JPH08259532A - Peptide-like compound or its pharmacologically acceptable salt - Google Patents

Abstract

PURPOSE: To obtain a peptide-like compound represented by a specific formula, excellent in stability in a body, capable of being easily absorbed in a digestive tract, enhanced in bioavailability, suitable for oral administration, and excellent in a HIV protease-inhibiting activity. CONSTITUTION: This compound of formula I [R1 is a 2-9C divalent hydrocarbon group or a vinylene group in which H atoms combined with carbon atoms are arranged in a trans configuration, when R1 is a 2C divalent hydrocarbon group; R2 is methylene, carbonyl; A is a monovalent group of formula II (R3 is a 1-6C hydrocarbon group; R4 is combined with the adjacent N and the adjacent C to form a five to seven-membered ring)]. For example, (R)-1-[(2R,3 S)-3-(3,3-dimethylsuccinyl)amino-2-hydroxy-4-phenylbutyl]dehydroisoqui noline-3-N'- t-butylcarboxamide. For example, an intermediate raw material compound of formula III is prepared, and an acyl group part replaced with a carboxyl group is introduced to the amino group of the intermediate raw material compound to obtain the objective compound.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel peptidomimetic compound or a pharmacologically acceptable salt thereof, and particularly to human immunodeficiency virus (HIV).
(rus) -derived protease (HIV protease) that inhibits the enzyme activity of a protease, which is an HIV protease inhibitor, or a pharmacologically acceptable salt thereof, and an HIV protease inhibitor comprising the peptide-like compound.

[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 a complex protein. This complex protein is a protease (HIV
Only after being cleaved to a specific size by a protease) can each function be exerted. 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, and one of them is a synthetic peptidomimetic compound called a substrate transition-state mimetic (T. Robins, J. Plattner, J. Acqu
ir. Immun. Defic. Syndr., 6, 162 (1993), etc.). For example, Ro 31-8959 containing a phenylalanine ψ [CH (OH) CH ₂ N] decahydroisoquinolinecarboxylic acid skeleton similar to -Tyr ... Pro- or -Phe ... Pro-, which is an amino acid sequence selectively cleaved by HIV protease. (NA R
oberts et al., Science 248, 358-361 (1990) etc.) or a peptide derivative containing a norstatin skeleton such as phenylalanine ψ [CH (OH) C (O) N] proline (TF Tam et al.,
J. Med. Chem. 35 , 1318-1320 (1992), etc.) and hydroxymethylamide-type derivatives are reported to be useful as HIV protease inhibitors. The present applicant has also previously found that a group of synthetic peptide compounds, which are substrate transition state mimetics containing 3-amino-2-hydroxy-4-phenylbutanoic acid in their skeleton structure, have a very strong HIV protease activity. It was found to be useful as an anti-AIDS drug, and it was proposed as an HIV protease inhibitor (see JP-A-5-170722).

These substrate transition state mimetics are used as nucleic acid derivative reverse transcriptase inhibitors such as AZT (azidothymidine), dideoxycytidine (DDC) and dideoxyinosine (DDI) which are already clinically used as anti-AIDS drugs. Next most promising as a next-generation anti-AIDS drug, clinical trials and research are underway. That is, the clinical application as an anti-AIDS drug that suppresses the onset of AIDS is attempted by utilizing the HIV protease inhibitory activity and suppressing the formation of the virus particles in the host cell to inhibit the proliferation and infection of HIV. (Nakajima et al., Monthly Pharmaceutical Affairs Vol. 35 , 29
83-2989 (1993) etc.).

However, these peptidomimetic compounds are often reported to have problems such as (1) poor solubility in water, (2) instability in the body, and (3) low oral absorption rate. There (Yuaki Mitsuya, Science Vol. 64 , No.7 p46
2-470 (1994)). That is, it is said that a poorly soluble peptide-based drug is generally difficult to be absorbed in the digestive tract and has low bioavailability when orally administered. Particularly, since the anti-AIDS drug is a drug which takes a long-term and continuous administration form, there is a demand for the development of a compound having further improved bioavailability, especially when used in oral administration. Specifically, HI is highly soluble in water, has a relatively small molecular weight, and is not easily degraded by various digestive enzymes and proteolytic enzymes in the digestive tract.
There is a demand for the development of peptidomimetic compounds having excellent V protease inhibitory activity.

[0005]

DISCLOSURE OF THE INVENTION The present invention has been made to solve the above problems, and the object of the present invention is to provide excellent stability in the body, easy absorption in the digestive tract, and bioavailability. Another object of the present invention is to provide a novel peptidomimetic compound having a high HIV protease inhibitory activity suitable for oral administration. Further, it is to provide an HIV protease inhibitor comprising the peptidomimetic compound.

[0006]

The inventors of the present invention have various synthetic peptidomimetic compounds, namely hydroxyethylamine [CH (OH) CH ₂ N], which have already been proposed as HIV protease inhibitors for this purpose. Type derivatives or hydroxymethylamide [CH (OH) C (O) N] type derivatives, and various novel compounds that preserve the substrate transition state pseudostructure essential for HIV protease inhibitory activity of the peptidomimetic compounds Created. Next, these new compounds are superior in solubility in water, have a relatively low molecular weight, and H
When a peptide-like compound excellent in IV protease inhibitory activity was selected, it was found that a series of compounds represented by the following general formula (1) satisfy these selection conditions, and the present invention has been completed.

That is, the peptidomimetic compound of the present invention or a pharmacologically acceptable salt thereof has the following general formula (1):

[Chemical 6] [In the formula, R ₁ is 2 to 9 carbon atoms which may have a branch.
Represents a valent hydrocarbon group, wherein the group R ₁ is a divalent hydrocarbon group having 2 carbon atoms.
When it is a valent hydrocarbon group, a hydrogen atom bonded to the carbon atom is a vinylene group having a trans orientation, and R ₂ is
Methylene group (-CH _2- ) or carbonyl group (-C (O)-)
Where A is the general formula (2) below.

[Chemical 7] [In the formula, R ₃ represents an optionally branched hydrocarbon group having 1 to 6 carbon atoms, and R ₄ forms a 5 to 7-membered ring together with the nitrogen atom and carbon atom to which it binds. A valent hydrocarbon group, wherein the group R ₄ may have one or more of the carbon atoms contained therein replaced by a heteroatom, may further be condensed with another 5 to 7 membered ring, or may be substituted. It may have a group. ] The monovalent group represented by this is shown. ] It is a compound represented by these, or its pharmacologically acceptable salt. Furthermore, the HIV protease inhibitor of the present invention has the general formula (1) above.
A drug containing the compound represented by or a pharmaceutically acceptable salt thereof as an active ingredient.

In the peptidomimetic compound of the present invention, the conformation of the 3-amino-2-hydroxy-4-phenylbutanoyl skeleton constituting it is the (2S, 3S) -form, or 3-amino. The conformation of the 2-hydroxy-4-phenylbutyl skeleton is the (2R, 3S) -form, and in the α-aminocarboxamide of the group A, the conformation is that the corresponding α-amino acid is (L). -It means the body. Further, the hetero atom replacing the carbon atom means a nitrogen atom, a sulfur atom,
Or, it means an oxygen atom, and the sulfur atom may be present as a sulfinyl group or a sulfonyl group in addition to the thio group.

The peptidomimetic compounds of the present invention are
Substrate transition-state pseudo structures essential for protease inhibitory activity can be roughly classified into hydroxyethylamine-type derivatives or hydroxymethylamide-type derivatives. Specifically, the hydroxyethylamine-type derivative is represented by the following general formula (6) in which a methylene group (—CH ₂ —) is selected as the divalent group R _2.

Embedded image (In the formula, R ₁ represents the same divalent group as R ₁ in the general formula (1), R ₃ represents the same group as R ₃ in the general formula (2), and R ₄ represents , A group of compounds represented by the above-mentioned R _{4 of} the general formula (2)), and a hydroxymethylamide derivative is a divalent group R ₂ having a carbonyl group (-C ( The following general formula (7) is selected by selecting O)-).

[Chemical 9] (In the formula, R ₁ represents the same divalent group as R ₁ in the general formula (1), R ₃ represents the same group as R ₃ in the general formula (2), and R ₄ represents , The same group as R _{4 of} the above-mentioned general formula (2) is shown).

In the peptidomimetic compound of the present invention, the group R ₁ is preferably a branched and divalent hydrocarbon group having 3 to 9 carbon atoms, which is represented by the following general formula (3).

[Chemical 10] (In the formula, R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₄ each represent a hydrogen atom or a hydrocarbon group, and none of them is a hydrogen atom, and any one of R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₄ Two or more may form a ring with each other), or a divalent hydrocarbon group represented by the following formula (4)

[Chemical 11] (In the formula, R ₁₅ and R ₁₆ each represent a hydrogen atom or a hydrocarbon group, and R ₁₅ and R ₁₆ may form a ring with each other.) Any of divalent hydrocarbon groups It is more preferable to select Furthermore, it is more preferable to select a branched aliphatic hydrocarbon group having 3 to 9 carbon atoms as the group R ₁ , and a propylene group, 1,1-dimethylethylene group, 1, Examples thereof include 2-dimethylethylene group. In particular, in the above general formula (3), R
_A methyl group for ₁₁ , a propylene group for selecting hydrogen atoms for R ₁₂ , R ₁₃ and R ₁₄ , and a methyl group for R ₁₁ and R ₁₃ ,
A 1,2-dimethylethylene group for selecting a hydrogen atom for R ₁₂ and R ₁₄ , or a methyl group for R ₁₁ and R ₁₂ , R ₁₃ and R ₁₄
More preferred is a 1,1-dimethylethylene group for selecting a hydrogen atom for each, or a 1,1-dimethyltrimethylene group for selecting a methyl group for R ₁₅ and R ₁₆ in the general formula (4). . In addition, in the above-mentioned divalent aliphatic hydrocarbon group having a branch at the 1-position, which is suitable for the group R ₁ , the carboxyl group which forms a bond therewith is a carbon atom at the 1-position where the branch exists. The presence on top makes it even more pleasing.

The group R ₃ is a hydrocarbon group having 1 to 6 carbon atoms, and in the group A represented by the general formula (2), the substituted carbamoyl group is a corresponding carboxyl group, Any one can be used as long as it can be formed by a reaction with a primary amine composed of the group R _3, but an aliphatic hydrocarbon group having 1 to 6 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, Isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group,
Hexyl group and the like are preferable, and further, branched alkyl group having 3 to 6 carbon atoms is more preferable.
-Butyl group and the like are more preferable.

In the peptidomimetic compounds of the present invention, the group R ₄ is 5 with the nitrogen and carbon atoms to which it is attached.
To a 7-membered ring to form an α-amino acid residue having a substituted amino group at the α-position of the carbamoyl group substituted by the group R ₃ and having an absolute configuration of α-amino group of the (L) -form. It is an amino acid residue. In the group R ₄ , the hetero atom replacing one or more carbon atoms contained therein is selected from a nitrogen atom, an oxygen atom, or a sulfur atom. In addition, it is preferable that the hetero atom does not form a bond with any of the nitrogen atom serving as the substituted amino group existing at the α-position and the carbon atom at the α-position. Further, the other 5- to 7-membered ring condensed with the ring group of the α-amino acid residue is preferably an ortho-condensed ring. Substituents which may be substituted on the group R ₄ are optionally branched aliphatic hydrocarbon groups having 1 to 6 carbon atoms, aromatic hydrocarbon groups or heteroaromatic groups, hydroxyl groups, and branched groups. An aliphatic hydrocarbon oxy group having 1 to 6 carbon atoms which may have, a halogen atom and the like are preferable, and the total number of substituents is more preferably 2 or less. In addition, when the number of the substituents substituting on the atom forming the same ring contained in the group R ₄ is 2, the two substituents may have a cyclic structure which forms a bond with each other, that is, a spiro bond is formed. Present as a bicyclic ring, or may form a double bond with the atom, such as an oxo group. Hereinafter, the α-amino acid residue of the 5- to 7-membered ring constituted by the group R ₄ will be described more specifically by way of example.

As the α-amino acid corresponding to a 5-membered ring for selecting a straight-chain hydrocarbon group having 3 carbon atoms as the group R ₄ , proline, 4-hydroxyproline having a substituent at the 4-position, 4- Benzyloxyproline, 4-phenylproline, 4-benzylproline, 4-methylthioproline,
4-phenylthioproline, 4-fluoroproline, etc. can be illustrated. As a ring condensed with another 5- to 7-membered ring,
Octahydroindole-2-carboxylic acid, which is condensed with cycloalkane, octahydroisoindo-
Indoline-2-carboxylic acid, isoindoline, which is condensed with an aromatic ring group or a heteroaromatic ring group such as ru-1-carboxylic acid and 2-azabicycloro [3.3.0] octane-3-carboxylic acid. Examples include -1-carboxylic acid. Further, a corresponding 5-membered ring α-amino acid for selecting a divalent group in which one of the carbon atoms contained in the linear hydrocarbon group having 3 carbon atoms is replaced by a hetero atom as the group R ₄ As 1,3-thiazolidine-4-carboxylic acid (Th
z) such as 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid having a substituent on the hetero 5-membered ring (Dm
t) and the like.

As the corresponding α-amino acid of the 6-membered ring for selecting a straight-chain hydrocarbon group having 4 carbon atoms as the group R ₄ , pipecolic acid (2-piperidinecarboxylic acid), and other 5 to 7
As those condensed with a member ring, those condensed with a cycloalkane, such as decahydroisoquinoline-3-carboxylic acid and decahydroisoquinoline-1-carboxylic acid, are condensed with an aromatic ring group or a heteroaromatic ring group. It is a ring,
1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-
1-carboxylic acid etc. can be illustrated. Further, in the group R ₄ ,
Select a divalent group in which one of the carbon atoms contained in a straight-chain hydrocarbon group having 4 carbon atoms is replaced by a hetero atom 6
As the corresponding α-amino acid of the member ring, piperazine-2-
A carboxylic acid etc. can be mentioned.

[0015] Peptide-like compounds hydroxyamide type derivatives of the present invention, i.e. the divalent group R ₂ to a carbonyl group (-C
(O)-) is represented by the above general formula (7), the α-amino acid residue of the 5- to 7-membered ring constituted by the group R ₄ exemplified above corresponds to α-amino acid with 5-membered proline, 1,3-thiazolidine-
4-carboxylic acid or the like, or an octahydroindole-2-carboxylic acid or an octahydroisoindole- which is a 5-ring ring condensed with another cycloalkane having a 5- to 7-membered ring 1-carboxylic acid, 2-azabicycloro [3.3.
[0] Octane-3-carboxylic acid or the like, or 5,5-dimethyl-1,3-thiazolidine-4 substituted with 2 or less aliphatic hydrocarbon groups having 1 to 6 carbon atoms which may have a branch. −
It is more preferable to use a carboxylic acid or the like. For example, group A
As a whole, the following general formula (5)

[Chemical 12] (Wherein, R ₃ represents the same group as R ₃ in the general formula (2) to the aforementioned, X represents methylene group (-CH ₂ -) or represents a sulfur atom, R _41, R ₄₂ are each hydrogen Represents a hydrocarbon group having 1 to 6 carbon atoms which may have an atom or a branch, and R
₄₁ and R ₄₂ may combine with each other to form a ring. It is more preferable to use a group represented by Specifically, the groups R ₄₁ and R ₄₂ existing in the α-amino acid consisting of the 5-membered ring are
In addition, it is more preferable to use proline, 1,3-thiazolidine-4-carboxylic acid, or 5,5-dimethyl-1,3-thiazolidine-4-carboxylic acid, which respectively select a hydrogen atom or a methyl group.

On the other hand, the peptidomimetic compound of the present invention is a hydroxyethylamine type derivative, that is, the above-mentioned general formula (6) wherein the methylene group (-CH _2- ) is selected as the divalent group R _2.
When represented by, the α-amino acid residue of the 5- to 7-membered ring constituted by the group R ₄ exemplified above corresponds to the corresponding α-
Amino acids include pipecolic acid (2-piperidinecarboxylic acid) consisting of a 6-membered ring, piperazine-2-carboxylic acid, etc.
Alternatively, the 6-membered ring is substituted by an aliphatic hydrocarbon group having 2 to 6 carbon atoms which may have a branch, or 2 or less, or a condensed ring with another cycloalkane having a 5- to 7-membered ring, for example, , Decahydroisoquinoline-3-carboxylic acid, decahydroisoquinoline-1-carboxylic acid and the like are more preferable. For example, as a group A as a whole, the following general formula (8)

[Chemical 13] (In the formula, R ₃ represents the same group as the above-mentioned general formula (2), Y represents a carbon atom or a nitrogen atom, and R ₄₃ and R ₄₄
Are each a hydrogen atom, or may have a branched carbon number 1 to
6 represents an aliphatic hydrocarbon group of 6, or an aromatic hydrocarbon group which may further have a substituent or a group derived from the substitution of a hetero atom thereof, and R ₄₃ and R ₄₄ are bonded to each other to form a ring. You may form. It is more preferable to use a group represented by Specifically, the α-amino acid is pipecolic acid (2-piperidinecarboxylic acid), piperazine-2-carboxylic acid, proline, or the groups R ₄₃ and R ₄₄ are bonded to each other to form a ring and condensed. Ring-forming decahydroisoquinoline-3-carboxylic acid, decahydroisoquinoline-
It is more preferable to use 1-carboxylic acid or the like.

In addition, the groups R ₃ and R ₄ , that is, the group A represented by the general formula (2), is excellent in the HIV ethyl derivative or hydroxyamide type derivative which has already been published in publications and the like. Various α-amino acid amides having a 5- to 7-membered ring, which are used in known derivative compounds reported to have protease inhibitory activity, can be preferably used in the present invention. It is more preferable that the amide groups of the various 5- to 7-membered α-amino acid amides have a (R) -configuration.

In the peptidomimetic compound of the present invention, HI
Suitable compounds having excellent V protease inhibitory activity are those which select the group R ₁ in the above-mentioned suitable range, and further, depending on the selection of the group R ₂ , the group A, that is, the group R ₃ , When R ₄ is selected within a suitable range, the compound is more excellent in HIV protease inhibitory activity and becomes a more preferable compound. Further, depending on the selection of the group R ₂ , the group R ₁ and the groups R ₃ and R ₄ are
The peptidomimetic compounds each selected from the above-mentioned more preferable range are more preferable.

As an example of compounds represented by the above general formula (1) suitable for HIV protease inhibitors, hydroxyethylamine type derivatives, that is, a methine group (—CH ₂ —) is selected as the group R ₂ is selected. (R) -1-[(2R, 3S) -3- (3,3-dimethylsuccinyl) amino-2-hydroxy-4-, which is roughly classified into the group of compounds represented by the following general formula (6): Phenylbutyl] decahydroisoquinoline-3-N'-t-butylcarboxamide, (R) -1-[(2R, 3S) -3- (2,3-dimethylsuccinyl)
Amino-2-hydroxy-4-phenylbutyl] decahydroisoquinoline-3-N'-t-butylcarboxamide, (R) -1-
[(2R, 3S) -3- (2,2-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutyl] decahydroisoquinoline-3-
N'-t-butylcarboxamide, (R) -1-[(2R, 3S) -3- (fumaryl) amino-2-hydroxy-4-phenylbutyl] decahydroisoquinoline-3-N'-t-butylcarboxamide ,
(R) -1-[(2R, 3S) -3- (3,3-dimethylsuccinyl) amino-2
-Hydroxy-4-phenylbutyl] decahydroisoquinoline-1-N'-t-butylcarboxamide, (R) -1-[(2R, 3S) -3
-(2,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutyl] decahydroisoquinoline-1-N'-t-butylcarboxamide, (R) -1-[(2R, 3S) -3- ( 2,2-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutyl] decahydroisoquinoline-1-N′-t-butylcarboxamide,
(R) -1-[(2R, 3S) -3- (Fumaryl) amino-2-hydroxy-4
-Phenylbutyl] decahydroisoquinoline-1-N'-t-butylcarboxamide and the like can be exemplified.

Further, it is roughly classified into a group of compounds represented by the general formula (7), which are hydroxymethylamide type derivatives, that is, a carbonyl group (—C (O) —) is selected as the group R _2. , 1-[(2S, 3S) -3- (3,3-dimethylsuccinyl) amino-
2-Hydroxy-4-phenylbutanoyl] -N'-t-butyl-L-
Prolinamide, 1-[(2S, 3S) -3- (2,3-dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -N'-t
-Butyl-L-prolinamide, 1-[(2S, 3S) -3- (2,2-dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -N'-t-butyl-L-prolinamide, (R) -3-[(2S, 3
S) -3- (3,3-Dimethylsuccinyl) amino-2-hydroxy-4
-Phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (2,2-dimethylsuccinyl) amino-2-hydroxy -4-Phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (fumaryl) amino-2-hydroxy-4- Phenylbutanoyl] -1,3-thiazolidine-4-N'-t-
Butylcarboxamide, (R) -3-[(2S, 3S) -3- (2,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'- t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (3-isopropylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-
Thiazolidine-4-N'-t-butylcarboxamide, (R) -3-
[(2S, 3S) -3- (3-Cyclopentylidenylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3
S) -3- (2-Cyclopentylidenylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4
-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (3-
Cyclopentylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (2- Cyclopentylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (3, 3-Dimethylglutaryl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N′-t-butylcarboxamide, (R) -3-[(2
S, 3S) -3- (4,4-Dimethylglutaryl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-
Butylcarboxamide, (R) -3-[(2S, 3S) -3- (3,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine -4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (2,3-dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -5,5 -Dimethyl-1,3-thiazolidine-4-N'-t-butylcarboxamide, etc. may be enumerated.

Among them, the compound has a (2S, 3S) -3-amino-2-hydroxy-4-phenylbutanoyl skeleton and
1,3-thiazolidine-4-N'-t-butylcarboxamide or
Comprising a 1,3-thiazolidine-4-carbonyl skeleton such as 5,5-dimethyl-1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (3,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,
3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3
-[(2S, 3S) -3- (2,2-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-
N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (fumaryl) amino-2-hydroxy-4-phenylbutanoyl]-
1,3-thiazolidine-4-N'-t-butylcarboxamide, (R)
-3-[(2S, 3S) -3- (2,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4
-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (3-
Isopropylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (3- Cyclopentyridenylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (2-Cyclopentylidenylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (3-Cyclopentylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-
Thiazolidine-4-N'-t-butylcarboxamide, (R) -3-
[(2S, 3S) -3- (2-Cyclopentylsuccinyl) amino-2-
Hydroxy-4-phenylbutanoyl] -1,3-thiazolidine
-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3-
(3,3-Dimethylglutaryl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (4,4-Dimethylglutaryl) amino-2-hydroxy-4-phenylbutanoyl]-
1,3-thiazolidine-4-N'-t-butylcarboxamide, (R)
-3-[(2S, 3S) -3- (3,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,3-
Thiazolidine-4-N'-t-butylcarboxamide, (R) -3-
[(2S, 3S) -3- (2,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-N'-t-butyl Carboxamide and the like are more preferable, and particularly, 3,3-dimethylsuccinyl group, or 2,
Having a 3-dimethylsuccinyl group, (R) -3-[(2S, 3S) -3
-(3,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (2,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide, (R) -3-[(2S, 3S) -3- (3,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-N′-t-butylcarboxamide, (R ) -3-[(2S, 3S) -3- (2,3-Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-N ' Further preferred is -t-butylcarboxamide and the like.

The pharmacologically acceptable salt of the peptidomimetic compound of the present invention is a salt formed with various pharmacologically acceptable monovalent cation species by using the carboxyl group present in the compound. It was done. Specifically, it means a pharmacologically acceptable salt such as sodium salt and ammonium salt. In addition, in the case where a nitrogen atom having basicity is present in the 5- to 7-membered ring of the above-mentioned group A, or a substituent which substitutes for it or another 5- to 7-membered ring which is condensed, the nitrogen atom is It also includes salts formed with various pharmacologically acceptable acids, and specifically includes pharmacologically acceptable salts such as hydrochlorides and acetates.

The peptide-like compounds of the present invention are characterized by a structure in which the dipeptide-like skeleton portion which is essential for HIV protease inhibitory activity and the acyl group portion which substitutes the carboxyl group form an amide bond. According to the general formula (9)

Embedded image (In the formula, R ₂ represents the same group as the above-mentioned general formula (1), and R ₃ and R ₄ respectively represent the same group as the above-mentioned general formula (2)), and has a dipeptide-like skeleton. It can be produced by preparing an intermediate raw material compound to be a moiety, and then introducing an acyl group moiety substituted by the carboxyl group into the amino group of the intermediate raw material by N-acylation reaction. Hereinafter, the outline of the production method will be described in more detail with respect to each of the hydroxyethylamine type derivative represented by the general formula (6) and the hydroxymethylamide type derivative represented by the general formula (7).

[1] Method for Producing Hydroxyethylamine Derivative Represented by General Formula (6) Step [1-1] Preparation of Intermediate Material Compound Represented by General Formula (9) Hydroxyethylamine Type Derived HIV
It corresponds to an intermediate in the method for synthesizing a protease inhibitor, and its preparation method has been reported in various publications (N.
A. Roberts et al., Science 248 , 358-361 (1990), B.
M. Kim et al., Bioorg. & Med. Chem. Lett. 4 , 2273-
2278 (1994), etc.). For example, the following general formula (1
0)

[Chemical 15] (Wherein R ₃ and R ₄ represent the same groups as R ₃ and R ₄ in the general formula (2), respectively), and an α-amino-carboxamide derivative represented by the following formula (11)

Embedded image The azide epoxide derivative represented by the formula (12) is heated to reflux in a solvent such as isopropanol to open the epoxide with the amine to give a compound represented by the following general formula (12).

[Chemical 17] (Wherein, R _3, R ₄ are each R _3, represents the same group as R ₄ in the general formula (2) to the aforementioned.) Ajidoaruko represented by - can lead to Le derivative. Then, the azido alcohol derivative is subjected to a hydrogenation reaction using a catalyst such as Pd / C in ethanol to convert the azido group into an amino group, which is represented by the general formula (9). , An intermediate raw material in which a methylene group is selected as the group R ₂ can be obtained. The conformation of the azidoepoxide derivative is intended (2R, 3
An optical isomer having the same conformation as the S) -form intermediate raw material is used.

Step [1-2] N-acylation reaction The following general formula (13)

Embedded image (In the formula, R _1,. Showing the same group as R ₁ in formula (1) to above) to the dicarboxylic acid represented by, DCC (N,
N'-dicyclohexylcarbodiimide) and other acid anhydrides such as acetic anhydride, trifluoroacetic anhydride

[Chemical 19] (In the formula, R _1, the general formula (1) represents the same group as R _1.) Prepared in advance an acid anhydride of the dicarboxylic acid represented by. The acid anhydride of the dicarboxylic acid represented by the general formula (14) and the general formula (9) above,
An intermediate raw material in which a methylene group is selected for the group R ₂ is, for example,
The reaction can be carried out in a solvent such as N, N-dimethylformamide (DMF) to obtain the target hydroxyethylamine derivative represented by the general formula (6) which is N-acylated.

Alternatively, from the dicarboxylic acids represented by the general formula (13) and the alcohols, the following general formula (1
5)

Embedded image (In the formula, R ₁ represents the same group as R ₁ in the general formula (1), and R ₆₁ represents an alkyl group or an aralkyl group.)
The dicarboxylic acid monoester represented by is prepared in advance. The dicarboxylic acid monoester represented by the general formula (15) and an intermediate raw material represented by the general formula (9), in which a methylene group is selected as the group R ₂ , can be prepared by using, for example, DCC,
EDC (1-ethyl-3- (3-N, N-dimethylaminopropyl)
Carbodiimides such as carbodiimide), BOP reagents (benzotriazol-1-yloxytris (N, N-dimethylaminophosphonium) hexafluorophosphate)
N-acylated with the following general formula (16)

[Chemical 21] (Wherein, R ₁ represents the same group as R ₁ in formula (1) to the, R _3, R ₄ is R each formula to the (2)
₃ , the same group as R ₄ is shown, and R ₆₁ is represented by the general formula (1
The same group as R _{61 in} 5) is shown. It is possible to obtain a monoester form of the hydroxyethylamine type derivative represented by). Then, the monoester is treated with an alkali,
The desired hydroxyethylamine derivative represented by the general formula (6) can be obtained by hydrolysis using an acid or an enzyme, or catalytic hydrogenolysis in the presence of a catalyst.

When the group R ₄ has a substituent which gives an unfavorable side reaction in the above-mentioned reaction, it is appropriately protected by a protecting group to carry out the reaction, followed by deprotection and then Of course, it can be used for reactions and the like.

[2] Method for Producing Hydroxymethylamide Derivative Represented by General Formula (7) Step [2-1] Preparation of Intermediate Material Compound Represented by General Formula (9) Hydroxymethyl Amide type HIV
It corresponds to an intermediate in a method for synthesizing a protease inhibitor, and its preparation method has been reported in various publications (Yoshiaki Kiso, Journal of Organic Synthetic Chemistry Vol. 52, 403-412 (1994).
Etc.). For example, an α-amino-carboxamide derivative represented by the above general formula (10) and the following general formula (17)

[Chemical formula 22] (In the formula, B is an amino-protecting group and can be deprotected with an acid.) (2S, 3S) -3-Amino-2-hydroxy-4-phenylbutanoic acid N -A protected derivative is, for example, a carbodiimide such as DCC or EDC, and an additive compound such as HONB (N-hydroxy-norbornene-2,3-dicarboximide) or HOBt (N-hydroxybenzotriazol). By forming a peptide bond by condensation using the following general formula (18)

[Chemical formula 23] (In the formula, B represents the same group as B in the general formula (17), and R ₃ and R ₄ respectively represent R in the general formula (2).
_The same groups as ₃ and R ₄ are shown. ) To a dipeptide N-protected derivative represented by Then the dipeptide N
-Deprotection of the amino group of the protected derivative using an acid such as hydrochloric acid in dioxane to obtain an intermediate raw material represented by the general formula (9) and having a carbonyl group as the group R _2. You can

Step [2-2] N-Acylation Reaction Step [1-2] In accordance with the N-acylation reaction, represented by the general formula (9) prepared in the above step [2-1]. Is
An intermediate raw material for selecting a carbonyl group for the group R ₂ can be reacted with a dicarboxylic acid represented by the general formula (13) to obtain a desired hydroxymethylamide derivative represented by the general formula (7). .

The hydroxyethylamine-type derivative represented by the general formula (6) or the hydroxymethylamide-type derivative represented by the general formula (7) produced by the above-mentioned steps may be recrystallized or the like, if necessary. It can be used as an HIV protease inhibitor by removing impurities by a purification method. Since the peptidomimetic compound of the present invention is produced by using the intermediate raw material represented by the general formula (9) and the dicarboxylic acid represented by the general formula (13) as raw materials, the molecular structure can be identified by the respective raw materials. This can be easily performed by referring to the structure derived from the compound and determining by a spectroscopic method such as a nuclear magnetic resonance method or an infrared absorption method.

In clinical application as an anti-AIDS drug, the peptidomimetic compound of the present invention can be administered in the form of a drug using conventional pharmaceutical carriers and excipients according to a conventional method. For example, the peptidomimetic compound of the present invention is superior in water solubility, and thus can be injected intravenously or intramuscularly as an injection, and can be parenterally administered as a spray, a suppository, a granule,
It can be orally administered as a capsule or tablet. Since the peptidomimetic compound of the present invention has excellent solubility in water, 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 determined according to the symptoms of the administration subject, or the purpose of treatment such as AIDS onset suppression and AIDS progression suppression, and is appropriately determined in consideration of age, sex, etc. ~ 1g per day 1
Dosage is divided into 4 doses. In addition, when making an oral administration agent,
The dosage forms applicable to oral administration of various synthetic peptide-like compounds that have already been proposed as HIV protease inhibitors (see JP-A-5-170722, etc.) can be generally adopted.

The peptidomimetic compound of the present invention and the method for producing the same will be described below with reference to specific examples. In addition, it is shown that the peptidomimetic compound of the present invention has high HIV protease inhibitory activity and low cytotoxicity and has properties suitable for pharmaceutical use.

In each of the following examples, H-AHPBA-Pro-NH-tBu (1-[(2S, 3S) -3-amino-2-
Hydroxy-4-phenylbutanoyl] -N'-t-butyl-L-prolinamide), H-AHPBA-Thz-NH-tBu ((R) -3-[(2S, 3S)-
3-Amino-2-hydroxy-4-phenylbutanoyl] -1,3-
Thiazolidine-4-N'-t-butylcarboxamide), H-AHPBA
-Dmt-NH-tBu ((R) -3-[(2S, 3S) -3-Amino-2-hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-N '-t-butylcarboxamide) etc. is H-AHPBA
((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) as raw materials, and according to the method already published in the publication, the dipeptide N- Prepared as a protected derivative.
Then, the amino group was deprotected and used.

Reference Example 1 1-[(2S, 3S) -3- (succinyl) amino-2-hydroxy-4-phenylbutanoyl] -N'-t-butyl-L-prolinamide H-AHPBA-Pro -NH-tBu 100 mg was dissolved in DMF 1.5 ml, succinic anhydride 45 mg and pyridine 50 μl were added,
It was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 10 ml of ethyl acetate, the ethyl acetate solution was washed with a 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 102 mg of the title compound. TLC: Rf 0.62 (chloroform: methanol: acetic acid = 5
0: 10: 2)

Reference Example 2 (R) -3-[(2S, 3S) -3- (succinyl) amino-2-hydroxy-
4-Phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 235 mg suspended in DMF 4.0 ml, succinic anhydride 66 mg, Triethylamine 90 μl
Was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was redissolved in 15 ml of ethyl acetate,
The ethyl acetate solution was washed with a 10% aqueous citric acid solution and saturated saline, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 172 mg of the title compound. TLC: Rf 0.51 (chloroform: methanol: water = 8:
3: 1 lower layer)

[0034]

Example 1 (R) -3-[(2S, 3S) -3- (3,3-dimethylsuccinyl) amino-2
-Hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide [Step 1-1] 2,2-Dimethylsuccinic anhydride 2,2-Dimethylsuccinic acid 104 mg DC in a solution of 2.0 ml of dichloromethane-diethyl ether (1: 1)
C 147 mg was added, and the mixture was stirred at room temperature for 2 hours. After filtering the reaction solution, the solvent was distilled off from the filtrate to recover the title acid anhydride.

[Step 1-2] (R) -3-[(2S, 3S) -3- (3,3-
Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 235 mg was suspended in DMF 4.0 ml. The liquid was added to the acid anhydride obtained in Step 1-1, triethylamine.
90 μl was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 15 ml of ethyl acetate, and the ethyl acetate solution was washed with a 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate.
Concentration under reduced pressure gave 228 mg of the title compound. TLC: Rf 0.62 (chloroform: methanol: water = 8:
3: 1 lower layer) FAB-MASS: [M + H] ⁺ 494 ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.86 (s; 3H dimethyls
uccinyl-CH ₃ ), 0.96 (s; 3H dimethylsuccinyl-CH ₃ ),
1.26 (s; 9H -NH- tBu ), 2.28 (q; 2H dimethylsuccin
yl-CH ₂ ), 2.60 (t; 2H AHPBA-CH ₂ ), 3.00 (m; 1H Thz
-5), 3.34 (m; 1H Thz-5), 4.08 (bs; 1H AHPBA-3),
4.44 (s; 1H AHPBA-2), 4.66 (d; 1H Thz-2), 4.76
(t; 1H Thz-4), 4.96 (d; 1H Thz-2), 7.16 (m; 3H
AHPBA-m, p- (Ph)), 7.39 (d; 2H AHPBA-o- (Ph)), 7.69
(s; 1H- NH -tBu), 8.07 (d; 1H AHPBA- NH ), 11.9 (bs
; dimethylsuccinyl- C00H )

[0036]

Example 2 (R) -3-[(2S, 3S) -3- (2,2-dimethylsuccinyl) amino-2
-Hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide [Step 2-1] 3,3-Dimethylsuccinic acid p-methoxybenzyl 2,2-dimethylsuccinic acid 1.0 g in dichloromethane-diethyl ether (1: 1) 20 ml, D
CC 1.41 g was added, and the mixture was stirred at room temperature for 3 hours. Then
Anise alcohol (p-methoxybenzyl alcohol)
Add 0.77 ml and 0.87 ml triethylamine, and add 1 at room temperature.
Stir for 4 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 30 ml of ethyl acetate, the ethyl acetate solution was washed with a 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 1.82 g of the title monoester compound. TLC: Rf 0.55 (chloroform: methanol = 10: 1)

[Step 2-2] (R) -3-[(2S, 3S) -3- (3- (4-
Methoxybenzyloxycarbonyl) -2,2-dimethylpropanoyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH- To the liquid obtained by suspending 392 mg of tBu in DMF 6.0 ml, 601 mg of the monoester compound obtained in Step 2-1, 314 μl of triethylamine, and 523 mg of BOP reagent were added,
It was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was redissolved in 25 ml of ethyl acetate, and the ethyl acetate solution was washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. Dried in. Concentration under reduced pressure gave 382 mg of the title compound. TLC: Rf 0.93 (chloroform: methanol: water = 8:
3: 1 lower layer)

[Step 2-3] (R) -3-[(2S, 3S) -3- (2,2-
Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide 275 mg of the compound obtained in Step 2-2 was added to 97 μl of anisole,
3 ml of trifluoroacetic acid was added, and the mixture was stirred for 1 hour under ice cooling. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate.
Redissolve in 2.0 ml and add triethylamine to adjust the pH to 8
It was set to ~ 9. Then, it extracted with water. After adjusting the pH to 3 by adding 1N hydrochloric acid to the separated aqueous layer, ethyl acetate was used.
2.0 ml was added for extraction. The organic layer (ethyl acetate layer) was washed with saturated brine and dried over anhydrous sodium sulfate.
Concentration under reduced pressure gave 147 mg of the title compound. TLC: Rf 0.43 (chloroform: methanol: water = 8:
3: 1 lower layer) FAB-MASS: [M + H] ⁺ 494

[0039]

Example 3 (R) -3-[(2S, 3S) -3- (Fumaryl) amino-2-hydroxy-4-
Phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide [Step 3-1] (R) -3-[(2S, 3S) -3- (trans-3-ethoxycarbonylpropenoyl ) Amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 235 mg was suspended in DMF 4.0 ml. , Ethyl fumarate 104 mg, triethylamine 10
0 μl and 318 mg of BOP reagent were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 15 ml of ethyl acetate, and this ethyl acetate solution was diluted with 5%.
The extract was washed with aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate.
Concentration under reduced pressure gave 319 mg of the title compound. TLC: Rf 0.82 (chloroform: methanol: water = 8:
3: 1 lower layer)

[Step 3-2] (R) -3-[(2S, 3S) -3- (Fumaryl) amino-2-hydroxy-4-phenylbutanoyl] -1,
3-thiazolidine-4-N'-t-butylcarboxamide 233 mg of the compound obtained in Step 3-1 was added to 5.0 ml of methanol.
1N sodium hydroxide aqueous solution 0.5
2 ml was added, and the mixture was stirred at room temperature for 14 hours. Water was added to the reaction solution and washed with diethyl ether. The aqueous layer was adjusted to pH 3 with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer (ethyl acetate layer) was washed with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 178 mg of the title compound. TLC: Rf 0.24 (chloroform: methanol: water = 8: 3:
1 Lower layer) FAB-MASS: [M + H] ⁺ 464

Comparative Example 1 (R) -3-[(2S, 3S) -3- (Maleyl) amino-2-hydroxy-4-
Phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu In a solution of 235 mg suspended in 4.0 ml DMF, maleic anhydride 64 mg, triethylamine 90
μl was added, and the mixture was stirred at room temperature for 14 hours. Add 15 ml of ethyl acetate to the reaction mixture, then add 1N hydrochloric acid to adjust the pH to 3
Adjusted to. Then, the ethyl acetate layer was separated, washed twice with 1N hydrochloric acid and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 195 mg of the title compound. TLC: Rf 0.62 (chloroform: methanol: water = 8: 3:
1 lower layer)

[0042]

Example 4 (R) -3-[(2S, 3S) -3- (2,3-dimethylsuccinyl) amino-2
-Hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide [Step 4-1] 2,3-Dimethylsuccinic anhydride meso-2,3-Dimethylsuccinic acid 73.1 500 mg of trifluoroacetic anhydride was added to mg and the mixture was stirred at room temperature for 4 hours. Excessive trifluoroacetic anhydride was distilled off from the reaction solution to obtain 64.0 mg of the title acid anhydride.

[Step 4-2] (R) -3-[(2S, 3S) -3- (2,3-
Dimethylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 201 mg was suspended in DMF 3.0 ml. The acid anhydride obtained in step 4-1 and 100 μl of pyridine were added to the liquid, and the mixture was stirred at room temperature for 14 hours. The reaction solution is concentrated under reduced pressure,
The obtained residue was redissolved in 15 ml of ethyl acetate, and this ethyl acetate solution was washed 3 times with a 10% aqueous citric acid solution, saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 220 mg of the title compound. TLC: Rf 0.61 (chloroform: methanol: acetic acid = 50:
10: 2) FAB-MASS: [M + H] ⁺ 494

[0044]

Example 5 (R) -3-[(2S, 3S) -3- (3-isopropylsuccinyl) amino
2-Hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide [Step 5-1] 2-isopropylsuccinic anhydride 2-isopropylsuccinic acid 82.4 mg to acetic anhydride 5 ml was added and the mixture was heated under reflux for 2 hours. Excess acetic anhydride was distilled off from the reaction solution to obtain 73.1 mg of the title acid anhydride.

[Step 5-2] (R) -3-[(2S, 3S) -3- (3-isopropylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4 -N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 183 mg was suspended in DMF 3.0 ml, the acid anhydride compound obtained in Step 5-1 and triethylamine 56 μl were added, and the mixture was stirred at room temperature. It was stirred for 14 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was mixed with 15 ml of ethyl acetate.
Redissolved in ethyl acetate, the ethyl acetate solution was washed 3 times with a 10% aqueous citric acid solution, saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 81.3 mg of the title compound. TLC: Rf 0.84 (chloroform: methanol: acetic acid = 5
0: 10: 2) FAB-MASS: [M + H] ⁺ 508

[0046]

Example 6 (R) -3-[(2S, 3S) -3- (3-Cyclopentylidenylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-
Thiazolidine-4-N'-t-butylcarboxamide [Step 6-1] 2-Cyclopentylidenylsuccinic Anhydride A known method (Journal of Pharmaceutical Science, 72 ,
83 (see 1983)), and prepared by dissolving 204 mg of 2-cyclopentylidenylsuccinic acid synthesized in 5.0 ml of dichloromethane-diethyl ether (1: 1) in DCC.
244 mg was added, and the mixture was stirred at room temperature for 3 hours. After filtering the reaction solution, the solvent was distilled off from the filtrate to obtain the title acid anhydride.

[Step 6-2] (R) -3-[(2S, 3S) -3- (3-Cyclopentylidenylsuccinyl) amino-2-hydroxy-4
-Phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 392 mg was suspended in DMF 6.0 ml and obtained in step 6-1. Acid anhydride, triethylamine
180 μl was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 20 ml of ethyl acetate, and this ethyl acetate solution was added with a 10% aqueous citric acid solution,
The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 474 mg of the title compound. TLC: Rf 0.32 (chloroform: methanol = 10: 1) FAB-MASS: [M + H] ⁺ 520

[0048]

Example 7 (R) -3-[(2S, 3S) -3- (2-Cyclopentylidenylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-
Thiazolidine-4-N'-t-butylcarboxamide [Step 7-1] p-Methoxybenzyl 3-cyclopentylidenylsuccinate 448 mg of the acid anhydride obtained in Step 6-1 of Example 6 was diluted with dichloromethane-diethyl ether. (1: 1) To a solution dissolved in 10 ml, anis alcohol 327 μl and triethylamine 367 μl 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 diluted with 15 ml of dichloromethane.
Was redissolved in, and the dichloromethane solution was washed with 5% aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 772 mg of the title monoester compound. TLC: Rf 0.42 (chloroform: methanol = 20: 1)

[Step 7-2] (R) -3-[(2S, 3S) -3- (3- (4-
(Methoxybenzyloxycarbonyl) -2-cyclopentyridenylpropanoyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH -To a liquid obtained by suspending 235 mg of tBu in 3.0 ml of DMF, 207 mg of the monoester compound obtained in Step 7-1, 90 µl of triethylamine, 136 mg of EDC, 109 mg of HOBt.
Was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the resulting residue was redissolved in 15 ml of ethyl acetate,
The ethyl acetate solution was washed with a 5% aqueous sodium hydrogen carbonate solution, a 10% aqueous citric acid solution and saturated saline, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to give the title compound
318 mg was obtained. TLC: Rf 0.51 (chloroform: methanol = 20: 1)

[Step 7-3] (R) -3-[(2S, 3S) -3- (2-cyclopentylidenylsuccinyl) amino-2-hydroxy-4
-Phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide To 150 mg of the compound obtained in Step 7-2, 51 μl of anisole,
2 ml of trifluoroacetic acid was added, and the mixture was stirred for 1 hour under ice cooling. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 3.0 ml of diethyl ether, and triethylamine was added.
The pH was adjusted to 8-9. Then, it was extracted with 3.0 ml of water. 1N Hydrochloric acid was added to the separated aqueous layer to adjust the pH to 3, and then 3.0 ml of ethyl acetate was added for extraction. The organic layer (ethyl acetate layer) was washed with saturated brine and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 121 mg of the title compound. TLC: Rf 0.24 (chloroform: methanol = 20: 1) FAB-MASS: [M + H] ⁺ 520

[0051]

Example 8 (R) -3-[(2S, 3S) -3- (3-Cyclopentylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N′- t-Butylcarboxamide [Step 8-1] 2-Cyclopentylsuccinic anhydride 2-Cyclopentylsuccinic acid 96 synthesized according to a known method (see J. Amer. Chem. Soc., 71 , 3618 (1949) etc.)
106 mg of DCC was added to a solution of mg dissolved in 5.0 ml of dichloromethane-3 drops of DMF, and the mixture was stirred at room temperature for 3 hours.
After filtering the reaction solution, the solvent was distilled off from the filtrate to obtain the title acid anhydride.

[Step 8-2] (R) -3-[(2S, 3S) -3- (3-Cyclopentylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4 -N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 156 mg suspended in DMF 3.0 ml was added to the acid anhydride and triethylamine obtained in Step 8-1.
60 μl was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 15 ml of ethyl acetate, and the ethyl acetate solution was washed with a 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate.
Concentration under reduced pressure gave 202 mg of the title compound. The obtained compound was a mixture of two kinds of stereoisomers, and each isomer was separated by reverse-phase HPLC and separated. Note that the isomer with a retention time of 25.2 min described below was converted to 3-cyclopentylsuccinyl-AHPBA-Thz-NH-tBu (pre-peak isomer) with a retention time of 2
The 6.2 min isomer is distinguished from the same (post-peak isomer). HPLC conditions Column: YMC AM302 column, φ 4.6 × 150 mm Eluent: 0.1% CF ₃ COOH-CH ₃ CL Elution conditions: 20% -80% Gradient; 30 min Flow rate: 0.7 ml / min Retention time: 25.2 min, 26.2 min FAB-MASS: [M + H] ⁺ 534

[0053]

Example 9 (R) -3-[(2S, 3S) -3- (2-Cyclopentylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N′- t-Butylcarboxamide [Step 9-1] p-Methoxybenzyl 3-cyclopentylsuccinate A solution of 496 mg of the acid anhydride obtained in Step 8-1 of Example 8 in 10 ml of dichloromethane was added to anis alcohol.
Add 288 μl and 323 μl triethylamine, and add 1 at room temperature.
Stir for 4 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 20 ml of ethyl acetate, and this ethyl acetate solution was added to the residue.
The extract was washed with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 300 mg of the title monoester compound. TLC: Rf 0.28 (chloroform: methanol = 20: 1)

[Step 9-2] (R) -3-[(2S, 3S) -3- (3- (4-
Methoxybenzyloxycarbonyl) -2-cyclopentylpropanoyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 298 300 mg of the monoester compound obtained in Step 9-1 was added to a liquid obtained by suspending mg in DMF 5.0 ml,
Triethylamine 114 μl, EDC 188 mg, HOBt 150
mg was added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 20 ml of ethyl acetate,
The ethyl acetate solution was washed with a 5% aqueous sodium hydrogen carbonate solution, a 10% aqueous citric acid solution and saturated saline, and dried over anhydrous sodium sulfate. Concentrate under reduced pressure to give the title compound
277 mg was obtained. TLC: Rf 0.28 (chloroform: methanol = 20: 1)

[Step 9-3] (R) -3-[(2S, 3S) -3- (2-Cyclopentylsuccinyl) amino-2-hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4 -N'-t-butylcarboxamide 66 mg of anisole to 200 mg of the compound obtained in Step 9-2,
2 ml of trifluoroacetic acid was added, and the mixture was stirred for 1 hour under ice cooling. The reaction mixture was concentrated under reduced pressure, and the obtained residue was extracted with ethyl acetate.
Redissolve in 2.0 ml and add triethylamine to adjust the pH to 8
After adjusting to -9, it was extracted with 4.0 ml of water. After adjusting the pH to 3 by adding 1N hydrochloric acid to the separated aqueous layer, ethyl acetate was used.
2.0 ml was added for extraction. The organic layer (ethyl acetate layer) was washed with saturated brine and dried over anhydrous sodium sulfate.
Concentration under reduced pressure gave 89 mg of the title compound. The obtained compound was a mixture of two kinds of stereoisomers, and each isomer was separated by reverse-phase HPLC and separated. The isomer with a retention time of 24.8 min described below was converted into 2-cyclopentylsuccinyl-AHPBA-Thz-NH-tBu (pre-peak isomer) with a retention time of 2
The 7.2 min isomer is distinguished from the same (post-peak isomer). HPLC conditions Column: YMC AM302 column, φ 4.6 × 150 mm Eluent: 0.1% CF ₃ COOH-CH ₃ CL Elution conditions: 20%-80% Gradient; 30 min Flow rate: 0.7 ml / min Retention time: 24.8 min, 27.2 min FAB-MASS: [M + H] ⁺ 534

[0056]

Example 10 (R) -3-[(2S, 3S) -3- (3,3-Dimethylglutaryl) amino-2
-Hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 392 mg suspended in DMF 7.0 ml was mixed with 3, 3 -Dimethylglutaric anhydride 154.2 mg and triethylamine 149 µl were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure and the resulting residue was washed with ethyl acetate 30
redissolve in 1 ml of this ethyl acetate solution,
The extract was washed with saturated saline and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 286 mg of the title compound. TLC: Rf 0.52 (chloroform: methanol: water = 8:
3: 1 lower layer) FAB-MASS: [M + H] ⁺ 508

[0057]

Example 11 (R) -3-[(2S, 3S) -3- (4,4-dimethylglutaryl) amino-2
-Hydroxy-4-phenylbutanoyl] -1,3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Thz-NH-tBu 365 mg suspended in DMF 7.0 ml, 2, 2 -142 mg of dimethyl glutaric anhydride and 200 µl of pyridine were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 30 ml of ethyl acetate, the ethyl acetate solution was washed with a 10% aqueous citric acid solution and saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 450 mg of the title compound. TLC: Rf 0.70 (chloroform: methanol: acetic acid = 5
0: 10: 2) FAB-MASS: [M + H] ⁺ 508

[0058]

Example 12 (R) -3-[(2S, 3S) -3- (3,3-dimethylsuccinyl) amino-2
-Hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,
3-thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Dmt-NH-tBu 216 mg of a solution suspended in DMF 5.0 ml was obtained in Step 1-1 of Example 1 in 2,2- 64 mg of dimethylsuccinic anhydride and 200 μl of pyridine were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in ethyl acetate (ml), and this ethyl acetate solution was added.
Wash with 10% citric acid aqueous solution 3 times and saturated saline,
It was dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 267 mg of the title compound. TLC: Rf 0.71 (chloroform: methanol: acetic acid = 5
0: 10: 2) FAB-MASS: [M + H] ⁺ 522 ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.85 (s; 3H dimethyls
uccinyl-CH ₃ ), 0.95 (s; 3H dimethylsuccinyl-CH ₃ ),
1.27 (s; 9H -NH- tBu ), 1.40 (s; 3H Dmt-5-CH ₃ ), 1.
49 (s; 3H Dmt-5-CH ₃ ), 2.28 (q; 2H dimethylsuccin
yl-CH ₂ ), 2.62 (t; 2H AHPBA-CH ₂ ), 4.10 (bs; 1H AHP
BA-3), 4.41 (s; 1H AHPBA-2), 4.51 (s; 1H Dmt-4),
4.85 (d; 1H Dmt-2), 5.07 (d; 1H Dmt-2), 7.19 (m
; 3H AHPBA-m, p- (Ph)), 7.33 (d; 2H AHPBA-o- (Ph)),
7.66 (s; 1H- NH -tBu), 8.03 (d; 1H AHPBA- NH ), 11.
7 (bs; dimethylsuccinyl- C00H )

[0059]

Example 13 (R) -3-[(2S, 3S) -3- (2,3-dimethylsuccinyl) amino-2
-Hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,
3-Thiazolidine-4-N'-t-butylcarboxamide H-AHPBA-Dmt-NH-tBu 216 mg was suspended in a solution of DMF 4.0 ml to obtain a solution obtained in Step 4-1 of Example 4, 2,3- 64 mg of dimethylsuccinic anhydride and 200 μl of pyridine were added, and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated under reduced pressure, the obtained residue was redissolved in 20 ml of ethyl acetate, and this ethyl acetate solution was washed with 10% aqueous citric acid solution three times, saturated brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure gave 112 mg of the title compound. TLC: Rf 0.70 (chloroform: methanol: acetic acid = 5
0: 10: 2) FAB-MASS: [M + H] ⁺ 522

The following tests were carried out in order to verify that the peptidomimetic compound of the present invention has excellent HIV protease inhibitory activity, low cytotoxicity, and other properties suitable for pharmaceutical use.

[Test Example 1] HIV Protease Inhibitory Activity The HIV protease inhibitory activity of the peptide-like compound of the present invention has already been reported in a test method (Kiso Yoshiaki, Journal of Organic Synthetic Chemistry Vol. 52, 403-412). (1994), JP-A-5-
170722) and the like.
Two compounds were evaluated. As a comparative example, Comparative Example 1
Compound (maleyl-AHPBA-Thz-NH-tBu) of Example 1 and the compound of Reference Example 1 (succinyl-AHPBA-Pro-NH-) as a reference example.
tBu), the compound of Reference Example 2 (succinyl-AHPBA-Thz-NH-t
Bu) was used to perform a similar test.

Test method In place of the natural HIV protease, the literature (Science
230 , 949 (1985)), a recombinant HIV protease expressed in Escherichia coli having the native sequence of HIV protease (Bichemistry, 250 (9), 264 (199).
(See (0)) was used to evaluate the HIV protease inhibitory activity (see, for example, JP-A-5-170722).
In addition, a synthetic nonapeptide substrate (Ac-Arg-Ala-Ser-Gln-Asn-Ty) was used as a substrate for the recombinant HIV protease.
The protease activity was measured using r-Pro-Val-Val-NH ₂ · trifluoroacetate). Final concentration 100 mM MES buffer (pH 5.5), 40 mM of the substrate, 9.2 μg of the recombinant HIV
Proteases, and various concentrations of test compounds (eg,
Dissolve in DMSO etc. beforehand) to make 15 μl of reaction solution. This reaction is started by adding the recombinant HIV protease to the reaction solution at the end, allowing the reaction to proceed at 37 ° C. for 60 minutes, and then stopping the reaction by adding 15 μl acetonitrile. The peptide fragment generated by cleavage between -Tyr ... Pro- of the substrate is quantified by the reverse phase HPLC internal standard method. When the concentration of the test compound is zero, the protease activity is 10
0%, when the peptide fragment is not measured, the residual activity is defined as 0%, and the residual activity is calculated from the concentration of the peptide fragment to be quantified. When the residual activity is 0%, the index of HIV protease inhibitory activity and the inhibition rate are defined as 100%, and the inhibition rate is defined by a value obtained by subtracting the residual activity expressed as a percentage from 100%.

Table 1 shows an example of the evaluation results of the HIV protease inhibitory activity of the peptidomimetic compound of the present invention evaluated by the above method. The test results for the compound of Comparative Example 1 and the compounds of Reference Examples 1 and 2 are also shown in Table 1. It can be seen that all of these peptidomimetic compounds of the present invention exhibit high HIV protease inhibitory activity. It is also judged that the HIV protease inhibitory activity is comparable to the compounds of Reference Examples 1 and 2. On the other hand, the compound of Comparative Example 1 has no HIV protease inhibitory activity in this concentration range. The test compound concentration shown in Table 1 represents the final concentration in the reaction solution.

[0064]

[Table 1]

[Test Example 2] Anti-HIV activity The anti-HIV activity of the peptide-like 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 Test methods already reported in the literature (H. Nakasima et al.,
Antimicrob. Agents Chemother. 36 , 1249-1255 (1992)
Etc.) for anti-HIV activity. MT-4 cells were used as the target T cell lymphocytes, and HI
HTLV-II which is HIV type 1 virus as V virus
Using the I _B virus. In addition, the HTLV-III _B virus was infected with H immediately after infection using an infectious titer of 13 × 10 ⁴ PFU / ml.
IV infected MT-4 cells, predetermined number of cells (2.5 × 10 ⁴ / well, M
OI: 0.01) on a 96-well microtiter plate,
Add complete concentration of test medium and test compound at 37 ℃, 5
Incubate in a humidified atmosphere containing% CO ₂ . After culturing for 5 days, the number of surviving cells was determined by the MTT method (R. Pauwels et al.,
J. Virol. Methods 20 , 309-321 (1988) etc.)
And the measured value is indicated as (OD _T ) _HIV . at the same time,
HIV-uninfected MT-4 cells and HIV-infected MT-4 cells were similarly cultured with the concentration of the test compound being zero, and the number of surviving cells was measured.
D _C ) _MOCK and (OD _C ) _HIV , respectively. These measurements (OD
_T ) _HIV , (OD _C ) _MOCK , (OD _C ) _HIV , the inhibition rate to prevent the death of T cell lymphocytes associated with the HIV virus infection,
Calculate using the following formula.

[Equation 1] [(OD _T ) _HIV − (OD _C ) _HIV ] / [(OD _C ) _MOCK − (OD _C ) _HIV ]

The anti-HIV activity was evaluated by the EC _{50 and the} concentration of the test compound at which the calculated inhibition rate was 50%. Table 2 shows an example of the evaluation results of the anti-HIV activity EC ₅₀ . It can be seen that these peptidomimetic compounds of the present invention have anti-HIV activity. That is, it is understood that new HIV infection of MT-4 cells is suppressed by the action of being absorbed by T cell lymphocytes and inhibiting the production of HIV virus particles in the cells. As a control example, ddI that suppresses HIV infection by inhibiting reverse transcription of HIV virus
The results of a similar test conducted using (dideoxyinosine) are also shown in Table 2. The peptidomimetic compounds of the present invention are rated as anti-HIV activity as ddI.

[0068]

[Table 2]

Test Example 3 Cytotoxicity The cytotoxicity of the peptidomimetic compound of the present invention was evaluated by the following method.

Test Method As living cells to be tested , adult T-cell leukemia virus,
T4 cells infected with HTLV-1 virus (MT-4: mock-infec
ted T4 cell). 96-well microtiter plate
The MT-4 cells to a predetermined number of cells (2.5 × 10 ⁴ / well)
Sow, add the specified concentration of complete culture solution and test compound,
Incubate in a humidified atmosphere containing 5% CO ₂ at ℃. After culturing for 5 days, the number of surviving cells was determined by the MTT method (R.
al., J. Virol. Methods 20 , 309-321 (1988)). The survival rate is calculated by setting the number of surviving cells in the reference group in which the concentration of the test compound is zero as 100%. Cytotoxicity was assessed by the test compound concentration CC _50, which reduces the viability to 50%. In addition,
The concentration of the test compound represents the final concentration in the culture medium.

Table 3 shows an example of the evaluation results of the above-mentioned cytotoxicity CC ₅₀ . At the same time, as a control example, a tripeptide derivative having a (2S, 3S) -3amino-2-hydroxy-4-phenylbutanoyl skeleton, KNI-272 [5-Isoquinoline-
O-CH ₂ -CO- (CH ₃ SL-Ala) -AHPBA-Thz-NH-tBu: (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] and AZT (azidothymidine), the results of the same test were also shown in Table 3.
These peptidomimetic compounds of the invention are KNI-272,
Alternatively, it can be seen that the cytotoxicity is lower than that of AZT.
In addition, in the present test, the peptide-like compound of the present invention was not evaluated in the range exceeding the concentration of 1000 μg / ml, and when the calculated survival rate was 60% or more at the concentration of 1000 μg / ml, CC _{50 in} 3 is> 1000 μ
It was described as g / ml.

[0072]

[Table 3]

[Pharmaceutical Example] The above-described peptidomimetic compound of the present invention can be formulated into a capsule or the like according to the formulation described below, and can be orally administered. For example, a preparation containing the compound of Example 12 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 can be appropriately selected depending on the administration method and time interval.

[0074]

[Table 4]

[Test Example 4] In-vivo metabolic characteristics The metabolic characteristics of the peptide-like compound of the present invention were evaluated using rats as test animals. The evaluated administration methods are an example of intraperitoneal administration of a solution in which a required amount of a test compound is suspended, and an example of intravenous injection of an injection solution in which a required amount of a test compound is dissolved. After the administration, blood was collected from the test animal and the concentration of the test compound remaining in plasma was analyzed. As an example of the evaluation results, changes in plasma concentration after administration of the compound of Example 1 and the compound of Example 12 are shown in FIG.
It shows in contrast to. The dose of the test compound was 20 mg / kg for intraduodenal administration and 10 mg / kg for intravenous injection. In addition, an index indicating the metabolic characteristics in the body, AUC (area under the drug concentration curve in plasma), MRT (average residence time), t1 / 2 (λ)
Table 5 shows an example of the results of calculating F (bioavailability), the (final phase half-life), and an index representing the absorption characteristics of intraduodenal administration. As a control example, the tripeptide derivative KN
The results of intravenous injection of I-272 are also shown.

[0076]

[Table 5]

From these results, the peptidomimetic compound of the present invention is more excellent in in vivo stability and can maintain a high plasma concentration for a longer period of time as compared with the control compound KNI-272. It turns out that it is possible.

[0078]

INDUSTRIAL APPLICABILITY The peptidomimetic compound of the present invention has, in addition to a specific and high HIV protease inhibitory activity, a dipeptide-like skeleton portion which is essential for HIV protease inhibitory activity and an acyl group substituted with a carboxyl group are directly bonded. Since it has a structure of, due to the highly hydrophilic carboxyl group,
Excellent solubility in water. Furthermore, since the structure of the hydrocarbon group of the acyl group linked to the dipeptide-like skeleton portion by an amide bond achieves an appropriate balance of hydrophobicity and hydrophilicity, it is easily absorbed in the digestive tract and bioavailability is improved. Produce the advantage of increasing. Therefore, when suitable 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, since the peptidomimetic compound of the present invention is a peptidomimetic having a small molecular weight and having no natural peptide bond, it has further excellent in vivo stability.

[Brief description of drawings]

FIG. 1 shows the changes in plasma concentration after administration of the compound of Example 1 and the compound of Example 12 when administered intraduodenally (id) or intravenously (iv) for comparison.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical indication C07D 211/60 C07D 211/60 223/06 223/06 277/06 277/06 (72) Inventor Naoko Morohashi, 3-17-35, Shinzonan, Toda City, Saitama Prefecture, Japan Japan Energy Co., Ltd. (72) Inventor, Tominaga Fukazawa 3--3, 35, Shinzenan, Toda City, Saitama Prefecture, Japan Japan Energy Company, Ltd.

Claims (8)

[Claims] 1. The following general formula (1): [In the formula, R ₁ is 2 to 9 carbon atoms which may have a branch.
Represents a valent hydrocarbon group, wherein the group R ₁ is a divalent hydrocarbon group having 2 carbon atoms.
When it is a valent hydrocarbon group, a hydrogen atom bonded to the carbon atom is a vinylene group having a trans orientation, and R ₂ is
Methylene group (-CH _2- ) or carbonyl group (-C (O)-)
Where A is a general formula (2) below. [In the formula, R ₃ represents an optionally branched hydrocarbon group having 1 to 6 carbon atoms, and R ₄ forms a 5 to 7-membered ring together with the nitrogen atom and carbon atom to which it binds. A valent hydrocarbon group, wherein the group R ₄ may have one or more of the carbon atoms contained therein replaced by a heteroatom, may further be condensed with another 5 to 7 membered ring, or may be substituted. It may have a group. ] The monovalent group represented by this is shown. ] The peptide-like compound represented by these, or its pharmacologically acceptable salt. 2. In the above general formula (1), the group R
_1. The peptidomimetic compound or the pharmaceutically acceptable salt thereof according to claim 1, wherein ₁ is a branched divalent hydrocarbon group having 3 to 9 carbon atoms. 3. In the above general formula (1), the group R
₁ is the following general formula (3): (In the formula, R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₄ each represent a hydrogen atom or a hydrocarbon group, and none of them is a hydrogen atom, and any one of R ₁₁ , R ₁₂ , R ₁₃ , and R ₁₄ Two or more may form a ring with each other), or a divalent hydrocarbon group represented by the following formula, or a compound represented by the following general formula (4): (In the formula, R ₁₅ and R ₁₆ each represent a hydrogen atom or a hydrocarbon group, and R ₁₅ and R ₁₆ may form a ring with each other.) Any of divalent hydrocarbon groups The peptidomimetic compound or the pharmaceutically acceptable salt thereof according to claim 2, wherein 4. The group R ₁ is represented by the above general formula (3), a hydrogen atom is selected as at least two of the groups R ₁₁ , R ₁₂ , R ₁₃ and R ₁₄ , and the remaining group is a methyl group. The peptidomimetic compound or the pharmaceutically acceptable salt thereof according to claim 3, which is a group consisting of 5. The peptidomimetic compound according to claim 3, wherein the group R ₁ is represented by the general formula (4), and the groups R ₁₅ and R ₁₆ are both methyl groups. A pharmacologically acceptable salt thereof. 6. In the above general formula (1), the group R
_A carbonyl group is selected for 2 and the group A represented by the general formula (2) is represented by the following general formula (5): (Wherein, R ₃ represents the same group as R ₃ in the general formula (2) to the aforementioned, X represents methylene group (-CH ₂ -) or represents a sulfur atom, R _41, R ₄₂ are each hydrogen Represents a hydrocarbon group having 1 to 6 carbon atoms which may have an atom or a branch, and R
₄₁ and R ₄₂ may combine with each other to form a ring. ) The group represented by) is selected.
The peptidomimetic compound or the pharmaceutically acceptable salt thereof according to 1. 7. In the above general formula (5), the group R ₃
7. A tert-butyl group is selected as the compound, and a hydrogen atom or a methyl group is selected as each of the groups R ₄₁ and R ₄₂ , respectively. Salt. 8. A human immunodeficiency virus (HIV) protease inhibitor comprising the peptidomimetic compound or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 7 as an active ingredient.