-4,5
-Synthetic Step of Octanedione (Compound 13) 1. (3S) -3-tert-butoxycarbonyl
Production of amino-2-hydroxyhexanenitrile 1.29 g of N-tert-butoxycarbonyl-L-valinal was dissolved in 6 ml of ethyl acetate, 668 mg of sodium sulfite was dissolved in 5 ml of water, and the mixture was stirred overnight at room temperature. After further diluting with 20 ml of ethyl acetate,
A solution of 315 mg of sodium cyanide in 8 ml of water was added dropwise over 2 hours, and after completion of the dropwise addition, the mixture was stirred overnight at room temperature.
40 ml of ethyl acetate was added to the reaction solution, the organic layer was washed with water and then with a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was dried and concentrated. The obtained residue was subjected to silica gel column chromatography (Wako-gel ^™ C-200 20).
g, hexane-ethyl acetate = 5: 1) and the fraction containing the desired product was concentrated to dryness to obtain 643 mg of the title compound.

FABMS [M + H] ⁺ = 229 Step 2. (3S) -3-tert-butoxycarbonyl
Amino-2-tert-butyldimethylsiloxyhexa
1.15 g of the compound obtained in Step 1 of producing nitrile was converted into 16 ml of methylene chloride.
, Triethylamine 1.02 ml, tert-
Butyldimethylchlorosilane (1.26 g) and dimethylaminopyridine (383 mg) were added, and the mixture was stirred at room temperature for 2 days. 300 ml of ethyl acetate was added to the reaction solution, 1N hydrochloric acid,
The organic layer was dried and concentrated after washing with water, a saturated aqueous solution of sodium hydrogencarbonate, water and then saturated saline. The obtained residue is subjected to silica gel column chromatography (Wako-gel).
^TMC -200 20 g, hexane-ethyl acetate =
The fraction containing the desired compound was concentrated to dryness by 5: 1) to obtain 1.07 g of the title compound.

FABMS [M + H] ⁺ = 343 Step 3. (3S) -3-tert-butoxycarbonyl
Amino-4-tert-butyldimethylsiloxy-2-
Compound 431.8 mg obtained in the production step 2 of methyl-5-octanone was added to anhydrous THF 5
Dissolve the propylmagnesium bromide (0.
(95M THF solution) (8 ml) was added, and the mixture was stirred at room temperature overnight. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with 30 ml of ethyl acetate, the organic layer was washed with saturated brine, dried and concentrated under reduced pressure, and the resulting residue was subjected to silica gel column chromatography (Wako-gel ^™ C-2002).
The fraction containing the desired product was concentrated to dryness to give 244 mg of the title compound.

FABMS [M + H] ⁺ = 388 Step 4. (3S) -3-tert-butoxycarbonyl
Amino-4-hydroxy-2-methyl-5-octanone
Preparation of 175.8 mg of the compound obtained in Step 3 above was treated with anhydrous TH
After dissolving in 1 ml of F, 1 ml of tetra-n-butylammonium fluoride (1N-THF solution) was added, and the mixture was stirred at 0 ° C. for 1 hour. 40 ml of ethyl acetate was added to the reaction solution,
The extract was washed with saturated brine, dried and concentrated, and the obtained residue was purified by silica gel column chromatography (Wako-gel ^™).
C-200 20 g, hexane-ethyl acetate = 5:
The fraction containing the desired product in 1) was concentrated to dryness to give the title compound 9
9.7 mg was obtained.

FABMS [M + H] ⁺ = 274 Step 5. (3S) -3- (N-benzyloxycarbonyl)
L-L-alanyl-L-prolyl) amino-4-hydro
Production of xy-2-methyl-5-octanone 99.7 mg of the compound obtained in Step 4 above was dissolved in 2 ml of a 4N hydrochloric acid dioxane solution, and the mixture was stirred at room temperature for 1 hour.
The reaction mixture was concentrated to dryness, the residue was dissolved in 2 ml of anhydrous DMF, and N-benzyloxycarbonyl-L-leucyl-L-proline 126 mg and triethylamine 1 were dissolved at -15 ° C.
00 μl and DPPA 90 μl were added, and the mixture was stirred at room temperature overnight. Add 30 ml of ethyl acetate to the reaction mixture and add 1N.
After washing with hydrochloric acid, the organic layer was washed with water and then with saturated brine, dried and concentrated. The obtained residue was subjected to silica gel column chromatography (Wako-gel ^™ C-200 10).
g, chloroform-methanol = 100: 1, 50:
The fraction containing the desired compound was concentrated to dryness to give 40 mg of the title compound.

FABMS [M + H]⁺= 476Step 6. (3S) -3- (N-benzyloxycarbonyl)
L-L-alanyl-L-prolyl) amino-2-methyl
4,5-octanedione (Compound 17 )Manufacturing of 8 μl of oxalyl chloride was added to 0.2 m of anhydrous methylene chloride.
Dissolve in 1 l, add 13 μl of DMSO at -78 ° C and add 2
Stir for 0 minutes. Compound 19.0 obtained in Step 5 was added to the reaction solution.
0.5 mg of anhydrous methylene chloride in 0.5 ml was added, and -15
Stirred at 1.5 ° C. for 1.5 hours. Triethylamine 25 μl
Was added at -78 ° C, and the mixture was stirred at -15 ° C for 20 minutes. Anti
After adding 30 ml of ethyl acetate to the reaction solution, washing with 1N hydrochloric acid,
The organic layer was washed with water and then saturated brine, dried and concentrated. Profit
The resulting residue is subjected to silica gel column chromatography (W
ako-gel^TM C-200 3g, chloroform
Mu-methanol = 100: 1 and then 50: 1)
The fraction containing the target compound was concentrated to dryness to obtain 8.6 mg of the compound.

FABMS [M + H] ⁺ = 474 The compounds of Examples 4 to 10 were prepared in the same manner as in Example 1. Example 4 (4S) -4- (N-isohexanoyl-L-prolyl) amino-1-phenyl-2,3-heptanedione (Compound 2) FABMS [M + H] ⁺ = 415 Example 5 (4S)- 4- (N-acetyl-L-leucyl-L-prolyl) amino-1-phenyl-2,3-pentanedione (Compound 3) FABMS [M + H] ⁺ = 444 Example 6 (4S) -4- (N- Benzyloxycarbonyl-L-
Leucyl-L-prolyl) amino-1-phenyl-2,
3-Heptanedione (Compound 6) FABMS [M + H] ⁺ = 564 Example 7 (4S) -4- (N-acetyl-L-alanyl-L-prolyl) amino-1-phenyl-2,3-heptanedione ( Compound 7) FABMS [M + H] ⁺ = 430 Example 8 (4S) -4- (N-acetyl-L-alanyl-L-prolyl) amino-5-methyl-1-phenyl-2,3-
Hexanedione (Compound 8) FABMS [M + H] ⁺ = 430 Example 9 (4S) -4- (N-acetyl-L-leucyl-L-prolyl) amino-5-methyl-1-phenyl-2,3-
Hexanedione (Compound 11) FABMS [M + H] ⁺ = 472 Example 10 (4S) -4- (N-benzyloxycarbonyl-L-)
Alanyl-L-prolyl) amino-5-methyl-1-phenyl-2,3-hexanedione (Compound 12) FABMS [M + H] ⁺ = 522 The compounds of Examples 11 to 14 were prepared in the same manner as in Example 2. did. Example 11 (5S) -5- (N-Benzyloxycarbonyl-L-leucyl-L-prolyl) amino-1-cyclohexyl-3,4-octanedione (Compound 5) FABMS [M + H] ⁺ = 584 Example 12 (4S) -4- (N-acetyl-L-alanyl-L-prolyl) amino-1-cyclohexyl-5-methyl-
2,3-Hexanedione (Compound 9) FABMS [M + H] ⁺ = 436 Example 13 (5S) -5- (N-acetyl-L-alanyl-L-prolyl) amino-1-cyclohexyl-6-methyl-
3,4-Heptanedione (Compound 10) FABMS [M + H] ⁺ = 450 Example 14 (4S) -4- (N-tert-butoxycarbonyl-
L-alanyl-L-prolyl) amino-1-cyclohexyl-5-methyl-2,3-hexanedione (Compound 1
5) FABMS [M + H] ⁺ = 494 The compounds of Examples 15 to 17 were prepared in the same manner as in Example 3. Example 15 (3S) -3- (N-benzyloxycarbonyl-L-
Alanyl-L-prolyl) amino-2-methyl-4,5
-Nonanedione (Compound 14) FABMS [M + H] ⁺ = 488 Example 16 (3S) -3- (N-tert-butoxycarbonyl-
L-leucyl-L-prolyl) amino-2-methyl-
4,5-Octanedione (Compound 16) FABMS [M + H] ⁺ = 482 Example 17 (6S) -6- (N-benzyloxycarbonyl-L-
Leucyl-L-prolyl) amino-2-methyl-4,5
-Nonanedione (Compound 20) FABMS [M + H] ⁺ = 530

[0073]

The compounds of the present invention strongly inhibit the elastase of human leukocytes, and are expected to be used as therapeutic agents for acute arteritis, emphysema, arteriosclerosis, rheumatoid arthritis, metastasis / invasion of cancer, etc.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/40 ACD AED 9454-4C 38/55 ABG ADU (72) Inventor Morishima Tsukuba Tsukuba City, Ibaraki Prefecture Okubo No. 3 Banyu Pharmaceutical Co., Ltd. in Tsukuba Research Institute (72) Inventor Kyozo Naito Tsukuba City, Ibaraki Prefecture Okubo No. 3 Banyu Pharmaceutical Co., Ltd. in Tsukuba Research Institute (72) Inventor Yu Okuyama No. 3 Okubo, Tsukuba City, Ibaraki Pref. Tsukuba Research Institute, Inc.

Claims (5)

[Claims] 1. A general formula: [In the formula, R represents a hydrogen atom, a lower alkanoylamino group, a lower alkyloxycarbonylamino group or an aralkyloxycarbonylamino group, R ¹ and R ² represent the same or different lower alkyl groups, and R ³ represents a carbon number. 3 to 6 lower alkyl groups, cycloalkyl lower alkyl groups or aryl lower alkyl groups are shown. ] The compound or its hydrate represented by these. 2. The compound according to claim 1, wherein R ³ is a cycloalkyl lower alkyl group or an aryl lower alkyl group, or a hydrate thereof. 3. The compound according to claim 1, wherein R ³ is a cycloalkyl lower alkyl group, or a hydrate thereof. 4. The compound according to claim 1, wherein R ³ is an aryl lower alkyl group, or a hydrate thereof. 5. (4S) -4- (N-acetyl-L-leucyl-L-prolyl) amino-1-phenyl-2,3-
Heptanedione, (4S) -4- (N-isohexanoyl-L-prolyl) amino-1-phenyl-2,3-heptanedione, (4S) -4- (N-acetyl-L-leucyl-L- Prolyl) amino-1-phenyl-2,3
-Pentanedione, (4S) -4- (N-benzyloxycarbonyl-L-leucyl-L-prolyl) amino-
1-cyclohexyl-2,3-heptanedione, (5
S) -5- (N-benzyloxycarbonyl-L-leucyl-L-prolyl) amino-1-cyclohexyl-
3,4-octanedione, (4S) -4- (N-benzyloxycarbonyl-L-leucyl-L-prolyl) amino-1-phenyl-2,3-heptanedione, (4
S) -4- (N-Acetyl-L-alanyl-L-prolyl) amino-1-phenyl-2,3-heptanedione,
(4S) -4- (N-Acetyl-L-alanyl-L-prolyl) amino-5-methyl-1-phenyl-2,3-
Hexanedione, (4S) -4- (N-acetyl-L-
Alanyl-L-prolyl) amino-1-cyclohexyl-5-methyl-2,3-hexanedione, (5S) -5
-(N-Acetyl-L-alanyl-L-prolyl) amino-1-cyclohexyl-6-methyl-3,4-heptanedione, (4S) -4- (N-acetyl-L-leucyl-L-prolyl) Amino-5-methyl-1-phenyl-2,3-hexanedione, (4S) -4- (N-benzyloxycarbonyl-L-alanyl-L-prolyl)
Amino-5-methyl-1-phenyl-2,3-hexanedione (3S) -3- (N-benzyloxycarbonyl-L-alanyl-L-prolyl) amino-2-methyl-
4,5-octanedione, (3S) -3- (N-benzyloxycarbonyl-L-alanyl-L-prolyl) amino-2-methyl-4,5-nonanedione, (4S)-
4- (N-tert-butoxycarbonyl-L-alanyl-L-prolyl) amino-1-cyclohexyl-5-
Methyl-2,3-hexanedione, (3S) -3- (N
-Tert-butoxycarbonyl-L-leucyl-L-
Prolyl) amino-2-methyl-4,5-octanedione or (6S) -6- (N-benzyloxycarbonyl-L-leucyl-L-prolyl) amino-2-methyl-4,5-nonanedione. Item 1. The compound according to Item 1.