JP3408379B2 - Novel dipeptide compound or pharmacologically acceptable salt thereof and pharmaceutical use thereof - Google Patents

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel dipeptide compound having an action of inhibiting the enzymatic activity of a protease derived from HIV virus. In particular, it relates to a novel dipeptide compound having an acyl group derived from a monocyclic compound carboxylic acid as an acyl group bonded to the amino group at the N-terminal of the dipeptide skeleton. The present invention also relates to a pharmaceutical use which utilizes the inhibitory activity of the novel dipeptide compound against a protease derived from HIV virus to achieve an action of suppressing HIV virus growth in the body.

[0002]

2. Description of the Related Art Human immunodeficiency virus (HIV) which is a causative virus of AIDS
Is the Ga used for the formation of the viral particle in the host cell.
G protein and reverse transcriptase are produced as precursor proteins. This precursor protein is a protease (HIV
Only after being cleaved to a specific size by a protease) can each function be exhibited. Therefore, H
By inhibiting the enzymatic activity of HIV protease, an IV protease inhibitor becomes a compound that exhibits antiviral activity by blocking the formation and maturation of infectious virus particles. Several types of HIV protease inhibitors have already been reported, one of which is the substrate transition state mimic (trans).
There is a synthetic peptidomimetic compound called ition-state mimetic) (T. Robins, J. Plattner, J. Acquir. Immun. De
fic. Syndr., 6, 162 (1993), etc.). For example,
An amino acid sequence that HIV protease selectively cleaves,
Ro 31-8959 (NA Roberts et al., Sci containing a phenylalanine ψ [CH (OH) CH2N] decahydroisoquinolinecarboxylic acid skeleton similar to -Tyr… Pro- or -Phe… Pro-
ence 248, 358-361 (1990), etc.) or phenylalanine ψ [CH (O
(H) C (O) N] proline and other peptide derivatives containing a norstatin skeleton (TF Tam et al., J. Med. Chem. 35, 131
8-1320 (1992), etc.) and hydroxymethylcarboxamide-type derivatives are reported to be useful as HIV protease inhibitors. The present inventors also previously
A group of synthetic peptide compounds, which are substrate transition state pseudo-substances containing a 3-amino-2-hydroxy-4-phenylbutanoic acid residue in their skeleton structure, very strongly inhibit the activity of HIV protease, and are anti-AIDS agents. And was proposed as an HIV protease inhibitor (see Japanese Patent Laid-Open No. 5-707722).

These substrate transition state mimics are nucleic acid derivative type reverse transcriptase inhibitors such as AZT (azidothymidine), dideoxycytidine (DDC) and dideoxyinosine (DDI) which are already clinically used as anti-AIDS drugs. The next most promising next-generation anti-AIDS drug is clinical use, clinical trials and research. That is, by utilizing the HIV protease inhibitory activity, the formation of the virus particles is suppressed in the host cell, and HIV proliferation /
Clinical application as an anti-AIDS drug that suppresses the onset of AIDS by inhibiting infection has been attempted (see Nakajima et al., Monthly Yakuji Vol. 35, 2983-2989 (1993)).

However, among these peptidomimetic compounds, the conventional compounds belonging to the hydroxymethylcarboxamide type derivative which are excellent in HIV protease inhibitory activity have a structure in which an acyl group is bonded to the N-terminal amino group of the tripeptide chain. ing. Therefore, it is often reported that they have problems such as (1) poor solubility in water, (2) instability in the body, and (3) low oral absorption rate (Hiroaki Mitsuya, Science Vol. 64, No. 7 p462-470 (1994)). In particular, since the anti-AIDS drug is a drug that takes a long-term and continuous administration form, it is easily absorbed especially in oral administration,
In addition, there is a demand for the development of compounds that are more stable in vivo and have improved bioavailability. There is a demand for the development of a compound having a relatively small molecular weight and being excellent in HIV protease inhibitory activity which is not easily degraded by various digestive enzymes and proteolytic enzymes in the digestive tract. Specifically, there is a demand for the development of a novel dipeptide compound containing a dipeptide substrate state pseudostructure having a smaller molecular weight as the substrate transition state pseudostructure, and having an acyl group or the like bonded to the N-terminal amino group thereof.

[0005]

DISCLOSURE OF THE INVENTION Problems to be Solved by the Invention The problem to be solved by the present invention is a peptide compound having a tripeptide chain conventionally proposed as an anti-AIDS drug, which is a substrate transition state mimic of HIV protease, and HIV protease inhibition. It is an object of the present invention to provide a novel dipeptide compound having a comparable activity and a smaller molecular weight. That is, the object of the present invention is different from various hydroxymethylcarboxamide type tripeptide compounds conventionally proposed as HIV protease inhibitors in the peptide chain length, and has an excellent HIV protease inhibitory activity or HIV.
It is an object of the present invention to provide a novel dipeptide compound having a viral growth inhibitory action. Further, an object of the present invention is to provide an HIV virus growth inhibitor for treating AIDS, which comprises the novel dipeptide compound as an active ingredient.

[0006]

[Means for Solving the Problems] In order to solve the above-mentioned problems, the inventors of the present invention have conducted earnest researches, and conducted HIV research
Although there are similarities in structure with conventional hydroxymethylcarboxamide-type peptide compounds that have been proposed as ze inhibitors, some have clear structural differences.
By designing and creating new dipeptide compounds and confirming that these dipeptide compounds have the desired HIV protease inhibitory activity or inhibitory effect on HIV virus growth, they found that they exhibit excellent activity. The present invention has been completed. That is, the present invention is described in the following items (1) to (7).

(1) General formula (I):

[Chemical 7] (In the formula, R ₁ represents a 5- or 6-membered monocyclic hydrocarbon group, or a heterocyclic group in which one or more carbon atoms of the monocyclic hydrocarbon group are replaced by heteroatoms, It may have a substituent on the ring group, the number of which does not exceed 3. X is a methylene group.
(-CH _2- ), chloromethylene (-CH (Cl)-), an oxygen atom or a sulfur atom, or a sulfonyl group (-SO _2- ) is shown. R ₂₁ ,
R ₂₂ each represents a hydrogen atom or an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and may be a straight chain type or branched. R ₃ represents a monovalent group derived from an aliphatic hydrocarbon group having 1 to 6 carbon atoms or an aromatic monocyclic hydrocarbon having a total number of carbon atoms of 12 or less, and a carbon constituting the hydrocarbon group. The chain skeleton may be linear or may have a branch, and a halogen atom may be substituted on the aromatic monocycle of the aromatic monocyclic hydrocarbon group. However, X is chloro
Methylene (-CH (Cl)-), and R ₂₁ and R ₂₂ are both hydrogen
When it is an atom, R ₁ is a group selected from the α group below.
An optionally substituted aryl group or a substituent
Teloaryl group, R ₃ is alkyl having 1 to 6 carbons
Group, cycloalkyl group having 3 to 8 carbon atoms, 1 carbon atom
Selected from up to 6 hydroxyalkyl groups or β groups below
The aralkyl group which may have a substituent is excluded. [Α group] Alkyl group having 1 to 4 carbon atoms, hydroxyl group, carbon
Alkoxy group having 1 to 4 carbon atoms, Al having 1 to 4 carbon atoms
Kirthio group, halogen atom, trifluoromethyl group,
Rumil group, nitro group, amino group [β group] alkyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms
A novel dipeptide compound represented by 4 alkoxy groups, halogen atoms) or a pharmaceutically acceptable salt thereof.

(2) General formula (II):

[Chemical 8] (In the formula, X, R ₂₁ , R ₂₂ , and R ₃ each represent a group having the same meaning as in formula (I). R ₁₁ represents a hydrogen atom, an amino group, or a hydroxyl group, and R ₁₂ represents a hydrogen atom. or represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms, serial to (1) represented by the linear may be type, may have a branched.)
The novel dipeptide compound described above or a pharmaceutically acceptable salt thereof.

(2) General formula (III):

[Chemical 9] (In the formula, X, R ₂₁ and R ₂₂ each represent a group having the same meaning as in the general formula (I), and R ₁₁ and R ₁₂ respectively represent a group having the same meaning as in the general formula (II)). Described in (1) above
The novel dipeptide compound or a pharmacologically acceptable salt of.

(4) General formula (IV):

[Chemical 10] (In the formula, X, R ₂₁ and R ₂₂ each represent a group having the same meaning as in the general formula (I), and R ₁₁ and R ₁₂ respectively represent a group having the same meaning as in the general formula (II). R ₃₁ , R ₃₂ , and R ₃₃ each represent a hydrogen atom, a halogen atom, or an aliphatic hydrocarbon group having 1 to 4 carbon atoms, and may be linear or branched. The novel dipeptide compound or a pharmaceutically acceptable salt thereof described in (1) above .

(5) General formula (V):

[Chemical 11] (In the formula, R ₁₁ represents an amino group or a hydroxyl group,
R ₁₂ represents a methyl group or an ethyl group. R ₂₁ and R ₂₂ are
Each represents a hydrogen atom or a methyl group. ] The novel dipeptide compound shown by these, or its pharmacologically acceptable salt.

(6) General formula (VI):

[Chemical 12] (In the formula, R ₁₁ represents an amino group or a hydroxyl group,
R ₁₂ represents a hydrogen atom, a methyl group or an ethyl group.
R ₂₁ and R ₂₂ each represent a hydrogen atom or a methyl group.
R ₃₁ , R ₃₂ and R ₃₃ each represent a hydrogen atom, a halogen atom or a methyl group. ] The novel dipeptide compound shown by these, or its pharmacologically acceptable salt.

(7) An anti-AIDS drug comprising as an active ingredient any of the novel dipeptide compounds or pharmacologically acceptable salts thereof described in the above items (1) to (6).

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The dipeptide compound of the present invention is linked to a 3-amino-2-hydroxy-4-phenylbutanoyl residue by an amide bond as a substrate transition state pseudo structure essential for its HIV protease inhibitory activity. It has an α-aminocarboxamide containing a cyclic group, and can be roughly classified into hydroxymethylcarboxamide-type derivatives. In this dipeptide compound of the present invention, the configuration of the 3-amino-2-hydroxy-4-phenylbutanoyl residue constituting it is preferably the (2S, 3S) -form,
Further, in the α-aminocarboxamide containing a 5-membered ring group containing X, it is preferable to use the configuration in which the corresponding cyclic α-amino acid is the (L) -form. The group R ₃ substituting the nitrogen atom of the carbamoyl group of the α-aminocarboxamide is one derived from an aliphatic hydrocarbon group having 1 to 6 carbon atoms or an aromatic monocyclic hydrocarbon having 12 or less carbon atoms in total. In the carbon chain skeleton which is a valent group and constitutes these hydrocarbon groups, an aliphatic hydrocarbon group having a chain carbon chain skeleton, or a chain formula existing as a side chain in an aromatic monocyclic hydrocarbon group Any of the hydrocarbon groups may be linear or branched. Here, the monovalent group derived from an aromatic monocyclic hydrocarbon means both a group having a bond on the aromatic monocycle and a group having a bond on the aromatic side chain. In addition, a halogen atom may be substituted on the aromatic monocyclic ring of the aromatic monocyclic hydrocarbon group. That is, any can be used as long as the substituted carbamoyl group can be formed by the reaction of the corresponding carboxyl group and the primary amine composed of the group R ₃ .

In the aliphatic hydrocarbon group having 1 to 6 carbon atoms used for the group R ₃ , an alkyl group having 1 to 6 carbon atoms such as methyl group, ethyl group, propyl group, isopropyl group, butyl group and isobutyl group. Group, sec-butyl group, tert
A -butyl group, a pentyl group, a hexyl group and the like are preferable, a branched alkyl group having 3 to 5 carbon atoms is more preferable, and a tert-butyl group is more preferable.
On the other hand, as the aromatic monocyclic hydrocarbon group having a total carbon number of 12 or less, a hydrocarbon group-substituted phenyl group having a free valence on the ring and having a phenyl group and a chain hydrocarbon group as a side chain , And a benzyl group having a free valence in the side chain, and a 2-methylbenzyl group, 2,6-dimethylbenzyl group, which is a hydrocarbon group-substituted benzyl group having a side chain on the ring, and 2 Examples thereof include a 4,4,6-trimethylbenzyl group. The halogen atom which may be substituted on the aromatic monocycle may be a chlorine atom, a bromine atom or a fluorine atom, and a chlorine atom is preferable. Among these various aromatic monocyclic hydrocarbon groups, a benzyl group having a free valence in the side chain, a phenethyl group, and a hydrocarbon group-substituted benzyl group having a side chain on the ring are preferable. A benzyl group and a hydrocarbon group-substituted benzyl group having a side chain on the ring are more preferable, and any of the 2-position having the ortho-position, the 6-position, or the 4-position having the para-position is particularly preferable. A hydrocarbon group-substituted benzyl group present in
Specifically, a 2-methylbenzyl group, a 2,6-dimethylbenzyl group, a 2,4,6-trimethylbenzyl group and the like are more preferable. In these benzyl groups and hydrocarbon group-substituted benzyl groups having a side chain at any of the 2-position, 4-position, and 6-position thereof, the side chain is preferably an alkyl group having 1 to 4 carbon atoms, and particularly, the side chain is A 2-methylbenzyl group, which is a methyl group,
A 2,6-dimethylbenzyl group and a 2,4,6-trimethylbenzyl group are more preferable. In particular, a mono- or di-substituted benzyl group which is present in either or both of the 2-position and the 6-position in which an alkyl group having 1 to 4 carbon atoms in the side chain is in the ortho position, and a benzyl group,
Among them, those whose side chain is a methyl group, specifically, benzyl group, 2-methylbenzyl group and 2,6-dimethylbenzyl group are even more preferable. In addition, in the benzyl group, those in which a halogen atom is substituted at any of the 2-position, 6-position which is the ortho-position, or the 4-position which is the para-position are also preferable. A 2-chlorobenzyl group in which an atom is substituted is more preferable. Particularly, in the benzyl group, a mono- or di-substituted benzyl group in which a halogen atom is substituted at either or both of the 2-position and the 6-position which are ortho positions, and above all, a 2-chlorobenzyl group in which a chlorine atom is substituted as a halogen atom. Are even more preferable.

X contained in the 5-membered ring group constituting the α-aminocarboxamide is any of a methylene group (-CH _2- ), a chloromethylene group (-CH (Cl)-), an oxygen atom or a sulfur atom. The sulfur atom may be present as a sulfinyl group or a sulfonyl group in addition to the thio group.
That is, when both R ₂₁ and R ₂₂ are hydrogen atoms, the corresponding 5-membered α-amino acid has a methylene group (-CH _2- )
Proline, chloromethylene group (-CH (Cl)-) is selected, 4-chloropyrrolidine-2-carboxylic acid, oxygen atom is selected, 1,3-oxazolidine-4-carboxylic acid, sulfur atom To select 1,3-thiazolidine-4
-Carboxylic acid, 1,3-thiazolidine-1,1-dioxide-4-carboxylic acid having a sulfur atom as a sulfonyl group and the like can be mentioned. The groups R ₂₁ and R ₂₂ present on the 5-membered ring group are each selected from a hydrogen atom or an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and the aliphatic hydrocarbon group is a straight chain type. Or may have a branch. For R ₂₁ and R ₂₂ , a hydrogen atom or an alkyl group having 1 to 4 carbon atoms is preferable, and a hydrogen atom or a methyl group is more preferable. Particularly, 1,3-thiazolidine-4-carboxylic acid having a sulfur atom selected as X, 1,3-thiazolidine-1,1-dioxide-4-carboxylic acid having a sulfur atom as a sulfonyl group, X 4-chloropyrrolidine-2 is selected as the chloromethylene group.
-Carboxylic acid or the like, or 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid or the like in which R ₂₁ or R ₂₂ selected from a hydrogen atom or a methyl group is substituted, is more preferable.

An acyl group R ₁ -CO- substituting the N-terminal amino group of the 3-amino-2-hydroxy-4-phenylbutanoyl skeleton characterizing the dipeptide compound of the present invention.
Wherein the monocyclic group R ₁ is a 5- or 6-membered ring,
It may be a cyclic hydrocarbon group or a heterocyclic group in which one or more carbon atoms of the cyclic hydrocarbon group are replaced by hetero atoms. The hetero atom means a nitrogen atom, a sulfur atom or an oxygen atom, and the sulfur atom may be present as a sulfinyl group or a sulfonyl group in addition to the thio group. Further, one in which one of the carbon atoms is replaced with oxo oxygen to form a carbonyl group is also included. In addition, the ring group R ₁ may have a further substituent whose number is not more than 3. Below, the ring group R ₁
Will be described more specifically by way of example.

When the ring group R ₁ is a 6-membered ring, it is a phenyl group which is an aromatic ring group, or a corresponding 4-aromatic ring group substituted with a nitrogen atom, a 4-pyridyl group or a 2-pyridyl group. An alicyclic group such as a 3-pyridyl group, a 2-pyrimidinyl group, a 4-pyrimidinyl group, and a 5-pyrimidinyl group.
A cyclohexyl group and its corresponding heterocyclic group, 4-
In addition to a piperidyl group, a 2-morpholinyl group, etc., these 6-membered rings further have an alkyl group having 1 to 6 carbon atoms, a carboxyl group, a carbamoyl group, a hydroxyl group, an amino group, a nitro group, an alkylamino group, an alkoxycarbonyl group. Examples of the ring group include a ring group in which the number of substituents such as is not more than 3. As a specific example, a 4-carboxyphenyl group substituted with a carboxyl group such as a tolyl group, a xylyl group, a cumenyl group, and a mesityl group in which 1 to 3 alkyl groups having 1 to 6 carbon atoms are present as a substituent, 4-carboxyphenyl group substituted by a carbamoyl group such as 2-carboxyphenyl group and 3-carboxyphenyl group, 4-hydroxyphenyl group substituted by a hydroxyl group such as 4-carbamoylphenyl group, 2-carbamoylphenyl group and 3-carbamoylphenyl group, 2-hydroxyphenyl group, 3-hydroxyphenyl group, 3-hydroxy-2
-Methylphenyl group, 3-ethyl-2-hydroxyphenyl group, etc., substituted with amino group, 4-aminophenyl group, 2-aminophenyl group, 3-aminophenyl group, etc., substituted with nitro group, 3,5 -Substituted by an alkylamino group such as a dinitrophenyl group, substituted by an alkoxycarbonyl group such as a 3-methylaminophenyl group, 4
Examples thereof include a -methoxycarbonylphenyl group, a 2-methoxycarbonylphenyl group, and a 3-methoxycarbonylphenyl group.

When the ring group R ₁ has a 5-membered ring, it is a heteroaromatic ring group such as 2-furyl group, 3-furyl group, 2-thienyl group, 3-thienyl group and 2-pyrrolyl group. Group, 3-pyrrolyl group, etc., alicyclic group, cyclopentyl group, 2-cyclopenten-1-yl group, etc., corresponding heterocyclic group, pyrrolidin-2-yl group, pyrrolin-2-yl group , 2-tetrohydrofuryl group, 2-tetrohydrothienyl group, and the like, in addition to these 5-membered rings,
Further, a cyclic group in which the number of substituents such as an alkyl group having 1 to 6 carbon atoms, a carboxyl group, a carbamoyl group, a hydroxyl group, an amino group, a nitro group, an alkylamino group, an alkoxycarbonyl group and the like does not exceed 3 Can be mentioned.

In the dipeptide compound of the present invention, the ring group R ₁ is preferably an aromatic ring group or a heteroaromatic ring group which may have a substitution of not more than 3, and preferably has a substitution of not more than 3. A 6-membered aromatic ring group or heteroaromatic ring group is more preferable. Among them, 2 and 3 of the phenyl group
Substituted phenyl groups having a substitution of not more than 2 at the position are more preferable, and particularly, the following general formula (VII):

[0021]

[Chemical 13] (In the formula, R ₁₁ represents an amino group or a hydroxyl group,
R ₁₂ represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms, and may be a straight chain type or branched. And more preferably a disubstituted phenyl group represented by In addition, the general formula (VI
In the disubstituted phenyl group represented by I), it is particularly preferable to select a hydroxyl group for R ₁₁ and a methyl group or an ethyl group for R ₁₂ .

In the dipeptide compound of the present invention represented by the above general formula (I), R ₁ , R ₃ and X are
When at least 2 or more of the above are selected in a suitable range, a more preferable dipeptide compound is obtained. For example, the group R ₁
And R ₃ are both selected within a suitable range, for example, for R ₁ ,
The disubstituted phenyl group represented by the general formula (VII) is replaced by R ₃
A dipeptide compound that selects a tert-butyl group, that is, the following general formula (III):

[Chemical 14] (In the formula, X represents a group having the same meaning as X in the general formula (I). R ₁₁ represents an amino group or a hydroxy group,
₁₂ represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms, which may be linear or branched. R ₂₁ and R ₂₂ are
Each represents a hydrogen atom or an aliphatic hydrocarbon group having 1 to 6 carbon atoms, and may be linear or branched. The dipeptide compound represented by () becomes more preferable.

Alternatively, in R ₁ , a disubstituted phenyl group represented by the above general formula (VII) is used, and in R ₃ , a benzyl group and a 4-position in which the side chain is in the ortho position, 6-position or para-position. In a hydrocarbon group-substituted benzyl group present in any of the following, or in these benzyl group and hydrocarbon group-substituted benzyl group,
A substituted benzyl group in which a halogen atom is further substituted at any of the 2-position or 6-position which is the ortho-position or the 4-position which is the para-position, specifically, the following general formula (VIII):

[Chemical 15] (In the formula, R ₃₁ , R ₃₂ , and R ₃₃ each represent a hydrogen atom, a halogen atom, or an aliphatic hydrocarbon group having 1 to 4 carbon atoms,
It may be straight-chain or branched. ), A dipeptide compound for selecting a hydrocarbon group-substituted benzyl group whose total number of carbon atoms does not exceed 12, that is, the following general formula (IV):

[Chemical 16] (In the formula, X represents a group having the same meaning as X in the general formula (I). R ₁₁ represents an amino group or a hydroxyl group, and R _{12 represents}
Represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms, which may be a straight chain type or branched. R ₂₁ and R ₂₂ each represent a hydrogen atom or an aliphatic hydrocarbon group having 1 to 6 carbon atoms, which may be linear or branched. R
₃₁ , R ₃₂ , and R ₃₃ each represent a hydrogen atom, a halogen atom, or an aliphatic hydrocarbon group having 1 to 4 carbon atoms, and may be linear or branched. The dipeptide compound represented by () is also more preferable. It is more preferable to select a chlorine atom as the halogen atom. In the above-mentioned general formula (IV), a mono- or di-substituted benzyl group present at either or both of the 2-position and the 6-position, which are ortho positions, is selected as the substituted benzyl group present at the C-terminus, which is a more preferable compound.

The above-mentioned general formula (V) or general formula (V
The dipeptide compound shown in I) is a compound in which the group X in the general formula (III) or general formula (IV) is selected in a more preferable range, and is more preferable. As an example of a series of compounds represented by this general formula (V) or general formula (VI), (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- [3 -Hydroxy-2-methylbenzoyl] amino
-4-Phenylbutanoyl] -1,3-thiazolidine-4-carboxamide, (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- [3-amino-2- Methylbenzoyl] amino-4
-Phenylbutanoyl] -1,3-thiazolidine-4-carboxamide, (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- [2-ethyl-3-hydroxybenzoyl] 〕amino
-4-Phenylbutanoyl] -1,3-thiazolidine-4-carboxamide, (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- [3-amino-2- Ethylbenzoyl] amino-4
-Phenylbutanoyl] -1,3-thiazolidine-4-carboxamide, (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- [3-hydroxy-2-methylbenzoyl 〕amino
-4-Phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R) -N-tert-butyl-3-
[(2S, 3S) -2-Hydroxy-3- [3-amino-2-methylbenzoyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R ) -N-tert
-Butyl-3-[(2S, 3S) -2-hydroxy-3- [2-ethyl-3
-Hydroxybenzoyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R) -N-tert-butyl-3-[(2S, 3S) -2- Hydroxy
-3- [3-Amino-2-ethylbenzoyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4
-Carboxamide, (R) -N- (2-methylbenzyl) -3-[(2
S, 3S) -2-Hydroxy-3- [3-hydroxy-2-methylbenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide, (R) -N- (2-methyl Benzyl) -3-[(2S, 3S) -2-hydroxy-3- [3-amino-2-methylbenzoyl] amino-4-phenylbutanoyl] -1,3-
Thiazolidine-4-carboxamide, (R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3- [2-ethyl-3-
[Hydroxybenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide, (R) -N- (2
-Methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3- [3-
Amino-2-ethylbenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide, (R)-
N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-
[3-Hydroxy-2-methylbenzoyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4
-Carboxamide, (R) -N- (2-methylbenzyl) -3-[(2
S, 3S) -2-Hydroxy-3- [3-amino-2-methylbenzoyl] amino-4-phenylbutanoyl] -5,5-dimethyl-
1,3-thiazolidine-4-carboxamide, (R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3- [2-ethyl-3-hydroxybenzoyl] amino- 4-Phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-
Hydroxy-3- [3-amino-2-ethylbenzoyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (2R, 4S) -N-tert-butyl
-3-[(2S, 3S) -3- (2-Ethyl-3-hydroxybenzoyl)
Amino-2-hydroxy-4-phenylbutanoyl] -4-chloropyrrolidine-2-carboxamide, (R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -3- (3 -Hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide, (R) -N- (2-
(Chlorobenzyl) -3-[(2S, 3S) -3- (3-hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine- 4-carboxamide, (R) -N- (2-chlorobenzyl) -3-[(2S, 3S) -3- (3-
Specific examples thereof include hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide.

The pharmacologically acceptable salt of the dipeptide compound of the present invention means, for example, the group R present in the compound.
_{In the case} where a nitrogen atom having basicity is present in the 5- to 7-membered ring of 1 or a substituent substituting the 5- to 7-membered ring, or a condensed 5 to 7-membered ring, it is pharmacologically acceptable with the nitrogen atom. It also includes salts formed with various acids, and specifically includes pharmacologically acceptable salts such as hydrochlorides, acetates and methanesulfonates. Alternatively, by using a carboxyl group substituted for the group R ₁ or a phenolic hydroxyl group,
A salt is formed with various pharmaceutically acceptable monovalent cation species. Specifically, it means a pharmacologically acceptable salt such as sodium salt and ammonium salt.

The series of dipeptide compounds represented by the above general formula (I) can be prepared according to the production method outlined below. That is, the process of N-acylation will be outlined. Once, a hydroxymethylcarboxamide type dipeptide having no substitution at the N-terminal amino group, that is, the following general formula (IX):

[Chemical 17] (Wherein, X, R _3, R _21, R _22, the X in the general formula (I), R _3, R _21, respectively R ₂₂ show the same group.) The represented by compounds as an intermediate material , By the reaction described below,
It can lead to the N-acylated form.

The N-acylated dipe of the general formula (I)
Process for Producing Peptide Compound [1] Preparation of Intermediate Raw Material Compound Represented by General Formula (IX) Corresponds to an intermediate in the previously published method for synthesizing a hydroxymethylcarboxamide-type HIV protease inhibitor, and its preparation method. Have been reported in various publications (Kiso Yoshiaki, Journal of Organic Synthetic Chemistry, Vol. 52, 403-412 (1
994) and so on). For example, for example, the following general formula (X):

[Chemical 18] (Wherein, X, R _3, R _21, R _22, the X in the general formula (I), R _3, R _21, respectively R ₂₂ show the same group.) Represented by α- amino - carboxamide derivatives And the following general formula (XI):

[Chemical 19] (In the formula, B represents an amino-protecting group and can be deprotected with an acid.) (2S, 3S) -3-Amino-2-hydroxy-4-phenylbutanoic acid N A protected derivative, for example, DCC (N, N′-dicyclohexylcarbodiimide), EDC (1-ethyl-3- (3
-N, N-dimethylaminopropyl) carbodiimide)
And carbodiimide reagents such as HONB (N-hydroxy-norbornene-2,3-dicarboximide), HOB
By using an additive compound such as t (N-hydroxybenzotriazole) and the like to form a peptide bond by condensation, the following general formula (XII):

[Chemical 20] (Wherein, B represents the same group as B in formula (XI) to _{the, X, R 3, R 21} , R 22 is X in the general formula (I) for the, R _3, R _21, R ₂₂ represents the same group as R ₂₂ ).
Next, the dipeptide N-protected derivative is subjected to deprotection of the amino group using an acid such as hydrochloric acid in dioxane, and an intermediate raw material for the hydroxymethylcarboxamide dipeptide represented by the general formula (IX). Can be obtained. B used as a protecting group for the amino group is te
It is preferable to use a rt-butyloxycarbonyl group or the like which is commonly used for protecting the α-amino group of an α-amino acid in peptide chemistry.

Step [2] N-acylation reaction First, the following general formula (XIII):

[Chemical 21] (Wherein, R ₁ is the general formula (showing the same group as R ₁ I).) From a carboxylic acid represented by using the additive compounds such as carbodiimide reagents and HOBt such EDC, the Leads to the active ester form of carboxylic acid. Alternatively, a chloroformic acid ester type acid chloride such as isobutyl chloroformate is allowed to act to lead to a mixed acid anhydride of the carboxylic acid. That is, the following general formula (XIV):

[Chemical formula 22] (In the formula, R _1,. Showing the same group as R ₁ in formula (I) to above) is converted into a derivative of the carboxylic acid represented by, performing pre-activated. The atomic group Y is derived from the additive compound or acid chloride.

The derivative of the carboxylic acid represented by the general formula (IX) and the intermediate raw material represented by the general formula (XIV) are prepared, for example, from N, N-dimethylformamide (DMF).
It is possible to obtain the desired hydroxymethylcarboxamide-type derivative represented by the general formula (I) that is N-acylated by reacting in a solvent such as. When a carbodiimide reagent is used, activation of the carboxylic acid and subsequent N-
Needless to say, the acylation reaction may be carried out simultaneously in the same reaction solution.

In the N-acylation reaction using these acid anhydrides, the substituents present on the group R ₁ , such as an amino group, a hydroxyl group, and a carboxyl group, may be removed when unnecessary side reactions occur. It goes without saying that the group is previously protected with a general-purpose protecting group, the reaction is carried out, and then the deprotection operation is carried out.

The hydroxymethylcarboxamide-type derivative represented by the general formula (I), which is produced according to the above-mentioned steps, is purified by a purification method such as recrystallization or column chromatography to remove impurities, if necessary. Can be used as Since the dipeptide compound of the present invention is produced from an intermediate raw material represented by the general formula (IX) and an activated derivative of a carboxylic acid represented by the general formula (XIV) as raw materials, its molecular structure can be identified. Determined by referring to the structure derived from each of the starting compounds and using any of these conventional analytical means such as nuclear magnetic resonance method, spectroscopic method such as infrared absorption method, or fragment analysis by mass spectrometry. This can be done easily.

The dipeptide compound of the present invention is its HIV
It has an α-aminocarboxamide containing a ring group linked to a 3-amino-2-hydroxy-4-phenylbutanoyl residue and an amide bond, as a substrate transition state pseudostructure essential for protease inhibitory activity. , Which is roughly classified into the hydroxymethylcarboxamide-type derivatives already reported, becomes an HIV protease inhibitor like the tripeptide compound. That is, utilizing this HIV protease inhibitory activity, as shown in the test example described below, the antiviral activity is blocked by blocking the formation and maturation of infectious virus particles in T cell lymphocytes of HIV virus. It becomes the compound shown. Therefore, it has a medicinal use as an anti-AIDS drug based on the effect of suppressing the formation and maturation of infectious virus particles.

When the dipeptide compound of the present invention is clinically applied as an anti-AIDS drug, it can be administered in the form of a drug using a conventional pharmaceutical carrier or excipient according to a conventional method. In general, the dipeptide compound of the present invention can be intravenously or intramuscularly injected as an injection, parenterally administered as a spray, suppository, etc., granules, capsules, tablets, etc. according to a conventional method. It can be administered orally. In addition, since the dipeptide compound of the present invention is also excellent in absorbability in the digestive tract, it is appropriate to orally administer it in a dosage form such as granules and capsules that keeps the compound in a solid state. The dose is 10 mg per adult, although it may be appropriately determined in consideration of age, sex, etc., depending on the symptoms of the administration subject, or the purpose of treatment such as the onset of AIDS, the inhibition of the progression of AIDS, etc. The dose is in the range of ˜1 g in 1 to 4 divided doses per day. When used as an orally-administered agent, generally, the dosage form (see JP-A-5-170722, etc.) applied to the oral administration of various synthetic peptide compounds already proposed as HIV protease inhibitors should be adopted. You can

The dipeptide compound of the present invention and the method for producing the same will be described below with reference to specific examples. Further, it is shown that the dipeptide compound of the present invention exhibits excellent anti-HIV activity due to its high HIV protease inhibitory activity and has properties suitable for pharmaceutical use such as low cytotoxicity.

In each of the following examples, the intermediate raw material (2S, 3S) -H-AHPBA-Pro-NH-tBu (1-[(2S, 3S) -3-amino-2-hydroxy-4- Phenylbutanoyl] -N'-tert-
Butyl-L-prolinamide), (2S, 3S) -H-AHPBA-Thz-NH-t
Bu ((R) -3-[(2S, 3S) -3-Amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-tert-butylcarboxamide), (2S, 3S) -H-AHPBA-Dmt-NH-tBu
((R) -3-[(2S, 3S) -3-Amino-2-hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-
N'-tert-butylcarboxamide) etc. is (2S, 3S) -HA
HPBA ((2S, 3S) -3-Amino-2-hydroxy-4-phenylbutanoic acid), Pro (L-proline), Thz ((R) -1,3-thiazolidine-4-carboxylic acid), Dmt ( (R) -5,5-Dimethyl-
1,3-thiazolidine-4-carboxylic acid), NH ₂ -tBu (tert-
(Butylamine) and the like as raw materials and prepared in advance as the dipeptide N-protected derivative according to the method already published in the publication. Then, the amino group was deprotected and used.

[0036]

Example 1 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[Benzoyl] amino-4-phenylbutanoyl] -1,3-
Thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365 mg, benzoic acid 122 mg
To the solution suspended in 3 ml of DMF, EDCHCl (1-ethyl-3- (3-N,
N-dimethylaminopropyl) carbodiimide hydrochloride) 192
mg, HOBt ・ H ₂ O (N-hydroxybenzotriazole) 153mg
Was added and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. The product was purified and recovered from the obtained residue by the following operations. The obtained residue was dissolved in 25 ml of ethyl acetate, this solution was washed successively with 10% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solution was concentrated again under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol system) and then reprecipitated from ethyl acetate / n-hexane to obtain 296 mg of the purified title compound. The compound was analyzed by HPLC under the following conditions, and the peak was detected at a retention time of 19.55 min.
As a result of time-of-flight mass spectrometry, the molecular weight was 4
It was 69 and was confirmed to be the target compound. HPLC retention time: 19.55 min HPLC conditions Column: YMC AM302 column, φ 4.6 x 150 mm Eluent: 0.1% TFA (trifluoroacetic acid) water-CH ₃ CN Elution conditions: 0%-100% Gradient; 30 min Flow rate: 1 ml / min TOF-MASS (time of flight mass spectrometry): [M + H] ⁺ 470

[0037]

Example 2 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[2-Methylbenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, o-toluic acid 136
In a solution in which 3 mg of DMF was suspended in 3 ml of EMF, HCl192 mg, HOBt.H ₂
O 153 mg was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, Example 1
The same purification as in (1) was performed to obtain 295 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 19.95 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 484

[0038]

Example 3 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[3-Methylbenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, m-toluic acid 136
In a solution in which 3 mg of DMF was suspended in 3 ml of EMF, HCl192 mg, HOBt.H ₂
O 153 mg was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 406 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 20.36 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 484

[0039]

Example 4 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[4-Methylbenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, p-toluic acid 136
In a solution in which 3 mg of DMF was suspended in 3 ml of EMF, HCl192 mg, HOBt.H ₂
O 153 mg was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, Example 1
The same purification as in (1) was performed to obtain 406 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 20.27 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 484

[0040]

Example 5 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[2-Hydroxybenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, salicylic acid 138mg
Was suspended in 3 ml of DMF, EDC ・ HCl192mg, HOBt ・ H ₂ O
153 mg was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 202 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 23.89 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 486

[0041]

Example 6 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[3-Hydroxybenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365 mg, m-hydroxybenzoic acid 138 mg to DMF 3 ml. To the suspended liquid, EDC ・ HCl192mg,
HOBt · H ₂ O (153 mg) was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. After that,
The same purification as in Example 1 was carried out to obtain 418 mg of the title compound.
The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 20.69 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 486

[0042]

Example 7 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[4-Hydroxybenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365 mg, m-hydroxybenzoic acid 138 mg to DMF 3 ml. To the suspended liquid, EDC ・ HCl192mg,
HOBt · H ₂ O (153 mg) was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. After that,
The same purification as in Example 1 was carried out to obtain 392 mg of the title compound.
The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 20.35 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 486

[0043]

Example 8 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[2-Aminobenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, 2- (t-butyloxycarbonylamino) ) Benzoic acid 237mg, HOBt 135mg DM
To the solution suspended in F3 ml, add 210 mg of EDC / HCl and
Stir for hours. Dichloromethane and 3% aqueous sodium carbonate solution were added to this reaction solution, and the mixture was stirred and then separated, and the organic layer was separated. Then, the protecting group t-butyloxycarbonyl group was deprotected, and the product was recovered by the following procedure. The separated organic layer was washed with 3% sodium carbonate aqueous solution and 1N hydrochloric acid to obtain 2
It was washed once with 5% saline, and dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off and concentrated, 5 ml of dichloromethane and 5 ml of 4N hydrogen chloride dioxane solution were added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was washed with water, 3% aqueous sodium carbonate solution, 5% brine and dried over anhydrous magnesium sulfate. The mixture was concentrated again under reduced pressure, and the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol system) to obtain 184 mg of the title compound. The compound was confirmed to be the target compound from the results of time-of-flight mass spectrometry described below. TOF-MASS: [M + H] ⁺ 485

[0044]

Example 9 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[3-Aminobenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, 3- (t-butyloxycarbonylamino) ) Benzoic acid 237mg, HOBt 135mg DM
To the solution suspended in F3 ml, add 210 mg of EDC / HCl and
Stir for hours. Dichloromethane and 3% aqueous sodium carbonate solution were added to this reaction solution, and the mixture was stirred and then separated, and the organic layer was separated. Thereafter, deprotection of the t-butyloxycarbonyl group and purification of the product were carried out in the same manner as in Example 8 to obtain the title compound 74
to obtain mg. The compound was confirmed to be the target compound from the results of time-of-flight mass spectrometry described below. TOF-MASS: [M + H] ⁺ 485

[0045]

Example 10 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[4-Aminobenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, 4- (t-butyloxycarbonylamino) ) Benzoic acid 237mg, HOBt 135mg DM
To the solution suspended in F3 ml, add 210 mg of EDC / HCl and
Stir for hours. Dichloromethane and 3% aqueous sodium carbonate solution were added to this reaction solution, and the mixture was stirred and then separated, and the organic layer was separated. The separated organic layer was treated with a 3% sodium carbonate aqueous solution,
The extract was washed twice with 1N hydrochloric acid successively with 5% saline and dried over anhydrous magnesium sulfate. Magnesium sulfate is filtered off,
After concentration, 5 ml of dichloromethane and 5 ml of 4N hydrogen chloride dioxane solution were added, and the mixture was stirred at room temperature for 1 hour. Next, water was added to the reaction solution, the mixture was stirred and then separated, and the aqueous layer was separated to collect a product in which the t-butyloxycarbonyl group as a protecting group was deprotected. Sodium carbonate was added to this aqueous layer to adjust the pH to 8-9.
And extracted with dichloromethane. The organic layer obtained by extraction was washed with 5% saline and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol system) and then reprecipitated from ethyl acetate / n-hexane to obtain 330 mg of the title compound. The compound was confirmed to be the target compound from the results of time-of-flight mass spectrometry described below. TOF-MASS: [M + H] ⁺ 485

[0046]

Example 11 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[2-Carboxybenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg suspended in DMF 3ml, anhydrous Phthalic acid (146 mg) and pyridine (0.5 ml) were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 25 ml of ethyl acetate. 10% of this solution
It was washed with an aqueous citric acid solution and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol system) and then reprecipitated from ethyl acetate / n-hexane to obtain 498 mg of the title compound. The compound is
From the results of the following HPLC analysis and time-of-flight mass spectrometry,
It was confirmed to be the target compound. HPLC retention time: 17.96 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 514

[0047]

Example 12 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[3-Carboxybenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, isophthalic acid 166
In a solution in which 3 mg of DMF was suspended in 3 ml of EMF, HCl192 mg, HOBt.H ₂
O 153 mg was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, and the obtained residue was dissolved in 25 ml of ethyl acetate. The solution was washed with 10% aqueous citric acid solution and saturated saline, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by preparative HPLC under the following conditions to give the title compound. In addition, the compound is the following HP
From the results of LC analysis and time-of-flight mass spectrometry, it was confirmed to be the target compound. Preparative HPLC conditions Column: YMC-Pack ODS, φ20 × 250 mm Eluent: 0.1% TFA water-CH ₃ CN Elution conditions: 0% -50% gradient; 50% after 60 min Isocratic flow rate: 5 ml / min Elution Time: 67 min to 70 min HPLC retention time: 17.96 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 514

[0048]

Example 13 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[4-Carboxybenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, monomethyl terephthalate 180mg suspended in DMF 3ml EDC ・ HCl192m
g, HOBt.H ₂ O 153 mg were added, and the mixture was stirred at room temperature for 14 hours.
The reaction mixture was concentrated under reduced pressure, and the obtained residue was washed with ethyl acetate 25
dissolved in ml. This solution was washed successively with 10% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution and saturated saline solution,
It was dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol system) to obtain 289 mg of the methyl ester of the title compound. This methyl ester compound was dissolved in 5 ml of methanol to prepare a 1N aqueous sodium hydroxide solution 5
ml was added, and the mixture was stirred at room temperature for 1 hour. After this ester hydrolysis, concentrated hydrochloric acid was added to the reaction solution to adjust the pH to about 3, and the mixture was extracted with dichloromethane. The extracted organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The obtained residue was reprecipitated from ethyl acetate / n-hexane to obtain 220 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 20.35 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 514

[0049]

Example 14 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[2-Pyridylcarbonyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, picolinic acid 123mg
Was suspended in 3 ml of DMF, EDC ・ HCl192mg, HOBt ・ H ₂ O
153 mg was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. The obtained residue was dissolved in 25 ml of ethyl acetate, this solution was washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. After concentration under reduced pressure, the obtained residue was purified by silica gel column chromatography (dichloromethane / methanol system) and then reprecipitated from ethyl acetate / n-hexane to obtain 364 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 19.18 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 471

[0050]

Example 15 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[3-Pyridylcarbonyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, nicotinic acid 123mg
Was suspended in 3 ml of DMF, EDC ・ HCl192mg, HOBt ・ H ₂ O
153 mg was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 14 was carried out to obtain 312 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 15.36 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 471

[0051]

Example 16 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[4-Pyridylcarbonyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, isonicotinic acid 1
In a liquid obtained by suspending 23 mg in 3 ml of DMF, EDC ・ HCl192 mg, HOBt ・
153 mg of H ₂ O was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Example later
The same purification as in 14 was carried out to obtain 305 mg of the title compound. In addition,
The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 16.70 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 471

[0052]

Example 17 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[2-thienylcarbonyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365 mg, 2-thiophenecarboxylic acid 128 mg to DMF 3 ml In the suspended liquid, EDC ・ HCl192m
g, HOBt.H ₂ O 153 mg were added, and the mixture was stirred at room temperature for 14 hours.
The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 361 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 19.14 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 476

[0053]

Example 18 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[3-thienylcarbonyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365 mg, 3-thiophenecarboxylic acid 128 mg to DMF 3 ml In the suspended liquid, EDC ・ HCl192m
g, HOBt.H ₂ O 153 mg were added, and the mixture was stirred at room temperature for 14 hours.
The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 390 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 18.90 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 476

[0054]

Example 19 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[2-Furylcarbonyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, 2-furancarboxylic acid 112mg in DMF 3ml To the suspended liquid, EDC ・ HCl192mg, HO
153 mg of Bt.H ₂ O was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 372 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 18.16 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 460

[0055]

Example 20 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[3-furylcarbonyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, 3-furancarboxylic acid 112mg in DMF 3ml To the suspended liquid, EDC ・ HCl192mg, HO
153 mg of Bt.H ₂ O was added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 331 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 18.36 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 460

[0056]

Example 21 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[3-Hydroxy-2-methylbenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-tBu 365mg, 3-hydroxy-2 -
To a solution prepared by suspending 152 mg of methylbenzoic acid in 3 ml of DMF, add EDC
HCl 192 mg and HOBt.H ₂ O 153 mg were added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to give the title compound 380
to obtain mg. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry, and further by giving the following ¹ H-NMR spectrum. HPLC retention time: 17.67 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 500 FAB-MASS: [M + H] ⁺ 500 ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.26 (s; 9H), 1.82 (s; 3
H), 2.74 (m; 2H), 3.02 (m; 1H), 3.32 (m; 1H), 4.35
(bs; 1H), 4.58 (bs; 1H), 4.78 (m; 2H), 5.09 (d; 1
H), 5.21 (d; 1H), 6.56 (d; 1H), 6.77 (d; 1H), 6.94
(t; 1H), 7.15 (t; 1H), 7.23 (t; 2H), 7.38 (d; 2H),
7.64 (s; 1H), 8.22 (d; 1H), 9.38 (s; 1H)

[0057]

Example 22 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[3-Hydroxy-2-methylbenzoyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4
-Carboxamide (2S, 3S) -H-AHPBA-Dmt-NH-tBu 197mg, 3-hydroxy-2-
EDC was added to the suspension of 76.1 mg of methylbenzoic acid in 1.5 ml of DMF.
_{· HCl 96mg, HOBt · H 2} O 76.5mg and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to give the title compound 1
Obtained 74 mg. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry, and further by giving the following ¹ H-NMR spectrum. HPLC retention time: 18.97 min (conditions are
Same as Example 1. ) TOF-MASS: [M + H] ⁺ 528 FAB-MASS: [M + H] ⁺ 528 ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.27 (s; 9H), 1.40 (s; 3)
H), 1.49 (s; 3H), 1.80 (s; 3H), 2.75 (m; 2H), 3.2-
3.4 (m; 1H), 4.35 (bs; 1H), 4.52 (bs and s; 2H), 4.
98 (d; 1H), 5.18 (d; 1H), 5.27 (d; 1H), 6.55 (d; 1
H), 6.76 (d; 1H), 6.94 (t; 1H), 7.13 (t; 1H), 7.23
(t; 2H), 7.36 (d; 2H), 7.63 (s; 1H), 8.22 (d; 1H),
9.36 (s; 1H)

[0058]

Example 23 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
[2-carbamoylbenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide Compound obtained in Example 11, (R) -N-tert-butyl-3-
[(2S, 3S) -2-hydroxy-3- [2-carboxybenzoyl] amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (145 mg) was dissolved in DMF (2 ml) to obtain EDC.
_{HCl 54.3mg, HOBt · H 2 O} 43.3mg and the mixture was stirred for 1 hour at room temperature. After the reaction, add 25% aqueous ammonia solution to this reaction solution 1
9.2 μl was added, and the mixture was subsequently stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. After that,
The same purification as in Example 1 was carried out to obtain 122 mg of the title compound.
The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 16.38 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 513

[0059]

Example 24 N-tert-butyl-1-[(2S, 3S) -2-hydroxy-3-N- [3-hydroxy-2-methylbenzoyl] amino-4-phenylbutanoyl] -L-prolinamide (2S, 3S) -H-AHPBA-Pro-NHtBu 347 mg, 3-hydroxy-2-
A solution of 152 mg of methylbenzoic acid suspended in 5 ml of DMF was added to EDC.
-HCl 192 mg and HOBt 135 mg were added, and it stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to give the title compound 276
to obtain mg. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 16.80 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 482

[0060]

Example 25 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (3-amino-2-methylbenzoyl) amino-4-phenylbutanoyl] -1 E.
HCl 211 mg, the HOBt · H ₂ O 153mg was added, and stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 153 mg of the title compound. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 14.57 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 499

[0061]

Example 26 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (2,3-
Dimethylbenzoyl) amino-4-phenylbutanoyl]-
1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NHtBu 365 mg, 2,3-dimethylbenzoic acid 150 mg suspended in DMF 4 ml, EDC.HCl 201
mg, HOBt · H ₂ O 153mg and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain the title compound 280
to obtain mg. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 19.77 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 498

[0062]

Example 27 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (2-amino-3-hydroxybenzoyl) amino-4-phenylbutanoyl] -1 3,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NHtBu 365 mg, 2-amino-3-hydroxybenzoic acid 168 mg suspended in DMF 4 ml, EDC
・ Add HCl 211mg, HOBt ・ H ₂ O 168 mg, and add at room temperature for 14
Stir for hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 130 mg of the title compound. The compound is the following HPL
As a result of C analysis and time-of-flight mass spectrometry, it was confirmed to be the target compound. HPLC retention time: 15.55 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 501

[0063]

Example 28 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (2-methyl-3-hydroxybenzoyl) amino-4-phenylbutanoyl] -1 , 3-Thiazolidine-1,1-dioxide-4-carboxamide [Step 1] (R) -N-tert-butyl-3-[(2S, 3S) -3- (tert-butoxycarbonyl) amino-2-hydroxy -4-Phenylbutanoyl] -1,3-thiazolidine-1,1-dioxide-4-carboxamide Boc-AHPBA-Thz-NHtBu (1.40g; 3.0mmol) in MeOH (24
ml): H ₂ O (12 ml), OXONE (2.17 g; 3.6 mmol) was added, and the mixture was stirred at room temperature overnight (about 14 hours). CH ₂ Cl ₂ and H ₂ O were added to the reaction solution for extraction. The organic layer extracted and separated was washed with a 5% NaCl aqueous solution and dried over anhydrous MgSO ₄ . After distilling off the solvent, the resulting residue was toluene: n-
It was recrystallized from a mixed solvent of hexane. The obtained crystals were purified by silica column chromatography (n-hexane: ethyl acetate system). After concentrating again, the residue obtained is toluene / n-
Recrystallize from a mixed solvent of hexane to give the title compound 0.25g
(Yield 17%) was obtained.

[Step 2] (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (2-methyl-3-hydroxybenzoyl) amino-4-phenylbutanoyl] -1,3-thiazolidine-1,1-dioxide-4-carboxamide Boc-AHPBA-Thz (O ₂ ) -NHtBu 200 mg obtained in Step 1
To this, 2 ml of 4N-HCl / dioxane solution was added, and the mixture was stirred at room temperature for 3 hours. After the reaction solution was concentrated, the obtained residue was dissolved in DMF (6 ml) and neutralized with Et ₃ N (0.06 ml). Then, 3-hydroxy-2-methylbenzoic acid 64 mg, HOBt.H ₂ O 64 mg, EDC
-HCl 84 mg was added and it stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 60 mg of the title compound. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 16.52 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 532

[0065]

Example 29 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (3,5-
Dihydroxybenzol) amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NHtBu 365 mg, 3,5-dihydroxybenzoic acid 170 mg DMF 5 ml In the liquid suspended in
l 211 mg, HOBt.H ₂ O 168 mg were added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to give the title compound 70
to obtain mg. As a result of the following HPLC analysis and time-of-flight mass spectrometry, the compound was confirmed to be the target compound. HPLC retention time: 15.68 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 502

[0066]

Example 30 (4S, 5R) -N-tert-Butyl-3-[(2S, 3S) -2-hydroxy-3-
(2-Methyl-3-hydroxybenzoyl) amino-4-phenylbutanoyl] -5-methyl-1,3-oxazolidine-4-carboxamide [Step 1] (4S, 5R) -3-tert-butoxycarbonyl-4 -N-tert-butylcarbamoyl-5-methyl-1,3-oxazolidine (4S, 5R) -3-tert-butoxycarbonyl-5-methyl-1,3-
Oxazolidine-4-carboxylic acid Boc-Oxz (Me) -OH 4.13g
, HOSu 2.06g in CH ₂ Cl ₂ 100ml solution, EDC ・ HCl 3.76
g was added, and the mixture was stirred at room temperature for 2 hours. Then, 3.75 ml of tert-butylamine was added, and the mixture was stirred as it was for 3 hours. The reaction solution was washed successively with 3% Na ₂ CO ₃ aqueous solution, 1N-HCl, and 5% NaCl aqueous solution, and dried over anhydrous MgSO ₄ . After evaporating the solvent, the obtained residue was recrystallized from n-hexane to obtain 3.94 g (yield 77%) of the title compound. The compound gave the following ¹ H-NMR spectrum and was confirmed to be the target compound. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.26 (s, 9H), 1.39 (s, 9
H), 3.7-3.8 (br, 1H), 4.1-4.2 (br, 2H), 4.72 (br, 1
H), 4.82 (br, 1H), 7.53 (br, 1H)

[Step 2] (2S, 3S) -3-tert-Butoxycarbonylamino-2-hydroxy-4-phenylbutanoic acid benzyl ester Boc-AHPBA-OH.DCHA 4.76 g of DMF in 20 ml of solution was treated with benzyl bromide. 1.19 ml was added, and the mixture was stirred at room temperature overnight (about 14 hours). The reaction solution was filtered and the filtrate was concentrated. The residue obtained is dissolved in ethyl acetate and treated with 5% aqueous citric acid solution, 3% N
a ₂ CO ₃ aqueous solution and 5% NaCl aqueous solution, and wash with anhydrous M
Dried with gSO ₄ . After distilling off the solvent, the residue obtained is n
-Recrystallization from hexane gave 3.11 g of the title compound (yield 81
%) Was obtained.

[Step 3] (2S, 3S) -3- (2-Methyl-3-hydroxybenzoyl) amino-2-hydroxy-4-phenylbutanoic acid benzyl ester Boc-AHPBA-OBzl 1.15 g obtained in Step 2 CH ₂ Cl ₂ 20
20 ml of 4N-HCl / dioxane was added to the ml solution, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture, the resulting residue is DMF
It was dissolved in 30 ml and neutralized with 0.42 ml Et ₃ N. Then 3-
Hydroxy-2-methylbenzoic acid 0.46 g, HOBt ・ H ₂ O 0.46
g, EDC ・ HCl 0.63g, and left at room temperature overnight (about 1
It stirred for 4 hours. After that, CH ₂ Cl ₂ and 5% were added to the reaction solution.
Aqueous NaHCO ₃ solution was added and stirred. After separating the organic layer (CH ₂ Cl ₂ layer), the resulting organic layer was washed with 5% NaHCO ₃ aqueous solution, 1N-
It was washed successively with HCl and a 5% NaCl aqueous solution. During this period, crystals precipitated from the organic layer were collected by filtration. The filtrate is anhydrous M
After drying with gSO ₄ , the filtrate was concentrated and the resulting residue was also collected. The precipitated crystals and the residue were combined and recrystallized from ethyl acetate to obtain 0.71 g (yield 56%) of the title compound.

[Step 4] (2S, 3S) -3- (2-Methyl-3-hydroxybenzoyl) amino-2-hydroxy-4-phenylbutanoic acid Obtained in Step 3 (3-hydroxy-2-methylbenzoyl) -AHPBA
A solution of 0.64 g of OBzl in 20 ml of MeOH was treated with hydrogen gas overnight (about 14 hours) in the presence of 30 mg of 10% Pd / C. The reaction solution was filtered, the filtrate was concentrated, and then recrystallized from a mixed solvent of acetone / n-hexane to give 0.56 g of the title compound (yield: 100
%) Was obtained. The compound gives the following ¹ H-NMR spectrum, and from the results of time-of-flight mass spectrometry,
It was confirmed to be the target compound. TOF-MASS: [M + H] ⁺ 330 ¹ H-NMR (CDCl ₃ ) δ ppm: 1.98 (s; 3H), 2.91 (d; 2H,
J = 7.5Hz), 4.34 (d; 1H, J = 3.6Hz), 4.74 (m; 1H), 6.60
(d; 1H, 7.5Hz), 6.80 (d; 1H, J = 7.5Hz), 6.91 (dd;
1H, 7.5Hz, 7.5Hz), 7.1-7.3 (m; 5H), 7.62 (s; 1H),
8.8-9.0 (br; 1H)

[Step 5] (4S, 5R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3-
(2-Methyl-3-hydroxybenzoyl) amino-4-phenylbutanoyl] -5-methyl-1,3-oxazolidine-4-carboxamide Boc-Oxz (Me) -NHtBu 286 mg, 4N-HCl / dioxane solution
2.5 ml was added, and the mixture was stirred at room temperature for 3 hours. After concentrating the reaction mixture, the resulting residue is dissolved in 4 ml DMF and 0.13 ml Et ₃ N is added.
Neutralized with. Then, (3-hydroxy-2-methylbenzoyl) -AH
PBA-OH 362mg, HOBt · H 2 O 164 mg, the EDC · HCl 211 mg, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 210 mg of the title compound. The compound gave the ¹ H-NMR spectrum described below, and as a result of HPLC analysis and time-of-flight mass spectrometry, it was confirmed to be the target compound. HPLC retention time: 15.55 min (conditions are the same as in Example 1.) TOF-MASS: [M + H] ⁺ 501 ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.27 (s; 9H), 1.32 ( d; 3
H, J = 5.1Hz), 1.60 (s; 3H), 4.00 (m; 3H), 4.28 (br;
3H), 5.06 (d; 1H, J = 5.4Hz), 5.43 (d; 1H, J = 3.6Hz),
5.55 (d; 1H, J = 6.4Hz), 6.57 (d; 1H, J = 8.9Hz), 6.7
8 (d; 1H, J = 8.9Hz), 6.94 (dd; 1H, J = 7.9Hz, 7.9Hz),
7.16 (d; 1H, J = 7.5Hz), 7.24 (t; 2H, J = 7.5Hz, 7.5H
z), 7.33 (d; 2H, J = 7.5Hz), 7.74 (s; 1H), 8.15 (d; 1
H, J = 7.9Hz), 9.34 (s; 1H)

[0071]

Example 31 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (2-ethyl-3-hydroxybenzoyl) amino-4-phenylbutanoyl] -1 3,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NHtBu 365 mg, 2-ethyl-3-hydroxybenzoic acid 183 mg suspended in DMF 4 ml, EDC
_{· HCl 211mg, HOBt · H 2} O 168mg and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to give the title compound
319 mg was obtained. Incidentally, the compounds, HPLC analysis and time of flight mass spectrometry following, further, the following ¹ H-
By giving an NMR spectrum, it was confirmed to be the target compound. HPLC retention time: 17.28 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 514 ¹ H-NMR (DMSO-d ₆ ) δ ppm: 0.85 (t; 3H, J = 7.5) Hz, 7.5
Hz), 1.25 (s; 9H), 2.35 (m; 2H), 2.74 (m; 2H), 3.0
0 (m; 1H), 3.20-3.40 (m; 1H), 4.35 (br; 1H), 4.55
(br; 1H), 4.77 (m; 2H), 5.05 (d; 1H, J = 9.3Hz), 5.2
5 (d; 1H, J = 7.1Hz), 6.55 (d; 1H, J = 7.1Hz), 6.78
(d; 1H, J = 8.6Hz), 6.94 (dd; 1H, J = 7.9Hz, 7.9Hz),
7.18 (d; 1H, J = 6.6Hz), 7.22 (t; 2H, J = 7.1Hz, 7.1H
z), 7.38 (d; 2H, J = 7.5Hz), 7.63 (s; 1H), 8.21 (d; 1
H, J = 7.9Hz), 9.31 (s; 1H)

[0072]

Example 32 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (3-hydroxy-2-propylbenzoyl) amino-4-phenylbutanoyl] -1 , 3-Thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NHtBu 365mg, 3-hydroxy-2-
168 mg of propylbenzoic acid was suspended in 4 ml of DMF, and ED
C.HCl 211 mg and HOBt.H ₂ O 168 mg were added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 130 mg of the title compound. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 18.04 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 528

[0073]

Example 33 (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (3,5-
Diamino-2-methylbenzoyl) amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide [Step 1] (R) -N-tert-butyl-3-[(2S, 3S) -2- Hydroxy-3- (2-methyl-3,5-dinitrobenzoyl) amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NHtBu 1.10 g, 2-Methyl-3,5-dinitrobenzoic acid (3,5-dinitro-o-toluic acid) 0.75g
Was suspended in DMF 15ml, EDC ・ HCl 0.63g, HOBt
· H ₂ O 0.45 g, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to obtain 1.08 g of the title compound. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 19.42 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 574

[Step 2] (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (3,5-
Diamino-2-methylbenzoyl) amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (R) -N-tert-butyl-3-[(2S, 3S) -2-hydroxy-3- (2-Methyl-3,5-dinitrobenzoyl) amino-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide 287mg
Iron powder 279 mg, 10
A 15% aqueous acetic acid solution (15 ml) was added dropwise, and the mixture was stirred at 50 ° C for 1 hr. 1N
-After adding 5 ml of HCl, 40m of 5% sodium hydrogen carbonate solution
The pH of the mixture was adjusted to 7.5 and the mixture was extracted with 40 ml of dichloromethane. The extract was dried over anhydrous MgSO ₄ and concentrated under reduced pressure to give a residue containing the product. After the residue was purified by silica chromatography, 30 mg of a crude product was obtained.
Further purify by HPLC fractionation to obtain 15 mg of the title compound.
Got The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 13.45 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 514

[0075]

Example 34 (R) -N- (2-Methylbenzyl) -3-[(2S, 3S) -3- (3-hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenylbutanoyl ] -1,3-Thiazolidine-4-carboxamide [Step 1] (R) -N- (2-methylbenzyl) -1,3-thiazolidine-4-carboxamide (H-Thz-NH-Bzl (2-Me) ) Boc-Thz-OH 6.99g, HOBt ・ H ₂ O 4.05g CH ₂ Cl ₂ 100m
EDC.HCl6.30g was added to the l solution, and the mixture was stirred at room temperature for 3 hours. Then, 4.46 ml of 2-methylbenzylamine was added, and the mixture was stirred as it was overnight (about 14 hours). The reaction solution, 3
% Na ₂ CO ₃ aqueous solution, 1N-HCl, 5% NaCl aqueous solution, and then washed successively, and dried over anhydrous MgSO ₄ . After evaporating the solvent, the obtained residue was redissolved in 100 ml of CH ₂ Cl ₂ , 5.86 ml of methanesulfonic acid was added, and the mixture was stirred at room temperature for 1 hr. Then H ₂ O
After adding 150 ml and stirring, the layers were separated. CH ₂ Cl ₂ 100 ml was added to the separated aqueous layer, and the pH was adjusted to 8 using Na ₂ CO ₃ . The separated CH ₂ Cl ₂ layer was washed with a 5% NaCl aqueous solution and dried over anhydrous MgSO ₄ . After the solvent was distilled off, the obtained residue was recrystallized from a mixed solvent of ethyl acetate / n-hexane to obtain 6.04 g (yield 85%) of the title compound. ¹ H-NMR (DMSO-d ₆ ) δ ppm: 2.56 (s, 3H), 2.85-3.05
(m, 3H), 3.2-3.4 (m, 1H), 3.86 (m, 1H), 4.0-4.2
(m, 2H), 4.2-4.3 (br, 2H), 7.0-7.2 (br, 4H), 8.34
(br, 1H)

[Step 2] (R) -N- (2-Methylbenzyl) -3-[(2S, 3S) -3-amino-2-
Hydroxy-4-phenylbutanoyl] -1,3-thiazolidine
-4-Carboxamide ((2s, 3s) -H-AHPBA-Thz-NH-Bzl (2-M
e)) H-Thz-NH-Bzl (2-Me) 5.83g, Boc-AHPBA-OH 7.29g, HO
Bt ・ H₂O 3.34g CH₂Cl₂EDC ・ HCl 5.
Add 19 g and stir at room temperature overnight (about 14 hours).
It was React the reaction mixture with 3% Na₂CO₃Aqueous solution, 1N-HCl, 5% NaC
l Washed sequentially with aqueous solution, dried over anhydrous MgSO_FourDried in. Solvent
After evaporation, the residue obtained is₂Cl₂(Redissolved in 150 ml
Then add 4.82 ml of methanesulfonic acid and stir at room temperature for 1 hour.
I stirred. Then H₂O 150 ml and 5N-NaOH aqueous solution 14.8 m
l was added and the layers were separated. CH collected₂Cl ₂Layer 5% NaCl
Washed with aqueous solution, anhydrous MgSO_FourDried in. Evaporate the solvent
After heating, dissolve the residue in 150 ml of ethyl acetate by heating and leave
The insoluble material was filtered off. The solvent of the filtrate is distilled off to obtain a crude product.
7.00 g of powder was obtained. 2.00 g of this powder is added to silica gel
After chromatograph purification (CH₂Cl₂/ MeOH system), leaving crude product
Collected as a residue. The resulting crude product is ethyl acetate / n
-Recrystallized from a mixed solvent of hexane to give the title compound 1.4.
8 g (yield 52%) was obtained.¹ H-NMR (CDCl₃) δ ppm: 0.2-1.4 (br, 2H), 2.20 (s;
3H), 2.2-2.4 (m, 1H), 2.4-2.6 (m, 1H), 3.14 (d, 2H,
 J = 16.8Hz), 3.21 (t, 1H, J = 5.4Hz), 3.48 (d; 1H, J =
9.6Hz), 3.94 (d; 1H, J = 9.6Hz), 4.1-4.3 (m; 1H), 4.
3-4.5 (m, 1H), 4.55 (d, 1H, J = 7.5Hz), 6.8-7.1 (m, 6
H), 7.1-7.4 (m, 3H), 7.9-8.1 (br, 1H)

[Step 3] (R) -N- (2-methylbenzyl) -3-[(2S, 3S) -3- (3-hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenyl Butanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-Bzl (2-Me) 414 mg, 3-hydroxy-2-methylbenzoic acid 167 mg in DMF 4 ml To the suspended liquid, EDC 211 mg and HOBt 149 mg were added, and the mixture was stirred at room temperature for 14 hours. The reaction solution was concentrated under reduced pressure to obtain a residue containing a product. Thereafter, the same purification as in Example 1 was carried out to give the title compound 5
I got 00mg. The compound was analyzed by the following HPLC analysis and time-of-flight mass spectrometry, and further, ¹ H-NMR
By giving a spectrum, it was confirmed to be the target compound. HPLC retention time: 19.34 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 548 ¹ H-NMR (DMSO-d ₆ ) δ ppm: 1.83 (s; 3H), 2.23 ( s; 3
H), 2.78 (m; 2H), 3.10 (m; 1H), 3.20-3.40 (m; 1H),
4.18 (d; 1H, J = 6.0Hz), 4.30 (d; 1H, J = 7.1Hz), 4.38
(m; 2H), 4.78 (d; 1H, J = 8.7Hz), 4.87 (t; 1H, J = 6.
4Hz, 6.4Hz), 5.03 (d; 1H, J = 10.0Hz), 5.45 (d; 1H,
J = 6.4Hz), 6.55 (d; 1H, J = 7.2Hz), 6.77 (d; 1H, J = 8.1
Hz), 6.93 (dd; 1H, J = 6.4Hz, 6.4Hz), 7.12 (bs; 4H),
7.23 (bs; 3H), 7.32 (d; 2H, J = 6.0Hz), 8.15 (d; 1
H, J = 7.9Hz), 8.35 (br; 1H), 9.37 (s; 1H)

[0078]

Example 35 (R) -N- (2-methylbenzyl) -3-[(2S, 3S) -3- (2-ethyl-3)
-Hydroxybenzoyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NH-Bzl (2-Me) 414 mg, 2 -ethyl
-3-Hydroxybenzoic acid (167 mg) was used for the same condensation and purification as in Example 1 to obtain the title compound (500 mg). In addition,
As a result of the following HPLC analysis and time-of-flight mass spectrometry, the compound was confirmed to be the target compound. HPLC retention time: 19.61 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 562

[0079]

Example 36 (R) -N-tert-Butyl-3-[(2S, 3S) -3- (2-Ethyl-3-hydroxybenzoyl) amino-2-hydroxy-4-phenylbutanoyl] -5 , 5-Dimethyl-1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Dmt-NHtBu 414 mg, 2-ethyl-3-hydroxybenzoic acid 167 mg After condensation and purification, 500 mg of the title compound was obtained. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 19.61 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 542

[0080]

Example 37 (R) -N- (2-Methylbenzyl) -3-[(2S, 3S) -3- (3-hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenylbutanoyl ] -5,5-Dimethyl-1,3-thiazolidine-4
-Carboxamide (2S, 3S) -H-AHPBA-Dmt-NHBzl (2-Me) 414 mg and 3-hydroxy-2-methylbenzoic acid 167 mg were used, condensed and purified in the same manner as in Example 1 to give the title 500 mg of compound was obtained. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 19.89 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 576

[0081]

Example 38 (R) -N- (2-methylbenzyl) -3-[(2S, 3S) -3- (2-ethyl)
-3-Hydroxybenzoyl) amino-2-hydroxy-4-
Phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Dmt-NH-Bzl (2-Me) 414mg, 2-ethyl-3
-Using 167 mg of hydroxybenzoic acid, the same condensation and purification as in Example 1 were carried out to obtain 500 mg of the title compound. The compound was confirmed to be the target compound from the results of HPLC analysis and time-of-flight mass spectrometry described below. HPLC retention time: 19.61 min The conditions are the same as in Example 1. ) TOF-MASS: [M + H] ⁺ 590

[0082]

Example 39 (R) -Nn-Butyl-3-[(2S, 3S) -3- (3-hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3 -Thiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Thz-NHnBu 183 mg, 3-hydroxy-2-
Using 76 mg of methylbenzoic acid, condensation and purification were carried out in the same manner as in Example 1 to obtain 160 mg of the title compound. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 17.24 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 500

[0083]

Example 40 (2S, 4S) -N-tert-butyl-3-[(2S, 3S) -3- (2-methyl-3-
(Hydroxybenzoyl) amino-2-hydroxy-4-phenylbutanoyl] -4-chloropyrrolidine-2-carboxamide Boc-Pro [4 (S) -Cl] -NHtBu 152 mg, (2S, 3S)-(3-hydroxy
Example 2 using 173 mg of 2-methylbenzoyl) -AHPBA-OH
Condensation and purification were carried out in the same manner as in 0 to obtain 240 mg of the title compound. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 17.95 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 517

[0084]

Example 41 (2S, 4S) -N- (2-Methylbenzyl) -3-[(2S, 3S) -3- (3-hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-
Phenylbutanoyl] -4-chloropyrrolidine-2-carboxamide Boc-Pro [4 (S) -Cl] -NHBzl (2-Me) 171mg, (3-hydroxy-2-m
Ethylbenzoyl) -AHPBA-OH 168 mg was condensed and purified in the same manner as in Example 30 to obtain 230 mg of the title compound. The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 20.44 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 564

[0085]

Example 42 (R) -N- (2-chlorobenzyl) -3-[(2S, 3S) -3- (3-hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenylbutanoyl ] -1,3-thiazolidine-4-carboxamide Boc-AHPBA-Thz-NH-Bzl (2-Cl) 276 mg and 2-methyl-3-hydroxybenzoic acid 83 mg were condensed in the same manner as in Example 30. After purification, 160 mg of the title compound was obtained. In addition,
As a result of the following HPLC analysis and time-of-flight mass spectrometry, the compound was confirmed to be the target compound. HPLC retention time: 20.06 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 569

[0086]

Example 43 (2S, 4S) -N-tert-butyl-3-[(2S, 3S) -3- (2-ethyl-3-
(Hydroxybenzoyl) amino-2-hydroxy-4-phenylbutanoyl] -4-chloropyrrolidine-2-carboxamide Boc-AHPBA-Pro [4 (S) -Cl] NHtBu 429 mg, 2-ethyl-3-hydroxybenzoic acid Using 155 mg, condensation and purification were carried out in the same manner as in Example 32 to obtain 328 mg of the title compound.
The compound was confirmed to be the target compound by the following HPLC analysis and time-of-flight mass spectrometry. HPLC retention time: 20.33 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 531

[0087]

Example 44 (R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -3- (3-hydroxy-2-methylbenzoyl) amino-2-hydroxy-4
-Phenylbutanoyl] -1,3-thiazolidine-4-carboxamide Prepared from 173 mg of 3-hydroxy-2-methylbenzoic acid in the same manner as in Example 30 (3-hydroxy-2-methylbenzo
yl) AHPBA-OH and H-Thz-NH-Bzl (2,6-Me) 125 mg were condensed and purified to obtain 234 mg of the title compound. As a result of the following HPLC analysis and time-of-flight mass spectrometry, the compound was confirmed to be the target compound. HPLC retention time: 20.69 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 562

[0088]

Example 45 (R) -N- (2-chlorobenzyl) -3-[(2S, 3S) -3- (3-hydroxy-2-methylbenzoyl) amino-2-hydroxy-4-phenylbutanoyl ] -5,5-Dimethylthiazolidine-4-carboxamide (2S, 3S) -H-AHPBA-Dmt-NH-Bzl (2-Cl) 138 mg, 3-hydroxy-2-methylbenzoic acid 50 mg The same condensation and purification as in Example 1 were carried out to obtain 100 mg of the title compound. In addition,
As a result of the following HPLC analysis and time-of-flight mass spectrometry, the compound was confirmed to be the target compound. HPLC retention time: 20.91 min (conditions are the same as in Example 1) TOF-MASS: [M + H] ⁺ 597

The following tests were carried out in order to verify that the dipeptide compound of the present invention has excellent HIV protease inhibitory activity and low cytotoxicity and is suitable for pharmaceutical use. [Test Example 1] HIV Protease Inhibitory Activity In order to verify that each of the dipeptide compounds of the present invention exhibits high HIV protease inhibitory activity, a test method already reported in the literature (Yoshiaki Kiso, Journal of Synthetic Organic Chemistry, Japan).
52, 403-412 (1994), JP-A-5-170722, etc.), and the compounds of Examples 1 to 45 were evaluated. In addition,
As a positive control, the compound KNI-272, which has been reported in the literature to exhibit high HIV protease inhibitory activity
(Yoshiaki Kiso, Journal of Organic Synthetic Chemistry Vol. 52, 403-412 (199
Similar tests were also performed for 4), etc.) and compared.

Test Method Recombinant HIV-1 protease (Biochemistry, 250
(9), 264 (1990), synthetic heptapeptide substrate (H-Ser-Gl
Protease activity was measured using (n-Asn-Tyr-Pro-Ile-Val-OH.trifluoroacetate). Tyr-Pro of the substrate after reacting at 37 ° C. for 60 minutes in the presence of various concentrations of a test compound
The peptide fragment H-Pro-Ile-Val-OH produced by cleavage between the two was quantified by reverse phase HPLC to calculate the inhibition rate. (JP-A
(See the 5-170722 publication)

Table 1 shows an example of the evaluation results of the HIV protease inhibitory activity of the dipeptide compound of the present invention evaluated by the above method. In addition, a KNI-272 having a (2S, 3S) -3amino-2-hydroxy-4-phenylbutanoyl skeleton, which is a hydroxymethylcarboxamide type tripeptide compound similar to the dipeptide compound of the present invention.
[(R) -3-[(2S, 3S) -3- (N- (isoquinolin-5-yloxy) acetyl-methylthio-L-alanyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3 -Thiazolidine
-4-N'-t-butylcarboxamide] was used as a positive control, and the results of the same evaluation are also shown in Table 1. As shown in these evaluation results, it can be seen that the peptide compounds of the present invention all exhibit high HIV protease inhibitory activity. The test compound concentration shown in Table 1 represents the final concentration in the reaction solution.

[0092]

[Table 1]

[Test Example 2] Anti-HIV activity and cytotoxicity The anti-HIV activity of the dipeptide compound of the present invention was evaluated by the following method. That is, H that infects T cell lymphocytes
The effect of IV virus on inhibiting virus particle production was evaluated by its ability to prevent T cell lymphocyte death associated with the HIV virus infection. Test methods for anti-HIV activity and cytotoxicity Test methods already reported in the literature (H. Nakashima et a
l., Antimicrob. Agents Chemother. 36, 1249-1255 (19
92) and the like), anti-HIV activity was evaluated using MT-4 cells and HTLV-IIIB. HIV-infected MT in 96-well microtiter plates with various concentrations of test compound.
-4 cells (2.5 x 10 ⁴ well, MOI: 001) are added immediately after infection.
In order to know the cytotoxicity of the test substance on MT-4 cells, virus-uninfected cells are similarly cultured with various test compounds. After culturing in a CO ₂ incubator at 37 ℃ for 5 days, measure the number of viable cells by the MTT method. Antiviral activity is a concentration that provides 50% protection against cell damage caused by HIV infection.
_{(EC 50, 50% effective concentration} ) :, Cytotoxicity 50% cytotoxicity concentration by test compounds (CC _{50, 50%} cytotoxic
concentration). The virus had an infectious titer of 3.8 x 10 ⁴ TCID50 / ml. Anti-HI
Example of evaluation result of V activity EC ₅₀ , and cytotoxic CC ₅₀
Table 2 also shows an example of the evaluation result. Table 2 also shows the results of the same test using the above KNI-272 as a positive control. As shown in these results, it can be seen that the peptide compound of the present invention has anti-HIV activity. In addition, it can be seen that the cytotoxicity is low. That is, compared with the concentration required to effectively suppress new infection with HIV virus, the concentration at which the cytotoxicity becomes remarkable is in a significantly high range.

[0094]

[Table 2]

Test Example 3 Pharmacokinetic Test The metabolic characteristics of the dipeptide compound of the present invention were evaluated using rats as test animals. The evaluated administration methods are a method in which a liquid in which a required amount of a test compound is dissolved is administered into the duodenum of a test animal, and a method in which it is administered intravenously.
After the administration, blood was collected from the test animal and the concentration of the test compound remaining in plasma was analyzed. The dose of the test compound is as shown in Table 3. In addition, pharmacokinetic index, AUC (area under the plasma drug concentration curve), MRT
Table 3 shows an example of the results of calculating F (average residence time), t _1/2 (λ) (final phase half-life), and bioavailability during intraduodenal administration. As a control example, the results for the tripeptide derivative KNI-272 are also shown.

[0096]

[Table 3]

From these results, the dipeptide compound of the present invention is more excellent in in vivo stability than the compound of the control example, KNI-272, and can maintain a high plasma concentration for a longer period of time. It can be seen that it is.

[0098]

[Example 46] [Formulation example] The dipeptide compound of the present invention described above can be formulated into a capsule or the like according to the formulation described below and used for oral administration. For example, a preparation containing the compound of Example 21 as an active ingredient can be mixed with fine powdered lactose and magnesium stearate and sealed in a gelatin capsule to give a capsule. The amount of the peptidomimetic compound per tablet is the administration method,
It can be appropriately selected according to the time interval.

[0099]

[Table 4] ─────────────────────── Composition in capsule ─────────────────────── Compound of Example 21 20.0% (wt./wt.) Lactose 79.5% (wt./wt.) Magnesium stearate 0.5% (wt./wt.) ───────────────────────

[0100]

INDUSTRIAL APPLICABILITY The novel dipeptide compound of the present invention or a pharmacologically acceptable salt thereof has, in addition to a specific and high HIV protease inhibitory activity, a dipeptide skeleton portion essential for HIV protease inhibitory activity and its N-terminal amino acid. It is a dipeptide compound that has a structure in which an acyl group is bonded to the base, and since it has a low molecular weight, it is easily absorbed in the digestive tract,
The process of excretion as bile from blood is reduced. Therefore, when used for clinical application as an anti-AIDS drug by oral administration, in order to produce a desired drug effect, it is possible to significantly reduce the oral dose required to obtain a desired blood concentration of the peptide-like compound as an active ingredient. Bring the benefits you can.
On the other hand, the dipeptide compound of the present invention is not only a small molecular weight but also a peptidomimetic which does not have a natural peptide bond, so that it has further excellent in vivo stability.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁷ Identification code FI C07D 207/16 C07D 207/16 263/06 263/06 277/06 277/06 (72) Inventor Naoko Morohashi Shinso, Toda City, Saitama Prefecture Minami 3-chome 35-35 Incorporation company Japan Energy (72) Inventor Yoshiaki Kiso 15-26 Inaba-cho, Ibaraki-shi, Osaka (56) References JP-A-8-311024 (JP, A) JP-A-9- 194355 (JP, A) JP-A-6-100533 (JP, A) (58) Fields investigated (Int.Cl. ⁷ , DB name) A61K 31/401-31/80 A61P 31/00-31/22 A61P 37/04 C07D 207/16 C07D 263/06 C07D 277/06 CA (STN) REGISTRY (STN) WPI (DIALOG)

Claims (7)

(57) [Claims] 1. A compound represented by the general formula (I): (In the formula, R ₁ represents a 5- or 6-membered monocyclic hydrocarbon group, or a heterocyclic group in which one or more carbon atoms of the monocyclic hydrocarbon group are replaced by heteroatoms, It may have a substituent on the ring group, the number of which does not exceed 3. X is a methylene group.
(-CH 2 _-), chloromethylene (-CH (Cl) _-) - shows the oxygen atom or a sulfur atom or a sulfonyl group (-SO 2).
R ₂₁ and R ₂₂ are each a hydrogen atom or a carbon number of 1 to 6.
The aliphatic hydrocarbon group is represented by the formula (1), which may be linear or branched. R ₃ represents a monovalent group derived from an aliphatic hydrocarbon group having 1 to 6 carbon atoms or an aromatic monocyclic hydrocarbon having a total number of carbon atoms of 12 or less, and a carbon constituting the hydrocarbon group. The chain skeleton may be linear, may have a branch, and a halogen atom may be substituted on the aromatic monocycle of the aromatic monocyclic hydrocarbon group. However, X
There chloromethylene (-CH (Cl) -) in and R ₂₁ and R ₂₂ Gato
When it is a hydrogen atom, R ₁ is selected from the following α group
Optionally substituted aryl group or hete
A lower aryl group, R ₃ is an alkyl group having 1 to 6 carbon atoms,
Cycloalkyl group having 3 to 8 carbon atoms, 1 to 6 carbon atoms
Hydroxyalkyl group or selected from the following β group
The aralkyl group which may have a substituent is excluded. [Α group] Alkyl group having 1 to 4 carbon atoms, hydroxyl group, carbon
Alkoxy group having 1 to 4 carbon atoms, Al having 1 to 4 carbon atoms
Kirthio group, halogen atom, trifluoromethyl group,
Rumil group, nitro group, amino group [β group] alkyl group having 1 to 4 carbon atoms, 1 to 4 carbon atoms
A novel dipeptide compound represented by 4 alkoxy groups, halogen atoms) or a pharmaceutically acceptable salt thereof. 2. General formula (II): (In the formula, X, R ₂₁ , R ₂₂ and R ₃ each represent a group having the same meaning as in formula (I). R ₁₁ represents a hydrogen atom, an amino group or a hydroxyl group, and R ₁₂ represents hydrogen. atoms or represents an aliphatic hydrocarbon group having 1 to 4 carbon atoms, serial to claim 1 represented by the linear may be type, may have a branched.)
The novel dipeptide compound described above or a pharmaceutically acceptable salt thereof. 3. General formula (III): (In the formula, X, R ₂₁ and R ₂₂ each represent a group having the same meaning as in the general formula (I), and R ₁₁ and R ₁₂ respectively represent a group having the same meaning as in the general formula (II)). Claimed as claimed in claim 1.
The novel dipeptide compound or a pharmacologically acceptable salt of. 4. A compound represented by the general formula (IV): (Wherein, X, R _21, R ₂₂ represents a group of the same meaning as the general formula (I) respectively, R _11, R ₁₂ are, .R ₃₁ showing a group synonymous with the general formula (II), respectively , R ₃₂ , and R ₃₃ each represent a hydrogen atom, a halogen atom, or an aliphatic hydrocarbon group having 1 to 4 carbon atoms, and may be linear or branched. The novel dipeptide compound according to claim 1 or a pharmaceutically acceptable salt thereof. 5. General formula (V): (In the formula, R ₁₁ represents an amino group or a hydroxyl group,
R ₁₂ represents a methyl group or an ethyl group, and R ₂₁ and R ₂₂ are
Each represents a hydrogen atom or a methyl group. ] The novel dipeptide compound shown by these, or its pharmacologically acceptable salt. 6. A compound represented by the general formula (VI): (In the formula, R ₁₁ represents an amino group or a hydroxyl group,
R ₁₂ represents a methyl group or an ethyl group. R ₂₁ and R ₂₂ are
Each represents a hydrogen atom or a methyl group. R ₃₁ , R ₃₂ , R
₃₃ represents a hydrogen atom, a halogen atom or a methyl group, respectively. ] The novel dipeptide compound shown by these, or its pharmacologically acceptable salt. 7. An anti-AIDS drug comprising as an active ingredient any of the novel dipeptide compounds or pharmacologically acceptable salts thereof according to any one of claims 1 to 6.