JP2002138048A - Medicine comprising heyerocyclic compound - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a medicine comprising a new compound which has an excellent human neutrophil elastase inhibiting action and is useful as a medicament for preventing or treating various disorders, particularly acute pneumonopathy. SOLUTION: This medicine comprises a heterocyclic compound expressed by formula (1) (wherein, A and B are the same of different and each a lower alkylene which may be replaced with an oxo; D is a mononucleated heterocycle in which an oxo, or the like, is substituted; R1 and R2 are the same or different and each a lower alkyl; and R3 is 2-benzoxazolyl, trifluoromethyl, benzylaminocarbonyl, or the like), or an ester or physiologically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a novel heterocyclic compound having a human neutrophil elastase inhibitory activity, a medicament comprising an ester or a physiologically acceptable salt thereof, and a pharmaceutical composition.

[0002]

BACKGROUND OF THE INVENTION Human neutrophil elastase (hereinafter sometimes simply referred to as elastase) is a serine protease released in large amounts from neutrophil granules that appear during infections and inflammatory diseases. Is a kind of Elastase is an enzyme that degrades proteins such as elastin, collagen, proteoglycan, and fibronectin, which constitute stroma of in vivo connective tissues such as lung, cartilage, vascular wall, and skin. It is also being shown to act on other proteins and cells.

In vivo, elastase is an endogenous inhibitor protein α ₁ -protease inhibitor, α ₂
-Maintains the homeostasis of the living body while its action is controlled by macroglobulin, secretory leukocyte protease inhibitor and the like. However, if the balance between elastase and endogenous inhibitors is impaired due to excessive release of elastase or a decrease in inhibitor level in the inflamed area, control of elastase action is lost, and tissue is damaged.

[0004] Diseases that have been suggested to be involved in the pathogenesis of elastase include, for example, emphysema, adult respiratory distress syndrome (ARDS), idiopathic pulmonary fibrosis (IIP), cystic pulmonary fibrosis, chronic interstitial pneumonia , Chronic bronchitis, chronic respiratory tract infection, diffuse panbronchiolitis, bronchiectasis, asthma, pancreatitis, nephritis, liver failure, rheumatoid arthritis, arthrosclerosis, osteoarthritis, psoriasis, periodontitis, atherosclerosis Sclerosis, rejection in organ transplantation, premature rupture, bullous disease, shock,
Sepsis, systemic lupus erythematosus (SLE), Crohn's disease, disseminated intravascular coagulation (DIC), tissue damage during ischemia-reperfusion, formation of corneal scar tissue, myelitis and the like are known.

[0005] Therefore, elastase inhibitors are expected to be useful as therapeutic or preventive agents for these diseases. Under such expectations, various elastase inhibitors have been reported.

For example, European Patent Publication No. 189305
(Hereinafter sometimes referred to as Ref. 1) has the following general formula (A
-1), which describes that this compound is useful as an elastase inhibitor.

[0007]

Embedded image Wherein R ¹ is lower alkyl containing 1 to 5 carbon atoms,
R ² is lower alkyl containing 1 to 10 carbon atoms, R ⁴ is hydrogen atom, A is —CO—, n is 0, 1 or 2.]

The above formula also includes compounds of the following formula:

Embedded image R ³ in the above formula (A-2) includes various substituents, but does not include a specific substituent in a compound according to the present invention described later.

[0009] Further, European Patent Publication No. 291234 is disclosed.
(Hereinafter sometimes referred to as Ref. 2) has the following general formula (B−
The compound represented by 1) is described, and it is described that the compound has a leukocyte elastase inhibitory action.

[0010]

Embedded image Wherein Q is an orthophenylene group which may have a substituent such as halogen, X is an oxygen atom or a sulfur atom,
A represents -CO-, etc., L represents phenylene, (C1-C6) alkanediyl, etc., and R ⁴ represents acylsulfonamide, etc.]

Further, the following compound (a) is described in Example 2 (63) of US Pat. No. 5,017,610 (hereinafter sometimes referred to as Ref. 3). The chemical structure of this compound (a) is completely different from the compound of the present invention described later. However, this compound (a) is notable for being most developed as a water-soluble elastase inhibitor.

[0012]

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[0013]

The present invention provides the following general formula:
The present invention relates to a novel heterocyclic compound represented by (I) and having a strong elastase inhibitory activity, a drug comprising an ester thereof or a physiologically acceptable salt thereof, and a pharmaceutical composition.

[0014]

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Wherein A and B are the same or different and are a lower alkylene group which may be substituted with oxo, D is a monocyclic heterocyclic group represented by the following formula,

Embedded image

(Where D ¹ is a methylene group or an ethylene group, these groups may be substituted by oxo, and the ring G further comprises a nitrogen atom, an oxygen atom and / or
Or a 5- to 14-membered monocyclic saturated or unsaturated heterocyclic group which may have another hetero atom selected from a sulfur atom, wherein the heterocyclic group is substituted with a substituent T ¹ May be

Wherein T ¹ is (i) an oxo group, (ii) a substituted or unsubstituted lower alkyl group, (iii) a substituted or unsubstituted amino group, (iv) a substituted or unsubstituted carbamoyl group, (v) a carboxyl group Or a lower alkoxycarbonyl group, (vi) a halogen, a phenyl group optionally substituted with lower alkoxy or lower alkyl, and (vii) a substituted or unsubstituted lower alkylcarbonyl group, Group),

R ¹ and R ² are the same or different lower alkyl groups, and R ³ has the following formula:

[0019]

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(Where X ¹ and X ² are halogen atoms, Y ¹ is a hydrogen atom, a halogen atom, a lower alkoxycarbonyl group, a lower alkylaminocarbonyl group, an aralkylaminocarbonyl group, an aralkyloxycarbonyl group, a lower alkyl A carbonyl group or an aralkylcarbonyl group, or a group represented by the following formula:

[0021]

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[0022] (wherein, U is an oxygen atom or a sulfur atom, Q is a vinylene group or T ² with an optionally substituted ortho-phenylene group wherein T ² are optionally substituted by halogen Lower alkyl group, lower alkoxy group, lower alkylsulfonyl group, lower alkylcarbonyloxy group and 1 to 3 groups selected from amino groups optionally substituted with lower alkyl), n is 0,
1 or 2, and m is an integer of 0 to 5).

Hereinafter, the compound (I) according to the present invention will be further described. The compound represented by the general formula (I)
(Hereinafter also referred to as ketone bodies) has an excellent elastase inhibitory action and is useful as a medicine. The partial structure represented by HOOC-ADB- in formula (I) greatly contributes to the development of such excellent properties of compound (I) according to the present invention. In this part, it is also clearly distinguished from the known compounds described above.

Therefore, the first feature of the chemical structure of the compound (I) according to the present invention is that it has the specific partial structure. The second feature of the chemical structure of the compound (I) according to the present invention resides in the combination of the specific partial structure and the remaining structure.

Next, the definition of each substituent will be described.
The term "lower", unless stated otherwise, means that the radical to which it is assigned contains 1 to 5, preferably 1 to 4, carbon atoms. Thus, a "lower alkyl group"
It means a linear or branched hydrocarbon having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl and the like. “Lower alkylene group” means a group in which one hydrogen atom is removed from the lower alkyl. The “lower alkoxy group” is a lower alkyloxy group in which the lower alkyl moiety has the above-mentioned meaning, and examples include methoxy, ethoxy, and butoxy.

The "lower alkylene group optionally substituted with oxo" defined for A and B is, for example, a lower alkylene group such as methylene, ethylene, propylene and -CH ₂ CO-. Group and -COC
Lower alkylene group substituted by such oxo malonyl group, and the like represented by H ₂ CO-, methylene is preferable.

D in the general formula (I) is defined as described above, and will be further described. D is the aforementioned monocyclic heterocyclic group, a nitrogen atom which is a hetero atom in the ring,
The number of oxygen atoms or sulfur atoms is 3 or less. The size of the ring is not particularly limited, but is usually a 4- to 9-membered ring, preferably a 5- or 6-membered ring. This heterocyclic group may be saturated or unsaturated.

Among the substituents T ¹ on the ring G, the substituted lower alkyl group includes an amino group, a lower alkylamino group, a carboxyl group, a phenyl group or a phenylamino group.
(These phenyl may be substituted with a halogen atom, a lower alkoxy group or a lower alkyl group) and a lower alkyl group having one or more substituents selected from lower alkylcarbonyl groups; a substituted amino group As an amino group substituted by one or two selected from a lower alkyl group, a phenyl group (which may be substituted with a halogen atom, a lower alkoxy group or a lower alkyl group) and a lower alkylcarbonyl group; Examples of the group include one or two substituents selected from a lower alkyl group, a phenyl group (which may be substituted with a halogen atom, a lower alkoxy group or a lower alkyl group) and a lower alkylcarbonyl group on the amino group. Having a carbamoyl group; as a substituted lower alkylcarbonyl group, One or more substituents selected from an amino group, a lower alkylamino group, a carboxyl group, a phenyl group (which may be substituted with a halogen atom, a lower alkoxy group or a lower alkyl group) and a lower alkylcarbonyl group; And a lower alkylcarbonyl group.

Preferred examples of the substituent T ¹ on the ring G include an oxo group, a lower alkyl group, an amino lower alkyl group, a mono- or di-lower alkylamino lower alkyl group, a phenyl lower alkyl group and a phenylamino lower alkyl group. A carboxy lower alkyl group, an amino group, a mono- or di-lower alkylamino group, a phenylamino group, a phenyl group, a lower alkylphenyl group, a carboxyl group,
A carbamoyl group; a mono- or di-lower alkylcarbamoyl group; In addition, the phenyl mentioned here may be substituted with halogen, lower alkoxy or lower alkyl.

Preferred examples of the group represented by -ADB- include a group represented by the following formula.

[0031]

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(Wherein A ¹ is a methylene group or —CH ₂ C
O-, wherein B ¹ is a methylene group or -C
OCH ₂ —, wherein D ² and D ³ are the same or different and are a vinylene group optionally substituted by lower alkyl, or a methylene group optionally substituted by oxo or lower alkyl And D ¹ is the same as described above. However, unless D ² and D ³ are both vinylene groups which may be substituted with lower alkyl)

Next, specific examples of the group represented by HOOC-ADB- will be described. Among these, (1) to (6), especially
(1) or (2) is preferred.

[0034]

Embedded image

As an example of a "lower alkyl group" defined for R ¹ and R ² , isopropyl is most preferred;
Other examples include methyl, ethyl, propyl, butyl, sec-butyl, tert-butyl, 2-methylbutyl and the like. The carbon atom to which R ¹ and R ² are bonded is an asymmetric carbon.

R ³ may be any of the groups included in the above [Chemical formula 14] or [Chemical formula 15],
More specifically, a lower alkylcarbonyl group such as n-butylcarbonyl; an aralkylcarbonyl group such as benzylcarbonyl; a lower alkoxycarbonyl group such as methoxycarbonyl or n-propyloxycarbonyl; an aralkyloxycarbonyl group such as benzyloxycarbonyl; a lower alkylcarbonyldifluoromethyl group such as n-propylcarbonyldifluoromethyl; an aralkylcarbonyldifluoromethyl group such as benzylcarbonyldifluoromethyl; a lower alkyloxycarbonyldifluoromethyl group such as n-propyloxycarbonyldifluoromethyl; An aralkyloxycarbonyldifluoromethyl group such as n-propylaminocarbonyldifluoromethyl; Alkylaminocarbonyldifluoromethyl group; aralkylaminocarbonyldifluoromethyl group such as benzylaminocarbonyldifluoromethyl; lower alkylaminocarbonyl group such as n-propylaminocarbonyl; aralkylaminocarbonyl group such as benzylaminocarbonyl; trifluoromethyl and monochloromethyl And a substituted or unsubstituted monocyclic or bicyclic heterocyclic group containing a nitrogen atom and an oxygen atom or a sulfur atom such as benzoxazolyl which may be substituted. Particularly preferred R ³ is a trifluoromethyl group, a benzoxazolyl group or a benzylaminocarbonyl group.

From the viewpoint of the degree of elastase inhibitory activity and solubility in an aqueous solvent, the compound according to the present invention, which is more preferable as an elastase inhibitor, is a compound represented by the following general formula (Ia): It is a pharmaceutically acceptable salt.

[0038]

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[Wherein A¹, B¹, D¹, D^Two, D^Threeand
R^ThreeIs the same as above. Where D ^TwoAnd D^ThreeGato
Also a vinylene group optionally substituted by lower alkyl
(Except in some cases)

Among the compounds included in the general formula (Ia), the following compounds or their physiologically acceptable salts are preferred. Above all, compound 1 and compound 2 and their physiologically acceptable salts are particularly preferred.

Compound 1: 2- (3-carboxymethyl-
2-oxo-1-imidazolidinyl) acetyl-L-valyl-N-[(1S) -3,3,3-trifluoro-1-isopropyl-2-oxopropyl] -L-prolinamide

Compound 2: 2- (3-carboxymethyl-
2,4-dioxo-1-pyrimidinyl) acetyl-L-valyl-N-[(1S) -2- (2-benzoxazolyl)-
1-isopropyl-2-oxoethyl] -L-prolinamide

Compound 3: 2- (4-carboxymethyl-
2,3-dioxo-1-piperazinyl) acetyl-L-valyl-N-[(1S) -2- (2-benzoxazolyl)-
1-isopropyl-2-oxoethyl] -L-prolinamide

Compound 4: 2- (3-carboxymethyl-
2,4-dioxo-1-pyrimidinyl) acetyl-L-valyl-N-[(1S) -3-benzylamino-1-isopropyl-2,3-dioxopropyl] -L-prolinamide

Compound 5: 2- (4-carboxymethyl-
2,5-dioxo-1-piperazinyl) acetyl-L-valyl-N-[(1S) -2- (2-benzoxazolyl)-
1-isopropyl-2-oxoethyl] -L-prolinamide

Compound 6: 2- (3-carboxymethyl-
2,5-dioxo-1-imidazolidinyl) acetyl-L
-Valyl-N-[(1S) -3,3,3-trifluoro-1
-Isopropyl-2-oxopropyl] -L-prolinamide

Compound 7: [[4- (2-carboxyacetyl) -1-piperazinyl] malonyl] -L-valyl-N-
[(1S) -2- (2-benzoxazolyl) -1-isopropyl-2-oxoethyl] -L-prolinamide

In addition, the compounds included in the compound (I) according to the present invention include those specifically described in Test Examples and Production Examples described later.

The ester of the compound (I) according to the present invention may include any of those having a known ester residue, but includes lower alkyl esters such as methyl ester, ethyl ester, propyl ester and tert-butyl ester; A lower alkoxy lower alkyl ester such as methyl ester; an aralkyloxy lower alkyl ester such as benzyloxy methyl ester; a benzyl ester; one heteroatom such as pyridyl methyl ester, 2-morpholinyl methyl ester, or 3-furyl methyl ester; A lower alkyl ester substituted with a saturated or unsaturated 5- or 6-membered monovalent monocyclic group which may contain two; a halogen atom, lower alkyl, lower alkoxy, nitro, lower alkylamino or / and lower Alkoxyka And phenyl esters which may be substituted with rubonyl.

The salt of compound (I) according to the present invention is not particularly restricted but includes, for example, salts with organic bases such as trimethylamine, triethylamine and N-methylmorpholine; and inorganic metals such as sodium and potassium. And salts thereof. Some of the compounds (I) form acid addition salts. Such acid addition salts include tartaric acid, fumaric acid, acetic acid, lactic acid,
Succinic acid, methanesulfonic acid, maleic acid, malonic acid,
Examples thereof include salts with organic acids such as amino acids such as gluconic acid and aspartic acid, and salts with inorganic acids such as hydrochloric acid and phosphoric acid.

Compound (I) sometimes exists as a hydrate or solvate. Compound (I) exists as an optically active substance, a stereoisomer or a mixture thereof.

Next, the inhibitory action of the compound according to the present invention on human neutrophil elastase will be described with reference to test examples.

Test Example 1 Human neutrophil elastase inhibitory activity
Sex This test was to test the inhibitory activity of compound (I) on human neutrophil elastase in vitro.

1.9 M sodium chloride, 0.38% polyethylene glycol 6000 and 0.0019% Brij-35
1.9 in HEPES (133 mM, pH 7.5) buffer containing
A solution in which m units / ml human neutrophil elastase (Sigma) was dissolved was prepared. 210 μl of this solution and 40 μl of a solution of the test compound (10 ⁻⁸ to 10 ⁻⁵ M) are mixed and mixed at 37 ° C. for 6 hours.
Play incubation for minutes. To this was added 50 μl of 4 mM succinyl-alanyl-prolyl-alanyl-4-methylcoumaryl-7-amide (substrate solution, Peptide Institute) and 100 μl of distilled water, and the mixture was further reacted at 37 ° C. for 20 minutes. -Amino-4-methylcoumarin concentration was determined by the fluorescence intensity (excitation wavelength 380 nm, fluorescence wavelength 460 n
m) was measured. The “Brij-35” means polyoxyethylene (23) lauryl ether, and HEPE
S is N- (2-hydroxyethyl) piperazine-N ′-(2
-Ethanesulfonic acid).

The elastase inhibitory activity (inhibition rate) was calculated based on the following formula, and a 50% inhibitory concentration (IC ₅₀ value) was calculated from a concentration-inhibition rate curve of the test compound. First result
It is shown in the table. In the following formula, A means the fluorescence intensity when the test compound is added, and B means the fluorescence intensity when the test compound is not added.

[0056]

(Equation 1)

[0057]

[Table 1]

[0058]

[Table 2]

[0059]

[Table 3]

As shown in Table 1, 50% inhibitory concentration of the compounds according to the present invention on human neutrophil elastase
(IC ₅₀ ) was less than 0.082 μM, some of which were almost equivalent to the control compound (a). As already mentioned, the control compound (a) was prepared according to US Pat. No. 5,017,610.
This is a human neutrophil elastase inhibitor currently under development, which is described in Example 2 (63) of the Japanese Patent Publication No. 2000-216, and has a compound code known as “ONO-5046”.

The inhibitory activity (IC ₅₀ ) of the compound according to the present invention on human neutrophilic elastase was much stronger than the control compound (b) shown in Table 1.
The control compound (b) is novel, but is not included in the general formula (Ia) in that it has no group represented by HOOC-A-.

Test Example 2 Human Neutrophil Elastase-Induced Lung
Inhibition of bleeding; Intrabronchial administration of human neutrophil elastase to hamsters induces bleeding in the lungs. Hemoglobin is detected in the bronchoalveolar lavage fluid obtained by translucentally lavaging the lungs after a certain period of elastase administration. In this experiment, the hemoglobin concentration was measured to examine the extent to which the compound according to the present invention suppressed this bleeding. Hamsters (Syrian strain, 8-10 weeks old male) were divided into the following three groups (5 animals per group), and the following treatment was performed for each group.

(A) Vehicle-administered control group (non-treated group): 0.2 ml of physiological saline was administered into the bronchus of hamsters, and 1 hour later, the alveoli were intratracheally administered with 2.5 ml of physiological saline. The hemoglobin concentration in 12.5 ml of the alveolar lavage fluid (4
Absorbance at 14 nm) was measured. The measured value was A.

(B) Human Neutrophil Elastase Administration Group (Test
Compound non-administration group): 25 units of human neutrophil elastase
0.2m of physiological saline with (Elastin Products) dissolved
l was administered into the bronchi of hamsters to induce pulmonary hemorrhage. One hour after the administration of elastase, the hemoglobin concentration in the alveolar lavage fluid was measured in the same manner as in (A). The measured value was B.

(C) Human Neutrophil Elastase Administration Group (Test
Compound administration group): phosphate buffered saline in hamster
A predetermined amount of a test compound dissolved in (pH 7.4) was administered by the method described below, and human neutrophil elastase was administered by the same method as described above. And one hour later
The hemoglobin concentration in the alveolar lavage fluid was measured in the same manner as in (A). The measured value was C.

Administration of test compound : The test compound was administered to hamsters in two different ways. One method is to rapidly administer a solution containing the test compound 5 minutes before elastase administration (Intravenous bolus-administratio).
n) and another method is to use 10% of elastase administration.
Intravenous infusion of the test compound-containing solution for 70 minutes from the beginning of the test. Bleeding control rate
(%) Was calculated according to the following equation (average of 5 cases). In the equation,
A, B and C have the above-mentioned meaning, and the experimental results are shown in Table 2.

[0067]

(Equation 2)

[0068]

[Table 4]

As shown in Table 2, the compounds according to the present invention exhibited much better inhibitory effects on human neutrophil human elastase-induced pulmonary hemorrhage than the control compound (a).

Test Example 3 Acute toxicity test in mice:
The test compound was dissolved in phosphate buffered saline (pH 7.4) and administered to the tail vein of 7-week-old male Std: ddy mice (6 mice per group). After 24 hours, life and death were determined, and the results shown in Table 3 below were obtained.

[0071]

[Table 5]

Test Example 4 Solubility in Aqueous Solution: The solubility of the compound according to the present invention in an aqueous solvent was measured, and the results shown in Table 4 were obtained. The pH values in Table 4 are values obtained when the compounds are dissolved in distilled water.

[0073]

[Table 6]

As shown in Table 4, the solubility of the compound according to the present invention in an aqueous solvent was 100 mg / ml or more, which was superior to the control compound (a).

From the results of the above test examples, the compounds according to the present invention are excellent water-soluble elastase inhibitors and are useful as therapeutic agents for various diseases, especially acute lung diseases.

The dose of the compound according to the present invention varies depending on the administration method, symptoms, age, etc., but is usually about 2 to 5000 mg, preferably about 10 to 2000 mg, particularly preferably 30 to 2000 mg per 60 kg of body weight per day. 1500 mg. The administration route may be oral administration, but parenteral administration,
Intravenous administration is particularly recommended.

The compounds according to the invention are generally administered in the form of a formulation. These preparations can be prepared by mixing the compound (I) with a preparation carrier.
For example, as a pharmaceutical carrier in a liquid preparation for parenteral administration, water, a solvent such as physiological saline is an essential component,
In addition, auxiliary components such as isotonic agents, soothing agents, pH adjusters, buffers, and preservatives are appropriately added.

A liquid preparation such as an injection can be prepared by dissolving the compound (I) in a solvent such as physiological saline for injection, and, if desired, before or after dissolution, and blending other auxiliary components. Lyophilized formulations can be prepared by lyophilizing such solutions and redissolving them upon administration.

Next, a method for producing the compound (I) according to the present invention will be described. The structure of compound (I) according to the present invention is a tripeptide derivative in which one proline has two amino acids bonded to both ends. Thus, compound (I)
It can be produced mainly by an amidation reaction. More specifically, compound (I) is produced according to [Reaction Scheme 1] described below.

In Reaction Scheme 1, any carboxyl-protecting group R can be easily removed without adversely affecting the desired main reaction and without destroying other partial structures when desired. Good. Carboxyl protecting group R
Are classified into two types by their desorption means. One of the desorption means is an acid / base decomposition method, and the other is a hydrogenolysis method. Examples of the carboxyl protecting group which is eliminated by the acid / base decomposition method include methyl, ethyl, tert-butyl,
Examples include trityl, methoxymethyl, benzyl, phenyl, phenacyl and the like, and examples of the carboxyl protecting group which is eliminated by hydrogenolysis include benzyl, trityl and benzyloxymethyl. W in [Reaction formula 1] is a hydroxyl group or a halogen atom, X ³ is a halogen atom, and other symbols are the same as described above.

[0081]

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In the above [Reaction Scheme 1], Step 1 comprises:
In this step, the known compounds (II) and (III) are reacted to form a compound (IV). This process involves sodium hydride and lithium
The reaction can be carried out by mixing and stirring both starting compounds in a solvent such as anhydrous dimethylformamide in the presence of a base such as tert-butoxy. This step is performed at 0 to 45 ° C for 0.5 to 20 hours.

Step 2 is a step of reacting compound (IV) produced in step 1 with compound (V) to give compound (VI).
This step can be performed in the same manner as in step 1. Here, the carboxyl protecting group R in compound (V)
May be the same as that in compound (IV),
Different ones are preferred. For example, when one is an acid / base decomposable group such as tert-butyl, the other is a hydrogen decomposable group such as benzyl.

The compound (VI) thus obtained is used as a starting material in Step 3. Step 3 comprises removing the carboxyl-protecting group R on the side to which B is bonded in the compound (VI) to obtain a compound (VII) in which W is a hydroxyl group, and converting this to a halogen atom or the like as necessary. Can be implemented.

The acid-base decomposition reaction, which is one of the methods for removing the carboxyl protecting group R, is carried out at a temperature of -30 to 100 ° C., preferably 0 ° C. to room temperature, in a solvent using the compound (VI) and an acid or base. It can be carried out by contact. Here, the acid includes trifluoroacetic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, acetic acid and the like, and the base includes sodium hydroxide and sodium carbonate. Examples of the solvent include water, ethanol, methylene chloride, ethyl acetate, tetrahydrofuran, benzene, toluene or a mixture thereof.

The elimination of the carboxyl protecting group R by hydrogenolysis can be advantageously carried out by treating compound (VI) with hydrogen gas in a solvent in the presence of a catalyst. Examples of the catalyst include platinum, palladium, and Raney nickel, and examples of the solvent include ethyl acetate and ethanol. This hydrogenolysis reaction is carried out at about 60 ° C. or lower, usually at room temperature.

The elimination of the carboxyl protecting group results in W
Is a hydroxyl group, it is easy to convert this hydroxyl group to another active group or a halogen atom if desired.

The compound (VII) thus obtained is used as a starting material in Step 4. Step 4 comprises compound (VII) and compound
This is a step of producing a compound (IX) by bonding the compound (VIII) with an amide bond. That is, this step can be performed according to a conventional method for peptide production. For example, this step 4 can be carried out by mixing and stirring the compound (VII) and the compound (VIII) in the presence or absence of a base such as triethylamine, in the absence of a solvent, or in a solvent such as methylene chloride or dimethylformamide. . When W in compound (VII) is a hydroxyl group, this step 4 comprises 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide, N, N′-dicyclohexylcarbodiimide, 1,1′-carbonyldiimidazole, carbonate Advantageously, it is carried out in the presence of a condensing agent such as N, N'-disuccinimidyl. Further, when W is a hydroxyl group, this step is to react compound (VII) with ethyl chloroformate in the presence of a tertiary amine such as triethylamine or N-methylmorpholine, preferably N-methylmorpholine, Subsequently, the reaction may be carried out by reacting compound (VIII).

Most of the compounds (VIII) are known, and those which are not known are described, for example, in Production Examples 6 and 7 below.
Or a method analogous thereto.

The compound (IX) thus obtained (hereinafter OH)
Is also new and is used in the next step 5 as a direct source of compound (I) (ketone body) useful as an elastase inhibitor. Step 5 is a compound (I)
Is a step of oxidizing the hydroxyl group of the carboxylic acid and then optionally removing the carboxyl protecting group by the method described above. The oxidation reaction in this step is methylene chloride, dimethylformamide,
It can be carried out by reacting compound (IX) with an oxidizing agent in a solvent such as tetrahydrofuran, ethyl acetate or toluene.

Examples of the oxidizing agent include Dess-Martin reagent, which is an iodobenzene derivative. Further, oxidation with phosphorus pentoxide in the presence of dimethyl sulfoxide, and oxidation with phosphorus pentoxide in the presence of dimethyl sulfoxide.
- ethyl-3- (3-dimethylaminopropyl) oxidation with a combination of oxidation or Oki monkeys chloride and triethylamine by carbodiimide -Cl ₂ CHCOOH
(Swan: Swern oxidation) is also a promising method.

When free amino groups or carboxyl groups are present in the D portion or the like throughout the entire process, these groups may be protected with ordinary protecting groups as necessary, and the protecting groups may be protected in desired steps. Desorption is recommended.

When the thus obtained compound (I) is an ester, it is optionally converted to a carboxylic acid, and when the compound (I) is a carboxylic acid, it is optionally converted to an ester or converted to a salt. Can be. Also,
When the compounds according to the present invention are various isomers, these can be separated by a conventional method.

[0094]

Production Examples Next, the present invention will be described in more detail with reference to Production Examples and Preparation Examples of compound (I) according to the present invention.

In the following, abbreviations having the following meanings may be used. t-Bu: tert-butyl group, Bn: benzyl group, LSIMS: liquid secondary ion mass spectrometry, ¹ H-NMR: proton nuclear magnetic resonance spectroscopy, A
PCIMS (or APCI-MS): Atmospheric pressure chemical ionization mass spectrometry, IR: Infrared spectroscopy

Production Example 1 Production of Compound (VI-1) (Step 1)
And 2):

[0097]

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To 10 ml of anhydrous dimethylformamide containing 0.30 g of 2-oxoimidazolidine and 1.50 g of tert-butyl bromoacetate, 0.60 g of lithium tert-butoxide was added under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes, and then stirred at room temperature. For 1 hour. The reaction solution was poured into ice, and the precipitated crystals were washed with water and dried by blowing. The crude crystals were recrystallized from ethyl acetate to obtain the desired 0.86 g of 1,3-bis (t
(ert-butoxycarbonylmethyl) -2-oxoimidazolidin was obtained as white crystals.

Melting point 100-102 ° C. LSIMS (m / z):
315 [(M + H) ⁺ ]. ¹ H-NMR (300 MHz, CDC
l ₃ , δ): 1.46 (18H, s), 3.54 (4H, s), 3.89 (4H, s)

Production Example 2: Production of compound (VI-2) (Step 1)
And 2): Step 1: Preparation of compound (IV):

[0101]

Embedded image

To 10 ml of anhydrous dimethylformamide solution containing 1.0 g of 2,4-dioxopyrimidine was added 2.5 g of benzyl bromoacetate and 2.5 g of potassium carbonate, and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the precipitated crystals were washed with diethyl ether to obtain the desired 1-benzyloxycarbonylmethyl-2,4-dioxopyrimidine (1.4 g) as colorless crystals.

Melting point 192-194 ° C. LSIMS (m / z):
261 [(M + H) ⁺ ]. ¹ H-NMR (300 MHz, d ₆ -D
MSO, δ): 4.59 (2H, s), 5.20 (2H, s), 5.62 (1H,
d), 7.37 (5H, m), 7.65 (1H, d), 11.4 (1H, s)

Step 2: Preparation of compound (VI-2):

[0105]

Embedded image

To 10 ml of anhydrous dimethylformamide containing 1.0 g of the compound obtained in the previous step, 0.18 g of sodium hydride (purity: 60%) was gradually added under ice-cooling, and then 1 ml under ice-cooling.
Stir for 5 minutes. Then tert-butyl bromoacetate 0.9
After stirring at room temperature for 1 hour, saturated aqueous ammonium chloride was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The extract was washed with saturated saline and dried over anhydrous magnesium sulfate.
The solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography [solvent: n-hexane-ethyl acetate (2:
1)] to give 1.2 g of the desired 1-benzyloxycarbonylmethyl-3-tert-butoxycarbonylmethyl-2,4-dioxopyrimidine as a colorless oil.

LSIMS (m / z): 375 [(M + H) ⁺ ]. ¹
H-NMR (300 MHz, CDCl ₃ , δ): 1.46 (9H,
s), 4.51 (2H, s), 4.58 (2H, s), 5.21 (2H, s), 5.81
(1H, d), 7.10 (1H, d), 7.36 (5H, m)

Production Example 3: Production of Compound (VII-1) (Step)
3):

[0109]

Embedded image

1.14 g of 1,3-bis (t) obtained in Production Example 1
(ert-butoxycarbonylmethyl) -2-oxoimidazolidine containing ethanol and water in an equal volume of 20 ml
0.22 g of potassium hydroxide was added to the mixture, and the mixture was stirred at 70 ° C. for 5 hours. After ethanol was distilled off under reduced pressure, a saturated aqueous solution of sodium hydrogen carbonate was added to the residue, and the aqueous layer was washed with ethyl acetate. Next, the aqueous layer was made acidic with 10% hydrochloric acid, and extracted with ethyl acetate. After the extract was dried over magnesium sulfate, the solvent was distilled off under reduced pressure, and the precipitated crystals were recrystallized from ethyl acetate to give the desired 2-[(3-tert-butoxycarbonylmethyl) -2-oxo-1-imidazolidinyl. ] Acetic acid
30 g were obtained as colorless crystals.

Melting point: 112-113 ° C. LSIMS (m /
z): 259 [(M + H) ⁺ ]. ¹ H-NMR (300 MHz, C
DCl ₃ , δ): 1.46 (9H, s), 3.53 (4H, s), 3.89 (2H,
s), 4.01 (2H, s), 7.11 (1H, br s)

Production Example 4: Production of Compound (VII-2) (Step)
3):

[0113]

Embedded image

1-benzyloxycarbonylmethyl-3- (tert-butoxycarbonylmethyl)-obtained in Production Example 2
Ethyl acetate 2 containing 1.2 g of 2,4-dioxopyrimidine
50 mg of 20% palladium hydroxide was added to 0 ml, and the mixture was stirred at room temperature for 1 hour under a hydrogen stream. After filtering off the catalyst, the filtrate was concentrated under reduced pressure to obtain 0.7 g (colorless powder) of the desired 2- (3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl) acetic acid.

¹ H-NMR (300 MHz, CDCl ₃ ,
δ): 1.46 (9H, s), 4.51 (2H, s), 4.59 (2H, s), 5.86
(1H, d), 7.17 (1H, d)

Production Example 5 Production of Compound (VII) (Step 3):
The compound (VI) obtained in the same manner as in Production Example 1 or Production Example 2 was treated in the same manner as in Production Example 3 or Production Example 4 to obtain a compound (VII) shown in Table 5 below.

[0117]

[Table 7]

[0118]

[Table 8]

Production Example 6: Production of compound (VIII-1): (1) Production of benzylamino compound (benzylamination):

[0120]

Embedded image

A suspension consisting of 1.2 g of lithium aluminum hydride and 200 ml of tetrahydrofuran was stirred under reflux for 1.5 hours. After the reaction solution was cooled to room temperature, 17.3 g of benzylamine was added dropwise. Then (3S) -3
-Benzyloxycarbonylamino-2-hydroxy-
150 ml of tetrahydrofuran containing 10 g of ethyl 4-methylbutyrate was added dropwise, and the mixture was stirred at room temperature for 12 hours. After carefully adding water to the reaction solution, the mixture was extracted with ethyl acetate. After the extract was dried over magnesium sulfate and the solvent was distilled off under reduced pressure, the residue was purified by silica gel column chromatography [solvent: n-hexane-ethyl acetate (1: 1)] to obtain the desired (1S) -3-. Benzylamino-1-benzyloxycarbonylamino-1-isopropyl-2
9.2 g of -hydroxy-3-oxopropane were obtained as a colorless oil.

LSIMS (m / z): 371 [(M + H) ⁺ ]. ¹ H
_{-NMR (300MHz, CDCl 3, δ} ): 0.96 (3H, d),
1.02 (3H, d), 2.23 (1H, m), 3.47 (1H, br t), 4.23-
4.55 (4H, m), 5.01 (2H, s), 5.19 (1H, m), 5.59 (1
H, m), 7.06-7.44 (10H, m)

(2) Production of raw OH form (deletion of amino protecting group)
Release):

[0124]

Embedded image

A catalytic amount of 20% palladium hydroxide was added to 200 ml of ethanol containing 9.2 g of the compound obtained in the previous step.
Hydrogenolysis was performed at room temperature. After removing the catalyst by filtration, the filtrate was concentrated under reduced pressure to obtain 5.9 g of the desired (1S) -1-amino-3-benzylamino-1-isopropyl-2-hydroxy-3-oxopropane as a colorless oil. Was. This product was subjected to the next reaction without purification.

(3) Compound (VIII) having an amino group protected
Production (amidation)

[0127]

Embedded image

N- (benzyloxycarbonyl)-was added to 200 ml of methylene chloride containing 5.9 g of the compound obtained in the preceding step.
9.7 g of L-valyl-L-proline and 1-ethyl-3
5.3 g of-(3-dimethylaminopropyl) carbodiimide hydrochloride was added, and the mixture was stirred at room temperature for 12 hours and then concentrated at room temperature under reduced pressure. Ethyl acetate was added to the residue, and the mixture was washed with 1 mol / liter hydrochloric acid, water, a saturated aqueous solution of sodium hydrogencarbonate, and then with saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography [solvent: chloroform-methanol (1
00: 1)] to give the desired N-benzyloxycarbonyl-L-valyl-N-[(1S) -3-benzylamino-2-hydroxy-1-isopropyl-3-
7.5 g of [oxopropyl] -L-prolinamide was obtained as a colorless oil.

LSIMS (m / z): 567 [(M + H) ⁺ ]. ¹ H
_{-NMR (300MHz, CDCl 3, δ} ): 0.79-1.06 (12H,
m), 1.77-2.35 (5H, m), 3.56 (1H, m), 3.73 (1H,
m), 4.23-4.45 (4H, m), 5.06 (1H, d), 5.11 (1H, d),
5.48 (1H, br t), 7.17-7.42 (10H, m)

(4) Production of Compound (VIII-1) (Amino Protection
Removal of the group):

[0131]

Embedded image

To a solution of 9.2 g of the compound obtained in the preceding step in 200 ml of ethanol, a catalytic amount of 20% palladium hydroxide was added.
The mixture was stirred at room temperature under a hydrogen stream for 1 hour. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure and the desired L-valyl-N-[(1S)-
(3-benzylamino-1-isopropyl-2-hydroxy-3-oxopropyl) -L-prolinamide 5.9
g were obtained as a colorless oil. This product was used as a raw material in Production Example 10 without purification.

Production Example 7: Production of compound (VIII-2): (1) Production method of raw oxazolidine derivative (cyclization):

[0134]

Embedded image

To a 500 ml toluene solution of 25.1 g (0.1 mol) of N-benzyloxycarbonyl-L-valine was added 4.0 g of paraformaldehyde and 1.0 g of p-toluenesulfonic acid monohydrate, and the mixture was heated for 30 minutes. Refluxed. Meanwhile, water was removed with a Dean-Stark tube. The reaction solution was washed with a 5% aqueous sodium hydrogen carbonate solution and then with a saturated saline solution, dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was recrystallized from toluene to obtain 25.0 g (yield 95%) of (4S) -4-isopropyl-5-oxo-1,3-oxazolidine-3-carboxylic acid benzyl ester.

Melting point 54-55 ° C. [α] _D ²⁴ +98.2 (c = 1.0, chloroform). IR (K
Br) cm ^-1 : 1786, 1691. ¹ H NMR (300M
Hz, CDCl ₃ ): δ 7.32-7.41 (5H, m), 5.15-5.60
(4H, m), 4.23 (1H, brs), 2.35 (1H, m), 1.08 (3H,
d, J = 6.78 Hz), 1.01 (3H, d, J = 6.78 Hz). APCI-M
S: 264 (MH ⁺ )

(2) 5-trifluoromethyloxazolidy
Preparation of CF derivative (CF ₃ conversion):

[0138]

Embedded image

(4S) -4-isopropyl-5 obtained in the preceding section
-Oxo-1,3-oxazolidine-3-carboxylic acid benzyl ester (5 g, 0.019 mol) was dissolved in tetrahydrofuran (15 ml), and cesium fluoride (0.58 g, 0.003 g) was obtained.
8 mol), then slowly add 3.5 ml (0.024 mol) of trimethyl (trifluoromethyl) silane.
Stirred for 0 minutes.

Subsequently, 15 ml of methanol was added to the above tetrahydrofuran solution, stirred for 5 minutes, concentrated under reduced pressure, and the residue was subjected to silica gel column chromatography, eluting with n-hexane-ethyl acetate (15: 1 → 10: 1).・ After purification, recrystallization from diisopropyl ether (4S, 5
5.83 g (92% yield) of benzyl S) -5-hydroxy-4-isopropyl-5-trifluoromethyl-1,3-oxazolidine-3-carboxylate was obtained.

Mp 73-74 ° C. [α] _D ²⁴ +48.2 (c
= 1.0, chloroform). ¹ H NMR (300 MHz, C
DCl ₃ ): δ 7.34-7.40 (5H, m), 5.42 (1H, brs), 5.
20 (1H, d, J = 12.3 Hz), 5.15 (1H, d, J = 12.3 Hz), 4.8
4 (1H, d, 4.92 Hz), 4.22 (1H, brs), 3.63 (1H, br
s), 2.17-2.26 (1H, m), 1.05 (3H, d, J = 5.67 Hz),
1.00 (3H, d, J = 6.75 Hz). APCI-MS: 334 (M
H ⁺ ).

(3) Method for producing 5-trifluoromethyl derivative
(Ring open):

[0143]

Embedded image

5.0 g (0.015 mol) of the ester obtained in the preceding section
20 ml of a t-butyl methyl ether solution of 2.
0 g (0.015 mol) and sodium borohydride 1.1
g (0.029 mol) was added dropwise to a 80 ml t-butyl methyl ether solution and stirred at room temperature for 15 hours. 80 ml of a saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with 50 ml of ethyl acetate. After the extract was washed with a saturated saline solution, the organic layer was dried over magnesium sulfate. After the solvent was distilled off under reduced pressure, methanol and water (25 ml each) and potassium carbonate (3.
1 g was added and stirred for 1 hour. After the reaction solvent was distilled off under reduced pressure, 50 ml of water was added, and the mixture was extracted three times with 50 ml of ethyl acetate. After the extract was washed with saturated saline, the organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure. The precipitated crystals were collected by filtration, washed with hexane, and N-[(1S, 2S)-
3,3,3-trifluoro-2-hydroxy-1- (isopropyl) propyl] carbamic acid benzyl ester 3.
0 g (87% yield) was obtained.

Melting point: 103-104 ° C. [α] _D ²⁴ -22.3
(c = 1.0, chloroform). ¹ H NMR (CDCl ₃ ):
δ7.26-7.45 (5H, m), 5.14 (1H, d, J = 12.1 Hz), 5.10
(1H, d, J = 12.1 Hz), 4.84 (1H, d, J = 9.0 Hz), 3.99
-4.15 (1H, m), 3.81 (2H, m), 1.90-2.07 (1H, m),
1.01 (3H, d, J = 6.6 Hz), 0.96 (3H, J = 6.6 Hz). AP
CI-MS: 306 (MH ^<+> ).

(4) Production of Raw OH Form ( Deletion of Amino Protecting Group)
Release):

[0147]

Embedded image

N-[(1S, 2S) obtained in the same manner as in the previous section.
-3,3,3-trifluoro-2-hydroxy-1- (isopropyl) propyl] carbamic acid benzyl ester 7
40 g (2.42 mol) are dissolved in 1500 ml of ethyl acetate,
30 g of 20% palladium hydroxide was added, and the mixture was stirred at room temperature under a hydrogen stream for 7 hours. The catalyst was removed by filtration, and the filtrate was concentrated under reduced pressure to give (2S, 3S) -3-amino-1,1,1-trifluoro-4-methyl-2-pentanol (420 g, yield: quantitative) as an oil. Obtained as a product.

¹ H NMR (CDCl ₃ ): δ3.95-4.02 (1
H, m), 2.56-2.63 (1H, m), 1.77-1.92 (1H, m), 1.01
(3H, d, J = 6.6 Hz), 0.99 (3H, d, J = 6.6 Hz). APC
I-MS: 172 (MH ^<+> ).

(5) Production of Compound (VIII-2) (Amidation /
Elimination of amino protecting group):

[0151]

Embedded image

(2S, 3S) -3-amino-1,
1,1-trifluoro-4-methyl-2-pentanol and N- (benzyloxycarbonyl) -L-valyl-L-
Proline was reacted in the same manner as in Example 6 (3), and the product was treated in the same manner as in Example 6 (4) to remove benzyloxycarbonyl, which is an amino-protecting group. Valyl-N-[(1S, 2S) -3,3,3-trifluoro-1-isopropyl-2-hydroxypropyl)
-L-prolinamide hydrochloride was obtained.

Production Example 8: Production of Compound (IX-1) (Step)
4):

[0154]

Embedded image

33 g of 2-[(3-tert-butoxycarbonylmethyl-2-oxo-1-imidazolidinyl)] acetic acid obtained in Production Example 3 and L-valyl-N- [obtained in Production Example 7- (5) (1S, 2S)-(3,3,3-trifluoro-1
-Isopropyl-2-hydroxypropyl)]-methylene chloride 10 containing 46.4 g of L-prolinamide hydrochloride
4 ml of 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride and 38.5 g of triethylamine were added to 00 ml, and the mixture was stirred at room temperature for 12 hours and then concentrated at room temperature under reduced pressure. Ethyl acetate was added to the residue,
l / liter hydrochloric acid, water, saturated aqueous sodium hydrogen carbonate solution,
Next, after washing with saturated saline, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [solvent: chloroform-methanol (100: 3)] to give the desired 2- (3-t
ert-butoxycarbonylmethyl-2-oxo-1-imidazolidinyl) acetyl-L-valyl-N-[(1S,
2S)-(3,3,3-trifluoro-1-isopropyl-
2-hydroxypropyl))-L-prolinamide 79.
5 g were obtained as a colorless oil.

APCIMS (m / z): 608 [(M + H) ⁺ ]

Production Example 9 Production of Compound (IX-2) (Step)
4):

[0158]

Embedded image

Pyridine 2 containing 1.0 g of L-valyl-N-[(1S) -2- (2-benzoxazolyl) -1-isopropyl-2-hydroxyethyl] -L-prolinamide
0.7 g of 2- (3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl) acetic acid obtained in Production Example 4 and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in 0 ml 0.6 g was added and the mixture was stirred at room temperature for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with 1 mol / liter hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate and then with a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain the desired 2- (3-tert-butoxycarbonylmethyl-2,
4-dioxo-1-pyrimidinyl) acetyl-L-valyl-N-[(1S) -2- (2-benzoxazolyl) -1
-Isopropyl-2-hydroxyethyl] -L-prolinamide (1.5 g) was obtained as a powder.

LSIMS (m / z): 683 [(M + H) ⁺ ]

Preparation 10: Preparation of compound (IX) (Step 4): Preparation of compound (VIII) prepared in Preparation 6 or 7 to Preparation 8
Alternatively, the compound (I) shown in Table 6 below was treated in the same manner as in 9.
X).

[0162]

[Table 9]

[0163]

[Table 10]

[0164]

[Table 11]

[0165]

[Table 12]

Production Example 11 Production of Compound (I-1) (Step
5): Step 5-1: Production of ketone body (oxidation):

[0167]

Embedded image

The 2- (3-tert-butoxycarbonylmethyl-2-oxo-1-imidazolidinyl) acetyl-L-valyl-N-[(1S, 2S) -3,3,3 obtained in Production Example 8
Dess-Martin in 1000 ml of methylene chloride containing 79.5 g of 3-trifluoro-1-isopropyl-2-hydroxypropyl] -L-prolinamide
After adding 112.3 g of the reagent and stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. Ethyl acetate was added to the residue, and a saturated aqueous solution of sodium thiosulfate, water, a saturated aqueous solution of sodium hydrogen carbonate,
Next, after washing with saturated saline, it was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography [solvent: chloroform-methanol (100: 3)] to give the desired 2- (3-t
ert-butoxycarbonylmethyl-2-oxo-1-imidazolidinyl) acetyl-L-valyl-N-[(1S)
-(3,3,3-trifluoro-1-isopropyl-2-
Oxopropyl)]-L-prolinamide was obtained as a colorless oil.

APCIMS (m / z): 606 [(M + H) ⁺ ]. ¹
H-NMR (300 MHz, CDCl ₃ , δ): 0.83-1.02
(12H, m), 1.47 (9H, s), 1.89-2.32 (6H, m), 3.48-4.
06 (10H, m), 4.58 (1H, dd), 4.64 (1H, dd), 4.84 (1
H, dd), 7.35 (1H, d), 7.72 (1H, d).

Step 5-2: Preparation of Compound (I-1)
Elimination of the boxyl protecting group):

Embedded image

The ester 34.9 obtained in the previous step (5-1)
After adding 200 ml of trifluoroacetic acid at room temperature to 200 ml of methylene chloride containing g and stirring at room temperature for 1 hour, the mixture was concentrated under reduced pressure. Diisopropyl ether was added to the residue, and the precipitated crystals were collected by filtration and crystallized from ethyl acetate.
Further, the desired 2- (3-carboxymethyl-2-oxo-) was recrystallized from ethyl acetate-methyl ethyl ketone.
1-imidazolidinyl) acetyl-L-valyl-N-
[(1S) -3,3,3-trifluoro-1-isopropyl-2-oxopropyl] -L-prolinamide 17.3 g
Was obtained as colorless crystals. According to high performance liquid chromatography analysis, the purity of the product was 98.71%, 0.78%
It was found that the isomers were mixed.

177-178 ° C. [Α] _D ²⁰ -6
3.0 (c = 1.0, chloroform). APCIMS (m / z)
: 550 [(M + H) ⁺ ]. ¹ H-NMR (300 MHz, CD
Cl ₃ , δ): 0.85-1.02 (12H, m), 1.90-2.31 (6H, m),
3.51 (4H, m), 3.68 (1H, m), 3.81-4.13 (5H, m), 4.5
8 (2H, m), 4.92 (1H, dd), 7.45 (2H, m).

Production Example 12 Production of Compound (I-2) (Step
5): Step 5-1: Production of ketone body (oxidation):

[0174]

Embedded image

2- (3-tert-butoxycarbonylmethyl-2,4-dioxo-1-pyrimidinyl) acetyl-L-valyl-N-[(1S) -2- (2-benzoxa) obtained in Production Example 9 To 30 ml of methylene chloride containing 1.5 g of zolyl) -1-isopropyl-2-hydroxyethyl] -L-prolinamide was added 0.16 g of t-butyl alcohol and 1.9 g of Dess-Martin reagent, Stirred at room temperature for 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium thiosulfate, and extracted with ethyl acetate. The extract was washed with a saturated aqueous solution of sodium thiosulfate, a saturated aqueous solution of sodium bicarbonate and then with a saturated saline solution, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
t-butoxycarbonylmethyl-2,4-dioxo-1-
Pyrimidinyl) acetyl-L-valyl-N-[(1S) -2
-(2-benzoxazolyl) -1-isopropyl-2-
1.2 g of [oxoethyl] -L-prolinamide were obtained as a powder.

LSIMS (m / z): 681 [(M + H) ⁺ ]. ¹ H
-NMR (300 MHz, CDCl ₃ , δ): 0.90-1.09 (12
H, m), 1.44 (9H, s), 1.90-2.30 (5H, m), 2.50 (1H,
m), 3.67 (1H, m), 3.78 (1H, m), 4.26 (1H, d), 4.54
-4.75 (5H, m), 5.69 (1H, dd), 5.83 (1H, d), 7.42-7.
57 (4H, m), 7.66 (1H, d), 7.91 (1H, d)

Step 5-2: Preparation of Compound (I-2)
Elimination of the boxyl protecting group):

[0178]

Embedded image

1.2 g of the ester obtained in the previous step (5-1)
Trifluoroacetic acid in 30 ml of methylene chloride solution containing
5 ml was added, and the mixture was stirred at room temperature for 1 hour. After the reaction solution was concentrated under reduced pressure, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, ether was added to the residue to form a powder, and the residue was recrystallized using dichloroethane to obtain the desired 2- (3-carboxymethyl-2, 1.2 g of 4-dioxo-1-pyrimidinyl) acetyl-L-valyl-N-[(1S) -2- (2-benzoxazolyl) -1-isopropyl-2-oxoethyl] -L-prolinamide Obtained as a product. According to high performance liquid chromatography analysis, the purity of the product was 92%, and it was found that 7.1% of isomers were present.

135-140 ° C. LSIMS (m / z):
625 [(M + H) ⁺ ]. ¹ H-NMR (300 MHz, d ₆ −
DMSO, δ): 0.85-1.05 (12H, m), 1.70-2.05 (5H,
m), 2.38 (1H, m), 3.55 (1H, m), 3.64 (1H, m), 4.32
(1H, dd), 4.40-4.55 (5H, m), 5.28 (1H, dd), 5.75 (1
H, d), 7.55 (1H, dd), 7.64 (2H, m), 7.90 (1H, d),
8.01 (1H, d), 8.45 (2H, m), 12.9 (1H, s)

Preparation 13: Preparation of Compound (I) (Step 5): Compound (I) shown in Table 7 below was obtained in the same manner as in Preparation 11 or 12.

[0182]

[Table 13]

[0183]

[Table 14]

[0184]

[Table 15]

[0185]

[Table 16]

[0186]

[Table 17]

[0187]

[Table 18]

[0188]

[Table 19]

[0189]

[Table 20]

[0190]

[Table 21]

[0191]

[Table 22]

[0192]

[Table 23]

[0193]

[Table 24]

[0194]

[Table 25]

Example A: Method for producing liquid preparation:

[0196]

[Table 26]

Compound (I-1) and sorbitol were dissolved in a part of distilled water for injection, and the remaining distilled water was added thereto.
The pH of the solution was adjusted to 4.0. This solution was filtered through a membrane filter (0.22 μm) to obtain a liquid preparation for injection.

Example B: Preparation of a freeze-dried preparation:

[0199]

[Table 27]

Compound (I-1) and mannitol were dissolved in a part of distilled water for injection, and the remaining distilled water was added thereto.
The pH of the solution was adjusted to 4.0. This solution was filtered through a membrane filter (0.22 μm), which was lyophilized to obtain a powder for injection.

[0201]

The present invention provides a medicament comprising a novel compound. The compound according to the present invention has an excellent human neutrophil elastase inhibitory activity, and is useful as an agent for preventing or treating various diseases, especially acute lung diseases.

Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat II (reference) A61P 7/00 A61P 7/02 7/02 9/08 9/08 9/10 101 9/10 101 11/00 11 / 00 11/06 11/06 13/12 13/12 17/04 17/04 17/06 17/06 19/02 19/02 21/00 21/00 29/00 101 29/00 101 31/04 31 / 04 37/06 37/06 43/00 111 43/00 111 A61K 37/02 (72) Inventor Ryotaro Shiratake 3-17-17 Narita Higashigaoka, Neyagawa, Osaka (72) Inventor, Seiji Honda Kobe, Hyogo Prefecture 2-7-8 Nagaminedai, Nada-ku (72) Inventor Masanobu Komiya 3-14, Babai Torida, Nagaokakyo-shi, Kyoto (72) Inventor Tadashi Takemura 4-12-11-503, Hanmachi, Minoo-shi, Osaka 11-503, Japan F-term (reference) 4C084 AA02 BA01 BA08 BA15 BA23 BA27 BA28 BA32 MA01 NA14 ZA332 ZA392 ZA452 ZA542 ZA592 ZA662 ZA672 ZA752 ZA892 ZA962 ZB082 ZB152 ZC202

Claims (6)

[Claims] 1. A heterocyclic compound represented by the general formula (I):
A pharmaceutical comprising the ester or a physiologically acceptable salt thereof; Wherein A and B are the same or different and are a lower alkylene group which may be substituted by oxo, D is a monocyclic heterocyclic group represented by the following formula, (Where D ¹ is a methylene group or an ethylene group, these groups may be substituted by oxo,
May further have another hetero atom selected from a nitrogen atom, an oxygen atom and / or a sulfur atom.
A 14-membered monocyclic saturated or unsaturated heterocyclic group, which may be substituted with a substituent T ¹ ;
Here, T ¹ represents (i) an oxo group, (ii) a substituted or unsubstituted lower alkyl group, (iii) a substituted or unsubstituted amino group, (iv) a substituted or unsubstituted carbamoyl group, (v) a carboxyl group or a lower alkoxy group. A carbonyl group, (vi) a phenyl group which may be substituted with halogen, lower alkoxy or lower alkyl, and (vii) 1 to 3 identical or different groups selected from substituted or unsubstituted lower alkylcarbonyl groups. ), R ¹
And R ² are the same or different lower alkyl groups,
R ³ is the following formula: (Where X ¹ and X ² are halogen atoms,
Y ¹ is a hydrogen atom, a halogen atom, a lower alkoxycarbonyl group, a lower alkylaminocarbonyl group, an aralkylaminocarbonyl group, an aralkyloxycarbonyl group,
A lower alkylcarbonyl group or an aralkylcarbonyl group, or a group represented by the following formula: (Wherein, U is an oxygen atom or a sulfur atom, Q is a vinylene group or T ² may ortho-phenylene group optionally substituted with, where T ² are a lower alkyl group optionally substituted by halogen A lower alkoxy group, a lower alkylsulfonyl group, a lower alkylcarbonyloxy group and an amino group which may be substituted with a lower alkyl), and n is 0, 1 or 2. m is an integer of 0 to 5). 2. The medicine according to claim 1, wherein the group represented by -ADB- is a group represented by the following formula: (Wherein A ¹ is a methylene group or a group represented by —CH ₂ CO—, B ¹ is a methylene group or a group represented by —COCH ₂ —, and D ² and D ³ are the same or different. hand,
It is a vinylene group which may be substituted with lower alkyl, or a methylene group which may be substituted with oxo or lower alkyl, and D ¹ is the same as defined in claim 1. However, the case where both D ² and D ³ are vinylene groups which may be substituted with lower alkyl) is excluded. 3. The medicament according to claim 1, wherein the compound is represented by the following general formula (Ia): [Wherein D ¹ and R ³ are the same as defined in claim 1, and A ¹ , B ¹ , D ² and D ³ are the same as defined in claim 2]. 4. The medicament according to claim 3, wherein the compound is selected from the following group: Compound 1: 2- (3-carboxymethyl-2-oxo-
1-imidazolidinyl) acetyl-L-valyl-N-
[(1S) -3,3,3-trifluoro-1-isopropyl-2-oxopropyl] -L-prolinamide, compound 2: 2- (3-carboxymethyl-2,4-dioxo-1-pyrimidinyl) Acetyl-L-valyl-N-
[(1S) -2- (2-benzoxazolyl) -1-isopropyl-2-oxoethyl] -L-prolinamide, compound 3: 2- (4-carboxymethyl-2,3-dioxo-1-piperazinyl ) Acetyl-L-valyl-N-
[(1S) -2- (2-benzoxazolyl) -1-isopropyl-2-oxoethyl] -L-prolinamide, compound 4: 2- (3-carboxymethyl-2,4-dioxo-1-pyrimidinyl ) Acetyl-L-valyl-N-
[(1S) -3-benzylamino-1-isopropyl-2,
3-dioxopropyl] -L-prolinamide, compound 5: 2- (4-carboxymethyl-2,5-dioxo-1-piperazinyl) acetyl-L-valyl-N-
[(1S) -2- (2-benzoxazolyl) -1-isopropyl-2-oxoethyl] -L-prolinamide, compound 6: 2- (3-carboxymethyl-2,5-dioxo-1-imidazolidinyl ) Acetyl-L-valyl-N
-[(1S) -3,3,3-trifluoro-1-isopropyl-2-oxopropyl] -L-prolinamide, and compound 7: [[4- (2-carboxyacetyl) -1-piperazinyl] malonyl ] -L-Valyl-N-[(1S) -2-
(2-Benzoxazolyl) -1-isopropyl-2-oxoethyl] -L-prolinamide. 5. A compound having 90% or more of 2- (3-carboxymethyl-2-oxo-1-imidazolidinyl) acetyl-L-valyl-N-[(1S) -3,3,3-trifluoro-1. -Isopropyl-2-oxopropyl] -L-
The medicament according to claim 1, which is a mixture of prolinamide (compound 1) or a salt thereof and the balance substantially consisting of a stereoisomer of compound 1 or a salt thereof. 6. A compound represented by the following general formula (I): [Wherein A, B, D, R ¹ , R ² and R ³ are the same as defined in claim 1], an ester thereof, or a physiologically acceptable salt thereof. A pharmaceutical composition characterized by containing as an active ingredient.