JP2005047874A - New dipeptide compound effective to hiv - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new dipeptide having excellent action on drug-resistant virus, compared with a conventional HIV protease composed of a substrate transition state derivative. <P>SOLUTION: The present invention provides a new dipeptide compound represented by formula (1) [R<SP>1</SP>is formula (a) or formula (b); R<SP>2</SP>, R<SP>3</SP>and R<SP>4</SP>are each a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a low alkoxy group, a lower alkoxy-lower alkoxy group, a lower alkenyloxy group or a lower alkylamino group or R<SP>3</SP>and R<SP>4</SP>are combined together and may exhibit a methylenedioxy group, an ethyleneoxy group or a propylene group; R<SP>5</SP>, R<SP>6</SP>, R<SP>7</SP>, R<SP>8</SP>and R<SP>9</SP>are each a hydrogen atom, a halogen atom, a lower alkyl group or a lower alkoxy group; R<SP>10</SP>and R<SP>11</SP>are each a hydrogen atom or a lower alkyl group; X is methylene, a sulfur atom or an oxygen atom] or its pharmaceutically acceptable salt. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a novel compound that inhibits the enzyme activity of HIV protease, and an anti-AIDS drug that suppresses HIV proliferation in the body using the inhibitory action of the compound on HIV protease.

Human immunodeficiency virus (HIV), which is the cause of AIDS, is produced as a precursor protein using a Gag protein, reverse transcriptase, or the like used to form the virus particles in the host cell. This precursor protein exhibits its functions only after being cleaved to a specific size by a virus-derived protease (HIV protease). HIV protease inhibitors that inhibit the activity of this HIV protease and block the formation and maturation of infectious viral particles can be used as antiviral agents, and several HIV protease inhibitors are already in clinical use.
However, although conventional HIV protease inhibitors have shown sufficient efficacy in clinical practice, it is known that mutants that are resistant to drugs will emerge over long periods of time, and these mutants are not compatible with other drugs. Cross resistance, which is also resistant to the problem, is a big problem. Aiming to overcome this cross-resistance, J. Erickson et al. Discloses that urethane-type hydroxyethylaminosulfonamide compounds having a bis-tetrahydrofuran skeleton are effective for HIV that has acquired resistance to multiple drugs (patent) Reference 1).

The present inventors also previously described that a dipeptide derivative containing 3-amino-2-hydroxy-4-phenylbutanoic acid (AHPBA, hydroxymethylcarboxamide derivative) as a basic structure strongly inhibits the activity of HIV protease and is a strong antiviral agent. It has been found that it exhibits activity (Patent Documents 2 and 3), and it has been confirmed that a certain compound is effective against a drug-resistant virus (Non-Patent Document 1).
Separately from this, A. Ghosh et al. Disclosed a urethane type hydroxyethylene compound having a bis-tetrahydrofuran skeleton at the amino terminus (Patent Document 4), and Yabe et al. And SC Koch et al. A methyl carboxamide derivative has been proposed as an anti-AIDS drug (Patent Documents 5 and 6). However, the current situation is not necessarily satisfactory in terms of overcoming crossover tolerance.
From the above, development of a drug having a new skeleton structure is eagerly desired as a compound having a more excellent action against drug-resistant viruses.

WO 99/67254 US 5932550 WO 01/47948 WO 94/26749 JP 11-286478 A WO 02/100844 K. Yoshimura et al., Proc. Natl. Acad. Sci. USA, 96, 8675 (1999)

  The present invention has been made in view of the above-mentioned present situation, and is to provide a novel dipeptide compound having an action superior to a drug resistant virus as compared with an HIV protease inhibitor comprising a conventional substrate transition state derivative.

  As a result of various studies to solve the above-mentioned problems, the present inventors, among urethane type hydroxymethyl carboxamide compounds, are particularly compounds having a benzylamine structure at the carboxyl terminal and a bis-tetrahydrofuran-like skeleton at the amino terminal. It has been found that it has a more excellent effect on drug-resistant HIV protease and drug-resistant virus, and has completed the present invention.

That is, the present invention
[1] Formula (1)

（式中、Ｒ^１は式（ａ）または式（ｂ）を示し、

(Wherein R ¹ represents formula (a) or formula (b),

Ｒ^２、Ｒ^３、およびＲ^４はそれぞれ水素原子、ハロゲン原子、低級アルキル基、低級アルケニル基、低級アルコキシ基、低級アルコキシ低級アルコキシ基、低級アルケニルオキシ基、または低級アルキルアミノ基を示し、またＲ^３とＲ^４とは互いに結合してメチレンジオキシ基、エチレンジオキシ基またはプロピレン基を示しても良く、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、およびＲ^９はそれぞれ水素原子、ハロゲン原子、低級アルキル基、または低級アルコキシ基を示し、Ｒ¹⁰およびＲ¹¹はそれぞれ水素原子または低級アルキル基を示し、Ｘはメチレン、硫黄原子または酸素原子を示す。）で表される新規なジペプチド化合物またはその薬学的に許容される塩、
〔２〕式（２）

R ² , R ³ , and R ⁴ each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkenyloxy group, or a lower alkylamino group, and R ³ and R ⁴ may be bonded to each other to represent a methylenedioxy group, an ethylenedioxy group or a propylene group, and R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are a hydrogen atom or a halogen atom, respectively. , A lower alkyl group or a lower alkoxy group, R ¹⁰ and R ¹¹ each represent a hydrogen atom or a lower alkyl group, and X represents a methylene, sulfur atom or oxygen atom. ) Or a pharmaceutically acceptable salt thereof,
[2] Formula (2)

（式中、Ｒ^１、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８、Ｒ^９、Ｒ¹⁰およびＲ¹¹は前記［１］と同義を表す。）で表される前記［１］記載の新規ジペプチド化合物またはその薬学的に許容される塩、
〔３〕式（３）

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ have the same meanings as [1] above). The novel dipeptide compound according to the above [1] or a pharmaceutically acceptable salt thereof,
[3] Formula (3)

（式中、Ｒ^２、Ｒ^３、Ｒ^４、Ｒ^５、Ｒ^６、Ｒ^７、Ｒ^８およびＲ^９は前記［１］と同義を表す。）で表される前記［２］記載の新規ペプチド化合物またはその薬学的に許容される塩、
〔４〕Ｒ^２、Ｒ^３およびＲ^４がそれぞれ水素原子、メトキシ基またはエトキシ基であり、Ｒ^５およびＲ^９がそれぞれ水素原子、メチル基またはクロロ基であり、Ｒ^６、Ｒ^７およびＲ^８が水素原子であり、Ｘがはメチレンまたは硫黄原子である前記［３］記載の新規ペプチド化合物またはその薬学的に許容される塩、
〔５〕式（４）

(Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ have the same meanings as the above [1]). A compound or a pharmaceutically acceptable salt thereof,
[4] R ² , R ³ and R ⁴ are each a hydrogen atom, a methoxy group or an ethoxy group, R ⁵ and R ⁹ are each a hydrogen atom, a methyl group or a chloro group, and R ⁶ , R ⁷ and R ⁸ The novel peptide compound or the pharmaceutically acceptable salt thereof according to [3], wherein is a hydrogen atom and X is a methylene or sulfur atom,
[5] Formula (4)

（式中、Ｒ^２’、Ｒ^３’およびＲ^４’はそれぞれ水素原子、メトキシ基またはエトキシ基を示し、Ｒ^５’およびＲ^９’はそれぞれ水素原子、メチル基またはクロロ基を示し、Ｘ’はメチレンまたは硫黄原子を示す）で表される前記［４］記載の新規ペプチド化合物またはその薬学的に許容される塩、
〔６〕前記［１］〜[５]のいずれかに記載された新規ジペプチド化合物またはその薬学的に許容される塩を有効成分とする抗エイズ薬、

Wherein R ^{2 ′} , R ^{3 ′} and R ^{4 ′} each represent a hydrogen atom, a methoxy group or an ethoxy group, R ^{5 ′} and R ^{9 ′} each represent a hydrogen atom, a methyl group or a chloro group, and X ′ Represents a methylene or sulfur atom), the novel peptide compound of the above-mentioned [4] or a pharmaceutically acceptable salt thereof,
[6] An anti-AIDS drug comprising the novel dipeptide compound or the pharmaceutically acceptable salt thereof according to any one of [1] to [5] as an active ingredient,

  The compounds of the present invention have high HIV protease inhibitory activity, and compounds exhibiting antiviral activity by blocking the formation and maturation of infectious viral particles in HIV T cell lymphocytes by utilizing this property It is. In addition, the compound of the present invention exhibits a strong inhibitory effect against drug-resistant viruses because it exhibits a strong inhibitory effect against HIV-1 protease that has acquired resistance against existing HIV-1 protease inhibitors. It has a medicinal use as a novel anti-AIDS drug that has reduced the problem of drug resistance.

The present invention will be specifically described below.
Examples of the lower alkyl group include a straight chain or branched chain having 1 to 4 carbon atoms such as methyl, ethyl, propyl, butyl, isopropyl, sec-butyl, or tert-butyl. Preferably, a methyl group or an ethyl group is mentioned.
Examples of the lower alkenyl group include straight-chain or branched C2-C4 such as vinyl group, allyl group, isopropenyl group, 1-propenyl group, 1-butenyl group and 2-butenyl group. Preferably, a vinyl group or an allyl group is used.
Examples of the lower alkoxy group include a straight chain or branched chain having 1 to 4 carbon atoms such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, an isopropoxy group, a sec-butoxy group, or a tert-butoxy group. Preferably, a methoxy group or an ethoxy group is mentioned.

Examples of the lower alkoxy lower alkoxy group having a straight chain or branched chain having 2 to 8 carbon atoms such as methoxymethoxy group, ethoxymethoxy group, 2-methoxyethoxy group, 3-methoxypropoxy group, 3-ethoxypropoxy group, Examples include 4-methoxybutoxy group, propoxy-tert-butoxy group, and the like, preferably methoxymethoxy group or ethoxymethoxy group.
Examples of the lower alkenyloxy group include straight-chain or branched C1-C4 such as vinyloxy group, allyloxy group, isopropenyloxy group, 1-propenyloxy group, 1-butenyloxy group, etc. Includes a vinyloxy group or an allyloxy group.

The lower alkylamino group is an amino group in which the lower alkyl group is mono- or di-substituted, for example, methylamino group, ethylamino group, propylamino group, butylamino group, dimethylamino group, diethylamino group, dipropylamino group , Dibutylamino group, methyl (ethyl) amino group, and the like, preferably methylamino group and dimethylamino group.
As a halogen atom, a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom is mentioned, Preferably a fluorine atom or a chlorine atom is mentioned.
X includes a methylene group, an oxygen atom, and a sulfur atom, preferably a methylene group or a sulfur atom.

The preferred configuration of the hexahydrofuro [2,3-b] furan ring of formula (a) representing R ¹ is as follows: carbon atom * 1 is R configuration, carbon atom * 2 is S configuration, and carbon atom * 3 is R configuration In the case of having a configuration, a configuration in which carbon atom * 1 has an S configuration, carbon atom * 2 has an R configuration, and carbon atom * 3 has an S configuration, and carbon atom * 1 is particularly preferably an R configuration, carbon The configuration in which the atom * 2 has an S configuration and the carbon atom * 3 has an R configuration, and the preferred configuration of the hexahydro-4H-furo [2,3-b] pyran ring of the formula (b) is When carbon atom * 1 has R configuration, carbon atom * 2 has S configuration, and carbon atom * 3 has R configuration, carbon atom * 1 has S configuration, carbon atom * 2 has R configuration, and carbon atom * 3 has This is a three-dimensional configuration with an S configuration.

  The novel dipeptide compound of the present invention can be produced according to the following reaction formula.

1) Production of Compound (7) Compound (7) can be prepared from Compound (5) according to a known synthesis method (Mihon et al., J. Med. Chem., 42, 1789 (1999), WO 01/47948, etc.). In an inert solvent, compound (6) is allowed to act on a mixed acid anhydride formed by the action of diphenyl phosphate chloride or chlorocarbonate in the presence of a base such as triethylamine to form an amide bond. It can be produced by reacting an acid such as hydrochloric acid or by deprotecting the amino group by catalytic hydrogenolysis using Pd or the like as a catalyst.
In addition, the compound (5) as a raw material can be synthesized by a known synthesis method (Sanbon et al., Ibid., Morgan, Barry Arnold et al., DE 2609154, R. Sharma et al. )) Or commercially available amino acids can be used. In addition, the racemic mixture of compound (5) can be divided only into the L form, which is a more preferred configuration, by forming a salt with the optically active form. In addition, after forming a diastereomer in the subsequent steps, it can also be led to a compound containing only the S isomer having a more preferred configuration by column chromatography or recrystallization.
Compound (6) can be produced according to generally known methods for synthesizing benzylamines such as reduction of benzonitriles or reductive amination of benzaldehydes.

2) Production of Compound (9) Compound (9) is prepared by combining compound (7) and compound (8) in an inert solvent according to a known synthesis method (such as Sanbon et al., Ibid., Patent Document 3). In the presence of additives such as HOBt (N-hydroxybenzotriazole) and HOSu (N-hydroxysuccinimide), DCC (N, N'-dicyclohexylcarbodiimide) and EDC (1-ethyl-3- (3-N, N ' -Dimethylaminopropyl) carbodiimide) and other carbodiimide reagents are reacted to form an amide bond, and then an acid such as hydrochloric acid is allowed to act on this, or the amino group is removed by catalytic hydrogenolysis using Pd as a catalyst. It can be manufactured by performing protection.
The compound (8) as a raw material is synthesized by known methods for synthesizing α-hydroxy-β-amino acids (Nishizawa et al., J. Med. Chem., 20, 510 (1977), Umezawa et al., JP 56-90050 A). W. Yuan et al., J. Med. Chem., 36, 211 (1993), Matsumoto et al., JP-A-10-59909, or Suzuki et al., JP-A-9-157247, Perasini et al., JP-A-2-28144, Nishiyama et al. , WO 00/53575)).

3) Production of Compound (1) Compound (1) is prepared from Compound (9) and Compound (10) according to a known synthesis method (AK Ghosh et al., J. Med. Chem., 17, 3278, (1996), etc.) Can be made to react in an inert solvent.
The starting compound (10) is hydroxyhexahydrofuro [2,3-b] furan synthesized by the method reported by AK Ghosh et al. (Tetrahedron Lett. 36, 505, 1995) or hydroxyhexahydro -4H-furo [2,3-b] pyran with disucciimidyl carbonate, dipyridyl carbonate, nitrophenyl carbonate, etc. in the presence of tertiary amines such as triethylamine and diisopropylamine in solvents such as methylene chloride, acetonitrile and tetrahydrofuran It can be produced by reacting a carbonate ester derived by reaction.
The chemical structure of the novel dipeptide compound of the present invention obtained by the above method can be easily determined by spectroscopic techniques such as nuclear magnetic resonance and infrared absorption, and mass spectrometry.

Examples of the novel dipeptide compound obtained in the present invention include the following compounds.
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl] amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl] amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,

(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,

(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,

(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,

(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2-Methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,

(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,

(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2-Methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl]-3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,

(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2-Methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,

(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-methoxyphenyl) butanoyl]-3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran-3-yl- Oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(S) -N- (2-Methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(S) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b] pyran -3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4-(4-ethoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine-2-carboxamide,

(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-ethoxyphenyl) butanoyl]-3,3-dimethylpyrrolidine-2-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-oxazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-oxazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-oxazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1,3-oxazolidine-4-carboxamide,

(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methylphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methylphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-methylphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-methylphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-chlorophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-chlorophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-chlorophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3-chlorophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-allylphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-allylphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-allylphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-allylphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-allyloxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-allyloxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-allyloxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-allyloxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-methoxymethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-methoxymethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-methoxymethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-methoxymethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-methylaminophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-methylaminophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-methylaminophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-methylaminophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-dimethylaminophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (4-dimethylaminophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-dimethylaminophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (4-dimethylaminophenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3,4-methylenedioxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3,4-methylenedioxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3,4-methylenedioxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3,4-methylenedioxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3,4-dimethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3,4-dimethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3,4-dimethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3,4-dimethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3,5-dimethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3,5-dimethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 7aR) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3,5-dimethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,
(R) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 7aS) -hexahydro-4H-furo [2,3-b ] Pyran-3-yl-oxycarbonyl) amino-4- (3,5-dimethoxyphenyl) butanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide.

Specific examples of the pharmaceutically acceptable salt of the novel dipeptide compound of the present invention include hydrochloride, acetate, methanesulfonate, oxalate, citrate, and succinate.
The novel dipeptide compound of the present invention or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the present invention. Furthermore, the novel dipeptide compounds of the present invention have one or more stereoisomers based on asymmetric carbon atoms, and all such isomers and mixtures thereof are included in the scope of the present invention.

  The novel dipeptide compound of the present invention or a pharmaceutically acceptable salt thereof can be administered as a pharmaceutical dosage form according to a conventional method using a conventional pharmaceutical substance or excipient when clinically applied as an anti-AIDS drug. it can. That is, it can be administered intravenously or intramuscularly as an injection, parenterally administered as a spray, suppository, or the like, or orally administered as a granule, capsule, liquid, tablet or the like. The novel dipeptide compound of the present invention or a pharmaceutically acceptable salt thereof is a low molecular compound excellent in in vivo stability and has excellent gastrointestinal absorbability, so that it is a granule, capsule, liquid, tablet. It is appropriate to orally administer as such. The dose is appropriately determined in consideration of age, sex, etc. depending on the symptom of the administration subject or the purpose of treatment such as suppression of the onset of AIDS and progression of AIDS. Administer 1 to 4 times daily in the range of mg to 2 g.

  Further, the compounds of the present invention and antiretroviral compounds, such as the reverse transcriptase inhibitors AZT, 3TC, DDC, nevirapine, delavirdine, efavirenz, and the like, protease inhibitors saquinavir, ritonavir, indinavir, nelfinavir, lopinavir, amprena Combinations with Bill, Atazanavir, L708906, which is an integrase inhibitor, T20, T1249, which are fusion inhibitors, TAK779, AMD3100, which are receptor inhibitors, and the like can also be used as pharmaceuticals.

  Hereinafter, the present invention will be described in detail using examples and test examples, but the present invention is not limited to these examples.

(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4-phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -5,5- Dimethyl-1,3-thiazolidine-4-carboxamide

Hexahydrofuro [2,3-b] -furan-3-ol (racemic mixture of (3R, 3aS, 6aR) and (3S, 3aR, 6aS)) (59 mg) in acetonitrile-methylene chloride mixed solution (6 ml ) Was added N, N-disuccimidyl carbonate (121 mg) in the presence of triethylamine (120 μl) and stirred overnight. (R) -N- (2-methylbenzyl) -3-[(2S, 3S) -3-amino-2-hydroxy-4-phenylbutanoyl] -5,5-dimethyl-1,3- Thiazolidine-4-carboxamide (158 mg) was added and stirred for 3 hours. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed with 5% aqueous sodium carbonate solution (x 2), 1N aqueous hydrochloric acid solution, 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography to obtain the title compound (113 mg) as a diastereo mixture.
¹ H NMR (DMSO-d6) δ (ppm); 1.2-1.5 (br, 1H), 1.33 (s, 3H), 1.49 (s, 3H), 1.6-2.0 (m, 1H), 2.25 (s, 3H ), 2.3-3.0 (m, 3H), 3.3-4.0 (m, 5H), 4.16 (dd, 1H, J = 4.7 Hz, 15.0 Hz), 4.3-4.4 (m, 2H), 4.48 (s, 1H) , 4.8-5.0 (m, 3H), 5.39 (t, 1H, J = 6.8 Hz), 5.49-5.54 (m, 1H), 7.1-7.3 (m, 9H), 7.4-7.5 (m, 1H), 8.3 -8.4 (br, 1H):

Process 1
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -3-amino-2-hydroxy-4- (3-methoxy) phenylbutanoyl] -5,5-dimethyl-1, 3-thiazolidine-4-carboxamide

To a solution of (R) -N- (2-methylbenzyl) -5,5-dimethyl-1,3-thiazolidine-4-carboxamide (0.97 g) in ethyl acetate (5 ml), (2S, 3S) -3- ( Add tert-butoxycarbonyl) amino-2-hydroxy-4- (3-methoxyphenyl) butanoic acid (260 mg), 1-hydroxybenzotriazole (108 mg), N, N'-dicyclohexylcarbodiimide (181 mg) overnight Stir. The reaction mixture was filtered, washed with 5% aqueous sodium carbonate solution (x 2), 1N aqueous hydrochloric acid solution, 5% brine, and dried over MgSO ₄ . After filtration and concentration, 4N hydrochloric acid / ethyl acetate (5 ml) was added, and the mixture was stirred for 1 hr. After concentration, the product was dissolved in water and the insoluble material was removed by filtration. After drying, recrystallization from ethyl acetate-n-hexane gave the title compound (274 mg).
¹ H NMR (DMSO-d6) δ (ppm); 1.11.2 (br, 2H), 1.34 (s, 3H), 1.53 (s, 3H), 2.17 (s, 3H), 2.1-2.3 (m, 1H ), 2.6-2.8 (m, 1H), 3.06 (d, 1H, J = 10.5 Hz), 3.75 (s, 3H), 4.03-4.09 (m, 1H), 4.1-4.3 (m, 2H), 4.36 ( s, 1H), 4.90 (s, 2H), 5.29 (d, 1H, J = 8.4 Hz), 6.70-6.80 (m, 3H), 6.96 (s, 3H), 7.13-7.23 (m, 2H), 8.53 (t, 1H, J = 5.13 Hz);

Process 2
(R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (3-methoxy) phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R) -N- (2-methylbenzyl) -3 -[(2S, 3S) -2-Hydroxy-3-((3S, 3aR, 6aS) -Hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl) amino-4- (3-methoxy ) Phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide

Hexahydrofuro [2,3-b] -furan-3-ol (racemic mixture of (3R, 3aS, 6aR) and (3S, 3aR, 6aS)) (39 mg) in acetonitrile-methylene chloride mixed solution (6 ml ) Was added N, N-disuccimidyl carbonate (77 mg) in the presence of triethylamine (83 μl) and stirred overnight. The compound obtained in Step 1 (94 mg) was added to the reaction solution and stirred for 7 hours. Chloroform was added to the reaction solution, washed with 5% aqueous sodium carbonate solution (x 2), 1N aqueous hydrochloric acid solution, 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography, and n-hexane was added to the concentrated residue and solidified to obtain the title compound (31 mg) as a diastereo mixture.
¹ H NMR (DMSO-d6) δ (ppm); 1.33 (s, 3H), 1.4-1.5 (m, 1H), 1.49 (s, 3H), 1.6-2.0 (m, 1H), 2.25 (s, 3H ), 2.5-3.0 (m, 3H), 3.4-3.9 (m, 8H), 4.1-4.2 (m, 1H), 4.33-4.45 (m, 2H), 4.50 (s, 1H), 4.8-5.0 (m , 3H), 5.3-5.4 (m, 1H), 5.49-5.54 (m, 1H), 6.6-6.9 (m, 3H), 7.06-7.13 (m, 4H), 7.2-7.3 (m, 1H), 7.4 -7.5 (m, 1H), 8.37 (br, 1H):

Process 1
(R) -N- (2,6-methylbenzyl) -3-[(2S, 3S) -3-amino-2-hydroxy-4- (3-methoxyphenyl) butanoyl] -5,5-dimethyl-1 , 3-Thiazolidine-4-carboxamide

To a solution of (R) -N- (2,6-dimethylbenzyl) -5,5-dimethyl-1,3-thiazolidine-4-carboxamide (417 mg) in ethyl acetate (10 ml), (2S, 3S)- 3- (tert-Butoxycarbonyl) amino-2-hydroxy-4- (3-methoxyphenyl) butanoic acid (488 mg), 1-hydroxybenzotriazole (203 mg), N, N'-dicyclohexylcarbodiimide (371 mg) And stirred overnight. The reaction mixture was filtered, washed with 5% aqueous sodium carbonate solution (x 2), 1N aqueous hydrochloric acid solution, 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, 4N hydrochloric acid / ethyl acetate (10 ml) was added, and the mixture was stirred for 1 hr. After concentration, it was dissolved in water, filtered, crystallized with 3N aqueous sodium hydroxide to pH 10 and filtered. After drying, recrystallization from ethyl acetate gave the title compound (530 mg).
¹ H NMR (DMSO-d6) δ (ppm); 0.650.75 (br, 2H), 1.34 (s, 3H), 1.52 (s, 3H), 2.0-2.1 (m, 1H), 2.11 (s, 6H ), 2.4-2.5 (m, 1H), 3.07 (d, 1H, J = 11.1 Hz), 3.79 (s, 3H), 3.99 (t, 1H, J = 8.6 Hz), 4.10 (d, 2H, J = 3.2 Hz), 4.27 (s, 1H), 4.84 (s, 2H), 5.24 (d, 1H, J = 8.1 Hz), 6.64-6.75 (m, 5H), 6.83-6.87 (m, 1H), 7.25 ( t, 1H, J = 8.1 Hz), 8.15 (br, 1H);

Process 3
(R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxy) phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R) -N- (2,6-dimethyl (Benzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl) amino-4- (3-Methoxy) phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide

Hexahydrofuro [2,3-b] -furan-3-ol (racemic mixture of (3R, 3aS, 6aR) and (3S, 3aR, 6aS)) (81 mg) in acetonitrile (2 ml) and triethylamine In the presence of (163 μl), N, N-disuccimidyl carbonate (148 mg) was added and stirred for 7 hours. Chloroform (2 ml), the compound obtained in Step 1 (281 mg) and triethylamine (89 ul) were added to the reaction mixture, and the mixture was stirred overnight. After the reaction solution was concentrated, the residue was dissolved in ethyl acetate, washed with 5% aqueous sodium carbonate solution (x 2), 1N aqueous hydrochloric acid solution, 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography to obtain the title compound (222 mg) as a diastereo mixture.
¹ H NMR (DMSO-d6) δ (ppm); 1.2-1.5 (br, 1H), 1.33 (s, 3H), 1.44 (s, 3H), 1.6-2.0 (m, 1H), 2.29 (s, 6H ), 2.5-3.0 (m, 3H), 3.6-3.9 (m, 8H), 4.1-4.2 (m, 1H), 4.3-4.5 (m, 2H), 4.53 (s, 1H), 4.8-5.0 (m , 3H), 5.1-5.2 (m, 1H), 5.4-5.6 (m, 1H), 6.7-6.8 (m, 1H), 6.8-7.2 (m, 6H), 7.54 (d, 1H, J = 8.2 Hz ), 8.0-8.2 (br, 1H):

 (R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxy) phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

The title compound was obtained in the same manner as above using (3R, 3aS, 6aR) -hexahydrofuro [2,3-b] -furan-3-ol.
¹ H NMR (DMSO-d6) δ (ppm); 1.2-1.5 (br, 2H), 1.33 (s, 3H), 1.44 (s, 3H), 2.29 (s, 6H), 2.5-3.0 (m, 3H ), 3.5-3.8 (m, 6H), 3.8-3.9 (m, 2H), 4.16 (dd, 1H, J = 3.1 Hz, 13.9 Hz), 4.3-4.5 (m, 2H), 4.53 (s, 1H) , 4.84-4.99 (m, 3H), 5.20 (d, 1H, J = 7.1 Hz), 5.51 (d, 1H, J = 5.1 Hz), 6.6-6.7 (m, 1H), 6.91 (d, 1H, J = 7.7 Hz), 6.9-7.1 (m, 5H), 7.53 (d, 1H, J = 8.6 Hz), 8.0-8.1 (br, 1H):

 (R) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxy) phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide,

The title compound was obtained in the same manner as above using (3S, 3aR, 6aS) -hexahydrofuro [2,3-b] -furan-3-ol.
¹ H NMR (DMSO-d6) δ (ppm); 1.33 (s, 3H), 1.44 (s, 3H), 1.7-1.8 (m, 1H), 1.9-2.0 (m, 1H), 2.29 (s, 6H ), 2.5-2.7 (m, 2H), 2.9-3.0 (m, 1H), 3.41 (dd, 1H, J = 6.4 Hz, 9.3 Hz), 3.5-3.9 (m, 7H), 4.17 (dd, 1H, J = 3.3 Hz, 13.7 Hz), 4.25-4.42 (m, 2H), 4.44 (s, 1H), 4.5-5.0 (m, 3H), 5.1-5.2 (br, 1H), 5.54 (d, 1H, J = 5.1 Hz), 6.6-6.8 (m, 1H), 6.91 (d, 1H, J = 7.5 Hz), 6.99-7.16 (m, 5H), 7.53 (d, 1H, J = 8.6 Hz), 8.0-8.1 (br, 1H):

 (R) -N-benzyl-3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl ) Amino-4- (3-methoxy) phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R) -N-benzyl-3-[(2S, 3S) -2- Hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl) amino-4- (3-methoxy) phenylbutanoyl] -5,5- Dimethyl-1,3-thiazolidine-4-carboxamide

¹ H NMR (DMSO-d6) δ (ppm); 1.32 (s, 3H), 1.4-1.5 (m, 1H), 1.49 (s, 3H), 1.6-2.0 (m, 1H), 2.5-3.0 (m , 3H), 3.4-4.0 (m, 8H), 4.1-4.2 (m, 1H), 4.35-4.45 (m, 3H), 4.8-5.1 (m, 3H), 5.3-5.4 (br, 1H), 5.49 -5.54 (m, 1H), 6.6-6.9 (m, 3H), 7.06-7.31 (m, 6H), 7.24-7.47 (m, 1H), 8.46-8.50 (m, 1H):

 (R) -N- (2-methylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan-3 -Yl-oxycarbonyl) amino-4- (4-ethoxy) phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide, (R) -N- (2-methylbenzyl) -3 -[(2S, 3S) -2-Hydroxy-3-((3S, 3aR, 6aS) -Hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl) amino-4- (4-ethoxy ) Phenylbutanoyl] -5,5-dimethyl-1,3-thiazolidine-4-carboxamide

¹ H NMR (DMSO-d6) δ (ppm); 1.28 (t, 3H, J = 6.9 Hz), 1.33 (s, 3H), 1.4-1.5 (m, 1H), 1.48 (s, 3H), 1.6- 2.0 (m, 1H), 2.25 (s, 3H), 2.5-3.0 (m, 3H), 3.3-4.0 (m, 7H), 4.1-4.2 (m, 1H), 4.3-4.4 (m, 2H), 4.48 (s, 1H), 4.8-5.0 (m, 3H), 5.3-5.6 (m, 2H), 6.7-6.8 (m, 2H), 7.0-7.2 (m, 3H), 7.27-7.31 (m, 1H ), 7.36-7.39 (m, 1H), 8.33 (br, 1H):

Process 1
(RS) -N- (2,6-Dimethylbenzyl) -3,3-dimethylpyrrolidine-2-carboxamide

To a solution of (2RS) -N-tert-butoxycarbonyl-3,3-dimethylpyrrolidine-2-carboxylic acid (1.05 g) and triethylamine (0.72 ml) in ethyl acetate (30 ml), diphenyl phosphate chloride ( 0.98 ml) was added, and the mixture was stirred for 3 hours. Further, 2,6-dimethylbenzylamine.hydrochloride (0.81 g) and triethylamine (1.50 ml) were added and stirred overnight. The reaction mixture was washed with 5% aqueous sodium carbonate solution, 1N hydrochloric acid, 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, 4N hydrochloric acid / ethyl acetate (20 ml) was added and the mixture was stirred for 3 hr. The reaction mixture was neutralized with 2N aqueous sodium hydroxide solution under ice cooling, the organic layer was washed with 5% brine, and dried over anhydrous magnesium sulfate. did. After filtration and concentration, the residue was purified by silica gel column chromatography and recrystallized from n-heptane to obtain the title compound (0.92 g).
¹ H-NMR (DMSO-d6) δ (ppm); 0.79 (s, 3H), 1.11 (s, 3H), 2.31 (s, 6H), 2.78-2.91 (m, 3H), 3.11 (s, 1H) , 4.27 (d, 2H, J = 3.8 Hz), 7.01-7.11 (m, 3H), 7.62 (t, 1H, J = 4.5 Hz).

Process 2
(S) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -3-Amino-2-hydroxy-4- (3-methoxyphenyl) butanoyl] -3,3-dimethylpyrrolidine- 2-carboxamide

To a solution of the compound obtained in step 1 (1.37 g, 5.3 mmol) in dimethylformamide (5 ml), add (2S, 3S) -3- (tert-butoxycarbonyl) amino-2-hydroxy-4- (3-methoxy Phenyl) butanoic acid (1.72 g), 1-hydroxybenzotriazole (0.71 g), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (1.11 g) was added and stirred overnight. After adding ethyl acetate to the reaction solution, it was washed with 5% aqueous sodium carbonate solution, 1N hydrochloric acid, 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, 4N hydrochloric acid / ethyl acetate (20 ml) was added, and the mixture was stirred for 1 hr. Water was added to the reaction mixture, and the mixture was adjusted to pH 9-10 with 3N aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, purification by silica gel column chromatography (thin layer chromatography, diastereomer having a large Rf value with a developing solvent of dichloromethane: methanol = 9: 1) was obtained, and mixed with ethyl acetate / n-hexane Recrystallization from the solvent gave the title compound (1.06 g).
¹ H NMR (DMSO-d6) δ (ppm); 0.8-1.0 (br, 2H), 0.94 (s, 3H), 1.07 (s, 3H), 1.5-1.8 (m, 2H), 2.14 (s, 6H ), 2.31 (s, 1H), 2.5-2.6 (m, 1H), 3.0-3.1 (m, 1H), 3.50-3.58 (m, 1H), 3.7-3.8 (m, 4H), 3.86-3.92 (m , 2H), 4.04-4.24 (m, 2H), 5.01 (d, 1H, J = 8.4 Hz), 6.68-6.83 (m, 6H), 7.22 (t, 1H, J = 8.1 Hz), 8.06 (br, 1H).

Process 3
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxy) phenylbutanoyl] -3,3-dimethyl-pyrrolidine-2-carboxamide, (S) -N- (2,6-dimethylbenzyl) -3 -[(2S, 3S) -2-Hydroxy-3-((3S, 3aR, 6aS) -Hexahydrofuro [2,3-b] furan-3-yl-oxycarbonyl) amino-4- (3-methoxy ) Phenylbutanoyl] -3,3-dimethyl-pyrrolidine-2-carboxamide,

Hexahydrofuro [2,3-b] -furan-3-ol (racemic mixture of (3R, 3aS, 6aR) and (3S, 3aR, 6aS)) (65 mg) in acetonitrile-methylene chloride mixed solution (6 ml ) Was added N, N-disuccimidyl carbonate (256 mg) in the presence of triethylamine (139 μl) and stirred overnight. The compound obtained in Step 3 (117 mg) was added to the reaction mixture, and the mixture was stirred overnight. Chloroform was added to the reaction solution, washed with 5% aqueous sodium carbonate solution (x 2), 1N aqueous hydrochloric acid solution, 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography, and n-hexane was added to the concentrated residue and solidified to obtain the title compound (143 mg) as a diastereo mixture.
¹ H NMR (DMSO-d6) δ (ppm); 0.97 (s, 3H), 1.01 (s, 3H), 1.3-1.5 (m, 1H), 1.6-1.7 (br, 1H), 1.8-2.0 (m , 2H), 2.29 (s, 6H), 2.4-3.0 (m, 3H), 3.3-3.9 (m, 10H), 4.10 (s, 1H), 4.14 (br, 1H), 4.2-4.4 (br, 1H ), 4.4-4.5 (m, 1H), 4.8-5.0 (m, 2H), 5.5-5.6 (m, 1H), 6.7 (br, 1H), 6.91 (d, 1H, J = 7.1 Hz), 6.99- 7.16 (m, 5H), 7.5-7.6 (m, 1H), 8.0-8.1 (m, 1H):

 (S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxy) phenylbutanoyl] -3,3-dimethyl-pyrrolidine-2-carboxamide,

The title compound was obtained in the same manner as above using (3R, 3aS, 6aR) -hexahydrofuro [2,3-b] -furan-3-ol.
¹ H NMR (DMSO-d6) δ (ppm); 0.97 (s, 3H), 1.01 (s, 3H), 1.4-1.5 (m, 2H), 1.6-1.7 (br, 1H), 1.8-1.9 (m , 1H), 2.29 (s, 6H), 2.4-2.7 (m, 2H), 2.76-2.84 (m, 1H), 3.47-3.77 (m, 7H), 3.82-3.94 (m, 3H), 4.10 (s , 1H), 4.14 (br, 1H), 4.27 (dd, 1H, J = 2.5 Hz, 7.3 Hz), 4.46 (dd, 1H, J = 6.5 Hz, 14.0 Hz), 4.85-4.92 (m, 2H), 5.51 (d, 1H, J = 5.3 Hz), 6.6-6.8 (m, 1H), 6.91 (d, 1H, J = 7.3 Hz), 6.98-7.14 (m, 5H), 7.53 (d, 1H, J = 8.8 Hz), 8.0-8.2 (br, 1H):

 (S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4- (3-methoxy) phenylbutanoyl] -3,3-dimethyl-pyrrolidine-2-carboxamide,

The title compound was obtained in the same manner as above using (3S, 3aR, 6aS) -hexahydrofuro [2,3-b] -furan-3-ol.
¹ H NMR (DMSO-d6) δ (ppm); 0.97 (s, 3H), 1.01 (s, 3H), 1.6-1.8 (m, 2H), 1.8-2.0 (m, 2H), 2.28 (s, 6H ), 2.4-2.7 (m, 2H), 2.9-3.0 (m, 1H), 3.42 (dd, 1H, J = 6.4 Hz, 9.3 Hz), 3.5-4.0 (m, 9H), 4.10 (s, 1H) , 4.15 (d, 1H, J = 2.9 Hz), 4.25-4.35 (m, 1H), 4.45 (dd, 1H, 6.4 Hz, 13.8 Hz), 4.85-4.92 (m, 2H), 5.55 (d, 1H, J = 5.1 Hz), 6.6-6.8 (m, 1H), 6.91 (d, 1H, J = 7.5 Hz), 6.99-7.16 (m, 5H), 7.52 (d, 1H, J = 8.8 Hz), 8.0- 8.1 (m, 1H):

Process 1
(S) -N- (2,6-Dimethylbenzyl) -3-[(2S, 3S) -3-Amino-2-hydroxy-4-phenylbutanoyl] -3,3-dimethylpyrrolidine-2-carboxamide

Example 8 To a solution of the compound obtained in Step 1 (780 mg) in dimethylformamide (5 ml) was added (2S, 3S) -3- (tert-butoxycarbonyl) amino-2-hydroxy-4-phenylbutanoic acid ( 885 mg), 1-hydroxybenzotriazole (405 mg), 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (630 mg) was added and stirred overnight. After adding ethyl acetate to the reaction solution, it was washed with 5% aqueous sodium carbonate solution, 1N hydrochloric acid, 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, 4N hydrochloric acid / dioxane (10 ml) was added, and the mixture was stirred for 30 min. Water was added to the reaction mixture, and the mixture was adjusted to pH 9-10 with 3N aqueous sodium hydroxide solution, extracted with ethyl acetate, washed with 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, purification by silica gel column chromatography (thin layer chromatography, diastereomer having a large Rf value with a developing solvent of chloroform: methanol = 9: 1) was obtained, and mixed with ethyl acetate / n-hexane Recrystallization from the solvent gave the title compound (450 mg).
¹ H NMR (DMSO-d6) δ (ppm); 0.8-1.0 (br, 2H), 0.94 (s, 3H), 1.07 (s, 3H), 1.5-1.8 (m, 2H), 2.14 (s, 6H ), 2.31 (s, 1H), 2.5-2.7 (m, 1H), 3.0-3.1 (m, 1H), 3.49-3.58 (m, 1H), 3.7-3.8 (m, 1H), 3.86-3.93 (m , 2H), 4.04-4.24 (m, 2H), 5.02 (d, 1H, J = 8.6 Hz), 6.71-6.83 (m, 3H), 7.03-7.33 (m, 5H), 8.03 (br, 1H).

Process 2
(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3R, 3aS, 6aR) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethyl-pyrrolidine-2-carboxamide,

(3R, 3aS, 6aR) -Hexahydrofuro [2,3-b] -furan-3-ol (59 mg) in methylene chloride mixed solution (6 ml) in the presence of triethylamine (125 μl), N, N -Disuccinimidyl carbonate (115 mg) was added and stirred overnight. The compound obtained in Step 1 (140 mg) was added to the reaction solution and stirred for 3 hours. Chloroform was added to the reaction solution, washed with 5% aqueous sodium carbonate solution (x 2), 1N aqueous hydrochloric acid solution, 5% brine, and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified by silica gel column chromatography, and n-hexane was added to the concentrated residue and solidified to obtain the title compound (128 mg).
¹ H NMR (DMSO-d6) δ (ppm); 0.98 (s, 3H), 1.01 (s, 3H), 1.3-1.5 (m, 2H), 1.5-1.7 (br, 1H), 1.8-2.0 (m , 1H), 2.29 (s, 6H), 2.4-2.7 (m, 2H), 2.7-2.9 (m, 1H), 3.4-3.9 (m, 7H), 4.10 (s, 1H), 4.14 (br, 1H ), 4.2-4.3 (m, 1H), 4.47 (dd, 1H, J = 6.4 Hz, 13.8 Hz), 4.84-4.93 (m, 2H), 5.50 (d, 1H, J = 5.3 Hz), 6.98-7.34 (m, 8H), 7.51 (d, 1H, J = 8.8 Hz), 8.0-8.1 (br, 1H):

(S) -N- (2,6-dimethylbenzyl) -3-[(2S, 3S) -2-hydroxy-3-((3S, 3aR, 6aS) -hexahydrofuro [2,3-b] furan -3-yl-oxycarbonyl) amino-4-phenylbutanoyl] -3,3-dimethyl-pyrrolidine-2-carboxamide,

The title compound was obtained in the same manner as above using (3S, 3aR, 6aS) -hexahydrofuro [2,3-b] -furan-3-ol.
¹ H NMR (DMSO-d6) δ (ppm); 0.98 (s, 3H), 1.01 (s, 3H), 1.6-2.0 (m, 4H), 2.29 (s, 6H), 2.4-2.8 (m, 2H ), 2.9-3.0 (m, 1H), 3.41 (dd, 1H, J = 6.6 Hz, 9.3 Hz), 3.5-4.0 (m, 6H), 4.10 (s, 1H), 4.14 (d, 1H, J = 2.9 Hz), 4.25-4.35 (m, 1H), 4.46 (dd, 1H, 6.6 Hz, 13.8 Hz), 4.85-4.95 (m, 2H), 5.54 (d, 1H, J = 5.1 Hz), 6.98-7.17 (m, 4H), 7.23 (t, 2H, J = 7.2 Hz), 7.34 (d, 2H, J = 7.0 Hz), 7.50 (d, 1H, J = 8.4 Hz), 8.0-8.1 (m, 1H) :

Test Example 1) Measurement of HIV protease inhibitory activity (Ki value) HIV protease expressed by gene recombination using E. coli was purified by column chromatography. To 25 μl of 0.2 M MES buffer (containing 1 M NaCl, 2 mM EDTA-2Na, 2 mM DTT; pH 5.5), 10 μl of HIV protease solution and 5 μl of dimethyl sulfoxide solution of inhibitor were added, followed by 0.5 mM fluorescent substrate (H The enzyme reaction was started by adding 10 μl of a solution of -Lys-Ala-Arg-Val-Tyr- [p-nitro] -Phe-Glu-Ala-Nle-NH2 (Bachem). After incubation at 37 ° C. for 15 minutes, 75 μl of 1N hydrochloric acid was added to stop the enzyme reaction, and the resulting C-terminal fragment peptide was quantified by reverse phase HPLC to determine the enzyme reaction rate. Then, the enzyme reaction rate data when the inhibitor concentration was changed was fitted to the mathematical model formula of Tight-binding inhibitor (Williams, JW, and Morrison, Method Enzymol. 63, 437 (1979)), and the Ki value was calculated. Calculated. The test results are shown in Table 1.

2) In vitro anti-HIV activity The anti-HIV activity was evaluated according to a method already reported (CJ Petropoulos et. Al., Antimicrob. Agents Chemother., 44, 920-928, 2000). Specifically, wild-type or drug-resistant HIV-1 gene was introduced into HEK293 cells (human embryonic kidney cell line) and cultured for about 16 hours to recover virus-infected cells. The cells were replated in a 96-well plate for assay, cultured in the presence of various concentrations of the test compound, and the viral load was measured about 48 hours after introduction of the HIV-1 gene. The antiviral activity of the test compound was shown by the drug concentration (IC50 value) necessary to inhibit virus growth by 50%. The test results are shown in Table 2 (Table 3 shows protease mutation positions of drug-resistant HIV).

これらの例より明らかなように、本発明の化合物は、野生株に対してのみならず既存のHIV-1プロテアーゼ阻害剤に対して耐性を獲得した薬剤耐性型変異株に対しても強力な増殖抑制効果を有することが示された。

As is clear from these examples, the compounds of the present invention are capable of potent growth not only against wild-type strains but also against drug-resistant mutant strains that have acquired resistance to existing HIV-1 protease inhibitors. It was shown to have a suppressive effect.

The novel dipeptide compound of the present invention exhibits a strong inhibitory effect against drug-resistant viruses and is useful as a novel anti-AIDS drug with reduced drug resistance problems.

Claims (6)

Formula (1)

(Wherein R ¹ represents formula (a) or formula (b),

R ² , R ³ , and R ⁴ each represent a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkenyl group, a lower alkoxy group, a lower alkoxy lower alkoxy group, a lower alkenyloxy group, or a lower alkylamino group, and R ³ and R ⁴ may be bonded to each other to represent a methylenedioxy group, an ethylenedioxy group or a propylene group, and R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are a hydrogen atom or a halogen atom, respectively. , A lower alkyl group or a lower alkoxy group, R ¹⁰ and R ¹¹ each represent a hydrogen atom or a lower alkyl group, and X represents a methylene, sulfur atom or oxygen atom. ) Or a pharmaceutically acceptable salt thereof. Formula (2)

(Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , R ⁹ , R ¹⁰ and R ¹¹ represent the same meaning as in claim 1). The novel dipeptide compound according to claim 1 or a pharmaceutically acceptable salt thereof. Formula (3)

(Wherein R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as defined in claim 1) or a novel peptide compound according to claim 2 Its pharmaceutically acceptable salt. R ² , R ³ and R ⁴ are each a hydrogen atom, methoxy group or ethoxy group, R ⁵ and R ⁹ are each a hydrogen atom, methyl group or chloro group, and R ⁶ , R ⁷ and R ⁸ are hydrogen atoms. The novel peptide compound or a pharmaceutically acceptable salt thereof according to claim 3, wherein X is a methylene or sulfur atom. Formula (4)

(Wherein R ^{2 ′} , R ^{3 ′} and R ^{4 ′} each represent a hydrogen atom, a methoxy group or an ethoxy group, R ^{5 ′} and R ^{9 ′} each represent a hydrogen atom, a methyl group or a chloro group, and X ′ Represents a methylene or sulfur atom), or a pharmaceutically acceptable salt thereof. An anti-AIDS drug comprising the novel dipeptide compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5 as an active ingredient.