JP3840668B2 - Prolinamide derivatives - Google Patents

Description

[0001]
[Industrial application fields]
The present invention relates to a novel proline derivative, and more particularly to a proline derivative having proteolytic enzyme inhibitory activity or a pharmaceutically acceptable salt thereof and a proteolytic enzyme inhibitor containing them as an active ingredient.
[0002]
[Background Art and Problems to be Solved by the Invention]
It is well known that various proteolytic enzymes exist in the living body. For example, thrombin, factor Xa, factor IXa, factor VIIa, trypsin, plasmin, tissue plasminogen activator, kallikrein, complement A group of serine proteases such as C1 enzyme, C3 / C5 convertase and tryptase are known. Furthermore, it is known that when these proteolytic enzymes are activated abnormally for some reason, various diseases are caused. Therefore, substances showing inhibitory activity against these proteolytic enzymes are useful as clinical therapeutic agents. For example, antithrombin, anti-factor Xa and anti-VIIa are useful for the treatment of thrombosis, antitrypsin is useful for the treatment of pancreatitis, antiplasmin is a hemostatic agent, antiallergic agent, anti-inflammatory It is useful as an agent, an anti-kallikrein agent is useful as a therapeutic agent for inflammation and ulcer, and an anti-complement agent is useful as a therapeutic agent for nephritis or rheumatism. Development of a protease inhibitor having such an action has been underway, but it has not been sufficient for practical use as a pharmaceutical in terms of protease inhibitory activity, in vivo stability, and the like. For example, tripeptide derivatives including arginine derivatives are known as protease inhibitors. That is, D-phenylalanyl-L-prolyl-L-arginal is known as a thrombin inhibitor (for example, Folia Haematol., 109 , 22 (1982)) is relatively unstable in vivo (J. Med. Chem., 33 1729 (1990)). Further, similarly, an arginal derivative (Japanese Patent Laid-Open No. 4-89498) or an amidinophenylalanine derivative (Thromb. Res., 17 , 425 (1980)) has been reported as a protease inhibitor, but its inhibitory activity is low.
[0003]
[Means for Solving the Problems]
In view of the above circumstances, the present inventors have conducted a search for drugs that have practically sufficient enzyme inhibitory activity and in vivo stability and are structurally novel. As a result, a specific proline amide derivative is desired. The inventors have found that the object can be achieved and have completed the present invention.
That is, the gist of the present invention is the following general formula (I)
[0004]
[Chemical 8]
[0005]
[In said formula, A represents a carbon atom or a nitrogen atom, n represents the integer of 0-2, and a broken line does not exist or represents a single bond.
[Chemical 9]
{D and E are each independently a single bond or branched C ₁ ~ C ₆ Represents an alkylene group.
[0006]
R ^Four Is C ₁ ~ C ₆ An alkyl group of ⁶ (R ⁶ Is a hydrogen atom, C ₁ ~ C ₆ An alkyl group and a C which may have a substituent ₆ ~ C _Ten Aryl group and C which may have a substituent _Three ~ C ₈ Optionally having a cycloalkyl group or a substituent ₇ ~ C ₁₂ Represents an aralkyl group of ⁷ (R ⁷ Is C ₁ ~ C ₆ An alkyl group and a C which may have a substituent ₆ ~ C _Ten Aryl group and C which may have a substituent _Three ~ C ₈ Optionally having a cycloalkyl group or a substituent ₇ ~ C ₁₂ Represents an aralkyl group of ⁸ (R ⁸ May have a substituent ₆ ~ C _Ten Optionally having an aryl group or a substituent _Three ~ C ₈ Represents a cycloalkyl group of ₂ R ⁹ (R ⁹ May have a substituent ₆ ~ C _Ten Optionally having an aryl group or a substituent _Three ~ C ₈ Represents a cycloalkyl group of ^Ten (R ^Ten Is a hydroxyl group, C ₁ ~ C ₆ An alkoxy group of C, which may have a substituent ₆ ~ C _Ten Optionally having an aryl group or a substituent _Three ~ C ₈ A cycloalkyl group), -NHR ¹¹ (R ¹¹ Is C ₁ ~ C ₆ An alkyl group and a C which may have a substituent ₆ ~ C _Ten Aryl group and C which may have a substituent _Three ~ C ₈ Optionally having a cycloalkyl group or a substituent ₇ ~ C ₁₂ Represents an aralkyl group of ¹² (R ¹² Is C ₁ ~ C ₆ An alkoxy group of C, which may have a substituent ₆ ~ C _Ten Aryl group and C which may have a substituent _Three ~ C ₈ Optionally having a cycloalkyl group or a substituent ₇ ~ C ₁₂ Represents an aralkyloxy group of ₂ R ¹³ (R ¹³ Is C ₁ ~ C ₆ An alkyl group and a C which may have a substituent ₆ ~ C _Ten Aryl group and C which may have a substituent _Three ~ C ₈ Of cycloalkyl group, optionally having C ₇ ~ C ₁₂ An aralkyl group or a 5- to 10-membered heterocyclic residue optionally having a substituent), and optionally having C ₆ ~ C _Ten Aryl group and C which may have a substituent _Three ~ C ₈ A cycloalkyl group, an optionally substituted 5- to 10-membered heterocyclic residue or -SiR ¹⁴ R ¹⁵ R ¹⁶ (R ¹⁴ , R ¹⁵ And R ¹⁶ Are each independently C ₁ ~ C ₆ Represents an alkyl group.
[0007]
R ^Five Is -OR ¹⁷ (R ¹⁷ Is a hydrogen atom, -SiR ^{twenty two} R ^{twenty three} R ^{twenty four} (R ^{twenty two} , R ^{twenty three} And R ^{twenty four} Are each independently C ₁ ~ C ₆ Represents an alkyl group of ₁ ~ C ₆ A 5- to 10-membered heterocyclic residue optionally having an alkyl group or a substituent), -OCOR ¹⁸ (R ¹⁸ Is a hydrogen atom, C ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ Alkoxy group, amino group, C ₁ ~ C ₆ An alkylamino group of C ₂ ~ C ₁₂ Dialkylamino group or C ₂ ~ C ₇ Represents -alkenylamino group), -NHR ¹⁹ (R ¹⁹ Is a hydrogen atom, C ₁ ~ C ₆ Optionally having an alkyl group or a substituent ₇ ~ C ₁₂ Represents an aralkyl group of ²⁰ (R ²⁰ Is a hydrogen atom, C ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ A haloalkyl group of C ₁ ~ C ₆ An alkoxy group of C, which may have a substituent _Three ~ C ₈ A cycloalkyl group of ₂ ~ C ₇ A carboxyalkyloxy group of C ₂ ~ C ₇ An alkenyloxy group which may have a substituent ₆ ~ C _Ten Aryl group and C which may have a substituent ₆ ~ C _Ten Aryloxy group of C _Three ~ C ₉ An alkoxycarbonylalkoxy group of C ₂ ~ C ₁₂ Dialkylamino group or C which may have a substituent ₇ ~ C ₁₂ Represents an aralkyloxy group of) or -NHSO ₂ R ^{twenty one} (R ^{twenty one} Is C ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ A haloalkyl group of C ₂ ~ C ₇ Carboxyalkyl group, C which may have a substituent ₆ ~ C _Ten Aryl group of _Three ~ C ₉ Which may have an alkoxycarbonylalkyl group or a substituent of ₇ ~ C ₁₂ Represents an aralkyl group.
[0008]
m represents 0 or 1; }
Represents R ² Is a hydrogen atom or C ₁ ~ C ₆ Represents an alkyl group of R ^Three Is -C (= NR ^{twenty five} ) NH ₂ (R ^{twenty five} Is a hydrogen atom, C ₁ ~ C ₆ Alkyl group of ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An acyloxy group, C ₁ ~ C ₆ An alkoxy group of ₂ ~ C ₇ An alkoxycarbonyl group of C ₂ ~ C ₇ Alkoxycarbonyloxy group, hydroxyl group or C ₂ ~ C ₇ Represents a hydroxyalkylcarbonyloxy group of), -NH-C (= NR ^{twenty five} ) NH ₂ (R ^{twenty five} Are the same as defined above) or -NHR ²⁶ (R ²⁶ Is a hydrogen atom, C ₁ ~ C ₆ Alkyl group of ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An alkoxycarbonyl group or 5-C ₁ ~ C _Three Represents an alkyl-1,3-dioxol-2-one-4-ylmethyl group). However, when A represents a nitrogen atom, R ^Three Is -C (= NR ^{twenty five} ) NH ₂ (R ^{twenty five} Is the same as defined above. )
Or a salt thereof or a hydrate thereof, and a pharmaceutical use thereof.
[0009]
Hereinafter, the present invention will be described in detail.
The proline amide derivative of the present invention is represented by the formula (I). C which may be branched in the above definition ₁ ~ C ₆ As the alkylene group, ₂ -,-(CH ₂ ) ₂ -,-(CH ₂ ) _Three -,-(CH ₂ ) _Four -,-(HC ₂ ) _Five -,-(CH ₂ ) ₆ -, -CH (CH _Three )-, -C (CH _Three ) ₂ -, -CH (CH _Three ) CH ₂ -, -CH ₂ CH (CH _Three )-, -C (CH _Three ) ₂ CH ₂ -, -CH ₂ C (CH _Three ) ₂ -, -CH (CH _Three ) CH (CH _Three )-And the like. C ₁ ~ C _Three Examples of the alkylene group include those having 3 or less carbon atoms among those exemplified above. C ₁ ~ C ₆ Examples of the alkyl group include methyl, ethyl, n-propyl, i-propyl, n-butyl, s-butyl, i-butyl, t-butyl, n-pentyl, and n-hexyl. Groups and the like. Also C ₁ ~ C _Three Examples of the alkyl group include those having 3 or less carbon atoms among those exemplified above. C ₁ ~ C ₆ As the alkoxy group, methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butyloxy group, s-butyloxy group, i-butyloxy group, t-butyloxy group, n-pentyloxy group, n- A hexyloxy group etc. are mentioned. C ₂ ~ C ₇ As the alkoxycarbonyl group, methoxycarbonyl group, ethoxycarbonyl group, n-propoxycarbonyl group, i-propoxycarbonyl group, n-butyloxycarbonyl group, t-butyloxycarbonyl group, n-pentyloxycarbonyl group, n- Examples include a hexyloxycarbonyl group. C _Three ~ C ₈ Examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, and a cyclooctyl group. C ₆ ~ C _Ten Examples of the aryl group include a phenyl group, a tolyl group, and a naphthyl group. C ₇ ~ C ₁₂ Examples of the aralkyl group include a benzyl group, a phenylethyl group, a phenylpropyl group, and a naphthylmethyl group. C ₆ ~ C _Ten Examples of the aryloxy group include a phenyloxy group and a naphthyloxy group. C ₇ ~ C ₁₂ Examples of the aralkyloxy group include benzyloxy group, phenylethyloxy group, phenylpropyloxy group, naphthylmethyloxy group and the like. The heterocyclic residue has 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and the total number of atoms constituting the ring is 5 to 10, specifically a furan ring , Tetrahydrofuran ring, pyran ring, benzofuran ring, chroman ring, thiophene ring, benzothiophene ring, pyrrole ring, imidazole ring, pyrazole ring, triazole ring, pyridine ring, piperidine ring, pyrazine ring, piperazine ring, pyrimidine ring, indole ring, Examples thereof include benzimidazole ring, purine ring, quinoline ring, phthalazine ring, quinazoline ring, cinnoline ring, oxozal ring, thiazole ring, and morpholine ring. C ₁ ~ C ₆ As the haloalkyl group, chloromethyl group, bromomethyl group, dichloromethyl group, 1-chloroethyl group, 2-chloroethyl group, 3-chloropropyl group, 4-chlorobutyl group, 5-chloropentyl group, 6-chlorohexyl group, A difluoromethyl group, a trifluoromethyl group, etc. are mentioned. C ₂ ~ C ₇ Examples of the carboxyalkyl group include a carboxymethyl group, a 2-carboxyethyl group, a 3-carboxypropyl group, a 4-carboxybutyl group, a 5-carboxypentyl group, and a 6-carboxyhexyl group. C ₂ ~ C ₇ Examples of the carboxyalkyloxy group include a carboxymethoxy group, a 2-carboxyethoxy group, a 3-carboxypropoxy group, a 4-carboxybutyloxy group, a 5-carboxypentyloxy group, and a 6-carboxyhexyloxy group. C ₂ ~ C ₇ Examples of the alkenyloxy group include a vinyloxy group, an allyloxy group, a 2-propenyloxy group, an isopropenyloxy group, a 3-butenyloxy group, a 4-pentenyloxy group, and a 5-hexenyloxy group. C ₂ ~ C ₇ Examples of the alkenylamino group include a vinylamino group, an allylamino group, a 2-propenylamino group, an isopropenylamino group, a 3-butenylamino group, a 4-pentenylamino group, and a 5-hexenylamino group. C ₁ ~ C ₆ Examples of the alkylamino group include a methylamino group, an ethylamino group, an n-propylamino group, and an n-butylamino group. C ₂ ~ C ₁₂ Examples of the dialkylamino group include a dimethylamino group, a methylethylamino group, a diethylamino group, and a di-n-propylamino group. C ₂ ~ C ₇ Examples of the acyl group include acetyl group, propionyl group, butyryl group, isobutyryl group, valeryl group, isovaleryl group, pivaloyl group, hexanoyl group, heptanoyl group and the like. C ₂ ~ C ₇ Examples of the acyloxy group include acetyloxy group, propionyloxy group, butyryloxy group, isobutyryloxy group, valeryloxy group, isovaleryloxy group, pivaloyloxy group, hexanoyloxy group, heptanoyloxy group and the like. C ₂ ~ C ₇ Examples of the alkoxycarbonyloxy group include methoxycarbonyloxy group, ethoxycarbonyloxy group, n-propoxycarbonyloxy group, n-butyloxycarbonyloxy group, n-pentyloxycarbonyloxy group, n-hexyloxycarbonyloxy group, and the like. Can be mentioned. C ₂ ~ C ₇ As the hydroxyalkylcarbonyloxy group, hydroxymethylcarbonyloxy group, 2-hydroxyethylcarbonyloxy group, 3-hydroxypropylcarbonyloxy group, 4-hydroxybutylcarbonyloxy group, 5-hydroxypentylcarbonyloxy group, 6-hydroxy A hexyl carbonyloxy group etc. are mentioned. C _Three ~ C ₉ Examples of the alkoxycarbonylalkoxy group include a methoxycarbonylmethoxy group, an ethoxycarbonylmethoxy group, a propoxycarbonylmethoxy group, a methoxycarbonylethoxy group, an ethoxycarbonylethoxy group, and a propoxycarbonylethoxy group. C _Three ~ C ₉ Examples of the alkoxycarbonylalkyl group include methoxycarbonylmethyl group, ethoxycarbonylmethyl group, propoxycarbonylmethyl group, methoxycarbonylethyl group, methoxycarbonylmethyl group, propoxycarbonylethyl group and the like.
[0010]
In addition, in the definition of the substituent in the general formula, the substituent which may be “optionally substituted” includes the above-described C ₁ ~ C ₆ An alkyl group of C; ₁ ~ C ₆ A haloalkyl group of C; ₁ ~ C ₆ An alkoxy group; a hydroxyl group; a carboxyl group; ₂ ~ C ₇ A carboxyalkyl group of C; ₂ ~ C ₇ A carboxyalkyloxy group of C; ₂ ~ C ₇ An acyl group of C; ₂ ~ C ₇ The acyloxy group of C; ₂ ~ C ₇ An alkoxycarbonyl group of C; ₂ ~ C ₇ An alkoxycarbonyloxy group such as benzyloxycarbonyl group, phenylethyloxycarbonyl group, phenylpropyloxycarbonyl group, naphthylmethyloxycarbonyl group, etc. ₈ ~ C ₁₃ An aralkyloxycarbonyl group; a halogen atom such as a fluorine atom, a chlorine atom or a bromine atom;
[0011]
In the compound represented by the general formula (I), the 5- to 10-membered heterocyclic residue has 1 to 4 heteroatoms selected from an oxygen atom, a sulfur atom and a nitrogen atom, and constitutes a ring. Those having a total number of atoms of 5 to 10 are preferred, and the substituent of each group is C ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ A haloalkyl group of C ₁ ~ C ₆ Alkoxy group, hydroxyl group, carboxyl group, C ₂ ~ C ₇ A carboxyalkyl group of C ₂ ~ C ₇ A carboxyalkyloxy group of C ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An acyloxy group, C ₂ ~ C ₇ An alkoxycarbonyl group of C ₂ ~ C ₇ An alkoxycarbonyloxy group of C ₈ ~ C ₁₃ An aralkyloxycarbonyl group of C _Three ~ C ₉ Of these, a group selected from alkoxycarbonylalkoxy groups and halogen atoms is preferred.
In the compound of the present invention represented by the general formula (I), A is preferably a carbon atom.
As a preferable compound of the present invention, in the general formula (I), A represents a carbon atom, n represents 1 or 2,
[0012]
[Chemical Formula 10]
{D and E are each independently a single bond or branched C ₁ ~ C ₆ Represents an alkylene group.
[0013]
R ^Four Is C ₁ ~ C ₆ Alkyl group: -OR ⁶ (R ⁶ Is C ₁ ~ C ₆ Alkyl group: C ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ Alkoxy group, halogen atom, hydroxyl group, carboxyl group, C ₂ ~ C ₇ An alkoxycarbonyl group of C ₂ ~ C ₇ A carboxyalkyl group of C ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An acyloxy group, C ₂ ~ C ₇ An alkoxycarbonyloxy group of C _Three ~ C ₉ Optionally having one or more substituents selected from the group consisting of an alkoxycarbonylalkoxy group and a benzyloxycarbonyl group ₆ ~ C _Ten An aryl group of ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ Alkoxy group, halogen atom, hydroxyl group, carboxyl group, C ₂ ~ C ₇ An alkoxycarbonyl group of C ₂ ~ C ₇ A carboxyalkyl group of C ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An acyloxy group, C ₂ ~ C ₇ An alkoxycarbonyloxy group of C _Three ~ C ₉ Optionally having one or more substituents selected from the group consisting of an alkoxycarbonylalkoxy group and a benzyloxycarbonyl group ₇ ~ C ₁₂ Represents an aralkyl group of
-SR ⁷ (R ⁷ Is C ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ Alkoxy group, halogen atom, hydroxyl group, carboxyl group, C ₂ ~ C ₇ An alkoxycarbonyl group of C ₂ ~ C ₇ A carboxyalkyl group of C ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An acyloxy group, C ₂ ~ C ₇ An alkoxycarbonyloxy group of C _Three ~ C ₉ Optionally having one or more substituents selected from the group consisting of an alkoxycarbonylalkoxy group and a benzyloxycarbonyl group ₆ ~ C _Ten An aryl group of ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ Alkoxy group, halogen atom, hydroxyl group, carboxyl group, C ₂ ~ C ₇ An alkoxycarbonyl group of C ₂ ~ C ₇ A carboxyalkyl group of C ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An acyloxy group, C ₂ ~ C ₇ An alkoxycarbonyloxy group of C _Three ~ C ₉ Optionally having one or more substituents selected from the group consisting of an alkoxycarbonylalkoxy group and a benzyloxycarbonyl group ₇ ~ C ₁₂ Represents an aralkyl group of:)-COOH: C ₁ ~ C ₆ Alkyl group of ₁ ~ C ₆ Alkoxy group, halogen atom, hydroxyl group, carboxyl group, C ₂ ~ C ₇ An alkoxycarbonyl group of C ₂ ~ C ₇ A carboxyalkyl group of C ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An acyloxy group, C ₂ ~ C ₇ An alkoxycarbonyloxy group of C _Three ~ C ₉ Optionally having one or more substituents selected from the group consisting of an alkoxycarbonylalkoxy group and a benzyloxycarbonyl group ₆ ~ C _Ten Aryl group: C _Three ~ C ₈ A cycloalkyl group: or -SiR ¹⁴ R ¹⁵ R ¹⁶ (R ¹⁴ , R ¹⁵ And R ¹⁶ Are each independently C ₁ ~ C ₆ Represents an alkyl group.
[0014]
R ^Five Is -OH, -OCOR ¹⁸ (R ¹⁸ Is C ₁ ~ C ₆ An alkoxy group or C ₂ ~ C ₇ Represents -alkenylamino group), -NH ₂ , -NHCOR ²⁰ (R ²⁰ Is C ₁ ~ C ₆ An alkoxy group of ₆ ~ C _Ten Aryloxy group of C _Three ~ C ₉ An alkoxycarbonylalkoxy group of C ₂ ~ C ₁₂ Dialkylamino group or C ₇ ~ C ₁₂ Represents an aralkyloxy group of) or -NHSO ₂ R ^{twenty one} (R ^{twenty one} Is C ₁ ~ C ₆ Alkyl group of ₂ ~ C ₇ A carboxyalkyl group of C ₆ ~ C _Ten Aryl group of _Three ~ C ₉ An alkoxycarbonylalkyl group or C ₇ ~ C ₁₂ Represents an aralkyl group.
[0015]
m represents 0 or 1; },
R ² Represents a hydrogen atom,
R ^Three Is -C (= NR ^{twenty five} ) NH ₂ (R ^{twenty five} Is a hydrogen atom, C ₂ ~ C ₇ Represents an alkoxycarbonyl group or a hydroxyl group, and —NH—C (═NR ^{twenty five} ) NH ₂ (R ^{twenty five} Are the same as defined above) or -NHR ²⁶ (R ²⁶ Is a hydrogen atom, C ₂ ~ C ₇ An alkoxycarbonyl group or 5-C ₁ ~ C _Three A compound representing an alkyl-1,3-dioxol-2-one-4-ylmethyl group).
[0016]
As a more preferred compound of the present invention, in the general formula (I), A represents a carbon atom, n represents 1,
[0017]
Embedded image
{D and E are each independently a single bond or branched C ₁ ~ C ₆ Represents an alkylene group.
[0018]
R ^Four Is C ₁ ~ C ₆ An alkyl group of ⁶ (R ⁶ Is C ₁ ~ C ₆ Alkyl group, halogen atom, carboxyl group, C ₂ ~ C ₇ Optionally having one or more substituents selected from the group consisting of a carboxyalkyl group and a benzyloxycarbonyl group ₆ ~ C _Ten Aryl group or C ₇ ~ C ₁₂ Represents an aralkyl group of
-SR ⁷ (R ⁷ Is C ₁ ~ C ₆ Represents an alkyl group of ₁ ~ C ₆ Alkyl group, halogen atom, carboxyl group, C ₂ ~ C ₇ Optionally having one or more substituents selected from the group consisting of a carboxyalkyl group and a benzyloxycarbonyl group ₆ ~ C _Ten An aryl group of _Three ~ C ₆ Represents a cycloalkyl group.
[0019]
R ^Five Is —OH, —NH ₂ , -NHCOR ²⁰ (R ²⁰ Is C ₁ ~ C ₆ An alkoxy group or C ₇ ~ C ₁₂ Represents an aralkyloxy group of) or -NHSO ₂ R ^{twenty one} (R ^{twenty one} Is C ₁ ~ C ₆ An alkyl group or C ₆ ~ C _Ten Represents an aryl group of
m represents 1. },
R ² Represents a hydrogen atom,
R ^Three Is -C (= NR ^{twenty five} ) NH ₂ (R ^{twenty five} Represents a hydrogen atom or a hydroxyl group) or -NH ₂ The compound which represents is mentioned.
As a more preferred compound of the present invention, in the general formula (I), A represents a carbon atom, n represents 1,
[0020]
Embedded image
[0021]
{D represents a single bond, E represents a single bond or C ₁ ~ C ₆ Represents an alkylene group.
R ^Four Is C ₁ ~ C ₆ An alkyl group of ⁶ (R ⁶ Is C ₁ ~ C ₆ Alkyl group, halogen atom, carboxyl group, C ₂ ~ C ₇ Optionally having one or more substituents selected from the group consisting of a carboxyalkyl group and a benzyloxycarbonyl group ₆ ~ C _Ten Aryl group or C ₇ ~ C ₁₂ Represents an aralkyl group of
-SR ⁷ (R ⁷ Is C ₁ ~ C ₆ Represents an alkyl group of ₁ ~ C ₆ Alkyl group, halogen atom, carboxyl group, C ₂ ~ C ₇ Optionally having one or more substituents selected from the group consisting of a carboxyalkyl group and a benzyloxycarbonyl group ₆ ~ C _Ten An aryl group of _Three ~ C ₆ Represents a cycloalkyl group.
R ^Five Is -NH ₂ , -NHCOR ²⁰ (R ²⁰ Is C ₁ ~ C ₆ An alkoxy group or C ₇ ~ C ₁₂ Represents an aralkyloxy group of) or -NHSO ₂ R ^{twenty one} (R ^{twenty one} Is C ₁ ~ C ₆ An alkyl group or C ₆ ~ C _Ten Represents an aryl group of
m represents 1. },
R ² Is a hydrogen atom,
R ^Three Is -C (= NR ^{twenty five} ) NH ₂ (R ^{twenty five} Represents a hydrogen atom or a hydroxyl group) or -NH ₂ The compound which represents is mentioned.
As a still more preferable compound of the present invention, in the general formula (I), A represents a carbon atom, n represents 1,
[0022]
Embedded image
[0023]
{D represents a single bond, E represents a single bond or C ₁ ~ C _Three Represents an alkylene group of R ^Four Is C _Three ~ C ₆ An alkyl group of ⁶ (R ⁶ Is C ₁ ~ C ₆ A phenyl group or C _Three ~ C ₆ Represents a cycloalkyl group of R ^Five Is —OH, —NH ₂ , -NHCOR ²⁰ (R ²⁰ Is C ₁ ~ C ₆ Or -NHSO ₂ R ^{twenty one} (R ^{twenty one} Is C ₁ ~ C _Three Represents an alkyl group, and m represents 1},
R ² Represents a hydrogen atom,
R ^Three Is -C (= NR ^{twenty five} ) NH ₂ (R ^{twenty five} Represents a hydrogen atom or a hydroxyl group) or -NH ₂ The compound which represents is mentioned.
As a particularly preferred compound of the present invention, in the general formula (I), A represents a carbon atom, n represents 1,
[0024]
Embedded image
[0025]
{D represents a single bond, E represents a single bond or C ₁ ~ C ₆ Represents an alkylene group.
R ^Four Is C ₁ ~ C ₆ Represents an alkyl group of R ^Five Is -NHCOR ²⁰ (R ²⁰ Is C ₁ ~ C ₆ Represents an alkoxy group, and m represents 1)}
R ² Represents a hydrogen atom,
R ^Three Is -C (= NR ^{twenty five} ) NH ₂ (R ^{twenty five} Represents a hydrogen atom or a hydroxyl group).
[0026]
The most preferred compound of the present invention is trans-4-[(S) -N-[(R) -2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Example 33). And compound No. 461) in Table 1.
[0027]
The proline amide derivative represented by the general formula (I) can take various steric structures. For example, when an asymmetric carbon atom is mainly considered, the absolute configuration thereof may be any of (D), (L), and (DL), and all of them are included in the compound of the present invention.
[0028]
Examples of the salt that can be formed by the compound of the general formula (I) include inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, phosphate, and succinic acid. Organic salts such as salt, oxalate, fumarate, maleate, lactate, tartrate, citrate, acetate, glycolate, methanesulfonate, toluenesulfonate, etc. it can. The proline amide derivative of the general formula (I) having a free carboxyl group can form a salt with a pharmaceutically acceptable base. Examples of such salts include alkali metal salts, alkaline earth metal salts, ammonium or alkylammonium salts.
The proline amide derivative represented by the general formula (I) and a salt thereof can also form a hydrate.
Specific examples of the compound of the present invention are shown below.
[0029]
[Table 1]
[0030]
[Table 2]
[0031]
[Table 3]
[0032]
[Table 4]
[0033]
[Table 5]
[0034]
[Table 6]
[0035]
[Table 7]
[0036]
[Table 8]
[0037]
[Table 9]
[0038]
[Table 10]
[0039]
[Table 11]
[0040]
[Table 12]
[0041]
[Table 13]
[0042]
[Table 14]
[0043]
[Table 15]
[0044]
[Table 16]
[0045]
[Table 17]
[0046]
[Table 18]
[0047]
[Table 19]
[0048]
[Table 20]
[0049]
[Table 21]
[0050]
[Table 22]
[0051]
[Table 23]
[0052]
[Table 24]
[0053]
[Table 25]
[0054]
[Table 26]
[0055]
[Table 27]
[0056]
[Table 28]
[0057]
[Table 29]
[0058]
[Table 30]
[0059]
[Table 31]
[0060]
[Table 32]
[0061]
[Table 33]
[0062]
[Table 34]
[0063]
[Table 35]
[0064]
[Table 36]
[0065]
[Table 37]
[0066]
[Table 38]
[0067]
[Table 39]
[0068]
[Table 40]
[0069]
[Table 41]
[0070]
[Table 42]
[0071]
[Table 43]
[0072]
[Table 44]
[0073]
[Table 45]
[0074]
[Table 46]
[0075]
[Table 47]
[0076]
[Table 48]
[0077]
[Table 49]
[0078]
[Table 50]
[0079]
[Table 51]
[0080]
[Table 52]
[0081]
[Table 53]
[0082]
[Table 54]
[0083]
[Table 55]
[0084]
[Table 56]
[0085]
[Table 57]
[0086]
[Table 58]
[0087]
[Table 59]
[0088]
[Table 60]
[0089]
[Table 61]
[0090]
[Table 62]
[0091]
[Table 63]
[0092]
[Table 64]
[0093]
[Table 65]
[0094]
[Table 66]
[0095]
[Table 67]
[0096]
[Table 68]
[0097]
[Table 69]
[0098]
[Table 70]
[0099]
[Table 71]
[0100]
[Table 72]
[0101]
[Table 73]
[0102]
[Table 74]
[0103]
[Table 75]
[0104]
[Table 76]
[0105]
[Table 77]
[0106]
[Table 78]
[0107]
[Table 79]
[0108]
[Table 80]
[0109]
[Table 81]
[0110]
[Table 82]
[0111]
[Table 83]
[0112]
[Table 84]
[0113]
[Table 85]
[0114]
[Table 86]
[0115]
[Table 87]
[0116]
[Table 88]
[0117]
[Table 89]
[0118]
[Table 90]
[0119]
[Table 91]
[0120]
[Table 92]
[0121]
[Table 93]
[0122]
[Table 94]
[0123]
[Table 95]
[0124]
[Table 96]
[0125]
[Table 97]
[0126]
[Table 98]
[0127]
[Table 99]
[0128]
[Table 100]
[0129]
[Table 101]
[0130]
[Table 102]
[0131]
[Table 103]
[0132]
[Table 104]
[0133]
[Table 105]
[0134]
[Table 106]
[0135]
[Table 107]
[0136]
[Table 108]
[0137]
[Table 109]
[0138]
[Table 110]
[0139]
[Table 111]
[0140]
[Table 112]
[0141]
[Table 113]
[0142]
Next, a method for producing the compound of the present invention will be described.
The compound of the present invention can be produced by a combination of reactions suitable for the target compound. Typical reaction schemes are illustrated below, but are not limited to the methods described below.
[0143]
Embedded image
[0144]
Embedded image
[0145]
Embedded image
[0146]
(In the above reaction scheme, R ¹ , R ² , R ^{twenty five} , N and a broken line are the same as defined above, Q represents an amino-protecting group such as a benzyloxycarbonyl group or a tert-butyloxycarbonyl group, Z represents a halogen atom, a methanesulfonyloxy group, a toluenesulfonyloxy group, It represents a leaving group such as a trifluoromethylsulfonyloxy group or an acetoxy (acetyloxy) group. R ²⁷ , R ²⁸ And R ²⁹ Is R ^{twenty five} And R ²⁶ Represents a specific substituent contained in R ²⁷ Is C ₁ ~ C ₆ Alkyl group of ₂ ~ C ₇ Acyl group or C ₂ ~ C ₇ Represents an alkoxycarbonyl group of R ²⁸ Is C ₁ ~ C ₆ Alkyl group of ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An alkoxycarbonyl group or C ₂ ~ C ₇ Represents a hydroxyalkylcarbonyl group of R ²⁹ Is C ₁ ~ C ₆ Alkyl group of ₂ ~ C ₇ An acyl group of C ₂ ~ C ₇ An alkoxycarbonyl group or 5-C ₁ ~ C _Three Represents an alkyl-1,3-dioxol-2-one-4-ylmethyl group; )
[0147]
In the above reaction scheme, a known amide synthesis method is used in the synthesis of compounds (IV), (VI), (XII), (XIV), (XIX), and (XXI). Usable methods include dicyclohexylcarbodiimide, 1-ethyl-3- (dimethylaminopropyl) carbodiimide, carbonyldiimidazole and other dehydrating condensing agents, azide method, acid halide method, acid anhydride method, active ester method, etc. (See, for example, “The Chemical Society of Japan, 4th edition, Experimental Chemistry Course, 22, Organic Synthesis IV, p259- (1992), Maruzen Co., Ltd.”). The reaction is carried out according to a conventional method using an inert solvent such as tetrahydrofuran, diethyl ether, dichloromethane, etc. under cooling or at room temperature to warming. In the above scheme, the compounds (V), (XIII), (XV), and (XX) are deprotected by a known method in peptide chemistry (see, for example, Nobuo Izumiya “Basics and Experiments of Peptide Synthesis” Maruzen). Is synthesized.
[0148]
Compound (VII) can be prepared by reacting (VI) with an imidate obtained by reacting an alcohol and an inorganic acid such as hydrochloric acid with ammonia or ammonium salt, or (VI) with an organic compound such as triethylamine or pyridine. It is synthesized by reacting a thioamide compound obtained by the action of hydrogen sulfide in the presence of a base with a lower alkyl halogen compound such as methyl iodide, and further reacting the resulting thioimidate compound with ammonia or an ammonium salt. Compound (IX) is synthesized by reacting (VI) with hydroxyamine or an acid adduct thereof in a suitable solvent such as water, alcohol, tetrahydrofuran, or the like at room temperature or warming.
[0149]
Further, the compounds (VIII), (X) and (XVII) can be used in the presence of an organic or inorganic base in an inert solvent such as tetrahydrofuran, ether, dichloromethane or the like with respect to the compounds (VII), (IX) and (XV). R ²⁷ -Z, R ²⁸ -Z or R ²⁹ It is synthesized by reacting -Z under cooling or at room temperature to warming.
Furthermore, compound (XVI) is obtained by reacting compound (XV) with a guanidation reagent such as a 2-alkylisothiourea derivative or an acid adduct thereof in a suitable solvent such as water, alcohol, tetrahydrofuran or the like at room temperature or warming. Is synthesized.
[0150]
Each compound obtained as described above is isolated and purified by ordinary chemical operations such as extraction, crystallization, recrystallization, and various chromatography.
In clinical application of such a compound of the present invention, the ratio of the therapeutically effective component to the carrier component can vary between 1% and 90% by weight. For example, the compound of the present invention may be administered orally in the form of granules, fine granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions or liquids, or injections. It may be administered intravenously, intramuscularly or subcutaneously. It can also be used as a suppository. Alternatively, it may be prepared as a powder for injection and used. Pharmaceutical organic or inorganic, solid or liquid carriers or diluents suitable for oral, enteral and parenteral use can be used to prepare the agents of the present invention. Examples of excipients used in producing a solid preparation include lactose, sucrose, starch, talc, cellulose, dextrin, kaolin, calcium carbonate and the like. Liquid preparations for oral administration, i.e. emulsions, syrups, suspensions, solutions, etc., contain generally used inert diluents such as water or vegetable oils. In addition to the inert diluent, the preparation may contain adjuvants such as wetting agents, suspending aids, sweeteners, fragrances, coloring agents or preservatives. Liquid preparations may be included in capsules of absorbable substances such as gelatin. Examples of the solvent or suspending agent used in the preparation of parenteral preparations, that is, injections, suppositories and the like include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecithin and the like. Examples of bases used for suppositories include cocoa butter, emulsified cocoa butter, laurin butter, witepsol and the like. The preparation method of a formulation may be a conventional method.
[0151]
When used by oral administration, the clinical dose is generally 0.01 to 1000 mg, preferably 10 to 1000 mg per day as a compound of the present invention for adults. It is more preferable to increase or decrease appropriately. The daily dose of the drug of the present invention may be administered once a day, divided into 2 or 3 times a day at an appropriate interval, or may be administered intermittently.
[0152]
When used as an injection, it is desirable to administer a continuous dose or intermittent dose of 0.001 to 100 mg as a compound of the present invention to an adult.
[0153]
【Example】
Hereinafter, the present invention will be described in detail with reference to examples. However, the present invention is not limited to the examples as long as the gist thereof is not exceeded.
In the following examples, the following conventional abbreviations are used.
THF = tetrahydrofuran, DMF = N, N-dimethylformamide
DMSO = dimethyl sulfoxide, CDI = carbonyldiimidazole,
DPPA = diphenylphosphoryl azide, Z = benzyloxycarbonyl,
Boc = tert-butyloxycarbonyl
NMR in the physical property values means a nuclear magnetic resonance spectrum, and the numbers are δ (delta) values usually used to display chemical shifts, and the unit is ppm. TMS (tetramethylsilane) was used as an internal standard. The number in parentheses displayed next to the δ value is the number of hydrogen atoms, and the subsequent display is s for a single line, d for a double line, t for a triple line, q for a quadruple line, and m for multiple lines. Lines and br mean broad absorption peaks.
[0154]
IR means infrared absorption spectrum, and measured as a potassium bromide tablet unless otherwise specified. Number indicates wave number, unit is cm ^-1 It is. Only the main absorption peak was shown. mp means melting point, and the unit is ° C., indicating an uncorrected value.
[0155]
Example 1
Synthesis of 4-amidino-[(S) -N-[(R) -2-methylsulfonylamino-cyclohexylacetyl] prolyl] aminomethylbenzene (Compound No. 105 in Table 1) hydrochloride
a) N-4-cyanobenzylphthalimide
To a solution of phthalimide potassium salt (76 g, 410 mmol) in DMF (250 ml) is added 4-cyanobenzyl bromide (73 g, 373 mmol) in THF (250 ml), and the mixture is stirred at 50 ° C. for 3 hours.
[0156]
Water (500 ml) is added to the mixture, and the precipitated crystals are collected, washed with water and dried to give 96 g (99%) of the title compound. mp 189-191 ° C
b) 4-cyano-[(S) -prolyl] aminomethylbenzene hydrochloride
To a solution of the compound obtained in a) (39 g, 150 mmol) in methanol (250 ml), hydrazine-hydrate (9 ml) is added and heated to reflux for 6 hours. After the solvent is distilled off, 300 ml of 40% aqueous sodium hydroxide solution is added and stirred.
[0157]
The reaction mixture is extracted with toluene, and the organic layer is washed once with water and once with saturated brine, and then dried over sodium sulfate. 15 g (73%) of the crude product obtained by distilling off the solvent is used as it is.
To a solution of (S) -N-Boc-proline (23.7 g, 110 mmol) in THF (250 ml) at 0 ° C. is added CDI (17.8 g, 110 mmol).
[0158]
After stirring the reaction solution for 2 hours, a solution of the crude product obtained in the above reaction in THF (150 ml) is added. After stirring for 6 hours, the solvent is distilled off and water (300 ml) is added to the reaction mixture. This is extracted with chloroform, and the organic layer is washed three times with water and once with saturated brine. After drying over sodium sulfate, the solvent is distilled off and the residue is purified by silica gel chromatography (hexane-ethyl acetate).
[0159]
The obtained oil is dissolved in ethyl acetate (100 ml), 4N hydrogen chloride ethyl acetate solution (69 ml) is added, and the mixture is stirred at 0 ° C. for 3 hr. The resulting white solid is collected, washed with ethyl acetate, and dried under reduced pressure to give 25.9 g (89%) of the title compound.
NMR (DMSO-d ⁶ )
1.80-1.96 (m, 3H), 2.30-2.40 (m, 1H), 3.21 (br, 2H), 4.26 (br, 1H), 4.44 (d, 2H), 7.49 (d, 2H), 7.82 (d, 2H), 8.59 (br, 1H), 9.39 (t, 1H), 10.07 (br, 1H)
[0160]
c) 4-cyano-[(S) -N-[(R) -2-t-butoxycarbonylamino-cyclohexylacetyl] prolyl] aminomethylbenzene
In a solution of 21 g (79 mmol) of the product obtained in b) and 20.4 g (79 mmol) of (R) -Nt-butoxycarbonylcyclohexylglycine in DMF (200 ml) at 0 ° C., 22 ml (159 mmol) of triethylamine and 22 g of DPPA A solution of (79 mmol) in DMF (50 ml) is added. Stir for 12 hours after warming to room temperature. Water (400 ml) is added to the reaction mixture and extracted with toluene-ethyl acetate (1: 2). The organic layer is washed 3 times with water and once with saturated brine, and then dried over sodium sulfate. After distilling off the solvent, the residue is purified by silica gel chromatography (chloroform-methanol) to obtain 26.7 g (72%) of the title compound.
[0161]
NMR (CDCl _Three )
1.01-1.43 (m, 15H), 1.65-2.38 (m, 9H), 3.57 (q, 1H), 3.96-4.06 (m, 2H), 4. 47 (dq, 2H), 4.69 (d, 1H), 5.12 (d, 1H), 7.35 (d, 2H), 7.59 (d, 2H), 7.73 (t, 1H) )
[0162]
d) 4-cyano-[(S) -N-[(R) -2-methylsulfonylamino-cyclohexylacetyl] -prolyl] aminomethylbenzene
To a solution of the compound obtained in c) (26.7 g, 57 mmol) in chloroform (50 ml) is added 4N hydrochloric acid ethyl acetate solution (30 ml) at 0 ° C. After stirring for 3 hours, the solvent is distilled off. The resulting residue is dissolved in dichloromethane (250 ml) and 19 ml of triethylamine is added. Add a solution of methanesulfonyl chloride (7.9 g, 68 mmol) in dichloromethane (50 ml) at 0 ° C. and stir for 3 hours. The organic layer is washed once with a saturated aqueous solution of sodium hydrogen carbonate, once with water and once with saturated brine, and then dried over sodium sulfate. The obtained residue is purified by silica gel chromatography (hexane-ethyl acetate) to give 18.6 g (73%) of the title compound.
[0163]
NMR (CDCl _Three )
0.9-1.29 (m, 5H), 1.60-1.85 (m, 5H), 2.0-2.4 (m, 5H), 2.89 (s, 3H), 3. 55 (q, 1H), 3.80-3.88 (m, 2H), 4.43 (d, 2H), 4.61 (d, 2H), 5.60 (d, 2H), 7.31 (T, 1H), 7.37 (d, 2H), 7.60 (d, 2H)
[0164]
e) 4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-cyclohexylacetyl] prolyl] aminomethylbenzene hydrochloride
To a solution of 18.6 g (42 mmol) of the compound obtained in d) in chloroform (100 ml) is added 37% hydrochloric acid ethanol solution (100 ml) at 0 ° C. After leaving to stand at 0 ° C. for 48 hours, the solvent is distilled off under reduced pressure. The resulting residue is dissolved in methanol (100 ml) and 16 g (166 mmol) of ammonium carbonate is added at 0 ° C. After stirring for 6 hours, the solvent is distilled off, and the resulting residue is purified by silica gel chromatography (chloroform-methanol) to give 15.2 g (73%) of the title compound.
[0165]
NMR (DMSO-d ⁶ )
9.39 (br, 4H), 8.66 (t, 1H), 7.81 (d, 2H), 7.48 (d, 2H), 7.40 (m, 1H), 4.47-4 .14 (m, 3H), 3.90 (m, 1H), 3.71 (m, 1H), 3.59 (m, 1H), 2.79 (s, 3H), 2.13 (m, 1H), 1.88 (m, 3H), 1.69-1.53 (m, 5H), 1.14 (m, 6H)
IR: 3366, 2930, 2855, 1636, 1541, 1489, 1451, 1152
The compounds shown in Examples 2 to 14 below were synthesized by the same method.
[0166]
Example 2
4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylbenzene (Compound No. 104 in Table 1) methanesulfonate
NMR (DMSO-d ⁶ )
9.31 (br, 2H), 9.11 (br, 2H), 8.60 (t, 1H), 7.76 (d, 2H), 7.47 (d, 2H), 7.42 (d , 2H), 4.50-4.06 (m, 4H), 3.49 (m, 1H), 3.71 (m, 1H), 2.71 (s, 3H), 2.40 (s, 3H), 2.13 (m, 1H), 1.98 (m, 2H), 1.84 (m, 1H), 1.48 (d, 2H), 0.98 (s, 9H)
IR: 3274, 2957, 1640, 1208, 1150, 1049
[0167]
Example 3
4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-3-cyclohexylpropionyl] prolyl] aminomethylbenzene (Compound No. 106 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.41 (br, 2H), 9.20 (br, 2H), 8.68 (t, 1H), 7.78 (d, 2H), 7.47 (d, 2H), 7.41 (d , 2H), 4.49-4.23 (m, 3H), 4.13 (m, 1H), 3.69 (m, 1H), 3.48 (m, 1H), 2.72 (s, 3H), 2.12 (m, 1H), 1.97 (m, 1H), 1.83 (m, 2H), 1.64 (m, 5H), 1.40 (m, 2H), 1. 19 (m, 4H), 0.94 (m, 2H)
IR: 3366, 2924, 1640, 1543, 1489, 1449, 1422
[0168]
Example 4
4-Amidino-[(S) -N-[(R) -N'-methylsulfonylphenylalanyl] prolyl] aminomethylbenzene (Compound No. 108 in Table 1) methanesulfonate
NMR (DMSO-d ⁶ )
9.31 (br, 2H), 9.08 (br, 2H), 8.57 (t, 1H), 7.75 (d, 2H), 7.71 (d, 1H), 7.47 (d , 2H), 7.29 (m, 5H), 4.52-4.21 (m, 3H), 3.54 (m, 2H), 3.28 (m, 2H), 3.04 (m, 1H), 2.90 (m, 2H), 2.71 (s, 3H), 2.50 (s, 3H), 1.88 (m, 2H)
IR: 3375, 1663, 1630, 1454, 1327, 1225, 1154, 1046
[0169]
Example 5
4-Amidino-[(S) -N-[(R) -N'-methylsulfonylmethionyl] prolyl] aminomethylbenzene (Compound No. 110 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.45 (br, 2H), 9.26 (br, 2H), 8.68 (t, 1H), 7.80 (d, 2H), 7.55 (d, 2H), 7.48 (d , 2H), 4.44-4.17 (m, 4H), 3.70 (m, 1H), 3.59 (m, 1H), 2.87 (s, 3H), 2.56 (m, 3H), 2.13 (m, 1H), 2.08 (s, 3H), 1.97-1.63 (m, 4H)
IR: 3368, 1638, 1543, 1489, 1426, 1314, 1150
[0170]
Example 6
4-Amidino-[(S) -N-[(R) -N'-formylphenylalanyl] prolyl] aminomethylbenzene (Compound No. 94 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.56 (br, 2H), 9.36 (br, 2H), 8.97 (t, 1H), 8.70-8.60 (m, 1H), 7.86 (d, 1H), 7 .83 (d, 2H), 7.46 (d, 2H), 7.37-7.17 (m, 5H), 4.36-4.16 (m, 4H), 3.60-2.70 (M, 4H), 2.40-1.20 (m, 4H)
IR: 3370, 1647, 1541, 1489, 1454, 1404, 704
[0171]
Example 7
4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-hexanoyl] prolyl] aminomethylbenzene (Compound No. 109 in Table 1) methanesulfonate
NMR (DMSO-d ⁶ )
9.32 (br, 2H), 9.11 (br, 2H), 8.58 (t, 1H), 7.76 (d, 2H), 7.48 (d, 2H), 7.42 (d , 1H), 4.47-4.23 (m, 2H), 4.20-3.90 (m, 3H), 3.54-3.45 (m, 1H), 3.80-3.66. (M, 1H), 2.74 (s, 3H), 2.43 (s, 3H), 2.20-0.79 (m, 13H)
IR: 3272, 1638, 1543, 1424, 1316, 1206, 1155, 1047
[0172]
Example 8
4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-4- (4'-methoxycarbonylphenyl) butanoyl] prolyl] aminomethylbenzene (Compound No. 127 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.35-9.23 (m, 4H), 8.59 (t, 1H), 7.90 (d, 2H), 7.77 (d, 2H), 7.61 (d, 1H), 7 .47 (d, 2H), 7.40 (d, 2H), 4.44-4.21 (m, 3H), 4.07 (m, 1H), 3.84 (s, 3H), 3. 48 (m, 2H), 2.92-2.63 (m, 3H), 2.77 (s, 3H), 2.12 (m, 1H), 1.84 (m, 4H) IR: 3370, 1638, 1541, 1489, 1437, 1287, 1150
[0173]
Example 9
4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-3- (3'-carboxyphenoxy) propanoyl] prolyl] aminomethylbenzene (Compound No. 130 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.35 (br, 4H), 8.64 (t, 1H), 7.78 (d, 2H), 7.71 (d, 1H), 7.58-7.40 (m, 5H), 7 .20 (m, 1H), 4.62 (m, 1H), 4.36 (m, 3H), 4.22 (m, 2H), 3.72 (m, 2H), 2.89 (s, 3H), 2.12 (m, 1H), 1.94 (m, 3H)
IR: 3856, 1644, 1543, 1489, 1449, 1316, 1256, 1154
[0174]
Example 10
4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-3- (2'-benzyloxycarbonylphenoxy) propanoyl] prolyl] aminomethylbenzene (Compound No. 123 in Table 1) hydrochloric acid salt
NMR (DMSO-d ⁶ )
9.24 (br, 4H), 8.60 (t, 1H), 7.77 (d, 2H), 7.71 (m, 1H), 7.57 (m, 1H), 7.49-7 .35 (m, 8H), 7.16 (d, 1H), 7.07 (t, 1H), 5.29 (s, 2H), 4.62 (t, 1H), 4.37 (m, 3H), 4.28 (m, 1H), 4.17 (t, 1H), 3.67 (m, 2H), 2.91 (s, 3H), 2.15 (m, 1H), 1. 88 (m, 3H)
IR: 3366, 1642, 1491, 1451, 1314, 1248, 1082
[0175]
Example 11
4-Amidino-[(S) -N-[(R) -2-ethoxycarbonylamino-3-methyl-3-methylthiobutanoyl] prolyl] aminomethylbenzene (Compound No. 98 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.89 (br, 2H), 8.66 (br, 2H), 7.77 (d, 2H), 7.33 (d, 2H), 6.27 (d, 1H), 4.65 (m , 1H), 4.46 (d, 1H), 4.37 (m, 2H), 3.97-3.72 (m, 4H), 2.62 (m, 1H), 2.15 (br, 3H), 2.04 (s, 3H), 1.40 (s, 3H), 1.36 (s, 3H), 1.05 (t, 3H)
IR: 3323, 2926, 1635, 1535, 1439, 1242, 1055
[0176]
Example 12
4-Amidino-[(S) -N-[(R) -2-carboxymethylsulfonylaminoheptanoyl] prolyl] aminomethylbenzene (Compound No. 152 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.80 (br, 2H), 9.23 (br, 2H), 8.80 (t, 1H), 7.69 (d, 2H), 7.42 (d, 2H), 7.23 (d , 1H), 4.51-4.17 (m, 5H), 3.70 (m, H), 2.11 (m, 1H), 1.92 (m, 3H), 1.57-1. 28 (m, 8H), 0.87 (m, 3H)
IR: 3366, 2957, 1636, 1543, 1489, 1416, 1318, 1136
[0177]
Example 13
4-Amidino-[(S) -N- (4-phenylbutanoyl) prolyl] aminomethylbenzene (Compound No. 3 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.39 (br, 2H), 9.22 (br, 2H), 8.55 (t, 1H), 7.80 (d, 2H), 7.48 (d, 2H), 7.31-7 .13 (m, 5H), 4.37-4.30 (m, 3H), 3.60-3.30 (m, 2H), 2.60 (t, 2H), 2.34-1.75 (M, 8H)
IR: 3264, 1618, 1541, 1491, 1451, 702
[0178]
Example 14
4-Amidino-[(S) -N- (2-benzyloxyacetyl) prolyl] aminomethylbenzene (Compound No. 55 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.41 (br, 2H), 9.23 (br, 2H), 8.66 (t, 1H), 7.80 (d, 2H), 7.49 (d, 2H), 7.42-7 .27 (m, 5H), 4.61-4.08 (m, 7H), 3.56-3.40 (m, 2H), 2.20-1.78 (m, 4H)
IR: 3262, 1645, 1539, 1489, 1454, 740
[0179]
Example 15
Synthesis of trans-4-amidino-[(S) -N-[(R) -2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexane (Compound No. 263 in Table 1) hydrochloride
a) trans-4-N-benzyloxycarbonylaminomethyl-cyclohexylnitrile
[0180]
To a solution of 25 g (159 mmol) of trans-4-aminomethylcyclohexanecarboxylic acid and 20 g (191 mmol) of sodium carbonate in water (300 ml), 27 ml (190 mmol) of benzyloxycarbonyl chloride is added at 0 ° C. After stirring for 6 hours, 1N hydrochloric acid is added until the pH reaches 2, and the precipitated white solid is collected, washed with water and dried. The obtained white solid is dissolved in THF (300 ml), and 21 g (130 mmol) of CDI is added at 0 ° C. After stirring for 3 hours, the reaction mixture is added dropwise at 0 ° C. to a mixture of concentrated aqueous ammonia (50 ml) and THF (150 ml). After stirring for 5 hours, the solvent is distilled off, water (500 ml) is added, and the precipitated white solid is collected, washed with water and dried.
[0181]
To a 1,2-dichloroethane (500 ml) solution of the obtained compound, 19 ml (260 mmol) of thionyl chloride is added and heated to an internal temperature of 70 ° C. After stirring for 5 hours, the reaction mixture is poured into ice water and neutralized with 1N aqueous sodium hydroxide solution. Chloroform extraction is performed, and the organic layer is washed twice with water and once with saturated brine, and dried over sodium sulfate. After distilling off the solvent, the resulting crude product is recrystallized (hexane-ethyl acetate) to give 22.8 g (53%) of the title compound. mp90-92 ° C
b) The compound obtained with trans-4- (S) -prolylaminomethyl-cyclohexylnitrile a) is dissolved in ethanol (250 ml) and subjected to catalytic reduction at normal temperature and pressure in the presence of palladium black (1 g). After completion of the reaction, the catalyst is filtered off and the solvent is distilled off.
[0182]
To a solution of (S) -N-benzyloxycarbonylproline 20.7 g (83 mmol) in THF (150 ml) is added CDI 13.5 g (83 mmol) at 0 ° C. After stirring for 3 hours, a THF (200 ml) solution of the compound obtained by the above reduction reaction is added at 0 ° C. After stirring for 12 hours, the solvent is distilled off, and chloroform (400 ml) is added to the resulting residue. The organic layer is washed 3 times with water and once with saturated brine, and then dried over sodium sulfate. The solvent is distilled off, and the resulting residue is purified by silica gel column chromatography (chloroform-methanol).
[0183]
The obtained compound is dissolved in ethanol (250 ml), and catalytic reduction is carried out at normal temperature and pressure in the presence of palladium black (1 g). After completion of the reaction, the catalyst is filtered off and the solvent is distilled off to obtain 18.8 g (95%) of the title compound.
NMR (DMSO-d ⁶ )
0.88-1.06 (m, 2H), 1.38-1.52 (m, 3H), 1.68-2.03 (m, 7H), 2.20-2.40 (m, 1H) ), 2.52-2.67 (m, 1H), 2.80-3.20 (m, 4H), 4.03-4.10 (m, 1H), 7.53 (br, 1H), 8.65-8.70 (m, 1H)
[0184]
c) trans-4-amidino-[(S) -N-[(R) -2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexane hydrochloride
The title compound is synthesized from the compound obtained in b) and (R) -2-t-butyloxycarbonylamino-4,4-dimethylpentanoic acid by the same method as in c) to e) of Example 1. .
[0185]
NMR (DMSO-d ⁶ )
8.95 (br, 2H), 8.69 (br, 2H), 7.60 (br, 1H), 6.32 (br, 1H), 4.56 (m, 1H), 4.39 (m , 1H), 4.18 (q, 2H), 4.10 (m, 1H), 3.52 (m, 1H), 3.19 (m, 1H), 2.89 (m, 1H), 2 .69 (m, 1H), 2.14-1.59 (m, 12H), 1.26 (t, 3H), 0.98 (s, 9H), 0.98-0.89 (m, 2H) )
IR: 3314, 2954, 1686, 1639, 1543, 1449, 1250, 1059
The compounds shown in Examples 16 to 23 below were synthesized by the same method.
[0186]
Example 16
Synthesis of trans-4-amidino-[(S) -N-[(R) -2-ethoxycarbonylamino-3-cyclohexylpropanoyl] prolyl] aminomethylcyclohexane (Compound No. 227 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.93 (br, 2H), 8.81 (br, 2H), 7.53 (br, 1H), 7.38 (t, 1H), 4.40-4.15 (m, 1H), 4 .10-3.90 (m, 2H), 3.73-3.17 (m, 2H), 3.05-2.80 (m, 3H), 2.39 (br, 1H), 2.00 -0.68 (m, 29H)
IR: 3297, 2926, 2853, 1684, 1543, 1449, 1262, 1053
[0187]
Example 17
Trans-4-Amidino-[(S) -N-[(R) -2-isopropoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexane (Compound No. 265 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.91 (br, 2H), 8.78 (br, 2H), 7.55 (br, 1H), 7.28 (t, 1H), 4.78-4.70 (m, 1H), 4 .30-3.92 (m, 1H), 3.80-3.20 (m, 3H), 3.0-2.75 (m, 2H), 2.50-1.37 (m, 14H) 1.18-1.00 (m, 6H), 1.0-0.81 (m, 1H)
IR: 3285, 2953, 2870, 1684, 1541, 1449, 1250, 1111
[0188]
Example 18
Trans-4-Amidino-[(S) -N-[(R) -N'-methylsulfonylphenylalanyl] prolyl] aminomethylcyclohexane (Compound No. 250 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.88 (br, 2H), 8.75 (br, 2H), 7.85 (t, 1H), 7.65 (d, 1H), 4.27 (m, 1H), 4.16 (m , 1H), 3.51-3.41 (m, 4H), 2.99-2.70 (m, 4H), 2.78 (s, 3H), 2.38 (t, 1H), 1. 90-1.40 (m, 9H), 1.08-0.87 (m, 2H)
IR: 3375, 2930, 1637, 1452, 1309, 1149, 1097, 983
[0189]
Example 19
Trans-4-Amidino-[(S) -N-[(R) -N'-methylsulfonylleucyl] prolyl] aminomethylcyclohexane (Compound No. 269 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.89 (br, 2H), 8.85 (br, 2H), 6.56 (d, 1H), 4.53 (m, 1H), 4.17 (m, 1H), 3.86 (m , 1H), 3, 47 (m, 1H), 3.07 (m, 2H), 2.97 (s, 3H), 2.13-1.80 (m, 10H), 1.63-1. 54 (m, 4H), 1.33 (m, 1H), 0.98-0.87 (m, 2H), 0.97 (d, 6H)
IR: 3261, 9322, 1639, 1450, 1313, 1143, 1087, 985
[0190]
Example 20
Trans-4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-3-cyclohexylpropanoyl] prolyl] aminomethylcyclohexane (Compound No. 230 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.95 (br, 2H), 8.53 (br, 2H), 7.27 (m, 1H), 6.51 (d, 1H), 4.51 (m, 1H), 4.19 (m , 1H), 3.83 (m, 1H), 3.66 (m, 1H), 3.41 (m, 2H), 3.04 (m, 2H), 3.04 (m, 2H), 2 .95 (s, 3H), 2.46 (t, 1H), 2.12-0.92 (m, 24H)
IR: 3265, 2926, 1639, 1545, 1448, 1315, 1143, 985
[0191]
Example 21
Trans-4-Amidino-[(S) -N-[(R) -2-isopropoxycarbonylamino-2-cyclohexylacetyl] prolyl] aminomethylcyclohexane (Compound No. 228 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.91 (br, 2H), 8.69 (br, 2H), 7.36 (br, 1H), 5.99 (d, 1H), 4.84-4.79 (m, 1H), 4 .58 (br, 2H), 4.53-4.50 (m, 2H), 4.10-3.90 (m, 2H), 3.60-3.40 (m, 1H), 2.50 -0.97 (m, 30H)
IR: 3297, 2980, 2930, 2855, 1684, 1539, 1451, 1258
[0192]
Example 22
Trans-4-Amidino-[(S) -N-[(R) -2-ethoxycarbonylamino-4-ethyl-hexanoyl] prolyl] aminomethylcyclohexane (Compound No. 264 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.91 (br, 2H), 8.70 (br, 2H), 7.54 (m, 1H), 6.34 (m, 1H), 4.56 (m, 1H), 4.38 (m , 1H), 4.11 (m, 3H), 3.48 (m, 1H), 3.21 (m, 1H), 2.88 (m, 1H), 2.68 (m, 1H), 2 .30-1.19 (m, 18H), 1.26 (t, 3H), 0.96 (m, 2H), 0.86 (t, 6H)
IR: 3279, 2962, 1685, 1639, 1541, 1448, 1257, 1059, 752
[0193]
Example 23
Trans-4-Amidino-[(S) -N-[(R) -2-t-butoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexane (Compound No. 266 in Table 1) glycolic acid salt
NMR (DMSO-d ⁶ )
9.54 (br, 2H), 8.72 (br, 2H), 7.54 (br, 1H), 7.01 (t, 1H), 4.60-4.00 (m, 4H), 3 .40 (m, 2H), 3.10-2.75 (m, 3H), 2.35 (br, 1H), 2.00-1.20 (m, 24H), 0.91 (s, 9H) )
IR: 3316, 2953, 1686, 1543, 1449, 1368, 1167
[0194]
Example 24
Synthesis of 4-[(S) -N-[(R) -2-t-butoxycarbonylamino-cyclohexylacetyl] prolyl] aminomethyl-benzamide oxime (Compound No. 396 in Table 1)
To a solution of 0.94 g (2 mmol) of the compound obtained in c) of Example 1 in ethanol (15 ml), a solution of sodium carbonate 0.17 g (1.6 mmol) in water (3 ml) and 0.22 g of hydroxyamine hydrochloride ( 3.2 mmol) is added. The reaction mixture is heated to reflux for 8 hours, and then the solvent is distilled off. The obtained residue is purified by silica gel column chromatography (chloroform-methanol) to obtain 0.84 g (84%) of the title compound.
[0195]
NMR (CDCl _Three )
1.0-1.49 (m, 14H), 1.5-2.4 (m, 10H), 3.56 (br, 1H), 3.97 (br, 1H), 4.09 (t, 1H), 4.41 (dq, 2H), 4.67 (d, 1H), 4.94 (br, 2H), 5.41 (d, 1H), 7.20 (d, 2H), 7. 23-7.27 (m, 1H), 7.50 (d, 2H), 7.75 (br, 1H)
IR: 3345, 2978, 2930, 2855, 1640, 1528, 1449, 1167
The compounds shown in Examples 25 to 47 below were synthesized by the same method.
[0196]
Example 25
4-[(S) -N-phenylacetylprolyl] aminomethyl-benzamide oxime (Compound No. 374 in Table 1)
NMR (CDCl _Three )
8.11 (t, 1H), 7.37 (d, 2H), 7.28-7.23 (m, 5H), 7.08 (d, 2H), 4.88 (s, 2H), 4 .68 (d, 1H), 4.51 (m, 1H), 4.21 (m, 1H), 3.71 (s, 2H), 3.63-3.51 (m, 2H), 2. 40-2.01 (m, 4H)
IR: 3315, 2968, 1637, 1543, 1244, 1155, 927, 709
[0197]
Example 26
4-[(S) -N-[(R) -N'-ethoxycarbonylphenylalanyl] prolyl] aminomethyl-benzamide oxime (Compound No. 387 in Table 1)
NMR (CDCl _Three )
7.54 (d, 2H), 7.27-7.19 (m, 7H), 6.31 (d, 1H), 5.05 (br, 2H), 4.65-4.42 (m, 3H), 4.24-4.10 (m, 1H), 3.80-3.40 (m, 3H), 3.10-2.95 (m, 2H), 2.60-2.50 ( m, 1H), 2.14 (br, 1H), 1.95-1.50 (m, 3H), 0.99 (t, 3H)
IR: 3339, 1641, 1539, 1451, 1260, 752, 702
[0198]
Example 27
4-[(S) -N-[(R) -2-t-butoxycarbonylamino-3-cyclohexylpropanoyl] prolyl] aminomethyl-benzamide oxime (Compound No. 397 in Table 1)
NMR (CDCl _Three )
7.75 (br, 1H), 7.50 (d, 2H), 7.21 (d, 2H), 5.40 (d, 1H), 4.94 (br, 2H), 4.64 (br , 1H), 4.40-4.25 (m, 3H), 3.95 (br, 1H), 3.50-3.40 (m, 1H), 2.0-0.80 (m, 26H) )
IR: 3337, 2978, 2924, 2851, 1642, 1536, 1449, 1167
[0199]
Example 28
4-[(S) -N-[(R) -2-ethoxycarbonylamino-3-methyl-3-methylthiobutanoyl] propyl] aminomethyl-benzamide oxime (Compound No. 419 in Table 1)
NMR (CDCl _Three )
7.66 (t, 1H), 7.53 (d, 2H), 7.23 (d, 2H), 5.64 (d, 1H), 4.91 (s, 2H), 4.68 (d , 1H), 4.58-4.30 (m, 3H), 3.90 (m, 1H), 3.87-3.76 (m, 2H), 3.62 (m, 1H), 2. 37 (m, 1H), 2.09-2.00 (m, 3H), 2.06 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H), 1.09 (T, 3H)
IR: 3339, 2978, 1641, 1535, 1439, 1249, 1057, 929, 754
[0200]
Example 29
4-[(S) -N-[(R) -Phenylalanyl] prolyl] aminomethyl-benzamide oxime (Compound No. 390 in Table 1) dihydrochloride
NMR (DMSO-d ⁶ )
11.24 (br, 1H), 9.02 (br, 2H), 8.91 (t, 1H), 8.80 (br, 3H), 7.66 (d, 2H), 7.44 (d , 2H), 7.35-7.22 (m, 5H), 4.30-4.16 (m, 4H), 3.57-2.95 (m, 3H), 2.45-2.30. (M, 1H), 1.90-1.20 (m, 4H)
IR: 3059, 1649, 1539, 1491, 1454
[0201]
Example 30
Trans-4-[(S) -N-[(R) -2-isopropoxycarbonylamino-2-cyclohexylacetyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 430 in Table 1)
NMR (CDCl _Three )
7.14 (br, 1H), 5.70 (d, 1H), 4.85-4.80 (m, 1H), 4.70-4.50 (m, 3H), 4.17-4. 08 (m, 2H), 3.96 (br, 1H), 3.54 (q, 1H), 3.05 (t, 2H), 2.40-2.20 (m, 1H), 2.09 -0.88 (m, 30H)
IR: 3342, 2978, 2928, 2855, 1653, 1449, 1256, 1111
[0202]
Example 31
Trans-4-[(S) -N-[(R) -2-t-butoxycarbonylamino-3-cyclohexylpropanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 435 in Table 1)
NMR (CDCl _Three )
7.14 (br, 1H), 5.40 (d, 1H), 4.60-4.33 (m, 5H), 3.88 (br, 1H), 3.43 (q, 1H), 3 20-3.11 (m, 1H), 3.0-2.96 (m, 1H), 2.40-2.30 (m, 1H), 2.0-0.84 (m, 35H)
IR: 3356, 2926, 2853, 1649, 1537, 1448, 1167
[0203]
Example 32
Trans-4-[(S) -N-[(R) -2-t-butoxycarbonylamino-2-cyclohexylacetyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 433 in Table 1)
NMR (CDCl _Three )
7.15 (br, 1H), 5.28 (d, 1H), 4.58 (br, 4H), 4.09 (t, 1H), 3.92 (br, 1H), 3.53 (q , 1H), 3.20-2.90 (m, 2H), 2.40 (br, 1H), 2.10-0.91 (m, 33H)
IR: 3347, 2930, 2855, 1649, 1541, 1451, 1169
[0204]
Example 33
Trans-4-[(S) -N-[(R) -2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 461 in Table 1)
NMR (CDCl _Three )
7.06 (t, 1H), 5.56 (d, 1H), 4.57-4.39 (m, 4H), 4.11 (q, 2H), 3.98 (m, 1H), 3 .47 (m, 1H), 3.05 (m, 2H), 2.39 (m, 1H), 2.04-1.78 (m, 10H), 1.57 (d, 2H), 1. 56-1.12 (m, 2H), 1.24 (t, 3H), 0.99 (s, 9H), 0.99-0.89 (m, 2H)
IR: 3356, 2934, 1649, 1541, 1446, 1249, 1059, 927
[0205]
Example 34
Trans-4-[(S) -N-[(R) -2-methoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 458 in Table 1)
NMR (CDCl _Three )
7.04 (t, 1H), 5.53 (d, 1H), 4.68 (s, 2H), 4.56 (d, 1H), 4.43 (m, 1H), 3.98 (m , 1H), 3.66 (s, 3H), 3.47 (m, 1H), 3.07 (m, 2H), 2.39 (m, 1H), 2.19-1.77 (m, 8H), 1.57 (d, 2H), 1.55-1.25 (m, 4H), 0.99 (s, 9H), 0.93 (m, 2H)
IR: 3344, 2949, 1712, 1649, 1548, 1448, 1249, 1059
[0206]
Example 35
Trans-4-[(S) -N-[(R) -2-t-butoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 467 in Table 1)
NMR (CDCl _Three )
7.12 (t, 1H), 5.14 (d, 1H), 4.58 (d, 1H), 4.53 (s, 2H), 4.37 (m, 1H), 3.92 (m , 1H), 3.45 (m, 1H), 3.19 (m, 1H), 2.95 (m, 1H), 2.42 (m, 1H), 2.06-1.79 (m, 8H), 1.53 (d, 2H), 1.52-1.34 (m, 4H), 1.43 (s, 9H), 0.99 (s, 9H), 1.00-0.89 (M, 2H)
IR: 3358, 2930, 1649, 1535, 1448, 1367, 1249, 1168
[0207]
Example 36
Trans-4-[(S) -N-[(R) -2-benzyloxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 469 in Table 1)
NMR (CDCl _Three )
7.36-7.27 (m, 5H), 7.04 (t, 1H), 5.63 (d, 1H), 5.16-5.00 (m, 2H), 4.58-4. 46 (m, 4H), 3.97 (m, 1H), 3.47 (m, 1H), 3.06-2.92 (m, 2H), 2.43-2.38 (m, 1H) 2.01-1.72 (m, 8H), 1.58 (d, 2H), 1.50-1.23 (m, 4H), 0.98 (s, 9H), 0.98-0 .88 (m, 2H)
IR: 3356, 2928, 1649, 1541, 1448, 1249, 1053, 929
[0208]
Example 37
Trans-4-[(S) -N-[(R) -2-isopropoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 464 in Table 1)
NMR (CDCl _Three )
7.11 (t, 1H), 5.49 (d, 1H), 4.83 (m, 1H), 4.56 (m, 3H), 4.42 (dd, 1H), 3.98 (m , 1H), 3.47 (dd, 1H), 3.04 (m, 2H), 2.40 (m, 1H), 2.01 (m, 2H), 1.92 (m, 3H), 1 .80 (m, 3H), 1.57 (d, 2H), 1.39 (m, 4H), 1.21 (m, 6H), 0.99 (s, 9H), 0.94 (m, 2H)
IR: 3343, 1649, 1541, 1449, 1275
[0209]
Example 38
Trans-4-[(S) -N-[(R) -2-isopropoxycarbonylamino-2-cyclopentylacetyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 429 in Table 1)
NMR (CDCl _Three )
7.14 (t, 1H), 5.42 (d, 1H), 4.83 (m, 1H), 4.60 (d, 1H), 4.52 (s, 2H), 4.13 (m , 1H), 3.98 (m, 1H), 3.56 (m, 1H), 3.04 (m, 2H), 2.35 (m, 1H), 2.24 (m, 1H), 2 .10-1.30 (m, 20H), 1.23 (dd, 6H), 1.01-0.93 (m, 2H)
IR: 3344, 2934, 1649, 1541, 1448, 1275, 1111, 754
[0210]
Example 39
Trans-4-[(S) -N-[(R) -2-t-butoxycarbonylamino-2-cyclopentylacetyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 432 in Table 1)
NMR (CDCl _Three )
7.16 (t, 1H), 5.16 (d, 1H), 4.60 (d, 1H), 4.51 (s, 2H), 4.14 (t, 1H), 3.94 (m , 1H), 3.52 (m, 1H), 3.01 (m, 2H), 2.38 (m, 1H), 2.23-1.39 (m, 21H), 1.43 (s, 9H), 1.17-0.90 (m, 2H)
IR: 3350, 2932, 1649, 1541, 1448, 1367, 1251, 1167, 929
[0211]
Example 40
Trans-4-[(S) -N-[(R) -2-ethoxycarbonylamino-3-cyclohexylpropanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 428 in Table 1)
NMR (CDCl _Three )
7.08 (br, 1H), 5.53 (d, 1H), 4.80-4.40 (m, 4H), 4.10-3.85 (m, 4H), 3.44 (q, 1H), 3.06 (t, 3H), 2.15-0.90 (m, 29H)
IR: 3343, 2926, 2853, 1649, 1541, 1449, 1260, 1053
[0212]
Example 41
Trans-4-[(S) -N-[(R) -2-isopropoxycarbonylamino-3-cyclohexylpropanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 431 in Table 1)
NMR (CDCl _Three )
7.12 (br, 1H), 5.51 (d, 1H), 4.85-4.70 (m, 1H), 4.60-4.30 (m, 4H), 4.0-3. 85 (m, 1H), 3.44 (q, 1H), 3.10-2.95 (m, 3H), 2.45-2.35 (m, 1H), 2.05-0.80 ( m, 32H)
IR: 3347, 2978, 2926, 2853, 1649, 1539, 1449, 1261, 1111
[0213]
Example 42
Trans-4-[(S) -N-[(R) -2-isopropoxycarbonylamino-4-ethyl-hexanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 463 in Table 1)
NMR (CDCl _Three )
7.11 (t, 1H), 5.41 (d, 1H), 4.83 (m, 1H), 4.56 (m, 3H), 4.39 (m, 1H), 3.94 (m , 1H), 3.46 (m, 1H), 3.02 (m, 2H), 2.39 (m, 1H), 2.10-1.20 (m, 20H), 1.22 (dd, 6H), 1.02-0.84 (m, 2H), 0.86 (t, 6H)
IR: 3346, 2962, 2930, 1653, 1541, 1448, 1271, 1113
[0214]
Example 43
Trans-4-[(S) -N-[(R) -2-t-butoxycarbonylamino-4-ethyl-hexanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 466 in Table 1)
NMR (CDCl _Three )
7.19 (t, 1H), 5.14 (d, 1H), 4.60 (d, 1H), 4.50 (s, 2H), 4.33 (m, 1H), 3.89 (m , 1H), 3.43 (m, 1H), 3.15 (m, 1H), 2.95 (m, 1H), 2.40 (m, 1H), 2.10-1.19 (m, 20H), 1.43 (s, 9H), 1.04-0.89 (m, 2H), 0.86 (t, 6H)
IR: 3346, 2964, 2930, 1649, 1541, 1448, 1367, 1280, 1251, 1168, 929
[0215]
Example 44
Trans-4-[(S) -N-[(R) -2-Ethoxycarbonylamino-heptanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 459 in Table 1)
NMR (CDCl _Three )
7.08 (t, 1H), 5.60 (d, 1H), 4.58 (m, 3H), 4.35 (m, 1H), 4.07 (m, 2H), 3.92 (m , 1H), 3.48 (m, 1H), 3.06 (m, 2H), 2.40 (m, 1H), 2.04-1.32 (m, 20H), 1.24 (t, 3H), 0.89 (t, 3H), 0.98 (m, 2H)
IR: 3346, 2928, 1649, 1541, 1448, 1255, 1055, 927
[0216]
Example 45
Trans-4-[(S) -N-[(R) -N'-t-butoxycarbonyl-methionyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 468 in Table 1)
NMR (CDCl _Three )
7.07 (m, 1H), 5.31 (d, 1H), 4.55 (m, 4H), 3.56 (m, 1H), 3.10 (m, 2H), 2.57 (t , 2H), 2.37 (m, 1H), 2.11 (s, 3H), 2.06-1.29 (m, 14H), 1.43 (s, 9H), 1.00 (m, 2H)
IR: 3354, 2928, 1647, 1541, 1448, 1367, 1251, 1167
[0217]
Example 46
Trans-4-[(S) -N-[(R) -2-hydroxy-4,4-dimethyl-pentanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 454 in Table 1)
NMR (CDCl _Three )
7.19 (t, 1H), 4.68 (s, 2H), 4.50 (d, 1H), 4.36 (t, 1H), 3.64 (t, 1H), 3.39 (m , 1H), 3.06 (m, 2H), 2.35 (m, 2H), 2.16-1.79 (m, 9H), 1.44 (d, 2H), 1.43-1. 25 (m, 3H), 1.00-0.95 (m, 2H), 1.02 (s, 9H)
IR: 3337, 2944, 1653, 1620, 1566, 1448, 1386, 1248, 1087
[0218]
Example 47
Trans-4-[(S) -N-[(R) -2-Ethoxycarbonylamino-4-ethyl-hexanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 460 in Table 1)
NMR (CDCl _Three )
7.07 (t, 1H), 5.53 (d, 1H), 4.56 (m, 3H), 4.40 (m, 1H), 4.11 (q, 2H), 3.96 (m , 1H), 3.45 (m, 1H), 3.05 (m, 2H), 2.36 (m, 1H), 2.09-1.77 (m, 10H), 1.61-1. 21 (m, 8H), 1.24 (t, 3H), 1.02-0.83 (m, 2H), 0.86 (t, 6H)
IR: 3342, 2962, 2930, 1649, 1541, 1448, 1379, 1269, 1059, 929
[0219]
Example 48
Trans-4-[(S) -N-[(R) -2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide O-methoxycarbonyloxime (Compound No. 531 in Table 1) To a solution of 4.2 g (8.9 mmol) of the compound obtained in Synthesis Example 33 and 1.9 ml (13.3 mmol) of triethylamine in dichloromethane (100 ml) at 0 ° C., 1.0 g (10 mmol) of methyl chlorocarbonate in dichloromethane Add (10 ml) solution. After stirring for 4 hours, the organic layer is washed once with a saturated aqueous solution of sodium bicarbonate, once with water and once with saturated brine. After drying over sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel column chromatography (ethyl acetate-methanol) to give 2.9 g (62%) of the title compound.
[0220]
NMR (CDCl _Three )
0.89-1.07 (m, 11H), 1.21-1.60 (m, 8H), 1.79-2.40 (m, 9H), 3.0-3.10 (m, 2H) ), 3.40-3.50 (m, 1H), 3.84 (s, 3H), 3.84-4.20 (m, 3H), 4.35-4.40 (m, 1H), 4.55 (d, 1H), 4.81 (br, 2H), 5.19 (d, 1H), 7.12 (t, 1H)
IR: 3345, 2953, 1763, 1699, 1645, 1541, 1443, 1256
The compounds shown in Examples 49 to 51 below were synthesized in the same manner.
[0221]
Example 49
4-[(S) -N-[(R) -2-hydroxy-2-cyclohexylacetyl] prolyl] aminomethylbenzamide O-ethoxycarbonyloxime (Compound No. 543 in Table 1)
NMR (CDCl _Three )
7.56 (d, 2H), 7.47 (t. 1H), 7.22 (d, 2H), 5.35 (s, 2H), 4.53 (m, 2H), 4.37 (d , 2H), 4.30 (q, 2H), 4.07 (m, 1H), 3.64 (m, 1H), 3.47 (m, 1H), 3.39 (m, 1H), 2 .35-1.17 (m, 15H), 1.35 (t, 3H)
IR: 3368, 2928, 1772, 1628, 1554, 1452, 1404, 1228, 1087, 856
[0222]
Example 50
Trans-4-[(S) -N-[(R) -2-hydroxy-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide O-methoxycarbonyloxime (Compound No. 534 in Table 1)
NMR (DCCl _Three )
7.07 (t, 1H), 4.77 (s, 2H), 4.52 (d, 1H), 4.34 (m, 1H), 3.85 (s, 3H), 3.58 (t , 1H), 3.37 (m, 1H), 3.22 (d, 1H), 3.12-3.05 (m, 2H), 2.26-2.21 (m, 1H), 1. 97-1.37 (m, 13H), 1.03 (s, 9H), 1.09-0.95 (m, 2H)
IR: 3346,2953,1763,1643,1442,1257,1089,879
[0223]
Example 51
Trans-4-[(S) -N-[(R) -2-hydroxy-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide O-ethoxycarbonyloxime (Compound No. 556 in Table 1)
NMR (DCCl _Three )
7.05 (t, 1H), 4.73 (s, 2H), 4.52 (d, 1H), 4.34 (t, 1H), 4.27 (q, 2H), 3.58 (m , 1H), 3.45 (m, 1H), 3.08 (m, 2H), 2.44 (m, 1H), 2.30-1.30 (m, 13H), 1.32 (t, 3H), 1.03 (s, 9H), 1.07-0.92 (m, 2H)
IR: 3373, 2953, 1759, 1641, 1450, 1369, 1248, 1093
[0224]
Example 52
Trans-4-amino-[(S) -N-[(R) -N'-methanesulfonylphenylalanyl] prolyl] aminomethylcyclohexane (Compound No. 776 in Table 1) Synthesis of L-tartrate
a) trans-4-t-butoxycarbonylamino-benzyloxycarbonylaminomethylcyclohexane
[0225]
To a solution of 15.7 g (100 mmol) of trans-aminomethylcyclohexanecarboxylic acid and 4.0 g (100 mmol) of sodium hydroxide in water (30 ml), 15.6 ml (110 mmol) of benzyloxycarbonyl chloride and sodium hydroxide 4. A solution of 4 g (110 mmol) in water (30 ml) is slowly added dropwise at the same time. After stirring for 4 hours, the mixture is extracted once with ether, and 1N hydrochloric acid is added to the aqueous layer until the pH is 2. The precipitated white solid is collected and dried.
[0226]
To a solution of 12.8 g (50 mmol) of the compound obtained above in t-butanol (150 ml), add 8.3 ml (60 mmol) of triethylamine and 13.7 g (50 mmol) of DPPA, and heat to reflux for 8 hours. After distilling off the solvent, water is added and the mixture is extracted with chloroform. The organic layer is washed once with 5% aqueous sodium carbonate solution, once with 5% aqueous potassium hydrogen sulfate solution, twice with water and once with saturated saline. After drying over sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel column chromatography (hexane-ethyl acetate) to give 8.6 g (47%) of the title compound.
[0227]
NMR (CDCl _Three )
0.85-1.37 (m, 14H), 1.60-1.85 (m, 4H), 2.84 (t, 1H), 3.12 (br, 1H), 5.00 (s, 2H), 6.62 (d, 1H), 7.23-7.39 (m, 6H)
b) trans-4-t-butoxycarbonylamino-[(S) -N-benzyloxycarbonylprolyl] aminomethylcyclohexane
4.4 g (12 mmol) of the compound obtained in a) is dissolved in methanol (200 ml) and subjected to catalytic reduction at normal temperature and pressure in the presence of palladium black (0.4 g). After completion of the reaction, the catalyst is filtered off and the solvent is distilled off.
[0228]
To a solution of 3.0 g (12 mmol) of (S) -Z-proline in THF (30 ml), 2.0 g (12 mmol) of CDI is added at 0 ° C. After stirring for 3 hours, a THF (150 ml) solution of the compound obtained above is added at 0 ° C. After stirring for 6 hours, the solvent is distilled off and water (50 ml) is added. The mixture is extracted with chloroform, and the organic layer is washed 3 times with water and once with saturated brine. After drying with sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel chromatography (chloroform-methanol) to give 4.2 g (77%) of the title compound.
[0229]
NMR (CDCl _Three )
0.85-1.06 (m, 4H), 1.44 (s, 9H), 1.60-2.35 (m, 9H), 2.94-3.20 (m, 2H), 3. 20-3.55 (m, 3H), 4.31 (br, 1H), 4.47 (br, 1H), 5.14 (s, 2H), 6.90 (br, 1H), 7.15 -7.40 (m, 5H)
c) trans-4-t-butoxycarbonylamino-[(S) -N-[(R) -N'-benzyloxycarbonylphenylalanyl] prolyl] aminomethylcyclohexane
3.6 g (7.9 mmol) of the compound obtained in b) is dissolved in methanol (50 ml), and catalytically reduced at normal temperature and pressure in the presence of palladium black (0.3 g). After completion of the reaction, the catalyst is filtered off and the solvent is distilled off.
[0230]
To a solution of (R) -Z-phenylalanine 2.4 g (7.9 mmol) in THF (30 ml), CDI 1.3 g (7.9 mmol) is added at 0 ° C. After stirring for 4 hours, a solution of the compound obtained above in THF (60 ml) is added. After stirring for 8 hours, the solvent is distilled off, water is added to the reaction mixture, and the mixture is extracted with chloroform. The organic layer is washed 3 times with water and once with saturated brine and dried over sodium sulfate. The solvent is distilled off and the residue is purified by silica gel column chromatography (chloroform-methanol) to obtain 4.2 g (89%) of the title compound.
[0231]
NMR (CDCl _Three )
0.85-1.06 (m, 5H), 1.33-2.0 (m, 15H), 2.10-2.22 (m, 1H), 2.50-2.60 (m, 1H) ), 2.94-3.01 (m, 5H), 3.30 (br, 1H), 3.57 (t, 1H), 4.32-4.59 (m, 3H), 5.08 ( d, 2H), 5.69 (d, 1H), 7.02 (br, 1H), 7.18-7.37 (m, 10H)
[0232]
d) trans-4-amino-[(S) -N-[(R) -N'-methanesulfonylphenylalanyl] pronyl] aminomethylcyclohexane L-tartrate
2.4 g (3.9 mmol) of the compound obtained in c) is dissolved in methanol (40 ml) and subjected to catalytic reduction at room temperature and normal pressure in the presence of 0.2 g of palladium black. After completion of the reaction, the catalyst is filtered off and the solvent is distilled off. To a solution of the obtained compound in dichloromethane (40 ml), 0.65 ml (4.7 mmol) of triethylamine is added, and further at 0 ° C., a solution of 0.47 g (4.1 mmol) of methanesulfonyl chloride in dichloromethane (10 ml) is added. After stirring for 3 hours, a saturated aqueous sodium hydrogen carbonate solution is added, and the organic layer is washed once with water and once with saturated brine. After drying over sodium sulfate, the solvent is distilled off, and the residue is purified by silica gel chromatography (chloroform-methanol).
[0233]
The obtained compound is dissolved in chloroform (10 ml), and 4N hydrochloric acid dioxane solution (10 ml) is added at 0 ° C. After stirring for 2 hours, the solvent is distilled off, and chloroform (10 ml) and 1N sodium hydroxide solution (10 ml) are added to the residue, followed by stirring for 10 minutes. The organic layer is dried over sodium sulfate and a solution of 0.34 g (2.26 mn) of L-tartaric acid in methanol (5 ml) is added.
[0234]
The solvent is distilled off, ether (20 ml) is added, and the precipitated white solid is collected and dried to give 1.36 g (58%) of the title compound.
NMR (DMSO-d ⁶ )
7.77 (m, 4H), 7.28 (m, 5H), 4.28 (m, 1H), 4.16 (m, 1H), 3.57-3.45 (m, 8H), 2 .73 (s, 3H), 1.91-1.75 (m, 9H), 1.54 (m, 1H), 1.25 (m, 4H), 0.93 (m, 2H)
IR: 3324, 2934, 1734, 1638, 1545, 1453, 1308, 1148
The compounds shown in Examples 53 to 64 below were synthesized by the same method.
[0235]
Example 53
Trans-4-amino-[(S) -N-[(R) -2-methylsulfonylamino-2-cyclohexylacetyl] prolyl] aminomethylcyclohexane (Compound No. 759 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.09 (br, 3H), 7.80 (t, 1H), 7.39 (d, 1H), 4.30-4.26 (m, 1H), 3.87 (t, 1H), 3 .80-3.45 (m, 2H), 3.0-2.80 (m, 3H), 2.85 (s, 3H), 2.10-0.80 (m, 24H)
IR: 3382, 2930, 2857, 1638, 1543, 1451, 1154
[0236]
Example 54
Trans-4-amino-[(S) -N-[(S) -N'-benzenesulfonyl-α-glutamyl] prolyl] aminomethylcyclohexane (Compound No. 792 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.04 (br, 3H), 7.75-7.50 (m, 5H), 4.05 (q, 1H), 3.77-3.30 (m, 5H), 3.0-2. 70 (m, 3H), 2.28 (t, 2H), 2.0-1.52 (m, 10H), 1.31-1.11 (m, 3H), 1.0-0.85 ( m, 2H)
IR: 3400, 2937, 1637, 1449, 1161
[0237]
Example 55
Trans-4-amino-[(S) -N-[(RS) -3-methylsulfonylamino-3-phenylpropanoyl] prolyl] aminomethylcyclohexane (Compound No. 777 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.08 (m, 3H), 7.34 (m, 5H), 4.78 (m, 1H), 4.15 (m, 2H), 3.51 (m, 1H), 3.36 (m , 2H), 2.86 (m, 4H), 2.68 (s, 3H), 2.51 (m, 2H), 2.00-1.69 (m, 6H), 1.27 (m, 4H), 0.92 (m, 2H)
IR: 3409, 2936, 1638, 1453, 1314, 1148
[0238]
Example 56
Trans-4-amino-[(S) -N-[(R) -2-isopropoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexane (Compound No. 797 in Table 1)
NMR (CDCl _Three )
7.19 (m, 1H), 5.32 (d, 1H), 4.82 (m, 1H), 4.53 (m, 2H), 4.00 (m, 1H), 3.48 (m , 1H), 3.03-2.16 (m, 6H), 2.00-1.81 (m, 6H), 1.57 (d, 2H), 1.49 (m, 4H),. 24 (m, 6H), 1.00 (s, 9H), 0.95 (m, 2H)
IR: 3326, 2949, 1640, 1541, 1449, 1248
[0239]
Example 57
Trans-4-amino-[(S) -N-[(R) -N'-ethoxycarbonyl-phenylalanyl] prolyl] aminomethylcyclohexane (Compound No. 780 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
7.98 (m, 3H), 7.37 (t, 1H), 7.26 (m, 5H), 4.37 (dd, 1H), 4.16 (m, 1H), 4.02 (m , 2H), 3.88 (m, 1H), 3.59 (m, 1H), 3.43 (m, 1H), 2.86 (m, 5H), 1.93-1.75 (m, 7H), 1.28 (m, 4H), 1.15 (t, 3H), 0.92 (m, 2H)
IR: 3349, 2936, 1642, 1537, 1451, 1258
[0240]
Example 58
Trans-4-amino-[(S) -N-[(R) -phenylalanyl] prolyl] aminomethylcyclohexane (Compound No. 779 in Table 1) dihydrochloride
NMR (DMSO-d ⁶ )
8.69 (br, 3H), 8.09 (br, 4H), 7.37-7.20 (m, 5H), 4.19 (br, 1H), 4.09-4.06 (m, 1H), 3.20-2.82 (m, 5H), 2.0-0.85 (m, 15H)
IR: 3426, 2936, 1649, 1539, 1497, 1454
[0241]
Example 59
Trans-4-amino-[(S) -N-[(R) -2-ethoxycarbonyloxy-3-phenylpropanoyl] prolyl] aminomethylcyclohexane (Compound No. 785 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
7.78 (m, 3H), 7.30 (m, 5H), 7.15 (d, 1H), 5.22 (t, 1H), 4.20 (m, 1H), 4.08 (m , 3H), 3.64 (m, 1H), 3.02-2.88 (m, 5H), 1.92-1.72 (m, 7H), 1.20-0.94 (m, 9H) )
IR: 3397, 2938, 1740, 1655, 1453, 1269
[0242]
Example 60
Trans-4-amino-[(S) -N-[(R) -2-allylcarbamoyloxy-3-phenylpropanoyl] prolyl] aminomethylcyclohexane (Compound No. 787 in Table 1) hydrobromide
NMR (DMSO-d ⁶ )
7.90 (m, 3H), 7.30 (m, 5H), 7.14 (m, 1H), 5.72 (m, 2H), 5.06 (m, 2H), 4.76 (m , 1H), 4.17 (m, 1H), 3.60 (m, 1H), 2.98-2.85 (m, 5H), 1.87-1.70 (m, 7H), 1. 23 (m, 7H), 0.90 (m, 2H)
IR: 3364, 2936, 1707, 1645, 1543, 1454, 1256
[0243]
Example 61
Trans-4-amino-[(S) -N-[(R) -2-hydroxy-2-cyclohexylacetyl] prolyl] aminomethylcyclohexane (Compound No. 768 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.21 (br, 3H), 7.95 (m, 1H), 4.53 (m, 1H), 4.18 (d, 1H), 3.95 (m, 1H), 3.07 (m , 3H), 2.18-1.55 (m, 22H), 1.30-1.03 (m, 2H)
IR: 3422, 2928, 2854, 1637, 1450, 1388, 1240, 1114, 1045
[0244]
Example 62
Trans-4-amino-[(S) -N-[(R) -2-hydroxy-2-phenylacetyl] prolyl] aminomethylcyclohexane (Compound No. 783 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
7.98 (br, 3H), 7.37-7.28 (m, 5H), 5.48 (br, 1H), 5.23 (d, 1H), 4.23 (d, 1H), 3 .70-3.35 (m, 2H), 3.0-2.80 (m, 4H), 2.0-1.60 (m, 8H), 1.40-0.90 (m, 5H)
IR: 3329, 2935, 1667, 1626, 1552, 1448
[0245]
Example 63
Trans-4-amino-[(RS) -1-[(R) -N'-methylsulfonylphenylalanyl] -2-piperidinecarboxyl] aminomethylcyclohexane (Compound No. 834 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.07 (m, 3H), 7.28 (m, 5H), 4.64 (m, 1H), 4.39 (m, 1H), 3.99 (m, 1H), 3.67 (m , 1H), 2.87 (m, 7H), 2.84 (s, 3H), 1.91-1.68 (m, 5H), 1.33-0.92 (m, 10H)
IR: 3385, 2936, 1638, 1535, 1453, 1314, 1150
[0246]
Example 64
Trans-4-amino-[(S) -N-[(R) -2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexane (Compound No. 794 in Table 1)
NMR (CDCl _Three )
7.16 (m, 1H), 5.68 (d, 1H), 4.53 (d, 1H), 4.38 (m, 1H), 4.10 (q, 2H), 4.01 (m , 1H), 3.46-3.07 (m, 4H), 2.30-1.81 (m, 8H), 1.58 (m, 5H), 1.26 (t, 3H), 1. 00 (s, 9H), 0.95 (m, 2H)
IR: 3329, 2949, 1642, 1541, 1447, 1248, 1059
[0247]
Example 65
Trans-4- (5-Methyl-1,3-dioxo-2-one-4-ylmethyl) amino-[(S) -N-[(R) -2-ethoxycarbonylamino-4,4-dimethylpentanoyl ] Prolyl] Synthesis of aminomethylcyclohexane (Compound No. 968 in Table 1)
To a solution of 5.4 g (11.7 mmol) of the compound obtained in Example 64 in DMF (40 ml) was added 3.2 g (23.4 mmol) of sodium carbonate, and 4-bromomethyl-5-methyl-1,3 was further added at 0 ° C. Add a solution of 4.0 g (17.6 mmol) of dioxo-2-one in DMF (5 ml). After stirring for 48 hours, the solvent is distilled off, water is added to the residue and the mixture is extracted with ethyl acetate. The organic layer is washed 3 times with water and once with saturated brine, and then dried over sodium sulfate. The solvent is distilled off, and the residue is purified by silica gel column chromatography (chloroform-methanol) to obtain 2.8 g (44%) of the title compound.
[0248]
NMR (CDCl _Three )
7.07 (m, 1H), 5.15 (d, 1H), 4.56 (d, 1H), 4.41 (m, 1H), 4.10 (q, 2H), 4.00 (m , 2H), 3.48 (s, 2H), 3.45 (m, 2H), 3.04 (t, 1H), 2.62 (m, 1H), 2.38 (m, 1H), 2 .11 (s, 3H), 2.00 (m, 3H), 1.82 (m, 2H), 1.73-1.43 (m, 4H), 1.28 (t, 3H), 1. 26 (m, 3H), 1.00 (s, 9H), 0.96 (m, 2H)
IR: 3329, 2934, 2870, 1823, 1649, 1539, 1445, 1223
In the same manner, the compound shown in Example 66 below was synthesized.
[0249]
Example 66
Trans-4-t-butoxycarbonylamino-[(S) -N-[(R) -N'-methanesulfonylphenylalanyl] prolyl] aminomethylcyclohexane (Compound No. 955 in Table 1)
NMR (CDCl _Three )
7.29 (m, 3H), 7.24 (m, 2H), 6.67 (t, 1H), 5.61 (d, 1H), 4.40 (m, 2H), 4.29 (dd , 1H), 3.58 (m, 1H), 3.34 (m, 1H), 2.99 (m, 4H), 2.82 (s, 3H), 2.69 (m, 1H), 2 .18-1.74 (m, 9H), 1.43 (s, 9H), 1.02 (m, 4H)
IR: 3376, 2932, 1655, 1526, 1453, 1322
[0250]
Example 67
Synthesis of trans-4-guanidino-[(S) -N-[(R) -N'-methanesulfonylphenylalanyl] prolyl] aminomethylcyclohexane (Compound No. 646 in Table 1) sulfate
To a solution of 0.45 g (1 mmol) of the compound obtained in Example 52 in ethanol (15 ml) is added a solution of 0.14 g (0.5 mmol) of 2-methylisothiourea sulfate in water (5 ml), and the mixture is heated to reflux for 6 hours. The solvent was distilled off, ether (20 ml) was added and the precipitated white solid was collected, washed with ether and dried under reduced pressure to give 0.44 g (81%) of the title compound.
[0251]
NMR (DMSO-d ⁶ )
8.04-2.0 (m, 13H), 2.60-3.96 (m, 7H), 2.77 (s, 3H), 4.14-4.28 (m, 2H), 5. 47 (br, 1H), 6.75 (br, 1H), 7.20-7.36 (m, 5H), 7.83 (br, 1H), 8.40 (br, 4H)
IR: 3322, 2932, 2193, 2153, 1644, 1545, 1451, 1319, 1150
[0252]
The following compounds of Examples 68 to 78 were synthesized by the same method as in Example 1.
Example 68
4-Amidino-[(S) -N-[(R) -2-hydroxy-cyclohexylacetyl] prolyl] aminomethylbenzene (Compound No. 82 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.29 (br, 2H), 8.93 (br, 2H), 8.51 (t, 1H), 7.75 (d, 2H), 7.49 (d, 2H), 4.37 (m , 3H), 3.96 (d, 1H), 3.70 (m, 1H), 3.60-3.40 (m, 2H), 2.20-1.0 (m, 14H)
IR: 3227, 2922, 1657, 1607, 1539, 1485, 1458, 1323, 1246, 1032
[0253]
Example 69
4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-3,3-dimethylbutanoyl] prolyl] aminomethylbenzene (Compound No. 114 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.41 (br, 2H), 9.24 (br, 2H), 8.63 (t, 1H), 7.81 (d, 2H), 7.47 (d, 2H), 7.20 (d , 1H), 4.42 (dd, 1H), 4.35 (t, 2H), 3.96 (d, 1H), 3.80-3.60 (m, 2H), 2.85 (s, 3H), 2.20-1.80 (m, 4H), 0.97 (s, 9H)
IR: 3273, 2970, 2365, 1630, 1541, 1483, 1412, 1304, 1153, 715
[0254]
Example 70
4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-6-ethoxycarbonyl-hexanoyl] prolyl] aminomethylbenzene (Compound No. 117 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.35 (br, 4H), 8.66 (t, 1H), 7.79 (d, 1H), 7.48 (d, 2H), 4.35 (m, 3H), 4.65 (q , 2H), 3.69 (m, 1H), 3.55 (m, 1H), 2.75 (s, 3H), 2.29 (t, 2H), 2.13 (m, 2H), 1 .94 (m, 2H), 1.85 (m, 2H), 1.52 (m, 7H), 1.18 (t, 3H)
IR: 3382, 1644, 1547, 1427, 1375, 1314, 1150, 1111
[0255]
Example 71
4-Amidino-[(S) -N-[(R) -2-methylsulfonylamino-4- (3'-carboxy) -phenyl-butanoyl] prolyl] aminomethylbenzene (Compound No. 119 in Table 1) Hydrochloric acid salt
NMR (DMSO-d ⁶ )
9.45 (s, 2H), 9.38 (s, 2H), 8.62 (t, 1H), 7.84 (m, 2H), 7.79 (d, 2H), 7.64 (d , 1H), 7.47 (d, 2H), 7.42 (m, 2H), 4.33 (m, 3H), 4.10 (m, 1H), 3.57-3.37 (m, 2H), 2.85 (m, 1H), 2.78 (s, 3H), 2.73 (m, 1H), 2.12 (m, 1H), 1.95-1.81 (m, 6H) )
IR: 3366, 1638, 1543, 1489, 1449, 1311, 1150, 754, 527
[0256]
Example 72
4-Amidino-[(S) -N-[(R) -N'-methylsulfonyl-O- (4'-carboxyphenyl) -seryl] prolyl] aminomethylbenzene (Compound No. 970 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.31 (s, 2H), 9.00 (s, 2H), 8.59 (t, 1H), 7.90 (d, 2H), 7.83 (d, 1H), 7.75 (d , 2H), 7.48 (d, 2H), 7.03 (d, 2H), 4.35 (m, 4H), 4.22 (m, 2H), 4.12 (dd, 1H), 3 .72 (m, 2H), 2.89 (s, 3H), 2.20-1.80 (m, 4H)
IR: 3376, 1647, 1607, 1424, 1318, 1252, 1154, 1119, 774, 633, 525
[0257]
Example 73
4-Amidino-[(S) -N-[(R) -N'-methylsulfonyl-O-ethoxycarbonylmethyl-tyrosyl] prolyl] aminomethylbenzene (Compound No. 971 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.41 (br, 2H), 9.20 (br, 2H), 8.56 (t, 1H), 7.80 (d, 2H), 7.65 (d, 1H), 7.48 (d , 2H), 7.18 (dd, 2H), 6.84 (dd, 2H), 4.75 (q, 1H), 4.30 (dd, 1H), 4.30-4.25 (m, 2H), 3.70-3.42 (m, 3H), 3.47 (q, 2H), 3.18 (t, 1H), 2.83 (d, 2H), 2.72 (s, 3H) ), 1.89-1.60 (m, 4H), 1.14 (dt, 3H)
IR: 3370, 2365, 1742, 1636, 1541, 1512, 1445, 1308
[0258]
Example 74
4-Amidino-[(S) -N-[(R) -N'-ethoxycarbonylphenylalanyl] prolyl] aminomethylbenzene hydrochloride (Compound No. 972 in Table 1)
NMR (DMSO-d ⁶ )
9.40 (br, 2H), 9.24 (br, 2H), 8.14 (t, 1H), 7.80 (d, 2H), 7.59 (t, 1H), 7.45 (d , 2H), 7.31-7.15 (m, 5H), 4.50-4.26 (m, 4H), 3.90-3.57 (m, 3H), 3.0-2.7. (M, 3H), 1.9-1.6 (m, 4H), 1.10-1.0 (m, 3H)
IR: 3279, 2364, 1637, 1539, 1491, 1450, 1255, 704
[0259]
Example 75
4-Amidino-[(S) -N-[(R) -2-methylsulfonylaminoheptanoyl] prolyl] aminomethylbenzene (Compound No. 973 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.37 (s, 2H), 9.16 (s, 2H), 8.60 (t, 1H), 7.76 (d, 2H), 7.48 (d, 2H), 7.40 (d , 1H), 4.50-4.23 (m, 3H), 4.08 (m, 1H), 3.69 (m, 1H), 3.36 (m, 1H), 2.74 (s, 3H), 2.15 (m, 1H), 2.09-1.84 (m, 3H), 1.61-1.22 (m, 8H), 0.87 (m, 3H) IR: 3366, 2957, 1638, 1543, 1489, 1426, 1314, 1154, 718, 527
[0260]
Example 76
4-Amidino-[(S) -N-[(R) -N'-methylsulfonyl-O- (3'-carboxymethyl-phenyl) -seryl] prolyl] aminomethylbenzene (Compound No. 974 in Table 1) Hydrochloride
NMR (DMSO-d ⁶ )
9.46 (s, 2H), 9.31 (s, 2H), 8.70 (t, 1H), 7.83 (m, 3H), 7.48 (d, 2H), 7.19 (m , 2H), 6.89 (d, 2H), 4.58 (dd, 1H), 4.37 (m, 4H), 4.14 (d, 2H), 3.70 (m, 1H), 3 .60 (m, 3H), 2.89 (s, 3H), 2.11 (m, 1H), 2.01-1.82 (m, 3H)
IR: 3382, 1724, 1640, 1543, 1489, 1447, 1316, 1262, 1154, 768, 527
[0261]
Example 77
4-Amidino-[(S) -N-[(R) -N'-methylsulfonyl-O- (4'-carboxymethyl-phenyl) -seryl] prolyl] aminomethylbenzene (Compound No. 975 in Table 1) Hydrochloride
NMR (DMSO-d ⁶ )
9.45 (s, 2H), 9.29 (s, 2H), 8.70 (t, 1H), 7.83 (d, 2H), 7.82 (d, 2H), 7.48 (d , 2H), 7.24 (d, 1H), 6.82 (d, 2H), 4.59 (dd, 1H), 4.37 (m, 4H), 4.14 (d, 2H), 3 .70 (m, 1H), 3.61 (m, 3H), 2.89 (s, 3H), 2.11 (m, 1H), 2.01-1.82 (m, 3H)
IR: 3383, 1640, 1545, 1514, 1437, 1312, 1242, 1152, 824, 523
[0262]
Example 78
4-Amidino-[(S) -N-[(R) -2-ethoxycarbonylmethylsulfonylamino-heptanoyl] prolyl] aminomethylbenzene (Compound No. 976 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
9.36 (s, 2H), 9.15 (s, 2H), 8.49 (t, 1H), 7.81 (d, 1H), 7.77 (d, 2H), 7.47 (d , 2H), 4.35 (m, 3H), 4.21 (d, 1H), 4.15 (m, 1H), 4.06 (q, 2H), 3.93 (d, 1H), 3 .73 (m, 1H), 3.53 (m, 1H), 2.14 (m, 1H), 1.94 (m, 3H), 1.67-1.18 (m, 8H), 1. 14 (t, 3H), 0.89 (m, 3H)
IR: 3274, 2957, 2872, 1821, 1738, 1647, 1541, 1422, 1319, 1159, 1022, 723, 628, 527
In the same manner as in Example 15, the following compounds of Examples 79 to 86 were synthesized.
[0263]
Example 79
Trans-4-Amidino-[(S) -N-[(R) -N'-ethoxycarbonyl-Ot-butoxy-seryl] prolyl] aminomethylcyclohexane (Compound No. 240 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.88 (br, 2H), 8.71 (br, 2H), 7.72 (m, 1H), 6.39 (m, 1H), 4.59 (m, 1H), 4.52 (m , 1H), 4.11 (m, 2H), 3.86-3.71 (m, 2H), 3.58 (m, 2H), 3.22 (m, 2H), 2.79-0. 88 (m, 15H), 1.24 (t, 3H), 1.15 (s, 9H)
IR: 3271, 2976, 1685, 1647, 1541, 1448, 1257, 1192, 1095, 1055
[0264]
Example 80
Trans-4-amidino-[(S) -N-[(R) -N'-isopropoxycarbonyl-O- (1 ', 1'-dimethylpropyl) -seryl] prolyl] aminomethylcyclohexane (compounds in Table 1 No. 977) Hydrochloride
NMR (DMSO-d ⁶ )
8.74 (br, 4H), 7.68 (m, 1H), 6.01 (m, 1H), 4.83 (m, 1H), 4.57 (m, 2H), 3.74 (m , 2H), 3.50 (m, 2H), 3.14 (m, 1H), 2.97 (m, 1H), 2.5-0.9 (m, 16H), 1.24 (dd, 6H), 1.09 (s, 6H), 0.81 (t, 3H)
IR: 3314, 2978, 1693, 1641, 1543, 1450, 1375, 1261, 1111, 1059
[0265]
Example 81
Trans-4-Amidino-[(S) -N-[(R) -N'-ethoxycarbonyl-O- (1 ', 1'-dimethylpropyl) -seryl] prolyl] aminomethylcyclohexane (Compound No. in Table 1) .978) Hydrochloride
NMR (DMSO-d ⁶ )
8.75 (br, 4H), 7.55 (m, 1H), 6.40 (m, 1H), 4.52 (m, 2H), 4.13 (m, 2H), 3.88-3 .70 (m, 2H), 3.55 (m, 2H), 3.28 (m, 1H), 2.87-2.70 (m, 1H), 2.20-1.20 (m, 14H) ), 1.27 (t, 3H), 1.09 (s, 6H), 6.81 (t, 3H), 1.10-0.90 (m, 2H)
IR: 3292, 2974, 1689, 1645, 1543, 1448, 1259, 1095, 1055
[0266]
Example 82
Trans-4-amidino-[(S) -N-[(R) -N'-isopropoxycarbonyl-O- (1'-ethyl-1'-methyl-propyl) -seryl] prolyl] aminomethylcyclohexane (table 1 Compound No. 979) Hydrochloride
NMR (DMSO-d ⁶ )
8.78 (s, 2H), 8.69 (s, 2H), 7.55 (br, 1H), 5.99 (br, 1H), 4.84 (m, 1H), 4.54 (m , 2H), 3.71 (m, 2H), 3.49 (m, 2H), 3.20-0.90 (m, 16H), 1.64 (q, 4H), 1.23 (t, 6H), 1.03 (s, 3H), 0.78 (t, 6H)
IR: 3315, 2976, 2934, 1685, 1641, 1543, 1450, 1375, 1261, 1111
[0267]
Example 83
Trans-4-Amidino-[(S) -N-[(R) -N'-ethoxycarbonyl-St-butyl-cystinyl] prolyl] aminomethylcyclohexane (Compound No. 980 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.82 (br, 2H), 8.74 (br, 2H), 7.47 (m, 1H), 6.63 (m, 1H), 4.60-4.40 (m, 2H), 4 20-4.21 (m, 2H), 4.00 (m, 1H), 3.72 (m, 1H), 3.24 (m, 1H), 2.87 (m, 2H), 2. 65 (m, 1H), 2.18-1.31 (m, 12H), 1.31 (s, 9H), 1.27 (t, 3H), 1.10-0.90 (m, 2H)
IR: 3298, 2932, 1693, 1641, 1541, 1448, 1304, 1257, 1161, 1047
[0268]
Example 84
Trans-4-Amidino-[(S) -N-[(R) -N'-isopropoxycarbonyl-O- (1'-methylcyclopentyl) -seryl] propyl] aminomethylcyclohexane (Compound No. 981 in Table 1) ) Hydrochloride
NMR (DMSO-d ⁶ )
8.79 (br, 4H), 7.64 (m, 1H), 5.97 (m, 1H), 4.83 (m, 1H), 4.55 (m, 2H), 3.76 (m , 2H), 3.52 (m, 2H), 3.15-1.20 (m, 22H), 1.27-1.13 (m, 9H), 1.13-0.95 (m, 2H) )
IR: 3329,2934,1684,1639,1541,1450,1261,1182,1111,1060,918
[0269]
Example 85
Trans-4-Amidino-[(S) -N-[(R) -N'-isopropoxycarbonyl-Ot-butyl-threonyl] prolyl] aminomethylcyclohexane (Compound No. 982 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.74 (br, 4H), 7.80 (m, 1H), 5.66 (m, 1H), 4.85 (m, 1H), 4.57 (m, 1H), 4.29 (m , 1H), 3.80-3.60 (m, 3H), 3.05 (m, 2H), 2.60 (m, 1H), 2.50-1.20 (m, 11H), 1. 27-1.22 (m, 15H), 1.15 (d, 3H), 1.10-0.90 (m, 2H)
IR: 3331, 2978, 1697, 1639, 1543, 1450, 1375, 1265, 1182, 1111
[0270]
Example 86
Trans-4-amidino-[(S) -N-[(R) -2-ethoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl] prolyl] aminomethylcyclohexane (Compound No. 983 in Table 1) hydrochloric acid salt
NMR (DMSO-d ⁶ )
9.13 (br, 2H), 8.46 (br, 2H), 7.30 (m, 1H), 5.85 (m, 1H), 4.55 (m, 1H), 4.30 (m , 1H), 4.15-3.85 (m, 3H), 3.69 (m, 1H), 3.02 (m, 2H), 2.30 (m, 1H), 2.00-1. 20 (m, 13H), 1.48 (s, 3H), 1.33 (s, 3H), 1.30-1.20 (m, 9H), 1.05-0.85 (m, 2H)
IR: 3420, 2974, 1635, 1556, 1521, 1448, 1385, 1298, 1259, 1060
The following compounds of Examples 87 to 113 were synthesized in the same manner as in Example 24.
[0271]
Example 87
4-[(S) -N-[(R) -2-hydroxy-2-cyclohexylacetyl] prolyl] aminomethylbenzamide oxime (Compound No. 391 in Table 1)
NMR (DMSO-d ⁶ )
9.55 (br, 1H), 8.31 (t, 1H), 7.59 (d, 2H), 7.24 (d, 2H), 5.73 (br, 2H), 4.57 (m , 1H), 4.26-4.32 (m, 3H), 3.91 (br, 1H), 3.40-3.60 (m, 2H), 2.05-0.80 (m, 15H) )
IR: 3375, 2926, 2853, 1638, 1561, 1451, 1385, 1244
[0272]
Example 88
4-[(S) -N-[(R) -N'-isopropoxycarbonyl-phenylalanyl] prolyl] aminomethylbenzamide oxime (Compound No. 395 in Table 1)
NMR (CDCl _Three )
7.65 (br, 1H), 7.53 (d, 2H), 7.29-7.19 (m, 8H), 5.89 (d, 2H), 5.01 (br, 2H), 4 .58-4.45 (m, 4H), 4.27 (dd, 1H), 3.65 (br, 1H), 3.10-2.93 (m, 2H), 2.58 (q, 1H) ), 2.17 (br, 1H), 1.90-1.50 (m, 2H), 1.11 (d, 4H), 0.96 (d, 2H)
IR: 3331, 2980, 2880, 2365, 1639, 1539, 1452, 1261
[0273]
Example 89
4-[(S) -N-[(R) -2-ethoxycarbonylamino-2-phenylacetyl] prolyl] aminomethylbenzamide oxime (Compound No. 403 in Table 1)
NMR (CDCl _Three )
7.80 (br, 1H), 7.47 (d, 2H), 7.40-7.14 (m, 8H), 6.11 (dd, 1H), 5.43 (dd, 1H), 4 .98 (br, 2H), 4.70-4.54 (m, 2H), 4.50-4.20 (m, 1H), 4.15-4.00 (m, 1H), 4.00 -3.80 (m, 2H), 3.25-3.19 (m, 1H), 2.30-1.80 (m, 4H), 1.16 (dt, 3H)
IR: 3339, 2980, 2365, 1641, 1524, 1437, 1385, 1057
[0274]
Example 90
4-[(S) -N-[(R) -N'-ethoxycarbonyl-valyl] prolyl] aminomethylbenzamide oxime (Compound No. 407 in Table 1)
NMR (CDCl _Three )
7.57 (br, 1H), 7.54 (d, 2H), 7.20 (d, 2H), 5.98 (d, 1H), 4.97 (br, 2H), 4.68-4 .59 (m, 2H), 4.24 (dd, 1H), 4.07 (t, 1H), 4.10-4.00 (m, 1H), 3.90-3.80 (m, 1H) ), 3.60-3.45 (m, 2H), 2.31 (br, 1H), 2.20-1.95 (m, 4H), 1.88 (d, 1H), 1.01 ( t, 3H), 0.97 (d, 6H)
IR: 3337, 2971, 2878, 2363, 1640, 1539, 1445, 1277, 1238
[0275]
Example 91
4-[(S) -N-[(R) -2-ethoxycarbonylamino-3,3-dimethylbutanoyl] prolyl] aminomethyl-benzamide oxime (Compound No. 409 in Table 1)
NMR (DMSO-d ⁶ )
8.01 (br, 1H), 7.59 (d, 2H), 7.21 (d, 2H), 7.19-7.15 (m, 1H), 5.73 (br, 2H), 4 .36-4.24 (m, 4H), 4.00-3.60 (m, 4H), 2.10-1.80 (m, 5H), 1.06 (t, 3H), 0.96 (S, 9H)
IR: 3345, 2866, 2364, 1647, 1535, 1443, 1240
[0276]
Example 92
4-[(S) -N-[(R) -2-ethoxycarbonylamino-heptanoyl] prolyl] aminomethylbenzamide oxime (Compound No. 411 in Table 1)
NMR (CDCl _Three )
7.63 (m, 1H), 7.51 (d, 2H), 7.20 (d, 2H), 5.85 (d, 2H), 4.99 (br, 1H), 4.67-4 .58 (m, 2H), 4.35-4.28 (m, 2H), 3.99 (br, 1H), 3.86-3.80 (m, 1H), 3.58-3.50 (M, 2H), 2.31 (br, 1H), 2.07-1.90 (m, 3H), 1.80-1.50 (m, 2H), 1.40-1.10 (m , 5H), 1.03 (t, 3H), 1.01-0.84 (m, 3H)
IR: 3347, 2961, 2363, 2342, 1641, 1541, 1447, 1263, 1049
[0277]
Example 93
4-[(S) -N-[(R) -2-t-butyloxycarbonylamino-heptanoyl] prolyl] aminomethylbenzamide oxime (Compound No. 412 in Table 1)
NMR (CDCl _Three )
7.74-7.70 (m, 1H), 7.49 (d, 2H), 7.27 (t, 1H), 7.20 (d, 2H), 5.43 (d, 1H), 4 .93 (br, 2H), 4.65 (d, 1H), 4.48-4.25 (m, 3H), 3.93 (br, 1H), 3.50 (q, 1H), 2. 40-2.30 (m, 1H), 2.10-1.90 (m, 3H), 1.70-1.50 (m, 2H), 1.42-1.21 (m, 13H), 0.92-0.80 (m, 3H)
IR: 3337,2961,934,2363,1641,1535,1449,1368,1165
[0278]
Example 94
4-[(S) -N-[(R) -2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylbenzamide oxime (Compound No. 418 in Table 1)
NMR (CDCl _Three )
7.58-7.51 (m, 1H), 7.53 (d, 2H), 7.20 (d, 2H), 5.87 (d, 1H), 5.01 (br, 2H), 4 .64-4.56 (m, 2H), 4.40 (q, 1H), 4.26 (dd, 1H), 4.10-4.00 (m, 1H), 3.84-3.78 (M, 1H), 3.53-3.47 (m, 2H), 2.32 (br, 1H), 2.10-1.90 (m, 3H), 1.61 (d, 2H), 1.00 (t, 3H), 0.97 (s, 9H)
IR: 3324, 2957, 2263, 2342, 1642, 1541, 1445, 1248, 1059
[0279]
Example 95
4-[(S) -N-[(R) -N'-ethoxycarbonylmethyloxycarbonyl-phenylalanyl] prolyl] aminomethylbenzamide oxime (Compound No. 984 in Table 1)
NMR (CDCl _Three )
7.54 (d, 2H), 7.41 (br, 1H), 7.28-7.20 (m, 8H), 6.70 (d, 1H), 5.09 (br, 2H), 4 .66 (dd, 1H), 4.60-4.55 (m, 2H), 4.22-4.00 (m, 4H), 4.03 (q, 2H), 3.62 (br, 1H) ), 3.10-3.02 (m, 2H), 2.60-2.40 (m, 1H), 2.14 (br, 1H), 2.00-1.50 (m, 3H), 1.22 (t, 3H)
IR: 3356, 3063, 2980, 2364, 1717, 1641, 1539, 1451, 1213, 702
[0280]
Example 96
4-[(S) -N-[(R) -2-ethoxycarbonylamino-2-cyclohexylacetyl] prolyl] aminomethylbenzamide oxime (Compound No. 985 in Table 1)
NMR (CDCl _Three )
7.52 (d, 2H), 7.54-7.50 (m, 1H), 7.20 (d, 2H), 6.03 (br, 1H), 4.97 (br, 2H), 4 .68 (q, 2H), 4.22 (dd, 1H), 4.12-4.03 (m, 2H), 3.64-3.47 (m, 1H), 3.20 (s, 3H) ), 2.32 (br, 1H), 2.05-1.60 (m, 9H), 1.28-0.97 (m, 6H)
IR: 3343, 2928, 2853, 2365, 1639, 1541, 1449, 1260
[0281]
Example 97
4-[(S) -N-[(R) -2-ethoxycarbonylamino-2'-thienylacetyl] prolyl] aminomethylbenzamide oxime (Compound No. 986 in Table 1)
NMR (CDCl _Three )
7.80-7.60 (m, 1H), 7.46 (dd, 2H), 7.40-6.95 (m, 5H), 6.13 (dd, 1H), 5.71 (dd, 1H), 4.99 (br, 2H), 4.75-4.20 (m, 3H), 4.00-3.80 (m, 2H), 3.70-3.50 (m, 1H) 3.40-3.30 (m, 1H), 2.40-1.80 (m, 4H), 1.16 (dt, 3H)
IR: 3337, 2978, 2364, 1641, 1524, 1443, 1240, 1057, 710
[0282]
Example 98
4-[(S) -N-[(R) -2-ethoxycarbonylamino-4'-fluorophenylacetyl] prolyl] aminomethylbenzamide oxime (Compound No. 987 in Table 1)
NMR (CDCl _Three )
7.80 (t, 1H), 7.46-7.27 (m, 4H), 7.19-6.92 (m, 4H), 6.19-6.15 (m, 1H), 5. 50 (dd, 1H), 5.02 (br, 2H), 4.70-4.20 (m, 3H), 4.10-3.70 (m, 4H), 3.22-3.15 ( m, 1H), 2.25-1.80 (m, 4H), 1.16 (dt, 3H)
IR: 3345, 3073, 2980, 2363, 2344, 1641, 1510, 1143
[0283]
Example 99
4-[(S) -N-[(R) -N'-benzyloxycarbonyl-phenylalanyl] prolyl] aminomethylbenzamide oxime (Compound No. 988 in Table 1)
NMR (CDCl _Three )
7.50 (d, 2H), 7.49-7.30 (m, 1H), 7.26-7.12 (m, 12H), 6.40-6.10 (m, 1H), 4. 85 (br, 2H), 4.90-4.70 (m, 1H), 4.55-4.40 (m, 4H), 4.30-4.20 (m, 1H), 3.70- 3.60 (m, 1H), 3.03-2.95 (m, 1H), 2.20-2.15 (m, 1H), 2.00-1.45 (m, 3H)
[0284]
Example 100
4-[(S) -N-[(R) -2-t-butoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethyl-benzamide oxime (Compound No. 989 in Table 1)
NMR (CDCl _Three )
7.67 (t, 1H), 7.53 (d, 2H), 7.22 (d, 2H), 5.34 (d, 1H), 4.91 (br, 2H), 4.65 (d , 1H), 4.42-4.34 (m, 3H), 4.00-3.90 (m, 1H), 3.48 (q, 1H), 2.40-2.30 (m, 1H) ), 2.02-1.95 (m, 3H), 1.56-1.53 (m, 2H), 1.31 (s, 9H), 0.98 (s, 9H) IR: 3345, 2959 , 2367, 1641, 1535, 1446, 1367, 1167
[0285]
Example 101
4-[(S) -N-[(R) -N'-dimethylcarbamoyl-phenylalanyl] prolyl] aminomethylbenzamide oxime (Compound No. 990 in Table 1)
NMR (DMSO-d ⁶ )
9.56 (s, 1H), 8.11 (t, 1H), 7.56 (d, 2H), 7.18 (d, 2H), 7.29-7.16 (m, 5H), 6 .70 (d, 1H), 5.74 (br, 2H), 4.40-4.05 (m, 4H), 2.94 (d, 2H), 2.93-2.70 (m, 2H) ), 2.60 (s, 6H), 1.90-1.60 (m, 4H)
IR: 3306, 2932, 2880, 2363, 2341, 1634, 1541, 1453
[0286]
Example 102
4-[(S) -N-[(S) -N′-benzyloxycarbonyl-β-t-butylaspartyl] prolyl] aminomethyl-benzamide oxime (Compound No. 991 in Table 1)
NMR (CDCl _Three )
7.63 (br, 1H), 7.51 (d, 2H), 7.33-7.26 (m, 5H), 7.18 (d, 2H), 6.07 (d, 1H), 5 .08 (dd, 2H), 4.92 (br, 2H), 4.90-4.70 (m, 1H), 4.66 (d, 1H), 4.40 (d, 2H), 3. 90-3.80 (m, 2H), 3.0-2.90 (m, 1H), 2.55 (dd, 1H), 2.35-2.20 (m, 1H), 2.08- 1.90 (m, 3H), 1.25 (s, 9H)
IR: 3364, 3063, 2978, 2363, 2343, 1717, 1641, 1539, 1450, 1369, 1253, 1157
[0287]
Example 103
Trans-4-[(S) -N-[(R) -N'-ethoxycarbonyl-Ot-butoxy-seryl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 485 in Table 1)
NMR (CDCl _Three )
7.16 (m, 1H), 5.53 (m, 1H), 4.60-4.53 (m, 2H), 4.47 (s, 2H), 4.13-4.06 (m, 2H), 3.76 (br, 2H), 3.60-3.50 (m, 2H), 3.07 (br, 2H), 2.41 (m, 2H), 2.04-1.20 (M, 12H), 1.27 (t, 3H), 1.16 (s, 9H), 1.03-0.94 (m, 2H)
IR: 3352, 2930, 1701, 1651, 1541, 1448, 1259, 1053, 754
[0288]
Example 104
Trans-4-[(S) -N-[(R) -N'-isopropoxycarbonyl-Ot-butylseryl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 486 in Table 1)
NMR (CDCl _Three )
7.19 (m, 1H), 5.40 (d, 1H), 4.87 (m, 1H), 4.61-4.53 (m, 2H), 4.47 (br, 2H), 3 .75 (m, 2H), 3.60-3.40 (m, 2H), 3.08 (t, 2H), 2.40 (m, 1H), 2.20-1.20 (m, 12H) ), 1.21 (dd, 6H), 1.19 (s, 9H), 1.10-0.90 (m, 2H)
IR: 3356,2976,1697,1649,1541,1448,1261,1190,1109,1022
[0289]
Example 105
Trans-4-[(S) -N-[(R) -N′-ethoxycarbonyl-O- (1 ′, 1′-dimethylpropyl) -seryl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. in Table 1) .487)
NMR (CDCl _Three )
7.14 (m, 1H), 5.51 (d, 1H), 4.60-4.50 (m, 2H), 4.48 (br, 2H), 4.09 (m, 2H), 3 .78 (m, 2H), 3.55-3.45 (m, 2H), 3.06 (m, 2H), 2.35 (m, 1H), 2.20-0.90 (m, 16H) ), 1.24 (t, 3H), 1.10 (s, 6H), 0.82 (t, 3H)
IR: 3346, 2976, 2930, 1649, 1543, 1448, 1261, 1176, 1095, 1055
[0290]
Example 106
Trans-4-[(S) -N-[(R) -N'-isopropoxycarbonyl-O- (1 ', 1'-dimethylpropyl) -seryl] prolyl] aminomethylcyclohexanecarboxamide oxime (compounds in Table 1 No. 488)
NMR (CDCl _Three )
7.18 (m, 1H), 5.38 (d, 1H), 4.86 (m, 1H), 4.61-4.50 (m, 2H), 4.47 (br, 2H), 3 .77 (m, 2H), 3.57-3.42 (m, 2H), 3.06 (t, 2H), 2.39 (m, 1H), 2.20-0.90 (m, 16H) ), 1.23 (dd, 6H), 1.10 (s, 6H), 0.82 (t, 3H)
IR: 3346, 2976, 1703, 1651, 1541, 1448, 1263, 1178, 1109, 1030
[0291]
Example 107
Trans-4-[(S) -N-[(R) -N'-isopropoxycarbonyl-O- (1'-ethyl-1'-methyl-propyl) -seryl] prolyl] aminomethylcyclohexanecarboxamide oxime (table 1 Compound No. 490)
NMR (CDCl _Three )
7.17 (br, 1H), 5.35 (br, 1H), 4.86 (m, 1H), 4.60-4.50 (m, 2H), 4.47 (br, 2H), 3 .78 (m, 2H), 3.53-3.38 (m, 2H), 3.07 (t, 2H), 2.37-1.20 (m, 17H), 1.23 (t, 6H) ), 1.06 (s, 3H), 1.06-0.82 (m, 2H), 0.79 (t, 6H)
IR: 3350, 2976, 2932, 1651, 1541, 1450, 1375, 1263, 1109, 1026
[0292]
Example 108
Trans-4-[(S) -N-[(R) -N′-ethoxycarbonyl-St-butyl-cystinyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 492 in Table 1)
NMR (CDCl _Three )
7.27 (m, 1H), 5.81 (m, 1H), 4.60-4.40 (m, 2H), 4.88 (br, 2H), 4.11 (m, 2H), 3 .87 (m, 1H), 3.68 (m, 1H), 3.06 (m, 2H), 2.90-2.70 (m, 2H), 2.37 (m, 1H), 2. 10-1.20 (m, 12H), 1.32 (s, 9H), 1.25 (t, 3H), 1.10-0.90 (m, 2H)
IR: 3346, 2930, 1699, 1649, 1541, 1448, 1257, 1163, 1051, 929
[0293]
Example 109
Trans-4-[(S) -N-[(R) -2-Ethoxycarbonylamino-3-isopropylthio-3-methyl-butanoyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 497 in Table 1)
NMR (CDCl _Three )
7.16 (m, 1H), 5.62 (m, 1H), 4.61 (d, 1H), 4.47 (br, 2H), 4.35 (d, 1H), 4.12 (m , 2H), 3.96 (m, 1H), 3.76 (m, 1H), 3.10 (m, 1H), 3.00 (m, 2H), 2.38 (m, 1H), 2 .00-1.20 (m, 12H), 1.47 (s, 3H), 1.40 (s, 3H), 1.33-1.25 (m, 9H), 1.00-0.90 (M, 2H)
IR: 3354, 2928, 1653, 1541, 1446, 1367, 1302, 1251, 1155, 1055
[0294]
Example 110
Trans-4-[(S) -N-[(S) -N'-t-butoxycarbonyl-seryl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 992 in Table 1)
NMR (CDCl _Three )
7.76 (br, 1H), 6.10 (br, 1H), 5.40 (br, 1H), 4.60 (br, 4H), 3.96 (br, 4H), 3.16-1 .21 (m, 15H), 1.40 (s, 9H), 0.99 (br, 2H)
IR: 3314, 2978, 1691, 1639, 1541, 1450, 1367, 1165, 1049
[0295]
Example 111
Trans-4-[(S) -N-[(R) -N'-isopropoxycarbonyl-Ot-butyl-threonyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 993 in Table 1)
NMR (CDCl _Three )
7.24 (m, 1H), 5.43 (d, 1H), 4.85 (m, 1H), 4.57 (d, 1H), 4.47 (br, 2H), 4.23 (t , 1H), 3.92 (t, 1H), 3.80-3.70 (m, 2H), 3.06 (m, 2H), 2.36 (m, 1H), 2.00-1. 20 (m, 12H), 1.23 (s, 9H), 1.23 (dd, 6H), 1.15 (d, 3H), 1.10-0.90 (m, 2H)
IR: 3354, 2978, 1699, 1649, 1543, 1448, 1373, 1257, 1192, 1111, 1032
[0296]
Example 112
Trans-4-[(S) -N-[(R) -2-acetoxy-cyclohexylacetyl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 994 in Table 1)
NMR (CDCl _Three )
6.80 (br, 1H), 4.61 (t, 2H), 4.49 (br, 2H), 3.90-3.84 (m, 1H), 3.51-3.40 (m, 1H), 3.10-2.85 (m, 2H), 2.38 (br, 1H), 2.11 (s, 3H), 2.06-0.80 (m, 25H)
IR: 3484, 3389, 2928, 2855, 1725, 1649, 1451, 1250
[0297]
Example 113
Trans-4-[(S) -N-[(R) -N'-isopropoxycarbonyl-O- (1'-methylcyclopentyl) -seryl] prolyl] aminomethylcyclohexanecarboxamide oxime (Compound No. 995 in Table 1) )
NMR (CDCl _Three )
7.18 (m, 1H), 5.42 (m, 1H), 4.85 (m, 2H), 4.60-4.49 (m, 4H), 3.73 (m, 2H), 3 57-3.42 (m, 2H), 3.08 (m, 1H), 2.40 (m, 1H), 2.04-1.20 (m, 21H), 1.27-1.20. (M, 9H), 1.03-0.94 (m, 2H)
IR: 3356, 2932, 1695, 1653, 1541, 1448, 1263, 1111, 1030, 918
In the same manner as in Example 48, the following compounds of Examples 114 to 122 were synthesized.
[0298]
Example 114
Trans-4-[(S) -N-[(R) -2-t-butoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexanecarboxamide-O-methoxycarbonyloxime (Compound No. in Table 1) .533)
NMR (CDCl _Three )
7.14 (br, 1H), 5.04 (d, 1H), 4.74 (br, 1H), 4.58 (d, 1H), 4.40-4.30 (m, 1H), 4 .00-3.85 (m, 1H), 3.94 (s, 3H), 3.46 (q, 1H), 3.30-3.20 (m, 1H), 2.95-2.88 (M, 1H), 2.42 (br, 1H), 2.26 (t, 1H), 2.00-1.73 (m, 11H), 1.54-1.26 (m, 4H), 1.43 (s, 9H), 1.00 (s, 9H)
IR: 3347, 2955, 2870, 1765, 1645, 1539, 1443, 1254, 1169, 879
[0299]
Example 115
Trans-4-[(S) -N-[(R) -N'-isopropoxycarbonyl-leucyl] prolyl] aminomethylcyclohexanecarboxamide-O-methoxycarbonyloxime (Compound No. 540 in Table 1)
NMR (CDCl _Three )
7.11 (br, 1H), 5.18 (d, 1H), 4.90-4.70 (m, 1H), 4.77 (br, 2H), 4.56 (t, 1H), 4 .40-4.30 (m, 1H), 3.95-3.86 (m, 1H), 3.85 (s, 3H), 3.46 (q, 1H), 3.20-2.95 (M, 2H), 2.40-2.30 (m, 1H), 2.30-2.10 (m, 1H), 2.00-1.20 (m, 13H), 1.23 (dd , 6H), 1.04-0.89 (m, 8H)
IR: 3354, 2957, 2932, 2872, 2363, 2341, 1763, 1643, 1541, 1443, 1260
[0300]
Example 116
Trans-4-[(S) -N-[(R) -N'-ethoxycarbonyl-Ot-butyl-seryl] prolyl] aminomethylcyclohexanecarboxamide-O-methoxycarbonyloxime (Compound No. 996 in Table 1) )
NMR (CDCl _Three )
7.20 (m, 1H), 5.34 (m, 1H), 4.70 (s, 2H), 4.61 (m, 1H), 4.50 (m, 1H), 4.12-4 .06 (m, 2H), 3.85 (s, 3H), 3.74 (m, 2H), 3.60-3.39 (m, 2H), 3.06 (m, 2H), 2. 41-1.20 (m, 13H), 1.25 (t, 3H), 1.16 (s, 9H), 1.08-0.94 (m, 2H)
IR: 3348, 2976, 1768, 1703, 1645, 1541, 1442, 1255, 1053, 879, 752
[0301]
Example 117
Trans-4-[(S) -N-[(R) -2-hydroxy-4-methyl-pentanoyl] prolyl] aminomethylcyclohexanecarboxamide-O-ethoxycarbonyloxime (Compound No. 997 in Table 1)
NMR (CDCl _Three )
7.07 (m, 1H), 4.73 (br, 2H), 4.52 (d, 1H), 4.23 (m, 4H), 3.56 (m, 1H), 3.40 (m , 1H), 3.13 (m, 3H), 2.41 (m, 1H), 2.30-0.90 (m, 15H), 1.33 (t, 3H), 0.97 (dd, 6H)
IR: 3346, 2932, 1759, 1641, 1450, 1369, 1251, 1078, 920, 846
[0302]
Example 118
Trans-4-[(S) -N-[(R) -N'-ethoxycarbonyl-Ot-butyl-seryl] prolyl] aminomethylcyclohexanecarboxamide-O-acetyloxime (Compound No. 998 in Table 1)
NMR (CDCl _Three )
7.20 (m, 1H), 5.33 (m, 1H), 4.69 (s, 2H), 4.60 (m, 1H), 4.51 (m, 1H), 4.17-4 .07 (m, 2H), 3.77-3.65 (m, 2H), 3.60-3.46 (m, 2H), 3.09-3.04 (m, 2H), 2.40 -1.00 (m, 13H), 2.15 (s, 3H), 1.25 (t, 3H), 1.16 (s, 9H), 1.14 to 0.94 (m, 2H)
IR: 3346,2976,1641,1541,1448,1234,1053,754
[0303]
Example 119
Trans-4-[(S) -N-[(R) -N'-isopropoxycarbonyl-Ot-butyl-seryl] prolyl] aminomethylcyclohexanecarboxamide-O-methoxycarbonyloxime (compound no. 999)
NMR (CDCl _Three )
7.23 (t, 1H), 5.26 (d, 1H), 4.85 (m, 1H), 4.71 (m, 1H), 4.59 (d, 1H), 4.49 (m , 1H), 3.85 (s, 3H), 3.73 (m, 2H), 3.61-3.49 (m, 2H), 3.06 (t, 2H), 2.36 (m, 1H), 2.26 (t, 3H), 2.10-1.20 (m, 11H), 1.21 (dd, 6H), 1.16 (s, 9H), 1.10-0.90 (M, 2H)
IR: 3348, 2978, 1768, 1703, 1649, 1541, 1444, 1259, 1192, 1109
[0304]
Example 120
4-N-ethoxycarbonyl-amidino-[(S) -N-[(R) -2-methylsulfonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylbenzene (Compound No. 1000 in Table 1)
NMR (CDCl _Three )
7.29 (d, 2H), 7.30 (d, 2H), 7.23 (t, 1H), 5.53 (br, 1H), 4.52-4.37 (m, 2H), 4 .24-4.17 (m, 2H), 4.20 (q, 2H), 3.90-3.80 (m, 1H), 3.50-3.40 (m, 1H), 2.77 (S, 3H), 2.28-2.20 (m, 4H), 1.84 (br, 2H), 1.60-1.40 (m, 2H), 1.34 (t, 3H), 1.02 (s, 9H)
IR: 3378, 2957, 2876, 2364, 2230, 1628, 1267, 1147
[0305]
Example 121
4-N-methoxycarbonyl-amidino-[(S) -N-[(R) -2-methylsulfonylamino-cyclohexylacetyl] prolyl] aminomethylbenzene (Compound No. 1001 in Table 1)
NMR (CDCl _Three )
7.78 (d, 2H), 7.29 (d, 2H), 7.27 (t, 1H), 5.49 (d, 1H), 4.56 (d, 1H), 4.42 (dq , 2H), 3.77 (s, 3H), 3.80-3.70 (m, 2H), 3.60-3.51 (m, 1H), 2.79 (s, 3H), 2. 28-1.60 (m, 12H), 1.20-0.95 (m, 5H)
IR: 3376, 2930, 2855, 2365, 1626, 1528, 1501, 1439, 1271, 1144
[0306]
Example 122
Trans-4-N-methoxycarbonyl-amidino-[(S) -N-[(R) -2-ethoxycarbonylamino-4,4-dimethylpentanoyl] prolyl] aminomethylcyclohexane (Compound No. 599 in Table 1) )
NMR (CDCl _Three )
7.08 (br, 1H), 5.17 (d, 1H), 4.56 (d, 1H), 4.50-4.40 (m, 1H), 4.20-3.80 (m, 3H), 3.70 (s, 3H), 3.47 (q, 1H), 3.20-3.00 (m, 2H), 2.45-2.30 (m, 1H), 2.20 -1.30 (m, 15H), 1.24 (t, 3H), 0.99 (s, 9H), 1.10-0.89 (m, 2H)
IR: 3366, 2953, 2365, 1780, 1697, 1640, 1533, 1441, 1271, 1055
The following compounds of Examples 123 to 125 were synthesized in the same manner as in Example 52.
[0307]
Example 123
Trans-4-amino-[(S) -N-[(R) -2-carboxymethylsulfonylamino-heptanoyl] prolyl] aminomethylcyclohexane (Compound No. 791 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
7.97 (m, 2H), 7.57 (m, 1H), 4.19 (m, 2H), 4.01 (d, 1H), 3.80 (d, 1H), 3.68 (m , 1H), 3.50 (m, 1H), 2.88 (m, 3H), 2.04 (m, 1H), 1.90 (m, 5H), 1.73 (m, 4H), 1 .58-1.13 (m, 12H), 1.00-0.84 (m, 5H)
IR: 3387, 2934, 1726, 1637, 1553, 1452, 1325, 1159, 1090, 1046, 604
[0308]
Example 124
Trans-4-amino-[(S) -N-[(R) -N'-methylsulfonyl-O-methyltyrosyl] prolyl] aminomethylcyclohexane (Compound No. 1002 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.10 (br, 3H), 7.77 (t, 1H), 7.67 (d, 1H), 7.17 (d, 2H), 6.87 (d, 2H), 4.25-4 .16 (m, 1H), 3.75 (br, 2H), 3.73 (s, 3H), 3.57-3.40 (m, 1H), 3.00-2.70 (m, 5H) ), 2.77 (s, 3H), 2.00-1.71 (m, 8H), 1.40-1.20 (m, 3H), 1.00-0.80 (m, 2H)
IR: 3385, 2936, 2363, 1639, 1514, 1450, 1304, 1248, 1149
[0309]
Example 125
Trans-4-amino-[(S) -N-[(R) -N'-ethoxycarbonyl-Ot-butyloxy-seryl] prolyl] aminomethylcyclohexane (Compound No. 1003 in Table 1) hydrochloride
NMR (DMSO-d ⁶ )
8.29 (s, 3H), 7.20 (s, 1H), 5.69 (d, 1H), 4.58-4.47 (m, 2H), 4.12 (m, 2H), 3 .82 (m, 1H), 3.61-3.48 (m, 2H), 3.09 (m, 2H), 2.32-0.86 (m, 1H), 1.27 (t, 3H) ), 1.16 (s, 9H)
IR: 3358, 2974, 1645, 1541, 1448, 1257, 1192, 1053
The following compounds of Examples 126 to 130 were synthesized in the same manner as in Example 67.
[0310]
Example 126
Trans-4- (5-Methyl-1,3-dioxo-2-one-4-ylmethyl) amino-[(S) -N-[(R) -2-hydroxy-2-cyclohexylacetyl] prolyl] aminomethyl Cyclohexane (Compound No. 966 in Table 1)
NMR (CDCl _Three )
7.08 (m, 1H), 4.54 (d, 1H), 4.06 (m, 1H), 3.59 (m, 1H), 3.49 (s, 2H), 3.46 (m , 1H), 3.07 (m, 2H), 2.48 (m, 2H), 2.11 (s, 3H), 2.01 (m, 2H), 1.90-1.70 (m, 10H), 1.58 (m, 3H), 1.41-0.94 (m, 10H)
IR: 3387, 2928, 2855, 1821, 1736, 1638, 1543, 1451, 1387, 1223, 1107, 999, 712
[0311]
Example 127
Trans-4- (5-Methyl-1,3-dioxo-2-one-4-ylmethyl) amino-[(S) -N-[(R) -N'-methylsulfonyl-phenylalanyl] prolyl] amino Methylcyclohexane (Compound No. 967 in Table 1)
NMR (CDCl _Three )
7.35-7.20 (m, 5H), 6.71 (t, 1H), 5.48 (d, 1H), 4.44 (m, 1H), 4.25 (m, 1H), 3 .60 (m, 1H), 3.48 (s, 2H), 3.09 (m, 1H), 2.96 (m, 3H), 2.78 (s, 3H), 2.77 (m, 1H), 2.50 (m, 1H), 2.20 (m, 1H), 2.11 (s, 3H), 1.88-1.56 (m, 8H), 1.42 (m, 1H) ), 1.24 (m, 2H), 0.96 (m, 2H)
IR: 3387, 2930, 1819, 1736, 1649, 1541, 1499, 1451, 1318, 1223, 1152, 999
[0312]
Example 128
Trans-4- (5-Methyl-1,3-dioxo-2-one-4-ylmethyl) amino-[(S) -N-[(R) -2-ethoxycarbonylamino-2-cyclohexylacetyl] prolyl] Aminomethylcyclohexane (Compound No. 1004 in Table 1)
NMR (CDCl _Three )
7.11 (m, 1H), 5.31 (m, 1H), 4.58 (d, 1H), 4.10 (t, 2H), 4.04 (m, 1H), 3.94 (m , 1H), 3.56 (m, 1H), 3.49 (s, 2H), 3.04 (m, 2H), 2.52 (m, 1H), 2.36 (m, 2H), 2 .12 (s, 3H), 2.00 (m, 3H), 1.92-1.62 (m, 10H), 1.43 (m, 2H), 1.25 (q, 3H), 1. 22 (m, 4H), 1.06 (m, 4H)
IR: 3353, 2930, 2855, 1823, 1653, 1537, 1449, 1223, 1040, 999, 772, 627
[0313]
Example 129
Trans-4- (5-Methyl-1,3-dioxo-2-one-4-ylmethyl) amino-[(S) -N-[(R) -2-isopropoxycarbonylamino-4,4-dimethyl- Pentanoyl] prolyl] aminomethylcyclohexane (Compound No. 1005 in Table 1)
NMR (CDCl _Three )
7.10 (m, 1H), 5.07 (d, 1H), 4.83 (m, 1H), 4.57 (d, 1H), 4.40 (m, 1H), 3.96 (m , 1H), 3.48 (s, 2H), 3.45 (m, 2H), 3.04 (m, 2H), 2.50 (m, 1H), 2.39 (m, 1H), 2 .11 (s, 3H), 2.00 (m, 3H), 1.83 (m, 3H), 1.69 (m, 5H), 1.57-1.42 (m, 3H), 1. 25 (d, 3H), 1.22 (d, 3H), 1.00 (s, 9H)
IR: 3349, 2934, 2872, 1823, 1653, 1537, 1445, 1225, 1047, 999, 712, 627
[0314]
Example 130
Trans-4- (5-Methyl-1,3-dioxo-2-one-4-ylmethyl) amino-[(S) -N-[(R) -2-methylsulfonylamino-2-cyclohexylacetyl] prolyl] Aminomethylcyclohexane (Compound No. 1006 in Table 1)
NMR (CDCl _Three )
6.69 (t, 1H), 5.26 (d, 1H), 3.82 (m, 2H), 3.54 (m, 2H), 3.49 (s, 2H), 3.13 (m , 1H), 3.00 (m, 1H), 2.96 (s, 3H), 2.51 (m, 1H), 2.30 (m, 1H), 2.11 (s, 3H), 2 .02 (m, 4H), 1.80 (m, 9H), 1.61 (m, 2H), 1.43 (m, 1H), 1.20 (m, 5H), 0.97 (m, 3H)
IR: 3376,2930,2855,1642,1536,1451,1352,1154,984,760,619,517
[0315]
Test Example 1 Measurement of antithrombin activity
i) Method for measuring hydrolysis inhibition of synthetic substrate (S-2238)
S-2238 (kabi) is dissolved in Tris-HCl buffer (pH 8.3) to prepare an S-2238 0.4M Tris-HCl solution having a concentration of 80 μM. To this 175 μl, 515 μl of an aqueous solution of the compound of the present invention is added, and after incubation at 37 ° C. for 1 minute, 10 μl of 4.4 units / ml of bovine thrombin (Mochida) is added. The substrate hydrolysis rate is determined by measuring the change in absorbance at 405 nm at 37 ° C.
[0316]
The concentration of the inhibitor showing the absorbance of 1/2 when the inhibitor (the compound of the present invention) is not added is I ₅₀ (ΜM).
ii) Measurement method for inhibition of coagulation of rat plasma
The compound of the present invention is dissolved in water or physiological saline to make a total of 0.1 ml, and 0.1 ml of rat plasma is added thereto and incubated at 37 ° C. for 30 seconds. 0.1 ml of bovine thrombin (Mochida) 8 unit / ml solution is added thereto, and the coagulation time is measured at 37 ° C. The concentration of the inhibitor that doubles the coagulation time when no inhibitor (the compound of the present invention) is added is I ₅₀ (ΜM).
[0317]
iii) Method for measuring plasma antithrombin activity after oral administration to rats
To rats fasted overnight, 30 mg / kg of the compound of the present invention is orally administered in an aqueous solution or suspension using an oral sonde.
One hour later, 2 ml of blood is collected from the abdominal vena cava, and the antithrombin activity in the plasma is measured using the method ii). Compared with rat blood to which the inhibitor (the compound of the present invention) was not administered, the effect of extending the clotting time was expressed as a thrombin time extension rate with a value of 1 as a control.
[0318]
Test Example 2 Measurement of antitrypsin activity
i) Method for measuring hydrolysis inhibition of synthetic substrate (S-2222)
S-2222 (kabi) is dissolved in Tris-HCl buffer (pH 8.3) to prepare an S-2222 0.4M Tris-HCl solution having a concentration of 400 μM. To this 175 μl, 515 μl of an aqueous solution of the compound of the present invention is added, and after incubation at 37 ° C. for 1 minute, 10 μl of a bovine trypsin (Sigma) 1-2 mg / ml solution is added. The substrate hydrolysis rate is determined by measuring the change in absorbance at 405 nm at 37 ° C.
[0319]
The concentration of the inhibitor exhibiting an absorbance of 1/2 when no inhibitor (the compound of the present invention) is added is I ₅₀ (ΜM).
The above results are summarized in Table 2.
[0320]
[Table 114]
[0321]
[Table 115]
[0322]
Rat acute toxicity test
Test Example 3 Acute toxicity test
An oral acute toxicity test was conducted using rats to determine the approximate lethal dose. The results are shown in Table 3.
[0323]
[Table 116]
[0324]
【The invention's effect】
The proline amide derivative of the present invention or a salt thereof has a strong inhibitory activity against proteolytic enzymes such as thrombin and trypsin. In addition, since the compound is excellent in oral absorption, the compound of the present invention is effective as an oral antithrombin agent, that is, an oral anticoagulant, or an oral antitrypsin agent, that is, a therapeutic agent for pancreatic diseases such as pancreatitis.

Claims (6)

The following general formula (I)
[In the above formula, A represents a carbon atom, n represents 1, and the broken line does not exist or represents a single bond.
R1 is
{D represents a single bond, E represents a single bond or a C1-C6 alkylene group.
R4 represents -SR7 (R7 represents a C1-C6 alkyl group).
R5 is -NH2,
-NHCOR20 (R20 represents a C1-C6 alkoxy group or a C7-C12 aralkyloxy group) or -NHSO2R21 (R21 represents a C1-C6 alkyl group or a C6-C10 aryl group).
m represents 1. },
R2 represents a hydrogen atom.
R3 represents -C (= NR25) NH2 (R25 represents a hydrogen atom or a hydroxyl group) or -NH2.
Represents. ]
Or a salt thereof, or a hydrate thereof. 4-amidino - [(S) -N - [(R)-N'-methylsulfonyl-methionyl] prolyl] aminomethyl benzene or a salt or hydrate thereof. 4-[(S) -N-[(R) -2-ethoxycarbonylamino-3-methyl-3-methylthiobutanoyl] prolyl ] aminomethyl-benzamide oxime or a salt thereof or a hydrate thereof. A protease inhibitor comprising the compound according to any one of claims 1 to 3 as an active ingredient. The antithrombin agent which uses the compound in any one of Claims 1-3 as an active ingredient. The anticoagulant which uses the compound in any one of Claims 1-3 as an active ingredient.